Diacylglycerol kinase modulating compounds

CROSS-REFERENCES TO RELATED APPLICATIONS

0001This application claims the benefit of priority to <patcit id="pcit0001" dnum="JP2019232938A"><text>Japan Application Nos. 2019-232938, filed December 24, 2019</text></patcit>, and <patcit id="pcit0002" dnum="JP2020135810A"><text>2020-135810, filed August 11, 2020</text></patcit>, each of which is incorporated herein in its entirety.

BACKGROUND

0002Diacylglycerol (DAG) is known as a second messenger of signaling molecule and takes an important role in cellular proliferation, differentiation and/or metabolism (<nplcit id="ncit0001" npl-type="s"><text>Carrasco, S., Merida, I. Trends Biochem. Sci. 2007, 32, 27-36</text></nplcit>.) Intracellular concentration and localization of DAG is strictly controlled, and diacylglycerol kinase (DGK) is one of enzymes controlling them. DGK is an enzyme that synthesizes a phosphatidic acid (PA) by transferring a phosphoryl group to DAG. Ten human isozymes (α, β, γ, 8, ε, ζ, η, θ, , κ) are known (<nplcit id="ncit0002" npl-type="s"><text>Joshi, R.P., Koretzky,G.A. Int. J. Mol. Sci., 2013, 14, 6649-6673</text></nplcit>.) Each isozyme is believed to localize and associate with different proteins and/or with different cell types. DGK is reported to be involved in pathogenesis of multiple diseases including cancers, immune diseases, neurodegenerative diseases, and diabetes (<nplcit id="ncit0003" npl-type="s"><text>Sakane, F., et al. Front. Cell Dev. Biol., 2016, 4, 82</text></nplcit>.)

0003DGKα has been a target of research, including research into possible cancer treatment. For example, an inhibitory activity on proliferation of glioblastoma cells was reported as a result of knockdown caused by RNA-interference targeting DGKα (<nplcit id="ncit0004" npl-type="s"><text>Dominguez, C.L., et al. Cancer Discov., 2013, 782-797</text></nplcit>.) An inhibitory effect was also reported on a human colon carcinoma cell line in three-dimensional cell culture, and the knockdown of DGKα was further reported to inhibit tumor proliferation in a mouse model (<nplcit id="ncit0005" npl-type="s"><text>Torres-Ayuso, P., et al. Oncotarget, 2014, 5, 9710-9726</text></nplcit>.) Inhibition of DGKα has been disclosed in <patcit id="pcit0003" dnum="WO2007114239A"><text>WO 2007/114239</text></patcit>. Accordingly, a compound with an inhibitory activity on DGKα may be useful for therapeutics, such as treating a cancer in which DGKα is involved in its proliferation.

0004In recent years, cancer immunotherapy has attracted attention as a potential cancer treatment. An immune checkpoint inhibitor such as anti-CTLA-4 (Cytotoxic T lymphocyte antigen 4) antibody, anti-PD-1 (Programmed death receptor 1) antibody, anti-PD-L1 (Programmed death ligand 1) antibody etc. could be administered and an antitumor immune response can be potentiated in a patient. Some immune checkpoint inhibitors have been already approved as a medicine for antitumor therapy. However, the antitumor effects are often limited to a few patients. Further, some patients become resistant to the inhibitors (<nplcit id="ncit0006" npl-type="s"><text>Spranger,S., Gajewski,T.F., Nat. Rev. Cancer., 2018, 18, 139-147</text></nplcit>.)

0005DGKα is expressed in a T-cell, mediating a signaling of T-cell receptor (TCR,) and is believed to play a role in T-cell activation (Joshi et al. as above and<nplcit id="ncit0007" npl-type="s"><text> Merida,I. et al., Adv. Biol. Regul., 2017, 63, 22-31</text></nplcit>.) When a T-cell is under a condition of immunological unresponsiveness such as anergy, expression of DGKα can be increased, and an overexpression of DGKα has been reported to induce a condition of anergy (<nplcit id="ncit0008" npl-type="s"><text>Zha,Y. et al., Nat.Immunol., 2006, 7, 1166-1173</text></nplcit>.) Further, activation of a T-cell has been reported as a result of knockdown of DGKα in the T-cell by means of RNA-interference (<nplcit id="ncit0009" npl-type="s"><text>Avila-Flores, A., et al. Immunol Cell. Biol., 2017, 95, 549-563</text></nplcit>.) Accordingly, a compound with an activity to control DGKα may be useful for preventing and/or treating diseases related to a T-cell, such as immunologic or inflammatory diseases.

0006Recently CAR (Chimeric Antigen Receptor) T cell therapy has also attracted attention as a promising immune cancer therapy. It has been reported that DGKα-deficient CAR T cells have high effector function and anti-tumor effect on a solid cancer (<nplcit id="ncit0010" npl-type="s"><text>Riese, M.J. et al. Cancer Res., 2013, 73, 3566-3577</text></nplcit>; <nplcit id="ncit0011" npl-type="s"><text>Jung, I.Y., et al. Cancer Res., 2018, 78, 4692-4703</text></nplcit>.) Hence, use of a compound having inhibitory effect on DGKα may be complementary with CAR T cell therapy.

0007However, there remains a need for DGKα inhibitors, for example, with desirable pharmaceutical and therapeutic properties.

BRIEF SUMMARY

0008In one embodiment, the present disclosure provides a compound of Formula (I-1): <chemistry id="chem0001" num="0001"><img file="EP4445902A2_D0001.tif" /></chemistry> or a pharmaceutically acceptable salt thereof, wherein <ul id="ul0001" list-style="none" compact="compact"><li>R¹, R², R³ and R⁴ are independently a hydrogen atom, a halogen atom, a hydroxy group, a carboxy group, a formyl group, a cyano group, an amino group, a nitro group, a nitroso group, a alkoxycarbonyl group, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted cycloalkyl group, an optionally substituted alkoxy group, an optionally substituted alkylamino group, an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted acyl group, an optionally substituted carbamoyl group, an optionally substituted acylamino group, an optionally substituted saturated heterocyclo group or an optionally substituted alkylsulfonylamino group;</li><li>R⁵ is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkynyl group, or an optionally substituted aryl group; and</li><li>R⁶ is an optionally substituted alkyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, or R⁵ and R⁶ together with a nitrogen atom which they bound, may form a nitrogen-containing saturated heterocyclo ring to which an aryl ring is fused, and the fused ring may be substituted;</li><li>provided that the compound is not <chemistry id="chem0002" num="0002"><img file="EP4445902A2_D0002.tif" /></chemistry> or <chemistry id="chem0003" num="0003"><img file="EP4445902A2_D0003.tif" /></chemistry></li></ul>

0009In another embodiment, the present disclosure provides a compound of Formula (I): <chemistry id="chem0004" num="0004"><img file="EP4445902A2_D0004.tif" /></chemistry> or a pharmaceutically acceptable salt thereof, wherein <ul id="ul0002" list-style="none" compact="compact"><li>R¹ is hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 alkoxy, halogen, C_1-6 haloalkyl, C_1-6 haloalkoxy, or -CN;</li><li>R² is hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_1-6 alkoxy, C_2-6 alkoxyalkyl, halogen, C_1-6 haloalkyl, C_1-6 haloalkoxy, -CN, -NO, -NO₂, - C(O)R^2a, -C(O)OR^2a, -OC(O)R^2a, -C(O)N(R^2a)(R^2b), -N(R^2a)C(O)R^2b, - OC(O)N(R^2a)(R^2b), -N(R^2a)C(O)OR^2b, -C(=NR^2a)N(R^2b)(R^2c), -N(R^2a)(R^2b), - N(R^2a)N(R^2b)(R^2c), -N(R^2a)N=C(R^2b)(OR^2c), -OR^2a, -SR²³, -S(O)R^2a, -S(O)(NR^2a)(R^2b), - S(NR^2a)(NR^2b)(R^2c), -S(O)₂R^2a, -S(O)2N(R^2a)(R^2b), -N(R^2a)S(O)2(R^2b), -P(R^2a)(R^2b), - P(O)(R^2a)(R^2b), -P(O)(OR^2a)(R^2b), -P(O)(OR^2a)(OR^2b), C_3-10 cycloalkyl, C_1-6 alkyl-C_3-10 cycloalkyl, C_6-12 aryl, C_1-6 alkyl-C_6-12 aryl, heterocycloalkyl, C_1-6 alkyl-(heterocycloalkyl), heteroaryl, or C_1-6 alkyl-(heteroaryl), wherein each alkyl, alkenyl or alkynyl is independently optionally substituted with 1 to 3 R^2d groups, each cycloalkyl is optionally substituted with 1 to 3 R^2e groups, each aryl is optionally substituted with 1 to 3 R^2f groups, each heterocycloalkyl is optionally substituted with 1 to 3 R²⁹ groups, and each heteroaryl is optionally substituted with 1 to 3 R^2h groups;</li><li>each R^2a, R^2b, and R^2c is independently hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_2-6 alkoxyalkyl, C_1-6 haloalkyl, C_3-10 cycloalkyl, C_1-6 alkyl-C_3-10 cycloalkyl, C_6-12 aryl, C_1-6 alkyl-C_6-12 aryl, heterocycloalkyl, C_1-6 alkyl-(heterocycloalkyl), heteroaryl, or C_1-6 alkyl-(heteroaryl), wherein the aryl or heteroaryl is optionally substituted with 1 to 3 R^2j;</li><li>alternatively, R^2a, R^2b, and R^2c when attached to the same atom can be combined with the atom to which they are attached to form a heterocycloalkyl;</li><li>each R^2d is independently -CN, -C(O)R^2d1, -C(O)OR^2d1, -OC(O)R^2d1, -C(O)N(R^2d1)(R^2d2), - N(R^2d1)C(O)R^2d2, -OC(O)N(R^2d1)(R^2d2), -N(R^2d1)C(O)OR^2d2, -N(R^2d1)(R^2d2), =O, -OR^2d1, -SR^2d1, -S(O)R^2d1, -S(O)(NR^2d1)(R^2d2), -S(O)₂R^2d1, -S(O)N(R^2d1)(R^2d2), - N(R^2d1)S(O)₂R^2d2, C_3-10 cycloalkyl, C_1-6 alkyl-C_3-10 cycloalkyl, C_6-12 aryl, C_1-6 alkyl-C_6-12 aryl, heterocycloalkyl, C_1-6 alkyl-(heterocycloalkyl), heteroaryl, or C_1-6 alkyl-(heteroaryl);</li><li>each R^2d1 and R^2d2 is independently hydrogen, C_1-6 alkyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_2-6 alkoxyalkyl, or C_1-6 haloalkyl;</li><li>each R^2e, R^2f, R^2g, and R^2h is independently hydrogen, C_1-6 alkyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_1-6 alkoxy, C_2-6 alkoxyalkyl, halogen, C_1-6 haloalkyl, C_1-6 haloalkoxy, -CN, or -OH;</li><li>each R^2j is independently C_1-6 alkyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_1-6 alkoxy, C_2-6 alkoxyalkyl, halogen, C_1-6 haloalkyl, or C_1-6 haloalkoxy;</li><li>R³ is hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_1-6 alkoxy, C_2-6 alkoxyalkyl, halogen, C_1-6 haloalkyl, C_1-6 haloalkoxy, -CN, -NO, -NO₂, - C(O)R^3a, -C(O)OR^3a, -OC(O)R^3a, -C(O)N(R^3a)(R^3b), -N(R^3a)C(O)R^3b, - OC(O)N(R^3a)(R^3b), -N(R^3a)C(O)OR^3b, -C(=NR^3a)N(R^3b)(R^3c), -N(R^3a)(R^3b), - N(R^3a)N(R^3b)(R^3c), -N(R^3a)N=C(R^3b)(OR^3c), -OR^3a, -SR^3a, -S(O)R^3a, -S(O)(NR^3a)(R^3b), - S(NR^3a)(NR^3b)(R^3c), ^_S(^p)zR^3a, -S(O)2N(R^3a)(R^3b), -N(R^3a)S(O)2(R^3b), -P(R^3a)(R^3b), - P(O)(R^3a)(R^3b), -P(O)(OR^3a)(R^3b), -P(O)(OR^3a)(OR^3b), C_3-10 cycloalkyl, C_1-6 alkyl-C_3-10 cycloalkyl, C_6-12 aryl, C_1-6 alkyl-C_6-12 aryl, heterocycloalkyl, C_1-6 alkyl-(heterocycloalkyl), heteroaryl, or C_1-6 alkyl-(heteroaryl), wherein each alkenyl or alkynyl is independently optionally substituted with 1 to 3 R^3d groups, each cycloalkyl is optionally substituted with 1 to 3 R^3e groups, each aryl is optionally substituted with 1 to 3 R^3f groups, each heterocycloalkyl is optionally substituted with 1 to 3 R^3g groups, and each heteroaryl is optionally substituted with 1 to 3 R^3h groups;</li><li>each R^3a, R^3b, and R^3c is independently hydrogen, C_1-6 alkyl, C_1-6 hydroxyalkyl, C_2-6 alkoxyalkyl, C_1-6 haloalkyl, C_3-10 cycloalkyl, C_1-6 alkyl-C_3-10 cycloalkyl, C_6-12 aryl, C_1-6 alkyl-C_6-12 aryl, heterocycloalkyl, or heteroaryl;</li><li>alternatively, R^3a, R^3b, and R^3c when attached to the same atom can be combined with the atom to which they are attached to form a heterocycloalkyl;</li><li>each R^3d is independently -N(R^3d1)(R^3d2), -OR^3d1, C_3-10 cycloalkyl, C_1-6 alkyl-C_3-10 cycloalkyl, C_6-12 aryl, C_1-6 alkyl-C_6-12 aryl, heterocycloalkyl, or heteroaryl;</li><li>each R^3d1 and R^3d2 is independently hydrogen, C_1-6 alkyl, or -C(O)O-(C_1-6 alkyl);</li><li>each R^3e, R^3f, R^3g, and R^3h is independently hydrogen, C_1-6 alkyl, C_1-6 alkoxy, halogen, C_1-6 haloalkyl or C_1-6 haloalkoxy;</li><li>R⁴ is hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 alkoxy, halogen, C_1-6 haloalkyl, C_1-6 haloalkoxy, or -CN;</li><li>R⁵ is hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 hydroxyalkyl, C_2-6 alkoxyalkyl, C_1-6 haloalkyl, C_3-10 cycloalkyl, C_1-6 alkyl-C_3-10 cycloalkyl, C_6-12 aryl, C_1-6 alkyl-C_6-12 aryl, heterocycloalkyl, C_1-6 alkyl-(heterocycloalkyl), heteroaryl, or C_1-6 alkyl-(heteroaryl), wherein the alkyl is optionally substituted with R^5a;</li><li>R⁵³ is -OSi(R^5a1)(R^5a2)(R^5a3);</li><li>R^5a1, R^5a2, and R^5a3 are each independently C_1-6 alkyl; and</li><li>R⁶ is C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 haloalkyl, C_6-12 aryl, or heteroaryl, wherein the aryl or heteroaryl are each optionally substituted with 1 to 3 R^6a;</li><li>each R^6a is independently C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_1-6 alkoxy, C_2-6 alkoxyalkyl, halogen, C_1-6 haloalkyl, C_1-6 haloalkoxy, -CN, -NO₂, -C(O)R^6b, ^_C(O)OR^6b, -OC(O)R^6b, -C(O)N(R^6b)(R^6c), -N(R^6b)C(O)R^6c, - C(=NR^6b)N(R^6c)(R^6d), -N(R^6b)(R^6c), -OR^6b, -SR^6b, -S(O)R^6b, -S(O)₂R^6b, - S(NR^6b)(NR^6c)R^6d, -S(O)(NR^6b)(R^6c), -S(O)₂N(R^6b)(R^6c), -N(R^6b)S(O)₂(R^6c), - P(R^6b)(R^6c), -P(O)(R^6b)(R^6c), -P(O)(OR^6b)(R^6c), -P(O)(OR^6b)(OR^6c), C_3-10 cycloalkyl, C_1-6 alkyl-C_3-10 cycloalkyl, C_6-12 aryl, C_1-6 alkyl-C_6-12 aryl, heterocycloalkyl, C_1-6 alkyl-(heterocycloalkyl), heteroaryl, or C_1-6 alkyl-(heteroaryl), wherein the cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is each optionally substituted with 1 to 3 R^6e, the alkyl is optionally substituted with R^6f, and the alkynyl is optionally substituted with 1 to 4 R^6j;</li><li>each R^6b, R^6c and R^6d is independently hydrogen, C_1-6 alkyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_2-6 alkoxyalkyl, C_1-6 haloalkyl, C_3-10 cycloalkyl, C_1-6 alkyl-C_3-10 cycloalkyl, C_6-12 aryl, C_1-6 alkyl-C_6-12 aryl, heterocycloalkyl, C_1-6 alkyl-(heterocycloalkyl), heteroaryl, or C_1-6 alkyl-(heteroaryl), wherein the cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is optionally substituted by 1 to 3 R^6k,</li><li>each R^6k is independently C_1-6 alkyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_1-6 alkoxy, C_2-6 alkoxyalkyl, C_1-6 haloalkyl, C_1-6 haloalkoxy, C_3-10 cycloalkyl, C_1-6 alkyl-C_3-10 cycloalkyl, heterocycloalkyl, or C_1-6 alkyl-(heterocycloalkyl);</li><li>each R^6e is independently C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_1-6 alkoxy, C_2-6 alkoxyalkyl, halogen, C_1-6 haloalkyl, C_1-6 haloalkoxy, -CN, -NO₂, -C(O)R^6e1, -C(O)OR^6e1, -OC(O)R^6e1, -C(O)N(R^6e1)(R^6e2), -N(R^6e1)C(O)R^6e2, - OC(O)N(R^6e1)(R^6e2), -N(R^6e1)C(O)OR^6e2, -C(=NR^6e1)N(R^6e2)(R^6e3), -N(R^6e1)(R^6e2), =O, - OR^6e1, -SR^6e1, -S(O)R^6e1, -S(NR^6e1)(NR^6e2), -S(O)(NR^6e1)(R^6e2), -S(O)₂R^6e1, - S(O)₂N(R^6e1)(R^6e2), -SF₅, -N(R^6e1)S(O₂(R6^e2), -P(R^6e1)(R^6e2), -P(O)(R^6e1)(R^6e2), - P(O)(OR^6e1)(R^6e2), -P(O)(OR^6e1)(OR^6e2), -Si(R^6e1)(R^6e2)(R^6e3), C_3-10 cycloalkyl, C_1-6 alkyl-C_3-10 cycloalkyl, C_6-12 aryl, C_1-6 alkyl-C_6-12 aryl, heterocycloalkyl, C_1-6 alkyl-heterocycloalkyl, heteroaryl, or C_1-6 alkyl-heteroaryl, wherein the cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is each optionally substituted with 1 to 3 R^6h, and the alkyl is optionally substituted with 1 to 3 R^6m;</li><li>each R^6e1, R^6e2, and R^6e3 is independently hydrogen, C_1-6 alkyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_1-6 alkoxyalkyl, C_1-6 haloalkyl, C_3-10 cycloalkyl, C_1-6 alkyl-C_3-10 cycloalkyl, C_6-10 aryl, C_1-6 alkyl-C_6-10 aryl, heterocycloalkyl, C_1-6 alkyl-(heterocycloalkyl), heteroaryl, or C_1-6 alkyl-(heteroaryl), wherein the cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is optionally substituted with 1 to 3 R⁶ⁿ;</li><li>each R⁶ⁿ is C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_1-6 alkoxy, C_2-6 alkoxyalkyl, halogen, C_1-6 haloalkyl, C_1-6 haloalkoxy, -CN, -C(O)R⁶ⁿ¹, -C(O)OR⁶ⁿ¹, -OC(O)R⁶ⁿ¹, -C(O)N(R⁶ⁿ¹)(R⁶ⁿ²), -N(R⁶ⁿ¹)C(O)R⁶ⁿ², -OC(O)N(R⁶ⁿ¹)(R⁶ⁿ²), - N(R⁶ⁿ¹)C(O)OR⁶ⁿ², -C(=NR⁶ⁿ¹)N(R⁶ⁿ²)(R⁶ⁿ³), -N(R⁶ⁿ¹)(R⁶ⁿ²), =O, -OH, -SR⁶ⁿ¹, - S(O)R⁶ⁿ¹, -S(NR⁶ⁿ¹)(NR⁶ⁿ²)R⁶ⁿ³, -S(O)(NR⁶ⁿ¹)(R⁶ⁿ²), -S(O)₂R⁶ⁿ¹, -S(O)₂N(R⁶ⁿ¹)(R⁶ⁿ²), or -N(R⁶ⁿ¹)S(O)₂(R⁶ⁿ²);</li><li>each R⁶ⁿ¹, R⁶ⁿ² and R⁶ⁿ³ is independently hydrogen, C_1-6 alkyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_2-6 alkoxyalkyl, C_1-6 haloalkyl, C_3-10 cycloalkyl, C_1-6 alkyl-C_3-10 cycloalkyl, C_6-10 aryl, C_1-6 alkyl-C_6-10 aryl, heterocycloalkyl, C_1-6 alkyl-(heterocycloalkyl), heteroaryl, or C_1-6 alkyl-(heteroaryl);</li><li>each R^6h is independently C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_1-6 alkoxy, C_2-6 alkoxyalkyl, halogen, C_1-6 haloalkyl, C_1-6 haloalkoxy, -CN, -C(O)R^6h1, -C(O)OR^6h1, -OC(O)R^6h1, -C(O)N(R^6h1)(R^6h2), -N(R^6h1)C(O)R^6h2, - OC(O)N(R^6h1)(R^6h2), -N(R^6h1)C(O)OR^6h2, -C(=NR^6h1)N(R^6h2)(R^6h3), -N(R^6h1)(R^6h2), =O, -OH, -SR^6h1, -S(O)R^6h1, -S(NR^6h1)(NR^6h2)R^6h3, -S(O)(NR^6h1)(R^6h2), -S(O)₂R^6h1, - S(O)₂N(R^6h1)(R^6h2), -N(R^6h1)S(O)₂(R^6h2), C_3-10 cycloalkyl, C_1-6 alkyl-C_3-10 cycloalkyl, heterocycloalkyl, or C_1-6 alkyl-(heterocycloalkyl);</li><li>each R^6h1, R^6h2, and R^6h3 is independently hydrogen, C_1-6 alkyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_2-6 alkoxyalkyl, C_1-6 haloalkyl, C_3-10 cycloalkyl, C_1-6 alkyl-C_3-10 cycloalkyl, C_6-10 aryl, C_1-6 alkyl-C_6-10 aryl, heterocycloalkyl, C_1-6 alkyl-(heterocycloalkyl), heteroaryl, or C_1-6 alkyl-(heteroaryl);</li><li>each R^6m is independently halogen, C_1-6 haloalkyl, C_1-6 haloalkoxy, -CN, -C(O)R^6m1, - C(O)OR^6m1, -OC(O)R^6m1, -C(O)N(R^6m1)(R^6m2), -N(R^6m3)C(O)R^6m2, - OC(O)N(R^6m1)(R^6m2), -N(R^6m1)C(O)OR^6m2, -C(=NR^6m3)N(R^6m1)(R^6m2), -N(R^6m1)(R^6m2), =O, -OH, -SR^6m1, -S(O)R^6m1, -S(NR^6m1)(NR^6m2)R^6m3, -S(O)(NR^6m1)(R^6m2), -S(O)₂R^6m1, - S(O)₂N(R^6m1)(R^6m2), or -N(R^6m3)S(O)₂(R^6m2);</li><li>each R^6m1, R^6m2, and R^6m3 is independently hydrogen, C_1-6 alkyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_2-6 alkoxyalkyl, C_1-6 haloalkyl, C_3-10 cycloalkyl, C_1-6 alkyl-C_3-10 cycloalkyl, C_6-10 aryl, C_1-6 alkyl-C_6-10 aryl, heterocycloalkyl, C_1-6 alkyl-(heterocycloalkyl), heteroaryl, or C_1-6 alkyl-(heteroaryl);</li><li>R^6f is -OSi(R^6f1)(R^6f2)(R^6f3);</li><li>R^6f1, R^6f2, and R^6f3 are each independently C_1-6 alkyl;</li><li>each R^6j is independently C_2-6 alkoxyalkyl, halogen, C_1-6 haloalkyl, C_1-6 haloalkoxy, -CN, - C(O)R^6j1, -C(O)OR^6j1, -OC(O)R^6j1, -C(O)N(R^6j1)(R^6j2), -N(R^6j3)C(O)R^6j2, - OC(O)N(R^6j1)(R^6j2), -N(R^6j1)C(O)OR^6j2, -C(=NR^6j3)N(R^6j1)(R^6j2), -N(R^6j1)(R^6j2), =O, - OR^6j1, -SR^6j1, ^_S(O)R^6j1, -S(NR^6j1)(NR^6j2), -S(NR^6j1)(NR^6j2)R^6j3, -S(O)(NR^6j1)(R^6j2), - S(O)₂R^6j1, -S(O)₂N(R^6j1)(R^6j2), -N(R^6j1)S(O)₂(R^6j2), -Si(R^6j1)(R^6j2)(R^6j3), C_3-10 cycloalkyl, C_6-12 aryl, heterocycloalkyl, or heteroaryl, wherein the cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is optionally substituted with 1 to 3 R^6p;</li><li>each R^6j1, R^6j2, and R^6j3 is independently hydrogen, C_1-6 alkyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_2-6 alkoxyalkyl, C_1-6 haloalkyl, C_3-10 cycloalkyl, C_1-6 alkyl-C_3-10 cycloalkyl, C_6-10 aryl, C_1-6 alkyl-C_6-10 aryl, heterocycloalkyl, C_1-6 alkyl-(heterocycloalkyl), heteroaryl, or C_1-6 alkyl-(heteroaryl);</li><li>each R^6p is independently C_1-6 alkyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_1-6 alkoxy, C_2-6 alkoxyalkyl, halogen, C_1-6 haloalkyl, C_1-6 haloalkoxy, -CN, -C(O)R^6p1, -C(O)OR^6p1, - OC(O)R^6p1, -C(O)N(R^6p1)(R^6p2), -N(R^6p1)C(O)R^6p2, -OC(O)N(R^6p1)(R^6p2), - N(R^6p1)C(O)OR^6p2, -C(=NR^6p3)N(R^6p1)(R^6p2), -N(R^6p1)(R^6p2), =O, -OH, -SR^6p1, - S(O)R^6p1, -S(NR^6p1)(NR^6p2)R^6p3, -S(O)(NR^6p1)(R^6p2), -S(O)2R^6p1, -S(O)₂N(R^6p1)(R^6p2), or -N(R^6p1)S(O)₂(R^6p2);</li><li>each R^6p1, R^6p2, and R^6p3 is independently hydrogen, C_1-6 alkyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_2-6 alkoxyalkyl, C_1-6 haloalkyl, C_3-10 cycloalkyl, C_1-6 alkyl-C_3-10 cycloalkyl, C_6-10 aryl, C_1-6 alkyl-C_6-10 aryl, heterocycloalkyl, C_1-6 alkyl-(heterocycloalkyl), heteroaryl, or C_1-6 alkyl-(heteroaryl);</li><li>or R⁵ and one R^6a together with the atoms to which they are attached form a heterocycloalkyl, optionally substituted with 1 to 3 R^6g;</li><li>each R^6g is independently C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_2-6 alkoxyalkyl, halogen, C_1-6 haloalkyl, C_1-6 haloalkoxy, or -CN;</li><li>R⁷ is hydrogen, C_1-6 alkyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_1-6 alkoxy, C_2-6 alkoxyalkyl, C_1-6 alkylthio, halogen, C_1-6 haloalkyl, -CN,-OH, -NH₂, C_3-10 cycloalkyl, C_1-6 alkyl-C_3-10 cycloalkyl, heterocycloalkyl, or C_1-6 alkyl-(heterocycloalkyl);</li><li>each heterocycloalkyl is a 3 to 20 membered ring having 1 to 4 heteroatoms each independently N, O or S; and</li><li>each heteroaryl is a 5 to 18 membered ring having 1 to 4 heteroatoms each independently N, O or S;</li><li>provided that R⁵ and R⁶ are not both C_1-4 alkyl; and when R⁵ is hydrogen, R⁶ is not isopropyl or phenyl substituted with 2-Me.</li></ul>

0010In another embodiment, the present disclosure provides a pharmaceutical composition comprises a pharmaceutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

0011In another embodiment, the present disclosure provides a method of inhibiting DGKα in a subject in need thereof comprises administering to the subject a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

0012In another embodiment, the present disclosure provides a method of inhibiting DGKα in a subject in need thereof comprises administering to the subject a therapeutically effective amount of a compound of Formula (I): <chemistry id="chem0005" num="0005"><img file="EP4445902A2_D0005.tif" /></chemistry> or a pharmaceutically acceptable salt thereof, wherein <ul id="ul0003" list-style="none" compact="compact"><li>R¹ is hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 alkoxy, halogen, C_1-6 haloalkyl, C_1-6 haloalkoxy, or -CN;</li><li>R² is hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_1-6 alkoxy, C_2-6 alkoxyalkyl, halogen, C_1-6 haloalkyl, C_1-6 haloalkoxy, -CN, -NO, -NO₂, - C(O)R^2a, -C(O)OR^2a, -OC(O)R^2a, -C(O)N(R^2a)(R^2b), -N(R^2a)C(O)R^2b, - OC(O)N(R^2a)(R^2b), -N(R^2a)C(O)OR^2b, -C(=NR2a)N(R^2b)(R^2c), -N(R^2a)(R^2b), _ N(R^2a)N(R^2b)(R^2c), -N(R^2a)N=C(R^2b)(OR^2c), -OR^2a, -SR²³, -S(O)R^2a, -S(O)(NR^2a)(R^2b), - S(NR^2a)(NR^2b)(R^2c), -S(O)2R^2a, -S(O)2N(R^2a)(R^2b), -N(R^2a)S(O)2(R^2b), -P(R^2a)(R^2b), - P(O)(R^2a)(R^2b), -P(O)(OR^2a)(R^2b), -P(O)(OR^2a)(OR^2b), C_3-10 cycloalkyl, C_1-6 alkyl-C_3-10 cycloalkyl, C_6-12 aryl, C_1-6 alkyl-C_6-12 aryl, heterocycloalkyl, C_1-6 alkyl-(heterocycloalkyl), heteroaryl, or C_1-6 alkyl-(heteroaryl), wherein each alkyl, alkenyl or alkynyl is independently optionally substituted with 1 to 3 R^2d groups, each cycloalkyl is optionally substituted with 1 to 3 R^2e groups, each aryl is optionally substituted with 1 to 3 R^2f groups, each heterocycloalkyl is optionally substituted with 1 to 3 R²⁹ groups, and each heteroaryl is optionally substituted with 1 to 3 R^2h groups;</li><li>each R^2a, R^2b, and R^2c is independently hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_2-6 alkoxyalkyl, C_1-6 haloalkyl, C_3-10 cycloalkyl, C_1-6 alkyl-C_3-10 cycloalkyl, C_6-12 aryl, C_1-6 alkyl-C_6-12 aryl, heterocycloalkyl, C_1-6 alkyl-(heterocycloalkyl), heteroaryl, or C_1-6 alkyl-(heteroaryl), wherein the aryl or heteroaryl is optionally substituted with 1 to 3 R^2j;</li><li>alternatively, R^2a, R^2b, and R^2c when attached to the same atom can be combined with the atom to which they are attached to form a heterocycloalkyl;</li><li>each R^2d is independently -CN, -C(O)R^2d1, -C(O)OR^2d1, -OC(O)R^2d1, -C(O)N(R^2d1)(R^2d2), - N(R^2d1)C(O)R^2d2, -OC(O)N(R^2d1)(R^2d2), -N(R^2d1)C(O)OR^2d2, -N(R^2d1)(R^2d2), =O, -OR^2d1, -SR^2d1, -S(O)R^2d1, -S(O)(NR^2d1)(R^2d2), -S(O)₂R^d1, -S(O)N(R^2d1)(R^2d2), - N(R^2d1)S(O)₂R^2d2, C_3-10 cycloalkyl, C_1-6 alkyl-C_3-10 cycloalkyl, C_6-12 aryl, C_1-6 alkyl-C_6-12 aryl, heterocycloalkyl, C_1-6 alkyl-(heterocycloalkyl), heteroaryl, or C_1-6 alkyl-(heteroaryl);</li><li>each R^2d1 and R^2d2 is independently hydrogen, C_1-6 alkyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_2-6 alkoxyalkyl, or C_1-6 haloalkyl;</li><li>each R^2e, R^2f, R^2g, and R^2h is independently hydrogen, C_1-6 alkyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_1-6 alkoxy, C_2-6 alkoxyalkyl, halogen, C_1-6 haloalkyl, C_1-6 haloalkoxy, -CN, or -OH;</li><li>each R^2j is independently C_1-6 alkyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_1-6 alkoxy, C_2-6 alkoxyalkyl, halogen, C_1-6 haloalkyl, or C_1-6 haloalkoxy;</li><li>R³ is hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_1-6 alkoxy, C_2-6 alkoxyalkyl, halogen, C_1-6 haloalkyl, C_1-6 haloalkoxy, -CN, -NO, -NO₂, - C(O)R^3a, -C(O)OR^3a, -OC(O)R^3a, -C(O)N(R^3a)(R^3b), -N(R^3a)C(O)R^3b, - OC(O)N(R^3a)(R^3b), -N(R^3a)C(O)OR^3b, -C(=NR^3a)N(R^3b)(R^3c), -N(R^3a)(R^3b), - N(R^3a)N(R^3b)(R^3c), -N(R^3a)N=C(R^3b)(OR^3c), -OR^3a, -SR^3a, -S(O)R^3a, -S(O)(NR^3a)(R^3b), - S(NR^3a)(NR^3b)(R^3c), -S(O)2R^3a, -S(O)2N(R^3a)(R^3b), -N(R^3a)S(O)2(R^3b), -P(R^3a)(R^3b), - P(O)(R^3a)(R^3b), -P(O)(OR^3a)(R^3b), -P(O)(OR^3a)(OR^3b), C_3-10 cycloalkyl, C_1-6 alkyl-C_3-10 cycloalkyl, C_6-12 aryl, C_1-6 alkyl-C_6-12 aryl, heterocycloalkyl, C_1-6 alkyl-(heterocycloalkyl), heteroaryl, or C_1-6 alkyl-(heteroaryl), wherein each alkenyl or alkynyl is independently optionally substituted with 1 to 3 R^3d groups, each cycloalkyl is optionally substituted with 1 to 3 R^3e groups, each aryl is optionally substituted with 1 to 3 R^3f groups, each heterocycloalkyl is optionally substituted with 1 to 3 R^3g groups, and each heteroaryl is optionally substituted with 1 to 3 R^3h groups;</li><li>each R^3a, R^3b, and R^3c is independently hydrogen, C_1-6 alkyl, C_1-6 hydroxyalkyl, C_2-6 alkoxyalkyl, C_1-6 haloalkyl, C_3-10 cycloalkyl, C_1-6 alkyl-C_3-10 cycloalkyl, C_6-12 aryl, C_1-6 alkyl-C_6-12 aryl, heterocycloalkyl, or heteroaryl;</li><li>alternatively, R^3a, R^3b, and R^3c when attached to the same atom can be combined with the atom to which they are attached to form a heterocycloalkyl;</li><li>each R^3d is independently -N(R^3d1)(R^3d2), -OR^3d1, C_3-10 cycloalkyl, C_1-6 alkyl-C_3-10 cycloalkyl, C_6-12 aryl, C_1-6 alkyl-C_6-12 aryl, heterocycloalkyl, or heteroaryl;</li><li>each R^3d1 and R^3d2 is independently hydrogen, C_1-6 alkyl, or -C(O)O-(C_1-6 alkyl);</li><li>each R^3e, R^3f, R^3g, and R^3h is independently hydrogen, C_1-6 alkyl, C_1-6 alkoxy, halogen, C_1-6 haloalkyl or C_1-6 haloalkoxy;</li><li>R⁴ is hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 alkoxy, halogen, C_1-6 haloalkyl, C_1-6 haloalkoxy, or -CN;</li><li>R⁵ is hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 hydroxyalkyl, C_2-6 alkoxyalkyl, C_1-6 haloalkyl, C_3-10 cycloalkyl, C_1-6 alkyl-C_3-10 cycloalkyl, C_6-12 aryl, C_1-6 alkyl-C_6-12 aryl, heterocycloalkyl, C_1-6 alkyl-(heterocycloalkyl), heteroaryl, or C_1-6 alkyl-(heteroaryl), wherein the alkyl is optionally substituted with R^5a;</li><li>R^5a is -OSi(R^5a1)(R^5a2)(R^5a3);</li><li>R^5a1, R^5a2, and R^5a3 are each independently C_1-6 alkyl; and</li><li>R⁶ is C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 haloalkyl, C_6-12 aryl, or heteroaryl, wherein the aryl or heteroaryl are each optionally substituted with 1 to 3 R^6a;</li><li>each R^6a is independently C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_1-6 alkoxy, C_2-6 alkoxyalkyl, halogen, C_1-6 haloalkyl, C_1-6 haloalkoxy, -CN, -NO₂, -C(O)R^6b, -C(O)OR^6b, -OC(O)R^6b, -C(O)N(R^6b)(R^6c), -N(R^6b)C(O)R^6c, _ C(=NR^6b)N(R^6c)(R^6d), -N(R^6b)(R^6c), -OR^6b, -SR^6b, -S(O)R^6b, -S(O)2R^6b, - S(NR^6b)(NR^6c)R^6d, -S(O)(NR^6b)(R^6c), -S(O)₂N(R^6b)(R^6c), -N(R^6b)S(O)₂(R^6c), - P(R^6b)(R^6c), -P(O)(R^6b)(R^6c), -P(O)(OR^6b)(R^6c), -P(O)(OR^6b)(OR^6c), C_3-10 cycloalkyl, C_1-6 alkyl-C_3-10 cycloalkyl, C_6-12 aryl, C_1-6 alkyl-C_6-12 aryl, heterocycloalkyl, C_1-6 alkyl-(heterocycloalkyl), heteroaryl, or C_1-6 alkyl-(heteroaryl), wherein the cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is each optionally substituted with 1 to 3 R^6e, the alkyl is optionally substituted with R^6f, and the alkynyl is optionally substituted with 1 to 4 R^6j;</li><li>each R^6b, R^6c and R^6d is independently hydrogen, C_1-6 alkyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_2-6 alkoxyalkyl, C_1-6 haloalkyl, C_3-10 cycloalkyl, C_1-6 alkyl-C_3-10 cycloalkyl, C_6-12 aryl, C_1-6 alkyl-C_6-12 aryl, heterocycloalkyl, C_1-6 alkyl-(heterocycloalkyl), heteroaryl, or C_1-6 alkyl-(heteroaryl), wherein the cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is optionally substituted by 1 to 3 R^6k;</li><li>each R^6k is independently C_1-6 alkyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_1-6 alkoxy, C_2-6 alkoxyalkyl, C_1-6 haloalkyl, C_1-6 haloalkoxy, C_3-10 cycloalkyl, C_1-6 alkyl-C_3-10 cycloalkyl, heterocycloalkyl, or C_1-6 alkyl-(heterocycloalkyl);</li><li>each R^6e is independently C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_1-6 alkoxy, C_2-6 alkoxyalkyl, halogen, C_1-6 haloalkyl, C_1-6 haloalkoxy, -CN, -NO₂, -C(O)R^6e1, -C(O)OR^6e1, -OC(O)R^6e1, -C(O)N(R^6e1)(R^6e2), -N(R^6e1)C(O)R^6e2, _ OC(O)N(R^6e1)(R^6e2), -N(R^6e1)C(O)OR^6e2, -C(=NR^6e1)N(R^6e2)(R^6e3), -N(R^6e1)(R^6e2), =O, _ OR^6e1, -SR^6e1, -S(O)R^6e1, -S(NR^6e1)(NR^6e2), -S(O)(NR^6e1)(R^6e2), -S(O)₂R^6e1, - S(O)₂N(R^6e1)(R^6e2), -SF₅, -N(R^6e1)S(O)₂(R^6e2), -P(R^6e1)(R^6e2), -P(O)(R^6e1)(R^6e2), - P(O)(OR^6e1)(R^6e2), -P(O)(OR^6e1)(OR^6e2), -Si(R^6e1)(R^6e2)(R^6e3), C_3-10 cycloalkyl, C1-6 alkyl-C_3-10 cycloalkyl, C_6-12 aryl, C_1-6 alkyl-C_6-12 aryl, heterocycloalkyl, C_1-6 alkyl-heterocycloalkyl, heteroaryl, or C_1-6 alkyl-heteroaryl, wherein the cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is each optionally substituted with 1 to 3 R^6h, and the alkyl is optionally substituted with 1 to 3 R^6m;</li><li>each R^6e1, R^6e2, and R^6e3 is independently hydrogen, C_1-6 alkyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_1-6 alkoxyalkyl, C_1-6 haloalkyl, C_3-10 cycloalkyl, C_1-6 alkyl-C_3-10 cycloalkyl, C_6-10 aryl, C_1-6 alkyl-C_6-10 aryl, heterocycloalkyl, C_1-6 alkyl-(heterocycloalkyl), heteroaryl, or C_1-6 alkyl-(heteroaryl), wherein the cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is optionally substituted with 1 to 3 R⁶ⁿ;</li><li>each R⁶ⁿ is C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_1-6 alkoxy, C_2-6 alkoxyalkyl, halogen, C_1-6 haloalkyl, C_1-6 haloalkoxy, -CN, -C(O)R⁶ⁿ¹, -C(O)OR⁶ⁿ¹, -OC(O)R⁶ⁿ¹, -C(O)N(R⁶ⁿ¹)(R⁶ⁿ²), -N(R⁶ⁿ¹)C(O)R⁶ⁿ², -OC(O)N(R⁶ⁿ¹)(R⁶ⁿ²), - N(R⁶ⁿ¹)C(O)OR⁶ⁿ², -C(=NR⁶ⁿ¹)N(R⁶ⁿ²)(R⁶ⁿ³), -N(R⁶ⁿ)(R⁶ⁿ²), =O, -OH, -SR⁶ⁿ¹, - S(O)R⁶ⁿ¹, -S(NR⁶ⁿ¹)(NR⁶ⁿ²)R⁶ⁿ³, -S(O)(NR⁶ⁿ¹)(R⁶ⁿ²), -S(O)₂R⁶ⁿ¹, -S(O)₂N(R⁶ⁿ¹)(R⁶ⁿ²), or -N(R⁶ⁿ¹)S(O)₂(R⁶ⁿ²);</li><li>each R⁶ⁿ¹, R⁶ⁿ² and R⁶ⁿ³ is independently hydrogen, C_1-6 alkyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_2-6 alkoxyalkyl, C_1-6 haloalkyl, C_3-10 cycloalkyl, C_1-6 alkyl-C_3-10 cycloalkyl, C_6-10 aryl, C_1-6 alkyl-C_6-10 aryl, heterocycloalkyl, C_1-6 alkyl-(heterocycloalkyl), heteroaryl, or C_1-6 alkyl-(heteroaryl);</li><li>each R^6h is independently C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_1-6 alkoxy, C_2-6 alkoxyalkyl, halogen, C_1-6 haloalkyl, C_1-6 haloalkoxy, -CN, -C(O)R^6h1, -C(O)OR^6h1, -OC(O)R^6h1, -C(O)N(R^6h1)(R^6h2), -N(R^6h1)C(O)R^6h2, - OC(O)N(R^6h1)(R^6h2), -N(R^6h1)C(O)OR^6h2, -C(=NR^6h1)N(R^6h2)(R^6h3), -N(R^6h1)(R^6h2), =O, -OH, -SR^6h1, -S(O)R^6h1, -S(NR^6h1)(NR^6h2)R^6h3, -S(O)(NR^6h1)(R^6h2), -S(O)₂R^6h1, - S(O)₂N(R^6h1)(R^6h2), -N(R^6h1)S(O)₂(R^6h2), C_3-10 cycloalkyl, C_1-6 alkyl-C_3-10 cycloalkyl, heterocycloalkyl, or C_1-6 alkyl-(heterocycloalkyl);</li><li>each R^6h1, R^6h2, and R⁶ⁿ³ is independently hydrogen, C_1-6 alkyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_2-6 alkoxyalkyl, C_1-6 haloalkyl, C_3-10 cycloalkyl, C_1-6 alkyl-C_3-10 cycloalkyl, C_6-10 aryl, C_1-6 alkyl-C_6-10 aryl, heterocycloalkyl, C_1-6 alkyl-(heterocycloalkyl), heteroaryl, or C_1-6 alkyl-(heteroaryl);</li><li>each R^6m is independently halogen, C_1-6 haloalkyl, C_1-6 haloalkoxy, -CN, -C(O)R^6m1, - C(O)OR^6m1, -OC(O)R^6m1, -C(O)N(R^6m1)(R^6m2), -N(R^6m3)C(O)R^6m2, - OC(O)N(R^6m1)(R^6m2), -N(R^6m1)C(O)OR^6m2, -C(=NR^6m3)N(R^6m1)(R^6m2), -N(R^6m1)(R^6m2), =O, -OH, -SR^6m1, -S(O)R^6m1, -S(NR^6m1)(NR^6m2)R^6m3, -S(O)(NR^6m1)(R^6m2), -S(O)₂R^6m1, - S(O)₂N(R^6m1)(R^6m2), or -N(R^6m3)S(O)₂(R^6m2);</li><li>each R^6m1, R^6m2, and R^6m3 is independently hydrogen, C_1-6 alkyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_2-6 alkoxyalkyl, C_1-6 haloalkyl, C_3-10 cycloalkyl, C_1-6 alkyl-C_3-10 cycloalkyl, C_6-10 aryl, C_1-6 alkyl-C_6-10 aryl, heterocycloalkyl, C_1-6 alkyl-(heterocycloalkyl), heteroaryl, or C_1-6 alkyl-(heteroaryl);</li><li>R^6f is -OSi(R^6f1)(R^6f2)(R^6f3);</li><li>R^6f1, R^6f2, and R^6f3 are each independently C_1-6 alkyl;</li><li>each R^6j is independently C_2-6 alkoxyalkyl, halogen, C_1-6 haloalkyl, C_1-6 haloalkoxy, -CN, - C(O)R^6j1, -C(O)OR^6j1, -OC(O)R^6j1, -C(O)N(R^6j1)(R^6j2), -N(R^6j3)C(O)R^6j2, _ OC(O)N(R^6j1)(R^6j2), -N(R^6j1)C(O)OR^6j2, -C(=NR^6j3)N(R^6j1)(R^6j2), -N(R^6j1)(R^6j2), =O, - OR^6j1, -SR^6j1, -S(O)R^6j1, -S(NR^6j1)(NR^6j2), -S(NR^6j1)(NR^6j2)R^6j3, -S(O)(NR^6j1)(R^6j2), - S(O)₂R^6j1, -S(O)₂N(R^6j1)(R^6j2), -N(R^6j1)S(O)₂(R^6j2), -Si(R^6j1)(R^6j2)(R^6j3), C_3-10 cycloalkyl, C_6-12 aryl, heterocycloalkyl, or heteroaryl, wherein the cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is optionally substituted with 1 to 3 R^6p;</li><li>each R^6j1, R^6j2, and R^6j3 is independently hydrogen, C_1-6 alkyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_2-6 alkoxyalkyl, C_1-6 haloalkyl, C_3-10 cycloalkyl, C_1-6 alkyl-C_3-10 cycloalkyl, C_6-10 aryl, C_1-6 alkyl-C_6-10 aryl, heterocycloalkyl, C_1-6 alkyl-(heterocycloalkyl), heteroaryl, or C_1-6 alkyl-(heteroaryl);</li><li>each R^6p is independently C_1-6 alkyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_1-6 alkoxy, C_2-6 alkoxyalkyl, halogen, C_1-6 haloalkyl, C_1-6 haloalkoxy, -CN, -C(O)R^6p1, -C(O)OR^6p1, - OC(O)R^6p1, -C(O)N(R^6p1)(R^6p2), -N(R^6p1)C(O)R^6p2, -OC(O)N(R^6p1)(R^6p2), - N(R^6p1)C(O)OR^6p2, -C(=NR^6p3)N(R^6p1)(R^6p2), -N(R^6p1)(R^6p2), =O, -OH, -SR^6p1, - S(O)R^6p1, -S(NR^6p1)(NR^6p2)R^6p3, -S(O)(NR^6p1)(R^6p2), -S(O)₂R^6p1, -S(O)₂N(R^6p1)(R^6p2), or -N(R^6p1)S(O)₂(R^6p2);</li><li>each R^6p1, R^6p2, and R^6p3 is independently hydrogen, C_1-6 alkyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_2-6 alkoxyalkyl, C_1-6 haloalkyl, C_3-10 cycloalkyl, C_1-6 alkyl-C_3-10 cycloalkyl, C_6-10 aryl, C_1-6 alkyl-C_6-10 aryl, heterocycloalkyl, C_1-6 alkyl-(heterocycloalkyl), heteroaryl, or C_1-6 alkyl-(heteroaryl);</li><li>or R⁵ and one R^6a together with the atoms to which they are attached form a heterocycloalkyl, optionally substituted with 1 to 3 R^6g;</li><li>each R^6g is independently C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_2-6 alkoxyalkyl, halogen, C_1-6 haloalkyl, C_1-6 haloalkoxy, or -CN;</li><li>R⁷ is hydrogen, C_1-6 alkyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_1-6 alkoxy, C_2-6 alkoxyalkyl, C_1-6 alkylthio, halogen, C_1-6 haloalkyl, -CN,-OH, -NH₂, C_3-10 cycloalkyl, C_1-6 alkyl-C_3-10 cycloalkyl, heterocycloalkyl, or C_1-6 alkyl-(heterocycloalkyl);</li><li>each heterocycloalkyl is a 3 to 20 membered ring having 1 to 4 heteroatoms each independently N, O or S; and</li><li>each heteroaryl is a 5 to 18 membered ring having 1 to 4 heteroatoms each independently N, O or S.</li></ul>

0013In another embodiment, the present disclosure provides a method of treating cancer in a subject in need thereof comprises administering to the subject a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

0014In another embodiment, the present disclosure provides a method of treating an HIV or a hepatitis B virus infection in a subject in need thereof comprises administering to the subject a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

DETAILED DESCRIPTION

I. DEFINITIONS

0015"Alkyl" is a linear or branched saturated monovalent hydrocarbon. For example, an alkyl group can have 1 to 18 carbon atoms (i.e., C_1-18 alkyl) or 1 to 8 carbon atoms (i.e., C_1-8 alkyl) or 1 to 6 carbon atoms (i.e., C_1-6 alkyl) or 1 to 4 carbon atoms (i.e., C_1-4 alkyl). Examples of alkyl groups include, but are not limited to, methyl (Me, -CH₃), ethyl (Et, -CH₂CH₃), 1-propyl (n-Pr, n-propyl, -CH₂CH₂CH₃), 2-propyl (i-Pr, i-propyl, -CH(CH₃)₂), 1-butyl (n-Bu, n-butyl, - CH₂CH₂CH₂CH₃), 2-methyl-1-propyl (i-Bu, i-butyl, -CH₂CH(CH₃)₂), 2-butyl (s-Bu, <i>s-</i>butyl, -CH(CH₃)CH₂CH₃), 2-methyl-2-propyl (t-Bu, t-butyl, -C(CH₃)₃), 1-pentyl (n-pentyl, -CH₂CH₂CH₂CH₂CH₃), 2-pentyl (-CH(CH₃)CH₂CH₂CH₃), 3-pentyl (-CH(CH₂CH₃)₂), 2-methyl-2-butyl (-C(CH₃)₂CH₂CH₃), 3-methyl-2-butyl (-CH(CH₃)CH(CH₃)₂), 3-methyl-1-butyl (-CH₂CH₂CH(CH₃)₂), 2-methyl-1-butyl (-CH₂CH(CH₃)CH₂CH₃), 1-hexyl (-CH₂CH₂CH₂CH₂CH₂CH₃), 2-hexyl (-CH(CH₃)CH₂CH₂CH₂CH₃), 3-hexyl (-CH(CH₂CH₃)(CH₂CH₂CH₃)), 2-methyl-2-pentyl (-C(CH₃)₂CH₂CH₂CH₃), 3-methyl-2-pentyl (-CH(CH₃)CH(CH₃)CH₂CH₃), 4-methyl-2-pentyl (-CH(CH₃)CH₂CH(CH₃)₂), 3-methyl-3-pentyl (-C(CH₃)(CH₂CH₃)₂), 2-methyl-3-pentyl (-CH(CH₂CH₃)CH(CH₃)₂), 2,3-dimethyl-2-butyl (-C(CH₃)₂CH(CH₃)₂), and 3,3-dimethyl-2-butyl (-CH(CH₃)C(CH₃)₃. Other alkyl groups include heptyl, octyl, nonyl, decyl, undecyl, dodecyl, pentadcyl, hexadecyl, heptadecyl and octadecyl.

0016"Alkylene" refers to a straight or branched, saturated, aliphatic radical having the number of carbon atoms indicated, and linking at least two other groups, <i>i.e.,</i> a divalent hydrocarbon radical. The two moieties linked to the alkylene can be linked to the same atom or different atoms of the alkylene group. For instance, a straight chain alkylene can be the bivalent radical of -(CH₂)_n-, where n is 1, 2, 3, 4, 5 or 6. Representative alkylene groups include, but are not limited to, methylene, ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene, pentylene and hexylene. Alkylene groups can be substituted or unsubstituted.

0017"Alkenyl" refers to a straight chain or branched hydrocarbon having at least 2 carbon atoms and at least one double bond. Alkenyl can include any number of carbons, such as C₂, C_2-3, C_2-4, C_2-5, C_2-6, C_2-7, C_2-8, C_2-9, C_2-10, C₃, C_3-4, C_3-5, C_3-6, C₄, C_4-5, C_4-6, C₅, C_5-6, and C₆. Alkenyl groups can have any suitable number of double bonds, including, but not limited to, 1, 2, 3, 4, 5 or more. Examples of alkenyl groups include, but are not limited to, vinyl (ethenyl), propenyl, isopropenyl, 1-butenyl, 2-butenyl, isobutenyl, butadienyl, 1-pentenyl, 2-pentenyl, isopentenyl, 1,3-pentadienyl, 1,4-pentadienyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1,3-hexadienyl, 1,4-hexadienyl, 1,5-hexadienyl, 2,4-hexadienyl, or 1,3,5-hexatrienyl. Alkenyl groups can be substituted or unsubstituted.

0018"Alkynyl" refers to either a straight chain or branched hydrocarbon having at least 2 carbon atoms and at least one triple bond. Alkynyl can include any number of carbons, such as C₂, C_2-3, C_2-4, C_2-5, C_2-6, C_2-7, C_2-8, C_2-9, C_2-10, C₃, C_3-4, C_3-5, C_3-6, C₄, C_4-5, C_4-6, C₅, C_5-6, and C₆. Examples of alkynyl groups include, but are not limited to, acetylenyl, propynyl, 1-butynyl, 2-butynyl, butadiynyl, 1-pentynyl, 2-pentynyl, isopentynyl, 1,3-pentadiynyl, 1,4-pentadiynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 1,3-hexadiynyl, 1,4-hexadiynyl, 1,5-hexadiynyl, 2,4-hexadiynyl, or 1,3,5-hexatriynyl. Alkynyl groups can be substituted or unsubstituted.

0019"Alkoxy" refers to an alkyl group having an oxygen atom that connects the alkyl group to the point of attachment: alkyl-O-. As for alkyl group, alkoxy groups can have any suitable number of carbon atoms, such as C_1-6. Alkoxy groups include, for example, methoxy, ethoxy, propoxy, iso-propoxy, butoxy, 2-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, pentoxy, hexoxy, etc. The alkoxy groups can be further substituted with a variety of substituents described within. Alkoxy groups can be substituted or unsubstituted.

0020"Alkoxyalkyl" refers an alkoxy group linked to an alkyl group which is linked to the remainder of the compound such that the alkyl group is divalent. Alkoxyalkyl can have any suitable number of carbon, such as from 2 to 6 (C_2-6 alkoxyalkyl), 2 to 5 (C_2-5 alkoxyalkyl), 2 to 4 (C_2-4 alkoxyalkyl), or 2 to 3 (C_2-3 alkoxyalkyl). The number of carbons refers to the total number of carbons in the alkoxy and the alkyl group. For example, C₆ alkoxyalkyl refers to ethoxy (C₂ alkoxy) linked to a butyl (C₄ alkyl), and n-propoxy (C₃ alkoxy) linked to a isopropyl (C₃ alkyl). Alkoxy and alkyl are as defined above where the alkyl is divalent, and can include, but is not limited to, methoxymethyl (CH₃OCH₂-), methoxyethyl (CH₃OCH₂CH₂-) and others.

0021"Aminoalkyl" refers to an amino group linked to an alkyl group which is linked to the remainder of the compound such that the alkyl group is divalent. The amino group may be unsubstituted amino (-NH₂) or substituted with an alkyl group, e.g., monosubstituted amino (e.g., -NHCH₃), or disubstituted amino (e.g., -N(CH₃)₂). Aminoalkyl can have any suitable number of carbons, such as from 1 to 8 (C_1-8 aminoalkyl), 1 to 6 (C_1-6 aminoalkyl), 2 to 6 (C_2-6 aminoalkyl), 2 to 4 (C_2-4 aminoalkyl), or 2 to 3 (C_2-3 aminoalkyl). The number of carbons refers to the total number of carbons in the amino and the alkyl group. For example, C₆ aminoalkyl refers to -N(CH₃)₂ (C₂ amino) linked to a butyl (C₄ alkyl), and -NHCH₂CH₂CH₃ (C₃ amino) linked to a isopropyl (C₃ alkyl). Alkyl is as defined above where the alkyl is divalent. Aminoalkyl can include, but is not limited to, aminomethyl (H₂NCH₂-), methylaminomethyl (CH₃NHCH₂-), dimethylaminomethyl ((CH₃)₂NCH₂-), dimethylaminoethyl ((CH₃)₂NCH₂CH₂-), and others.

0022"Alkoxy-alkoxy" refers an alkoxy group linked to a second alkoxy group which is linked to the remainder of the compound. Alkoxy is as defined above, and can include, but is not limited to, methoxy-methoxy (CH₃OCH₂O-), methoxy-ethoxy (CH₃OCH₂CH₂O-) and others.

0023"Halo" or "halogen" as used herein refers to fluoro (-F), chloro (-Cl), bromo (-Br) and iodo (-I).

0024"Haloalkyl" as used herein refers to an alkyl as defined herein, wherein one or more hydrogen atoms of the alkyl are independently replaced by a halo substituent, which may be the same or different. For example, C_1-4 haloalkyl is a C_1-4 alkyl wherein one or more of the hydrogen atoms of the C_1-4 alkyl have been replaced by a halo substituent. Examples of haloalkyl groups include but are not limited to fluoromethyl, fluorochloromethyl, difluoromethyl, difluorochloromethyl, trifluoromethyl, 1,1,1-trifluoroethyl and pentafluoroethyl.

0025"Haloalkoxy" refers to an alkoxy group where some or all of the hydrogen atoms are substituted with halogen atoms. As for an alkyl group, haloalkoxy groups can have any suitable number of carbon atoms, such as C_1-6. The alkoxy groups can be substituted with 1, 2, 3, or more halogens. When all the hydrogens are replaced with a halogen, for example by fluorine, the compounds are per-substituted, for example, perfluorinated. Haloalkoxy includes, but is not limited to, trifluoromethoxy, 2,2,2,-trifluoroethoxy, perfluoroethoxy, etc.

0026"Cycloalkyl" refers to a single saturated or partially unsaturated all carbon ring having 3 to 20 annular carbon atoms (i.e., C_3-20 cycloalkyl), for example from 3 to 12 annular atoms, for example from 3 to 10 annular atoms, or 3 to 8 annular atoms, or 3 to 6 annular atoms, or 3 to 5 annular atoms, or 3 to 4 annular atoms. The term "cycloalkyl" also includes multiple condensed, saturated and partially unsaturated all carbon ring systems (e.g., ring systems comprising 2, 3 or 4 carbocyclic rings). Accordingly, cycloalkyl includes multicyclic carbocyles such as a bicyclic carbocycles (e.g., bicyclic carbocycles having 6 to 12 annular carbon atoms such as bicyclo[3.1.0]hexane and bicyclo[2.1.1]hexane), and polycyclic carbocycles (e.g., tricyclic and tetracyclic carbocycles with up to 20 annular carbon atoms). The rings of a multiple condensed ring system can be connected to each other via fused, spiro and bridged bonds when allowed by valency requirements. Non-limiting examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl and 1-cyclohex-3-enyl.

0027"Alkyl-cycloalkyl" refers to a radical having an alkyl component and a cycloalkyl component, where the alkyl component links the cycloalkyl component to the point of attachment. The alkyl component is as defined above, except that the alkyl component is at least divalent, an alkylene, to link to the cycloalkyl component and to the point of attachment. In some instances, the alkyl component can be absent. The alkyl component can include any number of carbons, such as C_1-6, C_1-2, C_1-3, C_1-4, C_1-5, C_2-3, C_2-4, C_2-5, C_2-6, C_3-4, C_3-5, C_3-6, C_4-5, C_4-6 and C_5-6. The cycloalkyl component is as defined within. Exemplary alkyl-cycloalkyl groups include, but are not limited to, methyl-cyclopropyl, methyl-cyclobutyl, methylcyclopentyl and methyl-cyclohexyl.

0028"Heterocyclyl" or "heterocycle" or "heterocycloalkyl" as used herein refers to a single saturated or partially unsaturated non-aromatic ring or a multiple ring system having at least one heteroatom in the ring (i.e., at least one annular heteroatom selected from oxygen, nitrogen, and sulfur) wherein the multiple ring system includes at least non-aromatic ring containing at least one heteroatom. The multiple ring system can also include other aromatic rings and non-aromatic rings. Unless otherwise specified, a heterocyclyl group has from 3 to 20 annular atoms, for example from 3 to 12 annular atoms, for example from 3 to 10 annular atoms, or 3 to 8 annular atoms, or 3 to 6 annular atoms, or 3 to 5 annular atoms, or 4 to 6 annular atoms, or 4 to 5 annular atoms. Thus, the term includes single saturated or partially unsaturated rings (e.g., 3, 4, 5, 6 or 7-membered rings) having from 1 to 6 annular carbon atoms and from 1 to 3 annular heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur in the ring. The heteroatoms can optionally be oxidized to form -N(-OH)-, =N(-O^-)-, -S(=O)- or -S(=O)₂-. The rings of the multiple condensed ring (e.g. bicyclic heterocyclyl) system can be connected to each other via fused, spiro and bridged bonds when allowed by valency requirements. Heterocycles include, but are not limited to, azetidine, aziridine, imidazolidine, morpholine, oxirane (epoxide), oxetane, thietane, piperazine, piperidine, pyrazolidine, piperidine, pyrrolidine, pyrrolidinone, tetrahydrofuran, tetrahydrothiophene, dihydropyridine, tetrahydropyridine, quinuclidine, 2-oxa-6-azaspiro[3.3]heptan-6-yl, 6-oxa-1-azaspiro[3.3]heptan-1-yl, 2-thia-6-azaspiro[3.3]heptan-6-yl, 2,6-diazaspiro[3.3]heptan-2-yl, 2-azabicyclo[3.1.0]hexan-2-yl, 3-azabicyclo[3.1.0]hexanyl, 2-azabicyclo[2.1.1]hexanyl, 2-azabicyclo[2.2.1]heptan-2-yl, 4-azaspiro[2.4]heptanyl, 5-azaspiro[2.4]heptanyl, and the like.

0029Heterocycloalkyl rings also include 9 to 15 membered fused ring heterocycloalkyls having 2, 3, or more rings wherein at least one ring is an aryl ring and at least one ring is a non-aromatic ring containing at least one heteroatom. Representative fused bicyclic heterocycloalkyls include, but are not limited to, indoline (dihydroindole), isoindoline (dihydroisoindole), indazoline (dihydroindazole), benzo[d]imidazole, dihydroquinoline, dihydroisoquinoline, dihydrobenzofuran, dihydroisobenzofuran, benzo[d][1,3]dioxol, dihydrobenzo[b]dioxine, dihydrobenzo[d]oxazole, dihydrobenzo[b]thiophene, dihydroisobenzo[c]thiophene, dihydrobenzo[d]thiazole, dihydrobenzo[c]isothiazole, and benzo[b][1,4]thiazine, as shown in the structures below: <chemistry id="chem0006" num="0006"><img file="EP4445902A2_D0006.tif" /></chemistry><chemistry id="chem0007" num="0007"><img file="EP4445902A2_D0007.tif" /></chemistry><chemistry id="chem0008" num="0008"><img file="EP4445902A2_D0008.tif" /></chemistry> Fused bicyclic heterocycloalkyls can also be represented by the following structure: <chemistry id="chem0009" num="0009"><img file="EP4445902A2_D0009.tif" /></chemistry> wherein X¹, X², X³ and X⁴ are each independently absent, -CH₂-, -NH-, -O- or -S-, at least one of X¹, X², X³ and X⁴ is -NH-, -O- or -S-, and the dashed circle represents a saturated or partially unsaturated non-aromatic ring. The fused bicyclic heterocycloalkyls are optionally substituted.

0030"Alkyl-heterocycloalkyl" refers to a radical having an alkyl component and a heterocycloalkyl component, where the alkyl component links the heterocycloalkyl component to the point of attachment. The alkyl component is as defined above, except that the alkyl component is at least divalent, an alkylene, to link to the heterocycloalkyl component and to the point of attachment. The alkyl component can include any number of carbons, such as C_0-6, C_1-2, C_1-3, C_1-4, C_1-5, C_1-6, C_2-3, C_2-4, C_2-5, C_2-6, C_3-4, C_3-5, C_3-6, C_4-5, C_4-6 and C_5-6. In some instances, the alkyl component can be absent. The heterocycloalkyl component is as defined above. Alkyl-heterocycloalkyl groups can be substituted or unsubstituted.

0031"Aryl" as used herein refers to a single all carbon aromatic ring or a multiple condensed all carbon ring system wherein at least one of the rings is aromatic. For example, in some embodiments, an aryl group has 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 12 carbon atoms. Aryl includes a phenyl radical. Aryl also includes multiple condensed ring systems (e.g., ring systems comprising 2, 3 or 4 rings) having 9 to 20 carbon atoms, e.g., 9 to 16 carbon atoms, in which at least one ring is aromatic and wherein the other rings may be aromatic or not aromatic (i.e., carbocycle). Such multiple condensed ring systems are optionally substituted with one or more (e.g., 1, 2 or 3) oxo groups on any carbocycle portion of the multiple condensed ring system. The rings of the multiple condensed ring system can be connected to each other via fused, spiro and bridged bonds when allowed by valency requirements. It is also to be understood that when reference is made to a certain atom-range membered aryl (e.g., 6-10 membered aryl), the atom range is for the total ring atoms of the aryl. For example, a 6-membered aryl would include phenyl and a 10-membered aryl would include naphthyl and 1,2,3,4-tetrahydronaphthyl. Non-limiting examples of aryl groups include, but are not limited to, phenyl, indenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, anthracenyl, and the like.

0032"Alkyl-aryl" refers to a radical having an alkyl component and an aryl component, where the alkyl component links the aryl component to the point of attachment. The alkyl component is as defined above, except that the alkyl component is at least divalent, an alkylene, to link to the aryl component and to the point of attachment. The alkyl component can include any number of carbons, such as C_0-6, C_1-2, C_1-3, C_1-4, C_1-5, C_1-6, C_2-3, C_2-4, C_2-5, C_2-6, C_3-4, C_3-5, C_3-6, C_4-5, C_4-6 and C_5-6. In some instances, the alkyl component can be absent. The aryl component is as defined above. Examples of alkyl-aryl groups include, but are not limited to, benzyl and ethyl-benzene. Alkyl-aryl groups can be substituted or unsubstituted.

0033"Heteroaryl" as used herein refers to a single aromatic ring that has at least one atom other than carbon in the ring, wherein the atom is selected from the group consisting of oxygen, nitrogen and sulfur; "heteroaryl" also includes multiple condensed ring systems that have at least one such aromatic ring, which multiple condensed ring systems are further described below. Thus, "heteroaryl" includes single aromatic rings of from 1 to 6 carbon atoms and 1-4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur. The sulfur and nitrogen atoms may also be present in an oxidized form provided the ring is aromatic. Exemplary heteroaryl ring systems include but are not limited to pyridyl, pyrimidinyl, oxazolyl or furyl. "Heteroaryl" also includes multiple condensed ring systems (e.g., ring systems comprising 2, 3 or 4 rings) wherein a heteroaryl group, as defined above, is condensed with one or more rings selected from heteroaryls (to form for example 1,8-naphthyridinyl), heterocycles, (to form for example 1,2,3,4-tetrahydro-1,8-naphthyridinyl), carbocycles (to form for example 5,6,7,8-tetrahydroquinolyl) and aryls (to form for example indazolyl) to form the multiple condensed ring system. Thus, a heteroaryl (a single aromatic ring or multiple condensed ring system) has 1-20 carbon atoms and 1-6 heteroatoms within the heteroaryl ring. Such multiple condensed ring systems may be optionally substituted with one or more (e.g., 1, 2, 3 or 4) oxo groups on the carbocycle or heterocycle portions of the condensed ring. The rings of the multiple condensed ring system can be connected to each other via fused, spiro and bridged bonds when allowed by valency requirements. It is to be understood that the individual rings of the multiple condensed ring system may be connected in any order relative to one another. It is to be understood that the point of attachment for a heteroaryl or heteroaryl multiple condensed ring system can be at any suitable atom of the heteroaryl or heteroaryl multiple condensed ring system including a carbon atom and a heteroatom (e.g., a nitrogen). It also to be understood that when a reference is made to a certain atom-range membered heteroaryl (e.g., a 5 to 10 membered heteroaryl), the atom range is for the total ring atoms of the heteroaryl and includes carbon atoms and heteroatoms. For example, a 5-membered heteroaryl would include a thiazolyl and a 10-membered heteroaryl would include a quinolinyl. Exemplary heteroaryls include but are not limited to pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, thienyl, indolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, furyl, oxadiazolyl, thiadiazolyl, quinolyl, isoquinolyl, benzothiazolyl, benzoxazolyl, indazolyl, quinoxalyl, quinazolyl, 5,6,7,8-tetrahydroisoquinolinyl benzofuranyl, benzimidazolyl, thianaphthenyl, pyrrolo[2,3-b]pyridinyl, quinazolinyl-4(3H)-one, and triazolyl.

0034"Alkyl-heteroaryl" refers to a radical having an alkyl component and a heteroaryl component, where the alkyl component links the heteroaryl component to the point of attachment. The alkyl component is as defined above, except that the alkyl component is at least divalent, an alkylene, to link to the heteroaryl component and to the point of attachment. The alkyl component can include any number of carbons, such as C_0-6, C_1-2, C_1-3, C_1-4, C_1-5, C_1-6, C_2-3, C_2-4, C_2-5, C_2-6, C_3-4, C_3-5, C_3-6, C_4-5, C_4-6 and C_5-6. In some instances, the alkyl component can be absent. The heteroaryl component is as defined within. Alkyl-heteroaryl groups can be substituted or unsubstituted.

0035A "compound of the present disclosure" includes compounds disclosed herein, for example a compound of the present disclosure includes compounds of Formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), and (IIc-8), including the compounds of the Examples.

0036"Composition" as used herein is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product, which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. By "pharmaceutically acceptable" it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and deleterious to the recipient thereof.

0037"Pharmaceutically effective amount" refers to an amount of a compound of the present disclosure in a formulation or combination thereof, that provides the desired therapeutic or pharmaceutical result.

0038"Pharmaceutically acceptable excipient" includes without limitation any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier which has been approved by the United States Food and Drug Administration as being acceptable for use in humans or domestic animals.

0039"Treatment" or "treat" or "treating" as used herein refers to an approach for obtaining beneficial or desired results. For purposes of the present disclosure, beneficial or desired results include, but are not limited to, alleviation of a symptom and/or diminishment of the extent of a symptom and/or preventing a worsening of a symptom associated with a disease or condition. In some embodiments, "treatment" or "treating" includes one or more of the following: a) inhibiting the disease or condition (e.g., decreasing one or more symptoms resulting from the disease or condition, and/or diminishing the extent of the disease or condition); b) slowing or arresting the development of one or more symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, delaying the worsening or progression of the disease or condition); and c) relieving the disease or condition, e.g., causing the regression of clinical symptoms, ameliorating the disease state, delaying the progression of the disease, increasing the quality of life, and/or prolonging survival.

0040"Therapeutically effective amount" or "effective amount" as used herein refers to an amount that is effective to elicit the desired biological or medical response, including the amount of a compound that, when administered to a subject for treating a disease, is sufficient to effect such treatment for the disease. The effective amount can vary depending on the compound, the disease, and its severity and the age, weight, etc., of the subject to be treated. The effective amount can include a range of amounts. As is understood in the art, an effective amount may be in one or more doses, <i>i.e.,</i> a single dose or multiple doses may be required to achieve the desired treatment endpoint. An effective amount may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered to be given in an effective amount if, in conjunction with one or more other agents, a desirable or beneficial result may be or is achieved. Suitable doses of any co-administered compounds may optionally be lowered due to the combined action (e.g., additive or synergistic effects) of the compounds.

0041"Administering" refers to oral administration, administration as a suppository, topical contact, parenteral, intravenous, intraperitoneal, intramuscular, intralesional, intranasal or subcutaneous administration, intrathecal administration, or the implantation of a slow-release device e.g., a mini-osmotic pump, to the subject. The administration can be carried out according to a schedule specifying frequency of administration, dose for administration, and other factors.

0042"Co-administration" as used herein refers to administration of unit dosages of the compounds disclosed herein before or after administration of unit dosages of one or more additional therapeutic agents, for example, administration of the compound disclosed herein within seconds, minutes, or hours of the administration of one or more additional therapeutic agents. For example, in some embodiments, a unit dose of a compound of the present disclosure is administered first, followed within seconds or minutes by administration of a unit dose of one or more additional therapeutic agents. Alternatively, in other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed by administration of a unit dose of a compound of the present disclosure within seconds or minutes. In some embodiments, a unit dose of a compound of the present disclosure is administered first, followed, after a period of hours (e.g., 1-12 hours), by administration of a unit dose of one or more additional therapeutic agents. In other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed, after a period of hours (e.g., 1-12 hours), by administration of a unit dose of a compound of the present disclosure. Co-administration of a compound disclosed herein with one or more additional therapeutic agents generally refers to simultaneous or sequential administration of a compound disclosed herein and one or more additional therapeutic agents, such that therapeutically effective amounts of each agent are present in the body of the patient.

0043"Subject" refers to animals such as mammals, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice and the like. In some embodiments, the subject is a human.

0044"Disease" or "condition" refer to a state of being or health status of a patient or subject capable of being treated with a compound, pharmaceutical composition, or method provided herein. The disease may be an autoimmune, inflammatory, cancer, infectious (e.g., a viral infection), metabolic, developmental, cardiovascular, liver, intestinal, endocrine, neurological, or other disease. In some embodiments, the disease is cancer (e.g. lung cancer, ovarian cancer, osteosarcoma, bladder cancer, cervical cancer, liver cancer, kidney cancer, skin cancer (e.g., Merkel cell carcinoma), testicular cancer, leukemia, lymphoma, head and neck cancer, colorectal cancer, prostate cancer, pancreatic cancer, melanoma, breast cancer, neuroblastoma).

0045"Cancer" refers to all types of cancer, neoplasm or malignant tumors found in mammals, including leukemias, lymphomas, melanomas, neuroendocrine tumors, carcinomas and sarcomas. Exemplary cancers that may be treated with a compound, pharmaceutical composition, or method provided herein include lymphoma, sarcoma, bladder cancer, bone cancer, brain tumor, cervical cancer, colon cancer, esophageal cancer, gastric cancer, head and neck cancer, kidney cancer, myeloma, thyroid cancer, leukemia, prostate cancer, breast cancer (e.g. triple negative, ER positive, ER negative, chemotherapy resistant, herceptin resistant, HER2 positive, doxorubicin resistant, tamoxifen resistant, ductal carcinoma, lobular carcinoma, primary, metastatic), ovarian cancer, pancreatic cancer, liver cancer (e.g. hepatocellular carcinoma), lung cancer (e.g. non-small cell lung carcinoma, squamous cell lung carcinoma, adenocarcinoma, large cell lung carcinoma, small cell lung carcinoma, carcinoid, sarcoma), glioblastoma multiforme, glioma, melanoma, prostate cancer, castration-resistant prostate cancer, breast cancer, triple negative breast cancer, glioblastoma, ovarian cancer, lung cancer, squamous cell carcinoma (e.g., head, neck, or esophagus), colorectal cancer, leukemia, acute myeloid leukemia, lymphoma, B cell lymphoma, or multiple myeloma.

0046Additional examples include, cancer of the thyroid, endocrine system, brain, breast, cervix, colon, head &amp; neck, esophagus, liver, kidney, lung, non-small cell lung, melanoma, mesothelioma, ovary, sarcoma, stomach, uterus or Medulloblastoma, Hodgkin's Disease, Non-Hodgkin's Lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia, primary brain tumors, cancer, malignant pancreatic insulanoma, malignant carcinoid, urinary bladder cancer, premalignant skin lesions, testicular cancer, lymphomas, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia, endometrial cancer, adrenal cortical cancer, neoplasms of the endocrine or exocrine pancreas, medullary thyroid cancer, medullary thyroid carcinoma, melanoma, colorectal cancer, papillary thyroid cancer, hepatocellular carcinoma, Paget's Disease of the Nipple, Phyllodes Tumors, Lobular Carcinoma, Ductal Carcinoma, cancer of the pancreatic stellate cells, cancer of the hepatic stellate cells, or prostate cancer.

0047"Leukemia" refers broadly to progressive, malignant diseases of the blood-forming organs and is generally characterized by a distorted proliferation and development of leukocytes and their precursors in the blood and bone marrow. Leukemia is generally clinically classified on the basis of (1) the duration and character of the disease-acute or chronic; (2) the type of cell involved; myeloid (myelogenous), lymphoid (lymphogenous), or monocytic; and (3) the increase or non-increase in the number abnormal cells in the blood-leukemic or aleukemic (subleukemic). Exemplary leukemias that may be treated with a compound, pharmaceutical composition, or method provided herein include, for example, acute nonlymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, aleukemic leukemia, a leukocythemic leukemia, basophylic leukemia, blast cell leukemia, bovine leukemia, chronic myelocytic leukemia, leukemia cutis, embryonal leukemia, eosinophilic leukemia, Gross' leukemia, hairy-cell leukemia, hemoblastic leukemia, hemocytoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphatic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphogenous leukemia, lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocyte leukemia, micromyeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myelocytic leukemia, myeloid granulocytic leukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cell leukemia, multiple myeloma, plasmacytic leukemia, promyelocytic leukemia, Rieder cell leukemia, Schilling's leukemia, stem cell leukemia, subleukemic leukemia, or undifferentiated cell leukemia.

0048"Sarcoma" generally refers to a tumor which is made up of a substance like the embryonic connective tissue and is generally composed of closely packed cells embedded in a fibrillar or homogeneous substance. Sarcomas that may be treated with a compound, pharmaceutical composition, or method provided herein include a chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abemethy's sarcoma, adipose sarcoma, liposarcoma, alveolar soft part sarcoma, ameloblastic sarcoma, botryoid sarcoma, chloroma sarcoma, chorio carcinoma, embryonal sarcoma, Wilms' tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewing's sarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmented hemorrhagic sarcoma, immunoblastic sarcoma of B cells, lymphoma, immunoblastic sarcoma of T-cells, Jensen's sarcoma, Kaposi's sarcoma, Kupffer cell sarcoma, angiosarcoma, leukosarcoma, malignant mesenchymoma sarcoma, parosteal sarcoma, reticulocytic sarcoma, Rous sarcoma, serocystic sarcoma, synovial sarcoma, or telangiectaltic sarcoma.

0049"Melanoma" is taken to mean a tumor arising from the melanocytic system of the skin and other organs. Melanomas that may be treated with a compound, pharmaceutical composition, or method provided herein include, for example, acral-lentiginous melanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman's melanoma, S91 melanoma, Harding-Passey melanoma, juvenile melanoma, lentigo maligna melanoma, malignant melanoma, nodular melanoma, subungal melanoma, or superficial spreading melanoma.

0050"Carcinoma" refers to a malignant new growth made up of epithelial cells tending to infiltrate the surrounding tissues and give rise to metastases. Exemplary carcinomas that may be treated with a compound, pharmaceutical composition, or method provided herein include, for example, medullary thyroid carcinoma, familial medullary thyroid carcinoma, acinar carcinoma, acinous carcinoma, adenocystic carcinoma, adenoid cystic carcinoma, carcinoma adenomatosum, carcinoma of adrenal cortex, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, carcinoma basocellulare, basal oid carcinoma, basosquamous cell carcinoma, bronchioalveolar carcinoma, bronchiolar carcinoma, bronchogenic carcinoma, cerebriform carcinoma, cholangiocellular carcinoma, chorionic carcinoma, colloid carcinoma, comedo carcinoma, corpus carcinoma, cribriform carcinoma, carcinoma en cuirasse, carcinoma cutaneum, cylindrical carcinoma, cylindrical cell carcinoma, duct carcinoma, ductal carcinoma, carcinoma durum, embryonal carcinoma, encephaloid carcinoma, epiermoid carcinoma, carcinoma epitheliale adenoides, exophytic carcinoma, carcinoma ex ulcere, carcinoma fibrosum, gelatiniforni carcinoma, gelatinous carcinoma, giant cell carcinoma, carcinoma gigantocellulare, glandular carcinoma, granulosa cell carcinoma, hair-matrix carcinoma, hematoid carcinoma, hepatocellular carcinoma, Hurthle cell carcinoma, hyaline carcinoma, hypernephroid carcinoma, infantile embryonal carcinoma, carcinoma in situ, intraepidermal carcinoma, intraepithelial carcinoma, Krompecher's carcinoma, Kulchitzky-cell carcinoma, large-cell carcinoma, lenticular carcinoma, carcinoma lenticulare, lipomatous carcinoma, lobular carcinoma, lymphoepithelial carcinoma, carcinoma medullare, medullary carcinoma, melanotic carcinoma, carcinoma molle, mucinous carcinoma, carcinoma muciparum, carcinoma mucocellulare, mucoepidermoid carcinoma, carcinoma mucosum, mucous carcinoma, carcinoma myxomatodes, nasopharyngeal carcinoma, oat cell carcinoma, carcinoma ossificans, osteoid carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, prickle cell carcinoma, pultaceous carcinoma, renal cell carcinoma of kidney, reserve cell carcinoma, carcinoma sarcomatodes, schneiderian carcinoma, scirrhous carcinoma, carcinoma scroti, signet-ring cell carcinoma, carcinoma simplex, small-cell carcinoma, solanoid carcinoma, spheroidal cell carcinoma, spindle cell carcinoma, carcinoma spongiosum, squamous carcinoma, squamous cell carcinoma, string carcinoma, carcinoma telangiectaticum, carcinoma telangiectodes, transitional cell carcinoma, carcinoma tuberosum, tubular carcinoma, tuberous carcinoma, verrucous carcinoma, or carcinoma villosum.

0051"Metastasis," "metastatic," and "metastatic cancer" can be used interchangeably and refer to the spread of a proliferative disease or disorder, e.g., cancer, from one organ or another non-adjacent organ or body part. Cancer occurs at an originating site, e.g., breast, which site is referred to as a primary tumor, e.g., primary breast cancer. Some cancer cells in the primary tumor or originating site acquire the ability to penetrate and infiltrate surrounding normal tissue in the local area and/or the ability to penetrate the walls of the lymphatic system or vascular system circulating through the system to other sites and tissues in the body. A second clinically detectable tumor formed from cancer cells of a primary tumor is referred to as a metastatic or secondary tumor. When cancer cells metastasize, the metastatic tumor and its cells are presumed to be similar to those of the original tumor. Thus, if lung cancer metastasizes to the breast, the secondary tumor at the site of the breast consists of abnormal lung cells and not abnormal breast cells. The secondary tumor in the breast is referred to a metastatic lung cancer. Thus, the phrase metastatic cancer refers to a disease in which a subject has or had a primary tumor and has one or more secondary tumors. The phrases non-metastatic cancer or subjects with cancer that is not metastatic refers to diseases in which subjects have a primary tumor but not one or more secondary tumors. For example, metastatic lung cancer refers to a disease in a subject with or with a history of a primary lung tumor and with one or more secondary tumors at a second location or multiple locations, e.g., in the breast.

0052"Associated" or "associated with" in the context of a substance or substance activity or function associated with a disease (e.g., diabetes, cancer (e.g. prostate cancer, renal cancer, metastatic cancer, melanoma, castration-resistant prostate cancer, breast cancer, triple negative breast cancer, glioblastoma, ovarian cancer, lung cancer, squamous cell carcinoma (e.g., head, neck, or esophagus), colorectal cancer, leukemia, acute myeloid leukemia, lymphoma, B cell lymphoma, or multiple myeloma)) means that the disease (e.g. lung cancer, ovarian cancer, osteosarcoma, bladder cancer, cervical cancer, liver cancer, kidney cancer, skin cancer (e.g., Merkel cell carcinoma), testicular cancer, leukemia, lymphoma, head and neck cancer, colorectal cancer, prostate cancer, pancreatic cancer, melanoma, breast cancer, neuroblastoma) is caused by (in whole or in part), or a symptom of the disease is caused by (in whole or in part) the substance or substance activity or function.

0053Provided are also pharmaceutically acceptable salts, hydrates, solvates, tautomeric forms, polymorphs, and prodrugs of the compounds described herein. "Pharmaceutically acceptable" or "physiologically acceptable" refer to compounds, salts, compositions, dosage forms and other materials which are useful in preparing a pharmaceutical composition that is suitable for veterinary or human pharmaceutical use.

0054The compounds of the present disclosure as described herein may be prepared and/or formulated as pharmaceutically acceptable salts or when appropriate as a free base. Pharmaceutically acceptable salts are non-toxic salts of a free base form of a compound that possesses the desired pharmacological activity of the free base. These salts may be derived from inorganic or organic acids or bases. Examples of a pharmaceutically acceptable salt of the compound of Formula (I) of the present disclosure include an inorganic acid salt such as hydrochloride, sulfate, carbonate, and phosphate etc., and an organic acid salt such as fumarate, maleate, methanesulfonate, and p-toluenesulfonate etc. Further salts with an alkaline metal such as sodium, potassium etc., with an alkaline earth metal such as magnesium or calcium etc., with an organic amine such as a lower alkyl amine, or a lower alcoholamine, with a basic amino acid such as lysine, arginine, ornithine, or an ammonium salt is also included. For example, a compound that contains a basic nitrogen may be prepared as a pharmaceutically acceptable salt by contacting the compound with an inorganic or organic acid. Non-limiting examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen-phosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1,4-dioates, hexyne-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, methylsulfonates, propylsulfonates, besylates, xylenesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, γ-hydroxybutyrates, glycolates, tartrates, and mandelates. Lists of other suitable pharmaceutically acceptable salts are found in Remington: The Science and Practice of Pharmacy, 21^st Edition, Lippincott Wiliams and Wilkins, Philadelphia, Pa., 2006.

0055Examples of "pharmaceutically acceptable salts" of the compounds disclosed herein also include salts derived from an appropriate base, such as an alkali metal (for example, sodium, potassium), an alkaline earth metal (for example, magnesium), ammonium and NX₄⁺ (wherein X is C₁-C₄ alkyl). Also included are base addition salts, such as sodium or potassium salts.

0056Provided are also compounds described herein or pharmaceutically acceptable salts, isomers, or a mixture thereof, in which from 1 to n hydrogen atoms attached to a carbon atom may be replaced by a deuterium atom or D, in which n is the number of hydrogen atoms in the molecule. As known in the art, the deuterium atom is a non-radioactive isotope of the hydrogen atom. Such compounds may increase resistance to metabolism, and thus may be useful for increasing the half-life of the compounds described herein or pharmaceutically acceptable salts, isomer, or a mixture thereof when administered to a mammal. <i>See, e.g.,</i><nplcit id="ncit0012" npl-type="s"><text>Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism", Trends Pharmacol. Sci., 5(12):524-527 (1984</text></nplcit>). Such compounds are synthesized by means well known in the art, for example by employing starting materials in which one or more hydrogen atoms have been replaced by deuterium.

0057Examples of isotopes that can be incorporated into the disclosed compounds also include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, 18^O, ³¹P, ³²P, ³⁵S, ¹⁸F, ³⁶Cl, ¹²³I, and ¹²⁵I, respectively. Substitution with positron emitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵O and ¹³N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. Isotopically-labeled compounds of Formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the Examples as set out below using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously employed.

0058The compounds of the embodiments disclosed herein, or their pharmaceutically acceptable salts may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (<i>R</i>)<i>-</i> or (<i>S</i>)- or, as (D)- or (L)- for amino acids. The present disclosure is meant to include all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (-), (<i>R</i>)<i>-</i> and (<i>S</i>)-, or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, for example, chromatography and fractional crystallization. Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included. Where compounds are represented in their chiral form, it is understood that the embodiment encompasses, but is not limited to, the specific diastereomerically or enantiomerically enriched form. Where chirality is not specified but is present, it is understood that the embodiment is directed to either the specific diastereomerically or enantiomerically enriched form; or a racemic or scalcmic mixture of such compound(s) As used herein, "scalemic mixture" is a mixture of stereoisomers at a ratio other than 1:1.

0059"Racemates" refers to a mixture of enantiomers. The mixture can comprise equal or unequal amounts of each enantiomer.

0060"Stereoisomer" and "stereoisomers" refer to compounds that differ in the chirality of one or more stereocenters. Stereoisomers include enantiomers and diastereomers. The compounds may exist in stereoisomeric form if they possess one or more asymmetric centers or a double bond with asymmetric substitution and, therefore, can be produced as individual stereoisomers or as mixtures. Unless otherwise indicated, the description is intended to include individual stereoisomers as well as mixtures. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art (see, e.g., <nplcit id="ncit0013" npl-type="b"><text>Chapter 4 of Advanced Organic Chemistry, 4th ed., J. March, John Wiley and Sons, New York, 1992</text></nplcit>).

0061"Tautomer" refers to alternate forms of a compound that differ in the position of a proton, such as enol-keto and imine-enamine tautomers, or the tautomeric forms of heteroaryl groups containing a ring atom attached to both a ring -NH- and a ring =N- such as pyrazoles, imidazoles, benzimidazoles, triazoles, and tetrazoles.

0062Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. A dash at the front or end of a chemical group is a matter of convenience; chemical groups may be depicted with or without one or more dashes without losing their ordinary meaning. A wavy line drawn through a line in a structure indicates a point of attachment of a group. A dashed line indicates an optional bond. Unless chemically or structurally required, no directionality is indicated or implied by the order in which a chemical group is written or the point at which it is attached to the remainder of the molecule. For instance, the group "-SO₂CH₂-" is equivalent to "-CH₂SO₂-" and both may be connected in either direction. Similarly, an "arylalkyl" group, for example, may be attached to the remainder of the molecule at either an aryl or an alkyl portion of the group. A prefix such as "C_u-v" or (C_u-C_v) indicates that the following group has from u to v carbon atoms. For example, "C_1-6alkyl" and "C₁-C₆ alkyl" both indicate that the alkyl group has from 1 to 6 carbon atoms.

0063"Solvate" as used herein refers to the result of the interaction of a solvent and a compound. Solvates of salts of the compounds described herein are also provided. Hydrates of the compounds described herein are also provided.

0064"Prodrug" as used herein refers to a derivative of a drug that upon administration to the human body is converted to the parent drug according to some chemical or enzymatic pathway.

II. COMPOUNDS

0065The present disclosure provides compounds of Formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), and (IIc-8), and pharmaceutically acceptable salts thereof.

0066In some embodiments, the compound has the structure of Formula (I-1): <chemistry id="chem0010" num="0010"><img file="EP4445902A2_D0010.tif" /></chemistry> or a pharmaceutically acceptable salt thereof.

0067In some embodiments, the compound of Formula (I-1), or a pharmaceutically acceptable salt thereof, is the compound wherein <ul id="ul0004" list-style="none" compact="compact"><li>R¹, R², R³ and R⁴ are independently a hydrogen atom, a halogen atom, a hydroxy group, a carboxy group, a formyl group, a cyano group, an amino group, a nitro group, a nitroso group, a alkoxycarbonyl group, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted cycloalkyl group, an optionally substituted alkoxy group, an optionally substituted alkylamino group, an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted acyl group, an optionally substituted carbamoyl group, an optionally substituted acylamino group, an optionally substituted saturated heterocyclo group or an optionally substituted alkylsulfonylamino group;</li><li>R⁵ is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkynyl group, or an optionally substituted aryl group; and</li><li>R⁶ is an optionally substituted alkyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, or R⁵ and R⁶ together with a nitrogen atom which they bound, may form a nitrogen-containing saturated heterocyclo ring to which an aryl ring is fused, and the fused ring may be substituted;</li><li>provided that the compound is not <chemistry id="chem0011" num="0011"><img file="EP4445902A2_D0011.tif" /></chemistry> or <chemistry id="chem0012" num="0012"><img file="EP4445902A2_D0012.tif" /></chemistry></li></ul>

0068Examples of a substituent for R¹ to R⁴ in a compound of Formula (I-1) include a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom or an iodine atom; a hydroxy group; a carboxy group; a formyl group; a cyano group; an amino group; a nitro group; a nitroso group; an optionally substituted alkyl group(e.g., an optionally substituted C_1-6 alkyl group, or an optionally substituted aralkyl group is exemplified. In addition, a substituent of the substituted alkyl includes a hydroxy group, a methoxy group, a dimethylamino group, a morpholino group, a 4-methylpiperazin-1-yl group, and a piperidin-1-yl group.); an optionally substituted alkenyl(e.g., an optionally substituted C_2-6 alkenyl such as a vinyl group, an allyl group, an isopropenyl group, a butenyl group, an isobutenyl group etc.), an optionally substituted alkynyl group(e.g., an optionally substituted C_2-6 alkynyl group such as an ethynyl group, a 1-propynyl group, and a propargyl group was exemplified, and an amino group, a cyclopropyl group, a hydroxy group, a phenyl group and the like are included in a substituent of the substituted alkynyl group. In addition, the amino group may be protected by an amino-protecting group, an optionally substituted cycloalkyl group (e.g., an optionally substituted C_3-7 cycloalkyl group is exemplified), an optionally substituted alkoxy group (e.g., an optionally substituted C_1-6 alkoxy group), an optionally substituted alkylamino group (e.g., mono-C_1-6 alkylamino group, di-C_1-6 alkylamino group are exemplified, and a hydroxy group, a methoxy group and the like are included in a substituent of the substituted alkylamino group), an optionally substituted acylamino group (e.g., an optionally substituted C_1-4 aliphatic acylamino group or an arylacylamino group is exemplified and an acetylamino group, a benzoylamino group or a pyridylcarbonylamino group is included), an alkoxycarbonyl group (e.g., an optionally substituted C_1-4 alkoxycarbonyl group), an optionally substituted acyl group (an alkyl- or aryl-substituted carbonyl group is exemplified and e.g., an acetyl group or a benzoyl group is included), an optionally substituted carbamoyl group (e.g., an optionally substituted C_1-4 alkylcarbamoyl group), an optionally substituted ureido group (e.g., an optionally substituted C_1-4 alkylureido group), an optionally substituted aryl group (e.g., an optionally substituted phenyl group), an optionally substituted saturated heterocyclo group (e.g., an optionally substituted morpholinyl group, a 4-methylpiperazin-1-yl group, a piperidin-1-yl group, or a pyrrolidinyl group), an optionally substituted heteroaryl group (e.g., an optionally substituted pyridyl group, thienyl group or furanyl group), an optionally substituted thioalkyl group (e.g., an optionally substituted C_1-4 thioalkyl group), an optionally substituted alkylsulfonyl group (e.g., an optionally substituted C_1-4 alkylsulfonyl group), an optionally substituted alkylsulfonylamino group (e.g., an optionally substituted C_1-4 alkylsulfonylamino group) and the like.

0069Examples of R⁵ in a compound of Formula (I-1) include a hydrogen atom, an optionally substituted alkyl group (e.g., an optionally substituted C_1-6 alkyl group is exemplified, and a C_3-6 cycloalkyl group, a hydroxy group, a methoxy group, a phenyl group and the like are included as a substituent of the substituted alkyl group. In addition, the hydroxy group may be protected by a OH-protecting group explained later), an optionally substituted alkynyl group (e.g., an optionally substituted C_2-6 alkynyl group is exemplified), an optionally substituted aryl group (an optionally substituted phenyl group is exemplified) and the like.

0070Examples of R⁶ in a compound of Formula (I-1) include an optionally substituted alkyl group (e.g., an optionally substituted C_1-6 alkyl group is exemplified, and a C_3-6 cycloalkyl group, a hydroxy group, a methoxy group and the like are included as a substituent of the substituted alkyl group. In addition, the hydroxy group may be protected by a OH-protecting group explained later), an optionally substituted alkynyl group, an optionally substituted aryl group (e.g., a phenyl group and biphenyl group etc. are exemplified, and a halogen atom, a hydroxy group, a methoxy group, a cyano group, a nitro group, a C_1-4 alkyl group, a carboxy group, a carbamoyl group, an amino group, a methoxycarbonyl group, a cyclopropyl group, a formyl group, a fluoromethyl group, a trifluoromethyl group, a hydroxymethyl group, a methoxymethyl group, an acetylamino group , a phenyl group, 5- or 6-membered saturated or unsaturated heterocyclo group etc. are included as a substituent of these groups. In addition, the hydroxy group may be protected by a OH-protecting group explained later), and an optionally substituted heteroaryl group (e.g., a pyridyl group or a thienyl group is included) and the like.

0071Examples in a compound of Formula (Ic), (IIc), or (IIc-1) of a nitrogen-containing, 5-to 8-membered saturated heterocyclo ring which is formed by R⁵ and R^6a together with a nitrogen atom and an aryl ring (e.g., a phenyl group) is fused include e.g., 1,2,3,4-tetrahydroquinoline, 3,4-dihydro-2H-1,4-benzooxazine, tetrahydrobenzoazepine and hexahydrobenzoazocine etc.

0072In some embodiments, the present disclosure provides a compound of Formula (I): <chemistry id="chem0013" num="0013"><img file="EP4445902A2_D0013.tif" /></chemistry> or a pharmaceutically acceptable salt thereof, wherein <ul id="ul0005" list-style="none" compact="compact"><li>R¹ is hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 alkoxy, halogen, C_1-6 haloalkyl, C_1-6 haloalkoxy, or -CN;</li><li>R² is hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_1-6 alkoxy, C_2-6 alkoxyalkyl, halogen, C_1-6 haloalkyl, C_1-6 haloalkoxy, -CN, -NO, -NO₂, - C(O)R^2a, -C(O)OR^2a, -OC(O)R^2a, -C(O)N(R^2a)(R^2b), -N(R^2a)C(O)R^2b, - OC(O)N(R^2a)(R^2b), -N(R^2a)C(O)OR^2b, -C(=NR^2a)N(R^2b)(R^2c), -N(R^2a)(R^2b), _ N(R^2a)N(R^2b)(R^2c), -N(R^2a)N=C(R^2b)(OR^2c), -OR^2a, -SR^2a, -S(O)R^2a, -S(O)(NR^2a)(R^2b), - S(NR^2a)(NR^2b)(R^2c), -S(O)₂R^2a, -S(O)₂N(R^2a)(R^2b), -N(R^2a)S(O)₂(R^2b), -P(R^2a)(R^2b), - P(O)(R^2a)(R^2b), -P(O)(OR^2a)(R^2b), -P(O)(OR^2a)(OR^2b), C_3-10 cycloalkyl, C_1-6 alkyl-C_3-10 cycloalkyl, C_6-12 aryl, C_1-6 alkyl-C_6-12 aryl, heterocycloalkyl, C_1-6 alkyl-(heterocycloalkyl), heteroaryl, or C_1-6 alkyl-(heteroaryl), wherein each alkyl, alkenyl or alkynyl is independently optionally substituted with 1 to 3 R^2d groups, each cycloalkyl is optionally substituted with 1 to 3 R^2e groups, each aryl is optionally substituted with 1 to 3 R^2f groups, each heterocycloalkyl is optionally substituted with 1 to 3 R^2g groups, and each heteroaryl is optionally substituted with 1 to 3 R^2h groups;</li><li>each R^2a, R^2b, and R^2c is independently hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_2-6 alkoxyalkyl, C_1-6 haloalkyl, C_3-10 cycloalkyl, C_1-6 alkyl-C_3-10 cycloalkyl, C_6-12 aryl, C_1-6 alkyl-C_6-12 aryl, heterocycloalkyl, C_1-6 alkyl-(heterocycloalkyl), heteroaryl, or C_1-6 alkyl-(heteroaryl), wherein the aryl or heteroaryl is optionally substituted with 1 to 3 R^2j;</li><li>alternatively, R^2a, R^2b, and R^2c when attached to the same atom can be combined with the atom to which they are attached to form a heterocycloalkyl;</li><li>each R^2d is independently -CN, -C(O)R^2d1, -C(O)OR^2d1, -OC(O)R ^2d1, -C(O)N(R^2d1)(R^2d2), - N(R^2d1)C(O)R^2d2, -OC(O)N(R^2d1)(R^2d2), -N(R^2d1)C(O)OR^2d2, -N(R^2d1)(R^2d2), =O, -OR^2d1, -SR^2d1, -S(O)R^2d1, -S(O)(NR^2d1)(R^2d2), -S(O)₂R^2d1, -S(O)N(R^2d1)(R^2d2), - N(R^2d1)S(O)₂R^2d2, C_3-10 cycloalkyl, C_1-6 alkyl-C_3-10 cycloalkyl, C_6-12 aryl, C_1-6 alkyl-C_6-12 aryl, heterocycloalkyl, C_1-6 alkyl-(heterocycloalkyl), heteroaryl, or C_1-6 alkyl-(heteroaryl);</li><li>each R^2d1 and R^2d2 is independently hydrogen, C_1-6 alkyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_2-6 alkoxyalkyl, or C_1-6 haloalkyl;</li><li>each R^2e, R^2f, R^2g, and R^2h is independently hydrogen, C_1-6 alkyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_1-6 alkoxy, C_2-6 alkoxyalkyl, halogen, C_1-6 haloalkyl, C_1-6 haloalkoxy, -CN, or -OH;</li><li>each R^2j is independently C_1-6 alkyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_1-6 alkoxy, C_2-6 alkoxyalkyl, halogen, C_1-6 haloalkyl, or C_1-6 haloalkoxy;</li><li>R³ is hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_1-6 alkoxy, C_2-6 alkoxyalkyl, halogen, C_1-6 haloalkyl, C_1-6 haloalkoxy, -CN, -NO, -NO₂, - C(O)R^3a, -C(O)OR^3a, -OC(O)R^3a, -C(O)N(R^3a)(R^3b), -N(R^3a)C(O)R^3b, - OC(O)N(R^3a)(R^3b), -N(R^3a)C(O)OR^3b, -C(=NR^3a)N(R^3b)(R^3c), -N(R^3a)(R^3b), - N(R^3a)N(R^3b)(R^3c), -N(R^3a)N=C(R^3b)(OR^3c), -OR^3a, -SR^3a, -S(O)R^3a, -S(O)(NR^3a)(R^3b), - S(NR^3a)(NR^3b)(R^3c), -S(O)₂R^3a, -S(O)₂N(R^3a)(R^3b), -N(R^3a)S(O)₂(R^3b), -P(R^3a)(R^3b), - P(O)(R^3a)(R^3b), -P(O)(OR^3a)(R^3b), -P(O)(OR^3a)(OR^3b), C_3-10 cycloalkyl, C_1-6 alkyl-C_3-10 cycloalkyl, C_6-12 aryl, C_1-6 alkyl-C_6-12 aryl, heterocycloalkyl, C_1-6 alkyl-(heterocycloalkyl), heteroaryl, or C_1-6 alkyl-(heteroaryl), wherein each alkenyl or alkynyl is independently optionally substituted with 1 to 3 R^3d groups, each cycloalkyl is optionally substituted with 1 to 3 R^3e groups, each aryl is optionally substituted with 1 to 3 R^3f groups, each heterocycloalkyl is optionally substituted with 1 to 3 R^3g groups, and each heteroaryl is optionally substituted with 1 to 3 R^3h groups;</li><li>each R^3a, R^3b, and R^3c is independently hydrogen, C_1-6 alkyl, C_1-6 hydroxyalkyl, C_2-6 alkoxyalkyl, C_1-6 haloalkyl, C_3-10 cycloalkyl, C_1-6 alkyl-C_3-10 cycloalkyl, C_6-12 aryl, C_1-6 alkyl-C_6-12 aryl, heterocycloalkyl, or heteroaryl;</li><li>alternatively, R^3a, R^3b, and R^3c when attached to the same atom can be combined with the atom to which they are attached to form a heterocycloalkyl;</li><li>each R^3d is independently -N(R^3d1)(R^3d2), -OR^3d1, C_3-10 cycloalkyl, C_1-6 alkyl-C_3-10 cycloalkyl, C_6-12 aryl, C_1-6 alkyl-C_6-12 aryl, heterocycloalkyl, or heteroaryl;</li><li>each R^3d1 and R^3d2 is independently hydrogen, C_1-6 alkyl, or -C(O)O-(C_1-6 alkyl);</li><li>each R^3e, R^3f, R^3g, and R^3h is independently hydrogen, C_1-6 alkyl, C_1-6 alkoxy, halogen, C_1-6 haloalkyl or C_1-6 haloalkoxy;</li><li>R⁴ is hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 alkoxy, halogen, C_1-6 haloalkyl, C_1-6 haloalkoxy, or -CN;</li><li>R⁵ is hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 hydroxyalkyl, C_2-6 alkoxyalkyl, C_1-6 haloalkyl, C_3-10 cycloalkyl, C_1-6 alkyl-C_3-10 cycloalkyl, C_6-12 aryl, C_1-6 alkyl-C_6-12 aryl, heterocycloalkyl, C_1-6 alkyl-(heterocycloalkyl), heteroaryl, or C_1-6 alkyl-(heteroaryl), wherein the alkyl is optionally substituted with R^5a;</li><li>R^5a is -OSi(R^5a1)(R^5a2)(R^5a3);</li><li>R^5a1, R^5a2, and R^5a3 are each independently C_1-6 alkyl; and</li><li>R⁶ is C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 haloalkyl, C_6-12 aryl, or heteroaryl, wherein the aryl or heteroaryl are each optionally substituted with 1 to 3 R^6a;</li><li>each R^6a is independently C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_1-6 alkoxy, C_2-6 alkoxyalkyl, halogen, C_1-6 haloalkyl, C_1-6 haloalkoxy, -CN, -NO₂, -C(O)R^6b, -C(O)OR^6b, -OC(O)R^6b, -C(O)N(R^6b)(R^6c), -N(R^6b)C(O)R^6c, _ C(=NR^6b)N(R^6c)(R^6d), -N(R^6b)(R^6c), -OR^6b, -SR^6b, -S(O)R^6b, -S(O)₂R^6b, - S(NR^6b)(NR^6c)R^6d, -S(O)(NR^6b)(R^6c), -S(O)₂N(R^6b)(R^6c), -N(R^6b)S(O)₂(R^6c), - P(R^6b)(R^6c), -P(O)(R^6b)(R^6c), -P(O)(OR^6b)(R^6c), -P(O)(OR^6b)(OR^6c), C_3-10 cycloalkyl, C_1-6 alkyl-C_3-10 cycloalkyl, C_6-12 aryl, C_1-6 alkyl-C_6-12 aryl, heterocycloalkyl, C_1-6 alkyl-(heterocycloalkyl), heteroaryl, or C_1-6 alkyl-(heteroaryl), wherein the cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is each optionally substituted with 1 to 3 R^6e, the alkyl is optionally substituted with R^6f, and the alkynyl is optionally substituted with 1 to 4 R^6j;</li><li>each R^6b, R^6c and R^6d is independently hydrogen, C_1-6 alkyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_2-6 alkoxyalkyl, C_1-6 haloalkyl, C_3-10 cycloalkyl, C_1-6 alkyl-C_3-10 cycloalkyl, C_6-12 aryl, C_1-6 alkyl-C_6-12 aryl, heterocycloalkyl, C_1-6 alkyl-(heterocycloalkyl), heteroaryl, or C_1-6 alkyl-(heteroaryl), wherein the cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is optionally substituted by 1 to 3 R^6k,</li><li>each R^6k is independently C_1-6 alkyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_1-6 alkoxy, C_2-6 alkoxyalkyl, C_1-6 haloalkyl, C_1-6 haloalkoxy, C_3-10 cycloalkyl, C_1-6 alkyl-C_3-10 cycloalkyl, heterocycloalkyl, or C_1-6 alkyl-(heterocycloalkyl);</li><li>each R^6e is independently C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_1-6 alkoxy, C_2-6 alkoxyalkyl, halogen, C_1-6 haloalkyl, C_1-6 haloalkoxy, -CN, -NO₂, -C(O)R^6e1, -C(O)OR^6e1, -OC(O)R^6e1, -C(O)N(R^6e1)(R^6e2), -N(R^6e1)C(O)R^6e2, - OC(O)N(R^6e1)(R^6e2), -N(R^6e1)C(O)OR^6e2, -C(=NR^6e1)N(R^6e2)(R^6e3), -N(R^6e1)(R^6e2), =O, - OR^6e1, -SR^6e1, -S(O)R^6e1, -S(NR^6e1)(NR^6e2), -S(O)(NR^6e1)(R^6e2), -S(O)₂R^6e1, - S(O)₂N(R^6e1)(R^6e2), -SF₅, -N(R^6e1)S(O)₂(R^6e2), -P(R^6e1)(R^6e2), -P(O)(R^6e1)(R^6e2), - P(O)(OR^6e1)(R^6e2), -P(O)(OR^6e1)(OR^6e2), -Si(R^6e1)(R^6e2)(R^6e3), C_3-10 cycloalkyl, C_1-6 alkyl-C_3-10 cycloalkyl, C_6-12 aryl, C_1-6 alkyl-C_6-12 aryl, heterocycloalkyl, C_1-6 alkyl-heterocycloalkyl, heteroaryl, or C_1-6 alkyl-heteroaryl, wherein the cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is each optionally substituted with 1 to 3 R^6h, and the alkyl is optionally substituted with 1 to 3 R^6m;</li><li>each R^6e1, R^6e2, and R^6e3 is independently hydrogen, C_1-6 alkyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_1-6 alkoxyalkyl, C_1-6 haloalkyl, C_3-10 cycloalkyl, C_1-6 alkyl-C_3-10 cycloalkyl, C_6-10 aryl, C_1-6 alkyl-C_6-10 aryl, heterocycloalkyl, C_1-6 alkyl-(heterocycloalkyl), heteroaryl, or C_1-6 alkyl-(heteroaryl), wherein the cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is optionally substituted with 1 to 3 R⁶ⁿ;</li><li>each R⁶ⁿ is C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_1-6 alkoxy, C_2-6 alkoxyalkyl, halogen, C_1-6 haloalkyl, C_1-6 haloalkoxy, -CN, -C(O)R⁶ⁿ¹, -C(O)OR⁶ⁿ¹, -OC(O)R⁶ⁿ¹, -C(O)N(R⁶ⁿ¹)(R⁶ⁿ²), -N(R⁶ⁿ¹)C(O)R⁶ⁿ², -OC(O)N(R⁶ⁿ¹)(R⁶ⁿ²), - N(R⁶ⁿ¹)C(O)OR⁶ⁿ², -C(=NR⁶ⁿ¹)N(R⁶ⁿ²)(R⁶ⁿ³), -N(R⁶ⁿ¹)(R⁶ⁿ²), =O, -OH, -SR⁶ⁿ¹, - S(O)R⁶ⁿ¹, -S(NR⁶ⁿ¹)(NR⁶ⁿ²)R⁶ⁿ³, -S(O)(NR⁶ⁿ¹)(R⁶ⁿ²), -S(O)₂R⁶ⁿ¹, -S(O)₂N(R⁶ⁿ¹)(R⁶ⁿ²), or -N(R⁶ⁿ¹)S(O)₂(R⁶ⁿ²);</li><li>each R⁶ⁿ¹, R⁶ⁿ² and R⁶ⁿ³ is independently hydrogen, C_1-6 alkyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_2-6 alkoxyalkyl, C_1-6 haloalkyl, C_3-10 cycloalkyl, C_1-6 alkyl-C_3-10 cycloalkyl, C_6-10 aryl, C_1-6 alkyl-C_6-10 aryl, heterocycloalkyl, C_1-6 alkyl-(heterocycloalkyl), heteroaryl, or C_1-6 alkyl-(heteroaryl);</li><li>each R^6h is independently C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_1-6 alkoxy, C_2-6 alkoxyalkyl, halogen, C_1-6 haloalkyl, C_1-6 haloalkoxy, -CN, -C(O)R^6h1, -C(O)OR^6h1, -OC(O)R^6h1, -C(O)N(R^6h1)(R^6h2), -N(R^6h1)C(O)R^6h2, - OC(O)N(R^6h1)(R^6h2), -N(R^6h1)C(O)OR^6h2, -C(=NR^6h1)N(R^6h2)(R^6h3), -N(R^6h1)(R^6h2), =O, -OH, -SR^6h1, -S(O)R^6h1, -S(NR^6h1)(NR^6h2)R^6h3, -S(O)(NR^6h1)(R^6h2), -S(O)₂R^6h1, - S(O)₂N(R^6h1)(R^6h2), -N(R^6h1)S(O)₂(R^6h2), C_3-10 cycloalkyl, C_1-6 alkyl-C_3-10 cycloalkyl, heterocycloalkyl, or C_1-6 alkyl-(heterocycloalkyl);</li><li>each R^6h1, R^6h2, and R⁶ⁿ³ is independently hydrogen, C_1-6 alkyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_2-6 alkoxyalkyl, C_1-6 haloalkyl, C_3-10 cycloalkyl, C_1-6 alkyl-C_3-10 cycloalkyl, C_6-10 aryl, C_1-6 alkyl-C_6-10 aryl, heterocycloalkyl, C_1-6 alkyl-(heterocycloalkyl), heteroaryl, or C_1-6 alkyl-(heteroaryl);</li><li>each R^6m is independently halogen, C_1-6 haloalkyl, C_1-6 haloalkoxy, -CN, -C(O)R^6m1, - C(O)OR^6m1, -OC(O)R^6m1, -C(O)N(R^6m1)(R^6m2), -N(R^6m3)C(O)R^6m2,-OC(O)N(R^6m1)(R^6m2), -N(R^6m1)C(O)OR^6m2, -C(=NR^6m3)N(R6^m1)(R^6m2), -N(R^6m1)(R^6m2), =O, -OH, -SR^6m1, -S(O)R^6m1, -S(NR^6m1)(NR^6m2)R^6m3, -S(O)(NR^6m1)(R^6m2), -S(O)₂R^6m1, - S(O)₂N(R^6m1)(R^6m2), or -N(R^6m3)S(O)₂(R^6m2);</li><li>each R^6m1, R^6m2, and R^6m3 is independently hydrogen, C_1-6 alkyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_2-6 alkoxyalkyl, C_1-6 haloalkyl, C_3-10 cycloalkyl, C_1-6 alkyl-C_3-10 cycloalkyl, C_6-10 aryl, C_1-6 alkyl-C_6-10 aryl, heterocycloalkyl, C_1-6 alkyl-(heterocycloalkyl), heteroaryl, or C_1-6 alkyl-(heteroaryl);</li><li>R^6f is -OSi(R^6f1)(R^6f2)(R^6f3);</li><li>R^6f1, R^6f2, and R^6f3 are each independently C_1-6 alkyl;</li><li>each R^6j is independently C_2-6 alkoxyalkyl, halogen, C_1-6 haloalkyl, C_1-6 haloalkoxy, -CN, - C(O)R^6j1, -C(O)OR^6j1, -OC(O)R^6j1, -C(O)N(R^6j1)(R^6j2), -N(R^6j3)C(O)R^6j2, - OC(O)N(R^6j1)(R^6j2), -N(R^6j1)C(O)OR^6j2, -C(=NR^6j3)N(R^6j1)(R^6j2), -N(R^6j1)(R^6j2), =O, - OR^6j1, -SR^6j1, -S(O)R^6j1, -S(NR^6j1)(NR^6j2), -S(NR^6j1)(NR^6j2)R^6j3, -S(O)(NR^6j1)(R^6j2), - S(O)₂R^6j1, -S(O)₂N(R^6j1)(R^6j2), -N(R^6j1)S(O)₂(R^6j2), -Si(R^6j1)(R^6j2)(R^6j3), C_3-10 cycloalkyl, C_6-12 aryl, heterocycloalkyl, or heteroaryl, wherein the cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is optionally substituted with 1 to 3 R^6p;</li><li>each R^6j1, R^6j2, and R^6j3 is independently hydrogen, C_1-6 alkyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_2-6 alkoxyalkyl, C_1-6 haloalkyl, C_3-10 cycloalkyl, C_1-6 alkyl-C_3-10 cycloalkyl, C_6-10 aryl, C_1-6 alkyl-C_6-10 aryl, heterocycloalkyl, C_1-6 alkyl-(heterocycloalkyl), heteroaryl, or C_1-6 alkyl-(heteroaryl);</li><li>each R^6p is independently C_1-6 alkyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_1-6 alkoxy, C_2-6 alkoxyalkyl, halogen, C_1-6 haloalkyl, C_1-6 haloalkoxy, -CN, -C(O)R^6p1, -C(O)OR^6p1, - OC(O)R^6p1, -C(O)N(R^6p1)(R^6p2), -N(R^6p1)C(O)R^6p2, -OC(O)N(R^6p1)(R^6p2), - N(R^6p1)C(O)OR^6p2, -C(=NR^6p3)N(R^6p1)(R^6p2), -N(R^6p1)(R^6p2), =O, -OH, -SR^6p1, - S(O)R^6p1, -S(NR^6p1)(NR^6p2)R^6p3, -S(O)(NR^6p1)(R^6p2), -S(O)₂R^6p1, -S(O)₂N(R^6p1)(R^6p2), or -N(R^6p1)S(O)₂(R^6p2);</li><li>each R^6p1, R^6p2, and R^6p3 is independently hydrogen, C_1-6 alkyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_2-6 alkoxyalkyl, C_1-6 haloalkyl, C_3-10 cycloalkyl, C_1-6 alkyl-C_3-10 cycloalkyl, C_6-10 aryl, C_1-6 alkyl-C_6-10 aryl, heterocycloalkyl, C_1-6 alkyl-(heterocycloalkyl), heteroaryl, or C_1-6 alkyl-(heteroaryl);</li><li>or R⁵ and one R^6a together with the atoms to which they are attached form a heterocycloalkyl, optionally substituted with 1 to 3 R^6g;</li><li>each R^6g is independently C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_2-6 alkoxyalkyl, halogen, C_1-6 haloalkyl, C_1-6 haloalkoxy, or -CN;</li><li>R⁷ is hydrogen, C_1-6 alkyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_1-6 alkoxy, C_2-6 alkoxyalkyl, C_1-6 alkylthio, halogen, C_1-6 haloalkyl, -CN,-OH, -NH₂, C_3-10 cycloalkyl, C_1-6 alkyl-C_3-10 cycloalkyl, heterocycloalkyl, or C_1-6 alkyl-(heterocycloalkyl);</li><li>each heterocycloalkyl is a 3 to 20 membered ring having 1 to 4 heteroatoms each independently N, O or S; and</li><li>each heteroaryl is a 5 to 18 membered ring having 1 to 4 heteroatoms each independently N, O or S;</li><li>provided that R⁵ and R⁶ are not both C_1-4 alkyl; and when R⁵ is hydrogen, R⁶ is not isopropyl or phenyl substituted with 2-Me.</li></ul>

0073In some embodiments, the present disclosure provides a compound of Formula (I): <chemistry id="chem0014" num="0014"><img file="EP4445902A2_D0014.tif" /></chemistry> or a pharmaceutically acceptable salt thereof, wherein <ul id="ul0006" list-style="none" compact="compact"><li>R¹ is hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 alkoxy, halogen, C_1-6 haloalkyl, C_1-6 haloalkoxy, or -CN;</li><li>R² is hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 hydroxyalkyl, C_1-6 alkoxy, C_2-6 alkoxyalkyl, halogen, C_1-6 haloalkyl, C_{1 -6} haloalkoxy, -CN, -NO, -NO₂, -C(O)R^2a, - C(O)OR^2a, -OC(O)R^2a, -C(O)N(R^2a)(R^2b), -N(R^2a)C(O)R^2b, -OC(O)N(R^2a)(R^2b), - N(R^2a)C(O)OR^2b, -C(=NR^2a)N(R^2b)(R^2c), -N(R^2a)(R^2b), -OR^2a, -SR^2a, -S(O)R^2a, - S(O)₂R^2a, -S(O)₂N(R^2a)(R^2b), -N(R^2a)S(O)₂(R^2b), -P(O)(R^2a)(R^2b), -P(O)(OR^2a)(R^2b), - P(O)(OR^2a)(OR^2b), C_3-10 cycloalkyl, C_1-6 alkyl-C_3-10 cycloalkyl, C_6-12 aryl, C_1-6 alkyl-C_6-12 aryl, heterocycloalkyl, or heteroaryl, wherein each alkenyl or alkynyl is independently optionally substituted with 1 to 3 R^2d groups, each cycloalkyl is optionally substituted with 1 to 3 R^2e groups, each aryl is optionally substituted with 1 to 3 R^2f groups, each heterocycloalkyl is optionally substituted with 1 to 3 R^2g groups, and each heteroaryl is optionally substituted with 1 to 3 R^2h groups;</li><li>each R^2a, R^2b, and R^2c is independently hydrogen, C_1-6 alkyl, C_1-6 hydroxyalkyl, C_2-6 alkoxyalkyl, C_1-6 haloalkyl, C_3-10 cycloalkyl, C_1-6 alkyl-C_3-10 cycloalkyl, C_6-12 aryl, C_1-6 alkyl-C_6-12 aryl, heterocycloalkyl, or heteroaryl;</li><li>alternatively, R^2a, R^2b, and R^2c when attached to the same atom can be combined with the atom to which they are attached to form a heterocycloalkyl;</li><li>each R^2d is independently -N(R^2d1)(R^2d2), -OR^2d1, C_3-10 cycloalkyl, C_1-6 alkyl-C_3-10 cycloalkyl, C_6-12 aryl, C_1-6 alkyl-C_6-12 aryl, heterocycloalkyl, or heteroaryl;</li><li>each R^2d1 and R^2d2 is independently hydrogen, C_1-6 alkyl, or -C(O)O-(C_1-6 alkyl);</li><li>each R^2e, R^2f, R^2g, and R^2h is independently hydrogen, C_1-6 alkyl, C_1-6 alkoxy, halogen, C_1-6 haloalkyl or C_1-6 haloalkoxy;</li><li>R³ is hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 hydroxyalkyl, C_1-6 alkoxy, C_2-6 alkoxyalkyl, halogen, C_1-6 haloalkyl, C_1-6 haloalkoxy, -CN, -NO, -NO₂, -C(O)R^3a, - C(O)OR^3a, -OC(O)R^3a, -C(O)N(R^3a)(R^3b), -N(R^3a)C(O)R^3b, -OC(O)N(R^3a)(R^3b), - N(R^3a)C(O)OR^3b, -C(=NR^3a)N(R^3b)(R^3c), -N(R^3a)(R^3b), -OR^3a, -SR^3a, -S(O)R^3a, - S(O)₂R^3a, -S(O)₂N(R^3a)(R^3b), -N(R^3a)S(O)₂(R^3b), -P(O)(R^3a)(R^3b), -P(O)(OR^3a)(R^3b), - P(O)(OR^3a)(OR^3b), C_3-10 cycloalkyl, C_1-6 alkyl-C_3-10 cycloalkyl, C_6-12 aryl, C_1-6 alkyl-C_6-12 aryl, heterocycloalkyl, or heteroaryl, wherein each alkenyl or alkynyl is independently optionally substituted with 1 to 3 R^3d groups, each cycloalkyl is optionally substituted with 1 to 3 R^3e groups, each aryl is optionally substituted with 1 to 3 R^3f groups, each heterocycloalkyl is optionally substituted with 1 to 3 R^3g groups, and each heteroaryl is optionally substituted with 1 to 3 R^3h groups;</li><li>each R^3a, R^3b, and R^3c is independently hydrogen, C_1-6 alkyl, C_1-6 hydroxyalkyl, C_2-6 alkoxyalkyl, C_1-6 haloalkyl, C_3-10 cycloalkyl, C_1-6 alkyl-C_3-10 cycloalkyl, C_6-12 aryl, C_1-6 alkyl-C_6-12 aryl, heterocycloalkyl, or heteroaryl;</li><li>alternatively, R^3a, R^3b, and R^3c when attached to the same atom can be combined with the atom to which they are attached to form a heterocycloalkyl;</li><li>each R^3d is independently -N(R^3d1)(R^3d2), -OR^3d1, C_3-10 cycloalkyl, C_1-6 alkyl-C_3-10 cycloalkyl, C_6-12 aryl, C_1-6 alkyl-C_6-12 aryl, heterocycloalkyl, or heteroaryl;</li><li>each R^3d1 and R^3d2 is independently hydrogen, C_1-6 alkyl, or -C(O)O-(C_1-6 alkyl);</li><li>each R^3e, R^3f, R^3g, and R^3h is independently hydrogen, C_1-6 alkyl, C_1-6 alkoxy, halogen, C_1-6 haloalkyl or C_1-6 haloalkoxy;</li><li>R⁴ is hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 alkoxy, halogen, C_1-6 haloalkyl, C_1-6 haloalkoxy, or -CN;</li><li>R⁵ is hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 hydroxyalkyl, C_2-6 alkoxyalkyl, C_1-6 haloalkyl, C_3-10 cycloalkyl, C_1-6 alkyl-C_3-10 cycloalkyl, C_6-12 aryl, C_1-6 alkyl-C_6-12 aryl, heterocycloalkyl, C_1-6 alkyl-(heterocycloalkyl), heteroaryl, or C_1-6 alkyl-(heteroaryl), wherein the alkyl is optionally substituted with R^5a;</li><li>R^5a is -OSi(R5^a1)(R^5a2)(R^5a3);</li><li>R^5a1, R^5a2, and R^5a3 are each independently C_1-6 alkyl; and</li><li>R⁶ is C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 haloalkyl, C_6-12 aryl, or heteroaryl, wherein the aryl or heteroaryl are each optionally substituted with 1 to 3 R^6a;</li><li>each R^6a is independently C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 hydroxyalkyl, C_1-6 alkoxy, C_2-6 alkoxyalkyl, halogen, C_1-6 haloalkyl, C_1-6 haloalkoxy, -CN, -NO₂, -C(O)R^6b, - C(O)OR^6b, -OC(O)R^6b, -C(O)N(R^6b)(R^6c), -N(R^6b)C(O)R^6c, -C(=NR^6b)N(R^6c)(R^6d), - N(R^6b)(R^6c), -OR^6b, -SR^6b, -S(O)R^6b, -S(O)2R^6b, -S(O)₂N(R^6b)(R^6c), -N(R^6b)S(O)₂(R^6c), C_3-10 cycloalkyl, C_6-12 aryl, heterocycloalkyl, or heteroaryl, wherein the cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is each optionally substituted with 1 to 3 R^6e, and the alkyl is optionally substituted with R^6f;</li><li>or R⁵ and one R^6a together with the atoms to which they are attached form a heterocycloalkyl, optionally substituted with 1 to 3 R^6g;</li><li>each R^6b, R^6c and R^6d is independently hydrogen, C_1-6 alkyl, C_1-6 hydroxyalkyl, C_2-6 alkoxyalkyl, C_1-6 haloalkyl, C_3-10 cycloalkyl, C_1-6 alkyl-C_3-10 cycloalkyl, C_6-12 aryl, C_1-6 alkyl-C_6-12 aryl, heterocycloalkyl, or heteroaryl;</li><li>each R^6e is independently C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 hydroxyalkyl, C_1-6 alkoxy, C_2-6 alkoxyalkyl, halogen, C_1-6 haloalkyl, C_1-6 haloalkoxy, -CN, -NO₂, -C(O)R^6e1, - C(O)OR^6e1, -OC(O)R^6e1, -C(O)N(R^6e1)(R^6e2), -N(R^6e1)C(O)R^6e2, -C(=NR^6e1)N(R^6e2)(R^6e3), -N(R^6e1)(R^6e2), -OR^6e1, -SR^6e1, -S(O)R^6e1, -S(O)₂R^6e1, -S(O)₂N(R^6e1)(R^6e2), -N(R^6e1)S(O)₂(R^6e2), C_3-10 cycloalkyl, C_6-12 aryl, heterocycloalkyl, or heteroaryl, wherein the cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is each optionally substituted with 1 to 3 R^6h;</li><li>each R^6e1, R^6e2, and R^6e3 is independently hydrogen or C_1-6 alkyl;</li><li>R^6f is -OSi(R^6f1)(R^6f2)(R^6f3);</li><li>R^6f1, R^6f2, and R^6f3 are each independently C_1-6 alkyl;</li><li>each R^6g is independently C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, halogen, C_1-6 haloalkyl, C_1-6 haloalkoxy, or -CN;</li><li>each R^6h is independently C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 alkoxy, halogen, C_1-6 haloalkyl, C_1-6 haloalkoxy, -C(O)R^6h1, -C(O)OR^6h1, -OC(O)R^6h1, -C(O)N(R^6h1)(R^6h2), - N(R^6h1)C(O)R^6h2, -C(=NR^6h1)N(R^6h2)(R^6h3), -N(R^6h1)(R^6h2), -OH, -SR^6h1, -S(O)R^6h1, - S(O)₂R^6h1, -S(O)₂N(R^6h1)(R^6h2), or -N(R^6h1)S(O)₂(R^6h2);</li><li>each R^6h1, R^6h2, and R^6h3 is independently hydrogen or C_1-6 alkyl;</li><li>R⁷ is hydrogen, C_1-6 alkyl, halogen, C_1-6 haloalkyl, -CN, or -OH;</li><li>each heterocycloalkyl is a 3 to 10 membered ring having 1 to 4 heteroatoms each independently N, O or S; and</li><li>each heteroaryl is a 5 to 10 membered ring having 1 to 4 heteroatoms each independently N, O or S, provided that R⁵ and R⁶ are not both C_1-4 alkyl; and when R⁵ is hydrogen, R⁶ is not isopropyl or phenyl substituted with 2-Me.</li></ul>

0074In some embodiments, the compound of Formula (I) or (I-1), or a pharmaceutically acceptable salt thereof, is the compound wherein R⁵ is C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 hydroxyalkyl, C_2-6 alkoxyalkyl, C_1-6 haloalkyl, C_3-10 cycloalkyl, C_1-6 alkyl-C_3-10 cycloalkyl, C_6-12 aryl, C_1-6 alkyl-C_6-12 aryl, heterocycloalkyl, C_1-6 alkyl-(heterocycloalkyl), heteroaryl, or C_1-6 alkyl-(heteroaryl), wherein the alkyl is optionally substituted with R^5a; and R⁶ is C_6-12 aryl or heteroaryl, wherein the aryl or heteroaryl are each optionally substituted with 1 to 3 R^6a; or R⁵ and R^6a together with the atoms to which they are attached form a heterocycloalkyl, optionally substituted with 1 to 3 R^6g.

0075In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ib), (Ic), (IIa), (IIc), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein R¹ is hydrogen, C_1-6 alkyl, C_1-6 alkoxy, halogen, C_1-6 haloalkyl, or-CN. In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ib), (Ic), (IIa), (IIc), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein R¹ is hydrogen, C_1-3 alkyl, C_1-3 alkoxy, or halogen. In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ib), (Ic), (IIa), (IIc), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein R¹ is hydrogen, Me, -OMe, F, or Cl. In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ib), (Ic), (IIa), (IIc), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein R¹ is hydrogen or F. In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ib), (Ic), (IIa), (IIc), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein R¹ is hydrogen. In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ib), (Ic), (IIa), (IIc), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein R¹ is F.

0076In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein R² is hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 hydroxyalkyl, C_1-6 alkoxy, C_2-6 alkoxyalkyl, halogen, C_1-6 haloalkyl, C_1-6 haloalkoxy, -CN, -NO, -NO₂, -C(O)R^2a, -C(O)OR^2a, -OC(O)R^2a, -C(O)N(R^2a)(R^2b), -N(R^2a)C(O)R^2b, -OC(O)N(R^2a)(R^2b), -N(R^2a)C(O)OR^2b, -N(R^2a)(R^2b), -OR^2a, -S(O)₂N(R^2a)(R^2b), -N(R^2a)S(O)₂(R^2b), C_3-10 cycloalkyl, C_1-6 alkyl-C_3-10 cycloalkyl, C_6-12 aryl, C_1-6 alkyl-C_6-12 aryl, heterocycloalkyl, or heteroaryl, wherein each alkenyl or alkynyl is independently optionally substituted with 1 to 3 R^2d groups, and each aryl is optionally substituted with 1 to 3 R^2f groups. In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein R² is hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 hydroxyalkyl, C_1-6 alkoxy, C_2-6 alkoxyalkyl, halogen, C_1-6 haloalkyl, -CN, -NO, -NO₂, -C(O)R^2a, -C(O)OR^2a, -N(R^2a)C(O)R^2b, -N(R^2a)(R^2b), _ OR^2a,-N(R^2a)S(O)₂(R^2b), C_3-10 cycloalkyl, C_6-10 aryl, heterocycloalkyl, or heteroaryl, wherein each alkenyl or alkynyl is independently optionally substituted with 1 to 3 R^2d groups, and each aryl is optionally substituted with 1 to 3 R^2f groups. In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein R² is hydrogen, C_1-3 alkyl, C_2-3 alkenyl, C_2-6 alkynyl, C_1-3 hydroxyalkyl, C_1-3 alkoxy, C_2-3 alkoxyalkyl, halogen, C_1-3 haloalkyl, -CN, -NO, -NO₂, -C(O)R^2a, -C(O)OR^2a, -N(R^2a)C(O)R^2b, -N(R^2a)(R^2b), -N(R^2a)S(O)₂(R^2b), C_3-6 cycloalkyl, phenyl, heterocycloalkyl, or heteroaryl, wherein each alkenyl or alkynyl is independently optionally substituted with 1 R^2d group, and each phenyl is optionally substituted with 1 R^2f group. In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein R² is hydrogen, C_1-3 alkyl, C_2-3 alkenyl, C_2-6 alkynyl, C_1-3 hydroxyalkyl, C_2-3 alkoxyalkyl, halogen, -CN, -NO, -NO₂, -C(O)R^2a, -N(R^2a)C(O)R^2b, -N(R^2a)(R^2b), -OR^2a, or heteroaryl; and the heteroaryl is a 5 to 6 membered ring having 1 to 3 heteroatoms each independently N, O, or S.

0077In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein each R^2a and R^2b is independently hydrogen, C_1-6 alkyl, C_1-6 hydroxyalkyl, or C_2-6 alkoxyalkyl. In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein each R^2a and R^2b is independently hydrogen, C_1-3 alkyl, C_1-3 hydroxyalkyl, or C_2-3 alkoxyalkyl. In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein each R^2a and R^2b is independently hydrogen or C_1-3 alkyl. In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein each R^2a and R^2b is independently hydrogen or Me.

0078In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein each R^2d is independently -N(R^2d1)(R^2d2), -OR^2d1, C_3-10 cycloalkyl, or C_6-12 aryl. In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein each R^2d is independently -N(R^2d1)(R^2d2), -OR^2d1, C_3-8 cycloalkyl, or phenyl.

0079In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein each R^2d1 and R^2d2 is independently hydrogen, C_1-4 alkyl, or -C(O)O(C_1-4 alkyl). In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein each R^2d1 and R^2d2 is independently hydrogen or -C(O)O(C_1-4 alkyl). In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein each R^2d1 and R^2d2 is independently hydrogen or -C(O)OtBu. In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ia-1), (Ib) or (Ic), or a pharmaceutically acceptable salt thereof, is the compound wherein each R^2d1 and R^2d2 is hydrogen.

0080In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein each R^2f is independently C_1-6 alkoxy or halogen. In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein each R^2f is independently C_1-3 alkoxy or halogen. In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein each R^2f is independently - OMe or F.

0081In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein R² is hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 hydroxyalkyl, C_1-6 alkoxy, C_2-6 alkoxyalkyl, halogen, C_1-6 haloalkyl, C_1-6 haloalkoxy, -CN, -NO, -NO₂, -C(O)R^2a, -C(O)OR^2a, -OC(O)R^2a, -C(O)N(R^2a)(R^2b), -N(R^2a)C(O)R^2b, -OC(O)N(R^2a)(R^2b), -N(R^2a)C(O)OR^2b, -N(R^2a)(R^2b), -OR^2a, -S(O)₂N(R^2a)(R^2b), -N(R^2a)S(O)₂(R^2b), C_3-10 cycloalkyl, C_1-6 alkyl-C_3-10 cycloalkyl, C_6-12 aryl, C_1-6 alkyl-C_6-12 aryl, a 3 to 8 membered heterocycloalkyl ring having 1 to 3 heteroatoms each independently N, O, or S, or a 5 to 10 membered heteroaryl ring having 1 to 3 heteroatoms each independently N, O, or S, wherein each alkenyl or alkynyl is independently optionally substituted with 1 to 3 R^2d groups, and each aryl is optionally substituted with 1 to 3 R^2f groups; each R^2a and R^2b is independently hydrogen, C_1-6 alkyl, C_1-6 hydroxyalkyl, C_2-6 alkoxyalkyl, or C_1-6 haloalkyl; each R^2d is independently -N(R^2d1)(R^2d2), -OR^2d1, C_3-10 cycloalkyl, C_1-6 alkyl-C_3-10 cycloalkyl, C_6-12 aryl, C_1-6 alkyl-C_6-12 aryl; each R^2d1 and R^2d2 is independently hydrogen, C_1-6 alkyl, or -C(O)O-(C_1-6 alkyl); and each R^2f is independently hydrogen, C_1-6 alkyl, C_1-6 alkoxy, or halogen.

0082In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein R² is hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 hydroxyalkyl, C_1-6 alkoxy, C_2-6 alkoxyalkyl, halogen, C_1-6 haloalkyl, -CN, -NO, -NO₂, -C(O)R^2a, -C(O)OR^2a, -N(R^2a)C(O)R^2b, -N(R^2a)(R^2b), -OR^2a, - N(R^2a)S(O)₂(R^2b), C_3-10 cycloalkyl, C_6-10 aryl, a 5 to 8 membered heterocycloalkyl ring having 1 to 2 heteroatoms each independently N, O, or S, or a 5 to 6 membered heteroaryl ring having 1 to 3 heteroatoms each independently N, O, or S, wherein each alkenyl or alkynyl is independently optionally substituted with 1 to 3 R^2d groups, and each aryl is optionally substituted with 1 to 3 R^2f groups; each R^2a and R^2b is independently hydrogen, C_1-6 alkyl, C_1-6 hydroxyalkyl, or C_2-6 alkoxyalkyl; each R^2d is independently -N(R^2d1)(R^2d2), -OR^2d1, C_3-10 cycloalkyl, or C_6-12 aryl; each R^2d1 and R^2d2 is independently hydrogen, C_1-4 alkyl, or -C(O)O-(C_1-4 alkyl); and each R^2f is independently C_1-6 alkoxy or halogen.

0083In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein R² is hydrogen, C_1-3 alkyl, C_2-3 alkenyl, C_2-6 alkynyl, C_1-3 hydroxyalkyl, C_1-3 alkoxy, C_2-3 alkoxyalkyl, halogen, C_1-3 haloalkyl, -CN, -NO, -NO₂, -C(O)R^2a, -C(O)OR^2a, -N(R^2a)C(O)R^2b, -N(R^2a)(R^2b), -N(R^2a)S(O)₂(R^2b), C_3-6 cycloalkyl, phenyl, 5 to 6 membered heterocycloalkyl ring having 1 to 2 heteroatoms each independently N or O, or a 5 to 6 membered heteroaryl ring having 1 to 2 heteroatoms each independently N, O, or S, wherein each alkenyl or alkynyl is independently optionally substituted with 1 R^2d group, and each phenyl is optionally substituted with 1 R^2f group; each R^2a and R^2b is independently hydrogen, C_1-3 alkyl, C_1-3 hydroxyalkyl, or C_2-3 alkoxyalkyl; each R^2d is independently -N(R^2d1)(R^2d2), -OR^2d1, C_3-8 cycloalkyl, or phenyl; each R^2d1 and R^2d2 is independently hydrogen or -C(O)O-(C_1-4 alkyl); and each R^2f is independently C_1-3 alkoxy or halogen.

0084In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein R² is hydrogen, Me, Et, iPr, - CH=CH₂, -CH=CHMe, -C(Me)=CH₂, -CMe=CHMe, -CH=C(Me)₂, -CH=CHEt, -C=CH, -C=C-Me, -C≡C-Et, -C=C-tBu, -C≡C-CH₂OH, -C≡C-CMe₂(OH), -C≡C-CH₂NH₂, -C=C-CH₂NHC(O)OtBu, -C≡C-CMe₂(SO₂Me), -CH₂OH, -CH₂CH₂CH₂OH, -CH(OH)CH₂CH₃, -OMe, -OEt, -OCH₂CH=CH₂, -CH₂OMe, -CH₂NHMe, -CH₂NMe₂, -CH₂CH₂COOEt, F, Cl, Br, I, -CF₃, -CN, -NO, -NO₂, -C(O)H, -COOH, -COOMe, -NHCOMe, -NH₂, -NHMe, -NMe₂, - NHCH₂CH₂OH, -NHCH₂CH₂OMe, -NHSO₂Me, -OH, -NH-N=CH-OEt, -NH₂-NH₂, SMe, SO₂Me, cyclopropyl, <chemistry id="chem0015" num="0015"><img file="EP4445902A2_D0015.tif" /></chemistry><chemistry id="chem0016" num="0016"><img file="EP4445902A2_D0016.tif" /></chemistry><chemistry id="chem0017" num="0017"><img file="EP4445902A2_D0017.tif" /></chemistry>

0085In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein R² is hydrogen, Me, Et, iPr, - CH=CH₂, -C(Me)=CH₂, -C=C-Me, -C=C-tBu, -C≡C-CH₂OH, -C≡C-CH₂NH₂, -C≡C-CH₂NHC(O)OtBu, -CH₂OH, -OMe, -CH₂OMe, F, Cl, Br, I, -CF₃, -CN, -NO, -NO₂, -C(O)H, -COOH, -COOMe, -NHCOMe, -NH₂, -NHMe, -NMe₂, -NHCH₂CH₂OH, -NHCH₂CH₂OMe, -NHSO₂Me, -OH, cyclopropyl, <chemistry id="chem0018" num="0018"><img file="EP4445902A2_D0018.tif" /></chemistry><chemistry id="chem0019" num="0019"><img file="EP4445902A2_D0019.tif" /></chemistry><chemistry id="chem0020" num="0020"><img file="EP4445902A2_D0020.tif" /></chemistry>

0086In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein R³ is hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 hydroxyalkyl, C_1-6 alkoxy, C_2-6 alkoxyalkyl, halogen, C_1-6 haloalkyl, C_1-6 haloalkoxy, -CN, -NO, -NO₂, -C(O)R^3a, -C(O)OR^3a, -OC(O)R^3a, -C(O)N(R^3a)(R^3b), -N(R^3a)C(O)R^3b, -OC(O)N(R^3a)(R^3b), -N(R^3a)C(O)OR^3b, -N(R^3a)(R^3b), -OR^3a, -S(O)₂N(R^3a)(R^3b), -N(R^3a)S(O)₂(R^3b), C_3-10 cycloalkyl, C_1-6 alkyl-C_3-10 cycloalkyl, C_6-12 aryl, C_1-6 alkyl-C_6-12 aryl, heterocycloalkyl, or heteroaryl, wherein each alkenyl or alkynyl is independently optionally substituted with 1 to 3 R^3d groups, and each aryl is optionally substituted with 1 to 3 R^3f groups.

0087In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein R³ is hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 hydroxyalkyl, C_1-6 alkoxy, C_2-6 alkoxyalkyl, halogen, C_1-6 haloalkyl, C_1-6 haloalkoxy, -CN, -NO, -NO₂, -C(O)R^3a, -C(O)OR^3a, -OC(O)R^3a, -C(O)N(R^3a)(R^3b), -N(R^3a)C(O)R^3b, -OC(O)N(R^3a)(R^3b), -N(R^3a)C(O)OR^3b, -N(R^3a)(R^3b), -OR^3a, -S(O)₂N(R^3a)(R^3b), -N(R^3a)S(O)₂(R^3b), C_3-10 cycloalkyl, C_1-6 alkyl-C_3-10 cycloalkyl, C_6-12 aryl, C_1-6 alkyl-C_6-12 aryl, a 3 to 8 membered heterocycloalkyl ring having 1 to 3 heteroatoms each independently N, O, or S, or a 5 to 10 membered heteroaryl ring having 1 to 3 heteroatoms each independently N, O, or S, wherein each alkenyl or alkynyl is independently optionally substituted with 1 to 3 R^3d groups, and each aryl is optionally substituted with 1 to 3 R^3f groups; each R^3a and R^3b is independently hydrogen, C_1-6 alkyl, C_1-6 hydroxyalkyl, or C_2-6 alkoxyalkyl; each R^3d is independently -N(R^3d1)(R^3d2), -OR^3d1, C_3-10 cycloalkyl, or C_6-12 aryl; each R^3d1 and R^3d2 is independently hydrogen, C_1-4 alkyl, or -C(O)O-(C_1-4 alkyl); and each R^3f is independently C_1-6 alkoxy or halogen.

0088In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein R³ is hydrogen, C_1-6 alkyl, C_1-6 hydroxyalkyl, C_1-6 alkoxy, C_2-6 alkoxyalkyl, halogen, C_1-6 haloalkyl, -CN, -NO₂, - C(O)OR^3a, -C(O)N(R^3a)(R^3b), -N(R^3a)(R^3b), -N(R^3a)S(O)₂(R^3b), or a 5 to 6 membered heteroaryl ring having 1 to 3 heteroatoms each independently N, O, or S; and each R^3a and R^3b is independently hydrogen or C_1-6 alkyl. In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein R³ is hydrogen, C_1-3 alkyl, C_1-3 hydroxyalkyl, C_1-3 alkoxy, C_2-3 alkoxyalkyl, halogen, C_1-3 haloalkyl, - CN, -NO₂, -C(O)OR^3a, -C(O)N(R^3a)(R^3b), -N(R^3a)(R^3b), -N(R^3a)S(O)₂(R^3b), or a 5 to 6 membered heteroaryl ring having 1 or 2 heteroatoms each N; and each R^3a and R^3b is independently hydrogen or C_1-3 alkyl. In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein R³ is hydrogen, Me, Et, - CH₂OH, -OMe, -CH₂OMe, F, Cl, Br, -CF₃, -CN, -NO₂, -COOMe, -CONH₂, -NH₂, -NHSO₂Me, or <chemistry id="chem0021" num="0021"><img file="EP4445902A2_D0021.tif" /></chemistry>

0089In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein R³ is hydrogen, C_1-6 alkyl, C_1-6 hydroxyalkyl, C_1-6 alkoxy, C_2-6 alkoxyalkyl, halogen, -CN, -NO₂, -C(O)OR^3a, - C(O)N(R^3a)(R^3b), -N(R^3a)(R^3b), -N(R^3a)S(O)₂(R^3b), or a 5 to 6 membered heteroaryl ring having 1 to 3 heteroatoms each independently N, O, or S; and each R^3a and R^3b is independently hydrogen or C_1-6 alkyl. In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein R³ is hydrogen, C_1-3 alkyl, C_1-3 hydroxyalkyl, C_1-3 alkoxy, C_2-3 alkoxyalkyl, halogen, -CN, -NO₂, -C(O)OR^3a, - C(O)N(R^3a)(R^3b), -N(R^3a)(R^3b), -N(R^3a)S(O)₂(R^3b), or heteroaryl. In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein R³ is hydrogen, C_1-3 alkyl, C_1-3 hydroxyalkyl, C_1-3 alkoxy, C_2-3 alkoxyalkyl, halogen, -CN, -NO₂, -C(O)OR^3a, -C(O)N(R^3a)(R^3b), -N(R^3a)(R^3b), -N(R^3a)S(O)₂(R^3b), or a 5 to 6 membered heteroaryl ring having 1 or 2 heteroatoms each N; and each R^3a and R^3b is independently hydrogen or C_1-3 alkyl.

0090In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein R³ is hydrogen, C_1-3 alkyl, halogen, -CN or -NO₂. In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein R³ is hydrogen, Me, Et, - CH₂OH, -OMe, -CH₂OMe, F, Cl, Br, -CN, -NO₂, -COOMe, -CONH₂, -NH₂, -NHSO₂Me, or <chemistry id="chem0022" num="0022"><img file="EP4445902A2_D0022.tif" /></chemistry>

0091In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein R² is hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 hydroxyalkyl, C_1-6 alkoxy, C_2-6 alkoxyalkyl, halogen, C_1-6 haloalkyl, -CN, -NO, -NO₂, -C(O)R^2a, -C(O)OR^2a, -N(R^2a)C(O)R^2b, -N(R^2a)(R^2b), -OR^2a, - N(R^2a)S(O)₂(R^2b), C_3-10 cycloalkyl, C_6-10 aryl, heterocycloalkyl, or heteroaryl, wherein each alkenyl or alkynyl is independently optionally substituted with 1 to 3 R^2d groups, and each aryl is optionally substituted with 1 to 3 R^2f groups; each R^2a and R^2b is independently hydrogen, C_1-6 alkyl, C_1-6 hydroxyalkyl, or C_2-6 alkoxyalkyl; each R^2d is independently -N(R^2d1)(R^2d2), -OR^2d1, C_3-10 cycloalkyl, or C_6-12 aryl; each R^2f is independently C_1-6 alkoxy or halogen; the heterocycloalkyl is a 5 to 8 membered ring having 1 to 2 heteroatoms each independently N, O, or S; R³ is hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 hydroxyalkyl, C_1-6 alkoxy, C_2-6 alkoxyalkyl, halogen, C_1-6 haloalkyl, C_1-6 haloalkoxy, -CN, -NO, -NO₂, -C(O)R^3a, -C(O)OR^3a, -OC(O)R^3a, -C(O)N(R^3a)(R^3b), -N(R^3a)C(O)R^3b, -OC(O)N(R^3a)(R^3b), -N(R^3a)C(O)OR^3b, -N(R^3a)(R^3b), -OR^3a, -S(O)₂N(R^3a)(R^3b), -N(R^3a)S(O)₂(R^3b), C_3-10 cycloalkyl, C_1-6 alkyl-C_3-10 cycloalkyl, C_6-12 aryl, C_1-6 alkyl-C_6-12 aryl, heterocycloalkyl, or heteroaryl, wherein each alkenyl or alkynyl is independently optionally substituted with 1 to 3 R^3d groups, and each aryl is optionally substituted with 1 to 3 R^3f groups; and the heteroaryl is a 5 to 6 membered ring having 1 to 3 heteroatoms each independently N, O, or S.

0092In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein R² is hydrogen, C_1-3 alkyl, C_2-3 alkenyl, C_2-6 alkynyl, C₁₃ hydroxyalkyl, C_1-3 alkoxy, C_2-3 alkoxyalkyl, halogen, C_1-3 haloalkyl, -CN, -NO, -NO₂, -C(O)R^2a, -C(O)OR^2a, -N(R^2a)C(O)R^2b, -N(R^2a)(R^2b), -N(R^2a)S(O)₂(R^2b), C_3-6 cycloalkyl, phenyl, heterocycloalkyl, or heteroaryl, wherein each alkenyl or alkynyl is independently optionally substituted with 1 R^2d group, and each phenyl is optionally substituted with 1 R^2f group; each R^2a and R^2b is independently hydrogen, C_1-3 alkyl, C_1-3 hydroxyalkyl, or C_2-3 alkoxyalkyl; each R^2d is independently -N(R^2d1)(R^2d2), -OR^2d1, C_3-8 cycloalkyl, or phenyl; each R^2f is independently C_1-3 alkoxy or halogen; R³ is hydrogen, C_1-3 alkyl, C_1-3 hydroxyalkyl, C_1-3 alkoxy, C_2-3 alkoxyalkyl, halogen, -CN, -NO₂, -C(O)OR^3a, -C(O)N(R^3a)(R^3b), -N(R^3a)(R^3b), -N(R^3a)S(O)₂(R^3b), or heteroaryl; each R^3a and R^3b is independently hydrogen or C_1-3 alkyl; the heterocycloalkyl is a 5 to 6 membered ring having 1 to 2 heteroatoms each independently N or O; and the heteroaryl is a 5 to 6 membered ring having 1 to 2 heteroatoms each independently N, O, or S.

0093In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ib), (Ic), (IIa), (IIc), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein R² is hydrogen, F or Cl. In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ib), (Ic), (IIa), (IIc), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein R² is hydrogen. In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ib), (Ic), (IIa), (IIc), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein R² is F. In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ib), (Ic), (IIa), (IIc), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein R² is Cl.

0094In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein R² is hydrogen, Me, Et, iPr, - CH=CH₂, -C(Me)=CH₂, -C=C-Me, -C=C-tBu, -C≡C-CH₂OH, -C≡C-CH₂NH₂, -C=C-CH₂NHC(O)OtBu, -CH₂OH, -OMe, -CH₂OMe, F, Cl, Br, I, -CF₃, -CN, -NO, -NO₂, -C(O)H, - COOH, -COOMe, -NHCOMe, -NH₂, -NHMe, -NMe₂, -NHCH₂CH₂OH, -NHCH₂CH₂OMe, -NHSO₂Me, -OH, cyclopropyl, <chemistry id="chem0023" num="0023"><img file="EP4445902A2_D0023.tif" /></chemistry><chemistry id="chem0024" num="0024"><img file="EP4445902A2_D0024.tif" /></chemistry><chemistry id="chem0025" num="0025"><img file="EP4445902A2_D0025.tif" /></chemistry> and R³ is hydrogen, Me, Et, -CH₂OH, -OMe, -CH₂OMe, F, Cl, Br, -CN, -NO₂, -COOMe, -CONH₂, -NH₂, -NHSO₂Me, or <chemistry id="chem0026" num="0026"><img file="EP4445902A2_D0026.tif" /></chemistry>

0095In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ib), (Ic), (IIa), (IIc), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein R³ is hydrogen, F or Cl. In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ib), (Ic), (IIa), (IIc), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein R³ is hydrogen. In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ib), (Ic), (IIa), (IIc), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein R³ is F.

0096In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ib), (Ic), (IIa), (IIc), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein R⁴ is hydrogen, C_1-6 alkyl, C_1-6 alkoxy, halogen, C_1-6 haloalkyl, or-CN. In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ib), (Ic), (IIa), (IIc), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein R⁴ is hydrogen, C_1-6 alkyl, or halogen. In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ib), (Ic), (IIa), (IIc), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein R⁴ is hydrogen, C_1-3 alkyl, or halogen. In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ib), (Ic), (IIa), (IIc), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein R⁴ is hydrogen, Me, F, Cl, or Br. In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ib), (Ic), (IIa), (IIc), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein R⁴ is hydrogen, F, or Cl. In some embodiments, the compound of Formula (1), (I-1), (Ia), (Ib), (Ic), (IIa), (IIc), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein R⁴ is hydrogen. In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ib), (Ic), (IIa), (IIc), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein R⁴ is F.

0097In some embodiments, the compound of Formula (I), (Ic), (IIa), (IIc), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein R¹ and R² are each hydrogen. In some embodiments, the compound of Formula (I), (Ic), (IIa), (IIc), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein R¹ and R³ are each hydrogen. In some embodiments, the compound of Formula (I), (Ic), (IIa), (IIc), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein R¹ and R⁴ are each hydrogen. In some embodiments, the compound of Formula (I), (Ic), (IIa), (IIc), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein R² and R³ are each hydrogen. In some embodiments, the compound of Formula (I), (Ic), (IIa), (IIc), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein R² and R⁴ are each hydrogen. In some embodiments, the compound of Formula (I), (Ic), (IIa), (IIc), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8),or a pharmaceutically acceptable salt thereof, is the compound wherein R³ and R⁴ are each hydrogen.

0098In some embodiments, the compound of Formula (I), (Ic), (IIa), (IIc), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein R¹, R², and R³ are each hydrogen. In some embodiments, the compound of Formula (I), (Ic), (IIa), (IIc), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8),or a pharmaceutically acceptable salt thereof, is the compound wherein R¹, R², and R⁴ are each hydrogen. In some embodiments, the compound of Formula (I), (Ic), (IIa), (IIc), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein R¹, R³, and R⁴ are each hydrogen. In some embodiments, the compound of Formula (I), (Ic), (IIa), (IIc), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein R², R³, and R⁴ are each hydrogen.

0099In some embodiments, the compound of Formula (I), (Ic), (IIa), (IIc), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein R¹ is hydrogen; R² is hydrogen, C_1-3 alkyl, C_2-3 alkenyl, C_2-6 alkynyl, C_1-3 hydroxyalkyl, C_2-3 alkoxyalkyl, halogen, -CN, -NO, -NOz, -C(O)R^2a, -N(R^2a)C(O)R^2b, -N(R^2a)(R^2b), -OR^2a, or a 5 to 6 membered heteroaryl ring having 1 to 2 heteroatoms each independently N, O, or S; R^2a and R^2b are each independently hydrogen or C_1-3 alkyl; R³ is hydrogen, C_1-3 alkyl, halogen, -CN or -NO₂; R⁴ is hydrogen or halogen; and R⁷ is hydrogen or C_1-3 alkyl.

0100In some embodiments, the compound of Formula (I), (Ic), (IIa), (IIc), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein R¹ is hydrogen; R² is hydrogen, C_1-3 alkyl, C_2-3 alkenyl, C_2-6 alkynyl, C_1-3 hydroxyalkyl, C_2-3 alkoxyalkyl, halogen, -CN, -NO, -NO₂, -C(O)R^2a, -N(R^2a)C(O)R^2b, -N(R^2a)(R^2b), -OR^2a, or a 5 to 6 membered heteroaryl ring having 1 to 2 heteroatoms each independently N, O, or S; R^2a and R^2b are each independently hydrogen or C_1-3 alkyl; R³ is hydrogen, C_1-3 alkyl, halogen, -CN or -NO₂; R⁴ is hydrogen; and R⁷ is hydrogen.

0101In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ib), (Ic), (IIa), (IIc), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein R¹ is hydrogen; R² is hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 hydroxyalkyl, C_1-6 alkoxy, C_2-6 alkoxyalkyl, halogen, C_1-6 haloalkyl, -CN, -NO, -NOz, -C(O)R^2a, -C(O)OR^2a, -N(R^2a)C(O)R^2b, -N(R^2a)(R^2b), -OR^2a, -N(R^2a)S(O)₂(R^2b), C_3-10 cycloalkyl, C_6-10 aryl, heterocycloalkyl, or heteroaryl, wherein each alkenyl or alkynyl is independently optionally substituted with 1 to 3 R^2d groups, and each aryl is optionally substituted with 1 to 3 R^2f groups; each R^2a and R^2b is independently hydrogen, C_1-6 alkyl, C_1-6 hydroxyalkyl, or C_2-6 alkoxyalkyl; each R^2d is independently -N(R^2d1)(R^2d2), -OR^2d1, C_3-10 cycloalkyl, or C_6-12 aryl; each R^2f is independently C_1-6 alkoxy or halogen; the heterocycloalkyl is a 5 to 8 membered ring having 1 to 2 heteroatoms each independently N, O, or S; R³ is hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 hydroxyalkyl, C_1-6 alkoxy, C_2-6 alkoxyalkyl, halogen, C_1-6 haloalkyl, C_1-6 haloalkoxy, -CN, -NO, -NOz, -C(O)R^3a, -C(O)OR^3a, -OC(O)R^3a, -C(O)N(R^3a)(R^3b), - N(R^3a)C(O)R^3b, -OC(O)N(R^3a)(R^3b), -N(R^3a)C(O)OR^3b, -N(R^3a)(R^3b), -OR^3a, -S(O)2N(R^3a)(R^3b), -N(R^3a)S(O)₂(R^3b), C_3-10 cycloalkyl, C_1-6 alkyl-C_3-10 cycloalkyl, C_6-12 aryl, C_1-6 alkyl-C_6-12 aryl, heterocycloalkyl, or heteroaryl, wherein each alkenyl or alkynyl is independently optionally substituted with 1 to 3 R^3d groups, and each aryl is optionally substituted with 1 to 3 R^3f groups; and the heteroaryl is a 5 to 6 membered ring having 1 to 3 heteroatoms each independently N, O, or S; and R⁴ is hydrogen.

0102In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ib), (Ic), (IIa), (IIc), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein R¹ is hydrogen or F; R² is hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 hydroxyalkyl, C_2-6 alkoxyalkyl, halogen, -CN, -NO, -NO₂, -C(O)R^2a, - N(R^2a)C(O)R^2b, -N(R^2a)(R^2b), -OR^2a, or a 5 to 6 membered heteroaryl ring having 1 to 2 heteroatoms each independently N, O, or S; R^2a and R^2b are each independently hydrogen or C_1-6 alkyl; R³ is hydrogen, C_1-6 alkyl, halogen, -CN or -NO₂; and R⁴ is hydrogen, F, or Cl.

0103In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ib), (Ic), (IIa), (IIc), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein R¹ is hydrogen; R² is hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 hydroxyalkyl, C_2-6 alkoxyalkyl, halogen, -CN, -NO, -NOz, -C(O)R^2a, -N(R^2a)C(O)R^2b, -N(R^2a)(R^2b), -OR^2a, or a 5 to 6 membered heteroaryl ring having 1 to 2 heteroatoms each independently N, O, or S; R^2a and R^2b are each independently hydrogen or C_1-6 alkyl; R³ is hydrogen, C_1-6 alkyl, halogen, -CN or -NO₂; and R⁴ is hydrogen.

0104In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ib), (Ic), (IIa), (IIc), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein R¹ is hydrogen; R² is hydrogen, C_1-3 alkyl, C_2-3 alkenyl, C_2-6 alkynyl, C_1-3 hydroxyalkyl, C_2-3 alkoxyalkyl, halogen, -CN, -NO, -NOz, -C(O)R^2a, -N(R^2a)C(O)R^2b, -N(R^2a)(R^2b), -OR^2a, or a 5 to 6 membered heteroaryl ring having 1 to 2 heteroatoms each independently N, O, or S; R^2a and R^2b are each independently hydrogen or C_1-3 alkyl; R³ is hydrogen, C_1-3 alkyl, halogen, -CN or -NO₂; and R⁴ is hydrogen.

0105In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ib), (Ic), (IIa), (IIc), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein R¹ is hydrogen; R² is hydrogen, C_1-3 alkyl, C_2-3 alkenyl, C_2-6 alkynyl, C_1-3 hydroxyalkyl, C_2-3 alkoxyalkyl, halogen, -CN, -NO, -NOz, -C(O)R^2a, -N(R^2a)C(O)R^2b, -N(R^2a)(R^2b), -OR^2a, or heteroaryl; R^2a and R^2b are each independently hydrogen or C_1-3 alkyl; R³ is hydrogen; R⁴ is hydrogen; and the heteroaryl is a 5 to 6 membered ring having 1 to 2 heteroatoms each independently N, O, or S.

0106In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ia-1), (Ib), (IIa), or (IIa-1), or a pharmaceutically acceptable salt thereof, is the compound wherein R⁵ is C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 hydroxyalkyl, C_2-6 alkoxyalkyl, C_1-6 haloalkyl, C_3-10 cycloalkyl, C_1-6 alkyl-C_3-10 cycloalkyl, C_6-12 aryl, C_1-6 alkyl-C_6-12 aryl, C_1-6 alkyl-(heterocycloalkyl), or C_1-6 alkyl-(heteroaryl), wherein the alkyl is optionally substituted with R^5a; R^5a is - OSi(R^5a1)(R^5a2)(R^5a3); R^5a1, R^5a2, and R^5a3 are each independently C_1-4 alkyl; and the heterocycloalkyl is a 5 to 8 membered ring having 1 to 2 heteroatoms each independently N, O, or S; and the heteroaryl is a 5 to 6 membered ring having 1 to 2 heteroatoms each independently N, O, or S. In some embodiments, the compound of Formula (1), (I-1), (Ia), (Ia-1), (Ib), (IIa), or (IIa-1), or a pharmaceutically acceptable salt thereof, is the compound wherein R⁵ is C_1-6 alkyl, C_2-6 alkynyl, C_2-6 alkoxyalkyl, C_1-6 haloalkyl, C_3-10 cycloalkyl, C_1-6 alkyl-C_3-10 cycloalkyl, C_6-12 aryl, C_1-6 alkyl-C_6-12 aryl, or C_1-6 alkyl-(heterocycloalkyl), wherein the alkyl is optionally substituted with R^5a; R^5a is -OSi(R^5a1)(R^5a2)(R^5a3); R^5a1, R^5a2, and R^5a3 are each independently C_1-4 alkyl, wherein R^5a1 and R^5a2 are different; and the heterocycloalkyl is a 5 to 6 membered ring having 1 to 2 heteroatoms each independently N or O. In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ia-1), (Ib), (IIa), or (IIa-1), or a pharmaceutically acceptable salt thereof, is the compound wherein R⁵ is C_1-6 alkyl, C_2-6 alkynyl, C_2-3 alkoxyalkyl, C_1-3 haloalkyl, C_3-8 cycloalkyl, C_1-3 alkyl-C_3-8 cycloalkyl, phenyl, C_1-3 alkyl-phenyl, or C_1-3 alkyl-(heterocycloalkyl), wherein the alkyl is optionally substituted with R^5a; R^5a is - OSi(R^5a1)(R^5a2)(R^5a3); R^5a1, R^5a2, and R^5a3 are each independently Me or tBu, wherein R^5a1 and R^5a2 are different; and the heterocycloalkyl is a 6 membered ring having 1 heteroatom N or O. In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ia-1), (Ib), (IIa), or (IIa-1), or a pharmaceutically acceptable salt thereof, is the compound wherein R⁵ is Me, Et, nPr, nBu, - CH₂CMe₃, -CH₂C≡CMe, -CH₂CH₂C≡CH, -CH₂CH₂OMe, -CH₂CH₂OSi(Me)₂(tBu), CF₃, -CH₂CF₂H, -CH₂CF₃, <chemistry id="chem0027" num="0027"><img file="EP4445902A2_D0027.tif" /></chemistry>

0107In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ia-1), (Ib), (IIa), or (IIa-1), or a pharmaceutically acceptable salt thereof, is the compound wherein R⁵ is C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 hydroxyalkyl, C_2-6 alkoxyalkyl, C_1-6 haloalkyl, C_1-6 alkyl-C_3-10 cycloalkyl, C_6-12 aryl, C_1-6 alkyl-C_6-12 aryl, C_1-6 alkyl-(heterocycloalkyl), or C_1-6 alkyl-(heteroaryl), wherein the alkyl is optionally substituted with R^5a; R^5a is -OSi(R^5a1)(R^5a2)(R^5a3); R^5a1, R^5a2, and R^5a3 are each independently C_1-4 alkyl; the heterocycloalkyl is a 5 to 8 membered ring having 1 to 2 heteroatoms each independently N, O, or S; and the heteroaryl is a 5 to 6 membered ring having 1 to 2 heteroatoms each independently N, O, or S. In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ia-1), (Ib), (IIa), or (IIa-1), or a pharmaceutically acceptable salt thereof, is the compound wherein R⁵ is C_1-6 alkyl, C_2-6 alkynyl, C_2-6 alkoxyalkyl, C_1-6 alkyl-C_3-10 cycloalkyl, C_6-12 aryl, C_1-6 alkyl-C_6-12 aryl, or C_1-6 alkyl-(heterocycloalkyl), wherein the alkyl is optionally substituted with R^5a; R^5a is -OSi(R^5a1)(R^5a2)(R^5a3); R^5a1, R^5a2, and R^5a3 are each independently C_1-4 alkyl, wherein R^5a1 and R^5a2 are different; and the heterocycloalkyl is a 5 to 6 membered ring having 1 to 2 heteroatoms each independently N or O. In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ia-1), (Ib), (IIa), or (IIa-1), or a pharmaceutically acceptable salt thereof, is the compound wherein R⁵ is C_1-6 alkyl, C_2-6 alkynyl, C_2-3 alkoxyalkyl, C_1-3 alkyl-C_3-8 cycloalkyl, phenyl, C_1-3 alkyl-phenyl, or C_1-3 alkyl-(heterocycloalkyl), wherein the alkyl is optionally substituted with R^5a; R^5a is - OSi(R^5a1)(R^5a2)(R^5a3); R^5a1, R^5a2, and R^5a3 are each independently Me or tBu, wherein R^5a1 and R^5a2 are different; and the heterocycloalkyl is a 6 membered ring having 1 heteroatom N or O.

0108In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ia-1), (Ib), (IIa), or (IIa-1), or a pharmaceutically acceptable salt thereof, is the compound wherein R⁵ is Me, Et, nPr, nBu, -CH₂CMe₃, -CH₂C≡CMe, -CH₂CH₂C≡CH, -CH₂CH₂OMe, -CH₂CH₂OSi(Me)₂(tBu), <chemistry id="chem0028" num="0028"><img file="EP4445902A2_D0028.tif" /></chemistry>

0109In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ia-1), (Ib), (IIa), or (IIa-1), or a pharmaceutically acceptable salt thereof, is the compound wherein R^5a1, R^5a2, and R^5a3 are each independently C_1-4 alkyl. In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ia-1), or (Ib), or a pharmaceutically acceptable salt thereof, is the compound wherein R^5a1 and R^5a2 are each Me or tBu. In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ia-1), (Ib), (IIa), or (IIa-1), or a pharmaceutically acceptable salt thereof, is the compound wherein R^5a1 and R^5a2 are different.

0110In some embodiments, the compound of Formula (I) or (I-1), or a pharmaceutically acceptable salt thereof, is the compound wherein R⁶ is phenyl, naphthyl, thienyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, or dibenzofuryl, which are each optionally substituted with 1 or 2 R^6a.

0111In some embodiments, the compound of Formula (I) or (I-1), or a pharmaceutically acceptable salt thereof, is the compound wherein R⁶ is phenyl or a 5 to 6 membered heteroaryl ring having 1 to 3 heteroatoms each independently N, O, or S, which are each optionally substituted with 1 or 2 R^6a. In some embodiments, the compound of Formula (I) or (I-1), or a pharmaceutically acceptable salt thereof, is the compound wherein R⁶ is phenyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl, pyrazolyl, pyridyl, or pyrimidinyl, which are each optionally substituted with 1 or 2 R^6a. In some embodiments, the compound of Formula (I) or (I-1), or a pharmaceutically acceptable salt thereof, is the compound wherein R⁶ is phenyl, thienyl, or pyridyl, optionally substituted with 1 or 2 R^6a. In some embodiments, the compound of Formula (I) or (I-1), or a pharmaceutically acceptable salt thereof, is the compound wherein R⁶ is <chemistry id="chem0029" num="0029"><img file="EP4445902A2_D0029.tif" /></chemistry><chemistry id="chem0030" num="0030"><img file="EP4445902A2_D0030.tif" /></chemistry>

0112In some embodiments, the compound of Formula (I) or (I-1), or a pharmaceutically acceptable salt thereof, is the compound wherein R⁶ is <chemistry id="chem0031" num="0031"><img file="EP4445902A2_D0031.tif" /></chemistry><chemistry id="chem0032" num="0032"><img file="EP4445902A2_D0032.tif" /></chemistry><chemistry id="chem0033" num="0033"><img file="EP4445902A2_D0033.tif" /></chemistry><chemistry id="chem0034" num="0034"><img file="EP4445902A2_D0034.tif" /></chemistry><chemistry id="chem0035" num="0035"><img file="EP4445902A2_D0035.tif" /></chemistry>

0113In some embodiments, the compound of Formula (I) or (I-1), or a pharmaceutically acceptable salt thereof, is the compound wherein R⁶ is <chemistry id="chem0036" num="0036"><img file="EP4445902A2_D0036.tif" /></chemistry><chemistry id="chem0037" num="0037"><img file="EP4445902A2_D0037.tif" /></chemistry><chemistry id="chem0038" num="0038"><img file="EP4445902A2_D0038.tif" /></chemistry><chemistry id="chem0039" num="0039"><img file="EP4445902A2_D0039.tif" /></chemistry>

0114In some embodiments, the compound of Formula (I), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein R⁷ is hydrogen, Me, Et, OMe, -CHzOH, -CHzOMe, - CH₂NMe₂, Cl, CHF₂, OH, NH₂, SMe, or <chemistry id="chem0040" num="0040"><img file="EP4445902A2_D0040.tif" /></chemistry> In some embodiments, the compound of Formula (I), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein R⁷ is hydrogen, Me, -CH₂OMe, CHF₂, or NH₂.

0115In some embodiments, the compound of Formula (I), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein R⁷ is hydrogen, Me, Et, OMe, -CH₂NMe₂, Cl, OH, NH₂, SMe, or <chemistry id="chem0041" num="0041"><img file="EP4445902A2_D0041.tif" /></chemistry> In some embodiments, the compound of Formula (I), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein R⁷ is hydrogen or Me. In some embodiments, the compound of Formula (I) , (IIa), (IIa-1), (IIc), (IIc-1), or (IIc-2), or a pharmaceutically acceptable salt thereof, is the compound wherein R⁷ is hydrogen. In some embodiments, the compound of Formula (I) , (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein R⁷ is Me.

0116In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof, is a compound that has the structure of Formula (I-1): <chemistry id="chem0042" num="0042"><img file="EP4445902A2_D0042.tif" /></chemistry> or a pharmaceutically acceptable salt thereof.

0117In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof, is a compound that has the structure of Formula (IIa): <chemistry id="chem0043" num="0043"><img file="EP4445902A2_D0043.tif" /></chemistry> wherein n is 0, 1, 2, or 3. In some embodiments, the compound of Formula (IIa) or a pharmaceutically acceptable salt thereof, is a compound wherein n is 0. In some embodiments, the compound of Formula (IIa), or a pharmaceutically acceptable salt thereof, is a compound wherein n is 1. In some embodiments, the compound of Formula (IIa), or a pharmaceutically acceptable salt thereof, is a compound wherein n is 2. In some embodiments, the compound of Formula (IIa), or a pharmaceutically acceptable salt thereof, is a compound wherein n is 3.

0118In some embodiments, the compound of Formula (I) or (I-1), or a pharmaceutically acceptable salt thereof, is a compound that has the structure of Formula (Ia): <chemistry id="chem0044" num="0044"><img file="EP4445902A2_D0044.tif" /></chemistry> wherein n is 0, 1, 2, or 3. In some embodiments, the compound of Formula (Ia), or a pharmaceutically acceptable salt thereof, is a compound wherein n is 0. In some embodiments, the compound of Formula (Ia), or a pharmaceutically acceptable salt thereof, is a compound wherein n is 1. In some embodiments, the compound of Formula (Ia), or a pharmaceutically acceptable salt thereof, is a compound wherein n is 2. In some embodiments, the compound of Formula (Ia), or a pharmaceutically acceptable salt thereof, is a compound wherein n is 3.

0119In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound that has the structure of Formula (IIa-1): <chemistry id="chem0045" num="0045"><img file="EP4445902A2_D0045.tif" /></chemistry>

0120In some embodiments, the compound of Formula (I), (I-1), or (Ia), or a pharmaceutically acceptable salt thereof, is a compound that has the structure of Formula (Ia-1): <chemistry id="chem0046" num="0046"><img file="EP4445902A2_D0046.tif" /></chemistry>

0121In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ia-1), or (Ic), or a pharmaceutically acceptable salt thereof, is the compound wherein each R^6a is independently a hydrogen atom, an optionally substituted C₁-C₆ alkyl group(a methyl group and an ethyl group, for example), an optionally substituted C₂-C₆ alkenyl group, an optionally substituted C₂-C₆ alkynyl group (a 1-propynyl group for example; a halogen atom, a hydroxy group and a methoxy group etc. are exemplified as the substituent of these alkyl, alkenyl and alkynyl groups), an optionally substituted C₁-C₆ alkoxy group (a halogen atom is exemplified as the substituent), C₃-C₆ cycloalkyl group(a cyclopropyl group and a cyclohexyl group for example), a hydroxy group, a halogen atom, a nitro group, a cyano group, an amino group, an acetylamino group, a methoxycarbonyl group, a carboxy group, a carbamoyl group, a formyl group, a 5- or 6-membered saturated cyclic amino group (a morpholino group, a pyrrolidyl group, a piperidyl group are exemplified), a 5- or 6-membered heteroaryl group (a furanyl group, a thienyl group, an imidazolyl group, a pyrrolyl group, a pyrazolyl group, a methylpyrazolyl group, a pyridyl group, a pyrimidyl group etc. are exemplified), a phenyl group, a substituted phenyl group (examples of the substituent include C₁-C₆ alkyl group, C₃-C₆ cycloalkyl group, a halogen atom, a methoxy group, a trifluoromethyl group, an acetylamino group etc.) and the like.

0122In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ia-1), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein each R^6a is independently C_1-6 alkyl, C_2-6 alkynyl, C_1-6 hydroxyalkyl, C_1-6 alkoxy, C_2-6 alkoxyalkyl, halogen, C_1-6 haloalkyl, C_1-6 haloalkoxy, -CN, -NO₂, -C(O)R^6b, -C(O)OR^6b, -C(O)N(R^6b)(R^6c), -N(R^6b)(R^6c), -OR^6b, C_3-10 cycloalkyl, C_6-12 aryl, heterocycloalkyl, or heteroaryl, wherein the cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is each optionally substituted with 1 to 3 R^6e, and the alkyl is optionally substituted with R^6f.

0123In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ia-1), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein each R^6a is independently C_1-6 alkyl, C_2-6 alkynyl, C_1-6 hydroxyalkyl, C_1-6 alkoxy, C_2-6 alkoxyalkyl, halogen, C_1-6 haloalkyl, C_1-6 haloalkoxy, -CN, -NO₂, -C(O)R^6b, -C(O)OR^6b, -C(O)N(R^6b)(R^6c), -N(R^6b)(R^6c), -OR^6b, C_3-10 cycloalkyl, C_6-12 aryl, heterocycloalkyl, or heteroaryl, wherein the cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is each optionally substituted with 1 to 3 R^6e, and the alkyl is optionally substituted with R^6f; each R^6b and R^6c is independently hydrogen or C_1-6 alkyl; each R^6e is independently C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 hydroxyalkyl, C_1-6 alkoxy, C_2-6 alkoxyalkyl, halogen, C_1-6 haloalkyl, -C(O)OR^6e1, -OC(O)R^6e1, -C(O)N(R^6e1)(R^6e2), - N(R^6e1)C(O)R^6e2, -OR^6e1, -S(O)₂N(R^6e1)(R^6e2), -N(R^6e1)S(O)₂(R^6e2); each R^6e1 and R^6e2 is independently hydrogen or C_1-6 alkyl; R^6f is -OSi(R^6f1)(R^6f2)(R^6f3); and R^6f1, R^6f2, and R^6f3 are each independently C_1-6 alkyl. In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ia-1), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein each R^6a is independently C_1-3 alkyl, C_2-3 alkynyl, C_1-3 hydroxyalkyl, C_1-3 alkoxy, C_2-3 alkoxyalkyl, halogen, C_1-3 haloalkyl, C_1-3 haloalkoxy, -CN, -NOz, -C(O)R^6b, -C(O)OR^6b, -C(O)N(R^6b)(R^6c), - N(R^6b)(R^6c), -OR^6b, C_3-8 cycloalkyl, phenyl, a 5 to 6 membered heterocycloalkyl ring having 1 to 2 heteroatoms each independently N or O, or a 5 to 6 membered heteroaryl ring having 1 to 2 heteroatoms each independently N, O, or S, wherein the cycloalkyl, phenyl, heterocycloalkyl, or heteroaryl is each optionally substituted with 1 to 2 R^6e, and the alkyl is optionally substituted with R^6f; each R^6b and R^6c is independently hydrogen or C_1-3 alkyl; each R^6e is independently C_1-6 alkyl, C_1-6 hydroxyalkyl, C_1-6 alkoxy, C_2-6 alkoxyalkyl, halogen, C_1-6 haloalkyl, -C(O)OR^6e1,-OC(O)R^6e1, -N(R^6e1)C(O)R^6e2, -OR^6e1; each R^6e1 and R^6e2 is independently hydrogen or C_1-6 alkyl; R^6f is -OSi(R^6f1)(R^6f2)(R^6f3); and R^6f1, R^6f2, and R^6f3 are each independently Me or tBu.

0124In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ia-1), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein each R^6b and R^6c is independently hydrogen, C_1-6 alkyl, C_1-6 hydroxyalkyl, C_2-6 alkoxyalkyl, C_1-6 haloalkyl, or C_3-10 cycloalkyl. In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ia-1), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein each R^6b and R^6c is independently hydrogen, C_1-6 alkyl, or C_1-6 haloalkyl. In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ia-1), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein each R^6b and R^6c is independently hydrogen or C_1-6 alkyl. In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ia-1), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein each R^6b and R^6c is independently hydrogen or C_1-3 alkyl. In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ia-1), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein each R^6b and R^6c is independently hydrogen or Me.

0125In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ia-1), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein each R^6b, R^6c and R^6d is independently hydrogen, C_1-6 alkyl, C_1-6 hydroxyalkyl, C_2-6 alkoxyalkyl, C_1-6 haloalkyl, or C_3-10 cycloalkyl. In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ia-1), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein each R^6b, R^6c and R^6d is independently hydrogen, C_1-6 alkyl, or C_1-6 haloalkyl. In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ia-1), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein each R^6b, R^6c and R^6d is independently hydrogen or C_1-6 alkyl. In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ia-1), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein each R^6b, R^6c and R^6d is independently hydrogen or C_1-3 alkyl. In some embodiments, the compound of Formula (I), (1-1), (Ia), (Ia-1), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein each R^6b, R^6c and R^6d is independently hydrogen or Me.

0126In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein each R^6e is independently a hydrogen atom, a C₁-C₆ alkyl group (a methyl group, an ethyl group, and a tert-butyl group are exemplified), a C₂-C₆ alkenyl group, a C₂-C₆ alkynyl group, a C₁-C₆ alkoxy group (a methoxy group, for example), a C₃-C₆ cycloalkyl group, a hydroxy group, a halogen atom, a nitro group, a cyano group, a carbamoyl group, a formyl group, an acetylamino group and the like.

0127In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8),, or a pharmaceutically acceptable salt thereof, is the compound wherein each R^6e is independently C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 hydroxyalkyl, C_1-6 alkoxy, C_2-6 alkoxyalkyl, halogen, C_1-6 haloalkyl, -C(O)OR^6e1, -OC(O)R^6e1, -C(O)N(R^6e1)(R^6e2), -N(R^6e1)C(O)R^6e2, -OR^6e1, - S(O)₂N(R^6e1)(R^6e2), -N(R^6e1)S(O)₂(R^6e2); and each R^6e1 and R^6e2 is independently hydrogen or C_1-6 alkyl. In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein each R^6e is independently C_1-6 alkyl, C_1-6 hydroxyalkyl, C_1-6 alkoxy, C_2-6 alkoxyalkyl, halogen, C_1-6 haloalkyl, -C(O)OR^6e1, - OC(O)R^6e1, -N(R^6e1)C(O)R^6e2, -OR^6e1; and each R^6e1 and R^6e2 is independently hydrogen or C_1-6 alkyl. In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein each R^6e is independently C_1-6 alkyl, C_1-3 alkoxy, halogen, C_1-6 haloalkyl, -N(R^6e1)C(O)R^6e2, or -OR^6e1; and each R^6e1 and R^6e2 is independently hydrogen or C_1-3 alkyl.

0128In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein each R⁶ⁿ is C_1-6 alkyl, C_1-6 hydroxyalkyl, -C(O)OR⁶ⁿ¹, -OC(O)R⁶ⁿ¹, -C(O)N(R⁶ⁿ¹)(R⁶ⁿ²), -N(R⁶ⁿ¹)C(O)R⁶ⁿ², - OC(O)N(R⁶ⁿ¹)(R⁶ⁿ²), -N(R⁶ⁿ¹)C(O)OR⁶ⁿ², =O, or -OH; wherein each R⁶ⁿ¹ and R⁶ⁿ² is independently hydrogen, C_1-6 alkyl, or C_1-6 hydroxyalkyl. In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein each R⁶ⁿ is C_1-6 alkyl, -C(O)OR⁶ⁿ¹, or -OC(O)R⁶ⁿ¹, -C(O)N(R⁶ⁿ¹)(R⁶ⁿ²), - N(R⁶ⁿ¹)C(O)R⁶ⁿ², -OC(O)N(R⁶ⁿ¹)(R⁶ⁿ²), -N(R⁶ⁿ¹)C(O)OR⁶ⁿ², =O, or -OH; wherein each R⁶ⁿ¹ and R⁶ⁿ² is independently hydrogen or C_1-6 alkyl. In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein each R⁶ⁿ is independently Me or CO₂tBu.

0129In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein each R^6h is independently C_1-6 alkyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_1-6 alkoxy, C_2-6 alkoxyalkyl, halogen, C_1-6 haloalkyl, -CN, -C(O)R^6h1, -C(O)OR^6h1, -OC(O)R^6h1, -C(O)N(R^6h1)(R^6h2), -N(R^6h1)C(O)R^6h2, - OC(O)N(R^6h1)(R^6h2), -N(R^6h1)C(O)OR^6h2, -N(R^6h1)(R^6h2), =O, -OH, -SR^6h1, -S(O)R^6h1, - S(O)₂R^6h1, -S(O)₂N(R^6h1)(R^6h2), -N(R^6h1)S(O)₂(R^6h2), C_3-10 cycloalkyl, C_1-6 alkyl-C_3-10 cycloalkyl, heterocycloalkyl, or C_1-6 alkyl-(heterocycloalkyl); wherein each R⁶ⁿ¹ and R^6h2 is independently hydrogen, C_1-6 alkyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_2-6 alkoxyalkyl, C_1-6 haloalkyl, C_3-10 cycloalkyl, or C_1-6 alkyl-C_3-10 cycloalkyl. In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein each R^6h is independently C_1-6 alkyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_1-6 alkoxy, C_1-6 haloalkyl, -C(O)R⁶ⁿ¹, -C(O)OR⁶ⁿ¹, -N(R^6h1)(R^6h2), =O, or heterocycloalkyl; wherein each R^6h1 and R^6h2 is independently hydrogen, C_1-6 alkyl, or C_1-6 hydroxyalkyl. In some embodiments, the compound of Formula (1), (1-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein each R^6h is independently Me, -CH₂OH, -CH₂NHMe, OMe, NH₂, CF₃, CN, - (CO)Me, -(CO)tBu, -(CO)-CH₂OH, CO₂Me, CO₂tBu, =O, or <chemistry id="chem0047" num="0047"><img file="EP4445902A2_D0047.tif" /></chemistry>

0130In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein each R^6m is independently halogen, C_1-6 haloalkyl, -CN, -C(O)R^6m1, -C(O)OR^6m1, -OC(O)R^6m1, -C(O)N(R^6m1)(R^6m2), - N(R^6m3)C(O)R^6m2, -OC(O)N(R^6m1)(R^6m2), -N(R^6m1)C(O)OR^6m2, -C(=NR^6m3)N(R^6ml)(R^6m2), - N(R^6m1)(R^6m2), =O, -OH, -SR^6m1, -S(O)R^6m1, -S(O)(NR^6m1)(R^6m2), -S(O)₂R^6m1, or - S(O)₂N(R^6m1)(R^6m2); wherein each R^6m1 and R^6m2 is independently hydrogen, C_1-6 alkyl, C_1-6 hydroxyalkyl, C_1-6 haloalkyl, C_3-10 cycloalkyl, or heterocycloalkyl. In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8),, or a pharmaceutically acceptable salt thereof, is the compound wherein each R^6m is independently C_1-6 haloalkyl, -CN, -C(O)R^6m1, -C(O)OR^6m1, - C(O)N(R^6m1)(R^6m2), -N(R^6m1)(R6^m2), =O, -OH, or -S(O)₂R^6m1; wherein each R^6m1 and R^6m2 is independently hydrogen, C_1-6 alkyl, or heterocycloalkyl. In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein each R^6m is independently OH, CF₃, CN, CO₂H, CONH₂, NMe₂, SO₂Me, or <chemistry id="chem0048" num="0048"><img file="EP4445902A2_D0048.tif" /></chemistry>

0131In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein each R^6e is independently Me, Et, iPr, tBu, -CH₂OH, -C(OH)Me₂, -OMe, -OEt, -OCH₂CH₂CH₃, -CH₂OMe, - OCH₂CH₂NMe₂, F, Cl, Br, CHF₂, -CF₃, -CH₂CHF₂, -CH₂CF₃, -CF₂CH₃, -C(CH₃)₂CF₃, OCF₃, - OCH₂CF₃, -OCH(CH₃)CF₃, CN, -C(O)Me, -C(O)tBu, COzH, COzMe, CO₂tBu, C(O)NH₂, =O, OH, NH₂, NMe₂, -NMeCH₂CH₂OMe, -NHC(O)Me, -NHC(O)tBu, -NHCO₂tBu, SO₂Me, SO₂Et, SO₂(iPr), SO₂(iBu), SO₂CF₃, -CH₂SO₂Me, SO(N=H)Me, SO₂NH₂, SOzNHMe, SO₂NMe₂, - SO₂NHCH₂CH₂OH, -NHSO₂Me, SF₅, -POMe₂, <chemistry id="chem0049" num="0049"><img file="EP4445902A2_D0049.tif" /></chemistry><chemistry id="chem0050" num="0050"><img file="EP4445902A2_D0050.tif" /></chemistry><chemistry id="chem0051" num="0051"><img file="EP4445902A2_D0051.tif" /></chemistry><chemistry id="chem0052" num="0052"><img file="EP4445902A2_D0052.tif" /></chemistry><chemistry id="chem0053" num="0053"><img file="EP4445902A2_D0053.tif" /></chemistry><chemistry id="chem0054" num="0054"><img file="EP4445902A2_D0054.tif" /></chemistry><chemistry id="chem0055" num="0055"><img file="EP4445902A2_D0055.tif" /></chemistry>

0132In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein each R^6e is Me, Et, iPr, tBu, - CH₂OH, -C(OH)Me₂, -OMe, -OEt, -OCH₂CH₂CH₃, -CH₂OMe, -OCH₂CH₂NMe₂, F, Cl, Br, CHF₂, -CF₃, -CH₂CHF₂, -CH₂CF₃, -CF₂CH₃, -C(CH₃)₂CF₃, OCF₃, -OCH₂CF₃, -OCH(CH₃)CF₃, CN, -C(O)Me, -C(O)tBu, CO₂H, CO₂Me, CO₂tBu, C(O)NH₂, =O, OH, NH₂, NMe₂, - NMeCH₂CH₂OMe, -NHC(O)Me, -NHC(O)tBu, -NHCO₂tBu, SO₂Me, SO₂Et, SO₂(iPr), SO₂(iBu), SO₂CF₃, -CH₂SO₂Me, SO(N=H)Me, SO₂NH₂, SO₂NHMe, SO₂NMe₂, - SO₂NHCH₂CH₂OH, -NHSO₂Me, SF₅, -POMe₂, <chemistry id="chem0056" num="0056"><img file="EP4445902A2_D0056.tif" /></chemistry><chemistry id="chem0057" num="0057"><img file="EP4445902A2_D0057.tif" /></chemistry><chemistry id="chem0058" num="0058"><img file="EP4445902A2_D0058.tif" /></chemistry><chemistry id="chem0059" num="0059"><img file="EP4445902A2_D0059.tif" /></chemistry><chemistry id="chem0060" num="0060"><img file="EP4445902A2_D0060.tif" /></chemistry><chemistry id="chem0061" num="0061"><img file="EP4445902A2_D0061.tif" /></chemistry><chemistry id="chem0062" num="0062"><img file="EP4445902A2_D0062.tif" /></chemistry> In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein each R^6e is independently Me, Et, tBu, -OMe, F, Cl, -CF₃, -NHC(O)Me, or -OH.

0133In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein each R^6e1, R^6e2, and R^6e3 is independently hydrogen, C_1-6 alkyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_1-6 alkoxyalkyl, C_1-6 haloalkyl, C_3-10 cycloalkyl, C_1-6 alkyl-C_3-10 cycloalkyl, heterocycloalkyl, or C_1-6 alkyl-(heterocycloalkyl), wherein the cycloalkyl or heterocycloalkyl is optionally substituted with 1 to 3 R⁶ⁿ. In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein each R^6e1, R^6e2, and R6^e3 is independently hydrogen, C_1-6 alkyl, C_1-6 hydroxyalkyl, C_1-6 alkoxyalkyl, C_3-10 cycloalkyl, C_1-6 alkyl-C_3-10 cycloalkyl, or heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally substituted with 1 to 3 R⁶ⁿ.

0134In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein each R^6j is independently halogen, C_1-6 haloalkyl, -C(O)R^6j1, -C(O)OR^6j1, -OC(O)R^6j1, -C(O)N(R^6j1)(R^6j2), - N(R^6j3)C(O)R^6j2, -OC(O)N(R^6j1)(R^6j2), -N(R^6j1)C(O)OR^6j2, -N(R^6j1)(R^6j2), =O, -OR^6j1, - S(O)₂R^6j1, -Si(R^6j1)(R^6j2)(R^6j3), C_3-10 cycloalkyl, C_6-12 aryl, heterocycloalkyl, or heteroaryl, wherein the cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is optionally substituted with 1 to 3 R^6p; wherein each R^6j1, R^6j2, and R^6j3 is independently hydrogen or C_1-6 alkyl.

0135In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein each R^6j is independently OH, OMe, CH₂OMe, F, CHF₂, CF₃, CN, NH₂, NH(CO)CF₃, NH(CO)OtBu, SO₂Me, Si(iPr)₃, <chemistry id="chem0063" num="0063"><img file="EP4445902A2_D0063.tif" /></chemistry><chemistry id="chem0064" num="0064"><img file="EP4445902A2_D0064.tif" /></chemistry><chemistry id="chem0065" num="0065"><img file="EP4445902A2_D0065.tif" /></chemistry>

0136In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein each R^6j is independently OH, OMe, F, CHF₂, CF₃, NH₂, NH(CO)OtBu, SO₂Me, Si(iPr)₃, <chemistry id="chem0066" num="0066"><img file="EP4445902A2_D0066.tif" /></chemistry><chemistry id="chem0067" num="0067"><img file="EP4445902A2_D0067.tif" /></chemistry>

0137In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein each R^6p is independently C_1-6 alkyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_1-6 alkoxy, C_2-6 alkoxyalkyl, halogen, C_1-6 haloalkyl, C_1-6 haloalkoxy, -CN, -C(O)R^6p1, -C(O)OR^6p1, -OC(O)R^6p1, -C(O)N(R^6p1)(R^6p2), - N(R^6p1)C(O)R^6p2, -OC(O)N(R^6p1)(R^6p2), -N(R^6p1)C(0)OR^6p2, -C(=NR^6p3)N(R^6p1)(R^6p2), - N(R^6p1)(R^6p2), =O, -OH, -SR^6p1, -S(O)R^6p1, -S(NR^6p1)(NR^6p2)R^6p3, -S(O)(NR^6p1)(R^6p2), - S(O)₂R^6p1, -S(O)₂N(R^6p1)(R^6p2), or -N(R^6p1)S(O)₂(R^6p2); wherein each R^6p1, R^6p2, and R^6p3 is independently hydrogen, C_1-6 alkyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_2-6 alkoxyalkyl, C_1-6 haloalkyl, C_3-10 cycloalkyl, C_1-6 alkyl-C_3-10 cycloalkyl, C_6-10 aryl, C_1-6 alkyl-C_6-10 aryl, heterocycloalkyl, C_1-6 alkyl-(heterocycloalkyl), heteroaryl, or C_1-6 alkyl-(heteroaryl). In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein each R^6p is independently C_1-6 alkyl, C_1-6 hydroxyalkyl, C_1-6 alkoxy, C_2-6 alkoxyalkyl, halogen, C_1-6 haloalkyl, -CN, -C(O)R^6p1, -C(O)OR^6p1, - OC(O)R^6p1, -C(O)N(R^6p1)(R^6p2), -N(R^6p1)C(O)R^6p2, -OC(O)N(R^6p1)(R^6p2), -N(R^6p1)C(O)OR^6p2, - N(R^6p1)(R^6p2), =O, -OH, -SR^6p1, -S(O)R^6p1, -S(O)₂R^6p1, -S(O)₂N(R^6p1)(R^6p2), or - N(R^6p1)S(O)₂(R^6p2); wherein each R^6p1 and R^6p2 is independently hydrogen or C_1-6 alkyl.

0138In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein each R^6p is independently Me, Et, iPr, F, Cl, CH₂F, CHF₂, CF₃, CF₂CH₃, CH₂CF₃, =O, or OH.

0139In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein each R^6p is independently Me, Cl, CF₃, =O, or OH.

0140In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein each R^6a is independently <chemistry id="chem0068" num="0068"><img file="EP4445902A2_D0068.tif" /></chemistry><chemistry id="chem0069" num="0069"><img file="EP4445902A2_D0069.tif" /></chemistry><chemistry id="chem0070" num="0070"><img file="EP4445902A2_D0070.tif" /></chemistry><chemistry id="chem0071" num="0071"><img file="EP4445902A2_D0071.tif" /></chemistry><chemistry id="chem0072" num="0072"><img file="EP4445902A2_D0072.tif" /></chemistry><chemistry id="chem0073" num="0073"><img file="EP4445902A2_D0073.tif" /></chemistry><chemistry id="chem0074" num="0074"><img file="EP4445902A2_D0074.tif" /></chemistry><chemistry id="chem0075" num="0075"><img file="EP4445902A2_D0075.tif" /></chemistry><chemistry id="chem0076" num="0076"><img file="EP4445902A2_D0076.tif" /></chemistry><chemistry id="chem0077" num="0077"><img file="EP4445902A2_D0077.tif" /></chemistry><chemistry id="chem0078" num="0078"><img file="EP4445902A2_D0078.tif" /></chemistry><chemistry id="chem0079" num="0079"><img file="EP4445902A2_D0079.tif" /></chemistry><chemistry id="chem0080" num="0080"><img file="EP4445902A2_D0080.tif" /></chemistry><chemistry id="chem0081" num="0081"><img file="EP4445902A2_D0081.tif" /></chemistry><chemistry id="chem0082" num="0082"><img file="EP4445902A2_D0082.tif" /></chemistry><chemistry id="chem0083" num="0083"><img file="EP4445902A2_D0083.tif" /></chemistry><chemistry id="chem0084" num="0084"><img file="EP4445902A2_D0084.tif" /></chemistry><chemistry id="chem0085" num="0085"><img file="EP4445902A2_D0085.tif" /></chemistry><chemistry id="chem0086" num="0086"><img file="EP4445902A2_D0086.tif" /></chemistry><chemistry id="chem0087" num="0087"><img file="EP4445902A2_D0087.tif" /></chemistry><chemistry id="chem0088" num="0088"><img file="EP4445902A2_D0088.tif" /></chemistry><chemistry id="chem0089" num="0089"><img file="EP4445902A2_D0089.tif" /></chemistry><chemistry id="chem0090" num="0090"><img file="EP4445902A2_D0090.tif" /></chemistry><chemistry id="chem0091" num="0091"><img file="EP4445902A2_D0091.tif" /></chemistry><chemistry id="chem0092" num="0092"><img file="EP4445902A2_D0092.tif" /></chemistry><chemistry id="chem0093" num="0093"><img file="EP4445902A2_D0093.tif" /></chemistry><chemistry id="chem0094" num="0094"><img file="EP4445902A2_D0094.tif" /></chemistry><chemistry id="chem0095" num="0095"><img file="EP4445902A2_D0095.tif" /></chemistry><chemistry id="chem0096" num="0096"><img file="EP4445902A2_D0096.tif" /></chemistry><chemistry id="chem0097" num="0097"><img file="EP4445902A2_D0097.tif" /></chemistry><chemistry id="chem0098" num="0098"><img file="EP4445902A2_D0098.tif" /></chemistry><chemistry id="chem0099" num="0099"><img file="EP4445902A2_D0099.tif" /></chemistry><chemistry id="chem0100" num="0100"><img file="EP4445902A2_D0100.tif" /></chemistry><chemistry id="chem0101" num="0101"><img file="EP4445902A2_D0101.tif" /></chemistry><chemistry id="chem0102" num="0102"><img file="EP4445902A2_D0102.tif" /></chemistry><chemistry id="chem0103" num="0103"><img file="EP4445902A2_D0103.tif" /></chemistry><chemistry id="chem0104" num="0104"><img file="EP4445902A2_D0104.tif" /></chemistry><chemistry id="chem0105" num="0105"><img file="EP4445902A2_D0105.tif" /></chemistry><chemistry id="chem0106" num="0106"><img file="EP4445902A2_D0106.tif" /></chemistry><chemistry id="chem0107" num="0107"><img file="EP4445902A2_D0107.tif" /></chemistry><chemistry id="chem0108" num="0108"><img file="EP4445902A2_D0108.tif" /></chemistry><chemistry id="chem0109" num="0109"><img file="EP4445902A2_D0109.tif" /></chemistry><chemistry id="chem0110" num="0110"><img file="EP4445902A2_D0110.tif" /></chemistry><chemistry id="chem0111" num="0111"><img file="EP4445902A2_D0111.tif" /></chemistry><chemistry id="chem0112" num="0112"><img file="EP4445902A2_D0112.tif" /></chemistry><chemistry id="chem0113" num="0113"><img file="EP4445902A2_D0113.tif" /></chemistry><chemistry id="chem0114" num="0114"><img file="EP4445902A2_D0114.tif" /></chemistry><chemistry id="chem0115" num="0115"><img file="EP4445902A2_D0115.tif" /></chemistry><chemistry id="chem0116" num="0116"><img file="EP4445902A2_D0116.tif" /></chemistry> or <chemistry id="chem0117" num="0117"><img file="EP4445902A2_D0117.tif" /></chemistry>

0141In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ia-1), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein each R^6a is independently <chemistry id="chem0118" num="0118"><img file="EP4445902A2_D0118.tif" /></chemistry><chemistry id="chem0119" num="0119"><img file="EP4445902A2_D0119.tif" /></chemistry><chemistry id="chem0120" num="0120"><img file="EP4445902A2_D0120.tif" /></chemistry><chemistry id="chem0121" num="0121"><img file="EP4445902A2_D0121.tif" /></chemistry><chemistry id="chem0122" num="0122"><img file="EP4445902A2_D0122.tif" /></chemistry><chemistry id="chem0123" num="0123"><img file="EP4445902A2_D0123.tif" /></chemistry><chemistry id="chem0124" num="0124"><img file="EP4445902A2_D0124.tif" /></chemistry><chemistry id="chem0125" num="0125"><img file="EP4445902A2_D0125.tif" /></chemistry><chemistry id="chem0126" num="0126"><img file="EP4445902A2_D0126.tif" /></chemistry><chemistry id="chem0127" num="0127"><img file="EP4445902A2_D0127.tif" /></chemistry><chemistry id="chem0128" num="0128"><img file="EP4445902A2_D0128.tif" /></chemistry><chemistry id="chem0129" num="0129"><img file="EP4445902A2_D0129.tif" /></chemistry><chemistry id="chem0130" num="0130"><img file="EP4445902A2_D0130.tif" /></chemistry><chemistry id="chem0131" num="0131"><img file="EP4445902A2_D0131.tif" /></chemistry><chemistry id="chem0132" num="0132"><img file="EP4445902A2_D0132.tif" /></chemistry><chemistry id="chem0133" num="0133"><img file="EP4445902A2_D0133.tif" /></chemistry><chemistry id="chem0134" num="0134"><img file="EP4445902A2_D0134.tif" /></chemistry><chemistry id="chem0135" num="0135"><img file="EP4445902A2_D0135.tif" /></chemistry><chemistry id="chem0136" num="0136"><img file="EP4445902A2_D0136.tif" /></chemistry><chemistry id="chem0137" num="0137"><img file="EP4445902A2_D0137.tif" /></chemistry><chemistry id="chem0138" num="0138"><img file="EP4445902A2_D0138.tif" /></chemistry><chemistry id="chem0139" num="0139"><img file="EP4445902A2_D0139.tif" /></chemistry><chemistry id="chem0140" num="0140"><img file="EP4445902A2_D0140.tif" /></chemistry><chemistry id="chem0141" num="0141"><img file="EP4445902A2_D0141.tif" /></chemistry><chemistry id="chem0142" num="0142"><img file="EP4445902A2_D0142.tif" /></chemistry><chemistry id="chem0143" num="0143"><img file="EP4445902A2_D0143.tif" /></chemistry><chemistry id="chem0144" num="0144"><img file="EP4445902A2_D0144.tif" /></chemistry><chemistry id="chem0145" num="0145"><img file="EP4445902A2_D0145.tif" /></chemistry><chemistry id="chem0146" num="0146"><img file="EP4445902A2_D0146.tif" /></chemistry><chemistry id="chem0147" num="0147"><img file="EP4445902A2_D0147.tif" /></chemistry><chemistry id="chem0148" num="0148"><img file="EP4445902A2_D0148.tif" /></chemistry><chemistry id="chem0149" num="0149"><img file="EP4445902A2_D0149.tif" /></chemistry><chemistry id="chem0150" num="0150"><img file="EP4445902A2_D0150.tif" /></chemistry><chemistry id="chem0151" num="0151"><img file="EP4445902A2_D0151.tif" /></chemistry><chemistry id="chem0152" num="0152"><img file="EP4445902A2_D0152.tif" /></chemistry><chemistry id="chem0153" num="0153"><img file="EP4445902A2_D0153.tif" /></chemistry><chemistry id="chem0154" num="0154"><img file="EP4445902A2_D0154.tif" /></chemistry><chemistry id="chem0155" num="0155"><img file="EP4445902A2_D0155.tif" /></chemistry><chemistry id="chem0156" num="0156"><img file="EP4445902A2_D0156.tif" /></chemistry><chemistry id="chem0157" num="0157"><img file="EP4445902A2_D0157.tif" /></chemistry><chemistry id="chem0158" num="0158"><img file="EP4445902A2_D0158.tif" /></chemistry><chemistry id="chem0159" num="0159"><img file="EP4445902A2_D0159.tif" /></chemistry><chemistry id="chem0160" num="0160"><img file="EP4445902A2_D0160.tif" /></chemistry><chemistry id="chem0161" num="0161"><img file="EP4445902A2_D0161.tif" /></chemistry><chemistry id="chem0162" num="0162"><img file="EP4445902A2_D0162.tif" /></chemistry>

0142In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ia-1), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8),or a pharmaceutically acceptable salt thereof, is the compound wherein each R^6a is independently Me, Et, -C<img file="EP4445902A2_D0163.tif" /> CMe, - OMe, -CH₂OH, -CH₂OMe, -CH₂OSi(Me)₂(tBu), F, Cl, Br, I, -CH₂F, -CF₃, -OCF₃, -CN, -NO₂, - C(O)H, -COOH, -COOMe, -CONH₂, -NH₂, -OH, cyclopropyl, cyclohexyl, phenyl, <chemistry id="chem0163" num="0163"><img file="EP4445902A2_D0164.tif" /></chemistry><chemistry id="chem0164" num="0164"><img file="EP4445902A2_D0165.tif" /></chemistry><chemistry id="chem0165" num="0165"><img file="EP4445902A2_D0166.tif" /></chemistry><chemistry id="chem0166" num="0166"><img file="EP4445902A2_D0167.tif" /></chemistry>

0143In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ia-1), (Ib), (IIa), or (IIa-1), or a pharmaceutically acceptable salt thereof, is the compound wherein R⁵ is C_1-6 alkyl, C_2-6 alkynyl, C_2-6 alkoxyalkyl, C_1-6 alkyl-C_3-8 cycloalkyl, phenyl, C_1-6 alkyl-phenyl, or C_1-6 alkyl-(heterocycloalkyl); R⁶ is phenyl, optionally substituted with 1 or 2 R^6a; each R^6a is independently C_1-6 alkyl, C_2-6 alkynyl, C_1-6 hydroxyalkyl, C_1-6 alkoxy, C_2-6 alkoxyalkyl, halogen, C_1-6 haloalkyl, C_1-6 haloalkoxy, -CN, -NOz, -C(O)R^6b, -C(O)OR^6b, -C(O)N(R^6b)(R^6c), -N(R^6b)(R^6c), -OR^6b, or phenyl, wherein the phenyl is optionally substituted with 1 or 2 R^6e; R^6b and R^6c are each independently hydrogen or C_1-6 alkyl; each R^6e is independently C_1-6 alkyl, halogen, C_1-6 haloalkyl, -N(R^6e1)C(O)R^6e2, or -OR^6e1; each R^6e1 and R^6e2 is independently hydrogen or C_1-6 alkyl; and the heterocycloalkyl is a 5 or 6 membered ring having 1 heteroatom N or O. In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ia-1), (Ib), (IIa), or (IIa-1), or a pharmaceutically acceptable salt thereof, is the compound wherein R⁵ is C_1-6 alkyl, C_2-6 alkynyl, C_2-3 alkoxyalkyl, C_1-3 alkyl-C_3-8 cycloalkyl, phenyl, C_1-3 alkyl-phenyl, or C_1-3 alkyl-(heterocycloalkyl); R⁶ is phenyl, optionally substituted with R^6a; R^6a is independently C_1-3 alkyl, C_2-3 alkynyl, C_1-3 hydroxyalkyl, C_1-3 alkoxy, C_2-3 alkoxyalkyl, halogen, C_1-3 haloalkyl, C_1-3 haloalkoxy, -CN, -NOz, -C(O)R^6b, -C(O)OR^6b, -C(O)N(R^6b)(R^6c), -N(R^6b)(R^6c), -OH, or phenyl, wherein the phenyl is optionally substituted with R^6e; R^6b and R^6c are each independently hydrogen or C_1-3 alkyl; R^6e is C_1-6 alkyl, halogen, C_1-3 haloalkyl, -N(R^6e1)C(O)R^6e2, or -OR^6e1, R^6e1 and R^6e2 is independently hydrogen or C_1-3 alkyl; and the heterocycloalkyl is a 6 membered ring having 1 heteroatom N or O.

0144In some embodiments, the compound of Formula (I), (I-1), or (Ia), or a pharmaceutically acceptable salt thereof, is a compound that has the structure of Formula (Ib): <chemistry id="chem0167" num="0167"><img file="EP4445902A2_D0168.tif" /></chemistry> wherein m is 0, 1, 2, or 3. In some embodiments, the compound of Formula (I), (I-1), or (Ia), or a pharmaceutically acceptable salt thereof, is a compound wherein m is 0. In some embodiments, the compound of Formula (I), (I-1), or (Ia), or a pharmaceutically acceptable salt thereof, is a compound wherein m is 1. In some embodiments, the compound of Formula (I), (I-1), or (Ia), or a pharmaceutically acceptable salt thereof, is a compound wherein m is 2. In some embodiments, the compound of Formula (I), (I-1), or (Ia), or a pharmaceutically acceptable salt thereof, is a compound wherein m is 3.

0145In some embodiments, the compound of Formula (I) or (I-1), or a pharmaceutically acceptable salt thereof, is the compound wherein R⁶ is <chemistry id="chem0168" num="0168"><img file="EP4445902A2_D0169.tif" /></chemistry><chemistry id="chem0169" num="0169"><img file="EP4445902A2_D0170.tif" /></chemistry><chemistry id="chem0170" num="0170"><img file="EP4445902A2_D0171.tif" /></chemistry><chemistry id="chem0171" num="0171"><img file="EP4445902A2_D0172.tif" /></chemistry><chemistry id="chem0172" num="0172"><img file="EP4445902A2_D0173.tif" /></chemistry><chemistry id="chem0173" num="0173"><img file="EP4445902A2_D0174.tif" /></chemistry><chemistry id="chem0174" num="0174"><img file="EP4445902A2_D0175.tif" /></chemistry><chemistry id="chem0175" num="0175"><img file="EP4445902A2_D0176.tif" /></chemistry><chemistry id="chem0176" num="0176"><img file="EP4445902A2_D0177.tif" /></chemistry><chemistry id="chem0177" num="0177"><img file="EP4445902A2_D0178.tif" /></chemistry><chemistry id="chem0178" num="0178"><img file="EP4445902A2_D0179.tif" /></chemistry><chemistry id="chem0179" num="0179"><img file="EP4445902A2_D0180.tif" /></chemistry><chemistry id="chem0180" num="0180"><img file="EP4445902A2_D0181.tif" /></chemistry><chemistry id="chem0181" num="0181"><img file="EP4445902A2_D0182.tif" /></chemistry><chemistry id="chem0182" num="0182"><img file="EP4445902A2_D0183.tif" /></chemistry><chemistry id="chem0183" num="0183"><img file="EP4445902A2_D0184.tif" /></chemistry><chemistry id="chem0184" num="0184"><img file="EP4445902A2_D0185.tif" /></chemistry><chemistry id="chem0185" num="0185"><img file="EP4445902A2_D0186.tif" /></chemistry><chemistry id="chem0186" num="0186"><img file="EP4445902A2_D0187.tif" /></chemistry><chemistry id="chem0187" num="0187"><img file="EP4445902A2_D0188.tif" /></chemistry><chemistry id="chem0188" num="0188"><img file="EP4445902A2_D0189.tif" /></chemistry><chemistry id="chem0189" num="0189"><img file="EP4445902A2_D0190.tif" /></chemistry><chemistry id="chem0190" num="0190"><img file="EP4445902A2_D0191.tif" /></chemistry><chemistry id="chem0191" num="0191"><img file="EP4445902A2_D0192.tif" /></chemistry><chemistry id="chem0192" num="0192"><img file="EP4445902A2_D0193.tif" /></chemistry><chemistry id="chem0193" num="0193"><img file="EP4445902A2_D0194.tif" /></chemistry><chemistry id="chem0194" num="0194"><img file="EP4445902A2_D0195.tif" /></chemistry><chemistry id="chem0195" num="0195"><img file="EP4445902A2_D0196.tif" /></chemistry><chemistry id="chem0196" num="0196"><img file="EP4445902A2_D0197.tif" /></chemistry><chemistry id="chem0197" num="0197"><img file="EP4445902A2_D0198.tif" /></chemistry><chemistry id="chem0198" num="0198"><img file="EP4445902A2_D0199.tif" /></chemistry><chemistry id="chem0199" num="0199"><img file="EP4445902A2_D0200.tif" /></chemistry><chemistry id="chem0200" num="0200"><img file="EP4445902A2_D0201.tif" /></chemistry><chemistry id="chem0201" num="0201"><img file="EP4445902A2_D0202.tif" /></chemistry><chemistry id="chem0202" num="0202"><img file="EP4445902A2_D0203.tif" /></chemistry><chemistry id="chem0203" num="0203"><img file="EP4445902A2_D0204.tif" /></chemistry><chemistry id="chem0204" num="0204"><img file="EP4445902A2_D0205.tif" /></chemistry><chemistry id="chem0205" num="0205"><img file="EP4445902A2_D0206.tif" /></chemistry><chemistry id="chem0206" num="0206"><img file="EP4445902A2_D0207.tif" /></chemistry><chemistry id="chem0207" num="0207"><img file="EP4445902A2_D0208.tif" /></chemistry><chemistry id="chem0208" num="0208"><img file="EP4445902A2_D0209.tif" /></chemistry><chemistry id="chem0209" num="0209"><img file="EP4445902A2_D0210.tif" /></chemistry><chemistry id="chem0210" num="0210"><img file="EP4445902A2_D0211.tif" /></chemistry><chemistry id="chem0211" num="0211"><img file="EP4445902A2_D0212.tif" /></chemistry><chemistry id="chem0212" num="0212"><img file="EP4445902A2_D0213.tif" /></chemistry><chemistry id="chem0213" num="0213"><img file="EP4445902A2_D0214.tif" /></chemistry><chemistry id="chem0214" num="0214"><img file="EP4445902A2_D0215.tif" /></chemistry><chemistry id="chem0215" num="0215"><img file="EP4445902A2_D0216.tif" /></chemistry><chemistry id="chem0216" num="0216"><img file="EP4445902A2_D0217.tif" /></chemistry><chemistry id="chem0217" num="0217"><img file="EP4445902A2_D0218.tif" /></chemistry><chemistry id="chem0218" num="0218"><img file="EP4445902A2_D0219.tif" /></chemistry><chemistry id="chem0219" num="0219"><img file="EP4445902A2_D0220.tif" /></chemistry><chemistry id="chem0220" num="0220"><img file="EP4445902A2_D0221.tif" /></chemistry><chemistry id="chem0221" num="0221"><img file="EP4445902A2_D0222.tif" /></chemistry><chemistry id="chem0222" num="0222"><img file="EP4445902A2_D0223.tif" /></chemistry><chemistry id="chem0223" num="0223"><img file="EP4445902A2_D0224.tif" /></chemistry><chemistry id="chem0224" num="0224"><img file="EP4445902A2_D0225.tif" /></chemistry><chemistry id="chem0225" num="0225"><img file="EP4445902A2_D0226.tif" /></chemistry><chemistry id="chem0226" num="0226"><img file="EP4445902A2_D0227.tif" /></chemistry><chemistry id="chem0227" num="0227"><img file="EP4445902A2_D0228.tif" /></chemistry><chemistry id="chem0228" num="0228"><img file="EP4445902A2_D0229.tif" /></chemistry><chemistry id="chem0229" num="0229"><img file="EP4445902A2_D0230.tif" /></chemistry><chemistry id="chem0230" num="0230"><img file="EP4445902A2_D0231.tif" /></chemistry><chemistry id="chem0231" num="0231"><img file="EP4445902A2_D0232.tif" /></chemistry><chemistry id="chem0232" num="0232"><img file="EP4445902A2_D0233.tif" /></chemistry><chemistry id="chem0233" num="0233"><img file="EP4445902A2_D0234.tif" /></chemistry><chemistry id="chem0234" num="0234"><img file="EP4445902A2_D0235.tif" /></chemistry><chemistry id="chem0235" num="0235"><img file="EP4445902A2_D0236.tif" /></chemistry><chemistry id="chem0236" num="0236"><img file="EP4445902A2_D0237.tif" /></chemistry><chemistry id="chem0237" num="0237"><img file="EP4445902A2_D0238.tif" /></chemistry><chemistry id="chem0238" num="0238"><img file="EP4445902A2_D0239.tif" /></chemistry><chemistry id="chem0239" num="0239"><img file="EP4445902A2_D0240.tif" /></chemistry><chemistry id="chem0240" num="0240"><img file="EP4445902A2_D0241.tif" /></chemistry><chemistry id="chem0241" num="0241"><img file="EP4445902A2_D0242.tif" /></chemistry><chemistry id="chem0242" num="0242"><img file="EP4445902A2_D0243.tif" /></chemistry><chemistry id="chem0243" num="0243"><img file="EP4445902A2_D0244.tif" /></chemistry><chemistry id="chem0244" num="0244"><img file="EP4445902A2_D0245.tif" /></chemistry><chemistry id="chem0245" num="0245"><img file="EP4445902A2_D0246.tif" /></chemistry><chemistry id="chem0246" num="0246"><img file="EP4445902A2_D0247.tif" /></chemistry><chemistry id="chem0247" num="0247"><img file="EP4445902A2_D0248.tif" /></chemistry><chemistry id="chem0248" num="0248"><img file="EP4445902A2_D0249.tif" /></chemistry><chemistry id="chem0249" num="0249"><img file="EP4445902A2_D0250.tif" /></chemistry><chemistry id="chem0250" num="0250"><img file="EP4445902A2_D0251.tif" /></chemistry><chemistry id="chem0251" num="0251"><img file="EP4445902A2_D0252.tif" /></chemistry><chemistry id="chem0252" num="0252"><img file="EP4445902A2_D0253.tif" /></chemistry><chemistry id="chem0253" num="0253"><img file="EP4445902A2_D0254.tif" /></chemistry><chemistry id="chem0254" num="0254"><img file="EP4445902A2_D0255.tif" /></chemistry><chemistry id="chem0255" num="0255"><img file="EP4445902A2_D0256.tif" /></chemistry><chemistry id="chem0256" num="0256"><img file="EP4445902A2_D0257.tif" /></chemistry><chemistry id="chem0257" num="0257"><img file="EP4445902A2_D0258.tif" /></chemistry><chemistry id="chem0258" num="0258"><img file="EP4445902A2_D0259.tif" /></chemistry> or <chemistry id="chem0259" num="0259"><img file="EP4445902A2_D0260.tif" /></chemistry>

0146In some embodiments, the compound of Formula (I) or (I-1), or a pharmaceutically acceptable salt thereof, is the compound wherein R⁶ is <chemistry id="chem0260" num="0260"><img file="EP4445902A2_D0261.tif" /></chemistry><chemistry id="chem0261" num="0261"><img file="EP4445902A2_D0262.tif" /></chemistry><chemistry id="chem0262" num="0262"><img file="EP4445902A2_D0263.tif" /></chemistry><chemistry id="chem0263" num="0263"><img file="EP4445902A2_D0264.tif" /></chemistry><chemistry id="chem0264" num="0264"><img file="EP4445902A2_D0265.tif" /></chemistry><chemistry id="chem0265" num="0265"><img file="EP4445902A2_D0266.tif" /></chemistry><chemistry id="chem0266" num="0266"><img file="EP4445902A2_D0267.tif" /></chemistry><chemistry id="chem0267" num="0267"><img file="EP4445902A2_D0268.tif" /></chemistry><chemistry id="chem0268" num="0268"><img file="EP4445902A2_D0269.tif" /></chemistry><chemistry id="chem0269" num="0269"><img file="EP4445902A2_D0270.tif" /></chemistry><chemistry id="chem0270" num="0270"><img file="EP4445902A2_D0271.tif" /></chemistry><chemistry id="chem0271" num="0271"><img file="EP4445902A2_D0272.tif" /></chemistry><chemistry id="chem0272" num="0272"><img file="EP4445902A2_D0273.tif" /></chemistry><chemistry id="chem0273" num="0273"><img file="EP4445902A2_D0274.tif" /></chemistry><chemistry id="chem0274" num="0274"><img file="EP4445902A2_D0275.tif" /></chemistry><chemistry id="chem0275" num="0275"><img file="EP4445902A2_D0276.tif" /></chemistry><chemistry id="chem0276" num="0276"><img file="EP4445902A2_D0277.tif" /></chemistry><chemistry id="chem0277" num="0277"><img file="EP4445902A2_D0278.tif" /></chemistry><chemistry id="chem0278" num="0278"><img file="EP4445902A2_D0279.tif" /></chemistry><chemistry id="chem0279" num="0279"><img file="EP4445902A2_D0280.tif" /></chemistry><chemistry id="chem0280" num="0280"><img file="EP4445902A2_D0281.tif" /></chemistry><chemistry id="chem0281" num="0281"><img file="EP4445902A2_D0282.tif" /></chemistry><chemistry id="chem0282" num="0282"><img file="EP4445902A2_D0283.tif" /></chemistry><chemistry id="chem0283" num="0283"><img file="EP4445902A2_D0284.tif" /></chemistry><chemistry id="chem0284" num="0284"><img file="EP4445902A2_D0285.tif" /></chemistry><chemistry id="chem0285" num="0285"><img file="EP4445902A2_D0286.tif" /></chemistry><chemistry id="chem0286" num="0286"><img file="EP4445902A2_D0287.tif" /></chemistry><chemistry id="chem0287" num="0287"><img file="EP4445902A2_D0288.tif" /></chemistry><chemistry id="chem0288" num="0288"><img file="EP4445902A2_D0289.tif" /></chemistry><chemistry id="chem0289" num="0289"><img file="EP4445902A2_D0290.tif" /></chemistry><chemistry id="chem0290" num="0290"><img file="EP4445902A2_D0291.tif" /></chemistry><chemistry id="chem0291" num="0291"><img file="EP4445902A2_D0292.tif" /></chemistry><chemistry id="chem0292" num="0292"><img file="EP4445902A2_D0293.tif" /></chemistry><chemistry id="chem0293" num="0293"><img file="EP4445902A2_D0294.tif" /></chemistry><chemistry id="chem0294" num="0294"><img file="EP4445902A2_D0295.tif" /></chemistry><chemistry id="chem0295" num="0295"><img file="EP4445902A2_D0296.tif" /></chemistry><chemistry id="chem0296" num="0296"><img file="EP4445902A2_D0297.tif" /></chemistry><chemistry id="chem0297" num="0297"><img file="EP4445902A2_D0298.tif" /></chemistry><chemistry id="chem0298" num="0298"><img file="EP4445902A2_D0299.tif" /></chemistry><chemistry id="chem0299" num="0299"><img file="EP4445902A2_D0300.tif" /></chemistry><chemistry id="chem0300" num="0300"><img file="EP4445902A2_D0301.tif" /></chemistry><chemistry id="chem0301" num="0301"><img file="EP4445902A2_D0302.tif" /></chemistry><chemistry id="chem0302" num="0302"><img file="EP4445902A2_D0303.tif" /></chemistry><chemistry id="chem0303" num="0303"><img file="EP4445902A2_D0304.tif" /></chemistry><chemistry id="chem0304" num="0304"><img file="EP4445902A2_D0305.tif" /></chemistry><chemistry id="chem0305" num="0305"><img file="EP4445902A2_D0306.tif" /></chemistry><chemistry id="chem0306" num="0306"><img file="EP4445902A2_D0307.tif" /></chemistry><chemistry id="chem0307" num="0307"><img file="EP4445902A2_D0308.tif" /></chemistry><chemistry id="chem0308" num="0308"><img file="EP4445902A2_D0309.tif" /></chemistry><chemistry id="chem0309" num="0309"><img file="EP4445902A2_D0310.tif" /></chemistry><chemistry id="chem0310" num="0310"><img file="EP4445902A2_D0311.tif" /></chemistry><chemistry id="chem0311" num="0311"><img file="EP4445902A2_D0312.tif" /></chemistry><chemistry id="chem0312" num="0312"><img file="EP4445902A2_D0313.tif" /></chemistry><chemistry id="chem0313" num="0313"><img file="EP4445902A2_D0314.tif" /></chemistry><chemistry id="chem0314" num="0314"><img file="EP4445902A2_D0315.tif" /></chemistry><chemistry id="chem0315" num="0315"><img file="EP4445902A2_D0316.tif" /></chemistry><chemistry id="chem0316" num="0316"><img file="EP4445902A2_D0317.tif" /></chemistry><chemistry id="chem0317" num="0317"><img file="EP4445902A2_D0318.tif" /></chemistry><chemistry id="chem0318" num="0318"><img file="EP4445902A2_D0319.tif" /></chemistry><chemistry id="chem0319" num="0319"><img file="EP4445902A2_D0320.tif" /></chemistry><chemistry id="chem0320" num="0320"><img file="EP4445902A2_D0321.tif" /></chemistry><chemistry id="chem0321" num="0321"><img file="EP4445902A2_D0322.tif" /></chemistry><chemistry id="chem0322" num="0322"><img file="EP4445902A2_D0323.tif" /></chemistry><chemistry id="chem0323" num="0323"><img file="EP4445902A2_D0324.tif" /></chemistry><chemistry id="chem0324" num="0324"><img file="EP4445902A2_D0325.tif" /></chemistry><chemistry id="chem0325" num="0325"><img file="EP4445902A2_D0326.tif" /></chemistry><chemistry id="chem0326" num="0326"><img file="EP4445902A2_D0327.tif" /></chemistry><chemistry id="chem0327" num="0327"><img file="EP4445902A2_D0328.tif" /></chemistry><chemistry id="chem0328" num="0328"><img file="EP4445902A2_D0329.tif" /></chemistry><chemistry id="chem0329" num="0329"><img file="EP4445902A2_D0330.tif" /></chemistry><chemistry id="chem0330" num="0330"><img file="EP4445902A2_D0331.tif" /></chemistry><chemistry id="chem0331" num="0331"><img file="EP4445902A2_D0332.tif" /></chemistry><chemistry id="chem0332" num="0332"><img file="EP4445902A2_D0333.tif" /></chemistry><chemistry id="chem0333" num="0333"><img file="EP4445902A2_D0334.tif" /></chemistry><chemistry id="chem0334" num="0334"><img file="EP4445902A2_D0335.tif" /></chemistry><chemistry id="chem0335" num="0335"><img file="EP4445902A2_D0336.tif" /></chemistry><chemistry id="chem0336" num="0336"><img file="EP4445902A2_D0337.tif" /></chemistry><chemistry id="chem0337" num="0337"><img file="EP4445902A2_D0338.tif" /></chemistry><chemistry id="chem0338" num="0338"><img file="EP4445902A2_D0339.tif" /></chemistry><chemistry id="chem0339" num="0339"><img file="EP4445902A2_D0340.tif" /></chemistry><chemistry id="chem0340" num="0340"><img file="EP4445902A2_D0341.tif" /></chemistry><chemistry id="chem0341" num="0341"><img file="EP4445902A2_D0342.tif" /></chemistry>

0147In some embodiments, the compound of Formula (I) or (I-1), or a pharmaceutically acceptable salt thereof, is the compound wherein R⁶ is <chemistry id="chem0342" num="0342"><img file="EP4445902A2_D0343.tif" /></chemistry><chemistry id="chem0343" num="0343"><img file="EP4445902A2_D0344.tif" /></chemistry><chemistry id="chem0344" num="0344"><img file="EP4445902A2_D0345.tif" /></chemistry><chemistry id="chem0345" num="0345"><img file="EP4445902A2_D0346.tif" /></chemistry><chemistry id="chem0346" num="0346"><img file="EP4445902A2_D0347.tif" /></chemistry><chemistry id="chem0347" num="0347"><img file="EP4445902A2_D0348.tif" /></chemistry><chemistry id="chem0348" num="0348"><img file="EP4445902A2_D0349.tif" /></chemistry><chemistry id="chem0349" num="0349"><img file="EP4445902A2_D0350.tif" /></chemistry><chemistry id="chem0350" num="0350"><img file="EP4445902A2_D0351.tif" /></chemistry><chemistry id="chem0351" num="0351"><img file="EP4445902A2_D0352.tif" /></chemistry><chemistry id="chem0352" num="0352"><img file="EP4445902A2_D0353.tif" /></chemistry><chemistry id="chem0353" num="0353"><img file="EP4445902A2_D0354.tif" /></chemistry><chemistry id="chem0354" num="0354"><img file="EP4445902A2_D0355.tif" /></chemistry>

0148In some embodiments, the compound of Formula (I) or (I-1), or a pharmaceutically acceptable salt thereof, is a compound wherein R⁵ and R⁶, together with the nitrogen to which they are bound, have a structure: <chemistry id="chem0355" num="0355"><img file="EP4445902A2_D0356.tif" /></chemistry><chemistry id="chem0356" num="0356"><img file="EP4445902A2_D0357.tif" /></chemistry><chemistry id="chem0357" num="0357"><img file="EP4445902A2_D0358.tif" /></chemistry><chemistry id="chem0358" num="0358"><img file="EP4445902A2_D0359.tif" /></chemistry><chemistry id="chem0359" num="0359"><img file="EP4445902A2_D0360.tif" /></chemistry><chemistry id="chem0360" num="0360"><img file="EP4445902A2_D0361.tif" /></chemistry><chemistry id="chem0361" num="0361"><img file="EP4445902A2_D0362.tif" /></chemistry><chemistry id="chem0362" num="0362"><img file="EP4445902A2_D0363.tif" /></chemistry><chemistry id="chem0363" num="0363"><img file="EP4445902A2_D0364.tif" /></chemistry><chemistry id="chem0364" num="0364"><img file="EP4445902A2_D0365.tif" /></chemistry><chemistry id="chem0365" num="0365"><img file="EP4445902A2_D0366.tif" /></chemistry>

0149In some embodiments, the compound of Formula (I) or (I-1), or a pharmaceutically acceptable salt thereof, is a compound that has the structure of Formula (Ic): <chemistry id="chem0366" num="0366"><img file="EP4445902A2_D0367.tif" /></chemistry> wherein Ring A is a 5 to 8 membered heterocycloalkyl optionally having 1 to 2 additional heteroatoms each independently N, O, or S, and optionally wherein Ring A is substituted with 1 or 2 R^6g; and n is 0, 1, or 2. In some embodiments, the compound of Formula (Ic), or a pharmaceutically acceptable salt thereof, is a compound wherein Ring A is a 5 to 8 membered heterocycloalkyl optionally having 1 to 2 additional heteroatoms each independently N, O, or S; and n is 0, 1, or 2. In some embodiments, the compound of Formula (Ic), or a pharmaceutically acceptable salt thereof, is a compound wherein n is 0. In some embodiments, the compound of Formula (Ic), or a pharmaceutically acceptable salt thereof, is a compound wherein n is 1. In some embodiments, the compound of Formula (Ic), or a pharmaceutically acceptable salt thereof, is a compound wherein n is 2. In some embodiments, the compound of Formula (Ic), or a pharmaceutically acceptable salt thereof, is a compound wherein Ring A is a 5 to 8 membered heterocycloalkyl. In some embodiments, the compound of Formula (Ic), or a pharmaceutically acceptable salt thereof, is a compound wherein Ring A is a 6 membered heterocycloalkyl having one additional heteroatom O.

0150In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound that has the structure of Formula (IIc): <chemistry id="chem0367" num="0367"><img file="EP4445902A2_D0368.tif" /></chemistry> wherein Ring A is a 5 to 8 membered heterocycloalkyl optionally having 1 to 2 additional heteroatoms each independently N, O, or S, and optionally wherein Ring A is substituted with 1 or 2 R^6g; and n is 0, 1, or 2. In some embodiments, the compound of Formula (IIc), or a pharmaceutically acceptable salt thereof, is a compound wherein Ring A is a 5 to 8 membered heterocycloalkyl optionally having 1 to 2 additional heteroatoms each independently N, O, or S; and n is 0, 1, or 2. In some embodiments, the compound of Formula (IIc), or a pharmaceutically acceptable salt thereof, is a compound wherein n is 0. In some embodiments, the compound of Formula (IIc), or a pharmaceutically acceptable salt thereof, is a compound wherein n is 1. In some embodiments, the compound of Formula (IIc), or a pharmaceutically acceptable salt thereof, is a compound wherein n is 2. In some embodiments, the compound of Formula (IIc), or a pharmaceutically acceptable salt thereof, is a compound wherein Ring A is a 5 to 8 membered heterocycloalkyl. In some embodiments, the compound of Formula (IIc), or a pharmaceutically acceptable salt thereof, is a compound wherein Ring A is a 6 membered heterocycloalkyl having one additional heteroatom O.

0151In some embodiments, the compound of Formula (Ic) (IIc), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein R¹ is hydrogen or halogen. In some embodiments, the compound of Formula (Ic) (IIc), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein R¹ is hydrogen or F.

0152In some embodiments, the compound of Formula (Ic) (IIc), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein R⁴ is hydrogen, C_1-3 alkyl, or halogen. In some embodiments, the compound of Formula (Ic) (IIc), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein R⁴ is hydrogen, Me, or F.

0153In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound that has the structure of Formula (IIc-1): <chemistry id="chem0368" num="0368"><img file="EP4445902A2_D0369.tif" /></chemistry> wherein Ring A is a 5 to 8 membered heterocycloalkyl optionally having 1 to 2 additional heteroatoms each independently N, O, or S, and optionally wherein Ring A is substituted with 1 or 2 R^6g; and n is 0, 1, or 2. In some embodiments, the compound of Formula (IIc-1), or a pharmaceutically acceptable salt thereof, is a compound wherein Ring A is a 5 to 8 membered heterocycloalkyl optionally having 1 to 2 additional heteroatoms each independently N, O, or S; and n is 0, 1, or 2. In some embodiments, the compound of Formula (IIc-1), or a pharmaceutically acceptable salt thereof, is a compound wherein n is 0. In some embodiments, the compound of Formula (IIc-1), or a pharmaceutically acceptable salt thereof, is a compound wherein n is 1. In some embodiments, the compound of Formula (IIc-1), or a pharmaceutically acceptable salt thereof, is a compound wherein n is 2. In some embodiments, the compound of Formula (IIc-1), or a pharmaceutically acceptable salt thereof, is a compound wherein Ring A is a 5 to 8 membered heterocycloalkyl. In some embodiments, the compound of Formula (IIc-1), or a pharmaceutically acceptable salt thereof, is a compound wherein Ring A is a 6 membered heterocycloalkyl having one additional heteroatom O.

0154In some embodiments, the compound of Formula (Ic), (IIc), or (IIc-1), or a pharmaceutically acceptable salt thereof, is a compound wherein <chemistry id="chem0369" num="0369"><img file="EP4445902A2_D0370.tif" /></chemistry> has the structure <chemistry id="chem0370" num="0370"><img file="EP4445902A2_D0371.tif" /></chemistry> or <chemistry id="chem0371" num="0371"><img file="EP4445902A2_D0372.tif" /></chemistry>

0155In some embodiments, the compound of Formula (I) or (Ic), or a pharmaceutically acceptable salt thereof, is a compound wherein each R^6g is independently C_1-6 alkyl, halogen, C_1-6 haloalkyl, or -CN. In some embodiments, the compound of Formula (I) or (Ic), or a pharmaceutically acceptable salt thereof, is a compound wherein each R^6g is independently C_1-6 alkyl or halogen. In some embodiments, the compound of Formula (I) or (Ic), or a pharmaceutically acceptable salt thereof, is a compound wherein each R^6g is independently methyl.

0156In some embodiments, the compound of Formula (Ic), (IIc), or (IIc-1), or a pharmaceutically acceptable salt thereof, is a compound wherein <chemistry id="chem0372" num="0372"><img file="EP4445902A2_D0373.tif" /></chemistry><chemistry id="chem0373" num="0373"><img file="EP4445902A2_D0374.tif" /></chemistry><chemistry id="chem0374" num="0374"><img file="EP4445902A2_D0375.tif" /></chemistry><chemistry id="chem0375" num="0375"><img file="EP4445902A2_D0376.tif" /></chemistry><chemistry id="chem0376" num="0376"><img file="EP4445902A2_D0377.tif" /></chemistry><chemistry id="chem0377" num="0377"><img file="EP4445902A2_D0378.tif" /></chemistry><chemistry id="chem0378" num="0378"><img file="EP4445902A2_D0379.tif" /></chemistry><chemistry id="chem0379" num="0379"><img file="EP4445902A2_D0380.tif" /></chemistry><chemistry id="chem0380" num="0380"><img file="EP4445902A2_D0381.tif" /></chemistry><chemistry id="chem0381" num="0381"><img file="EP4445902A2_D0382.tif" /></chemistry><chemistry id="chem0382" num="0382"><img file="EP4445902A2_D0383.tif" /></chemistry>

0157In some embodiments, the compound of Formula (Ic), (IIc), or (IIc-1), or a pharmaceutically acceptable salt thereof, is a compound wherein <chemistry id="chem0383" num="0383"><img file="EP4445902A2_D0384.tif" /></chemistry> has the structure <chemistry id="chem0384" num="0384"><img file="EP4445902A2_D0385.tif" /></chemistry><chemistry id="chem0385" num="0385"><img file="EP4445902A2_D0386.tif" /></chemistry><chemistry id="chem0386" num="0386"><img file="EP4445902A2_D0387.tif" /></chemistry>

0158In some embodiments, the compound of Formula (Ic), or a pharmaceutically acceptable salt thereof, is a compound in which <chemistry id="chem0387" num="0387"><img file="EP4445902A2_D0388.tif" /></chemistry> has the structure <chemistry id="chem0388" num="0388"><img file="EP4445902A2_D0389.tif" /></chemistry>

0159In some embodiments, the compound of Formula (Ic), (IIc), or (IIc-1), or a pharmaceutically acceptable salt thereof, is a compound wherein <chemistry id="chem0389" num="0389"><img file="EP4445902A2_D0390.tif" /></chemistry> has the structure <chemistry id="chem0390" num="0390"><img file="EP4445902A2_D0391.tif" /></chemistry> In some embodiments, the compound of Formula (Ic), (IIc), or (IIc-1), or a pharmaceutically acceptable salt thereof, is a compound wherein <chemistry id="chem0391" num="0391"><img file="EP4445902A2_D0392.tif" /></chemistry> has the structure <chemistry id="chem0392" num="0392"><img file="EP4445902A2_D0393.tif" /></chemistry> In some embodiments, the compound of Formula (Ic), (IIc), or (IIc-1), or a pharmaceutically acceptable salt thereof, is a compound wherein <chemistry id="chem0393" num="0393"><img file="EP4445902A2_D0394.tif" /></chemistry> has the structure <chemistry id="chem0394" num="0394"><img file="EP4445902A2_D0395.tif" /></chemistry>

0160In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound that has the structure of Formula (IIc-2): <chemistry id="chem0395" num="0395"><img file="EP4445902A2_D0396.tif" /></chemistry> wherein n is 0, 1, or 2.

0161In some embodiments, the compound of Formula (Ic), (IIc), or (IIc-1), or a pharmaceutically acceptable salt thereof, is a compound wherein <chemistry id="chem0396" num="0396"><img file="EP4445902A2_D0397.tif" /></chemistry> has the structure <chemistry id="chem0397" num="0397"><img file="EP4445902A2_D0398.tif" /></chemistry>

0162In some embodiments, the compound of Formula (I), (IIa), or (IIc), or a pharmaceutically acceptable salt thereof, is a compound that has the structure: <chemistry id="chem0398" num="0398"><img file="EP4445902A2_D0399.tif" /></chemistry><chemistry id="chem0399" num="0399"><img file="EP4445902A2_D0400.tif" /></chemistry><chemistry id="chem0400" num="0400"><img file="EP4445902A2_D0401.tif" /></chemistry>

0163In some embodiments, the compound of Formula (IIc) is the compound of Formula (IIc-3), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (IIc) is the compound of Formula (IIc-4), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (IIc) is the compound of Formula (IIc-5), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (IIc) is the compound of Formula (IIc-6), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (IIc) is the compound of Formula (IIc-7), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (IIc) is the compound of Formula (IIc-8), or a pharmaceutically acceptable salt thereof.

0164In some embodiments, the compound of Formula (I), (IIa), (IIa-1), (IIc), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is a compound wherein R¹ is hydrogen, C_1-3 alkyl, or halogen; R² is hydrogen, C_1-3 alkyl, C_1-3 hydroxyalkyl, C_2-3 alkoxyalkyl, halogen, or -CN; R³ is hydrogen, C_1-3 alkyl, or halogen; R⁴ is hydrogen, C_1-3 alkyl, or halogen; each R^6a is independently C_1-3 alkyl, C_2-3 alkenyl, or C_2-3 alkynyl, wherein the alkynyl is optionally substituted with 1 to 3 R^6j; each R^6j is independently C_2-3 alkoxyalkyl, halogen, C_1-3 haloalkyl, C_1-3 haloalkoxy, -CN, C_3-8 cycloalkyl, or heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally substituted with 1 to 3 R^6p; each R^6p is independently C_1-3 alkyl, C_1-3 hydroxyalkyl, C_2-3 alkoxyalkyl, halogen, C_1-3 haloalkyl, C_1-3 haloalkoxy, or -CN; and R⁷ is hydrogen, C_1-3 alkyl, C_2-3 alkoxyalkyl, C_1-3 haloalkyl, or -NH₂.

0165In some embodiments, the compound of Formula (I), (IIa), (IIa-1), (IIc), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is a compound wherein R¹ is hydrogen, C_1-3 alkyl, or halogen; R² is hydrogen, C_1-3 alkyl, C_1-3 hydroxyalkyl, C_2-3 alkoxyalkyl, halogen, or -CN; R³ is hydrogen, C_1-3 alkyl, or halogen; R⁴ is hydrogen, C_1-3 alkyl, or halogen; each R^6a is independently C_1-3 alkyl, C_2-3 alkenyl, or C_2-3 alkynyl, wherein the alkynyl is optionally substituted with 1 to 3 R^6j; each R^6j is independently C_2-3 alkoxyalkyl, halogen, C_1-3 haloalkyl, C_1-3 haloalkoxy, -CN, C_3-8 cycloalkyl, or heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally substituted with 1 to 3 R^6p; each R^6p is independently C_1-3 alkyl, C_1-3 hydroxyalkyl, C_2-3 alkoxyalkyl, halogen, C_1-3 haloalkyl, C_1-3 haloalkoxy, or -CN; and R⁷ is hydrogen or C_1-3 alkyl.

0166In some embodiments, the compound of Formula (I), (IIa), (IIa-1), (IIc), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is a compound wherein R¹ is hydrogen or F; R² is hydrogen, F or Cl; R³ is hydrogen or F; R⁴ is hydrogen or F; each R^6a is independently C_1-3 alkyl, C_2-3 alkenyl, or C_2-3 alkynyl, wherein the alkynyl is optionally substituted with 1 to 3 R^6j; each R^6j is independently C_2-3 alkoxyalkyl, halogen, C_1-3 haloalkyl, C_1-3 haloalkoxy, -CN, C_3-8 cycloalkyl, or heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally substituted with 1 to 3 R^6p; each R^6p is independently C_1-3 alkyl, C_1-3 hydroxyalkyl, C_2-3 alkoxyalkyl, halogen, C_1-3 haloalkyl, C_1-3 haloalkoxy, or -CN; and R⁷ is hydrogen or Me.

0167In some embodiments, the compound of Formula (Ic), (IIc), or (IIc-1), or a pharmaceutically acceptable salt thereof, is a compound wherein R² is hydrogen, C_1-3 alkyl, C_1-3 hydroxyalkyl, C_2-3 alkoxyalkyl, halogen, or -CN; R³ is hydrogen, C_1-3 alkyl, or halogen; each R^6a is independently C_1-3 alkyl, C_2-3 alkenyl, or C_2-3 alkynyl, wherein the alkynyl is optionally substituted with 1 to 3 R^6j; each R^6j is independently C_2-3 alkoxyalkyl, halogen, C_1-3 haloalkyl, C_1-3 haloalkoxy, -CN, C_3-8 cycloalkyl, or heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally substituted with 1 to 3 R^6p; each R^6p is independently C_1-3 alkyl, C_1-3 hydroxyalkyl, C_2-3 alkoxyalkyl, halogen, C_1-3 haloalkyl, C_1-3 haloalkoxy, or -CN; R⁷ is hydrogen or C_1-3 alkyl; and <chemistry id="chem0401" num="0401"><img file="EP4445902A2_D0402.tif" /></chemistry> has the structure <chemistry id="chem0402" num="0402"><img file="EP4445902A2_D0403.tif" /></chemistry>

0168In some embodiments, the compound of Formula (Ic), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is a compound wherein R² is hydrogen, halogen, or -CN. In some embodiments, the compound of Formula (Ic), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is a compound wherein R² is hydrogen, F, or Cl.

0169In some embodiments, the compound of Formula (Ic), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is a compound wherein R³ is hydrogen, F, or Cl.

0170In some embodiments, the compound of Formula (Ic), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is a compound wherein each R^6a is independently C_2-3 alkynyl or halogen, wherein the alkynyl is optionally substituted with 1 to 3 R^6j. In some embodiments, the compound of Formula (Ic), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is a compound wherein each R^6a is <chemistry id="chem0403" num="0403"><img file="EP4445902A2_D0404.tif" /></chemistry> substituted with 1 R^6j.

0171In some embodiments, the compound of Formula (Ic), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is a compound wherein each R^6j is independently C_2-3 alkoxyalkyl, halogen, C_1-3 haloalkyl, -CN, C_3-6 cycloalkyl, or heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally substituted with 1 to 3 R^6p, and each heterocycloalkyl is a 3 to 6 membered ring having 1 to 2 heteroatoms each independently N, O or S. In some embodiments, the compound of Formula (Ic), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is a compound wherein each R^6j is independently halogen, C_1-3 haloalkyl, C_3-6 cycloalkyl, or heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally substituted with 1 to 2 R^6p, and each heterocycloalkyl is a 3 to 6 membered ring having 1 to 2 heteroatoms each independently N, O or S. In some embodiments, the compound of Formula (Ic), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is a compound wherein each R^6j is independently halogen, C_1-3 haloalkyl, or C_3-6 cycloalkyl, wherein the cycloalkyl is optionally substituted with one R^6p. In some embodiments, the compound of Formula (Ic), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is a compound wherein each R^6j is independently F, CH₂F, CHF₂, CF₃, CH₂CF₃, CF₂CH₃, or cyclopropyl, wherein the cyclopropyl is optionally substituted with one R^6p.

0172In some embodiments, the compound of Formula (Ic), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is a compound wherein each R^6p is independently C_1-3 alkyl, C_1-3 hydroxyalkyl, halogen, C_1-3 haloalkyl, or -CN. In some embodiments, the compound of Formula (Ic), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is a compound wherein each R^6p is independently Me, Et, CH₂OH, F, CH₂F, CHF₂, CF₃, CH₂CF₃, CF₂CH₃, or -CN.

0173In some embodiments, the compound of Formula (Ic), (IIc), or (IIc-1), or a pharmaceutically acceptable salt thereof, is a compound wherein <chemistry id="chem0404" num="0404"><img file="EP4445902A2_D0405.tif" /></chemistry> has the structure <chemistry id="chem0405" num="0405"><img file="EP4445902A2_D0406.tif" /></chemistry><chemistry id="chem0406" num="0406"><img file="EP4445902A2_D0407.tif" /></chemistry>

0174In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1)(IIc-2), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein the heterocycloalkyl is a 5 to 8 membered ring having 1 to 2 heteroatoms each independently N, O, or S. In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1)(IIc-2), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein the heterocycloalkyl is a 5 to 6 membered ring having 1 to 2 heteroatoms each independently N or O. In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1)(IIc-2), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein the heterocycloalkyl is a 6 membered ring having 1 heteratom N or O.

0175In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1)(IIc-2), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein the heteroaryl is a 5 to 6 membered ring having 1 to 2 heteroatoms each independently N, O, or S. In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein the heteroaryl is a 6 membered ring having 1 to 2 heteroatoms each N.

0176In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1)(IIc-2), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound wherein the heterocycloalkyl is a 5 to 6 membered ring having 1 to 2 heteroatoms each independently N or O; and the heteroaryl is a 5 to 6 membered ring having 1 to 2 heteroatoms each independently N, O, or S.

0177In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound having the structure of a compound in Table 1A, Table 1B, Table 1C, Table 1D, Table 1E, Table 1F, Table 1G, Table 1H, Table 1I, Table 1J, Table 2A, Table 2B, Table 2C, Table 2D, Table 2E, Table 2F, Table 2G, Table 2H, Table 2I, Table 2J, Table 2K, Table 2L, Table 3A, Table 3B, Table 3C, Table 3D, Table 3E, Table 3F, Table 3G, Table 3H, Table 3I, Table 3J, or Table 3K. In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is the compound having the structure of a compound in Table 3F, Table 3H, Table 3I, Table 3J, or Table 3K. <tables id="tabl0001" num="0001"><table frame="all"><title><b>Table 1A. Compounds</b></title><tgroup cols="2"><colspec colnum="1" colname="col1" colwidth="15mm" align="center" /><colspec colnum="2" colname="col2" colwidth="46mm" align="center" /><thead valign="middle"><row><entry><b>Ex.</b></entry><entry><b>Chemical Structure</b></entry></row></thead><tbody valign="middle"><row><entry>1</entry><entry><chemistry id="chem0407" num="0407"><img file="EP4445902A2_D0408.tif" /></chemistry></entry></row><row><entry>2</entry><entry><chemistry id="chem0408" num="0408"><img file="EP4445902A2_D0409.tif" /></chemistry></entry></row><row><entry>4</entry><entry><chemistry id="chem0409" num="0409"><img file="EP4445902A2_D0410.tif" /></chemistry></entry></row><row><entry>5</entry><entry><chemistry id="chem0410" num="0410"><img file="EP4445902A2_D0411.tif" /></chemistry></entry></row><row><entry>6</entry><entry><chemistry id="chem0411" num="0411"><img file="EP4445902A2_D0412.tif" /></chemistry></entry></row><row><entry>8</entry><entry><chemistry id="chem0412" num="0412"><img file="EP4445902A2_D0413.tif" /></chemistry></entry></row><row><entry>9</entry><entry><chemistry id="chem0413" num="0413"><img file="EP4445902A2_D0414.tif" /></chemistry></entry></row><row><entry>10</entry><entry><chemistry id="chem0414" num="0414"><img file="EP4445902A2_D0415.tif" /></chemistry></entry></row><row><entry>11</entry><entry><chemistry id="chem0415" num="0415"><img file="EP4445902A2_D0416.tif" /></chemistry></entry></row><row><entry>12</entry><entry><chemistry id="chem0416" num="0416"><img file="EP4445902A2_D0417.tif" /></chemistry></entry></row><row><entry>13</entry><entry><chemistry id="chem0417" num="0417"><img file="EP4445902A2_D0418.tif" /></chemistry></entry></row><row><entry>14</entry><entry><chemistry id="chem0418" num="0418"><img file="EP4445902A2_D0419.tif" /></chemistry></entry></row><row><entry>15</entry><entry><chemistry id="chem0419" num="0419"><img file="EP4445902A2_D0420.tif" /></chemistry></entry></row><row><entry>16</entry><entry><chemistry id="chem0420" num="0420"><img file="EP4445902A2_D0421.tif" /></chemistry></entry></row><row><entry>17</entry><entry><chemistry id="chem0421" num="0421"><img file="EP4445902A2_D0422.tif" /></chemistry></entry></row><row><entry>18</entry><entry><chemistry id="chem0422" num="0422"><img file="EP4445902A2_D0423.tif" /></chemistry></entry></row><row><entry>19</entry><entry><chemistry id="chem0423" num="0423"><img file="EP4445902A2_D0424.tif" /></chemistry></entry></row><row><entry>20</entry><entry><chemistry id="chem0424" num="0424"><img file="EP4445902A2_D0425.tif" /></chemistry></entry></row><row><entry>21</entry><entry><chemistry id="chem0425" num="0425"><img file="EP4445902A2_D0426.tif" /></chemistry></entry></row><row><entry>22</entry><entry><chemistry id="chem0426" num="0426"><img file="EP4445902A2_D0427.tif" /></chemistry></entry></row></tbody></tgroup></table></tables><tables id="tabl0002" num="0002"><table frame="all"><title><b>Table 1B. Compounds</b></title><tgroup cols="2"><colspec colnum="1" colname="col1" colwidth="15mm" align="center" /><colspec colnum="2" colname="col2" colwidth="47mm" align="center" /><thead valign="middle"><row><entry><b>Ex.</b></entry><entry><b>Chemical Structure</b></entry></row></thead><tbody valign="middle"><row><entry>23</entry><entry><chemistry id="chem0427" num="0427"><img file="EP4445902A2_D0428.tif" /></chemistry></entry></row><row><entry>24</entry><entry><chemistry id="chem0428" num="0428"><img file="EP4445902A2_D0429.tif" /></chemistry></entry></row><row><entry>25</entry><entry><chemistry id="chem0429" num="0429"><img file="EP4445902A2_D0430.tif" /></chemistry></entry></row><row><entry>26</entry><entry><chemistry id="chem0430" num="0430"><img file="EP4445902A2_D0431.tif" /></chemistry></entry></row><row><entry>27</entry><entry><chemistry id="chem0431" num="0431"><img file="EP4445902A2_D0432.tif" /></chemistry></entry></row><row><entry>28</entry><entry><chemistry id="chem0432" num="0432"><img file="EP4445902A2_D0433.tif" /></chemistry></entry></row><row><entry>29</entry><entry><chemistry id="chem0433" num="0433"><img file="EP4445902A2_D0434.tif" /></chemistry></entry></row><row><entry>30</entry><entry><chemistry id="chem0434" num="0434"><img file="EP4445902A2_D0435.tif" /></chemistry></entry></row><row><entry>31</entry><entry><chemistry id="chem0435" num="0435"><img file="EP4445902A2_D0436.tif" /></chemistry></entry></row><row><entry>32</entry><entry><chemistry id="chem0436" num="0436"><img file="EP4445902A2_D0437.tif" /></chemistry></entry></row><row><entry>33</entry><entry><chemistry id="chem0437" num="0437"><img file="EP4445902A2_D0438.tif" /></chemistry></entry></row><row><entry>34</entry><entry><chemistry id="chem0438" num="0438"><img file="EP4445902A2_D0439.tif" /></chemistry></entry></row><row><entry>35</entry><entry><chemistry id="chem0439" num="0439"><img file="EP4445902A2_D0440.tif" /></chemistry></entry></row><row><entry>36</entry><entry><chemistry id="chem0440" num="0440"><img file="EP4445902A2_D0441.tif" /></chemistry></entry></row><row><entry>37</entry><entry><chemistry id="chem0441" num="0441"><img file="EP4445902A2_D0442.tif" /></chemistry></entry></row><row><entry>38</entry><entry><chemistry id="chem0442" num="0442"><img file="EP4445902A2_D0443.tif" /></chemistry></entry></row><row><entry>39</entry><entry><chemistry id="chem0443" num="0443"><img file="EP4445902A2_D0444.tif" /></chemistry></entry></row><row><entry>40</entry><entry><chemistry id="chem0444" num="0444"><img file="EP4445902A2_D0445.tif" /></chemistry></entry></row><row><entry>41</entry><entry><chemistry id="chem0445" num="0445"><img file="EP4445902A2_D0446.tif" /></chemistry></entry></row><row><entry>42</entry><entry><chemistry id="chem0446" num="0446"><img file="EP4445902A2_D0447.tif" /></chemistry></entry></row><row><entry>43</entry><entry><chemistry id="chem0447" num="0447"><img file="EP4445902A2_D0448.tif" /></chemistry></entry></row><row><entry>44</entry><entry><chemistry id="chem0448" num="0448"><img file="EP4445902A2_D0449.tif" /></chemistry></entry></row><row><entry>45</entry><entry><chemistry id="chem0449" num="0449"><img file="EP4445902A2_D0450.tif" /></chemistry></entry></row><row><entry>46</entry><entry><chemistry id="chem0450" num="0450"><img file="EP4445902A2_D0451.tif" /></chemistry></entry></row><row><entry>47</entry><entry><chemistry id="chem0451" num="0451"><img file="EP4445902A2_D0452.tif" /></chemistry></entry></row></tbody></tgroup></table></tables><tables id="tabl0003" num="0003"><table frame="all"><title><b>Table 1C. Compounds</b></title><tgroup cols="2"><colspec colnum="1" colname="col1" colwidth="15mm" align="center" /><colspec colnum="2" colname="col2" colwidth="46mm" align="center" /><thead valign="middle"><row><entry><b>Ex.</b></entry><entry><b>Chemical Structure</b></entry></row></thead><tbody valign="middle"><row><entry>48</entry><entry><chemistry id="chem0452" num="0452"><img file="EP4445902A2_D0453.tif" /></chemistry></entry></row><row><entry>49</entry><entry><chemistry id="chem0453" num="0453"><img file="EP4445902A2_D0454.tif" /></chemistry></entry></row><row><entry>50</entry><entry><chemistry id="chem0454" num="0454"><img file="EP4445902A2_D0455.tif" /></chemistry></entry></row><row><entry>51</entry><entry><chemistry id="chem0455" num="0455"><img file="EP4445902A2_D0456.tif" /></chemistry></entry></row><row><entry>52</entry><entry><chemistry id="chem0456" num="0456"><img file="EP4445902A2_D0457.tif" /></chemistry></entry></row><row><entry>53</entry><entry><chemistry id="chem0457" num="0457"><img file="EP4445902A2_D0458.tif" /></chemistry></entry></row><row><entry>54</entry><entry><chemistry id="chem0458" num="0458"><img file="EP4445902A2_D0459.tif" /></chemistry></entry></row><row><entry>55</entry><entry><chemistry id="chem0459" num="0459"><img file="EP4445902A2_D0460.tif" /></chemistry></entry></row><row><entry>56</entry><entry><chemistry id="chem0460" num="0460"><img file="EP4445902A2_D0461.tif" /></chemistry></entry></row><row><entry>57</entry><entry><chemistry id="chem0461" num="0461"><img file="EP4445902A2_D0462.tif" /></chemistry></entry></row><row><entry>58</entry><entry><chemistry id="chem0462" num="0462"><img file="EP4445902A2_D0463.tif" /></chemistry></entry></row><row><entry>59</entry><entry><chemistry id="chem0463" num="0463"><img file="EP4445902A2_D0464.tif" /></chemistry></entry></row><row><entry>60</entry><entry><chemistry id="chem0464" num="0464"><img file="EP4445902A2_D0465.tif" /></chemistry></entry></row><row><entry>61</entry><entry><chemistry id="chem0465" num="0465"><img file="EP4445902A2_D0466.tif" /></chemistry></entry></row><row><entry>62</entry><entry><chemistry id="chem0466" num="0466"><img file="EP4445902A2_D0467.tif" /></chemistry></entry></row><row><entry>63</entry><entry><chemistry id="chem0467" num="0467"><img file="EP4445902A2_D0468.tif" /></chemistry></entry></row><row><entry>64</entry><entry><chemistry id="chem0468" num="0468"><img file="EP4445902A2_D0469.tif" /></chemistry></entry></row><row><entry>65</entry><entry><chemistry id="chem0469" num="0469"><img file="EP4445902A2_D0470.tif" /></chemistry></entry></row><row><entry>66</entry><entry><chemistry id="chem0470" num="0470"><img file="EP4445902A2_D0471.tif" /></chemistry></entry></row><row><entry>67</entry><entry><chemistry id="chem0471" num="0471"><img file="EP4445902A2_D0472.tif" /></chemistry></entry></row><row><entry>68</entry><entry><chemistry id="chem0472" num="0472"><img file="EP4445902A2_D0473.tif" /></chemistry></entry></row><row><entry>69</entry><entry><chemistry id="chem0473" num="0473"><img file="EP4445902A2_D0474.tif" /></chemistry></entry></row><row><entry>70</entry><entry><chemistry id="chem0474" num="0474"><img file="EP4445902A2_D0475.tif" /></chemistry></entry></row><row><entry>71</entry><entry><chemistry id="chem0475" num="0475"><img file="EP4445902A2_D0476.tif" /></chemistry></entry></row></tbody></tgroup></table></tables><tables id="tabl0004" num="0004"><table frame="all"><title><b>Table 1D. Compounds</b></title><tgroup cols="2"><colspec colnum="1" colname="col1" colwidth="15mm" align="center" /><colspec colnum="2" colname="col2" colwidth="46mm" align="center" /><thead valign="middle"><row><entry><b>Ex.</b></entry><entry><b>Chemical Structure</b></entry></row></thead><tbody valign="middle"><row><entry>72</entry><entry><chemistry id="chem0476" num="0476"><img file="EP4445902A2_D0477.tif" /></chemistry></entry></row><row><entry>73</entry><entry><chemistry id="chem0477" num="0477"><img file="EP4445902A2_D0478.tif" /></chemistry></entry></row><row><entry>74</entry><entry><chemistry id="chem0478" num="0478"><img file="EP4445902A2_D0479.tif" /></chemistry></entry></row><row><entry>75</entry><entry><chemistry id="chem0479" num="0479"><img file="EP4445902A2_D0480.tif" /></chemistry></entry></row><row><entry>76</entry><entry><chemistry id="chem0480" num="0480"><img file="EP4445902A2_D0481.tif" /></chemistry></entry></row><row><entry>77</entry><entry><chemistry id="chem0481" num="0481"><img file="EP4445902A2_D0482.tif" /></chemistry></entry></row><row><entry>78</entry><entry><chemistry id="chem0482" num="0482"><img file="EP4445902A2_D0483.tif" /></chemistry></entry></row><row><entry>79</entry><entry><chemistry id="chem0483" num="0483"><img file="EP4445902A2_D0484.tif" /></chemistry></entry></row><row><entry>80</entry><entry><chemistry id="chem0484" num="0484"><img file="EP4445902A2_D0485.tif" /></chemistry></entry></row><row><entry>81</entry><entry><chemistry id="chem0485" num="0485"><img file="EP4445902A2_D0486.tif" /></chemistry></entry></row><row><entry>82</entry><entry><chemistry id="chem0486" num="0486"><img file="EP4445902A2_D0487.tif" /></chemistry></entry></row><row><entry>83</entry><entry><chemistry id="chem0487" num="0487"><img file="EP4445902A2_D0488.tif" /></chemistry></entry></row><row><entry>84</entry><entry><chemistry id="chem0488" num="0488"><img file="EP4445902A2_D0489.tif" /></chemistry></entry></row><row><entry>85</entry><entry><chemistry id="chem0489" num="0489"><img file="EP4445902A2_D0490.tif" /></chemistry></entry></row><row><entry>86</entry><entry><chemistry id="chem0490" num="0490"><img file="EP4445902A2_D0491.tif" /></chemistry></entry></row><row><entry>87</entry><entry><chemistry id="chem0491" num="0491"><img file="EP4445902A2_D0492.tif" /></chemistry></entry></row><row><entry>88</entry><entry><chemistry id="chem0492" num="0492"><img file="EP4445902A2_D0493.tif" /></chemistry></entry></row><row><entry>89</entry><entry><chemistry id="chem0493" num="0493"><img file="EP4445902A2_D0494.tif" /></chemistry></entry></row></tbody></tgroup></table></tables><tables id="tabl0005" num="0005"><table frame="all"><title><b>Table 1E. Compounds</b></title><tgroup cols="2"><colspec colnum="1" colname="col1" colwidth="15mm" align="center" /><colspec colnum="2" colname="col2" colwidth="54mm" align="center" /><thead valign="middle"><row><entry><b>Ex.</b></entry><entry><b>Chemical Structure</b></entry></row></thead><tbody valign="middle"><row><entry>90</entry><entry><chemistry id="chem0494" num="0494"><img file="EP4445902A2_D0495.tif" /></chemistry></entry></row><row><entry>91</entry><entry><chemistry id="chem0495" num="0495"><img file="EP4445902A2_D0496.tif" /></chemistry></entry></row><row><entry>92</entry><entry><chemistry id="chem0496" num="0496"><img file="EP4445902A2_D0497.tif" /></chemistry></entry></row><row><entry>93</entry><entry><chemistry id="chem0497" num="0497"><img file="EP4445902A2_D0498.tif" /></chemistry></entry></row><row><entry>94</entry><entry><chemistry id="chem0498" num="0498"><img file="EP4445902A2_D0499.tif" /></chemistry></entry></row><row><entry>95</entry><entry><chemistry id="chem0499" num="0499"><img file="EP4445902A2_D0500.tif" /></chemistry></entry></row><row><entry>96</entry><entry><chemistry id="chem0500" num="0500"><img file="EP4445902A2_D0501.tif" /></chemistry></entry></row><row><entry>97</entry><entry><chemistry id="chem0501" num="0501"><img file="EP4445902A2_D0502.tif" /></chemistry></entry></row><row><entry>98</entry><entry><chemistry id="chem0502" num="0502"><img file="EP4445902A2_D0503.tif" /></chemistry></entry></row><row><entry>99</entry><entry><chemistry id="chem0503" num="0503"><img file="EP4445902A2_D0504.tif" /></chemistry></entry></row><row><entry>100</entry><entry><chemistry id="chem0504" num="0504"><img file="EP4445902A2_D0505.tif" /></chemistry></entry></row><row><entry>101</entry><entry><chemistry id="chem0505" num="0505"><img file="EP4445902A2_D0506.tif" /></chemistry></entry></row><row><entry>102</entry><entry><chemistry id="chem0506" num="0506"><img file="EP4445902A2_D0507.tif" /></chemistry></entry></row><row><entry>103</entry><entry><chemistry id="chem0507" num="0507"><img file="EP4445902A2_D0508.tif" /></chemistry></entry></row><row><entry>104</entry><entry><chemistry id="chem0508" num="0508"><img file="EP4445902A2_D0509.tif" /></chemistry></entry></row><row><entry>105</entry><entry><chemistry id="chem0509" num="0509"><img file="EP4445902A2_D0510.tif" /></chemistry></entry></row><row><entry>106</entry><entry><chemistry id="chem0510" num="0510"><img file="EP4445902A2_D0511.tif" /></chemistry></entry></row><row><entry>107</entry><entry><chemistry id="chem0511" num="0511"><img file="EP4445902A2_D0512.tif" /></chemistry></entry></row><row><entry>108</entry><entry><chemistry id="chem0512" num="0512"><img file="EP4445902A2_D0513.tif" /></chemistry></entry></row><row><entry>109</entry><entry><chemistry id="chem0513" num="0513"><img file="EP4445902A2_D0514.tif" /></chemistry></entry></row><row><entry>110</entry><entry><chemistry id="chem0514" num="0514"><img file="EP4445902A2_D0515.tif" /></chemistry></entry></row><row><entry>111</entry><entry><chemistry id="chem0515" num="0515"><img file="EP4445902A2_D0516.tif" /></chemistry></entry></row><row><entry>112</entry><entry><chemistry id="chem0516" num="0516"><img file="EP4445902A2_D0517.tif" /></chemistry></entry></row><row><entry>113</entry><entry><chemistry id="chem0517" num="0517"><img file="EP4445902A2_D0518.tif" /></chemistry></entry></row></tbody></tgroup></table></tables><tables id="tabl0006" num="0006"><table frame="all"><title><b>Table 1F. Compounds</b></title><tgroup cols="2"><colspec colnum="1" colname="col1" colwidth="15mm" align="center" /><colspec colnum="2" colname="col2" colwidth="57mm" align="center" /><thead valign="middle"><row><entry><b>Ex.</b></entry><entry><b>Chemical Structure</b></entry></row></thead><tbody valign="middle"><row><entry>114</entry><entry><chemistry id="chem0518" num="0518"><img file="EP4445902A2_D0519.tif" /></chemistry></entry></row><row><entry>115</entry><entry><chemistry id="chem0519" num="0519"><img file="EP4445902A2_D0520.tif" /></chemistry></entry></row><row><entry>116</entry><entry><chemistry id="chem0520" num="0520"><img file="EP4445902A2_D0521.tif" /></chemistry></entry></row><row><entry>117</entry><entry><chemistry id="chem0521" num="0521"><img file="EP4445902A2_D0522.tif" /></chemistry></entry></row><row><entry>118</entry><entry><chemistry id="chem0522" num="0522"><img file="EP4445902A2_D0523.tif" /></chemistry></entry></row><row><entry>119</entry><entry><chemistry id="chem0523" num="0523"><img file="EP4445902A2_D0524.tif" /></chemistry></entry></row><row><entry>120</entry><entry><chemistry id="chem0524" num="0524"><img file="EP4445902A2_D0525.tif" /></chemistry></entry></row><row><entry>121</entry><entry><chemistry id="chem0525" num="0525"><img file="EP4445902A2_D0526.tif" /></chemistry></entry></row><row><entry>122</entry><entry><chemistry id="chem0526" num="0526"><img file="EP4445902A2_D0527.tif" /></chemistry></entry></row><row><entry>123</entry><entry><chemistry id="chem0527" num="0527"><img file="EP4445902A2_D0528.tif" /></chemistry></entry></row><row><entry>124</entry><entry><chemistry id="chem0528" num="0528"><img file="EP4445902A2_D0529.tif" /></chemistry></entry></row><row><entry>125</entry><entry><chemistry id="chem0529" num="0529"><img file="EP4445902A2_D0530.tif" /></chemistry></entry></row><row><entry>126</entry><entry><chemistry id="chem0530" num="0530"><img file="EP4445902A2_D0531.tif" /></chemistry></entry></row><row><entry>127</entry><entry><chemistry id="chem0531" num="0531"><img file="EP4445902A2_D0532.tif" /></chemistry></entry></row><row><entry>128</entry><entry><chemistry id="chem0532" num="0532"><img file="EP4445902A2_D0533.tif" /></chemistry></entry></row><row><entry>129</entry><entry><chemistry id="chem0533" num="0533"><img file="EP4445902A2_D0534.tif" /></chemistry></entry></row><row><entry>130</entry><entry><chemistry id="chem0534" num="0534"><img file="EP4445902A2_D0535.tif" /></chemistry></entry></row><row><entry>131</entry><entry><chemistry id="chem0535" num="0535"><img file="EP4445902A2_D0536.tif" /></chemistry></entry></row><row><entry>132</entry><entry><chemistry id="chem0536" num="0536"><img file="EP4445902A2_D0537.tif" /></chemistry></entry></row><row><entry>133</entry><entry><chemistry id="chem0537" num="0537"><img file="EP4445902A2_D0538.tif" /></chemistry></entry></row><row><entry>134</entry><entry><chemistry id="chem0538" num="0538"><img file="EP4445902A2_D0539.tif" /></chemistry></entry></row><row><entry>135</entry><entry><chemistry id="chem0539" num="0539"><img file="EP4445902A2_D0540.tif" /></chemistry></entry></row><row><entry>136</entry><entry><chemistry id="chem0540" num="0540"><img file="EP4445902A2_D0541.tif" /></chemistry></entry></row><row><entry>137</entry><entry><chemistry id="chem0541" num="0541"><img file="EP4445902A2_D0542.tif" /></chemistry></entry></row></tbody></tgroup></table></tables><tables id="tabl0007" num="0007"><table frame="all"><title><b>Table 1G. Compounds</b></title><tgroup cols="2"><colspec colnum="1" colname="col1" colwidth="15mm" align="center" /><colspec colnum="2" colname="col2" colwidth="65mm" align="center" /><thead valign="middle"><row><entry><b>Ex.</b></entry><entry><b>Chemical Structure</b></entry></row></thead><tbody valign="middle"><row><entry>138</entry><entry><chemistry id="chem0542" num="0542"><img file="EP4445902A2_D0543.tif" /></chemistry></entry></row><row><entry>139</entry><entry><chemistry id="chem0543" num="0543"><img file="EP4445902A2_D0544.tif" /></chemistry></entry></row><row><entry>140</entry><entry><chemistry id="chem0544" num="0544"><img file="EP4445902A2_D0545.tif" /></chemistry></entry></row><row><entry>141</entry><entry><chemistry id="chem0545" num="0545"><img file="EP4445902A2_D0546.tif" /></chemistry></entry></row><row><entry>142</entry><entry><chemistry id="chem0546" num="0546"><img file="EP4445902A2_D0547.tif" /></chemistry></entry></row><row><entry>143</entry><entry><chemistry id="chem0547" num="0547"><img file="EP4445902A2_D0548.tif" /></chemistry></entry></row><row><entry>144</entry><entry><chemistry id="chem0548" num="0548"><img file="EP4445902A2_D0549.tif" /></chemistry></entry></row><row><entry>145</entry><entry><chemistry id="chem0549" num="0549"><img file="EP4445902A2_D0550.tif" /></chemistry></entry></row><row><entry>146</entry><entry><chemistry id="chem0550" num="0550"><img file="EP4445902A2_D0551.tif" /></chemistry></entry></row><row><entry>147</entry><entry><chemistry id="chem0551" num="0551"><img file="EP4445902A2_D0552.tif" /></chemistry></entry></row><row><entry>148</entry><entry><chemistry id="chem0552" num="0552"><img file="EP4445902A2_D0553.tif" /></chemistry></entry></row><row><entry>149</entry><entry><chemistry id="chem0553" num="0553"><img file="EP4445902A2_D0554.tif" /></chemistry></entry></row><row><entry>150</entry><entry><chemistry id="chem0554" num="0554"><img file="EP4445902A2_D0555.tif" /></chemistry></entry></row><row><entry>151</entry><entry><chemistry id="chem0555" num="0555"><img file="EP4445902A2_D0556.tif" /></chemistry></entry></row><row><entry>152</entry><entry><chemistry id="chem0556" num="0556"><img file="EP4445902A2_D0557.tif" /></chemistry></entry></row><row><entry>153</entry><entry><chemistry id="chem0557" num="0557"><img file="EP4445902A2_D0558.tif" /></chemistry></entry></row><row><entry>154</entry><entry><chemistry id="chem0558" num="0558"><img file="EP4445902A2_D0559.tif" /></chemistry></entry></row><row><entry>155</entry><entry><chemistry id="chem0559" num="0559"><img file="EP4445902A2_D0560.tif" /></chemistry></entry></row><row><entry>156</entry><entry><chemistry id="chem0560" num="0560"><img file="EP4445902A2_D0561.tif" /></chemistry></entry></row><row><entry>157</entry><entry><chemistry id="chem0561" num="0561"><img file="EP4445902A2_D0562.tif" /></chemistry></entry></row><row><entry>158</entry><entry><chemistry id="chem0562" num="0562"><img file="EP4445902A2_D0563.tif" /></chemistry></entry></row><row><entry>159</entry><entry><chemistry id="chem0563" num="0563"><img file="EP4445902A2_D0564.tif" /></chemistry></entry></row><row><entry>160</entry><entry><chemistry id="chem0564" num="0564"><img file="EP4445902A2_D0565.tif" /></chemistry></entry></row><row><entry>161</entry><entry><chemistry id="chem0565" num="0565"><img file="EP4445902A2_D0566.tif" /></chemistry></entry></row></tbody></tgroup></table></tables><tables id="tabl0008" num="0008"><table frame="all"><title><b>Table 1H. Compounds</b></title><tgroup cols="2"><colspec colnum="1" colname="col1" colwidth="15mm" align="center" /><colspec colnum="2" colname="col2" colwidth="65mm" align="center" /><thead valign="middle"><row><entry><b>Ex.</b></entry><entry><b>Chemical Structure</b></entry></row></thead><tbody valign="middle"><row><entry>162</entry><entry><chemistry id="chem0566" num="0566"><img file="EP4445902A2_D0567.tif" /></chemistry></entry></row><row><entry>163</entry><entry><chemistry id="chem0567" num="0567"><img file="EP4445902A2_D0568.tif" /></chemistry></entry></row><row><entry>164</entry><entry><chemistry id="chem0568" num="0568"><img file="EP4445902A2_D0569.tif" /></chemistry></entry></row><row><entry>165</entry><entry><chemistry id="chem0569" num="0569"><img file="EP4445902A2_D0570.tif" /></chemistry></entry></row><row><entry>166</entry><entry><chemistry id="chem0570" num="0570"><img file="EP4445902A2_D0571.tif" /></chemistry></entry></row><row><entry>167</entry><entry><chemistry id="chem0571" num="0571"><img file="EP4445902A2_D0572.tif" /></chemistry></entry></row><row><entry>168</entry><entry><chemistry id="chem0572" num="0572"><img file="EP4445902A2_D0573.tif" /></chemistry></entry></row><row><entry>169</entry><entry><chemistry id="chem0573" num="0573"><img file="EP4445902A2_D0574.tif" /></chemistry></entry></row><row><entry>170</entry><entry><chemistry id="chem0574" num="0574"><img file="EP4445902A2_D0575.tif" /></chemistry></entry></row><row><entry>171</entry><entry><chemistry id="chem0575" num="0575"><img file="EP4445902A2_D0576.tif" /></chemistry></entry></row><row><entry>172</entry><entry><chemistry id="chem0576" num="0576"><img file="EP4445902A2_D0577.tif" /></chemistry></entry></row><row><entry>173</entry><entry><chemistry id="chem0577" num="0577"><img file="EP4445902A2_D0578.tif" /></chemistry></entry></row><row><entry>174</entry><entry><chemistry id="chem0578" num="0578"><img file="EP4445902A2_D0579.tif" /></chemistry></entry></row><row><entry>175</entry><entry><chemistry id="chem0579" num="0579"><img file="EP4445902A2_D0580.tif" /></chemistry></entry></row><row><entry>176</entry><entry><chemistry id="chem0580" num="0580"><img file="EP4445902A2_D0581.tif" /></chemistry></entry></row><row><entry>177</entry><entry><chemistry id="chem0581" num="0581"><img file="EP4445902A2_D0582.tif" /></chemistry></entry></row><row><entry>178</entry><entry><chemistry id="chem0582" num="0582"><img file="EP4445902A2_D0583.tif" /></chemistry></entry></row><row><entry>179</entry><entry><chemistry id="chem0583" num="0583"><img file="EP4445902A2_D0584.tif" /></chemistry></entry></row><row><entry>180</entry><entry><chemistry id="chem0584" num="0584"><img file="EP4445902A2_D0585.tif" /></chemistry></entry></row></tbody></tgroup></table></tables><tables id="tabl0009" num="0009"><table frame="all"><title><b>Table 11: Compounds</b></title><tgroup cols="2"><colspec colnum="1" colname="col1" colwidth="15mm" align="center" /><colspec colnum="2" colname="col2" colwidth="66mm" align="center" /><thead valign="middle"><row><entry><b>Ex.</b></entry><entry><b>Chemical Structure</b></entry></row></thead><tbody valign="middle"><row><entry>181</entry><entry><chemistry id="chem0585" num="0585"><img file="EP4445902A2_D0586.tif" /></chemistry></entry></row><row><entry>182</entry><entry><chemistry id="chem0586" num="0586"><img file="EP4445902A2_D0587.tif" /></chemistry></entry></row><row><entry>183</entry><entry><chemistry id="chem0587" num="0587"><img file="EP4445902A2_D0588.tif" /></chemistry></entry></row><row><entry>184</entry><entry><chemistry id="chem0588" num="0588"><img file="EP4445902A2_D0589.tif" /></chemistry></entry></row><row><entry>185</entry><entry><chemistry id="chem0589" num="0589"><img file="EP4445902A2_D0590.tif" /></chemistry></entry></row><row><entry>186</entry><entry><chemistry id="chem0590" num="0590"><img file="EP4445902A2_D0591.tif" /></chemistry></entry></row><row><entry>187</entry><entry><chemistry id="chem0591" num="0591"><img file="EP4445902A2_D0592.tif" /></chemistry></entry></row><row><entry>188</entry><entry><chemistry id="chem0592" num="0592"><img file="EP4445902A2_D0593.tif" /></chemistry></entry></row><row><entry>189</entry><entry><chemistry id="chem0593" num="0593"><img file="EP4445902A2_D0594.tif" /></chemistry></entry></row><row><entry>190</entry><entry><chemistry id="chem0594" num="0594"><img file="EP4445902A2_D0595.tif" /></chemistry></entry></row><row><entry>191</entry><entry><chemistry id="chem0595" num="0595"><img file="EP4445902A2_D0596.tif" /></chemistry></entry></row><row><entry>192</entry><entry><chemistry id="chem0596" num="0596"><img file="EP4445902A2_D0597.tif" /></chemistry></entry></row><row><entry>193</entry><entry><chemistry id="chem0597" num="0597"><img file="EP4445902A2_D0598.tif" /></chemistry></entry></row><row><entry>194</entry><entry><chemistry id="chem0598" num="0598"><img file="EP4445902A2_D0599.tif" /></chemistry></entry></row><row><entry>195</entry><entry><chemistry id="chem0599" num="0599"><img file="EP4445902A2_D0600.tif" /></chemistry></entry></row><row><entry>196</entry><entry><chemistry id="chem0600" num="0600"><img file="EP4445902A2_D0601.tif" /></chemistry></entry></row><row><entry>197</entry><entry><chemistry id="chem0601" num="0601"><img file="EP4445902A2_D0602.tif" /></chemistry></entry></row><row><entry>198</entry><entry><chemistry id="chem0602" num="0602"><img file="EP4445902A2_D0603.tif" /></chemistry></entry></row><row><entry>199</entry><entry><chemistry id="chem0603" num="0603"><img file="EP4445902A2_D0604.tif" /></chemistry></entry></row></tbody></tgroup></table></tables><tables id="tabl0010" num="0010"><table frame="all"><title><b>Table 1J: Compounds</b></title><tgroup cols="2"><colspec colnum="1" colname="col1" colwidth="15mm" align="center" /><colspec colnum="2" colname="col2" colwidth="64mm" align="center" /><thead valign="middle"><row><entry><b>Ex.</b></entry><entry><b>Chemical Structure</b></entry></row></thead><tbody valign="middle"><row><entry>200</entry><entry><chemistry id="chem0604" num="0604"><img file="EP4445902A2_D0605.tif" /></chemistry></entry></row><row><entry>201</entry><entry><chemistry id="chem0605" num="0605"><img file="EP4445902A2_D0606.tif" /></chemistry></entry></row><row><entry>202</entry><entry><chemistry id="chem0606" num="0606"><img file="EP4445902A2_D0607.tif" /></chemistry></entry></row><row><entry>203</entry><entry><chemistry id="chem0607" num="0607"><img file="EP4445902A2_D0608.tif" /></chemistry></entry></row><row><entry>204</entry><entry><chemistry id="chem0608" num="0608"><img file="EP4445902A2_D0609.tif" /></chemistry></entry></row><row><entry>205</entry><entry><chemistry id="chem0609" num="0609"><img file="EP4445902A2_D0610.tif" /></chemistry></entry></row><row><entry>206</entry><entry><chemistry id="chem0610" num="0610"><img file="EP4445902A2_D0611.tif" /></chemistry></entry></row><row><entry>207</entry><entry><chemistry id="chem0611" num="0611"><img file="EP4445902A2_D0612.tif" /></chemistry></entry></row><row><entry>208</entry><entry><chemistry id="chem0612" num="0612"><img file="EP4445902A2_D0613.tif" /></chemistry></entry></row><row><entry>209</entry><entry><chemistry id="chem0613" num="0613"><img file="EP4445902A2_D0614.tif" /></chemistry></entry></row><row><entry>210</entry><entry><chemistry id="chem0614" num="0614"><img file="EP4445902A2_D0615.tif" /></chemistry></entry></row><row><entry>211</entry><entry><chemistry id="chem0615" num="0615"><img file="EP4445902A2_D0616.tif" /></chemistry></entry></row><row><entry>212</entry><entry><chemistry id="chem0616" num="0616"><img file="EP4445902A2_D0617.tif" /></chemistry></entry></row><row><entry>213</entry><entry><chemistry id="chem0617" num="0617"><img file="EP4445902A2_D0618.tif" /></chemistry></entry></row><row><entry>214</entry><entry><chemistry id="chem0618" num="0618"><img file="EP4445902A2_D0619.tif" /></chemistry></entry></row><row><entry>215</entry><entry><chemistry id="chem0619" num="0619"><img file="EP4445902A2_D0620.tif" /></chemistry></entry></row><row><entry>216</entry><entry><chemistry id="chem0620" num="0620"><img file="EP4445902A2_D0621.tif" /></chemistry></entry></row><row><entry>217</entry><entry><chemistry id="chem0621" num="0621"><img file="EP4445902A2_D0622.tif" /></chemistry></entry></row><row><entry>218</entry><entry><chemistry id="chem0622" num="0622"><img file="EP4445902A2_D0623.tif" /></chemistry></entry></row><row><entry>219</entry><entry><chemistry id="chem0623" num="0623"><img file="EP4445902A2_D0624.tif" /></chemistry></entry></row><row><entry>220</entry><entry><chemistry id="chem0624" num="0624"><img file="EP4445902A2_D0625.tif" /></chemistry></entry></row></tbody></tgroup></table></tables><tables id="tabl0011" num="0011"><table frame="all"><title><b>Table 2A: Compounds</b></title><tgroup cols="2"><colspec colnum="1" colname="col1" colwidth="15mm" align="center" /><colspec colnum="2" colname="col2" colwidth="69mm" align="center" /><thead valign="middle"><row><entry><b>Ex.</b></entry><entry><b>Chemical Structure</b></entry></row></thead><tbody valign="middle"><row><entry>221</entry><entry><chemistry id="chem0625" num="0625"><img file="EP4445902A2_D0626.tif" /></chemistry></entry></row><row><entry>222</entry><entry><chemistry id="chem0626" num="0626"><img file="EP4445902A2_D0627.tif" /></chemistry></entry></row><row><entry>223</entry><entry><chemistry id="chem0627" num="0627"><img file="EP4445902A2_D0628.tif" /></chemistry></entry></row><row><entry>224</entry><entry><chemistry id="chem0628" num="0628"><img file="EP4445902A2_D0629.tif" /></chemistry></entry></row><row><entry>225</entry><entry><chemistry id="chem0629" num="0629"><img file="EP4445902A2_D0630.tif" /></chemistry></entry></row><row><entry>226</entry><entry><chemistry id="chem0630" num="0630"><img file="EP4445902A2_D0631.tif" /></chemistry></entry></row><row><entry>227</entry><entry><chemistry id="chem0631" num="0631"><img file="EP4445902A2_D0632.tif" /></chemistry></entry></row><row><entry>228</entry><entry><chemistry id="chem0632" num="0632"><img file="EP4445902A2_D0633.tif" /></chemistry></entry></row><row><entry>229</entry><entry><chemistry id="chem0633" num="0633"><img file="EP4445902A2_D0634.tif" /></chemistry></entry></row><row><entry>230</entry><entry><chemistry id="chem0634" num="0634"><img file="EP4445902A2_D0635.tif" /></chemistry></entry></row><row><entry>231</entry><entry><chemistry id="chem0635" num="0635"><img file="EP4445902A2_D0636.tif" /></chemistry></entry></row><row><entry>232</entry><entry><chemistry id="chem0636" num="0636"><img file="EP4445902A2_D0637.tif" /></chemistry></entry></row><row><entry>233</entry><entry><chemistry id="chem0637" num="0637"><img file="EP4445902A2_D0638.tif" /></chemistry></entry></row><row><entry>234</entry><entry><chemistry id="chem0638" num="0638"><img file="EP4445902A2_D0639.tif" /></chemistry></entry></row><row><entry>235</entry><entry><chemistry id="chem0639" num="0639"><img file="EP4445902A2_D0640.tif" /></chemistry></entry></row><row><entry>236</entry><entry><chemistry id="chem0640" num="0640"><img file="EP4445902A2_D0641.tif" /></chemistry></entry></row><row><entry>237</entry><entry><chemistry id="chem0641" num="0641"><img file="EP4445902A2_D0642.tif" /></chemistry></entry></row><row><entry>238</entry><entry><chemistry id="chem0642" num="0642"><img file="EP4445902A2_D0643.tif" /></chemistry></entry></row><row><entry>239</entry><entry><chemistry id="chem0643" num="0643"><img file="EP4445902A2_D0644.tif" /></chemistry></entry></row><row><entry>240</entry><entry><chemistry id="chem0644" num="0644"><img file="EP4445902A2_D0645.tif" /></chemistry></entry></row><row><entry>241</entry><entry><chemistry id="chem0645" num="0645"><img file="EP4445902A2_D0646.tif" /></chemistry></entry></row><row><entry>242</entry><entry><chemistry id="chem0646" num="0646"><img file="EP4445902A2_D0647.tif" /></chemistry></entry></row><row><entry>243</entry><entry><chemistry id="chem0647" num="0647"><img file="EP4445902A2_D0648.tif" /></chemistry></entry></row><row><entry>244</entry><entry><chemistry id="chem0648" num="0648"><img file="EP4445902A2_D0649.tif" /></chemistry></entry></row><row><entry>245</entry><entry><chemistry id="chem0649" num="0649"><img file="EP4445902A2_D0650.tif" /></chemistry></entry></row><row><entry>246</entry><entry><chemistry id="chem0650" num="0650"><img file="EP4445902A2_D0651.tif" /></chemistry></entry></row><row><entry>247</entry><entry><chemistry id="chem0651" num="0651"><img file="EP4445902A2_D0652.tif" /></chemistry></entry></row><row><entry>248</entry><entry><chemistry id="chem0652" num="0652"><img file="EP4445902A2_D0653.tif" /></chemistry></entry></row><row><entry>249</entry><entry><chemistry id="chem0653" num="0653"><img file="EP4445902A2_D0654.tif" /></chemistry></entry></row></tbody></tgroup></table></tables><tables id="tabl0012" num="0012"><table frame="all"><title><b>Table 2B: Compounds</b></title><tgroup cols="2"><colspec colnum="1" colname="col1" colwidth="15mm" align="center" /><colspec colnum="2" colname="col2" colwidth="72mm" align="center" /><thead valign="top"><row><entry><b>Ex.</b></entry><entry><b>Chemical Structure</b></entry></row></thead><tbody><row><entry>250</entry><entry><chemistry id="chem0654" num="0654"><img file="EP4445902A2_D0655.tif" /></chemistry></entry></row><row><entry>251</entry><entry><chemistry id="chem0655" num="0655"><img file="EP4445902A2_D0656.tif" /></chemistry></entry></row><row><entry>252</entry><entry><chemistry id="chem0656" num="0656"><img file="EP4445902A2_D0657.tif" /></chemistry></entry></row><row><entry>253</entry><entry><chemistry id="chem0657" num="0657"><img file="EP4445902A2_D0658.tif" /></chemistry></entry></row><row><entry>254</entry><entry><chemistry id="chem0658" num="0658"><img file="EP4445902A2_D0659.tif" /></chemistry></entry></row><row><entry>255</entry><entry><chemistry id="chem0659" num="0659"><img file="EP4445902A2_D0660.tif" /></chemistry></entry></row><row><entry>256</entry><entry><chemistry id="chem0660" num="0660"><img file="EP4445902A2_D0661.tif" /></chemistry></entry></row><row><entry>257</entry><entry><chemistry id="chem0661" num="0661"><img file="EP4445902A2_D0662.tif" /></chemistry></entry></row><row><entry>258</entry><entry><chemistry id="chem0662" num="0662"><img file="EP4445902A2_D0663.tif" /></chemistry></entry></row><row><entry>259</entry><entry><chemistry id="chem0663" num="0663"><img file="EP4445902A2_D0664.tif" /></chemistry></entry></row><row><entry>260</entry><entry><chemistry id="chem0664" num="0664"><img file="EP4445902A2_D0665.tif" /></chemistry></entry></row><row><entry>261</entry><entry><chemistry id="chem0665" num="0665"><img file="EP4445902A2_D0666.tif" /></chemistry></entry></row><row><entry>262</entry><entry><chemistry id="chem0666" num="0666"><img file="EP4445902A2_D0667.tif" /></chemistry></entry></row><row><entry>263</entry><entry><chemistry id="chem0667" num="0667"><img file="EP4445902A2_D0668.tif" /></chemistry></entry></row><row><entry>264</entry><entry><chemistry id="chem0668" num="0668"><img file="EP4445902A2_D0669.tif" /></chemistry></entry></row><row><entry>265</entry><entry><chemistry id="chem0669" num="0669"><img file="EP4445902A2_D0670.tif" /></chemistry></entry></row><row><entry>266</entry><entry><chemistry id="chem0670" num="0670"><img file="EP4445902A2_D0671.tif" /></chemistry></entry></row><row><entry>267</entry><entry><chemistry id="chem0671" num="0671"><img file="EP4445902A2_D0672.tif" /></chemistry></entry></row><row><entry>268</entry><entry><chemistry id="chem0672" num="0672"><img file="EP4445902A2_D0673.tif" /></chemistry></entry></row><row><entry>269</entry><entry><chemistry id="chem0673" num="0673"><img file="EP4445902A2_D0674.tif" /></chemistry></entry></row><row><entry>270</entry><entry><chemistry id="chem0674" num="0674"><img file="EP4445902A2_D0675.tif" /></chemistry></entry></row><row><entry>271</entry><entry><chemistry id="chem0675" num="0675"><img file="EP4445902A2_D0676.tif" /></chemistry></entry></row><row><entry>272</entry><entry><chemistry id="chem0676" num="0676"><img file="EP4445902A2_D0677.tif" /></chemistry></entry></row><row><entry>273</entry><entry><chemistry id="chem0677" num="0677"><img file="EP4445902A2_D0678.tif" /></chemistry></entry></row><row><entry>274</entry><entry><chemistry id="chem0678" num="0678"><img file="EP4445902A2_D0679.tif" /></chemistry></entry></row><row><entry>275</entry><entry><chemistry id="chem0679" num="0679"><img file="EP4445902A2_D0680.tif" /></chemistry></entry></row><row><entry>276</entry><entry><chemistry id="chem0680" num="0680"><img file="EP4445902A2_D0681.tif" /></chemistry></entry></row><row><entry>277</entry><entry><chemistry id="chem0681" num="0681"><img file="EP4445902A2_D0682.tif" /></chemistry></entry></row><row><entry>278</entry><entry><chemistry id="chem0682" num="0682"><img file="EP4445902A2_D0683.tif" /></chemistry></entry></row><row><entry>279</entry><entry><chemistry id="chem0683" num="0683"><img file="EP4445902A2_D0684.tif" /></chemistry></entry></row></tbody></tgroup></table></tables><tables id="tabl0013" num="0013"><table frame="all"><title><b>Table 2C: Compounds</b></title><tgroup cols="2"><colspec colnum="1" colname="col1" colwidth="15mm" align="center" /><colspec colnum="2" colname="col2" colwidth="71mm" align="center" /><thead valign="top"><row><entry><b>Ex.</b></entry><entry><b>Chemical Structure</b></entry></row></thead><tbody><row><entry>280</entry><entry><chemistry id="chem0684" num="0684"><img file="EP4445902A2_D0685.tif" /></chemistry></entry></row><row><entry>281</entry><entry><chemistry id="chem0685" num="0685"><img file="EP4445902A2_D0686.tif" /></chemistry></entry></row><row><entry>282</entry><entry><chemistry id="chem0686" num="0686"><img file="EP4445902A2_D0687.tif" /></chemistry></entry></row><row><entry>283</entry><entry><chemistry id="chem0687" num="0687"><img file="EP4445902A2_D0688.tif" /></chemistry></entry></row><row><entry>284</entry><entry><chemistry id="chem0688" num="0688"><img file="EP4445902A2_D0689.tif" /></chemistry></entry></row><row><entry>285</entry><entry><chemistry id="chem0689" num="0689"><img file="EP4445902A2_D0690.tif" /></chemistry></entry></row><row><entry>286</entry><entry><chemistry id="chem0690" num="0690"><img file="EP4445902A2_D0691.tif" /></chemistry></entry></row><row><entry>287</entry><entry><chemistry id="chem0691" num="0691"><img file="EP4445902A2_D0692.tif" /></chemistry></entry></row><row><entry>288</entry><entry><chemistry id="chem0692" num="0692"><img file="EP4445902A2_D0693.tif" /></chemistry></entry></row><row><entry>289</entry><entry><chemistry id="chem0693" num="0693"><img file="EP4445902A2_D0694.tif" /></chemistry></entry></row><row><entry>290</entry><entry><chemistry id="chem0694" num="0694"><img file="EP4445902A2_D0695.tif" /></chemistry></entry></row><row><entry>291</entry><entry><chemistry id="chem0695" num="0695"><img file="EP4445902A2_D0696.tif" /></chemistry></entry></row><row><entry>292</entry><entry><chemistry id="chem0696" num="0696"><img file="EP4445902A2_D0697.tif" /></chemistry></entry></row><row><entry>293</entry><entry><chemistry id="chem0697" num="0697"><img file="EP4445902A2_D0698.tif" /></chemistry></entry></row><row><entry>294</entry><entry><chemistry id="chem0698" num="0698"><img file="EP4445902A2_D0699.tif" /></chemistry></entry></row><row><entry>295</entry><entry><chemistry id="chem0699" num="0699"><img file="EP4445902A2_D0700.tif" /></chemistry></entry></row><row><entry>296</entry><entry><chemistry id="chem0700" num="0700"><img file="EP4445902A2_D0701.tif" /></chemistry></entry></row><row><entry>297</entry><entry><chemistry id="chem0701" num="0701"><img file="EP4445902A2_D0702.tif" /></chemistry></entry></row><row><entry>298</entry><entry><chemistry id="chem0702" num="0702"><img file="EP4445902A2_D0703.tif" /></chemistry></entry></row><row><entry>299</entry><entry><chemistry id="chem0703" num="0703"><img file="EP4445902A2_D0704.tif" /></chemistry></entry></row><row><entry>300</entry><entry><chemistry id="chem0704" num="0704"><img file="EP4445902A2_D0705.tif" /></chemistry></entry></row><row><entry>301</entry><entry><chemistry id="chem0705" num="0705"><img file="EP4445902A2_D0706.tif" /></chemistry></entry></row><row><entry>302</entry><entry><chemistry id="chem0706" num="0706"><img file="EP4445902A2_D0707.tif" /></chemistry></entry></row><row><entry>303</entry><entry><chemistry id="chem0707" num="0707"><img file="EP4445902A2_D0708.tif" /></chemistry></entry></row><row><entry>304</entry><entry><chemistry id="chem0708" num="0708"><img file="EP4445902A2_D0709.tif" /></chemistry></entry></row><row><entry>305</entry><entry><chemistry id="chem0709" num="0709"><img file="EP4445902A2_D0710.tif" /></chemistry></entry></row><row><entry>306</entry><entry><chemistry id="chem0710" num="0710"><img file="EP4445902A2_D0711.tif" /></chemistry></entry></row><row><entry>307</entry><entry><chemistry id="chem0711" num="0711"><img file="EP4445902A2_D0712.tif" /></chemistry></entry></row><row><entry>308</entry><entry><chemistry id="chem0712" num="0712"><img file="EP4445902A2_D0713.tif" /></chemistry></entry></row><row><entry>309</entry><entry><chemistry id="chem0713" num="0713"><img file="EP4445902A2_D0714.tif" /></chemistry></entry></row><row><entry>310</entry><entry><chemistry id="chem0714" num="0714"><img file="EP4445902A2_D0715.tif" /></chemistry></entry></row></tbody></tgroup></table></tables><tables id="tabl0014" num="0014"><table frame="all"><title><b>Table 2D: Compounds</b></title><tgroup cols="2"><colspec colnum="1" colname="col1" colwidth="15mm" align="center" /><colspec colnum="2" colname="col2" colwidth="64mm" align="center" /><thead valign="top"><row><entry><b>Ex.</b></entry><entry><b>Chemical Structure</b></entry></row></thead><tbody><row><entry>311</entry><entry><chemistry id="chem0715" num="0715"><img file="EP4445902A2_D0716.tif" /></chemistry></entry></row><row><entry>312</entry><entry><chemistry id="chem0716" num="0716"><img file="EP4445902A2_D0717.tif" /></chemistry></entry></row><row><entry>313</entry><entry><chemistry id="chem0717" num="0717"><img file="EP4445902A2_D0718.tif" /></chemistry></entry></row><row><entry>314</entry><entry><chemistry id="chem0718" num="0718"><img file="EP4445902A2_D0719.tif" /></chemistry></entry></row><row><entry>315</entry><entry><chemistry id="chem0719" num="0719"><img file="EP4445902A2_D0720.tif" /></chemistry></entry></row><row><entry>316</entry><entry><chemistry id="chem0720" num="0720"><img file="EP4445902A2_D0721.tif" /></chemistry></entry></row><row><entry>317</entry><entry><chemistry id="chem0721" num="0721"><img file="EP4445902A2_D0722.tif" /></chemistry></entry></row><row><entry>318</entry><entry><chemistry id="chem0722" num="0722"><img file="EP4445902A2_D0723.tif" /></chemistry></entry></row><row><entry>319</entry><entry><chemistry id="chem0723" num="0723"><img file="EP4445902A2_D0724.tif" /></chemistry></entry></row><row><entry>320</entry><entry><chemistry id="chem0724" num="0724"><img file="EP4445902A2_D0725.tif" /></chemistry></entry></row><row><entry>321</entry><entry><chemistry id="chem0725" num="0725"><img file="EP4445902A2_D0726.tif" /></chemistry></entry></row><row><entry>322</entry><entry><chemistry id="chem0726" num="0726"><img file="EP4445902A2_D0727.tif" /></chemistry></entry></row><row><entry>323</entry><entry><chemistry id="chem0727" num="0727"><img file="EP4445902A2_D0728.tif" /></chemistry></entry></row><row><entry>324</entry><entry><chemistry id="chem0728" num="0728"><img file="EP4445902A2_D0729.tif" /></chemistry></entry></row><row><entry>325</entry><entry><chemistry id="chem0729" num="0729"><img file="EP4445902A2_D0730.tif" /></chemistry></entry></row><row><entry>326</entry><entry><chemistry id="chem0730" num="0730"><img file="EP4445902A2_D0731.tif" /></chemistry></entry></row><row><entry>327</entry><entry><chemistry id="chem0731" num="0731"><img file="EP4445902A2_D0732.tif" /></chemistry></entry></row><row><entry>328</entry><entry><chemistry id="chem0732" num="0732"><img file="EP4445902A2_D0733.tif" /></chemistry></entry></row><row><entry>329</entry><entry><chemistry id="chem0733" num="0733"><img file="EP4445902A2_D0734.tif" /></chemistry></entry></row><row><entry>330</entry><entry><chemistry id="chem0734" num="0734"><img file="EP4445902A2_D0735.tif" /></chemistry></entry></row><row><entry>331</entry><entry><chemistry id="chem0735" num="0735"><img file="EP4445902A2_D0736.tif" /></chemistry></entry></row><row><entry>332</entry><entry><chemistry id="chem0736" num="0736"><img file="EP4445902A2_D0737.tif" /></chemistry></entry></row><row><entry>333</entry><entry><chemistry id="chem0737" num="0737"><img file="EP4445902A2_D0738.tif" /></chemistry></entry></row><row><entry>334</entry><entry><chemistry id="chem0738" num="0738"><img file="EP4445902A2_D0739.tif" /></chemistry></entry></row><row><entry>335</entry><entry><chemistry id="chem0739" num="0739"><img file="EP4445902A2_D0740.tif" /></chemistry></entry></row><row><entry>336</entry><entry><chemistry id="chem0740" num="0740"><img file="EP4445902A2_D0741.tif" /></chemistry></entry></row><row><entry>337</entry><entry><chemistry id="chem0741" num="0741"><img file="EP4445902A2_D0742.tif" /></chemistry></entry></row><row><entry>338</entry><entry><chemistry id="chem0742" num="0742"><img file="EP4445902A2_D0743.tif" /></chemistry></entry></row><row><entry>339</entry><entry><chemistry id="chem0743" num="0743"><img file="EP4445902A2_D0744.tif" /></chemistry></entry></row><row><entry>340</entry><entry><chemistry id="chem0744" num="0744"><img file="EP4445902A2_D0745.tif" /></chemistry></entry></row></tbody></tgroup></table></tables><tables id="tabl0015" num="0015"><table frame="all"><title><b>Table 2E: Compounds</b></title><tgroup cols="2"><colspec colnum="1" colname="col1" colwidth="15mm" align="center" /><colspec colnum="2" colname="col2" colwidth="68mm" align="center" /><thead valign="top"><row><entry><b>Ex.</b></entry><entry><b>Chemical Structure</b></entry></row></thead><tbody><row><entry>341</entry><entry><chemistry id="chem0745" num="0745"><img file="EP4445902A2_D0746.tif" /></chemistry></entry></row><row><entry>342</entry><entry><chemistry id="chem0746" num="0746"><img file="EP4445902A2_D0747.tif" /></chemistry></entry></row><row><entry>343</entry><entry><chemistry id="chem0747" num="0747"><img file="EP4445902A2_D0748.tif" /></chemistry></entry></row><row><entry>344</entry><entry><chemistry id="chem0748" num="0748"><img file="EP4445902A2_D0749.tif" /></chemistry></entry></row><row><entry>345</entry><entry><chemistry id="chem0749" num="0749"><img file="EP4445902A2_D0750.tif" /></chemistry></entry></row><row><entry>346</entry><entry><chemistry id="chem0750" num="0750"><img file="EP4445902A2_D0751.tif" /></chemistry></entry></row><row><entry>347</entry><entry><chemistry id="chem0751" num="0751"><img file="EP4445902A2_D0752.tif" /></chemistry></entry></row><row><entry>348</entry><entry><chemistry id="chem0752" num="0752"><img file="EP4445902A2_D0753.tif" /></chemistry></entry></row><row><entry>349</entry><entry><chemistry id="chem0753" num="0753"><img file="EP4445902A2_D0754.tif" /></chemistry></entry></row><row><entry>350</entry><entry><chemistry id="chem0754" num="0754"><img file="EP4445902A2_D0755.tif" /></chemistry></entry></row><row><entry>351</entry><entry><chemistry id="chem0755" num="0755"><img file="EP4445902A2_D0756.tif" /></chemistry></entry></row><row><entry>352</entry><entry><chemistry id="chem0756" num="0756"><img file="EP4445902A2_D0757.tif" /></chemistry></entry></row><row><entry>353</entry><entry><chemistry id="chem0757" num="0757"><img file="EP4445902A2_D0758.tif" /></chemistry></entry></row><row><entry>354</entry><entry><chemistry id="chem0758" num="0758"><img file="EP4445902A2_D0759.tif" /></chemistry></entry></row><row><entry>355</entry><entry><chemistry id="chem0759" num="0759"><img file="EP4445902A2_D0760.tif" /></chemistry></entry></row><row><entry>356</entry><entry><chemistry id="chem0760" num="0760"><img file="EP4445902A2_D0761.tif" /></chemistry></entry></row><row><entry>357</entry><entry><chemistry id="chem0761" num="0761"><img file="EP4445902A2_D0762.tif" /></chemistry></entry></row><row><entry>358</entry><entry><chemistry id="chem0762" num="0762"><img file="EP4445902A2_D0763.tif" /></chemistry></entry></row><row><entry>359</entry><entry><chemistry id="chem0763" num="0763"><img file="EP4445902A2_D0764.tif" /></chemistry></entry></row><row><entry>360</entry><entry><chemistry id="chem0764" num="0764"><img file="EP4445902A2_D0765.tif" /></chemistry></entry></row><row><entry>361</entry><entry><chemistry id="chem0765" num="0765"><img file="EP4445902A2_D0766.tif" /></chemistry></entry></row><row><entry>362</entry><entry><chemistry id="chem0766" num="0766"><img file="EP4445902A2_D0767.tif" /></chemistry></entry></row><row><entry>363</entry><entry><chemistry id="chem0767" num="0767"><img file="EP4445902A2_D0768.tif" /></chemistry></entry></row><row><entry>364</entry><entry><chemistry id="chem0768" num="0768"><img file="EP4445902A2_D0769.tif" /></chemistry></entry></row><row><entry>365</entry><entry><chemistry id="chem0769" num="0769"><img file="EP4445902A2_D0770.tif" /></chemistry></entry></row><row><entry>366</entry><entry><chemistry id="chem0770" num="0770"><img file="EP4445902A2_D0771.tif" /></chemistry></entry></row><row><entry>367</entry><entry><chemistry id="chem0771" num="0771"><img file="EP4445902A2_D0772.tif" /></chemistry></entry></row><row><entry>368</entry><entry><chemistry id="chem0772" num="0772"><img file="EP4445902A2_D0773.tif" /></chemistry></entry></row><row><entry>369</entry><entry><chemistry id="chem0773" num="0773"><img file="EP4445902A2_D0774.tif" /></chemistry></entry></row><row><entry>370</entry><entry><chemistry id="chem0774" num="0774"><img file="EP4445902A2_D0775.tif" /></chemistry></entry></row><row><entry>371</entry><entry><chemistry id="chem0775" num="0775"><img file="EP4445902A2_D0776.tif" /></chemistry></entry></row></tbody></tgroup></table></tables><tables id="tabl0016" num="0016"><table frame="all"><title><b>Table 2F: Compounds</b></title><tgroup cols="2"><colspec colnum="1" colname="col1" colwidth="15mm" align="center" /><colspec colnum="2" colname="col2" colwidth="69mm" align="center" /><thead valign="top"><row><entry><b>Ex.</b></entry><entry><b>Chemical Structure</b></entry></row></thead><tbody><row><entry>372</entry><entry><chemistry id="chem0776" num="0776"><img file="EP4445902A2_D0777.tif" /></chemistry></entry></row><row><entry>373</entry><entry><chemistry id="chem0777" num="0777"><img file="EP4445902A2_D0778.tif" /></chemistry></entry></row><row><entry>374</entry><entry><chemistry id="chem0778" num="0778"><img file="EP4445902A2_D0779.tif" /></chemistry></entry></row><row><entry>375</entry><entry><chemistry id="chem0779" num="0779"><img file="EP4445902A2_D0780.tif" /></chemistry></entry></row><row><entry>376</entry><entry><chemistry id="chem0780" num="0780"><img file="EP4445902A2_D0781.tif" /></chemistry></entry></row><row><entry>377</entry><entry><chemistry id="chem0781" num="0781"><img file="EP4445902A2_D0782.tif" /></chemistry></entry></row><row><entry>378</entry><entry><chemistry id="chem0782" num="0782"><img file="EP4445902A2_D0783.tif" /></chemistry></entry></row><row><entry>379</entry><entry><chemistry id="chem0783" num="0783"><img file="EP4445902A2_D0784.tif" /></chemistry></entry></row><row><entry>380</entry><entry><chemistry id="chem0784" num="0784"><img file="EP4445902A2_D0785.tif" /></chemistry></entry></row><row><entry>381</entry><entry><chemistry id="chem0785" num="0785"><img file="EP4445902A2_D0786.tif" /></chemistry></entry></row><row><entry>382</entry><entry><chemistry id="chem0786" num="0786"><img file="EP4445902A2_D0787.tif" /></chemistry></entry></row><row><entry>383</entry><entry><chemistry id="chem0787" num="0787"><img file="EP4445902A2_D0788.tif" /></chemistry></entry></row><row><entry>384</entry><entry><chemistry id="chem0788" num="0788"><img file="EP4445902A2_D0789.tif" /></chemistry></entry></row><row><entry>385</entry><entry><chemistry id="chem0789" num="0789"><img file="EP4445902A2_D0790.tif" /></chemistry></entry></row><row><entry>386</entry><entry><chemistry id="chem0790" num="0790"><img file="EP4445902A2_D0791.tif" /></chemistry></entry></row><row><entry>387</entry><entry><chemistry id="chem0791" num="0791"><img file="EP4445902A2_D0792.tif" /></chemistry></entry></row><row><entry>388</entry><entry><chemistry id="chem0792" num="0792"><img file="EP4445902A2_D0793.tif" /></chemistry></entry></row><row><entry>389</entry><entry><chemistry id="chem0793" num="0793"><img file="EP4445902A2_D0794.tif" /></chemistry></entry></row><row><entry>390</entry><entry><chemistry id="chem0794" num="0794"><img file="EP4445902A2_D0795.tif" /></chemistry></entry></row><row><entry>391</entry><entry><chemistry id="chem0795" num="0795"><img file="EP4445902A2_D0796.tif" /></chemistry></entry></row><row><entry>392</entry><entry><chemistry id="chem0796" num="0796"><img file="EP4445902A2_D0797.tif" /></chemistry></entry></row><row><entry>393</entry><entry><chemistry id="chem0797" num="0797"><img file="EP4445902A2_D0798.tif" /></chemistry></entry></row><row><entry>394</entry><entry><chemistry id="chem0798" num="0798"><img file="EP4445902A2_D0799.tif" /></chemistry></entry></row><row><entry>395</entry><entry><chemistry id="chem0799" num="0799"><img file="EP4445902A2_D0800.tif" /></chemistry></entry></row><row><entry>396</entry><entry><chemistry id="chem0800" num="0800"><img file="EP4445902A2_D0801.tif" /></chemistry></entry></row><row><entry>397</entry><entry><chemistry id="chem0801" num="0801"><img file="EP4445902A2_D0802.tif" /></chemistry></entry></row><row><entry>398</entry><entry><chemistry id="chem0802" num="0802"><img file="EP4445902A2_D0803.tif" /></chemistry></entry></row><row><entry>399</entry><entry><chemistry id="chem0803" num="0803"><img file="EP4445902A2_D0804.tif" /></chemistry></entry></row><row><entry>400</entry><entry><chemistry id="chem0804" num="0804"><img file="EP4445902A2_D0805.tif" /></chemistry></entry></row></tbody></tgroup></table></tables><tables id="tabl0017" num="0017"><table frame="all"><title><b>Table 2G: Compounds</b></title><tgroup cols="2"><colspec colnum="1" colname="col1" colwidth="15mm" align="center" /><colspec colnum="2" colname="col2" colwidth="68mm" align="center" /><thead valign="top"><row><entry><b>Ex.</b></entry><entry><b>Chemical Structure</b></entry></row></thead><tbody><row><entry>401</entry><entry><chemistry id="chem0805" num="0805"><img file="EP4445902A2_D0806.tif" /></chemistry></entry></row><row><entry>402</entry><entry><chemistry id="chem0806" num="0806"><img file="EP4445902A2_D0807.tif" /></chemistry></entry></row><row><entry>403</entry><entry><chemistry id="chem0807" num="0807"><img file="EP4445902A2_D0808.tif" /></chemistry></entry></row><row><entry>404</entry><entry><chemistry id="chem0808" num="0808"><img file="EP4445902A2_D0809.tif" /></chemistry></entry></row><row><entry>405</entry><entry><chemistry id="chem0809" num="0809"><img file="EP4445902A2_D0810.tif" /></chemistry></entry></row><row><entry>406</entry><entry><chemistry id="chem0810" num="0810"><img file="EP4445902A2_D0811.tif" /></chemistry></entry></row><row><entry>407</entry><entry><chemistry id="chem0811" num="0811"><img file="EP4445902A2_D0812.tif" /></chemistry></entry></row><row><entry>408</entry><entry><chemistry id="chem0812" num="0812"><img file="EP4445902A2_D0813.tif" /></chemistry></entry></row><row><entry>409</entry><entry><chemistry id="chem0813" num="0813"><img file="EP4445902A2_D0814.tif" /></chemistry></entry></row><row><entry>410</entry><entry><chemistry id="chem0814" num="0814"><img file="EP4445902A2_D0815.tif" /></chemistry></entry></row><row><entry>411</entry><entry><chemistry id="chem0815" num="0815"><img file="EP4445902A2_D0816.tif" /></chemistry></entry></row><row><entry>412</entry><entry><chemistry id="chem0816" num="0816"><img file="EP4445902A2_D0817.tif" /></chemistry></entry></row><row><entry>413</entry><entry><chemistry id="chem0817" num="0817"><img file="EP4445902A2_D0818.tif" /></chemistry></entry></row><row><entry>414</entry><entry><chemistry id="chem0818" num="0818"><img file="EP4445902A2_D0819.tif" /></chemistry></entry></row><row><entry>415</entry><entry><chemistry id="chem0819" num="0819"><img file="EP4445902A2_D0820.tif" /></chemistry></entry></row><row><entry>416</entry><entry><chemistry id="chem0820" num="0820"><img file="EP4445902A2_D0821.tif" /></chemistry></entry></row><row><entry>417</entry><entry><chemistry id="chem0821" num="0821"><img file="EP4445902A2_D0822.tif" /></chemistry></entry></row><row><entry>418</entry><entry><chemistry id="chem0822" num="0822"><img file="EP4445902A2_D0823.tif" /></chemistry></entry></row><row><entry>419</entry><entry><chemistry id="chem0823" num="0823"><img file="EP4445902A2_D0824.tif" /></chemistry></entry></row><row><entry>420</entry><entry><chemistry id="chem0824" num="0824"><img file="EP4445902A2_D0825.tif" /></chemistry></entry></row><row><entry>421</entry><entry><chemistry id="chem0825" num="0825"><img file="EP4445902A2_D0826.tif" /></chemistry></entry></row><row><entry>422</entry><entry><chemistry id="chem0826" num="0826"><img file="EP4445902A2_D0827.tif" /></chemistry></entry></row><row><entry>423</entry><entry><chemistry id="chem0827" num="0827"><img file="EP4445902A2_D0828.tif" /></chemistry></entry></row><row><entry>424</entry><entry><chemistry id="chem0828" num="0828"><img file="EP4445902A2_D0829.tif" /></chemistry></entry></row><row><entry>425</entry><entry><chemistry id="chem0829" num="0829"><img file="EP4445902A2_D0830.tif" /></chemistry></entry></row><row><entry>426</entry><entry><chemistry id="chem0830" num="0830"><img file="EP4445902A2_D0831.tif" /></chemistry></entry></row><row><entry>427</entry><entry><chemistry id="chem0831" num="0831"><img file="EP4445902A2_D0832.tif" /></chemistry></entry></row><row><entry>428</entry><entry><chemistry id="chem0832" num="0832"><img file="EP4445902A2_D0833.tif" /></chemistry></entry></row><row><entry>429</entry><entry><chemistry id="chem0833" num="0833"><img file="EP4445902A2_D0834.tif" /></chemistry></entry></row><row><entry>430</entry><entry><chemistry id="chem0834" num="0834"><img file="EP4445902A2_D0835.tif" /></chemistry></entry></row></tbody></tgroup></table></tables><tables id="tabl0018" num="0018"><table frame="all"><title><b>Table 2H: Compounds</b></title><tgroup cols="2"><colspec colnum="1" colname="col1" colwidth="15mm" align="center" /><colspec colnum="2" colname="col2" colwidth="69mm" align="center" /><thead valign="top"><row><entry><b>Ex.</b></entry><entry><b>Chemical Structure</b></entry></row></thead><tbody><row><entry>431</entry><entry><chemistry id="chem0835" num="0835"><img file="EP4445902A2_D0836.tif" /></chemistry></entry></row><row><entry>432</entry><entry><chemistry id="chem0836" num="0836"><img file="EP4445902A2_D0837.tif" /></chemistry></entry></row><row><entry>433</entry><entry><chemistry id="chem0837" num="0837"><img file="EP4445902A2_D0838.tif" /></chemistry></entry></row><row><entry>434</entry><entry><chemistry id="chem0838" num="0838"><img file="EP4445902A2_D0839.tif" /></chemistry></entry></row><row><entry>435</entry><entry><chemistry id="chem0839" num="0839"><img file="EP4445902A2_D0840.tif" /></chemistry></entry></row><row><entry>436</entry><entry><chemistry id="chem0840" num="0840"><img file="EP4445902A2_D0841.tif" /></chemistry></entry></row><row><entry>437</entry><entry><chemistry id="chem0841" num="0841"><img file="EP4445902A2_D0842.tif" /></chemistry></entry></row><row><entry>438</entry><entry><chemistry id="chem0842" num="0842"><img file="EP4445902A2_D0843.tif" /></chemistry></entry></row><row><entry>439</entry><entry><chemistry id="chem0843" num="0843"><img file="EP4445902A2_D0844.tif" /></chemistry></entry></row><row><entry>440</entry><entry><chemistry id="chem0844" num="0844"><img file="EP4445902A2_D0845.tif" /></chemistry></entry></row><row><entry>441</entry><entry><chemistry id="chem0845" num="0845"><img file="EP4445902A2_D0846.tif" /></chemistry></entry></row><row><entry>442</entry><entry><chemistry id="chem0846" num="0846"><img file="EP4445902A2_D0847.tif" /></chemistry></entry></row><row><entry>443</entry><entry><chemistry id="chem0847" num="0847"><img file="EP4445902A2_D0848.tif" /></chemistry></entry></row><row><entry>444</entry><entry><chemistry id="chem0848" num="0848"><img file="EP4445902A2_D0849.tif" /></chemistry></entry></row><row><entry>445</entry><entry><chemistry id="chem0849" num="0849"><img file="EP4445902A2_D0850.tif" /></chemistry></entry></row><row><entry>446</entry><entry><chemistry id="chem0850" num="0850"><img file="EP4445902A2_D0851.tif" /></chemistry></entry></row><row><entry>447</entry><entry><chemistry id="chem0851" num="0851"><img file="EP4445902A2_D0852.tif" /></chemistry></entry></row><row><entry>448</entry><entry><chemistry id="chem0852" num="0852"><img file="EP4445902A2_D0853.tif" /></chemistry></entry></row><row><entry>449</entry><entry><chemistry id="chem0853" num="0853"><img file="EP4445902A2_D0854.tif" /></chemistry></entry></row><row><entry>450</entry><entry><chemistry id="chem0854" num="0854"><img file="EP4445902A2_D0855.tif" /></chemistry></entry></row><row><entry>451</entry><entry><chemistry id="chem0855" num="0855"><img file="EP4445902A2_D0856.tif" /></chemistry></entry></row><row><entry>452</entry><entry><chemistry id="chem0856" num="0856"><img file="EP4445902A2_D0857.tif" /></chemistry></entry></row><row><entry>453</entry><entry><chemistry id="chem0857" num="0857"><img file="EP4445902A2_D0858.tif" /></chemistry></entry></row><row><entry>454</entry><entry><chemistry id="chem0858" num="0858"><img file="EP4445902A2_D0859.tif" /></chemistry></entry></row><row><entry>455</entry><entry><chemistry id="chem0859" num="0859"><img file="EP4445902A2_D0860.tif" /></chemistry></entry></row><row><entry>456</entry><entry><chemistry id="chem0860" num="0860"><img file="EP4445902A2_D0861.tif" /></chemistry></entry></row><row><entry>457</entry><entry><chemistry id="chem0861" num="0861"><img file="EP4445902A2_D0862.tif" /></chemistry></entry></row><row><entry>458</entry><entry><chemistry id="chem0862" num="0862"><img file="EP4445902A2_D0863.tif" /></chemistry></entry></row><row><entry>459</entry><entry><chemistry id="chem0863" num="0863"><img file="EP4445902A2_D0864.tif" /></chemistry></entry></row></tbody></tgroup></table></tables><tables id="tabl0019" num="0019"><table frame="all"><title><b>Table 2I: Compounds</b></title><tgroup cols="2"><colspec colnum="1" colname="col1" colwidth="15mm" align="center" /><colspec colnum="2" colname="col2" colwidth="69mm" align="center" /><thead valign="top"><row><entry><b>Ex.</b></entry><entry><b>Chemical Structure</b></entry></row></thead><tbody><row><entry>460</entry><entry><chemistry id="chem0864" num="0864"><img file="EP4445902A2_D0865.tif" /></chemistry></entry></row><row><entry>461</entry><entry><chemistry id="chem0865" num="0865"><img file="EP4445902A2_D0866.tif" /></chemistry></entry></row><row><entry>462</entry><entry><chemistry id="chem0866" num="0866"><img file="EP4445902A2_D0867.tif" /></chemistry></entry></row><row><entry>463</entry><entry><chemistry id="chem0867" num="0867"><img file="EP4445902A2_D0868.tif" /></chemistry></entry></row><row><entry>464</entry><entry><chemistry id="chem0868" num="0868"><img file="EP4445902A2_D0869.tif" /></chemistry></entry></row><row><entry>465</entry><entry><chemistry id="chem0869" num="0869"><img file="EP4445902A2_D0870.tif" /></chemistry></entry></row><row><entry>466</entry><entry><chemistry id="chem0870" num="0870"><img file="EP4445902A2_D0871.tif" /></chemistry></entry></row><row><entry>467</entry><entry><chemistry id="chem0871" num="0871"><img file="EP4445902A2_D0872.tif" /></chemistry></entry></row><row><entry>468</entry><entry><chemistry id="chem0872" num="0872"><img file="EP4445902A2_D0873.tif" /></chemistry></entry></row><row><entry>469</entry><entry><chemistry id="chem0873" num="0873"><img file="EP4445902A2_D0874.tif" /></chemistry></entry></row><row><entry>470</entry><entry><chemistry id="chem0874" num="0874"><img file="EP4445902A2_D0875.tif" /></chemistry></entry></row><row><entry>471</entry><entry><chemistry id="chem0875" num="0875"><img file="EP4445902A2_D0876.tif" /></chemistry></entry></row><row><entry>472</entry><entry><chemistry id="chem0876" num="0876"><img file="EP4445902A2_D0877.tif" /></chemistry></entry></row><row><entry>473</entry><entry><chemistry id="chem0877" num="0877"><img file="EP4445902A2_D0878.tif" /></chemistry></entry></row><row><entry>474</entry><entry><chemistry id="chem0878" num="0878"><img file="EP4445902A2_D0879.tif" /></chemistry></entry></row><row><entry>475</entry><entry><chemistry id="chem0879" num="0879"><img file="EP4445902A2_D0880.tif" /></chemistry></entry></row><row><entry>476</entry><entry><chemistry id="chem0880" num="0880"><img file="EP4445902A2_D0881.tif" /></chemistry></entry></row><row><entry>477</entry><entry><chemistry id="chem0881" num="0881"><img file="EP4445902A2_D0882.tif" /></chemistry></entry></row><row><entry>478</entry><entry><chemistry id="chem0882" num="0882"><img file="EP4445902A2_D0883.tif" /></chemistry></entry></row><row><entry>479</entry><entry><chemistry id="chem0883" num="0883"><img file="EP4445902A2_D0884.tif" /></chemistry></entry></row><row><entry>480</entry><entry><chemistry id="chem0884" num="0884"><img file="EP4445902A2_D0885.tif" /></chemistry></entry></row><row><entry>481</entry><entry><chemistry id="chem0885" num="0885"><img file="EP4445902A2_D0886.tif" /></chemistry></entry></row><row><entry>482</entry><entry><chemistry id="chem0886" num="0886"><img file="EP4445902A2_D0887.tif" /></chemistry></entry></row><row><entry>483</entry><entry><chemistry id="chem0887" num="0887"><img file="EP4445902A2_D0888.tif" /></chemistry></entry></row><row><entry>484</entry><entry><chemistry id="chem0888" num="0888"><img file="EP4445902A2_D0889.tif" /></chemistry></entry></row><row><entry>485</entry><entry><chemistry id="chem0889" num="0889"><img file="EP4445902A2_D0890.tif" /></chemistry></entry></row><row><entry>486</entry><entry><chemistry id="chem0890" num="0890"><img file="EP4445902A2_D0891.tif" /></chemistry></entry></row><row><entry>487</entry><entry><chemistry id="chem0891" num="0891"><img file="EP4445902A2_D0892.tif" /></chemistry></entry></row><row><entry>488</entry><entry><chemistry id="chem0892" num="0892"><img file="EP4445902A2_D0893.tif" /></chemistry></entry></row><row><entry>489</entry><entry><chemistry id="chem0893" num="0893"><img file="EP4445902A2_D0894.tif" /></chemistry></entry></row><row><entry>490</entry><entry><chemistry id="chem0894" num="0894"><img file="EP4445902A2_D0895.tif" /></chemistry></entry></row></tbody></tgroup></table></tables><tables id="tabl0020" num="0020"><table frame="all"><title><b>Table 2J: Compounds</b></title><tgroup cols="2"><colspec colnum="1" colname="col1" colwidth="15mm" align="center" /><colspec colnum="2" colname="col2" colwidth="62mm" align="center" /><thead valign="top"><row><entry><b>Ex.</b></entry><entry><b>Chemical Structure</b></entry></row></thead><tbody><row><entry>491</entry><entry><chemistry id="chem0895" num="0895"><img file="EP4445902A2_D0896.tif" /></chemistry></entry></row><row><entry>492</entry><entry><chemistry id="chem0896" num="0896"><img file="EP4445902A2_D0897.tif" /></chemistry></entry></row><row><entry>493</entry><entry><chemistry id="chem0897" num="0897"><img file="EP4445902A2_D0898.tif" /></chemistry></entry></row><row><entry>494</entry><entry><chemistry id="chem0898" num="0898"><img file="EP4445902A2_D0899.tif" /></chemistry></entry></row><row><entry>495</entry><entry><chemistry id="chem0899" num="0899"><img file="EP4445902A2_D0900.tif" /></chemistry></entry></row><row><entry>496</entry><entry><chemistry id="chem0900" num="0900"><img file="EP4445902A2_D0901.tif" /></chemistry></entry></row><row><entry>497</entry><entry><chemistry id="chem0901" num="0901"><img file="EP4445902A2_D0902.tif" /></chemistry></entry></row><row><entry>498</entry><entry><chemistry id="chem0902" num="0902"><img file="EP4445902A2_D0903.tif" /></chemistry></entry></row><row><entry>499</entry><entry><chemistry id="chem0903" num="0903"><img file="EP4445902A2_D0904.tif" /></chemistry></entry></row><row><entry>500</entry><entry><chemistry id="chem0904" num="0904"><img file="EP4445902A2_D0905.tif" /></chemistry></entry></row><row><entry>501</entry><entry><chemistry id="chem0905" num="0905"><img file="EP4445902A2_D0906.tif" /></chemistry></entry></row><row><entry>502</entry><entry><chemistry id="chem0906" num="0906"><img file="EP4445902A2_D0907.tif" /></chemistry></entry></row><row><entry>503</entry><entry><chemistry id="chem0907" num="0907"><img file="EP4445902A2_D0908.tif" /></chemistry></entry></row><row><entry>504</entry><entry><chemistry id="chem0908" num="0908"><img file="EP4445902A2_D0909.tif" /></chemistry></entry></row><row><entry>505</entry><entry><chemistry id="chem0909" num="0909"><img file="EP4445902A2_D0910.tif" /></chemistry></entry></row><row><entry>506</entry><entry><chemistry id="chem0910" num="0910"><img file="EP4445902A2_D0911.tif" /></chemistry></entry></row><row><entry>507</entry><entry><chemistry id="chem0911" num="0911"><img file="EP4445902A2_D0912.tif" /></chemistry></entry></row><row><entry>508</entry><entry><chemistry id="chem0912" num="0912"><img file="EP4445902A2_D0913.tif" /></chemistry></entry></row><row><entry>509</entry><entry><chemistry id="chem0913" num="0913"><img file="EP4445902A2_D0914.tif" /></chemistry></entry></row><row><entry>510</entry><entry><chemistry id="chem0914" num="0914"><img file="EP4445902A2_D0915.tif" /></chemistry></entry></row><row><entry>511</entry><entry><chemistry id="chem0915" num="0915"><img file="EP4445902A2_D0916.tif" /></chemistry></entry></row><row><entry>512</entry><entry><chemistry id="chem0916" num="0916"><img file="EP4445902A2_D0917.tif" /></chemistry></entry></row><row><entry>513</entry><entry><chemistry id="chem0917" num="0917"><img file="EP4445902A2_D0918.tif" /></chemistry></entry></row><row><entry>514</entry><entry><chemistry id="chem0918" num="0918"><img file="EP4445902A2_D0919.tif" /></chemistry></entry></row><row><entry>515</entry><entry><chemistry id="chem0919" num="0919"><img file="EP4445902A2_D0920.tif" /></chemistry></entry></row><row><entry>516</entry><entry><chemistry id="chem0920" num="0920"><img file="EP4445902A2_D0921.tif" /></chemistry></entry></row><row><entry>517</entry><entry><chemistry id="chem0921" num="0921"><img file="EP4445902A2_D0922.tif" /></chemistry></entry></row><row><entry>518</entry><entry><chemistry id="chem0922" num="0922"><img file="EP4445902A2_D0923.tif" /></chemistry></entry></row><row><entry>519</entry><entry><chemistry id="chem0923" num="0923"><img file="EP4445902A2_D0924.tif" /></chemistry></entry></row></tbody></tgroup></table></tables><tables id="tabl0021" num="0021"><table frame="all"><title><b>Table 2K: Compounds</b></title><tgroup cols="2"><colspec colnum="1" colname="col1" colwidth="15mm" align="center" /><colspec colnum="2" colname="col2" colwidth="69mm" align="center" /><thead valign="top"><row><entry><b>Ex.</b></entry><entry><b>Chemical Structure</b></entry></row></thead><tbody><row><entry>520</entry><entry><chemistry id="chem0924" num="0924"><img file="EP4445902A2_D0925.tif" /></chemistry></entry></row><row><entry>521</entry><entry><chemistry id="chem0925" num="0925"><img file="EP4445902A2_D0926.tif" /></chemistry></entry></row><row><entry>522</entry><entry><chemistry id="chem0926" num="0926"><img file="EP4445902A2_D0927.tif" /></chemistry></entry></row><row><entry>523</entry><entry><chemistry id="chem0927" num="0927"><img file="EP4445902A2_D0928.tif" /></chemistry></entry></row><row><entry>524</entry><entry><chemistry id="chem0928" num="0928"><img file="EP4445902A2_D0929.tif" /></chemistry></entry></row><row><entry>525</entry><entry><chemistry id="chem0929" num="0929"><img file="EP4445902A2_D0930.tif" /></chemistry></entry></row><row><entry>526</entry><entry><chemistry id="chem0930" num="0930"><img file="EP4445902A2_D0931.tif" /></chemistry></entry></row><row><entry>527</entry><entry><chemistry id="chem0931" num="0931"><img file="EP4445902A2_D0932.tif" /></chemistry></entry></row><row><entry>528</entry><entry><chemistry id="chem0932" num="0932"><img file="EP4445902A2_D0933.tif" /></chemistry></entry></row><row><entry>529</entry><entry><chemistry id="chem0933" num="0933"><img file="EP4445902A2_D0934.tif" /></chemistry></entry></row><row><entry>530</entry><entry><chemistry id="chem0934" num="0934"><img file="EP4445902A2_D0935.tif" /></chemistry></entry></row><row><entry>531</entry><entry><chemistry id="chem0935" num="0935"><img file="EP4445902A2_D0936.tif" /></chemistry></entry></row><row><entry>532</entry><entry><chemistry id="chem0936" num="0936"><img file="EP4445902A2_D0937.tif" /></chemistry></entry></row><row><entry>533</entry><entry><chemistry id="chem0937" num="0937"><img file="EP4445902A2_D0938.tif" /></chemistry></entry></row><row><entry>534</entry><entry><chemistry id="chem0938" num="0938"><img file="EP4445902A2_D0939.tif" /></chemistry></entry></row><row><entry>535</entry><entry><chemistry id="chem0939" num="0939"><img file="EP4445902A2_D0940.tif" /></chemistry></entry></row><row><entry>536</entry><entry><chemistry id="chem0940" num="0940"><img file="EP4445902A2_D0941.tif" /></chemistry></entry></row><row><entry>537</entry><entry><chemistry id="chem0941" num="0941"><img file="EP4445902A2_D0942.tif" /></chemistry></entry></row><row><entry>538</entry><entry><chemistry id="chem0942" num="0942"><img file="EP4445902A2_D0943.tif" /></chemistry></entry></row><row><entry>539</entry><entry><chemistry id="chem0943" num="0943"><img file="EP4445902A2_D0944.tif" /></chemistry></entry></row><row><entry>540</entry><entry><chemistry id="chem0944" num="0944"><img file="EP4445902A2_D0945.tif" /></chemistry></entry></row><row><entry>541</entry><entry><chemistry id="chem0945" num="0945"><img file="EP4445902A2_D0946.tif" /></chemistry></entry></row><row><entry>542</entry><entry><chemistry id="chem0946" num="0946"><img file="EP4445902A2_D0947.tif" /></chemistry></entry></row><row><entry>543</entry><entry><chemistry id="chem0947" num="0947"><img file="EP4445902A2_D0948.tif" /></chemistry></entry></row><row><entry>544</entry><entry><chemistry id="chem0948" num="0948"><img file="EP4445902A2_D0949.tif" /></chemistry></entry></row><row><entry>545</entry><entry><chemistry id="chem0949" num="0949"><img file="EP4445902A2_D0950.tif" /></chemistry></entry></row><row><entry>546</entry><entry><chemistry id="chem0950" num="0950"><img file="EP4445902A2_D0951.tif" /></chemistry></entry></row><row><entry>547</entry><entry><chemistry id="chem0951" num="0951"><img file="EP4445902A2_D0952.tif" /></chemistry></entry></row><row><entry>548</entry><entry><chemistry id="chem0952" num="0952"><img file="EP4445902A2_D0953.tif" /></chemistry></entry></row></tbody></tgroup></table></tables><tables id="tabl0022" num="0022"><table frame="all"><title><b>Table 2L: Compounds</b></title><tgroup cols="2"><colspec colnum="1" colname="col1" colwidth="15mm" align="center" /><colspec colnum="2" colname="col2" colwidth="69mm" align="center" /><thead valign="top"><row><entry><b>Ex.</b></entry><entry><b>Chemical Structure</b></entry></row></thead><tbody><row><entry>549</entry><entry><chemistry id="chem0953" num="0953"><img file="EP4445902A2_D0954.tif" /></chemistry></entry></row><row><entry>550</entry><entry><chemistry id="chem0954" num="0954"><img file="EP4445902A2_D0955.tif" /></chemistry></entry></row><row><entry>551</entry><entry><chemistry id="chem0955" num="0955"><img file="EP4445902A2_D0956.tif" /></chemistry></entry></row><row><entry>552</entry><entry><chemistry id="chem0956" num="0956"><img file="EP4445902A2_D0957.tif" /></chemistry></entry></row><row><entry>553</entry><entry><chemistry id="chem0957" num="0957"><img file="EP4445902A2_D0958.tif" /></chemistry></entry></row><row><entry>554</entry><entry><chemistry id="chem0958" num="0958"><img file="EP4445902A2_D0959.tif" /></chemistry></entry></row><row><entry>555</entry><entry><chemistry id="chem0959" num="0959"><img file="EP4445902A2_D0960.tif" /></chemistry></entry></row><row><entry>556</entry><entry><chemistry id="chem0960" num="0960"><img file="EP4445902A2_D0961.tif" /></chemistry></entry></row><row><entry>557</entry><entry><chemistry id="chem0961" num="0961"><img file="EP4445902A2_D0962.tif" /></chemistry></entry></row><row><entry>558</entry><entry><chemistry id="chem0962" num="0962"><img file="EP4445902A2_D0963.tif" /></chemistry></entry></row><row><entry>559</entry><entry><chemistry id="chem0963" num="0963"><img file="EP4445902A2_D0964.tif" /></chemistry></entry></row><row><entry>560</entry><entry><chemistry id="chem0964" num="0964"><img file="EP4445902A2_D0965.tif" /></chemistry></entry></row><row><entry>561</entry><entry><chemistry id="chem0965" num="0965"><img file="EP4445902A2_D0966.tif" /></chemistry></entry></row><row><entry>563</entry><entry><chemistry id="chem0966" num="0966"><img file="EP4445902A2_D0967.tif" /></chemistry></entry></row><row><entry>564</entry><entry><chemistry id="chem0967" num="0967"><img file="EP4445902A2_D0968.tif" /></chemistry></entry></row><row><entry>565</entry><entry><chemistry id="chem0968" num="0968"><img file="EP4445902A2_D0969.tif" /></chemistry></entry></row><row><entry>566</entry><entry><chemistry id="chem0969" num="0969"><img file="EP4445902A2_D0970.tif" /></chemistry></entry></row><row><entry>567</entry><entry><chemistry id="chem0970" num="0970"><img file="EP4445902A2_D0971.tif" /></chemistry></entry></row><row><entry>569</entry><entry><chemistry id="chem0971" num="0971"><img file="EP4445902A2_D0972.tif" /></chemistry></entry></row><row><entry>570</entry><entry><chemistry id="chem0972" num="0972"><img file="EP4445902A2_D0973.tif" /></chemistry></entry></row><row><entry>571</entry><entry><chemistry id="chem0973" num="0973"><img file="EP4445902A2_D0974.tif" /></chemistry></entry></row><row><entry>572</entry><entry><chemistry id="chem0974" num="0974"><img file="EP4445902A2_D0975.tif" /></chemistry></entry></row><row><entry>573</entry><entry><chemistry id="chem0975" num="0975"><img file="EP4445902A2_D0976.tif" /></chemistry></entry></row><row><entry>574</entry><entry><chemistry id="chem0976" num="0976"><img file="EP4445902A2_D0977.tif" /></chemistry></entry></row><row><entry>575</entry><entry><chemistry id="chem0977" num="0977"><img file="EP4445902A2_D0978.tif" /></chemistry></entry></row><row><entry>576</entry><entry><chemistry id="chem0978" num="0978"><img file="EP4445902A2_D0979.tif" /></chemistry></entry></row></tbody></tgroup></table></tables><tables id="tabl0023" num="0023"><table frame="all"><title><b>Table 3A: Compounds</b></title><tgroup cols="2"><colspec colnum="1" colname="col1" colwidth="15mm" align="center" /><colspec colnum="2" colname="col2" colwidth="58mm" align="center" /><thead valign="middle"><row><entry><b>Ex.</b></entry><entry><b>Chemical Structure</b></entry></row></thead><tbody valign="middle"><row><entry>587</entry><entry><chemistry id="chem0979" num="0979"><img file="EP4445902A2_D0980.tif" /></chemistry></entry></row><row><entry>589</entry><entry><chemistry id="chem0980" num="0980"><img file="EP4445902A2_D0981.tif" /></chemistry></entry></row><row><entry>590</entry><entry><chemistry id="chem0981" num="0981"><img file="EP4445902A2_D0982.tif" /></chemistry></entry></row><row><entry>591</entry><entry><chemistry id="chem0982" num="0982"><img file="EP4445902A2_D0983.tif" /></chemistry></entry></row><row><entry>592</entry><entry><chemistry id="chem0983" num="0983"><img file="EP4445902A2_D0984.tif" /></chemistry></entry></row><row><entry>593</entry><entry><chemistry id="chem0984" num="0984"><img file="EP4445902A2_D0985.tif" /></chemistry></entry></row><row><entry>594</entry><entry><chemistry id="chem0985" num="0985"><img file="EP4445902A2_D0986.tif" /></chemistry></entry></row><row><entry>595</entry><entry><chemistry id="chem0986" num="0986"><img file="EP4445902A2_D0987.tif" /></chemistry></entry></row><row><entry>596</entry><entry><chemistry id="chem0987" num="0987"><img file="EP4445902A2_D0988.tif" /></chemistry></entry></row><row><entry>597</entry><entry><chemistry id="chem0988" num="0988"><img file="EP4445902A2_D0989.tif" /></chemistry></entry></row><row><entry>598</entry><entry><chemistry id="chem0989" num="0989"><img file="EP4445902A2_D0990.tif" /></chemistry></entry></row><row><entry>599</entry><entry><chemistry id="chem0990" num="0990"><img file="EP4445902A2_D0991.tif" /></chemistry></entry></row><row><entry>600</entry><entry><chemistry id="chem0991" num="0991"><img file="EP4445902A2_D0992.tif" /></chemistry></entry></row><row><entry>601</entry><entry><chemistry id="chem0992" num="0992"><img file="EP4445902A2_D0993.tif" /></chemistry></entry></row><row><entry>602</entry><entry><chemistry id="chem0993" num="0993"><img file="EP4445902A2_D0994.tif" /></chemistry></entry></row><row><entry>603</entry><entry><chemistry id="chem0994" num="0994"><img file="EP4445902A2_D0995.tif" /></chemistry></entry></row><row><entry>604</entry><entry><chemistry id="chem0995" num="0995"><img file="EP4445902A2_D0996.tif" /></chemistry></entry></row><row><entry>606</entry><entry><chemistry id="chem0996" num="0996"><img file="EP4445902A2_D0997.tif" /></chemistry></entry></row><row><entry>607</entry><entry><chemistry id="chem0997" num="0997"><img file="EP4445902A2_D0998.tif" /></chemistry></entry></row><row><entry>608</entry><entry><chemistry id="chem0998" num="0998"><img file="EP4445902A2_D0999.tif" /></chemistry></entry></row><row><entry>609</entry><entry><chemistry id="chem0999" num="0999"><img file="EP4445902A2_D1000.tif" /></chemistry></entry></row><row><entry>610</entry><entry><chemistry id="chem1000" num="1000"><img file="EP4445902A2_D1001.tif" /></chemistry></entry></row><row><entry>611</entry><entry><chemistry id="chem1001" num="1001"><img file="EP4445902A2_D1002.tif" /></chemistry></entry></row><row><entry>612</entry><entry><chemistry id="chem1002" num="1002"><img file="EP4445902A2_D1003.tif" /></chemistry></entry></row><row><entry>613</entry><entry><chemistry id="chem1003" num="1003"><img file="EP4445902A2_D1004.tif" /></chemistry></entry></row></tbody></tgroup></table></tables><tables id="tabl0024" num="0024"><table frame="all"><title><b>Table 3B: Compounds</b></title><tgroup cols="2"><colspec colnum="1" colname="col1" colwidth="15mm" align="center" /><colspec colnum="2" colname="col2" colwidth="62mm" align="center" /><thead valign="middle"><row><entry><b>Ex.</b></entry><entry><b>Chemical Structure</b></entry></row></thead><tbody valign="middle"><row><entry>614</entry><entry><chemistry id="chem1004" num="1004"><img file="EP4445902A2_D1005.tif" /></chemistry></entry></row><row><entry>615</entry><entry><chemistry id="chem1005" num="1005"><img file="EP4445902A2_D1006.tif" /></chemistry></entry></row><row><entry>616</entry><entry><chemistry id="chem1006" num="1006"><img file="EP4445902A2_D1007.tif" /></chemistry></entry></row><row><entry>617</entry><entry><chemistry id="chem1007" num="1007"><img file="EP4445902A2_D1008.tif" /></chemistry></entry></row><row><entry>618</entry><entry><chemistry id="chem1008" num="1008"><img file="EP4445902A2_D1009.tif" /></chemistry></entry></row><row><entry>619</entry><entry><chemistry id="chem1009" num="1009"><img file="EP4445902A2_D1010.tif" /></chemistry></entry></row><row><entry>620</entry><entry><chemistry id="chem1010" num="1010"><img file="EP4445902A2_D1011.tif" /></chemistry></entry></row><row><entry>621</entry><entry><chemistry id="chem1011" num="1011"><img file="EP4445902A2_D1012.tif" /></chemistry></entry></row><row><entry>622</entry><entry><chemistry id="chem1012" num="1012"><img file="EP4445902A2_D1013.tif" /></chemistry></entry></row><row><entry>623</entry><entry><chemistry id="chem1013" num="1013"><img file="EP4445902A2_D1014.tif" /></chemistry></entry></row><row><entry>624</entry><entry><chemistry id="chem1014" num="1014"><img file="EP4445902A2_D1015.tif" /></chemistry></entry></row><row><entry>625</entry><entry><chemistry id="chem1015" num="1015"><img file="EP4445902A2_D1016.tif" /></chemistry></entry></row><row><entry>626</entry><entry><chemistry id="chem1016" num="1016"><img file="EP4445902A2_D1017.tif" /></chemistry></entry></row><row><entry>627</entry><entry><chemistry id="chem1017" num="1017"><img file="EP4445902A2_D1018.tif" /></chemistry></entry></row><row><entry>628</entry><entry><chemistry id="chem1018" num="1018"><img file="EP4445902A2_D1019.tif" /></chemistry></entry></row><row><entry>785</entry><entry><chemistry id="chem1019" num="1019"><img file="EP4445902A2_D1020.tif" /></chemistry></entry></row><row><entry>793</entry><entry><chemistry id="chem1020" num="1020"><img file="EP4445902A2_D1021.tif" /></chemistry></entry></row><row><entry>811</entry><entry><chemistry id="chem1021" num="1021"><img file="EP4445902A2_D1022.tif" /></chemistry></entry></row></tbody></tgroup></table></tables><tables id="tabl0025" num="0025"><table frame="all"><title><b>Table 3C: Compounds</b></title><tgroup cols="2"><colspec colnum="1" colname="col1" colwidth="15mm" align="center" /><colspec colnum="2" colname="col2" colwidth="58mm" align="center" /><thead valign="middle"><row><entry><b>Ex.</b></entry><entry><b>Chemical Structure</b></entry></row></thead><tbody valign="middle"><row><entry>629</entry><entry><chemistry id="chem1022" num="1022"><img file="EP4445902A2_D1023.tif" /></chemistry></entry></row><row><entry>630</entry><entry><chemistry id="chem1023" num="1023"><img file="EP4445902A2_D1024.tif" /></chemistry></entry></row><row><entry>631</entry><entry><chemistry id="chem1024" num="1024"><img file="EP4445902A2_D1025.tif" /></chemistry></entry></row><row><entry>632</entry><entry><chemistry id="chem1025" num="1025"><img file="EP4445902A2_D1026.tif" /></chemistry></entry></row><row><entry>633</entry><entry><chemistry id="chem1026" num="1026"><img file="EP4445902A2_D1027.tif" /></chemistry></entry></row><row><entry>634</entry><entry><chemistry id="chem1027" num="1027"><img file="EP4445902A2_D1028.tif" /></chemistry></entry></row><row><entry>635</entry><entry><chemistry id="chem1028" num="1028"><img file="EP4445902A2_D1029.tif" /></chemistry></entry></row><row><entry>814</entry><entry><chemistry id="chem1029" num="1029"><img file="EP4445902A2_D1030.tif" /></chemistry></entry></row><row><entry>815</entry><entry><chemistry id="chem1030" num="1030"><img file="EP4445902A2_D1031.tif" /></chemistry></entry></row><row><entry>816</entry><entry><chemistry id="chem1031" num="1031"><img file="EP4445902A2_D1032.tif" /></chemistry></entry></row><row><entry>817</entry><entry><chemistry id="chem1032" num="1032"><img file="EP4445902A2_D1033.tif" /></chemistry></entry></row><row><entry>818</entry><entry><chemistry id="chem1033" num="1033"><img file="EP4445902A2_D1034.tif" /></chemistry></entry></row><row><entry>819</entry><entry><chemistry id="chem1034" num="1034"><img file="EP4445902A2_D1035.tif" /></chemistry></entry></row><row><entry>820</entry><entry><chemistry id="chem1035" num="1035"><img file="EP4445902A2_D1036.tif" /></chemistry></entry></row><row><entry>821</entry><entry><chemistry id="chem1036" num="1036"><img file="EP4445902A2_D1037.tif" /></chemistry></entry></row><row><entry>822</entry><entry><chemistry id="chem1037" num="1037"><img file="EP4445902A2_D1038.tif" /></chemistry></entry></row><row><entry>823</entry><entry><chemistry id="chem1038" num="1038"><img file="EP4445902A2_D1039.tif" /></chemistry></entry></row><row><entry>824</entry><entry><chemistry id="chem1039" num="1039"><img file="EP4445902A2_D1040.tif" /></chemistry></entry></row></tbody></tgroup></table></tables><tables id="tabl0026" num="0026"><table frame="all"><title><b>Table 3D: Compounds</b></title><tgroup cols="2"><colspec colnum="1" colname="col1" colwidth="15mm" align="center" /><colspec colnum="2" colname="col2" colwidth="58mm" align="center" /><thead valign="middle"><row><entry><b>Ex.</b></entry><entry><b>Chemical Structure</b></entry></row></thead><tbody valign="middle"><row><entry>656</entry><entry><chemistry id="chem1040" num="1040"><img file="EP4445902A2_D1041.tif" /></chemistry></entry></row><row><entry>657</entry><entry><chemistry id="chem1041" num="1041"><img file="EP4445902A2_D1042.tif" /></chemistry></entry></row><row><entry>658</entry><entry><chemistry id="chem1042" num="1042"><img file="EP4445902A2_D1043.tif" /></chemistry></entry></row><row><entry>659</entry><entry><chemistry id="chem1043" num="1043"><img file="EP4445902A2_D1044.tif" /></chemistry></entry></row><row><entry>660</entry><entry><chemistry id="chem1044" num="1044"><img file="EP4445902A2_D1045.tif" /></chemistry></entry></row><row><entry>661</entry><entry><chemistry id="chem1045" num="1045"><img file="EP4445902A2_D1046.tif" /></chemistry></entry></row><row><entry>662</entry><entry><chemistry id="chem1046" num="1046"><img file="EP4445902A2_D1047.tif" /></chemistry></entry></row><row><entry>663</entry><entry><chemistry id="chem1047" num="1047"><img file="EP4445902A2_D1048.tif" /></chemistry></entry></row><row><entry>664</entry><entry><chemistry id="chem1048" num="1048"><img file="EP4445902A2_D1049.tif" /></chemistry></entry></row><row><entry>665</entry><entry><chemistry id="chem1049" num="1049"><img file="EP4445902A2_D1050.tif" /></chemistry></entry></row><row><entry>667</entry><entry><chemistry id="chem1050" num="1050"><img file="EP4445902A2_D1051.tif" /></chemistry></entry></row><row><entry>668</entry><entry><chemistry id="chem1051" num="1051"><img file="EP4445902A2_D1052.tif" /></chemistry></entry></row><row><entry>669</entry><entry><chemistry id="chem1052" num="1052"><img file="EP4445902A2_D1053.tif" /></chemistry></entry></row><row><entry>670</entry><entry><chemistry id="chem1053" num="1053"><img file="EP4445902A2_D1054.tif" /></chemistry></entry></row><row><entry>671</entry><entry><chemistry id="chem1054" num="1054"><img file="EP4445902A2_D1055.tif" /></chemistry></entry></row><row><entry>672</entry><entry><chemistry id="chem1055" num="1055"><img file="EP4445902A2_D1056.tif" /></chemistry></entry></row><row><entry>673</entry><entry><chemistry id="chem1056" num="1056"><img file="EP4445902A2_D1057.tif" /></chemistry></entry></row><row><entry>674</entry><entry><chemistry id="chem1057" num="1057"><img file="EP4445902A2_D1058.tif" /></chemistry></entry></row><row><entry>675</entry><entry><chemistry id="chem1058" num="1058"><img file="EP4445902A2_D1059.tif" /></chemistry></entry></row><row><entry>676</entry><entry><chemistry id="chem1059" num="1059"><img file="EP4445902A2_D1060.tif" /></chemistry></entry></row><row><entry>677</entry><entry><chemistry id="chem1060" num="1060"><img file="EP4445902A2_D1061.tif" /></chemistry></entry></row><row><entry>678</entry><entry><chemistry id="chem1061" num="1061"><img file="EP4445902A2_D1062.tif" /></chemistry></entry></row><row><entry>679</entry><entry><chemistry id="chem1062" num="1062"><img file="EP4445902A2_D1063.tif" /></chemistry></entry></row><row><entry>680</entry><entry><chemistry id="chem1063" num="1063"><img file="EP4445902A2_D1064.tif" /></chemistry></entry></row></tbody></tgroup></table></tables><tables id="tabl0027" num="0027"><table frame="all"><title><b>Table 3E: Compounds</b></title><tgroup cols="2"><colspec colnum="1" colname="col1" colwidth="15mm" align="center" /><colspec colnum="2" colname="col2" colwidth="58mm" align="center" /><thead valign="middle"><row><entry><b>Ex.</b></entry><entry><b>Chemical Structure</b></entry></row></thead><tbody valign="middle"><row><entry>681</entry><entry><chemistry id="chem1064" num="1064"><img file="EP4445902A2_D1065.tif" /></chemistry></entry></row><row><entry>682</entry><entry><chemistry id="chem1065" num="1065"><img file="EP4445902A2_D1066.tif" /></chemistry></entry></row><row><entry>683</entry><entry><chemistry id="chem1066" num="1066"><img file="EP4445902A2_D1067.tif" /></chemistry></entry></row><row><entry>684</entry><entry><chemistry id="chem1067" num="1067"><img file="EP4445902A2_D1068.tif" /></chemistry></entry></row><row><entry>685</entry><entry><chemistry id="chem1068" num="1068"><img file="EP4445902A2_D1069.tif" /></chemistry></entry></row><row><entry>686</entry><entry><chemistry id="chem1069" num="1069"><img file="EP4445902A2_D1070.tif" /></chemistry></entry></row><row><entry>687</entry><entry><chemistry id="chem1070" num="1070"><img file="EP4445902A2_D1071.tif" /></chemistry></entry></row><row><entry>688</entry><entry><chemistry id="chem1071" num="1071"><img file="EP4445902A2_D1072.tif" /></chemistry></entry></row><row><entry>689</entry><entry><chemistry id="chem1072" num="1072"><img file="EP4445902A2_D1073.tif" /></chemistry></entry></row><row><entry>690</entry><entry><chemistry id="chem1073" num="1073"><img file="EP4445902A2_D1074.tif" /></chemistry></entry></row><row><entry>691</entry><entry><chemistry id="chem1074" num="1074"><img file="EP4445902A2_D1075.tif" /></chemistry></entry></row><row><entry>692</entry><entry><chemistry id="chem1075" num="1075"><img file="EP4445902A2_D1076.tif" /></chemistry></entry></row><row><entry>693</entry><entry><chemistry id="chem1076" num="1076"><img file="EP4445902A2_D1077.tif" /></chemistry></entry></row><row><entry>694</entry><entry><chemistry id="chem1077" num="1077"><img file="EP4445902A2_D1078.tif" /></chemistry></entry></row><row><entry>695</entry><entry><chemistry id="chem1078" num="1078"><img file="EP4445902A2_D1079.tif" /></chemistry></entry></row><row><entry>698</entry><entry><chemistry id="chem1079" num="1079"><img file="EP4445902A2_D1080.tif" /></chemistry></entry></row><row><entry>699</entry><entry><chemistry id="chem1080" num="1080"><img file="EP4445902A2_D1081.tif" /></chemistry></entry></row><row><entry>705</entry><entry><chemistry id="chem1081" num="1081"><img file="EP4445902A2_D1082.tif" /></chemistry></entry></row><row><entry>706</entry><entry><chemistry id="chem1082" num="1082"><img file="EP4445902A2_D1083.tif" /></chemistry></entry></row><row><entry>707</entry><entry><chemistry id="chem1083" num="1083"><img file="EP4445902A2_D1084.tif" /></chemistry></entry></row><row><entry>708</entry><entry><chemistry id="chem1084" num="1084"><img file="EP4445902A2_D1085.tif" /></chemistry></entry></row><row><entry>709</entry><entry><chemistry id="chem1085" num="1085"><img file="EP4445902A2_D1086.tif" /></chemistry></entry></row><row><entry>731</entry><entry><chemistry id="chem1086" num="1086"><img file="EP4445902A2_D1087.tif" /></chemistry></entry></row><row><entry>732</entry><entry><chemistry id="chem1087" num="1087"><img file="EP4445902A2_D1088.tif" /></chemistry></entry></row><row><entry>733</entry><entry><chemistry id="chem1088" num="1088"><img file="EP4445902A2_D1089.tif" /></chemistry></entry></row><row><entry>734</entry><entry><chemistry id="chem1089" num="1089"><img file="EP4445902A2_D1090.tif" /></chemistry></entry></row><row><entry>735</entry><entry><chemistry id="chem1090" num="1090"><img file="EP4445902A2_D1091.tif" /></chemistry></entry></row><row><entry>736</entry><entry><chemistry id="chem1091" num="1091"><img file="EP4445902A2_D1092.tif" /></chemistry></entry></row><row><entry>737</entry><entry><chemistry id="chem1092" num="1092"><img file="EP4445902A2_D1093.tif" /></chemistry></entry></row><row><entry>738</entry><entry><chemistry id="chem1093" num="1093"><img file="EP4445902A2_D1094.tif" /></chemistry></entry></row></tbody></tgroup></table></tables><tables id="tabl0028" num="0028"><table frame="all"><title><b>Table 3F: Compounds</b></title><tgroup cols="2"><colspec colnum="1" colname="col1" colwidth="15mm" align="center" /><colspec colnum="2" colname="col2" colwidth="44mm" align="center" /><thead valign="middle"><row><entry><b>Ex.</b></entry><entry><b>Chemical Structure</b></entry></row></thead><tbody valign="middle"><row><entry>655</entry><entry><chemistry id="chem1094" num="1094"><img file="EP4445902A2_D1095.tif" /></chemistry></entry></row><row><entry>700</entry><entry><chemistry id="chem1095" num="1095"><img file="EP4445902A2_D1096.tif" /></chemistry></entry></row><row><entry>701</entry><entry><chemistry id="chem1096" num="1096"><img file="EP4445902A2_D1097.tif" /></chemistry></entry></row><row><entry>702</entry><entry><chemistry id="chem1097" num="1097"><img file="EP4445902A2_D1098.tif" /></chemistry></entry></row><row><entry>703</entry><entry><chemistry id="chem1098" num="1098"><img file="EP4445902A2_D1099.tif" /></chemistry></entry></row><row><entry>710</entry><entry><chemistry id="chem1099" num="1099"><img file="EP4445902A2_D1100.tif" /></chemistry></entry></row><row><entry>711</entry><entry><chemistry id="chem1100" num="1100"><img file="EP4445902A2_D1101.tif" /></chemistry></entry></row><row><entry>712</entry><entry><chemistry id="chem1101" num="1101"><img file="EP4445902A2_D1102.tif" /></chemistry></entry></row><row><entry>713</entry><entry><chemistry id="chem1102" num="1102"><img file="EP4445902A2_D1103.tif" /></chemistry></entry></row><row><entry>714</entry><entry><chemistry id="chem1103" num="1103"><img file="EP4445902A2_D1104.tif" /></chemistry></entry></row><row><entry>715</entry><entry><chemistry id="chem1104" num="1104"><img file="EP4445902A2_D1105.tif" /></chemistry></entry></row><row><entry>716</entry><entry><chemistry id="chem1105" num="1105"><img file="EP4445902A2_D1106.tif" /></chemistry></entry></row><row><entry>717</entry><entry><chemistry id="chem1106" num="1106"><img file="EP4445902A2_D1107.tif" /></chemistry></entry></row><row><entry>718</entry><entry><chemistry id="chem1107" num="1107"><img file="EP4445902A2_D1108.tif" /></chemistry></entry></row><row><entry>723</entry><entry><chemistry id="chem1108" num="1108"><img file="EP4445902A2_D1109.tif" /></chemistry></entry></row><row><entry>724</entry><entry><chemistry id="chem1109" num="1109"><img file="EP4445902A2_D1110.tif" /></chemistry></entry></row><row><entry>725</entry><entry><chemistry id="chem1110" num="1110"><img file="EP4445902A2_D1111.tif" /></chemistry></entry></row><row><entry>726</entry><entry><chemistry id="chem1111" num="1111"><img file="EP4445902A2_D1112.tif" /></chemistry></entry></row><row><entry>727</entry><entry><chemistry id="chem1112" num="1112"><img file="EP4445902A2_D1113.tif" /></chemistry></entry></row><row><entry>728</entry><entry><chemistry id="chem1113" num="1113"><img file="EP4445902A2_D1114.tif" /></chemistry></entry></row><row><entry>729</entry><entry><chemistry id="chem1114" num="1114"><img file="EP4445902A2_D1115.tif" /></chemistry></entry></row><row><entry>730</entry><entry><chemistry id="chem1115" num="1115"><img file="EP4445902A2_D1116.tif" /></chemistry></entry></row></tbody></tgroup></table></tables><tables id="tabl0029" num="0029"><table frame="all"><title><b>Table 3G: Compounds</b></title><tgroup cols="2"><colspec colnum="1" colname="col1" colwidth="15mm" align="center" /><colspec colnum="2" colname="col2" colwidth="59mm" align="center" /><thead valign="middle"><row><entry><b>Ex.</b></entry><entry><b>Chemical Structure</b></entry></row></thead><tbody valign="middle"><row><entry>704</entry><entry><chemistry id="chem1116" num="1116"><img file="EP4445902A2_D1117.tif" /></chemistry></entry></row><row><entry>739</entry><entry><chemistry id="chem1117" num="1117"><img file="EP4445902A2_D1118.tif" /></chemistry></entry></row><row><entry>740</entry><entry><chemistry id="chem1118" num="1118"><img file="EP4445902A2_D1119.tif" /></chemistry></entry></row><row><entry>741</entry><entry><chemistry id="chem1119" num="1119"><img file="EP4445902A2_D1120.tif" /></chemistry></entry></row><row><entry>742</entry><entry><chemistry id="chem1120" num="1120"><img file="EP4445902A2_D1121.tif" /></chemistry></entry></row><row><entry>743</entry><entry><chemistry id="chem1121" num="1121"><img file="EP4445902A2_D1122.tif" /></chemistry></entry></row><row><entry>744</entry><entry><chemistry id="chem1122" num="1122"><img file="EP4445902A2_D1123.tif" /></chemistry></entry></row><row><entry>745</entry><entry><chemistry id="chem1123" num="1123"><img file="EP4445902A2_D1124.tif" /></chemistry></entry></row><row><entry>746</entry><entry><chemistry id="chem1124" num="1124"><img file="EP4445902A2_D1125.tif" /></chemistry></entry></row><row><entry>752</entry><entry><chemistry id="chem1125" num="1125"><img file="EP4445902A2_D1126.tif" /></chemistry></entry></row><row><entry>753</entry><entry><chemistry id="chem1126" num="1126"><img file="EP4445902A2_D1127.tif" /></chemistry></entry></row><row><entry>754</entry><entry><chemistry id="chem1127" num="1127"><img file="EP4445902A2_D1128.tif" /></chemistry></entry></row><row><entry>755</entry><entry><chemistry id="chem1128" num="1128"><img file="EP4445902A2_D1129.tif" /></chemistry></entry></row><row><entry>756</entry><entry><chemistry id="chem1129" num="1129"><img file="EP4445902A2_D1130.tif" /></chemistry></entry></row><row><entry>757</entry><entry><chemistry id="chem1130" num="1130"><img file="EP4445902A2_D1131.tif" /></chemistry></entry></row><row><entry>758</entry><entry><chemistry id="chem1131" num="1131"><img file="EP4445902A2_D1132.tif" /></chemistry></entry></row><row><entry>759</entry><entry><chemistry id="chem1132" num="1132"><img file="EP4445902A2_D1133.tif" /></chemistry></entry></row><row><entry>760</entry><entry><chemistry id="chem1133" num="1133"><img file="EP4445902A2_D1134.tif" /></chemistry></entry></row><row><entry>761</entry><entry><chemistry id="chem1134" num="1134"><img file="EP4445902A2_D1135.tif" /></chemistry></entry></row><row><entry>762</entry><entry><chemistry id="chem1135" num="1135"><img file="EP4445902A2_D1136.tif" /></chemistry></entry></row><row><entry>763</entry><entry><chemistry id="chem1136" num="1136"><img file="EP4445902A2_D1137.tif" /></chemistry></entry></row><row><entry>764</entry><entry><chemistry id="chem1137" num="1137"><img file="EP4445902A2_D1138.tif" /></chemistry></entry></row><row><entry>765</entry><entry><chemistry id="chem1138" num="1138"><img file="EP4445902A2_D1139.tif" /></chemistry></entry></row><row><entry>766</entry><entry><chemistry id="chem1139" num="1139"><img file="EP4445902A2_D1140.tif" /></chemistry></entry></row><row><entry>788</entry><entry><chemistry id="chem1140" num="1140"><img file="EP4445902A2_D1141.tif" /></chemistry></entry></row><row><entry>796</entry><entry><chemistry id="chem1141" num="1141"><img file="EP4445902A2_D1142.tif" /></chemistry></entry></row><row><entry>801</entry><entry><chemistry id="chem1142" num="1142"><img file="EP4445902A2_D1143.tif" /></chemistry></entry></row><row><entry>802</entry><entry><chemistry id="chem1143" num="1143"><img file="EP4445902A2_D1144.tif" /></chemistry></entry></row><row><entry>803</entry><entry><chemistry id="chem1144" num="1144"><img file="EP4445902A2_D1145.tif" /></chemistry></entry></row><row><entry>804</entry><entry><chemistry id="chem1145" num="1145"><img file="EP4445902A2_D1146.tif" /></chemistry></entry></row><row><entry>805</entry><entry><chemistry id="chem1146" num="1146"><img file="EP4445902A2_D1147.tif" /></chemistry></entry></row><row><entry>806</entry><entry><chemistry id="chem1147" num="1147"><img file="EP4445902A2_D1148.tif" /></chemistry></entry></row><row><entry>807</entry><entry><chemistry id="chem1148" num="1148"><img file="EP4445902A2_D1149.tif" /></chemistry></entry></row></tbody></tgroup></table></tables><tables id="tabl0030" num="0030"><table frame="all"><title><b>Table 3H: Compounds</b></title><tgroup cols="2"><colspec colnum="1" colname="col1" colwidth="15mm" align="center" /><colspec colnum="2" colname="col2" colwidth="44mm" align="center" /><thead valign="middle"><row><entry><b>Ex.</b></entry><entry><b>Chemical Structure</b></entry></row></thead><tbody valign="middle"><row><entry>577</entry><entry><chemistry id="chem1149" num="1149"><img file="EP4445902A2_D1150.tif" /></chemistry></entry></row><row><entry>578</entry><entry><chemistry id="chem1150" num="1150"><img file="EP4445902A2_D1151.tif" /></chemistry></entry></row><row><entry>579</entry><entry><chemistry id="chem1151" num="1151"><img file="EP4445902A2_D1152.tif" /></chemistry></entry></row><row><entry>580</entry><entry><chemistry id="chem1152" num="1152"><img file="EP4445902A2_D1153.tif" /></chemistry></entry></row><row><entry>581</entry><entry><chemistry id="chem1153" num="1153"><img file="EP4445902A2_D1154.tif" /></chemistry></entry></row><row><entry>582</entry><entry><chemistry id="chem1154" num="1154"><img file="EP4445902A2_D1155.tif" /></chemistry></entry></row><row><entry>583</entry><entry><chemistry id="chem1155" num="1155"><img file="EP4445902A2_D1156.tif" /></chemistry></entry></row><row><entry>584</entry><entry><chemistry id="chem1156" num="1156"><img file="EP4445902A2_D1157.tif" /></chemistry></entry></row><row><entry>747</entry><entry><chemistry id="chem1157" num="1157"><img file="EP4445902A2_D1158.tif" /></chemistry></entry></row><row><entry>748</entry><entry><chemistry id="chem1158" num="1158"><img file="EP4445902A2_D1159.tif" /></chemistry></entry></row><row><entry>749</entry><entry><chemistry id="chem1159" num="1159"><img file="EP4445902A2_D1160.tif" /></chemistry></entry></row><row><entry>750</entry><entry><chemistry id="chem1160" num="1160"><img file="EP4445902A2_D1161.tif" /></chemistry></entry></row><row><entry>751</entry><entry><chemistry id="chem1161" num="1161"><img file="EP4445902A2_D1162.tif" /></chemistry></entry></row><row><entry>767</entry><entry><chemistry id="chem1162" num="1162"><img file="EP4445902A2_D1163.tif" /></chemistry></entry></row><row><entry>768</entry><entry><chemistry id="chem1163" num="1163"><img file="EP4445902A2_D1164.tif" /></chemistry></entry></row><row><entry>769</entry><entry><chemistry id="chem1164" num="1164"><img file="EP4445902A2_D1165.tif" /></chemistry></entry></row><row><entry>770</entry><entry><chemistry id="chem1165" num="1165"><img file="EP4445902A2_D1166.tif" /></chemistry></entry></row><row><entry>771</entry><entry><chemistry id="chem1166" num="1166"><img file="EP4445902A2_D1167.tif" /></chemistry></entry></row><row><entry>772</entry><entry><chemistry id="chem1167" num="1167"><img file="EP4445902A2_D1168.tif" /></chemistry></entry></row><row><entry>773</entry><entry><chemistry id="chem1168" num="1168"><img file="EP4445902A2_D1169.tif" /></chemistry></entry></row><row><entry>774</entry><entry><chemistry id="chem1169" num="1169"><img file="EP4445902A2_D1170.tif" /></chemistry></entry></row><row><entry>775</entry><entry><chemistry id="chem1170" num="1170"><img file="EP4445902A2_D1171.tif" /></chemistry></entry></row><row><entry>776</entry><entry><chemistry id="chem1171" num="1171"><img file="EP4445902A2_D1172.tif" /></chemistry></entry></row><row><entry>777</entry><entry><chemistry id="chem1172" num="1172"><img file="EP4445902A2_D1173.tif" /></chemistry></entry></row></tbody></tgroup></table></tables><tables id="tabl0031" num="0031"><table frame="all"><title><b>Table 3I: Compounds</b></title><tgroup cols="2"><colspec colnum="1" colname="col1" colwidth="15mm" align="center" /><colspec colnum="2" colname="col2" colwidth="45mm" align="center" /><thead valign="middle"><row><entry><b>Ex.</b></entry><entry><b>Chemical Structure</b></entry></row></thead><tbody valign="middle"><row><entry>585</entry><entry><chemistry id="chem1173" num="1173"><img file="EP4445902A2_D1174.tif" /></chemistry></entry></row><row><entry>586</entry><entry><chemistry id="chem1174" num="1174"><img file="EP4445902A2_D1175.tif" /></chemistry></entry></row><row><entry>605</entry><entry><chemistry id="chem1175" num="1175"><img file="EP4445902A2_D1176.tif" /></chemistry></entry></row><row><entry>645</entry><entry><chemistry id="chem1176" num="1176"><img file="EP4445902A2_D1177.tif" /></chemistry></entry></row><row><entry>646</entry><entry><chemistry id="chem1177" num="1177"><img file="EP4445902A2_D1178.tif" /></chemistry></entry></row><row><entry>666</entry><entry><chemistry id="chem1178" num="1178"><img file="EP4445902A2_D1179.tif" /></chemistry></entry></row><row><entry>719</entry><entry><chemistry id="chem1179" num="1179"><img file="EP4445902A2_D1180.tif" /></chemistry></entry></row><row><entry>720</entry><entry><chemistry id="chem1180" num="1180"><img file="EP4445902A2_D1181.tif" /></chemistry></entry></row><row><entry>721</entry><entry><chemistry id="chem1181" num="1181"><img file="EP4445902A2_D1182.tif" /></chemistry></entry></row><row><entry>722</entry><entry><chemistry id="chem1182" num="1182"><img file="EP4445902A2_D1183.tif" /></chemistry></entry></row><row><entry>778</entry><entry><chemistry id="chem1183" num="1183"><img file="EP4445902A2_D1184.tif" /></chemistry></entry></row><row><entry>779</entry><entry><chemistry id="chem1184" num="1184"><img file="EP4445902A2_D1185.tif" /></chemistry></entry></row><row><entry>780</entry><entry><chemistry id="chem1185" num="1185"><img file="EP4445902A2_D1186.tif" /></chemistry></entry></row><row><entry>781</entry><entry><chemistry id="chem1186" num="1186"><img file="EP4445902A2_D1187.tif" /></chemistry></entry></row><row><entry>782</entry><entry><chemistry id="chem1187" num="1187"><img file="EP4445902A2_D1188.tif" /></chemistry></entry></row><row><entry>783</entry><entry><chemistry id="chem1188" num="1188"><img file="EP4445902A2_D1189.tif" /></chemistry></entry></row><row><entry>784</entry><entry><chemistry id="chem1189" num="1189"><img file="EP4445902A2_D1190.tif" /></chemistry></entry></row><row><entry>786</entry><entry><chemistry id="chem1190" num="1190"><img file="EP4445902A2_D1191.tif" /></chemistry></entry></row><row><entry>789</entry><entry><chemistry id="chem1191" num="1191"><img file="EP4445902A2_D1192.tif" /></chemistry></entry></row></tbody></tgroup></table></tables><tables id="tabl0032" num="0032"><table frame="all"><title><b>Table 3J: Compounds</b></title><tgroup cols="2"><colspec colnum="1" colname="col1" colwidth="15mm" align="center" /><colspec colnum="2" colname="col2" colwidth="42mm" align="center" /><thead valign="middle"><row><entry><b>Ex.</b></entry><entry><b>Chemical Structure</b></entry></row></thead><tbody valign="middle"><row><entry>588</entry><entry><chemistry id="chem1192" num="1192"><img file="EP4445902A2_D1193.tif" /></chemistry></entry></row><row><entry>636</entry><entry><chemistry id="chem1193" num="1193"><img file="EP4445902A2_D1194.tif" /></chemistry></entry></row><row><entry>637</entry><entry><chemistry id="chem1194" num="1194"><img file="EP4445902A2_D1195.tif" /></chemistry></entry></row><row><entry>638</entry><entry><chemistry id="chem1195" num="1195"><img file="EP4445902A2_D1196.tif" /></chemistry></entry></row><row><entry>639</entry><entry><chemistry id="chem1196" num="1196"><img file="EP4445902A2_D1197.tif" /></chemistry></entry></row><row><entry>640</entry><entry><chemistry id="chem1197" num="1197"><img file="EP4445902A2_D1198.tif" /></chemistry></entry></row><row><entry>641</entry><entry><chemistry id="chem1198" num="1198"><img file="EP4445902A2_D1199.tif" /></chemistry></entry></row><row><entry>642</entry><entry><chemistry id="chem1199" num="1199"><img file="EP4445902A2_D1200.tif" /></chemistry></entry></row><row><entry>643</entry><entry><chemistry id="chem1200" num="1200"><img file="EP4445902A2_D1201.tif" /></chemistry></entry></row><row><entry>787</entry><entry><chemistry id="chem1201" num="1201"><img file="EP4445902A2_D1202.tif" /></chemistry></entry></row><row><entry>790</entry><entry><chemistry id="chem1202" num="1202"><img file="EP4445902A2_D1203.tif" /></chemistry></entry></row><row><entry>791</entry><entry><chemistry id="chem1203" num="1203"><img file="EP4445902A2_D1204.tif" /></chemistry></entry></row><row><entry>792</entry><entry><chemistry id="chem1204" num="1204"><img file="EP4445902A2_D1205.tif" /></chemistry></entry></row><row><entry>794</entry><entry><chemistry id="chem1205" num="1205"><img file="EP4445902A2_D1206.tif" /></chemistry></entry></row><row><entry>795</entry><entry><chemistry id="chem1206" num="1206"><img file="EP4445902A2_D1207.tif" /></chemistry></entry></row><row><entry>797</entry><entry><chemistry id="chem1207" num="1207"><img file="EP4445902A2_D1208.tif" /></chemistry></entry></row><row><entry>798</entry><entry><chemistry id="chem1208" num="1208"><img file="EP4445902A2_D1209.tif" /></chemistry></entry></row><row><entry>799</entry><entry><chemistry id="chem1209" num="1209"><img file="EP4445902A2_D1210.tif" /></chemistry></entry></row><row><entry>800</entry><entry><chemistry id="chem1210" num="1210"><img file="EP4445902A2_D1211.tif" /></chemistry></entry></row><row><entry>808</entry><entry><chemistry id="chem1211" num="1211"><img file="EP4445902A2_D1212.tif" /></chemistry></entry></row></tbody></tgroup></table></tables><tables id="tabl0033" num="0033"><table frame="all"><title><b>Table 3K: Compounds</b></title><tgroup cols="2"><colspec colnum="1" colname="col1" colwidth="15mm" align="center" /><colspec colnum="2" colname="col2" colwidth="44mm" align="center" /><thead valign="middle"><row><entry><b>Ex.</b></entry><entry><b>Chemical Structure</b></entry></row></thead><tbody valign="middle"><row><entry>644</entry><entry><chemistry id="chem1212" num="1212"><img file="EP4445902A2_D1213.tif" /></chemistry></entry></row><row><entry>647</entry><entry><chemistry id="chem1213" num="1213"><img file="EP4445902A2_D1214.tif" /></chemistry></entry></row><row><entry>648</entry><entry><chemistry id="chem1214" num="1214"><img file="EP4445902A2_D1215.tif" /></chemistry></entry></row><row><entry>649</entry><entry><chemistry id="chem1215" num="1215"><img file="EP4445902A2_D1216.tif" /></chemistry></entry></row><row><entry>650</entry><entry><chemistry id="chem1216" num="1216"><img file="EP4445902A2_D1217.tif" /></chemistry></entry></row><row><entry>651</entry><entry><chemistry id="chem1217" num="1217"><img file="EP4445902A2_D1218.tif" /></chemistry></entry></row><row><entry>652</entry><entry><chemistry id="chem1218" num="1218"><img file="EP4445902A2_D1219.tif" /></chemistry></entry></row><row><entry>653</entry><entry><chemistry id="chem1219" num="1219"><img file="EP4445902A2_D1220.tif" /></chemistry></entry></row><row><entry>654</entry><entry><chemistry id="chem1220" num="1220"><img file="EP4445902A2_D1221.tif" /></chemistry></entry></row><row><entry>696</entry><entry><chemistry id="chem1221" num="1221"><img file="EP4445902A2_D1222.tif" /></chemistry></entry></row><row><entry>697</entry><entry><chemistry id="chem1222" num="1222"><img file="EP4445902A2_D1223.tif" /></chemistry></entry></row><row><entry>809</entry><entry><chemistry id="chem1223" num="1223"><img file="EP4445902A2_D1224.tif" /></chemistry></entry></row><row><entry>810</entry><entry><chemistry id="chem1224" num="1224"><img file="EP4445902A2_D1225.tif" /></chemistry></entry></row><row><entry>812</entry><entry><chemistry id="chem1225" num="1225"><img file="EP4445902A2_D1226.tif" /></chemistry></entry></row><row><entry>813</entry><entry><chemistry id="chem1226" num="1226"><img file="EP4445902A2_D1227.tif" /></chemistry></entry></row><row><entry>825</entry><entry><chemistry id="chem1227" num="1227"><img file="EP4445902A2_D1228.tif" /></chemistry></entry></row><row><entry>826</entry><entry><chemistry id="chem1228" num="1228"><img file="EP4445902A2_D1229.tif" /></chemistry></entry></row><row><entry>827</entry><entry><chemistry id="chem1229" num="1229"><img file="EP4445902A2_D1230.tif" /></chemistry></entry></row><row><entry>828</entry><entry><chemistry id="chem1230" num="1230"><img file="EP4445902A2_D1231.tif" /></chemistry></entry></row><row><entry>829</entry><entry><chemistry id="chem1231" num="1231"><img file="EP4445902A2_D1232.tif" /></chemistry></entry></row></tbody></tgroup></table></tables><tables id="tabl0034" num="0034"><table frame="all"><title><b>Table 1A-1. Compounds</b></title><tgroup cols="2"><colspec colnum="1" colname="col1" colwidth="15mm" align="center" /><colspec colnum="2" colname="col2" colwidth="34mm" align="center" /><thead valign="middle"><row><entry><b>Ex.</b></entry><entry><b>Chemical Structure</b></entry></row></thead><tbody valign="middle"><row><entry>3</entry><entry><chemistry id="chem1232" num="1232"><img file="EP4445902A2_D1233.tif" /></chemistry></entry></row><row><entry>7</entry><entry><chemistry id="chem1233" num="1233"><img file="EP4445902A2_D1234.tif" /></chemistry></entry></row></tbody></tgroup></table></tables>

0178Also falling within the scope herein are the <i>in vivo</i> metabolic products of the compounds described herein, to the extent such products are novel and unobvious over the prior art. Such products may result for example from the oxidation, reduction, hydrolysis, amidation, esterification and the like of the administered compound, primarily due to enzymatic processes. Accordingly, included are novel and unobvious compounds produced by a process comprising contacting a compound with a mammal for a period of time sufficient to yield a metabolic product thereof. Such products typically are identified by preparing a radiolabelled (e.g. ¹⁴C or ³H) compound, administering it parenterally in a detectable dose (e.g. greater than about 0.5 mg/kg) to an animal such as rat, mouse, guinea pig, monkey, or to man, allowing sufficient time for metabolism to occur (typically from about 30 seconds to about 30 hours) and isolating its conversion products from the urine, blood or other biological samples. These products are easily isolated since they are labeled (others are isolated by the use of antibodies capable of binding epitopes surviving in the metabolite). The metabolite structures are determined in conventional fashion, e.g. by MS or NMR analysis. In general, analysis of metabolites is done in the same way as conventional drug metabolism studies well-known to those skilled in the art.

0179In some embodiments, a compound of the present disclosure has selectivity for DGKα over one or more of the other DGK isoforms, e.g., β, γ, δ, ε, ζ, η, θ, <img file="EP4445902A2_D1235.tif" /> , and/or κ. Selectivity can be measured by relative values in corresponding biochemical assays, e.g., activity to inhibit a DGK isoform. In some embodiments, the compound comprises an activity against DGKβ, DGKγ, DGKδ, DGKε, DGKζ, DGKη, DGKθ, DGKκ, and/or DGKκ, wherein the IC₅₀ is greater than about 30 µM in a biochemical assay.

0180In some embodiments, a compound of the present disclosure has selectivity for DGKα of at least about 1.2, about 1.5, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 15, about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90, about 100, about 200, about 300, about 400, about 500, about 1000, about 2000, about 3000, about 4000, about 5000, or about 10000-fold or more over one or more, e.g., 2, 3, 4, 5, 6, 7, 8, or 9 or more, other DGK isoforms including DGKβ, DGKγ, DGKδ, DGKε, DGKζ, DGKη, DGKθ, DGKκ, and/or DGKκ. In some embodiments, the compound has selectivity for DGKα of at least about 1.2, about 1.5, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 15, about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90, about 100, about 200, about 300, about 400, about 500, about 1000, about 2000, about 3000, about 4000, about 5000, or about 10000-fold or more over DGKβ and/or DGKγ. In some embodiments, the compound has selectivity for DGKα of at least about 1.2, about 1.5, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 15, about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90, about 100, about 200, about 300, about 400, about 500, about 1000, about 2000, about 3000, about 4000, about 5000, or about 10000-fold or more over DGKβ. In some embodiments, the compound has selectivity for DGKα of at least about 1.2, about 1.5, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 15, about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90, about 100, about 200, about 300, about 400, about 500, about 1000, about 2000, about 3000, about 4000, about 5000, or about 10000-fold or more over DGKγ. In some embodiments, the compound has selectivity for DGKα of at least about 1.2, about 1.5, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 15, about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90, about 100, about 200, about 300, about 400, about 500, about 1000, about 2000, about 3000, about 4000, about 5000, or about 10000-fold or more over DGKδ. In some embodiments, the compound has selectivity for DGKα of at least about 1.2, about 1.5, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 15, about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90, about 100, about 200, about 300, about 400, about 500, about 1000, about 2000, about 3000, about 4000, about 5000, or about 10000-fold or more over DGKε. In some embodiments, the compound has selectivity for DGKα of at least about 1.2, about 1.5, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 15, about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90, about 100, about 200, about 300, about 400, about 500, about 1000, about 2000, about 3000, about 4000, about 5000, or about 10000-fold or more over DGKζ. In some embodiments, the compound has selectivity for DGKα of at least about 1.2, about 1.5, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 15, about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90, about 100, about 200, about 300, about 400, about 500, about 1000, about 2000, about 3000, about 4000, about 5000, or about 10000-fold or more over DGKη. In some embodiments, the compound has selectivity for DGKα of at least about 1.2, about 1.5, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 15, about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90, about 100, about 200, about 300, about 400, about 500, about 1000, about 2000, about 3000, about 4000, about 5000, or about 10000-fold or more over DGKθ. In some embodiments, the compound has selectivity for DGKα of at least about 1.2, about 1.5, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 15, about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90, about 100, about 200, about 300, about 400, about 500, about 1000, about 2000, about 3000, about 4000, about 5000, or about 10000-fold or more over DGK<img file="EP4445902A2_D1236.tif" /> . In some embodiments, the compound has selectivity for DGKα of at least about 1.2, about 1.5, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 15, about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90, about 100, about 200, about 300, about 400, about 500, about 1000, about 2000, about 3000, about 4000, about 5000, or about 10000-fold or more over DGKκ.

III. PHARMACEUTICAL FORMULATIONS

0181In some embodiments, the present disclosure provides a pharmaceutical formulation comprising a pharmaceutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. Also provided herein is a pharmaceutical formulation comprising a pharmaceutically effective amount of a compound of Formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt, solvate, and/or ester thereof, and a pharmaceutically acceptable carrier or excipient.

0182In some embodiments, the pharmaceutical composition further comprises one or more additional therapeutic agents. Any suitable additional therapeutic agent or combination therapy can be used with the compounds of Formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, such as the agents and therapies described within.

0183In some embodiments, the pharmaceutical composition comprises a compound of Formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), and an additional therapeutic agent, wherein the additional therapeutic agent is an anticancer agent. In some embodiments, the pharmaceutical composition is the pharmaceutical composition wherein the additional therapeutic agent is independently an anti-neoplastic agent, nivolumab, pembrolizumab, atezolizumab, ipilimumab, chemotherapy, radiation therapy, or resection therapy. In some embodiments, the pharmaceutical composition is the pharmaceutical composition wherein the additional therapeutic agent is independently rituxan, doxorubicin, gemcitabine, nivolumab, pembrolizumab, artezolizumab, nivolumab, pembrolizumab, atezolizumab, or ipilimumab. In some embodiments, the pharmaceutical composition is the pharmaceutical composition wherein the additional therapeutic agent is a PD-1/PD-L1 inhibitor. In some embodiments, the pharmaceutical composition is the pharmaceutical composition wherein the additional therapeutic agent is a vaccine.

0184In some embodiments, the pharmaceutical composition is the pharmaceutical composition wherein the additional therapeutic agent comprises one or more populations of immune cells, such as natural killer (NK) cells, NK-T cells, T cells, cytokine-induced killer (CIK) cells, macrophage (MAC) cells, tumor infiltrating lymphocytes (TILs) and dendritic cell (DCs).

0185In some embodiments, the pharmaceutical composition is the pharmaceutical composition wherein the additional therapeutic agent comprises one or more chimeric antigen receptors (CARs).

0186In some embodiments, the pharmaceutical composition is the pharmaceutical composition wherein the additional therapeutic agent comprises an immunotherapy, an immunostimulatory therapy, a cytokine therapy, a chemokine therapy, a cellular therapy, a gene therapy, or combinations thereof.

0187In some embodiments, the pharmaceutical composition comprises a compound of Formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), and an additional therapeutic agent, wherein the additional therapeutic agent is an agent effective against a viral infection. In some embodiments, the viral infection is HIV. In some embodiments, the viral infection is hepatitis B virus. In some embodiments, the pharmaceutical composition comprises a compound of Formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), and an additional therapeutic agent, wherein additional therapeutic agent comprises a vaccine.

0188In some embodiments, the pharmaceutical composition is for use in treating a cancer.

0189In some embodiments, the pharmaceutical composition is for use in treating an HIV or hepatitis B infection.

0190In some embodiments, compounds disclosed herein are formulated with conventional carriers and excipients, which can be selected in accord with ordinary practice. Tablets can contain excipients, glidants, fillers, binders and the like. Aqueous formulations can be prepared in sterile form, and can be isotonic, for instance when intended for delivery by other than oral administration. In some embodiments, formulations can optionally contain excipients such as those set forth in the "Handbook of Pharmaceutical Excipients" (1986). Excipients can include, for example, ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextran, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid and the like. The pH of the formulations ranges from about 3 to about 11, for example from about 7 to about 10.

0191In some embodiments, the compounds disclosed herein are administered alone. In some embodiments, compounds disclosed herein are administered in pharmaceutical formulations. In some embodiments a formulation, for veterinary and/or for human use, comprises at least one compound of Formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt, solvate, and/or ester thereof, together with one or more acceptable carriers and optionally other therapeutic ingredients, such as those additional therapeutic ingredients discussed herein. In some embodiments, carrier(s) are "acceptable" in the sense of being compatible with the other ingredients of the formulation and physiologically innocuous to the recipient thereof.

0192In some embodiments, formulations of the disclosure include those suitable for the foregoing administration routes. In some embodiments, formulations are presented in unit dosage form. Formulations may be prepared by methods known in the art of pharmacy. Techniques and formulations can be found, for example, in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA). Such methods include, for instance, a step of bringing into association the active ingredient with a carrier comprising one or more accessory ingredients. In some embodiments, formulations are prepared by bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, in some embodiments, shaping the product.

0193Formulations suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of active ingredient, such as a compound of Formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt, solvate, and/or ester thereof; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. In some embodiments, an active ingredient is administered as a bolus, electuary or paste.

0194A tablet can be made, for example, by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared, for example, by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active or dispersing agent. Molded tablets may be made, for instance, by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent. The tablets may optionally be coated or scored. In some embodiments, tablets are formulated so as to provide slow or controlled release of the active ingredient therefrom.

0195For infections of the eye or other external tissues e.g. mouth and skin, the formulations can be applied as a topical ointment or cream containing a compound of Formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8) in an amount of, for example, about 0.075 to about 20% w/w (including active ingredient(s) in a range between about 0.1% and about 20% in increments of about 0.1% w/w such as about 0.6% w/w, about 0.7% w/w, etc.), such as about 0.2 to about 15% w/w and such as about 0.5 to about 10% w/w. When formulated in an ointment, a compound of Formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8) may be employed with either a paraffinic or a water-miscible ointment base. Alternatively, a compound of Formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8) may be formulated in a cream with an oil-in-water cream base.

0196If desired, the aqueous phase of the cream base may include, for example, at least about 30% w/w of a polyhydric alcohol, i.e. an alcohol having two or more hydroxyl groups such as propylene glycol, butane 1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol (including PEG 400) and mixtures thereof. The topical formulations may in some embodiments include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethyl sulfoxide and related analogs.

0197The oily phase of the emulsions may be constituted from known ingredients in a known manner. While the phase may comprise merely an emulsifier (otherwise known as an emulgent), it can comprise, for example, a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. In some embodiments, a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabilizer. In some embodiments, an emulsion includes both an oil and a fat. Together, the emulsifier(s) with or without stabilizer(s) make up the so-called emulsifying wax, and the wax together with the oil and fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations.

0198Emulgents and emulsion stabilizers suitable for use in the formulation include, for instance, Tween^® 60, Span^® 80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl mono-stearate and sodium lauryl sulfate.

0199The choice of suitable oils or fats for the formulation is based on achieving the desired properties. The cream can be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers. Straight or branched chain, mono- or dibasic alkyl esters such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters known as Crodamol CAP may be used. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils can be used.

0200In some embodiments, pharmaceutical formulations herein comprise a combination together with one or more pharmaceutically acceptable carriers or excipients and optionally other therapeutic agents. Pharmaceutical formulations containing the active ingredient may be in any form suitable for the intended method of administration. When used for oral use for example, tablets, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, solutions, syrups or elixirs may be prepared. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents including sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a palatable preparation. Tablets containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipient which are suitable for manufacture of tablets are acceptable. These excipients may be, for example, inert diluents, such as calcium or sodium carbonate, lactose, calcium or sodium phosphate; granulating and disintegrating agents, such as maize starch, or alginic acid; binding agents, such as starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.

0201Formulations for oral use may be also presented as hard gelatin capsules where the active ingredient is mixed with an inert solid diluent, for example calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil.

0202Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include a suspending agent, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcelluose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as a naturally-occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethyleneoxycetanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate). The aqueous suspension may also contain one or more preservatives such as ethyl or n-propyl p-hydroxy-benzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose or saccharin.

0203Oil suspensions may be formulated by suspending the active ingredient in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oral suspensions may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid.

0204Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those disclosed above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.

0205The pharmaceutical compositions may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, such as olive oil or arachis oil, a mineral oil, such as liquid paraffin, or a mixture of these. Suitable emulsifying agents include naturally-occurring gums, such as gum acacia and gum tragacanth, naturally-occurring phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsion may also contain sweetening and flavoring agents. Syrups and elixirs may be formulated with sweetening agents, such as glycerol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, a flavoring or a coloring agent.

0206The pharmaceutical compositions may be in the form of a sterile injectable or intravenous preparations, such as a sterile injectable aqueous or oleaginous suspension. Such suspensions may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. Sterile injectable or intravenous preparations may also include a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butane-diol or prepared as a lyophilized powder. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils may conventionally be employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid may likewise be used in the preparation of injectables.

0207The amount of active ingredient that may be combined with the carrier material to produce a single dosage form can vary depending upon the host treated and the particular mode of administration. For example, a time-release formulation intended for oral administration to humans may contain about 1 to about 1000 mg of active material compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95% of the total compositions (weight:weight). The pharmaceutical composition can be prepared to provide easily measurable amounts for administration. For example, an aqueous solution intended for intravenous infusion may contain from about 3 to about 500 µg of the active ingredient per milliliter of solution in order that infusion of a suitable volume at a rate of about 30 mL/hr can occur.

0208Formulations suitable for topical administration to the eye also include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient. The active ingredient can be present in such formulations in a concentration of about 0.5 to about 20%, such as about 0.5 to about 10%, for example about 1.5% w/w.

0209Formulations suitable for topical administration in the mouth include, for example, lozenges comprising the active ingredient in a flavored basis, such as sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis, such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.

0210Formulations for rectal administration may be presented as a suppository with a suitable base comprising, for example, cocoa butter or a salicylate.

0211Formulations suitable for intrapulmonary or nasal administration have a particle size, for example, in the range of about 0.1 to about 500 microns, such as about 0.5, about 1, about 30, or about 35, etc., which is administered by rapid inhalation through the nasal passage or by inhalation through the mouth so as to reach the alveolar sacs. Suitable formulations include aqueous or oily solutions of the active ingredient. Formulations suitable for aerosol or dry powder administration may be prepared according to conventional methods and may be delivered with other therapeutic agents such as compounds heretofore used in the treatment of cancer as described below.

0212In some embodiments, an inhalable composition comprises a compound of Formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof. In some embodiments, the inhalable composition is suitable for treating cancer. In some embodiments, pharmaceutically acceptable salts are inorganic acid salts including hydrochloride, hydrobromide, sulfate or phosphate salts. For example, such salts may cause less pulmonary irritation relative to other salts. In some embodiments, an inhalable composition is delivered to the endobronchial space in an aerosol comprising particles with a mass median aerodynamic diameter (MMAD) between about 1 and about 5 µm. In some embodiments, the compound of Formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8) is formulated for aerosol delivery using a nebulizer, pressurized metered dose inhaler (pMDI), or dry powder inhaler (DPI).

0213Non-limiting examples of nebulizers include atomizing, jet, ultrasonic, pressurized, vibrating porous plate, or equivalent nebulizers including those nebulizers utilizing adaptive aerosol delivery technology (<nplcit id="ncit0014" npl-type="s"><text>Denyer, J. Aerosol medicine Pulmonary Drug Delivery 2010, 23 Supp 1, S1-S10</text></nplcit>). A jet nebulizer utilizes air pressure to break a liquid solution into aerosol droplets. An ultrasonic nebulizer works by a piezoelectric crystal that shears a liquid into small aerosol droplets. A pressurized nebulization system forces solution under pressure through small pores to generate aerosol droplets. A vibrating porous plate device utilizes rapid vibration to shear a stream of liquid into appropriate droplet sizes.

0214In some embodiments, a formulation for nebulization is delivered to the endobronchial space in an aerosol comprising particles with a MMAD predominantly between about 1 µm and about 5 µm using a nebulizer able to aerosolize the formulation of the compound of Formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8) into particles of the required MMAD. To be optimally therapeutically effective and to avoid upper respiratory and systemic side effects, the majority of aerosolized particles should not have a MMAD greater than about 5 µm. If an aerosol contains a large number of particles with a MMAD larger than about 5 µm, the particles are deposited in the upper airways decreasing the amount of drug delivered to the site of inflammation and bronchoconstriction in the lower respiratory tract. If the MMAD of the aerosol is smaller than about 1 µm, then the particles can in some cases remain suspended in the inhaled air and may be subsequently exhaled during expiration.

0215When formulated and delivered according to methods herein, the aerosol formulation for nebulization delivers a therapeutically efficacious dose of the compound of Formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8) to a therapeutic target, such as the site of a cancer. The amount of drug administered can be adjusted to reflect the efficiency of the delivery of a therapeutically efficacious dose of the compound of Formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8). In some embodiments, a combination of the aqueous aerosol formulation with the atomizing, jet, pressurized, vibrating porous plate, or ultrasonic nebulizer permits, depending on the nebulizer, from about 20 to about 90%, such as about 70% delivery of the administered dose of the compound of Formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8) into the airways. In some embodiments, from about 30 to about 50% of the active compound is delivered. For example, from about 70 to about 90% of the active compound can be delivered.

0216In some embodiments, a compound of Formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8) or a pharmaceutically acceptable salt thereof, is delivered as a dry inhalable powder. The compounds are administered endobronchially as a dry powder formulation to efficacious deliver fine particles of compound into the endobronchial space using dry powder or metered dose inhalers. For delivery by DPI, the compound of Formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8) is processed into particles with, predominantly, MMAD between about 1 µm and about 5 µm by milling spray drying, critical fluid processing, or precipitation from solution. Media milling, jet milling and spray-drying devices and procedures capable of producing the particle sizes with a MMAD between about 1 µm and about 5 µm are well known in the art. In some embodiments, excipients are added to the compound of Formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8) before processing into particles of the required sizes. In some embodiments, excipients are blended with the particles of the required size to aid in dispersion of the drug particles, for example by using lactose as an excipient.

0217Particle size determinations are made using devices well known in the art. For example a multi-stage Anderson cascade impactor or other suitable method such as those specifically cited within the US Pharmacopoeia Chapter 601 as characterizing devices for aerosols within metered-dose and dry powder inhalers.

0218In some embodiments, a compound of Formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8) can be delivered as a dry powder using a device such as a dry powder inhaler or other dry powder dispersion devices. Non-limiting examples of dry powder inhalers and devices include those disclosed in <patcit id="pcit0004" dnum="US5458135A"><text>US5,458,135</text></patcit>; <patcit id="pcit0005" dnum="US5740794A"><text>US5,740,794</text></patcit>; <patcit id="pcit0006" dnum="US5775320A"><text>US5775320</text></patcit>; <patcit id="pcit0007" dnum="US5785049A"><text>US5,785,049</text></patcit>; <patcit id="pcit0008" dnum="US3906950A"><text>US3,906,950</text></patcit>; <patcit id="pcit0009" dnum="US4013075A"><text>US4,013,075</text></patcit>; <patcit id="pcit0010" dnum="US4069819A"><text>US4,069,819</text></patcit>; <patcit id="pcit0011" dnum="US4995385A"><text>US4,995,385</text></patcit>; <patcit id="pcit0012" dnum="US5522385A"><text>US5,522,385</text></patcit>; <patcit id="pcit0013" dnum="US4668218A"><text>US4,668,218</text></patcit>; <patcit id="pcit0014" dnum="US4667668A"><text>US4,667,668</text></patcit>; <patcit id="pcit0015" dnum="US4805811A"><text>US4,805,811</text></patcit> and <patcit id="pcit0016" dnum="US5388572A"><text>US5,388,572</text></patcit>. There are two major designs of dry powder inhalers. One design is a metering device in which a reservoir for the drug is place within the device and the patient adds a dose of the drug into the inhalation chamber. The second design is a factory-metered device in which each individual dose has been manufactured in a separate container. Both systems depend on the formulation of the drug into small particles of MMAD from about 1 µm to about 5 µm and often involve co-formulation with larger excipient particles such as, but not limited to, lactose. Drug powder is placed in the inhalation chamber (either by device metering or by breakage of a factory-metered dosage) and the inspiratory flow of the patient accelerates the powder out of the device and into the oral cavity. Non-laminar flow characteristics of the powder path cause the excipient-drug aggregates to decompose, and the mass of the large excipient particles causes their impaction at the back of the throat, while the smaller drug particles are deposited deep in the lungs. In some embodiments, a compound of Formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (Ila), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is delivered as a dry powder using either type of dry powder inhaler as described herein, wherein the MMAD of the dry powder, exclusive of any excipients, is predominantly in the range of about 1 µm to about 5 µm.

0219In some embodiments, a compound of Formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8) is delivered as a dry powder using a metered dose inhaler. Non-limiting examples of metered dose inhalers and devices include those disclosed in <patcit id="pcit0017" dnum="US5261538A"><text>US5,261,538</text></patcit>; <patcit id="pcit0018" dnum="US5544647A"><text>US5,544,647</text></patcit>; <patcit id="pcit0019" dnum="US5622163A"><text>US5,622,163</text></patcit>; <patcit id="pcit0020" dnum="US4955371A"><text>US4,955,371</text></patcit>; <patcit id="pcit0021" dnum="US3565070A"><text>US3,565,070</text></patcit>; <patcit id="pcit0022" dnum="US3361306A"><text>US3,361,306</text></patcit> and <patcit id="pcit0023" dnum="US6116234A"><text>US6,116,234</text></patcit>. In some embodiments, a compound of Formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is delivered as a dry powder using a metered dose inhaler wherein the MMAD of the dry powder, exclusive of any excipients, is predominantly in the range of about 1 to about 5 µm.

0220Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.

0221Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.

0222The formulations are presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injection, immediately prior to use. Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules and tablets of the kind previously described. Unit dosage formulations include those containing a daily dose or unit daily sub-dose, as herein above recited, or an appropriate fraction thereof, of the active ingredient.

0223It should be understood that in addition to the ingredients particularly mentioned above the formulations may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.

0224Further provided are veterinary compositions comprising at least one active ingredient as above defined together with a veterinary carrier therefor.

0225Veterinary carriers are materials useful for the purpose of administering the composition and may be solid, liquid or gaseous materials which are otherwise inert or acceptable in the veterinary art and are compatible with the active ingredient. These veterinary compositions may be administered orally, parenterally or by any other desired route.

0226Compounds herein are used to provide controlled release pharmaceutical formulations containing as active ingredient one or more of the compounds ("controlled release formulations") in which the release of the active ingredient is controlled and regulated to allow less frequency dosing or to improve the pharmacokinetic or toxicity profile of a given active ingredient.

0227Effective dose of active ingredient depends at least on the nature of the condition being treated, toxicity, the method of delivery, and the pharmaceutical formulation, and can be determined by the clinician using conventional dose escalation studies. It can be expected to be from about 0.0001 to about 100 mg/kg body weight per day; typically, from about 0.01 to about 10 mg/kg body weight per day; more typically, from about 0.01 to about 5 mg/kg body weight per day; most typically, from about 0.05 to about 0.5 mg/kg body weight per day. For example, the daily candidate dose for an adult human of about 70 kg body weight can range from about 1 mg to about 1000 mg, such as between about 5 mg and about 500 mg, and may take the form of single or multiple doses.

IV.

ROUTES OF ADMINISTRATION

0228One or more of the compounds of Formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8) (herein referred to as the active ingredients) are administered by any route appropriate to the condition to be treated. Suitable routes include oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural), and the like. It will be appreciated that the route may vary with for example the condition of the recipient. An advantage of the compounds herein is that they are orally bioavailable and can be dosed orally.

0229The compounds of the present disclosure (also referred to herein as the active ingredients), can be administered by any route appropriate to the condition to be treated. Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), transdermal, vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural), and the like. It will be appreciated that the route may vary with for example the condition of the recipient. An advantage of certain compounds disclosed herein is that they are orally bioavailable and can be dosed orally.

0230A compound of the present disclosure may be administered to an individual in accordance with an effective dosing regimen for a desired period of time or duration, such as at least about one month, at least about 2 months, at least about 3 months, at least about 6 months, or at least about 12 months or longer. In some embodiments, the compound is administered on a daily or intermittent schedule for the duration of the individual's life.

0231The dosage or dosing frequency of a compound of the present disclosure may be adjusted over the course of the treatment, based on the judgment of the administering physician.

0232The compound may be administered to an individual (e.g., a human) in an effective amount. In some embodiments, the compound is administered once daily.

0233The compound can be administered by any useful route and means, such as by oral or parenteral (e.g., intravenous) administration. Therapeutically effective amounts of the compound may include from about 0.00001 mg/kg body weight per day to about 10 mg/kg body weight per day, such as from about 0.0001 mg/kg body weight per day to about 10 mg/kg body weight per day, or such as from about 0.001 mg/kg body weight per day to about 1 mg/kg body weight per day, or such as from about 0.01 mg/kg body weight per day to about 1 mg/kg body weight per day, or such as from about 0.05 mg/kg body weight per day to about 0.5 mg/kg body weight per day, or such as from about 0.3 mg to about 30 mg per day, or such as from about 30 mg to about 300 mg per day.

0234A compound of the present disclosure may be combined with one or more additional therapeutic agents in any dosage amount of the compound of the present disclosure (e.g., from about 1 mg to about 1000 mg of compound). Therapeutically effective amounts may include from about 1 mg per dose to about 1000 mg per dose, such as from about 50 mg per dose to about 500 mg per dose, or such as from about 100 mg per dose to about 400 mg per dose, or such as from about 150 mg per dose to about 350 mg per dose, or such as from about 200 mg per dose to about 300 mg per dose. Other therapeutically effective amounts of the compound of the present disclosure are about 100, about 125, about 150, about 175, about 200, about 225, about 250, about 275, about 300, about 325, about 350, about 375, about 400, about 425, about 450, about 475, or about 500 mg per dose. Other therapeutically effective amounts of the compound of the present disclosure are about 100 mg per dose, or about 125, about 150, about 175, about 200, about 225, about 250, about 275, about 300, about 325, about 350, about 375, about 400, about 425, about 450, or about 500 mg per dose. A single dose can be administered hourly, daily, or weekly. For example, a single dose can be administered once about every 1 hour, about 2, about 3, about 4, about 6, about 8, about 12, about 16 or once about every 24 hours. A single dose can also be administered once about every 1 day, about 2, about 3, about 4, about 5, about 6, or once about every 7 days. A single dose can also be administered once about every 1 week, about 2, about 3, or once about every 4 weeks. In some embodiments, a single dose can be administered once about every week. A single dose can also be administered once about every month.

0235Other therapeutically effective amounts of the compound of the present disclosure are about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 65, about 70, about 75, about 80, about 85, about 90, about 95, or about 100 mg per dose.

0236The frequency of dosage of the compound of the present disclosure can be determined by the needs of the individual patient and can be, for example, once per day or twice, or more times, per day. Administration of the compound continues for as long as necessary to treat the disease or condition. For example, a compound can be administered to a human having cancer for a period of from about 20 days to about 180 days or, for example, for a period of from about 20 days to about 90 days or, for example, for a period of from about 30 days to about 60 days.

0237Administration can be intermittent, with a period of several or more days during which a patient receives a daily dose of the compound of the present disclosure followed by a period of several or more days during which a patient does not receive a daily dose of the compound. For example, a patient can receive a dose of the compound every other day, or three times per week. Again by way of example, a patient can receive a dose of the compound each day for a period of from about 1 to about 14 days, followed by a period of about 7 to about 21 days during which the patient does not receive a dose of the compound, followed by a subsequent period (e.g., from about 1 to about 14 days) during which the patient again receives a daily dose of the compound. Alternating periods of administration of the compound, followed by non-administration of the compound, can be repeated as clinically required to treat the patient.

0238In some embodiments, pharmaceutical compositions comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in combination with one or more <i>(e.g.,</i> one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents, and a pharmaceutically acceptable excipient are provided.

0239In some embodiments, kits comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in combination with one or more <i>(e.g.,</i> one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents are provided.

0240In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with one, two, three, four or more additional therapeutic agents. In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with two additional therapeutic agents. In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with three additional therapeutic agents. In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with four additional therapeutic agents. The one, two, three, four or more additional therapeutic agents can be different therapeutic agents selected from the same class of therapeutic agents, and/or they can be selected from different classes of therapeutic agents.

0241In some embodiments, when a compound of the present disclosure is combined with one or more additional therapeutic agents as described herein, the components of the composition are administered as a simultaneous or sequential regimen. When administered sequentially, the combination may be administered in two or more administrations.

0242In some embodiments, a compound of the present disclosure is combined with one or more additional therapeutic agents in a unitary dosage form for simultaneous administration to a patient, for example as a solid dosage form for oral administration.

0243In some embodiments, a compound of the present disclosure is co-administered with one or more additional therapeutic agents.

0244In order to prolong the effect of a compound of the present disclosure, it is often desirable to slow the absorption of a compound from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending a compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of a compound in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping a compound in liposomes or microemulsions that are compatible with body tissues.

V. COMBINATION THERAPY

0245The compounds of the present disclosure and compositions provided herein are also used in combination with other active therapeutic agents. The other active therapeutic agents may be anti-cancer or antiviral, e.g., anti-HIV or anti-hepatitis B virus, agents as appropriate.

A. Combination Therapies

1. Cancer

0246In some embodiments, a compound as described herein, is combined with one or more additional therapeutic agents, <i>e.g</i>., an inhibitory immune checkpoint blocker or inhibitor, a stimulatory immune checkpoint stimulator, agonist or activator, a chemotherapeutic agent, an anti-cancer agent, a radiotherapeutic agent, an anti-neoplastic agent, an anti-proliferation agent, an anti-angiogenic agent, an anti-inflammatory agent, an immunotherapeutic agent, a therapeutic antigen-binding molecule (mono- and multi-specific antibodies and fragments thereof in any format (<i>e.g.</i>, including without limitation DARTs^®, Duobodies^®, BiTEs^®, BiKEs, TriKEs, XmAbs^®, TandAbs^®, scFvs, Fabs, Fab derivatives), bi-specific antibodies, non-immunoglobulin antibody mimetics (<i>e.g</i>., including without limitation adnectins, affibody molecules, affilins, affimers, affitins, alphabodies, anticalins, peptide aptamers, armadillo repeat proteins (ARMs), atrimers, avimers, designed ankyrin repeat proteins (DARPins^®), fynomers, knottins, Kunitz domain peptides, monobodies, and nanoCLAMPs), antibody-drug conjugates (ADC), antibody-peptide conjugate), an oncolytic virus, a gene modifier or editor, a cell comprising a chimeric antigen receptor (CAR), <i>e.g</i>., including a T-cell immunotherapeutic agent, an NK-cell immunotherapeutic agent, or a macrophage immunotherapeutic agent, a cell comprising an engineered T-cell receptor (TCR-T), or any combination thereof.

Illustrative Targets

0247In some embodiments, the one or more additional therapeutic agents include, without limitation, an inhibitor, agonist, antagonist, ligand, modulator, stimulator, blocker, activator or suppressor of a target (<i>e.g</i>., polypeptide or polynucleotide) including without limitation: Abelson murine leukemia viral oncogene homolog 1 gene (ABL, such as ABL1), Acetyl-CoA carboxylase (such as ACC1/2), activated CDC kinase (ACK, such as ACK1), Adenosine deaminase, adenosine receptor (such as A2BR, A2aR, A3aR), Adenylate cyclase, ADP ribosyl cyclase-1, adrenocorticotropic hormone receptor (ACTH), Aerolysin, AKT1 gene, Alk-5 protein kinase, Alkaline phosphatase, Alpha 1 adrenoceptor, Alpha 2 adrenoceptor, Alpha-ketoglutarate dehydrogenase (KGDH), Aminopeptidase N, AMP activated protein kinase, anaplastic lymphoma kinase (ALK, such as ALK1), Androgen receptor, Angiopoietin (such as ligand-1, ligand-2), Angiotensinogen (AGT) gene, murine thymoma viral oncogene homolog 1 (AKT) protein kinase (such as AKT1, AKT2, AKT3), apolipoprotein A-I (APOA1) gene, Apoptosis inducing factor, apoptosis protein (such as 1, 2), apoptosis signal-regulating kinase (ASK, such as ASK1), Arginase (I), Arginine deiminase, Aromatase, Asteroid homolog 1 (ASTE1) gene, ataxia telangiectasia and Rad 3 related (ATR) serine/threonine protein kinase, Aurora protein kinase (such as 1, 2), Axl tyrosine kinase receptor, 4-1BB ligand (CD137L), Baculoviral IAP repeat containing 5 (BIRC5) gene, Basigin, B-cell lymphoma 2 (BCL2) gene, Bcl2 binding component 3, Bcl2 protein, BCL2L11 gene, BCR (breakpoint cluster region) protein and gene, Beta adrenoceptor, Beta-catenin, B-lymphocyte antigen CD19, B-lymphocyte antigen CD20, B-lymphocyte cell adhesion molecule, B-lymphocyte stimulator ligand, Bone morphogenetic protein-10 ligand, Bone morphogenetic protein-9 ligand modulator, Brachyury protein, Bradykinin receptor, B-Raf proto-oncogene (BRAF), Brc-Abl tyrosine kinase, Bromodomain and external domain (BET) bromodomain containing protein (such as BRD2, BRD3, BRD4), Bruton's tyrosine kinase (BTK), Calmodulin, calmodulin-dependent protein kinase (CaMK, such as CAMKII), Cancer testis antigen 2, Cancer testis antigen NY-ESO-1, cancer/testis antigen 1B (CTAG1) gene, Cannabinoid receptor (such as CB1, CB2), Carbonic anhydrase, casein kinase (CK, such as CKI, CKII), Caspase (such as caspase-3, caspase-7, Caspase-9), caspase 8 apoptosis-related cysteine peptidase CASP8-FADD-like regulator, Caspase recruitment domain protein-15, Cathepsin G, CCRS gene, CDK-activating kinase (CAK), Checkpoint kinase (such as CHK1, CHK2), chemokine (C-C motif) receptor (such as CCR2, CCR4, CCR5, CCR8), chemokine (C-X-C motif) receptor (such as CXCR1, CXCR2, CXCR3 and CXCR4), Chemokine CC21 ligand, Cholecystokinin CCK2 receptor, Chorionic gonadotropin, c-Kit (tyrosine-protein kinase Kit or CD 117), CISH (Cytokine-inducible SH2-containing protein), Claudin (such as 6, 18), cluster of differentiation (CD) such as CD4, CD27, CD29, CD30, CD33, CD37, CD40, CD40 ligand receptor, CD40 ligand, CD40LG gene, CD44, CD45, CD47, CD49b, CD51, CD52, CD55, CD58, CD66e (CEACAM6), CD70 gene, CD74, CD79, CD79b, CD79B gene, CD80, CD95, CD99, CD117, CD122, CDw123, CD134, CDw137, CD158a, CD158b1, CD158b2, CD223, CD276 antigen; clusterin (CLU) gene, Clusterin, c-Met (hepatocyte growth factor receptor (HGFR)), Complement C3, Connective tissue growth factor, COP9 signalosome subunit 5, CSF-1 (colony-stimulating factor 1 receptor), CSF2 gene, CTLA-4 (cytotoxic T-lymphocyte protein 4) receptor, C-type lectin domain protein 9A (CLEC9A), Cyclin D1, Cyclin G1, cyclin-dependent kinases (CDK, such as CDK1, CDK12, CDK1B, CDK2-9), cyclooxygenase (such as COX1, COX2), CYP2B1 gene, Cysteine palmitoyltransferase porcupine, Cytochrome P450 11B2, Cytochrome P450 17, cytochrome P450 17A1, Cytochrome P450 2D6, cytochrome P450 3A4, Cytochrome P450 reductase, cytokine signalling-1, cytokine signalling-3, Cytoplasmic isocitrate dehydrogenase, Cytosine deaminase, cytosine DNA methyltransferase, cytotoxic T-lymphocyte protein-4, DDR2 gene, DEAD-box helicase 6 (DDX6), Death receptor 5 (DRS, TRAILR2), Death receptor 4 (DR4, TRAILR1), Delta-like protein ligand (such as 3, 4), Deoxyribonuclease, Deubiquitinating enzymes (DUBs), Dickkopf-1 ligand, dihydrofolate reductase (DHFR), Dihydropyrimidine dehydrogenase, Dipeptidyl peptidase IV, discoidin domain receptor (DDR, such as DDR1), Diacylglycerol kinase zeta (DGKZ), DNA binding protein (such as HU-beta), DNA dependent protein kinase, DNA gyrase, DNA methyltransferase, DNA polymerase (such as alpha), DNA primase, dUTP pyrophosphatase, L-dopachrome tautomerase, E3 ubiquitin-protein ligase (such as RNF128, CBL-B), echinoderm microtubule like protein 4, EGFR tyrosine kinase receptor, Elastase, Elongation factor 1 alpha 2, Elongation factor 2, Endoglin, Endonuclease, endoplasmic reticulum aminopeptidase (ERAP, such as ERAP 1, ERAP2), Endoplasmin, Endosialin, Endostatin, endothelin (such as ET-A, ET-B), Enhancer of zeste homolog 2 (EZH2), Ephrin (EPH) tyrosine kinase (such as Epha3, Ephb4), Ephrin B2 ligand, epidermal growth factor, epidermal growth factor receptors (EGFR), epidermal growth factor receptor (EGFR) gene, Epigen, Epithelial cell adhesion molecule (EpCAM), Erb-b2 (v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2) tyrosine kinase receptor, Erb-b3 tyrosine kinase receptor, Erb-b4 tyrosine kinase receptor, E-selectin, Estradiol 17 beta dehydrogenase, Estrogen receptor (such as alpha, beta), Estrogen related receptor, Eukaryotic translation initiation factor 5A (EIF5A) gene, Exportin 1, Extracellular signal related kinase (such as 1, 2), Extracellular signal-regulated kinases (ERK), Hypoxia-inducible factor prolyl hydroxylase (HIF-PH or EGLN), Factor (such as Xa, VIIa), farnesoid x receptor (FXR), Fas ligand, Fatty acid synthase (FASN), Ferritin, FGF-2 ligand, FGF-5 ligand, fibroblast growth factor (FGF, such as FGF1, FGF2, FGF4), Fibronectin, focal adhesion kinase (FAK, such as FAK2), folate hydrolase prostate-specific membrane antigen 1 (FOLH1), Folate receptor (such as alpha), Folate, Folate transporter 1, FYN tyrosine kinase, paired basic amino acid cleaving enzyme (FURIN), Beta-glucuronidase, Galactosyltransferase, Galectin-3, Ganglioside GD2, Glucocorticoid, glucocorticoid-induced TNFR-related protein GITR receptor, Glutamate carboxypeptidase II, glutaminase, Glutathione S-transferase P, glycogen synthase kinase (GSK, such as 3-beta), Glypican 3 (GPC3), gonadotropin-releasing hormone (GNRH), Granulocyte macrophage colony stimulating factor (GM-CSF) receptor, Granulocyte-colony stimulating factor (GCSF) ligand, growth factor receptor-bound protein 2 (GRB2), Grp78 (78 kDa glucose-regulated protein) calcium binding protein, molecular chaperone groEL2 gene, Heme oxygenase 1 (HO1), Heme oxygenase 2 (HO2), Heat shock protein (such as 27, 70, 90 alpha, beta), Heat shock protein gene, Heat stable enterotoxin receptor, Hedgehog protein, Heparanase, Hepatocyte growth factor, HERV-H LTR associating protein 2, Hexose kinase, Histamine H2 receptor, Histone methyltransferase (DOT1L), histone deacetylase (HDAC, such as 1, 2, 3, 6, 10, 11), Histone H1, Histone H3, HLA class I antigen (A-2 alpha), HLA class II antigen, HLA class I antigen alpha G (HLA-G), Non-classical HLA, Homeobox protein NANOG, HSPB1 gene, Human leukocyte antigen (HLA), Human papillomavirus (such as E6, E7) protein, Hyaluronic acid, Hyaluronidase, Hypoxia inducible factor-1 alpha (HIF1α), Imprinted Maternally Expressed Transcript (H19) gene, mitogen-activated protein kinase 1 (MAP4K1), tyrosine-protein kinase HCK, I-Kappa-B kinase (IKK, such as IKKbe), IL-1 alpha, IL-1 beta, IL-12, IL-12 gene, IL-15, IL-17, IL-2 gene, IL-2 receptor alpha subunit, IL-2, IL-3 receptor, IL-4, IL-6, IL-7, IL-8, immunoglobulin (such as G, G1, G2, K, M), Immunoglobulin Fc receptor, Immunoglobulin gamma Fc receptor (such as I, III, IIIA), indoleamine 2,3-dioxygenase (IDO, such as IDO1 and IDO2), indoleamine pyrrole 2,3-dioxygenase 1 inhibitor, insulin receptor, Insulin-like growth factor (such as 1, 2), Integrin alpha-4/beta-1, integrin alpha-4/beta-7, Integrin alpha-5/beta-1, Integrin alpha-V/beta-3, Integrin alpha-V/beta-5, Integrin alpha-V/beta-6, Intercellular adhesion molecule 1 (ICAM-1), interferon (such as alpha, alpha 2, beta, gamma), Interferon inducible protein absent in melanoma 2 (AIM2), interferon type I receptor, Interleukin 1 ligand, Interleukin 13 receptor alpha 2, interleukin 2 ligand, interleukin-1 receptor-associated kinase 4 (IRAK4), Interleukin-2, Interleukin-29 ligand, Interleukin 35 (IL-35), isocitrate dehydrogenase (such as IDH1, IDH2), Janus kinase (JAK, such as JAK1, JAK2), Jun N terminal kinase, kallikrein-related peptidase 3 (KLK3) gene, Killer cell Ig like receptor, Kinase insert domain receptor (KDR), Kinesin-like protein KIF11, Kirsten rat sarcoma viral oncogene homolog (KRAS) gene, Kisspeptin (KiSS-1) receptor, KIT gene, v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (KIT) tyrosine kinase, lactoferrin, Lanosterol-14 demethylase, LDL receptor related protein-1, Leukocyte immunoglobulin-like receptor subfamily B member 1 (ILT2), Leukocyte immunoglobulin-like receptor subfamily B member 2 (ILT4), Leukotriene A4 hydrolase, Listeriolysin, L-Selectin, Luteinizing hormone receptor, Lyase, lymphocyte activation gene 3 protein (LAG-3), Lymphocyte antigen 75, Lymphocyte function antigen-3 receptor, lymphocyte-specific protein tyrosine kinase (LCK), Lymphotactin, Lyn (Lck/Yes novel) tyrosine kinase, lysine demethylases (such as KDM1, KDM2, KDM4, KDM5, KDM6, A/B/C/D), Lysophosphatidate-1 receptor, lysosomal-associated membrane protein family (LAMP) gene, Lysyl oxidase homolog 2, lysyl oxidase protein (LOX), 5-Lipoxygenase (5-LOX), Hematopoietic Progenitor Kinase 1 (HPK1), Hepatocyte growth factor receptor (MET) gene, macrophage colony-stimulating factor (MCSF) ligand, Macrophage migration inhibitory fact, MAGEC1 gene, MAGEC2 gene, Major vault protein, MAPK-activated protein kinase (such as MK2), Mas-related G-protein coupled receptor, matrix metalloprotease (MMP, such as MMP2, MMP9), Mcl-1 differentiation protein, Mdm2 p53-binding protein, Mdm4 protein, Melan-A (MART-1) melanoma antigen, Melanocyte protein Pmel 17, melanocyte stimulating hormone ligand, melanoma antigen family A3 (MAGEA3) gene, Melanoma associated antigen (such as 1, 2, 3, 6), Membrane copper amine oxidase, Mesothelin, MET tyrosine kinase, Metabotropic glutamate receptor 1, Metalloreductase STEAP1 (six transmembrane epithelial antigen of the prostate 1), Metastin, methionine aminopeptidase-2, Methyltransferase, Mitochondrial 3 ketoacyl CoA thiolase, mitogen-activate protein kinase (MAPK), mitogen-activated protein kinase (MEK, such as MEK1, MEK2), mTOR (mechanistic target of rapamycin (serine/threonine kinase), mTOR complex (such as 1,2), mucin (such as 1, 5A, 16), mut T homolog (MTH, such as MTH1), Myc proto-oncogene protein, myeloid cell leukemia 1 (MCL1) gene, myristoylated alanine-rich protein kinase C substrate (MARCKS) protein, NAD ADP ribosyltransferase, natriuretic peptide receptor C, Neural cell adhesion molecule 1, Neurokinin 1 (NK1) receptor, Neurokinin receptor, Neuropilin 2, NF kappa B activating protein, NIMA-related kinase 9 (NEK9), Nitric oxide synthase, NK cell receptor, NK3 receptor, NKG2 A B activating NK receptor, NLRP3 (NACHT LRR PYD domain protein 3) modulators, Noradrenaline transporter, Notch (such as Notch-2 receptor, Notch-3 receptor, Notch-4 receptor), Nuclear erythroid 2-related factor 2, Nuclear Factor (NF) kappa B, Nucleolin, Nucleophosmin, nucleophosmin-anaplastic lymphoma kinase (NPM-ALK), 2 oxoglutarate dehydrogenase, 2,5-oligoadenylate synthetase, O-methylguanine DNA methyltransferase, Opioid receptor (such as delta), Omithine decarboxylase, Orotate phosphoribosyltransferase, orphan nuclear hormone receptor NR4A1, Osteocalcin, Osteoclast differentiation factor, Osteopontin, OX-40 (tumor necrosis factor receptor superfamily member 4 TNFRSF4, or CD134) receptor, P3 protein, p38 kinase, p38 MAP kinase, p53 tumor suppressor protein, Parathyroid hormone ligand, peroxisome proliferator-activated receptors (PPAR, such as alpha, delta, gamma), P-Glycoprotein (such as 1), phosphatase and tensin homolog (PTEN), phosphatidylinositol 3-kinase (PI3K), phosphoinositide-3 kinase (PI3K such as alpha, delta, gamma), phosphorylase kinase (PK), PKN3 gene, placenta growth factor, platelet-derived growth factor (PDGF, such as alpha, beta), Platelet-derived growth factor (PDGF, such as alpha, beta), Pleiotropic drug resistance transporter, Plexin B1, PLK1 gene, polo-like kinase (PLK), Polo-like kinase 1, Poly (ADP- ribose) polymerase (PARP, such as PARP1, PARP2 and PARP3, PARP7, and mono-PARPs), Preferentially expressed antigen in melanoma (PRAME) gene, Prenyl-binding protein (PrPB), Probable transcription factor PML, Progesterone receptor, Programmed cell death 1 (PD-1), Programmed cell death ligand 1 inhibitor (PD-L1), Prosaposin (PSAP) gene, Prostanoid receptor (EP4), Prostaglandin E2 synthase, prostate specific antigen, Prostatic acid phosphatase, proteasome, Protein E7, Protein farnesyltransferase, protein kinase (PK, such as A, B, C), protein tyrosine kinase, Protein tyrosine phosphatase beta, Proto-oncogene serine/threonine-protein kinase (PIM, such as PIM-1, PIM-2, PIM-3), P-Selectin, Purine nucleoside phosphorylase, purinergic receptor P2X ligand gated ion channel 7 (P2X7), Pyruvate dehydrogenase (PDH), Pyruvate dehydrogenase kinase, Pyruvate kinase (PYK), 5-Alpha-reductase, Raf protein kinase (such as 1, B), RAF1 gene, Ras gene, Ras GTPase, RET gene, Ret tyrosine kinase receptor, retinoblastoma associated protein, retinoic acid receptor (such as gamma), Retinoid X receptor, Rheb (Ras homolog enriched in brain) GTPase, Rho (Ras homolog) associated protein kinase 2, ribonuclease, Ribonucleotide reductase (such as M2 subunit), Ribosomal protein S6 kinase, RNA polymerase (such as I, II), Ron (Recepteur d'Origine Nantais) tyrosine kinase, ROS1 (ROS proto-oncogene 1 , receptor tyrosine kinase) gene, Ros1 tyrosine kinase, Runt-related transcription factor 3, Gamma-secretase, S100 calcium binding protein A9, Sarco endoplasmic calcium ATPase, Second mitochondria-derived activator of caspases (SMAC) protein, Secreted frizzled related protein-2, Secreted phospholipase A2, Semaphorin-4D, Serine protease, serine/threonine kinase (STK), serine/threonine-protein kinase (TBK, such as TBK1), signal transduction and transcription (STAT, such as STAT-1, STAT-3, STAT-5), Signaling lymphocytic activation molecule (SLAM) family member 7, six-transmembrane epithelial antigen of the prostate (STEAP) gene, SL cytokine ligand, smoothened (SMO) receptor, Sodium iodide cotransporter, Sodium phosphate cotransporter 2B, Somatostatin receptor (such as 1, 2, 3, 4, 5), Sonic hedgehog protein, Son of sevenless (SOS), Specific protein 1 (Sp1) transcription factor, Sphingomyelin synthase, Sphingosine kinase (such as 1, 2), Sphingosine-1-phosphate receptor-1, spleen tyrosine kinase (SYK), SRC gene, Src tyrosine kinase, Stabilin-1 (STAB 1), STAT3 gene, Steroid sulfatase, Stimulator of interferon genes (STING) receptor, stimulator of interferon genes protein, Stromal cell-derived factor 1 ligand, SUMO (small ubiquitin-like modifier), Superoxide dismutase, Suppressor of cytokine signaling modulators (SOCS), Survivin protein, Synapsin 3, Syndecan-1, Synuclein alpha, T cell surface glycoprotein CD28, tank-binding kinase (TBK), TATA box-binding protein-associated factor RNA polymerase I subunit B (TAF1B) gene, T-cell CD3 glycoprotein zeta chain, T-cell differentiation antigen CD6, T-cell immunoglobulin and mucin-domain containing-3 (TIM-3), T-cell surface glycoprotein CD8, Tec protein tyrosine kinase, Tek tyrosine kinase receptor, telomerase, Telomerase reverse transcriptase (TERT) gene, Tenascin, Three prime repair exonuclease 1 (TREX1), Three prime repair exonuclease 2 (TREX2), Thrombopoietin receptor, Thymidine kinase, Thymidine phosphorylase, Thymidylate synthase, Thymosin (such as alpha 1), Thyroid hormone receptor, Thyroid stimulating hormone receptor, Tissue factor, TNF related apoptosis inducing ligand, TNFR1 associated death domain protein, TNF-related apoptosis-inducing ligand (TRAIL) receptor, TNFSF11 gene, TNFSF9 gene, Toll-like receptor (TLR such as 1-13), topoisomerase (such as I, II, III), Transcription factor, Transferase, transferrin (TF), transforming growth factor alpha (TGFα), transforming growth factor beta (TGFB) and isoforms thereof, TGF beta 2 ligand, Transforming growth factor TGF-β receptor kinase, Transglutaminase, Translocation associated protein, Transmembrane glycoprotein NMB, Trop-2 calcium signal transducer, trophoblast glycoprotein (TPBG) gene, Trophoblast glycoprotein, Tropomyosin receptor kinase (Trk) receptor (such as TrkA, TrkB, TrkC), tryptophan 2,3-dioxygenase (TDO), Tryptophan 5-hydroxylase, Tubulin, Tumor necrosis factor (TNF, such as alpha, beta), Tumor necrosis factor 13C receptor, tumor progression locus 2 (TPL2), Tumor protein 53 (TP53) gene, Tumor suppressor candidate 2 (TUSC2) gene, Tumor specific neoantigens, Tyrosinase, Tyrosine hydroxylase, tyrosine kinase (TK), Tyrosine kinase receptor, Tyrosine kinase with immunoglobulin-like and EGF-like domains (TIE) receptor, Tyrosine protein kinase ABL1 inhibitor, Ubiquitin, Ubiquitin carboxyl hydrolase isozyme L5, Ubiquitin thioesterase-14, Ubiquitin-conjugating enzyme E2I (UBE2I, UBC9), Ubiquitin-specific-processing protease 7 (USP7), Urease, Urokinase plasminogen activator, Uteroglobin, Vanilloid VR1, Vascular cell adhesion protein 1, vascular endothelial growth factor receptor (VEGFR), V-domain Ig suppressor of T-cell activation (VISTA), VEGF-1 receptor, VEGF-2 receptor, VEGF-3 receptor, VEGF-A, VEGF-B, Vimentin, Vitamin D3 receptor, Proto-oncogene tyrosine-protein kinase, Mer (Mer tyrosine kinase receptor modulators), YAP (Yes-associated protein modulators)es, Wee-1 protein kinase, Werner Syndrome RecQ Like Helicase (WRN), Wilms' tumor antigen 1, Wilms' tumor protein, WW domain containing transcription regulator protein 1 (TAZ), X-linked inhibitor of apoptosis protein, Zinc finger protein transcription factor or any combination thereof.

Illustrative Mechanisms of Action

0248In some embodiments, the one or more additional therapeutic agents may be categorized by their mechanism of action into, for example, the following groups: <ul id="ul0007" list-style="none"><li>anti-metabolites/anti-cancer agents, such as pyrimidine analogs floxuridine, capecitabine, cytarabine, CPX-351 (liposomal cytarabine, daunorubicin), and TAS-118;</li><li>Alpha 1 adrenoceptor/Alpha 2 adrenoceptor antagonists, such as phenoxybenzamine hydrochloride (injectable, pheochromocytoma);</li><li>Androgen receptor antagonists, such as nilutamide;</li><li>anti-cadherin antibodies, such as HKT-288;</li><li>anti-leucine-rich repeat containing 15 (LRRC15) antibodies, such as ABBV-085. ARGX-110;</li><li>angiotensin receptor blockers, nitric oxide donors;</li><li>antisense oligonucleotides, such as AEG35156, IONIS-KRAS-2.5Rx, EZN-3042, RX-0201, IONIS-AR-2.5Rx, BP-100 (prexigebersen), IONIS-STAT3-2.5Rx;</li><li>anti-angiopoietin (ANG)-2 antibodies, such as MEDI3617, and LY3127804;</li><li>anti-ANG-1/ANG-2 antibodies, such as AMG-780;</li><li>anti-CSF1R antibodies, such as emactuzumab, LY3022855, AMG-820, FPA-008 (cabiralizumab);</li><li>anti-endoglin antibodies, such as TRC105 (carotuximab);</li><li>anti-ERBB antibodies, such as CDX-3379, HLX-02, seribantumab;</li><li>anti-HER2 antibodies, such as HERCEPTIN^® (trastuzumab), trastuzumab biosimimar, margetuximab, MEDI4276, BAT-8001, Pertuzumab (Perjeta), RG6264, ZW25 (a bispecific HER2-directed antibody targeting the extracellular domains 2 and 4; Cancer Discov. 2019 Jan;9(1):8; PMID: 30504239);</li><li>anti-HLA-DR antibodies, such as IMMU-114;</li><li>anti-IL-3 antibodies, such as JNJ-56022473;</li><li>anti-TNF receptor superfamily member 18 (TNFRSF18, GITR; NCBI Gene ID: 8784) antibodies, such as MK-4166, MEDI1873, FPA-154, INCAGN-1876, TRX-518, BMS-986156, MK-1248, GWN-323; and those described, e.g. in Intl. Patent Publ. Nos. <patcit id="pcit0024" dnum="WO2017096179A"><text>WO 2017/096179</text></patcit>, <patcit id="pcit0025" dnum="WO2017096276A"><text>WO 2017/096276</text></patcit>, <patcit id="pcit0026" dnum="WO2017096189A"><text>WO 2017/096189</text></patcit>; and <patcit id="pcit0027" dnum="WO2018089628A"><text>WO 2018/089628</text></patcit>;</li><li>anti-EphA3 antibodies, such as KB-004;</li><li>anti-CD37 antibodies, such as otlertuzumab (TRU-016);</li><li>anti-FGFR-3 antibodies, such as LY3076226, B-701;</li><li>anti-FGFR-2 antibodies, such as GAL-F2;</li><li>anti-C5 antibodies, such as ALXN-1210;</li><li>anti-EpCAM antibodies, such as VB4-845;</li><li>anti-CEA antibodies, such as RG-7813;</li><li>CD66C) antibodies, such as BAY-1834942, NEO-201 (CEACAM 5/6);</li><li>anti-GD2 antibodies, such as APN-301;</li><li>anti-interleukin-17 (IL-17) antibodies, such as CJM-112;</li><li>anti-interleukin-1 beta antibodies, such as canakinumab (ACZ885), VPM087;</li><li>anti-carbonic anhydrase 9 (CA9, CAIX) antibodies, such as TX-250;</li><li>anti-CD38 antibodies, such as isatuximab, MOR-202, TAK-079;</li><li>anti-CD38-attenukine, such as TAK573;</li><li>anti-Mucin 1 (MUC1) antibodies, such as gatipotuzumab, Mab-AR-20.5;</li><li>anti-CD33 antibodies, such as IMGN-779;</li><li>anti-KMA antibodies, such as MDX-1097;</li><li>anti-CD55 antibodies, such as PAT-SC1;</li><li>anti-c-Met antibodies, such as ABBV-399;</li><li>anti-PSMA antibodies, such as ATL-101;</li><li>anti-CD100 antibodies, such as VX-15;</li><li>anti-EPHA3 antibodies, such as fibatuzumab;</li><li>anti-APRIL antibodies, such as BION-1301;</li><li>anti-fibroblast activation protein (FAP)/IL-2R antibodies, such as RG7461;</li><li>anti-fibroblast activation protein (FAP)/TRAIL-R2 antibodies, such as RG7386;</li><li>anti-fucosyl-GM1 antibodies, such as BMS-986012;</li><li>anti-IL-8 (Interleukin-8) antibodies, such as HuMax-Inflam;</li><li>anti-myostatin inhibitors, such as landogrozumab;</li><li>anti-delta-like protein ligand 3 (DDL3) antibodies, such as rovalpituzumab tesirine;</li><li>anti-DLL4 (delta like ligand 4) antibodies, such as demcizumab;</li><li>anti-clusterin antibodies, such as AB-16B5;</li><li>anti-Ephrin-A4 (EFNA4) antibodies, such as PF-06647263;</li><li>anti-RANKL antibodies, such as denosumab;</li><li>anti-mesothelin antibodies, such as BMS-986148, Anti-MSLN-MMAE;</li><li>anti- sodium phosphate cotransporter 2B (NaP2B) antibodies, such as lifastuzumab</li><li>anti-TGFb antibodies, such as SAR439459;</li><li>anti-transforming growth factor-beta (TGF-beta) antibodies, such as ABBV-151, LY3022859, NIS793, XOMA 089;</li><li>purine analogs, folate antagonists (such as pralatrexate), cladribine, pentostatin, fludarabine and related inhibitors;</li><li>antiproliferative/antimitotic agents including natural products, such as vinca alkaloids (vinblastine, vincristine) and microtubule disruptors such as taxane (paclitaxel, docetaxel), vinblastin, nocodazole, epothilones, vinorelbine (NAVELBINE^®), and epipodophyllotoxins (etoposide, teniposide);</li><li>DNA damaging agents, such as actinomycin, amsacrine, busulfan, carboplatin, chlorambucil, cisplatin, cyclophosphamide (CYTOXAN^®), dactinomycin, daunorubicin, doxorubicin, DEBDOX, epirubicin, iphosphamide, melphalan, merchlorethamine, mitomycin C, mitoxantrone, nitrosourea, procarbazine, taxol, Taxotere, teniposide, etoposide, and triethylenethiophosphoramide;</li><li>DNA-hypomethylating agents, such as guadecitabine (SGI-110), ASTX727;</li><li>antibiotics such as dactinomycin, daunorubicin, doxorubicin, idarubicin, anthracyclines, mitoxantrone, bleomycins, plicamycin (mithramycin);</li><li>enzymes such as L-asparaginase which systemically metabolizes L-asparagine and deprives cells which do not have the capacity to synthesize their own asparagine;</li><li>DNAi oligonucleotides targeting Bcl-2, such as PNT2258; agents that activate or reactivate latent human immunodeficiency virus (HIV), such as panobinostat and romidepsin;</li><li>asparaginase stimulators, such as crisantaspase (Erwinase^®) and GRASPA (ERY-001, ERY-ASP), calaspargase pegol, pegaspargase;</li><li>pan-Trk, ROS1 and ALK inhibitors, such as entrectinib, TPX-0005;</li><li>anaplastic lymphoma kinase (ALK) inhibitors, such as alectinib, ceritinib, alecensa (RG7853), ALUNBRIG^® (brigatinib);</li><li>antiproliferative/antimitotic alkylating agents, such as nitrogen mustard cyclophosphamide and analogs (<i>e.g</i>., melphalan, chlorambucil, hexamethylmelamine, thiotepa), alkyl nitrosoureas (<i>e.g.,</i> carmustine) and analogs, streptozocin, and triazenes <i>(e.g.,</i> dacarbazine);</li><li>antiproliferative/antimitotic antimetabolites, such as folic acid analogs (methotrexate);</li><li>platinum coordination complexes (<i>e.g</i>., cisplatin, oxiloplatinim, and carboplatin), procarbazine, hydroxyurea, mitotane, and aminoglutethimide;</li><li>hormones, hormone analogs (<i>e.g</i>., estrogen, tamoxifen, goserelin, bicalutamide, and nilutamide), and aromatase inhibitors (<i>e.g.</i>, letrozole and anastrozole);</li><li>antiplatelet agents; anticoagulants such as heparin, synthetic heparin salts, and other inhibitors of thrombin;</li><li>fibrinolytic agents such as tissue plasminogen activator, streptokinase, urokinase, aspirin, dipyridamole, ticlopidine, and clopidogrel;</li><li>antimigratory agents; antisecretory agents (<i>e.g</i>., breveldin);</li><li>immunosuppressives, such as tacrolimus, sirolimus, azathioprine, and mycophenolate;</li><li>growth factor inhibitors, and vascular endothelial growth factor inhibitors;</li><li>fibroblast growth factor inhibitors, such as FPA14;</li><li>AMP activated protein kinase stimulators, such as metformin hydrochloride;</li><li>ADP ribosyl cyclase-1 inhibitors, such as daratumumab (DARZALEX^®);</li><li>Caspase recruitment domain protein-15 stimulators, such as mifamurtide (liposomal);</li><li>CCRS chemokine antagonists, such as MK-7690 (vicriviroc);</li><li>CDC7 protein kinase inhibitors, such as TAK-931;</li><li>Cholesterol side-chain cleavage enzyme inhibitors, such as ODM-209;</li><li>Dihydropyrimidine dehydrogenase/Orotate phosphoribosyltransferase inhibitors, such as Cefesone (tegafur + gimeracil + oteracil potassium);</li><li>DNA polymerase/Ribonucleotide reductase inhibitors, such as clofarabine;</li><li>DNA interference oligonucleotides, such as PNT2258, AZD-9150;</li><li>Estrogen receptor modulators, such as bazedoxifene;</li><li>Estrogen receptor agonists/Progesterone receptor antagonists, such as TRI-CYCLEN LO (norethindrone + ethinyl estradiol);</li><li>HLA class I antigen A-2 alpha modulators, such as FH-MCVA2TCR;</li><li>HLA class I antigen A-2 alpha/MART-1 melanoma antigen modulators, such as MART-1 F5 TCR engineered PBMC;</li><li>Human Granulocyte Colony Stimulating Factors, such as PF-06881894;</li><li>GNRH receptor agonists, such as leuprorelin acetate, leuprorelin acetate sustained release depot (ATRIGEL), triptorelin pamoate, goserelin acetate;</li><li>GNRH receptor antagonists, such as elagolix, relugolix, degarelix;</li><li>Endoplasmin modulators, such as anlotinib;</li><li>H+ K+ ATPase inhibitors, such as omeprazole, esomeprazole;</li><li>ICAM-1/CD55 modulators, such as cavatak (V-937);</li><li>IL-15/ IL-12 modulators, such as SAR441000;</li><li>Interleukin 23A inhibitors, such as guselkumab;</li><li>Lysine specific histone demethylase 1 inhibitors, such as CC-90011;</li><li>IL-12 Mrna, such as MEDI1191;</li><li>RIG-I modulators, such as RGT-100;</li><li>NOD2 modulators, such as SB-9200, and IR-103.</li><li>Progesterone receptor agonists, such as levonorgestrel;</li><li>Protein cereblon modulators, such as CC-92480, CC-90009 ;</li><li>Protein cereblon modulators/DNA binding protein Ikaros inhibitors/Zinc finger binding protein Aiolos inhibitors, such as iberdomide;</li><li>Retinoid X receptor modulators, such as alitretinoin, bexarotene (oral formulation);</li><li>RIP-1 kinase inhibitors, such as GSK-3145095;</li><li>selective oestrogen receptor degraders, such as AZD9833;</li><li>SUMO inhibitors, such as TAK-981;</li><li>Thrombopoietin receptor agonists, such as eltrombopag;</li><li>Thyroid hormone receptor agonists, such as levothyroxine sodium;</li><li>TNF agonists, such as tasonermin;</li><li>Tyrosine phosphatase substrate 1 inhibitors, such as CC-95251;</li><li>HER2 inhibitors, such as neratinib, tucatinib (ONT-380);</li><li>EGFR/ErbB2/Ephb4 inhibitors, such as tesevatinib;</li><li>EGFR/HER2 inhibitors, such as TAK-788;</li><li>EGFR family tyrosine kinase receptor inhibitors, such as DZD-9008</li><li>EGFR/ErbB-2 inhibitors, such as varlitinib;</li><li>Mutant selective EGFR inhibitors, such as PF-06747775, EGF816 (nazartinib), ASP8273, ACEA-0010, BI-1482694;</li><li>epha2 inhibitors, such as MM-310;</li><li>polycomb protein (EED) inhibitors, such as MAK683;</li><li>DHFR inhibitor/Folate transporter 1 modulator/Folate receptor antagonist, such as pralatrexate;</li><li>DHFR/GAR transformylase/Thymidylate synthase/Transferase inhibitors, such as pemetrexed disodium;</li><li>p38 MAP kinase inhibitors, such as ralimetinib;</li><li>PRMT inhibitors, such as MS203, PF-06939999, GSK3368715, GSK3326595;</li><li>Sphingosine kinase 2 (SK2) inhibitors, such as opaganib;</li><li>Nuclear erythroid 2-related factor 2 stimulators, such as omaveloxolone (RTA-408);</li><li>Tropomyosin receptor kinase (TRK) inhibitors, such as LOXO-195, ONO-7579;</li><li>Mucin 1 inhibitors, such as GO-203-2C;</li><li>MARCKS protein inhibitors, such as BIO-11006;</li><li>Folate antagonists, such as arfolitixorin;</li><li>Galectin-3 inhibitors, such as GR-MD-02;</li><li>Phosphorylated P68 inhibitors, such as RX-5902;</li><li>CD95/TNF modulators, such as ofranergene obadenovec;</li><li>pan-PIM kinase inhibitors, such as INCB-053914;</li><li>IL-12 gene stimulators, such as EGEN-001, tavokinogene telseplasmid;</li><li>Heat shock protein HSP90 inhibitors, such as TAS-116, PEN-866;</li><li>VEGF/HGF antagonists, such as MP-0250;</li><li>VEGF ligand inhibitors, such as bevacizumab biosimilar;</li><li>VEGF receptor antagonists/VEGF ligand inhibitors, such as ramucirumab;</li><li>VEGF-1/VEGF-2/VEGF-3 receptor antagonists; such as fruquintinib;</li><li>VEGF-1/VEGF-2 receptor modulators, such as HLA-A2402/HLA-A0201 restricted epitope peptide vaccine;</li><li>Placenta growth factor ligand inhibitor/VEGF-A ligand inhibitor, such as aflibercept;</li><li>SYK tyrosine kinase/ JAK tyrosine kinase inhibitors, such as ASN-002;</li><li>Trk tyrosine kinase receptor inhibitors, such as larotrectinib sulfate;</li><li>JAK3/JAK1/TBK1 kinase inhibitors, such as CS-12912;</li><li>IL-24 antagonist, such as AD-IL24;</li><li>NLRP3 (NACHT LRR PYD domain protein 3) modulators, such as BMS-986299;</li><li>RIG-I agonists, such as RGT-100;</li><li>Aerolysin stimulators, such as topsalysin;</li><li>P-Glycoprotein 1 inhibitors, such as HM-30181A;</li><li>CSF-1 antagonists, such as ARRY-382, BLZ-945;</li><li>CCR8 inhibitors, such as 1-309, SB-649701, HG-1013, RAP-310;</li><li>anti-Mesothelin antibodies, such as SEL-403;</li><li>Thymidine kinase stimulators, such as aglatimagene besadenovec;</li><li>Polo-like kinase 1 inhibitors, such as PCM-075, onvansertib;</li><li>NAE inhibitors, such as pevonedistat (MLN-4924), TAS-4464;</li><li>Pleiotropic pathway modulators, such as avadomide (CC-122);</li><li>Amyloid protein binding protein-1 inhibitorS/Ubiquitin ligase modulators, such as pevonedistat;</li><li>FoxM1 inhibitors, such as thiostrepton;</li><li>UBA1 inhibitors, such as TAK-243;</li><li>Src tyrosine kinase inhibitors, such as VAL-201;</li><li>VDAC/HK inhibitors, such as VDA-1102;</li><li>Elf4a inhibitors, such as rohinitib, eFT226;</li><li>TP53 gene stimulators, such as ad-p53;</li><li>Retinoic acid receptor agonists, such as tretinoin;</li><li>Retinoic acid receptor alpha (RARα) inhibitors, such as SY-1425;</li><li>SIRT3 inhibitors, such as YC8-02;</li><li>Stromal cell-derived factor 1 ligand inhibitors, such as olaptesed pegol (NOX-A12);</li><li>IL-4 receptor modulators, such as MDNA-55;</li><li>Arginase-I stimulators, such as pegzilarginase;</li><li>Topoisomerase I inhibitors, such as irinotecan hydrochloride, Onivyde;</li><li>Topoisomerase I inhibitory hypoxia inducible factor-1 alpha inhibitors, such as PEG-SN38 (firtecan pegol);</li><li>Hypoxia inducible factor-1 alpha inhibitors, such as PT-2977, PT-2385;</li><li>CD122 (IL-2 receptor) agonists, such as proleukin (aldesleukin, IL-2); pegylated IL-2 (eg NKTR-214); modified variants of IL-2 (eg THOR-707);</li><li>TLR7/TLR8 agonist, such as NKTR-262;</li><li>TLR7 agonists, such as DS-0509, GS-9620, LHC-165, TMX-101 (imiquimod);</li><li>p53 tumor suppressor protein stimulators such as kevetrin;</li><li>Mdm4/Mdm2 p53-binding protein inhibitors, such as ALRN-6924;</li><li>kinesin spindle protein (KSP) inhibitors, such as filanesib (ARRY-520);</li><li>CD80-fc fusion protein inhibitors, such as FPT-155;</li><li>Menin and mixed lineage leukemia (MLL) inhibitors such as KO-539;</li><li>Liver x receptor agonists, such as RGX-104;</li><li>IL-10 agonists, such as Pegilodecakin (AM-0010);</li><li>VEGFR/PDGFR inhibitors, such as vorolanib;</li><li>IRAK4 inhibitors, such as CA-4948;</li><li>anti-TLR-2 antibodies, such as OPN-305;</li><li>Calmodulin modulators, such as CBP-501;</li><li>Glucocorticoid receptor antagonists, such as relacorilant (CORT-125134);</li><li>Second mitochondria-derived activator of caspases (SMAC) protein inhibitors, such as BI-891065;</li><li>Lactoferrin modulators, such as LTX-315;</li><li>KIT proto-oncogene, receptor tyrosine kinase (KIT) inhibitors, such as PLX-9486;</li><li>platelet derived growth factor receptor alpha (PDGFRA)/ KIT proto-oncogene, receptor tyrosine kinase (KIT) mutant-specific antagonists/inhibitors such as BLU-285, DCC-2618;</li><li>Exportin 1 inhibitors, such as eltanexor;</li><li>CHST15 gene inhibitors, such as STNM-01;</li><li>Somatostatin receptor antagonist, such as OPS-201;</li><li>CEBPA gene stimulators, such as MTL-501;</li><li>DKK3 gene modulators, such as MTG-201;</li><li>Chemokine (CXCR1/CXCR2) inhibitors, such as SX-682;</li><li>p70s6k inhibitors, such as MSC2363318A;</li><li>methionine aminopeptidase 2 (MetAP2) inhibitors, such as M8891, APL-1202;</li><li>arginine N-methyltransferase 5 inhibitors, such as GSK-3326595;</li><li>CD71 modulators, such as CX-2029 (ABBV-2029);</li><li>ATM (ataxia telangiectasia) inhibitors, such as AZD0156, AZD1390;</li><li>CHK1 inhibitors, such as GDC-0575, LY2606368 (prexasertib), SRA737, RG7741 (CHK1/2);</li><li>CXCR4 antagonists, such as BL-8040, LY2510924, burixafor (TG-0054), X4P-002, X4P-001-IO, Plerixafor;</li><li>EXH2 inhibitors, such as GSK2816126;</li><li>KDM1 inhibitors, such as ORY-1001, IMG-7289, INCB-59872, GSK-2879552;</li><li>CXCR2 antagonists, such as AZD-5069;</li><li>GM-CSF antibodies, such as lenzilumab;</li><li>DNA dependent protein kinase inhibitors, such as MSC2490484A (nedisertib), VX-984, AsiDNA (DT-01); protein kinase C (PKC) inhibitors, such as LXS-196, sotrastaurin;</li><li>Selective estrogen receptor downregulators (SERD), such as fulvestrant (Faslodex^®), RG6046, RG6047, RG6171, elacestrant (RAD-1901), SAR439859 and AZD9496;</li><li>Selective estrogen receptor covalent antagonists (SERCAs), such as H3B-6545;</li><li>selective androgen receptor modulator (SARM), such as GTX-024, darolutamide;</li><li>transforming growth factor-beta (TGF-beta) kinase antagonists, such as galunisertib, LY3200882 ; TGF-beta inhibitors described in <patcit id="pcit0028" dnum="WO2019103203A"><text>WO 2019/103203</text></patcit>;</li><li>TGF beta receptor 1 inhibitors, such as PF-06952229;</li><li>bispecific antibodies, such as ABT-165 (DLL4/VEGF), MM-141 (IGF-1/ErbB3), MM-111 (Erb2/Erb3), JNJ-64052781 (CD19/CD3), PRS-343 (CD-137/HER2), AFM26 (BCMA/CD16A), JNJ-61186372 (EGFR/cMET), AMG-211 (CEA/CD3), RG7802 (CEA/CD3), ERY-974 (CD3/GPC3) vancizumab (angiopoietins/VEGF), PF-06671008 (Cadherins/CD3), AFM-13 (CD16/CD30), APVO436 (CD123/CD3), flotetuzumab (CD123/CD3), REGN-1979 (CD20/CD3), MCLA-117 (CD3/CLEC12A), MCLA-128 (HER2/HER3), JNJ-0819, JNJ-7564 (CD3/heme), AMG-757 (DLL3-CD3), MGD-013 (PD-1/LAG-3), FS-118 (LAG-3/PD-L1) MGD-019 (PD-1/CTLA-4), KN-046 (PD-1/CTLA-4), MEDI-5752 (CTLA-4/PD-1), RO-7121661 (PD-1/TIM-3), XmAb-20717 (PD-1/CTLA-4), AK-104 (CTLA-4/PD-1), AMG-330 (CD33/CD3), AMG-420 (BCMA/CD3), BI-836880 (VEFG/ANG2), JNJ-63709178 (CD123/CD3), MGD-007 (CD3/gpA33), MGD-009 (CD3/B7H3), AGEN1223, IMCgp100 (CD3/gp100), AGEN-1423, ATOR-1015 (CTLA-4/OX40), LY-3415244 (TIM-3/PDL1), INHIBRX-105 (4-1BB/PDL1), faricimab (VEGF-A/ANG-2), FAP-4-IBBL (4-1BB/FAP), XmAb-13676 (CD3/CD20), TAK-252 (PD-1/OX40L), TG-1801 (CD19/CD47), XmAb-18087 (SSTR2/CD3), catumaxomab (CD3/EpCAM), SAR-156597 (IL4/IL13), EMB-01 (EGFR/cMET), REGN-4018 (MUC16/CD3), REGN-1979 (CD20/CD3), RG-7828 (CD20/CD3), CC-93269 (CD3/BCMA), REGN-5458 (CD3/BCMA), navicixizumab (DLL4/VEGF), GRB-1302 (CD3/Erbb2), vanucizumab (VEGF-A/ANG-2), GRB-1342 (CD38/CD3), GEM-333 (CD3/CD33), IMM-0306 (CD47/CD20), RG6076, MEDI5752 (PD-1/CTLA-4), LY3164530 (MET/EGFR);</li><li>Alpha-ketoglutarate dehydrogenase (KGDH) inhibitors, such as CPI-613;</li><li>XPO1 inhibitors, such as selinexor (KPT-330);</li><li>Isocitrate dehydrogenase 2 (IDH2) inhibitors, such as enasidenib (AG-221);</li><li>IDH1 inhibitors such as AG-120, and AG-881 (IDH1 and IDH2), IDH-305, BAY-1436032;</li><li>IDH1 gene inhibitors, such as ivosidenib;</li><li>interleukin-3 receptor (IL-3R) modulators, such as SL-401;</li><li>Arginine deiminase stimulators, such as pegargiminase (ADI-PEG-20);</li><li>claudin-18 inhibitors, such as claudiximab;</li><li>β-catenin inhibitors, such as CWP-291;</li><li>chemokine receptor 2 (CCR) inhibitors, such as PF-04136309, CCX-872, BMS-813160 (CCR2/CCRS)</li><li>thymidylate synthase inhibitors, such as ONX-0801;</li><li>ALK/ROS1 inhibtors, such as lorlatinib;</li><li>tankyrase inhibitors, such as G007-LK;</li><li>Mdm2 p53-binding protein inhibitors, such as CMG-097, HDM-201; c-PIM inhibitors, such as PIM447;</li><li>sphingosine kinase-2 (SK2) inhibitors, such as Yeliva^® (ABC294640);</li><li>DNA polymerase inhibitors, such as sapacitabine;</li><li>Cell cycle/Microtubule inhibitors, such as eribulin mesylate;</li><li>c-MET inhibitors, such as AMG-337, savolitinib, tivantinib (ARQ-197), capmatinib, and tepotinib, ABT-700, AG213, AMG-208, JNJ-38877618 (OMO-1), merestinib, HQP-8361;</li><li>c-Met/VEGFR inhibitors, such as BMS-817378, TAS-115;</li><li>c-Met/RON inhibitors, such as BMS-777607;</li><li>BCR/ABL inhibitors, such as rebastinib, asciminib, ponatinib (ICLUSIG^®);</li><li>MNK1/MNK2 inhibitors, such as eFT-508;</li><li>Cytochrome P450 11B2/Cytochrome P450 17/AKT protein kinase inhibitors, such as LAE-201;</li><li>Cytochrome P450 3A4 stimulators, such as mitotane;</li><li>lysine-specific demethylase-1 (LSD1) inhibitors, such as CC-90011;</li><li>CSF1R/KIT and FLT3 inhibitors, such as pexidartinib (PLX3397);</li><li>Flt3 tyrosine kinase /Kit tyrosine kinase inhibitor and PDGF receptor antagonists, such as quizartinib dihydrochloride;</li><li>kinase inhibitors, such as vandetanib;</li><li>E selectin antagonists, such as GMI-1271;</li><li>differentiation inducers, such as tretinoin;</li><li>epidermal growth factor receptor (EGFR) inhibitors, such as osimertinib (AZD-9291), cetuximab;</li><li>topoisomerase inhibitors, such as Adriamycin, doxorubicin, daunorubicin, dactinomycin, DaunoXome, Caelyx, eniposide, epirubicin, etoposide, idarubicin, irinotecan, mitoxantrone, pixantrone, sobuzoxane, topotecan, irinotecan, MM-398 (liposomal irinotecan), vosaroxin and GPX-150, aldoxorubicin, AR-67, mavelertinib, AST-2818, avitinib (ACEA-0010), irofulven (MGI-114);</li><li>corticosteroids, such as cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisone, prednisolone;</li><li>growth factor signal transduction kinase inhibitors;</li><li>nucleoside analogs, such as DFP-10917;</li><li>Axl inhibitors, such as BGB-324 (bemcentinib), SLC-0211;</li><li>Axl/Flt3 inhibitors, such as gilteritinib;</li><li>Inhibitors of bromodomain and extraterminal motif (BET) proteins, including ABBV-744, BRD2 (NCBI Gene ID: 6046), BRD3 (NCBI Gene ID: 8019), BRD4 (NCBI Gene ID: 23476), and bromodomain testis-specific protein (BRDT; NCBI Gene ID: 676), such as INCB-054329, INCB057643, TEN-010, AZD-5153, ABT-767, BMS-986158, CC-90010, GSK525762 (molibresib), NHWD-870, ODM-207, GSK-2820151, GSK-1210151A, ZBC246, ZBC260, ZEN3694, FT-1101, RG-6146, CC-90010, CC-95775, mivebresib, BI-894999, PLX-2853, PLX-51107, CPI-0610, GS-5829;</li><li>PARP inhibitors, such as olaparib (MK7339), rucaparib, veliparib, talazoparib, ABT-767, BGB-290, fluzolepali (SHR-3162), niraparib (JNJ-64091742), bendamustine hydrochloride,</li><li>PARP/Tankyrase inhibitors such as 2X-121 (e-7499);</li><li>IMP-4297, SC-10914, IDX-1197, HWH-340, CK-102, simmiparib;</li><li>Proteasome inhibitors, such as ixazomib (NINLARO^®), carfilzomib (Kyprolis^®), marizomib, bortezomib;</li><li>Glutaminase inhibitors, such as CB-839 (telaglenastat), bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl)ethyl sulfide (BPTES);</li><li>mitochondrial complex I inhibitors, such as metformin, phenformin;</li><li>Vaccines, such as peptide vaccine TG-01 (RAS), GALE-301, GALE-302, nelipepimut-s, SurVaxM, DSP-7888, TPIV-200, PVX-410, VXL-100, DPX-E7, ISA-101, 6MHP, OSE-2101, galinpepimut-S, SVN53-67/M57-KLH, IMU-131, peptide subunit vaccine (acute lymphoblastic leukemia, University Children's Hospital Tuebingen); bacterial vector vaccines such as CRS-207/GVAX, axalimogene filolisbac (ADXS11-001); adenovirus vector vaccines such as nadofaragene firadenovec; autologous Gp96 vaccine; dendritic cells vaccines, such as CVactm, tapuldencel-T, eltrapuldencel-T, SL-701, BSK01TM, rocapuldencel-T (AGS-003), DCVAC, CVactm , stapuldencel-T, eltrapuldencel-T, SL-701, BSK01TM, ADXS31-142, autologous dendritic cell vaccine (metastatic malignant melanoma, intradermal/intravenous, Universitatsklinikum Erlangen); oncolytic vaccines such as, talimogene laherparepvec, pexastimogene devacirepvec, GL-ONC1, MG1-MA3, parvovirus H-1, ProstAtak, enadenotucirev, MG1MA3, ASN-002 (TG-1042); therapeutic vaccines, such as CVAC-301, CMP-001, CreaVax-BC, PF-06753512, VBI-1901, TG-4010, ProscaVax^™; tumor cell vaccines, such as Vigil^® (IND-14205), Oncoquest-L vaccine; live attenuated, recombinant, serotype 1 poliovirus vaccine, such as PVS-RIPO; Adagloxad simolenin; MEDI-0457; DPV-001 a tumor-derived, autophagosome enriched cancer vaccine; RNA vaccines such as, CV-9209, LV-305; DNA vaccines, such as MEDI-0457, MVI-816, INO-5401; modified vaccinia virus Ankara vaccine expressing p53, such as MVA-p53; DPX-Survivac; BriaVax^™; GI-6301; GI-6207; GI-4000; IO-103; Neoantigen peptide vaccines, such as AGEN-2017, GEN-010, NeoVax, RG-6180, GEN-009, PGV-001 (TLR-3 agonist), GRANITE-001, NEO-PV-01; Peptide vaccines that target heat shock proteins, such as PhosphoSynVax^™; Vitespen (HSPPC-96-C), NANT Colorectal Cancer Vaccine containing aldoxorubicin, autologous tumor cell vaccine + systemic CpG-B + IFN-alpha (cancer), IO-120 + IO-103 (PD-L1/PD-L2 vaccines), HB-201, HB-202, HB-301, TheraT^®*-based vaccines;</li><li>TLR-3 agonist/interferon inducers, such as Poly-ICLC (NSC-301463);</li><li>STAT-3 inhibitors, such as napabucasin (BBI-608);</li><li>ATPase p97 inhibitors, such as CB-5083;</li><li>smoothened (SMO) receptor inhibitors, such as Odomzo^® (sonidegib, formerly LDE-225), LEQ506, vismodegib (GDC-0449), BMS-833923, glasdegib (PF-04449913), LY2940680, and itraconazole;</li><li>interferon alpha ligand modulators, such as interferon alpha-2b, interferon alpha-2a biosimilar (Biogenomics), ropeginterferon alfa-2b (AOP-2014, P-1101, PEG IFN alpha-2b), Multiferon (Alfanative, Viragen), interferon alpha 1b, Roferon-A (Canferon, Ro-25-3036), interferon alfa-2a follow-on biologic (Biosidus)(Inmutag, Inter 2A), interferon alfa-2b follow-on biologic (Biosidus - Bioferon, Citopheron, Ganapar, Beijing Kawin Technology - Kaferon), Alfaferone, pegylated interferon alpha-1b, peginterferon alfa-2b follow-on biologic (Amega), recombinant human interferon alpha-1b, recombinant human interferon alpha-2a, recombinant human interferon alpha-2b, veltuzumab-IFN alpha 2b conjugate, Dynavax (SD-101), and interferon alfa-n1 (Humoferon, SM-10500, Sumiferon);</li><li>interferon gamma ligand modulators, such as interferon gamma (OH-6000, Ogamma 100);</li><li>IL-6 receptor modulators, such as tocilizumab, AS-101 (CB-06-02, IVX-Q-101);</li><li>Heat shock protein inhibitors/IL-6 receptor antagonists, such as siltuximab;</li><li>Telomerase modulators, such as, tertomotide (GV-1001, HR-2802, Riavax) and imetelstat (GRN-163, JNJ-63935937);</li><li>DNA methyltransferases inhibitors, such as temozolomide (CCRG-81045), decitabine, guadecitabine (S-110, SGI-110), KRX-0402, RX-3117, RRx-001, and azacytidine (CC-486);</li><li>DNA gyrase inhibitors, such as pixantrone and sobuzoxane;</li><li>DNA gyrase inhibitors/Topoisimerase II inhibitors, such as amrubicin;</li><li>Bcl-2 family protein inhibitors, such as ABT-263, venetoclax (ABT-199), ABT-737, RG7601, and AT-101;</li><li>Bcl-2/Bcl-XL inhibitors, such as novitoclax;</li><li>Notch inhibitors, such as LY3039478 (crenigacestat), tarextumab (anti-Notch2/3), BMS-906024;</li><li>hyaluronidase stimulators, such as PEGPH-20;</li><li>Erbb2 tyrosine kinase receptor inhibitors/Hyaluronidase stimulators, such as Herceptin Hylecta;</li><li>Wnt pathway inhibitors, such as SM-04755, PRI-724, WNT-974;</li><li>gamma-secretase inhibitors, such as PF-03084014, MK-0752, RO-4929097;</li><li>Grb-2 (growth factor receptor bound protein-2) inhibitors, such as BP1001;</li><li>TRAIL pathway-inducing compounds, such as ONC201, ABBV-621;</li><li>TRAIL modulators, such as SCB-313;</li><li>Focal adhesion kinase inhibitors, such as VS-4718, defactinib, GSK2256098;</li><li>hedgehog inhibitors, such as saridegib, sonidegib (LDE225), glasdegib;</li><li>Aurora kinase inhibitors, such as alisertib (MLN-8237), and AZD-2811, AMG-900, barasertib, ENMD-2076;</li><li>HSPB1 modulators (heat shock protein 27, HSP27), such as brivudine, apatorsen;</li><li>ATR inhibitors, such as BAY-937, AZD6738, AZD6783, VX-803, VX-970 (berzosertib) and VX-970;</li><li>Hsp90 inhibitors, such as AUY922, onalespib (AT13387), SNX-2112, SNX5422;</li><li>Murine double minute (mdm2) oncogene inhibitors, such as DS-3032b, RG7775, AMG-232, HDM201, and idasanutlin (RG7388);</li><li>CD137 agonists, such as urelumab, utomilumab (PF-05082566), AGEN2373, ADG-106, BT-7480;</li><li>STING agonists, such as ADU-S100 (MIW-815), SB-11285, MK-1454, SR-8291, AdVCA0848, GSK-532, SYN-STING, MSA-1, SR-8291, GSK3745417 ;</li><li>FGFR inhibitors, such as FGF-401, INCB-054828, BAY-1163877, AZD4547, JNJ-42756493, LY2874455, Debio-1347;</li><li>fatty acid synthase (FASN) inhibitors, such as TVB-2640;</li><li>Antigen CD19 inhibitors, such as MOR208, MEDI-551, AFM-11, inebilizumab;</li><li>CD44 binders, such as A6;</li><li>protein phosphatease 2A (PP2A) inhibitors, such as LB-100;</li><li>CYP17 inhibitors, such as seviteronel (VT-464), ASN-001, ODM-204, CFG920, abiraterone acetate;</li><li>RXR agonists, such as IRX4204;</li><li>hedgehog/smoothened (hh/Smo) antagonists, such as taladegib, patidegib, vismodegib;</li><li>complement C3 modulators, such as Imprime PGG;</li><li>IL-15 agonists, such as ALT-803, NKTR-255, interleukin-15/Fc fusion protein, AM-0015, NIZ-985, and hetIL-15;</li><li>EZH2 (enhancer of zeste homolog 2) inhibitors, such as tazemetostat, CPI-1205, GSK-2816126, PF-06821497;</li><li>Oncolytic viruses, such as pelareorep, CG-0070, MV-NIS therapy, HSV-1716, DS-1647, VCN-01, ONCOS-102, TBI-1401, tasadenoturev (DNX-2401), vocimagene amiretrorepvec, RP-1, CVA21, Celyvir, LOAd-703, OBP-301, IMLYGIC^®;</li><li>DOT1L (histone methyltransferase) inhibitors, such as pinometostat (EPZ-5676);</li><li>toxins such as Cholera toxin, ricin, Pseudomonas exotoxin, Bordetella pertussis adenylate cyclase toxin, diphtheria toxin, and caspase activators;</li><li>DNA plasmids, such as BC-819</li><li>PLK inhibitors of PLK 1, 2, and 3, such as volasertib (PLK1);</li><li>WEE1 inhibitors, such as AZD-1775 (adavosertib); Rho kinase (ROCK) inhibitors, such as AT13148, KD025;</li><li>Inhibition of Apoptosis Protein (IAP) inhibitors, such as ASTX660, debio-1143, birinapant, APG-1387, LCL-161;</li><li>RNA polymerase inhibitors, such has lurbinectedin (PM-1183), CX-5461;</li><li>Tubulin inhibitors, such as PM-184, BAL-101553 (lisavanbulin), and OXI-4503, fluorapacin (AC-0001), plinabulin, vinflunine ;</li><li>Toll-like receptor 4 (TLR-4) agonists, such as G100, GSK1795091, and PEPA-10;</li><li>Elongation factor 1 alpha 2 inhibitors, such as plitidepsin;</li><li>Elongation factor 2 inhibitors/Interleukin-2 ligands/NAD ADP ribosyltransferase stimulators, such as denileukin diftitox;</li><li>CD95 inhibitors, such as APG-101, APO-010, asunercept;</li><li>WT1 inhibitors, such as DSP-7888;</li><li>splicing factor 3B subunit1 (SF3B1) inhibitors, such as H3B-8800</li><li>retinoid Z receptor gamma (RORγ) agonists, such as LYC-55716; and</li><li>Microbiome modulators, such as SER-401, EDP-1503, MRx-0518.</li></ul>

0249In some embodiments, a compound as described herein, is co-administered with one or more additional therapeutic agents comprising an inhibitor or antagonist of: myeloid cell leukemia sequence 1 (MCL1) apoptosis regulator (NCBI Gene ID: 4170); mitogen-activated protein kinase 1 (MAP4K1) (also called Hematopoietic Progenitor Kinase 1 (HPK1), NCBI Gene ID: 11184); diacylglycerol kinase alpha (DGKA, DAGK, DAGK1 or DGK-alpha; NCBI Gene ID: 1606); 5'-nucleotidase ecto (NT5E or CD73; NCBI Gene ID: 4907); ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1 or CD39; NCBI Gene ID: 593); transforming growth factor beta 1 (TGFB1 or TGFβ; NCBI Gene ID: 7040); heme oxygenase 1 (HMOX1, HO-1 or HO1; NCBI Gene ID: 3162); heme oxygenase 2 (HMOX2, HO-2 or HO2; NCBI Gene ID: 3163); vascular endothelial growth factor A (VEGFA or VEGF; NCBI Gene ID: 7422); erb-b2 receptor tyrosine kinase 2 (ERBB2, HER2, HER2/neu or CD340; NCBI Gene ID: 2064), epidermal growth factor receptor (EGFR, ERBB, ERBB1 or HER1; NCBI Gene ID: 1956); ALK receptor tyrosine kinase (ALK, CD246; NCBI Gene ID: 238); poly(ADP-ribose) polymerase 1 (PARP1; NCBI Gene ID: 142); poly(ADP-ribose) polymerase 2 (PARP2; NCBI Gene ID: 10038); TCDD inducible poly(ADP-ribose) polymerase (TIPARP, PARP7; NCBI Gene ID: 25976); cyclin dependent kinase 4 (CDK4; NCBI Gene ID: 1019); cyclin dependent kinase 6 (CDK6; NCBI Gene ID: 1021); TNF receptor superfamily member 14 (TNFRSF14, HVEM, CD270; NCBI Gene ID: 8764); T cell immunoreceptor with Ig and ITIM domains (TIGIT; NCBI Gene ID: 201633); X-linked inhibitor of apoptosis (XIAP, BIRC4, IAP-3; NCBI Gene ID: 331); baculoviral IAP repeat containing 2 (BIRC2, cIAP1; NCBI Gene ID: 329); baculoviral IAP repeat containing 3 (BIRC3, cIAP2; NCBI Gene ID: 330); baculoviral IAP repeat containing 5 (BIRC5, surviving; NCBI Gene ID: 332); C-C motif chemokine receptor 2 (CCR2, CD192; NCBI Gene ID: 729230); C-C motif chemokine receptor 5 (CCRS, CD195; NCBI Gene ID: 1234); C-C motif chemokine receptor 8 (CCR8, CDw198; NCBI Gene ID: 1237); C-X-C motif chemokine receptor 2 (CXCR2, CD182; NCBI Gene ID: 3579); C-X-C motif chemokine receptor 3 (CXCR3, CD182, CD183; NCBI Gene ID: 2833); C-X-C motif chemokine receptor 4 (CXCR4, CD184; NCBI Gene ID: 7852); arginase (ARG1 (NCBI Gene ID: 383), ARG2 (NCBI Gene ID: 384)), carbonic anhydrase (CA1 (NCBI Gene ID: 759), CA2 (NCBI Gene ID: 760), CA3 (NCBI Gene ID: 761), CA4 (NCBI Gene ID: 762), CA5A (NCBI Gene ID: 763), CA5B (NCBI Gene ID: 11238), CA6 (NCBI Gene ID: 765), CA7 (NCBI Gene ID: 766), CA8 (NCBI Gene ID: 767), CA9 (NCBI Gene ID: 768), CA10 (NCBI Gene ID: 56934), CA11 (NCBI Gene ID: 770), CA12 (NCBI Gene ID: 771), CA13 (NCBI Gene ID: 377677), CA14 (NCBI Gene ID: 23632)), prostaglandin-endoperoxide synthase 1 (PTGS1, COX-1; NCBI Gene ID: 5742), prostaglandin-endoperoxide synthase 2 (PTGS2, COX-2; NCBI Gene ID: 5743), secreted phospholipase A2, prostaglandin E synthase (PTGES, PGES; Gene ID: 9536), arachidonate 5-lipoxygenase (ALOX5, 5-LOX; NCBI Gene ID: 240) and/or soluble epoxide hydrolase 2 (EPHX2, SEH; NCBI Gene ID: 2053); a secreted phospholipase A2 <i>(e.g.,</i> PLA2G1B (NCBI Gene ID: 5319); PLA2G7 (NCBI Gene ID: 7941), PLA2G3 (NCBI Gene ID: 50487), PLA2G2A (NCBI Gene ID: 5320); PLA2G4A (NCBI Gene ID: 5321); PLA2G12A (NCBI Gene ID: 81579); PLA2G12B (NCBI Gene ID: 84647); PLA2G10 (NCBI Gene ID: 8399); PLA2G5 (NCBI Gene ID: 5322); PLA2G2D (NCBI Gene ID: 26279); PLA2G15 (NCBI Gene ID: 23659)); indoleamine 2,3-dioxygenase 1 (IDO1; NCBI Gene ID: 3620); indoleamine 2,3-dioxygenase 2 (IDO2; NCBI Gene ID: 169355); hypoxia inducible factor 1 subunit alpha (HIF1A; NCBI Gene ID: 3091); angiopoietin 1 (ANGPT1; NCBI Gene ID: 284); Endothelial TEK tyrosine kinase (TIE-2, TEK, CD202B; NCBI Gene ID: 7010); Janus kinase 1 (JAK1; NCBI Gene ID: 3716); catenin beta 1 (CTNNB1; NCBI Gene ID: 1499); histone deacetylase 9 (HDAC9; NCBI Gene ID: 9734) and/or 5'-3' exoribonuclease 1 (XRN1; NCBI Gene ID: 54464).

<u>TCR Signaling Modulators</u>

0250In some embodiments, a compound as described herein, is combined with one or more agonist or antagonist of T-Cell Receptor (TCR) signaling modulators. Activation of T cells through the TCR and is essential for thymocyte development and effector T cell function. TCR activation promotes signaling cascades that ultimately determine cell fate through regulating cytokine production, cell survival, proliferation, and differentiation. Examples of TCR signaling modulators include without limitation CD2 (cluster of differentiation 2, LFA-2, T11, LFA-3 receptor), CD3 (cluster of differentiation 3), CD4 (cluster of differentiation 4), CD8 (cluster of differentiation 8), CD28 (cluster of differentiation 28), CD45 (PTPRC, B220, GP180), LAT (Linker for activation of T cells, LAT1), Lck, LFA-1 (ITGB2, CD18, LAD, LCAMB), Src, Zap-70, SLP-76, DGKalpha, CBL-b, CISH, HPK1.

0251Examples of agonist of cluster of differentiation 3 (CD3) that can be co-administered include without limitation MGD015.

0252In some embodiments, a compound as described herein, is combined with one or more blockers or inhibitors of inhibitory immune checkpoint proteins or receptors and/or with one or more stimulators, activators or agonists of one or more stimulatory immune checkpoint proteins or receptors. Blockade or inhibition of inhibitory immune checkpoints can positively regulate T-cell or NK cell activation and prevent immune escape of cancer cells within the tumor microenvironment. Activation or stimulation of stimulatory immune check points can augment the effect of immune checkpoint inhibitors in cancer therapeutics. In some embodiments, the immune checkpoint proteins or receptors regulate T cell responses (<i>e.g.,</i> reviewed in<nplcit id="ncit0015" npl-type="s"><text> Xu, et al., J Exp Clin Cancer Res. (2018) 37: 110</text></nplcit>). In some embodiments, the immune checkpoint proteins or receptors regulate NK cell responses (<i>e.g.,</i> reviewed in<nplcit id="ncit0016" npl-type="s"><text> Davis, et al., Semin Immunol. (2017) 31:64-75</text></nplcit> and <nplcit id="ncit0017" npl-type="s"><text>Chiossone, et al., Nat Rev Immunol. (2018) 18(11):671-688</text></nplcit>).

0253Examples of immune checkpoint proteins or receptors include without limitation CD27, CD70; CD40, CD40LG; CD47, CD48 (SLAMF2), transmembrane and immunoglobulin domain containing 2 (TMIGD2, CD28H), CD84 (LY9B, SLAMF5), CD96, CD160, MS4A1 (CD20), CD244 (SLAMF4); CD276 (B7H3); V-set domain containing T cell activation inhibitor 1 (VTCN1, B7H4); V-set immunoregulatory receptor (VSIR, B7H5, VISTA); immunoglobulin superfamily member 11 (IGSF11, VSIG3); natural killer cell cytotoxicity receptor 3 ligand 1 (NCR3LG1, B7H6); HERV-H LTR-associating 2 (HHLA2, B7H7); inducible T cell costimulator (ICOS, CD278); inducible T cell costimulator ligand (ICOSLG, B7H2); TNF receptor superfamily member 4 (TNFRSF4, OX40); TNF superfamily member 4 (TNFSF4, OX40L); TNFRSF8 (CD30), TNFSF8 (CD30L); TNFRSF10A (CD261, DR4, TRAILR1), TNFRSF9 (CD137), TNFSF9 (CD137L); TNFRSF10B (CD262, DR5, TRAILR2), TNFRSF10 (TRAIL); TNFRSF14 (HVEM, CD270), TNFSF14 (HVEML); CD272 (B and T lymphocyte associated (BTLA)); TNFRSF17 (BCMA, CD269), TNFSF13B (BAFF); TNFRSF18 (GITR), TNFSF18 (GITRL); MHC class I polypeptide-related sequence A (MICA); MHC class I polypeptide-related sequence B (MICB); CD274 (PDL1, PD-L1); programmed cell death 1 (PDCD1, PD-1, PD-1); cytotoxic T-lymphocyte associated protein 4 (CTLA4, CD152); CD80 (B7-1), CD28; nectin cell adhesion molecule 2 (NECTIN2, CD112); CD226 (DNAM-1); Poliovirus receptor (PVR) cell adhesion molecule (PVR, CD155); PVR related immunoglobulin domain containing (PVRIG, CD112R); T cell immunoreceptor with Ig and ITIM domains (TIGIT); T cell immunoglobulin and mucin domain containing 4 (TIMD4; TIM4); hepatitis A virus cellular receptor 2 (HAVCR2, TIMD3, TIM-3); galectin 9 (LGALS9); lymphocyte activating 3 (LAG-3, CD223); signaling lymphocytic activation molecule family member 1 (SLAMF1, SLAM, CD150); lymphocyte antigen 9 (LY9, CD229, SLAMF3); SLAM family member 6 (SLAMF6, CD352); SLAM family member 7 (SLAMF7, CD319); UL16 binding protein 1 (ULBP1); UL16 binding protein 2 (ULBP2); UL16 binding protein 3 (ULBP3); retinoic acid early transcript 1E (RAET1E; ULBP4); retinoic acid early transcript 1G (RAET1G; ULBP5); retinoic acid early transcript 1L (RAET1L; ULBP6); lymphocyte activating 3 (CD223); killer cell immunoglobulin like receptor(KIR); killer cell lectin like receptor C1 (KLRC1, NKG2A, CD159A); killer cell lectin like receptor K1 (KLRK1, NKG2D, CD314); killer cell lectin like receptor C2 (KLRC2, CD159c, NKG2C); killer cell lectin like receptor C3 (KLRC3, NKG2E); killer cell lectin like receptor C4 (KLRC4, NKG2F); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 1 (KIR2DL1); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 3 (KIR2DL3); killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 1 (KIR3DL1); killer cell lectin like receptor D1 (KLRD1).

0254In some embodiments, a compound as described herein, is combined with one or more blockers or inhibitors of one or more T-cell inhibitory immune checkpoint proteins or receptors. Illustrative T-cell inhibitory immune checkpoint proteins or receptors include without limitation CD274 ( PDL1, PD-L1); programmed cell death 1 ligand 2 (PDCD1LG2, PD-L2, CD273); programmed cell death 1 (PDCD1, PD1, PD-1); cytotoxic T-lymphocyte associated protein 4 (CTLA4, CD152); CD276 (B7H3); V-set domain containing T cell activation inhibitor 1 (VTCN1, B7H4); V-set immunoregulatory receptor (VSIR, B7H5, VISTA); immunoglobulin superfamily member 11 (IGSF11, VSIG3); TNFRSF14 (HVEM, CD270), TNFSF14 (HVEML); CD272 (B and T lymphocyte associated (BTLA)); PVR related immunoglobulin domain containing (PVRIG, CD1 12R); T cell immunoreceptor with Ig and ITIM domains (TIGIT); lymphocyte activating 3 (LAG-3, CD223); hepatitis A virus cellular receptor 2 (HAVCR2, TIMD3, TIM-3); galectin 9 (LGALS9); killer cell immunoglobulin like receptor(KIR); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 1 (KIR2DL1); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 3 (KIR2DL3); and killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 1 (KIR3DL1). In some embodiments, a compound as described herein, is combined with one or more agonist or activators of one or more T-cell stimulatory immune checkpoint proteins or receptors. Illustrative T-cell stimulatory immune checkpoint proteins or receptors include without limitation CD27, CD70; CD40, CD40LG; inducible T cell costimulator (ICOS, CD278); inducible T cell costimulator ligand (ICOSLG, B7H2); TNF receptor superfamily member 4 (TNFRSF4, OX40); TNF superfamily member 4 (TNFSF4, OX40L); TNFRSF9 (CD137), TNFSF9 (CD137L); TNFRSF18 (GITR), TNFSF18 (GITRL); CD80 (B7-1), CD28; nectin cell adhesion molecule 2 (NECTIN2, CD112); CD226 (DNAM-1); CD244 (2B4, SLAMF4), Poliovirus receptor (PVR) cell adhesion molecule (PVR, CD155). <i>See, e.g.,</i><nplcit id="ncit0018" npl-type="s"><text>Xu, et al., J Exp Clin Cancer Res. (2018) 37:110</text></nplcit>.

0255In some embodiments, a compound as described herein, is combined with one or more blockers or inhibitors of one or more NK-cell inhibitory immune checkpoint proteins or receptors. Illustrative NK-cell inhibitory immune checkpoint proteins or receptors include without limitation killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 1 (KIR, CD158E1); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 1 (KIR2DL1); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 3 (KIR2DL3); killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 1 (KIR3DL1); killer cell lectin like receptor C1 (KLRC1, NKG2A, CD159A); and killer cell lectin like receptor D1 (KLRD1, CD94). In some embodiments, a compound as described herein, is combined with one or more agonist or activators of one or more NK-cell stimulatory immune checkpoint proteins or receptors. Illustrative NK-cell stimulatory immune checkpoint proteins or receptors include without limitation CD16, CD226 (DNAM-1); CD244 (2B4, SLAMF4); killer cell lectin like receptor K1 (KLRK1, NKG2D, CD314); SLAM family member 7 (SLAMF7). <i>See, e.g.,</i><nplcit id="ncit0019" npl-type="s"><text>Davis, et al., Semin Immunol. (2017) 31:64-75</text></nplcit>; <nplcit id="ncit0020" npl-type="s"><text>Fang, et al., Semin Immunol. (2017) 31:37-54</text></nplcit>; and <nplcit id="ncit0021" npl-type="s"><text>Chiossone, et al., Nat Rev Immunol. (2018) 18(11):671-688</text></nplcit>.

0256In some embodiments, a compound as described herein, is combined with an inhibitor of CD47 (IAP, MER6, OA3; NCBI Gene ID: 961; UniProt Q08722). Examples of CD47 inhibitors include without limitation to anti-CD47 mAbs (Vx-1004), anti-human CD47 mAbs (CNTO-7108), CC-90002, CC-90002-ST-001, humanized anti-CD47 antibody (Hu5F9-G4), NI-1701, NI-1801, RCT-1938, ALX-148, TTI-621, RRx-001, DSP-107, VT-1021, TTI-621, TTI-622, and IMM-02 SGN-CD47M. Examples of anti-CD47 antibodies include IBI-188, TJC-4, SHR-1603, HLX-24, LQ-001, IMC-002, ZL-1201, IMM-01, B6H12, GenSci-059, TAY-018, PT-240, 1F8-GMCSF, SY-102, KD-015.

0257In some embodiments, the inhibitor of CD47 is a bi-specific antibody targeting CD47. Examples of bi-specific antibodies targeting CD47 include IBI-322 (CD47/PD-L1), IMM-0306 (CD47/CD20), TJ-L1C4 (CD47/PD-L1), HX-009 (CD47/PD-1), PMC-122 (CD47/PD-L1), PT-217, (CD47/DLL3), IMM-26011 (CD47/FLT3), IMM-0207 (CD47/VEGF), IMM-2902 (CD47/HER2), BH29xx (CD47/PD-L1), IMM-03 (CD47/CD20), IMM-2502 (CD47/PD-L1), HMBD-004B (CD47/BCMA), and HMBD-004A (CD47/CD33).

0258In some embodiments, the anti-CD47 targeting agent is one described in patent publication numbers <patcit id="pcit0029" dnum="WO199727873A"><text>WO199727873</text></patcit>, <patcit id="pcit0030" dnum="WO199940940A"><text>WO199940940</text></patcit>, <patcit id="pcit0031" dnum="WO2002092784A"><text>WO2002092784</text></patcit>, <patcit id="pcit0032" dnum="WO2005044857A"><text>WO2005044857</text></patcit>, <patcit id="pcit0033" dnum="WO2009046541A"><text>WO2009046541</text></patcit>, <patcit id="pcit0034" dnum="WO2010070047A"><text>WO2010070047</text></patcit>, <patcit id="pcit0035" dnum="WO2011143624A"><text>WO2011143624</text></patcit>, <patcit id="pcit0036" dnum="WO2012170250A"><text>WO2012170250</text></patcit>, <patcit id="pcit0037" dnum="WO2013109752A"><text>WO2013109752</text></patcit>, <patcit id="pcit0038" dnum="WO2013119714A"><text>WO2013119714</text></patcit>, <patcit id="pcit0039" dnum="WO2014087248A"><text>WO2014087248</text></patcit>, <patcit id="pcit0040" dnum="WO2015191861A"><text>WO2015191861</text></patcit>, <patcit id="pcit0041" dnum="WO2016022971A"><text>WO2016022971</text></patcit>, <patcit id="pcit0042" dnum="WO2016023040A"><text>WO2016023040</text></patcit>, <patcit id="pcit0043" dnum="WO2016024021A"><text>WO2016024021</text></patcit>, <patcit id="pcit0044" dnum="WO2016081423A"><text>WO2016081423</text></patcit>, <patcit id="pcit0045" dnum="WO2016109415A"><text>WO2016109415</text></patcit>, <patcit id="pcit0046" dnum="WO2016141328A"><text>WO2016141328</text></patcit>, <patcit id="pcit0047" dnum="WO2016188449A"><text>WO2016188449</text></patcit>, <patcit id="pcit0048" dnum="WO2017027422A"><text>WO2017027422</text></patcit>, <patcit id="pcit0049" dnum="WO2017049251A"><text>WO2017049251</text></patcit>, <patcit id="pcit0050" dnum="WO2017053423A"><text>WO2017053423</text></patcit>, <patcit id="pcit0051" dnum="WO2017121771A"><text>WO2017121771</text></patcit>, <patcit id="pcit0052" dnum="WO2017194634A"><text>WO2017194634</text></patcit>, <patcit id="pcit0053" dnum="WO2017196793A"><text>WO2017196793</text></patcit>, <patcit id="pcit0054" dnum="WO2017215585A"><text>WO2017215585</text></patcit>, <patcit id="pcit0055" dnum="WO2018075857A"><text>WO2018075857</text></patcit>, <patcit id="pcit0056" dnum="WO2018075960A"><text>WO2018075960</text></patcit>, <patcit id="pcit0057" dnum="WO2018089508A"><text>WO2018089508</text></patcit>, <patcit id="pcit0058" dnum="WO2018095428A"><text>WO2018095428</text></patcit>, <patcit id="pcit0059" dnum="WO2018137705A"><text>WO2018137705</text></patcit>, <patcit id="pcit0060" dnum="WO2018233575A"><text>WO2018233575</text></patcit>, <patcit id="pcit0061" dnum="WO2019027903A"><text>WO2019027903</text></patcit>, <patcit id="pcit0062" dnum="WO2019034895A"><text>WO2019034895</text></patcit>, <patcit id="pcit0063" dnum="WO2019042119A"><text>WO2019042119</text></patcit>, <patcit id="pcit0064" dnum="WO2019042285A"><text>WO2019042285</text></patcit>, <patcit id="pcit0065" dnum="WO2019042470A"><text>WO2019042470</text></patcit>, <patcit id="pcit0066" dnum="WO2019086573A"><text>WO2019086573</text></patcit>, <patcit id="pcit0067" dnum="WO2019108733A"><text>WO2019108733</text></patcit>, <patcit id="pcit0068" dnum="WO2019138367A"><text>WO2019138367</text></patcit>, <patcit id="pcit0069" dnum="WO2019144895A"><text>WO2019144895</text></patcit>, <patcit id="pcit0070" dnum="WO2019157843A"><text>WO2019157843</text></patcit>, <patcit id="pcit0071" dnum="WO2019179366A"><text>WO2019179366</text></patcit>, <patcit id="pcit0072" dnum="WO2019184912A"><text>WO2019184912</text></patcit>, <patcit id="pcit0073" dnum="WO2019185717A"><text>WO2019185717</text></patcit>, <patcit id="pcit0074" dnum="WO2019201236A"><text>WO2019201236</text></patcit>, <patcit id="pcit0075" dnum="WO2019238012A"><text>WO2019238012</text></patcit>, <patcit id="pcit0076" dnum="WO2019241732A"><text>WO2019241732</text></patcit>, <patcit id="pcit0077" dnum="WO2020019135A"><text>WO2020019135</text></patcit>, <patcit id="pcit0078" dnum="WO2020036977A"><text>WO2020036977</text></patcit>, <patcit id="pcit0079" dnum="WO2020043188A"><text>WO2020043188</text></patcit>, or <patcit id="pcit0080" dnum="WO2020009725A"><text>WO2020009725</text></patcit>.

0259In some embodiments, the one or more immune checkpoint inhibitors comprises a proteinaceous (e.g., antibody or fragment thereof, or antibody mimetic) inhibitor of PD-L1 (CD274), PD-1 (PDCD1) or CTLA4. In some embodiments, the one or more immune checkpoint inhibitors comprises a small organic molecule inhibitor of PD-L1 (CD274), PD-1 (PDCD1) or CTLA4.

0260Examples of inhibitors of CTLA4 that can be co-administered include without limitation ipilimumab, tremelimumab, BMS-986218, AGEN1181, AGEN1884, BMS-986249, MK-1308, REGN-4659, ADU-1604, CS-1002, BCD-145, APL-509, JS-007, BA-3071, ONC-392, AGEN-2041, JHL-1155, KN-044, CG-0161, ATOR-1144, PBI-5D3H5, BPI-002, HBM-4003, as well as multi-specific inhibitors FPT-155 (CTLA4/PD-L1/CD28), PF-06936308 (PD-1/ CTLA4), MGD-019 (PD-1/CTLA4), KN-046 (PD-1/CTLA4), MEDI-5752 (CTLA4/PD-1), XmAb-20717 (PD-1/CTLA4), and AK-104 (CTLA4/PD-1).

0261Examples of inhibitors/antibodies of PD-L1 (CD274) or PD-1 (PDCD1) that can be co-administered include without limitation pembrolizumab, nivolumab, cemiplimab, pidilizumab, AMG-404, AMP-224, MEDI0680 (AMP-514), spartalizumab, atezolizumab, avelumab, durvalumab, BMS-936559, CK-301, PF-06801591, BGB-A317 (tislelizumab), GEN-1046 (PD-L1/4-1BB), GLS-010 (WBP-3055), AK-103 (HX-008), AK-105, CS-1003, HLX-10, MGA-012, BI-754091, AGEN-2034, JS-001 (toripalimab), JNJ-63723283, genolimzumab (CBT-501), LZM-009, BCD-100, LY-3300054, SHR-1201, SHR-1210 (camrelizumab), Sym-021, ABBV-181, PD1-PIK, BAT-1306, (MSB0010718C), CX-072, CBT-502, TSR-042 (dostarlimab), MSB-2311, JTX-4014, BGB-A333, SHR-1316, CS-1001 (WBP-3155, KN-035, IBI-308 (sintilimab), HLX-20, KL-A167, STI-A1014, STI-A1015 (IMC-001), BCD-135, FAZ-053, TQB-2450, MDX1105-01, GS-4224, GS-4416, INCB086550, MAX10181, as well as multi-specific inhibitors FPT-155 (CTLA4/PD-L1/CD28), PF-06936308 (PD-1/ CTLA4), MGD-013 (PD-1/LAG-3), RO-7247669 (PD-1/LAG-3), FS-118 (LAG-3/PD-L1) MGD-019 (PD-1/CTLA4), KN-046 (PD-1/CTLA4), MEDI-5752 (CTLA4/PD-1), RO-7121661 (PD-1/TIM-3), XmAb-20717 (PD-1/CTLA4), AK-104 (CTLA4/PD-1), M7824 (PD-L1/TGFβ-EC domain), CA-170 (PD-L1/VISTA), CDX-527 (CD27/PD-L1), LY-3415244 (TIM-3/PDL1), RG7769 (PD-1/TIM-3) and INBRX-105 (4-1BB/PDL1), GNS-1480 (PD-L1/EGFR), RG-7446 (Tecentriq, atezolizumab), ABBV-181, nivolumab (OPDIVO^®, BMS-936558, MDX-1106), pembrolizumab (KEYTRUDA^®, MK-3477, SCH-900475, lambrolizumab, CAS Reg. No. 1374853-91-4), pidilizumab, PF-06801591, BGB-A317 (tislelizumab), GLS-010 (WBP-3055), AK-103 (HX-008), CS-1003, HLX-10, MGA-012, BI-754091, REGN-2810 (cemiplimab), AGEN-2034, JS-001 (toripalimab), JNJ-63723283, genolimzumab (CBT-501), LZM-009, BCD-100, LY-3300054, SHR-1201, SHR-1210 (camrelizumab), Sym-021, ABBV-181, AK-105, PD1-PIK, BAT-1306 , BMS-936559, atezolizumab (MPDL3280A), durvalumab (MEDI-4736), avelumab, CK-301,(MSB0010718C), MEDI-0680, CX-072, CBT-502, PDR-001 (spartalizumab), PDR001 + Tafinlar ^® + Mekinist ^®, MSB-2311, JTX-4014, BGB-A333, SHR-1316, CS-1001 (WBP-3155, KN-035, IBI-308 (sintilimab), HLX-20, KL-A167, STI-A1014, STI-A1015 (IMC-001), BCD-135, FAZ-053, TQB-2450, and MDX1105-01; and those described, e.g. in Intl. Patent Publ. Nos. <patcit id="pcit0081" dnum="WO2018195321A"><text>WO2018195321</text></patcit>, <patcit id="pcit0082" dnum="WO2020014643A"><text>WO2020014643</text></patcit>, <patcit id="pcit0083" dnum="WO2019160882A"><text>WO2019160882</text></patcit>, and <patcit id="pcit0084" dnum="WO2018195321A"><text>WO2018195321</text></patcit>.

0262Examples of inhibitors of PVRIG that can be co-administered include without limitation: COM-701.

0263Examples of inhibitors of TIGIT that can be co-administered include without limitation: BMS-986207, RG-6058, AGEN-1307, COM-902.

0264Examples of inhibitors of TIM-3 that can be co-administered include without limitation: TSR-022, LY-3321367, MBG-453, INCAGN-2390, RO-7121661 (PD-1/TIM-3), LY-3415244 (TIM-3/PDL1), RG7769 (PD-1/TIM-3).

0265Examples of inhibitors of LAG-3 that can be co-administered include without limitation: relatlimab (ONO-4482), LAG-525, MK-4280, REGN-3767, INCAGN2385, TSR-033, MGD-013 (PD-1/LAG-3), FS-118 (LAG-3/PD-L1).

0266Examples of anti- killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 1 (KIR3DL1; KIR; NCBI Gene ID: 3811) monoclonal antibodies, such as lirilumab (IPH-2102), IPH-4102.

0267Examples of anti-NKG2a antibodies that can be co-administered include without limitation: monalizumab.

0268Examples of anti-VISTA antibodies that can be co-administered include without limitation: HMBD-002, CA-170 (PD-L1/VISTA).

0269Examples of anti-CD70 antibodies that can be co-administered include without limitation: AMG-172.

0270Examples of anti-CD20 antibodies that can be co-administered include without limitation: obinutuzumab, IGN-002, PF-05280586.

0271Examples of anti-ICOS antibodies that can be co-administered include without limitation: JTX-2011, GSK3359609.

0272Examples of ICOS agonists that can be co-administered include without limitation: ICOS-L.COMP (<nplcit id="ncit0022" npl-type="s"><text>Gariepy, J. et al. 106th Annu Meet Am Assoc Immunologists (AAI) (May 9-13, San Diego) 2019, Abst 71.5</text></nplcit>).

TNF Receptor Superfamily (TNFRSF) Member Agonists or Activators

0273In some embodiments, a compound as described herein, is combined with an agonist of one or more TNF receptor superfamily (TNFRSF) members, e.g., an agonist of one or more of TNFRSF1A (NCBI Gene ID: 7132), TNFRSF1B (NCBI Gene ID: 7133), TNFRSF4 (OX40, CD134; NCBI Gene ID: 7293), TNFRSF5 (CD40; NCBI Gene ID: 958), TNFRSF6 (FAS, NCBI Gene ID: 355), TNFRSF7 (CD27, NCBI Gene ID: 939), TNFRSF8 (CD30, NCBI Gene ID: 943), TNFRSF9 (4-1BB, CD137, NCBI Gene ID: 3604), TNFRSF10A (CD261, DR4, TRAILR1, NCBI Gene ID: 8797), TNFRSF10B (CD262, DR5, TRAILR2, NCBI Gene ID: 8795), TNFRSF10C (CD263, TRAILR3, NCBI Gene ID: 8794), TNFRSF10D (CD264, TRAILR4, NCBI Gene ID: 8793), TNFRSF11A (CD265, RANK, NCBI Gene ID: 8792), TNFRSF11B (NCBI Gene ID: 4982), TNFRSF12A (CD266, NCBI Gene ID: 51330), TNFRSF13B (CD267, NCBI Gene ID: 23495), TNFRSF13C (CD268, NCBI Gene ID: 115650), TNFRSF16 (NGFR, CD271, NCBI Gene ID: 4804), TNFRSF17 (BCMA, CD269, NCBI Gene ID: 608), TNFRSF18 (GITR, CD357, NCBI Gene ID: 8784), TNFRSF19 (NCBI Gene ID: 55504), TNFRSF21 (CD358, DR6, NCBI Gene ID: 27242), and TNFRSF25 (DR3, NCBI Gene ID: 8718).

0274Example anti-TNFRSF4 (OX40) antibodies that can be co-administered include without limitation, MEDI6469, MEDI6383, MEDI0562 (tavolixizumab), MOXR0916, PF-04518600, RG-7888, GSK-3174998, INCAGN1949, BMS-986178, GBR-8383, ABBV-368, and those described in <patcit id="pcit0085" dnum="WO2016179517A"><text>WO2016179517</text></patcit>, <patcit id="pcit0086" dnum="WO2017096179A"><text>WO2017096179</text></patcit>, <patcit id="pcit0087" dnum="WO2017096182A"><text>WO2017096182</text></patcit>, <patcit id="pcit0088" dnum="WO2017096281A"><text>WO2017096281</text></patcit>, and <patcit id="pcit0089" dnum="WO2018089628A"><text>WO2018089628</text></patcit>.

0275Examples anti-TNF receptor superfamily member 10b (TNFRSF10B, DR5, TRAILR2) antibodies that can be co-administered include without limitation, such as DS-8273, CTB-006, INBRX-109, GEN-1029.

0276Example anti-TNFRSF5 (CD40) antibodies that can be co-administered include without limitation RG7876, SEA-CD40, APX-005M and ABBV-428, ABBV-927, JNJ-64457107.

0277In some embodiments, the anti-TNFRSF7 (CD27) antibody varlilumab (CDX-1127) is co-administered.

0278Example anti-TNFRSF9 (4-1BB, CD137) antibodies that can be co-administered include without limitation urelumab, utomilumab (PF-05082566), AGEN2373 and ADG-106.

0279In some embodiments, the anti-TNFRSF17 (BCMA) antibody GSK-2857916 is co-administered.

0280Example anti-TNFRSF18 (GITR) antibodies that can be co-administered include without limitation, MEDI1873, FPA-154, INCAGN-1876, TRX-518, BMS-986156, MK-1248, GWN-323, and those described in <patcit id="pcit0090" dnum="WO2017096179A"><text>WO2017096179</text></patcit>, <patcit id="pcit0091" dnum="WO2017096276A"><text>WO2017096276</text></patcit>, <patcit id="pcit0092" dnum="WO2017096189A"><text>WO2017096189</text></patcit>, and <patcit id="pcit0093" dnum="WO2018089628A"><text>WO2018089628</text></patcit>. In some embodiments, an antibody, or fragment thereof, co-targeting TNFRSF4 (OX40) and TNFRSF18 (GITR) is co-administered. Such antibodies are described, <i>e.g.,</i> in <patcit id="pcit0094" dnum="WO2017096179A"><text>WO2017096179</text></patcit> and <patcit id="pcit0095" dnum="WO2018089628A"><text>WO2018089628</text></patcit>.

0281Example anti-TRAILR1, anti-TRAILR2, anti-TRAILR3, anti-TRAILR4 antibodies that can be co-administered include without limitation ABBV-621.

0282Bi-specific antibodies targeting TNFRSF family members that can be co-administered include without limitation PRS-343 (CD-137/HER2), AFM26 (BCMA/CD16A), AFM-13 (CD16/CD30), REGN-1979 (CD20/CD3), AMG-420 (BCMA/CD3), INHIBRX-105 (4-1BB/PDL1), FAP-4-IBBL (4-1BB/FAP), XmAb-13676 (CD3/CD20), RG-7828 (CD20/CD3), CC-93269 (CD3/BCMA), REGN-5458 (CD3/BCMA), and IMM-0306 (CD47/CD20), AMG-424 (CD38.CD3).

Adenosine Generation and Signaling

0283In some embodiments, a compound as described herein, is combined with an agonist or antagonist of A1R, A2AR, A2BR, A3R, CD73, CD39, CD26.

0284Examples of Adenosine A3 receptor (A3R) agonists, such as namodenoson (CF102).

0285Examples of A2aR/A2bR antagonists, such as AB928.

0286Examples of anti-CD73 antibodies, such as MEDI-9447 (oleclumab), CPX-006, IPH-53, BMS-986179, NZV-930, CPI-006.

0287Examples of CD73 inhibitors, such as AB-680, PSB-12379, PSB-12441, PSB-12425, CB-708; and those described in Int Patent Publication No. <patcit id="pcit0096" dnum="WO19173692A"><text>WO19173692</text></patcit>..

0288Examples of CD39/CD73 inhibitors, such as PBF-1662.

0289Examples of anti-CD39 antibodies, such as TTX-030.

0290Examples of Adenosine A2A receptor antagonists, such as CPI-444, AZD-4635, preladenant, PBF-509.

0291Examples of Adenosine deaminase inhibitors, such as pentostatin, cladribine.

c-kit Targeting Agents

0292In various embodiments, a compound as described herein, is combined with an inhibitor of c-kit (PBT, SCFR, CD117, MASTC; NCBI Gene ID:3815; Uniprot - P10721).

0293Examples of c-kit inhibitors include imatinib mesylate, JSP-191, BLU-263, CD117-ADC, AZD3229 (c-kit/PDGFR inhibitor), telatinib (c-kit/PDGF/VEGF2 inhibitor), quizartinib dihydrochloride (FLT3/c-kit), pexidartinib hydrochloride (CSF1R/FLT3/c-kit), avapritinib (PDGFR/c-Kit inhibitor), vorolanib (multikinase VEGF/PDGFR/c-kit inhibitor), and ripretinib (c-kit/PDGFRα inhibitor).

0294Examples of c-kit multi-kinase inhibitors include dasatinib, imatinib, nilotinib, sorafenib, lenvatinib mesylate, cabozantinib malate, AL-8326, ZLJ-33, KBP-7018, sunitinib malate, pazopanib derivatives, AGX-73, rebastinib, NMS-088, lucitanib hydrochloride, midostaurin, cediranib, dovitinib, sitravatinib, tivozanib, masitinib, regorafenib, HQP-1351, cabozantinib, ponatinib, and famitinib L-malate. Examples of anti-c-kit antibodies include CDX-0158, CDX-0159 and FSI-174.

0295In some embodiments, the anti-c-kit targeting agent is one described in patent publication numbers <patcit id="pcit0097" dnum="WO199203459A"><text>WO199203459</text></patcit>, <patcit id="pcit0098" dnum="WO199221766A"><text>WO199221766</text></patcit>, <patcit id="pcit0099" dnum="WO2004080462A"><text>WO2004080462</text></patcit>, <patcit id="pcit0100" dnum="WO2005020921A"><text>WO2005020921</text></patcit>, <patcit id="pcit0101" dnum="WO2006009755A"><text>WO2006009755</text></patcit>, <patcit id="pcit0102" dnum="WO2007078034A"><text>WO2007078034</text></patcit>, <patcit id="pcit0103" dnum="WO2007092403A"><text>WO2007092403</text></patcit>, <patcit id="pcit0104" dnum="WO2007127317A"><text>WO2007127317</text></patcit>, <patcit id="pcit0105" dnum="WO2008005877A"><text>WO2008005877</text></patcit>, <patcit id="pcit0106" dnum="WO2012154480A"><text>WO2012154480</text></patcit>, <patcit id="pcit0107" dnum="WO2014100620A"><text>WO2014100620</text></patcit>, <patcit id="pcit0108" dnum="WO2014039714A"><text>WO2014039714</text></patcit>, <patcit id="pcit0109" dnum="WO2015134536A"><text>WO2015134536</text></patcit>, <patcit id="pcit0110" dnum="WO2017167182A"><text>WO2017167182</text></patcit>, <patcit id="pcit0111" dnum="WO2018112136A"><text>WO2018112136</text></patcit>, <patcit id="pcit0112" dnum="WO2018112140A"><text>WO2018112140</text></patcit>, <patcit id="pcit0113" dnum="WO2019155067A"><text>WO2019155067</text></patcit>, <patcit id="pcit0114" dnum="WO2020076105A"><text>WO2020076105</text></patcit>, and patent application no. <patcit id="pcit0115" dnum="US2019063091W"><text>PCT/US2019/063091</text></patcit>.

SIRPα Targeting Agents

0296In various embodiments, a compound as described herein, is combined with an inhibitor of SIRPα (NCBI Gene ID: 140885; UniProt P78324).

0297Examples of SIRPα inhibitors, such as AL-008, RRx-001, and CTX-5861.

0298Examples of anti-SIRPα-antibodies, such as FSI-189, ES-004, BI765063, ADU1805, and CC-95251.

0299In some embodiments, the SIRPα-targeting agent is one described in <patcit id="pcit0116" dnum="WO200140307A"><text>WO200140307</text></patcit>, <patcit id="pcit0117" dnum="WO2002092784A"><text>WO2002092784</text></patcit>, <patcit id="pcit0118" dnum="WO2007133811A"><text>WO2007133811</text></patcit>, <patcit id="pcit0119" dnum="WO2009046541A"><text>WO2009046541</text></patcit>, <patcit id="pcit0120" dnum="WO2010083253A"><text>WO2010083253</text></patcit>, <patcit id="pcit0121" dnum="WO2011076781A"><text>WO2011076781</text></patcit>, <patcit id="pcit0122" dnum="WO2013056352A"><text>WO2013056352</text></patcit>, <patcit id="pcit0123" dnum="WO2015138600A"><text>WO2015138600</text></patcit>, <patcit id="pcit0124" dnum="WO2016179399A"><text>WO2016179399</text></patcit>, <patcit id="pcit0125" dnum="WO2016205042A"><text>WO2016205042</text></patcit>, <patcit id="pcit0126" dnum="WO2017178653A"><text>WO2017178653</text></patcit>, <patcit id="pcit0127" dnum="WO2018026600A"><text>WO2018026600</text></patcit>, <patcit id="pcit0128" dnum="WO2018057669A"><text>WO2018057669</text></patcit>, <patcit id="pcit0129" dnum="WO2018107058A"><text>WO2018107058</text></patcit>, <patcit id="pcit0130" dnum="WO2018190719A"><text>WO2018190719</text></patcit>, <patcit id="pcit0131" dnum="WO2018210793A"><text>WO2018210793</text></patcit>, <patcit id="pcit0132" dnum="WO2019023347A"><text>WO2019023347</text></patcit>, <patcit id="pcit0133" dnum="WO2019042470A"><text>WO2019042470</text></patcit>, <patcit id="pcit0134" dnum="WO2019175218A"><text>WO2019175218</text></patcit>, <patcit id="pcit0135" dnum="WO2019183266A"><text>WO2019183266</text></patcit>, <patcit id="pcit0136" dnum="WO2020013170A"><text>WO2020013170</text></patcit>, or <patcit id="pcit0137" dnum="WO2020068752A"><text>WO2020068752</text></patcit>.

Bi-Specific T-Cell Engagers

0300In some embodiments, a compound as described herein, is combined with a bi-specific T-cell engager <i>(e.g.,</i> not having an Fc) or an anti-CD3 bi-specific antibody <i>(e.g.,</i> having an Fc). Illustrative anti-CD3 bi-specific antibodies or BiTEs that can be co-administered include AMG-160 (PSMA/CD3), AMG-212 (PSMA/CD3), AMG-330 (CD33/CD3), AMG-420 (BCMA/CD3), AMG-427 (FLT3/CD3), AMG-562 (CD19/CD3), AMG-596 (EGFRvIII/CD3), AMG-673 (CD33/CD3), AMG-701 (BCMA/CD3), AMG-757 (DLL3/CD3), JNJ-64052781 (CD19/CD3), AMG-211 (CEA/CD3), BLINCYTO^® (CD19/CD3), RG7802 (CEA/CD3), ERY-974 (CD3/GPC3), huGD2-BsAb (CD3/GD2), PF-06671008 (Cadherins/CD3), APVO436 (CD123/CD3), ERY974, flotetuzumab (CD123/CD3), GEM333 (CD3/CD33), GEMoab (CD3/PSCA), REGN-1979 (CD20/CD3), REGN-5678 (PSMA/CD28), MCLA-117 (CD3/CLEC12A), JNJ-0819, JNJ-7564 (CD3/heme), JNJ-63709178 (CD123/CD3), MGD-007 (CD3/gpA33), MGD-009 (CD3/B7H3), IMCgp100 (CD3/gp100), XmAb-14045 (CD123/CD3), XmAb-13676 (CD3/CD20), XmAb-18087 (SSTR2/CD3), catumaxomab (CD3/EpCAM), REGN-4018 (MUC16/CD3), RG6026, RG6076, RG6194, RG-7828 (CD20/CD3), CC-93269 (CD3/BCMA), REGN-5458 (CD3/BCMA), GRB-1302 (CD3/Erbb2), GRB-1342 (CD38/CD3), GEM-333 (CD3/CD33), PF-06863135 (BCMA/CD3), SAR440234 (CD3/CDw123). As appropriate, the anti-CD3 binding bi-specific molecules may or may not have an Fc. Illustrative bi-specific T-cell engagers that can be co-administered target CD3 and a tumor-associated antigen as described herein, including, <i>e.g.,</i> CD19 (<i>e.g.,</i> blinatumomab); CD33 (<i>e.g.,</i> AMG330); CEA (<i>e.g.,</i> MEDI-565); receptor tyrosine kinase-like orphan receptor 1 (ROR1) (<nplcit id="ncit0023" npl-type="s"><text>Gohil, et al., Oncoimmunology. (2017) May 17;6(7):e1326437</text></nplcit>); PD-L1 (<nplcit id="ncit0024" npl-type="s"><text>Horn, et al., Oncotarget. 2017 Aug 3;8(35):57964-57980</text></nplcit>); and EGFRvIII (<nplcit id="ncit0025" npl-type="s"><text>Yang, et al., Cancer Lett. 2017 Sep 10;403:224-230</text></nplcit>).

Bi-and Tri-Specific Natural Killer (NK)-Cell Engagers

0301In some embodiments, a compound as described herein, is combined with a bi-specific NK-cell engager (BiKE) or a tri-specific NK-cell engager (TriKE) (<i>e.g.,</i> not having an Fc) or bi-specific antibody (<i>e.g.,</i> having an Fc) against an NK cell activating receptor, <i>e.g.,</i> CD16A, C-type lectin receptors (CD94/NKG2C, NKG2D, NKG2E/H and NKG2F), natural cytotoxicity receptors (NKp30, NKp44 and NKp46), killer cell C-type lectin-like receptor (NKp65, NKp80), Fc receptor FcyR (which mediates antibody-dependent cell cytotoxicity), SLAM family receptors (<i>e</i>.<i>g</i>., 2B4, SLAM6 and SLAM7), killer cell immunoglobulin-like receptors (KIR) (KIR-2DS and KIR-3DS), DNAM-1 and CD137 (41BB). Illustrative anti-CD16 bi-specific antibodies, BiKEs or TriKEs that can be co-administered include AFM26 (BCMA/CD16A) and AFM-13 (CD16/CD30). As appropriate, the anti-CD16 binding bi-specific molecules may or may not have an Fc. Illustrative bi-specific NK-cell engagers that can be co-administered target CD16 and one or more tumor-associated antigens as described herein, including, e.g., CD19, CD20, CD22, CD30, CD33, CD123, EGFR, EpCAM, ganglioside GD2, HER2/neu, HLA Class II and FOLR1. BiKEs and TriKEs are described, <i>e.g.,</i> in <nplcit id="ncit0026" npl-type="s"><text>Felices, et al., Methods Mol Biol. (2016) 1441:333-346</text></nplcit>; <nplcit id="ncit0027" npl-type="s"><text>Fang, et al., Semin Immunol. (2017) 31:37-54</text></nplcit>.

MCL1 apoptosis regulator. BCL2 family member (MCL1) Inhibitors

0302In some embodiments, a compound as described herein, is combined with an inhibitor of MCL1 apoptosis regulator, BCL2 family member (MCL1, TM; EAT; MCL1L; MCL1S; Mcl-1; BCL2L3; MCL1-ES; bcl2-L-3; mcl1/EAT; NCBI Gene ID: 4170). Examples of MCL1 inhibitors include AMG-176, AMG-397, S-64315, and AZD-5991, 483-LM, A-1210477, UMI-77, JKY-5-037, and those described in <patcit id="pcit0138" dnum="WO2018183418A"><text>WO2018183418</text></patcit>, <patcit id="pcit0139" dnum="WO2016033486A"><text>WO2016033486</text></patcit>, and <patcit id="pcit0140" dnum="WO2017147410A"><text>WO2017147410</text></patcit>.

Hematopoietic Progenitor Kinase 1 (HPK1) Inhibitors

0303In some embodiments, a compound as described herein, is combined with an inhibitor of mitogen-activated protein kinase kinase kinase kinase 1 (MAP4K1, HPK1; NCBI Gene ID: 11184). Examples of Hematopoietic Progenitor Kinase 1 (HPK1) inhibitors include without limitation, those described in <patcit id="pcit0141" dnum="WO2018183956A"><text>WO-2018183956</text></patcit>, <patcit id="pcit0142" dnum="WO2018183964A"><text>WO-2018183964</text></patcit>, <patcit id="pcit0143" dnum="WO2018167147A"><text>WO-2018167147</text></patcit>, <patcit id="pcit0144" dnum="WO2018183964A"><text>WO-2018183964</text></patcit>, <patcit id="pcit0145" dnum="WO2016205942A"><text>WO-2016205942</text></patcit>, <patcit id="pcit0146" dnum="WO2018049214A"><text>WO-2018049214</text></patcit>, <patcit id="pcit0147" dnum="WO2018049200A"><text>WO-2018049200</text></patcit>, <patcit id="pcit0148" dnum="WO2018049191A"><text>WO-2018049191</text></patcit>, <patcit id="pcit0149" dnum="WO2018102366A"><text>WO-2018102366</text></patcit>, <patcit id="pcit0150" dnum="WO2018049152A"><text>WO-2018049152</text></patcit>, <patcit id="pcit0151" dnum="WO2020092528A"><text>WO2020092528</text></patcit>, <patcit id="pcit0152" dnum="WO2020092621A"><text>WO2020092621</text></patcit>, and <patcit id="pcit0153" dnum="WO2016090300A"><text>WO-2016090300</text></patcit>.

Apoptosis Signal-Regulating Kinase (ASK) Inhibitors

0304In some embodiments, a compound as described herein, is combined with an inhibitor of an ASK inhibitor, e.g., mitogen-activated protein kinase kinase kinase 5 (MAP3K5; ASK1, MAPKKK5, MEKK5; NCBI Gene ID: 4217). Examples of ASK1 inhibitors include without limitation, those described in <patcit id="pcit0154" dnum="WO2011008709A"><text>WO 2011/008709 (Gilead Sciences)</text></patcit> and <patcit id="pcit0155" dnum="WO2013112741A"><text>WO 2013/112741 (Gilead Sciences)</text></patcit>.

Bruton Tyrosine Kinase (BTK) Inhibitors

0305In some embodiments, a compound as described herein, is combined with an inhibitor of Bruton tyrosine kinase (BTK, AGMX1, AT, ATK, BPK, IGHD3, IMD1, PSCTK1, XLA; NCBI Gene ID: 695). Examples of BTK inhibitors include without limitation, (S)-6-amino-9-(1-(but-2-ynoyl)pyrrolidin-3-yl)-7-(4-phenoxyphenyl)-7H-purin-8(9H)-one, acalabrutinib (ACP-196), BGB-3111, CB988, HM71224, ibrutinib (Imbruvica), M-2951 (evobrutinib), M7583, tirabrutinib (ONO-4059), PRN-1008, spebrutinib (CC-292), TAK-020, vecabrutinib, ARQ-531, SHR-1459, DTRMWXHS-12, TAS-5315, Calquence + AZD6738, Calquence + danvatirsen.

Cyclin-dependent Kinase (CDK) Inhibitors

0306In some embodiments, a compound as described herein, is combined with an inhibitor of cyclin dependent kinase 1 (CDK1, CDC2; CDC28A; P34CDC2; NCBI Gene ID: 983); cyclin dependent kinase 2 (CDK2, CDKN2; p33(CDK2); NCBI Gene ID: 1017); cyclin dependent kinase 3 (CDK3, ; NCBI Gene ID: 1018); cyclin dependent kinase 4 (CDK4, CMM3; PSK-J3; NCBI Gene ID: 1019); cyclin dependent kinase 6 (CDK6, MCPH12; PLSTIRE; NCBI Gene ID: 1021); cyclin dependent kinase 7 (CDK7, CAK; CAK1; HCAK; MO15; STK1; CDKN7; p39MO15; NCBI Gene ID: 1022); cyclin dependent kinase 9 (CDK9, TAK; C-2k; CTK1; CDC2L4; PITALRE; NCBI Gene ID: 1025). Inhibitors of CDK 1, 2, 3, 4, 6, 7 and/or 9, include without limitation abemaciclib, alvocidib (HMR-1275, flavopiridol), AT-7519, dinaciclib, ibrance, FLX-925, LEE001, palbociclib, ribociclib, rigosertib, selinexor, UCN-01, SY1365, CT-7001, SY-1365, G1T38, milciclib, trilaciclib, PF-06873600, AZD4573, and TG-02.

Discoidin Domain Receptor (DDR) Inhibitors

0307In some embodiments, a compound as described herein, is combined with an inhibitor of discoidin domain receptor tyrosine kinase 1 (DDR1, CAK, CD167, DDR, EDDR1, HGK2, MCK10, NEP, NTRK4, PTK3, PTK3A, RTK6, TRKE; NCBI Gene ID: 780); and/or discoidin domain receptor tyrosine kinase 2 (DDR2, MIG20a, NTRKR3, TKT, TYRO10, WRCN; NCBI Gene ID: 4921). Examples of DDR inhibitors include without limitation, dasatinib and those disclosed in <patcit id="pcit0156" dnum="WO2014047624A"><text>WO2014/047624 (Gilead Sciences</text></patcit>), <patcit id="pcit0157" dnum="US20090142345A"><text>US 2009-0142345 (Takeda Pharmaceutical</text></patcit>), <patcit id="pcit0158" dnum="US20110287011A"><text>US 2011-0287011 (Oncomed Pharmaceuticals</text></patcit>), <patcit id="pcit0159" dnum="WO2013027802A"><text>WO 2013/027802 (Chugai Pharmaceutical</text></patcit>), and <patcit id="pcit0160" dnum="WO2013034933A"><text>WO2013/034933 (Imperial Innovations</text></patcit>).

Histone Deacetylase (HDAC) Inhibitors

0308In some embodiments, a compound as described herein, is combined with an inhibitor of a histone deacetylase, e.g., histone deacetylase 9 (HDAC9, HD7, HD7b, HD9, HDAC, HDAC7, HDAC7B, HDAC9B, HDAC9FL, HDRP, MITR; Gene ID: 9734). Examples of HDAC inhibitors include without limitation, abexinostat, ACY-241, AR-42, BEBT-908, belinostat, CKD-581, CS-055 (HBI-8000), CUDC-907 (fimepinostat), entinostat, givinostat, mocetinostat, panobinostat, pracinostat, quisinostat (JNJ-26481585), resminostat, ricolinostat, SHP-141, valproic acid (VAL-001), vorinostat, tinostamustine, remetinostat, entinostat, romidepsin, tucidinostat.

Indoleamine-pyrrole-2,3-dioxvgenase (IDO1) inhibitors

0309In some embodiments, a compound as described herein, is combined with an inhibitor of indoleamine 2,3-dioxygenase 1 (IDO1; NCBI Gene ID: 3620). Examples of IDO1 inhibitors include without limitation, BLV-0801, epacadostat, F-001287, GBV-1012, GBV-1028, GDC-0919, indoximod, NKTR-218, NLG-919-based vaccine, PF-06840003, pyranonaphthoquinone derivatives (SN-35837), resminostat, SBLK-200802, BMS-986205, and shIDO-ST, EOS-200271, KHK-2455, LY-3381916.

Janus Kinase (JAK) Inhibitors

0310In some embodiments, a compound as described herein, is combined with an inhibitor of Janus kinase 1 (JAK1, JAK1A, JAK1B, JTK3; NCBI Gene ID: 3716); Janus kinase 2 (JAK2, JTK10, THCYT3; NCBI Gene ID: 3717); and/or Janus kinase 3 (JAK3, JAK-3, JAK3HUMAN, JAKL, L-JAK, LJAK; NCBI Gene ID: 3718). Examples of JAK inhibitors include without limitation, AT9283, AZD1480, baricitinib, BMS-911543, fedratinib, filgotinib (GLPG0634), gandotinib (LY2784544), INCB039110 (itacitinib), lestaurtinib, momelotinib (CYT0387), NS-018, pacritinib (SB1518), peficitinib (ASP015K), ruxolitinib, tofacitinib (formerly tasocitinib), INCB052793, and XL019.

Matrix Metalloprotease (MMP) Inhibitors

0311In some embodiments, a compound as described herein, is combined with an inhibitor of a matrix metallopeptidase (MMP), <i>e.g.,</i> an inhibitor of MMP1 (NCBI Gene ID: 4312), MMP2 (NCBI Gene ID: 4313), MMP3 (NCBI Gene ID: 4314), MMP7 (NCBI Gene ID: 4316), MMP8 (NCBI Gene ID: 4317), MMP9 (NCBI Gene ID: 4318); MMP10 (NCBI Gene ID: 4319); MMP11 (NCBI Gene ID: 4320); MMP12 (NCBI Gene ID: 4321), MMP13 (NCBI Gene ID: 4322), MMP14 (NCBI Gene ID: 4323), MMP15 (NCBI Gene ID: 4324), MMP16 (NCBI Gene ID: 4325), MMP17 (NCBI Gene ID: 4326), MMP19 (NCBI Gene ID: 4327), MMP20 (NCBI Gene ID: 9313), MMP21 (NCBI Gene ID: 118856), MMP24 (NCBI Gene ID: 10893), MMP25 (NCBI Gene ID: 64386), MMP26 (NCBI Gene ID: 56547), MMP27 (NCBI Gene ID: 64066) and/or MMP28 (NCBI Gene ID: 79148). Examples of MMP9 inhibitors include without limitation, marimastat (BB-2516), cipemastat (Ro 32-3555), GS-5745 (andecaliximab) and those described in <patcit id="pcit0161" dnum="WO2012027721A"><text>WO 2012/027721 (Gilead Biologies</text></patcit>).

RAS and RAS Pathway Inhibitors

0312In some embodiments, a compound as described herein, is combined with an inhibitor of KRAS proto-oncogene, GTPase (KRAS; <i>a.k.a.,</i> NS; NS3; CFC2; RALD; K-Ras; KRAS1; KRAS2; RASK2; KI-RAS; C-K-RAS; K-RAS2A; K-RAS2B; K-RAS4A; K-RAS4B; c-Ki-ras2; NCBI Gene ID: 3845); NRAS proto-oncogene, GTPase (NRAS; <i>a.k.a.,</i> NS6; CMNS; NCMS; ALPS4; N-ras; NRAS1; NCBI Gene ID: 4893); HRas proto-oncogene, GTPase (HRAS; <i>a.k.a.,</i> CTLO; KRAS; HAMSV; HRAS1; KRAS2; RASH1; RASK2; Ki-Ras; p21ras; C-H-RAS; c-K-ras; H-RASIDX; c-Ki-ras; C-BAS/HAS; C-HA-RAS1; NCBI Gene ID: 3265); . The Ras inhibitors can inhibit Ras at either the polynucleotide <i>(e.g.,</i> transcriptional inhibitor) or polypeptide (e.g., GTPase enzyme inhibitor) level. In some embodiments, the inhibitors target one or more proteins in the Ras pathway, e.g., inhibit one or more of EGFR, Ras, Raf (A-Raf, B-Raf, C-Raf), MEK (MEK1, MEK2), ERK, PI3K, AKT and mTOR.

0313In some embodiments, a compound as described herein, is combined with an inhibitor of KRAS. Examples of KRAS inhibitors include AMG-510, COTI-219, MRTX-1257, ARS-3248, ARS-853, WDB-178, BI-3406, BI-1701963, ARS-1620 (G12C), SML-8-73-1 (G12C), Compound 3144 (G12D), Kobe0065/2602 (Ras GTP), RT11, MRTX-849 (G12C) and K-Ras(G12D)-selective inhibitory peptides, including KRpep-2 (Ac-RRCPLYISYDPVCRR-NH₂) (SEQ ID NO:108) and KRpep-2d (Ac-RRRRCPLYISYDPVCRRRR-NH₂) (SEQ ID NO:109).

0314In some embodiments, a compound as described herein, is combined with an inhibitor of <i>KRAS</i> mRNA. Illustrative <i>KRAS</i> mRNA inhibitors include anti-KRAS U1 adaptor, AZD-4785, siG12D-LODER^™, and siG12D exosomes.

0315In some embodiments, a compound as described herein, is combined with an inhibitor of MEK. Illustrative MEK inhibitors that can be co-administered include binimetinib, cobimetinib, PD-0325901, pimasertib, RG-7304, selumetinib, trametinib, selumetinib.

0316In some embodiments, a compound as described herein, is combined with an inhibitor of AKT. Illustrative AKT inhibitors that can be co-administered include RG7440, MK-2206, ipatasertib, afuresertib, AZD5363, and ARQ-092, capivasertib, triciribine, ABTL-0812 (PI3K/Akt/mTOR).

0317In some embodiments, a compound as described herein, is combined with an inhibitor of Raf. Illustrative Raf inhibitors that can be co-administered BGB-283 (Raf/EGFR), HM-95573, LXH-254, LY-3009120, RG7304, TAK-580, dabrafenib, vemurafenib, encorafenib (LGX818), PLX8394. RAF-265 (Raf/VEGFR), ASN-003 (Raf/PI3K).

0318In some embodiments, a compound as described herein, is combined with an inhibitor of ERK. Illustrative ERK inhibitors that can be co-administered include LTT-462, LY-3214996, MK-8353, ravoxertinib, GDC-0994, and ulixertinib.

0319In some embodiments, a compound as described herein, is combined with an inhibitor of PI3K. Illustrative PI3K inhibitors that can be co-administered include idelalisib (Zydelig^®), alpelisib, buparlisib, pictilisib. Illustrative PI3K/mTOR inhibitors that can be co-administered include dactolisib, omipalisib, voxtalisib, gedatolisib, GSK2141795, RG6114.

0320In some embodiments, a compound as described herein, is combined with an inhibitor of mTOR. Illustrative mTOR inhibitors that can be co-administered include as sapanisertib, vistusertib (AZD2014), ME-344, sirolimus (oral nano-amorphous formulation, cancer), TYME-88 (mTOR/cytochrome P450 3A4).

0321In some embodiments, Ras-driven cancers (e.g., NSCLC) having CDKN2A mutations can be inhibited by co-administration of the MEK inhibitor selumetinib and the CDK4/6 inhibitor palbociclib. <i>See, e.g.,</i><nplcit id="ncit0028" npl-type="s"><text>Zhou, et al., Cancer Lett. 2017 Nov 1;408:130-137</text></nplcit>. Also, K-RAS and mutant N-RAS can be reduced by the irreversible ERBB 1/2/4 inhibitor neratinib. <i>See, e.g.,</i><nplcit id="ncit0029" npl-type="s"><text>Booth, et al., Cancer Biol Ther. 2018 Feb 1;19(2):132-137</text></nplcit>.

0322In some embodiments, a compound as described herein, is combined with an inhibitor of RAS. Examples of RAS inhibitors include NEO-100, rigosertib.

0323In some embodiments, a compound as described herein, is combined with an antagonist of EGFR, such as AMG-595, necitumumab, ABBV-221, depatuxizumab mafodotin (ABT-414), tomuzotuximab, ABT-806, vectibix, modotuximab, RM-1929.

0324In some embodiments, a compound as described herein, is combined with an inhibitor of protein tyrosine phosphatase non-receptor type 11 (PTPN11; BPTP3, CFC, JMML, METCDS, NS1, PTP-1D, PTP2C, SH-PTP2, SH-PTP3, SHP2; NCBI Gene ID: 5781). Examples of SHP2 inhibitors include TNO155 (SHP-099), RMC-4550, JAB-3068, RMC-4630, SAR442720 and those described in <patcit id="pcit0162" dnum="WO2018172984A"><text>WO2018172984</text></patcit> and <patcit id="pcit0163" dnum="WO2017211303A"><text>WO2017211303</text></patcit>.

0325In some embodiments, a compound as described herein, is combined with an inhibitor of mitogen-activated protein kinase 7 (MAP2K7, JNKK2, MAPKK7, MEK, MEK 7, MKK7, PRKMK7, SAPKK-4, SAPKK4; NCBI Gene ID: 5609). Examples of MEK inhibitors include antroquinonol, binimetinib, CK-127, cobimetinib (GDC-0973, XL-518), MT-144, selumetinib (AZD6244), sorafenib, trametinib (GSK1120212), uprosertib + trametinib, PD-0325901, pimasertib, LTT462, AS703988, CC-90003, refametinib, TAK-733, CI-1040, RG7421.

Phosphatidylinositol 3-kinase (PI3K) Inhibitors

0326In some embodiments, a compound as described herein, is combined with an inhibitor of a phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit, e.g., phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA, CLAPO, CLOVE, CWS5, MCAP, MCM, MCMTC, PI3K, PI3K-alpha, p110-alpha; NCBI Gene ID: 5290); phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta (PIK3CB, P110BETA, PI3K, PI3KBETA, PIK3C1; NCBI Gene ID: 5291); phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma (PIK3CG, PI3CG, PI3K, PI3Kgamma, PIK3, p110gamma, p120-PI3K; Gene ID: 5494); and/or phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta (PIK3CD, APDS, IMD14, P110DELTA, PI3K, p110D, NCBI Gene ID: 5293). In some embodiments, the PI3K inhibitor is a pan-PI3K inhibitor. Examples of PI3K inhibitors include without limitation, ACP-319, AEZA-129, AMG-319, AS252424, AZD8186, BAY 10824391, BEZ235, buparlisib (BKM120), BYL719 (alpelisib), CH5132799, copanlisib (BAY 80-6946), duvelisib, GDC-0032, GDC-0077, GDC-0941, GDC-0980, GSK2636771, GSK2269557, idelalisib (Zydelig^®), INCB50465, IPI-145, IPI-443, IPI-549, KAR4141, LY294002, LY3023414, MLN1117, OXY111A, PA799, PX-866, RG7604, rigosertib, RP5090, RP6530, SRX3177, taselisib, TG100115, TGR-1202 (umbralisib), TGX221, WX-037, X-339, X-414, XL147 (SAR245408), XL499, XL756, wortmannin, ZSTK474, and the compounds described in <patcit id="pcit0164" dnum="WO2005113556A"><text>WO 2005/113556 (ICOS</text></patcit>), <patcit id="pcit0165" dnum="WO2013052699A"><text>WO 2013/052699 (Gilead Calistoga</text></patcit>), <patcit id="pcit0166" dnum="WO2013116562A"><text>WO 2013/116562 (Gilead Calistoga</text></patcit>), <patcit id="pcit0167" dnum="WO2014100765A"><text>WO 2014/100765 (Gilead Calistoga</text></patcit>), <patcit id="pcit0168" dnum="WO2014100767A"><text>WO 2014/100767 (Gilead Calistoga</text></patcit>), and <patcit id="pcit0169" dnum="WO2014201409A"><text>WO 2014/201409 (Gilead Sciences</text></patcit>).

Mitogen-activated Protein Kinase (MEK) Inhibitors

0327In some embodiments, a compound as described herein, is combined with an inhibitor of mitogen-activated protein kinase kinase 7 (MAP2K7, JNKK2, MAPKK7, MEK, MEK 7, MKK7, PRKMK7, SAPKK-4, SAPKK4; NCBI Gene ID: 5609). Examples of MEK inhibitors include antroquinonol, binimetinib, cobimetinib (GDC-0973, XL-518), MT-144, selumetinib (AZD6244), sorafenib, trametinib (GSK1120212), uprosertib + trametinib, PD-0325901, pimasertib, LTT462, AS703988, CC-90003, refametinib.

Spleen Tyrosine Kinase (SYK) Inhibitors

0328In some embodiments, a compound as described herein, is combined with an inhibitor of spleen associated tyrosine kinase (SYK, p72-Syk, Gene ID: 6850). Examples of SYK inhibitors include without limitation, 6-(1H-indazol-6-yl)-N-(4-morpholinophenyl)imidazo[1,2-a]pyrazin-8-amine, BAY-61-3606, cerdulatinib (PRT-062607), entospletinib, fostamatinib (R788), HMPL-523, NVP-QAB 205 AA, R112, R343, tamatinib (R406), and those described in <patcit id="pcit0170" dnum="US8450321B"><text>US 8450321 (Gilead Connecticut</text></patcit>) and those described in <patcit id="pcit0171" dnum="US20150175616A"><text>U.S. 2015/0175616</text></patcit>.

Toll-Like Receptor (TLR) Agonists

0329In some embodiments, a compound as described herein, is combined with an agonist of a toll-like receptor (TLR), <i>e.g.,</i> an agonist of TLR1 (NCBI Gene ID: 7096), TLR2 (NCBI Gene ID: 7097), TLR3 (NCBI Gene ID: 7098), TLR4 (NCBI Gene ID: 7099), TLR5 (NCBI Gene ID: 7100), TLR6 (NCBI Gene ID: 10333), TLR7 (NCBI Gene ID: 51284), TLR8 (NCBI Gene ID: 51311), TLR9 (NCBI Gene ID: 54106), and/or TLR10 (NCBI Gene ID: 81793). Example TLR7 agonists that can be co-administered include without limitation DS-0509, GS-9620, LHC-165, TMX-101 (imiquimod), GSK-2245035, resiquimod, DSR-6434, DSP-3025, IMO-4200, MCT-465, MEDI-9197, 3M-051, SB-9922, 3M-052, Limtop, TMX-30X, TMX-202, RG-7863, RG-7795, and the compounds disclosed in <patcit id="pcit0172" dnum="US20100143301A"><text>US20100143301 (Gilead Sciences</text></patcit>), <patcit id="pcit0173" dnum="US20110098248A"><text>US20110098248 (Gilead Sciences</text></patcit>), and <patcit id="pcit0174" dnum="US20090047249A"><text>US20090047249 (Gilead Sciences</text></patcit>), <patcit id="pcit0175" dnum="US20140045849A"><text>US20140045849 (Janssen</text></patcit>), <patcit id="pcit0176" dnum="US20140073642A"><text>US20140073642 (Janssen</text></patcit>), <patcit id="pcit0177" dnum="WO2014056953A"><text>WO2014/056953 (Janssen</text></patcit>), <patcit id="pcit0178" dnum="WO2014076221A"><text>WO2014/076221 (Janssen</text></patcit>), <patcit id="pcit0179" dnum="WO2014128189A"><text>WO2014/128189 (Janssen</text></patcit>), <patcit id="pcit0180" dnum="US20140350031A"><text>US20140350031 (Janssen</text></patcit>), <patcit id="pcit0181" dnum="WO2014023813A"><text>WO2014/023813 (Janssen</text></patcit>), <patcit id="pcit0182" dnum="US20080234251A"><text>US20080234251 (Array Biopharma</text></patcit>), <patcit id="pcit0183" dnum="US20080306050A"><text>US20080306050 (Array Biopharma</text></patcit>), <patcit id="pcit0184" dnum="US20100029585A"><text>US20100029585 (Ventirx Pharma</text></patcit>), <patcit id="pcit0185" dnum="US20110092485A"><text>US20110092485 (Ventirx Pharma</text></patcit>), <patcit id="pcit0186" dnum="US20110118235A"><text>US20110118235 (Ventirx Pharma</text></patcit>), <patcit id="pcit0187" dnum="US20120082658A"><text>US20120082658 (Ventirx Pharma</text></patcit>), <patcit id="pcit0188" dnum="US20120219615A"><text>US20120219615 (Ventirx Pharma</text></patcit>), <patcit id="pcit0189" dnum="US20140066432A"><text>US20140066432 (Ventirx Pharma</text></patcit>), <patcit id="pcit0190" dnum="US20140088085A"><text>US20140088085 (Ventirx Pharma</text></patcit>), <patcit id="pcit0191" dnum="US20140275167A"><text>US20140275167 (Novira Therapeutics</text></patcit>), and <patcit id="pcit0192" dnum="US20130251673A"><text>US20130251673 (Novira Therapeutics</text></patcit>). An TLR7/TLR8 agonist that can be co-administered is NKTR-262. Example TLR8 agonists that can be co-administered include without limitation E-6887, IMO-4200, IMO-8400, IMO-9200, MCT-465, MEDI-9197, motolimod, resiquimod, GS-9688, VTX-1463, VTX-763, 3M-051, 3M-052, and the compounds disclosed in <patcit id="pcit0193" dnum="US20140045849A"><text>US20140045849 (Janssen</text></patcit>), <patcit id="pcit0194" dnum="US20140073642A"><text>US20140073642 (Janssen</text></patcit>), <patcit id="pcit0195" dnum="WO2014056953A"><text>WO2014/056953 (Janssen</text></patcit>), <patcit id="pcit0196" dnum="WO2014076221A"><text>WO2014/076221 (Janssen</text></patcit>), <patcit id="pcit0197" dnum="WO2014128189A"><text>WO2014/128189 (Janssen</text></patcit>), <patcit id="pcit0198" dnum="US20140350031A"><text>US20140350031 (Janssen</text></patcit>), <patcit id="pcit0199" dnum="WO2014023813A"><text>WO2014/023813 (Janssen)</text></patcit>, <patcit id="pcit0200" dnum="US20080234251A"><text>US20080234251 (Array Biopharma</text></patcit>), <patcit id="pcit0201" dnum="US20080306050A"><text>US20080306050 (Array Biopharma</text></patcit>), <patcit id="pcit0202" dnum="US20100029585A"><text>US20100029585 (Ventirx Pharma</text></patcit>), <patcit id="pcit0203" dnum="US20110092485A"><text>US20110092485 (Ventirx Pharma</text></patcit>), <patcit id="pcit0204" dnum="US20110118235A"><text>US20110118235 (Ventirx Pharma</text></patcit>), <patcit id="pcit0205" dnum="US20120082658A"><text>US20120082658 (Ventirx Pharma</text></patcit>), <patcit id="pcit0206" dnum="US20120219615A"><text>US20120219615 (Ventirx Pharma</text></patcit>), <patcit id="pcit0207" dnum="US20140066432A"><text>US20140066432 (Ventirx Pharma</text></patcit>), <patcit id="pcit0208" dnum="US20140088085A"><text>US20140088085 (Ventirx Pharma</text></patcit>), <patcit id="pcit0209" dnum="US20140275167A"><text>US20140275167 (Novira Therapeutics</text></patcit>), and <patcit id="pcit0210" dnum="US20130251673A"><text>US20130251673 (Novira Therapeutics</text></patcit>). Example TLR9 agonists that can be co-administered include without limitation AST-008, CMP-001, IMO-2055, IMO-2125, litenimod, MGN-1601, BB-001, BB-006, IMO-3100, IMO-8400, IR-103, IMO-9200, agatolimod, DIMS-9054, DV-1079, DV-1179, AZD-1419, leftolimod (MGN-1703), CYT-003, CYT-003-QbG10 and PUL-042. Examples of TLR3 agonist include rintatolimod, poly-ICLC, RIBOXXON^®, Apoxxim, RIBOXXIM^®, IPH-33, MCT-465, MCT-475, and ND-1.1.

0330Examples of TLR8 inhibitors include, but are not limited to, E-6887, IMO-8400, IMO-9200 and VTX-763.

0331Examples of TLR8 agonists include, but are not limited to, MCT-465, motolimod, GS-9688, and VTX-1463.

0332Examples of TLR9 inhibitors include but are not limited to, AST-008, ,IMO-2055, IMO-2125, lefitolimod, litenimod, MGN-1601, and PUL-042.

0333Examples of TLR7/TLR8 agonist, such as NKTR-262, IMO-4200, MEDI-9197 (telratolimod), resiquimod.

0334Examples of TLR agonists include without limitation: lefitolimod, tilsotolimod, rintatolimod, DSP-0509, AL-034, G-100, cobitolimod, AST-008, motolimod, GSK-1795091, GSK-2245035, VTX-1463, GS-9688, LHC-165, BDB-001, RG-7854, telratolimod.

0335In some embodiments, the therapeutic agent is a stimulator of interferon genes (STING) In some embodiments, the STING receptor agonist or activator is selected from the group consisting ofADU-S100 (MIW-815), SB-11285, MK-1454, SR-8291, AdVCA0848, GSK-532, SYN-STING, MSA-1, SR-8291, 5,6-dimethylxanthenone-4-acetic acid (DMXAA), cyclic-GAMP (cGAMP) and cyclic-di-AMP.

Indoleamine-pyrrole-2,3-dioxygenase (IDO1) inhibitors

0336In some embodiments, a compound as described herein, is combined with an inhibitor of indoleamine 2,3-dioxygenase 1 (IDO1; NCBI Gene ID: 3620). Examples of IDO1 inhibitors include without limitation, BLV-0801, epacadostat, F-001287, GBV-1012, GBV-1028, GDC-0919, indoximod, NKTR-218, NLG-919-based vaccine, PF-06840003, pyranonaphthoquinone derivatives (SN-35837), resminostat, SBLK-200802, BMS-986205, and shIDO-ST, EOS-200271, KHK-2455, LY-3381916.

0337In some embodiments, the therapeutic agent is a small organic compound. In some embodiments, the therapeutic agent is an agonist or activator of a toll-like receptor (TLR) or a stimulator of interferon genes (STING) In some embodiments, the STING receptor agonist or activator is selected from the group consisting of ADU-S100 (MIW-815), SB-11285, MK-1454, SR-8291, AdVCA0848, GSK-532, SYN-STING, MSA-1, SR-8291, 5,6-dimethylxanthenone-4-acetic acid (DMXAA), cyclic-GAMP (cGAMP) and cyclic-di-AMP.

Tyrosine-kinase Inhibitors (TKIs)

0338In some embodiments, a compound as described herein, is combined with a tyrosine kinase inhibitor (TKI). TKIs may target epidermal growth factor receptors (EGFRs) and receptors for fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), and vascular endothelial growth factor (VEGF). Examples of TKIs include without limitation, axitinib, afatinib, ARQ-087 (derazantinib), asp5878, AZD3759, AZD4547, bosutinib, brigatinib, cabozantinib, cediranib, crenolanib, dacomitinib, dasatinib, dovitinib, E-6201, erdafitinib, erlotinib, gefitinib, gilteritinib (ASP-2215), FP-1039, HM61713, icotinib, imatinib, KX2-391 (Src), lapatinib, lestaurtinib, lenvatinib, midostaurin, nintedanib, ODM-203, olmutinib, osimertinib (AZD-9291), pazopanib, ponatinib, poziotinib, quizartinib, radotinib, rociletinib, sulfatinib (HMPL-012), sunitinib, famitinib L-malate, (MAC-4), tivoanib, TH-4000, tivoanib, and MEDI-575 (anti-PDGFR antibody), TAK-659, Cabozantinib.

Chemotherapeutic agents (standard of care)

0339In some embodiments, a compound as described herein, is combined with a chemotherapeutic agent or anti-neoplastic agent.

0340As used herein, the term "chemotherapeutic agent" or "chemotherapeutic" (or "chemotherapy" in the case of treatment with a chemotherapeutic agent) is meant to encompass any non-proteinaceous (<i>e.g</i>., non-peptidic) chemical compound useful in the treatment of cancer. Examples of chemotherapeutic agents include but not limited to: alkylating agents such as thiotepa and cyclophosphamide (CYTOXAN^®); alkyl sulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodepa, carboquone, meturedepa, and uredepa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimemylolomelamine; acetogenins, <i>e.g</i>., bullatacin and bullatacinone; a camptothecin, including synthetic analog topotecan; bryostatin, callystatin; CC-1065, including its adozelesin, carzelesin, and bizelesin synthetic analogs; cryptophycins, particularly cryptophycin 1 and cryptophycin 8;dolastatin; duocarmycin, including the synthetic analogs KW-2189 and CBI-TMI; eleutherobin; 5-azacytidine; pancratistatin; a sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlomaphazine, cyclophosphamide, glufosfamide, evofosfamide, bendamustine, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, and uracil mustard; nitrosoureas such as carmustine, chlorozotocin, foremustine, lomustine, nimustine, and ranimustine; antibiotics such as the enediyne antibiotics (<i>e.g</i>., calicheamicin, especially calicheamicin gammaII and calicheamicin phiI1), dynemicin including dynemicin A, bisphosphonates such as clodronate, an esperamicin, neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromomophores, aclacinomycins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, carminomycin, carzinophilin, chromomycins, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin (including morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin, and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, porfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, and zorubicin; anti-metabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as demopterin, methotrexate, pteropterin, and trimetrexate; purine analogs such as cladribine, pentostatin, fludarabine, 6-mercaptopurine, thiamiprine, and thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, and floxuridine; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, and testolactone; anti-adrenals such as aminoglutethimide, mitotane, and trilostane; folic acid replinishers such as frolinic acid; radiotherapeutic agents such as Radium-223; trichothecenes, especially T-2 toxin, verracurin A, roridin A, and anguidine; taxoids such as paclitaxel (TAXOL^®), abraxane ,docetaxel (TAXOTERE^®), cabazitaxel, BIND-014, tesetaxel; platinum analogs such as cisplatin and carboplatin, NC-6004 nanoplatin; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; hestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elformthine; elliptinium acetate; an epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; leucovorin; lonidamine; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidamol; nitracrine; pentostatin; phenamet; pirarubicin; losoxantrone; fluoropyrimidine; folinic acid; podophyllinic acid; 2-ethylhydrazide; procarbazine; polysaccharide-K (PSK); razoxane; rhizoxin; sizofiran; spirogermanium; tenuazonic acid; trabectedin, triaziquone; 2,2',2"-trichlorotriemylamine; urethane; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiopeta; chlorambucil; gemcitabine (GEMZAR^®); 6-thioguanine; mercaptopurine; methotrexate; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitroxantrone; vancristine; vinorelbine (NAVELBINE^®); novantrone; teniposide; edatrexate; daunomycin; aminopterin; xeoloda; ibandronate; CPT-11; topoisomerase inhibitor RFS 2000; difluoromethylomithine (DFMO); retinoids such as retinoic acid; capecitabine; NUC-1031; FOLFOX (folinic acid, 5-fluorouracil, oxaliplatin); FOLFIRI (folinic acid, 5-fluorouracil, irinotecan); FOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin, irinotecan), FOLFIRINOX (folinic acid, 5-fluorouracil, irinotecan, oxaliplatin), and pharmaceutically acceptable salts, acids, or derivatives of any of the above. Such agents can be conjugated onto an antibody or any targeting agent described herein to create an antibody-drug conjugate (ADC) or targeted drug conjugate.

Anti-hormonal Agents

0341Also included in the definition of "chemotherapeutic agent" are anti-hormonal agents such as anti-estrogens and selective estrogen receptor modulators (SERMs), inhibitors of the enzyme aromatase, anti-androgens, and pharmaceutically acceptable salts, acids or derivatives of any of the above that act to regulate or inhibit hormone action on tumors.

0342Examples of anti-estrogens and SERMs include, for example, tamoxifen (including NOLVADEXTM), raloxifene, droloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and toremifene (FARESTON^®).

0343Inhibitors of the enzyme aromatase regulate estrogen production in the adrenal glands. Examples include 4(5)-imidazoles, aminoglutethimide, megestrol acetate (MEGACE^®), exemestane, formestane, fadrozole, vorozole (RIVISOR^®), letrozole (FEMARA^®), and anastrozole (ARIMIDEX^®).

0344Examples of anti-androgens include apalutamide, abiraterone, enzalutamide, flutamide, galeterone, nilutamide, bicalutamide, leuprolide, goserelin, ODM-201, APC-100, ODM-204.

0345An example progesterone receptor antagonist includes onapristone.

Anti-Angiogenic Agents

0346In some embodiments, a compound as described herein, is combined with an anti-angiogenic agent. Anti-angiogenic agents that can be co-administered include, but are not limited to, retinoid acid and derivatives thereof, 2-methoxyestradiol, ANGIOSTATIN^®, ENDOSTATIN^®, regorafenib, necuparanib, suramin, squalamine, tissue inhibitor of metalloproteinase-1, tissue inhibitor of metalloproteinase-2, plasminogen activator inhibitor-1, plasminogen activator inbibitor-2, cartilage-derived inhibitor, paclitaxel (nab-paclitaxel), platelet factor 4, protamine sulphate (clupeine), sulphated chitin derivatives (prepared from queen crab shells), sulphated polysaccharide peptidoglycan complex (sp-pg), staurosporine, modulators of matrix metabolism including proline analogs such as l-azetidine-2-carboxylic acid (LACA), cishydroxyproline, d,I-3,4-dehydroproline, thiaproline, α,α'-dipyridyl, beta-aminopropionitrile fumarate, 4-propyl-5-(4-pyridinyl)-2(3h)-oxazolone, methotrexate, mitoxantrone, heparin, interferons, 2 macroglobulin-serum, chicken inhibitor of metalloproteinase-3 (ChIMP-3), chymostatin, beta-cyclodextrin tetradecasulfate, eponemycin, fumagillin, gold sodium thiomalate, d-penicillamine, beta-1-anticollagenase-serum, alpha-2-antiplasmin, bisantrene, lobenzarit disodium, n-2-carboxyphenyl-4-chloroanthronilic acid disodium or "CCA", thalidomide, angiostatic steroid, carboxy aminoimidazole, metalloproteinase inhibitors such as BB-94, inhibitors of S100A9 such as tasquinimod . Other anti-angiogenesis agents include antibodies, e.g., monoclonal antibodies against these angiogenic growth factors: beta-FGF, alpha-FGF, FGF-5, VEGF isoforms, VEGF-C, HGF/SF, and Ang-1/Ang-2.

Anti-fibrotic Agents

0347In some embodiments, a compound as described herein, is combined with an anti-fibrotic agent. Anti-fibrotic agents that can be co-administered include, but are not limited to, the compounds such as beta-aminoproprionitrile (BAPN), as well as the compounds disclosed in <patcit id="pcit0211" dnum="US4965288A"><text>US 4965288</text></patcit> relating to inhibitors of lysyl oxidase and their use in the treatment of diseases and conditions associated with the abnormal deposition of collagen and <patcit id="pcit0212" dnum="US4997854A"><text>US 4997854</text></patcit> relating to compounds which inhibit LOX for the treatment of various pathological fibrotic states, which are herein incorporated by reference. Further exemplary inhibitors are described in <patcit id="pcit0213" dnum="US4943593A"><text>US 4943593</text></patcit> relating to compounds such as 2-isobutyl-3-fluoro-, chloro-, or bromo-allylamine, <patcit id="pcit0214" dnum="US5021456A"><text>US 5021456</text></patcit>, <patcit id="pcit0215" dnum="US5059714A"><text>US 5059714</text></patcit>, <patcit id="pcit0216" dnum="US5120764A"><text>US 5120764</text></patcit>, <patcit id="pcit0217" dnum="US5182297A"><text>US 5182297</text></patcit>, <patcit id="pcit0218" dnum="US5252608A"><text>US 5252608</text></patcit> relating to 2-(1-naphthyloxymemyl)-3-fluoroallylamine, and <patcit id="pcit0219" dnum="US20040248871A"><text>US 2004-0248871</text></patcit>, which are herein incorporated by reference.

0348Exemplary anti-fibrotic agents also include the primary amines reacting with the carbonyl group of the active site of the lysyl oxidases, and more particularly those which produce, after binding with the carbonyl, a product stabilized by resonance, such as the following primary amines: emylenemamine, hydrazine, phenylhydrazine, and their derivatives; semicarbazide and urea derivatives; aminonitriles such as BAPN or 2-nitroethylamine; unsaturated or saturated haloamines such as 2-bromo-ethylamine, 2-chloroethylamine, 2-trifluoroethylamine, 3-bromopropylamine, and p-halobenzylamines; and selenohomocysteine lactone.

0349Other anti-fibrotic agents are copper chelating agents penetrating or not penetrating the cells. Exemplary compounds include indirect inhibitors which block the aldehyde derivatives originating from the oxidative deamination of the lysyl and hydroxylysyl residues by the lysyl oxidases. Examples include the thiolamines, particularly D-penicillamine, and its analogs such as 2-amino-5-mercapto-5-methylhexanoic acid, D-2-amino-3-methyl-3-((2-acetamidoethyl)dithio)butanoic acid, p-2-amino-3-methyl-3-((2-aminoethyl)dithio)butanoic acid, sodium-4-((p-1-dimethyl-2-amino-2-carboxyethyl)dithio)butane sulphurate, 2-acetamidoethyl-2-acetamidoethanethiol sulphanate, and sodium-4-mercaptobutanesulphinate trihydrate.

Anti-Inflammatory Agents

0350In some embodiments, a compound as described herein, is combined with an anti-inflammatory agent. Example anti-inflammatory agents include without limitation inhibitors of one or more of arginase (ARG1 (NCBI Gene ID: 383), ARG2 (NCBI Gene ID: 384)), carbonic anhydrase (CA1 (NCBI Gene ID: 759), CA2 (NCBI Gene ID: 760), CA3 (NCBI Gene ID: 761), CA4 (NCBI Gene ID: 762), CA5A (NCBI Gene ID: 763), CA5B (NCBI Gene ID: 11238), CA6 (NCBI Gene ID: 765), CA7 (NCBI Gene ID: 766), CA8 (NCBI Gene ID: 767), CA9 (NCBI Gene ID: 768), CA10 (NCBI Gene ID: 56934), CA11 (NCBI Gene ID: 770), CA12 (NCBI Gene ID: 771), CA13 (NCBI Gene ID: 377677), CA14 (NCBI Gene ID: 23632)), prostaglandin-endoperoxide synthase 1 (PTGS1, COX-1; NCBI Gene ID: 5742), prostaglandin-endoperoxide synthase 2 (PTGS2, COX-2; NCBI Gene ID: 5743), secreted phospholipase A2, prostaglandin E synthase (PTGES, PGES; Gene ID: 9536), arachidonate 5-lipoxygenase (ALOX5, 5-LOX; NCBI Gene ID: 240), soluble epoxide hydrolase 2 (EPHX2, SEH; NCBI Gene ID: 2053) and/or mitogen-activated protein kinase kinase kinase 8 (MAP3K8, TPL2; NCBI Gene ID: 1326). In some embodiments, the inhibitor is a dual inhibitor, <i>e.g.,</i> a dual inhibitor of COX-2/COX-1, COX-2/SEH, COX-2/CA, COX-2/5-LOX.

0351Examples of inhibitors of prostaglandin-endoperoxide synthase 1 (PTGS1, COX-1; NCBI Gene ID: 5742) that can be co-administered include without limitation mofezolac, GLY-230, and TRK-700.

0352Examples of inhibitors of prostaglandin-endoperoxide synthase 2 (PTGS2, COX-2; NCBI Gene ID: 5743) that can be co-administered include without limitation diclofenac, meloxicam, parecoxib, etoricoxib, AP-101, celecoxib, AXS-06, diclofenac potassium, DRGT-46, AAT-076, meisuoshuli, lumiracoxib, meloxicam, valdecoxib, zaltoprofen, nimesulide, Anitrazafen, Apricoxib, Cimicoxib, Deracoxib, Flumizole, Firocoxib, Mavacoxib, NS-398, Pamicogrel, Parecoxib, Robenacoxib, Rofecoxib, Rutecarpine, Tilmacoxib, and Zaltoprofen. Examples of dual COX1/COX2 inhibitors that can be co-administered include without limitation, HP-5000, lomoxicam, ketorolac tromethamine, bromfenac sodium, ATB-346, HP-5000. Examples of dual COX-2/carbonic anhydrase (CA) inhibitors that can be co-administered include without limitation polmacoxib and imrecoxib.

0353Examples of inhibitors of secreted phospholipase A2, prostaglandin E synthase (PTGES, PGES; Gene ID: 9536) that can be co-administered include without limitation LY3023703, GRC 27864, and compounds described in <patcit id="pcit0220" dnum="WO2015158204A"><text>WO2015158204</text></patcit>, <patcit id="pcit0221" dnum="WO2013024898A"><text>WO2013024898</text></patcit>, <patcit id="pcit0222" dnum="WO2006063466A"><text>WO2006063466</text></patcit>, <patcit id="pcit0223" dnum="WO2007059610A"><text>WO2007059610</text></patcit>, <patcit id="pcit0224" dnum="WO2007124589A"><text>WO2007124589</text></patcit>, <patcit id="pcit0225" dnum="WO2010100249A"><text>WO2010100249</text></patcit>, <patcit id="pcit0226" dnum="WO2010034796A"><text>WO2010034796</text></patcit>, <patcit id="pcit0227" dnum="WO2010034797A"><text>WO2010034797</text></patcit>, <patcit id="pcit0228" dnum="WO2012022793A"><text>WO2012022793</text></patcit>, <patcit id="pcit0229" dnum="WO2012076673A"><text>WO2012076673</text></patcit>, <patcit id="pcit0230" dnum="WO2012076672A"><text>WO2012076672</text></patcit>, <patcit id="pcit0231" dnum="WO2010034798A"><text>WO2010034798</text></patcit>, <patcit id="pcit0232" dnum="WO2010034799A"><text>WO2010034799</text></patcit>, <patcit id="pcit0233" dnum="WO2012022792A"><text>WO2012022792</text></patcit>, <patcit id="pcit0234" dnum="WO2009103778A"><text>WO2009103778</text></patcit>, <patcit id="pcit0235" dnum="WO2011048004A"><text>WO2011048004</text></patcit>, <patcit id="pcit0236" dnum="WO2012087771A"><text>WO2012087771</text></patcit>, <patcit id="pcit0237" dnum="WO2012161965A"><text>WO2012161965</text></patcit>, <patcit id="pcit0238" dnum="WO2013118071A"><text>WO2013118071</text></patcit>, <patcit id="pcit0239" dnum="WO2013072825A"><text>WO2013072825</text></patcit>, <patcit id="pcit0240" dnum="WO2014167444A"><text>WO2014167444</text></patcit>, <patcit id="pcit0241" dnum="WO2009138376A"><text>WO2009138376</text></patcit>, <patcit id="pcit0242" dnum="WO2011023812A"><text>WO2011023812</text></patcit>, <patcit id="pcit0243" dnum="WO2012110860A"><text>WO2012110860</text></patcit>, <patcit id="pcit0244" dnum="WO2013153535A"><text>WO2013153535</text></patcit>, <patcit id="pcit0245" dnum="WO2009130242A"><text>WO2009130242</text></patcit>, <patcit id="pcit0246" dnum="WO2009146696A"><text>WO2009146696</text></patcit>, <patcit id="pcit0247" dnum="WO2013186692A"><text>WO2013186692</text></patcit>, <patcit id="pcit0248" dnum="WO2015059618A"><text>WO2015059618</text></patcit>, <patcit id="pcit0249" dnum="WO2016069376A"><text>WO2016069376</text></patcit>, <patcit id="pcit0250" dnum="WO2016069374A"><text>WO2016069374</text></patcit>, <patcit id="pcit0251" dnum="WO2009117985A"><text>WO2009117985</text></patcit>, <patcit id="pcit0252" dnum="WO2009064250A"><text>WO2009064250</text></patcit>, <patcit id="pcit0253" dnum="WO2009064251A"><text>WO2009064251</text></patcit>, <patcit id="pcit0254" dnum="WO2009082347A"><text>WO2009082347</text></patcit>, <patcit id="pcit0255" dnum="WO2009117987A"><text>WO2009117987</text></patcit>, and <patcit id="pcit0256" dnum="WO2008071173A"><text>WO2008071173</text></patcit>. Metformin has further been found to repress the COX2/PGE2/STAT3 axis, and can be co-administered. <i>See, e.g.,</i><nplcit id="ncit0030" npl-type="s"><text>Tong, et al., Cancer Lett. (2017) 389:23-32</text></nplcit>; and <nplcit id="ncit0031" npl-type="s"><text>Liu, et al., Oncotarget. (2016) 7(19):28235-46</text></nplcit>.

0354Examples of inhibitors of carbonic anhydrase (<i>e</i>.<i>g</i>., one or more of CA1 (NCBI Gene ID: 759), CA2 (NCBI Gene ID: 760), CA3 (NCBI Gene ID: 761), CA4 (NCBI Gene ID: 762), CA5A (NCBI Gene ID: 763), CA5B (NCBI Gene ID: 11238), CA6 (NCBI Gene ID: 765), CA7 (NCBI Gene ID: 766), CA8 (NCBI Gene ID: 767), CA9 (NCBI Gene ID: 768), CA10 (NCBI Gene ID: 56934), CA11 (NCBI Gene ID: 770), CA12 (NCBI Gene ID: 771), CA13 (NCBI Gene ID: 377677), CA14 (NCBI Gene ID: 23632)) that can be co-administered include without limitation acetazolamide, methazolamide, dorzolamide, zonisamide, brinzolamide and dichlorphenamide. A dual COX-2/CA1/CA2 inhibitor that can be co-administered includes CG100649.

0355Examples of inhibitors of arachidonate 5-lipoxygenase (ALOX5, 5-LOX; NCBI Gene ID: 240) that can be co-administered include without limitation meclofenamate sodium, zileuton.

0356Examples of inhibitors of soluble epoxide hydrolase 2 (EPHX2, SEH; NCBI Gene ID: 2053) that can be co-administered include without limitation compounds described in <patcit id="pcit0257" dnum="WO2015148954A"><text>WO2015148954</text></patcit>. Dual inhibitors of COX-2/SEH that can be co-administered include compounds described in <patcit id="pcit0258" dnum="WO2012082647A"><text>WO2012082647</text></patcit>. Dual inhibitors of SEH and fatty acid amide hydrolase (FAAH; NCBI Gene ID: 2166) that can be co-administered include compounds described in <patcit id="pcit0259" dnum="WO2017160861A"><text>WO2017160861</text></patcit>.

0357Examples of inhibitors of mitogen-activated protein kinase kinase kinase 8 (MAP3K8, tumor progression loci-2, TPL2; NCBI Gene ID: 1326) that can be co-administered include without limitation GS-4875, GS-5290, BHM-078 and those described, <i>e.g</i>., in <patcit id="pcit0260" dnum="WO2006124944A"><text>WO2006124944</text></patcit>, <patcit id="pcit0261" dnum="WO2006124692A"><text>WO2006124692</text></patcit>, <patcit id="pcit0262" dnum="WO2014064215A"><text>WO2014064215</text></patcit>, <patcit id="pcit0263" dnum="WO2018005435A"><text>WO2018005435</text></patcit>, <nplcit id="ncit0032" npl-type="s"><text>Teli, et al., J Enzyme Inhib Med Chem. (2012) 27(4):558-70</text></nplcit>; <nplcit id="ncit0033" npl-type="s"><text>Gangwall, et al., Curr Top Med Chem. (2013) 13(9):1015-35</text></nplcit>; <nplcit id="ncit0034" npl-type="s"><text>Wu, et al., BioorgMed Chem Lett. (2009) 19(13):3485-8</text></nplcit>;<nplcit id="ncit0035" npl-type="s"><text> Kaila, et al., Bioorg Med Chem. (2007) 15(19):6425-42</text></nplcit>; and <nplcit id="ncit0036" npl-type="s"><text>Hu, et al., Bioorg Med Chem Lett. (2011) 21(16):4758-61</text></nplcit>.

Tumor Oxygenation Agents

0358In some embodiments, a compound as described herein, is combined with an agent that promotes or increases tumor oxygenation or reoxygenation, or prevents or reduces tumor hypoxia. Illustrative agents that can be co-administered include, <i>e.g</i>., Hypoxia inducible factor-1 alpha (HIF-1α) inhibitors, such as PT-2977, PT-2385; VEGF inhibitors, such as bevasizumab, IMC-3C5, GNR-011, tanibirumab, LYN-00101, ABT-165; and/or an oxygen carrier protein <i>(e.g.,</i> a heme nitric oxide and/or oxygen binding protein (HNOX)), such as OMX-302 and HNOX proteins described in <patcit id="pcit0264" dnum="WO2007137767A"><text>WO 2007/137767</text></patcit>, <patcit id="pcit0265" dnum="WO2007139791A"><text>WO 2007/139791</text></patcit>, <patcit id="pcit0266" dnum="WO2014107171A"><text>WO 2014/107171</text></patcit>, and <patcit id="pcit0267" dnum="WO2016149562A"><text>WO 2016/149562</text></patcit>.

Immunotherapeutic Agents

0359In some embodiments, a compound as described herein, is combined with an immunotherapeutic agent. Example immunotherapeutic agents that can be co-administered include without limitation abagovomab, ABP-980, adecatumumab, afutuzumab, alemtuzumab, altumomab, amatuximab, anatumomab, arcitumomab, bavituximab, bectumomab, bevacizumab, bivatuzumab, blinatumomab, brentuximab, cantuzumab, catumaxomab, CC49, cetuximab, citatuzumab, cixutumumab, clivatuzumab, conatumumab, dacetuzumab, dalotuzumab, daratumumab, detumomab, dinutuximab, drozitumab, duligotumab, dusigitumab, ecromeximab, elotuzumab, emibetuzumab, ensituximab, ertumaxomab, etaracizumab, farletuzumab, ficlatuzumab, figitumumab, flanvotumab, futuximab, ganitumab, gemtuzumab, girentuximab, glembatumumab, ibritumomab, igovomab, imgatuzumab, indatuximab, inotuzumab, intetumumab, ipilimumab (YERVOY^®, MDX-010, BMS-734016, and MDX-101), iratumumab, labetuzumab, lexatumumab, lintuzumab, lorvotuzumab, lucatumumab, mapatumumab, matuzumab, milatuzumab, minretumomab, mitumomab, mogamulizumab, moxetumomab, naptumomab, namatumab, necitumumab, nimotuzumab, nofetumomab, OBI-833, obinutuzumab, ocaratuzumab, ofatumumab, olaratumab, onartuzumab, oportuzumab, oregovomab, panitumumab, parsatuzumab, pasudotox, patritumab, pemtumomab, pertuzumab, pintumomab, pritumumab, racotumomab, radretumab, ramucirumab (Cyramza^®), rilotumumab, rituximab, robatumumab, samalizumab, satumomab, sibrotuzumab, siltuximab, solitomab, simtuzumab, tacatuzumab, taplitumomab, tenatumomab, teprotumumab, tigatuzumab, tositumomab, trastuzumab, tucotuzumab, ubilituximab, veltuzumab, vorsetuzumab, votumumab, zalutumumab, and 3F8. Rituximab can be used for treating indolent B-cell cancers, including marginal-zone lymphoma, WM, CLL and small lymphocytic lymphoma. A combination of Rituximab and chemotherapy agents is especially effective.

0360The exemplified therapeutic antibodies may be further labeled or combined with a radioisotope particle such as indium-111, yttrium-90 (90Y-clivatuzumab), or iodine-131.

0361In some embodiments, the immunotherapeutic agent is an antibody-drug conjugate (ADC). Illustrative ADCs that can be co-administered include without limitation drug-conjugated antibodies, fragments thereof, or antibody mimetics targeting the proteins or antigens listed above and herein. Example ADCs that can be co-administered include without limitation gemtuzumab, brentuximab, trastuzumab, inotuzumab, glembatumumab, anetumab, mirvetuximab, depatuxizumab, rovalpituzumab, vadastuximab, labetuzumab, sacituzumab, lifastuzumab, indusatumab, polatzumab, pinatuzumab, coltuximab, indatuximab, milatuzumab, rovalpituzumab, ABBV-399, AGS-16C3F, ASG-22ME, AGS67E, AMG172, AMG575, BAY1129980, BAY1187982, BAY94-9343, GSK2857916, Humax-TF-ADC, IMGN289, IMGN529, IMGN853, LOP628, PCA062, MDX-1203 (BMS936561), MEDI-547, PF-06263507, PF-06647020, PF-06647263, PF-06664178, RG7450, RG7458, RG7598, SAR566658, SGN-CD19A, SGN-CD33A, SGN-CD70A, SGN-LIV1A and SYD985. ADCs that can be co-administered are described, <i>e.g.,</i> in <nplcit id="ncit0037" npl-type="s"><text>Lambert, et al., Adv Ther (2017) 34: 1015-1035</text></nplcit> and in <nplcit id="ncit0038" npl-type="s"><text>de Goeij, Current Opinion in Immunology (2016) 40: 14-23</text></nplcit>.

0362Illustrative therapeutic agents (<i>e.g</i>., anticancer or antineoplastic agents) that can be conjugated to the drug-conjugated antibodies, fragments thereof, or antibody mimetics include without limitation monomethyl auristatin E (MMAE), monomethyl auristatin F (MMAF), a calicheamicin, ansamitocin, maytansine or an analog thereof (<i>e.g</i>., mertansine/emtansine (DM1), ravtansine/soravtansine (DM4)), an anthracyline (<i>e.g</i>., doxorubicin, daunorubicin, epirubicin, idarubicin), pyrrolobenzodiazepine (PBD) DNA cross-linking agent SC-DR002 (D6.5), duocarmycin, a microtubule inhibitors (MTI) <i>(e.g.,</i> a taxane, a vinca alkaloid, an epothilone), a pyrrolobenzodiazepine (PBD) or dimer thereof, a duocarmycin (A, B1, B2, C1, C2, D, SA, CC-1065), and other anticancer or anti-neoplastic agents described herein.

Cancer Gene Therapy and Cell Therapy

0363In some embodiments, a compound as described herein, is combined with a cancer gene therapy and cell therapy. Cancer gene therapies and cell therapies include the insertion of a normal gene into cancer cells to replace a mutated or altered gene; genetic modification to silence a mutated gene; genetic approaches to directly kill the cancer cells; including the infusion of immune cells designed to replace most of the patient's own immune system to enhance the immune response to cancer cells, or activate the patient's own immune system (T cells or Natural Killer cells) to kill cancer cells, or find and kill the cancer cells; genetic approaches to modify cellular activity to further alter endogenous immune responsiveness against cancer.

Cellular Therapies

0364In some embodiments, a compound as described herein, is combined with one or more cellular therapies. Illustrative cellular therapies include without limitation co-administration of one or more of a population of immune cells. In some embodiments, the immune cells are natural killer (NK) cells, NK-T cells, T cells, gamma delta T cells, B-cells, cytokine-induced killer (CIK) cells, macrophage (MAC) cells, tumor infiltrating lymphocytes (TILs) a granulocyte, an innate lymphoid cell, a megakaryocyte, a monocyte, a macrophage, a platelet, a thymocyte, a myeloid cell, and/or dendritic cells (DCs). In some embodiments, the cellular therapy entails a T cell therapy, <i>e.g</i>., co-administering a population of alpha/beta TCR T cells, gamma/delta TCR T cells, regulatory T (Treg) cells and/or TRuC^™ T cells. In some embodiments, the cellular therapy entails a NK cell therapy, <i>e.g</i>., co-administering NK-92 cells. As appropriate, a cellular therapy can entail the co-administration of cells that are autologous, syngeneic or allogeneic to the subject.

0365In some embodiments, the cellular therapy entails co-administering immune cells engineered to express chimeric antigen receptors (CARs) or T cell receptors (TCRs) TCRs. In particular embodiments, a population of immune cells is engineered to express a CAR, wherein the CAR comprises a tumor antigen-binding domain. In other embodiments, a population of immune cells is engineered to express T cell receptors (TCRs) engineered to target tumor derived peptides presented on the surface of tumor cells. In one embodiment, the immune cell engineered to express chimeric antigen receptors (CARs) or T cell receptors (TCRs) TCRs is a T cell. In another embodiment, the immune cell engineered to express chimeric antigen receptors (CARs) or T cell receptors (TCRs) TCRs is an NK cell.

0366With respect to the structure of a CAR, in some embodiments, the CAR comprises an antigen binding domain, a transmembrane domain, and an intracellular signaling domain. In some embodiments, the intracellular domain comprises a primary signaling domain, a costimulatory domain, or both of a primary signaling domain and a costimulatory domain. In some embodiments, the primary signaling domain comprises a functional signaling domain of one or more proteins selected from the group consisting of CD3 zeta, CD3 gamma, CD3 delta, CD3 epsilon, common FcR gamma (FCERIG), FcRbeta (Fc Epsilon Rlb), CD79a, CD79b, Fcgamma RIIa, DAP10, and DAP12 4-1BB/CD137, activating NK cell receptors, an Immunoglobulin protein, B7-H3, BAFFR, BLAME (SLAMF8), BTLA, CD100 (SEMA4D), CD103, CD160 (BY55), CD18, CD19, CD19a, CD2, CD247, CD27, CD276 (B7-H3), CD28, CD29, CD3 delta, CD3 epsilon, CD3 gamma, CD30, CD4, CD40, CD49a, CD49D, CD49f, CD69, CD7, CD84, CD8alpha, CD8beta, CD96 (Tactile), CD11a, CD11b, CD11c, CD11d, CDS, CEACAM1, CRT AM, cytokine receptor, DAP-10, DNAM1 (CD226), Fc gamma receptor, GADS, GITR, HVEM (LIGHTR), IA4, ICAM-1, ICAM-1, Ig alpha (CD79a), IL-2R beta, IL-2R gamma, IL-7R alpha, inducible T cell costimulator (ICOS), integrins, ITGA4, ITGA4, ITGA6, ITGAD, ITGAE, ITGAL, ITGAM, ITGAX, ITGB2, ITGB7, ITGB1, KIRDS2, LAT, LFA-1, LFA-1, ligand that binds with CD83, LIGHT, LIGHT, LTBR, Ly9 (CD229), Ly108), lymphocyte function-associated antigen-1 (LFA-1; CD1-1a/CD18), MHC class 1 molecule, NKG2C, NKG2D, NKp30, NKp44, NKp46, NKp80 (KLRF1), OX-40, PAG/Cbp, programmed death-1 (PD-1), PSGL1, SELPLG (CD162), Signaling Lymphocytic Activation Molecules (SLAM proteins), SLAM (SLAMF1; CD150; IPO-3), SLAMF4 (CD244; 2B4), SLAMF6 (NTB-A, SLAMF7, SLP-76, TNF receptor proteins, TNFR2, TNFSF14, a Toll ligand receptor, TRANCE/RANKL, VLA1, or VLA-6, or a fragment, truncation, or a combination thereof.

0367In some embodiments, the costimulatory domain comprises a functional domain of one or more proteins selected from the group consisting of CD27, CD28, 4-1BB(CD137), OX40, CD30, CD40, PD-1, ICOS, CD2, CD7, LIGHT, NKG2C, lymphocyte function-associated antigen-1 (LFA-1), MYD88, B7-H3, a ligand that specifically binds with CD83, CDS, ICAM-1, GITR, BAFFR, HVEM (LIGHTR), SLAMF7, NKp80 (KLRFI), CD160, CD19, CD4, CD8alpha, CD8beta, IL2R beta, IL2R gamma, IL7R alpha, ITGA4, VLA1, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, ITGAE, CD103, ITGAL, CD1A (NCBI Gene ID: 909), CD1B (NCBI Gene ID: 910), CD1C (NCBI Gene ID: 911), CD1D (NCBI Gene ID: 912), CD1E (NCBI Gene ID: 913), ITGAM, ITGAX, ITGB1, CD29, ITGB2 (CD18, LFA-1), ITGB7, TNFR2, TRANCE/RANKL, DNAM1 (CD226), SLAMF4 (CD244, 2B4), CD84, CD96 (Tactile), CEACAM1, CRTAM, Ly9 (CD229), CD160 (BY55), PSGL1, CD100 (SEMA4D), CD69, SLAMF6 (NTB-A, Ly108), SLAM (SLAMF1, CD150, IPO-3), BLAME (SLAMF8), SELPLG (CD162), LTBR, LAT, GADS, SLP-76, PAG/Cbp, NKp44, NKp30, NKp46, and NKG2D.

0368In some embodiments, the transmembrane domain comprises a transmembrane domain derived from a protein selected from the group consisting of the alpha, beta or zeta chain of the T-cell receptor, CD28, CD3 epsilon, CD3 delta, CD3 gamma, CD45, CD4, CD5, CD7, CD8 alpha, CD8 beta" CD9, CD11a, CD11b, CD11c, CD11d, CD16, CD18, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137, CD154, KIRDS2, OX40, CD2, CD27, ICOS (CD278), 4-1BB(CD137), GITR, CD40, BAFFR, HVEM (LIGHTR), SLAMF7, NKp80 (KLRF1), CD19, CD19a, IL2R beta, IL2R gamma, IL7R alpha, ITGA1, VLA1, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, CD1A, CD1B, CD1C, CD1D, CD1E, ITGAE, CD103, ITGAL, ITGAM, ITGAX, ITGB1, ITGB2, ITGB7, CD29, ITGB2 (LFA-1, CD18), ITGB7, TNFR2, DNAM1 (CD226), SLAMF4 (CD244, 2B4), CD84, CD96 (TACTILE), CEACAM1, CRTAM, Ly9 (CD229), CD160 (BY55), PSGL1, CD100 (SEMA4D), SLAMF6 (NTB-A, Ly108), SLAM (SLAMF1, CD150, IPO-3), BLAME (SLAMF8), SELPLG (CD162), LTBR, PAG/Cbp, NKp44, NKp30, NKp46, NKG2D, and NKG2C activating NK cell receptors, an Immunoglobulin protein, BTLA, CD247, CD276 (B7-H3), CD30, CD84, CDS, cytokine receptor, Fc gamma receptor, GADS, ICAM-1, Ig alpha (CD79a), integrins, LAT, a ligand that binds with CD83, LIGHT, MHC class 1 molecule, PAG/Cbp, TNFSF14, a Toll ligand receptor, TRANCE/RANKL, or a fragment, truncation, or a combination thereof.

0369In some embodiments, the CAR comprises a hinge domain. A hinge domain may be derived from a protein selected from the group consisting of the CD2, CD3 delta, CD3 epsilon, CD3 gamma, CD4, CD7, CD8.alpha., CD8.beta., CD11a (ITGAL), CD11b (ITGAM), CD11c (ITGAX), CD11d (ITGAD), CD18 (ITGB2), CD19 (B4), CD27 (TNFRSF7), CD28, CD28T, CD29 (ITGB1), CD30 (TNFRSF8), CD40 (TNFRSF5), CD48 (SLAMF2), CD49a (ITGA1), CD49d (ITGA4), CD49f (ITGA6), CD66a (CEACAM1), CD66b (CEACAM8), CD66c (CEACAM6), CD66d (CEACAM3), CD66e (CEACAM5), CD69 (CLEC2), CD79A (B-cell antigen receptor complex-associated alpha chain), CD79B (B-cell antigen receptor complex-associated beta chain), CD84 (SLAMF5), CD96 (Tactile), CD100 (SEMA4D), CD103 (ITGAE), CD134 (OX40), CD137 (4-1BB), CD150 (SLAMF1), CD158A (KIR2DL1), CD158B1 (KIR2DL2), CD158B2 (KIR2DL3), CD158C (KIR3DP1), CD158D (KIRDL4), CD158F1 (KIR2DL5A), CD158F2 (KIR2DL5B), CD158K (KIR3DL2), CD160 (BY55), CD162 (SELPLG), CD226 (DNAM1), CD229 (SLAMF3), CD244 (SLAMF4), CD247 (CD3-zeta), CD258 (LIGHT), CD268 (BAFFR), CD270 (TNFSF14), CD272 (BTLA), CD276 (B7-H3), CD279 (PD-1), CD314 (NKG2D), CD319 (SLAMF7), CD335 (NK-p46), CD336 (NK-p44), CD337 (NK-p30), CD352 (SLAMF6), CD353 (SLAMF8), CD355 (CRTAM), CD357 (TNFRSF18), inducible T cell co-stimulator (ICOS), LFA-1 (CD11a/CD18), NKG2C, DAP-10, ICAM-1, NKp80 (KLRF1), IL-2R beta, IL-2R gamma, IL-7R alpha, LFA-1, SLAMF9, LAT, GADS (GrpL), SLP-76 (LCP2), PAG1/CBP, a CD83 ligand, Fc gamma receptor, MHC class 1 molecule, MHC class 2 molecule, a TNF receptor protein, an immunoglobulin protein, a cytokine receptor, an integrin, activating NK cell receptors, or Toll ligand receptor, IgG1, IgG2, IgG3, IgG4, IgA, IgD, IgE, IgM or fragment or combination thereof.

0370In some embodiments, the one or more additional therapeutic agents comprises an immunotherapy, an immunostimulatory therapy, a cytokine therapy, a chemokine therapy, a cellular therapy, a gene therapy, and combinations thereof. In some embodiments, the immunotherapy comprises co-administering one or more antibodies or antigen-binding antibody fragments thereof, or antibody-drug conjugates thereof, CD3-targeting multi-specific molecules, CD16-targeting multi-specific molecules, or non-immunoglobulin antigen-binding domains or antibody mimetic proteins directed against one or more targets or tumor associated antigens (TAAs).

0371In some embodiments, the TCR or CAR antigen binding domain or the immunotherapeutic agent described herein (e.g., monospecific or multi-specific antibody or antigen-binding fragment thereof or antibody mimetic) binds a tumor-associated antigen (TAA). In some embodiments, the tumor-associated antigen is selected from the group consisting of: CD19; CD123; CD22; CD30; CD171; CS-1 (also referred to as CD2 subset 1, CRACC, SLAMF7, CD319, and 19A24); C-type lectin-like molecule-1 (CLL-1 or CLECLI); CD33; epidermal growth factor receptor variant III (EGFRvlll); ganglioside G2 (GD2); ganglioside GD3 (αNeuSAc(2-8)αNeuSAc(2-3)βDGaip(1-4)bDGIcp(1-1)Cer); ganglioside GM3 (αNeuSAc(2-3)βDGalp(1-4)(3DGlcp(1-1)Cer); GM-CSF receptor; TNF receptor superfamily member 17 (TNFRSF17, BCMA); B-lymphocyte cell adhesion molecule; Tn antigen ((Tn Ag) or (GaINAcu-Ser/Thr)); prostate-specific membrane antigen (PSMA); Receptor tyrosine kinase-like orphan receptor 1 (RORI); Tumor-associated glycoprotein 72 (TAG72); CD38; CD44v6; Carcinoembryonic antigen (CEA); Epithelial cell adhesion molecule (EPCAM); B7H3 (CD276); KIT (CD117); Interleukin-13 receptor subunit alpha-2 (IL-13Ra2 or CD213A2); Mesothelin; Interleukin 11 receptor alpha (IL-1 1Ra); prostate stem cell antigen (PSCA); Protease Serine 21 (Testisin or PRSS21); vascular endothelial growth factor receptor 2 (VEGFR2); HLA class I antigen A-2 alpha; HLA antigen; Lewis(Y)antigen; CD24; Platelet-derived growth factor receptor beta (PDGFR-beta); Stage-specific embryonic antigen-4 (SSEA-4); CD20; delta like 3 (DLL3); Folate receptor alpha; Folate receptor beta, GDNF alpha 4 receptor, Receptor tyrosine-protein kinase, ERBB2 (Her2/neu); Mucin 1, cell surface associated (MUC1); APRIL receptor; ADP ribosyl cyclase-1; Ephb4 tyrosine kinase receptor, DCAMKL1 serine threonine kinase, Aspartate beta-hydroxylase, epidermal growth factor receptor (EGFR); neural cell adhesion molecule (NCAM); Prostase; prostatic acid phosphatase (PAP);elongation factor 2 mutated (ELF2M); Ephrin B2; fibroblast activation protein alpha (FAP);insulin-like growth factor 1 receptor (IGF-I receptor), carbonic anhydrase IX (CAIX);Proteasome (Prosome, Macropain) Subunit, Beta Type, 9 (LMP2); glycoprotein 100 (gp100);oncogene fusion protein consisting of breakpoint cluster region (BCR) and Abelson murine leukemia viral oncogene homolog 1 (Abl) (bcr-abl); tyrosinase; ephrin type-A receptor 2 (EphA2); ephrin type-A receptor 3 (EphA3), Fucosyl GM1; sialyl Lewis adhesion molecule (sLe); transglutaminase 5 (TGS5); high molecular weight-melanomaassociatedantigen (HMWMAA); o-acetyl-GD2 ganglioside (OAcGD2); Folate receptor beta;tumor endothelial marker 1 (TEM1/CD248); tumor endothelial marker 7-related (TEM7R); six transmembrane epithelial antigen of the prostate I (STEAP1); claudin 6 (CLDN6); thyroid stimulating hormone receptor (TSHR); G protein-coupled receptor class C group 5, member D (GPRCSD); IL-15 receptor (IL-15); chromosome X open reading frame 61 (CXORF61); CD97; CD179a; anaplastic lymphoma kinase (ALK); Polysialic acid; placenta-specific 1 (PLAC1); hexasaccharide portion of globoH glycoceramide (GloboH); mammary gland differentiation antigen (NY-BR-1); uroplakin 2 (UPK2); Hepatitis A virus cellular receptor 1 (HAVCR1); adrenoceptor beta 3 (ADRB3); pannexin 3 (PANX3); G protein-coupled receptor 20 (GPR20); lymphocyte antigen 6 complex, locus K 9 (LY6K); Olfactory receptor 51E2 (ORS IE2); TCR Gamma Alternate Reading Frame Protein (TARP); Wilms tumor protein (WT1); Cancer/testis antigen 1 (NY-ESO-1); Cancer/testis antigen 2 (LAGE-la); Melanoma associated antigen 1 (MAGE-A1); Melanoma associated antigen 3 (MAGE-A3); Melanoma associated antigen 4 (MAGE-A4); T cell receptor beta 2 chain C; ETS translocation-variant gene 6, located on chromosome 12p (ETV6-AML); sperm protein 17 (SPA17); X Antigen Family, Member 1A (XAGE1); angiopoietin-binding cell surface receptor 2 (Tie 2); melanoma cancer testis antigen-1 (MADCT-1); melanoma cancer testis antigen-2 (MAD-CT-2); Fos-related antigen 1; tumor protein p53, (p53); p53 mutant; prostein; survivin; telomerase; prostate carcinoma tumor antigen-1 (PCTA-1 or Galectin 8), melanoma antigen recognized by T cells 1 (MelanA or MARTI); Rat sarcoma (Ras) mutant; human Telomerase reverse transcriptase (hTERT); sarcoma translocation breakpoints; melanoma inhibitor of apoptosis (ML-IAP); ERG (transmembrane protease, serine 2 (TMPRSS2) ETS fusion gene); N-Acetyl glucosaminyl-transferase V (NA17); paired box protein Pax-3 (PAX3); Androgen receptor; Cyclin-A1; Cyclin B 1;v-myc avian myelocytomatosis viral oncogene neuroblastoma derived homolog (MYCN); Ras Homolog Family Member C (RhoC); Tyrosinase-related protein 2 (TRP-2); Cytochrome P450 1B1(CYP IBI); CCCTC-Binding Factor (Zinc Finger Protein)-Like (BORIS or Brother of the Regulator of Imprinted Sites), Squamous Cell Carcinoma Antigen Recognized By T Cells 3 (SART3); Paired box protein Pax-5 (PAX5); proacrosin binding protein sp32 (OY-TES I); lymphocyte-specific protein tyrosine kinase (LCK); A kinase anchor protein 4 (AKAP-4); Peptidoglycan recognition protein, synovial sarcoma, X breakpoint 2 (SSX2); Receptor for Advanced Glycation Endproducts (RAGE-I); renal ubiquitous 1 (RUI); renal ubiquitous 2 (RU2); legumain; human papilloma virus E6 (HPV E6); human papilloma virus E7 (HPV E7); intestinal carboxyl esterase; heat shock protein 70-2 mutated (mut hsp70-2); CD79a; CD79b; CD72; Leukocyte-associated immunoglobulin-like receptor 1 (LAIRI); Fc fragment of IgA receptor (FCAR or CD89); Leukocyte immunoglobulin-like receptor subfamily A member 2 (LILRA2); CD300 molecule-like family member f (CD300LF); C-type lectin domain family 12 member A (CLEC12A); bone marrow stromal cell antigen 2 (BST2); EGF-like module containing mucin-like hormone receptor-like 2 (EMR2); lymphocyte antigen 75 (LY75); Glypican-2 (GPC2); Glypican-3 (GPC3); Fc receptor-like 5 (FCRL5); and immunoglobulin lambda-like polypeptide 1 (IGLL1). In some embodiments, the target is an epitope of the tumor associated antigen presented in an MHC.

0372In some embodiments, the tumor antigen is selected from CD150, 5T4, ActRIIA, B7, TNF receptor superfamily member 17 (TNFRSF17, BCMA), CA-125, CCNA1, CD123, CD126, CD138, CD14, CD148, CD15, CD19, CD20, CD200, CD21, CD22, CD23, CD24, CD25, CD26, CD261, CD262, CD30, CD33, CD362, CD37, CD38, CD4, CD40, CD40L, CD44, CD46, CD5, CD52, CD53, CD54, CD56, CD66a-d, CD74, CD8, CD80, CD92, CE7, CS-1, CSPG4, ED-B fibronectin, EGFR, EGFRvIII, EGP-2, EGP-4, EPHa2, ErbB2, ErbB3, ErbB4, FBP, HER1-HER2 in combination, HER2-HER3 in combination, HERV-K, HIV-1 envelope glycoprotein gp120, HIV-1 envelope glycoprotein gp41, HLA-DR, HLA class I antigen alpha G, HM1.24, K-Ras GTPase, HMW-MAA, Her2, Her2/neu, IGF-1R, IL-11Ralpha, IL-13R-alpha2, IL-2, IL-22R-alpha, IL-6, IL-6R, Ia, Ii, L1-CAM, L1-cell adhesion molecule, Lewis Y, Ll-CAM, MAGE A3, MAGE-A1, MART-1, MUC1, NKG2C ligands, NKG2D Ligands, NYESO-1, OEPHa2, PIGF, PSCA, PSMA, ROR1, T101, TAC, TAG72, TIM-3, TRAIL-R1, TRAIL-R1 (DR4), TRAIL-R2 (DR5), VEGF, VEGFR2, WT-I, a G-protein coupled receptor, alphafetoprotein (AFP), an angiogenesis factor, an exogenous cognate binding molecule (ExoCBM), oncogene product, anti-folate receptor, c-Met, carcinoembryonic antigen (CEA), cyclin (D 1), ephrinB2, epithelial tumor antigen, estrogen receptor, fetal acetylcholine e receptor, folate binding protein, gp100, hepatitis B surface antigen, Epstein-Barr nuclear antigen 1, Latent membrane protein 1, Secreted protein BARF1, P2X7 purinoceptor, Syndecan-1, kappa chain, kappa light chain, kdr, lambda chain, livin, melanoma-associated antigen, mesothelin, mouse double minute 2 homolog (MDM2), mucin 16 (MUC16), mutated p53, mutated ras, necrosis antigens, oncofetal antigen, ROR2, progesterone receptor, prostate specific antigen, tEGFR, tenascin, P2-Microgiobuiin, Fc Receptor-like 5 (FcRL5).

0373Examples of cell therapies include without limitation: AMG-119, Algenpantucel-L, ALOFISEL^®, Sipuleucel-T, (BPX-501) rivogenlecleucel <patcit id="pcit0268" dnum="US9089520B"><text>US9089520</text></patcit>, <patcit id="pcit0269" dnum="WO2016100236A"><text>WO2016100236</text></patcit>, AU-105, ACTR-087, activated allogeneic natural killer cells CNDO-109-AANK, MG-4101, AU-101, BPX-601, FATE-NK100, LFU-835 hematopoietic stem cells, Imilecleucel-T, baltaleucel-T, PNK-007, UCARTCS1, ET-1504, ET-1501, ET-1502, ET-190, CD19-ARTEMIS, ProHema, FT-1050-treated bone marrow stem cell therapy, CD4CARNK-92 cells, SNK-01, NEXI-001, CryoStim, AlloStim, lentiviral transduced huCART-meso cells, CART-22 cells, EGFRt/19-28z/4-1BBL CAR T cells, autologous 4H11-28z/fIL-12/EFGRt T cell, CCRS-SBC-728-HSPC, CAR4-1BBZ, CH-296, dnTGFbRII-NY-ESOc259T, Ad-RTS-IL-12, IMA-101, IMA-201, CARMA-0508, TT-18, CMD-501, CMD-503, CMD-504, CMD-502,CMD-601,CMD-602, CSG-005, LAAP T-cell therapy, PD-1 knockout T cell therapy (esophageal cancer/NSCLC), anti-MUC1 CAR T-cell therapy (esophageal cancer/NSCLC), anti-MUC1 CAR T-cell therapy + PD-1 knockout T cell therapy (esophageal cancer/NSCLC), anti-KRAS G12D mTCR PBL, anti-CD123 CAR T-cell therapy, anti-mutated neoantigen TCR T-cell therapy, tumor lysate/MUC1/survivin PepTivator-loaded dendritic cell vaccine, autologous dendritic cell vaccine (metastatic malignant melanoma, intradermal/intravenous), anti-LeY-scFv-CD28-zeta CAR T-cells, PRGN-3005, iC9-GD2-CAR-IL-15 T-cells, HSC-100, ATL-DC-101, MIDRIX4-LUNG, MIDRIXNEO, FCR-001, PLX stem cell therapy, MDR-101, GeniusVac-Mel4, ilixadencel, allogeneic mesenchymal stem cell therapy, romyelocel L, CYNK-001, ProTrans, ECT-100, MSCTRAIL, dilanubicel, FT-516, ASTVAC-2, E-CEL UVEC, CK-0801, allogenic alpha/beta CD3+ T cell and CD19+ B cell depleted stem cells (hematologic diseases, TBX-1400, HLCN-061, umbilical cord derived Hu-PHEC cells (hematological malignancies/aplastic anemia), AP-011, apceth-201, apceth-301, SENTI-101, stem cell therapy (pancreatic cancer), ICOVIR15-cBiTE, CD33HSC/CD33 CAR-T, PLX-Immune, SUBCUVAX, CRISPR allogeneic gamma-delta T-cell based gene therapy (cancer), ex vivo CRISPR allogeneic healthy donor NK-cell based gene therapy (cancer), ex-vivo allogeneic induced pluripotent stem cell-derived NK-cell based gene therapy (solid tumor), and anti-CD20 CAR T-cell therapy (non-Hodgkin's lymphoma).

Additional agents for targeting tumors include without limitation:

0374<ul id="ul0008" list-style="none"><li>Alpha-fetoprotein, such as ET-1402, and AFP-TCR;</li><li>Anthrax toxin receptor 1, such as anti-TEM8 CAR T-cell therapy;</li><li>TNF receptor superfamily member 17 (TNFRSF17, BCMA), such as bb-2121 (ide-cel), bb-21217, JCARH125, UCART-BCMA, ET-140, KITE-585, MCM-998, LCAR-B38M, CART-BCMA, SEA-BCMA, BB212, ET-140, P-BCMA-101, AUTO-2 (APRIL-CAR), JNJ-68284528;</li><li>Anti-CLL-1 antibodies, such as KITE-796. See, for example, <patcit id="pcit0270" dnum="US2017025573W"><text>PCT/US2017/025573</text></patcit>;</li><li>Anti-PD-L1-CAR tank cell therapy, such as KD-045;</li><li>Anti-PD-L1 t-haNK, such as PD-L1 t-haNK;</li><li>anti-CD45 antibodies, such as 131I-BC8 (lomab-B);</li><li>anti-HER3 antibodies, such as LJM716, GSK2849330;</li><li>anti-CD52 antibodies, such as alemtuzumab;</li><li>APRIL receptor modulator, such as anti-BCMA CAR T-cell therapy, Descartes-011;</li><li>ADP ribosyl cyclase-1/APRIL receptor modulator, such as dual anti-BCMA/anti-CD38 CAR T-cell therapy; CART-ddBCMA;</li><li>B7 homolog 6, such as CAR-NKp30 and CAR-B7H6;</li><li>B-lymphocyte antigen CD19, such as TBI-1501, CTL-119 huCART-19 T cells,! iso-cel, JCAR-015 <patcit id="pcit0271" dnum="US7446190B"><text>US7446190</text></patcit>, JCAR-014, JCAR-017, (<patcit id="pcit0272" dnum="WO2016196388A"><text>WO2016196388</text></patcit>, <patcit id="pcit0273" dnum="WO2016033570A"><text>WO2016033570</text></patcit>, <patcit id="pcit0274" dnum="WO2015157386A"><text>WO2015157386</text></patcit>), axicabtagene ciloleucel (KTE-C19, Yescarta^®), KTE-X19, <patcit id="pcit0275" dnum="US7741465B"><text>US7741465</text></patcit>, <patcit id="pcit0276" dnum="US6319494B"><text>US6319494</text></patcit>, UCART-19, EBV-CTL, T tisagenlecleucel-T (CTL019), <patcit id="pcit0277" dnum="WO2012079000A"><text>WO2012079000</text></patcit>, <patcit id="pcit0278" dnum="WO2017049166A"><text>WO2017049166</text></patcit>, CD19CAR-CD28-CD3zeta-EGFRt-expressing T cells, CD19/4-1BBL armored CAR T cell therapy, C-CAR-011, CIK-CAR.CD19, CD19CAR-28-zeta T cells, PCAR-019, MatchCART, DSCAR-01, IM19 CAR-T, TC-110; anti-CD19 CAR T-cell therapy (B-cell acute lymphoblastic leukemia, Universiti Kebangsaan Malaysia); anti-CD 19 CAR T-cell therapy (acute lymphoblastic leukemia/Non-Hodgkin's lymphoma, University Hospital Heidelberg), anti-CD 19 CAR T-cell therapy (silenced IL-6 expression, cancer, Shanghai Unicar-Therapy Bio-medicine Technology), MB-CART2019.1 (CD19/CD20), GC-197 (CD19/CD7), CLIC-1901, ET-019003, anti-CD19-STAR-T cells, AVA-001, BCMA-CD19 cCAR (CD19/APRIL), ICG-134, ICG-132 (CD19/CD20), CTA-101, WZTL-002, dual anti-CD19/anti-CD20 CAR T-cells (chronic lymphocytic leukemialB-cell lymphomas), HY-001, ET-019002, YTB-323, GC-012 (CD19/APRIL), GC-022 (CD19/CD22), CD19CAR-CD28-CD3zeta-EGFRt-expressing Tn/mem; UCAR-011, ICTCAR-014, GC-007F, PTG-01, CC-97540;</li><li>Allogeneic anti-CD 19 CART cells, such as GC-007G;</li><li>Allogenic T cells expressing CD20 CAR, such as LB-1905;</li><li>APRIL receptor modulator; SLAM family member 7 modulator, BCMA-CS1 cCAR;</li><li>Autologous dendritic cell tumor antigen (ADCTA), such as ADCTA-SSI-G;</li><li>B-lymphocyte antigen CD20, such as ACTR707 ATTCK-20, PBCAR-20A;</li><li>B-lymphocyte antigen CD19/B-lymphocyte antigen 22, such as TC-310;</li><li>B-lymphocyte antigen 22 cell adhesion, such as UCART-22, JCAR-018 <patcit id="pcit0279" dnum="WO2016090190A"><text>WO2016090190</text></patcit>;</li><li>NY-ESO-1 modulators, such as GSK-3377794, TBI-1301, GSK3537142;</li><li>Carbonic anhydrase, such as DC-Ad-GMCAIX;</li><li>Caspase 9 suicide gene, such as CaspaCIDe DLI, BPX-501;</li><li>CCRS, such as SB-728;</li><li>CCRS gene inhibitor/TAT gene/TRIM5 gene stimulator, such as lentivirus vector CCR5 shRNA/TRIM5alpha/TAR decoy-transduced autologous CD34-positive hematopoietic progenitor cells;</li><li>CDw123, such as MB-102, IM-23, JEZ-567, UCART-123;</li><li>CD4, such as ICG-122;</li><li>CD5 modulators, such as CD5.28z CART cells;</li><li>Anti-CD22, such as anti-CD22 CART;</li><li>Anti-CD30, such as TT-11;</li><li>CD33, such as CIK-CAR.CD33, CD33CART;</li><li>Dual anti-CD33/anti-CLL1, such as LB-1910;</li><li>CD38, such as T-007, UCART-38;</li><li>CD40 ligand, such as BPX-201, MEDI5083;</li><li>CD56, such as allogeneic CD56-positive CD3-negative natural killer cells (myeloid malignancies);</li><li>CD19/CD7 modulator, such as GC-197;</li><li>T-cell antigen CD7 modulator, such as anti-CD7 CAR T-cell therapy (CD7-positive hematological malignancies);</li><li>CD123 modulator, such as UniCAR02-T-CD123;</li><li>Anti-CD276, such as anti-CD276 CART;</li><li>CEACAM protein 5 modulators, such as MG7-CART;</li><li>Claudin 6, such as CSG-002;</li><li>Claudin 18.2, such as LB-1904;</li><li>Chlorotoxin, such as CLTX-CART;</li><li>EBV targeted, such as CMD-003;</li><li>MUC16EGFR, such as autologous 4H11-28z/fIL-12/EFGRt T cell;</li><li>Endonuclease, such as PGN-514, PGN-201;</li><li>Epstein-Barr virus specific T-lymphocytes, such as TT-10;</li><li>Epstein-Barr nuclear antigen 1/Latent membrane protein 1/Secreted protein BARF1 modulator, such as TT-10X;</li><li>Erbb2, such as CST-102, CIDeCAR;</li><li>Ganglioside (GD2), such as 4SCAR-GD2;</li><li>Gamma delta T cells, such as ICS-200;</li><li>folate hydrolase 1 (FOLH1, Glutamate carboxypeptidase II, PSMA; NCBI Gene ID: 2346), such as CIK-CAR.PSMA, CART-PSMA-TGFβRDN, P-PSMA-101;</li><li>Glypican-3(GPC3), such as TT-16, GLYCAR;</li><li>Hemoglobin, such as PGN-236;</li><li>Hepatocyte growth factor receptor, such as anti-cMet RNA CAR T;</li><li>HLA class I antigen A-2 alpha modulator, such as FH-MCVA2TCR;</li><li>HLA class I antigen A-2 alpha/Melanoma associated antigen 4 modulator, such as ADP-A2M4CD8;</li><li>HLA antigen modulator, such as FIT-001, NeoTCR-P1;</li><li>Human papillomavirus E7 protein, such as KITE-439. See, for example, <patcit id="pcit0280" dnum="US2015033129W"><text>PCT/US2015/033129</text></patcit>;</li><li>ICAM-1 modulator, such as AIC-100;</li><li>Immunoglobulin gamma Fc receptor III, such as ACTR087;</li><li>IL-12, such as DC-RTS-IL-12;</li><li>IL-12 agonist/mucin 16, such as JCAR-020;</li><li>IL-13 alpha 2, such as MB-101;</li><li>IL-15 receptor agonist, such as PRGN-3006, ALT-803; interleukin-15/Fc fusion protein (e.g., XmAb24306); recombinant interleukin-15 (e.g., AM0015, NIZ-985); pegylated IL-15 (e.g., NKTR-255);</li><li>IL-2, such as CST-101;</li><li>Interferon alpha ligand, such as autologous tumor cell vaccine + systemic CpG-B + IFN-alpha (cancer);</li><li>K-Ras GTPase, such as anti-KRAS G12V mTCR cell therapy;</li><li>Neural cell adhesion molecule L1 L1CAM (CD171), such as JCAR-023;</li><li>Latent membrane protein 1/Latent membrane protein 2, such as Ad5f35-LMPd1-2-transduced autologous dendritic cells;</li><li>MART-1 melanoma antigen modulator, such as MART-1 F5 TCR engineered PBMC;</li><li>Melanoma associated antigen 10, such as MAGE-A10C796T MAGE-A10 TCR;</li><li>Melanoma associated antigen 3/ Melanoma associated antigen 6 (MAGE A3/A6) such as KITE-718 (see, for example, <patcit id="pcit0281" dnum="US2013059608W"><text>PCT/US2013/059608</text></patcit>);</li><li>Mesothelin, such as CSG-MESO, TC-210;</li><li>Mucin 1 modulator, such as ICTCAR-052, Tn MUC-1 CAR-T, ICTCAR-053;</li><li>Anti-MICA/MICB, such as CYAD-02;</li><li>NKG2D, such as NKR-2;</li><li>Ntrkr1 tyrosine kinase receptor, such as JCAR-024;</li><li>PRAMET cell receptor, such as BPX-701;</li><li>Prostate stem cell antigen modulator, such as MB-105;</li><li>Roundabout homolog 1 modulator, such as ATCG-427;</li><li>Peptidoglycan recognition protein modulator, such as Tag-7 gene modified autologous tumor cell vaccine;</li><li>PSMA, such as PSMA-CAR T-cell therapy (lentiviral vector, castrate-resistant prostate cancer);</li><li>SLAM family member 7 modulator, such as IC9-Luc90-CD828Z;</li><li>TGF beta receptor modulator, such as DNR.NPC T-cells;</li><li>T-lymphocyte, such as TT-12;</li><li>T-lymphocyte stimulator, such as ATL-001;</li><li>TSH receptor modulator, such as ICTCAR-051;</li><li>Tumor infiltrating lymphocytes, such as LN-144, LN-145; and/or</li><li>Wilms tumor protein, such as JTCR-016, WT1-CTL.</li></ul>

Agonists of fins related receptor tyrosine kinase 3 (FLT3)

0375In some embodiments, a compound as described herein, is combined with an agonist of fins related receptor tyrosine kinase 3 (FLT3); FLK2; STK1; CD135; FLK-2; NCBI Gene ID: 2322). Examples of FLT3 agonists include CDX-301 and GS-3583.

MCL1 apoptosis regulator. BCL2 family member (MCL1) Inhibitors

0376In some embodiments, a compound as described herein, is combined with an inhibitor of MCL1 apoptosis regulator, BCL2 family member (MCL1, TM; EAT; MCL1L; MCL1S; Mcl-1; BCL2L3; MCL1-ES; bcl2-L-3; mcl1/EAT; NCBI Gene ID: 4170). Examples of MCL1 inhibitors include AMG-176, AMG-397, S-64315, and AZD-5991, 483-LM, A-1210477, UMI-77, JKY-5-037, and those described in <patcit id="pcit0282" dnum="WO2018183418A"><text>WO2018183418</text></patcit>, <patcit id="pcit0283" dnum="WO2016033486A"><text>WO2016033486</text></patcit>, <patcit id="pcit0284" dnum="WO2019222112A"><text>WO2019222112</text></patcit> and <patcit id="pcit0285" dnum="WO2017147410A"><text>WO2017147410</text></patcit>.

Cytokine inducible SH2 containing protein (CISH) Inhibitors

0377In some embodiments, a compound as described herein, is combined with an inhibitor of cytokine inducible SH2 containing protein (CISH; CIS; G18; SOCS; CIS-1; BACTS2; NCBI Gene ID: 1154). Examples of CISH inhibitors include those described in <patcit id="pcit0286" dnum="WO2017100861A"><text>WO2017100861</text></patcit>, <patcit id="pcit0287" dnum="WO2018075664A"><text>WO2018075664</text></patcit> and <patcit id="pcit0288" dnum="WO2019213610A"><text>WO2019213610</text></patcit>.

Gene Editors

0378In some embodiments, a compound as described herein, is combined with gene editor. Illustrative gene editing system that can be co-administered include without limitation a CRISPR/Cas9 system, a zinc finger nuclease system, a TALEN system, a homing endonucleases system (e.g., an ARCUS), and a homing meganuclease system.

Others drugs with unspecified targets

0379In some embodiments, a compound as described herein, is combined with human immunoglobulin (10% liquid formulation), Cuvitru (human immunoglobulin (20% solution), levofolinate disodium, IMSA-101, BMS-986288, IMUNO BGC Moreau RJ, R-OKY-034F, GP-2250, AR-23, calcium levofolinate, porfimer sodium, RG6160, ABBV-155, CC-99282, polifeprosan 20 with carmustine, Veregen, gadoxetate disodium, gadobutrol, gadoterate meglumine, gadoteridol, 99mTc-sestamibi, pomalidomide, pacibanil, or valrubicin.

2. Human Immunodeficiency Virus (HIV)

0380In some embodiments, the additional therapeutic agent may be an anti-HIV agent. In some instances, the additional therapeutic agent can be HIV protease inhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, HIV capsid inhibitors, HIV Tat or Rev inhibitors, immunomodulators, immunotherapeutic agents, antibody-drug conjugates, gene modifiers, gene editors (such as CRISPR/Cas9, zinc finger nucleases, homing nucleases, synthetic nucleases, TALENs), cell therapies (such as chimeric antigen receptor T-cell, CAR-T, and engineered T-cell receptors, TCR-T, autologous T-cell therapies, engineered B cells), latency reversing agents, , immune-based therapies, phosphatidylinositol 3-kinase (PI3K) inhibitors, HIV antibodies, bispecific antibodies and "antibody-like" therapeutic proteins, HIV p17 matrix protein inhibitors, IL-13 antagonists, peptidyl-prolyl cis-trans isomerase A modulators, protein disulfide isomerase inhibitors, complement C5a receptor antagonists, DNA methyltransferase inhibitor, HIV vif gene modulators, Vif dimerization antagonists, HIV-1 viral infectivity factor inhibitors, , HIV-1 Nef modulators, Hck tyrosine kinase modulators, mixed lineage kinase-3 (MLK-3) inhibitors, HIV-1 splicing inhibitors, integrin antagonists, nucleoprotein inhibitors, splicing factor modulators, COMM domain containing protein 1 modulators, HIV ribonuclease H inhibitors, retrocyclin modulators, CDK-9 inhibitors, dendritic ICAM-3 grabbing nonintegrin 1 inhibitors, HIV GAG protein inhibitors, HIV POL protein inhibitors, Complement Factor H modulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclin dependent kinase inhibitors, proprotein convertase PC9 stimulators, ATP dependent RNA helicase DDX3X inhibitors, reverse transcriptase priming complex inhibitors, G6PD and NADH-oxidase inhibitors, pharmacokinetic enhancers, HIV gene therapy, HIV vaccines, and combinations thereof.

0381In some embodiments, the additional therapeutic agent is selected from the group consisting of combination drugs for HIV, other drugs for treating HIV, HIV protease inhibitors, HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry (fusion) inhibitors, HIV maturation inhibitors, latency reversing agents, capsid inhibitors, immune-based therapies, PI3K inhibitors, HIV antibodies, and bispecific antibodies, and "antibody-like" therapeutic proteins, and combinations thereof.

3. Hepatitis B Virus

0382In some embodiments, a compound of the present disclosure, or pharmaceutically acceptable salt thereof, is combined with one, two, three, four or more additional therapeutic agents selected from HBV combination drugs, HBV vaccines, HBV DNA polymerase inhibitors, immunomodulators, toll-like receptor (TLR) modulators, interferon alpha receptor ligands, hyaluronidase inhibitors, hepatitis b core antigen (HBcAg) inhibitors, hepatitis b surface antigen (HBsAg) inhibitors, cytotoxic T-lymphocyte-associated protein 4 (ipi4) inhibitors, cyclophilin inhibitors, HBV viral entry inhibitors, antisense oligonucleotide targeting viral mRNA, short interfering RNAs (siRNA)and ddRNAi, endonuclease modulators, ribonucelotide reductase inhibitors, HBV E antigen inhibitors, covalently closed circular DNA (cccDNA) inhibitors, farnesoid X receptor agonists, STING agonists, anti-HBV antibodies, CCR2 chemokine antagonists, thymosin agonists, cytokines, nucleoprotein modulators, retinoic acid-inducible gene 1 stimulators, NOD2 stimulators, phosphatidylinositol 3-kinase (PI3K) inhibitors, indoleamine-2, 3-dioxygenase (IDO) pathway inhibitors, PD-1 inhibitors, PD-L1 inhibitors, recombinant thymosin alpha-1, bruton's tyrosine kinase (BTK) inhibitors, KDM inhibitors, HBV replication inhibitors, arginase inhibitors, gene therapy and cell therapy, gene editors, CAR-T cell therapy, TCR-T cell therapy, and other HBV drugs.

0383In some embodiments, a compound of the present disclosure, or pharmaceutically acceptable salt thereof, may be used or combined with one or more of a chemotherapeutic agent, an immunomodulator, an immunotherapeutic agent, a therapeutic antibody, a therapeutic vaccine, a bispecific antibody and "antibody-like" therapeutic protein (such as DARPins^®, anti-pMHC TCR-like antibodies, DARTs^®, Duobodies^®, Bites^®, XmAbs^®, TandAbs^®, Fab derivatives), an antibody-drug conjugate (ADC), gene modifiers or gene editors (such as CRISPR Cas9, zinc finger nucleases, homing endonucleases, homing meganucleases (<i>e</i>.<i>g</i>., ARCUS), synthetic nucleases, TALENs), cell therapies such as CAR-T (chimeric antigen receptor T-cell), and TCR-T (an engineered T cell receptor) agent or any combination thereof.

0384In some embodiments, an agent as described herein, is combined with one, two, three, four or more additional therapeutic agents, <i>e.g</i>., as 3-dioxygenase (IDO) inhibitors, apolipoprotein A1 modulator, arginase inhibitors, B- and T-lymphocyte attenuator inhibitors, Bruton's tyrosine kinase (BTK) inhibitors, CCR2 chemokine antagonist, CD 137 inhibitors, CD160 inhibitors, CD305 inhibitors, CD4 agonist and modulator, compounds targeting hepatitis B core antigen (HBcAg), core protein allosteric modulators, covalently closed circular DNA (cccDNA) inhibitors, cyclophilin inhibitors, cytotoxic T-lymphocyte-associated protein 4 (ipi4) inhibitors, DNA polymerase inhibitor, endonuclease modulators, epigenetic modifiers, Farnesoid X receptor agonists, HBV DNA polymerase inhibitors, HBV replication inhibitors, HBV RNAse inhibitors, HBV viral entry inhibitors, HBx inhibitors, Hepatitis B large envelope protein modulator, Hepatitis B large envelope protein stimulator, Hepatitis B structural protein modulator, hepatitis B surface antigen (HBsAg) inhibitors, hepatitis B surface antigen (HBsAg) secretion or assembly inhibitors, hepatitis B virus E antigen inhibitors, hepatitis B virus replication inhibitors, Hepatitis virus structural protein inhibitor, HIV-1 reverse transcriptase inhibitor, Hyaluronidase inhibitor, inhibitor of apoptosis proteins family proteins (IAPs) inhibitors, IL-2 agonist, IL-7 agonist, immunomodulators, indoleamine-2 inhibitors, inhibitors of ribonucleotide reductase, Interleukin-2 ligand, ipi4 inhibitors, lysine demethylase inhibitors, histone demethylase inhibitors, KDM1 inhibitors, KDM5 inhibitors, killer cell lectin-like receptor subfamily G member 1 inhibitors, lymphocyte-activation gene 3 inhibitors, lymphotoxin beta receptor activators, modulators of Ax1, modulators of B7-H3, modulators of B7-H4, modulators of CD160, modulators of CD161, modulators of CD27, modulators of CD47, modulators of CD70, modulators of GITR, modulators of HEVEM, modulators of ICOS, modulators of Mer, modulators of NKG2A, modulators of NKG2D, modulators of OX40, modulators of SIRPalpha, modulators of TIGIT, modulators of Tim-4, modulators of Tyro, Na+-taurocholate cotransporting polypeptide (NTCP) inhibitors, natural killer cell receptor 2B4 inhibitors, NOD2 gene stimulator, Nucleoprotein inhibitor, nucleoprotein modulators, OX-40 receptor agonist, PD-1 inhibitors, PD-L1 inhibitors, peptidylprolyl isomerase inhibitor, phosphatidylinositol-3 kinase (PI3K) inhibitors, Retinoic acid-inducible gene 1 stimulator, Reverse transcriptase inhibitor, Ribonuclease inhibitor, RNA DNA polymerase inhibitor, SLC10A1 gene inhibitor, SMAC mimetics, Src tyrosine kinase inhibitor, stimulator of interferon gene (STING) agonists, stimulators of NOD1, T cell surface glycoprotein CD28 inhibitor, T-cell surface glycoprotein CD8 modulator, Thymosin agonist, Thymosin alpha 1 ligand, Tim-3 inhibitors, TLR-3 agonists, TLR-7 agonists, TLR-9 agonists, TLR9 agonists or gene stimulator, toll-like receptor (TLR) modulators, viral ribonucleotide reductase inhibitors, and combinations thereof.

B. Exemplified Combination Therapies

1. Cancer

Lymphoma or Leukemia Combination Therapy

0385Some chemotherapy agents are suitable for treating lymphoma or leukemia. These agents include aldesleukin, alvocidib, amifostine trihydrate, aminocamptothecin, antineoplaston A10, antineoplaston AS2-1, anti-thymocyte globulin, arsenic trioxide, Bcl-2 family protein inhibitor ABT-263, beta alethine, BMS-345541bortezomib (VELCADE^®, PS-341), bryostatin 1, bulsulfan, campath-1H, carboplatin, carfilzomib (Kyprolis^®), carmustine, caspofungin acetate, CC-5103, chlorambucil, CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), cisplatin, cladribine, clofarabine, curcumin, CVP (cyclophosphamide, vincristine, and prednisone), cyclophosphamide, cyclosporine, cytarabine, denileukin diftitox, dexamethasone, docetaxel, dolastatin 10, doxorubicin, doxorubicin hydrochloride, DT-PACE (dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, and etoposide), enzastaurin, epoetin alfa, etoposide, everolimus (RAD001), FCM (fludarabine, cyclophosphamide, and mitoxantrone), FCR (fludarabine, cyclophosphamide, and rituximab), fenretinide, filgrastim, flavopiridol, fludarabine, FR (fludarabine and rituximab), geldanamycin (17 AAG), hyperCVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone, methotrexate, and cytarabine), ICE (iphosphamide, carboplatin, and etoposide), ifosfamide, irinotecan hydrochloride, interferon alpha-2b, ixabepilone, lenalidomide (REVLIMID^®, CC-5013), pomalidomide (POMALYST^®/IMNOVID^®)lymphokine-activated killer cells, MCP (mitoxantrone, chlorambucil, and prednisolone), melphalan, mesna, methotrexate, mitoxantrone hydrochloride, motexafin gadolinium, mycophenolate mofetil, nelarabine, obatoclax (GX15-070), oblimersen, octreotide acetate, omega-3 fatty acids, Omr-IgG-am (WNIG, Omrix), oxaliplatin, paclitaxel, palbociclib (PD0332991), pegfilgrastim, PEGylated liposomal doxorubicin hydrochloride, perifosin, prednisolone, prednisone, recombinant flt3 ligand, recombinant human thrombopoietin, recombinant interferon alfa, recombinant interleukin-11, recombinant interleukin-12, rituximab, R-CHOP (rituximab and CHOP), R-CVP (rituximab and CVP), R-FCM (rituximab and FCM), R-ICE (rituximab and ICE), and R MCP (rituximab and MCP), R-roscovitine (seliciclib, CYC202), sargramostim, sildenafil citrate, simvastatin, sirolimus, styryl sulphones, tacrolimus, tanespimycin, temsirolimus (CCl-779), thalidomide, therapeutic allogeneic lymphocytes, thiotepa, tipifarnib, vincristine, vincristine sulfate, vinorelbine ditartrate, SAHA (suberanilohydroxamic acid, or suberoyl, anilide, and hydroxamic acid), vemurafenib (Zelboraf ^®), venetoclax (ABT-199).

0386One modified approach is radioimmunotherapy, wherein a monoclonal antibody is combined with a radioisotope particle, such as indium-111, yttrium-90, and iodine-131. Examples of combination therapies include, but are not limited to, iodine-131 tositumomab (BEXXAR^®), yttrium-90 ibritumomab tiuxetan (ZEVALIN^®), and BEXXAR^® with CHOP.

0387The abovementioned therapies can be supplemented or combined with stem cell transplantation or treatment. Therapeutic procedures include peripheral blood stem cell transplantation, autologous hematopoietic stem cell transplantation, autologous bone marrow transplantation, antibody therapy, biological therapy, enzyme inhibitor therapy, total body irradiation, infusion of stem cells, bone marrow ablation with stem cell support, in vitro-treated peripheral blood stem cell transplantation, umbilical cord blood transplantation, immunoenzyme technique, low-LET cobalt-60 gamma ray therapy, bleomycin, conventional surgery, radiation therapy, and nonmyeloablative allogeneic hematopoietic stem cell transplantation.

Non-Hodgkin's Lymphomas Combination Therapy

0388Treatment of non-Hodgkin's lymphomas (NHL), especially those of B cell origin, includes using monoclonal antibodies, standard chemotherapy approaches (e.g., CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), CVP (cyclophosphamide, vincristine, and prednisone), FCM (fludarabine, cyclophosphamide, and mitoxantrone), MCP (Mitoxantrone, Chlorambucil, Prednisolone), all optionally including rituximab (R) and the like), radioimmunotherapy, and combinations thereof, especially integration of an antibody therapy with chemotherapy.

0389Examples of unconjugated monoclonal antibodies for the treatment of NHL/B-cell cancers include rituximab, alemtuzumab, human or humanized anti-CD20 antibodies, lumiliximab, anti-TNF-related apoptosis-inducing ligand (anti-TRAIL), bevacizumab, galiximab, epratuzumab, SGN-40, and anti-CD74.

0390Examples of experimental antibody agents used in treatment of NHL/B-cell cancers include ofatumumab, ha20, PRO131921, alemtuzumab, galiximab, SGN-40, CHIR-12.12, epratuzumab, lumiliximab, apolizumab, milatuzumab, and bevacizumab.

0391Examples of standard regimens of chemotherapy for NHL/B-cell cancers include CHOP, FCM, CVP, MCP, R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), R-FCM, R-CVP, and R MCP.

0392Examples of radioimmunotherapy for NHL/B-cell cancers include yttrium-90 ibritumomab tiuxetan (ZEVALIN^®) and iodine-131 tositumomab (BEXXAR^®).

Mantle Cell Lymphoma Combination Therapy

0393Therapeutic treatments for mantle cell lymphoma (MCL) include combination chemotherapies such as CHOP, hyperCVAD, and FCM. These regimens can also be supplemented with the monoclonal antibody rituximab to form combination therapies R-CHOP, hyperCVAD-R, and R-FCM. Any of the abovementioned therapies may be combined with stem cell transplantation or ICE in order to treat MCL.

0394An alternative approach to treating MCL is immunotherapy. One immunotherapy uses monoclonal antibodies like rituximab. Another uses cancer vaccines, such as GTOP-99, which are based on the genetic makeup of an individual patient's tumor.

0395A modified approach to treat MCL is radioimmunotherapy, wherein a monoclonal antibody is combined with a radioisotope particle, such as iodine-131 tositumomab (BEXXAR^®) and yttrium-90 ibritumomab tiuxetan (ZEVALIN^®). In another example, BEXXAR^® is used in sequential treatment with CHOP.

0396Other approaches to treating MCL include autologous stem cell transplantation coupled with high-dose chemotherapy, administering proteasome inhibitors such as bortezomib (VELCADE^® or PS-341), or administering antiangiogenesis agents such as thalidomide, especially in combination with rituximab.

0397Another treatment approach is administering drugs that lead to the degradation of Bcl-2 protein and increase cancer cell sensitivity to chemotherapy, such as oblimersen, in combination with other chemotherapeutic agents.

0398A further treatment approach includes administering mTOR inhibitors, which can lead to inhibition of cell growth and even cell death. Non-limiting examples are sirolimus, temsirolimus (TORISEL^®, CCI-779), CC-115, CC-223, SF-1126, PQR-309 (bimiralisib), voxtalisib, GSK-2126458, and temsirolimus in combination with RITUXAN^®, VELCADE^®, or other chemotherapeutic agents.

0399Other recent therapies for MCL have been disclosed. Such examples include flavopiridol, palbociclib (PD0332991), R-roscovitine (selicicilib, CYC202), styryl sulphones, obatoclax (GX15-070), TRAIL, Anti-TRAIL death receptors DR4 and DR5 antibodies, temsirolimus (TORISEL^®, CCl-779), everolimus (RAD001), BMS-345541, curcumin, SAHA, thalidomide, lenalidomide (REVLIMID^®, CC-5013), and geldanamycin (17 AAG).

Waldenstrom's Macroglobulinemia Combination Therapy

0400Therapeutic agents used to treat Waldenstrom's Macroglobulinemia (WM) include aldesleukin, alemtuzumab, alvocidib, amifostine trihydrate, aminocamptothecin, antineoplaston A10, antineoplaston AS2-1, anti-thymocyte globulin, arsenic trioxide, autologous human tumor-derived HSPPC-96, Bcl-2 family protein inhibitor ABT-263, beta alethine, bortezomib (VELCADE^®), bryostatin 1, busulfan, campath-1H, carboplatin, carmustine, caspofungin acetate, CC-5103, cisplatin, clofarabine, cyclophosphamide, cyclosporine, cytarabine, denileukin diftitox, dexamethasone, docetaxel, dolastatin 10, doxorubicin hydrochloride, DT-PACE, enzastaurin, epoetin alfa, epratuzumab (hLL2- anti-CD22 humanized antibody), etoposide, everolimus, fenretinide, filgrastim, fludarabine, ibrutinib, ifosfamide, indium-111 monoclonal antibody MN-14, iodine-131 tositumomab, irinotecan hydrochloride, ixabepilone, lymphokine-activated killer cells, melphalan, mesna, methotrexate, mitoxantrone hydrochloride, monoclonal antibody CD19 (such as tisagenlecleucel-T, CART-19, CTL-019), monoclonal antibody CD20, motexafin gadolinium, mycophenolate mofetil, nelarabine, oblimersen, octreotide acetate, omega-3 fatty acids, oxaliplatin, paclitaxel, pegfilgrastim, PEGylated liposomal doxorubicin hydrochloride, pentostatin, perifosine, prednisone, recombinant flt3 ligand, recombinant human thrombopoietin, recombinant interferon alfa, recombinant interleukin-11, recombinant interleukin-12, rituximab, sargramostim, sildenafil citrate (VIAGRA^®), simvastatin, sirolimus, tacrolimus, tanespimycin, thalidomide, therapeutic allogeneic lymphocytes, thiotepa, tipifarnib, tositumomab, ulocuplumab, veltuzumab, vincristine sulfate, vinorelbine ditartrate, vorinostat, WT1 126-134 peptide vaccine, WT-1 analog peptide vaccine, yttrium-90 ibritumomab tiuxetan, yttrium-90 humanized epratuzumab, and any combination thereof.

0401Examples of therapeutic procedures used to treat WM include peripheral blood stem cell transplantation, autologous hematopoietic stem cell transplantation, autologous bone marrow transplantation, antibody therapy, biological therapy, enzyme inhibitor therapy, total body irradiation, infusion of stem cells, bone marrow ablation with stem cell support, in vitro-treated peripheral blood stem cell transplantation, umbilical cord blood transplantation, immunoenzyme techniques, low-LET cobalt-60 gamma ray therapy, bleomycin, conventional surgery, radiation therapy, and nonmyeloablative allogeneic hematopoietic stem cell transplantation.

Diffuse Large

B-cell

Lymphoma Combination Therapy

0402Therapeutic agents used to treat diffuse large B-cell lymphoma (DLBCL) include cyclophosphamide, doxorubicin, vincristine, prednisone, anti-CD20 monoclonal antibodies, etoposide, bleomycin, many of the agents listed for WM, and any combination thereof, such as ICE and R ICE.

Chronic Lymphocytic Leukemia Combination Therapy

0403Examples of therapeutic agents used to treat chronic lymphocytic leukemia (CLL) include chlorambucil, cyclophosphamide, fludarabine, pentostatin, cladribine, doxorubicin, vincristine, prednisone, prednisolone, alemtuzumab, many of the agents listed for WM, and combination chemotherapy and chemoimmunotherapy, including the following common combination regimens: CVP, R-CVP, ICE, R-ICE, FCR, and FR.

Myelofibrosis Combination Therapy

0404Myelofibrosis inhibiting agents include, but are not limited to, hedgehog inhibitors, histone deacetylase (HDAC) inhibitors, and tyrosine kinase inhibitors. Non-limiting examples of hedgehog inhibitors are saridegib and vismodegib. Examples of HDAC inhibitors include, but are not limited to, pracinostat and panobinostat. Non-limiting examples of tyrosine kinase inhibitors are lestaurtinib, bosutinib, imatinib, radotinib, and cabozantinib.

Hyperproliferative Disorder Combination Therapy

0405Gemcitabine, nab-paclitaxel, and gemcitabine/nab-paclitaxel may be used with a JAK inhibitor and/or PI3Kδ inhibitor to treat hyperproliferative disorders.

Bladder cancer combination therapy

0406Therapeutic agents used to treat bladder cancer include atezolizumab, carboplatin, cisplatin, docetaxel, doxorubicin, fluorouracil (5-FU), gemcitabine, idosfamide, Interferon alfa-2b, methotrexate, mitomycin, nab-paclitaxel, paclitaxel, pemetrexed, thiotepa, vinblastine , and any combination thereof.

Breast cancer combination therapy

0407Therapeutic agents used to treat breast cancer include albumin-bound paclitaxel, anastrozole, capecitabine, carboplatin, cisplatin, cyclophosphamide, docetaxel, doxorubicin, epirubicin, everolimus, exemestane, fluorouracil, fulvestrant, gemcitabine, Ixabepilone, lapatinib, Letrozole, methotrexate, mitoxantrone, paclitaxel, pegylated liposomal doxorubicin, pertuzumab, tamoxifen, toremifene, trastuzumab, vinorelbine, and any combinations thereof.

Triple negative breast cancer combination therapy

0408Therapeutic agents used to treat triple negative breast cancer include cyclophosphamide, docetaxel, doxorubicin, epirubicin, fluorouracil, paclitaxel, and combinations thereof.

Colorectal cancer combination therapy

0409Therapeutic agents used to treat colorectal cancer include bevacizumab, capecitabine, cetuximab, fluorouracil, irinotecan, leucovorin, oxaliplatin, panitumumab, ziv-aflibercept, and any combinations thereof.

Castration-resistant prostate cancer combination therapy

0410Therapeutic agents used to treat castration-resistant prostate cancer include abiraterone, cabazitaxel, docetaxel, enzalutamide, prednisone, sipuleucel-T, and any combinations thereof.

Esophageal and esophagogastric junction cancer combination therapy

0411Therapeutic agents used to treat esophageal and esophagogastric junction cancer include capecitabine, carboplatin, cisplatin, docetaxel, epirubicin, fluoropyrimidine, fluorouracil, irinotecan, leucovorin, oxaliplatin, paclitaxel, ramucirumab, trastuzumab, and any combinations thereof.

Gastric cancer combination therapy

0412Therapeutic agents used to treat gastric cancer include capecitabine, carboplatin, cisplatin, docetaxel, epirubicin, fluoropyrimidine, fluorouracil, Irinotecan, leucovorin, mitomycin, oxaliplatin, paclitaxel, ramucirumab, trastuzumab, and any combinations thereof.

Head and neck cancer combination therapy

0413Therapeutic agents used to treat head &amp; neck cancer include afatinib, bleomycin, capecitabine, carboplatin, cetuximab, cisplatin, docetaxel, fluorouracil, gemcitabine, hydroxyurea, methotrexate, nivolumab, paclitaxel, pembrolizumab, vinorelbine, and any combinations thereof.

Hepatobiliary cancer combination therapy

0414Therapeutic agents used to treat hepatobiliary cancer include capecitabine, cisplatin, fluoropyrimidine, 5-fluorourcil, gemecitabine, oxaliplatin, sorafenib, and any combinations thereof.

Hepatocellular carcinoma combination therapy

0415Therapeutic agents used to treat hepatocellular carcinoma include capecitabine, doxorubicin, gemcitabine, sorafenib, and any combinations thereof.

Non-small cell lung cancer combination therapy

0416Therapeutic agents used to treat non-small cell lung cancer (NSCLC) include afatinib, albumin-bound paclitaxel, alectinib, bevacizumab, bevacizumab, cabozantinib, carboplatin, cisplatin, crizotinib, dabrafenib, docetaxel, erlotinib, etoposide, gemcitabine, nivolumab, paclitaxel, pembrolizumab, pemetrexed, ramucirumab, trametinib, trastuzumab, vandetanib, vemurafenib, vinblastine, vinorelbine, and any combinations thereof.

Small cell lung cancer combination therapy

0417Therapeutic agents used to treat small cell lung cancer (SCLC) include bendamustine, carboplatin, cisplatin, cyclophosphamide, docetaxel, doxorubicin, etoposide, gemcitabine, ipilimumab, irinotecan, nivolumab, paclitaxel, temozolomide, topotecan, vincristine, vinorelbine, and any combinations thereof.

Melanoma combination therapy

0418Therapeutic agents used to treat melanoma cancer include albumin bound paclitaxel, carboplatin, cisplatin, cobiemtinib, dabrafenib, dacrabazine, IL-2, imatinib, interferon alfa-2b, ipilimumab, nitrosourea, nivolumab, paclitaxel, pembrolizumab, pilimumab, temozolomide, trametinib, vemurafenib, vinblastine, and any combinations thereof.

Ovarian cancer combination therapy

0419Therapeutic agents used to treat ovarian cancer include 5-flourouracil, albumin bound paclitaxel, altretamine, anastrozole, bevacizumab, capecitabine, carboplatin, cisplatin, cyclophosphamide, docetaxel, doxorubicin, etoposide, exemestane, gemcitabine, ifosfamide, irinotecan, letrozole, leuprolide acetate, liposomal doxorubicin, megestrol acetate, melphalan, olaparib, oxaliplatin, paclitaxel, Pazopanib, pemetrexed, tamoxifen, topotecan, vinorelbine, and any combinations thereof.

Pancreatic cancer combination therapy

0420Therapeutic agents used to treat pancreatic cancer include 5-fluorourcil, albumin-bound paclitaxel, capecitabine, cisplatin, docetaxel, erlotinib, fluoropyrimidine, gemcitabine, irinotecan, leucovorin, oxaliplatin, paclitaxel, and any combinations thereof.

Renal cell carcinoma combination therapy

0421Therapeutic agents used to treat renal cell carcinoma include axitinib, bevacizumab, cabozantinib, erlotinib, everolimus, levantinib, nivolumab, pazopanib, sorafenib, sunitinib, temsirolimus, and any combinations thereof.

Serum Half-Life-Extending Fc Mutations

0422In some embodiments, the Fc region or Fc domain of the directed antibody comprise amino acid modifications that promote an increased serum half-life of the anti- binding molecule. Mutations that increase the half-life of an antibody have been described. In one embodiment, the Fc region or Fc domain of one or both of the CD3-targeting heavy chain and the HIV antigen-targeting heavy chain comprise a methionine to tyrosine substitution at position 252 (EU numbering), a serine to threonine substitution at position 254 (EU numbering), and a threonine to glutamic acid substitution at position 256 (EU numbering). See, <i>e.g.,</i><patcit id="pcit0289" dnum="US7658921B"><text>U.S. Patent No. 7,658,921</text></patcit>. This type of mutant, designated as a "YTE mutant" exhibits a four-fold increased half-life relative to wild-type versions of the same antibody (<nplcit id="ncit0039" npl-type="s"><text>Dall'Acqua, et al., J Biol Chem, 281: 23514-24 (2006</text></nplcit>); <nplcit id="ncit0040" npl-type="s"><text>Robbie, et al., Antimicrob Agents Chemotherap., 57(12):6147-6153 (2013</text></nplcit>)). In certain embodiments, the Fc region or Fc domain of one or both of the CD3-targeting heavy chain and the HIV antigen-targeting heavy chain comprise an IgG constant domain comprising one, two, three or more amino acid substitutions of amino acid residues at positions 251-257, 285-290, 308-314, 385-389, and 428-436 (EU numbering). Alternatively, M428L and N434S ("LS") substitutions can increase the pharmacokinetic half-life of the multi-specific antigen binding molecule. In other embodiments, the Fc region or Fc domain of one or both of the CD3-targeting heavy chain and the HIV antigen-targeting heavy chain comprise a M428L and N434S substitution (EU numbering). In other embodiments, the Fc region or Fc domain of one or both of the CD3-targeting heavy chain and the HIV antigen-targeting heavy chain comprise T250Q and M428L (EU numbering) mutations. In other embodiments, the Fc region or Fc domain of one or both of the CD3-targeting heavy chain and the HIV antigen-targeting heavy chain comprise H433K and N434F (EU numbering) mutations.

Effector Enhancing Fc Mutations

0423In some embodiments, the Fc region or Fc domain of the antibody comprise post-translational and/or amino acid modifications that increase effector activity, <i>e.g</i>., have improved FcyIIIa binding and increased antibody-dependent cellular cytotoxicity (ADCC). In some embodiments, the Fc region or Fc domain of the antibody comprises DE modifications (<i>i.e.,</i> S239D and I332E by EU numbering) in the Fc region. In some embodiments, the Fc region or Fc domain of the antibody comprises DEL modifications (<i>i.e.,</i> S239D, I332E and A330L by EU numbering) in the Fc region. In some embodiments, the Fc region or Fc domain of the antibody comprises DEA modifications (<i>i.e.,</i> S239D, I332E and G236A by EU numbering) in the Fc region. In some embodiments, the Fc region or Fc domain of the antibody comprises DEAL modifications <i>(i.e.,</i> S239D, I332E, G236A and A330L by EU numbering) in the Fc region. <i>See, e.g.,</i><patcit id="pcit0290" dnum="US7317091B"><text>U.S. Patent Nos. 7,317,091</text></patcit>; <patcit id="pcit0291" dnum="US7662925B"><text>7,662,925</text></patcit>; <patcit id="pcit0292" dnum="US8039592B"><text>8,039,592</text></patcit>; <patcit id="pcit0293" dnum="US8093357B"><text>8,093,357</text></patcit>; <patcit id="pcit0294" dnum="US8093359B"><text>8,093,359</text></patcit>; <patcit id="pcit0295" dnum="US8383109B"><text>8,383,109</text></patcit>; <patcit id="pcit0296" dnum="US8388955B"><text>8,388,955</text></patcit>; <patcit id="pcit0297" dnum="US8735545B"><text>8,735,545</text></patcit>; <patcit id="pcit0298" dnum="US8858937B"><text>8,858,937</text></patcit>; <patcit id="pcit0299" dnum="US8937158B"><text>8,937,158</text></patcit>; <patcit id="pcit0300" dnum="US9040041B"><text>9,040,041</text></patcit>; <patcit id="pcit0301" dnum="US9353187B"><text>9,353,187</text></patcit>; <patcit id="pcit0302" dnum="US10184000B"><text>10,184,000</text></patcit>; and <patcit id="pcit0303" dnum="US10584176B"><text>10,584,176</text></patcit>. Additional amino acid modifications that increase effector activity, e.g., have improved FcyIIIa binding and increased antibody-dependent cellular cytotoxicity (ADCC) include without limitation (EU numbering) F243L/R292P/Y300L/V305I/P396L; S298A/E333A/K334A; or L234Y/L235Q/G236W/S239M/H268D/D270E/S298A on a first Fc domain and D270E/K326D/A330M/K334E on a second Fc domain. Amino acid mutations that increase C1q binding and complement-dependent cytotoxicity (CDC) include without limitation (EU numbering) S267E/H268F/S324T or K326W/E333S. Fc region mutations that enhance effector activity are reviewed in, <i>e.g.,</i><nplcit id="ncit0041" npl-type="s"><text>Wang, et al., Protein Cell (2018) 9(1): 63-73</text></nplcit>; and <nplcit id="ncit0042" npl-type="s"><text>Saunders, Front Immunol. (2019) 10:1296</text></nplcit>.

0424In other embodiments, the antibody or antigen-binding fragment thereof has modified glycosylation, which, e.g., may be introduced post-translationally or through genetic engineering. In some embodiments, the antibody or antigen-binding fragment thereof is afucosylated, e.g., at a glycosylation site present in the antibody or antigen-binding fragment thereof. Most approved monoclonal antibodies are of the IgG1 isotype, where two N-linked biantennary complex-type oligosaccharides are bound to the Fc region. The Fc region exercises the effector function of ADCC through its interaction with leukocyte receptors of the FcyR family. Afucosylated monoclonal antibodies are monoclonal antibodies engineered so that the oligosaccharides in the Fc region of the antibody do not have any fucose sugar units.

2. Human

Immunodeficiency Virus (HIV)

0425In some embodiments, the agents described herein are combined with an HIV combination drug. Examples of combination drugs that can be employed with an agent of this disclosure include ATRIPLA^® (efavirenz, tenofovir disoproxil fumarate, and emtricitabine); COMPLERA^® (EVIPLERA^®; rilpivirine, tenofovir disoproxil fumarate, and emtricitabine); STRIBILD^® (elvitegravir, cobicistat, tenofovir disoproxil fumarate, and emtricitabine); TRUVADA^® (tenofovir disoproxil fumarate and emtricitabine; TDF+FTC); DESCOVY^® (tenofovir alafenamide and emtricitabine); ODEFSEY^® (tenofovir alafenamide, emtricitabine, and rilpivirine); GENVOYA^® (tenofovir alafenamide, emtricitabine, cobicistat, and elvitegravir); darunavir, tenofovir alafenamide hemifumarate, emtricitabine, and cobicistat; efavirenz, lamivudine, and tenofovir disoproxil fumarate; lamivudine and tenofovir disoproxil fumarate; tenofovir and lamivudine; tenofovir alafenamide and emtricitabine ;tenofovir alafenamide hemifumarate and emtricitabine; tenofovir alafenamide hemifumarate, emtricitabine, and rilpivirine; tenofovir alafenamide hemifumarate, emtricitabine, cobicistat, and elvitegravir; COMBIVIR^® (zidovudine and lamivudine; AZT+3TC); EPZICOM^® (LIVEXA^®; abacavir sulfate and lamivudine; ABC+3TC); KALETRA^® (ALUVIA^®; lopinavir and ritonavir); TRIUMEQ^® (dolutegravir, abacavir, and lamivudine); BIKTARVY (bictegravir + emtricitabine + tenofovir alafenamide), DOVATO, TRIZIVIR^® (abacavir sulfate, zidovudine, and lamivudine; ABC+AZT+3TC); atazanavir and cobicistat; atazanavir sulfate and cobicistat; atazanavir sulfate and ritonavir; darunavir and cobicistat; dolutegravir and rilpivirine; dolutegravir and rilpivirine hydrochloride; dolutegravir, abacavir sulfate, and lamivudine; lamivudine, nevirapine, and zidovudine; raltegravir and lamivudine; doravirine, lamivudine, and tenofovir disoproxil fumarate; doravirine, lamivudine, and tenofovir disoproxil; dolutegravir + lamivudine, lamivudine + abacavir + zidovudine, lamivudine + abacavir, lamivudine + tenofovir disoproxil fumarate, lamivudine + zidovudine + nevirapine, lopinavir + ritonavir, lopinavir + ritonavir + abacavir + lamivudine, lopinavir + ritonavir + zidovudine + lamivudine, tenofovir + lamivudine, and tenofovir disoproxil fumarate + emtricitabine + rilpivirine hydrochloride, lopinavir, ritonavir, zidovudine and lamivudine; cabotegravir + rilpivirine; elpida (elsulfavirine; VM-1500; VM-1500A).

0426Examples of other drugs for treating HIV that can be combined with an agent of this disclosure include acemannan, alisporivir, BanLec, deferiprone, Gamimune, metenkefalin, naltrexone, Prolastin, REP 9, RPI-MN, VSSP, H1viral, SB-728-T, 1,5-dicaffeoylquinic acid, rHIV7-shl-TAR-CCR5RZ, AAV-eCD4-Ig gene therapy, MazF gene therapy, BlockAide, ABX-464, AG-1105, APH-0812, BIT-225, CYT-107, HGTV-43, HPH-116, HS-10234, IMO-3100, IND-02, MK-1376, MK-2048, MK-4250, MK-8507, MK-8591, NOV-205, PA-1050040 (PA-040), PGN-007, SCY-635, SB-9200, SCB-719, TR-452, TEV-90110, TEV-90112, TEV-90111, TEV-90113, RN-18, Immuglo, and VIR-576.

HIV Protease Inhibitors

0427In some embodiments, the agents described herein are combined with an HIV protease inhibitor. Examples of HIV protease inhibitors that can be combined with an agent of this disclosure include amprenavir, atazanavir, brecanavir, darunavir, fosamprenavir, fosamprenavir calcium, indinavir, indinavir sulfate, lopinavir, nelfinavir, nelfinavir mesylate, ritonavir, saquinavir, saquinavir mesylate, tipranavir, DG-17, TMB-657 (PPL-100), T-169, BL-008, MK-8122, TMB-607, and TMC-310911.

HIV Reverse Transcriptase Inhibitors

0428In some embodiments, the agents described herein are combined with a non-nucleoside or non-nucleotide inhibitor. Examples of HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase that can be combined with an agent of this disclosure include dapivirine, delavirdine, delavirdine mesylate, doravirine, efavirenz, etravirine, lentinan, nevirapine, rilpivirine, ACC-007, AIC-292, KM-023, PC-1005, and elsulfavirine (VM-1500.).

0429In some embodiments, the agents described herein are combined with an HIV nucleoside or nucleotide inhibitor. Examples of HIV nucleoside or nucleotide inhibitors of reverse transcriptase that can be combined with an agent of this disclosure include adefovir, adefovir dipivoxil, azvudine, emtricitabine, tenofovir, tenofovir alafenamide, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, VIDEX^® and VIDEX EC^® (didanosine, ddl), abacavir, abacavir sulfate, alovudine, apricitabine, censavudine, didanosine, elvucitabine, festinavir, fosalvudine tidoxil, CMX-157, dapivirine, doravirine, etravirine, OCR-5753, tenofovir disoproxil orotate, fozivudine tidoxil, lamivudine, phosphazid, stavudine, zalcitabine, zidovudine, rovafovir etalafenamide (GS-9131), GS-9148, MK-8504, MK-8591, MK-8583, VM-2500 and KP-1461.

HIV Integrase Inhibitors

0430In some embodiments, the agents described herein are combined with an HIV integrase inhibitor. Examples of HIV integrase inhibitors that can be combined with an agent of this disclosure include elvitegravir, curcumin, derivatives of curcumin, chicoric acid, derivatives of chicoric acid, 3,5-dicaffeoylquinic acid, derivatives of 3,5-dicaffeoylquinic acid, aurintricarboxylic acid, derivatives of aurintricarboxylic acid, caffeic acid phenethyl ester, derivatives of caffeic acid phenethyl ester, tyrphostin, derivatives of tyrphostin, quercetin, derivatives of quercetin, raltegravir, dolutegravir, JTK-351, bictegravir, AVX-15567, cabotegravir (long-acting injectable), diketo quinolin-4-1 derivatives, integrase-LEDGF inhibitor, ledgins, M-522, M-532, NSC-310217, NSC-371056, NSC-48240, NSC-642710, NSC-699171, NSC-699172, NSC-699173, NSC-699174, stilbenedisulfonic acid, T-169, VM-3500 and cabotegravir.

0431In some embodiments, the agents described herein are combined with a HIV non-catalytic site, or allosteric, integrase inhibitor (NCINI). Examples of HIV non-catalytic site, or allosteric, integrase inhibitors (NCINI) that can be combined with an agent of this disclosure include CX-05045, CX-05168, and CX-14442.

HIV Entry Inhibitors

0432In some embodiments, the agents described herein are combined with an HIV entry inhibitor. Examples of HIV entry (fusion) inhibitors that can be combined with an agent of this disclosure include cenicriviroc, CCR5 inhibitors, gp41 inhibitors, CD4 attachment inhibitors, gp120 inhibitors, and CXCR4 inhibitors.

0433In some embodiments, the agents described herein are combined with a CCR5 inhibitor. Examples of CCR5 inhibitors that can be combined with an agent of this disclosure include aplaviroc, vicriviroc, maraviroc, cenicriviroc, leronlimab (PRO-140), adaptavir (RAP-101), nifeviroc (TD-0232), anti-GP120/CD4 or CCR5 bispecific antibodies, B-07, MB-66, polypeptide C25P, TD-0680, and vMIP (Haimipu).

0434In some embodiments, the agents described herein are combined with a gp41 inhibitor. Examples of gp41 inhibitors that can be combined with an agent of this disclosure include albuvirtide, enfuvirtide, BMS-986197, enfuvirtide biobetter, enfuvirtide biosimilar, HIV-1 fusion inhibitors (P26-Bapc), ITV-1, ITV-2, ITV-3, ITV-4, PIE-12 trimer and sifuvirtide.

0435In some embodiments, the agents are combined with a CD4 attachment inhibitor. Examples of CD4 attachment inhibitors that can be combined with an agent of this disclosure include ibalizumab and CADA analogs.

0436In some embodiments, the agents described herein are combined with a gp120 inhibitor. Examples of gp 120 inhibitors that can be combined with an agent of this disclosure include Radha-108 (receptol) 3B3-PE38, BanLec, bentonite-based nanomedicine, fostemsavir tromethamine, IQP-0831, and BMS-663068.

0437In some embodiments, the agent described herein are combined with a CXCR4 inhibitor. Examples of CXCR4 inhibitors that can be combined with an agent of this disclosure include plerixafor, ALT-1188, N15 peptide, and vMIP (Haimipu).

0438In some embodiments, the agents described herein are combined with a HIV maturation inhibitor. Examples of HIV maturation inhibitors that can be combined with an agent of this disclosure include BMS-955176, GSK-3640254 and GSK-2838232.

Latency Reversing Agents

0439In some embodiments, the agents described herein are combined with a latency reversing agent (LRA). Examples of latency reversing agents that can be combined with an agent of this disclosure include toll-like receptor (TLR) agonists (including TLR7 agonists, e.g., GS-9620), histone deacetylase (HDAC) inhibitors, proteasome inhibitors such as velcade, protein kinase C (PKC) activators, Smyd2 inhibitors, BET-bromodomain 4 (BRD4) inhibitors, ionomycin, IAP antagonists (inhibitor of apoptosis proteins, such as APG-1387, LBW-242), SMAC mimetics (including TL32711, LCL161, GDC-0917, HGS1029, AT-406), PMA, SAHA (suberanilohydroxamic acid, or suberoyl, anilide, and hydroxamic acid), NIZ-985, IL-15 modulating antibodies (including IL-15, IL-15 fusion proteins and IL-15 receptor agonists), JQ1, disulfiram, amphotericin B, and ubiquitin inhibitors such as largazole analogs, APH-0812, and GSK-343. Examples of PKC activators include indolactam, prostratin, ingenol B, and DAG-lactones.

Histone Deacetylase (HDAC) Inhibitors

0440In some embodiments, the agents as described herein are combined with an inhibitor of a histone deacetylase, e.g., histone deacetylase 9 (HDAC9, HD7, HD7b, HD9, HDAC, HDAC7, HDAC7B, HDAC9B, HDAC9FL, HDRP, MITR; Gene ID: 9734). Examples of HDAC inhibitors include without limitation, abexinostat, ACY-241, AR-42, BEBT-908, belinostat, CKD-581, CS-055 (HBI-8000), CUDC-907 (fimepinostat), entinostat, givinostat, mocetinostat, panobinostat, pracinostat, quisinostat (JNJ-26481585), resminostat, ricolinostat, romidepsin, SHP-141, valproic acid (VAL-001), vorinostat, tinostamustine, remetinostat, entinostat.

Capsid Inhibitor

0441In some embodiments, the agents described herein are combined with a capsid inhibitor. Examples of capsid inhibitors that can be combined with an agent of this disclosure include capsid polymerization inhibitors or capsid disrupting compounds, HIV nucleocapsid p7 (NCp7) inhibitors such as azodicarbonamide, HIV p24 capsid protein inhibitors, GS-6207, GS-CA1, AVI-621, AVI-101, AVI-201, AVI-301, and AVI-CAN1-15 series, and compounds described in this patent (GSK <patcit id="pcit0304" dnum="WO2019087016A"><text>WO2019/087016</text></patcit>)

Immune Checkpoint Modulators

0442In some embodiments, the agents as described herein, are combined with one or more blockers or inhibitors of inhibitory immune checkpoint proteins or receptors and/or with one or more stimulators, activators or agonists of one or more stimulatory immune checkpoint proteins or receptors. Blockade or inhibition of inhibitory immune checkpoints can positively regulate T-cell or NK cell activation and prevent immune escape of infected cells. Activation or stimulation of stimulatory immune check points can augment the effect of immune checkpoint inhibitors in infective therapeutics. In some embodiments, the immune checkpoint proteins or receptors regulate T cell responses <i>(e.g.,</i> reviewed in <nplcit id="ncit0043" npl-type="s"><text>Xu, et al., J Exp Clin Cancer Res. (2018) 37:110</text></nplcit>). In some embodiments, the immune checkpoint proteins or receptors regulate NK cell responses <i>(e.g.,</i> reviewed in <nplcit id="ncit0044" npl-type="s"><text>Davis, et al., Semin Immunol. (2017) 31:64-75</text></nplcit> and <nplcit id="ncit0045" npl-type="s"><text>Chiossone, et al., Nat Rev Immunol. (2018) 18(11):671-688</text></nplcit>).

0443Examples of immune checkpoint proteins or receptors include without limitation CD27, CD70; CD40, CD40LG; CD47, CD48 (SLAMF2), transmembrane and immunoglobulin domain containing 2 (TMIGD2, CD28H), CD84 (LY9B, SLAMF5), CD96, CD160, MS4A1 (CD20), CD244 (SLAMF4); CD276 (B7H3); V-set domain containing T cell activation inhibitor 1 (VTCN1, B7H4); V-set immunoregulatory receptor (VSIR, B7H5, VISTA); immunoglobulin superfamily member 11 (IGSF11, VSIG3); natural killer cell cytotoxicity receptor 3 ligand 1 (NCR3LG1, B7H6); HERV-H LTR-associating 2 (HHLA2, B7H7); inducible T cell co-stimulator (ICOS, CD278); inducible T cell costimulator ligand (ICOSLG, B7H2); TNF receptor superfamily member 4 (TNFRSF4, OX40); TNF superfamily member 4 (TNFSF4, OX40L); TNFRSF8 (CD30), TNFSF8 (CD30L); TNFRSF10A (CD261, DR4, TRAILR1), TNFRSF9 (CD137), TNFSF9 (CD137L); TNFRSF10B (CD262, DR5, TRAILR2), TNFRSF10 (TRAIL); TNFRSF14 (HVEM, CD270), TNFSF14 (HVEML); CD272 (B and T lymphocyte associated (BTLA)); TNFRSF17 (BCMA, CD269), TNFSF13B (BAFF); TNFRSF18 (GITR), TNFSF18 (GITRL); MHC class I polypeptide-related sequence A (MICA); MHC class I polypeptide-related sequence B (MICB); CD274 (CD274, PDL1, PD-L1); programmed cell death 1 (PDCD1, PD1, PD-1); cytotoxic T-lymphocyte associated protein 4 (CTLA4, CD152); CD80 (B7-1), CD28; nectin cell adhesion molecule 2 (NECTIN2, CD112); CD226 (DNAM-1); Poliovirus receptor (PVR) cell adhesion molecule (PVR, CD155); PVR related immunoglobulin domain containing (PVRIG, CD 112R); T cell immunoreceptor with Ig and ITIM domains (TIGIT); T cell immunoglobulin and mucin domain containing 4 (TIMD4; TIM4); hepatitis A virus cellular receptor 2 (HAVCR2, TIMD3, TIM3); galectin 9 (LGALS9); lymphocyte activating 3 (LAG3, CD223); signaling lymphocytic activation molecule family member 1 (SLAMF1, SLAM, CD150); lymphocyte antigen 9 (LY9, CD229, SLAMF3); SLAM family member 6 (SLAMF6, CD352); SLAM family member 7 (SLAMF7, CD319); UL16 binding protein 1 (ULBP1); UL16 binding protein 2 (ULBP2); UL16 binding protein 3 (ULBP3); retinoic acid early transcript 1E (RAET1E; ULBP4); retinoic acid early transcript 1G (RAET1G; ULBP5); retinoic acid early transcript 1L (RAET1L; ULBP6); lymphocyte activating 3 (CD223); killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 1 (KIR, CD158E1); killer cell lectin like receptor C1 (KLRC1, NKG2A, CD159A); killer cell lectin like receptor K1 (KLRK1, NKG2D, CD314); killer cell lectin like receptor C2 (KLRC2, CD159c, NKG2C); killer cell lectin like receptor C3 (KLRC3, NKG2E); killer cell lectin like receptor C4 (KLRC4, NKG2F); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 1 (KIR2DL1); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 3 (KIR2DL3); killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 1 (KIR3DL1); killer cell lectin like receptor D1 (KLRD1); and SLAM family member 7 (SLAMF7).

0444In some embodiments, the agents described herein, are combined with one or more blockers or inhibitors of one or more T-cell inhibitory immune checkpoint proteins or receptors. Illustrative T-cell inhibitory immune checkpoint proteins or receptors include without limitation CD274 (CD274, PDL1, PD-L1); programmed cell death 1 ligand 2 (PDCD1LG2, PD-L2, CD273); programmed cell death 1 (PDCD1, PD1, PD-1); cytotoxic T-lymphocyte associated protein 4 (CTLA4, CD 152); CD276 (B7H3); V-set domain containing T cell activation inhibitor 1 (VTCN1, B7H4); V-set immunoregulatory receptor (VSIR, B7H5, VISTA); immunoglobulin superfamily member 11 (IGSF11, VSIG3); TNFRSF14 (HVEM, CD270), TNFSF14 (HVEML); CD272 (B and T lymphocyte associated (BTLA)); PVR related immunoglobulin domain containing (PVRIG, CD1 12R); T cell immunoreceptor with Ig and ITIM domains (TIGIT); lymphocyte activating 3 (LAG3, CD223); hepatitis A virus cellular receptor 2 (HAVCR2, TIMD3, TIM3); galectin 9 (LGALS9); killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 1 (KIR, CD158E1); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 1 (KIR2DL1); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 3 (KIR2DL3); and killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 1 (KIR3DL1). In some embodiments, the agents, as described herein, are combined with one or more agonist or activators of one or more T-cell stimulatory immune checkpoint proteins or receptors. Illustrative T-cell stimulatory immune checkpoint proteins or receptors include without limitation CD27, CD70; CD40, CD40LG; inducible T cell costimulator (ICOS, CD278); inducible T cell costimulator ligand (ICOSLG, B7H2); TNF receptor superfamily member 4 (TNFRSF4, OX40); TNF superfamily member 4 (TNFSF4, OX40L); TNFRSF9 (CD137), TNFSF9 (CD137L); TNFRSF18 (GITR), TNFSF18 (GITRL); CD80 (B7-1), CD28; nectin cell adhesion molecule 2 (NECTIN2, CD112); CD226 (DNAM-1); CD244 (2B4, SLAMF4), Poliovirus receptor (PVR) cell adhesion molecule (PVR, CD155). <i>See, e.g.,</i><nplcit id="ncit0046" npl-type="s"><text>Xu, et al., J Exp Clin Cancer Res. (2018) 37:110</text></nplcit>.

0445In some embodiments, the agents as described herein, are combined with one or more blockers or inhibitors of one or more NK-cell inhibitory immune checkpoint proteins or receptors. Illustrative NK-cell inhibitory immune checkpoint proteins or receptors include without limitation killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 1 (KIR, CD158E1); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 1 (KIR2DL1); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 3 (KIR2DL3); killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 1 (KIR3DL1); killer cell lectin like receptor C1 (KLRC1, NKG2A, CD159A); and killer cell lectin like receptor D1 (KLRD1, CD94). In some embodiments, the agents as described herein, are combined with one or more agonist or activators of one or more NK-cell stimulatory immune checkpoint proteins or receptors. Illustrative NK-cell stimulatory immune checkpoint proteins or receptors include without limitation CD16, CD226 (DNAM-1); CD244 (2B4, SLAMF4); killer cell lectin like receptor K1 (KLRK1, NKG2D, CD314); SLAM family member 7 (SLAMF7). <i>See, e.g.,</i><nplcit id="ncit0047" npl-type="s"><text>Davis, et al., Semin Immunol. (2017) 31:64-75</text></nplcit>; <nplcit id="ncit0048" npl-type="s"><text>Fang, et al., Semin Immunol. (2017) 31:37-54</text></nplcit>; and <nplcit id="ncit0049" npl-type="s"><text>Chiossone, et al., Nat Rev Immunol. (2018) 18(11):671-688</text></nplcit>.

0446In some embodiments, the one or more immune checkpoint inhibitors comprises a proteinaceous (e.g., antibody or fragment thereof, or antibody mimetic) inhibitor of PD-L1 (CD274), PD-1 (PDCD1) or CTLA4. In some embodiments, the one or more immune checkpoint inhibitors comprises a small organic molecule inhibitor of PD-L1 (CD274), PD-1 (PDCD1) or CTLA4. In some embodiments, the small molecule inhibitor of CD274 or PDCD1 is selected from the group consisting of GS-4224, GS-4416, INCB086550 and MAX10181. In some embodiments, the small molecule inhibitor of CTLA4 comprises BPI-002.

0447Examples of inhibitors of CTLA4 that can be co-administered include without limitation ipilimumab, tremelimumab, BMS-986218, AGEN1181, AGEN1884, BMS-986249, MK-1308, REGN-4659, ADU-1604, CS-1002, BCD-145, APL-509, JS-007, BA-3071, ONC-392, AGEN-2041, JHL-1155, KN-044, CG-0161, ATOR-1144, PBI-5D3H5, BPI-002, as well as multi-specific inhibitors FPT-155 (CTLA4/PD-L1/CD28), PF-06936308 (PD-1/ CTLA4), MGD-019 (PD-1/CTLA4), KN-046 (PD-1/CTLA4), MEDI-5752 (CTLA4/PD-1), XmAb-20717 (PD-1/CTLA4), and AK-104 (CTLA4/PD-1).

0448Examples of inhibitors of PD-L1 (CD274) or PD-1 (PDCD1) that can be co-administered include without limitation pembrolizumab, nivolumab, cemiplimab, pidilizumab, AMP-224, MEDI0680 (AMP-514), spartalizumab, atezolizumab, avelumab, durvalumab, BMS-936559, CK-301, PF-06801591, BGB-A317 (tislelizumab), GLS-010 (WBP-3055), AK-103 (HX-008), AK-105, CS-1003, HLX-10, MGA-012, BI-754091, AGEN-2034, JS-001 (toripalimab), JNJ-63723283, genolimzumab (CBT-501), LZM-009, BCD-100, LY-3300054, SHR-1201, SHR-1210 (camrelizumab), Sym-021, ABBV-181, PD1-PIK, BAT-1306, (MSB0010718C), CX-072, CBT-502, TSR-042 (dostarlimab), MSB-2311, JTX-4014, BGB-A333, SHR-1316, CS-1001 (WBP-3155, KN-035, IBI-308 (sintilimab), HLX-20, KL-A167, STI-A1014, STI-A1015 (IMC-001), BCD-135, FAZ-053, TQB-2450, MDX1105-01, GS-4224, GS-4416, INCB086550, MAX10181, as well as multi-specific inhibitors FPT-155 (CTLA4/PD-L1/CD28), PF-06936308 (PD-1/ CTLA4), MGD-013 (PD-1/LAG-3), FS-118 (LAG-3/PD-L1) MGD-019 (PD-1/CTLA4), KN-046 (PD-1/CTLA4), MEDI-5752 (CTLA4/PD-1), RO-7121661 (PD-1/TIM-3), XmAb-20717 (PD-1/CTLA4), AK-104 (CTLA4/PD-1), M7824 (PD-L1/TGFβ-EC domain), CA-170 (PD-L1/VISTA), CDX-527 (CD27/PD-L1), LY-3415244 (TIM3/PDL1), and INBRX-105 (4-1BB/PDL1).

0449In some embodiments, the agents as described herein are combined with anti-TIGIT antibodies, such as BMS-986207, RG-6058, AGEN-1307

TNF Receptor Superfamily (TNFRSF) Member Agonists or Activators

0450In some embodiments, the agents as described herein are combined with an agonist of one or more TNF receptor superfamily (TNFRSF) members, e.g., an agonist of one or more of TNFRSF1A (NCBI Gene ID: 7132), TNFRSF1B (NCBI Gene ID: 7133), TNFRSF4 (OX40, CD134; NCBI Gene ID: 7293), TNFRSF5 (CD40; NCBI Gene ID: 958), TNFRSF6 (FAS, NCBI Gene ID: 355), TNFRSF7 (CD27, NCBI Gene ID: 939), TNFRSF8 (CD30, NCBI Gene ID: 943), TNFRSF9 (4-1BB, CD137, NCBI Gene ID: 3604), TNFRSF10A (CD261, DR4, TRAILR1, NCBI Gene ID: 8797), TNFRSF10B (CD262, DR5, TRAILR2, NCBI Gene ID: 8795), TNFRSF10C (CD263, TRAILR3, NCBI Gene ID: 8794), TNFRSF10D (CD264, TRAILR4, NCBI Gene ID: 8793), TNFRSF11A (CD265, RANK, NCBI Gene ID: 8792), TNFRSF11B (NCBI Gene ID: 4982), TNFRSF12A (CD266, NCBI Gene ID: 51330), TNFRSF13B (CD267, NCBI Gene ID: 23495), TNFRSF13C (CD268, NCBI Gene ID: 115650), TNFRSF16 (NGFR, CD271, NCBI Gene ID: 4804), TNFRSF17 (BCMA, CD269, NCBI Gene ID: 608), TNFRSF18 (GITR, CD357, NCBI Gene ID: 8784), TNFRSF19 (NCBI Gene ID: 55504), TNFRSF21 (CD358, DR6, NCBI Gene ID: 27242), and TNFRSF25 (DR3, NCBI Gene ID: 8718).

0451Example anti-TNFRSF4 (OX40) antibodies that can be co-administered include without limitation, MEDI6469, MEDI6383, MEDI0562 (tavolixizumab), MOXR0916, PF-04518600, RG-7888, GSK-3174998, INCAGN1949, BMS-986178, GBR-8383, ABBV-368, and those described in <patcit id="pcit0305" dnum="WO2016179517A"><text>WO2016179517</text></patcit>, <patcit id="pcit0306" dnum="WO2017096179A"><text>WO2017096179</text></patcit>, <patcit id="pcit0307" dnum="WO2017096182A"><text>WO2017096182</text></patcit>, <patcit id="pcit0308" dnum="WO2017096281A"><text>WO2017096281</text></patcit>, and <patcit id="pcit0309" dnum="WO2018089628A"><text>WO2018089628</text></patcit>.

0452Example anti-TNFRSF5 (CD40) antibodies that can be co-administered include without limitation RG7876, SEA-CD40, APX-005M and ABBV-428.

0453In some embodiments, the anti-TNFRSF7 (CD27) antibody varlilumab (CDX-1127) is co-administered.

0454Example anti-TNFRSF9 (4-1BB, CD137) antibodies that can be co-administered include without limitation urelumab, utomilumab (PF-05082566), AGEN2373 and ADG-106.

0455Example anti-TNFRSF18 (GITR) antibodies that can be co-administered include without limitation, MEDI1873, FPA-154, INCAGN-1876, TRX-518, BMS-986156, MK-1248, GWN-323, and those described in <patcit id="pcit0310" dnum="WO2017096179A"><text>WO2017096179</text></patcit>, <patcit id="pcit0311" dnum="WO2017096276A"><text>WO2017096276</text></patcit>, <patcit id="pcit0312" dnum="WO2017096189A"><text>WO2017096189</text></patcit>, and <patcit id="pcit0313" dnum="WO2018089628A"><text>WO2018089628</text></patcit>. In some embodiments, an antibody, or fragment thereof, co-targeting TNFRSF4 (OX40) and TNFRSF18 (GITR) is co-administered. Such antibodies are described, <i>e.g.,</i> in <patcit id="pcit0314" dnum="WO2017096179A"><text>WO2017096179</text></patcit> and <patcit id="pcit0315" dnum="WO2018089628A"><text>WO2018089628</text></patcit>.

Bi-and Tri-Specific Natural Killer (NK)-Cell Engagers

0456In some embodiments, the agents as described herein, are combined with a bi-specific NK-cell engager (BiKE) or a tri-specific NK-cell engager (TriKE) (<i>e.g.,</i> not having an Fc) or bi-specific antibody (<i>e.g.,</i> having an Fc) against an NK cell activating receptor, <i>e.g.,</i> CD16A, C-type lectin receptors (CD94/NKG2C, NKG2D, NKG2E/H and NKG2F), natural cytotoxicity receptors (NKp30, NKp44 and NKp46), killer cell C-type lectin-like receptor (NKp65, NKp80), Fc receptor FcyR (which mediates antibody-dependent cell cytotoxicity), SLAM family receptors (e.g., 2B4, SLAM6 and SLAM7), killer cell immunoglobulin-like receptors (KIR) (KIR-2DS and KIR-3DS), DNAM-1 and CD137 (41BB). As appropriate, the anti-CD16 binding bi-specific molecules may or may not have an Fc. Illustrative bi-specific NK-cell engagers that can be co-administered target CD 16 and one or more HIV-associated antigens as described herein. BiKEs and TriKEs are described, <i>e.g.,</i> in <nplcit id="ncit0050" npl-type="s"><text>Felices, et al., Methods Mol Biol. (2016) 1441:333-346</text></nplcit>; <nplcit id="ncit0051" npl-type="s"><text>Fang, et al., Semin Immunol. (2017) 31:37-54</text></nplcit>. Examples of a trispecific NK cell engager (TRiKE) include OXS-3550, and CD16-IL-15-B7H3 TriKe.

Indoleamine-pyrrole-2,3-dioxygenase (IDO1) inhibitors

0457In some embodiments, the agents as described herein, are combined with an inhibitor of indoleamine 2,3-dioxygenase 1 (IDO1; NCBI Gene ID: 3620). Examples of IDO1 inhibitors include without limitation, BLV-0801, epacadostat, F-001287, GBV-1012, GBV-1028, GDC-0919, indoximod, NKTR-218, NLG-919-based vaccine, PF-06840003, pyranonaphthoquinone derivatives (SN-35837), resminostat, SBLK-200802, BMS-986205, and shIDO-ST, EOS-200271, KHK-2455, LY-3381916.

Toll-Like Receptor (TLR) Agonists

0458In some embodiments, the agents as described herein, are combined with an agonist of a toll-like receptor (TLR), <i>e.g.,</i> an agonist of TLR1 (NCBI Gene ID: 7096), TLR2 (NCBI Gene ID: 7097), TLR3 (NCBI Gene ID: 7098), TLR4 (NCBI Gene ID: 7099), TLR5 (NCBI Gene ID: 7100), TLR6 (NCBI Gene ID: 10333), TLR7 (NCBI Gene ID: 51284), TLR8 (NCBI Gene ID: 51311), TLR9 (NCBI Gene ID: 54106), and/or TLR10 (NCBI Gene ID: 81793). Example TLR7 agonists that can be co-administered include without limitation AL-034, DSP-0509, GS-9620 (vesatolimod), LHC-165, TMX-101 (imiquimod), GSK-2245035, resiquimod, DSR-6434, DSP-3025, IMO-4200, MCT-465, MEDI-9197, 3M-051, SB-9922, 3M-052, Limtop, TMX-30X, TMX-202, RG-7863, RG-7854, RG-7795, and the compounds disclosed in <patcit id="pcit0316" dnum="US20100143301A"><text>US20100143301 (Gilead Sciences</text></patcit>), <patcit id="pcit0317" dnum="US20110098248A"><text>US20110098248 (Gilead Sciences</text></patcit>), and <patcit id="pcit0318" dnum="US20090047249A"><text>US20090047249 (Gilead Sciences</text></patcit>), <patcit id="pcit0319" dnum="US20140045849A"><text>US20140045849 (Janssen</text></patcit>), <patcit id="pcit0320" dnum="US20140073642A"><text>US20140073642 (Janssen</text></patcit>), <patcit id="pcit0321" dnum="WO2014056953A"><text>WO2014/056953 (Janssen</text></patcit>), <patcit id="pcit0322" dnum="WO2014076221A"><text>WO2014/076221 (Janssen</text></patcit>), <patcit id="pcit0323" dnum="WO2014128189A"><text>WO2014/128189 (Janssen</text></patcit>), <patcit id="pcit0324" dnum="US20140350031A"><text>US20140350031 (Janssen</text></patcit>), <patcit id="pcit0325" dnum="WO2014023813A"><text>WO2014/023813 (Janssen</text></patcit>), <patcit id="pcit0326" dnum="US20080234251A"><text>US20080234251 (Array Biopharma</text></patcit>), <patcit id="pcit0327" dnum="US20080306050A"><text>US20080306050 (Array Biopharma</text></patcit>), <patcit id="pcit0328" dnum="US20100029585A"><text>US20100029585 (Ventirx Pharma</text></patcit>), <patcit id="pcit0329" dnum="US20110092485A"><text>US20110092485 (Ventirx Pharma</text></patcit>), <patcit id="pcit0330" dnum="US20110118235A"><text>US20110118235 (Ventirx Pharma</text></patcit>), <patcit id="pcit0331" dnum="US20120082658A"><text>US20120082658 (Ventirx Pharma</text></patcit>), <patcit id="pcit0332" dnum="US20120219615A"><text>US20120219615 (Ventirx Pharma</text></patcit>), <patcit id="pcit0333" dnum="US20140066432A"><text>US20140066432 (Ventirx Pharma</text></patcit>), <patcit id="pcit0334" dnum="US20140088085A"><text>US20140088085 (Ventirx Pharma</text></patcit>), <patcit id="pcit0335" dnum="US20140275167A"><text>US20140275167 (Novira Therapeutics</text></patcit>), and <patcit id="pcit0336" dnum="US20130251673A"><text>US20130251673 (Novira Therapeutics</text></patcit>). An TLR7/TLR8 agonist that can be co-administered is NKTR-262, telratolimod and BDB-001. Example TLR8 agonists that can be co-administered include without limitation E-6887, IMO-4200, IMO-8400, IMO-9200, MCT-465, MEDI-9197, motolimod, resiquimod, GS-9688, VTX-1463, VTX-763, 3M-051, 3M-052, and the compounds disclosed in <patcit id="pcit0337" dnum="US20140045849A"><text>US20140045849 (Janssen</text></patcit>), <patcit id="pcit0338" dnum="US20140073642A"><text>US20140073642 (Janssen</text></patcit>), <patcit id="pcit0339" dnum="WO2014056953A"><text>WO2014/056953 (Janssen</text></patcit>), <patcit id="pcit0340" dnum="WO2014076221A"><text>WO2014/076221 (Janssen</text></patcit>), <patcit id="pcit0341" dnum="WO2014128189A"><text>WO2014/128189 (Janssen</text></patcit>), <patcit id="pcit0342" dnum="US20140350031A"><text>US20140350031 (Janssen</text></patcit>), <patcit id="pcit0343" dnum="WO2014023813A"><text>WO2014/023813 (Janssen</text></patcit>), <patcit id="pcit0344" dnum="US20080234251A"><text>US20080234251 (Array Biopharma</text></patcit>), <patcit id="pcit0345" dnum="US20080306050A"><text>US20080306050 (Array Biopharma</text></patcit>), <patcit id="pcit0346" dnum="US20100029585A"><text>US20100029585 (Ventirx Pharma</text></patcit>), <patcit id="pcit0347" dnum="US20110092485A"><text>US20110092485 (Ventirx Pharma</text></patcit>), <patcit id="pcit0348" dnum="US20110118235A"><text>US20110118235 (Ventirx Pharma</text></patcit>), <patcit id="pcit0349" dnum="US20120082658A"><text>US20120082658 (Ventirx Pharma</text></patcit>), <patcit id="pcit0350" dnum="US20120219615A"><text>US20120219615 (Ventirx Pharma</text></patcit>), <patcit id="pcit0351" dnum="US20140066432A"><text>US20140066432 (Ventirx Pharma</text></patcit>), <patcit id="pcit0352" dnum="US20140088085A"><text>US20140088085 (Ventirx Pharma</text></patcit>), <patcit id="pcit0353" dnum="US20140275167A"><text>US20140275167 (Novira Therapeutics</text></patcit>), and <patcit id="pcit0354" dnum="US20130251673A"><text>US20130251673 (Novira Therapeutics</text></patcit>). Example TLR9 agonists that can be co-administered include without limitation AST-008, cobitolimod, CMP-001, IMO-2055, IMO-2125, litenimod, MGN-1601, BB-001, BB-006, IMO-3100, IMO-8400, IR-103, IMO-9200, agatolimod, DIMS-9054, DV-1079, DV-1179, AZD-1419, lefitolimod (MGN-1703), CYT-003, CYT-003-QbG10, tilsotolimod and PUL-042. Examples of TLR3 agonist include rintatolimod, poly-ICLC, RIBOXXON^®, Apoxxim, RIBOXXIM^®, IPH-33, MCT-465, MCT-475, and ND-1.1. Examples of TLR4 agonist include G-100, and GSK-1795091.

STING agonists, RIG-I and NOD2 modulators

0459In some embodiments, the agents described herein are combined with a stimulator of interferon genes (STING). In some embodiments, the STING receptor agonist or activator is selected from the group consisting of ADU-S100 (MIW-815), SB-11285, MK-1454, SR-8291, AdVCA0848, GSK-532, SYN-STING, MSA-1, SR-8291, 5,6-dimethylxanthenone-4-acetic acid (DMXAA), cyclic-GAMP (cGAMP) and cyclic-di-AMP. In some embodiments, the agents described herein are combined with a RIG-I modulator such as RGT-100, or NOD2 modulator, such as SB-9200, and IR-103.

LAG-3 and TIM-3 inhibitors

0460In some embodiments, the agents as described herein are combined with an anti-TIM-3 antibody, such as TSR-022, LY-3321367, MBG-453, INCAGN-2390.

0461In some embodiments, the antibodies or antigen-binding fragments described herein are combined with an anti LAG-3 (Lymphocyte-activation) antibody, such as relatlimab (ONO-4482), LAG-525, MK-4280, REGN-3767, INCAGN2385.

Interleukin agonists

0462In some embodiments, the agents described herein are combined with an interleukin agonist, such as IL-2, IL-7, IL-15, IL-10, IL-12 agonists; examples of IL-2 agonists such as proleukin (aldesleukin, IL-2); pegylated IL-2 (eg NKTR-214); modified variants of IL-2 (eg THOR-707), bempegaldesleukin, AIC-284, ALKS-4230, CUI-101, Neo-2/15 ; examples of IL-15 agonists, such as ALT-803, NKTR-255, and hetIL-15, interleukin-15/Fc fusion protein, AM-0015, NIZ-985, SO-C101, IL-15 Synthorin (pegylated II-15), P-22339, and a IL-15 -PD-1 fusion protein N-809; examples of IL-7 include CYT-107.

0463Examples of additional immune-based therapies that can be combined with an agent of this disclosure include interferon alfa; interferon alfa-2b; interferon alfa-n3; pegylated interferon alfa; interferon gamma; Flt3 agonists; gepon; normferon, peginterferon alfa-2a, peginterferon alfa-2b, RPI-MN.

Phosphatidvlinositol 3-kinase (PI3K) Inhibitors

0464In some embodiments, the agents described herein are combined with a PI3K inhibitor. Examples of PI3K inhibitors that can be combined with an agent of this disclosure include idelalisib, alpelisib, buparlisib, CAI orotate, copanlisib, duvelisib, gedatolisib, neratinib, panulisib, perifosine, pictilisib, pilaralisib, puquitinib mesylate, rigosertib, rigosertib sodium, sonolisib, taselisib, AMG-319, AZD-8186, BAY-1082439, CLR-1401, CLR-457, CUDC-907, DS-7423, EN-3342, GSK-2126458, GSK-2269577, GSK-2636771, INCB-040093, LY-3023414, MLN-1117, PQR-309, RG-7666, RP-6530, RV-1729, SAR-245409, SAR-260301, SF-1126, TGR-1202, UCB-5857, VS-5584, XL-765, and ZSTK-474.

alpha-4/beta-7 antagonists

0465In some embodiments, the agents described herein are combined with an alpha-4/beta-7 antagonist. Examples of Integrin alpha-4/beta-7 antagonists that can be combined with an agent of this disclosure include PTG-100, TRK-170, abrilumab, etrolizumab, carotegrast methyl, and vedolizumab.

HIV targeting Antibodies

0466Examples of HIV antibodies, bispecific antibodies, and "antibody-like" therapeutic proteins that can be combined with an agent of this disclosure include DARTs^®, DUOBODIES^®, BITES^®, XmAbs^®, TandAbs^®, Fab derivatives, bNAbs (broadly neutralizing HIV-1 antibodies),, TMB-360, and those targeting HIV gp120 or gp41, antibody-Recruiting Molecules targeting HIV, anti-CD63 monoclonal antibodies , anti-GB virus C antibodies, anti-GP120/CD4, CCR5 bispecific antibodies, anti-Nef single domain antibodies, anti-Rev antibody, camelid derived anti-CD18 antibodies, camelid-derived anti-ICAM-1 antibodies, DCVax-001, gp140 targeted antibodies, gp41-based HIV therapeutic antibodies, human recombinant mAbs (PGT-121), ibalizumab, Immuglo, MB-66.

0467Various bNAbs are known in the art and may be used in this invention. Examples include, but are not limited to, those described in <patcit id="pcit0355" dnum="US8673307B"><text>U.S. Patent No. 8673307</text></patcit>, <patcit id="pcit0356" dnum="US9493549B"><text>9,493,549</text></patcit>, <patcit id="pcit0357" dnum="US9783594B"><text>9,783,594</text></patcit>, <patcit id="pcit0358" dnum="WO2014063059A"><text>WO2014/063059</text></patcit>, <patcit id="pcit0359" dnum="WO2012158948A"><text>WO2012/158948</text></patcit>, <patcit id="pcit0360" dnum="WO2015117008A"><text>WO2015/117008</text></patcit>, and <patcit id="pcit0361" dnum="LTS201541272W"><text>PCT/LTS2015/41272</text></patcit>, and <patcit id="pcit0362" dnum="WO2017096221A"><text>WO2017/096221</text></patcit>, including antibodies 12A12, 12A21, NIH45-46, bANC131, 8ANC134, IB2530, INC9, 8ANC195. 8ANC196, 10-259, 10-303, 10-410, 10- 847, 10-996, 10-1074, 10-1121, 10-1130, 10-1146, 10-1341, 10-1369, and 10-1074GM. Additional examples include those described in <nplcit id="ncit0052" npl-type="s"><text>Klein et al., Nature, 492(7427): 118-22 (2012</text></nplcit>), <nplcit id="ncit0053" npl-type="s"><text>Horwitz et al., Proc Natl Acad Sci USA, 110(41): 16538-43 (2013</text></nplcit>), <nplcit id="ncit0054" npl-type="s"><text>Scheid, et al., Science, 333 : 1633-1637 (2011</text></nplcit>), <nplcit id="ncit0055" npl-type="s"><text>Scheid, et al., Nature, 458:636-640 (2009</text></nplcit>), <nplcit id="ncit0056" npl-type="s"><text>Eroshkin et al, Nucleic Acids Res., 42 (Database issue):Dl 133-9 (2014</text></nplcit>), <nplcit id="ncit0057" npl-type="s"><text>Mascola et al., Immunol Rev., 254(1):225-44 (2013</text></nplcit>), such as 2F5, 4E10, M66.6, CAP206-CH12, 10E81 (all of which bind the MPERofgp41); PG9, PG16, CH01-04 (all of which bind V1V2-glycan), 2G12 (which binds to outer domain glycan); b12, HJ16, CH103-106, VRC01-03, VRC-PG04, 04b, VRC-CH30-34, 3BNC62, 3BNC89, 3BNC91, 3BNC95, 3BNC104, 3BNC176, and 8ANC131 (all of which bind to the CD4 binding site).

0468Additional broadly neutralizing antibodies which can be used as a second therapeutic agent in a combination therapy are described, e.g., in <patcit id="pcit0363" dnum="US8673307B"><text>U.S. Patent Nos. 8,673,307</text></patcit>; <patcit id="pcit0364" dnum="US9493549B"><text>9,493,549</text></patcit>; <patcit id="pcit0365" dnum="US9783594B"><text>9,783,594</text></patcit>; and <patcit id="pcit0366" dnum="WO2012154312A"><text>WO 2012/154312</text></patcit>; <patcit id="pcit0367" dnum="WO2012158948A"><text>WO2012/158948</text></patcit>; <patcit id="pcit0368" dnum="WO2013086533A"><text>WO 2013/086533</text></patcit>; <patcit id="pcit0369" dnum="WO2013142324A"><text>WO 2013/142324</text></patcit>; <patcit id="pcit0370" dnum="WO2014063059A"><text>WO2014/063059</text></patcit>; <patcit id="pcit0371" dnum="WO2014089152A"><text>WO 2014/089152</text></patcit>, <patcit id="pcit0372" dnum="WO2015048462A"><text>WO 2015/048462</text></patcit>; <patcit id="pcit0373" dnum="WO2015103549A"><text>WO 2015/103549</text></patcit>; <patcit id="pcit0374" dnum="WO2015117008A"><text>WO 2015/117008</text></patcit>; <patcit id="pcit0375" dnum="WO2016014484A"><text>WO2016/014484</text></patcit>; <patcit id="pcit0376" dnum="WO2016154003A"><text>WO 2016/154003</text></patcit>; <patcit id="pcit0377" dnum="WO2016196975A"><text>WO 2016/196975</text></patcit>; <patcit id="pcit0378" dnum="WO2016149710A"><text>WO 2016/149710</text></patcit>; <patcit id="pcit0379" dnum="WO2017096221A"><text>WO2017/096221</text></patcit>; <patcit id="pcit0380" dnum="WO2017133639A"><text>WO 2017/133639</text></patcit>; <patcit id="pcit0381" dnum="WO2017133640A"><text>WO 2017/133640</text></patcit>, which are hereby incorporated herein by reference in their entireties for all purposes. Additional examples include those described in <nplcit id="ncit0058" npl-type="s"><text>Sajadi, et al., Cell. (2018) 173(7):1783-1795</text></nplcit>; <nplcit id="ncit0059" npl-type="s"><text>Sajadi, et al., J Infect Dis. (2016) 213(1):156-64</text></nplcit>; <nplcit id="ncit0060" npl-type="s"><text>Klein et al., Nature, 492(7427): 118-22 (2012</text></nplcit>), <nplcit id="ncit0061" npl-type="s"><text>Horwitz et al., Proc Natl Acad Sci U S A, 110(41): 16538-43 (2013</text></nplcit>), <nplcit id="ncit0062" npl-type="s"><text>Scheid, et al., Science, 333 : 1633-1637 (2011</text></nplcit>), <nplcit id="ncit0063" npl-type="s"><text>Scheid, et al., Nature, 458:636-640 (2009</text></nplcit>), <nplcit id="ncit0064" npl-type="s"><text>Eroshkin et al, Nucleic Acids Res., 42 (Database issue):Dl 133-9 (2014</text></nplcit>),<nplcit id="ncit0065" npl-type="s"><text> Mascola et al., Immunol Rev., 254(1):225-44 (2013</text></nplcit>), such as 2F5, 4E10, M66.6, CAP206-CH12, 10E8, 10E8v4, 10E8-5R-100cF, DH511.11P, 7b2, and LN01 (all of which bind the MPER of gp41).

0469Examples of additional antibodies include bavituximab, UB-421, BF520.1, CH01, CH59, C2F5, C4E10, C2F5+C2G12+C4E10, 3BNC117, 3BNC117-LS, 3BNC60, , DH270.1, DH270.6, D1D2, 10-1074-LS, GS-9722, DH411-2, BG18, PGT145, PGT121, PGT-121.60, PGT-121.66, PGT122, PGT-123, PGT-124, PGT-125, PGT-126, PGT-151, PGT-130, PGT-133, PGT-134, PGT-135, PGT-128, PGT-136, PGT-137, PGT-138, PGT-139, MDX010 (ipilimumab), DH511, DH511-2, N6, N6LS, N49P6, N49P7, N49P7.1, N49P9, N49P11, N60P1.1, N60P25.1, N60P2.1, N60P31.1, N60P22, NIH 45-46, , PGC14, PGG14, PGT-142, PGT-143, PGT-144, PGDM1400, PGDM12, PGDM21, PCDN-33A, 2Dm2m, 4Dm2m, 6Dm2m, PGDM1400, MDX010 (ipilimumab), VRC01, VRC-01-LS, A32, 7B2, 10E8, VRC-07-523, VRC07-523LS, VRC24, VRC41.01, 10E8VLS, 3810109, 10E8v4, IMC-HIV, iMabm36, eCD4-Ig, IOMA, CAP256-VRC26.25, DRVIA7,VRC-HIVMAB080-00-AB, VRC-HIVMAB060-00-AB, P2G12, VRC07, 354BG8, 354BG18, 354BG42, 354BG33, 354BG129, 354BG188, 354BG411, 354BG426, VRC29.03, CAP256, CAP256-VRC26.08, CAP256-VRC26.09, CAP256-VRC26.25, PCT64-24E and VRC38.01, PGT-151, CAP248-2B, 35O22, ACS202, VRC34 and VRC34.01, 10E8, 10E8v4, 10E8-5R-100cF, 4E10, DH511.11P, 2F5, 7b2, and LN01.

0470Example of HIV bispecific and trispecific antibodies include MGD014, B12BiTe, TMB-bispecific, SAR-441236, VRC-01/PGDM-1400/10E8v4, 10E8.4/iMab, 10E8v4/PGT121-VRC01.

0471Example of in vivo delivered bnabs such as AAV8-VRC07; mRNA encoding anti-HIV antibody VRC01; and engineered B-cells encoding 3BNC117 (<nplcit id="ncit0066" npl-type="s"><text>Hartweger et al, J. Exp. Med. 2019, 1301</text></nplcit>).

Pharmacokinetic Enhancers

0472In some embodiments, the agents described herein are combined with a pharmacokinetic enhancer. Examples of pharmacokinetic enhancers that can be combined with an agent of this disclosure include cobicistat and ritonavir.

Additional Therapeutic Agents

0473Examples of additional therapeutic agents that can be combined with an agent of this disclosure include the compounds disclosed in <patcit id="pcit0382" dnum="WO2004096286A"><text>WO 2004/096286 (Gilead Sciences</text></patcit>), <patcit id="pcit0383" dnum="WO2006015261A"><text>WO 2006/015261 (Gilead Sciences</text></patcit>), <patcit id="pcit0384" dnum="WO2006110157A"><text>WO 2006/110157 (Gilead Sciences</text></patcit>), <patcit id="pcit0385" dnum="WO2012003497A"><text>WO 2012/003497 (Gilead Sciences</text></patcit>), <patcit id="pcit0386" dnum="WO2012003498A"><text>WO 2012/003498 (Gilead Sciences</text></patcit>), <patcit id="pcit0387" dnum="WO2012145728A"><text>WO 2012/145728 (Gilead Sciences</text></patcit>), <patcit id="pcit0388" dnum="WO2013006738A"><text>WO 2013/006738 (Gilead Sciences</text></patcit>), <patcit id="pcit0389" dnum="WO2013159064A"><text>WO 2013/159064 (Gilead Sciences</text></patcit>), <patcit id="pcit0390" dnum="WO2014100323A"><text>WO 2014/100323 (Gilead Sciences</text></patcit>), <patcit id="pcit0391" dnum="US20130165489A"><text>US 2013/0165489 (University of Pennsylvania</text></patcit>), <patcit id="pcit0392" dnum="US20140221378A"><text>US 2014/0221378 (Japan Tobacco</text></patcit>), <patcit id="pcit0393" dnum="US20140221380A"><text>US 2014/0221380 (Japan Tobacco</text></patcit>), <patcit id="pcit0394" dnum="WO2009062285A"><text>WO 2009/062285 (Boehringer Ingelheim</text></patcit>), <patcit id="pcit0395" dnum="WO2010130034A"><text>WO 2010/130034 (Boehringer Ingelheim</text></patcit>), <patcit id="pcit0396" dnum="WO2013006792A"><text>WO 2013/006792 (Pharma Resources</text></patcit>), <patcit id="pcit0397" dnum="US20140221356A"><text>US 20140221356 (Gilead Sciences</text></patcit>), <patcit id="pcit0398" dnum="US20100143301A"><text>US 20100143301 (Gilead Sciences</text></patcit>) and <patcit id="pcit0399" dnum="WO2013091096A"><text>WO 2013/091096 (Boehringer Ingelheim</text></patcit>).

HIV Vaccines

0474In some embodiments, the agents described herein are combined with an HIV vaccine. Examples of HIV vaccines that can be combined with an agent of this disclosure include peptide vaccines, recombinant subunit protein vaccines, live vector vaccines, DNA vaccines, CD4-derived peptide vaccines, vaccine combinations, adenoviral vector vaccines (an adenoviral vector such as Ad5, Ad26 or Ad35), simian adenovirus (chimpanzee, gorilla, rhesus i.e. rhAd), adeno-associated virus vector vaccines, Chimpanzee adenoviral vaccines (e.g., ChAdOX1, ChAd68, ChAd3, ChAd63, ChAd83, ChAd155, ChAd157, Pan5, Pan6, Pan7, Pan9), Coxsackieviruses based vaccines, enteric virus based vaccines, Gorilla adenovirus vaccines, lentiviral vector based vaccine, arenavirus vaccines (such as LCMV, Pichinde), bi-segmented or tri-segmented arenavirus based vaccine, measles virus based vaccine, flavivirus vector based vaccines, tobacco mosaic virus vector based vaccine, Varicella-zoster virus based vaccine, Human parainfluenza virus 3 (PIV3) based vaccines, poxvirus based vaccine (modified vaccinia virus Ankara (MVA), orthopoxvirus-derived NYVAC, and avipoxvirus-derived ALVAC (canarypox virus) strains); fowlpox virus based vaccine, rhabdovirus-based vaccines, such as VSV and marabavirus; recombinant human CMV (rhCMV) based vaccine, alphavirus-based vaccines, such as semliki forest virus, venezuelan equine encephalitis virus and sindbis virus; (see <nplcit id="ncit0067" npl-type="s"><text>Lauer, Clinical and Vaccine Immunology, 2017, DOI: 10.1128/CVI.00298-16</text></nplcit>); LNP formulated mRNA based therapeutic vaccines; LNP-formulated self-replicating RNA/self-amplifying RNA vaccines.

0475Examples of vaccines include: rgp120 (AIDSVAX), ALVAC HIV (vCP1521)/AIDSVAX B/E (gp120) (RV144), monomeric gp120 HIV-1 subtype C vaccine, Remune, ITV-1, Centre Vir, Ad5-ENVA-48, DCVax-001 (CDX-2401), Vacc-4x, Vacc-C5, VAC-3S, multiclade DNA recombinant adenovirus-5 (rAd5), rAd5 gag-pol env A/B/C vaccine, Pennvax-G, Pennvax-GP, Pennvax-G/MVA-CMDR, HIV-TriMix-mRNA vaccine, HIV-LAMP-vax, Ad35, Ad35-GRIN, NAcGM3/VSSP ISA-51, poly-ICLC adjuvanted vaccines, TatImmune, GTU-multiHIV (FIT-06), gp140[delta]V2.TV1+MF-59, rVSVIN HIV-1 gag vaccine, SeV-Gag vaccine, AT-20, DNK-4, ad35-Grin/ENV, TBC-M4, HIVAX, HIVAX-2, NYVAC-HIV-PT1, NYVAC-HIV-PT4, DNA-HIV-PT123, rAAV1-PG9DP, GOVX-B11, GOVX-B21, TVI-HIV-1, Ad-4 (Ad4-env Clade C+Ad4-mGag), Paxvax, EN41-UGR7C, EN41-FPA2, PreVaxTat, AE-H, MYM-V101, CombiHIVvac, ADVAX, MYM-V201, MVA-CMDR, DNA-Ad5 gag/pol/nef/nev (HVTN505), MVATG-17401, ETV-01, CDX-1401, rcAD26.MOS1.HIV-Env, Ad26.Mod.HIV vaccine, Ad26.Mod.HIV + MVA mosaic vaccine + gp140, AGS-004, AVX-101, AVX-201, PEP-6409, SAV-001, ThV-01, TL-01, TUTI-16, VGX-3300, IHV-001, and virus-like particle vaccines such as pseudovirion vaccine, CombiVICHvac, LFn-p24 B/C fusion vaccine, GTU-based DNA vaccine, HIV gag/pol/nef/env DNA vaccine, anti-TAT HIV vaccine, conjugate polypeptides vaccine, dendritic-cell vaccines (such as DermaVir), gag-based DNA vaccine, GI-2010, gp41 HIV-1 vaccine, HIV vaccine (PIKA adjuvant), i-key/MHC class II epitope hybrid peptide vaccines, ITV-2, ITV-3, ITV-4, LIPO-5, multiclade Env vaccine, MVA vaccine, Pennvax-GP, pp71-deficient HCMV vector HIV gag vaccine, , rgp160 HIV vaccine, RNActive HIV vaccine, SCB-703, Tat Oyi vaccine, TBC-M4, UBI HIV gp120, Vacc-4x + romidepsin, variant gp120 polypeptide vaccine, rAd5 gag-pol env A/B/C vaccine, DNA.HTI and MVA.HTI, VRC-HIVDNA016-00-VP + VRC-HIVADV014-00-VP, INO-6145, JNJ-9220, gp145 C.6980; eOD-GT8 60mer based vaccine, PD-201401, env (A, B, C, A/E)/gag (C) DNA Vaccine, gp120 (A,B,C,A/E) protein vaccine, PDPHV-201401, Ad4-EnvCN54, EnvSeq-1 Envs HIV-1 vaccine (GLA-SE adjuvanted), HIV p24gag prime-boost plasmid DNA vaccine, arenavirus vector-based vaccines (Vaxwave, TheraT), MVA-BN HIV-1 vaccine regimen, UBI HIV gp120, mRNA based prophylactic vaccines, and TBL-1203HI.

Birth control (contraceptive) combination therapy

0476In some embodiments, the agents described herein are combined with a birth control or contraceptive regimen. Therapeutic agents used for birth control (contraceptive) that can be combined with an agent of this disclosure include cyproterone acetate, desogestrel , dienogest, drospirenone, estradiol valerate , ethinyl Estradiol, ethynodiol, etonogestrel, levomefolate, levonorgestrel, lynestrenol , medroxyprogesterone acetate, mestranol, mifepristone , misoprostol, nomegestrol acetate, norelgestromin, norethindrone, noretynodrel, norgestimate, ormeloxifene , segestersone acetate, ulipristal acetate, and any combinations thereof.

0477In some embodiments, an agent disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with one, two, three, four or more additional therapeutic agents selected from ATRIPLA^® (efavirenz, tenofovir disoproxil fumarate, and emtricitabine); COMPLERA^® (EVIPLERA^®; rilpivirine, tenofovir disoproxil fumarate, and emtricitabine); STRIBILD^® (elvitegravir, cobicistat, tenofovir disoproxil fumarate, and emtricitabine); TRUVADA^® (tenofovir disoproxil fumarate and emtricitabine; TDF +FTC); DESCOVY^® (tenofovir alafenamide and emtricitabine); ODEFSEY^® (tenofovir alafenamide, emtricitabine, and rilpivirine); GENVOYA^® (tenofovir alafenamide, emtricitabine, cobicistat, and elvitegravir); BIKTARVY (bictegravir + emtricitabine + tenofovir alafenamide), adefovir; adefovir dipivoxil; cobicistat; emtricitabine; tenofovir; tenofovir disoproxil; tenofovir disoproxil fumarate; tenofovir alafenamide; tenofovir alafenamide hemifumarate; TRIUMEQ^® (dolutegravir, abacavir, and lamivudine); dolutegravir, abacavir sulfate, and lamivudine; raltegravir; raltegravir and lamivudine; maraviroc; enfuvirtide; ALUVIA^® (KALETRA^®; lopinavir and ritonavir); COMBIVIR^® (zidovudine and lamivudine; AZT+3TC); EPZICOM^® (LIVEXA^®; abacavir sulfate and lamivudine; ABC+3TC); TRIZIVIR^® (abacavir sulfate, zidovudine, and lamivudine; ABC+AZT+3TC); rilpivirine; rilpivirine hydrochloride; atazanavir sulfate and cobicistat; atazanavir and cobicistat; darunavir and cobicistat; atazanavir; atazanavir sulfate; dolutegravir; elvitegravir; ritonavir; atazanavir sulfate and ritonavir; darunavir; lamivudine; prolastin; fosamprenavir; fosamprenavir calcium efavirenz; etravirine; nelfinavir; nelfinavir mesylate; interferon; didanosine; stavudine; indinavir; indinavir sulfate; tenofovir and lamivudine; zidovudine; nevirapine; saquinavir; saquinavir mesylate; aldesleukin; zalcitabine; tipranavir; amprenavir; delavirdine; delavirdine mesylate; Radha-108 (receptol); lamivudine and tenofovir disoproxil fumarate; efavirenz, lamivudine, and tenofovir disoproxil fumarate; phosphazid; lamivudine, nevirapine, and zidovudine; abacavir; and abacavir sulfate.

0478In some embodiments, an agent disclosed herein, or a pharmaceutical composition thereof, is combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase and an HIV non-nucleoside inhibitor of reverse transcriptase. In another specific embodiment, an agent disclosed herein, or a pharmaceutical composition thereof, is combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, and an HIV protease inhibiting compound. In an additional embodiment, an agent disclosed herein, or a pharmaceutical composition thereof, is combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, an HIV non-nucleoside inhibitor of reverse transcriptase, and a pharmacokinetic enhancer. In some embodiments, an agent disclosed herein, or a pharmaceutical composition thereof, is combined with at least one HIV nucleoside inhibitor of reverse transcriptase, an integrase inhibitor, and a pharmacokinetic enhancer. In some embodiments, an agent disclosed herein, or a pharmaceutical composition thereof, is combined with two HIV nucleoside or nucleotide inhibitors of reverse transcriptase.

0479In some embodiments, an agent disclosed herein, or a pharmaceutical composition thereof, is combined with abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, tenofovir alafenamide, or tenofovir alafenamide hemifumarate.

0480In some embodiments, an agent disclosed herein, or a pharmaceutical composition thereof, is combined with tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, or tenofovir alafenamide hemifumarate.

0481In some embodiments, an agent disclosed herein, or a pharmaceutical composition thereof, is combined with a first additional therapeutic agent selected from the group consisting of abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate, and a second additional therapeutic agent selected from the group consisting of emtricitabine and lamivudine.

0482In some embodiments, an agent disclosed herein, or a pharmaceutical composition thereof, is combined with a first additional therapeutic agent selected from the group consisting of tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate, and a second additional therapeutic agent, wherein the second additional therapeutic agent is emtricitabine.

0483In some embodiments, an agent disclosed herein, or a pharmaceutical composition thereof, is combined with a first additional therapeutic agent (a contraceptive) selected from the group consisting of cyproterone acetate, desogestrel , dienogest, drospirenone, estradiol valerate , ethinyl Estradiol, ethynodiol, etonogestrel, levomefolate, levonorgestrel, lynestrenol , medroxyprogesterone acetate, mestranol, mifepristone , misoprostol, nomegestrol acetate, norelgestromin, norethindrone, noretynodrel, norgestimate, ormeloxifene , segestersone acetate, ulipristal acetate, and any combinations thereof.

Gene Therapy and Cell Therapy

0484In some embodiments, the agents described herein are combined with a gene or cell therapy regimen. Gene therapy and cell therapy include without limitation the genetic modification to silence a gene; genetic approaches to directly kill the infected cells; the infusion of immune cells designed to replace most of the patient's own immune system to enhance the immune response to infected cells, or activate the patient's own immune system to kill infected cells, or find and kill the infected cells; genetic approaches to modify cellular activity to further alter endogenous immune responsiveness against the infection. Examples of dendritic cell therapy include AGS-004. CCR5 gene editing agents include SB-728T. CCR5 gene inhibitors include Cal-1. In some embodiments, C34-CCR5/C34-CXCR4 expressing CD4-positive T-cells are co-administered with one or more multi-specific antigen binding molecules. In some embodiments, the agents described herein are co-administered with AGT-103-transduced autologous T-cell therapy or AAV-eCD4-Ig gene therapy.

Gene Editors

0485In some embodiments, the agents described herein are combined with a gene editor, <i>e.g.,</i> an HIV targeted gene editor. In some embodiments, the genome editing system can be selected from the group consisting of: a CRISPR/Cas9 complex, a zinc finger nuclease complex, a TALEN complex, a homing endonucleases complex, and a meganuclease complex. An illustrative HIV targeting CRISPR/Cas9 system includes without limitation EBT-101.

CAR-T-cell therapy

0486In some embodiments, the agents described herein can be co-administered with a population of immune effector cells engineered to express a chimeric antigen receptor (CAR), wherein the CAR comprises an HIV antigen binding domain. The HIV antigen include an HIV envelope protein or a portion thereof, gp120 or a portion thereof, a CD4 binding site on gp120, the CD4-induced binding site on gp120, N glycan on gp120, the V2 of gp120, the membrane proximal region on gp41. The immune effector cell is a T-cell or an NK cell. In some embodiments, the T-cell is a CD4+ T-cell, a CD8+ T-cell, or a combination thereof. Cells can be autologous or allogeneic. Examples of HIV CAR-T include VC-CAR-T, CMV-N6-CART, anti-CD4 CART-cell therapy, CD4 CAR+C34-CXCR4+CCR5 ZFN T-cells, autologous hematopoietic stem cells genetically engineered to express a CD4 CAR and the C46 peptide.

TCR-T-cell therapy

0487In some embodiments, the agents described herein are combined with a population of TCR-T-cells. TCR-T-cells are engineered to target HIV derived peptides present on the surface of virus-infected cells, for example ImmTAV

B-cell therapy

0488In some embodiments, the antibodies or antigen-binding fragments described herein are combined with a population of B cells genetically modified to express broadly neutralizing antibodies, such as 3BNC117 (<nplcit id="ncit0068" npl-type="s"><text>Hartweger et al, J. Exp. Med. 2019, 1301</text></nplcit>, <nplcit id="ncit0069" npl-type="s"><text>Moffett et al., Sci. Immunol. 4, eaax0644 (2019) 17 May 2019</text></nplcit>).

3. Hepatitis B Virus

0489Examples of other drugs for the treatment of HBV include alpha-hydroxytropolones, amdoxovir, antroquinonol, beta-hydroxycytosine nucleosides, , ARB-199, CCC-0975, ccc-R08, elvucitabine, ezetimibe, cyclosporin A, gentiopicrin (gentiopicroside), HH-003, hepalatide, JNJ-56136379, nitazoxanide, birinapant, NJK14047, NOV-205 (molixan, BAM-205), oligotide, mivotilate, feron, GST-HG-131, levamisole, Ka Shu Ning, alloferon, WS-007, Y-101 (Ti Fen Tai), rSIFN-co, PEG-IIFNm, KW-3, BP-Inter-014, oleanolic acid, HepB-nRNA, cTP-5 (rTP-5), HSK-II-2, HEISCO-106-1, HEISCO-106, Hepbama, IBPB-006IA, Hepuyinfen, DasHIoster 0014-01, ISA-204, Jiangantai (Ganxikang), MIV-210, OB-AI-004, PF-06, picroside, DasHIoster-0039, hepulantai, IMB-2613, TCM-800B, reduced glutathione, RO-6864018, RG-7834, QL-007sofosbuvir, ledipasvir, UB-551, and ZH-2N, and the compounds disclosed in <patcit id="pcit0400" dnum="US20150210682A"><text>US20150210682, (Roche</text></patcit>), <patcit id="pcit0401" dnum="US20160122344A"><text>US 2016/0122344 (Roche</text></patcit>), <patcit id="pcit0402" dnum="WO2015173164A"><text>WO2015173164</text></patcit> , <patcit id="pcit0403" dnum="WO2016023877A"><text>WO2016023877</text></patcit>, <patcit id="pcit0404" dnum="US2015252057A"><text>US2015252057A (Roche</text></patcit>), <patcit id="pcit0405" dnum="WO16128335A1"><text>WO16128335A1 (Roche</text></patcit>), <patcit id="pcit0406" dnum="WO16120186A1"><text>WO16120186A1 (Roche</text></patcit>), <patcit id="pcit0407" dnum="US2016237090A"><text>US2016237090A (Roche</text></patcit>), <patcit id="pcit0408" dnum="WO16107833A1"><text>WO16107833A1 (Roche</text></patcit>), <patcit id="pcit0409" dnum="WO16107832A1"><text>WO16107832A1 (Roche</text></patcit>), <patcit id="pcit0410" dnum="US2016176899A"><text>US2016176899A (Roche</text></patcit>), <patcit id="pcit0411" dnum="WO16102438A1"><text>WO16102438A1 (Roche</text></patcit>), <patcit id="pcit0412" dnum="WO16012470A1"><text>WO16012470A1 (Roche</text></patcit>), <patcit id="pcit0413" dnum="US2016220586A"><text>US2016220586A (Roche</text></patcit>), and <patcit id="pcit0414" dnum="US2015031687A"><text>US2015031687A (Roche</text></patcit>).

HBV Vaccines

0490HBV vaccines include both prophylactic and therapeutic vaccines. Examples of HBV prophylactic vaccines include Vaxelis, Hexaxim, Heplisav, Mosquirix, DTwP-HBV vaccine, Bio-Hep-B, D/T/P/HBV/M (LBVP-0101; LBVW-0101), DTwP-Hepb-Hib-IPV vaccine, Heberpenta L, DTwP-HepB-Hib, V-419, CVI-HBV-001, Tetrabhay, hepatitis B prophylactic vaccine (Advax Super D), Hepatrol-07, GSK-223192A, ENGERIX B^®, recombinant hepatitis B vaccine (intramuscular, Kangtai Biological Products), recombinant hepatitis B vaccine (Hansenual polymorpha yeast, intramuscular, Hualan Biological Engineering), recombinant hepatitis B surface antigen vaccine, Bimmugen, CARG-101, Euforavac, Eutravac, anrix-DTaP-IPV-Hep B, HBAI-20, Infanrix-DTaP-IPV-Hep B-Hib, Pentabio Vaksin DTP-HB-Hib, Comvac 4, Twinrix, Euvax-B, Tritanrix HB, Infanrix Hep B, Comvax, DTP-Hib-HBV vaccine, DTP-HBV vaccine, Yi Tai, Heberbiovac HB, Trivac HB, GerVax, DTwP-Hep B-Hib vaccine, Bilive, Hepavax-Gene, SUPERVAX, Comvac5, Shanvac-B, Hebsulin, Recombivax HB, Revac B mcf, Revac B+, Fendrix, DTwP-HepB-Hib, DNA-001, Shan5, Shan6, rhHBsAG vaccine, HBI pentavalent vaccine, LBVD, Infanrix HeXa, YS-HBV-001 and DTaP-rHB-Hib vaccine.

0491Examples of HBV therapeutic vaccines include HBsAG-HBIG complex, ARB-1598, Bio-Hep-B, NASVAC, abi-HB (intravenous), ABX-203, Tetrabhay, GX-110E, GS-4774, peptide vaccine (epsilonPA-44), Hepatrol-07, NASVAC (NASTERAP), IMP-321, BEVAC, Revac B mcf, Revac B+, MGN-1333, KW-2, CVI-HBV-002, AltraHepB, VGX-6200, FP-02, FP-02.2 (HepTcell), NU-500, HBVax, im/TriGrid/antigen vaccine, Mega-CD40L-adjuvanted vaccine, HepB-v, RG7944 (INO-1800), recombinant VLP-based therapeutic vaccine (HBV infection, VLP Biotech), AdTG-17909, AdTG-17910 AdTG-18202, ChronVac-B, TG-1050, VVX-001, GSK-3528869A (ChAd155-hli-HBV + MVA-HBV +Hbc-HBs/AS01B-4), VBI-2601, VTP-300 (ChAdOx1-SIi-HBV-CPmut-TPA-Ssh prime and MVA-SIi-HBV-CPmut-TPA-Ssh boost), MVA-BN, and Lm HBV. HBV Arenavirus vaccines are described, e.g., in <patcit id="pcit0415" dnum="WO2017076988A"><text>WO2017076988</text></patcit> and <patcit id="pcit0416" dnum="WO2017198726A"><text>WO2017198726</text></patcit>.

HBV DNA Polymerase Inhibitors

0492Examples of HBV DNA polymerase inhibitors include adefovir (HEPSERA^®), emtricitabine (EMTRIVA^®), tenofovir disoproxil fumarate (VIREAD^®), tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, tenofovir dipivoxil , tenofovir dipivoxil fumarate, tenofovir octadecyloxyethyl ester, CMX-157, tenofovir exalidex, besifovir, entecavir (BARACLUDE^®), entecavir maleate, telbivudine (TYZEKA^®), filocilovir, pradefovir, clevudine, ribavirin, lamivudine (EPIVIR-HBV^®), phosphazide, famciclovir, fusolin, metacavir, SNC-019754, FMCA, AGX-1009, AR-II-04-26, HIP-1302, tenofovir disoproxil aspartate, tenofovir disoproxil orotate, and HS-10234.

Immunomodulators

0493Examples of immunomodulators include rintatolimod, imidol hydrochloride, ingaron, dermaVir, plaquenil (hydroxychloroquine), proleukin, hydroxyurea, mycophenolate mofetil (MPA) and its ester derivative mycophenolate mofetil (MMF), JNJ-440,WF-10,AB-452, ribavirin, IL-12, INO-9112, polymer polyethyleneimine (PEI), Gepon, VGV-1, MOR-22, CRV-431, JNJ-0535, TG-1050, ABI-H2158, BMS-936559,GS-9688, RO-7011785, RG-7854,RO-6871765, AIC-649, and IR-103.

Toll-Like Receptor (TLR) Agonists

0494In some embodiments, the agents as described herein, are combined with an agonist of a toll-like receptor (TLR), <i>e.g.,</i> an agonist of TLR1 (NCBI Gene ID: 7096), TLR2 (NCBI Gene ID: 7097), TLR3 (NCBI Gene ID: 7098), TLR4 (NCBI Gene ID: 7099), TLR5 (NCBI Gene ID: 7100), TLR6 (NCBI Gene ID: 10333), TLR7 (NCBI Gene ID: 51284), TLR8 (NCBI Gene ID: 51311), TLR9 (NCBI Gene ID: 54106), and/or TLR10 (NCBI Gene ID: 81793), TLR11, TLR12 and TLR 13.

0495Examples of TLR3 modulators include rintatolimod, poly-ICLC, RIBOXXON^®, Apoxxim, RIBOXXIM^®, IPH-33, MCT-465, MCT-475 and ND-1.1.

Examples of TLR4 agonist include G-100, and GSK-1795091.

0496Example TLR7 agonists that can be co-administered include without limitation AL-034, DSP-0509, GS-9620 (vesatolimod), LHC-165, TMX-101 (imiquimod), GSK-2245035, resiquimod, DSR-6434, DSP-3025, IMO-4200, MCT-465, MEDI-9197, 3M-051, SB-9922, 3M-052, Limtop, TMX-30X, TMX-202, RG-7863, RG-7854, RG-7795, and the compounds disclosed in <patcit id="pcit0417" dnum="US20100143301A"><text>US20100143301 (Gilead Sciences</text></patcit>), <patcit id="pcit0418" dnum="US20110098248A"><text>US20110098248 (Gilead Sciences</text></patcit>), and <patcit id="pcit0419" dnum="US20090047249A"><text>US20090047249 (Gilead Sciences</text></patcit>), <patcit id="pcit0420" dnum="US20140045849A"><text>US20140045849 (Janssen</text></patcit>), <patcit id="pcit0421" dnum="US20140073642A"><text>US20140073642 (Janssen</text></patcit>), <patcit id="pcit0422" dnum="WO2014056953A"><text>WO2014/056953 (Janssen</text></patcit>), <patcit id="pcit0423" dnum="WO2014076221A"><text>WO2014/076221 (Janssen</text></patcit>), <patcit id="pcit0424" dnum="WO2014128189A"><text>WO2014/128189 (Janssen</text></patcit>), <patcit id="pcit0425" dnum="US20140350031A"><text>US20140350031 (Janssen</text></patcit>), <patcit id="pcit0426" dnum="WO2014023813A"><text>WO2014/023813 (Janssen</text></patcit>), <patcit id="pcit0427" dnum="US20080234251A"><text>US20080234251 (Array Biopharma</text></patcit>), <patcit id="pcit0428" dnum="US20080306050A"><text>US20080306050 (Array Biopharma</text></patcit>), <patcit id="pcit0429" dnum="US20100029585A"><text>US20100029585 (Ventirx Pharma</text></patcit>), <patcit id="pcit0430" dnum="US20110092485A"><text>US20110092485 (Ventirx Pharma</text></patcit>), <patcit id="pcit0431" dnum="US20110118235A"><text>US20110118235 (Ventirx Pharma</text></patcit>), <patcit id="pcit0432" dnum="US20120082658A"><text>US20120082658 (Ventirx Pharma</text></patcit>), <patcit id="pcit0433" dnum="US20120219615A"><text>US20120219615 (Ventirx Pharma</text></patcit>), <patcit id="pcit0434" dnum="US20140066432A"><text>US20140066432 (Ventirx Pharma</text></patcit>), <patcit id="pcit0435" dnum="US20140088085A"><text>US20140088085 (Ventirx Pharma</text></patcit>), <patcit id="pcit0436" dnum="US20140275167A"><text>US20140275167 (Novira Therapeutics</text></patcit>), and <patcit id="pcit0437" dnum="US20130251673A"><text>US20130251673 (Novira Therapeutics</text></patcit>).

0497An TLR7/TLR8 agonist that can be co-administered is NKTR-262, telratolimod and BDB-001.

0498Example TLR8 agonists that can be co-administered include without limitation E-6887, IMO-4200, IMO-8400, IMO-9200, MCT-465, MEDI-9197, motolimod, resiquimod, selgantolimod (GS-9688), VTX-1463, VTX-763, 3M-051, 3M-052, ZG-170607, and the compounds disclosed in <patcit id="pcit0438" dnum="US20140045849A"><text>US20140045849 (Janssen</text></patcit>), <patcit id="pcit0439" dnum="US20140073642A"><text>US20140073642 (Janssen</text></patcit>), <patcit id="pcit0440" dnum="WO2014056953A"><text>WO2014/056953 (Janssen</text></patcit>), <patcit id="pcit0441" dnum="WO2014076221A"><text>WO2014/076221 (Janssen</text></patcit>), <patcit id="pcit0442" dnum="WO2014128189A"><text>WO2014/128189 (Janssen</text></patcit>), <patcit id="pcit0443" dnum="US20140350031A"><text>US20140350031 (Janssen</text></patcit>), <patcit id="pcit0444" dnum="WO2014023813A"><text>WO2014/023813 (Janssen</text></patcit>), <patcit id="pcit0445" dnum="US20080234251A"><text>US20080234251 (Array Biopharma</text></patcit>), <patcit id="pcit0446" dnum="US20080306050A"><text>US20080306050 (Array Biopharma</text></patcit>), <patcit id="pcit0447" dnum="US20100029585A"><text>US20100029585 (Ventirx Pharma</text></patcit>), <patcit id="pcit0448" dnum="US20110092485A"><text>US20110092485 (Ventirx Pharma</text></patcit>), <patcit id="pcit0449" dnum="US20110118235A"><text>US20110118235 (Ventirx Pharma</text></patcit>), <patcit id="pcit0450" dnum="US20120082658A"><text>US20120082658 (Ventirx Pharma</text></patcit>), <patcit id="pcit0451" dnum="US20120219615A"><text>US20120219615 (Ventirx Pharma</text></patcit>), <patcit id="pcit0452" dnum="US20140066432A"><text>US20140066432 (Ventirx Pharma</text></patcit>), <patcit id="pcit0453" dnum="US20140088085A"><text>US20140088085 (Ventirx Pharma</text></patcit>), <patcit id="pcit0454" dnum="US20140275167A"><text>US20140275167 (Novira Therapeutics</text></patcit>), and <patcit id="pcit0455" dnum="US20130251673A"><text>US20130251673 (Novira Therapeutics</text></patcit>), <patcit id="pcit0456" dnum="US9670205B"><text>US Patent No. 9670205 (Gilead Sciences, Inc</text></patcit>.), <patcit id="pcit0457" dnum="US20160289229A"><text>US20160289229 (Gilead Sciences, Inc</text></patcit>.), <patcit id="pcit0458" dnum="WO2017048727A"><text>WO2017/048727 (Gilead Sciences, Inc</text></patcit>.), <patcit id="pcit0459" dnum="US20180065938A"><text>US20180065938 (Gilead Sciences, Inc</text></patcit>.), and <patcit id="pcit0460" dnum="US20180086755A"><text>US20180086755 (Gilead Sciences, Inc</text></patcit>.).

0499Example TLR9 agonists that can be co-administered include without limitation AST-008, cobitolimod, CMP-001, IMO-2055, IMO-2125, litenimod, MGN-1601, BB-001, BB-006, IMO-3100, IMO-8400, IR-103, IMO-9200, agatolimod, DIMS-9054, DV-1079, DV-1179, AZD-1419, lefitolimod (MGN-1703), CYT-003, CYT-003-QbG10, tilsotolimod and PUL-042.

0500Examples of TLR7, TLR8 and TLR9 modulators include the compounds disclosed in <patcit id="pcit0461" dnum="WO2017047769A"><text>WO2017047769 (Teika Seiyaku</text></patcit>), <patcit id="pcit0462" dnum="WO2015014815A"><text>WO2015014815 (Janssen</text></patcit>), <patcit id="pcit0463" dnum="WO2018045150A"><text>WO2018045150 (Gilead Sciences Inc</text></patcit>), <patcit id="pcit0464" dnum="WO2018045144A"><text>WO2018045144 (Gilead Sciences Inc</text></patcit>), <patcit id="pcit0465" dnum="WO2015162075A"><text>WO2015162075 (Roche</text></patcit>),<patcit id="pcit0466" dnum="WO2017034986A"><text>WO2017034986 (University of Kansas</text></patcit>), <patcit id="pcit0467" dnum="WO2018095426A"><text>WO2018095426 (Jiangsu Hengrui Medicine Co Ltd</text></patcit>), <patcit id="pcit0468" dnum="WO2016091698A"><text>WO2016091698(Roche</text></patcit>), <patcit id="pcit0469" dnum="WO2016075661A"><text>WO2016075661 (GlaxoSmithKline Biologicals</text></patcit>), <patcit id="pcit0470" dnum="WO2016180743A"><text>WO2016180743 (Roche</text></patcit>), <patcit id="pcit0471" dnum="WO2018089695A"><text>WO2018089695 (Dynavax Technologies</text></patcit>), <patcit id="pcit0472" dnum="WO2016055553A"><text>WO2016055553 (Roche</text></patcit>), <patcit id="pcit0473" dnum="WO2015168279A"><text>WO2015168279 (Novartis</text></patcit>), <patcit id="pcit0474" dnum="WO2016107536A"><text>WO2016107536 (Medshine Discovery</text></patcit>), <patcit id="pcit0475" dnum="WO2018086593A"><text>WO2018086593 (Livo (Shanghai) Pharmaceutical</text></patcit>), <patcit id="pcit0476" dnum="WO2017106607A"><text>WO2017106607 (Merck</text></patcit>), <patcit id="pcit0477" dnum="WO2017061532A"><text>WO2017061532 (Sumitomo Dainippon Pharma</text></patcit>), <patcit id="pcit0478" dnum="WO2016023511A"><text>WO2016023511 (Chia Tai Tianqing Pharmaceutical</text></patcit>), <patcit id="pcit0479" dnum="WO2017076346A"><text>WO2017076346 (Chia Tai Tianqing Pharmaceutical</text></patcit>), <patcit id="pcit0480" dnum="WO2017046112A"><text>WO2017046112 (Roche</text></patcit>), <patcit id="pcit0481" dnum="WO2018078149A"><text>WO2018078149 (Roche</text></patcit>), <patcit id="pcit0482" dnum="WO2017040233A"><text>WO2017040233 (3M Co</text></patcit>),<patcit id="pcit0483" dnum="WO2016141092A"><text>WO2016141092 (Gilead Sciences</text></patcit>), <patcit id="pcit0484" dnum="WO2018049089A"><text>WO2018049089 (BristolMyers Squibb</text></patcit>), <patcit id="pcit0485" dnum="WO2015057655A"><text>WO2015057655 (Eisai Co Ltd</text></patcit>), <patcit id="pcit0486" dnum="WO2017001307A"><text>WO2017001307 (Roche</text></patcit>), <patcit id="pcit0487" dnum="WO2018005586A"><text>WO2018005586 (BristolMyers Squibb</text></patcit>), <patcit id="pcit0488" dnum="WO201704023A"><text>WO201704023 (3M Co</text></patcit>), <patcit id="pcit0489" dnum="WO2017163264A"><text>WO2017163264 (Council of Scientific and Industrial Research (India</text></patcit>)), <patcit id="pcit0490" dnum="WO2018046460A"><text>WO2018046460 (GlaxoSmithKline Biologicals</text></patcit>), <patcit id="pcit0491" dnum="WO2018047081A"><text>WO2018047081 (Novartis</text></patcit>), <patcit id="pcit0492" dnum="WO2016142250A"><text>WO2016142250 (Roche</text></patcit>), <patcit id="pcit0493" dnum="WO2015168269A"><text>WO2015168269 (Novartis</text></patcit>), <patcit id="pcit0494" dnum="WO201804163A"><text>WO201804163 (Roche</text></patcit>), <patcit id="pcit0495" dnum="WO2018038877A"><text>WO2018038877 (3M Co</text></patcit>), <patcit id="pcit0496" dnum="WO2015057659A"><text>WO2015057659 (Eisai Co Ltd</text></patcit>), <patcit id="pcit0497" dnum="WO2017202704A"><text>WO2017202704 (Roche</text></patcit>), <patcit id="pcit0498" dnum="WO2018026620A"><text>WO2018026620 (BristolMyers Squibb</text></patcit>), <patcit id="pcit0499" dnum="WO2016029077A"><text>WO2016029077 (Janus Biotherapeutics</text></patcit>), <patcit id="pcit0500" dnum="WO201803143A"><text>WO201803143 (Merck</text></patcit>), <patcit id="pcit0501" dnum="WO2016096778A"><text>WO2016096778 (Roche</text></patcit>), <patcit id="pcit0502" dnum="WO2017190669A"><text>WO2017190669 (Shanghai De Novo Pharmatech</text></patcit>), <patcit id="pcit0503" dnum="US09884866B"><text>US09884866 (University of Minnesota</text></patcit>), <patcit id="pcit0504" dnum="WO2017219931A"><text>WO2017219931 (Sichuan KelunBiotech Biopharmaceutical</text></patcit>), <patcit id="pcit0505" dnum="WO2018002319A"><text>WO2018002319 (Janssen Sciences</text></patcit>), <patcit id="pcit0506" dnum="WO2017216054A"><text>WO2017216054 (Roche</text></patcit>),<patcit id="pcit0507" dnum="WO2017202703A"><text>WO2017202703 (Roche</text></patcit>), <patcit id="pcit0508" dnum="WO2017184735A"><text>WO2017184735 (IFM Therapeutics</text></patcit>), <patcit id="pcit0509" dnum="WO2017184746A"><text>WO2017184746 (IFM Therapeutics</text></patcit>), <patcit id="pcit0510" dnum="WO2015088045A"><text>WO2015088045 (Takeda Pharmaceutical</text></patcit>), <patcit id="pcit0511" dnum="WO2017038909A"><text>WO2017038909 (Takeda Pharmaceutical</text></patcit>), <patcit id="pcit0512" dnum="WO2015095780A"><text>WO2015095780 (University of Kansas</text></patcit>), <patcit id="pcit0513" dnum="WO2015023958A"><text>WO2015023958 (University of Kansas</text></patcit>).

0501In some embodiments, an agent as described herein is co-administered with a TLR7, TLR8 or TLR9 agonist.

Interferon Alpha Receptor Ligands

0502Examples of interferon alpha receptor ligands include interferon alpha-2b (INTRON A^®), pegylated interferon alpha-2a (PEGASYS^®), PEGylated interferon alpha-1b, interferon alpha 1b (HAPGEN^®), Veldona, Infradure, Roferon-A, YPEG-interferon alfa-2a (YPEG-rhIFNalpha-2a), P-1101, Algeron, Alfarona, Ingaron (interferon gamma), rSIFN-co (recombinant super compound interferon), Ypeginterferon alfa-2b (YPEG-rhIFNalpha-2b), MOR-22, peginterferon alfa-2b (PEG-INTRON^®), Bioferon, Novaferon, Inmutag (Inferon), MULTIFERON^®, interferon alfa-n1(HUMOFERON^®), interferon beta-1a (AVONEX^®), Shaferon, interferon alfa-2b (Axxo), Alfaferone, interferon alfa-2b (BioGeneric Pharma), interferon-alpha 2 (CJ), Laferonum, VIPEG, BLAUFERON-A, BLAUFERON-B, Intermax Alpha, Realdiron, Lanstion, Pegaferon, PDferon-B PDferon-B, interferon alfa-2b (IFN, Laboratorios Bioprofarma), alfainterferona 2b, Kalferon, Pegnano, Feronsure, PegiHep, interferon alfa 2b (Zydus-Cadila), interferon alfa 2a, Optipeg A, Realfa 2B, Reliferon, interferon alfa-2b (Amega), interferon alfa-2b (Virchow), ropeginterferon alfa-2b, rHSA-IFN alpha-2a (recombinant human serum albumin intereferon alpha 2a fusion protein), PEG-IFN-alpha , rHSA-IFN alpha 2b, recombinant human interferon alpha-(1b, 2a, 2b), peginterferon alfa-2b (Amega), peginterferon alfa-2a, Reaferon-EC, Proquiferon, Uniferon, Urifron, interferon alfa-2b (Changchun Institute of Biological Products), Anterferon, Shanferon, Layfferon, Shang Sheng Lei Tai, INTEFEN, SINOGEN, Fukangtai, Pegstat, rHSA-IFN alpha-2b, SFR-9216, and Interapo (Interapa).

Hyaluronidase Inhibitors

0503Examples of hyaluronidase inhibitors include astodrimer.

Hepatitis B Surface Antigen (HBsAg) Inhibitors

0504Examples of HBsAg inhibitors include AK-074, HBF-0259, PBHBV-001, PBHBV-2-15, PBHBV-2-1, REP-9AC, REP-9C, REP-9, REP-2139, REP-2139-Ca,, REP-2055, REP-2163, REP-2165, REP-2053, REP-2031,REP-006, and REP-9AC'.

0505Examples of HBsAg secretion inhibitors include BM601, GST-HG-131, AB-452

Cytotoxic T-lymphocyte-associated protein 4 (ipi4) inhibitors

0506Examples of Cytotoxic T-lymphocyte-associated protein 4 (ipi4) inhibitors include AGEN-2041, AGEN-1884, ipilumimab, belatacept, PSI-001, PRS-010, Probody mAbs, tremelimumab, and JHL-1155.

Cvclophilin Inhibitors

0507Examples of cyclophilin inhibitors include CPI-431-32, EDP-494, OCB-030, SCY-635, NVP-015, NVP-018, NVP-019, STG-175, and the compounds disclosed in <patcit id="pcit0514" dnum="US8513184B"><text>US8513184 (Gilead Sciences</text></patcit>), <patcit id="pcit0515" dnum="US20140030221A"><text>US20140030221 (Gilead Sciences</text></patcit>), <patcit id="pcit0516" dnum="US20130344030A"><text>US20130344030 (Gilead Sciences</text></patcit>), and <patcit id="pcit0517" dnum="US20130344029A"><text>US20130344029 (Gilead Sciences</text></patcit>).

HBV Viral Entry Inhibitors

0508Examples of HBV viral entry inhibitors include Myrcludex B.

Antisense Oligonucleotide Targeting Viral mRNA

0509Examples of antisense oligonucleotide targeting viral mRNA include ISIS-HBVRx, IONIS-HBVRx, IONIS-HBV-LRx, IONIS-GSK6-LRx, GSK-3389404, and RG-6004.

Short Interfering RNAs (siRNA)and ddRNAi

0510Examples of siRNA include TKM-HBV (TKM-HepB), ALN-HBV, SR-008, HepB-nRNA, ARC-520, ARC-521, ARB-1740, ARB-1467, AB-729, DCR-HBVS, RG-6084 (PD-L1), RG-6217, ALN-HBV-02, JNJ-3989 (ARO-HBV), STSG-0002, ALG-010133, ALG-ASO, LUNAR-HBV and DCR-HBVS (DCR-S219).

0511Examples of DNA-directed RNA interference (ddRNAi) include BB-HB-331.

Endonuclease Modulators

0512Examples of endonuclease modulators include PGN-514.

Ribonucleotide Reductase Inhibitors

0513Examples of inhibitors of ribonucleotide reductase include Trimidox.

Nonnucleoside Reverse Transcriptase Inhibitors

0514Examples of Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs) include the compounds disclosed in <patcit id="pcit0518" dnum="WO2018118826A"><text>WO2018118826 (Merck</text></patcit>), <patcit id="pcit0519" dnum="WO2018080903A"><text>WO2018080903(Merck</text></patcit>), <patcit id="pcit0520" dnum="WO2018119013A"><text>WO2018119013 (Merck</text></patcit>), <patcit id="pcit0521" dnum="WO2017100108A"><text>WO2017100108 (Idenix</text></patcit>), <patcit id="pcit0522" dnum="WO2017027434A"><text>WO2017027434 (Merck</text></patcit>), <patcit id="pcit0523" dnum="WO2017007701A"><text>WO2017007701 (Merck</text></patcit>), <patcit id="pcit0524" dnum="WO2008005555A"><text>WO2008005555 (Gilead)</text></patcit>.

HBV Replication Inhibitors

0515Examples of hepatitis B virus replication inhibitors include GP-31502, isothiafludine, IQP-HBV, RM-5038, and Xingantie.

Covalently Closed Circular DNA (cccDNA) Inhibitors

0516Examples of cccDNA inhibitors include BSBI-25, ccc-R08, and CHR-101.

Farnesoid X receptor agonist

0517Examples of famesoid x receptor agonists include, e.g., EYP-001, GS-9674, EDP-305, MET-409, Tropifexor, AKN-083, RDX-023, BWD-100, LMB-763, INV-3, NTX-023-1, EP-024297 and GS-8670.

Additional HBV Antibodies

0518Examples of HBV antibodies targeting the surface antigens of the hepatitis B virus include lenvervimab (GC-1102), XTL-17, XTL-19, KN-003, IV Hepabulin SN, VIR-3434, and fully human monoclonal antibody therapy (hepatitis B virus infection, Humabs BioMed).

0519Examples of HBV antibodies, including monoclonal antibodies and polyclonal antibodies, include Zutectra, Shang Sheng Gan Di, Uman Big (Hepatitis B Hyperimmune), Omri-Hep-B, Nabi-HB, Hepatect CP, HepaGam B, igantibe, Niuliva, CT-P24, hepatitis B immunoglobulin (intravenous, pH4, HBV infection, Shanghai RAAS Blood Products), and Fovepta (BT-088).

0520Examples of fully human monoclonal antibodies include HBC-34.

0521Antibodies against HBV viral peptide/major histocompatibility complex (MHC) class I (pMHC) complexes are described, <i>e.g.,</i> in <nplcit id="ncit0070" npl-type="s"><text>Sastry, et al., J Virol. 2011 Mar;85(5):1935-42</text></nplcit> and in <patcit id="pcit0525" dnum="WO2011062562A"><text>WO2011062562</text></patcit>.

CCR2 Chemokine Antagonists

0522Examples of CCR2 chemokine antagonists include propagermanium.

Thymosin Agonists

0523Examples of thymosin agonists include Thymalfasin, and recombinant thymosin alpha 1 (GeneScience).

Cytokines

0524Examples of cytokines include recombinant IL-7, CYT-107, interleukin-2 (IL-2, Immunex), recombinant human interleukin-2 (Shenzhen Neptunus), IL-15, IL-21, IL-24, and celmoleukin.

Interleukin agonists

0525In some embodiments, the agents described herein are combined with an interleukin agonist, such as IL-2, IL-7, IL-15, IL-10, IL-12 agonists; examples of IL-2 agonists such as proleukin (aldesleukin, IL-2); pegylated IL-2 (eg NKTR-214); modified variants of IL-2 (eg THOR-707), bempegaldesleukin, AIC-284, ALKS-4230, CUI-101, Neo-2/15 ; examples of IL-15 agonists, such as ALT-803, NKTR-255, and hetIL-15, interleukin-15/Fc fusion protein, AM-0015, NIZ-985, SO-C101, IL-15 Synthorin (pegylated Il-15), P-22339, and a IL-15 -PD-1 fusion protein N-809; examples of IL-7 include CYT-107.

Nucleoprotein modulators

0526Nucleoprotein modulators may be either HBV core or capsid protein inhibitors. Examples of nucleoprotein modulators include GS-4882, AB-423, AT-130, ALG-001075, ALG-001024, ALG-000184, EDP-514, GLS4, NVR-1221, NVR-3778, AL-3778, BAY 41-4109, morphothiadine mesilate, ARB-168786, ARB-880, ARB-1820, GST-HG-141, JNJ-379, JNJ-632, RG-7907, GST-HG-141, HEC-72702, KL-060332, AB-506, ABI-H0731, ABI-H3733, JNJ-440, ABI-H2158, CB-HBV-001 and DVR-23.

0527Examples of capsid inhibitors include the compounds disclosed in <patcit id="pcit0526" dnum="US20140275167A"><text>US20140275167 (Novira Therapeutics</text></patcit>), <patcit id="pcit0527" dnum="US20130251673A"><text>US20130251673 (Novira Therapeutics</text></patcit>), <patcit id="pcit0528" dnum="US20140343032A"><text>US20140343032 (Roche</text></patcit>), <patcit id="pcit0529" dnum="WO2014037480A"><text>WO2014037480 (Roche</text></patcit>), <patcit id="pcit0530" dnum="US20130267517A"><text>US20130267517 (Roche</text></patcit>), <patcit id="pcit0531" dnum="WO2014131847A"><text>WO2014131847 (Janssen</text></patcit>), <patcit id="pcit0532" dnum="WO2014033176A"><text>WO2014033176 (Janssen</text></patcit>), <patcit id="pcit0533" dnum="WO2014033170A"><text>WO2014033170 (Janssen</text></patcit>), <patcit id="pcit0534" dnum="WO2014033167A"><text>WO2014033167 (Janssen</text></patcit>), <patcit id="pcit0535" dnum="WO2015059212A"><text>WO2015/059212 (Janssen</text></patcit>), <patcit id="pcit0536" dnum="WO2015118057A"><text>WO2015118057(Janssen</text></patcit>), <patcit id="pcit0537" dnum="WO2015011281A"><text>WO2015011281 (Janssen</text></patcit>), <patcit id="pcit0538" dnum="WO2014184365A"><text>WO2014184365 (Janssen</text></patcit>), <patcit id="pcit0539" dnum="WO2014184350A"><text>WO2014184350 (Janssen</text></patcit>), <patcit id="pcit0540" dnum="WO2014161888A"><text>WO2014161888 (Janssen</text></patcit>), <patcit id="pcit0541" dnum="WO2013096744A"><text>WO2013096744 (Novira</text></patcit>), <patcit id="pcit0542" dnum="US20150225355A"><text>US20150225355 (Novira</text></patcit>), <patcit id="pcit0543" dnum="US20140178337A"><text>US20140178337 (Novira</text></patcit>), <patcit id="pcit0544" dnum="US20150315159A"><text>US20150315159 (Novira</text></patcit>), <patcit id="pcit0545" dnum="US20150197533A"><text>US20150197533 (Novira</text></patcit>), <patcit id="pcit0546" dnum="US20150274652A"><text>US20150274652 (Novira</text></patcit>), <patcit id="pcit0547" dnum="US20150259324A"><text>US20150259324, (Novira</text></patcit>), <patcit id="pcit0548" dnum="US20150132258A"><text>US20150132258 (Novira</text></patcit>), <patcit id="pcit0549" dnum="US9181288B"><text>US9181288 (Novira</text></patcit>), <patcit id="pcit0550" dnum="WO2014184350A"><text>WO2014184350 (Janssen</text></patcit>), <patcit id="pcit0551" dnum="WO2013144129A"><text>WO2013144129 (Roche</text></patcit>), <patcit id="pcit0552" dnum="WO2017198744A"><text>WO2017198744 (Roche</text></patcit>), <patcit id="pcit0553" dnum="US20170334882A"><text>US 20170334882 (Novira</text></patcit>), <patcit id="pcit0554" dnum="US20170334898A"><text>US 20170334898 (Roche</text></patcit>), <patcit id="pcit0555" dnum="WO2017202798A"><text>WO2017202798(Roche</text></patcit>), <patcit id="pcit0556" dnum="WO2017214395A"><text>WO2017214395 (Enanta</text></patcit>), <patcit id="pcit0557" dnum="WO2018001944A"><text>WO2018001944 (Roche</text></patcit>), <patcit id="pcit0558" dnum="WO2018001952A"><text>WO2018001952(Roche</text></patcit>), <patcit id="pcit0559" dnum="WO2018005881A"><text>WO2018005881 (Novira</text></patcit>), <patcit id="pcit0560" dnum="WO2018005883A"><text>WO2018005883 (Novira</text></patcit>), <patcit id="pcit0561" dnum="WO2018011100A"><text>WO2018011100(Roche</text></patcit>), <patcit id="pcit0562" dnum="WO2018011160A"><text>WO2018011160 (Roche</text></patcit>), <patcit id="pcit0563" dnum="WO2018011162A"><text>WO2018011162 (Roche</text></patcit>), <patcit id="pcit0564" dnum="WO2018011163A"><text>WO2018011163 (Roche</text></patcit>), <patcit id="pcit0565" dnum="WO2018036941A"><text>WO2018036941 (Roche</text></patcit>), <patcit id="pcit0566" dnum="WO2018043747A"><text>WO2018043747 (Kyoto Univ</text></patcit>), <patcit id="pcit0567" dnum="US20180065929A"><text>US20180065929 (Janssen</text></patcit>), <patcit id="pcit0568" dnum="WO2016168619A"><text>WO2016168619 (Indiana University</text></patcit>), <patcit id="pcit0569" dnum="WO2016195982A"><text>WO2016195982 (The Penn State Foundation</text></patcit>), <patcit id="pcit0570" dnum="WO2017001655A"><text>WO2017001655 (Janssen</text></patcit>), <patcit id="pcit0571" dnum="WO2017048950A"><text>WO2017048950 (Assembly Biosciences</text></patcit>), <patcit id="pcit0572" dnum="WO2017048954A"><text>WO2017048954 (Assembly Biosciences</text></patcit>), <patcit id="pcit0573" dnum="WO2017048962A"><text>WO2017048962 (Assembly Biosciences</text></patcit>), <patcit id="pcit0574" dnum="US20170121328A"><text>US20170121328 (Novira</text></patcit>), <patcit id="pcit0575" dnum="US20170121329A"><text>US20170121329 (Novira</text></patcit>).

0528Examples of transcript inhibitors include the compounds disclosed in <patcit id="pcit0576" dnum="WO2017013046A"><text>WO2017013046 (Roche</text></patcit>), <patcit id="pcit0577" dnum="WO2017016960A"><text>WO2017016960 (Roche</text></patcit>), <patcit id="pcit0578" dnum="WO2017017042A"><text>WO2017017042 (Roche</text></patcit>), <patcit id="pcit0579" dnum="WO2017017043A"><text>WO2017017043 (Roche</text></patcit>), <patcit id="pcit0580" dnum="WO2017061466A"><text>WO2017061466 (Toyoma chemicals</text></patcit>), <patcit id="pcit0581" dnum="WO2016177655A"><text>WO2016177655 (Roche</text></patcit>), <patcit id="pcit0582" dnum="WO2016161268A"><text>WO2016161268 (Enanta</text></patcit>). <patcit id="pcit0583" dnum="WO2017001853A"><text>WO2017001853 (Redex Pharma</text></patcit>), <patcit id="pcit0584" dnum="WO2017211791A"><text>WO2017211791 (Roche</text></patcit>), <patcit id="pcit0585" dnum="WO2017216685A"><text>WO2017216685 (Novartis</text></patcit>), <patcit id="pcit0586" dnum="WO2017216686A"><text>WO2017216686 (Novartis</text></patcit>), <patcit id="pcit0587" dnum="WO2018019297A"><text>WO2018019297 (Ginkgo Pharma</text></patcit>), <patcit id="pcit0588" dnum="WO2018022282A"><text>WO2018022282 (Newave Pharma</text></patcit>), <patcit id="pcit0589" dnum="US20180030053A"><text>US20180030053 (Novartis</text></patcit>), <patcit id="pcit0590" dnum="WO2018045911A"><text>WO2018045911 (Zhejiang Pharma</text></patcit>).

STING agonists. RIG-I and NOD2 modulators

0529In some embodiments, the agents described herein are combined with a stimulator of interferon genes (STING). In some embodiments, the STING receptor agonist or activator is selected from the group consisting of ADU-S100 (MIW-815), SB-11285, MK-1454, SR-8291, AdVCA0848, STINGVAX, GSK-532, SYN-STING, MSA-1, SR-8291, 5,6-dimethylxanthenone-4-acetic acid (DMXAA), cyclic-GAMP (cGAMP) and cyclic-di-AMP. In some embodiments, the agents described herein are combined with a RIG-I modulator such as RGT-100, or NOD2 modulator, such as SB-9200, and IR-103.

0530Examples of STING agonists include the compounds disclosed in <patcit id="pcit0591" dnum="WO2018065360A"><text>WO 2018065360 ("Biolog Life Science Institute Forschungslabor und Biochemica-Vertrieb GmbH, Germany</text></patcit>), <patcit id="pcit0592" dnum="WO2018009466A"><text>WO 2018009466 (Aduro Biotech</text></patcit>), <patcit id="pcit0593" dnum="WO2017186711A"><text>WO 2017186711 (InvivoGen</text></patcit>), <patcit id="pcit0594" dnum="WO2017161349A"><text>WO 2017161349 (Immune Sensor</text></patcit>), <patcit id="pcit0595" dnum="WO2017106740A"><text>WO 2017106740 (Aduro Biotech</text></patcit>), <patcit id="pcit0596" dnum="US20170158724A"><text>US 20170158724 (Glaxo Smithkiline</text></patcit>), <patcit id="pcit0597" dnum="WO2017075477A"><text>WO 2017075477 (Aduro Biotech</text></patcit>), <patcit id="pcit0598" dnum="US20170044206A"><text>US 20170044206 (Merck</text></patcit>), <patcit id="pcit0599" dnum="WO2014179760A"><text>WO 2014179760 (University of California</text></patcit>), <patcit id="pcit0600" dnum="WO2018098203A"><text>WO2018098203 (Janssn</text></patcit>), <patcit id="pcit0601" dnum="WO2018118665A"><text>WO2018118665 (Merck</text></patcit>), <patcit id="pcit0602" dnum="WO2018118664A"><text>WO2018118664 (Merck</text></patcit>), <patcit id="pcit0603" dnum="WO2018100558A"><text>WO2018100558 (Takeda</text></patcit>), <patcit id="pcit0604" dnum="WO2018067423A"><text>WO2018067423 (Merck</text></patcit>), <patcit id="pcit0605" dnum="WO2018060323A"><text>WO2018060323 (Boehringer</text></patcit>).

Retinoic Acid-inducible Gene 1 Stimulators

0531Examples of stimulators of retinoic acid-inducible gene 1 include inarigivir soproxil (SB-9200), SB-40, SB-44, ORI-7246, ORI-9350, ORI-7537, ORI-9020, ORI-9198, ORI-7170, and RGT-100.

NOD2 Stimulators

0532Examples of stimulators of NOD2 include inarigivir soproxil (SB-9200).

Phosphatidylinositol 3-kinase (PI3K) Inhibitors

0533Examples of PI3K inhibitors include idelalisib, ACP-319, AZD-8186, AZD-8835, buparlisib, CDZ-173, CLR-457, pictilisib, neratinib, rigosertib, rigosertib sodium, EN-3342, TGR-1202, alpelisib, duvelisib, IPI-549, UCB-5857, taselisib, XL-765, gedatolisib, ME-401, VS-5584, copanlisib, CAI orotate, perifosine, RG-7666, GSK-2636771, DS-7423, panulisib, GSK-2269557, GSK-2126458, CUDC-907, PQR-309, INCB-40093, pilaralisib, BAY-1082439, puquitinib mesylate, SAR-245409, AMG-319, RP-6530, ZSTK-474, MLN-1117, SF-1126, RV-1729, sonolisib, LY-3023414, SAR-260301,TAK-117, HMPL-689, tenalisib, voxtalisib, and CLR-1401.

Immune Checkpoint Modulators

0534In some embodiments, the agents as described herein, are combined with one or more blockers or inhibitors of inhibitory immune checkpoint proteins or receptors and/or with one or more stimulators, activators or agonists of one or more stimulatory immune checkpoint proteins or receptors. Blockade or inhibition of inhibitory immune checkpoints can positively regulate T-cell or NK cell activation and prevent immune escape of infected cells. Activation or stimulation of stimulatory immune check points can augment the effect of immune checkpoint inhibitors in infective therapeutics. In some embodiments, the immune checkpoint proteins or receptors regulate T cell responses <i>(e.g.,</i> reviewed in <nplcit id="ncit0071" npl-type="s"><text>Xu, et al., J Exp Clin Cancer Res. (2018) 37:110</text></nplcit>). In some embodiments, the immune checkpoint proteins or receptors regulate NK cell responses <i>(e.g.,</i> reviewed in<nplcit id="ncit0072" npl-type="s"><text> Davis, et al., Semin Immunol. (2017) 31:64-75</text></nplcit> and <nplcit id="ncit0073" npl-type="s"><text>Chiossone, et al., Nat Rev Immunol. (2018) 18(11):671-688</text></nplcit>).

0535Examples of immune checkpoint proteins or receptors include without limitation CD27, CD70; CD40, CD40LG; CD47, CD48 (SLAMF2), transmembrane and immunoglobulin domain containing 2 (TMIGD2, CD28H), CD84 (LY9B, SLAMF5), CD96, CD160, MS4A1 (CD20), CD244 (SLAMF4); CD276 (B7H3); V-set domain containing T cell activation inhibitor 1 (VTCN1, B7H4); V-set immunoregulatory receptor (VSIR, B7H5, VISTA); immunoglobulin superfamily member 11 (IGSF11, VSIG3); natural killer cell cytotoxicity receptor 3 ligand 1 (NCR3LG1, B7H6); HERV-H LTR-associating 2 (HHLA2, B7H7); inducible T cell costimulator (ICOS, CD278); inducible T cell costimulator ligand (ICOSLG, B7H2); TNF receptor superfamily member 4 (TNFRSF4, OX40); TNF superfamily member 4 (TNFSF4, OX40L); TNFRSF8 (CD30), TNFSF8 (CD30L); TNFRSF10A (CD261, DR4, TRAILR1), TNFRSF9 (CD137), TNFSF9 (CD137L); TNFRSF10B (CD262, DR5, TRAILR2), TNFRSF10 (TRAIL); TNFRSF14 (HVEM, CD270), TNFSF14 (HVEML); CD272 (B and T lymphocyte associated (BTLA)); TNFRSF17 (BCMA, CD269), TNFSF13B (BAFF); TNFRSF18 (GITR), TNFSF18 (GITRL); MHC class I polypeptide-related sequence A (MICA); MHC class I polypeptide-related sequence B (MICB); CD274 (CD274, PDL1, PD-L1); programmed cell death 1 (PDCD1, PD1, PD-1); cytotoxic T-lymphocyte associated protein 4 (CTLA4, CD152); CD80 (B7-1), CD28; nectin cell adhesion molecule 2 (NECTIN2, CD112); CD226 (DNAM-1); Poliovirus receptor (PVR) cell adhesion molecule (PVR, CD155); PVR related immunoglobulin domain containing (PVRIG, CD 112R); T cell immunoreceptor with Ig and ITIM domains (TIGIT); T cell immunoglobulin and mucin domain containing 4 (TIMD4; TIM4); hepatitis A virus cellular receptor 2 (HAVCR2, TIMD3, TIM3); galectin 9 (LGALS9); lymphocyte activating 3 (LAG3, CD223); signaling lymphocytic activation molecule family member 1 (SLAMF1, SLAM, CD150); lymphocyte antigen 9 (LY9, CD229, SLAMF3); SLAM family member 6 (SLAMF6, CD352); SLAM family member 7 (SLAMF7, CD319); UL16 binding protein 1 (ULBP1); UL16 binding protein 2 (ULBP2); UL16 binding protein 3 (ULBP3); retinoic acid early transcript 1E (RAET1E; ULBP4); retinoic acid early transcript 1G (RAET1G; ULBP5); retinoic acid early transcript 1L (RAET1L; ULBP6); lymphocyte activating 3 (CD223); killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 1 (KIR, CD158E1); killer cell lectin like receptor C1 (KLRC1, NKG2A, CD159A); killer cell lectin like receptor K1 (KLRK1, NKG2D, CD314); killer cell lectin like receptor C2 (KLRC2, CD159c, NKG2C); killer cell lectin like receptor C3 (KLRC3, NKG2E); killer cell lectin like receptor C4 (KLRC4, NKG2F); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 1 (KIR2DL1); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 3 (KIR2DL3); killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 1 (KIR3DL1); killer cell lectin like receptor D1 (KLRD1); and SLAM family member 7 (SLAMF7).

0536In some embodiments, the agents described herein, are combined with one or more blockers or inhibitors of one or more T-cell inhibitory immune checkpoint proteins or receptors. Illustrative T-cell inhibitory immune checkpoint proteins or receptors include without limitation CD274 (CD274, PDL1, PD-L1); programmed cell death 1 ligand 2 (PDCD1LG2, PD-L2, CD273); programmed cell death 1 (PDCD1, PD1, PD-1); cytotoxic T-lymphocyte associated protein 4 (CTLA4, CD 152); CD276 (B7H3); V-set domain containing T cell activation inhibitor 1 (VTCN1, B7H4); V-set immunoregulatory receptor (VSIR, B7H5, VISTA); immunoglobulin superfamily member 11 (IGSF11, VSIG3); TNFRSF14 (HVEM, CD270), TNFSF14 (HVEML); CD272 (B and T lymphocyte associated (BTLA)); PVR related immunoglobulin domain containing (PVRIG, CD112R); T cell immunoreceptor with Ig and ITIM domains (TIGIT); lymphocyte activating 3 (LAG3, CD223); hepatitis A virus cellular receptor 2 (HAVCR2, TIMD3, TIM3); galectin 9 (LGALS9); killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 1 (KIR, CD158E1); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 1 (KIR2DL1); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 3 (KIR2DL3); and killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 1 (KIR3DL1). In some embodiments, the agents, as described herein, are combined with one or more agonist or activators of one or more T-cell stimulatory immune checkpoint proteins or receptors. Illustrative T-cell stimulatory immune checkpoint proteins or receptors include without limitation CD27, CD70; CD40, CD40LG; inducible T cell costimulator (ICOS, CD278); inducible T cell costimulator ligand (ICOSLG, B7H2); TNF receptor superfamily member 4 (TNFRSF4, OX40); TNF superfamily member 4 (TNFSF4, OX40L); TNFRSF9 (CD137), TNFSF9 (CD137L); TNFRSF18 (GITR), TNFSF18 (GITRL); CD80 (B7-1), CD28; nectin cell adhesion molecule 2 (NECTIN2, CD112); CD226 (DNAM-1); CD244 (2B4, SLAMF4), Poliovirus receptor (PVR) cell adhesion molecule (PVR, CD155). <i>See, e.g.,</i><nplcit id="ncit0074" npl-type="s"><text>Xu, et al., J Exp Clin Cancer Res. (2018) 37:110</text></nplcit>.

0537In some embodiments, the agents as described herein, are combined with one or more blockers or inhibitors of one or more NK-cell inhibitory immune checkpoint proteins or receptors. Illustrative NK-cell inhibitory immune checkpoint proteins or receptors include without limitation killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 1 (KIR, CD158E1); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 1 (KIR2DL1); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 3 (KIR2DL3); killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 1 (KIR3DL1); killer cell lectin like receptor C1 (KLRC1, NKG2A, CD159A); and killer cell lectin like receptor D1 (KLRD1, CD94). In some embodiments, the agents as described herein, are combined with one or more agonist or activators of one or more NK-cell stimulatory immune checkpoint proteins or receptors. Illustrative NK-cell stimulatory immune checkpoint proteins or receptors include without limitation CD16, CD226 (DNAM-1); CD244 (2B4, SLAMF4); killer cell lectin like receptor K1 (KLRK1, NKG2D, CD314); SLAM family member 7 (SLAMF7). <i>See, e.g.,</i><nplcit id="ncit0075" npl-type="s"><text>Davis, et al., Semin Immunol. (2017) 31:64-75</text></nplcit>; <nplcit id="ncit0076" npl-type="s"><text>Fang, et al., Semin Immunol. (2017) 31:37-54</text></nplcit>; and <nplcit id="ncit0077" npl-type="s"><text>Chiossone, et al., Nat Rev Immunol. (2018) 18(11):671-688</text></nplcit>.

0538In some embodiments, the one or more immune checkpoint inhibitors comprises a proteinaceous (e.g., antibody or fragment thereof, or antibody mimetic) inhibitor of PD-L1 (CD274), PD-1 (PDCD1) or CTLA4. In some embodiments, the one or more immune checkpoint inhibitors comprises a small organic molecule inhibitor of PD-L1 (CD274), PD-1 (PDCD1) or CTLA4. In some embodiments, the small molecule inhibitor of CD274 or PDCD1 is selected from the group consisting of GS-4224, GS-4416, INCB086550 and MAX10181. In some embodiments, the small molecule inhibitor of CTLA4 comprises BPI-002.

0539Examples of inhibitors of CTLA4 that can be co-administered include without limitation ipilimumab, tremelimumab, BMS-986218, AGEN1181, AGEN1884, BMS-986249, MK-1308, REGN-4659, ADU-1604, CS-1002, BCD-145, APL-509, JS-007, BA-3071, ONC-392, AGEN-2041, JHL-1155, KN-044, CG-0161, ATOR-1144, PBI-5D3H5, BPI-002, as well as multi-specific inhibitors FPT-155 (CTLA4/PD-L1/CD28), PF-06936308 (PD-1/ CTLA4), MGD-019 (PD-1/CTLA4), KN-046 (PD-1/CTLA4), MEDI-5752 (CTLA4/PD-1), XmAb-20717 (PD-1/CTLA4), and AK-104 (CTLA4/PD-1).

0540Examples of inhibitors of PD-L1 (CD274) or PD-1 (PDCD1) that can be co-administered include without limitation pembrolizumab, nivolumab, cemiplimab, pidilizumab, AMP-224, MEDI0680 (AMP-514), spartalizumab, atezolizumab, avelumab, durvalumab, ALN-PDL, BMS-936559, CK-301, PF-06801591, BGB-108, BGB-A317 (tislelizumab), GLS-010 (WBP-3055), AK-103 (HX-008), GB-226, AK-105, CS-1003, HLX-10, MGA-012, BI-754091, PDR-001, AGEN-2034, JS-001 (toripalimab), JNJ-63723283, genolimzumab (CBT-501), LZM-009, BCD-100, LY-3300054, SHR-1201, SHR-1210 (camrelizumab), Sym-021, ABBV-181, PD1-PIK, BAT-1306, RO-6084 (PD-L1 antisense oligonucleotide), STI-1110, GX-P2, RG-7446, mDX-400, (MSB0010718C), CX-072, CBT-502, TSR-042 (dostarlimab), MSB-2311, JTX-4014, BGB-A333, SHR-1316, CS-1001 (WBP-3155), MEDI-0680, envafolimab (KN-035), KD-033, KY-1003, IBI-308 (sintilimab), HLX-20, KL-A167, STI-A1014, STI-A1015 (IMC-001), BCD-135, FAZ-053, TQB-2450, MDX1105-01, MSB-0010718C, GS-4224, GS-4416, INCB086550, MAX10181, as well as multi-specific inhibitors FPT-155 (CTLA4/PD-L1/CD28), PF-06936308 (PD-1/ CTLA4), MGD-013 (PD-1/LAG-3), FS-118 (LAG-3/PD-L1) MGD-019 (PD-1/CTLA4), KN-046 (PD-1/CTLA4), MEDI-5752 (CTLA4/PD-1), RO-7121661 (PD-1/TIM-3), XmAb-20717 (PD-1/CTLA4), AK-104 (CTLA4/PD-1), M7824 (PD-L1/TGFβ-EC domain), CA-170 (PD-L1/VISTA), CDX-527 (CD27/PD-L1), LY-3415244 (TIM3/PDL1), GNS-1480 (Epidermal growth factor receptor antagonist; Programmed cell death ligand 1 inhibitor), M-7824 (PD-L1/TGF-β bifunctional fusion protein), and INBRX-105 (4-1BB/PDL1).

0541Examples of PD-1inhibitors include the compounds disclosed in <patcit id="pcit0606" dnum="WO2017112730A"><text>WO2017112730 (Incyte Corp</text></patcit>), <patcit id="pcit0607" dnum="WO2017087777A"><text>WO2017087777(Incyte Corp</text></patcit>), <patcit id="pcit0608" dnum="WO2017017624A"><text>WO2017017624</text></patcit>, <patcit id="pcit0609" dnum="WO2014151634A"><text>WO2014151634 (BristolMyers Squibb Co</text></patcit>), <patcit id="pcit0610" dnum="WO201317322A"><text>WO201317322 (BristolMyers Squibb Co</text></patcit>), <patcit id="pcit0611" dnum="WO2018119286A"><text>WO2018119286 (Incyte Corp</text></patcit>), <patcit id="pcit0612" dnum="WO2018119266A"><text>WO2018119266 (Incyte Corp</text></patcit>), <patcit id="pcit0613" dnum="WO2018119263A"><text>WO2018119263(Incyte Corp</text></patcit>), <patcit id="pcit0614" dnum="WO2018119236A"><text>WO2018119236 (Incyte Corp</text></patcit>), <patcit id="pcit0615" dnum="WO2018119221A"><text>WO2018119221(Incyte Corp</text></patcit>), <patcit id="pcit0616" dnum="WO2018118848A"><text>WO2018118848 (BristolMyers Squibb Co</text></patcit>), <patcit id="pcit0617" dnum="WO20161266460A"><text>WO20161266460(BristolMyers Squibb Co</text></patcit>), <patcit id="pcit0618" dnum="WO2017087678A"><text>WO2017087678 (BristolMyers Squibb Co</text></patcit>), <patcit id="pcit0619" dnum="WO2016149351A"><text>WO2016149351 (BristolMyers Squibb Co</text></patcit>), <patcit id="pcit0620" dnum="WO2015033299A"><text>WO2015033299 (Aurigene Discovery Technologies Ltd</text></patcit>), <patcit id="pcit0621" dnum="WO2015179615A"><text>WO2015179615(Eisai Co Ltd; Eisai Research Institute</text></patcit>), <patcit id="pcit0622" dnum="WO2017066227A"><text>WO2017066227(BristolMyers Squibb Co</text></patcit>), <patcit id="pcit0623" dnum="WO2016142886A"><text>WO2016142886 (Aurigene Discovery Technologies Ltd</text></patcit>), <patcit id="pcit0624" dnum="WO2016142852A"><text>WO2016142852(Aurigene Discovery Technologies Ltd</text></patcit>), <patcit id="pcit0625" dnum="WO2016142835A"><text>WO2016142835 (Aurigene Discovery Technologies Ltd; Individual</text></patcit>), <patcit id="pcit0626" dnum="WO2016142833A"><text>WO2016142833 (Aurigene Discovery Technologies Ltd</text></patcit>), <patcit id="pcit0627" dnum="WO2018085750A"><text>WO2018085750 (BristolMyers Squibb Co</text></patcit>), <patcit id="pcit0628" dnum="WO2015033303A"><text>WO2015033303 (Aurigene Discovery Technologies Ltd</text></patcit>), <patcit id="pcit0629" dnum="WO2017205464A"><text>WO2017205464 (Incyte Corp</text></patcit>), <patcit id="pcit0630" dnum="WO2016019232A"><text>WO2016019232 (3M Co; Individual; Texas A&amp;M University System</text></patcit>), <patcit id="pcit0631" dnum="WO2015160641A"><text>WO2015160641 (BristolMyers Squibb Co</text></patcit>), <patcit id="pcit0632" dnum="WO2017079669A"><text>WO2017079669 (Incyte Corp</text></patcit>), <patcit id="pcit0633" dnum="WO2015033301A"><text>WO2015033301 (Aurigene Discovery Technologies Ltd</text></patcit>), <patcit id="pcit0634" dnum="WO2015034820A"><text>WO2015034820 (BristolMyers Squibb Co</text></patcit>), <patcit id="pcit0635" dnum="WO2018073754A"><text>WO2018073754 (Aurigene Discovery Technologies Ltd</text></patcit>), <patcit id="pcit0636" dnum="WO2016077518A"><text>WO2016077518 (BristolMyers Squibb Co</text></patcit>), <patcit id="pcit0637" dnum="WO2016057624A"><text>WO2016057624 (BristolMyers Squibb Co</text></patcit>), <patcit id="pcit0638" dnum="WO2018044783A"><text>WO2018044783 (Incyte Corp</text></patcit>), <patcit id="pcit0639" dnum="WO2016100608A"><text>WO2016100608 (BristolMyers Squibb Co</text></patcit>), <patcit id="pcit0640" dnum="WO2016100285A"><text>WO2016100285 (BristolMyers Squibb Co</text></patcit>), <patcit id="pcit0641" dnum="WO2016039749A"><text>WO2016039749 (BristolMyers Squibb Co</text></patcit>), <patcit id="pcit0642" dnum="WO2015019284A"><text>WO2015019284 (Cambridge Enterprise Ltd</text></patcit>), <patcit id="pcit0643" dnum="WO2016142894A"><text>WO2016142894 (Aurigene Discovery Technologies Ltd</text></patcit>), <patcit id="pcit0644" dnum="WO2015134605A"><text>WO2015134605 (BristolMyers Squibb Co</text></patcit>), <patcit id="pcit0645" dnum="WO2018051255A"><text>WO2018051255 (Aurigene Discovery Technologies Ltd</text></patcit>), <patcit id="pcit0646" dnum="WO2018051254A"><text>WO2018051254 (Aurigene Discovery Technologies Ltd</text></patcit>), <patcit id="pcit0647" dnum="WO2017222976A"><text>WO2017222976 (Incyte Corp</text></patcit>), <patcit id="pcit0648" dnum="WO2017070089A"><text>WO2017070089 (Incyte Corp</text></patcit>), <patcit id="pcit0649" dnum="WO2018044963A"><text>WO2018044963 (BristolMyers Squibb Co</text></patcit>), <patcit id="pcit0650" dnum="WO2013144704A"><text>WO2013144704 (Aurigene Discovery Technologies Ltd</text></patcit>), <patcit id="pcit0651" dnum="WO2018013789A"><text>WO2018013789 (Incyte Corp</text></patcit>), <patcit id="pcit0652" dnum="WO2017176608A"><text>WO2017176608 (BristolMyers Squibb Co</text></patcit>), <patcit id="pcit0653" dnum="WO2018009505A"><text>WO2018009505 (BristolMyers Squibb Co</text></patcit>), <patcit id="pcit0654" dnum="WO2011161699A"><text>WO2011161699 (Aurigene Discovery Technologies Ltd</text></patcit>), <patcit id="pcit0655" dnum="WO2015119944A"><text>WO2015119944 (Incyte Corp; Merck Sharp &amp; Dohme Corp</text></patcit>), <patcit id="pcit0656" dnum="WO2017192961A"><text>WO2017192961 (Incyte Corp</text></patcit>), <patcit id="pcit0657" dnum="WO2017106634A"><text>WO2017106634 (Incyte Corp</text></patcit>), <patcit id="pcit0658" dnum="WO2013132317A"><text>WO2013132317 (Aurigene Discovery Technologies Ltd</text></patcit>), <patcit id="pcit0659" dnum="WO2012168944A"><text>WO2012168944 (Aurigene Discovery Technologies Ltd</text></patcit>), <patcit id="pcit0660" dnum="WO2015036927A"><text>WO2015036927 (Aurigene Discovery Technologies Ltd</text></patcit>),<patcit id="pcit0661" dnum="WO2015044900A"><text>WO2015044900 (Aurigene Discovery Technologies Ltd</text></patcit>), <patcit id="pcit0662" dnum="WO2018026971A"><text>WO2018026971 (Arising International</text></patcit>).

0542In some embodiments, the agents as described herein are combined with anti-TIGIT antibodies, such as BMS-986207, RG-6058, AGEN-1307.

TNF Receptor Superfamily (TNFRSF) Member Agonists or Activators

0543In some embodiments, the agents as described herein are combined with an agonist of one or more TNF receptor superfamily (TNFRSF) members, e.g., an agonist of one or more of TNFRSF1A (NCBI Gene ID: 7132), TNFRSF1B (NCBI Gene ID: 7133), TNFRSF4 (OX40, CD134; NCBI Gene ID: 7293), TNFRSF5 (CD40; NCBI Gene ID: 958), TNFRSF6 (FAS, NCBI Gene ID: 355), TNFRSF7 (CD27, NCBI Gene ID: 939), TNFRSF8 (CD30, NCBI Gene ID: 943), TNFRSF9 (4-1BB, CD137, NCBI Gene ID: 3604), TNFRSF10A (CD261, DR4, TRAILR1, NCBI Gene ID: 8797), TNFRSF10B (CD262, DR5, TRAILR2, NCBI Gene ID: 8795), TNFRSF10C (CD263, TRAILR3, NCBI Gene ID: 8794), TNFRSF10D (CD264, TRAILR4, NCBI Gene ID: 8793), TNFRSF11A (CD265, RANK, NCBI Gene ID: 8792), TNFRSF11B (NCBI Gene ID: 4982), TNFRSF12A (CD266, NCBI Gene ID: 51330), TNFRSF13B (CD267, NCBI Gene ID: 23495), TNFRSF13C (CD268, NCBI Gene ID: 115650), TNFRSF16 (NGFR, CD271, NCBI Gene ID: 4804), TNFRSF17 (BCMA, CD269, NCBI Gene ID: 608), TNFRSF18 (GITR, CD357, NCBI Gene ID: 8784), TNFRSF19 (NCBI Gene ID: 55504), TNFRSF21 (CD358, DR6, NCBI Gene ID: 27242), and TNFRSF25 (DR3, NCBI Gene ID: 8718).

0544Example anti-TNFRSF4 (OX40) antibodies that can be co-administered include without limitation, MED16469, MED16383, MEDI0562 (tavolixizumab), MOXR0916, PF-04518600, RG-7888, GSK-3174998, INCAGN1949, BMS-986178, GBR-8383, ABBV-368, IBI-101 and those described in <patcit id="pcit0663" dnum="WO2016179517A"><text>WO2016179517</text></patcit>, <patcit id="pcit0664" dnum="WO2017096179A"><text>WO2017096179</text></patcit>, <patcit id="pcit0665" dnum="WO2017096182A"><text>WO2017096182</text></patcit>, <patcit id="pcit0666" dnum="WO2017096281A"><text>WO2017096281</text></patcit>, and <patcit id="pcit0667" dnum="WO2018089628A"><text>WO2018089628</text></patcit>.

0545Example anti-TNFRSF5 (CD40) antibodies that can be co-administered include without limitation RG7876, SEA-CD40, APX-005M and ABBV-428.

0546In some embodiments, the anti-TNFRSF7 (CD27) antibody varlilumab (CDX-1127) is co-administered.

0547Example anti-TNFRSF9 (4-1BB, CD137) antibodies that can be co-administered include without limitation urelumab, utomilumab (PF-05082566), AGEN2373 and ADG-106.

0548Example anti-TNFRSF18 (GITR) antibodies that can be co-administered include without limitation, MEDI1873, FPA-154, INCAGN-1876, TRX-518, BMS-986156, MK-1248, GWN-323, and those described in <patcit id="pcit0668" dnum="WO2017096179A"><text>WO2017096179</text></patcit>, <patcit id="pcit0669" dnum="WO2017096276A"><text>WO2017096276</text></patcit>, <patcit id="pcit0670" dnum="WO2017096189A"><text>WO2017096189</text></patcit>, and <patcit id="pcit0671" dnum="WO2018089628A"><text>WO2018089628</text></patcit>. In some embodiments, an antibody, or fragment thereof, co-targeting TNFRSF4 (OX40) and TNFRSF18 (GITR) is co-administered. Such antibodies are described, <i>e.g.,</i> in <patcit id="pcit0672" dnum="WO2017096179A"><text>WO2017096179</text></patcit> and <patcit id="pcit0673" dnum="WO2018089628A"><text>WO2018089628</text></patcit>.

Indoleamine-pyrrole-2,3-dioxygenase (IDO1) inhibitors

0549In some embodiments, the agents as described herein, are combined with an inhibitor of indoleamine 2,3-dioxygenase 1 (IDO1; NCBI Gene ID: 3620). Examples of IDO1 inhibitors include without limitation, BLV-0801, epacadostat, resminostat, F-001287, GBV-1012, GBV-1028, GDC-0919, indoximod, NKTR-218, NLG-919-based vaccine, PF-06840003, pyranonaphthoquinone derivatives (SN-35837), SBLK-200802, BMS-986205, and shIDO-ST, EOS-200271, KHK-2455, LY-3381916, and the compounds disclosed in <patcit id="pcit0674" dnum="US20100015178A"><text>US20100015178 (Incyte</text></patcit>), <patcit id="pcit0675" dnum="US2016137652A"><text>US2016137652 (Flexus Biosciences, Inc</text></patcit>.), <patcit id="pcit0676" dnum="WO2014073738A"><text>WO2014073738 (Flexus Biosciences, Inc</text></patcit>.), and <patcit id="pcit0677" dnum="WO2015188085A"><text>WO2015188085(Flexus Biosciences, Inc</text></patcit>.).

LAG-3 and TIM-3 inhibitors

0550In some embodiments, the agents as described herein are combined with an anti-TIM-3 antibody, such as TSR-022, LY-3321367, MBG-453, INCAGN-2390.

0551In some embodiments, the antibodies or antigen-binding fragments described herein are combined with an anti LAG-3 (Lymphocyte-activation) antibody, such as relatlimab (ONO-4482), LAG-525, MK-4280, REGN-3767, INCAGN2385.

0552Examples of additional immune-based therapies that can be combined with an agent of this disclosure include interferon alfa; interferon alfa-2b; interferon alfa-n3; pegylated interferon alfa; interferon gamma; Flt3 agonists; gepon; normferon, peginterferon alfa-2a, peginterferon alfa-2b, RPI-MN.

Inhibitor of apoptosis proteins family proteins (IAPs)

0553Examples of IAP inhibitors include APG-1387.

Recombinant Thymosin Alpha-1

0554Examples of recombinant thymosin alpha-1 include NL-004 and PEGylated thymosin alpha-1.

Bruton's Tyrosine Kinase (BTK) Inhibitors

0555Examples of BTK inhibitors include ABBV-105, acalabrutinib (ACP-196), ARQ-531, BMS-986142, dasatinib, ibrutinib, GDC-0853, PRN-1008, SNS-062, ONO-4059, BGB-3111, ML-319, MSC-2364447, RDX-022, X-022, AC-058, RG-7845, spebrutinib, TAS-5315, TP-0158, TP-4207, HM-71224, KBP-7536, M-2951, TAK-020, AC-0025, and the compounds disclosed in <patcit id="pcit0678" dnum="US20140330015A"><text>US20140330015 (Ono Pharmaceutical</text></patcit>), <patcit id="pcit0679" dnum="US20130079327A"><text>US20130079327 (Ono Pharmaceutical</text></patcit>), and <patcit id="pcit0680" dnum="US20130217880A"><text>US20130217880 (Ono Pharmaceutical</text></patcit>).

KDM Inhibitors

0556Examples of KDM5 inhibitors include the compounds disclosed in <patcit id="pcit0681" dnum="WO2016057924A"><text>WO2016057924 (Genentech/Constellation Pharmaceuticals</text></patcit>), <patcit id="pcit0682" dnum="US20140275092A"><text>US20140275092 (Genentech/Constellation Pharmaceuticals</text></patcit>), <patcit id="pcit0683" dnum="US20140371195A"><text>US20140371195 (Epitherapeutics</text></patcit>), <patcit id="pcit0684" dnum="US20140371214A"><text>US20140371214 (Epitherapeutics</text></patcit>), <patcit id="pcit0685" dnum="US20160102096A"><text>US20160102096 (Epitherapeutics</text></patcit>), <patcit id="pcit0686" dnum="US20140194469A"><text>US20140194469 (Quanticel</text></patcit>), <patcit id="pcit0687" dnum="US20140171432A"><text>US20140171432</text></patcit>, <patcit id="pcit0688" dnum="US20140213591A"><text>US20140213591 (Quanticel</text></patcit>), <patcit id="pcit0689" dnum="US20160039808A"><text>US20160039808 (Quanticel</text></patcit>), <patcit id="pcit0690" dnum="US20140275084A"><text>US20140275084 (Quanticel</text></patcit>), and <patcit id="pcit0691" dnum="WO2014164708A"><text>WO2014164708 (Quanticel</text></patcit>).

0557Examples of KDM1 inhibitors include the compounds disclosed in <patcit id="pcit0692" dnum="US9186337B2"><text>US9186337B2 (Oryzon Genomics</text></patcit>), GSK-2879552, RG-6016, and ORY-2001.

Arginase inhibitors

0558Examples of Arginase inhibitors include CB-1158, C-201, and resminostat.

Bi-and Tri-Specific Natural Killer (NK)-Cell Engagers

0559In some embodiments, the agents as described herein, are combined with a bi-specific NK-cell engager (BiKE) or a tri-specific NK-cell engager (TriKE) (<i>e.g.,</i> not having an Fc) or bi-specific antibody (<i>e.g.,</i> having an Fc) against an NK cell activating receptor, <i>e.g.,</i> CD16A, C-type lectin receptors (CD94/NKG2C, NKG2D, NKG2E/H and NKG2F), natural cytotoxicity receptors (NKp30, NKp44 and NKp46), killer cell C-type lectin-like receptor (NKp65, NKp80), Fc receptor FcyR (which mediates antibody-dependent cell cytotoxicity), SLAM family receptors (<i>e</i>.<i>g</i>., 2B4, SLAM6 and SLAM7), killer cell immunoglobulin-like receptors (KIR) (KIR-2DS and KIR-3DS), DNAM-1 and CD137 (41BB). As appropriate, the anti-CD16 binding bi-specific molecules may or may not have an Fc. Illustrative bi-specific NK-cell engagers that can be co-administered target CD 16 and one or more HBV-associated antigens as described herein. BiKEs and TriKEs are described, <i>e.g.,</i> in <nplcit id="ncit0078" npl-type="s"><text>Felices, et al., Methods Mol Biol. (2016) 1441:333-346</text></nplcit>; <nplcit id="ncit0079" npl-type="s"><text>Fang, et al., Semin Immunol. (2017) 31:37-54</text></nplcit>.

Long Acting Treatments

0560Long acting entecavir (subcutaneous depot), long acting tenofovir (TFD and TAF) implants (devices) or subcutaneous depot. An example of long acting entecavir is described in <nplcit id="ncit0080" npl-type="s"><text>Exploration of long-acting implant formulations of hepatitis B drug entecavir., Eur J Pharm Sci. 2019 Aug 1;136:104958</text></nplcit>;

Gene Therapy and Cell Therapy

0561In some embodiments, the agents described herein are combined with a gene or cell therapy regimen. Gene therapy and cell therapy include without limitation the genetic modification to silence a gene; genetic approaches to directly kill the infected cells; the infusion of immune cells designed to replace most of the patient's own immune system to enhance the immune response to infected cells, or activate the patient's own immune system to kill infected cells, or find and kill the infected cells; genetic approaches to modify cellular activity to further alter endogenous immune responsiveness against the infection.

Gene Editors

0562The genome editing system is selected from the group consisting of: a CRISPR/Cas9 system, a zinc finger nuclease system, a TALEN system, a homing endonucleases system, and a meganuclease system (<i>e.g.,</i> an ARCUS system); <i>e.g.,</i> cccDNA elimination via targeted cleavage, and altering one or more of the hepatitis B virus (HBV) viral genes. Altering (<i>e</i>.<i>g</i>., knocking out and/or knocking down) the <i>PreC,</i> C, <i>X, PreSI, PreS2,</i> S, <i>P or SP</i> gene refers to (1) reducing or eliminating <i>PreC, C</i>, <i>X, PreSI, PreS2,</i> S, <i>P or SP</i> gene expression, (2) interfering with Precore, Core, X protein, Long surface protein, middle surface protein, S protein (also known as HBs antigen and HBsAg), polymerase protein, and/or Hepatitis B spliced protein function (HBe, HBc, HBx, PreS1, PreS2, S, Pol, and/or HBSP or (3) reducing or eliminating the intracellular, serum and/or intraparenchymal levels of HBe, HBc, HBx, LHBs, MHBs, SHBs, Pol, and/or HBSP proteins. Knockdown of one or more of the <i>PreC,</i> C, <i>X, PreSI, PreS2,</i> S, <i>P</i> and/or <i>SP</i> gene(s) is performed by targeting the gene(s) within HBV cccDNA and/or integrated HBV DNA. Example of gene therapy, such as liver targeted anti-HBV gene therapy (using ARCUS technology), or using CRISPR/Cas9 gene editing technology, or EBT-106 (LNP-delivered CRISPR/CasX nuclease.

CAR-T cell therapy

0563CAR-T cell therapy includes a population of immune effector cells engineered to express a chimeric antigen receptor (CAR), wherein the CAR includes an HBV antigen-binding domain. In some embodiments, the antigen-binding domain is a domain disclosed herein. In some embodiments, the antigen-binding domain is other than a domain disclosed herein. In some embodiments, the antigen is HBsAg (i.e. HbsAg- CART). The immune effector cell is a T-cell or an NK cell. In some embodiments, the T-cell is a CD4+ T-cell, a CD8+ T-cell, a NK cell or a combination thereof. Cells can be autologous or allogeneic. An example of a CART directed to HBV is described in<nplcit id="ncit0081" npl-type="s"><text> Cytotherapy. 2018 May;20(5):697-705. doi: 10.1016/j.icyt.2018.02</text></nplcit>.

TCR-T cell therapy

0564TCR-T cell therapy includes T cells expressing HBV-specific T cell receptors. TCR-T cells are engineered to target HBV derived peptides presented on the surface of virus-infected cells. An example of a TCR directed to HBV is described in <nplcit id="ncit0082" npl-type="s"><text>Wisskirchen, K. et al. T cell receptor grafting allows virological control of hepatitis B virus infection. J Clin Invest. 2019;129(7):2932-2945</text></nplcit>.

0565TCR-T cell therapy includes T-Cells expressing HBV surface antigen (HBsAg)-specific TCR.

0566TCR-T cell therapy includes TCR-T therapy directed to treatment of HBV, such as LTCR-H2-1.

0567In another specific embodiment, an agent disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with an HBV DNA polymerase inhibitor, one or two additional therapeutic agents selected from the group consisting of immunomodulators, TLR modulators, HBsAg inhibitors, HBsAg secretion or assembly inhibitors, HBV therapeutic vaccines, HBV antibodies including HBV antibodies targeting the surface antigens of the hepatitis B virus and bispecific antibodies and "antibody-like" therapeutic proteins (such as DARTs^®, DUOBODIES^®, BITES^®, XmAbs^®, TandAbs^®, Fab derivatives, or TCR-like antibodies), cyclophilin inhibitors, stimulators of retinoic acid-inducible gene 1, stimulators of RIG-I like receptors, PD-1 inhibitors, PD-L1 inhibitors, Arginase inhibitors, PI3K inhibitors, IDO inhibitors, and stimulators of NOD2, and one or two additional therapeutic agents selected from the group consisting of HBV viral entry inhibitors, NTCP inhibitors, HBx inhibitors, cccDNA inhibitors, HBV antibodies targeting the surface antigens of the hepatitis B virus, siRNA, miRNA gene therapy agents, sshRNAs, KDM5 inhibitors, and nucleoprotein modulators (HBV core or capsid protein modulators).

0568In another specific embodiment, an agent disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with at least a second additional therapeutic agent selected from the group consisting of: HBV DNA polymerase inhibitors, immunomodulator, TLR modulators, HBsAg inhibitors, HBV therapeutic vaccines, HBV antibodies including HBV antibodies targeting the surface antigens of the hepatitis B virus and bispecific antibodies and "antibody-like" therapeutic proteins (such as DARPins^®, anti-pMHC TCR-like antibodies, DARTs^®, DUOBODIES^®, BITES^®, XmAbs^®, TandAbs^®, Fab derivatives, or TCR-like antibodies), cyclophilin inhibitors, stimulators of retinoic acid-inducible gene 1, stimulators of RIG-I like receptors, PD-1 inhibitors, PD-L1 inhibitors, Arginase inhibitors, PI3K inhibitors, IDO inhibitors, and stimulators of NOD2.

0569In another specific embodiment, an agent disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with at least a second additional therapeutic agent selected from the group consisting of: HBV DNA polymerase inhibitors, HBV viral entry inhibitors, NTCP inhibitors, HBx inhibitors, cccDNA inhibitors, HBV antibodies targeting the surface antigens of the hepatitis B virus, siRNA, miRNA gene therapy agents, sshRNAs, KDM5 inhibitors, and nucleoprotein modulators (HBV core or capsid protein inhibitors).

0570In a particular embodiment, an agent disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with compounds such as those disclosed in <patcit id="pcit0693" dnum="US20100143301A"><text>U.S. Publication No. 2010/0143301 (Gilead Sciences</text></patcit>), <patcit id="pcit0694" dnum="US20110098248A"><text>U.S. Publication No. 2011/0098248 (Gilead Sciences</text></patcit>), <patcit id="pcit0695" dnum="US20090047249A"><text>U.S. Publication No. 2009/0047249 (Gilead Sciences</text></patcit>), <patcit id="pcit0696" dnum="US8722054B"><text>U.S. Patent No. 8722054 (Gilead Sciences</text></patcit>), <patcit id="pcit0697" dnum="US20140045849A"><text>U.S. Publication No. 2014/0045849 (Janssen</text></patcit>), <patcit id="pcit0698" dnum="US20140073642A"><text>U.S. Publication No. 2014/0073642 (Janssen</text></patcit>), <patcit id="pcit0699" dnum="WO2014056953A"><text>WO2014/056953 (Janssen</text></patcit>), <patcit id="pcit0700" dnum="WO2014076221A"><text>WO2014/076221 (Janssen</text></patcit>), <patcit id="pcit0701" dnum="WO2014128189A"><text>WO2014/128189 (Janssen</text></patcit>), <patcit id="pcit0702" dnum="US20140350031A"><text>U.S. Publication No. 2014/0350031 (Janssen</text></patcit>), <patcit id="pcit0703" dnum="WO2014023813A"><text>WO2014/023813 (Janssen</text></patcit>), <patcit id="pcit0704" dnum="US20080234251A"><text>U.S. Publication No. 2008/0234251 (Array Biopharma</text></patcit>), <patcit id="pcit0705" dnum="US20080306050A"><text>U.S. Publication No. 2008/0306050 (Array Biopharma</text></patcit>), <patcit id="pcit0706" dnum="US20100029585A"><text>U.S. Publication No. 2010/0029585 (Ventirx Pharma</text></patcit>), <patcit id="pcit0707" dnum="US20110092485A"><text>U.S. Publication No. 2011/0092485 (Ventirx Pharma</text></patcit>), <patcit id="pcit0708" dnum="US20110118235A"><text>US2011/0118235 (Ventirx Pharma</text></patcit>), <patcit id="pcit0709" dnum="US20120082658A"><text>U.S. Publication No. 2012/0082658 (Ventirx Pharma</text></patcit>), <patcit id="pcit0710" dnum="US20120219615A"><text>U.S. Publication No. 2012/0219615 (Ventirx Pharma</text></patcit>), <patcit id="pcit0711" dnum="US20140066432A"><text>U.S. Publication No. 2014/0066432 (Ventirx Pharma</text></patcit>), <patcit id="pcit0712" dnum="US20140088085A"><text>U.S. Publication No. 2014/0088085 (Ventirx Pharma</text></patcit>), <patcit id="pcit0713" dnum="US20140275167A"><text>U.S. Publication No. 2014/0275167 (Novira Therapeutics</text></patcit>), <patcit id="pcit0714" dnum="US20130251673A"><text>U.S. Publication No. 2013/0251673 (Novira Therapeutics</text></patcit>) , <patcit id="pcit0715" dnum="US8513184B"><text>U.S. Patent No. 8513184 (Gilead Sciences</text></patcit>), <patcit id="pcit0716" dnum="US20140030221A"><text>U.S. Publication No. 2014/0030221 (Gilead Sciences</text></patcit>), <patcit id="pcit0717" dnum="US20130344030A"><text>U.S. Publication No. 2013/0344030 (Gilead Sciences</text></patcit>), <patcit id="pcit0718" dnum="US20130344029A"><text>U.S. Publication No. 2013/0344029 (Gilead Sciences</text></patcit>), <patcit id="pcit0719" dnum="US20140275167A"><text>US20140275167 (Novira Therapeutics</text></patcit>), <patcit id="pcit0720" dnum="US20130251673A"><text>US20130251673 (Novira Therapeutics</text></patcit>),<patcit id="pcit0721" dnum="US20140343032A"><text>U.S. Publication No. 2014/0343032 (Roche</text></patcit>), <patcit id="pcit0722" dnum="WO2014037480A"><text>WO2014037480 (Roche</text></patcit>), <patcit id="pcit0723" dnum="US20130267517A"><text>U.S. Publication No. 2013/0267517 (Roche</text></patcit>), <patcit id="pcit0724" dnum="WO2014131847A"><text>WO2014131847 (Janssen</text></patcit>), <patcit id="pcit0725" dnum="WO2014033176A"><text>WO2014033176 (Janssen</text></patcit>), <patcit id="pcit0726" dnum="WO2014033170A"><text>WO2014033170 (Janssen</text></patcit>), <patcit id="pcit0727" dnum="WO2014033167A"><text>WO2014033167 (Janssen</text></patcit>), <patcit id="pcit0728" dnum="WO2015059212A"><text>WO2015/059212 (Janssen</text></patcit>), <patcit id="pcit0729" dnum="WO2015118057A"><text>WO2015118057(Janssen</text></patcit>), <patcit id="pcit0730" dnum="WO2015011281A"><text>WO2015011281 (Janssen</text></patcit>), <patcit id="pcit0731" dnum="WO2014184365A"><text>WO2014184365 (Janssen</text></patcit>), <patcit id="pcit0732" dnum="WO2014184350A"><text>WO2014184350 (Janssen</text></patcit>), <patcit id="pcit0733" dnum="WO2014161888A"><text>WO2014161888 (Janssen</text></patcit>), <patcit id="pcit0734" dnum="WO2013096744A"><text>WO2013096744 (Novira</text></patcit>), <patcit id="pcit0735" dnum="US20150225355A"><text>US20150225355 (Novira</text></patcit>), <patcit id="pcit0736" dnum="US20140178337A"><text>US20140178337 (Novira</text></patcit>), <patcit id="pcit0737" dnum="US20150315159A"><text>US20150315159 (Novira</text></patcit>), <patcit id="pcit0738" dnum="US20150197533A"><text>US20150197533 (Novira</text></patcit>), <patcit id="pcit0739" dnum="US20150274652A"><text>US20150274652 (Novira</text></patcit>), <patcit id="pcit0740" dnum="US20150259324A"><text>US20150259324, (Novira</text></patcit>), <patcit id="pcit0741" dnum="US20150132258A"><text>US20150132258 (Novira</text></patcit>), <patcit id="pcit0742" dnum="US9181288B"><text>US9181288 (Novira</text></patcit>), <patcit id="pcit0743" dnum="WO2014184350A"><text>WO2014184350 (Janssen</text></patcit>), <patcit id="pcit0744" dnum="WO2013144129A"><text>WO2013144129 (Roche</text></patcit>), <patcit id="pcit0745" dnum="US20100015178A"><text>US20100015178 (Incyte</text></patcit>), <patcit id="pcit0746" dnum="US2016137652A"><text>US2016137652 (Flexus Biosciences, Inc</text></patcit>.), <patcit id="pcit0747" dnum="WO2014073738A"><text>WO2014073738 (Flexus Biosciences, Inc</text></patcit>.), <patcit id="pcit0748" dnum="WO2015188085A"><text>WO2015188085(Flexus Biosciences, Inc</text></patcit>.), <patcit id="pcit0749" dnum="US20140330015A"><text>U.S. Publication No. 2014/0330015 (Ono Pharmaceutical</text></patcit>), <patcit id="pcit0750" dnum="US20130079327A"><text>U.S. Publication No. 2013/0079327 (Ono Pharmaceutical</text></patcit>), <patcit id="pcit0751" dnum="US20130217880A"><text>U.S. Publication No. 2013/0217880 (Ono pharmaceutical</text></patcit>), <patcit id="pcit0752" dnum="WO2016057924A"><text>WO2016057924 (Genentech/Constellation Pharmaceuticals</text></patcit>), <patcit id="pcit0753" dnum="US20140275092A"><text>US20140275092 (Genentech/Constellation Pharmaceuticals</text></patcit>), <patcit id="pcit0754" dnum="US20140371195A"><text>US20140371195 (Epitherapeutics</text></patcit>) and <patcit id="pcit0755" dnum="US20140371214A"><text>US20140371214 (Epitherapeutics</text></patcit>). , <patcit id="pcit0756" dnum="US20160102096A"><text>US20160102096 (Epitherapeutics</text></patcit>), <patcit id="pcit0757" dnum="US20140194469A"><text>US20140194469 (Quanticel</text></patcit>), <patcit id="pcit0758" dnum="US20140171432A"><text>US20140171432</text></patcit>, <patcit id="pcit0759" dnum="US20140213591A"><text>US20140213591 (Quanticel</text></patcit>), <patcit id="pcit0760" dnum="US20160039808A"><text>US20160039808 (Quanticel</text></patcit>), <patcit id="pcit0761" dnum="US20140275084A"><text>US20140275084 (Quanticel</text></patcit>), <patcit id="pcit0762" dnum="WO2014164708A"><text>WO2014164708 (Quanticel</text></patcit>), <patcit id="pcit0763" dnum="US9186337B2"><text>US9186337B2 (Oryzon Genomics</text></patcit>), and other drugs for treating HBV, and combinations thereof.

0571In some embodiments, an agent disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 5-30 mg tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide. In some embodiments, an agent disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 5-10; 5-15; 5-20; 5-25; 25-30; 20-30; 15-30; or 10-30 mg tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide. In some embodiments, an agent disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 10 mg tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide. In some embodiments, an agent disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 25 mg tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide. An agent as disclosed herein may be combined with the agents provided herein in any dosage amount of the compound (e.g., from 50 mg to 500 mg of compound) the same as if each combination of dosages were specifically and individually listed.

0572In some embodiments, an agent disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 100-400 mg tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil. In some embodiments, an agent disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 100-150; 100-200, 100-250; 100-300; 100-350; 150-200; 150-250; 150-300; 150-350; 150-400; 200-250; 200-300; 200-350; 200-400; 250-350; 250-400; 350-400 or 300-400 mg tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil. In some embodiments, an agent disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 300 mg tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil. In some embodiments, an agent disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 250 mg tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil. In some embodiments, an agent herein, or a pharmaceutically acceptable salt thereof, is combined with 150 mg tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil. An agent as disclosed herein may be combined with the agents provided herein in any dosage amount of the compound (e.g., from 50 mg to 500 mg of compound) the same as if each combination of dosages were specifically and individually listed.

VI. METHODS OF TREATMENT

0573In some embodiments, the present disclosure provides method of inhibiting DGKα in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure. In some embodiments, the present disclosure provides method of inhibiting DGKα in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure, e.g., a compound of Formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

0574In some embodiments, the present disclosure provides a method of inhibiting DGKα in a subject in need thereof that comprises administering to the subject a therapeutically effective amount of a compound of Formula (I): <chemistry id="chem1234" num="1234"><img file="EP4445902A2_D1237.tif" /></chemistry> or a pharmaceutically acceptable salt thereof, wherein <ul id="ul0009" list-style="none" compact="compact"><li>R¹ is hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 alkoxy, halogen, C_1-6 haloalkyl, C_1-6 haloalkoxy, or -CN;</li><li>R² is hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_1-6 alkoxy, C_2-6 alkoxyalkyl, halogen, C_1-6 haloalkyl, C_1-6 haloalkoxy, -CN, -NO, -NO₂, - C(O)R^2a, -C(O)OR^2a, -OC(O)R^2a, -C(O)N(R^2a)(R^2b), -N(R^2a)C(O)R^2b, - OC(O)N(R^2a)(R^2b), -N(R^2a)C(O)OR^2b, -C(=NR^2a)N(R^2b)(R^2c), -N(R^2a)(R^2b), - N(R^2a)N(R^2b)(R^2c), -N(R^2a)N=C(R^2b)(OR^2c), -OR^2a, -SR^2a, -S(O)R^2a, -S(O)(NR^2a)(R^2b), - S(NR^2a)(NR^2b)(R^2c), -S(O)₂R^2a, -S(O)₂N(R^2a)(R^2b), -N(R^2a)S(O)₂(R^2b), -P(R^2a)(R^2b), - P(O)(R^2a)(R^2b), -P(O)(OR^2a)(R^2b), -P(O)(OR^2a)(OR^2b), C_3-10 cycloalkyl, C_1-6 alkyl-C_3-10 cycloalkyl, C_6-12 aryl, C_1-6 alkyl-C_6-12 aryl, heterocycloalkyl, C_1-6 alkyl-(heterocycloalkyl), heteroaryl, or C_1-6 alkyl-(heteroaryl), wherein each alkyl, alkenyl or alkynyl is independently optionally substituted with 1 to 3 R^2d groups, each cycloalkyl is optionally substituted with 1 to 3 R^2e groups, each aryl is optionally substituted with 1 to 3 R^2f groups, each heterocycloalkyl is optionally substituted with 1 to 3 R^2g groups, and each heteroaryl is optionally substituted with 1 to 3 R^2h groups;</li><li>each R^2a, R^2b, and R^2c is independently hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_2-6 alkoxyalkyl, C_1-6 haloalkyl, C_3-10 cycloalkyl, C_1-6 alkyl-C_3-10 cycloalkyl, C_6-12 aryl, C_1-6 alkyl-C_6-12 aryl, heterocycloalkyl, C_1-6 alkyl-(heterocycloalkyl), heteroaryl, or C_1-6 alkyl-(heteroaryl), wherein the aryl or heteroaryl is optionally substituted with 1 to 3 R^2j;</li><li>alternatively, R^2a, R^2b, and R^2c when attached to the same atom can be combined with the atom to which they are attached to form a heterocycloalkyl;</li><li>each R^2d is independently -CN, -C(O)R^2d1, -C(O)OR^2d1, -OC(O)R^2d1, -C(O)N(R^2d1)(R^2d2), - N(R^2d1)C(O)R^2d2, -OC(O)N(R^2d1)(R^2d2), -N(R^2d1)C(O)OR^2d2, -N(R^2d1)(R^2d2), =O, -OR^2d1, -SR^2d1, -S(O)R^2d1, -S(O)(NR^2d1)(R^2d2), -S(O)₂R^2d1, -S(O)N(R^2d1)(R^2d2), - N(R^2d1)S(O)₂R^2d2, C_3-10 cycloalkyl, C_1-6 alkyl-C_3-10 cycloalkyl, C_6-12 aryl, C_1-6 alkyl-C_6-12 aryl, heterocycloalkyl, C_1-6 alkyl-(heterocycloalkyl), heteroaryl, or C_1-6 alkyl-(heteroaryl);</li><li>each R^2d1 and R^2d2 is independently hydrogen, C_1-6 alkyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_2-6 alkoxyalkyl, or C_1-6 haloalkyl;</li><li>each R^2e, R^2f, R^2g, and R^2h is independently hydrogen, C_1-6 alkyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_1-6 alkoxy, C_2-6 alkoxyalkyl, halogen, C_1-6 haloalkyl, C_1-6 haloalkoxy, -CN, or -OH;</li><li>each R^2j is independently C_1-6 alkyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_1-6 alkoxy, C_2-6 alkoxyalkyl, halogen, C_1-6 haloalkyl, or C_1-6 haloalkoxy;</li><li>R³ is hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_1-6 alkoxy, C_2-6 alkoxyalkyl, halogen, C_1-6 haloalkyl, C_1-6 haloalkoxy, -CN, -NO, -NO₂, - C(O)R^3a, -C(O)OR^3a, -OC(O)R^3a, -C(O)N(R^3a)(R^3b), -N(R^3a)C(O)R^3b, - OC(O)N(R^3a)(R^3b), -N(R^3a)C(O)OR^3b, -C(=NR^3a)N(R^3b)(R^3c), -N(R^3a)(R^3b), - N(R^3a)N(R^3b)(R^3c), -N(R^3a)N=C(R^3b)(OR^3c), -OR^3a, -SR^3a, -S(O)R^3a, -S(O)(NR^3a)(R^3b), - S(NR^3a)(NR^3b)(R^3c), -S(O)₂R^3a, -S(O)₂N(R^3a)(R^3b), -N(R^3a)S(O)₂(R^3b), -P(R^3a)(R^3b), - P(O)(R^3a)(R^3b), -P(O)(OR^3a)(R^3b), -P(O)(OR^3a)(OR^3b), C_3-10 cycloalkyl, C_1-6 alkyl-C_3-10 cycloalkyl, C_6-12 aryl, C_1-6 alkyl-C_6-12 aryl, heterocycloalkyl, C_1-6 alkyl-(heterocycloalkyl), heteroaryl, or C_1-6 alkyl-(heteroaryl), wherein each alkenyl or alkynyl is independently optionally substituted with 1 to 3 R^3d groups, each cycloalkyl is optionally substituted with 1 to 3 R^3e groups, each aryl is optionally substituted with 1 to 3 R^3f groups, each heterocycloalkyl is optionally substituted with 1 to 3 R^3g groups, and each heteroaryl is optionally substituted with 1 to 3 R^3h groups;</li><li>each R^3a, R^3b, and R^3c is independently hydrogen, C_1-6 alkyl, C_1-6 hydroxyalkyl, C_2-6 alkoxyalkyl, C_1-6 haloalkyl, C_3-10 cycloalkyl, C_1-6 alkyl-C_3-10 cycloalkyl, C_6-12 aryl, C_1-6 alkyl-C_6-12 aryl, heterocycloalkyl, or heteroaryl;</li><li>alternatively, R^3a, R^3b, and R^3c when attached to the same atom can be combined with the atom to which they are attached to form a heterocycloalkyl;</li><li>each R^3d is independently -N(R^3d1)(R^3d2), -OR^3d1, C_3-10 cycloalkyl, C_1-6 alkyl-C_3-10 cycloalkyl, C_6-12 aryl, C_1-6 alkyl-C_6-12 aryl, heterocycloalkyl, or heteroaryl;</li><li>each R^3d1 and R^3d2 is independently hydrogen, C_1-6 alkyl, or -C(O)O-(C_1-6 alkyl);</li><li>each R^3e, R^3f, R^3g, and R^3h is independently hydrogen, C_1-6 alkyl, C_1-6 alkoxy, halogen, C_1-6 haloalkyl or C_1-6 haloalkoxy;</li><li>R⁴ is hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 alkoxy, halogen, C_1-6 haloalkyl, C_1-6 haloalkoxy, or -CN;</li><li>R⁵ is hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 hydroxyalkyl, C_2-6 alkoxyalkyl, C_1-6 haloalkyl, C_3-10 cycloalkyl, C_1-6 alkyl-C_3-10 cycloalkyl, C_6-12 aryl, C_1-6 alkyl-C_6-12 aryl, heterocycloalkyl, C_1-6 alkyl-(heterocycloalkyl), heteroaryl, or C_1-6 alkyl-(heteroaryl), wherein the alkyl is optionally substituted with R^5a;</li><li>R^5a is -OSi(R^5a1)(R^5a2)(R^5a3);</li><li>R^5a1, R^5a2, and R^5a3 are each independently C_1-6 alkyl; and</li><li>R⁶ is C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 haloalkyl, C_6-12 aryl, or heteroaryl, wherein the aryl or heteroaryl are each optionally substituted with 1 to 3 R^6a;</li><li>each R^6a is independently C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_1-6 alkoxy, C_2-6 alkoxyalkyl, halogen, C_1-6 haloalkyl, C_1-6 haloalkoxy, -CN, -NO₂, -C(O)R^6b, -C(O)OR^6b, -OC(O)R^6b, -C(O)N(R^6b)(R^6c), -N(R^6b)C(O)R^6c, - C(=NR^6b)N(R^6c)(R^6d), -N(R^6b)(R^6c), -OR^6b, -SR^6b, -S(O)R^6b, -S(O)₂R^6b, - S(NR^6b)(NR^6c)R^6d, -S(O)(NR^6b)(R^6c), -S(O)₂N(R^6b)(R^6c), -N(R^6b)S(O)₂(R^6c), - P(R^6b)(R^6c), -P(O)(R^6b)(R^6c), -P(O)(OR^6b)(R^6c), -P(O)(OR^6b)(OR^6c), C_3-10 cycloalkyl, C_1-6 alkyl-C_3-10 cycloalkyl, C_6-12 aryl, C_1-6 alkyl-C_6-12 aryl, heterocycloalkyl, C_1-6 alkyl-(heterocycloalkyl), heteroaryl, or C_1-6 alkyl-(heteroaryl), wherein the cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is each optionally substituted with 1 to 3 R^6e, the alkyl is optionally substituted with R^6f, and the alkynyl is optionally substituted with 1 to 4 R^6j;</li><li>each R^6b, R^6c and R^6d is independently hydrogen, C_1-6 alkyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_2-6 alkoxyalkyl, C_1-6 haloalkyl, C_3-10 cycloalkyl, C_1-6 alkyl-C_3-10 cycloalkyl, C_6-12 aryl, C_1-6 alkyl-C_6-12 aryl, heterocycloalkyl, C_1-6 alkyl-(heterocycloalkyl), heteroaryl, or C_1-6 alkyl-(heteroaryl), wherein the cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is optionally substituted by 1 to 3 R^6k,</li><li>each R^6k is independently C_1-6 alkyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_1-6 alkoxy, C_2-6 alkoxyalkyl, C_1-6 haloalkyl, C_1-6 haloalkoxy, C_3-10 cycloalkyl, C_1-6 alkyl-C_3-10 cycloalkyl, heterocycloalkyl, or C_1-6 alkyl-(heterocycloalkyl);</li><li>each R^6e is independently C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_1-6 alkoxy, C_2-6 alkoxyalkyl, halogen, C_1-6 haloalkyl, C_1-6 haloalkoxy, -CN, -NO₂, -C(O)R^6e1, -C(O)OR^6e1, -OC(O)R^6e1, -C(O)N(R^6e1)(R^6e2), -N(R^6e1)C(O)R^6e2, - OC(O)N(R^6e1)(R^6e2), -N(R^6e1)C(O)OR^6e2, -C(=NR^6e1)N(R^6e2)(R^6e3), -N(R^6e1)(R^6e2), =O, - OR^6e1, -SR^6e1, -S(O)R^6e1, -S(NR^6e1)(NR^6e2), -S(O)(NR^6e1)(R^6e2), -S(O)₂R^6e1, - S(O)₂N(R^6e1)(R^6e2), -SF₅, -N(R^6e1)S(O₂(R^6e2), -P(R^6e1)(R^6e2), -P(O)(R^6e1)(R^6e2), - P(O)(OR^6e1)(R^6e2), -P(O)(OR^6e1)(OR^6e2), -Si(R^6e1)(R^6e2)(R^6e3), C_3-10 cycloalkyl, C_1-6 alkyl-C_3-10 cycloalkyl, C_6-12 aryl, C_1-6 alkyl-C_6-12 aryl, heterocycloalkyl, C_1-6 alkyl-heterocycloalkyl, heteroaryl, or C_1-6 alkyl-heteroaryl, wherein the cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is each optionally substituted with 1 to 3 R^6h, and the alkyl is optionally substituted with 1 to 3 R^6m;</li><li>each R^6e1, R^6e2, and R^6e3 is independently hydrogen, C_1-6 alkyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_1-6 alkoxyalkyl, C_1-6 haloalkyl, C_3-10 cycloalkyl, C_1-6 alkyl-C_3-10 cycloalkyl, C_6-10 aryl, C_1-6 alkyl-C_6-10 aryl, heterocycloalkyl, C_1-6 alkyl-(heterocycloalkyl), heteroaryl, or C_1-6 alkyl-(heteroaryl), wherein the cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is optionally substituted with 1 to 3 R⁶ⁿ;</li><li>each R⁶ⁿ is C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_1-6 alkoxy, C_2-6 alkoxyalkyl, halogen, C_1-6 haloalkyl, C_1-6 haloalkoxy, -CN, -C(O)R⁶ⁿ¹, -C(O)OR⁶ⁿ¹, -OC(O)R⁶ⁿ¹, -C(O)N(R⁶ⁿ¹)(R⁶ⁿ²), -N(R⁶ⁿ¹)C(O)R⁶ⁿ², -OC(O)N(R⁶ⁿ¹)(R⁶ⁿ²), - N(R⁶ⁿ¹)C(O)OR⁶ⁿ², -C(=NR⁶ⁿ¹)N(R⁶ⁿ²)(R⁶ⁿ³), -N(R⁶ⁿ¹)(R⁶ⁿ²), =O, -OH, -SR⁶ⁿ¹, - S(O)R⁶ⁿ¹, -S(NR⁶ⁿ¹)(NR⁶ⁿ²)R⁶ⁿ³, -S(O)(NR⁶ⁿ¹)(R⁶ⁿ²), -S(O)₂R⁶ⁿ¹, -S(O)₂N(R⁶ⁿ¹)(R⁶ⁿ²), or -N(R⁶ⁿ¹)S(O)₂(R⁶ⁿ²);</li><li>each R⁶ⁿ¹, R⁶ⁿ² and R⁶ⁿ³ is independently hydrogen, C_1-6 alkyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_2-6 alkoxyalkyl, C_1-6 haloalkyl, C_3-10 cycloalkyl, C_1-6 alkyl-C_3-10 cycloalkyl, C_6-10 aryl, C_1-6 alkyl-C_6-10 aryl, heterocycloalkyl, C_1-6 alkyl-(heterocycloalkyl), heteroaryl, or C_1-6 alkyl-(heteroaryl);</li><li>each R^6h is independently C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_1-6 alkoxy, C_2-6 alkoxyalkyl, halogen, C_1-6 haloalkyl, C_1-6 haloalkoxy, -CN, -C(O)R^6h1, -C(O)OR^6h1, -OC(O)R^6h1, -C(O)N(R^6h1)(R^6h2), -N(R^6h1)C(O)R^6h2, - OC(O)N(R^6h1)(R^6h2), -N(R^6h1)C(O)OR^6h2, -C(=NR^6h1)N(R^6h2)(R^6h3), -N(R^6h1)(R^6h2), =O, -OH, -SR^6h1, -S(O)R^6h1, -S(NR^6h1)(NR^6h2)R^6h3, -S(O)(NR^6h1)(R^6h2), -S(O)₂R^6h1, - S(O)₂N(R^6h1)(R^6h2), -N(R^6h1)S(O)₂(R^6h2), C_3-10 cycloalkyl, C_1-6 alkyl-C_3-10 cycloalkyl, heterocycloalkyl, or C_1-6 alkyl-(heterocycloalkyl);</li><li>each R^6h1, R^6h2, and R^6h3 is independently hydrogen, C_1-6 alkyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_2-6 alkoxyalkyl, C_1-6 haloalkyl, C_3-10 cycloalkyl, C_1-6 alkyl-C_3-10 cycloalkyl, C_6-10 aryl, C_1-6 alkyl-C_6-10 aryl, heterocycloalkyl, C_1-6 alkyl-(heterocycloalkyl), heteroaryl, or C_1-6 alkyl-(heteroaryl);</li><li>each R^6m is independently halogen, C_1-6 haloalkyl, C_1-6 haloalkoxy, -CN, -C(O)R^6m1, - C(O)OR^6m1, -OC(O)R^6m1, -C(O)N(R^6m1)(R^6m2), -N(R^6m3)C(O)R^6m2, - OC(O)N(R^6m1)(R^6m2), -N(R^6m1)C(O)OR^6m2, -C(=NR^6m3)N(R^6ml)(R^6m2), -N(R^6m1)(R^6m2), =O, -OH, -SR^6m1, -S(O)R^6m1, -S(NR^6m1)(NR^6m2)R^6m3, -S(O)(NR^6m1)(R^6m2), -S(O)₂R^6m1, - S(O)_2N(R^6m1)(R^6m2), or -N(R^6m3)S(O)₂(R^6m2);</li><li>each R^6m1, R^6m2, and R^6m3 is independently hydrogen, C_1-6 alkyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_2-6 alkoxyalkyl, C_1-6 haloalkyl, C_3-10 cycloalkyl, C_1-6 alkyl-C_3-10 cycloalkyl, C_6-10 aryl, C_1-6 alkyl-C_6-10 aryl, heterocycloalkyl, C_1-6 alkyl-(heterocycloalkyl), heteroaryl, or C_1-6 alkyl-(heteroaryl);</li><li>R^6f is -OSi(R^6f1)(R^6f2)(R^6f3);</li><li>R^6f1, R^6f2, and R^6f3 are each independently C_1-6 alkyl;</li><li>each R^6j is independently C_2-6 alkoxyalkyl, halogen, C_1-6 haloalkyl, C_1-6 haloalkoxy, -CN, - C(O)R^6j1, -C(O)OR^6j1, -OC(O)R^6j1, -C(O)N(R^6j1)(R^6j2), -N(R^6j3)C(O)R^6j2, - OC(O)N(R^6j1)(R^6j2), -N(R^6j1)C(O)OR^6j2, -C(=NR^6j3)N(R^6j1)(R^6j2), -N(R^6j1)(R^6j2), =O, - OR^6j1, -SR^6j1, -S(O)R^6j1, -S(NR^6j1)(NR^6j2), -S(NR^6j1)(NR^6j2)R^6j3, -S(O)(NR^6j1)(R^6j2), - S(O)₂R^6j1, -S(O)₂N(R^6j1)(R^6j2), -N(R^6j1)S(O)₂(R^6j2), -Si(R^6j1)(R^6j2)(R^6j3), C_3-10 cycloalkyl, C_6-12 aryl, heterocycloalkyl, or heteroaryl, wherein the cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is optionally substituted with 1 to 3 R^6p;</li><li>each R^6j1, R^6j2, and R^6j3 is independently hydrogen, C_1-6 alkyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_2-6 alkoxyalkyl, C_1-6 haloalkyl, C_3-10 cycloalkyl, C_1-6 alkyl-C_3-10 cycloalkyl, C_6-10 aryl, C_1-6 alkyl-C_6-10 aryl, heterocycloalkyl, C_1-6 alkyl-(heterocycloalkyl), heteroaryl, or C_1-6 alkyl-(heteroaryl);</li><li>each R^6p is independently C_1-6 alkyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_1-6 alkoxy, C_2-6 alkoxyalkyl, halogen, C_1-6 haloalkyl, C_1-6 haloalkoxy, -CN, -C(O)R^6p1, -C(O)OR^6p1, - OC(O)R^6p1, -C(O)N(R^6p1)(R^6p2), -N(R^6p1)C(O)R^6p2, -OC(O)N(R^6p1)(R^6p2), - N(R^6p1)C(O)OR^6p2, -C(=NR^6p3)N(R^6p1)(R^6p2), -N(R^6p1)(R^6p2), =O, -OH, -SR^6p1, - S(O)R^6p1, -S(NR^6p1)(NR^6p2)R^6p3, -S(O)(NR^6p1)(R^6p2), -S(O)₂R^6p1, -S(O)₂N(R^6p1)(R^6p2), or -N(R^6p1)S(O)₂(R^6p2);</li><li>each R^6p1, R^6p2, and R^6p3 is independently hydrogen, C_1-6 alkyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_2-6 alkoxyalkyl, C_1-6 haloalkyl, C_3-10 cycloalkyl, C_1-6 alkyl-C_3-10 cycloalkyl, C_6-10 aryl, C_1-6 alkyl-C_6-10 aryl, heterocycloalkyl, C_1-6 alkyl-(heterocycloalkyl), heteroaryl, or C_1-6 alkyl-(heteroaryl);</li><li>or R⁵ and one R^6a together with the atoms to which they are attached form a heterocycloalkyl, optionally substituted with 1 to 3 R^6g;</li><li>each R^6g is independently C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_2-6 alkoxyalkyl, halogen, C_1-6 haloalkyl, C_1-6 haloalkoxy, or -CN;</li><li>R⁷ is hydrogen, C_1-6 alkyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_1-6 alkoxy, C_2-6 alkoxyalkyl, C_1-6 alkylthio, halogen, C_1-6 haloalkyl, -CN,-OH, -NH₂, C_3-10 cycloalkyl, C_1-6 alkyl-C_3-10 cycloalkyl, heterocycloalkyl, or C_1-6 alkyl-(heterocycloalkyl);</li><li>each heterocycloalkyl is a 3 to 20 membered ring having 1 to 4 heteroatoms each independently N, O or S; and</li><li>each heteroaryl is a 5 to 18 membered ring having 1 to 4 heteroatoms each independently N, O or S.</li></ul>

0575In some embodiments, the present disclosure provides a method of inhibiting DGKα in a subject in need thereof comprises administering to the subject a therapeutically effective amount of a compound of Formula (I): <chemistry id="chem1235" num="1235"><img file="EP4445902A2_D1238.tif" /></chemistry> or a pharmaceutically acceptable salt thereof, wherein <ul id="ul0010" list-style="none" compact="compact"><li>R' is hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 alkoxy, halogen, C_1-6 haloalkyl, C_1-6 haloalkoxy, or -CN;</li><li>R² is hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 hydroxyalkyl, C_1-6 alkoxy, C_2-6 alkoxyalkyl, halogen, C_1-6 haloalkyl, C_1-6 haloalkoxy, -CN, -NO, -NO₂, -C(O)R^2a, -C(O)OR^2a, -OC(O)R^2a, -C(O)N(R^2a)(R^2b), -N(R^2a)C(O)R^2b, -OC(O)N(R^2a)(R^2b), -N(R^2a)C(O)OR^2b, -C(=NR^2a)N(R^2b)(R^2c), -N(R^2a)(R^2b), -OR^2a, -SR^2a, -S(O)R^2a, -S(O)₂R^2a, -S(O)₂N(R^2a)(R^2b), -N(R^2a)S(O)₂(R^2b), -P(O)(R^2a)(R^2b), -P(O)(OR^2a)(R^2b), -P(O)(OR^2a)(OR^2b), C_3-10 cycloalkyl, C_1-6 alkyl-C_3-10 cycloalkyl, C_6-12 aryl, C_1-6 alkyl-C_6-12 aryl, heterocycloalkyl, or heteroaryl, wherein each alkenyl or alkynyl is independently optionally substituted with 1 to 3 R^2d groups, each cycloalkyl is optionally substituted with 1 to 3 R^2e groups, each aryl is optionally substituted with 1 to 3 R^2f groups, each heterocycloalkyl is optionally substituted with 1 to 3 R^2g groups, and each heteroaryl is optionally substituted with 1 to 3 R^2h groups;</li><li>each R^2a, R^2b, and R^2c is independently hydrogen, C_1-6 alkyl, C_1-6 hydroxyalkyl, C_2-6 alkoxyalkyl, C_1-6 haloalkyl, C_3-10 cycloalkyl, C_1-6 alkyl-C_3-10 cycloalkyl, C_6-12 aryl, C_1-6 alkyl-C_6-12 aryl, heterocycloalkyl, or heteroaryl;</li><li>alternatively, R^2a, R^2b, and R^2c when attached to the same atom can be combined with the atom to which they are attached to form a heterocycloalkyl;</li><li>each R^2d is independently -N(R^2d1)(R^2d2), -OR^2d1, C_3-10 cycloalkyl, C_1-6 alkyl-C_3-10 cycloalkyl, C_6-12 aryl, C_1-6 alkyl-C_6-12 aryl, heterocycloalkyl, or heteroaryl;</li><li>each R^2d1 and R^2d2 is independently hydrogen, C_1-6 alkyl, or -C(O)O-(C_1-6 alkyl);</li><li>each R^2e, R^2f, R^2g, and R^2h is independently hydrogen, C_1-6 alkyl, C_1-6 alkoxy, halogen, C_1-6 haloalkyl or C_1-6 haloalkoxy;</li><li>R³ is hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 hydroxyalkyl, C_1-6 alkoxy, C_2-6 alkoxyalkyl, halogen, C_1-6 haloalkyl, C_1-6 haloalkoxy, -CN, -NO, -NO₂, -C(O)R^3a, -C(O)OR^3a, -OC(O)R^3a, -C(O)N(R^3a)(R^3b), -N(R^3a)C(O)R^3b, -OC(O)N(R^3a)(R^3b), -N(R^3a)C(O)OR^3b, -C(=NR^3a)N(R^3b)(R^3c), -N(R^3a)(R^3b), -OR^3a, -SR^3a, -S(O)R^3a, -S(O)₂R^3a, -S(O)₂N(R^3a)(R^3b), -N(R^3a)S(O)₂(R^3b), -P(O)(R^3a)(R^3b), -P(O)(OR^3a)(R^3b), -P(O)(OR^3a)(OR^3b), C_3-10 cycloalkyl, C_1-6 alkyl-C_3-10 cycloalkyl, C_6-12 aryl, C_1-6 alkyl-C_6-12 aryl, heterocycloalkyl, or heteroaryl, wherein each alkenyl or alkynyl is independently optionally substituted with 1 to 3 R^3d groups, each cycloalkyl is optionally substituted with 1 to 3 R^3e groups, each aryl is optionally substituted with 1 to 3 R^3f groups, each heterocycloalkyl is optionally substituted with 1 to 3 R^3g groups, and each heteroaryl is optionally substituted with 1 to 3 R^3h groups;</li><li>each R^3a, R^3b, and R^3c is independently hydrogen, C_1-6 alkyl, C_1-6 hydroxyalkyl, C_2-6 alkoxyalkyl, C_1-6 haloalkyl, C_3-10 cycloalkyl, C_1-6 alkyl-C_3-10 cycloalkyl, C_6-12 aryl, C_1-6 alkyl-C_6-12 aryl, heterocycloalkyl, or heteroaryl;</li><li>alternatively, R^3a, R^3b, and R^3c when attached to the same atom can be combined with the atom to which they are attached to form a heterocycloalkyl;</li><li>each R^3d is independently -N(R^3d1)(R^3d2), -OR^3d1, C_3-10 cycloalkyl, C_1-6 alkyl-C_3-10 cycloalkyl, C_6-12 aryl, C_1-6 alkyl-C_6-12 aryl, heterocycloalkyl, or heteroaryl;</li><li>each R^3d1 and R^3d2 is independently hydrogen, C_1-6 alkyl, or -C(O)O-(C_1-6 alkyl);</li><li>each R^3e, R^3f, R^3g, and R^3h is independently hydrogen, C_1-6 alkyl, C_1-6 alkoxy, halogen, C_1-6 haloalkyl or C_1-6 haloalkoxy;</li><li>R⁴ is hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 alkoxy, halogen, C_1-6 haloalkyl, C_1-6 haloalkoxy, or -CN;</li><li>R⁵ is hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 hydroxyalkyl, C_2-6 alkoxyalkyl, C_1-6 haloalkyl, C_3-10 cycloalkyl, C_1-6 alkyl-C_3-10 cycloalkyl, C_6-12 aryl, C_1-6 alkyl-C_6-12 aryl, heterocycloalkyl, C_1-6 alkyl-(heterocycloalkyl), heteroaryl, or C_1-6 alkyl-(heteroaryl), wherein the alkyl is optionally substituted with R^5a;</li><li>R^5a is -OSi(R^5a1)(R^5a2)(R^5a3);</li><li>R^5a1, R^5a2, and R^5a3 are each independently C_1-6 alkyl; and</li><li>R⁶ is C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 haloalkyl, C_6-12 aryl, or heteroaryl, wherein the aryl or heteroaryl are each optionally substituted with 1 to 3 R^6a;</li><li>each R^6a is independently C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 hydroxyalkyl, C_1-6 alkoxy, C_2-6 alkoxyalkyl, halogen, C_1-6 haloalkyl, C_1-6 haloalkoxy, -CN, -NO₂, -C(O)R^6b, -C(O)OR^6b, -OC(O)R^6b, -C(O)N(R^6b)(R^6c), -N(R^6b)C(O)R^6c, -C(=NR^6b )N(R^6c)(R^6d), -N(R^6b)(R^6c), -OR^6b, -SR^6b, -S(O)R^6b, -S(O)₂R^6b, -S(O)₂N(R^6b)(R^6c), -N(R^6b)S(O)₂(R^6c), C_3-10 cycloalkyl, C_6-12 aryl, heterocycloalkyl, or heteroaryl, wherein the cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is each optionally substituted with 1 to 3 R^6e, and the alkyl is optionally substituted with R^6f;</li><li>or R⁵ and one R^6a together with the atoms to which they are attached form a heterocycloalkyl, optionally substituted with 1 to 3 R^6g;</li><li>each R^6b, R^6c and R^6d is independently hydrogen, C_1-6 alkyl, C_1-6 hydroxyalkyl, C_2-6 alkoxyalkyl, C_1-6 haloalkyl, C_3-10 cycloalkyl, C_1-6 alkyl-C_3-10 cycloalkyl, C_6-12 aryl, C_1-6 alkyl-C_6-12 aryl, heterocycloalkyl, or heteroaryl;</li><li>each R^6e is independently C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 hydroxyalkyl, C_1-6 alkoxy, C_2-6 alkoxyalkyl, halogen, C_1-6 haloalkyl, C_1-6 haloalkoxy, -CN, -NO₂, -C(O)R^6e1, -C(O)OR^6e1, -OC(O)R^6e1, -C(O)N(R^6e1)(R^6e2), -N(R^6e1)C(O)R^6e2, -C(=NR^6e1)N(R^6e2)(R^6e3), -N(R^6e1)(R^6e2), -OR^6e1, -SR^6e1, -S(O)R^6e1, -S(O)2R^6e1, -S(O)₂N(R^6e1)(R^6e2), -N(R^6e1)S(O)₂(R^6e2), C_3-10 cycloalkyl, C_6-12 aryl, heterocycloalkyl, or heteroaryl, wherein the cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is each optionally substituted with 1 to 3 R^6h;</li><li>each R^6e1, R^6e2, and R^6e3 is independently hydrogen or C_1-6 alkyl;</li><li>R^6f is -OSi(R^6f1)(R^6f2)(R^6f3);</li><li>R^6f1, R^6f2, and R^6f3 are each independently C_1-6 alkyl;</li><li>each R^6g is independently C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, halogen, C_1-6 haloalkyl, C_1-6 haloalkoxy, or -CN;</li><li>each R^6h is independently C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 alkoxy, halogen, C_1-6 haloalkyl, C_1-6 haloalkoxy, -C(O)R^6h1, -C(O)OR^6h1, -OC(O)R^6h1, -C(O)N(R^6h1)(R^6h2), -N(R^6h1)C(O)R^6h2, -C(=NR^6h1)N(R^6h2)(R^6h3), -N(R^6h1)(R^6h2), -OH, -SR^6h1, -S(O)R^6h1, -S(O)₂R^6h1, -S(O)₂N(R^6h1)(R^6h2), or -N(R^6h1)S(O)₂(R^6h2);</li><li>each R^6h1, R^6h2, and R⁶ⁿ³ is independently hydrogen or C_1-6 alkyl;</li><li>R⁷ is hydrogen, C_1-6 alkyl, halogen, C_1-6 haloalkyl,-CN, or -OH;</li><li>each heterocycloalkyl is a 3 to 10 membered ring having 1 to 4 heteroatoms each independently N, O or S; and</li><li>each heteroaryl is a 5 to 10 membered ring having 1 to 4 heteroatoms each independently N, O or S.</li></ul>

0576In some embodiments, a method of inhibiting DGKα in a subject in need thereof comprises administering to the subject a therapeutically effective amount of the compound having the structure of a compound in Table 1A, Table 1B, Table 1C, Table 1D, Table 1E, Table 1F, Table 1G, Table 1H, Table 1I, Table 1J, Table 2A, Table 2B, Table 2C, Table 2D, Table 2E, Table 2F, Table 2G, Table 2H, Table 2I, Table 2J, Table 2K, Table 2L, Table 3A, Table 3B, Table 3C, Table 3D, Table 3E, Table 3F, Table 3G, Table 3H, Table 3I, Table 3J, or Table 3K, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, a method of inhibiting DGKα in a subject in need thereof comprises administering to the subject a therapeutically effective amount of the compound having the structure of a compound in Table 3F, Table 3H, Table 3I, Table 3J, or Table 3K, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

0577In some embodiments, the present disclosure provides a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

0578In some embodiments, the cancer is pancreatic cancer, bladder cancer, colorectal cancer, breast cancer, prostate cancer, renal cancer, hepatocellular cancer, lung cancer, ovarian cancer, cervical cancer, gastric cancer, esophageal cancer, head and neck cancer, melanoma, neuroendocrine cancer, CNS cancer, brain cancer, bone cancer, soft tissue sarcoma, non-small cell lung cancer, small-cell lung cancer or colon cancer. In some embodiments, the cancer is acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), myelodysplastic syndrome (MDS), myeloproliferative disease (MPD), chronic myeloid leukemia (CML), multiple myeloma (MM), non-Hodgkin's lymphoma (NHL), mantle cell lymphoma (MCL), follicular lymphoma, Waldestrom's macroglobulinemia (WM), T-cell lymphoma, B-cell lymphoma or diffuse large B-cell lymphoma (DLBCL). In some embodiments, the cancer is brain (gliomas), glioblastomas, astrocytomas, glioblastoma multiforme, Bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, breast, colon, head and neck, kidney, lung, liver, melanoma, ovarian, pancreatic, adenocarcinoma, ductal adenocarcinoma, adenosquamous carcinoma, acinar cell carcinoma, glucagonoma, insulinoma, prostate, sarcoma or thyroid.

0579In some embodiments, the cancer is a solid tumor, a hematological cancer, or a metastatic lesion. In some embodiments, the solid tumor is a sarcoma, a fibroblastic sarcoma, a carcinoma, or an adenocarcinoma. In some embodiments, the hematological cancer is a leukemia, a lymphoma, or a myeloma.

0580In some embodiments, the cancer is a lung cancer, a melanoma, a renal cancer, a liver cancer, a myeloma, a prostate cancer, a breast cancer, an ovarian cancer, a colorectal cancer, a pancreatic cancer, a head and neck cancer, an anal cancer, a gastro-esophageal cancer, a mesothelioma, a nasopharyngeal cancer, a thyroid cancer, a cervical cancer, an epithelial cancer, a peritoneal cancer, a lymphoproliferative disease, an acute lymphoblastic leukemia (ALL), an acute myelogenous leukemia (AML), a chronic lymphocytic leukemia (CLL), a chronic myelogenous leukemia (CML), a chronic myelomonocytic leukemia (CMML), a hairy cell leukemia, a B cell lymphoma, a diffuse large B-cell lymphoma (DLBCL), an activated B-cell like (ABC) diffuse large B cell lymphoma, a germinal center B cell (GCB) diffuse large B cell lymphoma, a mantle cell lymphoma, a Hodgkin lymphoma, a non-Hodgkin lymphoma, a relapsed non-Hodgkin lymphoma, a refractory non-Hodgkin lymphoma, a recurrent follicular non-Hodgkin lymphoma, a Burkitt lymphoma, a small lymphocytic lymphoma, a follicular lymphoma, a lymphoplasmacytic lymphoma, or an extranodal marginal zone lymphoma.

0581In some embodiments, the cancer is an epithelial tumor (e.g., a carcinoma, a squamous cell carcinoma, a basal cell carcinoma, a squamous intraepithelial neoplasia), a glandular tumor (e.g., an adenocarcinoma, an adenoma, an adenomyoma), a mesenchymal or soft tissue tumor (e.g., a sarcoma, a rhabdomyosarcoma, a leiomyosarcoma, a liposarcoma, a fibrosarcoma, a dermatofibrosarcoma, a neurofibrosarcoma, a fibrous histiocytoma, an angiosarcoma, an angiomyxoma, a leiomyoma, a chondroma, a chondrosarcoma, an alveolar soft-part sarcoma, an epithelioid hemangioendothelioma, a Spitz tumor, a synovial sarcoma), or a lymphoma.

0582In some embodiments, the cancer is a solid tumor in or arising from a tissue or organ selected from the group consisting of: bone (e.g. , adamantinoma, aneurysmal bone cysts, angiosarcoma, chondroblastoma, chondroma, chondromyxoid fibroma, chondrosarcoma, chordoma, dedifferentiated chondrosarcoma, enchondroma, epithelioid hemangioendothelioma, fibrous dysplasia of the bone, giant cell tumour of bone, haemangiomas and related lesions, osteoblastoma, osteochondroma, osteosarcoma, osteoid osteoma, osteoma, periosteal chondroma, Desmoid tumor, Ewing sarcoma); lips and oral cavity (e.g., odontogenic ameloblastoma, oral leukoplakia, oral squamous cell carcinoma, primary oral mucosal melanoma); salivary glands (e.g., pleomorphic salivary gland adenoma, salivary gland adenoid cystic carcinoma, salivary gland mucoepidermoid carcinoma, salivary gland Warthin's tumors); esophagus (e.g., Barrett's esophagus, dysplasia and adenocarcinoma); gastrointestinal tract, including stomach (e.g., gastric adenocarcinoma, primary gastric lymphoma, gastrointestinal stromal tumors (GISTs), metastatic deposits, gastric carcinoids, gastric sarcomas, neuroendocrine carcinoma, gastric primary squamous cell carcinoma, gastric adenoacanthomas), intestines and smooth muscle (e.g., intravenous leiomyomatosis), colon (e.g., colorectal adenocarcinoma), rectum, anus; pancreas (e.g., serous neoplasms, including microcystic or macrocystic serous cystadenoma, solid serous cystadenoma, Von Hippel-Landau (VHL)-associated serous cystic neoplasm, serous cystadenocarcinoma, mucinous cystic neoplasms (MCN), intraductal papillary mucinous neoplasms (IPMN), intraductal oncocytic papillary neoplasms (IOPN), intraductal tubular neoplasms, cystic acinar neoplasms, including acinar cell cystadenoma, acinar cell cystadenocarcinoma, pancreatic adenocarcinoma, invasive pancreatic ductal adenocarcinomas, including tubular adenocarcinoma, adenosquamous carcinoma, colloid carcinoma, medullary carcinoma, hepatoid carcinoma, signet ring cell carcinoma, undifferentiated carcinoma, undifferentiated carcinoma with osteoclast-like giant cells, acinar cell carcinoma, neuroendocrine neoplasms, neuroendocrine microadenoma, neuroendocrine tumors (NET), neuroendocrine carcinoma (NEC), including small cell or large cell NEC, insulinoma, gastrinoma, glucagonoma, serotonin-producing NET, somatostatinoma, VIPoma, solid-pseudopapillary neoplasms (SPN), pancreatoblastoma); gall bladder (e.g. carcinoma of the gallbladder and extrahepatic bile ducts, intrahepatic cholangiocarcinoma); neuro-endocrine (e.g., adrenal cortical carcinoma, carcinoid tumors, phaeochromocytoma, pituitary adenomas); thyroid (e.g., anaplastic (undifferentiated) carcinoma, medullary carcinoma, oncocytic tumors, papillary carcinoma, adenocarcinoma); liver (e.g., adenoma, combined hepatocellular and cholangiocarcinoma, fibrolamellar carcinoma, hepatoblastoma, hepatocellular carcinoma, mesenchymal, nested stromal epithelial tumor, undifferentiated carcinoma, hepatocellular carcinoma, intrahepatic cholangiocarcinoma, bile duct cystadenocarcinoma, epithelioid hemangioendothelioma, angiosarcoma, embryonal sarcoma, rhabdomyosarcoma, solitary fibrous tumor, teratoma, York sac tumor, carcinosarcoma, rhabdoid tumor); kidney (e.g., ALK-rearranged renal cell carcinoma, chromophobe renal cell carcinoma, clear cell renal cell carcinoma, clear cell sarcoma, metanephric adenoma, metanephric adenofibroma, mucinous tubular and spindle cell carcinoma, nephroma, nephroblastoma (Wilms tumor), papillary adenoma, papillary renal cell carcinoma, renal oncocytoma, renal cell carcinoma, succinate dehydrogenase-deficient renal cell carcinoma, collecting duct carcinoma); breast (e.g., invasive ductal carcinoma, including without limitation, acinic cell carcinoma, adenoid cystic carcinoma, apocrine carcinoma, cribriform carcinoma, glycogen-rich/clear cell, inflammatory carcinoma, lipid-rich carcinoma, medullary carcinoma, metaplastic carcinoma, micropapillary carcinoma, mucinous carcinoma, neuroendocrine carcinoma, oncocytic carcinoma, papillary carcinoma, sebaceous carcinoma, secretory breast carcinoma, tubular carcinoma, lobular carcinoma, including without limitation, pleomorphic carcinoma, signet ring cell carcinoma, peritoneum (e.g., mesothelioma, primary peritoneal cancer)); female sex organ tissues, including ovary (e.g., choriocarcinoma, epithelial tumors, germ cell tumors, sex cord-stromal tumors), Fallopian tubes (e.g., serous adenocarcinoma, mucinous adenocarcinoma, endometrioid adenocarcinoma, clear cell adenocarcinoma, transitional cell carcinoma, squamous cell carcinoma, undifferentiated carcinoma, mullerian tumors, adenosarcoma, leiomyosarcoma, teratoma, germ cell tumors, choriocarcinoma, trophoblastic tumors), uterus (e.g., carcinoma of the cervix, endometrial polyps, endometrial hyperplasia, intraepithelial carcinoma (EIC), endometrial carcinoma (e.g., endometrioid carcinoma, serous carcinoma, clear cell carcinoma, mucinous carcinoma, squamous cell carcinoma, transitional carcinoma, small cell carcinoma, undifferentiated carcinoma, mesenchymal neoplasia), leiomyoma (e.g., endometrial stromal nodule, leiomyosarcoma, endometrial stromal sarcoma (ESS), mesenchymal tumors), mixed epithelial and mesenchymal tumors (e.g., adenofibroma, carcinofibroma, adenosarcoma, carcinosarcoma (malignant mixed mesodermal sarcoma - MMMT)), endometrial stromal tumors, endometrial malignant mullerian mixed tumours, gestational trophoblastic tumors (partial hydatiform mole, complete hydatiform mole, invasive hydatiform mole, placental site tumour)), vulva, vagina; male sex organ tissues, including prostate, testis (e.g., germ cell tumors, spermatocytic seminoma), penis; bladder (e.g., squamous cell carcinoma, urothelial carcinoma, bladder urothelial carcinoma); brain, (e.g., gliomas (e.g., astrocytomas, including non-infiltrating, low-grade, anaplastic, glioblastomas; oligodendrogliomas, ependymomas), meningiomas, gangliogliomas, schwannomas (neurilemmomas), craniopharyngiomas, chordomas, Non-Hodgkin lymphomas, pituitary tumors; eye (e.g., retinoma, retinoblastoma, ocular melanoma, posterior uveal melanoma, iris hamartoma); head and neck (e.g., nasopharyngeal carcinoma, Endolymphatic Sac Tumor (ELST), epidermoid carcinoma, laryngeal cancers including squamous cell carcinoma (SCC) (e.g., glottic carcinoma, supraglottic carcinoma, subglottic carcinoma, transglottic carcinoma), carcinoma in situ, verrucous, spindle cell and basaloid SCC, undifferentiated carcinoma, laryngeal adenocarcinoma, adenoid cystic carcinoma, neuroendocrine carcinomas, laryngeal sarcoma), head and neck paragangliomas (e.g., carotid body, jugulotympanic, vagal); thymus (e.g., thymoma); heart (e.g., cardiac myxoma); lung (e.g., small cell carcinoma (SCLC), non-small cell lung carcinoma (NSCLC), including squamous cell carcinoma (SCC), adenocarcinoma and large cell carcinoma, carcinoids (typical or atypical), carcinosarcomas, pulmonary blastomas, giant cell carcinomas, spindle cell carcinomas, pleuropulmonary blastoma); lymph (e.g., lymphomas, including Hodgkin's lymphoma, non-Hodgkin's lymphoma, Epstein-Barr virus (EBV)-associated lymphoproliferative diseases, including B cell lymphomas and T cell lymphomas (e.g., Burkitt lymphoma, large B cell lymphoma, diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, indolent B-cell lymphoma, low grade B cell lymphoma, fibrin-associated diffuse large cell lymphoma; primary effusion lymphoma; plasmablastic lymphoma; extranodal NK/T cell lymphoma, nasal type; peripheral T cell lymphoma, cutaneous T cell lymphoma, angioimmunoblastic T cell lymphoma; follicular T cell lymphoma; systemic T cell lymphoma), lymphangioleiomyomatosis); central nervous system (CNS) (e.g., gliomas including astrocytic tumors (e.g., pilocytic astrocytoma, pilomyxoid astrocytoma, subependymal giant cell astrocytoma, pleomorphic xanthoastrocytoma, diffuse astrocytoma, fibrillary astrocytoma, gemistocytic astrocytoma, protoplasmic astrocytoma, anaplastic astrocytoma, glioblastoma (e.g., giant cell glioblastoma, gliosarcoma, glioblastoma multiforme) and gliomatosis cerebri), oligodendroglial tumors (e.g., oligodendroglioma, anaplastic oligodendroglioma), oligoastrocytic tumors (e.g., oligoastrocytoma, anaplastic oligoastrocytoma), ependymal tumors (e.g., subependymom, myxopapillary ependymoma, ependymomas (e.g., cellular, papillary, clear cell, tanycytic), anaplastic ependymoma), optic nerve glioma, and non-gliomas (e.g., choroid plexus tumors, neuronal and mixed neuronal-glial tumors, pineal region tumors, embryonal tumors, medulloblastoma, meningeal tumors, primary CNS lymphomas, germ cell tumors, pituitary adenomas, cranial and paraspinal nerve tumors, stellar region tumors), neurofibroma, meningioma, peripheral nerve sheath tumors, peripheral neuroblastic tumours (including without limitation neuroblastoma, ganglioneuroblastoma, ganglioneuroma), trisomy 19 ependymoma); neuroendocrine tissues (e.g., paraganglionic system including adrenal medulla (pheochromocytomas) and extra-adrenal paraganglia ((extra-adrenal) paragangliomas); skin (e.g., clear cell hidradenoma, cutaneous benign fibrous histiocytomas, cylindroma, hidradenoma, melanoma (including cutaneous melanoma, mucosal melanoma), pilomatricoma, Spitz tumors); and soft tissues (e.g., aggressive angiomyxoma, alveolar rhabdomyosarcoma, alveolar soft part sarcoma, angiofibroma, angiomatoid fibrous histiocytoma, synovial sarcoma, biphasic synovial sarcoma, clear cell sarcoma, dermatofibrosarcoma protuberans, desmoid-type fibromatosis, small round cell tumor, desmoplastic small round cell tumor, elastofibroma, embryonal rhabdomyosarcoma, Ewing's tumors/primitive neurectodermal tumors (PNET), extraskeletal myxoid chondrosarcoma, extraskeletal osteosarcoma, paraspinal sarcoma, inflammatory myofibroblastic tumor, bpoblastoma, lipoma, chondroid lipoma, bposarcoma / malignant lipomatous tumors, bposarcoma, myxoid bposarcoma, fibromyxoid sarcoma, lymphangioleiomyoma, malignant myoepithelioma, malignant melanoma of soft parts, myoepithelial carcinoma, myoepithelioma, myxoinflammatory fibroblastic sarcoma, undifferentiated sarcoma, pericytoma, rhabdomyosarcoma, non rhabdomyosarcoma soft tissue sarcoma (NRSTS), soft tissue leiomyosarcoma, undifferentiated sarcoma, well-differentiated bposarcoma.

0583In some embodiments, the cancer is a melanoma, a gastric cancer, a triple-negative breast cancer (TNBC), a non-small cell lung cancer (NSCLC), a rectal adenocarcinoma, a colorectal cancer, a renal cell carcinoma, an ovarian cancer, a prostate cancer, an oral squamous cell carcinoma (SCC), a head and neck squamous cell carcinoma (HNSCC), a urothelial bladder cancer, a glioblastoma (GBM), a meningioma, adrenal cancer, or an endometrial cancer.

0584In some embodiments, the method further comprises administering one or more additional therapeutic agents to the subject. The additional therapeutic agent can include any therapeutic agent described above for combination therapy. In some embodiments, the additional therapeutic agent is independently an anti-neoplastic agent, nivolumab, pembrolizumab, atezolizumab, ipilimumab, chemotherapy, radiation therapy, or resection therapy. In some embodiments, the additional therapeutic agent is independently rituxan, doxorubicin, gemcitabine, nivolumab, pembrolizumab, artezolizumab, nivolumab, pembrolizumab, atezolizumab, or ipilimumab.

0585In some embodiments, the method comprises one or more additional therapeutic agents, wherein the additional therapeutic agent is a PD-1/PD-L1 inhibitor.

0586In some embodiments, the anti-neoplastic agent is an anti-microtubule agent, a platinum coordination complex, an alkylating agent, an antibiotic agent, a topoisomerase II inhibitor, an antimetabolite, a topoisomerase I inhibitor, a hormone or hormonal analogue, a signal transduction pathway inhibitor, a non-receptor tyrosine kinase angiogenesi, an inhibitor, an immunotherapeutic agent, a proapoptotic agent, a cell cycle signaling inhibitor, a proteasome inhibitor, a inhibitor of cancer metabolism, an anti-PD-L1 agent, a PD-1 antagonist, an immuno-modulator, a STING modulating compound, a CD39 inhibitor, an A2a and A2a adenosine antagonist, a TLR4 antagonist, an antibody to ICOS, or OX40.

0587In some embodiments, the compound or pharmaceutical composition is co-administered with one or more additional therapeutic agents comprising an activator or agonist of a fins related tyrosine kinase 3 (FLT3; CD 135) receptor, a toll-like receptor (TLR) or a stimulator of interferon genes (STING) receptor.

0588In some embodiments, the TLR agonist or activator is a TLR2 agonist, a TLR3 agonist, a TLR7 agonist, a TLR8 agonist and a TLR9 agonist.

0589In some embodiments, the STING receptor agonist or activator is ADU-S100 (MIW-815), SB-11285, MK-1454, SR-8291, AdVCA0848, GSK-532, SYN-STING, MSA-1, SR-8291, 5,6- dimethylxanthenone-4-acetic acid (DMXAA), cyclic-GAMP (cGAMP) and cyclic-di-AMP.

0590In some embodiments, the compound or pharmaceutical composition is co-administered with one or more additional therapeutic agents comprising an inhibitor or antagonist of: protein tyrosine phosphatase, non-receptor type 11 (PTPN11 or SHP2), myeloid cell leukemia sequence 1 (MCL1) apoptosis regulator; mitogen- activated protein kinase kinase kinase kinase 1 (MAP4K1) (also called Hematopoietic Progenitor Kinase 1 (HPK1)); diacylglycerol kinase alpha (DGKA, DAGK, DAGK1 or DGK-alpha); 5'-nucleotidase ecto (NT5E or CD73); transforming growth factor beta 1 (TGFB1 or TGF ); heme oxygenase 1 (HMOX1, HO-1 or HOl); vascular endothelial growth factor A (VEGFA or VEGF); erb-b2 receptor tyrosine kinase 2 (ERBB2 HER2, HER2/neu or CD340); epidermal growth factor receptor (EGFR, ERBB, ERBB1 or HER1); ALK receptor tyrosine kinase (ALK, CD246); poly(ADP- ribose) polymerase 1 (PARP1 or PARP); cyclin dependent kinase 4 (CDK4); cyclin dependent kinase 6 (CDK6); C-C motif chemokine receptor 8 (CCR8, CDwl98); CD274 molecule (CD274, PDL1 or PD-L1); programmed cell death 1 (PDCD1, PD1 or PD-1); and/or cytotoxic T-lymphocyte associated protein 4 (CTLA4, CTLA-4, CD 152).

0591In some embodiments, the inhibitor comprises an antigen binding molecule, an antibody or an antigen-binding fragment thereof.

0592In some embodiments, the inhibitor of MCL1 is AMG-176, AMG-397, S-64315, AZD-5991, 483-LM, A1210477, UMI-77, or JKY-5-037.

0593In some embodiments, the inhibitor of PTPN11 or SHP2 is TN0155 (SHP-099), RMC-4550, JAB-3068 and RMC-4630.

0594In some embodiments, the additional therapeutic agent is a chemotherapeutic, an anti-neoplastic, a radiotherapeutic, or a checkpoint targeting agent. In some embodiments, the one or more anti -neoplastic or chemotherapeutic agents are a nucleoside analog (e.g., 5-fluorouracil, gemcitabine, cytarabine), a taxane (e.g., paclitaxel, nab- paclitaxel, docetaxel, cabazitaxel), a platinum coordination complex (cisplatin, carboplatin, oxaliplatin, nedaplatin, triplatin tetranitrate, phenanthriplatin, picoplatin, satraplatin, dicycloplatin, eptaplatin, lobaplatin, miriplatin), a dihydrofolate reductase (DHFR) inhibitor (e.g., methotrexate, trimetrexate, pemetrexed), a topoisomerase inhibitor (e.g., doxorubicin, daunorubicin, dactinomycin, eniposide, epirubicin, etoposide, idarubicin, irinotecan, mitoxantrone, pixantrone, sobuzoxane, topotecan, irinotecan, MM-398 (liposomal irinotecan), vosaroxin and GPX-150, al doxorubicin, AR-67, mavelertinib, AST-2818, avitinib (ACEA-0010), irofulven (MGI-114)), an alkylating agent (e.g., a nitrogen mustard (e.g., cyclophosphamide, chlormethine, uramustine or uracil mustard, melphalan, chlorambucil, ifosfamide, bendamustine, temozolomide, carmustine), a nitrosourea (e.g., carmustine, lomustine, streptozocin), an alkyl sulfonate (e.g., busulfan)), or mixtures thereof.

0595In some embodiments, the checkpoint targeting agent is an antagonist anti-PD-1 antibody, an antagonist anti-PD- Ll antibody, an antagonist anti-PD-L2 antibody, an antagonist anti-CTLA-4 antibody, an antagonist anti-TIM-3 antibody, an antagonist anti-LAG-3 antibody, an antagonist anti-CEACAMl antibody, an agonist anti-GITR antibody, an antagonist anti-TIGIT antibody, an antagonist anti -VISTA antibody, an agonist anti-CD 137 antibody, or an agonist anti-OX40 antibody.

0596In some embodiments, the additional therapeutic agent comprises one or more cellular therapies. In some embodiments, the cellular therapy comprises one or more of a population of natural killer (NK) cells, NK-T cells, T cells, cytokine-induced killer (CIK) cells, macrophage (MAC) cells, tumor infiltrating lymphocytes (TILs) and/or dendritic cells (DCs). In some embodiments, the cellular therapy entails a T cell therapy, e.g., co-administering a population of alpha/beta TCR T cells, gamma/delta TCR T cells, regulatory T (Treg) cells and/or TRuC^™ T cells. In some embodiments, the cellular therapy entails a NK cell therapy, e.g., co-administering NK-92 cells. A cellular therapy can entail the co-administration of cells that are autologous, syngeneic or allogeneic to the subject. In some embodiments, the one or more of a population of immune cells comprise one or more chimeric antigen receptors (CARs).

0597In some embodiments, the additional therapeutic agent comprises an antibody or an antigen-binding fragment thereof, or antibody-drug conjugate thereof, CD3-targeting multi-specific molecule, CD16-targeting multi-specific molecule, non-immunoglobulin antigen binding molecule or antibody mimetic protein.

0598In some embodiments, the one or more additional therapeutic agents comprises an immunotherapy, an immunostimulatory therapy, a cytokine therapy, a chemokine therapy, a cellular therapy, a gene therapy, and combinations thereof. In some embodiments, the immunotherapy comprises co-administering one or more antibodies or antigen-binding antibody fragments thereof, or antibody-drug conjugates thereof, CD3-targeting multi-specific molecules, CD16-targeting multi-specific molecules, or non-immunoglobulin antigen-binding domains or antibody mimetic proteins directed against one or more targets or tumor associated antigens (TAAs).

0599In some embodiments, the present disclosure provides method of treating an HIV or hepatitis B virus infection in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the compound or pharmaceutical composition is co-administered with one or more additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents comprises a vaccine.

0600In some embodiments, a method for manufacturing a medicament for treating cancer in a subject in need thereof is characterized in that a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is used.

0601In some embodiments, a method for manufacturing a medicament for inhibiting cancer metastasis in a subject in need thereof is characterized in that a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is used.

0602In some embodiments, a method for manufacturing a medicament for treating an HIV or hepatitis B virus infection in a subject in need thereof is characterized in that a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is used.

0603In some embodiments, a use of the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is for the manufacture of a medicament for the treatment of cancer in a subject.

0604In some embodiments, a use of the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is for the manufacture of a medicament for inhibiting cancer metastasis in a subject.

0605In some embodiments, a use of the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is for the manufacture of a medicament for the treatment of an HIV or hepatitis B infection in a subject.

0606In some embodiments, a compound of the present disclosure is for use in therapy. In some embodiments, the compound is for use in the treatment of a cancer in a subject in need thereof. In some embodiments, the compound is for use in inhibiting cancer metastasis in a subject in need thereof. In some embodiments, the compound is for use in the treatment of an HIV or hepatitis B virus infection in a subject in need thereof.

VII. METHODS OF SYNTHESIS

0607<b>Abbreviations.</b> Certain abbreviations and acronyms are used in describing the experimental details. Although most of these would be understood by one skilled in the art, Table 4 contains a list of many of these abbreviations and acronyms. <tables id="tabl0035" num="0035"><table frame="all"><title><b>Table 4. List of abbreviations and acronyms.</b></title><tgroup cols="2"><colspec colnum="1" colname="col1" colwidth="23mm" /><colspec colnum="2" colname="col2" colwidth="113mm" /><thead valign="top"><row><entry>Abbreviation</entry><entry><u>Meaning</u></entry></row></thead><tbody><row><entry>Ac</entry><entry>acetyl</entry></row><row><entry>AcOEt</entry><entry>ethyl acetate (also EtOAc)</entry></row><row><entry>ACN</entry><entry>acetonitrile</entry></row><row><entry>Bn</entry><entry>benzyl</entry></row><row><entry>Boc</entry><entry>tert-butoxycarbonyl</entry></row><row><entry>BOP</entry><entry>benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate</entry></row><row><entry>BroP</entry><entry>bromotris(dimethylamino)phosphonium hexafluorophosphate</entry></row><row><entry>Bu</entry><entry>butyl</entry></row><row><entry>nBuLi</entry><entry>n-butyllithium</entry></row><row><entry>CDCl₃</entry><entry>Chloroform-<i>d</i></entry></row><row><entry>dba</entry><entry>dibenzylideneacetone</entry></row><row><entry>DBU</entry><entry>1,8-Diazabicyclo[5.4.0]undec-7-ene</entry></row><row><entry>DCM</entry><entry>dichloromethane</entry></row><row><entry>DMSO</entry><entry>dimethylsulfoxide</entry></row><row><entry>DMF</entry><entry>dimethylformamide</entry></row><row><entry>dppf</entry><entry>1,1'-Bis(diphenylphosphino)ferrocene</entry></row><row><entry>EA</entry><entry>Ethyl acetate</entry></row><row><entry>Et</entry><entry>ethyl</entry></row><row><entry>iBu</entry><entry>isobutyl</entry></row><row><entry>IPA</entry><entry>isopropanol</entry></row><row><entry>iPr</entry><entry>isopropyl</entry></row><row><entry>LC</entry><entry>liquid chromatography</entry></row><row><entry>LDA</entry><entry>lithium diisopropylamide</entry></row><row><entry>Me</entry><entry>methyl</entry></row><row><entry>m/z</entry><entry>mass to charge ratio</entry></row><row><entry>MS or ms</entry><entry>mass spectrum</entry></row><row><entry>NMP</entry><entry><i>N</i>-methyl-2-pyrrolidone</entry></row><row><entry>Ph</entry><entry>phenyl</entry></row><row><entry>Ph₃P</entry><entry>triphenylphosphine</entry></row><row><entry>prep. HPLC</entry><entry>preparative high performance liquid chromatography (also prep-HPLC)</entry></row><row><entry>RT</entry><entry>room temperature</entry></row><row><entry>SEM</entry><entry>2-(Trimethylsilyl)ethoxymethyl</entry></row><row><entry>SEM-Cl</entry><entry>2-(Trimethylsilyl)ethoxymethyl Chloride</entry></row><row><entry>Si-column</entry><entry>Silica column</entry></row><row><entry>tBu</entry><entry>tert-butyl</entry></row><row><entry>TFA</entry><entry>trifluoroacetic acid</entry></row><row><entry>THF</entry><entry>tetrahydrofuran</entry></row><row><entry>TLC</entry><entry>thin layer chromatography</entry></row><row><entry>δ</entry><entry>parts per million referenced to residual non-deuterated solvent peak</entry></row></tbody></tgroup></table></tables>

<u>General Synthetic Schemes</u>

0608Compounds of Formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8) of the present disclosure can be prepared, for example, according to the following schemes. During any of the processes for preparation of the subject compounds, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups as described in standard works, such as <nplcit id="ncit0083" npl-type="b"><text>T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis," 4th ed., Wiley, New York 2006</text></nplcit>. For example, in some embodiments, a protecting includes a benzyloxycarbonyl group or a tert-butyloxycarbonyl group as an amino-protecting group, and/or a tert-butylmethylsilyl group etc. as a hydroxy-protecting group. The protecting groups may be removed at a convenient subsequent stage using methods known from the art.

0609Exemplary chemical entities useful in methods of the embodiments will now be described by reference to illustrative synthetic schemes for their general preparation herein and the specific examples that follow. Artisans will recognize that, to obtain the various compounds herein, starting materials may be suitably selected so that the ultimately desired substituents will be carried through the reaction scheme with or without protection as appropriate to yield the desired product. Alternatively, it may be necessary or desirable to employ, in the place of the ultimately desired substituent, a suitable group that may be carried through the reaction scheme and replaced as appropriate with the desired substituent. Furthermore, one of skill in the art will recognize that the transformations shown in the schemes below may be performed in any order that is compatible with the functionality of the particular pendant groups. Each of the reactions depicted in the general schemes, unless otherwise specified, can be run at a temperature from about 0 °C to the reflux temperature of the organic solvent used. Each of variable sites disclosed in the following schemes is applicable to every functional group in the compounds of Formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8) provided by the present disclosure.

0610The embodiments are also directed to processes and intermediates useful for preparing the subject compounds or pharmaceutically acceptable salts thereof. <chemistry id="chem1236" num="1236"><img file="EP4445902A2_D1239.tif" /></chemistry>

0611Compounds of Formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8) can be prepared according to General Synthetic Scheme 1, wherein R¹, R², R³, R⁴, R⁵ and R⁶ are as described above.

0612In accordance with General Synthetic Scheme 1, a compound of Formula (1-a) can react with a compound of Formula (1-b) in a solvent to generate a compound of Formula (1-c). It is contemplated that any suitable non-reactive solvent can be used for this reaction, such as DMF. This reaction can be carried out at a time and temperature suitable to generate a desired quantity of a compound of Formula (1-c), for example at a temperature ranging from room temperature to 100°C and at a time ranging for several minutes to several hours, for instance at room temperature for an hour.

0613A compound of Formula (1-a), can be purchased or readily synthesized through methods known to those skilled in the art, such as methods described at <nplcit id="ncit0084" npl-type="s"><text>J.Med.Chem.2014,57,5141-5156</text></nplcit> or similar methods. Compounds of Formula (1-b) are commercially available, or can be readily prepared by persons skilled in the art according to known methods.

0614A compound of Formula (1-c) can be combined with hydrazine in a suitable solvent, such as an alcohol, to generate a compound of Formula (1-d). Suitable solvents can include non-reactive solvents, and the reaction can be carried out at a time and temperature suitable to generate a desired quantity of a compound of Formula (1-d), such as a temperature ranging from room temperature to 100°C and a time ranging from several minutes to several hours. For example, the reaction can be conducted in ethanol solvent at a temperature below 50°C for an hour.

0615A compound of Formula (1-d) can be converted to a compound of Formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8) by reacting 1 to 5 mole equivalents of triethyl orthoformate with a compound of Formula (1-d) at a time and temperature suitable to generate a desired quantity of a compound of Formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8). For example, a compound of Formula (1-d) can undergo reaction with triethyl orthoformate at a temperature ranging from room temperature to 120°C, for instance at a temperature of 100°C, for several minutes to several days, such as from one minute to an hour.

General Synthetic Scheme 2

0616A compound of Formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8) can also be prepared according to the following General Synthetic Scheme 2: <chemistry id="chem1237" num="1237"><img file="EP4445902A2_D1240.tif" /></chemistry> wherein R¹, R², R³, R⁴, R⁵ and R⁶ are as described herein.

0617In accordance with General Synthetic Scheme 2, a compound of Formula (2-a) can be combined with hydrazine in a suitable non-reactive solvent, such as an alcohol. The reaction can be carried out at a temperature ranging from room temperature to 100°C, at a time sufficient to produce a desired quantity of a compound of Formula (2-b), for example ranging from several minutes to several hours. For example, a compound of Formula (2-b) can be suitably generated at a temperature between room temperature and 50°C for an hour. A compound of Formula (2-a) can be obtained commercially or can be readily prepared by a person of ordinary skill in the art through known methods, such as through a reaction of a compound of Formula (1-a) with a base in a suitable solvent.

0618A compound of Formula (2-b) can be combined with 1 to 5 mole equivalents of triethyl orthoformate under suitable reaction conditions to produce a compound according to Formula (2-c). For example, a reaction to generate a compound of Formula (2-c) can be carried out at a temperature ranging from room temperature to 120°C at a time ranging from several minutes to several days. For example, a desired quantity of the compound of Formula (2-c) can be generated at a reaction temperature of 100°C for 1 minute to an hour.

0619A compound of Formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8) can be obtained, in accordance with General Synthetic Scheme 2, by reacting a compound of Formula (2-c) with 1 to 5 mole equivalents of a compound of Formula (1-b) using 1 to 5 mole equivalents of a dehydrating condensing agent in a solvent in the presence of a base. Any suitable solvent may be used, including solvents that are not reactive in the reaction. Non-limiting examples of suitable solvents for this reaction include acetonitrile, NMP, DMF, and the like. Suitable dehydrating condensing agents are known to those skilled in the art, including for instance, but not by way of limitation, a phosphonium-based dehydrating condensing agent such as BOP reagent. Exemplary bases suitable for this reaction include, for example, an inorganic base such as cesium carbonate, or an organic amine such as triethylamine.

0620The reaction can be carried out, for instance, using an acetonitrile solvent, using 1 to 5 mole equivalents of BroP (bromotris(dimethylamino)phosphonium hexafluorophosphate) reagent as the dehydrating condensing agent and 1 to 5 mole equivalents of DBU as the base at a temperature between room temperature and 120°C for several minutes to several days, such as at 50°C for 1 minute to an hour.

0621Alternatively, the conversion of a compound of Formula (2-c) to a compound of Formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8) can be carried out without using a dehydrating condensing agent. For example, a compound of Formula (2-c) can be reacted with 1 to 5 mole equivalents of the compound of Formula (1-b) in a solvent in the presence of a strong base. Any non-reactive solvent is contemplated as suitable for the reaction, such as an ether-based solvent, or for example THF. Non-limiting examples of suitable strong base include an organic base such as nBuLi. In some embodiments, 1 to 5 mole equivalents of LDA can be used. The reaction can be carried out at a temperature ranging from -100°C to 0°C for several minutes to several days. For example, a desired quantity of the compound of Formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8) can be generated by carrying out this reaction at a temperature of -78°C for 1 to 20 hours.

0622Further a compound of the present disclosure having a desired functional group at a desired position can be prepared by a suitable combination of the methods above, or a procedure usually carried out in an organic synthesis (for example, alkylation reaction of an amino group, oxidation reaction of an alkylthio group into a sulfoxide group or a sulfone group, converting reaction of an alkoxy group into a hydroxy group, or opposite converting reaction thereof).

VIII. EXAMPLES

0623Many general references providing commonly known chemical synthetic schemes and conditions useful for synthesizing the disclosed compounds are available (see, e.g., <nplcit id="ncit0085" npl-type="b"><text>Smith, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 7th edition, Wiley-Interscience, 2013</text></nplcit>.)

0624Compounds as described herein can be purified by any of the means known in the art, including chromatographic means, such as high performance liquid chromatography (HPLC), preparative thin layer chromatography, flash column chromatography and ion exchange chromatography. Any suitable stationary phase can be used, including normal and reversed phases as well as ionic resins. For example, disclosed compounds can be purified via silica gel chromatography. <i>See, e.g.,</i><nplcit id="ncit0086" npl-type="b"><text> Introduction to Modern Liquid Chromatography, 2nd ed., ed. L. R. Snyder and J. J. Kirkland, John Wiley and Sons, 1979</text></nplcit>; and<nplcit id="ncit0087" npl-type="b"><text> Thin Layer Chromatography, E. Stahl (ed.), Springer-Verlag, New York, 1969</text></nplcit>.

0625Compounds were characterized using standard instrumentation methods. Identification of the compound was carried out by hydrogen nuclear magnetic resonance spectrum (¹H-NMR) and mass spectrum (MS). ¹H-NMR was measured at 400 MHz, unless otherwise specified. In some cases, exchangeable hydrogen could not be clearly observed depending on the compound and measurement conditions. The designation br. or broad, used herein, refers to a broad signal. HPLC preparative chromatography was carried out by a commercially available ODS column in a gradient mode using water/methanol (containing formic acid) as eluents, unless otherwise specified.

0626The Examples provided herein describe the synthesis of compounds disclosed herein as well as intermediates used to prepare the compounds. It is to be understood that individual steps described herein may be combined. It is also to be understood that separate batches of a compound may be combined and then carried forth in the next synthetic step.

0627In the following description of the Examples, specific embodiments are described. These embodiments are described in sufficient detail to enable those skilled in the art to practice certain embodiments of the present disclosure. Other embodiments may be utilized and logical and other changes may be made without departing from the scope of the disclosure. The following description is, therefore, not intended to limit the scope of the present disclosure.

0628Representative syntheses of compounds of the present disclosure are described in schemes below, and the particular examples that follow.

A. Intermediates

Intermediate 1. <b>5-Chloro-[1,2,4]triazolo[4,3-a]quinazoline</b>

0629<chemistry id="chem1238" num="1238"><img file="EP4445902A2_D1241.tif" /></chemistry>

(Step 1) Synthesis of

2-Chloroquinazolin-4(1<i>H</i>)-one

0630<chemistry id="chem1239" num="1239"><img file="EP4445902A2_D1242.tif" /></chemistry>

0631To a stirred solution of 2,4-dichloroquinazoline (5.0 g, 25.12 mmol) in THF (50 mL) was added 1M NaOH solution (50 mL) at 0 °C and the mixture was stirred for 16 h at RT. The reaction mixture was acidified with acetic acid to pH ~ 6. The resulting solids were filtered and dried under vacuum to give the desired product. LCMS(m/z) 181.08 [M+H]+.

(Step 2) Synthesis of 2-Hydrazinylquinazolin-4(1<i>H</i>)-one

0632<chemistry id="chem1240" num="1240"><img file="EP4445902A2_D1243.tif" /></chemistry>

0633To a stirred solution of 2-chloroquinazolin-4(1<i>H</i>)-one (4.0 g, 22.22 mmol) in EtOH (80 mL) was added hydrazine hydrate (3.33 g, 66.66 mmol) at RT and the mixture was heated to 50 °C for 4 h. The reaction mixture was diluted with petroleum ether. The resulting solids were filtered and dried under vacuum to give the desired product. LCMS(m/z) 177.13 [M+H]+.

(Step 3) Synthesis of [1,2,4]Triazolo[4,3-a]quinazolin-5(4H)-one (Intermediate 2)

0634<chemistry id="chem1241" num="1241"><img file="EP4445902A2_D1244.tif" /></chemistry>

0635The mixture of 2-hydrazinylquinazolin-4(1<i>H</i>)-one (4.0 g, 22.22 mmol) and formic acid (80 mL) was heated to 100 °C for 16 h. The reaction mixture was evaporated under reduced pressure, and the residue was washed with ethanol and n-hexane. The resulting solids were purified by column chromatography (Si-column, hexane : AcOEt = 10 : 0 - 4 : 6) to give the desired product. LCMS(m/z) 187.05 [M+H]+.

(Step 4) Synthesis of 5-Chloro-[1,2,4]triazolo[4,3-a]quinazoline

0636The mixture of [1,2,4]triazolo[4,3-a]quinazolin-5(4H)-one (1.0 g, 5.37 mmol) and phosphorus oxychloride (20 mL) was heated to 110 °C for 6 h. The reaction mixture was evaporated under reduced pressure, and the residue was neutralized with sat. sodium bicarbonate solution at 0 °C. The resulting solids were filtered and dried under vacuum to give the desired product. LCMS(m/z) 204.93 [M+H]+.

<u>Intermediate 2. [1,2,4]triazolo[4,3-a]quinazolin-5(4H)-one</u>

0637<chemistry id="chem1242" num="1242"><img file="EP4445902A2_D1245.tif" /></chemistry>

0638[1,2,4]triazolo[4,3-a]quinazolin-5(4H)-one (Intermediate 2) can be alternatively synthesized according to the following route.

(Step 1) Synthesis of 2-chloro-4(3H)-quinazolinone

0639<chemistry id="chem1243" num="1243"><img file="EP4445902A2_D1246.tif" /></chemistry>

0640A mixture of 2,4-dichloroquinazoline (5 g, 25.1 mmol) in 2M NaOH solution (60 mL, 60 mmol) and THF (60 mL) was stirred for 1.5h at RT. The reaction mixture was cooled and adjusted to pH 5 with AcOH. The precipitated solids were collected and washed with water, EtOH to give the desired product. LCMS(m/z) 181.06 [M+H]+.

(Step 2) Synthesis of 2-Chloro-3-((2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3<i>H</i>)-one

0641<chemistry id="chem1244" num="1244"><img file="EP4445902A2_D1247.tif" /></chemistry>

0642A solution of 2-chloro-4(3H)-quinazolinone (3.9g, 21.60 mmol), SEM-Cl (4.21 ml, 23.76 mmol) and K₂CO₃ (3.58 g, 25.9 mmol) in DMF (50 mL) was stirred overnight at RT. The reaction mixture was diluted with EtOAc, washed successively with water and brine, dried over Na₂SO₄, and concentrated in vacuo. The crude was used for the next step without purification.

(Step 3) Synthesis of 2-Hydrazinyl-3-((2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3<i>H</i>)-

one

0643<chemistry id="chem1245" num="1245"><img file="EP4445902A2_D1248.tif" /></chemistry>

0644A solution of 2-Chloro-3-((2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3H)-one (170 mg, 0.547 mmol) in a mixture of hydrazine hydrate (0.5 mL, 15.93 mmol) and EtOH (2 mL) was stirred for 1.5h at RT. The reaction mixture was diluted with EtOAc, washed successively with water and brine, dried over Na₂SO₄, and concentrated in vacuo. The crude material was used for the next step without purification. LCMS(m/z) 307.18 [M+H]+.

(Step 4) Synthesis of 4-((2-(trimethylsilyl)ethoxy)methyl)-[1,2,4]triazolo[4,3-a]quinazolin-5(4<i>H</i>)-one

0645<chemistry id="chem1246" num="1246"><img file="EP4445902A2_D1249.tif" /></chemistry>

0646A solution of the resulting 2-hydrazinyl-3-((2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3H)-one in triethoxymethane (3 mL) was stirred for overnight at 100 °C. The reaction mixture was purified by column chromatography (Si-column, hexane : AcOEt = 100 : 0 - 0 : 100) to give the desired product.

(Step 5) Synthesis of [1,2,4]triazolo[4,3-<i>a</i>]quinazolin-5(4<i>H</i>)-one

0647A mixture of 4-((2-(trimethylsilyl)ethoxy)methyl)-[1,2,4]triazolo[4,3-a]quinazolin-5(4<i>H</i>)-one (187 mg, 0.591 mmol) and 2,2,2-trifluoroacetic acid (2 mL, 0.591 mmol) was stirred for 1 h at RT. The reaction mixture was concentrated in vacuo. The resulting solids were collected to give the desired product. LCMS(m/z) 187.11 [M+H]⁺; ¹H NMR (400 MHz, DMSO-<i>d</i>₆) δ 12.80 (s, 1H), 9.40 (s, 1H), 8.21 - 8.12 (m, 2H), 7.96 - 7.85 (m, 1H), 7.57 (ddd, <i>J</i> = 8.1, 7.4, 1.0 Hz, 1H).

<u>Intermediate 3. 8-bromo-5-chloro-[1,2,4]triazolo[4,3-a]quinazoline</u>

0648<chemistry id="chem1247" num="1247"><img file="EP4445902A2_D1250.tif" /></chemistry>

(Step 1) Synthesis of 7-Bromoquinazoline-2,4(1H,3H)-dione

0649<chemistry id="chem1248" num="1248"><img file="EP4445902A2_D1251.tif" /></chemistry>

0650A mixture of 2-amino-4-bromobenzoic acid (20 g, 92.59 mmol) and urea (55.55 g, 925.92 mmol) was heated to 150 °C for 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with ice-water and stirred for 30 min. The resulting solids were collected, and triturated with glacial acetic acid and washed with petroleum ether to give the desired product. LCMS(m/z) 241.06 [M+H]+.

(Step 2) Synthesis of 7-Bromo-2,4-dichloroquinazoline

0651<chemistry id="chem1249" num="1249"><img file="EP4445902A2_D1252.tif" /></chemistry>

0652To a stirred solution of 7-bromoquinazoline-2,4(1H,3H)-dione (19 g, 79.17 mmol) in phosphorus oxychloride (74 mL, 791.67 mmol) was added N, N-diisopropylethylamine (19.6 mL, 118.75 mmol) at 0 °C, and the mixture was heated to 110 °C for 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with ice-water and stirred for 30 min. The resulting solids were collected, and washed with cold water and dried under vacuum to afford the desired product. LCMS(m/z) 277.08 [M+H]+.

(Step 3) Synthesis of 7-Bromo-2-chloroquinazolin-4(3H)-one

0653<chemistry id="chem1250" num="1250"><img file="EP4445902A2_D1253.tif" /></chemistry>

0654To a stirred solution of 7-bromo-2,4-dichloroquinazoline (22.0 g, 79.71 mmol) in THF (200 mL) was added 1M NaOH (191 mL, 191.30 mmol) at 0 °C, and the mixture was stirred for 2 h at RT. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was acidified with glacial acetic acid to pH ~ 5. The resulting solids were filtered and dried under vacuum to give the desired product. LCMS(m/z) 259.17 [M+H]+.

(Step 4) Synthesis of 7-Bromo-2-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3H)-one

0655<chemistry id="chem1251" num="1251"><img file="EP4445902A2_D1254.tif" /></chemistry>

0656To a stirred solution of 7-bromo-2-chloroquinazolin-4(3H)-one (14.5 g, 56.20 mmol) in DMF (150 mL) were added potassium carbonate (8.53 g, 61.82 mmol) and 2-(trimethylsilyl)ethoxymethyl chloride (10.96 mL g, 61.82 mmol) at 0 °C, and the mixture was stirred for 4 h a RT. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed successively with water and brine, dried over Na₂SO₄, filtered and evaporated under reduced pressure to give the desired product.

(Step 5) Synthesis of 7-Bromo-2-hydrazinyl-3-((2-(trimethylsilyl)ethoxy)methyl)-quinazolin-4(3H)-one

0657<chemistry id="chem1252" num="1252"><img file="EP4445902A2_D1255.tif" /></chemistry>

0658To a stirred solution of 7-bromo-2-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3H)-one (15 g, 38.66 mmol) in EtOH (150 mL) was added hydrazine (386 mL, 386.60 mmol, 1.0 M in THF) at 0 °C, and the mixture was stirred for 2 h at RT. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with 10% methanol/dichloromethane. The organic layer was washed successively with water and brine, dried over Na₂SO₄, filtered and evaporated under reduced pressure to give the desired product. LCMS(m/z) 385.40 [M+H]+.

(Step 6) Synthesis of 8-Bromo-4-((2-(trimethylsilyl)ethoxy)methyl)-[1,2,4]triazolo[4,3-a] quinazolin-5(4H)-one

0659<chemistry id="chem1253" num="1253"><img file="EP4445902A2_D1256.tif" /></chemistry>

0660A mixture of 7-bromo-2-hydrazinyl-3-((2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3H)-one (17 g, 44.27 mmol) and triethylorthoformate (43.74 mL, 265.62 mmol) was heated to 100 °C for 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was evaporated under reduced pressure. The resulting residue was triturated with diethyl ether to give the desired product. LCMS(m/z) 397.35 [M+H+2, isotopic mass]+.

(Step 7) Synthesis of 8-Bromo-[1,2,4]triazolo[4,3-a]quinazolin-5(4<i>H</i>)- one

0661<chemistry id="chem1254" num="1254"><img file="EP4445902A2_D1257.tif" /></chemistry>

0662To a stirred solution of 8-bromo-4-((2-(trimethylsilyl)ethoxy)methyl)-[1,2,4]triazolo[4,3-a]quinazolin-5(4H)-one (1.5 g, 5.1 mmol) in methanol (15 mL) was added trifluoroacetic acid (1.5 mL) at RT,and the mixture was stirred at RT for 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture evaporated under reduced pressure. The resulting residue was triturated with diethyl ether to afford the desired product. LCMS(m/z) 265.27 [M+H]+; ¹H NMR (400 MHz, DMSO-d₆) δ = 12.88 (br. s, 1H), 9.41 (s, 1H), 8.55 (d, <i>J=</i> 1.5 Hz, 1H), 8.05 (d, <i>J=</i> 8.6 Hz, 1H), 7.75 (dd, <i>J =</i> 1.6, 8.4 Hz, 1H).

Synthesis of

8-Bromo-5-chloro-[1,2,4]triazolo[4,3-a]quinazoline

0663A mixture of 8-bromo-[1,2,4]triazolo[4,3-<i>a</i>]quinazolin-5(4<i>H</i>)-one (2.0 g, 7.57 mmol) in phosphorus oxychloride (15 mL) was refluxed for 6 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was evaporated under reduced pressure. The residue was dissolved in toluene and evaporated twice to afford the desired product: LCMS(m/z) 283.20 [M+H]+.

<u>Intermediate 4. 8-Nitro-[1,2,4]triazolo[4,3-a]quinazolin-5(4H)-one</u>

0664<chemistry id="chem1255" num="1255"><img file="EP4445902A2_D1258.tif" /></chemistry>

(Step 1) Synthesis of 7-Nitroquinazoline-2,4(1H,3H)-dione

0665<chemistry id="chem1256" num="1256"><img file="EP4445902A2_D1259.tif" /></chemistry>

0666A mixture of 2-amino-4-nitrobenzoic acid (10 g, 54.94 mmol) and urea (32.96 g, 549.45 mmol) was heated to 150 °C for 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with ice-water and stirred for 10 min. The resulting solids were collected and triturated with glacial acetic acid to give the desired product. LCMS(m/z) 208.14 [M+H]+.

(Step 2) Synthesis of 2,4-Dichloro-7-nitroquinazoline

0667<chemistry id="chem1257" num="1257"><img file="EP4445902A2_D1260.tif" /></chemistry>

0668To a stirred solution of 7-nitroquinazoline-2,4(1H,3H)-dione (10.3 g, 49.76 mmol) in phosphorus oxychloride (48 mL, 497.58 mmol) <i>and N, N</i>-diisopropylethylamine (13 mL, 74.64 mmol) at 0 °C and the mixture was heated to 110 °C for 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with crushed ice and stirred for 10 min. The resulting solids were filtered and dried under vacuum to give the desired product. LCMS(m/z) 244.11 [M+H]+.

(Step 3) Synthesis of 2-Chloro-7-nitroquinazolin-4(3H)-one

0669<chemistry id="chem1258" num="1258"><img file="EP4445902A2_D1261.tif" /></chemistry>

0670To a stirred solution of 2,4-dichloro-7-nitroquinazoline (20 g, 82.3 mmol) in THF (5 mL) was added 1M NaOH solution (197 mL, 197.53 mmol) at 0 °C and the mixture was stirred for 2 h at RT. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was acidified with acetic acid to pH ~ 5 at 0 °C. The resulting solids were filtered and dried under vacuum to give the desired product. LCMS(m/z) 226.21 [M+H]+.

(Step 4) Synthesis of 2-Chloro-7-nitro-3-((2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3H)-one

0671<chemistry id="chem1259" num="1259"><img file="EP4445902A2_D1262.tif" /></chemistry>

0672To a stirred solution of 2-chloro-7-nitroquinazolin-4(3H)-one (15.6 g, 69.33 mmol) in DMF (160 mL) were added potassium carbonate (10.54 g, 76.27 mmol) and 2-(trimethylsilyl)ethoxymethyl chloride (13.52 mL, 76.27 mmol) at 0 °C and the mixture was stirred for 4 h at RT. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed successively with water and brine, dried over Na₂SO₄, filtered and evaporated under reduced pressure to give the desired product. LCMS(m/z) 356.42 [M+H]+.

(Step 5) Synthesis of 2-Hydrazinyl-7-nitro-3-((2-(trimethylsilyl)ethoxy)methyl)-quinazolin-4(3<i>H</i>)-one

0673<chemistry id="chem1260" num="1260"><img file="EP4445902A2_D1263.tif" /></chemistry>

0674To a stirred solution of 2-chloro-7-nitro-3-((2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3H)-one 5 (crude, 10 g, 28.17 mmol) in EtOH (100 mL) was added hydrazine (281 mL, 281.69 mmol, 1.0M in THF) at 0 °C and the mixture was stirred for 2 h at RT. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with 10% methanol/dichloromethane. The organic layer was dried over Na₂SO₄, filtered and evaporated under reduced pressure to give the desired product. LCMS(m/z) 352.53 [M+H]+.

(Step 6) Synthesis of 8-Nitro-4-((2-(trimethylsilyl)ethoxy)methyl)-[1,2,4]triazolo[4,3-a] quinazolin-5(4<i>H</i>)-one

0675<chemistry id="chem1261" num="1261"><img file="EP4445902A2_D1264.tif" /></chemistry>

0676The mixture of 2-hydrazinyl-7-nitro-3-((2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3<i>H</i>)-one (crude, 12.0 g, 34.19 mmol) and triethylorthoformate (34.15 mL, 205.13 mmol, 6.0 eq.) was heated to 100 °C for 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was evaporated under reduced pressure, and the residue was washed with diethyl ether and dried under vacuum to give the desired product. LCMS(m/z) 362.40 [M+H]+.

(Step 7) Synthesis of S-Nitro-[1,2,4]triazolo [4,3-a] quinazolin-5(4H)-one

0677To a stirred solution of 8-nitro-4-((2-(trimethylsilyl)ethoxy)methyl)-[1,2,4]triazolo[4,3-a]quinazolin-5(4<i>H</i>)-one (6.3 g, 24.14 mmol) in MeOH (60 mL) was added triethylamine (6.09 mL, 43.45 mmol) at RT and the mixture was stirred for 16 h at the same temperature. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was evaporated under reduced pressure, and the residue was washed successively with diethyl ether, n-pentane, and dried under vacuum to afford the desired product: LCMS(m/z) 231.9 [M+H]+; ¹H NMR (500 MHz, DMSO-d₆) δ = 13.10 (brs, 1H), 9.65 (s, 1H), 9.10 (d, <i>J</i> = 2.1 Hz, 1H), 8.40 - 8.36 (m, 1H), 8.31 (dd, <i>J =</i> 2.0, 9.0 Hz, 1H).

<u>Intermediate 5. 5,8-Dichloro-[1,2,4]triazolo[4,3-a]quinazoline</u>

0678<chemistry id="chem1262" num="1262"><img file="EP4445902A2_D1265.tif" /></chemistry>

(Step 1) synthesis of 7-Chloroquinazoline-2,4(1H,3H)-dione

0679<chemistry id="chem1263" num="1263"><img file="EP4445902A2_D1266.tif" /></chemistry>

0680A mixture of 2-amino-4-chlorobenzoic acid (10 g, 58.48 mmol) and urea (35.09 g, 584.79 mmol) was stirred at 150 °C for 16 h. The reaction mixture was diluted with ice-cold water at 100 °C. The resulting solids were filtered, washed with water and dried under vacuum to give the desired product: LCMS(m/z) 197.13 [M+H]+.

(Step 2) synthesis of 2,4,7-Trichloroquinazoline

0681<chemistry id="chem1264" num="1264"><img file="EP4445902A2_D1267.tif" /></chemistry>

0682To a solution of 7-chloroquinazoline-2,4(1H,3H)-dione (9.1 g, 46.43 mmol) in phosphorus oxychloride (43.39 mL, 464.28 mmol) was added N, N-diisopropylethylamine (12.14 mL, 69.64 mmol) at 0 °C and the mixture was stirred at 110 °C for 16 h. The reaction mixture was diluted with ice-cold water, and the resulting solids were filtered, washed with water and dried under vacuum to give the desired product.

(Step 3) synthesis of 2,7-Dichloroquinazolin-4(3<i>H</i>)-one

0683<chemistry id="chem1265" num="1265"><img file="EP4445902A2_D1268.tif" /></chemistry>

0684To a solution of 2,4,7-trichloroquinazoline (10 g, 43.10 mmol) in THF (100 mL) was added 1M NaOH solution (103.45 mL, 103.45 mmol) at 0 °C and the mixture was stirred for 2 h at RT. The reaction mixture was acidified with acetic acid to pH ~ 5 at 0 °C. The resulting solids were filtered, washed with water, petroleum ether and dried under vacuum to give the desired product. LCMS(m/z) 215.09 [M+H]+.

(Step 4) synthesis of 2,7-Dichloro-3-((2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3<i>H</i>)-one

0685<chemistry id="chem1266" num="1266"><img file="EP4445902A2_D1269.tif" /></chemistry>

0686To a solution of 2,7-dichloroquinazolin-4(3H)-one (8.6 g, 40 mmol) in DMF (90 mL) were added potassium carbonate (6.07 g, 44 mmol) and 2-(trimethylsilyl)ethoxymethyl chloride (7.80 mL, 44 mmol) at 0 °C and the mixture was stirred for 4 h at RT. The reaction mixture was diluted with ice-water and extracted with ethyl acetate. The organic layer was washed with ice-water, brine, dried over Na₂SO₄, and evaporated under reduced pressure to give the desired product. LCMS(m/z) 345.33 [M+H]+.

(Step 5) synthesis of 7-Chloro-2-hydrazinyl-3-((2-(trimethylsilyl)ethoxy)methyl)-quinazolin-4(3H)-one

0687<chemistry id="chem1267" num="1267"><img file="EP4445902A2_D1270.tif" /></chemistry>

0688To a solution of 2,7-dichloro-3-((2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3<i>H</i>)-one (5 g, 14.53 mmol) in EtOH (50 mL) was added hydrazine (145 mL, 145.35 mmol, 1.0 M in THF) at 0 °C and the mixture was stirred for 2 h at RT. The reaction mixture was diluted with water and extracted with 10% methanol/dichloromethane. The organic layer was washed with brine, dried over Na₂SO₄, filtered and evaporated under reduced pressure. The residue was washed with diethyl ether to give the desired product. LCMS(m/z) 341.37 [M+H]+.

(Step 6) synthesis of 8-Chloro-4-((2-(trimethylsilyl)ethoxy)methyl)-[1,2,4]triazolo[4,3-a] quinazolin-5(4H)-one

0689<chemistry id="chem1268" num="1268"><img file="EP4445902A2_D1271.tif" /></chemistry>

0690A mixture of 7-chloro-2-hydrazinyl-3-((2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3H)-one (4.9 g, 14.41 mmol) and triethyl orthoformate (14.39 mL, 86.47 mmol) was stirred at 100 °C for 16 h. The reaction mixture was diluted with diethyl ether and evaporated under reduced pressure. The residue was dissolved in diethyl ether and evaporated to give the desired product. LCMS(m/z) 351.42 [M+H]+.

(Step 7) synthesis of 8-Chloro-4-(hydroxymethyl)-[1,2,4]triazolo[4,3-a]quinazolin-5(4H)-one

0691<chemistry id="chem1269" num="1269"><img file="EP4445902A2_D1272.tif" /></chemistry>

0692To a solution of 8-chloro-4-((2-(trimethylsilyl)ethoxy)methyl)-[1,2,4]triazolo[4,3-a]quinazolin-5(4H)-one 7 (2.18 g, 6.23 mmol) in dichloromethane (20 mL) was added trifluoroacetic acid (5.72 mL, 74.74 mmol) at 0 °C and the mixture was stirred for 16 h at RT. The reaction mixture was evaporated under reduced pressure, and the residue was dissolved in dichloromethane and evaporated. The resulting solids were washed with diethyl ether to give the desired product.

(Step 8) synthesis of 8-Chloro-[1,2,4]triazolo[4,3-a]quinazolin-5(4H)-one

0693<chemistry id="chem1270" num="1270"><img file="EP4445902A2_D1273.tif" /></chemistry>

0694To a solution of 8-chloro-4-(hydroxymethyl)-[1,2,4]triazolo[4,3-a]quinazolin-5(4H)-one (1.8 g, 7.2 mmol) in MeOH (20 mL) was added triethylamine (2.02 mL, 14.4 mmol) at 0 °C and the mixture was stirred for 16 h at RT. The reaction mixture was evaporated under reduced pressure, and the residue was dissolved in diethyl ether and evaporated. The resulting solids were washed with diethyl ether to give the desired product. LCMS(m/z) 221.21 [M+H]+.

(Step 9) synthesis of 5,8-Dichloro-[1,2,4]triazolo[4,3-a]quinazoline

0695A solution of 8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5(4H)-one (1.2 g, 5.45 mmol) in phosphorus oxychloride (15 mL) was stirred at 100 °C for 6 h. The reaction mixture was evaporated under reduced pressure. The residue was dissolved in toluene and evaporated to give the desired product. LCMS(m/z) 239.17 [M+H]+.

B. Examples

<u>Example 1. N-methyl-N-phenyl-[1,2,41triazolo[4,3-a]quinazolin-5-amine</u>

0696<chemistry id="chem1271" num="1271"><img file="EP4445902A2_D1274.tif" /></chemistry>

(Step 1) Synthesis of 2-chloro-N-methyl-N-phenylquinazolin-4-amine

0697N-methyl aniline (59.2 mg, 0.553 mmol) and sodium hydroxide(20 mg, 0.500 mmol) were added to a DMF solution(5 ml) of 2,4-dichloroquinazoline(100 mg, 0.502 mmol), and stirred at room temperature for 2 hours. Ethyl acetate and water were added to the reaction solution and an organic layer was separated. The organic layer was washed with a saturated aqueous ammonium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified with a silica gel column chromatography (hexane: ethyl acetate=1:0 to 4:1) to give 2-chloro-N-methyl-N-phenylquinazolin-4-amine: ¹ H-NMR (400 MHz, DMSO-d₆) δ 7.70 - 7.65 (m, 2H), 7.53 - 7.46 (m, 2H), 7.44 - 7.36 (m, 3H), 7.11 (ddd, J = 8.4, 4.8, 3.5 Hz, 1H), 6.83 (dt, J = 8.6, 1.0 Hz, 1H), 3.56); LCMS(m/z) 270.13 [M+H^]+.

(Step 2) Synthesis of 2-hydrazyl-N-methyl-7-phenylquinazolin-4-amine

0698An ethanol solution (3 ml) of 2-chloro-N-methyl-N-phenylquinazolin-4-amine(135 mmol, 0.500 mmol) and hydrazine monohydrate(75 mg, 1.50 mmol) was stirred at 50°C for an hour. The reaction mixture was cooled to room temperature, ethyl acetate and water were added, and the organic layer was separated. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 2-hydrazyl-N-methyl-7-phenylquinazolin-4-amine: ¹H NMR (400 MHz, Methanol-d₄) δ 8.36 (d, J = 8.3 Hz, 1H), 7.88 - 7.76 (m, 3H), 7.67 (d, J = 8.4 Hz, 1H), 7.59 (t, J = 7.7 Hz, 1H), 7.41 (t, J = 7.8 Hz, 2H), 7.21 (t, J = 7.4 Hz, 1H), 3.55 (s, 3H); LCMS(m/z) 266.13 [M+H]⁺.

(Step 3) Synthesis of N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

0699A mixture of 2-hydrazyl-N-methyl-7-phenylquinazolin-4-amine(78 mg, 0.294 mmol) and triethyl orthoformate(1 ml) was stirred at 50°C for an hour. The reaction mixture was cooled to room temperature and purified with a silica gel column chromatography (chloroform:methanol=1:0 to 10:1) to give the titled compound: ¹ H-NMR 400 MHz, DMSO-d₆) δ 9.62 (s, 1H), 8.29 (d, J = 8.3 Hz, 1H), 7.77 (ddd, J = 8.4, 6.7, 1.7 Hz, 1H), 7.44 - 7.21 (m, 7H), 3.32 (s, 3H).; LCMS(m/z) 276.1 [M+H]⁺.

<u>Example 2. N-(3-chlorophenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

0700<chemistry id="chem1272" num="1272"><img file="EP4445902A2_D1275.tif" /></chemistry>

(Step 1) Synthesis of 2-hydrazyl-quinazolin-4(3H)-one

0701An ethanol solution (2 ml) of 2-chloroquinazolin-4(3H)-one(50 mg, 0.277 mmol) and hydrazine monohydrate(41.6 mg, 0.831 mmol) was heated to 50°C and stirred for 1.5 hours. The reaction mixture was cooled to room temperature, ethyl acetate and water were added and the organic layer was separated. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated and 2-hydrazyl-quinazolin-4(3H)-one was obtained: ¹ H-NMR (DMSO-d₆) 8(ppm): 8.08 - 6.85 (m, 4H); LCMS(m/z) 177.11 [M+H]⁺ .

(Step 2) Synthesis of [1,2,4]-triazolo-[4,3-a]quinazolin-5(4H)-one

0702A mixture of 2-hydrazyl-quinazolin-4(3H)-one(1.26 g, 7.15 mmol) and triethyl orthoformate(10 ml) was heated to 80°C and stirred for 2 hours. The reaction mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure. The residue was purified with a silica gel chromatography (chloroform:methanol=1:0 to 20:1) to give [1,2,4]-triazolo-[4,3-a]quinazolin-5(4H)-one: ¹ H-NMR (DMSO-d₆) δ(ppm): 12.80 (s, 1H), 9.40 (s, 1H), 8.20 - 8.12 (m, 2H), 7.96 - 7.85 (m, 1H), 7.57 (ddd, J = 8.1, 7.4, 1.0 Hz, 1H); LCMS(m/z) 187.16 [M+H]⁺.

(Step 3) Synthesis of N-(3-chlorophenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

0703LDA(0.147 ml, 0.293 mmol) was added at 0°C to a THF solution(2 ml) of [1,2,4]-triazolo-[4,3-a]quinazolin-5(4H)-one(30 mg, 0.147 mmol) and stirred for 30 minutes. A THF solution(31 ml) of 3-chloro-N-methylalinin(31.1 mg, 0.22 mmol) was added to this solution and stirred at room temperature for an hour. Ethyl acetate and water were added to the reaction solution and the organic layer was separated. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified with a preparative HPLC chromatography to give the titled compound: ¹ H-NMR (DMSO-d₆) 8(ppm): 9.66 (s, 1H), 8.36 - 8.28 (m, 1H), 7.82 (ddd, J = 8.5, 6.4, 2.2 Hz, 1H), 7.48 (t, J = 2.1 Hz, 1H), 7.42 - 7.21 (m, 5H), 3.55 (s, 3H); LCMS(m/z) 310.13 [M+H]⁺ .

<u>Example 3. N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

0704<chemistry id="chem1273" num="1273"><img file="EP4445902A2_D1276.tif" /></chemistry>

(Step 1) Synthesis of 2-chloro-N-phenylquinazolin-4-amine

0705<chemistry id="chem1274" num="1274"><img file="EP4445902A2_D1277.tif" /></chemistry>

0706To a solution of 2,4-dichloroquinazoline (100 mg, 0.502 mmol) in DMF (2.5 mL) were added aniline (46.8 mg, 0.502 mmol) and sodium hydroxide (20.1 mg, 0.502 mmol), and the mixture was stirred for 30 min at RT. The reaction mixture was diluted with water, and extracted with AcOEt. The organic layer was concentrated in vacuo. The crude product was used for next step without further purification. LCMS(m/z) 256.09 [M+H]⁺.

(Step 2) Synthesis of N-phenyl- [1,2,4]triazolo[4,3-a] quinazolin-5-amine

0707A mixture of the resulting 2-chloro-N-phenylquinazolin-4-amine (70 mg, 0.274 mmol) and formohydrazide (32.9 mg, 0.548 mmol) in toluene (1.37 mL) was refluxed for 2.5 days. The reaction mixture was diluted with MeOH/AcOEt, concentrated in vacuo. The residue was dissolved in MeOH and evaporated to remove the residual solvent. The residue was suspended with MeOH, and the resulting solids were collected and washed to give the desired product: ¹H-NMR (DMSO-d₆) δ 9.80 (s, 1H), 9.53 (s, 1H), 8.67 (dd, J = 8.3, 1.2 Hz, 1H), 8.33 (dd, J = 8.3, 1.1 Hz, 1H), 7.99 (ddd, J = 8.4, 7.2, 1.2 Hz, 1H), 7.94 - 7.83 (m, 2H), 7.71 (ddd, J = 8.3, 7.2, 1.1 Hz, 1H), 7.49 - 7.38 (m, 2H), 7.23 - 7.14 (m, 1H); LCMS(m/z) 262.2 [M+H]⁺.

<u>Example 4. 5-(3,4-dihvdroquinolin-1(2H)-yl)-[1,2,4]triazolo[4,3-a]quinazoline</u>

0708<chemistry id="chem1275" num="1275"><img file="EP4445902A2_D1278.tif" /></chemistry>

(Step 1) Synthesis of 2-chloro-4-(3,4-dihydroquinolin-1(2H)-yl)quinazoline

0709<chemistry id="chem1276" num="1276"><img file="EP4445902A2_D1279.tif" /></chemistry>

0710To a solution of 2,4-dichloroquinazoline (150 mg, 0.615 mmol) in DMF (2.5 mL) were added 1,2,3,4-tetrahydroquinoline (66.9 mg, 0.502 mmol) and sodium hydride (22.1 mg, 0.553 mmol), and the mixture was stirred for 2 h at RT. The reaction mixture was diluted with AcOEt, and washed successively with water and brine, and dried over Na₂SO₄. The organic layer was concentrated in vacuo. The resultant residue was used for the next step without further purification. LCMS(m/z) 296.08 [M+H]⁺.

(Step 2) Synthesis of 5-(3,4-dihydroquinolin-1(2H)-yl)-[1,2,4]triazolo[4,3-a]quinazoline

0711A mixture of the resulting 2-chloro-4-(3,4-dihydroquinolin-1(2H)-yl)quinazoline (50 mg, 0.172 mmol) and formohydrazide (20.3 mg, 0.338 mmol) in toluene (0.84 mL) was refluxed for 2.5 days. The reaction mixture was diluted with MeOH/AcOEt and concentrated in vacuo. The residue was purified by prep. HPLC to afford the desired product: ¹ H-NMR (DMSO-d₆) δ 9.70 (s, 1H), 8.40 - 8.29 (m, 1H), 7.87 (ddd, J = 8.5, 7.3, 1.4 Hz, 1H), 7.57 (dd, J = 8.3, 1.3 Hz, 1H), 7.37 (ddd, J = 8.3, 7.2, 1.2 Hz, 1H), 7.27 (dd, J = 7.4, 1.6 Hz, 1H), 7.04 - 6.88 (m, 2H), 6.72 (dd, J = 8.0, 1.2 Hz, 1H), 3.92 (t, J = 6.5 Hz, 2H), 2.89 (t, J = 6.6 Hz, 2H), 2.12 - 1.96 (m, 2H). LCMS(m/z) 302.2 [M+H]⁺ .

<u>Example 5. N-(4-methoxyphenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

0712<chemistry id="chem1277" num="1277"><img file="EP4445902A2_D1280.tif" /></chemistry>

(Step 1) Synthesis of 2-chloro-N-(4-methoxyphenyl)-N-methylquinazolin-4-amine

0713<chemistry id="chem1278" num="1278"><img file="EP4445902A2_D1281.tif" /></chemistry>

0714To a solution of 2,4-dichloroquinazoline (100 mg, 0.502 mmol) in DMF (2.5 mL) were added 4-methoxy-N-methylaniline (68.9 mg, 0.502 mmol) and sodium hydroxide (20.1 mg, 0.502 mmol), and the mixture was stirred for 0.5 h at RT. The reaction mixture was diluted with AcOEt, washed successively with water and brine, and dried over Na₂SO₄. The organic layer was concentrated in vacuo. The resultant residue was used for the next step without further purification. LCMS(m/z) 300.08 [M+H]⁺.

(Step 2) Synthesis of N-(4-methoxyphenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

0715A mixture of the resulting 2-chloro-N-(4-methoxyphenyl)-N-methylquinazolin-4-amine (71 mg, 0.237 mmol) and formohydrazide (21.3 mg, 0.355 mmol) in toluene (1.18 mL) was stirred reflux for 2 days. The reaction mixture was diluted with MeOH/AcOEt, concentrated in vacuo. The residue was purified by prep. HPLC to afford the desired product: ¹ H-NMR (Methanol-d₄) δ 9.38 (d, J = 2.5 Hz, 1H), 8.10 (t, J = 6.6 Hz, 1H), 7.71 (t, J = 7.6 Hz, 1H), 7.21 - 7.16 (m, 4H), 6.97 (s, 1H), 6.85 - 6.72 (m, 1H), 3.82 (s, 3H), 3.60 (d, J = 2.6 Hz, 3H); LCMS(m/z) 306.2 [M+H]⁺ .

<u>Example 6. N-(2-fluorophenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

0716<chemistry id="chem1279" num="1279"><img file="EP4445902A2_D1282.tif" /></chemistry>

(Step 1) Synthesis of 2-chloro-N-(2-fluorophenyl)-N-methylquinazolin-4-amine

0717<chemistry id="chem1280" num="1280"><img file="EP4445902A2_D1283.tif" /></chemistry>

0718To a suspension of 2,4-dichloroquinazoline (100 mg, 0.502 mmol) in DMF (2.5 mL) were added 2-fluoro-N-methylaniline (62.9 mg, 0.502 mmol) and sodium hydroxide (20.1 mg, 0.502 mmol), and the mixture was stirred for 30 min at RT. The reaction mixture was diluted with AcOEt, washed successively with water and brine, and dried over Na₂SO₄. The organic layer was concentrated in vacuo. The residue was purified by column chromatography (Si-column, hexane : AcOEt = 10 : 0 - 6 : 4) to give the desired product. LCMS(m/z) 288.13 [M+H]+.

(Step 2) Synthesis of N-(2-fluorophenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

0719A mixture of 2-chloro-N-(2-fluorophenyl)-N-methylquinazolin-4-amine (47 mg, 0.163 mmol) and formohydrazide (19.62 mg, 0.327 mmol) in toluene (0.82 mL) was refluxed for 2 days. The reaction mixture was diluted with MeOH/AcOEt, concentrated in vacuo. The residue was dissolved in MeOH and evaporated. The residue was purified by prep-HPLC to afford the desired product: ¹ H-NMR (Methanol-d₄) δ 9.46 (s, 1H), 8.21 (d, J = 8.3 Hz, 1H), 7.80 (t, J = 7.8 Hz, 1H), 7.45 - 7.24 (m, 6H), 3.63 (s, 3H). LCMS(m/z) 294.2 [M+H]+.

<u>Example 7. N,N-dimethyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

0720<chemistry id="chem1281" num="1281"><img file="EP4445902A2_D1284.tif" /></chemistry>

(Step 1) Synthesis of 2-chloro-N,N-dimethylquinazolin-4-amine

0721<chemistry id="chem1282" num="1282"><img file="EP4445902A2_D1285.tif" /></chemistry>

0722To a suspension of 2,4-dichloroquinazoline (80 mg, 0.402 mmol) in DMF (2.01 ml) were added dimethylamine (18.12 mg, 0.402 mmol) and sodium hydroxide (16.08 mg, 0.402 mmol), and the mixture was stirred for 30 min at RT. The reaction mixture was diluted with AcOEt, and washed successively with water and brine. The organic layer was concentrated in vacuo to give the desired product, which was used for next step without further purification. LCMS(m/z) 208.10 [M+H]⁺.

(Step 2) Synthesis of N,N-dimethyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

0723A mixture of 2-chloro-N,N-dimethylquinazolin-4-amine (83 mg, 0.4 mmol) and formohydrazide (48 mg, 0.8 mmol) in toluene (2 mL) was refluxed for 2 days. The reaction mixture was dissolved in MeOH/AcOEt, and concentrated in vacuo. The residue was dissolved in MeOH, and evaporated. The residue was purified by prep-HPLC to afford the desired product: ¹ H-NMR (Methanol-d₄) δ 9.34 (s, 1H), 8.31 (dd, J = 8.4, 1.2 Hz, 1H), 8.19 (dd, J = 8.4, 1.1 Hz, 1H), 7.92 (ddd, J = 8.4, 7.3, 1.3 Hz, 1H), 7.65 (ddd, J = 8.4, 7.2, 1.2 Hz, 1H), 3.40 (s, 6H). LCMS(m/z) 214.1 [M+H]+.

<u>Example 8. 7-methoxy-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

0724<chemistry id="chem1283" num="1283"><img file="EP4445902A2_D1286.tif" /></chemistry>

(Step 1) Synthesis of 2-chloro-6-methoxy-N-methyl-N-phenylquinazolin-4-amine

0725<chemistry id="chem1284" num="1284"><img file="EP4445902A2_D1287.tif" /></chemistry>

0726To a suspension of 2,4-dichloro-6-methoxyquinazoline (100 mg, 0.437 mmol) in 2-Propanol (2.1 mL) were added N-methylaniline (46.8 mg, 0.437 mmol) and NaOH (15.62 mg, 0.428 mmol), and the mixture was stirred for 3 days at RT. The reaction mixture was filtered and washed with 2-propanol to give the desired product. The product was used for next step without further purification: LCMS(m/z) 309.09 [M+H]+.

(Step 2) Synthesis of 7-methoxy-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

0727A mixture of 2-chloro-6-methoxy-N-methyl-N-phenylquinazolin-4-amine (70 mg, 0.234 mmol) and formohydrazide (28.0 mg, 0.467 mmol) in Toluene (0.5 mL) was refluxed for 2 days. The reaction mixture was diluted with MeOH/AcOEt, concentrated in vacuo. The residue was dissolved in MeOH and evaporated, and the residue was purified by prep. HPLC to afford the desired product: ¹ H-NMR (Methanol-d4) δ 9.36 (s, 1H), 8.06 (d, J = 9.1 Hz, 1H), 7.53 - 7.40 (m, 2H), 7.38 - 7.27 (m, 4H), 6.74 (d, J = 2.7 Hz, 1H), 3.66 (s, 3H), 3.33 (s, 3H). LCMS(m/z) 306.2 [M+H]+.

<u>Example 9. N-(3-methoxyphenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

0728<chemistry id="chem1285" num="1285"><img file="EP4445902A2_D1288.tif" /></chemistry>

0729To a mixture of [1,2,4]triazolo[4,3-a]quinazolin-5(4H)-one (50 mg, 0.269 mmol) and DBU (0.061 mL, 0.403 mmol) in NMP (1 mL) was added BOP (143 mg, 0.322 mmol) at RT. The mixture was stirred for 10 min at RT. Then, 3-methoxy-N-methylaniline (47.9 mg, 0.349 mmol) was added to the mixture at RT, and the stirring was continued for 3h at RT and then overnight at 55 °C. The reaction mixture was purified by prep-LCMS (acidic condition) to afford crude product, which was purified by column chromatography (Si-column, hexane : AcOEt = 100 : 0 - 0 : 100, then MeOH) to afford the desired product: ¹ H-NMR (DMSO-d₆) δ 9.62 (s, 1H), 8.32 - 8.25 (m, 1H), 7.78 (ddd, J = 8.4, 7.2, 1.4 Hz, 1H), 7.37 - 7.20 (m, 3H), 6.93 (t, J = 2.3 Hz, 1H), 6.82 (m, 2H), 3.71 (s, 3H), 3.54 (s, 3H). LCMS(m/z) 306.1 [M+H]+.

<u>Example 10. 9-fluoro-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

0730<chemistry id="chem1286" num="1286"><img file="EP4445902A2_D1289.tif" /></chemistry>

(Step 1) Synthesis of 2-chloro-8-fluoro-N-methyl-N-phenylquinazolin-4-amine

0731<chemistry id="chem1287" num="1287"><img file="EP4445902A2_D1290.tif" /></chemistry>

0732To a suspension of 2,4-dichloro-8-fluoroquinazoline (120 mg, 0.553 mmol) in 2-propanol (2.7 mL) were added N-methylaniline (59.3 mg, 0.553 mmol) and sodium hydroxide (23 mg, 0.55 mmol), and the mixture was stirred for 30 min at RT. The reaction mixture was filtered and washed with 2-propanol to give the desired product, which was used for next step without further purification. LCMS(m/z) 288.08 [M+H]⁺.

(Step 2) Synthesis of 8-fluoro-2-hydrazinyl-N-methyl-N-phenylquinazolin-4-amine

0733<chemistry id="chem1288" num="1288"><img file="EP4445902A2_D1291.tif" /></chemistry>

0734A mixture of 2-chloro-8-fluoro-N-methyl-N-phenylquinazolin-4-amine (63 mg, 0.219 mmol) and hydrazine hydrate (54.8 mg, 1.095 mmol) in EtOH (1.1 mL) was stirred for 4 h at 55 °C. The reaction mixture was concentrated in vacuo. The resultant residue was used for the next step without further purification. LCMS(m/z) 284.18 [M+H]⁺.

(Step 3) Synthesis of 9-fluoro-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

0735A mixture of 8-fluoro-2-hydrazinyl-N-methyl-N-phenylquinazolin-4-amine (61 mg, crude) and triethoxymethane (17.26 mg, 0.116 mmol) was stirred at 70 °C for 3 h. A small amount of AcOH was added the reaction mixture, the reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (Si-column, CHCl₃: MeOH = 10 : 0 - 95 : 5) to afford the desired product: ¹ H-NMR (Methanol-d₄) δ 9.25 (t, J = 3.6 Hz, 1H), 7.67 - 7.56 (m, 1H), 7.42 (t, J = 7.7 Hz, 2H), 7.34 - 7.28 (m, 3H), 7.16 (dd, J = 7.9, 4.5 Hz, 2H), 3.66 (d, J = 1.9 Hz, 3H). LCMS(m/z) 294.1 [M+H]+.

<u>Example 11. 8-chloro-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

0736<chemistry id="chem1289" num="1289"><img file="EP4445902A2_D1292.tif" /></chemistry>

(Step 1) Synthesis of 2,7-dichloro-N-methyl-N-phenylquinazolin-4-amine

0737<chemistry id="chem1290" num="1290"><img file="EP4445902A2_D1293.tif" /></chemistry>

0738To a suspension of 2,4,7-trichloroquinazoline (513 mg, 2.197 mmol) in DMF (1.1 mL) were added N-methylaniline (235 mg, 2.197 mmol) and sodium hydroxide (111 mg, 2.78 mmol), and the mixture was stirred for 1 h at RT. The reaction mixture was diluted with AcOEt, washed successively with water and brine, and dried over Na₂SO₄. The organic layer was concentrated in vacuo to give the desired product. LCMS(m/z) 305.1 [M+H]⁺.

(Step 2) Synthesis of 7-chloro-2-hydrazinyl-N-methyl-N-phenylquinazolin-4-amine

0739<chemistry id="chem1291" num="1291"><img file="EP4445902A2_D1294.tif" /></chemistry>

0740To a solution of 2,7-dichloro-N-methyl-N-phenylquinazolin-4-amine (572 mg, 2.2 mmol) in EtOH (11 mL) was added hydrazine hydrate (0.11 g, 2.2 mmol), and the mixture was stirred for 2 h at 50 °C. The reaction mixture was diluted with AcOEt, washed successively with water and brine, and dried over Na₂SO₄. The organic layer was concentrated in vacuo to give the desired product. LCMS(m/z) 300.13 [M+H]⁺.

(Step 3) Synthesis of 8-chloro-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

0741A mixture of 7-chloro-2-hydrazinyl-N-methyl-N-phenylquinazolin-4-amine (659 mg, 2.2 mmol) and triethoxymethane (324 mg, 2.2 mmol) was stirred for 1 h at 100 °C. The reaction mixture was concentrated in vacuo, and the residue was purified by column chromatography (Si-column, CHCl₃: MeOH = 10 : 0 - 9 : 1) to afford the desired product: ¹ H-NMR (Methanol-d₄) δ 9.45 - 9.40 (m, 1H), 8.33 (d, J = 2.0 Hz, 1H), 7.49 - 7.39 (m, 2H), 7.34 - 7.13 (m, 5H), 3.65 (s, 3H). LCMS(m/z) 310.0 [M+H]+.

<u>Example 12. 9-methoxy-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

0742<chemistry id="chem1292" num="1292"><img file="EP4445902A2_D1295.tif" /></chemistry>

(Step 1) Synthesis of 2-chloro-8-methoxy-N-methyl-N-phenylquinazolin-4-amine

0743<chemistry id="chem1293" num="1293"><img file="EP4445902A2_D1296.tif" /></chemistry>

0744To a suspension of 2,4-dichloro-8-methoxyquinazoline (100 mg, 0.437 mmol) in DMF (2.2 mL) were added N-methylaniline (46.8 mg, 0.437 mmol) and sodium hydroxide (17.46 mg, 0.437 mmol), and the mixture was stirred for 1 h at RT. The reaction mixture was diluted with AcOEt, washed successively with water and brine, and dried over Na₂SO₄. The organic layer was concentrated in vacuo to give the desired product, which was used for next step without further purification. LCMS(m/z) 300.18 [M+H]⁺.

(Step 2) Synthesis of 2-hydrazinyl-8-methoxy-N-methyl-N-phenylquinazolin-4-amine

0745<chemistry id="chem1294" num="1294"><img file="EP4445902A2_D1297.tif" /></chemistry>

0746To a solution of 2-chloro-8-methoxy-N-methyl-N-phenylquinazolin-4-amine (131 mg, crude) in EtOH (2.2 mL) was added hydrazine hydrate (43.8 mg, 0.874 mmol), and the mixture was stirred for 2 h at 50 °C. The reaction mixture was diluted with AcOEt, washed successively with water and brine, and dried over Na₂SO₄. The organic layer was concentrated in vacuo to give the desired product, which was used for next step without further purification. LCMS(m/z) 296.18 [M+H]⁺.

(Step 3) Synthesis of 9-methoxy-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

0747A mixture of 2-hydrazinyl-8-methoxy-N-methyl-N-phenylquinazolin-4-amine (119 mg, crude) and triethoxymethane (259 mg, 1.748 mmol) and a drop of acetic acid (12.04 mg, 0.201 mmol) was stirred at 90 °C for 1 h. The reaction mixture was concentrated in vacuo, and the residue was purified by column chromatography (Si-column, CHCl₃: MeOH = 10 : 0 - 9 : 1 gradient) to afford the desired product: ¹ H-NMR (Methanol-d₄) δ 9.51 (s, 1H), 7.44 - 7.16 (m, 6H), 7.08 (t, J = 8.3 Hz, 1H), 6.87 (d, J = 8.4 Hz, 1H), 4.12 (s, 3H), 3.62 (s, 3H). LCMS(m/z) 306.1 [M+H]+.

<u>Example 13. N-(4-fluorophenyl)-N-methyl-[1,2,4]triazolo[4,3-alquinazolin-5-amine</u>

0748<chemistry id="chem1295" num="1295"><img file="EP4445902A2_D1298.tif" /></chemistry>

(Step 1) Synthesis of 2-chloro-N-(4-fluorophenyl)-N-methylquinazolin-4-amine

0749<chemistry id="chem1296" num="1296"><img file="EP4445902A2_D1299.tif" /></chemistry>

0750To a suspension of 2,4-dichloroquinazoline (100 mg, 0.502 mmol) in DMF (0.25 mL) were added N-methyl-4-fluoroaniline (62.9 mg, 0.502 mmol) and sodium hydroxide (20.1 mg, 0.502 mmol), and the mixture was stirred for 1 h at RT. The reaction mixture was diluted with AcOEt, washed successively with water and brine, and dried over Na₂SO₄. The resultant residue was used for the next step without further purification. LCMS(m/z) 288.03 [M+H]⁺.

(Step 2) Synthesis of N-(4-fluorophenyl)-2-hydrazinyl-N-methylquinazolin-4-amine

0751<chemistry id="chem1297" num="1297"><img file="EP4445902A2_D1300.tif" /></chemistry>

0752To a solution of 2-chloro-N-(4-fluorophenyl)-N-methylquinazolin-4-amine (68 mg, crude) in EtOH (1.2 mL) was added hydrazine hydrate (23.66 mg, 0.473 mmol), and the mixture was stirred for 2 h at 50 °C. The reaction mixture was diluted with AcOEt, washed successively with water and brine, and dried over Na₂SO₄. The organic layer was concentrated in vacuo. The resultant residue was used for the next step without further purification. LCMS(m/z) 284.13 [M+H]⁺.

(Step 3) Synthesis of N-(4-fluorophenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

0753A mixture of N-(4-fluorophenyl)-2-hydrazinyl-N-methylquinazolin-4-amine (51 mg, crude) and triethoxymethane (175 mg, 1.182 mmol) and acetic acid (12.04 mg, 0.201 mmol) at 90 °C. The reaction mixture was concentrated in vacuo, and the residue was purified by column chromatography (Si-column, CHCl₃ : MeOH = 10 : 0 - 9 : 1) to afford the desired product: ¹ H-NMR (Methanol-d₄) δ 9.44 (s, 1H), 8.19 (d, J = 7.9 Hz, 1H), 7.81 - 7.72 (m, 1H), 7.38 - 7.31 (m, 3H), 7.27 - 7.20 (m, 1H), 7.19 - 7.15 (m, 2H), 3.63 (s, 3H). LCMS(m/z) 294.1 [M+H]+.

<u>Example 14. 6-chloro-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

0754<chemistry id="chem1298" num="1298"><img file="EP4445902A2_D1301.tif" /></chemistry>

(Step 1) Synthesis of 2,5-dichloro-N-methyl-N-phenylquinazolin-4-amine

0755<chemistry id="chem1299" num="1299"><img file="EP4445902A2_D1302.tif" /></chemistry>

0756To a suspension of 2,4,5-trichloroquinazoline (100 mg, 0.428 mmol) in 2-propanol (2.1 mL) were added N-methylaniline (45.9 mg, 0.428 mmol) and conc. HCl (37%, 15.62 mg, 0.428 mmol), and the mixture was stirred for 1 h at RT. The precipitates were collected and washed with 2-propanol to give the desired product. LCMS(m/z) 304.08 [M+H]+.

(Step 2) Synthesis of 5-chloro-2-hydrazinyl-N-methyl-N-phenylquinazolin-4-amine

0757<chemistry id="chem1300" num="1300"><img file="EP4445902A2_D1303.tif" /></chemistry>

0758To a solution of 2,5-dichloro-N-methyl-N-phenylquinazolin-4-amine (61 mg, 0.201 mmol) in EtOH (1 mL) was added hydrazine hydrate (20.08 mg, 0.401 mmol), and the mixture was stirred for 2 h at 50 °C. The reaction mixture was diluted with AcOEt, washed successively with water and brine, and dried over Na₂SO₄. The organic layer was concentrated in vacuo to give the desired product. LCMS(m/z) 300.08 [M+H]+.

(Step 3) Synthesis of 6-chloro-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

0759A mixture of 5-chloro-2-hydrazinyl-N-methyl-N-phenylquinazolin-4-amine (54 mg, crude) and triethoxymethane (29.7 mg, 0.201 mmol) and a drop of acetic acid (12.04 mg, 0.201 mmol) was heated to 90 °C for 2 h. The reaction mixture was concentrated in vacuo, and the residue was purified by column chromatography (Si-column, CHCl₃ : MeOH = 10 : 0 - 9 : 1) to afford the desired product: ¹ H-NMR (Methanol-d₄) δ 9.46 (s, 1H), 8.17 (dd, J = 8.4, 0.9 Hz, 1H), 7.76 (t, J = 8.1 Hz, 1H), 7.40 - 7.33 (m, 1H), 7.25 - 7.15 (m, 2H), 7.08 (t, J = 7.4 Hz, 1H), 7.02 - 6.93 (m, 2H), 3.68 (s, 3H). LCMS(m/z) 310.1 [M+H]+.

<u>Example 15. N-ethyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

0760<chemistry id="chem1301" num="1301"><img file="EP4445902A2_D1304.tif" /></chemistry>

(Step 1) Synthesis of 2-chloro-N-ethyl-N-phenylquinazolin-4-amine

0761<chemistry id="chem1302" num="1302"><img file="EP4445902A2_D1305.tif" /></chemistry>

0762To a solution of 2,4-dichloroquinazoline (200 mg, 1.005 mmol) in DMF (5 mL) were added N-methylaniline (121 mg, 1.005 mmol) and sodium hydroxide (40.2 mg, 1.005 mmol), and the mixture was stirred for 3 h at RT. The mixture was diluted with AcOEt, washed successively with water and brine, dried over Na₂SO₄. The resultant residue was used for the next step without further purification. LCMS(m/z) 284.13 [M+H]⁺.

(Step 2) Synthesis of 2-hydrazinyl-N-ethyl-N-phenylquinazolin-4-amine

0763<chemistry id="chem1303" num="1303"><img file="EP4445902A2_D1306.tif" /></chemistry>

0764To a solution of 2-chloro-N-ethyl-N-phenylquinazolin-4-amine (210 mg, crude) in EtOH (3.7 mL) was added hydrazine hydrate (37 mg, 0.74 mmol), and the mixture was stirred for 2 h at 50 °C. The reaction mixture was diluted with AcOEt, washed successively with water and brine, and dried over Na₂SO₄. The organic layer was concentrated in vacuo. The resultant residue was used for the next step without further purification. LCMS(m/z) 280.18 [M+H]⁺.

(Step 3) Synthesis of N-ethyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

0765A mixture of 2-hydrazinyl-N-ethyl-N-phenylquinazolin-4-amine (185 mg, crude) and triethoxymethane (110 mg, 0.740 mmol) and acetic acid (12.04 mg, 0.201 mmol) at 90 °C. The reaction mixture was concentrated in vacuo, and the residue was purified by column chromatography (Si-column, CHCl₃: MeOH = 10 : 0 - 9 : 1) to afford the desired product: ¹H-NMR (CDCl₃) δ 8.92 (s, 1H), 7.78 (dd, J = 8.3, 1.1 Hz, 1H), 7.62 (ddd, J = 8.4, 7.2, 1.3 Hz, 1H), 7.43 - 7.32 (m, 2H), 7.32 - 7.22 (m, 2H), 7.19 - 7.04 (m, 3H), 4.25 (q, J = 7.0 Hz, 2H), 1.35 (t, J = 7.0 Hz, 3H). LCMS(m/z) 290.2 [M+H]+.

<u>Example 16. N,9-dimethyl-N-phenyl-[1,2,4]triazoloΓ4,3-alquinazolin-5-amine</u>

0766<chemistry id="chem1304" num="1304"><img file="EP4445902A2_D1307.tif" /></chemistry>

(Step 1) Synthesis of 8-methylquinazoline-2,4(1H,3H)-dione

0767<chemistry id="chem1305" num="1305"><img file="EP4445902A2_D1308.tif" /></chemistry>

0768To a suspension of 2-amino-3-methylbenzoic acid (500 mg, 3.31 mmol) in water (5 mL) was added acetic acid (0.5 mL), and the suspension was heated to 35 °C. A freshly prepared solution of potassium cyanate (268 mg, 3.31 mmol) in water (0.5 mL) was added dropwise to the suspension over the period of 1 h. The mixture was stirred for 1 h at 40°C. NaOH (8 g) was added portion-wise to the reaction mixture by maintaining the internal temperature below 50°C, and the mixture was further stirred for 2 h. The precipitate was collected by filtration to give the desired product. LCMS(m/z) 177.11 [M+H]⁺.

(Step 2) Synthesis of 2,4-dichloro-8-methylquinazoline

0769<chemistry id="chem1306" num="1306"><img file="EP4445902A2_D1309.tif" /></chemistry>

0770A mixture of 8-methylquinazoline-2,4(1H,3H)-dione (120 mg, 0.68 mmol) and phosphoryl trichloride (1521 mg, 9.92 mmol) was stirred for 3 h at 100 °C. The reaction mixture was concentrated in vacuo, and the resultant residue was used for the next step without further purification. LCMS(m/z) 213.10 [M+H]⁺.

(Step 3) Synthesis of 2-chloro-N,8-dimethyl-N-phenylquinazolin-4-amine

0771<chemistry id="chem1307" num="1307"><img file="EP4445902A2_D1310.tif" /></chemistry>

0772To a suspension of 2,4-dichloro-8-methylquinazoline (100 mg, 0.469 mmol) in DMF (2.35 mL) were added N-methylaniline (50.3 mg, 0.469 mmol) and sodium hydroxide (18.77 mg, 0.469 mmol), and the mixture was stirred for 1 h at RT. The reaction mixture was diluted with AcOEt, washed successively with water and brine, and dried over Na₂SO₄. The organic layer was concentrated in vacuo to give the desired product, which was used for the next step without further purification. LCMS(m/z) 284.8 [M+H]⁺.

(Step 4) Synthesis of 2-hydrazinyl-N,8-dimethyl-N-phenylquinazolin-4-amine

0773<chemistry id="chem1308" num="1308"><img file="EP4445902A2_D1311.tif" /></chemistry>

0774To a solution of 2-chloro-N,8-dimethyl-N-phenylquinazolin-4-amine (69 mg, 0.243 mmol) in EtOH (1.2 mL) was added hydrazine hydrate (24.35 mg, 0.486 mmol), and the mixture was stirred for 2 h at 50 °C. The reaction mixture was diluted with AcOEt, washed successively with water and brine, and dried over Na₂SO₄. The organic layer was concentrated in vacuo to give the desired product. LCMS(m/z) 280.18 [M+H]⁺.

(Step 5) Synthesis of N,9-dimethyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

0775A mixture of 2-hydrazinyl-N,8-dimethyl-N-phenylquinazolin-4-amine (54 mg, 0.192 mmol) and triethoxymethane (108 mg, 0.729 mmol) was stirred at 90 °C overnight. The reaction mixture was concentrated in vacuo, and the residue was purified by column chromatography (Si-column, CHCl₃: MeOH = 10 : 0 - 9 : 1) to afford the desired product: ¹ H-NMR (Methanol-d₄) δ 9.41 (s, 1H), 7.53 (d, J = 7.3 Hz, 1H), 7.39 - 7.31 (m, 2H), 7.25 (q, J = 8.3, 7.4 Hz, 2H), 7.17 (dd, J = 7.6, 2.0 Hz, 2H), 7.02 (t, J = 7.9 Hz, 1H), 3.62 (d, J = 1.9 Hz, 3H), 2.82 (s, 3H); LCMS(m/z) 290.1 [M+H]+.

<u>Example 17. N-(3-fluorophenyl)-N-methyl-[1,2,4]triazolo[4,3-alquinazolin-5-amine</u>

0776<chemistry id="chem1309" num="1309"><img file="EP4445902A2_D1312.tif" /></chemistry>

0777To a solution of 5-chloro-[1,2,4]triazolo[4,3-a]quinazoline (70 mg, 0.376 mmol), BOP (183 mg, 0.414 mmol) and DBU (0.068 ml, 0.451 mmol) in NMP (2 mL) was added 3-fluoro-N-methylaniline (51.8 mg, 0.414 mmol) at RT. The mixture was stirred for 4.5 h at 55 °C. The reaction mixture was purified by prep-LCMS to afford the desired product: ¹ H-NMR (DMSO-d₆) δ 9.66 (s, 1H), 8.32 (d, J = 8.2 Hz, 1H), 7.81 (ddd, J = 8.5, 7.0, 1.7 Hz, 1H), 7.44 - 7.23 (m, 4H), 7.14 - 7.02 (m, 2H), 3.56 (s, 3H). LCMS(m/z) 294.1 [M+H]+.

<u>Example 18. 6-fluoro-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

0778<chemistry id="chem1310" num="1310"><img file="EP4445902A2_D1313.tif" /></chemistry>

(Step 1) Synthesis of 2-chloro-5-fluoro-N-methyl-N-phenylquinazolin-4-amine

0779<chemistry id="chem1311" num="1311"><img file="EP4445902A2_D1314.tif" /></chemistry>

0780To a suspension of 2,4-dichloro-5-fluoroquinazoline (100 mg, 0.461 mmol) in 2-propanol (2.3 mL) were added N-methylaniline (49.4 mg, 0.461 mmol) and a drop of conc. HCl (37%), and the mixture was stirred for 30 min at RT. The reaction mixture was filtered and washed with 2-propanol to give the desired product. LCMS(m/z) 288.08 [M+H]⁺.

(Step 2) Synthesis of 5-fluoro-2-hydrazinyl-N-methyl-N-phenylquinazolin-4-amine

0781<chemistry id="chem1312" num="1312"><img file="EP4445902A2_D1315.tif" /></chemistry>

0782To a solution of 2-chloro-5-fluoro-N-methyl-N-phenylquinazolin-4-amine (43 mg, 0.149 mmol) in ethanol (0.75 mL) was added hydrazine hydrate (11.22 mg, 0.224 mmol), and the mixture was stirred for 2 h at 50 °C. The reaction mixture was diluted with AcOEt, washed successively with water and brine, and dried over Na₂SO₄. The organic layer was concentrated in vacuo to give the desired product, which was used for the next step without further purification. LCMS(m/z) 284.13 [M+H]⁺.

(Step 3) Synthesis of 6-fluoro-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

0783A mixture of 5-fluoro-2-hydrazinyl-N-methyl-N-phenylquinazolin-4-amine (39 mg, crude) and triethoxymethane (111 mg, 0.747 mmol) and acetic acid (12.04 mg, 0.201 mmol) for 2 h at 90 °C. The reaction mixture was concentrated in vacuo, and the residue was purified by column chromatography (Si-column, CHCl₃: MeOH = 10 : 0 - 9 : 1) to afford the desired product: ¹ H-NMR (Methanol-d₄) δ 9.44 (s, 1H), 8.02 (d, J = 8.3 Hz, 1H), 7.83 (td, J = 8.3, 5.1 Hz, 1H), 7.32 - 7.23 (m, 2H), 7.21 - 7.06 (m, 3H), 6.99 (dd, J = 11.6, 8.3 Hz, 1H), 3.64 (s, 3H); LCMS(m/z) 295.1 [M+H]+.

<u>Example 19. N-methyl-N,8-diphenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

0784<chemistry id="chem1313" num="1313"><img file="EP4445902A2_D1316.tif" /></chemistry>

0785A mixture of 8-bromo-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 28) (50 mg, 0.161 mmol), phenylboronic acid (49.2 mg, 0.404 mmol), cesium fluoride (73.6 mg, 0.484 mmol) and Bis[di-tert-butyl(4-dimethylaminophenyl)phosphine]palladium(0) (11 mg, 0.016 mmol) in dioxane (0.8 mL) was treated in a microwave reactor for 2 h at 100°C, then at 120°C for 2 h. The reaction mixture was concentrated in vacuo, and purified by column chromatography (Si-column, CHCl₃: MeOH = 10:0-9: 1 to afford the desired product: ¹ H-NMR (Methanol-d₄) δ 9.46 (s, 1H), 8.22 (d, J = 1.8 Hz, 1H), 7.67 - 7.57 (m, 2H), 7.43 - 7.36 (m, 5H), 7.33 - 7.26 (m, 2H), 7.21 (dd, J = 7.5, 1.5 Hz, 2H), 7.12 (d, J = 8.8 Hz, 1H), 3.58 (s, 3H). LCMS(m/z) 352.1 [M+H]+.

<u>Example 20. 8-methoxy-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

0786<chemistry id="chem1314" num="1314"><img file="EP4445902A2_D1317.tif" /></chemistry>

(Step 1) Synthesis of 2-chloro-7-methoxy-N-methyl-N-phenylquinazolin-4-amine

0787<chemistry id="chem1315" num="1315"><img file="EP4445902A2_D1318.tif" /></chemistry>

0788To a solution of 2,4-dichloro-7-methoxyquinazoline (100 mg, 0.44 mmol) in DMF (7 mL) were added N-methylaniline (46.7 mg, 0.44 mmol) and sodium hydroxide (18.4 mmol, 0.46 mmol). The mixture was stirred for 1 h at RT and for 2 h at 60 °C. The mixture was diluted with AcOEt, washed successively with water and brine, and dried over Na₂SO₄. The organic layer was concentrated in vacuo to give the desired product. LCMS(m/z) 300.08 [M+H]⁺.

(Step 2) Synthesis of 2-hydrazinyl-7-methoxy-N-methyl-N-phenylquinazolin-4-amine

0789<chemistry id="chem1316" num="1316"><img file="EP4445902A2_D1319.tif" /></chemistry>

0790To a solution of 2-chloro-7-methoxy-N-methyl-N-phenylquinazolin-4-amine (92 mg, 0.340 mmol) in EtOH (1.7 mL) was added hydrazine hydrate (17.01 mg, 0.340 mmol), and the mixture was stirred for 2 h at 50 °C. The reaction mixture was diluted with AcOEt, washed successively with water and brine, and dried over Na₂SO₄. The organic layer was concentrated in vacuo to give the desired product. LCMS(m/z) 296.18 [M+H]⁺.

(Step 3) Synthesis of 8-methoxy-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-

amine

0791A mixture of 2-hydrazinyl-7-methoxy-N-methyl-N-phenylquinazolin-4-amine (67 mg, crude) and triethoxymethane (201 mg, 1.359 mmol) and acetic acid (12.04 mg, 0.201 mmol) for 2 h at 90 °C. The reaction mixture was concentrated in vacuo, and the residue was purified by column chromatography (Si-column, CHCl₃: MeOH = 10 : 0 - 9 : 1) to afford the desired product: ¹ H-NMR (DMSO-d₆) δ 9.62 (s, 1H), 7.80 (d, J = 2.5 Hz, 1H), 7.43 - 7.33 (m, 2H), 7.31 - 7.20 (m, 3H), 7.15 (d, J = 9.3 Hz, 1H), 6.81 (dd, J = 9.3, 2.5 Hz, 1H), 3.91 (s, 3H), 3.51 (s, 3H). LCMS(m/z) 306.1 [M+H]+.

<u>Example 21. 7-fluoro-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

0792<chemistry id="chem1317" num="1317"><img file="EP4445902A2_D1320.tif" /></chemistry>

(Step 1) Synthesis of 2-chloro-6-fluoro-N-methyl-N-phenylquinazolin-4-amine

0793<chemistry id="chem1318" num="1318"><img file="EP4445902A2_D1321.tif" /></chemistry>

0794To a solution of N-methylaniline (148 mg, 1.382 mmol) and NaH (60.8 mg, 1.521 mmol) in DMF (10 mL) was added 2,4-dichloro-6-fluoroquinazoline (300 mg, 1.382 mmol) at RT, and the mixture was stirred for 3.5 h at RT. The reaction mixture was diluted with EtOAc, washed successively with water and brine, dried over Na₂SO₄, and concentrated in vacuo to give the desired product, which was used for the next step without purification. LCMS(m/z) 288.08 [M+H]⁺.

(Step 2) Synthesis of 6-fluoro-2-hydrazinyl-N-methyl-N-phenylquinazolin-4-amine

0795<chemistry id="chem1319" num="1319"><img file="EP4445902A2_D1322.tif" /></chemistry>

0796To a solution of 2-chloro-6-fluoro-N-methyl-N-phenylquinazolin-4-amine (398 mg, crude) in EtOH (5 mL) was added hydrazine hydrate (1 mL, 20.61 mmol) at RT, and the mixture was stirred overnight at 50 °C. The reaction mixture was cooled to RT, and filtered to give the desired product, which was used for the next step without purification. LCMS(m/z) 284.13 [M+H]⁺.

(Step 3) Synthesis of 7-fluoro-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

0797A mixture of 6-fluoro-2-hydrazinyl-N-methyl-N-phenylquinazolin-4-amine (42 mg, crude) and triethoxymethane (3 mL) was stirred for 2 h at 100 °C. The reaction mixture was cooled to RT and filtered to afford the crude product. The crude compound was purified by prep-LCMS to afford the desired product: ¹ H-NMR (DMSO-d₆) δ 9.63 (s, 1H), 8.38 (dd, J = 9.2, 4.9 Hz, 1H), 7.75 (ddd, J = 9.2, 8.0, 2.8 Hz, 1H), 7.48 - 7.38 (m, 2H), 7.38 - 7.27 (m, 3H), 6.81 (dd, J = 10.5, 2.8 Hz, 1H), 3.54 (s, 3H). LCMS(m/z) 294.2 [M+H]+.

<u>Example 22. N-methyl-N-(pyridin-2-yl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

0798<chemistry id="chem1320" num="1320"><img file="EP4445902A2_D1323.tif" /></chemistry>

(Step 1) Synthesis of 2-chloro-<i>N</i>-methyl-<i>N</i>-(pyridin-2-yl)quinazolin-4-amine

0799<chemistry id="chem1321" num="1321"><img file="EP4445902A2_D1324.tif" /></chemistry>

0800To a stirred solution of 2,4-dichloroquinazoline (0.5 g, 2.51 mmol) in DMF (10 mL) was added 60% sodium hydride (0.150 g, 3.77 mmol) at 0 °C and the mixture was stirred for 1 h at RT, followed by the addition of <i>N</i>-methylpyridin-2-amine (0.407 g, 3.77 mmol) at 0 °C, and the mixture was stirred for 1 h at RT. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with ice-water and extracted with ethyl acetate twice. The combined organic layers were washed with brine, dried over Na₂SO₄, filtered and evaporated under reduced pressure. The residue was purified by column chromatography (Si-column, AcOEt: petroleum ether=3:7 - 1:1) to give the desired product.

(Step 2) Synthesis of <i>N</i>-methyl-<i>N</i>-(pyridin-2-yl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

0801To a stirred solution of 2-chloro-N-methyl-N-(pyridin-2-yl)quinazolin-4-amine (0.1 g, 0.37 mmol) in toluene (2 mL) was added formohydrazide (0.044 g, 0.74 mmol) at RT, and the mixture was heated to 110 °C for 48 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was evaporated under reduced pressure. The residue was purified by prep. HPLC to afford the desired product: ¹ H-NMR (DMSO-d₆) δ 9.73 (s, 1H), 8.35 (d, J = 8.3 Hz, 1H), 8.22 (ddd, J = 5.0, 1.9, 0.9 Hz, 1H), 7.86 (ddd, J = 8.4, 6.9, 1.7 Hz, 1H), 7.78 (ddd, J = 8.2, 7.2, 2.0 Hz, 1H), 7.41 - 7.23 (m, 3H), 7.12 (ddd, J = 7.4, 4.9, 0.9 Hz, 1H), 3.64 (s, 3H); LCMS(m/z) 277.2 [M+H]+.

<u>Example 23. N-methyl-N-(pyridin-3-yl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

0802<chemistry id="chem1322" num="1322"><img file="EP4445902A2_D1325.tif" /></chemistry>

(Step 1) Synthesis of 2-chloro-<i>N</i>-methyl-<i>N</i>-(pyridin-3-yl)quinazolin-4-amine

0803<chemistry id="chem1323" num="1323"><img file="EP4445902A2_D1326.tif" /></chemistry>

0804To a stirred solution of 2,4-dichloroquinazoline (0.5 g, 2.51 mmol) in DMF (10 mL) was added 60% sodium hydride (0.150 g, 3.77 mmol) at 0 °C and the mixture was stirred at room temperature for 1 h, followed by the addition of <i>N</i>-methylpyridin-3-amine (0.407 g, 3.77 mmol) at 0 °C, and the mixture was stirred for 1 h at RT. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with ice-water and extracted with ethyl acetate twice. The combined organic layers were washed with brine, dried over Na₂SO₄, filtered and evaporated under reduced pressure. The residue was purified by column chromatography (Si-column, AcOEt: petroleum ether=3:7 - 1:1) to give the desired product.

(Step 2) Synthesis of <i>N</i>-methyl-<i>N</i>-(pyridin-3-yl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

0805To a stirred solution of 2-chloro-<i>N</i>-methyl-<i>N</i>-(pyridin-3-yl)quinazolin-4-amine (0.120 g, 0.44 mmol) in toluene (4 mL) was added formohydrazide (0.053 g, 0.88 mmol) at RT and the mixture was heated to 120 °C for 48 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was evaporated under reduced pressure. The residue was purified by prep. HPLC to afford the desired product: ¹ H-NMR (DMSO-d₆) δ 9.66 (s, 1H), 8.51 (d, J = 2.7 Hz, 1H), 8.42 (dd, J = 4.8, 1.4 Hz, 1H), 8.37 - 8.27 (m, 1H), 7.87 - 7.71 (m, 2H), 7.42 (ddd, J = 8.2, 4.7, 0.8 Hz, 1H), 7.33 - 7.23 (m, 2H), 3.58 (s, 3H); LCMS(m/z) 277.2 [M+H]+.

<u>Example 24. N-methyl-N-(pyridin-4-yl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

0806<chemistry id="chem1324" num="1324"><img file="EP4445902A2_D1327.tif" /></chemistry>

(Step 1) Synthesis of 2-chloro-<i>N</i>-methyl-N-(pyridin-4-yl)quinazolin-4-amine

0807<chemistry id="chem1325" num="1325"><img file="EP4445902A2_D1328.tif" /></chemistry>

0808To a stirred solution of 2,4-dichloroquinazoline (0.5 g, 2.51 mmol) in DMF (10 mL) were added sodium hydroxide (0.1 g, 2.51 mmol) and <i>N</i>-methylpyridin-4-amine (0.271 g, 2.51 mmol) at RT, and the mixture was stirred for 4 h at RT. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with ice-water and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na₂SO₄, filtered and evaporated under reduced pressure to give the desired product.

(Step 2) Synthesis of <i>N</i>-methyl-<i>N</i>-(pyridin-4-yl)-[1,2,4]triazolo[4,3-<i>a</i>]quinazolin-5-amine

0809To a stirred solution of 2-chloro-<i>N</i>-methyl-<i>N</i>-(pyridin-4-yl)quinazolin-4-amine (0.250 g, 0.92 mmol) in toluene (5 mL) was added formohydrazide (0.111 g, 1.85 mmol) at RT, and the mixture was heated to 120 °C for 48 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was evaporated under reduced pressure. The residue was purified by prep. HPLC to afford the desired product: ¹ H-NMR (DMSO-d₆) δ 9.80 (s, 1H), 8.57 - 8.29 (m, 3H), 7.92 (ddd, J = 8.5, 7.2, 1.4 Hz, 1H), 7.55 (dd, J = 8.3, 1.4 Hz, 1H), 7.43 (ddd, J = 8.2, 7.2, 1.1 Hz, 1H), 7.19 - 6.98 (m, 2H), 3.60 (s, 3H); LCMS(m/z) 277.2 [M+H]+.

<u>Example 25. N-(2-chloronhenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

0810<chemistry id="chem1326" num="1326"><img file="EP4445902A2_D1329.tif" /></chemistry>

0811To a solution of 5-chloro-[1,2,4]triazolo[4,3-a]quinazoline (50 mg, 0.269 mmol), Bromotris(dimethylamino)phosphonium hexafluorophosphate (BrOP) (125 mg, 0.322 mmol) and DBU (49.1 mg, 0.322 mmol) in acetonitrile (1 mL) was added to 2-chloro-N-methylaniline (41.8 mg, 0.295 mmol) at RT. The mixture was stirred overnight at 80 °C. The reaction mixture was concentrated in vacuo, and the residue was purified by column chromatography (Si-column, CHCl₃: MeOH = 100 : 0 - 95 : 5) to afford a crude product. The crude compound was further purified by prep-LCMS to afford the desired product: ¹ H-NMR (CDCl₃) δ 8.94 (s, 1H), 7.82 (ddd, J = 8.3, 1.2, 0.6 Hz, 1H), 7.66 (ddd, J = 8.4, 6.7, 1.8 Hz, 1H), 7.60 - 7.52 (m, 1H), 7.34 - 7.29 (m, 1H), 7.26 (td, J = 7.6, 1.7 Hz, 1H), 7.20 - 7.10 (m, 3H), 3.59 (s, 3H); LCMS(m/z) 310.2 [M+H]+.

<u>Example 26. N-(2-cyanophenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

0812<chemistry id="chem1327" num="1327"><img file="EP4445902A2_D1330.tif" /></chemistry>

0813To a solution of 5-chloro-[1,2,4]triazolo[4,3-a]quinazoline (80 mg, 0.430 mmol), BrOP (200 mg, 0.516 mmol) and DBU (79 mg, 0.516 mmol) in acetonitrile (2 mL) was added to 2-cyano-N-methylaniline (56.8 mg, 0.430 mmol) at RT. The mixture was stirred overnight at 80 °C. The reaction mixture was subjected to solid phase extraction (washed with MeOH, then eluted with NH3 in MeOH) using Bond Elut SCX cartridge (Agilent), and the collected fractions were concentrated in vacuo. Then, the residue was purified by preparative LCMS to afford the desired product: ¹ H-NMR (CDCl₃) δ 9.05 (s, 1H), 7.92 (d, J = 8.2 Hz, 1H), 7.81 (dd, J = 7.8, 1.6 Hz, 1H), 7.72 (ddd, J = 8.4, 5.2, 3.4 Hz, 1H), 7.54 (td, J = 7.9, 1.7 Hz, 1H), 7.41 (td, J = 7.7, 1.1 Hz, 1H), 7.24 - 7.14 (m, 2H), 7.10 (dd, J = 8.2, 1.1 Hz, 1H), 3.73 (s, 3H); LCMS(m/z) 301.2 [M+H]+.

<u>Example 27. N-(2-bromophenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

0814<chemistry id="chem1328" num="1328"><img file="EP4445902A2_D1331.tif" /></chemistry>

0815To a solution of 5-chloro-[1,2,4]triazolo[4,3-a]quinazoline (50 mg, 0.269 mmol), BrOP (125 mg, 0.322 mmol) and DBU (49.1 mg, 0.322 mmol) in acetonitrile (1 mL) was added to 2-bromo-N-methylaniline (50 mg, 0.269 mmol) at RT. The mixture was stirred overnight at 80 °C. The reaction mixture was subjected to solid phase extraction (washed with MeOH, then eluted with NH₃ in MeOH) using Bond Elut SCX cartridge (Agilent), and the collected fractions were concentrated in vacuo. Then, the residue was purified by prep-LCMS to afford the desired product: ¹ H-NMR (CDCl₃) δ 9.13 (s, 1H), 7.97 (d, J = 8.3 Hz, 1H), 7.79 - 7.65 (m, 2H), 7.29 (dt, J = 7.6, 1.6 Hz, 2H), 7.23 - 7.09 (m, 3H), 3.60 (s, 3H); LCMS(m/z) 355.6 [M+H]+.

<u>Example 28. 8-bromo-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

0816<chemistry id="chem1329" num="1329"><img file="EP4445902A2_D1332.tif" /></chemistry>

(Step 1) Synthesis of 7-bromo-2-chloro-N-methyl-N-phenylquinazolin-4-amine

0817<chemistry id="chem1330" num="1330"><img file="EP4445902A2_D1333.tif" /></chemistry>

0818To a solution of N-methylaniline (0.327 mL, 3.02 mmol) and NaH (121 mg, 3.02 mmol) in DMF (30 mL) was added 7-bromo-2,4-dichloroquinazoline (800 mg, 2.88 mmol) at RT. The reaction mixture was stirred for 5 h at RT. The mixture was diluted with AcOEt, washed successively with water and brine, and dried over Na₂SO₄. The organic layer was concentrated in vacuo. The resulting residue was used in the next step without further purification. LCMS(m/z) 347.98 [M+H]⁺.

(Step 2) Synthesis of 7-bromo-2-hydrazinyl-N-methyl-N-phenylquinazolin-4-amine

0819<chemistry id="chem1331" num="1331"><img file="EP4445902A2_D1334.tif" /></chemistry>

0820The resulting 7-bromo-2-chloro-N-methyl-N-phenylquinazolin-4-amine and hydrazine hydrate (2 mL) in EtOH (5 mL) was stirred for 1 h at 50 °C. The reaction mixture was cooled to room temperature, and then diluted with EtOAc. The solution was washed successively with water and brine, and dried over Na₂SO₄, and concentrated in vacuo. The crude was used in the next step without purification. LCMS(m/z) 344.08 [M+H]⁺.

(Step 3) Synthesis of 8-bromo-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

0821The resulting 7-bromo-2-hydrazinyl-N-methyl-N-phenylquinazolin-4-amine and triethoxymethane (5 mL) in EtOH (20 mL) was stirred overnight at 100 °C. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (Si-column, CHCl₃: MeOH = 100 : 0 - 95 : 5) to afford the desired product: ¹ H-NMR (Methanol-d₄) δ 9.29 (d, J = 2.3 Hz, 1H), 8.29 (d, J = 4.8 Hz, 1H), 7.32 (t, J = 7.6 Hz, 2H), 7.24 - 7.14 (m, 4H), 6.95 (t, J = 8.1 Hz, 1H), 3.51 (d, J = 2.2 Hz, 3H); LCMS(m/z) 355.0 [M+H]+.

<u>Example 29. N,8-dimethyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

0822<chemistry id="chem1332" num="1332"><img file="EP4445902A2_D1335.tif" /></chemistry>

(Step 1) Synthesis of 7-methylquinazoline-2,4(1H,3H)-dione

0823<chemistry id="chem1333" num="1333"><img file="EP4445902A2_D1336.tif" /></chemistry>

0824To a suspension of 2-amino-4-methylbenzoic acid (500 mg, 3.31 mmol) in water (5mL) was added acetic acid (0.5 mL), and the suspension was heated to 35 °C. A freshly prepared solution of potassium cyanate (268 mg, 3.31 mmol) in water (0.5 mL) was added dropwise to the suspension over the period of 1 h. The mixture was stirred for 1 h at 40°C. NaOH (8 g) was added portion-wise to the reaction mixture by maintaining the internal temperature below 50°C, and the mixture was further stirred for 2 h. The precipitate was collected by filtration to give the desired product. LCMS(m/z) 177.11 [M+H]⁺.

(Step 2) Synthesis of 2,4-dichloro-7-methylquinazoline

0825<chemistry id="chem1334" num="1334"><img file="EP4445902A2_D1337.tif" /></chemistry>

0826A mixture of 7-methylquinazoline-2,4(1H,3H)-dione (100 mg, 0.568 mmol) and phosphoryl trichloride (435 mg, 2.84 mmol) was heated to 100 °C for 3 h. The reaction mixture was concentrated in vacuo to give the desired product. LCMS(m/z) 213.05 [M+H]⁺.

(Step 3) Synthesis of 2-chloro-N,7-dimethyl-N-phenylquinazolin-4-amine

0827<chemistry id="chem1335" num="1335"><img file="EP4445902A2_D1338.tif" /></chemistry>

0828To a solution of 2,4-dichloro-7-methylquinazoline (100 mg, 0.47 mmol) in DMF (2.3 mL) were added N-methylaniline (55.3 mg, 0.516 mmol) and sodium hydroxide (18.77 mg, 0.469 mmol), and the mixture was stirred for 1 h at RT. The reaction mixture was diluted with AcOEt, washed successively with H₂O and brine, and dried over Na₂SO₄. The organic layer was concentrated in vacuo to give the desired product. LCMS(m/z) 284.8 [M+H]⁺.

(Step 4) Synthesis of 2-hydrazinyl-N,7-dimethyl-N-phenylquinazolin-4-amine

0829<chemistry id="chem1336" num="1336"><img file="EP4445902A2_D1339.tif" /></chemistry>

0830To a solution of 2-chloro-N,7-dimethyl-N-phenylquinazolin-4-amine (71 mg, 0.25 mmol) in EtOH (1.25 mL) was added hydrazine hydrate (25.05 mg, 0.5 mmol), and the mixture was stirred for 2 h at 50 °C. The reaction mixture was diluted with AcOEt, washed successively with water and brine, and dried over Na₂SO₄. The organic layer was concentrated in vacuo to give the desired product. LCMS(m/z) 280.18 [M+H]⁺.

(Step 5) Synthesis of N,8-dimethyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

0831A mixture of 2-hydrazinyl-N,7-dimethyl-N-phenylquinazolin-4-amine (68 mg, crude) and triethoxymethane (111 mg, 0.751 mmol) and a drop of acetic acid (12.04 mg, 0.201 mmol) was heated to 90 °C for 2 h. The reaction mixture was concentrated in vacuo, and purified by prep-HPLC to afford the desired product: ¹ H-NMR (Methanol-d₄) δ 9.39 (s, 1H), 7.99 (d, J = 1.5 Hz, 1H), 7.47 - 7.39 (m, 2H), 7.34 - 7.22 (m, 3H), 7.16 (d, J = 8.6 Hz, 1H), 6.99 (dd, J = 8.5, 1.6 Hz, 1H), 3.64 (s, 3H), 2.47 (s, 3H); LCMS(m/z) 290.2 [M+H]+.

<u>Example 30. 8-cyclopropyl-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

0832<chemistry id="chem1337" num="1337"><img file="EP4445902A2_D1340.tif" /></chemistry>

0833A mixture of 8-bromo-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 28) (20 mg, 0.056 mmol), K₃PO₄ (30.0 mg, 0.141 mmol), Pd(OAc)₂ (2.54 mg, 0.011 mmol), tricyclohexylphosphine (1.583 mg, 5.65 µmol) and cyclopropylboronic acid (12.13 mg, 0.141 mmol) in dioxane/water (0.28 mL) was treated in a microwave reactor at 120°C for 2 h. The reaction mixture was purified by column chromatography (Si-column, CHCl₃: MeOH = 10:0 - 9:1) to afford the desired product: ¹ H-NMR (Methanol-d₄) δ 9.44 (s, 1H), 7.81 (d, J = 1.9 Hz, 1H), 7.47 - 1.31 (m, 2H), 7.36 - 7.20 (m, 3H), 7.10 (dd, J = 8.9, 4.4 Hz, 1H), 6.84 (dt, J = 8.8, 2.1 Hz, 1H), 3.63 (s, 3H), 2.10 - 1.98 (m, 1H), 1.20 - 1.06 (m, 2H), 0.87 (dt, J = 7.0, 4.7 Hz, 2H); LCMS(m/z) 316.0 [M+H]+.

<u>Example 31. N-methyl-N-phenyl-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

0834<chemistry id="chem1338" num="1338"><img file="EP4445902A2_D1341.tif" /></chemistry>

0835A mixture of 8-bromo-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 28) (20 mg, 0.056 mmol), K₃PO₄ (30.0 mg, 0.141 mmol), Pd(OAc)₂ (2.54 mg, 0.011 mmol), tricyclohexylphosphine (1.583 mg, 5.65 µmοl) and pyridin-4-ylboronic acid (17.35 mg, 0.141 mmol) in dioxane/water (0.28 mL) was treated in a microwave reactor at 120°C for 2 h. The reaction mixture was concentrated in vacuo. The residue was purified by preparative-HPLC to afford the desired product: ¹ H-NMR (Methanol-d₄) δ 9.61 (s, 1H), 8.71 - 8.61 (m, 4H), 7.89 - 7.83 (m, 2H), 7.60 (dd, J = 8.8, 1.8 Hz, 1H), 7.46 (d, J = 8.2 Hz, 3H), 7.37 - 7.31 (m, 2H), 3.70 (s, 3H); LCMS(m/z) 353.2 [M+H]+.

<u>Example 32. N-(2-iodophenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

0836<chemistry id="chem1339" num="1339"><img file="EP4445902A2_D1342.tif" /></chemistry>

0837To a solution of 5-chloro-[1,2,4]triazolo[4,3-a]quinazoline (32 mg, 0.172 mmol), BrOP (73.3 mg, 0.189 mmol) and DBU (28.7 mg, 0.189 mmol) in acetonitrile (1 mL) was added to 2-iodo-N-methylaniline (40 mg, 0.172 mmol) at RT. The mixture was stirred overnight at 80 °C. The reaction mixture was concentrated in vacuo, and the residue was purified by column chromatography (Si-column, CHCl₃: MeOH = 100 : 0 - 95 : 5) to afford the crude product. The crude compound was further purified by prep-LCMS to afford the desired product: ¹ H-NMR (Methanol-d₄) δ 9.44 (s, 1H), 8.20 (dd, J = 8.4, 1.0 Hz, 1H), 8.07 (dd, J = 8.0, 1.4 Hz, 1H), 7.78 (ddd, J = 8.5, 7.2, 1.4 Hz, 1H), 7.46 (td, J = 7.6, 1.4 Hz, 1H), 7.33 (dd, J = 7.9, 1.6 Hz, 1H), 7.25 - 7.09 (m, 3H), 3.56 (s, 3H); LCMS(m/z) 402.1 [M+H]+.

<u>Example 33. N-methyl-N-(o-tolyl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

0838<chemistry id="chem1340" num="1340"><img file="EP4445902A2_D1343.tif" /></chemistry>

0839To a solution of 5-chloro-[1,2,4]triazolo[4,3-a]quinazoline (50 mg, 0.269 mmol), BrOP (115 mg, 0.295 mmol) and DBU (45 mg, 0.295 mmol) in acetonitrile (2 mL) was added to N,2-dimethylaniline (32.5 mg, 0.269 mmol) at RT. The mixture was stirred overnight at 80 °C. The reaction mixture was concentrated in vacuo, and the residue was purified by column chromatography (Si-column, CHCl₃: MeOH = 100 : 0 - 95 : 5) to give the crude product. The crude compound was further purified by prep-LCMS to afford the desired product: ¹ H-NMR (Methanol-d₄) δ 9.40 (s, 1H), 8.17 (dt, J = 8.3, 0.8 Hz, 1H), 7.74 (ddd, J = 8.4, 6.8, 1.8 Hz, 1H), 7.46 - 7.39 (m, 1H), 7.39 - 7.21 (m, 2H), 7.19 - 7.07 (m, 3H), 3.56 (s, 3H), 2.31 (s, 3H); LCMS(m/z) 290.2 [M+H]+.

<u>Example 34. N-methyl-N-(m-tolyl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

0840<chemistry id="chem1341" num="1341"><img file="EP4445902A2_D1344.tif" /></chemistry>

0841To a solution of 5-chloro-[1,2,4]triazolo[4,3-a]quinazoline (50 mg, 0.269 mmol), BrOP (115 mg, 0.295 mmol) and DBU (45.0 mg, 0.295 mmol) in acetonitrile (2 mL) was added to N,3-dimethylaniline (32.5 mg, 0.269 mmol) at RT. The mixture was stirred overnight at 50 °C. The reaction mixture was concentrated in vacuo, and the residue was purified by column chromatography (Si-column, CHCl₃: MeOH = 100 : 0 - 95 : 5) to give the crude product. The crude compound was further purified by prep-LCMS to afford the desired product: ¹ H-NMR (Methanol-d₄) δ 9.43 (s, 1H), 8.21 - 8.07 (m, 1H), 7.75 (ddd, J = 8.5, 7.2, 1.3 Hz, 1H), 7.37 - 7.24 (m, 2H), 7.23 - 7.11 (m, 3H), 7.11 - 7.03 (m, 1H), 3.65 (s, 3H), 2.33 (d, J = 0.8 Hz, 3H); LCMS(m/z) 290.2 [M+H]+.

<u>Example 35. 7-chloro-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

0842<chemistry id="chem1342" num="1342"><img file="EP4445902A2_D1345.tif" /></chemistry>

(Step 1) Synthesis of 2,6-dichloro-N-methyl-N-phenylquinazolin-4-amine

0843<chemistry id="chem1343" num="1343"><img file="EP4445902A2_D1346.tif" /></chemistry>

0844To a solution of N-methylaniline (138 mg, 1.285 mmol) and NaH (56.5 mg, 1.413 mmol) in DMF (10 mL) was added 2,4,6-trichloroquinazoline (300 mg, 1.285 mmol) at RT. The mixture was stirred for 1 h at RT. The reaction mixture was diluted with EtOAc, washed successively with water and brine, dried over Na₂SO₄, and concentrated in vacuo to give the desired product, which was used for the next step without purification. LCMS(m/z) 304.03 [M+H]+.

(Step 2) Synthesis of 6-chloro-2-hydrazinyl-N-methyl-N-phenylquinazolin-4-amine

0845<chemistry id="chem1344" num="1344"><img file="EP4445902A2_D1347.tif" /></chemistry>

0846To a solution of 2,6-dichloro-N-methyl-N-phenylquinazolin-4-amine (117 mg, crude) in EtOH (5 mL) was added hydrazine hydrate (2 mL) at RT. The mixture was stirred for 2 h at 50 °C. The reaction mixture was cooled to RT, diluted with EtOAc, washed successively with water and brine, dried over Na₂SO₄, and concentrated in vacuo. The crude product was used for the next step without purification. LCMS(m/z) 300.08 [M+H]+.

(Step 3) Synthesis of 7-chloro-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

0847A solution of crude 6-chloro-2-hydrazinyl-N-methyl-N-phenylquinazolin-4-amine in triethoxymethane (5 mL) was stirred overnight at 100 °C. The reaction mixture was concentrated in vacuo, and the residue was purified by column chromatography (Si-column, hexane : AcOEt = 100 : 0 - 0 : 100, then MeOH) to give the crude product. The crude compound was further purified by prep-LCMS to afford the desired product: ¹ H-NMR (DMSO-d₆) δ 9.62 (s, 1H), 8.33 (d, J = 8.8 Hz, 1H), 7.87 (dd, J = 8.9, 2.3 Hz, 1H), 7.49 - 7.28 (m, 5H), 7.10 (d, J = 2.3 Hz, 1H), 3.55 (s, 3H). LCMS(m/z) 310.1 [M+H]+.

<u>Example 36. N,7-dimethyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

0848<chemistry id="chem1345" num="1345"><img file="EP4445902A2_D1348.tif" /></chemistry>

(Step 1) Synthesis of 2-chloro-N,6-dimethyl-N-phenylquinazolin-4-amine

0849<chemistry id="chem1346" num="1346"><img file="EP4445902A2_D1349.tif" /></chemistry>

0850To a solution of N-methylaniline (151 mg, 1.408 mmol) and NaH (61.9 mg, 1.549 mmol) in DMF (10 mL) was added 2,4-dichloro-6-methylquinazoline (300 mg, 1.408 mmol) at RT. The mixture was stirred for 5h at RT. The reaction mixture was quenched with water, and diluted with AcOEt. The organic layer was washed with brine, dried over Na₂SO₄, and concentrated in vacuo to give the desired product. LCMS(m/z) 284.13 [M+H]+.

(Step 2) Synthesis of 2-hydrazinyl-N,6-dimethyl-N-phenylquinazolin-4-amine

0851<chemistry id="chem1347" num="1347"><img file="EP4445902A2_D1350.tif" /></chemistry>

0852A mixture of 2-chloro-N,6-dimethyl-N-phenylquinazolin-4-amine (123 mg, 0.43 mmol) and hydrazine hydrate (2 mL) in EtOH (5 mL) was stirred overnight at 50 °C. The reaction mixture was cooled to RT, diluted with EtOAc, washed successively with water and brine, dried over Na₂SO₄, and concentrated in vacuo to give the desired product, which was used for the next step without purification. LCMS(m/z) 280.18 [M+H]+.

(Step 3) Synthesis of N,7-dimethyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

0853A solution of 2-hydrazinyl-N,6-dimethyl-N-phenylquinazolin-4-amine (89 mg, crude) and triethoxymethane (5 mL) in EtOH (5 mL) was stirred for 4 h at 100 °C. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (Si-column, CHCl₃ : MeOH = 100 : 0 - 95 : 5) to give the crude product. The crude compound was further purified by prep-LCMS to afford the desired product: ¹ H-NMR (DMSO-d₆) δ 9.57 (s, 1H), 8.18 (d, J = 8.4 Hz, 1H), 7.61 (ddd, J = 8.4, 1.9, 0.7 Hz, 1H), 7.45 - 7.35 (m, 2H), 7.33 - 7.24 (m, 3H), 7.00 - 6.94 (m, 1H), 3.54 (s, 3H), 2.05 (s, 3H); LCMS(m/z) 290.2 [M+H]+.

<u>Example 37. N-methyl-N-phenyl-8-(prop-1-yn-1-yl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

0854<chemistry id="chem1348" num="1348"><img file="EP4445902A2_D1351.tif" /></chemistry>

0855A mixture of 8-bromo-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 28) (30 mg, 0.085 mmol), prop-1-yne (8.48 mg, 0.212 mmol), triethylamine (8.57 mg, 0.085 mmol), Pd(OAc)₂ (3.80 mg, 0.017 mmol), triphenylphosphine (19.99 mg, 0.076 mmol) and copper(I) iodide (3.23 mg, 0.017 mmol) in dioxane (0.4 mL) was treated in a microwave reactor at 120°C for 2 h. The reaction mixture was purified by column chromatography (Si-column, CHCl₃ : MeOH = 10:0 - 9: 1) to afford the desired product: ¹ H-NMR (CDCl₃) δ 8.90 (s, 1H), 7.77 (d, J = 1.5 Hz, 1H), 7.44 - 7.32 (m, 2H), 7.31 - 7.22 (m, 1H), 7.23 - 7.11 (m, 3H), 7.05 (dd, J = 8.7, 1.6 Hz, 1H), 3.67 (s, 3H), 2.08 (s, 3H); LCMS(m/z) 314.2 [M+H]+.

<u>Example 38. 5-(methyl(phenyl)amino)-[1,2,4]triazolo[4,3-a]quinazolin-8-ol</u>

0856<chemistry id="chem1349" num="1349"><img file="EP4445902A2_D1352.tif" /></chemistry>

0857To a solution 8-methoxy-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 20) (20 mg, 0.066 mmol) in 1,2-dichloroethane (1 mL) was added tribromoborane (0.197 mL, 0.197 mmol) at RT, and the mixture was stirred for 1 h at 50°C. The reaction mixture was concentrated in vacuo, and the residue was purified by column chromatography (Si-column, CHCl₃ : MeOH = 100 : 0 - 90 : 10) to afford the desired product: ¹ H-NMR (DMSO-d₆) δ 9.48 (s, 1H), 7.50 (d, J = 2.4 Hz, 1H), 7.38 (dd, J = 8.5, 7.1 Hz, 2H), 7.28 - 7.19 (m, 3H), 7.09 (d, J = 9.1 Hz, 1H), 6.62 (dd, J = 9.2, 2.4 Hz, 1H), 3.50 (s, 3H); LCMS(m/z) 292.2 [M+H]+.

<u>Example 39. N-phenyl-N-propyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

0858<chemistry id="chem1350" num="1350"><img file="EP4445902A2_D1353.tif" /></chemistry>

(Step 1) Synthesis of 2-chloro-<i>N</i>-phenyl-<i>N-</i>propylquinazolin-4-amine

0859<chemistry id="chem1351" num="1351"><img file="EP4445902A2_D1354.tif" /></chemistry>

0860To a solution of 60% sodium hydride (0.12 g, 3.01 mmol) in DMF (10 mL) was added N-propylaniline (0.339 g, 2.51 mmol) at 0 °C and the mixture was stirred for 1 h at RT, followed by the addition of 2,4-dichloroquinazoline (0.5 g, 2.51 mmol) at 0 °C, and the mixture was stirred for 16 h at RT. The reaction mixture was diluted with ice-water. The resulting solids were filtered and dried under vacuum to give the desired product. LCMS: 298.14 (M+H).

(Step 2) Synthesis of 2-hydrazinyl-<i>N</i>-phenyl-<i>N</i>-propylquinazolin-4-amine

0861<chemistry id="chem1352" num="1352"><img file="EP4445902A2_D1355.tif" /></chemistry>

0862To a stirred solution of 2-chloro-<i>N</i>-phenyl-<i>N</i>-propylquinazolin-4-amine (crude, 0.2 g, 0.67 mmol) in EtOH (5 mL) was added hydrazine hydrate (0.067 g, 1.34 mmol) at RT and the mixture was stirred at 50 °C for 16 h. The reaction mixture was evaporated under reduced pressure to give the desired product. LCMS: 294.09 (M+H).

(Step 3) Synthesis of <i>N-</i>phenyl-<i>N-</i>propyl-[1,2,4]triazolo[4,3-<i>a</i>]quinazolin-5-amine

0863A mixture of 2-hydrazinyl-<i>N</i>-phenyl-<i>N</i>-propylquinazolin-4-amine (crude, 0.15 g, 0.51 mmol) and triethyl orthoformate (3 mL) was stirred at 80 °C for 3 h. The reaction mixture was evaporated under reduced pressure, and the residue was purified by prep. HPLC to afford the desired product: ¹ H-NMR (DMSO-d₆) δ 9.60 (s, 1H), 8.27 (dd, J = 8.3, 1.1 Hz, 1H), 7.75 (ddd, J = 8.4, 7.0, 1.6 Hz, 1H), 7.43 - 7.33 (m, 2H), 7.30 - 7.14 (m, 5H), 4.13 - 3.94 (m, 2H), 1.74 (d, J = 7.5 Hz, 2H), 0.95 (t, J = 7.4 Hz, 3H); LCMS(m/z) 304.18 [M+H]+.

<u>Example 40. N-benzyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

0864<chemistry id="chem1353" num="1353"><img file="EP4445902A2_D1356.tif" /></chemistry>

0865To a solution of <i>N-</i>benzylaniline (0.018 g, 0.098 mmol) in THF (1 mL) was added LDA (0.1 mL, 0.2 mmol, 2.0 M in THF) at 0 °C and the mixture was stirred at RT for 1 h, followed by the addition of 5-chloro-[1,2,4]triazolo[4,3-a]quinazoline (0.02 g, 0.098 mmol) at 0 °C, and the mixture was stirred for 2 h at RT. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over Na₂SO₄, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 5% methanol/dichloromethane to afford the desired product: ¹ H-NMR (DMSO-d₆) δ 9.64 (s, 1H), 8.30 (d, J = 8.3 Hz, 1H), 7.55 - 7.05 (m, 13H), 5.40 (s, 2H); LCMS(m/z) 352.2 [M+H]+.

<u>Example 41. N-(cyclopropylmethyl)-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

0866<chemistry id="chem1354" num="1354"><img file="EP4445902A2_D1357.tif" /></chemistry>

(Step 1) Synthesis of <i>N</i>-(cyclopropylmethyl)aniline

0867<chemistry id="chem1355" num="1355"><img file="EP4445902A2_D1358.tif" /></chemistry>

0868To a solution of aniline (2.0 g, 21.47 mmol) in EtOH (20 mL) were added cyclopropanecarbaldehyde (3.01 g, 42.95 mmol) and a catalytic amount of acetic acid at RT and the mixture was stirred at RT for 1 h, followed by the addition of sodium triacetoxyborohydride (9.10 g, 42.95 mmol) at RT, and the mixture was stirred at RT for 2 h. The reaction mixture was evaporated under reduced pressure, the residue was purified by silica gel column chromatography and eluted with 10% ethyl acetate/petroleum ether to give the desired product. LCMS: 148.31 (M+H).

(Step 2) Synthesis of <i>N</i>-(cyclopropylmethyl)-<i>N</i>-phenyl-[1,2,4]triazolo[4,3-<i>a</i>]quinazolin-5-

amine

0869To a solution of <i>N</i>-(cyclopropylmethyl)aniline (crude, 0.014 g, 0.098 mmol) in THF (1 mL) was added LDA (0.15 mL, 0.20 mmol, 1.0 M in THF) at 0 °C and the mixture was stirred at RT for 0.5 h, followed by the addition of 5-chloro-[1,2,4]triazolo[4,3-a]quinazoline (0.02 g, 0.098 mmol) at 0 °C. The mixture was stirred at the RT for 1 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over Na₂SO₄, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with 100% ethyl acetate to afford the desired product: ¹ H-NMR (DMSO-d₆) δ 9.60 (s, 1H), 8.28 (dd, J = 8.3, 1.1 Hz, 1H), 7.76 (ddd, J = 8.4, 7.1, 1.4 Hz, 1H), 7.40 - 7.36 (m, 2H), 7.30 - 7.17 (m, 5H), 3.96 (d, J = 6.8 Hz, 2H), 1.45 - 1.31 (m, 1H), 0.44 - 0.33 (m, 2H), 0.20 - 0.09 (m, 2H); LCMS(m/z) 316.4 [M+H]+.

<u>Example 42. 4-([1,2,4]triazolo[4,3-a]quinazolin-5-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine</u>

0870<chemistry id="chem1356" num="1356"><img file="EP4445902A2_D1359.tif" /></chemistry>

(Step1) Synthesis of 4-(2-chloroquinazolin-4-yl)-3,4-dihydro-2<i>H</i>-benzo[<i>b</i>][1,4]oxazine

0871<chemistry id="chem1357" num="1357"><img file="EP4445902A2_D1360.tif" /></chemistry>

0872To a stirred solution of 60% sodium hydride (0.120 g, 3.01 mmol) in DMF (10 mL) was added 3,4-dihydro-2<i>H</i>-benzo[<i>b</i>][1,4]oxazine (0.339 g, 2.51 mmol) at 0 °C and the mixture was stirred for 2 h at RT, followed by the addition of 2,4-dichloroquinazoline (0.5 g, 2.51 mmol) at 0 °C, and the mixture was stirred for 8 h at RT. The reaction mixture was quenched with ice-water. The resulting solids were filtered and dried under vacuum to give the desired product. LCMS: 298.11 (M+H).

(Step 2) Synthesis of 4-(2-hydrazinylquinazolin-4-yl)-3,4-dihydro-2<i>H</i>-benzo[<i>b</i>][1,4]oxazine

0873<chemistry id="chem1358" num="1358"><img file="EP4445902A2_D1361.tif" /></chemistry>

0874To a solution of 4-(2-chloroquinazolin-4-yl)-3,4-dihydro-2<i>H</i>-benzo|<i>b</i>][1,4]oxazine (0.3 g, 1.01 mmol) in EtOH (10 mL) was added hydrazine hydrate (0.101 mL, 2.02 mmol) at RT and the mixture was stirred at 50 °C for 5 h. The reaction mixture was evaporated under reduced pressure. The residue was washed with n-pentane and diethyl ether to give the desired product. LCMS: 294.18 (M+H).

(Step 3) Synthesis of 4-([1,2,4]triazolo[4,3-<i>a</i>]quinazolin-5-yl)-3,4-dihydro-2<i>H-</i>benzo[<i>b</i>][1,4]oxazine

0875A mixture of 4-(2-hydrazinylquinazolin-4-yl)-3,4-dihydro-2<i>H</i>-benzo[<i>b</i>][1,4]oxazine (crude, 0.2 g, 0.68 mmol) and triethyl orthoformate (0.3 g, 2.05 mmol) was stirred at 90 °C for 2 h. The reaction mixture was diluted with ethanol and the resulting solids were collected by filtration to give a crude product. The crude product was purified by prep. HPLC to afford the desired product: ¹ H-NMR (500 MHz, DMSO-d₆) δ 9.74 (s, 1H), 8.41 (dd, J = 8.4, 1.1 Hz, 1H), 8.08 (dd, J = 8.3, 1.3 Hz, 1H), 7.97 (ddd, J = 8.5, 7.3, 1.4 Hz, 1H), 7.56 (ddd, J = 8.3, 7.3, 1.1 Hz, 1H), 7.00 - 6.92 (m, 2H), 6.92 - 6.84 (m, 1H), 6.71 (ddd, J = 8.4, 5.5, 3.3 Hz, 1H), 4.41 (dd, J = 5.2, 3.7 Hz, 2H), 4.03 (t, J = 4.5 Hz, 2H); LCMS(m/z) 304.2.

<u>Example 43. N,N-diphenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

0876<chemistry id="chem1359" num="1359"><img file="EP4445902A2_D1362.tif" /></chemistry>

(Step 1) Synthesis of 2-chloro-<i>N,N</i>-diphenylquinazolin-4-amine

0877<chemistry id="chem1360" num="1360"><img file="EP4445902A2_D1363.tif" /></chemistry>

0878To a solution of 2,4-dichloroquinazoline (1.0 g, 5.02 mmol) in DMF (20 mL) was added 60% sodium hydride (0.241 g, 6.03 mmol) at 0 °C and the mixture was stirred for 1 h at RT, followed by the addition of diphenylamine (0.849 g, 5.02 mmol) at 0 °C, and the mixture was stirred for 2 h at RT. The reaction mixture was diluted with ice-water and extracted with ethyl acetate twice. The combined organic layer was washed with brine, dried over anhydrous Na₂SO₄, filtered and evaporated under reduced pressure to give the desired product. LCMS: 332.15 (M+H).

(Step 2) Synthesis of 2-hydrazinyl-<i>N,N</i>-diphenylquinazolin-4-amine

0879<chemistry id="chem1361" num="1361"><img file="EP4445902A2_D1364.tif" /></chemistry>

0880To a solution of 2-chloro-<i>N,N-</i>diphenylquinazolin-4-amine (0.3 g, 0.90 mmol) in EtOH (10 mL) was added hydrazine hydrate (0.090 g, 1.8 mmol) at RT and the mixture was stirred at 50 °C for 16 h. The reaction mixture was evaporated under reduced pressure to give the desired product. LCMS: 328.23 (M+H).

(Step 3) Synthesis of N,N-diphenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

0881A mixture of 2-hydrazinyl-<i>N,N-</i>diphenylquinazolin-4-amine (0.3 g, 0.91 mmol) and triethyl orthoformate (0.407 g, 2.75 mmol) was stirred to 80 °C for 3 h. The reaction mixture was evaporated under reduced pressure. The residue was purified by prep. HPLC to afford the desired product: ¹ H-NMR (DMSO-d₆) δ 9.72 (s, 1H), 8.37 (dd, J = 8.3, 1.1 Hz, 1H), 7.87 (ddd, J = 8.5, 7.3, 1.3 Hz, 1H), 7.59 (dd, J = 8.5, 1.3 Hz, 1H), 7.48 - 7.29 (m, 5H), 7.29 - 7.10 (m, 6H); LCMS(m/z) 338.3 [M+H]+.

<u>Example 44. N-methyl-N-(thiophen-3-yl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

0882<chemistry id="chem1362" num="1362"><img file="EP4445902A2_D1365.tif" /></chemistry>

(Step 1) Synthesis of 2-chloro-N-methyl-N-(thiophen-3-yl)quinazolin-4-amine

0883<chemistry id="chem1363" num="1363"><img file="EP4445902A2_D1366.tif" /></chemistry>

0884To a stirred solution of N-methylthiophen-3-amine (0.051 g, 0.45 mmol) in DMF (3 mL) was added 60% sodium hydride (0.018 g, 0.45 mmol) at 0 °C and the mixture was stirred for 1 h at RT, followed by the addition of 2,4-dichloroquinazoline (0.09 g, 0.45 mmol) at 0 °C, and the mixture was stirred for 12 h at RT. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with ice-water and extracted with ethyl acetate twice. The combined organic layers were washed successively with water, brine, dried over Na₂SO₄, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with 4% methanol/ dichloromethane to give the desired product: LCMS(m/z) 276.07 [M+H]⁺.

(Step 2) Synthesis of N-methyl-N-(thiophen-3-yl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

0885To a stirred solution of 2-chloro-N-methyl-N-(thiophen-3-yl)quinazolin-4-amine (0.030 g, 0.11 mmol) in toluene (3 mL) was added formohydrazide (0.013 g, 0.22 mmol) at RT and the mixture was heated to 120 °C for 72 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was evaporated under reduced pressure. The residue was purified by prep. HPLC to afford the desired product: ¹ H-NMR (CDCl₃) δ 8.93 (s, 1H), 7.80 (dd, J = 8.4, 1.2 Hz, 1H), 7.68 (ddd, J = 8.5, 7.3, 1.3 Hz, 1H), 7.47 - 7.34 (m, 2H), 7.20 (ddd, J = 8.5, 7.3, 1.2 Hz, 1H), 7.04 - 6.95 (m, 1H), 6.85 (dd, J = 3.2, 1.5 Hz, 1H), 3.64 (s, 3H); LCMS(m/z) 282.1 [M+H]+.

<u>Example 45. 8-(furan-2-yl)-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

0886<chemistry id="chem1364" num="1364"><img file="EP4445902A2_D1367.tif" /></chemistry>

0887A mixture of 8-bromo-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 28) (30 mg, 0.085 mmol), K₃PO₄ (17.98 mg, 0.085 mmol), Pd(OAc)₂ (3.80 mg, 0.017 mmol), tricyclohexylphosphine (4.75 mg, 0.017 mmol) and furan-2-ylboronic acid (23.69 mg, 0.212 mmol) in dioxane/water (0.42 mL) was heated at 100 °C for 3 h. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (Si-column, CHCl₃: MeOH = 10:0 - 9: 1) to afford the desired product: ¹ H-NMR (Methanol-d₄) δ 9.32 (s, 1H), 8.06 (s, 1H), 7.97 (s, 1H), 7.49 (s, 1H), 7.30 (t, J = 7.7 Hz, 2H), 7.19 (t, J = 7.5 Hz, 1H), 7.13 (t, J = 7.5 Hz, 3H), 6.94 (d, J = 8.8 Hz, 1H), 6.81 (s, 1H), 3.49 (s, 3H); LCMS(m/z) 342.0.

<b>Example 46. N-methyl-N-phenyl-8-(1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]quinazolin-5-</b>amine

0888<chemistry id="chem1365" num="1365"><img file="EP4445902A2_D1368.tif" /></chemistry>

0889A mixture of 8-bromo-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 28) (20 mg, 0.056 mmol), K₃PO₄ (30.0 mg, 0.141 mmol), Pd(OAc)₂ (2.54 mg, 0.011 mmol), tricyclohexylphosphine (3.17 mg, 0.011 mmol) and (1H-pyrazol-4-yl)boronic acid (15.79 mg, 0.141 mmol) in dioxane/water (0.28 mL) was treated in a microwave reactor at 100°C for 3 h. The reaction mixture was purified by column chromatography (Si-column, CHCl₃: MeOH = 10:0 - 9:1) to afford the desired product: ¹ H-NMR (Methanol-d₄) δ 9.50 (s, 1H), 8.37 (s, 1H), 8.18 (s, 2H), 7.48 - 7.25 (m, 7H), 7.20 (d, J = 8.8 Hz, 1H), 3.64 (s, 3H); LCMS(m/z) 342.2 [M+H]+.

<u>Example 47. N-methyl-N-phenyl-8-(thiophen-2-yl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

0890<chemistry id="chem1366" num="1366"><img file="EP4445902A2_D1369.tif" /></chemistry>

0891A mixture of 8-bromo-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 28) (20 mg, 0.056 mmol), K₃PO₄ (23.97 mg, 0.113 mmol), Pd(OAc)₂ (2.54 mg, 0.011 mmol), tricyclohexylphosphine (3.17 mg, 0.011 mmol) and thiophen-2-ylboronic acid (18.06 mg, 0.141 mmol) in dioxane/water (0.28 ml) was heated at 120 °C for 2 h. The reaction mixture was concentrated in vacuo. The residue was column chromatography (Si-column, CHCl₃: MeOH = 10:0 - 9: 1) to afford the desired product: ¹ H-NMR (CDCl₃) δ 9.00 (s, 1H), 7.92 (d, J = 1.7 Hz, 1H), 7.46 (dd, J = 3.7, 1.1 Hz, 1H), 7.43 - 7.33 (m, 3H), 7.31 - 7.27 (m, 1H), 7.24 (s, 1H), 7.21 - 7.14 (m, 2H), 7.11 (dd, J = 5.1, 3.7 Hz, 1H), 3.65 (s, 3H); LCMS(m/z) 358.2 [M+H]+.

<u>Example 48. 4-([1,2,4]triazolo[4,3-a]quinazolin-5-yl(methyl)amino)phenol</u>

0892<chemistry id="chem1367" num="1367"><img file="EP4445902A2_D1370.tif" /></chemistry>

0893To a solution ofN-(4-methoxyphenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 5) (15 mg, 0.049 mmol) in 1,2-dichloroethane (1 mL) was added BBr₃ (0.147 mL, 0.147 mmol) at RT. The mixture was stirred for 1.5 h at 50 °C. The reaction mixture was concentrated in vacuo, and the residue was purified by prep-LCMS to afford the desired product: ¹ H-NMR (DMSO-d₆) δ 9.64 (s, 1H), 9.56 (s, 1H), 8.29 - 8.21 (m, 1H), 7.75 (ddd, J = 8.4, 7.1, 1.5 Hz, 1H), 7.28 (dd, J = 8.4, 1.4 Hz, 1H), 7.22 (ddd, J = 8.4, 7.1, 1.2 Hz, 1H), 7.16 - 7.02 (m, 2H), 6.84 - 6.71 (m, 2H), 3.46 (s, 3H); LCMS(m/z) 292.2 [M+H]+.

<u>Example 49. 2-([1,2,4]triazolo[4,3-a]quinazolin-5-yl(methyl)amino)phenol</u>

0894<chemistry id="chem1368" num="1368"><img file="EP4445902A2_D1371.tif" /></chemistry>

(Step 1) Synthesis of 2-chloro-N-(2-methoxyphenyl)-N-methylquinazolin-4-amine

0895<chemistry id="chem1369" num="1369"><img file="EP4445902A2_D1372.tif" /></chemistry>

0896To a suspension of 2,4-dichloroquinazoline (100 mg, 0.502 mmol) in DMF (2.5 mL) were added 2-methoxy-N-methylaniline (68.9 mg, 0.502 mmol) and sodium hydroxide (20.1 mg, 0.502 mmol), and the mixture was stirred for 2 h at RT. The reaction mixture was diluted with AcOEt, washed successively with water and brine, and dried over Na₂SO₄. The organic layer was concentrated in vacuo to give the desired product, which was used for the next step without further purification. LCMS: 300.18 (M+H).

(Step 2) Synthesis of N-(2-methoxyphenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

0897<chemistry id="chem1370" num="1370"><img file="EP4445902A2_D1373.tif" /></chemistry>

0898A mixture of 2-chloro-N-(2-methoxyphenyl)-N-methylquinazolin-4-amine (59 mg, crude) and formohydrazide (23.64 mg, 0.394 mmol) in toluene (1 mL) was stirred reflux for 3 days. The reaction mixture was dissolved in MeOH/AcOEt, concentrated in vacuo. The residue was dissolved in MeOH and evaporated, and the residue was purified by prep-HPLC to give the desired product. LCMS: 306.13 (M+H).

(Step 3) Synthesis of 2-([1,2,4]triazolo[4,3-a]quinazolin-5-yl(methyl)amino)phenol

0899To a solution ofN-(2-methoxyphenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (15 mg, 0.049 mmol) in 1,2-dichloroethane (1 mL) was added BBr₃ (0.147 mL, 0.147 mmol) at RT. The mixture was stirred for 1.5 h at 50 °C. The reaction mixture was concentrated in vacuo, and the residue was purified by prep-LCMS to afford the desired product: ¹ H-NMR (DMSO-d₆) δ 9.91 (s, 1H), 9.55 (s, 1H), 8.26 (dd, J = 8.5, 1.1 Hz, 1H), 7.75 (ddd, J = 8.4, 7.2, 1.4 Hz, 1H), 7.30 (dd, J = 8.4, 1.3 Hz, 1H), 7.23 - 7.11 (m, 3H), 6.96 (dd, J = 8.1, 1.4 Hz, 1H), 6.82 (td, J = 7.6, 1.4 Hz, 1H), 3.41 (s, 3H); LCMS(m/z) 292.2 [M+H]+.

<u>Example 50. 3-([1,2,4]triazolo[4,3-a]quinazolin-5-yl(methyl)amino)phenol</u>

0900<chemistry id="chem1371" num="1371"><img file="EP4445902A2_D1374.tif" /></chemistry>

0901To a solution ofN-(3-methoxyphenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 9) (10 mg, 0.033 mmol) in 1,2-dichloroethane (1 mL) was added BBr₃ (0.098 mL, 0.098 mmol) at RT. The mixture was stirred for 1.5 h at 50 °C. The reaction mixture was concentrated in vacuo, and the residue was purified by prep-LCMS to afford the desired product: ¹ H-NMR (Methanol-d₄) δ 9.42 (s, 1H), 8.16 (dd, J = 8.3, 1.0 Hz, 1H), 7.75 (ddd, J = 8.5, 7.3, 1.3 Hz, 1H), 7.46 (dd, J = 8.4, 1.2 Hz, 1H), 7.27 - 7.18 (m, 2H), 6.79 - 6.72 (m, 3H), 6.67 (t, J = 2.2 Hz, 1H), 3.63 (s, 3H); LCMS(m/z) 292.2 [M+H]+.

<u>Example 51. <i>N</i>-butyl-<i>N</i>-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

0902<chemistry id="chem1372" num="1372"><img file="EP4445902A2_D1375.tif" /></chemistry>

0903To a solution of N-butylaniline (0.036 g, 0.24 mmol) in THF (10 mL) was added LDA (0.24 mL, 0.49 mmol, 2.0 M in THF) at 0 °C and the mixture was stirred at RT for 1 h, followed by the addition of 5-chloro-[1,2,4]triazolo[4,3-a]quinazoline (0.05 g, 0.24 mmol) at 0 °C, and the mixture was stirred at RT for 2 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over Na₂SO₄, filtered and evaporated under reduced pressure. The residue was purified by prep. HPLC to afford the desired product: ¹ H-NMR (500 MHz, DMSO-d₆) δ 9.61 (s, 1H), 8.27 (dd, J = 8.3, 1.1 Hz, 1H), 7.75 (ddd, J = 8.4, 6.9, 1.6 Hz, 1H), 7.45 - 7.34 (m, 2H), 7.30 - 7.14 (m, 5H), 4.11 - 4.03 (m, 2H), 1.70 (ddt, J = 9.4, 7.5, 3.6 Hz, 2H), 1.38 (h, J = 7.4 Hz, 2H), 0.90 (t, J = 7.4 Hz, 3H); LCMS(m/z) 318.2 [M+H]+.

<u>Example 52. N-(2-methoxyethyl)-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

0904<chemistry id="chem1373" num="1373"><img file="EP4445902A2_D1376.tif" /></chemistry>

(Step 1) Synthesis of <i>N</i>-(2-methoxyethyl)aniline

0905<chemistry id="chem1374" num="1374"><img file="EP4445902A2_D1377.tif" /></chemistry>

0906To a solution of aniline (1.0 g, 10.74 mmol) in <i>N</i>-methyl 2 pyrrolidone (10 mL) were added potassium carbonate (1.48 g, 10.74 mmol) and 1-bromo-2-methoxyethane (1.18 g, 8.59 mmol) at RT and the mixture was stirred at 80 °C for 5 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over Na₂SO₄, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 20% ethyl acetate/petroleum ether to give the desired product. LCMS: 152.13 (M+H).

(Step 2) Synthesis of <i>N</i>-(2-methoxyethyl)-<i>N</i>-phenyl-[1,2,4]triazolo[4,3-<i>a</i>]quinazolin-5-amine

0907To a solution of <i>N</i>-(2-methoxyethyl)aniline (0.014 g, 0.098 mmol) in THF (1 mL) was added LDA (0.1 mL, 0.20 mmol, 2.0 M in THF) at RT and the mixture was stirred at RT for 10 mins, followed by the addition of 5-chloro-[1,2,4]triazolo[4,3-a]quinazoline (0.02 g, 0.098 mmol) at RT, and the mixture was stirred at RT for 2 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over Na₂SO₄, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 5% methanol/dichloromethane to afford the desired product: ¹ H-NMR (500 MHz, DMSO-d₆) δ 9.62 (s, 1H), 8.28 (dt, J = 8.3, 0.9 Hz, 1H), 7.76 (ddd, J = 8.4, 5.5, 3.0 Hz, 1H), 7.42 - 7.34 (m, 2H), 7.34 - 7.15 (m, 5H), 4.24 (t, J = 5.9 Hz, 2H), 3.69 (t, J = 5.9 Hz, 2H), 3.26 (s, 3H); LCMS(m/z) 320.1 [M+H]+.

<u>Example 53. N-(cyclohexylmethyl)-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

0908<chemistry id="chem1375" num="1375"><img file="EP4445902A2_D1378.tif" /></chemistry>

(Step 1) Synthesis of <i>N</i>-(cyclohexylmethyl)aniline

0909<chemistry id="chem1376" num="1376"><img file="EP4445902A2_D1379.tif" /></chemistry>

0910To a mixture of aniline (2.0 g, 21.47 mmol) and cyclohexanecarbaldehyde (2.59 mL, 21.47 mmol) in acetonitrile (20 mL) were added acetic acid (5 mL, 85.9 mmol) at 0 °C and the mixture was stirred for 1 h at RT, followed by the addition of sodium triacetoxyborohydride (13.66 g, 64.42 mmol) at 0 °C and the mixture was then stirred for 3 h at RT. The reaction mixture was diluted with ice-water and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na₂SO₄, filtered and evaporated under reduced pressure. The residue was purified by silica gel chromatography, eluted with 2% ethyl acetate/petroleum ether to give the desired product. LCMS: 190.12 (M+H).

(Step 2) Synthesis of 2-chloro-<i>N</i>-(cyclohexylmethyl)-N-phenylquinazolin-4-amine

0911<chemistry id="chem1377" num="1377"><img file="EP4445902A2_D1380.tif" /></chemistry>

0912To a mixture of 2,4-dichloroquinazoline (0.525 g, 2.64 mmol) and <i>N-</i>(cyclohexylmethyl)aniline (0.501 g, 2.64 mmol) in DMF (5 mL) was added sodium hydroxide (0.211 g, 5.28 mmol) at 0 °C and the mixture was stirred for 72 h at RT. The reaction mixture was diluted with ice-water and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na₂SO₄, filtered and evaporated under reduced pressure. The residue was purified by silica gel chromatography, eluted with 5% ethyl acetate/petroleum ether to give the desired product. LCMS: 352.32 (M+H).

(Step 3) Synthesis of <i>N</i>-(cyclohexylmethyl)-2-hydrazinyl-<i>N</i>-phenylquinazolin-4-amine

0913<chemistry id="chem1378" num="1378"><img file="EP4445902A2_D1381.tif" /></chemistry>

0914To a stirred solution of 2-chloro-<i>N</i>-(cyclohexylmethyl)-<i>N</i>-phenylquinazolin-4-amine (0.24 g, 0.68 mmol) in EtOH (5 mL) was added hydrazine hydrate (0.068 g, 1.36 mmol) at RT and the mixture was stirred at 50 °C for 16 h. The reaction mixture was evaporated under reduced pressure to give the desired product. LCMS: 348.22 (M+H).

(Step 4) Synthesis of N-(cyclohexylmethyl)-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

0915A mixture of <i>N</i>-(cyclohexylmethyl)-2-hydrazinyl-N-phenylquinazolin-4-amine (0.215 g, 0.62 mmol) and triethyl orthoformate (2 mL) was stirred at 100 °C for 16 h. The reaction mixture was evaporated under reduced pressure, and the residue was purified by prep. HPLC to afford the desired product: ¹ H-NMR (DMSO-d₆) δ 9.62 (s, 1H), 8.28 (dd, J = 8.4, 1.2 Hz, 1H), 7.76 (ddd, J = 8.5, 7.2, 1.4 Hz, 1H), 7.39 - 7.16 (m, 7H), 3.94 (d, J = 7.2 Hz, 2H), 1.91 (d, J = 12.0 Hz, 1H), 1.80 (d, J = 8.5 Hz, 2H), 1.70 - 1.57 (m, 3H), 1.13 (q, J = 10.8 Hz, 5H); LCMS(m/z) 358.3 [M+H]+.

<u>Example 54. N-neopentyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

0916<chemistry id="chem1379" num="1379"><img file="EP4445902A2_D1382.tif" /></chemistry>

(Step 1) Synthesis of <i>N</i>-neopentylaniline

0917<chemistry id="chem1380" num="1380"><img file="EP4445902A2_D1383.tif" /></chemistry>

0918To a solution of aniline (0.5 g, 5.37 mmol) in acetonitrile (10 mL) were added pivalaldehyde (0.508 g, 5.91 mmol) and acetic acid (1.288 g, 21.48 mmol) at 0 °C and the mixture was stirred for 2 h at RT, followed by the addition of sodium triacetoxyborohydride (2.27 g, 10.74 mmol) at 0 °C, and the mixture was stirred for 2 h at RT. The reaction mixture was diluted with ice-water and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na₂SO₄, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 5% ethyl acetate/petroleum ether to give the desired product. LCMS: 164.09 (M+H).

(Step 2) Synthesis of <i>N</i>-Neopentyl-<i>N</i>-phenyl-[1,2,4]triazolo[4,3-<i>a</i>]quinazolin-5-amine

0919To a solution of <i>N</i>-neopentylaniline (0.024 g, 0.15 mmol) in THF (2 mL) was added LDA (0.09 mL, 0.18 mmol, 2.0M in THF) at 0 °C and the mixture was stirred at RT for 1 h, followed by the addition of 5-chloro-[1,2,4]triazolo[4,3-a]quinazoline (0.025 g, 0.12 mmol) at 0 °C, and the mixture was stirred at RT for 1 h. The reaction mixture was quenched with ice-water and extracted with ethyl acetate twice. The combined organic layer was washed successively with water and brine, dried over Na₂SO₄, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 4% methanol/dichloromethane to afford the desired product: ¹ H-NMR (DMSO-d₆) δ 9.70 (s, 1H), 8.33 (dd, J = 8.3, 1.1 Hz, 1H), 7.81 (ddd, J = 8.4, 7.2, 1.4 Hz, 1H), 7.51 (dd, J = 8.4, 1.3 Hz, 1H), 7.35 - 7.24 (m, 3H), 7.19 - 7.07 (m, 3H), 4.09 (s, 2H), 0.98 (s, 9H); LCMS(m/z) 332.2 [M+H]+.

<u>Example 55. N-(But-2-yn-1-yl)-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

0920<chemistry id="chem1381" num="1381"><img file="EP4445902A2_D1384.tif" /></chemistry>

(Step 1) Synthesis of <i>N-</i>(but-2-yn-1-yl)aniline

0921<chemistry id="chem1382" num="1382"><img file="EP4445902A2_D1385.tif" /></chemistry>

0922To a solution of aniline (0.3 g, 3.22 mmol) in acetonitrile (10 mL) was added potassium carbonate (0.445 g, 3.22 mmol) at RT and the mixture was stirred at RT for 10 min, followed by the addition of 1-bromobut-2-yne (0.385 g, 2.90 mmol) at RT and the mixture was stirred at RT for 16 h. The reaction mixture was diluted with cold-water and extracted with ethyl acetate. The combined organic layers were washed successively with water and brine, dried over Na₂SO₄, filtered and evaporated under reduced pressure. The residue was purified by silica gel chromatography and eluted with 30% ethyl acetate/petroleum ether to give the desired product. LCMS(m/z) 146.09 [M+H]⁺.

(Step 2) Synthesis of <i>N-</i>(but-2-yn-1-yl)-2-chloro-<i>N-</i>phenylquinazolin-4-amine

0923<chemistry id="chem1383" num="1383"><img file="EP4445902A2_D1386.tif" /></chemistry>

0924To a solution of <i>N-</i>(but-2-yn-1-yl)aniline (0.131 g, 0.9 mmol) in DMF (5 mL) was added 60% sodium hydride (0.036 g, 0.90 mmol) at 0 °C and the mixture was stirred at RT for 1 h, followed by the addition of 2,4-dichloroquinazoline (0.180 g, 0.90 mmol) at RT and the mixture was then stirred at 80 °C for 16 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed successively with water and brine solution, dried over Na₂SO₄, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with 25% ethyl acetate/petroleum ether to give the desired product. LCMS(m/z) 308.23 [M+H]⁺.

(Step 3) Synthesis of <i>N</i>-(But-2-yn-1-yl)-<i>N</i>-phenyl-[1,2,4]triazolo[4,3-<i>a</i>]quinazolin-5-amine

0925To a stirred solution of <i>N-</i>(but-2-yn-1-yl)-2-chloro-<i>N-</i>phenylquinazolin-4-amine (0.07 g, 0.23 mmol) in toluene (4 mL) was added formohydrazide (0.027 g, 0.46 mmol) at RT and the mixture was stirred under reflux for 16 h. The reaction mixture was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography, followed by prep. HPLC to afford the desired product: ¹ H-NMR (500 MHz, DMSO-d₆) δ 9.64 (s, 1H), 8.29 (dd, J = 8.2, 1.1 Hz, 1H), 7.78 (ddd, J = 8.5, 6.9, 1.7 Hz, 1H), 7.44 - 7.36 (m, 2H), 7.33 - 7.17 (m, 5H), 4.80 (q, J = 2.3 Hz, 2H), 1.71 (t, J = 2.3 Hz, 3H). LCMS(m/z) 314.1 [M+H]+.

<u>Example 56. <i>N</i>-(but-3-yn-1-yl)-<i>N-</i>phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

0926<chemistry id="chem1384" num="1384"><img file="EP4445902A2_D1387.tif" /></chemistry>

(Step 1) Synthesis of <i>N-</i>(but-3-yn-1-yl)aniline

0927<chemistry id="chem1385" num="1385"><img file="EP4445902A2_D1388.tif" /></chemistry>

0928To a stirred solution of aniline (0.5 g, 5.38 mmol) in acetonitrile (5 mL) were added 4-bromobut-1-yne (0.643 g, 4.84 mmol) and potassium carbonate (0.742 g, 5.38 mmol) at RT and the mixture was stirred at RT for 16 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na₂SO₄, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with 10% ethyl acetate/petroleum ether to give the desired product. LCMS(m/z) 146.09 [M+H]⁺.

(Step 2) Synthesis of <i>N</i>-(but-3-yn-1-yl)-<i>N</i>-phenyl-[1,2,4]triazolo[4,3-<i>a</i>]quinazolin-5-amine

0929To a solution of <i>N-</i>(but-3-yn-1-yl)aniline (0.021 g, 0.15 mmol) in THF (2 mL) was added LDA (0.09 mL, 0.18 mmol, 2.0M in THF) at 0 °C and the mixture was stirred at RT for 1 h, followed by the addition of 5-chloro-[1,2,4]triazolo[4,3-a]quinazoline (0.025 g, 0.12 mmol) at 0 °C, and the mixture then was stirred at RT for 1 h. The reaction mixture was quenched with ice-water and extracted with ethyl acetate twice. The combined organic layer was washed successively with water and brine, dried over Na₂SO₄, filtered and evaporated under reduced pressure. The residue was purified by prep. HPLC to afford the desired product: ¹ H-NMR (DMSO-d₆) δ 9.63 (s, 1H), 8.29 (d, J = 8.3 Hz, 1H), 7.77 (ddd, J = 8.5, 6.3, 2.3 Hz, 1H), 7.44 - 7.15 (m, 7H), 4.20 (t, J = 7.3 Hz, 2H), 2.91 (t, J = 2.6 Hz, 1H), 2.66 (td, J = 7.5, 2.7 Hz, 2H); LCMS(m/z) 314.2 [M+H]+.

<u>Example 57. N-methyl-N-(thiophen-2-yl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

0930<chemistry id="chem1386" num="1386"><img file="EP4445902A2_D1389.tif" /></chemistry>

(Step 1) Synthesis of 2-chloro-N-methyl-N-(thiophen-2-yl)quinazolin-4-amine

0931<chemistry id="chem1387" num="1387"><img file="EP4445902A2_D1390.tif" /></chemistry>

0932To a stirred solution of 2,4-dichloroquinazoline (0.280 g, 1.40 mmol) in DMF (4 mL) was added 60% sodium hydride (0.056 g, 1.40 mmol) at 0 °C, and the mixture was stirred for 1 h at RT, followed by the addition of N-methylthiophen-2-amine hydrochloride (0.209 g, 1.40 mmol) at 0 °C and the mixture was stirred for 16 h at RT. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with ice-water and extracted with ethyl acetate twice. The combined organic layers were washed successively with water and brine, dried over Na₂SO₄, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 15% ethyl acetate/ petroleum ether to give the desired product. LCMS(m/z) 276.04 [M+H]⁺.

(Step 2) Synthesis of N-methyl-N-(thiophen-2-yl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

0933To a stirred solution of 2-chloro-N-methyl-N-(thiophen-2-yl)quinazolin-4-amine (0.06 g, 0.22 mmol) in toluene (4 mL) was added formohydrazide (0.026 g, 0.44 mmol) at RT and the mixture was stirred under reflux condition for 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with MeOH/ THF and evaporated under reduced pressure. The residue was diluted with AcOEt, and washed with brine, dried over Na₂SO₄, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with 4% methanol/ dichloromethane to afford the desired product: ¹ H-NMR (500 MHz, DMSO-d₆) δ 9.65 (s, 1H), 8.32 (dd, J = 8.5, 1.2 Hz, 1H), 7.83 (ddd, J = 8.5, 7.3, 1.3 Hz, 1H), 7.59 (dd, J = 8.4, 1.3 Hz, 1H), 7.44 - 7.27 (m, 2H), 7.03 - 6.89 (m, 2H), 3.57 (s, 3H); LCMS(m/z) 282.1 [M+H]+.

<u>Example 58. 2-([1,2,4]triazolo[4,3-a]quinazolin-5-yl(methyl)amino)benzoic acid</u>

0934<chemistry id="chem1388" num="1388"><img file="EP4445902A2_D1391.tif" /></chemistry>

0935To a solution of 5-chloro-[1,2,4]triazolo[4,3-a]quinazoline (600 mg, 3.22 mmol), BrOP (1376 mg, 3.55 mmol) and DBU (589 mg, 3.87 mmol) in Acetonitrile (10.0 ml) was added to methyl 2-(methylamino)benzoate (0.518 mL, 3.55 mmol) at RT. The mixture was stirred overnight at 80 °C. The reaction mixture was concentrated in vacuo, and the residue was purified by column chromatography (Si-column, CHCl₃: MeOH = 100 : 0 - 95 : 5) to give a crude product. The crude compound was further purified by prep-LCMS to afford the desired product: ¹ H-NMR (DMSO-d₆) δ 11.50 (s, 1H), 9.62 (s, 1H), 8.88 (d, J = 8.3 Hz, 1H), 8.40 (d, J = 8.2 Hz, 1H), 8.35 (d, J = 8.2 Hz, 1H), 8.08 (dd, J = 8.0, 1.6 Hz, 1H), 8.04 (t, J = 7.9 Hz, 1H), 7.81 (q, J = 8.3, 7.9 Hz, 2H), 7.30 (t, J = 7.5 Hz, 1H), 3.90 (s, 3H); LCMS(m/z) 320.2 [M+H]+.

<u>Example 59. N-methyl-8-nitro-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

0936<chemistry id="chem1389" num="1389"><img file="EP4445902A2_D1392.tif" /></chemistry>

(Step 1) Synthesis of 7-nitroquinazoline-2,4(1H,3H)-dione

0937<chemistry id="chem1390" num="1390"><img file="EP4445902A2_D1393.tif" /></chemistry>

0938A mixture of 2-amino-4-nitrobenzoic acid (3.34 g, 18.3 mmol) and urea (3.30 g, 55 mmol) in NMP (10 mL) was stirred for 5.5h at 160 °C. The reaction mixture was cooled to RT and diluted with water. The resulting precipitates were collected and washed with water, EtOH to give the desired product. LCMS(m/z) 206.01 [M-H]⁺.

(Step 2) Synthesis of 2,4-dichloro-7-nitroquinazoline

0939<chemistry id="chem1391" num="1391"><img file="EP4445902A2_D1394.tif" /></chemistry>

0940A mixture of 7-nitroquinazoline-2,4(1H,3H)-dione (500 mg, 2.414 mmol) and phosphoryl trichloride (10 mL, 2.414 mmol) was stirred at 100 °C for 6 h. The reaction was monitored by LCMS (quenched by MeOH). The reaction mixture was cooled to RT, and poured slowly over ice. The resulting solids were collected and dried. The obtained solids were used in the next step without further purification.

(Step 3) Synthesis of 2-chloro-N-methyl-7-nitro-N-phenylquinazolin-4-amine

0941<chemistry id="chem1392" num="1392"><img file="EP4445902A2_D1395.tif" /></chemistry>

0942To a solution of 2,4-dichloro-7-nitroquinazoline (1.5 g, 6.15 mmol) in DMF (30.7 mL) were added N-methylaniline (0.659 g, 6.15 mmol) and sodium hydride (0.148 g, 6.15 mmol), and the mixture was stirred at RT for 1 h. The mixture was diluted with AcOEt, washed successively with water and brine, and dried over Na₂SO₄. The organic layer was concentrated in vacuo. The resulting residue was used in the next step without further purification. LCMS(m/z) 315.03 [M+H]⁺.

(Step 4) Synthesis of 2-hydrazinyl-N-methyl-7-nitro-N-phenylquinazolin-4-amine

0943<chemistry id="chem1393" num="1393"><img file="EP4445902A2_D1396.tif" /></chemistry>

0944The resulting 2-chloro-N-methyl-7-nitro-N-phenylquinazolin-4-amine (1.2 g, 3.81 mmol) and hydrazine hydrate (0.191 g, 3.81 mmol) in ethanol (19.06 mL) was stirred at RT for 1 h. The mixture was diluted with AcOEt, washed successively with water and brine, and dried over Na₂SO₄. The organic layer was concentrated in vacuo. The resulting residue was used in the next step without further purification. LCMS(m/z) 311.08 [M+H]⁺.

(Step 5) Synthesis of N-methyl-8-nitro-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

0945A mixture of 2-hydrazinyl-N-methyl-7-nitro-N-phenylquinazolin-4-amine (800 mg, 2.58 mmol) and triethoxymethane (10 mL, 2.58 mmol) was stirred at 100 °C overnight. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (Si-column, CHCl₃: MeOH = 10:0 - 9:1) to afford the desired product: ¹ H-NMR (DMSO-d₆) δ 9.89 (s, 1H), 9.22 (d, J = 2.3 Hz, 1H), 7.99 (dd, J = 9.1, 2.3 Hz, 1H), 7.46 (d, J = 9.1 Hz, 1H), 7.43 - 7.38 (m, 2H), 7.37 - 7.32 (m, 2H), 7.32 - 7.25 (m, 1H), 3.56 (s, 3H); LCMS(m/z) 321.2.

<u>Example 60. N-(2,6-difluorophenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

0946<chemistry id="chem1394" num="1394"><img file="EP4445902A2_D1397.tif" /></chemistry>

0947To a solution of 5-chloro-[1,2,4]triazolo[4,3-a]quinazoline (50 mg, 0.269 mmol), BrOP (115 mg, 0.295 mmol) and DBU (82 mg, 0.537 mmol) in acetonitrile (2 mL) was added 2,6-difluoro-N-methylaniline hydrochloride (48.2 mg, 0.269 mmol) at RT. The mixture was stirred for 2h at 80 °C. The reaction mixture was subjected to solid phase extraction (washed with MeOH, then eluted with NH₃ in MeOH) using Bond Elut SCX cartridge (Agilent), and the collected fractions were concentrated in vacuo. Then, the residue was purified by prep-LCMS to afford the desired product: ¹ H-NMR (DMSO-d₆) δ 9.66 (s, 1H), 8.36 (dt, J = 8.4, 0.8 Hz, 1H), 7.87 (ddd, J = 8.4, 7.0, 1.6 Hz, 1H), 7.49 (tt, J = 8.0, 6.4 Hz, 1H), 7.38 - 7.24 (m, 4H), 3.49 (s, 3H); LCMS(m/z) 312.1 [M+H]+.

<u>Example 61. 5-(2,3,4,5-tetrahydrobenzo[b]azepin-1-yl)-[1,2,4]triazolo[4,3-a]quinazoline</u>

0948<chemistry id="chem1395" num="1395"><img file="EP4445902A2_D1398.tif" /></chemistry>

(Step 1) Synthesis of 1-(2-chloroquinazolin-4-yl)-2,3,4,5-tetrahydro-1<i>H</i>-benzo[<i>b</i>]azepine

0949<chemistry id="chem1396" num="1396"><img file="EP4445902A2_D1399.tif" /></chemistry>

0950To a stirred mixture of 2,4-dichloroquinazoline (0.15 g, 0.75 mmol) and 2,3,4,5-tetrahydro-1<i>H</i>-benzo[b]azepine (0.11 g, 0.75 mmol) in DMF (10 mL) was added sodium hydroxide (0.060 g, 1.5 mmol) at RT and the mixture was then stirred at the same temperature for 16 h. The reaction mixture was diluted with ice-water and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na₂SO₄, filtered and evaporated under reduced pressure to give the desired product. LCMS: 310.13 (M+H).

(Step 2) Synthesis of 1-(2-Hydrazinylquinazolin-4-yl)-2,3,4,5-tetrahydro-1<i>H-</i>benzo[<i>b</i>]azepine

0951<chemistry id="chem1397" num="1397"><img file="EP4445902A2_D1400.tif" /></chemistry>

0952To a stirred solution of 1-(2-chloroquinazolin-4-yl)-2,3,4,5-tetrahydro-1<i>H-</i>benzo[b]azepine (crude, 0.1 g, 0.32 mmol) in EtOH (10 mL) was added hydrazine hydrate (0.032 g, 0.65 mmol) at RT and the mixture was stirred at 70 °C for 16 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed successively with water and brine, dried over Na₂SO₄, filtered and evaporated under reduced pressure to give the desired product. LCMS: 306.21 (M+H).

(Step 3) Synthesis of 5-(2,3,4,5-tetrahydrobenzo[b]azepin-1-yl)-[1,2,4]triazolo[4,3-<i>a</i>]quinazoline

0953The mixture of 1-(2-hydrazinylquinazolin-4-yl)-2,3,4,5-tetrahydro-1<i>H-</i>benzo[<i>b</i>]azepine (0.1 g, 0.33 mmol) and triethyl orthoformate (0.145 g, 0.99 mmol) was stirred at 80 °C for 16 h. The reaction mixture was evaporated under reduced pressure, and the residue was purified by prep. HPLC to afford the desired product: ¹ H-NMR (DMSO-d₆) δ 9.57 (s, 1H), 8.26 (dd, J = 8.4, 1.1 Hz, 1H), 7.74 (ddd, J = 8.4, 7.2, 1.3 Hz, 1H), 7.46 (dd, J = 7.5, 1.5 Hz, 1H), 7.29 - 7.03 (m, 3H), 6.89 (ddd, J = 29.0, 8.1, 1.3 Hz, 2H), 4.44 - 3.57 (m, 2H), 3.01 (t, J = 5.8 Hz, 2H), 1.91 - 1.59 (m, 4H); LCMS(m/z) 316.2 [M+H]+.

<u>Example 62. 7-bromo-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

0954<chemistry id="chem1398" num="1398"><img file="EP4445902A2_D1401.tif" /></chemistry>

(Step 1) Synthesis of 6-bromo-2-chloro-N-methyl-N-phenylquinazolin-4-amine

0955<chemistry id="chem1399" num="1399"><img file="EP4445902A2_D1402.tif" /></chemistry>

0956To a solution of N-methylaniline (38.6 mg, 0.360 mmol) and NaH (14.39 mg, 0.360 mmol) in DMF (1.8 mL) was added 6-bromo-2,4-dichloroquinazoline (100 mg, 0.360 mmol) at RT. The mixture was stirred for 1h at RT. The reaction mixture was diluted with AcOEt, washed successively with water and brine, and dried over Na₂SO₄. The organic layer was concentrated in vacuo. The resulting residue was used in the next step without further purification. LCMS(m/z) 348.27 [M+H]⁺.

(Step 2) Synthesis of 6-bromo-2-hydrazinyl-N-methyl-N-phenylquinazolin-4-amine

0957<chemistry id="chem1400" num="1400"><img file="EP4445902A2_D1403.tif" /></chemistry>

0958The resulting 6-bromo-2-chloro-N-methyl-N-phenylquinazolin-4-amine (134 mg, 0.384 mmol) and hydrazine hydrate (38.5 mg, 0.769 mmol) in EtOH (3 mL) was stirred for 2h at 50 °C. The reaction mixture was cooled to RT, and then diluted with EtOAc. The solution was washed successively with water and brine, and dried over Na₂SO₄, and concentrated in vacuo. The resulting crude material was used in the next step without purification. LCMS(m/z) 346.10 [M+H]⁺.

(Step 3) Synthesis of 7-bromo-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

0959The resulting 6-bromo-2-hydrazinyl-N-methyl-N-phenylquinazolin-4-amine (136 mg, 0.158 mmol) and triethoxymethane (3 mL) was stirred overnight at 100 °C. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (Si-column, CHCl₃: MeOH = 100 : 0 - 95 : 5) to afford the desired product: ¹ H-NMR (Methanol-d₄) δ 9.42 (s, 1H), 8.11 (d, J = 8.8 Hz, 1H), 7.88 (dd, J = 8.8, 2.1 Hz, 1H), 7.53 - 7.28 (m, 6H), 4.99 - 4.77 (m, 3H); LCMS(m/z) 354.1 [M+H]+.

<u>Example 63. N-methyl-N-phenyl-8-(pyridin-3-yl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

0960<chemistry id="chem1401" num="1401"><img file="EP4445902A2_D1404.tif" /></chemistry>

0961A mixture of 8-bromo-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 28) (20 mg, 0.056 mmol), K₃PO₄ (23.97 mg, 0.113 mmol), Pd(OAc)₂ (2.54 mg, 0.011 mmol), tricyclohexylphosphine (3.17 mg, 0.011 mmol) and pyridin-3-ylboronic acid (17.35 mg, 0.141 mmol) in dioxane/water (0.28 ml) was heated at 120 °C for 2 h. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (Si-column, CHCl₃: MeOH = 10:0 - 9: 1) to afford the desired product: ¹ H-NMR (Methanol-d₄) δ 9.54 (d, J = 3.5 Hz, 1H), 8.90 (d, J = 2.4 Hz, 1H), 8.61 - 8.54 (m, 1H), 8.47 - 8.40 (m, 1H), 8.23 - 8.14 (m, 1H), 7.58 - 7.37 (m, 4H), 7.36 - 7.21 (m, 4H), 3.64 (d, J = 3.3 Hz, 3H); LCMS(m/z) 353.2 [M+H]+.

<u>Example 64. 8-iodo-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

0962<chemistry id="chem1402" num="1402"><img file="EP4445902A2_D1405.tif" /></chemistry>

(Step 1) Synthesis of 8-(hydroxyamino)-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a] quinazolin-5-amine

0963<chemistry id="chem1403" num="1403"><img file="EP4445902A2_D1406.tif" /></chemistry>

0964A mixture ofN-methyl-8-nitro-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 59) (30 mg, 0.094 mmol) and Pd/C (30 mg, 0.282 mmol) in EtOH (3 mL) was stirred for 3h at RT under H2 atmosphere. The reaction mixture was filtered through a bed of Celite and concentrated in vacuo to give the desired product.

(Step 2) Synthesis of 8-iodo-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

0965To a solution of 8-(hydroxyamino)-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (25 mg, 0.082 mmol) and diiodomethane (0.033 ml, 0.408 mmol) in THF (1 mL) was added tert-butyl nitrite (0.041 ml, 0.343 mmol) at RT. The mixture was stirred for 2 h at 60 °C. The reaction mixture was concentrated in vacuo, and the residue was purified by column chromatography (Si-column, CHCl₃: MeOH =100 : 0 - 95 : 5) to give the crude product. The crude compound was further purified by prep-LCMS to afford the desired product: ¹H-NMR (Methanol-d₄) δ 9.43 (s, 1H), 8.64 (d, J = 1.6 Hz, 1H), 7.49 (dd, J = 8.8, 1.6 Hz, 1H), 7.46 - 7.38 (m, 2H), 7.36 - 7.30 (m, 1H), 7.30 - 7.23 (m, 2H), 6.97 (d, J = 8.8 Hz, 1H), 3.63 (s, 3H); LCMS(m/z) 401.7 [M+H]+.

<u>Example 65. N-(4-bromophenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

0966<chemistry id="chem1404" num="1404"><img file="EP4445902A2_D1407.tif" /></chemistry>

0967To a solution ofN-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 1) (30 mg, 0.109 mmol) in DMF (0.55 mL) was added NBS (5.82 mg, 0.033 mmol), and the mixture was stirred for 30 min at 0 °C. Then the mixture was added another NBS (5.82 mg, 0.033mmol), and stirred for 1 h at 0 °C. The reaction mixture was subjected to solid phase extraction (washed with MeOH, then eluted with NH₃ in MeOH) using Bond Elut SCX cartridge (Agilent), and the collected fractions were concentrated in vacuo. The residue was purified by prep-LCMS to afford the desired product: ¹ H-NMR (Methanol-d₄) δ 9.45 (s, 1H), 8.17 (dd, J = 8.4, 1.0 Hz, 1H), 7.77 (ddd, J = 8.5, 7.2, 1.4 Hz, 1H), 7.61 - 7.50 (m, 2H), 7.37 (dd, J = 8.4, 1.2 Hz, 1H), 7.31 - 7.16 (m, 3H), 3.63 (s, 3H); LCMS(m/z) 354.3.

<u>Example 66. N-5-methyl-N5-phenyl-[1,2,4]triazolo[4,3-a]quinazoline-5,8-diamine</u>

0968<chemistry id="chem1405" num="1405"><img file="EP4445902A2_D1408.tif" /></chemistry>

0969A mixture ofN-methyl-8-nitro-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 59) (429 mg, 1.339 mmol) and Pd/C (20 mg) in ethanol (6.7 mL) was stirred at 60 °C under H2 atmosphere overnight. Pd/C was removed by filtration and, the filtrate was purified by column chromatography (Si-column, CHCl₃: MeOH = 10:0 - 9: 1) to afford the desired product: ¹ H-NMR (DMSO-d₆) δ 9.28 (s, 1H), 7.41 - 7.31 (m, 2H), 7.24 - 7.15 (m, 3H), 7.02 (d, J = 2.2 Hz, 1H), 6.92 (d, J = 9.1 Hz, 1H), 6.41 (s, 2H), 6.35 (dd, J = 9.1, 2.2 Hz, 1H), 3.47 (s, 3H); LCMS(m/z) 291.2 [M+H]+.

<u>Example 67. N,6-dimethyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

0970<chemistry id="chem1406" num="1406"><img file="EP4445902A2_D1409.tif" /></chemistry>

(Step 1) Synthesis of 5-methylquinazoline-2,4(1H,3H)-dione

0971<chemistry id="chem1407" num="1407"><img file="EP4445902A2_D1410.tif" /></chemistry>

0972To a suspension of 2-amino-6-methylbenzoic acid (1.5 g, 9.92 mmol) in water (10 mL) was added acetic acid (1 mL), and the suspension was heated to 35 °C. To this suspension, a freshly prepared solution of potassium cyanate (2.012 g, 24.81 mmol) in water (2 mL) was added dropwise over the period of 1 h. The mixture was stirred for 1 h at 40 °C. NaOH (20 g) was added portion-wise to the reaction mixture by maintaining the internal temperature below 50°C, and the mixture was further stirred for 2 h. The precipitates were collected by filtration to give the desired product. LCMS(m/z) 177.16 [M+H]+.

(Step 2) Synthesis of 2,4-dichloro-5-methylquinazoline

0973<chemistry id="chem1408" num="1408"><img file="EP4445902A2_D1411.tif" /></chemistry>

0974A solution of 5-methylquinazoline-2,4(1H,3H)-dione (300 mg, 1.703 mmol) in N,N-dimethylaniline (0.5 mL, 1.703 mmol) and POCl₃ (3 mL) was stirred for 3 h at 110°C. The reaction mixture was cooled to RT, diluted with EtOAc, washed successively with water and brine, dried over Na₂SO₄, and concentrated in vacuo. The residue was purified by column chromatography (Si-column, hexane : AcOEt = 100 : 0 - 80 : 20) to give the desired product.

(Step 3) Synthesis of 2-chloro-N,5-dimethyl-N-phenylquinazolin-4-amine

0975<chemistry id="chem1409" num="1409"><img file="EP4445902A2_D1412.tif" /></chemistry>

0976To a mixture of N-methylaniline (58.1 mg, 0.542 mmol) and sodium hydride (21.68 mg, 0.542 mmol) in DMF (5 mL) was added 2,4-dichloro-5-methylquinazoline (105 mg, 0.493 mmol) at RT. The mixture was stirred overnight at RT. The reaction mixture was diluted with EtOAc, washed successively with NH₄Cl(aq) and brine, dried over Na₂SO₄, and concentrated in vacuo. The residue was purified by column chromatography (Si-column, hexane : AcOEt = 100 : 0 - 90 : 10) to give the desired product. LCMS(m/z) 284.8 [M+H]+.

(Step 4) Synthesis of 2-hydrazinyl-N,5-dimethyl-N-phenylquinazolin-4-amine

0977<chemistry id="chem1410" num="1410"><img file="EP4445902A2_D1413.tif" /></chemistry>

0978A solution of 2-chloro-N,5-dimethyl-N-phenylquinazolin-4-amine (80 mg, 0.282 mmol) in hydrazine hydrate (1 mL) and EtOH (2 mL) was stirred for 1.5h at 50 °C. The reaction mixture was diluted with EtOAc, washed successively with water and brine, dried over Na₂SO₄, and concentrated in vacuo. The residue was used for the next step without purification. LCMS(m/z) 280.23 [M+H]+.

(Step 5) Synthesis of N,6-dimethyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

0979A solution of crude 2-hydrazinyl-N,5-dimethyl-N-phenylquinazolin-4-amine in triethoxymethane (1 mL) was stirred for 3 h at 100 °C. The reaction mixture was concentrated in vacuo, and the residue was purified by column chromatography (Si-column, CHCl₃: MeOH = 100 : 0 - 95 : 5) to afford the crude product. The crude compound was further purified by prep LCMS to afford the desired product: ¹ H-NMR (Methanol-d₄) δ 9.45 (s, 1H), 8.04 (ddd, J = 8.2, 1.3, 0.7 Hz, 1H), 7.70 (t, J = 7.9 Hz, 1H), 7.25 - 7.13 (m, 3H), 7.13 - 7.03 (m, 1H), 6.97 - 6.88 (m, 2H), 3.67 (s, 3H), 2.30 (s, 3H); LCMS(m/z) 290.2 [M+H]+.

<u>Example 68. N-(5-(methyl(phenyl)amino)-[1,2,4]triazolo[4,3-a]quinazolin-8-yl)acetamide</u>

0980<chemistry id="chem1411" num="1411"><img file="EP4445902A2_D1414.tif" /></chemistry>

0981A solution ofN5-methyl-N5-phenyl-[1,2,4]triazolo[4,3-a]quinazoline-5,8-diamine (Example 66) (50 mg, 0.172 mmol) and acetyl chloride (0.037 mL, 0.517 mmol) in DMA (1 mL) was stirred for 4h at 80°C. The reaction mixture was purified by column chromatography (Si-column, CHCl₃: MeOH = 10 : 0 - 95 : 5) and further purified by prep-LCMS to afford the desired product: ¹ H NMR (DMSO-d₆) δ 10.61 (s, 1H), 9.53 (s, 1H), 8.50 (d, J = 1.9 Hz, 1H), 7.42 (tt, J = 7.6, 2.1 Hz, 2H), 7.36 - 7.26 (m, 3H), 7.19 - 7.05 (m, 2H), 3.56 (s, 3H), 2.11 (s, 3H); LCMS(m/z) 333.2 [M+H]+.

<u>Example 69. N5,N8-dimethyl-N5-phenyl-[1,2,4]triazolo[4,3-a]quinazoline-5,8-diamine</u>

0982<chemistry id="chem1412" num="1412"><img file="EP4445902A2_D1415.tif" /></chemistry>

0983To a solution of N5-methyl-N5-phenyl-[1,2,4]triazolo[4,3-a]quinazoline-5,8-diamine (Example 66) (50 mg, 0.172 mmol) and AcOH (0.039 mL, 0.689 mmol) in CH₃CN (2 mL) was added formaldehyde (0.021 mL, 0.775 mmol) at RT. The mixture was stirred for 30 min at RT. Then, NaCNBH₄ (64.9 mg, 1.033 mmol) was added to the mixture at RT, and the mixture was stirred overnight at 60°C. The reaction mixture was subjected to solid phase extraction (washed with MeOH, then eluted with NH₃ in MeOH) using Bond Elut SCX cartridge (Agilent), and the collected fractions were concentrated in vacuo. The residue was purified by prep-LCMS to afford the desired product: ¹ H-NMR (DMSO-d₆) δ 9.50 (s, 1H), 7.40 - 7.30 (m, 2H), 7.23 - 7.14 (m, 3H), 7.03 (d, J = 2.3 Hz, 1H), 6.98 (q, J = 4.8 Hz, 1H), 6.91 (d, J = 9.2 Hz, 1H), 6.38 (dd, J = 9.3, 2.3 Hz, 1H), 3.47 (s, 3H), 2.81 (d, J = 4.9 Hz, 3H); LCMS(m/z) 305.0 [M+H]+.

<u>Example 70. N-methyl-N-(p-tolyl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

0984<chemistry id="chem1413" num="1413"><img file="EP4445902A2_D1416.tif" /></chemistry>

0985To a solution of 5-chloro-[1,2,4]triazolo[4,3-a]quinazoline (50 mg, 0.269 mmol), BrOP (115 mg, 0.295 mmol) and DBU (49.1 mg, 0.322 mmol) in acetonitrile (1 mL) was added to N,4-dimethylaniline (35.8 mg, 0.295 mmol) at RT. The mixture was stirred for 2 h at 50 °C. The reaction mixture was subjected to solid phase extraction (washed with MeOH, then eluted with NH₃ in MeOH) using Bond Elut SCX cartridge (Agilent), and the collected fractions were concentrated in vacuo. Then, the residue was purified by prep-LCMS to afford the desired product: ¹ H NMR (DMSO-d₆) δ 9.61 (s, 1H), 8.34 - 8.24 (m, 1H), 7.76 (ddd, J = 8.4, 7.1, 1.5 Hz, 1H), 7.35 - 7.14 (m, 6H), 3.50 (s, 3H), 2.30 (s, 3H); LCMS(m/z) 290.2 [M+H]+.

<u>Example 71. N-(4-chlorophenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

0986<chemistry id="chem1414" num="1414"><img file="EP4445902A2_D1417.tif" /></chemistry>

0987To a solution of 5-chloro-[1,2,4]triazolo[4,3-a]quinazoline (50 mg, 0.269 mmol), BrOP (115 mg, 0.295 mmol) and DBU (49.1 mg, 0.322 mmol) in acetonitrile (2 mL) was added to 4-chloro-N-methylaniline (41.8 mg, 0.295 mmol) at RT. The mixture was stirred for 2h at 50 °C. The reaction mixture was subjected to solid phase extraction (washed with MeOH, then eluted with NH₃ in MeOH) using Bond Elut SCX cartridge (Agilent), and the collected fractions were concentrated in vacuo. Then, the mixture was purified by prep-LCMS to afford the desired product: ¹ H NMR (Methanol-d₄) δ 9.44 (s, 1H), 8.16 (ddd, J = 8.4, 1.2, 0.5 Hz, 1H), 7.76 (ddd, J = 8.5, 7.2, 1.4 Hz, 1H), 7.45 - 7.38 (m, 2H), 7.36 (ddd, J = 8.5, 1.4, 0.5 Hz, 1H), 7.31 - 7.17 (m, 3H), 3.63 (s, 3H); LCMS(m/z) 310.0 [M+H]+.

<u>Example 72. 8-(furan-3-yl)-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

0988<chemistry id="chem1415" num="1415"><img file="EP4445902A2_D1418.tif" /></chemistry>

0989A mixture of 8-bromo-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 28) (15 mg, 0.042 mmol), K₃PO₄ (27.0 mg, 0.127 mmol), Pd(OAc)₂ (1.901 mg, 8.47 µmol), tricyclohexylphosphine (2.375 mg, 8.47 µmol) and 3-furylboronic Acid (13.68 mg, 0.040 mmol) in dioxane/water (0.21 mL) was heated at 120 °C for 2 h. The reaction mixture was subjected to solid phase extraction (washed with MeOH, then eluted with NH₃ in MeOH) using Bond Elut SCX cartridge (Agilent), and the collected fractions were concentrated in vacuo. The residue was purified by column chromatography (Si-column, CHCl₃ : MeOH = 10:0 - 9:1) to afford the desired product: ¹ H-NMR (CDCl₃) δ 9.02 (s, 1H), 7.91 - 7.83 (m, 2H), 7.54 (t, J = 1.7 Hz, 1H), 7.44 - 7.32 (m, 2H), 7.35 - 7.14 (m, 5H), 6.79 - 6.73 (m, 1H), 3.68 (s, 3H); LCMS(m/z) 342.0 [M+H]+.

<u>Example 73. N-methyl-N-phenyl-8-(thiophen-3-yl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

0990<chemistry id="chem1416" num="1416"><img file="EP4445902A2_D1419.tif" /></chemistry>

0991A mixture of 8-bromo-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 28) (15 mg, 0.042 mmol), K₃PO₄ (27.0 mg, 0.127 mmol, Pd(OAc)₂ (1.901 mg, 8.47 µmol), tricyclohexylphosphine (2.375 mg, 8.47 µmol) and thiophen-3-ylboronic acid (13.55 mg, 0.106 mmol) in dioxane/water (0.21 mL) was heated at 120 °C for 2 h. The reaction mixture was subjected to solid phase extraction (washed with MeOH, then eluted with NH₃ in MeOH) using Bond Elut SCX cartridge (Agilent), and the collected fractions were concentrated in vacuo. The residue was purified by column chromatography (Si-column, CHCl₃: MeOH = 10:0 - 9: 1) to afford the desired product: ¹ H-NMR (CDCl₃) δ 9.00 (s, 1H), 7.94 (d, J = 1.6 Hz, 1H), 7.64 (dd, J = 2.9, 1.4 Hz, 1H), 7.48 - 7.36 (m, 4H), 7.32 - 7.23 (m, 3H), 7.21 - 7.16 (m, 2H), 3.67 (s, 3H); LCMS(m/z) 358.1 [M+H]+.

<u>Example 74. N-methyl-N-phenyl-8-(1H-pyrazol-3-yl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

0992<chemistry id="chem1417" num="1417"><img file="EP4445902A2_D1420.tif" /></chemistry>

0993A mixture of 8-bromo-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 28) (15 mg, 0.042 mmol), K₃PO₄ (27.0 mg, 0.127 mmol), Pd(OAc)₂ (1.901 mg, 8.47 µmol), tricyclohexylphosphine (2.375 mg, 8.47 µmol) and (1H-pyrazol-3-yl)boronic acid (11.85 mg, 0.106 mmol) in dioxane/water (0.21 mL) was heated at 120 °C for 1 h. The reaction mixture was subjected to solid phase extraction (washed with MeOH, then eluted with NH₃ in MeOH) using Bond Elut SCX cartridge (Agilent), and the collected fractions were concentrated in vacuo. The residue was purified by column chromatography (Si-column, CHCl₃: MeOH = 10:0 - 9:1) to afford the desired product: ¹ H NMR (DMSO-d₆) δ 13.21 (s, 1H), 9.74 (s, 1H), 8.63 (d, J = 1.6 Hz, 1H), 7.91 - 7.85 (m, 1H), 7.66 (dd, J = 8.8, 1.6 Hz, 1H), 7.44 - 7.35 (m, 2H), 7.37 - 7.21 (m, 4H), 6.97 (t, J = 2.1 Hz, 1H), 3.55 (s, 3H); LCMS(m/z) 342.0 [M+H]+.

<u>Example 75. N-methyl-N-phenyl-7-(pyridin-4-yl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

0994<chemistry id="chem1418" num="1418"><img file="EP4445902A2_D1421.tif" /></chemistry>

0995A mixture of 7-bromo-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 62) (15 mg, 0.042 mmol), K₃PO₄ (27.0 mg, 0.127 mmol), Pd(OAc)₂ (1.901 mg, 8.47 µmol), tricyclohexylphosphine (2.375 mg, 8.47 µmol) and pyridin-4-ylboronic acid (13.01 mg, 0.106 mmol) in dioxane/water (0.21 mL) was heated at 120 °C for 1 h. The reaction mixture was subjected to solid phase extraction (washed with MeOH, then eluted with NH₃ in MeOH) using Bond Elut SCX cartridge (Agilent), and the collected fractions were concentrated in vacuo. The residue was purified by column chromatography (Si-column, CHCl₃ : MeOH = 10:0 - 9:1) to afford the desired product: ¹ H NMR (Methanol-d₄) δ 9.49 (s, 1H), 8.53 - 8.47 (m, 2H), 8.32 (d, J = 8.6 Hz, 1H), 8.16 (dd, J = 8.6, 2.0 Hz, 1H), 7.68 (d, J = 1.9 Hz, 1H), 7.60 - 7.50 (m, 2H), 7.50 - 7.37 (m, 3H), 7.21 - 7.13 (m, 2H), 3.72 (s, 3H); LCMS(m/z) 353.2 [M+H]+.

<u>Example 76. N5,N8,N8-trimethyl-N5-phenyl-[1,2,4]triazolo[4,3-a]quinazoline-5,8-diamine</u>

0996<chemistry id="chem1419" num="1419"><img file="EP4445902A2_D1422.tif" /></chemistry>

0997To a mixture of N5-methyl-N5-phenyl-[1,2,4]triazolo[4,3-a]quinazoline-5,8-diamine (Example 66) (30 mg, 0.103 mmol) and NaH (12.4 mg, 0.310 mmol) in DMF (2 mL) was added MeI (0.039 mL, 0.620 mmol) at RT. The mixture was stirred for 1.5 h at RT. The reaction mixture was quenched with water. The reaction mixture was subjected to solid phase extraction (washed with MeOH, then eluted with NH₃ in MeOH) using Bond Elut SCX cartridge (Agilent), and the collected fractions were concentrated in vacuo. The residue was purified by prep-LCMS to afford the desired product: ¹ H NMR (Methanol-d₄) δ 9.41 (s, 1H), 7.45 - 7.36 (m, 2H), 7.31 - 7.19 (m, 3H), 7.10 (d, J = 2.6 Hz, 1H), 7.07 (d, J = 9.5 Hz, 1H), 6.52 (dd, J = 9.5, 2.6 Hz, 1H), 3.60 (s, 3H), 3.10 (s, 6H); LCMS(m/z) 319.0 [M+H]+.

<u>Example 77. N-(cyclobutylmethyl)-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

0998<chemistry id="chem1420" num="1420"><img file="EP4445902A2_D1423.tif" /></chemistry>

(Step 1) Synthesis of <i>N</i>-(cyclobutylmethyl)aniline

0999<chemistry id="chem1421" num="1421"><img file="EP4445902A2_D1424.tif" /></chemistry>

1000To a mixture of aniline (0.2 g, 2.15 mmol) and cyclobutanecarbaldehyde (0.180 g, 2.15 mmol) in MeOH (10 mL) was added <i>N,</i> N-diisopropylethylamine (2.25 mL, 12.90 mmol) at 0 °C and the mixture was stirred at RT for 1 h, followed by the addition of sodium triacetoxyborohydride (0.338 g, 5.38 mmol) at 0 °C, and the mixture was stirred at RT for 3 h. The reaction mixture was diluted with ice-water and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na₂SO₄, filtered and evaporated under reduced pressure. The residue was purified by silica gel chromatography, eluted with 10% ethyl acetate/petroleum ether to give the desired product. LCMS: 162.08 (M+H).

(Step 2) Synthesis of 2-chloro-<i>N</i>-(cyclobutylmethyl)-<i>N</i>-phenylquinazolin-4-amine

1001<chemistry id="chem1422" num="1422"><img file="EP4445902A2_D1425.tif" /></chemistry>

1002To a mixture of 2,4-dichloroquinazoline (0.09 g, 0.45 mmol) and <i>N-</i>(cyclobutylmethyl)aniline (0.073 g, 0.45 mmol) in DMF (2 mL) was added sodium hydroxide (0.036 g, 0.90 mmol) at 0 °C and the mixture was stirred for 72 h at RT. The reaction mixture was diluted with ice-water and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na₂SO₄, filtered and evaporated under reduced pressure. The residue was purified by silica gel chromatography and eluted with 5% ethyl acetate/petroleum ether to give the desired product. LCMS: 324.13 (M+H).

(Step 3) Synthesis of <i>N</i>-(cyclobutylmethyl)-2-hydrazinyl-<i>N</i>-phenylquinazolin-4-amine

1003<chemistry id="chem1423" num="1423"><img file="EP4445902A2_D1426.tif" /></chemistry>

1004To a solution of 2-chloro-<i>N</i>-(cyclobutylmethyl)-<i>N</i>-phenylquinazolin-4-amine (0.045 g, 0.14 mmol) in EtOH (2 mL) was added hydrazine hydrate (0.014 g, 0.28 mmol) at RT and the mixture was stirred at 50 °C for 16 h. The reaction mixture was evaporated under reduced pressure to give the desired product. LCMS: 320.21 (M+H).

(Step 4) Synthesis of <i>N</i>-(Cyclobutylmethyl)-<i>N</i>-phenyl-[1,2,4]triazolo[4,3-<i>a</i>]quinazolin-5-

amine

1005A mixture of <i>N</i>-(cyclobutylmethyl)-2-hydrazinyl-<i>N</i>-phenylquinazolin-4-amine (0.045 g, 0.14 mmol) and triethyl orthoformate (1 mL) was stirred at 100 °C for 16 h. The reaction mixture was evaporated under reduced pressure, and the residue was purified by prep. HPLC to afford the desired product: ¹ H NMR (DMSO-d₆) δ 9.60 (s, 1H), 8.35 - 8.23 (m, 1H), 7.75 (ddd, J = 8.5, 7.1, 1.5 Hz, 1H), 7.37 - 7.12 (m, 7H), 4.13 (d, J = 7.2 Hz, 2H), 2.93 - 2.84 (m, 1H), 1.96 - 1.82 (m, 2H), 1.82 - 1.71 (m, 4H); LCMS(m/z) 330.2 [M+H]+.

<u>Example 78. <i>N-</i>phenyl-<i>N</i>-((tetrahydro-2<i>H</i>-pyran-4-yl)methyl)-[1,2,4]triazolo[4,3-<i>a</i>]quinazolin-5-amine</u>

1006<chemistry id="chem1424" num="1424"><img file="EP4445902A2_D1427.tif" /></chemistry>

(Step 1) Synthesis of <i>N-</i>((Tetrahydro-2<i>H-</i>pyran-4-yl)methyl)aniline

1007<chemistry id="chem1425" num="1425"><img file="EP4445902A2_D1428.tif" /></chemistry>

1008To a mixture of (tetrahydro-2H-pyran-4-yl)methanamine (0.4 g, 3.28 mmol) and phenylboronic acid (0.754 g, 6.56 mmol) in acetonitrile (10 mL) were added copper acetate (0.595 g, 3.28 mmol) and triethylamine (0.92 mL, 6.55 mmol) at RT and the mixture was stirred at 80 °C for 3 h. The reaction mixture was filtered through a bed of celite, and the filtrate was diluted with water and extracted with ethyl acetate. The organic layer was washed successively with water and brine, dried over Na₂SO₄, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 25% ethyl acetate/petroleum ether to give the desired product. LCMS(m/z) 192.18 [M+H]⁺.

(Step 2) Synthesis of 2-chloro-<i>N</i>-phenyl-<i>N</i>-((tetrahydro-2<i>H</i>-pyran-4-yl)methyl)quinazolin-4-amine

1009<chemistry id="chem1426" num="1426"><img file="EP4445902A2_D1429.tif" /></chemistry>

1010To a solution of <i>N</i>-((tetmhydro-2<i>H</i>-pyran-4-yl)methyl)aniline (0.240 g, 1.26 mmol) in DMF (6 mL) was added sodium hydroxide (0.050 g, 1.26 mmol) at 0 °C and the mixture was stirred for 1 h at RT, followed by the addition of 2,4-dichloroquinazoline (0.250 g, 1.26 mmol) at RT, and the mixture was stirred at RT for 24 h then heated to 80 °C for 2 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed successively with water and brine, dried over Na₂SO₄, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 25% ethyl acetate/petroleum ether to give the desired product. LCMS(m/z) 354.18 [M+H]⁺.

(Step 3) Synthesis of <i>N</i>-Phenyl-<i>N-</i>((tetrahydro-2<i>H-</i>pyran-4-yl)methyl)-[1,2,4]triazolo[4,3-<i>a</i>]quinazolin-5-amine

1011To a stirred solution of 2-chloro-<i>N</i>-phenyl-<i>N</i>-((tetrahydro-2<i>H</i>-pyran-4-yl)methyl)quinazolin-4-amine (0.1 g, 0.28 mmol) in toluene (5 mL) was added formohydrazide (0.034 g, 0.56 mmol) at room temperature and the mixture was refluxed for 72 h. The reaction mixture was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography, followed by preparative HPLC to afford the desired product: ¹ H NMR (DMSO-d₆) δ 9.64 (s, 1H), 8.29 (dd, J = 8.3, 1.2 Hz, 1H), 7.76 (ddd, J = 8.4, 7.2, 1.4 Hz, 1H), 7.39 - 7.17 (m, 7H), 3.99 (d, J = 7.2 Hz, 2H), 3.87 - 3.80 (m, 2H), 3.42 - 3.32 (m, 1H), 3.32 - 3.15 (m, 3H), 2.16 (ddd, J = 12.0, 9.2, 5.5 Hz, 1H), 1.46 - 1.34 (m, 2H); LCMS(m/z) 360.2 [M+H]+.

<u>Example 79. 5-(3,4,5,6-tetrahydrobenzo[b]azocin-1(2H)-yl)-[1,2,4]triazolo[4,3-alquinazoline</u>

1012<chemistry id="chem1427" num="1427"><img file="EP4445902A2_D1430.tif" /></chemistry>

(Step 1) Synthesis of 3,4,5,6-Tetrahydrobenzo[b]azocin-2(1H)-one

1013<chemistry id="chem1428" num="1428"><img file="EP4445902A2_D1431.tif" /></chemistry>

1014To a solution of 6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (4 g, 25 mmol) in concentrated HCl (40 mL) was added sodium azide (6.5 g, 100 mmol) at RT and the mixture was stirred at RT for 24 h. The reaction mixture was diluted with water, neutralized with saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate. The organic layer was dried over Na₂SO₄, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 50% ethyl acetate/petroleum ether to give the desired product. LCMS(m/z) 176.13 [M+H]⁺.

(Step 2) Synthesis of 1,2,3,4,5,6-hexahydrobenzo[b]azocine

1015<chemistry id="chem1429" num="1429"><img file="EP4445902A2_D1432.tif" /></chemistry>

1016To a stirred solution of 3,4,5,6-tetrahydrobenzo[b]azocin-2(1H)-one (1.2 g, 6.85 mmol) in tetrahydrofuran (20 mL) was added LDA (13.7 mL, 13.71 mmol, 1.0 M in THF) at 0 °C and the mixture was stirred at 70 °C for 16 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over Na₂SO₄, filtered and evaporated under reduced pressure to give the desired product. LCMS(m/z) 162.06 [M+H]⁺.

(Step 3) Synthesis of 5-(3,4,5,6-tetrahydrobenzo[b]azocin-1(2H)-yl)-[1,2,4]triazolo[4,3-a]quinazoline

1017To a solution of 1,2,3,4,5,6-hexahydrobenzo[b]azocine (0.024 g, 0.15 mmol) in THF (10 mL) was added LDA (0.17 mL, 0.17 mmol, 1.0 M in THF) at 0 °C and the mixture was stirred at RT for 1 h, followed by the addition of 5-chloro-[1,2,4]triazolo[4,3-a]quinazoline (0.03 g, 0.15 mmol) at 0 °C, and the mixture was stirred for 2 h at RT. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over Na₂SO₄, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography, followed by prep. HPLC to afford the desired product: ¹ H NMR (DMSO-d₆) δ 9.55 (s, 1H), 8.26 (dd, J = 8.2, 1.3 Hz, 1H), 7.74 (ddd, J = 8.4, 7.0, 1.5 Hz, 1H), 7.46 (dd, J = 7.6, 1.7 Hz, 1H), 7.40 (td, J = 7.5, 1.3 Hz, 1H), 7.28 (td, J = 7.6, 1.7 Hz, 1H), 7.15 (ddd, J = 8.4, 7.0, 1.2 Hz, 1H), 7.09 (ddd, J = 8.6, 3.3, 1.4 Hz, 2H), 4.06 - 3.93 (m, 2H), 2.77 (t, J = 5.9 Hz, 2H), 1.73 (s, 2H), 1.61 (d, J = 7.0 Hz, 4H); LCMS(m/z) 330.2 [M+H]+.

<u>Example 80. N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1018<chemistry id="chem1430" num="1430"><img file="EP4445902A2_D1433.tif" /></chemistry>

(Step 1) Synthesis of <i>N</i>-(2-((<i>tert</i>-butyldimethylsilyl)oxy)ethyl)aniline

1019<chemistry id="chem1431" num="1431"><img file="EP4445902A2_D1434.tif" /></chemistry>

1020To a solution of 2-(phenylamino)ethan-1-ol (0.2 g, 1.46 mmol) in dichloromethane (10 mL) were added <i>tert</i>-butyldiroetbylsilyl chloride (0.219 g, 1.46 mmol) and imidazole (0.099 g, 1.46 mmol) at RT and the mixture was stirred at RT for 16 h. The reaction mixture was diluted with water and extracted with dichloromethane. The organic layer was dried over Na₂SO₄, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with 20% ethyl acetate/petroleum ether to give the desired product. LCMS: 252.50 (M+H).

(Step 2) Synthesis of <i>N</i>-(2-((<i>tert</i>-butyldimethylsilyl)oxy)ethyl)-<i>N</i>-phenyl-[1,2,4]triazolo[4,3-<i>a</i>]quinazolin-5-amine

1021To a solution of <i>N-</i>(2-((<i>tert</i>-butyldimethylsilyl)oxy)ethyl)aniline (0.024 g, 0.098 mmol) in THF (2 mL) was added LDA (0.1 mL, 0.2 mmol, 2.0 M in THF) at 0 °C and the mixture was stirred for 1 h at RT, followed by the addition of 5-chloro-[1,2,4]triazolo[4,3-a]quinazoline (0.02 g, 0.098 mmol) at 0 °C, and the mixture was then stirred for 2 h at RT. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over Na₂SO₄, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 3% methanol/dichloromethane to afford the desired product: ¹ H NMR (DMSO-d₆) δ 9.63 (s, 1H), 8.37 - 8.23 (m, 1H), 7.76 (ddd, J = 8.5, 6.6, 2.1 Hz, 1H), 7.39 - 7.31 (m, 4H), 7.24 - 7.14 (m, 3H), 4.21 (t, J = 5.8 Hz, 2H), 3.95 (t, J = 5.8 Hz, 2H), 0.79 (s, 9H), -0.06 (s, 6H); LCMS(m/z) 420.2 [M+H]+.

<u>Example 81. <i>N</i>-methyl-<i>N</i>-(3-(trifluoromethyl)phenyl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1022<chemistry id="chem1432" num="1432"><img file="EP4445902A2_D1435.tif" /></chemistry>

1023To a stirred solution of N-methyl-3-(trifluoromethyl)aniline (0.052 g, 0.29 mmol) in THF (5 mL) was added LDA (0.22 mL, 0.44 mmol, 1.5 eq., 2.0 M in THF) at 0 °C and the mixture was stirred for 1 h at RT, followed by the addition of 5-chloro-[1,2,4]triazolo[4,3-a]quinazoline (0.067g, 0.29 mmol) at 0 °C, and the mixture was stirred for 1 h at RT. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with sat. NH₄Cl solution and extracted with ethyl acetate. The organic layer was dried over Na₂SO₄, filtered and evaporated under reduced pressure. The residue was purified by prep. HPLC to afford the desired product: ¹ H NMR (DMSO-d₆) δ 9.68 (s, 1H), 8.33 (dd, J = 8.3, 1.0 Hz, 1H), 7.81 (ddd, J = 8.4, 6.3, 2.3 Hz, 1H), 7.75 - 7.66 (m, 1H), 7.65 - 7.52 (m, 3H), 7.32 - 7.19 (m, 2H), 3.60 (s, 3H); LCMS(m/z) 344.1 [M+H]+.

<u>Example 82. N-methyl-N-(3-(trifluoromethoxv)phenyl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1024<chemistry id="chem1433" num="1433"><img file="EP4445902A2_D1436.tif" /></chemistry>

(Step 1) Synthesis of N-methyl-3-(trifluoromethoxy)aniline

1025<chemistry id="chem1434" num="1434"><img file="EP4445902A2_D1437.tif" /></chemistry>

1026To a stirred solution of 3-(trifluoromethoxy)aniline (1.0 g, 5.64 mmol) in MeOH (10 mL) were added 37% formaldehyde (0.254 g, 8.47 mmol) and sodium methoxide (1.52 g, 28.22 mmol) at 0 °C and the mixture was stirred for 3 h at RT, followed by the addition of sodium borohydride (0.214 g, 5.64 mmol) at 0 °C, and the mixture was heated to 60 °C for 3 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was evaporated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate. The organic layer was washed successively with water and brine, and dried over Na₂SO₄, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with 10% ethyl acetate/petroleum ether to give the desired product. LCMS: 192.11(M+H).

(Step 2) Synthesis of <i>N-</i>methyl-<i>N-</i>(3-(trifluoromethoxy)phenyl)-[1,2,4]triazolo[4,3-<i>a</i>]quinazolin-5-amine

1027To a stirred solution of <i>N</i>-methyl-3-(trifluoromethoxy)aniline (0.188 g, 0.98 mmol) in THF (10 mL) was added LDA (0.27 mL, 0.54 mmol, 2.0 M in THF) at 0 °C and the mixture was stirred at RT for 1 h, followed by the addition of 5-chloro-[1,2,4]triazolo[4,3-a]quinazoline (0.1 g, 0.49 mmol) at 0 °C, and the mixture was stirred at RT for 1 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with saturated NH₄Cl solution and extracted with ethyl acetate. The organic layer was dried over Na₂SO₄, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 1% methanol/dichloromethane and then prep. HPLC to afford the desired product: ¹ H NMR (DMSO-d₆) δ 9.67 (s, 1H), 8.32 (d, J = 8.3 Hz, 1H), 7.81 (ddd, J = 8.4, 5.5, 3.0 Hz, 1H), 7.50 (t, J = 8.1 Hz, 1H), 7.40 - 7.33 (m, 2H), 7.31 - 7.24 (m, 2H), 7.20 (ddt, J = 8.3, 2.3, 1.1 Hz, 1H), 3.58 (s, 3H); LCMS(m/z) 360.1 [M+H]+.

<u>Example 83. (3-([1,2,4]triazolo[4,3-a]quinazolin-5-yl(methyl)amino)phenyl)methanol</u>

1028<chemistry id="chem1435" num="1435"><img file="EP4445902A2_D1438.tif" /></chemistry>

1029To a solution of N-(3-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 104) (0.06 g, 0.14 mmol) in THF (4 mL) was added tetra-n-butylammonium fluoride (0.041 g, 0.16 mmol) at 0 °C and the mixture was stirred for 2 h at RT. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed successively with water and brine, dried over Na₂SO₄, filtered and evaporated under reduced pressure. The crude compound was purified by silica gel column chromatography, eluted with 4% methanol/dichloromethane, followed by prep. HPLC to afford the desired product: ¹ H NMR (DMSO-d₆) δ 9.62 (s, 1H), 8.29 (dd, J = 8.5, 1.2 Hz, 1H), 7.77 (ddd, J = 8.5, 7.1, 1.4 Hz, 1H), 7.33 - 7.18 (m, 5H), 7.14 - 7.08 (m, 1H), 5.23 (t, J = 5.7 Hz, 1H), 4.46 (d, J = 5.7 Hz, 2H), 3.53 (s, 3H); LCMS(m/z) 306.2 [M+H]+.

<u>Example 84. N-methyl-N-phenyl-8-(1H-pyrrol-2-yl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1030<chemistry id="chem1436" num="1436"><img file="EP4445902A2_D1439.tif" /></chemistry>

1031A mixture of 8-bromo-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 28) (15 mg, 0.042 mmol), K₃PO₄ (27.0 mg, 0.127 mmol), Pd(OAc)₂ (1.901 mg, 8.47 µmol), tricyclohexylphosphine (2.375 mg, 8.47 µmol) and tert-butyl 2-(5-(methyl(phenyl)amino)-[1,2,4]triazolo[4,3-a]quinazolin-8-yl)-1H-pyrrole-1-carboxylate (22.34 mg, 0.106 mmol) in dioxane/water (0.21 mL) was heated at 120 °C for 1 h. The reaction mixture was subjected to solid phase extraction (washed with MeOH, then eluted with NH₃ in MeOH) using Bond Elut SCX cartridge (Agilent), and the collected fractions were concentrated in vacuo. The residue was purified by column chromatography (Si-column, CHCl₃ : MeOH = 10:0 - 9:1) to afford the desired product: ¹ H-NMR (Methanol-d₄) δ 9.36 (s, 1H), 8.28 (d, J = 1.8 Hz, 1H), 7.48 - 7.39 (m, 2H), 7.38 - 7.26 (m, 5H), 7.21 (d, J = 8.9 Hz, 1H), 6.98 - 6.92 (m, 1H), 6.82 (dd, J = 3.6, 1.4 Hz, 1H), 6.27 - 6.20 (m, 1H), 3.65 (s, 3H); LCMS(m/z) 341.0 [M+H]+.

<u>Example 85. N-(5-(methyl(phenyl)amino)-[1,2,4]triazolo[4,3-a]quinazolin-8-yl)methanesulfonamide</u>

1032<chemistry id="chem1437" num="1437"><img file="EP4445902A2_D1440.tif" /></chemistry>

1033A mixture ofN5-methyl-N5-phenyl-[1,2,4]triazolo[4,3-a]quinazoline-5,8-diamine (Example 66) (40 mg, 0.138 mmol), triethylamine (0.192 mL, 1.378 mmol) and methanesulfonyl chloride (6M in 1,2-dichloroethane, 2 mL) was stirred for 4.5 h at 70°C. The reaction mixture was evaporated in vacuo. The residue was dissolved in DMA (2 mL), and methane sulfonyl chloride (6M in 1,2-dichloroethane, 2 mL) was added to the solution at RT. The mixture was stirred overnight at 110°C. The reaction mixture was subjected to solid phase extraction (washed with MeOH, then eluted with NH₃ in MeOH) using Bond Elut SCX cartridge (Agilent), and the collected fractions were concentrated in vacuo. The residue was purified by prep-LCMS to afford the desired product: ¹ H NMR (DMSO-d₆) δ 10.67 (s, 1H), 9.48 (s, 1H), 7.72 (s, 1H), 7.47 - 7.33 (m, 2H), 7.27 (dt, J = 8.2, 1.8 Hz, 3H), 7.13 (d, J = 9.1 Hz, 1H), 6.85 (dd, J = 9.1, 2.2 Hz, 1H), 3.51 (s, 3H), 3.19 (s, 3H); LCMS(m/z) 369.3 [M+H]+.

<u>Example 86. N-methyl-N-phenyl-8-(piperidin-1-yl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1034<chemistry id="chem1438" num="1438"><img file="EP4445902A2_D1441.tif" /></chemistry>

1035A mixture of 8-bromo-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 28) (20 mg, 0.056 mmol), K₂CO₃ (15.61 mg, 0.113 mmol), Pd(dba)₃ (0.011 mmol) and piperidine (5.77 mg, 0.068 mmol) in DMF (282 µL) was stirred for overnight at 100 °C. The reaction mixture was concentrated in vacuo, and the residue was purified by column chromatography (Si-column, CHCl₃: MeOH = 0-20%) to afford the desired product: ¹ H NMR (Methanol-d₄) δ 9.36 (s, 1H), 7.46 - 7.32 (m, 2H), 7.33 - 7.15 (m, 4H), 6.93 (d, J = 9.5 Hz, 1H), 6.58 (dd, J = 9.6, 2.6 Hz, 1H), 3.56 (s, 3H), 3.43 (dd, J = 6.2, 4.0 Hz, 4H), 1.72 - 1.61 (m, 6H); LCMS(m/z) 359.2 [M+H]+.

<u>Example 87. Methyl 5-(methyl(phenyl)amino)-[1,2,4]triazolo[4,3-a]quinazoline-8-carboxylate</u>

1036<chemistry id="chem1439" num="1439"><img file="EP4445902A2_D1442.tif" /></chemistry>

1037A mixture of 8-bromo-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 28) (10 mg, 0.028 mmol), Mo(CO)6 (7.45 mg, 0.028 mmol), Pd(OAc)₂ 1.268 mg, 0.0056 mmol) and Pd(dppf)₂ (0.0056 mmol) in DMA/MeOH (1: 1, 0.14 mL) was stirred for 2 h at 100 °C. The reaction mixture was filtered through a bed of celite with MeOH. The filtrate was concentrated in vacuo, and the residue was purified by prep-HPLC to afford the desired product: ¹ H NMR (Methanol-d₄) δ 9.74 (s, 1H), 8.90 (d, J = 1.6 Hz, 1H), 7.81 (dd, J = 8.9, 1.6 Hz, 1H), 7.61 - 7.50 (m, 3H), 7.47 - 7.40 (m, 2H), 7.30 (d, J = 8.8 Hz, 1H), 3.98 (s, 3H), 3.81 (s, 3H); LCMS(m/z) 334.2 [M+H]+.

<u>Example 88. N-methyl-N-(3-nitrophenyl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1038<chemistry id="chem1440" num="1440"><img file="EP4445902A2_D1443.tif" /></chemistry>

(Step 1) Synthesis of 2-chloro-A-methyl-N-(3-nitrophenyl)quinazolin-4-amine

1039<chemistry id="chem1441" num="1441"><img file="EP4445902A2_D1444.tif" /></chemistry>

1040To a stirred solution of N-methyl-3-nitrobenzenamine (0.382 g, 2.51 mmol) in DMF (10 mL) was added 60% sodium hydride (0.120 g, 3.01 mmol) at 0 °C and the mixture was stirred for 1 h at RT, followed by the addition of 2,4-dichloroquinazoline (0.5 g, 2.51 mmol) at 0 °C. The mixture was stirred for 3 h at RT. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with ice-water. The resulting solids were filtered and dried under vacuum to give the desired product. LCMS: 315.10 (M+H).

(Step 2) Synthesis of <i>N</i>-methyl-<i>N</i>-(3-nitrophenyl)-[1,2,4]triazolo[4,3-<i>a</i>]quinazolin-5-amine

1041To a stirred solution of 2-chloro-<i>N</i>-methyl-<i>N</i>-(3-nitrophenyl)quinazolin-4-amine (0.1 g, 0.32 mmol) in toluene (4 mL) was added formic hydrazide (0.038 g, 0.63 mmol) at RT and the mixture was heated to 120 °C for 72 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was evaporated under reduced pressure. The residue was washed with diethyl ether and purified by prep. HPLC to give the desired product: ¹ H NMR (DMSO-d₆) δ 9.70 (s, 1H), 8.42 - 8.33 (m, 1H), 8.19 (t, J = 2.2 Hz, 1H), 8.03 (ddd, J = 8.2, 2.3, 1.0 Hz, 1H), 7.83 (ddd, J = 8.4, 7.1, 1.4 Hz, 1H), 7.67 (ddd, J = 8.2, 2.2, 1.0 Hz, 1H), 7.58 (t, J = 8.1 Hz, 1H), 7.37 (dd, J = 8.3, 1.4 Hz, 1H), 7.32 (m, 1H), 3.63 (s, 3H); LCMS(m/z) 321.1 [M+H]+.

<u>Example 89. N-(3-(methoxymethyl)phenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1042<chemistry id="chem1442" num="1442"><img file="EP4445902A2_D1445.tif" /></chemistry>

1043To a solution of (3-([1,2,4]triazolo[4,3-a]quinazolin-5-yl(methyl)amino)phenyl)methanol (Example 83) (0.03 g, 0.098 mmol) in DMF (2 mL) was added 60% sodium hydride (0.005 g, 0.12 mmol) at 0 °C and the mixture was stirred for 15 min at RT, followed by the addition of methyl iodide (0.007 mL, 0.12 mmol) at 0 °C. The mixture was stirred for 16 h at RT. The reaction mixture was diluted with cold water and extracted with ethyl acetate. The organic layer was washed successively with water and brine, dried over Na₂SO₄, filtered and evaporated under reduced pressure. The residue was purified by prep. HPLC to afford the desired product: ¹ H-NMR (DMSO-d₆) δ 9.62 (s, 1H), 8.29 (dd, J = 8.3, 1.2 Hz, 1H), 7.77 (ddd, J = 8.5, 7.1, 1.5 Hz, 1H), 7.37 (td, J = 7.2, 1.9 Hz, 1H), 7.31 - 7.17 (m, 5H), 4.36 (s, 2H), 3.54 (s, 3H), 3.20 (s, 3H); LCMS(m/z) 320.2 [M+H]+.

<u>Example 90. N-(3-(fluoromethyl)phenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1044<chemistry id="chem1443" num="1443"><img file="EP4445902A2_D1446.tif" /></chemistry>

1045To a solution of (3-([1,2,4]triazolo[4,3-a]quinazolin-5-yl(methyl)amino)phenyl)methanol (Example 83) (0.05 g, 0.16 mmol) in dichloromethane (4 mL) was added diethylaminosulfur trifluoride (0.04 mL, 0.33 mmol) at -78 °C and the mixture was stirred for 2 h at RT. The reaction mixture was quenched with saturated sodium bicarbonate aqueous solution and extracted with dichloromethane. The organic layer was washed successively with water and brine, dried over Na₂SO₄, filtered and evaporated under reduced pressure. The residue was purified by prep. HPLC to afford the desired product: ¹ H-NMR (500 MHz, DMSO-d₆) δ 9.64 (s, 1H), 8.30 (dd, J = 8.3, 1.3 Hz, 1H), 7.78 (ddd, J = 8.4, 7.1, 1.5 Hz, 1H), 7.43 - 7.37 (m, 2H), 7.29 (ddd, J = 8.1, 4.4, 1.7 Hz, 3H), 7.25 - 7.22 (m, 1H), 5.37 (d, J = 47.5 Hz, 2H), 3.55 (s, 3H); LCMS(m/z) 308.1 [M+H]+.

<u>Example 91. N-(3-ethylphenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1046<chemistry id="chem1444" num="1444"><img file="EP4445902A2_D1447.tif" /></chemistry>

1047To a stirred solution of 3-ethyl-N-methylaniline (0.066 g, 0.49 mmol) in THF (3 mL) was added LDA (0.18 mL, 0.37 mmol, 2.0 M in THF) at 0 °C, and the mixture was stirred for 1 h at RT. Then, 5-chloro-[1,2,4]triazolo[4,3-a]quinazoline (0.05 g, 0.24 mmol) was added to the solution at 0 °C, and the mixture was stirred for 1 h at RT. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with ice-water and extracted with ethyl acetate. The organic layer was dried over Na₂SO₄, filtered and evaporated under reduced pressure. The residue was purified by prep. HPLC to afford the desired product: ¹ H-NMR (DMSO-d₆) δ 9.61 (s, 1H), 8.43 - 8.23 (m, 1H), 7.76 (ddd, J = 8.4, 7.0, 1.6 Hz, 1H), 7.34 - 7.16 (m, 3H), 7.15 - 7.08 (m, 3H), 3.53 (s, 3H), 2.65 - 2.51 (m, 2H), 1.08 (t, J = 7.6 Hz, 3H); LCMS(m/z) 304.2 [M+H]+.

<u>Example 92. 8-(cyclopropylethynyl)-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1048<chemistry id="chem1445" num="1445"><img file="EP4445902A2_D1448.tif" /></chemistry>

1049A mixture of 8-bromo-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 28) (20 mg, 0.056 mmol), prop-1-yne (0.02 mL, 2 mmol, 0.1 M THF solution), triethylamine (22.85 mg, 0.226 mmol), Pd(OAc)₂ (3.80 mg, 0.017 mmol), triphenylphosphine (19.99 mg, 0.076 mmol) and copper(I) iodide (3.23 mg, 0.017 mmol) in dioxane (0.4 mL) was treated in a microwave reactor at 120°C for 2 h. The reaction mixture was purified by column chromatography (Si-column, CHCl₃ : MeOH = 10:0 - 9:1) to afford the desired product: ¹H-NMR (CDCl₃) δ 8.91 (s, 1H), 7.73 (d, J = 1.5 Hz, 1H), 7.46 - 7.30 (m, 2H), 7.31 - 7.22 (m, 1H), 7.22 - 7.09 (m, 3H), 7.03 (dd, J = 8.7, 1.6 Hz, 1H), 3.67 (s, 3H), 1.44 - 1.30 (m, 1H), 0.48 - 0.35 (m, 2H), 0.20 - 0.10 (m, 2H); LCMS(m/z) 340.3 [M+H]+.

<u>Example 93. 9-chloro-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1050<chemistry id="chem1446" num="1446"><img file="EP4445902A2_D1449.tif" /></chemistry>

(Step 1) Synthesis of 2,8-dichloro-N-methyl-N-phenylquinazolin-4-amine

1051<chemistry id="chem1447" num="1447"><img file="EP4445902A2_D1450.tif" /></chemistry>

1052To a solution of 2,4,8-trichloroquinazoline (100 mg, 0.428 mmol) in DMF (2.1 mL) were added N-methylaniline (45.9 mg, 0.428 mmol) and sodium hydroxide (17.13 mg, 0.428 mmol), and the mixture was stirred for 1 h at RT. The reaction mixture was diluted with AcOEt, washed successively with water and brine, and dried over Na₂SO₄. The organic layer was concentrated in vacuo to give the desired product. LCMS(m/z) 303.98 [M-H]⁺.

(Step 2) Synthesis of 8-chloro-2-hydrazinyl-N-methyl-N-phenylquinazolin-4-amine

1053<chemistry id="chem1448" num="1448"><img file="EP4445902A2_D1451.tif" /></chemistry>

1054To a solution of 2,8-dichloro-N-methyl-N-phenylquinazolin-4-amine (61 mg, 0.201 mmol) in EtOH (1 mL) was added hydrazine hydrate (20.08 mg, 0.401 mmol), and the mixture was stirred for 2 h at 50 °C. The reaction mixture was diluted with AcOEt, washed successively with water and brine, and dried over Na₂SO₄. The organic layer was concentrated in vacuo to give the desired product. LCMS(m/z) 300.13 [M+H]⁺.

(Step 3) Synthesis of 9-chloro-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

1055A mixture of 8-chloro-2-hydrazinyl-N-methyl-N-phenylquinazolin-4-amine (53 mg, 0.177 mmol) and triethoxymethane (52 mg, 0.354 mmol) was stirred for 1 h at 100 °C. The reaction mixture was concentrated in vacuo, and the residue was purified by column chromatography (Si-column, CHCl₃ : MeOH = 10 : 0 - 9 : 1), followed by prep-HPLC to afford the desired product: ¹H NMR (Methanol-d₄) δ 10.02 (s, 1H), 7.89 (d, J = 7.9 Hz, 1H), 7.45 (t, J = 7.6 Hz, 2H), 7.40 - 7.13 (m, 5H), 3.71 (s, 3H); LCMS(m/z) 310.1 [M+H]+.

<u>Example 94. 5-(methyl(phenyl)amino)-[1,2,4]triazolo[4,3-a]quinazoline-8-carbonitrile</u>

1056<chemistry id="chem1449" num="1449"><img file="EP4445902A2_D1452.tif" /></chemistry>

1057To a solution of 8-bromo-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 28) (30 mg, 0.085 mmol) in DMF (423 µL) were added zinc cyanide (19.89 mg, 0.169 mmol) and Pd(PPh₃)₄ (19.57 mg, 0.017 mmol), and the mixture was treated in a microwave reactor for 2 h at 100 °C. The reaction mixture was subjected to solid phase extraction (washed with MeOH, then eluted with NH₃ in MeOH) using Bond Elut SCX cartridge (Agilent), and the collected fractions were concentrated in vacuo. The residue was purified by column chromatography (Si-column, CHCl₃ : MeOH = 10:0 - 9:1) to afford the desired product: ¹H NMR (Methanol-d₄) δ 9.45 (s, 1H), 8.65 (d, J = 1.5 Hz, 1H), 7.46 - 7.29 (m, 7H), 3.65 (s, 3H); LCMS(m/z) 301.2 [M+H]+.

Example 95. <b>N-methyl-N-phenyl-8-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]quinazolin-5-</b>amine

1058<chemistry id="chem1450" num="1450"><img file="EP4445902A2_D1453.tif" /></chemistry>

(Step 1) Synthesis of 7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione

1059<chemistry id="chem1451" num="1451"><img file="EP4445902A2_D1454.tif" /></chemistry>

1060A mixture of 2-amino-4-chlorobenzoic acid (5 g, 29.1 mmol) and urea (6.13 g, 102 mmol) was stirred overnight at 200 °C. The reaction mixture was cooled to RT, and diluted with water. The resulting solids were collected and washed with water to give the desired product.

(Step 2) Synthesis of 2,4-dichloro-7-(trifluoromethyl)quinazoline

1061<chemistry id="chem1452" num="1452"><img file="EP4445902A2_D1455.tif" /></chemistry>

1062A mixture of 7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione (500 mg, 2.17 mmol) and phosphoryl trichloride (833 mg, 5.43 mmol) was stirred for 6 h at 100 °C. The reaction mixture was concentrated in vacuo. Ice-water was added to the residue, and the resulting solids were collected and washed with water to give the desired product. The residue was used for the next step without further purification.

(Step 3) Synthesis of 2-chloro-N-methyl-N-phenyl-7-(trifluoromethyl)quinazolin-4-amine

1063<chemistry id="chem1453" num="1453"><img file="EP4445902A2_D1456.tif" /></chemistry>

1064To a solution of 2,4-dichloro-7-(trifluoromethyl)quinazoline (130 mg, crude) in DMF (2.4 mL) were added sodium hydride (11.68 mg, 0.487 mmol) and N-methylaniline (52.2 mg, 0.487 mmol), and the mixture was stirred for 30 min at RT. The mixture was diluted with AcOEt, washed successively with water and brine, and dried over Na₂SO₄. The organic layer was concentrated in vacuo. The residue was used for the next step without further purification. LCMS(m/z) 338.03 [M+H]⁺.

(Step 4) Synthesis of 2-hydrazinyl-N-methyl-N-phenyl-7-(trifluoromethyl)quinazolin-4-amine

1065<chemistry id="chem1454" num="1454"><img file="EP4445902A2_D1457.tif" /></chemistry>

1066To a solution of 2-chloro-N-methyl-N-phenyl-7-(trifluoromethyl)quinazolin-4-amine (171 mg, crude) in EtOH (2.5 mL) was added hydrazine hydrate (50.7 mg, 1.013 mmol), and the mixture was stirred for 2 h at 50 °C. The reaction mixture was diluted with AcOEt, washed successively with water and brine, and dried over Na₂SO₄. The organic layer was concentrated in vacuo. The residue was used for the next step. LCMS(m/z) 334.13 [M+H]⁺.

(Step 5) Synthesis of N-methyl-N-phenyl-8-(trifluoromethyl)-[1,2,4]triazolo[4,3-a] quinazolin-5-amine

1067A mixture of 2-hydrazinyl-N-methyl-N-phenyl-7-(trifluoromethyl)quinazolin-4-amine (162 mg, crude) and triethoxymethane (224 mg, 1.519 mmol) was stirred for 2 h at 90 °C. The mixture was concentrated in vacuo. The residue was purified by column chromatography (Si-column, CHCl₃ : MeOH = 10 : 0 - 9 : 1) and prep-HPLC to afford the desired product: ¹ H-NMR (Methanol-d₄) δ 9.70 (s, 1H), 8.75 (dt, J = 1.7, 0.8 Hz, 1H), 7.60 - 7.47 (m, 4H), 7.46 - 7.38 (m, 3H), 3.79 (s, 3H); LCMS(m/z) 344.2 [M+H]+.

<u>Example 96. N-methyl-N-phenyl-8-(prop-1-en-2-yl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1068<chemistry id="chem1455" num="1455"><img file="EP4445902A2_D1458.tif" /></chemistry>

1069A mixture of 8-bromo-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 28) (25 mg, 0.071 mmol), K₃PO₄ (17.98 mg, 0.085 mmol), Pd(OAc)₂ (7.92 mg, 0.035 mmol), tricyclohexylphosphine (19.79 mg, 0.071 mmol) and 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (11.86 mg, 0.071 mmol) in dioxane/water (0.35 mL) was heated at 67 °C for 1 h. The reaction mixture was subjected to solid phase extraction (washed with MeOH, then eluted with NH₃ in MeOH) using Bond Elut SCX cartridge (Agilent), and the collected fractions were concentrated in vacuo. The residue was purified by column chromatography (Si-column, CHCl₃ : MeOH = 10:0 - 9: 1) to afford the desired product: ¹ H-NMR (Methanol-d₄) δ 9.54 (s, 1H), 8.21 (d, J = 1.7 Hz, 1H), 7.50 - 7.16 (m, 7H), 5.65 - 5.64 (m, 1H), 5.33 - 5.32 (m, 1H), 3.65 (s, 3H), 2.20 (dd, J = 1.5, 0.8 Hz, 3H); LCMS(m/z) 316.2 [M+H]+.

<u>Example 97. 8-(2-fluorophenyl)-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1070<chemistry id="chem1456" num="1456"><img file="EP4445902A2_D1459.tif" /></chemistry>

1071A mixture of 8-bromo-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 28) (20 mg, 0.056 mmol), K₃PO₄ (23.97 mg, 0.113 mmol), Pd(OAc)₂ (2.54 mg, 0.011 mmol), tricyclohexylphosphine (3.17 mg, 0.011 mmol) and(2-fluorophenyl)boronic acid (15.80 mg, 0.113 mmol) in dioxane/water (0.28 ml) was heated at 100 °C for 1 h. The reaction mixture was subjected to solid phase extraction (washed with MeOH, then eluted with NH₃ in MeOH) using Bond Elut SCX cartridge (Agilent), and the collected fractions were concentrated in vacuo. The residue was purified by column chromatography (Si-column, CHCl₃: MeOH = 10:0 - 9:1) to afford the desired product: ¹ H NMR (Methanol-d₄) δ 9.49 (s, 1H), 8.31 (q, J = 1.0 Hz, 1H), 7.56 (td, J = 7.8, 1.8 Hz, 1H), 7.49 - 7.40 (m, 3H), 7.36 - 7.17 (m, 7H), 3.66 (s, 3H); LCMS(m/z) 370.3 [M+H]+.

<u>Example 98. 8-(4-fluorophenyl)-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1072<chemistry id="chem1457" num="1457"><img file="EP4445902A2_D1460.tif" /></chemistry>

1073A mixture of 8-bromo-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 28) (20 mg, 0.056 mmol), K₃PO₄ (23.97 mg, 0.113 mmol), Pd(OAc)₂ (2.54 mg, 0.011 mmol), tricyclohexylphosphine (3.17 mg, 0.011 mmol) and (4-fluorophenyl)boronic acid (19.75 mg, 0.141 mmol) in dioxane/water (0.28 ml) was heated at 100 °C for 1 h. The reaction mixture was subjected to solid phase extraction (washed with MeOH, then eluted with NH₃ in MeOH) using Bond Elut SCX cartridge (Agilent), and the collected fractions were concentrated in vacuo. The residue was purified by column chromatography (Si-column, CHCl₃ : MeOH = 10:0 - 9:1) to afford the desired product: ¹ H NMR (Methanol-d₄) δ 9.54 (s, 1H), 8.38 (d, J = 1.8 Hz, 1H), 7.83 - 7.73 (m, 2H), 7.49 - 7.38 (m, 3H), 7.36 - 7.27 (m, 4H), 7.25 - 7.17 (m, 2H), 3.66 (s, 3H); LCMS(m/z) 370.3 [M+H]+.

<u>Example 99. 5-(methyl(phenyl)amino)-[1,2,4]-triazolo[4,3-a]quinazoline-8-carbonitrile</u>

1074<chemistry id="chem1458" num="1458"><img file="EP4445902A2_D1461.tif" /></chemistry>

1075A mixture of 7-bromo-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 62) (20 mg, 0.056 mmol), zinc cyanide (13.26 mg, 0.113 mmol), and Pd(PPh₃)₄ (13.05 mg, 0.011 mmol) in dioxane/water (0.35 mL) was heated at 80 °C for 1 h. The reaction mixture was subjected to solid phase extraction (washed with MeOH, then eluted with NH3 in MeOH) using Bond Elut SCX cartridge (Agilent), and the collected fractions were concentrated in vacuo. The residue was purified by column chromatography (Si-column, CHCl₃ : MeOH = 10:0 - 9:1) to afford the desired product: ¹ H NMR (Methanol-d₄) δ 9.47 (s, 1H), 8.32 (d, J = 8.6 Hz, 1H), 8.03 (dd, J = 8.6, 1.7 Hz, 1H), 7.55 - 7.46 (m, 3H), 7.46 - 7.39 (m, 1H), 7.38 - 7.32 (m, 2H), 3.68 (s, 3H); LCMS(m/z) 301.2.

<u>Example 100. N-(3-bromophenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1076<chemistry id="chem1459" num="1459"><img file="EP4445902A2_D1462.tif" /></chemistry>

(Step 1) Synthesis of <i>N</i>-(3-bromophenyl)-2-chloro-<i>N</i>-methylquinazolin-4-amine

1077<chemistry id="chem1460" num="1460"><img file="EP4445902A2_D1463.tif" /></chemistry>

1078To a stirred mixture of 2,4-dichloroquinazoline (1.0 g, 5.02 mmol) and 3-bromo-N-methylaniline (0.96 mL, 7.54 mmol) in DMF (15 mL) was added sodium hydroxide (0.402 g, 10.05 mmol) at 0 °C and the mixture was stirred for 5 h at RT. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with ice-water. The resulting solids were filtered and dried under vacuum. The residue was purified by silica gel column chromatography, eluted with 19% ethyl acetate/petroleum ether to give the desired product. LCMS: 348.34 (M+H).

(Step 2) Synthesis of <i>N</i>-(3-bromophenyl)-<i>N</i>-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

1079To a stirred solution of <i>N</i>-(3-bromophenyl)-2-chloro-<i>N</i>-methylquinazolin-4-amine (0.1 g, 0.29 mmol) in toluene (3 mL) was added formic hydrazide (0.034 g, 0.57 mmol) at RT and the mixture was heated to 120 °C for 78 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was evaporated under reduced pressure. The residue was washed with diethyl ether and purified by prep. HPLC to afford the desired product: ¹ H-NMR (DMSO-d₆) δ 9.65 (s, 1H), 8.32 (dd, J = 8.3, 1.0 Hz, 1H), 7.81 (ddd, J = 8.5, 6.3, 2.3 Hz, 1H), 7.59 (t, J = 1.9 Hz, 1H), 7.42 (dt, J = 7.1, 2.0 Hz, 1H), 7.31 (ddt, J = 8.8, 4.0, 2.4 Hz, 4H), 3.55 (s, 3H); LCMS(m/z) 354.1 [M+H]+.

<u>Example 101. <i>N</i>-(3-iodophenyl)-<i>N</i>-methyl-[1,2,4]triazolo[4,3-<i>a</i>]quinazolin-5-amine</u>

1080<chemistry id="chem1461" num="1461"><img file="EP4445902A2_D1464.tif" /></chemistry>

1081To a stirred solution of 3-iodo-<i>N</i>-methylaniline (0.228 g, 0.98 mmol) in THF (5 mL) was added LDA (0.36 mL, 0.73 mmol, 2.0 M in THF) at 0 °C and the mixture was stirred for 1 h at RT. 5-chloro-[1,2,4]triazolo[4,3-a]quinazoline (0.1 g, 0.49 mmol) at 0 °C was added, and the mixture was stirred for 1 h at RT. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed successively with water and brine, and dried over Na₂SO₄, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 4% methanol/dichloromethane, and followed by prep. HPLC to afford the desired product: ¹H NMR (DMSO-d₆) δ 9.64 (s, 1H), 8.31 (d, J = 8.4 Hz, 1H), 7.81 (ddd, J = 8.5, 5.5, 3.1 Hz, 1H), 7.72 (t, J = 1.9 Hz, 1H), 7.59 (dt, J = 7.8, 1.2 Hz, 1H), 7.30 (dq, J = 4.8, 1.6, 1.1 Hz, 3H), 7.14 (t, J = 8.0 Hz, 1H), 3.53 (s, 3H); LCMS(m/z) 402.0 [M+H]+.

<u>Example 102. <i>N</i>1-([1,2,4]triazolo[4,3-a]quinazolin-5-yl)-<i>N</i>1-methylbenzene-1,3-diamine</u>

1082<chemistry id="chem1462" num="1462"><img file="EP4445902A2_D1465.tif" /></chemistry>

1083To a stirred solution of<i>N</i>-methyl-<i>N</i>-(3-nitrophenyl)-[1,2,4]triazolo[4,3-<i>a</i>]quinazolin-5-amine (Example 88) (0.350 g, 1.09 mmol) in EtOH/water (20 mL, 1:1) were added zinc (0.715 g, 10.94 mmol) and NH₄Cl (0.585 g, 10.94 mmol) at RT and the mixture was stirred for 16 h at the same temperature. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through a bed of celite and washed with ethyl acetate. The organic layer was dried over Na₂SO₄, filtered and evaporated under reduced pressure. The residue was purified by silica-gel column chromatography and eluted with 5% methanol/dichloromethane to afford the desired product: ¹H NMR (DMSO-d₆) δ 9.58 (s, 1H), 8.26 (dd, J = 8.3, 1.2 Hz, 1H), 7.77 (ddd, J = 8.4, 7.3, 1.3 Hz, 1H), 7.46 (dd, J = 8.5, 1.3 Hz, 1H), 7.26 (ddd, J = 8.4, 7.2, 1.2 Hz, 1H), 7.11 - 6.93 (m, 1H), 6.51 - 6.35 (m, 3H), 5.20 (s, 2H), 3.47 (s, 3H); LCMS(m/z) 291.2 [M+H]+.

<u>Example 103. Methyl 3-([1,2,4]triazolo[4,3-a]quinazolin-5-yl(methyl)amino)benzoate</u>

1084<chemistry id="chem1463" num="1463"><img file="EP4445902A2_D1466.tif" /></chemistry>

(Step 1) Synthesis of methyl-3-((tert-butoxycarbonyl)amino)benzoate (2)

1085<chemistry id="chem1464" num="1464"><img file="EP4445902A2_D1467.tif" /></chemistry>

1086To a stirred solution of methyl-3-aminobenzoate (10 g, 66.14 mmol) in THF/water (60 mL, 5:1) were added sodium bicarbonate (11.11 g, 132.27 mmol) and di-tert-butyl dicarbonate (14.42 g, 66.14 mmol) at RT and the mixture was stirred at RT for 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na₂SO₄, filtered and evaporated under reduced pressure. The crude compound was purified by silica gel column chromatography, eluted with 18% ethyl acetate/petroleum ether to give the desired product. LCMS(m/z) 252.11 [M+H]+.

(Step 2) Synthesis of methyl 3-((tert-butoxycarbonyl)(methyl)amino)benzoate

1087<chemistry id="chem1465" num="1465"><img file="EP4445902A2_D1468.tif" /></chemistry>

1088To a stirred solution of methyl-3-((tert-butoxycarbonyl)amino)benzoate (12.3 g, 48.96 mmol) in DMF (120 mL) was added 60% sodium hydride (1.95 g, 48.96 mmol) and methyl iodide (3.65 mL, 58.76 mmol) at 0 °C and the mixture was stirred for 2 h at RT. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with ice-water and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na₂SO₄, filtered and evaporated under reduced pressure to give the desired product. LCMS(m/z) 266.21 [M+H]+.

(Step 3) Synthesis of methyl 3-(methylamino)benzoate

1089<chemistry id="chem1466" num="1466"><img file="EP4445902A2_D1469.tif" /></chemistry>

1090To a stirred solution of methyl 3-((tert-butoxycarbonyl)(methyl)amino)benzoate (2.0 g, 7.55 mmol) in dichloromethane (20 mL) was added 4N HCl in 1,4-dioxane (15 mL) at 0 °C and the mixture was stirred for 2 h at RT. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was poured into ice-water, neutralized with sat. NaHCO₃ solution and extracted with dichloromethane. The organic layer was washed successively with water and brine, dried over Na₂SO₄, filtered and evaporated under reduced pressure to give the desired product. LCMS(m/z) 166.46 [M+H]+.

(Step 4) Synthesis of methyl 3-((2-chloroquinazolin-4-yl)(methyl)amino)benzoate

1091<chemistry id="chem1467" num="1467"><img file="EP4445902A2_D1470.tif" /></chemistry>

1092To a stirred solution of methyl 3-(methylamino)benzoate (crude, 0.249 g, 1.50 mmol) in DMF (6 mL) was added 60% sodium hydride (0.048 g, 1.21 mmol) at 0 °C and the mixture was stirred for 1 h at RT, followed by the addition of 2,4-dichloroquinazoline (0.2 g, 1.0 mmol) at 0 °C, and the mixture was stirred for 5 h at RT. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with ice-water and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na₂SO₄, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 10% ethyl acetate/petroleum ether to afford the desired product. LCMS(m/z) 328.18 [M+H]+.

(Step 5) Synthesis of methyl 3-((2-hydrazinylquinazolin-4-yl)(methyl)amino)benzoate

1093<chemistry id="chem1468" num="1468"><img file="EP4445902A2_D1471.tif" /></chemistry>

1094To a stirred solution of methyl 3-((2-chloroquinazolin-4-yl)(methyl)amino)benzoate (0.04 g, 0.12 mmol) in ethanol (2 mL) was added hydrazine hydrate (0.006 mL, 0.12 mmol) at RT and the mixture was heated to 50 °C for 4 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with petroleum ether. The obtained solids were filtered and dried under vacuum to give the desired product. LC-MS: 324.19 (M+H).

(Step 6) Synthesis of methyl 3-([1,2,4]triazolo[4,3-a]quinazolin-5-yl(methyl)amino)benzoate

1095The mixture of methyl 3-((2-hydrazinylquinazolin-4-yl)(methyl)amino)benzoate (0.035 g, 0.11 mmol) and triethyl orthoformate (2 mL) was heated to 80 °C for 4 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was purified by prep. HPLC to afford the desired product: ¹H NMR (DMSO-d₆) δ 9.65 (s, 1H), 8.31 (dd, J = 8.2, 1.1 Hz, 1H), 7.94 - 7.66 (m, 3H), 7.70 - 7.40 (m, 2H), 7.38 - 7.13 (m, 2H), 3.83 (s, 3H), 3.57 (s, 3H); LCMS(m/z) 334.2 [M+H]+.

<u>Example 104. N-(3-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1096<chemistry id="chem1469" num="1469"><img file="EP4445902A2_D1472.tif" /></chemistry>

(Step 1) Synthesis of 3-(((tert-butyldimethylsilyl)oxy)methyl)aniline

1097<chemistry id="chem1470" num="1470"><img file="EP4445902A2_D1473.tif" /></chemistry>

1098To a solution of (3-aminophenyl)methanol (1.0 g, 8.12 mmol) in DMF (10 mL) were added imidazole (0.828 g, 12.18 mmol) at 0 °C and the mixture was stirred at RT for 10 min, followed by the addition of tert-butyldimethylsilyl chloride (1.34 g, 8.93 mmol) at 0 °C, and the mixture was stirred for 16 h at RT. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed successively with water and brine, and dried over Na₂SO₄, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with 15% ethyl acetate/petroleum ether to give the desired product. LCMS: 238.57 (M+H).

(Step 2) Synthesis of 3-(((tert-butyldimethylsilyl)oxy)methyl)-N-methylaniline

1099<chemistry id="chem1471" num="1471"><img file="EP4445902A2_D1474.tif" /></chemistry>

1100To a stirred solution of 3-(((tert-butyldimethylsilyl)oxy)methyl)aniline (0.5 g, 2.11 mmol) in MeOH (10 mL) were added 37% formaldehyde (0.28 mL, 3.16 mmol) and sodium methoxide (0.228 g, 4.22 mmol) at 0 °C and the mixture was heated to 50 °C for 4 h, followed by the addition of sodium borohydride (0.159 g, 4.22 mmol) at RT. The mixture was stirred at RT for 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with water and extracted with dichloromethane. The organic layer was washed successively with water and brine, dried over Na₂SO₄, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 30% ethyl acetate/petroleum ether to give the desired product. LC-MS: 252.72 (M+H).

(Step 3) Synthesis of N-(3-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

1101To a stirred solution of 3-(((tert-butyldimethylsilyl)oxy)methyl)-N-methylaniline (0.22 g, 0.88 mmol) in THF (6 mL) was added LDA (0.65 mL, 1.31 mmol, 2.0M in THF) at 0 °C and the mixture was stirred for 1 h at RT, followed by the addition of 5-chloro-[1,2,4]triazolo[4,3-a]quinazoline (0.214 g, 1.05 mmol) at 0 °C, and the mixture was stirred for 1 h at RT. The reaction mixture was quenched with sat. NH4Cl solution and extracted with ethyl acetate. The organic layer was washed successively with water and brine, dried over Na₂SO₄, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with 30% ethyl acetate/petroleum ether to give the desired product: ¹H NMR (500 MHz, DMSO-d₆) δ 9.66 (d, J = 4.6 Hz, 1H), 8.35 - 8.23 (m, 1H), 7.79 (ddt, J = 8.4, 7.2, 1.3 Hz, 1H), 7.36 (dt, J = 24.6, 7.8 Hz, 1H), 7.30 - 7.11 (m, 5H), 4.55 (d, J = 87.9 Hz, 2H), 3.54 (d, J = 4.4 Hz, 3H), 3.35 - 3.25 (m, 9H), -0.05 (d, J = 5.8 Hz, 6H); LCMS(m/z) 420.2 [M+H]+.

<u>Example 105. N-(3-Cyclopropylphenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1102<chemistry id="chem1472" num="1472"><img file="EP4445902A2_D1475.tif" /></chemistry>

1103To a stirred solution of N-(3-iodophenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 101) (0.140 g, 0.35 mmol) in a mixture of toluene and water (7.5 mL, 4:1) were added cyclopropylboronic acid (0.060 g, 0.70 mmol) and potassium phosphate (0.222 g, 1.05 mmol) at RT and the mixture was deoxygenated with argon for 10 min, followed by the addition of tricyclohexylphosphine (0.019 g, 0.07 mmol) and palladium(II) acetate (0.004 g, 0.02 mmol) at RT, and the mixture was heated to 100 °C for 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through celite bed and washed with ethyl acetate. The organic layer was washed successively with water and brine, dried over Na₂SO₄, filtered and evaporated under reduced pressure. The residue was purified by prep. HPLC to afford the desired product: ¹H NMR (DMSO-d₆) δ 9.60 (s, 1H), 8.27 (dd, J = 8.2, 1.1 Hz, 1H), 7.76 (ddd, J = 8.4, 6.8, 1.9 Hz, 1H), 7.32 - 7.15 (m, 3H), 7.08 - 6.84 (m, 3H), 3.52 (s, 3H), 1.96 - 1.74 (m, 1H), 1.00 - 0.79 (m, 2H), 0.71 - 0.54 (m, 2H); LCMS(m/z) 316.2 [M+H]+.

<u>Example 106. N-([1,1'-biphenyl]-3-yl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1104<chemistry id="chem1473" num="1473"><img file="EP4445902A2_D1476.tif" /></chemistry>

1105The stirred mixture ofN-(3-iodophenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 101) (0.02 g, 0.05 mmol), sodium carbonate (0.011 g, 0.11 mmol) and phenylboronic acid (0.008 g, 0.07 mmol) in 1,4-dioxane/water (4 mL, 1:1) was deoxygenated with argon for 10 min, followed by the addition of triphenylphosphine (0.0026 g, 0.009 mmol) and palladium(II) acetate (0.0005 g, 0.002 mmol) at RT, and the mixture was heated to 100 °C for 3 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na₂SO₄, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 10% ethyl acetate/ petroleum ether to afford the desired product: ¹H NMR (DMSO-d₆) δ 9.62 (s, 1H), 8.29 (dd, J = 8.4, 1.2 Hz, 1H), 7.76 (ddd, J = 8.4, 7.2, 1.4 Hz, 1H), 7.67 - 7.59 (m, 3H), 7.57 (dt, J = 7.8, 1.3 Hz, 1H), 7.51 - 7.13 (m, 7H), 3.62 (s, 3H); LCMS(m/z) 352.2 [M+H]+.

Example <b>107. N-methyl-N-(3-(pyrrolidin-1-yl)phenyl)-[1,2,4]triazolo[4,3-a]quinazolin-5-</b>amine

1106<chemistry id="chem1474" num="1474"><img file="EP4445902A2_D1477.tif" /></chemistry>

1107To a stirred solution of N-(3-iodophenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 101) (0.1 g, 0.25 mmol) in 1,4-dioxane (6 mL) were added pyrrolidine (0.03 mL, 0.37 mmol) and NatOBu (0.048 g, 0.49 mmol) at RT, and the mixture was deoxygenated with argon for 10 min. Chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2',4', 6'-triisopropyl-1,1'-biphenyl][2-(2-aminoethyl)phenyl]palladium(II) (BrettphosPd-G1, 0.04 g, 0.05 mmol) and 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (RuPhos, 0.035 g, 0.07 mmol) were added at RT and the mixture was heated to 100 °C for 4 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through a bed of celite and washed with ethyl acetate. The organic layer was evaporated under reduced pressure and the residue was purified by silica gel column chromatography and eluted with 4% methanol/dichloromethane, followed by prep. HPLC to afford the desired product: ¹H NMR (DMSO-d₆) δ 9.57 (s, 1H), 8.45 - 8.12 (m, 1H), 7.75 (ddd, J = 8.3, 7.2, 1.3 Hz, 1H), 7.44 (dd, J = 8.4, 1.4 Hz, 1H), 7.23 (ddd, J = 8.5, 7.1, 1.2 Hz, 1H), 7.12 (t, J = 7.9 Hz, 1H), 6.59 - 6.10 (m, 3H), 3.53 (s, 3H), 3.21 - 3.00 (m, 4H), 2.11 - 1.78 (m, 4H); LCMS(m/z) 345.3 [M+H]+.

Example 108. <b>N-methyl-N-(3-morpholinophenyl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</b>

1108<chemistry id="chem1475" num="1475"><img file="EP4445902A2_D1478.tif" /></chemistry>

1109To a stirred solution of N-(3-iodophenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 101) (0.1 g, 0.25 mmol) in 1,4-dioxane (6 mL) were added morpholine (0.032 g, 0.37 mmol) and sodium tert-butoxide (0.048 g, 0.49 mmol) at RT and the mixture was deoxygenated with argon for 10 min, followed by the addition of Chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2',4', 6'-triisopropyl-1,1'-biphenyl][2-(2-aminoethyl)phenyl]palladium(II) (BrettphosPd-G1, 0.04 g, 0.05 mmol) and 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (RuPhos, 0.035 g, 0.07 mmol) at RT. The mixture was heated to 100 °C for 4 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through a bed of celite and washed with ethyl acetate. The organic layer was evaporated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 4% methanol/ dichloromethane, followed by prep. HPLC to afford the desired product: ¹H NMR (DMSO-d₆) δ 9.59 (s, 1H), 8.26 (dd, J = 8.4, 1.3 Hz, 1H), 7.76 (ddd, J = 8.5, 7.3, 1.4 Hz, 1H), 7.34 (dd, J = 8.5, 1.3 Hz, 1H), 7.27 - 7.17 (m, 2H), 6.92 - 6.80 (m, 2H), 6.75 - 6.61 (m, 1H), 3.73 - 3.64 (m, 4H), 3.53 (s, 3H), 3.11 - 2.98 (m, 4H); LCMS(m/z) 361.2 [M+H]+.

<u>Example 109. N-methyl-N-(3-(prop-1-yn-1-yl)phenyl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1110<chemistry id="chem1476" num="1476"><img file="EP4445902A2_D1479.tif" /></chemistry>

1111To a stirred solution of N-(3-iodophenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 101) (0.03 g, 0.07 mmol) in 1,4-dioxane (3 mL) was added triethylamine (0.01 mL, 0.07 mmol) at RT and the mixture was deoxygenated with argon for 10 min, followed by the addition of palladium(II) acetate (0.003 g, 0.01 mmol), triphenylphosphine (0.018 g, 0.07 mmol) and copper iodide (0.003 g, 0.014 mmol) at RT. The mixture was purged with prop-1-yne gas for 10 min, then treated in a microwave reactor at 120 °C for 1 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through a bed of celite and washed with ethyl acetate. The organic layer was evaporated under reduced pressure. The residue was purified by prep. HPLC to afford the desired product: ¹H NMR (DMSO-d₆) δ 9.63 (s, 1H), 8.42 - 8.25 (m, 1H), 7.79 (ddd, J = 8.5, 6.6, 2.0 Hz, 1H), 7.33 - 7.23 (m, 6H), 3.53 (s, 3H), 1.99 (s, 3H); LCMS(m/z) 314.2 [M+H]+.

<u>Example 110. N-methyl-N-phenyl-8-vinyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1112<chemistry id="chem1477" num="1477"><img file="EP4445902A2_D1480.tif" /></chemistry>

1113A mixture of 8-bromo-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 28) (50 mg, 0.141 mmol), K₃PO₄ (47.5 mg, 0.423 mmol), Pd(PPh₃)₄ (32.6 mg, 0.028 mmol) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (43.5 mg, 0.282 mmol) in BuOH (0.71 ml) was heated to 80 °C for 1 h. The reaction mixture was subjected to solid phase extraction (washed with MeOH, then eluted with NH₃ in MeOH) using Bond Elut SCX cartridge (Agilent), and the collected fractions were concentrated in vacuo. The residue was purified by column chromatography (Si-column, CHCl₃ : MeOH = 10 : 0 - 9 : 1) to afford the desired product: ¹H NMR (Methanol-d₄) δ 9.43 (s, 1H), 8.13 (d, J = 1.6 Hz, 1H), 7.47 - 7.37 (m, 2H), 7.37 - 7.07 (m, 5H), 6.80 (dd, J = 17.6, 10.9 Hz, 1H), 6.06 (d, J = 17.5 Hz, 1H), 5.51 (d, J = 10.9 Hz, 1H), 3.62 (s, 3H); LCMS(m/z) 302.2 [M+H]+.

<u>Example 111. 8-Isopropyl-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1114<chemistry id="chem1478" num="1478"><img file="EP4445902A2_D1481.tif" /></chemistry>

1115To a solution of N-methyl-N-phenyl-8-(prop-1-en-2-yl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 96) (20 mg, 0.063 mmol) in EtOH (0.32 mL) was added Pd/C (7 mg, 0.066 mmol), and the mixture was stirred for 3 h at RT under H₂ atmosphere. After removal of Pd/C by filtration, the filtrate was concentrated in vacuo. The residue was purified by column chromatography (Si-column, CHCl₃: MeOH = 10 : 0 - 9 : 1) to the desired product: ¹H NMR (CDCl₃) δ 8.94 (s, 1H), 7.58 (d, J = 1.7 Hz, 1H), 7.42 - 7.32 (m, 2H), 7.33 - 7.12 (m, 4H), 6.97 (dd, J = 8.9, 1.7 Hz, 1H), 3.66 (s, 3H), 3.01 (m, J = 6.9 Hz, 1H), 1.28 (d, J = 6.9 Hz, 6H); LCMS(m/z) 318.2 [M+H]+.

<u>Example 112. 8-Ethyl-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1116<chemistry id="chem1479" num="1479"><img file="EP4445902A2_D1482.tif" /></chemistry>

1117To a solution ofN-methyl-N-phenyl-8-vinyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 110) (20 mg, 0.066 mmol) in EtOH (0.33 mL) was added Pd/C (7 mg), and the mixture was stirred for 3 h at RT under H₂ atmosphere. After removal of Pd/C by filtration, the filtrate was concentrated in vacuo. The residue was purified by column chromatography (Si-column, CHCl₃: MeOH = 10 : 0 - 9 : 1) to afford the desired product: ¹H NMR (Methanol-d₄) δ 9.42 (d, J = 1.9 Hz, 1H), 8.02 - 7.95 (m, 1H), 7.45 - 7.36 (m, 2H), 7.35 - 7.11 (m, 4H), 7.00 (dq, J = 8.6, 1.6 Hz, 1H), 3.66 - 3.54 (m, 3H), 2.82 - 2.71 (m, 2H), 1.26 (td, J = 7.7, 0.8 Hz, 3H); LCMS(m/z) 304.2 [M+H]+.

<u>Example 113. N-methyl-N-phenyl-8-(phenylethynyl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1118<chemistry id="chem1480" num="1480"><img file="EP4445902A2_D1483.tif" /></chemistry>

1119A mixture of 8-bromo-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 28) (15 mg, 0.042 mmol), ethynylbenzene (6.49 mg, 0.064 mmol) and copper(I) iodide (8.07 mg, 0.042 mmol) in acetonitrile (0.21 mL) was heated at 80 °C for 1 h. The reaction mixture was subjected to solid phase extraction (washed with MeOH, then eluted with NH₃ in MeOH) using Bond Elut SCX cartridge (Agilent), and the collected fractions were concentrated in vacuo. The residue was purified by column chromatography (Si-column, CHCl₃ : MeOH = 0-20%), and prep-HPLC (general condition) to afford the desired product: ¹H NMR (CDCl₃) δ 8.94 (s, 1H), 7.91 (dd, J = 1.6, 0.6 Hz, 1H), 7.58 - 7.49 (m, 2H), 7.45 - 7.33 (m, 5H), 7.33 - 7.13 (m, 5H), 3.68 (s, 3H); LCMS(m/z) 376.3 [M+H]+.

<b>Example 114. 8-(2-Methoxyphenyl)-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-</b>amine

1120<chemistry id="chem1481" num="1481"><img file="EP4445902A2_D1484.tif" /></chemistry>

1121A mixture of 8-bromo-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 28) (20 mg, 0.056 mmol), K₃PO₄ (36.0 mg, 0.169 mmol), Pd(OAc)₂ (2.54 mg, 0.011 mmol), tricyclohexylphosphine (3.17 mg, 0.011 mmol) and (2-methoxyphenyl)boronic acid (21.45 mg, 0.141 mmol) in dioxane/water (0.28 mL) was heated at 100 °C for 1 h. The reaction mixture was subjected to solid phase extraction (washed with MeOH, then eluted with NH₃ in MeOH) using Bond Elut SCX cartridge (Agilent), and the collected fractions were concentrated in vacuo. The residue was purified by column chromatography (Si-column, CHCl₃: MeOH = 10:0 - 9:1) to afford the desired product: ¹H NMR (CDCl₃) δ 8.97 (s, 1H), 8.01 (t, J = 1.0 Hz, 1H), 7.44 - 7.36 (m, 3H), 7.34 - 7.20 (m, 6H), 7.09 - 6.99 (m, 2H), 3.82 (s, 3H), 3.70 (s, 3H); LCMS(m/z)382.3 [M+H]+.

<u>Example 115. 3-(5-(Methyl(phenyl)amino)-[1,2,4]triazolo[4,3-a]quinazolin-8-yl)prop-2-yn-1-ol</u>

1122<chemistry id="chem1482" num="1482"><img file="EP4445902A2_D1485.tif" /></chemistry>

(Step 1)Synthesis of N-methyl-N-phenyl-8-(((tetrahydro-2H-pyran-2-yl)oxy)ethynyl)-[1,2,4]triazolo [4,3-a] quinazolin-5-amine

1123<chemistry id="chem1483" num="1483"><img file="EP4445902A2_D1486.tif" /></chemistry>

1124A mixture of 8-bromo-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 28) (15 mg, 0.042 mmol), PdCl₂(dppf) (6.20 mg, 8.47 µmol), triethylamine (17.14 mg, 0.169 mmol), 2-(prop-2-yn-1-yloxy)tetrahydro-2H-pyran (17.81 mg, 0.127 mmol) and copper(I) iodide (1.613 mg, 8.47 µmol) in DMF (0.21 mL) was treated in a microwave reactor for 2 h at 80°C. The reaction mixture was purified by column chromatography (Si-column, CHCl₃: MeOH = 10 : 0 - 9 : 1) to give the desired product. LCMS(m/z) 414.28 [M+H]⁺.

(Step 2) Synthesis of 3-(5-(methyl(phenyl)amino)-[1,2,4]triazolo[4,3-a]quinazolin-8-

yl)prop-2-yn-1-ol

1125A mixture of N-methyl-N-phenyl-8-(((tetrahydro-2H-pyran-2-yl)oxy)ethynyl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (12 mg, 0.029 mmol) and 2N HCl aq. (1 mL) was stirred for 1 h at RT. The reaction mixture was neutralized with 2N NaOH aq. and the mixture was concentrated in vacuo. The residue was purified by column chromatography (Si-column, CHCl₃: MeOH = 10 : 0 - 8 : 2) to afford the desired product: ¹H NMR (CDCl₃) δ 10.13 (s, 1H), 8.79 (s, 1H), 7.51 (td, J = 10.8, 9.5, 4.3 Hz, 3H), 7.34 (d, J = 7.2 Hz, 2H), 7.12 (d, J = 8.7 Hz, 1H), 6.94 (d, J = 8.7 Hz, 1H), 4.47 (s, 2H), 3.79 (s, 3H); LCMS(m/z) 330.2 [M+H]+.

<b>Example 116. 8-(3-Fluorophenyl)-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-</b>amine

1126<chemistry id="chem1484" num="1484"><img file="EP4445902A2_D1487.tif" /></chemistry>

1127A mixture of 8-bromo-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 28) (20 mg, 0.056 mmol), K₃PO₄ (23.97 mg, 0.113 mmol), Pd(OAc)₂ (2.54 mg, 0.011 mmol), tricyclohexylphosphine (3.17 mg, 0.011 mmol) and (4-fluorophenyl)boronic acid (19.75 mg, 0.141 mmol) in dioxane/water (0.28 m 1) was heated at 100 °C for 1 h. The reaction mixture was subjected to solid phase extraction (washed with MeOH, then eluted with NH₃ in MeOH) using Bond Elut SCX cartridge (Agilent), and the collected fractions were concentrated in vacuo. The residue was purified by column chromatography (Si-column, CHCl₃ : MeOH = 10:0 - 9:1) to afford the desired product: ¹H NMR (CDCl₃) δ 9.06 (s, 1H), 7.95 (d, J = 1.7 Hz, 1H), 7.48 - 7.27 (m, 8H), 7.23 - 7.17 (m, 2H), 7.13 (tdd, J = 8.3, 2.6, 1.1 Hz, 1H), 3.69 (s, 3H); LCMS(m/z) 370.3 [M+H]+.

Example 117. 5-(Methyl(phenyl)amino)-[1<b>,2,4]</b>triazolo<b>[4,3-a]</b>quinazoline-8-carbaldehyde

1128<chemistry id="chem1485" num="1485"><img file="EP4445902A2_D1488.tif" /></chemistry>

1129To a solution ofN-methyl-N-phenyl-8-vinyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 110) (50 mg, 0.166 mmol) in acetone/water (1:1, 0.83 mL) were added osmium(VIII) oxide (8.44 mg, 0.033 mmol) and sodium periodate (42.6 mg, 0.199 mmol), and the mixture was stirred overnight at RT. The reaction mixture was subjected to solid phase extraction (washed with MeOH, then eluted with NH₃ in MeOH) using Bond Elut SCX cartridge (Agilent), and the collected fractions were concentrated in vacuo. The residue was purified with prep-HPLC to afford the desired product: ¹H NMR (Methanol-d₄) δ 9.49 (s, 1H), 7.44 (td, J = 6.9, 6.5, 1.6 Hz, 2H), 7.37 - 7.26 (m, 6H), 5.61 (s, 1H), 3.68 (s, 3H); LCMS(m/z) 304.2 [M+H]+.

<b>Example 118. 5-(Methyl(phenyl)amino)-[1,2,4]triazolo[4,3-a]quinazoline-8-carboxylic</b> acid

1130<chemistry id="chem1486" num="1486"><img file="EP4445902A2_D1489.tif" /></chemistry>

1131A mixture of 5-(methyl(phenyl)amino)-[1,2,4]triazolo[4,3-a]quinazoline-8-carbonitrile (Example 94) (50 mg, 0.166 mmol) and sulfuric acid (2 mL, 0.166 mmol) was heated to 80 °C for 5 h. The reaction mixture was cooled to 0 °C, and neutralized with 4N NaOH aq. The mixture was concentrated in vacuo. DMSO was added to the mixture, and the resulting solids were filtered off. The filtrate was purified by prep-HPLC to afford the desired product: ¹H NMR (Methanol-d₄) δ 9.52 (s, 1H), 8.65 (s, 1H), 7.68 (d, J = 8.6 Hz, 1H), 7.50 - 7.27 (m, 6H), 3.69 (s, 3H); LCMS(m/z) 320.2 [M+H]+.

<b>Example 119. N-([1,1'-Biphenyl]-3-yl)-N-methyl-8-nitro-[1,2,4]triazolo[4,3-a]quinazolin-5-</b>amine

1132<chemistry id="chem1487" num="1487"><img file="EP4445902A2_D1490.tif" /></chemistry>

(Step 1) Synthesis of N-(biphenyl-3-yl)-2-chloro-N-methyl-7-nitroquinazolin-4-amine

1133<chemistry id="chem1488" num="1488"><img file="EP4445902A2_D1491.tif" /></chemistry>

1134To a solution ofN-methylbiphenyl-4-amine (22.9 mg, 0.125 mmol) in DMF (0.62 mL) were added 2,4-dichloro-7-nitroquinazoline (30.5 mg, 0.125 mmol) and sodium hydride (3 mg, 0.125 mmol), and the mixture was stirred for 1 h at RT. The reaction mixture was diluted with AcOEt, and washed successively with water and brine, and dried with Na₂SO₄. The organic layer was concentrated in vacuo. The residue was used for the next step without further purification. LCMS(m/z) 391.18 [M+H]⁺.

(Step 2) Synthesis of N-(biphenyl-3-yl)-2-hydrazinyl-N-methyl-7-nitroquinazolin-4-amine

1135<chemistry id="chem1489" num="1489"><img file="EP4445902A2_D1492.tif" /></chemistry>

1136A mixture of N-(biphenyl-3-yl)-2-chloro-N-methyl-7-nitroquinazolin-4-amine (crude, 61 mg, 0.156 mmol) and hydrazine hydrate (15.63 mg, 0.312 mmol) in EtOH (0.78 mL) was stirred at RT to 50 °C to for 2 h. The reaction mixture was diluted with AcOEt, and washed successively with water and brine. The organic layer was concentrated in vacuo. The residue was used for the next step without further purification. LCMS(m/z) 387.23 [M+H]⁺.

(Step 3) Synthesis of

N-([1,1'-biphenyl]-3-yl)-N-methyl-8-nitro-[1,2,4]triazolo[4,3-

a] quinazolin-5-amine

1137A mixture ofN-(biphenyl-3-yl)-2-hydrazinyl-N-methyl-7-nitroquinazolin-4-amine (crude, 62 mg, 0.160 mmol) and triethoxymethane (71.3 mg, 0.481 mmol) was heated at 95 °C for 1 h. The reaction mixture was concentrated in vacuo, and the residue was purified by column chromatography (Si-column, CHCl₃ : MeOH = 10 : 0 - 9 : 1) to afford the desired product: ¹H NMR (CDCl₃) δ 9.08 (s, 1H), 8.66 (d, J = 2.2 Hz, 1H), 7.93 (dd, J = 9.1, 2.2 Hz, 1H), 7.66 - 7.33 (m, 9H), 7.17 (ddd, J = 7.8, 2.2, 1.1 Hz, 1H), 3.76 (s, 3H); LCMS(m/z) 397.3 [M+H]+.

<b>Example 120. N-(4'-Fluoro-[1,1'-biphenyl]-3-yl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-</b>5-amine

1138<chemistry id="chem1490" num="1490"><img file="EP4445902A2_D1493.tif" /></chemistry>

1139A mixture ofN-(3-iodophenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 101) (15 mg, 0.037 mmol), (4-fluorophenyl)boronic acid (13.08 mg, 0.093 mmol), K₃PO₄ (23.81 mg, 0.112 mmol), Pd(OAc)₂ (1.679 mg, 7.48 µmol) and tricyclohexylphosphine (2.097 mg, 7.48 µmol) in dioxane/water (0.2 mL) was heated at 100 °C for 1 h. The reaction mixture was subjected to solid phase extraction (washed with MeOH, then eluted with NH₃ in MeOH) using Bond Elut SCX cartridge (Agilent), and the collected fractions were concentrated in vacuo. The residue was purified by column chromatography (Si-column, CHCl₃: MeOH = 10:0 - 9:1) to afford the desired product: ¹H NMR (CDCl₃) δ 8.99 (s, 1H), 7.89 - 7.80 (m, 1H), 7.67 (ddd, J = 8.4, 7.2, 1.3 Hz, 1H), 7.46 - 7.40 (m, 5H), 7.32 (dq, J = 1.5, 0.9 Hz, 1H), 7.17 - 7.08 (m, 4H), 3.73 (s, 3H); LCMS(m/z) 370.3 [M+H]+.

Example <b>121. N-(3-(Furan-2-yl)phenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</b>

1140<chemistry id="chem1491" num="1491"><img file="EP4445902A2_D1494.tif" /></chemistry>

1141A mixture ofN-(3-iodophenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 101) (15 mg, 0.037 mmol), K₃PO₄ (15.87 mg, 0.075 mmol), Pd(OAc)₂ (1.679 mg, 0.0075 mmol), tricyclohexylphosphine (2.10 mg, 0.0075 mmol), and furan-2-ylboronic acid (6.27 mg, 0.056 mmol) in dioxane/water (0.2 mL) was heated at 100 °C for 1 h. The reaction mixture was subjected to solid phase extraction (washed with MeOH, then eluted with NH₃ in MeOH) using Bond Elut SCX cartridge (Agilent), and the collected fractions were concentrated in vacuo. The residue was purified by column chromatography (Si-column, CHCl₃: MeOH = 10:0 - 9:1) to afford the desired product: ¹H NMR (CDCl₃) δ 8.96 (s, 1H), 7.89 - 7.76 (m, 1H), 7.65 (ddd, J = 8.4, 7.3, 1.3 Hz, 1H), 7.60 - 7.41 (m, 4H), 7.36 (t, J = 7.9 Hz, 1H), 7.13 (ddd, J = 8.5, 7.3, 1.2 Hz, 1H), 7.01 (ddd, J = 7.9, 2.2, 1.0 Hz, 1H), 6.66 (dd, J = 3.4, 0.8 Hz, 1H), 6.47 (dd, J = 3.4, 1.8 Hz, 1H), 3.70 (s, 3H); LCMS(m/z) 342.2 [M+H]+.

Example 122. <b>3-([1,2,4]Triazolo[4,3-a]quinazolin-5-yl(methyl)amino)benzaldehyde</b>

1142<chemistry id="chem1492" num="1492"><img file="EP4445902A2_D1495.tif" /></chemistry>

1143To a stirred solution of (3-([1,2,4]triazolo[4,3-a]quinazolin-5-yl(methyl)amino)phenyl)methanol (Example 83) (0.06 g, 0.19 mmol) in dichloromethane (6 mL) was added manganese(IV) oxide (0.173 g, 1.97 mmol) at RT and the mixture was stirred at RT for 24 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through a bed of celite. The filtrate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography, eluted with 4% methanol/dichloromethane to afford the desired product: ¹H NMR (DMSO-d₆) δ 9.95 (s, 1H), 9.68 (s, 1H), 8.41 - 8.17 (m, 1H), 7.91 - 7.71 (m, 3H), 7.69 - 7.54 (m, 2H), 7.38 - 7.21 (m, 2H), 3.60 (s, 3H); LCMS(m/z) 304.1 [M+H]+.

<u>Example 123. 7-Ethyl-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1144<chemistry id="chem1493" num="1493"><img file="EP4445902A2_D1496.tif" /></chemistry>

(Step 1) Synthesis of 6-bromoquinazoline-2,4(1H,3H)-dione

1145<chemistry id="chem1494" num="1494"><img file="EP4445902A2_D1497.tif" /></chemistry>

1146A stirred mixture of 2-amino-5-bromobenzoic acid (2.0 g, 9.26 mmol) and urea (5.5 g, 92.59 mmol) was heated to 150 °C for 16 h. After cooling to RT, the reaction mixture was diluted with ice-water and stirred for 5 min. The resulting solids were filtered and dried under vacuum to give crude product. The crude compound was triturated with glacial acetic acid to give the desired product. LCMS(m/z) 241.07 [M+H]+.

(Step 2) Synthesis of 6-bromo-2,4-dichloroquinazoline

1147<chemistry id="chem1495" num="1495"><img file="EP4445902A2_D1498.tif" /></chemistry>

1148To a solution of 6-bromoquinazoline-2,4(1H,3H)-dione (1.7 g, 7.08 mmol) in phosphorus oxychloride (6.62 mL, 70.83 mmol) was added N, N-diisopropylethylamine (1.85 mL, 10.62 mmol) at 0 °C and the mixture was stirred at 120 °C for 3 h. The reaction mixture was diluted with ice-water, and the resulting solids were collected. The solids were dissolved in dichloromethane, and washed with water and brine, dried over Na₂SO₄, filtered and evaporated under reduced pressure to give the desired product. LCMS(m/z) 277.15 [M+H]+.

(Step 3) Synthesis of 6-bromo-2-chloro-N-methyl-N-phenylquinazolin-4-amine

1149<chemistry id="chem1496" num="1496"><img file="EP4445902A2_D1499.tif" /></chemistry>

1150To a solution of N-methylaniline (0.2 mL, 1.81 mmol) in DMF (10 mL) was added sodium hydroxide (0.072 g, 1.81 mmol) at 0 °C and the mixture was stirred for 1 h at RT, followed by the addition of 6-bromo-2,4-dichloroquinazoline (0.5 g, 1.81 mmol) at 0 °C. The mixture was then stirred at RT for 2 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed successively with water and brine, dried over Na₂SO₄, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 15% ethyl acetate/petroleum ether to give the desired product. LCMS(m/z) 348.27 [M+H]+.

(Step 4) Synthesis of 6-bromo-2-hydrazinyl-N-methyl-N-phenylquinazolin-4-amine

1151<chemistry id="chem1497" num="1497"><img file="EP4445902A2_D1500.tif" /></chemistry>

1152To a solution of 6-bromo-2-chloro-N-methyl-N-phenylquinazolin-4-amine (1 g, 2.87 mmol) in EtOH (15 mL) was added hydrazine hydrate (0.28 mL, 5.74 mmol) at RT and the mixture was stirred at 50 °C for 16 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed successively with water and brine, dried over Na₂SO₄, filtered and evaporated under reduced pressure to give the desired product. LCMS(m/z) 346.10 [M+H]+.

(Step 5) Synthesis of 7-bromo-<i>N</i>-methyl-<i>N</i>-phenyl-[1,2,4]triazolo[4,3-<i>a</i>]quinazolin-5-amine

1153<chemistry id="chem1498" num="1498"><img file="EP4445902A2_D1501.tif" /></chemistry>

1154A mixture of 6-bromo-2-hydrazinyl-N-methyl-N-phenylquinazolin-4-amine (0.9 g, 2.62 mmol) and triethyl orthoformate (1.3 mL, 7.87 mmol) was heated to 100 °C for 16 h. The reaction mixture was diluted with diethyl ether and stirred for few minutes. The resulting solids were filtered and dried under vacuum to give crude product. The crude compound was washed with diethyl ether to give the desired product. LCMS(m/z) 354.13 [M+H]+.

(Step 6) Synthesis of 7-ethyl-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

1155To a solution of 7-bromo-<i>N</i>-methyl-<i>N</i>-phenyl-[1,2,4]triazolo[4,3-<i>a</i>]quinazolin-5-amine (0.05 g, 0.14 mmol) in 1,4-dioxane/water (5 mL, 4:1) was added ethylboronic acid (0.026 g, 0.35 mmol) and potassium phosphate (0.090 g, 0.42 mmol) at RT and the mixture was deoxygenated with argon for 10 mins, followed by the addition of tricyclohexylphosphine (0.04 g, 0.14 mmol) and Pd(OAc)₂ (0.006 g, 0.03 mmol) at RT, and the mixture was treated in a microwave reactor at 110 °C for 2 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over Na₂SO₄, filtered and evaporated under reduced pressure to give crude product. The crude compound was purified by prep. HPLC to afford the desired product: ¹H NMR (DMSO-d₆) δ 9.57 (s, 1H), 8.19 (d, J = 8.4 Hz, 1H), 7.62 (dd, J = 8.5, 1.9 Hz, 1H), 7.41 (dd, J = 8.4, 7.2 Hz, 2H), 7.36 - 7.22 (m, 3H), 7.05 (d, J = 1.8 Hz, 1H), 3.55 (s, 3H), 2.38 (q, J = 7.6 Hz, 2H), 0.79 (t, J = 7.6 Hz, 3H); LCMS(m/z) 304.3 [M+H]+.

<u>Example 124. N-Methyl-7-nitro-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1156<chemistry id="chem1499" num="1499"><img file="EP4445902A2_D1502.tif" /></chemistry>

(Step 1) Synthesis of 6-Nitroquinazoline-2,4(1H,3H)-dione

1157<chemistry id="chem1500" num="1500"><img file="EP4445902A2_D1503.tif" /></chemistry>

1158A mixture of 2-amino-5-nitrobenzoic acid (4.0 g, 21.98 mmol) and urea (13.18 g, 219.78 mmol) was heated to 150 °C for 16 h. After cooling to RT, the reaction mixture was diluted with ice-water, and stirred for 5 min. The resulting solids were filtered and dried under vacuum to give crude product. The crude compound was triturated with glacial acetic acid to afford the desired product. LCMS(m/z) 208.06 [M+H]+.

(Step 2) Synthesis of 2,4-Dichloro-6-nitroquinazoline

1159<chemistry id="chem1501" num="1501"><img file="EP4445902A2_D1504.tif" /></chemistry>

1160To a solution of 6-nitroquinazoline-2,4(1H,3H)-dione (1.5 g, 7.24 mmol) in phosphorus oxychloride (6.94 mL, 72.46 mmol) was added N, N-diisopropylethylamine (1.89 mL, 10.87 mmol) at 0 °C and the mixture was stirred at 120 °C for 16 h. The reaction mixture was diluted with ice-water and extracted with ethyl acetate. The organic layer was washed successively with water and brine, dried over Na₂SO₄, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with 10% ethyl acetate/petroleum ether to give the desired product.

(Step 3) Synthesis of 2-chloro-<i>N</i>-methyl-6-nitro-<i>N</i>-phenylquinazolin-4-amine

1161<chemistry id="chem1502" num="1502"><img file="EP4445902A2_D1505.tif" /></chemistry>

1162To a solution of N-methylaniline (0.132 g, 1.23 mmol) in DMF (8 mL) was added sodium hydroxide (0.050 g, 1.23 mmol) at 0 °C and the mixture was stirred for 1 h at RT, followed by the addition of 2,4-dichloro-6-nitroquinazoline (0.3 g, 1.23 mmol) at 0 °C. The mixture was then stirred for 16 h at RT. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with ice-water, brine, dried over Na₂SO₄, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 20% ethyl acetate/petroleum ether to give the desired product. LCMS(m/z) 315.15 [M+H]⁺.

(Step 4) Synthesis of 2-Hydrazinyl-<i>N</i>-methyl-6-nitro-<i>N-</i>phenylquinazolin-4-amine

1163<chemistry id="chem1503" num="1503"><img file="EP4445902A2_D1506.tif" /></chemistry>

1164To a solution of 2-chloro-<i>N</i>-methyl-6-nitro-<i>N</i>-phenylquinazolin-4-amine 4 (0.38 g, 1.21 mmol) in EtOH (10 mL) was added hydrazine hydrate (0.12 mL, 2.42 mmol) at RT and the mixture was stirred at 50 °C for 16 h. The reaction mixture was evaporated under reduced pressure to give the desired product. LCMS(m/z) 311.01 [M+H]⁺.

(Step 5) Synthesis of N-methyl-7-nitro-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

1165A mixture of 2-hydrazinyl-<i>N</i>-methyl-6-nitro-<i>N</i>-phenylquinazolin-4-amine (0.3 g, 0.97 mmol) and triethyl orthoformate (1 mL, 5.80 mmol) was stirred at 100 °C for 16 h. The reaction mixture was diluted with diethyl ether and stirred for few minutes. The resulting solids were filtered and dried under vacuum to give crude product. The crude compound was washed with diethyl ether to afford the desired product: ¹H NMR (DMSO-d₆) δ 9.71 (s, 1H), 8.58 (dd, J = 9.1, 2.4 Hz, 1H), 8.50 (d, J = 9.1 Hz, 1H), 8.02 (d, J = 2.4 Hz, 1H), 7.53 - 7.39 (m, 4H), 7.38 - 7.29 (m, 1H), 3.59 (s, 3H); LCMS(m/z) 321.1 [M+H]+.

<u>Example 125. 5-(Methyl(phenyl)amino)-[1,2,4]triazolo[4,3-a]quinazoline-7-carboxamide</u>

1166<chemistry id="chem1504" num="1504"><img file="EP4445902A2_D1507.tif" /></chemistry>

(Step 1) Synthesis of 5-(methyl(phenyl)amino)-[1,2,4]triazolo[4,3-a]quinazoline-7-carbonitrile

1167<chemistry id="chem1505" num="1505"><img file="EP4445902A2_D1508.tif" /></chemistry>

1168To a solution of 7-bromo-<i>N</i>-methyl-<i>N</i>-phenyl-[1,2,4]triazolo[4,3-<i>a</i>]quinazolin-5-amine (0.1 g, 0.28 mmol) in DMF (4 mL) were added zinc cyanide (0.166 g, 1.42 mmol) and zinc dust (0.055 g, 0.84 mmol) at RT and the mixture was deoxygenated with argon for 10 mins, followed by the addition of tetrakis(triphenylphosphine)palladium(0) (0.065 g, 0.06 mmol) at RT. The mixture was then treated in a microwave reactor at 110 °C for 2 h. The reaction mixture was filtered through a bed of celite and washed with ethyl acetate. The filtrate was washed successively with water and brine, dried over Na₂SO₄, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 4% methanol/dichloromethane to give the desired product. LCMS(m/z) 301.31 [M+H]⁺.

(Step 2) Synthesis of 5-(methyl(phenyl)amino)-[1,2,4]triazolo[4,3-a]quinazoline-7-carboxamide

1169To a solution of 5-(methyl(phenyl)amino)-[1,2,4]triazolo[4,3-a]quinazoline-7-carbonitrile (0.1 g, 0.33 mmol) in MeOH (5 mL) were added nickel(ii) chloride hexahydrate (0.031 g, 0.13 mmol) and sodium borohydride (0.177 g, 4.66 mmol) at 0 °C and the mixture was stirred for 48 h at RT. The reaction mixture was quenched with saturated NH₄Cl solution and extracted with 10% methanol/dichloromethane. The organic layer was washed successively with water and brine, dried over Na₂SO₄, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 4% methanol/dichloromethane, followed by prep. HPLC to afford the desired product: ¹H NMR (DMSO-d₆) δ 9.63 (s, 1H), 8.34 (d, J = 8.6 Hz, 1H), 8.18 (dd, J = 8.6, 1.8 Hz, 1H), 7.87 (d, J = 1.9 Hz, 2H), 7.41 - 7.27 (m, 5H), 7.27 - 7.18 (m, 1H), 3.55 (s, 3H); LCMS(m/z) 319.3 [M+H]+.

<u>Example 126. N5-([1,1'-Biphenyl]-3-yl)-N5-methyl-[1,2,4]triazolo[4,3-a]quinazoline-5,8-diamine</u>

1170<chemistry id="chem1506" num="1506"><img file="EP4445902A2_D1509.tif" /></chemistry>

1171To a solution of N-([1,1'-biphenyl]-3-yl)-N-methyl-8-nitro-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 119) (23 mg, 0.058 mmol) in EtOH (0.29 ml) was added Pd/C (6.17 mg), and the mixture was stirred overnight at 70 °C under H₂ atmosphere. After removal of Pd/C by filtration, the filtrate was concentrated in vacuo. The residue was purified by prep-HPLC to afford the desired product: ¹H NMR (Methanol-d₄) δ 9.19 (s, 1H), 7.57 - 7.47 (m, 5H), 7.43 (ddd, J = 7.7, 6.9, 1.3 Hz, 2H), 7.39 - 7.31 (m, 1H), 7.22 (ddd, J = 7.8, 2.3, 1.2 Hz, 1H), 7.16 - 7.05 (m, 2H), 6.44 (dd, J = 9.2, 2.2 Hz, 1H), 3.68 (s, 3H); LCMS(m/z) 367.3 [M+H]+.

<u>Example 127. N-Methyl-N-(3-(pyridin-4-yl)phenyl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1172<chemistry id="chem1507" num="1507"><img file="EP4445902A2_D1510.tif" /></chemistry>

1173A mixture ofN-(3-iodophenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 101) (15 mg, 0.037 mmol), pyridin-4-ylboronic acid (4.60 mg, 0.037 mmol), K₃PO₄ (7.94 mg, 0.037 mmol), Pd(OAc)₂ (8.39 mg, 0.037 mmol) and tricyclohexylphosphine (10.48 mg, 0.037 mmol) in dioxane/water (0.2 mL) was heated at 100 °C for 1 h. The reaction mixture was subjected to solid phase extraction (washed with MeOH, then eluted with NH₃ in MeOH) using Bond Elut SCX cartridge (Agilent), and the collected fractions were concentrated in vacuo. The residue was purified by column chromatography (Si-column, CHCl₃ : MeOH = 10:0 - 9:1) to afford the desired product: ¹H NMR (CDCl₃) δ 8.99 (s, 1H), 8.80 - 8.73 (m, 1H), 8.68 - 8.58 (m, 2H), 7.91 - 7.81 (m, 1H), 7.68 (ddd, J = 8.4, 7.3, 1.3 Hz, 1H), 7.57 - 7.52 (m, 2H), 7.46 - 7.34 (m, 3H), 7.26 (d, J = 7.7 Hz, 1H), 7.16 (ddd, J = 8.5, 7.3, 1.2 Hz, 1H), 3.74 (s, 3H); LCMS(m/z) 353.3 [M+H]+.

<u>Example 128. N-([1,1'-Biphenyl]-3-yl)-8-bromo-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1174<chemistry id="chem1508" num="1508"><img file="EP4445902A2_D1511.tif" /></chemistry>

(Step 1) Synthesis of N-(biphenyl-3-yl)-7-bromo-2-chloro-N-methylquinazolin-4-amine

1175<chemistry id="chem1509" num="1509"><img file="EP4445902A2_D1512.tif" /></chemistry>

1176To a solution of 7-bromo-2,4-dichloroquinazoline (291 mg, 1.049 mmol) in DMF (5 mL) were added N-methylbiphenyl-4-amine (183 mg, 0.999 mmol) and sodium hydride (23.96 mg, 0.999 mmol). The mixture was stirred for 1 h at RT. The reaction mixture was diluted with AcOEt, and washed successively with water and brine, and dried over Na₂SO₄. The organic layer was concentrated in vacuo. The residue was used for the next step without further purification. LCMS(m/z) 424.13 [M+H]⁺.

(Step 2) Synthesis of N-(biphenyl-3-yl)-7-bromo-2-hydrazinyl-N-methylquinazolin-4-amine

1177<chemistry id="chem1510" num="1510"><img file="EP4445902A2_D1513.tif" /></chemistry>

1178A mixture of N-(biphenyl-3-yl)-7-bromo-2-chloro-N-methylquinazolin-4-amine (310 mg, crude) and hydrazine hydrate (73.1 mg, 1.460 mmol) in EtOH (3.6 mL) was stirred for 3 h at 50 °C. The reaction mixture was diluted with AcOEt, and washed successively with water and brine. The organic layer was concentrated in vacuo. The residue was used for the next step without further purification. LCMS(m/z) 420.18 [M+H]⁺.

(Step 3) Synthesis of N-([1,1'-biphenyl]-3-yl)-8-bromo-N-methyl-[1,2,4]triazolo[4,3-a] quinazolin-5-amine

1179A mixture of N-(biphenyl-3-yl)-7-bromo-2-hydrazinyl-N-methylquinazolin-4-amine (256 mg, crude) and triethoxymethane (89 mg, 0.603 mmol) was heated to 100 °C for 2 h. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (Si-column, CHCl₃: MeOH = 10 : 0 - 9 : 1) to afford the desired product: ¹H NMR (CDCl₃) δ 8.91 (s, 1H), 7.98 (dd, J = 1.6, 0.7 Hz, 1H), 7.54 - 7.36 (m, 8H), 7.28 - 7.24 (m, 2H), 7.14 (ddd, J = 7.8, 2.2, 1.1 Hz, 1H), 3.71 (s, 3H); LCMS(m/z) 432.2/433.2 [M+H]+.

<u>Example 129. 3-([1,2,4]Triazolo[4,3-a]quinazolin-5-yl(methyl)amino)benzamide</u>

1180<chemistry id="chem1511" num="1511"><img file="EP4445902A2_D1514.tif" /></chemistry>

(Step 1) Synthesis of 3-([1,2,4]triazolo[4,3-a]quinazolin-5-yl(methyl)amino)benzoic acid

1181<chemistry id="chem1512" num="1512"><img file="EP4445902A2_D1515.tif" /></chemistry>

1182To a stirred solution of methyl 3-([1,2,4]triazolo[4,3-a]quinazolin-5-yl(methyl)amino)benzoate (Example 103) (0.065 g, 0.19 mmol) in THF/water (4 mL, 1:1) was added lithium hydroxide monohydrate (0.025 g, 0.58 mmol) at RT and the mixture was stirred at RT for 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was evaporated under reduced pressure, and the residue was acidified with dilute HCl and evaporated under reduced pressure. The residue was purified by prep. HPLC to give the desired product. LCMS: 320.19 (M+H).

(Step 2) Synthesis of 3-([1,2,4]triazolo[4,3-a]quinazolin-5-yl(methyl)amino)benzamide

1183To a stirred solution of 3-([1,2,4]Triazolo[4,3-a]quinazolin-5-yl(methyl)amino)benzoic acid (0.040 g, 0.12 mmol) in DMF (1 mL) were added 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxidehexafluorophosphate (0.095 g, 0.25 mmol) and N, N-diisopropylethylamine (0.043 mL, 0.25 mmol) at RT , followed by the addition of 7N ammonia in methanol (12 mL) at 0 °C and the mixture was stirred for 16 h at RT. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was evaporated under reduced pressure. The residue was purified by prep. HPLC to afford the desired product: ¹H NMR (DMSO-d₆) δ 9.65 (s, 1H), 8.47 - 8.23 (m, 1H), 7.92 (brs, 1H), 7.83 - 7.70 (m, 3H), 7.47 - 7.44 (m, 2H), 7.38 (brs, 1H), 7.29 - 7.19 (m, 2H), 3.57 (s, 3H); LCMS(m/z) 319.3 [M+H]+.

<u>Example 130. (5-(Methyl(phenyl)amino)-[1,2,4]triazolo[4,3-a]quinazolin-7-yl)methanol</u>

1184<chemistry id="chem1513" num="1513"><img file="EP4445902A2_D1516.tif" /></chemistry>

(Step 1) Synthesis of N-methyl-N-phenyl-7-vinyl-[1,2,4]triazolo[4,3-a] quinazolin-5-amine

1185<chemistry id="chem1514" num="1514"><img file="EP4445902A2_D1517.tif" /></chemistry>

1186To a stirred solution of 7-bromo-<i>N</i>-methyl-<i>N</i>-phenyl-[1,2,4]triazolo[4,3-<i>a</i>]quinazolin-5-amine (0.5 g, 1.41 mmol) in n-butanol (10 mL) was added 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (0.48 mL, 2.82 mmol) at RT and the mixture was deoxygenated with argon for 10 mins, followed by the addition of potassium tert-butoxide (0.475 g, 4.23 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.325 g, 0.28 mmol) at RT. The mixture was then stirred at 80 °C for 2 h. The reaction mixture was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography, eluted with 5% methanol/dichloromethane to give the desired product. LCMS(m/z) 302.21 [M+H]⁺.

(Step 2) Synthesis of 5-(methyl(phenyl)amino)-[1,2,4]triazolo[4,3-a]quinazoline-7-carbaldehyde

1187<chemistry id="chem1515" num="1515"><img file="EP4445902A2_D1518.tif" /></chemistry>

1188To a solution ofN-methyl-N-phenyl-7-vinyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (0.5 g, 1.66 mmol) in acetonitrile/water (15 mL, 2:1) were added sodium periodate (0.426 g, 1.99 mmol) and potassium osmate(VI) dihydrate (0.122 g, 0.33 mmol) at 0 °C and the mixture was stirred at the RT for 16 h. The reaction mixture was evaporated under reduced pressure, and the residue was diluted with water and extracted with ethyl acetate. The organic layer was washed successively with water and brine, dried over Na₂SO₄, filtered and evaporated under reduced pressure to give the desired product. LCMS(m/z) 304.12 [M+H]⁺.

(Step 3) Synthesis of (5-(methyl(phenyl)amino)-[1,2,4]triazolo[4,3-a]quinazolin-7-yl)methanol

1189To a stirred solution of 5-(methyl(phenyl)amino)-[1,2,4]triazolo[4,3-a]quinazoline-7-carbaldehyde (crude, 0.480 g, 1.58 mmol) in MeOH (10 mL) was added sodium borohydride (0.120 g, 3.17 mmol) at 0 °C and the mixture was stirred for 3 h at RT. The reaction mixture was quenched with cold-water and extracted with dichloromethane. The organic layer was washed successively with water and brine, dried over Na₂SO₄, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 5% methanol/ dichloromethane to afford the desired product: ¹H NMR (DMSO-d₆) δ 9.58 (s, 1H), 8.24 (d, J = 8.5 Hz, 1H), 7.70 (dd, J = 8.5, 1.8 Hz, 1H), 7.44 - 7.34 (m, 2H), 7.32 - 7.17 (m, 4H), 5.13 (t, J = 5.5 Hz, 1H), 4.22 (d, J = 5.5 Hz, 2H), 3.55 (s, 3H); LCMS(m/z) 306.1 [M+H]+.

<u>Example 131. N5-Methyl-N5-phenyl-[1,2,4]triazolo[4,3-a]quinazoline-5,7-diamine</u>

1190<chemistry id="chem1516" num="1516"><img file="EP4445902A2_D1519.tif" /></chemistry>

1191To a solution ofN-methyl-7-nitro-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 124) (0.2 g, 0.62 mmol) in MeOH (10 mL) was added Pd/ C (0.04 g) at RT and the mixture was stirred under H₂ atmosphere for 3 h. The reaction mixture was filtered through a bed of celite and washed with methanol. The filtrate was evaporated under reduced pressure, and the residue was purified by prep. HPLC to afford the desired product: ¹H NMR (DMSO-d₆) δ 9.44 (s, 1H), 7.98 (d, J = 8.8 Hz, 1H), 7.46 - 7.27 (m, 2H), 7.28 - 7.11 (m, 3H), 7.01 (dd, J = 8.8, 2.4 Hz, 1H), 6.42 (d, J = 2.4 Hz, 1H), 5.29 (s, 2H), 3.49 (s, 3H); LCMS(m/z) 291.1 [M+H]+.

<u>Example 132. <i>N-</i>(5-(methyl(phenyl)amino)-[1,2,4]triazolo[4,3-a]quinazolin-7-vl)methanesulfonamide</u>

1192<chemistry id="chem1517" num="1517"><img file="EP4445902A2_D1520.tif" /></chemistry>

1193To a stirred solution of N5-methyl-N5-phenyl-[1,2,4]triazolo[4,3-a]quinazoline-5,7-diamine (Example 131) (0.08 g, 0.27 mmol) in THF (5 mL) were added triethylamine (0.058 mL, 0.41 mmol) and methanesulfonyl chloride (0.032 mL, 0.41 mmol) at 0 °C and the mixture was stirred for 24 h at RT. The reaction was quenched with water and extracted with ethyl acetate. The organic layer was washed successively with water and brine, dried over Na₂SO₄, filtered and evaporated under reduced pressure. The residue was purified by prep. HPLC to afford the desired product: ¹H NMR (DMSO-d₆) δ 9.94 (brs, 1H), 9.57 (s, 1H), 8.26 (d, J = 8.9 Hz, 1H), 7.49 (dd, J = 8.9, 2.4 Hz, 1H), 7.40 - 7.34 (m, 2H), 7.30 (d, J = 2.4 Hz, 1H), 7.28 - 7.23 (m, 2H), 7.24 - 7.19 (m, 1H), 3.52 (s, 3H), 2.50 (s, 3H); LCMS(m/z) 369.1 [M+H]+.

<u>Example 133. N-(2'-Fluoro-[1,1'-biphenyl]-3-yl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1194<chemistry id="chem1518" num="1518"><img file="EP4445902A2_D1521.tif" /></chemistry>

1195A mixture ofN-(3-iodophenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 101) (15 mg, 0.037 mmol), K3PO4 (15.87 mg, 0.075 mmol), Pd(OAc)₂ (1.679 mg, 7.48 µmol), tricyclohexylphosphine (2.097 mg, 7.48 µmol), and (1H-pyrazol-4-yl)boronic acid (6.28 mg, 0.056 mmol) in dioxane/water (0.20 mL) was heated at 100 °C for 1 h. The reaction mixture was subjected to solid phase extraction (washed with MeOH, then eluted with NH₃ in MeOH) using Bond Elut SCX cartridge (Agilent), and the collected fractions were concentrated in vacuo. The residue was purified by column chromatography (Si-column, CHCl₃: MeOH = 10:0 - 9:1) to afford the desired product: ¹H NMR (CDCl₃) δ 8.96 (s, 1H), 7.82 (dd, J = 8.3, 1.1 Hz, 1H), 7.66 (ddd, J = 8.3, 7.3, 1.1 Hz, 1H), 7.46 - 7.40 (m, 3H), 7.35 - 7.28 (m, 3H), 7.20 - 7.08 (m, 4H), 3.72 (s, 3H); LCMS(m/z) 370.3 [M+H]+.

<u>Example 134. N-(4'-Methoxy-[1,1'-biphenyl]-3-yl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1196<chemistry id="chem1519" num="1519"><img file="EP4445902A2_D1522.tif" /></chemistry>

1197A mixture ofN-(3-iodophenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 101) (15 mg, 0.037 mmol), K₃PO₄ (15.87 mg, 0.075 mmol), Pd(OAc)₂ (1.679 mg, 0.0075 mmol), tricyclohexylphosphine (2.097 mg, 0.0075 mmol), and (4-methoxyphenyl)boronic acid (8.52 mg, 0.056 mmol) in dioxane/water (0.2 mL) was heated at 100 °C for 1 h. The reaction mixture was subjected to solid phase extraction (washed with MeOH, then eluted with NH₃ in MeOH) using Bond Elut SCX cartridge (Agilent), and the collected fractions were concentrated in vacuo. The residue was purified by column chromatography (Si-column, CHCl₃: MeOH = 10:0 - 9:1) to afford the desired product: ¹H NMR (CDCl₃) δ 8.95 (s, 1H), 7.88 - 7.77 (m, 1H), 7.64 (ddd, J = 8.4, 7.3, 1.3 Hz, 1H), 7.47 - 7.39 (m, 5H), 7.33 (t, J = 1.9 Hz, 1H), 7.19 - 7.08 (m, 2H), 7.01 - 6.85 (m, 2H), 3.83 (s, 3H), 3.72 (s, 3H); LCMS(m/z) 382.3 [M+H]+.

<u>Example 135. N-(3'-Methoxy-[1,1'-biphenyl]-3-yl)-N-methyl-[1,2,4]triazolo[4,3-a]puinazolin-5-amine</u>

1198<chemistry id="chem1520" num="1520"><img file="EP4445902A2_D1523.tif" /></chemistry>

1199A mixture ofN-(3-iodophenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 101) (15 mg, 0.037 mmol), K₃PO₄ (15.87 mg, 0.075 mmol), Pd(OAc)₂ (1.679 mg, 0.0075 mmol), tricyclohexylphosphine (2.097 mg, 0.0075 mmol), and pyrimidin-5-ylboronic acid (6.95 mg, 0.056 mmol) in dioxane/water (0.20 ml) was heated at 100 °C for 1 h. The reaction mixture was subjected to solid phase extraction (washed with MeOH, then eluted with NH₃ in MeOH) using Bond Elut SCX cartridge (Agilent), and the collected fractions were concentrated in vacuo. The residue was purified by column chromatography (Si-column, CHCl₃: MeOH = 10:0 - 9: 1) to afford the desired product: ¹H NMR (Methanol-d₄) δ 9.40 (s, 1H), 8.13 (dd, J = 8.3, 1.2 Hz, 1H), 7.72 (ddd, J = 8.3, 7.2, 1.2 Hz, 1H), 7.58 - 7.46 (m, 3H), 7.37 (dd, J = 8.5, 1.4 Hz, 1H), 7.33 - 7.20 (m, 2H), 7.17 (ddd, J = 8.5, 7.2, 1.2 Hz, 1H), 7.07 (dt, J = 7.7, 1.3 Hz, 1H), 7.01 (t, J = 2.1 Hz, 1H), 6.87 (ddd, J = 8.2, 2.8, 1.0 Hz, 1H), 3.78 (s, 3H), 3.70 (s, 3H); LCMS(m/z) 382.3 [M+H]+.

<u>Example 136. 7-(Methoxymethyl)-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1200<chemistry id="chem1521" num="1521"><img file="EP4445902A2_D1524.tif" /></chemistry>

1201To a stirred solution of (5-(methyl(phenyl)amino)-[1,2,4]triazolo[4,3-a]quinazolin-7-yl)methanol (Example 130) (0.150 g, 0.49 mmol) in DMF (5 mL) was added 60% sodium hydride (0.023 g, 0.59 mmol) at 0 °C and the mixture was stirred for 10 mins at RT, followed by the addition of methyl iodide (0.036 mL, 0.59 mmol) at 0 °C, and the mixture was stirred for 16 h at RT. The reaction mixture was quenched with cold-water and extracted with ethyl acetate. The organic layer was washed successively with water and brine, dried over Na₂SO₄, filtered and evaporated under reduced pressure. The residue was purified by prep. HPLC to afford the desired product: ¹H NMR (DMSO-d₆) δ 9.60 (s, 1H), 8.27 (d, J = 8.5 Hz, 1H), 7.69 (dd, J = 8.5, 1.8 Hz, 1H), 7.42 - 7.37 (m, 2H), 7.33 - 7.29 (m, 2H), 7.28 - 7.24 (m, 1H), 7.20 (d, J = 1.8 Hz, 1H), 4.17 (s, 2H), 3.55 (s, 3H), 2.95 (s, 3H); LCMS(m/z) 320.4 [M+H]+.

<u>Example 137. N-methyl-N-(3-(pyridin-3-yl)phenyl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1202<chemistry id="chem1522" num="1522"><img file="EP4445902A2_D1525.tif" /></chemistry>

1203A mixture ofN-(3-iodophenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 101) (15 mg, 0.037 mmol), K₃PO₄ (15.87 mg, 0.075 mmol), Pd(OAc)₂ (1.679 mg, 0.0075 mmol), tricyclohexylphosphine (2.097 mg, 0.0075 mmol), and pyrimidin-5-ylboronic acid (6.95 mg, 0.056 mmol) in dioxane/water (0.2 mL) was heated at 100 °C for 1 h. The reaction mixture was subjected to solid phase extraction (washed with MeOH, then eluted with NH3 in MeOH) using Bond Elut SCX cartridge (Agilent), and the collected fractions were concentrated in vacuo. The residue was purified by column chromatography (Si-column, CHCl₃: MeOH = 10:0 - 9: 1) to afford the desired product: ¹H NMR (CDCl₃) δ 8.97 (s, 1H), 8.70 (dd, J = 2.4, 0.9 Hz, 1H), 8.58 (dd, J = 4.8, 1.6 Hz, 1H), 7.84 (dd, J = 8.4, 1.1 Hz, 1H), 7.77 (ddd, J = 7.9, 2.4, 1.6 Hz, 1H), 7.67 (ddd, J = 8.4, 7.3, 1.3 Hz, 1H), 7.53 - 7.45 (m, 2H), 7.41 (dd, J = 8.4, 1.3 Hz, 1H), 7.36 - 7.31 (m, 2H), 7.22 (dt, J = 7.0, 2.2 Hz, 1H), 7.15 (ddd, J = 8.5, 7.2, 1.2 Hz, 1H), 3.73 (s, 3H); LCMS(m/z) 353.3 [M+H]+.

<u>Example 138. N-(3-(1H-pyrazol-4-yl)phenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1204<chemistry id="chem1523" num="1523"><img file="EP4445902A2_D1526.tif" /></chemistry>

1205A mixture ofN-(3-iodophenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 101) (15 mg, 0.037 mmol), K3PO4 (15.87 mg, 0.075 mmol), Pd(OAc)₂ (1.679 mg, 0.0075 mmol), tricyclohexylphosphine (2.097 mg, 0.0075 mmol), and (1H-pyrazol-4-yl)boronic acid (6.28 mg, 0.056 mmol) in dioxane/water (0.2 mL) was heated at 100 °C for 1 h. The reaction mixture was subjected to solid phase extraction (washed with MeOH, then eluted with NH₃ in MeOH) using Bond Elut SCX cartridge (Agilent), and the collected fractions were concentrated in vacuo. The residue was purified by column chromatography (Si-column, CHCl₃: MeOH = 10:0 - 9: 1) to afford the desired product: ¹H NMR (CDCl₃) δ 8.96 (s, 1H), 7.90 - 7.74 (m, 3H), 7.65 (ddd, J = 8.4, 7.3, 1.3 Hz, 1H), 7.47 - 7.41 (m, 2H), 7.39 (dd, J = 7.7, 0.5 Hz, 1H), 7.31 (dd, J = 2.2, 1.5 Hz, 1H), 7.14 (ddd, J = 8.5, 7.3, 1.2 Hz, 1H), 7.03 (ddd, J = 7.7, 2.2, 1.2 Hz, 1H), 3.70 (s, 3H); LCMS(m/z) 342.3 [M+H]+.

<u>Example 139. (5-(Methyl(phenyl)amino)-[1,2,4]triazolo[4,3-a]quinazolin-8-yl)methanol</u>

1206<chemistry id="chem1524" num="1524"><img file="EP4445902A2_D1527.tif" /></chemistry>

1207To a solution of 5-(methyl(phenyl)amino)-[1,2,4]triazolo[4,3-a]quinazoline-8-carbaldehyde (Example 117) (89 mg, 0.293 mmol) in MeOH (1.48 mL) was added NaBH₄ (22.20 mg, 0.587 mmol), and the mixture was stirred for 1 h at RT. The reaction mixture was subjected to solid phase extraction (washed with MeOH, then eluted with NH₃ in MeOH) using Bond Elut SCX cartridge (Agilent), and the collected fractions were concentrated in vacuo. The residue was purified by column chromatography (Si-column, CHCl₃: MeOH = 10 : 0 - 9 : 1) to afford the desired product: ¹H NMR (Methanol-d₄) δ 9.44 (s, 1H), 8.14 (d, J = 1.5 Hz, 1H), 7.48 - 7.36 (m, 2H), 7.36 - 7.25 (m, 4H), 7.19 - 7.07 (m, 1H), 4.73 (s, 2H), 3.65 (s, 3H); LCMS(m/z) 306.2 [M+H]+.

<u>Example 140. N-methyl-N-(3-(1-methyl-1H-pyrazol-4-yl)phenyl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1208<chemistry id="chem1525" num="1525"><img file="EP4445902A2_D1528.tif" /></chemistry>

1209A mixture ofN-(3-iodophenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 101) (15 mg, 0.037 mmol), K₃PO₄ (15.87 mg, 0.075 mmol), Pd(OAc)₂ (1.679 mg, 0.0075 mmol), tricyclohexylphosphine (2.097 mg, 0.0075 mmol), and 1-methyl-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1H-pyrazole (11.67 mg, 0.056 mmol) in dioxane/water (0.20 ml) was heated at 100 °C for 1 h. The reaction mixture was subjected to solid phase extraction (washed with MeOH, then eluted with NH₃ in MeOH) using Bond Elut SCX cartridge (Agilent), and the collected fractions were concentrated in vacuo. The residue was purified by column chromatography (Si-column, CHCl₃ : MeOH = 10:0 - 9:1) to afford the desired product: ¹H NMR (CDCl₃) δ 8.95 (s, 1H), 7.81 (dd, J = 8.3, 1.2 Hz, 1H), 7.69 (d, J = 0.8 Hz, 1H), 7.64 (ddd, J = 8.4, 7.3, 1.3 Hz, 1H), 7.56 (dd, J = 13.9, 0.8 Hz, 2H), 7.43 - 7.40 (m, 2H), 7.37 - 7.36 (m, 1H), 7.25 (m, 1H), 7.01 (dt, J = 6.8, 2.1 Hz, 1H), 3.91 (s, 3H), 3.68 (s, 3H); LCMS(m/z) 356.3 [M+H]+.

<u>Example 141. N-Methyl-N-(3-(thiophen-3-yl)phenyl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1210<chemistry id="chem1526" num="1526"><img file="EP4445902A2_D1529.tif" /></chemistry>

1211A mixture ofN-(3-iodophenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 101) (15 mg, 0.037 mmol), K3PO4 (15.87 mg, 0.075 mmol),tricyclohexylphosphine (2.097 mg, 0.0075 mmol), Pd(OAc)₂ (1.679 mg, 0.0075 mmol), and thiophen-3-ylboronic acid (7.18 mg, 0.056 mmol) in dioxane/water (0.2 mL) was heated at 100 °C for 1 h. The reaction mixture was subjected to solid phase extraction (washed with MeOH, then eluted with NH₃ in MeOH) using Bond Elut SCX cartridge (Agilent), and the collected fractions were concentrated in vacuo. The residue was purified by column chromatography (Si-column, CHCl₃ : MeOH = 10:0 - 9:1) to afford the desired product: ¹H NMR (CDCl₃) δ 8.96 (s, 1H), 7.85 - 7.79 (m, 1H), 7.64 (ddd, J = 8.4, 7.3, 1.3 Hz, 1H), 7.50 (ddd, J = 7.7, 1.7, 1.0 Hz, 1H), 7.45 - 7.35 (m, 5H), 7.30 (dd, J = 5.0, 1.3 Hz, 1H), 7.12 (ddd, J = 8.4, 7.3, 1.3 Hz, 1H), 7.07 (ddd, J = 7.9, 2.2, 1.0 Hz, 1H), 3.70 (s, 3H); LCMS(m/z) 358.2 [M+H]+.

<u>Example 142. Methyl 5-(methyl(phenyl)amino)-[1,2,4]triazolo[4,3-a]quinazoline-7-carboxylate</u>

1212<chemistry id="chem1527" num="1527"><img file="EP4445902A2_D1530.tif" /></chemistry>

(Step 1) Synthesis of 5-(methyl(phenyl)amino)-[1,2,4]triazolo[4,3-a]quinazoline-7-carboxylic acid

1213<chemistry id="chem1528" num="1528"><img file="EP4445902A2_D1531.tif" /></chemistry>

1214To a stirred solution of 5-(methyl(phenyl)amino)-[1,2,4]triazolo[4,3-a]quinazoline-7-carbaldehyde (0.2 g, 0.66 mmol) in DMF (6 mL) was added oxone (0.405 g, 1.32 mmol) at RT and the mixture was stirred at RT for 16 h. The reaction mixture was quenched with cold-water and extracted with ethyl acetate. The organic layer was washed successively with water and brine, dried over Na₂SO₄, filtered and evaporated under reduced pressure. The residue was purified by prep. HPLC to give the desired product. LC-MS: 320.23 (M+H).

(Step 2) Synthesis of methyl 5-(methyl(phenyl)amino)-[1,2,4]triazolo[4,3-a]quinazoline-7-carboxylate

1215To a solution of 5-(methyl(phenyl)amino)-[1,2,4]triazolo[4,3-a]quinazoline-7-carboxylic acid (0.15 g, 0.47 mmol) in MeOH (6 mL) was added 4N HCl in MeOH (1 mL) at RT and the mixture was stirred at 80 °C for 3 h. The reaction mixture was evaporated under reduced pressure, and the residue was purified by prep. HPLC to afford the desired product: ¹H-NMR (DMSO-d₆) δ 9.65 (s, 1H), 8.37 (d, J = 8.7 Hz, 1H), 8.23 (dd, J = 8.7, 1.8 Hz, 1H), 7.89 (d, J = 1.8 Hz, 1H), 7.47 - 7.39 (m, 2H), 7.38 - 7.28 (m, 3H), 3.71 (s, 3H), 3.57 (s, 3H); LCMS(m/z) 334.3 [M+H]+.

<u>Example 143. 6-Bromo-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1216<chemistry id="chem1529" num="1529"><img file="EP4445902A2_D1532.tif" /></chemistry>

(Step 1) Synthesis of 5-bromoquinazoline-2,4(1H,3H)-dione

1217<chemistry id="chem1530" num="1530"><img file="EP4445902A2_D1533.tif" /></chemistry>

1218A mixture of 2-amino-6-bromobenzoic acid (5 g, 23.14 mmol) and urea (13.88 g, 231.37 mmol) was heated to 150 °C for 16 h. The reaction mixture was diluted with ice-water and stirred for 30 min. The resulting solids were collected, and the solids were triturated with glacial acetic acid and washed with water and dried under vacuum to give the desired product. LCMS(m/z) 241.02 [M+H]⁺.

(Step 2) Synthesis of 5-bromo-2,4-dichloroquinazoline

1219<chemistry id="chem1531" num="1531"><img file="EP4445902A2_D1534.tif" /></chemistry>

1220To a stirred solution of 5-bromoquinazoline-2,4(1H,3H)-dione (crude, 3.2 g, 13.33 mmol) in phosphorus oxychloride (13 mL, 133.33 mmol) was added N, N-diisopropylethylamine (3.48 mL, 19.99 mmol) at 0 °C and the mixture was stirred at 110 °C for 3 h. The reaction mixture was diluted with ice-water and stirred for 30 min. The resulting solids were filtered, washed with water and dried under vacuum to give the desired product. LCMS(m/z) 277.11 [M+H]⁺.

(Step 3) Synthesis of 5-bromo-2-chloro-N-methyl-N-phenylquinazolin-4-amine

1221<chemistry id="chem1532" num="1532"><img file="EP4445902A2_D1535.tif" /></chemistry>

1222To a stirred mixture of N-methylaniline (0.892 g, 8.33 mmol) in DMF (25 mL) was added sodium hydroxide (0.333 g, 8.33 mmol) at 0 °C and the mixture was stirred at the RT for 1 h, followed by the addition of 5-bromo-2,4-dichloroquinazoline (crude, 2.3 g, 8.33 mmol) at 0 °C. The mixture was then stirred for 2 h at RT. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed successively with water and brine, dried over Na₂SO₄, filtered and evaporated under reduced pressure to give the desired product. LCMS(m/z) 348.15 [M+H]⁺.

(Step 4) Synthesis of 5-bromo-2-hydrazinyl-N-methyl-N-phenylquinazolin-4-amine

1223<chemistry id="chem1533" num="1533"><img file="EP4445902A2_D1536.tif" /></chemistry>

1224To a stirred solution of 5-bromo-2-chloro-N-methyl-N-phenylquinazolin-4-amine (0.5 g, 1.44 mmol) in EtOH (6 mL) was added hydrazine hydrate (0.14 mL g, 2.87 mmol) at RT and the mixture was stirred at RT for 6 h. The reaction mixture was evaporated under reduced pressure to give the desired product. LCMS(m/z) 344.36 [M+H]⁺.

(Step 5) Synthesis of 6-bromo-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

1225The mixture of 5-bromo-2-hydrazinyl-N-methyl-N-phenylquinazolin-4-amine (0.5 g, 1.45 mmol) and triethyl orthoformate (1.45 mL, 8.72 mmol) was stirred at 100 °C for 16 h. The reaction mixture was diluted with diethyl ether and filtered. The filtrate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography, eluted with 5% methanol/dichloromethane and further purified by prep. HPLC to afford the desired product: ¹H-NMR (DMSO-d₆) δ 9.70 (s, 1H), 8.38 (dd, J = 8.3, 1.2 Hz, 1H), 7.75 (t, J = 8.0 Hz, 1H), 7.67 (dd, J = 8.0, 1.2 Hz, 1H), 7.24 - 7.12 (m, 2H), 7.07 - 6.91 (m, 3H), 3.51 (s, 3H); LCMS(m/z) 354.27/356.25 [M+H]+.

<u>Example 144. 8-(Methoxymethyl)-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1226<chemistry id="chem1534" num="1534"><img file="EP4445902A2_D1537.tif" /></chemistry>

1227To a solution of (5-(methyl(phenyl)amino)-[1,2,4]triazolo[4,3-a]quinazolin-8-yl)methanol (Example 139) (15 mg, 0.049 mmol) in DMF (0.25 mL) were added iodomethane (8.37 mg, 0.059 mmol) and sodium hydride (1.415 mg, 0.059 mmol), and the mixture was stirred for 3 h at RT. The reaction mixture was diluted with AcOEt, washed successively with water and brine. The organic layer was concentrated in vacuo, and purified by prep-HPLC to afford the desired product: ¹H NMR (Methanol-d₄) δ 9.46 (s, 1H), 8.16 - 8.14 (m, 1H), 7.46 - 7.40 (m, 2H), 7.35 - 7.31 (m, 1H), 7.30 - 7.26 (m, 3H), 7.17 - 7.06 (m, 1H), 4.57 (m, 2H), 3.66 (s, 3H), 3.43 (s, 3H); LCMS(m/z) 320.2 [M+H]+.

<u>Example 145. N-Methyl-N-(3-(pyrimidin-5-yl)phenyl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1228<chemistry id="chem1535" num="1535"><img file="EP4445902A2_D1538.tif" /></chemistry>

1229A mixture ofN-(3-iodophenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 101) (15 mg, 0.037 mmol), K₃PO₄ (15.87 mg, 0.075 mmol), Pd(OAc)₂ (1.679 mg, 0.0075 mmol), tricyclohexylphosphine (2.097 mg, 0.0075 mmol), and pyrimidin-5-ylboronic acid (6.95 mg, 0.056 mmol) in dioxane/water (0.2 mL) was heated at 100 °C for 1 h. The reaction mixture was subjected to solid phase extraction (washed with MeOH, then eluted with NH₃ in MeOH) using Bond Elut SCX cartridge (Agilent), and the collected fractions were concentrated in vacuo. The residue was purified by column chromatography (Si-column, CHCl₃: MeOH = 10:0 - 9: 1) to afford the desired product: ¹H NMR (CDCl₃) δ 8.81 (s, 1H), 7.76 - 7.68 (m, 1H), 7.66 (t, J = 1.9 Hz, 1H), 7.60 (ddd, J = 8.4, 7.3, 1.3 Hz, 1H), 7.49 (ddd, J = 7.9, 1.9, 1.0 Hz, 1H), 7.45 - 7.34 (m, 2H), 7.12 - 7.02 (m, 2H), 6.80 (td, J = 2.7, 1.5 Hz, 1H), 6.55 (ddd, J = 3.9, 2.6, 1.5 Hz, 1H), 6.30 - 6.19 (m, 1H), 3.61 (s, 3H); LCMS(m/z) 354.3 [M+H]+.

<u>Example 146. N-(3-(1H-Pyrrol-2-yl)phenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1230<chemistry id="chem1536" num="1536"><img file="EP4445902A2_D1539.tif" /></chemistry>

1231A mixture ofN-(3-iodophenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 101) (15 mg, 0.037 mmol), K3PO4 (15.87 mg, 0.075 mmol), Pd(OAc)₂ (1.679 mg, 0.0075 mmol), tricyclohexylphosphine (2.097 mg, 0.0075 mmol) and (1-(tert-butoxycarbonyl)-1H-pyrrol-2-yl)boronic acid (11.83 mg, 0.056 mmol) in dioxane/water (0.2 mL) was treated in a microwave reactor at 100 °C for 1 h. The reaction mixture was subjected to solid phase extraction (washed with MeOH, then eluted with NH₃ in MeOH) using Bond Elut SCX cartridge (Agilent), and the collected fractions were concentrated in vacuo. The residue was purified by column chromatography (Si-column, CHCl₃: MeOH = 10:0 - 9: 1) to afford the desired product: ¹H NMR (CDCl₃) δ 10.56 (s, 1H), 8.77 (s, 1H), 7.77 (t, J = 1.9 Hz, 1H), 7.69 (dd, J = 8.3, 1.2 Hz, 1H), 7.59 (ddd, J = 8.4, 7.2, 1.3 Hz, 1H), 7.51 (ddd, J = 7.9, 1.8, 1.1 Hz, 1H), 7.41 (t, J = 7.9 Hz, 1H), 7.36 (dd, J = 8.5, 1.2 Hz, 1H), 7.13 - 7.04 (m, 2H), 6.78 (td, J = 2.7, 1.5 Hz, 1H), 6.56 (ddd, J = 3.9, 2.7, 1.4 Hz, 1H), 6.21 (dt, J = 3.5, 2.5 Hz, 1H), 3.59 (s, 3H); LCMS(m/z) 341.3 [M+H]+.

<u>Example 147. 3-([1,2,4]Triazolo[4,3-a]quinazolin-5-yl(methyl)amino)benzonitrile</u>

1232<chemistry id="chem1537" num="1537"><img file="EP4445902A2_D1540.tif" /></chemistry>

1233A mixture ofN-(3-iodophenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 101) (20 mg, 0.050 mmol), zinc(II) cyanide (11.71 mg, 0.100 mmol) and Pd(PPh₃)₄ (11.52 mg, 0.010 mmol) in DMF (0.25 mL) was treated in a microwave reactor at 80 °C for 1 h. Then added zinc(II) cyanide (11.71 mg, 0.100 mmol) and Pd(PPh₃)₄ (11.52 mg, 0.010 mmol), and treated in a microwave reactor at 80 °C for 1 h. The reaction mixture was subjected to solid phase extraction (washed with MeOH, then eluted with NH₃ in MeOH) using Bond Elut SCX cartridge (Agilent), and the collected fractions were concentrated in vacuo. The residue was concentrated in vacuo. The residue was purified by column chromatography (Si-column, CHCl₃ : MeOH = 10:0 - 9: 1) to afford the desired product: ¹H NMR (Methanol-d₄) δ 9.50 (s, 1H), 8.23 (dd, J = 8.5, 1.1 Hz, 1H), 7.85 - 7.75 (m, 1H), 7.77 - 7.69 (m, 1H), 7.63 (ddd, J = 6.2, 2.5, 1.4 Hz, 1H), 7.60 - 7.53 (m, 2H), 7.36 (dd, J = 8.5, 1.4 Hz, 1H), 7.28 (ddd, J = 8.4, 7.2, 1.2 Hz, 1H), 3.68 (s, 3H); LCMS(m/z) 301.2 / 302.2 [M+H]+.

<u>Example 148. N-(2'-Methoxy-[1,1'-biphenyl]-3-yl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1234<chemistry id="chem1538" num="1538"><img file="EP4445902A2_D1541.tif" /></chemistry>

1235A mixture ofN-(3-iodophenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 101) (15 mg, 0.037 mmol), K₃PO₄ (15.87 mg, 0.075 mmol), Pd(OAc)₂ (1.679 mg, 0.0075 mmol), tricyclohexylphosphine (2.097 mg, 0.0075 mmol), and (2-methoxyphenyl)boronic acid (8.52 mg, 0.056 mmol) in dioxane/water (0.2 mL) was heated at 100 °C for 1 h. The reaction mixture was subjected to solid phase extraction (washed with MeOH, then eluted with NH₃ in MeOH) using Bond Elut SCX cartridge (Agilent), and the collected fractions were concentrated in vacuo. The residue was purified by column chromatography (Si-column, CHCl₃ : MeOH = 10:0 - 9:1) to afford the desired product: ¹H NMR (CDCl₃) δ 8.95 (d, J = 0.8 Hz, 1H), 7.82 (dt, J = 8.0, 0.8 Hz, 1H), 7.66 (ddd, J = 8.4, 7.3, 1.3 Hz, 1H), 7.48 - 7.39 (m, 3H), 7.34 - 7.27 (m, 2H), 7.21 (dd, J = 7.5, 1.8 Hz, 1H), 7.19 - 7.12 (m, 2H), 6.98 (td, J = 7.5, 1.1 Hz, 1H), 6.92 (dd, J = 8.3, 1.1 Hz, 1H), 3.71 (s, 3H), 3.64 (s, 3H); LCMS(m/z) 382.3 [M+H]+.

<u>Example 149. tert-Butyl (3-(5-(methyl(phenyl)amino)-[1,2,4]triazolo[4,3-a]quinazolin-8-yl)prop-2-yn-1-yl)carbamate</u>

1236<chemistry id="chem1539" num="1539"><img file="EP4445902A2_D1542.tif" /></chemistry>

1237A mixture of 8-bromo-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 28) (30 mg, 0.085 mmol), Pd(dppf)₂Cl (12.39 mg, 0.017 mmol), triethylamine (25.7 mg, 0.254 mmol), tert-butyl prop-2-yn-1-ylcarbamate (26.3 mg, 0.169 mmol) and copper(I) iodide (3.23 mg, 0.017 mmol) in acetonitrile (0.42 mL) was treated in a microwave reactor at 80°C for 2 h. The reaction mixture was subjected to solid phase extraction (washed with MeOH, then eluted with NH₃ in MeOH) using Bond Elut SCX cartridge (Agilent), and the collected fractions were concentrated in vacuo. The filtrate was purified by prep-HPLC to afford the desired product: ¹H NMR (Methanol-d₄) δ 9.40 (s, 1H), 8.24 (d, J = 1.5 Hz, 1H), 7.50 - 7.37 (m, 2H), 7.37 - 7.30 (m, 1H), 7.30 - 7.19 (m, 3H), 7.13 (dd, J = 8.7, 1.5 Hz, 1H), 4.08 (s, 2H), 3.64 (s, 3H), 1.45 (s, 9H); LCMS(m/z) 429.4 [M+H]+.

<u>Example 150. 8-(3-Aminoprop-1-yn-1-yl)-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1238<chemistry id="chem1540" num="1540"><img file="EP4445902A2_D1543.tif" /></chemistry>

1239A mixture oftert-butyl (3-(5-(methyl(phenyl)amino)-[1,2,4]triazolo[4,3-a]quinazolin-8-yl)prop-2-yn-1-yl)carbamate (Example 149) (25 mg, 0.058 mmol) and TFA (5 mL) was stirred for 3 h at RT, then stirred overnight at 50 °C. The reaction mixture was concentrated in vacuo. 4N HCl (5 mL) was added to the residue and the solution was stirred for 3 h at RT, then stirred for overnight at 50 °C. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (Si-column, CHCl₃ : MeOH = 10 : 0 - 9 : 1) to afford the desired product: ¹H NMR (Methanol-d₄) δ 9.64 (s, 1H), 8.54 (d, J = 1.5 Hz, 1H), 7.58 - 7.52 (m, 3H), 7.49 - 7.42 (m, 2H), 7.35 (dd, J = 8.8, 1.5 Hz, 1H), 7.17 (d, J = 8.8 Hz, 1H), 4.12 (s, 2H), 3.80 (s, 3H); LCMS(m/z) 329.2 [M+H]+.

<u>Example 151. N-Methyl-N-(4'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1240<chemistry id="chem1541" num="1541"><img file="EP4445902A2_D1544.tif" /></chemistry>

1241A mixture ofN-(3-iodophenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 101) (15 mg, 0.037 mmol), K₃PO₄ (15.87 mg, 0.075 mmol), Pd(OAc)₂ (1.679 mg, 0.0075 mmol), tricyclohexylphosphine (2.097 mg, 0.0075 mmol), and (4-(trifluoromethyl)phenyl)boronic acid (10.65 mg, 0.056 mmol) in dioxane/water (0.2 mL) was heated at 100 °C for 1 h. The reaction mixture was subjected to solid phase extraction (washed with MeOH, then eluted with NH₃ in MeOH) using Bond Elut SCX cartridge (Agilent), and the collected fractions were concentrated in vacuo. The residue was purified by column chromatography (Si-column, CHCl₃: MeOH = 10:0 - 9:1) to afford the desired product: ¹H NMR (Methanol-d₄) δ 9.42 (s, 1H), 8.13 (dd, J = 8.5, 1.2 Hz, 1H), 7.76 - 7.66 (m, 5H), 7.66 - 7.58 (m, 2H), 7.53 (t, J = 7.8 Hz, 1H), 7.37 (dd, J = 8.5, 1.3 Hz, 1H), 7.30 (ddd, J = 7.9, 2.2, 1.0 Hz, 1H), 7.17 (ddd, J = 8.5, 7.3, 1.2 Hz, 1H), 3.71 (s, 3H); LCMS(m/z) 420.3 [M+H]+.

<u>Example 152. N-Methyl-N-(4'-methyl-[1,1'-biphenyl]-3-yl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1242<chemistry id="chem1542" num="1542"><img file="EP4445902A2_D1545.tif" /></chemistry>

1243A mixture ofN-(3-iodophenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 101) (15 mg, 0.037 mmol), K₃PO₄ (15.87 mg, 0.075 mmol), Pd(OAc)₂ (1.679 mg, 0.0075 mmol), tricyclohexylphosphine (2.097 mg, 0.0075 mmol), and p-tolylboronic acid (7.62 mg, 0.056 mmol) in dioxane/water (0.2 mL) was heated to 100 °C for 1 h. The reaction mixture was subjected to solid phase extraction (washed with MeOH, then eluted with NH3 in MeOH) using Bond Elut SCX cartridge (Agilent), and the collected fractions were concentrated in vacuo. The residue was purified by column chromatography (Si-column, CHCl₃: MeOH = 10 : 0 - 9 : 1) to afford the desired product: ¹H NMR (Methanol-d₄) δ 9.40 (s, 1H), 8.19 - 8.08 (m, 1H), 7.70 (ddd, J = 8.5, 7.3, 1.3 Hz, 1H), 7.53 (ddd, J = 7.8, 1.8, 1.1 Hz, 1H), 7.50 - 7.42 (m, 2H), 7.42 - 7.31 (m, 3H), 7.19 - 7.16 (m, 3H), 7.15 - 7.12 (m, 1H), 3.68 (s, 3H), 2.32 (s, 3H); LCMS(m/z) 366.3 [M+H]+.

<u>Example 153. N-(3'-Fluoro-[1,1'-biphenyl]-3-yl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1244<chemistry id="chem1543" num="1543"><img file="EP4445902A2_D1546.tif" /></chemistry>

1245A mixture ofN-(3-iodophenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 101) (15 mg, 0.037 mmol), K₃PO₄ (15.87 mg, 0.075 mmol), Pd(OAc)₂ (1.679 mg, 0.0075 mmol), tricyclohexylphosphine (2.097 mg, 0.0075 mmol), and (4-(trifluoromethyl)phenyl)boronic acid (10.65 mg, 0.056 mmol) in dioxane/water (0.2 mL) was heated at 100 °C for 1 h. The reaction mixture was subjected to solid phase extraction (washed with MeOH, then eluted with NH₃ in MeOH) using Bond Elut SCX cartridge (Agilent), and the collected fractions were concentrated in vacuo. The residue was purified by column chromatography (Si-column, CHCl₃: MeOH = 10 : 0 - 9 : 1) to afford the desired product: ¹H-NMR (Methanol-d₄) δ 9.45 (s, 1H), 8.24 (d, J = 8.6 Hz, 1H), 8.02 (dd, J = 8.6, 2.0 Hz, 1H), 7.58 - 7.51 (m, 3H), 7.48 - 7.41 (m, 1H), 7.40 - 7.31 (m, 3H), 7.06 (tdd, J = 8.5, 2.6, 0.9 Hz, 1H), 6.93 (dt, J = 7.8, 1.2 Hz, 1H), 6.76 (dt, J = 10.3, 2.1 Hz, 1H), 3.71 (s, 3H); LCMS(m/z) 370.3 [M+H]+.

<u>Example 154. N8-(2-Methoxyethyl)-NS-methyl-N5-phenyl-[1,2,4]triazolo[4,3-a]quinazoline-5,8-diamine</u>

1246<chemistry id="chem1544" num="1544"><img file="EP4445902A2_D1547.tif" /></chemistry>

1247To a solution of 8-bromo-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 28) (20 mg, 0.056 mmol) in acetonitrile (0.28 mL) were added 2-methoxyethan-1-amine (4.24 mg, 0.056 mmol), K₂CO₃ (7.80 mg, 0.056 mmol), Pd(dba)₃ (0.056 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (32.7 mg, 0.056 mmol). The mixture was stirred for 2 h at 80 °C. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (Si-column, CHCl₃: MeOH = 10 : 0 - 85 : 15), and further purified by prep-HPLC to afford the desired product: ¹H NMR (Methanol-d₄) δ 9.32 (s, 1H), 7.49 - 7.37 (m, 2H), 7.32 - 7.25 (m, 1H), 7.25 - 7.19 (m, 2H), 7.04 (t, J = 1.8 Hz, 1H), 7.01 - 6.89 (m, 1H), 6.40 (ddd, J = 9.3, 2.4, 0.7 Hz, 1H), 3.62 - 3.57 (m, 5H), 3.41 (t, J = 5.3 Hz, 2H), 3.37 (s, 3H); LCMS(m/z) 349.3 [M+H]+.

<u>Example 155. 3'-([1,2,4]Triazolo[4,3-a]quinazolin-5-yl(methyl)amino)-[1,1'-biphenyl]-4-ol</u>

1248<chemistry id="chem1545" num="1545"><img file="EP4445902A2_D1548.tif" /></chemistry>

1249A mixture ofN-(3-iodophenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 101) (15 mg, 0.037 mmol), K₃PO₄ (15.87 mg, 0.075 mmol), Pd(OAc)₂ (1.679 mg, 0.0075 mmol), tricyclohexylphosphine (2.097 mg, 0.0075 mmol), and (4-hydroxyphenyl)boronic acid (7.74 mg, 0.056 mmol) in dioxane/water (0.2 mL) was heated at 100 °C for 1 h. The reaction mixture was subjected to solid phase extraction (washed with MeOH, then eluted with NH₃ in MeOH) using Bond Elut SCX cartridge (Agilent), and the collected fractions were concentrated in vacuo. The residue was purified by column chromatography (Si-column, CHCl₃: MeOH = 10 : 0 - 9 : 1) to afford the desired product: ¹H NMR (Methanol-d₄) δ 9.44 (s, 1H), 8.18 (dd, J = 8.3, 1.1 Hz, 1H), 7.75 (ddd, J = 8.5, 7.3, 1.3 Hz, 1H), 7.52 (ddd, J = 7.8, 1.8, 1.1 Hz, 1H), 7.48 - 7.43 (m, 3H), 7.41 - 7.35 (m, 2H), 7.24 - 7.14 (m, 2H), 6.83 - 6.80 (m, 2H), 3.71 (s, 3H); LCMS(m/z) 368.3 [M+H]+.

<u>Example 156. N-(4'-Chloro-[1,1'-biphenyl]-3-yl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1250<chemistry id="chem1546" num="1546"><img file="EP4445902A2_D1549.tif" /></chemistry>

1251A mixture ofN-(3-iodophenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 101) (15 mg, 0.037 mmol), K₃PO₄ (15.87 mg, 0.075 mmol), Pd(OAc)₂ (1.679 mg, 0.0075 mmol), tricyclohexylphosphine (2.097 mg, 0.0075 mmol), and (4-chlorophenyl)boronic acid (8.77 mg, 0.056 mmol) in dioxane/water (0.2 mL) was heated at 100 °C for 1 h. The reaction mixture was subjected to solid phase extraction (washed with MeOH, then eluted with NH₃ in MeOH) using Bond Elut SCX cartridge (Agilent), and the collected fractions were concentrated in vacuo. The residue was purified by column chromatography (Si-column, CHCl₃: MeOH = 10 : 0 - 9 : 1) to afford the desired product: ¹H NMR (Methanol-d₄) δ 9.44 (s, 1H), 8.26 - 8.08 (m, 1H), 7.75 (ddd, J = 8.5, 7.3, 1.3 Hz, 1H), 7.58 (ddd, J = 7.8, 1.8, 1.1 Hz, 1H), 7.56 - 7.48 (m, 4H), 7.44 - 7.34 (m, 3H), 7.28 (ddd, J = 7.9, 2.3, 1.1 Hz, 1H), 7.20 (ddd, J = 8.5, 7.3, 1.1 Hz, 1H), 3.71 (s, 3H); LCMS(m/z) 386.3 [M+H]+.

<u>Example 157. 2-((5-(Methyl(phenyl)amino)-[1,2,4]triazolo[4,3-a]quinazolin-8-vl)amino)ethanol</u>

1252<chemistry id="chem1547" num="1547"><img file="EP4445902A2_D1550.tif" /></chemistry>

1253To a solution of 8-bromo-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 28) (20 mg, 0.056 mmol) in acetonitrile (0.42 mL) were added 2-aminoethan-1-ol (6.21 mg, 0.102 mmol), K₂CO₃ (17.56 mg, 0.127 mmol) and Pd(dba)₃ (0.085 mmol). The mixture was stirred for 2 h at 80 °C. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (Si-column, CHCl₃ : MeOH = 10 : 0 - 85 : 15), and further purified by prep-HPLC to afford the desired product: ¹H NMR (Methanol-d₄) δ 9.31 (s, 1H), 7.43 - 7.37 (m, 2H), 7.30 - 7.25 (m, 1H), 7.25 - 7.20 (m, 2H), 7.02 (d, J = 2.3 Hz, 1H), 6.90 (d, J = 9.3 Hz, 1H), 6.39 (dd, J = 9.3, 2.3 Hz, 1H), 3.75 (t, J = 5.6 Hz, 2H), 3.59 (s, 3H), 3.37 (d, J = 5.6 Hz, 2H); LCMS(m/z) 335.3 [M+H]+.

<u>Example 158. 3'-([1,2,4]Triazolo[4,3-a]quinazolin-5-yl(methyl)amino)-[1,1'-biphenyl]-2-ol</u>

1254<chemistry id="chem1548" num="1548"><img file="EP4445902A2_D1551.tif" /></chemistry>

1255A mixture ofN-(3-iodophenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 101) (15 mg, 0.037 mmol), K₃PO₄ (15.87 mg, 0.075 mmol), Pd(OAc)₂ (1.679 mg, 0.0075 mmol), tricyclohexylphosphine (2.097 mg, 0.0075 mmol), and (2-hydroxyphenyl)boronic acid (7.74 mg, 0.056 mmol) in dioxane/water (0.2 mL) was heated at 100 °C for 1 h. The reaction mixture was subjected to solid phase extraction (washed with MeOH, then eluted with NH₃ in MeOH) using Bond Elut SCX cartridge (Agilent), and the collected fractions were concentrated in vacuo. The residue was purified by column chromatography (Si-column, CHCl₃: MeOH = 10 : 0 - 9 : 1) to afford the desired product: ¹H NMR (Methanol-d₄) δ 9.39 (s, 1H), 8.12 (dd, J = 8.4, 1.1 Hz, 1H), 7.72 (ddd, J = 8.4, 7.3, 1.3 Hz, 1H), 7.53 - 7.47 (m, 2H), 7.46 - 7.38 (m, 2H), 7.25 - 7.05 (m, 4H), 6.87 - 6.82 (m, 2H), 3.68 (s, 3H); LCMS(m/z) 368.3 [M+H]+.

<u>Example 159. N-Methyl-N-(3-(1-methyl-1H-pyrazol-5-yl)phenyl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1256<chemistry id="chem1549" num="1549"><img file="EP4445902A2_D1552.tif" /></chemistry>

1257A mixture ofN-(3-iodophenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 101) (15 mg, 0.037 mmol), K₃PO₄ (15.87 mg, 0.075 mmol), Pd(OAc)₂ (1.679 mg, 0.0075 mmol), tricyclohexylphosphine (2.097 mg, 0.0075 mmol), and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (11.67 mg, 0.056 mmol) in dioxane/water (0.2 mL) was heated at 100 °C for 1 h. The reaction mixture was subjected to solid phase extraction (washed with MeOH, then eluted with NH₃ in MeOH) using Bond Elut SCX cartridge (Agilent), and the collected fractions were concentrated in vacuo. The residue was purified by column chromatography (Si-column, CHCl₃ : MeOH = 10 : 0 - 9 : 1) to afford the desired product: ¹H NMR (Methanol-d₄) δ 9.44 (s, 1H), 8.24 - 8.10 (m, 1H), 7.76 (ddd, J = 8.5, 7.3, 1.3 Hz, 1H), 7.59 - 7.55 (m, 1H), 7.45 - 7.39 (m, 4H), 7.33 (t, J = 1.9 Hz, 1H), 7.24 (ddd, J = 8.6, 7.3, 1.3 Hz, 1H), 6.32 (d, J = 2.0 Hz, 1H), 3.71 (s, 3H), 3.62 (s, 3H); LCMS(m/z) 356.3 [M+H]+.

<u>Example 160. N-Methyl-N-(2'-methyl-[1,1'-biphenyl]-3-yl)-[1,2,4]triazolo[4,3-a] quinazolin-5-amine</u>

1258<chemistry id="chem1550" num="1550"><img file="EP4445902A2_D1553.tif" /></chemistry>

1259A mixture ofN-(3-iodophenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 101) (15 mg, 0.037 mmol), K₃PO₄ (15.87 mg, 0.075 mmol), Pd(OAc)₂ (1.679 mg, 0.0075 mmol), tricyclohexylphosphine (2.097 mg, 0.0075 mmol), and o-tolylboronic acid (7.62 mg, 0.056 mmol) in dioxane/water (0.2 mL) was heated at 100 °C for 1 h. The reaction mixture was subjected to solid phase extraction (washed with MeOH, then eluted with NH₃ in MeOH) using Bond Elut SCX cartridge (Agilent), and the collected fractions were concentrated in vacuo. The residue was purified by column chromatography (Si-column, CHCl₃: MeOH = 10 : 0 - 9 : 1) to afford the desired product: ¹H NMR (Methanol-d₄) δ 9.40 (s, 1H), 8.23 - 8.08 (m, 1H), 7.74 (ddd, J = 8.5, 7.2, 1.3 Hz, 1H), 7.51 (t, J = 7.8 Hz, 1H), 7.41 (dd, J = 8.5, 1.1 Hz, 1H), 7.34 (ddd, J = 8.1, 2.3, 1.1 Hz, 1H), 7.27 - 7.20 (m, 2H), 7.17 - 7.13 (m, 3H), 7.07 (t, J = 1.9 Hz, 2H), 3.68 (s, 3H), 2.02 (s, 3H); LCMS(m/z) 366.3 [M+H]+.

<u>Example 161. N-(4'-(tert-Butyl)-[1,1'-biphenyl]-3-yl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1260<chemistry id="chem1551" num="1551"><img file="EP4445902A2_D1554.tif" /></chemistry> NA mixture of N-(3-iodophenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 101) (15 mg, 0.037 mmol), K₃PO₄ (15.87 mg, 0.075 mmol), Pd(OAc)₂ (1.679 mg, 0.0075 mmol), tricyclohexylphosphine (2.097 mg, 0.0075 mmol), and (4-(tert-butyl)phenyl)boronic acid (9.98 mg, 0.056 mmol) in dioxane/water (0.2 mL) was heated at 100 °C for 1 h. The reaction mixture was subjected to solid phase extraction (washed with MeOH, then eluted with NH₃ in MeOH) using Bond Elut SCX cartridge (Agilent), and the collected fractions were concentrated in vacuo. The residue was purified by column chromatography (Si-column, CHCl₃: MeOH = 100 : 0 - 85 : 15) to afford the desired product: ¹H NMR (Methanol-d₄) δ 9.43 (s, 1H), 8.23 - 8.09 (m, 1H), 7.74 (ddd, J = 8.5, 7.3, 1.3 Hz, 1H), 7.58 (ddd, J = 7.8, 1.7, 1.0 Hz, 1H), 7.51 (dd, J = 4.1, 2.1 Hz, 1H), 7.48 - 7.41 (m, 6H), 7.29 - 7.11 (m, 2H), 3.71 (s, 3H), 1.32 (s, 9H); LCMS(m/z) 408.3.

<u>Example 162. N-(3'-([1,2,4]Triazolo[4,3-a]quinazolin-5-yl(methyl)amino)- [1,1'-biohenyl]-4-yl)acetamide</u>

1261<chemistry id="chem1552" num="1552"><img file="EP4445902A2_D1555.tif" /></chemistry>

1262A mixture ofN-(3-iodophenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 101) (15 mg, 0.037 mmol), K₃PO₄ (15.87 mg, 0.075 mmol), Pd(OAc)₂ (1.679 mg, 0.0075 mmol), tricyclohexylphosphine (2.097 mg, 0.0075 mmol), and (4-acetamidophenyl)boronic acid (9.98 mg, 0.056 mmol) in dioxane/water (0.2 mL) was heated at 100 °C for 1 h. The reaction mixture was subjected to solid phase extraction (washed with MeOH, then eluted with NH₃ in MeOH) using Bond Elut SCX cartridge (Agilent), and the collected fractions were concentrated in vacuo. The residue was purified by column chromatography (Si-column, CHCl₃: MeOH = 100 : 0 - 85 : 15) to afford the desired product: ¹H NMR (Methanol-d₄) δ 9.42 (s, 1H), 8.16 (d, J = 8.3 Hz, 1H), 7.77 - 7.69 (m, 1H), 7.60 - 7.55 (m, 3H), 7.50 (ddd, J = 10.8, 5.8, 3.2 Hz, 4H), 7.42 (m, 1H), 7.24 - 7.13 (m, 2H), 3.71 (s, 3H), 2.12 (s, 3H); LCMS(m/z) 409.3.

<u>Example 163. N5-(4'-Fluoro-[1,1'-biphenyl]-3-yl)-N5-methyl-[1,2,4]triazolo[4,3-a]quinazoline-5,8-diamine</u>

1263<chemistry id="chem1553" num="1553"><img file="EP4445902A2_D1556.tif" /></chemistry>

(Step 1) Synthesis of 2-chloro-N-(3-iodophenyl)-N-methyl-7-nitroquinazolin-4-amine

1264<chemistry id="chem1554" num="1554"><img file="EP4445902A2_D1557.tif" /></chemistry>

1265To a solution of 2-chloro-7-nitroquinazolin-4(3H)-one (400 mg, 1.639 mmol) in DMF (8.2 mL) were added 3-iodo-N-methylaniline (382 mg, 1.639 mmol) and sodium hydride (39.3 mg, 1.639 mmol), and the mixture was stirred for 0.5 h at RT. The reaction mixture was diluted with AcOEt, washed successively with water and brine. The organic layer was concentrated in vacuo. The residue was used for the next step without further purification. LCMS(m/z) 440.99 [M+H]⁺.

(Step 2) Synthesis of 2-hydrazinyl-N-(3-iodophenyl)-N-methyl-7-nitroquinazolin-4-amine

1266<chemistry id="chem1555" num="1555"><img file="EP4445902A2_D1558.tif" /></chemistry>

1267A mixture of 2-chloro-N-(3-iodophenyl)-N-methyl-7-nitroquinazolin-4-amine (crude, 256 mg, 0.581 mmol) and hydrazine hydrate (58.2 mg, 1.162 mmol) in EtOH (2.9 mL) was stirred for 2 h at 50 °C. The reaction mixture was diluted with AcOEt, washed successively with water and brine, and dried over Na₂SO₄. The organic layer was concentrated in vacuo. The residue was used for the next step without further purification. LCMS(m/z) 437.03 [M+H]⁺.

(Step 3) Synthesis of N-(3-iodophenyl)-N-methyl-8-nitro-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

1268<chemistry id="chem1556" num="1556"><img file="EP4445902A2_D1559.tif" /></chemistry>

1269A mixture of 2-hydrazinyl-N-(3-iodophenyl)-N-methyl-7-nitroquinazolin-4-amine (208 mg, 0.477 mmol) and triethoxymethane (5 mL, 0.477 mmol) was heated to 100 °C for overnight. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (Si-column, CHCl₃ : MeOH = 10 : 0 - 9 : 1) to give the desired product. LCMS(m/z) 447.04 [M+H]⁺.

(Step 4) Synthesis of N-(4'-fluoro-[1,1'-biphenyl]-3-yl)-N-methyl-8-nitro-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

1270<chemistry id="chem1557" num="1557"><img file="EP4445902A2_D1560.tif" /></chemistry>

1271A mixture of N-(3-iodophenyl)-N-methyl-8-nitro-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (50 mg, 0.112 mmol), tricyclohexylphosphine (6.28 mg, 0.022 mmol), K₃PO₄ (47.6 mg, 0.224 mmol), Pd(OAc)₂ (5.03 mg, 0.022 mmol) and (4-fluorophenyl)boronic acid (23.52 mg, 0.168 mmol) in dioxane/water (0.56 mL) was stirred for 1 h at 100 °C. The reaction mixture was subjected to solid phase extraction (washed with MeOH, then eluted with NH₃ in MeOH) using Bond Elut SCX cartridge (Agilent), and the collected fractions were concentrated in vacuo. The filtrate was concentrated in vacuo. The residue was used for the next step without further purification. LCMS(m/z) 415.18 [M+H]⁺.

(Step 5) Synthesis of N5-(4'-fluoro-[1,1'-biphenyl]-3-yl)-N5-methyl-[1,2,4]triazolo[4,3-a] quinazoline-5,8-diamine

1272A mixture of N-(4'-fluoro-[1,1'-biphenyl]-3-yl)-N-methyl-8-nitro-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (crude, 36 mg) and Pd/C (10 mg) in EtOH (0.43 mL) was stirred for overnight at 60 °C under H₂ atmosphere. After removal of Pd/C by filtration, the filtrate was concentrated in vacuo. The residue was purified by column chromatography (Si-column, CHCl₃ : MeOH = 10 : 0 - 85 : 15) to afford the desired product: ¹H NMR (CDCl₃) δ 8.81 (s, 1H), 7.52 - 7.39 (m, 4H), 7.30 (dd, J = 2.5, 1.4 Hz, 1H), 7.17 - 7.07 (m, 4H), 6.92 (d, J = 2.2 Hz, 1H), 6.36 (dd, J = 9.1, 2.3 Hz, 1H), 4.44 (s, 2H), 3.67 (s, 3H); LCMS(m/z) 385.3.

<u>Example 164. N-Methyl-N-(4'-methyl-[1,1'-biphenyl]-3-yl)-8-nitroso-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1273<chemistry id="chem1558" num="1558"><img file="EP4445902A2_D1561.tif" /></chemistry> To a solution of N-methyl-N-(4'-methyl-[1,1'-biphenyl]-3-yl)-8-nitro-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 179, Step 1, 41.0 mg, crude) in EtOH (0.5 mL) was added Pd/C (6 mg), and the suspension was stirred overnight at 60 °C under H₂ atmosphere. After removal of Pd/C by filtration, the filtrate was concentrated in vacuo. The residue was purified by column chromatography (Si-column, CHCl₃: MeOH = 10 : 0 - 85 : 15) to afford the desired product: ¹H NMR (Methanol-d₄) δ 8.05 (s, 1H), 6.21 (dt, J = 7.8, 1.4 Hz, 1H), 6.14 (m, 3H), 5.96 - 5.90 (m, 3H), 5.86 (ddd, J = 7.7, 2.2, 1.2 Hz, 1H), 5.79 (d, J = 9.3 Hz, 1H), 5.68 (d, J = 2.3 Hz, 1H), 5.09 (dd, J = 9.3, 2.3 Hz, 1H), 2.35 (s, 3H), 1.59 (s, 3H); LCMS(m/z) 395.3.

<u>Example 165. N-(3-Cyclohexylphenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1274<chemistry id="chem1559" num="1559"><img file="EP4445902A2_D1562.tif" /></chemistry>

(Step 1) Synthesis of N-(3-cyclohexenylphenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

1275<chemistry id="chem1560" num="1560"><img file="EP4445902A2_D1563.tif" /></chemistry>

1276A mixture ofN-(3-iodophenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 101) (20 mg, 0.050 mmol), tricyclohexylphosphine (2.80 mg, 0.010 mmol), K₃PO₄ (21.16 mg, 0.100 mmol), Pd(OAc)₂ (2.238 mg, 0.010 mmol) and cyclohex-1-en-1-ylboronic acid (9.42 mg, 0.075 mmol) in dioxane/water (0.25 mL) was treated in a microwave reactor for 1 h at 100 °C. The reaction mixture was subjected to solid phase extraction (washed with MeOH, then eluted with NH₃ in MeOH) using Bond Elut SCX cartridge (Agilent), and the collected fractions were concentrated in vacuo. The residue was used for the next step without further purification. LCMS: 356.18(M+H).

(Step 2) Synthesis of N-(3-cyclohexylphenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

1277To a solution ofN-(3-cyclohexenylphenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (crude, 31 mg, 0.087 mmol) in EtOH (0.436 mL) was added Pd/C (5 mg), and the mixture was stirred overnight at 50 °C under H₂ atmosphere. After removal of Pd/C by filtration, the filtrate was concentrated in vacuo. The residue was purified by column chromatography (Si-column, CHCl₃: MeOH = 10 : 0 - 9 : 1) to afford the desired product: ¹H NMR (Methanol-d₄) δ 9.39 (s, 1H), 8.09 (ddd, J = 8.4, 1.2, 0.6 Hz, 1H), 7.69 (ddd, J = 8.4, 7.2, 1.4 Hz, 1H), 7.34 (t, J = 7.8 Hz, 1H), 7.21 - 7.14 (m, 2H), 7.13 - 7.07 (m, 2H), 7.04 (t, J = 1.9 Hz, 1H), 3.62 (s, 3H), 2.45 (tt, J = 8.2, 3.6 Hz, 1H), 1.86 - 1.65 (m, 6H), 1.37 - 1.28 (m, 4H); LCMS(m/z) 358.3.

<u>Example 166. N-(4'-Ethyl-[1,1'-biphenyl]-3-yl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1278<chemistry id="chem1561" num="1561"><img file="EP4445902A2_D1564.tif" /></chemistry>

1279A mixture ofN-(3-iodophenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 101) (20 mg, 0.050 mmol), tricyclohexylphosphine (2.80 mg, 0.010 mmol), K₃PO₄ (21.16 mg, 0.100 mmol), Pd(OAc)₂ (2.238 mg, 0.010 mmol) and (4-ethylphenyl)boronic acid (11.21 mg, 0.075 mmol) in dioxane/water (0.25 mL) was treated in a microwave reactor at 100 °C for 1 h. The reaction mixture was subjected to solid phase extraction (washed with MeOH, then eluted with NH₃ in MeOH) using Bond Elut SCX cartridge (Agilent), and the collected fractions were concentrated in vacuo. The residue was purified by column chromatography (Si-column, CHCl₃ : MeOH = 10 : 0 - 9 : 1) to afford the desired product: ¹H NMR (Methanol-d₄) δ 9.40 (s, 1H), 8.18 - 8.05 (m, 1H), 7.70 (ddd, J = 8.4, 7.3, 1.3 Hz, 1H), 7.54 (ddd, J = 7.8, 1.8, 1.1 Hz, 1H), 7.49 - 7.39 (m, 4H), 7.35 (dd, J = 8.5, 1.3 Hz, 1H), 7.22 - 7.11 (m, 4H), 3.68 (s, 3H), 2.63 (q, J = 7.6 Hz, 2H), 1.21 (t, J = 7.6 Hz, 3H); LCMS (m/z) 380.3.

<u>Example 167. N5-(4'-Methoxy-[1,1'-biphenyl]-3-yl)-N5-methyl-[1,2,4]triazolo[4,3-a]quinazoline-5,8-diamine</u>

1280<chemistry id="chem1562" num="1562"><img file="EP4445902A2_D1565.tif" /></chemistry>

(Step 1) Synthesis of N-(4'-methoxy-[1,1'-biphenyl]-3-yl)-N-methyl-8-nitro-[1,2,4]triazolo [4,3-a] quinazolin-5-amine

1281<chemistry id="chem1563" num="1563"><img file="EP4445902A2_D1566.tif" /></chemistry>

1282A mixture of N-(3-iodophenyl)-N-methyl-8-nitro-[1,2,4]triazolo[4,3-a]quinazolin-5-amine 6 (40 mg, 0.090 mmol), tricyclohexylphosphine (5.03 mg, 0.018 mmol), K₃PO₄ (38.1 mg, 0.179 mmol), Pd(OAc)₂ (4.03 mg, 0.018 mmol) and (4-methoxyphenyl)boronic acid (20.43 mg, 0.134 mmol) in dioxane/water (0.45 mL) was treated in a microwave reactor for 1 h at 100 °C. The reaction mixture was subjected to solid phase extraction (washed with MeOH, then eluted with NH₃ in MeOH) using Bond Elut SCX cartridge (Agilent), and the collected fractions were concentrated in vacuo. The residue was used for the next step without further purification. LCMS(m/z) 427.18 [M+H]⁺.

(Step 2) Synthesis of N5-(4'-methoxy-[1,1'-biphenyl]-3-yl)-N5-methyl-[1,2,4]triazolo[4,3-a] quinazoline-5,8-diamine

1283To a solution of N-(4'-methoxy-[1,1'-biphenyl]-3-yl)-N-methyl-8-nitro-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (crude, 24 mg) in EtOH (0.28 mL) was added Pd/C (5 mg), and the mixture was stirred overnight at 60 °C under H₂ atmosphere. After removal of Pd/C by filtration, the filtrate was concentrated in vacuo. The residue was purified by column chromatography (Si-column, CHCl₃: MeOH = 10 : 0 - 9 : 1) to afford the desired product: ¹H NMR (Methanol-d₄) δ 9.16 (s, 1H), 8.22 (s, 1H), 7.53 - 7.38 (m, 4H), 7.13 (ddd, J = 7.8, 2.2, 1.1 Hz, 1H), 7.09 - 6.97 (m, 2H), 6.97 - 6.90 (m, 2H), 6.39 (dd, J = 9.2, 2.2 Hz, 1H), 3.80 (s, 3H), 3.63 (s, 3H). LCMS(m/z) 397.3.

<u>Example 168. N-(3'-((8-Amino-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino)-[1,1'-biphenyl] -4-yl)acetamide</u>

1284<chemistry id="chem1564" num="1564"><img file="EP4445902A2_D1567.tif" /></chemistry>

(Step 1) Synthesis of N-(3'-(methyl(8-nitro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)amino)-[1,1'-biphenyl]-4-yl)acetamide

1285<chemistry id="chem1565" num="1565"><img file="EP4445902A2_D1568.tif" /></chemistry>

1286A mixture ofN-(3-iodophenyl)-N-methyl-8-nitro-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (40 mg, 0.090 mmol), tricyclohexylphosphine (5.03 mg, 0.018 mmol), K₃PO₄ (38.1 mg, 0.179 mmol), Pd(OAc)₂ (4.03 mg, 0.018 mmol) and (4-acetamidophenyl)boronic acid (24.07 mg, 0.134 mmol) in dioxane/water (0.45 mL) was heated to 100 °C for 1 h. The reaction mixture was subjected to solid phase extraction (washed with MeOH, then eluted with NH₃ in MeOH) using Bond Elut SCX cartridge (Agilent), and the collected fractions were concentrated in vacuo. The residue was used for the next step without further purification. LCMS(m/z) 454.19 [M+H]⁺.

(Step 2) Synthesis of N-(3'-((8-amino-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino)-[1,1'-biphenyl]-4-yl)acetamide

1287To a solution ofN-(3'-(methyl(8-nitro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)amino)-[1,1'-biphenyl]-4-yl)acetamide (30 mg, crude) in EtOH (0.33 mL) was added Pd/C (5 mg), and the mixture was stirred under H₂ atmosphere for overnight at 50 °C. After removal of Pd/C by filtration, the filtrate was concentrated in vacuo. The residue was purified by column chromatography (Si-column, CHCl₃: MeOH = 10 : 0 - 9 : 1) to afford the desired product: ¹H NMR (Methanol-d₄) δ 9.16 (s, 1H), 7.67 - 7.37 (m, 7H), 7.19 - 7.13 (m, 1H), 7.07 - 7.00 (m, 2H), 6.39 (dd, J = 9.2, 2.2 Hz, 1H), 3.64 (s, 3H), 2.13 (s, 3H); LCMS(m/z) 424.3.

<u>Example 169. N5-(3-Fluorophenyl)-N5-methyl-[1,2,4]triazolo[4,3-quinazoline-5,8-diamine</u>

1288<chemistry id="chem1566" num="1566"><img file="EP4445902A2_D1569.tif" /></chemistry>

(Step 1) Synthesis of 2-chloro-N-(3-fluorophenyl)-N-methyl-7-nitroquinazolin-4-amine

1289<chemistry id="chem1567" num="1567"><img file="EP4445902A2_D1570.tif" /></chemistry>

1290To a solution of 2,4-dichloro-7-nitroquinazoline (100 mg, 0.41 mmol) in DMF (2.1 mL) were added 3-fluoro-N-methylaniline (51.3 mg, 0.41 mmol) and sodium hydride (9.83 mg, 0.41 mmol), and the mixture was stirred for 1 h at RT. The reaction mixture was diluted with AcOEt, washed successively with water and brine. The organic layer was concentrated in vacuo. The residue was used for the next step without further purification. LCMS(m/z) 332.8 [M+H]⁺.

(Step 2) Synthesis of N-(3-fluorophenyl)-2-hydrazinyl-N-methyl-7-nitroquinazolin-4-amine

1291<chemistry id="chem1568" num="1568"><img file="EP4445902A2_D1571.tif" /></chemistry>

1292To a solution of 2-chloro-N-(3-fluorophenyl)-N-methyl-7-nitroquinazolin-4-amine (crude, 114 mg, 0.343 mmol) in EtOH (1.7 mL) was added hydrazine hydrate (17.15 mg, 0.343 mmol), and the mixture was stirred for 1 h at 50 °C. The reaction mixture was diluted with AcOEt, washed successively with water and brine. The organic layer was concentrated in vacuo. The residue was used for the next step without further purification. LCMS(m/z) 328.9 [M+H]⁺.

(Step 3) Synthesis of N-(3-fluorophenyl)-N-methyl-8-nitro-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

1293<chemistry id="chem1569" num="1569"><img file="EP4445902A2_D1572.tif" /></chemistry>

1294A mixture of N-(3-fluorophenyl)-2-hydrazinyl-N-methyl-7-nitroquinazolin-4-amine (crude, 101 mg, 0.308 mmol) and triethoxymethane (3 mL, 0.308 mmol) was stirred at 100 °C overnight. The reaction mixture was concentrated in vacuo, and the residue was purified by column chromatography (Si-column, CHCl₃ : MeOH = 10 : 0 - 85 : 15) to give the desired product. LCMS(m/z) 339.08 [M+H]⁺.

(Step 4) Synthesis of N5-(3-fluorophenyl)-N5-methyl-[1,2,4]triazolo[4,3-a]quinazoline-5,8-diamine

1295To a solution of N-(3-fluorophenyl)-N-methyl-8-nitro-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (66 mg, 0.195 mmol) in EtOH (0.98 mL) was added Pd/C (10 mg), and the suspension was stirred under H2 atmosphere overnight at 60 °C. After removal of Pd/C by filtration, the filtrate was concentrated in vacuo. The residue was purified by column chromatography (Si-column, CHCl₃: MeOH = 10 : 0 - 85 : 15) to afford the desired product: ¹H NMR (Methanol-d₄) δ 9.15 (d, J = 1.8 Hz, 1H), 7.35 (td, J = 8.2, 6.5 Hz, 1H), 7.08 - 6.96 (m, 5H), 6.42 (dt, J = 9.4, 2.0 Hz, 1H), 3.56 (d, J = 1.3 Hz, 3H); LCMS(m/z) 309.1.

<u>Example 170. N5-Ethyl-N5-phenyl-[1,2,4]triazolo[4,3-a]quinazoline-5,8-diamine</u>

1296<chemistry id="chem1570" num="1570"><img file="EP4445902A2_D1573.tif" /></chemistry>

(Step 1) Synthesis of 2-chloro-N-ethyl-7-nitro-N-phenylquinazolin-4-amine

1297<chemistry id="chem1571" num="1571"><img file="EP4445902A2_D1574.tif" /></chemistry>

1298To a solution of 2,4-dichloro-7-nitroquinazoline (200 mg, 0.820 mmol) in DMF (4.1 mL) were added N-ethylaniline (99 mg, 0.820 mmol) and sodium hydride (19.67 mg, 0.820 mmol), and the mixture was stirred for 1 h at RT. The reaction mixture was diluted with AcOEt, washed successively with water and brine. The organic layer was concentrated in vacuo. The residue was used for the next step without further purification. LCMS(m/z) 329.08 [M+H]⁺.

(Step 2) Synthesis of N-ethyl-2-hydrazinyl-7-nitro-N-phenylquinazolin-4-amine

1299<chemistry id="chem1572" num="1572"><img file="EP4445902A2_D1575.tif" /></chemistry>

1300To a solution of 2-chloro-N-ethyl-7-nitro-N-phenylquinazolin-4-amine (crude, 171 mg, 0.52 mmol) in EtOH (2.6 mL) was added hydrazine hydrate (65.1 mg, 1.3 mmol), and the mixture was stirred for 3 h at RT. The reaction mixture was diluted with AcOEt, washed successively with water and brine, and dried over Na₂SO₄. The organic layer was concentrated vacuo. The residue was used for the next step without further purification. LCMS(m/z) 325.08 [M+H]⁺.

(Step 3) Synthesis of N-ethyl-8-nitro-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

1301<chemistry id="chem1573" num="1573"><img file="EP4445902A2_D1576.tif" /></chemistry>

1302A mixture of N-ethyl-2-hydrazinyl-7-nitro-N-phenylquinazolin-4-amine (147 mg, 0.453 mmol) and triethoxymethane (5 mL, 0.453 mmol) was stirred at 100 °C overnight. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (Si-column, CHCl₃ : MeOH = 10 : 0 - 9 : 1) to give the desired product. LCMS(m/z) 335.03 [M+H]⁺.

(Step 4) Synthesis of N5-ethyl-N5-phenyl-[1,2,4]triazolo[4,3-a]quinazoline-5,8-diamine

1303To a solution ofN-ethyl-8-nitro-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (102 mg, 0.305 mmol) in EtOH (1.5 mL) was added Pd/C (15 mg), and the suspension was stirred overnight at 60 °C under H₂ atmosphere. After removal of Pd/C by filtration, the filtrate was concentrated in vacuo. The residue was purified by column chromatography (Si-column, CHCl₃: MeOH = 10 : 0 - 9 : 1) to afford the desired product: ¹H NMR (CDCl₃) δ 8.78 (s, 1H), 7.35 (t, J = 7.6 Hz, 2H), 7.22 (s, 1H), 7.13 (d, J = 7.6 Hz, 2H), 7.00 (d, J = 9.3 Hz, 1H), 6.89 (s, 1H), 6.36 - 6.25 (m, 1H), 3.72 (q, J = 7.0 Hz, 2H), 1.31 (t, J = 7.0 Hz, 3H); LCMS(m/z) 305.2.

<u>Example 171. 5-(3,4-Dihydroquinolin-1(2H)-yl)-[1,2,4]triazolo[4,3-alquinazolin-8-amine</u>

1304<chemistry id="chem1574" num="1574"><img file="EP4445902A2_D1577.tif" /></chemistry>

(Step 1) Synthesis of 2-chloro-4-(3,4-dihydroquinolin-1(2H)-yl)-7-nitroquinazoline

1305<chemistry id="chem1575" num="1575"><img file="EP4445902A2_D1578.tif" /></chemistry>

1306To a solution of 2,4-dichloro-7-nitroquinazoline (500 mg, 2.049 mmol) in DMF (3.1 mL) were added 1,2,3,4-tetrahydroquinoline (273 mg, 2.049 mmol) and sodium hydride (49.2 mg, 2.049 mmol), and the mixture was stirred for 1 h at RT. The reaction mixture was diluted with AcOEt, washed successively with water and brine, and dried over Na₂SO₄. The organic layer was concentrated in vacuo. The residue was used for the next step without further purification. LCMS(m/z) 341.03 [M+H]⁺.

(Step 2) Synthesis of 4-(3,4-dihydroquinolin-1(2H)-yl)-2-hydrazinyl-7-nitroquinazoline

1307<chemistry id="chem1576" num="1576"><img file="EP4445902A2_D1579.tif" /></chemistry>

1308To a solution of 2-chloro-4-(3,4-dihydroquinolin-1(2H)-yl)-7-nitroquinazoline (462 mg, crude) in EtOH (6.8 mL) was added hydrazine hydrate (136 mg, 2.71 mmol), and the mixture was stirred for 1 h at RT. The reaction mixture was diluted with AcOEt and washed successively with water and brine. The organic layer was concentrated in vacuo. The residue was used for the next step without further purification. LCMS(m/z) 337.08 [M+H]⁺.

(Step 3) Synthesis of 5-(3,4-dihydroquinolin-1(2H)-yl)-8-nitro-[1,2,4]triazolo[4,3-a]quinazoline

1309<chemistry id="chem1577" num="1577"><img file="EP4445902A2_D1580.tif" /></chemistry>

1310A mixture of 4-(3,4-dihydroquinolin-1(2H)-yl)-2-hydrazinyl-7-nitroquinazoline (387 mg, 1.151 mmol) and triethoxymethane (171 mg, 1.151 mmol) was stirred at 100 °C overnight. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (Si-column, CHCl₃ : MeOH = 10 : 0 - 9 : 1). LCMS(m/z) 347.13 [M+H]⁺.

(Step 4) Synthesis of 5-(3,4-dihydroquinolin-1(2H)-yl)-[1,2,4]triazolo[4,3-a]quinazolin-8-amine

1311A mixture of 5-(3,4-dihydroquinolin-1(2H)-yl)-8-nitro-[1,2,4]triazolo[4,3-a]quinazoline (60 mg, 0.173 mmol) and Pd/C (5 mg) in EtOH (0.87 mL) was stirred overnight at 60 °C under H₂ atmosphere. After removal of Pd/C by filtration, the filtrate was concentrated in vacuo. The residue was purified by column chromatography (Si-column, CHCl₃ : MeOH = 10 : 0 - 9 : 1) to afford the desired product: ¹H NMR (Methanol-d₄) δ 9.14 (s, 1H), 7.17 (d, J = 9.1 Hz, 1H), 7.15 - 7.11 (m, 1H), 7.01 (d, J = 2.2 Hz, 1H), 6.91 - 6.82 (m, 2H), 6.55 (dd, J = 7.7, 1.6 Hz, 1H), 6.45 (dd, J = 9.1, 2.2 Hz, 1H), 3.86 (t, J = 6.6 Hz, 2H), 2.81 (t, J = 6.6 Hz, 2H), 2.02 (q, J = 6.6 Hz, 2H); LCMS(m/z) 317.2.

<u>Example 172. 8-Bromo-N-methyl-N-(4'-methyl-[1,1'-biphenyl]-3-yl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1312<chemistry id="chem1578" num="1578"><img file="EP4445902A2_D1581.tif" /></chemistry>

(Step1 ) Synthesis of N,4'-Dimethyl-[1,1'-biphenyl]-3-amine

1313<chemistry id="chem1579" num="1579"><img file="EP4445902A2_D1582.tif" /></chemistry>

1314To a stirred solution of 3-iodo-N-methylaniline (2.0 g, 8.58 mmol) and p-tolylboronic acid (2.33 g, 17.16 mmol) in 1,4-dioxane/water (30 mL, 5:1) were added sodium carbonate (1.82 g, 171.7 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (0.630 g, 0.86 mmol) at RT, and the mixture was heated to 80 °C for 3 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through a bed of celite and washed with ethyl acetate. The organic layer was washed with brine, dried over Na₂SO₄, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 10% ethyl acetate/ petroleum ether to give the desired product.

(Step 2) Synthesis of 8-bromo-N-methyl-N-(4'-methyl-[1,1'-biphenyl]-3-yl)-[1,2,4]triazolo [4,3-a] quinazolin-5-amine

1315To a stirred solution of 8-bromo-5-chloro-[1,2,4]triazolo[4,3-a]quinazoline (0.06 g, 0.21 mmol) and N,4'-dimethyl-[1,1'-biphenyl]-3-amine (0.063 g, 0.32 mmol) in MeOH (4 mL) was added triethylamine (0.06 mL, 0.42 mmol) at RT, and the mixture was stirred at RT for 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with water and extracted with 10% methanol/dichloromethane. The organic layer was washed with brine, dried over Na₂SO₄, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 4% methanol/dichloromethane and further purified by prep. HPLC to afford the desired product: ¹H NMR (DMSO-d₆) δ 9.63 (s, 1H), 8.66 (d, J = 2.0 Hz, 1H), 7.62 (t, J = 1.9 Hz, 1H), 7.59 - 7.51 (m, 3H), 7.48 - 7.40 (m, 2H), 7.32 - 7.19 (m, 4H), 3.59 (s, 3H), 2.32 (s, 3H); LCMS(m/z) 444.28/446.26.

<u>Example 173. 8-Bromo-N-(4'-methoxy-[1,1'-biphenyl]-3-yl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1316<chemistry id="chem1580" num="1580"><img file="EP4445902A2_D1583.tif" /></chemistry>

(Step 1) Synthesis of 3-iodo-N-methylaniline

1317<chemistry id="chem1581" num="1581"><img file="EP4445902A2_D1584.tif" /></chemistry>

1318To a stirred solution of 3-iodoaniline (10 g, 45.66 mmol) in methanol (150 mL) was added 37% formaldehyde solution (5.55 mL, 68.49 mmol), followed by the addition of sodium methoxide (4.93 g, 91.32 mmol) at RT and the mixture was heated to 60 °C for 3 h. Then sodium borohydride (3.45 g, 91.32 mmol) was added to the solution at RT and the mixture was stirred at RT for 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with dichloromethane. The organic layer was washed with brine, dried over Na₂SO₄, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 10% ethyl acetate/petroleum ether to give the desired product. LCMS(m/z) 234.08 [M+H]+.

(Step 2) Synthesis of 4'-Methoxy-<i>N</i>-methyl-[1,1'-biphenyl]-3-amine

1319<chemistry id="chem1582" num="1582"><img file="EP4445902A2_D1585.tif" /></chemistry>

1320To a stirred solution of 3-iodo-N-methylaniline (2 g, 8.58 mmol) in 1,4-dioxane/water (30 mL, 5:1) were added (4-methoxyphenyl)boronic acid (2.61 g, 17.17 mmol), sodium carbonate (1.82 g, 171.7 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (0.630 g, 0.86 mmol) at RT, and the mixture was heated to 80 °C for 3 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na₂SO₄, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 15% ethyl acetate/ petroleum ether to give the desired product. LCMS(m/z) 214.36 [M+H]+.

(Step 3) Synthesis of 8-bromo-N-(4'-methoxy-[1,1'-biphenyl]-3-yl)-N-methyl-[1,2,4]triazolo [4,3-a] quinazolin-5-amine

1321To a stirred solution of 8-bromo-5-chloro-[1,2,4]triazolo[4,3-a]quinazoline (0.04 g, 0.14 mmol) in MeOH (2 mL) were added 4'-methoxy-N-methyl-[1,1'-biphenyl]-3-amine (0.039 g, 0.18 mmol) and triethylamine (0.03 mL, 0.21 mmol) at RT, and the mixture was stirred at RT for 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with dichloromethane. The organic layer was washed with brine, dried over Na₂SO₄, filtered and evaporated under reduced pressure. The residue was purified by prep. HPLC to afford the desired product: ¹H NMR (DMSO-d₆) δ 9.64 (s, 1H), 8.67 (d, J = 2.0 Hz, 1H), 7.61 - 7.56 (m, 3H), 7.56 - 7.51 (m, 1H), 7.49 - 7.38 (m, 2H), 7.23 (dd, J = 8.4, 2.7 Hz, 2H), 7.03 - 6.91 (m, 2H), 3.77 (s, 3H), 3.59 (d, J = 2.1 Hz, 3H); LCMS(m/z) 460.19/462.20.

<u>Example 174. N-(3'-((8-Bromo-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino)-[1,1'-binhenvll-4-yl)acetamide</u>

1322<chemistry id="chem1583" num="1583"><img file="EP4445902A2_D1586.tif" /></chemistry>

(Step 1) Synthesis of N-(3'-(methylamino)-[1,1'-biphenyl]-4-yl)acetamide

1323<chemistry id="chem1584" num="1584"><img file="EP4445902A2_D1587.tif" /></chemistry>

1324To a stirred solution of 3-iodo-N-methylaniline (2.0 g, 8.58 mmol) and (4-acetamidophenyl)boronic acid (3.07 g, 17.16 mmol) in 1,4-dioxane/water (30 mL, 5:1) was added sodium carbonate (1.82 g, 171.7 mmol) at RT and the mixture was degassed with argon for 10 min, followed by the addition of [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (0.630 g, 0.86 mmol) at RT and the mixture was heated to 80 °C for 3 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through a bed of celite and washed with ethyl acetate. The organic layer was washed with brine, dried over Na₂SO₄, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with 20% ethyl acetate/petroleum ether to give the desired product. LCMS(m/z) 241.17 [M+H]⁺.

(Step 2) Synthesis of N-(3'-((8-bromo-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino)-[1,1'-biphenyl]-4-yl)acetamide

1325To a stirred solution of 8-bromo-5-chloro-[1,2,4]triazolo[4,3-a]quinazoline (0.110 g, 0.39 mmol) in MeOH (6 mL) were added N-(3'-(methylamino)-[1,1'-biphenyl]-4-yl)acetamide (0.140 g, 0.58 mmol) and triethylamine (0.109 mL, 0.78 mmol) at RT and the mixture was stirred at RT for 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with 10% methanol/dichloromethane. The organic layer was washed with water, brine, dried over Na₂SO₄, filtered and evaporated under reduced pressure. The residue was purified by prep. HPLC to afford the desired product: ¹H NMR (DMSO-d₆) δ 10.02 (s, 1H), 9.64 (s, 1H), 8.67 (d, J = 2.0 Hz, 1H), 7.70 - 7.50 (m, 6H), 7.47 - 7.39 (m, 2H), 7.24 (dd, J = 8.3, 4.8 Hz, 2H), 3.59 (s, 3H), 2.05 (s, 3H); LCMS(m/z) 486.8/488.8.

<b>Example 175. 8-Chloro-N-(4'-methoxy-[1,1'-biphenyl]-3-yl)-N-methyl-[1,2,4]triazolo[4,3-</b>a]<b>quinazolin-5-amine</b>

1326<chemistry id="chem1585" num="1585"><img file="EP4445902A2_D1588.tif" /></chemistry>

1327To a stirred solution of 5,8-dichloro-[1,2,4]triazolo[4,3-a]quinazoline (0.1 g, 0.42 mmol) in DMF (5 mL) were added 4'-methoxy-N-methyl-[1,1'-biphenyl]-3-amine (0.134 g, 0.63 mmol) and sodium hydroxide (0.34 g, 0.84 mmol) at RT and the mixture was stirred at RT for 3 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na₂SO₄, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 6% methanol/dichloromethane to afford the desired product: ¹H NMR (DMSO-d₆) δ 9.63 (s, 1H), 8.53 (t, J = 1.2 Hz, 1H), 7.61 - 7.57 (m, 3H), 7.54 (dt, J = 8.0, 1.3 Hz, 1H), 7.44 (t, J = 7.8 Hz, 1H), 7.31 (m, 2H), 7.23 (ddd, J = 8.0, 2.2, 1.1 Hz, 1H), 7.01 - 6.94 (m, 2H), 3.77 (s, 3H), 3.59 (s, 3H); LCMS(m/z) 416.3.

<b>Example 176. 8-Chloro-N-(4'-chloro-[1,1'-biphenyl]-3-yl)-N-methyl-[1,2,4]triazolo[4,3-</b>a]<b>quinazolin-5-amine</b>

1328<chemistry id="chem1586" num="1586"><img file="EP4445902A2_D1589.tif" /></chemistry>

1329To a stirred solution of 5,8-dichloro-[1,2,4]triazolo[4,3-a]quinazoline (0.150 g, 0.63 mmol) in DMF (10 mL) were added 4'-chloro-N-methyl-[1,1'-biphenyl]-3-amine (0.178 g, 0.82 mmol) and triethylamine (0.18 mL, 1.26 mmol) at RT and the mixture was stirred at RT for 16 h. The reaction mixture was diluted with water and extracted with dichloromethane. The organic layer was washed with brine, dried over Na₂SO₄, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 6% methanol/dichloromethane, followed by prep. HPLC purification to afford the desired product: ¹H NMR (DMSO-d₆) δ 9.64 (s, 1H), 8.54 (t, J = 1.3 Hz, 1H), 7.74 - 7.65 (m, 3H), 7.59 (dt, J = 8.0, 1.2 Hz, 1H), 7.54 - 7.43 (m, 3H), 7.36 - 7.24 (m, 3H), 3.59 (s, 3H); LCMS(m/z) 420.2.

<u>Example 177. 8-Bromo-N-ethyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1330<chemistry id="chem1587" num="1587"><img file="EP4445902A2_D1590.tif" /></chemistry>

(Step 1) Synthesis of 7-bromo-2-chloro-N-ethyl-N-phenylquinazolin-4-amine

1331<chemistry id="chem1588" num="1588"><img file="EP4445902A2_D1591.tif" /></chemistry>

1332To a solution of 7-bromo-2,4-dichloroquinazoline (300 mg, 1.079 mmol) in DMF (5.4 mL) were added sodium hydride (25.9 mg, 1.079 mmol) and N-ethylaniline (131 mg, 1.079 mmol), and the mixture was stirred for 1 h at RT. The mixture was diluted with AcOEt and washed successively with water and brine. The organic layer was concentrated in vacuo. The residue was used for the next step without further purification. LCMS(m/z) 363.7 [M+H]⁺.

(Step 2) Synthesis of 7-bromo-N-ethyl-2-hydrazinyl-N-phenylquinazolin-4-amine

1333<chemistry id="chem1589" num="1589"><img file="EP4445902A2_D1592.tif" /></chemistry>

1334To a solution of 7-bromo-2-chloro-N-ethyl-N-phenylquinazolin-4-amine (234 mg, crude) in EtOH (3.2 ml) was added hydrazine hydrate (64.6 mg, 1.290 mmol), and the mixture was stirred at RT for 1 h. The reaction mixture was diluted with AcOEt, washed successively with water and brine, and dried over Na₂SO₄. The organic layer was concentrated in vacuo. The residue was used for the next step without further purification. LCMS(m/z) 359.8 [M+H]⁺.

(Step 3) Synthesis of 8-bromo-N-ethyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

1335A mixture of 7-bromo-N-ethyl-2-hydrazinyl-N-phenylquinazolin-4-amine (198 mg, crude) and triethoxymethane (7 mL, 0.553 mmol) was stirred overnight at 100 °C. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (Si-column, CHCl₃ : MeOH = 10 : 0 - 85 : 15) to afford the desired product: ¹H NMR (Methanol-d₄) δ 9.38 (s, 1H), 8.37 (d, J = 1.9 Hz, 1H), 7.46 - 7.40 (m, 2H), 7.37 - 7.30 (m, 1H), 7.26 (d, J = 1.5 Hz, 3H), 7.02 (d, J = 9.0 Hz, 1H), 4.21 (q, J = 6.9 Hz, 2H), 1.29 (t, J = 6.9 Hz, 3H); LCMS(m/z) 368.0/380.1.

<u>Example 178. N5-(Cyclopropylmethyl)-N5-phenyl-[1,2,4]triazolo[4,3-a]quinazoline-5,8-diamine</u>

1336<chemistry id="chem1590" num="1590"><img file="EP4445902A2_D1593.tif" /></chemistry>

(Step 1) Synthesis of 2-chloro-N-(cyclopropylmethyl)-7-nitro-N-phenylquinazolin-4-amine

1337<chemistry id="chem1591" num="1591"><img file="EP4445902A2_D1594.tif" /></chemistry>

1338To a solution of 2,4-dichloro-7-nitroquinazoline (250 mg, 1.024 mmol) in DMF (5.1 mL) were added N-(cyclopropylmethyl)aniline (151 mg, 1.024 mmol) and sodium hydride (24.58 mg, 1.024 mmol), and the mixture was stirred for 1 h at RT. The reaction mixture was diluted with AcOEt and washed successively with water and brine. The organic layer was concentrated in vacuo. The residue was used for the next step without further purification. LCMS(m/z) 355.18 [M+H]+.

(Step 2) Synthesis of N-(cyclopropylmethyl)-2-hydrazinyl-7-nitro-N-phenylquinazolin-4-

amine

1339<chemistry id="chem1592" num="1592"><img file="EP4445902A2_D1595.tif" /></chemistry>

1340To a solution of 2-chloro-N-(cyclopropylmethyl)-7-nitro-N-phenylquinazolin-4-amine (302 mg, crude) in EtOH (4.3 mL) was added hydrazine hydrate (42.6 mg, 0.851 mmol) and the mixture was stirred for 30 min at 50 °C. The reaction mixture was diluted with AcOEt and washed successively with water and brine. The organic layer was concentrated in vacuo. The residue was used for the next step without further purification. LCMS(m/z) 351.18 [M+H]+.

(Step 3) Synthesis of N-(cyclopropylmethyl)-8-nitro-N-phenyl-[1,2,4]triazolo[4,3-a] quinazolin-5-amine

1341<chemistry id="chem1593" num="1593"><img file="EP4445902A2_D1596.tif" /></chemistry>

1342A mixture ofN-(cyclopropylmethyl)-2-hydrazinyl-7-nitro-N-phenylquinazolin-4-amine (238 mg, crude) and triethoxymethane (7 mL, 0.679 mmol) was stirred at 100 °C for 4 h. The reaction mixture was concentrated in vacuo, and purified by column chromatography (Si-column, CHCl₃: MeOH = 10 : 0 - 9 : 1) to give the desired product. LCMS(m/z) 361.13 [M+H]+.

(Step 4) NS-(cyclopropylmethyl)-NS-phenyl-[1,2,4]triazolo[4,3-a]quinazoline-5,8-diamine

1343To a solution ofN-(cyclopropylmethyl)-8-nitro-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (212 mg, 0.588 mmol) in EtOH (3.1 mL) was added Pd/C (10 mg) and the suspension was stirred overnight at 60 °C under H₂ atmosphere. After removal of Pd/C by filtration, the filtrate was concentrated in vacuo. The residue was purified by column chromatography (Si-column, CHCl₃ : MeOH = 10 : 0 - 85 : 15) to afford the desired product: ¹H NMR (Methanol-d₄) δ 9.23 (m, 1H), 7.45 - 7.36 (m, 2H), 7.30 - 7.21 (m, 3H), 7.04 - 6.91 (m, 2H), 6.42 - 6.22 (m, 1H), 4.00 (d, J = 6.8 Hz, 2H), 1.29 - 1.02 (m, 1H), 0.43 - 0.37 (m, 2H), 0.19 - 0.10 (m, 2H); LCMS(m/z) 331.1.

<u>Example 179. N5-Methyl-N5-(4'-methyl-[1,1'-biphenyl]-3-yl)-[1,2,4]triazolo[4,3-a]quinazoline-5,8-diamine</u>

1344<chemistry id="chem1594" num="1594"><img file="EP4445902A2_D1597.tif" /></chemistry>

(Step 1) Synthesis of N-methyl-N-(4'-methyl-[1,1'-biphenyl]-3-yl)-8-nitro-[1,2,4]triazolo [4,3-a] quinazolin-5-amine

1345<chemistry id="chem1595" num="1595"><img file="EP4445902A2_D1598.tif" /></chemistry>

1346A mixture of N-(3-iodophenyl)-N-methyl-8-nitro-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (50 mg, 0.112 mmol), Pd(OAc)₂ (5.03 mg, 0.022 mmol), K₃PO₄ (47.6 mg, 0.224 mmol), tricyclohexylphosphine (6.28 mg, 0.022 mmol) and p-tolylboronic acid (18.28 mg, 0.134 mmol) in dioxane/water (0.56 mL) was heated for 1 h at 100 °C. The reaction mixture was subjected to solid phase extraction (washed with MeOH, then eluted with NH₃ in MeOH) using Bond Elut SCX cartridge (Agilent), and the collected fractions were concentrated in vacuo. The residue was used for the next step without further purification. LCMS(m/z) 411.1 [M+H]⁺.

(Step 2) Synthesis of N5-methyl-N5-(4'-methyl-[1,1'-biphenyl]-3-yl)-[1,2,4]triazolo[4,3-a] quinazoline-5,8-diamine

1347To a solution of N-methyl-N-(4'-methyl-[1,1'-biphenyl]-3-yl)-8-nitro-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (45 mg, 0.110 mmol) in EtOH (0.55 mL) was added Pd/C (5 mg), and the suspension was heated to 60 °C under H₂ atmosphere overnight. After removal of Pd/C by filtration, the filtrate was concentrated in vacuo. The residue was purified by column chromatography (Si-column, CHCl₃ : MeOH = 10 : 0 - 80 : 20) to afford the desired product: ¹H NMR (Methanol-d₄) δ 9.17 (s, 1H), 7.53 - 7.47 (m, 1H), 7.44 - 7.41 (m, 3H), 7.24 - 7.21 (m, 3H), 7.20 - 7.14 (m, 1H), 7.09 (d, J = 9.2 Hz, 1H), 7.07 (d, J = 2.2 Hz, 1H), 6.41 (dd, J = 9.2, 2.2 Hz, 1H), 3.65 (s, 3H), 2.35 (s, 3H); LCMS(m/z) 381.2.

<u>Example 180. (5-(Ethyl(phenyl)amino)-[1,2,4]triazolo[4,3-a]quinazolin-8-yl)methanol</u>

1348<chemistry id="chem1596" num="1596"><img file="EP4445902A2_D1599.tif" /></chemistry>

(Step 1) Synthesis of N-ethyl-N-phenyl-8-vinyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

1349<chemistry id="chem1597" num="1597"><img file="EP4445902A2_D1600.tif" /></chemistry>

1350A mixture of 8-bromo-N-ethyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 177) (300 mg, 0.815 mmol), K₃PO₄ (346 mg, 1.629 mmol), Pd(OAc)₂ (36.6 mg, 0.163 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (188 mg, 1.222 mmol) and tricyclohexylphosphine (45.7 mg, 0.163 mmol) in dioxane/water (4.1 mL) was heated to 100 °C for 1 h. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (Si-column, CHCl₃ : MeOH = 10 : 0 - 9 : 1) to give the desired product. LCMS(m/z) 316.08 [M+H]⁺.

(Step 2) Synthesis of 5-(ethyl(phenyl)amino)-[1,2,4]triazolo[4,3-a]quinazoline-8-carbaldehyde

1351<chemistry id="chem1598" num="1598"><img file="EP4445902A2_D1601.tif" /></chemistry>

1352To a solution ofN-ethyl-N-phenyl-8-vinyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (100 mg, 0.317 mmol) in acetone/water (1:1, 1.6 mL) were added osmium(VIII) oxide (8.1 mg, 0.032 mmol) and sodium periodate (81 mg, 0.317 mmol), and the mixture was stirred overnight at RT. The reaction mixture was subjected to solid phase extraction (washed with MeOH, then eluted with NH₃ in MeOH) using Bond Elut SCX cartridge (Agilent), and the collected fractions were concentrated in vacuo. The residue was used for the next step without further purification. LCMS(m/z) 318.03 [M+H]⁺.

(Step 3) Synthesis of (5-(ethyl(phenyl)amino)-[1,2,4]triazolo[4,3-a]quinazolin-8-yl)methanol

1353To a solution of 5-(ethyl(phenyl)amino)-[1,2,4]triazolo[4,3-a]quinazoline-8-carbaldehyde (98 mg, 0.31 mmol) in MeOH (1.5 mL) was added NaBH₄ (12.90 mg, 0.341 mmol), and the mixture was stirred for 2 h at RT. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (Si-column, CHCl₃ : MeOH = 10 : 0 - 85 : 15) to afford the desired product: ¹H NMR (Methanol-d₄) δ 9.42 (d, J = 0.9 Hz, 1H), 8.13 (s, 1H), 7.48 - 7.21 (m, 6H), 7.12 (d, J = 8.7 Hz, 1H), 4.72 (s, 2H), 4.26 (q, J = 7.0 Hz, 2H), 3.35 (s, 1H), 1.36 - 1.32 (t, J = 7.0 Hz, 3H); LCMS(m/z) 320.1.

<u>Example 181. N-Ethyl-8-(methoxymethyl)-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1354<chemistry id="chem1599" num="1599"><img file="EP4445902A2_D1602.tif" /></chemistry>

1355To a solution of (5-(ethyl(phenyl)amino)-[1,2,4]triazolo[4,3-a]quinazolin-8-yl)methanol (Example 180) (50 mg, 0.157 mmol) in DMF (0.78 mL) were added iodomethane (24.44 mg, 0.172 mmol) and sodium hydride (4.51 mg, 0.188 mmol), and the mixture was stirred for 4 h at RT. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (Si-column, CHCl₃ : MeOH = 10 : 0 - 9 : 1) to afford the desired product: ¹H NMR (Methanol-d₄) δ 9.37 (s, 1H), 8.05 - 7.89 (m, 1H), 7.45 - 7.38 (m, 2H), 7.35 - 7.28 (m, 1H), 7.26 - 7.19 (m, 2H), 7.09 (d, J = 8.7 Hz, 1H), 7.00 (dd, J = 8.7, 1.7 Hz, 1H), 4.52 (s, 2H), 4.21 (q, J = 7.0 Hz, 2H), 3.42 (s, 3H), 1.29 (t, J = 7.0 Hz, 3H); LCMS(m/z) 334.1.

<u>Example 182. 7,8-Difluoro-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1356<chemistry id="chem1600" num="1600"><img file="EP4445902A2_D1603.tif" /></chemistry>

(Step 1) Synthesis of 6,7-difluoroquinazoline-2,4(1H,3H)-dione

1357<chemistry id="chem1601" num="1601"><img file="EP4445902A2_D1604.tif" /></chemistry>

1358A mixture of 2-amino-4,5-difluorobenzoic acid (1 g, 5.78 mmol) and urea (0.520 g, 8.66 mmol) in NMP (5 mL) was stirred for 15 h at 150 °C. The reaction mixture was poured onto ice, and the resulting solids were collected. The crude solids were used in the next step without further purification. LCMS(m/z) 199.19 [M+H]⁺.

(Step 2) Synthesis of 2,4-dichloro-6,7-difluoroquinazoline

1359<chemistry id="chem1602" num="1602"><img file="EP4445902A2_D1605.tif" /></chemistry>

1360A mixture of 6,7-difluoroquinazoline-2,4(1H,3H)-dione (1.26 g, 6.36 mmol) and phosphoryl trichloride (10 mL, 6.36 mmol) was stirred for 2 days at 110 °C. The reaction mixture was poured slowly into ice-water. The resulting solids were collected to give the desired product. The crude solids were used in the next step without further purification. LCMS(m/z) 235.09 [M+H]⁺.

(Step 3) Synthesis of 2-chloro-6,7-difluoro-N-methyl-N-phenylquinazolin-4-amine

1361<chemistry id="chem1603" num="1603"><img file="EP4445902A2_D1606.tif" /></chemistry>

1362To a solution of the resulting 2,4-dichloro-6, 7-difluoroquinazoline (450 mg, 1.915 mmol) in DMF (9.57 mL) were added sodium hydride (46.0 mg, 1.915 mmol) and N-methylaniline (215 mg, 2.011 mmol), and the mixture was stirred for 0.5 h at RT. The reaction mixture was diluted with AcOEt, washed successively with water and brine, and dried over Na₂SO₄. The organic layer was concentrated in vacuo. The resulting residue was used in the next step without further purification. LCMS(m/z) 306.03 [M+H]⁺.

(Step 4) Synthesis of 6,7-difluoro-2-hydrazinyl-N-methyl-N-phenylquinazolin-4-amine

1363<chemistry id="chem1604" num="1604"><img file="EP4445902A2_D1607.tif" /></chemistry>

1364Hydrazine hydrate (0.035 g, 0.697 mmol) was added slowly to a stirred solution of the resulting 2-chloro-6,7-difluoro-N-methyl-N-phenylquinazolin-4-amine (0.71 g, 2.32 mmol) in ethanol (11.6 mL) at RT. After 1h and 2h, additional portions of hydrazine hydrate (0.035 g x 2, 1.394 mmol) were added slowly to the solution, and the stirring was continued for 1h. The mixture was diluted with AcOEt, and then washed successively with water and brine and dried over Na₂SO₄. The organic layer was concentrated in vacuo. The resulting residue was used in the next step without further purification. LCMS(m/z) 302.10 [M+H]⁺.

(Step 5) Synthesis of 7,8-difluoro-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

1365A mixture of the resulting 6,7-difluoro-2-hydrazinyl-N-methyl-N-phenylquinazolin-4-amine (0.65 g, 2.16 mmol) and triethylorthoformate (7 mL, 2.18 mmol) was heated to 100 °C for 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the mixture was concentrated in vacuo. The residue was purified by column chromatography (Si-column, CHCl₃: MeOH = 10:0 - 9:1) to afford the desired product: ¹H NMR (Methanol-d₄) δ 9.37 (s, 1H), 8.27 (dd, J = 10.5, 7.0 Hz, 1H), 7.52 - 7.45 (m, 2H), 7.43 - 7.36 (m, 1H), 7.35 - 7.29 (m, 2H), 7.06 (dd, J = 12.1, 8.2 Hz, 1H), 3.65 (s, 3H); LCMS(m/z) 312.1.

<u>Example 183. N-Methyl-N-(4'-methyl-[1,1'-biphenyl]-3-yl)-8-(prop-1-yn-1-yl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1366<chemistry id="chem1605" num="1605"><img file="EP4445902A2_D1608.tif" /></chemistry>

1367To a stirred and degassed solution of 8-bromo-5-chloro-[1,2,4]triazolo[4,3-a]quinazoline (0.150 g, 0.34 mmol) in 1,4-dioxane (6 mL) was added triethylamine (0.047 mL, 0.34 mmol) at RT and the mixture was degassed with argon for 10 min, followed by the addition of triphenylphosphine (0.080 g, 0.30 mmol), copper iodide (0.013 g, 0.07 mmol), Pd(OAc)₂ (0.015 g, 0.07 mmol) and 1-propyne (0.13 mL, 1.69 mmol) at RT, and the mixture was heated to 100 °C for 4 h in a sealed tube. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through a bed of celite and washed with ethyl acetate. The filtrate was evaporated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 4% methanol/dichloromethane and further purified by prep. HPLC to afford the desired product: ¹H NMR (DMSO-d₆) δ 9.63 (s, 1H), 8.40 (d, J = 1.6 Hz, 1H), 7.62 - 7.49 (m, 4H), 7.45 (t, J = 7.8 Hz, 1H), 7.30 - 7.20 (m, 4H), 7.17 (dd, J = 8.7, 1.6 Hz, 1H), 3.59 (s, 3H), 2.31 (s, 3H), 2.09 (s, 3H); LCMS(m/z) 404.2.

<u>Example 184. N-(4'-Methoxv-[1,1'-biphenyl]-3-yl)-N-methyl-8-(prop-1-yn-1-yl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1368<chemistry id="chem1606" num="1606"><img file="EP4445902A2_D1609.tif" /></chemistry>

1369To a stirred and degassed solution of 8-bromo-N-(4'-methoxy-[1,1'-biphenyl]-3-yl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 173) (0.1 g, 0.22 mmol) in 1,4-dioxane (10 mL) were added triphenylphosphine (0.051 g, 0.19 mmol), triethylamine (0.03 mL, 0.22 mmol), copper iodide (0.008 g, 0.04 mmol), palladium acetate (0.010 g, 0.04 mmol) and 1-propyne (0.13 mL, 2.18 mmol) at RT, and the mixture was heated to 100 °C for 6 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na₂SO₄, filtered and evaporated under reduced pressure. The residue was purified by prep. HPLC to afford the desired product: ¹H NMR (DMSO-d₆) δ 9.63 (s, 1H), 8.40 (d, J = 1.6 Hz, 1H), 7.62 - 7.54 (m, 3H), 7.54 - 7.49 (m, 1H), 7.43 (t, J = 7.8 Hz, 1H), 7.27 (d, J = 8.7 Hz, 1H), 7.22 (ddd, J = 7.8, 2.2, 1.0 Hz, 1H), 7.17 (dd, J = 8.7, 1.6 Hz, 1H), 7.01 - 6.90 (m, 2H), 3.77 (s, 3H), 3.59 (s, 3H), 2.09 (s, 3H); LCMS(m/z) 420.2.

<u>Example 185. 8-Bromo-N-(4'-chloro-[1,1'-biphenyl]-3-yl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1370<chemistry id="chem1607" num="1607"><img file="EP4445902A2_D1610.tif" /></chemistry>

(Step 1) Synthesis of 7-bromoquinazoline-2,4(1H,3H)-dione

1371<chemistry id="chem1608" num="1608"><img file="EP4445902A2_D1611.tif" /></chemistry>

1372A mixture of 2-amino-4-bromobenzoic acid (20.0 g, 92.59 mmol) and urea (55.55 g, 925.92 mmol) was heated to 150 °C for 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with ice-water and stirred for 30 min. The resulting solids were filtered off and triturated with glacial acetic acid. The resulting solids were collected and washed with petroleum ether to give the desired product. LCMS(m/z) 241.06 [M+H]⁺.

(Step 2) Synthesis of 7-bromo-2,4-dichloroquinazoline

1373<chemistry id="chem1609" num="1609"><img file="EP4445902A2_D1612.tif" /></chemistry>

1374To a stirred solution of 7-bromoquinazoline-2,4(1H,3H)-dione (19.0 g, 79.17 mmol) in phosphorus oxychloride (74 mL, 791.67 mmol) was added N, N-diisopropylethylamine (19.6 mL, 118.75 mmol) at 0 °C, and the mixture was heated to 110 °C for 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with ice-water and stirred for 30 min. The resulting solid was filtered off, washed with cold water, and dried under vacuum to give the desired product as crude. LCMS(m/z) 279.06 [M+H]⁺.

(Step 3) Synthesis of 7-bromo-2-chloroquinazolin-4(3H)-one

1375<chemistry id="chem1610" num="1610"><img file="EP4445902A2_D1613.tif" /></chemistry>

1376To a stirred solution of 7-bromo-2,4-dichloroquinazoline (crude, 22.0 g, 79.71 mmol, crude) in tetrahydrofuran (200 mL) was added 1M sodium hydroxide (191 mL, 191.30 mmol) at 0 °C, and the mixture was stirred for 2 h at RT. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was acidified with glacial acetic acid to pH ~ 5. The resulting solid was filtered and dried under vacuum to give the desired product. LCMS(m/z) 259.17 [M+H]⁺.

(Step 4) Synthesis of 7-bromo-2-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3H)-one

1377<chemistry id="chem1611" num="1611"><img file="EP4445902A2_D1614.tif" /></chemistry>

1378To a stirred solution of 7-bromo-2-chloroquinazolin-4(3H)-one (14.5 g, 56.20 mmol) in <i>N</i>, <i>N</i>-dimethylformamide (150 mL) were added potassium carbonate (8.53 g, 61.82 mmol) and 2-(trimethylsilyl)ethoxymethyl chloride (10.96 mL, 61.82 mmol) at 0 °C, and the mixture was stirred for 4 h at RT. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over anhydrous Na₂SO₄, filtered and evaporated under reduced pressure to give the desired product.

(Step 5) Synthesis of 7-bromo-2-hydrazinyl-3-((2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3H)-one

1379<chemistry id="chem1612" num="1612"><img file="EP4445902A2_D1615.tif" /></chemistry>

1380To a stirred solution of 7-bromo-2-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3H)-one (15.0 g, 38.66 mmol) in ethanol (150 mL) was added hydrazine (386 mL, 386.60 mmol, 1.0 M in tetrahydrofuran) at 0 °C, and the mixture was stirred for 2 h at RT. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with 10% methanol/ dichloromethane. The organic layer was washed with water, brine, dried over anhydrous Na₂SO₄, filtered and evaporated under reduced pressure to give the desired product. LCMS(m/z) 385.44 [M+H]⁺.

(Step 6) Synthesis of 8-bromo-4-((2-(trimethylsilyl)ethoxy)methyl)-[1,2,4]triazolo[4,3-a]quinazolin-5(4H)-one (26)

1381<chemistry id="chem1613" num="1613"><img file="EP4445902A2_D1616.tif" /></chemistry>

1382A mixture of 7-bromo-2-hydrazinyl-3-((2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3H)-one (crude, 17 g, 44.27 mmol) and triethylorthoformate (43.74 mL, 265.62 mmol) was heated to 100 °C for 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was evaporated under reduced pressure to give crude compound. The crude compound was triturated with diethyl ether and collected to afford the desired product. LCMS(m/z) 397.35 [M+H]⁺.

(Step 7) Synthesis of 8-bromo-[1,2,4]triazolo[4,3-a]quinazolin-5(4H)-one

1383<chemistry id="chem1614" num="1614"><img file="EP4445902A2_D1617.tif" /></chemistry>

1384To a stirred solution of 8-bromo-4-((2-(trimethylsilyl)ethoxy)methyl)-[1,2,4]triazolo[4,3-a]quinazolin-5(4H)-one (1.5 g, 5.10 mmol) in methanol (15 mL) was added trifluoroacetic acid (1.5 mL) at RT, and the mixture was stirred for 16 h at RT. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture evaporated under reduced pressure to give crude compound. The crude compound was triturated with diethyl ether and collected to afford the desired product. LCMS(m/z) 265.27 [M+H]⁺.

(Step 8) Synthesis of 8-bromo-5-chloro-[1,2,4]triazolo[4,3-a]quinazoline

1385<chemistry id="chem1615" num="1615"><img file="EP4445902A2_D1618.tif" /></chemistry>

1386The mixture of 8-bromo-[1,2,4]triazolo[4,3-a]quinazolin-5(4H)-one (2.0 g, 7.57 mmol) in phosphorus oxychloride (15 mL) was stirred for 6 h under reflux condition. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was evaporated under reduced pressure to give crude product. The crude product was dissolved in toluene and evaporated twice to afford the desired product. LCMS(m/z) 283.20 [M+H]⁺.

(Step 9) Synthesis of 8-bromo-N-(4'-chloro-[1,1'-biphenyl]-3-yl)-N-methyl-[1,2,4]triazolo[4,3-a] quinazolin-5-amine

1387To a stirred solution of 8-bromo-5-chloro-[1,2,4]triazolo[4,3-a]quinazoline (0.1 g, 0.35 mmol) in <i>N</i>, <i>N</i>-dimethylformamide (5 mL) were added 4'-chloro-N-methylbiphenyl-3-amine (0.115 g, 0.53 mmol) and potassium carbonate (0.028 g, 0.71 mmol) at RT, and the mixture was stirred for 3 h at RT. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous Na₂SO₄, filtered and evaporated under reduced pressure to give crude residue. The residue was purified by prep. HPLC to afford the desired product: ¹H NMR (DMSO-d₆) δ 9.64 (s, 1H), 8.67 (d, J = 1.9 Hz, 1H), 7.71 - 7.65 (m, 3H), 7.59 (dt, J = 7.9, 1.2 Hz, 1H), 7.51 - 7.45 (m, 3H), 7.43 (dd, J = 8.9, 1.9 Hz, 1H), 7.31 (ddd, J = 7.9, 2.3, 1.0 Hz, 1H), 7.23 (d, J = 8.9 Hz, 1H), 3.59 (s, 3H); LCMS(m/z) 464.32/466.34.

<u>Example 186. 8-Bromo-N-(4'-(tert-butyl)-[1,1'-biphenyl]-3-yl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1388<chemistry id="chem1616" num="1616"><img file="EP4445902A2_D1619.tif" /></chemistry>

(Step 1) Synthesis of 4'-(tert-butyl)-N-methyl-[1,1'-biphenyl]-3-amine

1389<chemistry id="chem1617" num="1617"><img file="EP4445902A2_D1620.tif" /></chemistry>

1390To a stirred solution of 3-iodo-N-methylbenzenamine (0.8 g, 3.43 mmol) in 1,4-dioxane/water (20 mL, 3:1) were added (4-(tert-butyl)phenyl)boronic acid (1.22 g, 6.87 mmol), sodium carbonate (0.728 g, 6.87 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (0.250 g, 0.34 mmol) at RT, and the mixture was heated to 80 °C for 3 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na₂SO₄, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 15% ethyl acetate/petroleum ether to give the desired product. LCMS(m/z) 240.23 [M+H]⁺.

(Step 2) Synthesis of 8-bromo-N-(4'-(tert-butyl)-[1,1'-biphenyl]-3-yl)-N-methyl-[1,2,4]triazolo [4,3-a]quinazolin-5-amine

1391To a stirred solution of 8-bromo-5-chloro-[1,2,4]triazolo[4,3-a]quinazoline (0.5 g, 1.77 mmol) in DMF (10 mL) were added 4'-(tert-Butyl)-N-methyl-[1,1'-biphenyl]-3-amine (0.635 g, 2.66 mmol) and potassium carbonate (0.489 g, 3.54 mmol) at 0 °C, and the mixture was stirred for 3 h at RT. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na₂SO₄, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 10% methanol/dichloromethane, followed by prep. HPLC to afford the desired product: ¹H NMR (DMSO-d₆) δ 9.64 (s, 1H), 8.67 (d, J = 2.0 Hz, 1H), 7.61 - 7.50 (m, 4H), 7.48 (d, J = 7.8 Hz, 1H), 7.44 - 7.39 (m, 3H), 7.29 (ddd, J = 8.0, 2.2, 1.1 Hz, 1H), 7.22 (d, J = 8.9 Hz, 1H), 3.59 (s, 3H), 1.28 (s, 9H); LCMS(m/z) 486.14/488.14.

<u>Example 187. 8-Chloro-N-methyl-N-(4'-methyl-[1,1'-biphenyl]-3-yl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1392<chemistry id="chem1618" num="1618"><img file="EP4445902A2_D1621.tif" /></chemistry>

1393To a stirred solution of N,4'-dimethyl-[1,1'-biphenyl]-3-amine (0.124 g, 0.63 mmol) in DMF (6 mL) was added potassium carbonate (0.116 g, 0.84 mmol) at 0 °C and the mixture was stirred for 10 min at RT, followed by the addition of 5,8-dichloro-[1,2,4]triazolo[4,3-a]quinazoline (0.1 g, 0.42 mmol) at RT, and the mixture was stirred at RT for 3 h. The reaction mixture was diluted with ice-water and extracted with ethyl acetate. The organic layer was washed successively with water and brine, dried over Na₂SO₄, filtered and evaporated under reduced pressure. The residue was purified by prep. HPLC to afford the desired product: ¹H NMR (DMSO-d₆) δ 9.62 (s, 1H), 8.53 (t, J = 1.2 Hz, 1H), 7.62 (t, J = 1.9 Hz, 1H), 7.58 - 7.51 (m, 3H), 7.45 (t, J = 7.8 Hz, 1H), 7.31 (d, J = 1.2 Hz, 2H), 7.26 (ddd, J = 8.0, 2.3, 1.0 Hz, 1H), 7.24 - 7.18 (m, 2H), 3.59 (s, 3H), 2.32 (s, 3H); LCMS(m/z) 400.2.

<u>Example 188. N-(3'-((8-Chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino)-1,1'-biphenyl]-4-yl)acetamide</u>

1394<chemistry id="chem1619" num="1619"><img file="EP4445902A2_D1622.tif" /></chemistry>

1395To a stirred solution of N-(3'-(methylamino)-[1,1'-biphenyl]-4-yl)acetamide (0.151 g, 0.63 mmol) in DMF (5 mL) was added sodium hydroxide (0.033 g, 0.84 mmol) at 0 °C and the mixture was stirred for 10 min at RT, followed by the addition of 5,8-dichloro-[1,2,4]triazolo[4,3-a]quinazoline (0.1 g, 0.42 mmol) at RT, and the mixture was stirred at RT for 3 h. The reaction mixture was diluted with ice-water and extracted with ethyl acetate. The organic layer was washed successively with water and brine, dried over Na₂SO₄, filtered and evaporated under reduced pressure. The residue was purified by prep. HPLC to afford the desired product: ¹H NMR (DMSO-d₆) δ 10.02 (s, 1H), 9.63 (s, 1H), 8.54 (t, J = 1.2 Hz, 1H), 7.66 - 7.54 (m, 6H), 7.45 (t, J = 7.9 Hz, 1H), 7.31 (d, J = 1.2 Hz, 2H), 7.25 (ddd, J = 7.9, 2.2, 1.0 Hz, 1H), 3.59 (s, 3H), 2.04 (s, 3H); LCMS(m/z) 443.4.

<u>Example 189. (5-((3-Fluorophenyl)(methyl)amino)-[1,2,4]triazolo[4,3-a]quinazolin-8-vl)methanol</u>

1396<chemistry id="chem1620" num="1620"><img file="EP4445902A2_D1623.tif" /></chemistry>

(Step 1) Synthesis of 7-bromo-2-chloro-N-(3-fluorophenyl)-N-methylquinazolin-4-amine

1397<chemistry id="chem1621" num="1621"><img file="EP4445902A2_D1624.tif" /></chemistry>

1398To a solution of 7-bromo-2,4-dichloroquinazoline (450 mg, 1.619 mmol) in DMF (8.1 mL) were added 3-fluoro-N-methylaniline (203 mg, 1.619 mmol) and sodium hydride (38.9 mg, 1.619 mmol), and the mixture was stirred for 1 h at RT. The reaction mixture was diluted with AcOEt, washed successively with water and brine. The organic layer was concentrated in vacuo to give the desired product, which was used for the next step without further purification. LCMS(m/z) 367.98 [M+H]⁺.

(Step 2) Synthesis of 7-bromo-N-(3-fluorophenyl)-2-hydrazinyl-N-methylquinazolin-4-amine

1399<chemistry id="chem1622" num="1622"><img file="EP4445902A2_D1625.tif" /></chemistry>

1400To a solution of 7-bromo-2-chloro-N-(3-fluorophenyl)-N-methylquinazolin-4-amine (387 mg, crude) in EtOH (5.3 mL) was added hydrazine hydrate (52.8 mg, 1.056 mmol), and the mixture was stirred for 1 h at RT. The reaction mixture was diluted with AcOEt, washed successively with water and brine. The organic layer was concentrated in vacuo to give the desired product, which was used for the next step without further purification. LCMS(m/z) 363.18 [M+H]⁺.

(Step 3) Synthesis of 8-bromo-N-(3-fluorophenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

1401<chemistry id="chem1623" num="1623"><img file="EP4445902A2_D1626.tif" /></chemistry>

1402A mixture of 7-bromo-N-(3-fluorophenyl)-2-hydrazinyl-N-methylquinazolin-4-amine (300 mg, crude) and triethoxymethane (10 mL, 0.828 mmol) was stirred at 100 °C overnight. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (Si-column, CHCl₃ : MeOH = 10 : 0 - 9 : 1) to the desired product. LCMS(m/z) 373.13 [M+H]⁺.

(Step 4) Synthesis of N-(3-fluorophenyl)-N-methyl-8-vinyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

1403<chemistry id="chem1624" num="1624"><img file="EP4445902A2_D1627.tif" /></chemistry>

1404A mixture of 8-bromo-N-(3-fluorophenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (232 mg, 0.623 mmol), K₃PO₄ (265 mg, 1.247 mmol), Pd(OAc)₂ (28.0 mg, 0.125 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (144 mg, 0.935 mmol) and tricyclohexylphosphine (35.0 mg, 0.125 mmol) was stirred at 100 °C overnight. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (Si-column, CHCl₃ : MeOH = 10 : 0 - 9 : 1) to give the desired product. LCMS(m/z) 319.9 [M+H]⁺.

(Step 5) Synthesis of 5-((3-fluorophenyl)(methyl)amino)-[1,2,4]triazolo[4,3-a]quinazoline-8-carbaldehyde

1405<chemistry id="chem1625" num="1625"><img file="EP4445902A2_D1628.tif" /></chemistry>

1406To a solution ofN-(3-fluorophenyl)-N-methyl-8-vinyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (128 mg, 0.401 mmol) in acetone/water (1:1, 2 mL) were added osmium(VIII) oxide (0.2 N in BuOH, 0.4 mL, 0.080 mmol) and sodium periodate (103 mg, 0.481 mmol), and the mixture was stirred for overnight at RT. The reaction mixture was subjected to solid phase extraction (washed with MeOH, then eluted with NH₃ in MeOH) using Bond Elut SCX cartridge (Agilent), and the collected fractions were concentrated in vacuo. The residue was concentrated in vacuo to give the desired product. LCMS(m/z) 322.08 [M+H]⁺.

(Step 6) Synthesis of (5-((3-fluorophenyl)(methyl)amino)-[1,2,4]triazolo[4,3-a]quinazolin-8-yl)methanol

1407To a solution of 5-((3-fluorophenyl)(methyl)amino)-[1,2,4]triazolo[4,3-a]quinazoline-8-carbaldehyde (crude, 129 mg, 0.4 mmol) in MeOH (2 mL) was added NaBH4 (16.65 mg, 0.440 mmol), and the mixture was stirred overnight at RT. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (Si-column, CHCl₃ : MeOH = 10 : 0 - 9 : 1) to afford the desired product: ¹H NMR (Methanol-d₄) δ 9.48 (s, 1H), 8.18 (s, 1H), 7.48 - 7.33 (m, 2H), 7.23 (d, J = 8.8 Hz, 1H), 7.19 - 7.00 (m, 3H), 4.76 (s, 2H), 3.66 (s, 3H); LCMS(m/z) 324.1.

<u>Example 190. 5-((4'-Methoxy-[1,1'-biphenyl]-3-yl)(methyl)amino)-[1,2,4]triazolo[4,3-a]quinazoline-8-carbaldehvde</u>

1408<chemistry id="chem1626" num="1626"><img file="EP4445902A2_D1629.tif" /></chemistry>

1409To a stirred solution of N-(4'-methoxy-[1,1'-biphenyl]-3-yl)-N-methyl-8-vinyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 192) (0.150 g, 0.37 mmol) in THF/water (9 mL, 2:1) were added sodium periodate (0.235 g, 1.10 mmol) and potassium osmate (VI) dihydrate (0.007 g, 0.02 mmol) at 0 °C, and the mixture was stirred at RT for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na₂SO₄, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 8% methanol/dichloromethane to afford the desired product: ¹H NMR (DMSO-d₆) δ 10.05 (s, 1H), 9.78 (s, 1H), 8.81 (d, J = 1.5 Hz, 1H), 7.69 (dd, J = 8.5, 1.5 Hz, 1H), 7.64 - 7.50 (m, 5H), 7.44 (t, J = 7.9 Hz, 1H), 7.27 (ddd, J = 7.9, 2.3, 1.0 Hz, 1H), 7.01 - 6.92 (m, 2H), 3.76 (s, 3H), 3.62 (s, 3H); LCMS(m/z) 410.2.

<u>Example 191. <i>N</i>-(4'-(<i>tert</i>-Butyl)-[1,1'-biphenyl]-3-yl)-<i>N</i>-methyl-8-(prop-1-yn-1-yl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1410<chemistry id="chem1627" num="1627"><img file="EP4445902A2_D1630.tif" /></chemistry>

1411To a degassed solution of 8-bromo-N-(4'-(tert-butyl)-[1,1'-biphenyl]-3-yl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 186) (0.1 g, 0.21 mmol) in 1,4-dioxane (5 mL) were added triphenylphosphine (0.048 g, 0.18 mmol), triethylamine (0.029 mL, 0.21 mmol), copper iodide (0.0078 g, 0.04 mmol), palladium acetate (0.009 g, 0.04 mmol) and 1-propyne (0.06 mL, 1.03 mmol) at RT, and the mixture was heated to 100 °C for 6 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous Na₂SO₄, filtered and evaporated under reduced pressure. The residue was purified by prep. HPLC to afford the desired product: ¹H NMR (DMSO-d₆) δ 9.63 (s, 1H), 8.40 (d, J = 1.6 Hz, 1H), 7.58 - 7.50 (m, 4H), 7.50 - 7.37 (m, 3H), 7.33 - 7.24 (m, 2H), 7.17 (dd, J = 8.7, 1.6 Hz, 1H), 3.59 (s, 3H), 2.09 (s, 3H), 1.28 (s, 9H); LCMS(m/z) 446.3.

<u>Example 192. N-(4'-Methoxy-[1,1'-biphenyl]-3-yl)-N-methyl-8-vinyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1412<chemistry id="chem1628" num="1628"><img file="EP4445902A2_D1631.tif" /></chemistry>

1413To a stirred solution of 8-bromo-N-(4'-methoxy-[1,1'-biphenyl]-3-yl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 173) (0.1 g, 0.22 mmol) in t-butanol (5 mL) were added potassium tert-butoxide (0.048 g, 0.43 mmol), tetrakis(triphenylphosphine)palladium (0) (0.025 g, 0.02 mmol) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (0.05 g, 0.33 mmol) at RT, and the mixture was heated to 100 °C for 6 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na₂SO₄, filtered and evaporated under reduced pressure. The residue was purified by prep. HPLC to afford the desired product: ¹H NMR (DMSO-d₆) δ 9.62 (s, 1H), 8.39 (d, J = 1.7 Hz, 1H), 7.64 - 7.55 (m, 3H), 7.53 (dt, J = 7.9, 1.3 Hz, 1H), 7.43 (t, J = 7.8 Hz, 1H), 7.35 (dd, J = 8.9, 1.7 Hz, 1H), 7.28 (d, J = 8.7 Hz, 1H), 7.25 - 7.16 (m, 1H), 7.01 - 6.92 (m, 2H), 6.78 (dd, J = 17.6, 10.9 Hz, 1H), 6.16 (d, J = 17.6 Hz, 1H), 5.54 (d, J = 11.0 Hz, 1H), 3.77 (s, 3H), 3.60 (s, 3H); LCMS(m/z) 408.2.

<u>Example 193. N-(3'-(Methyl(8-vinyl-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)amino)-[1,1'-biphenyl] -4-yl)acetamide</u>

1414<chemistry id="chem1629" num="1629"><img file="EP4445902A2_D1632.tif" /></chemistry>

1415To a stirred solution of N-(3'-((8-bromo-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino)-[1,1'-biphenyl]-4-yl)acetamide (Example 174) (0.2 g, 0.41 mmol) in DMF (6 mL) was added cesium carbonate (0.267 g, 0.82 mmol) at RT and the mixture was degassed with argon for 10 min, followed by the addition of bis(triphenylphosphine)palladium(II) dichloride (0.029 g, 0.04 mmol) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (0.127 g, 0.82 mmol) at RT. The mixture was heated to 100 °C for 3 h in a sealed tube. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and stirred for a few minutes. The resulting solids were filtered and dried under vacuum. The residue was purified by prep. HPLC to afford the desired product: ¹H NMR (DMSO-d₆) δ 10.02 (s, 1H), 9.62 (s, 1H), 8.39 (d, J = 1.7 Hz, 1H), 7.66 - 7.59 (m, 5H), 7.55 (dt, J = 8.0, 1.2 Hz, 1H), 7.44 (t, J = 7.9 Hz, 1H), 7.35 (dd, J = 8.8, 1.6 Hz, 1H), 7.28 (d, J = 8.7 Hz, 1H), 7.23 (ddd, J = 8.0, 2.2, 1.0 Hz, 1H), 6.78 (dd, J = 17.6, 11.0 Hz, 1H), 6.16 (d, J = 17.6 Hz, 1H), 5.54 (d, J = 10.9 Hz, 1H), 3.60 (s, 3H), 2.04 (s, 3H); LCMS(m/z) 435.1.

Example 194. N-(4'-(tert-Butyl)-[1,1'-biphenyl]-3-yl)-N-methyl-8-vinyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

1416<chemistry id="chem1630" num="1630"><img file="EP4445902A2_D1633.tif" /></chemistry>

1417To a stirred solution of 8-bromo-N-(4'-(tert-butyl)-[1,1'-biphenyl]-3-yl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 186) (0.1 g, 0.21 mmol) in t-butanol (5 mL) were added potassium tert-butoxide (0.046 g, 0.41 mmol), tetrakis(triphenylphosphine)palladium (0) (0.024 g, 0.02 mmol) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (0.048 g, 0.31 mmol) at RT, and the mixture was heated to 100 °C for 6 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na₂SO₄, filtered and evaporated under reduced pressure. The residue was purified by prep. HPLC to afford the desired product: ¹H NMR (DMSO-d₆) δ 9.62 (s, 1H), 8.39 (d, J = 1.6 Hz, 1H), 7.60 - 7.50 (m, 4H), 7.49 - 7.39 (m, 3H), 7.34 (dd, J = 8.7, 1.6 Hz, 1H), 7.31 - 7.24 (m, 2H), 6.78 (dd, J = 17.6, 11.0 Hz, 1H), 6.16 (d, J = 17.6 Hz, 1H), 5.54 (d, J = 11.0 Hz, 1H), 3.60 (s, 3H), 1.28 (s, 9H); LCMS(m/z) 434.3.

<u>Example 195. N-(4'-(tert-Butyl)-[1,1'-biphenyl]-3-yl)-8-chloro-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1418<chemistry id="chem1631" num="1631"><img file="EP4445902A2_D1634.tif" /></chemistry>

1419To a stirred solution of 5,8-dichloro-[1,2,4]triazolo[4,3-<i>a</i>]quinazoline (0.1 g, 0.42 mmol) in DMF (5 mL) were added 4'-(tert-butyl)-N-methyl-[1,1'-biphenyl]-3-amine (0.150 g, 0.63 mmol) and potassium carbonate (0.115 g, 0.84 mmol) at RT and the mixture was stirred at RT for 4 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na₂SO₄, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 8% methanol/dichloromethane, followed by prep. HPLC to afford the desired product: ¹H NMR (DMSO-d₆) δ 9.63 (s, 1H), 8.65 - 8.42 (m, 1H), 7.60 - 7.52 (m, 4H), 7.48 (d, J = 8.0 Hz, 1H), 7.43 (dd, J = 8.4, 6.3 Hz, 2H), 7.33 - 7.25 (m, 3H), 3.59 (s, 3H), 1.28 (s, 9H); LCMS(m/z) 442.2.

<u>Example 196. 8-Ethyl-N-(3-fluorophenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1420<chemistry id="chem1632" num="1632"><img file="EP4445902A2_D1635.tif" /></chemistry>

1421To a solution ofN-(3-fluorophenyl)-N-methyl-8-vinyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (128 mg, 0.401 mmol) in acetone/water (1:1, 2 mL) were added osmium(VIII) oxide (0.2 N in BuOH, 0.4 mL, 0.080 mmol) and sodium periodate (103 mg, 0.481 mmol), and the mixture was stirred for overnight at RT. The reaction mixture was subjected to solid phase extraction (washed with MeOH, then eluted with NH₃ in MeOH) using Bond Elut SCX cartridge (Agilent), and the collected fractions were concentrated in vacuo. The residue was concentrated in vacuo, and the residue was purified by column chromatography (Si-column, CHCl₃ : MeOH = 10 : 0 - 9 : 1) to give the desired product: ¹H NMR (Methanol-d₄) δ 9.46 (s, 1H), 8.09 - 7.99 (m, 1H), 7.44 - 7.37 (m, 1H), 7.28 - 7.22 (m, 1H), 7.12 - 7.03 (m, 4H), 3.64 (s, 3H), 2.80 (q, J = 7.6 Hz, 2H), 1.30 - 1.26 (m, 3H); LCMS(m/z) 322.1.

<u>Example 197. (5-(3,4-Dihydroquinolin-1(2H)-yl)-[1,2,4]triazolo[4,3-a]quinazolin-8-yl)methanol</u>

1422<chemistry id="chem1633" num="1633"><img file="EP4445902A2_D1636.tif" /></chemistry>

(Step 1) Synthesis of 5-(3,4-dihydroquinolin-1(2H)-yl)-8-vinyl-[1,2,4]triazolo[4,3-a]quinazoline

1423<chemistry id="chem1634" num="1634"><img file="EP4445902A2_D1637.tif" /></chemistry>

1424A mixture of 8-bromo-5-(3,4-dihydroquinolin-1(2H)-yl)-[1,2,4]triazolo[4,3-a]quinazoline (Example 205) (600 mg, 1.578 mmol), K₃PO₄ (670 mg, 3.16 mmol), Pd(OAc)₂ (70.9 mg, 0.316 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (365 mg, 2.367 mmol) and tricyclohexylphosphine (89 mg, 0.316 mmol) in dioxane/water (7.9 mL) was heated for 1 h at 100 °C. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (Si-column, CHCl₃ : MeOH = 10 : 0 - 9 : 1) to give the desired product. LCMS(m/z) 328.13 [M+H]⁺.

(Step 2) Synthesis of 5-(3,4-dihydroquinolin-1(2H)-yl)-[1,2,4]triazolo[4,3-a]quinazoline-8-carbaldehyde

1425<chemistry id="chem1635" num="1635"><img file="EP4445902A2_D1638.tif" /></chemistry>

1426To a solution of 5-(3,4-dihydroquinolin-1(2H)-yl)-8-vinyl-[1,2,4]triazolo[4,3-a]quinazoline (630 mg) in acetone/water (1:1, 9.6 mL) were added osmium(VIII) oxide (98 mg, 0.385 mmol) and sodium periodate (823 mg, 3.85 mmol), and the mixture was stirred for overnight at RT. The reaction mixture was concentrated in vacuo to give the desired product as crude. The residue was used for the next step without further purification. LCMS(m/z) 330.08 [M+H]⁺.

(Step 3) Synthesis of (5-(3,4-dihydroquinolin-1(2H)-yl)-[1,2,4]triazolo[4,3-a]quinazolin-8-yl)methanol

1427To a solution of 5-(3,4-dihydroquinolin-1(2H)-yl)-[1,2,4]triazolo[4,3-a]quinazoline-8-carbaldehyde (crude, 680 mg, 2.065 mmol) in DMF (10 mL) was added NaBH₄ (86 mg, 2.271 mmol) and the mixture was stirred for overnight at RT. The mixture was concentrated in vacuo. The residue was purified by column chromatography (Si-column, CHCl₃ : MeOH = 10 : 0 - 85 : 15) to afford the desired product: ¹H NMR (Methanol-d₄) δ 9.50 (s, 1H), 8.19 (s, 1H), 7.59 - 7.47 (m, 1H), 7.36 - 7.25 (m, 2H), 7.05 (tt, J = 7.5, 1.0 Hz, 1H), 6.93 (t, J = 7.7 Hz, 1H), 6.68 (d, J = 8.0 Hz, 1H), 4.78 (s, 2H), 4.09 - 3.95 (m, 2H), 3.61 (q, J = 7.0 Hz, 1H), 2.93 (t, J = 6.6 Hz, 2H), 2.15 (p, J = 6.7 Hz, 2H); LCMS(m/z) 332.1.

<u>Example 198. 5-(Methyl(4'-methyl-[1.1'-biphenyl-3-yl)amino)- [1,2,4]triazolo[4,3-a]quinazoline-8-carbaldehyde</u>

1428<chemistry id="chem1636" num="1636"><img file="EP4445902A2_D1639.tif" /></chemistry>

1429To a stirred solution of N-methyl-N-(4'-methyl-[1,1'-biphenyl]-3-yl)-8-vinyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 204) (0.550 g, 1.40 mmol) in THF/water (15 mL, 2:1) were added sodium periodate (0.903 g, 4.22 mmol) and potassium osmate (VI) dihydrate (0.026 g, 0.07 mmol) at 0 °C, and the mixture was stirred for 16 h at RT. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with ice-water and stirred for few minutes. The resulting solids were filtered and dried under vacuum to afford the desired product: ¹H NMR (DMSO-d₆) δ 10.04 (s, 1H), 9.77 (s, 1H), 8.81 (d, J = 1.5 Hz, 1H), 7.68 (dd, J = 8.5, 1.5 Hz, 1H), 7.64 (t, J = 2.0 Hz, 1H), 7.56 (dt, J = 8.3, 1.4 Hz, 1H), 7.53 (d, J = 8.3 Hz, 3H), 7.46 (t, J = 7.8 Hz, 1H), 7.32 - 7.27 (m, 1H), 7.21 (d, J = 7.8 Hz, 2H), 3.62 (s, 3H), 2.31 (s, 3H); LCMS(m/z) 394.4.

<u>Example 199. N-(3'-((8-Formyl-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino)-[1,1'-biphenyl] -4-yl)acetamide</u>

1430<chemistry id="chem1637" num="1637"><img file="EP4445902A2_D1640.tif" /></chemistry>

1431To a stirred solution of N-(3'-(methyl(8-vinyl-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)amino)-[1,1'-biphenyl]-4-yl)acetamide (Example 193) (0.080 g, 0.18 mmol) in THF/water (6 mL, 2:1) were added sodium periodate (0.118 g, 0.55 mmol) and potassium osmate (VI) dihydrate (0.003 g, 0.009 mmol) at 0 °C, and the mixture was stirred at RT for 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and stirred for few min. The resulting solids were filtered and dried under vacuum. The residue was purified by silica gel column chromatography, eluted with 8% methanol/dichloromethane to afford the desired product: ¹H NMR (500 MHz, DMSO-d₆) δ 10.05 (s, 1H), 10.01 (s, 1H), 9.78 (s, 1H), 8.81 (d, J = 1.5 Hz, 1H), 7.69 (dd, J = 8.5, 1.5 Hz, 1H), 7.61 - 7.52 (m, 7H), 7.45 (t, J = 7.9 Hz, 1H), 7.28 (ddd, J = 8.0, 2.2, 1.0 Hz, 1H), 3.62 (s, 3H), 2.04 (s, 3H); LCMS(m/z) 437.2.

<u>Example 200. N-(3'-(Methyl(8-(prop-1-yn-1-yl)-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)amino)-[1,1'-biphenyl]-4-yl)acetamide</u>

1432<chemistry id="chem1638" num="1638"><img file="EP4445902A2_D1641.tif" /></chemistry>

1433To a stirred and degassed solution of N-(3'-((8-bromo-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino)-[1,1'-biphenyl]-4-yl)acetamide (Example 174) (0.2 g, 0.41 mmol) in 1,4-dioxane (8 mL) was added triethylamine (0.057 mL, 0.41 mmol) at RT and the mixture was degassed with argon for 10 min, followed by the addition of triphenylphosphine (0.097 g, 0.37 mmol), copper iodide (0.015 g, 0.08 mmol), palladium acetate (0.018 g, 0.07 mmol) and 1-propyne (0.15 mL, 2.06 mmol) at RT, and the mixture was heated to 100 °C for 3 h in a sealed tube. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through a bed of celite and washed with ethyl acetate. The filtrate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography, eluted with 4% methanol/dichloromethane and further purified by prep. HPLC to afford the desired product: ¹H NMR (DMSO-d₆) δ 10.01 (brs, 1H), 9.63 (s, 1H), 8.40 (d, J = 1.6 Hz, 1H), 7.66 - 7.52 (m, 6H), 7.44 (t, J = 7.8 Hz, 1H), 7.27 (d, J = 8.7 Hz, 1H), 7.23 (ddd, J = 8.1, 2.3, 1.0 Hz, 1H), 7.18 (dd, J = 8.7, 1.6 Hz, 1H), 3.58 (s, 3H), 2.09 (s, 3H), 2.04 (s, 3H); LCMS(m/z) 447.2.

<u>Example 201. (5-(Methyl(4'-methyl-[1,1'-biphenyl]-3-yl)amino)-[1,2,4]triazolo[4,3-a] quinazolin-8-yl)methanol</u>

1434<chemistry id="chem1639" num="1639"><img file="EP4445902A2_D1642.tif" /></chemistry>

1435To a stirred solution of 5-(methyl(4'-methyl-[1,1'-biphenyl]-3-yl)amino)-[1,2,4]triazolo[4,3-a]quinazoline-8-carbaldehyde (Example 198) (0.370 g, 0.94 mmol) in THF (10 mL) was added sodium borohydride (0.071 g, 1.88 mmol) at 0 °C, and the mixture was stirred for 4 h at RT. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with ice-water and stirred for few minutes. The resulting solid was filtered and dried under vacuum. The residue was purified by prep. HPLC to afford the desired product: ¹H NMR (DMSO-d₆) δ 9.63 (s, 1H), 8.21 (d, J = 1.6 Hz, 1H), 7.60 (t, J = 1.9 Hz, 1H), 7.58 - 7.51 (m, 3H), 7.44 (t, J = 7.8 Hz, 1H), 7.30 (d, J = 8.6 Hz, 1H), 7.25 - 7.20 (m, 3H), 7.14 (dd, J = 8.8, 1.5 Hz, 1H), 5.50 (s, 1H), 4.60 (s, 2H), 3.60 (s, 3H), 2.31 (s, 3H); LCMS(m/z) 396.4.

<u>Example 202. (5-((4'-Methoxy-[1,1'-biphenyl]-3-yl)(methyl)amino)-[1,2,4]triazolo[4,3-a]quinazolin-8-vl)methanol</u>

1436<chemistry id="chem1640" num="1640"><img file="EP4445902A2_D1643.tif" /></chemistry>

1437To a stirred solution of 5-((4'-Methoxy-[1,1'-biphenyl]-3-yl)(methyl)amino)-[1,2,4]triazolo[4,3-a]quinazoline-8-carbaldehyde (Example 190) (0.1 g, 0.24 mmol) in THF/water (5 mL, 1:1) was added sodium borohydride (0.018 g, 0.49 mmol) at 0 °C, and the mixture was stirred at RT for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na₂SO₄, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 8% methanol/dichloromethane to afford the desired product: ¹H NMR (DMSO-d₆) δ 9.64 (s, 1H), 8.21 (d, J = 1.6 Hz, 1H), 7.64 - 7.54 (m, 3H), 7.55 - 7.48 (m, 1H), 7.42 (t, J = 7.8 Hz, 1H), 7.30 (d, J = 8.6 Hz, 1H), 7.25 - 7.08 (m, 2H), 7.03 - 6.90 (m, 2H), 5.50 (t, J = 5.6 Hz, 1H), 4.60 (d, J = 5.6 Hz, 2H), 3.77 (s, 3H), 3.59 (s, 3H); LCMS(m/z) 412.5.

<u>Example 203. N-(3'-((8-(Hydroxymethyl)-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino)-[1,1'-biphenyl]-4-yl)acetamide</u>

1438<chemistry id="chem1641" num="1641"><img file="EP4445902A2_D1644.tif" /></chemistry>

1439To a stirred solution of N-(3'-((8-formyl-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino)-[1,1'-biphenyl]-4-yl)acetamide (Example 199) (0.220 g, 0.50 mmol) in THF (6 mL) was added sodium borohydride (0.038 g, 1.01 mmol) at 0 °C and the mixture was stirred at RT for 4 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and stirred for a few minutes. The resulting solids were filtered and dried under vacuum. The residue was purified by prep. HPLC to afford the desired product: ¹H NMR (DMSO-d₆) δ 10.01 (s, 1H), 9.64 (s, 1H), 8.21 (d, J = 1.6 Hz, 1H), 7.65 - 7.50 (m, 6H), 7.43 (t, J = 7.9 Hz, 1H), 7.30 (d, J = 8.6 Hz, 1H), 7.21 (ddd, J = 7.9, 2.1, 1.0 Hz, 1H), 7.14 (dd, J = 8.7, 1.6 Hz, 1H), 5.49 (t, J = 5.6 Hz, 1H), 4.60 (d, J = 5.6 Hz, 2H), 3.59 (s, 3H), 2.04 (s, 3H); LCMS(m/z) 439.2.

<u>Example 204. N-Methyl-N-(4'-methyl-[1,1'-biphenyl]-3-yl)-8-vinyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1440<chemistry id="chem1642" num="1642"><img file="EP4445902A2_D1645.tif" /></chemistry>

1441To a stirred solution of 8-bromo-N-methyl-N-(4'-methyl-[1,1'-biphenyl]-3-yl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 172) (0.3 g, 0.68 mmol) in t-butanol (10 mL) were added potassium tert-butoxide (0.228 g, 2.03 mmol) at RT and the mixture was degassed with argon for 10 min, followed by the addition of tetrakis(triphenylphosphine)palladium (0) (0.156 g, 0.13 mmol) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (0.208 g, 1.35 mmol) at RT, and the mixture was heated to 80 °C for 4 h in a sealed tube. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na₂SO₄, filtered and evaporated under reduced pressure. The residue was purified by prep. HPLC to afford the desired product: ¹H NMR (500 MHz, DMSO-d₆) δ 9.62 (s, 1H), 8.39 (d, J = 1.6 Hz, 1H), 7.62 (t, J = 1.9 Hz, 1H), 7.57 - 7.51 (m, 3H), 7.45 (t, J = 7.8 Hz, 1H), 7.35 (dd, J = 8.7, 1.7 Hz, 1H), 7.28 (d, J = 8.7 Hz, 1H), 7.26 - 7.20 (m, 3H), 6.78 (dd, J = 17.6, 11.0 Hz, 1H), 6.15 (d, J = 17.6 Hz, 1H), 5.54 (d, J = 11.0 Hz, 1H), 3.60 (s, 3H), 2.31 (s, 3H); LCMS(m/z) 392.3.

<u>Example 205. 8-Bromo-5-(3,4-dihydroquinolin-1(2H)-yl)-[1,2,4]triazolo[4,3-a]quinazoline</u>

1442<chemistry id="chem1643" num="1643"><img file="EP4445902A2_D1646.tif" /></chemistry>

(Step 1) Synthesis of 7-bromo-2-chloro-4-(3,4-dihydroquinolin-1(2H)-yl)quinazoline

1443<chemistry id="chem1644" num="1644"><img file="EP4445902A2_D1647.tif" /></chemistry>

1444To a solution of 6-bromo-2,4-dichloroquinazoline (2 g, 7.20 mmol) in DMF (36 mL) were added 1,2,3,4-tetrahydroquinoline (0.958 g, 7.20 mmol) and sodium hydride (0.173 g, 7.20 mmol), and the mixture was stirred for 1 h at RT. The reaction mixture was diluted with AcOEt, and washed successively with water and brine, and dried over Na₂SO₄. The organic layer was concentrated in vacuo. The residue was used for the next step without further purification. LCMS(m/z) 376.03 [M+H]⁺.

(Step 2) Synthesis of 7-bromo-4-(3,4-dihydroquinolin-1(2H)-yl)-2-hydrazinylquinazoline

1445<chemistry id="chem1645" num="1645"><img file="EP4445902A2_D1648.tif" /></chemistry>

1446To a solution of 7-bromo-2-chloro-4-(3,4-dihydroquinolin-1(2H)-yl)quinazoline (1.22 g, 3.26 mmol) in EtOH (16.28 mL) was added hydrazine hydrate (0.326 g, 6.51 mmol), and the mixture was stirred for 2 h at RT. The reaction mixture was diluted with AcOEt, and washed successively with water and brine. The organic layer was concentrated in vacuo. The residue was used for the next step without further purification. LCMS(m/z) 370.08 [M+H]+.

(Step 3) Synthesis of 8-bromo-5-(3,4-dihydroquinolin-1(2H)-yl)-[1,2,4]triazolo[4,3-a]quinazoline

1447A mixture of 7-bromo-4-(3,4-dihydroquinolin-1(2H)-yl)-2-hydrazinylquinazoline (crude, 1.1 g, 2.97 mmol) and triethoxymethane (15 mL, 2.97 mmol) was stirred overnight at 100 °C. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (Si-column, CHCl₃: MeOH = 10 : 0 - 9 : 1) to afford the desired product: ¹H NMR (DMSO-d₆) δ 9.71 (s, 1H), 8.74 (d, J = 1.9 Hz, 1H), 7.57 (dd, J = 8.8, 1.9 Hz, 1H), 7.45 (d, J = 8.8 Hz, 1H), 7.27 (d, J = 7.1 Hz, 1H), 7.01 (td, J = 7.4, 1.3 Hz, 1H), 6.95 (td, J = 7.6, 1.7 Hz, 1H), 6.78 - 6.74 (m, 1H), 3.90 (t, J = 6.5 Hz, 2H), 2.89 (t, J = 6.6 Hz, 2H), 2.08 (q, J = 6.6 Hz, 2H); LCMS(m/z) 380.1/382.1.

<u>Example 206. 7-Fluoro-N5-methyl-N5-phenyl-[1,2,4]triazolo[4,3-a]quinazoline-5,8-diamine</u>

1448<chemistry id="chem1646" num="1646"><img file="EP4445902A2_D1649.tif" /></chemistry>

(Step 1) Synthesis of 8-azido-7-fluoro-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a] quinazolin-5-amine

1449<chemistry id="chem1647" num="1647"><img file="EP4445902A2_D1650.tif" /></chemistry>

1450To a solution of 7,8-difluoro-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 182) (20 mg, 0.064 mmol) in DMSO (321 µL) was added sodium azide (20.68 mg, 0.318 mmol), and the mixture was heated to 90 °C for 2 h. The reaction mixture was diluted with AcOEt, washed successively with water and brine, and dried over Na₂SO₄. The organic layer was concentrated in vacuo. The resulting residue was used in the next step without further purification. LCMS(m/z) 336.14 [M+H]⁺.

(Step 2) Synthesis of 7-fluoro-N5-methyl-N5-phenyl-[1,2,4]triazolo[4,3-a]quinazoline-5,8-diamine

1451A mixture of the resulting 8-azido-7-fluoro-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (80 mg, 0.239 mmol) and Pd/C (10 mg) in ethanol (1.2 mL) was heated to 60 °C for 2 days under H₂ atmosphere. Pd/C was removed by filtration, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (Si-column, CHCl₃: MeOH = 0-15%) to afford the desired product: ¹H NMR (DMSO-d₆) δ 9.31 (s, 1H), 7.47 - 7.36 (m, 2H), 7.31 - 7.21 (m, 4H), 6.65 (d, J = 13.3 Hz, 1H), 6.58 (s, 2H), 3.48 (s, 3H); LCMS(m/z) 309.1.

<u>Example 207. N5-Ethyl-7-fluoro-N5-phenyl-[1,2,4]triazolo[4,3-a]quinazoline-5,8-diamine</u>

1452<chemistry id="chem1648" num="1648"><img file="EP4445902A2_D1651.tif" /></chemistry>

(Step 1) Synthesis of 2-chloro-<i>N</i>-ethyl-6,7-difluoro-<i>N</i>-phenylquinazolin-4-amine

1453<chemistry id="chem1649" num="1649"><img file="EP4445902A2_D1652.tif" /></chemistry>

1454To a solution of 2,4-dichloro-6,7-difluoroquinazoline (1.1 g, 4.68 mmol) in DMF (23.4 mL) were added sodium hydride (0.112 g, 4.68 mmol) and N-methylaniline (0.567 g, 4.68 mmol), and the mixture was stirred for 0.5 h at RT. The reaction mixture was diluted with AcOEt, washed successively with water and brine, and dried over Na₂SO₄. The organic layer was concentrated in vacuo. The resulting residue was used in the next step without further purification. LCMS(m/z) 320.14 [M+H]⁺.

(Step 2) Synthesis of N-ethyl-6,7-difluoro-2-hydrazinyl-N-phenylquinazolin-4-amine

1455<chemistry id="chem1650" num="1650"><img file="EP4445902A2_D1653.tif" /></chemistry>

1456Hydrazine hydrate (0.038 g, 0.760 mmol) was added slowly to a stirred solution of 2-chloro-<i>N</i>-ethyl-6,7-difluoro-<i>N</i>-phenylquinazolin-4-amine (crude, 0.81 g, 2.53 mmol) in ethanol (12.67 mL) at RT. After 1 h and 2 h, additional portions of hydrazine hydrate (0.038 g x 2, 1.520 mmol) were added slowly to the solution, and stirring was continued for 1 h. The mixture was diluted with AcOEt, washed successively with water and brine, and dried over Na₂SO₄. The organic layer was concentrated in vacuo. The resulting residue was used in the next step without further purification. LCMS(m/z) 316.14 [M+H]⁺.

(Step 3) Synthesis of N-ethyl-7,8-difluoro-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

1457<chemistry id="chem1651" num="1651"><img file="EP4445902A2_D1654.tif" /></chemistry>

1458A mixture of N-ethyl-6,7-difluoro-2-hydrazinyl-N-phenylquinazolin-4-amine (crude, 0.69 g, 2.188 mmol)) and triethylorthoformate (10 mL, 2.188 mmol) was heated to 100 °C for 3 h. After completion of the reaction, the mixture was concentrated in vacuo. The residue was purified by column chromatography (Si-column, CHCl₃ : MeOH = 10:0 - 9: 1) to give the desired product. LCMS(m/z) 326.14 [M+H]⁺.

(Step 4) Synthesis of 8-azido-N-ethyl-7-fluoro-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

1459<chemistry id="chem1652" num="1652"><img file="EP4445902A2_D1655.tif" /></chemistry>

1460To a solution ofN-ethyl-7,8-difluoro-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (crude, 400 mg, 1.23 mmol) in DMSO (6148 µL) was added sodium azide (84 mg, 1.291 mmol), and the mixture was heated to 60 °C for 2 h. The reaction mixture was diluted with AcOEt, and washed successively with water and brine, and dried over Na₂SO₄. The organic layer was concentrated in vacuo. The resulting residue was used in the next step without further purification. LCMS(m/z) 349.14 [M+H]⁺.

(Step 5) Synthesis of N5-ethyl-7-fluoro-N5-phenyl-[1,2,4]triazolo[4,3-a]quinazoline-5,8-diamine

1461A mixture of 8-azido-N-ethyl-7-fluoro-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (crude, 0.46 g, 1.321 mmol) and Pd/C (30 mg) in ethanol (6.6 mL) was heated to 60 °C for overnight. Pd/C was removed by filtration, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (Si-column, CHCl₃ : MeOH = 10:0 - 9:1) to afford the desired product: ¹H NMR (Methanol-d₄) δ 9.17 (s, 1H), 7.55 - 7.43 (m, 2H), 7.41 - 7.32 (m, 1H), 7.31 - 7.17 (m, 3H), 6.68 (dd, J = 13.5, 1.3 Hz, 1H), 4.22 (q, J = 6.9 Hz, 2H), 1.33 (t, J = 7.0 Hz, 3H); LCMS(m/z) 323.1.

<u>Example 208. 7-Fluoro-N5-(3-fluorophenyl)-N5-methyl-[1,2,4]triazolo[4,3-a]quinazoline-5,8-diamine</u>

1462<chemistry id="chem1653" num="1653"><img file="EP4445902A2_D1656.tif" /></chemistry>

(Step 1) Synthesis of 2-chloro-6,7-difluoro-N-(3-fluorophenyl)-N-methylquinazolin-4-amine

1463<chemistry id="chem1654" num="1654"><img file="EP4445902A2_D1657.tif" /></chemistry>

1464To a solution of 2,4-dichloro-6, 7-difluoroquinazoline (1.05 g, 4.47 mmol) in DMF (22.3 mL) were added 3-fluoro-N-methylaniline (0.559 g, 4.47 mmol) and sodium hydride (0.107 g, 4.47 mmol), and the mixture was stirred for 1 h at RT. The reaction mixture was diluted with AcOEt, then washed successively with water and brine and dried over Na₂SO₄. The organic layer was concentrated in vacuo. The resulting residue was used in the next step without further purification. LCMS(m/z) 324.04 [M+H]⁺.

(Step 2) Synthesis of 6,7-difluoro-N-(3-fluorophenyl)-2-hydrazinyl-N-methylquinazolin-4-amine

1465<chemistry id="chem1655" num="1655"><img file="EP4445902A2_D1658.tif" /></chemistry>

1466Hydrazine hydrate (0.118 g, 2.354 mmol) was added slowly to a stirred solution of 2-chloro-6,7-difluoro-N-(3-fluorophenyl)-N-methylquinazolin-4-amine (crude, 2.54 g, 7.85 mmol) in ethanol (39.2 mL) at RT. After 1 h and 2 h, additional portions of hydrazine hydrate (0.118 g x 4.708 mmol) were added slowly to the solution, and the stirring continued for 1 h. The mixture was diluted with AcOEt, washed successively with water and brine, and dried over Na₂SO₄. The organic layer was concentrated in vacuo. The resulting residue was used in the next step without further purification. LCMS(m/z) 320.14 [M+H]⁺.

(Step 3) Synthesis of 7,8-difluoro-N-(3-fluorophenyl)-N-methyl-[1,2,4]triazolo[4,3-a] quinazolin-5-amine

1467<chemistry id="chem1656" num="1656"><img file="EP4445902A2_D1659.tif" /></chemistry>

1468A mixture of 6,7-difluoro-N-(3-fluorophenyl)-2-hydrazinyl-N-methylquinazolin-4-amine (crude, 0.51 g, 1.597 mmol) and triethoxymethane (5 mL, 1.597 mmol) was stirred at 100 °C for 4 h. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (Si-column, CHCl₃ : MeOH = 0-15%) to give the desired product. LCMS(m/z) 330.09 [M+H]⁺.

(Step 4) Synthesis of 8-azido-7-fluoro-N-(3-fluorophenyl)-N-methyl-[1,2,4]triazolo[4,3-a] quinazolin-5-amine

1469<chemistry id="chem1657" num="1657"><img file="EP4445902A2_D1660.tif" /></chemistry>

1470To a solution of 7,8-difluoro-N-(3-fluorophenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (0.29 g, 0.881 mmol) in DMSO (2.94 mL) was added sodium azide (0.057 g, 0.881 mmol), and the mixture was stirred for 2 h at 60 °C. The reaction mixture was diluted with AcOEt, and then washed successively with water and brine, and dried over Na₂SO₄. The organic layer was concentrated in vacuo. The resulting residue was used in the next step without further purification.

(Step 5) Synthesis of 7-fluoro-N5-(3-fluorophenyl)-N5-methyl-[1,2,4]triazolo[4,3-a] quinazoline-5,8-diamine

1471To a solution of 8-azido-7-fluoro-N-(3-fluorophenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (crude, 0.32 g, 0.908 mmol) in ethanol (4.54 mL) was added Pd/C (30 mg), and the suspension was stirred for 5 h at 60 °C under H₂ gas atmosphere. Pd/C was removed by filtration, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (Si-column, CHCl₃ : MeOH = 10:0 - 9:1) to afford the desired product: ¹H NMR (DMSO-d₆) δ 9.37 (s, 1H), 7.38 (td, J = 8.2, 6.8 Hz, 1H), 7.28 (d, J = 7.9 Hz, 1H), 7.19 (dt, J = 10.8, 2.3 Hz, 1H), 7.10 - 6.97 (m, 2H), 6.77 (d, J = 12.9 Hz, 1H), 6.67 (s, 2H), 3.49 (s, 3H); LCMS(m/z) 327.1.

<u>Example 209. (5-((4'-Chloro-[1,1]-biphenyl]-3-yl)(methyl)amino)-[1,2,4]triazolo[4,3-a]quinazolin-8-yl)methanol</u>

1472<chemistry id="chem1658" num="1658"><img file="EP4445902A2_D1661.tif" /></chemistry>

1473To a stirred solution of 5-((4'-chloro-[1,1'-biphenyl]-3-yl)(methyl)amino)-[1,2,4]triazolo[4,3-a]quinazoline-8-carbaldehyde (Example 211) (0.1 g, 0.24 mmol) in tetrahydrofuran (5 mL) was added sodium borohydride (0.018 g, 0.48 mmol) at 0 °C, and the mixture was stirred for 3 h at RT. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with 10% methanol/ dichloromethane. The organic layer was washed with brine, dried over anhydrous Na₂SO₄, filtered and evaporated under reduced pressure to give crude compound. The crude was purified by prep. HPLC to afford the desired compound: ¹H NMR (DMSO-d₆) δ 9.64 (s, 1H), 8.21 (d, J = 1.6 Hz, 1H), 7.72 - 7.64 (m, 3H), 7.57 (dt, J = 8.1, 1.3 Hz, 1H), 7.50 - 7.43 (m, 3H), 7.32 - 7.24 (m, 2H), 7.14 (dd, J = 8.6, 1.6 Hz, 1H), 5.50 (t, J = 5.6 Hz, 1H), 4.61 (d, J = 5.4 Hz, 2H), 3.60 (s, 3H); LCMS(m/z) 416.4.

<u>Example 210. N-(4'-Chloro-[1,1'-biphenyl]-3-yl)-N-methyl-8-vinyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1474<chemistry id="chem1659" num="1659"><img file="EP4445902A2_D1662.tif" /></chemistry>

1475To a stirred solution of 8-bromo-N-(4'-chloro-[1,1'-biphenyl]-3-yl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 185) (0.2 g, 0.43 mmol) in t-butanol (5 mL) were added potassium tert-butoxide (0.096 g, 0.86 mmol), tetrakis(triphenylphosphine)palladium (0) (0.049 g, 0.04 mmol) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (0.099 g, 0.65 mmol) at RT, and the mixture was heated to 100 °C for 6 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous Na₂SO₄, filtered and evaporated under reduced pressure to give crude residue. The residue was purified by prep. HPLC to afford the desired product: ¹H NMR (DMSO-d₆) δ 9.63 (s, 1H), 8.39 (d, J = 1.6 Hz, 1H), 7.71 - 7.64 (m, 3H), 7.58 (dt, J = 8.1, 1.3 Hz, 1H), 7.51 - 7.44 (m, 3H), 7.35 (dd, J = 8.7, 1.6 Hz, 1H), 7.32 - 7.25 (m, 2H), 6.78 (dd, J = 17.6, 10.9 Hz, 1H), 6.16 (d, J = 17.6 Hz, 1H), 5.54 (d, J = 10.9 Hz, 1H), 3.60 (s, 3H); LCMS(m/z) 412.4.

<u>Example 211. 5-((4'-Chloro-[1,1'-biphenyl]-3-yl)(methyl)amino)-[1,2,4]triazolo[4,3-a]quinazoline-8-carbaldehyde</u>

1476<chemistry id="chem1660" num="1660"><img file="EP4445902A2_D1663.tif" /></chemistry>

1477To a stirred solution of N-(4'-chloro-[1,1'-biphenyl]-3-yl)-N-methyl-8-vinyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 210) (0.140 g, 0.34 mmol) in a mixture of tetrahydrofuran/water (13 mL, 10:3) were added sodium periodate (0.218 g, 1.02 mmol) and potassium osmate (VI) dihydrate (0.006 g, 0.02 mmol) at 0 °C, and the mixture was stirred for 2 h at RT. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with ice-water. The resulting solid was filtered and dried under vacuum to give crude residue. The residue was purified by silica gel column chromatography, eluted with 6% methanol/dichloromethane to afford the desired product: ¹H NMR (DMSO-d₆) δ 10.05 (s, 1H), 9.79 (s, 1H), 8.81 (d, J = 1.5 Hz, 1H), 7.72 - 7.64 (m, 4H), 7.62 - 7.57 (m, 1H), 7.53 (d, J = 8.5 Hz, 1H), 7.49 - 7.43 (m, 3H), 7.35 (ddd, J = 7.8, 2.1, 1.0 Hz, 1H), 3.62 (s, 3H); LCMS(m/z) 414.4.

<u>Example 212. 5-((4'-(tert-Butyl)-[1,1'-biphenyl]-3-yl)(methyl)amino)-[1,2,4]triazolo[4,3-a]quinazoline-8-carbaldehyde</u>

1478<chemistry id="chem1661" num="1661"><img file="EP4445902A2_D1664.tif" /></chemistry>

1479To a stirred solution of N-(4'-(tert-butyl)-[1,1'-biphenyl]-3-yl)-N-methyl-8-vinyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 194) (0.360 g, 0.83 mmol) in THF/water (20 mL, 2:1) were added sodium periodate (0.533 g, 2.49 mmol) and potassium osmate (VI) dihydrate (0.015 g, 0.04 mmol) at 0 °C, and the mixture was stirred at RT for 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with ice-water. The resulting solids were filtered and dried under vacuum. The crude solids were purified by prep. HPLC to afford the desired product: ¹H NMR (DMSO-d₆) δ 10.05 (s, 1H), 9.78 (s, 1H), 8.81 (d, J = 1.5 Hz, 1H), 7.68 (dd, J = 8.5, 1.5 Hz, 1H), 7.60 (m, 1H), 7.58 - 7.51 (m, 4H), 7.49 (m, 1H), 7.43 - 7.39 (m, 2H), 7.33 (ddd, J = 7.8, 2.2, 1.1 Hz, 1H), 3.63 (s, 3H), 1.27 (s, 9H); LCMS(m/z) 436.3.

<u>Example 213. (5-((4'-(tert-Butyl)-[1,1'-biphenyl]-3-yl)(methyl)amino)-[1,2,4]triazolo[4,3-a]quinazolin-8-yl)methanol</u>

1480<chemistry id="chem1662" num="1662"><img file="EP4445902A2_D1665.tif" /></chemistry>

1481To a stirred solution of 5-((4'-(tert-butyl)-[1,1'-biphenyl]-3-yl)(methyl)amino)-[1,2,4]triazolo[4,3-a]quinazoline-8-carbaldehyde (Example 212) (0.09 g, 0.21 mmol) in THF/water (5 mL, 1:1) was added sodium borohydride (0.015 g, 0.41 mmol) at 0 °C, and the mixture was stirred at RT for 4 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with ice-water and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na₂SO₄, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 4% methanol/dichloromethane to afford the desired product: ¹H NMR (DMSO-d₆) δ 9.63 (s, 1H), 8.21 (d, J = 1.6 Hz, 1H), 7.61 - 7.51 (m, 4H), 7.49 - 7.39 (m, 3H), 7.29 (d, J = 8.6 Hz, 1H), 7.25 (ddd, J = 8.0, 2.3, 1.1 Hz, 1H), 7.14 (d, J = 1.6 Hz, 1H), 5.49 (t, J = 5.6 Hz, 1H), 4.60 (d, J = 5.4 Hz, 2H), 3.60 (s, 3H), 1.28 (s, 9H); LCMS(m/z) 438.5.

<u>Example 214. N-(4'-Chloro-[1,1'-biphenyl]-3-yl)-N-methyl-8-(prop-1-yn-1-yl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1482<chemistry id="chem1663" num="1663"><img file="EP4445902A2_D1666.tif" /></chemistry>

1483To a stirred and degassed solution of 8-bromo-N-(4'-chloro-[1,1'-biphenyl]-3-yl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 185) (0.1 g, 0.21 mmol) in 1,4-dioxane (3 mL) were added triphenylphosphine (0.051 g, 0.19 mmol), triethylamine (0.03 mL, 0.21 mmol), copper iodide (0.008 g, 0.04 mmol), palladium acetate (0.010 g, 0.04 mmol) and 1-propyne (0.13 mL, 2.16 mmol) at RT and the mixture was heated to 100 °C for 6 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na₂SO₄, filtered and evaporated under reduced pressure. The residue was purified by prep. HPLC to afford the desired product: ¹H NMR (500 MHz, DMSO-d₆) δ 9.64 (s, 1H), 8.40 (d, J = 1.6 Hz, 1H), 7.69 - 7.63 (m, 3H), 7.57 (ddd, J = 7.9, 1.9, 1.1 Hz, 1H), 7.50 - 7.44 (m, 3H), 7.31 (ddd, J = 8.0, 2.2, 1.0 Hz, 1H), 7.27 (d, J = 8.7 Hz, 1H), 7.18 (dd, J = 8.6, 1.6 Hz, 1H), 3.59 (s, 3H), 2.09 (s, 3H); LCMS(m/z) 424.4.

<u>Example 215. 8-Bromo-7-fluoro-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1484<chemistry id="chem1664" num="1664"><img file="EP4445902A2_D1667.tif" /></chemistry>

1485To a solution of 7-fluoro-N5-methyl-N5-phenyl-[1,2,4]triazolo[4,3-a]quinazoline-5,8-diamine (Example 206) (25 mg, 0.081 mmol) in acetonitrile (1 mL) were added copper(II) bromide (49.1 mg, 0.220 mmol) and tert-butyl nitrite (24.75 mg, 0.240 mmol), and the mixture was stirred for 2 h at RT. The reaction mixture was diluted with AcOEt, washed successively with water and brine, and dried over Na₂SO₄. The organic layer was concentrated in vacuo. The resulting residue was purified by column chromatography (Si-column, CHCl₃ : MeOH = 0-15%) to give the crude product. The reaction mixture was purified by solid phase extraction (washed with MeOH, then eluted with NH₃ in MeOH) using Bond Elut SCX cartridge (Agilent), and the collected fractions were concentrated to afford the desired product: ¹H NMR (Methanol-d₄) δ 9.33 (s, 1H), 8.54 (d, J = 6.0 Hz, 1H), 7.41 - 7.36 (m, 2H), 7.33 - 7.27 (m, 1H), 7.25 - 7.21 (m, 2H), 6.82 (d, J = 10.3 Hz, 1H), 3.55 (s, 3H); LCMS(m/z) 374.1/375.2.

<u>Example 216. 7-Fluoro-5-(7-fluoro-3,4-dihydroquinolin-1(2H)-yl)-[1,2,4]triazolo[4,3-a]quinazolin-8-amine</u>

1486<chemistry id="chem1665" num="1665"><img file="EP4445902A2_D1668.tif" /></chemistry>

(Step 1) Synthesis of methyl 3-(4-fluoro-2-nitrophenyl)acrylate

1487<chemistry id="chem1666" num="1666"><img file="EP4445902A2_D1669.tif" /></chemistry>

1488A mixture of 4-fluoro-2-nitroaniline (200 mg, 1.281 mmol), methyl acrylate (132 mg, 1.537 mmol), tertbutyl nitrite (145 mg, 1.409 mmol) and Pd(OAc)₂ (57.5 mg, 0.256 mmol) in MeOH (6.4 mL) was stirred for 4 h at 60 °C. The reaction mixture was diluted with AcOEt and washed successively with water and brine. The organic layer was concentrated in vacuo to give the desired product.

(Step 2) Synthesis of 7-fluoro-3,4-dihydroquinolin-2(1H)-one

1489<chemistry id="chem1667" num="1667"><img file="EP4445902A2_D1670.tif" /></chemistry>

1490A mixture of methyl 3-(4-fluoro-2-nitrophenyl)acrylate (163 mg, 0.724 mmol) and Pd(OAc)₂ (163 mg, 0.724 mmol) in MeOH (3.6 mL) was stirred for overnight at 60 °C. The mixture was concentrated in vacuo. The residue was purified by column chromatography (Si-column, hexane : AcOEt = 10 : 0 - 9 : 1) to give the desired product. LCMS(m/z) 166.14 [M+H]⁺.

(Step 3) Synthesis of 7-fluoro-1,2,3,4-tetrahydroquinoline

1491<chemistry id="chem1668" num="1668"><img file="EP4445902A2_D1671.tif" /></chemistry>

1492A mixture of 7-fluoro-3,4-dihydroquinolin-2(1H)-one (97 mg, 0.587 mmol) and BH₃ in THF (0.2 M solution) (12.19 mg, 0.881 mmol) in THF (2.9 mL) was stirred overnight at 50 °C. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (Si-column, hexane : AcOEt = 10 : 0 - 9 : 1) to give the desired product: ¹H NMR (400 MHz, CDCl₃) δ 6.85 (ddt, J = 8.4, 6.6, 1.0 Hz, 1H), 6.27 (td, J = 8.5, 2.6 Hz, 1H), 6.15 (dd, J = 10.8, 2.6 Hz, 1H), 3.39 - 3.20 (m, 2H), 2.70 (t, J = 6.4 Hz, 2H), 2.05 - 1.83 (m, 2H).

(Step 4) Synthesis of 2-chloro-6,7-difluoro-4-(7-fluoro-3,4-dihydroquinolin-1(2H)-yl)quinazoline

1493<chemistry id="chem1669" num="1669"><img file="EP4445902A2_D1672.tif" /></chemistry>

1494To a solution of 2,4-dichloro-6,7-difluoroquinazoline (0.89 g, 3.79 mmol) in DMF (18.93 ml) were added 7-fluoro-1,2,3,4-tetrahydroquinoline (0.573 g, 3.79 mmol) and sodium hydride (0.091 g, 3.79 mmol), and the mixture was stirred for 2 h at RT. The reaction mixture was diluted with AcOEt and washed successively with water and brine. The organic layer was concentrated in vacuo. The residue was used for the next step without further purification. LCMS(m/z) 350.14 [M+H]⁺.

(Step 5) Synthesis of 6,7-difluoro-4-(7-fluoro-3,4-dihydroquinolin-1(2H)-yl)-2-hydrazinylquinazoline

1495<chemistry id="chem1670" num="1670"><img file="EP4445902A2_D1673.tif" /></chemistry>

1496To a solution of 2-chloro-6,7-difluoro-4-(7-fluoro-3,4-dihydroquinolin-1(2H)-yl)quinazoline (0.35 g, crude) in EtOH (5 mL) was added hydrazine hydrate (0.015 g, 0.3 mmol) slowly, and the mixture was stirred for 30 min at RT. After 0.5 h and 1 h, additional portions of hydrazine hydrate (0.015 g x 2, 0.6 mmol) were added slowly to the solution, and the stirring was continued for 1 h. The reaction mixture was diluted with AcOEt and washed successively with water and brine. The organic layer was concentrated in vacuo. The residue was used for the next step without further purification. LCMS(m/z) 346.14 [M+H]⁺.

(Step 6) Synthesis of 7,8-difluoro-5-(7-fluoro-3,4-dihydroquinolin-1(2H)-yl)-[1,2,4]triazolo [4,3-a] quinazoline

1497<chemistry id="chem1671" num="1671"><img file="EP4445902A2_D1674.tif" /></chemistry>

1498A mixture of 6,7-difluoro-4-(7-fluoro-3,4-dihydroquinolin-1(2H)-yl)-2-hydrazinylquinazoline (0.21 g, crude) and triethoxymethane (10 mL, 0.608 mmol) was stirred at 100 °C overnight. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (Si-column, CHCl₃ : MeOH = 10 : 0 - 85 : 15) to give the desired product. LCMS(m/z) 356.0 [M+H]+.

(Step 7) Synthesis of 8-azido-7-fluoro-5-(7-fluoro-3,4-dihydroquinolin-1(2H)-yl)-[1,2,4]triazolo[4,3-a]quinazoline

1499<chemistry id="chem1672" num="1672"><img file="EP4445902A2_D1675.tif" /></chemistry>

1500A mixture of 7,8-difluoro-5-(7-fluoro-3,4-dihydroquinolin-1(2H)-yl)-[1,2,4]triazolo[4,3-a]quinazoline (50 mg, 0.141 mmol) and sodium azide (4.57 mg, 0.07 mmol) in DMSO (0.35 mL) was stirred at 60 °C for 30 min. The mixture was diluted with AcOEt, washed successively with water and brine. The organic layer was concentrated in vacuo to give the desired product, which was used for the next step without further purification. LCMS(m/z) 379.19 [M+H]+.

(Step 8) Synthesis of 7-fluoro-5-(7-fluoro-3,4-dihydroquinolin-1(2H)-yl)-[1,2,4]triazolo[4,3-a]quinazolin-8-amine

1501A mixture of 8-azido-7-fluoro-5-(7-fluoro-3,4-dihydroquinolin-1(2H)-yl)-[1,2,4]triazolo[4,3-a]quinazoline (12mg, 0.032 mmol) and Pd/C (3 mg) in EtOH (0.16 mL) was stirred overnight at 60 °C under H₂ atmosphere. After removal of Pd/C by filtration, the filtrate was concentrated in vacuo. The residue was purified by column chromatography (Si-column, CHCl₃ : MeOH = 10 : 0 - 85 : 15) to afford the desired product: ¹H NMR (Methanol-d₄) δ 9.28 (s, 1H), 7.35 (d, J = 7.5 Hz, 1H), 7.23 (ddt, J = 8.4, 6.4, 0.9 Hz, 1H), 7.13 (d, J = 12.3 Hz, 1H), 6.72 (td, J = 8.4, 2.5 Hz, 1H), 6.47 - 6.37 (m, 1H), 3.95 (t, J = 6.4 Hz, 2H), 2.90 (t, J = 6.6 Hz, 2H), 2.12 (p, J = 6.5 Hz, 2H); LCMS(m/z) 353.3.

<u>Example 217. 5-(3,4-Dihydroquinolin-1(2H)-yl)-7-fluoro-[1,2,4]triazolo[4,3-a]quinazolin-8-amine</u>

1502<chemistry id="chem1673" num="1673"><img file="EP4445902A2_D1676.tif" /></chemistry>

(Step 1) Synthesis of 2-chloro-4-(3,4-dihydroquinolin-1(2H)-yl)-6,7-difluoroquinazoline

1503<chemistry id="chem1674" num="1674"><img file="EP4445902A2_D1677.tif" /></chemistry>

1504To a solution of 2,4-dichloro-6,7-difluoroquinazoline (1.1 g, 4.68 mmol) in DMF (23.4 mL) were added 1,2,3,4-tetrahydroquinoline (0.623 g, 4.68 mmol) and sodium hydride (0.112 g, 4.68 mmol), and the mixture was stirred for 1 h at RT. The mixture was diluted with AcOEt, washed successively with water and brine. The organic layer was concentrated in vacuo to give the desired product. LCMS(m/z) 332.19 [M+H]⁺.

(Step 2) Synthesis of 4-(3,4-dihydroquinolin-1(2H)-yl)-6,7-difluoro-2-hydrazinylquinazoline

1505<chemistry id="chem1675" num="1675"><img file="EP4445902A2_D1678.tif" /></chemistry>

1506To a solution of 2-chloro-4-(3,4-dihydroquinolin-1(2H)-yl)-6,7-difluoroquinazoline (0.35 g, 1.055 mmol) in EtOH (5.28 mL) was added hydrazine hydrate (0.017 g, 0.351 mmol), and the mixture was stirred for 0.5 h. After 0.5 h and 1 h, additional portions of hydrazine hydrate (0.017 g x 2, 0.7 mmol) were added slowly to the solution, and the stirring was continued for 1 h. The reaction mixture was diluted with AcOEt and washed successively with water and brine. The organic layer was concentrated in vacuo. The residue was used for the next step without further purification. LCMS(m/z) 328.14 [M+H]⁺.

(Step 3) Synthesis of 5-(3,4-dihydroquinolin-1(2H)-yl)-7,8-difluoro-[1,2,4]triazolo[4,3-a]quinazoline

1507<chemistry id="chem1676" num="1676"><img file="EP4445902A2_D1679.tif" /></chemistry>

1508A mixture of 4-(3,4-dihydroquinolin-1(2H)-yl)-6,7-difluoro-2-hydrazinylquinazoline (0.21 g, crude) and triethoxymethane (3 mL, 0.642 mmol) was stirred at 100 °C overnight. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (Si-column, CHCl₃ : MeOH = 10 : 0 - 85 : 15) to give the desired product. LCMS(m/z) 338.18 [M+H]⁺.

(Step 4) Synthesis of 8-azido-5-(3,4-dihydroquinolin-1(2H)-yl)-7-fluoro-[1,2,4]triazolo[4,3-a]quinazoline

1509<chemistry id="chem1677" num="1677"><img file="EP4445902A2_D1680.tif" /></chemistry>

1510A mixture of 5-(3,4-dihydroquinolin-1(2H)-yl)-7,8-difluoro-[1,2,4]triazolo[4,3-a]quinazoline (62 mg, 0.184 mmol) and sodium azide (12.55 mg, 0.193 mmol) in DMSO (0.92 mL) was stirred at 60 °C for 1 h. The reaction mixture was diluted with AcOEt and washed successively with water and brine. The organic layer was concentrated in vacuo to give the desired product, which was used for the next step without further purification. LCMS(m/z) 361.19 [M+H]⁺.

(Step 5) Synthesis of 5-(3,4-dihydroquinolin-1(2H)-yl)-7-fluoro-[1,2,4]triazolo[4,3-a]quinazolin-8-amine

1511A mixture of 8-azido-5-(3,4-dihydroquinolin-1(2H)-yl)-7-fluoro-[1,2,4]triazolo[4,3-a]quinazoline (51 mg, crude) and Pd/C (5 mg) in EtOH (0.71 mL) was stirred overnight at 60 °C under H₂ atmosphere. After removal of Pd/C by filtration, the filtrate was concentrated in vacuo. The residue was purified by column chromatography (Si-column, CHCl₃ : MeOH = 10 : 0 - 85 : 15) to afford the desired product: ¹H NMR (Methanol-d₄) δ 9.23 (s, 1H), 7.34 - 7.23 (m, 2H), 7.06 - 6.97 (m, 3H), 6.72 - 6.65 (m, 1H), 3.98 (t, J = 6.6 Hz, 2H), 2.91 (t, J = 6.6 Hz, 2H), 2.13 (t, J = 6.6 Hz, 2H); LCMS(m/z) 335.2.

<u>Example 218. 8-Fluoro-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1512<chemistry id="chem1678" num="1678"><img file="EP4445902A2_D1681.tif" /></chemistry>

(Step 1) Synthesis of 2-chloro-7-fluoro-N-methyl-N-phenylquinazolin-4-amine

1513<chemistry id="chem1679" num="1679"><img file="EP4445902A2_D1682.tif" /></chemistry>

1514To a suspension of 2,4-dichloro-7-fluoroquinazoline (100 mg, 0.461 mmol) in 2-propanol (2.3 mL) were added N-methylaniline (49.4 mg, 0.461 mmol) and concentrated HCl (37%, 15.62 mg, 0.428 mmol), and the mixture was stirred for 30 min at RT. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (Si-column, hexane : AcOEt = 10 : 0 - 6 : 4) to give the desired product: LCMS(m/z) 288.08 [M+H]+.

(Step 2) Synthesis of 7-fluoro-2-hydrazinyl-N-methyl-N-phenylquinazolin-4-amine

1515<chemistry id="chem1680" num="1680"><img file="EP4445902A2_D1683.tif" /></chemistry>

1516To 2-chloro-7-fluoro-N-methyl-N-phenylquinazolin-4-amine (25 mg, 0.087 mmol) was added hydrazine hydrate (21.75 mg, 0.434 mmol), and the reaction mixture was stirred for 3 h at RT. The reaction mixture was diluted with AcOEt and washed successively with water and brine. The organic layer was concentrated in vacuo. The residue was purified by column chromatography (Si-column, CHCl₃ : MeOH = 10 : 0 - 9 : 1) to give the desired product: LCMS(m/z) 284.13 [M+H]+.

(Step 3) Synthesis of 8-fluoro-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

1517A mixture of 7-fluoro-2-hydrazinyl-N-methyl-N-phenylquinazolin-4-amine (12 mg, 0.042 mmol) and triethoxymethane (18.83 mg, 0.127 mmol) was heated to 70 °C for 20 min. The reaction mixture was directly purified by column chromatography (Si-column, CHCl₃ : MeOH = 10 : 0 - 9 : 1) to afford the desired product: ¹H NMR (Methanol-d₄) δ 9.42 (s, 1H), 8.05 (dd, J = 9.1, 2.6 Hz, 1H), 7.44 - 7.32 (m, 6H), 7.04 - 6.94 (m, 1H), 3.67 (s, 3H); LCMS(m/z) 294.1.

<u>Example 219. 8-(3,3-Dimethylbut-1-yn-1-vl)-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1518<chemistry id="chem1681" num="1681"><img file="EP4445902A2_D1684.tif" /></chemistry>

1519A mixture of 8-bromo-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 28) (20 mg, 0.056 mmol), Pd(dppf)Cl₂ (8.26 mg, 0.011 mmol), triethylamine (17.14 mg, 0.169 mmol), 3,3-dimethylbut-1-yne (11.60 mg, 0.141 mmol) and copper(I) iodide (2.151 mg, 0.011 mmol) in acetonitrile (0.28 mL) was treated in a microwave reactor for 2 h at 80°C. The reaction mixture was subjected to solid phase extraction (washed with MeOH, then eluted with NH₃ in MeOH) using Bond Elut SCX cartridge (Agilent), and the collected fractions were concentrated in vacuo. The residue was purified by prep-HPLC to afford the desired product: ¹H NMR (Methanol-d₄) δ 9.57 (s, 1H), 7.55 (m, 7H), 7.14 (m, 1H), 3.79 (s, 3H), 3.67 (m, 9H); LCMS(m/z) 356.2.

<u>Example 220. 7-Fluoro-5-((3-fluorophenyl)(methyl)amino)-[1,2,4]triazolo[4,3-a]quinazoline-8-carboxylic acid</u>

1520<chemistry id="chem1682" num="1682"><img file="EP4445902A2_D1685.tif" /></chemistry>

(Step 1) Synthesis of 8-bromo-7-fluoro-N-(3-fluorophenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

1521<chemistry id="chem1683" num="1683"><img file="EP4445902A2_D1686.tif" /></chemistry>

1522To a solution of 7-fluoro-N5-(3-fluorophenyl)-N5-methyl-[1,2,4]triazolo[4,3-a]quinazoline-5,8-diamine (Example 208) (315 mg, 0.965 mmol) in acetonitrile (4.8 mL) were added tert-butyl nitrite (149 mg, 1.448 mmol) and copper(II) bromide (237 mg, 1.062 mmol), and the mixture was stirred for 2 h at RT. The reaction mixture was filtered, and washed successively with AcOEt and MeOH, and the filtrate was concentrated in vacuo. The residue was diluted with AcOEt and washed successively with water and brine. The organic layer was concentrated in vacuo. The residue was used for the next step without further purification. LCMS(m/z) 390.09 / 392.09 [M+H]⁺.

(Step2) Synthesis of 7-fluoro-N-(3-fluorophenyl)-N-methyl-8-vinyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

1523<chemistry id="chem1684" num="1684"><img file="EP4445902A2_D1687.tif" /></chemistry>

1524A mixture of 8-bromo-7-fluoro-N-(3-fluorophenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (200 mg, crude), K₃PO₄ (109 mg, 0.513 mmol), Pd(OAc)₂ (115 mg, 0.513 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (118 mg, 0.769 mmol) and tricyclohexylphosphine (28.7 mg, 0.103 mmol) in dioxane/water (1:1, 2.3 mL) was stirred at 100 °C for 1.5 h. The mixture was concentrated in vacuo. The residue was purified by column chromatography (Si-column, CHCl₃ : MeOH = 10 : 0 - 8 : 2) to give the desired product.

(Step 3) Synthesis of 7-fluoro-5-((3-fluorophenyl)(methyl)amino)-[1,2,4]triazolo[4,3-a]quinazoline-8-carboxylic acid

1525<chemistry id="chem1685" num="1685"><img file="EP4445902A2_D1688.tif" /></chemistry>

1526A mixture of 7-fluoro-N-(3-fluorophenyl)-N-methyl-8-vinyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (50 mg, 0.148 mmol), osmium(VIII) oxide (0.2 M in BuOH, 0.15 mL, 0.030 mmol) and sodium periodate (79 mg, 0.371 mmol) in acetone/water (1:1, 0.74 mL, ratio=1:1) was stirred overnight at RT. The reaction mixture was concentrated in vacuo, and the residue was purified by column chromatography (Si-column, CHCl₃ : MeOH = 10 : 0 - 8 : 2) to afford the desired product: ¹H NMR (DMSO-d₆) δ 9.86 (s, 1H), 8.82 (d, J = 6.2 Hz, 1H), 7.45 (dd, J = 8.3, 6.8 Hz, 1H), 7.40 - 7.33 (m, 1H), 7.25 - 7.14 (m, 2H), 6.96 (d, J = 11.7 Hz, 1H), 3.58 (s, 3H); LCMS(m/z) 356.2.

<u>Example 221. 7-fluoro-N5,N8-dimethyl-N5-phenyl-[1,2,4]triazolo[4,3-a]quinazoline-5,8-diamine</u>

1527<chemistry id="chem1686" num="1686"><img file="EP4445902A2_D1689.tif" /></chemistry>

1528A vigorously stirred mixture of Example 182 (7.1 mg, 23 µmol) and methylamine solution (9.8 M in methanol, 1.5 mL, 15 mmol) was heated to 110 °C in a microwave reactor. After 30 min, the reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure. The residue was purified by reverse-phase preparative HPLC (0.1% trifluoroacetic acid in acetonitrile/water) to give the title compound: ¹H NMR (400 MHz, DMSO-d₆) δ 9.83 (s, 1H), 7.53 (dd, J = 8.3, 6.9 Hz, 2H), 7.48 - 7.32 (m, 4H), 6.46 (d, J = 14.0 Hz, 1H), 3.61 (s, 3H), 2.91 (d, J = 4.7 Hz, 3H); LCMS(m/z) 323.3.

<u>Example 222. 7-fluoro-N5,N8,N8-trimethyl-N5-phenyl-[1,2,4]triazolo[4,3-a]quinazoline-5,8-diamine</u>

1529<chemistry id="chem1687" num="1687"><img file="EP4445902A2_D1690.tif" /></chemistry>

1530Example 222 was synthesized in a manner similar to Example 221, except using dimethylamine instead of methylamine. ¹H NMR (400 MHz, DMSO-d₆) δ 9.88 (s, 1H), 7.55 (dd, J = 8.3, 6.9 Hz, 2H), 7.51 - 7.35 (m, 4H), 6.46 (d, J = 17.0 Hz, 1H), 3.62 (s, 3H), 3.11 (d, J = 2.4 Hz, 6H); LCMS(m/z) 337.3.

<u>Example 223. 7-fluoro-8-methoxy-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1531<chemistry id="chem1688" num="1688"><img file="EP4445902A2_D1691.tif" /></chemistry>

1532Example 223 was synthesized in a manner similar to Example 221 using ammonia solution (7.0 M in methanol) instead of methylamine solution (9.8 M in methanol). ¹H NMR (400 MHz, DMSO-d₆) δ 9.89 (s, 1H), 8.15 (d, J = 7.7 Hz, 1H), 7.56 - 7.48 (m, 2H), 7.49 - 7.34 (m, 3H), 6.70 (d, J = 13.1 Hz, 1H), 4.07 (s, 3H), 3.62 (s, 3H); LCMS(m/z) 324.3.

<u>Example 224. 7-fluoro-8-methoxy-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1533<chemistry id="chem1689" num="1689"><img file="EP4445902A2_D1692.tif" /></chemistry>

1534Aqueous sodium hydroxide solution (2.0 M, 3.0 mL, 6.0 mmol) was added via syringe to a vigorously stirred mixture of Example 182 (64.5 mg, 0.207 mmol) in dimethyl sulfoxide (3.0 mL), and the resulting mixture heated to 90 °C. After 1 h, the resulting mixture was cooled to room temperature and was purified by reverse-phase preparative HPLC (0.1 % trifluoroacetic acid in acetonitrile/water) to give the title compound: ¹H NMR (400 MHz, DMSO-d₆) δ 11.64 (s, 1H), 9.50 (s, 1H), 7.70 (d, J = 7.6 Hz, 1H), 7.44 (t, J = 7.7 Hz, 2H), 7.38 - 7.20 (m, 4H), 6.79 (d, J = 12.7 Hz, 1H), 6.52 (s, 1H), 3.52 (s, 3H); LCMS(m/z) 310.3.

<u>Example 225. 8-ethoxy-7-fluoro-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1535<chemistry id="chem1690" num="1690"><img file="EP4445902A2_D1693.tif" /></chemistry>

1536Iodoethane (9.1 µL, 110 µmol) was added via syringe to a vigorously stirred mixture of potassium carbonate (15.6 mg, 0.113 mmol) and Example 224 (7.00 mg, 22.6 µmol) in acetone (0.5 mL), and the resulting mixture was heated to 50 °C. After 90 min, the reaction mixture was cooled to room temperature, and ethyl acetate (5 mL) and water (5 mL) were added sequentially. The organic layer was washed with brine, was dried over anhydrous magnesium sulfate, was filtered, and was concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC (0. 1% trifluoroacetic acid in acetonitrile/water) to give the title compound: ¹H NMR (400 MHz, DMSO-d₆) δ 9.72 (s, 1H), 8.04 (d, J = 7.6 Hz, 1H), 7.46 (t, J = 7.7 Hz, 2H), 7.35 (d, J = 7.9 Hz, 3H), 6.76 (d, J = 13.0 Hz, 1H), 4.33 (q, J = 7.0 Hz, 2H), 3.56 (s, 3H), 1.42 (t, J = 7.0 Hz, 3H); LCMS(m/z) 338.3.

<u>Example 226. 8-(allyloxy)-7-fluoro-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1537<chemistry id="chem1691" num="1691"><img file="EP4445902A2_D1694.tif" /></chemistry>

1538Example 226 was synthesized in a manner similar to Example 225, except using 3-bromoprop-1-ene instead of ethyl iodide. ¹H NMR (400 MHz, DMSO-d₆) δ 9.80 (s, 1H), 8.12 (d, J = 7.6 Hz, 1H), 7.58 - 7.34 (m, 5H), 6.72 (d, J = 13.0 Hz, 1H), 6.12 (ddt, J = 17.4, 10.8, 5.6 Hz, 1H), 5.52 (dt, J = 17.3, 1.6 Hz, 1H), 5.38 (dt, J = 10.5, 1.4 Hz, 1H), 4.87 (dt, J = 5.7, 1.4 Hz, 2H), 3.61 (d, J = 9.7 Hz, 3H); LCMS(m/z) 350.3.

<u>Example 227. 8-chloro-N-(3-(5-cyclopropylpyridin-3-yl)phenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1539<chemistry id="chem1692" num="1692"><img file="EP4445902A2_D1695.tif" /></chemistry>

1540A vigorously stirred mixture of Example 308 (9.5 mg, 24.4 µmol), (5-cyclopropyl-3-pyridyl)boronic acid (6.05 mg, 37.1 µmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.73 mg, 2.4 µmol), and aqueous sodium carbonate solution (2.0 M, 122 µL, 244 µmol) in 1,4-dioxane (0.5 mL) was heated to 100 °C. After 5 min, the resulting mixture was cooled to room temperature and was concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC (0.1% trifluoroacetic acid in acetonitrile/water) to give the title compound: ¹H NMR (400 MHz, Acetone-d₆) δ 9.48 (s, 1H), 8.63 (s, 1H), 8.53 - 8.24 (m, 2H), 7.80 (t, J = 2.1 Hz, 1H), 7.68 (q, J = 4.0, 2.2 Hz, 2H), 7.59 (t, J = 7.8 Hz, 1H), 7.48 (dd, J = 22.1, 8.2 Hz, 2H), 7.36 - 7.23 (m, 1H), 3.72 (s, 3H), 1.17 - 1.00 (m, 2H), 0.83 (dt, J = 6.6, 4.3 Hz, 2H); LCMS(m/z) 427.3.

<u>Example 228. 8-chloro-N-methyl-N-(3-(5-methylpyridin-3-yl)phenyl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1541<chemistry id="chem1693" num="1693"><img file="EP4445902A2_D1696.tif" /></chemistry>

1542Example 228 was synthesized in a manner similar to Example 227 using 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine instead of (5-cyclopropyl-3-pyridyl)boronic acid and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) instead of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II). ¹H NMR (400 MHz, Acetone-d₆) δ 9.46 (s, 1H), 8.66 (s, 1H), 8.48 - 8.33 (m, 2H), 7.92 (s, 1H), 7.78 (t, J = 2.1 Hz, 1H), 7.68 (d, J = 7.6 Hz, 2H), 7.56 (dd, J = 29.8, 8.4 Hz, 1H), 7.44 (d, J = 7.3 Hz, 1H), 7.28 (dd, J = 8.9, 2.2 Hz, 1H), 3.71 (s, 3H), 0.89 (s, 3H); LCMS(m/z) 401.3.

1543Compound 229-1 was prepared from the corresponding bromide Example 308 according to the procedure described in the first step of Example 413.

<u>Example 229. 8-chloro-N-(3-(5-((dimethylamino)methyl)pyrazin-2-yl)phenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1544<chemistry id="chem1694" num="1694"><img file="EP4445902A2_D1697.tif" /></chemistry>

1545Step 1: A vigorously stirred mixture of Compound 229-1 (50.0 mg, 11.5 µmol), 5-bromopyrazine-2-carbaldehyde (258 mg, 1.38 mmol), [2-(2-aminophenyl)phenyl]-chloro-palladium;dicyclohexyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane;dicyclohexyl-[3-(2,4,6-triisopropylphenyl)phenyl]phosphane (43.0 mg, 27.3 µmol), and aqueous sodium carbonate solution (2.0 M, 1.1 mL, 2.3 mmol) in 1,4-dioxane (3.0 mL) was heated to 60 °C. After 90 min, the resulting mixture was diluted with ethyl acetate (15 mL) and water (15 mL) sequentially. The organic layer was separated, was washed with brine (15 mL), was dried over anhydrous magnesium sulfate, was filtered, and was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0% to 100% methanol in dichloromethane) to give Compound 229-2.

1546Step 2: Dimethylamine solution (2.0 M in tetrahydrofuran, 140 µL, 290 µmol) was added to a vigorously stirring mixture of glacial acetic acid (16.3 µL, 289 µmol), sodium triacetoxyborohydride (61.2 mg, 289 µmol), and Compound 229-2 (15.0 mg, 36.1 µmol) in dichloromethane (1.5 mL). The reaction mixture was heated to 40 °C. After 10 min, solvent was removed under reduced pressure. The residue was purified by reverse-phase preparative HPLC (0. 1% trifluoroacetic acid in acetonitrile/water) to give the title compound: ¹H NMR (400 MHz, Methanol-d₄) δ 9.55 (s, 1H), 9.37 - 9.19 (m, 1H), 8.89 - 8.69 (m, 1H), 8.46 (d, J = 2.0 Hz, 1H), 8.32 - 8.14 (m, 2H), 7.71 (t, J = 7.9 Hz, 1H), 7.66 - 7.50 (m, 1H), 7.38 (d, J = 9.1 Hz, 1H), 7.29 (dd, J = 8.9, 2.1 Hz, 1H), 4.61 (s, 2H), 3.81 (s, 3H), 3.01 (s, 6H); LCMS(m/z) 445.2.

<u>Example 230. 8-chloro-N-methyl-N-(3-(5-(morpholinomethyl)pyrazin-2-yl)phenyl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1547<chemistry id="chem1695" num="1695"><img file="EP4445902A2_D1698.tif" /></chemistry>

1548Example 230 was synthesized in a manner similar to Example 229, except using neat morpholine instead of dimethylamine solution. ¹H NMR (400 MHz, Methanol-d₄) δ 9.57 (s, 1H), 9.37 - 9.15 (m, 1H), 8.78 (s, 1H), 8.48 (d, J = 2.1 Hz, 1H), 8.35 - 8.13 (m, 2H), 7.73 (t, J = 7.9 Hz, 1H), 7.59 (d, J = 7.9 Hz, 1H), 7.47 - 7.22 (m, 2H), 4.60 (s, 2H), 3.95 (s, 2H), 3.83 (s, 3H), 3.41 (s, 2H); LCMS(m/z) 487.3.

<u>Example 231. 2-(5-(3-((8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino)phenyl)pyrazin-2-yl)propan-2-ol</u>

1549<chemistry id="chem1696" num="1696"><img file="EP4445902A2_D1699.tif" /></chemistry>

1550Step 1: Bromo(methyl)magnesium (3.0 M in diethyl ether, 2.9 mL, 8.7 mmol) was added by syringe to a vigorously stirred mixture of methyl 5-chloropyrazine-2-carboxylate (Compound 231-1, 500 mg, 2.90 mmol) in tetrahydrofuran (12.1 mL) at 0 °C. After 1 h, the reaction was quenched with aqueous hydrochloric acid (2.0 M, 18 mL, 36 mmol), then extracted with ethyl acetate (2 x 30 mL). The organic layers were combined, were rinsed with brine (30 mL), were dried over anhydrous magnesium sulfate, were filtered, and were concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0% to 30% ethyl acetate in hexanes) to give Compound 231-2.

1551Step 2: 2-(5-Chloropyrazin-2-yl)propan-2-ol (24.2 mg, 140 µmol) was added to a vigorously stirred mixture containing Compound 229-1 (12.2 mg, 28.9 mmol), [2-(2-aminophenyl)phenyl]-chloro-palladium;dicyclohexyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane;dicyclohexyl-[3-(2,4,6-triisopropylphenyl)phenyl]phosphane (4.4 mg, 2.8 µmol), and aqueous sodium carbonate solution (2.0 M, 70.0 µL, 140 µmol) in 1,4-dioxane (1.0 mL). The reaction was sealed and heated to 60 °C. After 90 min, the reaction mixture was heated to 100 °C. After 20 min, the reaction was cooled to room temperature and was diluted with ethyl acetate (15 mL) and water (15 mL) sequentially. The organic layer was separated, was dried over anhydrous magnesium sulfate, was filtered, and was concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC (0.1% trifluoroacetic acid in acetonitrile/water) to give the title compound: ¹H NMR (400 MHz, Methanol-d₄) δ 9.53 (s, 1H), 8.99 (d, J = 34.1 Hz, 1H), 8.45 (s, 1H), 8.15 (s, 1H), 7.74 - 7.12 (m, 6H), 3.82 (s, 3H), 1.60 (s, 6H); LCMS(m/z) 446.3.

<u>Example 232. 3'-((8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino)-[1,1'-biphenyll-4-carboxylic acid</u>

1552<chemistry id="chem1697" num="1697"><img file="EP4445902A2_D1700.tif" /></chemistry>

1553Example 232 was synthesized in a manner similar to Example 227, except using 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid instead of (5-cyclopropyl-3-pyridyl)boronic acid. ¹H NMR (400 MHz, Methanol-d₄) δ 9.59 (s, 1H), 8.51 (d, J = 2.3 Hz, 1H), 8.23 - 8.05 (m, 2H), 7.92 - 7.79 (m, 2H), 7.79 - 7.65 (m, 3H), 7.50 (d, J = 7.9 Hz, 1H), 7.39 (dd, J = 9.1, 2.1 Hz, 1H), 7.36 - 7.28 (m, 1H), 3.87 (s, 3H); LCMS(m/z) 430.3.

<u>Example 233. 2-(3'-((8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino)-[1,1'-biphenyl]-4-yl)-2-methylpropanoic acid</u>

1554<chemistry id="chem1698" num="1698"><img file="EP4445902A2_D1701.tif" /></chemistry>

1555Example 233 was synthesized in a manner similar to Example 227, except using 2-(4-boronophenyl)-2-methyl-propanoic acid instead of (5-cyclopropyl-3-pyridyl)boronic acid. ¹H NMR (400 MHz, Methanol-d₄) δ 9.55 (s, 1H), 8.46 (s, 1H), 7.76 (d, J = 7.6 Hz, 1H), 7.70 (s, 1H), 7.66 - 7.54 (m, 3H), 7.48 (d, J = 8.2 Hz, 2H), 7.36 (dd, J = 19.1, 5.0 Hz, 3H), 3.83 (s, 3H), 1.59 (s, 6H); LCMS(m/z) 472.4.

<u>Example 234. 2-(3'-((8-chloro- [1,2,4]triazolo [4,3-a]quinazolin-5-yl)(methyl)amino)-[1,1'-biphenyl]-4-yl)-2-methylpropanamide</u>

1556<chemistry id="chem1699" num="1699"><img file="EP4445902A2_D1702.tif" /></chemistry>

1557Ammonia solution (0.4 M in tetrahydrofuran, 700 µL, 300 µmol) was added to a vigorously stirred mixture of 3-(ethyliminomethyleneamino)-<i>N,N</i>-dimethyl-propan-1-amine hydrochloride (26.4 mg, 138 µmol), <i>N,N-</i>dimethylpyridin-4-amine (33.7 mg, 275 µmol), and Example 233 (13.0 mg, 27.5 µmol) in dichloromethane (1.3 mL), and the resulting mixture was heated to 40 °C. After 2 h, solvent was removed under reduced pressure. The residue was purified by reverse-phase preparative HPLC (0.1% trifluoroacetic acid in acetonitrile/water) to give the title compound: ¹H NMR (400 MHz, Methanol-d₄) δ 9.59 (s, 1H), 8.51 (d, J = 1.8 Hz, 1H), 7.87 - 7.78 (m, 1H), 7.73 (t, J = 2.0 Hz, 1H), 7.72 - 7.56 (m, 2H), 7.53 - 7.42 (m, 3H), 7.38 (dd, J = 9.1, 2.2 Hz, 1H), 7.28 (d, J = 9.2 Hz, 1H), 3.87 (s, 3H), 1.58 (s, 6H); LCMS(m/z) 471.3.

<u>Example 235. 2-(3'-((8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino)-[1,1'-biphenyll]4-yl)-2-methylpropanenitrile</u>

1558<chemistry id="chem1700" num="1700"><img file="EP4445902A2_D1703.tif" /></chemistry>

1559Example 235 was synthesized in a manner similar to Example 227, except using [4-(1-cyano-1-methyl-ethyl)phenyl]boronic acid instead of (5-cyclopropyl-3-pyridyl)boronic acid. ¹H NMR (400 MHz, Methanol-d₄) δ 9.60 (s, 1H), 8.52 (d, J = 2.0 Hz, 1H), 7.88 - 7.80 (m, 1H), 7.80 - 7.74 (m, 1H), 7.74 - 7.59 (m, 5H), 7.53 - 7.44 (m, 1H), 7.44 - 7.34 (m, 1H), 7.30 (d, J = 9.2 Hz, 1H), 3.88 (s, 3H), 1.76 (s, 6H); LCMS(m/z) 453.3.

<u>Example 236. 8-chloro-N-(3'-methoxy-4'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1560<chemistry id="chem1701" num="1701"><img file="EP4445902A2_D1704.tif" /></chemistry>

1561Example 236 was synthesized in a manner similar to Example 227, except using [3-methoxy-4-(trifluoromethyl)phenyl]boronic acid instead of (5-cyclopropyl-3-pyridyl)boronic acid. ¹H NMR (400 MHz, Methanol-d₄) δ 9.58 (s, 1H), 8.49 (s, 1H), 7.81 (d, J = 18.6 Hz, 2H), 7.65 (s, 2H), 7.49 (s, 1H), 7.41 - 7.24 (m, 4H), 3.97 (s, 3H), 3.86 (s, 3H); LCMS(m/z) 484.3.

<u>Example 237. 8-chloro-N-(3'-fluoro-4'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1562<chemistry id="chem1702" num="1702"><img file="EP4445902A2_D1705.tif" /></chemistry>

1563Example 237 was synthesized in a manner similar to Example 227, except using [3-fluoro-4-(trifluoromethyl)phenyl]boronic acid instead of (5-cyclopropyl-3-pyridyl)boronic acid. ¹H NMR (400 MHz, Methanol-d₄) δ 9.61 (s, 1H), 8.52 (d, J = 2.1 Hz, 1H), 7.93 - 7.83 (m, 2H), 7.79 (t, J = 7.9 Hz, 1H), 7.76 - 7.49 (m, 4H), 7.39 (dd, J = 8.0, 3.2 Hz, 1H), 7.31 (d, J = 9.1 Hz, 1H), 3.87 (d, J = 4.5 Hz, 3H); LCMS(m/z) 472.3.

<u>Example 238. 8-chloro-N-(3'-chloro-4'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1564<chemistry id="chem1703" num="1703"><img file="EP4445902A2_D1706.tif" /></chemistry>

1565Example 238 was synthesized in a manner similar to Example 227, except using [3-chloro-4-(trifluoromethyl)phenyl]boronic acid instead of (5-cyclopropyl-3-pyridyl)boronic acid. ¹H NMR (400 MHz, Methanol-d₄) δ 9.61 (s, 1H), 8.52 (d, J = 2.3 Hz, 1H), 7.97 - 7.81 (m, 4H), 7.73 (dd, J = 20.9, 8.3 Hz, 2H), 7.55 (d, J = 8.2 Hz, 1H), 7.40 (dd, J = 9.2, 2.2 Hz, 1H), 7.36 - 7.28 (m, 1H), 3.87 (s, 3H); LCMS(m/z) 488.3.

<u>Example 239. N-(3',4'-bis(trifluoromethyl)-[1,1'-biphenyl]-3-vl)-8-chloro-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1566<chemistry id="chem1704" num="1704"><img file="EP4445902A2_D1707.tif" /></chemistry>

1567Example 239 was synthesized in a manner similar to Example 227, except using [3,4-bis(trifluoromethyl)phenyl]boronic acid instead of (5-cyclopropyl-3-pyridyl)boronic acid. ¹H NMR (400 MHz, Methanol-d₄) δ 9.50 (s, 1H), 8.41 (d, J = 2.1 Hz, 1H), 8.18 (s, 3H), 7.99 (s, 2H), 7.79 (d, J = 2.1 Hz, 1H), 7.74 (d, J = 7.8 Hz, 1H), 7.63 (t, J = 7.9 Hz, 1H), 7.46 - 7.37 (m, 1H), 7.29 (dd, J = 9.0, 2.1 Hz, 1H), 3.78 (s, 3H); LCMS(m/z) 522.3.

<u>Example 240. 8-chloro-N-methyl-N-(3-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)phenyl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1568<chemistry id="chem1705" num="1705"><img file="EP4445902A2_D1708.tif" /></chemistry>

1569Sodium hydride (4.3 mg, 190 µmol) was added to a vigorously stirred mixture of Example 286 (5.00 mg, 12.4 µmol) and 2,2,2-trifluoroethanol (13.3 µL, 185 µmol) in <i>N,N-</i>dimethylformamide (0.5 mL) at 0 °C. The reaction mixture was heated to 45 °C. After 50 min, the reaction mixture was cooled to room temperature. The mixture was purified by reverse-phase preparative HPLC (0.1% trifluoroacetic acid in acetonitrile/water) to give the title compound: ¹H NMR (400 MHz, Methanol-d₄) δ 9.56 (s, 1H), 8.48 (s, 1H), 8.42 (d, J = 2.5 Hz, 1H), 8.01 (dd, J = 8.6, 2.5 Hz, 1H), 7.77 - 7.69 (m, 2H), 7.64 (t, J = 7.9 Hz, 1H), 7.43 (d, J = 8.1 Hz, 1H), 7.36 - 7.30 (m, 2H), 7.00 (d, J = 8.6 Hz, 1H), 3.83 (s, 3H), 1.96 (s, 2H); LCMS(m/z) 485.3.

<u>Example 241. 8-chloro-N-methyl-N-(3-(6-((1,1,1-trifluoropropan-2-yl)oxy)pyridin-3-yl)phenyl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1570<chemistry id="chem1706" num="1706"><img file="EP4445902A2_D1709.tif" /></chemistry>

1571Example 241 was synthesized in a manner similar to Example 240, except using 1,1,1-trifluoropropan-2-ol instead of 2,2,2-trifluoroethanol. ¹H NMR (400 MHz, Methanol-d₄) δ 9.48 (s, 1H), 8.39 (d, J = 2.2 Hz, 2H), 7.98 (dd, J = 8.6, 2.6 Hz, 1H), 7.66 - 7.59 (m, 2H), 7.56 (t, J = 8.1 Hz, 1H), 7.41 (d, J = 9.0 Hz, 1H), 7.32 (d, J = 8.2 Hz, 1H), 7.26 (dd, J = 9.0, 2.1 Hz, 1H), 6.95 - 6.90 (m, 1H), 5.88 (p, J = 6.7 Hz, 1H), 3.75 (s, 3H), 1.50 (d, J = 6.5 Hz, 3H); LCMS(m/z) 499.3.

<u>Example 242. 4-(3-((8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino)phenyl)-2-cyclopropylbut-3-yn-2-ol</u>

1572<chemistry id="chem1707" num="1707"><img file="EP4445902A2_D1710.tif" /></chemistry>

15732-Cyclopropylbut-3-yn-2-ol (75% purity by wt, 44 µL, 240 µmol) was added to a vigorously stirred mixture of Example 308 (18.5 mg, 47.6 µmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (12.2 mg, 16.7 µmol), triethylamine (166 µL, 1.19 mmol), and zinc bromide (53.6 mg, 238 mmol) in 1-methylpyrrolidin-2-one (0.5 mL). The reaction mixture was sealed and heated to 110 °C. After 10 min, the reaction mixture was cooled to room temperature. The mixture was purified by reverse-phase preparative HPLC (0. 1% trifluoroacetic acid in acetonitrile/water) to give the title compound: ¹H NMR (400 MHz, Methanol-d₄) δ 9.49 (s, 1H), 8.40 (s, 1H), 8.09 (s, 1H), 7.50 - 7.22 (m, 5H), 3.68 (d, J = 6.0 Hz, 3H), 1.98 - 1.87 (m, 1H), 1.58 (s, 3H), 1.25 - 1.07 (m, 2H), 0.49 (q, J = 5.5, 4.6 Hz, 2H); LCMS(m/z) 418.1.

<u>Example 243. N-methyl-N-(naphthalen-1-yl)-8-nitro-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1574<chemistry id="chem1708" num="1708"><img file="EP4445902A2_D1711.tif" /></chemistry>

1575Synthesis of 5-chloro-8-nitro-[1,2,4]triazolo[4,3-a]quinazoline (Compound 243-2): A mixture of 8-nitro-[1,2,4]triazolo[4,3-a]quinazolin-5(4H)-one (Intemediate 4, 1.0 g, 4.33 mmol) and phosphoryl trichloride (13.3 g, 86 mmol) was stirred at 100 °C for 6 h. The reaction was monitored by LCMS. The reaction mixture was cooled to room temperature then evaporated under reduced pressure. The crude product was used in the next step without further purification.

1576Synthesis of N-methyl-N-(naphthalen-1-yl)-8-nitro-[1,2,4]triazolo[4,3-a]quinazolin-5-amine: To a solution of crude 5-chloro-8-nitro-[1,2,4]triazolo[4,3-a]quinazoline (50 mg, 0.20 mmol) in DMF (5 ml) was added N-methylnaphthalen-1-amine (22 mg, 0.14 mmol) and sodium hydride (5.6 mg, 0.14 mmol) at room temperature. The mixture was stirred for 1 h. The mixture was diluted with AcOEt, washed successively with water and brine, and dried over MgSO₄. The organic layer was concentrated <i>in vacuo.</i> The resulting residue was purified under reverse phase chromatography ACN/Water 15-95% 0.1 % TFA 15 min to obtain the title compound: ¹H NMR (400 MHz, Methanol-d₄) δ 9.83 (s, 1H), 9.24 (d, <i>J=</i> 2.3 Hz, 1H), 8.24 - 8.03 (m, 3H), 7.88 (dd, J = 9.3, 2.3 Hz, 1H), 7.77 - 7.67 (m, 2H), 7.65 - 7.45 (m, 2H), 7.15 (d, J = 9.3 Hz, 1H), 3.91 (s, 3H); LCMS(m/z) 371.3.

<u>Example 244. N-methyl-N-(naphthalen-2-yl)-8-nitro-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1577<chemistry id="chem1709" num="1709"><img file="EP4445902A2_D1712.tif" /></chemistry>

1578Example 244 was synthesized in a manner similar to Example 243, except using N-methylnaphthalen-2-amine instead of N-methylnaphthalen-1-amine. ¹H NMR (400 MHz, Chloroform-d) δ 9.34 (s, 1H), 8.94 (d, J = 2.2 Hz, 1H), 8.06 (d, J = 8.7 Hz, 1H), 8.00 - 7.92 (m, 1H), 7.88 (dd, J = 9.3, 2.1 Hz, 1H), 7.85 - 7.75 (m, 2H), 7.69 - 7.57 (m, 2H), 7.47 - 7.34 (m, 2H), 3.91 (s, 3H); LCMS(m/z) 371.3.

<u>Example 245. N-(2,2-difluoroethyl)-8-nitro-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1579<chemistry id="chem1710" num="1710"><img file="EP4445902A2_D1713.tif" /></chemistry>

1580Example 245 was synthesized in a manner similar to Example 243, except using N-(2,2-difluoroethyl)aniline instead of N-methylnaphthalen-1-amine. ¹H NMR (400 MHz, Chloroform-d) δ 9.42 (s, 1H), 8.99 (d, J = 2.2 Hz, 1H), 8.06 (d, J = 8.7 Hz, 1H), 8.00 - 7.93 (m, 1H), 7.88 - 7.76 (m, 2H), 7.67 - 7.56 (m, 2H), 7.44 (dd, J = 8.7, 2.2 Hz, 1H), 7.37 (d, J = 9.3 Hz, 1H), 4.0-3.8 (m, 3H); LCMS(m/z) 371.3.

<u>Example 246. N-methyl-N-(8-nitro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)benzo[d]thiazol-2-amine</u>

1581<chemistry id="chem1711" num="1711"><img file="EP4445902A2_D1714.tif" /></chemistry>

1582Example 246 was synthesized in a manner similar to Example 243, except using N-methylbenzo[d]thiazol-2-amine instead ofN-methylnaphthalen-1-amine. ¹H NMR (400 MHz, Chloroform-d) δ 9.42 (s, 1H), 8.99 (d, J = 2.2 Hz, 1H), 8.06 (d, J = 8.7 Hz, 1H), 8.00 - 7.93 (m, 1H), 7.89 - 7.75 (m, 1H), 7.69 - 7.57 (m, 1H), 7.48 - 7.33 (m, 2H), 3.90 (s, 3H); LCMS(m/z) 378.2.

<u>Example 247. N-methyl-N-(8-nitro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)benzo[d]thiazol-2-amine</u>

1583<chemistry id="chem1712" num="1712"><img file="EP4445902A2_D1715.tif" /></chemistry>

1584Example 247 was synthesized in a manner similar to Example 243, except using N,1-dimethyl-1H-indazol-6-amine instead of N-methylnaphthalen-1-amine. ¹H NMR (400 MHz, Chloroform-d) δ 7.49 (s, 1H), 7.36 (t, <i>J =</i> 7.9 Hz, 2H), 7.24 (d, <i>J =</i> 7.7 Hz, 1H), 7.20 - 7.10 (m, 2H), 6.90 (d, <i>J =</i> 8.5 Hz, 1H), 6.64 (t, <i>J =</i> 7.7 Hz, 1H), 3.59 (s, 3H), 2.09 - 1.97 (m, 3H); LCMS(m/z) 375.2.

<u>Example 248. 1-(5-(methyl(phenyl)amino)-[1,2,4]triazolo[4,3-a]quinazolin-8-yl)propan-1-ol</u>

1585<chemistry id="chem1713" num="1713"><img file="EP4445902A2_D1716.tif" /></chemistry>

1586A flask was evacuated and fed with nitrogen. After THF (6 mL) and 5-(metbyl(pbenyl)amino)-[1,2,4]triazolo[4,3-a]quinazoline-8-carbaldehyde (Example 117, 25 mg. 0.082 mmol) were added as a solution, the mixture was kept at 0 °C in ice water bath. Then EtMgBr was added (1.0 M, 0.082 mmol), the mixture was further stirred at room temperature for 24 h, and then water and DCM were added. The organic layer was washed successively with water and brine. The organic layer was dried over MgSO₄ and evaporated under reduced pressure. The crude products were subjected to reverse phase chromatography ACN/Water 15-95% with 0.1 % TFA for 15 min to obtain the title compound as a mixture of isomers: ¹H NMR (400 MHz, Methanol-d₄) δ 9.63 (s, 1H), 8.29 (d, J = 1.6 Hz, 1H), 7.63 - 7.50 (m, 3H), 7.48 - 7.41 (m, 2H), 7.29 (dd, J = 8.9, 1.7 Hz, 1H), 7.16 (d, J = 8.8 Hz, 1H), 4.74 (dd, J = 7.3, 5.4 Hz, 1H), 3.81 (s, 3H), 1.88 - 1.66 (m, 2H), 0.94 (t, J = 7.4 Hz, 3H); LCMS(m/z) 334.3.

<u>Example 249. 7,8-difluoro-N-(3-fluorophenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1587<chemistry id="chem1714" num="1714"><img file="EP4445902A2_D1717.tif" /></chemistry>

1588Synthesis of 2-chloro-6,7-difluoro-N-(3-fluorophenyl)-N-methylquinazolin-4-amine (Compound 249-2): To a solution of 2,4-dichloro-6,7-difluoroquinazoline (Compound 249-1, 3 g, 12.8 mmol) in DMF (20 ml) were added 3-fluoro-N-methylaniline (1.76 g, 14 mmol) and sodium hydride (587 mg, 14.7 mmol) then the mixture was stirred for 1 h at RT. Water was added to the reaction mixture and the mixture filtered. The resulting residue was used in the next step without further purification.

1589Synthesis of 6,7-difluoro-N-(3-fluorophenyl)-2-hydrazineyl-N-methylquinazolin-4-amine (Compound 249-3): Hydrazine hydrate (0.018 g, 0.23 mmol) was added slowly to a stirred solution of crude 2-chloro-6,7-difluoro-N-(3-fluorophenyl)-N-methylquinazolin-4-amine (Compound 249-2, 254 mg, 0.78 mmol) in ethanol (4 ml) at room temperature. The mixture was diluted with DCM, and then washed successively with water and brine, and dried over MgSO₄. The organic layer was concentrated <i>in vacuo.</i> The resulting residue was used in the next step without further purification.

1590Synthesis of 7,8-difluoro-N-(3-fluorophenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine: A mixture of crude 6,7-difluoro-N-(3-fluorophenyl)-2-hydrazinyl-N-methylquinazolin-4-amine (Compound 249-3) (340 mg, 1.06 mmol) and triethoxymethane (789 mg, 5.32 mmol) was stirred at 100 °C for 4 h. The reaction mixture was concentrated <i>in vacuo.</i> The residue was purified reverse phase chromatography ACN/Water 15-95% with 0.1 % TFA for 15 min to yield the title compound: ¹H NMR (400 MHz, Chloroform-d) δ 8.90 (s, 1H), 7.67 (dd, J = 9.3, 6.6 Hz, 1H), 7.40 (td, J = 8.2, 6.3 Hz, 1H), 7.18 (dd, J = 11.2, 8.0 Hz, 1H), 7.06 (td, J = 8.4, 2.2 Hz, 1H), 6.99 - 6.87 (m, 2H), 3.68 (s, 3H); LCMS(m/z) 330.3.

<u>Example 250. 8-chloro-7-fluoro-N-(3-fluorophenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1591<chemistry id="chem1715" num="1715"><img file="EP4445902A2_D1718.tif" /></chemistry>

1592Synthesis of 8-azido-7-fluoro-N-(3-fluorophenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Compound 250-2): To a solution of 7,8-difluoro-N-(3-fluorophenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 249, 2.4 g, 7.71 mmol) in DMSO (10 ml) was added sodium azide (2.5 g, 38.8 mmol), and the mixture was stirred for 2 h at 100 °C. The reaction mixture was diluted with DCM, and then washed successively with water and brine, and dried over MgSO₄. The organic layer was concentrated <i>in vacuo.</i> The resulting residue was used in the next step without further purification.

1593Synthesis of 7-fluoro-N5-(3-fluorophenyl)-N5-methyl-[1,2,4]triazolo[4,3-a]quinazoline-5,8-diamine (Compound 250-3): To a solution of crude 8-azido-7-fluoro-N-(3-fluorophenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (2) (0.6 g, 1.7 mmol) in ethanol (5 ml) was added Pd/C and the suspension was stirred for 5 h at room temperature under hydrogen gas atmosphere. Pd/C was removed by filtration, and the filtrate was concentrated <i>in vacuo.</i> The crude product was used in the next step.

1594Synthesis of 8-chloro-7-fluoro-N-(3-fluorophenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine: A solution of sodium nitrite (23.3 mg, 0.33 mmol) in water (2ml) was added dropwise to a stirred, suspension of 7-fluoro-N5-(3-fluorophenyl)-N5-methyl-[1,2,4]triazolo[4,3-a]quinazoline-5,8-diamine (100 mg, 0.306 mmol) in hydrochloric acid (37% w/v, 4 ml) at 0°C. The solution was stirred at 0 °C for 30 min and then added in portions to a stirred, boiling solution of copper (I) chloride (48 mg, 0.33 mmol) in hydrochloric acid (37% w/v, 2 ml). The stirred mixture was boiled for a further 15 min and left cool overnight. Water was added, and the product extracted into DCM. The etherate extract was washed with water, 10% w/v sodium hydroxide solution and then dried over MgSO₄. The solvent removed <i>in vacuo.</i> The residue was purified by reverse phase chromatography ACN/Water 15-95% with 0.1 % TFA for 15 min to yield the title compound: ¹H NMR (400 MHz, Chloroform-d) δ 9.22 (s, 1H), 8.31 (d, J = 7.7 Hz, 1H), 7.54 (q, J = 7.8 Hz, 1H), 7.24 (t, J = 8.1 Hz, 1H), 7.09 (dd, J = 11.8, 8.7 Hz, 2H), 6.89 (d, J = 10.2 Hz, 1H), 3.77 (d, J = 2.0 Hz, 3H); LCMS(m/z) 346.

<u>Example 251. (7-fluoro-5-((3-fluorophenvl)(methyl)amino)-[1,2,4]triazolo[4,3-a]quinazolin-8-yl)methanol</u>

1595<chemistry id="chem1716" num="1716"><img file="EP4445902A2_D1719.tif" /></chemistry>

1596To a solution of methylthiomelhyl p-tolyl sulfone (131 mg. 0.6 mmol) in DMF (5 mL) was added 60% sodium hydride (24 mg. 0.6 mmol). The resulting mixture was stirred at 0 °C for 1 h followed by addition of 7,8-difluoro-N-(3-fluorophenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 249, 100 mg. 0.30 mmol) The reaction was then carried out at room temperature for 24 h and was quenched by addition of 5 ml 10% HCl. To the mixture was added DCM and water. The organic phase was then washed with water and brine, dried over MgSO₄, and concentrated to dryness. The residue was purified reverse phase chromatography ACN/Water 15-95% with 0.1 % TFA for 15 min to yield the title compound: ¹H NMR (400 MHz, Methanol-d₄) δ 9.71 (s, 1H), 8.50 (d, J = 6.2 Hz, 1H), 7.72 - 7.53 (m, 1H), 7.43 - 7.18 (m, 3H), 6.80 (d, J = 11.5 Hz, 1H), 4.83 (s, 2H), 3.81 (s, 3H); LCMS(m/z) 342.2.

<u>Example 252. 8-chloro-N-(3-(6-(1,1-difluoroethyl)pyridin-3-yl)phenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1597<chemistry id="chem1717" num="1717"><img file="EP4445902A2_D1720.tif" /></chemistry>

1598Synthesis of N-(3-bromophenyl)-2,7-dichloro-N-methylquinazolin-4-amine (Compound 252-2): To a solution of 2,4,7-trichloroquinazoline (1 g, 4.28 mmol) in DMF (20 ml) were added 3-fluoro-N-methylaniline (837 mg, 4.5 mmol) and sodium hydride (965 mg, 24.1 mmol). The mixture was stirred for 24 h at room temperature. Water was added to the reaction mixture and the mixture filtered. The resulting residue was used in the next step without further purification.

1599Synthesis of N-(3-bromophenyl)-7-chloro-2-hydrazinyl-N-methylquinazolin-4-amine (Compound 252-3): Hydrazine hydrate (2.8 g, 56.4 mmol) was added slowly to a stirred solution of crude N-(3-bromophenyl)-2,7-dichloro-N-methylquinazolin-4-amine (252-2) (800 mg, 2.1 mmol) in ethanol (6 ml) and THF (1 ml). The mixture was stirred at room temperature for 4 hrs. The mixture was evaporated and then dissolved in DCM and then washed successively with water and brine, and dried over MgSO₄. The organic layer was concentrated <i>in vacuo.</i> The resulting residue was used in the next step without further purification.

1600Synthesis of N-(3-bromophenyl)-8-chloro-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Compound 252-4): A mixture of crude N-(3-bromophenyl)-7-chloro-2-hydrazineyl-N-methylquinazolin-4-amine (252-3) (550 mg, 1.45 mmol) and triethoxymethane (3.2 g, 21 mmol) was stirred at 100 °C for 4 h. Hexanes were added to reaction mixture to precipitate a crude product, which was used in the next step.

1601Synthesis of 8-chloro-N-(3-(6-(1,1-difluoroethyl)pyridin-3-yl)phenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine: To a solution of N-(3-bromophenyl)-8-chloro-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (252-4, 20 mg, 0.05 mmol) and 2-(1,1-difluoroethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (15 mg, 0.056 mmol) in 1,4-dioxane (5 ml) were added Pd(dppf)Cl₂ (8 mg, 0.01 mmol) and 2 ml of a saturated aqueous solution of Na₂CO₃. The mixture was stirred at 90 °C for 10 min. The residue was purified reverse phase chromatography ACN/Water 15-95% with 0.1 % TFA for 15 min to yield the title compound: ¹H NMR (400 MHz, Chloroform-d) δ 9.12 (s, 1H), 8.85 (s, 1H), 8.03 (s, 2H), 7.74 (d, J = 24.2 Hz, 3H), 7.64 - 7.34 (m, 2H), 7.26-7.3 (m, 2H), 3.86 (s, 3H), 2.06 (t, J = 18.1 Hz, 3H); LCMS(m/z) 451.4.

<u>Example 253. tert-butyl 4-(5-(3-((8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino)phenyl)pyridin-2-yl)piperazine-1-carboxylate</u>

1602<chemistry id="chem1718" num="1718"><img file="EP4445902A2_D1721.tif" /></chemistry>

1603Example 253 was prepared in a similar manner as Example 252. ¹H NMR (400 MHz, Chloroform-d) δ 9.14 (s, 1H), 8.51 (s, 1H), 8.08 (s, 1H), 8.00 (d, J = 9.3 Hz, 1H), 7.61 (d, J = 6.5 Hz, 2H), 7.43 (s, 1H), 7.36 (dt, J = 6.9, 2.2 Hz, 1H), 7.20 (s, 2H), 7.01 (d, J = 9.3 Hz, 1H), 3.75 (d, J = 12.5 Hz, 7H), 3.65 (dd, J = 6.8, 3.6 Hz, 4H), 1.49 (d, J = 20.5 Hz, 9H); LCMS(m/z) 571.3.

<u>Example 254. 8-chloro-N-methyl-N-(4'-(thiazol-2-yl)-[1,1'-biphenyl]-3-yl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1604<chemistry id="chem1719" num="1719"><img file="EP4445902A2_D1722.tif" /></chemistry>

1605Example 254 was prepared in a similar manner as Example 252. ¹H NMR (400 MHz, Chloroform-d) δ 9.10 (s, 1H), 8.15 - 7.92 (m, 4H), 7.78 (d, J = 7.7 Hz, 1H), 7.72 - 7.60 (m, 3H), 7.57 (s, 1H), 7.44 (d, J = 3.3 Hz, 1H), 7.32 (d, J = 7.7 Hz, 1H), 7.22 (q, J = 9.5 Hz, 3H), 3.86 (s, 3H); LCMS(m/z) 469.3.

<u>Example 255. N-(3-(1H-pyrrolo[3,2-blnvridin-6-yl)phenyl)-8-chloro-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1606<chemistry id="chem1720" num="1720"><img file="EP4445902A2_D1723.tif" /></chemistry>

1607Example 255 was prepared in a similar manner as Example 252. ¹H NMR (400 MHz, Methanol-d₄) δ 9.56 (s, 1H), 8.87 (d, J = 1.6 Hz, 1H), 8.75 (d, J = 1.3 Hz, 1H), 8.47 (d, J = 2.1 Hz, 1H), 8.17 (d, J = 3.2 Hz, 1H), 7.88 (d, J = 8.2 Hz, 2H), 7.71 (t, J = 7.8 Hz, 1H), 7.52 (d, J = 8.6 Hz, 1H), 7.42 (d, J = 9.0 Hz, 1H), 7.33 (dd, J = 9.0, 2.1 Hz, 1H), 6.90 (d, J = 3.4 Hz, 1H), 3.84 (s, 3H); LCMS(m/z) 426.2.

<u>Example 256. 8-chloro-N-(3'-methoxy-4'-(4-(oxetan-3-yl)piperazin-1-yl)-[1,1'-biphenyl]-3-yl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1608<chemistry id="chem1721" num="1721"><img file="EP4445902A2_D1724.tif" /></chemistry>

1609Example 256 was prepared in a similar manner as Example 252. ¹H NMR (400 MHz, Methanol-d₄) δ 9.57 (s, 1H), 8.49 (d, J = 2.0 Hz, 1H), 7.78 (dt, J = 8.0, 1.2 Hz, 1H), 7.71 (t, J = 2.0 Hz, 1H), 7.63 (t, J = 7.9 Hz, 1H), 7.44 - 7.28 (m, 3H), 7.22 (d, J = 7.4 Hz, 2H), 7.11 - 7.02 (m, 1H), 4.93 (t, J = 7.7 Hz, 4H), 4.50 (tt, J = 7.2, 5.6 Hz, 1H), 3.93 (s, 4H), 3.86 (s, 4H), 3.31 (d, J = 1.5 Hz, 3H); LCMS(m/z) 556.4.

<u>Example 257. 8-chloro-N-(4'-(1,1-difluoroethyl)-[1,1'-biphenyl]3-yl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1610<chemistry id="chem1722" num="1722"><img file="EP4445902A2_D1725.tif" /></chemistry>

1611Example 257 was prepared in a similar manner as Example 252. ¹H NMR (400 MHz, Chloroform-d) δ 9.04 (s, 1H), 8.03 (s, 1H), 7.70 (d, J = 7.8 Hz, 1H), 7.66 - 7.57 (m, 4H), 7.48 (d, J = 1.9 Hz, 1H), 7.30 (d, J = 1.7 Hz, 2H), 7.21 (s, 2H), 3.83 (s, 3H), 1.97 (d, J = 36.2 Hz, 3H); LCMS(m/z) 450.3.

<u>Example 258. 8-chloro-N-methyl-N-(3-(6-(piperazin-1-yl)pyridin-3-yl)phenyl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1612<chemistry id="chem1723" num="1723"><img file="EP4445902A2_D1726.tif" /></chemistry>

1613To a solution of tert-butyl 4-(5-(3-((8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino)phenyl)pyridin-2-yl)piperazine-1-carboxylate (Example 253, 20 mg, 0.05 mmol) in DCM (5 ml) was added TFA (2 ml) and then stirred at room temperature for 2 hr. The residue was evaporated under reduced pressure and then purified by reverse phase chromatography ACN/Water 15-95% with 0.1 % TFA for 15 min to yield the title compound: ¹H NMR (400 MHz, Chloroform-d) δ 9.04 (s, 1H), 8.03 (s, 1H), 7.70 (d, <i>J</i> = 7.8 Hz, 1H), 7.64 - 7.57 (m, 4H), 7.48 (d, <i>J=</i> 1.9 Hz, 1H), 7.30 (d, <i>J</i> = 1.7 Hz, 1H), 7.21 (s, 2H), 3.83 (s, 3H), 3.13 (s, 8H); LCMS(m/z) 471.3.

<u>Example 259. 2-(5-(3-((8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino)phenyl)pyridin-2-yl)propan-2-ol</u>

1614<chemistry id="chem1724" num="1724"><img file="EP4445902A2_D1727.tif" /></chemistry>

1615Example 259 was prepared in a similar manner as Example 252. ¹H NMR (400 MHz, Methanol-d₄) δ 9.62 (s, 1H), 8.87 (dd, J = 2.3, 0.7 Hz, 1H), 8.59 (dd, J = 8.5, 2.3 Hz, 1H), 8.53 (d, J = 2.0 Hz, 1H), 8.07 (dd, J = 8.5, 0.7 Hz, 1H), 7.96 - 7.87 (m, 2H), 7.75 (t, J = 8.2 Hz, 1H), 7.64 - 7.53 (m, 1H), 7.41 - 7.25 (m, 2H), 3.88 (s, 3H), 1.67 (s, 5H); LCMS(m/z) 445.3.

<u>Example 260. 2-(5-(3-((8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino)phenyl)pyridin-2-yl)propan-2-ol</u>

1616<chemistry id="chem1725" num="1725"><img file="EP4445902A2_D1728.tif" /></chemistry>

1617Example 260 was prepared in a similar manner as Example 252. ¹H NMR (400 MHz, Methanol-d₄) δ 9.57 (s, 1H), 8.49 (d, J = 2.0 Hz, 1H), 7.78 (dt, J = 8.0, 1.2 Hz, 1H), 7.71 (t, J = 2.0 Hz, 1H), 7.63 (t, J = 7.9 Hz, 1H), 7.44 - 7.27 (m, 2H), 7.10 - 7.03 (m, 1H), 4.93 (t, J = 7.7 Hz, 2H), 4.50 (tt, J = 7.2, 5.6 Hz, 1H), 3.93 (s, 3H); LCMS(m/z) 403.3.

<u>Example 261. 8-chloro-N-methyl-N-(3-(2-morpholinopyrimidin-5-yl)phenyl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1618<chemistry id="chem1726" num="1726"><img file="EP4445902A2_D1729.tif" /></chemistry>

1619Example 261 was prepared in a similar manner as Example 252. ¹H NMR (400 MHz, Chloroform-d) δ 9.14 (s, 1H), 8.51 (s, 1H), 8.08 (s, 1H), 8.00 (d, J = 9.3 Hz, 1H), 7.61 (d, J = 6.5 Hz, 2H), 7.43 (s, 1H), 7.36 (dt, J = 6.9, 2.2 Hz, 1H), 7.20 (s, 1H), 7.01 (d, J = 9.3 Hz, 1H), 3.75 (d, J = 12.5 Hz, 7H), 3.65 (dd, J = 6.8, 3.6 Hz, 4H); LCMS(m/z) 473.2.

<u>Example 262. N-(3-bromophenyl)-8-chloro-6-fluoro-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1620<chemistry id="chem1727" num="1727"><img file="EP4445902A2_D1730.tif" /></chemistry>

1621Synthesis of 7-chloro-5-fluoroquinazoline-2,4(1H,3H)-dione (Compound 262-2): To a solution of 2-amino-4-chloro-6-fluorobenzoic acid (5.0 g, 26.4 mmol) dissolved in acetic acid (20 ml) was added KOCN (3.2 g, 39.6 mmol) dissolved in 10 ml of water and then stirred at room temperature for 5 hrs. Another portion of KOCN (640 mg, 7.9 mmol) was added and the mixture was stirred for 5 more hours. A saturated aqueous solution of NaHCO₃ was added slowly to the mixture, and solids filtered out.

1622Synthesis of 2,4,7-trichloro-5-fluoroquinazoline (Compound 262-3): A mixture of 7-chloro-5-fluoroquinazoline-2,4(1H,3H)-dione (Compound 262-2, 1.3 g, 6.06 mmol), phosphoryl trichloride (2.3 g, 15.1 mmol) and DIPEA (2.2 ml, 12.12 mmol) was stirred at 100 °C for 1 h. The reaction was monitored by LCMS. The reaction mixture was cooled to room temperature, evaporated under reduced pressure. The residue was purified in normal phase chromatography Hex:EtOAc 1:2. Appropriate fractions were evaporated and used in the next step.

1623Synthesis of N-(3-bromophenyl)-2,7-dichloro-N-methylquinazolin-4-amine (Compound 262-4): A solution of 3-bromo-N-methylaniline (160 mg, 0.86 mmol) and sodium hydride (109 mg, 2.7 mmol) in DMF was stirred at room temperature for 30 min. To this mixture 2,4,7-trichloro-5-fluoroquinazoline (Compound 262-3, 173 mg, 0.68 mmol) was added and mixture was stirred for 24h at room temperature. Water and DCM were added to the mixture and the organic phase was dried over MgSO₄ and evaporated under reduced pressure. The crude product was used in the next step.

1624Synthesis of N-(3-bromophenyl)-7-chloro-2-hydrazineyl-N-methylquinazolin-4-amine (Compound 262-5): Hydrazine hydrate (1 g, 20.2 mmol) was added slowly to a stirred solution of crude N-(3-bromophenyl)-2,7-dichloro-N-methylquinazolin-4-amine (Compound 262-4) (300 mg, 0.74 mmol) in ethanol 6 ml and THF 1 ml at room temperature. The mixture was evaporated under reduced pressure and dissolved with DCM and then washed successively with water and brine and dried over MgSO₄. The organic layer was concentrated <i>in vacuo.</i> The resulting residue was used in the next step without further purification.

1625Synthesis of N-(3-bromophenyl)-8-chloro-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine: A mixture of crude N-(3-bromophenyl)-7-chloro-2-hydrazinyl-N-methylquinazolin-4-amine (Compound 262-5) (200 mg, 0.5 mmol) and triethoxymethane (1.4 g, 10 mmol) was stirred at 95 °C for 4 h. The residue was evaporated under reduced pressure and then purified reverse phase chromatography ACN/Water 15-95% with 0.1 % TFA for 15 min to give the title compound: ¹H NMR (400 MHz, Chloroform-d) δ 8.95 (s, 1H), 7.72 (s, 1H), 7.39 - 7.32 (m, 1H), 7.24 (d, J = 2.1 Hz, 1H), 7.16 (t, J = 8.0 Hz, 1H), 7.00 (dd, J = 11.0, 1.9 Hz, 1H), 6.96 - 6.89 (m, 1H), 3.68 (s, 3H); LCMS(m/z) 408.2.

<u>Example 263. N-(4'-(tert-butyl)-[1,1'-biphenyl]-3-yl)-8-chloro-6-fluoro-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1626<chemistry id="chem1728" num="1728"><img file="EP4445902A2_D1731.tif" /></chemistry>

1627Example 263 was prepared in a similar manner as Example 252, except using Example 262 instead of Compound 252-4 and (4-(tert-butyl)phenyl)boronic acid instead of 2-(1,1-difluoroethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine. ¹H NMR (400 MHz, Chloroform-d) δ 9.25 (s, 1H), 8.06 (s, 1H), 7.60 - 7.52 (m, 1H), 7.48 (d, J = 8.6 Hz, 2H), 7.46 - 7.38 (m, 3H), 7.35 (t, J = 1.9 Hz, 1H), 7.08 - 6.97 (m, 2H), 3.84 (s, 3H), 1.37 (s, 9H); LCMS(m/z) 460.4.

<u>Example 264. N-(6-(4-(tert-butvl)phenyl)pyridin-2-yl)-8-chloro-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1628<chemistry id="chem1729" num="1729"><img file="EP4445902A2_D1732.tif" /></chemistry>

1629Synthetic route to prepare 6-(4-(tert-butyl)phenyl)-N-methylpyridin-2-amine.(Compound 264-2) was analogous to that used in the preparation of Example 252.

1630Synthesis of N-(6-(4-(tert-butyl)phenyl)pyridin-2-yl)-8-chloro-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Compound 264-4): A solution of 2,4,7-trichloroquinazoline (173 mg, 0.68 mmol) in THF (5 ml) at -20 °C were added 6-(4-(tert-butyl)phenyl)-N-methylpyridin-2-amine (160 mg, 0.86 mmol) and LiHMDS in THF (1M, 0.3 ml, 0.32 mmol). The mixture was stirred for 2 hours at - 20 °C. Water and DCM were added to the mixture and the organic phase was dried over MgSO₄ and evaporated under reduced pressure. Solids were used in the next step.

1631Synthetic routes to prepare Compound 264-5 and the title compound were analogous to those described in the preparation of Example 252. ¹H NMR (400 MHz, Chloroform-d) δ 9.30 (s, 1H), 8.18 (d, J = 1.7 Hz, 1H), 7.82 (t, J = 7.8 Hz, 1H), 7.68 (dd, J = 15.3, 8.0 Hz, 3H), 7.44 (d, J = 8.2 Hz, 2H), 7.24 - 7.16 (m, 2H), 7.06 (d, J = 7.9 Hz, 1H), 3.88 (s, 3H), 1.35 (s, 9H); LCMS(m/z) 443.4.

<u>Example 265. 6-(3-((8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino)phenyl)-4-fluoro-1-methyl-1,3-dihydro-2H-benzo</u>[<u>d]imidazol-2-one</u>

1632<chemistry id="chem1730" num="1730"><img file="EP4445902A2_D1733.tif" /></chemistry>

1633Example 265 was prepared in a similar manner as Example 252. ¹H NMR (400 MHz, Methanol-d₄) δ 9.58 (s, 1H), 8.50 (d, J = 2.0 Hz, 1H), 7.76 (ddd, J = 7.9, 1.9, 1.0 Hz, 1H), 7.71 (t, J = 2.0 Hz, 1H), 7.64 (t, J = 7.9 Hz, 1H), 7.46 - 7.28 (m, 3H), 7.21 - 7.08 (m, 2H), 3.85 (s, 3H), 3.61 - 3.54 (m, 3H); LCMS(m/z) 474.4.

<u>Example 266. 6,-(3-((8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino)phenyl)spiro[cyclopropane-1,3'-indolin]-2'-one</u>

1634<chemistry id="chem1731" num="1731"><img file="EP4445902A2_D1734.tif" /></chemistry>

1635Example 266 was prepared in a similar manner as Example 252. ¹H NMR (400 MHz, Methanol-d₄) δ 9.59 (s, 1H), 8.50 (d, J = 2.0 Hz, 1H), 7.78 (dt, J = 7.8, 1.3 Hz, 1H), 7.71 (t, J = 2.0 Hz, 1H), 7.65 (t, J = 7.9 Hz, 1H), 7.44 (ddd, J = 7.9, 2.3, 1.0 Hz, 1H), 7.38 (dd, J = 9.1, 2.0 Hz, 1H), 7.30 (d, J = 9.2 Hz, 1H), 7.27 - 7.18 (m, 2H), 7.01 (d, J = 7.8 Hz, 1H), 3.86 (s, 3H), 1.78 - 1.53 (m, 4H); LCMS(m/z) 467.2.

<u>Example 267. 3-(3-((8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino)phenyl)dibenzo[b,f][1,4]oxazepin-11(10H)-one</u>

1636<chemistry id="chem1732" num="1732"><img file="EP4445902A2_D1735.tif" /></chemistry>

1637Example 267 was prepared in a similar manner as Example 252. ¹H NMR (400 MHz, Methanol-d₄) δ 9.60 (s, 1H), 8.52 (d, J = 2.0 Hz, 1H), 7.98 - 7.81 (m, 3H), 7.70 (t, J = 7.9 Hz, 1H), 7.62 - 7.47 (m, 3H), 7.39 (dd, J = 9.2, 2.0 Hz, 1H), 7.34 - 7.27 (m, 2H), 7.24 - 7.09 (m, 3H), 3.87 (s, 3H); LCMS(m/z) 519.4.

<u>Example 268. 8-chloro-N-(3-(6-(1,1-difluoroethyl)pyridin-3-yl)phenyl)-6-fluoro-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1638<chemistry id="chem1733" num="1733"><img file="EP4445902A2_D1736.tif" /></chemistry>

1639Example 268 was prepared in a similar manner as Example 252. ¹H NMR (400 MHz, Methanol-d₄) δ 9.60 (s, 1H), 8.74 (s, 1H), 8.38 (s, 1H), 8.12 (dd, J = 8.3, 2.3 Hz, 1H), 7.77 (d, J = 8.3 Hz, 1H), 7.72 - 7.51 (m, 3H), 7.38 (dd, J = 23.4, 9.8 Hz, 2H), 3.86 (s, 3H), 2.17 - 1.78 (m, 3H); LCMS(m/z) 469.4.

<u>Example 269. 8-chloro-N-methyl-N-(3-(6-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-3-yl)phenyl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1640<chemistry id="chem1734" num="1734"><img file="EP4445902A2_D1737.tif" /></chemistry>

1641A solution of 8-chloro-N-methyl-N-(3-(6-(piperazin-1-yl)pyridin-3-yl)phenyl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 258, 20 mg, 0.04 mmol) and oxetan-3-one (10 mg, 0.15 mmol) in THF (5 ml) at room temperature was added sodium triacetoxyborohydride (40 mg, 0.19 mmol). The mixture was stirred at room temperature for 1 hr. Water and DCM were added to the mixture and the organic phase was dried over MgSO₄ and evaporated under reduced pressure. The crude product was purified by reverse phase chromatography ACN/Water 15-95% with 0.1 % TFA for 15 min to afford the title compound: ¹H NMR (400 MHz, Methanol-d₄) δ 9.59 (s, 1H), 8.58 - 8.36 (m, 2H), 8.02 - 7.88 (m, 1H), 7.82 - 7.56 (m, 3H), 7.48 - 7.33 (m, 2H), 7.30 (d, J = 9.1 Hz, 1H), 7.07 (d, J = 8.9 Hz, 1H), 4.93 (d, J = 7.7 Hz, 4H), 4.40 (q, J = 6.3 Hz, 1H), 3.86 (s, 3H), 3.30 (s, 8H); LCMS(m/z) 527.3.

<u>Example 270. 1-(4-(5-(3-((8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino)phenyl)pyridin-2-yl)piperazin-1-yl)-2,2-dimethylpropan-1-one</u>

1642<chemistry id="chem1735" num="1735"><img file="EP4445902A2_D1738.tif" /></chemistry>

1643A solution of 8-chloro-N-methyl-N-(3-(6-(piperazin-1-yl)pyridin-3-yl)phenyl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 258, 20 mgs, 0.04 mmol) and pivalic anhydride (10 mgs, 0.15 mmol) in pyridine (5 ml) was stirred at room temperature for 24 hrs. reaction mixture was evaporated and then purified in reverse phase chromatography ACN/Water 15-95% with 0.1 % TFA for 15 min to afford the title compound: ¹H NMR (400 MHz, Methanol-d₄) δ 9.61 (s, 1H), 8.52 (d, J = 2.1 Hz, 1H), 8.33 (d, J = 2.5 Hz, 1H), 8.16 (dd, J = 9.3, 2.5 Hz, 1H), 7.85 - 7.73 (m, 2H), 7.68 (t, J = 7.8 Hz, 1H), 7.53 - 7.44 (m, 1H), 7.37 (dd, J = 9.1, 2.1 Hz, 1H), 7.30 (d, J = 9.1 Hz, 1H), 7.24 (d, J = 9.3 Hz, 1H), 3.88 (d, J = 10.9 Hz, 7H), 3.74 (dd, J = 6.7, 3.9 Hz, 4H), 1.34 (s, 9H); LCMS(m/z) 555.4.

<u>Example 271. 1-(4-(5-(3-((8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino)phenyl)pyridin-2-yl)piperazin-1-yl)-2,2-dimethylpropan-1-one</u>

1644<chemistry id="chem1736" num="1736"><img file="EP4445902A2_D1739.tif" /></chemistry>

1645Example 271 was prepared in an analogous procedure to the preparation of Example 270. ¹H NMR (400 MHz, Methanol-d₄) δ 9.60 (s, 1H), 8.51 (d, J = 2.0 Hz, 1H), 8.32 (d, J = 2.3 Hz, 1H), 8.07 (dd, J = 9.2, 2.5 Hz, 1H), 7.84 - 7.71 (m, 2H), 7.66 (t, J = 7.9 Hz, 1H), 7.45 (ddd, J = 8.0, 2.2, 1.0 Hz, 1H), 7.37 (dd, J = 9.1, 2.0 Hz, 1H), 7.30 (d, J = 9.1 Hz, 1H), 7.16 (d, J = 9.2 Hz, 1H), 3.86 (s, 3H), 3.76 (s, 3H), 3.74 - 3.62 (m, 8H); LCMS(m/z) 529.4.

<u>Example 272. 8-chloro-N-(6-(4-(1,1-difluoroethyl)phenyl)pyridin-2-yl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1646<chemistry id="chem1737" num="1737"><img file="EP4445902A2_D1740.tif" /></chemistry>

1647Synthesis of N-(6-bromopyridin-2-yl)-2,7-dichloro-N-methylquinazolin-4-amine (Compound 272-2): A solution of 2,4,7-trichloroquinazoline (280 mg, 1.2 mmol) in THF (5 ml) at -20 C were added 6-bromo-N-methylpyridin-2-amine (234 mg, 1.25 mmol) and LiHMDS in THF (1.0 M, 1.6 ml, 1.2 mmol). The mixture was stirred for 2 hours at -20 °C. Water and DCM were added to the mixture and the organic phase was dried over MgSO₄ and evaporated under reduced pressure. The crude product was used in the next step without further purification.

1648Synthesis of Compounds 272-3 and 272-4 were achieved through a similar procedure as described to synthesize Example 249.

1649The final step of the synthesis of 8-chloro-N-(6-(4-(1,1-difluoroethyl)phenyl)pyridin-2-yl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine was achieved through a similar procedure described in Example 252. ¹H NMR (400 MHz, Methanol-d₄) δ 9.67 (s, 1H), 8.55 (s, 1H), 8.03 (t, J = 7.8 Hz, 1H), 7.90 (d, J = 8.8 Hz, 2H), 7.62 - 7.51 (m, 2H), 7.41 (d, J = 8.7 Hz, 2H), 7.29 (d, J = 9.0 Hz, 1H), 6.87 (t, J = 8.3 Hz, 1H), 3.92 (s, 3H), 2.04 - 1.76 (m, 3H); LCMS(m/z) 451.4.

<u>Example 273. 8-chloro-N-methyl-N-(6-(2-morpholinopyrimidin-5-yl)pyridin-2-yl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1650<chemistry id="chem1738" num="1738"><img file="EP4445902A2_D1741.tif" /></chemistry>

1651Example 273 was synthesized in a similar manner as that described for Example 272. ¹H NMR (400 MHz, Methanol-d₄) δ 9.68 (s, 1H), 8.77 (s, 2H), 8.57 (d, J = 2.1 Hz, 1H), 7.99 (t, J = 7.9 Hz, 1H), 7.84 (d, J = 7.8 Hz, 1H), 7.50 - 7.34 (m, 2H), 7.34 - 7.13 (m, 1H), 3.99 - 3.68 (m, 11H); LCMS(m/z) 474.4.

<u>Example 274. 8-chloro-N-methyl-N-(6-(4-(methylsulfonyl)phenyl)pyridin-2-yl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1652<chemistry id="chem1739" num="1739"><img file="EP4445902A2_D1742.tif" /></chemistry>

1653Example 274 was synthesized in a similar manner as that described for Example 272. ¹H NMR (400 MHz, Methanol-d₄) δ 9.4 (s, 1H), 8.5 (s, 1H), 8.17 - 6.95 (m, 9H), 3.14 (s, 6H); LCMS(m/z) 465.3.

<u>Example 275. 8-chloro-N-(6'-(1,1-difluoroethyl)-[2,3'-bipyridin]-6-yl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1654<chemistry id="chem1740" num="1740"><img file="EP4445902A2_D1743.tif" /></chemistry>

1655Example 275 was synthesized in a similar manner as that described for Example 272. ¹H NMR (400 MHz, Methanol-d₄) δ 9.63 (s, 1H), 8.26 (s, 1H), 8.08 (s, 1H), 7.96 - 7.30 (m, 4H), 7.25 - 6.74 (m, 3H), 3.31 (s, 3H), 2.24 - 1.73 (m, 3H); LCMS(m/z) 452.3.

<u>Example 276. 8-chloro-N-(6-(4-chlorophenyl)pyridin-2-yl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1656<chemistry id="chem1741" num="1741"><img file="EP4445902A2_D1744.tif" /></chemistry>

1657Example 276 was synthesized in a similar manner as that described for Example 272. ¹H NMR (400 MHz, Methanol-d₄) δ 9.59 (s, 1H), 8.27 (s, 2H), 8.02 (s, 1H), 7.83 (s, 1H), 7.67 - 7.01 (m, 6H), 3.90 (s, 3H); LCMS(m/z) 421.3.

<u>Example 277. 8-chloro-N-methyl-N-(3-(oxetan-3-ylethynyl)phenyl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1658<chemistry id="chem1742" num="1742"><img file="EP4445902A2_D1745.tif" /></chemistry>

1659A vial with stir bar was charged with N-(3-bromophenyl)-8-chloro-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 308, 50 mg, 0.13 mmol), 3-ethynyloxetane (21 mg, 0.26 mmol), Pd(PPh₃)Cl₂ (0.9 mg, 0.0013 mmol), and CuI (1.2 mg, 0.0064 mmol). The vial was then charged with DMF (2.0 mL) and DIPEA (0.045 mL, 0.26 mmol) and the suspension bubbled with nitrogen for 5 minutes. The reaction was heated to 100 °C for 24 hours at which point LC/MS indicated incomplete conversion. An additional portion of alkyne, Pd, CuI, and DIPEA were added and the reaction heated for a further 24 hours. LC/MS indicated near complete conversion and the reaction was filtered through a plug of Celite and eluted with EtOAc. The filtrate was evaporated to a residue which was purified by normal phase flash chromatography using 3:1 EtOAc:EtOH in heptanes. The crude product was further purified via prep-HPLC to give the title compound: ¹H NMR (400 MHz, DMSO-d₆) δ 9.74 (s, 1H), 8.61 (d, J = 2.1 Hz, 1H), 7.51 - 7.47 (m, 1H), 7.46 - 7.35 (m, 4H), 7.23 (d, J = 9.0 Hz, 1H), 4.77 (dd, J = 8.5, 5.4 Hz, 2H), 4.58 (dd, J = 7.1, 5.4 Hz, 2H), 4.12 (ddd, J = 15.6, 8.5, 7.1 Hz, 1H), 3.57 (s, 3H); LCMS(m/z) 390.1.

<u>Example 278. 8-chloro-N-(4'-(2-(dimethylamino)ethoxy)-[1,1'-biphenyl]-3-yl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1660<chemistry id="chem1743" num="1743"><img file="EP4445902A2_D1746.tif" /></chemistry>

1661A vial with stir bar was charged with N-(3-bromophenyl)-8-chloro-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 308, 30 mg, 0.077 mmol), N,N-dimethyl-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]ethanamine (45 mg, 0.15 mmol), and (dtbpf)PdCl₂ (2.7 mg, 0.004 mmol). The vial was then flushed with nitrogen and charged with dioxane (1.0 mL) and nitrogen sparged 2M aqueous Na₂CO₃ (0.2 mL). The reaction was warmed to 50°C and monitored via LC/MS. Once complete (about 18 hours), the reaction was filtered through a plug of Celite and eluted with EtOAc. The filtrate was then evaporated, and the residue purified via prep-HPLC to give the title compound: ¹H NMR (400 MHz, DMSO-d₆) δ 9.72 (s, 1H), 9.57 (s, 1H), 8.59 (d, J = 2.1 Hz, 1H), 7.67 - 7.58 (m, 4H), 7.51 (t, J = 7.8 Hz, 1H), 7.40 - 7.29 (m, 2H), 7.28 (d, J = 9.0 Hz, 1H), 7.09 - 7.01 (m, 2H), 4.34 (t, J = 5.0 Hz, 2H), 3.64 (s, 3H), 3.52 (q, J = 5.0 Hz, 2H), 2.87 (s, 3H), 2.86 (s, 3H); LCMS(m/z) 473.2.

<u>Example 279. tert-butyl 4-((3'-((8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino)-[1,1'-biphenyl]-4-yl)oxy)piperidine-1-carboxylate</u>

1662<chemistry id="chem1744" num="1744"><img file="EP4445902A2_D1747.tif" /></chemistry>

1663Example 279 was synthesized according to a similar procedure as that described for Example 278. ¹H NMR (400 MHz, DMSO-d₆) δ 9.76 (s, 1H), 8.61 (d, J = 2.1 Hz, 1H), 7.66 (s, 1H), 7.63 (d, J = 7.9 Hz, 1H), 7.57 (d, J = 8.8 Hz, 2H), 7.51 (t, J = 7.9 Hz, 1H), 7.39 (dd, J = 9.0, 2.0 Hz, 1H), 7.36 - 7.30 (m, 1H), 7.27 (d, J = 9.0 Hz, 1H), 7.03 (d, J = 8.8 Hz, 2H), 4.64 - 4.55 (m, 1H), 3.69 - 3.60 (m, 5H), 3.27 - 3.12 (m, 2H), 1.98 - 1.83 (m, 2H), 1.59 - 1.45 (m, 2H), 1.40 (s, 9H); LCMS(m/z) 585.2.

<u>Example 280. 1-(3'-((8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino)-[1,1'-biphenyl]-4-yl)imidazolidin-2-one</u>

1664<chemistry id="chem1745" num="1745"><img file="EP4445902A2_D1748.tif" /></chemistry>

1665Example 280 was synthesized according to a similar procedure as that described for Example 278. ¹H NMR (400 MHz, DMSO-d₆) δ 9.75 (s, 1H), 8.61 (d, J = 2.1 Hz, 1H), 7.70 (s, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.61 (s, 4H), 7.51 (t, J = 7.9 Hz, 1H), 7.40 (dd, J = 9.0, 2.1 Hz, 1H), 7.35 - 7.30 (m, 1H), 7.28 (d, J = 9.0 Hz, 1H), 7.01 (s, 1H), 3.86 (dd, J = 9.3, 6.6 Hz, 2H), 3.66 (s, 3H), 3.46 - 3.36 (m, 2H); LCMS(m/z) 470.1.

<u>Example 281. 1-(3'-((8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino)-[1,1'-biphenyl]-4-yl)pyrrolidin-2-one</u>

1666<chemistry id="chem1746" num="1746"><img file="EP4445902A2_D1749.tif" /></chemistry>

1667A microwave reaction vial (0.5-2 mL) with stirring vane was charged with 1-(4-bromophenyl)pyrrolidin-2-one (15 mg, 0.064 mmol), bis(pinacolato)diboron (20 mg, 0.077 mmol), Pd(PPh₃)Cl₂ (4.5 mg, 0.0064 mmol), and KOAc (19 mg, 0.19 mmol). The vial was then flushed with nitrogen and charged with dioxane (1.0 mL). The reaction was irradiated (Biotage Initiator) at 120°C until complete conversion to the intermediate boronate was observed via LC/MS (typically 45-90 minutes). N-(3-bromophenyl)-8-chloro-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (25 mg, 0.064 mmol) and nitrogen sparged 2M aqueous Na₂CO₃ (0.16 mL) were then added and the reaction heated to 100°C until complete conversion was observed via LC/MS (typically 15-60 minutes). The reaction was then filtered through a plug of Celite and eluted with EtOAc. The filtrate was evaporated, and the residue purified via prep-HPLC to afford the title compound: ¹H NMR (400 MHz, Methanol-d₄) δ 9.56 (s, 1H), 8.48 (d, J = 2.1 Hz, 1H), 7.81 - 7.77 (m, 1H), 7.73 - 7.69 (m, 3H), 7.66 - 7.61 (m, 3H), 7.43 - 7.39 (m, 1H), 7.36 (dd, J = 9.2, 2.0 Hz, 1H), 7.28 (d, J = 9.2 Hz, 1H), 3.95 (t, J = 7.1 Hz, 2H), 3.84 (s, 3H), 2.61 (t, J = 8.1 Hz, 2H), 2.25 - 2.14 (m, 2H); LCMS(m/z) 469.1.

<u>Example 282. 8-chloro-N-methyl-N-(4'-(piperidin-4-yloxy)-[1,1'-biphenyl]-3-yl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1668<chemistry id="chem1747" num="1747"><img file="EP4445902A2_D1750.tif" /></chemistry>

1669To a solution of tert-butyl 4-[4-[3-[(8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)-methyl-amino]phenyl]phenoxy]piperidine-1-carboxylate (Example 279, 98 mg, 0.15 mL) in DCM (5 mL) was added TFA (0.23 mL, 3.0 mmol). After 3 hours, the reaction was evaporated. The resulting residue was purified via prep-HPLC to give the title compound: ¹H NMR (400 MHz, DMSO-d₆) δ 9.71 (s, 1H), 8.59 (d, J = 2.1 Hz, 1H), 8.43 (s, 1H), 7.64 - 7.57 (m, 4H), 7.50 (t, J = 7.8 Hz, 1H), 7.36 (dd, J = 9.0, 2.1 Hz, 1H), 7.34 - 7.30 (m, 1H), 7.28 (d, J = 9.0 Hz, 1H), 7.10 - 7.01 (m, 2H), 4.73 - 4.64 (m, 1H), 3.64 (s, 3H), 3.32 - 3.18 (m, 2H), 3.15 - 3.01 (m, 2H), 2.08 (dd, J = 15.3, 6.3 Hz, 2H), 1.87 - 1.73 (m, 2H); LCMS(m/z) 485.2.

<u>Example 283. 3-((3-((8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino)phenyl)ethynyl)oxetan-3-ol</u>

1670<chemistry id="chem1748" num="1748"><img file="EP4445902A2_D1751.tif" /></chemistry>

1671Example 283 was synthesized in a similar manner to the procedure described for Example 277. ¹H NMR (400 MHz, DMSO-d₆) δ 9.75 (s, 1H), 8.62 (d, J = 2.1 Hz, 1H), 7.57 - 7.50 (m, 1H), 7.50 - 7.38 (m, 4H), 7.23 (d, J = 9.0 Hz, 1H), 6.61 (s, 1H), 4.72 (d, J = 6.4 Hz, 2H), 4.57 (d, J = 6.4 Hz, 2H), 3.58 (s, 3H); LCMS(m/z) 406.1.

<u>Example 284. 1-(4-((3'-((8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino)-[1,1'-biphenyl]-4-yl)oxy)piperidin-1-yl)ethan-1-one</u>

1672<chemistry id="chem1749" num="1749"><img file="EP4445902A2_D1752.tif" /></chemistry>

1673A suspension of 8-chloro-N-methyl-N-[3-[4-(4-piperidyloxy)phenyl]phenyl]-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 282, 10 mg, 0.017 mmol) in DCM (0.75 mL) was treated with acetic anhydride (0.017 mmol) and stirred at ambient temperature. After 2 hours, triethylamine (0.002 mL, 0.017 mmol) was added and the solution stirred a further hour at which point LC/MS indicated complete conversion. The reaction was evaporated, and the residue purified via prep-HPLC to give the title compound: ¹H NMR (400 MHz, DMSO-d₆) δ 9.63 (s, 1H), 8.54 (d, J = 1.3 Hz, 1H), 7.61 - 7.51 (m, 4H), 7.44 (t, J = 7.8 Hz, 1H), 7.31 (s, 2H), 7.27 - 7.22 (m, 1H), 7.05 - 6.99 (m, 2H), 4.68 - 4.61 (m, 1H), 3.87 - 3.78 (m, 1H), 3.71 - 3.62 (m, 1H), 3.59 (s, 3H), 3.38 - 3.33 (m, 1H), 3.28 - 3.17 (m, 1H), 2.01 (s, 3H), 2.00 - 1.91 (m, 1H), 1.93 - 1.81 (m, 1H), 1.67 - 1.54 (m, 1H), 1.56 - 1.42 (m, 1H); LCMS(m/z) 527.2.

<u>Example 285. 8-chloro-N-methyl-N-(4'-((1-methylpiperidin-4-yl)oxy)-[1,1'-biphenyl]-3-yl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1674<chemistry id="chem1750" num="1750"><img file="EP4445902A2_D1753.tif" /></chemistry>

1675A suspension of 8-chloro-N-methyl-N-[3-[4-(4-piperidyloxy)phenyl]phenyl]-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 282, 15 mg, 0.025 mmol) in DCM (1.0 mL) was treated with formaldehyde (0.005 mL, 0.063 mmol) and stirred at ambient temperature for 5 minutes. Na(OAc)₃BH (5.8 mg, 0.028 mmol) was then added and the solution stirred at ambient for 3 hours. A second portion of borohydride was added, and the reaction stirred a further 45 minutes to affect complete conversion. The reaction was evaporated, and the residue purified via prep-HPLC to provide the title compound: ¹H NMR (400 MHz, DMSO-d₆) δ 9.70 (s, 1H), 8.58 (d, J = 2.0 Hz, 1H), 7.66 - 7.55 (m, 4H), 7.49 (t, J = 7.8 Hz, 1H), 7.39 - 7.25 (m, 3H), 7.12 - 7.00 (m, 2H), 4.81 - 4.51 (m, 1H), 3.63 (s, 3H), 3.51 (d, J = 12.4 Hz, 1H), 3.32 (d, J = 12.2 Hz, 1H), 3.23 - 3.02 (m, 2H), 2.82 (dd, J = 10.1, 4.8 Hz, 3H), 2.26 (d, J = 13.5 Hz, 1H), 2.07 (d, J = 14.8 Hz, 1H), 1.95 (t, J = 13.4 Hz, 1H), 1.79 - 1.64 (m, 1H); LCMS(m/z) 499.2.

<u>Example 286. 8-chloro-N-(3-(6-fluoropyridin-3-yl)phenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1676<chemistry id="chem1751" num="1751"><img file="EP4445902A2_D1754.tif" /></chemistry>

1677Example 286 was synthesized in a similar manner to the procedure described for Example 278. ¹H NMR (400 MHz, DMSO-d₆) δ 9.78 (s, 1H), 8.63 (d, J = 2.1 Hz, 1H), 8.54 (d, J = 2.6 Hz, 1H), 8.28 (td, J = 8.2, 2.7 Hz, 1H), 7.86 - 7.81 (m, 1H), 7.76 - 7.70 (m, 1H), 7.57 (t, J = 7.9 Hz, 1H), 7.46 - 7.36 (m, 2H), 7.32 - 7.25 (m, 2H), 3.67 (s, 3H); LCMS(m/z) 405.1.

<u>Example 287. 5-((3-bromophenyl)(methyl)amino)-8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-1(2H)-one</u>

1678<chemistry id="chem1752" num="1752"><img file="EP4445902A2_D1755.tif" /></chemistry>

1679A solution of N-(3-bromophenyl)-7-chloro-2-hydrazino-N-methyl-quinazolin-4-amine (216 mg, 0.46 mmol) and carbonyldiimidazole (CDI, 89 mg, 0.55 mmol) in THF (4 mL) was stirred at ambient temperature for 90 minutes. The solution was then evaporated, and the resultant residue purified by flash chromatography using 10% MeOH/DCM. A portion was further purified via prep-HPLC to afford the title compound: ¹H NMR (400 MHz, DMSO-d₆) δ 12.17 (s, 1H), 8.75 (d, J = 2.3 Hz, 1H), 7.63 (s, 1H), 7.46 - 7.41 (m, 1H), 7.36 - 7.28 (m, 2H), 7.24 (dd, J = 8.9, 2.2 Hz, 1H), 7.10 (d, J = 8.8 Hz, 1H), 3.45 (s, 3H); LCMS(m/z) 406.0/404.0.

<u>Example 288. 5-((4'-(tert-butyl)-[1,1'-biphenyl]-3-yl)(methyl)amino)-8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-1(2H)-one</u>

1680<chemistry id="chem1753" num="1753"><img file="EP4445902A2_D1756.tif" /></chemistry>

1681A vial with stir bar was charged with 5-(3-bromo-N-methyl-anilino)-8-chloro-2H-[1,2,4]triazolo[4,3-a]quinazolin-1-one (Example 287, 36 mg, 0.079 mmol), 4-tert-Butylphenylboronic acid (15 mg, 0.083 mmol), and Pd(PPh₃)Cl₂ (5.5 mg, 0.008 mmol). The vial was then flushed with nitrogen and charged with dioxane (1.0 mL) and nitrogen sparged 2M aqueous Na₂CO₃ (0.08 mL). The reaction was heated to 100°C for 18 hours at which point LC/MS indicated partial conversion. An additional portion of boronic acid, catalyst, and base were added and the reaction heated for a further 4.5 hours at which point LC/MS indicated near complete conversion. The reaction was filtered through a plug of Celite and eluted with EtOAc. The filtrate was evaporated, and the residue purified via prep-HPLC to give the title compound: ¹H NMR (400 MHz, DMSO-d₆) δ 12.11 (s, 1H), 8.75 (d, J = 2.0 Hz, 1H), 7.60 - 7.54 (m, 4H), 7.50 - 7.42 (m, 3H), 7.29 (dd, J = 7.4, 2.1 Hz, 1H), 7.19 -7.10 (m, 2H), 3.52 (s, 3H), 1.29 (s, 9H); LCMS(m/z) 458.2.

<u>Example 289. 8-chloro-N-methyl-N-(3-(6-(pyrrolidin-1-yl)pyridin-3-yl)phenyl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1682<chemistry id="chem1754" num="1754"><img file="EP4445902A2_D1757.tif" /></chemistry>

1683A solution of 8-chloro-N-[3-(6-fluoro-3-pyridyl)phenyl]-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 286, 16.5 mg, 0.037 mmol) in DMF (0.5 mL) was treated with pyrrolidine (0.005 mL, 0.055 mmol) and the reaction warmed to 80°C. After 18 hours LC/MS indicated partial conversion. Pyrrolidine (0.002 mL, 0.028 mmol) was added and the reaction heated a further 5 hours. The reaction was then diluted with EtOAc and washed once with saturated brine. The organic phase was then filtered through a plug of Celite, evaporated, and the residue purified via prep-HPLC to give the title compound: ¹H NMR (400 MHz, DMSO-d₆) δ 9.74 (s, 1H), 8.60 (d, J = 2.1 Hz, 1H), 8.20 (s, 1H), 8.11 (s, 1H), 7.72 (t, J = 2.0 Hz, 1H), 7.65 (d, J = 7.9 Hz, 1H), 7.52 (t, J = 7.9 Hz, 1H), 7.41 - 7.32 (m, 2H), 7.28 (d, J = 9.0 Hz, 1H), 6.92 (s, 1H), 3.65 (s, 3H), 3.54 - 3.44 (m, 4H), 2.06 - 1.95 (m, 4H); LCMS(m/z) 456.1.

<u>Example 290. 1-(3'-((8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino)-[1,1'-biphenyl]-4-yl)-3-methylimidazolidin-2-one</u>

1684<chemistry id="chem1755" num="1755"><img file="EP4445902A2_D1758.tif" /></chemistry>

1685Example 290 was synthesized according to the general route described for Example 281. ¹H NMR (400 MHz, DMSO-d₆) δ 9.76 (s, 1H), 8.61 (d, J = 2.1 Hz, 1H), 7.70 (t, J = 1.8 Hz, 1H), 7.69 - 7.64 (m, 1H), 7.62 (s, 4H), 7.52 (t, J = 7.9 Hz, 1H), 7.40 (dd, J = 9.1, 2.1 Hz, 1H), 7.35 - 7.31 (m, 1H), 7.28 (d, J = 9.0 Hz, 1H), 3.85 - 3.76 (m, 2H), 3.67 (s, 3H), 3.50 - 3.41 (m, 2H), 2.77 (s, 3H); LCMS(m/z) 484.2.

<u>Example 291. 8-chloro-N-(3-( 6-(4-methoxypiperidin-1-yl)pyridin-3-yl)phenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1686<chemistry id="chem1756" num="1756"><img file="EP4445902A2_D1759.tif" /></chemistry>

1687A solution of 8-chloro-N-[3-(6-fluoro-3-pyridyl)phenyl]-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 286, 20 mg, 0.045 mmol) in DMSO (0.75 mL) was treated with NaHCO₃ (19 mg, 0.22 mmol) and 4-Methoxy-piperidine (0.009 mL, 0.078 mmol). The reaction was heated at 100°C for 3.5 hours and 130°C for a further 18 hours. The reaction was then filtered and purified via prep-HPLC to give the title compound: ¹H NMR (400 MHz, DMSO-d₆) δ 9.76 (s, 1H), 8.61 (d, J = 2.1 Hz, 1H), 8.36 (d, J = 2.6 Hz, 1H), 7.87 (d, J = 9.1 Hz, 1H), 7.70 - 7.66 (m, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.51 (t, J = 7.8 Hz, 1H), 7.39 (dd, J = 9.0, 2.1 Hz, 1H), 7.32 (d, J = 8.9 Hz, 1H), 7.27 (d, J = 9.0 Hz, 1H), 6.97 (d, J = 9.0 Hz, 1H), 3.95 (dt, J = 13.4, 4.8 Hz, 2H), 3.66 (s, 3H), 3.48 - 3.38 (m, 1H), 3.27 (s, 3H), 3.25 - 3.19 (m, 2H), 1.94 - 1.83 (m, 2H), 1.48 - 1.36 (m, 2H); LCMS(m/z) 500.2.

<u>Example 292. 5-(3-((8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino)phenyl)indolin-2-one</u>

1688<chemistry id="chem1757" num="1757"><img file="EP4445902A2_D1760.tif" /></chemistry>

1689Example 292 was synthesized according to the general route described for Example 278. ¹H NMR (400 MHz, DMSO-d₆) δ 10.49 (s, 1H), 9.82 (s, 1H), 8.64 (d, J = 2.1 Hz, 1H), 7.69 (t, J = 2.0 Hz, 1H), 7.69 - 7.63 (m, 1H), 7.57 - 7.51 (m, 2H), 7.48 (dd, J = 8.1, 1.9 Hz, 1H), 7.44 (dd, J = 9.1, 2.1 Hz, 1H), 7.39 - 7.34 (m, 1H), 7.25 (d, J = 9.1 Hz, 1H), 6.87 (d, J = 8.1 Hz, 1H), 3.69 (s, 3H), 3.51 (s, 2H); LCMS(m/z) 441.1.

<u>Example 293. tert-butyl (3'-((8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino)-[1,1'-biphenyl]-4-yl)carbamate</u>

1690<chemistry id="chem1758" num="1758"><img file="EP4445902A2_D1761.tif" /></chemistry>

1691Example 293 was synthesized according to the general route described for Example 278. ¹H NMR (400 MHz, DMSO-d₆) δ 9.78 (s, 1H), 9.46 (s, 1H), 8.62 (d, J = 2.1 Hz, 1H), 7.69 (t, J = 2.0 Hz, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.59 - 7.49 (m, 5H), 7.41 (dd, J = 9.0, 2.1 Hz, 1H), 7.35 - 7.30 (m, 1H), 7.27 (d, J = 9.1 Hz, 1H), 3.67 (s, 3H), 1.48 (s, 9H); LCMS(m/z) 501.2.

<u>Example 294. 1-(3'-((8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino)-[1,1'-biphenyl]-4-yl)piperidin-2-one</u>

1692<chemistry id="chem1759" num="1759"><img file="EP4445902A2_D1762.tif" /></chemistry>

1693Example 294 was synthesized according to the general route described for Example 281. ¹H NMR (400 MHz, DMSO-d₆) δ 9.77 (s, 1H), 8.62 (d, J = 2.1 Hz, 1H), 7.74 (t, J = 2.0 Hz, 1H), 7.72 - 7.68 (m, 1H), 7.68 - 7.63 (m, 2H), 7.56 (t, J = 7.9 Hz, 1H), 7.42 - 7.37 (m, 2H), 7.37 - 7.32 (m, 2H), 7.27 (d, J = 9.1 Hz, 1H), 3.68 (s, 3H), 3.65 - 3.59 (m, 2H), 2.43 - 2.37 (m, 2H), 1.91 - 1.80 (m, 4H); LCMS(m/z) 483.2.

<u>Example 295. 1-(3'-((8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino)-[1,1'-biphenyl]-4-yl)piperid2-(3'-((8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino)-[1,1'-biphenyl]-4-yl)isothiazolidine 1,1-dioxide</u>

1694<chemistry id="chem1760" num="1760"><img file="EP4445902A2_D1763.tif" /></chemistry>

1695Example 295 was synthesized according to the general route described for Example 278. ¹H NMR (400 MHz, DMSO-d₆) δ 9.79 (s, 1H), 8.63 (d, J = 2.1 Hz, 1H), 7.73 (t, J = 2.0 Hz, 1H), 7.71 - 7.65 (m, 3H), 7.55 (t, J = 7.9 Hz, 1H), 7.42 (dd, J = 9.1, 2.1 Hz, 1H), 7.37 (dd, J = 7.6, 2.1 Hz, 1H), 7.29 - 7.23 (m, 3H), 3.77 (t, J = 6.5 Hz, 2H), 3.68 (s, 3H), 3.53 (t, J = 7.4 Hz, 2H), 2.42 (p, J = 6.9 Hz, 2H); LCMS(m/z) 505.1.

<u>Example 296.3-((3-((8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino)phenyl)ethynyl)-3-hydroxy-1-methylpyrrolidin-2-one</u>

1696<chemistry id="chem1761" num="1761"><img file="EP4445902A2_D1764.tif" /></chemistry>

1697Example 296 was synthesized according to the general route described for Example 277. ¹H NMR (400 MHz, DMSO-d₆) δ 9.74 (s, 1H), 8.62 (d, J = 2.1 Hz, 1H), 7.49 - 7.35 (m, 5H), 7.21 (d, J = 9.0 Hz, 1H), 3.58 (s, 3H), 3.37 - 3.26 (m, 2H), 2.77 (s, 3H), 2.43 - 2.35 (m, 1H), 2.20 - 2.10 (m, 1H); LCMS(m/z) 447.1.

<u>Example 297. 8-chloro-N-(3-(6-((2-methoxyethyl)(methyl)amino)pyridin-3-yl)phenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1698<chemistry id="chem1762" num="1762"><img file="EP4445902A2_D1765.tif" /></chemistry>

1699Example 297 was synthesized according to the general route described for Example 291. ¹H NMR (400 MHz, DMSO-d₆) δ 9.77 (s, 1H), 8.62 (d, J = 2.1 Hz, 1H), 8.30 (s, 1H), 7.91 (s, 1H), 7.68 (s, 1H), 7.64 (d, J = 7.9 Hz, 1H), 7.52 (t, J = 7.9 Hz, 1H), 7.39 (dd, J = 9.0, 2.1 Hz, 1H), 7.33 (d, J = 7.9 Hz, 1H), 7.27 (d, J = 9.0 Hz, 1H), 6.84 (s, 1H), 3.74 (t, J = 5.7 Hz, 2H), 3.66 (s, 3H), 3.51 (t, J = 5.6 Hz, 2H), 3.24 (s, 3H), 3.08 (s, 3H); LCMS(m/z) 474.2.

<u>Example 298.1-(3'-((8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino)-[1,1'-biphenyl]-4-yl)azetidin-2-one</u>

1700<chemistry id="chem1763" num="1763"><img file="EP4445902A2_D1766.tif" /></chemistry>

1701Example 298 was synthesized according to the general route described for Example 281. ¹H NMR (400 MHz, DMSO-d₆) δ 9.78 (s, 1H), 8.62 (d, J = 2.1 Hz, 1H), 7.73 (t, J = 2.0 Hz, 1H), 7.71 - 7.64 (m, 3H), 7.53 (t, J = 7.9 Hz, 1H), 7.44 - 7.37 (m, 3H), 7.37 - 7.33 (m, 1H), 7.27 (d, J = 9.1 Hz, 1H), 3.67 (s, 3H), 3.65 (t, J = 4.6 Hz, 2H), 3.10 (t, J = 4.5 Hz, 2H); LCMS(m/z) 455.1.

<u>Example 299. 5-(3-((8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino)phenyl)-1-methylindolin-2-one</u>

1702<chemistry id="chem1764" num="1764"><img file="EP4445902A2_D1767.tif" /></chemistry>

1703Example 299 was synthesized according to the general route described for Example 278. ¹H NMR (400 MHz, DMSO-d₆) δ 9.78 (s, 1H), 8.62 (d, J = 2.1 Hz, 1H), 7.73 (t, J = 2.0 Hz, 1H), 7.71 - 7.64 (m, 3H), 7.53 (t, J = 7.9 Hz, 1H), 7.44 - 7.37 (m, 3H), 7.37 - 7.33 (m, 1H), 7.27 (d, J = 9.1 Hz, 1H), 3.67 (s, 3H), 3.65 (t, J = 4.6 Hz, 2H), 3.10 (t, J = 4.5 Hz, 2H); LCMS(m/z) 455.1.

<u>Example 300. tert-butyl 6-(3-((8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino)phenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate</u>

1704<chemistry id="chem1765" num="1765"><img file="EP4445902A2_D1768.tif" /></chemistry>

1705Synthesis of benzyl N-(3-bromophenyl)-N-methyl-carbamate: A solution of 3-Bromo-N-methylaniline (500 mg, 2.7 mmol) in toluene (13 mL) was treated with potassium carbonate (743 mg, 5.4 mmol) and benzyl chloroformate (0.66 mL, 4.7 mmol). The reaction was warmed to 50°C and stirred for 16 hours. The reaction was then partitioned between EtOAc and water. The aqueous was extracted once with EtOAc and the combined organics were washed with brine and dried over MgSO₄. The organics were filtered, evaporated, and the resultant residue purified via normal phase flash chromatography using 30% EtOAc/Hexanes. ES/MS m/z: 322.0/320.1. <chemistry id="chem1766" num="1766"><img file="EP4445902A2_D1769.tif" /></chemistry>

1706Synthesis of tert-butyl 6-[3-[benzyloxycarbonyl(methyl)amino]phenyl]-2,6-diazaspiro[3.3]heptane-2-carboxylate: A vial with stir bar was charged with tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (650 mg, 3.3 mmol), RuPhos Pd Gen 4 (93 mg, 0.11 mmol), RuPhos (98 mg, 0.22 mmol), and Cs₂CO₃ (1780 mg, 5.5 mmol). The vial was then flushed with nitrogen and charged with benzyl N-(3-bromophenyl)-N-methyl-carbamate (700 mg, 2.2 mmol) as a solution in tert-amyl alcohol (8 mL). The reaction was warmed to 100°C for 2.5 hours and then filtered through a plug of Celite. Product was eluted with EtOAc and the filtrate was then evaporated. The crude material was purified via normal phase flash chromatography using 50% EtOAc/Hexanes to give purified product: ¹H NMR (400 MHz, Chloroform-d) δ 7.31 (d, <i>J =</i> 3.7 Hz, 5H), 7.17 (t, <i>J =</i> 8.0 Hz, 1H), 6.63 (dt, <i>J =</i> 8.0, 1.3 Hz, 1H), 6.35 - 6.27 (m, 2H), 5.16 (s, 2H), 4.07 (s, 4H), 3.92 (s, 4H), 3.29 (s, 3H), 1.45 (s, 9H); ES/MS m/z: 438.4. <chemistry id="chem1767" num="1767"><img file="EP4445902A2_D1770.tif" /></chemistry>

1707Synthesis of tert-butyl 6-[3-(methylamino)phenyl]-2,6-diazaspiro[3.3]heptane-2-carboxylate: 10% Pd/C (100 mg) was added to a nitrogen flushed vial and wet with EtOH (5 mL). tert-butyl 6-[3-[benzyloxycarbonyl(methyl)amino]phenyl]-2,6-diazaspiro[3.3]heptane-2-carboxylate (809 mg, 1.66 mmol) and EtOH (37 mL) were then added. The headspace was purged with nitrogen and then hydrogen gas was added via balloon. The mixture was stirred rapidly at ambient temperature for 2 hours before the catalyst was filtered off. The filtrate was evaporated to give product: ¹H NMR (400 MHz, DMSO-d₆) δ 6.85 (t, J = 7.9 Hz, 1H), 5.91 (ddd, J = 8.0, 2.2, 0.9 Hz, 1H), 5.64 (ddd, J = 7.9, 2.2, 0.9 Hz, 1H), 5.56 (t, J = 2.1 Hz, 1H), 5.42 (q, J = 5.0 Hz, 1H), 4.00 (s, 4H), 3.83 (s, 4H), 1.38 (s, 9H); ES/MS m/z: 304.3. <chemistry id="chem1768" num="1768"><img file="EP4445902A2_D1771.tif" /></chemistry>

1708Synthesis of tert-butyl 6-[3-[(2,7-dichloroquinazolin-4-yl)-methyl-amino]phenyl]-2,6-diazaspiro[3.3]heptane-2-carboxylate: A solution of tert-butyl 6-[3-(methylamino)phenyl]-2,6-diazaspiro[3.3]heptane-2-carboxylate (239 mg, 0.79 mmol) and 2,4,7-trichloroquinazoline (184 mg, 0.79 mmol) in DMF (2.0 m) was treated with DIPEA (0.34 mL, 2.0 mmol) and warmed to 50°C. After 45 minutes, the reaction was cooled and diluted with water. The mixture was extracted three times with EtOAc and the combined organics were dried over Na₂SO₄, filtered and evaporated. The residue was purified via normal phase flash chromatography using 40% EtOAc/Hexanes to provide product: ¹H NMR (400 MHz, DMSO-d₆) δ 7.72 (d, J = 2.2 Hz, 1H), 7.26 (dd, J = 8.8, 7.8 Hz, 1H), 7.19 (dd, J = 9.2, 2.3 Hz, 1H), 6.90 (d, J = 9.2 Hz, 1H), 6.66 - 6.61 (m, 1H), 6.49 - 6.43 (m, 2H), 4.00 (s, 4H), 3.91 (s, 4H), 3.51 (s, 3H), 1.37 (s, 9H); ES/MS m/z: 502.2/500.3. <chemistry id="chem1769" num="1769"><img file="EP4445902A2_D1772.tif" /></chemistry>

1709Synthesis of tert-butyl 6-[3-[(7-chloro-2-hydrazino-quinazolin-4-yl)-methyl-amino]phenyl]-2,6-diazaspiro[3.3]heptane-2-carboxylate: A solution of tert-butyl 6-[3-[(2,7-dichloroquinazolin-4-yl)-methyl-amino]phenyl]-2,6-diazaspiro[3.3]heptane-2-carboxylate (331 mg, 0.63 mmol) in EtOH (14 ml) and THF (6.9 ml) was treated with hydrazine hydrate (0.31 mL, 6.3 mmol). This was stirred at ambient temperature for 90 minutes and then warmed to 50°C for 21 hours. The volatiles were evaporated, and the residue triturated with heptanes to give product: ES/MS m/z: 496.4. <chemistry id="chem1770" num="1770"><img file="EP4445902A2_D1773.tif" /></chemistry>

1710Synthesis of tert-butyl 6-[3-[(8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)-methyl-amino]phenyl]-2,6-diazaspiro[3,3]heptane-2-carboxylate: tert-butyl 6-[3-[(7-chloro-2-hydrazino-quinazolin-4-yl)-methyl-amino]phenyl]-2,6-diazaspiro[3.3]heptane-2-carboxylate (312 mg, 0.63 mmol) was suspended in triethyl orthoformate (5.0 mL, 30 mmol) and heated to 100°C for 1 hour. The volatiles were evaporated. The residue was purified via normal phase flash chromatography using 80% (3:1 EtOAc:EtOH)/Heptanes to provide product. A small portion was purified via prep-HPLC to give the title compound: ¹H NMR (400 MHz, DMSO-d₆) δ 9.75 (s, 1H), 8.60 (d, J = 2.1 Hz, 1H), 7.42 (dd, J = 9.1, 2.1 Hz, 1H), 7.28 - 7.20 (m, 2H), 6.63 (dd, J = 7.8, 2.0 Hz, 1H), 6.49 - 6.38 (m, 2H), 4.00 (s, 4H), 3.90 (s, 4H), 3.58 (s, 3H), 1.37 (s, 9H); LCMS(m/z) 506.2.

<u>Example 301. N-(3-(2,6-diazaspiro[3.3]heptan-2-yl)phenyl)-8-chloro-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1711<chemistry id="chem1771" num="1771"><img file="EP4445902A2_D1774.tif" /></chemistry>

1712A solution of tert-butyl 6-[3-[(8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)-methyl-amino]phenyl]-2,6-diazaspiro[3.3]heptane-2-carboxylate (Example 300, 80 mg, 0.14 mmol) in DCM (3.0 mL) was treated with 85% aqueous phosphoric acid (0.029 mL, 0.43 mmol) and stirred at ambient temperature. After 30 minutes the reaction was evaporated, and the residue purified via prep-HPLC to afford the title compound: ¹H NMR (400 MHz, DMSO-d₆) δ 9.66 (s, 1H), 8.56 (d, J = 2.1 Hz, 1H), 7.34 (dd, J = 9.0, 2.1 Hz, 1H), 7.27 (d, J = 9.0 Hz, 1H), 7.20 (t, J = 8.0 Hz, 1H), 6.65 - 6.57 (m, 1H), 6.43 (t, J = 2.2 Hz, 1H), 6.41 - 6.37 (m, 1H), 4.13 (t, J = 6.1 Hz, 4H), 3.93 (s, 4H), 3.53 (s, 3H); LCMS(m/z) 406.1.

<u>Example 302.(6-(3-((8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino)phenyl)-2,6-diazaspiro[3.3]heptan-2-yl)(cyclopropyl)methanone</u>

1713<chemistry id="chem1772" num="1772"><img file="EP4445902A2_D1775.tif" /></chemistry>

1714A suspension of 8-chloro-N-[3-(2,6-diazaspiro[3.3]heptan-2-yl)phenyl]-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 301, 13 mg, 0.023 mmol) in DCM (1.0 mL) was treated with cyclopropanecarboxylic acid chloride (0.003 mL, 0.028 mmol) and TEA (0.010 mL, 0.068 mmol). The mixture was stirred at ambient temperature for 80 minutes and then evaporated. The residue was purified via prep-HPLC to give the title compound: ¹H NMR (400 MHz, DMSO-d₆) δ 9.74 (s, 1H), 8.60 (d, J = 2.1 Hz, 1H), 7.42 (dd, J = 9.0, 2.1 Hz, 1H), 7.29 - 7.20 (m, 2H), 6.63 (d, J = 7.9 Hz, 1H), 6.48 - 6.46 (m, 1H), 6.46 - 6.42 (m, 1H), 4.41 (s, 2H), 4.01 (s, 2H), 3.98 - 3.90 (m, 4H), 3.58 (s, 3H), 1.54 - 1.46 (m, 1H), 0.74 - 0.63 (m, 4H); LCMS(m/z) 474.2.

<u>Example 303. 8-chloro-N-(3-(6-(cyclopropylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)phenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1715<chemistry id="chem1773" num="1773"><img file="EP4445902A2_D1776.tif" /></chemistry>

1716A suspension of 8-chloro-N-[3-(2,6-diazaspiro[3.3]heptan-2-yl)phenyl]-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 301, 15 mg, 0.026 mmol) in DCM (1.2 mL) was treated with cyclopropanesulfonyl chloride (0.003 mL, 0.031 mmol) and TEA (0.011 mL, 0.078 mmol). The mixture was stirred at ambient temperature for 90 minutes and then evaporated. The residue was purified via prep-HPLC to give the title compound: ¹H NMR (400 MHz, DMSO-d₆) δ 9.76 (s, 1H), 8.61 (d, J = 2.1 Hz, 1H), 7.42 (dd, J = 9.0, 2.1 Hz, 1H), 7.28 - 7.21 (m, 2H), 6.68 - 6.61 (m, 1H), 6.49 - 6.46 (m, 1H), 6.46 - 6.43 (m, 1H), 4.08 (s, 4H), 3.95 (s, 4H), 3.58 (s, 3H), 2.79 - 2.69 (m, 1H), 1.05 - 0.98 (m, 2H), 0.96 - 0.89 (m, 2H); LCMS(m/z) 510.2.

<u>Example 304. 8-chloro-N-methyl-N-(3-(6-(2,2,2-trifluoroethyl)-2,6-diazaspiro[3.3]heptan-2-yl)phenyl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1717<chemistry id="chem1774" num="1774"><img file="EP4445902A2_D1777.tif" /></chemistry>

1718A solution of 8-chloro-N-[3-(2,6-diazaspiro[3.3]heptan-2-yl)phenyl]-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (13 mg, 0.022 mmol) in ACN (1.0 mL) was treated with 2,2,2-Trifluoroethyl trifluoromethanesulfonate (0.004 mL, 0.026 mmol) and DIPEA (0.011 mL, 0.066 mmol). The mixture was stirred at ambient temperature for 2 hours and then evaporated. The residue was purified via prep-HPLC to give product: ¹H NMR (400 MHz, Acetone-d₆) δ 9.49 (s, 1H), 8.43 (d, J = 2.0 Hz, 1H), 7.45 (d, J = 9.0 Hz, 1H), 7.31 (dd, J = 9.0, 2.1 Hz, 1H), 7.24 (t, J = 8.0 Hz, 1H), 6.68 - 6.61 (m, 1H), 6.49 (t, J = 2.1 Hz, 1H), 6.47 - 6.42 (m, 1H), 3.93 (s, 4H), 3.66 (s, 4H), 3.63 (s, 3H), 3.23 (q, J = 9.8 Hz, 2H); LCMS(m/z) 488.1.

<u>Example 305. 8-(but-1-yn-1-yl)-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1719<chemistry id="chem1775" num="1775"><img file="EP4445902A2_D1778.tif" /></chemistry>

1720A vigorously stirred mixture of 8-bromo-<i>N</i>-methyl-<i>N</i>-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 28, 10.0 mg, 28.2 µmol), but-1-yne (36.7 mg, 678 µmol), triethylamine (100 µL, 717 µmol), copper(I) iodide (5.4 mg, 28 µmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (9.1 mg, 19 µmol), tris(dibenzylideneacetone)palladium(0) (5.2 mg, 5.7 µmol), and 1-methylpyrrolidin-2-one (0.5 mL) was heated to 75 °C. After 4 h, the resulting mixture was cooled to room temperature and was purified by reverse phase preparative HPLC (0.1% trifluoroacetic acid in acetonitrile/water) to give the title compound: ¹H NMR (400 MHz, Acetone-d₆) δ 8.30 (s, 1H), 7.51 - 7.27 (m, 7H), 7.19 (d, J = 8.5 Hz, 1H), 2.49 (q, J = 7.5 Hz, 2H), 1.22 (t, J = 7.5 Hz, 3H); LCMS(m/z) 328.3.

<b>Example 306. (E)-N-methyl-N-phenyl-8-(prop-1-en-1-yl)-[1,2,4]triazolo[4,3-a]quinazolin-5-</b>amine

1721<chemistry id="chem1776" num="1776"><img file="EP4445902A2_D1779.tif" /></chemistry>

1722A vigorously stirred mixture of 8-bromo-<i>N</i>-methyl-<i>N</i>-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 28, 10.0 mg, 28.2 µmol), potassium <i>trans-</i>1-propenyltrifluoroborate (16.7 mg, 113 µmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (4.4 mg, 5.7 µmol), and 1,4-dioxane (0.5 mL) was heated to 100 °C. After 10 min, the resulting mixture was cooled to room temperature and was concentrated under reduced pressure. The residue was purified by reverse phase preparative HPLC (0.1% trifluoroacetic acid in acetonitrile/water) to give the title compound: ¹H NMR (400 MHz, Acetone-d₆) δ 9.58 (s, 1H), 8.36 (d, J = 1.7 Hz, 1H), 7.56 - 7.48 (m, 2H), 7.48 - 7.38 (m, 3H), 7.32 (dd, J = 8.8, 1.6 Hz, 1H), 7.21 (d, J = 8.8 Hz, 1H), 6.73 (dq, J = 15.6, 6.6 Hz, 1H), 6.57 (dd, J = 15.9, 1.9 Hz, 1H), 3.72 (s, 3H), 1.94 (dd, J = 6.6, 1.6 Hz, 3H); LCMS(m/z) 316.3.

<u>Example 307. 8-ethynyl-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1723<chemistry id="chem1777" num="1777"><img file="EP4445902A2_D1780.tif" /></chemistry>

1724Example 307 was synthesized in a manner similar to Example 306 except using potassium ethynyltrifluoroborate instead of potassium <i>trans</i>-1-propenyltrifluoroborate. ¹H NMR (400 MHz, Acetone-d₆) δ 9.51 (s, 1H), 8.42 (s, 1H), 7.51 - 7.24 (m, 8H), 4.07 (s, 1H), 3.65 (s, 3H); LCMS(m/z) 300.3.

<u>Example 308. N-(3-bromophenyl)-8-chloro-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1725<chemistry id="chem1778" num="1778"><img file="EP4445902A2_D1781.tif" /></chemistry>

1726Step 1: Sodium hydride (60% wt dispersion in mineral oil, 382 mg, 9.97 mmol) was added to a vigorously stirred mixture of 2,4,7-trichloroquinazoline (Compound 308-1, 1.94 g, 8.31 mmol) and 3-bromo-N-methylaniline (1.11 mL, 8.72 mmol) in <i>N</i>,<i>N</i>-dimethylformamide (30 mL) at 0 °C. After 60 min, sodium hydride (60% wt dispersion in mineral oil, 260 mg, 6.79 mmol) was added. After 2 h, the resulting mixture was poured into a mixture of saturated aqueous ammonium chloride solution (50 mL), brine (5100 mL), and ice (75 g), and the resulting suspension was swirled vigorously until all of the ice melted. The resulting suspension was filtered, and the filter cake was washed sequentially with ice-cold water (2 × 25 mL) and hexanes (25 mL) to give Compound 308-2.

1727Step 2: Hydrazine monohydrate (3.22 mL, 66.5 mmol) was added via syringe to a vigorously stirred solution of 308-2 (3.18 g, 8.31 mmol) in ethanol (60 mL) and tetrahydrofuran (40 mL) at room temperature. After 35 min, hydrazine monohydrate (6.00 mL, 123 mmol) was added via syringe. After 19 h, water (100 mL), brine (100 mL), ethyl acetate (150 mL), and tetrahydrofuran (75 mL) were added sequentially. The biphasic mixture was agitated, and the layers were separated. The aqueous layer was extracted with a mixture of ethyl acetate (200 mL) and tetrahydrofuran (100 mL). The combined organic layers were washed with a mixture of water (235 mL) and brine (115 mL), were dried over anhydrous sodium sulfate, were filtered, and were concentrated under reduced pressure to give Compound 308-3.

1728Step 3: A vigorously stirred mixture of Compound 308-3 (3.15 g, 8.31 mmol) and triethyl orthoformate (60 mL) was heated to 120 °C. After 212 min, the resulting mixture was heated to 150 °C. After 90 min, the resulting mixture was cooled to room temperature and was concentrated under reduced pressure until the volume of the resulting suspensions was approximately 10 mL. Hexanes (70 mL) were added, and the resulting crude material was triturated. The resulting suspension was cooled to 0 °C. After 20 min, the resulting suspension was filtered, and the filter cake was washed sequentially with a mixture of hexanes and diethyl ether (4:1 v:v, 60 mL) and hexanes (75 mL) and was dried under reduced pressure to give the title compound: ¹H NMR (400 MHz, DMSO-d₆) δ 9.67 (s, 1H), 8.58 (d, J = 2.1 Hz, 1H), 7.63 (q, J = 1.5 Hz, 1H), 7.48 - 7.37 (m, 2H), 7.35 - 7.26 (m, 3H), 3.54 (s, 3H); LCMS(m/z) 388.1.

<u>Example 309. (E)-7-fluoro-N-(3-fluorophenyl)-N-methyl-8-(prop-1-en-1-yl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1729<chemistry id="chem1779" num="1779"><img file="EP4445902A2_D1782.tif" /></chemistry>

1730Example 309 was synthesized in a manner similar to Example 306, except using 8-bromo-7-fluoro-<i>N</i>-(3-fluorophenyl)-<i>N</i>-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 215) instead of 8-bromo-<i>N</i>-methyl-<i>N</i>-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 28) and using potassium ethynyltrifluoroborate instead of potassium <i>trans-</i>1-propenyltrifluoroborate. ¹H NMR (400 MHz, Acetone-d₆) δ 9.58 (s, 1H), 8.58 (d, J = 6.6 Hz, 1H), 7.55 (td, J = 8.2, 6.5 Hz, 1H), 7.34 - 7.25 (m, 2H), 7.18 (tdd, J = 8.4, 2.5, 0.9 Hz, 1H), 6.98 (d, J = 12.1 Hz, 1H), 6.86 (dq, J = 15.9, 6.7 Hz, 1H), 6.70 - 6.56 (m, 1H), 3.70 (s, 3H), 1.99 (dd, J = 6.7, 1.7 Hz, 3H); LCMS(m/z) 352.3.

<u>Example 310. (Z)-N-methyl-N-phenyl-8-(prop-1-en-1-yl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1731<chemistry id="chem1780" num="1780"><img file="EP4445902A2_D1783.tif" /></chemistry>

1732Example 310 was synthesized in a manner similar to Example 306, except using <i>cis</i>-1-propen-1-ylboronic acid instead of potassium <i>trans</i>-1-propenyltrifluoroborate. ¹H NMR (400 MHz, Acetone-d₆) δ 9.56 (s, 1H), 8.24 (d, J = 1.5 Hz, 1H), 7.55 - 7.46 (m, 2H), 7.46 - 7.36 (m, 3H), 7.30 (d, J = 8.7 Hz, 1H), 7.24 (dd, J = 8.8, 1.6 Hz, 1H), 6.56 (dd, J = 11.7, 2.0 Hz, 1H), 6.09 (dq, J = 11.7, 7.3 Hz, 1H), 3.71 (s, 3H), 1.96 (dd, J = 7.3, 1.9 Hz, 3H); LCMS(m/z) 316.3.

<u>Example 311. (E)-8-(but-2-en-2-yl)-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1733<chemistry id="chem1781" num="1781"><img file="EP4445902A2_D1784.tif" /></chemistry>

1734Example 311 was synthesized in a manner similar to Example 306, except using potassium (2Z)-2-buten-2-yltrifluoroborate instead of potassium <i>trans</i>-1-propenyltrifluoroborate. ¹H NMR (400 MHz, Acetone-d₆) δ 9.67 (s, 1H), 8.35 (d, J = 1.9 Hz, 1H), 7.59 - 7.49 (m, 2H), 7.48 - 7.41 (m, 3H), 7.38 (dd, J = 8.9, 1.9 Hz, 1H), 7.22 (d, J = 8.9 Hz, 1H), 6.29 (q, J = 6.9 Hz, 1H), 3.72 (s, 3H), 2.11 (t, J = 1.3 Hz, 3H), 1.86 (dq, J = 6.9, 1.1 Hz, 3H); LCMS(m/z) 330.3.

<u>Example 312. 8-chloro-N-(4'-isopropyl-[1,1'-biphenyl]-3-yl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1735<chemistry id="chem1782" num="1782"><img file="EP4445902A2_D1785.tif" /></chemistry>

1736A vigorously stirred mixture of Example 308 (5.0 mg, 13 µmol), (4-isopropylphenyl)boronic acid (8.4 mg, 52 µmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.9 mg, 2.6 µmol), aqueous sodium carbonate solution (2.0 M, 97 µL, 190 µmol), and 1,4-dioxane (0.5 mL) was heated to 100 °C. After 5 min, the resulting mixture was cooled to room temperature and was concentrated under reduced pressure. The residue was purified by reverse phase preparative HPLC (0.1% trifluoroacetic acid in acetonitrile/water) to give the title compound: ¹H NMR (400 MHz, Acetone-d₆) δ 9.44 (s, 1H), 8.39 (d, J = 2.1 Hz, 1H), 7.66 (t, J = 2.0 Hz, 1H), 7.61 (dt, J = 7.9, 1.4 Hz, 1H), 7.59 - 7.47 (m, 4H), 7.39 - 7.29 (m, 3H), 7.26 (dd, J = 9.0, 2.1 Hz, 1H), 3.70 (s, 3H), 3.08 - 2.75 (m, 1H), 1.26 (d, J = 6.9 Hz, 6H); LCMS(m/z) 428.3.

<u>Example 313. 8-chloro-N-(4'-cyclopropyl-[1,1'-biphenyl]-3-yl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1737<chemistry id="chem1783" num="1783"><img file="EP4445902A2_D1786.tif" /></chemistry>

1738Example 313 was synthesized in a manner similar to Example 312, except using (4-cyclopropylphenyl)boronic acid instead of (4-isopropylphenyl)boronic acid. ¹H NMR (400 MHz, Acetone-d₆) δ 9.49 (s, 1H), 8.43 (d, J = 2.1 Hz, 1H), 7.67 (t, J = 2.0 Hz, 1H), 7.63 (ddd, J = 7.8, 1.8, 1.1 Hz, 1H), 7.57 - 7.45 (m, 4H), 7.36 (ddd, J = 7.9, 2.2, 1.1 Hz, 1H), 7.29 (dd, J = 9.0, 2.1 Hz, 1H), 7.18 - 7.06 (m, 2H), 3.72 (s, 3H), 2.03 - 1.85 (m, 1H), 1.03 - 0.93 (m, 2H), 0.77 - 0.64 (m, 2H); LCMS(m/z) 426.3.

<u>Example 314. 8-chloro-N-(4'-(difluoromethyl)-[1,1'-biphenyl]-3-yl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1739<chemistry id="chem1784" num="1784"><img file="EP4445902A2_D1787.tif" /></chemistry>

1740Example 314 was synthesized in a manner similar to Example 312, except using [4-(difluoromethyl)phenyl]boronic acid instead of (4-isopropylphenyl)boronic acid. ¹H NMR (400 MHz, Acetone-d₆) δ 9.47 (s, 1H), 8.42 (d, J = 2.1 Hz, 1H), 7.83 - 7.74 (m, 3H), 7.67 (dd, J = 13.3, 7.8 Hz, 3H), 7.58 (t, J = 7.9 Hz, 1H), 7.52 (d, J = 9.0 Hz, 1H), 7.43 (d, J = 8.0 Hz, 1H), 7.29 (dd, J = 9.0, 2.1 Hz, 1H), 6.95 (t, J = 56.1 Hz, 1H), 3.72 (s, 3H); LCMS(m/z) 436.3.

<u>Example 315.8-chloro-N-methyl-N-(2',4',6'-trimethyl-[1,1'-biphenyl]-3-yl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1741<chemistry id="chem1785" num="1785"><img file="EP4445902A2_D1788.tif" /></chemistry>

1742Example 315 was synthesized in a manner similar to Example 312, except using (2,4,6-trimethylphenyl)boronic acid instead of (4-isopropylphenyl)boronic acid. ¹H NMR (400 MHz, Acetone-d₆) δ 9.51 (s, 1H), 8.46 (d, J = 2.1 Hz, 1H), 7.64 (t, J = 7.8 Hz, 1H), 7.58 - 7.47 (m, 2H), 7.39 (dd, J = 9.0, 2.1 Hz, 1H), 7.16 (dt, J = 7.6, 1.3 Hz, 1H), 7.04 (t, J = 1.9 Hz, 1H), 6.88 (s, 2H), 3.73 (s, 3H), 2.25 (s, 3H), 1.89 (s, 6H); LCMS(m/z) 428.3.

<u>Example 316. N-methyl-8-(2-methylprop-1-en-1-yl)-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1743<chemistry id="chem1786" num="1786"><img file="EP4445902A2_D1789.tif" /></chemistry>

1744Example 316 was synthesized in a manner similar to Example 306 except using 4,4,5,5-tetramethyl-2-(2-methylprop-1-en-1-yl)-1,3,2-dioxaborolane instead of potassium <i>trans-</i>1-propenyltrifluoroborate. ¹H NMR (400 MHz, Acetone-d₆) δ 9.56 (s, 1H), 8.17 (d, J = 1.6 Hz, 1H), 7.56 - 7.47 (m, 2H), 7.47 - 7.37 (m, 3H), 7.26 (d, J = 8.7 Hz, 1H), 7.17 (dd, J = 8.8, 1.6 Hz, 1H), 6.41 (s, 1H), 3.71 (s, 3H), 1.97 (d, J = 1.5 Hz, 3H), 1.96 (d, J = 1.4 Hz, 3H); LCMS(m/z) 330.3.

<u>Example 317. N-(3-(6-(tert-butyl)pyridin-3-yl)phenyl)-8-chloro-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1745<chemistry id="chem1787" num="1787"><img file="EP4445902A2_D1790.tif" /></chemistry>

1746Example 317 was synthesized in a manner similar to Example 337, except using 5-bromo-2-tert-butyl-pyridine instead of 2-bromo-5-cyclopropylpyrazine and using chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) instead of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II). ¹H NMR (400 MHz, Acetone-d₆) δ 9.47 (s, 1H), 8.75 (d, J = 2.6 Hz, 1H), 8.42 (d, J = 2.2 Hz, 1H), 7.96 (dd, J = 8.3, 2.6 Hz, 1H), 7.77 - 7.72 (m, 1H), 7.68 - 7.63 (m, 1H), 7.59 (t, J = 8.0 Hz, 1H), 7.55 - 7.47 (m, 2H), 7.47 - 7.41 (m, 1H), 7.29 (dd, J = 8.9, 2.2 Hz, 1H), 3.72 (s, 3H), 1.37 (s, 9H); LCMS(m/z) 443.3.

<u>Example 318. N-(3-(5-(tert-butyl)pyridin-2-yl)phenyl)-8-chloro-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1747<chemistry id="chem1788" num="1788"><img file="EP4445902A2_D1791.tif" /></chemistry>

1748Example 318 was synthesized in a manner similar to Example 337, except using 5<i>-tert-</i>butyl-2-chloro-pyridine instead of 2-bromo-5-cyclopropylpyrazine and using chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) instead of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II). ¹H NMR (400 MHz, Acetone-d₆) δ 9.51 (s, 1H), 8.75 (s, 1H), 8.44 (d, J = 2.3 Hz, 1H), 8.15 (t, J = 2.1 Hz, 1H), 8.12 (d, J = 8.1 Hz, 1H), 7.94 - 7.83 (m, 2H), 7.58 (t, J = 7.8 Hz, 1H), 7.50 (d, J = 9.1 Hz, 1H), 7.47 - 7.33 (m, 1H), 7.30 (dd, J = 8.9, 2.2 Hz, 1H), 3.74 (s, 3H), 1.39 (s, 9H); LCMS(m/z) 443.3.

<u>Example 319.N-(3-(5-(tert-butyl)pyrimidin-2-yl)phenyl)-8-chloro-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1749<chemistry id="chem1789" num="1789"><img file="EP4445902A2_D1792.tif" /></chemistry>

1750Example 319 was synthesized in a manner similar to Example 337, except using 2-bromo-5-tert-butyl-pyrimidine instead of 2-bromo-5-cyclopropylpyrazine and using chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) instead of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II). ¹H NMR (400 MHz, Acetone-d₆) δ 9.46 (s, 1H), 8.76 (d, J = 5.3 Hz, 1H), 8.48 - 8.40 (m, 3H), 7.64 - 7.41 (m, 4H), 7.28 (dd, J = 9.0, 2.1 Hz, 1H), 3.71 (s, 3H), 1.40 (s, 9H); LCMS(m/z) 444.3.

<u>Example 320. N-(3-(2-(tert-butyl)pyrimidin-5-yl)phenyl)-8-chloro-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1751<chemistry id="chem1790" num="1790"><img file="EP4445902A2_D1793.tif" /></chemistry>

1752Example 320 was synthesized in a manner similar to Example 337, except using 5-bromo-2-tert-butyl-pyrimidine instead of 2-bromo-5-cyclopropylpyrazine and using chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) instead of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II). ¹H NMR (400 MHz, Acetone-d₆) δ 9.54 (s, 1H), 8.94 (s, 2H), 8.47 (d, J = 2.2 Hz, 1H), 7.84 (t, J = 2.0 Hz, 1H), 7.79 - 7.72 (m, 1H), 7.66 (t, J = 7.8 Hz, 1H), 7.58 - 7.46 (m, 2H), 7.32 (dd, J = 9.0, 2.1 Hz, 1H), 3.76 (s, 3H), 1.40 (s, 9H); LCMS(m/z) 444.3.

Example <b>321. N-(3-(6-(tert-butyl)pyridazin-3-yl)phenyl)-8-chloro-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</b>

1753<chemistry id="chem1791" num="1791"><img file="EP4445902A2_D1794.tif" /></chemistry>

1754Example 321 was synthesized in a manner similar to Example 337, except using 3-bromo-6-<i>tert</i>-butyl-pyridazine instead of 2-bromo-5-cyclopropylpyrazine and using chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) instead of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II). ¹H NMR (400 MHz, Acetone-d₆) δ 9.53 (s, 1H), 8.46 (d, J = 2.1 Hz, 1H), 8.23 (t, J = 2.0 Hz, 1H), 8.22 - 8.15 (m, 1H), 8.08 (d, J = 9.0 Hz, 1H), 7.80 (d, J = 9.0 Hz, 1H), 7.65 (t, J = 7.9 Hz, 1H), 7.58 - 7.51 (m, 2H), 7.31 (dd, J = 9.0, 2.1 Hz, 1H), 3.76 (s, 3H), 1.47 (s, 9H); LCMS(m/z) 444.3.

<u>Example 322. N-(3-(5-(tert-butyl)pyrazin-2-yl)phenyl)-8-chloro-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1755<chemistry id="chem1792" num="1792"><img file="EP4445902A2_D1795.tif" /></chemistry>

1756Example 322 was synthesized in a manner similar to Example 337, except using 2<i>-tert-</i>butyl-5-chloro-pyrazine instead of 2-bromo-5-cyclopropylpyrazine and using chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) instead of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II). ¹H NMR (400 MHz, Acetone-d₆) δ 9.50 (s, 1H), 9.06 (d, J = 1.6 Hz, 1H), 8.75 (d, J = 1.6 Hz, 1H), 8.43 (d, J = 2.1 Hz, 1H), 8.15 (t, J = 2.0 Hz, 1H), 8.12 (dt, J = 7.7, 1.3 Hz, 1H), 7.62 (t, J = 7.9 Hz, 1H), 7.55 - 7.46 (m, 2H), 7.29 (dd, J = 9.0, 2.1 Hz, 1H), 3.73 (s, 3H), 1.42 (s, 9H); LCMS(m/z) 444.3.

<u>Example 323. (E)-8-(but-1-en-1-yl)-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1757<chemistry id="chem1793" num="1793"><img file="EP4445902A2_D1796.tif" /></chemistry>

1758Example 323 was synthesized in a manner similar to Example 306, except using [(E)-but-1-enyl]boronic acid instead of potassium <i>trans</i>-1-propenyltrifluoroborate. ¹H NMR (400 MHz, Acetone-d₆) δ 9.56 (s, 1H), 8.38 (d, J = 1.7 Hz, 1H), 7.58 - 7.47 (m, 2H), 7.47 - 7.38 (m, 3H), 7.34 (dd, J = 8.8, 1.7 Hz, 1H), 7.22 (d, J = 8.8 Hz, 1H), 6.77 (dt, J = 16.0, 6.6 Hz, 1H), 6.55 (d, J = 15.9 Hz, 1H), 3.71 (s, 3H), 2.31 (pd, J = 7.5, 1.6 Hz, 2H), 1.10 (t, J = 7.4 Hz, 3H); LCMS(m/z) 330.3.

<u>Example 324. 8-(but-1-yn-1-yl)-7-fluoro-N-(3-fluorophenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1759<chemistry id="chem1794" num="1794"><img file="EP4445902A2_D1797.tif" /></chemistry>

1760Example 324 was synthesized in a manner similar to Example 305, except using 8-bromo-7-fluoro-<i>N</i>-(3-fluorophenyl)-<i>N</i>-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 215) instead of 8-bromo-<i>N</i>-methyl-<i>N</i>-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine. ¹H NMR (400 MHz, Acetone-d₆) δ 9.61 (s, 1H), 8.49 (d, J = 6.2 Hz, 1H), 7.55 (td, J = 8.1, 6.5 Hz, 1H), 7.37 - 7.26 (m, 2H), 7.22 - 7.17 (m, 1H), 7.05 (d, J = 10.7 Hz, 1H), 3.71 (s, 3H), 2.56 (q, J = 7.5 Hz, 2H), 1.25 (t, J = 7.5 Hz, 3H); LCMS(m/z) 364.3.

<u>Example 325. 8-(cyclopent-1-en-1-yl)-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1761<chemistry id="chem1795" num="1795"><img file="EP4445902A2_D1798.tif" /></chemistry>

1762Example 325 was synthesized in a manner similar to Example 306, except using cyclopenten-1-ylboronic acid instead of potassium <i>trans</i>-1-propenyltrifluoroborate. ¹H NMR (400 MHz, Acetone-d₆) δ 9.59 (s, 1H), 8.37 - 8.19 (m, 1H), 7.55 - 7.45 (m, 2H), 7.45 - 7.32 (m, 4H), 7.26 (d, J = 8.9 Hz, 1H), 6.75 - 6.60 (m, 1H), 3.68 (s, 3H), 2.86 - 2.71 (m, 2H), 2.65 - 2.48 (m, 2H), 2.15 - 1.98 (m, 2H); LCMS(m/z) 342.3.

<u>Example 326. 8-(cyclohex-1-en-1-yl)-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1763<chemistry id="chem1796" num="1796"><img file="EP4445902A2_D1799.tif" /></chemistry>

1764Example 326 was synthesized in a manner similar to Example 306, except using cyclohexen-1-ylboronic acid instead of potassium <i>trans</i>-1-propenyltrifluoroborate. ¹H NMR (400 MHz, Acetone-d₆) δ 9.65 (s, 1H), 8.32 (d, J = 1.9 Hz, 1H), 7.57 - 7.47 (m, 2H), 7.47 - 7.40 (m, 3H), 7.40 - 7.35 (m, 1H), 7.24 (d, J = 9.0 Hz, 1H), 6.54 (td, J = 4.1, 2.1 Hz, 1H), 3.70 (s, 3H), 2.55 - 2.44 (m, 2H), 2.35 - 2.23 (m, 2H), 1.88 - 1.74 (m, 2H), 1.74 - 1.62 (m, 2H); LCMS(m/z) 356.3.

<u>Example 327. N-methyl-8-(methylsulfonyl)-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1765<chemistry id="chem1797" num="1797"><img file="EP4445902A2_D1800.tif" /></chemistry>

1766A vigorously stirred mixture of 8-bromo-<i>N</i>-methyl-<i>N</i>-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 28, 10.0 mg, 28.2 µmol), sodium methane sulfinate (28.8 mg, 282 µmol), copper(I) iodide (53.8 mg, 282 µmol), and 1-methylpyrrolidin-2-one (0.5 mL) was heated to 140 °C. After 60 min, the resulting mixture was cooled to room temperature and was purified by reverse phase preparative HPLC (0.1% trifluoroacetic acid in acetonitrile/water) to give the title compound: ¹H NMR (400 MHz, Acetone-d₆) δ 9.67 (s, 1H), 8.77 (d, J = 1.7 Hz, 1H), 7.73 (dd, J = 8.7, 1.8 Hz, 1H), 7.62 (d, J = 8.7 Hz, 1H), 7.53 - 7.43 (m, 2H), 7.43 - 7.39 (m, 2H), 7.39 - 7.31 (m, 1H), 3.67 (s, 3H), 3.25 (s, 3H); LCMS(m/z) 354.3.

<u>Example 328. N-(3-bromophenyl)-8-(4-(tert-butyl)-1H-imidazol-1-yl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1767<chemistry id="chem1798" num="1798"><img file="EP4445902A2_D1801.tif" /></chemistry>

1768A vigorously stirred mixture of Example 308 (10.0 mg, 25.7 µmol), 4-(<i>tert</i>-butyl)-1<i>H-</i>imidazole (9.6 mg, 77 µmol), copper(I) iodide (2.5 mg, 13 µmol), potassium carbonate (17.9 mg, 129 µmol), _L-proline (3.0 mg, 26 µmol), and dimethylsulfoxide (0.7 mL) was heated to 90 °C. After 30 min, the resulting mixture was heated to 120 °C. After 13.5 h, the resulting mixture was cooled to room temperature and was purified by reverse phase preparative HPLC (0.1% trifluoroacetic acid in acetonitrile/water) to give the title compound: ¹H NMR (400 MHz, Acetone-d₆) δ 9.49 (s, 1H), 8.74 (d, J = 2.3 Hz, 1H), 8.64 (d, J = 1.5 Hz, 1H), 7.76 - 7.65 (m, 3H), 7.58 (d, J = 9.1 Hz, 1H), 7.53 (dt, J = 6.8, 1.9 Hz, 1H), 7.48 - 7.38 (m, 2H), 3.69 (s, 3H), 1.36 (s, 9H); LCMS(m/z) 476.3.

<u>Example 329. 8-chloro-N-(4',4'-dimethyl-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-3-yl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1769<chemistry id="chem1799" num="1799"><img file="EP4445902A2_D1802.tif" /></chemistry>

1770Example 329 was synthesized in a manner similar to Example 312, except using (4,4-dimethylcyclohex-1-en-1-yl)boronic acid instead of (4-isopropylphenyl)boronic acid. ¹H NMR (400 MHz, Acetone-d₆) δ 9.53 (s, 1H), 8.46 (d, J = 2.1 Hz, 1H), 7.52 - 7.36 (m, 4H), 7.33 (dd, J = 9.0, 2.1 Hz, 1H), 7.27 (dt, J = 7.3, 1.9 Hz, 1H), 6.13 (tt, J = 3.9, 1.7 Hz, 1H), 3.70 (s, 3H), 2.45 - 2.33 (m, 2H), 2.01 - 1.95 (m, 2H), 1.51 (t, J = 6.4 Hz, 2H), 0.95 (s, 6H); LCMS(m/z) 476.3.

<u>Example 330. N-(4'-(tert-butyl)-2'-methyl-[1,1,-biphenyl]-3-yl)-8-chloro-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1771<chemistry id="chem1800" num="1800"><img file="EP4445902A2_D1803.tif" /></chemistry>

1772Example 330 was synthesized in a manner similar to Example 337, except using <i>4-(tert-</i>butyl)-2-methylphenyl trifluoromethanesulfonate instead of 2-bromo-5-cyclopropylpyrazine and using chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) instead of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II). ¹H NMR (400 MHz, Acetone-d₆) δ 9.41 (s, 1H), 8.38 (s, 1H), 7.61 - 7.14 (m, 8H), 7.08 (d, J = 7.9 Hz, 1H), 3.67 (s, 3H), 2.81 (s, 3H), 1.31 (s, 9H); LCMS(m/z) 456.4.

<u>Example 331. N-(4'-(tert-butyl)-2'-chloro-[1,1'-biphenyl]-3-yl)-8-chloro-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1773<chemistry id="chem1801" num="1801"><img file="EP4445902A2_D1804.tif" /></chemistry>

1774Example 331 was synthesized in a manner similar to Example 337, except using 4-(<i>tert-</i>butyl)-2-chlorophenyl trifluoromethanesulfonate instead of 2-bromo-5-cyclopropylpyrazine and using chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) instead of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II). ¹H NMR (400 MHz, Acetone-d₆) δ 9.43 (s, 1H), 8.39 (d, J = 2.1 Hz, 1H), 7.65 - 7.40 (m, 6H), 7.40 - 7.25 (m, 3H), 3.68 (s, 3H), 1.34 (s, 9H); LCMS(m/z) 476.3.

<u>Example 332. 8-chloro-N-methyl-N-(3-(6-methylpyridin-3-yl)phenyl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine</u>

1775<chemistry id="chem1802" num="1802"><img file="EP4445902A2_D1805.tif" /></chemistry>