Inhibitors of AKT and uses thereof

Abstract

Disclosed are Akt kinase inhibitors represented by the following structural formula I. The variables in structural formula I are described herein. Also disclosed are methods of treating cancer with the disclosed Akt kinase inhibitors, in a subject in need thereof.

Description

[0001] 141039-01220

[0002] INHIBITORS OF AKT AND USES THEREOF

[0003] RELATED APPLICATIONS

[0004]

[0001] This application claims the benefit of priority to U.S. Provisional Application No. 63 / 679,367, filed August 5, 2024, the entire contents of which are incorporated herein by reference.

[0005] BACKGROUND

[0006]

[0002] Apoptosis (programmed cell death) plays essential roles in embryonic development and pathogenesis of various diseases, such as degenerative neuronal diseases, cardiovascular diseases and cancer. Recent work has led to the identification of various pro- and anti-apoptotic gene products that are involved in the regulation or execution of programmed cell death. Expression of anti-apoptotic genes, such as Bcl2 or Bcl-xL, inhibits apoptotic cell death induced by various stimuli. On the other hand, expression of pro-apoptotic genes, such as Bax or Bad, leads to programmed cell death (Adams et al. Science, 281: 1322-1326 (1998)). The execution of programmed cell death is mediated by caspase-1 related proteinases, including caspase-3, caspase-7, caspase-8 and caspase-9 etc (Thomberry et al. Science, 281: 1312-1316 (1998)).

[0007]

[0003] The phosphatidylinositol 3'-OH kinase (PI3K) / Akt pathway appears important for regulating cell survival / cell death (Kulik et al. Mol. Cell. Biol. 17: 1595-1606 (1997); Franke et al, Cell, 88:435- 437 (1997); Kauffinann-Zeh et al. Nature 385:544-548 (1997) Hemmings Science, 275:628-630 (1997); Dudek et al Science, 275:661-665 (1997)). Survival factors, such as platelet derived growth factor (PDGF), nerve growth factor (NGF) and insulin-like growth factor-1 (IGF-1), promote cell survival under various conditions by inducing the activity of PI3K (Kulik et al. 1997, Hemmings 1997). Activated PI3K leads to the production of phosphatidylinositol (3,4,5)-triphosphate (Ptdlns(3,4,5)-P3), which in turn binds to, and promotes the activation of, the serine / threonine kinase Akt, which contains a pleckstrin homology (PH)-domain (Franke et al Cell, 81:727-736 (1995); Hemmings Science, 277:534 (1997); Downward, Curr. Opin. Cell Biol. 10:262-267 (1998), Alessi et al EMBO J. 15: 6541-6551 (1996)). Specific inhibitors of PI3K or dominant negative Akt mutants abolish survival-promoting activities of these growth factors or cytokines. It has been previously disclosed that inhibitors of PI3K (LY294002 or wortmannin) blocked the activation of Akt by upstream kinases. In addition, introduction of constitutively active PI3K or Akt mutants promotes cell survival under conditions in which cells normally undergo apoptotic cell death (Kulik et al. 1997, Dudek et al. 1997).

[0008]

[0004] Three members of the Akt subfamily of second-messenger regulated serine / threonine protein kinases have been identified and termed Aktl / PKBa, Akt2 / PKBp, and Akt3 / PKBy (hereinafter referred to as “Aktl”, “Akt2” and “Akt3”), respectively. The isoforms are homologous, particularly in regions encoding the catalytic domains. Akts are activated by phosphorylation events occurring in response to PI3K signaling. PI3K phosphorylates membrane inositol phospholipids, generating the

[0009] 1

[0010] MEl\56585648.vl 141039-01220 second messengers phosphatidyl-inositol 3,4,5-trisphosphate and phosphatidylinositol 3,4- bisphosphate, which have been shown to bind to the PH domain of Akt. The current model of Akt activation proposes recruitment of the enzyme to the membrane by 3'-phosphorylated phosphoinositides, where phosphorylation of the regulatory sites of Akt by the upstream kinases occurs (B. A. Hemmings, Science 275:628-630 (1997); B. A. Hemmings, Science 276:534 (1997); J. Downward, Science 279:673-674 (1998)).

[0011]

[0005] Phosphorylation of Aktl occurs on two regulatory sites, Thr308 in the catalytic domain activation loop and on Ser473 near the carboxy terminus (D. R. Alessi et al. EMBO J. 15:6541-6551 (1996) and R. Meier et al. J. Biol. Chem. 272:30491-30497 (1997)). Equivalent regulatory phosphorylation sites occur in Akt2 and Akt3. The upstream kinase, which phosphorylates Akt at the activation loop site has been cloned and termed 3 '-phosphoinositide dependent protein kinase 1 (PDK1). PDK1 phosphorylates not only Akt, but also p70 ribosomal S6 kinase, p90RSK, serum and glucocorticoid-regulated kinase (SGK), and protein kinase C.

[0012]

[0006] The tumor suppressor PTEN, a protein and lipid phosphatase that specifically removes the 3' phosphate of Ptdlns(3,4,5) — P3, is a negative regulator of the PI3K / Akt pathway (Li et al. Science 275: 1943-1947 (1997), Stambolic et al. Cell 95:29-39 (1998), Sun et al. Proc. Natl. Acad. Sci. U.S.A. 96:6199-6204 (1999)). Germline mutations of PTEN are responsible for human cancer syndromes such as Cowden disease (Liaw et al. Nature Genetics 16:64-67 (1997)). PTEN is deleted in a large percentage of human tumors and tumor cell lines without functional PTEN show elevated levels of activated Akt (Li et al. supra, Guldberg et al. Cancer Research 57:3660-3663 (1997), Risinger et al.

[0013] Cancer Research 57:4736-4738 (1997)).

[0014]

[0007] These observations demonstrate that the PI3K / Akt pathway plays important roles for regulating cell survival or apoptosis in tumorigenesis.

[0015] SUMMARY

[0016]

[0008] Provided herein are compounds, or pharmaceutically acceptable salts thereof, and compositions which are useful for treating conditions responsive to Aktl kinase inhibition, such as cancer.

[0017]

[0009] A first aspect of the disclosure is a compound having the structural Formula I: or a pharmaceutically acceptable salt thereof, wherein

[0018] X1, X2, X3, X4X5, X6, and X7are each independently N or CRE;

[0019] 2

[0020] MEl\56585648.vl 141039-01220

[0021] Y is selected from OH or NHR9;

[0022] R1is heterocyclyl optionally substituted with 1 to 4 groups selected from RA;

[0023] R2is hydrogen, (Ci-C4)alkyl, or R1and R2taken together with the carbon atoms to which they are attached form a heterocyclyl optionally substituted with 1 to 4 groups selected from RB;

[0024] R3is selected from (Ci-C4)alkyl, halo(Ci-C4)alkyl, hydroxy(Ci-C4)alkyl, (Ci-C4)alkoxy, halo(Ci-C4)alkoxy, (Ci-C4)alkylene(Ci-C4)alkoxy, (C2-C4)alkenyl, halo(C2-C4)alkenyl, (C2- C4)alkynyl, halo(C2-C4)alkynyl, cyano, halo, NH(Ci-C4)alkyl, N[(Ci-C4)alkyl]2, NH2, hydroxy, (Ci- C4)alkylene [phenyl], (Ci-C4)alkylene [heterocyclyl], (Ci-C4)alkylene [cycloalkyl], (Ci- C4)alkylene [heteroaryl], O[ phenyl ], O [heterocyclyl], O [cycloalkyl], O [heteroaryl], phenyl, heterocyclyl, heteroaryl, and cycloalkyl, wherein each of said phenyl, heterocyclyl, heteroaryl, and cycloalkyl alone, or as part of a larger group, are optionally substituted by 1 to 3 groups selected from cyano, halo, (Ci-C4)alkyl, halo(Ci-C4)alkyl, (Ci-C4)alkoxy, and halo(Ci-C4)alkoxy;

[0025] RAand RBare each independently selected from (Ci-C4)alkyl, halo(Ci-C4)alkyl, hydroxy(Ci- C4)alkyl, (Ci-C4)alkoxy, halo(Ci-C4)alkoxy, cyano, halo, hydroxy, (C2-C4)alkenyl, halo(C2- C4)alkenyl, (C2-C4)alkynyl, halo(C2-C4)alkynyl, (Ci-C4)alkyl(Ci-C4)alkoxy, (Ci-C4)alkyleneC(O)R4, (Ci-C4)alkyleneC(O)OR4, (Ci-C4)alkyleneC(O)NR5R6, (Ci-C4)alkyleneNR5C(O)R6, (Ci- C4)alkyleneNR5C(O)NR6R7, (Ci-C4)alkylene[phenyl], (Ci-C4)alkylene [heterocyclyl], (Ci- C4)alkylene [cycloalkyl], (Ci-C4)alkylene [heteroaryl], phenyl, heteroaryl, heterocyclyl, cycloalkyl, - C(O)R4, -S(O)nR4,-C(O)OR4, -C(O)NR5R6, -NR5C(O)R6, -NR5C(O)NR6R7, oxo, NR5R6, (Ci- C4)alkyleneNR5R6, -(Ci-C4)alkoxyNR5R6, (C1-C4) alkoxyC(O)R4, (Ci-C4)alkoxyC(O)OR4, wherein each of said phenyl, heterocyclyl, heteroaryl, and cycloalkyl alone, or as part of a larger group, are optionally substituted with 1 to 3 groups selected from Rc;

[0026] R4is selected from hydrogen, (Ci-C4)alkyl, (Ci-C4)alkylene [phenyl], (Ci- C4)alkylene [heterocyclyl], (Ci-C4)alkyleneNR5R6, (Ci-C4)alkylene [cycloalkyl], (Ci- C4)alkylene [heteroaryl], heterocyclyl, heteroaryl, cycloalkyl, and phenyl, wherein each of said phenyl, heterocyclyl, heteroaryl, and cycloalkyl alone, or as part of a larger group, are optionally substituted with 1 to 3 groups selected from RD;

[0027] R4a, R5, R5a, R6, R6a, R7, and R7aare each independently selected from hydrogen, (Ci-C4)alkyl, halo(Ci-C4)alkyl, (C2-C4)alkenyl, (Ci-C4)alkylene [phenyl], (Ci-C4)alkylene[heterocyclyl], (Ci- C4)alkylene [cycloalkyl], (Ci-C4)alkylene [heteroaryl], heterocyclyl, heteroaryl, cycloalkyl, and phenyl, wherein each of said phenyl, heterocyclyl, heteroaryl, and cycloalkyl alone, or as part of a larger group, are optionally substituted with 1 to 3 groups selected from halo, hydroxy, (Ci-C4)alkyl, and halo(Ci-C4)alkyl; wherein when R4ais (C2-C4)alkenyl, the (C2-C4)alkenyl is optionally substituted with 1 or 2 substituents selected from halo, cyano, (Ci-C4)alkyl, (C3-Ce)cycloalkyl, and C(R5R6)NR5aR6a

[0028] Rcis selected from (Ci-C4)alkyl, halo(Ci-C4)alkyl, hydroxy(Ci-C4)alkyl, (Ci-C4)alkoxy, (Ci- C4)alkoxy(Ci-C4)alkyl, halo(Ci-C4)alkoxy, cyano, halo, hydroxy, oxo, C(O)OH, C(O)O(Ci-C4)alkyl,

[0029] 3

[0030] MEl\56585648.vl 141039-01220

[0031] (C2-C4)alkenyl, halo(C2-C4)alkenyl, (C2-C4)alkynyl, halo(C2-C4)alkynyl, (Ci-C4)alkylene [phenyl], (Ci -C4)alkylene [heterocyclyl] , (Ci -C4)alkylene [cycloalkyl] , (Ci -C4)alkylene [heteroaryl] , phenyl, heterocyclyl, heteroaryl, and cycloalkyl, wherein each of said phenyl, heterocyclyl, heteroaryl, and cycloalkyl alone, or as part of a larger group, are optionally substituted with 1 to 3 groups selected from RC1;

[0032] RC1is selected from (Ci-C4)alkyl, halo(Ci-C4)alkyl, (Ci-C4)alkoxy, halo(Ci-C4)alkoxy, (Ci- C4)alkyl(Ci-C4)alkoxy, cyano, halo, hydroxy, oxo, C(O)OH, C(O)O(Ci-C4)alkyl, phenyl, heterocyclyl, heteroaryl, and cycloalkyl;

[0033] RDis selected from hydroxy, cyano, halo, (Ci-C4)alkyl, halo(Ci-C4)alkyl, (Ci-C4)alkoxy, halo(Ci-C4)alkoxy, oxo, C(O)R4a, C(O)OR4a, -C(O)NR5aR6a, -NR5aC(O)R6a, 5-6 membered heteroaryl, and

[0034] -NR5aC(O)NR6aR7a, and NR8aR9a, wherein said heteroaryl is optionally substituted by 1 to 3 groups selected from RC1;

[0035] REis selected from hydrogen, halo, hydroxy, (Ci-C4)alkoxy, cyano, and (Ci-C4)alkyl;

[0036] R8is hydrogen or halo;

[0037] R8a, and R9aare each independently selected from hydrogen, (Ci-C4)alkyl, halo(Ci-C4)alkyl, (Ci-C4)alkoxy, halo(Ci-C4)alkoxy, and cyano.

[0038] R9is hydrogen or (Ci-C4)alkyl; n is 1 or 2; and z is 0, 1 or 2.

[0039]

[0010] Another embodiment of the disclosure is a pharmaceutical composition comprising a pharmaceutically acceptable carrier, excipient, or diluent, and a compound disclosed herein or a pharmaceutically acceptable salt thereof.

[0040] [OH] Another embodiment of the disclosure is a method of inhibiting the catalytic activity of Aktl in a subject in need thereof, comprising contacting Aktl kinase with an effective amount of the compound disclosed herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising a compound disclosed herein or a pharmaceutically acceptable salt thereof.

[0012] Another embodiment of the disclosure is the use of a compound disclosed herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising a compound disclosed herein or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for inhibiting the catalytic activity of Aktl in a subject in need thereof.

[0041]

[0013] Another embodiment of the disclosure is a compound disclosed herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising a compound disclosed herein or a pharmaceutically acceptable salt thereof for inhibiting the catalytic activity of Aktl in a subject in need thereof.

[0042] 4

[0043] MEl\56585648.vl 141039-01220

[0044]

[0014] Another embodiment of the disclosure is a method of treating an Aktl -dependent disorder or disease (e.g treating a cancer) in a subject in need thereof, comprising administering to the subject an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the compound(s).

[0045]

[0015] Another embodiment of the disclosure is the use of a compound disclosed herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the compound(s), for the preparation of a medicament for treating an Aktl -dependent disorder or disease (e.g treating a cancer) in a subject in need thereof.

[0046]

[0016] Another embodiment of the disclosure is a compound disclosed herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the compound(s), for use in treating an Aktl mutant-dependent disorder or disease (e.g treating a cancer) in a subject in need thereof.

[0047] DETAILED DESCRIPTION

[0048]

[0017] In one aspect, provided are compounds, compositions and methods for treating a disease or condition related to Aktl kinase activity. Example embodiments include:

[0049]

[0018] First aspect: a compound represented by Formula I: or a pharmaceutically acceptable salt thereof, wherein the definitions for the variables in Formula I are described in the summary above.

[0050]

[0019] First embodiment: a compound having the structural Formula I: or a pharmaceutically acceptable salt thereof, wherein

[0051] X1, X2, X3, X4X5, X6, and X7are each independently N or CRE;

[0052] Y is selected from OH or NHR9;

[0053] 5

[0054] MEl\56585648.vl 141039-01220

[0055] R1is heterocyclyl optionally substituted with 1 to 4 groups selected from RA;

[0056] R2is hydrogen or R1and R2taken together with the carbon atoms to which they are attached form a heterocyclyl optionally substituted with 1 to 4 groups selected from RB;

[0057] R3is selected from (Ci-C4)alkyl, halo(Ci-C4)alkyl, hydroxy(Ci-C4)alkyl, (Ci-C4)alkoxy, halo(Ci-C4)alkoxy, (Ci-C4)alkylene(Ci-C4)alkoxy, (C2-C4)alkenyl, halo(C2-C4)alkenyl, (C2- C4)alkynyl, halo(C2-C4)alkynyl, cyano, halo, NH(Ci-C4)alkyl, N[(Ci-C4)alkyl]2, NH2, hydroxy, (Ci- C4)alkylene [phenyl], (Ci-C4)alkylene [heterocyclyl], (Ci-C4)alkylene [cycloalkyl], (Ci- C4)alkylene [heteroaryl], O[ phenyl ], O [heterocyclyl], O [cycloalkyl], O [heteroaryl], phenyl, heterocyclyl, heteroaryl, and cycloalkyl, wherein each of said phenyl, heterocyclyl, heteroaryl, and cycloalkyl alone, or as part of a larger group, are optionally substituted by 1 to 3 groups selected from cyano, halo, (Ci-C4)alkyl, halo(Ci-C4)alkyl, (Ci-C4)alkoxy, and halo(Ci-C4)alkoxy;

[0058] RAand RBare each independently selected from (Ci-C4)alkyl, halo(Ci-C4)alkyl, hydroxy(Ci- C4)alkyl, (Ci-C4)alkoxy, halo(Ci-C4)alkoxy, cyano, halo, hydroxy, (C2-C4)alkenyl, halo(C2- C4)alkenyl, (C2-C4)alkynyl, halo(C2-C4)alkynyl, (Ci-C4)alkyl(Ci-C4)alkoxy, (Ci-C4)alkyleneC(O)R4, (Ci-C4)alkyleneC(O)OR4, (Ci-C4)alkyleneC(O)NR5R6, (Ci-C4)alkyleneNR5C(O)R6, (Ci- C4)alkyleneNR5C(O)NR6R7, (Ci-C4)alkylene[phenyl], (Ci-C4)alkylene [heterocyclyl], (Ci- C4)alkylene [cycloalkyl], (Ci-C4)alkylene [heteroaryl], phenyl, heteroaryl, heterocyclyl, cycloalkyl, - C(O)R4, -S(O)nR4,-C(O)OR4, -C(O)NR5R6, -NR5C(O)R6, -NR5C(O)NR6R7, oxo, NR5R6, (Ci- C4)alkyleneNR5R6, -(Ci-C4)alkoxyNR5R6, (C1-C4) alkoxyC(O)R4, (Ci-C4)alkoxyC(O)OR4, wherein each of said phenyl, heterocyclyl, heteroaryl, and cycloalkyl alone, or as part of a larger group, are optionally substituted with 1 to 3 groups selected from Rc;

[0059] R4is selected from hydrogen, (Ci-C4)alkyl, (Ci-C4)alkylene [phenyl], (Ci- C4)alkylene [heterocyclyl], (Ci-C4)alkyleneNR5R6, (Ci-C4)alkylene [cycloalkyl], (Ci- C4)alkylene [heteroaryl], heterocyclyl, heteroaryl, cycloalkyl, and phenyl, wherein each of said phenyl, heterocyclyl, heteroaryl, and cycloalkyl alone, or as part of a larger group, are optionally substituted with 1 to 3 groups selected from RD;

[0060] R4a, R5, R5a, R6, R6a, R7, and R7aare each independently selected from hydrogen, (Ci-C4)alkyl, halo(Ci-C4)alkyl, (C2-C4)alkenyl, (Ci-C4)alkylene [phenyl], (Ci-C4)alkylene[heterocyclyl], (Ci- C4)alkylene [cycloalkyl], (Ci-C4)alkylene [heteroaryl], heterocyclyl, heteroaryl, cycloalkyl, and phenyl, wherein each of said phenyl, heterocyclyl, heteroaryl, and cycloalkyl alone, or as part of a larger group, are optionally substituted with 1 to 3 groups selected from halo, hydroxy, (Ci-C4)alkyl, and halo(Ci-C4)alkyl;

[0061] Rcis selected from (Ci-C4)alkyl, halo(Ci-C4)alkyl, hydroxy(Ci-C4)alkyl, (Ci-C4)alkoxy, (Ci- C4)alkoxy(Ci-C4)alkyl, halo(Ci-C4)alkoxy, cyano, halo, hydroxy, oxo, C(O)OH, C(O)O(Ci-C4)alkyl, (C2-C4)alkenyl, halo(C2-C4)alkenyl, (C2-C4)alkynyl, halo(C2-C4)alkynyl, (Ci-C4)alkylene [phenyl], (Ci -C4)alkylene [heterocyclyl] , (Ci -C4)alkylene [cycloalkyl] , (Ci -C4)alkylene [heteroaryl] , phenyl, heterocyclyl, heteroaryl, and cycloalkyl, wherein each of said phenyl, heterocyclyl, heteroaryl, and

[0062] 6

[0063] MEl\56585648.vl 141039-01220 cycloalkyl alone, or as part of a larger group, are optionally substituted with 1 to 3 groups selected from RC1;

[0064] RC1is selected from (Ci-C4)alkyl, halo(Ci-C4)alkyl, (Ci-C4)alkoxy, halo(Ci-C4)alkoxy, (Ci- C4)alkyl(Ci-C4)alkoxy, cyano, halo, hydroxy, oxo, C(O)OH, C(O)O(Ci-C4)alkyl, phenyl, heterocyclyl, heteroaryl, and cycloalkyl;

[0065] RDis selected from hydroxy, cyano, (Ci-C4)alkyl, halo(Ci-C4)alkyl, (Ci-C4)alkoxy, halo(Ci- C4)alkoxy, oxo, C(O)R4a, C(O)OR4a, -C(O)NR5aR6a, -NR5aC(O)R6a, 5-6 membered heteroaryl, and - NR5aC(O)NR6aR7a, wherein said heteroaryl is optionally substituted by 1 to 3 groups selected from RC1;

[0066] REis selected from hydrogen, halo, hydroxy, (Ci-C4)alkoxy, cyano, and (Ci-C4)alkyl;

[0067] R8is hydrogen or halo;

[0068] R9is hydrogen or (Ci-C4)alkyl; n is 1 or 2; and z is 0, 1 or 2.

[0069]

[0020] Second embodiment: a compound represented by Formula I, or a pharmaceutically acceptable salt thereof, wherein X2is N and X1and X3are each CH; X1, X2, and X3are each N; X1is N and X2and X3are each CH; or X1and X2are N and X3is CH, wherein the definitions for the remaining variables are as defined for Formula I.

[0070]

[0021] Third embodiment: a compound represented by Formula la: or a pharmaceutically acceptable salt thereof, wherein the definitions for the variables in

[0071] Formula la are as defined for Formula I.

[0072]

[0022] Fourth embodiment: a compound represented by Formula lb:

[0073] 7

[0074] MEl\56585648.vl 141039-01220 or a pharmaceutically acceptable salt thereof, wherein the definitions for the variables in Formula lb are as defined for Formula I.

[0075]

[0023] Fifth embodiment: a compound represented by Formula Ic: or a pharmaceutically acceptable salt thereof, wherein the definitions for the variables in Formula Ic are as defined for Formula I.

[0076]

[0024] Sixth embodiment: a compound represented by Formula Id: or a pharmaceutically acceptable salt thereof, wherein the definitions for the variables in Formula Id are as defined for Formula I.

[0077]

[0025] Seventh embodiment: a compound represented by Formulae I, la, lb, Ic, or Id, or a pharmaceutically acceptable salt thereof, wherein REis hydrogen, and wherein the definitions for the other variables in Formulae I, la, lb, Ic, and Id are as defined for Formula I.

[0078]

[0026] Eighth embodiment: a compound represented by Formulae I, la, lb, Ic, or Id, or a pharmaceutically acceptable salt thereof, wherein X4is N, and wherein the definitions for the other variables in Formulae I, la, lb, Ic, and Id are as defined for Formula I or in the seventh embodiment.

[0079]

[0027] Ninth embodiment: a compound represented by Formulae I, la, lb, Ic, or Id, or a pharmaceutically acceptable salt thereof, wherein X4is CH, and wherein the definitions for the other variables in Formulae I, la, lb, Ic, and Id are as defined for Formula I or in the seventh embodiment.

[0028] Tenth embodiment: a compound represented by Formulae I, la, lb, Ic, or Id, or a pharmaceutically acceptable salt thereof, wherein R8is hydrogen, and wherein the definitions for the other variables in Formulae I, la, lb, Ic, and Id are as defined for Formula I or in any one of the seventh to ninth embodiments.

[0080] 8

[0081] MEl\56585648.vl 141039-01220

[0082]

[0029] Eleventh embodiment: a compound represented by Formulae I, la, lb, Ic, or Id, or a pharmaceutically acceptable salt thereof, wherein z is 1 or 2, and wherein the definitions for the other variables in Formulae I, la, lb, Ic, and Id are as defined for Formula I or in any one of the seventh to tenth embodiments.

[0083]

[0030] Twelfth embodiment: a compound represented by Formulae I, la, lb, Ic, or Id, or a pharmaceutically acceptable salt thereof, wherein Y is NHR9, and wherein the definitions for the other variables in Formulae I, la, lb, Ic, and Id are as defined for Formula I or in any one of the seventh to eleventh embodiments.

[0084]

[0031] Thirteenth embodiment: a compound represented by Formulae I, la, lb, Ic, or Id, or a pharmaceutically acceptable salt thereof, wherein R9is hydrogen, and wherein the definitions for the other variables in Formulae I, la, lb, Ic, and Id are as defined for Formula I or in any one of the seventh to twelfth embodiments.

[0085]

[0032] Fourteenth embodiment: a compound represented by Formulae I, la, lb, Ic, or Id, or a pharmaceutically acceptable salt thereof, wherein R3is selected from (Ci-C4)alkyl, halo(Ci-C4)alkyl, hydroxy(Ci-C4)alkyl, halo, (C2-C4)alkynyl, phenyl, heterocyclyl, and cycloalkyl, wherein each of said phenyl, heterocyclyl, heteroaryl, and cycloalkyl are optionally substituted by 1 to 3 groups selected from cyano, halo, (Ci-C4)alkyl, halo(Ci-C4)alkyl, (Ci-C4)alkoxy, and halo(Ci-C4)alkoxy, and wherein the definitions for the other variables in Formulae I, la, lb, Ic, and Id are as defined for Formula I or in any one of the seventh to thirteenth embodiments.

[0086]

[0033] Fifteenth embodiment: a compound represented by Formulae I, la, lb, Ic, or Id, or a pharmaceutically acceptable salt thereof, wherein R3is selected from (Ci-C4)alkyl, halo(Ci-C4)alkyl, hydroxy(Ci-C4)alkyl, halo, cyano, (C2-C4)alkynyl, phenyl, 5- to 7-membered heterocyclyl, and (C3- C6)cycloalkyl. Alternatively, as part of a fifteenth embodiment,

[0087]

[0034] Alternative Fifteenth embodiment: a compound represented by Formulae I, la, lb, Ic, or Id, or a pharmaceutically acceptable salt thereof, wherein R3is selected from (Ci-C4)alkyl, halo(Ci-C4)alkyl, hydroxy(Ci-C4)alkyl, halo, (C2-C4)alkynyl, phenyl, 5- to 7-membered heterocyclyl, and (C3- Ce)cycloalkyl, and wherein the definitions for the other variables in Formulae I, la, lb, Ic, and Id are as defined for Formula I or in any one of the seventh to fourteenth embodiments.

[0088]

[0035] Sixteenth embodiment: a compound represented by Formulae I, la, lb, Ic, or Id, or a pharmaceutically acceptable salt thereof, wherein R3is selected from bromo, fluoro, chloro, CF3, CH3, (CH2)2OH, CH(CH3)2OH, CCH, CN, phenyl, morpholinyl, pyrrolidinyl, and cyclopropyl, and wherein the definitions for the other variables in Formulae I, la, lb, Ic, and Id are as defined for Formula I or in any one of the seventh to fifteenth embodiments.

[0089]

[0036] Alternative Sixteenth embodiment: a compound represented by Formulae I, la, lb, Ic, or Id, or a pharmaceutically acceptable salt thereof, wherein R3is selected from bromo, fluoro, chloro, CF3, CH3, (CH2)2OH, CCH, phenyl, morpholinyl, pyrrolidinyl, and cyclopropyl, and wherein the

[0090] 9

[0091] MEl\56585648.vl 141039-01220 definitions for the other variables in Formulae I, la, lb, Ic, and Id are as defined for Formula I or in any one of the seventh to fifteenth embodiments.

[0092]

[0037] Seventeenth embodiment: a compound represented by Formulae I, la, lb, Ic, or Id, or a pharmaceutically acceptable salt thereof, wherein R3is phenyl, and wherein the definitions for the other variables in Formulae I, la, lb, Ic, and Id are as defined for Formula I or in any one of the seventh to sixteenth embodiments.

[0093]

[0038] Eighteenth embodiment: a compound represented by Formulae I, la, lb, Ic, or Id, or a pharmaceutically acceptable salt thereof, wherein z is 1 and R3is attached to the carbon atom adjacent to X2, and wherein the definitions for the other variables in Formulae I, la, lb, Ic, and Id are as defined for Formula I or in any one of the seventh to seventeenth embodiments.

[0094]

[0039] Nineteenth embodiment: a compound represented by Formulae I, la, lb, Ic, or Id, or a pharmaceutically acceptable salt thereof, wherein z is 2 and one R3is attached to the carbon atom adjacent to X2, and the other R3is attached to the carbon atom adjacent to X3, and wherein the definitions for the other variables in Formulae I, la, lb, Ic, and Id are as defined for Formula I or in any one of the seventh to seventeenth embodiments.

[0095]

[0040] Twentieth embodiment: a compound represented by Formulae I, la, lb, Ic, or Id, or a pharmaceutically acceptable salt thereof, wherein R1and R2taken together with the carbon atoms to which they are attached form a 5-6 membered heterocyclyl, optionally substituted with 1 to 4 groups selected from RB, and wherein the definitions for the other variables in Formulae I, la, lb, Ic, and Id are as defined for Formula I or in any one of the seventh to nineteenth embodiments.

[0096]

[0041] Twenty-first embodiment: a compound represented by Formulae I, la, lb, Ic, or Id, or a pharmaceutically acceptable salt thereof, wherein R1and R2taken together with the carbon atoms to which they are attached form a 1,2,3,6-tetrahydropyridinyl optionally substituted with 1 to 4 groups selected from RB, and wherein the definitions for the other variables in Formulae I, la, lb, Ic, and Id are as defined for Formula I or in any one of the seventh to twentieth embodiments.

[0097]

[0042] Twenty-second embodiment: a compound represented by Formulae I, la, lb, Ic, or Id, or a pharmaceutically acceptable salt thereof, wherein RBis -C(O)R4, and wherein the definitions for the other variables in Formulae I, la, lb, Ic, and Id are as defined for Formula I or in any one of the seventh to twenty-first embodiments.

[0098]

[0043] Twenty-third embodiment: a compound represented by Formulae I, la, lb, Ic, or Id, or a pharmaceutically acceptable salt thereof, wherein RBis -C(O)R4, -C(O)OR4, or -C(O)NR5R6, and wherein the definitions for the other variables in Formulae I, la, lb, Ic, and Id are as defined for Formula I or in any one of the seventh to twenty -second embodiments.

[0099]

[0044] Twenty-fourth embodiment: a compound represented by Formulae I, la, lb, Ic, or Id, or a pharmaceutically acceptable salt thereof, wherein R2is hydrogen, or CH,. and wherein the definitions

[0100] 10

[0101] MEl\56585648.vl 141039-01220 for the other variables in Formulae I, la, lb, Ic, and Id are as defined for Formula I or in any one of the seventh to nineteenth embodiments.

[0102]

[0045] Alternative Twenty-fourth embodiment: a compound represented by Formulae I, la, lb, Ic, or Id, or a pharmaceutically acceptable salt thereof, wherein R2is hydrogen, and wherein the definitions for the other variables in Formulae I, la, lb, Ic, and Id are as defined for Formula I or in any one of the seventh to nineteenth embodiments.

[0103]

[0046] Twenty-fifth embodiment: a compound represented by Formulae I, la, lb, Ic, or Id, or a pharmaceutically acceptable salt thereof, wherein R1is a 4-10 membered heterocyclyl optionally substituted with 1 to 4 groups selected from RA, and wherein the definitions for the other variables in Formulae I, la, lb, Ic, and Id are as defined in the twenty-fourth embodiment.

[0104]

[0047] Twenty-sixth embodiment: a compound represented by Formulae I, la, lb, Ic, or Id, or a pharmaceutically acceptable salt thereof, wherein R1is azetidinyl, pyrrolidinyl, piperidinyl, or 2,6- diazaspiro[3.4]octanyl, each of which are optionally substituted with 1 to 4 groups selected from RA, and wherein the definitions for the other variables in Formulae I, la, lb, Ic, and Id are as defined in the twenty-fourth or twenty-fifth embodiments.

[0105]

[0048] Twenty-seventh embodiment: a compound represented by Formulae I, la, lb, Ic, or Id, or a pharmaceutically acceptable salt thereof, wherein each RAis independently selected from (Ci- C4)alkyl, (Ci-C4)alkoxy, halo, hydroxy, (Ci-C4)alkyleneC(O)R4, (Ci-C4)alkyleneC(O)OR4, (Ci- C4)alkyleneC(O)NR5R6, (Ci-C4)alkyleneNR5C(O)R6, (Ci-C4)alkylene[phenyl], (Ci- C4)alkylene [heterocyclyl], (Ci-C4)alkylene [cycloalkyl], (Ci-C4)alkylene [heteroaryl], phenyl, heteroaryl, 5-9 membered heterocyclyl, cycloalkyl, -C(O)R4, -SO2R4, -C(O)OR4, -C(O)NR5R6, and (Ci-C4)alkyleneNR5R6, wherein each of said phenyl, heterocyclyl, heteroaryl, and cycloalkyl alone, or as part of a larger group, are optionally substituted with 1 to 3 groups selected from Rc, and wherein the definitions for the other variables in Formulae I, la, lb, Ic, and Id are as defined in any one of the twenty-fourth to twenty-sixth embodiments.

[0106]

[0049] Twenty-eighth embodiment: a compound represented by Formulae I, la, lb, Ic, or Id, or a pharmaceutically acceptable salt thereof, wherein each RAis independently selected from halo, hydroxy, (Ci-C4)alkyl, (Ci-C4)alkoxy, (Ci-C4)alkyleneC(O)R4, (Ci-C4)alkyleneC(O)OR4, (Ci- C4)alkylene [phenyl], (Ci-C4)alkylene [5 -9-membered heterocyclyl], (Ci-C4)alkylene[9 membered heteroaryl], phenyl, 6-9 membered heteroaryl, 5-9 membered heterocyclyl, (C3-Ce)cycloalkyl, - C(O)R4, -SO2R4, -C(O)OR4, and -C(O)NR5R6, wherein each of said phenyl, heterocyclyl, heteroaryl, and cycloalkyl alone, or as part of a larger group, are optionally substituted with 1 to 3 groups selected from Rc, and wherein the definitions for the other variables in Formulae I, la, lb, Ic, and Id are as defined in any one of the twenty-fourth to twenty-seventh embodiments.

[0107]

[0050] Alternative Twenty-eighth embodiment: a compound represented by Formulae I, la, lb, Ic, or Id, or a pharmaceutically acceptable salt thereof, wherein each RAis independently selected from

[0108] 11

[0109] MEl\56585648.vl 141039-01220 halo, hydroxy, (Ci-C4)alkyl, (Ci-C4)alkyleneC(O)R4, (Ci-C4)alkyleneC(O)OR4, (Ci- C4)alkylene [phenyl], (Ci-C4)alkylene [5 -9-membered heterocyclyl], (Ci-C4)alkylene[9 membered heteroaryl], phenyl, 6-9 membered heteroaryl, 5-9 membered heterocyclyl, (C3-Ce)cycloalkyl, - C(O)R4, -SO2R4, -C(O)OR4, and -C(O)NR5R6, wherein each of said phenyl, heterocyclyl, heteroaryl, and cycloalkyl alone, or as part of a larger group, are optionally substituted with 1 to 3 groups selected from Rc, and wherein the definitions for the other variables in Formulae I, la, lb, Ic, and Id are as defined in any one of the twenty-fourth to twenty-seventh embodiments.

[0110]

[0051] Twenty-ninth embodiment: a compound represented by Formulae I, la, lb, Ic, or Id, or a pharmaceutically acceptable salt thereof, wherein each RAis independently selected from fluoro, hydroxy, methoxy, methyl, -C(O)OR4, -C(O)R4, (Ci-C4)alkyleneC(O)R4, (Ci-C4)alkyleneC(O)OR4, (Ci-C4)alkylene [phenyl], -SO2R4, phenyl, (Ci-C4)alkylene(benzoisoxazolyl), benzoisoxazolyl, dihydrobenzoisothiazolyl, (Ci-C4)alkylene(dihydrobenzoisoxazolyl), (Ci-

[0111] C4)alkylene [isothiazolidinyl] , thiazinanyl, (Ci -C4)alkylene [thiazinanyl] , (Ci -C4)alkylene [indolinyl] , thiazepanyl, tetrahydro-2H-thiopyranyl, cyclobutyl, cyclohexyl, and -C(O)NR5R6, wherein each of the foregoing groups is optionally substituted with 1 to 3 groups selected from Rc, and wherein the definitions for the other variables in Formulae I, la, lb, Ic, and Id are as defined in any one of the twenty-fourth to twenty-eighth embodiments.

[0112]

[0052] Alternative Twenty-ninth embodiment: a compound represented by Formulae I, la, lb, Ic, or Id, or a pharmaceutically acceptable salt thereof, wherein each RAis independently selected from fluoro, hydroxy, methyl, -C(O)OR4, -C(O)R4, (Ci-C4)alkyleneC(O)R4, (Ci-C4)alkyleneC(O)OR4, (Ci- C4)alkylene [phenyl], -SO2R4, phenyl, (Ci-C4)alkylene(benzoisoxazolyl), benzoisoxazolyl, dihydrobenzoisothiazolyl, (Ci-C4)alkylene(dihydrobenzoisoxazolyl), (Ci-

[0113] C4)alkylene [isothiazolidinyl] , thiazinanyl, (Ci -C4)alkylene [thiazinanyl] , (Ci -C4)alkylene [indolinyl] , thiazepanyl, tetrahydro-2H-thiopyranyl, cyclobutyl, cyclohexyl, and -C(O)NR5R6, wherein each of the foregoing groups is optionally substituted with 1 to 3 groups selected from Rc, and wherein the definitions for the other variables in Formulae I, la, lb, Ic, and Id are as defined in any one of the twenty-fourth to twenty-eighth embodiments.

[0114]

[0053] Thirtieth embodiment: a compound represented by Formulae I, la, lb, Ic, or Id, or a pharmaceutically acceptable salt thereof, wherein each RAis independently selected from fluoro, hydroxy, methoxy, methyl, -C(O)OR4, -C(O)R4, (Ci-C4)alkyleneC(O)R4, (Ci-C4)alkyleneC(O)OR4, (Ci-C4)alkylene [phenyl], -SO2R4, phenyl, (Ci-C4)alkylene(benzo[d]isoxazolyl), benzo[d]isoxazolyl, 1 ,3 -dihydrobenzo [c]isothiazolyl, (Ci -C4)alkylene(2,3 -dihydrobenzo [d]isoxazolyl), (Ci - C4)alkylene [isothiazolidinyl], 1,2-thiazinanyl, (Ci-C4)alkylene[l,2-thiazinanyl], (Ci-

[0115] C4)alkylene [indolinyl], 1,2-thiazepanyl, tetrahydro-2H-thiopyranyl, cyclobutyl, cyclohexyl, and - C(O)NR5R6, wherein each of the foregoing groups is optionally substituted with 1 to 3 groups selected

[0116] 12

[0117] MEl\56585648.vl 141039-01220 from Rc, and wherein the definitions for the other variables in Formulae I, la, lb, Ic, and Id are as defined in any one of the twenty-fourth to twenty-ninth embodiments.

[0118]

[0054] Alternative Thirtieth embodiment: a compound represented by Formulae I, la, lb, Ic, or Id, or a pharmaceutically acceptable salt thereof, wherein each RAis independently selected from fluoro, hydroxy, methyl, -C(O)OR4, -C(O)R4, (Ci-C4)alkyleneC(O)R4, (Ci-C4)alkyleneC(O)OR4, (Ci- C4)alkylene [phenyl], -SO2R4, phenyl, (Ci-C4)alkylene(benzo[d]isoxazolyl), benzo[d]isoxazolyl, 1,3- dihydrobenzo[c]isothiazolyl, (Ci-C4)alkylene(2,3-dihydrobenzo[d]isoxazolyl), (Ci- C4)alkylene[isothiazolidinyl], 1,2-thiazinanyl, (Ci-C4)alkylene[l,2-thiazinanyl], (Ci- C4)alkylene[indolinyl], 1,2-thiazepanyl, tetrahydro-2H-thiopyranyl, cyclobutyl, cyclohexyl, and - C(O)NR5R6, wherein each of the foregoing groups is optionally substituted with 1 to 3 groups selected from Rc, and wherein the definitions for the other variables in Formulae I, la, lb, Ic, and Id are as defined in any one of the twenty-fourth to twenty-ninth embodiments.

[0119]

[0055] Thirty-first embodiment: a compound represented by Formulae I, la, lb, Ic, or Id, or a pharmaceutically acceptable salt thereof, wherein each Rcis independently selected from (Ci- C4)alkyl, halo(Ci-C4)alkyl, hydroxy(Ci-C4)alkyl, (Ci-C4)alkoxy, (Ci-C4)alkoxy(Ci-C4)alkyl, halo(Ci- C4)alkoxy, halo, hydroxy, oxo, -C(O)OH, -C(O)O(Ci-C4)alkyl, (Ci-C4)alkylene [phenyl], (Ci- C4)alkylene[heterocyclyl], (Ci-C4)alkylene [cycloalkyl], (Ci-C4)alkylene [heteroaryl], 5-6 membered heterocyclyl, and cycloalkyl, wherein each of said phenyl, heterocyclyl, heteroaryl, and cycloalkyl alone, or as part of a larger group, are optionally substituted with 1 to 3 groups selected from RC1, and wherein the definitions for the other variables in Formulae I, la, lb, Ic, and Id are as defined in any one of the twenty-fourth to thirtieth embodiments.

[0120]

[0056] Thirty-second embodiment: a compound represented by Formulae I, la, lb, Ic, or Id, or a pharmaceutically acceptable salt thereof, wherein each Rcis independently selected from (Ci- C4)alkyl, halo(Ci-C4)alkyl, hydroxy(Ci-C4)alkyl, (Ci-C4)alkoxy, (Ci-C4)alkoxy(Ci-C4)alkyl, halo(Ci- C4)alkoxy, halo, hydroxy, oxo, -C(O)OH, -C(O)O(Ci-C4)alkyl, and 5 membered heterocyclyl, wherein said heterocyclyl is optionally substituted with 1 to 3 groups selected from RC1, and wherein the definitions for the other variables in Formulae I, la, lb, Ic, and Id are as defined in any one of the twenty-fourth to thirty-first embodiments.

[0121]

[0057] Thirty-third embodiment: a compound represented by Formulae I, la, lb, Ic, or Id, or a pharmaceutically acceptable salt thereof, wherein each Rcis independently selected from, CH2OCH3, hydroxy, oxo, C(O)OH, C(O)OCH3, and dihydroisoxazolyl, wherein said dihydroisoxazolyl is optionally substituted with 1 to 3 groups selected from RC1, and wherein the definitions for the other variables in Formulae I, la, lb, Ic, and Id are as defined in any one of the twenty-fourth to thirty- second embodiments.

[0122]

[0058] Thirty-fourth embodiment: a compound represented by Formulae I, la, lb, Ic, or Id, or a pharmaceutically acceptable salt thereof, wherein each RC1is selected from (Ci-C4)alkyl, (Ci-

[0123] 13

[0124] MEl\56585648.vl 141039-01220

[0125] C^alkoxy, halo, hydroxy, and oxo, and wherein the definitions for the other variables in Formulae I, la, lb, Ic, and Id are as defined in any one of the twenty-fourth to thirty-third embodiments.

[0126]

[0059] Thirty-fifth embodiment: a compound represented by Formulae I, la, lb, Ic, or Id, or a pharmaceutically acceptable salt thereof, wherein RC1is oxo, and wherein the definitions for the other variables in Formulae I, la, lb, Ic, and Id are as defined in any one of the twenty-fourth to thirty-fourth embodiments.

[0127]

[0060] Thirty-sixth embodiment: a compound represented by Formulae I, la, lb, Ic, or Id, or a pharmaceutically acceptable salt thereof, wherein R4is selected from hydrogen, (Ci-C4)alkyl, (Ci- C4)alkylene [phenyl], (Ci-C4)alkylene[5-10 membered heterocyclyl], (Ci-C4)alkylene[6-10 membered heteroaryl], 6-10 membered heterocyclyl, 6-9 membered heteroaryl, and phenyl, wherein each of said phenyl, heterocyclyl, and heteroaryl are optionally substituted with 1 to 3 groups selected from RD, and wherein the definitions for the other variables in Formulae I, la, lb, Ic, and Id are as defined in any one of the twenty-fourth to thirty-fifth embodiments.

[0128]

[0061] Thirty-seventh embodiment: a compound represented by Formulae I, la, lb, Ic, or Id, or a pharmaceutically acceptable salt thereof, wherein R4is selected from hydrogen, (Ci-C4)alkyl, piperidinyl, piperazinlyl, azabicyclohexanyl, diazaspiroheptanyl, tetrahydroisoxazolopyridinyl, (Ci- C4)alkylene [phenyl], triazaspirooctanyl, (Ci-C4)alkylene(dihydrobenzoisothiazolyl), tetrahydropyrazolopyridinyl, hexahydrooxazolopyrazinyl, hexahydroimidazopyrazinyl, (Ci- C4)alkylene(hexahydroimidazopyrazinyl), azabicycloheptanyl, benzoisoxazolyl, phenyl, octahydroimidazopyrazinyl, octahydropyrrolopyrazinyl, triazaspirodecanyl, (Ci- C4)alkylene[isoxazolyl], and dihydrobenzoisothiazolyl, wherein each of the foregoing groups is optionally substituted with 1 to 3 groups selected from RD, and wherein the definitions for the other variables in Formulae I, la, lb, Ic, and Id are as defined in any one of the twenty-fourth to thirty-sixth embodiments.

[0129]

[0062] Thirty-eighth embodiment: a compound represented by Formulae I, la, lb, Ic, or Id, or a pharmaceutically acceptable salt thereof, wherein R4is selected from hydrogen, (Ci-C4)alkyl, piperidinyl, piperazinlyl, 3-azabicyclo[3.1.0]hexanyl, 2,6-diazaspiro[3.3]heptanyl, 4, 5,6,7- tetrahydroisoxazolopyridinyl, (Ci-C4)alkylene [phenyl], 2,5,7-triazaspiro[3.4]octanyl, 2- azaspiro[3.3]heptanyl (Ci-C4)alkylene(l,3-dihydrobenzoisothiazolyl), 4,5,6,7-tetrahydro-2H- pyrazolopyridinyl, hexahydro-3H-oxazolopyrazinyl, 3,5,6,7,8,8a-hexahydroimidazopyrazinyl, (Ci- C4)alkylene(3,5,6,7,8,8a-hexahydroimidazopyrazinyl), 3 -azabicyclo [3.1. l]heptanyl, benzoisoxazolyl, phenyl, 3,8-diazabicyclo[3.2.1]octanyl, octahydroimidazopyrazinyl, azetidinyl, octahydropyrrolopyrazinyl, l,3,8-triazaspiro[4.5]decanyl, (Ci-C4)alkylene[isoxazolyl], and 1,3- dihydrobenzoisothiazolyl, wherein each of the foregoing groups is optionally substituted with 1 to 3 groups selected from RD, and wherein the definitions for the other variables in Formulae I, la, lb, Ic, and Id are as defined in any one of the twenty-fourth to thirty-seventh embodiments.

[0130] 14

[0131] MEl\56585648.vl 141039-01220

[0132]

[0063] Alternative Thirty-eighth embodiment: a compound represented by Formulae I, la, lb, Ic, or Id, or a pharmaceutically acceptable salt thereof, wherein R4is selected from hydrogen, (Ci-C4)alkyl, piperidinyl, piperazinlyl, 3-azabicyclo[3.1.0]hexanyl, 2,6-diazaspiro[3.3]heptanyl, 4, 5,6,7- tetrahydroisoxazolopyridinyl, (Ci -Chalky lene [phenyl], 2,5,7-triazaspiro[3.4]octanyl, (Ci- C4)alkylene(l,3-dihydrobenzoisothiazolyl), 4,5,6,7-tetrahydro-2H-pyrazolopyridinyl, hexahydro-3H- oxazolopyrazinyl, 3,5,6,7,8,8a-hexahydroimidazopyrazinyl, (Ci-C4)alkylene(3,5,6,7,8,8a- hexahydroimidazopyrazinyl), 3 -azabicyclo [3. l.l]heptanyl, benzoisoxazolyl, phenyl, octahydroimidazopyrazinyl, octahydropyrrolopyrazinyl, l,3,8-triazaspiro[4.5]decanyl, (Ci- C4)alkylene[isoxazolyl], and 1,3-dihydrobenzoisothiazolyl, wherein each of the foregoing groups is optionally substituted with 1 to 3 groups selected from RD, and wherein the definitions for the other variables in Formulae I, la, lb, Ic, and Id are as defined in any one of the twenty-fourth to thirtyseventh embodiments.

[0133]

[0064] Thirty-ninth embodiment: a compound represented by Formulae I, la, lb, Ic, or Id, or a pharmaceutically acceptable salt thereof, wherein each RDis independently selected from hydroxy, halo, cyano, (Ci-C4)alkyl, halo(Ci-C4)alkyl, (Ci-C4)alkoxy, halo(Ci-C4)alkoxy, oxo, -C(O)R4a, - C(O)OR4a, -C(O)NR5aR6a, -NR5aC(O)R6a, 5-6 membered heteroaryl, -NR5aC(O)NR6aR7a, and NR8aR9a, wherein said heteroaryl is optionally substituted by 1 to 3 groups selected from RC1, and wherein the definitions for the other variables in Formulae I, la, lb, Ic, and Id are as defined in any one of the twenty-fourth to thirty-eighth embodiments.

[0134]

[0065] Alternative Thirty-ninth embodiment: a compound represented by Formulae I, la, lb, Ic, or Id, or a pharmaceutically acceptable salt thereof, wherein each RDis independently selected from hydroxy, cyano, (Ci-C4)alkyl, halo(Ci-C4)alkyl, (Ci-C4)alkoxy, halo(Ci-C4)alkoxy, oxo, -C(O)R4a, - C(O)OR4a, -C(O)NR5aR6a, -NR5aC(O)R6a, 5-6 membered heteroaryl, and -NR5aC(O)NR6aR7a, wherein said heteroaryl is optionally substituted by 1 to 3 groups selected from RC1, and wherein the definitions for the other variables in Formulae I, la, lb, Ic, and Id are as defined in any one of the twenty-fourth to thirty-eighth embodiments.

[0135]

[0066] Fortieth embodiment: a compound represented by Formulae I, la, lb, Ic, or Id, or a pharmaceutically acceptable salt thereof, wherein each RDis independently selected from hydroxy, fluoro, cyano, CH,. OMe, oxo, -C(O)R4a, -C(O)OR4a, -C(O)NR5aR6a; isoxazolyl, and NR8aR9a, wherein said isoxazolyl is optionally substituted by 1 to 3 groups selected from RC1, and wherein the definitions for the other variables in Formulae I, la, lb, Ic, and Id are as defined in any one of the twenty-fourth to thirty-ninth embodiments.

[0136]

[0067] Alternative Fortieth embodiment: a compound represented by Formulae I, la, lb, Ic, or Id, or a pharmaceutically acceptable salt thereof, wherein each RDis independently selected from hydroxy, cyano, CH,. OMe, oxo, -C(O)R4a, -C(O)OR4a, -C(O)NR5aR6a; and isoxazolyl, wherein said isoxazolyl is optionally substituted by 1 to 3 groups selected from RC1, and wherein the definitions for the other

[0137] 15

[0138] MEl\56585648.vl 141039-01220 variables in Formulae I, la, lb, Ic, and Id are as defined in any one of the twenty-fourth to thirty-ninth embodiments.

[0139]

[0068] Forty-first embodiment: a compound represented by Formulae I, la, lb, Ic, or Id, or a pharmaceutically acceptable salt thereof, wherein R4ais selected from hydrogen, (Ci-C4)alkyl, halo(Ci-C4)alkyl, and (C2-C4)alkenyl, wherein the (C2-C4)alkenyl is optionally substituted with 1 or 2 substituents selected from halo, cyano, (Ci-C4)alkyl, (C3-Ce)cycloalkyl, and C(R5R6)NR5aR6a., and wherein the definitions for the other variables in Formulae I, la, lb, Ic, and Id are as defined in any one of the twenty-fourth to fortieth embodiments.

[0140]

[0069] Alternative Forty-first embodiment: a compound represented by Formulae I, la, lb, Ic, or Id, or a pharmaceutically acceptable salt thereof, wherein R4ais selected from hydrogen, (Ci-C4)alkyl, halo(Ci-C4)alkyl, and (C2-C4)alkenyl, and wherein the definitions for the other variables in Formulae I, la, lb, Ic, and Id are as defined in any one of the twenty-fourth to fortieth embodiments.

[0141]

[0070] Forty-second embodiment: a compound represented by Formulae I, la, lb, Ic, or Id, or a pharmaceutically acceptable salt thereof, wherein R4ais selected from hydrogen, CH3, CH2CH3,

[0142] C(CH3)3, CF3, ethenyl, wherein the definitions for the other variables in Formulae I, la, lb, Ic, and Id are as defined in any one of the twenty-fourth to forty-first embodiments.

[0143]

[0071] Alternative Forty-second embodiment: a compound represented by Formulae I, la, lb, Ic, or Id, or a pharmaceutically acceptable salt thereof, wherein R4ais selected from hydrogen, CH3, CH2CH3, C(CH3)3, CF3, and ethenyl, and wherein the definitions for the other variables in Formulae I, la, lb, Ic, and Id are as defined in any one of the twenty-fourth to forty-first embodiments.

[0144]

[0072] Forty-third aspect: a compound represented by Formulae I, la, lb, Ic, or Id, or a pharmaceutically acceptable salt thereof, wherein R8a, and R9aare each independently selected from hydrogen and cyano, and wherein the definitions for the other variables in Formulae I, la, lb, Ic, and Id are as defined in any one of the twenty-fourth to forty-second embodiments.

[0145]

[0073] Forty-third embodiment: a compound represented by Formulae I, la, lb, Ic, or Id, or a pharmaceutically acceptable salt thereof, whereinR5, R5a, R6, and R6aare each independently selected from hydrogen, (Ci-C4)alkyl, and (Ci-C4)alkylene[5-9 membered heteroaryl], wherein each of said phenyl and heteroaryl are optionally substituted with 1 to 3 groups selected from halo, hydroxy, (Ci- C4)alkyl, and halo(Ci-C4)alkyl, and wherein the definitions for the other variables in Formulae I, la, lb, Ic, and Id are as defined in any one of the twenty-fourth to forty-second embodiments.

[0146]

[0074] Alternative Forty-third embodiment: a compound represented by Formulae I, la, lb, Ic, or Id, or a pharmaceutically acceptable salt thereof, wherein R5, R5a, R6, and R6aare each independently selected from hydrogen and (Ci-C4)alkylene[5-9 membered heteroaryl], wherein each of said phenyl

[0147] 16

[0148] MEl\56585648.vl 141039-01220 and heteroaryl are optionally substituted with 1 to 3 groups selected from halo, hydroxy, (Ci-C4)alkyl, and halo(Ci-C4)alkyl, and wherein the definitions for the other variables in Formulae I, la, lb, Ic, and Id are as defined in any one of the twenty-fourth to forty-second embodiments.

[0149]

[0075] Forty-fourth embodiment: a compound represented by Formulae I, la, lb, Ic, or Id, or a pharmaceutically acceptable salt thereof, wherein R5, R5a, R6, and R6aare each independently selected from hydrogen, CH,. and (Ci-C4)alkylene[isoxazolyl], wherein said isoxazolyl is optionally substituted with hydroxy, and wherein the definitions for the other variables in Formulae I, la, lb, Ic, and Id are as defined in any one of the twenty-fourth to forty-third embodiments.

[0150]

[0076] Alternative Forty-fourth embodiment: a compound represented by Formulae I, la, lb, Ic, or Id, or a pharmaceutically acceptable salt thereof, wherein R5, R5a, R6, and R6aare each independently selected from hydrogen and (Ci-C4)alkylene[isoxazolyl], wherein said isoxazolyl is optionally substituted with hydroxy, and wherein the definitions for the other variables in Formulae I, la, lb, Ic, and Id are as defined in any one of the twenty-fourth to forty-third embodiments.

[0151]

[0077] Forty-fifth embodiment: a compound represented by Formulae I, la, lb, Ic, or Id, or a pharmaceutically acceptable salt thereof, wherein R1is:

[0152] 17

[0153] MEl\56585648.vl 141039-01220

[0154] 18

[0155] MEl\56585648.vl 141039-01220

[0156] 19

[0157] MEl\56585648.vl 141039-01220

[0158] 20

[0159] MEl\56585648.vl 141039-01220

[0160] 21

[0161] MEl\56585648.vl 141039-01220 and wherein the definitions for the other variables in Formulae I, la, lb, Ic, and Id are as defined in any one of the twenty-fourth to forty-fourth embodiments.

[0162]

[0078] Alternative Forty-fifth embodiment: a compound represented by Formulae I, la, lb, Ic, or Id, or a pharmaceutically acceptable salt thereof, wherein R1is:

[0163] 22

[0164] MEl\56585648.vl 141039-01220

[0165] 23

[0166] MEl\56585648.vl 141039-01220

[0167] 24

[0168] MEl\56585648.vl 141039-01220

[0169] 25

[0170] MEl\56585648.vl 141039-01220

[0171] Formulae I, la, lb, Ic, and Id are as defined in any one of the twenty-fourth to forty-fourth embodiments.

[0172]

[0079] The disclosure also includes the compounds prepared in the Exemplification, in both the neutral form and pharmaceutically acceptable salts thereof. The synthetic protocol used to prepare the disclosed compounds is described in the Exemplification.

[0173]

[0080] Another embodiment of the disclosure is a compound disclosed herein, including a compound of any one of Formulae I, la, lb, Ic, or Id, or as disclosed in the Exemplification, or a pharmaceutically acceptable salt of any of the foregoing, in which one or more hydrogen atoms is replaced with deuterium. The deuterium enrichment at any one of the sites where hydrogen has been replaced by deuterium is at least 50%, 75%, 85%, 90%, 95%, 98% or 99%. Deuterium enrichment is a mole percent and is obtained by dividing the number of compounds with deuterium enrichment at the site of enrichment with the number of compounds having hydrogen or deuterium at the site of enrichment.

[0174] 26

[0175] MEl\56585648.vl 141039-01220

[0176]

[0081] The number of carbon atoms in a group is specified herein by the prefix “Cx-xx”, wherein x and xx are integers. For example, "C1-3 alkyl" is an alkyl group which has from 1 to 3 carbon atoms.

[0082] The suffix “yl” added to the end of a chemical name indicates that the named moiety is bonded to the molecule at one point, i.e monovalent. The suffix “ene” added to the end of a chemical name indicates that the named moiety is bonded to the molecule at two points, i.e bivalent.

[0177]

[0083] "Alkyl", when used alone or part of a larger moiety, refers to a fully saturated branched or unbranched hydrocarbon moiety. Unless otherwise specified, an alkyl comprises 1 to 6 carbon atoms, or 1 to 4 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, or n- hexyl. “Alkylene” refers to a bivalent alkyl group (e.g. methylene, ethylene). A “deuterated” alkyl group means that one or more hydrogen atoms is replaced with deuterium. The deuterium enrichment at any one of the sites where hydrogen has been replaced by deuterium is at least 50%, 75%, 85%, 90%, 95%, 98% or 99%. Deuterium enrichment is a mole percent and is obtained by dividing the number of deuterium atoms at all sites of enrichment with the number of hydrogen plus deuterium atoms at all of the sites of enrichment. For example, a compound with a deuterated methylene group has a 98.0% enrichment when 98.0% of the hydrogen atoms on the methylene group have been replaced with deuterium.

[0178]

[0084] "Alkenyl" refers to a branched or unbranched hydrocarbon moiety containing at least one double bond. Unless otherwise specified, an alkenyl group comprises 1 to 6 carbon atoms, or 1 to 4 carbon atoms. Representative examples of alkenyl include, but are not limited to, ethenyl, propenyl, 1- butenyl, 2-butenyl, 1-methypropenyl, 2-methypropenyl, 3-methypropenyl and the like. It is understood that compounds of the present invention may contain alkenyl groups, with all possible isomers (i.e cis (Z) and trans ( / ■.) isomers) being included in the present invention.

[0179]

[0085] "Alkynyl" refers to a branched or unbranched hydrocarbon moiety containing at least one triple bond. Unless otherwise specified, an alkynyl group comprises 1 to 6 carbon atoms, or 1 to 4 carbon atoms. Representative examples of alkynyl include, but are not limited to, ethynyl, propynyl, 1-butynyl, 2-butynyl, 1-methypropynyl, 2-methypropynyl, 3-methypropynyl and the like.

[0180]

[0086] "Alkoxy" refers to OR, where oxygen is singularly bonded to R, and R is an alkyl group. Examples of alkoxy include methoxy, ethoxy, isopropoxy, and the like. A “deuterated” alkoxy group means that one or more hydrogen atoms is replaced with deuterium. The deuterium enrichment at any one of the sites where hydrogen has been replaced by deuterium is at least 50%, 75%, 85%, 90%, 95%, 98% or 99%. Deuterium enrichment is a mole percent and is obtained by dividing the number of deuterium atoms at all sites of enrichment with the number of hydrogen plus deuterium atoms at all of the sites of enrichment. For example, a compound with two deuterated methyl groups has a 98.0% enrichment when 98.0% of the hydrogen atoms on the two methyl groups have been replaced with deuterium. 1

[0181] MEl\56585648.vl 141039-01220

[0182]

[0087] “Aryl”, when used alone or as part of another moiety such as aralkyl, refers to an aromatic hydrocarbon of six to 10 ring atoms, such as phenyl or naphthyl.

[0183]

[0088] "Halogen" or "halo" is fluoro, chloro, bromo or iodo.

[0184]

[0089] The term “haloalkyl” includes mono, poly, and perhaloalkyl groups where the halogens are independently selected from fluorine, chlorine, bromine, and iodine.

[0185]

[0090] “Haloalkoxy” is a haloalkyl group which is attached to another moiety via an oxygen atom such as, e g, -OCHF2 or -OCF3.

[0186]

[0091] “Cycloalkyl” refers to completely saturated monocyclic or bicyclic hydrocarbon group. Unless otherwise specified, a cycloalkyl has 3-10 ring carbon atoms, alternatively 3-8 ring carbon atoms. A cycloalkyl can be monocyclic, fused bicyclic and bridged bicyclic. A monocyclic cycloalkyl has 3-8 ring carbon atoms and includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentyl, cyclopheptyl and cyclooctyl. A fused bicyclic cycloalkyl has 6-10 ring carbon atoms and two rings which share two adjacent ring atoms, e.g a 4 to 7 membered cycloalkyl fused to a 3 to 6 membered cycloalkyl. A bridged bicyclic cycloalkyl has 5 to 10 ring carbon atoms and two monocyclic cycloalkyl groups which share three adjacent ring atoms.

[0187]

[0092] "Heteroaryl" refers to an aromatic 5- to 10-membered mono or bicyclic cyclic ring system, having 1 to 4 heteroatoms independently selected from O, N and S, and wherein N can be oxidized (e.g N(O)) or quatemized, and S can be optionally oxidized to sulfoxide and sulfone. A monocyclic heteroaryl has 5 or 6 ring atoms, i.e is 5 to 6 membered. Examples of 5- to 6-membered monocyclic heteroaryls include, but are not limited to, pyrrolyl, furanyl, thiophenyl (or thienyl), imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furazanyl, oxadiazolyl, thiadiazolyl, dithiazolyl, triazolyl, tetrazolyl, pyridinyl, pyranyl, thiopyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazinyl, thiazinyl, dioxinyl, dithiinyl, oxathianyl, triazinyl, tetrazinyl, and the like. A bicyclic heteroaryl has 8 to 10 ring atoms, i.e is 8 to 10 membered, and two rings which share two adjacent ring atoms. Examples of bicyclic heteroaryls include, but are not limited to, benzoisoxazolyl, benzoxazolyl, indolyl, benzimidazolyl, benzofuranyl, and the like.

[0188]

[0093] "Heterocyclyl" refers to a saturated or partially unsaturated monocyclic or bicyclic (e.g fused, spirocyclic, or bridged) ring system which has from 4- to 13 ring members, e.g 4-10 ring members, at least one of which is a heteroatom, and up to 4 (e.g. 1, 2, 3, or 4) of which may be heteroatoms, wherein the heteroatoms are independently selected from O, S and N, and wherein N can be oxidized (e.g. N(O)) or quatemized, and S can be optionally oxidized to sulfoxide and sulfone.

[0189]

[0094] Examples of 4-7 membered monocyclic heterocyclyls include, but are not limited to, oxetanyl, thietanyl, azetedinyl, pyrrolidinyl, tetrahydrofuranyl, thiolanyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, dihydroisoxazolyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, oxathiolanyl, piperidinyl, tetrahydropyranyl, thianyl, thiazinanyl, thiazepanyl,

[0190] 28

[0191] MEl\56585648.vl 141039-01220 tetrahydrothiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxanyl, dithianyl, trioxanyl, trithianyl, azepanyl, oxepanyl, thiepanyl, dihydrofuranyl, imidazolinyl, and dihydropyranyl.

[0192]

[0095] A fused bicyclic heterocyclyl has a 4-7 membered heterocyclyl which shares two adjacent ring atoms with a 4-7 membered heterocyclyl or a 3-7 membered cycloalkyl, i.e a 4 to 7 membered heterocyclyl fused to a 4 to 7 membered heterocyclyl or a 3 to 7 membered carbocyclyl. Examples include azabicyclohexanyl, azabicycloheptanyl, cyclopropylpyrrolidinyl, cyclopentapyrrolidinyl, cyclopentapiperidinyl, cyclopentaazapanyl, cyclohexapyrrolidinyl, cyclohexapiperidinyl, cyclohexaazapanyl, cycloheptapyrrolidinyl, cycloheptapiperidinyl, cycloheptaazapanyl, dihydrobenzoisothiazolyl, dihydrobenzoisoxazolyl, hexahydrooxazolopyrazinyl, hexahydroimidazopyrazinyl, indolinyl, octahydroimidazopyrazinyl, octahydropyrrolopyrazinyl, pyranopyrrolidinyl, pyranopiperidinyl, pyranoazapanyl, tetrahydroisoxazolopyridinyl, tetrahydropyrazolopyridinyl, and the like.

[0193]

[0096] A spirocyclic heterocyclyl has a 3-7 membered heterocyclyl which shares one ring atom with another ring, such as a 4-7 membered heterocyclyl or a 3-7 membered cycloalkyl. Examples include, but are not limited to, diazaspiroheptanyl, diazaspirooctanyl, triazaspirooctanyl, triazaspirodecanyl, and the like.

[0194]

[0097] A bridged bicyclic heterocyclyl has 7-10 members and comprises a 5 to 7 membered heterocyclyl which shares three ring atoms with a 5 to 7 membered heterocyclyl or a 5 to 7 membered non-aromatic cycloalkyl. Examples of nitrogen containing bridged bicyclics include 8- azabicyclo[3.2.1]octanyl, azabicyclo[2.2.1]hepantyl, azabicyclo[3.2.1]octanyl, azabicyclo

[0195] [3.3.1]nonanyl, diazabicyclo[2.2.1]hepantyl, diazabicyclo[3.2.1]octanyl and diazabicyclo

[0196] [3.3.1]nonanyl. Examples of oxygen containing bridged bicyclics include oxobicyclo[2.2.1]hepantyl, oxobicyclo[3.2.1]octanyl, oxobicyclo [3.3.1]nonanyl, oxa-azabicyclo[2.2.1]hepantyl, oxaazabicyclo [3.2.1 ]octanyl and oxa-azabicyclo [3.3.1]nonanyl.

[0197]

[0098] The term “substituted”, whether preceded by the term “optionally” or not, refers to the replacement of a hydrogen substituent in a given structure with a non-hydrogen substituent. Thus, for example, a substituted alkyl is an alkyl wherein at least one non-hydrogen substituent is in the place of a hydrogen substituent on the alkyl group. To illustrate, monofluoroalkyl is an alkyl substituted with a fluoro substituent, and difluoroalkyl is an alkyl substituted with two fluoro substituents. It should be recognized that if there is more than one substitution on a substituent, each non-hydrogen substituent can be identical or different (unless otherwise stated).

[0198]

[0099] If a group is described as “optionally substituted”, the group can be either (1) not substituted or (2) substituted. If a group is described as optionally substituted with up to a particular number of non-hydrogen substituents, that group can be either (1) not substituted; or (2) substituted by up to that particular number of non-hydrogen substituents or by up to the maximum number of substitutable positions on the substituent, whichever is less. Thus, for example, if a group is described as a

[0199] 29

[0200] MEl\56585648.vl 141039-01220 cycloalkyl optionally substituted with up to 3 non-hydrogen substituents, then any cycloalkyl with less than 3 substitutable positions would be optionally substituted by up to only as many nonhydrogen substituents as the cycloalkyl has substitutable positions.

[0201]

[0100] The described compounds include all tautomeric forms.

[0202]

[0101] Compounds having one or more chiral centers can exist in various stereoisomeric forms, i.e each chiral center can have an R or S configuration or can be a mixture of both. Stereoisomers are compounds that differ only in their spatial arrangement. Stereoisomers include all diastereomeric and enantiomeric forms of a compound. Enantiomers are stereoisomers that are non-superimposable mirror images of each other. Diastereomers are stereoisomers having two or more chiral centers that are not identical and are not mirror images of each other.

[0203]

[0102] When the stereochemical configuration at a chiral center in a compound having one or more chiral centers is depicted by its chemical name (e.g where the configuration is indicated in the chemical name by “R” or “S”) or structure (e.g the configuration is indicated by “wedge” bonds), the enrichment of the indicated configuration relative to the opposite configuration is greater than 50%, 60%, 70%, 80%, 90%, 99% or 99.9% “Enrichment of the indicated configuration relative to the opposite configuration” is a mole percent and is determined by dividing the number of compounds with the indicated stereochemical configuration at the chiral center(s) by the total number of all of the compounds with the same or opposite stereochemical configuration in a mixture.

[0204]

[0103] When the stereochemical configuration at a chiral center in a compound having one or more chiral centers is depicted by its chemical name (e.g where the configuration is indicated in the chemical name by “R” or “S”) or structure (e.g the configuration is indicated by “wedge” bonds), the enrichment of the indicated configuration relative to the opposite configuration is greater than 50%, 60%, 70%, 80%, 90%, 99% or 99.9% (except when the designation “rac” or “racemate accompanies the structure or name, as explained in the following two paragraphs). “Enrichment of the indicated configuration relative to the opposite configuration” is a mole percent and is determined by dividing the number of compounds with the indicated stereochemical configuration at the chiral center(s) by the total number of all of the compounds with the same or opposite stereochemical configuration in a mixture.

[0205]

[0104] When a compound is designated by a name or structure that indicates a single enantiomer, unless indicated otherwise, the compound is at least 60%, 70%, 80%, 90%, 99% or 99.9% optically pure (also referred to as “enantiomerically pure”). Optical purity is the weight in the mixture of the named or depicted enantiomer divided by the total weight in the mixture of both enantiomers.

[0206]

[0105] When an enantiomeric mixture of compounds is described by name or by structure, wherein said mixture was separated by chiral chromatography or other means known in the art, the assigned stereochemical configurations of the enantiomers are understood to be relative, not absolute, unless indicated otherwise.

[0207] 30

[0208] MEl\56585648.vl 141039-01220

[0209]

[0106] When the stereochemistry of a disclosed compound is named or depicted by structure, and the named or depicted structure encompasses more than one stereoisomer (e.g as in a diastereomeric pair), it is to be understood that, unless otherwise indicated, one of the encompassed stereoisomers or any mixture of the encompassed stereoisomers are included. It is to be further understood that the stereoisomeric purity of the named or depicted stereoisomers at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight. The stereoisomeric purity in this case is determined by dividing the total weight in the mixture of the stereoisomers encompassed by the name or structure by the total weight in the mixture of all of the stereoisomers.

[0210]

[0107] In cases where a compound provided herein is sufficiently basic or acidic to form stable nontoxic acid or base salts, preparation and administration of the compounds as pharmaceutically acceptable salts may be appropriate. Examples of pharmaceutically acceptable salts are organic acid addition salts formed with acids which form a physiological acceptable anion, for example, tosylate, methane sulfonate, acetate, citrate, malonate, tartarate, succinate, benzoate, ascorbate, a ketoglutarate, or a-glycerophosphate. Inorganic salts may also be formed, including hydrochloride, sulfate, nitrate, bicarbonate, and carbonate salts.

[0211]

[0108] Pharmaceutically acceptable salts may be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound such as an amine with a suitable acid affording a physiologically acceptable anion. Alkali metal (for example, sodium, potassium or lithium) or alkaline earth metal (for example calcium) salts of carboxylic acids can also be made.

[0212]

[0109] Pharmaceutically-acceptable base addition salts can be prepared from inorganic and organic bases. Salts from inorganic bases, can include but are not limited to, sodium, potassium, lithium, ammonium, calcium or magnesium salts. Salts derived from organic bases can include, but are not limited to, salts of primary, secondary or tertiary amines, such as alkyl amines, dialkyl amines, trialkyl amines, substituted alkyl amines, di(substituted alkyl) amines, tri(substituted alkyl) amines, alkenyl amines, dialkenyl amines, trialkenyl amines, substituted alkenyl amines, di(substituted alkenyl) amines, tri(substituted alkenyl) amines, cycloalkyl amines, di(cycloalkyl) amines, tri(cycloalkyl) amines, substituted cycloalkyl amines, disubstituted cycloalkyl amine, trisubstituted cycloalkyl amines, cycloalkenyl amines, di(cycloalkenyl) amines, tri(cycloalkenyl) amines, substituted cycloalkenyl amines, disubstituted cycloalkenyl amine, trisubstituted cycloalkenyl amines, aryl amines, diaryl amines, triaryl amines, heteroaryl amines, diheteroaryl amines, triheteroaryl amines, heterocycloalkyl amines, diheterocycloalkyl amines, triheterocycloalkyl amines, or mixed di- and triamines where at least two of the substituents on the amine can be different and can be alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, or heterocycloalkyl and the like. Also included are amines where the two or three substituents, together with the amino nitrogen, form a heterocycloalkyl or heteroaryl group. Non-limiting examples of amines can include, isopropylamine, trimethyl amine,

[0213] 31

[0214] MEl\56585648.vl 141039-01220 diethyl amine, tri(iso-propyl) amine, tri(n-propyl) amine, ethanolamine, 2-dimcthyNaminocthanol. trimethamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, N-alkylglucamines, theobromine, purines, piperazine, piperidine, morpholine, or N-ethylpiperidine, and the like. Other carboxylic acid derivatives can be useful, for example, carboxylic acid amides, including carboxamides, lower alkyl carboxamides, or dialkyl carboxamides, and the like.

[0215] [HO] As used herein, the terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein. In some aspects, treatment may be administered after one or more symptoms have developed, i.e, therapeutic treatment. In other aspects, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g, in light of a history of symptoms and / or in light of exposure to a particular organism, or other susceptibility factors), i.e, prophylactic treatment. Treatment may also be continued after symptoms have resolved, for example to delay their recurrence.

[0216] [Hl] Cancers which can be treated with the disclosed compounds or pharmaceutically acceptable salts thereof or pharmaceutically acceptable salts thereof or the disclosed pharmaceutical compositions include acute lymphoblastic leukemia, acute myeloid leukemia, adrenocortical carcinoma, AIDS-related cancers, AIDS-related lymphoma, anal cancer, bladder cancer, bone cancers, brain tumors, such as cerebellar astrocytoma, cerebral astrocytoma / malignant glioma, ependymoma, medulloblastoma, supratentorial primitive neuroectodermal tumors, visual pathway and hypothalamic glioma, breast cancer, central nervous system lymphoma, cerebellar astrocytoma, cervical cancer, colon cancer, gallbladder cancer, gastric cancer, head and neck cancer, heart cancer, hepatocellular (liver) cancer, kidney cancer, liver cancer, lung cancers, such as non-small cell and small cell lung cancer, ovarian cancer, ovarian epithelial cancer, ovarian germ cell tumor, pancreatic cancer, pancreatic cancer islet cell, prostate cancer, rectal cancer, renal cell carcinoma, skin cancers, skin carcinoma merkel cell, small intestine cancer or throat cancer.

[0217]

[0112] The compounds of the instant invention are inhibitors of the activity of Akt and are thus useful in the treatment of cancer, in particular cancers associated with irregularities in the activity of Akt and downstream cellular targets of Akt. Such cancers include, but are not limited to, ovarian, endometrial, pancreatic, breast and prostate cancer, as well as cancers (including glioblastoma) where the tumor suppressor PTEN is mutated (Cheng et al Proc. Natl. Acad. Sci. (1992) 89:9267-9271; Cheng et al Proc. Natl. Acad. ScL (1996) 93:3636-3641; Bellacosa et al Int. J. Cancer (1995) 64:280- 285; Nakatani et al J. Biol Chem. (1999) 274:21528-21532; Graff, Expert. Opin. Ther. Targets (2002) 6(1): 103-1 13; and Yamada and Araki, J. CellScience. (2001) 114:2375-2382; Mischel and Cloughesy, Brain Pathol. (2003) 13( 1): 52-61). Cancers where Akt itself is activated by gene amplification or mutations may also be treated by the compounds. Human breast, colorectal and ovarian cancers where

[0218] 32

[0219] MEl\56585648.vl 141039-01220 a somatic mutation in a pleckstrin homology domain (PH) of AKT1 (E17K mutant; the glutamic acid (E) at position 17 of the amino acid sequence of the PH domain of AKT1 is replaced by a lysine (K)) is reported (Carpten et al, Nature 448: 439-444 (2007)).

[0220]

[0113] The compounds, compositions and methods provided herein are particularly deemed useful for the treatment of cancer. Cancers that may be treated by the compounds, compositions and methods of the invention include, but are not limited to: Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung: non-small cell lung, bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Karposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma), colon, colorectal, rectal; Genitourinary tract: kidney (adenocarcinoma, Wilm's tumor [nephroblastoma], lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); Liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors; Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma [pinealomaj, glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma); Gynecological: uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervical dysplasia), ovaries (ovarian carcinoma [serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma], granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma) vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tubes (carcinoma); Hematologic: blood (myeloid leukemia [acute and chronic], acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma

[0221] 33

[0222] MEl\56585648.vl 141039-01220

[0223] [malignant lymphoma]; Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Karposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis; and Adrenal glands: neuroblastoma. Thus, the term "cancerous cell" as provided herein, includes a cell afflicted by any one of the above-identified conditions.

[0224]

[0114] Cancers that may be treated by the compounds, compositions and methods of the invention include, but are not limited to: breast, prostate, colon, colorectal, lung, non-small cell lung, brain, testicular, stomach, pancreas, skin, small intestine, large intestine, throat, head and neck, oral, bone, liver, bladder, kidney, thyroid and blood.

[0225]

[0115] Cancers that may be treated by the compounds, compositions and methods of the invention include: breast, prostate, colon, ovarian, colorectal, lung and non-small cell lung. Cancers that may be treated by the compounds, compositions and methods of the invention include: breast, colon, (colorectal) and lung (non-small cell lung).

[0226]

[0116] Cancers that may be treated by the compounds, compositions and methods of the invention include: lymphoma and leukemia.

[0227]

[0117] The compounds of the instant invention are useful for the treatment of breast cancer.

[0228]

[0118] The compounds of the instant invention are useful for the treatment of prostate cancer.

[0229]

[0119] In one aspect, the disclosed compounds or pharmaceutically acceptable salts thereof or disclosed pharmaceutical compositions can be part of a combination therapies with one or more other therapeutic agents.

[0230]

[0120] In some embodiments, the methods comprise administering an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with an effective amount of an anticancer agent, wherein the amounts of the combination and the chemotherapeutic are together effective in treating a subject with cancer. Many chemotherapeutics are presently known in the art and can be used in combination. In some embodiments, the chemotherapeutic is selected from the group consisting of mitotic inhibitors, alkylating agents, antimetabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, anti-hormones, angiogenesis inhibitors, and anti- androgens. Also described are methods for treating a subject with cancer comprising administering to the mammal an amount of an Akt inhibitor with radiation therapy, wherein the amounts of the Akt inhibitor in combination with the radiation therapy is effective in treating a subject with cancer. Techniques for administering radiation therapy are known in the art, and these techniques can be used in the combination therapy described herein.

[0231]

[0121] In some embodiments, the disclosure also relates to a method of inhibiting abnormal cell growth in a mammal which may comprise a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and an amount of one or more substances selected from anti-angiogenesis agents, signal transduction inhibitors, and antiproliferative agents. Anti-angiogenesis agents, such as

[0232] 34

[0233] MEl\56585648.vl 141039-01220

[0234] MMP-2 (matrix-metalloprotienase 2) inhibitors, MMP-9 (matrix-metalloprotienase 9) inhibitors, and COX-2 (cyclooxygenase 2) inhibitors, can be used in conjunction with a compound of the present invention and pharmaceutical compositions described herein. Examples of useful COX-2 inhibitors include CELEBREXTM (alecoxib), valdecoxib, and rofecoxib. Examples of useful matrix metalloproteinase inhibitors are described in WO 96 / 33172 (published October 24,1996), WO 96 / 27583 (published March 7,1996), European Patent Application No.97304971.1 (fded July 8,1997), European Patent Application No. 99308617.2 (fded October 29, 1999), WO 98 / 07697 (published February 26,1998), WO 98 / 03516 (published January 29.1998), WO 98 / 34918 (published August 13,1998), WO 98 / 34915 (published August 13.1998), WO 98 / 33768 (published August 6,1998), WO 98 / 30566 (published July 16, 1998), European Patent Publication 606,046 (published July 13,1994), European Patent Publication 931, 788 (published July 28,1999), WO 90 / 05719 (published May 31,1990), WO 99 / 52910 (published October 21,1999), WO 99 / 52889 (published October 21, 1999), WO 99 / 29667 (published June 17,1999), PCT International Application No. PCT / IB98 / 01113 (fded July 21,19911), European Patent Application No. 99302232.1 (fded March 25,1999), Great Britain Patent Application No. 9912961.1 (fded June 3, 1999), United States Provisional Application No. 60 / 148,464 (fded August 12,1999), United States Patent 5,863, 949 (issued January 26,1999), United States Patent 5,861, 510 (issued January 19,1999), and European Patent Publication 780,386 (published June 25, 1997). Some MMP-2 and MMP-9 inhibitors have little or no activity inhibiting MMP-1, while some selectively inhibit MMP-2 and / or AMP-9 relative to the other matrix- motalloproteinases (L e MAP-1, NEMP-3, MMP-4, M7vlP-5, MMP-6, MMP- 7, MMP-8, MMP-10, MMP-11, and MMP-13). Some specific examples of MlvlP inhibitors useful in the present invention are AG-3340, RU 32-3555, and RS 13-0830.

[0235]

[0122] In some embodiments, a compound disclosed herein or a pharmaceutically acceptable salt thereof, is administered with at least one additional therapeutic agent. In some embodiments, the therapeutic agent is a taxol, bortezomib or both. In further or additional embodiments, the therapeutic agent is selected from the group consisting of cytotoxic agents, anti-angiogenesis agents and anti neoplastic agents. In further or additional embodiments, the anti -neoplastic agents selected from the group of consisting of alkylating agents, anti-metabolites, epiclophyllotoxims; antineoplastic enzymes, topoisomerase inhibitors, procarbazine, mitoxantrone, platinum coordination complexes, biological response modifiers and growth inhibitors, hormonal / anti-hormonal therapeutic agents, and haematopoietic growth factors.

[0236]

[0123] Many chemotherapeutics are presently known in the art and can be used in combination with the compounds and compositions of the disclosure. In some embodiments, the chemotherapeutic is selected from the group consisting of mitotic inhibitors, alkylating agents, anti-metabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, anti-hormones, angiogenesis inhibitors, and anti -androgens.

[0237] 35

[0238] MEl\56585648.vl 141039-01220

[0239]

[0124] In some embodiments, the combination is administered in combination with an additional therapy. In further or additional embodiments, the additional therapy is radiation therapy, chemotherapy, surgery or any combination thereof. In further or additional embodiments, the combination is administered in combination with at least one additional therapeutic agent. In further or additional embodiments, the therapeutic agent is selected from the group of cytotoxic agents, antiangiogenesis agents and anti -neoplastic agents. In further or additional embodiments, the anti- neoplastic agent is selected from the group of consisting of alkylating agents, anti-metabolites, epidophyllotoxins; antineoplastic enzymes, topoisomerase inhibitors, procarbazines, mitoxantrones, platinum coordination complexes, biological response modifiers and growth inhibitors, hormonal / anti- hormonal therapeutic agents, and haematopoietic growth factors.

[0240]

[0125] In some embodiments, the second therapeutic is an agent for co-regulating MEK or RAF pathways. In some embodiments, the second therapeutic agent is a MEK or RAF inhibitor. In some embodiments, the RAF inhibitor is Vemurafenib (Zelboraf), Dabrafenib (Tafmlar), Encorafenib (Braftovi), Tovorafenib (Ojemda), XL-281, LGX-818, CEP-32496. ARQ-736, MEK-162, Sdumdinib, refametinib, E-620L pimasertib, WX-554, GDC-0973, naporafenib, or exarafenib. In some embodiments, the MEK inhibitor is Trametinib (Mekinist), Cobimetinib (Cotellic), Selumetinib (Koselugo), Binimetinib (Mektovi). In some embodiments, the second therapeutic agent is a MEK- RAF clamp such as avutometinib. In some embodiments, the second therapeutic agent is a MEK-pan- RAF stabilizing molecular glue such as NST-628, IK-595 or IMM-1-104.

[0241]

[0126] In some embodiments, the second therapeutic is an agent for co-regulating MAPK pathway. In some embodiments, the agent for co-regulating MAPK pathway is KRAS G12C mutant selective inhibitors including but not limited to Sotorasib (Lumakras), Adagrasib (Krazati), ARS-1620, ARS- 3248, LY3499446, MK-1084, divarasib (GDC-6036), RMC-6291; KRAS G12D mutant selective inhibitors including but not limited to RMC-9805, MRTX1133, QTX3046, LY3962673; pan KRAS inhibitors including but not limited to PF-07934040, QTX3034, BI-2865, BI-1701963; RAS(multi) inhibitor RMC-6036; Son of Sevenless 1 (SOS1) inhibitors (e.g BI1701963, BI-3406 and RMC-023); SHP2 inhibitors (e.g, TNO155, BBP-398 and ICP-189) ; EGFR inhibitors including but not limited to Erlotinib (Tarceva), Gefitinib (Iressa), Afatinib (Gilotrif), Osimertinib (Tagrisso), Dacomitinib (Vizimpro), Cetuximab (Erbitux), Necitumumab (Portrazza), lazertinib, aumolertinib (formerly almonertinib), olmutinib, nazartinib and osimertinib.

[0242]

[0127] In some embodiments, the second therapeutic is an inhibitor of Cyclin-dependent kinase (CDK). In some embodiments, the CDK inhibitor is a CDK4 / 6 inhibitor including but not limited to Palbociclib (Ibrance), Ribociclib (Kisqali), Abemaciclib (Verzenio), and Trilaciclib (Cosela).

[0243]

[0128] In some embodiments, the second therapeutic is anti-estrogen therapy including but not limited agents reviewed by Patel, et al (NPI Breast Cancer, 20 (2023). In some embodiments, the anti- estrogen agent is an estrogen receptor antagonist including but not limited to fulvestrant.

[0244] 36

[0245] MEl\56585648.vl 141039-01220

[0246]

[0129] In some embodiments, the second therapeutic is anti apoptosis inhibitor including but not limited BCL2 inhibitor Venetoclax (ABT- 199) and Navitoclax (ABT-263).

[0247]

[0130] In some embodiments, the second therapeutic is a PI3Ka inhibitor including but not limited to alpelisib or inavolisib. In some embodiments, the second therapeutic is a PI3Ka mutant selective inhibitor including but not limited to BBO-10203, LOXO-783, OKI-219, RLY-2608, STX-478 or TOS-358.

[0248]

[0131] In some embodiments, the second therapeutic agent is a anti HER2 antibody including but not limited to Trastuzumab (Herceptin), Pertuzumab (Pcrjcta). Ado-trastuzumab emtansine (Kadcyla), Margetuximab (Margenza), or Fam -trastuzumab deruxtecan-nxki (Enhertu).

[0249]

[0132] In some embodiments, the second therapeutic is an agent for mutant p53 reactivators (PC14586, JAB-30355, APR-246 and COTI-2).

[0250]

[0133] In some embodiments, the second therapeutic agent is selected from aspirin; diflunisal; salsalate; acetaminophen; ibuprofen; dexibuprofen; naproxen; fenoprofen; ketoprofen; dexketoprofen; flurbiprofen; oxaprozin; loxoprofen; indomethacin; tolmetin; sulindac; etodolac; ketorolac; diclofenac; aceclofenac; nabumetone; enolic acid; piroxicam; meloxicam; tenoxicam; droxicam; lomoxicam; isoxicam; mefenamic acid; meclofenamic acid; flufenamic acid; tolfenamic acid; sulfonanilides; clonixin; licofelone; dexamethasone; and prednisone.

[0251]

[0134] In some embodiments, the second therapeutic agent is selected from mechlorethamine; cyclophosphamide; melphalan; chlorambucil; ifosfamide; busulfan; N-nitroso-N-methylurea (MNU); carmustine (BCNU); lomustine (CCNU); semustine (MeCCNU); fotemustine; streptozotocin; dacarbazine; mitozolomide; temozolomide; thiotepa; mytomycin; diaziquone (AZQ); cisplatin; carboplatin; and oxaliplatin.

[0252]

[0135] In some embodiments, the second therapeutic agent is selected from vincristine; vinblastine; vinorelbine; vindesine; vinflunine; paclitaxel; docetaxel; etoposide; teniposide; tofacitinib; ixabepilone; irinotecan; topotecan; camptothecin; doxorubicin; mitoxantrone; and teniposide.

[0253]

[0136] In some embodiments, the second therapeutic agent is selected from actinomycin; bleomycin; plicamycin; mitomycin; daunombicin; epimbicin; idarubicin; pirarubicin; aclarubicin; mitoxantrone; cyclophosphamide; methotrexate; 5 -fluorouracil; prednisolone; folinic acid; methotrexate; melphalan; capecitabine; mechlorethamine; uramustine; melphalan; chlorambucil; ifosfamide; bendamustine; 6- mercaptopurine; and procarbazine.

[0254]

[0137] In some embodiments, the second therapeutic agent is selected from cladribine; pemetrexed; fludarabine; gemcitabine; hydroxyurea; nelarabine; cladribine; clofarabine; ytarabine; decitabine; cytarabine; cytarabine liposomal; pralatrexate; floxuridine; fludarabine; colchicine; thioguanine; cabazitaxel; larotaxel; ortataxel; tesetaxel; aminopterin; pemetrexed; pralatrexate; raltitrexed; pemetrexed; carmofur; and floxuridine.

[0255] 37

[0256] MEl\56585648.vl 141039-01220

[0257]

[0138] In some embodiments, the second therapeutic agent is selected from azacitidine; decitabine; hydroxycarbamide; topotecan; irinotecan; belotecan; teniposide; aclarubicin; epimbicin; idarubicin; amrubicin; pirarubicin; valrubicin; zombicin; mitoxantrone; pixantrone; mechlorethamine; chlorambucil; prednimu stine; uramustine; estramustine; carmustine; lomustine; fotemustine; nimustine; ranimustine; carboquone; thioTEPA; triaziquone; and triethylenemelamine.

[0258]

[0139] In some embodiments, the second therapeutic agent is selected from nedaplatin; satraplatin; procarbazine; dacarbazine; temozolomide; altretamine; mitobronitol; pipobroman; actinomycin; bleomycin; plicamycin; aminolevulinic acid; methyl aminolevulinate; efaproxiral; talaporfm; temoporfin; verteporfm; alvocidib; seliciclib; palbociclib; bortezomib; carfilzomib; anagrelide; masoprocol; olaparib; belinostat; panobinostat; romidepsin; vorinosta; idelalisib; atrasentan; bexarotene; testolactone; amsacrine; trabectedin; alitretinoin; tretinoin; demecolcine; elsamitrucin; etoglucid; lonidamine; lucanthone; mitoguazone; mitotane; oblimersen; omacetaxine mepe succinate; and eribulin.

[0259]

[0140] In some embodiments, the second therapeutic agent is selected from azathioprine; Mycophenolic acid; leflunomide; teriflunomide; tacrolimus; cyclosporin; pimecrolimus; abetimus; gusperimus; lenalidomide; pomalidomide; thalidomide; anakinra; sirolimus; everolimus; ridaforolimus; temsirolimus; umirolimus; zotarolimus; eculizumab; adalimumab; afelimomab; certolizumab pegol; golimumab; infliximab; nerelimomab; mepolizumab; omalizumab; faralimomab; elsilimomab; lebrikizumab; ustekinumab; etanercept; otelixizumab; teplizumab; visilizumab; clenoliximab; keliximab; zanolimumab; efalizumab; erlizumab; obinutuzumab; rituximab; and ocrelizumab.

[0260]

[0141] In some embodiments, the second therapeutic agent is selected from pascolizumab; gomiliximab; lumiliximab; teneliximab; toralizumab; aselizumab; galiximab; gavilimomab; ruplizumab; belimumab; blisibimod; ipilimumab; tremelimumab; bertilimumab; lerdelimumab; metelimumab; natalizumab; tocilizumab; odulimomab; basiliximab; daclizumab; inolimomab; zolimoma; atorolimumab; cedelizumab; fontolizumab; maslimomab; morolimumab; pexelizumab; reslizumab; rovelizumab; siplizumab; talizumab; telimomab; vapaliximab; vepalimomab; abatacept; belatacept; pegsunercept; aflibercept; alefacept; and rilonacept.

[0261]

[0142] In some embodiments, the second therapeutic agent is selected from Leuprolide Acetate (Lupron), Enzalutamide (Xtandi), Abiraterone Acetate (Zytiga), Apalutamide (Erleada), Degarelix (Firmagon), Sipuleucel-T (Provenge), Darolutamide (Nubeqa), Radium-223 Dichloride (Xofigo), Relugolix (Orgovyx), Pluvicto (Lutetium Lu 177 vipivotide tetraxetan), Rucaparib (Rubraca), Bicalutamide (Casodex), Triptorelin (Trelstar), Flutamide (Eulexin), Nilutamide (Nilandron), Goserelin (Zoladex), and Estramustine (Emcyt).

[0262]

[0143] In some embodiments, the second therapeutics is an immune checkpoint inhibitor such as a PD-1 inhibitor or a PD-L1 inhibitor. In some embodiments, the immune checkpoint inhibitor is an anti

[0263] 38

[0264] MEl\56585648.vl 141039-01220

[0265] PD-1 antibody selected from the group consisting of balstilimab, camrelizumab, cemiplimab, dostarlimab, geptanolimab, nivolumab, pembrolizumab, penpulimab, pidilizumab, prolgolimab, retifanlimab, sasanlimab, serplulimab, serplulimab, sintilimab, spartalizumab, sulituzumab, tebotelimab, teripalimab, tislelizumab, toripalimab, toripalimab, zimberelimab, AMP -224 (Medlmunne), AMP-514 (Medlmunne), AT-16201 (AIMM Therapeutics BV), AVI-102 (Ab Vision Inc), BAT-1308 (Bio-Thera Solutions Ltd), BH-2950 (Beijing Hanmi Pharmaceutical Co Ltd), BSI- 050K01 (Biosion Inc), CB-201 (Crescendo Biologies Ltd), CYTO-101 (Cytocom Inc), DB-004 (DotBio Pte Ltd), EX- 105 (Excelmab Inc), EX- 108 (Excelmab Inc), GNR-051 (Generium), HAB-21 (Suzhou Stainwei Biotech Inc), IBI-319 (Innovent Biologies Inc), IBI-321 (Innovent Biologies Inc), IKT-202 (Icell Kealex Therapeutics LLC), IMU-201 (Imugene Ltd), JS-201 (Shanghai Junshi Bioscience Co Ltd), LBL-006 (Leads Biolabs Inc), LBL-024 (Leads Biolabs Inc), LD-01 (Leidos Health Holdings LLC), LQ-005 (Shanghai Novamab Biopharmaceuticals Co Ltd), LQ-008 (Shanghai Novamab Biopharmaceuticals Co Ltd), MD-402 (MD Biosciences GmbH), OT-2 (OncoTrap Inc), PE-0105 (Shanghai Yunyi Health Technology Development Co Ltd), PF-07209960 (Pfizer Inc), PH- 762 (Phio Pharmaceuticals Corp), REGN-PD-l / XX (Regeneron), R07121661 (Genentech), SAUG-1 (Juvenescence UK Ltd), SCT-IIOA (Sinocelltech), SG-001 (CSPC Pharmaceutical Group Ltd), SI- BOOS (Systlmmune), SL-279137 (Shattuck Labs), SSI-361 (Lyvgen Biopharma Ltd), STI-Al l 10 (Servier), STM-418 (Stcube Inc), Sym-021 (Symphogen A / S), TSR-075 (GlaxoSmithKline Pic), TY101 (Tayu Huaxia Biotech), Twist-PD-1 (Twist Bioscience), XmAb-TGFpR2 (Xencor), XmAb- YYCD28 (Xencor), XmAb20717 (Xencor), XmAb23104 (Xencor), YBL-006 (Y Biologies), YBL- 019 (Y Biologies), and mDX-400 (Merck & Co Inc).

[0266]

[0144] Pharmaceutical compositions are disclosed that include one or more compounds provided herein or a pharmaceutically acceptable salt thereof, and typically at least one additional substance, such as an excipient, a known therapeutic other than those of the disclosure, and combinations thereof. In some embodiments, the disclosed compounds or pharmaceutically acceptable salts thereof can be used in combination with other agents known to have beneficial activity targeting diseases or disorders listed above. For example, disclosed compounds or pharmaceutically acceptable salts thereof can be administered alone or in combination with one or more anti -cancer or antiviral agent.

[0267]

[0145] The terms “administer”, “administering”, “administration”, and the like, as used herein, refer to methods that may be used to enable delivery of compositions to the desired site of biological action. These methods include, but are not limited to, intraarticular (in the joints), intravenous, intramuscular, intratumoral, intradermal, intraperitoneal, subcutaneous, orally, topically, intrathecally, inhalationally, transdermally, rectally, and the like. Administration techniques that can be employed with the agents and methods described herein are found in e.g Goodman and Gilman, The Pharmacological Basis of Therapeutics , current ed.; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co Easton, Pa.

[0268] 39

[0269] MEl\56585648.vl 141039-01220

[0270]

[0146] A “subject” is a mammal in need of medical treatment, preferably a human, but can also be an animal in need of veterinary treatment, e.g companion animals (e.g dogs, cats, and the like), farm animals (e.g cows, sheep, pigs, horses, and the like) and laboratory animals (e.g rats, mice, guinea pigs, and the like).

[0271]

[0147] The precise amount of compound or pharmaceutically acceptable salt thereof administered to provide an “effective amount” to the subject will depend on the mode of administration, the type, and severity of the disease or condition, and on the characteristics of the subject, such as general health, age, sex, body weight, and tolerance to drugs. The skilled artisan will be able to determine appropriate dosages depending on these and other factors. When administered in combination with other therapeutic agents, e.g when administered in combination with an anti -cancer or antiviral agent, an “effective amount” of any additional therapeutic agent(s) will depend on the type of drug used. Suitable dosages are known for approved therapeutic agents and can be adjusted by the skilled artisan according to the condition of the subject, the type of condition(s) being treated and the amount of a compound of the disclosure or a pharmaceutically acceptable salt thereof being used by following, for example, dosages reported in the literature and recommended in the Physician ’s Desk Reference (57th ed 2003).

[0272]

[0148] The term “effective amount” means an amount when administered to the subject which results in beneficial or desired results, including clinical results, e.g inhibits, suppresses or reduces the symptoms of the condition being treated in the subject as compared to a control. For example, a therapeutically effective amount can be given in unit dosage form (e.g 0.1 mg to about 50 g per day).

[0273]

[0149] The particular mode of administration and the dosage regimen will be selected by the attending clinician, taking into account the particulars of the case (e.g. the subject, the disease, the disease state involved, the particular treatment, and whether the treatment is prophylactic). Treatment can involve daily or multi-daily or less than daily (such as weekly or monthly etc.) doses over a period of a few days to months, or even years.

[0274]

[0150] The pharmaceutical composition of the disclosure is formulated to be compatible with its intended route of administration. In an embodiment, the composition is formulated in accordance with routine procedures as a pharmaceutical composition adapted for intravenous, subcutaneous, intramuscular, oral, intranasal, or topical administration to human beings. In preferred embodiments, the pharmaceutical composition is formulated for intravenous administration.

[0275]

[0151] “Pharmaceutically acceptable excipient” and “pharmaceutically acceptable carrier” refer to a substance that aids the formulation and / or administration of an active agent to and / or absorption by a subject and can be included in the compositions of the disclosure without causing a significant adverse toxicological effect on the subject. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal saline solutions, lactated Ringer’s, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions (such as

[0276] 40

[0277] MEl\56585648.vl 141039-01220

[0278] Ringer’s solution), alcohols, oils, gelatins, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethycellulose, polyvinyl pyrrolidine, and colors, and the like. Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and / or aromatic substances and the like that do not deleteriously react with or interfere with the activity of the compounds provided herein. One of ordinary skill in the art will recognize that other pharmaceutical excipients are suitable for use with disclosed compounds.

[0279] EXEMPLIFICATION

[0280]

[0152] The following examples are intended to be illustrative and are not meant in any way to be limiting.

[0281]

[0153] Unless otherwise specified, abbreviations used herein will have the meaning as commonly used in the art, some of which are provided below:

[0282] AcOH - acetic acid

[0283] Aq. - Aqueous

[0284] ACN - Acetonitrile

[0285] BOC - tert-Butyloxycarbonyl

[0286] BOC2O -Di- tert-butyl dicarbonate br s - Broad singlet

[0287] °C - degree Celsius

[0288] CBz - benzyloxycarbonyl

[0289] CD3CN - Deuterated acetonitrile

[0290] CDCI3 - Deuterated chloroform

[0291] CsF - Cesium fluoride d - Doublet dd - Doublet of doublet

[0292] 5 - Delta

[0293] DCE - 1,2-Dichloroethane

[0294] DCM - Dichloromethane

[0295] DIAD - Disopropyl azodicarboxylate

[0296] DIBAL - Diisobutylaluminium hydride

[0297] DIEA - Diisopropylethylamine

[0298] DIPA - N,N-diisopropylamine

[0299] DIPEA - N, A-Diisopropylethylamine

[0300] DMAP - 4-Dimethylaminopyridine

[0301] DMF - N, A-Dimethylformamide

[0302] 41

[0303] MEl\56585648.vl 141039-01220

[0304] DMAc or DMA - N, A-Dimcthylacctamidc

[0305] DMSO - Dimethyl sulfoxide

[0306] DMSO-de - Deuterated dimethyl sulfoxide

[0307] EDCI - l-Ethyl-3-(3-dimethylaminopropyl)carbodiimide

[0308] ESI - Electrospray ionization

[0309] EA or EtOAc - Ethyl acetate

[0310] EtOH - Ethanol

[0311] 19F NMR - Fluorine-19 nuclear magnetic resonance

[0312] FA - Formic acid g - Gram

[0313] GCMS - Gas chromatography-mass spectrometry hr - Hour

[0314] 'H NMR - Proton nuclear magnetic resonance

[0315] HATU - l-[Bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate

[0316] HC1 - Hydrochloric acid

[0317] HOBt - 1 -Hydroxybenzotriazole

[0318] HPLC - High performance liquid chromatography

[0319] Hz - Hertz

[0320] J - Coupling constant

[0321] K2CO3 - Potassium carbonate

[0322] KO Ac - Potassium acetate

[0323] LCMS - Liquid chromatography mass spectrometry

[0324] LiHMDS - Lithium bis(trimethylsilyl)amide

[0325] M+- Molecular ion m - Multiplet

[0326] Mel - Methyl iodide

[0327] MeOH - Methanol

[0328] MeOD - deuterated methanol mg - Milligrams min - Minutes

[0329] MHz - Mega Hertz (frequency) mb - Milliters mmol - Millimoles

[0330] MsCl - methanesulfonyl chloride

[0331] MTBE - methyl t-butyl ether

[0332] MS - Mass spectroscopy

[0333] 42

[0334] MEl\56585648.vl 141039-01220

[0335] Sat.NaHCOs - Saturated sodium hydrogencarbonate

[0336] Na2SC>4 - Sodium sulfate

[0337] NMP - N-Methyl-2-pyrrolidone

[0338] NBS - A'-Bromosuccinimidc

[0339] Pd / C - Palladium on carbon

[0340] Pd2(dba)s - Tris(dibenzylideneacetone)dipalladium

[0341] Pd(dppf)C12 - [1,1’ -Bis(diphenylphosphino)ferrocene]dichloropalladium(II)

[0342] PE - Petroleum ether

[0343] % - Percentage pH - potential of Hydrogen

[0344] PMB - para-methoxybenzyl ppm - Parts per million

[0345] Py - Pyridine q - Quartet

[0346] Rt - Retention time rt - room temperature

[0347] RuPhos - 2-Dicyclohexylphosphino-2',6'-diisopropoxybiphenyl s - Singlet

[0348] SFC - Supercritical fluid chromatography t - Triplet

[0349] TBAF - Tetrabutylammonium fluoride

[0350] TBSC1 - tert-Butyldimethylchlorosilane

[0351] TEA - Triethylamine

[0352] Tf- Tritiate

[0353] TFA- Trifluoroacetic acid

[0354] THF - Tetrahydrofuran

[0355] TLC - Thin layer chromatography

[0356] Prep TLC - Preparative thin layer chromatography

[0357] TMEDA - A.A.A'.A'-Tctramcthylcthanc- 1 ,2-diaminc pL - Microliters pm - Millimeters pmol - Micromoles

[0358] Xphos - dicyclohexyl[2',4',6'-tris(propan-2-yl) [1,1 '-biphenyl] -2-yl]phosphane

[0359] XantPhos - 9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane

[0360]

[0154] Intermediate 1. tert-butyl 3-[4-[2-(2-amino-3-pyridyl)-5-phenyl-imidazo[4,5-b]pyridin-3- yl]phenyl]pyrrolidine-l-carboxylate

[0361] 43

[0362] MEl\56585648.vl 141039-01220

[0363]

[0155] Step 1. N-(4-iodophenyl)-3-nitro-6-phenyl-pyridin-2-amine

[0364]

[0156] To a solution of 2-chloro-3-nitro-6-phenyl-pyridine (4 g, 17.05 mmol) in NMP (40 mL) were added 4-iodoaniline (4.11 g, 18.75 mmol) and DIEA (6.61 g, 51.14 mmol, 8.91 mL). The mixture was stirred at 120°C for 18h. The mixture was poured into water (100 mL). The aq. layer was extracted with EtOAc (200 mL x 3). The combined organic phase was washed with H2O (100 mL x 3) and brine (200 mL), dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The mixture was purified by flash chromatography on silica gel (DCM in PE = 0-25%) to afford N-(4-iodophenyl)-3-nitro-6-phenyl-pyridin-2-amine (5.2 g, 12.46 mmol, 73.11% yield) as solid. LCMS : m / z 418.0 [M+H]+

[0365]

[0157] Step 2. 3-[3-(4-iodophenyl)-5-phenyl-imidazo[4,5-b]pyridin-2-yl]pyridin-2-amine

[0366]

[0158] To a solution of N-(4-iodophenyl)-3-nitro-6-phenyl-pyridin-2 -amine (4.8 g, 11.51 mmol) in a mixed solvent of MeOH (10 mL) and DMSO (48 mL) were added Na2S2C>4 (5.01 g, 28.76 mmol, 6.26 mL) and 2-aminopyridine-3-carbaldehyde (1.55 g, 12.66 mmol). The mixture was stirred at 100°C for 18h. The mixture was poured into water (20 mL). The aq. layer was extracted with EtOAc (20 mLx3). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The mixture was purified by flash chromatography on silica gel (EtOAc in PE = 0-50%) to afford 3-[3-(4-iodophenyl)-5-phenyl-imidazo[4,5-b]pyridin-2- yl]pyridin-2-amine (2 g, 4.09 mmol, 35.53% yield). The 3-[3-(4-iodophenyl)-5-phenyl-imidazo[4,5- b]pyridin-2-yl]pyridin-2-amine (30 mg, 61.31 pmol) was purified by (column: C18 150x30 mm; mobile phase: [water(NH3H2O+NH4HCO3)-ACN] ; gradient: 60%-90% B over 7 min) to give 3-[3-(4- iodophenyl)-5-phenyl-imidazo[4,5-b]pyridin-2-yl]pyridin-2-amine (20 mg, 40.87 pmol, 66.67% yield) as solid. 'H NMR (400MHz CDCI3) 5 = 8.17-8.07 (m, 2H), 8.02 (d, J= 7.2 Hz, 2H), 7.90-7.79 (m, 3H), 7.51-7.35 (m, 3H), 7.22 (d, J= 8.4 Hz, 2H), 7.13 (dd, J= 1.6, 7.6 Hz, 1H), 6.57 (s, 2H), 6.46 (dd, J= 4.8, 8.0 Hz, 1H). LCMS: m / z 490.0 [M+H]+

[0367]

[0159] Step 3. tert-butyl 3-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin-3- yl)phenyl)-2,5-dihydro-lH-pyrrole-l-carboxylate

[0368] 44

[0369] MEl\56585648.vl 141039-01220

[0370]

[0160] To a solution of tert-butyl 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2,5- dihydropyrrole-1 -carboxylate (168.91 mg, 572.23 pmol) in a mixed solvent of 1,4-dioxane (4 mb) and H2O (1 mL) were added K2CO3 (169.48 mg, 1.23 mmol), Pd(PPh3)2C12 (28.69 mg, 40.87 pmol) and 3-[3-(4-iodophenyl)-5-phenyl-imidazo[4,5-b]pyridin-2-yl]pyridin-2-amine (200.00 mg, 408.74 pmol). The mixture was stirred at 95°C for 18 h. The mixture was concentrated. The mixture was purified by flash chromatography on silica gel (EtOAc in PE = 0-50%) to afford tert-butyl 3-(4-(2-(2- aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl)-2,5-dihydro-lH-pyrrole-l- carboxylate (200 mg, 376.92 pmol, 92.22% yield) as solid. The tert-butyl 3-[4-[2-(2-amino-3- pyridyl)-5-phenyl-imidazo[4,5-b]pyridin-3-yl]phenyl]-2,5-dihydropyrrole-l-carboxylate (13 mg, 24.50 pmol) was triturated with MeOH (2 mL) at 25°C for 30 min to give tert-butyl 3-[4-[2-(2-amino- 3 -pyridyl)-5 -phenyl -imidazo [4,5-b]pyridin-3 -yl]phenyl] -2,5 -dihydropyrrole- 1 -carboxylate (9 mg, 16.96 pmol, 69.23% yield) as solid. 'H NMR (400MHz CDCI3) 5 = 8.24-7.99 (m, 4H), 7.81 (d, J= 8.4 Hz, 1H), 7.48-7.41 (m, 7H), 7.18 (d, J= 9.2 Hz, 1H), 7.06 (s, 1H), 6.60 (s, 2H), 6.41 (dd, J= 5.2, 7.2 Hz, 1H), 3.99-3.86 (m, 2H), 3.22-2.97 (m, 2H), 1.53 (s, 9H). LCMS: m / z 531.3 [M+H]+

[0371]

[0161] Step 4. tert-butyl 3-[4-[2-(2-amino-3-pyridyl)-5-phenyl-imidazo[4,5-b]pyridin-3- yl]phenyl]pyrrolidine-l-carboxylate

[0372]

[0162] To a solution of tert-butyl 3-[4-[2-(2-amino-3-pyridyl)-5-phenyl-imidazo[4,5-b]pyridin-3- yl]phenyl]-2,5-dihydropyrrole-l-carboxylate (200 mg, 376.92 pmol) in THF (2 mL) was added Pd / C (40.11 mg, 37.69 pmol, 10% purity). The mixture was stirred at 50°C for 18h under H2. THF (10 mL) was added to the mixture. The mixture was fdtered through celite. The resulting fdter cake was washed with THF (20 mL), and the fdter cake was washed with DCM (50 mL x3). The fdtrate was concentrated. The mixture was purified by prep-HPLC (column: C18 150x30 mm; mobile phase: [water(NH3H2O+NH4HCO3)-ACN] ; gradient: 70%- 100% B over 7 min) to give tert-butyl 3-[4-[2-(2- amino-3-pyridyl)-5-phenyl-imidazo[4,5-b]pyridin-3-yl]phenyl]pyrrolidine-l-carboxylate (80 mg, 150.20 pmol, 39.85% yield). 'H NMR (400MHz CDCI3) 5 = 8.24-7.99 (m, 4H), 7.80 (d, J= 8.4 Hz, 1H), 7.48-7.41 (m, 7H), 7.17-7.05 (m, 1H), 6.58 (s, 2H), 6.44-6.34 (m, 1H), 3.92-3.76 (m, 1H), 3.71- 3.51 (m, 1H), 3.49-3.36 (m, 3H), 2.41-2.26 (m, 1H), 2.17-2.01 (m, 1H), 1.50 (s, 9H). LCMS: m / z 533.3 [M+H]+

[0373]

[0163] Intermediate 2. tert-butyl 3-[4-[2-(2-amino-3-pyridyl)-5-chloro-imidazo[4,5-b]pyridin-3- yl]phenyl]pyrrolidine-l-carboxylate

[0374] 45

[0375] MEl\56585648.vl 141039-01220

[0376]

[0164] Step 1. tert-butyl 3-(4-aminophenyl)-2,5-dihydropyrrole-l-carboxylate

[0377]

[0165] To a solution of 4-bromoaniline (10.50 g, 61.04 mmol) and tert-butyl 3-(4,4,5,5-tetramethyl- 1, 3, 2-dioxaborolan-2-yl)-2, 5 -dihydropyrrole- 1 -carboxylate (19.82 g, 67.14 mmol) in a mixture solution of dioxane (100 mL) and H2O (10 mL) were added K2CO3 (25.31 g, 183.12 mmol), Pd(PPh3)2Cl2(4.28 g, 6. 10 mmol) at 25°C. The mixture was stirred at 95°C for 16 h. After cooling to rt, the mixture was poured into water (50 mL), extracted with EtOAc (200 mL x 3). The combined organic phase was washed with H2O (200 mL x 3) and brine (200 mL), dried over anhydrous Na2SC>4, filtered and concentrated. This batch was combined with another batch prepared from 4-bromoaniline (5.20 g, 30.23 mmol). The combined residue was purified by flash chromatography on silica gel (EtOAc in PE = 0% - 18%) to give tert-butyl 3 -(4-aminophenyl)-2,5 -dihydropyrrole- 1 -carboxylate (10.50 g, 40.33 mmol, 65.24% yield) as a solid. 'H NMR (400MHz, CDCI3) 5 = 7.18 (d, J= 4.4 Hz, 2H), 6.64 (d, J= 7.6 Hz, 2H), 5.90 (d, J= 19.2 Hz, 1H), 4.51-4.34 (d, J= 23.2 Hz„ 2H), 4.33-4.18 (d, J= 20.4Hz„ 2H), 1.50 (d, J= 5.6 Hz, 9H). LCMS: m / z 261.0 [M+H]+

[0378]

[0166] Step 2. tert-butyl 3-(4-aminophenyl)pyrrolidine-l-carboxylate

[0379]

[0167] To a solution of tert-butyl 3-(4-aminophenyl)-2,5-dihydropyrrole-l-carboxylate (15.00 g, 57.62 mmol) in THF (100 mL) was added Pd / C (2.00 g, 10% purity) at 25°C under N2. The suspension was degassed under vacuum and purged with H2 for three times. The mixture was stirred under H2 (50 psi) at 25°C for 16 h. This batch was combined with another batch prepared from tertbutyl 3-(4-aminophenyl)-2,5-dihydropyrrole-l-carboxylate (0.20 g, 768.25 pmol). THF (200 mL) was added to the mixture, filtered, the resulting filter cake was washed with THF (500 mL) and the filtrate was concentrated to give tert-butyl 3-(4-aminophenyl)pyrrolidine-l-carboxylate (15.00 g, 57.18 mmol, 98.6% yield) as oil without further purification. ’H NMR (400MHz, CDCI3) 5 = 7.01 (d, J= 8.0 Hz, 2H), 6.63 (d, J= 8.0 Hz, 2H), 3.74-3.53 (m, 3H), 3.35-3.19 (m, 2H), 2.27-2.15 (m, 1H), 1.94-1.83 (m, 1H), 1.46 (d, J= 4.4 Hz, 9H). LCMS: m / z 207.0 [M+H]+

[0380]

[0168] Step 3. tert-butyl 3-[4-[(6-chloro-3-nitro-2-pyridyl)amino]phenyl]pyrrolidine-l- carboxylate

[0381] 46

[0382] MEl\56585648.vl 141039-01220

[0383]

[0169] To a solution of 2, 6-dichl oro-3 -nitro-pyridine (11.00 g, 57.00 mmol), tert-butyl 3-(4- aminophenyl)pyrrolidine-l -carboxylate (14.95 g, 57.00 mmol) in dioxane (150 mb) was added DIPEA (22.10 g, 171.00 mmol, 29.78 m ) at 25°C. The mixture was stirred at 120°C for 2 h. After cooling to rt, the mixture was poured into water (500 m ), extracted with EtOAc (500 mL x 3). The combined organic phase was washed with brine (500 mL), dried over anhydrous Na2SO4, fdtered and concentrated. The residue was purified by flash chromatography on silica gel (EtOAc in PE = 0% - 25%) to give tert-butyl 3-[4-[(6-chloro-3-nitro-2-pyridyl)amino]phenyl]pyrrolidine-l-carboxylate (12.00 g, 28.65 mmol, 50.26% yield) as oil. 'H NMR (400MHz, CDC13) 5 = 10.22 (s, 1H), 8.43 (d, J = 8.8 Hz, 1H), 7.58 (d, J= 8.4 Hz, 2H), 7.28-7.21 (m, 2H), 6.77 (d, J= 8.4 Hz, 1H), 3.89-3.73 (m, 1H), 3.66-3.47 (m, 1H), 3.40-3.30 (m, 2H), 2.31-2.18 (m, 1H), 2.01-1.89 (m, 2H), 1.46 (s, 9H). LCMS: m / z 363.0 [M+H]+

[0384]

[0170] Step 4. tert-butyl 3-[4-[(3-amino-6-chloro-2-pyridyl)amino]phenyl]pyrrolidine-l- carboxylate

[0385]

[0171] To a solution of tert-butyl 3-[4-[(6-chloro-3-nitro-2-pyridyl)amino]phenyl]pyrrolidine-l- carboxylate (11.50 g, 27.45 mmol) in a mixture solution of EtOH (200 mL) and H2O (20 mL) were added Fe (7.67 g, 137.27 mmol), NH4CI (14.69 g, 274.55 mmol) at 25°C. The mixture was stirred at 80°C for 2 h. After cooling to rt, the mixture was fdtered, the fdter cake was washted with EtOAc (500 mL x 3). The combined organic phase was washed with H2O (500 mL x 3) and brine (500 mL), dried over anhydrous Na2SO4, fdtered and concentrated under reduced pressure to give tert-butyl 3-[4- [(3-amino-6-chloro-2-pyridyl)amino]phenyl]pyrrolidine-l-carboxylate (9.50 g, 24.43 mmol, 88.98% yield) as a solid without further purification. LCMS: m / z 333.0 [M- C4Hs+H]+

[0386]

[0172] Step 5. tert-butyl 3-[4-[2-(2-amino-3-pyridyl)-5-chloro-imidazo[4,5-b]pyridin-3- yl]phenyl]pyrrolidine-l-carboxylate

[0387]

[0173] To a solution of tert-butyl 3-[4-[(3-amino-6-chloro-2-pyridyl)amino]phenyl]pyrrolidine-l- carboxylate (9.50 g, 24.43 mmol), 2-aminopyridine-3-carbaldehyde (3.58 g, 29.31 mmol) in EtOH (150 mL) was added InCE (540.30 mg, 2.44 mmol, 156.16 pL) at 25°C. The mixture was stirred at 80°C for 2 h under N2. After cooling to rt, Mn02 (10.62 g, 122.11 mmol) was added at 25°C. The mixture was stirred at 80°C for 2 h. After cooling to rt, the mixture was fdtered and the filtrate was concentrated. The residue was purified by flash chromatography on silica gel (EtOAc in PE = 0% - 100%) to give tert-butyl 3-[4-[2-(2-amino-3-pyridyl)-5-chloro-imidazo[4,5-b]pyridin-3- yl]phenyl]pyrrolidine-l-carboxylate (8.50 g, 17.31 mmol, 70.89% yield) as a solid. 50.00 mg of tertbutyl 3 -[4-[2-(2-amino-3 -pyridyl)-5 -chloro-imidazo [4,5 -b]pyridin-3 -yl]phenyl]pyrrolidine- 1 - carboxylate was purified by prep-HPLC(column: CD07-Daisogel SP-100-8-ODS-PK 150 x 25 x lOum; mobile phase: [water( NELHCC^-ACN]; gradient: 45% - 65% B over 10 min) to give tertbutyl 3 -[4-[2-(2-amino-3 -pyridyl)-5 -chloro-imidazo [4,5 -b]pyridin-3 -yl]phenyl]pyrrolidine- 1 - carboxylate (12.0 mg, 24.44 pmol, 24.00% yield) as a solid. ’H NMR (400MHz DMSO-t / e) 5 = 8.25

[0388] 47

[0389] MEl\56585648.vl 141039-01220

[0390] (d, J= 8.4 Hz, 1H), 7.99 (dd, J= 4.4, 7.6 Hz, 1H), 7.48-7.38 (m, 5H), 7.23-7.21 (m, 1H), 6.89 (s, 2H), 6.40 (dd, J= 5.2, 7.6 Hz, 1H), 3.78-3.76 (m, 1H), 3.51-3.47 (m, 2H), 3.22-3.17 (m, 2H), 2.27-2.25 (m, 1H), 2.02-1.97 (m, 1H), 1.415 (d, J= 3.6 Hz, 9H). LCMS: m / z 491.1 [M+H]+

[0391]

[0174] Intermediate 3. tert-butyl 3-[4-[2-(2-amino-3-pyridyl)imidazo[4,5-b]pyridin-3- yl]phenyl]pyrrolidine-l-carboxylate oc

[0392]

[0175] Step 1. tert-butyl 3-[4-[2-(2-amino-3-pyridyl)imidazo[4,5-b]pyridin-3- yl]phenyl]pyrrolidine-l-carboxylate

[0393]

[0176] To a solution of tert-butyl 3-[4-[2-(2-amino-3-pyridyl)-5-chloro-imidazo[4,5-b]pyridin-3- yl]phenyl]pyrrolidine-l -carboxylate (1.50 g, 3.06 mmol) in DMF (10 mL) were added EtsN (3.71 g, 36.66 mmol), HCOOH (792.56 mg, 16.50 mmol), Pd(PPh,)4 (353.03 mg, 305.51 pmol) at 25°C under N2. The mixture was stirred under N2 at 100°C for 3 h. After cooling to rt, the mixture was poured into water (100 mL), extracted with EtOAc (100 mL x 3). The combined organic phase was washed with brine (100 mL), dried over anhydrous Na2SC>4, filtered and concentrated. The residue was purified by flash chromatography on silica gel (EtOAc in PE = 0% - 75%) to give tert-butyl 3 - [4-[2- (2-amino-3-pyridyl)imidazo[4,5-b]pyridin-3-yl]phenyl]pyrrolidine-l-carboxylate (1.30 g, 2.85 mmol, 93.21% yield) as oil. 'H NMR (400MHz CDCh) 5 = 8.40-8.37 (m, 1H), 8.10-8.06 (m, 1H), 8.00 (s, 1H), 7.66-7.63 (m, 1H), 7.55-7.52 (m, 1H), 7.47-7.43 (m, 2H), 7.40-7.38 (m, 1H), 7.09 (t, J= 7.2 Hz, 1H), 6.64 (s, 2H), 6.39-6.37 (m, 1H), 3.92-3.78 (m, 1H), 3.67-3.52 (m, 1H), 3.50-3.34 (m, 3H), 2.34- 2.25 (m, 1H), 2.09-2.03 (m, 1H), 1.48 (s, 9H). LCMS: m / z 457.2 [M+H]+

[0394]

[0177] Intermediate 4. tert-butyl 3-[4-[2-(2-amino-3-pyridyl)-5-(trifluoromethyl)imidazo[4,5- b]pyridin-3-yl]phenyl]pyrrolidine-l-carboxylate

[0395]

[0178] Step 1. tert-butyl 3- [4- [[3-nitro-6-(trifluoromethyl)-2-pyridyl] amino] phenyl] pyrrolidine- 1-carboxylate

[0396]

[0179] To a solution of 2-chloro-3-nitro-6-(trifluoromethyl)pyridine (3 g, 13.24 mmol) and tert-butyl 3-(4-aminophenyl)pyrrolidine-l-carboxylate (3.82 g, 14.57 mmol) in dioxane (10 mL) was added

[0397] 48

[0398] MEl\56585648.vl 141039-01220

[0399] DIEA (5.13 g, 39.73 mmol, 6.92 mL). The mixture was stirred at 90°C for 16 h. The reaction mixture was quenched with H2O (50 mL) at 25 °C, and the resulting mixture was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL x 3), dried over anhydrous Na2SC>4, fdtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (EA in PE = 0 - 25%) to give tert-butyl 3-[4-[[3-nitro-6- (trifluoromethyl)-2-pyridyl]amino]phenyl]pyrrolidine-l-carboxylate (4.8 g, 10.61 mmol, 80.12% yield) as aoil. LCMS: m / z 475.2 [M+Na]+

[0400]

[0180] Step 2. tert-butyl 3-[4-[[3-amino-6-(trifluoromethyl)-2- pyridyl] amino] phenyl] pyrrolidine-l-carboxylate

[0401]

[0181] To a solution of tert-butyl 3-[4-[[3-nitro-6-(trifluoromethyl)-2- pyridyl] amino] phenyl] pyrrolidine-l-carboxylate (4.6 g, 10.17 mmol) in a mixed solution of EtOH (30 mL) and H2O (10 mL) were added Fe (2.84 g, 50.84 mmol) and NH4CI (5.44 g, 101.67 mmol). The mixture was stirred at 60°C for 16 h. After cooling to rt, the resulting mixture was filtered and concentrated under reduced pressure, the water layers was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give tert-butyl 3-[4-[[3-amino-6-(trifluoromethyl)-2- pyridyl] amino] phenyl] pyrrolidine-l-carboxylate (3.8 g, 9.00 mmol, 88.47% yield) was obtained as oil which was used to next step without purification. LCMS: m / z 445.0 [M+Na]+

[0402]

[0182] Step 3. tert-butyl 3-[4-[2-(2-amino-3-pyridyl)-5-(trifluoromethyl)imidazo[4,5-b]pyridin- 3-yl] phenyl] pyrrolidine-l-carboxylate

[0403]

[0183] To a solution of tert-butyl 3-[4-[[3-amino-6-(trifluoromethyl)-2- pyridyl] amino] phenyl] pyrrolidine-l-carboxylate (3.7 g, 8.76 mmol) and 2-aminopyridine-3- carbaldehyde (1.18 g, 9.63 mmol) in EtOH (30 mL) was added InCF (193.72 mg, 875.86 pmol, 55.99 pL) at 25°C. The mixture was stirred at 80°C for 16 h to give tert-butyl 3-[4-[2-(2-amino-3-pyridyl)- 5-(trifluoromethyl)-l,2-dihydroimidazo[4,5-b]pyridin-3-yl]phenyl]pyrrolidine-l-carboxylate (4.61 g, 8.76 mmol, 100% yield) was obtained as liquid, which was used to next step without purification. To a solution of tert-butyl 3-[4-[2-(2-amino-3-pyridyl)-5-(trifluoromethyl)-l,2-dihydroimidazo[4,5- b]pyridin-3-yl]phenyl]pyrrolidine-l-carboxylate (4.6 g, 8.74 mmol) in EtOH (20 mL) was added Mn02 (3.80 g, 43.68 mmol). The mixture was stirred at 80°C for 2 h. After cooling to rt, the resulting mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography on silica gel (EA in PE = 0 - 60%) to give tert-butyl 3-[4-[2-(2- amino-3-pyridyl)-5-(trifluoromethyl)imidazo[4,5-b]pyridin-3-yl]phenyl]pyrrolidine-l-carboxylate (1.5 g, 2.86 mmol, 32.73% yield) as a solid. 300 mg of tert-butyl 3-[4-[2-(2-amino-3-pyridyl) -5- (trifluoromethyl) imidazo[4,5-b]pyridin-3-yl] phenyl]pyrrolidine-l -carboxylate was purified by prep- HPLC (column: CD02-Waters Xbidge BEH C18 150 x 25 x 10pm; mobile phase:

[0404] [water( NELHCC^-ACN]; gradient:50%-80% B over 11 min ) to give tert-butyl 3-[4-[2-(2-amino-3-

[0405] 49

[0406] MEl\56585648.vl 141039-01220 pyridyl)-5-(tri fl uoromcthyl)imidazo| 4.5-b |pyridin-3-yl |phcnyl |pyrrolidinc- 1 -carboxylate (110 mg, 209.71 pmol, 36.67% yield) as a solid. 'H NMR (400MHz, DMSO-6) 5 = 8.44 (d, J= 8.0 Hz, 1H), 8.02 (dd, J= 1.6, 4.8 Hz, 1H), 7.87 (d, J= 8.4 Hz, 1H), 7.49-7.41 (m, 4H), 7.27-7.26 (m, 1H), 6.81 (s, 2H), 6.44 (dd, J= 5.2, 7.2 Hz, 1H), 3.81-3.73 (m, 1H), 3.56-3.35 (m, 3H), 3.24-3.15 (m, 1H), 2.30- 2.19 (m, 1H), 2.06-1.93 (m, 1H), 1.42 (s, 9H).19F NMR (376.5MHz, DMSO-6) 5 = -64.147. LCMS: m / z 525.2 [M+H]+

[0407]

[0184] Intermediate 5. tert-butyl 3-[4-[2-(2-amino-3-pyridyl)-6-bromo-benzimidazol-l- yl]phenyl]pyrrolidine-l-carboxylate

[0408]

[0185] Step 1. tert-butyl 3-[4-(5-bromo-2-nitro-anilino)phenyl]pyrrolidine-l-carboxylate

[0409]

[0186] To a solution of tert-butyl 3-(4-aminophenyl)pyrrolidine-l-carboxylate (15 g, 57.18 mmol) in THF (150 mb) was added LiHMDS (1 M, 114.35 mb). The mixture was stirred at -78 °C for 0.5 h. Then 4-bromo-2 -fluoro- 1 -nitro-benzene (13.84 g, 62.89 mmol) was added to the mixture. The mixture was stirred at -78 °C for 0.5 h. The mixture was added to the saturated NH4CI solution(300ml). Water (250 mb) and aq. layer was extracted with EtOAc (200 mb x 2). The combined organic layer was washed with brine (50 mb), dried over anhydrous Na2SC>4, fdtered and concentrated. The crude product was purified by flash silica gel chromatography (PE in EA from 0 to 10%) to give tert-butyl 3-[4-(5-bromo-2-nitro-anilino)phenyl]pyrrolidine-l-carboxylate (24 g, 51.91 mmol, 90.79% yield) as a oil. 'H NMR (400 MHz, DMSO- d6) 5 = 9.46 (s, 1H), 8.07 (d, J= 9.6 Hz, 1H), 7.35-7.28 (m, 2H), 7.24-7.21 (m, 2H), 6.91-6.82 (m, 1H), 4.00-3.78 (m, 1H), 3.72-3.54 (m, 1H), 3.47-3.22 (m, 3H), 2.37-2.25 (m, 1H), 2.02-1.94 (m, 1H), 1.49 (s, 9H).

[0410]

[0187] Step 2. tert-butyl 3-[4-(2-amino-5-bromo-anilino)phenyl]pyrrolidine-l-carboxylate

[0411]

[0188] To a solution of tert-butyl 3-[4-(5-bromo-2-nitro-anilino)phenyl]pyrrolidine-l-carboxylate (22 g, 47.58 mmol) in EtOH (200 mL) and H2O (20 mL) was added Fe (7.97 g, 142.75 mmol) and NH4CI (15.27 g, 285.51 mmol). The mixture was stirred at 100 °C forl2 hr. The resulting mixture was fdtered, and the fdter cake was washed with EtOAc (30 mL x 3). The fdtrate was concentrated, tert-butyl 3-[4-(2-amino-5-bromo-anilino)phenyl]pyrrolidine-l-carboxylate (20.57 g, 47.58 mmol, 100.00% yield) was obtained as solid, which was used next step without further purification. ’H

[0412] NMR (400 MHz, DMSO-d6) 5 = 7.16 (s, 1H), 7.10 (d, J= 8.0 Hz, 2H), 7.04 (s, 1H), 6.94-6.84 (m, 1H), 6.74 (d, J= 8.0 Hz, 2H), 6.66 (d,J= 8.4 Hz, 1H), 4.91 (br s, 2H), 3.68-3.61 (m, 1H), 3.48-3.39 (m, 1H), 3.29-3.19 (m, 2H), 3.13-3.05 (m, 1H), 2.20-2.06 (m, 1H), 1.92-1.85 (m, 1H), 1.43-1.38 (m,

[0413] 50

[0414] MEl\56585648.vl 141039-01220

[0415]

[0189] Step 3. tert-butyl 3-[4-[2-(2-amino-3-pyridyl)-6-bromo-benzimidazol-l- yl]phenyl]pyrrolidine-l-carboxylate

[0416]

[0190] To a solution of tert-butyl 3-[4-(2-amino-5-bromo-anilino)phenyl]pyrrolidine-l-carboxylate (20.57 g, 47.58 mmol) in EtOH (150 mL) was added InCL (1.05 g, 4.76 mmol, 304.13 pL) and 2- aminopyridine-3-carbaldehyde (6.97 g, 57.09 mmol) . The mixture was stirred at 80 °C for 12 hr. Then the mixture was cooled to 25 °C. Then MnCL (20.68 g, 237.88 mmol) was added to the mixture. The mixture was stirred at 80 °C for 2 hr. The resulting mixture was filtered, and the filter cake was washed with EtOAc (100 mL x 3). The filtrate was concentrated and The crude product was purified by flash silica gel chromatography (PE in EA from 0 to 50%) to give tert-butyl 3-[4-[2-(2-amino-3- pyridyl)-6-bromo-benzimidazol-l-yl]phenyl]pyrrolidine-l -carboxylate (11.7 g, 21.89 mmol, 46.01% yield) as a solid. 'H NMR (400 MHz, CDC13) 5 = 8.07-8.00 (m, 1H), 7.68 (d, J= 8.4 Hz, 1H), 7.46- 7.40 (m, 3H), 7.33 (s, 2H), 7.28-7.27 (m, 1H), 7.25-7.24 (m, 1H), 7.08-6.94 (m, 1H), 6.68 (br s, 2H), 6.39-6.32 (m, 1H), 4.00-3.79 (m, 1H), 3.74-3.58 (m, 1H), 3.49-3.27 (m, 3H), 2.42-2.30 (m, 1H), 2.07- 2.03 (m, 1H), 1.50 (s, 9H). LCMS: m / z 533.9 [M+H]+

[0417]

[0191] Intermediate 6. 3-[6-phenyl-l-(4-pyrrolidin-3-ylphenyl)benzimidazol-2-yl]pyridin-2- amine

[0418]

[0192] Step 1. tert-butyl 3-[4-[2-(2-amino-3-pyridyl)-6-phenyl-benzimidazol-l- yl]phenyl]pyrrolidine-l-carboxylate

[0419]

[0193] To a solution of tert-butyl 3-[4-[2-(2-amino-3-pyridyl)-6-bromo-benzimidazol-l- yl]phenyl]pyrrolidine-l -carboxylate (0.55 g, 1.03 mmol) and phenylboronic acid (250.96 mg, 2.06 mmol) in a mixed solution of H2O (1 mL), toluene (5 mL), EtOH (5 mL) were added Pd(dppf)C12 (150.60 mg, 205.82 pmol) and NaHCCf (259.36 mg, 3.09 mmol) at 25°C. The mixture was stirred at 100°C for 16 h under N2. After cooling to rt, the reaction mixture was added to water (50 mL). The aq. layer was extracted with EtOAc (50 mL x 3). The combined organic phase was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude was purified by flash chromatography on silica gel (MeOH in DCM = 0% - 6%) to give tert-butyl 3- [4-[2-(2-amino-3-pyridyl)-6-phenyl-benzimidazol-l-yl]phenyl]pyrrolidine-l-carboxylate (0.54 g, 1.02 mmol, 98.70% yield) as a solid. 40 mg of tert-butyl 3-[4-[2-(2-amino-3-pyridyl)-6-phenyl- benzimidazol-l-yl]phenyl]pyrrolidine-l-carboxylate was purified by prep-HPLC (column: CD24- XPT C18 150 x 25 x 7um; mobile phase: [water( NH4HCO3) - ACN]; gradient: 55% - 85% B over 10 min) to give tert-butyl 3-[4-[2-(2-amino-3-pyridyl)-6-phenyl-benzimidazol-l-yl]phenyl]pyrrolidine-l- carboxylate (8.10 mg, 15.24 pmol, 20.25% yield) as a solid. ’H NMR (400MHz, DMSO-t / e) 5 =

[0420] 51

[0421] MEl\56585648.vl 141039-01220

[0422] 7.97 (d, J= 3.2 Hz, 1H), 7.88 (d, J= 8.4 Hz, 1H), 7.80-7.60 (m, 3H), 7.51-7.42 (m, 6H), 7.36-7.29 (m, 2H), 7.16-7.09 (m, 1H), 7.02 (s, 2H), 6.45-6.31 (m, 1H), 3.79-3.74 (m, 1H), 3.56-3.44 (m, 3H), 3.23-3.18 (m, 1H), 2.26-2.24 (m, 1H), 2.08-1.97 (m, 1H), 1.41 (s, 9H). LCMS: m / z 532.2 [M+H]+

[0423]

[0194] Intermediate 7. tert-butyl-3-[4-[2-(2-amino-3-pyridyl)-5-cyclopropyl-imidazo[4,5- b]pyridin-3-yl]phenyl]pyrrolidine-l-carboxylate

[0424]

[0195] Step 1. tert-butyl-3-[4-[2-(2-amino-3-pyridyl)-5-cyclopropyl-imidazo[4,5-b]pyridin-3- yl]phenyl]pyrrolidine-l-carboxylate

[0425]

[0196] To a solution of tert-butyl-3-[4-[2-(2-amino-3-pyridyl)-5-chloro-imidazo[4,5-b]pyridin-3- yl]phenyl]pyrrolidine-l -carboxylate (500 mg, 1.02 mmol) and cyclopropylboronic acid (437.37 mg, 5.09 mmol) in dioxane (lOmL) were added [2-(2-aminophenyl)phenyl]-methylsulfonyloxy- palladium;DCM;tricyclohexylphosphane (74.86 mg, 101.84 pmol) and CS2CO3 (3 M in H2O, 1.02 mL) at 25 °C. Then the mixture was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100°C under N2 for 12 h. After cooling to rt, the resulting mixture was filtered and the filter cake was washed with DCM (20 mL) and EtOAc (20 mL) at 25 °C. Then the combined organic phase was concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography on silica gel (MeOH in DCM = 0 - 10 %) to give tert-butyl-3-[4-[2-(2-amino-3- pyridyl)-5-cyclopropyl-imidazo[4,5-b]pyridin-3-yl]phenyl]pyrrolidine-l-carboxylate (400 mg, 805.47 pmol, 79.09% yield) as oil. 'H NMR (400 MHz, DMSO-6) 5 = 8.07-7.92 (m, 2H), 7.43 (d, J= 8.4 Hz, 2H), 7.33 (d, J= 8.4 Hz, 2H), 7.24 (d, J= 8.0 Hz, 1H), 7.10 (d, J= 7.6 Hz, 1H), 6.86 (s, 2H), 6.43-6.33 (m, 1H), 3.80-3.72 (m, 1H), 3.52-3.46 (m, 2H), 3.24-3.15 (m, 2H), 2.28-2.14 (m, 2H), 2.04- 1.96 (m, 1H), 1.42 (s, 9H), 0.97-0.89 (m, 2H), 0.86-0.78 (m, 2H). LCMS: m / z 497.2 [M+H]+

[0426]

[0197] Intermediate 8. 3-[6-bromo-3-(4-pyrrolidin-3-ylphenyl)imidazo[4,5-b]pyridin-2- yl]pyridin-2- amine

[0427]

[0198] Step 1. tert-butyl 3-[4-[(5-bromo-3-nitro-2-pyridyl)amino]phenyl]pyrrolidine-l- carboxylate

[0428] 52

[0429] MEl\56585648.vl 141039-01220

[0430]

[0199] To a solution of tert-butyl 3-(4-aminophenyl)pyrrolidine-l-carboxylate (13 g, 49.55 mmol) in dioxane (200 mb) was added 5 -bromo-2-chloro-3 -nitro-pyridine (12.94 g, 54.51 mmol) and DIEA (19.21 g, 148.66 mmol, 25.89 m ). The mixture was stirred at 120 °C for 2hr. Water (200 m ) and aq. layer was extracted with EtOAc (250 mb x 2). The combined organic layer was washed with brine (250 mb), dried over anhydrous Na2SC>4, fdtered and concentrated. The crude product was purified by flash silica gel chromatography (PE in EA from 0 to 10%) to give tert-butyl 3-[4-[(5- bromo-3-nitro-2-pyridyl)amino]phenyl]pyrrolidine-l-carboxylate (16 g, 34.53 mmol, 69.69% yield) as asolid. 'H NMR (400 MHz, DMSO-6) 5 = 9.92 (s, 1H), 8.67 (d, J= 2.0 Hz, 1H), 8.59 (s, 1H), 7.52 (d, J= 8.0 Hz, 2H), 7.28 (d, J= 8.0 Hz, 2H), 3.74-3.67 (m, 1H), 3.51-3.44 (m, 1H), 3.39-3.35 (m, 1H), 3.31-3.25 (m, 1H), 3.21-3.11 (m, 1H), 2.24-2.18 (m, 1H), 1.98-1.88 (m, 1H), 1.43-1.39 (m, 9H).

[0431]

[0200] Step 2. tert-butyl 3-[4-[(3-amino-5-bromo-2-pyridyl)amino]phenyl]pyrrolidine-l- carboxylate

[0432]

[0201] To a solution of tert-butyl 3-[4-[(5-bromo-3-nitro-2-pyridyl)amino]phenyl]pyrrolidine-l- carboxylate (14 g, 30.22 mmol) in EtOH (100 mb) and H2O (10 mb) was added be (8.44 g, 151.08 mmol) and NH4CI (16.16 g, 302.16 mmol). The mixture was stirred at 100 °C for 12hr. The resulting mixture was fdtered, and the fdter cake was washed with EtOAc (30 mb x 3). The fdtrate was concentrated, tert-butyl 3-[4-[(3-amino-5-bromo-2-pyridyl)amino]phenyl]pyrrolidine-l-carboxylate (13.09 g, 30.21 mmol, 100.00% yield) was obtained as solid, which was used next step without further purification. 'H NMR (400 MHz, DMSO-6) 5 = 7.82 (s, 1H), 7.56-7.44 (m, 3H), 7.16 (d, J = 8.4 Hz, 2H), 7.02 (d, J= 2.4 Hz, 1H), 5.40 (br s, 2H), 3.73-3.63 (m, 1H), 3.46-3.42 (m, 1H), 3.31-3.22 (m, 2H), 3.15-3.05 (m, 1H), 2.20-2.09 (m, 1H), 1.94-1.86 (m, 1H), 1.43-1.39 (m, 9H).

[0433]

[0202] Step 3. tert-butyl 3- [4- [2-(2-amino-3-pyridyl)-6-bromo-imidazo [4,5-b] pyridin-3- yl]phenyl]pyrrolidine-l-carboxylate

[0434]

[0203] To a solution of tert-butyl 3-[4-[(3-amino-5-bromo-2-pyridyl)amino]phenyl]pyrrolidine-l- carboxylate (13.09 g, 30.21 mmol) in EtOH (150 mb) was added InCis (668.12 mg, 3.02 mmol, 193.10 ph) and 2-aminopyridine-3-carbaldehyde (4.43 g, 36.25 mmol) . The mixture was stirred at 80 °C for 12 hr. Then the mixture was cooled to 25 °C. Then Mn02 (13.13 g, 151.04 mmol) was added to the mixture. The mixture was stirred at 80 °C for 2 hr. The resulting mixture was fdtered, and the fdter cake was washed with EtOAc (100 mb x 3). The fdtrate was concentrated and purified by flash silica gel chromatography (PE in EA from 0 to 50%) to give tert-butyl 3-[4-[2-(2-amino-3- pyridyl)-6-bromo-imidazo[4,5-b]pyridin-3-yl]phenyl]pyrrolidine-l-carboxylate (6.4 g, 11.95 mmol, 39.57% yield) as a solid. 'H NMR (400 MHz, CDCI3) 5 = 8.50-8.35 (m, 1H), 8.24-8.20 (m, 1H), 8.1.3-8.02 (m, 1H), 7.40 (d, J= 8.0 Hz, 2H), 7.31 (d, J= 8.0 Hz, 2H), 7.11-7.01 (m, 1H), 6.64 (br s, 2H), 6.41-6.21 (m, 1H), 4.00-3.76 (m, 1H), 3.73-3.55 (m, 1H), 3.47-3.28 (m, 3H), 2.39-2.24 (m, 1H), 1.98-1.83 (m, 1H), 1.48(s, 9H). LCMS: m / z 535.1 [M+H]+.

[0435] 53

[0436] MEl\56585648.vl 141039-01220

[0437]

[0204] Intermediate 9. tert-butyl 3- [4- [2-(2-amino-3-pyridyl)-6-phenyl-imidazo [4,5-b] pyridin-3- yl]phenyl]pyrrolidine-l-carboxylate

[0438]

[0205] Step 1. tert-butyl 3-[4-[2-(2-amino-3-pyridyl)-6-phenyl-imidazo[4,5-b]pyridin-3- yl]phenyl]pyrrolidine-l-carboxylate

[0439]

[0206] A mixture of tert-butyl 3-[4-[2-(2-amino-3-pyridyl)-6-bromo-imidazo[4,5-b]pyridin-3- yl]phenyl]pyrrolidine-l -carboxylate (300 mg, 560.29 pmol), Pd(dppf)C12 (81.99 mg, 112.06 pmol), NaHCOs (141.21 mg, 1.68 mmol) and phenylboronic acid (136.63 mg, 1.12 mmol) in a mixed solution of H2O (1 mL) and dioxane (5 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100°C for 12 h under N2 atmosphere. The reaction mixture was diluted with EtOAc (20 mL) and washed with brine (10 mL x 3). The combined organic layers were dried over anhydrous Na2SC>4, filtered and concentrated. The crude product was purified by flash chromatography on silica gel (EA in PE = 0 - 100%) to give tert-butyl 3-[4-[2-(2-amino-3-pyridyl)-6- phenyl-imidazo[4,5-b]pyridin-3-yl]phenyl]pyrrolidine-l-carboxylate (260 mg, 488.14 pmol, 87.12% yield) as a solid. LCMS: m / z 533.3[M+H]+

[0440]

[0207] Intermediate 10. tert-butyl 3-[4-[(3-amino-6-phenyl-pyrazin-2- yl)amino]phenyl]pyrrolidine-l-carboxylate

[0441]

[0208] Step 1. 5-phenylpyrazin-2-amine

[0442]

[0209] A mixture of 5-bromopyrazin-2-amine (10 g, 57.47 mmol), phenylboronic acid (7.71 g, 63.22 mmol), K2CO3 (23.83 g, 172.42 mmol), Pd(dppf)C12 (4.21 g, 5.75 mmol) and phenylboronic acid (7.71 g, 63.22 mmol) in a mixed solvent of DMF (12 mL), H2O (47.5 mL) and toluene (67 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 90 °C for 16 hr under N2 atmosphere. After cooling to rt, the resulting mixture was filtered and concentrated under reduced

[0443] 54

[0444] MEl\56585648.vl 141039-01220 pressure. The water layer was extracted with EtOAc (150 mL x 3). The combined organic layers were washed with brine (150 mL x 3), dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography on silica gel (EA in PE = 0 - 40%) to give 5-phenylpyrazin-2-amine (6.9 g, 40.30 mmol, 70.12% yield) as a solid. 'H NMR (400MHz, DMSO-6) 5 = 8.51 (d, J= 1.2 Hz, 1H), 7.98 (d, J= 1.2 Hz, 1H), 7.91 (d, J= 7.2 Hz, 2H), 7.41 (t, J= 7.6 Hz, 2H), 7.34-7.27 (m, 1H), 6.57 (s, 2H))

[0445]

[0210] Step 2. 3-bromo-5-phenyl-pyrazin-2-amine

[0446]

[0211] A mixture of 5-phenylpyrazin-2-amine (2 g, 11.68 mmol), tetrabutyl ammonium tribromide (6.76 g, 14.02 mmol) in CHCL (80 mL) and Py (15 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 55°C for 3 hr under N2 atmosphere. After cooling to rt, the mixture was diluted with saturated NaHCCE solution (50 mL), extracted with DCM (50 mL x 3). The combined organic layers were washed with H2O (50 mL x 3), dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography on silica gel (EA in PE = 0 - 20%) to give 3-bromo-5-phenyl-pyrazin-2-amine (2.5 g, 10.00 mmol, 85.57% yield) as a solid. 'H NMR (400MHz, DMSO-6) 5 = 8.60 (s, 1H), 7.92-7.86 (m, 2H), 7.48-7.41 (m, 2H), 7.38-7.30 (m, 1H), 6.87 (s, 2H).

[0447]

[0212] Step 3. tert-butyl 3-[4-[(3-amino-6-phenyl-pyrazin-2-yl)amino]phenyl]pyrrolidine-l- carboxylate

[0448]

[0213] A mixture of 3 -bromo-5 -phenyl -pyrazin-2 -amine (2 g, 8.00 mmol), tert-butyl 3-(4- aminophenyl)pyrrolidine-l -carboxylate (2.52 g, 9.60 mmol), RuPhos Pd G4 (1.36 g, 1.60 mmol), CS2CO3 (7.82 g, 23.99 mmol) and tert-butyl 3 -(4-aminophenyl)pyrrolidine-l -carboxylate (2.52 g, 9.60 mmol) in dioxane (20 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100°C for 16 h under N2 atmosphere. The reaction mixture was quenched with H2O (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (EA in PE = 0 - 100%) to give tert-butyl 3- [4-[(3-amino-6-phenyl -pyrazin-2 -yl)amino]phenyl]pyrrolidine-l -carboxylate (1.5 g, 3.48 mmol, 43.47% yield) as a solid. LCMS: m / z 432.1 [M+H]+

[0449]

[0214] Step 4. tert-butyl 3-[4-[2-(2-amino-3-pyridyl)-5-phenyl-imidazo[4,5-b]pyrazin-3- yl]phenyl]pyrrolidine-l-carboxylate

[0450]

[0215] To a solution of tert-butyl 3-[4-[(3-amino-6-phenyl-pyrazin-2-yl)amino]phenyl]pyrrolidine-l- carboxylate (900 mg, 2.09 mmol) in DML (9 mL) were added disodium;BLAH (472.06 mg, 2.71 mmol, 590.08 pL) and 2-aminopyridine-3-carbaldehyde (254.70 mg, 2.09 mmol). The mixture was stirred at 100°C for 16 h. The reaction mixture was quenched with H2O (50 mL) at 25°C, and the resulting mixture was filtered and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated under

[0451] 55

[0452] MEl\56585648.vl 141039-01220 reduced pressure. The residue was purified by flash chromatography on silica gel (MeOH in DCM = 0 - 10%) to give tert-butyl 3-[4-[2-(2-amino-3-pyridyl)-5-phenyl-imidazo[4,5-b]pyrazin-3- yl]phenyl]pyrrolidine-l-carboxylate (800 mg, 1.50 mmol, 71.88% yield) as a solid. LCMS: m / z 534.1 [M+H]+

[0453]

[0216] Intermediate 11. tert-butyl 3-[4-[2-(2-amino-3-pyridyl)-6,7-difluoro-benzimidazol-l- yl]phenyl]pyrrolidine-l-carboxylate

[0454]

[0217] Step 1. tert-butyl 3-[4-(2,3-difluoro-6-nitro-anilino)phenyl]pyrrolidine-l-carboxylate

[0455]

[0218] To a solution of tert-butyl 3-(4-aminophenyl)pyrrolidine-l-carboxylate (8.5 g, 32.40 mmol) in THF (100 mb) was added LiHMDS (1 M, 64.80 mb) . The mixture was stirred at -78 °C for 0.5 h. Then l,2,3-trifluoro-4-nitro-benzene (6.31 g, 35.64 mmol, 4.10 mb) was added to the mixture. The mixture was stirred at -78 °C for 0.5 h. The mixture was added to the saturated NH4CI solution (300ml). Water (250 mb) and aq. layer was extracted with EtOAc (200 mb x 2). The combined organic layer was washed with brine (50 mb), dried over anhydrous Na2SC>4, filtered and concentrated. The crude product was batched with other product (7.99 g ) and purified by flash silica gel chromatography (PE in EA from 0 to 10%) to give tert-butyl 3-[4-(2,3-difluoro-6-nitro- anilino)phenyl] pyrrolidine -1 -carboxylate (17 g, 40.53 mmol, 79.18% yield) as a oil.1H NMR (400 MHz, DMSO-d6) 5 = 8.90 (s, 1H), 8.18-7.88 (m, 1H), 7.34-7.14 (m, 3H), 6.98-6.83 (m, 2H), 3.70- 3.63 (m, 1H), 3.53-3.39 (m, 1H), 3.32-3.22 (m, 2H), 3.16-3.03 (m, 1H), 2.22-2.10 (m, 1H), 1.96-1.82 (m, 1H), 1.42-1.35 (m, 9H) F-NMR (400 MHz, DMSO-d6) 5 = -127.071 -127.092 -140.402 -140.514 -140.568.

[0456]

[0219] Step 2. tert-butyl 3-[4-(6-amino-2,3-difluoro-anilino)phenyl]pyrrolidine-l-carboxylate

[0457]

[0220] To a solution of tert-butyl 3-[4-(2,3-difluoro-6-nitro-anilino)phenyl]pyrrolidine-l-carboxylate (15 g, 35.76 mmol) in EtOH (80 mL) and H2O (8 mL) was added Fe (9.99 g, 178.82 mmol) and NH4CI (19.13 g, 357.64 mmol). The mixture was stirred at 100 °C for 12hr. The resulting mixture was filtered, and the filter cake was washed with EtOAc (30 mL x 3). The filtrate was concentrated, tert-butyl 3-[4-(6-amino-2,3-difluoro-anilino)phenyl]pyrrolidine-l-carboxylate (13.93 g, 35.77 mmol, 100.00% yield) was obtained as solid, which was used next step without further purification. ’H NMR (400 MHz, DMSO-d6) 5 = 7.35-7.11 (m, 2H), 7.04 (d, J= 8.0 Hz, 2H), 6.99-6.90 (m, 1H), 6.51 (d, J= 8.0 Hz, 2H), 4.94 (br s, 2H), 3.67-3.54 (m, 1H), 3.27-3.13 (m, 3H), 3.08-2.99 (m, 1H), 2.17-

[0458] 56

[0459] MEl\56585648.vl 141039-01220

[0460] 2.02 (m, 1H), 1.92-1.72 (m, 1H), 1.40-1.35 (m, 9H). F-NMR (400 MHz, DMSO-d6) 5 = -145.700 - 145.764 -153.713.

[0461]

[0221] Step 3. tert-butyl 3-[4-[2-(2-amino-3-pyridyl)-6,7-difluoro-benzimidazol-l- yl]phenyl]pyrrolidine-l-carboxylate

[0462]

[0222] To a solution of tert-butyl 3-[4-(6-amino-2,3-difluoro-anilino)phenyl]pyrrolidine-l- carboxylate (13.93 g, 35.77 mmol) in EtOH (150 mL) was added InCL, (791.15 mg, 3.58 mmol, 228.66 pL) and 2-aminopyridine-3-carbaldehyde (5.24 g, 42.92 mmol) . The mixture was stirred at 80 °C for 12 hr. Then the mixture was cooled to 25 °C. Then MnCL (15.55 g, 178.85 mmol) was added to the mixture. The mixture was stirred at 80 °C for 2 hr. The resulting mixture was fdtered, and the fdter cake was washed with EtOAc (100 mL x 3). The fdtrate was concentrated and purified by flash silica gel chromatography (PE in EA from 0 to 50%) to give tert-butyl 3-[4-[2-(2-amino-3- pyridyl)-6,7-difluoro-benzimidazol-l-yl]phenyl]pyrrolidine-l-carboxylate (10 g, 20.34 mmol, 56.88% yield) as a solid. 'H NMR (400 MHz, CDC13) 5 = 8.01-7.86 (m, 1H), 7.49-7.40 (m, 1H), 7.28-7.22 (m, 4H), 7.14-7.03 (m, 1H), 6.94-6.89 (m, 1H), 7.25-7.24 (m, 1H), 6.42 (br s, 2H), 6.32-6.21 (m, 1H), 3.89-3.71 (m, 1H), 3.63-3.49 (m, 1H), 3.39-3.23 (m, 3H), 2.31-2.22 (m, 1H), 2.02-1.96 (m, 1H), 1.42 (s, 9H). F-NMR (400 MHz, CDCI3) 5 = -144.337 -144.041 -156.126 -156.182 -156.209 -156.264.

[0463] LCMS: m / z 492.1 [M+H]+

[0464]

[0223] Intermediate 12. 3-(5-(2-(2-aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin-3- yl)pyridin-2-yl)pyrrolidin-3-ol

[0465]

[0224] Step 1. tert-butyl 3-(5-bromopyridin-2-yl)-3-hydroxypyrrolidine-l-carboxylate

[0466]

[0225] N-BuLi (2.5M, 5.6 mL, 13.93 mmol) was added dropwise to a mixture of 2,5- dibromopyridine (3.0 g, 12.66 mmol) in toluene (30 mL) at -78 °C. The mixture was stirred at -78 °C for 1 h. Then tert-butyl 3 -oxopyrrolidine-1 -carboxylate (2.14 g, 11.52 mmol) in toluene (20 mL) was added at -78 °C. The mixture was stirred at RT for 16 h. After completion of the reaction, the mixture was quenched with saturated aq. ammonium chloride solution (30 mL). The separated aq. phase was extracted with EA (50 mL x 3). The combined organic phases were washed with brine (50 mL) and dried over Na2SC>4 and concentrate under reduced pressure. The residue was purified by column chromatography (SiC>2, 0-33% EA in PE) to afford tert-butyl 3-(5-bromopyridin-2-yl)-3-

[0467] 57

[0468] MEl\56585648.vl 141039-01220 hydroxypyrrolidine- 1 -carboxylate as a solid (1.9 g, 44% yield). ‘H NMR (400 MHz, DMSO-t / e) 5 8.65 (d, J= 2.2 Hz, 1H), 8.07 (dd, J= 8.6, 2.4 Hz, 1H), 7.66 (d, J= 8.6 Hz, 1H), 5.77 (s, 1H), 3.63 (dd, J= 15.8, 11.2 Hz, 1H), 3.55 - 3.41 (m, 3H), 2.39 - 2.27 (m, 1H), 1.99 - 1.93 (m, 1H), 1.41 (d, J = 11.2 Hz, 9H). LCMS: m / z, 287.5 [(M-t-Bu+H)+] .

[0469]

[0226] Step 2. tert-butyl 3-(5-(((benzyloxy)carbonyl)amino)pyridin-2-yl)-3-hydroxypyrrolidine- 1-carboxylate

[0470]

[0227] A mixture of tert-butyl 3-(5-bromopyridin-2-yl)-3-hydroxypyrrolidine-l-carboxylate (1.54 g, 4.49 mmol), Cbz-NH2 (814 mg, 5.39 mmol), Pd2(dba)s (411 mg, 0.45 mmol), XantPhos (520 mg, 0.90 mmol) and CS2CO3 (4.39 g, 13.47 mmol) in dioxane (25 mb) was stirred at 100 °C for 16 h. After completion of the reaction, the mixture was quenched with saturated aq. ammonium chloride solution (30 mL). The separated aq. phase was extracted with EA (40 m x 3). The combined organic phases were washed with brine (40 mL) and dried over Na2SC>4 and concentrate under reduced pressure. The residue was purified by column chromatography (SiC 0-50% EA in PE) to afford tert-butyl 3-(5- (((benzyloxy)carbonyl)amino)pyridin-2-yl)-3-hydroxypyrrolidine-l-carboxylate (670 mg, 37% yield) as a solid. LCMS: m / z, 414.2 [(M+H)+],

[0471]

[0228] Step 3. tert-butyl 3-(5-aminopyridin-2-yl)-3-hydroxypyrrolidine-l-carboxylate

[0472]

[0229] Tert-butyl 3 -(5 -(((benzyloxy)carbonyl)amino)pyridin-2-yl)-3 -hydroxypyrrolidine- 1- carboxylate (670 mg, 1.62 mmol) was dissolved in EA (12 mL). To the mixture was added 10% Pd / C (268 mg). The mixture was stirred at RT under H2 atmosphere for 16 h. Removed Pd / C by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiCE, 0-8% MeOH in DCM) to afford tert-butyl 3-(5-aminopyridin-2-yl)-3- hydroxypyrrolidine-1 -carboxylate (340 mg, 75% yield) as a solid. LCMS: m / z, 280.2 [(M+H)+],

[0473]

[0230] Step 4. tert-butyl 3-hydroxy-3-(5-((3-nitro-6-phenylpyridin-2-yl)amino)pyridin-2- yl)pyrrolidine-l-carboxylate

[0474]

[0231] A mixture of tert-butyl 3-(5-aminopyridin-2-yl)-3-hydroxypyrrolidine-l-carboxylate (260 mg, 0.93 mmol), 2-chloro-3-nitro-6-phenylpyridine (221 mg, 0.93 mmol), Pd2(dba)s (86 mg, 0.09 mmol), RuPhos (133 mg, 0.28 mmol) and CS2CO3 (913 mg, 2.79 mmol) in dioxane (20 mL) was stirred at

[0475] 90 °C for 16 h. After completion of the reaction, the mixture was quenched with water (20 mL) and extracted with EA (30 mL x 3). The combined organic phases were washed with saturated brine (30 mL) and dried over Na2SC>4 and concentrate under reduced pressure. The residue was purified by column chromatography (SiC 0-50% EA in PE) to afford tert-butyl 3-hydroxy-3-(5-((3-nitro-6- phenylpyridin-2-yl)amino)pyridin-2-yl)pyrrolidine-l-carboxylate (360 mg, 81% yield) as a orange solid. LCMS: m / z, 478.5 [(M+H)+],

[0476]

[0232] Step 5. 3-(5-(2-(2-aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin-3-yl)pyridin-2- yl)pyrrolidin-3-ol

[0477] 58

[0478] MEl\56585648.vl 141039-01220

[0479]

[0233] A mixture of tert-butyl 3-hydroxy-3-(5-((3-nitro-6-phenylpyridin-2-yl)amino)pyridin-2- yl)pyrrolidine-l -carboxylate (300 mg, 0.63 mmol), 2-aminonicotinaldehyde (115 mg, 0.94 mmol) and sodium dithionite (547 mg, 3.14 mmol) in DMSO (7 mL) and MeOH (7 mb) was stirred at 120 °C for 16 h and 140 °C for 8 h. The mixture was diluted with water (5 mL), extracted with EA (20 mL x 3). The organic layer was dried over Na2SC>4 and evaporated under reduced pressure. The residue was purified by reversed phase column (MeCN / water / lOMm NH4HCO3) to give TM (160 mg, 57% yield) as a solid. 5 mg was re-purified by prep-HPLC (MeCN / water / 0.1% FA) to get 3-(5-(2-(2- aminopyridin-3 -yl)-5 -phenyl-3H-imidazo[4,5 -b]pyridin-3 -yl)pyridin-2-yl)pyrrolidin-3 -ol ( 1.40 mg, 1.0 eq. FA salt) as a light- solid. 'H NMR (400 MHz, MeOD) 5 8.71 (d, J= 2.2 Hz, 1H), 8.23 (d, J = 8.4 Hz, 1H), 8.07 - 8.03 (m, 4H), 7.97 (t, J= 7.6 Hz, 2H), 7.46 - 7.37 (m, 4H), 6.58 (dd, J= 7.6, 5.0 Hz, 1H), 4.59 (s, 2H), 3.82 (d,J= 11.8 Hz, 1H), 3.68 - 3.57 (m, 2H), 3.46 (dd,J= 11.8, 1.4 Hz, 1H), 2.65 - 2.57 (m, 1H), 2.36 - 2.29 (m, 1H). LCMS: m / z, 450.2 [(M+H)+],

[0480]

[0234] Intermediate 13. 3-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin-3- yl)phenyl)-4,4-difluoropyrrolidin-3-ol

[0481]

[0235] Step 1. ((l-(4-bromophenyl)vinyl)oxy)trimethylsilane

[0482]

[0236] A solution of TMSOTf (7.36 g, 33.17 mmol) in DCM (10 mL) was added dropwise to a solution of l-(4-bromophenyl)ethan-l-one (6.0 g, 30.14 mmol) and TEA (6.70 g, 66.33 mmol) in DCM (50 mL) at 0 °C. The mixture was stirred at 0-5 °C for 30 mins, and then it was allowed to warm to RT and stirred for 1 h. Then it was concentrated under reduced pressure at RT. The residue was purified by column chromatography (SiC>2, 0-1% EA in PE) to afford ((l-(4- bromophenyl)vinyl)oxy)trimethylsilane (4.8 g, 59% yield) as a colorless oil liquid. ’H NMR (400 MHz, CDCh) 57.47 - 7.42 (m, 4H), 4.90 (d,J= 1.8 Hz, 1H), 4.44 (d, J= 1.8 Hz, 1H), 0.26 (s, 9H).

[0483]

[0237] Step 2. 3-bromo-l-(4-bromophenyl)-2,2-difluoropropan-l-one

[0484] 59

[0485] MEl\56585648.vl 141039-01220

[0486]

[0238] The ((l-(4-bromophenyl)vinyl)oxy)trimethylsilane (800 mg, 2.95 mmol) was transferred into a reaction tube, the tube was evacuated and fdled with argon. Then, MeCN (10 mb), MesSiCF2Br (903 mg, 4.44 mmol) and BmNBr (191 mg, 0.59 mmol) were successively added at RT. The mixture was stirred for 1.5 h at 80 °C, and then cooled to RT. NBS (683 mg, 3.84 mmol) was added, and the mixture was stirred for 10 mins at RT. For the workup, the mixture was diluted with water (20 mb) and aq. phase was extracted with EA (20 mb x 3). The combined organic layers were fdtered through Na2SC>4, concentrated under vacuum, and the residue was purified by column chromatography (SiCE, 0-3% EA in PE) to afford 3-bromo-l-(4-bromophenyl)-2,2-difluoropropan-l-one (400 mg, 41% yield) as a colorless crystals. 'H NMR (400 MHz, CDC13) 5 7.97 (d, J= 8.6 Hz, 2H), 7.70 - 7.65 (m, 2H), 3.90 (t, J= 14.6 Hz, 2H).

[0487]

[0239] Step 3. 2-(2-bromo-l,l-difluoroethyl)-2-(4-bromophenyl)oxirane

[0488]

[0240] In a Schlenk tube, MeOTf (691 mg, 4.21 mmol) was added dropwise by a syringe to a solution of tetrahydrothiophene (355 mg, 4.02 mmol) in DCM (3 mb) at -10 °C. The mixture was allowed to warm to RT over 40 mins. Then, all volatiles were evaporated under vacuum, the tube was filled with argon followed by addition of THF (2 mb). The mixture was cooled to -78 °C, and a solution of 2.5 M n-BuLi (1.61 mb, 4.02 mmol) was added dropwise, and the mixture was stirred for 20 mins at -78 °C. A solution of 3-bromo-l-(4-bromophenyl)-2,2-difluoropropan-l-one (1.2 g, 3.66 mmol) in THF (2 mb) was added. The mixture was stirred for 20 mins at -78 °C and then was allowed to warm to RT over 30 mins. For the workup, all volatiles were evaporated under vacuum, and the residue was purified by column chromatography (SiC 0-4% EA in PE) to afford 2-(2-bromo-l,l- difluoroethyl)-2-(4-bromophenyl)oxirane (1.0 g, 81% yield) as a colorless oil liquid. ’H NMR (400 MHz, CDCh) 5 7.54 (d, J= 8.2 Hz, 2H), 7.44 (d, J= 8.2 Hz, 2H), 3.61 - 3.39 (m, 3H), 2.89 - 2.84 (m, 1H).

[0489]

[0241] Step 4. l-benzyl-3-(4-bromophenyl)-4,4-difluoropyrrolidin-3-ol

[0490]

[0242] The reaction tube with a screw cap was charged with 2-(2-bromo-l,l-difluoroethyl)-2-(4- bromophenyl)oxirane (630 mg, 1.85 mmol), phenyhnethanamine (297 mg, 2.78 mmol), K2CO3 (639 mg, 4.63 mmol), and DMF (2 mb), and the mixture was stirred at 75 °C for 1 h. The mixture was cooled to RT, water (10 mb) was added, and the aq. phase was extracted with EA (20 mL x 3). The combined organic layers were filtered through Na2SC>4 and concentrated under vacuum, and the residue was purified by column chromatography (SiC 0-20% EA in PE) to afford l-benzyl-3-(4- bromophenyl)-4,4-difluoropyrrolidin-3-ol (600 mg, 88% yield) as a colorless oil liquid. LCMS: m / z, 368.3 [(M+H)+],

[0491]

[0243] Step 5. tert-butyl (4-(l-benzyl-4,4-difluoro-3-hydroxypyrrolidin-3-yl)phenyl)carbamate

[0492]

[0244] A mixture of l-benzyl-3-(4-bromophenyl)-4,4-difluoropyrrolidin-3-ol (830 mg, 2.25 mmol), NH2B0C (793 mg, 6.77 mmol), Pd2(dba)3 (207 mg, 0.23 mmol), RuPhos (316 mg, 0.68 mmol) and CS2CO3 (2.21 g, 6.77 mmol) in dioxane (15 mL) was stirred at 110 °C for 18 h in MW. After

[0493] 60

[0494] MEl\56585648.vl 141039-01220 completion of the reaction, quench with water (20 mL). The separated aq. phase was extracted with EA (30 mL x 3). The combined organic phases were washed with saturated brine (30 mL) and dried over Na2SC>4 and concentrate under reduced pressure. The residue was purified by column chromatography (SiC>2, 0-23% EA in PE) to afford tert-butyl (4-(l-benzyl-4,4-difluoro-3- hydroxypyrrolidin-3-yl)phenyl)carbamate (820 mg, 90% yield) as a oil liquid. LCMS: m / z, 405.3 [(M+H)+

[0495]

[0245] Step 6. 3-(4-aminophenyl)-l-benzyl-4,4-difluoropyrrolidin-3-ol

[0496]

[0246] A mixture of tert-butyl (4-(l-benzyl-4,4-difluoro-3-hydroxypyrrolidin-3-yl)phenyl)carbamate (500 mg, 1.24 mmol) in TFA (1 mL) and DCM (3 mL) was stirred at RT for 1 h. Then the mixture was diluted with H2O (10 mL) and adjusted pH to 9 with TEA. The remaining mixture was extracted with 5% MeOH in DCM (20 mL x 3). The combined organic phases were dried over Na2SC>4 and concentrated to afford 376 mg crude 3-(4-aminophenyl)-l-benzyl-4,4-difluoropyrrolidin-3-ol as a oil liquid, which was used directly without further purification. LCMS: m / z, 305.2 [(M+H)+],

[0497]

[0247] Step 7. l-benzyl-4,4-difluoro-3-(4-((3-nitro-6-phenylpyridin-2- yl)amino)phenyl)pyrrolidin-3-ol

[0498]

[0248] A mixture of 3-(4-aminophenyl)-l-benzyl-4,4-difluoropyrrolidin-3-ol (376 mg, 1.24 mmol), 2-chloro-3-nitro-6-phenylpyridine (290 mg, 1.24 mmol), Pd2(dba)s (114 mg, 0.12 mmol), RuPhos (174 mg, 0.37 mmol) and CS2CO3 (1.21 g, 3.72 mmol) in dioxane (10 mL) was stirred at 90 °C for 3 h. After completion of the reaction, quench with water (10 mL). The separated aq. phase was extracted with EA (20 mL x 3). The combined organic phases were washed with saturated brine (20 mL) and dried over Na2SC>4 and concentrate under reduced pressure. The residue was purified by column chromatography (SiC>2, 0-23% EA in PE) to afford l-benzyl-4,4-difluoro-3-(4-((3-nitro-6- phenylpyridin-2-yl)amino)phenyl)pyrrolidin-3-ol (500 mg, 80% yield over 2 steps) as a orange-red solid. 'H NMR (400 MHz, DMSO-6) 5 10.15 (s, 1H), 8.62 (d, J= 8.8 Hz, 1H), 8.11 (dd, J = 6.6, 3.2 Hz, 2H), 7.77 (d, J= 8.8 Hz, 2H), 7.63 - 7.53 (m, 6H), 7.42 - 7.34 (m, 4H), 7.28 (t, J= 6.8 Hz, 1H), 6.15 (s, 1H), 3.85 - 3.76 (m, 2H), 3.41 (dd, J = 10.4, 2.6 Hz, 1H), 3.22 - 3.12 (m, 2H), 3.01 (dd, J = 10.6, 2.8 Hz, 1H). LCMS: m / z, 503.3 [(M+H)+],

[0499]

[0249] Step 8. (3-(5-(2-(2-aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin-3-yl)pyridin- 2-yl)-3-hydroxypyrrolidin-l-yl)(3-hydroxy-4,7-dihydroisoxazolo[5,4-c]pyridin-6(5H)- yl)methanone

[0500]

[0250] A mixture of 1 -benzyl -4, 4-difluoro-3 -(4-((3 -nitro-6-phenylpyridin-2 - yl)amino)phenyl)pyrrolidin-3-ol (40 mg, 0.08 mmol), 2-aminonicotinaldehyde (15 mg, 0.12 mmol), sodium dithionite (69 mg, 0.40 mmol) in DMSO (2 mL) and MeOH (2 mL) was stirred at 120 °C for 1 h and 140 °C for 7 h, then 125 °C for 15 h. The mixture was diluted with water (5 mL), extracted with EA (10 mL x 3) and dried over Na2SO4. The organic layer was evaporated under reduced pressure. The residue was purified by column chromatography (SiO2, 0-4% MeOH in DCM) to afford TM (30

[0501] 61

[0502] MEl\56585648.vl 141039-01220 mg, crude), which 10 mg was re-purified by prep-HPLC (MeCN / water / lOmM NH4HCO3) to get 2.65 mg (3 -(5 -(2-(2-aminopyridin-3 -y 1) -5 -phenyl-3H-imidazo [4,5 -b]pyridin-3 -yl)pyridin-2-yl)-3 - hydroxypyrrolidin-l-yl)(3 -hydroxy-4, 7-dihydroisoxazolo [5 ,4-c]pyridin-6(5H)-yl)methanone as a solid fortesting. 'H NMR (400 MHz, DMSO-tL) 5 8.28 (d, J= 8.4 Hz, 1H), 8.04 - 7.98 (m, 4H), 7.73 (d, J= 8.6 Hz, 2H), 7.51 - 7.45 (m, 4H), 7.42 - 7.34 (m, 5H), 7.28 (t, J= 7.0 Hz, 1H), 7.16 (dd, J = 7.8, 1.8 Hz, 1H), 6.97 (s, 2H), 6.37 (dd, J= 7.8, 4.8 Hz, 1H), 6.33 (s, 1H), 3.80 (s, 2H), 3.44 (dd, J = 10.4, 2.4 Hz, 1H), 3.22 - 3.14 (m, 2H), 3.01 (dd, J= 10.6, 2.6 Hz, 1H). LCMS: m / z, 575.2 [(M+H)+],

[0251] Step 9. 3-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl)- 4,4-difluoropyrrolidin-3-ol

[0503]

[0252] 3 -(4-(2-(2-aminopyridin-3 -yl) -5 -phenyl-3H-imidazo [4,5 -b]pyridin-3 -yl)phenyl)- 1 -benzyl -4,4- difluoropyrrolidin-3-ol (10 mg, 0.02 mmol) and HCOONH4 (300 mg, 4.76 mmol) were dissolved in MeOH (5 mb). To the mixture was added 10% Pd / C (26 mg). The mixture was stirred at RT for 2 h. The Pd / C was remove by fdtration and fdtrate was purified by prep-HPLC (MeCN / water / lOmM NH4HCO3) to afford 3-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin-3- yl)phenyl)-4,4-difhioropyrrolidin-3-ol (2.18 mg, 26% yield) as a solid. ’H NMR (400 MHz, DMSO- d6) 5 8.28 (d, J= 8.4 Hz, 1H), 8.05 - 7.98 (m, 4H), 7.71 (d, J= 8.4 Hz, 2H), 7.53 - 7.46 (m, 4H), 7.40 (t, J= 7.4 Hz, 1H), 7.20 (dd, J= 7.6, 1.8 Hz, 1H), 6.93 (s, 2H), 6.40 (dd, J= 7.6, 4.8 Hz, 1H), 6.26 (s, 1H), 3.58 (d, J= 12.2 Hz, 1H), 3.51 - 3.40 (m, 1H), 3.22 (q, J= 12.4 Hz, 2H). NH was not observed.

[0504] LCMS: m / z, 485.0 [(M+H)+],

[0505]

[0253] Intermediate 14. 2-(2-fluoro-6-nitrophenyl)-5-phenyl-3-(4-(pyrrolidin-3-yl)phenyl)-3H-

[0506]

[0254] Step 1. tert-butyl 3-(4-((3-amino-6-phenylpyridin-2-yl)amino)phenyl)pyrrolidine-l- carboxylate

[0507]

[0255] A mixture of tert-butyl 3-(4-((3-amino-6-chloropyridin-2-yl)amino)phenyl)pyrrolidine-l- carboxylate (200 mg, 0.51 mmol), phenylboronic acid (94 mg, 0.77 mmol), Pd(dppf)C12 (75 mg, 0.10 mmol), K2CO3 (142 mg, 1.03 mmol) in 1,4-dioxane (5 mL) and H2O (1 mL) was stirred at 100 °C under microwave under N2 atmosphere for 3 h. The mixture was diluted with water (20 mL) and extracted with EA (20 mL x 2). The combined organic layer was dried over Na2SC>4 and concentrated. The residue was purified by column chromatography (SiCK 0-50% EA in PE) to afford tert-butyl 3- (4-((3-amino-6-phenylpyridin-2-yl)amino)phenyl)pyrrolidine-l -carboxylate (200 mg, 90% yield) as solid. 'H NMR (400 MHz, DMSO-t / .) 5 7.92 (d, J= 7.4 Hz, 2H), 7.84 (s, 1H), 7.74 (d, J= 8.4 Hz, 2H), 7.39 (t, J= 7.6 Hz, 2H), 7.27 - 7.19 (m, 4H), 6.97 (d, J= 7.8 Hz, 1H), 5.26 (s, 2H), 3.69 (dd, J =

[0508] 62

[0509] MEl\56585648.vl 141039-01220

[0510] 10.0, 7.6 Hz, 1H), 3.47 (t, J = 9.2 Hz, 1H), 3.26 (s, 2H), 3.15 (t, J= 9.8 Hz, 1H), 2.17 (s, 1H), 1.98 - 1.88 (m, 1H), 1.42 (d, J= 3.8 Hz, 9H). LCMS: m / z, 431.2 [(M+H)+],

[0511]

[0256] Step 2. tert-butyl 3-(4-(2-(2-fluoro-6-ntrophenyl)-5-phenyl-3H-imidazo[4,5-b]pyridin-3- yl)phenyl)pyrrolidine-l-carboxylate

[0512]

[0257] A mixture of tert-butyl 3-(4-((3-amino-6-phenylpyridin-2-yl)amino)phenyl)pyrrolidine-l- carboxylate (200 mg, 0.46 mmol), 2-fluoro-6-nitrobenzaldehyde (78 mg, 0.46 mmol) in AcOH (4 mL) was stirred at 130 °C under N2 atmosphere for 2 h. The mixture was concentrated to give a residue. Then the residue was dissolved in DCM (5 mL) and then to the mixture was added (Boc)2O (91 mg, 0.42 mmol) and TEA (1 mL ). The resulting mixture was stirred at RT for 3 h. The mixture was diluted with water (20 mL) and extracted with DCM (20 mL x 2). The combined organic layer was dried over Na2SC>4 and concentrated. The residue was purified by column chromatography (SiCK 0- 50% EA in PE) to afford tert-butyl 3-(4-(2-(2-fluoro-6-nitrophenyl)-5-phenyl-3H-imidazo[4,5- b]pyridin-3-yl)phenyl)pyrrolidine-l -carboxylate (180 mg, 67% yield) as solid. ’H NMR (400 MHz, CDCh) 58.25 (d, J= 8.4 Hz, 1H), 8.05 - 7.98 (m, 3H), 7.88 (d, J= 8.4 Hz, 1H), 7.69 (td, J= 8.3, 5.4 Hz, 1H), 7.49 - 7.40 (m, 6H), 7.30 (d, J= 8.4 Hz, 2H), 3.90 - 3.73 (m, 1H), 3.60 (s, 1H), 3.46 - 3.36 (m, 2H), 3.32 (dd, J= 17.2, 7.4 Hz, 1H), 2.33 - 2.25 (m, 1H), 1.98 (dd, J= 20.6, 10.1 Hz, 1H), 1.48 (s, 9H). LCMS: m / z, 580.1 [(M+H)+],

[0513]

[0258] Step 3. 2-(2-fluoro-6-nitrophenyl)-5-phenyl-3-(4-(pyrrolidin-3-yl)phenyl)-3H- imidazo[4,5-b]pyridine

[0514]

[0259] To a solution of tert-butyl 3-(4-(2-(2-fhioro-6-nitrophenyl)-5-phenyl-3H-imidazo[4,5- b]pyridin-3-yl)phenyl)pyrrolidine-l -carboxylate (180 mg, 0.31 mmol) in DCM (5 mL) was added TLA (2 mL). The mixture was stirred for 3 h at RT. The mixture was concentrated under reduce pressure. The residue was purified by column chromatography (SiCK 0-20% MeOH in DCM) to afford 2-(2-fluoro-6-nitrophenyl)-5-phenyl-3-(4-(pyrrolidin-3-yl)phenyl)-3H-imidazo[4,5-b]pyridine (140 mg, 94% yield) as solid. 1H NMR (400 MHz, DMSO-d6) 5 8.33 (d, J = 8.4 Hz, 1H), 8.12 (d, J = 8.1 Hz, 1H), 8.05 (t, J = 8.7 Hz, 3H), 7.94 - 7.87 (m, 1H), 7.80 (t, J = 8.6 Hz, 1H), 7.50 (t, J = 7.4 Hz, 2H), 7.44 (d, J = 7.7 Hz, 5H), 3.17 (d, J = 4.4 Hz, 2H), 3.09 (s, 2H), 2.98 (dd, J = 18.2, 7.8 Hz, 1H), 2.80 - 2.72 (m, 1H), 2.22 (d, J = 7.8 Hz, 1H), 1.75 (dd, J = 12.4, 8.6 Hz, 1H). LCMS: m / z, 480.0 [(M+H)+].

[0515]

[0260] Intermediate 15. 3-[4-fluoro-l-(4-pyrrolidin-3-ylphenyl)-6- (trifluoromethyl)benzimidazol-2-yl]pyridin-2-amine

[0516] 63

[0517] MEl\56585648.vl 141039-01220

[0518]

[0261] Step 1. 2-[4-(l-tert-butoxycarbonylpyrrolidin-3-yl)anilino]-6-fluoro-4- (trifluoromethyl)benzoic acid

[0519]

[0262] To a solution of 2,6-difluoro-4-(trifluoromethyl)benzoic acid (2 g, 8.85 mmol) and tert-butyl 3-(4-aminophenyl)pyrrolidine-l-carboxylate (2.32 g, 8.85 mmol) in THF (30 mL) was added LiHMDS (1.0 M in THF, 26.54 mL, 26.54 mmol) slowly at 0°C under N2. Then the mixture was stirred at 25°C for 16 hr. The mixture was quenched with sat. NH4CI solution (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic phase was dried over anhydrous Na2SC>4, filtered and concentrated. The residue was purified by flash chromatography on silica gel (MeOH in DCM = 0-5%) to give 2-[4-(l-tert-butoxycarbonylpyrrolidin-3-yl)anilino]-6-fluoro-4-(trifluoromethyl) benzoic acid (3.5 g, 7.47 mmol, 84.54% yield) as oil. 'H NMR (400 MHz, DMSO-6) 5 = 9.92 (s, 1H), 7.26 (d, J= 8.0 Hz, 2H), 7.10 (d, J= 8.0 Hz, 3H), 6.78 (d, J= 9.6 Hz, 1H), 3.69 (dd, J= 7.6, 10.4 Hz, 1H), 3.51-3.41 (m, 3H), 3.13 (t, J= 9.6 Hz, 1H), 2.27-2.12 (m, 1H), 2.06-1.82 (m, 1H), 1.41 (d, J = 4.8 Hz, 9H).19F NMR (376.5 MHz, DMSO-t / ,.) 5 = -61.631, -108.609 ppm.

[0520]

[0263] Step 2. tert-butyl 3-[4-[4-fluoro-2-oxo-6-(trifluoromethyl)-3H-benzimidazol-l- yl]phenyl]pyrrolidine-l-carboxylate

[0521]

[0264] To a stirred solution of 2-[4-(l-tert-butoxycarbonylpyrrolidin-3-yl)anilino]-6-fluoro-4- (trifhroromethyl)benzoic acid (1 g, 2.13 mmol) and TEA (648.04 mg, 6.40 mmol, 891.39 pL) in THF (20 mL) was added DPPA (1.17 g, 4.27 mmol, 921.54 pL) slowly. Then the solution was stirred at 60°C for 2 hr. The mixture was diluted with water (20 mL) and extracted with EtOAc (10 mL x 3). The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated directly. The residue was purified by flash chromatography on silica gel (MeOH in DCM = 0-1%) to give tertbutyl 3-[4-[4-fluoro-2-oxo-6-(trifluoromethyl)-3H-benzimidazol- 1 -yl]phenyl]pyrrolidine- 1 - carboxylate (750 mg, 1.61 mmol, 75.48% yield) as a solid. ’H NMR (400 MHz, CDCh) 5 = 9.41 (s, 1H), 7.51-7.38 (m, 4H), 7.20 (d, J= 10.0 Hz, 1H), 7.08 (s, 1H), 3.99-3.75 (m, 1H), 3.74-3.53 (m, 1H), 3.53-3.34 (m, 3H), 2.43-2.25 (m, 1H), 2.10-1.98 (m, 1H), 1.49 (s, 9H).19F NMR (376.5 MHz, CDCh) 5 = -61.228, -132.151 ppm.

[0522] 64

[0523] MEl\56585648.vl 141039-01220

[0524]

[0265] Step 3. 2-chloro-4-fluoro-l-(4-pyrrolidin-3-ylphenyl)-6-(trifluoromethyl)benzimidazole

[0525]

[0266] A solution of tert-butyl 3-(4-(4-fhioro-2-oxo-6-(trifluoromethyl)-2,3-dihydro-lH- benzo[d]imidazol-l-yl)phenyl)pyrrolidine-l -carboxylate (700 mg, 1.50 mmol) in POCI3 (5 mL) was stirred at 100°C for 12 h under N2. After cooled to 25°C, the mixture was added into water (20 mL) dropwise slowly. Sat.NaHCOs (80 mL) was added adjust to pH=8, extracted with EtOAc (40 mL x 2), the organic layer was dried over anhydrous Na2SC>4, filtered and concentrated. The residue was twice purified by flash chromatography on silica gel (MeOH in DCM = 0-20%) to give 2-chloro-4- fluoro-l-(4-pyrrolidin-3-ylphenyl)-6-(trifluoromethyl)benzimidazole (100 mg, 260.57 pmol, 17.33% yield) as oil. 'H NMR (400 MHz, CDCh) 5 = 10.30 (br s, 1H), 7.54 (d, J= 8.4 Hz, 2H), 7.40 (d, J= 8.0 Hz, 2H), 7.28 (s, 1H), 7.21 (s, 1H), 3.81 (dd, J= 8.8, 11.6 Hz, 1H), 3.68-3.59 (m, 2H), 3.46-3.36 (m, 1H), 3.36-3.29 (m, 1H), 2.58-2.46 (m, 1H), 2.25-2.10 (m, 1H).19F NMR (376.5 MHz, CDCh) 5 = -61.170, -124.719 ppm.

[0526]

[0267] Step 4. 3-[4-fluoro-l-(4-pyrrolidin-3-ylphenyl)-6-(trifluoromethyl)benzimidazol-2- yl]pyridin-2-a mine

[0527]

[0268] To a solution of 2-chloro-4-fluoro-l-(4-pyrrolidin-3-ylphenyl)-6- (trifhioromethyl)benzimidazole (50 mg, 130.29 pmol) and 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan- 2-yl)pyridin-2-amine (43.01 mg, 195.43 pmol) in dioxane (1 mL) and H2O (0.1 mL) were added Pd(PPh3)2Cl2(9.14 mg, 13.03 pmol) and CS2CO3 (127.35 mg, 390.86 pmol) under N2. The mixture was stirred at 100°C for 1 h. The mixture was concentrated. The residue was purified by flash chromatography on silica gel (MeOH in DCM =0-10%) and prep-HPLC (column: Welch Xtimate C18 150*30mm*5pm; mobile phase: [water (FA)-ACN]; gradient: 19%-49% B over 9 min) to give 3-[4- fluoro- l-(4-pyrrolidin-3-ylphenyl)-6-(trifluoromethyl)benzimidazol-2-yl]pyridin-2 -amine (20 mg, 42.64 pmol, 32.73% yield, 0.6FA) as a solid. 'H NMR (400 MHz, DMSO-6) 5 = 8.40 (s, 0.6H, FA), 8.01 (dd, J = 2.0, 5.2 Hz, 1H), 7.61 (d,J= 10.0 Hz, 1H), 7.51 (d, J= 8.4 Hz, 2H), 7.45 (d, J = 8.4 Hz, 2H), 7.34-7.17 (m, 2H), 6.78 (s, 2H) 6.44 (dd, J= 4.8, 7.6 Hz, 1H), 3.42-3.40 (m, 1H), 3.37-3.35 (m, 1H), 3.21-3.16 (m, 1H), 3.09-3.03 (m, 1H), 2.94-2.85 (m, 1H), 2.38-2.21 (m, 1H), 1.92-1.74 (m, 1H).19F NMR (376.5 MHz, DMSO-6) 5 = -59.226, -126.598 ppm. LCMS: m / z 442.3 [M+H]+

[0528]

[0269] Intermediate 16. tert-butyl 3-[4-[2-(2-amino-3-pyridyl)-6-pyrrolidin-l-yl-imidazo[4,5- b]pyridin-3-yl]phenyl]pyrrolidine-l-carboxylate

[0529] 65

[0530] MEl\56585648.vl 141039-01220

[0531]

[0270] Step 1. tert-butyl 3-[4-[2-(2-amino-3-pyridyl)-6-pyrrolidin-l-yl-imidazo[4,5-b]pyridin-3- yl]phenyl]pyrrolidine-l-carboxylate

[0532]

[0271] A mixture of tert-butyl 3-[4-[2-(2-amino-3-pyridyl)-6-bromo-imidazo[4,5-b]pyridin-3- yl]phenyl]pyrrolidine-l -carboxylate (300 mg, 560.29 pmol), pyrrolidine (199.24 mg, 2.80 mmol, 233.85 pL), CS2CO3 (547.66 mg, 1.68 mmol) and l,3-bis[2,6-bis(l-propylbutyl)phenyl]-4,5-dichloro- 2H-imidazol-l-ium-2-ide;3-chloropyridine;dichloropalladium (54.50 mg, 56.03 pmol, Cas no.

[0533] 1814936-54-3) in dioxane (3 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 90°C for 12 h under N2 atmosphere. The reaction mixture was diluted with EtOAc (20 mL) and washed with brine (10 mL x 3). The combined organic layers were dried over anhydrous Na2SC>4, filtered and concentrated. The crude product was purified by flash chromatography on silica gel (EA in PE = 0 - 100%) to give tert-butyl 3-[4-[2-(2-amino-3-pyridyl)-6-pyrrolidin-l-yl- imidazo[4,5-b]pyridin-3-yl]phenyl]pyrrolidine-l-carboxylate (290 mg, 551.71 pmol, 98.47% yield) as a solid. LCMS: m / z 526.2 [M+H]+

[0534]

[0272] Intermediate 17. tert-butyl 3-(4-(2-(2-aminopyridin-3-yl)-6-methyl-3H-imidazo[4,5- b]pyridin-3-yl)phenyl)pyrrolidine-l-carboxylate

[0535]

[0273] To a solution of tert-butyl 3-[4-[2-(2-amino-3-pyridyl)-6-bromo-imidazo[4,5-b]pyridin-3- yl]phenyl]pyrrolidine-l -carboxylate (150 mg, 280.15 pmol) in a mixture of dioxane (1.5 mL) and H2O (0.5 mL) were added methylboronic acid (33.54 mg, 560.29 pmol), K2CO3 (77.44 mg, 560.29 pmol) and Pd(dppf)C12 (20.50 mg, 28.01 pmol) After the mixture was degassed and purged with N2 for 3 times, it was stirred at 100°C for 16 hr under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (MeOH in DCM = 0-5% ) to give tert-butyl 3-[4-[2-(2-amino-3-pyridyl)-6-methyl- imidazo[4,5-b]pyridin-3-yl]phenyl]pyrrolidine-l-carboxylate (90 mg, 191.26 pmol, 68.27% yield)as a solid. LCMS: m / z 471.3 [M+H-100]+

[0536]

[0274] Intermediate 18. tert-butyl-3-[4-[2-(2-amino-3-pyridyl)-6-cyclopropyl-imidazo[4,5- b]pyridin-3-yl]phenyl]pyrrolidine-l-carboxylate

[0537] 66

[0538] MEl\56585648.vl 141039-01220

[0539]

[0275] Step 1. tert-butyl-3-[4-[2-(2-amino-3-pyridyl)-6-cyclopropyl-imidazo[4,5-b]pyridin-3- yl]phenyl]pyrrolidine-l-carboxylate

[0540]

[0276] To a solution of tert-butyl-3-[4-[2-(2-amino-3-pyridyl)-6-bromo-imidazo[4,5-b]pyridin-3- yl]phenyl]pyrrolidine-l-carboxylate (500 mg, 933.82 pmol) and potassium;cyclopropyl(trifluoro)boranuide (1.38 g, 9.34 mmol) in dioxane (20 mL) were added [2-(2- aminophenyl)phenyl]-methylsulfonyloxypalladium;DCM;tricyclohexylphosphane (205.93 mg, 280.15 pmol, Cas no. 1353658-81-7) and CS2CO3 (3 M in H2O, 1.56 mL) at 25°C. Then the mixture was degassed and purged with N2for 3 times, and then the mixture was stirred at 100°C under N2for 12 h. After cooling to rt, the resulting mixture was filtered and the filter cake was washed with DCM (50mL) and EtOAc (50 mL) at 25 °C. Then the combined mixture was concentrated under reduced pressure to give a residue. H2O (100 mL) was added to the residue. The resulting mixture was extracted with EtOAc (50 mL x 3). The combined organic phase was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel (MeOH in DCM= 0 - 10 %) to give tert-butyl-3-[4-[2-(2-amino-3- pyridyl)-6-cyclopropyl-imidazo[4,5-b]pyridin-3-yl]phenyl]pyrrolidine-l-carboxylate (450 mg, 906. 16 pmol, 97.04% yield) as a solid. 'H NMR (400 MHz, DMSO-6) 5 = 8.19 (s, 1H), 7.98 (d, J= 3.6 Hz, 1H), 7.81 (s, 1H), 7.47-7.32 (m, 4H), 7.18 (d, J= 7.2 Hz, 1H), 7.03-6.88 (m, 2H), 6.44-6.36 (m, 1H), 3.78-3.72 (m, 1H), 3.55-3.39 (m, 3H), 3.22-3.17 (m, 1H), 2.28-2.20 (m, 1H), 2.16-2.06 (m, 1H), 2.03-1.95 (m, 1H), 1.41 (s, 9H), 0.46-0.38 (m, 2H), 0.35-0.28 (m, 2H).

[0541]

[0277] Intermediate 19 and Intermediate 20. tert-butyl (3R)-3-[4-[2-(2-amino-3-pyridyl)-5- chloro-imidazo [4,5-b]pyridin-3-yl] phenyl] pyrrolidine-l-carboxylate, tert-butyl (3S)-3- [4- [2-(2- amino-3-pyridyl)-5-chloro-imidazo[4,5-b]pyridin-3-yl]phenyl]pyrrolidine-l-carboxylate

[0542]

[0278] The tert-butyl 3-[4-[2-(2-amino-3-pyridyl)-5-chloro-imidazo[4,5-b]pyridin-3- yl]phenyl]pyrrolidine-l-carboxylate (8 g, 16.29 mmol) was purified by prep-HPLC (column: DAICEL CHIRALPAK AD (250 mm x 30 mm, 10 pm); mobile phase: [CO2-ACN / i-PrOH (0.1%

[0543] 67

[0544] MEl\56585648.vl 141039-01220

[0545] NH3H2O)]; B%:50%, isocratic elution mode) to give tert-butyl (3R)-3-[4-[2-(2-amino-3-pyridyl)-5- chloro-imidazo[4,5-b]pyridin-3-yl]phenyl]pyrrolidine-l-carboxylate (3.5 g, 7.13 mmol, 87.50% yield) and tert-butyl (3 S)-3 -[4- [2-(2-amino-3 -pyridyl)-5 -chloro-imidazo [4,5 -b]pyridin-3 - yl]phenyl]pyrrolidine-l-carboxylate (2.8 g, 5.70 mmol, 70.00% yield) as a solid. Assigned stereochemical configurations of products are relative, not absolute. Peak 1, Intermediate 19, LCMS: m / z 435.0 [M-C4H7]+Peak 2, Intermediate 20, LCMS: m / z 435.0 [M-C4H7]+

[0546]

[0279] Intermediate 21. tert-butyl 3-[4-[2-(2-amino-3-pyridyl)-6-(trifluoromethyl)benzimidazol- l-yl]phenyl]pyrrolidine-l-carboxylate

[0547]

[0280] Step 1. tert-butyl 3-[4-[2-nitro-5-(trifluoromethyl)anilino]phenyl]pyrrolidine-l- carboxylate

[0548]

[0281] To a solution of tert-butyl 3-(4-aminophenyl)pyrrolidine-l -carboxylate (1.38 g, 5.26 mmol,) in anhydrous THF (10 mL) was added dropwise LiHMDS (1 M in THF, 9.56 mL) at -78°C under N2 over 0.5 h. This mixture was stirred at -78°C for 0.5 h. Then 2-fluoro-l-nitro-4-

[0549] (trifluoromethyl)benzene (1 g, 4.78 mmol) in THF (5 mb) was added at -78°C under N2. This mixture was stirred at -78°C for 0.5 h. The reaction mixture was poured into water (50 ml) at 0°C. The aq. layer was extracted with EtOAc (10 ml x 3). The combined organic layers were washed with brine and dried over Na2SO4, filtered and concentrated to afford tert-butyl 3-[4-[2-nitro-5- (trifluoromethyl)anilino]phenyl]pyrrolidine-l -carboxylate (2 g, 4.43 mmol, 92.64% yield) as oil, which was used into next step without any purification. LCMS: m / z 474. 1[M+Na]+

[0550]

[0282] Step 2. tert-butyl 3-[4-[2-amino-5-(trifluoromethyl)anilino]phenyl]pyrrolidine-l- carboxylate

[0551]

[0283] To a solution of tert-butyl 3-[4-[2-nitro-5-(trifluoromethyl)anilino]phenyl]pyrrolidine-l- carboxylate (2 g, 4.43 mmol) in EtOH (20 mL) and H2O (4 mL) were added NELC1 (1.18 g, 22.15 mmol) and Fe (742.23 mg, 13.29 mmol) at 25°C. This mixture was stirred at 80°C for 2 h. The reaction mixture was concentrated under reduced pressure to remove EtOH, then slowly added to H2O (100 mL) at 25°C, then extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (lOOmL) and dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford tert-butyl 3-[4-[2-amino-5-(trifluoromethyl)anilino]phenyl]pyrrolidine-l- carboxylate (1.8 g, 4.27 mmol, 96.40% yield) as oil, which was used into the next step without further purification. LCMS: m / z 444.1 [M+Na]+

[0552]

[0284] Step 3. tert-butyl 3-[4-[2-(2-amino-3-pyridyl)-6-(trifluoromethyl)benzimidazol-l- yl]phenyl]pyrrolidine-l-carboxylate

[0553] 68

[0554] MEl\56585648.vl 141039-01220

[0555]

[0285] To a solution of tert-butyl 3-[4-[2-amino-5-(trifluoromethyl)anilino]phenyl]pyrrolidine-l- carboxylate (200.00 mg, 474.55 pmol) and 2-aminopyridine-3-carbaldehyde (63.75 mg, 522.00 pmol) in DMF (5 mb) was added Na2S20s (117.28 mg, 616.91 pmol) at 25°C. This mixture was stirred at 100°C for 12 h. The reaction mixture was poured into water (30 ml). The aq. layer was extracted with EtOAc (30 ml x 3). The combined organic layers were washed with brine and dried over Na2SC>4, fdtered and concentrated. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 0 - 30%) to give tert-butyl 3-[4-[2-(2-amino-3-pyridyl)-6- (trifluoromethyl)benzimidazol-l-yl]phenyl]pyrrolidine-l -carboxylate (121 mg, 231.12 pmol, 48.70% yield) as oil. LCMS: m / z 524.1 [M+H]+

[0556]

[0286] Intermediate 22. 3-(l-(4-iodophenyl)-6-phenyl-lH-pyrrolo[2,3-b]pyridin-2-yl)pyridin-2- amine

[0557]

[0287] Step 1. 6-chloro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[2,3-b]pyridine

[0558]

[0288] To a solution of 6-chloro-lH-pyrrolo[2,3-b]pyridine (4.0 g, 26.22 mmol) in dry DMF (40 mL) was cooled to 0°C then added NaH (1.6 g, 39.32 mmol, 60%). The mixture was stirred at 0 °C for 30 minutes. SEM-C1 (5.2 g, 31.46 mmol) was slowly added to the mixture and stirred at 0°C for another 30 minutes. LC-MS showed that the reaction was completed. The reaction mixture was diluted with water (200 mL) then extracted with EA (100 mL x 3). The combined organic layer was washed with brine, dried over Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiCE, 0-6% EA in PE) to afford 6-chloro-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[2,3-b]pyridine (6.1 g, 82% yield) as a light oil. LCMS: m / z 283.1 [M+H]+

[0559]

[0289] Step 2. 6-chloro-2-iodo-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[2,3-b]pyridine

[0560]

[0290] To a solution of 6-chloro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[2,3-b]pyridine (6.0 g, 21.21 mmol) in dry THF (60 mL) was cooled to -78°C then added LDA (17 mL, 34.00 mmol, 2.0 M). The mixture was stirred at -78 °C for 1 h. L (7.0 g, 27.58 mmol in 15 mL THF) was slowly added to the mixture and allowed to warmed to RT for 16h. LC-MS showed that the reaction was completed.

[0561] 69

[0562] MEl\56585648.vl 141039-01220

[0563] The reaction mixture was diluted with water (150 mL) then extracted with EA (80 mL x 3). The combined organic layer was washed with brine, dried over Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiCE, 0-3% EA in PE) to afford 6-chloro-2-iodo-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[2,3-b]pyridine (6.0 g, 69% yield) as a oil. LCMS: m / z 408.9 [M+H]+

[0564]

[0291] Step 3. 3-(6-chloro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[2,3-b]pyridin-2- yl)pyridin-2- amine

[0565]

[0292] To a solution of 6-chloro-2-iodo-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[2,3- b]pyridine (3.0 g, 7.34 mmol) in Dioxane(20 mL) and H2O (4 mL) was added 3-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)pyridin-2-amine (1.78 g, 8.07 mmol), K2CC>3(2.53 g, 18.35 mmol) and Pd(dppf)C12 (537 mg, 0.73 mmol). The mixture was stirred at 85 °C for 16 h. LC-MS showed that the reaction was completed. The reaction mixture was diluted with water (150 mL) then extracted with EA (80 mL x 3). The combined organic layer was washed with brine, dried over Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiC>2, 0-47% EA in PE) to afford 3-(6-chloro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[2,3- b]pyridin-2-yl)pyridin-2 -amine (1.5 g, 83% yield) as a light oil and recycled 1.0 g 6-chloro-2-iodo-l- ((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[2,3-b]pyridine. LCMS: m / z 375.1 [M+H]+

[0566]

[0293] Step 4. 3-(6-phenyl-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[2,3-b]pyridin-2- yl)pyridin-2- amine

[0567]

[0294] To a solution of 3-(6-chloro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[2,3-b]pyridin-2- yl)pyridin-2 -amine (760 mg, 2.03 mmol) in Dioxane(5 mL) and H2O (1 mL) was added phenylboronic acid (272 mg, 2.23 mmol), K2CO3 (560 mg, 4.05 mmol) and Pd(dppf)C12 (297 mg, 0.41 mmol). The mixture was stirred at 85 °C for 16 h. The reaction mixture was diluted with water (80 mL) then extracted with EA (60 mL x 3). The combined organic layer was washed with brine, dried over Na2SC>4, filtered and concentrated under reduced pressure. The crude product (combined with V5820-012) was purified by column chromatography (SiC 0-40% EA in PE) to afford 3-(6-phenyl-

[0568] 1-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[2,3-b]pyridin-2-yl)pyridin-2-amine (600 mg, 68% yield) as a light solid. LCMS: m / z 417.2 [M+H]+

[0569]

[0295] Step 5. 3-(6-phenyl-lH-pyrrolo[2,3-b]pyridin-2-yl)pyridin-2-amine

[0570]

[0296] To a solution of 3-(6-phenyl-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[2,3-b]pyridin-

[0571] 2-yl)pyridin-2-amine (100 mg, 0.26 mmol) in DCM (1.0 mL) was added TFA(1.0 mL). The mixture was stirred at RT for 2 h. The mixture was concentrated then added 7M NH3 / MeOH (5 mL). The mixture was stirred at RT for another 1.5h. LC-MS showed that the reaction was completed. The reaction mixture was concentrated to afford crude product (55 mg). 15 mg of crude product was purified with prep-HPLC (MeCN / water / lOmM NH4HCO3) to afford 3-(6-phenyl-lH-pyrrolo[2,3- b]pyridin-2-yl)pyridin-2 -amine (2.04 mg, 14 % yield) as a pale- solid. The rest crude product was

[0572] 70

[0573] MEl\56585648.vl 141039-01220 used in the next step without further purification. ’H NMR (400 MHz, DMSO-de) 5 12.00 (s, 1H), 8.12 (d, J= 7.6 Hz, 2H), 8.07 - 7.95 (m, 2H), 7.77 (d, J= 7.6 Hz, 1H), 7.69 (d, J= 8.2 Hz, 1H), 7.49 (t, J= 7.6 Hz, 2H), 7.43 - 7.36 (m, 1H), 6.81 (s, 1H), 6.76 - 6.68 (m, 1H), 6.00 (s, 2H). LCMS: m / z 287.2 [M+H]+

[0574]

[0297] Step 6. 3-(l-(4-iodophenyl)-6-phenyl-lH-pyrrolo[2,3-b]pyridin-2-yl)pyridin-2-amine

[0575]

[0298] To a solution of 3-(6-phenyl-lH-pyrrolo[2,3-b]pyridin-2-yl)pyridin-2-amine (230 mg, 0.80 mmol) in dry Dioxane (10 mL) was added 1,4-diiodobenzene (265 mg, 0.80 mmol), K3PO4 (426 mg, 2.01 mmol), trans- 1,2-cyclohexanediamine (34 mg, 0.24 mmol) and Cui (31 mg, 0.16 mmol). The mixture was stirred at 95 °C for 20h. The reaction mixture (combined with V5820-053) was poured into water (80 mL) and extracted with EA (50 mL x 3). The combined organic layer was washed with brine, dried over Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiC>2, 0-36% EA in PE) to afford 3-(l-(4-iodophenyl)-6-phenyl- lH-pyrrolo[2,3-b]pyridin-2-yl)pyridin-2 -amine (65 mg, 44% yield) as a solid. LCMS: m / z 489.1 [M+H]+

[0576]

[0299] Step 7. 3-(l-(4-iodophenyl)-6-phenyl-lH-pyrrolo[2,3-b]pyridin-2-yl)pyridin-2-amine

[0577]

[0300] To a solution of 3-(l-(4-iodophenyl)-6-phenyl-lH-pyrrolo[2,3-b]pyridin-2-yl)pyridin-2 -amine (65 mg, 0.13 mmol) in Dioxane(2 mL) and H2O (0.4 mL) was added tert-butyl 3-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)-2,5-dihydro-lH-pyrrole-l-carboxylate (39 g, 0.13 mmol), K2CO3 (71 mg, 0.33 mmol) and Pd(dppf)C12 (5 mg, 0.03 mmol). The mixture was stirred at 85 °C for 2h. LC-MS showed that the reaction was completed. The reaction mixture was diluted with water (60 mL) and extracted with EA (40 mL x 3). The combined organic layer was washed with brine, dried over Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiCK 0-50% EA in PE) to afford product (60 mg, 68% yield, contained 20% EA) as a solid. 10 mg of crude product was re-purified by prep-HPLC (MeCN / water / lOmM NH4HCO3) to afford 3-(l-(4-iodophenyl)-6-phenyl-lH-pyrrolo[2,3-b]pyridin-2-yl)pyridin-2-amine (1.46 mg, 15% yield) as a solid. 1H NMR (4OO MHz, DMSO-d6) 5 8.15 (d, J = 8.0 Hz, 1H), 8.05 (dd, J = 6.6, 2.1 Hz, 2H), 7.92 (dd, J = 4.8, 2.3 Hz, 1H), 7.83 (dd, J = 8.2, 1.0 Hz, 1H), 7.57 - 7.50 (m, 2H), 7.48 -

[0578] 7.41 (m, 4H), 7.34 (dd, J = 25.8, 7.2 Hz, 2H), 6.79 (s, 1H), 6.55 - 6.39 (m, 2H), 5.83 (s, 2H), 4.47 -

[0579] 4.41 (m, 2H), 4.33 - 4.21 (m, 2H), 1.45 (d, J = 3.2 Hz, 9H). LCMS: m / z 530.5 [(M+H)+],

[0580]

[0301] Step 8. 3-(l-(4-iodophenyl)-6-phenyl-lH-pyrrolo[2,3-b]pyridin-2-yl)pyridin-2-amine

[0581]

[0302] To a solution of 3-(l-(4-iodophenyl)-6-phenyl-lH-pyrrolo[2,3-b]pyridin-2-yl)pyridin-2 -amine (18 mg, 0.03 mmol) in THF (2 mL) was added 10% Pd / C (10 mg). The mixture was stirred at RT for 2h. LC-MS showed that the reaction was completed. The reaction mixture was filtered and concentrated under reduced pressure. The crude product was purified with Prep-HPLC (MeCN / water / lOmM NH4HCO3) to afford 3-(l-(4-iodophenyl)-6-phenyl-lH-pyrrolo[2,3-b]pyridin-2- yl)pyridin-2 -amine (8 mg, 44% yield) as a solid. LCMS: m / z 532.3 [M+H]+

[0582] 71

[0583] MEl\56585648.vl 141039-01220

[0584]

[0303] Intermediate 23 and Intermediate 24. tert-butyl (R)-3-(4-(2-(2-aminopyridin-3-yl)-5- (trifluoromethyl)-3H-imidazo[4,5-b]pyridin-3-yl)phenyl)pyrrolidine-l-carboxylate and tertbutyl (S)-3-(4-(2-(2-aminopyridin-3-yl)-5-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-3- yl)phenyl)pyrrolidine-l-carboxylate

[0585]

[0304] 700 mg of racemic mixture was purified by prep-HPLC (column: DAICEL CHIRALPAK AD(250mm*30mm,10um);mobile phase: [CO2-i-PrOH(0.1%NH3H2O)];B%:35%, isocratic elution mode) to give tert-butyl (3R)-3-[4-[2-(2-amino-3-pyridyl)-5-(trifluoromethyl)imidazo[4,5-b]pyridin- 3-yl]phenyl]pyrrolidine-l-carboxylate (300 mg, 571.93 pmol, 42.86% yield) as solid and tert-butyl (3S)-3-[4-[2-(2-amino-3-pyridyl)-5-(trifluoromethyl)imidazo[4,5-b]pyridin-3-yl]phenyl]pyrrolidine-l- carboxylate (300 mg, 571.93 pmol, 42.86% yield) as solid. Peak 1, Intermediate 23, LCMS: m / z 525.8 [M+H]+. Peak 2, Intermediate 24, LCMS: m / z 525.8 [M+H]+. Assigned stereochemical configurations of products are relative, not absolute.

[0586]

[0305] Intermediate 25. tert-butyl 3-[4-[2-(2-amino-3-pyridyl)imidazo[4,5-b]pyridin-3- yl] phenyl] azetidine- 1-carboxylate

[0587]

[0306] Step 1. tert-butyl 3-(4-nitrophenyl)azetidine-l-carboxylate

[0588]

[0307] 1,2 -dibromoethane (1.59 g, 8.48 mmol, 639.59 pL) was added to Zn (4.50 g, 68.82 mmol) in THF (17.5 mL) under N2. The resulting suspension was heated at 80°C for 10 minutes. TMSC1 (863.44 mg, 7.95 mmol, 1.01 mL) in THF (8.75 mL) was added at 25°C and after stirring for 4 min, and then tert-butyl 3 -iodoazetidine -1 -carboxylate (15 g, 52.98 mmol) in THF (17.5 mL) solution was dropped for 15 min. The resulting mixture at 25°C for 2 hrs, then Pd2(dba)s (2.43 g, 2.65 mmol) and tris(2-furyl)phosphane (1.85 g, 7.95 mmol) were added follow by l-iodo-4-nitro-benzene (14.51 g, 58.28 mmol) in THF (90 mL). The resulting mixture was heated at 55°C for 3 h. The mixture was added to brine (100 mL), the aq. layer was extracted with EtOAc (100 mL x 3). The combined organic phase was washed with brine (100 mL), dried over anhydrous Na2SC>4, filtered and

[0589] 72

[0590] MEl\56585648.vl 141039-01220 concentrated under reduced pressure. The crude was purified by flash column chromatography on silica gel (EtOAc in PE=0-15%) to give tert-butyl 3 -(4-nitrophenyl)azetidine- 1 -carboxylate (5.6 g, 20.12 mmol, 37.97% yield) as oil. 'H NMR (400MHz, CDC13) 5 = 8.24-8.16 (m, 2H), 7.52-7.45 (m, 2H), 4.45 (t, J= 8.4 Hz, 2H), 4.04 (s, 2H), 3.90-3.78 (m, 1H), 1.48 (s, 9H).

[0591]

[0308] Step 2. tert-butyl 3-(4-aminophenyl)azetidine-l-carboxylate

[0592]

[0309] To a solution of tert-butyl 3-(4-nitrophenyl)azetidine-l-carboxylate (3.4 g, 12.22 mmol) in EtOH (20 mL) and H2O (5 mL) were added Fe (2.05 g, 36.65 mmol), NH4CI (6.53 g, 122.17 mmol). The mixture was stirred at 80°C for 2 h. After cooling to rt, the mixure was filtrated and concentrated. Water (50 mL) was added and the mixture were extracted with EtOAc (50 mL x 2). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated. The crude was purified by flash column chromatography on silica gel (EtOAc in PE=0-20%) to give tert-butyl 3-(4-aminophenyl)azetidine-l- carboxylate (3 g, 12.08 mmol, 98.89% yield) as oil. 'H NMR (400MHz, CDCh) 5 = 7.12-7.06 (m, 2H), 6.69-6.64 (m, 2H), 4.27 (t, J= 8.8 Hz, 2H), 3.93-3.87 (m, 2H), 3.65-3.59 (m, 1H), 1.46 (s, 9H).

[0593]

[0310] Step 3. tert-butyl 3-[4-[(3-nitro-2-pyridyl)amino]phenyl]azetidine-l-carboxylate

[0594]

[0311] To a solution of 2-chloro-3-nitro-pyridine (1.28 g, 8.05 mmol) in dioxane (10 mL) were added tert-butyl 3-(4-aminophenyl)azetidine-l-carboxylate (1 g, 4.03 mmol) and DIEA (1.56 g, 12.08 mmol, 2.10 mL). The mixture was stirred at 80°C for 2 h. After cooling to rt, the mixture was concentrated. The crude was purified by flash column chromatography on silica gel (EtOAc in PE=0-20%) to give tert-butyl 3-[4-[(3-nitro-2-pyridyl)amino]phenyl]azetidine-l-carboxylate (1.3 g, 3.51 mmol, 87.25% yield) as oil. 'H NMR (400MHz, CDCh) 5 = 10.10 (s, 1H), 8.55-8.46 (m, 2H), 7.65-7.58 (m, 2H), 7.36-7.28 (m, 2H), 6.86-6.81 (m, 1H), 4.00 (t, J= 8.8 Hz, 2H), 4.01-3.95 (m, 2H), 3.80-3.69 (m, 1H), 1.47 (s, 9H).

[0595]

[0312] Step 4. tert-butyl 3-[4-[(3-amino-2-pyridyl)amino]phenyl]azetidine-l-carboxylate

[0596]

[0313] To a solution of tert-butyl 3-[4-[(3-nitro-2-pyridyl)amino]phenyl]azetidine-l-carboxylate (1.2 g, 3.24 mmol) in EtOH (20 mL) and H2O (5 mL) were added Fe (542.77 mg, 9.72 mmol) and NH4CI (1.73 g, 32.40 mmol). The mixture was stirred at 80°C for 2 h. After cooling to rt, the mixture was filtrated and concentrated. Water (40 mL) was added and the mixture were extracted with EtOAc (40 mL x 2). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated to give tertbutyl 3-[4-[(3-amino-2-pyridyl)amino]phenyl]azetidine-l-carboxylate (1.1 g, 3.23 mmol, 99.74% yield) as oil, which was used into next step without further purification. LCMS: m / z 341.2 [M+H]+

[0597]

[0314] Step 5. tert-butyl 3-[4-[2-(2-amino-3-pyridyl)imidazo[4,5-b]pyridin-3- yl] phenyl] azetidine- 1-carboxylate

[0598]

[0315] To a solution of tert-butyl 3-[4-[(3-amino-2-pyridyl)amino]phenyl]azetidine-l-carboxylate (1.05 g, 3.08 mmol) in EtOH (10 mL) were added 2-aminopyridine-3-carbaldehyde (489.69 mg, 4.01 mmol) and InCT, (68.22 mg, 308.44 pmol, 19.72 pL). The mixture was stirred at 80°C for 16 h. Then Mn02 (1.07 g, 12.34 mmol) was added above mixture. The mixture was stirred at 80°C for 2 h. After

[0599] 73

[0600] MEl\56585648.vl 141039-01220 cooling to rt, the mixture was filtrated and concentrated. Water (40 mL) was added and the mixture were extracted with EtOAc (40 mL x 2). The organic layer was dried over anhydrous Na2SC>4, filtered and concentrated. The crude was purified by flash column chromatography on silica gel (EtOAc in PE = 0-75%) to give tert-butyl 3-[4-[2-(2-amino-3-pyridyl)imidazo[4,5-b]pyridin-3- yl]phenyl] azetidine- 1 -carboxylate (740 mg, 1.67 mmol, 54.22% yield) as oil.1H NMR (400MHz, CDCh) 5 = 8.40 (d, J = 4.0 Hz, 1H), 8.11 (d, J= 8.0 Hz, 1H), 8.05 (dd, J= 1.6, 4.8 Hz, 1H), 7.51-7.46 (m, 2H), 7.41-7.32 (m, 3H), 7.13 (d, J= 7.6 Hz, 1H), 6.83 (s, 2H), 6.41-6.36 (m, 1H), 4.41-4.36 (m, 2H), 4.06-4.03 (m, 2H), 3.86-3.80 (m, 1H), 1.48 (s, 9H).

[0601]

[0316] Intermediate 26. 2-[(4-methoxyphenyl)methyl]-3-oxo-l,2-benzoxazole-6-carboxylic acid

[0602]

[0317] Step 1. 6-bromo-3-[(4-methoxyphenyl)methoxy]-l,2-benzoxazole and 6-bromo-2-[(4- methoxyphenyl)methyl]-l,2-benzoxazol-3-one

[0603]

[0318] To a solution of 6-bromo-l,2-benzoxazol-3-ol (2 g, 9.35 mmol) in DMF (10 mL) was added K2CO3 (1.94 g, 14.02 mmol) and PMB-C1 (1.61 g, 10.28 mmol, 1.40 mL) at 25°C. The mixture was stirred at 25°C for 16 h. After cooling to rt, the resulting mixture was concentrated under reduced pressure H2O (40 mL) was added to the residue. After that the aq. layer was extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (40 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography on silica gel (EA in PE = 0-10%) to give 6-bromo-2-[(4- methoxyphenyl)methyl]-l,2-benzoxazol-3-one (1 g, 2.99 mmol, 32.02% yield) and 6-bromo-3-[(4- methoxyphenyl)methoxy]-l,2-benzoxazole (1.5 g, 4.49 mmol, 48.03% yield) as a solid. Product 1 'H NMR (400MHz, DMSO-t / ,.) 5 = 8.01 (d, J= 1.2 Hz, 1H), 7.67 (d, J= 8.4 Hz, 1H), 7.53-7.46 (m, 3H), 6.97 (d, J= 8.4 Hz, 2H), 5.38 (s, 2H), 3.77 (s, 3H). Product 2 'H NMR (400MHz, DMSO-6) 5 = 7.88 (d, J= 0.8 Hz, 1H), 7.76 (d, J= 8.4 Hz, 1H), 7.52 (dd, J= 1.2, 8.4 Hz, 1H), 7.26 (d, J= 8.8 Hz, 2H), 6.95-6.89 (m, 2H), 5.12 (s, 2H), 3.73 (s, 3H).

[0604]

[0319] Step 2. 2-[(4-methoxyphenyl)methyl]-3-oxo-l,2-benzoxazole-6-carboxylic acid

[0605]

[0320] To a solution of 6-bromo-2-[(4-methoxyphenyl)methyl]-l,2-benzoxazol-3-one (500.00 mg, 1.50 mmol) in a mixed solution of THF (5 mL) and H2O (0.5 mL) were added Xantphos (86.58 mg, 149.63 pmol), Pd(OAc)2 (16.80 mg, 74.81 pmol,) and TEA (302.82 mg, 2.99 mmol, 416.53 pL) at 25°C under N2. After that the suspension was degassed under vacuum and purged with CO for three times. The mixture was stirred under CO (50Psi) at 65°C for 16 h. The solvent is removed in a

[0606] 74

[0607] MEl\56585648.vl 141039-01220 vacuum and the residue is divided between DCM (20 mL) and water (20 mL). Adjust the pH of the aq. solution to 10-11 with aq.2 M NaOH, water layer rinse 2 x 15 mL DCM. The water layer was acidified to give pH 2 with aq HC1 (6M) and extracted with EA (3 x 15 mL) filtered and concentrated to give 2-[(4-methoxyphenyl)methyl]-3-oxo-l,2-benzoxazole-6-carboxylic acid (250 mg, 835.34 pmol, 55.83% yield) as a solid, which was used into next step without purification. ’H NMR (400MHz, DMSO-d6) 5 = 7.97-7.85 (m, 3H), 7.28 (d, J= 8.8 Hz, 2H), 6.92 (d, J= 8.8 Hz, 2H), 5.17 (s, 2H), 3.72 (s, 3H). LCMS: m / z 298.0 [M-H]’

[0608]

[0321] Intermediate 27. 2-chloro-l-(3-hydroxy-5,7-dihydro-4H-isoxazolo[5,4-c]pyridin-6- yl)ethanone

[0609]

[0322] To a solution of 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol;hydrochloride (100 mg, 566.25 pmol) and EtsN (171.90 mg, 1.70 mmol, 236.45 pL) in DCM (3 mL) was added 2- chloroacetyl chloride (63.95 mg, 566.25 pmol, 45.10 pL) at 0°C. The mixture was stirred at 25°C for 1 h. 2-chloro-l -(3 -hydroxy-5, 7-dihydro-4H-isoxazolo [5, 4-c]pyridin-6-yl)ethanone (122.66 mg, 566.24 pmol, 100.00% yield) was obtained as liquid, which was used into next step without purification. LCMS: m / z 217.0 [M+H]+

[0610]

[0323] Intermediate 28. tert-butyl 3-(4-(2-(2-aminopyridin-3-yl)-6-cyclopropyl-lH- benzo[d]imidazol-l-yl)phenyl)pyrrolidine-l-carboxylate

[0611]

[0324] To a solution of tert-butyl 3-[4-[2-(2-amino-3-pyridyl)-6-bromo-benzimidazol-l- yl]phenyl]pyrrolidine-l -carboxylate (300 mg, 561.33 pmol) in a mixture of dioxane (6 mL) and H2O (2 mL) were added cyclopropylboronic acid (241.08 mg, 2.81 mmol), K2CO3 (155.16 mg, 1.12 mmol) and Pd(dppf)C12 (20.54 mg, 28.07 pmol). The mixture was degassed and purged with N2 for 3 times. The reaction mixture was stirred at 80°C for 16 hr under N2 atmosphere. The residue was purified by flash silica gel chromatography (MeOH in DCM = 0-5% ) to givetert-butyl 3-[4-[2-(2-amino-3- pyridyl)-6-cyclopropyl-benzimidazol-l-yl]phenyl]pyrrolidine-l-carboxylate (278 mg, 560.92 pmol, 99.93% yield)as a solid. LCMS: m / z 496.4 [M+H]+

[0612]

[0325] Intermediate 29. 3-(3-(4-(2,6-diazaspiro[3.4]octan-6-yl)phenyl)-5-phenyl-3H- imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine

[0613] 75

[0614] MEl\56585648.vl 141039-01220

[0615]

[0326] Step 1. tert-butyl 7-[4-[2-(2-amino-3-pyridyl)-5-phenyl-imidazo[4,5-b]pyridin-3- yl] phenyl] -2,7-diazaspiro [3.4] octane-2-carboxylate

[0616]

[0327] A mixture of 3-[3-(4-bromophenyl)-5-phenyl-imidazo[4,5-b]pyridin-2-yl]pyridin-2-amine (1 g, 2.26 mmol), tert-butyl 2,7-diazaspiro[3.4]octane-2-carboxylate (767.92 mg, 3.62 mmol), Pd2(dba)s (103.52 mg, 113.04 pmol), BINAP (140.78 mg, 226.09 pmol,) and t-BuONa (651.83 mg, 6.78 mmol) in dioxane (15 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100°C for 16 h under N2 atmosphere. The reaction mixture was quenched with H2O (30 mL) at

[0617] 25 °C, and the resulting mixture was extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (30 mL x 3), dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel ( EA in PE = 0 - 20%) to give tert-butyl 7-[4-[2-(2-amino-3-pyridyl)-5-phenyl-imidazo[4,5-b]pyridin-3-yl]phenyl]-2,7- diazaspiro[3.4]octane-2-carboxylate (502.5 mg, 875.91 pmol, 38.74% yield) as a solid. ‘H NMR (400 MHz, CDCh) 5 = 8.11 (d, J= 8.0 Hz, 1H), 8.02 (d, J= 7.2 Hz, 3H), 7.78 (d, J= 8.4 Hz, 1H),

[0618] 7.44-7.40 (m, 2H), 7.38-7.29 (m, 3H), 7.24 (s, 1H), 7.18-6.90 (m, 2H), 6.63 (d, J= 8.8 Hz, 2H), 6.43 (dd, J= 4.8, 7.6 Hz, 1H), 4.00-3.90 (m, 4H), 3.54 (s, 2H), 3.45 (t, J= 7.2 Hz, 2H), 2.26 (t, J= 6.8 Hz, 2H), 1.47 (s, 9H). LCMS: m / z 574.3 [M+H]+

[0619]

[0328] Step 2. 3-[3-[4-(2,6-diazaspiro[3.4]octan-6-yl)phenyl]-5-phenyl-imidazo[4,5-b]pyridin-2- yl]pyridin-2- amine

[0620]

[0329] To a solution of tert-butyl 7-[4-[2-(2-amino-3-pyridyl)-5-phenyl-imidazo[4,5-b]pyridin-3- yl]phenyl]-2,7-diazaspiro[3.4]octane-2-carboxylate (350 mg, 610.09 pmol) in DCM (6 mL) was added TFA (3.07 g, 26.92 mmol, 2 mL). The mixture was stirred at 0°C for 0.3 h. The mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep- HPLC (column: Waters x bridge 150*25mm 10um;mobile phase: [water( NH4HCO3)-

[0621] ACN] gradient: 30%-60% B over 10 min ) to give 3-[3-[4-(2,6-diazaspiro[3.4]octan-6-yl)phenyl]-5- phenyl-imidazo[4,5-b]pyridin-2-yl]pyridin-2-amine (80 mg, 168.93 pmol, 27.69% yield) as a solid. 'H NMR (400 MHz, CDCL) 5 = 8.09 (d, J= 8.0 Hz, 1H), 8.07-8.01 (m, 3H), 7.77 (d, J= 8.4 Hz, 1H),

[0622] 7.44-7.39 (m, 2H), 7.37-7.32 (m, 1H), 7.29-7.27 (m, 1H), 7.26-7.25 (m, 1H), 7.23 (s, 1H), 6.68 - 6.59 (m, 4H), 6.42 (dd, J= 4.8, 7.6 Hz, 1H), 3.73 (d, J= 8.0 Hz, 2H), 3.62 (d, J= 8.0 Hz, 2H), 3.54 (s, 2H), 3.40 (t, J= 6.8 Hz, 2H), 2.29 (t, J= 6.8 Hz, 2H). LCMS: m / z 474.0 [M+H]+

[0623]

[0330] Intermediate 30. tert-butyl 4-[4-[2-(2-amino-3-pyridyl)-5-phenyl-imidazo[4,5-b]pyridin- 3-yl]phenyl]piperidine-l-carboxylate

[0624] 76

[0625] MEl\56585648.vl 141039-01220

[0626]

[0331] Step 1. tert-butyl 4-[4-[(6-chloro-3-nitro-2-pyridyl)amino]phenyl]piperidine-l- carboxylate

[0627]

[0332] To a solution of tert-butyl 4-(4-aminophenyl)piperidine- 1 -carboxylate (23 g, 83.22 mmol) in dioxane (200 mL) were added 2,6-dichloro-3-nitro-pyridine (16.06 g, 83.22 mmol) and DIEA (32.27 g, 249.66 mmol, 43.49 mL). The mixture was stirred at 80°C for 2 h. After cooling to room temperature, water (70 mL) was added and the mixture were extracted with EtOAc (50 mL x 4). The organic layer was dried over anhydrous Na2SC>4, filtered and concentrated to give tert-butyl 4-[4-[(6- chloro-3-nitro-2-pyridyl)amino]phenyl]piperidine-l -carboxylate (36.03 g, 83.23 mmol, 100.00% yield) as oil, which was used into the next step directly. ‘H NMR (400MHz, CDCL) 5 = 10.24 (s, 1H), 8.46 (d, J= 8.4 Hz, 1H), 7.59 (d, J= 8.4 Hz, 2H), 7.25-7.20 (m, 2H), 6.79 (d, J= 8.4 Hz, 1H), 4.32-4.20 (m, 2H), 2.95-2.55 (m, 4H), 1.90-1.75 (m, 3H), 1.70-1.62 (m, 1H), 1.49 (s, 9H).

[0628]

[0333] Step 2. tert-butyl 4-[4-[(3-amino-6-chloro-2-pyridyl)amino]phenyl]piperidine-l- carboxylate

[0629]

[0334] To a solution of tert-butyl 4-[4-[(6-chloro-3-nitro-2-pyridyl)amino]phenyl]piperidine-l- carboxylate (33 g, 76.23 mmol) in EtOH (300 mL) and H2O (60 mL) were added Ee (12.77 g, 228.69 mmol), NH4CI (40.78 g, 762.30 mmol). The mixture was stirred at 80°C for 2 h. The reaction mixture was filtered and the filter cake was washed with EtOAc (100 mL x3). The filtrate was added into H2O (50 mL) and extracted with EtOAc (80 ml x 2). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated to give tert-butyl 4-[4-[(3-amino-6-chloro-2- pyridyl)amino]phenyl]piperidine-l -carboxylate (27.3 g, 67.76 mmol, 88.88% yield) as a solid, which was used into the next step directly. LCMS: m / z 403.2 [M+H]+

[0630]

[0335] Step 3. tert-butyl 4-[4-[2-(2-amino-3-pyridyl)-5-chloro-imidazo[4,5-b]pyridin-3- yl]phenyl]piperidine-l-carboxylate

[0631]

[0336] To a solution of tert-butyl 4-[4-[(3-amino-6-chloro-2-pyridyl)amino]phenyl]piperidine-l- carboxylate (27.3 g, 67.76 mmol) in EtOH (250 mL) were added 2-aminopyridine-3-carbaldehyde

[0632] 77

[0633] MEl\56585648.vl 141039-01220

[0634] ( . 1 g, 67.76 mmol) and InCL (1.50 g, 6.78 mmol, 433.12 pL). The mixture was stirred at 80°C for 2 h. Then MnCL (17.67 g, 203.27 mmol) was added. The mixture was stirred at 80°C for 4 h. After cooling to room temperature, the resulting mixture was fdtered, and the filter cake was washed with EtOAc (100 mL x5). The filtrate was concentrated. The crude product was purified by flash chromatography on silica gel (EtOAc in Petroleum ether = 0-100%) to give tert-butyl 4-[4-[2-(2- amino-3-pyridyl)-5-chloro-imidazo[4,5-b]pyridin-3-yl]phenyl]piperidine-l-carboxylate (32 g, 63.37 mmol, 93.52% yield) as oil. tert-butyl 4-[4-[2-(2-amino-3-pyridyl)-5-chloro-imidazo[4,5-b]pyridin- 3-yl]phenyl]piperidine-l-carboxylate (200 mg, 396.03 pmol) was purified by Prep-HPLC (column: Phenomenex Cl 8 80 x 30mm x 5pm;mobile phase: [wate^NEEEEO+NELJTCOs)- ACN];gradient:58%-88% B over 7 min) and Prep-HPLC (column: C18 150 x 30mm;mobile phase: [water(NH3H2O+NELHCO3)-ACN] gradient: 63 %-93% B over 7 min) to give tert-butyl 4-[4-[2-(2- amino-3-pyridyl)-5-chloro-imidazo[4,5-b]pyridin-3-yl]phenyl]piperidine-l-carboxylate (40 mg, 79.21 pmol, 20.00% yield) as a solid. 'H NMR (400MHz, CDC13) 5 = 8.09-8.00 (m, 2H), 7.31-7.27 (m, 5H), 7.02 (d, J= 6.4 Hz, 1H), 6.61-6.50 (m, 2H), 6.38-6.27 (m, 1H), 4.37-4.11 (m, 2H), 2.92-2.66 (m, 3H), 1.89 (d, J= 12.8 Hz, 2H), 1.73-1.66 (m, 2H), 1.49 (s, 9H). LCMS: m / z 505.2 [M+H]+

[0635]

[0337] Step 4. tert-butyl 4-[4-[2-(2-amino-3-pyridyl)-5-phenyl-imidazo[4,5-b]pyridin-3- yl]phenyl]piperidine-l-carboxylate

[0636]

[0338] To a solution of tert-butyl 4-[4-[2-(2-amino-3-pyridyl)-5-chloro-imidazo[4,5-b]pyridin-3- yl]phenyl]piperidine-l -carboxylate (4 g, 7.92 mmol) in toluene (40 mL) and H2O (4 mL) were added phenylboronic acid (1.45 g, 11.88 mmol), K3PO4 (4.54 g, 21.39 mmol), SPhos (650.33 mg, 1.58 mmol) and Pd2(dba)3 (725.31 mg, 792.06 pmol). The mixture was stirred at 100°C for 12 h. The resulting mixture was fdtered, and the fdter cake was washed with EtOAc (50 mL x 3). H2O (50 mL) was added. The aqueous layer was extracted with EtOAc (30 mL x 2). The combined organic phase was washed with brine (50 mL), dried over anhydrous Na2SO4, fdtered and concentrated. The crude product was purified by flash chromatography on silica gel (EtOAc in Petroleum ether = 0-70%) to give tert-butyl 4-[4-[2-(2-amino-3-pyridyl)-5-phenyl-imidazo[4,5-b]pyridin-3-yl]phenyl]piperidine-l- carboxylate (2.8 g, 5.12 mmol, 64.67% yield) as a solid, tert-butyl 4-[4-[2-(2-amino-3-pyridyl)-5- phenyl-imidazo[4,5-b]pyridin-3-yl]phenyl]piperidine-l-carboxylate (100 mg, 182.93 pmol) was Prep- HPLC (column: C18 150 x 30mm ;mobile phase: [water(NH3H2O+NH4HCO3)-ACN] gradient: 70%- 100% B over 7 min) to give tert-butyl 4-[4-[2-(2-amino-3-pyridyl)-5-phenyl-imidazo[4,5-b]pyridin-3- yl]phenyl]piperidine-l -carboxylate (60 mg, 109.76 pmol, 60.00% yield) as a solid. ’H NMR (400MHz, CDCI3) 5 = 8.13 (d, J= 8.4 Hz, 1H), 8.09-8.05 (m, 1H), 8.03-7.97 (m, 2H), 7.80 (d, J= 8.4 Hz, 1H), 7.48-7.33 (m, 7H), 7.12-7.04 (m, 1H), 6.65-6.55 (m, 2H), 6.41-6.33 (m, 1H), 4.48-4.10 (m, 2H), 2.95-2.70 (m, 3H), 1.97-1.88 (m, 2H), 1.75-1.67 (m, 2H), 1.50 (s, 9H). LCMS: m / z 569.3 [M+Na]+

[0637] 78

[0638] MEl\56585648.vl 141039-01220

[0639]

[0339] Intermediate 31. 3-(5-chloro-3-(4-(pyrrolidin-3-yl)phenyl)-3H-imidazo[4,5-b]pyridin-2- yl)pyridin-2- amine

[0640]

[0340] Step 1. 3-(5-chloro-3-(4-(pyrrolidin-3-yl)phenyl)-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-

[0641] 2-amine

[0642]

[0341] To a solution of tert-butyl 3-[4-[2-(2-amino-3-pyridyl)-5-chloro-imidazo[4,5-b]pyridin-3- yl]phenyl]pyrrolidine-l-carboxylate (2.00 g, 4.07 mmol) in MeOH (5 mL) was added HCl / MeOH (2 M, 2 mL) at 25°C. The mixture was stirred at 25°C for 2 h. The mixture was filtered and concentrated to give the title compound (1.59 g, 4.07 mmol, 100% yield) as a solid, which was used into the next step without further purification.1H NMR (400MHz DMSO-t / e) 5 = 9.89-9.64 (m, 2H), 8.55-8.41 (m, 2H), 8.22 (dd, J= 1.2, 6.4 Hz, 1H), 8.05-7.95 (m, 1H), 7.65-7.48 (m, 5H), 7.00-6.92 (m, 1H), 3.77-3.57 (m, 2H), 3.51-3.42 (m, 1H), 3.32-3.16 (m, 2H), 2.48-2.40 (m, 1H), 2.14-1.94 (m, 1H).

[0643]

[0342] The intermediates in the table below were synthesized as described for Intermediate 31 from appropriate starting materials.

[0644] 79

[0645] MEl\56585648.vl 141039-01220

[0646] 80

[0647] MEl\56585648.vl 141039-01220

[0648] 81

[0649] MEl\56585648.vl 141039-01220

[0650] 82

[0651] MEl\56585648.vl 141039-01220

[0652] Intermediate 32. 2-chloro-6-cyclopropyl-3-nitropyridine

[0653] Step 1. 2-chloro-6-cyclopropyl-3-nitropyridine

[0654] A suspension of 6-bromo-2-chloro-3-nitropyridine (5.0 g, 21.0 mmol, 1 equiv, CAS: 1430341-84-6), cyclopropylboronic acid (5.4 g, 63.2 mmol, 3 equiv), Pd(OAc)2 (945 mg, 4.2 mmol, 0.2 equiv), PCys (1.8 g, 6.3 mmol, 0.3 equiv) and K2CO3 (7.3 g, 52.6 mmol, 2.5 equiv) in dioxane (50 mb) and H2O (10 mL) was stirred at 80 °C for 16 h. The mixture was added water (400 mL) and extracted with EA (80 mL x 3). The organic phase was concentrated in vacuo. The residue was purified by prep-HPLC (MeCN / water / lOmM NH4CO3) to afford 2-chloro-6-cyclopropyl-3-nitropyridine (3.3 g, 79%) as solid. LCMS (M + H) m / z: 199.1

[0655] Intermediate 33. tert-butyl (7?)-3-(5-(2-(2-aminopyridin-3-yl)-5-cyclopropyl-3 / 7-imidazo[4,5- Z>]pyridin-3-yl)pyridin-2-yl)-3-methoxypyrrolidine-l-carboxylate and tert-butyl (5)-3-(5-(2-(2- aminopyridin-3-yl)-5-cyclopropyl-3 / 7-imidazo[4,5-Z>]pyridin-3-yl)pyridin-2-yl)-3- methoxypyrrolidine-l-carboxylate

[0656] 83

[0657] MEl\56585648.vl 141039-01220

[0658] Step 1. tert-butyl 3-(5-nitropyridin-2-yl)-2,5-dihydro-LH-pyrrole-l-carboxylate

[0659] To a solution of 2-bromo-5 -nitropyridine (1.0 g, 4.9 mmol, 1.00 equiv, CAS: 4487-59-6) in toluene (15 mL) and water (5 mL) was added tert-butyl 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2,5- dihydro- 1 / / -pyrrole- 1 -carboxylate (1.6 g, 5.4 mmol, 1.1 equiv), Pd(dppf)C12 (721 mg, 0.99 mmol, 0.2 equiv) and K2CO3 (1.7 g, 12.3 mmol, 2.5 equiv). The reaction mixture was stirred under N2 atmosphere at 100 °C for 16 h. The reaction mixture was quenched with H2O (100 mL). The mixture was extracted with EA (3 x 100 mL). The combined organic layers were dried over Na2SC>4. After filtration via Celite pad, the organic layer was concentrated under reduced pressure. The crude product was purified by silica gel chromatography eluted with EA in PE ( 10%-35%) to give tert-butyl 3-(5-nitropyridin-2-yl)-2.5-dihydro- l / / -pyrrolc- l -carboxylatc (1.25 g, 86%) as solid. LCMS (M - t- Bu + H)+m / z: 236.1.

[0660] Step 2. tert-butyl 3-hydroxy-3-(5-nitropyridin-2-yl)pyrrolidine-l-carboxylate

[0661] A solution of tert-butyl 3-(5-nitropyridin-2-yl)-2.5-dihydro- l / / -pyrrolc- l -carboxylatc (1.15 g, 3.95 mmol, 1 equiv) in z-PrOH (10 mL) and DCM (8 mL) was cooled to 0 °C, Then phenylsilane (854 mg, 7.90 mmol, 2.0 equiv) and Mn(dpm)s (119 mg, 0.20 mmol, 0.05 equiv) in DCM (2 mL) were added. The reaction mixture was stirred under O2 atmosphere at RT for 2 h. The reaction mixture was quenched with H2O (50 mL). The mixture was extracted with DCM (3 x 50 mL). The combined organic layers were dried over Na2SC>4. After filtration via Celite pad, the organic layer was concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluted with EA in PE ( 10%-35 %) to give tert-butyl 3-hydroxy-3-(5-nitropyridin-2-yl)pyrrolidine-l- carboxylate (750 mg, 61%) as solid. LCMS (M - t-Bu + H)+m / z: 254.1

[0662] Step 3. tert-butyl 3-methoxy-3-(5-nitropyridin-2-yl)pyrrolidine-l-carboxylate

[0663] To a solution of tert-butyl 3-hydroxy-3-(5-nitropyridin-2-yl)pyrrolidine-l-carboxylate (750 mg, 2.42 mmol, 1 equiv) in DML (10 mL) was cooled to 0 °C, Then NaH (194 mg, 4.85 mmol, 2.0 equiv, wt.

[0664] 84

[0665] MEl\56585648.vl 141039-01220

[0666] 60%) was added. The mixture stirred under N2 atmosphere at 0 °C for 0.5 h. Mel (413 mg, 2.91 mmol) was added. The reaction mixture was stirred at RT for 2 h. The reaction mixture was quenched quenched with H2O (100 mL). The mixture was extracted with EA (3 x 100 mL). The combined organic layers were dried over Na2SC>4. After filtration via Celite pad, the organic layer was concentrated under reduced pressure. The crude product was purified by silica gel chromatography eluted with EA in PE (10%-25%) to give tert-butyl 3-methoxy-3-(5-nitropyridin-2-yl)pyrrolidine-l- carboxylate (700 mg, 89%) as solid. LCMS (M - t-Bu + H)+m / z: 268.2

[0667] Step 4. tert-butyl 3-(5-aminopyridin-2-yl)-3-methoxypyrrolidine-l-carboxylate

[0668] To a solution of tert-butyl 3-methoxy-3-(5-nitropyridin-2-yl)pyrrolidine-l-carboxylate (650 mg, 2.01 mmol, 1 equiv) in MeOH (10 mL) was added 10% Pd / C (150 mg). The reaction mixture was stirred under H2 atmosphere at RT for 2 h. The suspension was filtered through a pad of Celite and filter cake was washed with MeOH (20 mL x 3). The combined filtrates were concentrated to dryness to give tert-butyl 3-(5-aminopyridin-2-yl)-3-methoxypyrrolidine-l-carboxylate (600 mg, crude) as solid. LCMS (M + H)+m / z: 294.2

[0669] Step 5. tert-butyl 3-(5-((6-cyclopropyl-3-nitropyridin-2-yl)amino)pyridin-2-yl)-3- methoxypyrrolidine-l-carboxylate

[0670] A suspension of tert-butyl 3-(5-aminopyridin-2-yl)-3-methoxypyrrolidine-l-carboxylate (4.9 g, 16.7 mmol, 1 equiv), 2-chloro-6-cyclopropyl-3-nitropyridine (4.0 g, 20.0 mmol, 1.2 equiv), Pd(OAc)2 (375 mg, 1.67 mmol, 0.1 equiv), Xantphos (1.9 g, 3.34 mmol, 0.2 equiv) and CS2CO3 (10.9 g, 33.4 mmol, 2 equiv) in dry dioxane (40 mL) was stirred at 90 °C for 1 h. The mixture was added water (400 mL) and extracted with EA (3 x 80 mL). The organic phase was concentrated in vacuo. The residue was purified by silica gel column chromatography, eluted with EA in PE (0%-30%) to afford tert-butyl 3- (5-((6-cyclopropyl-3-nitropyridin-2-yl)amino)pyridin-2-yl)-3-methoxypyrrolidine-l-carboxylate (6.4 g, 84%) as solid. LCMS (M + H)+m / z: 456.2

[0671] Step 6. tert-butyl 3-(5-((3-amino-6-cyclopropylpyridin-2-yl)amino)pyridin-2-yl)-3- methoxypyrrolidine-l-carboxylate

[0672] To a solution of tert-butyl 3-(5-((6-cyclopropyl-3-nitropyridin-2-yl)amino)pyridin-2-yl)-3- methoxypyrrolidine-1 -carboxylate (6.4 g, 14.7 mmol, 1 equiv) in EtOH (60 mL) and H2O (12 mL) was added Le (8.2 g, 147.0 mmol, 10 equiv) and NH4CI (7.9 g, 147.0 mmol, 10 equiv). The reaction was stirred at 80 °C for 1 h. The catalyst was removed by filter, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography, eluted with MeOH in DCM (0%-5%) to afford tert-butyl 3-(5-((3-amino-6-cyclopropylpyridin-2-yl)amino)pyridin-2-yl)-3- methoxypyrrolidine-1 -carboxylate (6.1 g, 96%) as solid. LCMS (M + H)+m / z: 426.2

[0673] Step 7. tert-butyl 3-(5-(2-(2-aminopyridin-3-yl)-5-cyclopropyl-3 / 7-imidazo[4,5- / >]pyridin-3- yl)pyridin-2-yl)-3-methoxypyrrolidine-l-carboxylate

[0674] To a solution of tert-butyl 3-(5-((3-amino-6-cyclopropylpyridin-2-yl)amino)pyridin-2-yl)-3- methoxypyrrolidine-1 -carboxylate (6.1 g, 14.3 mmol, 1 equiv) in AcOH (55 mL) and MeOH (6 mL)

[0675] 85

[0676] MEl\56585648.vl 141039-01220 was added 2-aminonicotinaldehyde (1.9 g, 15.8 mmol, 1.1 equiv). The reaction was stirred at RT for 1.5 h, then stirred at 55 °C for 16 h in the air. The mixture was poured into Na2COs solution (400 mL) and extracted with EA (3 x 80 mL). The combined organic layer was dried over Na2SC>4and the solvent was removed in vacuo. The residue was purified by silica gel column chromatography, eluted with EA in PE (50-100%) to afford tert-butyl 3-(5-(2-(2-aminopyridin-3-yl)-5-cyclopropyl-3H- i idazo|4.5- / ?|pyridin-3-yl)pyridin-2-yl)-3- cthoxypyrrolidinc- 1 -carboxylate (6.5 g, 86%) as solid. LCMS (M + H)+m / z: 528.1

[0677] Step 8. tert-butyl (7?)-3-(5-(2-(2-aminopyridin-3-yl)-5-cyclopropyl-3 / 7-imidazo[4,5-6]pyridin-3- yl)pyridin-2-yl)-3-methoxypyrrolidine-l-carboxylate and tert-butyl (5)-3-(5-(2-(2-aminopyridin- 3-yl)-5-cyclopropyl-3 / 7-imidazo[4,5-6]pyridin-3-yl)pyridin-2-yl)-3-methoxypyrrolidine-l- carboxylate tert-butyl 3-(5-(2-(2-aminopyridin-3-yl)-5-cyclopropyl-3H-imidazo[4,5-6]pyridin-3-yl)pyridin-2-yl)- 3 -methoxypyrrolidine -1 -carboxylate (1.37 g) was purified by SFC (Daicel AS-3 (25*250mm,10 um), CC>2 / IPA[0.5%NH3(7M in MeOH)]=75 / 25) to afford tert-butyl (R)-3-(5-(2-(2-aminopyridin-3-yl)-5- cyclopropyl-3H-imidazo[ 4,5-6 ]pyridin-3-yl)pyridin-2-yl)-3-methoxypyrrolidine- 1 -carboxylate (634 mg, e.e. 100.0%, peak 1) as solid and tert-butyl (5)-3-(5-(2-(2-aminopyridin-3-yl)-5-cyclopropyl-3H- imidazo|4.5-6|pyridin-3-yl)pyridin-2-yl)-3-mcthoxypyrrolidinc- 1 -carboxylate (627 mg, e.e. 99.6%, peak 2) as solid.

[0678] Intermediate 34. 3-(5-(2-(2-aminopyridin-3-yl)-5-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-3- yl)pyridin-2-yl)pyrrolidin-3-ol

[0679] Step 1. tert-butyl 3-(5-aminopyridin-2-yl)-2,5-dihydro-LH-pyrrole-l-carboxylate

[0680] To the mixture of 6-bromopyridin-3 -amine (5.00 g, 28.9 mmol, 1.0 equiv, CAS: 13534-97-9), tertbutyl 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2,5-dihydro-lH-pyrrole-l-carboxylate (10.24 g, 34.68 mmol, 1.2 equiv, CAS: 212127-83-8) and K2CO3 (9.99 g, 72.25 mmol, 2.5 equiv) in toluene (21 mL) and H2O (7 mL) was added Pd(dppf)C12 (4.23 g, 5.78 mmol, 0.2 equiv). The reaction mixture was stirred for 16 h at 85 °C under N2 atmosphere. Water (100 mL) was added to the reaction mixture and extracted with EA (3 x 100 mL). The combined organic phase was washed with brine (3 x 100

[0681] 86

[0682] MEl\56585648.vl 141039-01220 mL), dried over Na2SC>4 and concentrated under reducing pressure. The residue was purified by silica gel column chromatography, eluted with EA in PE (0%-70%) to afford tert-butyl 3-(5-aminopyridin- 2-yl)-2,5-dihydro-lH-pyrrole- 1 -carboxylate (6.123 g, 81%) as a solid. LCMS (M + H)+m / z 262.2 Step 2. tert-butyl 3-hydroxy-3-(5-nitropyridin-2-yl)pyrrolidine-l-carboxylate

[0683] To the mixture of tert-butyl 3-(5-aminopyridin-2-yl)-2.5-dihydro- l / / -pyrrolc- l -carboxylatc (2040 mg, 7.79 mmol, 1.0 equiv) and phenylsilane (1687 mg, 15.59 mmol, 2.0 equiv) in z-PrOH (30 mL) under O2 atmosphere at 0°C was added Mn(dpm)s (1185 mg, 1.96 mmol, 0.1 equiv) in DCM (15 mL). The reaction mixture was stirred at 0 °C to RT for 2h under O2 atmosphere. The mixture was diluted with H2O (100 mL) and extracted with DCM (3 x 100 mL). The combined organic phase was washed with brine (3 x 100 mL), dried over Na2SC>4 and evaporated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with MeOH in DCM (0%-5%) to afford tertbutyl 3 -(6-chloropyridazin-3-yl)-3 -hydroxypyrrolidine- 1 -carboxylate (1914 mg, 88%) as a solid. LCMS (M + H)+m / z: 280.3.

[0684] Step 3. tert-butyl 3-hydroxy-3-(5-((3-nitro-6-(trifluoromethyl)pyridin-2-yl)amino)pyridin-2- yl)pyrrolidine-l-carboxylate

[0685] To the solution of tert-butyl 3-(5-aminopyridin-2-yl)-3-hydroxypyrrolidine-l-carboxylate (560 mg, 2.00 mmol, 1 equiv) and 2-chloro-3-nitro-6-(trifluoromethyl)pyridine (454 mg, 2.00 mmol, 1 equiv) in dioxane (10 mL) was added Ruphos (373 mg, 0.80 mmol, 0.4 equiv) and Pd2(dba)s (366 mg, 0.40 mmol, 0.2 equiv). The mixture was stirred at 90 °C for 5 h under N2 protection. The reaction solution was poured into water (100 mL), extracted with EA (3 x 80 mL). The organic phase was concentrated in vacuo. The residue was purified by silica gel column chromatography, eluted with EA in PE (0%- 65%) to afford tert-butyl 3-hydroxy-3-(5-((3-nitro-6-(trifluoromethyl)pyridin-2-yl)amino)pyridin-2- yl)pyrrolidine-l -carboxylate (590 mg, 63%) as an solid. LCMS (M+H)+m / zAlOA.

[0686] Step 4. tert-butyl 3-(5-(2-(2-aminopyridin-3-yl)-5-(trifluoromethyl)-317-imidazo[4,5- / >]pyridin-3- yl)pyridin-2-yl)-3-hydroxypyrrolidine-l-carboxylate

[0687] To the solution of tert-butyl 3-hydroxy-3-(5-((3-nitro-6-(trifluoromethyl)pyridin-2-yl)amino)pyridin- 2-yl)pyrr°lidine-l -carboxylate (590 mg, 1.26 mmol, 1 equiv) in the solution of MeOH (5 mL) and DMSO (5 mL) were added 2-aminonicotinaldehyde (307 mg, 2.51 mmol, 2 equiv) and Na2S2O4 (1.1 g, 6.28 mmol, 5 equiv). The mixture was stirred at 120 °C for 1 h under N2 protection. The mixture was stirred at 120 °C for 16 h under air. Then the mixture was stirred at 140 °C for another 8 h. (BOC)2O (275 mg, 1.26 mmol, 1 equiv) and TEA (254 mg, 2.51 mmol, 2 equiv) were added to the mixture, and stirred at RT for 1 h. The reaction solution was poured into water (100 mL), extracted with EA (5 x 150 mL). The organic phase was concentrated in vacuo. The residue was purified by silica gel column chromatography, eluted with EA in PE (0%-100%) to afford tert-butyl 3-(5-(2-(2- aminopyridin-3 -yl)-5 -(trifl uoromcthy I )-3H-im idazo| 4.5 - / ? | py ridi n-3 -y I )py ridin-2-y I )-3 - hydroxypyrrolidine- 1 -carboxylate (130 mg, 19%) as a solid. LCMS (M+H)+m / z: 542.6.

[0688] 87

[0689] MEl\56585648.vl 141039-01220

[0690] Step 5. 3-(5-(2-(2-aminopyridin-3-yl)-5-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-3- yl)pyridin-2-yl)pyrrolidin-3-ol

[0691] To the solution of tert-butyl 3-(5-(2-(2-aminopyridin-3-yl)-5-(trifluoromethyl)-3H-imidazo[4,5- / ? |pyridin-3-yl)pyridin-2-yl)-3-hydroxypyrrolidinc- 1 -carboxylate (15 mg, 0.03 mmol) in DCM (1 mL) was added TFA (1 mL). The mixture was stirred at RT for 1 h. The reaction solution was concentrated in vacuo. The residue was basified with 7M Nff / McOH. and then the mixture was concentrated in vacuo. The residue was purification by prep-HPLC (MeCN / water / lOmM NH4HCO3) to give 3-(5-(2- (2-aminopyridin-3 -yl) -5 -(trifl uoromcthyl )-3 / / -im idazo 14.5 - / ? | py ridin-3 -yl)pyridin-2-yl)pyrrolidin-3 -ol (2.56 mg, 20%) as an solid. LCMS (M+H)+m / z 442.4.

[0692] Example 1. l-(4-(3-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin-3- yl)phenyl)pyrrolidine-l-carbonyl)piperazin-l-yl)prop-2-en-l-one

[0693]

[0343] Step 1. tert-butyl 4-(3-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin-3- yl)phenyl)pyrrolidine-l-carbonyl)piperazine-l-carboxylate

[0694]

[0344] To a solution of 3-[5-phenyl-3-(4-pyrrolidin-3-ylphenyl)imidazo[4,5-b]pyridin-2-yl]pyridin- 2-amine (200 mg, 462.41 pmol) in DMF (1 mL) was added DIPEA (179.29 mg, 1.39 mmol, 241.63 pL) and 4-tert-butyl l-(4-nitrophenyl) piperazine- 1,4-di carboxylate (243.70 mg, 693.61 pmol). The mixture was stirred at 50°C for 3 h. The reaction mixture was diluted with EtOAc (20 mL) and washed with brine (10 mL x 3). The combined organic layers were dried over anhydrous Na2SC>4, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (MeOH in DCM = 0 - 10%) to give the title compound (185 mg, 286.93 pmol, 62.05% yield) as an oil. 'H NMR (400MHz, DMSO-tL) 5 = 8.27 (d, J= 8.0 Hz, 1 H), 8.06- 7.95 (m, 4 H), 7.53-7.43 (m, 6 H), 7.43-7.36 (m, 1 H), 7.20 (dd, J= 2.0, 7.6 Hz, 1 H), 6.93 (s, 2 H), 6.43 (dd, J= 4.8, 7.6 Hz, 1 H), 3.80-3.65 (m, 1 H), 3.59-3.48 (m, 1 H), 3.47-3.33 (m, 6 H), 3.30-3.25 (m, 1 H), 3.25-3.16 (m, 2 H), 3.16-3.07 (m, 2 H), 2.31-2.20 (m, 1 H), 2.05-1.90 (m, 1 H), 1.40 (s, 9 H).

[0695]

[0345] Step 2. (3-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin-3- yl)phenyl)pyrrolidin-l-yl)(piperazin-l-yl)methanone

[0696]

[0346] A solution of tert-butyl 4-[3-[4-[2-(2-amino-3-pyridyl)-5-phenyl-imidazo[4,5-b]pyridin-3- yl]phenyl]pyrrolidine-l-carbonyl]piperazine-l -carboxylate (15 mg, 23.26 pmol) and HCl / MeOH (2

[0697] 88

[0698] MEl\56585648.vl 141039-01220

[0699] M, 1 mL) in MeOH (0.5 mL) was stirred at 25°C for 1 h. The reaction mixture was concentrated. The residue was purified by prep-HPLC (column: CD01- Phenomenex luna C18 150 * 25 * 10 um; mobile phase: [water (FA) - ACN]; gradient: 10% - 40% B over 10 min) to give the title compound (5 mg, 8.46 pmol, 36.4% yield, FA) as a solid. 'H NMR (400MHz, DMSO-6) 5 = 8.31-8.22 (m, 2 H), 8.07-7.92 (m, 4 H), 7.52-7.36 (m, 7 H), 7.20 (dd, J= 1.6, 8.0 Hz, 1 H), 6.93 (s, 2 H), 6.42 (dd, J= 4.8, 7.6 Hz, 1 H), 3.72-3.67 (m, 2 H), 3.25-3.15 (m, 4 H), 3.15-3.05 (m, 3 H), 2.81-2.68 (m, 4 H), 2.31- 2.19 (m, 1 H), 2.05-1.89 (m, 1 H). LCMS: m / z 545.1 [M+H]+

[0700]

[0347] Step 3. l-(4-(3-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin-3- yl)phenyl)pyrrolidine-l-carbonyl)piperazin-l-yl)prop-2-en-l-one

[0701]

[0348] To a solution of[3-[4-[2-(2-amino-3-pyridyl)-5-phenyl-imidazo[4,5-b]pyridin-3- yl]phenyl]pyrrolidin-l-yl] -piperazin- 1-yl -methanone (143 mg, 217.10 pmol, TFA) and DIPEA (280.58 mg, 2.17 mmol, 378.15 pL) in DCM (2 mL) was added prop-2-enoyl chloride (19.65 mg, 217.10 pmol, 17.64 pL) dropwise at -60°C. The mixture was stirred at -60°C for 1 h. The reaction mixture was added saturated NaHCOs (10 mL) and extracted with DCM (10 mL x 2). The combined organic phase was washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by prep-HPLC (column: CD24-XPT C18 150 x 25 x 7um; mobile phase: [water (TFA) - ACN]; gradient: 22% - 52% B over 10 min) to give the title compound (42 mg, 58.93 pmol, 27.14% yield, TFA) as a solid. 'H NMR (400MHz, DMSO-6) 5 = 8.32 (d, J= 8.4 Hz, 1 H), 8.11-7.98 (m, 4 H), 7.64 (d, J= 7.2 Hz, 1 H), 7.57-7.38 (m, 7 H), 6.85-6.69 (m, 2 H), 6.12 (dd, J= 2.4, 16.8 Hz, 1 H), 5.70 (dd,J= 2.4, 10.4 Hz, 1 H), 3.80-3.70 (m, 1 H), 3.65-3.50 (m, 6 H), 3.45-3.38 (m, 2 H), 3.31-3.10 (m, 4 H), 2.34-2.22 (m, 1 H), 2.07-1.91 (m, 1 H).19F NMR (400MHz, DMSO-d6) 5 = -74.278. LCMS: m / z 599.1 [M+H]+

[0702]

[0349] Example 1-1 and 1-2. SFC separation of (R)-l-(4-(3-(4-(2-(2-aminopyridin-3-yl)-5- phenyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl)pyrrolidine-l-carbonyl)piperazin-l-yl)prop-2-en- 1-one (peak 1) and (S)-l-(4-(3-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin-3- yl)phenyl)pyrrolidine-l-carbonyl)piperazin-l-yl)prop-2-en-l-one (peak 2)

[0703]

[0350] 35 mg (58.46 pmol) of l-[4-[3-[4-[2-(2-amino-3-pyridyl)-5-phenyl-imidazo[4,5-b]pyridin-3- yl]phenyl]pyrrolidine-l-carbonyl]piperazin-l-yl]prop-2-en-l-one was purified by SFC (column: DAICEL CHIRALPAK IE(50 x 250mm, lOum); mobile phase: [Hexane- EtOH]; B%: 67%, isocratic elution mode) to give l-[4-[(3R)-3-[4-[2-(2-amino-3-pyridyl)-5-phenyl-imidazo[4,5-b]pyridin-3- yl]phenyl]pyrrolidine-l-carbonyl]piperazin-l-yl]prop-2-en-l-one (6.3 mg, 10.52 pmol, 18.00% yield) as a solid and l-[4-[(3S)-3-[4-[2-(2-amino-3-pyridyl)-5-phenyl-imidazo[4,5-b]pyridin-3- yl]phenyl]pyrrolidine-l-carbonyl]piperazin-l-yl]prop-2-en-l-one (8.9 mg, 14.87 pmol, 25.43% yield) as a solid. Assigned stereochemical configurations of products are relative, not absolute.

[0704]

[0351] Example 1-28. Alternate Step 1. tert-butyl 4-[3-[4-[2-(2-amino-3-pyridyl)-5-phenyl- imidazo[4,5-b]pyridin-3-yl]phenyl]pyrrolidin-l-yl]sulfonylpiperidine-l-carboxylate

[0705] 89

[0706] MEl\56585648.vl 141039-01220

[0707]

[0352] To a solution of 3-[5-phenyl-3-(4-pyrrolidin-3-ylphenyl)imidazo[4,5-b]pyridin-2-yl]pyridin- 2-amine (200 mg, 426.46 pmol, HC1) in DMF (4 mL) were added K2CO3 (176.82 mg, 1.28 mmol) and tert-butyl 4-chlorosulfonylpiperidine- 1 -carboxylate (242.03 mg, 852.92 pmol). The mixture was stirred at 50°C for 12 h. The reaction mixture was diluted with EtOAc (20 mL) and washed with brine (10 mL x 3). The combined organic layers were dried over anhydrous Na2SC>4, filtered and concentrated. The crude product was purified by flash chromatography on silica gel (Methanol in Dichloromethane = 0 - 10%) to give tert-butyl 4-[3-[4-[2-(2-amino-3-pyridyl)-5-phenyl-imidazo[4,5- b]pyridin-3-yl]phenyl]pyrrolidin-l-yl]sulfonylpiperidine-l-carboxylate (130 mg, 191.22 pmol. 44.84% yield) as oil. LCMS: m / z 680.3 [M+H]+

[0708]

[0353] Example 1-33. l-(4-((3-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin-

[0709] 3-yl)phenyl)pyrrolidin-l-yl)sulfonyl)piperidin-l-yl)prop-2-en-l-one

[0710]

[0354] Example 1-33. Alternate Step 1 and 2: tert-butyl 4-chlorosulfonylpiperazine-l-carboxylate

[0711]

[0355] To a solution of tert-butyl piperazine- 1 -carboxylate (1 g, 5.37 mmol) and EtsN (1.09 g, 10.74 mmol, 1.49 mL) in anhydrous DCM (20 mL) was added sulfuryl chloride (797.13 mg, 5.91 mmol, 590.47 pL) dropwise ly at 0°C. Then the mixture was degassed and purged with N2 for 3 times, and then the mixture was stirred at 25°C under N2 for 2 h. The reaction mixture was quenched with HC1 (IM in H2O, 10 mL) at 0°C, and the resulting mixture was washed with H2O (10 mL). The organic phase was washed with brine (10 mL), dried over anhydrous Na2SC>4, filtered and concentrated. The

[0712] 90

[0713] MEl\56585648.vl 141039-01220 residue was purified by flash chromatography on silica gel (EtOAc in Petroleum ether = 0 - 10%) to give tert-butyl 4-chlorosulfonylpiperazine-l -carboxylate (600 mg, 2.11 mmol, 39.24% yield) as a solid. 'H NMR (400 MHz, DMSO-6) 5 = 3.92 (br s, 4H), 3.55 (s, 4H), 1.41 (s, 9H).

[0714]

[0356] tert-butyl-4-[3-[4-[2-(2-amino-3-pyridyl)-5-phenyl-imidazo[4,5-b]pyridin-3- yl]phenyl]pyrrolidin-l-yl]sulfonylpiperazine-l-carboxylate

[0715]

[0357] To a solution of 3-[5-phenyl-3-(4-pyrrolidin-3-ylphenyl)imidazo[4,5-b]pyridin-2-yl]pyridin- 2-amine (150 mg, 346.81 pmol) and DIPEA (179.29 mg, 1.39 mmol, 241.63 pL) in anhydrous DCM (2 mb) was added tert-butyl 4-chlorosulfonylpiperazine-l -carboxylate (98.76 mg, 346.81 pmol) dropwise at 0°C. Then the mixture was degassed and purged with N2 for 3 times, and then the mixture was stirred at 25°C under N2 for 12 h. After the reaction was complete, the resulting mixture was quenched with H2O (10 mb). The resulting mixture was extracted with DCM (5 mb x 3). The combined organic phase was washed with brine (10 mb), dried over anhydrous Na2SC>4, filtered and concentrated. The residue was purified by flash chromatography on silica gel (MeOH in DCM = 0 - 10 %) to give tert-butyl4-[3-[4-[2-(2-amino-3-pyridyl)-5-phenyl-imidazo[4,5-b]pyridin-3- yl]phenyl]pyrrolidin-l-yl] sulfonylpiperazine- 1 -carboxylate (230 mg, 337.83 pmol, 97.41% yield) as asolid. 'H NMR (400 MHz, DMSO-t / ,.) 5 = 8.26 (d, J= 8.4 Hz, 1H), 8.07-7.93 (m, 4H), 7.54-7.38 (m, 7H), 7.19 (dd, J= 1.6, 7.6 Hz, 1H), 6.93 (s, 2H), 6.45-6.38 (m, 1H), 3.78 (t, J= 8.0 Hz, 1H), 3.57- 3.49 (m, 2H), 3.42-3.37 (m, 5H), 3.24 (t, J= 9.2 Hz, 1H), 3.17-3.13 (m, 4H), 2.39-2.32 (m, 1H), 2.14- 2.04 (m, 1H), 1.40 (s, 9H).

[0716]

[0358] The compounds in the table below were synthesized as described in Examples 1 and 3-1 from appropriate intermediates.

[0717] 91

[0718] MEl\56585648.vl 141039-01220

[0719] 92

[0720] MEl\56585648.vl 141039-01220

[0721] 93

[0722] MEl\56585648.vl 141039-01220

[0723] 94

[0724] MEl\56585648.vl 141039-01220

[0725] 95

[0726] MEl\56585648.vl 141039-01220

[0727] 96

[0728] MEl\56585648.vl 141039-01220

[0729] 97

[0730] MEl\56585648.vl 141039-01220

[0731] 98

[0732] MEl\56585648.vl 141039-01220

[0733] 99

[0734] MEl\56585648.vl 141039-01220

[0735] 100

[0736] MEl\56585648.vl 141039-01220

[0737] 101

[0738] MEl\56585648.vl 141039-01220

[0739] 102

[0740] MEl\56585648.vl 141039-01220

[0741] 103

[0742] MEl\56585648.vl 141039-01220

[0743] 104

[0744] MEl\56585648.vl 141039-01220

[0745] 105

[0746] MEl\56585648.vl 141039-01220

[0747] 106

[0748] MEl\56585648.vl 141039-01220

[0749] 107

[0750] MEl\56585648.vl 141039-01220

[0751] 108

[0752] MEl\56585648.vl 141039-01220

[0753] 109

[0754] MEl\56585648.vl 141039-01220

[0755] 110

[0756] MEl\56585648.vl 141039-01220

[0757] 111

[0758] MEl\56585648.vl 141039-01220

[0759] 112

[0760] MEl\56585648.vl 141039-01220

[0761] 113

[0762] MEl\56585648.vl 141039-01220

[0763] 114

[0764] MEl\56585648.vl 141039-01220

[0765]

[0359] Example 2. l-(4-(3-(4-(2-(2-amino-6-fluorophenyl)-5-phenyl-3H-imidazo[4,5-b]pyridin- 3-yl)phenyl)pyrrolidine-l-carbonyl)piperazin-l-yl)prop-2-en-l-one

[0766]

[0360] Step 1. 2-(2-fluoro-6-nitrophenyl)-5-phenyl-3-(4-(pyrrolidin-3-yl)phenyl)-3 / f- imidazo[4,5-Z>]pyridine

[0767]

[0361] To the solution of tert-butyl 3-(4-((3-amino-6-phenylpyridin-2-yl)amino)phenyl)pyrrolidine- 1-carboxylate (60 mg, 0.14 mmol, 1 equiv) in NMP (2 mb) were added 2-fluoro-6-nitrobenzaldehyde (48 mg, 0.28 mmol, 2 equiv) and TsOH (96 mg, 0.56 mmol, 4 equiv). The mixture solution was stirred at 130 °C for 2 h. The reaction solution was poured into water (50 mL), extracted with EA (3 x 30 mL), the combined organic phase was concentrated in vacuo. The residue was purified by silica gel column chromatography, eluted with MeOH in DCM (0%- 15%) to afford 2-(2-fluoro-6-nitrophenyl)- 5-phenyl-3-(4-(pyrrolidin-3-yl)phenyl)-3H-imidazo[4,5-6]pyridine (100 mg, crude, contains NMP) as a solid. LCMS (M + H)+m / z 480.3.

[0768]

[0362] Step 2. tert-butyl 4-(3-(4-(2-(2-fluoro-6-nitrophenyl)-5-phenyl-3 / f-imidazo[4,5-Z>]pyridin- 3-yl)phenyl)pyrrolidine-l-carbonyl)piperazine-l-carboxylate

[0769]

[0363] To the solution of 2-(2-fluoro-6-nitrophenyl)-5-phenyl-3-(4-(pyrrolidin-3-yl)phenyl)-3H- imidazo[4,5-6]pyridine (100 mg, 0.21 mmol, 1 equiv) in DMF (1 mL) were added 1 -(tert-butyl) 4-(4- nitrophenyl) piperazine- 1,4-di carboxylate (58 mg, 0.16 mmol, 0.8 equiv) and TEA (85 mg, 0.84

[0770] 115

[0771] MEl\56585648.vl 141039-01220 mmol, 4 equiv). The mixture was stirred at 80 °C for 6 h under N2 atmosphere. The reaction solution was poured into water (15 mL), extracted with EA (3 x 20 mL). The organic phase was concentrated in vacuo. The residue was purified by silica gel column chromatography, eluted with MeOH in DCM (0%-10%) to afford tert-butyl 4-(3-(4-(2-(2-fluoro-6-nitrophcnyl)-5-phcnyl-j / / -imidazo|4.5- / ?|pyridm-3-yl)phcnyl)pyrrolidinc- 1 -carbonyl)pipcrazinc- 1 -carboxylate (55 mg, 38%) as a light solid. LCMS (M + H)+m / z:692A.

[0772]

[0364] Step 3. tert-butyl 4-(3-(4-(2-(2-amino-6-fluorophenyl)-5-phenyl-3 / f-imidazo[4,5- Z>]pyridin-3-yl)phenyl)pyrrolidine-l-carbonyl)piperazine-l-carboxylate

[0773]

[0365] To the solution of tert-butyl 4-(3-(4-(2-(2-fluoro-6-nitrophcnyl)-5-phcnyl-3H-imidazo|4.5- / ?|pyridm-3-yl)phcnyl)pyrrolidinc- 1 -carbonyl)pipcrazinc- 1 -carboxylate (45 mg, 0.07 mmol, 1 equiv) in THF (3 mL) was added 10% Pd / C (60 mg). The mixture was stirred at RT for 2 h under H2 atmosphere. The reaction solution was filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography, eluted with EA in PE (0%-100%) to afford tertbutyl 4-(3 -(4-(2-(2-amino-6-fluorophenyl)-5 -phcny I -3H-im idazo [4,5 - / ? | py ridin-3 - yl)phenyl)pyrrolidine-l-carbonyl)piperazine-l -carboxylate (50 mg, 95%) as a light solid. LCMS (M + H)+m / z: 662.4.

[0774]

[0366] Step 4. (3-(4-(2-(2-amino-6-fluorophenyl)-5-phenyl-3 / 7-imidazo[4,5-Z>]pyridin-3- yl)phenyl)pyrrolidin-l-yl)(piperazin-l-yl)methanone

[0775]

[0367] To the solution of tert-butyl 4-(3-(4-(2-(2-amino-6-fluorophcnyl)-5-phcnyl-3H-imidazo|4.5- / ?|pyridm-3-yl)phcnyl)pyrrolidinc- 1 -carbonyl)pipcrazinc- 1 -carboxylate (50 mg, 0.08 mmol, 1 equiv) in DCM (1.5 mL) was added TFA (0.5 mL). The solution was stirred at RT for 1 h. The reaction solution was concentrated in vacuo to afford (3-(4-(2-(2-amino-6-fluorophcnyl)-5-phcnyl-3H- imidazo[4,5-6]pyridin-3-yl)phenyl)pyrrolidin-l-yl)(piperazin-l-yl)methanone (80 mg, crude, TFA salt) as a oil, which was used next step without further purification. LCMS (M + H)+m / z: 562.7.

[0776]

[0368] Step 5. l-(4-(3-(4-(2-(2-amino-6-fluorophenyl)-5-phenyl-3H-imidazo[4,5-b]pyridin-3- yl)phenyl)pyrrolidine-l-carbonyl)piperazin-l-yl)prop-2-en-l-one

[0777]

[0369] To the solution of (3-(4-(2-(2-amino-6-fluorophenyl)-5-phenyl-3H-imidazo[4,5-b]pyridin-3- yl)phenyl)pyrrolidin-l-yl)(piperazin-l-yl)methanone (60 mg, 0.11 mmol, 1 equiv) in MeCN (1 mL) were added TEA (46 mg, 0.44 mmol, 4 equiv), acrylic anhydride (14 mg, 0.11 mmol, 1 equiv). The solution was stirred at RT for 2 h. The reaction solution was purified by prep-HPLC (MeCN / water / lOmM NH4HCO3) to afford l-(4-(3-(4-(2-(2-amino-6-fluorophenyl)-5-phenyl-3H- imidazo [4,5 -b]pyridin-3 -yl)phenyl)pyrrolidine- 1 -carbonyl)piperazin- 1 -yl)prop-2-en- 1 -one (15.88 mg, 17%) as an off-white solid. 'H NMR (400 MHz, DMSO-6) 5 8.27 (d, J= 8.4 Hz, 1H), 8.04 (d, J = 7.2 Hz, 2H), 7.98 (d, J= 8.4 Hz, 1H), 7.50 - 7.48 (m, 2H), 7.46 - 7.40 (m, 5H), 7.11 (dd, J= 15.2, 8.2 Hz, 1H), 6.78 (dd, J= 16.8, 10.5 Hz, 1H), 6.58 - 6.50 (m, 1H), 6.28 - 6.19 (m, 1H), 6.14 - 6.09 (m, 1H), 5.74 (s, 2H), 5.71 - 5.67 (m, 1H), 3.75 - 3.66 (m, 1H), 3.65 - 3.47 (m, 5H), 3.45 - 3.39 (m, 1H),

[0778] 116

[0779] MEl\56585648.vl 141039-01220

[0780] 3.38 - 3.34 (m, 2H), 3.28 - 3.24 (m, 1H), 3.23 - 3.10 (m, 3H), 2.28 - 2.19 (m, 1H), 2.02 - 1.91 (m, 1H). LCMS (M + H)+m / z.' 616.9.

[0781]

[0370] Example 3. 4-(3-(4-(2-(2-aminopyridin-3-yl)-5-(trifluoromethyl)-3H-imidazo[4,5- b]pyridin-3-yl)phenyl)pyrrolidine-l-carbonyl)piperazine-l-carbonitrile

[0782]

[0371] Step 1. 4-nitrophenyl piperazine-l-carboxylate

[0783]

[0372] To a solution of 1 -(tert-butyl) 4-(4-nitrophenyl) piperazine- 1,4-dicarboxylate (50 mg, 0.14 mmol, 1 equiv) in DCM (3 mL) was added TFA (1 mL). The mixture was stirred at RT for 2h. The reaction mixture was concentrated under reduced pressure to afford the title compound (50 mg, crude, TFA salt) as a solid. LCMS [M + H]+m / z: 252. 1.

[0784]

[0373] Step 2. 4-nitrophenyl 4-cyanopiperazine-l-carboxylate

[0785]

[0374] To a solution of 4-nitrophenyl piperazine-l-carboxylate (40 mg, 0.16 mmol, TFA salt, 1 eqiuv) in DCM (2 mL) was added DIPEA (103 mg, 0.80 mmol, 5 equiv) and BrCN (20 mg, 0.19 mmol, 1.2 equiv) at 0°C. The mixture was stirred at RT for 2h. The reaction mixture was diluted with water (40 mL) and extracted with DCM (3 x 30 mL). The combined organic layer was washed with brine, dried over Na2SC>4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography, eluted with EA in PE (0%-50%) to afford the title compound (32 mg, 81%) as a solid. LCMS [M + H]+m / z: 277.1.

[0786]

[0375] Step 3. 4-(3-(4-(2-(2-aminopyridin-3-yl)-5-(trifluoromethyl)-3 / f-imidazo[4,5-Z>]pyridin-3- yl)phenyl)pyrrolidine-l-carbonyl)piperazine-l-carbonitrile

[0787]

[0376] To a solution of 4-nitrophenyl 4-cyanopiperazine-l -carboxylate (32 mg, 0.12 mmol, lequiv.) in DMF (1.5 mL) was added TEA (35 mg, 0.35 mmol, 3 equiv) and 3-(3-(4-(pyrrolidin-3-yl)phenyl)- 5-(trifluoromcthyl)-3 / / -imidazo|4.5- / ? |pyridin-2-yl)pyridin-2 -amine (49 mg, 0.12 mmol, 1 equiv). The mixture was stirred at 80°C for 16h. The reaction mixture was diluted with water (30 mL) and extracted with EA (3 x 30 mL). The combined organic layer was washed with brine, dried over Na2SC>4, filtered, and concentrated under reduced pressure. The crude product was purified by Prep- HPLC (ACN / water / 10 mmol NH4HCO3) to afford the title compound (14.24 mg, 22%) as a solid. ‘H NMR (400 MHz, DMSO-6) 5 8.44 (d, J= 8.2 Hz, 1H), 8.02 (dd, J= 4.8, 1.8 Hz, 1H), 7.88 (d, J=

[0788] 117

[0789] MEl\56585648.vl 141039-01220

[0790] 8.2 Hz, 1H), 7.46 (dd, J= 23.2, 8.5 Hz, 4H), 7.28 (dd, J= 7.6, 1.8 Hz, 1H), 6.80 (s, 2H), 6.45 (dd, J = 7.6, 4.8 Hz, 1H), 3.75 - 3.66 (m, 1H), 3.55 - 3.46 (m, 1H), 3.44 - 3.36 (m, 3H), 3.29 - 3.27 (m, 1H), 3.27 - 3.24 (m, 2H), 3.24 - 3.22 (m, 2H), 3.22 - 3.19 (m, 2H), 3.19 - 3.15 (m, 1H), 2.30 - 2.20 (m, 1H), 2.04 - 1.91 (m, 1H). LCMS [M + H]+m / z: 562.6.

[0791]

[0377] Example 3-1 Alternate Step 1. tert-butyl 4-(3-(4-(2-(2-aminopyridin-3-yl)-5- (trifluoromethyl)-3 / 7-imidazo[4,5-Z>]pyridin-3-yl)phenyl)pyrrolidine-l-carbonyl)piperidine-l- carboxylate

[0792]

[0378] To a solution of l-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (54 mg, 0.24 mmol, 1 equiv) in DMF (1.5 mL) was added DIPEA (71 mg, 0.71 mmol, 3 equiv), 3-(3-(4-(pyrrolidin-3- yl)phenyl)-5-(trifluoromethyl)-3H-imidazo[4,5-6]pyridin-2-yl)pyridin-2-amine (100 mg, 0.24 mmol, 1 equiv) and HATU (107 mg, 0.28 mmol, 1.2 equiv). The mixture was stirred at RT for 3h. The reaction mixture was diluted with water (50 mL) and extracted with EA (3 x 40 mL). The combined organic layer was washed with brine, dried over Na2SC>4, fdtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography, eluted with MeOH in DCM (0%-10%) to afford tert-butyl 4-(3-(4-(2-(2-aminopyridin-3-yl)-5-(trifluoromcthyl)-3H- imidazo|4.5- / ?|pyridin-3-yl)phcnyl)pyrrolidinc- 1 -carbonyl)pipcridinc- 1 -carboxylate (120 mg, 80%) as a solid. LCMS [M + H]+m / z: 636.2.

[0793]

[0379] The compounds in the table below were synthesized as described in Example 3 from appropriate intermediates.

[0794] 118

[0795] MEl\56585648.vl 141039-01220

[0796] 119

[0797] MEl\56585648.vl 141039-01220

[0798]

[0380] Example 4. l-(3-(5-(2-(2-aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin-3- yl)pyridin-2-yl)-3-hydroxypyrrolidine-l-carbonyl)piperidine-4-carboxylic acid

[0799]

[0381] Step 1. 4-ethyl l-(4-nitrophenyl) piperidine-l,4-dicarboxylate

[0800]

[0382] To the mixture of ethyl piperidine-4-carboxylate (250 mg, 1.59 mmol), TEA (643 mg, 6.37 mmol) in DCM (3 mL) was added a solution of 4-nitrophenyl carbonochloridate (320 mg, 1.59 mmol) in DCM (3 mL) at 0 °C. The mixture was stirred at RT for 1 h. After completion of the reaction, quenched the reaction with water (10 mL). The separated aqueous phase was extracted with DCM (20 mL x 3). The combined organic phases were washed with saturated brine (20 mL) and dried over Na2SC>4 and concentrated under reduced pressure. The residue was purified by column chromatography (SiCK 0-30% EA in PE) to afford 4-ethyl 1 -(4-nitrophenyl) piperidine-

[0801] 120

[0802] MEl\56585648.vl 141039-01220

[0803] 1,4 -dicarboxylate (260 mg, 51% yield) as a colorless oil liquid. ‘H NMR (400 MHz, CDCh) 5 8.28 - 8.22 (m, 2H), 7.33 - 7.27 (m, 2H), 4.21 - 4.11 (m, 4H), 3.19 (t, J= 11.4 Hz, 1H), 3.06 (t, J= 11.2 Hz, 1H), 2.56 (tt, J= 10.8, 3.8 Hz, 1H), 2.06 - 1.97 (m, 2H), 1.80 (d, J= 4.4 Hz, 2H), 1.28 (t, J= 7.2 Hz, 3H). LCMS: m / z, 323.3 [(M+H)+],

[0804]

[0383] Step 2. Ethyl l-(3-(5-(2-(2-aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin-3- yl)pyridin-2-yl)-3-hydroxypyrrolidine-l-carbonyl)piperidine-4-carboxylate

[0805]

[0384] A mixture of 3-(5-(2-(2-aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin-3- yl)pyridin-2-yl)pyrrolidin-3-ol (78 mg, 0.17 mmol), 4-ethyl l-(4-nitrophenyl) piperidine- 1,4- dicarboxylate (112 mg, 0.35 mmol) and TEA (103 mg, 1.02 mmol) in DMF (2 mL) was stirred at 65 °C for 16 h. The mixture was diluted with water (10 mL) and extracted with EA (10 mL x 3). The organic layer was dried over Na2SC>4 and evaporated under reduced pressure. The residue was purified by column chromatography (SiCE, 0-6% MeOH in DCM) to afford ethyl l-(3-(5-(2-(2- aminopyridin-3 -yl)-5 -phenyl-3H-imidazo[4,5 -b]pyridin-3 -yl)pyridin-2-yl)-3 -hydroxypyrrolidine- 1 - carbonyl)piperidine-4-carboxylate (67 mg, 62% yield) as a solid. LCMS: m / z, 633.5 [(M+H)+],

[0806]

[0385] Step 3. l-(3-(5-(2-(2-aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin-3- yl)pyridin-2-yl)-3-hydroxypyrrolidine-l-carbonyl)piperidine-4-carboxylic acid

[0807]

[0386] A mixture of ethyl l-(3-(5-(2-(2-aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin-3- yl)pyridin-2-yl)-3-hydroxypyrrolidine-l-carbonyl)piperidine-4-carboxylate (30 mg, 0.05 mmol) in IM NaOH (1 mL) and MeOH (1 mL) was stirred at RT for 1 h. Then adjusted pH to 2 with 2M HC1 aqueous. The remaining mixture was diluted with water (1 mL), and extracted with 5% MeOH in DCM (10 mL x 3). The combined organic phases were dried over Na2SO4 and evaporated under reduced pressure. The residue was purified by prep-HPLC (MeCN / water / 0.1% FA) to afford l-(3- (5 -(2-(2-aminopyridin-3 -yl)-5-phenyl-3H-imidazo[4,5 -b]pyridin-3 -yl)pyridin-2-yl)-3 - hydroxypyrrolidine- l-carbonyl)piperidine-4-carboxylic acid (21.96 mg, 77% yield) as a solid. ’H NMR (400 MHz, DMSO-6) 5 12.19 (brs, 1H), 8.72 (d, J= 2.2 Hz, 1H), 8.30 (d, J= 8.4 Hz, 1H), 8.06 - 7.97 (m, 5H), 7.87 (d, J= 8.4 Hz, 1H), 7.49 (t, J= 7.4 Hz, 2H), 7.41 (t, J= 7.4 Hz, 1H), 7.35 (dd, J= 7.6, 1.8 Hz, 1H), 6.73 (s, 2H), 6.50 (dd, J= 7.6, 4.8 Hz, 1H), 5.75 (s, 1H), 3.92 (d, J= 10.8 Hz, 1H), 3.79 - 3.72 (m, 1H), 3.64 - 3.55 (m, 2H), 3.44 - 3.38 (m, 2H), 2.84 - 2.70 (m, 2H), 2.44 - 2.36 (m, 2H), 2.01 (dd, J= 12.4, 6.0 Hz, 1H), 1.83 - 1.75 (m, 2H), 1.59 - 1.38 (m, 2H). LCMS: m / z, 605.2 [(M+H)+],

[0808]

[0387] The compounds in the table below were synthesized as described in Example 4 from appropriate intermediates.

[0809] 121

[0810] MEl\56585648.vl 141039-01220

[0811]

[0388] Example 5. (3-(5-(2-(2-aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin-3- yl)pyridin-2-yl)-3-hydroxypyrrolidin-l-yl)(3-hydroxy-4,7-dihydroisoxazolo[5,4-c]pyridin-6(5H)- yl)methanone

[0812]

[0389] Step 1. 4-nitrophenyl 3-hydroxy-4,7-dihydroisoxazolo[5,4-c]pyridine-6(5H)-carboxylate

[0813]

[0390] To a solution of 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (500 mg, 2.83 mmol, HC1) in DCM (15 mL) were added TEA (859.47 mg, 8.49 mmol, 1.18 mL) and (4- nitrophenyl)carbonochloridate (570.68 mg, 2.83 mmol). The mixture was stirred at 25°C for 1 h. The mixture was filtered and concentrated to give the title compound as an oil (830 mg, 2.72 mmol, 96% yield) which was used into next step without further purification. ‘H NMR (400MHz, DMS0-< ) 5 = 8.29 (d, J= 9.2 Hz, 2H), 7.49 (d, J= 9.2 Hz, 2H), 4.72 (S, 1H), 4.54 (S, 1H), 3.81 (t, J= 5.2 Hz, 1H), 3.68 (t, J= 5.2 Hz, 1H), 3.47 - 3.27 (m, 1H), 2.45 - 2.38 (m, 1H).

[0814] 122

[0815] MEl\56585648.vl 141039-01220

[0816]

[0391] Step 2. (3-(5-(2-(2-aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin-3-yl)pyridin- 2-yl)-3-hydroxypyrrolidin-l-yl)(3-hydroxy-4,7-dihydroisoxazolo[5,4-c]pyridin-6(5H)- yl)methanone

[0817]

[0392] A mixture of 3-(5-(2-(2-aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin-3-yl)pyridin- 2-yl)pyrrolidin-3-ol (20 mg, 0.04 mmol), 4-nitrophenyl 3-hydroxy-4,7-dihydroisoxazolo[5,4- c]pyridine-6(5H)-carboxylate (20 mg, 0.07 mmol) and TEA (45 mg, 0.44 mmol) in DMF (2 mL) was stirred at 65 °C for 16 h. The mixture was diluted with water (10 mL), extracted with EA (10 mL x 3) and dried over Na2SC>4. The organic layer was evaporated under reduced pressure. The residue was purified by column chromatography (SiCE, 0-10% MeOH in DCM) to afford 8 mg crude product, which was further purified by prep-HPLC (ACN / water / lOmM NH4HCO3) to get the title compound (5.02 mg, 18% yield) as a solid. 'H NMR (400 MHz, DMSO-6) 5 11.35 (brs, 1H), 8.72 (d, J= 2.4 Hz, 1H), 8.30 (d, J= 8.4 Hz, 1H), 8.09 - 7.96 (m, 5H), 7.88 (d, J= 8.4 Hz, 1H), 7.49 (t, J= 7.4 Hz, 2H), 7.44 - 7.39 (m, 1H), 7.35 (dd, J= 7.6, 1.8 Hz, 1H), 6.73 (s, 2H), 6.50 (dd, J= 7.6, 4.8 Hz, 1H), 5.81 (s, 1H), 4.26 (s, 2H), 3.98 (d, J= 10.8 Hz, 1H), 3.84 - 3.74 (m, 1H), 3.66 - 3.57 (m, 1H), 3.52 - 3.43 (m, 2H), 3.20 - 3.14 (m, 1H), 2.44 - 2.38 (m, 2H), 2.32 - 2.23 (m, 1H), 2.08 - 2.00 (m, 1H). LCMS: m / z, 616.2 [(M+H)+],

[0818]

[0393] The compounds in the table below were synthesized as described in Example 5 from appropriate intermediates.

[0819] 123

[0820] MEl\56585648.vl 141039-01220

[0821]

[0394] Example 6. 5-[3-[4-[2-(2-amino-3-pyridyl)imidazo[4,5-b]pyridin-3-yl]phenyl]azetidin-l- yl]-l,2-benzoxazol-3-ol

[0822]

[0395] A mixture of 3-[3-[4-(azetidin-3-yl)phenyl]imidazo[4,5-b]pyridin-2-yl]pyridin-2-amine (150 mg, 438.09 pmol), 5-bromo-l,2-benzoxazol-3-ol (78.13 mg, 365.07 pmol), t-BuONa (2 M in THF, 547.61 pL), [2-(2-aminophenyl)phenyl]-methylsulfonyloxy-palladium;ditert-butyl-[2-(2,4,6- triisopropylphenyl)phenyl]phosphane (87.00 mg, 109.52 pmol) in 3-methylbutan-l-ol (2 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 90°C for 16 h under N2 atmosphere. The reaction mixture without work-up. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0-10% DCM / MeOH @ 40 mL / min) and prep-HPLC (column: CD07-Daisogel SP-100-8-ODS-PK 150 x 25 x 10 pm; mobile phase: [water( NFLHCCD-ACN] ; gradient: 10%-30% B over 10 min) to give the title compound (7.7 mg, 16.19 pmol, 4.44% yield) as a solid. 'H NMR (400MHz, DMSO-6) 5 = 8.36-8.28 (m, 1H), 8.20 (dd, J= 1.2, 8.0 Hz, 1H), 7.99 (dd, J= 1.6, 4.8 Hz, 1H), 7.58-7.51 (m, 2H), 7.45-7.32 (m, 4H), 7.26- 7.20 (m, 1H), 6.97 (s, 2H), 6.85-6.78 (m, 1H), 6.70 (d, J= 2.0 Hz, 1H), 6.41 (dd, J= 4.8, 7.6 Hz, 1H), 4.27 (t, J= 7.6 Hz, 2H), 4.08-3.99 (m, 1H), 3.88-3.80 (m, 2H). LCMS m / z, 476.2 [(M+H)+]

[0823]

[0396] Example 7. 6-[3-[4-[2-(2-amino-3-pyridyl)imidazo[4,5-b]pyridin-3-yl]phenyl]azetidine- l-carbonyl]-2-[(4-methoxyphenyl)methyl]-l,2-benzoxazol- 3-one

[0824] 124

[0825] MEl\56585648.vl 141039-01220

[0826]

[0397] Step 1. 6-[3-[4-[2-(2-amino-3-pyridyl)imidazo[4,5-b]pyridin-3-yl]phenyl]azetidine-l- carbonyl]-2-[(4-methoxyphenyl)methyl]-l,2-benzoxazol-3-one

[0827]

[0398] To a solution of 3-[3-[4-(azetidin-3-yl)phenyl]imidazo[4,5-b]pyridin-2-yl]pyridin-2-amine (100 mg, 292.06 pmol) and 2-[(4-methoxyphenyl)methyl]-3-oxo-l,2-benzoxazole-6-carboxylic acid (87.41 mg, 292.06 pmol) in DCM (2 mL) were added HATU (166.57 mg, 438.09 pmol,) and DIEA (75.49 mg, 584.12 pmol, 101.74 pL). The mixture was stirred at 25°C for 2 h. The reaction mixture was quenched with H2O 20 mL at 25°C, and the resulting mixture was extracted with DCM (30 mL x 3). The combined organic layers were washed with brine (30 mL x 3), dried over anhydrous Na2SC>4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (EA in PE = 0-100%) to give the title compound (70 mg, 112.24 pmol, 38.43% yield) as a solid. LCMS m / z, 624.3 [(M+H)+]

[0828]

[0399] Step 2. 6-[3-[4-[2-(2-amino-3-pyridyl)imidazo[4,5-b]pyridin-3-yl]phenyl]azetidine-l- carbonyl]-2-[(4-methoxyphenyl)methyl]-l,2-benzoxazol-3-one

[0829]

[0400] To a solution of [3-[4-[2-(2-amino-3-pyridyl)imidazo[4,5-b]pyridin-3-yl]phenyl]azetidin-l- yl]-[3-[(4-methoxyphenyl)methoxy]-l,2-benzoxazol-6-yl]methanone (40 mg, 64.14 pmol) in TLA (2 mL) was added trifluoromethanesulfonic acid (48.13 mg, 320.69 pmol, 28.38 pL). The mixture was stirred at 50°C for 4 h. The reaction mixture was quenched by addition H2O (50 ml) at 25 °C. The resulting mixture was extracted with DCM (50 mL x 3). The combined organic layers were washed with brine (50 mL x 3), dried over anhydrous Na2SC>4, adjusted to pH>7 with NtL / McOH (7M), filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: CD02-Waters Xbridge BEH C18 150 x 25 x 10 pm; mobile phase: [water( NELHCCLj-ACN] ; gradient: 6%-36% B over 10 min ) to give the title compound (15.4 mg, 30.59 pmol, 47.69% yield) as a solid. 'H NMR (400MHz, DMSO-6) 5 = 8.32 (dd, J= 1.2, 4.8 Hz, 1H), 8.20 (dd, J= 1.2, 8.0 Hz, 1H), 7.99 (dd, J= 1.6, 4.8 Hz, 1H), 7.87-7.80 (m, 2H), 7.61-7.56 (m, 3H), 7.43 (d, J= 8.4 Hz, 2H), 7.39 (dd, J= 4.8, 8.0 Hz, 1H), 7.23 (dd, J= 1.6, 7.6 Hz, 1H), 6.95 (s, 2H), 6.41 (dd, J= 4.8, 7.6 Hz, 1H), 4.71 (t, J= 8.4 Hz, 1H), 4.60-4.44 (m, 2H), 4.17-3.98 (m, 2H). LCMS m / z, 504.2 [(M+H)+]

[0830]

[0401] Example 8. 2-[3-[4-[2-(2-amino-3-pyridyl)imidazo[4,5-b]pyridin-3-yl]phenyl]azetidin-l- yl]-l-(3-hydroxy-5,7-dihydro-4H-isoxazolo[5,4-c]pyridin-6-yl)ethanone

[0831]

[0402] To a solution of 2-chloro-l-(3-hydroxy-5,7-dihydro-4H-isoxazolo[5,4-c]pyridin-6- yl)ethanone (120 mg, 553.96 pmol) and 3-[3-[4-(azetidin-3-yl)phenyl]imidazo[4,5-b]pyridin-2-

[0832] 125

[0833] MEl\56585648.vl 141039-01220 yl]pyridin-2-amine (227.61 mg, 664.75 pmol) in DCM (3 mL) was added EtsN (112.11 mg, 1.11 mmol, 154.21 pL). The mixture was stirred at 25°C for 1 h. The mixture was acidified with HCl / MeOH (2M) solution until pH~3 and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150 x 25mm x 10 pm; mobile phase: [water(FA)-ACN] ; gradient: 1%-18% B over 8 min ) to give the title compound (23.6 mg, 45.16 pmol, 8.15% yield) as a solid. 'H NMR (400 MHz, DMSO-6) 5 = 8.32 (d, J= 4.0 Hz, 1H), 8.23-8.12 (m, 2H), 7.99 (d, J= 3.2 Hz, 1H), 7.54-7.44 (m, 2H), 7.43-7.33 (m, 3H), 7.22 (d, J= 7.2 Hz, 1H), 6.96 (s, 2H), 6.46 - 6.37 (m, 1H), 4.65-4.48 (m, 2H), 3.85-3.62 (m, 6H), 3.57-3.51 (m, 3H), 2.45-2.26 (m, 2H). LCMS m / z, 523.2 [(M+H)+]

[0834]

[0403] Example 9. [4-[4-[2-(2-amino-3-pyridyl)-5-phenyl-imidazo[4,5-b]pyridin-3-yl]phenyl]-l- piperidyl] -(3-hydroxy-5,7-dihydro-4H-isoxazolo [5,4-c] pyridin-6-yl)methanone

[0835]

[0404] To a solution of (4-nitrophenyl) 3-hydroxy-5,7-dihydro-4H-isoxazolo[5,4-c]pyridine-6- carboxylate (153.80 mg, 503.87 pmol) in DMF (2 mL) were added 3-[5-phenyl-3-[4-(4- piperidyl)phenyl]imidazo[4,5-b]pyridin-2-yl]pyridin-2-amine (150 mg, 335.91 pmol) and DIEA (130.24 mg, 1.01 mmol, 175.53 pL). The mixture was stirred at 90°C for 16 h. The mixture was concentrated. The crude was purified by prep-HPLC (column: C18 150 x 40 mm; mobile phase: [water(HCl)-ACN]; gradient: 30%-60% B over 7 min) to give [4-[4-[2-(2-amino-3-pyridyl)-5-phenyl- imidazo [4,5 -b]pyridin-3 -yl]phenyl] - 1 -piperidyl] -(3 -hydroxy-5 ,7-dihydro-4H-isoxazolo [5 ,4-c]pyridin- 6-yl)methanone (19.6 mg, 31.99 pmol, 9.52% yield) as solid. ’H NMR (400MHz, MeOD) 5 = 8.33 (d, J= 8.4 Hz, 1H), 8.14-8.10 (m, 1H), 8.09-8.00 (m, 4H), 7.80 (dd, J= 12, 1.2 Hz, 1H), 7.51-7.39 (m, 7H), 6.95-6.91 (m, 1H), 6.86 (t, J= 6.4 Hz, 1H), 4.26 (s, 2H), 3.76-3.71 (m, 2H), 3.37 (t, J= 5.2 Hz, 2H), 2.96-2.78 (m, 3H), 2.45-2.32 (m, 2H), 1.87-1.81 (m, 2H), 1.72-1.60 (m, 2H). LCMS m / z, 613.3 [(M+H)+]

[0836]

[0405] Examples 10 and 11: methyl (ls,3s)-3-(6-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3H- imidazo[4,5-b]pyridin-3-yl)phenyl)-2,6-diazaspiro[3.4]octan-2-yl)cyclobutane-l-carboxylate and methyl (lr,3r)-3-(6-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin-3- yl)phenyl)-2,6-diazaspiro[3.4]octan-2-yl)cyclobutane-l-carboxylate. Assigned stereochemical configurations of products are relative, not absolute.

[0837] 126

[0838] MEl\56585648.vl 141039-01220

[0839]

[0406] To a solution of 3-[3-[4-(2,6-diazaspiro[3.4]octan-6-yl)phenyl]-5-phenyl-imidazo[4,5- b]pyridin-2-yl]pyridin-2 -amine (200 mg, 422.32 pmol) in THF (5 mL) was added methyl 3- oxocyclobutanecarboxylate (54.11 mg, 422.32 pmol). After 1 hr, the NaBH(OAc)3 (268.52 mg, 1.27 mmol)was added at 0°C. The mixture was stirred at 0-25°C for 16h. The mixture was fdtered and concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography on silica gel (MeOH in DCM= 0 - 9%) and prep-HPLC (column: Phenomenex luna C18 150*25mm* lOumpnobile phase: [water(FA)-ACN];gradient: 15%-45% B over 8 min ) to give methyl 3-[7-[4-[2-(2-amino-3-pyridyl)-5-phenyl-imidazo[4,5-b]pyridin-3-yl]phenyl]-2,7- diazaspiro[3.4]octan-2-yl]cyclobutanecarboxylate (60 mg, 102.44 pmol, 24.26% yield) as a solid. 20 mg solid was purified by SFC (column: DAICEL CHIRALPAK AD(250mm*30mm,10um);mobile phase: [CO2-ACN / i-PrOH(0.1% NH3H2O)];B%:60%, isocratic elution mode) to give methyl 3-[7-[4- [2-(2-amino-3-pyridyl)-5-phenyl-imidazo[4,5-b]pyridin-3-yl]phenyl]-2,7-diazaspiro[3.4]octan-2- yl] cyclobutanecarboxylate (1.1 mg, 1.88 pmol, 5.50% yield) and methyl 3-[7-[4-[2-(2-amino-3- pyridyl)-5-phenyl-imidazo[4,5-b]pyridin-3-yl]phenyl]-2,7-diazaspiro[3.4]octan-2- yl] cyclobutanecarboxylate (5.6 mg, 9.56 pmol, 28.00% yield) as a solid. ‘H NMR (400 MHz,CDC13) 5 = 8.09 (d, J= 8.4 Hz, 1H), 8.07-7.99 (m, 3H), 7.77 (d, J= 8.4 Hz, 1H), 7.45-7.39 (m, 2H), 7.38- 7.32 (m, 1H), 7.28 (d, J= 1.6 Hz, 1H), 7.24 (d, J= 8.8 Hz, 2H), 6.70 - 6.57 (m, 4H), 6.42 (dd, J= 4.8, 7.6 Hz, 1H), 3.69 (s, 3H), 3.50 (s, 2H), 3.40 (t, J= 6.8 Hz, 2H), 3.30-3.24 (m, 4H), 3.23-3.15 (m, 1H), 2.82-2.73 (m, 1H), 2.28-2.21 (m, 4H), 2.20-2.14 (m, 2H). LCMS m / z, 586.1 [(M+H)+] 'H NMR (400 MHz, CDC13) 5 = 8.09 (d, J= 8.4 Hz, 1H), 8.06-8.01 (m, 3H), 7.77 (d, J= 8.0 Hz, 1H), 7.44-7.40 (m, 2H), 7.37-7.33 (m, 1H), 7.28 (d, J= 2.0 Hz, 1H), 7.23 (s, 2H), 6.64-6.60 (m, 4H), 6.42 (dd, J= 4.8, 8.0 Hz, 1H), 3.70 (s, 3H), 3.51 (s, 2H), 3.40 (t, J= 6.8 Hz, 2H), 3.27-3.20 (m, 5H), 3.13-3.12 (m, 1H), 2.33-2.28 (m, 2H), 2.23 (t, J= 7.2 Hz, 2H), 2.11-2.05 (m, 2H). LCMS m / z, 586.2 [(M+H)+]

[0840]

[0407] Example 12 and 13: (ls,3s)-3-(6-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5- b]pyridin-3-yl)phenyl)-2,6-diazaspiro[3.4]octan-2-yl)cyclobutane-l-carboxylic acid and (lr,3r)- 3-(6-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl)-2,6- diazaspiro[3.4]octan-2-yl)cyclobutane-l-carboxylic acid. Assigned stereochemical configurations of products are relative, not absolute.

[0841] 127

[0842] MEl\56585648.vl 141039-01220

[0843]

[0408] To a solution of methyl 3-[7-[4-[2-(2-amino-3-pyridyl)-5-phenyl-imidazo[4,5-b]pyridin-3- yl]phenyl]-2,7-diazaspiro[3.4]octan-2-yl]cyclobutanecarboxylate (40 mg, 68.29 pmol) in MeOH (2 mb) and H2O (1 mL) was added LiOH.H2O (28.66 mg, 682.95 pmol). The mixture was stirred at 25°C for 2 h. The mixture was fdtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150*25mm* 10um;mobile phase: [water(FA)-ACN];gradient:6%-36% B over 10 min) and SFC (column: DAICEL CHIRALPAK AS(250mm*30mm,10um);mobile phase: [CO2-ACN / EtOH(0.1% NH3H2O)];B%:55%, isocratic elution mode ) to give (ls,3s)-3-(6-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin- 3-yl)phenyl)-2,6-diazaspiro[3.4]octan-2-yl)cyclobutane-l-carboxylic acid (7.0 mg, 12.24 pmol, 17.93% yield) and (lr,3r)-3-(6-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin-3- yl)phenyl)-2,6-diazaspiro[3.4]octan-2-yl)cyclobutane-l-carboxylic acid (1.6 mg, 2.80 pmol, 4.10% yield) as a solid. 'H NMR (400 MHZ,CDC13) 5 = 8.10 (d, J= 8.0 Hz, 1H), 8.05-8.00 (m, 3H), 7.77 (d, J= 8.4 Hz, 1H), 7.45-7.39 (m, 2H), 7.37-7.32 (m, 1H), 7.28-7.27 (m, 1H), 7.26-7.23 (m, 2H), 6.82 (br s, 2H), 6.62 (d, J= 8.8 Hz, 2H), 6.42 (dd, J= 5.2, 8.0 Hz, 1H), 3.61-3.50 (m, 6H), 3.45 (t, J= 6.8 Hz, 2H), 3.34-3.28 (m, 1H), 3.17-3.10 (m, 1H), 2.57-2.54 (m, 2H), 2.32 (t, J= 6.8 Hz, 2H), 2.13-2.07 (m, 2H) LCMS m / z, 572.2 [(M+H)+] 'H NMR (400 MHZ,CDC13) 5 = 8.09 (d, J= 8.4 Hz, 1H), 8.02 (d, J= 7.2 Hz, 3H), 7.77 (d, J= 8.4 Hz, 1H), 7.44-7.39 (m, 2H), 7.38-7.32 (m, 1H), 7.28 (d, J= 1.6 Hz, 1H), 7.24 (d, J= 8.8 Hz, 2H), 6.90 (s, 2H), 6.60 (d, J= 8.8 Hz, 2H), 6.42 (dd, J= 4.8, 7.6 Hz, 1H), 3.52-3.47 (m, 6H), 3.40 (t, J= 6.4 Hz, 2H), 3.20-3.11 (m, 1H), 2.44-2.40 (m, 1H), 2.30-2.18 (m, 6H). LCMS m / z, 572.0 [(M+H)+]

[0844] Example 14. (7?)-l-(4-(3-(5-(2-(2-aminopyridin-3-yl)-5-cyclopropyl-3 / 7-imidazo[4,5-Z>]pyridin-3- yl)pyridin-2-yl)-3-methoxypyrrolidine-l-carbonyl)piperazin-l-yl)prop-2-en-l-one

[0845] 128

[0846] MEl\56585648.vl 141039-01220

[0847]

[0409] Step 1. (7?)-3-(5-cyclopropyl-3-(6-(3-methoxypyrrolidin-3-yl)pyridin-3-yl)-3 / f- imidazo[4,5-Z>]pyridin-2-yl)pyri din-2- amine

[0848]

[0410] To the mixture of tert-butyl ( / ?)-3-(5-(2-(2-aminopyridin-3-yl)-5-cyclopropyl-3H- imidazo|4.5- / ? |pyridin-3-yl)pyridin-2-yl)-3-mcthoxypyrrolidinc- 1 -carboxylate (41 mg, 0.08 mmol, 1.0 equiv) in DCM (1 mb) was added TFA (1 mb). The reaction mixture was stirred for 1 h at RT under N2 atmosphere. The reaction mixture was concentrated under reducing pressure to afford ( / ?)-3-(5- cy clopropyl-3-(6-(3-mcthoxypyrrolidin-3-yl)pyridin-3-yl)-3H-imidazo|4.5- / ? |pyridin-2-yl)pyridin-2- amine (33 mg, crude) as a oil. The crude product was used for the next step directly without further purification. LCMS (M + H)+m / z 428.3.

[0849]

[0411] Step 2. tert-butyl (7?)-4-(3-(5-(2-(2-aminopyridin-3-yl)-5-cyclopropyl-3 / f-imidazo[4,5- Z>]pyridin-3-yl)pyridin-2-yl)-3-methoxypyrrolidine-l-carbonyl)piperazine-l-carboxylate

[0850]

[0412] To the mixture of ( / ?)-3-(5-cyclopropyl-3-(6-(3-mcthoxypyrrolidin-3-yl)pyridin-3-yl)-3H- imidazo|4.5- / ? |pyridin-2-yl)pyridin-2 -amine (33 mg, 0.08 mmol, 1.0 equiv) and TEA (0.4 mb) in DMF (2 mL) was added 1 -(tert-butyl) 4-(4-nitrophenyl) piperazine- 1,4-dicarboxylate (28 mg, 0.08 mmol, 1.0 equiv). The reaction mixture was stirred for 16 h at 80 °C under N2 atmosphere. Water (50 mL) was added to the reaction mixture and extracted with EA (3 x 50 mL). The combined organic phase was washed with brine (3 x 50 mL), dried over Na2SC>4 and concentrated under reducing pressure. The residue was purified by silica gel column chromatography, eluted with MeOH in DCM (0%-5%) to afford tert-butyl ( / )-4-(3-(5-(2-(2-aminopyridin-3-yl)-5-cyclopropyl-3H-imidazo|4.5- / ? |pyridin-3-yl)pyridin-2-yl)-3-mcthoxypyrrolidinc- 1 -carbonyl)pipcrazinc- 1 -carboxylate (30 mg, 61%) as a solid. LCMS (M + H)+m / z. 640.3

[0851]

[0413] Step 3. (7?)-(3-(5-(2-(2-aminopyridin-3-yl)-5-cyclopropyl-3 / f-imidazo[4,5-Z>]pyridin-3- yl)pyridin-2-yl)-3-methoxypyrrolidin-l-yl)(piperazin-l-yl)methanone

[0852]

[0414] To the mixture of tert-butyl ( / ?)-4-(3-(5-(2-(2-aminopyridin-3-yl)-5-cyclopropyl-3H- imidazo [4,5 - / ? |pyridin-3 -yl)pyridin-2-yl)-3 -methoxypyrrolidine- 1 -carbonyl)piperazine- 1 -carboxylate (30 mg, 0.05 mmol, 1.0 equiv) in DCM (1 mL) was added TFA (1 mL). The reaction mixture was stirred for 1 h at RT under N2 atmosphere. The mixture was concentrated under reducing pressure to afford ( / )-(3-(5-(2-(2-aminopyridin-3-yl)-5-cy clopropyl-3H-imidazo|4.5- / ? |pyridin-3-yl)pyridin-2- yl)-3-methoxypyrrolidin-l-yl)(piperazin-l-yl)methanone (25 mg, crude) as a oil. The crude product was used for the next step directly without further purification. LCMS (M + H)+m / z: 540.3.

[0853]

[0415] Step 4. (7?)-l-(4-(3-(5-(2-(2-aminopyridin-3-yl)-5-cyclopropyl-3 / f-imidazo[4,5-Z>]pyridin- 3-yl)pyridin-2-yl)-3-methoxypyrrolidine-l-carbonyl)piperazin-l-yl)prop-2-en-l-one

[0854] 129

[0855] MEl\56585648.vl 141039-01220

[0856]

[0416] To the mixture of ( / ?)-(3-(5-(2-(2-aminopyridin-3-yl)-5-cyclopropyl-3 / / -imidazo|4.5- 6]pyridin-3-yl)pyridin-2-yl)-3-methoxypyrrolidin-l-yl)(piperazin-l-yl)methanone (25 mg, 0.05 mmol, 1.0 equiv) and TEA (0.02 mL) in MeCN (1 mL) was added acrylic anhydride (7 mg, 0.05 mmol, 1.1 equiv). The reaction mixture was stirred for 0.5 h at RT under N2 atmosphere. NH4CI (sat aq 50 mL) was added to the reaction mixture and extracted with EA (3 x 50 mL). The combined organic phase was washed with brine (3 x 100 mL), dried over Na2SC>4 and concentrated under reducing pressure. The residue was purified by prep-HPLC (MeCN / water / 0.1% LAC) to afford (R)-l-(4-(3-(5-(2-(2- aminopyridin-3 -yl ) -5 -cyclopropy 1 -3H-im idazo [4,5 - / ? | py ridin-3 -yl)pyridin-2-yl)-3 - methoxypyrrolidine- l-carbonyl)piperazin-l-yl)prop-2-en-l -one (8.16 mg, 30%) as a solid. LCMS (M + H)+m / z: 594.3.

[0857]

[0417] The compounds in the table below were synthesized as described for Example 14 from appropriate starting materials.

[0858] 130

[0859] MEl\56585648.vl 141039-01220

[0860] 131

[0861] MEl\56585648.vl 141039-01220

[0862] 132

[0863] MEl\56585648.vl 141039-01220

[0864] 133

[0865] MEl\56585648.vl 141039-01220

[0866] 134

[0867] MEl\56585648.vl 141039-01220

[0868]

[0418] Example 15. (7?)-l-(4-(3-(5-(2-(2-aminopyridin-3-yl)-5-(trifluoromethyl)-3 / f-imidazo[4,5- Z>]pyridin-3-yl)pyridin-2-yl)-3-hydroxypyrrolidine-l-carbonyl)piperazin-l-yl)prop-2-en-l-one and (5)-l-(4-(3-(5-(2-(2-aminopyridin-3-yl)-5-(trifluoromethyl)-3 / f-imidazo[4,5-Z>]pyridin-3- yl)pyridin-2-yl)-3-hydroxypyrrolidine-l-carbonyl)piperazin-l-yl)prop-2-en-l-one

[0869]

[0419] Step 1. tert-butyl 4-(3-(5-(2-(2-aminopyridin-3-yl)-5-(trifluoromethyl)-3 / f-imidazo[4,5- Z>]pyridin-3-yl)pyridin-2-yl)-3-hydroxypyrrolidine-l-carbonyl)piperazine-l-carboxylate

[0870]

[0420] To the solution of 3-(5-(2-(2-aminopyridin-3-yl)-5-(trifhioromethyl)-3H-imidazo[4,5- / ?|pyridin-3-yl)pyridin-2-yl)pyrrolidin-3-ol (17 mg, 0.04 mmol, 1 equiv) in DMF (1 mL) were added 1 -(tert-butyl) 4-(4-nitrophenyl) piperazine- 1,4-dicarboxylate (13 mg, 0.04 mmol, 1 equiv) and TEA (23 mg, 0.23 mmol, 6 equiv). The mixture was stirred at 65 °C for 16 h under N2 atmosphere. The reaction solution was poured into water (15 mL), extracted with EA (3 x 20 mL). The organic phase was concentrated in vacuo. The residue was purified by silica gel column chromatography, eluted with MeOH in DCM (0%-5%) to afford tert-butyl 4-(3-(5-(2-(2-aminopyridin-3-yl)-5- (trifluoromethyl)-3H-imidazo[4,5-6]pyridin-3-yl)pyridin-2-yl)-3-hydroxypyrrolidine-l- carbonyl)piperazine-l -carboxylate (15 mg, 60%) as a solid. LCMS (M + H)+m / z 654.6.

[0871]

[0421] Step 2. (3-(5-(2-(2-aminopyridin-3-yl)-5-(trifluoromethyl)-3 / 7-imidazo[4,5-Z>]pyridin-3- yl)pyridin-2-yl)-3-hydroxypyrrolidin-l-yl)(piperazin-l-yl)methanone

[0872]

[0422] To the solution of tert-butyl 4-(3-(5-(2-(2-aminopyridin-3-yl)-5-(trifluoromethyl)-3H- imidazo[4,5-b]pyridin-3-yl)pyridin-2-yl)-3-hydroxypyrrolidine-l-carbonyl)piperazine-l-carboxylate (15 mg, 0.02 mmol, 1 equiv) in DCM (1 mL) was added TFA (1 mL). The solution was stirred at RT for 2 h. The reaction solution was concentrated in vacuo to give (3-(5-(2-(2-aminopyridin-3-yl)-5- (trifluoromethyl)-3H-imidazo[4,5-6]pyridin-3-yl)pyridin-2-yl)-3-hydroxypyrrolidin-l-yl)(piperazin-l- yl)methanone (20 mg, crude, TFA salt) as a oil. The crude was used next step without further purification. LCMS (M + H)+m / z 554.5.

[0873]

[0423] Step 3. l-(4-(3-(5-(2-(2-aminopyridin-3-yl)-5-(trifluoromethyl)-3 / 7-imidazo[4,5- Z>]pyridin-3-yl)pyridin-2-yl)-3-hydroxypyrrolidine-l-carbonyl)piperazin-l-yl)prop-2-en-l-one

[0874] 135

[0875] MEl\56585648.vl 141039-01220

[0876]

[0424] To the solution of (3-(5-(2-(2-aminopyridin-3-yl)-5-(trifluoromcthyl)-3 / / -imidazo|4.5- 6]pyridin-3-yl)pyridin-2-yl)-3-hydroxypyrrolidin-l-yl)(piperazin-l-yl)methanone (15 mg, 0.03 mmol, 1 equiv) in MeCN (1 mL) were added TEA (17 mg, 0.16 mmol, 6 equiv) and acrylic anhydride (4 mg, 0.03 mmol, 1.1 equiv). The mixture was stirred at RT for 0.5 h. The reaction solution was purification by prep-HPLC (MeCN / water / lOmM NH4HCO3) to afford l-(4-(3-(5-(2-(2-aminopyridin-3-yl)-5- (trifluoromethyl)-3H-imidazo[4,5-6]pyridin-3-yl)pyridin-2-yl)-3-hydroxypyrrolidine-l- carbonyl)piperazin-l-yl)prop-2-en-l-one (3.04 mg, 18%) as an solid. LCMS (M + H)+m / z'. 608.5.

[0877]

[0425] Step 4. (7?)-l-(4-(3-(5-(2-(2-aminopyridin-3-yl)-5-(trifluoromethyl)-3 / 7-imidazo[4,5- Z>]pyridin-3-yl)pyridin-2-yl)-3-hydroxypyrrolidine-l-carbonyl)piperazin-l-yl)prop-2-en-l-one & (A)-l-(4-(3-(5-(2-(2-aminopyridin-3-yl)-5-(trifluoromethyl)-3 / 7-imidazo[4,5-Z>]pyri din-3- yl)pyridin-2-yl)-3-hydroxypyrrolidine-l-carbonyl)piperazin-l-yl)prop-2-en-l-one

[0878]

[0426] 1 -(4-(3 -(5 -(2-(2-aminopyridin-3 -yl) -5 -(trifl uoromcthyl )-3 / / -im idazo| 4.5 - / | py ridin-3 - yl)pyridin-2-yl)-3-hydroxypyrrolidine-l-carbonyl)piperazin-l-yl)prop-2-en-l-one (35 mg, 0.06 mmol) was purified by SFC (Regis (R,R)Whelk-Ol (25*250mm,10um), CO2 / EtOH=60 / 40) to afford ( / ?)- 1 -(4-(3 -(5-(2-(2-aminopyridin-3 -yl) -5 -(trifl uoromethyl )-3H-im idazo [4,5 - / | py ridin-3 -yl)pyridin-2- yl)-3-hydroxypyrrolidine-l-carbonyl)piperazin-l-yl)prop-2-en-l-one (16.52 mg, 47%) as an and (.8)-

[0879] 1 -(4-(3 -(5 -(2-(2-aminopyridin-3 -yl) -5 -(trifl uoromethyl )-3 / / -im idazo| 4.5 - / ? | py ridin-3 -yl)pyridin-2-yl)- 3 -hydroxypyrrolidine- l-carbonyl)piperazin-l-yl)prop-2-en-l -one (15.21 mg, 43%) as a solid.

[0880]

[0427] The compounds in the table below were synthesized as described for Example 15 from appropriate starting materials.

[0881] 136

[0882] MEl\56585648.vl 141039-01220

[0883] 137

[0884] MEl\56585648.vl 141039-01220

[0885] 138

[0886] MEl\56585648.vl 141039-01220

[0887] 139

[0888] MEl\56585648.vl 141039-01220

[0889] 140

[0890] MEl\56585648.vl 141039-01220

[0891] Biological assays to measure the activities of AKT1 and AKT2

[0892]

[0428] Biological Example 1. Active AKT1 and AKT2 PhosphoSens kinase assay

[0893]

[0429] Assay principle

[0894]

[0430] Phosphosens kinase assay utilizes a sulfonamido-oxine (Sox) fluorophore modified peptide as substrate. When the target serine / threonine / tyrosine residue on the substrate peptide is phosphorylated, it forms a complex with magnesium ion and the sulfonamido-oxine (Sox) fluorophore. The complex allows a continuous fluorescent readout with Ex of 360 nm and Em of 490 nm. The slope of the fluorescence represents the kinase activity.

[0895]

[0431] Materials

[0896]

[0432] The following materials are used in the assay: active wt AKT1 (1-480, co-expressed with 3- Phosphoinositide dependent protein kinase-1 in presence of A-443654 and okadaic acid to achieve full activation); active AKT1 E17K (1-480, co-expressed with 3 -Phosphoinositide dependent protein kinase-1 in presence of A-443654 and okadaic acid to achieve full activation); wt AKT2 (2-480, coexpressed with 3 -Phosphoinositide dependent protein kinase-1 in presence of A-443654 and okadaic acid to achieve full activation); AssayQuant AKT1 substrate, AQT0536; lipid and phosphatidylinositol 3,4,5 trisphosphate (PIP3) mixture ( 500 uM PIP3 in lipid mix consisted of POPC, DOPS, POPE and cholesterol); Assay buffer: 50 mM HEPES pH 7.5, 0.004%Tween-20, ImM DTT, lOmM MgCE. Controls: Selleckchem Cat#s S8500 and S8339.

[0897]

[0433] Procedures

[0898]

[0434] On a 384-well LDV microplate, prepared 10 pl of example compound stock solution and prepared 5.5 pl DMSO in the intermediate plate. 10-point and 3-fold serial dilutions were performed by an Echo on the LDV microplate. Then 200 nl of compounds and DMSO, in duplicated wells, were transferred to a ProxiPlate-384 microplate by the Echo. 4.8 uL enzyme mix containing 10.8 nM kinase solution and 31.2 uM Lipid PIP3 mix was added to the assay plate, then 5 uL of substrate solution containing 100 uM ATP and 30 uM AQT0536 was added to initiate the reaction. The plate was spun for 1 min at 500 rpm, then read on Ensight for 2 h with 5 min interval under Ex360 / Em490. The slope was calculated from the raw data and each slope was normalized by no enzyme (100%

[0899] 141

[0900] MEl\56585648.vl 141039-01220 inhibition) and enzyme only (0% inhibition). IC50 was calculated using a four-parameter (top, bottom, hill slope and IC50 equation) fitting.

[0901]

[0435] Data in Table 1 collected using Biological Example 1. Activity values as follows: A > 1001 nM; 1000 nM > B > 101 nM; 101 nM > C.

[0902] Table 1

[0903] 142

[0904] MEl\56585648.vl 141039-01220

[0905] 143

[0906] MEl\56585648.vl 141039-01220

[0907] 144

[0908] MEl\56585648.vl 141039-01220

[0909] 145

[0910] MEl\56585648.vl 141039-01220

[0911] 146

[0912] MEl\56585648.vl

Claims

141039-01220CLAIMSWhat is claimed is:

1. A compound having the structural Formula I:or a pharmaceutically acceptable salt thereof, whereinX1, X2, X3, X4X5, X6, and X7are each independently N or CRE;Y is selected from OH or NHR9;R1is heterocyclyl optionally substituted with 1 to 4 groups selected from RA;R2is hydrogen, (Ci-C4)alkyl, or R1and R2taken together with the carbon atoms to which they are attached form a heterocyclyl optionally substituted with 1 to 4 groups selected from RB;R3is selected from (Ci-C4)alkyl, halo(Ci-C4)alkyl, hydroxy(Ci-C4)alkyl, (Ci-C4)alkoxy, halo(Ci-C4)alkoxy, (Ci-C4)alkylene(Ci-C4)alkoxy, (C2-C4)alkenyl, halo(C2-C4)alkenyl, (C2- C4)alkynyl, halo(C2-C4)alkynyl, cyano, halo, NH(Ci-C4)alkyl, N[(Ci-C4)alkyl]2, NH2, hydroxy, (Ci- C4)alkylene [phenyl], (Ci-C4)alkylene [heterocyclyl], (Ci-C4)alkylene [cycloalkyl], (Ci- C4)alkylene [heteroaryl], O[ phenyl ], O [heterocyclyl], O [cycloalkyl], O [heteroaryl], phenyl, heterocyclyl, heteroaryl, and cycloalkyl, wherein each of said phenyl, heterocyclyl, heteroaryl, and cycloalkyl alone, or as part of a larger group, are optionally substituted by 1 to 3 groups selected from cyano, halo, (Ci-C4)alkyl, halo(Ci-C4)alkyl, (Ci-C4)alkoxy, and halo(Ci-C4)alkoxy;RAand RBare each independently selected from (Ci-C4)alkyl, halo(Ci-C4)alkyl, hydroxy(Ci- C4)alkyl, (Ci-C4)alkoxy, halo(Ci-C4)alkoxy, cyano, halo, hydroxy, (C2-C4)alkenyl, halo(C2- C4)alkenyl, (C2-C4)alkynyl, halo(C2-C4)alkynyl, (Ci-C4)alkyl(Ci-C4)alkoxy, (Ci-C4)alkyleneC(O)R4, (Ci-C4)alkyleneC(O)OR4, (Ci-C4)alkyleneC(O)NR5R6, (Ci-C4)alkyleneNR5C(O)R6, (Ci- C4)alkyleneNR5C(O)NR6R7, (Ci-C4)alkylene[phenyl], (Ci-C4)alkylene [heterocyclyl], (Ci- C4)alkylene [cycloalkyl], (Ci-C4)alkylene [heteroaryl], phenyl, heteroaryl, heterocyclyl, cycloalkyl, - C(O)R4, -S(O)nR4,-C(O)OR4, -C(O)NR5R6, -NR5C(O)R6, -NR5C(O)NR6R7, oxo, NR5R6, (Ci- C4)alkyleneNR5R6, -(Ci-C4)alkoxyNR5R6, (C1-C4) alkoxyC(O)R4, (Ci-C4)alkoxyC(O)OR4, wherein each of said phenyl, heterocyclyl, heteroaryl, and cycloalkyl alone, or as part of a larger group, are optionally substituted with 1 to 3 groups selected from Rc;R4is selected from hydrogen, (Ci-C4)alkyl, (Ci-C4)alkylene [phenyl], (Ci- C4)alkylene [heterocyclyl], (Ci-C4)alkyleneNR5R6, (Ci-C4)alkylene [cycloalkyl], (Ci- C4)alkylene [heteroaryl], heterocyclyl, heteroaryl, cycloalkyl, and phenyl, wherein each of said phenyl,147MEl\56585648.vl141039-01220 heterocyclyl, heteroaryl, and cycloalkyl alone, or as part of a larger group, are optionally substituted with 1 to 3 groups selected from RD;R4a, R5, R5a, R6, R6a, R7, and R7aare each independently selected from hydrogen, (Ci-C4)alkyl, halo(Ci-C4)alkyl, (C2-C4)alkenyl, (Ci-C4)alkylene [phenyl], (Ci-C4)alkylene[heterocyclyl], (Ci- C4)alkylene [cycloalkyl], (Ci-C4)alkylene [heteroaryl], heterocyclyl, heteroaryl, cycloalkyl, and phenyl, wherein each of said phenyl, heterocyclyl, heteroaryl, and cycloalkyl alone, or as part of a larger group, are optionally substituted with 1 to 3 groups selected from halo, hydroxy, (Ci-C4)alkyl, and halo(Ci-C4)alkyl; wherein when R4ais (C2-C4)alkenyl, the (C2-C4)alkenyl is optionally substituted with 1 or 2 substituents selected from halo, cyano, (Ci-C4)alkyl, (C3-Ce)cycloalkyl, and C(R5R6)NR5aR6aRcis selected from (Ci-C4)alkyl, halo(Ci-C4)alkyl, hydroxy(Ci-C4)alkyl, (Ci-C4)alkoxy, (Ci- C4)alkoxy(Ci-C4)alkyl, halo(Ci-C4)alkoxy, cyano, halo, hydroxy, oxo, C(O)OH, C(O)O(Ci-C4)alkyl, (C2-C4)alkenyl, halo(C2-C4)alkenyl, (C2-C4)alkynyl, halo(C2-C4)alkynyl, (Ci-C4)alkylene [phenyl], (Ci -C4)alkylene [heterocyclyl] , (Ci -C4)alkylene [cycloalkyl] , (Ci -C4)alkylene [heteroaryl] , phenyl, heterocyclyl, heteroaryl, and cycloalkyl, wherein each of said phenyl, heterocyclyl, heteroaryl, and cycloalkyl alone, or as part of a larger group, are optionally substituted with 1 to 3 groups selected from RC1;RC1is selected from (Ci-C4)alkyl, halo(Ci-C4)alkyl, (Ci-C4)alkoxy, halo(Ci-C4)alkoxy, (Ci- C4)alkyl(Ci-C4)alkoxy, cyano, halo, hydroxy, oxo, C(O)OH, C(O)O(Ci-C4)alkyl, phenyl, heterocyclyl, heteroaryl, and cycloalkyl;RDis selected from hydroxy, cyano, halo, (Ci-C4)alkyl, halo(Ci-C4)alkyl, (Ci-C4)alkoxy, halo(Ci-C4)alkoxy, oxo, C(O)R4a, C(O)OR4a, -C(O)NR5aR6a, -NR5aC(O)R6a, 5-6 membered heteroaryl, and -NR5aC(O)NR6aR7a, and NR8aR9a, wherein said heteroaryl is optionally substituted by 1 to 3 groups selected from RC1;REis selected from hydrogen, halo, hydroxy, (Ci-C4)alkoxy, cyano, and (Ci-C4)alkyl;R8is hydrogen or halo;R8a, and R9aare each independently selected from hydrogen, (Ci-C4)alkyl, halo(Ci-C4)alkyl, (Ci-C4)alkoxy, halo(Ci-C4)alkoxy, and cyano.R9is hydrogen or (Ci-C4)alkyl; n is 1 or 2; and z is 0, 1 or 2.

2. The compound of Claim 1, or a pharmaceutically acceptable salt thereof, whereinR2is hydrogen or R1and R2taken together with the carbon atoms to which they are attached form a heterocyclyl optionally substituted with 1 to 4 groups selected from RB;148MEl\56585648.vl141039-01220R4a, R5, R5a, R6, R6a, R7, and R7aare each independently selected from hydrogen, (Ci-C4)alkyl, halo(Ci-C4)alkyl, (C2-C4)alkenyl, (Ci-C4)alkylene [phenyl], (Ci-C4)alkylene[heterocyclyl], (Ci- C4)alkylene [cycloalkyl], (Ci-C4)alkylene [heteroaryl], heterocyclyl, heteroaryl, cycloalkyl, and phenyl, wherein each of said phenyl, heterocyclyl, heteroaryl, and cycloalkyl alone, or as part of a larger group, are optionally substituted with 1 to 3 groups selected from halo, hydroxy, (Ci-C4)alkyl, and halo(Ci-C4)alkyl;RDis selected from hydroxy, cyano, (Ci-C4)alkyl, halo(Ci-C4)alkyl, (Ci-C4)alkoxy, halo(Ci- C4)alkoxy, oxo, C(O)R4a, C(O)OR4a, -C(O)NR5aR6a, -NR5aC(O)R6a, 5-6 membered heteroaryl, and - NR5aC(O)NR6aR7a, wherein said heteroaryl is optionally substituted by 1 to 3 groups selected from RC1.

3. The compound of Claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein X2is N and X1and X3are each CH; X1, X2, and X3are each N; X1is N and X2and X3are each CH; or X1and X2are N and X3is CH.

4. The compound of any one of Claims 1 to 3, wherein the compound is of the structuralFormula la:or a pharmaceutically acceptable salt thereof.

5. The compound of any one of Claims 1 to 3, wherein the compound is of the structuralFormula lb:or a pharmaceutically acceptable salt thereof.149MEl\56585648.vl141039-012206. The compound of any one of Claims 1 to 3, wherein the compound is of the structuralFormula Ic:or a pharmaceutically acceptable salt thereof.

7. The compound of any one of Claims 1 to 3, wherein the compound is of the structuralFormula Id:or a pharmaceutically acceptable salt thereof.

8. The compound of any one of Claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein REis hydrogen.

9. The compound of any one of Claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein X4is N.

10. The compound of any one of Claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein X4is CH.

11. The compound of any one of Claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein R8is hydrogen.

12. The compound of any one of Claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein z is 1 or 2.150MEl\56585648.vl141039-0122013. The compound of any one of Claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein Y is NHR9.

14. The compound of any one of Claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein R9is hydrogen.

15. The compound of any one of Claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein R3is selected from (Ci-C4)alkyl, halo(Ci-C4)alkyl, hydroxy(Ci-C4)alkyl, halo, (C2- C4)alkynyl, phenyl, heterocyclyl, and cycloalkyl, wherein each of said phenyl, heterocyclyl, heteroaryl, and cycloalkyl are optionally substituted by 1 to 3 groups selected from cyano, halo, (Ci- C4)alkyl, halo(Ci-C4)alkyl, (Ci-C4)alkoxy, and halo(Ci-C4)alkoxy.

16. The compound of any one of Claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein R3is selected from (Ci-C4)alkyl, halo(Ci-C4)alkyl, hydroxy(Ci-C4)alkyl, halo, cyano, (C2- C4)alkynyl, phenyl, 5- to 7-membered heterocyclyl, and (C3-C6)cycloalkyl.

17. The compound of any one of Claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein R3is selected from (Ci-C4)alkyl, halo(Ci-C4)alkyl, hydroxy(Ci-C4)alkyl, halo, (C2- C4)alkynyl, phenyl, 5- to 7-membered heterocyclyl, and (C3-C6)cycloalkyl.

18. The compound of any one of Claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein R3is selected from bromo, fluoro, chloro, CF3, CH3, (QT^OH, CH(CH3)2OH, CCH, CN, phenyl, morpholinyl, pyrrolidinyl, and cyclopropyl.

19. The compound of any one of Claims 1 to 18, or a pharmaceutically acceptable salt thereof, wherein R3is selected from bromo, fluoro, chloro, CF3, CH3, (CFF^OH, CCH, phenyl, morpholinyl, pyrrolidinyl, and cyclopropyl.

20. The compound of any one of Claims 1 to 19, or a pharmaceutically acceptable salt thereof, wherein R3is phenyl.

21. The compound of any one of Claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein z is 1 and R3is attached to the carbon atom adjacent to X2.

22. The compound of any one of Claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein z is 2 and one R3is attached to the carbon atom adjacent to X2, and the other R3is attached to the carbon atom adjacent to X3.151MEl\56585648.vl141039-0122023. The compound of any one of Claims 1 to 22, or a pharmaceutically acceptable salt thereof, wherein R1and R2taken together with the carbon atoms to which they are attached form a 5-6 membered heterocyclyl, optionally substituted with 1 to 4 groups selected from RB.

24. The compound of any one of Claims 1 to 23, or a pharmaceutically acceptable salt thereof, wherein R1and R2taken together with the carbon atoms to which they are attached form a 1, 2,3,6- tetrahydropyridinyl optionally substituted with 1 to 4 groups selected from RB.

25. The compound of any one of Claims 1 to 24, or a pharmaceutically acceptable salt thereof, wherein RBis -C(O)R4, -C(O)OR4, or -C(O)NR5R6.

26. The compound of any one of Claims 1 to 22, or a pharmaceutically acceptable salt thereof, wherein RBis -C(O)R4.

27. The compound of any one of Claims 1 to 22, or a pharmaceutically acceptable salt thereof, wherein R2is hydrogen, or CH,.

28. The compound of any one of Claims 1 to 22 or 27, or a pharmaceutically acceptable salt thereof, wherein R2is hydrogen.

29. The compound of Claim 27 or 28, or a pharmaceutically acceptable salt thereof, wherein R1is a 4-10 membered heterocyclyl optionally substituted with 1 to 4 groups selected from RA.

30. The compound of any one of Claims 27 to 29, or a pharmaceutically acceptable salt thereof, wherein R1is azetidinyl, pyrrolidinyl, piperidinyl, or 2,6-diazaspiro[3.4]octanyl, each of which are optionally substituted with 1 to 4 groups selected from RA.

31. The compound of any one of Claims 27 to 30, or a pharmaceutically acceptable salt thereof, wherein each RAis independently selected from (Ci-C4)alkyl, (Ci-C4)alkoxy, halo, hydroxy, (Ci- C4)alkyleneC(O)R4, (Ci-C4)alkyleneC(O)OR4, (Ci-C4)alkyleneC(O)NR5R6, (Ci- C4)alkyleneNR5C(O)R6, (Ci-C4)alkylene [phenyl], (Ci-C4)alkylene [heterocyclyl], (Ci-C4)alkylene [cycloalkyl], (Ci-C4)alkylene [heteroaryl], phenyl, heteroaryl, 5-9 membered heterocyclyl, cycloalkyl, -C(O)R4, -SO2R4, -C(O)OR4, -C(O)NR5R6, and (Ci-C4)alkyleneNR5R6, wherein each of said phenyl, heterocyclyl, heteroaryl, and cycloalkyl alone, or as part of a larger group, are optionally substituted with 1 to 3 groups selected from Rc.152MEl\56585648.vl141039-0122032. The compound of any one of Claims 27 to 31, or a pharmaceutically acceptable salt thereof, wherein each RAis independently selected from halo, hydroxy, (Ci-C4)alkyl, (Ci-C4)alkoxy, (Ci- C4)alkyleneC(O)R4, (Ci-C4)alkyleneC(O)OR4, (Ci-C4)alkylene [phenyl], (Ci-C4)alkylene[5-9- membered heterocyclyl], (Ci-C4)alkylene[9 membered heteroaryl], phenyl, 6-9 membered heteroaryl, 5-9 membered heterocyclyl, (C3-Ce)cycloalkyl, -C(O)R4, -SO2R4, -C(O)OR4, and -C(O)NR5R6, wherein each of said phenyl, heterocyclyl, heteroaryl, and cycloalkyl alone, or as part of a larger group, are optionally substituted with 1 to 3 groups selected from Rc.

33. The compound of any one of Claims 27 to 32, or a pharmaceutically acceptable salt thereof, wherein each RAis independently selected from halo, hydroxy, (Ci-C4)alkyl, (Ci-C4)alkyleneC(O)R4, (Ci-C4)alkyleneC(O)OR4, (Ci-C4)alkylene [phenyl], (Ci-C4)alkylene [5 -9-membered heterocyclyl], (Ci-C4)alkylene[9 membered heteroaryl], phenyl, 6-9 membered heteroaryl, 5-9 membered heterocyclyl, (C3-Ce)cycloalkyl, -C(O)R4, -SO2R4, -C(O)OR4, and -C(O)NR5R6, wherein each of said phenyl, heterocyclyl, heteroaryl, and cycloalkyl alone, or as part of a larger group, are optionally substituted with 1 to 3 groups selected from Rc.

34. The compound of any one of Claims 27 to 33, or a pharmaceutically acceptable salt thereof, wherein each RAis independently selected from fluoro, hydroxy, methoxy, methyl, -C(O)OR4, - C(O)R4, (Ci-C4)alkyleneC(O)R4, (Ci-C4)alkyleneC(O)OR4, (Ci-C4)alkylene [phenyl], -SO2R4, phenyl, (Ci-C4)alkylene(benzoisoxazolyl), benzoisoxazolyl, dihydrobenzoisothiazolyl, (Ci- C4)alkylene(dihydrobenzoisoxazolyl), (Ci-C4)alkylene[isothiazolidinyl], thiazinanyl, (Ci- C4)alkylene[thiazinanyl], (Ci-C4)alkylene[indolinyl], thiazepanyl, tetrahydro-2H-thiopyranyl, cyclobutyl, cyclohexyl, and -C(O)NR5R6, wherein each of the foregoing groups is optionally substituted with 1 to 3 groups selected from Rc.

35. The compound of any one of Claims 27 to 34, or a pharmaceutically acceptable salt thereof, wherein each RAis independently selected from fluoro, hydroxy, methyl, -C(O)OR4, -C(O)R4, (Ci- C4)alkyleneC(O)R4, (Ci-C4)alkyleneC(O)OR4, (Ci-C4)alkylene [phenyl], -SO2R4, phenyl, (Ci- C4)alkylene(benzoisoxazolyl), benzoisoxazolyl, dihydrobenzoisothiazolyl, (Ci- C4)alkylene(dihydrobenzoisoxazolyl), (Ci-C4)alkylene[isothiazolidinyl], thiazinanyl, (Ci- C4)alkylene [thiazinanyl], (Ci-C4)alkylene[indolinyl], thiazepanyl, tetrahydro-2H-thiopyranyl, cyclobutyl, cyclohexyl, and -C(O)NR5R6, wherein each of the foregoing groups is optionally substituted with 1 to 3 groups selected from Rc.

36. The compound of any one of Claims 27 to 35, or a pharmaceutically acceptable salt thereof, wherein each RAis independently selected from fluoro, hydroxy, methoxy, methyl, -C(O)OR4, - C(O)R4, (Ci-C4)alkyleneC(O)R4, (Ci-C4)alkyleneC(O)OR4, (Ci-C4)alkylene [phenyl], -SO2R4, phenyl,153MEl\56585648.vl141039-01220(Ci-C4)alkylene(benzo[d]isoxazolyl), benzo[d]isoxazolyl, l,3-dihydrobenzo[c]isothiazolyl, (Ci- C4)alkylene(2,3-dihydrobenzo[d]isoxazolyl), (Ci-C4)alkylene[isothiazolidinyl], 1,2-thiazinanyl, (Ci- C4)alkylene [ 1 ,2-thiazinanyl] , (Ci -C4)alkylene [indolinyl] , 1 ,2-thiazepanyl, tetrahydro-2H-thiopyranyl, cyclobutyl, cyclohexyl, and -C(O)NR5R6, wherein each of the foregoing groups is optionally substituted with 1 to 3 groups selected from Rc.

37. The compound of any one of Claims 27 to 36, or a pharmaceutically acceptable salt thereof, wherein each RAis independently selected from fluoro, hydroxy, methyl, -C(O)OR4, -C(O)R4, (Ci- C4)alkyleneC(O)R4, (Ci-C4)alkyleneC(O)OR4, (Ci-C4)alkylene [phenyl], -SO2R4, phenyl, (Ci- C4)alkylene(benzo[d]isoxazolyl), benzo [d]isoxazolyl, l,3-dihydrobenzo[c]isothiazolyl, (Ci- C4)alkylene(2,3-dihydrobenzo[d]isoxazolyl), (Ci-C4)alkylene[isothiazolidinyl], 1,2-thiazinanyl, (Ci- C4)alkylene [ 1 ,2-thiazinanyl] , (Ci -C4)alkylene [indolinyl] , 1 ,2-thiazepanyl, tetrahydro-2H-thiopyranyl, cyclobutyl, cyclohexyl, and -C(O)NR5R6, wherein each of the foregoing groups is optionally substituted with 1 to 3 groups selected from Rc.

38. The compound of any one of Claims 27 to 37, or a pharmaceutically acceptable salt thereof, wherein each Rcis independently selected from (Ci-C4)alkyl, halo(Ci-C4)alkyl, hydroxy(Ci-C4)alkyl, (Ci-C4)alkoxy, (Ci-C4)alkoxy(Ci-C4)alkyl, halo(Ci-C4)alkoxy, halo, hydroxy, oxo, -C(O)OH, - C(O)O(Ci-C4)alkyl, (Ci-C4)alkylene [phenyl], (Ci-C4)alkylene[heterocyclyl], (Ci-C4)alkylene [cycloalkyl], (Ci-C4)alkylene [heteroaryl], 5-6 membered heterocyclyl, and cycloalkyl, wherein each of said phenyl, heterocyclyl, heteroaryl, and cycloalkyl alone, or as part of a larger group, are optionally substituted with 1 to 3 groups selected from RC1.

39. The compound of any one of Claims 27 to 38, or a pharmaceutically acceptable salt thereof, wherein each Rcis independently selected from (Ci-C4)alkyl, halo(Ci-C4)alkyl, hydroxy(Ci-C4)alkyl, (Ci-C4)alkoxy, (Ci-C4)alkoxy(Ci-C4)alkyl, halo(Ci-C4)alkoxy, halo, hydroxy, oxo, -C(O)OH, - C(O)O(Ci-C4)alkyl, and 5 membered heterocyclyl, wherein said heterocyclyl is optionally substituted with 1 to 3 groups selected from RC1.

40. The compound of any one of Claims 27 to 39, or a pharmaceutically acceptable salt thereof, wherein each Rcis independently selected from, CH2OCH3, hydroxy, oxo, C(O)OH, C(O)OCH3, and dihydroisoxazolyl, wherein said dihydroisoxazolyl is optionally substituted with 1 to 3 groups selected from RC1.

41. The compound of any one of Claims 27 to 40, or a pharmaceutically acceptable salt thereof, wherein each RC1is selected from (Ci-C4)alkyl, (Ci-C4)alkoxy, halo, hydroxy, and oxo.154MEl\56585648.vl141039-0122042. The compound of any one of Claims 27 to 41, or a pharmaceutically acceptable salt thereof, wherein RC1is oxo.

43. The compound of any one of Claims 27 to 42, or a pharmaceutically acceptable salt thereof, wherein R4is selected from hydrogen, (Ci-C4)alkyl, (Ci-C4)alkylene [phenyl], (Ci-C4)alkylene[5-10 membered heterocyclyl], (Ci-C4)alkylene[6-10 membered heteroaryl], 6-10 membered heterocyclyl, 6-9 membered heteroaryl, and phenyl, wherein each of said phenyl, heterocyclyl, and heteroaryl are optionally substituted with 1 to 3 groups selected from RD.

44. The compound of any one of Claims 27 to 43, or a pharmaceutically acceptable salt thereof, wherein R4is selected from hydrogen, (Ci-C4)alkyl, piperidinyl, piperazinlyl, azabicyclohexanyl, diazaspiroheptanyl, tetrahydroisoxazolopyridinyl, (Ci-C4)alkylene[phenyl], triazaspirooctanyl, (Ci- C4)alkylene(dihydrobenzoisothiazolyl), tetrahydropyrazolopyridinyl, hexahydrooxazolopyrazinyl, hexahydroimidazopyrazinyl, (Ci -C4)alkylene(hexahydroimidazopyrazinyl), azabicycloheptanyl, benzoisoxazolyl, phenyl, octahydroimidazopyrazinyl, octahydropyrrolopyrazinyl, triazaspirodecanyl, (Ci-C4)alkylene[isoxazolyl], and dihydrobenzoisothiazolyl, wherein each of the foregoing groups is optionally substituted with 1 to 3 groups selected from RD.

45. The compound of any one of Claims 27 to 44, or a pharmaceutically acceptable salt thereof, wherein R4is selected from hydrogen, (Ci-C4)alkyl, piperidinyl, piperazinlyl, 3- azabicyclo[3.1.0]hexanyl, 2,6-diazaspiro[3.3]heptanyl, 4,5,6,7-tetrahydroisoxazolopyridinyl, (Ci- C4)alkylene [phenyl], 2,5,7-triazaspiro[3.4]octanyl, 2-azaspiro[3.3]heptanyl (Ci-C4)alkylene(l,3- dihydrobenzoisothiazolyl), 4,5,6,7-tetrahydro-2H-pyrazolopyridinyl, hexahydro-3H- oxazolopyrazinyl, 3,5,6,7,8,8a-hexahydroimidazopyrazinyl, (Ci-C4)alkylene(3,5,6,7,8,8a- hexahydroimidazopyrazinyl), 3 -azabicyclo [3. l.l]heptanyl, benzoisoxazolyl, phenyl, 3,8- diazabicyclo[3.2.1]octanyl, octahydroimidazopyrazinyl, azetidinyl, octahydropyrrolopyrazinyl, 1,3,8- triazaspiro[4.5]decanyl, (Ci-C4)alkylene[isoxazolyl], and 1,3-dihydrobenzoisothiazolyl, wherein each of the foregoing groups is optionally substituted with 1 to 3 groups selected from RD.

46. The compound of any one of Claims 27 to 45, or a pharmaceutically acceptable salt thereof, wherein R4is selected from hydrogen, (Ci-C4)alkyl, piperidinyl, piperazinlyl, 3- azabicyclo[3.1.0]hexanyl, 2,6-diazaspiro[3.3]heptanyl, 4,5,6,7-tetrahydroisoxazolopyridinyl, (Ci- C4)alkylene [phenyl] , 2,5 ,7-triazaspiro [3 ,4]octanyl, (Ci -C4)alkylene( 1 ,3 -dihydrobenzoisothiazolyl), 4,5,6,7-tetrahydro-2H-pyrazolopyridinyl, hexahydro-3H-oxazolopyrazinyl, 3,5,6,7,8,8a- hexahydroimidazopyrazinyl, (Ci-C4)alkylene(3,5,6,7,8,8a-hexahydroimidazopyrazinyl), 3- azabicyclo[3.1.1]heptanyl, benzoisoxazolyl, phenyl, octahydroimidazopyrazinyl, octahydropyrrolopyrazinyl, l,3,8-triazaspiro[4.5]decanyl, (Ci-C4)alkylene[isoxazolyl], and 1,3-155MEl\56585648.vl141039-01220 dihydrobenzoisothiazolyl, wherein each of the foregoing groups is optionally substituted with 1 to 3 groups selected from RD.

47. The compound of any one of Claims 27 to 46, or a pharmaceutically acceptable salt thereof, wherein each RDis independently selected from hydroxy, halo, cyano, (Ci-C4)alkyl, halo(Ci-C4)alkyl, (Ci-C4)alkoxy, halo(Ci-C4)alkoxy, oxo, -C(O)R4a, -C(O)OR4a, -C(O)NR5aR6a, -NR5aC(O)R6a, 5-6 membered heteroaryl, -NR5aC(O)NR6aR7a, and NR8aR9a, wherein said heteroaryl is optionally substituted by 1 to 3 groups selected from RC1.

48. The compound of any one of Claims 27 to 47, or a pharmaceutically acceptable salt thereof, wherein each RDis independently selected from hydroxy, cyano, (Ci-C4)alkyl, halo(Ci-C4)alkyl, (Ci- C4)alkoxy, halo(Ci-C4)alkoxy, oxo, -C(O)R4a, -C(O)OR4a, -C(O)NR5aR6a, -NR5aC(O)R6a, 5-6 membered heteroaryl, and -NR5aC(O)NR6aR7a, wherein said heteroaryl is optionally substituted by 1 to 3 groups selected from RC1.

49. The compound of any one of Claims 27 to 48, or a pharmaceutically acceptable salt thereof, wherein each RDis independently selected from hydroxy, fluoro, cyano, CH,. OMe, oxo, -C(O)R4a, - C(O)OR4a, -C(O)NR5aR6a; isoxazolyl, and NR8aR9a, wherein said isoxazolyl is optionally substituted by 1 to 3 groups selected from RC1.

50. The compound of any one of Claims 27 to 49, or a pharmaceutically acceptable salt thereof, wherein each RDis independently selected from hydroxy, cyano, C h. OMe, oxo, -C(O)R4a, - C(O)OR4a, -C(O)NR5aR6a; and isoxazolyl, wherein said isoxazolyl is optionally substituted by 1 to 3 groups selected from RC1.

51. The compound of any one of Claims 27 to 50, or a pharmaceutically acceptable salt thereof, wherein R4ais selected from hydrogen, (Ci-C4)alkyl, halo(Ci-C4)alkyl, and (C2-C4)alkenyl, wherein the (C2-C4)alkenyl is optionally substituted with 1 or 2 substituents selected from halo, cyano, (Ci- C4)alkyl, (C3-Ce)cycloalkyl, and C(R5R6)NR5aR6a.

52. The compound of any one of Claims 27 to 51, or a pharmaceutically acceptable salt thereof, wherein R4ais selected from hydrogen, (Ci-C4)alkyl, halo(Ci-C4)alkyl, and (C2-C4)alkenyl.156MEl\56585648.vl141039-0122053. The compound of any one of Claims 27 to 52, or a pharmaceutically acceptable salt thereof,54. The compound of any one of Claims 27 to 53, or a pharmaceutically acceptable salt thereof, wherein R4ais selected from hydrogen, C h. CH2CH3, C(CH3)3, CF3, and ethenyl.

55. The compound of any one of Claims 27 to 54, or a pharmaceutically acceptable salt thereof, wherein R8a, and R9aare each independently selected from hydrogen and cyano.

56. The compound of any one of Claims 27 to 55, or a pharmaceutically acceptable salt thereof, wherein R5, R5a, R6, and R6aare each independently selected from hydrogen, (Ci-C4)alkyl, and (Ci- C4)alkylene[5-9 membered heteroaryl], wherein each of said phenyl and heteroaryl are optionally substituted with 1 to 3 groups selected from halo, hydroxy, (Ci-C4)alkyl, and halo(Ci-C4)alkyl.

57. The compound of any one of Claims 27 to 56, or a pharmaceutically acceptable salt thereof, wherein R5, R5a, R6, and R6aare each independently selected from hydrogen and (Ci-C4)alkylene[5-9 membered heteroaryl], wherein each of said phenyl and heteroaryl are optionally substituted with 1 to 3 groups selected from halo, hydroxy, (Ci-C4)alkyl, and halo(Ci-C4)alkyl.

58. The compound of any one of Claims 27 to 57, or a pharmaceutically acceptable salt thereof, wherein R5, R5a, R6, and R6aare each independently selected from hydrogen, CH3, and (Ci- C4)alkylene[isoxazolyl], wherein said isoxazolyl is optionally substituted with hydroxy.

59. The compound of any one of Claims 27 to 58, or a pharmaceutically acceptable salt thereof, wherein R5, R5a, R6, and R6aare each independently selected from hydrogen and (Ci- C4)alkylene [isoxazolyl], wherein said isoxazolyl is optionally substituted with hydroxy.

60. The compound of any one of Claims 27 to 59, or a pharmaceutically acceptable salt thereof, wherein R1is157MEl\56585648.vl141039-01220158MEl\56585648.vl141039-01220159MEl\56585648.vl141039-01220160MEl\56585648.vl141039-01220161MEl\56585648.vl141039-01220162MEl\56585648.vl141039-0122061. The compound of any one of Claims 27 to 60, or a pharmaceutically acceptable salt thereof, wherein R1is163MEl\56585648.vl141039-01220164MEl\56585648.vl141039-01220165MEl\56585648.vl141039-01220166MEl\56585648.vl141039-0122061. The compound of Claim 1, wherein the compound is selected from any one of those exemplified herein, or a pharmaceutically acceptable salt of any of the foregoing.

62. A pharmaceutical composition comprising: i) the compound of any one of claims 1-61 or a pharmaceutically acceptable salt thereof; and ii) a pharmaceutically acceptable carrier, excipient or diluent.

63. A method of treating a subject with cancer, comprising administering to the subject an effective amount of the compound of claims 1-61 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 62.

64. The method of claim 63, wherein the cancer is characterized by irregularities in the activity of Akt and downstream cellular targets of Akt , or Akt activation by gene amplification.

65. The method of claim 63 or 64, wherein the cancer is breast cancer, prostate cancer, colon cancer, ovarian cancer, colorectal cancer, lung cancer or non-small cell lung cancer.

66. A method for inhibition of Aktl in a subject in need thereof, comprising administering to the subject an effective amount of the compound of claims 1-61 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 62.167MEl\56585648.vl

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