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Sister Ar'a's background

The present invention relates to some fused tricyclic ring derivatives that act as inhibitors of the Src Homology-2 Phosphatase (SHP2) phosphatase enzyme and are therefore useful for the treatment of mother Earth that can

<p dir="rtl">5 Treated by inhibiting SHP2. Pharmaceutical formulations containing these compounds and processes for preparing those compounds are also provided.</p>

SRC HOMOLOGY PHOSPHATASE 2 is a non-receptor protein phosphatase enzyme that is generally expressed in various types of tissues and cells (see reference: 2016 Tajan M et al., Eur J Med Genet

58(10):509-25; Grossmann KS et al., Adv Cancer Res 2010 106:53- 10

<p dir="rtl">(89). The enzyme SRC Homology 2-SHP2 (SRC Homology 2-SHP2) consists of two Src homology domains (N-SH2) and C-SH2 at its NH2 end, a catalytic PTP (protein-tyrosine phosphatase) domain. And a tip ending in C with structured properties In the ground state, intermolecular interactions operate between two domains</p>

<p dir="rtl">15 SH2 and the PTP domain prevent access of substrates to the catalytic pocket,</p>

Maintaining the enzyme SRC phosphatase 2-SHP2 (SRC HOMOLOGY) in a closed, self-inhibiting conformation. In response to stimulation, SHP2 activating proteins bearing phosphor-tyrosine repeats bind to SHP2 domains, leading to exposure of the active site and enzymatic activation of SHP2.

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The enzyme SRC phosphatase 2-SHP2 (SRC HOMOLOGY) plays an important role in basic cellular interactions such as reproduction, differentiation, and maintaining the cell cycle and movement. By dephosphorylating its signaling molecules, the enzyme homologates

SRC HOMOLOGY-2 PHOSPHATASE SRC-2 regulated by many (SHP2)

<p dir="rtl">5 Of the signaling pathways within the cell in response to many growth factors, cytokines, and hormones. Cell signaling processes involved in SRC HOMOLOGY PHOSPHATASE 2 (SHP2) include both the RAS-MAPK (mitosis-activating protein kinase) and PI3K (phosphoinositol 3-kinase, AKT) pathways. )phosphoinositol 3-kinase</p>

<p dir="rtl">10 AND JAK-STAT.</p>

The RAS-MAPK signaling pathway is vital for tumor formation and maintenance. Various components of the genes coding for this pathway are mutated, such as RTKs (receptor tyrosine kinases), SRC phosphatase NF1 (SHP2), SRC Homology-2 (SHP2), formation of RAS, or RAF in cancer types, leading to increased signaling. MAPK controllably

<p dir="rtl">15 in it. SHP2 also plays a role in enhancing signaling along this pathway, acting after RTKs and before RAS. RTK-derived cancer cells have been shown to depend on the enzyme SRC homology-2 phosphatase (SRC phosphatase SHP2) for survival. Therefore, an SHP2 inhibitor has been proposed as an effective treatment for RTK-derived cancers (see</p>

Prahallad, A. et al. Cell Reports 12, 1978–1985 (2015); Chen YN, Nature 535, 148-152 (2016) 20

Much effort has been made to develop pharmacological agents that target various nodes along the RAS MAPK pathway, such as RTK inhibitors, BRAF inhibitors, and MEK inhibitors, to treat cancer. Although these agents have good initial efficacy, resistance to these agents always occurs. One common resistance mechanism involves activation of...

<p dir="rtl">25 RTKs that stimulate the reactivation of MAPK signaling. Due to the need for a 2-SRC homolog enzyme</p>

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For post kit RTKs (SHP2) SRC HOMOLOGY-2 PHOSPHATASE

Transducing the signal, inhibition of SHP2 may provide a general strategy to prevent resistance to cancer drugs that target the MAPK pathway. Recent studies in preclinical models have shown that inhibiting the enzyme SRC phosphatase 2-SHP2 (SRC HOMOLOGY)

<p dir="rtl">5 PHOSPHATASE overcomes resistance and provides synergistic therapeutic effects when combined with an inhibitor</p>

MEK or inhibitor, Dardaei L et al. Nat Med. 24, 512-17 (2018) return (ALK

Mainardi, S. et al. Nat. Med.<a href="https://doi.org/10.1038/s41591-018-">https://doi.org/10.1038/s41591-018-</a> Ref(0023-9 (2018); Ruess, DA et al. Nat. Med.

<a href="https://doi.org/10.1038/s41591-018-0024-8">https://doi.org/10.1038/s41591-018-0024-8</a> (2018); Wong, G.S. et al.

Nat. Med.<a href="https://doi.org/10.1038/s41591-018-0022-x">https://doi.org/10.1038/s41591-018-0022-x</a> (2018); Fedele 10

C et al. Cancer Disco pii: CD-18-0444. doi: 10.1158/2159-8290.CD-

Prahallad, A. et al. Cell Reports 12, refer (BRAF 2018) 0444-18 (or inhibitor)

<p dir="rtl">(2015) 1978–1985). In particular, it has been shown that combined inhibition of MEK/SHP2 can treat cancers derived from KRAS, the most mutational oncogene. Although</p>

<p dir="rtl">15 Years of effort, but no success, have been achieved in developing inhibitors that directly target KRAS for clinical use. Inhibition of MEK, the downstream action of KRAS, only temporarily suppresses MAPK signaling. The discovery of dual inhibition of MEK/SHP2 has advanced important steps in the long effort to further understand and therapeutically target KRAS-derived cancer.</p>

Taking into account the basic physiological functions performed by the SRC-2 homoenzyme

<p dir="rtl">20 SRC HOMOLOGY-2 PHOSPHATASE), deregulating SHP2 targeting is expected to have broad therapeutic applications. There has been a causal association between the acquisition of functional mutations in PTPN11, the gene encoding SHP2, and several human diseases, such as Noonan Syndrome, juvenile myelomonocytic leukemias, acute myeloid leukemia,</p>

<p dir="rtl">25 myelodysplastic syndrome, and B-cell lymphoblastic leukemia</p>

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Acute B lymphoblastic lymphoblastic leukemia. SRC HOMOLOGY-2 PHOSPHATASE (SRC 2 phosphatase) functions as an oncogene, and its overexpression and/or activated mutation has been reported in several solid tumors, such as neuroblastoma, breast cancer, and colon cancer.

<p dir="rtl">5 Colon cancer, lung cancer, melanoma, and hepatocellular carcinoma.</p>

Furthermore, 2-SHP is thought to mediate inhibitory immune checkpoint signaling to multiple receptors (such as PD-1) by dephosphorylating CD28. In support of this idea, dominant negative 2-SHP abolishes PD signaling pathways and restores CD28 cell function. CAR T is cytotoxic. Therefore,

<p dir="rtl">10 SHP-2 inhibitors may be used in combination therapy with current targeted immuno-oncology (IO) agents.</p>

In addition to human tumors, an increase in the expression or activity of an enzyme has been implicated

IN (SHP2) SRC HOMOLOGY-2 PHOSPHATASE SRC PHOSPHATASE-2 HOMOLOGY

Or autoimmune diseases such as systemic lupus erythematosus

Wang J et al. J Clin Invest. 2016 Jun 1; (lupus erythematosus 15

2077-92:(6)126) and rheumatoid arthritis (refer

Stanford S.M et al. Arthritis rheum. 2013 May; 65(5):1171-80;

Recently, the enzyme was classified (Maeshima K et al. JCI Insight. 2016 May 19; 1(7)

ON (SHP2) SRC HOMOLOGY-2 PHOSPHATASE SRC PHOSPHATASE-2 HOMOLOGY

<p dir="rtl">20 It is a molecular blocker of JAK2/STAT3 signaling preceded by TGFβ, indicating that inhibiting</p>

Zehender A et al. Nat Commun. May provide therapeutic benefit for the treatment of fibrosis (refer to SHP2).

3259:(1)9;14 Aug 2018. Thus, SHP2 represents a very attractive target for the development of new therapeutics for various diseases on Earth.

General description of the invention

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In the first aspect, a compound with the formula (I) is provided:

<img file="SA15151B1_D0001.tif" />

(I)

where:

<p dir="rtl">5 A and E are selected individually from the bonds, S, NH, O, CH2, and 2(S(O);</p>

Z consists of hydrogen, alkyl, halo, haloalkyl, haloalkoxy, cyano, cycloalkyl, heterocyclyl, heteroaryl (where cycloalkyl, heterocyclyl, and heteroaryl are formed in the form Optional replace them with one 10 to three halo S(O)2Rd-, S(O)Rc-, O(alk)ORb-, O(alk)yRa-,)halo, -

,NRgSO2Rh- ,NReC(O)Rf

- NRpRq-, S(O)2NRnRo-, C(O)NRkRm-, OC(O)NRiRj-

NRrC(O)C(O)Rs or -YM (where Y is a ligand, O, or SO2 and M is an alkyl, haloalkyl, cycloalkyl, heterocyclyl, or heteroaryl). Replacement of alkyl, haloalkyl, cycloalkyl, heterocyclyl and heteroaryl with -,O(alk)yRa

<p>- NRgSO2Rh-, NReC(O)Rf-, S(O)2Rd-, S(O)Rc-, O(alk)ORb-, C(O)NRkRm-, OC(O)NRiRj</p>

20 -NRpRq-, S(O)2NRnRo, or -NRrC(O)C(O)Rs, cycloalkyl, cyclyl

Heterocyclyl and heteroaryl are also optionally replaced with 1 to 3 halo(s; where each y is 0 or 1, each alk is a

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Alkylene, and each Rh, Rf, Rd, Rc, and Rs individually are an alkyl, cycloalkyl, cycloalkyl, cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, aryl Optional replacement

<p dir="rtl">5 substituted aryl, an optionally substituted aralkyl, an optionally substituted heteroaryl, or an optionally substituted heteroaralkyl; Each Rg, Re, Rb, Ra, Rr, Rq, Rp, Ro, Rn, Rm, Rk, Rj, Ri, and Rs are individually hydrogen, alkyl, cycloalkyl, cycloalkyl, cycloalkylalkyl.</p>

<p dir="rtl">10 hydroxyalkyl, alkoxyalkyl, aminoalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted aralkyl, aryl optionally substituted heteroaryl, or</p>

<p dir="rtl">15 an optionally substituted heteroaralkyl; or,</p>

Independently of each other, Ri and Rk, Rj and Rn, Rm and Ro, and Rp and Rq, together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl;

R3, R2, R1, and R4 are selected individually from hydrogen, alkyl,

<p dir="rtl">20 cycloalkyl, halo, haloalkyl, haloalkoxy, alkoxy, cyano, hydroxy, hydroxylalkyl, amino, and aminoalkyl;</p>

Or one of R1 and R2, and R3 and R4, when attached to the same carbon atom, fuse to form an oxo, an alkyldieenyl, or a cycloalkylene from 3 to 6.

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10

dha, or an optionally substituted heterocyclylene from 4 to 6 dha;

R5 and R6 are individually selected from hydrogen, alkyl, cycloalkyl, halo, haloalkyl, haloalkoxy, alkoxy, hydroxy, cyano, hydroxylalkyl, amino, and aminoalkyl, or one of R5 and R6. It is a heterocyclic with an optionally substituted heterocyclyl and the other of R5 and R6 is chosen from hydrogen, alkyl, cycloalkyl, halo, haloalkyl, haloalkoxy, alkoxy, hydroxy, cyano, hydroxylalkyl, amino, and aminoalkyl;

L is a ligand, S(O)2, S(O), S, O, or CR7R8, where R7 and R8 are individually hydrogen or alkyl;

Z1 is a set of the form (a) or (b):

<img file="SA15151B1_D0002.tif" />

<img file="SA15151B1_D0003.tif" />

15

20

(b) (a)

where:

R9 is a hydrogen, alkyl, halo, hydroxy, amino, or haloalkyl;

R10 consists of hydrogen, alkyl, halo, hydroxy, hydroxyalkyl CD2OH-, hydroxyalkyl, alkylsulfoxide, alkylsulfonyl, amino, aminoalkyl, aminosulfonyl.

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aminosulfonyl, aminocarbonyl, carboxy, cyano, or alkoxycarbonyl;

R13 is a hydrogen, alkyl, halo, hydroxy, amino, or haloalkyl;

<p dir="rtl">5 R14 is a hydrogen, alkyl, or haloalkyl;</p>

R11 and R15 are selected from amino and aminoalkyl;

R12 and R16 are chosen from hydrogen, cyano, halo, alkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, aryl, heterocyclyl, and heteroaryl, where the alkyl,

<p dir="rtl">10 cycloalkyl, aryl, heterocyclyl and heteroaryl are optionally replaced by one to three individually selected alkyl, halo, haloalkyl, haloalkoxy, alkoxy, and cyano substitution groups;</p>

Or R11, R12, R15, and R16 are all formed with a carbon atom that is bonded to

<p dir="rtl">15 It has a ring of the form (c):</p><img file="SA15151B1_D0004.tif" />

where:

e can be 0, 1, or 2;

k can be 0, 1, or 2 provided that e + k is 1, 2, or 3;

20

q can be 0, 1, 2, or 3;

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R17 and R18 are selected separately from hydrogen, alkyl, cycloalkyl, and haloalkyl;

Each R19 is individually selected from hydrogen, alkyl, halo, haloalkoxy, alkoxy, hydroxy, 5-cyano, alkylsulfoxide, alkylsulfonyl, oxo, cycloalkyl, and cyclyl Heterogeneous optionally substituted heterocyclyl, and optionally substituted heteroaryl; or

When two R19 groups are bonded to the same carbon atom, the two R19 groups together form a 10 with the carbon atom to which they are bonded, a cycloalkylene or cyclene.

Heterocyclylene.

The D-ring is absent or present; where:

(1) When the D ring is not present, then one of Q and W is S(O, CH2, S(O)2, or NH; the other of Q and W is CH2; and

<p dir="rtl">15 (2) When the D ring is present, then Q and W are individually N or C provided that only one of Q and W is N; the D ring is a phenyl or heteroaryl ring of 5 or 6 y Which, including Q and W, contain one to three individually selected heteroatoms of O, N, and S and the D ring has optional substitution with one or two individually selected substitution groups of alkyl, cycloalkyl</p>

<p dir="rtl">20 cycloalkyl, halo, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, aminoalkyl, carboxy, and optionally substituted heterocyclyl;</p>

or a pharmaceutically acceptable salt thereof.

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In a second aspect, a compound with the formula (IA) is provided:

<img file="SA15151B1_D0005.tif" />

(IA)

where:

<p dir="rtl">5 A and E are selected individually from the bonds, S, NH, O, CH2, and 2(S(O);</p>

Z consists of hydrogen, alkyl, halo, haloalkyl, haloalkoxy, cyano, cycloalkyl, heterocyclyl, heteroaryl (where cycloalkyl, heterocyclyl, and heteroaryl are optionally formed Replace it with one

<p dir="rtl">10 To three halo S(O)2Rd-, S(O)Rc-, O(alk)ORb-, O(alk)yRa-,)halo, -</p>

,NRgSO2Rh- ,NReC(O)Rf

<p>- NRpRq-, S(O)2NRnRo-, C(O)NRkRm-, OC(O)NRiRj-</p>

NRrC(O)C(O)Rs or -YM (where Y is ligand, O, or SO2 and M is alkyl, haloalkyl, cycloalkyl, heterocyclic

<p dir="rtl">15 heterocyclyl, or heteroaryl in which the alkyl, haloalkyl, cycloalkyl, heterocyclyl and heteroaryl are replaced by -, O(alk)yRa</p>

<p>- NRgSO2Rh-, NReC(O)Rf-, S(O)2Rd-, S(O)Rc-, O(alk)ORb-, C(O)NRkRm-, OC(O)NRiRj</p>

<p dir="rtl">20 -NRpRq-, S(O)2NRnRo, or -NRrC(O)C(O)Rs, cycloalkyl, cyclyl</p>

Heterocyclyl and heteroaryl are also optionally replaced with 1 to 3 halo(s; where each y is 0 or 1, each alk is a

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Alkylene, and each Rh, Rf, Rd, Rc, and Rs individually are an alkyl, cycloalkyl, cycloalkyl, cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, aryl Optional replacement

<p dir="rtl">5 substituted aryl, an optionally substituted aralkyl, an optionally substituted heteroaryl, or an optionally substituted heteroaralkyl; Each Rg, Re, Rb, Ra, Rr, Rq, Rp, Ro, Rn, Rm, Rk, Rj, Ri, and Rs are individually hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, 10-hydroxyalkyl. , alkoxyalkyl, aminoalkyl, heterocyclic optionally substituted heterocyclyl, an optionally substituted heterocyclyl alkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted heteroaryl, or a heteroaryl 15 optionally substituted heteroaralkyl; Or, independently of each other, each Ri and Rk, Rj and Rn, Rm and Ro, and Rp and Rq, all together form a nitrogen atom The nitrogen atom to which they are attached is a heterocyclic cyclase with an optional substitution</p>

;optionally substituted heterocyclyl

R3, R2, R1, and R4 are selected individually from hydrogen, alkyl, cycloalkyl, 20 cycloalkyl, halo, haloalkyl, haloalkoxy, alkoxy.

alkoxy, cyano, hydroxy, hydroxylalkyl, amino, and aminoalkyl;

Or one of R1 and R2, and R3 and R4, when attached to the same carbon atom, fuse to form an oxo, an alkyldieenyl, or a cycloalkylene from 3 to 6.

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10

dha, or an optionally substituted heterocyclylene from 4 to 6 dha;

R5 and R6 are individually selected from hydrogen, alkyl, cycloalkyl, halo, haloalkyl, haloalkoxy, alkoxy, hydroxy, cyano, hydroxylalkyl, amino, and aminoalkyl, or where one of R5 and R6 It is a heterocyclic with an optionally substituted heterocyclyl and the other of R5 and R6 is chosen from hydrogen, alkyl, cycloalkyl, halo, haloalkyl, haloalkoxy, alkoxy, hydroxy, cyano, hydroxylalkyl, amino, and aminoalkyl;

L is a ligand, S(O)2, S(O), S, O, or CR7R8, where R7 and R8 are individually hydrogen or alkyl;

Z1 is a set of the form (a) or (b):

<img file="SA15151B1_D0006.tif" />

<img file="SA15151B1_D0007.tif" />

(a)(b)

15

where:

R9 is a hydrogen, alkyl, halo, hydroxy, amino, or haloalkyl;

20

R10 consists of hydrogen, alkyl, halo, hydroxy, hydroxyalkyl CD2OH-, hydroxyalkyl, alkylsulfoxide, alkylsulfonyl, amino, aminoalkyl, aminosulfonyl.

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aminosulfonyl, aminocarbonyl, carboxy, cyano, or alkoxycarbonyl;

R13 is a hydrogen, alkyl, halo, hydroxy, amino, or haloalkyl;

<p dir="rtl">5 R14 is a hydrogen, alkyl, or haloalkyl;</p>

R11 and R15 are selected from amino and aminoalkyl;

R12 and R16 are chosen from hydrogen, cyano, halo, alkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, aryl, heterocyclyl, and heteroaryl, where the alkyl,

<p dir="rtl">10 cycloalkyl, aryl, heterocyclyl and heteroaryl are optionally replaced by one to three individually selected alkyl, halo, haloalkyl, haloalkoxy, alkoxy, and cyano substitution groups;</p>

Or R11, R12, R15, and R16 are all formed with a carbon atom that is bonded to

<p dir="rtl">15 It has a ring of the form (c):</p><img file="SA15151B1_D0008.tif" />

where:

e can be 0, 1, or 2;

k can be 0, 1, or 2 provided that e + k is 1, 2, or 3;

20 q can be 0, 1, 2, or 3;

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R17 and R18 are selected separately from hydrogen, alkyl, cycloalkyl and haloalkyl.

Each R19 is individually selected from hydrogen, alkyl, halo, haloalkyl, haloalkoxy, alkoxy, hydroxy, 5-cyano, alkylsulfoxide, alkylsulfonyl, oxo, cycloalkyl, and heterocyclic cyclyl. optionally substituted heterocyclyl, optionally substituted heteroaryl; or

When two R19 groups are bonded to the same carbon atom, the two R19 groups together form a 10 with the carbon atom to which they are attached to a cycloalkylene or heterocyclylene.

The D-ring is absent or present; where:

(1) When the D ring is not present, then one of Q and W is S(O, CH2, S(O)2, or NH; the other of Q and W is CH2; and

<p dir="rtl">15 (2) When the D ring is present, then Q and W are individually N or C provided that only one of Q and W is N; the D ring is a phenyl or heteroaryl ring of 5 or 6 y Which, including Q and W, contain one to three individually selected heteroatoms of O, N, and S and the D ring has optional substitution with one or two individually selected substitution groups of alkyl, cycloalkyl</p>

<p dir="rtl">20 cycloalkyl, halo, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, aminoalkyl, carboxy, and optionally substituted heterocyclyl;</p>

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or a pharmaceutically acceptable salt thereof; Provided that when the compound has formula (I), or is a pharmaceutically acceptable salt

From it, it is a compound with the formula

Or acceptable salt

Pharmaceutical form, where R9 is a hydrogen, R10 is a discordance group

hydrogen, amino, and aminoalkyl, and R11, L, and R12 are formed

<p dir="rtl">5 As defined in formula (I), then:</p>

<p dir="rtl">(I) When four of R5, R4, R3, R2, R1, and R6 are hydrogen and the remaining two of R5, R4, R3, R2, R1, and R6 are individually selected from hydrogen, alkyl, and cycloalkyl. , amino, halo, haloalkyl, alkoxy, haloalkoxy, hydroxy,</p>

<p dir="rtl">10 hydroxyalkyl, cyano, and aminoalkyl; Then Z is a group other than hydrogen, alkyl, halo, haloalkyl, haloalkoxy, cyano, ORa- (where Ra is hydrogen or alkyl), -O-, OC(O)NH2-tetrahydrofuran-3. -yl, -O-oxetan-3-yl, cyano, p-aryzol-1-yl,</p>

,CH2OCH3- 15

<p dir="rtl">Cyclopropyl -OCH2-OCH2OCH3, -O-CH2CH2OCH3, and -SO2CH3,</p>

(2) When R5 and R6 are hydrogen and two of R3, R2, R1, and R4 are

hydrogen, and one of a) R1 and R2 and b) R3 and R4 is hydrogen

hydrogen and the other from a) R1 and R2, and b) R3 and R4 are attached to the carbon atom

20 atom itself and are combined to form alkylidene, cycloalkylene 3 to 6

One or 4 to 6 heterocyclylenes, so Z is a non-hydrogen group, alkyl, halo, haloalkyl, haloalkoxy.

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haloalkoxy, cyano, cycloalkyl, ORa- cycloalkyl (where Ra is a hydrogen or alkyl),

<p dir="rtl">-NH2, and -YM (where Y is a ligand and M is an alkyl replaced by -ORa or -NRpRq, where each Ra is a hydrogen or an alkyl, and Rp and Rq</p>

<p dir="rtl">5 They are each individually hydrogen, alkyl, hydroxyalkyl, or alkoxyalkyl, or Rp and Rq, which together, along with the nitrogen atom to which they are attached, form an optionally substituted heterocyclyl (and</p>

(3) When Z is hydrogen, one of a) R1 and R2, and b) R3 and R4 is

<p dir="rtl">10 They are attached to the same carbon atom and are combined to form 3 to 6 cycloalkylene or 4 to 6 heterocyclylene, and three of the residues of R5, R4, R3, R2, R1, and R6 form hydrogen, from Then the remaining one of R5, R4, R3, R2, R1, and R6 is not hydrogen, alkyl, cycloalkyl, halo, haloalkyl, haloalkyl.</p>

<p dir="rtl">15 Cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, aminoalkyl, or amino.</p>

In a third aspect, a compound with the formula (IB:) is provided

<img file="SA15151B1_D0009.tif" />

(IB)

20 where:

A and E are selected separately from the bonds, S, NH, O, CH2, and 2(S(O);

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Z is a hydrogen, alkyl, haloalkyl, cyano, cycloalkyl, heterocyclyl, heteroaryl (where the cycloalkyl, heterocyclyl, and heteroaryl are optionally replaced by one to three halo halo(,

<p>- NReC(O)Rf-, S(O)2Rd-, S(O)Rc-, O(alk)ORb-, O(alk)yRa- 5</p>

,OC(O)NRiRj- ,NRgSO2Rh

NRrC(O)C(O)Rs-, NRpRq-, S(O)2NRnRo-, C(O)NRkRm- or -YM (where Y is a ligand, O, or SO2 and M is an alkyl, haloalkyl, haloalkyl cycloalkyl, heterocyclyl, or heteroaryl

<p dir="rtl">10 heteroaryl where the alkyl, haloalkyl, cycloalkyl, heterocyclyl and heteroaryl are replaced by -O(alk)yRa,</p>

<p>- NRgSO2Rh-, NReC(O)Rf-, S(O)2Rd-, S(O)Rc-, O(alk)ORb-, C(O)NRkRm-, OC(O)NRiRj</p>

<p dir="rtl">-NRpRq-, S(O)2NRnRo, or -NRrC(O)C(O)Rs, cycloalkyl, cyclyl</p>

<p dir="rtl">15 Heterocyclyl and heteroaryl are also optionally replaced with 1 to 3 halo (where each y is 0 or 1, each alk is an alkylene, and each Rh, Rf, Rd, Rc, and Rs are each unit is an alkyl, cycloalkyl, cycloalkyl, cycloalkylalkyl, optionally substituted heterocyclyl, substituted heterocyclyl</p>

<p dir="rtl">20 optionally substituted heterocyclylalkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted heteroaryl, or an optionally substituted heteroaryl; And each Rg, Re, Rb, Ra, Rr, Rq, Rp, Ro, Rn, Rm, Rk, Rj, Ri, and Rs are individually considered hydrogen.</p>

<p dir="rtl">25 hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, non-cyclyl</p>

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an optionally substituted heterocyclyl, an optionally substituted heterocyclyl alkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted heteroaryl, or an optionally substituted heteroaryl.

<p dir="rtl">5 optionally substituted heteroaralkyl; Or, independently of each other, each Ri and Rk, Rj and Rn, Rm and Ro, and Rp and Rq, together with the nitrogen atom to which they are attached form a heterocyclic cyclyl with an optional substitution</p>

;optionally substituted heterocyclyl

R3, R2, R1, and R4 are selected individually from hydrogen, alkyl, and cycloalkyl.

<p dir="rtl">10 cycloalkyl, halo, haloalkyl, haloalkoxy, alkoxy, cyano, hydroxy, hydroxylalkyl, amino, and aminoalkyl;</p>

Or one of R1, R2, R3, and R4, when attached to the same carbon atom, fuses to form an oxo, an alkyldieenyl, or a cycloalkylene from 3 to 6.

<p dir="rtl">15 dha, or an optionally substituted heterocyclylene from 4 to 6 dha;</p>

R5 and R6 are individually selected from hydrogen, alkyl, cycloalkyl, halo, haloalkyl, haloalkoxy, alkoxy, hydroxy, cyano, hydroxylalkyl, amino, and 20-aminoalkyl, or where one of R5 R6 is a heterocyclic cyclase

optionally substituted heterocyclyl and the other R5 and R6 are chosen from hydrogen, alkyl, cycloalkyl, halo, haloalkyl, haloalkoxy, alkoxy, hydroxy, cyano, hydroxylalkyl, amino, and aminoalkyl;

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L is a ligand, S(O)2, S(O), S, O, or CR7R8, where R7 and R8 are individually hydrogen or alkyl;

Z1 is a set of the form (a) or (b):

or

(a)(b) 5

where:

<p dir="rtl">R9 is a hydrogen, alkyl, halo, hydroxy, amino, or haloalkyl;</p>

R10 consists of hydrogen, alkyl, halo, hydroxy, hydroxyalkyl 10 CD2OH-, hydroxyalkyl, alkylsulfoxide, alkylsulfonyl, amino, aminoalkyl, aminosulfonyl, aminocarbonyl, carboxy, cyano. , or alkoxycarbonyl

;alkoxycarbonyl

R13 is a hydrogen, alkyl, halo, hydroxy, amino, 15 or haloalkyl;

R14 is a hydrogen, alkyl, or haloalkyl;

R11 and R15 are selected from amino and aminoalkyl;

R12 and R16 are chosen from hydrogen, cyano, halo, alkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, 20 aryl, heterocyclyl, and heteroaryl, where the alkyl,

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cycloalkyl, aryl, heterocyclyl and heteroaryl are optionally replaced by one to three individually selected alkyl, halo, haloalkyl, haloalkoxy, alkoxy, and cyano substitution groups;

5 Or R11, R12, R15, and R16, together with the carbon atom to which they are connected, form a ring with the formula (c):

<img file="SA15151B1_D0010.tif" />

where:

e can be 0, 1, or 2;

<p dir="rtl">10 k can be 0, 1, or 2 provided that e + k is 1, 2, or 3;</p>

q can be 0, 1, 2, or 3;

R17 and R18 are selected separately from hydrogen, alkyl, cycloalkyl and haloalkyl.

Each R19 is individually selected from hydrogen, alkyl, halo, and haloalkyl.

<p dir="rtl">15 haloalkyl, haloalkoxy, alkoxy, hydroxy, cyano, alkyl</p>

alkylsulfoxide, alkylsulfonyl, oxo, cycloalkyl, optionally substituted heterocyclyl, and optionally substituted heteroaryl; or

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When two R19 groups are bonded to the same carbon atom, the two R19 groups together with the carbon atom to which they are attached form a cycloalkylene or heterocyclylene.

The D-ring is absent or present; where:

<p dir="rtl">5 (1) When the D ring is not present, then one of Q and W is S(O, CH2, S(O)2, or NH; the other of Q and W is CH2; and</p>

(2) When the D ring is present, then Q and W are individually N or C provided that only one of Q and W is N; the D ring is a phenyl or heteroaryl ring of 5 or 6. t which, including Q and W, contains one to

<p dir="rtl">10 Three individually selected heteroatoms of the O, N, and S ring and the D ring are optionally replaced by one or two individually selected substitution groups of alkyl, cycloalkyl, halo, haloalkyl, alkoxy, haloalkoxy, Hydroxy, hydroxyalkyl, cyano, amino, aminoalkyl, carboxy, and optionally substituted heterocyclic</p>

;optionally substituted heterocyclyl 15

or a pharmaceutically acceptable salt thereof; Provided that when the compound has formula (I), or is a pharmaceutically acceptable salt

From it, it is a compound with the formula

Or acceptable salt

Pharmaceutical form, where R9 is a hydrogen, R10 is a discordance group

hydrogen, amino, and aminoalkyl, and R11, L, and R12 are formed

20 As defined in the formula (IB); Then

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(I) When four of R5, R4, R3, R2, R1, and R6 are hydrogen and the remaining two of R5, R4, R3, R2, R1, and R6 are individually selected from hydrogen, alkyl, and cycloalkyl, Halo, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, and aminoalkyl hence Z is an odds group

hydrogen, halo, alkyl, haloalkyl, cyano, cycloalkyl, heterocyclyl, heteroaryl (where cycloalkyl, heterocyclyl, and heteroaryl are optionally replaced by one to three halo ORa). -,)halo, -

<p>- OC(O)NRiRj-, NRgSO2Rh-, NReC(O)Rf-, S(O)2Rd-, S(O)Rc 10, C(O)NRkRm</p>

NRrC(O)C(O)Rs-, NRpRq-, S(O)2NRnRo- (where Rh, Rf, Rd, Rc, and Rs are each individually an alkyl, cycloalkyl, cycloalkyl alkyl, cycloalkylalkyl, a heterogeneous cyclyl with Optionally substituted heterocyclyl, cyclyl

<p dir="rtl">15 an optionally substituted heterocyclylalkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted heteroaryl, or an optionally substituted heteroaryl; And, Ra Rq, Rp, Ro, Rn, Rm, Rk, Rj, Ri, Rg, Re, and Rr are each individually a</p>

<p dir="rtl">20 hydrogen, alkyl, cycloalkylalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, a optionally substituted aralkyl,</p>

<p dir="rtl">25 an optionally substituted heteroaryl, or an optionally substituted heteroaralkyl; Or, independently of</p>

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Each other, Ri and Rk, Rj and Rn, Rm and Ro, and Rp and Rq, together, along with the nitrogen atom to which they are attached, form a heterocyclic cyclyl with an optional substitution.

O is a ligand or Y (where (a) Y-M and optionally substituted heterocyclyl)

M is an alkyl substituted with -ORa or -NRpRq, where Ra is

<p dir="rtl">5 The hydrogen, alkyl, Rp, and Rq are individually hydrogen, alkyl, hydroxyalkyl, or alkoxyalkyl, or Rp and Rq. Together, the nitrogen atom to which they are bonded is a heterocyclic</p>

SO2 is optionally substituted heterocyclyl

M is a cycloalkyl (substituted with -ORa), a heteroaryl aryl

<p dir="rtl">10 the heteroaryl or heterocyclyl, wherein the heteroaryl or heterocyclyl is each individually replaced by -ORa, -S(O)2Rd, or -NRpRq; Where Ra is a hydrogen or alkyl, Rd is an alkyl, and Rp and Rq are individually hydrogen or alkyl, and the cycloalkyl can also optionally be replaced by one of the halo and non-cyclyl.</p>

<p dir="rtl">15 The heterocyclyl and heteroaryl aryls are also optionally replaced with 1 or 2 halo(s);</p>

(2) When R5 and R6 are each hydrogen, two of R3, R2, R1, and R4 are each hydrogen, and one of a) R1 and R2, and b) R3 and R4 are hydrogen, and the other of a) R1, R2, and b) R3 and R4 are attached to a carbon atom

<p dir="rtl">20 carbon atom itself and are combined together to form an alkyldine, a 3-6 cycloalkylene or a 4-6 heterocyclylene, so Z is a non-hydrogen, alkyl, halo, haloalkyl, cyano, cycloalkyl group. cycloalkyl, ORa (where Ra is a hydrogen or alkyl), -NH2, and -YM (where Y is a ligand and M is an alkyl).</p>

<p dir="rtl">25 Replace with -ORa or</p>

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<p dir="rtl">-NRpRq, where each Ra is a hydrogen or alkyl, and Rp and Rq are individually hydrogen, alkyl, hydroxyalkyl, or alkoxyalkyl, or Rp and Rq, all of which together form a nitrogen atom to which they are bonded as a heterocyclic cyclase. optionally substituted</p>

<p dir="rtl">5 heterocyclyl(; f</p>

(3) When Z is a hydrogen, one of a) R1 and R2, and b) R3 and R4 are attached to the same carbon atom and combined to form a 3- to 6-atomic cycloalkylene or a 4 to 6-atomic non-cycline. homogeneous

heterocyclylene and three of the residues of R5, R4, R3, R2, R1, and R6 form hydrogen.

<p dir="rtl">10 hydrogen, then the remaining one from R5, R4, R3, R2, R1, and R6 is not hydrogen, alkyl, halo, haloalkyl, cyano, cycloalkyl, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl. hydroxyalkyl, aminoalkyl, or amino.</p>

On side 4, a compound with the formula (IC) is provided:

15

(IC)

where:

A and E are selected individually from the bonds, S, NH, O, CH2, and 2(S(O);

Z consists of hydrogen, alkyl, halo, haloalkyl, haloalkyl.

20 haloalkoxy, cyano, cycloalkyl, heterocyclyl, heteroaryl (where cycloalkyl, non-cyclyl

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The heterocyclyl and heteroaryl aryls are optionally replaced by one to three halo S(O)2Rd-, S(O)Rc-, O(alk)ORb-, O(alk)yRa-,)halo, -

,NRgSO2Rh- ,NReC(O)Rf

<p>- NRpRq-, S(O)2NRnRo-, C(O)NRkRm-, OC(O)NRiRj-</p>

<p dir="rtl">5 NRrC(O)C(O)Rs or -YM (where Y is a ligand, O, or SO2 and M is an alkyl, haloalkyl, cycloalkyl, heterocyclyl, or heteroaryl in which an alkyl is substituted , haloalkyl, cycloalkyl, heterocyclyl and heteroaryl with -, O(alk)yRa</p>

<p>- NRgSO2Rh-, NReC(O)Rf-, S(O)2Rd-, S(O)Rc-, O(alk)ORb- 10</p>

,C(O)NRkRm- ,OC(O)NRiRj

<p dir="rtl">-NRpRq-, S(O)2NRnRo, or -NRrC(O)C(O)Rs, cycloalkyl, heterocyclyl, and heteroaryl aryls are also optionally replaced with 1 to 3 halo(s; where each y is 0 or 1, each alk is a</p>

<p dir="rtl">15 Alkylene, and each Rh, Rf, Rd, Rc, and Rs individually are an alkyl, cycloalkyl, cycloalkyl, cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, aryl optionally substituted aralkyl, a non-aryl</p>

<p dir="rtl">20 an optionally substituted heteroaryl, or an optionally substituted heteroaryl; Each Rg, Re, Rb, Ra, Rr, Rq, Rp, Ro, Rn, Rm, Rk, Rj, Ri, and Rs are individually hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, non-cyclyl</p>

<p dir="rtl">25 optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, aryl substituted</p>

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optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted heteroaryl, or an optionally substituted heteroaralkyl; Or, independently of each other, each Ri and Rk, Rj and Rn, Rm and Ro, and Rp and Rq, all together form an atom

<p dir="rtl">5 The nitrogen atom to which they are attached is a heterocyclic cyclase with an optional substitution</p>

;optionally substituted heterocyclyl

R3, R2, R1, and R4 are individually selected from hydrogen, alkyl, cycloalkyl, halo, haloalkyl, haloalkoxy, alkoxy, cyano, hydroxy, hydroxylalkyl, amino.

<p dir="rtl">10 amino, aminoalkyl;</p>

Or one of R1, R2, R3, and R4, when attached to the same carbon atom, fuse to form an oxo, an alkyldieenyl, a cycloalkylene from 3 to 6 ether, or an optionally substituted heterocyclylene from 4 to 6 ether ;

<p dir="rtl">15 R5 and R6 are individually selected from hydrogen, alkyl, cycloalkyl, halo, haloalkyl, haloalkoxy, alkoxy, hydroxy, cyano, hydroxylalkyl, amino, and aminoalkyl, or where one of R5 R6 is a heterocyclyl with an optionally substituted heterocyclyl and the other is chosen.</p>

<p dir="rtl">20 of hydrogen, alkyl, cycloalkyl, halo, haloalkyl, haloalkoxy, alkoxy, hydroxy, cyano, hydroxylalkyl, amino, and aminoalkyl;</p>

L is a ligand, S(O)2, S(O), S, O, or CR7R8, where R7 and R8 are individually hydrogen or alkyl;

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Z1 is a set of the form (a) or (b):

<img file="SA15151B1_D0011.tif" />

<img file="SA15151B1_D0012.tif" />

(a)(b)

where:

<p dir="rtl">5 R9 is a hydrogen, alkyl, halo, hydroxy, amino, or haloalkyl;</p>

R10 consists of hydrogen, alkyl, halo, hydroxy, hydroxy, CD2OH-, hydroxyalkyl, alkylsulfoxide, alkylsulfonyl, amino, aminoalkyl, aminosulfonyl.

<p dir="rtl">10 aminosulfonyl, aminocarbonyl, carboxy, cyano, or</p>

alkoxycarbonyl;

R13 is a hydrogen, alkyl, halo, hydroxy, amino, or haloalkyl;

R14 is a hydrogen, alkyl, or haloalkyl;

<p dir="rtl">15 R11 and R15 are selected from amino and aminoalkyl;</p>

R12 and R16 are chosen from hydrogen, cyano, halo, alkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, aryl, heterocyclyl, and heteroaryl, where the alkyl, cycloalkyl, aryl, and heteroaryl are Heterocyclyl and aryl heterocyclic

<p dir="rtl">20 heteroaryl is optionally replaced by one to three of the selected substitution groups each</p>

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Separately from alkyl, halo, haloalkyl, haloalkoxy, alkoxy, and cyano;

Or R11, R12, R15, and R16, together with the carbon atom to which they are connected, form a ring with the formula (c):

<img file="SA15151B1_D0013.tif" />

5

where:

e can be 0, 1, or 2;

k can be 0, 1, or 2 provided that e + k is 1, 2, or 3;

q can be 0, 1, 2, or 3;

<p dir="rtl">10 R17 and R18 are selected individually from hydrogen, alkyl, and cycloalkyl</p>

cycloalkyl, haloalkyl;

Each R19 is individually selected from hydrogen, alkyl, halo, haloalkyl, haloalkoxy, alkoxy, hydroxy, cyano, alkylsulfoxide, alkylsulfonyl, oxo.

<p dir="rtl">15 cycloalkyl, optionally substituted heterocyclyl, and optionally substituted heteroaryl; or</p>

When two R19 groups are bonded to the same carbon atom, the two R19 groups together with the carbon atom to which they are attached form a cycloalkylene or cyclene.

<p dir="rtl">20 Heterocyclylene.</p>

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The D-ring is absent or present; where:

(1) When the D ring does not exist, then one of the Q and W is S, O, CH2,

(S(O)2, S(O, or NH; the other of Q and W is CH2; and

(2) When the ring D is present, then Q and W are individually N or C provided that

<p dir="rtl">5 Only one of Q and W is N; The D ring is a phenyl or heteroaryl ring with 5 or 6 strands.</p>

Which, including Q and W, contain one to three individually selected heteroatoms of O, N, and S and the D ring has optional substitution with one or two individually selected substitution groups of alkyl, cycloalkyl, or halo , haloalkyl

<p dir="rtl">10 haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, aminoalkyl, carboxy, and optionally substituted heterocyclic</p>

;heterocyclyl

or a pharmaceutically acceptable salt thereof; Provided that the compound with the formula (IC) is not considered a compound of

<p dir="rtl">15 Any of the forms 37 to 42 and 45 to 63 disclosed herein below and the forms included therein, or a pharmaceutically acceptable salt thereof.</p>

In a fifth aspect, the present disclosure relates to a pharmaceutical composition comprising a compound having the formula (I),

(IB), (IA), or (IC) (or any of its forms described in the present document), or one of its pharmaceutically acceptable salts; and a pharmaceutically acceptable excipient.

<p dir="rtl">20 In a sixth aspect, a method is provided for treating a disease that can be cured by inhibiting the homologous enzyme</p>

In a patient (SHP2) SRC HOMOLOGY-2 PHOSPHATASE SRC phosphatase -2

Wherein the method includes administering to a patient, preferably a patient in need of such treatment, a therapeutically effective quantity of a compound having the formula (IB), (IA), (I), or (IC) (or any of the forms thereof described in the present document), or It involves giving the patient, preferably the patient receiving that treatment, a formulation

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A pharmaceutical drug comprising a compound having the formula (IB), (IA), (I), or (IC) (or any of its embodiments described in the present document), and a pharmaceutically acceptable excipient. In one embodiment, the disease is cancer. In another embodiment, The disease is cancer, as it is selected from lung cancer, stomach, liver, colon, kidney, breast, pancreatitis, and juvenile myeloid leukemia.

<p dir="rtl">5 myelomonocytic leukemias, neuroblastoma, melanoma, and acute myeloid leukemia. In one embodiment, the disease is selected from Noonan Syndrome and Leopard Syndrome.</p>

In a seventh aspect, a compound having the formula (IB), (IA), (I), or (IC) (or any of the forms thereof described herein) or a pharmaceutically acceptable salt thereof for use as a drug is provided.

<p dir="rtl">10 In an eighth aspect, a compound having the formula (IB), (IA), (I), or (IC) or a pharmaceutically acceptable salt thereof (and any of the embodiments thereof disclosed herein) is provided for use in the manufacture of a drug for the treatment of a disease in a patient who This treatment is needed where SRC HOMOLOGY-2 PHOSPHATASE activity contributes to the occurrence and/or symptoms of the disease.</p>

<p dir="rtl">15 In a ninth aspect, a method is provided for inhibiting the SRC phosphatase enzyme (SRC2) HOMOLOGY-2 PHOSPHATASE, where the method includes contacting SHP2 with a compound having the formula (IB), (IA), (I), or (IC) or any of its embodiments described in the present document) or one of its pharmaceutically acceptable salts; or contact of SHP2 with a pharmaceutical composition containing the compound of the present disclosure (or any of its embodiments described in the present document) or one of its pharmaceutically acceptable salts, and an excipient</p>

<p dir="rtl">20 Pharmaceutical acceptable.</p>

In a tenth aspect, an intermediate compound with the formula (V) is provided:

<img file="SA15151B1_D0014.tif" />

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where:

Q is a halo or SH;

A and E are selected individually from the bonds, S, NH, O, CH2, and 2(S(O);

Z consists of hydrogen, alkyl, halo, haloalkyl, haloalkyl.

<p dir="rtl">5 haloalkoxy, cyano, cycloalkyl, heterocyclyl, heteroaryl (where cycloalkyl, heterocyclyl, and heteroaryl are optionally replaced by one to three halo S(O)2Rd-S,) O)Rc-, O(alk)ORb-, O(alk)yRa-,)halo, -</p>

,NRgSO2Rh- ,NReC(O)Rf

<p>- NRpRq-, S(O)2NRnRo-, C(O)NRkRm-, OC(O)NRiRj- 10</p>

NRrC(O)C(O)Rs or -YM (where Y is a ligand, O, or SO2 and M is an alkyl, haloalkyl, cycloalkyl, heterocyclyl, or heteroaryl in which an alkyl is substituted , haloalkyl, cycloalkyl, heterocyclyl and heteroaryl

<p dir="rtl">15 heteroaryl with -,O(alk)yRa</p>

<p>- NRgSO2Rh-, NReC(O)Rf-, S(O)2Rd-, S(O)Rc-, O(alk)yORb-, C(O)NRkRm-, OC(O)NRiRj</p>

<p dir="rtl">-NRpRq-, S(O)2NRnRo, or -NRrC(O)C(O)Rs - cycloalkyl, heterocyclyl, and heteroaryl are also substituted.</p>

<p dir="rtl">20 Optional using 1 to 3 halo (where each y is 0 or 1, each alk is an alkylene, and each Rh, Rf, Rd, Rc, and Rs are individually alkyl, cycloalkyl, cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl</p>

<p dir="rtl">25 substituted aryl, an optionally substituted aralkyl, a non-aryl</p>

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an optionally substituted heteroaryl, or an optionally substituted heteroaryl; Each Rg, Re, Rb, Ra, Rr, Rq, Rp, Ro, Rn, Rm, Rk, Rj, Ri, and R s are individually hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, hydroxy.

<p dir="rtl">5 hydroxyalkyl, alkoxyalkyl, aminoalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted aralkyl, non-aryl Optionally substituted heteroaryl, or a heteroaryl</p>

<p dir="rtl">10 optionally substituted heteroaralkyl; Or, independently of each other, each Ri and Rk, Rj and Rn, Rm and Ro, and Rp and Rq, together with the nitrogen atom to which they are attached form a heterocyclic cyclyl with an optional substitution</p>

;optionally substituted heterocyclyl

R3, R2, R1, and R4 are selected individually from hydrogen, alkyl, and cycloalkyl.

<p dir="rtl">15 cycloalkyl, halo, haloalkyl, haloalkoxy, alkoxy, cyano, hydroxy, hydroxylalkyl, amino, and aminoalkyl;</p>

Or one of R1 and R2, and R3 and R4, when attached to the same carbon atom, fuse to form an oxo, an alkyldieenyl, or a cycloalkylene from 3 to 6.

<p dir="rtl">20 dha, or an optionally substituted heterocyclylene from 4 to 6 dha;</p>

R5 and R6 are individually selected from hydrogen, alkyl, cycloalkyl, halo, haloalkyl, haloalkoxy, alkoxy, hydroxy, cyano, hydroxylalkyl, amino

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amino, aminoalkyl, or where one of R5 and R6 is an optionally substituted heterocyclyl and the other of R5

R6 is chosen from hydrogen, alkyl, cycloalkyl, halo, haloalkyl, haloalkoxy, alkoxy, hydroxy,

<p dir="rtl">5 cyano, hydroxylalkyl, amino, and aminoalkyl;</p>

Or acceptable salt.

In a first form of the tenth aspect, Q is a halo. In a sub-form of the first model, Q is a chloro, bromo, or iodo.

In a second form of the tenth aspect, Q is a -+SM where +M is a metal ion. in

<p dir="rtl">10 A subform of the second form, M+ is either sodium or potassium.</p>

In the third model of any of the aspects of the tenth aspect, the first and second models and sub-models

contained therein,

<img file="SA15151B1_D0015.tif" />

He is

<img file="SA15151B1_D0016.tif" />

In Embodiment Four of any one of the .

Detailed description:

Certain structures presented here are drawn with one or more floating substitution groups. Unless otherwise stated or made clear from the context, substitution group(s) can exist on any atom of the ring to which it is attached, wherever chemically possible and valence rules allow. For example

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Example, in structure:

<img file="SA15151B1_D0017.tif" />

Replacement sets R4, R3, and Z can solve

Replace any hydrogen on the 6-atomic ring containing group A, including one or both hydrogen atoms, in group CH2 when A is

CH2, including NH hydrogen when A is NH. In another example, in

5 The loop has the form (c):

<img file="SA15151B1_D0018.tif" />

When the D ring is not present and the Q and/or W are CH2, one or both hydrogen atoms are optionally replaced by one or two R19 groups.

Definitions:

<p dir="rtl">10 Unless otherwise stated, the following terms are defined in the following description and protections to achieve the purposes of the present application and have the following meanings:</p>

“Alkyl” refers to a straight monovalent saturated hydrocarbon radical with one to six carbons or a monovalent saturated branched hydrocarbon radical with three to six carbons, such as methyl, ethyl, 2-propyl, or 2-propyl. , butyl, pentyl 15, and the like. A person of skill in the art will recognize that the term “alkyl” may include:

“alkylene groups.”

“Alkylene” refers to a linear saturated divalent hydrocarbon radical with one to six carbons or a branched divalent hydrocarbon radical with one to six carbons unless otherwise noted, e.g., methylene

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methylene,ethylene,propylene-1,propylene-methylpropylene-1

2 , methylpropylene, 2-methylpropylene, butylene, butylene pentylene, and the like.

“Alkenyl” refers to a straight monovalent hydrocarbon radical with two to six carbon atoms, or a radical

<p dir="rtl">5 A monovalent branched hydrocarbon with three to six carbon atoms containing double bonds, e.g., propyl, butenyl, and the like.</p>

“Alkyl dienyl” is an alkenyl, as previously defined, that is connected via the divalent terminal carbon. For example, in the compound below:

The alkyl dienyl group is enclosed in the box indicated by the arrow.

<p dir="rtl">10 “Alkyl thio” refers to the -SR moiety where the R is an alkyl as previously defined, e.g., methyl</p>

thio, ethylthio, and the like.

“Alkylsulfonyl” refers to the SO2R moiety – where R is an alkyl as previously defined, e.g., methylsulfonyl, ethylsulfonyl, and the like.

<p dir="rtl">“Alkyl sulfoxide” refers to the SOR moiety – where R is an alkyl as previously defined, e.g., 15-methyl sulfoxide, ethyl sulfoxide, and the like.</p>

“Amino” refers to NH2–.

“Alkyl-amino” refers to the NHR moiety where the R is an alkyl as previously defined, e.g., amino-methyl, amino-ethyl, propyl, or 2-propyl, and the like.

“Amino acyl” refers to the NHC(O)R moiety – where R is an alkyl as previously defined,

<p dir="rtl">20 Such as, acetyl amino, propionoyl amino, and the like.</p>

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“Aminoalkyl” refers to a straight monovalent hydrocarbon radical with one to six carbons or a monovalent branched hydrocarbon radical with three to six carbons substituted by “NR'R” - where 'R' and 'R' stand alone. of a hydrogen, alkyl, haloalkyl, hydroxyalkyl, or alkoxyalkyl, or the 'R' and 'R5' formation with the nitrogen atom attached to it as a heterocyclyl having an optional substitution, each as defined in the present document, such as , aminomethyl, aminoethyl, Methyl amino methyl, morpholinyl ethyl, p-arzine-1-yl ethyl, and the like.

“Alkoxy” refers to the -OR radical where the R is an alkyl as previously defined, e.g., methoxy, ethoxy, propoxy, or 2-propoxy, n-, iso-, or t-butoxy, and the like.

<p dir="rtl">10 “Alkoxyalkyl” refers to the straight moiety of a monovalent hydrocarbon with one to</p>

Six-carbon or monovalent branched hydrocarbon radical having three to six carbons substituted with at least one alkoxy group, such as one or two alkoxy groups, as previously defined, such as 2-methoxyethyl, 1-,2 -, or 3-methoxypropyl, 2-ethoxyethyl, and the like.

<p dir="rtl">15 “Alkoxycarbonyl” refers to the C(O)OR radical – where R is a</p>

Alkyl as previously defined, e.g., methoxycarbonyl, ethoxycarbonyl, and the like.

“Aryl” refers to an aromatic monocyclic or dicyclic hydrocarbon moiety with 6 to 10 cyclic atoms, such as phenyl or naphthyl.

“Arlkyl” refers to R-)alkylene, where R is an aryl as previously defined20, such as benzyl or phenethyl.

“Cyloalkyl” refers to a monovalent saturated monocyclic hydrocarbon moiety with three to ten carbons optionally replaced by one or two independently selected alkyl, halo, alkoxy, hydroxy, and cyano substitution groups.

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Stated otherwise. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, and the like.

“Cyloalkyl alkyl” refers to the R-)alkylene moiety where R is a cycloalkyl as previously defined, e.g., cyclopropylmethyl, cyclohexylmethyl, and the like.

<p dir="rtl">5 Unless otherwise indicated, “cycloalkylene” refers to a divalent saturated monocyclic hydrocarbon moiety having three to six carbon atoms optionally substituted by one or two independently selected alkyl, halo, or alkoxy substitution groups. , hydroxy, and cyano, each as defined in the present document. Examples include, but are not limited to, cyclopropylene, cyclobutylene, cyclopentylene, or cyclohexylene, and the like.</p>

<p dir="rtl">10 that.</p>

“Carboxy” refers to C(O)OH–.

“Dialkylamino” refers to the -'NRR moiety where R and 'R are alkyls as previously defined, e.g., dimethylamino, methylethylamino, and the like.

“Aminosulfonyl” refers to the 'SO2NRR' moiety - where R and 'R' are independently...

<p dir="rtl">15 hydrogen, alkyl, haloalkyl, hydroxyalkyl, or alkoxyalkyl, each as defined in the present document, such as, aminosulfonyl, methylaminosulfonyl, dimethylaminosulfonyl, and the like.</p>

Aminocarbonyl refers to the 'CONRR' moiety - where R and 'R' are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, or

<p dir="rtl">20 alkoxyalkyl, each as defined in the present document, such as, aminocarbonyl, aminocarbonyl, dimethylaminocarbonyl, ethyl methylaminocarbonyl, and the like.</p>

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“Aminocarboxy” refers to the 'C(O)ONRR' moiety - where R and 'R' are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, or alkoxyalkyl, each as defined in the present document, e.g. , amino carbonyl oxy, methyl amino carbonyl oxy, dimethyl amino carbonyl oxy, and the like.

<p dir="rtl">5 “Incorporated heteroaryl” refers to a dicyclic or tricyclic ring into which it is fused</p>

A heteroaryl ring with a heterocyclyl ring, where each ring is as defined herein. Examples include, but are not limited to, 7,8,9,a6-tetrahydro-H6-pyrido[3,2-b[pyrrolo]1,2-1,4[ ]d[oxazine, 7,8,9, a5,6,6-hexahydropyrrolo[1,2-1,8] [a] naphthyridine, 7,8-dihydro-H6-

10 Pyrrolo]2',1':2,3[ imidazo]4,5-b[ pyridine, H8,'H6'- spiro [oxetane-3,7'-pyrrolo]2',1':2,3[ imidazo [4,5-b]pyridine[,5,6,8,9-tetrahydropyrano[4',3':4,5]pyrrolo[2,3-b]pyridine,5,7,8,9-tet Arno[3',4':4,5]-pyrrolo[2,3-b] pyridine, H1- pyrrolo[2,3-b[ pyridine, H1- pyrrolo[3,2-b] pyridine, 5 6,7,9-tetarhydro-bi-arno[3',4':4,5]pyrrolo[3,2-b[pyridine, 7,8,9,a6-tetarhydro-H6-pyrido]3,2- b[pyrrolo]1,2-

15 1,4[[d]oxazine, (7,8,9,a6-)S-tetrahydro-H6-pyrido[3,2-b]pyrrolo[1,2-1,4[d]

Oxazine, f)7,8,9,a6-)R-tetrahydro-H6-pyrido[3,2-b[pyrrolo[1,2-1,4][d]oxazine.

“Halo” refers to fluoro, chloro, bromo, or iodo, preferably fluoro or chloro.

“Haloalkyl” refers to an alkyl radical as previously defined, which has one or more halogen atoms substituted for it, such as one to five halogen atoms, such as fluorine or chlorine, including those

<p dir="rtl">20 Which are replaced by different halogens, such as -CH2CF3-, CHF2-, CF3-, CH2Cl, -CF(CH3)2-, CF2CF3, and the like. When an alkyl has only a fluorosubstituent, it may be referred to in the present application as a fluoroalkyl.</p>

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“Haloalkoxy” refers to the OR– radical, where R is a haloalkyl as previously defined, such as -OCHF2-, OCF3, and the like. When R is a haloalkyl in which the alkyl is only substituted by a fluoro, it is referred to in the present application as a fluoroalkoxy.

“Hydroxyalkyl” refers to a straight monovalent hydrocarbon radical with one

<p dir="rtl">5 To a six-carbon or monovalent branched hydrocarbon radical having three to six carbon atoms replaced by one or two hydroxy groups, provided that if two hydroxy groups are present, they are not both on the same carbon atom. Representative examples include, but are not limited to: hydroxymethyl, 2-hydroxy-ethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl ,4</p>

<p dir="rtl">10 Hydroxybutyl, 2,3-dihydroxypropyl, 1-(hydroxymethyl)-2-hydroxyethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl and 2-(hydroxymethyl)-3-hydroxypropyl, Preferably 2-hydroxyethyl, 2,3-dihydroxypropyl, and 1-(hydroxymethyl)-2-hydroxyethyl.</p>

Heterocyclyl refers to a monovalent saturated or unsaturated ring.

<p dir="rtl">15 A monocyclic or bicyclic atom with 4 to 10 cyclic atoms, where one, two, or three of the cyclic atoms are heteroatoms chosen from O, N, and S(O)n, where n is an integer. It goes from 0 to 2, where the rest of the cyclic atoms are C. In addition, one or two of the cyclic carbon atoms in the heterocyclic ring can optionally be replaced by a CO–- group. More specifically, the term cyclic is heterogeneous</p>

<p dir="rtl">20 Heterocyclyl includes, but is not limited to, pyrrolidino, piperidino, homopipyridino, 2-oxo-pyrrolidinyl, 2-oxo-pipyridinyl, morpholino, p-arzino, t-t-arhydro-arnyl, thio-morpholino, 6, 7, 8, 9-tt-t-arhydro. -H4-pyrido[1, 2-a] pyrimidine-4-one, 6, 7-dihydropyrimido[2, 1-4, 1] [c]oxazine-4(H9)-one, and the like. When The heterocyclic ring is unsaturated and may contain one or two cyclic bonds, provided that:</p>

<p dir="rtl">25 The ring is non-aromatic. When the heterocyclic silyl group contains a nitrogen atom</p>

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At least one, herein referred to as a heterocyclic cycloamino, is a subset of the heterocyclyl group.

“Heterocyclylene” refers, unless otherwise stated, to a monocyclic or bicyclic divalent saturated or unsaturated ring with 4 to 6 cyclic atoms, where

<p dir="rtl">5 One, two, or three of the cyclic atoms are heteroatoms chosen from O, N, and S(O)n, where n is an integer ranging from 0 to 2, and the remaining cyclic atoms are For C. cyclins can be heterogeneous by optional substitution with one or two independently selected alkyl, halo, halo-alkyl, halo-alkoxy, cyano, or hydroxy substitution groups, each as defined in the present document.</p>

<p dir="rtl">10 “Heteroaryl” refers to a monovalent monocyclic or bicyclic aromatic moiety with 5 to 10 cyclic atoms, unless otherwise stated, where one or more of (in one embodiment, one, two, or three) The ring atom is a heteroatom chosen from O, N, or S, where the remaining ring atoms are carbon. Representative examples include, but are not limited to, pyrryl, thienyl, thazolyl, imidazolyl, and photoarnyl. ,indolyl,</p>

<p dir="rtl">15 Isoindolyl, oxazolyl, isoxazolyl, benzothiazole, benzoxazolyl, quinoline, isoquinoline, pyridinyl, pyridinyl, p-arzenyl, pyridazinyltriazolyl, t-arzolyl, and the like. As defined in the present document,</p>

The terms “heteroaryl” and “aryl” are interchangeably exclusive. When a heteroaryl ring contains 5 or 6 cyclic atoms, it can also be referred to in the present document as a heteroaryl aryl with 5 or 6 cyclic atoms. Art.

“Heteroaryl” refers to R-)alkylene, where R is a heteroaryl as previously defined, such as benzyl or phenethyl.

The term “oxo” as used in the present document, either alone or in combination, refers to =(O).

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When needed, the definitions in the present document may be used in conjunction with any other definition to describe a complex structural group. By convention, the successor element of any such definition is the element associated with the parent slot. For example, an alkoxyalkyl group means that the alkoxy group is attached to the parent molecule through an alkyl group.

<p dir="rtl">5 The present disclosure also includes protected derivatives of compounds of the formula (IB), (IA), (I), or (IC). For example, when the compounds of the formula (IB), (IA), (I), or (IC) contain On groups such as hydroxy, carboxy, thiol or any group containing a nitrogen atom, these groups can be protected with appropriate protecting groups. You can find</p>

TW Greene, Protective Groups in A list of suitable protection groups in

Organic Synthesis, 5th Ed., John Wiley &amp; Sons, Inc., which falls under (2014) 10

Disclosed in the present document by reference in its entirety. Protected derivatives of compounds with the formula (IB), (IA), (I), or (IC) can be prepared by methods known in the art.

The present invention also includes polymorphic and heterogeneous forms of compounds having the formula (IB), (IA), (I), or (IC). The term “prodrug” refers to a compound that is

<p dir="rtl">15 More active within the body of a living organism. Certain compounds disclosed herein may exist in prodrug form, as described in Hydrolysis in Drug and Prodrug</p>

Metabolism: Chemistry, Biochemistry, and Enzymology (Testa, Bernard Pharmacology and Mayer, Joachim M. Wiley-VHCA, Zurich, Switzerland 2003)

The primary compounds described in the present document are structurally modified forms of the compound to which they are subjected

<p dir="rtl">20 Easily undergoes chemical changes under physiological conditions to provide the active compound. Prodrugs are often useful because, in some cases, they may be easier to administer than the original compound or drug. They may, for example, be bioavailable by oral administration while the parent drug is not. A variety of prodrug derivatives are known in the art, such as those based on hydrolytic cleavage or oxidative activation of the prodrug. For example no</p>

<p dir="rtl">25 Limitation: An example of a prodrug is a compound that is administered as an ester (“prodrug”), but it is...</p>

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It is metabolically hydrolyzed to carboxylic acid, which is the active entity. Additional examples include peptidyl derivatives of the compound.

“Pharmaceutical acceptable salt” of a compound with the formula (IB), (IA), (I), or (IC) refers to a salt that is pharmaceutically acceptable and has the desired pharmacological effect of the parent compound. These salts include the following:

<p dir="rtl">5 Acid addition salts, composed of inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; Or composed of organic acids such as formic acid, acetic acid, propionic acid, hexanoic acid.</p>

<p dir="rtl">10 hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, malic acid, fumaric acid, acid tartaric acid, citric acid, benzoic acid</p>

15 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanesulfonic acid 1 ,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, acid

20 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, glucoheptonic acid, 4,4'-methylene bis acid. (3-Hydroxy-2-ene-1-carboxylic acid) (4,4'-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid)

25 3-phenylpropionic acid, trimethylacetic acid

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trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid

<p dir="rtl">5 acid, and the like; or</p>

Salts formed when an acidic proton is present in the parent compound whether it is replaced by a metal ion, such as an alkali metal ion, an alkaline earth ion, or an aluminum ion; Or it is consistent with an organic base such as ethanolamine, diethanolamine, diethanolamine, tromethamine, N-methylglucamine, and the like. It is understood that pharmaceutically accepted salts are non-toxic. Additional information can be found on

Remington's Pharmaceutical Sciences, 17th 10 suitable pharmaceutically acceptable salts in which the present document is included, ed., Mack Publishing Company, Easton, PA, 1985

For reference in its entirety.

Compounds with the formula (IB), (IA), (I), or (IC) may contain asymmetric centers. It is possible to isolate compounds with the formula (IB), (IA), (I), or (IC) containing On an improperly substituted atom

<p dir="rtl">15 Isomorphic in optically active or tracery forms. Individual enantiomers of compounds are prepared from commercially available starting materials containing K-centers or by preparing mixtures of enantiomers and then separation, such as conversion to a mixture of enantiomers followed by separation or recrystallization, chromatographic techniques, or direct separation of enantiomers. On Array chromatography columns, or by any other suitable method known in the art. All chiral forms, dimers</p>

<p dir="rtl">20 All mixtures of chiral or diastereomeric forms, and formal forms are within the scope of this disclosure, unless stereochemistry or specific isomeric forms are specified. As a person of skill in the art will realize, when a compound is referred to as an enantiomer (R), it may contain the corresponding enantiomer (S) as an impurity, and vice versa.</p>

Some compounds with the formula (IB), (IA), (I), or (IC) can exist as compounds

<p dir="rtl">25 Tray and/or geometric isomart. All possible atomic compounds and isomer t arns and cis, where</p>

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Individual forms and mixtures thereof are within the scope of this disclosure. In addition, as used in the present document, the term alkyl includes all possible isomeric forms of the alkyl group mentioned, although only a few examples are given. Moreover, when the ring groups such as aryl, heteroaryl, and heterocyclic cyclyls are substituted, they include all

<p dir="rtl">5 Topical Isomeart, although only a few examples were mentioned. In addition, all Head Art</p>

The formula compound, (IB), (IA), (I), or (IC) falls within the scope of this disclosure.

Also, compounds with the formula (IB), (IA), (I), or (IC) may contain abnormal amounts of isotopes at one or more of the atoms that make up those compounds. Abnormal amounts of isotopes can be defined as Go from the amount found in nature to the amount of 100% of the atom

<p dir="rtl">10 concerned, which differ only in the presence of one or more isotope-enriched atoms. Examples of isotopes that may be included in compounds of the present invention, such as a compound of formula (IB), (IA), (I), or (IC) (and any form thereof disclosed in the present document including specific compounds) are isotopes Hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as 32P, 18O, 17O, 15O, 15N, 13N, 14C, 13C, 11C, 3H, 2H,</p>

<p dir="rtl">15 123I, 36Cl, 18F, 35S, 33P, and 1251, respectively. Compounds may be labeled</p>

Isotopes (such as those labeled 3H and 14C) are useful in compound or substrate tissue distribution experiments. Isotopes treated with tritium (i.e., 3H) and carbon-14 (i.e., 14C) can be useful because of their ease of preparation and detectability. Furthermore, substitution with heavier isotopes Such deuterium (i.e., 2H2) may provide certain therapeutic advantages resulting from increased metabolic stability (i.e., increased half-life).

<p dir="rtl">20 (in the body of the organism or under low dose conditions). In some embodiments, in the compounds mentioned in the present document, and shown in Table 1 below, one or more of the hydrogen atoms are replaced by 2H or 3H, or one or more of the carbon atoms are replaced With carbon enriched with 13C- or 14C-carbon, positron-emitting isotopes such as 15O, 13N, 11C, and 15F are useful in positron emission tomography (PET) studies to examine off-occupancy.</p>

<p dir="rtl">25 Substrate receptors. Isotope-labeled compounds can generally be prepared following similar procedures</p>

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for those detected in the diagrams or in examples given in the present document, by replacing an isotope-labeled detector with a non-isotope-labeled detector.

“Selectively substituted aryl” refers to an aryl that is optionally substituted with one, two, or three independently selected alkyl, hydroxyl, cycloalkyl, or substituent groups.

<p dir="rtl">5 Carboxy, alkoxycarbonyl, hydroxy, alkoxy, alkyl thio, alkyl sulfonyl, amino, alkyl amino, dialkyl amino, halo, halo alkyl, halo alkoxy, and cyano.</p>

“A aryl with a selective substitution” refers to an alkylene (R-)alkylene, where R is an aryl with a selective substitution as previously defined.

<p dir="rtl">10 “Heteroaryl with an optional substitution” refers to a heteroaryl aryl</p>

Heteroaryl as previously defined has optional substitution with one, two, or three independently selected substitution groups of alkyl, alkylthio, alkylsulfonyl, hydroxyl, cycloalkyl, carboxy, alkoxycarbonyl, hydroxy, alkoxy, Halo, halo alkyl, halo alkoxy, amino, alkyl

<p dir="rtl">15 Amino, dialkyl amino, and cyano</p>

<p dir="rtl">“A heteroaryl with an optional substitution” refers to an alkylene (R-)alkylene, where R is a heteroaryl with an optional substitution as previously defined.</p>

“Heterocyclyl with optional substitution” refers to a heterocyclyl as previously defined that has optional substitution with one, two, or three groups.

<p dir="rtl">20 The substitutions are independently selected from alkyl, alkylthio, alkylsulfonyl, hydroxyl, cycloalkyl, carboxy, alkoxycarbonyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, aminoalkyl, halo, haloalkyl, Haloalkoxy and cyano.</p>

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“Heterocyclylalkyl with optional substitution” refers to an alkylene (R-)alkylene, where R is a heterocyclyl with optional substitution as previously defined.

“Pharmaceutical acceptable carrier or excipient” generally refers to a carrier or excipient useful in preparing a formulation

<p dir="rtl">5 A pharmaceutical that is generally safe, non-toxic, and not biologically or for any other reason undesirable, and includes a carrier or excipient acceptable for veterinary use as well as human pharmaceutical use. “Pharmaceutical acceptable carrier/excipient” as used in the standard and safeguards includes one or more of those excipients.</p>

The term "about", as used in the present document is intended to specify the numerical values it describes,

<p dir="rtl">10 It refers to that value as a variable within the margin of error. When there is no specified margin of error, such as a standard deviation to a mean value given in a chart or spreadsheet, the term “about” should be understood to mean the range within ±10%, preferably ±5%, of the value given and the range given .</p>

The term “disease” as used in the present document is generally intended to be synonymous with, and is...

<p dir="rtl">15 It is used interchangeably with the terms "disorder", "syndrome", and "condition" (as a medical condition), as it reflects an abnormal condition in the human or animal body or any of its parts that hinders normal performance, and is usually manifested through distinctive signs and symptoms, and causes Reducing the duration or quality of human or animal life.</p>

The term “combination therapy” means the administration of two or more therapeutic agents to treat a disease or disorder described in the present invention. This includes co-administration of these therapeutic agents

<p dir="rtl">20 In a highly simultaneous manner, such as a single capsule with a fixed ratio of active ingredients or in multiple separate capsules for each active ingredient. In addition, this administration also includes the use of each type of therapeutic agent in a sequential manner. In either case, the treatment regimen will provide beneficial effects of the drug combination in treating the conditions or disorders described in the present document.</p>

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The term "sick" is generally synonymous with "under treatment" and includes all mammals, including humans. Examples of patients include humans, livestock such as cows, goats, sheep, pigs, rabbits, and domestic animals such as dogs, cats, rabbits, and horses. It is preferable that the patient is a human being. “Treatment” or “treatment” of the disease includes:

<p dir="rtl">5 Preventing disease, i.e. preventing the appearance of clinical symptoms of disease in a mammal that may be exposed to or predisposed to disease but has not yet shown symptoms of the disease;</p>

Disease suppression, i.e. stopping or reducing the progression of the disease or its clinical symptoms; or

Alleviating the disease, i.e., causing remission of the disease or its clinical symptoms. In one embodiment, treatment or treatment means (2) or (3) above.

10 “Therapeutically effective amount” refers to the amount of a compound of formula (IB), (IA), (I), or (IC) and/or one of

Its pharmaceutically acceptable salts, which, given to a patient to cure a disease, are sufficient to effect that cure of the disease. The “therapeutically effective amount” varies depending on the compound, the disease, its severity, and the age, weight, etc., of the mammal to be treated.

The terms “prevention” and “reduction” or any forms thereof in relation to SRC HOMOLOGY-2 PHOSPHATASE 15-2 include any reduction or

Complete inhibition can be measured to achieve the desired result. For example, there may be a reduction of about, at most, or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or more, or any range within that, in SRC homolog phosphatase 2 (SHP2) activity

<p dir="rtl">20 SRC HOMOLOGY-2 PHOSPHATASE compared to the normal range.</p>

Representative compounds with formula (I) are disclosed in Table (1) below

Table 1

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<tr><td><p dir="rtl">the name</p></td><td><p dir="rtl">Structure</p></td><td><p dir="rtl">number</p><p dir="rtl">The compound</p></td></tr><tr><td><p>-4- (S4,S3)(-3)</p><p dir="rtl">Amino-3-methyl-2-oxa-8-</p><p dir="rtl">Aispyro]4,5[decane-8-yl(-6-)))S(-7,8,9,a6-tt-arhydro-H6-pyrido]3,2-b[pyrrolo]1,2-</p><p dir="rtl">1,4[]d[oxazine-4-yl(thio(p-arzine-2-yl)methanol)</p></td><td></td><td><p>1</p></td></tr><tr><td><p>-4- (S4,S3)(-3)</p><p dir="rtl">Amino-3-methyl-2-oxa-8-</p><p dir="rtl">Aazpyro]4,5[decane-8-yl(-6-)))R(-7,8,9,a6-tetarhydro-H6-pyrido]3,2-b[pyrrolo]1,2-</p><p dir="rtl">1,4[]d[oxazine-4-yl(thio(p-arzine-2-yl)methanol)</p></td><td></td><td><p>2</p></td></tr>

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<tr><td><p>-4- (S4,S3)(-3)</p><p dir="rtl">Amino-3-methyl-2-oxa-8-</p><p dir="rtl">aispyro]4,5[decane-8-yl(-6-)))S8,aS6(-8-fluoro-7,8,9,a6-tetarhydro-H6-pyrido]3,2-b[pyrrolo]1 2-1,4[]d[oxazine-4-yl(thio(p-arzine-2-yl)methanol)</p></td><td></td><td><p>3</p></td></tr><tr><td><p>-4- (S4,S3)(-3)</p><p dir="rtl">Amino-3-methyl-2-oxa-8-</p><p dir="rtl">aispyro]4,5[decane-8-yl(-6-)))R8,aS6(-8-fluoro-7,8,9,a6-tetarhydro-H6-pyrido]3,2-b[pyrrolo]1 2-1,4[]d[oxazine-4-yl(thio(p-arzine-2-yl)methanol)</p></td><td></td><td><p>4</p></td></tr>

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<tr><td><p>-4- (S4,S3)(-3)</p><p dir="rtl">Amino-3-methyl-2-oxa-8-</p><p dir="rtl">aaspyro]4,5[decane-8-yl(-6-)))S8,aS6(-8-methoxy-7,8,9,a6-tt-arhydro-H6-pyrido]3,2-b[pyrrolo]1 2-1,4[]d[oxazine-4-yl(thio(p-arzine-2-yl)methanol)</p></td><td></td><td><p>5</p></td></tr><tr><td><p>-4- (S4,S3)(-3)</p><p dir="rtl">Amino-3-methyl-2-oxa-8-</p><p dir="rtl">aaspyro]4,5[decane-8-yl(-6-)))R8,aS6(-8-methoxy-7,8,9,a6-tt-arhydro-H6-pyrido]3,2-b[pyrrolo]1 2-1,4[]d[oxazine-4-yl(thio(p-arzine-2-yl)methanol)</p></td><td></td><td><p>6</p></td></tr>

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<tr><td><p>-5((-4-)S8,aS6)</p><p dir="rtl">)(4-)S4,S3-amino-3-methyl-2-oxa-8-a azspiro[4.5[decane-8-yl(-6-)hydroxymethyl(p-arzine-2-yl(thio)-7) ,8,9,a6-tetarhydro-H6-pyrido]3,2-b[pyrrolo]1,2-1,4[]d[oxazine-8-ol]</p></td><td></td><td><p>7</p></td></tr><tr><td><p>-5((-4-)R8,aS6)</p><p dir="rtl">)(4-)S4,S3-amino-3-methyl-2-oxa-8-a azspiro[4.5[decane-8-yl(-6-)hydroxymethyl(p-arzine-2-yl(thio)-7) ,8,9,a6-tetarhydro-H6-pyrido]3,2-b[pyrrolo]1,2-1,4[]d[oxazine-8-ol]</p></td><td></td><td><p>8</p></td></tr>

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<tr><td><p>-4- (S4,S3)(-3)</p><p dir="rtl">Amino-3-methyl-2-oxa-8-</p><p dir="rtl">aazpyro]4,5[decane-8-yl(-6-)))R8,aR6(-8-methoxy-7,8,9,a6-tt-arhydro-H6-pyrido]3,2-b[pyrrolo]1 2-1,4[]d[oxazine-4-yl(thio(p-arzine-2-yl)methanol)</p></td><td></td><td><p>9</p></td></tr><tr><td><p>-4- (S4,S3)(-3)</p><p dir="rtl">Amino-3-methyl-2-oxa-8-</p><p dir="rtl">aazpyro]4,5[decane-8-yl(-6-)))S8,aR6(-8-methoxy-7,8,9,a6-tt-arhydro-H6-pyrido]3,2-b[pyrrolo]1 2-1,4[]d[oxazine-4-yl(thio(p-arzine-2-yl)methanol)</p></td><td></td><td><p>10</p></td></tr>

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<tr><td><p>-4- (S4,S3)(-3)</p><p dir="rtl">Amino-3-methyl-2-oxa-8-</p><p dir="rtl">azspiro[4.5[decane-8-yl(-6-))(S8,aS6(-)</p><p>-(S)((-8</p><p dir="rtl">Tetrahydrofuran-3-yl(oxy(-7,8,9,a6-tetrahydro-H6-pyrido]3,2-b[pyrrolo]1,2-1,4[]d[oxazine-4-yl(thio) P-arzine-2-yl(methanol).</p></td><td></td><td><p>11</p></td></tr><tr><td><p>-4- (S4,S3)(-3)</p><p dir="rtl">Amino-3-methyl-2-oxa-8-</p><p dir="rtl">azspiro[4.5[decane-8-yl(-6-))(S8,aS6(-)</p><p>-(R)((-8</p><p dir="rtl">Tetarthydrofuran-3-yl(oxy(-7,8,9,a6-tetarthydro-H6-pyrido]3,2-b[pyrrolo]1,2-</p></td><td></td><td><p>12</p></td></tr>

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1,4[]d[oxazine-4-yl(thio(p-arzine-2-yl)methanol)

13

<img file="SA15151B1_D0019.tif" />

<p>-4- (S4,S3)(-3)</p>

Amino-3-methyl-2-oxa-8-

aaspyro]4,5[decane-8-yl(-6-)))S8,aS6(-8-)oxetane-3-yloxy(-7,8,9,a6-tetarhydro-H6-pyrido]3,2 -b[pyrrolo]1,2-1,4[]d[oxazine-4-yl(thio(p-arzine-2-yl)methanol)

14

<img file="SA15151B1_D0020.tif" />

<p>-4- (S4,S3)(-3)</p>

Amino-3-methyl-2-oxa-8-

azspiro[4,5[decane-8-yl(-6-)))S8,aS6(-8-)methoxymethoxy(-7,8,9,a6-tetarhydro-H6-pyrido]3,2-b] Pirolo]1,2-

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1,4[]d[oxazine-4-yl(thio(p-arzine-2-yl)methanol)

15

<img file="SA15151B1_D0021.tif" />

16

<img file="SA15151B1_D0022.tif" />

<p>-4- (S4,S3)(-3)</p>

Amino-3-methyl-2-oxa-8-

aaspyro]4,5[decane-8-yl(-6-)))S8,aS6(-8-)2-methoxyethoxy(-7,8,9,a6-tetarhydro-H6-pyrido]3,2-b [Pyrrolo]1,2-1,4[]d[oxazine-4-yl(thio(p-arzine-2-yl)methanol)

<p>-4- (S4,S3)(-3)</p>

Amino-3-methyl-2-oxa-8-

azspiro[4,5[decane-8-yl(-6-)))S8,aS6(-8-)cyclopropylmethoxy(-7,8,9,a6-tetarhydro-H6-pyrido]3,2-b] Pirolo]1,2-

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<tr><td><p dir="rtl">1,4[]d[oxazine-4-yl(thio(p-arzine-2-yl)methanol)</p></td><td></td><td></td></tr><tr><td><p>-4- (S4,S3)(-3)</p><p dir="rtl">Amino-3-methyl-2-oxa-8-</p><p dir="rtl">aispyro]4,5[decane-8-yl(-6-)))7,a'6-)S-'dihydro-H-9,'H6'spiro]cyclopropane-1,8'-pyrido]3, 2-b[pyrrolo]1,2-1,4[]d[oxazine[-4'-yl(thio(p-arzine-2-yl)methanol)</p></td><td></td><td><p>17</p></td></tr><tr><td><p>-5((-4-)S8,aS6)</p><p dir="rtl">)(4-)S4,S3-amino-3-methyl-2-oxa-8-a azspiro[4,5[decane-8-yl(-6-)hydroxymethyl(p-arzine-2-yl(thio)-8) -Methyl-7,8,9,a6-tetarhydro-H6-pyrido]3,2-</p></td><td></td><td><p>18</p><p>19</p></td></tr>

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<tr><td><p dir="rtl">b[pyrrolo]1,2-1,4[]d[oxazine-8-ol</p><p>-5((-4-)R8,aS6)</p><p dir="rtl">)(4-)S4,S3-amino-3-methyl-2-oxa-8-a azspiro[4,5[decane-8-yl(-6-)hydroxymethyl(p-arzine-2-yl(thio)-8) - Methyl-7,8,9,a6-tetarhydro-H6-pyrido]3,2-b[pyrrolo]1,2-1,4[]d[oxazine-8-ol]</p></td><td></td><td></td></tr><tr><td><p>-5((-4-)S8,aS6)</p><p dir="rtl">)(4-)S4,S3-amino-3-methyl-2-oxa-8-a azspiro[4.5[decane-8-yl(-6-)hydroxymethyl(p-arzine-2-yl(thio)-7) ,8,9,a6-tetarhydro-H6-pyrido]3,2-b[pyrrolo]1,2-</p></td><td></td><td><p>20</p></td></tr>

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<tr><td><p dir="rtl">1,4[]d[oxazine-8-carbonitrile</p></td><td></td><td></td></tr><tr><td><p>-4- (S4,S3)(-3)</p><p dir="rtl">Amino-3-methyl-2-oxa-8-</p><p dir="rtl">aispyro[4,5]decane-8-yl(-6-))S8,aS6(-8-)methylsulfonyl(-7,8,9,a6-tetarhydro-H6-pyrido[3,2-b] Pyrrolo[1,2-1,4[]d[oxazine-4-yl(thio(p-arzine-2-yl)methanol)</p></td><td></td><td><p>21</p></td></tr><tr><td><p>-5((-4-)S8,aS6)</p><p dir="rtl">)(4-)S4,S3-amino-3-methyl-2-oxa-8-a azspiro[4.5[decane-8-yl(-6-)hydroxymethyl(p-arzine-2-yl(thio)-7) ,8,9,a6-tetarhydro-H6-pyrido]3,2-b[pyrrolo]1,2-</p></td><td></td><td><p>22</p></td></tr>

15151

-60-

<tr><td><p dir="rtl">1,4[]d[oxazine-8-yl carbamate</p></td><td></td><td></td></tr><tr><td><p>-5((-4-)R8,aS6)</p><p dir="rtl">)(4-)S4,S3-amino-3-methyl-2-oxa-8-a azspiro[4.5[decane-8-yl(-6-)hydroxymethyl(p-arzine-2-yl(thio)-7) 8,9,a6-tetarhydro-H6-pyrido]3,2-b[pyrrolo]1,2-1,4[]d[oxazine-8-yl carbamate</p></td><td></td><td><p>23</p></td></tr><tr><td><p>-8-(S8,aS6)((-6)</p><p dir="rtl">(H1-bi-aryzol-1-yl)-7,8,9,a6-tetarhydro-H6-pyrido]3,2-b[pyrrolo]1,2-1,4[]d[oxazine-4-yl] (Thio(-3-))-)S4,S3 4-amino-3-methyl-2-oxa-8-</p></td><td></td><td><p>24</p></td></tr>

15151

-61-

Azspiro]4.5[decane-8-

yl(p-arzine-2-yl(methanol).

26

27

<img file="SA15151B1_D0023.tif" />

<img file="SA15151B1_D0024.tif" />

-8-(R8,aS6)((-6)

(H1-bi-aryzol-1-yl)-7,8,9,a6-tetarhydro-H6-pyrido]3,2-b[pyrrolo]1,2-1,4[]d[oxazine-4-yl] (Thio(-3-))-)S4,S3 4-amino-3-methyl-2-oxa-8-

Azspiro]4,5[decane-8-yl(p-arzine-2-yl(methanol)

-4- (S4,S3)(-3)

Amino-3-methyl-2-oxa-8-

Aazspiro[4.5[decane-8-yl(-6-)))R(-7,9,10,a6-tetarhydro-

-H6

[1,4[oxazino]4,3-d[pyrido]3,2-1,4[]b[oxazine-4-

15151

-62-

yl(thio(p-arzine-2-yl)methanol

-4- (S4,S3)(-3)

Amino-3-methyl-2-oxa-8-

Aazspiro[4,5[decane-8-yl(-6-)))S(-7,9,10,a6-tetarhydro-

-H6

[1,4[oxazino]4,3-d[pyrido]3,2-

1,4[]b[oxazine-4-yl(thio(p-arzine-2-yl)methanol)

28

<img file="SA15151B1_D0025.tif" />

-4-(S4,S3)(-5)(-4

Amino-3-methyl-2-oxa-8-

Azspiro]4,5[decane-8-yl(-6-)hydroxymethyl(p-arzine-2-yl(thio(-7,9,10,a6-tet-arhydro-H6-pyrido)]3,2-1,4) []b[thiazino]4,3-

15151

-63-

<tr><td><p dir="rtl">1,4[]d[oxazine 8,8-dioxide</p></td><td></td><td></td><td></td></tr><tr><td><p>-4- (S4,S3)(-3)</p><p dir="rtl">Amino-3-methyl-2-oxa-8-</p><p dir="rtl">azspiro[4,5[decane-8-yl(-6-))S8,aS6(-8-)methoxymethyl(-7,8,9,a6-tetarhydro-H6-pyrido]3,2-b] Pyrrolo[1,2-1,4[]d[oxazine-4-yl(thio(p-arzine-2-yl)methanol)</p></td><td></td><td></td><td><p>29</p></td></tr><tr><td><p>-4- (S4,S3)(-3)</p><p dir="rtl">Amino-3-methyl-2-oxa-8-</p><p dir="rtl">azspiro[4,5[decane-8-yl(-6-)))R8,aS6(-8-)methoxymethyl(-7,8,9,a6-tetarhydro-H6-pyrido]3,2-b] Pyrrolo]1,2-1,4[]d[oxazine-4-</p></td><td></td><td></td><td><p>30</p></td></tr>

15151

-64-

yl(thio(p-arzine-2-yl)methanol

31

<img file="SA15151B1_D0026.tif" />

<p>-4- (S4,S3)(-3)</p>

Amino-3-methyl-2-oxa-8-

aSpyro]4,5[decane-8-yl(-6-))S8,aS6(-8-))methoxymethoxy(methyl(-7,8,9,a6-tet-arhydro-H6-pyrido]3,2) -b[pyrrolo]1,2-1,4[]d[oxazine-4-yl(thio(p-arzine-2-yl)methanol)

32

<img file="SA15151B1_D0027.tif" />

<p>-4- (S4,S3)(-3)</p>

Amino-3-methyl-2-oxa-8-

aSpyro[4,5[decane-8-yl(-6-)))S8,aS6(-8-))2-methoxyethoxy(methyl(-7,8,9,a6-tetarhydro-H6-pyrido]3, 2-

15151

-65-

b[pyrrolo]1,2-

1,4[]d[oxazine-4-yl(thio(p-arzine-2-yl)methanol)

33

<img file="SA15151B1_D0028.tif" />

<p>-4- (S4,S3)(-3)</p>

Amino-3-methyl-2-oxa-8-

azspiro]4,5[decane-8-yl(-6-)))S8,aS6(-8-))cyclopropylmethoxy(methyl(-7,8,9,a6-tetarhydro-H6-pyrido]3,2) -b[pyrrolo]1,2-1,4[]d[oxazine-4-yl(thio(p-arzine-2-yl)methanol)

34

<img file="SA15151B1_D0029.tif" />

<p>-4- (S4,S3)(-3)</p>

Amino-3-methyl-2-oxa-8-

azspiro[4,5[decane-8-yl(-6-)))S8,aS6(-8-))oxetane-3-ylmethoxy(methyl)-7,8,9,a6-tetarhydro-

15151

-66-

H6-pyrido]3,2-b[pyrrolo]1,2-1,4[]d[oxazine-4-yl(thio(p-arzine-2-yl)methanol)

35

<img file="SA15151B1_D0030.tif" />

36

37

<img file="SA15151B1_D0031.tif" />

<img file="SA15151B1_D0032.tif" />

-4- (S4,S3)(-3)

Amino-3-methyl-2-oxa-8-

Aispyro]4,5[decane-8-yl(-6-)))2-)S-amino-7,8,9,a6-tetarhydro-H6-pyrido]3,2-b[pyrrolo]1,2 -1,4[]d[oxazine-4-yl(thio(p-arzine-2-yl)methanol formate)

(3-))5-)S-amino-5,7-dihydrospiro[cyclopenta]b[pyridine-6,4-' piperidine[-1'-yl)-6-

-8-(S8,aS6)(((

(methoxymethyl)-7,8,9,a6-tetarhydro-H6-pyrido]3,2-b[pyrrolo]1,2-

15151

-67-

<tr><td><p dir="rtl">1,4[]d[oxazine-4-yl(thio(p-arzine-2-yl)methanol)</p><p dir="rtl">(3-))5-)S-amino-5,7-dihydrospiro[cyclopenta]b[pyridine-6,4-' piperidine[-1'-yl)-6-</p><p>-8-(R8,aS6)(((</p><p dir="rtl">(methoxymethyl)-7,8,9,a6-tetarhydro-H6-pyrido[3,2-b[pyrrolo]1,2-1,4[d[oxazine-4-yl(thio(p-arzine)) 2-yl(methanol</p></td><td></td><td></td></tr><tr><td><p dir="rtl">(3-))5- (S-amino-13-oxa-9-as dispiro[3.1.56.24]tridecane-9-yl)-6-</p><p>-8-(S8,aS6)(((</p><p dir="rtl">(methoxymethyl)-7,8,9,a6-tetarhydro-H6-pyrido]3,2-b[pyrrolo]1,2-1,4[]d[oxazine-4-</p></td><td></td><td><p>38</p></td></tr>

15151

-68-

39

<img file="SA15151B1_D0033.tif" />

<img file="SA15151B1_D0034.tif" />

yl(thio(p-arzine-2-yl)methanol

)3-))5-)S-amino-13-oxa-9-az-day

<img file="SA15151B1_D0035.tif" />

Spiro]3.1.56.24[tari

Deccan-9-yl(-6-

-8-(S8,aS6)(((

)(Methoxy(methyl)-7,8,9,a6-tetArhydro-H6-

pyrido]3,2-b[pyrrolo]1,2-1,4[]d[oxazine-4-yl(thio(p-arzine-2-yl)methanol)

40

<img file="SA15151B1_D0036.tif" />

-4- (S4,S3)(-3)

Amino-3-methyl-2-oxa-8-

azspiro[4,5[decane-8-yl(-6-)))S8,aS6(-8-)))methoxy(methoxy(methyl)-7,8,9,a6-tetarhydro-H6-

15151

-69-

pyrido]3,2-b[pyrrolo]1,2-1,4[]d[oxazine-4-yl(thio(p-arzine-2-yl)methanol)

41

<img file="SA15151B1_D0037.tif" />

-4- (S4,S3)(-3)

Amino-3-methyl-2-oxa-8-

aaspyro[4,5]decane-8-yl(-6-))S8,aS6(-8-(hydroxymethyl)-7,8,9,a6-tetarhydro-H6-pyrido[3,2-b] Pyrrolo[1,2-1,4[]d[oxazine-4-yl(thio(p-arzine-2-yl)methanol)

42

<img file="SA15151B1_D0038.tif" />

-5(-8-)S4,S3(

-8-(S8,aS6)(((

)(Methoxy(methyl)-7,8,9,a6-tetarhydro-H6-pyrido]3,2-b[pyrrolo]1,2-1,4[]d[oxazine-4-

15151

-70-

yl(thio(p-arzine-2-yl(-3-methyl-2-oxa-8-aispyro[4.5]decane-4-amine)

43

<img file="SA15151B1_D0039.tif" />

-5(-8-)S4,S3(

-8-(S8,aS6)(((

(methoxymethyl)-7,8,9,a6-tetarhydro-H6-pyrido[3,2-b[pyrrolo]1,2-1,4[d[oxazine-4-yl(thio(p-arzine)) 2-yl(-3-methyl-2-oxa-8-aispyro[4.5]decane-4-amine

44

<img file="SA15151B1_D0040.tif" />

(6(-8-)S4,S3-Amino-

-8-)S8,aS6)((-5

((Methoxy)methyl)-7,8,9,a6-tetarhydro-H6-pyrido[3,2-b[pyrrolo]1,2-1,4[d[oxazine-4-yl(thio) P-Arzine-2-yl(-3-methyl-2-oxa-8-

15151

-71-

Azspiro]4,5[decane-4-amine

45

<img file="SA15151B1_D0041.tif" />

(6(-8-)S4,S3-Amino-

-8-)S8,aS6)((-5

(methoxymethyl)-7,8,9,a6-tetarhydro-H6-pyrido[3,2-b[pyrrolo]1,2-1,4[d[oxazine-4-yl(thio(p-arzine)) 2-yl(-3-methyl-2-oxa-8-aispyro[4.5]decane-4-amine

46

<img file="SA15151B1_D0042.tif" />

-5(-'1-)S(

-8-(S8,aS6)(((

((Methoxy)methyl)-7,8,9,a6-tetarhydro-H6-pyrido[3,2-b[pyrrolo]1,2-1,4[d[oxazine-4-yl(thio) P-arzine-2-yl(-5,7-dihydrospiro]cyclo

15151

-72-

penta]b[pyridine-6,4-' piperidine[-5-amine

47

<img file="SA15151B1_D0043.tif" />

(6(-'1-)S-Amino-5-

<p>-8-(S8,aS6)(((</p>

((Methoxy)methyl)-7,8,9,a6-tetarhydro-H6-pyrido[3,2-b[pyrrolo]1,2-1,4[d[oxazine-4-yl(thio) p-arzine-2-yl(-5,7-dihydrospiro]cyclopenta]b[pyridine-6,4-' piperidine[-5-amine]

48

<img file="SA15151B1_D0044.tif" />

(3-))5-)S-amino-5,7-dihydrospiro[cyclopenta]b[pyridine-6,4-' piperidine[-1'-yl)-6-

<p>-8-(S8,aS6)(((</p>

((methoxy)methyl)-7,8,9,a6-

tetArhydro-H6-pyrido]3,2-b[pyrrolo]1,2-

15151

-73-

1,4[]d[oxazine-4-yl(thio(p-arzine-2-yl)methanol)

49

<img file="SA15151B1_D0045.tif" />

<p>-4- (S4,S3)(-3)</p>

Amino-3-methyl-2-oxa-8-

aSpyro]4,5[decane-8-yl(-6-))S8,aS6(-8-))methoxymethoxy(methyl(-7,8,9,a6-tet-arhydro-H6-pyrido]3,2) -b[pyrrolo]1,2-1,4[]d[oxazine-4-yl(thio(-5-methylarzine-2-yl)methanol)

50

<img file="SA15151B1_D0046.tif" />

<p>-4- (S4,S3)(-3)</p>

Amino-3-methyl-2-oxa-8-

aSpyro]4,5[decane-8-yl(-6-)))R8,aS6(-8-))methoxymethoxy(methyl(-7,8,9,a6-tetarhydro-H6-pyrido]3,2) -

15151

-74-

51

<img file="SA15151B1_D0047.tif" />

52

<img file="SA15151B1_D0048.tif" />

b[pyrrolo]1,2-1,4[]d[oxazine-4-yl(thio(p-arzine-2-yl)methanol)

<p>-4- (S4,S3)(-3)</p>

Amino-3-methyl-2-oxa-8-

azspiro[4,5[decane-8-yl(-6-)))S8,aR6(-8-))methoxy(methyl(-7,8,9,a6-tet-arhydro-H6-pyrido]3,2) -b[pyrrolo]1,2-1,4[]d[oxazine-4-yl(thio(p-arzine-2-yl)methanol)

<p>-4- (S4,S3)(-3)</p>

Amino-3-methyl-2-oxa-8-

azspiro[4,5[decane-8-yl(-6-)))R8,aR6(-8-))methoxy(methyl)-7,8,9,a6-tetarhydro-H6-

15151

-75-

53

<img file="SA15151B1_D0049.tif" />

54

<img file="SA15151B1_D0050.tif" />

pyrido]3,2-b[pyrrolo]1,2-1,4[]d[oxazine-4-yl(thio(p-arzine-2-yl)methanol)

<p>-4- (S4,S3)(-3)</p>

Amino-3-methyl-2-oxa-8-

aSpyro]4,5[decane-8-yl(-6-))8-)S8,aS6-(methoxymethyl)-7,8,9,a6-tetarhydro-H6-pyrido]3,2-b[pyrrolo [1,2-1,4[]d[oxazine-4-yl(p-arzine-2-yl(methanol)

<p>-4- (S4,S3)(-3)</p>

Amino-3-methyl-2-oxa-8-

Azspiro[4,5]decane-8-yl(-6-))8-)S8,aS6-)(methoxymethoxy)methyl(-7,8,9,a6-)

ttArhydro-H6-pyrido]3,2-

15151

-76-

<tr><td><p dir="rtl">b[pyrrolo]1,2-</p><p dir="rtl">1,4[]d[oxazine-4-yl(p-arzine-2-yl(methanol)</p></td><td></td><td></td></tr>

Additional compounds with formula (I) are disclosed in Table 2 below.

Table 2

-II

1

<img file="SA15151B1_D0051.tif" />

6-Amino-2-)(4-)S4,S3-Amino-3-methyl-2-oxa-8-aispyro[4.5[decane-8-yl)-

-8-)S8,aS6)((-5

((Methoxy)methyl)-7,8,9,a6-tetarhydro-H6-pyrido[3,2-b[pyrrolo]1,2-1,4[d[oxazine-4-yl(thio) -3- Methylpyrimidine-4)-)H3 One

-II

2

<img file="SA15151B1_D0052.tif" />

2-))4-)S4,S3-amino-3-methyl-2-oxa-8-

Azspiro]4.5[decane-8-yl(-)

-8-)S8,aS6)((-5

((Methoxy)methyl)-7,8,9,a6-tetarhydro-H6-pyrido[3,2-b[pyrrolo]1,2-1,4[d[oxazine-4-yl(thio) -

15151

-77-

<p dir="rtl">3 - Methyl pyrimidine-4(H3)-one</p>

-II

3

<img file="SA15151B1_D0053.tif" />

-II

4

<img file="SA15151B1_D0054.tif" />

6-Amino-2-))4-)S4,S3-Amino-3-methyl-2-oxa-8-aS6 -(methoxymethyl)-7,8,9,a6-tetarhydro-H6-pyrido]3,2-b[pyrrolo]1,2-

1,4[]d[oxazine-4-yl(thio(-3-methylpyrimidine-4)-)H3one

2-))4-)S4,S3-amino-3-methyl-2-oxa-8-

aSpyro[4,5[decane-8-yl(-5-)))8-)S8,aS6-(methoxymethyl)-7,8,9,a6-tetarhydro-H6-pyrido[3,2-b] Pirolo]1,2-

1,4[]d[oxazine-4-yl(thio(-3-methylpyrimidine-4)-)H3one

15151

-78-

-II

-II

7

<img file="SA15151B1_D0055.tif" />

<img file="SA15151B1_D0056.tif" />

<img file="SA15151B1_D0057.tif" />

(3-))4-)S4,S3-amino-3-methyl-2-oxa-8-

aSpyro[4,5[decane-8-yl(-6-)))8-)S8,aS6-(methoxymethyl)-7,8,9,a6-tetarhydro-H6-pyrido[3,2-b] Pirolo]1,2-

1,4[]d[oxazine-4-yl(thio(-5-methylarzine-2-yl)methanol)

-8-(S8,aS6)((-5(-'1-)S)

(methoxymethyl)-7,8,9,a6-tetarhydro-H6-pyrido[3,2-b[pyrrolo]1,2-1,4[d[oxazine-4-yl(thio(p-arzine)) 2-yl(-5,7-dihydrospiro]cyclo

penta]b[pyridine-6,4-'piperidine[-5-amine

(6(-'1-)S-Amino-5-

)))8-)S8,aS6-)methoxy

Methyl(-7,8,9,a6-ttt-Arhydro-

H6-pyrido]3,2-

b[pyrrolo]1,2-

1,4[]d[oxazine-4-

yl(thio(p-arzine-2-yl(-5,7-)

15151

-79-

Dihydrospiro]cyclo

penta]b[pyridine-6,4-'piperidine[-

5-Amen

-5(-8-)S4,S3(

)))8-)S8,aS6-)(cyclopropylmethoxy)methyl(-7,8,9,a6-tetarhydro-H6-

<img file="SA15151B1_D0058.tif" />

-II

8

pyrido]3,2-b[pyrrolo]1,2-

1,4[]d[oxazine-4-

yl(thio(p-arzine-2-yl(-3-methyl-2-oxa-8-)

Azspiro]4,5[decane-4-amine

-II

9

-II

10

<img file="SA15151B1_D0059.tif" />

<img file="SA15151B1_D0060.tif" />

(6(-8-)S4,S3-amino-5-))8-)S8,aS6-)(cyclopropylmethoxy)methyl(-7,8,9,a6-tetarhydro-H6-pyrido]3, 2-b[pyrrolo]1,2-1,4[]d[oxazine-4-yl(thio(b-arzine-2-yl(-3-methyl-2-oxa-8-aispyro]4.5[decane- 4-Amen

6-Amino-2-))4-)S4,S3-Amino-3-methyl-2-oxa-8-aS6 -))Cyclo

15151

-80-

<tr><td><p dir="rtl">Propylmethoxy(methyl(-7,8,9,a6-tetrahhydro-H6-pyrido]3,2-b[pyrrolo]1,2-1,4[]d[oxazine-4-yl(thio(-3-) Methylpyrimidine-4)-)H3 One</p></td><td></td><td></td></tr><tr><td><p dir="rtl">2-))4-)S4,S3-amino-3-methyl-2-oxa-8-</p><p dir="rtl">azspiro]4,5[decane-8-yl(-5-)))8-)S8,aS6-)(cyclopropylmethoxy(methyl)-7,8,9,a6-tetarhydro-H6-pyrido]3,2 -b[pyrrolo]1,2-1,4[]d[oxazine-4-yl(thio(-3-methylpyrimidine-4)-)H3 one</p></td><td></td><td><p>-II</p><p>11</p></td></tr><tr><td><p dir="rtl">)3-))5-)S-amino-5,7-dihydrospiro[cyclopenta]b[pyridine-6,4-'piperidine[-1'-yl(-6-)))8-)R8,aS6 -)(Methoxy(methyl)-7,8,9,a6-tetarhydro-H6-pyrido]3,2-b[pyrrolo]1,2-1,4[]d[oxazine-4-yl(thio) P-arzine-2-yl(methanol).</p></td><td></td><td><p>-II</p><p>12</p></td></tr>

15151

-81-

-II

13

<img file="SA15151B1_D0061.tif" />

(3-))5-)S-amino-5,7-

Dihydrospiro]cyclo

penta]b[pyridine-6,4-'piperidine[-1'-yl(-6-)))8-)R8,aR6-

)(Methoxy(methyl)-7,8,9,a6-tetArhydro-H6-

pyrido]3,2-b[pyrrolo]1,2-1,4[]d[oxazine-4-yl(thio(p-arzine-2-yl)methanol)

-II

14

<img file="SA15151B1_D0062.tif" />

<img file="SA15151B1_D0063.tif" />

<img file="SA15151B1_D0064.tif" />

(3-))5-)S-amino-5,7-

Dihydrospiro]cyclo

penta]b[pyridine-6,4-'piperidine[-

1'-yl(-6-)))8-)S8,aR6-

)(Methoxy(methyl)-7,8,9,a6-tetArhydro-H6-

pyrido]3,2-b[pyrrolo]1,2-1,4[]d[oxazine-4-yl(thio(p-arzine-2-yl)methanol)

-II

15

<img file="SA15151B1_D0065.tif" />

<img file="SA15151B1_D0066.tif" />

-8-(R8,aS6)((-5(-'1-)S)

)(methoxymethoxy(methyl)-

7,8,9,a6-tttArhydro-H6-

pyrido]3,2-b[pyrrolo]1,2-1,4[]d[oxazine-4-yl(thio(p-arzine-2-yl(-5,7-dihydrospiro)cyclo)

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<tr><td><p dir="rtl">penta]b[pyridine-6,4-'piperidine[-5-amine</p></td><td></td></tr><tr><td><p>-(R8,aR6)((-5(-'1-)S)</p><p dir="rtl">8-)(Methoxymethoxy)methyl(-7,8,9,a6-tetarhydro-H6-pyrido]3,2-b[pyrrolo]1,2-1,4[]d[oxazine-4-yl) thio(p-arzine-2-yl(-5,7-dihydrospiro]cyclopenta]b[pyridine-6,4-'piperidine[-5-amine)</p></td><td><p>1^-6^II</p></td></tr><tr><td><p>-8-(S8,aR6)((-5(-'1-)S)</p><p dir="rtl">((Methoxy)methyl)-7,8,9,a6-tetarhydro-H6-pyrido[3,2-b[pyrrolo]1,2-1,4[d[oxazine-4-yl(thio) p-arzine-2-yl(-5,7-dihydrospiro[cyclopenta]b[pyridine-6,4-'piperidine[-5-amine]</p></td><td><p>17</p></td></tr><tr><td><p dir="rtl">(6(-'1-)S-amino-5-))8-)R8,aS6-)(methoxymethoxy)methyl(-7,8,9,a6-tet-arhydro-H6-pyrido]3,2 -</p></td><td><p>-II</p><p>18</p></td></tr>

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b[pyrrolo]1,2-

1,4[]d[oxazine-4-yl(thio(p-arzine-2-yl(-5,7-dihydrospiro)cyclo)

penta]b[pyridine-6,4-'piperidine[-5-amine

-II

19

<img file="SA15151B1_D0067.tif" />

-II

20

<img file="SA15151B1_D0068.tif" />

(6(-'1-)S-amino-5-))8-)R8,aR6-)(methoxymethoxy)methyl)-7,8,9,a6-tetarhydro-H6-pyrido]3,2 -b[pyrrolo]1,2-1,4[]d[oxazine-4-yl(thio(p-arzine-2-yl(-5,7-dihydrospiro)cyclo)

penta]b[pyridine-6,4-'piperidine[-5-amine

(6(-'1-)S-amino-5-))8-)S8,aR6-)(methoxymethoxy)methyl(-7,8,9,a6-tet-arhydro-H6-pyrido]3,2 -b[pyrrolo]1,2-1,4[]d[oxazein-4-yl(thio(p-arzine-2-yl(-5,7-dihydrospiro)cyclo)

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<tr><td><p dir="rtl">penta]b[pyridine-6,4-'piperidine[-5-amine</p></td><td></td><td></td></tr>

Models:

In other embodiments 1-36 below, the present disclosure includes:

1.In Embodiment 1, a compound having the formula (IB), (IA), (I), or (IC) as disclosed in the disclosure of the invention above, or a pharmaceutically acceptable salt thereof, is provided.

5 In a first sub-embodiment of Embodiment 1, the compound is a compound of formula (I), or a pharmaceutically acceptable salt thereof. In a second sub-embodiment of Embodiment 1, the compound is a compound of formula (IA), or a pharmaceutically acceptable salt thereof.

In a third sub-embodiment of Model 1, the compound is a compound with the formula (IB), or a pharmaceutically acceptable salt thereof. In a fourth sub-embodiment of Model 1, the compound is a compound with the formula (IC), or

10 Pharmaceutical acceptable salt thereof.

2.In Model 2, the composite according to any one of Models 1 and the submodels included in the model

1, or a pharmaceutically acceptable salt thereof such that it has a structure of formula (II): (i.e., Z1 is a group of formula (a))

(II) 15

3. In Embodiment 3, the compound according to any of Embodiments 1 and 2 and the sub-embodiment therein, or a pharmaceutically acceptable salt thereof, the compound having the structure having the formula (IIA):

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<img file="SA15151B1_D0069.tif" />

(IIA)

<p dir="rtl">4 In Embodiment 5, the composite according to any one of Embodiments 1 and the submodel included in the model</p>

<p dir="rtl">1 , or a pharmaceutically acceptable salt of which the compound has the structure having the formula (III): (i.e., Z1</p>

<p dir="rtl">5 It is a set with the formula (b)</p><img file="SA15151B1_D0070.tif" />

(III)

<p dir="rtl">5 In Embodiment 5, the compound according to any one of Embodiments 1 and 4 and the sub-embodies therein, or a pharmaceutically acceptable salt thereof, the compound having the structure having the formula (IIIA):</p><img file="SA15151B1_D0071.tif" />

(IIIA).

10

<p dir="rtl">6 In Embodiment 6, the compound according to any of Embodiments 1 to 5 and the sub-embodiment therein, or a pharmaceutically acceptable salt thereof such that E is O and A is CH or ligand.</p>

<p dir="rtl">7 .in Embodiment 7, the composite according to any of Embodiments 1 through 5 and a sub-embodiment therein, or a salt</p>

15 A pharmaceutically acceptable form is such that E is O and A is ligand.

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<p dir="rtl">8 In Embodiment 8, the compound of Embodiment 3 and the sub-embodiment therein, or a pharmaceutically acceptable salt thereof, has a structure of the formula (IIB):</p><img file="SA15151B1_D0072.tif" />

(IIB)

5 9. In Embodiment 9, the compound of Embodiment 5 and the sub-embodiment therein, or a pharmaceutically acceptable salt thereof having the structure having the formula (IIIB):

<img file="SA15151B1_D0073.tif" />

(IIIB)

<p dir="rtl">10 In Embodiment 10, the compound according to any of Embodiments 1 to 9 and the sub-embodiment therein, or 10 pharmaceutically acceptable salt thereof such that Z is a hydrogen, alkyl, halo</p>

halo, haloalkyl, haloalkoxy, cyano, cycloalkyl, heterocyclyl, heteroaryl (where cycloalkyl, heterocyclyl, and heteroaryl are optionally replaced by one to three halo O(alk) yRa-,)halo,-

15 NRpRq-, S(O)2NRnRo-, OC(O)NRiRj-, S(O)2Rd-, O(alk)ORb, or -YM

(Where Y is a ligand, O, or SO2 and M is an alkyl, haloalkyl, cycloalkyl, heterocyclyl, or heteroaryl where the alkyl, haloalkyl, cycloalkyl, cycloalkyl is replaced

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Heterocyclyl and heteroaryl with -O(alk)yRa, -S(O)2Rd-, O(alk)ORb, or -NRpRq. Cycloalkyl, heterocyclyl, and heteroaryl are also optionally replaced. Using 1 to 3 halo

<p dir="rtl">5 11.In Embodiment 11, the composite pursuant to any of Embodiments 1 through 9 and a sub-form contained therein, or</p>

A pharmaceutically acceptable salt thereof is such that Z is -YM (where Y is ligand or O and M is an alkyl, haloalkyl, cycloalkyl, heterocyclyl, or heteroaryl in which the alkyl, haloalkyl is substituted , cycloalkyl, heterocyclyl and heterocyclic aryl

10 heteroaryl with -- NRgSO2Rh-, NReC(O)Rf-, S(O)2Rd-, O(alk)ORb- C(O)NRkRm-, OC(O)NRiRj, or

S(O)2NRnRo-.

<p dir="rtl">12 In Embodiment 12, the compound according to any of Embodiments 1 through 9 and the sub-embodiment therein, or a pharmaceutically acceptable salt thereof such that Z is -YM (where Y is a ligand).</p>

<p dir="rtl">15 M is an alkyl, haloalkyl, cycloalkyl, heterocyclyl, or heteroaryl, where the alkyl, haloalkyl, cycloalkyl, heterocyclyl, and heteroaryl are replaced by -O-Ra, where Ra is an expression Of the alkyl, cycloalkyl, cycloalkylalkyl, aminoalkyl, heterocyclic with optional substitution</p>

<p dir="rtl">20 optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, or optionally substituted heteroaryl.</p>

<p dir="rtl">13. In Embodiment 13, the compound according to any of Embodiments 1 to 9 and the sub-embodiment therein, or a pharmaceutically acceptable salt thereof such that Z is a -YM (where Y is a ligand</p>

<p dir="rtl">25 M is an alkyl, haloalkyl, cycloalkyl, and non-cyclyl.</p>

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Heterocyclyl, or heteroaryl in which the alkyl, haloalkyl, cycloalkyl, heterocyclyl and heteroaryl are substituted

With heteroaryl

<p dir="rtl">-O(alk)ORa where Ra is an alkyl, cycloalkyl, cycloalkyl alkyl.</p>

<p dir="rtl">5 cycloalkylalkyl, aminoalkyl, heterocyclic with optional substitution</p>

optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclyl.

<p dir="rtl">14 .in Embodiment 14, composite according to any of Embodiments 1 through 9 and a sub-embodiment therein, or</p>

10 A pharmaceutically acceptable salt thereof is such that Z is -ORa where Ra is an alkyl, cycloalkyl, cycloalkylalkyl, aminoalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl , a substituted aryl, or an optionally substituted heteroaryl

.substituted heteroaryl 15

<p dir="rtl">15 In Embodiment 15, the compound according to any of Embodiments 1 to 9 and the sub-embodiment therein, or a pharmaceutically acceptable salt thereof is such that Z is -O(alk)ORb where Rb is an alkyl, cycloalkyl, cycloalkylalkyl, amino aminoalkyl, a heterocyclic with optionally substituted</p>

20 heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclyl, or optionally substituted heteroaryl.

<p dir="rtl">16 In Embodiment 16, the compound according to any of Embodiments 1 to 9 and the sub-embodiment therein, or a pharmaceutically acceptable salt thereof such that Z is hydrogen, fluoro, cyano.</p>

25 cyano, methoxy, hydroxy, cyclopentyloxy, tetrahydrofuran-3-yloxy,

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oxetane-3-yloxy, methoxymethyloxy, methoxyethyloxy, methylsulfonyl, aminocarbonyloxy, p-aryzol-1-yl, hydroxymethyl, methoxymethyl, ethoxymethyl, methoxymethyloxymethyl, ethoxymethyloxymethyl, methoxyethyloxymethyl, cyclopropylmethyloxy, Or oxytan-3-yl methyloxymethyl.

<p dir="rtl">5 17.In Embodiment 17, composite according to any of Embodiments 1 through 9 and a sub-form contained therein, or</p>

A pharmaceutically acceptable salt thereof such that Z is methoxymethyloxy, methoxyethoxy, methoxymethyl, methoxymethyloxymethyl, ethoxymethyloxymethyl, methoxyethyloxymethyl, cyclopropylmethyloxy, or oxetane-3-ylmethyloxymethyl.

<p dir="rtl">18 .in Embodiment 18, composite according to any of Embodiments 1 through 9 and a sub-embodiment therein, or</p>

<p dir="rtl">10 A pharmaceutically acceptable salt thereof such that Z is methoxymethyl, methoxymethyloxymethyl, ethoxymethyloxymethyl, methoxyethyloxymethyl, cyclopropylmethyloxymethyl, or oxetane-3-ylmethyloxymethyl.</p>

<p dir="rtl">19 .In Embodiment 18, the compound according to any of Embodiments 1 through 9 and the sub-embodiment therein, or a pharmaceutically acceptable salt thereof such that Z is a fluoro.</p>

15 20.In Embodiment 20, composite according to any of Embodiments 1 through 19 and sub-embodiments therein, or

A pharmaceutically acceptable salt thereof such that R9 and R13 form hydrogen.

<p dir="rtl">21 .in Embodiment 21, the composite according to any of Embodiments 1 through 19 and a sub-embodiment therein, or</p>

A pharmaceutically acceptable salt thereof such that R9 and R13 are amino.

21a. In Form 21A, the composite according to any of Embodiments 1 through 19 and a subform therein,

20 or a pharmaceutically acceptable salt thereof such that R9 and R13 are methyl.

21b. In Embodiment 21B, the compound according to any of Embodiments 1 through 19 and the sub-embodiment therein, or a pharmaceutically acceptable salt thereof such that R9 and R13 are individually hydrogen, alkyl, or amino.

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<p dir="rtl">22 In Embodiment 22, the compound according to any of Embodiments 1 to 21B and the subembodiments therein, or a pharmaceutically acceptable salt thereof such that L is S.</p>

<p dir="rtl">23 In Embodiment 23, the compound according to any of Embodiments 1 through 21B and the subembodiments therein, or a pharmaceutically acceptable salt thereof such that L is S(O) or 2(S(O).</p>

<p dir="rtl">5 24.In Embodiment 24, composite according to any of Embodiments 1 through 21B and sub-embodiments therein,</p>

Or a pharmaceutically acceptable salt thereof such that L is a ligand.

<p dir="rtl">25 In Embodiment 25, the compound according to any of Embodiments 1 through 24 and the subembodiments therein, or a pharmaceutically acceptable salt thereof such that L is a CR7R8 where R5 and R6 are individually hydrogen or alkyl. In one subembodiment of Form 10, L</p>

10 It is CH2. In another sub-embodiment of embodiment 10, L is 2(C(CH3).

<p dir="rtl">26 In Embodiment 26, the compound according to any of Embodiments 1 to 3, 6 to 8, and 10 to 25 and the sub-embodies therein, or a pharmaceutically acceptable salt thereof such that R10 is a hydroxyalkyl. In a first sub-embodiment of Form 11, R10 is a hydroxymethyl.</p>

<p dir="rtl">15 27.In Embodiment 27, the composite according to any of Embodiments 1 to 3, 6 to 8, and 10 to 25 and Embodiments</p>

subcontained therein, or a pharmaceutically acceptable salt thereof such that R10 is an alkylsulfonyl. In a first subembodiment of embodiment 27, R2 is a methylsulfonyl or ethylsulfonyl.

27a. In Embodiment 27A, the compound according to any of Embodiments 1 to 3, 6 to 8, and 10 to 25 and sub-Embodiments 20 therein, or a pharmaceutically acceptable salt thereof such that R10 is hydrogen

.hydrogen

<p dir="rtl">28 In Embodiment 28, the compound according to any of Embodiments 11 through 25 and the subembodiments therein, or a pharmaceutically acceptable salt thereof such that R14 is hydrogen.</p>

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<p dir="rtl">29 In Embodiment 29, the compound according to any of Embodiments 11 through 25 and the sub-embodies therein, or a pharmaceutically acceptable salt thereof such that R14 is an -alkyl. In a first submodel, R14 is methylated.</p>

<p dir="rtl">30 In Embodiment 30, the compound according to any of Embodiments 1 through 29 and the subembodiments therein, or 5 pharmaceutically acceptable salt thereof is where:</p>

R11 and R15 are selected from amino and aminoalkyl; R12 and R16 are chosen from hydrogen, cyano, halo, alkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, aryl, heterocyclyl, and heteroaryl, where alkyl, cycloalkyl, aryl, 10 cyclyl Heterocyclyl and heteroaryl are optionally made

Replace them with one to three individually selected substitution groups of alkyl, halo, haloalkyl, haloalkoxy, alkoxy, and cyano. In a sub-embodiment of Form 30, R11 and R15 are aminomethyl, and R12 and R16 are methyl.

15 31.In Embodiment 31, composite according to any of Embodiments 1 through 29 and sub-embodiments therein, or

A pharmaceutically acceptable salt of it is where: R11, R12, R15 and R16 all form with the carbon atom to which they are attached a ring with the formula (c):

<img file="SA15151B1_D0074.tif" />

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In a first sub-embodiment of embodiment 31, a loop of the form (c):

<img file="SA15151B1_D0075.tif" />

<img file="SA15151B1_D0076.tif" />

<img file="SA15151B1_D0077.tif" />

<img file="SA15151B1_D0078.tif" />

<img file="SA15151B1_D0079.tif" />

<img file="SA15151B1_D0080.tif" />

<img file="SA15151B1_D0081.tif" />

In a second subembodiment of Embodiment 31, a loop of the form (c) is

<p dir="rtl">32 .in Embodiment 32, composite according to any one of 1 through 29 and subembodiments therein, or</p>

5 A pharmaceutically acceptable salt of it is such that R11, R12, R15 and R16 all form, with the carbon atom to which they are attached, a ring with the formula (c):

<img file="SA15151B1_D0082.tif" />

In a first embodiment of embodiment 32, a loop of the form (c):

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<img file="SA15151B1_D0083.tif" />

<img file="SA15151B1_D0084.tif" />

<img file="SA15151B1_D0085.tif" />

<img file="SA15151B1_D0086.tif" />

<img file="SA15151B1_D0087.tif" />

<img file="SA15151B1_D0088.tif" />

<img file="SA15151B1_D0089.tif" />

<p dir="rtl">33 In Embodiment 33, the compound according to any of Embodiments 1 through 32 and the sub-embodies therein, or a pharmaceutically acceptable salt thereof is such that R3, R2, R1, and R4 are individually selected from a hydrogen, alkyl, halo, haloalkyl, and haloalkoxy. haloalkoxy, 5 alkoxy, cyano, or hydroxy, amino. In the first submodel 33,</p>

One of R3, R2, R1, and R4 is hydrogen and the remaining three are hydrogen.

R3, R2, R1, and R4 are individually selected from hydrogen, methyl, fluoro, methoxy, hydroxy, or amino. In a second sub-embodiment 33, two or three of R1, R3, R2, and R4 are hydrogen and the remaining one or two of R2, R1,

<p dir="rtl">10 R3 and R4 are individually selected from hydrogen, methyl, fluoro, methoxy,</p>

Hydroxy, or amino. In a third sub-embodiment 33, R3, R2, R1, and R4 form hydrogen.

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<p dir="rtl">34 In Embodiment 34, the compound according to any of Embodiments 1 through 32 and the sub-embodiments therein, or a pharmaceutically acceptable salt thereof is such that R5 is a hydrogen, alkyl, halo, or amino and R6 is a hydrogen, alkyl, halo. , haloalkyl, haloalkoxy, alkoxy, hydroxy, or cyano</p>

.cyano 5

<p dir="rtl">35 In Embodiment 35, the compound according to any of Embodiments 1 through 32 and the sub-embodiments therein, or a pharmaceutically acceptable salt thereof such that R5 is hydrogen, chloro, methyl, or amino and R6 is hydrogen, methyl, chloro, or trihydrogen. Fluoromethyl, terefluoromethoxy, or methoxy.</p>

10 36.In Embodiment 34, composite according to any of Embodiments 1 through 32 and sub-embodiments therein, or

A pharmaceutically acceptable salt of which R5 and R6 form hydrogen.

It is understood that the above embodiments include all combinations of the embodiments and sub-embodiments contained therein. For example, the loop of formula (c) of Embodiment 31 and the first and second subembodiments of Embodiment 31 may be separately combined with one or more of Embodiments 1-30 15 and 32-36 and/or the subembodiments contained therein. .

Additional forms include Forms 37-63 below:

<p dir="rtl">37 A compound with the formula ('I):</p><img file="SA15151B1_D0090.tif" />

(I')

20 where:

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A is or is replaced by Rb, Ra, and/or Rc where Ra and Rb are

Selected individually from hydrogen, alkyl, amino, cycloalkyl, alkyldienyl, alkenyl, halo, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl

<p dir="rtl">5 hydroxyalkyl, alkoxyalkyl, cyano, aminoalkyl carboxy, alkoxycarbonyl and Rc are hydrogen, alkyl, halo, hydroxy, alkoxy, optionally substituted heterocyclyl, substituted aryl optionally substituted aryl</p>

<p>- NR'C(O)R-, OR'-, C(O)R-, S(O)2R-, substituted heteroaryl 10</p>

NR'R”- S(O)2NR’R”, C(O)NR’R”- OC(O)NR’R”, NR’SO2R”, or -NR’C(O)C) O)R where R is an alkyl, cycloalkyl, cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclyl

<p dir="rtl">15 heterocyclylalkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted heteroaryl, or an optionally substituted heteroaryl, or an optionally substituted heteroaryl</p>

substituted heteroaralkyl, and 'R' and 'R' are individually hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, cycloalkylalkyl, substituted heteroaralkyl

optionally substituted heterocyclyl, an optionally substituted heterocyclylalkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted heteroaryl, or a heteroaryl

<p dir="rtl">25 It has optionally substituted heteroaralkyl, or 'R' and 'R' form together</p>

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In addition to the nitrogen atom to which it is attached, there is an optionally substituted heterocyclyl; Or when Rc and Ra are bonded to the same carbon atom of the cycloalkyl or heteroaryl ring, then Rc and Ra together next to the carbon atom to which they are attached form

<p dir="rtl">5 cycloalkylene or heterocyclylene;</p>

Or A has the structure (d):

<img file="SA15151B1_D0091.tif" />

(d)

where:

<p dir="rtl">10 t can be 0, 1 or 2;</p>

The E ring is a 4- to 7-atom heterocyclic ring containing 1 or 2 heteroatoms selected separately from S, N, O, and SO2, where the remaining atoms are carbon; W is CH2, O, or N; It is replaced by Rb, Ra, and/or Rc, where Ra and Rb are chosen separately from hydrogen, amino, alkyl, alkyldieenyl, alkenyl,

<p dir="rtl">15 Halo, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, cyano, aminoalkyl, carboxy, alkoxycarbonyl and Rc are hydrogen, alkyl, halo, hydroxy, or alkoxy ; Or when Ra and Rc are attached to the same carbon atom, Ra and Rc are together next to the carbon atom</p>

<p dir="rtl">20 The two bound atoms form a cycloalkylene or a heterocycline</p>

heterocyclylene

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Q1 is N or CR1, where R1 is hydrogen or deuterium;

Q2 is N, CH, or CD;

R2 is alkyl, halo, hydroxy, hydroxyalkyl

CD2OH-hydroxyalkyl, alkylsulfoxide, alkylsulfonyl, aminosulfonyl, aminocarbonyl, carboxy, cyano, or alkoxycarbonyl;

L is a ligand, S(O)2, S(O), S, O, or CR5R6, where R5 and R6 are individually hydrogen or alkyl;

10

It is a ring with the form (a) or (b):

<img file="SA15151B1_D0092.tif" />

15

where:

m be 0, 1; or 2;

n can be 0, 1, or 2, where when n is 2 then one of CH2 is replaced by S, O, or

SO2; Provided that m + n is 1, 2, or 3;

k can be 0, 1 or 2;

z can be 0, 1, or 2;

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Each Rd is individually a hydrogen, alkyl, or halogen;

Re and Re1 are individually hydrogen, alkyl, halogen, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, cyano or oxo; or

<p dir="rtl">5 When Re and Re1 are bonded to the same carbon atom, then Re and Re1 together with the carbon atom attached to them form a cycloalkylene or heterocyclylene;</p>

Rf and Rg are individually hydrogen, alkyl, or haloalkyl;

Each Rh is individually an alkyl, halo, haloalkyl, and alkoxy.

<p dir="rtl">10 hydroxyalkyl, alkoxyalkyl, hydroxy, cyano, or oxo; or</p>

When one Rh is attached to carbon 2 or 3 of the piperidine (B) ring and the second Rh is attached to carbon 5 or 6 of the piperidine (B) ring, the position of the nitrogen atom is 1, then the first and second Rh combine to form a chain alkylene;

<p dir="rtl">15 The D ring is a phenyl, phenyl, or heteroaryl ring, a 5- or 6-membered ring that, including X and Optional substitution with one or two individually selected alkyl groups, halo, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl</p>

<p dir="rtl">20 hydroxyalkyl, cyano, amino, aminoalkyl, carboxy, cycloalkyl, heterocyclyl, heteroaryl, and acyl amino;</p>

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X and X1 are each individually N or C provided that only one of X and X1 is N;

R3 is an amino or aminoalkyl;

R4 is an alkyl, cycloalkyl, halo, hydroxy.

<p dir="rtl">5 hydroxy, amino, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, aryl alkyl, heterocyclic alkyl, cycloalkylalkyl, heterocyclic alkyl, heteroaryl aryl of 5 or 6 ether, or heterocyclyl From 4 to 6, where the heteroaryl or heterocyclyl by itself or as part of an alkyl or</p>

<p dir="rtl">10 A heteroaryl alkyl substituent with Ri and/or Rj, each selected individually from</p>

hydrogen, alkyl, halo, haloalkyl, haloalkoxy, alkoxy, hydroxy, cyano, amino, aminoalkyl, alkylsulfoxide, or alkylsulfonyl; or

R3 and R4 together with the carbon atom to which they are attached form a ring with the formula:

:(c) 15

where:

1m be 0, 1; or 2;

<p dir="rtl">1n can be 0, 1, or 2; Provided that 1+ n 1m is 1, 2, or 3;</p>

<p dir="rtl">20 Rk and Rm are individually hydrogen, alkyl, or haloalkyl;</p>

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One of Y and Z is S(O)2, S(O), S, O, CH2, or NH; The other of X and Y is CH2; Where the ring having the formula (c) is substituted with Rn and/or Ro, each of them is selected separately from hydrogen, alkyl, alkyldienyl, alkenyl, halo, haloalkyl, haloalkoxy, alkoxy, hydroxy.

<p dir="rtl">5 hydroxy, cyano, alkylsulfoxide, alkylsulfonyl, oxo, cycloalkyl, heterocyclyl, and heteroaryl; or</p>

When Rn and Ro are bonded to the same carbon atom, then Rn and Ro together along with the carbon atom to which they are bonded form a cycloalkylene or heterocyclylene; or

Pharmaceutical acceptable salt thereof.

<p dir="rtl">38.The compound of form 37 has a structure with the formula (I'A):</p><img file="SA15151B1_D0093.tif" />

(I'A)

<p dir="rtl">15 where:</p>

A is or is replaced by Rb, Ra, and/or Rc where Ra and Rb are

Selected individually from hydrogen, alkyl, amino, cycloalkyl, alkyldienyl, alkenyl, halo, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl

<p dir="rtl">20 Hydroxyalkyl, cyano, aminoalkyl, carboxy, alkoxycarbonyl and Rc are hydrogen, alkyl, halo,</p>

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hydroxy, alkoxy, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, S(O)R-, optionally substituted heteroaryl

,S(O)2R

5

Or -NR'C(O)C(O)R where R is an alkyl, cycloalkyl, cycloalkylalkyl, optionally substituted heterocyclyl, aryl with optionally substituted heterocyclylalkyl. Optional substitution substituted aryl, a substituted aryl

<p dir="rtl">10 optionally substituted aralkyl, an optionally substituted heteroaryl, or an optionally substituted heteroaralkyl, and 'R' and 'R' are individually hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl alkoxyalkyl, aminoalkyl, cycloalkylalkyl, heterocyclic substituted</p>

<p dir="rtl">15 optionally substituted heterocyclyl, an optionally substituted heterocyclylalkyl, an optionally substituted heterocyclylalkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted heteroaryl, or an optionally substituted heteroaryl. Optionally substituted heteroaralkyl or 'R' and 'R' form together</p>

<p dir="rtl">20 In addition to the nitrogen atom to which it is attached, there is an optionally substituted heterocyclyl; Or when Rc and Ra are bonded to the same carbon atom of the cycloalkyl or heteroaryl ring, then Rc and Ra together with the carbon atom to which they are attached form a cycloalkylene or heterocyclylene;</p>

<p dir="rtl">25 A has the structure (d):</p>

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<img file="SA15151B1_D0094.tif" />

(d)

where:

t can be 0, 1 or 2;

<p dir="rtl">5 The E ring is a 4- to 7-atom heterocyclic ring containing 1 or 2 heteroatoms selected separately from S, N, O, and SO2, where the remaining atoms are carbon; W is CH2, O, or N; It has optional replacement with Rb, Ra, and/or Rc, where Ra and Rb are selected separately from hydrogen, amino, alkyl, alkyldienyl, alkenyl, halo, haloalkyl, alkoxy, haloalkoxy.</p>

<p dir="rtl">10 haloalkoxy, hydroxy, hydroxyalkyl, cyano, aminoalkyl, carboxy, alkoxycarbonyl and Rc are hydrogen, alkyl, halo, hydroxy, or alkoxy; Or when Ra and Rc are bonded to the same carbon atom, Ra and Rc together along with the carbon atom they are attached to form a cycloalkylene or</p>

<p dir="rtl">15 heterocyclylene;</p>

Q1 is N or CR1, where R1 is hydrogen or deuterium;

Q2 is N, CH, or CD;

<p dir="rtl">R2 is alkyl, halo, hydroxy, hydroxyalkyl</p>

<p dir="rtl">20 CD2OH-hydroxyalkyl, alkylsulfoxide, alkylsulfonyl, aminosulfonyl, aminocarbonyl, carboxy, cyano, or alkoxycarbonyl;</p>

15151

-103-

L is a ligand, S(O)2, S(O), S, O, or CR5R6, where R5 and R6 are individually hydrogen or alkyl;

^And

<img file="SA15151B1_D0095.tif" />

It is a ring with the form (a) or (b):

<img file="SA15151B1_D0096.tif" />

where:

<p dir="rtl">m be 0, 1; or 2;</p>

n can be 0, 1, or 2; Provided that m + n is 1, 2, or 3;

k can be 0, 1 or 2

<p dir="rtl">10 z can be 0, 1, or 2</p>

Each Rd is individually a hydrogen, alkyl, or halogen;

Re consists of hydrogen, alkyl, halogen, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, cyano or oxo;

<p dir="rtl">15 Rf and Rg are individually hydrogen, alkyl, or haloalkyl;</p>

Each Rh is individually an alkyl, halo, haloalkyl, alkoxy, hydroxyalkyl, alkoxyalkyl, hydroxy, cyano, or oxo; or

15151

-104-

When one Rh is attached to carbon 2 or 3 of the piperidine (B) ring and the second Rh is attached to carbon 5 or 6 of the piperidine (B) ring, the position of the nitrogen atom is 1, then the first and second Rh combine to form a chain alkylene;

The D ring is a phenyl or heteroaryl ring with a 5 or 6 strand.

<p dir="rtl">5 Which, including X and haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, aminoalkyl, carboxy</p>

<p dir="rtl">10 carboxy, cycloalkyl, heterocyclyl, heteroaryl</p>

heteroaryl, acyl amino;

X and X1 are each individually N or C provided that only one of X and X1 is N;

R3 is an amino or aminoalkyl;

<p dir="rtl">15 R4 is an alkyl, cycloalkylalkyl, halo, hydroxy, amino, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, aryl alkyl, heterocyclic alkyl, cycloalkylalkyl, heterocyclic alkyl, heterocyclic alkyl A heteroaryl of 5 or 6 ether, or a heterocyclyl of 4 to 6 ether where the aryl is</p>

<p dir="rtl">20 A heteroaryl or heterocyclyl alone or as part of an alkyl or a heteroaryl with a substitution with Ri and/or Rj each selected separately from hydrogen, alkyl, halo, haloalkyl, haloalkoxy, alkoxy , hydroxy, cyano, amino, aminoalkyl, alkylsulfoxide, or alkylsulfonyl; or</p>

15151

-105-

R3 and R4 together with the carbon atom to which they are attached form a ring with the formula:

:)c(

where:

<p dir="rtl">5 1m be 0, 1; or 2;</p>

<p dir="rtl">1n can be 0, 1, or 2; Provided that 1+ n 1m is 1, 2, or 3;</p>

Rk and Rm are individually hydrogen, alkyl, or haloalkyl;

One of Y and Z is S(O)2, S(O), S, O, CH2, or NH; The other of X and Y is an expression

<p dir="rtl">About CH2; Where the ring of formula (c) is replaced by Rn and/or Ro, each is chosen</p>

<p dir="rtl">10 Separately from hydrogen, alkyl, alkyldienyl, alkyl, halo, haloalkyl, haloalkoxy, alkoxy, hydroxy, cyano, alkylsulfoxide, alkylsulfonyl, oxo, cycloalkyl, cyclase Heterocyclyl allyl , heteroaryl; or</p>

<p dir="rtl">15 Pharmaceutical acceptable salt thereof.</p>

<p dir="rtl">39. A compound with the formula (I'B):</p><img file="SA15151B1_D0097.tif" />

(I'B)

where:

15151

-106-

A is or is replaced by Rb, Ra, and/or Rc where Ra and Rb are

Selected individually from hydrogen, alkyl, halo, haloalkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, cyano, aminoalkyl, carboxy, and alkoxy.

<p dir="rtl">5 The alkoxycarbonyl and Rc are hydrogen, alkyl, halo hydroxy, alkoxy, optionally substituted heterocyclyl, substituted aryl, aryl.</p>

Optionally substituted heteroaryl, S(O)R-

NR'SO2R-, NR'C(O)R-, C(O)R-, S(O)2R

<p dir="rtl">10 -“NR'R”-, S(O)2NR’R”-, C(O)NR’R, or -NR’C(O)C(O)R where R is an expression</p>

About alkyl, cycloalkyl, cycloalkyl Alkyl cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted aralkyl, non-aryl

<p dir="rtl">15 An optionally substituted heteroaryl, or a heteroaryl alkyl</p>

optionally substituted heteroaralkyl, and 'R' and 'R' are individually hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, cycloalkylalkyl, optionally substituted heterocyclyl , cyclyl alkyl non

<p dir="rtl">20 an optionally substituted heterocyclylalkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted heteroaryl, or an optionally substituted heteroaryl</p>

R' and R' form or optionally substituted heteroaralkyl

All together, next to the nitrogen atom to which a heterocyclic bond is attached

25 optionally substituted heterocyclyl;

15151

-107-

Q1 is N or CR1, where R1 is hydrogen or deuterium;

Q2 is N, CH, or CD;

R2 is alkyl, halo, hydroxy, hydroxyalkyl

<p dir="rtl">5 CD2OH-hydroxyalkyl, alkylsulfoxide, alkylsulfonyl, aminosulfonyl, aminocarbonyl, carboxy, cyano, or alkoxycarbonyl;</p>

L is a ligand, S(O)2, S(O), S, O, or CR5R6, where R5 and R6 are individually hydrogen or alkyl;

10 And

<img file="SA15151B1_D0098.tif" />

It is a ring with the form (a) or (b):

<img file="SA15151B1_D0099.tif" />

where:

m be 0, 1; or 2;

15 n can be 0, 1, or 2; Provided that m + n is 1, 2, or 3;

k can be 0, 1 or 2

z can be 0, 1, or 2

Each Rd is individually a hydrogen, alkyl, or halogen;

15151

-108-

Re consists of hydrogen, alkyl, halogen, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, cyano or oxo;

Rf and Rg are individually hydrogen, alkyl, or haloalkyl;

<p dir="rtl">5 Each Rh is individually an alkyl, halo, haloalkyl, alkoxy, hydroxyalkyl, alkoxyalkyl, hydroxy, cyano, or oxo; or</p>

When one Rh is attached to carbon 2 or 3 of the piperidine (B) ring and the second Rh is attached to carbon 5 or 6 of the piperidine (B) ring, the position of the nitrogen atom is

<p dir="rtl">10 is 1, then the first and second Rhes combine to form an alkylene chain;</p>

The D ring is a phenyl or heteroaryl ring of 5 or 6 atoms which, including X and Optional with one or two individually selected groups of alkyl, halo, haloalkyl, alkoxy

<p dir="rtl">15 alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, aminoalkyl, carboxy, cycloalkyl, heterocyclyl, heteroaryl, and acyl amino;</p>

X and X1 are each individually N or C provided that only one of X and

<p dir="rtl">20 N;</p>

R3 is an amino or aminoalkyl;

R4 is an alkyl, cycloalkyl alkyl, halo, hydroxy, amino, alkoxycarbonyl, hydroxy alkyl

15151

-109-

hydroxyalkyl, alkoxyalkyl, aryl alkyl, heterocyclic alkyl, cycloalkyl alkyl, cycloalkylalkyl, heterocyclic alkyl, heteroaryl of 5 or 6 ter, or heterocyclyl of 4 to 6 ter, where the aryl is heteroaryl Or a heterocyclyl on its own or as part of an alkyl

<p dir="rtl">5 A heteroaryl alkyl substituent with Ri and/or Rj, each selected individually from</p>

hydrogen, alkyl, halo, haloalkyl, haloalkoxy, alkoxy, hydroxy, cyano, amino, aminoalkyl, alkylsulfoxide, or alkylsulfonyl; or

<p dir="rtl">R3 and R4 together with the carbon atom to which they are attached form a ring with the formula:</p>

:(c) 10

where:

<p dir="rtl">1m be 0, 1; or 2;</p>

<p dir="rtl">1n can be 0, 1, or 2; Provided that 1+ n 1m is 1, 2, or 3;</p>

<p dir="rtl">15 Rk and Rm are individually hydrogen, alkyl, or haloalkyl;</p>

One of Y and Z is S(O)2, S(O), S, O, CH2, or NH; The other of X and Y is CH2; Where the ring of formula (c) is substituted with Rn and/or Ro, each of them is selected separately from hydrogen, alkyl, halo, haloalkyl, haloalkoxy, alkoxy, hydroxy, cyano, alkyl 20 sulfoxide. alkylsulfoxide, alkylsulfonyl, oxo, cycloalkyl

cycloalkyl, heterocyclyl, and heteroaryl; or

15151

-110-

Pharmaceutical acceptable salt thereof.

<p dir="rtl">40. A compound with the formula (I'C):</p><img file="SA15151B1_D0100.tif" />

(I'C)

<p dir="rtl">5 where:</p>

A is or is replaced by Rb, Ra, and/or Rc where Ra and Rb are

Selected individually from hydrogen, alkyl, amino, cycloalkyl, alkyldienyl, alkenyl, halo, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl

<p dir="rtl">10 Hydroxyalkyl, cyano, aminoalkyl, carboxy, alkoxycarbonyl and Rc are hydrogen, alkyl, halo, hydroxy, alkoxy, optionally substituted heterocyclyl, substituted aryl. Optionally substituted heteroaryl, or</p>

<p dir="rtl">15 - “NR'R where R is an alkyl, cycloalkyl, heterocyclic</p>

optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, or an optionally substituted heteroaralkyl, and 'R' and 'R' are each hydrogen or Alkyl or 'R

<p dir="rtl">20 And “R” forms all of them together with the nitrogen atom to which they are attached to the cyclyl non</p>

optionally substituted heterocyclyl; Or when Rc and Ra are attached to the same carbon atom of a cycloalkyl or a heteroaryl aryl.

15151

-111-

heteroaryl ring, then Rc and Ra together with the carbon atom attached to them form a cycloalkylene or heteroaryl cyclone

;heterocyclylene

A has the structure (d):

5

(d)

where:

t can be 0, 1 or 2;

The E ring is a 4- to 7-membered heterocyclic ring containing 1 or 2 heterogeneous rings.

<p dir="rtl">10 Selected separately from S, N, O, and SO2 where the remaining atoms are carbon; W is CH2, O, or N; It has optional substitution with Rb, Ra, and/or Rc, where Ra and Rb are selected separately from hydrogen, amino, alkyl, alkyldienyl, alkenyl, halo, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxy. Hydroxyalkyl, cyano, amino</p>

<p dir="rtl">15 The aminoalkyl, carboxy, alkoxycarbonyl and Rc are hydrogen, alkyl, halo, hydroxy, or alkoxy; Or when Ra and Rc are bonded to the same carbon atom, Ra and Rc together along with the carbon atom to which they are bonded form a cycloalkylene or heterocyclylene.</p>

<p dir="rtl">20 Q1 is N or CR1, where R1 is hydrogen or deuterium;</p>

Q2 is CH, N, or CD;

15151

-112-

R2 is alkyl, halo, hydroxy, hydroxyalkyl

CD2OH-hydroxyalkyl, alkylsulfoxide, alkylsulfonyl, aminosulfonyl, aminocarbonyl, carboxy, cyano, or alkoxycarbonyl;

<p dir="rtl">5 L is a ligand, SO2, SO, S, O, or CR5R6, where R5 and R6 are individually hydrogen or alkyl;</p>

^And

<img file="SA15151B1_D0101.tif" />

It is a ring with the form (a) or (b):

<img file="SA15151B1_D0102.tif" />

<p dir="rtl">10 where:</p>

<p dir="rtl">m be 0, 1; or 2;</p>

<p dir="rtl">n can be 0, 1, or 2; Provided that m + n is 1, 2, or 3;</p>

Rd is a hydrogen or alkyl;

Re can be hydrogen, alkyl, halogen, or oxo;

<p dir="rtl">15 Rhes are individually alkyl, halo, haloalkyl, alkoxy, hydroxyalkyl, alkoxyalkyl, hydroxy, cyano, or oxo;</p>

15151

-113-

The D ring is a phenyl or heteroaryl ring of 5 or 6 atoms which, including X and Optional alkyl substitution;

X and X1 are each individually N or C provided that only one of X and

5 N;

R3 is an amino or aminoalkyl;

R4 can be an alkyl, cycloalkylalkyl, halo, hydroxy, amino, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, heteroaryl of 5 or 6 10 ether, or a heterocyclyl of 4 To 6 thiart where aryl heterocyclic

A heteroaryl or heterocyclyl substituent with Ri and/or Rj each selected separately from hydrogen, alkyl, halo, haloalkyl, haloalkoxy, alkoxy, hydroxy, cyano, alkylsulfoxide, or alkylsulfonyl; or

<p dir="rtl">15 R3 and R4 together with the carbon atom to which they are attached form a ring with the formula:</p>

:)c(

where:

1m be 0, 1; or 2;

<p dir="rtl">20 1n can be 0, 1, or 2; Provided that 1+ n 1m is 1, 2, or 3;</p>

15151

-114-

One of Y and Z is SO2, SO, S, O, CH2, or NH; The other of X and Y is CH2; Where the ring having the formula (c) has a substitution with Rn and/or Ro, each of them is selected separately from hydrogen, alkyl, alkyldieenyl, alkenyl, halo, haloalkyl, haloalkoxy, alkoxy, hydroxy, 5 Cyano, alkylsulfoxide, alkylsulfonyl, or oxo

oxo; or

Pharmaceutical acceptable salt thereof.

41. A compound with the formula (I'D):

<img file="SA15151B1_D0103.tif" />

(I'D) 10

where:

A is or is replaced by Rb, Ra, and/or Rc where Ra and Rb are

Selected individually from hydrogen, alkyl, halo, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl

<p dir="rtl">15 Hydroxyalkyl, cyano, aminoalkyl, carboxy, alkoxycarbonyl and Rc are hydrogen, alkyl, halo, hydroxy, alkoxy, optionally substituted heterocyclyl, substituted aryl. Optionally substituted heteroaryl, or -</p>

<p dir="rtl">20 “NR'R where R is an alkyl, cycloalkyl, heterocyclic</p>

optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heterocyclyl

15151

-115-

A heteroaryl, or an optionally substituted heteroaralkyl, the 'R' and 'R' being individually hydrogen, the alkyl, or the 'R' and 'R' together forming the nitrogen atom to which they are bonded to a heteroaryl cyclyl optionally substituted heterocyclyl;

<p dir="rtl">5 Q1 is N or CR1, where R1 is hydrogen or deuterium;</p>

<p dir="rtl">Q2 is CH, N, or CD;</p>

<p dir="rtl">R2 is alkyl, halo, hydroxy, hydroxyalkyl</p>

CD2OH-hydroxyalkyl, alkylsulfoxide, alkylsulfonyl

<p dir="rtl">10 alkylsulfonyl, aminosulfonyl, aminocarbonyl, carboxy, cyano, or alkoxycarbonyl;</p>

L is a ligand, SO2, SO, S, O, or CR5R6, where R5 and R6 are individually hydrogen or alkyl;

15

^And

<img file="SA15151B1_D0104.tif" />

It is a ring with the form (a) or (b):

<img file="SA15151B1_D0105.tif" />

where:

m be 0, 1; or 2;

n can be 0, 1, or 2; Provided that m + n is 1, 2, or 3;

15151

-116-

Rd is a hydrogen or alkyl;

Re can be hydrogen, alkyl, halogen, or oxo;

Rhes are individually alkyl, halo, haloalkyl, alkoxy, hydroxyalkyl, alkoxyalkyl, hydroxy, 5-cyano, or oxo;

The D ring is a phenyl or heteroaryl ring of 5 or 6 atoms which, including X and Optional alkyl substitution;

<p dir="rtl">X and X1 are each individually N or C provided that only one of X and</p>

<p dir="rtl">10 N;</p>

R3 is an amino or aminoalkyl;

R4 can be an alkyl, cycloalkylalkyl, halo, hydroxy, amino, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, heteroaryl of 5 or 6 15 ether, or a heterocyclyl of 4 To 6 thiart where aryl heterocyclic

A heteroaryl or heterocyclyl substituent with Ri and/or Rj each selected separately from hydrogen, alkyl, halo, haloalkyl, haloalkoxy, alkoxy, hydroxy, cyano, alkylsulfoxide, or alkylsulfonyl; or

<p dir="rtl">20 R3 and R4 together with the carbon atom to which they are attached form a ring with the formula:</p>

:)c(

15151

-117-

where:

<p dir="rtl">1m be 0, 1; or 2;</p>

<p dir="rtl">1n can be 0, 1, or 2; Provided that 1+ n 1m is 1, 2, or 3;</p>

<p dir="rtl">5 One of Y and Z is SO2, SO, S, O, CH2, or NH; The other of X and Y is CH2; Where the ring of formula (c) is substituted with Rn and/or Ro, each of them is selected separately from hydrogen, alkyl, halo, haloalkyl, haloalkoxy, alkoxy, hydroxy, cyano, alkylsulfoxide. , alkylsulfonyl, or oxo;</p>

<p dir="rtl">10 Pharmaceutical acceptable salt thereof.</p>

<p dir="rtl">42 In Embodiment 42, the compound according to any of Embodiments 37 to 41, or a pharmaceutically acceptable salt thereof having the structure having the formula ('III):</p><img file="SA15151B1_D0106.tif" />

(III')

15 43.In Embodiment 43, the compound according to any of Embodiments 37 to 41, or a pharmaceutically acceptable salt thereof.

The structure has the formula ('IV):

<img file="SA15151B1_D0107.tif" />

15151

-118-

(IV')

<p dir="rtl">44 In Embodiment 44, the compound according to any of Embodiments 37 to 41, or a pharmaceutically acceptable salt thereof having the structure having the formula ('V) or ('VI):</p><img file="SA15151B1_D0108.tif" /><img file="SA15151B1_D0109.tif" />

(V') (VI') 5

In one subembodiment of embodiment 4, the compound or a pharmaceutically acceptable salt thereof has structure (V). In another subembodiment of embodiment 4, the compound or a pharmaceutically acceptable salt thereof has the structure (VI).

<p dir="rtl">45 In Embodiment 45, the compound according to any of Embodiments 37 to 43 and the sub-embodies therein, or a pharmaceutically acceptable salt thereof such that R1 is hydrogen.</p>

<p dir="rtl">10 46.In Embodiment 46, composite according to any of Embodiments 37 to 43 and a sub-embodiment therein,</p>

or a pharmaceutically acceptable salt thereof such that R1 is deuterium.

<p dir="rtl">47 In Embodiment 7, the compound according to any of Embodiments 37 to 46 and the sub-embodies therein, or a pharmaceutically acceptable salt thereof such that L is S.</p>

<p dir="rtl">48 .in Embodiment 8, composite according to any of Embodiments 37 through 46 and the subembodiments therein, or</p>

<p dir="rtl">15 A pharmaceutically acceptable salt thereof is such that L is S(O) or 2(S(O).</p>

<p dir="rtl">49 In Embodiment 49, the compound according to any of Embodiments 37 to 46 and the subembodiments therein, or a pharmaceutically acceptable salt thereof such that L is a ligand.</p>

<p dir="rtl">50 .in Embodiment 50, composite according to any of Embodiments 37 through 46 and sub-embodiments therein,</p>

Or a pharmaceutically acceptable salt thereof such that L is CR5R6, where R5 and R6 are each

20 It is either a hydrogen or an alkyl. In one subform of Form 50,

L is CH2. In another subembodiment of embodiment 50, L is 2(C(CH3).

15151

-119-

<p dir="rtl">51 In Embodiment 11, the compound according to any of Embodiments 37 to 50 and the subembodiments therein, or a pharmaceutically acceptable salt thereof such that R2 is a hydroxyalkyl. In a first subembodiment of embodiment 51, R2 is a hydroxymethyl.</p>

<p dir="rtl">52 .in Embodiment 52, composite according to any of Embodiments 37 through 50 and sub-embodiments therein,</p>

<p dir="rtl">5 or a pharmaceutically acceptable salt thereof such that R2 is an alkylsulfonyl. In a first subembodiment of embodiment 52, R2 is a methylsulfonyl or ethylsulfonyl.</p>

<p dir="rtl">53 In Embodiment 53, composite according to any of Embodiments 37 through 50 and sub-embodiments therein,</p>

or a pharmaceutically acceptable salt thereof such that R2 is an alkyl sulfoxide

alkylsulfoxide. In a first subembodiment of Embodiment 53, R2 is methyl sulfoxide, 10-ethyl sulfoxide, or isopropyl sulfoxide. In a second subembodiment of Embodiment 53, R2 is methyl sulfoxide.

<p dir="rtl">54 In Embodiment 54, the compound according to any of Embodiments 37 to 50 and sub-embodies therein, or a pharmaceutically acceptable salt thereof such that R2 is CD2OH-.</p>

<p dir="rtl">55 In Embodiment 55, composite according to any of Embodiments 37 through 50 and sub-embodiments therein,</p>

<p dir="rtl">15 or a pharmaceutically acceptable salt thereof such that R2 is an alkoxycarbonyl, aminosulfonyl or aminocarbonyl. In a first sub-embodiment of model 55, R2 is S(O)2NH2–. In a second subembodiment of Form 55, R2 is -CONH2. In a third sub-embodiment of model 55, R2 is C(O)CH3–.</p>

<p dir="rtl">56 In Embodiment 16, composite according to any of Embodiments 37 through 50 and the sub-embodiments therein,</p>

<p dir="rtl">20 Or a pharmaceutically acceptable salt thereof such that R2 is hydroxy.</p>

<p dir="rtl">57 In Embodiment 57, the compound according to any of Embodiments 37 to 50 and sub-embodiments therein, or a pharmaceutically acceptable salt thereof such that R2 is a halo. In a subembodiment of embodiment 17, R2 is a chloro.</p>

15151

-120-

<p dir="rtl">58 In Embodiment 58, the compound according to any of Embodiments 37 to 57 and the subembodiments therein, or a pharmaceutically acceptable salt thereof is where:</p><img file="SA15151B1_D0110.tif" />

It is a ring with the formula

:(a)

<img file="SA15151B1_D0111.tif" />

<p dir="rtl">5 where:</p>

<p dir="rtl">m be 0, 1; or 2;</p>

<p dir="rtl">n is 0, 1, or 2 where when n is 2 then one of the CH2 is replaced by S, O, or SO2; Provided that m + n is 1, 2, or 3;</p>

<p dir="rtl">k can be 0, 1 or 2</p>

10 z can be 0, 1, or 2

Each Rd is individually a hydrogen, alkyl, or halogen;

Re and Re1 are individually hydrogen, alkyl, halogen, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, cyano or oxo; or

15 When Re and Re1 are bonded to the same carbon atom, then Re and Re1 together with the carbon atom attached to them form a cycloalkylene or heterocyclylene.

In a first form of Form 58,

15151

-121-

<img file="SA15151B1_D0112.tif" />

It is a loop with the formula:

<img file="SA15151B1_D0113.tif" />

<img file="SA15151B1_D0114.tif" />

<img file="SA15151B1_D0115.tif" />

<p dir="rtl">59 In Embodiment 59, the compound according to any of Embodiments 37 to 57 and the subembodiments therein, or a pharmaceutically acceptable salt thereof is where:</p><img file="SA15151B1_D0116.tif" />

It is a ring with the formula

:(a)

<img file="SA15151B1_D0117.tif" />

<img file="SA15151B1_D0118.tif" />

In the first subform of Form 59,

be:

<img file="SA15151B1_D0119.tif" />

In a second subform of Form 59,

be:

15151

-122-

<img file="SA15151B1_D0120.tif" />

<img file="SA15151B1_D0121.tif" />

<img file="SA15151B1_D0122.tif" />

<img file="SA15151B1_D0123.tif" />

<img file="SA15151B1_D0124.tif" />

<img file="SA15151B1_D0125.tif" />

In a third subform of Form 59,

<img file="SA15151B1_D0126.tif" />

Be

or

<img file="SA15151B1_D0127.tif" />

<p dir="rtl">60 In Embodiment 60, composite according to any of Embodiments 37 through 57 and sub-embodiments therein,</p>

Or a pharmaceutically acceptable salt thereof that is such that

<img file="SA15151B1_D0128.tif" />

<img file="SA15151B1_D0129.tif" />

Preferably where z is 1, and

Where R3 is an amino or aminoalkyl; And

R4 is an alkyl, cycloalkyl alkyl, halo, hydroxy, amino, alkoxycarbonyl, hydroxy alkyl

15151

-123-

hydroxyalkyl, alkoxyalkyl, heteroaryl of 5 or 6

A heterocyclyl from 4 to 6 where a heteroaryl or heterocyclyl substituent with Ri and/or Rj is chosen separately from a hydrogen, alkyl, halo, halo alkyl, haloalkyl

<p dir="rtl">5 Haloalkoxy, alkoxy, hydroxy, cyano, alkylsulfoxide, or alkylsulfonyl. In a subembodiment of embodiment 20, z is 0, R3 is aminomethyl, and R4 is methyl.</p>

61.In Embodiment 61, composite according to any of Embodiments 37 through 57 and sub-embodiments therein,

Or a pharmaceutically acceptable salt thereof that is such that

<img file="SA15151B1_D0130.tif" />

10 Preferably where z is 1, and

Where R3 and R4 together with the carbon atom to which they are connected form a ring with the formula (c):

where:

15 1m be 0, 1; or 2;

1n can be 0, 1, or 2; Provided that 1+ n 1m is 1, 2, or 3;

Rk and Rm are individually hydrogen, alkyl, or haloalkyl;

15151

-124-

One of Y and Z is S(O)2, S(O), S, O, CH2, or NH; The other of X and Y is CH2; Where the ring having the formula (c) is substituted with Rn and/or Ro, each of them is selected separately from hydrogen, alkyl, alkyldienyl, alkenyl, halo, haloalkyl, haloalkoxy, alkoxy, hydroxy.

<p dir="rtl">5 hydroxy, cyano, alkylsulfoxide, alkylsulfonyl, oxo, cycloalkyl, heterocyclyl, and heteroaryl; or</p>

When Rn and Ro are bonded to the same carbon atom, then Rn and Ro together along with the carbon atom they are bonded to form a cycloalkylene or non-cycline.

10 heterocyclylene;

<img file="SA15151B1_D0131.tif" />

.62

<img file="SA15151B1_D0132.tif" />

<img file="SA15151B1_D0133.tif" />

<img file="SA15151B1_D0134.tif" />

In the first subform of Form 61,

<img file="SA15151B1_D0135.tif" />

15151

-125-

In Embodiment 62, composite according to any of Embodiments 37 through 57 and subembodiments therein, or

A pharmaceutically acceptable salt of it is such that

<img file="SA15151B1_D0136.tif" />

<img file="SA15151B1_D0137.tif" />

Preferably where z is 1, and

Where R3 and R4 together form a ring with the carbon atom to which they are attached

<p dir="rtl">5 Formula (c):</p>

where:

<p dir="rtl">1m be 0, 1; or 2;</p>

<p dir="rtl">1n can be 0, 1, or 2; Provided that 1+ n 1m is 1, 2, or 3;</p>

<p dir="rtl">10 Rk and Rm are individually hydrogen, alkyl, or haloalkyl;</p>

One of Y and Z is S(O)2, S(O), S, O, CH2, or NH; The other of X and Y is CH2; Where the ring having the formula (c) is substituted with Rn and/or Ro, each of them is selected separately from hydrogen, alkyl, alkyldienyl, alkenyl, halo, haloalkyl, haloalkoxy, alkoxy, hydroxy.

<p dir="rtl">15 hydroxy, cyano, alkylsulfoxide, alkylsulfonyl</p>

Oxo, cycloalkyl, heterocyclyl, and heteroaryl.

15151

-126-

<img file="SA15151B1_D0138.tif" />

be:

In the first subform of Form 62,

<img file="SA15151B1_D0139.tif" />

<img file="SA15151B1_D0140.tif" />

In a second subform of Form 62,

be:

<img file="SA15151B1_D0141.tif" />

<img file="SA15151B1_D0142.tif" />

<img file="SA15151B1_D0143.tif" />

5 In a third subform of Form 62,

<img file="SA15151B1_D0144.tif" />

be:

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<img file="SA15151B1_D0145.tif" />

<img file="SA15151B1_D0146.tif" />

In subform four of Form 62,

<img file="SA15151B1_D0147.tif" />

<img file="SA15151B1_D0148.tif" />

<p dir="rtl">63. In Embodiment 63, the compound according to any of Embodiments 37 to 60 and the sub-embodies therein, or a pharmaceutically acceptable salt thereof Ra and Rb individually selected from hydrogen,</p>

<p dir="rtl">5 Alkyl, amino, cycloalkyl, alkyldienyl, alkyl, halo, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, cyano, aminoalkyl, carboxy, alkoxycarbonyl and Rc It is hydrogen hydrogen, alkyl, halo, hydroxy, alkoxy, heterocyclic substituted</p>

<p dir="rtl">10 optionally substituted heterocyclyl, optionally substituted heteroaryl, -</p>

,S(O)2R,S(O)R

NR'R”-, S(O)2NR’R”-, C(O)NR’R”-, NR’SO2R-, NR’C(O)R-, C(O)R-

Or -NR'C(O)C(O)R where R is an alkyl, cycloalkyl, cycloalkyl.

<p dir="rtl">15 Alkyl cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, Or a heteroaryl alkyl with an optionally substitution</p>

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substituted heteroaralkyl, 'R' and 'R' are each hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, cycloalkylalkyl, optionally substituted heterocyclyl, non-cyclic alkyl Homogeneous by replacement

<p dir="rtl">5 optionally substituted heterocyclylalkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted heteroaryl, or an optionally substituted heteroaryl, or 'R' and 'R' forming the whole Together, next to the nitrogen atom to which they are attached, there is a heterocyclic substituent</p>

<p dir="rtl">10 optionally substituted heterocyclyl; or</p>

When Rc and Ra are bonded to the same carbon atom of the cycloalkyl or heteroaryl ring, then Rc and Ra together with the carbon atom to which they are bonded form a cycloalkylene or heteroaryl ring.

.heterocyclylene

<p dir="rtl">15 In a first sub-embodiment of embodiment 63, Ra and Rb are individually selected from hydrogen, alkyl, amino, cycloalkyl, alkyl dienyl, alkenyl, halo, haloalkyl, alkoxy, haloalkoxy, hydroxy, cyano and Rc. It is either hydrogen or -”NR’R, where ‘R’ and “R” are individually hydrogen, alkyl, hydroxyalkyl.</p>

<p dir="rtl">20 hydroxyalkyl, alkoxyalkyl, aminoalkyl, or optionally substituted heterocyclyl.</p>

In a second sub-embodiment of embodiment 63, Ra and Rb are individually selected from hydrogen, alkyl, halo, haloalkyl, alkoxy, haloalkoxy, hydroxy, and cyano and Rc is hydrogen.

<p dir="rtl">25 hydrogen or -”NR’R, where ‘R’ and ‘R’ are individually hydrogen</p>

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Alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, or optionally substituted heterocyclic

.heterocyclyl

In a third sub-model of Model 63, Ra and Rb are selected separately from hydrogen

<p dir="rtl">5 hydrogen, alkyl, halo, haloalkyl, alkoxy, haloalkoxy, hydroxy, and cyano and Rc are hydrogen or “NR’R” where “R” and “R” are individually hydrogen, alkyl hydrogen, hydroxyalkyl, alkoxyalkyl, aminoalkyl, or optionally substituted heterocyclic</p>

.heterocyclyl 10

In four sub-embodiments of embodiment 63, Ra and Rb are individually selected from hydrogen, methyl, ethyl, methoxy, ethoxy, chloro, fluoro, difluoromethyl, tarifluoromethyl, difluoromethoxy, tarifluoromethoxy, hydroxy, or cyano. cyano and Rc are hydrogen.

<p dir="rtl">15 In a fifth sub-embodiment of embodiment 63, and a first sub-embodiment thereof, loop A has the structure (d):</p><img file="SA15151B1_D0149.tif" />

(d)

where:

t can be 0, 1 or 2;

<p dir="rtl">20 The E ring is a 4- to 7-atom heterocyclic ring containing 1 or 2 heteroatoms selected separately from S, N, O, and SO2, where the remaining atoms are carbon; W is CH2, O, or N; It can be replaced with Rb, Ra, and/or Rc, where Ra and Rb are each chosen</p>

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Separately from hydrogen, amino, alkyl, alkyldienyl, alkyl, halo, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, cyano, aminoalkyl, carboxy, alkoxycarbonyl and Rc are It is hydrogen

<p dir="rtl">5 hydrogen, alkyl, halo, hydroxy, or alkoxy; or</p>

When Ra and Rc are bonded to the same carbon atom, Ra and Rc together with the carbon atom to which they are bonded form a cycloalkylene or heterocyclylene.

In a first embodiment, of the fifth sub-embodiment, loop A is

<img file="SA15151B1_D0150.tif" />

. In a second model,

10 Of the four submodels, loop A is:

<img file="SA15151B1_D0151.tif" />

<img file="SA15151B1_D0152.tif" />

<img file="SA15151B1_D0153.tif" />

In a second embodiment of the fifth submodel, loop A is:

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<img file="SA15151B1_D0154.tif" />

<img file="SA15151B1_D0155.tif" />

<img file="SA15151B1_D0156.tif" />

<img file="SA15151B1_D0157.tif" />

<img file="SA15151B1_D0158.tif" />

<img file="SA15151B1_D0159.tif" />

In a sixth sub-embodiment of Form 63, loop A is:

<img file="SA15151B1_D0160.tif" />

<img file="SA15151B1_D0161.tif" />

<img file="SA15151B1_D0162.tif" />

<img file="SA15151B1_D0163.tif" />

<img file="SA15151B1_D0164.tif" />

<img file="SA15151B1_D0165.tif" />

<img file="SA15151B1_D0166.tif" />

<img file="SA15151B1_D0167.tif" />

<img file="SA15151B1_D0168.tif" />

<img file="SA15151B1_D0169.tif" />

<img file="SA15151B1_D0170.tif" />

<img file="SA15151B1_D0171.tif" />

It is understood that Embodiments 37 through 63 above include all combinations of embodiments and subembodiments contained therein. For example, ring A of the fifth subform of Form 63,

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They may be combined individually with one or more of Embodiments 35 through 62 and/or sub-embodiments therein.

Additional forms include Forms 66 through 112 below:

<p dir="rtl">66. A compound with the formula (I):</p>

5

(I)

where:

A and E are selected individually from the bonds, S, NH, O, CH2, and 2(S(O);

Z consists of hydrogen, alkyl, halo, haloalkyl, haloalkyl.

10 haloalkoxy, cyano, cycloalkyl, heterocyclyl, heteroaryl (where cycloalkyl, heterocyclyl, and heteroaryl are optionally replaced by one to three halo S(O)2Rd-S,) O)Rc-, O(alk)ORb-, O(alk)yRa-,)halo, -

,NRgSO2Rh- ,NReC(O)Rf

<p>- NRpRq-, S(O)2NRnRo-, C(O)NRkRm-, OC(O)NRiRj- 15</p>

NRrC(O)C(O)Rs or -YM (where Y is a ligand, O, or SO2 and M is an alkyl, haloalkyl, cycloalkyl, heterocyclyl, or heteroaryl in which an alkyl is substituted , haloalkyl, cycloalkyl, heterocyclyl and heteroaryl

20 heteroaryl with -,O(alk)yRa

- NRgSO2Rh-, NReC(O)Rf-, S(O)2Rd-, S(O)Rc-, O(alk)ORb-

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,C(O)NRkRm- ,OC(O)NRiRj

<p dir="rtl">-NRpRq-, S(O)2NRnRo, or -NRrC(O)C(O)Rs, cycloalkyl, heterocyclyl, and heteroaryl aryls are also optionally replaced with 1 to 3 halo(s; where each y is 0 or 1, each alk is a</p>

<p dir="rtl">5 Alkylene, and each Rh, Rf, Rd, Rc, and Rs individually are an alkyl, cycloalkyl, cycloalkyl, cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, aryl an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted heteroaryl, or a heteroaryl</p>

optionally substituted heteroaralkyl; Each Rg, Re, Rb, Ra, Rr, Rq, Rp, Ro, Rn, Rm, Rk, Rj, Ri, and Rs are individually hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl substituted aryl, an optionally substituted aralkyl, an optionally substituted heteroaryl, or an optionally substituted heteroaralkyl; Or, independently of

<p dir="rtl">20 Each other, Ri and Rk, Rj and Rn, Rm and Ro, and Rp and Rq, together, along with the nitrogen atom to which they are attached, form a heterocyclic cyclyl with an optional substitution.</p>

;optionally substituted heterocyclyl

R3, R2, R1, and R4 are selected individually from hydrogen, alkyl, cycloalkyl, halo, haloalkyl, haloalkoxy, alkoxy.

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alkoxy, cyano, hydroxy, hydroxylalkyl, amino, and aminoalkyl;

Or one of R1, R2, R3, and R4, when attached to the same carbon atom, fuses to form an oxo, an alkyldieenyl, or a cycloalkylene from 3 to 6.

<p dir="rtl">5 dha, or an optionally substituted heterocyclylene from 4 to 6 dha;</p>

R5 and R6 are individually selected from hydrogen, alkyl, cycloalkyl, halo, haloalkyl, haloalkoxy, alkoxy, hydroxy, cyano, hydroxylalkyl, amino

<p dir="rtl">10 amino, aminoalkyl, or where one of R5 and R6 is an optionally substituted heterocyclyl and the other R5 and R6 are chosen from hydrogen, alkyl, cycloalkyl, halo, haloalkyl, haloalkoxy, alkoxy, hydroxy, cyano, hydroxylalkyl, amino, and aminoalkyl;</p>

15 L is a ligand, S(O)2, S(O), S, O, or CR7R8, where R7 and R8 are individually hydrogen or alkyl;

Z1 is a set of the form (a) or (b):

or

(a)(b)

20 where:

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R9 is a hydrogen, alkyl, halo, hydroxy, amino, or haloalkyl;

R10 consists of hydrogen, alkyl, halo, hydroxy, hydroxy, CD2OH-, hydroxyalkyl, alkylsulfoxide, alkyl 5-sulfonyl, amino, aminoalkyl, aminosulfonyl.

aminosulfonyl, aminocarbonyl, carboxy, cyano, or alkoxycarbonyl;

R13 is a hydrogen, alkyl, halo, hydroxy, amino, or haloalkyl;

<p dir="rtl">10 R14 is a hydrogen, alkyl, or haloalkyl;</p>

R11 and R15 are selected from amino and aminoalkyl;

R12 and R16 are chosen from hydrogen, cyano, halo, alkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, aryl, heterocyclyl, and heteroaryl, where the alkyl,

<p dir="rtl">15 cycloalkyl, aryl, heterocyclyl and heteroaryl are optionally replaced by one to three individually selected alkyl, halo, haloalkyl, haloalkoxy, alkoxy, and cyano substitution groups;</p>

Or R11, R12, R15, and R16 are all formed with a carbon atom that is bonded to

<p dir="rtl">20 It has a ring of the form (c):</p><img file="SA15151B1_D0172.tif" />

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where:

e be 0, 1; or 2;

k can be 0, 1, or 2 provided that e + k is 1, 2, or 3;

q can be 0, 1, 2, or 3;

<p dir="rtl">5 R17 and R18 are selected individually from hydrogen, alkyl, and cycloalkyl</p>

cycloalkyl and haloalkyl;

Each R19 is individually selected from hydrogen, alkyl, halo, haloalkyl, haloalkoxy, alkoxy, hydroxy, cyano, alkylsulfoxide, alkylsulfonyl, oxo.

<p dir="rtl">10 cycloalkyl, optionally substituted heterocyclyl, and optionally substituted heteroaryl; or</p>

When two R19 groups are bonded to the same carbon atom, the two R19 groups together with the carbon atom to which they are attached form a cycloalkylene or cyclene.

<p dir="rtl">15 Heterocyclylene.</p>

The D-ring is absent or present; where:

(1) When the D ring does not exist, then one of the Q and W is S, O, CH2,

(S(O)2, S(O, or NH; the other of Q and W is CH2; and

(2) When the ring D is present, then Q and W are individually N or C provided that

<p dir="rtl">20 Only one of Q and W is N; The D ring is a phenyl or heteroaryl ring, a 5- or 6-atom ring that, including Q and W, contains one to three individually selected heteroaryl atoms of O, N, and S. The D ring is replaced by</p>

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Optional with one or two individually selected substitution groups of alkyl, cycloalkyl, halo, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, aminoalkyl, carboxy, and cyclyl Heterogeneous by substitution

<p dir="rtl">5 optionally substituted heterocyclyl;</p>

or a pharmaceutically acceptable salt thereof.

<p dir="rtl">67 The compound of Form 66, or a pharmaceutically acceptable salt thereof, is the compound having the structure having the formula (II):</p>

(II) 10

<p dir="rtl">68 The compound of Form 67 or 68, or a pharmaceutically acceptable salt thereof, is the compound having the structure having the formula (IIA):</p>

.(IIA)

15 69.The compound of Form 66, or a pharmaceutically acceptable salt thereof, is the compound having the structure having

Formula (III):

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<img file="SA15151B1_D0173.tif" />

(III)

70. The compound of Form 66 or 69, or a pharmaceutically acceptable salt thereof, is the compound having the structure having the formula (IIIA):

<img file="SA15151B1_D0174.tif" />

(IIIA)

71-The compound according to the protecting element of any of Embodiments 66 to 70, or a pharmaceutically acceptable salt thereof where E is O and A is CH2 or ligand.

72-The compound according to the protecting element of any of Embodiments 66 to 70, or a pharmaceutically acceptable salt thereof where

10 E is O and A is ligament.

73-The compound according to element 68, or a pharmaceutically acceptable salt thereof, having a structure with the formula (IIB):

.(IIB)

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74-The compound according to element 70, or a pharmaceutically acceptable salt thereof having the structure having the formula

:(IIIB)

<img file="SA15151B1_D0175.tif" />

(IIIB)

<p dir="rtl">5 75-The compound according to the protecting element of any of Embodiments 66 to 74, or a pharmaceutically acceptable salt thereof where</p>

Z is a hydrogen, alkyl, halo, haloalkyl, haloalkoxy, cyano, cycloalkyl, heterocyclyl, heteroaryl (where cycloalkyl, heterocyclyl, and heteroaryl are optionally Replace it with one to three

<p dir="rtl">10 From Halo, O(alk)ORb-, O(alk)yRa-,)halo</p>

-NRpRq-, S(O)2NRnRo-, OC(O)NRiRj-, S(O)2Rd, or -YM (where Y is a ligand, O, or SO2 and M is an alkyl, haloalkyl, or cycloalkyl). , a heterocyclyl, or a heteroaryl aryl in which an alkyl, haloalkyl, cycloalkyl, or heteroaryl is substituted.

<p dir="rtl">15 The heterocyclyl and heteroaryl with -O(alk)ORb-, O(alk)yRa, -S(O)2Rd, or -NRpRq and the cycloalkyl, heterocyclyl, and heteroaryl are also optionally replaced with 1 to 3 Halo</p>

.)halo

76 - The compound according to the protecting element in any of Embodiments 66 to 74, or a pharmaceutically acceptable salt thereof wherein 20 Z is -YM (where Y is a ligand or O and M is an alkyl, haloalkyl, cycloalkyl, heterocyclic heterocyclyl, or heteroaryl in which the alkyl, haloalkyl, or cycloalkyl is substituted

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cycloalkyl, heterocyclyl and heteroaryl -

NReC(O)Rf-, S(O)2Rd-, O(alk)ORb

<p dir="rtl">-C(O)NRkRm-, OC(O)NRiRj-, NRgSO2Rh, or -S(O)2NRnRo.</p>

<p dir="rtl">77-The compound according to the protecting element of any of Embodiments 66 to 74, or a pharmaceutically acceptable salt thereof where</p>

<p dir="rtl">5 Z is -YM (where Y is a ligand and M is an alkyl, haloalkyl, cycloalkyl, heterocyclyl, or heteroaryl where the alkyl, haloalkyl, cycloalkyl, or heterocyclyl is substituted And a heteroaryl with -O-Ra, where Ra is an alkyl, cycloalkyl, cycloalkylalkyl, amino.</p>

<p dir="rtl">10 an aminoalkyl, an optionally substituted heterocyclyl, an optionally substituted heterocyclyl, an optionally substituted heterocyclyl, or an optionally substituted heteroaryl.</p>

78 - The compound according to the protecting element of any of Embodiments 66 to 74, or a pharmaceutically acceptable salt thereof wherein Z is -YM (where Y is a ligand and M is an alkyl, haloalkyl, cycloalkyl, heterocyclyl, Or heteroaryl, where the alkyl, haloalkyl, cycloalkyl, heterocyclyl, and heteroaryl are replaced by -O(alk)ORa, where Ra is an alkyl, cycloalkyl, cycloalkyl, cycloalkyl, amino.

<p dir="rtl">20 an aminoalkyl, an optionally substituted heterocyclyl, an optionally substituted heterocyclyl, an optionally substituted heterocyclyl, or an optionally substituted heteroaryl.</p>

79-The compound according to the protecting element of any of Embodiments 66 to 74, or a pharmaceutically acceptable salt thereof where

<p dir="rtl">25 Z is -ORa where Ra is an alkyl, cycloalkyl, cycloalkyl</p>

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cycloalkylalkyl, aminoalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, substituted aryl, or optionally substituted heteroaryl.

<p dir="rtl">5 80-The compound according to the protecting element of any of Embodiments 66 to 74, or a pharmaceutically acceptable salt thereof where</p>

Z is -O(alk)ORb where Rb is an alkyl, cycloalkyl, cycloalkyl, aminoalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, aryl Optional replacement

<p dir="rtl">10 substituted aryl, or optionally substituted heteroaryl</p>

.heteroaryl

81-The compound according to the protecting element in any of Embodiments 66 to 74, or a pharmaceutically acceptable salt thereof wherein Z is hydrogen, fluoro, cyano, methoxy, hydroxy, cyclopentyloxy, tetrahydrofuran-3-yloxy, oxytane-3-yloxy , methoxy

<p dir="rtl">15 Methyloxy, methoxyethyloxy, methylsulfonyl, aminocarbonyloxy, paryzol-1-yl, hydroxymethyl, methoxymethyl, ethoxymethyl, methoxymethyloxymethyl, ethoxymethyloxymethyl, methoxyethyloxymethyl, cyclopropylmethyloxy, or oxetane-3-ylmethyloxy Methyl.</p>

82-The compound according to the protecting element of any of Embodiments 66 to 74, or a pharmaceutically acceptable salt thereof where

<p dir="rtl">20 Z is methoxymethyloxy, methoxyethoxy, methoxymethyl, methoxymethyloxymethyl, ethoxymethyloxymethyl, methoxyethyloxymethyl, cyclopropylmethyloxy, or oxetane-3-ylmethyloxymethyl.</p>

83-The compound according to the protecting element of any of Embodiments 66 to 74, or a pharmaceutically acceptable salt thereof wherein Z is methoxymethyl, methoxymethyloxymethyl, ethoxymethyloxymethyl,

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Methoxyethyloxymethyl, cyclopropylmethyloxymethyl, or oxetane-3-ylmethyloxymethyl.

84-The compound according to the protecting element of any of Embodiments 66 to 74, or a pharmaceutically acceptable salt thereof wherein Z is a fluoro.

<p dir="rtl">5 85-The compound according to the protecting element of any of Embodiments 66 to 84, or a pharmaceutically acceptable salt thereof where</p>

R9 and R13 form hydrogen.

86-The compound according to the protecting element of any of Embodiments 66 to 84, or a pharmaceutically acceptable salt thereof wherein R9 and R13 are amino.

87-The compound according to the protecting element of any of Embodiments 66 to 84, or a pharmaceutically acceptable salt thereof where

<p dir="rtl">10 R9 and R13 are amino.</p>

88-The compound according to the protecting element of any of Embodiments 66 to 84, or a pharmaceutically acceptable salt thereof wherein R9 and R13 are methyl.

89-The compound according to the protecting element of any of Embodiments 66 to 84, or a pharmaceutically acceptable salt thereof, wherein R9 and R13 are individually hydrogen, alkyl, or amino.

<p dir="rtl">15 90-The compound according to the protecting element of any of Embodiments 66 to 89, or a pharmaceutically acceptable salt thereof where</p>

L is S.

91-The compound according to the protecting element of any of Embodiments 66 to 89, or a pharmaceutically acceptable salt thereof wherein L is S(O) or 2(S(O).

92-The compound according to the protecting element of any of Embodiments 66 to 89, or a pharmaceutically acceptable salt thereof where

<p dir="rtl">20 L is a ligament.</p>

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93-The compound according to the protecting element of any of Embodiments 66 to 89, or a pharmaceutically acceptable salt thereof, where L is a CR7R8 and where R5 and R6 are individually hydrogen or alkyl.

94-The compound according to the element protecting any of Embodiments 66 to 68, 71 to 73 and 75 to 93, or

<p dir="rtl">5 A pharmaceutically acceptable salt of which R10 is a hydroxyalkyl.</p>

95-The compound according to the protecting element of any of Forms 66 to 68, 71 to 73 and 75 to 93, or a pharmaceutically acceptable salt thereof wherein R10 is a hydroxymethyl.

96-The compound according to the protecting element of any of Embodiments 66, 69 to 72, and 74 to 93, or a pharmaceutically acceptable salt thereof such that R14 is hydrogen or methyl.

<p dir="rtl">10 97-The compound according to the protecting element of any of Forms 66 to 96, or a pharmaceutically acceptable salt thereof where:</p>

R11 and R15 are selected from amino and aminoalkyl; R12 and R16 are individually selected from hydrogen, cyano, halo, alkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, aryl, heterocyclyl, and heteroaryl, where alkyl, cycloalkyl

<p dir="rtl">15 Cycloalkyl, aryl, heterocyclyl and heteroaryl are optionally replaced by one to three individually selected substitution groups of alkyl, halo, haloalkyl, haloalkoxy, alkoxy, and cyano.</p>

<p dir="rtl">98 The compound of Embodiments 97, or a pharmaceutically acceptable salt thereof, wherein R11 and R15 are aminomethyl 20 and R12 and R16 are methyl.</p>

99 - The compound according to the protecting element in any of Embodiments 66 to 96, or a pharmaceutically acceptable salt thereof, wherein R11, R12, R15 and R16 together form with the carbon atom to which they are attached a ring having the formula (c):

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<img file="SA15151B1_D0176.tif" />

<p dir="rtl">100 The compound of Form 99, or a pharmaceutically acceptable salt thereof wherein the ring has the formula</p>

:)c(

<img file="SA15151B1_D0177.tif" />

<img file="SA15151B1_D0178.tif" />

<img file="SA15151B1_D0179.tif" />

<img file="SA15151B1_D0180.tif" />

<img file="SA15151B1_D0181.tif" />

<img file="SA15151B1_D0182.tif" />

5 101 - The compound according to the protecting element of any of Embodiments 66 to 96, or a pharmaceutically acceptable salt thereof, wherein R11, R12, R15 and R16 together form with the carbon atom to which they are attached a ring having the formula (c):

<img file="SA15151B1_D0183.tif" />

<p dir="rtl">102 The compound of Form 101, or a pharmaceutically acceptable salt thereof where the ring has the formula</p>

:(c) 10

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<img file="SA15151B1_D0184.tif" />

<img file="SA15151B1_D0185.tif" />

<img file="SA15151B1_D0186.tif" />

<img file="SA15151B1_D0187.tif" />

<img file="SA15151B1_D0188.tif" />

<img file="SA15151B1_D0189.tif" />

103. The compound according to any of Embodiments 66 to 102, or a pharmaceutically acceptable salt thereof wherein R2, R1, R3, and R4 are individually selected from hydrogen, alkyl, halo, haloalkyl, haloalkoxy, alkoxy, cyano, And hydroxy, amino.

10

<p dir="rtl">104 . The compound of Form 103, or a pharmaceutically acceptable salt thereof, wherein R3, R2, R1, and R4 are hydrogen and the remaining three of R3, R2, R1, and R4 are individually selected hydrogen, methyl, fluoro, methoxy, and hydroxy And amino.</p>

<p dir="rtl">105 The compound of Form 103, or a pharmaceutically acceptable salt thereof, where R3, R2, R1, and R4 form hydrogen.</p>

<p dir="rtl">106 The compound according to any of Embodiments 66 to 105, or a pharmaceutically acceptable salt wherein R5 is a hydrogen, alkyl, halo, or amino and R6 is a hydrogen.</p>

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hydrogen, alkyl, halo, haloalkyl, haloalkoxy, alkoxy, hydroxy, or cyano.

<p dir="rtl">107 The compound of Form 106, or a pharmaceutically acceptable salt thereof wherein R5 and R6 are hydrogens.</p>

.hydrogen

<p dir="rtl">5 108. A pharmaceutical composition comprising a compound, or a pharmaceutically acceptable salt thereof, of any of Embodiments 66 to 107 and a pharmaceutically acceptable excipient.</p>

<p dir="rtl">109 A method of treating a disease that can be cured by inhibiting the enzyme SRC homolog 2-phosphatase</p>

(SRC HOMOLOGY-2 PHOSPHATASE) in a patient wherein the method comprises administering to the patient, preferably to a patient in need of such treatment, a therapeutically effective amount of 10 of the compound, or a pharmaceutically acceptable salt thereof, of any of Embodiments 66 to 107 or wherein the method comprises Administering to a patient, preferably a patient in need of such treatment, a pharmaceutical composition comprising a compound, or a pharmaceutically acceptable salt thereof, of any of Forms 66 to 107 and a pharmaceutically acceptable excipient.

<p dir="rtl">110 .Method according to Form 109 where the disease is cancer.</p>

<p dir="rtl">15 111. The method according to Model 110, where the cancer is selected from lung cancer, stomach, liver, colon, kidney, breast, pancreatitis, juvenile myeloid leukemia, melanoma, and acute myeloid leukemia.</p>

.leukemia

112.Method according to Model 109 where the disease is selected from Noonan Syndrome

<p dir="rtl">20 Syndrome and Leopard Syndrome.</p>

General synthetic diagrams

The compounds of the present invention may be prepared by the methods shown in the reaction schemes shown below.

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The starting materials and reagents used to prepare these compounds are available either from commercial suppliers such as Bachem (Torrance, Aldrich Chemical Co Calif.), Aldrich Chemical Co. (Milwaukee, Wis.), or Sigma (St. Louis, Mo.). Methods known to those skilled in the field by following the procedures stipulated in references such as Fieser and Fieser's

Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 5 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and

Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March's Advanced Organic Larock's Comprehensive and Chemistry, (John Wiley and Sons, 4th Edition)

Organic Transformations (VCH Publishers Inc., 1989) 10

These diagrams are merely an illustration of some of the methods by which the compounds of the present invention can be synthesized, and various modifications can be made to these diagrams and will become clear to a person skilled in the art when reading this disclosure.

Starting materials, intermediates, and final reaction products can be isolated and purified when needed using

<p dir="rtl">15 Conventional methods, including but not limited to filtration, distillation, crystallization, chromatography, etc.</p>

These materials can be classified using conventional methods, including physical constants and spectroscopic data.

Unless otherwise specified, the reactions described in the present document take place at atmospheric pressure over a 20°C temperature range from about -78°C to about 150°C, e.g.

From about 0°C to about 125°C and above at room (or ambient) temperature, for example, at about 20°C.

General synthetic diagram

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Compounds having the formula (IB), (IA), (I), or (IC) in which L is S and other combinations as specified in the disclosure of the invention may be prepared as shown and described in Scheme 1 below.

Scheme 1

<img file="SA15151B1_D0190.tif" />

10

15

It provides a compound coupling having the formula 1-A, where It is specified in the disclosure of the invention, with a compound having the formula 1-d, where M1 is a substance such as sodium or potassium, in the presence of a transition metal catalyst such as 3(Pd2(dba) and azantiphos under standard coupling conditions, compounds having the formula (I). (. If a compound with the formula 1-A has a substitution with an amino group, then the amino group can be protected with a suitable protecting group such as t-butyl carbamate before the conjugation reaction. It thus provides the removal of the amino protecting group by methods well known to those skilled in the art. A compound with the formula (IA), (I), (IB), or (IC)

Alternatively, compounds having the formula (IB), (IA), (I), or (IC) may be prepared by reacting a compound of formula 1-a with the 3-mercaptopropanoate ester in the presence of a transition metal catalyst such as

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3(Pd2(dba) and azantiphos under standard coupling conditions to provide a compound with formula 1-b where 'R' is an alkyl group such as 3-methylheptane. It provides treatment of a compound with formula 1-b with a base such as potassium t-butoxide, sodium t- Butoxide, sodium methoxide, etc., a compound having the formula 1-C in the form of a thio salt, where +M is a metal ion such as potassium or sodium that provides the 1-conjugate

5 C With a compound having the formula 1-E or the formula 1-F, where X2 or a) or (b), separately.

Compounds having the formula 1-A may be prepared, where Or a group of a substance that produces another, as shown and described in Methods 1 and 2

below.

Method (1):

<img file="SA15151B1_D0191.tif" />

<img file="SA15151B1_D0192.tif" />

<img file="SA15151B1_D0193.tif" />

<img file="SA15151B1_D0194.tif" />

Conjugate a compound having the formula 2-b having R5 and R6 as specified in the invention disclosure or

<p dir="rtl">15 A cross-producing group with an alcohol of formula 2-a where PG is a suitable protective amino group such as Boc, under Mitsunobu conditions, for example, using diethyl azo dicarboxylate and tri-phenylphosphine a compound of formula 2-c. Compounds with the formula 2-b</p>

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It is commercially available or can be prepared by methods known in the art. For example, 2-fluoropyridin-3-ol is commercially available. Compounds with formula 2-a are commercially available or can be prepared by methods known in the art. For example, t-butyl(2-)S-)hydroxymethyl(pyrrolidine-1-carboxylate), and t-butyl(2-)R-)hydroxymethyl(pyrrolidine-1-)

5 Carboxylate, t-butyl (4-)S4,S2-fluoro-2-(hydroxymethyl)-pyrrolidin-1-carboxylate, and t-butyl (4-)R4,S2-fluoro-2-(hydroxymethyl)pyrrolidin-1 -carboxylate, t-butyl (4,4-(S-difluoro-2-(hydroxymethyl)pyrrolidine-1-carboxylate, and t-butyl)2-(R4,S2-(hydroxymethyl)-4-methoxypyrrolidine- 1-carboxylate, t-butyl (2-)S4, S2-(hydroxymethyl)-4-methoxypyrrolidine-1-

10 Carboxylate, t-butyl (6-)S-(hydroxymethyl)-5-a-az spiro[2,4] heptane-5-carboxylate, t-butyl (3-(R-hydroxymethyl) morpholine-4-carboxylate , t-butyl (S)-3-(hydroxymethyl) morpholine-4-carboxylate, t-butyl (2-)R-(hydroxymethyl) istidine-1-carboxylate, t-butyl (2-)S-(hydroxymethyl) Methyl(istidine-1-carboxylate) compounds are commercially available.

<p dir="rtl">15 Removal of the protective amino group provides the formula 2-D. For example, the Boc group can be cleaved under acidic conditions such as HCl in dioxane. Cyclification of compound 2-d with a base such as K2CO3, sodium carbonate, and the like provides a compound with the formula 2-e. Treatment of compound 2-e with lithium using an alkyl lithium such as n-BuLi, followed by iodization provides a compound with the formula 1-a.</p>

20 Method (2)

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<img file="SA15151B1_D0195.tif" />

<img file="SA15151B1_D0196.tif" />

<img file="SA15151B1_D0197.tif" />

10

15

Alternatively, a conjugate provides a compound having formula 3-a where For example, using diethyl azodicarboxylate and triphenylphosphine, a compound with the formula 3-b. Compounds with formula 3a are commercially available or can be prepared by methods well known in the art. For example, 2-fluoro-4-iodopyridine-3-ol is commercially available. Compound 3-c is converted to a compound with the formula 1-a as described in Scheme 1 above.

the use

Src homology-2 phosphatase (SHP2) is a protein tyrosine phosphatase encoded by the PTPNl gene 1 that contributes to multiple cellular functions such as proliferation, differentiation, cell cycle maintenance and migration. SHP2 is involved in signaling through the Ras-mitogen-activated protein kinase, JAK-STAT or phosphoinositol 3-kinase-AKT pathways. SRC PHOSPHATASE 2 (SRC HOMOLOGY 2) mediates activation of the MAP kinases Erkl and Erk (Erk2), Erkl/2, by receptor tyrosine kinases such as ErbBl, ErbB2, and c-Met.

The SRC homology 2 enzyme ( SRC HOMOLOGY PHOSPHATASE 2-SHP2) contains two N-terminal Src homology 2 domains (N and C-SH2), and a

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PROTEIN-TYROSINE PHOSPHATASE (PTP catalytic)

<p dir="rtl">((), and a C-terminal end. The two SH2 domains control the cellular localization and functional organization of SHP2. The molecule exists in an inactive form, which inhibits its activity via a binding network that includes residues from the N-SH2 domains and the protein-tyrosine phosphatase (PTP). .</p>

<p dir="rtl">5 In response to growth factor stimulation, the SRC HOMOLOGY-2 PHOSPHATASE binds to specific tyrosine phosphorylated sites on docking proteins such as Gabl and Gab2 via its SH2 domains. This leads to a conformational change that results in the activation of the enzyme SRC phosphatase 2-SHP2 (SRC HOMOLOGY).</p>

PHOSPHATASE

<p dir="rtl">10 Mutations in PTPN11 have been identified in many human diseases, such as Noonan Syndrome, Leopard Syndrome, Juvenile Myeloid Leukemia, Neuroblastoma, Melanoma, Acute Myeloid Leukemia, and Breast, Lung, and Colon Cancers. Homogenization enzyme - SRC</p>

It is a transmitter molecule (SHP2) SRC HOMOLOGY-2 PHOSPHATASE 2

<p dir="rtl">15 It is important for a variety of tyrosine kinase receptors, including factor receptors</p>

Platelet-derived growth factor (PDGF-R), fibroblast growth factor (FGF-R) and epidermal growth factor (EGF-R). SHP2 is also an important signaling molecule downstream of activation of the activating protein (MAP) kinase pathway that can lead to cell transformation, which is a prerequisite for cancer development. Inactivation of the enzyme SRC phosphatase 2-SHP2 (SRC HOMOLOGY) resulted in

<p dir="rtl">20 PHOSPHATASE has been shown to significantly inhibit cell growth in lung cancer cell lines with SHP2 mutation or EML4/ALK translocations as well as EGFR amplification of breast cancer and esophageal cancer. SRC HOMOLOGY-2 PHOSPHATASE is also activated downstream of oncogenes in gastric carcinoma, anaplastic large cell lymphoma, and glioblastoma.</p>

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Noonan Syndrome (NS) and Leopard Syndrome (LS): PTPN11 mutations cause both LS (multiple lenticules, electrical conduction abnormalities of the heart, ocular hypertension, pulmonary stenosis, abnormal reproductive organs, growth retardation, sensorineural deafness) and NS (congenital malformations Such as heart defects, cardiac malformations and short stature. Both conditions are part of...

<p dir="rtl">5 A family of autosomal dominant syndromes caused by germline mutations in components of the RAS/RAF/MEK/ERK-activated protein kinase pathway, which is essential for normal cell growth and differentiation. Aberrant regulation of this pathway has profound effects, especially on heart development, leading to various abnormalities, such as valvular septal defects and/or hypertrophic cardiomyopathy (HCM). Disorders in the MAPK signaling pathway have been identified as central to these disorders and have been identified</p>

<p dir="rtl">10 Several candidate genes are along this pathway in humans, including mutations in KRAS, NRAS, SOS1, RAF1, BRAF, MEK1, MEK2, SHOC2, and CBL. The most common mutated gene in NS and LS is PTPNl1. Germline mutations in PTPNl(1) (SHP2) are found in ∼50% of NS cases and in almost all patients with LS who share certain features with NS. For the NS, Y62D and Y63C substitutions in the protein,</p>

<p dir="rtl">15 They are largely constant and are among the most common mutations. These two mutations affect the catalytically inactive conformation of SHP2 without disrupting the binding of the phosphatase to its phosphorylation signaling partners.</p>

Juvenile myelomonocytic leukemias (JMML): - PTPNl 1 (SHP2) somatic mutations occur in about 35% of patients with JMML.

<p dir="rtl">20 It is a condition characterized by childhood myeloproliferation (MPD). Gain-of-function mutations are usually point mutations in the N-SH2 domain or in the phosphatase domain, which prevent autoinhibition between the catalytic domain and the N-SH2 domain, resulting in SRC homodimer 2-phosphatase activity.</p>

(SHP2) SRC HOMOLOGY-2 PHOSPHATASE

Acute myeloid leukemia: 1 PTPNl mutation has been identified

<p dir="rtl">25 In: -10% of pediatric acute leukemias, such as myelodysplastic syndrome (MDS)</p>

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myelodysplastic syndrome; -7% of B-cell acute lymphoblastic leukemia (ALL) and -4% of acute myeloid leukemia (AML).

NS mutations and leukemia cause changes in the amino acids present at the interface formed by the N-SH2 domains and the protein-tyrosine phosphatase PROTEIN-TYROSINE.

<p dir="rtl">5 (PHOSPHATASE (PTP in the formation of SRC homolog 2- phosphatase SHP2) SRC)</p>

HOMOLOGY-2 PHOSPHATASE is self-inhibiting, disrupting the intramolecular inhibitory interaction, leading to hyperactivity of the catalytic domain.

SRC HOMOLOGY PHOSPHATASE 2 (SHP2) acts as a positive regulator of receptor tyrosine kinase (RTK) signaling. Include

<p dir="rtl">10 Cancers that contain alterations in FGFR amp Her2, EGFR amp (RTK 15" 31 Met), are the punctate/activated RTK, i.e. BCR/ABL, ALK) both esophageal, breast, lung, colon, stomach, glioma, neck, and breast cancer.</p>

Esophageal cancer (or esophageal carcinoma) is a malignant tumor of the esophagus. There are many different subtypes, mainly squamous cell carcinoma (&gt;50%) and adenocarcinoma. There is a high incidence of

<p dir="rtl">15 of expression of RTK in esophageal cancer and squamous cell carcinoma. Thus, the SRC HOMOLOGY PHOSPHATASE 2-SHP2 inhibitor of the invention can be used in innovative treatment strategies.</p>

Breast cancer is one of the main types of cancer and a major cause of death in women, as the patient develops resistance to current medications. There are four main subtypes of cancers

<p dir="rtl">20 Breast including lumen A, lumen B, Her2-like, and triple-negative/basal-like. Triple-negative breast cancer (TNBC) is an aggressive breast cancer that lacks specific targeted therapy. Epidermal growth factor receptor 1 (EGFR) has emerged as a promising target in TNBC. Inhibition of Her2 as well as EGFR via SRC phosphatase (SRC) homology-2 (SRC phosphatase) may be a promising treatment for breast cancer.</p>

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NSCLC - lung cancer is currently a major cause of cancer-related deaths, accounting for approximately 85% of lung cancers (mostly adenocarcinomas and squamous cell carcinomas). Although cytotoxic chemotherapy remains an important part of treatment, Targeted therapies based on genetic alterations such as EGFR and ALK in the tumor are likely to benefit from 5 targeted therapy.

Colon cancer - Approximately 30% to 50% of colorectal tumors are known to have mutated (abnormal) KRAS, and BRAF mutations occur in 10 to 15% of colorectal cancers. For the subset of patients who have been shown to have or colorectal tumors with overexpression of EGFR, these patients show a clinical response to treatment

<p dir="rtl">10 Anti-EGFR.</p>

Stomach cancer is one of the most common types of cancer. Aberrant expression of tyrosine kinases, as reflected by aberrant tyrosine phosphorylation in gastric cancer cells, is well known in the field. Three tyrosine kinase receptors, c-met (HGF receptor), FGF receptor 2, and erbB2/neu, are frequently upregulated in gastric cancers. Thus, disruption of different signaling pathways may contribute to the emergence of different types of gastric cancers15.

Neuroblastoma is considered a tumor that affects children in the developing sympathetic nervous system, and it represents about 8% of childhood cancers. Genomic alterations of the anaplastic lymphoma kinase (ALK) gene have been hypothesized to contribute to neuroblastoma.

.neuroblastoma

<p dir="rtl">20 Squamous cell carcinoma of the neck (SCCHN). High levels of expression of EGFR are associated with poor prognosis and resistance to radiotherapy in a variety of cancers, mostly in squamous cell carcinoma of the neck (SCCHN). Blocking EGFR signaling inhibits receptor stimulation and cell proliferation and reduces invasiveness and metastasis. Therefore, EGFR is a major target for novel anticancer therapy in SCCHN.</p>

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The present invention relates to compounds capable of inhibiting the activity of the SRC HOMOLOGY-2 PHOSPHATASE enzyme. The invention also provides a process for preparing the compounds of the invention and pharmaceutical preparations comprising such compounds. Another aspect of the present invention relates to a method for treating disorders mediated by the SRC-2 homoenzyme.

<p dir="rtl">5 SRC HOMOLOGY-2 PHOSPHATASE (SHP2), which includes the step of administering to a patient in need a therapeutically effective quantity of a compound having formula I as shown in the disclosure portion of the invention.</p>

In certain embodiments, the present invention relates to the above-mentioned method, whereby the SRC phosphatase 2-homology (SHP2) homodimerization process is formed.

<p dir="rtl">10 PHOSPHATASE Cancers are selected from, but are not limited to, the following: JMML; AML; MDS; B-ALL; Neuroblastoma; esophagus. Esophageal cancer, breast cancer; lung cancer; Colon cancer; Stomach cancer, neck and neck cancer.</p>

Compounds of the present invention may also be useful in the treatment of osteoarthritis or other activity-related conditions

<p dir="rtl">15 Abnormal enzyme SRC phosphatase 2-SHP2 (SRC HOMOLOGY) PHOSPHATASE. Thus, as an additional aspect, the invention relates to a method for treating a disorder selected from: NS; LS; JMML; AML; MDS; B-ALL; Neuroblastoma; Esophageal cancer; breast cancer; lung cancer; Colon cancer; stomach cancer; Cancer of the neck and neck.</p>

20 The SRC HOMOLOGY PHOSPHATASE 2 (SHP2) inhibitor of the present invention can be advantageously combined with another pharmaceutically active compound, or with two or more pharmaceutically active compounds, particularly in the treatment of cancer. For example, the compound of the present invention or a pharmaceutically acceptable salt thereof, as defined above, may be administered simultaneously, sequentially or separately in combination with one or more selected agents.

<p dir="rtl">25 Chemotherapy, for example, mitotic inhibitors such as taxanes, alkaloids</p>

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Vinca, paclitaxel, docetaxel, vincristine, vinblastine, vinorelbine or vinflunine, and other anti-cancer agents, eg cisplatin, 5-fluoroarcel or 5-fluoro-2-4(1H,3H)-pyrimidine (5FU), flutamide or Gemcitabine These combinations may offer significant advantages, including synergistic activity, in treatment.

<p dir="rtl">5 In certain embodiments, the present invention relates to the aforementioned method, wherein said compound is administered other than through the gastrointestinal tract.</p>

In certain embodiments, the present invention relates to the above method, wherein said compound is administered intramuscularly, intravenously, subcutaneously, orally, intrapulmonally, intrathecally, topically or intranasally. .

<p dir="rtl">10 In certain embodiments, the present invention relates to the method described above, wherein said compound is administered systemically.</p>

In certain embodiments, the present invention relates to the method described above, wherein the patient is a mammal.

In certain embodiments, the present invention relates to the method described above, wherein the patient is...

<p dir="rtl">15 Primates.</p>

In certain embodiments, the present invention relates to the above method, where the patient is a human being.

In another aspect, the present invention relates to a method of treating an ARB disorder mediated by the enzyme SRC HOMOLOGY-2 PHOSPHATASE, which includes the step of: administering to a patient who requires it a therapeutically effective amount of a chemotherapy agent along with an amount

<p dir="rtl">20 A therapeutically effective compound of formula I as defined in the disclosure of the invention. In addition to human cancer, inhibition of the HOMOLOGY-2 phosphatase (SRC2) also has therapeutic potential for the treatment of lupus erythematosus.</p>

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rheumatoid and rheumatoid arthritis systemic lupus erythematosus

arthritis and fibrosis.

I wanted to hide

The inhibitory activity of SRC phosphatase 2 (SRC homolog 2) can be tested.

<p dir="rtl">5 HOMOLOGY-2 PHOSPHATASE for compounds of formula (IB), (IA), (I), and (IC) using the in vitro test described in Bio Examples 1 below.</p>

Pharmaceutical formulations

In general, compounds of this disclosure may be administered in a therapeutically effective amount by any of the accepted routes of administration for agents with similar uses. The therapeutically effective quantities of the compounds in this disclosure may range from

<p dir="rtl">10 About 0.01 to about 500 mg per kilogram of the patient's body weight per day, which can be taken in a single dose or in multiple doses. The appropriate dose level may range from about 0.1 to about 250 mg/kg per day; About 0.5 to about 100 mg/kg per day. An appropriate dose level would be about 0.01 to about 250 mg/kg per day, or about 0.05 to about 100 mg/kg per day, or about 0.1 to about 50 mg/kg per day. Within this range, it can</p>

<p dir="rtl">15 The dose is about 0.05 to about 0.5, about 0.5 to about 5 or about 5 to about 50 mg/kg per day. For oral administration, the formulations may be supplied in the form of tablets containing from about 1.0 to about 1000 milligrams of the active ingredient, and especially tablets of about 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, 1000 milligrams of the active ingredient. The actual amount of this compound may depend</p>

<p dir="rtl">20 Detection, that is, the active ingredient, depends on many factors such as the severity of the disease to be treated, the age and relative health of the patient, the effectiveness of the compound used, the method and form of administration, and other factors.</p>

In general, compounds of this disclosure may be administered as drug compositions by any of the following routes: for example, intra-painfully, systemically (e.g. transdermally, intranasally or suppositories), or non-gastrointestinal route (e.g. intramuscularly or Intravenous or subcutaneous). Method

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The preference for administration is orally using an appropriate daily dosing regimen, which can be adjusted according to the degree of infection. Compositions may take the form of tablets, pills, capsules, semi-solids, powders, sustained-release formulations, solutions, suspensions, elixirs, sprays, or other suitable formulations.

<p dir="rtl">5 The choice of formulation depends on various factors such as the route of administration of the drug (for example, for oral administration, preparations in the form of tablets, pills or capsules are preferred, such as coated or delayed-release tablets, pills or capsules) and the bioavailability of the drug substance .</p>

The compositions generally consist of a compound of this disclosure in combination with at least one pharmaceutically acceptable excipient. Acceptable excipients are non-toxic, aid administration, and do not adversely affect benefit

<p dir="rtl">10 Therapeutic properties of the compound of this disclosure. This excipient may be any solid, liquid, semi-solid, or, in the case of an aerosol formulation, a gaseous excipient generally available to a person of skill in the art.</p>

Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, monoglycerin, sodium chloride, skimmed milk powder, etc. Similar.

<p dir="rtl">15 Liquid and semi-solid excipients can be selected from glycerol, propylene glycol, water, ethanol and various oils, such as petroleum, animal, vegetable or manufactured oils, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. Preferred liquid carriers, especially injectable solutions, include water, saline, aqueous dextrose, and glycolate.</p>

<p dir="rtl">20 Compounds may be formulated for non-gastrointestinal administration, e.g., by bolus injection or continuous infusion. Injectable formulations may be provided as a unit dosage, for example, in ampoules or in multi-dose containers, with an added preservative. Compositions may take forms such as suspensions, solutions, or emulsions in oil or aqueous compounds, and may contain formulation agents such as suspending, stabilizing, and/or dispersing agents. The lotion can be given at</p>

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Single-dose or multi-dose containers, e.g. ampoules and sealed vials, which may be stored in powder form or in a freeze-dried (lyophilized) state requiring the addition of only a sterile liquid carrier, e.g. saline or sterile fever-free water, Immediately before use, improvised injection solutions and suspensions can be prepared from powders and granules

<p dir="rtl">5 Sterile tablets of the type previously described.</p>

Non-gastrointestinal administration formulations include sterile aqueous and non-aqueous (oily) injection solutions of active compounds that may contain antioxidants, buffer solutions, bacteriostatics and solutes that make the formulation isotonic with the blood of the intended recipient; and sterile aqueous and non-aqueous suspensions that Suitable solvents or lipophilic compounds may include suspending agents and thickening agents, such as fatty oils such as sesame oil, or acid esters.

Synthetic lipids, such as ethyl oleate, triglycerides, or liposomes. Suspensions for aqueous injection may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dext arn. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compounds to allow the preparation of highly concentrated solutions.

<p dir="rtl">15 In addition to the formulas described previously, compounds can also be formulated as a depot preparation. These long-acting formulations can be administered by implantation (e.g. subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds may be formulated with suitable polymeric materials or hydrophilic materials (e.g. as an emulsion in an acceptable oil (or ion exchange resins, or as poorly soluble derivatives, for example, as a low salt</p>

20 Dissolution.

For buccal or sublingual administration, formulations may take the form of lozenges, lozenges, lozenges, or conventionally formulated gels. These compositions may include the active ingredient on a flavoring basis such as sucrose, acacia or cacao.

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The compounds may also be formulated into rectal formulations as suppositories or enemas which, for example, contain traditional suppository bases such as cocoa butter, polyethylene glycol, or other glycerides.

Certain compounds disclosed herein may be administered topically, i.e. by non-administration

<p dir="rtl">5 Systemic. This includes applying a compound disclosed herein to the skin or buccal cavity or instilling such compound into the ear, eye, or nose, such that the compound does not enter substantially into the bloodstream. In contrast, systemic administration refers to oral, intravenous, intraperitoneal and intramuscular administration.</p>

Formulations suitable for topical administration include suitable liquid or semi-liquid preparations

<p dir="rtl">10 To penetrate the skin to the site of inflammation, such as gels, ointments, lotions, creams, ointments, or</p>

Pastes and drops suitable for administration to the eyes, ears or nose. The active ingredient for topical administration may comprise, for example, an amount ranging from 0.001% to 10% weight/weight (wt) of the formulation. In certain embodiments, the active ingredient may comprise up to 10% weight/weight. In Other models, it may contain less than 5% w/w In certain models, it may

<p dir="rtl">15 The active ingredient comprises from 2% w/w to 5% w/w. In other embodiments, it may comprise from 0.1% to 1% w/w of the formula.</p>

For inhalation administration, compounds can be easily delivered from a sprayer, pressurized canisters of an inhaler or other convenient means of delivering an aerosol spray. Pressurized packages may include a suitable propellant such as dichlorodifluoromethane or trichlorofluoromethane

<p dir="rtl">20 or dichlorobutane, carbon dioxide or other suitable gas. In the case of pressurized aerosol, the dose unit can be determined by providing a measured quantity delivery valve. Alternatively, for administration by inhalation or inhalation, compounds according to this disclosure may take the form of a dry powder composition, for example: a powder mixture of the compound and a suitable powder base such as lactose or starch. The powder formulation may be provided in unit dosage form, e.g.</p>

<p dir="rtl">25 Capsules, cartridges, gelatin or blister packs through which the powder can be administered with the help of a device</p>

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Inhaler or blower. Other suitable pharmaceutical excipients and their formulations have been described in

<p>E. W. Martin (Mack, edited by Remington's Pharmaceutical Sciences Publishing Company, 20th ed., 2000)</p>

The level of compound in a formula may vary over the full range that those skilled at use it

<p dir="rtl">5 the field. Typically, the formulation may contain, on a weight percentage (wt%) basis, of about 0.0199.99 by weight of a compound in accordance with this disclosure based on the overall formulation, wherein the weight is one or more suitable pharmaceutical excipients. For example, the compound is present at a It varies from about 1-80% by weight.</p>

Combinations and combined treatments

<p dir="rtl">10 Compounds of this disclosure may be used in conjunction with one or more other medications in the treatment of pain or conditions where compounds of this disclosure or other medications may be beneficial. Such other drug(s) may be administered, in a commonly used manner and quantity, and, therefore, concomitantly or sequentially with a compound having the formula (I). When the compound of the present invention is used in combination with one or more other drugs, it is preferable to use the composition Pharmaceuticals in unit dosage form contain those</p>

<p dir="rtl">15 Other medications and formula compound (I). However, combination therapy may also include treatments in which a compound of this disclosure and one or more other drugs are administered in different overlapping schedules. It is also possible that when used with one or more of the other active ingredients, the compounds of Formula I and the other active ingredients may be used in lower doses than if each were used alone.</p>

Accordingly, pharmaceutical compositions of formulation (I) also include compositions containing a drug

<p dir="rtl">20 One or more other elements, in addition to the formula compound (I).</p>

The above combinations include combinations of the compound of this disclosure with not only one other drug, but also with two or more other active drugs. Also, a compound of this disclosure may be used with other medicines used to prevent, treat, control, improve or reduce the risk of diseases or conditions in which a compound of this disclosure would be useful. These other medications may be given,

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In a manner and quantity commonly used therefore, simultaneously or sequentially with a compound of this disclosure. When a compound of this disclosure is used concomitantly with one or more other medicines, the pharmaceutical composition may be used containing those other medicines in addition to the compound of this disclosure. Accordingly, pharmaceutical compositions of this disclosure also include compositions that also contain one or more of

<p dir="rtl">5 Other active ingredients, in addition to the compound of the present invention. The weight ratio of the compound of this disclosure to the second active ingredient may vary and depends on the effective dose of each ingredient. In general, an effective dose of each can be used.</p>

When a person in need has cancer or is at risk of developing it, the subject may be treated with the compound of this disclosure in any combination with one or more other anticancer agents.

<p dir="rtl">10 Cancer including but not limited to:</p>

MAP kinase (RAS/RAF/MEK/ERK) pathway inhibitors including but not limited to: vemourvanib (PLX4032), daparfenib, encorafenib (TQ-LGX818), Cas No. 1029872- 29-4 (XL-518), B3233, provided by ACC Corp);

15 Pemacertinib, binimetinib, arfametinib, cobimetinib (0973-BVD-, AZD8330, GDC 523, AR385, LTTib2), and any RAS inhibitors are disclosed in International Patent Nos. 2016049565, 2016164675, 2016168540, 201701 5562, 2017058728, 2017058768, 2017058792 , 2017058805, 2017058807, 2017058902, 2017058915, 2017070256, 2017087528, 2017100546,

20 2017172979، 2017201161، 2018064510، 2018068017، 2018119183.

CSF1R inhibitors (LY3022855, PLX3397, etc.) and antibodies

CSF1R beta kinase inhibitors (IMC-054, RG7155) such as LY2157299.

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BTK inhibitor such as ibrutinib; BCR-ABL inhibitors: imatinib (Gleevec®); Nilotinib Hydrochloride Nilotinib (Tasigna®); dasatinib (345825-BMS); bosutinib (606-SKI); Ponatinib (AP24534); bavitinib (INNO406); Danosretib -PHA) (739358, (1133385-83-7 AT9283) (CAS); saartinib (AZD0530)); (Trifluoromethyl)-2-pyrimidinyl[amino]-

<p dir="rtl">1,2,3,4-Tarthydronaphthalene-1,4-Imine-9-yl[-2-oxyethyl[acetamide)-PF</p>

.)CAS 942487-16-3,03814735

ALK inhibitors; crizotinib (PF-2341066):

<p dir="rtl">2)-N2-(isopropylsulfonyl)phenyl)-2(-N2-methoxy-4- (4-(4-methyl p-arzine-1-10yl)pipyridine-1-yl(phenyl)pyrimidine-2,4 - Diamine; GSK1838705 A;</p>

CH5424802; Ceritinib (Zykadia); TQ-B3139, TQ-B3101 inhibitors

lH (-2[-4-yl[PI3K-Indazol-4-yl(-6-]]4-methylsulfonyl(-BP-arzine-1-yl[methyl[thieno]3,2-d[pyrimidine-4-yl[) Moholin (also known as GDC 0941 and described in PCT Publication Nos. 09/036082 and 09/055730), 2-methyl-215[4-[3-methyl-2-oxo-8-(quinoline-3-yl)- 1,2-Dihydroimdazo[4,5-c]

Quinoline-1-yl[phenyl-1]propionitrile also known as 235 BEZ or 235 NVP-BEZ, described in PCT Publication No. 06/122806).

Vascular endothelial growth factor (VEGF) receptor inhibitors: bevacizumab (sold under the Avastin® brand name by Genentech/Roche), axitinib, (N-methyl-2-20 [[3-])2-(E-birdie-2-) yl[-lH-indazol-6-yl[sulfanyl]benzmid, also known as

As AG013736, described in PCT Publication No. 01/002369 (Bevanib alaninate (4(-4(-1-)(R)– (S-fluoro-2-methyl- lH-indole-5-yloxy) -5- Methylpyrrolol [2,1- 4,2,1] [f]triazine-6-yloxy)propan-2-yl(2-aminopropanoate, also known as 582664-BMS), motesanib (2,3) -N-Dihydro253,3-dimethyl-lH-indole-6-yl(-2-])4-pyridinylmethyl(amino[-3-pyridine)

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Carboxamide, described in PCT Publication No. 02/066470, pasireotide (also known as SOM230, described in PCT Publication No. 02/010192), sorafenib (sold under the trade name Nexavar®); AL-2846 inhibitor MET such as fortinib, carboazantib, or crizotine.

<p dir="rtl">5 FLT3 inhibitors: Sunitinib malate (sold under the brand name Sutent® by Pfizer); PKC412 (Midostaurin);</p>

Epidermal endothelial growth factor receptor inhibitors (EGFR): Gefitnib (sold under the trade name Iressa®3[-4[-N), (Iressa-chloro-4-fluorophenyl(aminol[-7-]]3 “S”)-10). Tetrahydro-3-loarnyl[oxy]-6-quinazolinyl[-4(dimethylamino)-2-butaneamide, sold

Under the trade name Tovok® by Boehringer Ingelheim), Stockimab (sold under the trade name Erbitux® by Bristol-Myers Squibb), Panitoma (sold under the trade name Vectibix® by Amgen).

HER2 receptor inhibitors: aristosomob (sold under the brand name HER2).

<p dir="rtl">15 Herceptin® by Genentech/Roche), ne-artinib (also known as 272-HKI, (3[[-4[-N-(2E-chloro-4-])pyridin-2-yl)methoxy[phenyl[amino] 3-Cyano-7-ethoxyquinoline-6-yl[-4-(dimethylamino)but-2-ene amide, which is described in PCT Publication No. 05/028443), lapatinib or lapatinib DI Tosilat (sold under the brand name Tykerb® by GlaxoSmithKline);</p>

<p dir="rtl">20 Emtansine (in the United States, ado- trastuzumab emtansine, trade name Kadcyla) - an antibody-drug conjugate consisting of the monoclonal antibody arestuzumab (Herceptin) linked to the cytotoxic agent mertansine (DM1).</p>

HER inhibitors: pertuzumab (sold under the brand name Omnitarg®, by Genentech).

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CD20 antibodies: rituximab (sold under the brands Riuxan® and MabThera® by Genentech/Roche), tositumomab (sold under the brand names Bexxar® by GlaxoSmithKline), ofatumumab (sold under the brand name Arzerra® by GlaxoSmithKline).

<p dir="rtl">5 Tyrosine kinase inhibitors: erlotinib hydrochloride (sold under the brand name Tarceva® by Genentech / Roche), lenifanib (3)-4[-N-amino-lH-indazol-4-yl)phenyl[-'2)-N-fluoro - 5-methylphenyl urea, also known as ABT, 869 available from Genentech), sunitinib malate (sold under the brand name Sutent® by Pfizer), bosutinib (4-[2,4-dichloro-5-methoxyphenyl) Amino-6-methoxy-7- ]3</p>

<p dir="rtl">10 (4-Methyl BP-arzine-1-yl)propoxy[ketolin-3-carbonitrile, also known as -SKI</p>

606, described in US Patent No. 6,780,996), dasatinib (sold under the brand name Sprycel® by Bristol-Myers Squibb), Armala (also known as pazopanib, sold under the trade name Votrient® by GlaxoSmithKline), and imatinib and imatinib mesylate (sold under Trade names: Gilvec® and Gleevec® from Novartis.

<p dir="rtl">15 DNA synthesis inhibitors: capecitabine (sold under the brand name 6-Methoxy-purine-8-yl(-5-(Herdoxymethyl)oxolan-3,4-diol, sold under the trade names Arranon® and Atriance® by GlaxoSmithKline).</p>

<p dir="rtl">20 Antineoplastic agents: Oxaliplatin (sold under the trade name Eloxatin® and Sanofi Aventis and described in US Patent No. 4,169,846).</p>

Human granulocyte colony-stimulating factors (G-CSF): Viligerestim (sold under the brand name Neupogen® by Amgen).

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Immunomodulators: Afotuzumab (available from Roche®), PeakVill Arstim (sold under the trade name Neulasta® by Amgen), nallidomide (also known as 5013-CC, sold under the trade name Revlimid®), thalidomide (sold under the trade name Revlimid®). )Thalomid

CD40 inhibitors: dacetuzumab (also known as 40-SGN or huS2C6,

<p dir="rtl">5 PARAs (provided by Seattle Genetics, Inc.): dolanermin (also known as 951-AMG, supplied by Amgen/Genentech);</p>

Hedgehog antagonists: 2-chloro-4[-N-chloro-3-(2-pyridinyl)phenyl[-4-(methylsulfonyl)-

Bin Azmid (also known as 0449-GDC, described in the PCT Publication

<p dir="rtl">10 PCT No. 06/028958);</p>

Phospholipase A2 inhibitors: anagrelide (sold under the brand name Agrylin®);

BCL-2 inhibitors: 4[-4-chlorophenyl(-5,5-dimethyl-1-cyclohexene-1-yl]methyl[-1-b-arsenyl[-4(-3-(lR))[[ - 4[[- N-morpholynyl(-1-](phenylthio)methyl[propyl]amino[-3-](trifluoromethyl)sulfonyl[phenyl[sulfonyl]benazamide (also known as

<p dir="rtl">15 263-ABT and described in PCT Publication No. 09/155386);</p>

MIK665 inhibitors: MCl-1 inhibitors, S64315, 397 AMG, and AZD5991;

Aromatase inhibitors: exemestane (sold under the brand name Aromasin® by Pfizer), letrozole (sold under the brand name Femara® by Novartis), anastrozole (sold under the brand name Arimidex®);

<p dir="rtl">20 Topotecan inhibitors: Irinotecan (sold under the brand name Camptosar® by Pfizer), topotecan hydrochloride (sold under the brand name Hycamtin® by GlaxoSmithKline);</p>

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Topo isomerase II inhibitors: etoposide (also known as 16-VP and etoposide phosphate, sold under the brand names Toposar®, VePesid®, and Etopophos®), teniposide (also known as 26-VM, sold under the trade name Vumon®);

mTOR inhibitors: temsirolimus (sold under the brand name Torisel® by

5 Pfizer), ridafluorolimus (formally known as difluorolimus, (2R)] -4-(4S, 2R, lR)-

28Z, 26E, 24E, 23S, 21R, 19R, 18R, 16E, 15R, 12S, 9S, 1R([ -2

<p dir="rtl">18 Dihydroxy-19, 30-dimethoxy-15, 17, 21, 23, 29, 35-hexamethyl-2, 3, 10, 14, 20- penta-oxo-11, 30S, 32S, 1-)35R. 36, dioxa-4- az tare cyclo [30. 3. 1. 4' 9[Haksa T Ariakunta-16, 24, 26, 28-Tatar N-12-YL]</p>

10 Propyl[-2-methoxycyclohexyldimethylphosphinate, also known as AP23573 and MK8669, described in PCT Publication No. 03/064383), everolimus (sold under the trade name Afinitor® by Novartis);

A proteasome inhibitor such as carfilomib, MLN9708, delanezomib, or bortezomib BET inhibitors such as CPI-0610, OTX015, INCB054329; inhibitors

15 LSD1 such as INCB059872, GSK2979552; HIF-2α inhibitors such as PT2977 and PT2385;

Osteoclastic resorption inhibitors: 1-hydroxy-2-imidazole-1-yl-phosphonoethyl(phosphonic acid) monohydrate (sold under the brand name Zometa® by Novartis); drug and anti-CD33 antibody combinations: gemtuzumab ozogamcin (sold under the brand name Zometa® by Novartis);

20 Under the trade name Mylotarg® by Pfizer/Wyeth(;

Drug and anti-CD22 antibody conjugates: inotuzumab azogamecin (also referred to as 544-CMC and 207294-WAY, supplied by Hangzhou Sage Chemical Co., Ltd.);

Drug combination and anti-CD20 antibody: ibritumumab tioxetan (sold under the brand name

Zevalin®(;

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Somatostin analogues: octreotide (also known as octreotide acetate, sold under the brand names Sandostatin® and Sandostatin LAR®); synthetic enterokine-1111

<p dir="rtl">(IL-11): aprevilcaine (sold under the brand name Neumega® by Pfizer/Wyeth);</p>

Synthetic erythropoietin: darbepoetin alfa (sold under the trade name Aranesp® by Amgen);

<p dir="rtl">5 Receptor activator for nuclear factor κ B inhibitors: detuzumab (sold under the brand name Prolia® by Amgen);</p>

Thrombopoietin-mimicking peptides: romiplostim (sold under the brand name Nplate® by Amgen;

Cell growth stimulant: palifermin (sold under the brand name Kepivance® by Amgen);

<p dir="rtl">10 Antibodies to insulin-like growth factor-1 (IGF-1R): vegetumumab (also known as 751-871, CP, available from ACC Corp), rupatumumab (934235-44-CAS No. 6);</p>

Anti-CSl antibody: Elotuzumab (915296-00-3 HuLuc63, CAS No.);

CD52 antibodies: alemtuzumab (sold under the brand name Campath®);

<p dir="rtl">15 Histone deacetylase inhibitors (HDI): voninostat (sold under the brand name Zolinza® by Merck);</p>

Alkylating agents: Temozolomide (sold under the trade names Temodar® and Temodal®).

By Schering-Plow/Merck), dactinomycin (also known as actinomycin-D and sold under the trade name Cosmegen®), melphalan (also known as L-PAM).

<p dir="rtl">20 Sarcolysine and phenylalanine mustard, sold under the trade name Alkeran®, Altretamine (also known as Hexamethylmelamine (HMM), sold under the trade name Hexalen®), Carmustine (sold under the trade name BiCNU®), Bendamustine (sold under the trade name BiCNU®). Treanda(,</p>

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Busulfan (sold under the brand names Busulfex® and Myleran®), Carboplatin (sold under the trade name Paraplatin®), Lomistine (also known as CCNU, sold under the trade name CeeNU®), Cisplatin (also known as CDDP, sold under the trade names Platinol®). Platinol®-AQ), chlorambucil (sold under the brand name Leukeran®), and cyclophosphamide

<p dir="rtl">5 (sold under the trade names Cytoxan® and Neosar®), dacarbazine (also known as DTIC, DIC, and imidazole carboxamide, sold under the trade name DTIC -Dome®), tretamine (also known as Hexamethylmelamine (HMM) sold under the trade name Hexalen®), Ifosamide (sold under the trade name Ifex®), Procarbazine (sold under the trade name Matulane®), Mechlorethamine (also known as nitrogen mustard, Mustaine, and Mechlor</p>

<p dir="rtl">10 Ethamine hydrochloride, sold under the trade name Mustargen®, Streptozocin (sold under the trade name Zanosar®), Thiotepa (also known as thiophosphomide, TESPA and TSPA, sold under the trade name Thioplex®; Biological response modifiers: Bacille Calmette-Gernes (brand name theraCys® and TICE® BCG), deneloquin diphthetox (brand name Ontak®);</p>

<p dir="rtl">15 Anti-oral antibiotics: doxorubicin (sold under the brand names Adriamycin® and Rubex®), bleomycin (sold under the brand name Lenoxane®), daunorubicin (also known as Dorubicin Hydrochloride, Danomycin, and Rubidomycin Hydrochloride, sold under the trade name Cerubidine®) Daunorubicin Lipid (daunorubicin Setart liposomal, sold under the brand name DaunoXome®), mitoxantrone (known as</p>

<p dir="rtl">20 Also known as DHAD, sold under the brand name Novantrone®, Epiromycin (sold under the brand name</p>

Ellence™, idarubicin (brand name Idamycin® PFS), mitomycin C (brand name Mutamycin®);

Anti-microtubule agents: Armustine ester (sold under the trade name Emcyl®);

Cathepsin K inhibitors: odanacatib (also known as MK-0822-1(-N).

25 Cynanocycloboryl(-4-fluoro-2-2,2-)1 S({ -N-tarifluoro-1- [4'-)methyl)

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sulfonyl)ba-phenyl-4-yl[ethyl{-L-lucinamide, supplied by Lanzhou Chon Chemicals, ACC Corp. and ChemieTek, and described in PCT Publication No. 03/075836); erbuthilone B analogues: ixabepilone (sold as Commercial Lxempra® by

;)Bristol-Myers Squibb

<p dir="rtl">5 Heat shock protein (HSP) inhibitors: tanespymycin (17-allyl amino-17-AAG, supplied by SIGMA, described in US Patent No. 4261,989), NVP-HSP990, 9090-STA, 9090-STA, AUY922, AT13387, Debio 0932, 2478-KW, and TAS -116,XL888 CNF2024</p>

TpoR adjuvants: eltrombopag (sold under the brand names Promacta® and Revolade®

<p dir="rtl">10 ByGlaxoSmithKline(;</p>

Anti-mitotic agents: Docetaxel (sold under the trade name Taxotere® by Sanofi-Aventis); adrenal steroid inhibitors: aminoglutethimide (sold under the trade name Cytadren®);

Antiandrogens: nilutamide (sold under the brand names Nilandron® and Anandron®),

<p dir="rtl">15 igalutamide (brand name Casodex®, flutamide (brand name Fulexin™);</p>

Types of androgens: Fluoxymesterone (sold under the brand name Halotestin®);

Proteasome inhibitors: bortezomib (sold under the brand name Velcade®);

CDK8, CDK7, CDK5, CDK3, CDK2, or CDK1 inhibitors

<p dir="rtl">20 or CDK9) including but not limited to arlfosidib (pan-CDK inhibitor, also known as fluvopridol or 1275-2(-2-chlorophenyl(-5,7- dihydroxy-8-])3-)4R, 3S-Hydroxy-1-methyl-4-pipredinyl[-4-chrominone, described in US Patent No. 5621002);</p>

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CDK4/6 inhibitors pabociclib, abemaciclib, and laxiciclib; CDK9 inhibitors: 4573 TP-1287, AT7519M, P276-00, AZD;

Gonadotropin-releasing hormone (GnRH) receptor antagonists: leuprolide or leuprolide acetate (sold under the brand names Viadure® by Bayer AG, Eligard®

<p dir="rtl">5 Sanofi-Aventis and Lupron® by Abbott Lab)</p>

Anti-orum taxane agents: cabazitaxyl (1-hydroxy-7, 10-dimethoxy-9-oxo-5, 20-epoxytax-11-yn-2a, 4,13a, taryl-4-acetate-2). - Benzoate-13-])t([{ -3-)3S,2R-butoxy(carbonyl[-amino{-2-hydroxy-3-phenylpropanoate(, larotaxyl))10,4-)13α,10β,7α α2-Bis(acetyloxy(13-)}2R, 5β, 4α, 3ξ,

10 t([-3-)3S-butoxycarbonyl)amino[-2-hydroxy-3-phenylpropanoyl{oxy(-1-)

hydroxy-8-oxo-5,20-epoxy-7,9-cyclotax-11-yn-2-yl benzoate(;

5HTla receptor antagonists: azliprodine (also known as SR57746-1, 2)-2[-1-naphyl) ethyl[-4-[3-(trifluoromethyl)phenyl[-1,2,3,6-tetrahydropyridine, Described in U.S. Patent No. 5,266,573 (Cervarix®: HPC vaccines sold by

<p dir="rtl">15 Gardasil®, GlaxoSmithKline sold by Merck; Iron-chelating agents: Divarcinox (sold under the trade name Exjade® by Novartis);</p>

Antimetabolites: Claribin (3-chlorodeoxyadenosine), sold under the brand name

5, Leustatin-Fluorarcil® (brand name Adrucil-Thioguanine® 6), Pemerexid (brand name Alimta®), Seta Arpine

<p dir="rtl">20 Arbinosylcytosine (also known as Ara-C) (sold under the trade name Cytosar-U®), Cetaarbin Liposomal (also known as Liposomal Ara-C, sold under the trade name DepoCyt™), Decitabine (sold under the trade name Dacogen® Hydroxyurea (sold under the brand names Droxia™, Hydrea® and Mylocel™), Fludaarbine (sold under the brand name Fludara®), Floxuridine (sold under the trade name FUDR®), Cladribine (known as</p>

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Also known as 2-chlorodeoxyadenosine (2-CdA) (sold under the trade name Leustatin™), Methotrexate (also known as Amethoprine, Methotrexate Sodium (MTX), sold under the trade names Rheumatrex® and Trexall™), Pentostatin (sold under the trade name Nipent® (;

Bisphosphonates: pamidronate (sold under the trade name Aredia®), zoledronic acid (sold as

<p dir="rtl">5 under the trade name Zometa®; demethylation agents: 5-a azacytidine (sold under the trade name Vidaza®), decitabine (sold under the trade name Dacogen®);</p>

Vegetable alkaloids: protein-bound paclitaxel (sold under the brand name Abraxane®), vinblastine (also known as vinblastine sulfate, vincloblastine and VLB, sold under the brand names Alkaban-AQ® and Velban®), vincristine (also known as vincristine sulfate,

<p dir="rtl">10 LCR, VCR, (sold under the brand names Oncovin® and Vincasar Pfs®), paclitaxel (sold under the trade names Taxol and Onxal™);</p>

<p dir="rtl">Retinoids: alitretinoin (sold under the trade name Panretin®), tretinoin (L-trans-retinoic acid, also known as ATRA, sold under the trade name Vesanoid®), isotretinoin (sold under the trade name Amnesteem®). ,Accutane</p>

Oratane®, Izotech®, Isotane®, Decutan®, Clarus®, Claravis®15,

Bexarotene®, Isotret® and Sotret® (sold under the trade name Targretin®);

Glucocorticosteroids: Hydrocortisone (also known as cortisone, hydrocortisone sodium succinate, hydrocortisone sodium phosphate, sold under the brand names -Ala).

Hydrocortisone Phosphate, Cort®, Solu-Cortef®, Hydrocort Acetate®

20 (Lanacort®) and (Lanacort®) dexamethasone (16R, 14S, 13S, lS, 10S, 9R, 8S,

<p dir="rtl">9 -(17R-Fluoro-11,17-Dihydroxy-17-(2-Hydroxyacetyl)-10,13,16-Tarimethyl-6,7,8,9,10,11,12,13,14,15 16, 17-Dodecahydro-3H-cyclopenta[a]phenanthrene-3-one), prednisolone (sold under the brand names Delta-Cortel®, Orapred®, Pediapred®, and Prelone®), prednisone (sold under the brand names</p>

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Meticorten®, Liquid Red®, Deltasone® and Orasone®, Methylprednisolone (also known as 6-methylprednisolone, methylprednisolone acetate, methylprednisolone sodium succinate), sold under the brand names Medrolone® - Prednisol®, Duralone® and Solu® Medrol(;

5 Cytokines: interleukin-2 (also known as aldesleukin and IL-2, sold under the brand name Proleukin®), interleukin-11 (also known as oprevelkin, sold under the brand name Neumega®), interferon alpha (also known as IFN-alpha) [00209] Estrogen receptor modulators: Fulvest Arnet (sold under the trade name Faslodex®);

<p dir="rtl">10 Antiestrogens: tamoxifen (sold under the trade name Novadex®); toremifene (sold under the trade name Fareston®);</p>

Selective estrogen receptor modulators (SERMs): arloxfene (sold under the brand name Evista®);

Luteinizing hormone (LHRH)-releasing aids: Goserelin (sold under the brand name).

<p dir="rtl">15 Zoladex®; progestins: Megestrol (also known as Megestrol acetate, sold under the trade name Megace®);</p>

Various cytotoxic agents: arsenic trioxide (sold under the trade name Trisenox®), aspa-arginase (also known as Erwinia L-asparaginase, L-asparaginase, sold under the trade names Elspar® and Kidrolase®);

<p dir="rtl">20 One or more additional immune checkpoint inhibitors may be used in combination with any of the compounds listed in this document to treat pain, disorders, or conditions associated with SRC HOMOLOGY-2 PHOSPHATASE. Typical immune checkpoint inhibitors include inhibitors (pigment molecules or substances).</p>

Biotin) against immune checkpoint molecules such as CD27, CD28, CD40, CD122 and CD96

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CD73, CD39, CD47, OX40, GITR, CSF1R, JAK, PI3K delta, PI3K gamma, TAM kinase, arginase, CD137 (also known as A2AR, ICOS), 4-1BB,

VISTA, TIM3, LAG3, CTLA-4, BTLA, B7-H4, B7-H3, HIF-2α, A2BR

PD-1, TIGIT, CD96, PD-L1 and PD-L2. In some embodiments, it is a barrier molecule

<p dir="rtl">5 Immunomodulator is a stimulating checkpoint molecule selected from CD27, CD28, CD40, ICOS, OX40, GITR, CD137 and STING. In some embodiments, the immune checkpoint molecule is an inhibitory checkpoint molecule selected from B7-H3, B7-H4, BTLA, 4-CTLA, IDO, TDO, Arginase, KIR, LAG3, 1-PD, TIM3, CD96, TIGIT, and VISTA. In some embodiments, the compounds contained herein may be used in combination with one or more agents</p>

<p dir="rtl">10 Selected from KIR inhibitors, TIGIT inhibitors, LAIR1 inhibitors, CD160 inhibitors, 2B4 inhibitors, and TGFR beta inhibitors.</p>

In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of PD-1, e.g., an anti-PD-1 monoclonal antibody. In some embodiments, the antibody is monoclonal

<p dir="rtl">15 The anti-PD-1 is nivolumab, pembrolizumab (also known as 3475-MK), bedelizumab, 1210-SHR, PDR001, or 224-AMP. In some embodiments, the anti-PD-1 monoclonal antibody is nivolumab, pembrolizumab or PDR001 In some embodiments, the anti-PD1 antibody is pembrolizumab.</p>

In some embodiments, the immune checkpoint molecule inhibitor is a PD-L1 inhibitor, e.g.

<p dir="rtl">20 Anti-PD-L1 monoclonal antibody. In some embodiments, the anti-PD-L1 monoclonal antibody is 935559-BMS, MEDI4736, MPDL3280A (also known as RG7446), or MSB0010718C. In some embodiments, the anti-PD-L1 monoclonal antibody is MPDL3280A (atezolizumab). or MEDI4736 (arvalumab).</p>

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In some embodiments, the immune checkpoint molecule inhibitor is an inhibitor of 4-CTLA, e.g., an anti-4-CTLA antibody. In some embodiments, the anti-4-CTLA antibody is ipilimumab or tremethlimumab. In some embodiments, the immune checkpoint molecule inhibitor is an inhibitor of LAG3, e.g., an anti-LAG3 antibody. In some embodiments, the anti-LAG3 antibody is

<p dir="rtl">5 986016-BMS or LAG525. In some embodiments, an inhibitor is an immune checkpoint molecule</p>

An inhibitor of GITR, eg, anti-GITR antibody. In some embodiments, the anti-GITR antibody is TRX518, 4166-MK, INCAGN01876, or 1248-MK. In some embodiments, the immune checkpoint molecule inhibitor is an OX40 inhibitor, e.g., an anti-OX40 antibody or an OX40L fusion protein. In some embodiments, an anti-OX40 antibody

or GSK-3174998 or GSK2831781 or INCAGN01949 or MEDI0562 10 is

0916-MOXR or 04518600-PF or LAG525. In some embodiments, the OX40L fusion protein is MEDI6383.

The compounds of the invention may also be used to augment or enhance the immune response, including increasing the immune response to an antigen; or in improving immunization, including increasing vaccine effectiveness; And in

<p dir="rtl">15 Increased inflammation. In some embodiments, the compounds of the invention may be claimed to enhance the immune response to vaccines including, but not limited to, listeria vaccines, oncolytic viral vaccines, and cancer vaccines such as GVAX® (genetically transfected tumor cell vaccine). Granulocyte phagocytes (GM-CF). Anticancer vaccines include dendritic cells, synthetic peptides, DNA vaccines and viruses.</p>

<p dir="rtl">20 The creature. Other immunomodulatory agents also include those that inhibit immune cell migration such as chemokine receptor antagonists, including CCR2 and CCR4; Antagonists and Toll receptor agonists.</p>

Other anticancer agents also include those that strengthen the immune system such as adjuvants or adoptive T cell transfer. Compounds of the present invention may be effective in combination with a CAR

25 (Chimeric antigen receptor) as an enhancer of T cell activation.

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The patented compound can also be used with the following adjuvant treatments:

Anti-nausea medications: NK-1 receptor antagonists: Casopitant (sold under the brand name).

Rezonic® and Zunrisa® by GlaxoSmithKline)

Cytoprotective agents: Amifostine (sold under the well-known brand name Ethyol®, Leucovorin).

<p dir="rtl">5 Also known as leucovorin calcium; Citroform factor and folinic acid.</p>

Examples

The following preparations of intermediate (reference) compounds of formula (I) are explained to enable those skilled in the art to understand and implement the present invention. They should not be considered as limiting the scope of the invention, but rather are merely illustrative and representative examples thereof.

10 Reference 1

Synthesis of 5,6-(S5-dihydrospiro]pipyridine-4,4-pyrrolo[1,2-b]piaryzol[-5-amine]

Dihydrochloride

<img file="SA15151B1_D0198.tif" />

Step 1: 1-[1-](tert-butoxy)((hydroxy)methyl] -4-[hydroxy(methoxy)methyl]

15 Pipyridine-4-yl[ethane-1-yl

<img file="SA15151B1_D0199.tif" />

<img file="SA15151B1_D0200.tif" />

To a solution of [1-[tert-butoxy)(hydroxy(methyl]pipyridin-4-yl] (methoxy(methanol) (20 g, 80.86 mmol, 1.0 equiv) in 200 ml THF) at -78°C was added LDA (48.52 ml, 97.03 mmol, 1.2 equiv) dropwise under a nitrogen atmosphere. After stirring

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For 1.5 hours at -78°C - ~60°C, to the previous mixture acetaldehyde (5.34 g, 121.29 mmol, 1.5 eq) was added dropwise over 5 minutes at -78°C and the resulting mixture was stirred for an additional 2 hours at -~78°C. The reaction mixture was then poured into a saturated aqueous solution of NH4Cl and extracted with EtOAc. The organic layer was washed with salt solution, dried over anhydrous Na2SO4, and the remaining amount was purified with silica gel column chromatography (PE/EtOAc, 0-50%). To give 12 g)50. 9% (product) of the title compound is in the form of a light yellow oil.

Step 2: 1- Tert-butyl-4-methyl-4-[1-)trifluoromethane sulfonyloxy(ethyl[pipyridine-1,4-dicarboxylate)

<img file="SA15151B1_D0201.tif" />

<img file="SA15151B1_D0202.tif" />

10

15

To a solution of 1-tert-butyl-4-methyl-4-(1-hydroxyethyl)pipyridine-1,4-dicarboxylate (9.5 g, 33.06 mmol, 1 equiv) in 100 DCM (100 ml) pyridine (10.4 g) was added (131.48 mmol, 4.0 equiv) and (trifluoromethane) sulfonyltrifluoromethane sulfonate (18.7 g, 66.27 mmol, 2.0 equiv) dropwise at 0°C under a nitrogen atmosphere. After stirring for two hours at 0°C, the The reaction mixture was quenched with water at 0°C and the resulting mixture was extracted with CH2Cl2. The organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give 20 g(crude) of the title compound. This crude product was used directly in the next step without further purification.

20

Step 3: 1-tert-butyl-4-methyl-4-ethynylpipyridine-1,4-dicarboxylate

<img file="SA15151B1_D0203.tif" />

<img file="SA15151B1_D0204.tif" />

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To a stirred solution of 1-tert-butyl-4-methyl-4-[1-(trifluoromethane sulfonyloxy)-ethyl]pipyridine-1,4-dicarboxylate (20 g, crude) in 300 DCM (300 ml) was added (28.50 DBU ml, 187.18 mmol) at room temperature under a nitrogen atmosphere. After stirring for 4 hours at room temperature, the reaction mixture was concentrated under low pressure

<p dir="rtl">5 The remaining amount was purified by silica gel column chromatography (PE/EtOAc, 6%) to give the title compound (4.5 g, 55.2% two-step product) in the form of a light yellow oil.</p>

Step 4: 1-[tear-butoxy(carbonyl]-4-ethynylpipyridine-4-carboxylic acid

<img file="SA15151B1_D0205.tif" />

To a solution of 1-tert-butyl-4-methyl-4-ethynylpipyridine-1,4-dicarboxylate (4.8

<p dir="rtl">10 g, 17.82 mmol, 1.0 eq) in 40 ml MeOH (40 ml) and water (10 ml) and LiOH (2.35 g, 98.01 mmol, 5.5 eq) were added at room temperature. After stirring for 16 hours at room temperature The mixture was acidified to pH 5 using 0.5 M aqueous solution of HCL. The reaction mixture was extracted with CH2Cl2, the combined organic layers were washed with salt solution, dried over anhydrous Na2SO4 and concentrated to give the compound</p>

<p dir="rtl">15 Title (4.5 g, 98.9% yield) is a light yellow oil that is used for the next step without further purification.</p>

Step 5: Tert-butyl-4-ethyl-4-[methoxy(methyl)carbamoyl]pipyridine-1-carboxylate

<img file="SA15151B1_D0206.tif" />

to a solution of 1-[tear-butoxy(carbonyl]-4-ethylpipyridine-4-carboxylic acid.

20 (4.5 g, 17.62 mmol, 1.0 equiv) and methoxy(methyl)amine (1.61 g, 26.43 mM)

mol, 1.5 eq) in 70 DCM ml) 13.40 g HATU added, 35.25 mmol,

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<p dir="rtl">2.0 eq) and 5.35 g Et3N, 52.86 mmol, 3.0 equiv) at room temperature under a nitrogen atmosphere. After stirring for 12 hours at room temperature, the reaction mixture was quenched with water at room temperature and extracted with DCM The organic layer was washed with salt solution, dried over anhydrous Na2SO4, and the remaining amount was purified with silica gel column chromatography (5% EtOAc/PE) to give the title compound (5 g, 95% yield) as a white solid.</p>

Step 6: Tert-butyl-4-acetyl-4-ethynylpipyridine-1-carboxylate

<img file="SA15151B1_D0207.tif" />

10

15

To a solution of tert-butyl-4-ethynyl-4-[methoxy(methyl)carbamoyl] piperidine-1-carboxylate (5 g, 16.75 mmol, 1.0 equiv) in 60 (60 ml THF) was added 2.5 moles of 16.76 (16.76 mmol) CH3MgBr ml. (41.89 mmol, 2.50 eq) dropwise at 0°C under a nitrogen atmosphere. After stirring for 12 hours at room temperature, the reaction was quenched with a saturated aqueous solution of NH4Cl at 0°C and the mixture was extracted with EtOAc. The layer was washed Organics with brine, drying over anhydrous Na2SO4 and concentration. The remaining amount was purified with silica gel column chromatography (PE/EtOAc, 1/3) to give the title compound (3.5 g, 82.4% yield) in the form of a light yellow oil.

Step 7: Tert-butyl-4-])3-)Z2-)dimethylamino(prop-2-enol[-4-ethynylpipyridine-1-carboxylate)

<img file="SA15151B1_D0208.tif" />

A solution of tert-butyl-4-acetyl-4-ethynylpipyridine-1-carboxylate (2.2 g) was stirred,

20 8.68 mmol, 1.0 equiv) in [(tert-butoxy(dimethylamino)methyl]dimethyl

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amine (2 mL, 9.69 mmol, 1.1 equiv) for 4 h at 100 °C under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure. The remaining amount was purified by silica gel column chromatography, and eluted with 1:1 EtOAc/ PE) to give the title compound (1.6 g, 59.7% yield) in the form of a light yellow oil.

5 Step 8: Tert-butyl-4-ethyl-4-(H1-pyrrazol-5-yl)pipyridine-1-carboxylate

<img file="SA15151B1_D0209.tif" />

To a stirred solution of tert-butyl-4-[(3-(Z2-dimethylamino(prop-2-enol)-4-ethynylpipyridine-1-carboxylate) (2.2 g, 7.13 mmol, 1.0 eq.) at 50 (EtOH ml) Arzine monohydrate (0.54 g, 10.78 mmol, 1.5 equiv) was added at 25 °C under an atmosphere of nitrogen. After stirring for 16 hours at 25 °C, the reaction was quenched with water and the

The resulting mixture was mixed with DCM. The organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated. The remaining amount was purified by silica gel column chromatography, and elution with 30%-60% PE/EtOAc) to give the title compound (1.6 g, 80.8% yield) as a white solid.

15 Step 9: Tert-butyl-4-(oxyarn-2-yl(-4-(H1-paryzol-5-yl)pipyridine-1-

Carboxylate

<img file="SA15151B1_D0210.tif" />

to a mixture of tert-butyl-4-ethynyl-4-(H1-pyrrazol-5-yl)pipyridine-1-carboxylate (2 g, 7.2 mmol, 1.0 equiv) and methyltearoxo-rhenium(179.72) (VII mg, 0.72). Milli

20 mol, 0.1 equiv) in 30 DCM ml) Pyridine (228.14 mg, 2.88 mmol) added,

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(0.4 eq) and 1.23 (30%) H2O2 (10.85 mmol, 1.5 eq) at room temperature. After stirring for 16 hours at room temperature, the reaction was quenched with water and extracted with DCM. The organic layer was washed with Salt, drying over anhydrous Na2SO4 and concentrating the remaining amount was purified by silica gel column chromatography, and sequential filtration using

5 30%-60% PE /EtOAc) to give the title compound (0.8 g, 37.82%) as a solid

White.

Step 10: Tert-butyl 5-hydroxy-5,6-dihydrospiro]pipyridine-4,4-pyrrolo[1,2-b[pyrrazole]-1-carboxylate

<img file="SA15151B1_D0211.tif" />

<p dir="rtl">10 To a stirred solution of tert-butyl-4-(oxyarn-2-yl)-4-(H1-pyrrazol-5-yl)pipyridine-1-carboxylate (0.7 g, 2.38 mmol, 1.0 equiv) in 10 THF. Added 0.62 ml (0.62 g LiBr, 7.15 mmol, 3.0 equiv) and CH3COOH (0.43 g, 7.15 mmol, 3.0 equiv) at room temperature. After stirring for 16 hours at room temperature, the mixture was stirred Reaction at 45°C for 8 hours. After cooling to room temperature, the mixture was quenched</p>

<p dir="rtl">15 The reaction was carried out with a saturated aqueous solution of NaHCO3, and the mixture was extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated. The remainder was purified by silica gel column chromatography, and eluted with 30%-100% (PE/EtOAc) to give the title compound (0.4 g, 57.1% yield) as a white solid.</p>

Step 11: Tert-butyl-5-oxo-5,6-dihydropyridine-4,4-pyrrolo[1,2]

<p dir="rtl">20 b[P-Arzole[-1-carboxylate</p><img file="SA15151B1_D0212.tif" /><img file="SA15151B1_D0213.tif" />

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To a solution of tert-butyl 5-hydroxy-5,6-dihydrospiro]pipyridine-4,4-pyrrolo[1,2-b]pyrrazole[-1-carboxylate (0.4 g, 1.36 mmol, 1.0 equiv) in 8 (8 ml) Dess-Martin (0.87 g DCM, 2.04 mmol, 1.5 equiv) were added at room temperature. After stirring for 4 hours at room temperature, the reaction mixture was quenched.

<p dir="rtl">5 With a saturated aqueous solution of NaHCO3 at room temperature and extraction with DCM. The organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated. The remaining amount was purified by silica gel column chromatography (PE/EtOAc, 20%-60%) to give the title compound (0.36 g, 90.62%) as a white solid.</p>

Step 12: Tert-butyl(2-(R)([-5-)S-methylpropane-2-sulfinyl(amino[-5,6-di)

10 Hydrospiro]pipyridine-4,4-pyrrolo[1,2-b[bi-arysole]-1-carboxylate

<img file="SA15151B1_D0214.tif" />

<img file="SA15151B1_D0215.tif" />

to a solution of tert-butyl 5-oxo-5,6-dihydrospiro]pipyridine-4,4-pyrrolo[1,2-b]pyrazol[-1-carboxylate (0.36 g, 1.23 mmol, 1.0 eq.) In 6 ml of THF was added (2-)R-methylpropane-2-sulfenamide (0.30 g, 2.47 mmol, 2.0

<p dir="rtl">15 eq.) and 4(1.13) Ti(OEt g, 4.94 mmol, 4.0 eq.) at room temperature under a nitrogen atmosphere. After stirring for 4 hours at 75 C, the reaction mixture was cooled to -20 C. to the previous mixture. 1 ml MeOH and 40.38 mg LiBH4 (1.85 mmol, 1.50 equiv) were added at -20°C. After stirring for an additional 6 hours at 0°C, the reaction mixture was quenched with a saturated aqueous solution of NH4Cl at 0°C. Then the mixture was filtered and done</p>

<p dir="rtl">20 Wash the filter cake with EtOAc. The filtrate was concentrated under reduced pressure and the remaining amount was dissolved in 3 ml MeOH. To the previous mixture was added 80.75 mg LiBH4 (3.71 mmol, 3.0 equiv) at room temperature. The resulting mixture was stirred for an additional 8 hours. At 45°C, the reaction mixture was quenched with a saturated aqueous solution of NH4Cl at zero degrees</p>

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Percentile. The resulting mixture was extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The remaining amount was purified by silica gel column chromatography, and eluted with 30%-70% PE/EtOAc) to give the title compound (200 mg, 40.8% yield) as a white solid.

Step 13: (5,6-(S5-dihydrospiro]pipyridine-4,4-pyrrolo[1,2-b]bi-aryzol]-5-aminodihydrochloride

<img file="SA15151B1_D0216.tif" />

<img file="SA15151B1_D0217.tif" />

10

15

to a stirred solution of tert-butyl(2-(R)([-5-)S-methylpropane-2-sulfinyl(amino[-5,6-dihydrospiro]pipyridine-4,4-pyrrolo[1,2- b[Pyrrazole]-1-carboxylate (100 mg, 0.252 mmol, 1.0 equiv) in 1,4-dioxane (0.5 mL) HCl in dioxane (4 M, 0.50 mL) solution was added dropwise at room temperature. After stirring for 30 minutes at room temperature, the reaction mixture was concentrated under reduced pressure. To the remaining amount, 1 ml (Et2O) was added, and the precipitate was collected by filtration to give the title compound (60 mg, 89.7% yield) as a white solid.

Example 1

Synthesis of (3-))4-)S4, S3- Amino-3- Methyl-2- Oxa-8-Az Spiro [4.5]decane-8-yl(-6-)))9,8,7,a6- Methanol

<img file="SA15151B1_D0218.tif" />

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Step 1: Tert-butyl(2)([[-2-(S2-fluoropyridine-3-yl)oxy[methyl]pyrrolidine-

<p dir="rtl">1- Carboxylate</p><img file="SA15151B1_D0219.tif" />

to a stirred mixture of 2-fluoropyridine-3-ol (1 g, 8.84 mmol, 1.00 equiv) and t

<p dir="rtl">5 -Butyl(2-(S2-(hydroxymethyl)pyrrolidine-1-carboxylate) (2.14 g, 10.61 ml)</p>

In 15 ml THF (1.2 eq. mol), PPh3 (3.48 g, 13.26 mmol, 1.50 eq) and DEAD (2.31 g, 13.26 mmol, 1.5 eq) were added at room temperature under a nitrogen atmosphere. After stirring for 16 hours at room temperature, the reaction mixture was concentrated under low pressure, and the residue was purified by silica gel column chromatography.

<p dir="rtl">10 And sequential filtering using PE/EtOAc (15:1) to give the title compound (2.5 g, 95.4% yield) in the form of light yellow oil.</p>

Step 2: 2-Fluoro-3-]](S2)-pyrrolidine-2-yl[methoxy[pyridine dihydrochloride

<img file="SA15151B1_D0220.tif" />

to a stirred solution of tert-butyl(2)[[-2-(S2-fluoropyridin-3-yl)oxy[methyl]-

<p dir="rtl">15 Pyrrolidine-1-carboxylate (2500 mg, 8.43 mmol, 1.00 equiv) in 15 DCM</p>

(15 ml) of hydrogen chloride (4 molar) in dioxane (15 ml) was added at

The room temperature. After stirring at room temperature for 4 hours, the reaction mixture was concentrated in vacuo to give the title compound (2.20 g, 96.8% yield) as a white solid.

Step 3: (S-tetrahydro-H6-pyrido [3, 2-b] pyrrolo [1, 1, 2-4] [d] 7, 8, 9, a6-)

20 Oxazine

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<img file="SA15151B1_D0221.tif" />

To a stirred solution of 2-fluoro-3-](S2)-pyrrolidin-2-yl[methoxy[pyridine dihydrochloride (2.20 g, 8.17 mmol, 1.00 equiv) in ethanol (50 ml) 5.64 g K2CO3 was added. 40.87 mmol, 5.00 equivalent at room temperature, and the resulting mixture 5 was stirred for 12 hours at 65°C. Then the mixture was filtered and the filtrate was concentrated under

low pressure. The residue was purified by silica gel column chromatography and elution with 3:1 PE/EtOAc to give the title compound (1.34 g, 93% yield) as a colorless oil.

Step 4: (4-)S-iodo-9,8,7,a6-tetrahydro-H6-pyrido [3, 2-b] pyrrolo [1, 210 4, 1[]d] oxazine

<img file="SA15151B1_D0222.tif" />

To a stirred solution of (9, 8, 7, a6-)S-tetrahydro-H6- pyrido [3, 2-b] pyrrolo [1, 24, 1] [d] oxazine (600 mg, 3.41 mmol, 1.00 eq. In 15 ml THF (15 ml) n-butyllithium solution was added dropwise (2.5 M in hexane, 3.4 ml, 8.5 mmol,

<p dir="rtl">15 2.50 equiv) at 78°C under an N2 atmosphere. The reaction mixture was allowed to warm to zero</p>

°C and stirred for 1.5 hours. The above mixture was added to a solution of (950.60 mg I2, 3.74 mmol, 1.10 equiv) in THF (2 ml) by distillation at -78°C. The reaction mixture was left to warm to room temperature and stirred for 2 hours at room temperature The reaction mixture was quenched with a saturated aqueous solution of NH4Cl and diluted with EtOAc

<p dir="rtl">20 Wash the organic layer with brine, dilute with anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Arf chromatography</p>

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Silica gel column, and sequential filtration with PE/EtOAc (3:1) to give the title compound (700 mg, 68% yield) as a clear solid.

Step 5: 2- Ethylhexyl 3-)))9, 8, 7, a6-)S- tetrahydro-H6-pyrido [3, 2-b] pyrrolo [1, 2-4, 1[]d] oxazine -4- Ly(Thio)propanoate

<img file="SA15151B1_D0223.tif" />

10

15

To a stirred mixture of (4-)S-iodo-9,8,7,a6-tetrahydro-H6-pyrido[3,2-b]pyrrolo[1,2-4,1[d]oxazine (150.00 mg). 2-ethylhexyl 3-sulfanylpropanoate (162.62 mg, 0.745 mmol, 1.50 equiv), 22.73 mg (22.73 mg Pd2(dba), 0.025 mmol, 0.05 equiv) and azentphos (14.36 mg, 0.025 mmol, 0.05 equiv) in 1,4-dioxane (2 ml) DiEA (192.51 mg, 1.489 mmol, 3.00 equiv) was added at room temperature under a nitrogen atmosphere. After stirring for 1 h at 90 °C, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and elution with 0-30% EtOAc/PE to give the title compound (160 mg, 82% yield) as a light yellow solid.

Step 6: Potassium (9,8,7,a6-)S-tetrahydro-H6-pyrido [3, 2-b] pyrrolo [1, 2]

4 ,1[]d[oxazine-4- thiols

<img file="SA15151B1_D0224.tif" />

To a stirred solution of 2-ethylhexyl 3-)))9,8,7,a6-)S-tetaryhydro-H6-pyrido [3].

20 2-b[- Pyrrolo [1, 2-4, 1][d]oxazine-4-yl(thio)propanoate (140.00 mg, 0.357

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1.0 mmol (1.0 equiv) in THF (2 ml) was added - 1.0 M tert (0.43 ml BuOK, 0.43 mmol, 1.20 equiv) at -10 °C. After stirring for 0.5 h at 0 °C, the reaction mixture was diluted. Using petroleum ether, the precipitated solids were collected by filtration and washing with ethyl acetate to give the title compound (75 mg, 85% yield) as a light yellow solid.

Step 7: Methyl 6- Bromo-3-](4-)S4,S3-]](Tert-Butoxy)Carbonyl[Amino[-3-Methyl-2- Oxa-8-Az Spiro[4.5]decane-8- L[p-arzine-2-carboxylate

<img file="SA15151B1_D0225.tif" />

A solution of methyl 3,6-dibromo-p-arzine-2-carboxylate (500 mg, 1.690) was stirred.

<p dir="rtl">10 (493.05 mg, 2.028 mmol, 1.2 equiv) (493.05 mg, 2.028 mmol, 1.2 equiv) DIEA mg, 8.448 mmol, 5.0 equiv) in 10 DMA ml) for 2 hours at 55 °C. Then di-tert-butyl dicarbonate (552.33 mg, 2.531 mmol, 1.5 equiv) was added and the resulting mixture was stirred for 2 hours At room temperature, the reaction mixture was diluted</p>

<p dir="rtl">15 Using water and extracting it with EtOAc. The organic layer was washed with water and brine, diluted with anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography, and sequential elution with PE/EtOAc = 1:1 to give the title compound (615 mg, 75% two-step yield) as a yellow oil.</p>

Step 8: Tert-butyl 5[-8-(S3,S4)[-N-bromo-3-(hydroxymethyl)p-arzine-20-2-yl[-3-methyl-2-oxa-8-aas spiro] 4.5[decane-4-yl]carbamate

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<img file="SA15151B1_D0226.tif" />

To a stirred solution of methyl-6-bromo-3-](4-)S4, S3-]](tert-butoxy)carbonyl[-amino[-3-methyl-2- oxa-8- azspiro[4.5]decane- 8-L[Py-Arzine-2-Carboxylate (150 mg, 0.309 mmol, 1 equiv) in 3.75 ml (DCM) Di-H-BAL added

5 (1.0 molar in 1.24 ml DCM, 1.240 mmol, 4.01 equiv) by distillation at 78°

Celsius under a nitrogen atmosphere. The resulting mixture was stirred for 30 min at 78 °C under a nitrogen atmosphere, warmed to room temperature and then quenched by adding an aqueous solution of saturated Rochelle's salt. The resulting mixture was extracted with EtOAc. The organic layer was washed with brine, diluted with anhydrous Na2SO4 and concentrated. Purified

<p dir="rtl">10 The residue was chromatographed with a silica gel column, and sequentially filtered with 50% EtOAc/PE (0) to give the title compound (65 mg, 46%) as a clear solid.</p>

Step 9: Tert-butyl(3(-8-)S3, S3- (Hydroxymethyl(-5-)))8, 7, a6-)S, 9-tetrahydro-H6-pyrido [3, 2-b]. [Pyrrolo [1, 2-4, 1][d]oxazine-4-yl(thio(p-arzine-2-yl)-3-methyl-2-oxa-8-azinespiro[4.5]decane-4-yl (Carbamate

<img file="SA15151B1_D0227.tif" />

15

To a stirred mixture of tert-butyl 5[-8-(S3,S4)[-N-bromo-3-(hydroxymethyl)pyarzine-2-yl[-3-methyl-2-oxa-8-aas spiro] 4.5[decane-4-yl]carbamate (25.00 mg, 0.055 mmol, 1.00 equiv), potassium (9,8,7,a6-)S-tetrahydro-H6-pyrido[3,2-b]pyrrolo[1, 1[[d]oxazine-4-thiolate (20.20 mg, 0.082)

20 Azantphos (9.49 mg, 0.0164 mmol, 0.30 equiv) in 1,4-dioxane (1 mL)

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Addition of 21.19 mg EA (21.19 mmol, 0.164 mmol, 3.00 equiv) at room temperature under a nitrogen atmosphere. After stirring for 1.5 h at 100 °C, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, and sequential elution with 50%-100% EtOAc/PE) to give the title compound (25 mg, 78% yield)

<p dir="rtl">5 It is a light yellow solid.</p>

Step 10: (3-))4-)S4, S3- amino-3- methyl-2- oxa-8- aaz spiro[4.5]decane-8-yl(-6-)))9,8,7, a6-(S-tetrahydro-H6-pyrido[3,2-b]pyrrolo [1,24,1][d]oxazine-4-yl)thio(pyrzine-2-yl)methanol formate

<img file="SA15151B1_D0228.tif" />

<p dir="rtl">10 To a stirred solution of tert-butyl(3(-8-)S4, S3- (hydroxymethyl(-5-)))a6-)S, 7, 8, 9- tetrahydro-H6- pyrido [3, 2- b[ pyrrolo [1, 2-4, 1][d] oxazine-4-yl(thio(p-arzine-2-yl)-3-methyl-2- oxa-8- az spiro [4.5] decane-4- l) Carbamate (20.00 mg, 0.034 mmol, 1.0 equiv) in 1.5 DCM (1.5 ml) TFA (0.3 ml) was added at room temperature. After stirring for 5 hours at room temperature, the mixture was concentrated</p>

<p dir="rtl">15 Reaction under low pressure. The crude product was purified using preparative HPLC to give the title compound (7 mg, 39% yield) as a light yellow solid. (MS (ES, m/z)</p>

.[M+1]+ = 485.2

Example 2

Synthesis of (3-))4-)S4, S3- Amino-3- Methyl-2- Oxa-8-Az Spiro [4.5] Decane-8

<p dir="rtl">20 yl(-6-)))9,8,7,a6-)R-tetrahydro-H6-pyrido [3, 2-b] pyrrolo [1, 2-4, 1[]d] oxazine-4-yl (Thio(p-arzine-2-yl)methanol</p>

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<img file="SA15151B1_D0229.tif" />

Compound 2 was synthesized by the method described in Example 1 using tert-butyl (2-)R2-

(Hydroxymethyl)pyrrolidine-1-carboxylate instead of tert-butyl (2-)S2-

(Hydroxymethyl)-pyrrolidine-1-carboxylate in step 1. (M+1]+ MS (ES, m/z]

<p dir="rtl">5 .485.3 =</p>

Example 3

Synthesis of (3-))4-)S3, Amino-3- Methyl-2- Oxa-8-Az Spiro [4.5] Decane-8-yl(-6-)))8-)S8, aS6- Fluoro a6, 7, 8, 9- tetrahydro-H6- pyrido [3, 2-b] pyrrolo [1, 2-1, 4] [d] oxazine-4-yl(thio(p-arzine-2-yl) Methanol

<img file="SA15151B1_D0230.tif" />

10

Step 1: Tert-butyl (S2,4-4-fluoro-2-(hydroxymethyl)pyrrolidine-1-carboxylate)

<img file="SA15151B1_D0231.tif" />

To a stirred solution of (1-(S4, S2-(tert-butoxycarbonyl)-4-fluoro)acid.

15 Pyrrolidine-2-carboxylate (2.33 g, 9.99 mmol, 1.0 equiv) in THF (25 ml) (2.8 ml BH3-Me2S, 29.5 mmol, 3.0 equiv) was added by distillation at 0-5°C under a nitrogen atmosphere and The resulting mixture was stirred overnight at room temperature. The mixture was cooled to 0 °C and quenched with MeOH. The resulting mixture was concentrated under pressure

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The residue was purified by silica gel column chromatography, and sequential elution using 1/1 (EtOAc/PE) to give the title compound (2.0 g, 91.3%).

Step 2: Tert-butyl (4-(S2,4-fluoro-2-][)2-fluoro-4-iodopyridin-3-yl)oxy[methyl]pyrrolidin-1-carboxylate

<img file="SA15151B1_D0232.tif" />

<img file="SA15151B1_D0233.tif" />

To a stirred solution of 2-fluoro-4-iodopyridine-3-ol (436 mg, 1.82 mmol,

<p dir="rtl">1 0 equiv), tert-butyl (S2-fluoro-2-(S4), 4-(hydroxymethyl) pyrrolidine-1-carboxylate (400 mg, 1.82 mmol, 1.0 equiv) and PPh3 (717 mg, 2.73 mmol, 1.5 equiv). (4.00 ml THF equivalent) (476 mg DEAD, 2.73 mmol) added,</p>

<p dir="rtl">10 1.5 equivalent) by distillation at 0°C under a nitrogen atmosphere. The resulting mixture was stirred</p>

Overnight at room temperature under a nitrogen atmosphere. The reaction mixture was quenched with water and the resulting mixture was extracted with EtOAc. The collected organic layers were washed with water and brine, diluted with anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography, elution with 0-50% EtOAc/PE,

15 To give the title compound (610 mg, 75.5%).

Step 3: 2-Fluoro-3-))4-(S4,S2-Fluoropyrrolidine-2-yl)methoxy(-4-iodo)

Pyridine hydrochloride

<img file="SA15151B1_D0234.tif" />

<img file="SA15151B1_D0235.tif" />

To a stirred solution of tert-butyl (4-)S4, S2-fluoro-2-])2-fluoro-4-iodo

20 Pyridine-3-yl(oxy[methyl]pyrrolidin-1-carboxylate) 560 mg, 1.272 mmol,

<p dir="rtl">1 .0 equiv) in 1,4-dioxane (5 ml) A solution of 3.3 M HCl in 1,4-dioxane was added.</p>

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Dioxane (5 mL, 16.5 mmol, 13 equiv) was distilled at 0 °C. After stirring at room temperature for 1 hour, the reaction mixture was concentrated under reduced pressure and the residue was crushed with Et2O. The solid was collected by filtration and dried in vacuo To give the product in the form of salt (375 mg HCl, 78.3%).

Step 4: (aS6, 8-)S8-fluoro-4-iodo-9, 8, 7, a6- tetrahydro-H6-pyrido [3, 2-b] pyrrolo [1, 2-4, 1[]d [Oxazine

<img file="SA15151B1_D0236.tif" />

10

15

A mixture of 2-fluoro-3-((4-)S4, S2-fluoropyrrolidin-2-yl)methoxy(-4-iodopyridine hydrochloride (370 mg, 0.983 mmol, 1.0 equiv) and 407 mg K2CO3 was stirred. (2.95 mmol, 3.0 equiv) in 4 ml EtOH for 2 hours at 60 °C. The resulting mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with water and brine, diluted with anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography, and elution with 0% EtOAc/PE-30 (0), to give the title compound (245 mg, 77.9%).

Step 5: 2- Ethylhexyl 3-)[5-])4-)S4, S3-](Tert-Butoxycarbonyl) Amino[-3-Methyl-2- Oxa-8-Az Spiro[4.5]decane-8 -yl[-6-(hydroxymethyl)p-arzine-2-yl[sulfanyl)propanoate

<img file="SA15151B1_D0237.tif" />

20

A solution of tert-butyl 5[-8-(S3,S4)[-N-bromo-3-(hydroxymethyl)pyarzine-2-yl[-3-methyl-2-oxa-8-aaz spiro] was stirred. 4.5[decane-4-yl]carbamate (580.0 mg, 1.27 mmol, 1.0 equiv), 2-ethylhexyl 3-sulfanylpropanoate

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(332.29 mg, 1.52 mmol, 1.2 equiv), 116.1(3) mg Pd2(dba), 0.127 mmol, 0.10 equiv), azantiphos (73.38 mg, 0.127 mmol, 0.10 equiv) and DIEA (491.69 mg, 3.804 mmol, 3.00 equiv) in 1,4-dioxane (12.0 mL) for 1 hour at 100 °C under a nitrogen atmosphere. The resulting mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography, eluting with 0-50% EtOAc/PE), to give the title compound (600 mg, 79.54%).

Step 6: Sodium 5-(4-)S4, S3-(Tert-Butoxycarbonyl) Amino(-3- Methyl-2-Oxa-8-Azspiro[4.5]-decane-8-yl) -6- (Hydroxymethyl)p-arzine-2-thiolate

<img file="SA15151B1_D0238.tif" />

<img file="SA15151B1_D0239.tif" />

10

15

20

To a stirred solution of 2-ethylhexyl 3-)[5-])4-)S4, S3-](tert-butoxycarbonyl)amino[-3-methyl-2- oxa-8- azspiro[4.5] decane - 8-yl[-6-(hydroxymethyl)pyarzine-2-yl]sulfanyl(propanoate) (680.0 mg, 1.14 mmol, 1.0 equiv) in CH3OH (6.80 ml) added 247.04 mg (247.04 mmol CH3ONa) 30% in MeOH) by distillation at 5°C.

After stirring at room temperature for 16 h, the reaction mixture was concentrated in vacuo and the residue was pulverized with Et2O to give the title compound (390 mg, crude), which was used for the next step without further purification.

Step 7: Tert-butyl (8-)S8, aS6)((-5(-8-)S4, S3-fluoro-9,8,7,a6-tetarhydro-H6-pyrido [3, 2-b] [1,2-4,1][d]oxazine-4-yl(thio(-3-(hydroxymethyl)p-arzine-2-yl)-3-methyl-2-oxa-8-asespiro] 4.5[decane-4-yl)carbamate

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<img file="SA15151B1_D0240.tif" />

A solution of (aS6, 8-)S8-fluoro-4-iodo-9, 8, 7, a6- tetrahydro-H6-pyrido [3, 2-b] pyrrolo [1, 1, 4-2] was stirred. d[Oxazine (30.00 mg, 0.094 mmol, 1.0 equiv), Sodium 5-(4-)S4, S3-(Tert-Butoxycarbonyl) Amino)-3-methyl-25 Oxa-8-Az Spiro [4.5] [decane-8-yl(-6-(hydroxymethyl)p-arzine-2-thiolate)

(48.64 mg, 0.112 mmol, 1.2 equiv), 25.75(3) mg Pd2(dba), 0.028 mmol, 0.30 equiv), azentphos (16.27 mg, 0.028 mmol, 0.30 equiv) and DIEA (36.34 mg, 0.281 mmol, 3.00 equivalent) in dioxane (0.90 mL) for 1 hour at 80°C under a nitrogen atmosphere. After cooling to room temperature, the mixture was diluted

10 Reaction with water, extraction with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography, and elution with 0-10% MeOH/CH2Cl2, to give the title compound (32 mg, 56.4%).

Step 8: (3-)(4-(S-amino-2- oxa-8- aaz-spiro[4.5]decane-8-yl)-6

15 )))8-)S8, aS6- fluoro-9, 8, 7, a6- tetrahydro-H6- pyrido [3, 2-b] pyrrolo [1, 2

4 1[[d]oxazine-4-yl(thio(p-arzine-2-yl)methanol

<img file="SA15151B1_D0241.tif" />

To a solution of tert-butyl (aS6, 8-(S8))(-5(-8-)S3, fluoro-9, 8, 7, a6-tetarhydro-H6- pyrido [3, 2-b]. Pyrrolo [1, 2-4, 1][d]oxazine-4-yl(thio)-3

20 (Hydroxymethyl)p-arzine-2-yl)-3-methyl-2-oxa-8-asespiro[4.5]decane-

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<p dir="rtl">4 - l) Carbamate (26 mg, 0.043 mmol, 1.00 equiv) in 1.2 ml DCM (0.4 ml TFA, 5.23 mmol, 122 equiv) was added dropwise at 5°C. After stirring at room temperature for 1 hour The reaction mixture was concentrated in vacuo and the residue was purified using preparative HPLC to give the title compound (3.1 mg, 14.30%). MS (ES).</p>

m/z): [M+1]+ = 503.2. 5

Example 4

Synthesis of (3-))4-)S3, Amino-3- Methyl-2- Oxa-8-Az Spiro [4.5] Decane-8-yl(-6-)))8-)R8, aS6- Fluoro a6, 7, 8, 9- tetrahydro-H6- pyrido [3, 2-b] pyrrolo [1, 2-1, 4] [d] oxazine-4-yl(thio(p-arzine-2-yl) Methanol

<img file="SA15151B1_D0242.tif" />

10

The title compound was synthesized by the method described in Example 3 using S2-(1-)R4, S2-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid in step 1, MS (ES).

m/z): [M+1]+ = 503.3.

Example 5

15 Synthesis of (3-))4-)S3, Amino-3- Methyl-2- Oxa-8-Az Spiro [4.5] Decane-8-yl(-6-)))8-)S8, aS6- Methoxy a6, 7, 8, 9- tetrahydro-H6- pyrido [3, 2-b] pyrrolo [1, 2-1, 4] [d] oxazine-4-yl(thio(p-arzine-2-yl) Methanol

<img file="SA15151B1_D0243.tif" />

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Step 1: 1- tert-butyl-2-methyl (4-(S4,S2-[(tert-butyldimethylsilyl) oxy[pyrrolidine-1,2-dicarboxylate)

To a stirred solution of 1-tert-butyl-2-methyl (4-)S2-hydroxypyrrolidine-1-methyl,

<p dir="rtl">5 2- Dicarboxylate (6.0 g, 24.46 mmol, 1.0 equiv) and imidazole (2.5 g, 36.72</p>

(5.53 mmol, 1.50 eq) in 60 ml DCM (5.53 g Cl-TBS, 36.69 mmol, 1.50 eq) were added aliquots at 0-5°C. After stirring overnight at room temperature, the The reaction mixture was mixed with MeOH and water, and the resulting mixture was extracted with EtOAc. The combined organic layers were washed with water and salt solution, and diluted with

<p dir="rtl">10 Na2SO4 anhydrous and concentration. The residue was purified by silica gel column chromatography, and elution with 0-10% EtOAc/PE, to give the title compound (9.0 g, 102.3%).</p>

Step 2: Tert-butyl (4-(S4,S2-)[Tert-butyldimethylsilyl)oxy[-2-(hydroxymethyl)pyrrolidine-1-carboxylate

15

to a stirred mixture of 1-tert-butyl-2-methyl (4-(S4,2-[(tert-butyldimethylsilyl) oxy[-pyrrolidine-1,2-dicarboxylate) (3.0 g, 8.344 mmol, 1.0 eq. In 30 ml THF (475 mg LiAlH4, 12.516 mmol, 1.50 equiv) were added portionwise at 0°C under a nitrogen atmosphere and the resulting mixture was stirred for 20 hours at room temperature under a nitrogen atmosphere. After Cooling to zero degrees Celsius, done

Quench the reaction mixture with a saturated aqueous Na2SO4 solution. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography.

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And sequential elution with 0-100% EtOAc/PE, to give the title compound (1.6 g, 57.8%).

Step 3: Tert-butyl (4-(S4,S2-[(Tert-butyldimethylsilyl) oxy[-2][2-fluoro-4-iodopyridin-3-yl) oxy[methyl]pyrrolidine-1) - Carboxylate

5

to a stirred mixture of 2-fluoro-4-iodopyridin-3-ol (400 mg, 1.674 mmol, 1.0 equiv), tert-butyl (S2-4, 4-[(tert-butyldimethylsilyl) oxy] -2-(Hydroxymethyl)pyrrolidine-1-carboxylate (555 mg, 1.674 mmol, 1.00 equiv) and PPh3) 658 mg, 2.511 mmol, 1.50 equiv) in THF (4 ml) DEAD added

<p dir="rtl">10 (437 mg, 2.51 mmol, 1.50 equiv) by distillation at 0°C under an atmosphere of</p>

Nitrogen. The resulting mixture was stirred for 2 hours at room temperature under a nitrogen atmosphere, then quenched with 0°C water and extracted with EtOAc. The collected organic layers were washed with water and brine, diluted with anhydrous Na2SO4 and concentrated. The residues were purified by silica gel column chromatography, and sequential elution using...

<p dir="rtl">15 0-30% EtOAc/PE), to give the title compound (735 mg, 79.4%).</p>

Step 4: (2)[[-5-(S3,5)-fluoro-4-iodopyridin-3-yl)oxy[methyl[pyrrolidin-3-ol hydrochloride

To a stirred solution of tert-butyl (4-(S2-, S4-)[(tert-butyldimethylsilyl))

20 Oxy[-2-](2-fluoro-4-iodopyridin-3-yl)oxy[methyl]pyrrolidin-1-carboxylate (750 mg, 1.357 mmol, 1.0 equiv) was added to a 3.0 M solution.

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HCl in 1,4-dioxane (5 mL, 15 mmol, 11 equiv) was distilled at 0-5 °C. After stirring at room temperature for 1 hour, the reaction mixture was concentrated under reduced pressure and the residue was pulverized with Et2O. The sediment was collected by filtration and dried under low pressure to give the title compound (400 mg, 78.7%).

5 Step 5: (aS6, 4-)S8- iodo-9, 8, 7, a6- tetrahydro-H6- pyrido [3, 2-b] pyrrolo [1, 2-4, 1] [d] oxazine-8 - First

<img file="SA15151B1_D0244.tif" />

A mixture of (2)[[-5-(S3,5-fluoro-4-iodopyridin-3-yl)oxy[methyl]pyrrolidin-3-ol hydrochloride (400 mg, 1.068 mmol, 1.00 equiv) and K2CO3 was stirred.

10 (443 mg, 3.205 mmol, 3.00 equiv) in EtOH (4 ml) for 2 hours at 60°

percentage. After cooling to room temperature, the resulting mixture was diluted with water and extracted with EtOAc. The collected organic layers were washed with water and brine, diluted with anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography, and elution using 0-40% EtOAc/PE, to give the title compound (300).

15 mg, 88.3%).

Step 6: (aS6, 4-)S8- iodo-8- methoxy-9, 8, 7, a6- tetrahydro-H6- pyrido [3, 2-b] pyrrolo [1, 2-4, 1[]d [Oxazine

<img file="SA15151B1_D0245.tif" />

To a stirred solution of (4-)S8, aS6- iodo-9, 8, 7, a6- tetrahydro-H6- pyrido [3].

20 2-b[pyrrolo[1,2-4,1[]d]oxazin-8-ol (100.00 mg, 0.314 mmol, 1.0

Ag2O (364.23 mg equivalent), 1.572 mmol, 5.0 equivalent (5.0 equivalent) in DMF (1.00 ml).

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Add 133.86 mg MeI (133.86 mg, 0.943 mmol, 3.00 equiv) dropwise at room temperature and the resulting mixture was stirred for 4 h at 50 °C. After cooling to room temperature, the reaction mixture was filtered. The filtrate was washed with H2O And brine solution, diluted with anhydrous Na2SO4 and concentration. The residue was purified by silica gel column chromatography.

5 And sequential filtration using 1/2 (PE/EA), to give the title compound (89 mg, 85.2%).

Step 7: Tert-butyl(3(-8-)S3-)Hydroxymethyl(-5-))8-)S8, aS6-methoxy-9,8-7,a6-tetrahydro-H6-pyrido [3, 2-b] pyrrolo [1, 2-4, 1] [d] oxazine-4-yl(thio(p-arzine-2-yl)-3-methyl-2- oxa-8- aazine [4.5] [decane-4-yl(carbamate

<img file="SA15151B1_D0246.tif" />

<img file="SA15151B1_D0247.tif" />

To a stirred mixture of (4-S8, aS6- iodo-8- methoxy-9, 8, 7, a6- tetrahydro-H6-pyrido [3, 2-b] pyrrolo [1, 2-4, 1[]d). [Oxazine (30.00 mg, 0.090 mmol, 1.0 equiv) tert-butyl-3[-8-(S3,S4)[-N-(hydroxymethyl)-5-sulfanylp-arzine-2-yl[-3-methyl- 2- Oxa-8-aaz spiro [4.5]decane-4-yl]carbamate (37.08 mg,

15 0.090 mmol, 1.0 equiv) in dioxane (0.30 ml) 24.81(3) Pd2(dba) added

(mg, 0.027 mmol, 0.30 equiv), azantiphos (15.68 mg, 0.027 mmol, 0.30 equiv) and DIEA (35.02 mg, 0.271 mmol, 3.0 equiv) at room temperature under an N2 atmosphere. The resulting mixture was stirred for 1 One hour at 80 °C under an atmosphere of N2. After cooling to room temperature, the reaction mixture was concentrated in vacuo and the residue was purified by

20 Silica gel column chromatography, and sequential elution with 1/10 DCM/MeOH, to give the title compound (25 mg, 45.6%).

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Step 8: (3-))4-)S4, S3- amino-3- methyl-2- oxa-8- aaSpiro[4.5]decane-8-yl(-6-)))8-)S8, aS6 -Methoxy-9,8,7,a6-tetrahydro-H6-pyrido[3,2-b]pyrrolo[1,2-4,1[d]oxazine-4-yl(thio)p-arzine-2- yl) methanol formate

<img file="SA15151B1_D0248.tif" />

5 1.3 ml of TFA was added to a solution of tert-butyl(3(-8-)S3-)hydroxymethyl(-5-))8-)S8-)aS6-methoxy-9,8,7-)S3-) a6- tetrahydro-H6- pyrido [3, 2-b] pyrrolo [1, 2-4, 1] [d] oxazine-4-yl(thio(pyrzine-2-yl) -3- methyl-2- Oxa-8-aasespiro[4.5]decane-4-yl)carbamate (130.0 mg, 0.21 mmol, 1.0 equiv) in 3.0 DCM (3.0 ml) at room temperature. After stirring at room temperature for 2 hours,

<p dir="rtl">10 The reaction solution was concentrated and the residue was purified using preparative HPLC to give the product (19 mg,</p>

.MS (ES, m/z): [M+1]+ = 515.3 .)% 16.1

Example 6

Synthesis of (3-))4-)S3, Amino-3- Methyl-2- Oxa-8-Az Spiro [4.5] Decane-8-yl(-6-)))8-)R8, aS6- Methoxy A6, 7, 8, 9- Tetrahydro-H6-pyrido [3, 2-b] 15 pyrrolo [1, 1, 2-4] [d] oxazine-4-yl(thio) p-arzine-2-yl (Methanol

<img file="SA15151B1_D0249.tif" />

Step 1: (4-)R8, aS6- iodo-8- methoxy-9, 8, 7, a6- tetrahydro-H6- pyrido [3, 2-b] pyrrolo [1, 2-4, 1[]d [Oxazine

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The compound was synthesized (4-R8, aS6- iodo-8- methoxy-9, 8, 7, a6- tetrahydro-H6-pyrido [3, 2-b] pyrrolo [1, 2-4, 1[]d). [oxazine] by the method described in Example 5, steps 1-6 using 1-(tert-butyl(2-methyl)4-)S2-hydroxypyrrolidine-1,2-dicarboxylate in step 1.

Step 2: (3-))4-)S4, S3- Amino-3- Methyl-2- Oxa-8-Az Spiro [4.5] Decane-8-yl(-6-)))8-)R8, aS6 -Methoxy-9,8,7,a6-tetrahydro-H6-pyrido[3,2-b]pyrrolo[1,2-4,1[d]oxazine-4-yl(thio)p-arzine-2- yl(methanol

<img file="SA15151B1_D0250.tif" />

10

(3-))4-)S4, S3- amino-3- methyl-2- oxa-8- aaSpiro[4.5]decane-8-yl(-6-)))8-)R8, aS6- was synthesized. Methoxy-9,8,7,a6-tetrahydro-H6-pyrido[3,2-b]pyrrolo[1,2-4-1[d]oxazine-4-yl(thio)pyrzine-2-yl (Methanol using a method similar to the method described in Example 5, steps 7-8. = +[1+MS (ES, m/z): [M

<p dir="rtl">515.3.</p>

15

Example 7

Synthesis of (4-(S3, S4))-5(-4-)S8, aS6- amino-3- methyl-2- oxa-8- az spiro[4.5]decane-8-yl)-6- (hydroxy) Methyl(p-arzine-2-yl)thio(-9,8,7,a6-tetrahydro-H6-pyrido[3,2-b]pyrrolo[1,2-4,1[d]oxazine-8-ol

<img file="SA15151B1_D0251.tif" />

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The title compound was synthesized by the method described in Example 5, steps 7-8 using (aS6, 4-)S8- iodo-9, 8, 7, a6- tetaryhydro-H6-pyrido [3, 2-b] pyrrolo [1, 2-4, 1[]d[oxazine-8-ol in step 7. 501.3 = +[1+MS (ES, m/z): [M.

Example 8

Synthesis of (4-(S3, S4))-5(-4-)R8, aS6- amino-3- methyl-2- oxa-8- aase spiro[4.5]decane-8-yl)-6- (hydroxy) Methyl(p-arzine-2-yl(thio)-9,8,7,a6-tetrahydro-H6-pyrido[3,2-b]pyrrolo[1,2-4,1[d]oxazine-8-ol

<img file="SA15151B1_D0252.tif" />

10

The title compound was synthesized using a method similar to that described in Example 7. ,MS (ES

.m/z): [M+1]+ = 501.3

Example 9

Synthesis of (3-))4-)S4, S3- amino-3- methyl-2- oxa-8- aaz spiro[4.5]decane-8-yl(-6-)))8-)R8, aR6- methoxy a6-7,8-9-tetrahydro-H6-pyrido[3,2-b]pyrrolo[1,2-1,4[d]oxazine-4-yl(thio(pyrzine-2-yl)methanol

<img file="SA15151B1_D0253.tif" />

15

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The title compound was synthesized using a method similar to that described in Example 5, Steps 2-8 using 1-tert-butyl-2-methyl(4-)R2,4-methoxy-pyrrolidin-1,2-dicarboxylate in Step 2. 515.3 = +[1+MS (ES, m/z): [M.

Example 10

<p dir="rtl">5 Synthesis of (3-))4-)S3, Amino-3- Methyl-2- Oxa-8-Az Spiro [4.5] Decane-8-yl(-6-)))8-)S8, aR6- Methoxy a6, 7, 8, 9- tetrahydro-H6- pyrido [3, 2-b] pyrrolo [1, 2-1, 4] [d] oxazine-4-yl(thio(p-arzine-2-yl) Methanol</p><img file="SA15151B1_D0254.tif" />

The title compound was synthesized using a method similar to that described in Example 5 Steps 2-8

<p dir="rtl">10 Using tert-butyl(2-)S4, R2- (hydroxymethyl)-4-methoxypyrrolidine-1-carboxylate in step 2. 515.2 = +[1+MS (ES, m/z): [M.</p>

Example 11

Synthesis of (3-)(4-)S4, S3- Amino-3- Methyl-2- Oxa-8-Az Spiro [4.5]decane-8-yl(-6-))(S)((-8-) S8,aS6(- tetrahydrofuran-3-yl(oxy)-9,8,7,a6-

<p dir="rtl">15 Tetrahydro-H6-pyrido[3,2-b]pyrrolo[1,2-4,1[d]oxazine-4-yl(thio)p-arzine-</p>

<p dir="rtl">2- yl(methanol</p><img file="SA15151B1_D0255.tif" />

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Step 1: (4-(S8, aS6- iodo-8-)((S)- tetrahydro-furn-3-yl)oxy)-7, a6, 8, 9- tetrahydro-H6- pyrido [3, 2] -b[ pyrrolo [1, 2-4, 1[]d[ oxazine

<img file="SA15151B1_D0256.tif" />

to a stirred solution of (R3)-oxolane-3-yl-4-methylbenzenesulfonate (457 mg,

<p dir="rtl">5 1.886 mmol, 3 equiv (f)4-)aS6-iodo-9,8,7,a6-tetrahydro-H6-</p>

Pyrido [3, 2-b] Pyrrolo [1, 2-4, 1[[d] Oxazin-8-ol (200 mg, 0.629 mmol, 1.00 equiv) in 2.00 ml (DMF) 88 mg NaH was added, 2,200 mmol, 3.5 equiv, 60%) in portions at 0°C under a nitrogen atmosphere, and the resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. After cooling to 0°C

<p dir="rtl">10 Celsius, the reaction was quenched with water and the resulting mixture was diluted with water and extracted with EtOAc. The collected organic layers were washed with water and brine, diluted with anhydrous Na2SO4 and concentrated. The residue was purified by preparative TLC (EtOAc 100%) to give the title compound (70 mg, 28.7%).</p>

Step 2: (3-)(4-)S3, Amino-3- Methyl-2- Oxa-8-Az Spiro [4.5] Decane-15-8-yl)-6-)((S)()(- 8- (S8,aS6)- tetahrohydrofuran-3-yl(oxy)-9,8,7,a6-

Tetrahydro-H6-pyrido[3,2-b]pyrrolo[1,2-4,1[d]oxazine-4-yl(thio(pyrzine-2-yl)methanol

<img file="SA15151B1_D0257.tif" />

The title compound was synthesized from (aS6, 4-(S8-iodo-8-((S)- tetrahydrofuran-3-yl)

20 Oxy)-9,8,7,a6-tetrahydro-H6-pyrido [3, 2-b] pyrrolo [1, 2-4, 1][d]

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oxazine using a method similar to the method described in Example 5, Steps 7-8. ,MS (ES

.m/z): [M+1]+ = 571.3

Example 12

Synthesis of (3-))4-)S4, S3- Amino-3- Methyl-2- Oxa-8-Az Spiro [4.5] Decane-8

5 yl(-6-))(R)((-8-)S8, aS6(- tetrahydrofuran-3- yl(oxy)-9, 8, 7, a6- tetrahydro-H6- pyrido [3, 2] -b[pyrrolo[1,2-4,1][d]oxazine-4-yl(thio(p-arzine-2-yl)methanol

<img file="SA15151B1_D0258.tif" />

The title compound was synthesized from (S3)-oxolan-3-yl-4-methylbenzenesulfonate using the method

10 Similar to the method described in Example 11. 571.3 = +[1+MS (ES, m/z): [M.

Example 13

Synthesis of (3-))4-)S4, S3- Amino-3- Methyl-2- Oxa-8-Az Spiro [4.5] Decane-8-yl(-6-)))8-)S8, aS6- ) Oxazine-3-yloxy(a6-7,8-9-tetrahydro-H6-pyrido[3,2-b]pyrrolo[1,1,4-2[d]oxazine-4-yl(thio) P-arzine-2-yl)methanol

<img file="SA15151B1_D0259.tif" />

Step 1: (aS6, 4-)R8- iodo-9, 8, 7, a6- tetrahydro-H6- pyrido [3, 2-b] pyrrolo [1, 2-4, 1] [d] oxazine-8 -Tarifluoromethane sulfonate

15

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<img file="SA15151B1_D0260.tif" />

<img file="SA15151B1_D0261.tif" />

To a stirred solution of (4-)R8, aS6- iodo-9, 8, 7, a6- tetrahydro-H6- pyrido[3, 2-b]- pyrrolo [1, 2-4, 1[]d] oxazine - 8- The first (400 mg, 1.257 mmol, 1.00 equiv) and 244 mg DIEA (1.886 mmol, 1.50 equiv) in DCM (4.00 ml) was done

5 Add 426 mg Tf2O, 1.509 mmol, 1.20 equiv) dropwise at 5°C. The reaction solution was stirred at 5°C for 30 minutes and then concentrated in vacuo. The residue was purified by silica gel column chromatography, and eluted with 0 (EtOAc/PE-40%) to give the title compound (300 mg, 53.0%) as a white solid.

Step 2: (4-)S8,aS6- iodo-8- (oxytan-3-yloxy)-9,8,7,a6-

10 Tetrahydro-H6-pyrido [3, 2-b] pyrrolo [1, 2-4, 1[]d] oxazine

<img file="SA15151B1_D0262.tif" />

<img file="SA15151B1_D0263.tif" />

To a stirred solution of oxetane-3-ol (99 mg, 1.336 mmol, 2.00 equiv) in DMF (3.00 ml) 67% NaH (60 mg, 1.67 mmol, 2.50 equiv) was added at 5 °C. The mixture was stirred at This temperature for 1 hour (aS6, R8-4-iodo).

15 9,8,7,a6-tetrahydro-H6-pyrido [3, 2-b] pyrrolo [1, 2-4, 1[]d] oxazine-8-yl

Trifluoromethane sulfonate (300.00 mg, 0.666 mmol, 1.00 equiv) was added at 20°C. The reaction mixture was allowed to warm to 50°C and stirred for 10 minutes. The reaction was quenched with water at 5°C and the resulting mixture was extracted with EtOAc The collected organic layers were washed with water and saline, diluted with...

20 Na2SO4 is anhydrous. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, and elution with 0% EtOAc/PE-100 (0) to give the title compound (20 mg, 8.0%) as a white solid.

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Step 3: (3-))4-)S4, S3- amino-3- methyl-2- oxa-8- aaSpyro[4.5]decane-8-yl(-6-)))8-)S8, aS6 - (Oxatane-3-yl oxy) -9, 8, 7, a6- tetrahydro-H6- pyrido [3, 2-b] pyrrolo [1, 2-4, 1] [d] oxazine-4- yl) Thio(pyarzine-2-yl)methanol

<img file="SA15151B1_D0264.tif" />

The title compound was synthesized using a method similar to the method described in Example 5 Steps 7-8 using (aS6, 4-)S8- iodo-8- (oxetane-3-yloxy)-a6, 7, 8-9- tetrahydro-H6. - Pyrido [3, 2-b] pyrrolo [1, 2-4, 1[]d] oxazine in step 7. (MS (ES, m/z)

.[M+1]+ = 557.3

10 Example 14

Synthesis of (3-))4-)S4, S3- Amino-3- Methyl-2- Oxa-8-Az Spiro [4.5] Decane-8-yl(-6-)))8-)S8, aS6- ) Methoxy(-9,8,7,a6-tetrahydro-H6-pyrido[3,2-b]pyrrolo[1,2-4-1[d]oxazine-4-yl(thio)p-arzine-2 -yl) methanol

<img file="SA15151B1_D0265.tif" />

15 Step 1: (aS6, 4-)S8- iodo-8- (methoxymethoxy)-a6, 7, 8-9- tetrahydro-H6-pyrido [3, 2-b] pyrrolo [1, 1, 4-2] [d]oxazine

<img file="SA15151B1_D0266.tif" />

<img file="SA15151B1_D0267.tif" />

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To a stirred solution of (4-)S8, aS6- iodo-9, 8, 7, a6- tetrahydro-H6- pyrido [3, 2-b] pyrrolo [1, 2-4, 1[-]d] oxazine - 8- First (60 mg, 0.189 mmol, 1.00 equiv) and 49) DIEA mg, 0.377 mmol, 2.00 equiv) in 1.00 ml DME) bromo(methoxy)methane (35.35 mg, 0.283 mmol, 1.50 equiv) was added. By distillation at

<p dir="rtl">5 Room temperature under an N2 atmosphere. The resulting mixture was stirred for 4 hours at room temperature under an N2 atmosphere and then quenched with H2O. The resulting mixture was extracted with EA and the combined organic layers were dried with anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, and elution with 1/1 (PE/EA) to give the title compound (50 mg, 73.2%) as a light yellow solid.</p>

Step 2: (3-))4-)S4, S3- Amino-3- Methyl-2- Oxa-8-Az Spiro [4.5] Decane -

8- yl(-6-)))8-)S8, aS6- (methoxymethoxy)-9,8,7,a6- tetrahydro-H6-pyrido [3, 2-b] pyrrolo [1, 2-4] 1[[d]oxazine-4-yl(thio(p-arzine-2-yl)methanol

<img file="SA15151B1_D0268.tif" />

15 The title compound was synthesized using a method similar to the method described in Example 5 Steps 7-8 using tert-butyl(-3(-8-)S4, S3-)hydroxymethyl(-5-)))8-)S8, aS6-). Methoxy(-9,8,7,a6-tetrahydro-H6-pyrido[3,2-b]pyrrolo[1,2-1][d,4]oxazine-4-yl(thio)p-arzine-2 -yl)-3-methyl-2-oxa-8-aasespiro[4.5]decane-4-yl(carbamate) in step 7. 545.2 = +[1+MS (ES, m/z): [M.

20 Example 15

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Synthesis of (3-))4-)S4, S3- amino-3- methyl-2- oxa-8- az spiro[4.5]decane-8-yl(-6-))(2(-8-)S8, aS6-methoxyethoxy(-9,8,7,a6-tetrahydro-H6-pyrido[3,2-b]pyrrolo[1,2-4,1[d]oxazine-4-yl(thio)p-arzine -2- yl(methanol

<img file="SA15151B1_D0269.tif" />

5 The title compound was synthesized using a method similar to that described in Example 14 using 2-bromoethyl methyl ether in Step 1. 559.3 = +[1+MS (ES, m/z): [M.

Example 16

Synthesis of (3-))4-)S4, S3- Amino-3- Methyl-2- Oxa-8-Az Spiro [4.5] Decane-8-yl(-6-)))8-)S8, aS6- ) Cyclopropyl methoxy(-9,8,7,a6-tetrahydro-H6-10pyrido[3,2-b]pyrrolo[1,2-4,1[d]oxazine-4-yl(thio)p-arzine -2- yl(methanol

<img file="SA15151B1_D0270.tif" />

The title compound was synthesized using a method similar to that described in Example 14 using (bromomethyl)cyclopropane in Step 1. 555.4 = +[1+MS (ES, m/z): [M.

Example 17

15 Synthesis of (3-))4-)S4, S3- Amino-3- Methyl-2- Oxa-8-Az Spiro [4.5]decane-8-yl(-6-)))7,a'6-)S '-Dihydro-H9,'H6'-spiro[cyclopropane-1,8'-pyrido[3,2-b]pyrrolo[1,2-4,1[d]oxazine[-4'-yl) thio (P-arzine-2-yl)methanol

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<img file="SA15151B1_D0271.tif" />

Step 1: (4-)S'- iodo-6'7, a'- dihydro-H9, 'H6'- spiro[cyclopropane-1,8'- pyrido [3, 2-b] pyrrolo [1, 2] -4,1[-]d[oxazine]

<img file="SA15151B1_D0272.tif" />

5 The compound was synthesized (4-)S'- iodo-6'7, a'- dihydro-H9, 'H6'- spiro]cyclopropane-1,8'-pyrido [3, 2-b]pyrrolo [1, 2]. 1,4[[d]oxazine] using a method similar to the method described in Example 1, steps 1-4 using 5-tert-butyl-6-methyl (5-)S6-azine spiro[2,4]heptane-5,6-di Carboxylate in step 1.

Step 2: (3-))4-)S4, S3- Amino-3- Methyl-2- Oxa-8-Az Spiro [4.5] Decane -

10 8-yl(-6-)))7,a'6-)S'- dihydro-H9,'H6'-spiro]cyclopropane-1,8'-pyrido

[3, 2-b] pyrrolo [1, 2-4, 1] [d] oxazine[-4'-yl)thio(p-arzine-2-yl)methanol

<img file="SA15151B1_D0273.tif" />

The title compound was synthesized using a method similar to that described in Example 1, steps 5-8.

.MS (ES, m/z): [M+1]+=511.3

15 Examples 18 and 19

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Synthesis of (4-(S3, S4))-5(-4-)S8, aS6- amino-3- methyl-2- oxa-8- az spiro[4.5]decane-8-yl)-6- (hydroxy) Methyl(p-arzine-2-yl(thio)-8- Methyl-7,a6,8,9-tetrahydro-H6-pyrido [3,2-b]-pyrrolo [1,2-4,1][d] Oxazine-8-ol and (4-(S4, S3)(-5)(-4-)R8, aS6- amino-3- methyl-2- oxa-8- aaz spiro [4.5]

5 Decane-8-yl)-6-(hydroxymethyl)p-arzine-2-yl(thio)-8-methyl-9,8-7,a6-tetrahydro-H6-pyrido[3,2-b]pyrrolo[1] , 2-4,1[]d[oxazine-8-ol

<img file="SA15151B1_D0274.tif" />

Step 1: (4-)S-iodo-7, a6- dihydro-H6- pyrido [3, 2-b] pyrrolo [1, 2-1[]d,

4[Oxazine-8(H9)-On

10