Pyrimidine derivatives as kinase inhibitors.

PIRIMIDINE DERIVATIVES AS KINASA INHIBITORS

FIELD OF THE INVENTION

The field of this invention is compounds, pharmaceutical compositions and methods, especially as they are related to the compositions and methods for the treatment of a proliferation disorder, a cancer, a tumor, an inflammatory disease, an autoimmune disease, psoriasis, dry eyes or an immunologically related disease, and in some modalities kinase dysregulation related diseases or disorders such as, but not limited to, EGFR (including HER), Alk, PDGFR, BLK, BMX / ETK, BTK, FLT3 (D835Y), ITK, JAK such as JAK1, JAK2, JAK3, TEC and TXK, and the respective paths.

BACKGROUND OF THE INVENTION

Protein kinases are a group of enzymes that regulate various important biological processes, including cell growth, proliferation, survival, invasion and differentiation, organ formation, tissue repair and regeneration, etc. Protein kinases exert their physiological functions by catalyzing protein phosphorylation and thus modulating cellular activities.

Because protein kinases have profound effects on cells, their activities are highly regulated. Kinases are activated or deactivated by phosphorylation (sometimes by autophosphorylation), by binding of activator proteins or inhibitor proteins, or small molecules, or by controlling their location in the cell relative to their substrates. Dysfunctions in kinase activities are known to arise from genetic abnormalities or environmental factors, which are associated with many diseases. Various serious disease states, including cancer and chronic inflammation, are associated with stimulation of intracellular signaling, and since kinases positively retransmit signaling events, their inhibition offers a powerful way to inhibit or control signal transduction cascades.

The epidermal growth factor receptor (EGFR; ErbB-1; HERI in humans) is a member of the ErbB family of receptors, a closely related subfamily of four receptor tyrosine kinases: EGFR (ErbB-1), HER2 / cneu ( ErbB-2), Her 3 (ErbB-3) and Her 4 (ErbB-4). EGFR is the cell surface receptor for members of the epidermal growth factor family (EGF family) of extracellular protein ligands. Mutations that affect EGFR expression or activity could result in cancer. EGFR is reported to be dysregulated in most types of solid tumors ie lung cancer, breast cancer and brain tumor. Mutations, amplifications, or regulatory errors of EGFR or family members are estimated to be involved in approximately 30% of all epithelial cancers. Therapeutic methods have been developed based on the inhibition of EGFR by any of the antibody drugs or small molecular inhibitory drug, such as gefitinib and erlotinib. In the case of non-small cell lung cancer, gefitinib and erlotinib have shown benefit for approximately 10 to 40% of patients. However, acquired resistance to gefitinib or erlotinib after a period of treatment becomes a major clinical problem. Research has confirmed that a major reason for the developed resistance is due to the presence of a new T790M mutation, which is the gatekeeper for EGFR. Subsequently, inhibitors have been developed that can overcome this T790M and show advantage in the clinical trial, such as BIBW2992. However, these EGFR inhibitor-targeted T790Ms still have relative inhibitory activity towards wild-type EGFRs that limit clinical application. It is necessary to further develop the efficient type of EGFR inhibitor that will target the mutation only and not the wild-type protein.

Other protein kinases that are useful targets for small molecule pharmaceuticals include B cell lymphoid tyrosine kinase (BLK), bone marrow kinase on the X chromosome (BMX / ETK), Bruton tyrosine kinase (BTK), Janus kinase 1 ( JAK1), janus kinase 2 (JAK2), Janus 3 kinase (JAK3), hepatocellular carcinoma-expressed tyrosine kinase (TEC), resting lymphocyte kinase (TXK, also known as RLK), FMS-like tyrosine kinase 3 (FLT3 ), and FLT3 (D835Y).

SUMMARY OF THE INVENTION

In one aspect, the present disclosure provides a heterocyclic compound having a structure according to Formula I:

R1 r₆ where

R¹ is H, or

NR^cR^d where R^c is

H, alkyl Ci_₄ or cyclic ring of

3-7 members, and R^d is H, alkyl C₄-₄, optionally substituted with OZ, where Z is H or Ci_alkyl₄; or 3-7 membered cyclic ring substituted with R^to where R^to it is Ci-s alkyl optionally substituted with halo;

<td>R²</td><td>is</td><td>H</td><td>halo, alkyl</td><td>C1-4 _F</td><td> 0</td><td>alkoxy</td><td>Ci-₄;</td>

<td>R³</td><td>is</td><td>H</td><td>halo, alkyl</td><td>Ci-₄,</td><td> 0</td><td>alkoxy</td><td>Ci_₄;</td>

<td>R⁵</td><td>is</td><td>H</td><td>halo, alkyl</td><td>Ci-₄,</td><td> 0</td><td>alkoxy</td><td>Ci-₄;</td>

<td>R⁶</td><td>is</td><td>H</td><td>halo, alkyl</td><td>Ci-₄,</td><td> 0</td><td>alkoxy</td><td>Ci-₄; 0</td>

<td>R¹</td><td>and</td><td>R⁵</td><td>are part of the</td><td colspan="3">cyclic ring</td><td>3-7 member co</td>

optionally substituted with Ci_alkyl₄ substituted with OZ, where Z is H or Ci- alkyl₄; or

R and R are part of the 3-7 membered cyclic ring, optionally substituted with Ci- alkyl₄ substituted with OZ, where Z is H or Ci- alkyl₄; or

R and R are part of the 3-7 membered cyclic ring, optionally substituted with Ci- alkyl₄ substituted with OZ, where Z is H or Ci_alkyl₄; or

R⁴ is alkenyl C₂ optionally substituted with alkyl Ci-₄, -ch₂och₃, or -ch₂n (ch₃)₂; and

X is O, alkyl Ci_₄ optionally substituted with halo, or NR^b, where R^b is H, or alkyl Ci-₈ optionally substituted with halo,

Y is CH optionally substituted with halo, or N, where at least one of R², R³, R⁵ and R⁶ it is not H;

or a pharmaceutically acceptable salt thereof.

In another aspect, the present disclosure provides a heterocyclic compound having a structure according to Formula II:

<img file="MX368491B_D0001.tif" />

<img file="MX368491B_D0002.tif" />

(Π) where

R¹ is H, or

NR^cR^d where R^c is H, C1-.4 alkyl or 3-7 membered cyclic ring, and R^d is H, C1-4 alkyl, optionally substituted with OZ, where Z is H or Ci_alkyl₄; or

NR^andR^F where R^and is C1-4alkyl, and R^F it is 3-7 membered cyclic ring optionally substituted with C 1-4 alkyl optionally substituted with halo; or

OR^g where R^g is C1-4alkyl substituted with CH₃OR-,

<img file="MX368491B_D0003.tif" />

<img file="MX368491B_D0004.tif" />

CH₃CH₂O-, CH₃(OR) ₂S-, cf₃o-, o

<td>R²</td><td>is</td><td>H</td><td>halo,</td><td>I rent</td><td>C1-4,</td><td> 0</td><td>alkoxy</td><td>C1-4;</td>

<td>R³</td><td>is</td><td>H</td><td>halo,</td><td>I rent</td><td>Ci_₄,</td><td> 0</td><td>alkoxy</td><td>Ci-4;</td>

<td>R⁵</td><td>is</td><td>H</td><td>halo,</td><td>I rent</td><td>C1-4,</td><td> 0</td><td>alkoxy</td><td>C1-4;</td>

<td>R⁶</td><td>is</td><td>H</td><td>halo,</td><td>I rent</td><td>C1-4,</td><td> 0</td><td>alkoxy</td><td>Ci-₄; 0</td>

R¹ and R⁵ they are part of the 3-7 membered cyclic ring, optionally substituted with Ci-alkyl₄ substituted with OZ, where Z is H or Ci- alkyl₄; or

R and R are part of the 3-7 membered cyclic ring, optionally substituted with Ci- alkyl₄ substituted with OZ, where Z is H or alkyl C_x_₄; or

R² and R⁶ are part of the 3-7 membered cyclic ring, optionally substituted with Ci_alkyl₄ substituted with OZ, where Z is H or Ci- alkyl₄; or

R⁴ is alkenyl C₂ optionally substituted with alkyl Ci-₄, -CH2OCH3, or -CH₂N (CH₃)₂; and

X is O, alkyl Οχ_₄ optionally substituted with halo, or NR^b, where R^b is H, or alkyl Ci_₈ optionally substituted with halo,

Y is CH optionally substituted with halo, or N, or a pharmaceutically acceptable salt thereof.

In yet another aspect, the present disclosure provides a heterocyclic compound having a

<img file="MX368491B_D0005.tif" />

(the) where

R¹ is H, or

NR^cR^d where

R^c is H, alkyl Ci_₄, alkenyl Ci-₄, or cyclic ring of

3-7 members, the alkyl Ci_₄, alkenyl Ci-₄, or 3-7 membered cyclic ring being optionally substituted with OZ or NR11R12, where Z, Rn, R_i2 are independently H or Ci- alkyl₄, or the 3-7 membered cyclic ring being optionally substituted with Ci-alkyl₄ which is further optionally substituted with OZ or NRnRi2 &lt;where Z, Rn, R12 are independently H or Ci- alkyl₄, or the 37-membered cyclic ring being optionally substituted with SO2 (CH₂)_whatH, where q is 1-4, or the 3-7 membered cyclic ring being optionally substituted with Ci- alkyl₄ which is also optionally substituted with SO2 (CH₂)_whatH, where q is 1-4, or the 3-7 membered cyclic ring being optionally substituted with R₈CO, where R_s is Ci_alkyl₄, and

R^d is H, alkyl Ci-₄, alkenyl Ci_₄, or 3-7 membered cyclic ring, the Ci_alkyl₄, alkenyl Ci-₄ or 3-7 membered cyclic ring being optionally substituted with OZ or NRnR₁₂, where Z, R_n, R₁₂ are independently H or alkyl Ci_₄; or 3-7 membered cyclic ring substituted with R^to where R^to is Ci_alkyl₈ optionally substituted with halo, Ci-4 alkoxy or SO₂(CH₂) qH, where q is 1-4; or

O (CH₂)_mSW₂ (CH₂)_nH, where m is 1-4 and n is 1-4;

R is absent, H, halo, Ci- alkyl₄, alkoxy Ci-₄, or alkylamine (NRnRi₂), where R_or and R₁₂ are independently H or Ci- alkyl₄;

R³ is H, hydroxyl, halo, Ci_alkyl₄, alkoxy Ci-₄, or alkylamine (NRnRi₂), where Rn and R_i2 are independently H or Ci- alkyl₄;

R⁵ is absent, H, halo, C-alkyl_x-₄, alkoxy Ci_₄, or alkylamine (NRnR₁₂), where Rn and R_i2 are independently H or Ci- alkyl₄;

R⁶ is H, halo, Ci- alkyl₄, alkoxy Ci-₄; or alkylamine (NR11R12), where Rn and R12 are independently H or alkyl

Ci-4;

R⁷ is H, halo, Ci- alkyl₄, alkoxy Ci-₄, or alkylamine (NR11R12), where Rn and R₁₂ sor. independently H or C1-4 alkyl;

R⁹ is H, hydroxyl, halo, C1-4alkyl, C1-4alkoxy, or alkylamine (NR11R12), where Rn and R_i2 are independently H or Ci- alkyl₄;

R is H, hydroxyl, halo, C1-4alkyl, C1-4alkoxy, or alkylamine (NRnRi₂), where Rn and R_i2 are independently H or alkyl Ci_₄; or

R¹ and R⁵ are part of the 3-7 membered cyclic ring, the 3-7 membered cyclic being optionally substituted with Ci-alkyl₄ optionally substituted with OZ or NRnRi₂ where Z, Rn and R12 are independently H or Ci_alkyl₄, or the 3-7 membered cyclic being optionally substituted with R₈CO, where R₈ is alkyl Ci-₄, or the 3-7 membered cyclic being optionally substituted with SO₂(CH2)_whatH, where q is 1-4; or

R¹ and R² are part of the 3-7 membered cyclic ring, optionally substituted with Ci_alkyl₄, C1-4alkyl further optionally substituted with halo, OZ, or NRnRi₂ where Z, Rn and R₁₂ are independently H or alkyl Ci_₄, or one or more members of the 3-7 membered cyclic ring is optionally part of a carbonyl group or a sulfonyl group; or

R² and R⁶ they are part of the 3-7 membered cyclic ring, optionally substituted with Ci-alkyl₄ optionally substituted with OZ or NRnRi₂ where Z, Rn and R_i2 are independently H or Ci- alkyl₄;

R⁴ is alkenyl C₂ optionally substituted with alkyl

Ci-4, -ch₂och₃, O -ch₂n (ch₃)₂;

X is O, alkyl Ci-₄ optionally substituted with halo, or NR^b, where R^b is H, or alkyl Ci-₈ optionally substituted with halo;

Y is C, CH optionally substituted with halo, or N;

Ά is C, CH optionally substituted with halo or N; and where at least one of R², R³, R⁵ and R⁶ it is not H;

or a pharmaceutically acceptable salt thereof.

In yet another aspect, the present disclosure provides a heterocyclic compound having a structure according to Formula lia:

<img file="MX368491B_D0006.tif" />

(lia) where

R¹ is H, or

NR^cR^d where R^c is H, C1-4alkyl or cyclic ring of

3-7 membered, the 3-7 membered cyclic ring optionally substituted with C 1-4 alkyl optionally substituted with OZ or NRiqRh where Z, R₁₀ and R_or they are independently H or C1-4alkyl, or the 3-7 membered cyclic ring being optionally substituted with R₈CO, where R₈ it is C1-4alkyl, or the 3-7 membered cyclic ring being optionally substituted with SO₂(CH₂)_whatH, where q is 1-4, and R^d is H, C1-4alkyl, optionally substituted with OZ or NR10R11 where Z, Rio and Ru are H or Ci- alkyl₄; or

NR^andR^F where R^and is C1-4alkyl, and R^F it is 3-7 membered cyclic ring optionally substituted with C 1-4 alkyl optionally substituted with halo; or

OR^g where R^g is alkyl Ci-₄ replaced with CH₃OR-,

CH₃CH₂O-, CH₃(OR) ₂s-, cf₃3-7 membered cyclic ring substituted with R^to where R^to is Ci_alkyl₈ optionally substituted with halo, Ci-4 alkoxy or SO₂(CH₂)_whatH, where q is 1-4, or the 3-7 membered cyclic ring being optionally substituted with R₈CO, where R₈ is alkyl Ci-₄;

R is absent, H, halo, Ci_alkyl₄, alkoxy Ci_₄, or alkylamine (NRi₀Rn), where Rio and Rn are independently H or alkyl Ci-₄;

R³ is absent, H, halo, Ci- alkyl₄, or C-alkoxy₄, or alkylamine (NRioRn), where R₁₀ and Rn are independently H or Ci_alkyl₄;

R⁵ is absent, H, halo, Ci- alkyl₄, or Ci_alkoxy₄, or alkylamine (NRi₀Rn), where R_i0 and Ru are independently H or Ci- alkyl₄;

R⁶ is H, halo, alkyl Ci_₄, or C-alkoxy₄, or alkylamine (NRioRn), where Rio and Rn are independently H or Ci- alkyl₄;

R⁷ is H, halo, alkyl Ci_₄, alkoxy Ci-₄, or alkylamine (NRioRn), where Rio and Rn are independently H or Ci_4 alkyl;

R⁹ is H, halo, alkyl Ci_₄, or C-alkoxy₄, or alkylamine (NRioRn), where Rio and Ru are independently H or C1-4 alkyl; or

R¹ and R⁵ are part of the 3-7 membered cyclic ring, optionally substituted with C1-4 alkyl optionally substituted with OZ or NRi₀Rn where Z, Rio and Ru are independently H or alkyl Ci_₄; or

R¹ and R² are part of the 3-7 membered cyclic ring, optionally substituted with C1-4 alkyl optionally substituted with OZ or Rio and Ru where Z, R_í0 and R_or are independently H or alkyl Ci_₄; or

R² and R^s they are part of the 3-7 membered cyclic ring, optionally substituted with C 1-4 alkyl optionally substituted with OZ or Rio and Ru where Z, Rio and Ru are independently H or C-alkyl₄;

R⁴ is C2 alkenyl optionally substituted with C1-4alkyl, -CH2OCH3, or -CH₂N (CH₃)₂;

X is O, C1-4 alkyl optionally substituted by halo, or NR^b, where R^b it is H, or Ci-g alkyl optionally substituted with halo;

<td>AND</td><td>is</td><td>c,</td><td>CH</td><td>optionally</td><td>replaced</td><td>with</td><td>halo,</td><td> 0</td><td>N;</td>

<td>TO</td><td>is</td><td>c,</td><td>CH</td><td>optionally</td><td>replaced</td><td>with</td><td>halo,</td><td> 0</td><td>N; and</td>

<td>B</td><td>is</td><td>c,</td><td>CH</td><td>optionally</td><td>replaced</td><td>with</td><td>halo,</td><td> 0</td><td>N,</td>

or a pharmaceutically acceptable salt thereof.

The compound described above can be used for any suitable purpose. In some embodiments, the compound described above can be used in therapy.

In yet another aspect, the present disclosure provides a pharmaceutical composition comprising a compound described above mixed with at least one pharmaceutically acceptable carrier or excipient.

In yet another aspect, the present disclosure provides a method of treating and / or preventing a proliferation disorder, a cancer, a tumor, an inflammatory disease, an autoimmune disease, psoriasis, dry eyes, or an immunologically related disease, or lupus, which it comprises administering to a subject in need thereof an effective amount of a compound described above or a pharmaceutical composition described above.

In yet another aspect, the present disclosure provides a use of a compound described above for the manufacture of a medicament.

In yet another aspect, the present disclosure provides a combination for treating and / or preventing a proliferation disorder, cancer, tumor, inflammatory disease, autoimmune disease, psoriasis, dry eyes, or an immunologically related disease or lupus in a subject. , the combination of which comprises an effective amount of a compound described above, or a pharmaceutically acceptable salt thereof, and an effective amount of a second therapeutic or prophylactic agent for treating and / or preventing a proliferation disorder, a cancer, a tumor, an inflammatory disease, an autoimmune disease, psoriasis, dry eyes or an immunologically related disease or lupus in a subject. .

In yet another aspect, the present disclosure provides a method of treating and / or preventing a proliferation disorder, cancer, tumor, inflammatory disease, autoimmune disease, psoriasis, dry eyes, or an immunologically related disease or lupus in a subject. , whose methods comprise administering to a subject in need thereof an effective amount of the combination described above.

In yet another aspect, the present disclosure provides a method of inhibiting an activity of a Bruton tyrosine kinase (Btk or BTK) or a Janus kinase (JAK), EGFR (including HER), Alk, PDGFR, BLK, BMX / ETK, FLT3 (D835Y), ITK, TEC, TXK, and the respective pathways, in a cell or subject, the methods of which comprise administering to an cell or subject in need thereof an effective amount of a compound described above, or a pharmaceutical composition described above , or a combination described above.

BRIEF DESCRIPTION OF THE FIGURES

Figures 1A-1C show reduction of Btk Tyr223 phosphorylation in Ramos cells by exemplary compounds. Figure 1A shows reduction of Btk Tyr223 phosphorylation in Ramos cells by PCI-32765 (Ibrutinib). Figure IB shows reduction of Btk Tyr223 phosphorylation in Ramos cells by compound No. 1-1. Figure 1C shows reduction of Btk Tyr223 phosphorylation in Ramos cells by compound No. 1-2.

Figures 2A and 2B show that compounds 1-1 and I2 irreversibly inhibit BTK phosphorylation in Ramos cells.

Figure 3 shows dose-dependent inhibition of BTK phosphorylation in Ramos cells by compound 1-1.

Figures 4A, 4B, 4C, 4D, 4E, 4F, 4G, 4H, 41, 4J, 4K, 4L and 4N show exemplary western blotting images of IC curves.₅₀ of various compounds, while PCI-32765 serves as a positive Btk inhibitor.

Figures 5A and 5B show that compounds 1-1 and I2 inhibit BTK phosphorylation in Ramos cells after 8 hours of elimination.

Figures 6A, 6B, 6C, 6D, 6E, 6F, 6G, 6H, 61, 6J, 6K and 6L show exemplary Btk Target Site Occupation ELISA results of various compounds.

DETAILED DESCRIPTION OF THE INVENTION

General Definitions:

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as is commonly understood by someone of ordinary skill in the art to which this invention pertains. All publications, requests, published requests and other publications referred to herein are incorporated as^: reference in their totalities. If a definition set forth in this section is contrary to or otherwise inconsistent with a definition set forth in a patent, application, or other publication that is incorporated herein by reference, the definition set forth in this section prevails over the definition incorporated herein. as reference.

<td>How</td><td>it's used</td><td>herein, an or</td><td>one means</td><td>to the</td>

<td>minus one '¹</td><td>'or one</td><td>or more.</td><td></td><td></td>

<td colspan="2">The term</td><td>alkyl how to use</td><td>at the moment</td><td>I know</td>

<td>It refers to</td><td>groups</td><td>saturated hydrocarbon</td><td colspan="2">in a configuration</td>

straight, branched, or cyclic or any combination thereof, and particularly contemplated alkyl groups include those having ten or fewer carbon atoms, especially 1-6 carbon atoms and lower alkyl groups having 1-4 carbon atoms. Exemplary alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, seo-butyl, tertiary butyl, pentyl, isopentyl, hexyl, cyclopropyl, etc.

The alkyl groups can be unsubstituted, or they can be substituted to the extent that such substitution makes them chemically sensitive. Typical substituents include, but are not limited to, halo, = 0, = N-CN, = N-OR^to, = NR^to, -0R^to, -NR^to2, -SR^to, -SO2R^to, -SO2NR^to2, -NR^toSO2R^to, -NR^toC0NR^to2, NR^toCOOR^to, -NR^toC0R^to, -CN, -COOR^to, -CONR^to2, -OOCR^to, -COR^to, and -NO2, where each R^to is independently H, C1-C8 alkyl, C2-C8 heteroalkyl, C3-C8 heterocyclyl, C4-C10 heterocyclylalkyl, C1-C8 acyl, C2-C8 heteroacyl, C2-C8 alkenyl, C2-C8 alkynyl, C2-C8 alkynyl, heteroalkynyl C2-C8, C6-C10 aryl, or C5-C10 heteroaryl, and each R^to is optionally substituted with halo, = 0, = N-CN, = N0R^b, = NR^b, 0R^b, NR^b2, SR^bSO2R^bSO2NR^b2, NR^bSO2R^b, NR^bCONR^b2, NR^bC00R^b, NR^bCOR^b, CN, COOR^b, CONR^b2, OOCR^b, COR^b, and N02, where each R^b it is independently H, C1-C8 alkyl, C2-C8 heteroalkyl, C3-C8 heterocyclyl, C4-C10 heterocyclylalkyl, C1-C8 acyl, C2-C8 heteroacyl, C6-C10 aryl or C5-C10 heteroaryl. The alkyl, alkenyl, and alkynyl groups can also be substituted by C1-C8 acyl, C2-C8 heteroacyl, C6-C10 aryl, or C5-C10 heteroaryl, each of which can be substituted by substituents that are appropriate for the particular group. Where a substituent group contains two R groups^to or R^b on the same or adjacent atoms (eg, -NR^b2, or -NR^b-C (O) R^b), the two R groups^to or R^b they can optionally be taken together with the atoms in the substituent group to which they are attached to form a ring having 5-8 ring members, which can be substituted as allowed for R^to or R^b by itself, and may contain an additional heteroatom (N, 0, or S) as a ring member.

The term alkenyl as used herein refers to an alkyl as defined above having at least two carbon atoms and at least one carbon-carbon double bond. Thus, particularly contemplated alkenyl groups include straight, branched, or cyclic alkenyl groups having two to ten carbon atoms (eg, ethenyl, propenyl, butenyl, pentenyl, etc.) or 5-10 atoms for cyclic alkenyl groups. . Alkenyl groups are optionally substituted with groups suitable for alkyl groups as set forth herein.

Similarly, the term "alkynyl" as used herein refers to an alkyl or alkenyl as defined above and having at least two (preferably three) carbon atoms and at least one carbon-carbon triple bond. Especially contemplated alkynyls include straight, branched, or cyclic alkynes having two to ten total carbon atoms (eg, ethynyl, propynyl, butynyl, cyclopropylethyl, etc.). Alkynyl groups are optionally substituted with groups suitable for alkyl groups as set forth herein.

The term cycloalkyl as used herein refers to a cyclic alkane (ie, in which a chain of carbon atoms from a hydrocarbon forms a ring), preferably including three to eight carbon atoms. Thus, exemplary cycloalkanes include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Cycloalkyls also include one or two double bonds, which form the cycloalkenyl groups. Cycloalkyl groups are optionally substituted with groups suitable for alkyl groups as set forth herein.

The term aryl or aromatic moiety as used herein refers to an aromatic ring system, which may further include one or more non-carbon atoms. These are typically isolated 5-6 membered rings, or 8-10 membered bicyclic groups, and may be substituted. Thus, contemplated aryl groups include (eg, phenyl, naphthyl, etc.) and pyridyl. Additional contemplated aryl groups may be fused (i.e., covalently bonded to 2 atoms in the first aromatic ring) with one or two 5- or 6-membered heterocyclic or aryl groups, and are thus referred to as fused aryl or fused aromatic.

Aromatic groups contain one or more heteroatoms (typically N, 0, or S) as ring members can be referred to as heteroaryl or heteroaromatic groups. Typical heteroaromatic groups include monocyclic C5-C6 aromatic groups such as pyridyl, pyrimidyl, pyrazinyl, thienyl, furanyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, and imidazolyl and the fused bicyclic moieties formed by fusing one of these monocyclic groups. with a phenyl ring or with any of the heteroaromatic monocyclic groups to form a C8-C10 bicyclic group such as indolyl, benzimidazolyl, indazolyl, benzotriazolyl, isoquinolyl, quinolyl, benzothiazolyl, benzofuranyl, pyrazolopyridyl, pyrazolopyrimidyl, quinazolinyl, quinoxalinyl, cinolinyl, and the like. Any bicyclic monocyclic or fused ring system that has the characteristics of aromaticity in terms of electron distribution throughout the ring system is included in this definition. It also includes bicyclic groups where at least the ring which is directly attached to the rest of the molecule has the characteristics of aromaticity. Typically, ring systems contain 5-12 ring member atoms.

Also as used herein, the terms heterocycle, cycloheteroalkyl, and heterocyclic moieties are used interchangeably herein and refer to any compound in which a plurality of atoms forms a ring by means of a plurality of covalent bonds, wherein the ring includes at least one atom other than a carbon atom as a member in the ring. Particularly contemplated heterocyclic rings include 5- and 6-membered rings with nitrogen, sulfur, or oxygen as the non-carbon atom (eg, imidazole, pyrrole, triazole, dihydropyrimidine, indole, pyridine, tlazole, tetrazole etc.). These rings typically contain 0-1 oxygen or sulfur atoms, at least one and typically 2-3 carbon atoms, and up to four nitrogen atoms as ring members. Additional contemplated heterocycles may be fused (i.e. covalently bonded with two atoms in the first heterocyclic ring) to one or two carbocyclic rings or heterocycles, and are thus referred to as fused heterocycle or fused heterocyclic ring or portions

4 fused heterocyclics as used herein. Where the ring is aromatic, these may be referred to herein as 'heteroaryl' or heteroaromatic groups.

Non-aromatic heterocyclic groups may be substituted with groups suitable for alkyl group substituents, as set forth above.

The aryl and heteroaryl groups can be substituted where allowed. Suitable substituents include, but are not limited to, halo, -OR^to, -NR^to2, -SR^to, -SO2R^to, -SO2NR^to2, -NR^toSO2R^to, -NR^toCONR^to2, -NR^toCOOR^to, -NR^toCOR^to, -CN, -COOR^to, -CONR^to2, -OOCR^to, COR^to, and -NO2, where each R^to is independently H, C1-C8 alkyl, C2-C8 heteroalkyl, C3-C8 heterocyclyl, C4-C10 heterocyclylalkyl, C1-C8 acyl, C2-C8 heteroacyl, C2-C8 alkenyl, C2-C8 alkynyl, C2-C8 alkynyl, heteroalkynyl C2-C8, C6-C10 aryl, or C5-C10 heteroaryl, and each R^to is optionally substituted with halo, = 0, = N-CN, = N-OR^b, = NR^b, OR^b, NR^b2, SR^bSO2R^bSO2NR^b2, NR^bSO2R^b, NR^bCONR^b2, NR^bCOOR^b, NR^bCOR^b, CN, COOR^b, CONR^b2, OOCR^b, COR^b, and N02, where each R^b it is independently H, C1-C8 alkyl, C2-C8 heteroalkyl, C3-C8 heterocyclyl, C4-C10 heterocyclylalkyl, C1-C8 acyl, C2-C8 heteroacyl, C6-C10 aryl or C5-C10 heteroaryl. The alkyl, alkenyl, and alkynyl groups can also be substituted by C1-C8 acyl, C2-C8 heteroacyl, C6-C10 aryl, or C5-C10 heteroaryl, each of which can be substituted by substituents that are appropriate for the particular group. Where a substituent group contains two R groups^to or R^b on the same or adjacent atoms (eg, -NR^b2, or -NR^b-C (O) R^b), the two R groups^to or R^b they can optionally be taken together with the atoms in the substituent group to which they are attached to form a ring having 5-8 ring members, which can be substituted as allowed for R^to or R^b itself, and may contain an additional heteroatom (N, O, or S) as a ring member.

As also used herein, the terms imidazopyridine or imidazopyrimidine or thiazopyridine or thiazopyrimidine herein refer to any compound in which the two designated heterocyclic rings are fused by either of two adjacent atoms in the two heterocyclic rings.

The term alkoxy as used herein refers to a hydrocarbon group connected via an oxygen atom, for example, -O-Hc, where the hydrocarbon portion He can have any number of carbon atoms, typically 1- 10 carbon atoms may further include a double or triple bond and may include one or two oxygen, sulfur, or nitrogen atoms in the alkyl chains, and may be substituted with aryl, heteroaryl, cycloalkyl, and / or heterocyclyl groups. For example, suitable alkoxy groups include methoxy, ethoxy, propyloxy, isopropoxy, methoxyethoxy, benzyloxy, allyloxy, and the like. Similarly, the term "alkylthio" refers to alkylsulfides of the general formula-S-Hc, wherein the hydrocarbon portion He is as described for alkoxy groups. For example, contemplated alkylthio groups include methylthio, ethylthio, isopropylthio, methoxyethylthio, benzylthio, allylthio, and the like.

The term 'amino' as used herein refers to the group -NH₂. The term "alkylamino" refers to amino groups where one or both of the hydrogen atoms are replaced by a hydrocarbon group He as described above, where the amino nitrogen N can be replaced by one or two He groups as established by alkoxy groups described above. Exemplary alkylamino groups include methylamino, dimethylamino, ethylamino, diethylamino, etc. Also, the term "substituted amino" refers to amino groups where one or more hydrogen atoms are replaced by a hydrocarbon group He as described above, where the amino nitrogen N can be substituted by one or two He groups as established for alkoxy groups described above.

The term 'acyl' as used herein refers to a group of the formula —C (= 0) —D, where D represents an alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocycle as described above . Typical examples are groups where D is a C1-C10 alkyl, C2-C10 alkenyl or alkynyl, or phenyl, each of which is optionally substituted. In some embodiments, D can be H, Me, Et, isopropyl, propyl, butyl, C1-C4 alkyl substituted with -OH, -OMe, or NH2, phenyl, halophenyl, alkylphenyl, and the like.

The term "aryloxy" as used herein refers to an aryl group connected to an oxygen atom, wherein the aryl group can be further substituted. For example suitable aryloxy groups include phenyloxy, etc. Similarly, the term arylthio as used herein refers to an aryl group connected to a sulfur atom, where the aryl group can be further substituted. For example, suitable arylthio groups include phenylthio, etc.

The hydrocarbon portion of each alkoxy, alkylthio, alkylamino, and aryloxy, etc. It can be substituted as appropriate for the relevant hydrocarbon portion.

The term halogen as used herein refers to fluorine, chlorine, bromine, and iodine. Where it occurs as a substituent group, halogen or halo typically refers to F or C1 or Br, more typically F or C1.

The term haloalkyl refers to an alkyl group as described above, where one or more hydrogen atoms in the alkyl group have been replaced with a halo group. Examples of such groups include, without limitation, fluoroalkyl groups, such as fluoroethyl, trifluoromethyl, difluoromethyl, trifluoroethyl, and the like.

The term "haloalkoxy" refers to the alkyl-O- group wherein one or more hydrogen atoms in the alkyl group have been substituted with a halo group and include, by way of example, groups such as trifluoromethoxy, and the like.

The term sulfonyl refers to the group S0₂-alkyl, SO₂-substituted alkyl, S0₂-alkenyl, S0₂-substituted alkenyl, S0₂-cycloalkyl, S0₂-substituted cycloalkyl, S0₂-cycloalkenyl, S0₂-substituted cycloalkenyl, S0₂-aryl, S0₂-substituted aryl, S0₂-heteroaryl, S0₂-substituted heteroaryl, S0₂-heterocyclic and S0₂-substituted heterocyclic wherein each alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and heterocyclic are defined as being substituted. the present. Sulfonyl includes, by way of example, methyl-SO₂-, phenyl-SO₂-, and 4-methylphenyl-SO₂-.

The term sulfonylamino refers to the group

NR SO2R, where R and R are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic and where R²¹ and R²² optionally attached together with the atoms bonded thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, aryl substituted, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.

The term aminosulfonyl refers to the group SO₂NR R, where R and R are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, substituted heterocyclic and where R²¹ and R²² they are optionally linked together with the nitrogen attached thereto to form a heterocyclic or substituted heterocyclic group and alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl , substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.

The term acylamino refers to groups

NR²⁰C (O) alkyl, -NR²⁰C (O) substituted alkyl,

NR²⁰C (O) cycloalkyl, -NR²⁰C (O) substituted cycloalkyl, NR²⁰C (O) cycloalkenyl, -NR²⁰C (O) substituted cycloalkenyl, NR²⁰C (O) alkenyl, -NR²⁰C (O) substituted alkenyl,

NR²⁰C (O) alkynyl, -NR²⁰C (O) substituted alkynyl,

NR²⁰C (O) aryl, -NR²⁰C (O) substituted aryl, -NR²⁰C (O) heteroaryl, -NR²⁰C (0) substituted heteroaryl, -NR²⁰C (0) heterocyclic and substituted heterocyclic NR20C (O), where R²⁰ is hydrogen or alkyl and where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined at the moment.

The term alkoxycarbonylamino refers to the group

NRC (O) OR where each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, or heterocyclyl where alkyl, substituted alkyl, aryl, heteroaryl, and heterocyclyl are as defined herein.

The term aminocarbonylamino refers to the group NR²⁰C (O) NR²¹R²², where R²⁰ is hydrogen or alkyl and R²¹ and R²²they are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic and heterocyclic and where R²¹ and R²² optionally attached together with the nitrogen linked thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, aryl substituted, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.

It should further be recognized that all of the groups defined above can also be substituted with one or more substituents, which in turn can be substituted with hydroxy, amino, cyano, C 1 -C 4 -alkyl, halo, or haloC 1 -C 4 alkyl. For example, a hydrogen atom in an alkyl or aryl can be replaced by an amino, halo, or haloalkyl Cl4 or alkyl group.

The term "substituted" as used herein refers to a replacement of a hydrogen atom from the unsubstituted group with a functional group, and particularly contemplated functional groups include nucleophilic groups (eg, -NH₂, -OH, -SH, -CN, etc.), electrophilic groups (for example, C (O) OR, C (X) OH, etc.), polar groups (for example, -OH), nonpolar groups ( eg, heterocycle, aryl, alkyl, alkenyl, alkynyl, etc.), ionic groups (eg, -NH₃⁺), and halogens (eg -F, -Cl), NHCOR, NHCONH₂, OCH2COOH, OCH2CONH2, OCH2CONHR, NHCH2COOH, NHCH2CONH2, NHSO2R, OCH₂-heterocycles, PO₃H, 'SO₃H, amino acids, and all chemically reasonable combinations thereof. On the other hand, the term substituted also includes multiple degrees of substitution, and where multiple substituents are described or claimed, the substituted compound may be independently substituted by one or more of the described or claimed substituent portions.

In addition to the description herein, in a certain embodiment, a group that is substituted has 1, 2, 3, or 4 substituents, 1, 2, or 3 substituents, 1 or 2 substituents, or 1 substituent.

It is understood that in all of the substituted groups defined above, the compounds came by defining the substituents with additional substituents for themselves (eg, substituted aryl having an aryl group substituted as a substituent which is itself substituted with an aryl group substituted, which is further substituted by a substituted aryl group, etc.) are not intended for inclusion herein. In such cases, the maximum number of such substitutions is three. For example, the serial substitutions of specifically substituted aryl groups contemplated herein are limited to substituted aryl- (substituted aryl) -substituted aryl.

Unless otherwise indicated, the nomenclature of substituents not explicitly defined herein is referred to as the terminal portion of the functionality followed by the functionality adjacent to the point of attachment. For example, the substituent arylalkyloxycarbonyl refers to the group (aryl) (alkyl) -OC (O) -.

As for any of the groups described herein that contain one or more substituents, it is understood, of course, that such groups do not contain any substitutions or substitution patterns which are spherically impractical and / or synthetically infeasible. Furthermore, the compounds in question include all stereochemical isomers arising from the substitution of these compounds.

The term "pharmaceutically acceptable salt" means a salt which is acceptable for administration to a patient, such as a mammal, such as human (salts with counterions that have acceptable mammalian safety for a given dosage regimen). Such salts can be derived from pharmaceutically acceptable organic or inorganic bases and from pharmaceutically acceptable organic or inorganic acids. Pharmaceutically Acceptable Salt refers to pharmaceutically acceptable salts of a compound, the salts of which are derived from a variety of organic and inorganic counterions well known in the art and include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium , and the like; and when the molecule contains basic functionality, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, formate, tartrate, besilate, mesylate, acetate, maleate, oxalate, and the like.

The term salt thereof means a compound formed when a proton of an acid is replaced by a cation, such as a metal cation or an organic cation and the like. Where applicable, the salt is a pharmaceutically acceptable salt, although it is not required for salts of intermediates that are not intended for administration to a patient. Ά by way of example, the salts of the present compounds include those where the compound is protonated by organic or inorganic acid to form a cation, with the conjugate base of the organic or inorganic acid as the anionic component of the salt.

The compounds and compositions described herein can be administered to a subject in need of treatment for a cell proliferation disorder such as cancer, particularly selected cancers of leukemia, lymphoma, lung cancer, colon cancer, CNS cancer, melanoma, cancer of ovaries, kidney cancer, prostate cancer, breast cancer, head and neck cancers, and pancreatic cancer. The subject is typically a mammal diagnosed as being in need of treatment for one or more of such proliferative disorders, and frequently the subject is a human. The methods comprise administering an effective amount of at least one compound of the invention; optionally the compound can be administered in combination with one or more additional therapeutic agents, particularly therapeutic agents known to be useful for treating cancer or proliferative disorder suffering from the particular subject.

Exemplary compounds

Formula i

In one aspect, the present disclosure provides a compound of Formula (I):

R1

<img file="MX368491B_D0007.tif" />

where

R¹ is H, or

NR^cR^d where R^c is H, Ci-4-alkyl or 3-7-membered cyclic ring, and R^d is H, Ci-4 alkyl, optionally substituted with OZ, where Z is H or Ci- alkyl₄; or 3-7 membered cyclic ring substituted with R^to where R^to is Ci_alkyl₈ optionally substituted with halo;

R² is H, halo, C1-4alkyl, or alkoxyCiR³ is H, halo, alkyl Ci_₄, or alkoxyCi_

R⁵ is H, halo, Ci- alkyl₄, or alkoxyCi_

R⁶ is H, halo, alkyl Ci_₄, or C-alkoxy₄; or

R¹ and R⁵ are part of the 3-7 membered cyclic ring, optionally substituted with Ci_alkyl₄ substituted with OZ, where Z is H or Ci_alkyl₄; or

R¹ and R² they are part of the 3-7 membered cyclic ring, optionally substituted with Ci-alkyl₄ substituted with OZ, where Z is H or Ci- alkyl₄; or

R² and R⁶ they are part of the 3-7 membered cyclic ring, optionally substituted with Ci-alkyl₄ substituted with OZ, where Z is H or Ci- alkyl₄; or

R⁴ is alkenyl C₂ optionally substituted with Ci-4 alkyl, -CH₂OCH₃, or -ch₂n (ch₃)₂; and

X is O, alkyl Ci-₄ optionally substituted with halo, or NR^b, where R^b is H, or alkyl Ci_₈ optionally substituted with halo,

Y is CH optionally substituted with halo, or N, where at least one of R², R³, R⁵ and R⁶ it is not H;

or a pharmaceutically acceptable salt thereof.

In some modalities, R¹ is H, and R² and R⁶ they are part of the 3-7 membered cyclic ring, optionally substituted with OZ, where Z is H or Ci_alkyl₄eg methyl. The 3-7 membered cyclic ring can be a 3, 4, 5, 6, or 7 membered cyclic ring. It can be a carbon ring or hetero ring.

In some modalities, R¹ is NR^cR^d and R^c it is methyl. In other modalities, R¹ is NR^cR^d and R^c it is a 3-7 membered cyclic ring. The 3-7 membered cyclic ring can be a 3, 4, 5, 6, or 7 membered cyclic ring. It can be a carbon ring or a hetero ring. For example, the 3-7 membered cyclic ring may be a C cyclic ring₃. R^d it can be C2-alkyl substituted with OZ, and Z is H or C1-4-alkyl, for example methyl.

In some modalities, R¹ is 3-7 membered cyclic ring substituted with R^to. The 3-7 membered cyclic ring can be a 3, 4, 5, 6, or 7 membered cyclic ring. It can be a carbon ring or a hetero ring.

For example

R¹ can be

<img file="MX368491B_D0008.tif" />

<img file="MX368491B_D0009.tif" />

In some modalities

<img file="MX368491B_D0010.tif" />

R^to may be C1-4alkyl optionally substituted with halo or Ci_alkoxy₄.

For example, R^to it can be fluorine-substituted C1-4alkyl or fluorine-substituted C1-8alkyl. In other modalities, R¹ is

R^to'N

<img file="MX368491B_D0011.tif" />

H N.

R^to it can be C1-4alkyl optionally substituted with halo or C1-4alkoxy. For example,

R^to it can be fluorine-substituted C1-4alkyl or fluorine-substituted C1-8alkyl.

In some modalities, R² can be H. In other modalities, R² it can be halo, for example fluorine. Still in other modalities, R² can be alkyl Ci-₄, for example, methyl, or Ci- alkoxy₄eg methoxy.

In some modalities, R⁵ can be H. In other modalities, R⁵ it can be halo, for example fluorine. Still in other modalities, R⁵ can be alkyl Ci-₄, for example, methyl, or Ci_alkoxy₄eg methoxy.

In some modalities, R⁶ can be H. In other modalities, R⁶ it can be halo, for example fluorine. Still in other modalities, R⁶ can be alkyl Ci_₄, for example, methyl, or Ci- alkoxy₄eg methoxy.

In some modalities, R¹ and R⁵ they may be part of the 3-7 membered cyclic ring, optionally substituted with Ci-4 alkyl substituted with OZ, wherein Z is H or Ci-4 alkyl, eg methyl. In other modalities, R¹ and R² they may be part of the 3-7 membered cyclic ring, optionally substituted with Ci-4 alkyl substituted with OZ, where Z is H or C-alkyl₄eg methyl. Still in other modalities, R² and R⁶ they can be part of the 37-membered cyclic ring, optionally substituted with alkyl Ci-₄substituted with OZ, where Z is H or Ci_alkyl₄eg methyl. The 3-7 membered cyclic ring can be a 3, 4, 5, 6, or 7 membered cyclic ring. It can be a carbon ring or a hetero ring. For example, the 3-7 membered cyclic ring may be a 5 membered cyclic ring. The 5-membered cyclic ring can be a heterocyclic ring, for example, a 5-membered heterocyclic ring comprising an N atom. C1-4alkyl can be Ci, C-alkyl₂, C₃, or C₄. For example, Z can be methyl.

In some modalities, R⁰ can be H. In other modalities, R³ it can be halo, for example fluorine. Still in other modalities, R³ it may be C1-4alkyl, for example, methyl, or C1-4alkoxy, for example, methoxy.

In some modalities, R², R⁵, or R⁶ is H or halo and R³ it is halo, C1-4alkyl, for example methyl, or C1-4alkoxy.

In some modalities, R⁴ it may be unsubstituted C2 alkenyl. In other modalities, R⁴ may be C2-alkenyl substituted with C1-4-alkyl, -CH₂OCH₃, or -CH₂N (CH₃)₂.

In some embodiments, X may be O. In other embodiments, X may be C1-4alkyl optionally substituted with halo. For example, X can be unsubstituted C1-4alkyl, eg CH₂. In another example, X may be halo substituted C1-4alkyl, eg CF₂. In still other modalities, X can be NR^b, and R^b it can be H, or C1-8 alkyl optionally substituted with halo. For example, R^b can be H. In another example, R^b can be Ci_8 alkyl. In yet another example, R^b is C1-4alkyl, for example, Ci, C2, C alkyl₃, or C₄. C1-4alkyl or Ci_alkyl₈ it can be substituted with halo, for example fluorine.

In some embodiments, Y can be CH. In other modalities, Y can be CE or N.

In some embodiments the present disclosure provides a compound selected from the group consisting of the

12, compound 1-1, 1-2, 1-3, 1-4, 1-5

1-13, 1-14, 1-15, 1-16

1-23, 1-24, 1-25 and 1-41

22,

<img file="MX368491B_D0012.tif" />

<img file="MX368491B_D0013.tif" />

<img file="MX368491B_D0014.tif" />

1-6, 1-7,

1-8, 1-9, I1-17, 1-18, 1-19, 1-20, 1-21, which has the following Formula.

<img file="MX368491B_D0015.tif" />

<img file="MX368491B_D0016.tif" />

<img file="MX368491B_D0017.tif" />

<img file="MX368491B_D0018.tif" />

<img file="MX368491B_D0019.tif" />

<img file="MX368491B_D0020.tif" />

<img file="MX368491B_D0021.tif" />

<img file="MX368491B_D0022.tif" />

ΗΝ

<img file="MX368491B_D0023.tif" />

<img file="MX368491B_D0024.tif" />

<img file="MX368491B_D0025.tif" />

<img file="MX368491B_D0026.tif" />

<img file="MX368491B_D0027.tif" />

<img file="MX368491B_D0028.tif" />

<img file="MX368491B_D0029.tif" />

1-21 (X = O, NH, CH2, CF2; Y = CH, CF, N; R³= OCH3, F)

<img file="MX368491B_D0030.tif" />

1-22 (X = O, NH, CH2, CF2; Y = CH, CF, N; R³= OCH3, F)

<img file="MX368491B_D0031.tif" />

<img file="MX368491B_D0032.tif" />

<img file="MX368491B_D0033.tif" />

1-25 (X = O, NH, CH2, CF2; R³= OCH3, F)

Formula ii

In another respect, the compound of

1-24 (X = O, NH, CH2, CF2; R³= OCH3, F)

<img file="MX368491B_D0034.tif" />

1-41 (X = O, NH, CH2, CF2; Y = CH, CF, N; R³= OCH3, F) present description provides a Formula (II):

HN

<img file="MX368491B_D0035.tif" />

R₄

<img file="MX368491B_D0036.tif" />

<img file="MX368491B_D0037.tif" />

<img file="MX368491B_D0038.tif" />

(Π) where

R¹ is H, or

NR^cR^d where R^c is H, alkyl Ci_₄ or cyclic ring of

3-7 members, and R^d is H, alkyl Ci_₄, optionally substituted with OZ, where Z is H or Ci_alkyl₄; or

NR^andR^F where R^and is Ci_4 alkyl, and R^F it is 3-7 membered cyclic ring optionally substituted with Ci_4 alkyl optionally substituted with halo; or

0R^g where R^g is alkyl Ci-₄ replaced with CH₃OR-,

CH₃CH₂O-, CH₃(OR) ₂scf₃or-,

<img file="MX368491B_D0039.tif" />

R² is H, halo,

R³ is H, halo,

R⁵ is H, halo,

R⁶ is H, halo, alkyl Ci_₄, alkyl Ci_₄, alkyl Ci-₄, alkyl Ci_₄, or Ci_alkoxy₄;

or alkoxy Ci_₄;

or C-alkoxy₄;

or alkoxy Ci_₄; or

R¹ and R⁵ are part of the 3-7 membered cyclic ring, optionally substituted with Ci_alkyl₄ substituted with OZ, where Z is H or Ci_alkyl₄; or

R and R are part of the 3-7 membered cyclic ring, optionally substituted with C1-4 alkyl substituted with OZ, where Z is H or Ci_alkyl₄; or

R and R are part of the 3-7 membered cyclic ring, optionally substituted with Ci- alkyl₄ substituted with OZ, where Z is H or Ci- alkyl₄; or

R⁴ is alkenyl C₂ optionally substituted with alkyl

C1-4, -CH₂OCH₃, or -CH₂N (CH₃)₂; and

X is O, alkyl Ci_₄ optionally substituted with halo, or NR^b, where R^b is H, or Ci-e alkyl optionally substituted with halo,

Y is CH optionally substituted with halo, or N, or a pharmaceutically acceptable salt thereof.

In some modalities, R¹ can be H, and R² and R⁶ may be part of 3-7 membered cyclic ring, optionally substituted with Ci_alkyl₄ substituted with OZ, where Z is H or Ci- alkyl₄eg methyl. The 3-7 membered cyclic ring can be a 3, 4, 5, 6, or 7 membered cyclic ring. It can be a carbon ring or a hetero ring.

In some modalities, R¹ can be NR^cR^d and R^c it may be CX-4 alkyl, for example methyl. In other modalities, R¹can be NR^cR^d and R^c It can be a 3-7 membered cyclic ring. The 3-7 membered cyclic ring can be a 3, 4, 5, 6, or 7 membered cyclic ring. It can be a carbon ring or a hetero ring. For example, the 3-7 membered cyclic ring may be C3 cyclic ring. R^d can be C2-alkyl substituted with OZ, and Z can be C-alkyl₄eg methyl.

In some modalities, R¹ can be NR^andR^F, R^and can be Ci-4 alkyl, and R^F may be optionally 3-7 membered cyclic ring substituted with Cx-alkyl₄ optionally

7 replaced with halo. The 3-7 membered cyclic ring can be a 3, 4, 5, 6, or 7 membered cyclic ring. It can be a carbon ring or a hetero ring. For example, the 3-7 membered cyclic ring may be a 5 membered cyclic ring. In another example, the 5-membered cyclic ring may be a heterocyclic ring, eg, the 5-membered heterocyclic ring comprising an N atom. The 3-7 membered cyclic ring may be substituted with FCH2CH2-. The alkyl Ci_₄ can be alkyl Ci, C₂, C₃, or C₄.

In some modalities, R¹ is OR⁹ and R⁹ is alkyl Ci-₄

---- Ο_χ replaced with CH₃O-, CH₃CH₂O-, CH₃(OR) ₂S-, CF₃O-, o. The alkyl Ci_₄ can be alkyl Ci, C₂,

C₃, or C₄, for example, alkyl C₂.

In some modalities, R² can be H. In other modalities, R² it can be halo, for example fluorine. Still in other modalities, R² can be alkyl C₄-₄, for example, methyl, or Ci- alkoxy₄eg methoxy.

In some modalities, R⁵ can be H. In other modalities, R⁵ it can be halo, for example fluorine. Still in other modalities, R⁵ can be alkyl Ci-₄, for example, methyl, or Ci_alkoxy₄eg methoxy.

In some modalities, R⁶ it can be H. In other ζ:

modalities, R may be halo, eg fluorine. Still in other modalities, R⁶ can be alkyl Ci_₄, for example, methyl, or Ci_alkoxy₄eg methoxy.

In some modalities, R¹ and R⁵ they may be part of the 3-7 membered cyclic ring, optionally substituted with Ci-4 alkyl substituted with OZ, wherein Z is H or Ci-4 alkyl, eg methyl. In other modalities, R¹ and R² they may be part of the 3-7 membered cyclic ring, optionally substituted with Ci_4 alkyl substituted with OZ, where Z is H or Ci- alkyl₄eg methyl. Still in other modalities, R² and R⁶ they can be part of the 37-membered cyclic ring, optionally substituted with alkyl Ci-₄substituted with OZ, where Z is H or Ci- alkyl₄eg methyl. The 3-7 membered cyclic ring can be a 3, 4, 5, 6, or 7 membered cyclic ring. It can be a carbon ring or a hetero ring. For example, the 3-7 membered cyclic ring may be a 5 membered cyclic ring. The 5-membered cyclic ring may be a heterocyclic ring, for example, a 5-membered heterocyclic ring comprising an N atom.₄ can be alkyl Ci, C₂, C₃, or C₄. For example, Z can be methyl.

In some modalities, R³ can be H. In other modalities, R³ it can be halo, for example fluorine. Still in other modalities, R³ can be alkyl Ci_₄, for example, methyl, or Ci- alkoxy₄eg methoxy.

In some modalities, R², R⁵, or R⁶ is H or halo and R³ is halo, alkyl Ci_₄, for example, methyl, or Ci_alkoxy₄.

In some modalities, R⁴ it may be unsubstituted C2 alkenyl. In other modalities, R⁴ can be C2 alkenyl substituted with Ci_alkyl₄, -CH₂OCH₃, or -CH₂N (CH₃)₂.

In some embodiments, X may be O. In other embodiments, X may be alkyl Ci_₄ optionally substituted with halo. For example, X can be alkyl Ci_₄ unsubstituted, eg CH₂. In another example, X can be Ci- alkyl.₄substituted with halo, for example CF₂. In still other modalities, X can be NR^b, and R^b it can be H, or Ci_8 alkyl optionally substituted with halo. For example, R^b can be H. In another example, R^b can be Ci_8 alkyl. In yet another example, R^b is alkyl Ci-₄, for example, alkyl Ci, C₂, C₃, or C₄. The alkyl Ci_₄ or alkyl Ci_₈ it can be substituted with halo, for example fluorine.

In some embodiments, Y can be CH. In other modalities, Y can be CF or N.

In some modalities, R¹ is 0R^g where R^g is Ci-4 alkyl substituted with CH₃O-, CH₃CH₂O-, CH₃(OR) ₂S-, CF₃O-, and R², R³, R⁵ and R⁶ are H. In one example, R^g can be alkyl

In some modalities, R⁶ not H. For example, one, R², R³, R⁵ and -R⁶ is or are not H.

C2 replaced with CH₃OR-.

at least one of R¹, R², R³, R⁵ and two, three, four or five of R¹,

In some embodiments, the present disclosure provides a compound selected from the group consisting of compound 1-10, 1-11, 1-26, 1-27, 1-28, 1-29, 1-30, 1-31, 1 -32, 1-33, 1-34, 1-35, 1-36, 1-37, 1-38, 1-39, and 1-40 having the following Formula.

<img file="MX368491B_D0040.tif" />

1-10

<img file="MX368491B_D0041.tif" />

<img file="MX368491B_D0042.tif" />

<img file="MX368491B_D0043.tif" />

1-26 (X = O, NH, CH2, CF2; Y = CH, CF, N)

1-27 (X = O, NH, CH2, CF2; Y = CH, CF, N)

<img file="MX368491B_D0044.tif" />

1-28 (X = O, NH, CH2, CF2)

1-29 (X = O, NH, CH2, CF2)

<img file="MX368491B_D0045.tif" />

1-38

1-39

<img file="MX368491B_D0046.tif" />

1-40 (Y = CH, CF, N)

Formula III

In another aspect, the present description provides a compound of Formula (III):

<img file="MX368491B_D0047.tif" />

where ^r'n

R¹ is where R^to is CO-C1-4alkyl-CONH (alkyl

C1-4-O) m-alkyl

C1-4-NH- (Detect Tag), m being an integer 1-4;

R² is

H, halo, alkyl

C1-4, or Ci- alkoxy₄;

R³ is

H, halo, alkyl

C1-4, or C1-4 alkoxy;

R⁵ is H, halo, Ci- alkyl₄, or C-alkoxy₄;

R⁶ is H, halo, alkyl Ci_₄, or C-alkoxy₄; or

R¹ and R⁵ they are part of the 3-7 membered cyclic ring, optionally substituted with Ci-alkyl₄ substituted with OZ, where Z is H or Ci_alkyl₄; or

R¹ and R² they are part of the 3-7 membered cyclic ring, optionally substituted with Ci-alkyl₄ substituted with OZ, where Z is H or Ci- alkyl₄; or

R² and R⁶ they are part of the 3-7 membered cyclic ring, optionally substituted with Ci-alkyl₄ substituted with OZ, where Z is H or Ci_alkyl₄; or

R⁴ is alkenyl C₂ optionally substituted with alkyl Ci-₄, -CH2OCH3, or -CH₂N (CH₃)₂; and

X is O, alkyl Ci_₄ optionally substituted with halo, or NR^b, where R^b is H, or alkyl Ci_₈ optionally substituted with halo,

Y is CH optionally substituted with halo, or N, or a pharmaceutically acceptable salt thereof.

In some modalities, in R^to alkyl Ci_₄ can be alkyl C_x, C₂, C3, or C₄.

In some modes, m can be 1, 2, 3, or 4.

Any suitable Detect Tag can be used. In some embodiments, the Detect tag is diotin.

In some modalities, R² can be H. In other modalities, R² it can be halo, for example fluorine. Still in other modalities, R² can be alkyl Ci_₄, for example, methyl, or Ci_alkoxy₄eg methoxy.

In some modalities, R⁵ can be H. In other modalities, R⁵ it can be halo, for example fluorine. Still in other modalities, R⁵ can be alkyl Ci_₄, for example, methyl, or C-alkoxy_x_₄eg methoxy.

In some modalities, R⁶ can be H. In other modalities, R⁶ it can be halo, for example fluorine. Still in other modalities, R⁶ can be alkyl Ci_₄, for example, methyl, or Ci_alkoxy₄eg methoxy.

In some modalities, R¹ and R⁵ they may be part of the 3-7 membered cyclic ring, optionally substituted with Ci-4 alkyl substituted with OZ, wherein Z is H or Ci-4 alkyl, eg methyl. In other modalities, R¹ and R² they may be part of the 3-7 membered cyclic ring, optionally substituted with Ci-4 alkyl substituted with OZ, where Z is H or Ci_alkyl₄eg methyl. Still in other modalities, R² and R⁶ they can be part of the 37-membered cyclic ring, optionally substituted with alkyl Ci-₄substituted with OZ, where Z is H or Ci_alkyl₄eg methyl. The 3-7 membered cyclic ring can be a 3, 4, 5, 6, or 7 membered cyclic ring. It can be a carbon ring or a hetero ring. For example, the 3-7 membered cyclic ring may be a 5 membered cyclic ring. The 5-membered cyclic ring may be a heterocyclic ring, for example, a 5-membered heterocyclic ring comprising an N atom. Ci_alkyl₄ can be alkyl C_x, C₂, C₃, or C₄. For example, Z can be methyl.

In some modalities, R³ can be H. In other modalities, R³ it can be halo, for example fluorine. Still in other modalities, R³ can be alkyl C_x_₄, for example, methyl, or Ci_alkoxy₄eg methoxy.

In some modalities, R², R⁵, or R⁶ is H or halo and R³ is halo, alkyl Ci-₄, for example, methyl, or Ci_alkoxy₄.

In some modalities, R⁴ it may be unsubstituted C2 alkenyl. In other modalities, R⁴ can be C2 alkenyl substituted with Ci_alkyl₄, -CH₂OCH₃, or -CH₂N (CH₃)₂.

In some modes, X can be 0. In other ways, X can be alkyl Ci_₄ optionally substituted with halo. For example, X can be alkyl Ci-₄ unsubstituted, eg CH₂. In another example, X can be C alkyl._x_₄substituted with halo, for example CF₂. In still other modalities, X can be NR^b, and R^b it can be H, or Ci_8 alkyl optionally substituted with halo. For example, R^b can be H. In another example, R^b it can be Ci-8 alkyl. In yet another example, R^b is Ci_alkyl₄, for example, alkyl Ci, C₂, C₃, or

C₄. The alkyl Ci_₄ or alkyl Ci_₈ it can be substituted with halo, for example fluorine.

In some embodiments, Y can be CH. In other modalities, Y can be CE or N.

In some embodiments, the present disclosure provides a compound 1-42 having the following Formula.

<img file="MX368491B_D0048.tif" />

Formula la

In yet another aspect, the present disclosure provides a compound of Formula (la):

<img file="MX368491B_D0049.tif" />

(the) where

R¹ is H, or

NR^cR^d where

R^c is H, alkyl Ci-₄, alkenyl Ci-₄, or cyclic ring of

3-7 members, the alkyl Ci_₄, alkenyl Ci-₄, or 3-7 membered cyclic ring being optionally substituted with OZ or NR11R12, where Z, R_llz R₁₂ are independently H or Ci- alkyl₄, or the 3-7 membered cyclic ring being optionally substituted with Ci_alkyl₄ which is also optionally substituted with OZ or NRnRi₂, where Z, Rn, R_i2 are independently H or alkyl Ci_₄, or the 37-membered cyclic ring being optionally substituted with SO₂(CH₂)_whatH, where q is 1-4, or the 3-7 membered cyclic ring being optionally substituted with Ci- alkyl₄ which is also optionally substituted with SO₂(CH₂) qH, where q is 1-4, or the 3-7 membered cyclic ring being optionally substituted with RgCO, where R₈ is Ci_alkyl₄, and

R^d is H, alkyl Ci_₄, alkenyl Ci_₄, or 3-7 membered cyclic ring, the Ci_alkyl₄, alkenyl Ci-₄ or 3-7 membered cyclic ring being optionally substituted with OZ or NR11R12, where Z, R_n, R₁₂ are independently H or alkyl Ci_₄; or 3-7 membered cyclic ring substituted with R^to where R^to is Ci-8 alkyl optionally substituted with halo,

<td>C1-4 alkoxy 0 SO₂(CH₂)_whatH</td><td>in</td><td>where</td><td>q is 1-4</td><td> ; 0</td>

<td>O (CH₂)_mSW₂ (CH₂)_nH</td><td>in</td><td>where</td><td>m is 1-4</td><td>and n is 1-4;</td>

<td> 2 _zR is absent,</td><td>H</td><td>halo,</td><td>I rent</td><td>Ci_₄, alkoxy Ci-₄, 0</td>

alkylamine (NRhRi₂), where Rn and R_i2 are independently H or Ci- alkyl₄;

R³ is H, hydroxyl, halo, Ci_alkyl₄, alkoxy Ci_₄, or alkylamine (NRnR₁₂), where Rn and R₁₂ are independently H or alkyl Ci_₄;

R⁵ is absent, H, halo, Ci_alkyl₄, alkoxy Ci_₄, or alkylamine (NRnR₁₂), where Rn and R_i2 are independently H or Ci- alkyl₄;

R⁶ is H, halo, alkyl Ci_₄, alkoxy Ci_₄; or alkylamine (NR11R12) &lt;where Rn and R₁₂ are independently H or alkyl

Ci_₄;

R⁷ is H, halo, alkyl Ci_₄, alkoxy Ci_₄, or alkylamine (NR11R12), where Rn and R₁₂ are independently H or Ci- alkyl₄;

R⁹ is H, hydroxyl, halo, Ci_alkyl₄, alkoxy Ci_₄, or alkylamine (NRnRi₂), where Rn and R₁₂ are independently H or alkyl Ci_₄;

R¹⁰ is H, hydroxyl, halo, Ci_alkyl₄, alkoxy Ci_₄, or alkylamine (NRnR₁₂), where Rn and Ri₂ are independently H or alkyl Ci_₄; or

R¹ and R⁵ are part of the 3-7 membered cyclic ring, the 3-7 membered cyclic being optionally substituted with Ci-alkyl₄ optionally substituted with OZ or NR_orRi2 where Z, Rn and R12 are independently H or Ci_alkyl₄, or the 3-7 membered cyclic being optionally substituted with R₈CO, where Rg is alkyl Ci-₄, or the 3-7 membered cyclic being optionally substituted with SO₂(CH₂) qH, where q is 1-4; or

R and R are part of the 3-7 membered cyclic ring, optionally substituted with Ci_alkyl₄, the alkyl Ci_₄further optionally substituted with halo, OZ, or NRnR₁₂ where Z, Rn and R₁₂ are independently H or alkyl Ci_₄, or one or more members of the 3-7 membered cyclic ring is optionally part of a carbonyl group or a sulfonyl group; or

R² and R⁶ are part of the 3-7 membered cyclic ring, optionally substituted with C1-4 alkyl optionally substituted with OZ or NRnR₁₂ where Z, R_X1 and R₁₂ are independently H or alkyl Ci_₄;

R⁴ is alkenyl C₂ optionally substituted with C1.4 alkyl, -CH₂OCH₃, or -CH₂N (CH₃)₂;

X is O, C1-4 alkyl optionally substituted by halo, or NR^b, where R^b is H, or alkyl Ci_₈ optionally substituted with halo;

Y is C, CH optionally substituted with halo, or N;

A is C, CH optionally substituted with halo or N; and where at least one of R², R³, R⁵ and R⁶ it is not H;

or a pharmaceutically acceptable salt thereof.

In some modalities, R¹ is H, and R² and R⁶ they are part of the 3-7 membered cyclic ring, optionally substituted with C1-4 alkyl substituted with OZ or NRnR ^ where Z, R_n and R_i2they are independently H or C1-4 alkyl.

In some modalities, R¹ is NR^cR^d and R^c it's H.

In some modalities, R¹ is NR^cR^d and R^c is alkyl Ci-₄, eg methyl, optionally substituted with OZ or NR11R12, where Z, Rn, R₁₂ they are independently H or alkyl 01-4.

In some modalities, R¹ is NR^cR^d and R^c is alkenyl Ci₄, optionally substituted with OZ or NRnRi₂, where Z, Rn,

R12 are independently H or Ci- alkyl₄.

In some modalities, R¹ is NR^cR^d and R^c is 3-7 membered cyclic ring, optionally substituted with OZ or NRnRi2 &lt;where Z, Rn, R_X2 they are independently H or Cl-4 alkyl.

In some modalities, R¹ is NR^cR^d and R^c is 3-7 membered cyclic ring being optionally substituted with Ci-alkyl₄ which is also optionally substituted with OZ or NR11R12, where Z, Rn, R₁₂ are independently H or Ci- alkyl₄.

In some modalities, R¹ is NR^cR^d and R^c it is 3-7 membered cyclic ring being optionally substituted with SO₂(CH₂)_whatH, where q is 1-4.

In some embodiments, the 3-7 membered cyclic ring is a 5 membered cyclic ring comprising an N atom, the H linked to the N atom is substituted with SO₂(CH₂) qH, where q is 1-4, for example, q is 1.

In some modalities, R¹ is NR^cR^d and R^c is 3-7 membered cyclic ring being optionally substituted with Ci-alkyl₄ which is also optionally substituted with SO₂(CH₂)_whatH, where q is 1-4. The 3-7 membered cyclic ring may be a 5 membered cyclic ring comprising an N atom, the H linked to the N atom is substituted with Ci_alkyl₄ which is also replaced with SO₂(CH₂)_whatH, where q is 1-4. The H linked to the N atom is substituted with alkyl C₂ which is also replaced with SO2CH3.

In some modalities, R¹ is NR^cR^d and R^c it is 3-7 membered cyclic ring being optionally substituted with R8CO, where R8 is Cj-4 alkyl. R¹ can be NR^cR^d and R^c is a 5-membered cyclic ring comprising an N atom, the H linked to the N atom is substituted with R8CO, where R₈ is Ci_alkyl₄. The H linked to the N atom can be substituted with CH3CO.

In some modalities, R^d is H. In other modalities, R^dit is Ci_4alkyl, optionally substituted with OZ or NRnR12, where Z, Rn, R12 are independently H or Ci_4alkyl. Still in other modalities, R^d is C1-4 alkenyl, optionally substituted with OZ or NRnR12, where Z, R_or, R₁₂they are independently H or C1-4 alkyl. Still in other modalities, R^d is 3-7 membered cyclic ring, optionally substituted with OZ or NR_nRi₂, where Z, Rn, R₁₂they are independently H or C1-4 alkyl.

In some modalities, R^c is a 5-membered cyclic ring comprising an N atom, the H linked to the N atom is substituted with Ci-4 alkyl which is further substituted with OZ, where Z is independently Οχ-4 alkyl, and R^d it is 3-7 membered cyclic ring, eg C3 cyclic ring.

In some modalities, R¹ is 3-7 membered cyclic ring substituted with R^to where R^to is Ci_alkyl₈optionally substituted with halo, Ci_alkoxy₄ bear₂(CH₂)_whatH, where q is 1-4. The 3-7 membered cyclic ring may comprise an N atom. The H attached to the N atom may be substituted with halo, C-alkoxy.₄ bear₂(CH₂)_whatH, where q is 14.

R¹ it can be any suitable 3-7 membered cyclic ring. In some modalities, R¹ is selected from the group consisting of

<img file="MX368491B_D0050.tif" />

substituted with halo, alkoxy Ci_₄ bear₂(CH₂)_whatH, where q is 14, and R^b is H or alkyl Ci_₈ optionally substituted with halo, Ci- alkoxy₄ bear₂(CH₂)_whatH, where q is 1-4. In other modalities, R¹ is selected from the group consisting of

Ra

Rb

Rb

<img file="MX368491B_D0051.tif" />

Rb

Rb

Ra

N

Ra

Still in other modalities, R¹ is

<img file="MX368491B_D0052.tif" />

and R^to C2-alkyl is further substituted by methoxy. Still in other modalities, R¹ is and R^to is alkyl C₂ also replaced with SO2CH3.

In some modalities, R¹ is O (CH2) mSO2 (CH2) nH, where m is 1-4 and n is 1-4. For example, R¹ can be O (CH2) 2SO2CH3.

In some modalities, R² is absent, H or halo. In other modalities, R² it is Ci_4alkyl or Ci_4alkoxy. Still in other modalities, R² it is alkylamine (NR11R12), and R11 and R12 are independently H or Ci_4 alkyl.

In some modalities, R³ is H. In other modalities, R³it is hydroxyl. Still in other modalities, R³ is halo, alkyl Ci_₄, alkoxy Ci_₄, or alkylamine (NR11R12), wherein Rn and R12 are independently H or Ci- alkyl₄.

Still in other modalities, R¹ is ^r'n, and R^to is Ci-8 alkyl optionally substituted with halo, Ci_alkoxy₄ or

SW₂(CH₂)_whatH, where q is 14.

In some modalities, R⁵ is absent or H. In other modalities, R⁵ it's halo. Still in other modalities, R⁵ is Ci_4 alkyl. Still in other modalities, R⁵ is Ci_4 alkoxy. Still in other modalities, R⁵ is alkylamine (NR11R12), where Rn and R12 are independently H or Ci_alkyl₄.

In some modalities, R⁶ is H. In other modalities, R⁶it's halo. Still in other modalities, R⁶ it is Ci-4 alkyl. Still in other modalities, R⁶ is Ci-4 alkoxy. Still in other modalities, R⁶ is alkylamine (NRuR₁₂), where Rn and R_i2 are independently H or alkyl Ci_₄.

In some embodiments, R 'is H. In other embodiments, R⁷it's halo. Still in other modalities, R⁷ it is Ci-4 alkyl. Still in other modalities, R⁷ it is Ci-4 alkoxy, for example methoxy. Still in other modalities, R⁷ is alkylamine (NRnRi₂), where Rn and R₁₂ are independently H or Ci- alkyl₄.

In some modalities, R⁹ is H. In other modalities, R⁹it's halo. Still in other modalities, R⁹ it is Ci-4 alkyl. Still in other modalities, R⁹ is Ci_4 alkoxy. Still in other modalities, R⁹ is alkylamine (NR11R12), where Rn and R_i2 are independently H or alkyl C_x_₄.

In some modalities, R¹⁰ is H. In other modalities, R¹⁰ it's halo. Still in other modalities, R¹⁰ it is Ci-4 alkyl. Still in other modalities, R¹⁰ is Ci_4 alkoxy. Still in other modalities, R¹⁰ is alkylamine (NRnR₁₂), where Rn and R₁₂are independently H or alkyl C_X-₄.

In some modalities, R¹ and R⁵ they are part of the 3-7 membered cyclic ring, the 3-7 membered cyclic being optionally substituted with Ci_4 alkyl optionally substituted with OZ or NRnR12 where Z, Rn and R12 are independently H or Ci_4 alkyl. In other modalities, R¹and R⁵ are part of the 3-7 membered cyclic ring, the 3-7 membered cyclic being optionally substituted with R8CO, where R₈ is Ci_alkyl₄. For example, the 37-membered cyclic ring is substituted with CH₃CO. Still in other modalities, R¹ and R⁵ are part of the 3-7 membered cyclic ring, the 3-7 membered cyclic being optionally substituted with SO₂(CH₂)_whatH, where q is 1-4. For example, the 3-7 membered cyclic is substituted with SO₂CH₃.

In some modalities, R¹ and R² are part of the 3-7 membered cyclic ring, optionally substituted with Ci_alkyl₄, the alkyl Ci_₄ optionally further substituted with halo, OZ, or NRnR₁₂ where Z, R_or and R₁₂ are independently H or alkyl Ci_₄. In other modalities, R¹ and R² they are part of the 3-7 membered cyclic ring, and one or more members of the 3-7 membered cyclic ring is optionally part of a carbonyl group or a sulfonyl group. The carbonyl group can be an amide or an ester group.

In some modalities, R² and R⁶ are part of the 3-7 membered cyclic ring, optionally substituted with Ci_4 alkyl optionally substituted with OZ or NR_orRi₂ where Z, R_n and Ri₂ are independently H or alkyl Ci_₄.

In some modalities, R⁴ it is unsubstituted C2 alkenyl. In other modalities, R⁴ is C2 alkenyl substituted with Ci_alkyl₄. For example, R⁴ may be alkenyl C₂ replaced with -CH₂OCH₃, or -CH₂N (CH₃)₂.

In some embodiments, X is O. In other embodiments, X is C-alkyl.₄ unsubstituted, eg CH₂, or alkyl Ci_₄substituted with halo, for example CF₂. Still in other modes, X is NR^b, and R^b is H, or alkyl Ci_₈ optionally substituted with halo.

In some embodiments, Y is C. In other embodiments, Y is CH or CH substituted with halo, eg, CF₂. In still other modalities, Y is N.

In some embodiments, A is C. In other embodiments, A is CH or CH substituted with halo, eg CF₂. In still other modalities, A is N.

In some embodiments, the 3-7 cyclic ring

<td>members</td><td>is</td><td>a ring</td><td>cyclic</td><td>of</td><td>3 members. In</td><td>others</td>

<td colspan="2">modalities,</td><td>the ring</td><td>cyclical</td><td> 3-7</td><td>members is a</td><td>ring</td>

<td>cyclic</td><td>of</td><td>4 members</td><td>Still</td><td>in</td><td colspan="2">other modalities, the</td>

3-7 membered cyclic ring is a 5 membered cyclic ring. Still in modalities, the 3-7 membered cyclic ring is a 6 membered cyclic ring. Still in modalities, the 3-7 membered cyclic ring is a 7 membered cyclic ring.

In some embodiments, the 3-7 membered cyclic ring is a 3-7 membered hydrocarbon cyclic ring. In other embodiments, the 3-7 membered cyclic ring is a heterocyclic ring. For example, the heterocyclic ring can comprise one or more N atoms.

In some embodiments, the present disclosure provides a compound selected from the group consisting of compound 1-1, 1-2, 1-3, 1-4, 1-5, 1-6, 1-7, 1-8, 1 -9, I12, 1-13, 1-14, 1-15, 1-16, 1-17, 1-18, 1-19, 1-20, 1-21, I22, 1-23, 1-24 , 1-25, 1-41, I-23a, I-25a, I-28a, I-29a, I30a, I-31a, I-32a, I-33a, I-34a, I-35a, I-38a , I-39a, I-42a, I-43a, I-44a, I-45a, I-50a, I-51a, I-52a, I-53a, I-54a, I55a, I-56a, I-57a , I-58a, I-59a, I-60a, I-66a, I-70a, and I72a.

Formula Ha

In yet another aspect, the present disclosure provides a compound of Formula (lia):

<img file="MX368491B_D0053.tif" />

(Ha) where

R¹ is H, or

NR^cR^d where R^c is H, C1-4alkyl or cyclic ring of

3-7 membered, the 3-7 membered cyclic ring optionally substituted with C1-4 alkyl optionally substituted with OZ or NR10R11 where Z, Rio and R11 are independently H or C1-4 alkyl, or the 3-7 cyclic ring members being optionally substituted with R₈CO, where R₈ is C1-4alkyl, or the 3-7 membered cyclic ring being optionally substituted with

<td>SW₂(CH₂)_whatH, where q</td><td>is 1-4,</td><td>and R^d</td><td>is</td><td>H, C1-4alkyl,</td>

<td>optionally substituted</td><td>with OZ 0</td><td>NRiqRh</td><td>in</td><td>where Z, Rio and Rn</td>

<td>are H 0 alkyl Ci_₄; 0</td><td></td><td></td><td></td><td></td>

<td>NR^andR^F where R^and is</td><td>I rent</td><td>C1-4, and</td><td>R^F</td><td>cyclic ring</td>

3-7 membered optionally substituted with Ci_alkyl₄optionally substituted with halo; or

OR^g where R^g is Ci_alkyl₄ replaced with CH₃OR-,

CH₃CH₂O-, CH₃(OR) ₂s-, cf₃3-7 membered cyclic ring substituted with R^to where R^to is Ci_s alkyl optionally substituted with halo, Ci-4 alkoxy or SO₂(CH₂)_whatH, where q is 1-4, or the 3-7 membered cyclic ring being optionally substituted with RgCO, where Rg is Ci_alkyl₄;

R is absent, H, halo, Ci- alkyl₄, alkoxy Ci-₄, or alkylamine (NR₁₀Rn), where Rio and Rn are independently H or alkyl Ci_₄;

R³ is absent, H, halo, Ci_alkyl₄, or C-alkoxy₄, or alkylamine (NR10R11), where Rio and Rn are independently H or Ci- alkyl₄;

R⁵ is absent, H, halo, C1-4alkyl, or Ci_alkoxy₄, or alkylamine (NRi₀Rn), where Rio and Rn are independently H or alkyl Ci-₄;

R⁶ is H, halo, Ci- alkyl₄, or C-alkoxy₄, or alkylamine (NRioRn), where Rio and R11 are independently H or Ci_4 alkyl;

R⁷ is H, halo, alkyl Ci_₄, alkoxy Ci_₄, or alkylamine (NRiqRh), where Rio and Rn are independently H or alkyl

Ci-4;

R is H, halo, Ci- alkyl₄, or C-alkoxy₄, or alkylamine (NRiqRh), where R₁₀ and Ru are independently H or Ci_alkyl₄; or

R and R are part of the 3-7 membered cyclic ring, optionally substituted with Ci_alkyl₄ optionally substituted with OZ or NR₁₀Rn where Z, R₁₀ and R_or are independently H or alkyl Ci_₄; or

R and R are part of the 3-7 membered cyclic ring, optionally substituted with Ci- alkyl₄ optionally substituted with OZ or Rio and R ^ where Z, R ^ and R ^ are independently are H or Ci- alkyl₄; or

R and R are part of the 3-7 membered cyclic ring, optionally substituted with Ci_alkyl₄ optionally substituted with OZ or Rio and Ru where Z, Riq and Ru are independently H or Ci_alkyl₄;

R⁴ is alkenyl C₂ optionally substituted with alkyl Ci-₄, -CH₂OCH₃, or -CH₂N (CH₃)₂;

X is O, alkyl Ci_₄ optionally substituted with halo, or NR^b, where R^b it is H, or C1-8 alkyl optionally substituted with halo;

Y is C, CH optionally substituted with halo, or N;

A is C, CH optionally substituted with halo, or N; and

B is C, CH optionally substituted with halo, or N, or a pharmaceutically acceptable salt thereof.

In some modalities, R¹ is H, and R² and R⁶ are part of the 3-7 membered cyclic ring, optionally substituted with Ci_alkyl₄ optionally substituted with OZ or Ri₀ and Rn where Z, R₁₀ and R_X1 are independently H or alkyl Ci_₄.

In some modalities, R¹ is NR^cR^d and R^c is H. In other modalities, R¹ is NR^cR^d and R^c is alkyl Ci-₄.

In some modalities, R¹ is NR^cR^d and R^c is 3-7 membered cyclic ring, the 3-7 membered cyclic ring optionally substituted with Ci-alkyl₄ optionally substituted with OZ or NRi₀Rn where Z, R₁₀ and Rn are independently H or Ci- alkyl₄. The 3-7 membered cyclic ring can be substituted with C-alkyl₂ substituted with methoxy.

In some modalities, R¹ is NR^cR^d and R^c is 3-7 membered cyclic ring, the 3-7 membered cyclic ring being optionally substituted with R₈CO, where R₈ is Ci_alkyl₄. The 3-7 membered cyclic ring can be replaced with CH₃CO.

In some modalities, R¹ is NR^cR^d and R^c is 3-7 membered cyclic ring, the 3-7 membered cyclic ring being optionally substituted with SO₂(CH₂)_whatH, where q is 1-4. For example, the 3-7 membered cyclic ring can be substituted with CH₃SW₂.

In some modalities, R^d is H. In other modalities, R^dis alkyl Ci-₄, optionally substituted with OZ or NRi₀R_or where Z, R_i0 and R_n they are H or C1-4 alkyl.

In some modalities, R¹ is NR^andR^F and R^and is Ci_alkyl₄. In other modalities, R¹ is NR^andR^F and R^F it is a 37 membered cyclic ring optionally substituted with C 1-4 alkyl optionally substituted with halo.

In some modalities, R¹ is OR⁹ where R^g is C1-4alkyl substituted with CH₃O-, CH₃CH₂O-, CH₃(OR) ₂S-, CF₃OR-,

In some modalities, R¹ is 3-7 membered cyclic ring substituted with R^to where R^to it is C1-8 alkyl optionally substituted with halo, Ci-4 alkoxy or SO2 (CH2) qH, where q is 1-4. For example, R^to it can be C2-alkyl substituted with methoxy. In another example, R^to is CH₃SW₂CH₂CH₂.

In some modalities, R¹ is 3-7 membered cyclic ring, the 3-7 membered cyclic ring being optionally substituted with R₈CO, where R₈ is Ci_alkyl₄. For example, the 3-7 membered cyclic ring can be substituted with CH₃CO.

R¹ it can be any suitable 3-7 membered cyclic ring. In some modalities, R¹ is selected from the group consisting of

4

<img file="MX368491B_D0054.tif" />

<img file="MX368491B_D0055.tif" />

Ci-8 optionally substituted with halo, Ci- alkoxy₄ bear₂(CH₂)_whatH, where q is 1-4, and R^b is H or alkyl C_x_8 optionally substituted with halo, Ci_alkoxy₄ bear₂(CH2)_whatH, where q is 1-

Four. In other modalities, R¹ is selected from the group that

<img file="MX368491B_D0056.tif" />

modalities

<img file="MX368491B_D0057.tif" />

and R^to is alkyl C₂ further substituted with methoxy. Still in other modalities

<img file="MX368491B_D0058.tif" />

and R^to is C2 alkyl further substituted with SO2CH3.

In some modalities, R² is absent or H. In other modalities, R² it's halo

Still in other modalities

R² it is C1-4alkyl or C1-4alkoxy. Still in modalities, R² is alkylamine (NRi₀Rn), where Rio and Rn are independently

H or C1-4 alkyl.

In some modalities, R³ he's absent. In other modalities, R³ is H. Still in other modalities, R³ it's halo. Still in modalities, R³ it is C1-4alkyl. Still in modalities, R³ it is C1-4 alkoxy. Still in modalities, R³ is alkylamine (NR₁₀Rn) where R₁₀ and Rn are independently

H or C1-4 alkyl.

In some modalities, R⁵ he's absent. In other modalities, R⁵ is H. Still in other modalities, R⁵ it's halo. Still in modalities, R⁵ it is C1-4alkyl. Still in modalities, R⁵ it is C1-4 alkoxy. Still in modalities, R⁵ is alkylamine (NRi₀R_n), where Rio and Rn are independently

H or C1-4 alkyl.

In some modalities, R⁶ is H. In other modalities, R⁶ it's halo. Still in other modalities, R⁶ it is C1-4alkyl. Still in modalities, R⁶ is alkoxy Ci_₄. Still in modalities, R⁶ is alkylamine (NR10R11), where Rio and Rn are independently

6

Η or alkyl Ci-₄.

In some modalities, R⁷ is H. In other modalities, R⁷it's halo. Still in other modalities, R⁷ is Ci_4 alkyl. Still in modalities, R 'is Ci_4 alkoxy. Still in modalities, R⁷ it is alkylamine (NRioRn), where Rio and Rn are independently H or Ci-4 alkyl.

In some modalities, R⁹ is H. In other modalities, R⁹it's halo. Still in other modalities, R⁹ it is Ci-4 alkyl. Still in modalities, R⁹ is alkoxy Cx_₄. Still in modalities, R⁹ is alkylamine (NRioRn), where Rio and Rn are independently H or Ci_alkyl₄.

In some modalities, R¹ and R⁵ they are part of the 3-7 membered cyclic ring, optionally substituted with Ci-alkyl₄ optionally substituted with OZ or NRioRn where Z, R₁₀ and Rn are independently H or Ci_alkyl₄.

In some modalities, R¹ and R² are part of the 3-7 membered cyclic ring, optionally substituted with C-alkyl_b4 optionally substituted with OZ or R_i0 and Rn where Z, R₁₀and Rn are independently H or Ci- alkyl₄.

In some modalities, R² and R⁶ are part of the 3-7 membered cyclic ring, optionally substituted with Ci-4 alkyl optionally substituted with OZ or Rio and Rn where Z, R₁₀and Rn are independently H or Ci- alkyl₄.

In some embodiments, X is O. In other embodiments, X is alkyl Ci_₄ unsubstituted, eg CH₂, or alkyl Ci-₄substituted with halo, for example CF₂. Still in other modes, X is NR^b, and R^b it is H, or Ci_g alkyl optionally substituted with halo.

<td></td><td>In</td><td>some modalities, Y is C.</td><td>In others</td><td>modalities,</td><td>AND</td>

<td>is</td><td>CH or</td><td>CH substituted with halo for</td><td>example,</td><td>CF. Still</td><td>in</td>

<td colspan="3">other modalities, Y is N.</td><td></td><td></td><td></td>

<td></td><td>In</td><td>some modalities, A is C.</td><td>In others</td><td>modalities,</td><td>TO</td>

<td>is</td><td>CH or</td><td>CH substituted with halo for</td><td>example,</td><td>CF. Still</td><td>in</td>

<td colspan="3">other modalities, A is N.</td><td></td><td></td><td></td>

<td></td><td>In</td><td>some modalities, B is C.</td><td>In others</td><td>modalities,</td><td>B</td>

<td>is</td><td>CH or</td><td>CH substituted with halo for</td><td>example,</td><td>CF. Still</td><td>in</td>

other modalities, B is N.

In some embodiments, the 3-7 cyclic ring

<td>members</td><td>is</td><td>a ring</td><td>cyclic</td><td>of</td><td>3 members.</td><td>In</td><td>others</td>

<td colspan="2">modalities,</td><td>the ring</td><td>cyclical</td><td> 3-7</td><td>members is</td><td>a</td><td>ring</td>

<td>cyclic</td><td>of</td><td>4 members</td><td>. Still</td><td>in</td><td colspan="3">other modalities, the</td>

3-7 membered cyclic ring is a 5 membered cyclic ring. Still in modalities, the 3-7 membered cyclic ring is a 6 membered cyclic ring. Still in modalities, the 3-7 membered cyclic ring is a 7 membered cyclic ring.

In some embodiments, the 3-7 membered cyclic ring is a 3-7 membered hydrocarbon cyclic ring. In other embodiments, the 3-7 membered cyclic ring is a heterocyclic ring. For example, the heterocyclic ring can comprise one or more N atoms.

In some embodiments, the present disclosure provides a compound selected from the group consisting of compound 1-10, 1-11, 1-26, 1-27, 1-28, 1-29, 1-30, 1-31, 1 -32, 1-33, 1-34, 1-35, 1-36, 1-37, 1-38, 1-39, 1-40, I-24a, I-26a, I-27a, I-36a , I-37a, I-40a, I-41a, I-46a, I-47a, I48a, I-49a, I-61a, I-62a, I-63a, I-64a, I-65a, I-67a , I-68a, I-69a, and I-71a.

Pharmaceutical compositions, combinations, and other related uses

In yet another aspect, the present disclosure provides a pharmaceutical composition comprising a compound described above mixed with at least one pharmaceutically acceptable carrier or excipient.

The compounds described above can be used for any suitable purpose. For example, the present compounds can be used in therapy and / or testing.

In yet another aspect, the present disclosure provides a method of treating and / or preventing a proliferation disorder, a cancer, a tumor, an inflammatory disease, an autoimmune disease, psoriasis, dry eyes, or an immunologically related disease, or lupus, which it comprises administering to a subject in need thereof an effective amount of a compound described above or a pharmaceutical composition described above.

In yet another aspect, the present disclosure provides a use of a compound described above for the manufacture of a medicament.

In yet another aspect, the present disclosure provides a combination for treating and / or preventing a proliferation disorder, cancer, tumor, inflammatory disease, autoimmune disease, psoriasis, dry eyes, or an immunologically related disease or lupus in a subject. , the combination of which comprises an effective amount of a compound described above, or a pharmaceutically acceptable salt thereof, and an effective amount of a second therapeutic or prophylactic agent for treating and / or preventing a proliferation disorder, a cancer, a tumor, an inflammatory disease, an autoimmune disease, psoriasis, dry eyes or an immunologically related disease or lupus in a subject. .

In yet another aspect, the present disclosure provides a method of treating and / or preventing a proliferation disorder, cancer, tumor, inflammatory disease, autoimmune disease, psoriasis, dry eyes, or an immunologically related disease or lupus in a subject. , whose methods comprise administering to a subject in need thereof an effective amount of the combination described above.

In yet another aspect, the present disclosure provides a method of inhibiting an activity of a Bruton tyrosine kinase (Btk or BTK) or a Janus kinase (JAK) EGFR (including HER), Alk, PDGFR, BLK, BMX / ETK, FLT3 (D835Y), ITK, TEC, TXK, and the respective pathways, in a cell or subject, the methods of which comprise administering to a cell or subject in need thereof an effective amount of a compound described above, or a pharmaceutical composition described above, or a combination described above.

The present methods can be used to inhibit an activity of any suitable Btk, BTK or JAK. In some embodiments, the present methods can be used to inhibit an activity of JAK1, JAK2, or JAK3.

The present methods can be used for any suitable purpose. In some embodiments, the present methods can be used to treat and / or prevent a proliferation disorder, cancer, tumor, inflammatory disease, autoimmune disease, psoriasis, dry eyes, or an immunologically related disease or lupus in the subject. The present methods can be used to treat and / or prevent any suitable proliferation disorder.

Exemplary proliferation disorders include sarcoma, epidermoid cancer, fibrosarcoma, cervical cancer, gastric carcinoma, skin cancer, leukemia, lymphoma, lung cancer, non-small cell lung cancer, colon cancer, CNS cancer, melanoma, ovarian cancer, kidney cancer, prostate cancer, breast cancer, liver cancer, head and neck cancers, and pancreatic cancer.

In some embodiments, any of the compound selected from the group consisting of compound 1-1, 1-2, 1-3, 1-4, 1-5, 1-6, 1-7, 1-8, 1-9, 1-12, 1-13, 1-14, 1-15, I16, 1-17, 1-18, 1-19, 1-20, 1-21, 1-22, 1-23, 1-24, 1-25, I41, I-23a, I-25a, I-28a, I-29a, I-30a, I-31a, I-32a, I-33a, I-34a, I-35a, I-38a, I-39a, I-42a, I-43a, I-44a, I-45a, I50a, I-51a, I-52a, I-53a, I-54a, I-55a, I-56a, I-57a, I-58a, I-59a, I-60a, I-66a, I-70a, I-72a, 1-10, 1-11, 1-26, 1-27, I28, 1-29, 1-30, 1-31, 1-32, 1-33, 1-34, 1-35, 1-36, 1-37, I38, 1-39, 1-40, I-24a, I-26a, I-27a, I-36a, I-37a, I-40a, I41a, I-46a, I-47a, I-48a, I-49a, I-61a, I-62a, I-63a, I-64a, I-65a, I-67a, I-68a, I-69a, and I-71a can be used in the pharmaceutical compositions, combinations, and other related uses or methods above.

Formulations

Any suitable formulation of the compounds described herein can be prepared. See generally,

Remington's Pharmaceutical Sciences, (2000) Hoover, JE editor, 20^to edition, Lippincott Williams and Wilkins Publishing Company, Easton, Pa., pages 780-857. A formulation is selected to be suitable by an appropriate route of administration. In cases where the compounds are sufficiently basic or acidic to form stable non-toxic base or acid salts, administration of the compounds as salts may be appropriate. Examples of pharmaceutically acceptable salts are organic acid addition salts formed with acids that form a physiologically acceptable anion, for example, tosylate, methanesulfonate, acetate, citrate, malonate, tartarate, succinate, benzoate, ascorbate, α-ketoglutarate, and a- glycerophosphate. Suitable inorganic salts can also be formed, including hydrochloride, sulfate, nitrate, bicarbonate, and carbonate salts. Pharmaceutically acceptable salts are obtained using standard procedures well known in the art, for example, by a sufficiently basic compound such as an amine with a suitable acid, providing a physiologically acceptable anion. The alkali metal (eg, sodium, potassium, or lithium) or alkaline earth metal (eg, calcium) salts of carboxylic acids are also made.

Where the contemplated compounds are administered in a pharmacological composition, it is contemplated that the compounds may be formulated in admixture with a pharmaceutically acceptable carrier and / or excipient. For example, the contemplated compounds can be administered orally as neutral compounds or as pharmaceutically acceptable salts, or intravenously in a physiological saline solution. Conventional buffer solutions such as phosphates, bicarbonates, or citrates can be used for this purpose. Of course, someone of ordinary skill in the art can modify the formulations within the teachings of the specification to provide numerous numbers for a particular route of administration. In particular, the contemplated compounds can be modified to make them more soluble in water or another vehicle, which for example, can easily be performed with fewer modifications (salt formulation, esterification, etc.) that are within ordinary skill in the art. It is also within the ordinary skill of the art to modify the route of administration and dosage regimen of a particular compound in order to administer the pharmacokinetics of the present compounds for maximum beneficial effect in a pacifier.

Compounds having formula I-III as described herein are generally soluble in organic solvents such as chloroform, dichloromethane, ethyl acetate, ethanol, methanol, isopropanol, acetonitrile, glycerol, Ν, Ν-dimethylformamide, N, N -dimethylacetamide, dimethyl sulfoxide, etc. In one embodiment, the present invention provides formulations prepared by mixing a compound having formula I-III with a pharmaceutically acceptable carrier. In one aspect, the formulation can be prepared using a method comprising: a) dissolving a disclosed compound in a water-soluble organic solvent, a non-ionic solvent, a water-soluble lipid, a cyclodextrin, a vitamin such as tocopherol, an acid fatty, a fatty acid ester, a phospholipid, or a combination thereof, to provide a solution; and b) add a saline or buffer solution containing 1-10% carbohydrate solution. In one example, the carbohydrate comprises dextrose. The pharmaceutical compositions obtained using the present methods are stable and useful for animal and clinical applications.

Illustrative examples of water soluble organic solvents for use in the present methods include and are not limited to polyethylene glycol (PEG), alcohols, acetonitrile, N-methyl-2-pyrrolidone, N, N-dimethylformamide, Ν, Ν-dimethylacetamide , dimethyl sulfoxide, or a combination thereof. Examples of alcohols include IW but are not limited to methanol, ethanol, isopropanol, glycerol, or propylene glycol.

Illustrative examples of water soluble nonionic surfactants for use in the present methods include and are not limited to CREMOPHOR® EL, CREMOPHOR® modified by polyethylene glycol (polyoxyethylene glyceroltryricinoleat 35), CREMOPHOR® RH40 hydrogenated, CREMOPHOR® RH60 hydrogenated, 20, polysorbate 80, SOLUTOL® HS (polyethylene glycol 660 12-hydroxystearate), sorbitan monooleate, poloxamer, LABRAFIL® (ethoxylated persian oil), LABRASOL® (capryl-caproyl macrogol-8-glyceride), GELUCIRE® (glycerol ester), SOFTIGEN® (caprylic glyceride PEG 6), glycerin, glycol-polysorbate, or a combination thereof.

Illustrative examples of water soluble lipids for use in the present methods include but are not limited to vegetable oils, triglycerides, plant oils, or a combination thereof. Examples of lipid oils include but are not limited to castor oil, polyoxyl castor oil, corn oil, olive oil, cottonseed oil, peanut oil, peppermint oil, safflower oil, sesame oil , soybean oil, hydrogenated vegetable oil, hydrogenated soybean oil, a coconut oil triglyceride, palm kernel oil, and hydrogenated forms thereof, or a combination thereof.

Illustrative examples of fatty acids and fatty acid esters for use in the present methods include but are not limited to oleic acid, monoglycerides, diglycerides, a mono- or di-fatty acid ester of PEG, or a combination thereof.

Illustrative examples of cyclodextrins for use in the present methods include but are not limited to alpha-cyclodextrin, beta-cyclodextrin, hydroxypropyl-beta-cyclodextrin, or sulfobutyl-beta-cyclodextrin ester.

Illustrative examples of phospholipids for use in the present methods include but are not limited to soy phosphatidylcholine, or distearoyl phosphatidylglycerol,

<td>and hydrogenated forms of</td><td>themselves, or</td><td>a</td><td>combination</td><td>of</td><td>the</td>

<td>themselves.</td><td></td><td></td><td></td><td></td><td></td>

<td>Someone of experience</td><td>ordinary</td><td>in</td><td>The technique</td><td colspan="2">can</td>

<td>modify the formulations</td><td>within</td><td>the</td><td>teachings</td><td>of</td><td>the</td>

specification to provide numerous formulations for a particular route of administration. In particular, the compounds can be modified to make them more soluble in water or another vehicle. It is also within the ordinary skill of the art to modify the route of administration and dosage regimen of a particular compound in order to administer the pharmacokinetics of the present compounds for maximum beneficial effect in a patient.

Drug combinations

The methods of the embodiments comprise administering an effective amount of at least one exemplary compound of the present disclosure; optionally the compound can be administered in combination with one or more additional therapeutic agents, particularly therapeutic agents known to be useful for treating a proliferation disorder, cancer, tumor, inflammatory disease, autoimmune disease, psoriasis, dry eyes or disease immunologically related affecting the subject.

The additional active ingredients may be administered in a separate pharmaceutical composition of at least one exemplary compound of the present disclosure or may be included with at least one exemplary compound of the present disclosure in a single pharmaceutical composition. The additional active ingredients can be administered simultaneously with, before, or after the administration of at least one exemplary compound of the present disclosure.

Methods for using the exemplary compounds and pharmaceutical compositions thereof

The present invention also provides pharmaceutical compositions for the treatment and / or prevention of a proliferation disorder, a cancer, a tumor, an inflammatory disease, an autoimmune disease, psoriasis, dry eyes, or an immunologically related disease, comprising any compound having formula I or II, or any of the compounds from 1-1 to 1-41.

To practice the method of the present invention , the compounds having the formula and pharmaceutical compositions thereof can be administered orally, parenterally, by inhalation, topically, rectally, nasally, orally, vaginally, by means of an implanted reservoir, or other drug administration methods. The term parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional, and intracranial injection or infusion techniques.

<td>A</td><td>composition</td><td>sterile injectable,</td><td>such as</td><td>a</td>

<td>suspension</td><td>oilseed</td><td>or aqueous injection</td><td>sterile,</td><td>can</td>

<td>formulate</td><td>agree</td><td colspan="2">with known techniques in the</td><td>art</td>

using suitable suspending agents and wetting or dispersing agents. The sterile injectable preparation may also be a sterile suspension or injectable solution in a non-toxic parenterally acceptable solvent or diluent. Acceptable solvents and vehicles that can be used include mannitol, water, Ringer's solution, and isotonic sodium chloride solution. Suitable carriers and other components of the pharmaceutical composition are typically sterile.

In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium (eg, synthetic mono or diglycerides). Fatty acids, such as oleic acid and its glyceride derivatives, are useful in the preparation of injectables, as are pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol dispersant or diluent, or carboxymethyl cellulose or similar dispersing agents. Various emulsifying or bioavailability enhancing agents which are commonly used in the manufacture of solid, pharmaceutically acceptable liquid forms, or other dosage forms can also be used for the purpose of the formulation.

A composition for oral administration can be any orally acceptable dosage form including, but not limited to, tablets, capsules, aqueous emulsions and suspensions, dispersions and solutions. In the case of tablets for oral use, commonly used carriers include lactose and corn starch. Lubricating agents, such as magnesium stearate, can also be added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When the aqueous emulsions or suspensions are administered orally, the active ingredient can be suspended or dissolved in an oily phase combined with suspending or emulsifying agents. If necessary, certain sweetening, flavoring, or coloring agents may be added. Compositions by inhalation or nasal spray can be prepared according to techniques well known in the art of pharmaceutical formulation and can be prepared as solutions in, for example saline, using suitable preservatives (for example benzyl alcohol), absorption promoters to increase bioavailability, and / or other dispersing or solubilizing agents known in the art.

Furthermore, compounds having formula I or II, or any of compounds 1-1 to 1-41, can be administered alone or in combination with other therapeutic agents, for example, anticancer agents, for the treatment of various disorders of proliferation, cancer, tumor, inflammatory disease, autoimmune disease, psoriasis, dry eyes or immunologically related disease. Combination therapies according to the present invention comprise the administration of at least one exemplary compound of the present disclosure and at least one other pharmaceutically active agent. The active ingredients and pharmaceutically active agents can be administered separately or together. The amounts of the active ingredients and pharmaceutically active agents and the relative times of administration will be selected in order to achieve the desired combined therapeutic effect. Biological selection and anticancer activity:

Some exemplary examples and assays for evaluating the therapeutic efficacy, eg, anti-cancer effects, of exemplary compounds of the invention are described as follows.

In vitro cell based selection using real time cellular electronic sensing system (RT-CES)

Some of the exemplary heterocyclic compounds in the present invention are developed for anticancer activities for cancer cells with certain molecular targets, i.e., EGFR (epidermal growth factor receptor). The anticancer efficacy of these heterocyclic compounds and their analogues described above can be preliminarily selected in vitro using an EGFR cancer cell line binding by ACEA Biosciences, Inc. Real-time Electronic Cell Sensing System (RT-CES) (or xCELLigence system Roche Applied Sciences / ACEA Biosciences Inc.), which provides dynamic cellular response information after exposure to an anticancer agent.

The details of this cellular electronic sensing technology, called real-time cellular electronic sensing (RT-CES®), and associated devices, systems, and methods of use are described in United States Patent No. 7,732,127; patent number 7,192,752; Patent Number 7,459,303; Patent Number 7,468,255; Patent Number 7,470,533; Patent Number 7,560,269; provisional application of the United States of America number 60 / 397,749, filed on July 2, 2002; provisional application of the United States of America number 60 / 435,400, filed on December 20, 2002; provisional application of the United States of America 60 / 469,572, filed on May 9, 2003, PCT application number PCT / US03 / 22557, filed on July 18, 2003; PCT application number PCT / US03 / 22537, filed on July 18, 2003; PCT application number PCT / US04 / 37696, filed on November 12, 2004;

PCT Application PCT / US05 / 04481, filed on February 9, 2005; United States of America Patent Application No. 10 / 705,447, filed on November 10, 2003; United States of America patent application number 10 / 705,615, filed on November 10, 2003; United States of America patent application number 10 / 987,732, filed on November 12, 2004; United States of America patent application number 11 / 055,639, filed on February 9, 2005, each of which is incorporated by reference. The additional details of the RT-CES technology is further described in provisional application of the United States of America number

60 / 519,567, filed on November 12, 2003, and application

<td>provisional</td><td>of the</td><td>state</td><td>United</td><td>of</td><td colspan="2">America number</td>

<td> 60/542,927,</td><td>filed</td><td>The 9</td><td colspan="2">February</td><td> 2004,</td><td>request</td>

<td>provisional</td><td>of the</td><td>state</td><td>United</td><td>of</td><td colspan="2">America number</td>

<td> 60/548,713,</td><td>filed</td><td>the 27th</td><td colspan="2">February</td><td> 2004,</td><td>request</td>

<td>provisional</td><td>of the</td><td>state</td><td>United</td><td>of</td><td colspan="2">America number</td>

<td> 60/598,608,</td><td>filed</td><td>the 4</td><td>of August</td><td>of</td><td> 2004;</td><td>request</td>

<td>provisional</td><td>of the</td><td>state</td><td>United</td><td>of</td><td colspan="2">America number</td>

<td> 60/598,609,</td><td>filed</td><td>the 4</td><td>of August</td><td>of</td><td> 2004 ;</td><td>request</td>

<td>provisional</td><td>of the</td><td>state</td><td>United</td><td>of</td><td colspan="2">America number</td>

<td> 60/613,749,</td><td>filed</td><td colspan="3">on September 27,</td><td> 2004;</td><td>request</td>

provisional of the United States of America number

4

60 / 613,872, filed on September 27, 2004; provisional application of the United States of America number 60 / 614,601, filed on September 29, 2004; provisional application of the United States of America number 60 / 630,071, filed on November 22, 2004; provisional application of the United States of America number 60 / 630,131, filed on November 22, 2004, each of which is incorporated herein by reference.

For measuring the impedance of the cell electrode or cell substrate using RT-CES technology, microelectrodes having appropriate geometries are fabricated on the bottom surfaces of the microtiter plate or similar device, facing the wells. Cells enter the wells of the devices, make contact with and bind to the electrode surfaces. The presence, absence, or change of cell properties affects the electronic and ionic passage on the electrode sensor surfaces. Measuring the impedance between or between the electrodes provides important information about the biological state of the cells present in the sensors. When these are changes to the biological state of the cell analog, the electronic read signals are automatically and real-time measured, and converted to digital signals for processing and analysis.

In an RT-CES system, a cell index is automatically derived and provided based on the measured electrode impedance values. The cell index obtained for a given well reflects: 1) how many cells bind to the electrode surfaces in this well; 2) how cells from the well bind to the electrode surfaces in this well. In this way, the more cells of the same type that bind the electrode surfaces in similar physiological conditions, the higher the cell index. And, the better cells are attached to the electrode surfaces (for example, the cells further extended to have larger contact areas, or the cells more tightly attached to the electrode surfaces), the larger the cell index. We have found that addictive cMet cell lines should produce a transient impedance response profile when treated with positively controlled EGFR inhibitors (epidermal growth factor receptor).

Through the use of the RT-CES system, the heterocyclic compounds described in the examples above have been shown to produce a similar cellular response impedance profile in the RT-CES system to that generated by positive control inhibitors. Furthermore, these compounds have been shown to inhibit EGFR (epidermal growth factor receptor) induced cell migration in various cell lines. Furthermore, these compounds have shown no or negligible effects when used to treat addictive cancer cell lines without cMet.

The RT-CES system (or xCELLigence RTCA system) comprises three components, an electronic sensor analyzer, a device station, and devices from the 16X or 96X microtiter plate (i.e. E 16 plate or E 96 plate). The microelectrode sensor configuration was fabricated on glass slides with lithographic microfabrication methods, and the electrode-containing slides are assembled to plastic trays to form electrode-containing wells. Each 16X (or 96X) microtiter plate device used in the RT-CES system comprises up to 16 (or 96) of such electrode-containing wells. The device station receives the 16X or 96X microtiter plate devices and is capable of electronically swapping any one of the wells for the sensor analyzer for impedance measurement. In operation, devices with cells grown in the wells are placed in a device station (xCELLigence RTCA SP station or RT-CES SP station) located inside an incubator. Electrical cables connect the device station to the sensor analyzer (xCELLigence RTCA analyzer or RT-CES analyzer).

Under the control of RT-CES or xCELLigence RTCA software, the sensor analyzer can automatically select wells to be measured and continuously leads to impedance measurements. The analyzer's impedance data is transferred to a computer, analyzed and processed by the integrated software.

The measured impedance between the electrodes in an individual well depends on the geometry of the electrode, ion concentration in the well, and whether there are cells attached to the electrodes. In the absence of cells, the impedance of the electrode is primarily determined by the environment of the ions at both the electrode / solution interface and the volume solution. In the presence of the cells, the cells attached to the surfaces of the electrode sensor will alter the local ionic environment at the electrode / solution interface, leading to an increase in impedance. The more cells that exist in the electrodes, the greater the increase in the impedance of the cell electrode. Additionally, the change in impedance also depends on cell morphology and the extent to which cells are attached to the electrodes.

To quantify the cellular state based on the measured cell electrode impedance, a parameter called Cell Index is derived, according to where and dependent on the

CI = max /=1.....N ^Rcell (/)) ^Rcell (/) ^{J 7} are the frequency electrode resistors (an impedance component) without cells or with cells present, respectively. N is the number of the frequency points at which the impedance is measured. In this way, the Cell Index is a quantitative measurement of the state of cells in a well containing an electrode. Under the same physiological conditions, more cells attached on the electrodes leads to value^Rce11^^ higher, leading to a higher value for the Cellular index. Additionally, for the same number of cells present in the well, a change in cell status such as morphology will lead to a change in Cell Index. For example, an increase in cell adhesion or cell extension leads to the larger cell electrode contact area which will lead to an increase in^cell(·/) and _ist_to way a higher value for the Cellular index. The Cellular index can also be calculated using a different formula than the one described here. Other methods for calculating the Cell Index based on the impedance measurement can be found in United States Patent No. 7,732,127; patent number 7,192,752; Patent Number 7,459,303; patent number

7,468,255; Patent Number 7,470,533; Patent Number 7,560,269; PCT application PCT / US04 / 37696, filed on November 12, 2004, PCT application PCT / US05 / 04481, filed on February 9, 2005, US patent application number 10 / 987,732, filed on November 12, 2004, and US patent application number 11 / 055,639, filed on February 9, 2005.

Test control compounds

The following compounds can be used as comparison compounds to test the compounds in the present disclosure.

WZ4002 is an irreversible inhibitor against EGFR T790M. (Nature December 24, 2009; 462 (7276): 1070-1074) The structure of WZ4002 is shown below:

• Cl

OCH₃^H

BIBW2992 (Afatinib) is an irreversible EGFR / HER2 inhibitor, (Oncogene 2008; 27: 4702-4711) The structure of

BIBW2992 is shown below:

100

<img file="MX368491B_D0059.tif" />

<img file="MX368491B_D0060.tif" />

Erlotinib is a reversible tyrosine kinase inhibitor that works on EGFR. (Drugs

2000, 60 Suppl 1: 15-23;

discussion 41-2.) The structure of erlotinib is shown below:

<img file="MX368491B_D0061.tif" />

EXAMPLES

Example 1

Synthesis of N- (3- (5-methoxy-2- (4- (4-methylpiperazin-l-yl) phenylamino) pyrimidin-4-yloxy) phenyl) acrylamide (1-1) and N (3 - ((2- ((3-fluoro-4- (4-methylpiperazin-l yl) phenyl) amino) pyrimidin-4-yl) oxy) phenyl) acrylamide (1-2)

The synthetic reaction scheme for compounds 1-1 and 1-2 are shown below:

101

<img file="MX368491B_D0062.tif" />

<img file="MX368491B_D0063.tif" />

X-Phos, Pd₂ (dba) j

<img file="MX368491B_D0064.tif" />

K₂CO₃, z-BuOH

<img file="MX368491B_D0065.tif" />

4a: R = H

4b- R = F

H₂, Pd / C 25MPa, 80¡ae THF

<img file="MX368491B_D0066.tif" />

Step 1: Synthesis of 2-chloro-5-methoxy-4- (3-nitrophenoxy) pyrimidine (3)

<img file="MX368491B_D0067.tif" />

A mixture of 2,4-dichloro-5-methoxypyrimidine 1 (130.0 g,

726.3 mmol), 3-nitrophenol 2 (106.7 g, 767.0 mmol), and K2CO3 (193 g, 1.40mol) in DMF (625 mL) was stirred at 30 ° C for 24 h. Then water (3.12 L) was added to the reaction mixture. The mixture was stirred for -10 min. Precipitation was collected, washed with water (200 mL * 3), and dried overnight to provide compound 3 (196.0 g, M + H⁺= 282.6) as a white solid.

102

Step 2: Synthesis of 5-methoxy-N- (4- (4-methylpiperazin-lyl) phenyl) -4- (3-nitrophenoxy) pyrimidin-2-amine (5a)

<img file="MX368491B_D0068.tif" />

A mixture of compound 3 (80.0 g, 284.0 mmol), 4— (4— methylpiperazin-l-yl) aniline 4 (54.3 g, 284.0 mmol), XPhos (8.0 g, 56.8 mmol), Pd₂(dba) 3 (8.0g, 28.4mmol), K2CO3 (78.5g, 568.1mmol) in t-BuOH (1.0L) was stirred at reflux for 4h. The mixture was allowed to cool completely to room temperature and was then filtered. The solvent was evaporated under reduced pressure. To the residue, water (400 mL) was added. The mixture was extracted with DCM (400 mLx3). The organic layers were combined, and treated with activated charcoal (for discoloration), and then filtered. The filtrate was completely concentrated under reduced pressure. The crude was further purified by crystallization from ethyl acetate to provide 6 yellow crystals (92.0 g, M + H⁺= 437.5).

103

Step 3: Synthesis of 4- (3-aminophenoxy) -5-methoxy-N- (4- (4-methylpiperazin-l-yl) phenyl) pyrimidin-2-amine (6a) or nh₂

H

6th

A solution of 5a (65.Og, 143.0 mmol) in THF (150 mL) and 10% Pd / C (3.4g, 5%) were stirred at 25 MPA of hydrogen gas at 80 ° C for 12h. The mixture was cooled and filtered, and the organic solvent was removed under reduced pressure. The crude was further purified by crystallization from ethyl acetate to provide 6a (42.Og, M + H⁺= 407.5).

Synthesis ______ of ______ N- (3- (5-methoxy-2- (4- (4-methylpiperazin-lyl) phenylamino) pyrimidin-4-yloxy) phenyl) acrylamide (I — 1)

To a mixture of 6a (42.Og, 103.3mmol), DIEA (22.4g, 173.6mmol) in MeOH (420mL) and THF (150mL), acryloyl chloride (15.7g, 173.6mmol) was added at 0 ° C . The mixture was stirred for lh. The organic solvent was removed under reduced pressure. The residue was redissolved in DCM (800 mL) and washed with saturated aqueous sodium bicarbonate (400ml). The

104 Organic layer was separated and the solvent was removed under reduced pressure. The crude was further purified by crystallization from THF / H₂O (3:10) to provide compound 1-1 (25.0 g, M + H⁺=461.5). ^XH NMR (500 MHz, DMSO-d₆) δ 10.34 (s, 1H), 9.01

<td>(s,</td><td>1 HOUR) ,</td><td> 8.17</td><td>(s, 1H), 7.64 - 7.59</td><td>(m,</td><td>2H),</td><td> 7.43</td><td>(t,</td><td>J = 8.4</td>

<td>Hz,</td><td>1 HOUR) ,</td><td> 7.28</td><td>(d, J = 9.0 Hz, 2H),</td><td> 6.95</td><td>(m,</td><td>1 HOUR) ,</td><td> 6.64</td><td>(d, J =</td>

<td> 9.1</td><td>Hz,</td><td>2H),</td><td>6.44 (dd, J = 17.0,</td><td> 10.1</td><td>Hz,</td><td>1 HOUR) ,</td><td> 6.35</td><td> - 6.19</td>

(m, 1H), 5.78 (dd, J = 10.1, 1.9 Hz, 1H), 3.87 (s, 3H), 3.02

- 2.91 (m, 4H), 2.48 - 2.39 (m, 4H), 2.23 (s, 3H). ¹³C NMR (126 MHz, DMSO-d₆) δ 165.32 (s), 161.43 (s), 155.79 (s),

154.79 (s), 147.52 (s), 145.95 (s), 142.27 (s), 136.62 (s), 135.09 (s), 133.70 (s), 131.87 (s), 129.25 (s), 121.10 (s, 2C ), 118.76 (s), 118.17 (s), 117.71 (s, 2C), 114.94 (s),

59.63 (s), 56.65 (s, 2C), 50.92 (s, 2C), 47.71 (s).

Compound (1-2) N- (3- (2- (3-fluoro-4- (4-methylpiperazin-l-yl) phenyl amino) -5-methoxypyrimidin-4yloxy) phenyl) acrylamide was synthesized using similar procedures as the Compound 1-1 with similar performance. Compound (1-2): M + H⁺=479.5. ^XH NMR (500 MHz, MeOD) δ 8.07 (s,

<td>1 HOUR) ,</td><td> 7.69</td><td>(t,</td><td>J = 2.0</td><td>Hz,</td><td>1H), 7.57</td><td>(dd,</td><td>J = 8.2, 1.0</td><td>Hz,</td>

<td>1 HOUR) ,</td><td> 7.43</td><td>(t,</td><td>J = 8.2</td><td>Hz,</td><td>1H), 7.30</td><td>(dd,</td><td>J = 15.2, 2.5</td><td>Hz,</td>

<td>1 HOUR) ,</td><td> 7.03</td><td> - 6.</td><td colspan="2">88 (m, 2H), 6,</td><td>.78 (t, J =</td><td> -- 9.5</td><td>Hz, 1H), 6.45</td><td>(dd,</td>

<td>J =</td><td> 17.0,</td><td> 9.9</td><td>Hz, 1H),</td><td> 6.37</td><td>(dd, J =</td><td> 17.0,</td><td>2.0 Hz, 1H),</td><td> 5.78</td>

<td>(dd,</td><td>J =</td><td> 9.9,</td><td>2.0 Hz,</td><td>1 HOUR) ,</td><td>3.94 (s,</td><td>3H),</td><td>2.99 (br s,</td><td>4H),</td>

105

2.62 (br s, 4H), 2.35 (s, J = 6.2 Hz, 3H). ¹³C NMR (126 MHz, MeOD) δ 166.29 (s), 162.07 (s), 158.04 (s), 156.11 (s), 155.29 (s), 154.60 (s), 144.75 (s), 141.44 (s), 138.09 (d, J = 11.1 Hz), 137.15 (s), 134.70 (d, J = 9.8 Hz), 132.55 (s),

131.07 (s), 128.26 (s), 120.31 (d, J = 4.1 Hz), 118.88 (s),

118.28 (s), 115.45 - 115.14 (m), 107.96 (d, J = 26.4 Hz),

58.81 (s), 56.19 (s, 2C), 51.83 (d, J = 2.6 Hz, 2C), 46.25 (s).

Example 2 Synthesis of key intermediaries (I, II, III, IV and V)

Intermediate I (the synthetic reaction scheme is shown below):

intermediary I

Step 1: Synthesis of 3- (2-chloro-5-methoxypyrimidin-4-yloxy) aniline

To a solution of compound 3 (35 g) in THF (200 mL), water (30 mL), NH4C1 (17 g) and Fe (15 g) were added. The reaction mixture was heated to reflux with stirring for 3h. The reaction mixture was completely cooled and filtered, and the THF layer was concentrated under reduced pressure. The crude was redissolved in ethyl acetate (200 mL) and the

106 pH was adjusted with aqueous sodium bicarbonate solution, and then washed with water (100 mL x3). The organic layer was separated and the solvent was removed under reduced pressure to obtain the title product (13 g, M + H⁺ = 252.5).

Step 2: Synthesis of N- (3- (2-chloro-5-methoxypyrimidin-4yloxy) phenyl) acryl amide (I)

To a solution of 3- (2-chloro-5-methoxypyrimidin-4-yloxy) aniline (7.5 g) and DIEA (6 g) in THF (150 mL), acryloyl chloride (2.7 g,) in THF (10 mL) ) was added dropwise at 0 ° C with an ice bath over 20 min. After the reaction mixture was stirred overnight, aqueous NaOH (1M, 40 mL) was added. The reaction mixture was stirred at room temperature for another 0.5h. The THF layer was separated, and the aqueous layer was extracted with ethyl acetate (100 mL). The combined organic layer was concentrated under reduced pressure. The residue was redissolved in ethyl acetate (200 mL), washed with water (100 mL x3). The organic layer was separated and the solvent was removed under reduced pressure to provide the crude, which was further purified by flash column chromatography to give the desired intermediate I (4 g, M + H⁺= 306.5).

Intermediate II (the synthetic reaction scheme is shown below):

107

<img file="MX368491B_D0069.tif" />

Intermediary II

Stage 1: the synthesis of 2-chloro-5-fluoro-4- (3-nitrophenoxy) pyrimidine

A mixture of 2,4-dichloro-5-fluoropyrimidine (10.20 g), 3-nitrophenol (8.6 g), and K2CO3 (15.30 g) in DMF (80 mL) was stirred overnight at room temperature. Water (300 mL) was added. The reaction mixture was stirred for 30 min and then filtered. The precipitate was collected, washed with water (100 mL x2) and dried. The solid was redissolved in ethyl acetate (200 mL), washed with water (100 mL x3). The organic layer was separated and the solvent was removed under reduced pressure. The crude was further purified by crystallization from ethyl acetate / petroleum ether (20 ml) to provide 3 yellow crystals (9.8 g, M + H⁺= 270.6).

Stage 2: the synthesis of 3- (2-chloro-5-fluoropyrimidin-4-yloxy) aniline

Ά A solution of 2-chloro-5-fluoro-4- (3-nitrophenoxy) pyrimidine (6.8 g) in THF (100 mL), water (20 mL), NH4C1 (6.5 g) and Fe (6.5 g) were added. The reaction mixture was stirred at reflux for 5h, cooled to room temperature, and then filtered. The filtrate was concentrated under reduced pressure. The

108 The residue was redissolved in ethyl acetate (200 mL) and the pH was adjusted with aqueous sodium bicarbonate solution. The mixture was washed with water (100 mL x3). The organic layer was separated and the solvent was removed under reduced pressure to provide the desired product with, 66.2% yield (4g, M + H⁺= 240.5) .

Step 3: the synthesis of N- (3- (2-chloro-5-fluoropyrimidin-4yloxy) phenyl) acrylamide (II)

To a solution of 3- (2-chloro-5-fluoropyrimidin-4-yloxy) aniline (3.9 g) and DIEA (3 g) in THE (60 mL), acryloyl chloride (1.6 g) in THE (5 mL) added dropwise at 0 ° C (ice bath) over 15 min. After the reaction mixture was stirred for 4 hr, aqueous sodium bicarbonate (50 mL) was added dropwise. The reaction mixture was stirred for another 0.5h. The organic layer was separated. The aqueous layer was extracted with ethyl acetate (100 mL). The combined organic layers were fully concentrated under reduced pressure. The residue was redissolved in ethyl acetate (200 mL), washed with water (100 mL x3). The organic layer was separated and the solvent was removed under reduced pressure. The crude was further purified by flash column chromatography to provide the desired intermediate II (4g, M + H⁺= 294.5).

Intermediate III (the synthetic reaction scheme

109

<img file="MX368491B_D0070.tif" />

shown below):

<img file="MX368491B_D0071.tif" />

K₂CO₃

DMF

<img file="MX368491B_D0072.tif" />

Intermediary III

Synthesis _________ of _________ N- (3- (2-chloro-5-methoxypyrimidin-4ylamino) phenyl) acrylamide (III)

To a solution of 2,4-dichloro-5-methoxypyrimidine 1 (2.55 g) and N- (3-aminophenyl) acrylamide (2.32 g) in DMF (30mL), K2CO3 (4.14 g) was added. The reaction mixture was stirred at 50 ° C for 16h. CCD (petroleum ether: ethyl acetate = 1: 1 as elution) indicates completion of the reaction. Ethyl acetate (200 mL) was added, washed with water (200 mL x3). The organic layer was separated, and the solvent was removed under reduced pressure. The crude was further purified by flash column chromatography to provide the desired product III (3.5g, M + H⁺= 305.7).

Intermediate IV (the synthetic reaction scheme is shown below):

110

<img file="MX368491B_D0073.tif" />

ch₃cn

80 ° C

<img file="MX368491B_D0074.tif" />

<img file="MX368491B_D0075.tif" />

<img file="MX368491B_D0076.tif" />

Intermediary IV

Stage 1: the synthesis of 1- (2-fluoro-4-nitrophenyl) piperazine

In a round bottom flask, 1,2-difluoro-4-nitrobenzene (23g, 144.57mmol) was added to a solution of piperazine (21.66g, 251.46mmol) in MeCN (200mL). The mixture was stirred at 80 ° C for 3h until the reaction was complete indicated by CCD (petroleum ether: ethyl acetate = 3: 1). The mixture was concentrated followed by adding water (300 mL), extracted by ethyl acetate (200 mL&gt; &lt;3). The organic layers were combined, dried over Na₂SW₄ and concentrated under reduced pressure to provide the yellow crude product (30 g, M + H⁺ = 226.5) .

Stage 2: the synthesis of 1- (2-fluoro-4-nitrophenyl) -4- (2fluoroethyl) piperazine

L-Bromo-2-fluoroethane (5.4 g,

42.63 mmol), DMF (48 mL), 1- (2-fluoro-4-nitrophenyl) piperazine (8 g, 35.52 mmol) and Cs2CO3 (25.2 g, 77.34 mmol) to the flask. The reaction mixture was stirred at 80 ° C for 7h until the reaction was complete indicated by CCD (ethyl acetate: ether

111 oil = 1: 3). After cooling to room temperature, the mixture was filtered. The filtrate was emptied into water (700 mL) with vigorous stirring. The precipitate was collected, washed with water, and dried to provide the crude product (9 g, M + H⁺ = 272.5).

Stage_____3: ______ the _____ synthesis _____ of _____ 3-fluoro-4- (4- (2fluoroethyl) piperazin-l-yl) aniline (IV)

A solution of 1- (2-fluoro-4-nitrophenyl) -4- (2fluoroethyl) piperazine (L., 4.06 mmol) and Pd / C (10%) (0.2 g, 1. 87 mmol) in 1.4 -Dioxane (10 mL) was hydrogenated for 12h at room temperature until the reaction was complete indicated by CCD (MeOH: DCM = 1: 4). The mixture was filtered through a pad of Celite, and washed with 1,4-dioxane (5 mL). The filtrate was concentrated under reduced pressure to give crude product IV (1 g, M + H⁺= 242.5), which was used for the next step without further purification.

Intermediate V (the synthetic reaction scheme is shown below):

<img file="MX368491B_D0077.tif" />

Using similar chemistry as for the intermediary

112

IV, the intermediate (V) 4- (4- (2-fluoroethyl) piperazin-1yl) aniline was synthesized.

Example 3

Synthesis of N- (3- (2- (3-fluoro-4- (4- (2-fluoroethyl) piperazin-1yl) phenylamino) -5-methoxypyrimidin-4-yloxy) phenyl) acrylamide (I3)

The synthetic reaction scheme for compound 1-3 is shown below:

<img file="MX368491B_D0078.tif" />

1-3

N- (2- (2-Chloro-5-methoxypyrimidin-4-yloxy) phenyl) acrylamide (300mg, 0.981mmol), 3-fluoro-4- (4 - (2-fluoroethyl) piperazin-l-yl) were added sequentially aniline (236.8 mg, 0.981 mmol), potassium carbonate (175 mg, 1.27 mmol), tris (dibenzylideneacetone) dipalladium (35 mg, 0.07 mmol) and dicyclohexyl (2 ', 4', 6'-triisopropylbiphenyl-2-yl) phosphine (35 mg, 0.038 mmol) and t-BuOH (3 mL) to a 10 mL round bottom flask with a magnetite. The flask was placed in an oil bath and stirred under N₂, The reaction mixture was heated to reflux for 5 ~ 7 hr until the reaction was complete indicated by CCD (ethyl acetate / ether of

113 oil / TEA = 1/1 / 0.1 as elution). The mixture was concentrated under reduced pressure, followed by the addition of EtOAc (10 mL) and activated charcoal (0.1 g). After stirring for 15 min, the mixture was filtered through Celite®, and the filter cake was washed with ethyl acetate (10 mL). The filtrate was concentrated under reduced pressure. The crude was further purified by flash column chromatography (ethyl acetate / petroleum ether = 1/1 to 100% EtOAc as elution) to give the title compound 1-3 (120mg, 26% yield, 97.35% purity) , M + H⁺ = 511.5) as a white solid. ^XH NMR (500 MHz, DMSO-d_AND) δ 10.32 (s, 1H), 9.28 (s, 1H), 8.22 (s, 1H), 7.67 (t, J = 2.1 Hz, 1H), 7.56 (dd, J = 8.2, 1.0 Hz, 1H), 7.43 (t, J = 8.1 Hz, 1H), 7.35 (dd, J = 15.5, 1.9 Hz, 1H), 7.11 (dd, J = 8.7, 1.9 Hz, 1H), 6.97 (m,

1H), 6.79 - 6.71 (m, 1H), 6.43 (dd, J = 17.0, 10.2 Hz, 1H),

6.26 (dd, J = 17.0, 1.9 Hz, 1H), 5.77 (dd, J = 10.1, 1.9 Hz, 1H), 4.61 (t, J = 4.9 Hz, 1H), 4.51 (t, J = 4.9 Hz, 1H ), 3.89 (s, 3H), 2.93 - 2.81 (m, 4H), 2.69 (t, J = 4.9 Hz, 1H), 2.63 (t, J = 4.9 Hz, 1H), 2.57 (br s, 4H). ¹³C NMR (126 MHz, DMSOd₆) δ 165.32 (s), 161.39 (s), 157.66 (s), 155.73 (s), 154.92 (d, J = 65.0 Hz), 145.45 (s), 142.39 (s), 138.17 (d, J = 11.0

Hz), 137.16 (s), 135.13 (d, J = 9.3 Hz), 133.71 (s), 131.94 (s), 129.23 (s), 120.92 (s), 118.70 (s), 118.25 (s), 115.73 ( s), 114.68 (s), 107.96 (d, J = 26.1 Hz), 83.84 (d, J = 164.5

114

Hz), 59.62 (s), 59.46 (s), 55.05 (s, 2C), 52.54 (s, 2C).

Example 4

Synthesis of N- (3 - ((5-fluoro-2 - ((3-fluoro-4- (4- (2fluoroethyl) piperazin-lil) phenyl) amino) pyrimidin-4yl) amino) phenyl) acrylamide (1-4 )

The synthetic reaction scheme for compound 1-4 is shown below:

<img file="MX368491B_D0079.tif" />

<img file="MX368491B_D0080.tif" />

N- (3- (2-Chloro-5-fluoro-pyrimidin-4-ylamino) phenyl) acrylamide (878 mg), 1,4-dioxane (30) were added sequentially

3-fluoro-4- (4- (2fluoroethyl) cyclohexyl) aniline (730 mg) and TEA (0.7 mL) to the flask. The reaction mixture was stirred under reflux for 24

h. CCD (petroleum ether: ethyl acetate = 2: 1 as elution) indicates completion of the reaction. The reaction mixture was concentrated under reduced pressure. The crude was redissolved in ethyl acetate (100 mL), adjusted to pH 8 with aqueous sodium bicarbonate solution, and washed with water (100 mL x3). The organic layer was separated, and the solvent was removed under reduced pressure. The crude oil was further purified

115 by flash column chromatography to provide the title compound 1-4 (480 mg, M + H⁺= 498.5 32% yield). NMR (500 MHz, MeOD) δ 8.08 (s, 1H), 7.93 (d, J = 3.8 Hz, 1H), 7.57 (dd, J = 15.1, 2.5 Hz, 1H), 7.48 - 7.39 (m, 2H), 7.32 (t, J = 8.1 Hz, 1H), 7.23 - 7.13 (m, 1H), 6.90 (t, J = 9.2 Hz, 1H), 6.46 (dd, J = 17.0, 9.9 Hz, 1H), 6.38 (dd , J = 17.0, 1.9 Hz, 1H), 5.79 (dd, J = 9.9, 1.9 Hz, 1H), 4.68 (t, J = 4.5 Hz, 1H), 4.58 (t, J = 4.5 Hz, 1H), 3.11 3.03 (m, 4H), 2.81 (t, J = 4.5 Hz, 1H), 2.76 - 2.70 (m, 5H).

<td>¹³C NMR</td><td> (126</td><td colspan="2">MHz, MeOD)</td><td>δ 166.30</td><td>(s), 158.11 (s),</td><td> 157.14</td><td>(s)</td>

<td> 156.17</td><td>(s),</td><td> 152.12</td><td>(d,</td><td>J = 10.</td><td>.7 Hz), 143.43 (s</td><td> ), 141.</td><td> . 61</td>

<td> 140.82</td><td>(m),</td><td> 140.37</td><td>(d,</td><td>J = 35.4</td><td>Hz), 138.06 (d, J</td><td> = 10.8</td><td>Hz)</td>

<td> 135.17</td><td>(d,</td><td>J = 9.7</td><td>Hz)</td><td> , 132.75</td><td>(s), 130.22 (s),</td><td> 128.07</td><td>(s)</td>

<td> 120.36</td><td>(d,</td><td>J = 4.0</td><td>Hz)</td><td> , 119.38</td><td>(s), 117.04 (s),</td><td> 116.11</td><td>(s)</td>

<td> 115.41</td><td>(s),</td><td> 108.84</td><td>(d,</td><td>J = 25.9</td><td>Hz), 82.71 (d, J =</td><td> = 166.3</td><td>Hz)</td>

<td> 59.44</td><td>(d, J</td><td> = 19.8</td><td>Hz),</td><td> . 54.75 (</td><td>s, 2C), 51.95 (d,</td><td>J = 2.</td><td>6 Hz</td>

<td>2 C) .</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

Example 5

Synthesis of N- (3- (2- (4- (4- (2-fluoroethyl) piperazin-lil) phenylamino) -5-methoxypyrimidin-4-yloxy) phenyl) acrylamide (I5)

The synthetic reaction scheme for compound 1-5 is shown below:

116

Cl

<img file="MX368491B_D0081.tif" />

<img file="MX368491B_D0082.tif" />

OR

<img file="MX368491B_D0083.tif" />

Added

N

<img file="MX368491B_D0084.tif" />

NH₂

TFA

<img file="MX368491B_D0085.tif" />

sequentially

N- (3- (2-Chloro-5-methoxypyrimidin-4-ylamino) phenyl) acrylamide (1,089 g,), 4- (4 (2-fluoroethyl) piperazin-l-yl) aniline (0.800 potassium carbonate (1,231g) , tris (dibenzylidene ketone) dipalladium (0.300 dicyclohexyl phosphine

4 ', 6'- triisopropylbiphenyl-2-yl) (0.300 t-BuOH (30 mL) to a lOOmL round bottom flask with a magnetite. The flask was placed in an oil bath and stirred under a flow of N₂. The reaction mixture was heated to reflux for 5 ~ 7 hr until the reaction was complete indicated by CCD (ethyl acetate / petroleum ether / TEA = 1/1 / 0.1 as elution). The mixture was concentrated under reduced pressure, followed by the addition of EtOAc (50 mL) and activated charcoal (0.5 g). After stirring for 15min, the mixture was filtered through

Celite®. The filter cake was washed with ethyl acetate (50 mL). The filtrate was concentrated under reduced pressure and the crude was further purified by flash column chromatography (ethyl acetate / petroleum ether - 1/1 to

117

100% ethyl acetate as elution) to give the title compound 1-5 (750mg, 42.65% yield, 95.8% purity,

M + H⁺ = 492.5) as a white solid. ^XH NMR (500 MHz, DMSO-d₆) δ

<td> 10.09 (</td><td>yes</td><td>1H), 8.69</td><td>(s, 1H), 8.58</td><td>(s, 1H),</td><td> 7.98</td><td>(t, J =</td><td> 1.8</td>

<td>Hz, 1H)</td><td> , 7</td><td>.82 (s, 1H</td><td> ), 7.55 - 7.49</td><td>(m, 3H),</td><td> 7.42</td><td>(d, J =</td><td> 8.6</td>

<td>Hz, 1H)</td><td> , 7</td><td>.26 (t, J</td><td>= 8.1 Hz, 1H),</td><td>6.77 (d,</td><td>J =</td><td>9.1 Hz,</td><td>2H),</td>

<td colspan="2">6.47 (dd,</td><td>J = 17.0,</td><td>10.2 Hz, 1H), 6</td><td>.27 (dd,</td><td>J = 1</td><td> .7.0, 2.0</td><td>Hz,</td>

<td>1H), 5.</td><td> 76</td><td>(dd, J =</td><td>10.1, 2.0 Hz,</td><td>1H), 4.65</td><td> - 4</td><td>.59 (m,</td><td>1 HOUR) ,</td>

<td> 4.56 -</td><td colspan="2">4.50 (m, 1H),</td><td>3.85 (s, 3H),</td><td> 3.05 - 2</td><td> . 95 (</td><td>m, 4H),</td><td> 2.70</td>

<td>(t, J</td><td> = 4</td><td>.9 Hz, 1H)</td><td>, 2.64 (t, J =</td><td>4.9 Hz,</td><td>1 HOUR) ,</td><td> 2.62 -</td><td> 2.54</td>

<td>(m, 4H)</td><td colspan="2"> . ¹³C NMR (12 &lt;</td><td>6 MHz, DMSO-d₆)</td><td>δ 165.06</td><td>(s),</td><td> 156.09</td><td>(s),</td>

<td> 153.81</td><td>(s)</td><td> , 147.29</td><td>(s), 141.66 (s)</td><td> , 140.88</td><td>(s),</td><td> 139.29</td><td>(s),</td>

<td> 136.26</td><td>(s)</td><td> , 135.95</td><td>(s), 134.03 (s)</td><td> , 130.53</td><td>(s),</td><td> 128.76</td><td>(s),</td>

<td> 121.28</td><td>(s)</td><td> , 119.17</td><td>(s), 118.00 (s)</td><td> , 116.38</td><td>(s),</td><td> 115.43</td><td>(s),</td>

<td>83.91 l</td><td>! d,</td><td>J = 164.3</td><td>Hz), 59.58 (d,</td><td>J = 19 ..</td><td>5 Hz)</td><td> , 59.00</td><td>(s),</td>

<td> 55.05 (</td><td>yes</td><td>2C), 51.30</td><td>(s, 2C).</td><td></td><td></td><td></td><td></td>

Example 6

Synthesis of N- (2- (5-fluoro-2- (4- (4- (2-fluoroethyl) piperazin-lil) phenylamino) pyrimidin-4-ylamino) phenyl) acrylamide (1-6)

The synthetic reaction scheme for compound 1-6 is shown below:

118

<img file="MX368491B_D0086.tif" />

<img file="MX368491B_D0087.tif" />

1-6

N- (2- (2-Chloro-5 fluoropyrimidin-4-ylamino) phenyl) acrylamide (2,010 g, 6,849 mmol), 4- (4- (2-fluoroethyl) piperazin-l-yl) aniline (2,008) were added sequentially g,

8,969 mmol), potassium carbonate (1,880 g, 13,698 mmol), tris (dibenzylideneacetone) dipalladium (630 mg, 0.685 mmol) and dicyclohexyl (2 ', 4', 6'-triisopropylbiphenyl-2-yl) phosphine (627 mg, 1,370 mmol) and t-BuOH (20mL) in a 100 mL round bottom flask with a magnetite. The flask was placed in an oil bath and stirred under a flow of N₂. The reaction mixture was heated to reflux for 5 ~ 7 hr until the reaction was complete indicated by CCD (EtOAc / petroleum ether / TEA = 3/1 / 0.1 as elution). The mixture was concentrated under reduced pressure, followed by the addition of EtOAc (50 mL) and activated charcoal (0.5 g). After stirring for 15min, the mixture was filtered through Celite®. The filter cake was washed with ethyl acetate (50 mL). The filtrate was concentrated under reduced pressure. The crude was further purified by flash column chromatography (EtOAc / petroleum ether = 3/1 for EtOAc as elution) to

119 give the title compound 1-6 (1.85 g, yield of

<td> 56.23%,</td><td colspan="2">purity 95%,</td><td>M + H⁺</td><td> = 480.2</td><td colspan="3">) as solid</td><td colspan="3">light yellow.</td>

<td>^XH NMR</td><td> (500</td><td colspan="2">MHz, MeOD)</td><td> &gt;8.07 (</td><td>Yeah</td><td> 11</td><td>I), 7.88</td><td>(d,</td><td>J = 3.7</td><td>Hz,</td>

<td>1H), 7.</td><td> 50 -</td><td> 7.39 (</td><td>m, 4H</td><td> ), 7.29</td><td>(t</td><td></td><td>J = 8.1</td><td>Hz,</td><td>1H), 6.</td><td> 92 -</td>

<td>6.85 (m</td><td>, 2H)</td><td> , 6.46</td><td>(dd,</td><td>J = 17.</td><td>or,</td><td> 9.</td><td>8 Hz, 11</td><td>I), 6</td><td>.39 (dd,</td><td>J =</td>

<td> 17.0, 2</td><td colspan="2">.1 Hz, 1H),</td><td> 5.80</td><td colspan="2">(dd, J =</td><td> 9</td><td> .8, 2.1</td><td>Hz,</td><td>1H), 4.</td><td> 71 -</td>

<td>4.65 (m</td><td>, 1 HOUR)</td><td> , 4.61</td><td colspan="3">- 4.55 (m, 1H),</td><td> 3</td><td> .17 - 3.</td><td colspan="2">10 (m, 4H),</td><td> 2.84</td>

<td> - 2.78</td><td colspan="2">(m, 1H), 2.7</td><td> 8-2.</td><td>.69 (m,</td><td>5H)</td><td> •</td><td>¹³C NMR</td><td> (126</td><td colspan="2">MHz, MeOD) δ</td>

<td> 166.25</td><td>(s),</td><td> 157.72</td><td>(s),</td><td> 152.10</td><td>(d,</td><td>J</td><td> ' = 10.7</td><td>Hz),</td><td> 148.08</td><td>(s),</td>

<td> 143.16</td><td>(s),</td><td> 141.20</td><td>(s),</td><td> 141.12</td><td>(s)</td><td></td><td> 140.96</td><td>(s),</td><td> 140.66</td><td>(s),</td>

<td> 140.07</td><td>(s),</td><td> 135.13</td><td>(s),</td><td> 132.74</td><td>(s)</td><td></td><td> 130.13</td><td>(s),</td><td> 128.15</td><td>(s),</td>

<td> 122.40</td><td>(s),</td><td> 119.20</td><td>(s),</td><td> 118.27</td><td>(s)</td><td></td><td> 116.94</td><td>(s),</td><td> 115.33</td><td>(s),</td>

<td colspan="2">82.76 (d, J</td><td> = 166.</td><td>4 Hz)</td><td> , 59.42</td><td>(d</td><td>t</td><td>J = 19.</td><td>7 Hz)</td><td> ), 54.71</td><td>(s,</td>

<td>2C), 51</td><td> .15 (</td><td>s, 2C).</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

Example 7

Synthesis of N- (2- (2- (3-fluoro-4- (4- (2-fluoroethyl) piperazin-1yl) phenylamino) -5-methoxypyrimidin-4-ylamino) phenyl) acrylamide

The synthetic reaction scheme for compound 1-7 is shown below:

120

<img file="MX368491B_D0088.tif" />

<img file="MX368491B_D0089.tif" />

<img file="MX368491B_D0090.tif" />

N- (2- (2-Chloro-5-methoxypyrimidin-4-ylamino) phenyl) acrylamide (1,521 g, 5 mmol), 3-fluoro-4- (4- (2-fluoroethyl) piperazin-l-yl) were added sequentially aniline (1,210 g, 5 mmol), potassium carbonate (1,383 g, 10 mmol), tris (dibenzylideneacetone) dipalladium (460 mg, 0.5 mmol), and dicyclohexyl (2 ', 4', 6'-triisopropylbiphenyl-2-yl) phosphine (4.775 mg, lmmol) and t-BuOH (50 mL) in a 100 mL round-bottom flask with a magnetite. The flask was placed in an oil bath and stirred under a flow of N₂. The reaction mixture was heated to reflux for 5 ~ 7 hr until the reaction was complete indicated by CCD (EtOAc / petroleum ether / TEA = 1/1 / 0.1 as elution). The mixture was concentrated under reduced pressure, followed by the addition of EtOAc (50 mL) and activated charcoal (0.5 g). After stirring for 15min, the mixture was filtered through Celite®, and the filter cake was washed with ethyl acetate (50 mL). The filtrate was concentrated and the crude was further purified by flash column chromatography (EtOAc / petroleum ether = 1/1 for EtOAc as elution) to provide the

121 title compound 1-7 (1,537 g, yield 60.2%, purity 95.33%, M + H⁺ = 510.3) as a light yellow solid.

NMR (500 MHz, DMSO-d₆) δ 10.08 (s, 1H), 8.89 (s, 1H), 8.77 (s, 1H), 7.96 (t, J = 1.8 Ηζ, 1H), 7.86 (s, 1H), 7.67 (dd, J = 15.7, 2.4 Ηζ, 1H), 7.51 (d, J = 8.0 Ηζ, 1H), 7.44 (d, J =

8.7 Ηζ, 1H), 7.31 (dd, J = 8.7, 2.0 Ηζ, 1H), 7.27 (t, J = 8.1 Ηζ, 1H), 6.84 (dd, 9.8, 9.1 Ηζ, 1H), 6.46 (dd, J = 17.0,

10.2 Ηζ, 1H), 6.25 (dd, J = 17.0, 2.0 Ηζ, 1H), 5.75 (dd, J =

10.1, 2.0 Ηζ, 1H), 4.61 (t, J = 4.9 Ηζ, 1H), 4.52 (t, J = 4.9 Hz, 1H), 3.87 (s, 3H), 2.97 - 2.86 (m, 4H), 2.70 ( t, J = 4.9

Ηζ, 1H), 2.64 (t, J = 4.9 Ηζ, 1H), 2.59 (s, 4H). ¹³C NMR (126

MHz, DMSO-dg) δ 165.07 (s), 157.89 (s), 155.97 (s), 155.49 (s), 153.84 (s), 141.51 (s), 141.07 (s), 139.06 (d, J = 11.0

Hz), 138.82 (s), 136.67 (s), 134.63 (d, J = 9.4 Hz), 134.06 (s), 130.60 (s), 128.67 (s), 121.06 (d, J = 4.0 Hz), 119.34 ( s), 116.48 (s), 115.75 - 115.32 (m), 107.95 (d, J = 26.1 Hz), 83.85 (d, J = 164.4 Hz), 59.57 (d, J = 19.6 Hz), 58.89 (s), 55.11 (s, 2C), 52.65 (s, 2C).

Example 8

Synthesis of N- (2- (5-fluoro-2- (3-fluoro-4- (4- (2-fluoroethyl) piperazin-l-yl) phenylamino) pyrimidin-4yloxy) phenyl) acrylamide (1-8)

The synthetic reaction scheme for compound 1-8 is shown below:

122

<img file="MX368491B_D0091.tif" />

N- (2- (2-Chloro-5fluoropyrimidin-4-yloxy) phenyl) acrylamide (1,461g, 5mmol), 3-fluoro-4- (4- (2-fluoroethyl) piperazin-l-yl) were added sequentially aniline (1,210 g, 5 mmol), potassium carbonate (1,380 g, 10 mmol), tris (dibenzylideneacetone) dipalladium (460 mg, 0.5 mmol) and dicyclohexyl (2 ', 4', 6'-triisopropylbiphenyl-2-yl) phosphine (475 mg, 1 mmol) and t-BuOH (50 mL) in a 100 mL round bottom flask with a magnetite. The flask was placed in an oil bath and stirred under a flow of N₂. The reaction mixture was heated to reflux for 5-7 hr until the reaction was complete indicated by CCD (EtOAc / petroleum ether / TEA = 1/1 / 0.1 as elution). The mixture was concentrated under reduced pressure, followed by the addition of EtOAc (50 mL) and activated charcoal (0.5 g). After stirring for 15min, the mixture was filtered through Celite®, and the filter cake was washed with ethyl acetate (50 mL). The filtrate was concentrated under reduced pressure, and the crude was further purified by flash column chromatography (EtOAc / petroleum ether = 1/1 for EtOAc as elution) to

123 give the title compound 1-8 (1.72 g, yield of

69.1%, purity 98.67%, M + H⁺ = 499.3) as a light yellow solid. ^ΣΗ NMR (500 MHz, DMSO-d₆) δ 10.35 (s, 1H), 9.60 (s, 1H), 8.49 (d, 3.0 Hz, 1H), 7.74 (t, J = 2.0 Hz, 1H), 7.61

- 7.55 (m, 1H), 7.46 (t, J = 8.2 Hz, 1H), 7.32 (d, J = 15.1 Hz, 1H), 7.10 (d, J = 8.2 Hz, 1H), 7.04 (m, 1H) , 6.77 (t, J =

9.4 Hz, 1H), 6.44 (dd, J = 17.0, 10.2 Hz, 1H), 6.27 (dd, J = 17.0, 1.9 Hz, 1H), 5.78 (dd, J = 10.1, 1.9 Hz, 1H), 4.61 ( t, J = 4.9 Hz, 1H), 4.51 (t, J = 4.9 Hz, 1H), 2.94 - 2.83 (m, 4H), 2.69 (t, J = 4.9 Hz, 1H), 2.63 (t, J = 4.9 Hz, 1H), 2.57 (s, 4H). ¹³C NMR (126 MHz, DMSO-d₆) δ 165.36 (s), 159.02 (d, J

<td> = 11.0</td><td>Hz), 157.52</td><td>(s)</td><td>i, 156.87</td><td>(d,</td><td>J = 3.4</td><td>Hz),</td><td> 155.</td><td> 59</td><td>(s),</td>

<td> 153.97</td><td>(s), 147.89</td><td>(d,</td><td>J = 22.1</td><td>Hz)</td><td> , 142.88</td><td>(s),</td><td> 142.</td><td> 47</td><td>(s),</td>

<td> 140.90</td><td>(s), 137.36</td><td>(d,</td><td>J = 10.9</td><td>Hz)</td><td> , 135.82</td><td>(d, J</td><td> ' = 9</td><td> .3</td><td>Hz),</td>

<td> 133.67</td><td>(s), 132.04</td><td>(s)</td><td> , 129.30</td><td>(s),</td><td> 120.86</td><td>(d, J</td><td> = 3</td><td> . 9</td><td>Hz),</td>

<td> 118.70</td><td>(s), 116.34</td><td>(s)</td><td> , 114.68</td><td>(s),</td><td> 108.54</td><td>(d, J</td><td> = 26</td><td> . 0</td><td>Hz),</td>

<td> 83.83</td><td>(d, J = 164.</td><td colspan="2">4 Hz), 59.53</td><td>(d,</td><td>J = 19,</td><td>.5 Hz)</td><td> , 55</td><td> . 01</td><td>(s,</td>

<td>2C), 5:</td><td>2.46 (d, J =</td><td> 2.4</td><td>Hz, 2C).</td><td></td><td></td><td></td><td></td><td></td><td></td>

Example 9

Synthesis of N- (2- (2- (3-fluoro-4- (4- (2-fluoroethyl) piperazin-1yl) phenylamino) -5-methoxypyrimidin-4-yloxy) phenyl) aorylamide (I9)

The synthetic reaction scheme for compound 1-9 is shown below:

124

<img file="MX368491B_D0092.tif" />

<img file="MX368491B_D0093.tif" />

1-9

N- (2- (2-Chloro-5-methoxypyrimidin-4-yloxy) phenyl) acrylamide (1,360 g, 4.48 mmol), 4- (4- (2-fluoroethyl) piperazin-l-yl) aniline 1 (1,002) were added sequentially g,

4.48 mmol), potassium carbonate (1,380 g, 10 mmol), tris (dibenzylideneacetone) dipalladium (460 mg, 0.5 mmol) and dicyclohexyl (2 ', 4', 6'-triisopropylbiphenyl-2-yl) phosphine (475 mg, 1 mmol) and t-BuOH (50 mL) in a 10 mL round bottom flask with a magnetite. The flask was placed in an oil bath and stirred under a flow of N₂. The reaction mixture was heated to reflux for 5 ~ 7 hr until the reaction was complete indicated by CCD (EtOAc / petroleum ether / TEA = 1/1 / 0.1 as elution). The mixture was concentrated under reduced pressure, followed by the addition of EtOAc (50 mL) and activated charcoal (0.5 g). After stirring for 15min, the mixture was filtered through Celite®, and the filter cake was washed with EA (50 mL). The filtrate was concentrated and the crude was further purified by flash column chromatography (EtOAc / petroleum ether = 1/1 for EtOAc as elution) to provide the title compound 1-9 (840

125

<td>mg,</td><td>performance</td><td>38%,</td><td>purity 96.93%,</td><td>M + H⁺ =</td><td colspan="2">= 493.5) as</td>

<td colspan="2">white solid. ^XH</td><td>NMR (500</td><td>MHz, DMSO-ds)</td><td>δ 10.32</td><td>(s,</td><td>1H), 9.00</td>

<td>(s,</td><td>J = 24.8 Hz,</td><td>1H), 8.17</td><td>(s, 1H), 7.59</td><td> - 7.63</td><td>(m,</td><td>2H), 7.43</td>

<td>(t,</td><td>J = 8.4 Hz,</td><td>1H), 7.29</td><td>(d, J = 9.0</td><td>Hz, 2H)</td><td> , 7</td><td> .03 - 6.89</td>

<td>(m,</td><td>1H), 6.65 (d,</td><td>J = 9.1</td><td>Hz, 2H), 6.44</td><td colspan="2">(dd, J -</td><td> 17.0, 10.1</td>

<td>Hz,</td><td>1H), 6.28 (dd</td><td>, J = 17.</td><td>0, 1.9 Hz, 1H)</td><td> , 5.78</td><td>(dd,</td><td>J = 10.1,</td>

<td> 1.9</td><td colspan="2">Hz, 1H), 4.62 (t, J =</td><td>4.9 Hz, 1H),</td><td>4.52 (t</td><td>, J</td><td>= 4.9 Hz,</td>

<td>1 HOUR) ,</td><td>3.87 (s, J =</td><td>15.8 Hz,</td><td>3H), 3.05-2</td><td>.89 (m,</td><td>4H)</td><td>, 2.69 (t,</td>

<td>J -</td><td>4.9 Hz, 1H),</td><td>2.63 (t,</td><td>J = 4.9 Hz,</td><td>1H), 2.</td><td> 61 </td><td>- 2.53 (m,</td>

<td>4H). ¹³</td><td>C NMR</td><td> (126</td><td>MHz,</td><td>DMSO-d₆)</td><td>δ 165.32</td><td>(s), 161.44</td><td>(s),</td>

<td> 155.80</td><td>(s),</td><td> 154.79</td><td>(s),</td><td> 147.56 (</td><td>s), 145.97</td><td>(s), 142.27</td><td>(s),</td>

<td> 136.63</td><td>(s),</td><td> 135.12</td><td>(s),</td><td> 133.70 (</td><td>s), 131.88</td><td>(s), 129.26</td><td>(s),</td>

<td> 121.13</td><td>(s,</td><td>2C), 1</td><td> .18.76</td><td colspan="2">(s), 118.16 (s),</td><td>117.74 (s,</td><td> 20 ,</td>

<td> 114.95</td><td>(s),</td><td> 83.90</td><td>(d, J</td><td> = 164.3</td><td>Hz), 59.64</td><td>(s), 59.48</td><td>(s),</td>

54.99 (s, 2C), 51.13 (s, 2C).

Example 10

Synthesis of N- (3- (2- (4- (2-methoxyethoxy) phenylamino) -7Hpyrrolo [2,3-d] pyrimidin-4-yloxy) phenyl) acrylamide (1-10)

The synthetic reaction scheme for compound 1-10 is shown below:

126

<img file="MX368491B_D0094.tif" />

<img file="MX368491B_D0095.tif" />

Step 1: Synthesis of 1- (2-methoxyethoxy) -4-nitrobenzene (3)

<img file="MX368491B_D0096.tif" />

To a solution of 4-nitrophenol (18.2g, 130mmol) and 1bromo-2-methoxyethane (20g, 144mmol) in DMF (60ml), K2CO3 (36g, 260mmol) was added. The reaction mixture was stirred at 65-70 ° C for 4h and then cooled to room temperature. Water (200 mL) was added and the mixture was extracted with ethyl acetate (200 mL x3). The combined organic layers were washed with water (200 ml x3), dried over Na₂SW₄. The solvent was removed under reduced pressure to provide

127 the desired product (3) as a white solid (25 g, 97.6% yield), which was used for the next step without further purification.

Step 2: Synthesis of 4- (2-methoxyethoxy) aniline (4) h₂n- ^, and

<img file="MX368491B_D0097.tif" />

To a solution of compound 3 (25 g, 127 mmol) in THF (180 mL), water (60 mL) was added. After stirring for ~ 5 min, NH was added sequentially₄C1 (28g, 523mmol) and Fe (36g, 635mmol). The reaction mixture was heated to reflux and stirred for 4h. After cooling to room temperature, the mixture was filtered through Celite® and washed with ethyl acetate (200 mL). The filtrate was concentrated under reduced pressure. The crude was redissolved in ethyl acetate (500 mL), washed with saturated NaHCOg (200 mL) and water (200 mL). The organic layer was concentrated under reduced pressure. The crude was further purified by flash column chromatography to provide the desired product 4 (12g, 56.7% yield, M + H⁺= 168.5).

128

Step____3: _____ Synthesis ____ of ____ pivalate ____ of _____ (2- (4- (2-methoxyethoxy) phenylamino) -4- (3-nitrophenoxy) -7H-pyrrolo [2,3d] pyrimidin-7-yl) methyl (6)

POM

<img file="MX368491B_D0098.tif" />

To a solution of (2-chloro-4- (3-nitrophenoxy) -7H-pyrrolo [2,3-d] pyrimidin-7-yl) methyl (4 g, 10 mmol) pivalate, compound 4 (1.67 g, 10 mmol) ) in t-BuOH (40 mL), potassium carbonate (2.8 g, 20 mmol), tris (dibenzylideneacetone) dipalladium (500 mg), and dicyclohexyl (2 ', 4', 6'-triisopropylbiphenyl-2-yl) were added sequentially. ) phosphine (500 mg). The reaction mixture was stirred under flow of N₂ and heated to reflux. After stirring for 3 ~ 4, CCD (DCM / MeOH = 10/1 as elution) indicates completion of the reaction. The mixture was cooled to 40 ~ 50 ° C, filtered through Celite®. The filter cake was washed with t-BuOH. The filtrate was concentrated under reduced pressure. The residue was redissolved in ethyl acetate (200 mL), washed with water, and concentrated under reduced pressure. The crude was further purified by flash column chromatography to provide the desired product 6 (5.9 g, M + H⁺=536.5).

9

Stage 4; Synthesis of N- (4- (2-methoxyethoxy) phenyl) -4- (3nitrophenoxy) -7H-pyrrolo [2,3-d] pyrimidin-2-amine (7)

<img file="MX368491B_D0099.tif" />

6 (5.9 g, 0.01 mol) and MeOH (120 mL) were charged to a reactor (250mL). When 6 completely dissolved, the solution was cooled in an ice bath to ~ 10 ° C. Then NaOH solution (2.5 M, 8 mL) was added over 45 min, keeping the temperature under 16 ° C throughout the addition. When the addition was complete, the reaction mixture was stirred for 4 ~ 5h at ~ 16 ° C. The completion of the reaction was monitored by CCD and LC-MS indicating the consumption of 6 and low content (less than 8%) of an intermediate (PM: 493). Water (300mL) was added to the reaction over 90 min, keeping the temperature below 20 ° C. Desired product 8 was precipitated during the addition of water. The mixture was stirred for another 15 min after the addition of the water. The precipitate (crude) was collected and washed with water (200 mL). The crude was redissolved in ethyl acetate (200 mL) and washed with water (200 mLx3). The mixture was passed through Celite® to remove the insoluble solid. The solvent was removed under reduced pressure. The residue was further purified

130 by recrystallization from ethyl acetate / petroleum ether (5: 4) to provide the desired product 7 (3 g, 71.2% yield, M + H⁺=422.5).

Step _____ 5: _____ Synthesis _____ of _____ 4- (3-aminophenoxy) -N- (4- (2 methoxyethoxy) phenyl) -7H-pyrrolo [2,3-d] pyrimidin-2-amine (8)

<img file="MX368491B_D0100.tif" />

To a solution of compound 7 (3 g, 7.1 mmol) in THF (40 mL), water (15 mL), NH4C1 (1.5 g, 28.4 mmol) and Fe (2 g, 35.5 mmol) were added. The reaction mixture was heated to reflux for 4h and then cooled to room temperature. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was redissolved in ethyl acetate (50 mL) and washed with saturated NaHCOs (30 mL) and water (50 mL x3). The organic solvent was removed under reduced pressure. The crude was further purified by re-crystallization from ethyl acetate / PE (1: 1) to provide the desired product 8 (2.4g, 86.2% yield, M + H⁺=392.5).

131

Step 6: Synthesis of N- (3- (2- (4- (2-methoxyethoxy) phenylamino) 7H-pyrrolo [2,3-d] pyrimidin-4-yloxy) phenyl) acrylamide (1-10)

<img file="MX368491B_D0101.tif" />

To a solution of compound 8 (328 mg, 0.83 mmol) and DIEA (112 mg, 0.87 mmol) in THE (5 mL) with ice bath at 20 ° C, acryloyl chloride (79 mg, 0.87 mmol) was added during 5 min, keeping the temperature around -10 ° C throughout the addition. The reaction mixture was stirred for another 30min at the same temperature after the addition. After warming to room temperature, ethyl acetate (50 mL) was added. The mixture was washed with water (50 mL x3). The organic solvent was removed under reduced pressure. The crude was further purified by flash column chromatography to provide the desired product ΙΙΟ (350mg, 94.6% yield, M + H⁺=446.5). ^XH NMR (500 MHz, DMSO-d₆) δ 11.51 (s, J = 26.7 Hz, 1H), 10.31 (s, 1H), 8.92 (s, J = 7.3 Hz, 1H), 7.66 (t, J = 2.1 Hz, 1H), 7.61 7.56 (m, 1H), 7.51 (d, J = 8.9 Hz, 2H), 7.43 (t, J = 8.1 Hz, 1H), 7.06 (dd, J = 3.5, 2.3 Hz, 1H), 7.00 (m, 1H), 6.70 ( d, J = 9.0 Hz, 2H), 6.44 (dd, 17.0, 10.2 Hz, 1H), 6.30 - 6.23 (m, 2H), 5.77 (dd, J = 10.1, 1.9 Hz, 1H), 4.02 - 3.96 (m ,

132

<td>2H), 3.66 - 3.60 (m,</td><td>2H)</td><td> 1, 3.31</td><td>(s,</td><td>J = 2.3</td><td>Hz,</td><td>3H). ¹³C</td><td>NMR</td>

<td>(126 MHz, DMSO-dg) δ</td><td colspan="2">165.33 (s</td><td> ) ,</td><td>163.90 l</td><td>S),</td><td> 157.42</td><td>(s),</td>

<td>157.35 (s), 155.32 (s</td><td></td><td> 154.64 (</td><td>) s),</td><td> 142.24</td><td>(s),</td><td> 136.59</td><td>(s),</td>

<td>133.71 (s), 131.81 (s</td><td></td><td> 129.26 (</td><td>: s),</td><td> 123.61</td><td>(S),</td><td> 121.74</td><td>(s),</td>

<td>118.97 (s), 117.98 (s</td><td> ) _r</td><td> 116.07</td><td>(s)</td><td> , 114.95</td><td>(s),</td><td> 100.28</td><td>(s,</td>

<td>2C), 72.53 (s), 69.00</td><td>(s)</td><td> , 60.17</td><td>(s)</td><td></td><td></td><td></td><td></td>

Example 11

Synthesis of N- (3- (2- (4- (2-methoxyethoxy) phenylamino) -7Hpyrrolo [2,3-d] pyrimidin-4-ylamino) phenyl) acrylamide (1-11)

The synthetic reaction scheme for compound 1-11 is shown below:

<img file="MX368491B_D0102.tif" />

<img file="MX368491B_D0103.tif" />

<img file="MX368491B_D0104.tif" />

1-11

133

Step 1: Synthesis of (2,4-dichloro-7Hpyrrolo [2,3-d] pyrimidin-7-yl) methyl pivalate (2)

<img file="MX368491B_D0105.tif" />

NaH (80%, 3.54 g, 0.117 mol) was slowly added to a solution of 2,4-dichloro-7H-pyrrolo [2,3-d] pyrimidine 1 (20.03 g, 0.106 mol) in THF (20C mL), and kept the temperature between 0 ~ -5 ° C. The mixture was stirred for another 15 min until the evolution of hydrogen ceased. A solution of POMC1 (18.96 g, 0.12 mol) in THF (70 mL) was added over 30 min. The reaction mixture was allowed to warm to room temperature and stirred for 3 ~ 4 h. When HPLC indicates that 1 was consumed, the reaction mixture was filtered through Celite®, washed with ethyl acetate (100 mL). The combined organic layers were concentrated under reduced pressure. The residue was redissolved in ethyl acetate (300 mL), washed with water (100 mL x2) and brine (100 mL). The organic layer was separated and the solvent was removed under reduced pressure to provide the desired product 2 as a yellow solid, which was used directly for the next step without further purification.

134

Stage_____2: _____ Synthesis _____ of _____ pivalate _____ of _____ (4- (3 (tertbutoxycarbonylamino) -2-chloro-7H-pyrrolo [2,3-d] pyrimidine

7-yl) methyl (3)

NHBoc

<img file="MX368491B_D0106.tif" />

TEA (7 mL) was added to a mixture of pyrimidine 2 (6.1 g, 0.02 mol) and tert-butyl 3-aminophenylcarbamate (4.3 g, 0.019 mol) in nBuOH (110 mL). The reaction mixture was heated to reflux and stirred for 12 ~ 18h. When HPLC indicates that Compound 2 was consumed, the mixture was cooled to room temperature. Water (200 mL) and ethyl acetate (100 mL) were added to this mixture, which was stirred and separated into layers. The organic layer was washed with 1N HCI (20mL), then NaHCO₃ 5% (50 mL), dried over sodium sulfate. The organic solvent was removed under reduced pressure to give a light oil, in which hexane (60 mL) was added and stirred for 2 ~ 3 h. The precipitate was collected and dried to provide the desired product (3.92 g, M + H⁺= 474.5) as a white solid.

135 íW

Step____3; ____ Synthesis ____ of ____ (4- (3- (tert-butoxycarbonylamino) phenylamino) -2- (4- (2-methoxyethoxy) phenylamino) -7H-pyrrolo [2,3-d] pyrimidin-7yl) methyl (4)

NHBoc

<img file="MX368491B_D0107.tif" />

T-BuOH (80 mL) was added to a RBF (250mL) equipped with magic stirring. Compound 3 (3.92 g, 8.3 mmol) and 4- (2-methoxyethoxy) aniline (1.5 g, 9 mmol) were added sequentially and stirred for 5-10 min. Potassium carbonate (2.28 g, 16.5 mmol), tris (dibenzylideneacetone) dipalladium (750 mg, 0.9 mmol) and dicyclohexyl (2 ', 4', 6'-triisopropylbiphenyl-2-yl) phosphine (750 mg, 18) were added sequentially. mmol) and an additional portion of t-BuOH (20 mL) was added. The flask was placed in an oil bath and stirred under a flow of N₂. The reaction mixture was heated to reflux. After stirring for 3 ~ 4 h, the reaction was complete indicated by CCD (DCM / MeOH = 10/1 as elution). The mixture was cooled to 40 ~ 50 ° C and filtered through Celite®. The filter cake was washed with ethyl acetate (50 mL). Filtering is

136 concentrated under reduced pressure. The crude was then purified by flash column chromatography (ethyl acetate: Hexane = l: 10 ~ l: 3) to provide the desired product 4 (1.74 g, M + H⁺= 605.5) as a brown solid.

Step 4: tert-Butyl (5) 3- (2- (4- (2-methoxyethoxy) phenylamino) -7H-pyrrolo [2,3d] pyrimidin-4-ylamino) phenylcarbamate

<img file="MX368491B_D0108.tif" />

To a solution of compound 4 (1.74 g) in MeOH (25 mL) and THE (15 mL) in an ice bath, NaOH solution (2.5 M, 2.3 mL) was added for 5 min, (the temperature was kept around 6 ~ 10 ° C throughout the addition). After the reaction mixture was stirred for 4-5 hr at the same temperature, NH3 (gas) was bubbled into this reaction for 2 ~ 3 hr. Once the reaction was complete indicated by CCD and LC-MS with the consumption of 4 and low content (less than 2%) of an intermediate (PM = 521). Water (100 mL), and ethyl acetate (60 mL) were added. The mixture was stirred. The organic phase was separated and dried over sodium sulfate. The solvent was removed under reduced pressure to give the desired product 5 (1.35 g, M + H⁺= 491.5) as brown oil, which was used directly for the next stage without purification

137 additional.

Step_____5: _____ Synthesis of _____ N- (3-aminophenyl) -N- (4- (2 methoxyethoxy) phenyl) -7H-pyrrolo [2,3-d] pyrimidine-2,4-diamine (6)

<img file="MX368491B_D0109.tif" />

TEA (5.6 mL) was added to a solution of 5 in DCM (49 mL). The mixture was stirred at room temperature for 4h. At this point the reaction was complete indicated by HPLC showing that compound 5 was consumed. The organic solvent was removed under reduced pressure. The crude was treated with cold saturated sodium bicarbonate (0 ° C) (30 mL) and ethyl acetate (60 mL). The mixture was stirred. The organic phase was separated and dried over sodium sulfate. The organic solvent was removed under reduced pressure. The crude (brown oil) was further purified by flash column chromatography (Hexane: ethyl acetate = 1: 5) to provide the desired product (918 mg, M + H⁺= 391.5) as a brown solid.

138

Step 6: Synthesis of N- (3- (2- (4- (2-methoxyethoxy) phenylamino) 7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) phenyl) acrylamide (1-11)

<img file="MX368491B_D0110.tif" />

To a solution of 6 (918 mg, 2.35 mmol) and DIEA (320 mg,

2.48 mmol) in THE (20 mL) cooled with an ice bath (10 ° C), acryloyl chloride (226 mg,

2.48 mmol). The reaction mixture was stirred for 20 min. At this point, CCD (DCM / MeOH = 8/1 as elution) indicates completion of the reaction. Saturated NaHCO3 solution (8 mL) was added to quench the reaction. THE was removed, and the residue was redissolved in ethyl acetate (50 mL) and water (20 mL). The mixture was stirred. The organic phase was separated and dried over sodium sulfate. The organic solvent was removed under reduced pressure. The crude (orange oil) was further purified by flash column chromatography (100% ethyl acetate) to provide the desired product 1-11 (652 mg, M + H⁺= 445.5) as a white solid. ^XH NMR (500 MHz, DMSO-d₆) δ 11.15 (s, 3H), 10.07 (s, 3H), 9.18 (s, 3H), 8.51 (s, 3H), 8.13 (s, 3H), 7.77 (d, J = 8.0 Ηζ, 3H),

7.73

7.66 (m, 6H), 7.33 (d, J = 8.5 Ηζ, 3H), 7.27 (t, J

139

8.0 Hz, 3H), 6.88 (dd, J = 3.4, 2.2 Hz, 3H), 6.85 - 6.79 (m, 6H), 6.67 (dd, J = 3.5, 2.0 Hz, 3H), 6.48 (dd, J = 17.0 , 10.2 Hz, 3H), 6.29 (dd, J = 17.0, 2.0 Hz, 3H), 5.77 (dd, J = 10.1, 2.0 Hz, 3H), 4.04 - 4.01 (m, 7H), 3.67 - 3.63 (m, 6H), 3.32 (s, 9H). ¹³C NMR (126 MHz, DMSO-d₆) δ 165.08 (s), 157.81 (s),

155.89 (s), 154.61 (s), 154.48 (s), 142.86 (s), 140.98 (s),

137.20 (s), 134.07 (s), 130.62 (s), 128.71 (s), 121.86 (s,

2C), 120.80 (s), 118.30 (s), 116.24 (s, 2C), 115.39 (s), 114.09 (s), 101.24 (s), 100.12 (s), 72.59 (s), 69.08 (s),

60.19 (s).

Example 12

Synthesis of N- (2- (5-fluoro-2 - ((4- (4- (2-flu oroethyl) piperazin-

1-yl) phenylamino) pyrimidin-4-yloxy) phenyl) acrylamide (1-12)

The synthetic reaction scheme for compound 1-12 is shown below:

1-12

To a solution of N- (3- (2-chloro-5-fluoropyrimidin-4yloxy) phenyl) acrylamide (1.3 g, 4.4 mmol), 4- (4- (2 (fluoroethyl) piperazin-l-yl) aniline (lg, 4.4 mmol) in t-BuOH (15 mL), potassium carbonate (1.2 g, 8.8 mmol), tris (dibenzylideneacetone) dipalladium (400

140 mg) and dicyclohexyl (2 ', 4', 6'-triisopropylbiphenyl-2-yl) phosphine (400 mg). The reaction mixture was heated to reflux and stirred under flow of N₂ for 2 h. At this point, CCD (petroleum ether: ethyl acetate = 1: 1 as elution) indicates completion of the reaction. The mixture was allowed to cool to 40 ~ 50 ° C, filtered through Celite®, and washed with t-BuOH. The filtrate was concentrated under reduced pressure. The residue was redissolved in ethyl acetate (100 mL), washed with water. The organic solvent was removed under reduced pressure. The crude was further purified by flash column chromatography to provide the desired product 1-12 (1.2g, 56.8% yield, M + H⁺=

481.5). ^XH NMR (500 MHz, DMSO-d₆) δ 10.36 (s, 1H), 9.33 (s, 1H), 8.43 (d, J = 3.0 Hz, 1H), 7.68 (t, J = 2.1 Hz, 1H), 7.63 (d, J = 8.2 Hz, 1H ), 7.45 (t, J = 8.1 Hz, 1H), 7.27 (d, J =

<td> 8.4</td><td>Hz, 2H),</td><td>7.02 (m, 1H),</td><td>6.66 (d, J</td><td colspan="3">= 8.8 Hz, 2H), 6.45</td>

<td>(dd,</td><td>J = 17.0</td><td>, 10.1 Hz, 1H)</td><td>, 6.28 (dd, J</td><td> = 17.0,</td><td> 1.9</td><td>Hz, 1H),</td>

<td> 5.79</td><td>(dd, J =</td><td>10.1, 1.9 Hz,</td><td>1H), 4.66-</td><td>4.58 (m,</td><td>1 HOUR</td><td> ), 4.56 -</td>

<td> 4.49</td><td>(m, 1H),</td><td> 3.04 - 2.93 (</td><td>m, 4H), 2.69</td><td>(t, J =</td><td> 4.9</td><td>Hz, 1H),</td>

<td> 2.63</td><td>(t, J =</td><td>4.9 Hz, 1H),</td><td>2.60 - 2.54 i</td><td>(m, 4H).</td><td>¹³c</td><td>NMR (126</td>

<td>MHz,</td><td>DMSO-d₆)</td><td>δ 165.37 (s)</td><td>, 158.94 (s),</td><td> 158.86</td><td>(s:</td><td> 1, 157.34</td>

<td>(s),</td><td> 157.31 (</td><td>: s), 154.09 (s</td><td>), 148.11 (s)</td><td> , 142.33</td><td>(s</td><td> ), 134.28</td>

<td>(s),</td><td>133.65 I</td><td>(s), 131.99 (s</td><td>), 129.34 (s)</td><td> , 121.74</td><td>(s</td><td> ), 118.76</td>

<td>(s),</td><td> 118.63 (</td><td>s), 117.59 (s)</td><td>, 114.94 (s),</td><td> 83.90 (</td><td>d,</td><td>J = 164.4</td>

1

Hz), 59.55 (d, J = 19.5 Hz), 54.96 (s, 2C), 50.96 (s, 2C).

Synthesis of intermediaries (Sl and Rl):

Intermediate Sl: _____ (S) -N- (1- (2-fluoroethyl) pyrrolidin-3yl) benzene-1,4-diamine

The synthetic reaction scheme is shown below:

<img file="MX368491B_D0111.tif" />

S-1

<img file="MX368491B_D0112.tif" />

FCgHiBr, Et₃N

CH₃CN, 60 C _H stage 3

Stage 1

A 3 neck round bottom flask (250 mL) equipped with a condenser was charged with 4-fluoro-nitrobenzene (7.3 g), (3S) - (-) - 1- (t-Butoxycarbonyl) -3aminopyrrolidine (11.2 g) and TEA (19 g) in dimethyl sulfoxide (58 mL). The reaction was heated to 100 ° C overnight. After the completion of the reaction, the reaction mixture was emptied into water. The mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. The organic solvent was removed under reduced pressure. The resulting crude product (22.75 g)

142 it was used directly for the next reaction step without further purification.

Stage 2

To the crude product from step 1 (22.7 g) in a 3-necked round bottom flask (250 mL) was added TFA (74 mL) at room temperature. The reaction mixture was stirred for 2 h at room temperature. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove unreacted TFA. The residue was redissolved in MeOH and then made basic using K2CO3 below 0 ° C. The crude product (29.95 g) was obtained after removal of K₂CO₃ unreacted and solvent.

Stage 3

To the crude from stage 2 (27 g) in MeCN (170 mL), TEA (35 mL) and 1,2-bromofluoroethane (12 g) were added. The reaction mixture was heated at 60 ° C for 25 hours. After the completion of the reaction, the reaction mixture was emptied into water. The mixture was extracted with ethyl acetate. The organic layer was separated, washed with brine, and dried over sodium sulfate. The organic solvent was removed under reduced pressure. The resulting crude was purified by flash chromatography to provide the desired product (11.3 g, 86% yield over 3 steps) as a yellow solid.

143

Stage 4

A solution of the above product from step 3 (2,183 g) and Pd / C (0.798 g) in 1,4-dioxane (43 mL) was hydrogenated for 22 hours at room temperature. After completion of the reaction, the reaction mixture was filtered through a pad of Celite. The Celite pad was washed with 1,4-dioxane. The filtrate was concentrated to provide the desired amine (2,022 g) as a dark oil which was used directly for the next reaction step without further purification.

(R) -N- (1- (2-fluoroethyl) pyrrolidin-3-yl) benzene-l, 4-diamine (3-1)

NH

Rl

The title compound was synthesized using similar procedures and chemistry described above with start from (3R) - (+) - 1- (t-Butoxycarbonyl) -3-aminopyrrolidine.

The synthetic reaction scheme for example XIII until

XX is shown below:

144

<img file="MX368491B_D0113.tif" />

ΗΝ

<img file="MX368491B_D0114.tif" />

R

X-Phos, Pd₂(dba)₃

K2CO3, t-BuOH reflux

<img file="MX368491B_D0115.tif" />

R

CI N

2a: X = O, R = MeO; 2b: X = 0, R = F;

2c: X = N, R = MeO; 2d: X = N, R = F;

Example 13

Synthesis of (S) -N- (3- (2- (4- (1- (2-fluoroethyl) pyrrolidin-3 ylmlno) phenylamino) -5-methoxypyrimidin-4yloxy) phenyl) acrylamide (1-13)

F

1-13

A mixture of 2a above (828 mg, 2.71 mmol), Sl (630 mg, 2.82 mmol), tris (dibenzylideneacetone) dipalladium (79 mg,

0.086 mmol), dicyclohexyl (2 ', 4', 6'-triisopropylbiphenyl-2yl) phosphine (84 mg, 0.176 mmol) and potassium carbonate (758 mg, 5.48 mmol) in tert-butanol (26 mL) was stirred under argon at reflux temperature for 3.5 h. After the

145 cooling to ΤΑ, the reaction mixture was filtered through Celite. Celite was washed with ethyl acetate. The combined filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (DCM / MeOH = 50/1) to give the title compound (1.07 g, 81% yield, M + H⁺ = 493.5). ^XH NMR (500 MHz, DMSO-d₆) δ 10.32 (s, 1H), 8.80 (s, 1H), 8.13 (s, 1H), 7.65 - 7.53 (m,

2H), 7.41 (t, J = 8.1 Hz, 1H), 7.13 (d, 8.7 Hz, 2H), 6.94 (m, 1H), 6.44 (dd, J = 17.0, 10.1 Hz, 1H), 6.35 - 6.20 ( m,

3H), 5.78 (dd, J = 10.1, 1.9 Hz, 1H), 5.23 (d, J = 7.0 Hz,

1H), 4.56 (t, J = 5.0 Hz, 1H), 4.46 (t, J = 5.0 Hz, 1H), 3.85 (s, 3H), 3.79 - 3.71 (m, 1H), 2.82 (dd, J = 9.2 , 6.9 Hz, 1H),

2.77 - 2.60 (m, 3H), 2.55 - 2.47 (m, 2H), 2.36 (dd, 9.3, 4.6 Hz, 1H), 2.20 - 2.10 (m, 1H), 1.57 - 1.43 (m, 1H). ¹³C NMR (126 MHz, DMSO-dg) δ 165.30 (s), 161.44 (s), 156.14 (s), 154.83 (s), 146.15 (s), 145.00 (s), 142.28 (s), 136.28 (s) ,

133.69 (s), 132.06 (s), 131.79 (s), 129.28 (s), 122.07 (s),

118.79 (s), 117.96 (s), 114.70 (s), 114.33 (s), 84.85 (d, J =

164.4 Hz), 62.73 (s), 59.70 (s), 57.21 (d, J = 19.5 Hz),

55.14 (s), 53.86 (s), 33.88 (s).

6

Example 14

Synthesis of (R) -N- (3- (2- (4- (1- (2-fluoroethyl) pyrrolidin-3ilaraino) phenylamino) -5-methoxypyrimidin-4yloxy) phenyl) acrylamide (1-14)

<img file="MX368491B_D0116.tif" />

1-14

A mixture of 2a above (1.5g, 4.91mmol), Rl (l.lg, 4.91mmol), tris (dibenzylideneacetone) dipalladium (400mg, 0.437mmol), dicyclohexyl (2 ', 4', 6'-triisopropylbiphenyl- 2-yl) phosphine (400 mg, 5.87 mmol) and potassium carbonate (1.36g, 9.84 mmol) in tert-butanol (100 mL) were stirred under argon at reflux temperature for 5 h. After cooling to RT, the reaction mixture was filtered through Celite. Celite was washed with ethyl acetate, and the combined filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (EA / PE = 10/1) to give the title compound (0.94 g, 40%, M + H⁺ = 493.5) . ¹H NMR (500 MHz, DMSO-d₆) δ 10.32 (s, 1H), 8.80 (s, 1H), 8.13 (s, 1H), 7.65 - 7.53 (m, 2H), 7.41 (t, J = 8.1 Hz, 1H), 7.13

147

<td>(d,</td><td colspan="2">J = 8.7 Hz, 2H), 6.94</td><td>(m, 1H),</td><td>6.44 (dd,</td><td>T = 17.0, 10.1</td>

<td>Hz,</td><td>1H), 6.35 - 6.20</td><td>(m,</td><td colspan="2">3H), 5.78 (dd, J =</td><td>10.1, 1.9 Hz,</td>

<td>1 HOUR) ,</td><td>5.23 (d, J = 7.0</td><td>Hz,</td><td>1H), 4.56</td><td>(t, J = 5.0</td><td>Hz, 1H), 4.46</td>

<td>(t,</td><td>J = 5.0 Hz, 1H),</td><td> 3.85</td><td>(s, 3H),</td><td> 3.79 - 3.71</td><td>(m, 1H), 2.82</td>

<td>(dd,</td><td>J = 9.2, 6.9 Hz,</td><td>1 HOUR)</td><td> , 2.77 -</td><td>2.60 (m, 3H)</td><td> , 2.55 - 2.47</td>

<td>(m,</td><td>2H), 2.36 (dd, J =</td><td> = 9.3</td><td>, 4.6 Hz,</td><td>1H), 2.20 -</td><td>2.10 (m, 1H),</td>

1.57 - 1.43 (m, 1H). ¹³C NMR (126 MHz, DMSO-d₆) δ 165.30 (s),

<td> 161.44</td><td>(s]</td><td></td><td> 156.14</td><td>(s), 154.83</td><td>(s), 146.15</td><td>(s), 145.00</td><td>(s),</td>

<td> 142.28</td><td>(s;</td><td></td><td> 136.28</td><td>(s), 133.69</td><td>(s), 132.06</td><td>(s), 131.79</td><td>(s),</td>

<td> 129.28</td><td>(s;</td><td></td><td> 122.07</td><td>(s), 118.79</td><td>(s), 117.96</td><td>(s), 114.70</td><td>(s),</td>

<td> 114.33</td><td>(s:</td><td></td><td> 84.85</td><td>(d, J = 164.</td><td>4 Hz), 62.73</td><td>(s), 59.70</td><td>(s),</td>

<td> 57.21</td><td>(d,</td><td></td><td> = 19.5</td><td>Hz), 55.14 (s</td><td>), 53.86 (s),</td><td>33.88 (s).</td><td></td>

Example 15

Synthesis of (S) -N- (3- (5-fluoro-2- (4- (1- (2fluoroethyl) pyrrolidin-3-ylamino) phenylamino) pyrimidin-4ylamino) phenyl) acrylamide (1-15)

<img file="MX368491B_D0117.tif" />

1-15

A mixture of 2d from above (812 mg), Sl (621 mg), tris (dibenzylideneacetone) dipalladium (262 mg), dicyclohexyl

148 (2 ', 4', 6'-triisopropylbiphenyl-2-yl) phosphine (271mg,) and potassium carbonate (818mg,) in tert-butanol (20mL) were stirred under argon at reflux temperature for 3.5h. After cooling to RT, the reaction mixture was filtered through Celite and Celite was washed with ethyl acetate. The combined filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (ethyl acetate / EtOH = 10/1) to give the title compound (100mg, 7.4% yield, M + H⁺ = 480.5). NMR (500 MHz, DMSO-d₆) δ 10.12 (s, J = 14.4 Hz, 1H), 9.30 (s, 1H), 8.67 (s, 1H), 8.02 (d, J = 3.7 Hz, 1H), 7.94 (s, 1H), 7.55 (d , J = 7.9 Hz, 1H),

7.42 (d, J = 8.1 Hz, 1H), 7.31 (d, J = 8.8 Hz, 2H), 7.24 (t, J = 8.1 Hz, 1H), 6.53 - 6.39 (m, 3H), 6.28 (dd, J = 17.0, 2.0 Hz, 1H), 5.84 - 5.69 (m, 1H), 5.30 (d, J = 7.1 Hz, 1H), 4.56 (t, J = 5.0 Hz, 1H), 4.47 (t, J = 5.0 Hz , 1H), 3.87 - 3.74 (m, 1H), 2.84 (dd, J = 9.2, 6.9 Hz, 1H), 2.77 - 2.71 (m, 1H), 2.71 -

2.62 (m, 2H), 2.57 - 2.48 (m, 2H), 2.40 (dd, J = 9.3, 4.5 Hz,

1H), 2.22 - 2.11 (m, 1H), 1.61 - 1.48 (m, 1H). ¹³C NMR (126

MHz, DMSO-dg) δ 163.53 (s), 156.57 (s), 150.06 (d, J = 10.5 Hz), 143.84 (s), 141.73 - 141.13 (m), 139.74 (s), 139.55 (s),

139.48 (s), 132.41 (s), 130.46 (s), 129.00 (s), 127.25 (s),

121.71 (s), 117.51 ​​(s), 114.88 (s), 113.42 (s), 112.86 (s),

83.31 (d, J = 164.4 Hz), 61.21 (s), 55.66 (d, J = 19.5 Hz),

53.60 (s), 52.33 (s), 32.35 (s).

9

Example 16

Synthesis of (S) -N- (3- (2- (4- (1- (2-fluoroethyl) pyrrolidin-3-amino) phenylamino) -5-methoxypyrimidin-4-amino) phenyl) acrylamide (1-16)

1-16

A mixture of above 2c (873mg, 2.87mmol), Sl (640mg, 2.87mmol), tris (dibenzylideneacetone) dipalladium (250mg, 0.272mmol), dicyclohexyl (2 ', 4', 6'-triisopropylbiphenyl-2yl ) phosphine (250 mg, 0.544 mmol) and potassium carbonate (795 mg, 5.84 mmol) in tert-butanol (20 mL) was stirred under argon at reflux temperature for 3.5 h. After cooling to RT, the reaction mixture was filtered through Celite and Celite was washed with ethyl acetate. The combined filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (DCM / MeOH = 50/1) to give the title compound (407 mg, 28.89% yield, M + H⁺ = 492.6). ^XH NMR (500 MHz, DMSOd₆) δ 10.06 (s, 1H), 8.63 (s, 1H), 8.32 (s, 1H), 7.97 (s, 1H), 7.78 (s, J = 5.0 Hz, 1H), 7.59 (d, J = 8.1 Hz) , 1H), 7.40

150 (d, J = 8.3 Hz, 1H), 7.35 (d, J = 8.9 Hz, 2H), 7.23 (t, J =

8.1 Hz, 1H), 6.53 - 6.38 (m, 3H), 6.27 (dd, J = 17.0, 2.0 Hz,

1H), 5.76 (dd, J = 10.1, 2.0 Hz, 1H), 5.21 (d, J = 6.2 Hz, 1H), 4.57 (t, J = 5.0 Hz, 1H), 4.47 (t, J = 5.0 Hz, 1H), 3.83 (s, 3H), 3.81 (br s, 1H), 2.84 (dd, J = 9.2, 6.9 Hz, 1H),

2.77 - 2.71 (m, 1H), 2.71 - 2.62 (m, 2H), 2.56 - 2.47 (m,

2H), 2.40 (dd, J = 9.3, 4.6 Hz, 1H), 2.16 (qd, J = 13.4, 7.9 Hz, 1H), 1.55 (dq, J = 7.7, 6.3 Hz, 1H). ¹³C NMR (126 MHz, DMSO-d₆) δ 165.06 (s), 156.50 (s), 153.76 (s), 144.87 (s),

141.82 (s), 140.91 (s), 139.47 (s), 136.04 (s), 134.03 (s),

132.85 (s), 130.46 (s), 128.74 (s), 122.60 (s, 2C), 118.91 (s), 116.05 (s), 114.92 (s), 114.56 (s, 2C), 84.88 (d, J =

164.4 Hz), 62.81 (s), 59.08 (s), 57.24 (d, J = 19.5 Hz), 55.16 (s), 53.98 (s), 33.94 (s).

Example 17

Synthesis of (R) -N- (3- (2- (4- (1- (2-fluoroethyl) pyrrolidin-3 ylamino) phenylamino) -5-methoxypyrimidin-4 ylamino) phenyl) acrylamide (1-17)

1-17

151

A mixture of 2c from above (1412 mg), Pl (1048 mg), tris (dibenzylideneacetone) dipalladium (312 mg), dicyclohexyl (2 ', 4', 6'-triisopropylbiphenyl-2-yl) phosphine (324mg,) and Potassium carbonate (1246 mg,) in tert-butanol (40 mL) was stirred under argon at reflux temperature for 3.5 h. After cooling to RT, the reaction mixture was filtered through Celite, and Celite was washed with EA. The combined filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (ethyl acetate / EtOH = 10/1) to give the title compound (800 mg, 34.6% yield, M + H⁺ = 492.5). ^:H NMR (500 MHz, DMSO-d₆) δ 10.06 (s, 1H), 8.63 (s, 1H), 8.32 (s, 1H), 7.97 (s, 1H), 7.78 (s, J = 5.0 Hz, 1H), 7.59 (d, J = 8.1 Hz, 1H), 7.40 (d, J = 8.3 Hz, 1H), 7.35 (d, J = 8.9 Hz, 2H),

7.23 (t, J = 8.1 Hz, 1H), 6.53 - 6.38 (m, 3H), 6.27 (dd, J = 17.0, 2.0 Hz, 1H), 5.76 (dd, J = 10.1, 2.0 Hz, 1H), 5.21 (d, J = 6.2 Hz, 1H), 4.57 (t, &lt;J = 5.0 Hz, 1H), 4.47 (t, J = 5.0

<td>Hz,</td><td>1H), 3.83 (s,</td><td>3H),</td><td>3.81 (br</td><td>s, 1H), 2.84</td><td>(dd, J =</td><td> 9.2,</td>

<td> 6.9</td><td>Hz, 1H), 2.77 -</td><td> 2.71</td><td>(m, 1H),</td><td> 2.71 - 2.62 (</td><td>m, 2H), 2.</td><td> 56 -</td>

<td> 2.47</td><td>(m, 2H), 2.40</td><td>(dd,</td><td>J = 9.3,</td><td>4.6 Hz, 1H),</td><td>2.16 (qd,</td><td>J =</td>

<td> 13.4</td><td>, 7.9 Hz, 1H),</td><td> 1.55</td><td>(dq, J</td><td>= 7.7, 6.3 Hz</td><td>, 1 HOUR) . ¹³C</td><td>NMR</td>

<td> (126</td><td>MHz, DMSO-d₆)</td><td>δ 1</td><td>65.06 (s</td><td>), 156.50 (s)</td><td> , 153.76</td><td>(s),</td>

<td> 144 .</td><td>87 (s), 141.82</td><td>(s),</td><td> 140.91 (</td><td>s), 139.47 (s (</td><td> ), 136.04</td><td>(s),</td>

<td> 134 .</td><td>03 (s), 132.85</td><td>(s),</td><td> 130.46</td><td>(s), 128.74 (_£</td><td> 5), 122.60</td><td>(S,</td>

152

2C), 118.91 (s), 116.05 (s), 114.92 (s), 114.56 (s, 2C),

84.88 (d, J = 164.4 Hz), 62.81 (s), 59.08 (s), 57.24 (d, J = 19.5 Hz), 55.16 (s), 53.98 (s), 33.94 (s).

Example 18

Synthesis of (R) -N- (3- (5-fluoro-2- (4- (1- (2-fluoroethyl) pyrrolidin-3-ylamino) phenylamino) pyrimidin-4yloxy) phenyl) acrylamide (1-18)

<img file="MX368491B_D0118.tif" />

1-18

A mixture of 2d from above (870mg, 2.97mmol), Rl (660mg, 2.96mmol) tris (dibenzylideneacetone) dipalladium (172mg, 0.188mmol), dicyclohexyl (2 ', 4', 6'-triisopropylbiphenyl-2yl) phosphine ( 172 mg, 0.360 mmol) and potassium carbonate (800 mg, 5.79 mmol) in tert-butanol (50 mL) were stirred under argon at reflux temperature for 5 h. After cooling to RT, the reaction mixture was filtered through Celite, and Celite was washed with ethyl acetate. The combined filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (ethyl acetate / petroleum ether = 10/1) to give the title compound

153 (0.58 g, 41% yield, M + H⁺ = 480.5). ¹H NMR (500 MHz,

DMSO-dg) δ 10.12 (s, J = 14.4 Hz, 1H), 9.30 (s, 1H), 8.67 (s,

1H), 8.02 (d, J = 3.7 Hz, 1H), 7.94 (s, 1H), 7.55 (d, J = 7.9

Hz, 1H), 7.42 (d, J = 8.1 Hz, 1H), 7.31 (d, J = 8.8 Hz, 2H),

7.24 (t, J = 8.1 Hz, 1H), 6.53 - 6.39 (m, 3H), 6.28 (dd, J =

17.0, 2.0 Hz, 1H), 5.84 - 5.69 (m, 1H), 5.30 (d, J = 7.1 Hz, 1H), 4.56 (t, J = 5.0 Hz, 1H), 4.47 (t, J = 5.0 Hz, 1H), 3.87

- 3.74 (m, 1H), 2.84 (dd, J = 9.2, 6.9 Hz, 1H), 2.77 -2.71 (m, 1H), 2.71 - 2.62 (m, 2H), 2.57 - 2.48 (m, 2H), 2.40 (dd,

J = 9.3, 4.5 Hz, 1H), 2.22 - 2.11 (m, 1H), 1.61 - 1.48 (m, 1H). ¹³C NMR (126 MHz, DMSO-d₆) δ 163.53 (s), 156.57 (s),

150.06 (d, J = 10.5 Hz), 143.84 (s), 141.73 - 141.13 (m),

139.74 (s), 139.55 (s), 139.48 (s), 132.41 (s), 130.46 (s),

129.00 (s), 127.25 (s), 121.71 (s), 117.51 ​​(s), 114.88 (s),

113.42 (s), 112.86 (s), 83.31 (d, J = 164.4 Hz), 61.21 (s),

55.66 (d, J = 19.5 Hz), 53.60 (s), 52.33 (s), 32.35 (s).

154

Example 19

Synthesis of (R) -N- (3- (5-fluoro-2- (4- (1- (2-fluoroethyl) pyrrolidin-3-ylamino) phenylamino) pyrimidin-4yloxy) phenyl) acrylamide (1-19)

1-19

A mixture of the above 2b (1408 mg), Rl (1062 mg), tris (dibenzylideneacetone) dipalladium (353 mg), dicyclohexyl (2 ', 4', 6'-triisopropylbiphenyl-2-yl) phosphine (359mg,) and Potassium carbonate (1260mg,) in tert-butanol (35mL) was stirred under argon at reflux temperature for 4.5h. After cooling to RT, the reaction mixture was filtered through Celite, and Celite was washed with ethyl acetate. The combined filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (ethyl acetate / EtOH = 10/1) to give the title compound (987 mg, 42.9% yield, M + H⁺ =

481.5). ^]H NMR (500 MHz, DMSO-d₆) δ 10.35 (s, 1H), 9.13 (s, 1H), 8.38 (d, J = 3.0 Hz, 1H), 7.67 (t, J = 1.9 Hz, 1H), 7.61 (d, J = 8.2 Hz, 1H ), 7.43 (t, J = 8.2 Hz, 1H), 7.12 (d, J =

155

<td> 7.8</td><td>Hz,</td><td>2H),</td><td>7.02 (m,</td><td>1 HOUR) ,</td><td> 6.45</td><td colspan="4">(dd, J = 17.0, 10.1 Hz,</td><td>1 HOUR) ,</td>

<td> 6.35</td><td> -</td><td> 6.24</td><td>(m, 3H),</td><td> 5.79</td><td>(dd,</td><td>J = 10</td><td> .1,</td><td> 1.9</td><td>Hz, 1H),</td><td> 5.32</td>

<td>(d,</td><td>J =</td><td> : 6.8</td><td>Hz, 1H),</td><td> 4.56</td><td>(t, J</td><td> = 5.0</td><td>Hz,</td><td>1 HOUR) ,</td><td>4.46 (t</td><td>, J =</td>

<td> 5.0</td><td>Hz,</td><td>1 HOUR) ,</td><td> 3.83 - 3</td><td colspan="2">.69 (m, 1H)</td><td> , 2.82</td><td>(dd,</td><td>J =</td><td> = 9.1, 7.</td><td>0 Hz,</td>

<td>1 HOUR) ,</td><td> 2.</td><td> 77 -</td><td>2.71 (m,</td><td>1 HOUR) ,</td><td> 2.71</td><td> - 2.60</td><td>(m,</td><td>2H)</td><td> , 2.55 -</td><td> 2.47</td>

(m

1 HOUR)

2H), 2.37 (dd, J = 9.2, 4.5 Hz, 1H), 2.19 - 2.10 (m

165.35

1.59

NMR (12 6 MHz, DMSO-d₆) δ

1.45 (m, 1H). ¹³C

<td> 158.84</td><td>(d, J = 11.0</td><td>Hz)</td><td> , 157.58</td><td>(d,</td><td>J = 2.8</td><td>Hz),</td>

<td> 147.88</td><td>(d, J = 21.9</td><td>Hz)</td><td> , 145.58</td><td>(s)</td><td> , 142.35</td><td>(s),</td>

<td> 133.66</td><td>(s), 131.90</td><td>(s),</td><td> 131.24</td><td>(S),</td><td> 129.34</td><td>(s),</td>

<td> 118.78</td><td>(s), 118.43</td><td>(s),</td><td colspan="2">114.69 (s),</td><td> 114.23 (</td><td>s), 84</td>

<td> 164.5</td><td>Hz), 62.69 (</td><td>s),</td><td>57.19 (d</td><td>F</td><td> ' = 19.5</td><td>Hz),</td>

<td> 53.80</td><td>(s), 33.85 (s)</td><td></td><td></td><td></td><td></td><td></td>

154.14

140.31

122.68

55.13

Example 20 .84 (d

Synthesis of (S) -N- (3- (5-fluoro-2- (4- (1- (2 fluoroethyl) pyrrolidin-3-ylamino) phenylamino) pyrimidin-420

<img file="MX368491B_D0119.tif" />

<img file="MX368491B_D0120.tif" />

1-20

A mixture of 2b from above (791 mg), Sl (607mg)

156 tris (dibenzylideneacetone) dipalladium (193mg), dicyclohexyl (2 ', 4', 6'- triisopropylbiphenyl-2-yl) phosphine (200mg,) and potassium carbonate (758mg,) in tert-butanol (30mL) were stirred under argon at reflux temperature for 7 h. After cooling to RT, the reaction mixture was filtered through Celite, and Celite was washed with ethyl acetate. The combined filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (ethyl acetate / EtOH = 10/1) to give the title compound (441 mg, 34.1% yield, M + H⁺ = 481.5). ^XH NMR (500 MHz, DMSO-dg) δ 10.35 (s, 1H), 9.13 (s, 1H), 8.38 (d, J = 3.0 Hz, 1H), 7.67 (t, 1.9 Hz, 1H), 7.61 (d , J = 8.2 Hz,

1H), 7.43 (t, J = 8.2 Hz, 1H), 7.12 (d, J = 7.8 Hz, 2H), 7.02 (m, 1H), 6.45 (dd, J = 17.0, 10.1 Hz, 1H), 6.35 - 6.24 (m,

3H), 5.79 (dd, J = 10.1, 1.9 Hz, 1H), 5.32 (d, J = 6.8 Hz,

1H), 4.56 (t, J = 5.0 Hz, 1H), 4.46 (t, J = 5.0 Hz, 1H), 3.83

- 3.69 (m, 1H), 2.82 (dd, J = 9.1, 7.0 Hz, 1H), 2.77 - 2.71 (m, 1H), 2.71 - 2.60 (m, 2H), 2.55 - 2.47 (m, 2H), 2.37 (dd, J = 9.2, 4.5 Hz, 1H), 2.19 - 2.10 (m, 1H), 1.59 - 1.45 (m, 1H). ¹³C NMR (126 MHz, DMSO-d₆) δ 165.35 (s), 158.84 (d, J = 11.0 Hz), 157.58 (d, J = 2.8 Hz), 154.14 (s), 147.88 (d, J =

21.9 Hz), 145.58 (s), 142.35 (s), 140.31 (s), 133.66 (s),

131.90 (s), 131.24 (s), 129.34 (s), 122.68 (s), 118.78 (s),

118.43 (s), 114.69 (s), 114.23 (s), 84.84 (d, J =

164.5 Hz),

157

62.69 (s), 57.19 (d, J = 19.5 Hz), 55.13 (s), 53.80 (s),

33.85 (s).

Example 21 Synthesis of the Biotin-substituted Compound (1-42)<img file="MX368491B_D0121.tif" /><img file="MX368491B_D0122.tif" /><img file="MX368491B_D0123.tif" />

1-42

Stage 1:

<img file="MX368491B_D0124.tif" />

158

To a round bottom flask with a stir bar, biotin (2.0 g, 8.2 mmol) and DMF (60 mL) were added. After the solid dissolved with heat, Nhydroxysuccinimide (0.944g, 8.2mmol) and DCC (2.2g, 10.7mmol) were added. The reaction mixture was stirred at room temperature overnight. The white solid was filtered, and the DMF was evaporated under reduced pressure. The resulting residue was further purified by recrystallization from isopropanol to give the desired product 2 (2.7 g, M + H⁺ = 342.5) as white crystals.

Stage 2:

To a solution of 4,7,10-trioxododecanol, 13-diamine (6.7 g, 30.4 mmol) in anhydrous DMF (100 mL) was added dropwise a solution of 2 (2.0 g, 5.86 mmol) in dry DMF (50 mL) over a period of 30 min under N₂. The resulting thick white suspension was stirred for 30 min. The precipitate was filtered and washed with DMF. The combined filtrate was concentrated and diethyl ester was added. The precipitate (sticky solid) was collected and purified by flash chromatography (DCM / MeOH = 5/1) to give the desired compound 3 (2.44 g, 93% yield, M + H⁺ = 448.5) .

159

<img file="MX368491B_D0125.tif" />

Stage 3:

At a dry (1: 1,

5.35 mmol)

H

<img file="MX368491B_D0126.tif" />

H

OH solution of 3 (2.44 g, 5.44 mmol) in methanol / DCM mL) glutaric anhydride (0.61 g,

The mixture of h, and then diisopropyl reaction with the resulting solvent solvent is instantaneous (DCM / MeOH (1.3 g, yield of anhydrous ethylamine (2.5 g, 19 mmol).

Stirred at room temperature during stirring under reduced pressure. He purified by column chromatography = 5/1) to give the

43%, M + H⁺ = 561.5).

desired compound 4

Stage 4:

<img file="MX368491B_D0127.tif" />

To a solution of 4 (290 mg, 0.516 mmol) in dry methanol / DCM (3: 5, 16 mL) was added N-hydroxysuccinimide (89 mg,

0.775 mmol) and DCC (160 mg, 0.775 mmol). The mixture was stirred at room temperature for 3h, and then a solution of 5 (synthesized separately) in methanol / dry DCM was added

160 (1: 1, 6 mL). The reaction mixture was stirred overnight, and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (DCM / MeOH = from 50/1 to 15/1) to give the desired product 1-42 (174mg, 44% yield, M + H⁺ = 1017.6).

Example 22

Synthesis of N- (3- (2- (3-fluoro-4- (4-methylpiperazin-lyl) phenylamino) -5-hydroxypyrimidin-4-yloxy) phenyl) acrylamide (I-23a)

<img file="MX368491B_D0128.tif" />

AIBr₃, TEA

PhCI, 120 ° C

<img file="MX368491B_D0129.tif" />

I-2 l-23a

To an AlBr solution₃ (2,733 g) in chlorobenzene (20 mL) TEA (0.434 g, 4.8 mmol) was added dropwise. Then compound 1-2 (0.518 g) was added. The reaction mixture was stirred at 120 ° C for 4.5h. Then MeOH (10 mL) was added inside to quench the reaction. Water was added inside, and the mixture was extracted with ethyl acetate. The organic layers were combined, dried, and concentrated under reduced pressure.

The crude was purified by column chromatography (DCM / MeOH =

15/1 as mobile phase) to give the desired product I-23a

161 (0.07 g, 13.88%, M + H + = 465.5).

Example 23

Synthesis of N- (3- (2- (3-fluoro-4- (2-methoxyethoxy) phenylamino) 7H-pyrrolo [2,3-d] pyrimidin-4-yloxy) phenyl) acrylamide (I-24a)

<img file="MX368491B_D0130.tif" />

K₂CO₃

DMF, 70 ° C

OR₂N

<img file="MX368491B_D0131.tif" />

Pt₂, h₂

EtOH

<img file="MX368491B_D0132.tif" />

2

<img file="MX368491B_D0133.tif" />

P.S₂(dba)₃, X-phos K₂CO₃, f-BuOH

<img file="MX368491B_D0134.tif" />

5

<img file="MX368491B_D0135.tif" />

Synthesis of 2-fluoro-l- (2-methoxyethoxy) -4-nitrobenzene (1)

A mixture of 2-fluoro-4-nitrophenol (7,940 g, 50.57 mmol), l-bromo-2-methoxyethane (7,656 g, 55.09 mmol), K₂CO₃(13.880 g, 100.57 mmol) in DMF (50 mL) was stirred at 70-75 ° C for 3 hr until CCD (DCM / MeOH = 50/1 as mobile phase) indicates completion of the reaction. The mixture was allowed to cool completely to room temperature and then poured into ice water (180 mL). The yellow precipitate was collected, washed with water (100 mL) and dried under vacuum for 5

162 hours to provide 2-fluoro-1- (2-methoxyethoxy) -4-nitrobenzene 1 (10.33 g, 95.81%).

Synthesis of 3-fluoro-4- (2-methoxyethoxy) aniline (2)

A mixture of 1 (5.15 g, 23.93 mmol) and PtO₂ (0.143 g, 0.63 mmol) in EtOH (100 mL) was stirred at room temperature with a hydrogen balloon overnight. After completion of the reaction, the reaction mixture was filtered through Celite®. The Celite layer was washed with EtOH. The combined filtrate was concentrated under reduced pressure to provide 2 (4g, 91%, M + H⁺= 186.5) without further purification.

Synthesis of (2- (3-fluoro-4- (2-methoxyethoxy) phenylamino) -4- (3-nitrophenoxy) -7H-pyrrolo [2,3d] pyrimidin-7-yl) methyl (4)

Compound 2 (4,432 g, 23.95 mmol), compound 3 (9,752 &lt;3, 24 mmol), K₂CO3 (6,659 g, 48.25 mmol), tris (dibenzylideneacetone) dipalladium (1,027 g, 1.12 mol), dicyclohexyl (2 ', 4', 6'- triisopropylbiphenyl-2-yl) phosphine (1,121 g, 2.36 mmol) and t- BuOH (50 mL) were added sequentially to a round bottom flask. The reaction mixture was stirred under reflux under N flow₂. After the reaction for 3 ~ 4 h, CCD (DCM / MeOH = 10/1 as mobile phase) indicates that the reaction is complete. The reaction mixture was allowed to cool completely to 40 ~ 50 ° C and then

163 filtered through Celite®. The Celite layer was washed with ethyl acetate (30 mL). The combined filtrate was concentrated under reduced pressure. The crude was purified by column chromatography (Ethyl acetate: Petroleum ether = from 50% to 100% as mobile phase) to give 4 (9.61 g, 72.39%, M + H⁺= 554.5) as a light yellow solid.

Synthesis of N- (3-fluoro-4- (2-methoxyethoxy) phenyl) -4- (3nitrophenoxy) -7H-pyrrolo [2,3-d] pyrimidin-2-amine (5)

To a round bottom flask (250 mL) was charged Compound 4 (9,608 g, 17.36 mmol) and MeOH (60 mL). After compound 4 completely dissolved, the solution was completely cooled to -10 ° C with an ice bath. NaOH aq solution (2.5 M, 20 mL) was slowly added into the flask with temperature maintained around 16 ° C during the addition. The mixture was continued to stir for another 2 h at this temperature. Water (150 mL) was slowly added to the flask over 45 min with temperature maintained below 20 ° C during the addition of water. The precipitate was collected, washed with water (50 mL) and dried under vacuum to provide the desired product 5 (4,232 g, 55%, M + H⁺ = 440.6), which was used for the next step without further purification.

164 íW

Synthesis of 4- (3-aminophenoxy) -N- (3-fluoro-4- (2methoxyethoxy) phenyl) -7H-pyrrolo [2,3-d] pyrimidin-2-amine (6)

A mixture of 5 (4,232 g, 9.6mmol) and PtO₂ (0.101 g, 0.45 mmol) in THF (40 mL) was stirred at room temperature with a hydrogen balloon overnight. After completion of the reaction, the reaction mixture was filtered through Celite®. The filtrate was concentrated under reduced pressure to provide the desired product 6 (3.35 g, 85%, M + H⁺ = 410.5) as a white solid.

Synthesis of N- (3- (2- (3-fluoro-4- (2-methoxyethoxy) phenylamino) 7H-pyrrolo [2,3-d] pyrimidin-4-yloxy) phenyl) acrylamide (I-24a)

To a solution of compound 6 (2.05 g, 4 mmol) and DIEA (1,341 g, 10.4 mmol) in THF (50 mL) at 0 ° C, acryloyl chloride (0.434 g, 4.8 mmol) was added dropwise over 5 min. . The reaction mixture was stirred for 1 h at 0 ° C. At this point, CCD indicates that the reaction is complete. Solution ac were added. NaOH (1 M, 4 mL) and water (20 mL) to quench the reaction. The resulting mixture was continued to stir for another 10 min. The upper THF phase was separated and the solvent was removed under reduced pressure. The resulting crude was purified by column chromatography (Ethyl acetate: Petroleum ether from 50% to 100% as mobile phase) to give I-24a (1,420 g, 76.67%, M + H⁺ = 464.6) as a white solid.

165

Example 24

Synthesis of N- (3- (5-methoxy-2- (4- (4- (2-methoxyethyl) piperazin-lyl) phenylamino) pyrimidin-4-yloxy) phenyl) acrylamide (I-25a)

<img file="MX368491B_D0136.tif" />

<img file="MX368491B_D0137.tif" />

<img file="MX368491B_D0138.tif" />

<img file="MX368491B_D0139.tif" />

CH₃CN, reflux

<img file="MX368491B_D0140.tif" />

DMF, Et₃N ° C

<img file="MX368491B_D0141.tif" />

Pd / C, H₂

THF, ta

<img file="MX368491B_D0142.tif" />

<img file="MX368491B_D0143.tif" />

P.S₂(dba)₃, X-phos, K₂CO₃, t-BuOH

<img file="MX368491B_D0144.tif" />

l-25a

Synthesis of 1- (4-nitrophenyl) piperazine (1)

A mixture of 4-nitrofluorobenzene (70.7 g), piperazine (49.8 g), and acetonitrile (400 mL) was stirred under reflux overnight. The reaction was monitored by CCD. After the reaction was complete, the reaction mixture was allowed to cool completely to room temperature, made basic with K solution₂CO₃ saturated (500 mL), and then extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over Na₂SW₄, and concentrated under reduced pressure to provide 1— (4 -

166 nitrophenyl) piperazine 2 (88.4 g, 85.1%, M + H⁺= 208.5) as a yellow solid.

Synthesis of 1- (2-methoxyethyl) -4- (4-nitrophenyl) piperazine (2)

Et was added to a solution of l-bromo-2-methoxyethane (60.5 g) and 1 (78.5 g) in DMF (400 mL) at room temperature.₃N (65.6 g). The mixture was then heated to 80 ° C and stirred for 4.5h. At this point, CCD indicates that the reaction is complete. The reaction mixture was poured into ice water (1 L). The yellow precipitate was collected and dissolved with ethyl acetate. The solution was washed with water, brine, and dried over Na2SO4. The organic solvent was removed under reduced pressure. The crude residue was redissolved with ethyl acetate (300 mL), and then petroleum ether (250 mL) was added. The resulting precipitate was removed (undesired product). The filtrate was concentrated under reduced pressure to provide the desired product 2 (65.4 g, 65.1%, M + H⁺= 266.6) as a yellow solid.

Synthesis of 4- (4- (2-methoxyethyl) piperazin-l-yl) aniline (3)

A solution of 2 (63.4 g) and Pd / C (4,634 g, 10% activated carbon) in THF (500 mL) was stirred at room temperature with a hydrogen balloon overnight. After completion of the reaction, the reaction mixture was filtered through Celite®. Celite was washed with ethyl acetate. The combined filtrate was concentrated under reduced pressure to

167 provide crude compound 3 (54.0 g, 96.0%, M + H⁺=

236.6) without further purification.

Synthesis of N- (3- (5-methoxy-2- (4- (4- (2-methoxyethyl) piperazin-1yl) phenylamino) pyrimidin-4-yloxy) phenyl) acrylamide (I-25a)

Compound 3 (0.835 g), compound 4 (1.1 g), K2CO3 (0.964 g), tris (dibenzylideneacetone) dipalladium (0.164 g), dicyclohexyl (2 ', 4', 6'-triisopropylbiphenyl-2-yl) phosphine ( 0.157 g) and t-BuOH (20 mL) were added sequentially to a round bottom flask. The reaction mixture was stirred under reflux under N flow₂. After the reaction for 3-4 h, CCD (DCM / MeOH = 10/1 as mobile phase) indicates that the reaction is complete. The reaction mixture was allowed to cool completely to 40 ~ 50 ° C, and was filtered through Celite®. The Celite layer was washed with ethyl acetate (30 mL). The combined filtrate was concentrated under reduced pressure. The crude was further purified by column chromatography (EtOAc: EtOH = 20: 1 as mobile phase) to give I-25a (0.923 g, 98.37%, M + H⁺= 505.6) as a white solid.

8

Example 25

Synthesis of (S) -N- (3- (2- (4 - ((1- (2-fluoroethyl) pyrrolidin-3yl) (methyl) amino) phenylamino) -7H-pyrrolo [2,3-d] pyrimidin- 4yloxy) phenyl) acrylamide (I-26a)

<img file="MX368491B_D0145.tif" />

<img file="MX368491B_D0146.tif" />

<img file="MX368491B_D0147.tif" />

l-26a

Synthesis of (S) -1- (2-fluoroethyl) -N-methyl-N- (4 nitrophenyl) pyrrolidin-3-amine (2)

NaH (0.35 g, 80% dispersion in mineral oil) and CH were sequentially added to a solution of 1 (see previous section of intermediate Sl, 2,572 g) in DMF (28 mL) at 0 ° C.₃I (1.65 g). The resulting mixture was allowed to warm to room temperature and stirred for 1 h. At this point, CCD indicates that the reaction is complete. The

169 Reaction mixture was then quenched with water and extracted with ethyl acetate. The combined organic layers were washed with water and dried over Na₂SW₄. The organic solvent was removed under reduced pressure to provide crude product 2 (2,501 g, 91.1%, M + H⁺= 268.5), which was used directly in the next step without further purification.

Synthesis of (S) -N¹- (1- (2-fluoroethyl) pyrrolidin-3-yl) -N¹methylbenzene-1,4-diamine (3)

A mixture of 2 (2,501 g) and Pd / C (0.495 g, 10% activated carbon) in MeOH (39 mL) was stirred at room temperature with a hydrogen balloon for 4.5 h. At this point, CCD shows that the reaction is complete. The reaction mixture was filtered through Celite®. The Celite layer was washed with MeOH. The combined filtrate was concentrated under reduced pressure to provide dark oil. The oil residue was redissolved in ethyl acetate. The resulting mixture was washed with water and dried over Na₂SW₄. The organic solvent was removed under reduced pressure to provide crude compound 3 (1.4g, 63.1%, M + H⁺= 238.5), which was used in the next step without further purification.

170

Synthesis of (S) -N- (3- (2- (4 - ((1- (2-fluoroethyl) pyrrolidin-3yl) (methyl) amino) phenylamino) -7H-pyrrolo [2,3-d] pyrimidin- 4yloxy) phenyl) acrylamide (I-26a)

Compound 3 (1,401 g), compound 4 (1,985 g), K2CO3 (1,460 g), tris (dibenzylideneacetone) dipalladium (0.65 g), dicyclohexyl (2 ', 4', 6'-triisopropylbiphenyl-2-yl) phosphine ( 0.65 g) and t-BuOH (32 mL) were added sequentially in a round bottom flask. The reaction mixture was stirred under reflux under N flow₂ for 3-4 h. At this point, CCD (DCM / MeOH = 10/1 as mobile phase) indicates that the reaction is complete. The mixture was allowed to cool completely to 40 ~ 50 ° C and then filtered through Celite®. The Celite layer was washed with ethyl acetate (30 mL). The combined filtrate was concentrated under reduced pressure to give the crude product, which was further purified by column chromatography to provide I-26a (415 mg, 13.16%, M + H⁺=

516.6).

171 $000

Example 26

Synthesis of (S) -N- (3- (2- (4- (1- (2-fluoroethyl) pyrrolidin-3-amino) phenylamino) -7H-pyrrolo [2,3-d] pyrimidin-4yloxy) phenyl) acrylamide ( I-27a)

<img file="MX368491B_D0148.tif" />

Compound 1 (see previous section on intermediary Sl, 1,010 g), compound 2 (1,415 g), K₂CO₃ (1.30 g), tris (dibenzylideneacetone) dipalladium (0.602 g), dicyclohexyl (2 ', 4', 6'-triisopropylbiphenyl-2-yl) phosphine (0.601 g) and tBuOH (28 mL) were added sequentially to a flask of round bottom. The reaction mixture was stirred under reflux under N flow₂ for 3 ~ 4 h. At this point, CCD (DCM / MeOH = 10/1 as mobile phase) indicates that the reaction is complete. The reaction mixture was allowed to cool completely to 40 ~ 50 ° C and filtered through Celite®. The Celite layer was washed with ethyl acetate (30 mL). The combined filtrate was concentrated under reduced pressure to give a crude product, which was further purified by column chromatography to provide I-27a (400mg, 17.81%, M + H⁺= 502.6) as a gray solid.

172

Example 27

Synthesis of N- (3- (5-methoxy-2- (1- (2-methoxyethyl) indolin-4ylamino) pyrimidin-4-yloxy) phenyl) acrylamide (I-28a)

<img file="MX368491B_D0149.tif" />

DMF, NaH (60%) rt - 60 ° C

<img file="MX368491B_D0150.tif" />

<img file="MX368491B_D0151.tif" />

<img file="MX368491B_D0152.tif" />

<img file="MX368491B_D0153.tif" />

<img file="MX368491B_D0154.tif" />

P.S₂(dba)₃, X-phos, K₂CO₃, f-BuOH

<img file="MX368491B_D0155.tif" />

Synthesis of 1- (2-methoxyethyl) -4-nitro-lH-indole (1)

To a solution of 4-nitro-lH-indole (5.1 g, 30.77 mmol), l-bromo-2-methoxyethane (5,134 g, 37 mmol) in DMF (30 mL), NaH (1,610 g, 80% dispersion in mineral oil, 40 mmol) was added in portions at room temperature. The mixture was stirred at 60 ° C for 3 hr until CCD (petroleum ether: ethyl acetate = 6: 1 as mobile phase) indicates completion of the reaction. The mixture was allowed to cool completely to room temperature, and then was poured into water (60 mL) and extracted with ethyl acetate (50 mL χ4). The combined organic layers were washed with water and brine, dried and concentrated. The residue was purified by

173 column chromatography (1/10 to 1/3 ethyl acetate / petroleum ether as mobile phase) to give compound 1 (4,778 g, 21.5 mmol, 69%) as a yellow solid.

Synthesis of 1- (2-methoxyethyl) -lH-indole-4-amine (2)

A mixture of 1- (2-methoxyethyl) -4-nitro-lH-indole 1 (4,778 g, 21 mmol) and PtO₂ (0.091 g, 0.40 mmol) in EtOH (40 mL) was stirred at room temperature with a hydrogen balloon overnight. CCD indicates that the reaction is complete. The reaction mixture was filtered through Celite®. The Celite layer was washed with EtOH. The combined filtrate was concentrated under reduced pressure to provide compound 2 (3.67 g, 91%, M + H⁺= 191.2), which was used for the next reaction stage without further purification.

Synthesis of 1- (2-methoxyethyl) indolin-4-amine (3)

Ά a solution of 1- (2-methoxyethyl) -lH-indole-4-amine 2 (1,590 g, 7.16 mmol) in CH₃COOH (10 mL) at 0 ° C NaBH was added₃CN (1,286 g, 20.74 mmol) in portions. The mixture was stirred for 3 h until CCD (petroleum ether / ethyl acetate = 1/2 as mobile phase) indicates that the reaction is complete. After the solvent was removed, the residue was made basic with NaHCO₃ saturated (50 mL) and then extracted with ethyl acetate (30 mL χ4). The organic layers were combined, dried over Na₂SW₄, and concentrated under reduced pressure. The crude was purified by column chromatography

174 (ethyl acetate / petroleum ether from 1/3 to 3/1 as the mobile phase) to give compound 3 (0.96 g, 4.37 mmol, 61%, M + H⁺= 193.5) as a yellow solid.

Synthesis of N- (3- (5-methoxy-2- (1- (2-methoxyethyl) indolin-4 5-ylamino) pyrimidin-4-yloxy) phenyl) acrylamide (I-28a)

Compound 3 (0.430 g, 2.24 mmol), compound 4 (0.936 g, 3,063 mmol), K₂CO₃ (0.660 g, 4,783 mmol), tris (dibenzylideneacetone) dipalladium (0.270 g, 0.295 mmol), dicyclohexyl (2 ', 4', 6'-triisopropylbiphenyl-2-yl) phosphine (0.243 mg, 0.512 mmol) and t-BuOH (30 mL) were added sequentially to the flask. The reaction mixture was stirred under reflux under N flow₂. After 5-7 h, CCD (Ethyl Acetate: Petroleum Ether: TEA = 1: 1: 0.1 as mobile phase) indicates that the reaction is complete. The reaction mixture_Sand allowed to cool completely to 40-50 ° C and filtered through Celite®. The Celite layer was washed with ethyl acetate (50 mL). The filtrate was concentrated under reduced pressure. The crude was purified by column chromatography (Ethyl acetate: Petroleum ether from 50% to 100% as

<td> 20</td><td>phase</td><td>mobile)</td><td>to give</td><td>I-28a</td><td>(773 mg,</td><td>79.89%, M + H⁺ = 462.5)</td>

<td></td><td>how</td><td colspan="2">a white solid.</td><td></td><td></td><td></td>

<td></td><td></td><td>^ΧΗ NMR</td><td>(500 MHz,</td><td>CDC1₃)</td><td>δ 7.98</td><td>(s, 1H), 7.92 (s, 1H),</td>

<td></td><td> 7.54</td><td>(s, 1H)</td><td>, 7.48 (d,</td><td>J = 7.</td><td>9 Hz, 1H)</td><td>, 7.36 (t, J = 8.1 Hz,</td>

1H), 7.04 (t, J = 14.6 Hz, 1H), 6.97 (d, J = 7.8 Hz, 1H),

175

<td> 6.84</td><td colspan="2">(t, J</td><td> = 8</td><td>.0 Hz, 1H), 6.57</td><td colspan="2">(s, 1H),</td><td> 6.42 (</td><td>d,</td><td colspan="2">J = 16.8</td><td>Hz,</td>

<td>1 HOUR) ,</td><td> 6.</td><td>23 i</td><td>(dd,</td><td>J = 16.8, 10.2</td><td>Hz</td><td>, 1 HOUR) ,</td><td>6.16 i</td><td>(d,</td><td>, J =</td><td> 7.8</td><td>Hz,</td>

<td>1 HOUR) ,</td><td> 5.</td><td> 74</td><td>(d,</td><td>J = 10.8 Hz, 1H)</td><td></td><td> 3.94 (</td><td>s, 3H)</td><td>r</td><td> 3.60</td><td>(t,</td><td>J =</td>

<td> 5.7</td><td>Hz,</td><td>2H)</td><td> , 3</td><td>.42 (s, 3H), 3.36</td><td> (</td><td>t, J =</td><td>8.3 Hz</td><td>r</td><td>2H),</td><td> 3.23</td><td>(t,</td>

<td>J =</td><td> 5.7</td><td>Hz,</td><td>2H (</td><td>), 2.74 (t, J = 8</td><td> . 3</td><td>Hz, 2H</td><td> ) ,</td><td></td><td></td><td></td><td></td>

Example 28

Synthesis of N- (3- (5-methoxy-2- (1- (2-methoxyethyl) indolin-4-amino) pyrimidin-4-ylamino) phenyl) acrylamide (I-29a)

<img file="MX368491B_D0156.tif" />

2 l-29a

Compound 1 (0.403 g, 2,099 mmol), compound 2 (0.880 g, 2,890 mmol), K₂CO₃ (0.643 g, 4.659 mmol), tris (dibenzylideneacetone) dipalladium (0.233 g, 0.255 mmol), dicyclohexyl (2 ', 4', 6'-triisopropylbiphenyl-2-yl) phosphine (0.243 mg, 0.512 mmol) and t-BuOH (30 mL) were added sequentially to a flask. The reaction mixture was stirred at reflux under N flow₂. After 5 ~ 7 h, CCD (Ethyl Acetate; Petroleum Ether: TEA = 1: 1: 0.1 as mobile phase) indicates that the reaction is complete. The reaction mixture was allowed to cool completely to 40 ~ 50 ° C and filtered through Celite®. The Celite layer was washed with acetate

6 ethyl (50 mL). The filtrate was concentrated under reduced pressure. The crude was purified by column chromatography (Ethyl acetate: Petroleum ether from 50% to 100% as mobile phase) to give I-29a (646 mg, 62.7%, M + H⁺ = 461.5) as a white solid.

<td></td><td></td><td>NMR</td><td colspan="2">(500 MHz, CDC1₃) δ 8.24 (s,</td><td>- 1 HOUR) ,</td><td> 7.68</td><td>(s, 1H),</td>

<td> 7.58</td><td>(s</td><td colspan="2">, 1H), 7.57</td><td>(d, &lt;7 = 7.0 Hz, H),</td><td> 7.26</td><td>(dt, &lt;7</td><td> = 10.6,</td>

<td> 4.1</td><td>Hz,</td><td>3H)</td><td> , 7.13</td><td>(d, J = 6.8 Hz, 1H),</td><td> 7.08</td><td>(t, J =</td><td>7.9 Hz,</td>

<td>1 HOUR) ,</td><td> 6.</td><td> 68 (</td><td>s, 1H),</td><td>6.45 (d, J = 16.9 Hz,</td><td>1 HOUR) ,</td><td> 6.32 -</td><td>6.19 (m,</td>

<td>2H),</td><td> 5.</td><td>78 i</td><td>id, J =</td><td>10.3 Hz, 1H), 3.89 (</td><td>s, 3H)</td><td> , 3.62</td><td>(t, J =</td>

<td> 5.8</td><td>Hz,</td><td>2H)</td><td> , 3.45 (</td><td>t, J = 8.3 Hz, 2H), 3</td><td>.41 (s</td><td>, 3H),</td><td>3.30 (t,</td>

<td>J =</td><td> 5.7</td><td>Hz,</td><td>2H), 2.</td><td>95 (t, J = 8.3 Hz, 2H</td><td></td><td></td><td></td>

177

Example 29

Synthesis of (S) -N- (3- (5-methoxy-2- (4- (1- (2 methoxyethyl) pyrrolidin-3-ylamino) phenylamino) pyrimidin-4yloxy) phenyl) acrylamide (I-30a) no₂

<img file="MX368491B_D0157.tif" />

HN¿S&gt;

NH

MeOC₂H₄Br, Et₃N

CH₃CN, 80 ° C

<img file="MX368491B_D0158.tif" />

<img file="MX368491B_D0159.tif" />

<img file="MX368491B_D0160.tif" />

P.S₂(dba)₃, X-phos, K₂CO₃, f-BuOH

<img file="MX368491B_D0161.tif" />

<img file="MX368491B_D0162.tif" />

l-30a

Synthesis of (S) -1- (2-methoxyethyl) -N- (4-nitrophenyl) pyrrolidin3-amine (2)

To compound 1 (10 g) in MeCN (70 mL) was added Et₃N (6.5 g) and 2-bromoethyl methyl ether (6.5 g). The reaction was stirred at 80 ° C for 28h. Once the reaction was complete, the organic solvent was removed under reduced pressure. The residue was redissolved in ethyl acetate, and a small amount of aqueous solution of

K₂CO₃ saturated. After shaking for a few

178 minutes, the organic layer was separated, washed with brine and dried over Na₂SW₄. The solution was concentrated under reduced pressure. The resulting crude was purified by flash chromatography to provide the desired product 2 (6,213 g, 48%, M + H⁺ =

266.5) as a yellow solid.

Synthesis of (S) -N¹- (1- (2-methoxyethyl) pyrrolidin-3-yl) benzene 1,4-diamine (3)

A solution of 2 (6,213 g) and Pd / C (0.584 g, 10% activated carbon) in THE (50 mL) was hydrogenated with a hydrogen balloon at room temperature overnight. At this point, CCD indicated that the reaction is complete. The reaction mixture was filtered through Celite®. The Celite layer was washed with MeOH. The combined layers were concentrated under reduced pressure to provide the desired product 3 (4.8g, 87.3%, M + H + = 236.5) without further purification.

Synthesis of (S) -N- (3- (5-methoxy-2- (4- (1- (2methoxyethyl) pyrrolidin-3-ylamino) phenylamino) pyrimidin-4yloxy) phenyl) acrylamide (I-30a)

Compound 3 (0.786 g), compound 4 (1,083 g), K2CO3 (1,154 g), tris (dibenzylideneacetone) dipalladium (0.117 g), dicyclohexyl (2 ', 4', 6'-triisopropylbiphenyl-2-yl) phosphine ( 0.120 g) and t-BuOH (20 mL) were added sequentially to a flask. The reaction mixture was stirred under reflux under N flow₂. After 6 h, CCD (DCM: MeOH = 10: 1 as mobile phase)

9 indicates that the reaction is complete. The reaction mixture was allowed to cool completely to 40 ~ 50 ° C and filtered through Celite®. The Celite layer was washed with ethyl acetate (30 mL). The filtrate was concentrated under reduced pressure. The crude was purified by column chromatography (Ethyl acetate: MeOH = 9: 1 as mobile phase) to give I-30a (1.2 g, 72.56%, M + H⁺ = 505.6).

Example 30

Synthesis of (S) -N- (3- (5-methoxy-2- (4- (1- (2 methoxyethyl) pyrrolidin-3-ylamino) phenylamino) pyrimidin-4ylamino) phenyl) acrylamide (I-31a)

<img file="MX368491B_D0163.tif" />

Compound 1 (0.789 g), compound 2 (1,041 g), Κ₂ΟΟ₃ (0.686 g), tris (dibenzylideneacetone) dipalladium (0.148 g), dicyclohexyl (2 ', 4', 6'- triisopropylbiphenyl-2-yl) phosphine (0.156 g) and t-BuOH (30 mL) were added sequentially to a flask. The reaction mixture was stirred under reflux under N flow₂. After 18 h, CCD (DCM: MeOH = 10: 1 as mobile phase) indicates that the reaction is complete. The reaction mixture was allowed to cool completely to 40 ~ 50 ° C and

180 filtered through Celite®. The Celite layer was washed with ethyl acetate (30 mL). The filtrate was concentrated under reduced pressure. The resulting crude was purified by column chromatography (Ethyl acetate: MeOH - 10: 1 as mobile phase) to give I-31a (0.2 g, 12%, M + H⁺ = 504.6).

Example 31

Synthesis of N- (3- (5-methoxy-2- (4- (2-methoxyethylamino) phenylamino) pyrimidin-4-yloxy) phenyl) acrylamide (I-32a)

<img file="MX368491B_D0164.tif" />

Pt₂, h₂

THF

<img file="MX368491B_D0165.tif" />

<img file="MX368491B_D0166.tif" />

P.S₂(dba)₃, X-phos, K₂CO₃, t-BuOH

<img file="MX368491B_D0167.tif" />

l-32a

Synthesis of N¹- (2-methoxyethyl) benzene-1,4-diamine (2)

A mixture of compound 1 (1,496 g) and PtO₂ (0.060 g) in

THF (15 mL) was hydrogenated at room temperature during the

181 night. At this point, CCD indicated that the reaction is complete. The reaction mixture was filtered through Celite®. The Celite layer was washed with ethyl acetate. The combined layers were concentrated under reduced pressure to provide the desired product 2 (1,201 g, 94.43%, M + H + =

236.5) without further purification.

Synthesis of N- (3- (5-methoxy-2- (4- (2 methoxyethylaniino) phenylamino) pyrimidin-4-yloxy) phenyl) anri lamide (I-32a)

Compound 2 (0.532 g), compound 3 (0.925 g), K₂CO₃(0.931 g), tris (dibenzylideneacetone) dipalladium (0.145 g), dicyclohexyl (2 ', 4', 6'- triisopropylbiphenyl-2-yl) phosphine (0.150 g) and t-BuOH (10 mL) were added sequentially to the flask . The reaction mixture was stirred under reflux under N flow₂. After 2 h, CCD (DCM: MeOH - 10: 1 as mobile phase) indicates that the reaction is complete. The reaction mixture was allowed to cool completely to 40 ~ 50 ° C and was filtered through Celite®. The Celite layer was washed with ethyl acetate (50 mL). The filtrate was concentrated under reduced pressure. The resulting crude was purified by column chromatography (Ethyl acetate: MeOH = 10: 1 as mobile phase) to give I-32a (0.672 g, 48.2%, M + H⁺ = 436.2).

^XH NMR (500 MHz, CDC1₃) δ 7.96 (s, 1H), 7.79 (s, 1H), 7.58 (d, J = 7.7 Hz, 1H), 7.45 (s, 1H), 7.36 (t, J = 8.1 Hz,

182

<td>1 HOUR) ,</td><td>7.11 (d,</td><td colspan="2">J = 8.8</td><td>Hz, 2H), 6.97 l</td><td>¡D, J = 7.0 Hz,</td><td colspan="2">1H), 6.78</td>

<td>(s,</td><td>1H), 6.47</td><td>(d,</td><td>J =</td><td> 8.8 Hz, 2H),</td><td>6.43 (dd, J =</td><td> 16.9, 1</td><td> .0</td>

<td>Hz,</td><td>1H), 6.23</td><td>(dd,</td><td>J</td><td> = 16.8, 10.2</td><td>Hz, 1H), 5.75</td><td>(dd, J</td><td></td>

<td> 10.3</td><td>, 1.0 Hz,</td><td>1 HOUR) ,</td><td> 3.</td><td>92 (s, 3H), 3.</td><td>58 (t, J = 5.2</td><td>Hz, 2H</td><td> )</td>

<td> 3.39</td><td>(s, 3H),</td><td> 3.22</td><td>(t,</td><td>J = 5.2 Hz, 2H</td><td></td><td></td><td></td>

Example 32

Synthesis of N- (3- (5-methoxy-2- (6 - ((2 methoxyethyl) (methyl) amino) pyridin-3-ylamino) pyrimidin-4yloxy) phenyl) acrylamide (I-33a)

<img file="MX368491B_D0168.tif" />

<img file="MX368491B_D0169.tif" />

<img file="MX368491B_D0170.tif" />

P.S₂(dba)₃, X-phos

K₂CO₃, t-BuOH

<img file="MX368491B_D0171.tif" />

l-33a

Synthesis of N- (2-methoxyethyl) -5-nitropyridin-2-amine (1)

A mixture of 2-chloro-5-nitropyridine (1,578 g), 2methoxyethylamine (1,522 g) and Et₃N (2,070 g) in DCM (10 mL) was stirred at room temperature for 6 h. Then the mixture was heated to and stirred under reflux for another 2 h. Added

183

CH₃CN (5 mL) inside, and refluxed overnight. At this point, CCD indicates that the reaction is complete. The reaction was quenched with water, and then extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over Na2SO₄, filtered and concentrated under reduced pressure to give the desired compound 1 (1,868 g, 95%, M + H⁺ = 198.2) .

Synthesis of N- (2-methoxyethyl) -N-methyl-5-nitropyridin-2-amine (2)

To a solution of 1 (1,648 g) in DMF (15 mL) with ice water bath, NaH (0.302 g, 80% dispersion in mineral oil) and CH were sequentially added₃I (1,418 g). The resulting mixture was then stirred at 0 ° C for 10 min. The reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layer was washed with water, dried over Na₂SW₄, filtered and concentrated under reduced pressure. The resulting crude product 2 (2.0 g, M + H⁺= 212.2) was used directly in the next step without further purification.

Synthesis of N²- (2-methoxyethyl) -N²-methylpyridine-2,5-diamine (3)

A solution of 2 (2.0 g) and Pd / C (0.300 g, 10% activated carbon) in THE (20 mL) was hydrogenated at 40 ° C overnight. At this point, CCD indicates that the reaction is complete. The reaction mixture was filtered through Celite®. The Celite layer was washed with MeOH. Filtering

184 Combined it was concentrated under reduced pressure to provide the desired product 3 (1,687 g, 98%, M + H⁺= 182.3) without further purification.

Synthesis of N- (3- (5-methoxy-2- (6 - ((2 methoxyethyl) (methyl) amino) pyridin-3-ylamino) pyriniidin-4yloxy) phenyl) acrylamide (I-33a)

Compound 3 (1,687 g), compound 4 (2,827 g), K2CO3 (2,570 g), tris (dibenzylideneacetone) dipalladium (0.6 g), dicyclohexyl (2 ', 4', 6'-triisopropylbiphenyl-2-yl) phosphine ( 0.6 g) and t-BuOH (60 mL) were added sequentially to a flask. The reaction mixture was stirred under reflux under N flow₂. After 3 h, CCD (Ethyl Acetate: EtOH = 10: 1 as mobile phase) indicates that the reaction is complete. The reaction mixture was allowed to cool completely to 40 ~ 50 ° C and filtered through Celite®. The Celite layer was washed with ethyl acetate (50 mL). The combined filtrate was concentrated under reduced pressure. The resulting crude was purified by column chromatography (Ethyl acetate as mobile phase) to give I-33a (2,591 g, 62.4%, M + H⁺ = 451.5).

185

Example 33

Synthesis of N- (3- (5-methoxy-2- (1- (2-methoxyethyl) indolin-5ylamino) pyrimidin ~ 4-yloxy) phenyl) acrylamide (I-34a)

<img file="MX368491B_D0172.tif" />

<img file="MX368491B_D0173.tif" />

l-34a

Synthesis of 1- (2-methoxyethyl) -5-nitroindoline (1)

To a solution of 5-nitroindoline (5,718 g) in DMF (60 mL) at 0 ° C, NaH (1,348 g, 60% dispersion in mineral oil) and l-bromo-2-methoxyethane (5,368 g) were sequentially added. The mixture was stirred at 0 ° C for 2 hr, then allowed to warm to room temperature and stirred for another 3 hr. At this point, CCD indicates that the reaction is complete. The reaction mixture was poured into ice water. The precipitate was collected, and redissolved in ethyl acetate. The organic layer was washed with water, brine, and concentrated under reduced pressure to provide the desired product 1 (7,292 g, 94%, M + H⁺= 223.3) as a yellow solid.

186

Synthesis of 1- (2-methoxyethyl) indolin-5-amine (2)

A solution of 1 (7,272 g) and PtO₂ (0.202 g) in THF (100 mL) was hydrogenated at room temperature overnight. At this point, CCD indicates that the reaction is complete. The reaction mixture was filtered through Celite®. The Celite layer was washed with ethyl acetate. The combined filtrate was concentrated under reduced pressure to provide the desired product 2 (6,247 g, 99.3%, M + H⁺= 193.5) which was used for the next step without further purification.

Synthesis of N- (3- (5-methoxy-2- (1- (2-methoxyethyl) indolin-5-amino) pyrimidin-4-yloxy) phenyl) acrylamide (I-34a)

Compound 2 (1,059 g), compound 3 (1,813 g), K₂CO₃(1,037 g), tris (dibenzylideneacetone) dipalladium (0.146 g), dicyclohexyl (2 ', 4', 6'-triisopropylbiphenyl-2-yl) phosphine (0.152 g) and t-BuOH (50 mL) were added sequentially to a flask. The reaction mixture was stirred under reflux under N flow₂. After 5 h, CCD (Ethyl Acetate: Petroleum Ether = 1: 1 as mobile phase) indicates that the reaction is complete. The reaction mixture was allowed to cool completely to 40 ~ 50 ° C and filtered through Celite®. The Celite layer was washed with ethyl acetate (50 mL). The combined filtrate was concentrated under reduced pressure. The resulting crude was purified by column chromatography (Ethyl acetate: petroleum ether = 1: 3 as mobile phase)

187 to give the desired product I-34a (1,368 g, 53.9%, M + H⁺ =

62.6) .

Example 34

Synthesis of N- (3- (5-methoxy-2- (4 - ((2methoxyethyl) (methyl) amino) phenylamino) pyrimidin-4yloxy) phenyl) acrylamide (I-35a)

<img file="MX368491B_D0174.tif" />

<img file="MX368491B_D0175.tif" />

P.S₂(dba)₃, X-phos

K₂CO₃, t-BuOH

<img file="MX368491B_D0176.tif" />

l-35a

Synthesis of N- (2-methoxyethyl) -4-nitroaniline (1)

A mixture of 1-fluoro-4-nitrobenzene (2,820 g), 2-methoxyethylamine (3.00 g), and Et₃N (4.04 g) in CH₃CN (20 mL) was stirred at 50 ° C overnight. The reaction was quenched with water, then extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over Na₂SW₄, filtered and then concentrated under reduced pressure to give

188 desired compound 1 (3.9 g, 99%, M + H⁺= 197.3), which was used for the next step without further purification.

Synthesis of N- (2-methoxyethyl) -N-methyl-4-nitroaniline (2)

To a solution of 1 (1,047 g) in DMF (15 mL) with ice-water bath, NaH (0.200 g) and CH were sequentially added₃I (0.906 g). The resulting mixture was then stirred at 0 ° C 10 min. The reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layer was washed with water, dried over Na₂SW₄, filtered and concentrated under reduced pressure. The resulting crude 2 (1.0 g, 89%, M + H⁺ = 211.3) was used directly in the next step without further purification.

Synthesis of N¹- (2-methoxyethyl) -l ^ -methylbenzene-l, 4-diamine (3)

A mixture of 1 (1.0 g) and Pd / C (0.100 g, 10% activated carbon) in THF (20 mL) was hydrogenated at 40 ° C overnight. At this point, CCD indicates that the reaction is complete. The reaction mixture was filtered through Celite®. The Celite layer was washed with ethyl acetate. The combined filtrate was concentrated under reduced pressure to provide the desired product 3 (1,058 g, M + H⁺= 181.3) without further purification.

Synthesis of N- (3- (5-methoxy-2- (4- ((2 methoxyethyl) (methyl) amino) phenylamino) pyrimidin-4yloxy) phenyl) acrylamide (I-35a)

Compound 3 (1,058 g), compound 80 (4 g), K2CO3

189 (1,630 g), tris (dibenzylideneacetone) dipalladium (0.3 g), dicyclohexyl (2 ', 4', 6'- triisopropylbiphenyl-2-yl) phosphine (0.3 g) and t-BuOH (50 mL) were added sequentially to the flask . The reaction mixture was stirred under reflux under N flow₂. After 5 h, CCD (Ethyl Acetate: Ethanol = 10: 1 as mobile phase) indicates that the reaction is complete. The reaction mixture was allowed to cool completely to 40 ~ 50 ° C and was filtered through Celite®. The Celite layer was washed with ethyl acetate (50 mL). The combined filtrate was concentrated under reduced pressure. The resulting crude was purified by column chromatography (Ethyl acetate as mobile phase) to give the desired product I-35a (1.8 g, 68.7%, M + H⁺ = 450.6).

190

Example 35

Synthesis of N- (3- (2- (1- (2-methoxyethyl) indolin-5-ylamino) -7Hpyrrolo [2,3-d] pyrimidin-4-yloxy) phenyl) acrylamide (I-36a)

<img file="MX368491B_D0177.tif" />

<img file="MX368491B_D0178.tif" />

l-36a

Synthesis of (2- (1- (2-methoxyethyl) indolin-5ylamino) -4- (3-nitrophenoxy) -7H-pyrrolo [2,3-d] pyrimidin-7yl) methyl (3) pivalate

Compound 1 (0.7 g), compound 2 (1,780 g), K₂CO₃(1.01 g), tris (dibenzylideneacetone) dipalladium (0.4 g), dicyclohexyl (2 ', 4', 6'- triisopropylbiphenyl-2-yl) phosphine (0.401 g) and t-BuOH (16 mL) were added sequentially to the flask . The reaction mixture was stirred under reflux under N flow₂. After 3.5 h, CCD (Ethyl Acetate: Ethanol = 10: 1 as mobile phase) indicates that the reaction is complete. The

191 Reaction mixture was allowed to cool completely to 40 ~ 50 ° C and was filtered through Celite®. The Celite layer was washed with ethyl acetate (50 mL). The combined filtrate was concentrated under reduced pressure. The resulting crude was purified by column chromatography to give compound 3 (0.7g, 34.2%).

Synthesis of N- (1- (2-methoxyethyl) indolin-5-yl) -4- (3 nitrophenoxy) -7H-pyrrolo [2,3-d] pyrimidin-2-amine (4)

A round bottom flask (250 mL) was charged with compound 3 (700 mg), MeOH (6 mL), and THF (1 mL). When compound 3 was completely dissolved, the reaction mixture was fully cooled to ~ 10 ° C with an ice bath. Then the NaOH solution (2.5 M, 2 mL) was added in a flask slowly, maintaining the temperature at ~ 16 ° C throughout the addition. The mixture was stirred for 2 h at this temperature and then water (20 mL) was added. The mixture was extracted with ethyl acetate. The organic layers were combined and concentrated under reduced pressure. The resulting crude was purified by column chromatography to provide compound 4 (320 mg, 57.4%, M + H⁺= 447.6).

Synthesis of 4- (3-aminophenoxy) -N- (1- (2-methoxyethyl) indolin-5yl) -7H-pyrrolo [2,3-d] pyrimidin-2-amine (5)

A mixture of 4 (320 mg) and PtO₂ (8 mg) in THF (5 ml) was hydrogenated with a hydrogen balloon at room temperature

192 overnight. At this point, CCD indicates that the reaction is complete. The reaction mixture was filtered through Celite®. The Celite layer was washed with ethyl acetate. The combined filtrate was concentrated under reduced pressure. The resulting crude was purified by column chromatography to provide the desired compound 5 (0.25g, 83.75%).

Synthesis of N- (3- (2- (l- (2-methoxyethyl) indolin-5-ylamino) -7Hpyrrolo [2,3-d] pyrimidin-4-yloxy) phenyl) acrylamide (I-36a)

Acryloyl chloride (82 mg) was added dropwise to a mixture of compound 5 (0.25 g) and DIEA (125 mg) in THF (4 mL) at 0 ° C over 5 min. The mixture was stirred for 2 h at this temperature. The NaOH solution (1M, 2 mL) was added to quench the reaction. The mixture was stirred for 30 min, and then diluted with water (30 mL) before extracting with ethyl acetate (30 mL). The organic layer was separated and concentrated under reduced pressure. The resulting crude was purified by column chromatography to give I-36a (186mg, 65.85%, M + H + = 471.6).

193

Example 36

Synthesis of N- (3- (2- (3,5-difluoro-4- (2methoxyethoxy) phenylamino) -7H-pyrrolo [2,3-d] pyrimidin-4yloxy) phenyl) acrylamide (I-37a)

<img file="MX368491B_D0179.tif" />

l-37a

Synthesis of 1,3-difluoro-2- (2-methoxyethoxy) -5-nitrobenzene (1)

NaH (0.815 g, 80% dispersion) was added to a solution of 1,2,3-trifluoro-5-nitrobenzene (2,625 g, 14 mmol) and 2-methoxyethanol (1.3 g, 17 mmol) in DMF (20 mL) in mineral oil).

The mixture was stirred at room temperature for 3 h until

194 that CCD (petroleum: Ethyl acetate = 1: 6 as mobile phase) indicates that the reaction is complete. The mixture was emptied into water (60 mL) and extracted with EA (40 mL * 4). The organic layer was combined, dried over Na₂SW₄, filtered and concentrated under reduced pressure. The resulting crude was purified by column chromatography (EtOAc / Petroleum Ether from 1/7 to 1/3 as mobile phase) to give 1 (2,609 g, 80%) as a dark yellow solid.

Synthesis of 3,5-difluoro-4- (2-methoxyethoxy) aniline (2)

A mixture of 1 (3.88 g) and PtO₂ (0.089 g) in EtOH (30 mL) was hydrogenated at room temperature overnight. At this point, CCD indicates that the reaction is complete. The reaction mixture was filtered through Celite® and washed with ethyl acetate. The combined filtrate was concentrated under reduced pressure to provide the desired product 2 (2.7 g, 95%) without further purification.

Synthesis of (2- (3,5-Difluoro-4- (2methoxyethoxy) phenylamino) -4- (3-nitrophenoxy) -7H-pyrrolo [2,3d] pyrimidin-7-yl) methyl (4)

Compound 2 (2.7g, 13.3mmol), compound 3 (6,075g, 15mmol), K₂CO₃ (4,140 g, 30 mmol), tris (dibenzylideneacetone) dipalladium (0.064 g, 0.07 mol), dicyclohexyl (2 ', 4', 6'- triisopropylbiphenyl-2-yl) phosphine (0.065 g, 0.14 mmol) and t-BuOH (50 mL) were added

195 sequentially to a flask. The reaction mixture was stirred under reflux under N flow₂. After 3-4 h, CCD (DCM: Methanol = 10: 1 as mobile phase) indicates that the reaction is complete. The reaction mixture was allowed to cool completely to 40 ~ 50 ° C and filtered through Celite®. The Celite layer was washed with ethyl acetate (30 mL). The combined filtrate was concentrated under reduced pressure. The resulting crude was purified by column chromatography (50% to 100% EtOAc / Petroleum Ether) to give Compound 4 (4,932 g, 65%) as a light yellow solid.

Synthesis of N- (3,5-difluoro-4- (2-methoxyethoxy) phenyl) -4- (3nitrophenoxy) -7H-pyrrolo [2,3-d] pyrimidin-2-ainine (5)

A round bottom flask (250 mL) was charged with compound 4 (4,932 g, 8.64 mmol) and MeOH (40 mL). When Compound 4 completely dissolved, the solution was completely cooled to ~ 10 ° C with an ice bath. The NaOH solution (2.5 M, 10 mL) was then added into the flask slowly, maintaining the temperature at ~ 16 ° C during the addition. The mixture was stirred for 2 h at this temperature. Water (100 mL) was added to the flask for 15 min, keeping the temperature below 20 ° C. The mixture was continuously stirred for another 15 min. The precipitate was collected, washed with water (50 mL) and dried under vacuum to provide the compound (1,579 g, 40%).

196

Synthesis of 4- (3-aminophenoxy) -N- (3,5-difluoro-4- (2methoxyethoxy) phenyl) -7H-pyrrolo [2,3-d] pyrimidin-2-amine (6)

A mixture of 5 (1,579 g, 3,456 mmol) and PtO₂ (16 mg, 0.07 mmol) in THF (30 mL) was hydrogenated with a hydrogen balloon at room temperature overnight. At this point, CCD indicates that the reaction is complete. The reaction mixture was filtered through Celite® and washed with ethyl acetate. The combined filtrate was concentrated to provide the desired compound 6 (1,401 g, 95%) as a white solid.

Synthesis of N- (3- (2- (3,5-difluoro-4- (2 methoxyethoxy) phenylamino) -7H-pyrrolo [2,3-d] pyrimidin-4yloxy) phenyl) acrylamide (I-37a)

To a solution of compound 6 (1.401g, 3.28mmol) and DIEA (0.464g, 3.6mmol) in THF (50mL) at 0 ° C, acryloyl chloride (0.307g, 3.4mmol) was added dropwise over 5 min. . The mixture was stirred for 1 h at this temperature. The NaOH solution (1M, 3 mL) and water (20 mL) were added to quench the reaction. The mixture was stirred for an additional 10 min, and the upper THF phase was separated and evaporated under reduced pressure. The resulting crude was purified by column chromatography (50% to 100% EtOAc / Petroleum Ether as mobile phase) to give I-37a (1090 g, 63%, M + H⁺ = 482.2) as a white solid.

197

Example 37

Synthesis of N- (3- (5-methoxy-2- (4 - ((2 methoxyethyl) (propyl) amino) phenylamino) pyrimidin-4yloxy) phenyl) acrylamide (I-38a)

<img file="MX368491B_D0180.tif" />

<img file="MX368491B_D0181.tif" />

l-38a

Synthesis of N-cyclopropyl-N- (2-methoxyethyl) -4-nitroaniline (2)

A mixture of compound 1 (1,001 g), cyclopropyl bromide (2,300 g), Pd₂(dba)₃ (0.132 g), X-Phos (0.100 g) and potassium carbonate (1070 g) in t-butanol (20 mL) were stirred under argon at reflux overnight. CCD indicates that the reaction is complete. After cooling to room temperature, the reaction mixture was filtered through Celite®, and washed with ethyl acetate. The combined filtrate was concentrated under reduced pressure. The resulting crude was purified by flash column chromatography to provide the desired compound 2 (700 mg,

58.13%).

198

Synthesis of N¹- (2-methoxyethyl) -N¹-propylbenzene-l, 4-diamine (3)

A mixture of 2 (0.556 g) and PtO₂ (0.060 g) in THF (15 mL) was hydrogenated at room temperature overnight. CCD indicates that the reaction is complete. The reaction mixture was filtered through Celite®, and washed with ethyl acetate. The combined filtrate was concentrated under reduced pressure to provide crude product 3 (0.55 g), which was used for the next step without further purification.

Synthesis of N- (3- (5-methoxy-2- (4 - ((2methoxyethyl) (propyl) amino) phenylamino) pyrimidin-4yloxy) phenyl) acrylamide (I-38a)

Compound 3 (0.550 g), compound 4 (0.571 g), K₂CO₃(0.075 g), tris (dibenzylideneacetone) dipalladium (0.075 g), dicyclohexyl (2 ', 4', 6'- triisopropylbiphenyl-2-yl) phosphine (0.071 g) and t-BuOH (15 mL) were added sequentially to the flask . The reaction mixture was stirred under reflux under N flow₂. After 3 h, CCD (Ethyl Acetate: Ethanol = 10: 1 as mobile phase) indicates that the reaction is complete. The reaction mixture was allowed to cool completely to 40 ~ 50 ° C and filtered through Celite®. The Celite layer was washed with ethyl acetate (10 mL). The combined filtrate was concentrated under reduced pressure. The resulting crude was purified by column chromatography (50% to 100% EtOAc / Petroleum Ether) to give compound I-38a

199 (0.182 g, 21.2%, M + H⁺=478.6).

^XH NMR (500 MHz, CDC1₃) δ 7.94 (s, 1H), 7.65 (s, 1H),

7.54 - 7.46 (m, 2H), 7.36 (t, J = 8.1 Hz, 1H), 7.12 (d, J =

8.9 Hz, 2H), 6.96 ((dd, J = 7.9, 1.0 Hz, 1H), 6.61 (s, 1H),

6.50 (d, J = 8.9 Hz, 2H), 6.42 (dd, J = 16.8, 1.2 Hz, 1H),

6.22 (dd, J = 16.8, 10.2 Hz, 1H), 5.75 (dd, J = 10.2, 1.1 Hz,

1H), 3.90 (s, 3H), 3.48 (t, J = 5.8 Hz, 2H), 3.42 (t, J = 6.0

Hz, 2H), 3.35 (s, 3H), 3.19 (t, J = 6.0 Hz, 2H), 1.58 - 1.49 (m, 2H), 0.88 (t, J = 7.4 Hz, 3H).

200

Example 38

Synthesis of N- (3- (2- (4- (cyclopropyl (2methoxyethyl) amino) phenylamino) -5-methoxypyrimidin-4yloxy) phenyl) acrylamide (I-39a)

<img file="MX368491B_D0182.tif" />

<img file="MX368491B_D0183.tif" />

Synthesis of l ^ -cyclopropyl-N¹- (2-methoxyethyl) benzene-1, 4-diamine (2)

Compound 1 (0.580 g) in EtOH / H₂O (24 mL, 17: 7) was treated with iron (0.62 g) followed by ammonium chloride (2,092 g). The mixture was stirred at reflux for 2 h. The reaction mixture was filtered through Celite®. The filtrate was made basic with NaHCCu (aq, 30 mL) and extracted with ethyl acetate (30 mL x4). The organic layer was combined, dried and

201 Concentrated to provide crude compound 2 (0.545g which was used in the next step without further purification.

Synthesis of N- (3- (2- (4- (cyclopropyl (2methoxyethyl) amino) phenylamino) -5-methoxypyrimidin-4yloxy) phenyl) acrylamide (I-39a)

Compound 2 (0.5 g), compound 3 (0.745 g), K₂CO₃(0.890 g), tris (dibenzylideneacetone) dipalladium (0.232 g), dicyclohexyl (2 ', 4', 6'- triisopropylbiphenyl-2-yl) phosphine (0.240 g) and t-BuOH (20 mL) were added sequentially to the flask . The reaction mixture was stirred under reflux under N flow₂. After 4 h, CCD (Ethyl Acetate: Ethanol = 10: 1 as mobile phase) indicates that the reaction is complete. The reaction mixture was allowed to cool completely to

40 ~ 50 ° C and filtered through Celite®. The Celite layer was washed with ethyl acetate (10 mL). The combined filtrate was concentrated under reduced pressure. The resulting crude was purified by column chromatography to give compound I39a (0.228 g, 17.4%, M + H⁺=476.6).

^XH NMR (500 MHz, DMSO) δ 10.33 (s, 1H), 8.86 (s, 1H),

<td> 8.13</td><td>(s, 1H)</td><td>, 7.60 (s, 1H)</td><td> , 7.59</td><td>(d, J =</td><td> 8.5</td><td>Hz, 1H)</td><td>r</td><td> 7.39</td>

<td>(dd,</td><td>J = 26.</td><td>8, 18.9 Hz, 1H</td><td> ), 7.18</td><td>(d, J =</td><td> 8.3</td><td>Hz, 2H)</td><td> 1</td><td> 6.94</td>

<td>(d,</td><td>J = 7.9</td><td>Hz, 1H), 6.44</td><td>(dd, J</td><td> = 19.2,</td><td> 9.1</td><td>Hz, 3H)</td><td>t</td><td> 6.27</td>

<td>(d,</td><td>J = 17.0</td><td>Hz, 1H), 5.76</td><td>(dd, J</td><td> = 17.6,</td><td> 7.7</td><td>Hz, 2H)</td><td>F</td><td> 5.09</td>

<td>(d,</td><td>J = 13.0</td><td>Hz, 2H), 3.85</td><td>(s, 3H),</td><td> 3.89-3.</td><td> 80 (</td><td>m, 2H),</td><td> 3.</td><td> .47 -</td>

202

<td> 3.32</td><td>(m, 4H),</td><td> 3.2</td><td>5 (s, 3H)</td><td> •</td><td></td><td></td><td></td><td></td>

<td></td><td>¹³C NMR</td><td> (126</td><td colspan="2">MHz, DMSO)</td><td>δ 165.31</td><td>(s</td><td> ), 161.44</td><td>(s), 156.04</td>

<td>(s),</td><td> 154.80</td><td>(s),</td><td> 146.07 (</td><td>) s)</td><td> , 144.92</td><td>(s)</td><td> ), 142.28</td><td>(s), 136.95</td>

<td>(s),</td><td> 136.35</td><td>(s),</td><td> 133.67 (</td><td>: s)</td><td> , 132.17</td><td>(s:</td><td> ), 131.82</td><td>(s), 129.29</td>

<td>(s),</td><td> 121.98</td><td>(s),</td><td> 118.79 (</td><td>: s)</td><td> , 118.01</td><td>(s:</td><td> ), 117.82</td><td>(s), 114.78</td>

<td>(s),</td><td> 114.05 (</td><td>s),</td><td>71.98 (s</td><td> ),</td><td>60.24 (s)</td><td>t</td><td>59.67 (s),</td><td>55.20 (s),</td>

<td> 51.87</td><td>(s).</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

Example 39

Synthesis of (S) -N- (3- (2- (4- (1- (2-methoxyethyl) pyrrolidin-3ylamine) phenylamino) -7H-pyrrolo [2,3-d] pyrimidin-4 yloxy) phenyl) acrylamide (I-40a)

<img file="MX368491B_D0184.tif" />

<img file="MX368491B_D0185.tif" />

Synthesis of (S) - (4- (3-acrylamidophenoxy) -2- (4- (1 (2-methoxyethyl) pyrrolidin-3-ylamino) phenylamino) -7H pyrrolo [2,3-d] pyrimidin-7 pivalate -yl) methyl (3)

Compound 1 (1,008 g, 4,289 mmol), compound 2 (2,143

203 g, 5,007 mmol), K₂CO₃ (1,455 g, 10,543 mmol), tris (dibenzylideneacetone) dipalladium (0.432 g, 0.472 mmol), dicyclohexyl (2 ', 4', 6'-triisopropylbiphenyl-2-yl) phosphine (0.434 g, 0.992 mmol) and t-BuOH (20 mL) were added sequentially to the flask. The reaction mixture was stirred under reflux under N flow₂. After 5-7 h, CCD (DCM: Methanol = 10: 1 as mobile phase) indicates that the reaction is complete. The reaction mixture was allowed to cool completely to 40 ~ 50 ° C, concentrated under reduced pressure, and followed by the addition of ethyl acetate (50 mL) and activated charcoal (0.5 g). The mixture was stirred for 15 min and then filtered through Celite®. The Celite layer was washed with ethyl acetate (50 mL). The combined filtrate was concentrated under reduced pressure to provide crude 3 (1,723 g, 64%) as a white solid, which was used for the next step without further purification.

Synthesis of (S) -N- (3- (2- (4- (1- (2-methoxyethyl) pyrrolidin-3-ylamino) phenylamino) -7H-pyrrolo [2,3-d] pyrimidin-4-yloxy) phenyl) acrylamide ( I-40a)

A round bottom flask (250 mL) was charged with compound 3 (0.550 g, 0.877 mmol) and MeOH (20 mL). After Compound 3 was completely dissolved, the mixture was fully cooled to ~ 10 ° C with an ice bath. The NaOH solution (2.5 M, 2 mL) was then added to the flask

204 slowly, keeping the temperature below 16 ° C during the addition. The mixture was stirred for 1 h at this temperature. Then water (100 mL) was added slowly to the flask over 15 min (keeping the temperature below 20 ° C). The mixture was extracted with ethyl acetate (30 mL * 4). The combined organic layers were concentrated under reduced pressure. The resulting crude was purified by column chromatography (Ethyl Acetate / Petroleum Ether = from 10% to 100% as mobile phase) to give I-40a (0.17 g, 29%, M + H⁺= 514.5) as a yellow solid.

205

Example 40

Synthesis of N- (3- (2- (4 - ((2methoxyethyl) (methyl) amino) phenylamino) -7H-pyrrolo [2,3d] pyrimidin-4-yloxy) phenyl) acrylamide (I-41a)

<img file="MX368491B_D0186.tif" />

(2- (4 - ((2 Synthesis methoxyethyl) (methyl) amino) phenylamino) -4- (3-nitrophenoxy) -7Hpyrrolo [2,3-d] pyrimidin-7-yl) methyl (3)

Compound 1 (3.0 g), compound 2 (7.1 g), K₂CO₃ (4.78 g), tris (dibenzylideneacetone) dipalladium (1.2 g), dicyclohexyl (2 ', 4', 6'- triisopropylbiphenyl-2-yl) phosphine (1.2 g) and t-BuOH (100 mL) were added sequentially to the flask . The reaction mixture was stirred under reflux under N flow₂. After 3 h,

206

CCD (DCM: Methanol = 10: 1 as mobile phase) indicates that the reaction is complete. The reaction mixture was allowed to cool completely to 40 ~ 50 ° C, and then filtered through Celite®. The Celite layer was washed with ethyl acetate (50 mL). The combined filtrate was concentrated under reduced pressure. The resulting crude was further purified by column chromatography to provide compound 3 (6,010 g, 65.8%).

Synthesis of N¹- (2-methoxyethyl) -N¹-methyl-N '¹- (4- (3-nitrophenoxy) 7H-pyrrolo [2,3-d] pyrimidin-2-yl) benzene-1,4-diamine (4)

A round bottom flask (250 mL) was charged with compound 3 (6.01 g) and MeOH (50 mL). When Compound 3 completely dissolved, the solution was completely cooled to ~ 10 ° C with an ice bath. The NaOH solution (2.5M, 10 mL) was then added slowly into the flask with the temperature remaining below 16 ° C during the addition. The mixture was stirred for 2.5 h at this temperature. Then water (150 mL) was slowly added into the flask over 15 min with the temperature remaining below 20 ° C during the addition. The mixture was extracted with ethyl acetate (100 mL χ2). The organic layers were combined, and concentrated under reduced pressure. The resulting crude was redissolved in MeOH / DCM (1: 1, 50 mL) and the resulting solution was bubbled with NH₃(g) at room temperature. After 7 hr, LC-MS

207 indicates that the reaction is complete. The organic solvent was removed under reduced pressure to provide 4 (4.5 g, 94.7%), which was used in the next step without further purification.

Synthesis of N¹- (4- (3-aminophenoxy) -7H-pyrrolo [2,3-d] pyrimidin 2-yl) -N⁴- (2-methoxyethyl) -N⁴-methylbenzene-l, 4-diamine (5)

A mixture of 4 (4.5 g) and PtO₂ (50 mg) in THE (52 mL) was hydrogenated with a hydrogen balloon at room temperature for 44 h. CCD and LC-MS indicates incompleteness of the reaction due to slow conversion of hydroxylamine to amine. The reaction mixture was filtered through Celite®. The filtrate was concentrated. The residue was treated with an iron / NH system₄Cl ac / EtOH for 24 h. The crude was purified by column chromatography to provide the desired compound 5 (2.1g, 50%) as a white solid.

Synthesis of N— (3— (2— (4 - ((2— methoxyethyl) (methyl) amino) phenylamino) -7H-pyrrolo [2,3 d] pyrimidin-4-yloxy) phenyl) acrylamide (I-41a)

To a solution of compound 5 (2.1 g) and DIEA (1.01 g) in THE (30 mL) at 0 ° C, acryloyl chloride (0.810 g) was added dropwise over 5 min. The mixture was stirred for 3 h at this temperature. The NaOH solution (1M, 3 mL) and water (50 mL) were added to quench the reaction. The resulting mixture was stirred for another 10 min, and then extracted

208 with ethyl acetate. The organic layers were combined and concentrated under reduced pressure. The resulting crude was purified by column chromatography (DCM / MeOH = 20/1 as mobile phase) to give compound I-41a (0.605 g, 95.9%,

M + H⁺=459.5).

Example 41

Synthesis of (S) -N- (3- (5-methoxy-2- (4 - ((1- (2 methoxyethyl) pyrrolidin-3-yl) (methyl) amino) phenylamino) pyrimidin4-yloxy) phenyl) acrylamide ( I-42a)

<img file="MX368491B_D0187.tif" />

OR

HN

<img file="MX368491B_D0188.tif" />

<img file="MX368491B_D0189.tif" />

l-42a

Synthesis of (S) -l- (2-methoxyethyl) -N-methyl-N- (4 nitrophenyl) pyrrolidin-3-amine (2)

To a solution of 1 (2.7 g) in DMF (15 mL) at 0 ° C, NaH (0.611 g, 80% dispersion in

209 mineral oil) and CH₃I (1.5 g). The resulting mixture was stirred for 3 h at this temperature. The reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with water, dried over Na₂SW₄, filtered and concentrated under reduced pressure. Crude 2 (2.3 g) was used directly in the next step without further purification.

Synthesis of (S) -N¹- (1- (2-methoxyethyl) pyrrolidin-3-yl) -N¹methylbenzene-1,4-diamine (3)

A mixture of 2 (2.3 g) and PtO₂ (0.057 g) in THF (40 mL) was hydrogenated with a hydrogen balloon at room temperature for 41 h. CCD shows that the reaction is complete. The reaction mixture was filtered through Celite®. The filtrate was concentrated under reduced pressure to provide crude compound 3 (1.7 g) without further purification.

Synthesis of (S) -N- (3- (5-methoxy-2- (4 - ((1- (2-methoxyethyl) pyrrolidin-3-yl) (methyl) amino) phenylamino) pyrimidine-

4-yloxy) phenyl) acrylamide (I-42a)

Compound 3 (0.7 g), compound 4 (0.905 g), K₂CO₃(0.838 g), tris (dibenzylideneacetone) dipalladium (0.275 g), dicyclohexyl (2 ', 4', 6'- triisopropylbiphenyl-2-yl) phosphine (0.271 g) and t-BuOH (15 mL) were added sequentially to a flask. The reaction mixture was stirred under reflux under N flow₂. After 5 h, CCD (DCM: Methanol = 10: 1 as phase

210 mobile) indicates that the reaction is complete. The reaction mixture was allowed to cool completely to 40 ~ 50 ° C, and then filtered through Celite®. The Celite layer was washed with ethyl acetate (50 mL). The combined filtrate was concentrated under reduced pressure. The resulting crude was further purified by column chromatography to provide compound I-42a (0.66 g, 45.4%, M + H⁺=519.6).

^XH NMR (500 MHz, DMSO) δ 10.36 (s, 1H), 8.94 (s, 1H), 8.15 (s, 1H), 7.74 - 7.53 (m, 2H), 7.42 (t, J = 8.4 Hz, 1H) , 7.23 (d, J = 8.9 Hz, 2H), 7.09 - 6.85 (m, 1H), 6.55 (d, J =

<td> 9.0</td><td>Hz,</td><td>2H),</td><td colspan="3">6.45 (dd, J = 16.9, 10.1 Hz,</td><td>1H), 6.</td><td>28 (dd, J =</td>

<td> 17.0</td><td>, i.</td><td>8 Hz,</td><td>1H), 5.78</td><td>(dd,</td><td>J = 10.1, 1</td><td>. 8 Hz,</td><td>1H), 4.24 -</td>

<td> 4.08</td><td>(m,</td><td>1 HOUR) ,</td><td>3.86 (s,</td><td>3H),</td><td> 3.47 - 3.37</td><td>(m, 2H</td><td>), 3.24 (s,</td>

<td>3H),</td><td colspan="2">2.71 (td</td><td>, J = 8.5,</td><td colspan="2">4.3 Hz, 1H), 2.65</td><td>(s, 3H)</td><td>, 2.58 (dt,</td>

<td>J =</td><td> 8.1,</td><td> 6.0</td><td>Hz, 2H), 2.</td><td> 55 -</td><td>2.45 (m, 2H)</td><td> , 2.33</td><td>(q, J = 7.7</td>

<td>Hz,</td><td>1 HOUR) ,</td><td> 2.05</td><td>, - 1.90 (m</td><td>, 1 HOUR)</td><td>, 1.57 (td,</td><td>J = 13</td><td>.4, 7.8 Hz,</td>

<td>1 HOUR) .</td><td>¹³C</td><td>NMR (</td><td colspan="2">126 MHz, DMSO) δ</td><td>165.32 (s),</td><td> 161.43</td><td>(s), 155.90</td>

<td>(s),</td><td> 154</td><td> .78 (</td><td>s), 147.40</td><td>(s),</td><td>145.98 (s),</td><td> 142.28</td><td>(s), 136.44</td>

<td>(s),</td><td> 133</td><td colspan="2">.57 (d, J = 18.4</td><td>Hz),</td><td>131.87 (s),</td><td> 129.30</td><td>(s), 121.49</td>

<td>(s),</td><td> 118</td><td> . 77 (</td><td>s), 118.09</td><td>(s),</td><td>116.72 (s),</td><td> 114.93</td><td>(s), 72.92</td>

<td>(s),</td><td> 60.</td><td>02 (s</td><td>), 59.79 (s</td><td> ), 59</td><td>.62 (s), 59.</td><td>30 (s),</td><td>56.79 (s),</td>

55.89 (s), 35.77 (s), 29.76 (s).

211

Example 42

Synthesis of N- (3- (2- (1- (2-fluoroethyl) -ÍH-indole-5-ylamino) -5methoxypyrimidin-4-yloxy) phenyl) acrylamide (I-43a)

<img file="MX368491B_D0190.tif" />

Synthesis of 1- (2-fluoroethyl) -5-nitro-lH-indole (1)

To a solution of 5-nitro-lH-indole (1,618 g, 10 mmol) in DMF (10 ml) at 0 ° C, NaH (0.805 g, 60% dispersion in mineral oil) and l-bromo-2 were sequentially added. -methoxyethane (1.32 g). The mixture was stirred at 60 ° C for 3 hr until CCD (Petroleum Ether: Ethyl Acetate = 5: 1 as mobile phase) indicates that the reaction is complete. The mixture was allowed to cool completely to room temperature, emptied into water (60 mL), and then extracted with ethyl acetate (50 mL x4). The organic layers were combined and the solvent was removed under reduced pressure. The resulting residue was purified by column chromatography (EtOAc / Petroleum Ether from 1/10 to 1/3 as mobile phase) to give 1

212 (1.767 g, 8.5 mmol, 85%) as a yellow solid.

Synthesis of 1- (2-fluoroethyl) -lH-indole-5-amine (2)

A mixture of 1 (1,767 g, 8.5 mmol) and PtO₂ (0.046 g, 0.20 mmol) in EtOH (40 mL) was hydrogenated with a hydrogen balloon at room temperature overnight. At this point, CCD indicates that the reaction is complete. The reaction mixture was filtered through Celite® and washed with a small amount of ethanol. The combined filtrates were concentrated under reduced pressure to provide 2 (1,347 g, 89%), which was used in the next step without further purification.

Synthesis of N- (3- (2- (l- (2-fluoroethyl) -lH-indole-5-ylamino) -5methoxypyrimidin-4-yloxy) phenyl) acrylamide (I-43a)

Compound 2 (0.877 g, 4,867 mmol), compound 3 (1,902 g, 6,327 mmol), K₂CO₃ (1,347 g, 9,743 mmol), tris (dibenzylideneacetone) dipalladium (0.455 g, 0.487 mmol), dicyclohexyl (2 ', 4', 6'-triisopropylbiphenyl-2-yl) phosphine (0.471 g, 0.974 mmol) and t-BuOH (30 mL) were added sequentially to the flask. The reaction mixture was stirred under reflux under N flow₂. After 5 h, CCD (EtOAc / Petroleum Ether / TEA = 1: 1: 0.1 as mobile phase) indicates that the reaction is complete. The reaction mixture was allowed to cool completely to 40 ~ 50 ° C, and then filtered through Celite®. The Celite layer was washed with ethyl acetate (50 mL). The combined filtrate was concentrated under

213 reduced pressure. The resulting crude was further purified by column chromatography to provide compound I-43a (1.66g, 74%, M + H⁺= 448.6) as a light yellow solid.

Example 43

Synthesis of N- (3- (5-methoxy-2- (4- (2 (methylsulfonyl) ethoxy) phenylamino) pyrimidin-4yloxy) phenyl) acrylamide (I-44a)

<img file="MX368491B_D0191.tif" />

Ho — SMe

DIAD, PPh₃

PhMe, 0 ° C to ta

<img file="MX368491B_D0192.tif" />

SMe m-CPBA

No J _or^ x ^ SO₂I

DCM, 0 ° C to ta

<img file="MX368491B_D0193.tif" />

_or^ -x ^ SO₂I

N0₂

Fe, NH4CI ac

THF, reflux

<img file="MX368491B_D0194.tif" />

NH₂

<img file="MX368491B_D0195.tif" />

Synthesis of methyl (2- (4-nitrophenoxy) ethyl) sulfan (1)

To a solution of 4-nitrophenol (1,413 g), 2 (methylthio) ethanol (0.948 g) and PPh₃ (3,216 g) in toluene (30 mL) at 0 ° C DIAD (4 mL) was slowly added. The mixture was allowed to warm to room temperature and stirred overnight. The solvent was evaporated under reduced pressure. The residue was purified by column chromatography (EtOAc / Petroleum Ether from 1:20 to 1:10 as the mobile phase) to provide Compound 1 (1,879 g, 86.7%) as an oil

214 yellow.

Synthesis of 1- (2- (methylsulfonyl) ethoxy) -4-nitrobenzene (2)

A solution of 1 (1,490 g) in DCM (10 mL) at 0 ° C was treated with 3-chloroperbenzoic acid (2,511 g). The resulting mixture was stirred at room temperature overnight. The reaction was quenched with saturated aqueous NaHCCb solution, and then extracted with DCM. The organic layer was separated, dried over Na₂SW₄, filtered, and concentrated under reduced pressure to provide crude compound 2 (4,542 g), which was used directly in the next step without further purification.

Synthesis of 4- (2- (methylsulfonyl) ethoxy) aniline (3)

A solution of 2 (4,542 g) in THF (50 mL) was treated with iron (5,823 g) and saturated aqueous ammonium chloride (5 mL).

<td>15 The mixture is</td><td>waved</td><td colspan="2">at reflux for 2.5</td><td>h.</td><td>Then</td><td>of the</td>

<td>cooling</td><td>until</td><td>temperature</td><td>environment,</td><td>the</td><td>mixture</td><td>of</td>

<td>reaction is</td><td>filter</td><td>through</td><td>Celite®.</td><td>The</td><td>filtered out</td><td>I know</td>

Concentrated under reduced pressure to provide crude product 3 (2,785 g), which was used for the next reaction 20 without further purification.

Synthesis of N- (3- (5-methoxy-2- (4- (2 (methylsulfonyl) ethoxy) phenylamino) pyrimidin-4yloxy) phenyl) acrylamide (I-44a)

Compound 3 (2,304 g), compound 4 (2,270 g), K₂CO₃

215 (3,270 g), tris (dibenzylideneacetone) dipalladium (0.517 g), dicyclohexyl (2 ', 4', 6'- triisopropylbiphenyl-2-yl) phosphine (0.512 g) and t-BuOH (60 mL) were added sequentially to a flask. The reaction mixture was stirred under reflux under N flow₂. After 3.5 h, CCD (EtOAc / Petroleum Ether / TEA = 1: 1: 0.1 as mobile phase) indicates that the reaction is complete. The reaction mixture was allowed to cool completely to 40 ~ 50 ° C, and then filtered through Celite®. The Celite layer was washed with ethyl acetate (50 mL). The combined filtrate was concentrated under reduced pressure. The resulting crude was further purified by column chromatography to provide compound I-44a (1.8g, 29.1%, M + H⁺= 485.5) as a light yellow solid.

<td></td><td colspan="3">^XH NMR (500 MHz, DMSO)</td><td>δ 10.37 (</td><td>s, 1H), 9.14 (s,</td><td>1 HOUR) ,</td>

<td> 8.19</td><td>(s,</td><td>1H), 7.63 i</td><td>(t, J = 2.</td><td>0 Hz, 1H)</td><td>, 7.56 (d, J = 9.1</td><td>Hz,</td>

<td>1 HOUR) ,</td><td> 7.44</td><td>(t, J = 8.</td><td>1 Hz, 1H)</td><td>, 7.37 (d,</td><td>J = 9.0 Hz, 2H),</td><td> 6.96</td>

<td>(ddd,</td><td>J =</td><td> 8.1, 2.3,</td><td>0.8 Hz,</td><td>1H), 6.69</td><td>(d, J = 9.1 Hz,</td><td>2H),</td>

<td> 6.44</td><td>(dd,</td><td>J = 17.0,</td><td>10.1 Hz,</td><td>1H), 6.27</td><td>(dd, J = 17.0, 1.9</td><td>Hz,</td>

<td>1 HOUR) ,</td><td> 5.78</td><td>(dd, J =</td><td> 10.1, 1.9</td><td>Hz, 1H),</td><td>4.23 (t, J = 5.6</td><td>Hz,</td>

<td>2H),</td><td> 3.87</td><td>(s, 3H), 3</td><td>.57 (t, J</td><td>= 5.6 Hz,</td><td>2H), 3.05 (s, 3H),</td><td></td>

216

Example 44

Synthesis of N- (3- (5-methoxy-2- (1- (2-methoxyethyl) -lH-indole-5-amino) pyrimidin-4-yloxy) phenyl) acrylamide (I-45a)

<img file="MX368491B_D0196.tif" />

NaH, THF ta up to 60 ° C

OMe

<img file="MX368491B_D0197.tif" />

<img file="MX368491B_D0198.tif" />

P.S₂(dba)₃, X-phos

K₂CO₃, t-BuOH

PtO₂, H₂

THF

<img file="MX368491B_D0199.tif" />

<img file="MX368491B_D0200.tif" />

1- (2-methoxyethyl) -5-nitro-lH-indole (1)

To a solution of 5-nitro-l # -indol (1,620 g) and 1-bromine-

2- methoxyethane (1,412 g) in THF (15 mL) at room temperature, NaH (0.420 g, 80% dispersion in mineral oil) was added. The mixture was stirred at 60 ° C for 6h. Another portion of l-bromo-2-methoxyethane (0.301 g) was added, and the mixture was continuously stirred at 60 ° C overnight. The reaction mixture was cooled and poured into ice water. The precipitates were filtered, washed with water, and dried to provide 1 (2.10 g, 95.45%) as a yellow solid.

Synthesis of 1- (2-methoxyethyl) -lH-indole-5-amine (2)

A solution of 1 (2,052 g) and PtO₂ (0.062 g) in THF (20 mL) was hydrogenated with a hydrogen balloon at temperature

217 atmosphere during the night. At this point, CCD indicates that the reaction is complete. The reaction mixture was filtered through Celite®. The filtrate was concentrated under reduced pressure to provide 2 (1,600 g), which was used for the next step without further purification.

Synthesis of N- (3- (5-methoxy-2- (1- (2-methoxyethyl) -lH-indole-5-amino) pyrimidin-4-yloxy) phenyl) acrylamide (I-45a)

Compound 2 (1,001 g), compound 3 (1,624 g), K₂CO₃(1,495 g), tris (dibenzylideneacetone) dipalladium (0.456g), dicyclohexyl (2 ', 4', 6'-triisopropylbiphenyl-2-yl) phosphine (0.480 g) and t-BuOH (15 mL) were added sequentially to a flask. The reaction mixture was stirred under reflux under N flow₂. After 6 h, CCD (EtOAc / Petroleum Ether / TEA = 1: 1: 0.1 as mobile phase) indicates that the reaction is complete. The reaction mixture was allowed to cool completely to 40 ~ 50 ° C, and then filtered through Celite®. The Celite layer was washed with ethyl acetate (50 mL). The combined filtrate was concentrated under reduced pressure. The resulting crude was further purified by column chromatography to provide compound I-45a

<td> (1.5</td><td>g, 62.5%</td><td>, M + H⁺= 460.5) as</td><td>a</td><td>solid</td><td>White.</td><td></td><td></td>

<td></td><td>^:H NMR (</td><td>500 MHz, DMSO) δ</td><td> 10.</td><td>37 (s,</td><td>1H), 9.06</td><td>(s,</td><td>1 HOUR) ,</td>

<td> 8.20</td><td>(s, 1H),</td><td>7.70 - 7.66 (m,</td><td>2H),</td><td> 7.64</td><td>(d, J = 8.2</td><td>Hz,</td><td>1 HOUR) ,</td>

<td> 7.51</td><td> - 7.36 (</td><td>m, 1H), 7.22-7.</td><td> 16 (</td><td>m, 2H)</td><td>, 7.10 (dd,</td><td>J =</td><td> 8.8,</td>

218

1.9 Hz, 1H), 6.99 (ddd, J = 8.1, 2.3, 0.7 Hz, 1H), 6.44 (dd,

J = 17.0, 10.1 Hz, 1H), 6.27 (dd, J = 17.0, 1.9 Hz, 1H), 6.11 (d, J = 2.9 Hz, 1H), 5.77 (dd, J = 10.1, 1.9 Hz, 1H), 4.21 (t, J = 5.3 Hz, 2H), 3.88 (s, 3H), 3.59 (t, J = 5.4 Hz, 2H),

3.19 (s, 3H).

<td></td><td>¹³C NMR</td><td colspan="2">(126 MHz, DMSO) δ 165.36</td><td>(s), 161.45</td><td>(s), 156.17</td>

<td>s),</td><td> 154.90</td><td>(s), 146.13</td><td>(s), 142.38</td><td>(s), 136.38</td><td>(s), 134.91</td>

<td>s),</td><td> 133.62</td><td>(d, J = 14.8</td><td>Hz), 131.92</td><td>(s), 130.87</td><td>(s), 129.95</td>

<td>S),</td><td> 129.31</td><td>(s),. 118.93</td><td>(s), 118.06</td><td>(s), 116.55</td><td>(s), 114.68</td>

<td>s),</td><td> 111.23</td><td>(s), 111.10</td><td>(d, J = 27.6</td><td>Hz), 102.25</td><td>(s), 73.05</td>

<td>s),</td><td> 60.05 (</td><td>s), 5 9.67 (s)</td><td>, 47.31 (s).</td><td></td><td></td>

219

Example 45

Synthesis of N- (3- (2- (6 - ((2-methoxyethyl) (methyl) amino) pyridin-3ylamino) -7H-pyrrolo [2,3-d] pyrimidin-4-yloxy) phenyl) acrylamide (I -46a)

<img file="MX368491B_D0201.tif" />

Synthesis of (2- (6 - ((2methoxyethyl) (methyl) amino) pyridin-3-ylamino) -4- (3-nitrophenoxy) 7H-pyrrolo [2,3-d] pyrimidin-7-yl) methyl pivalate (3)

Compound 1 (3.1 g), compound 2 (10.0 g), K₂CO₃ (5.2 g), tris (dibenzylideneacetone) dipalladium (1.2 g), dicyclohexyl (2 ', 4', 6'-triisopropylbiphenyl-2-yl) phosphine (1.2 g) and t-BuOH (100 mL) were added sequentially to a flask. The reaction mixture was stirred under reflux under N flow₂. After

220

3.5 h, CCD (DCM / MeOH = 10/1 as mobile phase) indicates that the reaction is complete. The reaction mixture was allowed to cool completely to 40 ~ 50 ° C, and then filtered through Celite®. The Celite layer was washed with ethyl acetate (50 mL). The combined filtrate was concentrated under reduced pressure. The resulting crude was further purified by column chromatography to provide compound 3 (6,875 g, 62.5).

Synthesis of N²- (2-methoxyethyl) -N²-methyl-N⁵- (4- (3-nitrophenoxy) 7H-pyrrolo [2,3-d] pyrimidin-2-yl) pyridine-2,5-diamine (4)

A round bottom flask (250 mL) was charged with compound 3 (6,857 g) and MeOH (120 mL). When Compound 3 completely dissolved, the solution was cooled in an ice bath to around 10 ° C. The NaOH solution (2.5 M, 10 ml) was then added into the flask slowly, keeping the temperature below 16 ° C during the addition. The mixture was stirred for 1 h at this temperature followed by the addition of THE (50 mL). After 1.5 h, water (100 mL) was added to the flask for 15 min, keeping the temperature below 20 ° C. The mixture was extracted with ethyl acetate. The combined organic layers were concentrated under reduced pressure. Solvents (50 mL, ethyl acetate / petroleum ether = 1: 4) were added to this crude product, and stirred for 2 h. The resulting solid was filtered and dried to provide

221 (5.13 g), which was used for the next step without further purification.

Synthesis of N⁵- (4- (3-aminophenoxy) -7H-pyrrolo [2,3-d] pyrimidin-

2-yl) -N²- (2-methoxyethyl) -N²-methylpyridine-2,5-diamine (5)

A mixture of 4 (5.13 g) and PtO₂ (117 mg) in THF (50 mL) was hydrogenated with a hydrogen balloon at 40 ° C overnight. At this point, CCD indicates that the reaction is complete. The reaction mixture was filtered through Celite® and washed with ethyl acetate. The combined filtrate was concentrated under reduced pressure to provide crude compound 5 (4.69 g), which was used for the next step without further purification.

Synthesis of N- (3- (2- (6 - ((2-methoxyethyl) (methyl) amino) pyridin-3ylamino) -7H-pyrrolo [2,3-d] pyrimidin-4-yloxy) phenyl) acrylamide (I -46a)

Acryloyl chloride (1,133 g) was added dropwise to a solution of compound 5 (3,734 g) and DIEA (1,480 g) in THF (30 mL) at 0 ° C over 5 min. The mixture was stirred for 1 at this temperature. NaHCO added₃ saturated aqueous (10 mL) to quench the reaction. The resulting mixture was stirred for 10 min, and then extracted with ethyl acetate. The organic layers were combined and concentrated under reduced pressure. The resulting crude was purified by column chromatography to provide compound I-46a (1.2 g,

222

28.4%, Μ + Η⁺=460.5).

^ΧΗ NMR (500 MHz, DMSO) δ 11.48 (s, 1H), 10.31 (s, 1H),

8.73 (s, 1H), 8.28 (s, 1H), 7.72 (dd, J = 9.0, 2.4 Hz, 1H),

7.63 (t, J = 2.0 Hz, 1H), 7.58 (d, J = 8.2 Hz, 1H), 7.41 (t, J = 8.1 Hz, 1H), 7.03 (dd, J = 3.4, 2.3 Hz, 1H), 6.99 (dd, J = 8.1, 1.5 Hz, 1H), 6.43 (dd, J = 16.9, 10.1 Hz, 2H), 6.27 (dd, J = 17.0, 1.9 Hz, 1H), 6.22 (dd, J = 3.4, 1.9 Hz, 1H),

5.82 - 5.75 (m, 1H), 3.62 (t, J = 5.8 Hz, 2H), 3.46 (t, J =

5.8 Hz, 2H), 3.24 (s, 3H), 2.95 (s, 3H).

Example 46

Synthesis of N- (3- (2- (4- (4- (2-methoxyethyl) piperazin-l-yl) phenylamino) -7H-pyrrolo [2,3-d] pyrimidin-4yloxy) phenyl) acrylamide (I-47a )

<img file="MX368491B_D0202.tif" />

<img file="MX368491B_D0203.tif" />

HN

<img file="MX368491B_D0204.tif" />

l-47a

Synthesis of (4- (3-acrylamidophenoxy) -2- (4- (4- (2 methoxyethyl) piperazin-l-yl) phenylamino) -7H-pyrrolo [2,3223 djpiriinidin-7-yl) methyl (3 )

Compound 1 (2,445 g), compound 2 (4,325 g), K₂CO₃(2,801 g), tris (dibenzylideneacetone) dipalladium (0.416 g), dicyclohexyl (2 ', 4', 6'-triisopropylbiphenyl-2-yl) phosphine (0.404 g) and t-BuOH (60 mL) were added sequentially to a flask. The reaction mixture was stirred under reflux under N flow₂. After 5 h, CCD (DCM / MeOH = 10/1 as mobile phase) indicates that the reaction is complete. The reaction mixture was allowed to cool completely to 40 ~ 50 ° C, and then filtered through Celite®. The Celite layer was washed with ethyl acetate (50 mL). The combined filtrate was concentrated under reduced pressure. The resulting crude was further purified by column chromatography to provide Compound 3 (4.6g, 72.7%).

Synthesis of N- (3- (2- (4- (4- (2-methoxyethyl) piperazin-1yl) phenylamino) -7H-pyrrolo [2,3-d] pyrimidin-4yloxy) phenyl) acrylamide (I-47a)

A round bottom flask (250 mL) was charged with compound 3 (4.5 g), MeOH (30 mL), and THF (30 mL). When Compound 3 completely dissolved, the solution was completely cooled to around 10 ° C with an ice bath. The NaOH solution (2.5 M, 6 mL) was then added into the flask slowly, keeping the temperature below 16 ° C throughout the addition. The mixture was stirred for 1.5 h at this

224 temperature. Then water (200 mL) was added to the flask for 15 min, keeping the temperature below 20 ° C. The mixture was extracted with ethyl acetate (500 mL). The combined organic layers were separated, dried over Na₂SW₄ and concentrated under reduced pressure. The resulting crude was purified by column chromatography (EtOAc as mobile phase) to give I47a (2.96 g, 80.4%, M + H⁺= 514.6) as a white solid.

225

Example 47

Synthesis of N- (3- (2- (3-fluoro-4- (4- (2-methoxyethyl) piperazin-1yl) phenylamino) -7H-pyrrolo [2,3-d] pyrimidin-4yloxy) phenyl) acrylamide ( I-48a)

<img file="MX368491B_D0205.tif" />

3 or

<img file="MX368491B_D0206.tif" />

or

<img file="MX368491B_D0207.tif" />

HN

<img file="MX368491B_D0208.tif" />

l-48a

Synthesis of 1- (2-fluoro-4-nitrophenyl) piperazine (1)

A mixture of 1,2-difluoro-4-nitrobenzene (15.9 g), piperazine (10.39 g), and acetonitrile (100 mL) was stirred at reflux for 7 h. CCD shows that the reaction is

226 complete. After cooling, the mixture was made basic with aqueous solution of K₂CO₃ saturated (100 mL), and extracted with ethyl acetate. The combined organic layers were washed with water, dried over Na₂SW₄, and concentrated under reduced pressure. Solvents (40 mL, petroleum ether / ethyl acetate = 1: 1) were added in the test and stirred overnight. The resulting precipitates were collected and dried to provide the desired product 1, (13.5 g) as a yellow solid.

Synthesis of 1- (2-fluoro-4-nitrophenyl) -4- (2 methoxyethyl) piperazine (2)

Et was added to a solution of l-bromo-2-methoxyethane (8.7 g) and 1 (11-4 g) in DMF (100 mL) at room temperature.₃N (8.2 g). The mixture was stirred at 54 ° C overnight. The reaction mixture was poured into ice water (300 mL). The precipitate was collected and redissolved in ethyl acetate (200 mL). The organic layer was washed with brine and concentrated under reduced pressure to provide the desired compound 2 (14.0 g, 98%), which was used for the next step without further purification.

Synthesis of 3-fluoro-4- (4- (2-methoxyethyl) piperazin-lil) aniline (3)

A mixture of 2 (7.0 g) and Pd / C (0.586 g, 10% activated carbon) in THF (100 mL) was hydrogenated with a hydrogen balloon

227 at room temperature overnight. At this point, CCD indicates that the reaction is complete. The reaction mixture was filtered through Celite®. The filtrate was concentrated under reduced pressure to provide 3 (6.3 g), which was used for the next step without further purification.

Synthesis of (4- (3-acrylamidophenoxy) -2- (3-fluoro- pivalate

4- (4- (2-methoxyethyl) piperazin-l-yl) phenylamino) -7H-pyrrolo [2,3d] pyrimidin-7-yl) methyl (5)

Compound 3 (1,051 g), compound 4 (1,806 g), K2CO3 (0.936 g), tris (dibenzylideneacetone) dipalladium (0.166 g), dicyclohexyl (2 ', 4', 6'-triisopropylbiphenyl-2-yl) phosphine ( 0.195 g) and t-BuOH (60 mL) were added sequentially to a flask. The reaction mixture was stirred under reflux under N flow₂. After 6 h, CCD (DCM / MeOH = 10/1 as mobile phase) indicates that the reaction is complete. The mixture was allowed to cool completely to 40 ~ 50 ° C, filtered through Celite®. The Celite layer was washed with ethyl acetate (50 mL). The combined filtrate was concentrated under reduced pressure. The resulting crude was purified by column chromatography to provide Compound 5 (2,316g, 90.9%).

Synthesis of N- (3- (2- (3-fluoro-4- (4- (2-methoxyethyl) piperazin-lyl) phenylamino) -7H-pyrrolo [2,3-d] pyrimidin-4yloxy) phenyl) acrylamide ( I-48a)

A round bottom flask (250 mL) was charged with the

228 compound 5 (2.3 g), MeOH (10 mL) and THF (10 mL). When compound 5 completely dissolved, the solution was completely cooled to around 10 ° C with an ice bath. The NaOH solution (2.5 M, 3.5 mL) was then added into the flask slowly, keeping the temperature below 16 ° C throughout the addition. The mixture was continuously stirred for

<td>other</td><td>at this temperature. Then water (40 mL) was added to the</td>

flask for 15 min, keeping the temperature below 20 ° C. The mixture was extracted with ethyl acetate (500 mL). The combined organic layers were separated, dried over Na₂SO4 and concentrated under reduced pressure. The resulting crude was purified by column chromatography to give I-48a (0.814 g, 42.5%, M + H⁺=532.6).

<td></td><td>³H NMR (500 MHz, CDC1₃) δ 9.81 (s, 1H), 8.06 (s, 1H),</td>

<td> 7.64</td><td>(s, 1H), 7.51 - 7.37 (m, 2H), 7.33 (t, J = 8.0 Hz, 1H),</td>

<td> 7.26</td><td>(s, 1H), 6.99 (d, J = 7.3 Hz, 1H), 6.84 (d, J = 8.0 Hz,</td>

<td>1 HOUR) ,</td><td>6.71 (t, J = 9.1 Hz, 1H), 6.67 (s, 1H), 6.40 (d, J =</td>

<td> 16.8</td><td>Hz, 1H), 6.29 - 6.17 (m, 2H), 5.70 (d, J = 10.2 Hz, 1H),</td>

<td> 3.56</td><td>(dd, J = 15.9, 11.0 Hz, 2H), 3.38 (s, 3H), 3.00 (s, 4H),</td>

<td> 2.66</td><td>(d, J = 4.7 Hz, 6H).¹³C NMR (126 MHz, CDC1₃) δ 171.28 (s), 163.75 (s), 162.68</td>

<td>(s),</td><td>156.59 (s), 155.11 (d, J = 9.0 Hz), 154.65 (s), 153.45</td>

<td>(S),</td><td>138.98 (s), 135.62 (d, J = 11.0 Hz), 134.26 (d, J = 9.3</td>

<td>Hz),</td><td>130.98 (s), 129.75 (s), 128.04 (s), 120.68 (s), 119.07</td>

229 (s), 117.96 (s), 116.88 (s), 114.53 (s), 114.08 (s), 107.60 (d, J = 26.0Hz), 99.56 (s), 99.39 (s), 69.91 (s), 58.91 (s),

57.96 (s), 53.63 (s), 50.69 (s).

Example 48

Synthesis of (S) -N- (3- (2- (4 - ((1- (2-methoxyethyl) pyrrolidin-3yl) (methyl) amino) phenylamino) -7H-pyrrolo [2,3-d] pyrimidin- 4-yloxy) phenyl) acrylamide (I-49a)

<img file="MX368491B_D0209.tif" />

<img file="MX368491B_D0210.tif" />

<img file="MX368491B_D0211.tif" />

l-49a

Synthesis of (S) - (2- (4 - ((1- (2methoxyethyl) pyrrolidin-3-yl) (methyl) amino) phenylamino) -4- (3 nitrophenoxy) -7H-pyrrolo [2,3- d] pyrimidin-7-yl) methyl (3)

Compound 1 (1,010 g), compound 2 (1,642 g), K2CO3

230 (1,262 g), tris (dibenzylideneacetone) dipalladium (0.371 g), dicyclohexyl (2 ', 4', 6'- triisopropylbiphenyl-2-yl) phosphine (0.367 g) and t-BuOH (15 mL) were added sequentially to a flask. The reaction mixture was stirred under reflux under N flow₂. After 22.5 h, CCD (DCM: Methanol = 10: 1 as mobile phase) indicates that the reaction is complete. The reaction mixture was allowed to cool completely to 40 ~ 50 ° C, and then filtered through Celite®. The Celite layer was washed with ethyl acetate (30 mL). The combined filtrate was concentrated under reduced pressure. The resulting crude was further purified by column chromatography (Ethyl acetate / MeOH = 20: 1 as mobile phase) to provide Compound 3 (1.74 g, 70.24%) as a brown oil.

Synthesis of (S) -N¹- (1- (2-methoxyethyl) pyrrolidin-3-yl) -B ^ -motilN⁴- (4- (3-nitrophenoxy) -7H-pyrrolo [2,3-d] pyrimidin-2yl) benzene-l, 4-diamine (4)

A round bottom flask (250 mL) was charged with compound 3 (1.74 g), THF (10 mL) and MeOH (20 mL). After compound 3 was completely dissolved, the solution was cooled to ~ 10 ° C with an ice bath. The NaOH solution (2.5M, 3 mL) was then added into the flask slowly, keeping the temperature below 16 ° C during the addition. The mixture was stirred for 5.5 h at this temperature. Water (50 mL) was slowly added to the flask over 15 min keeping the

231 temperature below 20 ° C during addition. The mixture was extracted with ethyl acetate. The combined organic layers were concentrated under reduced pressure to provide compound 4 (1.2 g).

Synthesis of (S) -N¹- (4- (3-aminophenoxy) -7H-pyrrolo [2,3d] pyrimidin-2-yl) -N⁴- (1- (2-methoxyethyl) pyrrolidin-3-yl) -N⁴methylbenzene-1,4-diamine (5)

A mixture of 4 (1.2 g) and PtO₂ (33 mg) in THF (15 mL) was hydrogenated with a hydrogen balloon at 50 ° C for 40 h. CCD and LC-MS indicates that the reaction was not complete. The reaction mixture was filtered through Celite® and the filtrate was concentrated under reduced pressure. The resulting residue was treated with an iron / NH system₄Cl ac / EtOH for 4 h. At this point, CCD and LC / MS indicates that the reaction is complete. The mixture was extracted with ethyl acetate. The combined organic layers were concentrated under reduced pressure to provide crude product 5 (1.1 g), which was used for the next step without further purification.

Synthesis of (S) -N- (3- (2- (4 - ((1- (2-methoxyethyl) pyrrolidin-3yl) (methyl) amino) phenylamino) -7H-pyrrolo [2,3-d] pyrimidin- 4yloxy) phenyl) acrylamide (I-49a)

To a solution of compound 5 (1.1 g) and DIEA (1,001 g) in THF / MeOH (4: 1, 25 mL) at 0 ° C, acryloyl chloride (0.462 g) was added dropwise over 5 min. The mixture was stirred for

232 at this temperature. At this point, CCD and LC / MS indicates that the reaction is complete. Na aqueous solution was added₂CO₃saturated (50 mL) to quench the reaction. The resulting mixture was stirred for 10 min, and extracted with ethyl acetate. The combined organic layers were combined and concentrated under reduced pressure. The resulting crude was further purified by column chromatography to give compound I-49a (0.7g, 57.1%, M + H⁺=528.6).

Example 49 Synthesis of N- (3- (5-methoxy-2- (2- (2-methoxyethyl) isoindolin-5-amino) pyrimidin-4-yloxy) phenyl) acrylamide (I-50a)<img file="MX368491B_D0212.tif" /><img file="MX368491B_D0213.tif" />

Et₃N, CH₃CN

<img file="MX368491B_D0214.tif" />

<img file="MX368491B_D0215.tif" />

<img file="MX368491B_D0216.tif" />

<img file="MX368491B_D0217.tif" />

Synthesis of 5-nitroisoindoline (1)

To concentrated sulfuric acid (3 mL) at -10 ° C was added isoindoline hydrochloride (1,569 g). The mixture was stirred at

233

10 ° C for 15 min. Fuming nitric acid (3 mL) was added dropwise. The resulting mixture was stirred for 35 min at room temperature and then heated to and stirred at 50 ° C for 35 min. After cooling to room temperature, the mixture was diluted with ethyl acetate (5 mL) and poured into ice water. The resulting precipitate was collected, washed with a small amount of ethyl acetate, and dried to provide 5-nitroisoindoline 1 hydrosulfate (1,644 g, 62.7%).

Synthesis of 2- (2-methoxyethyl) -5-nitroisoindoline (2)

To a solution of l-bromo-2-methoxyethane (0.5 g) and 1 (0.5 g) in CH₃CN (15 mL) Et was added₃N (0.8 g). The mixture was then heated to 80 ° C and stirred for 7h. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with brine and concentrated under reduced pressure to provide the desired compound 2 (650 mg, 96%), which was used for the next step without further purification.

Synthesis of 2- (2-methoxyethyl) isoindolin-5-amine (3)

A mixture of 2 (650 mg) and PtO₂ (0.025 g) in THF (10 mL) was hydrogenated with a hydrogen balloon at room temperature overnight. CCD indicates that the reaction is complete. The reaction mixture was filtered through Celite® and washed with ethyl acetate. The combined filtrates are

2. 3. 4 They concentrated under reduced pressure to provide the desired product 3 (0.50 g), which was used for the next step without further purification.

Synthesis of N- (3- (5-methoxy-2- (2- (2-methoxyethyl) isoindolin-5-lamino) pyrimidin-4-yloxy) fenxl) acrylamide (I-50a)

Compound 3 (0.5g), Compound 4 (0.8g), K₂CO₃ (0.787 g)_r tris (dibenzylideneacetone) dipalladium (0.116 g), dicyclohexyl (2 ', 4', 6'-triisopropylbiphenyl-2-yl) phosphine (0.126 g) and t-BuOH (20 mL) were added sequentially to a flask. The reaction mixture was stirred under reflux under N flow₂. After 19 h, CCD (DCM: Methanol = 10: 1 as mobile phase) indicates that the reaction is complete. The reaction mixture was allowed to cool completely to 40 ~ 50 ° C, and

<td>then I know</td><td>filter</td><td>through</td><td>Celite®.</td><td>Celite's cape</td><td>I know</td>

<td>washed with</td><td>acetate</td><td>ethyl</td><td>(50 mL). The</td><td>combined filtering</td><td>I know</td>

<td>concentrated</td><td>low</td><td>Pressure</td><td>reduced. The</td><td>resulting crude</td><td>I know</td>

<td>purified</td><td colspan="2">also by</td><td>chromatography</td><td colspan="2">column for</td>

provide compound I-50a (0.512 g, 42.7%, M + H⁺=462.5).

235

Example 50

Synthesis of (S) -N- (3- (2- (4- (ethyl (1- (2-methoxyethyl)) pyrrolidin-

3-yl) amino) phenylamino) -5-methoxypyrimidin-4-yloxy) phenyl) acrylamide (I-51a)

<img file="MX368491B_D0218.tif" />

(S) -N-ethyl-1- (2-methoxyethyl) -N- (4 Synthesis nitrophenyl) pyrrolidin-3-amine (2)

NaH (0.318 g, 80% dispersion in mineral oil, 13.25 mmol) and C were sequentially added to a solution of 1 (1,969 g, 7,428 mmol) in DMF (10 ml) at 0 ° C.₂H₅I (1,330 g,

8.52 mmol). The mixture was stirred at 60 ° C for 3h. The reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with water, dried over Na₂SW₄, filtered and concentrated under reduced pressure. The resulting crude was further purified by column chromatography (ethyl acetate / petroleum ether from 33.3% to

100% as mobile phase) to give 2 (0.280 g, 0.9 mmol, 13%)

236 like a yellow oil.

Synthesis of (S) -l ^ -ethyl-N¹- (1- (2-methoxyethyl) pyrrolidin-3yl) benzene-1,4-diamine (3)

To compound 2 (0.280 g, 0.9 mmol) in THF / H2O (20 mL / 3 mL) was added iron (0.280 g, 5 mmol) and NH₄C1 (0.535 g, 10 mmol). The mixture was stirred at reflux for 2 h. At this point, CCD indicates that the reaction is complete. The mixture was filtered. The filtrate was diluted with ethyl acetate and washed with saturated NaHCOs. The organic layer was dried over NajSOo filtered and concentrated under reduced pressure to provide the desired compound 3 (0.191 g, 81%), which was used for the next step without further purification.

Synthesis of (S) -N- (3- (2- (4- (ethyl (1- (2-methoxyethyl)) pyrrolidin-

3-yl) amino) phenylamino) -5-methoxypyrimidin-4-yloxy) phenyl) acrylamide (I-51a)

Compound 3 (0.191g, 0.73mmol), compound 4 (0.315g, 1mmol), K₂CO₃ (0.330 g, 2.5 mmol), tris (dibenzylideneacetone) dipalladium (0.096 g, 0.1 mmol), dicyclohexyl (2 ', 4', 6'-triisopropylbiphenyl-2-yl) phosphine (0.094 g, 0.2 mmol) and t-BuOH (20 mL) were added sequentially to the flask. The reaction mixture was stirred under reflux under N flow₂. After 5 h, CCD (DCM: Methanol = 10: 1 as mobile phase) indicates that the reaction is complete. The reaction mixture was allowed to cool completely to

237

40 ~ 50 ° C, and then filtered through Celite®. The Celite layer was washed with ethyl acetate (50 mL). The combined filtrate was concentrated under reduced pressure. The resulting crude was further purified by column chromatography to provide compound I-51a (0.150g, 32%,

M + H⁺=433.6) .

^XH NMR (500 MHz, CDC1₃) δ 8.33 (s, 1H), 7.96 (s, 1H),

7.66 (s, 1H), 7.47 (d, J = 7.7 Hz, 1H), 7.33 (t, J = 8.1 Hz, 1H), 7.16 (d, J = 8.7 Hz, 2H), 7.01 - 6.91 (m, 2H ), 6.69 (d,

<td>J =</td><td> 8.8</td><td>Hz,</td><td colspan="2">2H), 6.41 (d, J</td><td colspan="2">= 16.7 Hz, 1H), 6.28 (dd,</td><td>J =</td>

<td> 16.8</td><td> , 10</td><td> .2</td><td>Hz, 1H), 5.71</td><td>(d,</td><td>J = 10.4 Hz, 1H), 4</td><td> .21 -</td><td> 4.00</td>

<td>(m,</td><td>1 HOUR) ,</td><td> 3.!</td><td>93 (d, J = 16.2</td><td>Hz,</td><td>3H), 3.51 (t, J = 5.</td><td>6 Hz,</td><td>2H),</td>

<td> 3.37</td><td>(s,</td><td colspan="2">3H), 3.20 - 3.11</td><td>(m,</td><td>2H), 2.85 (d, J = 10.</td><td>0 Hz,</td><td>1 HOUR) ,</td>

<td> 2.79</td><td> - 2</td><td> . 67</td><td>(m, 2H), 2.67</td><td> - 2.</td><td>.52 (m, 2H), 2.43 (dd</td><td>, J -</td><td> 9.0,</td>

<td> 7.3</td><td>Hz,</td><td>1 HOUR)</td><td> , 2.17 - 2.01</td><td>(m,</td><td>1H), 1.80 - 1.63 (m,</td><td>1 HOUR) ,</td><td> 0.99</td>

<td>(t,</td><td>J = '</td><td> 7.0</td><td>Hz, 3H).</td><td></td><td></td><td></td><td></td>

<td></td><td>¹³C</td><td>NMR</td><td colspan="2">(126 MHz, CDCI3) δ</td><td>163.73 (s), 160.38 (</td><td colspan="2">s), 154.20</td>

<td>(s),</td><td> 152</td><td> . 97</td><td>(s), 144.59 (</td><td>s),</td><td>142.94 (s), 139.24 '(</td><td colspan="2">s), 135.36</td>

<td>(s),</td><td> 131</td><td> . 91</td><td>(s), 131.07 (</td><td>s),</td><td>129.61 (s), 127.97 (</td><td colspan="2">s), 120.12</td>

<td>(s),</td><td> 118</td><td> .43</td><td>(s), 117.96</td><td>(s),</td><td>116.76 (s), 114.05</td><td>(s),</td><td> 71.14</td>

<td>(S),</td><td> 58.</td><td> 87</td><td>(s), 58.60 (s)</td><td> , 58</td><td>.53 (s), 58.06 (s),</td><td> 55.76</td><td>(s),</td>

53.89 (s), 44.13 (s), 29.32 (s), 13.36 (s).

238

Example 51

Synthesis of N- (3- (5-methoxy-2- (1- (2-methoxyethyl) -2-oxoindolin5-ylamino) pyrimidin-4-yloxy) phenyl) acrylamide (I-52a)

<img file="MX368491B_D0219.tif" />

Synthesis of 1- (2-methoxyethyl) -5-nitroindolin-2-one (1)

A solution of 2- (2-fluoro-5-nitrophenyl) acetic acid (1,001 g) and 2-methoxyethanamine (1,892 g) in DMSO (5 mL) was stirred at 45 ° C overnight. Excess 2-methoxyethanamine was removed under reduced pressure before HC1 (2M, 3 mL) was added to the mixture. The mixture was stirred at 45 ° C for 1 hr. The reaction was quenched with water and extracted with ethyl acetate. The combined organic layers were dried over Na2SO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (DCM / petru = 5/1 with drops of AcOH as the mobile phase) to give 1 (0.720 g, 60.7% yield) as a yellow solid.

239

Synthesis of 5-amino-l- (2-methoxyethyl) indolin-2-one (2)

A mixture of 1 (0.401 g) and PtO₂ (0.019 g) in THF (15 mL) was hydrogenated with a hydrogen balloon at room temperature overnight. After completion of the reaction, the reaction mixture was filtered through Celite®. The filtrate was concentrated under reduced pressure, and the residue was redissolved with ethyl acetate. The solution was washed with water. The aqueous layer was separated and extracted with ethyl acetate (50 mLx3). The combined organic layers were dried over Na₂SW₄, filtered and concentrated under reduced pressure to provide the desired product 2 (0.345 g), which was used for the next step without further purification.

Synthesis of N- (3- (5-methoxy-2- (1- (2-methoxyethyl) -2-oxoindolin 5-ylamino) pyrimidin-4-yloxy) phenyl) acrylamide (I-52a)

Compound 2 (0.360 g), compound 3 (0.650 g), K₂CO₃(0.610 g), tris (dibenzylideneacetone) dipalladium (0.05 g), dicyclohexyl (2 ', 4', 6'- triisopropylbiphenyl-2-yl) phosphine (0.11 g) and t-BuOH (13 mL) were added sequentially to the flask . The reaction mixture was stirred under reflux under N flow₂. After 6 h, CCD (DCM: Methanol = 10: 1 as mobile phase) indicates that the reaction is complete. The reaction mixture was allowed to cool completely to 40 ~ 50 ° C, and then filtered through Celite®. The Celite cape is

240 washed with ethyl acetate (50 mL). Combined filtering is

<td>concentrated under pressure</td><td>reduced. The</td><td>raw</td><td>resulting is</td>

<td>further purified by</td><td>chromatography</td><td>of</td><td>column for</td>

<td>provide the compound</td><td>I-52a (0.47 g,</td><td> 56.6%,</td><td>M + H⁺=476.5).</td>

<td></td><td>Example 52</td><td></td><td></td>

Synthesis of (S) -N- (3- (2- (4- (cyclopropyl (1- (2methoxyethyl) pyrrolidin-3-yl) amino) phenylamino) -5methoxypyrimidin-4-yloxy) phenyl) acrylamide (I-53a)

<img file="MX368491B_D0220.tif" />

Synthesis of (S) -N-cyclopropyl-1- (2-methoxyethyl) -N- (4nitrophenyl) pyrrolidin-3-amine (2)

A mixture of compound 1 (1,090 g), cyclopropyl bromide (1,825 g), Pd₂(dba)₈ (0.200 g), X-Phos (0.201 g) and potassium carbonate (2,032 g) in t-butanol (15 mL) were stirred under argon at reflux overnight. After cooling to room temperature, the reaction mixture was filtered through Celite®, and washed with

241 ethyl. The combined filtrates were concentrated under reduced pressure. The residue was purified by flash column chromatography to provide the desired compound 2 (260mg, 21.85%).

Synthesis of (S) -l ^ -cyclopropyl-N¹- (1- (2-methoxyethyl) pyrrolidin 3-yl) benzene-l, 4-diamine (3)

For compound 2 (260 mg) in EtOH / H₂Or (5: 2, 14 mL) iron (201 mg) and NH were added₄C1 (800 mg). The mixture was stirred at reflux for 2 h. The reaction leaked. The filtrate was diluted with ethyl acetate and washed with aqueous NaHCO solution₃ saturated. The organic layer was separated, dried over Na₂SO4, and concentrated under reduced pressure to provide the desired compound 3 (200 mg, 85.47%), which was used for the next step without further purification.

Synthesis of (S) -N- (3- (2- (4- (cyclopropyl (1- (2 methoxyethyl) pyrrolidin-3-yl) amino) phenylamino) -5methoxypyrimidin-4-yloxy) phenyl) acrylamide (I-53a )

Compound 3 (0.188 g), compound 4 (0.235 g), K₂CO₃(0.250 g), tris (dibenzylideneacetone) dipalladium (0.076 g), dicyclohexyl (2 ', 4', 6'- triisopropylbiphenyl-2-yl) phosphine (0.085 g) and t-BuOH (10 mL) were added sequentially to the flask . The reaction mixture was stirred under reflux under N flow₂. After 5 h, CCD (DCM: Methanol = 10: 1 as mobile phase) indicates that the reaction is complete. The mixture of

242 Reaction was allowed to cool completely to 40 ~ 50 ° C, and then filtered through Celite®. The Celite layer was washed with ethyl acetate (50 mL). The combined filtrate was concentrated under reduced pressure. The resulting crude was further purified by column chromatography to provide compound I-53a (70mg, 18.8%, M + H⁺=545.6).

Example 53

Synthesis of N- (3- (5-methoxy-2- (4- (4- (2 (methylsulfonyl) ethyl) piperazin-l-yl) phenylamino) pyrimidin-4yloxy) phenyl) acrylamide (I-54a)

<img file="MX368491B_D0221.tif" />

THF

<img file="MX368491B_D0222.tif" />

<img file="MX368491B_D0223.tif" />

I

<img file="MX368491B_D0224.tif" />

P.S₂(dba)₃, X-phos

K₂CO₃, t-BuOH

<img file="MX368491B_D0225.tif" />

l-54a

Synthesis of l-bromo-2- (methylsulfonyl) ethane (1)

A solution of 2- (methylsulfonyl) ethanol (2.5 g) and pyridine (0.1 mL) in DCM (30 mL) at 0 ° C was added PBr₃ (6.3 g).

243

The mixture was warmed and stirred at room temperature for 4 h. At this point, CCD indicates that the reaction is complete. The mixture was cooled to 0 ° C and water was added to quench the reaction. The organic layer was separated, washed with saturated NaHCCh aqueous solution, dried over Na₂SW₄, and concentrated under reduced pressure to provide crude product 1 (0.841 g, 22%), which was used for the next step without further purification.

Synthesis of 1- (2- (methylsulfonyl) ethyl) -4- (4 nitrophenyl) piperazine (3)

Et was added to a solution of l-bromo-2- (methylsulfonyl) ethane 1 (0.841 g) and 2 (1.212 g) in CH3CN (20 mL) at room temperature.₃N (1 mL). The mixture was then heated to and stirred at 70 ° C overnight. The organic solvent was removed under reduced pressure. The residue was washed with ethyl acetate, THF, and water. The resulting solid was collected and separated to provide crude compound 3 (1.2 g, 85%), which was used for the next step without further purification.

Synthesis of 4- (4- (2- (methylsulfonyl) ethyl) piperazin-1 yl) aniline (4)

A solution of 3 (1.2 g) in THF / H₂Or (30 ml / 5 ml) was treated with iron (2.1 g) and ammonium chloride (1.0 g). The mixture was stirred at reflux for 2 h. The mixture was filtered to

244 through Celite® and washed with ethyl acetate (100 mL). The filtrate was washed with saturated aqueous NaHCCb solution and water, and then dried over Na₂SO4 and concentrated under reduced pressure to provide crude product 4 (0.380 g, 35%), which was used for the next step without further purification.

Synthesis

N- (3- (5-methoxy-2- (4- (4- (2 (methylsulfonyl) ethyl) piperazin-l-yl) phenylamino) pyrimidin-4yloxy) phenyl) acrylamide (I-54a)

Compound 4 (0.38 g), compound 5 (0.4 63 g), K₂CO₃ (0.440 g), tris (dibenzylideneacetone) dipalladium (0.913 g), dicyclohexyl (2 ', 4', 6'- triisopropylbiphenyl-2-yl) phosphine (0.860 g) and t-BuOH (10 mL) were added sequentially to the flask . The reaction mixture was stirred under reflux under N flow₂. After 5 h, CCD (DCM: Methanol = 10: 1 as mobile phase) indicates that the reaction is complete. The reaction mixture was allowed to cool completely to

40 ~ 50 ° C then filtered through

Celite®.

The cape

Celite was washed with ethyl acetate (50 mL). The combined filtrate was concentrated under reduced pressure. The resulting crude was further purified by column chromatography to provide compound I-54a (0.564g, 74.1%, M + H⁺=553.6).

245

Example 54

Synthesis of (S) -N- (3- (5-methoxy-2- (2-methoxy-4 - ((1- (2 methoxyethyl) pyrrolidin-3-yl) (methyl) amino) phenylamino) pyrimidin-

4-yloxy) phenyl) acrylaxnide (I-55a)

<img file="MX368491B_D0226.tif" />

<img file="MX368491B_D0227.tif" />

Et₃N

DMSO, 100C

<img file="MX368491B_D0228.tif" />

2

<img file="MX368491B_D0229.tif" />

_Br^ \ ^ OMe

Et₃N

CH₃CN, 60 C

<img file="MX368491B_D0230.tif" />

Synthesis of 3- (3-methoxy-4-nitrophenylamino) pyrrolidine-1-carboxylate (S) -tert-butyl (1)

4-Fluoro-2-methoxy-l-nitrobenzene (4,594 g) and (3S) - (-) - 1- (tButoxycarbonyl) -3 were charged into a 3-neck round bottom flask (250 mL) equipped with a reflux condenser. -aminopyrrolidine (5.0 g), TEA (3,030 g) in DMSO (50 mL). The reaction was heated to and stirred at 80 ° C

246 overnight. After CCD indicates that the reaction is complete, the reaction mixture was quenched with water and stirred for 0.5 h at room temperature. The resulting precipitation was filtered and dried to provide crude compound 1 (10.0 g) which was used for the next step without further purification.

Synthesis of (S) -N- (3-methoxy-4-nitrophenyl) pyrrolidin-3-amine (2)

To the crude compound 1 (10.0 g) in DCM (25 mL) was added TFA (10 mL). The reaction mixture was stirred at room temperature overnight. After CCD indicates that the reaction is complete, the reaction mixture was concentrated under reduced pressure (to remove most of the TFA). The residue was diluted with ethyl acetate and made basic by the addition of saturated NaHC0 (aq) at 0 ° C. The organic layer was separated, washed with brine, dried over Na2SO₄, and concentrated under reduced pressure to provide crude compound 2 (12 g), which was used for the next step without further purification.

Synthesis of (S) -N- (3-methoxy-4-nitrophenyl) -1- (2methoxyethyl) pyrrolidin-3-amine (3)

EtaN (6.0 g) was added to a solution of 2-bromoethyl methyl ether (4,500 g) and 2 (3,512 g) in CH3CN (100 mL) at room temperature. The mixture was heated to and stirred under reflux

247 for 2.5 h. The reaction mixture was concentrated under reduced pressure. The residue was redissolved in ethyl acetate (200 mL) and the resulting solution was washed with water. The aqueous layer was separated and extracted with ethyl acetate. The organic layers were combined, dried over Na₂SW₄, and concentrated under reduced pressure. The crude material was washed with solvents (petroleum ether / ethyl acetate = 2: 1) to provide the desired compound 3 (8.59 g, 57.5%).

(S) -N- (3-methoxy-4-nitrophenyl) -1- (2-methoxyethyl) -Nmethylpyrrolidin-3-amine (4)

To a solution of compound 3 (8,590 g) in DMF (5 mL) at 0 ° C, NaH (1.1 g, 80% dispersion in mineral oil) and CH were sequentially added₃I (5.55 g). The resulting mixture was then stirred for 0.5 hr. The reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with water, dried over Na₂SW₄, and concentrated under reduced pressure. Crude material 4 (3.80 g, 42.2%) was used directly in the next step without further purification.

Synthesis of (S) -3-methoxy-N¹- (1- (2-methoxyethyl) pyrrolidin-3yl) -l ^ -methylbenzene-l, 4-diamine (5)

A mixture of 4 (3.8 g) and PtO₂ (0.130 g) in THF (30 mL) was hydrogenated with a hydrogen balloon at room temperature overnight. Once the reaction was completed by

248

CCD, the reaction mixture was filtered through Celite®. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate / EtOH = 8/2, with 0.5% TEA as the mobile phase) to provide the desired compound 5 (2,323 g, 67.7%).

Synthesis of (S) -N- (3- (5-methoxy-2- (2-methoxy-4 - ((1- (2methoxyethyl) pyrrolidin-3-yl) (methyl) amino) phenylamino) pyrimidin-

4-yloxy) phenyl) acrylamide (I-55a)

Compound 5 (2,323 g), compound 6 (3,036 g), K₂CO₃(2,289 g), tris (dibenzylideneacetone) dipalladium (0.380 g), dicyclohexyl (2 ', 4', 6'- triisopropylbiphenyl-2-yl) phosphine (0.380 g) and t-BuOH (40 mL) were added sequentially to the flask . The reaction mixture was stirred under reflux under N flow₂. After 5 h, CCD (DCM: Methanol = 10: 1 as mobile phase) indicates that the reaction is complete. The reaction mixture was allowed to cool completely to 40 ~ 50 ° C, and

<td>then I know</td><td>filter</td><td>through</td><td>Celite®.</td><td>Celite's cape</td><td>I know</td>

<td>washed with</td><td>acetate</td><td>ethyl</td><td>(50 mL). The</td><td>combined filtering</td><td>I know</td>

<td>concentrated</td><td>low</td><td>Pressure</td><td>reduced. The</td><td>resulting crude</td><td>I know</td>

<td>purified</td><td colspan="2">also by</td><td>chromatography</td><td colspan="2">column for</td>

providing compound I-55a (2,845 g, 62.4%, M + H⁺=549.6).

9 íW

Example 55

Synthesis of N- (3- (2- (l-acetylindolin-5-ylamino) -5methoxypyrimidin-4-yloxy) phenyl) acrylamide (I-56a)

<img file="MX368491B_D0231.tif" />

Synthesis of 1- (5-nitroindolin-l-yl) ethanone (1)

Acetyl chloride (0.610 g, 7.82 mmol) was added slowly to a solution of 5-nitroindoline (1,010 g, 6,159 mmol), TEA (0.810 g, 8,020 mmol) in DCM (30 mL) at 0 ° C. The mixture was warmed and stirred at room temperature for 0.5 h. The reaction was quenched with water (30 mL) and extracted with DCM (25 mL χ4). The organic layers were combined, dried and concentrated under reduced pressure to provide crude 1 (1,015 g, 4,927 mmol, 85%), which was used for the next step without further purification.

Synthesis of 1- (5-aminoindolin-l-yl) ethanone (2)

A mixture of 1 (1,015 g, 4,927 mmol) and PtO₂ (0.028 g,

250

0.14 mmol) in THF (30 mL) was hydrogenated with a hydrogen balloon at room temperature overnight. Once the reaction was complete indicated by CCD, the reaction mixture was filtered through Celite®. The filtrate was concentrated under reduced pressure to provide the desired product 2 (0.798 g, 92%), which was used for the next step without further purification.

Synthesis of N- (3- (2- (l-acetylindolin-5-ylamino) -5methoxypyrimidin-4-yloxy) phenyl) acrylamide (I-56a)

Compound 2 (0.798 g, 4,531 mmol), compound 3 (1,956 g, 6,774 mmol), K₂CO₃ (1,553 g, 11 mmol), tris (dibenzylideneacetone) dipalladium (0.313 g, 0.34 mmol), dicyclohexyl (2 ', 4', 6'-triisopropylbiphenyl-2-yl) phosphine (0.360 g, 0.68 mmol) and t-BuOH (40 mL) were added sequentially to the flask. The reaction mixture was stirred under reflux under N flow₂. After 5 h, CCD (DCM: Methanol = 10: 1 as mobile phase) indicates that the reaction is complete. The reaction mixture was allowed to cool completely to 40 ~ 50 ° C, and then filtered through Celite®. The Celite layer was washed with ethyl acetate (50 mL). The combined filtrate was concentrated under reduced pressure. The resulting crude was further purified by column chromatography to provide compound I-56a (1.71 g, 84.8%, M + H⁺=446.6) .

251

Example 56

Synthesis of (S) -N- (3- (5-methoxy-2- (4- (methyl (1- (2 (methylsulfonyl) ethyl) pyrrolidin-3yl) amino) phenylamino) pyrimidin-4-yloxy) phenyl) acrylamide (I57a)

<img file="MX368491B_D0232.tif" />

de (S) -1- (2- (methylsulfonyl) ethyl) -N- (4Synthesis nitrophenyl) pyrrolidin-3-amine (3)

To a solution of l-bromo-2- (methylsulfonyl) ethane (2,

3,824 g) and 1 (3,512 g) in CH₃CN (40 mL) at room temperature Et was added₃N (3,490 g). The mixture was heated to and stirred under reflux for 5 h. The reaction mixture was then

252 emptied into ice water (150 mL). The resulting precipitate was collected, washed and dried to provide the desired compound 3 (3,484, 65.83%) as a yellow solid, which was used for the next step without further purification.

(S) -N-methyl-1- (2- (methylsulfonyl) ethyl) -N- (4nitrophenyl) pyrrolidin-3-amine (4)

To a solution of 3 (1.5 g) in DMF (10 mL) at 0 ° C, NaH (0.399 g, 80% dispersion in mineral oil) and CH were sequentially added₃I (0.924 g). The resulting mixture was then stirred for 1 hr. The reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with water, dried over Na2SO₄, and concentrated under reduced pressure. The resulting crude material 4 (1,664 g) was used directly in the next step without further purification.

Synthesis of (5) - ^ - methyl-N¹- (1- (2 (methylsulfonyl) ethyl) pyrrolidin-3-yl) benzene-1,4-diamine (5)

A solution of 4 (1,664 g) in EtOH / H2O (30 mL / Ι mL) was treated with iron (1,143 g) and ammonium chloride (4,512 g). The mixture was stirred at reflux for 2 h. The reaction was cooled to room temperature, and filtered through Celite®. The filtrate was extracted with ethyl acetate. The combined organic layers were washed with solution of Κ2 &lt;00₃ saturated aqueous, and concentrated under reduced pressure to provide the product

253 crude 5 (0.758 g, 50%), which was used for the next step without further purification.

(S) -N- (3- (5-methoxy-2- (4- (methyl (1- (2 (methylsulfonyl) ethyl) pyrrolidin-3yl) amino) phenylamino) pyrimidin-4-yloxy) phenyl) acrylamide (I57a )

Compound 5 (0.654 g), compound 6 (0721 g), K₂CO₃(0.702 g), tris (dibenzylideneacetone) dipalladium (0.182 g), dicyclohexyl (2 ', 4', 6'- triisopropylbiphenyl-2-yl) phosphine (0.191 g) and t-BuOH (30 ml) were added sequentially to the flask . The reaction mixture was stirred under reflux under N flow₂. After 4.5 h, CCD (DCM: Methanol = 10: 1 as mobile phase) indicates that the reaction is complete. The reaction mixture was allowed to cool completely to 40 ~ 50 ° C, and then filtered through Celite®. The Celite layer was washed with ethyl acetate (50 mL). The combined filtrate was concentrated under reduced pressure. The resulting crude was further purified by column chromatography to provide compound I-57a (662 mg, 53.13%, M + H⁺=567.6).

254

Example 57

Synthesis of (S) -N- (3- (2- (4 - ((l-acetylpyrrolidin-3yl) (methyl) amino) phenylamino) -5-methoxypyrimidin-4yloxy) phenyl) acrylamide (I-58a)

<img file="MX368491B_D0233.tif" />

Synthesis of (S) -tert-butyl (2) methyl (4-nitrophenyl) amino) pyrrolidine-1-carboxylate

To a solution of (S) -tert-butyl 3- (4-nitrophenylamino) pyrrolidine-1-carboxylate (1.0995 g, 3.257 mmol) in DMF (5 mL) at 0 ° C, NaH (0.165 g, 80) was sequentially added % dispersion in mineral oil) and CH₃I (0.705 g, 4.88 mmol). The resulting mixture was stirred for 0.5 hr. The reaction mixture was quenched with water and extracted with ethyl acetate.

255

The combined organic layers were washed with water, dried over Na2SO₄, and concentrated under reduced pressure. The resulting crude material 2 (0.894g, 2931mmol, 90%) was collected, washed, dried, and used directly in the next step without further purification.

Synthesis of (S) -N-methyl-N- (4-nitrophenyl) pyrrolidin-3-amine (3)

For crude compound 2 (0.894 g, 2,931 mmol) in DCM (10 mL), TEA (2 mL) was added. The reaction mixture was stirred at room temperature until CCD (petroleum ether / ethyl acetate = 1/3 as mobile phase) indicates that the reaction is complete. The reaction mixture was concentrated under reduced pressure to remove most of the TEA. The residue was made basic with NaHCOs (aq, 30 mL) and extracted with ethyl acetate (30 mL * 4). The organic layers were combined, dried and concentrated under reduced pressure to provide crude 3 (0.504g, 2.28 mmol, 78%), which was used in the next step without further purification.

Synthesis of (S) -1- (3- (methyl (4-nitrophenyl) amino) pyrrolidin-lil) ethanone (4)

Acetyl chloride (0.610 g, 7.82 mmol) was slowly added to a solution of 3 (0.504 g, 2.28 mmol), TEA (0.303 g, 3 mmol) in DCM (20 mL) at 0 ° C. The mixture was warmed and stirred at room temperature for 0.5 h. The reaction died down with

256 water (30 mL) and extracted with DCM (25 mL * 4). The organic layers were combined, dried and concentrated under reduced pressure to provide crude 4 (0.492 g, 1.87 mmol, 82%), which was used for the next step without further purification.

Synthesis of (S) -1- (3 - ((4-aminophenyl) (methyl) amino) pyrrolidinl-yl) ethanone (5)

A solution of 4 (0.320 g, 1.217 mmol) in THF / H₂Or (20 mL / 3 mL) was treated with iron (0.280 g, 5 mmol) and ammonium chloride (0.535 g, 10 mmol). The mixture was stirred at reflux for 2 h. The reaction was filtered through Celite®. The

<td>filtered out</td><td>I know</td><td>made basic with</td><td>NaHCO₃</td><td>(ac,</td><td>30 mL)</td><td>and extracted with</td>

<td>acetate</td><td>of</td><td>ethyl (30 mL</td><td> *4) .</td><td>The</td><td>layers</td><td>organic se</td>

<td colspan="2">combined,</td><td colspan="2">dried and concentrated</td><td>low</td><td>Pressure</td><td>reduced for</td>

provide crude product 5 (0.230 g, 1 mmol, 82%), which was used for the next step without further purification.

Synthesis of (S) -N- (3- (2- (4 - ((l-acetylpyrrolidin-3yl) (methyl) amino) phenylamino) -5-methoxypyrimidin-4yloxy) phenyl) acrylamide (I-58a)

Compound 5 (0.230g, 1mmol), compound 6 (0.368g, 1.217mmol), K₂CO₃ (0.376 g, 2.5 mmol), tris (dibenzylideneacetone) dipalladium (0.058 g, 0.06 mmol), dicyclohexyl (2 ', 4', 6'- triisopropylbiphenyl-2-i ) phosphine

257 (0.060 g, 0.12 mmol) and t-BuOH (20 mL) were added sequentially to the flask. The reaction mixture was stirred under reflux under N flow₂. After 4.5 h, CCD (DCM: Methanol - 10: 1 as mobile phase) indicates that the reaction is complete. The reaction mixture was allowed to cool completely to 40 ~ 50 ° C, and then filtered through Celite®. The Celite layer was washed with ethyl acetate (50 mL). The combined filtrate was concentrated under reduced pressure. The resulting crude was further purified by column chromatography to provide compound I-58a (0.15g, 30%, M + H⁺=503.6).

<td></td><td>³H NMR</td><td>(500 MHz, DMSO) δ 10.35 (</td><td>s, 1H), 8.99</td><td>(d,</td><td>J = 4.3</td>

<td>Hz,</td><td>1H), 8.</td><td>16 (s, 1H), 7.67 - 7.56</td><td>(m, 2H), 7.49</td><td> -</td><td>7.37 (m,</td>

<td>1 HOUR) ,</td><td> 7.28 (</td><td>dd, J = 9.0, 2.1 Hz, 2H),</td><td>. 6.95 (dd, J</td><td> =</td><td> 8.0, 1.6</td>

<td>Hz,</td><td>1H), 6.</td><td>65 (dd, J = 9.1, 3.4 Hz,</td><td>2H), 6.44 (dd</td><td></td><td>T = 16.9,</td>

<td> 10.1</td><td>Hz, 1H</td><td>), 6.27 (dd, J = 17.0, 1.</td><td>2 Hz, 1H), 5.</td><td> 77</td><td>(dd, J =</td>

<td> 10.1</td><td colspan="3">, 1.9 Hz, 1H), 4.24 - 3.99 (m, 1H), 3.87 (s,</td><td>3H)</td><td> , 3.63 -</td>

<td> 3.46</td><td>(m, 2H:</td><td>), 3.33 - 3.07 (m, 2H), 2.</td><td>63 (d, J = 15</td><td> . 0</td><td>Hz, 3H),</td>

<td> 1.93</td><td>(d, J -</td><td>= 1.6 Hz, 3H), 2.06 - 1.80</td><td>(m, 2H).</td><td></td><td></td>

<td></td><td>¹³C NMR</td><td>(126 MHz, DMSO) δ 168.77</td><td>(d, J = 6.8</td><td>Hz)</td><td> , 163.80</td>

<td>(s),</td><td> 159.89</td><td>(s), 154.25 (d, J = 1.6</td><td>Hz), 153.24</td><td>(s)</td><td> , 145.45</td>

<td>(d,</td><td>J = 7.3</td><td>; Hz), 144.39 (s), 140.70</td><td>(s), 135.05</td><td>(d,</td><td>J = 2.5</td>

<td>Hz),</td><td> 133.41</td><td>(s), 133.13 (s), 132.07</td><td>(s), 130.33</td><td>(s)</td><td> , 127.75</td>

(s), 119.79 (d, J = 4.9 Hz), 117.23 (s), 116.62 (d, J = 5.8

258

Hz), 113.41 (s), 59.72 (s), 58.58 (s), 58.07 (s), 48.76 (s),

47.70 (s), 45.94 (s), 44.16 (s), 35.59 (s), 34.90 (s), 29.04 (s), 27.37 (s), 22.73 (s), 22.19 (s).

Example 58

Synthesis of N- (3- (5-methoxy-2- (1- (methylsulfonyl) indolin-5ylamino) pyrimidin-4-yloxy) phenyl) acrylamide (I-59a)

<img file="MX368491B_D0234.tif" />

Synthesis of 1- (methylsulfonyl) -5-nitroindoline (1)

A solution of 5-nitroindoline (1,033 g, 6.30 mmol), TEA (0.827g, 8.19 mmol) in DCM (30 mL) at 0 ° C, methylsufonyl chloride (0.868 g, 7.56 mmol) was slowly added. The mixture was warmed and stirred at room temperature for 0.5 h. The reaction was quenched with water (30 mL) and extracted with DCM (25 mL x4). The organic layers were combined, dried and concentrated under reduced pressure to provide crude 1 (1,427 g, 5.9 mmol, 95% yield), which was used for the next step without further purification.

259

Synthesis of 1- (methylsulfonyl) indolin-5-amine (2)

A solution of 1 (1,427 g, 5.9 mmol) in THF / H2O (20 mL / 3 mL) was treated with iron (1,372 g, 24.5 mmol) and ammonium chloride (2,621 g, 49 mmol). The mixture was stirred at reflux for 2 h. The reaction was filtered through Celite®. Filtering was made basic with NaHCO₃ (ac, 30 mL) and extracted with ethyl acetate (30 mL * 4). The organic layers were combined, dried and concentrated under reduced pressure to provide crude product 2 (0.742g, 3.5mmol, 59.3%), which was used for the next step without further purification.

Synthesis of N- (3- (5-methoxy-2- (1- (methylsulfonyl) indolin-5ylamino) pyrimidin-4-yloxy) phenyl) acrylamide (I-59a)

Compound 2 (0.420g, 2mmol), compound 3 (0.660g, 2.3mmol), K2CO3 (0.4 94g, 3mmol), tris (dibenzylideneacetone) dipalladium (0.093g, 0.1mmol), dicyclohexyl (2 ', 4 ', 6'-triisopropylbiphenyl-2-yl) phosphine (0.115 g, 0.22 mmol) and t-BuOH (20 mL) were added sequentially to the flask. The reaction mixture was stirred under reflux under N flow₂. After 5 h, CCD (DCM: Methanol = 10: 1 as mobile phase) indicates that the reaction is complete. The reaction mixture was allowed to cool completely to 40 ~ 50 ° C, and then filtered through Celite®. The Celite layer was washed with ethyl acetate (50 mL). Filtering

260 Combined, concentrated under reduced pressure. The resulting crude was further purified by column chromatography to provide compound I-59a (0.24g, 25%,

M + H⁺=482.5).

Example 59

Synthesis of (S) -N- (3- (5-methoxy-2- (4- (methyl (1 (methylsulfonyl) pyrrolidin-3-yl) amino) phenylamino) pyrimidin-4yloxy) phenyl) acrylamide (I-60a)

<img file="MX368491B_D0235.tif" />

(S) -N-methyl-1- (methylsulfonyl) -N- (4de

Synthesis of nitrophenyl) pyrrolidin-3-amine (2)

A solution of 1 (0.504 g, 3 mmol), TEA (0.404 g, 4 mmol) in DCM (20 mL) at 0 ° C, methylsufonyl chloride (0.402 g, 3.5 mmol) was added slowly. The mixture was warmed and stirred at room temperature for 0.5 h. The reaction was quenched with water (30 mL) and extracted with DCM (25 mL χ4). The

261 Organic layers were combined, dried and concentrated under reduced pressure to provide crude 2 (0.762g, 2.55mmol, 85% yield), which was used for the next step without further purification.

(S) -N ^ '- methyl-N¹- (1- (methylsulfonyl) pyrrolidin-3-yl) benzene-1,4-diamine (3)

A solution of 2 (0.762 g, 2.55 mmol) in THF / H₂Or (20 mL / 3 mL) was treated with iron (0.560 g, 10 mmol) and ammonium chloride (1,070 g, 20 mmol). The mixture was stirred at reflux for 2 h. The reaction mixture was filtered through Celite®. Filtering was made basic with NaHCO₃ (ac, 30 mL) and extracted with ethyl acetate (30 mL x4). The organic layers were combined, dried, and concentrated under reduced pressure to provide crude product 3 (0.511 g, 1.9 mmol, 75%), which was used for the next step without further purification.

Synthesis of (S) -N- (3- (5-methoxy-2- (4- (methyl (1 (methylsulfonyl) pyrrolidin-3-yl) amino) phenylamino) pyrimidin-4yloxy) phenyl) acrylamide (I-60a)

Compound 3 (0.340 g, 1.5 mmol), compound 4 (0.550 g,

1.8 mmol), K₂CO₃ (0.414 g, 3 mmol), tris (dibenzylideneacetone) dipalladium (0.137 g, 0.15 mmol), dicyclohexyl (2 ', 4', 6'-triisopropylbiphenyl-2-yl) phosphine (0.143 g, 0.3 mmol) and t-BuOH (20 mL) were added

<td></td><td> 262</td>

sequentially to the flask. The reaction mixture was stirred at

<td>reflux low N flow₂.</td><td>After 5 h, CCD (DCM: Methanol =</td>

10: 1 as mobile phase) indicates that the reaction is complete. The reaction mixture was allowed to cool completely to 40 ~ 50 ° C, and then filtered through Celite®. The Celite layer was washed with ethyl acetate (50 mL). Filtering

<td>combined concentrated</td><td>under reduced pressure. The crude</td>

Resulting was further purified by column chromatography to provide compound I-60a (0.33g, 41%, M + H⁺=539.6).

^XH NMR (500 MHz, CDC1₃) δ 8.48 (s, 1H), 7.94 (s, 1H),

7.67 (s, 1H), 7.48 (d, J = 7.8 Hz, 1H), 7.33 (t, J = 8.1 Hz,

<td>1H), 7.22 (s, J = 14.5</td><td>Hz, 1H), 7.16 (d, J = 8.8 Hz, 2H),</td>

<td>6.92 (d, J = 7.1 Hz, 1H),</td><td>, 6.68 (d, J = 8.8 Hz, 2H), 6.38 (dd,</td>

J = 16.8, 1.3 Hz, 1H), 6.29 (dd, J = 16.9, 10.0 Hz, 1H), 5.68

<td>(dd, J = 10.1, 1.3 Hz,</td><td>1H), 4.07 - 3.97 (m, 1H), 3.89 (s,</td>

<td>3H), 3.51 - 3.41 (m, 2H)</td><td>, 3.37 - 3.26 (m, 1H), 3.17 (dd, J =</td>

<td>10.2, 6.7 Hz, 1H), 2.84</td><td>(s, 3H), 2.70 (s, 3H), 2.14 - 2.05</td>

<td>(m, 1H), 2.03 - 1.94 (m,</td><td>1 HOUR) .</td>

¹³C NMR (126 MHz, CDC1₃) δ 163.90 (s), 160.47 (s), 153.91

<td>s), 152.97 (s), 145.41</td><td>(s), 142.83 (s), 139.37 (s), 135.46</td>

<td>s), 133.38 (s), 131.13</td><td>(s), 129.61 (s), 127.92 (s), 119.96</td>

<td>s, x2), 118.61 (s, x2),</td><td>117.87 (s), 116.88 (s), 114.16 (s),</td>

60.56 (s), 58.04 (s), 49.98 (s), 46.60 (s), 37.28 (s), 34.79

29.24 (s).

263

Example 60

Synthesis of (S) -N- (3- (2- (4- (l-acetylpyrrolidin-3ylamino) phenylamino) -7H-pyrrolo [2,3-d] pyrimidin-4yloxy) phenyl) acrylamide (I-61a)

<img file="MX368491B_D0236.tif" />

<img file="MX368491B_D0237.tif" />

<img file="MX368491B_D0238.tif" />

<img file="MX368491B_D0239.tif" />

NaOH (2.5 M)

MeOH / THF

<img file="MX368491B_D0240.tif" />

1-61 to

Synthesis of (S) -1- (3- (4-nitrophenylamino) pyrrolidin-lil) ethanone (2)

A solution of compound 1 (2,139 g), TEA (1,568 g) in

THF (40 mL) at -10 ° C acetyl chloride (0.806 g, dissolved in 4 mL THF) was added slowly. The mixture was stirred at this

264 temperature for 4 h. The reaction was quenched with water and extracted with ethyl acetate. The organic layers were combined, dried and concentrated under reduced pressure to provide crude 2 (1.88 g, 73.2%), which was used for the next step without further purification.

Synthesis of (S) -1- (3- (4-aminophenylamino) pyrrolidin-li) ethanone (3)

A mixture of 2 (1.88 g) and Pd / C (0.198 g, 10% activated carbon) in THF (30 mL) was hydrogenated with a hydrogen balloon at room temperature overnight. Once the reaction was complete indicated by CCD, the reaction mixture was filtered through Celite®. The filtrate was concentrated under reduced pressure to provide 3 (1.65g) (which was used for the next step) without further purification.

Synthesis of (S) - (2- (4- (l-acetylpyrrolidin-3-melamine) phenylamino) -4- (3-acrylamidophenoxy) -7H-pyrrolo [2,3d] pyrimidin-7-yl) methyl (5)

Compound 3 (1.6 g), compound 4 (3.1 g), K₂CO₃ (2.0 g), tris (dibenzylideneacetone) dipalladium (0.3 g), dicyclohexyl (2 ', 4', 6'-triisopropylbiphenyl-2-yl) phosphine (0.3 g) and t-BuOH (50 mL) were added sequentially to the flask . The reaction mixture was stirred under reflux under N flow₂. After 5 h, CCD (DCM: Methanol = 10: 1 as mobile phase) indicates that the

265 reaction is complete. The reaction mixture was allowed to cool completely to 40 ~ 50 ° C, and then filtered through Celite®. The Celite layer was washed with ethyl acetate (50 mL). The combined filtrate was concentrated under reduced pressure. The resulting crude was further purified by column chromatography to provide Compound 5 (2.4g, 54.2%).

Synthesis of (S) -N- (3- (2- (4- (l-acetylpyrrolidin-3ylamino) phenylamino) -7H-pyrrolo [2,3-d] pyrimidin-4yloxy) phenyl) acrylamide (I-61a)

A round bottom flask (250 mL) was charged with compound 5 (2.4 g), MeOH (15 mL), and THF (15 mL). After compound 5 completely dissolved, the solution was completely cooled to -5 ° C. Then aqueous NaOH solution (2.5 M, 3.1 mL) was added into the flask slowly. The mixture was stirred for 2 h at this temperature. Then water (80 mL) was added inside to quench the reaction. The mixture was extracted with ethyl acetate. The organic layers were combined, dried, and concentrated under reduced pressure. The resulting crude was further purified by column chromatography to give I-61a (1.4g, 71.8%, M + H⁺=498.6).

266

Example 61 (S) -N- (3- (2- (4- (1- (methylsulfonyl) pyrrolidin-3 -lamino) phenylamino) -7H-pyrrolo [2,3-d] pyrimidin-4yloxy) phenyl) acrylamide (I- 62a)

<img file="MX368491B_D0241.tif" />

<img file="MX368491B_D0242.tif" />

P.S₂(dba)₃, X-phos

K₂CO₃, f-BuOH

<img file="MX368491B_D0243.tif" />

<img file="MX368491B_D0244.tif" />

Synthesis of (S) -1- (methylsulfonyl) -N- (4-nitrophenyl) pyrrolidin

3-amine (2)

A solution of compound 1 (4,158 g), TEA (3,026 g) in

THE (50 mL) at -10 ° C methylsufonyl chloride (2.3 g, dissolved in 5 mL THF) was added slowly. The mixture is

267 stirred at this temperature for 3 h. The reaction was quenched with water (100 mL) and extracted with ethyl acetate (150 mL). The organic layers were combined, dried and concentrated under reduced pressure to provide crude 2 (4.3 g, 75.2%), which was used for the next step without further purification.

Synthesis of (S) -N¹- (1- (methylsulfonyl) pyrrolidin-3-yl) benzene 1,4-diamine (3)

A solution of 2 (4.3 g) in THF / H₂Or (90 mL / 30 mL) was treated with iron (3.3 g) followed by ammonium chloride (4.8 g). The mixture was stirred at reflux for 4.5 h. After cooling to room temperature completely, the reaction mixture was filtered through Celite®. Filtering was made basic with NaHCO₃ (ac, 30 mL) and extracted with ethyl acetate (30 mL χ4). The organic layer was combined, dried, and concentrated under reduced pressure to provide crude compound 3 (3.1g, 80.7%), which was used for the next step without further purification.

Synthesis of (S) - (4- (3-acrylaxnidophenoxy) -2- (4- (1 (methylsulfonyl) pyrrolidin-3-ylamino) phenylamino) -7Hpirrolo [2,3-d] pyrimidin-7-yl) pivalate methyl (5)

Compound 3 (3.1 g), compound 4 (5.2 g), K₂CO₃ (2.5 g), tris (dibenzylideneacetone) dipalladium (0.6 g), dicyclohexyl (2 ', 4', 6'- triisopropylbiphenyl-2-yl) phosphine (0.6 g) and t-BuOH

268 (80 mL) were added sequentially to the flask. The reaction mixture was stirred under reflux under N flow₂. After 4 h, CCD (DCM: Methanol = 10: 1 as mobile phase) indicates that the reaction is complete. The reaction mixture was allowed to cool completely to 40 ~ 50 ° C, and then filtered through Celite®. The Celite layer was washed with ethyl acetate (50 mL). The combined filtrate was concentrated under reduced pressure. The resulting crude was further purified by column chromatography to provide Compound 5 (4.1g, 52.2%).

Synthesis of (S) -N- (3- (2- (4- (1- (methylsulfonyl) pyrrolidin-3ylamino) phenylamino) -7H-pyrrolo [2,3-d] pyrimidin-4yloxy) phenyl) acrylamide (I- 62a)

A round bottom flask (250 mL) was charged with compound 5 (2.1 g), MeOH (12 mL), and THF (12 mL). After compound 5 completely dissolved, the solution was completely cooled to -5 ° C. The NaOH solution (2.5M, 3 mL) was then added into the flask slowly. The mixture was stirred for 1 h at this temperature. Then water (40 mL) was added inside to quench the reaction. The mixture was extracted with ethyl acetate. The organic layers were combined, dried, and concentrated under reduced pressure. The resulting crude was purified by column chromatography to give I-62a (1.0 g, 57.8%, M + H⁺=498.6).

269

Example 62 (S) -N- (3- (2- (4- (methyl (1- (methylsulfonyl) pyrrolidin-3yl) amino) phenylamino) -7H-pyrrolo [2,3-d] pyrimidin-4yloxy) phenyl) acrylamide (I-63a)

<img file="MX368491B_D0245.tif" />

NaOH (2.5 M)

MeOH / THF

<img file="MX368491B_D0246.tif" />

Synthesis of tert-butyl carbonate from (S) - (4- (3-acrylamidophenoxy) -2- (4- (methyl (1- (methylsulfonyl) pyrrolidin-3yl) amino) phenylamino) -7H-pyrrolo [2,3-d ] pyrimidin-7-yl) methyl (3)

Compound 1 (0.5g), Compound 2 (0.87 6g), K2CO3 (0.512g), Tris (Dibenzylideneacetone) Dipalladium (0.102g), Dicyclohexyl (2 ', 4', 6'-triisopropylbiphenyl-2-yl) phosphine (0.104 g) and t-BuOH (30 mL) were added sequentially to the flask. The reaction mixture was stirred at reflux under flow

270 from N₂. After 3.5 h, CCD (DCM: Methanol = 10: 1 as mobile phase) indicates that the reaction is complete. The reaction mixture was allowed to cool completely to 4C-50 ° C, and

<td>then I know</td><td>filter</td><td>through</td><td>Celite®.</td><td>The layer</td><td>from Celite</td><td>I know</td>

<td>washed with</td><td>acetate</td><td>ethyl</td><td>(50 mL). The</td><td colspan="2">combined filtering</td><td>I know</td>

<td>concentrated</td><td>low</td><td>Pressure</td><td>reduced. The</td><td>raw</td><td>resulting</td><td>I know</td>

<td>purified</td><td colspan="2">also by</td><td>chromatography</td><td>of</td><td colspan="2">column for</td>

provide compound 3 (0.8g, 59.3%).

Synthesis of (S) -N- (3- (2- (4- (methyl (1 (methylsulfonyl) pyrrolidin-3-yl) amino) phenylamino) -7Hpyrrolo [2,3-d] pyrimidin-4-yloxy) phenyl ) acrylamide (I-63a)

A round bottom flask (250 mL) was charged with compound 3 (0.8 g), MeOH (20 mL), and THF (2 mL). After compound 3 was completely dissolved, the solution was completely cooled to -5 ° C. The NaOH solution (2.5M, 1.5 mL) was then added into the flask slowly. The mixture was stirred for 2 h at this temperature. Water (40 mL) was added inside to quench the reaction. The mixture was extracted with ethyl acetate. The organic layers were combined, dried, and concentrated under reduced pressure. The resulting crude was purified by column chromatography to give I-63a (0.25 g, 37.8%, M + H⁺=548.6) .

271

Example 63

Synthesis of (S) -N- (3- (2- (4 - ((l-acetylpyrrolidin-3yl) (methyl) amino) phenylamino) -7H-pyrrolo [2,3-d] pyrimidin-4yloxy) phenyl) acrylamide (I-64a)

<img file="MX368491B_D0247.tif" />

l-64a

Synthesis of tert-butyl carbonate from (S) - (2- (4 - ((1acetylpyrrolidin-3-yl) (methyl) amino) phenylamino) -4- (3-acrylamidophenoxy) -7H-pyrrolo [2,3-d] pyrimidin-7-yl) methyl (3)

Compound 1 (0.9 g), compound 2 (1.65 g), K₂CO₃ (1.07 g), tris (dibenzylideneacetone) dipalladium (0.35 g), dicyclohexyl (2 ', 4', 6'- triisopropylbiphenyl-2-yl) phosphine (0.35 g) and t-BuOH (20 mL) were added sequentially to the flask . The reaction mixture was stirred under reflux under N flow₂. After 4 h, CCD (DCM: Methanol = 10: 1 as phase

272 mobile) indicates that the reaction is complete. The reaction mixture was allowed to cool completely to 40 ~ 50 ° C, and then filtered through Celite®. The Celite layer was washed with ethyl acetate (50 mL). The combined filtrate was concentrated under reduced pressure. The resulting crude was further purified by column chromatography to provide Compound 3 (1.24g, 51.7%).

Synthesis of (S) -N- (3- (2- (4 - ((l-acetylpyrrolidin-3yl) (methyl) amino) phenylamino) -7H-pyrrolo [2,3-d] pyrimidin-4yloxy) phenyl) acrylamide (I-64a)

<td>Yet</td><td>flask</td><td>of</td><td>round bottom (</td><td> 250</td><td>mL)</td><td>I know</td><td>loaded with</td>

<td>compound</td><td> 3 (1.24</td><td>g),</td><td>MeOH (10 mL) and</td><td>THE</td><td> (5</td><td>mL).</td><td>When the</td>

<td>compound</td><td colspan="3">3 completely dissolved,</td><td>the</td><td colspan="2">solution</td><td>He cooled</td>

fully down to -5 ° C. The NaOH solution (2.5M, 1.6 mL) was then added into the flask slowly. The mixture was stirred for 1 h at this temperature. Water (40 mL) was added inside to quench the reaction. The mixture was extracted with ethyl acetate. The organic layers were combined, dried, and concentrated under reduced pressure. The resulting crude was further purified by column chromatography to give I-64a (0.265 g, 26.2%, M + H⁺=512.6).

273

Example 64

Synthesis of N- (3- (2- (4- (4- (2-methoxyethyl) piperazin-lyl) phenylamino) -9H-purin-6-yloxy) phenyl) acrylamide (I-65a)

<img file="MX368491B_D0248.tif" />

Synthesis of N- (3- (2-chloro-9- (tetrahydro-2H-pyran-2-yl) -9Hpurin-6-yloxy) phenyl) acrylamide (3)

K2CO3 (2.2 g) was added to a mixture of purine 1 (2.7 g) and phenol 2 (1.6 g) in DMF (40 mL). The reaction mixture was stirred at 90 ° C for 4h. Once CCD indicates that the reaction is complete, the mixture was emptied into water (150 mL). The resulting precipitate was collected, washed with water (100 ml), and dried under vacuum to provide the desired compound 3 (3.2 g, 80%) as a white solid.

274

Synthesis of N- (3- (2- (4- (4- (2-methoxyethyl) piperazin-1yl) phenylamino) -9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6yloxy) phenyl) acrylamide (5)

Compound 3 (1.6 g), compound 4 (0.8 g), K2CO3 (0.97 g), tris (dibenzylideneacetone) dipalladium (0.115 g), dicyclohexyl (2 ', 4', 6'-triisopropylbiphenyl-2-yl) phosphine ( 0.126 g) and t-BuOH (20 mL) were added sequentially to the flask. The reaction mixture was stirred under reflux under N flow₂. After 23 h, CCD (DCM: Methanol = 10: 1 as mobile phase) indicates that the reaction is complete. The reaction mixture was allowed to cool completely to 40 ~ 50 ° C, and

<td>then I know</td><td>filter</td><td>through</td><td>of</td><td>Celite</td><td> ®</td><td>The layer</td><td>from Celite</td><td>I know</td>

<td>washed with</td><td>acetate</td><td>ethyl</td><td> (50</td><td>mL).</td><td>The</td><td>filtered out</td><td>combined</td><td>I know</td>

<td>concentrated</td><td>ba j 0</td><td>Pressure</td><td colspan="2">reduced.</td><td>The</td><td colspan="2">resulting crude</td><td>I know</td>

further purified by column chromatography (EtOAc / MeOH = 15: 1 as mobile phase) to provide compound 5 (1.1 g, 54.2%, M + H⁺= 599) as a light yellow solid.

Synthesis of N- (3- (2- (4- (4- (2-methoxyethyl) piperazin-1yl) phenylamino) -9H-purin-6-yloxy) phenyl) acrylamide (I-65a)

To a solution of compound 5 (0.6 g) in EtOH (10 mL) was HC1 a. (2 mL, 1N). The mixture was stirred at room temperature for 3 h. Another portion of HC1 ac. (0.5 mL, ~ 12 M) was then added inside and the reaction was stirred for another 3.5 h before quenching and basic with K₂CO3 (1.3

275 g in 10 mL of water). The mixture was extracted with ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Ethyl acetate (30 mL) was added to this crude material (600 mg) and stirred for 1.5 h. The solution was concentrated until the volume was up to 10 mL. The resulting precipitate was collected, washed, and dried to provide the desired compound I-65a (250mg, 48.5%, M + H⁺=515.6)

Example 65 Synthesis of (S) -N- (3- (2- (4 - ((l-acetylpyrrolidin-3yl) amino) phenylamino) -5-methoxypyrimidin-4yloxy) phenyl) acrylamide (I-66a)

<img file="MX368491B_D0249.tif" />

1-66 can be synthesized using the synthetic scheme above. We isolate I-66a as a (non-methylated) by-product of I-58a synthesis.

276

Example 66

Synthesis of (S) -N- (3- (2- (4- (1- (2-methoxyethyl) pyrrolidin-3-ylamino) phenylamino) -9H-purin-6-yloxy) phenyl) acrylamide (I-67a)

<img file="MX368491B_D0250.tif" />

<img file="MX368491B_D0251.tif" />

MeO

OR

<img file="MX368491B_D0252.tif" />

MeO

HN

<img file="MX368491B_D0253.tif" />

l-67a

Synthesis of N- (3- (2- (4 - ((S) -1- (2-methoxyethyl) pyrrolidin-3-amino) phenylamino) -9- (tetrahydro-2H-pyran-2-yl) -9H-purin- 6yloxy) phenyl) acrylamide (3)

Compound 1 (0.99 g), compound 2 (1.53 g), K2CO3 (1.90 g), tris (dibenzylideneacetone) dipalladium (0.21 g), dicyclohexyl (2 ', 4', 6'-triisopropylbiphenyl-2-yl) phosphine ( 0.23 g) and t-BuOH (25 mL) were added sequentially to the flask. The reaction mixture was stirred under reflux under N flow₂. After 20 h, CCD (DCM: Methanol = 10: 1 as mobile phase) indicates that the reaction is complete. The reaction mixture was allowed to cool completely to 40 ~ 50 ° C, and then filtered through Celite®. The Celite cape is

277 washed with ethyl acetate (50 mL). The combined filtrate was concentrated under reduced pressure. The resulting crude was further purified by column chromatography (EtOAc / EtOH = 10: 1 as mobile phase) to provide Compound 3 (1.0g, 43.7%) as a light yellow solid.

Synthesis of (S) -N- (3- (2- (4- (1- (2-methoxyethyl) pyrrolidin-3-amino) phenylamino) -9H-purin-6-yloxy) phenyl) acrylamide (I-67a)

To a solution of compound 3 (1.0 g) in EtOH (10 mL) was HC1 aq. (3 mL, 4N). The mixture was stirred at room temperature overnight. The reaction was quenched and made basic with aqueous NaHCO solution₃. The mixture was extracted with ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude was purified by column chromatography (EtOAc / EtOH = 10/1 as mobile phase) to give compound I-67a (0.41 g, 47.7%, M + H⁺=515.6).

278

Example 67 Synthesis of N- (3- (2- (4- (4-acetylpiperazin-l-yl) phenylamino) 9H-purin-6-yloxy) phenyl) acrylamide (I-68a)<img file="MX368491B_D0254.tif" /><img file="MX368491B_D0255.tif" /> l-68a

Synthesis of 1- (4- (4-nitrophenyl) piperazin-l-yl) ethanone (2)

A solution of compound 1 (10 g), TEA (5,891 g) in

THF (50 mL) at 0 ° C acetyl chloride (4,605 ​​g) was slowly added. The mixture was stirred at this temperature for 1.5

h. The solvent was removed. The resulting residue was diluted

9 with water (30 mL), made basic with aqueous solution of K₂CO₃(saturated, 20 mL) and then extracted with ethyl acetate. The organic layers were combined, dried, and concentrated under reduced pressure to provide the crude compound 2 (10.2 g), which was used for the next step without further purification.

Synthesis of 1- (4- (4-aminophenyl) piperazin-l-yl) ethanone (3)

A solution of 2 (9.0 g) and Pd / C (0.700 g, 10% activated carbon) in THF (30 mL) and 1,4-dioxane (30 mL) were hydrogenated with a hydrogen balloon at room temperature overnight . Once CCD indicates that the reaction is complete, the reaction mixture is filtered through

Celite®. The filtrate was concentrated under reduced pressure to provide compound 3 (9.7 g), which was used for the next step without further purification.

N- (3- (2- (4- (4-acetylpiperazin-l-yl) phenylamino) -9- (tetrahydro2H-pyran-2-yl) -9H-purin-6-yloxy) phenyl) acrylamide (5)

Compound 3 (0.798 g), compound 4 (1,605 g), K₂CO₃(1.32 g), tris (dibenzylideneacetone) dipalladium (0.167 g), dicyclohexyl (2 ', 4', 6'- triisopropylbiphenyl-2-yl) phosphine (0.172 g) and t-BuOH (30 mL) were added sequentially to the flask . The reaction mixture was stirred under reflux under N flow₂. After 5.5 h, CCD (DCM: Methanol = 10: 1 as mobile phase) indicates that the reaction is complete. The mixture of

280 reaction allowed to cool completely to 40 ~ 50 ° C, and

<td>then I know</td><td>filter</td><td>through</td><td>of</td><td>Celite</td><td> ®</td><td>The layer</td><td>from Celite</td><td>I know</td>

<td>washed with</td><td>acetate</td><td>ethyl</td><td> (50</td><td>mL).</td><td>The</td><td>filtered out</td><td>combined</td><td>I know</td>

<td>concentrated</td><td>ba j 0</td><td>Pressure</td><td colspan="2">reduced.</td><td>The</td><td colspan="2">resulting crude</td><td>I know</td>

Further purified by column chromatography (EtOAc / EtOH = 25: 1 as mobile phase) to provide Compound 5 (1.4g, 66.0%) as a brown solid.

Synthesis of N- (3- (2- (4- (4-acetylpiperazin-l-yl) phenylamino) 9H-purin ~ 6-yloxy) phenyl) acrylamide (I-68a)

To a solution of compound 5 (1.4 g) in EtOH (10 mL), HC1 aq was added. (4.6 mL, 4N). The mixture was stirred at room temperature for 5 h. HC1 ac added. Additional (1 mL, ~ 12M) and the reaction was stirred for another 18 h. CCD indicates that the reaction is complete. The reaction was quenched and made basic with ac K2CO3. The mixture was extracted with ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude was further purified by column chromatography (EtOAc / EtOH = 15/1 as mobile phase) to give compound I

68a (0.254 g, 21.2%, M + H + = 499.6).

281

Example 68

Synthesis of N- (3- (2- (4- (4- (2- (methylsulfonyl) ethyl) piperazin-lil) phenylamino) -9H-purin-6-yloxy) phenyl) acrylamide (I-69a)

<img file="MX368491B_D0256.tif" />

HCI 4M ac

EtOH

<img file="MX368491B_D0257.tif" />

l-69a

Synthesis of N- (3- (2- (4- (4- (2- (methylsulfonyl) ethyl) piperazin-1yl) phenylamino) -9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6iloxy ) phenyl) acrylamide (3)

Compound 1 (1,033 g), compound 2 (1,616 g), K₂CO₃(0.97 g), tris (dibenzylideneacetone) dipalladium (0.170 g), dicyclohexyl (2 ', 4', 6'- triisopropylbiphenyl-2-yl) phosphine (0.185 g) and t-BuOH (30 mL) were added sequentially to the flask . The reaction mixture was stirred under reflux under N flow₂. After 6 h, CCD (EtOAc: EtOH = 5: 1 as mobile phase) indicates that the reaction is complete. The mixture of

282 Reaction was allowed to cool completely to 40 ~ 50 ° C, and then filtered through Celite®. The Celite layer was washed with ethyl acetate (50 mL). The combined filtrate was concentrated under reduced pressure. The resulting crude was further purified by column chromatography (EtOAc / EtOH = 15: 1 as mobile phase) to provide Compound 5 (1.4g, 59.3%, M + H⁺= 647) as a light yellow solid.

Synthesis of N- (3- (2- (4- (4- (2- (methylsulfonyl) ethyl) piperazin-1yl) phenylamino) -9H-purxn-6-yloxy) phenyl) acrylamide (I-69a)

To a solution of compound 3 (1.4 g) in EtOH (50 mL) was HC1 aq. (4.5 mL, 4N). The mixture was stirred at room temperature for 5 h. HC1 ac added. (1 mL, ~ 12M) and the reaction was stirred for another 60 h. CCD indicates that the reaction is complete. The reaction was quenched and made basic with ac K2CO3. The reaction mixture was extracted with ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude was purified by column chromatography (EtOAc / EtOH = 20/1 as mobile phase) to give compound I69a (0.22 g, 18%, M + H⁺ = 563.5).

283

Example 69

Synthesis of N- (3 - ((2 - ((2,2-dioxide-l, 3dihydrobenzo [c] isothiazol-5-yl) amine) -5-methoxypyrimidin-410

H ^N° ^ SO

<img file="MX368491B_D0258.tif" />

H₂, PtO₂

NOT₂

O ™

O 'il) oxy) phenyl) acrylamide

H ^N° hS

OR'

<img file="MX368491B_D0259.tif" />

(I-70a) nh₂

Cl

OR

<img file="MX368491B_D0260.tif" />

OMe

P.S₂(dba)₃, X-phos

K₂CO₃, f-BuOH

<img file="MX368491B_D0261.tif" />

l-70a

Synthesis of

2,2-dioxide

5-amino-1,3-dihydrobenzo [c] isothiazole (2):

A mixture of 1 (180 mg, synthesized according to

W02005 / 12295) and PtO₂ (10 mg) in THF (4 mL) was hydrogenated with a hydrogen balloon at room temperature overnight.

CCD indicates that the reaction is complete. The reaction mixture was filtered through Celite®. Filtering is

284 Concentrated under reduced pressure to provide 2 (0.11 g), which was used for the next step without further purification.

Synthesis of N- (3 - ((2 - ((2,2-dioxide-l, 3-dihydrobenzo [c] isothiazol-5-yl) amino) -5-methoxypyrimidin-4yl) oxy) phenyl) acrylamide (I-70a )

Compound 2 (0.11 g), compound 3 (0.219 g), K2CO3 (0.22 g), tris (dibenzylideneacetone) dipalladium (0.02 g), dicyclohexyl (2 ', 4', 6'-triisopropylbiphenyl-2-yl) phosphine ( 0.04 g) and t-BuOH (3 mL) were added sequentially to the flask. The reaction mixture was stirred under reflux under N flow₂. After 7.5 h, CCD (DCM: MeOH = 10: 1 as mobile phase) indicates that the reaction is complete. The reaction mixture was allowed to cool completely to 40 ~ 50 ° C, and then filtered through Celite®. The Celite layer was washed with ethyl acetate (50 mL). The combined filtrate was concentrated under reduced pressure. The resulting crude was further purified by column chromatography (DCM / MeOH = 50: 1 as mobile phase) to provide compound I-70a (26 mg, 11.1%, M + H⁺= 454.5) as a light yellow solid.

285

Example 70

Synthesis of (S) -N- (3- (2- (4- (methyl (1 (methylsulfonyl) pyrrolydin-3-yl) amino) phenylamino) -9H-purin-6iloxy) phenyl) acrylamide (I-71a) „ ^N ° ^ s /^SOR

<img file="MX368491B_D0262.tif" />

nh₂ or

<img file="MX368491B_D0263.tif" />

P.S₂(dba)₃, X-phos

K₂CO₃, t-BuOH

N jl

Cr n N

THP 2

<img file="MX368491B_D0264.tif" />

° '' YES / Ό

HCI 3N ac

EtOH

<img file="MX368491B_D0265.tif" />

/ θ l-71a yl) amino) phenylamino) -9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6yloxy) phenyl) acrylamide (3)

Compound 1 (0.35 g), compound 2 (0.532 g), K2CO3 (0.362 g), tris (dibenzylideneacetone) dipalladium (0.064 dicyclohexyl (2 ', 4', 6'-triisopropylbiphenyl-2-yl) phosphine (0.063 g) and t-BuOH (10 mL) were added sequentially to the flask.The reaction mixture was stirred at reflux under flow of N₂. After 5 h, CCD (DCM: MeOH = 25: 1 as mobile phase) indicates that the reaction is complete. The reaction mixture was allowed to cool completely to 40 ~ 50 ° C, then filtered through Celite®. Celite cape was washed with

6 ethyl acetate (50 mL). The combined filtrate was concentrated under reduced pressure to provide compound 3 (664 mg), which was used for the next step without further purification.

Synthesis of (S) -N- (3- (2- (4- (methyl (1 (methylsulfonyl) pyrrolidin-3-yl) amino) phenylamine) -9H-purin-6iloxy) phenyl) acrylamide (I-71a)

To a solution of compound 3 (1.4 g) in EtOH (20 mL) was HC1 aq. (6 mL, 3N). The mixture was stirred at room temperature for 16h. CCD indicates that the reaction is complete. The reaction was quenched and made basic with ac K2CO3. The mixture was extracted with ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude was further purified by column chromatography (DCM / MeOH = 20/1 as mobile phase) to give compound I-71a (0.31 g, 53.88%, M + H⁺ = 549.6).

287

Example 71

Synthesis of (R) -N- (3- (2- (4 - ((l-acetylpyrrolidin-3yl) (methyl) amino) phenylamino) -5-methoxypyrimidin-4yloxy) phenyl) acrylamide (I-72a)

<img file="MX368491B_D0266.tif" />

DMF.NaH ta - 30 ° C ch₃i

<img file="MX368491B_D0267.tif" />

<img file="MX368491B_D0268.tif" />

DCM.TEA

0 ° C - ta

<img file="MX368491B_D0269.tif" />

<img file="MX368491B_D0270.tif" />

Synthesis of 3- (methyl (4-nitrophenyl) amino) pyrrolidine-1-carboxylate (R) -tert-butyl (2)

To a solution of (R) -tert-butyl 3- (4-nitrophenylamino) pyrrolidine-1-carboxylate (1, 5.1 g) in DMF (50 mL) at 0 ° C, NaH (0.6 g, 80% dispersion) was added sequentially in mineral oil) and CH₃I (2.7 g). The resulting mixture was then stirred for 3 hr. The reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layer is

288 washed with water, dried over Na₂SW₄, and concentrated under reduced pressure. The resulting crude 2 (5.38 g) was used directly in the next step without further purification.

Synthesis of (R) -N-methyl-N- (4-nitrophenyl) pyrrolidin-3-amine (3)

TEA (6.8 mL) was added to crude 2 (5.3 g) in DCM (15 mL). The reaction mixture was stirred at room temperature until CCD (petroleum ether / ethyl acetate = 1: 3 as mobile phase) indicates that the reaction is complete. The reaction mixture was concentrated under reduced pressure to remove most of the TEA. The resulting residue was made basic with NaHCO₃ (ac, 30 mL) and extracted with EA (30 mL x4). The organic layers were combined, dried and concentrated under reduced pressure to provide crude 3 (4.54 g), which was used for the next step without further purification.

(R) -1- (3- (methyl (4-nitrophenyl) amino) pyrrolidin-l-yl) ethanone (4)

A solution of 3 (4.0 g), TEA (2.31 g) in MeOH (60 ml) at 0 ° C, acetyl chloride (1.84 g) was slowly added. The mixture was warmed and stirred at room temperature for 0.5 h. The reaction was quenched with water (30 mL) and extracted with DCM (25 mL χ4). The organic layers were combined, dried, and concentrated to provide crude 4 (3.72 g), which was used for the next step without further purification.

289

Synthesis of (R) -1- (3 - ((4-aminophenyl) (methyl ·) amino) pyrrolidinl-yl) ethanone (5)

A mixture of 4 (3.56 g) and Pd / C (310 mg, 10% activated carbon) in THF (60 mL) was hydrogenated with a hydrogen balloon at room temperature overnight. After the reaction was complete indicated by CCD, the reaction mixture was filtered through Celite®. The filtrate was concentrated under reduced pressure to provide 5 (3.21 g), which was used for the next step without further purification.

Synthesis of (R) -N- (3- (2- (4 - ((l-acetylpyrrolidin-3 yl) (methyl) amino) phenylamino) -5-methoxypyrimidin-4yloxy) phenyl) acrylamide (I-72a)

Compound 5 (3.21 g), compound 6 (4.26 g), K₂CO₃(2.87 g), tris (dibenzylideneacetone) dipalladium (0.64 g), dicyclohexyl (2 ', 4', 6'- triisopropylbiphenyl-2-yl) phosphine (0.65 g) and t-BuOH (80 mL) were added sequentially to the flask . The reaction mixture was stirred under reflux under N flow₂. After 17 h, CCD indicates that the reaction is complete. The reaction mixture was allowed to cool completely to 40 ~ 50 ° C, and then filtered through Celite®. The Celite layer was washed with ethyl acetate (50 mL). The combined filtrate was concentrated under reduced pressure. The resulting crude was further purified by column chromatography (ethyl acetate / EtOH = 20: 1 as

290 mobile phase) to provide compound I-72a (1.5 g, 22%, M + H⁺=503.6).

Example 72 Btk Tyr223 Phosphorylation Inhibition Assays Material and Methods

Cell culture and reagents

The Ramos cell line was obtained from the American Type Culture Collection and maintained at 37 ° C with 5% CO2, in medium supplemented with 10% fetal bovine serum, penicillin (100 units / mL) and streptomycin (100 pg / mL). Goat Anti-Human F (ab ') 2 IgM-UNLB was obtained from SouthernBiotech.

Western blotting test

Ramos cells were treated with compounds at indicated doses for 45 min at room temperature, followed by stimulation of 12 pg / mL IgM for 30 min, and then lysed. Western blots were performed in the cell lysate using Phospho-Btk (Tyr223), Phospho-Btk (Tyr551), Btk, Phospho-PLCv2 (Tyrl217), PLCy2, Phospho-p44 / 42 MAPK (Erkl / 2) (Thr202 / Tyr204) and p44 / 42 MAPK (Erkl / 2) (Cell Signaling Technology). The blotting band density was acquired using ImageJ software, and the IC₅₀ Btk phosphorylation (Tyr223) was fixed using a nonlinear regression model by GraphPad Prism version 4.0.

291

Impulse chase western blotting assay for compound irreversibility evaluation

Ramos cells were treated with Compound 1-1 at 100 nM for 45 min. The cells were then resuspended in the compound-free medium and stimulated with 6 pg / ml IgM at 0, 4, 6 or 8 hours after removal of the compound. Cells were then lysed after 30 min of IgM challenge. West blotting analyzes were then performed.

ELISA Test of Occupancy of the Btk Target Site

Ramos cells were treated with Compound 1-1 at indicated concentrations for 1 hr, followed by stimulation with 6 pg / mL IgM for 30 min, and then lysed. Lysates were incubated with Compound 1-21 (labeled biotin) at a final concentration of IpM in a PBS, 0.05% Tween-20, 1% BSA solution while stirring for lh at room temperature. The samples were transferred to a streptavidin-coated 96-well ELISA plate and mixed while stirring for 1 h at room temperature. The Btk antibody (BD 611116, 1: 1000 dilution in PBS + 0.05% Tween-20 + 0.5% BSA) was then applied and incubated for 1 h at room temperature. After washing, goat anti-mouse-HRP (Pierce 31432, 1: 1000 dilutions in PBS + 0.05% Tween-20 + 0.5% BSA) was added and

292 incubated for 1 h at room temperature. The ELISA was developed with the addition of tetramethyl benzidine (TMB) followed by stop solution and read at OD 450 nM.

Results

Compounds significantly reduce Btk phosphorylation

Tyr223 in Ramos cells

The results of this test were shown in Table 1 below. Compounds that have an activity

<td>designated as</td><td colspan="3">A provide an IC₅₀ - 10</td><td>nM;</td><td>the</td>

<td>compounds that</td><td>have</td><td>a</td><td>designated activity</td><td>how</td><td>B</td>

<td>provide a</td><td>IC₅₀ 10-</td><td> 100</td><td>nM; the compounds that</td><td>have</td><td>a</td>

<td colspan="2">activity designated as</td><td>C</td><td>provide an IC50&gt;</td><td>100 nM.</td><td></td>

Table 1

<td>Compound #</td><td>BTK inhibition</td>

<td> 1-1</td><td>TO</td>

<td> 1-2</td><td>TO</td>

<td> 1-3</td><td>TO</td>

<td> 1-4</td><td>TO</td>

<td> 1-5</td><td>TO</td>

<td> 1-6</td><td>TO</td>

<td> 1-7</td><td>B</td>

<td> 1-8</td><td>TO</td>

<td> 1-9</td><td>TO</td>

<td> 1-10</td><td>TO</td>

<td> 1-11</td><td>B</td>

<td> 1-12</td><td>B</td>

293

<td> 1-13</td><td>TO</td>

<td> 1-14</td><td>B</td>

<td> 1-15</td><td>TO</td>

<td> 1-16</td><td>TO</td>

<td> 1-17</td><td>TO</td>

<td> 1-18</td><td>TO</td>

Ramos cells were treated with compounds at indicated concentrations for 45 min, and BTK phosphorylations and potential downstream effectors PLCy2 and Erk were monitored. Most dose-dependent compounds inhibit phosphorylation of BTK protein, Compound 1-1 achieves inhibition of IC₅₀ at 1.1 nM and Compound 1-2 achieves IC inhibition₅₀ at 5.0 nM.

Compounds 1-1 and 1-2 irreversibly inhibit BTK phosphorylation in Ramos cells

Ramos cells were treated with Compound 1-1 and Compound 1-2 at 100 nM for 45 min, and inhibition of BTK phosphorylation was monitored 4, 6 and 8 hrs after removal of Compound 1-1 and Compound 1-2. BTK remains inhibited for up to 8 hrs after treatment with the Compound

1-1 and Covalently Linked Compound 1-2, indicating that Compound 1-1 and Compound 1-2 are strong irreversible inhibitors of the BTK protein.

294

Compounds 1-1 and 1-2 irreversibly inhibit BTK phosphorylation in Ramos cells

The BTK target site occupancy ELISA was used to detect the BTK protein free from Ramos cells treated with increased concentrations of compounds 1-1. As shown in Table 2 and Figure 3, compound 1-1 of BTK protein dose-dependent occupancy correlates with its BTK kinase inhibitory activity, achieving IC₅₀ at 0.5 nM.

Table 2

<td>Compound 1-1 (nM)</td><td>OD 450 (average)</td><td>Free btk (pg)</td>

<td> 3000</td><td> -0.0487</td><td> -689</td>

<td> 750</td><td> -0.0456</td><td> -646</td>

<td> 188</td><td> -0.0207</td><td> -290</td>

<td> 47</td><td> 0.0114</td><td> 168</td>

<td> 12</td><td> -0.0161</td><td> -224</td>

<td> 3</td><td> 0.1219</td><td> 1747</td>

<td> 0.7</td><td> 0.1811</td><td> 2592</td>

<td> 0.2</td><td> 0.1686</td><td> 2414</td>

<td> 0</td><td> 0.3888</td><td> 5560</td>

Example 73

Material and methods Cell culture and reagents

All cell lines were obtained from the American Type Culture Collection and maintained at 37 ° C with CO2 at

295

5%. The Ramos cell line was maintained in medium supplemented with 10% fetal bovine serum, penicillin (100 units / mL) and streptomycin (100 pg / mL). The NK-92 cell line was maintained in medium supplemented with 10% fetal bovine serum and 10% horse serum, penicillin (100 units / mL) and streptomycin (100 pg / mL), IL-2 lOng / mL. Goat Anti-Human F (ab ') 2 IgM-UNLB was obtained from SouthernBiotech. IL-2 was obtained from Peprotech.

Western blotting test for Btk

Ramos cells were treated with compounds at indicated doses for 45 min at room temperature, followed by stimulation of 6 pg / mL of anti-IgM for 30 min, and then used. Western blots were performed in Cellular using antibodies Phospho-Btk (Tyr223), Phospho-Btk (Tyr551), Btk, Phospho-PLCy2 (Tyrl217), PLCy2, Phospho-p44 / 42 MAPK (Erkl / 2) (Thr202 / Tyr204) and p44 / 42 MAPK (Erkl / 2) (Cell Signaling Technology). The blotting band density was acquired using ImageJ software, and the Btk phosphorylation IC50 (Tyr223) was set using a nonlinear regression model by GraphPad Prism.

Western blotting test for Jak3 and Stat5

NK-92 cells were treated with compounds at the indicated dose for 1 hour in the incubator, followed by stimulation of IL-2 for 15 minutes. Cells then

296 collected and used to prepare the cell extraction. Western blots were performed in the cell lysate using Phospho-Jak3, Jak3, Phospho-Stat5, Stat5 (Cell Signaling Technology) antibodies. Blotting band intensity was acquired using Image Lab software (BioRad), and the IC₅₀ Target was generated with GraphPad Prism.

Impulse chase western blotting assay to assess compound bound property

Ramos cells were treated with compounds at 100 nM for 45 min. The cells were then resuspended in the compound-free medium and stimulated with 6 pg / ml anti-IgM at 0, 4, 6 or 8 hours after removal of the compound. Cells were then used after 30 min of anti-IgM stimulation. Western blotting analysis was then performed.

ELISA test of occupancy of the target site Btk

Ramos cells were treated with compounds at indicated concentrations for 1 hr, followed by stimulation with 6 pg / mL of anti-IgM for 30 min, and then used. The Usuates were incubated with Compound 1-21 (labeled biotin) to a final concentration of ΙμΜ in a PBS, 0.05% Tween-20, 1% BSA solution while shaking for Ih at room temperature. Samples were transferred to a 96-well ELISA plate coated with

297 streptavidin and mixed while stirring for Ih at room temperature. The Btk antibody (BD 611116, 1: 1000 diluted in PBS + 0.05% Tween-20 + 0.5% BSA) was then applied and incubated for 1 h at room temperature. After washing, goat anti-mouse-HRP (Pierce 31432, 1: 1000 diluted in PBS + 0.05% Tween-20 + 0.5% BSA) was added and incubated for 1 h at room temperature. The ELISA was developed with the addition of tetramethylbenzidine (TMB) followed by stop solution and read in OD 450nM.

Results 1. Compounds significantly reduce Btk Tyr223 phosphorylation in Ramos cells

The results of the western blotting assay for Btk were shown in Table 3 below. Compounds having an activity designated as A provide an IC₅₀ &lt;10 nM; Compounds having an activity designated as B provide an IC50 of 10-10OOnM; compounds that have an activity designated as C provide an IC_5O^ 100 nM. N / A means that the compound has not been tested. PCI-327265 was used as the positive control.

Table 3

<td>Compound #</td><td>Btk inhibition</td>

<td></td><td>A: &lt;10 nM B: 10-100 nM C:&gt; 100nM</td>

298

<td> 1-1</td><td>TO</td>

<td> 1-2</td><td>TO</td>

<td> 1-3</td><td>TO</td>

<td> 1-4</td><td>TO</td>

<td> 1-5</td><td>TO</td>

<td> 1-6</td><td>TO</td>

<td> 1-7</td><td>B</td>

<td> 1-8</td><td>N / A</td>

<td> 1-9</td><td>TO</td>

<td> 1-10</td><td>TO</td>

<td> 1-11</td><td>B</td>

<td> 1-12</td><td>B</td>

<td> 1-13</td><td>TO</td>

<td> 1-14</td><td>B</td>

<td> 1-15</td><td>TO</td>

<td> 1-16</td><td>TO</td>

<td> 1-17</td><td>TO</td>

<td> 1-18</td><td>TO</td>

<td> 1-19</td><td>TO</td>

<td> 1-20</td><td>TO</td>

<td> 1-21</td><td>N / A</td>

<td> 1-22</td><td>C</td>

<td>I-23a</td><td>B</td>

<td>I-24a</td><td>B</td>

<td>I-25a</td><td>TO</td>

<td>I-26a</td><td>B</td>

<td>I-27a</td><td>TO</td>

<td>I-28a</td><td>B</td>

<td>I-29a</td><td>C</td>

<td>I-30a</td><td>TO</td>

<td>I-31a</td><td>TO</td>

<td>I-32a</td><td>TO</td>

<td>I-33a</td><td>B</td>

<td>I-34a</td><td>TO</td>

299

<td>I-35a</td><td>TO</td>

<td>I-36a</td><td>B</td>

<td>I-37a</td><td>B</td>

<td>I-38a</td><td>B</td>

<td>I-39a</td><td>B</td>

<td>I-40a</td><td>TO</td>

<td>I-41a</td><td>B</td>

<td>I-42a</td><td>TO</td>

<td>I-43a</td><td>TO</td>

<td>I-44a</td><td>TO</td>

<td>I-45a</td><td>B</td>

<td>I-46a</td><td>B</td>

<td>I-47a</td><td>TO</td>

<td>I-48a</td><td>TO</td>

<td>I-49a</td><td>TO</td>

<td>I-50a</td><td>B</td>

<td>I-51a</td><td>TO</td>

<td>I-52a</td><td>TO</td>

<td>I-53a</td><td>TO</td>

<td>I-54a</td><td>TO</td>

<td>I-55a</td><td>C</td>

<td>I-56a</td><td>TO</td>

<td>I-57a</td><td>TO</td>

<td>I-58a</td><td>TO</td>

<td>I-59a</td><td>TO</td>

<td>I-60a</td><td>TO</td>

<td>I-61a</td><td>TO</td>

<td>I-62a</td><td>TO</td>

<td>I-63a</td><td>TO</td>

<td>I-64a</td><td>TO</td>

<td>I-65a</td><td>TO</td>

<td>I-66a</td><td>TO</td>

<td>I-67a</td><td>B</td>

<td>I-68a</td><td>B</td>

300

I-69a B

<td>I-70a</td><td>B</td>

<td>I-71a</td><td>TO</td>

<td>I-72a</td><td>TO</td>

The exemplary western blotting image of several of the compounds above is listed below in the left panel in Figure 4, while PCI-32765 serves as a positive Btk inhibitor. IC curves_5G are displayed in the right panel in Figure 4.

2. Compounds reduce Jak3 phosphorylation in NK-92 cells

The results of the western blotting assay for Jak3 were shown in Table 4 below. Compounds having an activity designated as A provide an IC50-200 nM; compounds having an activity designated as B provide an IC₅₀ 200-400 nM; compounds having an activity designated as C provide an IC₅₀^ 400 nM.

Table 4

<td>Compound #</td><td>Jak3 inhibition</td>

<td></td><td>A: &lt;200 nM B: 200-400 nM C: &gt; 400 nM</td>

<td> 1-1</td><td>TO</td>

<td> 1-2</td><td>B</td>

<td>I-25^to</td><td>C</td>

301

3. Compounds reduce Stat5 phosphorylation in NK-92 cells

The results of the western blotting assay for Stat5 were shown in Table 5 below. Compounds having an activity designated as A provide an IC50 &lt;200 nM; compounds having an activity designated as B provide an IC₅₀ 200-400 nM; compounds that have an activity designated as C provide an IC₅₀^ 400 nM.

Table 5

<td>Compound #</td><td>Stat5 inhibition</td>

<td></td><td>A: &lt;200 nM B: 200 ~ 400 nM C:&gt; 400 nM</td>

<td> 1-1</td><td>C</td>

<td> 1-2</td><td>B</td>

<td> 1-3</td><td>B</td>

<td> 1-4</td><td>B</td>

<td> 1-5</td><td>B</td>

<td> 1-6</td><td>B</td>

<td> 1-7</td><td>C</td>

<td> 1-9</td><td>B</td>

<td> 1-10</td><td>B</td>

<td> 1-11</td><td>C</td>

<td> 1-12</td><td>B</td>

<td> 1-13</td><td>C</td>

<td> 1-14</td><td>C</td>

<td> 1-15</td><td>C</td>

<td> 1-16</td><td>C</td>

<td> 1-17</td><td>C</td>

<td> 1-18</td><td>B</td>

302

<td>I-23a</td><td>C</td>

<td>I-25a</td><td>C</td>

<td>I-30a</td><td>TO</td>

<td>I-31a</td><td>C</td>

<td>I-32a</td><td>C</td>

<td>I-33a</td><td>C</td>

<td>I-34a</td><td>C</td>

<td>I-35a</td><td>B</td>

<td>I-36a</td><td>B</td>

<td>I-37a</td><td>C</td>

<td>I-38a</td><td>C</td>

<td>I-39a</td><td>c</td>

<td>I-40a</td><td>c</td>

<td>I-41a</td><td>B</td>

<td>I-42a</td><td>C</td>

<td>I-43a</td><td>B</td>

<td>I-44a</td><td>B</td>

<td>I-45a</td><td>B</td>

<td>I-46a</td><td>C</td>

<td>I-47a</td><td>B</td>

<td>I-48a</td><td>B</td>

<td>I-49a</td><td>C</td>

<td>I-50a</td><td>C</td>

<td>I-51a</td><td>C</td>

<td>I-52a</td><td>C</td>

<td>I-53a</td><td>C</td>

<td>I-54a</td><td>C</td>

<td>I-56a</td><td>B</td>

<td>I-57a</td><td>B</td>

<td>I-58a</td><td>C</td>

Four. Impulse chase western blotting assay to assess the binding property of compounds

303

As shown in Figures 5A and 5B, the result after compound 1-1 and 1-2 is treated and removed, the long-lasting effect of inhibition was observed after removal of compounds up to 8 hours. This strong bond of the compound to the target enzyme indicates the strong bond of compound 1-1 and 1-2, which was chemically designed to covalently bind the Btk protein at the specific position.

As shown in Figures 5A and 5B, compounds 1-1 and 1-2 inhibit BTK phosphorylation in Ramos cells after 8 hours of removal. Ramos cells were treated with Compound 1-1 and Compound 1-2 at lOOnM for 45mins, and inhibition of Btk phosphorylation was monitored 4, 6 and 8hrs after removal of Compound 1-1 and Compound 1-2 . Btk remains inhibited for up to 8 hrs after treatment with Compound 1-1 and Covalently Bound Compound 1-2, indicating that Compound 1-1 and Compound 1-2 are strong irreversible inhibitors of the Btk protein.

5. ELISA test of occupancy of the target site Btk

The Btk target site occupancy ELISA was used to detect free Btk protein from Ramos cells treated with increased concentrations of various compounds. Dose-dependent occupancy compounds of

304 Btk proteins correlate with their Btk kinase inhibitory activity as shown in Table 6 below and in Figures 6A-6L.

Table 6

<td>Compound #</td><td>Btk occupancy test (IC₅₀)</td>

<td></td><td>A: &lt;10 nM B: 10-100 nM C:&gt; lOOnM</td>

<td> 1-1</td><td>TO</td>

<td> 1-10</td><td>B</td>

<td> 1-13</td><td>TO</td>

<td> 1-20</td><td>TO</td>

<td>I-25a</td><td>TO</td>

<td>I-58a</td><td>TO</td>

The present invention is further illustrated by the following exemplary embodiments:

one. A compound of Formula (I):

O y

HN R⁴

<img file="MX368491B_D0271.tif" />

305 where

R¹ is H, or

NR^cR^d where R^c is H, Ci-4-alkyl or 3-7-membered cyclic ring, and R^d is H, Ci_4 alkyl, optionally substituted with OZ, where Z is H or Ci- alkyl₄; or 3-7 membered cyclic ring substituted with R^to where R^tois Ci_alkyl₈ optionally substituted with halo;

<td>R²</td><td>is</td><td>H</td><td>halo,</td><td>I rent</td><td>Ci-₄,</td><td>or</td><td>alkoxy</td><td>Ci-₄;</td>

<td>R³</td><td>is</td><td>H</td><td>halo,</td><td>I rent</td><td>Ci_₄,</td><td>or</td><td>alkoxy</td><td>Ci_4;</td>

<td>R⁵</td><td>is</td><td>H</td><td>halo,</td><td>I rent</td><td>Cl-4,</td><td>or</td><td>alkoxy</td><td>Ci-₄;</td>

<td>R⁵</td><td>is</td><td>H</td><td>halo,</td><td>I rent</td><td>C1-4,</td><td>or</td><td>alkoxy</td><td>Ci-4;</td>

<td>R¹ and R⁵ are</td><td>Part of</td><td>cyclic ring</td><td>of</td><td>3-7 members</td>

<td>optionally</td><td>replaced</td><td>with Ci_4 alkyl</td><td colspan="2">replaced with OZ</td>

<td>where Z is</td><td>H or alkyl</td><td>Ci_₄; or</td><td></td><td></td>

<td>R¹ and R² are</td><td>Part of</td><td>cyclic ring</td><td>of</td><td>3-7 members</td>

<td>optionally</td><td>replaced</td><td>with alkyl Ci_₄</td><td>substitu</td><td>ituido with OZ</td>

<td>where Z is</td><td>H or alkyl</td><td>Cl-4, 'o</td><td></td><td></td>

<td>R² and R⁶ are</td><td>Part of</td><td>cyclic ring</td><td>of</td><td>3-7 members</td>

<td>optionally</td><td>replaced</td><td>with alkyl Ci_₄</td><td>substitu</td><td>ituido with OZ</td>

<td>where Z is</td><td>H or alkyl</td><td>Ci-₄; or</td><td></td><td></td>

R⁴ is alkenyl C₂ optionally substituted with Ci_alkyl₄, ch₂och₃, or -ch₂n (ch₃)₂; and

X is O, alkyl Ci_₄ optionally substituted with halo, or NR^b, where R^b is H, or alkyl Ci-₈ optionally replaced with

306 halo

Y is CH optionally substituted with halo, or N where at least one of R², R³, R⁵ and R⁶ it is not H;

or a pharmaceutically acceptable salt thereof.

2.

R² and R⁶

The compound of embodiment 1, wherein they are part of the 3-7 cyclic ring optionally substituted with

OZ, where

Z is H or

R^c

R^c cyclic

6.

R¹ is H, and Ci3 alkyl members.

is .

is

5.

<td>The</td><td>compound</td><td>of</td><td>the</td>

<td colspan="2">methyl.</td><td></td><td></td>

<td>The</td><td>compound</td><td>of</td><td>the</td>

<td colspan="2">cyclic ring</td><td>of</td><td> 3-7</td>

<td>The</td><td>compound</td><td>of</td><td>the</td>

Membership modality.

3-7 member mode is

The cyclic ring compound where where where where ring

R¹ is NR^cR^d

R¹ is NR^cR^d where the ring c₃.

any of the modalities 3-5

R¹ is

R^d is alkyl C₂ replaced with OZ

The substituted 3-7 membered cyclic modality compound

The compound of modality 7

<img file="MX368491B_D0272.tif" />

R^toNot

<img file="MX368491B_D0273.tif" />

H N.

9. The modality compound with

Z is methyl.

where R¹ is

R^to.

where

8, where R¹ is

7

10. The compound of modality 9, where R^to is alkyl Ci-₄ optionally substituted with halo or Ci- alkoxy₄.

eleven. The compound of modality 9 or 10, where R^to is Ci_alkyl₄ substituted with fluoro or Ci- alkyl₈ replaced with fluoro.

12. The compound of modality 8, where R¹ is

13. The compound of modality 12, where R^to is alkyl Ci-₄ optionally substituted with halo or Ci_alkoxy₄,

14. The compound of modality 12 or 13, where R^tois Ci_alkyl₄ substituted with fluoro or Ci_alkyl₈ replaced with fluoro.

fifteen. The compound of any of modalities 1-14, wherein R² it's H.

16. The compound of any of modalities 1-14, wherein R² it's halo.

17. The compound of any of modalities 1-14, wherein R² is alkyl Ci-₄ or C-alkoxy₄.

18. The compound of any of modalities 1-14, wherein R⁵ it's H.

19. The compound of any of modalities 1-14, wherein R⁵ it's halo.

twenty. The compound of any of modalities 1-14

308 where R⁵ is Ci_alkyl₄ or alkoxy C_x-₄.

twenty-one. The compound of any of modalities 1-14, wherein R⁶ it's H.

22. The compound of any of modalities 1-14, wherein R⁶ it's halo.

2. 3. The compound of any of modalities 1-14, wherein R⁶ is Ci_alkyl₄ or alkoxy Ci_₄.

24. The compound of modality 1, where R¹ and R⁵ are part of the 3-7 membered cyclic ring, optionally substituted with Ci_alkyl₄ substituted with OZ, where Z is H or Ci_alkyl₄.

25. The compound of modality 1, where R¹ and R² are part of the 3-7 membered cyclic ring, optionally substituted with Ci_alkyl₄ substituted with OZ, where Z is H or Ci_alkyl₄.

26. The compound of modality 1, where R² and R⁶ are part of the 3-7 membered cyclic ring, optionally substituted with Ci_alkyl₄ substituted with OZ, where Z is H or Ci_alkyl₄.

27. The compound of any one of modalities 2426, wherein the 3-7 membered cyclic ring is a 5 membered ring.

'28. The compound of embodiment 27, wherein the 5-membered cyclic ring is a heterocyclic ring.

309

29. The compound of embodiment 28, wherein the 5-membered heterocyclic ring comprises an N atom.

30. The compound of any of the modalities 2429, where the alkyl Ci_₄ is alkyl C₂.

31. The compound of embodiment 30, wherein Z is methyl.

<td></td><td> 32.</td><td>Compound</td><td>of</td><td>anyone</td><td>of</td><td>the</td><td>modalities</td><td> 1-31</td>

<td>in</td><td>where</td><td>R³ it's H.</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td> 33.</td><td>Compound</td><td>of</td><td>anyone</td><td>of</td><td>the</td><td>modalities</td><td> 1-31</td>

<td>in</td><td>where</td><td>R³ it's halo.</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td> 34.</td><td>Compound</td><td>of</td><td>anyone</td><td>of</td><td>the</td><td>modalities</td><td> 1-31</td>

<td>in</td><td>where</td><td>R³ it's alkyl</td><td>Ci-4</td><td>or alkoxy C</td><td> 1-4 ·</td><td></td><td></td><td></td>

<td></td><td> 35.</td><td>Compound</td><td>of</td><td>anyone</td><td>of</td><td>the</td><td>modalities</td><td> 1-34</td>

where R², R⁵, or R⁶ is H or halo and R³ is halo, alkyl Ci_₄ or alkoxy Ci_₄.

<td></td><td> 36.</td><td>The</td><td>compound</td><td>of</td><td>anyone</td><td>of</td><td>the</td><td>modalities</td><td> 1-35,</td>

<td>in</td><td>where</td><td colspan="2">R⁴ is alkenyl</td><td>or C</td><td colspan="3">₂ not replaced.</td><td></td><td></td>

<td></td><td> 37.</td><td>The</td><td>compound</td><td>of</td><td>anyone</td><td>of</td><td>the</td><td>modalities</td><td> 1-35,</td>

<td>in</td><td>where</td><td>R⁴</td><td colspan="2">is alkenyl</td><td colspan="4">C₂ substituted with alkyl C</td><td>l-4z</td>

<td colspan="2">CH₂OCH₃, '</td><td colspan="2">or -CH₂N (CH₃)₂.</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td> 38.</td><td>The</td><td>compound</td><td>of</td><td>anyone</td><td>of</td><td>the</td><td>modalities</td><td> 1-37,</td>

<td>in</td><td>where</td><td>X is</td><td> &gt; 0.</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td> 39.</td><td>The</td><td>compound</td><td>of</td><td>anyone</td><td>of</td><td>the</td><td>modalities</td><td> 1-37,</td>

where X is alkyl Ci_₄ optionally substituted with halo.

310

40. The compound of embodiment 39, where X is Ci_alkyl₄ not replaced.

41. The compound of modality 40, where X is CH₂.

42. The compound of embodiment 39, where X is Ci_alkyl₄ replaced with halo.

43. The compound of modality 42, where X is CF₂.

44. The compound of any one of modalities 1-37, where X is NR^b, and R^b it is H, or Ci_e alkyl optionally substituted with halo.

Four. Five. The compound of modality 44, where R^b it's H.

<td> 46.</td><td>The</td><td>compound</td><td>of</td><td>modality</td><td> 44</td><td>, where</td><td>R^b is</td>

<td>I rent</td><td>C1-8</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> 47.</td><td>The</td><td>compound</td><td>of</td><td>modality</td><td> 46</td><td>, where</td><td>R^b is</td>

<td>I rent</td><td>Ci_₄.</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> 48.</td><td>The</td><td>compound</td><td>of</td><td>modality</td><td> . 46</td><td>&gt; or 47, in</td><td>where</td>

<td>I rent</td><td>Ci-₄ or</td><td>alkyl C</td><td>i-8</td><td>is replaced &lt;</td><td>with</td><td>halo.</td><td></td>

<td> 49.</td><td>The</td><td>compound</td><td>of</td><td>any of</td><td>the</td><td>modalities</td><td> 1-48,</td>

<td>where</td><td>And it is</td><td>CH.</td><td></td><td></td><td></td><td></td><td></td>

<td> 50.</td><td>The</td><td>compound</td><td>of</td><td>any of</td><td>the</td><td>modalities</td><td> 1-48,</td>

<td>where</td><td>And it is</td><td>CF or N.</td><td></td><td></td><td></td><td></td><td></td>

<td> 51.</td><td>The</td><td>compound</td><td>of</td><td>modality</td><td> 1,</td><td colspan="2">which is selected</td>

from the group consisting of compound 1-1, 1-2, 1-3, 1-4, 1-5,

1-6, 1-7, 1-8, 1-9, 1-12, 1-13, 1-14, 1-15, 1-16, 1-17, 1-18,

1-19, 1-20, 1-21, 1-22, 1-23, 1-24, 1-25 and 1-41.

311

<img file="MX368491B_D0274.tif" />

52. A compound of Formula (II):

<img file="MX368491B_D0275.tif" />

<img file="MX368491B_D0276.tif" />

(II) where

R¹ is H, or

NR^cR^d where R^c is H, alkyl Ci-₄ or 3-7 membered cyclic ring, and R^d is H, alkyl Ci_₄, optionally substituted with OZ, where Z is H or Ci_alkyl₄; or

NR^andR^F where R^and is Ci-4 alkyl, and R^F it is a 37 membered cyclic ring optionally substituted with Ci-4 alkyl optionally substituted with halo; or

OR⁵ where R^g is alkyl Ci-₄ replaced with CH₃O-, CH₃CH₂OR-,

CH₃(OR) ₂S-, CF₃OR-,

312

<td>R²</td><td>is</td><td>H</td><td>halo,</td><td>I rent</td><td>Cl-4,</td><td>OR</td><td>alkoxy</td><td>Ci-4;</td>

<td>R³</td><td>is</td><td>H</td><td>halo,</td><td>I rent</td><td>Cl-₄ ,</td><td>OR</td><td>alkoxy</td><td>Ci-4;</td>

<td>R⁵</td><td>is</td><td>H</td><td>halo,</td><td>I rent</td><td>Cl-4t</td><td>OR</td><td>alkoxy</td><td>Ci-4;</td>

<td>R⁶</td><td>is</td><td>H</td><td>halo,</td><td>I rent</td><td>Cl-4t</td><td>OR</td><td>alkoxy</td><td>Ci_₄; or</td>

<td>R¹ and R⁵ are</td><td>Part of</td><td>cyclic ring</td><td>of</td><td>3-7 members,</td>

<td>optionally</td><td>replaced</td><td>with alkyl Ci-₄</td><td colspan="2">replaced with OZ,</td>

<td>where Z is</td><td>H or alkyl</td><td>Ci-4, 'o</td><td></td><td></td>

<td>R¹ and R² are</td><td>Part of</td><td>cyclic ring</td><td>of</td><td>3-7 members,</td>

<td>optionally</td><td>replaced</td><td>with alkyl Ci-₄</td><td colspan="2">replaced with OZ,</td>

<td>where Z is</td><td>H or alkyl</td><td>Cl-4, * o</td><td></td><td></td>

<td>R² and R⁶ are</td><td>Part of</td><td>cyclic ring</td><td>of</td><td>3-7 members,</td>

<td>optionally</td><td>replaced</td><td>with alkyl Ci-₄</td><td colspan="2">replaced with OZ,</td>

<td>where Z is</td><td>H or alkyl</td><td>Ci_₄; or</td><td></td><td></td>

R⁴ is alkenyl C₂ optionally substituted with C1-4alkyl, ch₂och₃, or -ch₂n (ch₃)₂; and

X is O, alkyl Ci_₄ optionally substituted with halo, or NR^b, where R^b is H, or alkyl Ci__B optionally substituted with halo,

Y is CH optionally substituted with halo, or N, or a pharmaceutically acceptable salt thereof.

53. The compound of modality 52, where R¹ is H, and R² and R⁶ they are part of the 3-7 membered cyclic ring, optionally substituted with Ci-alkyl₄ substituted with OZ, where Z is H or methyl.

313

<td></td><td colspan="2"> 54 .</td><td>The</td><td>compound</td><td>of</td><td>the</td><td>modality 52,</td><td>in</td><td>where</td><td>R¹ is</td>

<td>NR^cR^d</td><td>and</td><td>R^c</td><td>is</td><td>methyl.</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td> 55</td><td> •</td><td>The</td><td>compound</td><td>of</td><td>the</td><td>modality 52,</td><td>in</td><td>where</td><td>R¹ is</td>

<td>NR^cR^d</td><td>and</td><td>R^c</td><td>is</td><td colspan="2">cyclic ring</td><td>of</td><td>3-7 members.</td><td></td><td></td><td></td>

<td></td><td> 56</td><td> •</td><td>The</td><td>compound</td><td colspan="3">of modality 55, in</td><td colspan="2">where he</td><td>ring</td>

3-7 membered cyclic is cyclic C ring₃.

57. The compound of any of the modalities 5456, where R^d is alkyl C₂ substituted with OZ, and Z is methyl.

58. The compound of modality 52, where R¹ is NR^andR^F, R^and is C1-4alkyl, and R^F it is 3-7 membered cyclic ring optionally substituted with C 1-4 alkyl optionally substituted with halo.

59. The compound of embodiment 58, wherein the 3-7 membered cyclic ring is a 5 membered cyclic ring.

<td> 60.</td><td>The</td><td>compound</td><td>of</td><td>the</td><td>modality</td><td>59 in</td><td>where</td><td>the</td><td>ring</td>

<td>cyclic</td><td>of 5</td><td>members</td><td>is</td><td colspan="3">heterocyclic ring.</td><td></td><td></td><td></td>

<td> 61.</td><td>The</td><td>compound</td><td>of</td><td>the</td><td>modality</td><td>60 in</td><td>where</td><td>the</td><td>ring</td>

The 5-membered heterocyclic comprises an N atom.

62. The compound of any one of the 5861 modalities, wherein the 3-7 membered cyclic ring is substituted with FCH₂CH₂-.

63. The compound of modality 52, where R¹ that^g and R^g is C1-4alkyl substituted with CH₃O-, CH₃CH₂O-, CH₃(OR) ₂S-,

314

<img file="MX368491B_D0277.tif" />

<td></td><td> 65.</td><td>The</td><td>compound</td><td>of</td><td>anyone</td><td>of</td><td>the</td><td>modalities</td><td> 52-</td>

<td> 64,</td><td colspan="2">where</td><td>R² it's H.</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td> 66.</td><td>The</td><td>compound</td><td>of</td><td>anyone</td><td>of</td><td>the</td><td>modalities</td><td> 52-</td>

<td> 64,</td><td colspan="2">where</td><td>or R is halo</td><td> •</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td> 67.</td><td>The</td><td>compound</td><td>of</td><td>anyone</td><td>of</td><td>the</td><td>modalities</td><td> 52-</td>

<td> 64,</td><td colspan="2">where</td><td colspan="2">2 R is alkyl</td><td colspan="2">Ci_4 or alkoxy Ci</td><td> -4 .</td><td></td><td></td>

<td></td><td> 68.</td><td>The</td><td>compound</td><td>of</td><td>anyone</td><td>of</td><td>the</td><td>modalities</td><td> 52-</td>

<td> 64,</td><td colspan="2">where</td><td>R⁵ it's H.</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td> 69.</td><td>The</td><td>compound</td><td>of</td><td>anyone</td><td>of</td><td>the</td><td>modalities</td><td> 52-</td>

<td> 64,</td><td colspan="2">where</td><td>R⁵ it's halo</td><td> •</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td> 70.</td><td>The</td><td>compound</td><td>of</td><td>anyone</td><td>of</td><td>the</td><td>modalities</td><td> 52-</td>

<td> 64,</td><td colspan="2">where</td><td colspan="2">R⁵ it's alkyl</td><td colspan="2">Ci_4 or alkoxy Ci</td><td> -4 ·</td><td></td><td></td>

<td></td><td> 71.</td><td>The</td><td>compound</td><td>of</td><td>anyone</td><td>of</td><td>the</td><td>modalities</td><td> 52-</td>

<td> 64,</td><td colspan="2">where</td><td>R⁶ it's H.</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td> 72.</td><td>The</td><td>compound</td><td>of</td><td>anyone</td><td>of</td><td>the</td><td>modalities</td><td> 52-</td>

<td> 64,</td><td colspan="2">where</td><td>R⁶ it's halo</td><td> •</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td> 73.</td><td>The</td><td>compound</td><td>of</td><td>anyone</td><td>of</td><td>the</td><td>modalities</td><td> 52-</td>

<td> 64,</td><td colspan="2">where</td><td colspan="2">R⁶ it's alkyl</td><td colspan="2">Ci-4 or Ci alkoxy</td><td> -4 .</td><td></td><td></td>

74. The compound of modality 52, where R¹ and R⁵

315 are part of the 3-7 membered cyclic ring, optionally substituted with Ci_alkyl₄ substituted with OZ, where Z is H or Ci- alkyl₄.

75. The compound of modality 52, where R¹ and R²they are part of the 3-7 membered cyclic ring, optionally substituted with Ci-alkyl₄ substituted with OZ, where Z is H or Ci- alkyl₄.

76. The compound of modality 52, where R² and R⁶they are part of the 3-7 membered cyclic ring, optionally substituted with Ci-alkyl₄ substituted with OZ, where Z is H or Ci- alkyl₄.

<td></td><td> 77</td><td>. The</td><td>compound</td><td>from anyone</td><td>of the</td><td colspan="3">modalities 74-</td>

<td> 76,</td><td>in</td><td>where</td><td>the ring</td><td>3-7 cyclic</td><td colspan="2">members is</td><td>a</td><td>ring</td>

<td>of</td><td colspan="2">5 members</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td> 78</td><td>. The</td><td>compound</td><td>of the modality</td><td>77 in</td><td>where</td><td>the</td><td>ring</td>

<td colspan="2">cyclic</td><td>of 5</td><td colspan="3">members is heterocyclic ring.</td><td></td><td></td><td></td>

<td></td><td> 79</td><td>. The</td><td>compound</td><td>of the modality</td><td>78 in</td><td>where</td><td>the</td><td>ring</td>

The 5-membered heterocyclic comprises an N atom.

<td>80. The</td><td>compound</td><td>of</td><td>anyone</td><td>of</td><td>the</td><td>modalities</td><td> 74-</td>

<td>79, where</td><td>the alkyl</td><td>Ci-</td><td>₄ it's alkyl</td><td>c₂.</td><td></td><td></td><td></td>

<td>81. The</td><td>compound</td><td>of</td><td colspan="2">modality</td><td> 80,</td><td>where Z</td><td>is</td>

<td>methyl.</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>82. The</td><td>compound</td><td>of</td><td>anyone</td><td>of</td><td>the</td><td>modalities</td><td> 52-</td>

81, where R³ it's H.

316

<td></td><td colspan="2">83. The</td><td>compound</td><td>anyone</td><td>of</td><td>the</td><td>modalities</td><td> 52-</td>

<td> 81,</td><td>in</td><td>where</td><td>R³ it's halo.</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td> 84</td><td>. The</td><td>compound</td><td>anyone</td><td>of</td><td>the</td><td>modalities</td><td> 52-</td>