Pyridopyrazoles as ddr inhibitors for treatment of fibrotic conditions and cancer

Abstract

The present invention relates to novel compounds and pharmaceutical compositions comprising the same. More specifically, the present invention relates to compounds useful as inhibitors of discoidin domain receptor 1 (DDR1) and discoidin domain receptor 2 (DDR2). The compounds are particularly useful in the treatment of cancer and fibrotic diseases.

Description

Technical Field

[0001] The present invention relates to novel compounds and pharmaceutical compositions comprising the novel compounds. More specifically, the present invention relates to compounds useful as inhibitors of discoidin domain receptor 1 (DDR1) and discoidin domain receptor 2 (DDR2). The compounds are particularly useful for treating cancer and fibrotic diseases. Background Art

[0002] Discoidin domain receptor (DDR) DDR1 and DDR2 are type 1 transmembrane receptor tyrosine kinases (RTKs) with collagen receptor function (Vogel et al., Mol. Cell, 1997). DDR contains a characteristic collagen-binding discoidin domain in the N-terminal extracellular domain. These domains are arranged in accordance with the extracellular juxtamembrane domain, single transmembrane domain, cytoplasmic juxtamembrane domain and catalytic kinase domain before the short C-terminal tail. Five subtypes of DDR1 (DRR1a-e) have been identified, which are produced by selective splicing of the cytoplasmic region. Alternative subtypes of DDR2 have not yet been identified. DDR1 and DDR2 have extensive (but not completely) mutually exclusive expression profiles in epithelial cells and matrix, respectively. DDR is activated by binding to collagen, and the binding has a wide spectrum of specificity, but has a clear preference for certain collagen types. It is known that after activation, DDR regulates cell adhesion, proliferation and remodeling of the extracellular matrix. It is well established that the DDR is upregulated in response to cellular activity and many forms of tissue damage, and therefore has been implicated in diseases including cancer, atherosclerosis, and diseases characterized by fibrosis and inflammation. Inhibitors of DDR kinase activity may be beneficial as therapeutic agents in these disease areas.

[0003] As summarized in a recent review, overexpression and / or activation of DDR1 and DDR2 are associated with various forms of cancer (Elkamhawy et al., Int. J. Mol. Sci., 2021). Studies have shown that elevated DDR expression levels and / or mutations can be found in many cancer cell lines and primary tumor tissues including lung, pancreas, prostate, breast, brain, ovary, liver, etc. DDR1 was found to be a prognostic marker for patients with non-small cell lung cancer (NSCLC). A recent study showed that siRNA-mediated downregulation of DDR1 inhibited the malignancy, migration, invasion, and survival of melanoma cells. DDR1 protein was also found to be expressed in 63% of serous ovarian cancer tissues, but not in normal ovarian surface epithelium. The involvement of DDR1 in glioblastoma cell invasion and epithelial-mesenchymal transition (EMT) has also been confirmed. DDR1 was found to be expressed in 50.5% of gastric cancer tissues. DDR1 was found to control the growth of triple-negative breast cancer by regulating tumor-infiltrating CD4+ and CD8+ T cells. There is also strong evidence that DDR2 may be a potential biomarker and molecular target for a variety of cancers. For example, DDR2 overexpression has been reported to lead to NSCLC, thyroid cancer, Hodgkin's lymphoma, nasopharyngeal carcinoma, prostate cancer, and head and neck squamous cell carcinoma. According to studies, DDR2 promotes breast cancer metastasis by stabilizing the SNAIL1 protein. DDR2 has also been shown to be a favorable independent predictor of recurrence and outcome in primary breast cancer. In addition to the important role of wild-type DDR in cancer pathology and prognosis, various mutations of DDR1 and / or DDR2 have been reported in many types of cancer cells, for example, G1486T (DDR1) and A496S (DDR1) in lung cancer, N502S (DDR1), A533S (DDR1), and A803V (DDR1) in acute myeloid leukemia (AML), and S768R (DDR2) in squamous cell carcinoma. DDRs also play a role in cancer growth by controlling how tumor cells interact with their surrounding collagen matrix. This role of DDRs becomes more prominent when their role as extracellular matrix receptors is considered. The extracellular matrix (ECM) confers structural properties to the tissue surrounding tumors and regulates cell proliferation, survival, migration, and invasion. In metastatic cancers, the physiological interaction between tumor cells and their immediate microenvironment represented by the extracellular matrix is ​​disrupted. As a key component of the tumor extracellular matrix, type I collagen exhibits a high density and distorted structure in malignant cancers, linking it to tumor formation and metastasis. Therefore, the discovery of DDRs as collagen receptors represents a new target in the regulation of tumor progression.

[0004] DDR also seems to play an important role in the regulation of inflammation and fibrosis. The regulation of fibrosis and inflammation has been confirmed in multiple organs including lungs and kidneys. In lung DDR-1-deficient mice, bleomycin-induced lung damage was shown to be reduced (Vogel et al., Am. J. Respir. Crit. Care Med., 2006), and DDR1 and DDR2 have been shown to be expressed in patients with fibrotic lung disease (Bian et al., ERJ Open Res., 2016). In the kidney, DDR1 expression is increased in patients with lupus nephritis and Goodpasture syndrome and in glomerulonephritis mouse models (Kerroch et al., FASEB journal, 2012) and in the tubules of mice with unilateral ureteral obstruction (UUO) (Guerrot et al., Am. J. Pathol., 2011). Several studies have demonstrated that DDR1-deficient mice are protected from angiotensin II-mediated proteinuria, glomerular fibrosis, and inflammation and show reduced collagen deposition, tubular macrophage infiltration, and proinflammatory cytokine levels after the UUO process. Finally, COL3A3 KO mice (a mouse model of human Alport syndrome) crossed with DDR1-deficient mice have reduced renal fibrosis and inflammation due to reduced TGF-β-mediated signaling and reduced levels of the proinflammatory cytokine IL-6 (Dorison, Cell Adhesion and Migration, 2018).

[0005] Small molecule inhibitors of DDR1 and DDR2 kinase activity have been disclosed in the prior art, and it has been demonstrated that the inhibitory activity of DDR1 and / or DDR2 produces effective effects in mouse models of cancer and fibrotic diseases (Richter et al., ACS Chem. Biol., 2019; Wang et al., J. Med. Chem., 2018; Zhu et al., J. Med. Chem., 2019). These reports support the hypothesis that inhibitors of DDR kinase activity may be beneficial as therapeutic agents for treating human cancer and fibrotic diseases.

[0006] In addition, the purpose of certain embodiments of the present invention is to provide new compounds for treating diseases such as cancer and fibrotic diseases. These compounds can be inhibitors of DDR1 and / or DDR2. The purpose of certain embodiments of the present invention is to provide compounds with activity comparable to that of existing DDR1 and / or DDR2 inhibitors. The purpose of certain embodiments of the present invention is to provide compounds with enhanced activity relative to existing DDR1 and / or DDR2 inhibitors.

[0007] Certain embodiments of the present invention meet some or all of the above objectives. Summary of the invention

[0008] The present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof:

[0009] in

[0010] X 1 , X 2 and X 3 Each independently selected from carbon and nitrogen, wherein X 1 , X 2 and X 3 At least two of them are carbon;

[0011] X 4 , X 5 , X 6 and X 7 Each independently selected from carbon and nitrogen, wherein X 4 , X 5 , X 6 and X 7 At least two of them are carbon;

[0012] R 1 is independently selected at each occurrence from halogen, nitro, cyano, NR 9 R 10 , OR 11 , SR 9 、SO2NR 9 R 9 、SO2R 9 、CO2R 9 、C(O)R 9 ,CONR 9 R 9 、C1-C4-alkyl、NR 9 R 10 Substituted C1-C4-alkyl, 11 substituted C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and cyclopropyl;

[0013] R 3 independently selected from H and C1-C4-alkyl;

[0014] R 4 independently selected from C1-C6-alkyl, C1-C6-haloalkyl, C0-C4-alkylene-R 4a ; where R 4a independently selected from: C3-C8-cycloalkyl, phenyl, 5, 6, 9 or 10-membered heteroaryl and 4 to 10-membered heterocycloalkyl; wherein the heterocycloalkyl or heteroaryl may be monocyclic or bicyclic; wherein the cycloalkyl or heterocycloalkyl is optionally substituted by a single R12 group and / or 1 to 4 R 13 wherein the phenyl or heteroaryl group is optionally substituted by a single R 12 group and / or 1 to 3 R 14 Group substitution;

[0015] or R 3 and R 4 Together with the nitrogen atom to which they are attached, they form a 4- to 10-membered heterocycloalkyl or a 5- or 9-membered heteroaryl; wherein the heterocycloalkyl or heteroaryl may be monocyclic or bicyclic; wherein the heterocycloalkyl is optionally substituted by a single R 12 group and / or 1 to 4 R 13 wherein the heteroaryl group is optionally substituted by a single R 12 group and / or 1 to 3 R 14 Group substitution;

[0016] R 5 are independently selected at each occurrence from H, halogen and C1-C4-alkyl, or two R 5 The groups and the carbon atoms to which they are attached may together form a C3-C6-cycloalkyl ring;

[0017] R 6 is independently selected at each occurrence from halogen, nitro, cyano, NR 9 R 10 , OR 11 , SR 9 、SO2NR 9 R 9 、SO2R 9 、CO2R 9 、C(O)R 9 ,CONR 9 R 9 、C1-C4-alkyl、NR 9 R 10 Substituted C1-C4-alkyl, 11 substituted C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and cyclopropyl;

[0018] R 7 is independently selected at each occurrence from halogen, nitro, cyano, NR 9 R 10 , OR 11 , SR 9 、SO2NR 9 R 9 、SO2R 9 、CO2R 9 、C(O)R 9 ,CONR9 R 9 、C1-C4-alkyl、NR 9 R 10 Substituted C1-C4-alkyl, 11 substituted C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and cyclopropyl;

[0019] R 8a are independently selected from H, halogen, nitro, cyano, NR 9 R 10 , OR 11 , SR 9 、SO2NR 9 R 9 、SO2R 9 、CO2R 9 、C(O)R 9 ,CONR 9 R 9 、C1-C4-alkyl、NR 9 R 10 Substituted C1-C4-alkyl, 11 Substituted C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and C0-C4-alkylene-R 8c ;

[0020] R 8b independently selected from H, C1-C4-alkyl, 9 R 9 Substituted C1-C4-alkyl, NR 9 R 10 Substituted C2-C4-alkyl, 11 Substituted C2-C4-alkyl, C3-C4-alkenyl, C3-C4-alkynyl, C1-C4-haloalkyl and C0-C4-alkylene-R 8c ;

[0021] R 8c independently selected from C3-C6-cycloalkyl and 3 to 7 membered heterocycloalkyl; wherein the heterocycloalkyl is attached to the C0-C4-alkylene via a carbon atom in the heterocycloalkyl ring; wherein the cycloalkyl or heterocycloalkyl is optionally substituted by 1 to 4 R 13 Group substitution;

[0022] R 9 are independently selected at each occurrence from H and C1-C4-alkyl; or two R 9 The groups together with the nitrogen atom to which they are attached form an optionally substituted group consisting of 0 to 4 R 13 C5-C8 heterocycloalkyl substituted with a group;

[0023] R 10 is independently selected at each occurrence from H, C1-C4-alkyl, C(O)-C1-C4-alkyl and S(O)2-C1-C4-alkyl; or R 9 and R 10 Together with the nitrogen atom to which they are attached, they form an optionally substituted 0 to 4 R 13 C5-C8 heterocycloalkyl substituted with a group;

[0024] R 11 is independently selected at each occurrence from H, C1-C4-alkyl, C(O)-C1-C4-alkyl and C1-C4-haloalkyl;

[0025] R 12 independently selected from C3-C6-cycloalkyl, phenyl, 5- or 6-membered heteroaryl and 3- to 6-membered heterocycloalkyl; wherein the cycloalkyl or heterocycloalkyl is optionally substituted by 1 to 4 R 13 wherein the phenyl or heteroaryl group is optionally substituted by 1 to 3 R 14 group substitution;

[0026] R 13 is independently selected at each occurrence from =O, halogen, nitro, cyano, NR 8 R 9 , OR 14 , SR 8 、SO2NR 8 R 8 、CO2R 8 、C(O)R 8 ,CONR 8 R 8 , C1-C4-alkyl, OR 11 Substituted C1-C4-alkyl, NR 9 R 10 Substituted C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl, C6-C 10 - aryl and C3-C6-cycloalkyl;

[0027] R 14 is independently selected at each occurrence from halogen, nitro, cyano, NR 8 R 9 , OR 10 , SR 8 、SO2R 8 、SO2NR 8 R 8 、CO2R 8 、C(O)R 8 ,CONR 8R 8 , C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl, 11 Substituted C1-C4-alkyl, NR 8 R 9 Substituted C1-C4-alkyl and cyclopropyl;

[0028] m is an integer selected from 0, 1, 2, 3 and 4;

[0029] n is an integer selected from 0, 1, 2, 3 and 4;

[0030] p is an integer selected from 0, 1 and 2;

[0031] wherein any of the above alkyl, alkylene or cyclopropyl groups is optionally substituted, where chemically possible, by 1 to 5 substituents, each of which is independently selected at each occurrence from the group consisting of halogen, oxo, fluoro, nitro, cyano, NR a R b , OR a , SR a 、CO2R a 、C(O)R a ,CONR a R a , C1-C4-alkyl, C1-C4-haloalkyl and cyclopropyl; wherein R a is independently selected at each occurrence from H, C1-C4-alkyl and C1-C4-haloalkyl; and R b is independently selected at each occurrence from H, C1-C4-alkyl, C(O)-C1-C4-alkyl and S(O)2-C1-C4-alkyl.

[0032] In one embodiment, the compound of formula (I) is a compound of formula (II):

[0033]

[0034] Where X 4 , X 5 , X 6 , X 7 , R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8a , R 8b , m, n and p are as described above for the compound of formula (I).

[0035] In one embodiment, the compound of formula (I) is a compound of formula (III):

[0036]

[0037] Where X 1 , X 2 , X 3 , R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8a , R 8b , m, n and p are as described above for the compound of formula (I).

[0038] In one embodiment, the compound of formula (I) is a compound of formula (IV):

[0039]

[0040] Where R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8a , R 8b , m, n and p are as described above for the compound of formula (I).

[0041] In one embodiment, the compound of formula (I) is a compound of formula (V):

[0042]

[0043] Where X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , R 1 , R 3 , R 4 , R 6 , R 7 , R 8a , R 8b , m, n and p are as described above for the compound of formula (I).

[0044] In one embodiment, the compound of formula (I) is a compound of formula (VI):

[0045]

[0046] Where X 1 , X 2, X 3 , X 4 , X 5 , X 6 , X 7 , R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8b , m, n and p are as described above for the compound of formula (I).

[0047] In one embodiment, the compound of formula (I) is a compound of formula (VII):

[0048]

[0049] Where X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , R 1 , R 3 , R 4 , R 6 , R 7 , R 8b , m, n and p are as described above for the compound of formula (I).

[0050] In one embodiment, the compound of formula (I) is a compound of formula (VIII):

[0051]

[0052] Where X 4 , X 5 , X 6 , X 7 , R 1 , R 3 , R 4 , R 6 , R 7 , R 8b , m, n and p are as described above for the compound of formula (I).

[0053] In one embodiment, the compound of formula (I) is a compound of formula (IX):

[0054]

[0055] Where R 1 , R 3 , R 4 , R 6, R 7 , R 8b , m, n and p are as described above for the compound of formula (I).

[0056] In one embodiment, the compound of formula (I) is a compound of formula (X):

[0057]

[0058] Where R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8a , R 8b , m and p are as described above for the compound of formula (I), and n is an integer selected from 0, 1, 2 and 3.

[0059] In one embodiment, the compound of formula (I) is a compound of formula (XI):

[0060]

[0061] Where R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8a , R 8b , m and p are as described above for the compound of formula (I), and n is an integer selected from 0, 1, 2 and 3.

[0062] In one embodiment, the compound of formula (I) is a compound of formula (XII):

[0063]

[0064] Where R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8a , R 8b , m and p are as described above for the compound of formula (I), and n is an integer selected from 0, 1 and 2.

[0065] The following embodiments are applicable to compounds of any formula (I)-(XII). These embodiments are independent and interchangeable. Where chemically permitted, any one embodiment may be combined with any other embodiment. In other words, any feature described in the following embodiments may be combined with the feature described in one or more other embodiments (where chemically permitted). In particular, where compounds are illustrated or explained in this specification, any two or more of the embodiments listed below that contain the compounds expressed at any general level may be combined to provide further embodiments forming a part of the present disclosure.

[0066] Can be X 1 It is carbon. It can be X 2 It is carbon. It can be X 3 It is carbon. It can be X 1 and X 2 All are carbon. It can be X 2 and X 3 All are carbon. It can be X 1 and X 3 All are carbon. It can be X 1 , X 2 and X 3 Each is carbon.

[0067] Can be X 1 , X 2 and X 3 One of them is nitrogen. It can be X 1 is nitrogen. It can be X 2 is nitrogen. It can be X 3 It's nitrogen.

[0068] Can be X 4 It is carbon. It can be X 5 It is carbon. It can be X 6 It is carbon. It can be X 7 It is carbon. It can be X 4 and X 5 All are carbon. It can be X 4 and X 6 All are carbon. It can be X 4 and X 7 All are carbon. It can be X 5 and X 6 All are carbon. It can be X 5 and X 7 All are carbon. It can be X 6 and X 7 All are carbon. It can be X 4 , X 5 and X 6 Each is carbon. It can be X 4 , X5 and X 7 Each is carbon. It can be X 4 , X 6 and X 7 Each is carbon. It can be X 5 , X 6 and X 7 Each is carbon. It can be X 4 , X 5 , X 6 and X 7 Each is carbon.

[0069] Can be X 4 , X 5 , X 6 and X 7 At least one of them is nitrogen. It can be X 4 , X 5 , X 6 and X 7 One of them is nitrogen. It can be X 5 is nitrogen. It can be X 4 is nitrogen. It can be X 4 , X 5 , X 6 and X 7 Two of them are nitrogen. It can be X 4 and X 5 Each is nitrogen. It can be X 4 and X 7 Each is nitrogen. It can be X 5 and X 7 Each is nitrogen. It can be X 4 and X 6 Each is nitrogen.

[0070] m may be selected from 0 and 1. m may be 0. m may be 1. m may be 2. m may be 3. m may be 4.

[0071] R 1 Each occurrence may be independently selected from halogen, nitro, cyano, OR 11 、C1-C4-alkyl、NR 9 R 10 Substituted C1-C4-alkyl, 11 Substituted C1-C4-alkyl, C1-C4-haloalkyl and cyclopropyl. 1 can be independently selected at each occurrence from halogen, OR 11 NR 9 R 10 , cyano, C1-C4-alkyl and C1-C4-haloalkyl. 1 can be independently selected at each occurrence from halogen, OR11 , C1-C4-alkyl, C1-C4-haloalkyl and cyclopropyl. 1 R at each occurrence may be independently selected from halogen and C1-C4-alkyl. 1 R at each occurrence may independently be a halogen, such as fluorine. 1 Each occurrence may independently be C1-C4-alkyl, for example methyl.

[0072] Can be X 1 Not CH. Can be X 1 Selected from nitrogen and R 1 substituted carbon. m may be at least 1, X 1 is carbon, and R 1 Group connected to X 1 On carbon. It can be m is 1, X 1 is carbon, and R 1 Group connected to X 1 Carbon. Relative to no R 1 Group connected to X 1 Compounds on carbon with attachment to X 1 R on Carbon 1 In these embodiments, compounds connected to X 1 R 1 The radical may be C1-C4-alkyl, for example methyl.

[0073] R 5 R at each occurrence may be independently selected from H, fluorine and C1-C4-alkyl. 5 may be independently selected at each occurrence from H, fluorine and C1-C4-alkyl, or two R 5 The groups together with the carbon atoms to which they are attached may form a C3-C6 cycloalkyl ring. 5 can be independently selected at each occurrence from H and C1-C4-alkyl, or two R 5 The groups together with the carbon atoms to which they are attached may form a C3-C6 cycloalkyl ring. 5 may be independently selected at each occurrence from H and C1-C4-alkyl, such as methyl.

[0074] It can be R 5 H at every occurrence. Can be R 5 In one occurrence it is H and in the other occurrences it is C1-C4-alkyl, for example methyl. It can be R 5 At each occurrence it is C1-C4-alkyl, for example methyl.

[0075] n may be selected from 0 and 1. n may be 0. n may be 1. n may be 2. n may be 3. n may be 4.

[0076] R 6 can be independently selected from halogen, nitro, cyano, OR 11 、C1-C4-alkyl、NR 9 R 10 Substituted C1-C4-alkyl, 11 Substituted C1-C4-alkyl, C1-C4-haloalkyl and cyclopropyl. 6 can be independently selected from halogen, OR 11 , C1-C4-alkyl, C1-C4-haloalkyl and cyclopropyl. 6 may be independently selected from halogen and C1-C4-alkyl. 6 It may be a halogen, such as fluorine. 6 It may be C1-C4-alkyl, for example methyl.

[0077] p may be selected from 0 and 1. p may be 0. p may be 1. p may be 2.

[0078] R 7 can be independently selected from halogen, nitro, cyano, OR 11 、C1-C4-alkyl、NR 9 R 10 Substituted C1-C4-alkyl, 11 Substituted C1-C4-alkyl, C1-C4-haloalkyl and cyclopropyl. 7 can be independently selected from halogen, OR 11 , C1-C4-alkyl, C1-C4-haloalkyl and cyclopropyl. 7 may be independently selected from halogen and C1-C4-alkyl. 7 It may be a halogen, such as fluorine. 7 It may be C1-C4-alkyl, for example methyl.

[0079] R 8a It can be H. R 8a Can be selected from halogen, C1-C4-alkyl, NR 9 R 10 Substituted C1-C4-alkyl, 11 Substituted C1-C4-alkyl, C1-C4-haloalkyl and C0-C4-alkylene-R 8c . R 8a R may be selected from H, halogen, C1-C4-alkyl, C1-C4-haloalkyl and cyclopropyl. 8aR may be selected from H, C1-C4-alkyl, C1-C4-haloalkyl and cyclopropyl. 8a R may be selected from C1-C4-alkyl (eg methyl) and C1-C4-haloalkyl (eg CF3). 8a It may be C1-C4-alkyl (eg methyl).

[0080] R 8b It can be H. R 8b Can be selected from C1-C4-alkyl, CONR 9 R 9 Substituted C1-C4-alkyl, NR 9 R 10 Substituted C2-C4-alkyl, 11 Substituted C2-C4-alkyl, C1-C4-haloalkyl and C0-C4-alkylene-R 8c . R 8b R may be selected from H, C1-C4-alkyl and cyclopropyl. 8b It may be C1-C4-alkyl (eg methyl).

[0081] R 8b can be independently selected from H, C1-C4-alkyl, NR 9 R 10 Substituted C2-C4-alkyl, 11 Substituted C2-C4-alkyl, C3-C4-alkenyl, C3-C4-alkynyl, C1-C4-haloalkyl and C0-C4-alkylene-R 8c .

[0082] It can be R 8a Yes H, R 8b is C1-C4-alkyl (e.g. methyl). 8a and R 8b Each is H. Can be R 8a and R 8b Each is C1-C4-alkyl (eg methyl).

[0083] It can be R 9 is independently selected at each occurrence from H and C1-C4-alkyl.

[0084] It can be R 10 is independently selected at each occurrence from H, C1-C4-alkyl, C(O)-C1-C4-alkyl and S(O)2-C1-C4-alkyl. 10 is independently selected at each occurrence from H and C1-C4-alkyl.

[0085] It can be R 11is independently selected at each occurrence from H, C1-C4-alkyl and C1-C4-haloalkyl. 11 is independently selected at each occurrence from H and C1-C4-alkyl. 11 is independently at each occurrence C1-C4-alkyl, for example methyl.

[0086] R 12 may be independently selected from 5 or 6 membered heteroaryl, wherein the heteroaryl is optionally substituted by 1 to 3 R 14 Group substitution. 12 can be independently selected from 5-membered heteroaryl, such as imidazole, wherein the heteroaryl is optionally substituted by 1 to 3 R 14 Group substitution.

[0087] R 13 Each occurrence may be independently selected from oxo, fluoro, OR 11 、CO2R 9 、CO2NR 9 R 9 、C1-C4-alkyl、NR 9 R 10 Substituted C1-C4-alkyl, 11 Substituted C1-C4-alkyl, C1-C4-haloalkyl and cyclopropyl. 13 Each occurrence may be independently selected from oxo, OR 11 , C1-C4-alkyl and cyclopropyl. 13 R at each occurrence may be independently selected from oxo and C1-C4-alkyl. 13 Each occurrence may independently be C1-C4-alkyl, for example methyl.

[0088] R 14 Each occurrence may be independently selected from halogen, nitro, cyano, OR 11 、C1-C4-alkyl、NR 8 R 9 Substituted C1-C4-alkyl, 11 Substituted C1-C4-alkyl, C1-C4-haloalkyl and cyclopropyl. 14 can be independently selected at each occurrence from halogen, OR 11 , C1-C4-alkyl, C1-C4-haloalkyl and cyclopropyl. 14 R at each occurrence may be independently selected from halogen and C1-C4-alkyl. 14 R at each occurrence may independently be a halogen, such as fluorine. 14 Each occurrence may independently be C1-C4-alkyl, for example methyl.

[0089] It can be:

[0090] R 3 is H; and

[0091] R 4 independently selected from C1-C6-alkyl, C1-C6-haloalkyl, C0-C4-alkylene-R 4a ; where R 4a independently selected from: C3-C8-cycloalkyl, phenyl, 5, 6, 9 or 10-membered heteroaryl and 4 to 10-membered heterocycloalkyl; wherein the heterocycloalkyl or heteroaryl may be monocyclic or bicyclic; wherein the cycloalkyl or heterocycloalkyl is optionally substituted by a single R 12 group and / or 1 to 4 R 13 wherein the phenyl or heteroaryl group is optionally substituted by a single R 12 group and / or 1 to 3 R 14 group substitution;

[0092] or R 3 and R 4 Together with the nitrogen atom to which they are attached, they form a 4- to 10-membered heterocycloalkyl or a 5- or 9-membered heteroaryl; wherein the heterocycloalkyl is optionally substituted by a single R 12 group and / or 1 to 4 R 13 wherein the heteroaryl group is optionally substituted by a single R 12 group and / or 1 to 3 R 14 Group substitution.

[0093] It can be:

[0094] R 3 is H; and

[0095] R 4 independently selected from C1-C6-alkyl, C1-C6-haloalkyl, C0-C4-alkylene-R 4a ; where R 4a independently selected from: C3-C8-cycloalkyl, phenyl, 5, 6, 9 or 10-membered heteroaryl and 4 to 10-membered heterocycloalkyl; wherein the heterocycloalkyl or heteroaryl may be monocyclic or bicyclic; wherein the cycloalkyl or heterocycloalkyl is optionally substituted by 1 to 4 R 13 wherein the phenyl or heteroaryl group is optionally substituted by 1 to 3 R 14 group substitution;

[0096] or R 3 and R 4 Together with the nitrogen atom to which they are attached, they form a 4- to 10-membered heterocycloalkyl or a 5- or 9-membered heteroaryl; wherein the heterocycloalkyl is optionally substituted by 1 to 4 R 13 wherein the heteroaryl group is optionally substituted by 1 to 3 R14 Group substitution.

[0097] It can be R 3 It's H.

[0098] It can be R 4 is selected from C1-C6-alkyl, C1-C6-haloalkyl and C0-C4-alkylene-R 4a .

[0099] It can be R 4 is selected from C1-C6-alkyl and C1-C6-haloalkyl. 4 is selected from C2-C3-alkyl and C2-C3-haloalkyl. 4 is a C1-C4-haloalkyl group. 4 is a C2-C3-haloalkyl group. 4 It is 2,2,2-trifluoroethyl.

[0100] Exemplary R 4 Groups include:

[0101]

[0102] It can be R 4 is C0-C4-alkylene-R 4a . It can be R 4 It is CH2-R 4a . It can be R 4 YesR 4a .

[0103] It can be R 4a independently selected from C3-C8-cycloalkyl, phenyl, 5, 6, 9 or 10-membered heteroaryl, 4 to 10-membered heterocycloalkyl, wherein the heterocycloalkyl or heteroaryl may be monocyclic or bicyclic; wherein the cycloalkyl or heterocycloalkyl is optionally substituted by 1 to 4 R 13 wherein the phenyl or heteroaryl group is optionally substituted by 1 to 3 R 14 Group substitution.

[0104] It can be R 4a is selected from C3-C8-cycloalkyl and 4- to 10-membered heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally substituted by a single R 12 group and / or 1 to 4 R 13 It can be R 4a is selected from C3-C8-cycloalkyl and 4- to 10-membered heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally substituted by 1 to 4 R 13 Group substitution.

[0105] It can be R 4is selected from CH2-C3-C8-cycloalkyl and CH2-4 to 10-membered heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally substituted by a single R 12 group and / or 1 to 4 R 13 It can be R 4 is selected from CH2-C3-C8-cycloalkyl and CH2-4 to 10-membered heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally substituted by 1 to 4 R 13 Group substitution.

[0106] It can be R 4 is selected from C3-C8-cycloalkyl and 4- to 10-membered heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally substituted by a single R 12 group and / or 1 to 4 R 13 It can be R 4 is selected from C3-C8-cycloalkyl and 4- to 10-membered heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally substituted by 1 to 4 R 13 Group substitution.

[0107] Exemplary R 4 Groups include:

[0108]

[0109] It can be R 4a independently selected from: phenyl and 5 or 6 membered heteroaryl; wherein the phenyl or heteroaryl is optionally substituted by a single R 12 group and / or 1 to 3 R 14 It can be R 4a Independently selected from: phenyl and 5 or 6 membered heteroaryl; wherein the phenyl or heteroaryl is optionally substituted by 1 to 3 R 14 It can be R 4a is independently phenyl; wherein the phenyl is optionally substituted by a single R 12 group and / or 1 to 3 R 14 It can be R 4a is independently phenyl; wherein the phenyl is optionally substituted by 1 to 3 R 14 It can be R 4a is independently a 5- or 6-membered heteroaryl; wherein the heteroaryl is optionally substituted by a single R 12 group and / or 1 to 3 R 14 It can be R 4a is independently a 5- or 6-membered heteroaryl; wherein the heteroaryl is optionally substituted by 1 to 3 R 14 Group substitution.

[0110] It can be R 4independently selected from CH2-phenyl and CH2-5 or 6-membered heteroaryl, wherein the phenyl or heteroaryl is optionally substituted by a single R 12 group and / or 1 to 3 R 14 It can be R 4 independently selected from CH2-phenyl and CH2-5 or 6-membered heteroaryl, wherein the phenyl or heteroaryl is optionally substituted by 1 to 3 R 14 It can be R 4 is independently CH2-phenyl, wherein the phenyl group is optionally substituted with a single R 12 group and / or 1 to 3 R 14 It can be R 4 is independently CH2-phenyl, wherein the phenyl group is optionally substituted with 1 to 3 R 14 It can be R 4 is independently CH2-5 or 6 membered heteroaryl, wherein said heteroaryl is optionally substituted with a single R 12 group and / or 1 to 3 R 14 It can be R 4 is independently CH2-5 or 6 membered heteroaryl, wherein the heteroaryl is optionally substituted by 1 to 3 R 14 Group substitution.

[0111] It can be R 4 independently selected from phenyl or 5 or 6 membered heteroaryl, wherein the phenyl or heteroaryl is optionally substituted by a single R 12 group and / or 1 to 3 R 14 It can be R 4 is independently selected from phenyl or 5 or 6 membered heteroaryl, wherein the phenyl or heteroaryl is optionally substituted by 1 to 3 R 14 It can be R 4 is independently phenyl, wherein the phenyl is optionally substituted with a single R 12 group and / or 1 to 3 R 14 It can be R 4 is independently phenyl, wherein the phenyl group is optionally substituted with 1 to 3 R 14 It can be R 4 is independently a 5- or 6-membered heteroaryl, wherein the heteroaryl is optionally substituted with a single R 12 group and / or 1 to 3 R 14 It can be R 4 is independently a 5- or 6-membered heteroaryl, wherein the heteroaryl is optionally substituted by 1 to 3 R 14 Group substitution.

[0112] It can be R 4 independently selected from phenyl or 6-membered heteroaryl, wherein the phenyl or 6-membered heteroaryl is optionally substituted at the meta position by 1 R14 It can be R 14 The group is selected from OR 11 Substituted C1-C4-alkyl, C1-C4-alkyl and C1-C4-haloalkyl. 14 The group is OR 11 Substituted C1-C4-alkyl, for example -(CH3)2-OH. R may be in the meta position 14 The radical is a C1-C4-haloalkyl radical, for example CF3.

[0113] It can be R 4 is a 6-membered heteroaryl. 4 is phenyl. It can be R 4 It is in the interposition by 1 R 14 Phenyl substituted with a group. It can be R 14 YesR 14a . Exemplary R 4 Groups include:

[0114] Where R 14a Selected from halogen, nitro, cyano, NR 8 R 9 , OR 10 , SR 8 、SO2R 8 、SO2NR 8 R 8 、CO2R 8 、C(O)R 8 ,CONR 8 R 8 , C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl, 11 Substituted C1-C4-alkyl, NR 8 R 9 substituted C1-C4-alkyl and cyclopropyl; and wherein z is an integer selected from 1 and 2.

[0115] Exemplary R 4 Groups include:

[0116]

[0117]

[0118] It can be R 3 and R 4 Together with the nitrogen atom to which they are attached, they form a 4- to 10-membered heterocycloalkyl or a 5- or 9-membered heteroaryl; wherein the heterocycloalkyl is optionally substituted by a single R 12group and / or 1 to 4 R 13 wherein the heteroaryl group is optionally substituted by a single R 12 group and / or 1 to 3 R 14 It can be R 3 and R 4 Together with the nitrogen atom to which they are attached, they form a 4- to 10-membered heterocycloalkyl or a 5- or 9-membered heteroaryl; wherein the heterocycloalkyl is optionally substituted by 1 to 4 R 13 wherein the heteroaryl group is optionally substituted by 1 to 3 R 14 Group substitution.

[0119] It can be R 3 and R 4 Together with the nitrogen atom to which they are attached, they form a 5- or 9-membered heteroaryl group; wherein the heteroaryl group is optionally substituted by a single R 12 group and / or 1 to 3 R 14 It can be R 3 and R 4 Together with the nitrogen atom to which they are attached, they form a 5- or 9-membered heteroaryl group; wherein the heteroaryl group is optionally substituted by 1 to 3 R 14 It can be R 3 and R 4 Together with the nitrogen atom to which they are attached, they form a 5-membered heteroaryl group; wherein the heteroaryl group is optionally substituted by a single R 12 group and / or 1 to 3 R 14 It can be R 3 and R 4 Together with the nitrogen atom to which they are attached, they form a 5-membered heteroaryl group; wherein the heteroaryl group is optionally substituted by 1 to 3 R 14 Group substitution.

[0120] Exemplary NR 3 R 4 Groups include:

[0121]

[0122] It can be R 3 and R 4 Together with the nitrogen atom to which they are attached, they form a 4- to 10-membered heterocycloalkyl group; wherein said heterocycloalkyl group is optionally substituted with a single R 12 group and / or 1 to 4 R 13 It can be R 3 and R 4 Together with the nitrogen atom to which they are attached, they form a 4- to 10-membered heterocycloalkyl group; wherein the heterocycloalkyl group is optionally substituted by 1 to 4 R 13The heterocyclic group may be substituted with a 7- to 10-membered bicyclic heterocyclic alkyl. The heterocyclic group may be a 7- to 10-membered bridged bicyclic heterocyclic alkyl. The heterocyclic group may be a monocyclic 4- to 7-membered heterocyclic alkyl. The heterocyclic group may be a monocyclic 5- to 6-membered heterocyclic alkyl. The heterocyclic group may be pyrrolidine. The heterocyclic group may be piperidine. The heterocyclic group may be morpholine. The heterocyclic group may be piperazine. For the avoidance of doubt, the heterocyclic alkyl groups mentioned in this paragraph are optionally substituted with a single R 12 group and / or 1 to 4 R 13 The heterocycloalkyl group mentioned in this paragraph may be optionally substituted with 1 to 4 R 13 The heterocyclic group may be pyrrolidine, and is substituted by one R at the 2 position. 13 The heterocyclic group may be pyrrolidine, and the 3-position is replaced by one R 13 The heterocyclic group may be piperidine, and the 2-position is replaced by one R 13 The heterocyclic group may be piperidine, and the 3-position is replaced by one R 13 The heterocyclic group may be piperidine, and the 4-position is replaced by one R 13 The heterocyclic group may be morpholine, and is substituted by one R at the 2 position. 13 The heterocyclic group may be morpholine, and the 3-position is replaced by one R 13 It can be R 13 The group is selected from C1-C4-alkyl, 11 Substituted C1-C4-alkyl (eg -(CH3)2-OH) and C1-C4-haloalkyl (eg -CF3).

[0123] Exemplary NR 3 R 4 Groups include:

[0124]

[0125] You can choose R 3 and R 4 , making NR 3 R 4 Contains a CHF2 group or a CF3 group.

[0126] It can be NR 3 R 4 With formula in

[0127] a is an integer selected from 1 and 2;

[0128] R 4bis selected from H and F at each occurrence; wherein at least one R 4b The group is F;

[0129] R 3a independently selected from H and C1-C4-alkyl;

[0130] R 4c is independently selected at each occurrence from H, C1-C4-alkyl and C4-C6-cycloalkyl; or

[0131] R 3a and a single R 4c Together with the carbon and nitrogen to which they are attached they form a 4- to 6-membered heterocycloalkyl.

[0132] a can be 1. a can be 2.

[0133] It can be NR 3 R 4 With formula in

[0134] R 4b is selected from H and F at each occurrence; wherein at least one R 4b The group is F;

[0135] R 3a independently selected from H and C1-C4-alkyl;

[0136] R 4c is independently selected from H, C1-C4-alkyl and C4-C6-cycloalkyl; or

[0137] R 3a and R 4c Together with the carbon and nitrogen to which they are attached they form a 4- to 6-membered heterocycloalkyl.

[0138] There can be at least two R 4b The group is F. There can be two R 4b The group is F, and one R 4b The group is H. Each R 4b The groups are all F.

[0139] It can be R 3a It's H.

[0140] It can be R 3a are independently selected from H and C1-C4-alkyl; and R 4c is independently selected from H, C1-C4-alkyl and C4-C6-cycloalkyl. 3a is H; and R 4c is independently selected from H, C1-C4-alkyl and C4-C6-cycloalkyl. The alkyl or cycloalkyl may be unsubstituted.

[0141] It can be R 4c is selected at each occurrence from C1-C4-alkyl and H. It may be R 4c It is H at every occurrence.

[0142] It can be R 3a and R 4c Together with the carbon and nitrogen to which they are attached, they form a 4- to 6-membered heterocycloalkyl group. 3a and R 4c Together with the carbon and nitrogen to which they are attached, they form a 5-membered heterocycloalkyl. 3a and R 4c Together with the carbon and nitrogen to which they are attached, they form a 6-membered heterocycloalkyl. The heterocycloalkyl may be unsubstituted.

[0143] The compound of formula (I) may be selected from:

[0144]

[0145]

[0146]

[0147]

[0148]

[0149]

[0150] The compound of formula (I) may be selected from

[0151]

[0152]

[0153]

[0154] It may be that the compound of formula (I) is not

[0155]

[0156] In one aspect of the present invention there is provided a compound of the present invention for use as a medicament.

[0157] According to another aspect, compounds of the invention are provided for use in treating conditions modulated by DDR1 and / or DDR2.Compounds of any of the formulae disclosed herein are useful for treating conditions treatable by inhibition of DDR1 and / or DDR2.

[0158] In another aspect of the invention there is provided a compound of the invention for use in treating a disease or disorder selected from the group consisting of renal conditions, liver conditions, inflammatory conditions, cardiovascular conditions, acute and chronic organ transplant rejection, fibrotic diseases and cancer.

[0159] In one aspect of the present invention, there is provided a method of treating a disease or condition modulated by DDR1 and / or DDR2, wherein the method comprises administering to a patient in need thereof a therapeutic amount of a compound of the present invention.

[0160] The method of treatment may be a method of treating a condition treatable by inhibition of DDR1 and / or DDR2.

[0161] The present invention also provides a method of treating a disease or disorder selected from the group consisting of renal conditions, liver conditions, inflammatory conditions, cardiovascular conditions, acute and chronic organ transplant rejection, fibrotic diseases and cancer, wherein the method comprises administering to a patient in need thereof a therapeutic amount of a compound of any formula disclosed herein.

[0162] Kidney conditions include acute kidney injury and chronic kidney disease with or without proteinuria, including end-stage renal disease (ESRD). This includes reduced creatinine clearance and reduced glomerular filtration rate, microalbuminuria, albuminuria and proteinuria, glomerular sclerosis (particularly diabetic nephropathy and amyloidosis) with or without the expansion of the mesangial matrix with obvious excessive cells, focal thrombosis (particularly thrombotic microangiopathy) of glomerular capillaries, overall fibrinoid necrosis, ischemic lesions, malignant nephrosclerosis (such as ischemic retraction, reduced renal blood flow and renal artery disease), (endothelial and mesangial) capillary and / or swelling and proliferation of extracapillary cells (crescents), such as glomerulonephritis entities, focal segmental glomerulosclerosis, IgA nephropathy, vasculitis / systemic diseases and acute and chronic renal transplant rejection. Early and late Alport syndrome is also included in the kidney condition.

[0163] Inflammatory conditions include arthritis, osteoarthritis, multiple sclerosis, systemic lupus erythematosus, inflammatory bowel disease, abnormal emptying disorders, etc., and inflammatory airway diseases, such as idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD), or chronic asthma. Other conditions of the respiratory system include other diffuse lung parenchymal diseases of different etiologies, including iatrogenic drug-induced fibrosis, occupational and / or environmentally induced fibrosis, systemic diseases and vasculitis, granulomatous diseases (sarcoidosis, hypersensitivity pneumonitis), collagen vascular disease, radiation-induced fibrosis.

[0164] Vascular conditions include atherosclerosis, thrombotic vascular disease and thrombotic microangiopathy, proliferative arteriopathy (e.g., swollen myoendothelial cells surrounded by a mucinous extracellular matrix and nodular thickening), atherosclerosis, decreased vascular compliance (e.g., stiffness, decreased ventricular compliance, and decreased vascular compliance), endothelial dysfunction, etc.

[0165] Cardiovascular conditions include acute coronary syndrome, coronary heart disease, myocardial infarction, arterial and pulmonary hypertension, arrhythmias such as atrial fibrillation, stroke and other vascular injuries.

[0166] Fibrotic diseases include, but are not limited to, myocardial and vascular fibrosis, renal fibrosis, hepatic fibrosis, pulmonary fibrosis, cutaneous fibrosis, scleroderma and encapsulating peritonitis, systemic sclerosis, Alport syndrome, chronic kidney disease, NASH, interstitial lung disease, and systemic sclerosis.

[0167] In certain embodiments, the compounds of the present invention are used to treat cancer or in a method for treating cancer. Examples include, but are not limited to, liver cancer, bladder cancer, hepatoma, squamous carcinoma of the lung, non-small cell lung cancer, adenocarcinoma of the lung, small cell lung cancer, various head and neck cancers, breast cancer, colon cancer, colorectal cancer, peritoneal cancer, hepatocellular carcinoma, gastrointestinal cancer, esophageal cancer, endometrial cancer or uterine cancer, salivary gland cancer, squamous cell carcinoma, pituitary cancer, astrocytoma, soft tissue sarcoma, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, kidney cancer, liver cancer, prostate cancer, vulvar cancer, thyroid cancer, liver cancer, brain cancer, endometrial cancer, testicular cancer, bile duct cancer, gallbladder cancer, gastric cancer, and melanoma. In certain embodiments, the cancer is selected from bladder cancer, pancreatic cancer, breast cancer, lung cancer, ovarian cancer, and glioblastoma.

[0168] In another aspect of the present invention, a pharmaceutical composition is provided, wherein the composition comprises a compound of the present invention and a pharmaceutically acceptable excipient.

[0169] In one embodiment, the pharmaceutical composition may be a combination product comprising an additional pharmaceutically active agent.

[0170] In one aspect of the invention there is provided the use of a compound of the invention in the manufacture of a medicament for the treatment of any of the conditions disclosed herein. DETAILED DESCRIPTION

[0171] The following are definitions of terms used in this application. Any term not defined herein has the ordinary meaning understood by those skilled in the art.

[0172] The term "halogen" refers to a halogen from group 17 of the periodic table. The term refers in particular to fluorine, chlorine, bromine and iodine. Preferably, the term refers to chlorine or fluorine.

[0173] The term "alkyl" refers to a straight or branched hydrocarbon chain. For example, the term "C 1-6 "Alkyl" refers to a straight or branched hydrocarbon chain containing 1, 2, 3, 4, 5 or 6 carbon atoms, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl and n-hexyl. An "alkylene" group can likewise be straight or branched and is divalent, i.e. it is attached to the rest of the molecule at two positions. Furthermore, an alkylene group can, for example, correspond to one of those alkyl groups listed in this paragraph. Alkyl and alkylene groups can be unsubstituted or substituted by one or more substituents.

[0174] The term "haloalkyl" refers to a hydrocarbon chain substituted with at least one halogen atom independently selected at each occurrence from, for example, fluorine, chlorine, bromine and iodine. 1-6 "Haloalkyl" refers to a straight or branched hydrocarbon chain containing 1, 2, 3, 4, 5 or 6 carbon atoms substituted by at least one halogen. The halogen atom may be present at any position on the hydrocarbon chain. For example, C 1-6 Haloalkyl may refer to chloromethyl, fluoromethyl, trifluoromethyl, chloroethyl (e.g., 1-chloromethyl and 2-chloroethyl), trichloroethyl (e.g., 1,2,2-trichloroethyl, 2,2,2-trichloroethyl), fluoroethyl (e.g., 1-fluoromethyl and 2-fluoroethyl), trifluoroethyl (e.g., 1,2,2-trifluoroethyl and 2,2,2-trifluoroethyl), chloropropyl, trichloropropyl, fluoropropyl, trifluoropropyl. The term "fluoroalkyl" refers to a hydrocarbon chain substituted with at least one fluorine atom.

[0175] The term "alkenyl" refers to a branched or straight hydrocarbon chain containing at least one double bond. For example, the term "C 2-6 "Alkenyl" refers to a branched or straight hydrocarbon chain containing at least one double bond and having 2, 3, 4, 5 or 6 carbon atoms. The double bond can exist as an E or Z isomer. The double bond can be in any possible position of the hydrocarbon chain. For example, "C 2-6 The "alkenyl" may be ethenyl, propenyl, butenyl, butadienyl, pentenyl, pentadienyl, hexenyl and hexadienyl.

[0176] The term "alkynyl" refers to a branched or straight hydrocarbon chain containing at least one triple bond. 2-6 "Alkynyl" refers to a branched or straight hydrocarbon chain containing at least one triple bond and having 2, 3, 4, 5 or 6 carbon atoms. The triple bond can be in any possible position of the hydrocarbon chain. For example, "C 2-6 The term "alkynyl" may include ethynyl, propynyl, butynyl, pentynyl and hexynyl.

[0177] The term "heteroalkyl" refers to a branched or straight hydrocarbon chain containing at least one heteroatom selected from N, O and S between any carbons in the chain or at the end of the chain. 1-6"Heteroalkyl" refers to a branched or straight hydrocarbon chain containing 1, 2, 3, 4, 5 or 6 carbon atoms and at least one heteroatom selected from N, O and S and located between any carbons in the chain or at the end of the chain. For example, the hydrocarbon chain may contain one or two heteroatoms. 1-6 A heteroalkyl group can be bonded to the rest of the molecule through a carbon or heteroatom. For example, "C 1-6 "Heteroalkyl" may be C 1-6 N-alkyl, C 1-6 N,N-alkyl or C 1-6 O-alkyl.

[0178] The term "heterocycle" refers to a saturated, unsaturated or aromatic ring system containing at least one heteroatom selected from N, O or S. A "heterocycle" system can contain 1, 2, 3 or 4 heteroatoms, such as 1 or 2. A "heterocycle" system can be a monocyclic or fused polycyclic system, such as a bicyclic or tricyclic system. A "heterocycle" moiety can contain 3 to 14 carbon atoms, such as 3 to 8 carbon atoms in a monocyclic system and 7 to 14 carbon atoms in a polycyclic system. A "heterocycle" comprises a heterocycloalkyl moiety, a heterocycloalkenyl moiety and a heteroaryl moiety. For example, a heterocyclic group can be: oxirane, aziridine, azetidine, oxetane, tetrahydrofuran, pyrrolidine, imidazolidine, succinimide, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, piperidine, morpholine, thiomorpholine, piperazine and tetrahydropyran. Heteroaryl groups include groups such as pyridone and N-alkyl-pyridone.

[0179] The term "C 3-8 "Cycloalkyl" refers to a saturated hydrocarbon ring system containing 3, 4, 5, 6, 7 or 8 carbon atoms. For example, "C 3-8 The "cycloalkyl" may be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

[0180] The term "C 3-8 "Cycloalkenyl" refers to a non-aromatic, unsaturated hydrocarbon ring system containing 3, 4, 5, 6, 7 or 8 carbon atoms. The ring may contain more than one double bond, provided that the ring system is not aromatic. For example, "C 3-8 The "cycloalkyl" may be cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, cyclooctenyl and cycloatadienyl.

[0181] The term "heterocycloalkyl" refers to a saturated hydrocarbon ring system containing carbon atoms and at least one heteroatom selected from N, O and S in the ring. For example, there may be 1, 2 or 3 heteroatoms, optionally 1 or 2. "Heterocycloalkyl" may be bonded to the rest of the molecule via any carbon atom or heteroatom. "Heterocycloalkyl" may have one or more, such as one or two, bonds to the rest of the molecule: these bonds may be through any atom in the ring. For example, "heterocycloalkyl" may be "C 3-8 Heterocycloalkyl". The term "C 3-8 "Heterocycloalkyl" refers to a saturated hydrocarbon ring system containing 3, 4, 5, 6, 7 or 8 atoms, wherein at least one atom in the ring is a heteroatom selected from N, O and S. "Heterocycloalkyl" can be oxirane, aziridine, azetidine, oxetane, tetrahydrofuran, pyrrolidine, imidazolidine, succinimide, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, piperidine, morpholine, thiomorpholine, piperazine and tetrahydropyran.

[0182] The term "aromatic" when applied to a substituent as a whole refers to a monocyclic or polycyclic ring system having 4n+2 electrons in a conjugated π system within the ring or ring system, wherein all atoms contributing to the conjugated π system are in the same plane.

[0183] The term "aryl" refers to an aromatic hydrocarbon ring system. The ring system has 4n+2 electrons in a conjugated π system within the ring, where all atoms contributing to the conjugated π system are in the same plane. For example, "aryl" can be phenyl and naphthyl. The aryl system itself can be substituted by other groups.

[0184] The term "heteroaryl" refers to an aromatic hydrocarbon ring system having at least one heteroatom selected from O, N and S in a monocyclic or fused ring system. The ring or ring system has 4n+2 electrons in a conjugated π system, wherein all atoms contributing to the conjugated π system are in the same plane. For example, "heteroaryl" can be imidazole, oxazole, isoxazole, thiazole, isothiazole, thiene, furan, thianthrene, pyrrole, benzimidazole, pyrazole, pyrazine, pyridine, pyrimidine and indole.

[0185] by A bond ending in means that the bond is attached to another atom not shown in the structure. A bond that ends inside a cyclic structure and does not terminate on an atom in the ring structure means that the bond can be attached to any atom in the ring structure if valency permits.

[0186] Where chemically possible, bonds drawn as solid and dashed lines represent bonds that can be either single or double bonds. For example, the bond drawn below can be either a single bond or a double bond.

[0187]

[0188] When a moiety is substituted, it may be substituted at any point on the moiety where chemically possible and consistent with valence requirements. The moiety may be substituted with one or more substituents, such as 1, 2, 3 or 4 substituents; optionally, 1 or 2 substituents are present on a group. When there are two or more substituents, the substituents may be the same or different.

[0189] Substituents are present only at positions where they are chemically possible, and one skilled in the art can readily determine (either experimentally or theoretically) which substitutions are chemically possible and which are not.

[0190] Ortho, meta and para substitution are terms well known in the art. For the avoidance of doubt, "ortho" substitution is a substitution pattern in which adjacent carbons have substituents, whether simple groups, such as the fluorine group in the example below, or other parts of the molecule, such as The key at the end is shown.

[0191]

[0192] "Meta" substitution is a substitution pattern where the two substituents are on carbons that are one carbon away from each other, i.e. there is one carbon atom between the substituted carbons. In other words, there is a substituent on the second atom away from the atom with the other substituent. For example, the following group is meta-substituted.

[0193]

[0194] "Para" substitution is a substitution pattern where the two substituents are on carbons that are two carbons away from each other, i.e. there are two carbon atoms between the substituted carbons. In other words, there is a substituent on a third atom away from the atom with the other substituent. For example, the following groups are para-substituted:

[0195]

[0196] Throughout the specification, disclosure of compounds also includes pharmaceutically acceptable salts, solvates and stereoisomers thereof.

[0197] When the compound has a stereocenter, the present invention contemplates (R) and (S) stereoisomers, and likewise, mixtures of stereoisomers or racemic mixtures are accomplished by the present application. When the compound of the present invention has two or more stereocenters, any combination of (R) and (S) stereoisomers is contemplated. The combination of (R) and (S) stereoisomers can produce a diastereomeric mixture or a single diastereoisomer. The compounds of the present invention can exist in the form of a single stereoisomer, or can be a mixture of stereoisomers, such as a racemic mixture and other enantiomeric mixtures, and a diastereomeric mixture. When the mixture is a mixture of enantiomers, the enantiomeric excess can be any of those disclosed above. When the compound is a single stereoisomer, the compound may still contain other diastereomers or enantiomers as impurities. Thus, a single stereoisomer does not necessarily have an enantiomeric excess (ee) or diastereomeric excess (de) of 100%, but may have an ee or de of about at least 85%, at least 60%, or less. For example, the ee or de may be 90% or more, 90% or more, 80% or more, 70% or more, 60% or more, 50% or more, 40% or more, 30% or more, 20% or more, or 10% or more.

[0198] The present invention contemplates pharmaceutically acceptable salts of the compounds of the present invention. These may include acid addition salts and base salts of the compounds. These may be acid addition salts and base salts of the compounds. In addition, the present invention contemplates solvates of the compounds. These may be hydrates or other solvated forms of the compounds.

[0199] Suitable acid addition salts are formed from acids that form non-toxic salts. Examples include acetate, aspartate, benzoate, benzenesulfonate, bicarbonate / carbonate, bisulfate / sulfate, borate, camphorsulfonate, citrate, edisylate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, methanesulfonate, methylsulfate, naphthylate, 1,5-naphthalenedisulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrogenphosphate, sucrose, stearate, succinate, tartrate, toluenesulfonate and trifluoroacetate.

[0200] Suitable alkali salts are formed from bases that form non-toxic salts. Examples include aluminum salts, arginine salts, benzathine salts, calcium salts, choline salts, diethylamine salts, diethanolamine salts, glycine salts, lysine salts, magnesium salts, meglumine salts, ethanolamine salts, potassium salts, sodium salts, tromethamine salts, and zinc salts. Hemi-salts of acids and bases, such as hemisulphates and hemicalcium salts, can also be formed. For a review of suitable salts, see Stahl and Wermuth's "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" (Wiley-VCH, Weinheim, Germany, 2002).

[0201] Pharmaceutically acceptable salts of compounds of formula (I) can be prepared by one or more of three methods:

[0202] (i) by reacting a compound of the present invention with a desired acid or base;

[0203] (ii) by removing an acid- or base-labile protecting group from a suitable precursor of the compound of the invention, or by ring-opening a suitable cyclic precursor (e.g., a lactone or lactam), using the desired acid or base; or

[0204] (iii) converting one salt of a compound of the invention into another salt by reaction with a suitable acid or base or by passing through a suitable ion exchange column.

[0205] All three reactions are usually carried out in solution. The resulting salt may precipitate out and be collected by filtration, or it may be recovered by evaporation of the solvent. The degree of ionization of the resulting salt may range from completely ionized to almost non-ionized.

[0206] The compounds of the present invention may exist in unsolvated and solvated forms. The term "solvate" is used herein to describe a molecular complex comprising a compound of the present invention and a stoichiometric amount of one or more pharmaceutically acceptable solvent molecules (e.g., ethanol). When the solvent is water, the term "hydrate" is used.

[0207] Included within the scope of the present invention are complexes, such as clathrates, drug-host inclusion complexes, in which, in contrast to the above-mentioned solvates, the drug and host are present in stoichiometric or non-stoichiometric amounts. Also included are drug complexes containing two or more organic and / or inorganic components, which may be in stoichiometric or non-stoichiometric amounts. The resulting complexes may be ionized, partially ionized or non-ionized. For a review of such complexes, see Haleblian, J Pharm Sci, 64(8), 1269-1288 (August 1975).

[0208] Hereinafter, all references to compounds of any formula include references to salts, solvates and complexes thereof, and references to solvates and complexes of salts thereof.

[0209] The compounds of the invention include compounds of the various formulae as defined herein, including all polymorphs and crystal habits thereof, prodrugs and isomers (including optical isomers, geometric isomers and tautomers) thereof as defined below, and isotopically labeled compounds of the invention.

[0210] The present invention also includes all pharmaceutically acceptable isotopically labeled compounds of the present invention, wherein one or more atoms are replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number most commonly found in nature.

[0211] Examples of suitable isotopes for inclusion in the compounds of the present invention include isotopes of hydrogen (e.g. 2 H and 3 H), carbon isotopes (such as 11 C. 13 C and 14 C), isotopes of chlorine (such as 36 Cl), fluorine isotopes (such as 18 F), isotopes of iodine (such as 123 I and 125 I), nitrogen isotopes (such as 13 N and 15 N), oxygen isotopes (such as 15 O. 17 O and 18 O), phosphorus isotopes (such as 32 P) and sulfur isotopes (such as 35 S).

[0212] Certain isotopically labeled compounds, e.g., those incorporating radioactive isotopes, are useful in drug and / or substrate tissue distribution studies. 3 H) and carbon-14 (i.e. 14 C) are particularly suitable for this purpose because they are easy to incorporate and have readily available means of detection.

[0213] Using heavier isotopes such as deuterium (i.e. 2 H) Substitutions may offer certain therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and thus may be preferred in some circumstances.

[0214] Before purification, depending on the synthetic procedure used, the compounds of the present invention may exist in the form of a mixture of enantiomers. Enantiomers may be separated by conventional techniques known in the art. Therefore, the present invention encompasses single enantiomers and mixtures thereof.

[0215] For some steps of the method for preparing the compounds of this invention, it may be necessary to protect the potential reactive functional groups that do not wish to react, and therefore the blocking group is cracked. In this case, any compatible protected free radical can be used. In particular, the method for protection and deprotection can be used, such as TWGREENE (Protective Groups in Organic Synthesis, A. Wiley-lnterscience Publication, 1981) or PJ Kocienski (Protecting groups, Georg Thieme Verlag, 1994) described method. The preparation of all the above-mentioned reactions and the new raw materials used in the aforementioned method is conventional, and reference precedents and examples related thereto and preparations to realize their performance or the suitable reagents and reaction conditions prepared and the program for separating the desired product are well known to those skilled in the art.

[0216] Furthermore, the compounds of the present invention and the intermediates used in their preparation can be purified according to various well-known methods, such as crystallization or chromatography.

[0217] One or more compounds of the invention can be combined with one or more agents, such as anti-inflammatory agents, anti-fibrotic agents, chemotherapeutic agents, anti-cancer agents, immunosuppressive agents, anti-tumor vaccines, cytokine therapy, or tyrosine kinase inhibitors, for the treatment of conditions modulated by inhibition of the DDR, such as fibrotic diseases, autoimmunity, inflammatory fibrotic conditions, inflammatory conditions, central nervous system disorders, or cancer.

[0218] The therapeutic methods or compounds defined above for the treatment of renal conditions, liver conditions, inflammatory conditions, cardiovascular conditions, acute and chronic organ transplant rejection, fibrotic diseases and cancer may be applied as a monotherapy or as a combination therapy in combination with additional active agents.

[0219] Therapeutic methods or compounds for treating renal conditions, liver conditions, inflammatory conditions, cardiovascular conditions, acute and chronic organ transplant rejection, fibrotic diseases and cancer. The additional active agent can be one or more active agents for treating the conditions treated by the compounds of the invention and the additional active agent. The additional active agent can include one or more of the following active agents:

[0220] (i) steroids, such as corticosteroids, including glucocorticoids and mineralocorticoids, for example, alclomethasone, alclomethasone dipropionate, aldosterone, amcinonide, beclomethasone, beclomethasone dipropionate, betamethasone, betamethasone dipropionate, betamethasone sodium phosphate, betamethasone valerate, budesonide, clobetasone, clobetasone butyrate, clobetasol propionate, clopredniol, cortisone, cortisone acetate, cortivazole, deoxycorticosterone, desonide, desoximetasone, dexamethasone, dexamethasone sodium phosphate, dexamethasone isonicotinate, diflucortolone, fluclorololone, flumethasone, flunisolide, fluocinolone acetonide, fluocinolone acetate, fluocinolone butyl, fluocinolone acetonide Corticosteroids, fluocortolone, fluocortolone caproate, fluocortolone pivalate, fluorometholone, fluprednidine, fluprednisolone acetate, flurandrenolide, fluticasone, fluticasone propionate, halcinonide, hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone acetate propionate, hydrocortisone propionate butyrate, hydrocortisone valerate, icomethasone, icomethasone acetate butyrate, methylprednisone, methylprednisolone, mometasone, paramethasone, mometasone furoate monohydrate, prednicasone, prednisolone, prednisone, tixocortol, tixocortol pivalate, triamcinolone acetonide, triamcinolone acetonide acetate, triamcinolone acetonide alcohol, and their respective pharmaceutically acceptable derivatives. Combinations of steroids may be used, such as combinations of two or more of the steroids mentioned in this paragraph;

[0221] (ii) TNF inhibitors, such as etanercept; monoclonal antibodies (e.g., infliximab (Remicade), adalimumab (Humira), cefixime (Cimzia), golimumab (Simponi)); fusion proteins (e.g., etanercept (Enbrel)); and 5-HT 2A agonists (e.g., 2,5-dimethoxy-4-iodoamphetamine, TCB-2, lysergic acid diethylamide (LSD), lysergic acid dimethylazetidine);

[0222] (iii) anti-inflammatory drugs, such as nonsteroidal anti-inflammatory drugs;

[0223] (iv) dihydrofolate reductase inhibitors / antifolates, such as methotrexate, trimethoprim, bromoprim, tetraoxaprine, iclaprim, pemetrexed, ralitrexed, and pralatrexate; and

[0224] (v) Immunosuppressants, such as cyclosporine, tacrolimus, sirolimus, pimecrolimus, angiotensin II inhibitors (e.g. valsartan, telmisartan, losartan, irbesartan, azilsartan, olmesartan, candesartan, eprosartan) and ACE inhibitors, such as sulfhydryl-containing agents (e.g. captopril, zofenopril), dicarboxylate-containing agents (e.g. enalapril, ramipril, quinapril, perindopril, lisinopril, benazepril, imidapril, zofenopril, trandolapril), phosphate-containing agents (e.g. fosinopril), casokinin, lactokinin and lactotripeptide.

[0225] (vi) anti-fibrotic agents, for example: pirfenidone, nintedanib, anti-IL-13 monoclonal antibodies (e.g., tralokinumab, QAX576, lebrikizumab), simtuzumab, FG-3019, lysophosphatidic acid receptor antagonists (e.g., BMS-986020, AM966), LOXL2 inhibitors, BET bromodomain inhibitors (e.g., JQ1), HDAC inhibitors (e.g., vorinostat), thrombin inhibitors (e.g., dabigatran etexilate), factor Xa inhibitors (e.g., apixaban, rivaroxaban), 15PGDH inhibitors, anti-αvβ6 monoclonal antibodies (e.g., BG00011), anti-CTGF monoclonal antibodies (FG-3019), PAR1 inhibitors, Nox4 inhibitors, and PAI-1 inhibitors.

[0226] In addition to the compounds of the present invention, the therapeutic methods or compounds used to treat cancer may also include conventional surgery or radiotherapy or chemotherapy. Such chemotherapy may include one or more of the following classes of anti-tumor agents:

[0227] (i) antiproliferative / antineoplastic drugs and combinations thereof, such as alkylating agents (e.g., cisplatin, oxaliplatin, carboplatin, cyclophosphamide, mechlorethamine, uracil mechlorethamine, bendamustine, melphalan, chlorambucil, mechlorethamine, busulfan, temozolomide, nitrosoureas, ifosfamide, melphalan, pipobroman, triethylene-melamine, triethylenethiophoporamine, carmustine, lomustine, streptozocin, and dacarbazine); antimetabolites (e.g., gemcitabine and antifolates such as fluoropyrimidines (e.g., 5-fluorouracil and tegafur), raltitrexed, methotrexate, pemetrexed, cytosine arabinoside, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate , pentostatin, gemcitabine, and hydroxyurea); antibiotics (e.g., anthracyclines such as doxorubicin, bleomycin, doxorubicin, daunorubicin, epirubicin, idarubicin, mitomycin-C, dactinomycin, and mithramycin); antimitotics (e.g., vinca alkaloids such as vincristine, vinblastine, vindesine, and vinorelbine, and taxanes such as paclitaxel and taxotere, and multikinase inhibitors); proteasome inhibitors such as carfilzomib and bortezomib; interferon therapy; and topoisomerase inhibitors (e.g., epipodophyllotoxins such as etoposide and teniposide, amsacrine, topotecan, mitoxantrone, and camptothecin); bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, cytarabine, paclitaxel (Taxol TM ), albumin-bound paclitaxel (nabpaclitaxel), docetaxel, mithramycin, deoxyco-formycin, mitomycin-C, L-asparaginase, interferon (especially IFN-a), etoposide, and teniposide;

[0228] (ii) cytostatic agents, such as antiestrogens (e.g. tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene), antiandrogens (e.g. bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (e.g. goserelin, leuprolide and buserelin), progestins (e.g. megestrol acetate), aromatase inhibitors (e.g. anastrozole, letrozole, vorazole and exemestane) and 5α-reductase inhibitors, such as finasteride; and navelbene, CPT-11, anastrozole, letrozole, capecitabine, reloxafme, cyclophosphamide, ifosfamide and droloxafine;

[0229] (iii) anti-invasive agents, such as dasatinib and bosutinib (SKI-606), as well as metalloproteinase inhibitors, inhibitors of urokinase plasminogen activator receptor function, or heparanase antibodies;

[0230] (iv) Inhibitors of growth factor function: For example, such inhibitors include growth factor antibodies and growth factor receptor antibodies, such as the anti-erbB2 antibody trastuzumab [Herceptin TM ], anti-EGFR antibody panitumumab, anti-erbB1 antibody cetuximab, tyrosine kinase inhibitors, such as inhibitors of the epidermal growth factor family (e.g. EGFR family tyrosine kinase inhibitors, such as gefitinib, erlotinib, 6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)-quinazolin-4-amine (CI 1033), erbB2 tyrosine kinase inhibitors, such as lapatinib) and antibodies to costimulatory molecules (such as CTLA-4, 4-1BB and PD-1), or antibodies to cytokines (IL-10, TGF-β); inhibitors of the hepatocyte growth factor family; inhibitors of the insulin growth factor family; modulators of apoptosis protein regulators (e.g. Bcl-2 inhibitors); inhibitors of the platelet-derived growth factor family, such as imatinib and / or nilotinib (AMN107); inhibitors of serine / threonine kinases (e.g. Ras / Raf signaling inhibitors, such as farnesyl transferase inhibitors, e.g., sorafenib, tipifarnib, and lonafarnib), inhibitors of cell signaling through MEK and / or AKT kinases, c-kit inhibitors, abl kinase inhibitors, PI3 kinase inhibitors, Plt3 kinase inhibitors, CSF-1R kinase inhibitors, IGF receptor, kinase inhibitors; Aurora kinase inhibitors and cyclin-dependent kinase inhibitors, e.g., CDK2 and / or CDK4 inhibitors; and CCR2, CCR4, or CCR6 modulators;

[0231] (v) anti-angiogenic agents, such as those that inhibit the action of vascular endothelial growth factor, such as the anti-vascular endothelial growth factor antibody bevacizumab (Avastin TM ); thalidomide; lenalidomide; and, for example, VEGF receptor tyrosine kinase inhibitors such as vandetanib, vatalanib, sunitinib, axitinib, and pazopanib;

[0232] (vi) gene therapy approaches, including, for example, approaches to replace abnormal genes such as abnormal p53 or abnormal BRCA1 or BRCA2;

[0233] (vii) Immunotherapy approaches, including, for example, antibody therapies such as alemtuzumab, rituximab, ibritumomab and ofatumumab; interferons, such as interferon alpha; interleukins, such as IL-2 (aldesleukin); interleukin inhibitors, such as IRAK4 inhibitors; cancer vaccines, including preventive and therapeutic vaccines, such as HPV vaccines, such as Gardasil, Cervarix, Oncophage, and Sipuleucel-T (Provenge); gp100; dendritic cell-based vaccines (such as Ad.p53 DC); and toll-like receptor modulators, such as TLR-7 or TLR-9 agonists; and

[0234] (viii) Cytotoxic agents, such as fludarabine, cladribine, pentostatin TM );

[0235] (ix) steroids, such as corticosteroids, including glucocorticoids and mineralocorticoids, for example, alclomethasone, alclomethasone dipropionate, aldosterone, amcinonide, beclomethasone, beclomethasone dipropionate, betamethasone, betamethasone dipropionate, betamethasone sodium phosphate, betamethasone valerate, budesonide, clobetasone, clobetasone butyrate, clobetasol propionate, clopredniol, cortisone, cortisone acetate, cortivazole, deoxycorticosterone, desonide, desoximetasone, dexamethasone, dexamethasone sodium phosphate, dexamethasone isonicotinate, diflucortolone, fluclorololone, flumethasone, flunisolide, fluocinolone acetonide, fluocinolone acetate, fluocinolone butyl, fluocinolone acetonide , fluocortolone, fluocortolone caproate, fluocortolone pivalate, fluorometholone, fluprednidine, fluprednisolone acetate, flurandrenolide, fluticasone, fluticasone propionate, halcinonide, hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone acetate propionate, hydrocortisone propionate butyrate, hydrocortisone valerate, icomethasone, icomethasone acetate butyrate, methylprednisone, methylprednisolone, mometasone, paramethasone, mometasone furoate monohydrate, prednicasone, prednisolone, prednisone, tixocortol, tixocortol pivalate, triamcinolone acetonide, triamcinolone acetonide acetate, triamcinolone acetonide alcohol, and their respective pharmaceutically acceptable derivatives. Combinations of steroids may be used, such as combinations of two or more of the steroids mentioned in this paragraph;

[0236] (x) targeted therapies, such as PI3Kd inhibitors, e.g., idelalisib and perifosine; PD-1, PD-L1, PD-L2, and CTL4-A modulators, antibodies, and vaccines; other IDO inhibitors (e.g., indoximod); anti-PD-1 monoclonal antibodies (e.g., MK-3475 and nivolumab); anti-PD-L1 monoclonal antibodies (e.g., MEDI-4736 and RG-7446); anti-PD-L2 monoclonal antibodies; and anti-CTLA-4 antibodies (e.g., ipilimumab);

[0237] (xii) Chimeric antigen receptors, anticancer vaccines and arginase inhibitors.

[0238] Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate administration of the individual components of the treatment.Such combination products employ the compounds of this invention within the therapeutically effective dosage range described above and the other pharmaceutically active agent within its approved dosage range.

[0239] The compounds of the present invention may exist in a single crystal form or a mixture of crystalline forms, or they may be amorphous. Therefore, the compounds of the present invention for pharmaceutical use may be administered as crystalline or amorphous products. They may be obtained, for example, as solid plugs, powders or films by methods such as precipitation, crystallization, freeze drying or spray drying or evaporative drying. Microwave or radio frequency drying may be used for this purpose.

[0240] For the above-mentioned compounds of the present invention, the dosage will certainly vary with the compound used, mode of administration, desired treatment and indicated disease. For example, if the compound of the present invention is administered orally, the daily dosage of the compound of the present invention can be in the range of 0.01 microgram / kilogram body weight (μg / kg) to 100 milligrams / kilogram body weight (mg / kg).

[0241] The compounds of the present invention or their pharmaceutically acceptable salts can be used alone, but are usually administered in the form of a pharmaceutical composition in which the compounds of the present invention or their pharmaceutically acceptable salts are combined with a pharmaceutically acceptable adjuvant, diluent or carrier. The conventional procedures for selecting and preparing suitable pharmaceutical preparations are described in, for example, "Pharmaceuticals-The Science of Dosage Form Designs", ME Aulton, Churchill Livingstone, 1988.

[0242] Depending on the mode of administration of the compound of the present invention, the pharmaceutical composition for administering the compound of the present invention will preferably contain 0.05 to 99% w (weight percentage) of the compound of the present invention, more preferably 0.05 to 80% w of the compound of the present invention, still more preferably 0.10 to 70% w of the compound of the present invention, and even more preferably 0.10 to 50% w of the compound of the present invention, all weight percentages being based on the total composition.

[0243] The pharmaceutical composition can be applied topically (e.g., to the skin) in the form of, for example, a cream, gel, lotion, solution, suspension, or systemically, for example, orally in the form of tablets, capsules, syrups, powders or granules; or parenterally (including intravenous, subcutaneous, intramuscular, intravascular or infusion) in the form of a sterile solution, suspension or emulsion for injection; rectally in the form of a suppository; or inhaled in the form of an aerosol.

[0244] For oral administration, the compounds of the invention can be mixed with adjuvants or carriers, such as lactose, sucrose, sorbitol, mannitol; starches, such as potato starch, corn starch or pullulan; cellulose derivatives; binders, such as gelatin or polyvinyl pyrrolidone; and / or lubricants, such as magnesium stearate, calcium stearate, polyethylene glycol, wax, paraffin, etc., and then compressed into tablets. If coated tablets are required, the core prepared as described above can be coated with a concentrated sugar solution, which can contain, for example, gum arabic, gelatin, talc and titanium dioxide. Alternatively, the tablets can be coated with a suitable polymer dissolved in a volatile organic solvent.

[0245] In order to prepare soft gelatin capsules, the compound of the present invention can be mixed with, for example, vegetable oil or polyethylene glycol. Hard gelatin capsules can contain compound particles prepared using the above-mentioned excipients for tablets. In addition, liquid or semisolid preparations of the compounds of the present invention can be filled into hard gelatin capsules. Liquid preparations for oral use can be in the form of syrup or suspension, such as solutions containing the compounds of the present invention, and the remainder is a mixture of sugar and ethanol, water, glycerol and propylene glycol. Optionally, this liquid preparation can contain coloring agents, flavoring agents, sweeteners (such as saccharin), preservatives and / or carboxymethyl cellulose as thickeners or other excipients known to those skilled in the art.

[0246] For intravenous (parenteral) administration, the compounds of the present invention may be administered as sterile aqueous or oily solutions.

[0247] According to well-known medical principles, the size of the dose of the compounds of the present invention for therapeutic purposes will naturally vary depending on the nature and severity of the condition, the age and sex of the animal or patient and the route of administration.

[0248] Dosage levels, dosing frequency and duration of treatment with the compounds of the invention are expected to vary depending on the formulation and the clinical indication, age and comorbid medical conditions of the patient.

[0249] Throughout the description and claims of this specification, the words "comprise" and "comprising" and their variations mean "including but not limited to", and they are not intended to (and do not) exclude other parts, additives, ingredients, integers or steps. Throughout the description and claims of this specification, the singular includes the plural unless the context requires otherwise. In particular, where the indefinite article is used, the specification should be understood as contemplating plurality as well as singularity, unless the context requires otherwise.

[0250] Features, integers, characteristics, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein unless incompatible therewith. All features disclosed in this specification (including any accompanying claims, abstract and drawings), and / or all steps of any method or process so disclosed, may be combined in any combination, except combinations in which at least some of such features and / or steps are mutually exclusive. The invention is not limited to the details of any foregoing embodiments. The invention extends to any novel one or any novel combination of the features disclosed in this specification (including any accompanying claims, abstract and drawings), or to any novel one or any novel combination of the steps of any method or process so disclosed.

[0251] The reader's attention is directed to all papers and documents filed concurrently with or prior to this specification in connection with this application, which are disclosed to the public with this specification, and the contents of all these papers and documents are incorporated herein by reference.

[0252] The compounds of the invention can be prepared according to or in analogy to general schemes 1 to 4. Alternatively, the compounds of the invention can be prepared according to or in analogy to examples 1 to 105.

[0253] Examples and Synthesis

[0254] Experimental Procedure

[0255] Unless otherwise stated, solvents, reagents and raw materials were purchased from commercial suppliers and used as received. Unless otherwise stated, all reactions were carried out at room temperature. Compounds were identified and purity confirmed using Waters Acquity SQ detector 2 (ACQ-SQD2#LCA081) by LCMS UV. The diode array detector wavelength was set to obtain a spectrum at a wavelength of 254nM, and MS was in positive and negative electrospray mode (m / z: 150-800). 2 μL aliquots were injected sequentially into a guard column (0.2 μm x 2mm filter) and a UPLC column (C18, 50x 2.1mm, <2 μm) maintained at 40°C. According to the gradient listed in Table 1 below, a mobile phase system consisting of A (0.1% (v / v) formic acid in water) and B (0.1% (v / v) formic acid in acetonitrile) was used to elute the sample at a flow rate of 0.6 mL / min (methods 1 and 2). Retention time RT was in minutes. When described throughout the experimental section, the following methods were also used, with gradients detailed in Table 1. Method 3 utilized a Shimadzu 2020 series spectrometer equipped with a binary pump and a diode array detector (collection wavelengths 214 and 254 nm), with the MS in positive and negative electrospray mode (m / z: 100-900). A 2 μL aliquot was injected onto an Agilent Poroshell 120EC-C18 column (2.7 μm, 4.6×50 mm) maintained at 35°C and eluted at 1.0 ml / min using a mobile phase consisting of: A: 0.05% formic acid in water (v / v), B: 0.05% formic acid in ACN (v / v). Method 4 utilized an Agilent Technologies 1290 series spectrometer equipped with a binary pump and a diode array detector (collection wavelengths 214 and 254 nm), with the MS in positive electrospray mode (m / z: 70-1000). A 2 μL aliquot was injected onto an Agilent Eclipse Plus RRHDC18 column (1.8 μm, 3.0×50 mm) maintained at 40° C. and eluted at 0.8 ml / min using a mobile phase consisting of: A: 0.05% formic acid in water (v / v), B: 0.05% formic acid in ACN (v / v).

[0256] Table 1

[0257]

[0258]

[0259] NMR was also used to characterize the final compounds. NMR spectra were obtained on a Bruker AVIII400 Nanobay with a 5 mm BBFO probe. Optionally, the Rf values ​​of the compounds were measured on silica gel thin layer chromatography (TLC) plates.

[0260] Compound purification was performed by silica gel flash column chromatography or preparative LCMS. LCMS purification was performed using a Waters 3100 mass spectrometer in positive and negative electrospray mode (m / z: 150-800) and a Waters 2489 UV / Vis detector. TM The sample was eluted on a preparative C18 5μM OBD 19×100 mm column at a flow rate of 20 mL / min using a mobile phase system consisting of A (0.1% (v / v) formic acid in water) and B (0.1% (v / v) formic acid in acetonitrile).

[0261] Table 2

[0262] Time (min) ％A ％B 0 90 10 1.5 90 10 11.7 5 95 13.7 5 95 14 90 90 15 90 90

[0263] General routes and plans

[0264]

[0265] General Scheme 1

[0266] Compounds of formula (I) can be prepared from intermediates represented by vi in ​​general scheme 1. In step 1, an o-fluoronitroaryl compound is subjected to a nucleophilic substitution reaction with an aryl or heteroaryl amine (wherein A represents a halogen capable of participating in a metal-mediated cross-coupling reaction such as a Suzuki or Stille reaction, such as Cl, Br or I) in the presence of a base such as sodium hydride to give a compound of structure i. In step 2, the nitro group of i can be reduced by transition metal catalysis in the presence of hydrogen, or using an alternative hydrogen source such as ammonium chloride to produce a compound of structure ii. In step 3, reaction with a carbonyl equivalent (e.g., CDI) gives a cyclized product represented by iii. In step 4, the free NH of iii is reacted with a suitable α-haloester, wherein A is a halogen such as Br and OAlk represents an alkoxy group such as ethanolate, followed by hydrolysis to the corresponding carboxylic acid with KOH or LiOH under alkaline conditions in step 5 to give a compound of structure v. In step 6, reaction with a suitable amine using a carboxylic acid activating reagent such as HATU and a base such as DIPEA affords the intermediate represented by vi.

[0267]

[0268] General Scheme 2

[0269] Compounds of formula I can be synthesized from intermediates represented by general structure vi by two routes described in general scheme 2. According to step 1a, vi (wherein A represents a halogen such as Br or another leaving group capable of participating in a metal-catalyzed cross-coupling reaction, such as a triflate) is subjected to a transition metal-catalyzed cross-coupling with an azaindazole of structure ix, wherein B is a boronic acid, a boronate ester, or a stannyl (trialkyltin) capable of participating in a Suzuki or Stille type reaction with a compound of structure vi. As an example, A can be a pinacol boronic acid ester and B can be a bromide, and these groups are subjected to a Suzuki reaction catalyzed by Pd(dppf)Cl2.DCM in the presence of KOAc in step 1a to obtain compounds of formula I. Alternatively, according to step 1, the intermediate of structure vi can be converted to the boronate or stannane of formula vii by reaction with bis(pinacolato)diboron or tributyltin chloride (wherein B is boronic acid, boronate or stanyl (trialkyltin)), respectively, and in step 2, a subsequent Suzuki or Stille reaction with an azaindazole of structure viii, where A is a halogen such as Br, Cl or I, to give a compound of formula (I).

[0270]

[0271] General solution 3

[0272] Compounds of formula (I) can also be obtained by reordering the steps of general schemes 1 and 2 as described in general scheme 3. The definitions of the groups A, B and OAlk in the structure shown in general scheme 3 are the same as those described in general schemes 1 and 2. In step 1, the intermediate of structure iv is subjected to a metal-catalyzed cross-coupling reaction, such as a Suzuki or Stille reaction with a boronate or stannane derivative of an azaindazole represented by ix. In step 2, the cross-coupled product (xi) is subjected to base-mediated ester hydrolysis as described above, followed by amide coupling in step 3 to obtain compounds of formula (I). Alternatively, the cross-coupling partner can be reversed by converting the halide or triflate iv to the corresponding boronate or stannane in step 1a and reacting it with a halogenated azaindazole of structure viii in step 2b to obtain an intermediate of structure xi.

[0273]

[0274] General Scheme 4

[0275] General Scheme 4 outlines an alternative route to prepare intermediates of structure iv, which are then converted to intermediates vi (General Scheme 1), which are then converted to compounds of formula (I) by the methods described in General Scheme 2. In step 1, the appropriate benzimidazolone or azabenzimidazolone derivative (xiii) is mono-Boc protected using NaH and di-tert-butyl dicarbonate. In step 2, the remaining free NH of xiv is alkylated with a suitable α-haloester. In step 3, the boc protecting group of xv is removed using TFA to allow for a Chan-Lam type coupling of xvi and a suitable arylboronic acid using copper (II) acetate as a catalyst and air as an oxygen source in step 4 to provide intermediates of structure iv.

[0276] In general schemes 2, 3 and 4, the azaindazole substituent R of the compound of formula I is 8b is H, steps 1a and 2 (general scheme 2) and steps 1 and 1a (general scheme 3) can use a 2-tetrahydropyranyl group as R 8b In these cases, a final deprotection step may be required to remove the tetrahydropyranyl group and form R 8b =H compounds. The deprotection step can be carried out by reaction with hydrogen chloride in an organic solvent such as 1,4-dioxane. In addition, in the case where no experimental procedures are described in the following intermediate syntheses, the azaindazole derivatives shown in general schemes 1-4 were prepared by methods previously described in the publicly available scientific literature.

[0277] Synthesis of intermediates Synthetic intermediate I-4, ethyl 2-[3-(4-bromophenyl)-2-oxobenzimidazol-1-yl]acetate

[0278]

[0279] Solution 1

[0280] Step ASynthesis of intermediate I-1, tert-butyl 2-oxo-3H-benzimidazole-1-carboxylate: To a solution of 2-hydroxybenzimidazole (3 g, 22 mmol) in DMF (90 mL) was added 60% sodium hydride dispersed in mineral oil (900 mg, 22.5 mmol), and the reaction mixture was stirred at room temperature for 2 h. A solution of (Boc)2O (4.9 g, 22 mmol) in DMF (10 mL) was added dropwise. The reaction mixture was stirred at room temperature for 16 h and then evaporated to dryness. The residue was diluted with ethyl acetate and washed with saturated NH4Cl aqueous solution (2×30 mL). The layers were separated and the aqueous phase was extracted with ethyl acetate (2×30 mL). The organic layer was washed with brine (2×30 mL), then dried with Na2SO4 and evaporated to dryness to give tert-butyl 2-oxo-3H-benzimidazole-1-carboxylate (intermediate I-1, 5.7 g, 24 mmol, 100% yield) as an off-white solid. UPLC-MS(ES + , Method 2):1.73min,m / z 233.2[MH] - . 1 H NMR (400MHz, DMSO-d6): δ11.24(s br ,1H),7.64(ddd,0.5,1.2,8.0Hz,1H),7.12(dt,J=1.2,7.6Hz,1H),7.05(dt,J=1.4,7.8Hz,1H),6.99(ddd,J=0.5,1.4,7.7Hz,1H),1.59(s,9H)ppm.

[0281] Step B Synthesis of intermediate I-2, tert-butyl 3-(2-ethoxy-2-oxo-ethyl)-2-oxobenzimidazole-1-carboxylate: A mixture of Cs2CO3 (9.5 g, 29 mmol), tert-butyl 2-oxo-3H-benzimidazole-1-carboxylate (intermediate I-1, 5.2 g, 22 mmol) and ethyl bromoacetate (2.7 mL, 25 mmol) in MeCN (120 mL) was heated to 80°C and stirred for 2 h. The mixture was cooled to room temperature and the solvent was removed in vacuo. The residue was suspended in brine (50 mL) and H2O (60 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were dried over Na2SO4 and the solvent was removed in vacuo. The crude product was dry loaded onto silica and purified by normal phase flash chromatography (SiO2, 0-20% EtOAc in petroleum ether) to give tert-butyl 3-(2-ethoxy-2-oxoethyl)-2-oxobenzimidazole-1-carboxylate (Intermediate I-2, 6.1 g, 19 mmol, 85% yield) as a yellow oil. UPLC-MS (ESI) +, method 2): 1.90min, m / z 321.1[M+H] + . 1 H NMR (400MHz, CDCl3): δ7.85 (dd, J=1.7, 7.5Hz, 1H), 7.18 (dt, J=1.5, 7.6Hz, 1H), 7.14 (dt, J=1.6, 7.7Hz) ,6.85(dd,J=1.3,7.7Hz,1H),4.59(s,2H),4.23(q,J=7.15,2H),1.67(s,9H),1.26(t,J=7.14Hz,3H)ppm.

[0282] Step C Synthesis of intermediate I-3, ethyl 2-(2-oxo-3H-benzimidazol-1-yl)acetate: To a solution of tert-butyl 3-(2-ethoxy-2-oxoethyl)-2-oxobenzimidazole-1-carboxylate (intermediate I-2, 6.1 g, 19 mmol) in DCM (90 mL) was added trifluoroacetic acid (14.6 mL, 190 mmol) dropwise, and the mixture was stirred at room temperature for 2 h. The reaction was quenched with saturated aqueous Na2CO3 solution (50 mL). The layers were separated and the aqueous layer was extracted with DCM (3×50 mL). The combined organic layers were dried over Na2SO4 and the solvent was removed in vacuo to give ethyl 2-(2-oxo-3H-benzimidazol-1-yl)acetate (intermediate I-3, 3.7 g, 17 mmol, 89% yield) as a white solid which was used in the next step without further purification. UPLC-MS (ES + , method 2): 1.51min, m / z 221.2[M+H] + . 1 H NMR (400MHz, DMSO-d6): δ10.95(s,1H),7.06-7.11(m,1H),6.96-7.03(m,3H),4.66(s,2H),4.15(q,J=7.1Hz,2H),1.21(t,J=7.1Hz,3H)ppm.

[0283] Step DSynthesis of intermediate I-4, ethyl 2-[3-(4-bromophenyl)-2-oxobenzimidazole-1-yl]acetate: In a round-bottom flask equipped with a condenser open to air, 4-bromophenylboronic acid (4.1 g, 20 mmol), ethyl 2-(2-oxo-3H-benzimidazole-1-yl)acetate (intermediate I-3, 2.2 g, 10 mmol) and copper (II) acetate (3.7 g, 20 mmol) were suspended in MeCN (90 mL). EtN (4.2 mL, 30 mmol) was added and the suspension was stirred at room temperature for 16 h. The solvent was removed in vacuo. The residue was dissolved in DCM (50 mL) and washed with H O (50 mL) and saturated NH Cl aqueous solution (50 mL). The aqueous layer was extracted with DCM (3 x 50 mL). The combined organic layers were dried with Na SO and concentrated in vacuo. The crude product was dry loaded onto silica and purified by phase flash chromatography (25 g SiO2, 5-90% EtOAc in petroleum ether) to give ethyl 2-[3-(4-bromophenyl)-2-oxobenzimidazol-1-yl]acetate (Intermediate I-4, 3.4 g, 9.2 mmol, 90% yield) as a white solid. UPLC-MS (ESI) + , method 2): 1.88min, m / z 375.0 / 376.9 [M+H] + . 1 H NMR (400MHz, DMSO-d6): δ7.79(td,J=2.5,9.6,2H),7.54(td,J=2.5,9.6,2H),7.30(d,J=7. 6Hz,1H),7.07-7.20(m,3H),4.82(s,2H),4.19(q,J=7.1Hz,2H),1.24(t,J=7.1Hz,3H)ppm.

[0284] Step E Synthesis of intermediate I-5, 2-[3-(4-bromophenyl)-2-oxobenzimidazol-1-yl]acetic acid: A suspension of ethyl 2-[3-(4-bromophenyl)-2-oxobenzimidazol-1-yl]acetate (intermediate I-4, 3.3 g, 8.9 mmol) and KOH (1.5 g, 27 mmol) in ethanol (140 mL) was heated to 80° C. and stirred for 2 h. The reaction mixture was evaporated to dryness. The residue was dissolved in H2O and slowly acidified to pH 2-3 by adding 1M HCl dropwise, which produced a white precipitate that was collected by filtration to give 2-[3-(4-bromophenyl)-2-oxobenzimidazol-1-yl]acetic acid (intermediate I-5, 3.0 g, 8.6 mmol, 97% yield) as a white solid. UPLC-MS (ES +, method 2): 1.63min, m / z 346.9 / 348.9 [M+H] + . 1 H NMR (400MHz, DMSO-d6): δ13.19(s,1H),7.78(td,J=2.5,9.7Hz,2H),7.54(td,J=2.6,9.7,2H),7.29(d br ,J=7.6Hz,1H),7.06-7.18(m,3H),4.69(s,2H)ppm.

[0285] Step F Synthesis of intermediate I-6, 2-[3-(4-bromophenyl)-2-oxo-benzimidazol-1-yl]-N-(2,2,2-trifluoroethyl)acetamide: To a stirred solution of 2-[3-(4-bromophenyl)-2-oxo-benzimidazol-1-yl]acetic acid (intermediate I-5, 1.7 g, 4.9 mmol) and trifluoroethylamine (0.5 mL, 6 mmol) in DMF (30 mL) was added HATU (2.2 g, 6 mmol) and DIPEA (1.7 mL, 9.8 mmol), and the mixture was stirred at room temperature for 2 h. The mixture was poured into brine (50 mL) and DCM (50 mL). The layers were separated, and the aqueous layer was extracted with DCM, and the combined organic layers were washed with saturated NH4Cl aqueous solution (3 x 30 mL) and brine, dried over Na2SO4, and concentrated in vacuo. The crude product was purified by flash chromatography (40 g SiO2, 5-90% EtOAc in petroleum ether) to give 2-[3-(4-bromophenyl)-2-oxobenzimidazol-1-yl]-N-(2,2,2-trifluoroethyl)acetamide (Intermediate I-6, 1.8 g, 4.1 mmol, 85% yield) as an off-white solid. UPLC-MS (ES + , method 2): 1.86min, m / z 428.0 / 429.9 [M+H] + . 1 H NMR (400MHz, DMSO-d6): δ8.97(t,J=6.3Hz,1H),7.79(td,J=2.5,9.6Hz,2H),7.55(td,J=2.5,9.6Hz,2H),7.06 -7.17(m,4H),4.66(s,2H),3.97(dq,J=6.3,9.8Hz,2H)ppm.

[0286] Table 3 describes the intermediates synthesized following the same procedure as intermediate I-6 (Scheme 1) substituting the described building blocks for 4-bromophenylboronic acid in step D and / or trifluoroethylamine in step F.

[0287] Table 3

[0288]

[0289] Synthetic intermediate I-11, 2-[3-(4-bromo-3-fluorophenyl)-2-oxobenzimidazol-1-yl]-N-(2,2,2-trifluoroethyl)acetamide

[0290]

[0291] Solution 2

[0292] Step A Synthesis of intermediate I-9, 2-(2-oxo-3H-benzimidazol-1-yl)acetic acid: A solution of tert-butyl 3-(2-ethoxy-2-oxoethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-carboxylate (Intermediate I-3, 2.00 g, 6.25 mmol) and LiOH.H2O (1.31 g, 31.2 mmol) in THF (10 mL) and H2O (10 mL) was stirred at 25°C for 3 h. The mixture was treated with HCl (1 M) (35 mL), diluted with water, and extracted with EtOAc (×3). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to give 2-(2-oxo-3H-benzimidazol-1-yl)acetic acid (Intermediate I-9, 1.08 g, 5.62 mmol, 90% yield) as a white solid. LC-MS (ES + , method 3): 4.10min, m / z 193.15[M+H] + . 1 H NMR (400MHz, DMSO-d6): δ10.93(s,1H),7.12(m c ,1H),7.06–7.01(m,2H),4.59(s,2H)ppm.

[0293] Step BSynthesis of intermediate I-10, 2-(2-oxo-3H-benzoimidazol-1-yl)-N-(2,2,2-trifluoroethyl)acetamide: A mixture of 2-(2-oxo-2,3-dihydro-1H-benzoimidazol-1-yl)acetic acid (I-9, 1.00 g, 5.20 mmol), 2,2,2-trifluoroethane-1-amine (567 mg, 5.7 mmol), EDCI (970 mg, 6.24 mmol), HOBT (843 mg, 6.24 mmol) and DIPEA (2.0 g, 15.6 mmol) in DMF (15 mL) was stirred overnight at 25° C. The mixture was diluted with EtOAc and washed with water (×3). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to give 2-(2-oxo-3H-benzoimidazol-1-yl)-N-(2,2,2-trifluoroethyl)acetamide (Intermediate I-10, 1.00 g, 3.66 mmol, 70% yield). LC-MS (ES + , method 4): 0.66min, m / z, 274.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6): δ10.90(s,1H),8.90(t,J=6.2Hz,1H),7.05–6.94(m,4H),4.53(s,2H),3.96(dq,J=6.3,9.7Hz,2H)ppm.

[0294] Step C Synthesis of intermediate I-11, 2-[3-(4-bromo-3-fluorophenyl)-2-oxobenzimidazol-1-yl]-N-(2,2,2-trifluoroethyl)acetamide: A solution of 2-(2-oxo-3H-benzimidazol-1-yl)-N-(2,2,2-trifluoroethyl)acetamide (intermediate I-10, 420 mg, 1.54 mmol), (4-bromo-3-fluoro-phenyl)boronic acid (480 mg, 2.19 mmol), NEt3 (445 mg, 4.40 mmol), Cu(OAc)2 (533 mg, 2.93 mmol) in MeCN (12 mL) was stirred overnight at 25°C under N2. The reactant was concentrated to dryness, and the residue was dissolved in EtOAc. The organic layer was washed with saturated aqueous NH4Cl solution (×2) and brine (×2), dried over Na2SO4, concentrated in vacuo and purified by column chromatography (SiO2, EtOAc in petroleum ether, 5%-10%) to give 2-[3-(4-bromo-3-fluoro-phenyl)-2-oxobenzimidazol-1-yl]-N-(2,2,2-trifluoroethyl)acetamide (Intermediate I-11, 280 mg, 0.63 mmol, 29%). LC-MS (ES +, Method 4): 2.033min, m / z, 447.95 [M+H] + . 1 H NMR (400MHz, DMSO-d6): δ8.97(t,J=6.2Hz,1H),7.95(t,J=8.3Hz,1H),7.69(dd,J=2.4,10.0Hz,1H),7.45(d d,J=1.7,8.6Hz,1H),7.23(d,J=7.6Hz,1H),7.21–7.09(m,3H),4.68(s,2H),3.99(dq,J=6.5,9.8Hz,2H)ppm.

[0295] Described in Table 4 are intermediates synthesized following the same procedure as intermediate 1-11 (Scheme 2) substituting the described building blocks for (4-bromo-3-fluoro-phenyl)boronic acid in step C.

[0296] Table 4

[0297]

[0298]

[0299] Synthetic intermediate I-18, 2-[3-(4-bromophenyl)-4-methyl-2-oxobenzimidazol-1-yl]-N-(2,2,2-trifluoroethyl)acetamide

[0300]

[0301] Solution 3

[0302] Step A Synthesis of intermediate I-13, N-(4-bromophenyl)-2-methyl-6-nitroaniline: NaH (6.2 g, 261 mmol) was added to a solution of 4-bromoaniline (30 g, 174 mmol) in anhydrous DMF (150 mL) at 0 ° C and N2. The mixture was stirred at this temperature for 30 min, then 2-fluoro-1-methyl-3-nitrobenzene (32.5 g, 209 mmol) was added, and the mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc (1.0 L), washed with water (3×1.0 L) and brine (500 mL), dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash chromatography (120 g SiO2, 1% EtOAc in petroleum ether) to give N-(4-bromophenyl)-2-methyl-6-nitroaniline (Intermediate I-13, 39.4 g, 86 mmol, 49% yield) as a white solid. 1H NMR (400MHz, DMSO-d6): δ8.03(s,1H),7.70(d,J=8.3Hz,1H),7.63(t,J=7.6Hz,1H), 7.54(d,J=7.7Hz,1H),7.20(d,J=8.8Hz,2H),6.43(d,J=8.7Hz,2H),2.09(s,3H)ppm.

[0303] Step B Synthesis of intermediate I-14, N2-(4-bromophenyl)-3-methylphenyl-1,2-diamine: A mixture of N-(4-bromophenyl)-2-methyl-6-nitroaniline (intermediate I-13, 34 g, 0.11 mol), Fe (31 g, 0.56 mol) and NH4Cl (30 g, 0.56 mol) in EtOH (600 mL) and water (200 mL) was stirred at 80 ° C for 2 h. The mixture was filtered through filter paper, washed with MeOH, and concentrated in vacuo to give N2-(4-bromophenyl)-3-methylphenyl-1,2-diamine (intermediate I-14, 18.2 g, 66 mmol, 59% yield) as a brown oil. UPLC-MS (ES + , method 2): 1.86min, m / z 277.0[M+H] +

[0304] Step C Synthesis of intermediate I-15, 3-(4-bromophenyl)-4-methyl-1H-benzimidazol-2-one: A mixture of N2-(4-bromophenyl)-3-methylphenyl-1,2-diamine (intermediate I-14, 3.7 g, 13.4 mmol) and CDI (6.5 g, 40 mmol) in DMF (40 mL) was stirred at 100 ° C for 16 h under N2 atmosphere. The mixture was diluted with EtOAc (200 mL) and washed with water (3×100 mL) and brine (100 mL), dried over Na2SO4 and concentrated in vacuo to give 3-(4-bromophenyl)-4-methyl-1H-benzimidazol-2-one (intermediate I-15, 5 g, 13 mmol, 98% yield) as a white solid, which was used in the next step without further purification. UPLC-MS (ES + , method 2): 2.17min, m / z 303.0[M+H] + . 1 H NMR (400MHz, DMSO-d6): δ7.18(s,1H),6.91(d,J=8.4Hz,2H),6.55(d,J=8.6Hz,2H),6.23–6.16(m,2H),6.02(d,J=6.8Hz,1H),1.07(s,3H)ppm.

[0305] Step D Synthesis of intermediate I-16, ethyl 2-[3-(4-bromophenyl)-4-methyl-2-oxobenzimidazol-1-yl]acetate: A mixture of 3-(4-bromophenyl)-4-methyl-1H-benzimidazol-2-one (intermediate I-15, 4 g, 13 mmol), ethyl 2-bromoacetate (3.3 g, 20 mmol) and CsCO (8.6 g, 26 mmol) in MeCN (60 mL) was stirred at room temperature for 2 h. The mixture was concentrated in vacuo, water (200 mL) and EtOAc (200 mL) were added and the layers were separated. The aqueous layer was extracted with EtOAc (2×200 mL), and the combined organic layers were washed with brine (100 mL), dried over Na 2 SO 4 and concentrated in vacuo to afford ethyl 2-[3-(4-bromophenyl)-4-methyl-2-oxobenzoimidazol-1-yl]acetate (Intermediate I-16, 4.8 g, 10 mmol, 75% yield) as an off-white solid, which was used in the next step without further purification. UPLC-MS (ES + , method 2): 2.65min, m / z 389.1[M+H] + . 1 HNMR (400MHz, DMSO-d6): δ7.76(d,J=8.6Hz,2H),7.43(d,J=8.7Hz,2H),7.13(d,J=7.7Hz,1H),7.05(t,J=7. 8Hz,1H),6.89(d,J=7.8Hz,1H),4.78(s,2H),4.19(q,J=7.5Hz,2H),1.85(s,3H),1.24(t,J=7.5Hz,3H)ppm.

[0306] Step ESynthesis of intermediate I-17, 2-[3-(4-bromophenyl)-4-methyl-2-oxobenzimidazol-1-yl]acetic acid: A mixture of ethyl 2-[3-(4-bromophenyl)-4-methyl-2-oxobenzimidazol-1-yl]acetate (intermediate I-16, 300 mg, 0.77 mmol) and LiOH·H2O (97 mg, 2.32 mmol) in MeOH (2 mL), THF (2 mL) and H2O (2 mL) was stirred at room temperature for 2 h. The reaction was treated with 6M HCl (0.5 mL). The mixture was concentrated in vacuo, diluted with water (20 mL), and extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4 and concentrated in vacuo to give 2-[3-(4-bromophenyl)-4-methyl-2-oxobenzimidazol-1-yl]acetic acid (Intermediate I-17, 270 mg, 0.75 mmol, 97% yield) as a white solid, which was used in the next step without further purification.

[0307] UPLC-MS(ES + , method 2): 2.09min, m / z 361.0[M+H] + . 1 H NMR (400MHz, DMSO-d6): δ7.75 (d, J = 8.6 Hz, 2H), 7.43 (d, J = 8.6 Hz, 2H), 7.12 (d, J = 7. 8Hz,1H),7.04(t,J=7.8Hz,1H),6.86(d,J=7.6Hz,1H),4.67(s,2H),1.84(s,3H)ppm.

[0308] Step F Synthesis of intermediate I-18, 2-[3-(4-bromophenyl)-4-methyl-2-oxobenzoimidazol-1-yl]-N-(2,2,2-trifluoroethyl)acetamide: A mixture of 2-(3-(4-bromophenyl)-4-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)acetic acid (Intermediate I-17, 270 mg, 0.75 mmol), 2,2,2-trifluoroethane-1-amine (111.4 mg, 1.125 mmol), HATU (428 mg, 1.125 mmol) and DIPEA (291 mg, 2.25 mmol) in DMF (3 ml) was stirred at room temperature overnight and diluted with water. The precipitate was collected by filtration and dried in vacuo to give 2-[3-(4-bromophenyl)-4-methyl-2-oxobenzimidazol-1-yl]-N-(2,2,2-trifluoroethyl)acetamide (Intermediate I-18, 260 mg, 0.59 mmol, 79%) as an off-white solid. LC-MS (ES +, Method 4):2.42min,m / z,442.1[M+H]. 1 H NMR (400MHz, DMSO-d6): δ8.94(t,J=6.2Hz,1H),7.76(d,J=8.6Hz,2H),7.43(d,J=8.6Hz,2H),7.03(t,J=7.6Hz ,1H),6.99(d,J=7.2Hz,1H),6.86(d,J=7.2Hz,1H),4.63(s,2H),3.95(dq,J=6.4,16.2Hz,2H),1.84(s,3H)ppm.

[0309] Table 5 describes the intermediates synthesized by following the same procedure as intermediate I-18 (Scheme 3) by replacing 2-fluoro-1-methyl-3-nitrobenzene and 4-bromoaniline with appropriate building blocks in step A, or replacing 2,2,2-trifluoroethane-1-amine with appropriate building blocks in step F.

[0310] Table 5

[0311]

[0312]

[0313]

[0314]

[0315]

[0316]

[0317] Intermediates similar to intermediate 1-16 (Scheme 3) were synthesized following the same synthetic route and procedure, substituting appropriate building blocks for 2-fluoro-1-methyl-3-nitrobenzene and 4-bromoaniline in step A. These intermediates are shown in Table 6.

[0318] Table 6

[0319]

[0320]

[0321]

[0322]

[0323] Table 6 describes the intermediates synthesized by following the same procedure as intermediate iv-1 (route 1), replacing 3-(5-bromo-2-pyridinyl)-4-methyl-1H-benzimidazol-2-one with the described structural units in step D, and by following the same procedure as intermediate iv-4 (route 4), replacing ethyl 2-(2-oxo-3H-benzimidazol-1-yl)acetate with the described structural units in step D.

[0324]

[0325] Synthetic intermediate I-31, 2-[3-[4-(1-methylpyrazolo[3,4-c]pyridin-4-yl)phenyl]-2-oxobenzimidazol-1-yl]acetic acid

[0326]

[0327] Solution 4

[0328] Step A Synthesis of intermediate I-28, ethyl 2-[3-(4-bromophenyl)-2-oxobenzimidazole-1-yl]acetate: In a round-bottom flask equipped with a condenser open to air, 4-bromo-phenylboronic acid (4.1 g, 20 mmol), ethyl 2-(2-oxo-3H-benzimidazole-1-yl)acetate (intermediate I-3, 2.2 g, 10 mmol) and copper (II) acetate (3.7 g, 20 mmol) were suspended in MeCN (90 mL). EtN (4.2 mL, 30 mmol) was added, and the suspension was stirred at room temperature for 16 h. The solvent was removed in vacuo. The residue was dissolved in DCM (50 mL) and washed with H O (50 mL) and saturated NH Cl aqueous solution (50 mL). The aqueous layer was extracted with DCM (3x50 mL). The combined organic layers were dried with Na SO and concentrated in vacuo. The crude product was dry loaded onto silica and purified by flash chromatography (25 g SiO2, 5-90% EtOAc in petroleum ether) to give ethyl 2-[3-(4-bromophenyl)-2-oxobenzimidazol-1-yl]acetate (Intermediate I-28, 3.4 g, 9.2 mmol, 90% yield) as a white solid. UPLC-MS (ESI): + , method 2): 1.88min, m / z 375.0 / 376.9 [M+H] + . 1H NMR (400MHz, DMSO-d6): δ7.79(td,J=2.5,9.6,2H),7.54(td,J=2.5,9.6,2H),7.30(d,J=7. 6Hz,1H),7.07-7.20(m,3H),4.82(s,2H),4.19(q,J=7.1Hz,2H),1.24(t,J=7.1Hz,3H)ppm.

[0329] Step B Synthesis of intermediate I-29, ethyl 2-[2-oxo-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]benzimidazol-1-yl]acetate: A mixture of ethyl 2-[3-(4-bromophenyl)-2-oxobenzimidazol-1-yl]acetate (intermediate I-28, 500 mg, 1.33 mmol), bis(pinacolato)diboron (508 mg, 2.0 mmol), Pd2(dba)3 (122 mg, 0.13 mmol), Xphos (127 mg, 0.27 mmol) and KOAc (392 mg, 4.0 mmol) in THF (10 mL) was stirred at 70° C. under N2 for 16 h. The mixture was diluted with EtOAc (100 mL) and washed with water (100 mL) and brine (100 mL). The combined aqueous layers were extracted with EtOAc (2 x 100 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo to afford ethyl 2-[2-oxo-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]benzimidazol-1-yl]acetate (Intermediate I-29, 1.2 g, 1.14 mmol, 40% yield) as a brown solid which was used in the next step without further purification. LC-MS (ESI): + , Method 4): 4.55min, m / z 423.3[M+H] +

[0330] Step CSynthesis of intermediate I-30, ethyl 2-[3-[4-(1-methylpyrazolo[3,4-c]pyridin-4-yl)phenyl]-2-oxobenzimidazol-1-yl]acetate: A degassed mixture of ethyl 2-[2-oxo-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]benzimidazol-1-yl]acetate (intermediate I-29, 1.00 g, 2.37 mmol), 4-bromo-1-methyl-1H-pyrazolo[3,4-c]pyridine (502 mg, 2.37 mmol), Pd(dppf)Cl2·DCM (193 mg, 0.24 mmol) and KOAc (930 mg, 9.47 mmol) in 1,4-dioxane (30 mL) and water (3 mL) was stirred at 90 °C under N2 for 16 h. The mixture was concentrated in vacuo and purified by normal phase chromatography (1-2.5% MeOH in DCM) to give ethyl 2-[3-[4-(1-methylpyrazolo[3,4-c]pyridin-4-yl)phenyl]-2-oxobenzimidazol-1-yl]acetate (Intermediate I-30, 400 mg, 0.94 mmol, 40% yield) as an off-white solid. LC-MS (ESI): + , method 4):1.533min,m / z,428.15[M+H] + . 1 HNMR (400MHz, DMSO-d6): δ9.24(s,1H),8.52(s,1H),8.44(s,1H),8.05(d,J=8.4Hz,2H),7.78(d,J=8.4Hz,2H),7.34(dd,J=1.0,7.5,1H),7.25(dd,J= 1.0,7.5Hz,1H,),7.20(dt,J=1.0,7.5Hz,1H),7.15(dt,J=1.0,7.5Hz,1H) ,4.87(s,2H),4.27(s,3H),4.22(q,J=7.1Hz,2H),1.26(t,J=7.1Hz,3)ppm.

[0331] Step DSynthesis of Intermediate I-31, 2-[3-[4-(1-methylpyrazolo[3,4-c]pyridin-4-yl)phenyl]-2-oxobenzimidazol-1-yl]acetic acid: A mixture of ethyl 2-[3-[4-(1-methylpyrazolo[3,4-c]pyridin-4-yl)phenyl]-2-oxobenzimidazol-1-yl]acetate (Intermediate I-30, 470 mg, 1.10 mmol) and LiOH (58 mg, 2.42 mmol) in THF (15 mL), MeOH (10 mL) and water (5 mL) was stirred at room temperature for 16 h. The mixture was concentrated in vacuo, diluted with water, and extracted with ethyl acetate (×3). The combined organics were washed with brine, dried over Na2SO4 and concentrated in vacuo to give 2-[3-[4-(1-methylpyrazolo[3,4-c]pyridin-4-yl)phenyl]-2-oxobenzimidazol-1-yl]acetic acid (Intermediate I-31, 446 mg, 1.10 mmol, 100% yield) as a white solid. LC-MS (ESI): + , method 4):1.967min,m / z,400.05[M+H] + . 1 H NMR (400MHz, DMSO-d6): δ9.39(s,1H),8.59(s,1H),8.55(s,1H),8.08(d,J=8.6Hz,2H),7.81(d,J=8.6Hz,2H),7.34 (d,J=7.7Hz,1H),7.25(d,J=7.7Hz,1H),7.20(t,J=7.6Hz,1H),7.15(t,J=7.6Hz,1H),4.76(s,2H),4.31(s,3H)ppm.

[0332] Synthetic intermediate I-34, 2-[4-methyl-3-[4-(1-methylpyrazolo[3,4-c]pyridin-4-yl)phenyl]-2-oxobenzimidazol-1-yl]acetic acid

[0333]

[0334] Solution 5

[0335] Step ASynthesis of intermediate I-32, ethyl 2-[4-methyl-2-oxo-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]benzimidazol-1-yl]acetate: A mixture of ethyl 2-(3-(4-bromophenyl)-4-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)acetate (intermediate I-16, 2.00 g, 5.15 mmol), B2pin2 (2.617 g, 10.31 mmol), Pd2(dba)3 (472 mg, 0.5154 mmol), XPhos (491.5 mg, 1.031 mmol) and KOAc (1.517 g, 15.46 mmol, 3.0 equiv) in degassed THF (30 mL) was stirred at 70 °C under N2 atmosphere overnight. The mixture was cooled to room temperature, filtered, concentrated in vacuo, and purified by flash chromatography (SiO2, 0-50% EtOAc in petroleum ether) to give ethyl 2-[4-methyl-2-oxo-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]benzimidazol-1-yl]acetate (Intermediate I-32, 2.20 g, 5.04 mmol, 98%) as an off-white solid. LC-MS (Method 3): 4.579 min, m / z 437.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6): δ7.84(d,J=8.2Hz,2H),7.45(d,J=8.2Hz,2H),7.12(d,J=7.8Hz,1H),7.04(t,J=7.8Hz,1H ),6.86(d,J=7.8Hz,1H),4.78(s,2H),4.19(q,J=7.1Hz,2H),1.81(s,3H),1.35(s,12H),1.24(t,J=7.1Hz,3H)ppm.

[0336] Step BSynthesis of intermediate I-33, ethyl 2-[4-methyl-3-[4-(1-methylpyrazolo[3,4-c]pyridin-4-yl)phenyl]-2-oxobenzoimidazol-1-yl]acetate: 4-bromo-1-methyl-1H-pyrazolo[3,4-c]pyridine (709 mg, 3.36 mmol), ethyl 2-(4-methyl-2-oxo-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl]acetate A mixture of (intermediate I-32, 2.2 g, 5.04 mmol), Pd(dppf)Cl2 (245 mg, 0.336 mmol) and K2CO3 (1.39 g, 10.08 mmol) in degassed DMF (15 mL) was stirred overnight at 80°C under N2 atmosphere. The reactant was diluted with EtOAc (200 mL) and washed with water (50 mL×3). The combined organic layers were washed with brine (100 mL) and dried over Na2SO4. The mixture was purified by column chromatography (SiO2, 0-5% Purification by HPLC-MS / MS (MeOH in DCM) gave ethyl 2-[4-methyl-3-[4-(1-methylpyrazolo[3,4-c]pyridin-4-yl)phenyl]-2-oxo-benzoimidazol-1-yl]acetate (Intermediate I-33, 710 mg, 1.61 mmol, 48%) as a white solid. LC-MS (Method 4): 1.54 min, m / z 442.15 [M+H] + .

[0337] 1 H NMR (400MHz, DMSO-d6): δ9.25(s,1H),8.54(s,1H),8.43(s,1H),8.02(d,J=8.3Hz,2H),7.64(d,J=8.3Hz,2H),7.16(d,J=7.8Hz,1H), 7.07(t,J=7.8Hz,1H),6.90(d,J=7.8Hz,1H),4.82(s,2H),4.21(s,3H),4.21(q,J=7.1Hz,2H),1.93(s,3H),1.26(t,J=7.1Hz,3H)ppm.

[0338] Step CSynthesis of intermediate I-34, 2-[4-methyl-3-[4-(1-methylpyrazolo[3,4-c]pyridin-4-yl)phenyl]-2-oxobenzimidazol-1-yl]acetic acid: A mixture of ethyl 2-[4-methyl-3-[4-(1-methylpyrazolo[3,4-c]pyridin-4-yl)phenyl]-2-oxobenzimidazol-1-yl]acetate (intermediate I-33, 710 mg, 1.61 mmol) and LiOH·H2O (202.6 mg, 4.828 mmol) in MeOH (4 mL), THF (4 mL) and H2O (4 mL) was stirred at room temperature for 2 h. The reaction was treated with 1M HCl (5 mL) and the precipitate was filtered to give 2-[4-methyl-3-[4-(1-methylpyrazolo[3,4-c]pyridin-4-yl)phenyl]-2-oxo-benzoimidazol-1-yl]acetic acid (Intermediate I-34, 620 mg, 1.50 mmol, 93%) as an off-white solid. LC-MS (Method 3): 3.050 min, m / z 414.0 [M+H] +

[0339] 1 H NMR (400MHz, DMSO-d6): δ9.26(s,1H),8.55(s,1H),8.44(s,1H),8.02(d,J=8.3Hz,2H),7.65(d,J=8.3Hz,2H), 7.16(d,J=7.8Hz,1H),7.08(t,J=7.8Hz,1H),6.90(d,J=7.8Hz,1H),4.72(s,2H),4.29(s,3H),1.94(s,3H)ppm.

[0340] Table 7 describes the intermediates synthesized following the same procedure as intermediate 1-34 (Scheme 5) substituting appropriate building blocks for Step A for 2-fluoro-1-methyl-3-nitrobenzene and 4-bromoaniline in Step A of Scheme 3.

[0341] Table 7

[0342]

[0343]

[0344]

[0345]

[0346]

[0347] Intermediates I-90 to I-95 were synthesized following the same procedure as intermediate I-95 (Scheme 13, step 6), as shown in the table below.

[0348]

[0349]

[0350] Synthesis of tributyl-(1-methylpyrazolo[3,4-c]pyridin-4-yl)stannane (I-96)

[0351]

[0352] A mixture of 4-bromo-1-methyl-1H-pyrazolo[3,4-c]pyridine (5.0 g, 23.58 mmol), bis(tributyltin) (14.3 mL, 28.3 mmol) and Pd(PPh3)4 (2.72 g, 2.36 mmol) in m-xylene (50 mL) was stirred at 130°C under N2 for 48 h. The crude material was purified by flash column chromatography eluting with EtOAc in petroleum ether to give tributyl-(1-methylpyrazolo[3,4-c]pyridin-4-yl)stannane (6.7 g, 15.9 mmol, 67% yield).

[0353] LC-MS(ES-API,Aglient-LCMS-01-P2):2.82min,m / z,422.1[M] +

[0354]

[0355]

[0356] Synthesis of potassium trifluoro(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)borate (I-101)

[0357]

[0358] Synthesis of potassium trifluoro(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)borate (I-101): A mixture of 4-bromo-1-methyl-1H-pyrazolo[3,4-c]pyridine (10 g, 47.2 mmol) and B(OiPr)3 (1.5 eq) in dry THF (100 mL) was cooled to -78 °C and nBuLi (1.5 eq, 2.5 M in hexanes) was added dropwise while keeping the temperature below -70 °C. The reaction mixture was then stirred at -78 °C for 30 min. The reactants were warmed to 0 °C. KHF2 (6.0 eq) was then added followed by water. The resulting mixture was stirred at room temperature for 12 h. The precipitate was filtered and dried under vacuum at 55 °C for 48 h to give potassium trifluoro(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)borate. LC-MS (ES-API): m / z, 200.0 [M-39]

[0359] Example

[0360] Example 1: 2-[3-[4-(1-methylpyrazolo[3,4-c]pyridin-4-yl)phenyl]-2-oxobenzimidazol-1-yl]-N-(2,2,2-trifluoroethyl)acetamide

[0361]

[0362] Solution 6

[0363] Step ASynthesis of intermediate I-36, 2-[2-oxo-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl]benzimidazol-1-yl]-N-(2,2,2-trifluoroethyl)acetamide: Purged a suspension of 2-[3-(4-bromophenyl)-2-oxo-benzimidazol-1-yl]-N-(2,2,2-trifluoroethyl)acetamide (Intermediate I-6, 1.99 g, 4.65 mmol), potassium acetate (1.60 g, 16.28 mmol), bis(pinacolato)diboron (1.77 g, 6.98 mmol) in 1,4-dioxane (80 mL) and DMF (8 mL) (3x vacuum, 3x N2). After adding Pd(dppf)Cl2·DCM (570 mg, 0.7 mmol), the suspension was purged again (3x vacuum, 3x N2) and heated to 95 ° C under N2 atmosphere. After 17 h, the mixture was filtered through filter paper. The filter was thoroughly rinsed with EtOAc, the filtrate was concentrated in vacuo, and purified by flash chromatography (SiO2, 25 g, 5-95% EtOAc in petroleum ether) to give 2-[2-oxo-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]benzimidazol-1-yl]-N-(2,2,2-trifluoroethyl)acetamide (Intermediate I-36, 2.10 g, 4.41 mmol, 98%) as a brown solid. UPLC-MS (ES+, Method 2): 1.92 min, m / z 476.0 [M+H]+

[0364] . 1 H NMR (400 MHz, CDCl3): δ 8.00 (d br ,J=8.3Hz,2H),7.56(d br ,J=8.3Hz,2H),7.11-7.24(m,4H),6.83(t,J=6.5Hz,1H),4.64(s,2H),3.90(dq,J=6.5,8.9Hz,2H),1.37(s,12H)ppm.

[0365] Step BSynthesis Example 1, 2-[3-[4-(1-methylpyrazolo[3,4-c]pyridin-4-yl)phenyl]-2-oxobenzimidazol-1-yl]-N-(2,2,2-trifluoroethyl)acetamide: Purge 2-[2-oxo-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]benzimidazol-1-yl]-N-(2,2,2-trifluoroethyl)acetamide A suspension of (intermediate I-36, 80 mg, 0.17 mmol), potassium acetate (50 mg, 0.50 mmol), Pd(dppf)Cl2·DCM (21 mg, 0.03 mmol), 4-bromo-1-methyl-1H-pyrazolo[3,4-c]pyridine (71 mg, 0.34 mmol) in 1,4-dioxane (2.5 mL) and water (0.5 mL) (3x vacuum, 3x N2) and heated to 100°C under N2 atmosphere. After 16 h, the mixture was cooled to room temperature and purified by flash chromatography (SiO2, 0-20% MeOH in EtOAc, then 0-20% MeOH in DCM) to give 2-[3-[4-(1-methylpyrazolo[3,4-c]pyridin-4-yl)phenyl]-2-oxobenzimidazol-1-yl]-N-(2,2,2-trifluoroethyl)acetamide (Example 1, 23 mg, 0.05 mmol, 28%) as a white solid. UPLC-MS (ES) + , method 1): 3.07min, m / z 481.6[M+H] + . 1 H-NMR (400MHz, DMSO-d6): δ9.23 (s, 1H), 9.00 (t, J = 6.3Hz, 1H), 8.51 (s, 1H), 8.43 (d,J=0.8Hz,1H),8.05(td,J=2.3,9.0Hz,2H),7.77(td,J=2.3,9.0Hz,2H),7.23(d br ,J=7.3Hz,1H),7.10–7.21(m,4H),4.70(s,2H),4.26(s,3H),3.99(dq,J=6.0,9.9Hz,2H)ppm.

[0366] Table 8 describes an example of the synthesis following the same procedure as Example 1 (Scheme 6) by replacing intermediate I-6 with a suitable building block for step A and replacing 4-bromo-1-methyl-1H-pyrazolo[3,4-c]pyridine with a suitable building block in step B.

[0367] Table 8

[0368]

[0369]

[0370]

[0371]

[0372]

[0373]

[0374]

[0375]

[0376] Example 17: 2-[3-[4-(1-methylpyrazolo[3,4-c]pyridin-4-yl)phenyl]-2-oxobenzimidazol-1-yl]-N-(2,2,2-trifluoro-1-methylethyl)acetamide

[0377]

[0378] Solution 7

[0379] A solution of 2-[3-[4-(1-methylpyrazolo[3,4-c]pyridin-4-yl)phenyl]-2-oxo-benzoimidazol-1-yl]acetic acid (Intermediate I-31, 40 mg, 0.10 mmol), 1,1,1-trifluoro-2-propylamine (12.5 mg, 0.110 mmol), EDCI (23 mg, 0.120 mmol), HOBT (16.2 mg, 0.120 mmol) and DIPEA (39 mg, 0.300 mmol) in DMF (2 mL) was stirred at room temperature overnight. The mixture was poured into water (30 mL), extracted with EtOAc (×3), washed with brine (×3), dried over Na2SO4 and concentrated in vacuo, and purified by preparative HPLC to give 2-[3-[4-(1-methylpyrazolo[3,4-c]pyridin-4-yl)phenyl]-2-oxobenzimidazol-1-yl]-N-(2,2,2-trifluoro-1-methyl-ethyl)acetamide (Example 17, 13 mg, 0.026 mmol, 26%) as a white solid. LC-MS (ES + , method 4): 1.533min, m / z 495.10[M+H] + . 1H-NMR (400MHz, DMSO-d6): δ9.23(s,1H),8.95(d,J=8.1Hz,1H),8.52(s,1H),8.44(s,1H),8.05(d,J=7.9Hz ,2H),7.78(d,J=7.9Hz,2H),7.28–7.08(m,4H),4.72–4.59(m,3H),4.30(s,3H),1.32(d,J=6.6Hz,3H)ppm.

[0380] Table 9 describes examples synthesized following the same procedure as Example 17 (Scheme 7) using appropriate building blocks and reagents in place of intermediate 1-31, amine coupling partner and coupling reagents EDCI and HOBT.

[0381] Table 9

[0382]

[0383]

[0384]

[0385]

[0386]

[0387]

[0388]

[0389]

[0390]

[0391]

[0392]

[0393]

[0394]

[0395]

[0396]

[0397]

[0398]

[0399]

[0400]

[0401]

[0402]

[0403]

[0404]

[0405] Embodiment 41: 2-[2-Oxo-3-[4-(1H-pyrazolo[3,4-c]pyridin-4-yl)phenyl]benzimidazol-1-yl]-N-(2,2,2-trifluoroethyl)acetamide

[0406]

[0407] Solution 8

[0408] Step A: Synthesis of 2-[2-oxo-3-[4-(1-tetrahydropyran-2-ylpyrazolo[3,4-c]pyridin-4-yl)phenyl]benzimidazol-1-yl]-N-(2,2,2-trifluoroethyl)acetamide. A mixture of 4-bromo-1-tetrahydropyran-2-yl-pyrazolo[3,4-c]pyridine (100 mg, 0.35 mmol), 2-[2-oxo-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]benzimidazol-1-yl]-N-(2,2,2-trifluoroethyl)acetamide (202 mg, 0.42 mmol), Pd(dppf)Cl2 (26 mg, 0.03 mmol) and K2CO3 (147 mg, 1.06 mmol) in degassed 1,4-dioxane (5 mL) and degassed H2O (0.5 mL) was stirred at 90° C. under N2 atmosphere for 16 h. The mixture was diluted with water and extracted with EtOAc. The organic layer was dried over Na2SO2, concentrated in vacuo and purified by preparative TLC (50% EtOAc in petroleum ether) to give 2-[2-oxo-3-[4-(1-tetrahydropyran-2-ylpyrazolo[3,4-c]pyridin-4-yl)phenyl]benzimidazol-1-yl]-N-(2,2,2-trifluoroethyl)acetamide (97 mg) as an off-white solid. LC-MS (ES) + , method 4): 1.06min, m / z 551[M+H] + .

[0409] Step B:Synthetic Example 41, 2-[2-oxo-3-[4-(1H-pyrazolo[3,4-c]pyridin-4-yl)phenyl]benzimidazol-1-yl]-N-(2,2,2-trifluoroethyl)acetamide. A mixture of 2-[2-oxo-3-[4-(1-tetrahydropyran-2-ylpyrazolo[3,4-c]pyridin-4-yl)phenyl]benzimidazol-1-yl]-N-(2,2,2-trifluoroethyl)acetamide (97 mg, 0.18 mmol), 4N HCl (4N in HCl, 1.0 mL, 4.0 mmol) in MeOH (1.5 mL) was stirred at room temperature for 1 h. The mixture was adjusted to pH>7 with NaHCO3 (saturated aqueous solution), diluted with water and extracted with EtOAc. The organic layer was dried over Na2SO4, concentrated in vacuo and purified by preparative HPLC to give 2-[2-oxo-3-[4-(1H-pyrazolo[3,4-c]pyridin-4-yl)phenyl]benzimidazol-1-yl]-N-(2,2,2-trifluoroethyl)acetamide (Example 41, 7.6 mg, 0.016 mmol, 5%) as a white solid. LC-MS (ES + , Method 3): 3.68min, m / z 467.25[M+H] + . 1 H NMR (400MHz, DMSO-d6): δ13.88(s,1H),9.06(s,1H),8.96(t,J=6.3Hz,1H),8.44(s,1H),8.43(s,1H),8.01(d,J=8.1H z,2H),7.73(d,J=8.1Hz,2H),7.19(d,J=7.5Hz,1H),7.16–7.03(m,3H),4.66(s,2H),3.95(dq,J=6.1,9.6Hz,2H)ppm.

[0410] Example 44: 2-[4-methyl-2-oxo-3-[4-(1-tetrahydropyran-2-ylpyrazolo[3,4-c]pyridin-4-yl)phenyl]benzimidazol-1-yl]-N-(2,2,2-trifluoroethyl)acetamide

[0411]

[0412] Solution 9

[0413] Step A:2-[4-methyl-2-oxo-3-[4-(1-tetrahydropyran-2-ylpyrazolo[3,4-c]pyridin-4-yl)phenyl]benzimidazol-1-yl]-N-(2,2,2-trifluoroethyl)acetamide. A mixture of 2-(3-(4-bromophenyl)-4-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(2,2,2-trifluoroethyl)acetamide (I-18) (313 mg, 0.71 mmol), 1-(tetrahydro-2H-pyran-2-yl)-4-(tributyltinyl)-1H-pyrazolo[3,4-c]pyridine (420 mg, 0.85 mmol), Pd(PPh3)4 (82 mg, 0.071 mmol), CuI (75 mg, 0.355 mmol) and LiCl (90 mg, 2.13 mmol) in toluene (5 ml) was stirred at 120°C under N2 atmosphere overnight. The reaction was filtered and purified by preparative TLC (DCM / MeOH, 20:1) to give 2-[4-methyl-2-oxo-3-[4-(1-tetrahydropyran-2-ylpyrazolo[3,4-c]pyridin-4-yl)phenyl]benzimidazol-1-yl]-N-(2,2,2-trifluoroethyl)acetamide as a colorless solid (30 mg, 7.5%). LC-MS (ES + , method 4): 1.44min, m / z 565.0[M+H] + .

[0414] Step B: 2-[4-methyl-2-oxo-3-[4-(1H-pyrazolo[3,4-c]pyridin-4-yl)phenyl]benzimidazol-1-yl]-N-(2,2,2-trifluoroethyl)acetamide. A solution of 2-(4-methyl-2-oxo-3-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-4-yl)phenyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(2,2,2-trifluoroethyl)acetamide (25 mg, 0.044 mmol) in MeOH (0.5 mL) and 4M HCl (in 1,4-dioxane, 1.5 ml) was stirred at room temperature for 1 h. The reaction was concentrated and purified by preparative TLC (DCM:MeOH, 20:1) to give 2-[4-methyl-2-oxo-3-[4-(1H-pyrazolo[3,4-c]pyridin-4-yl)phenyl]benzimidazol-1-yl]-N-(2,2,2-trifluoroethyl)acetamide (Example 44) (18.1 mg, 85%) as an off-white solid. LC-MS (ES + , Method 4): 1.25min, m / z, 481.15 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ9.08(s,1H),8.98(t,J=8.2Hz,1H),8.45(d,J=6.3Hz,2H),8.00(d,J=8.2Hz,2H),7.6 2(d,J=8.2Hz,2H),7.05-6.98(m,2H),6.86(d,J=7.4Hz,1H),4.65(s,2H),3.99-3.95(m,2H),1.90(s,3H)ppm.

[0415] Example 47: 2-[4-methyl-3-[5-(1-methylpyrazolo[3,4-c]pyridin-4-yl)pyrazin-2-yl]-2-oxo-benzoimidazol-1-yl]-N-(2,2,2-trifluoroethyl)acetamide

[0416]

[0417] Solution 10

[0418] Step A: Ethyl 2-[4-methyl-3-[6-methyl-5-(1-methylpyrazolo[3,4-c]pyridin-4-yl)pyrazin-2-yl]-2-oxo-benzimidazol-1-yl]acetate. A solution of ethyl 2-[3-(5-bromo-6-methyl-pyrazol-2-yl)-4-methyl-2-oxo-benzimidazol-1-yl]acetate (Intermediate I-37) (300 mg, 0.74 mmol), tributyl-(1-methylpyrazolo[3,4-c]pyridin-4-yl)stannane (375 mg, 0.89 mmol), Pd(PPh3)4 (86 mg, 0.07 mmol), LiCl (94 mg, 2.22 mmol) and CuI (70 mg, 0.37 mmol) in toluene (10 mL) was stirred at 100 °C under N2 atmosphere overnight. The mixture was cooled to room temperature, diluted with water (100 mL), and extracted with ethyl acetate (100 mL×3). The combined organic layers were dried over Na2SO4 and concentrated under vacuum, and purified by silica gel column chromatography (DCM / MeOH, 100:1 to DCM / MeOH, 50:1) to give ethyl 2-[4-methyl-3-[6-methyl-5-(1-methylpyrazolo[3,4-c]pyridin-4-yl)pyrazine-2-yl]-2-oxo-benzimidazol-1-yl]acetate (220 mg, 65%) as a yellow solid. LC-MS (ES + , method 4): 1.60min, m / z, 458.15 [M+H] +

[0419] Step B: 2-[4-methyl-3-[5-(1-methylpyrazolo[3,4-c]pyridin-4-yl)pyrazin-2-yl]-2-oxo-benzimidazol-1-yl]acetic acid. A mixture of ethyl 2-[7-[(1-methylpyrazolo[3,4-b]pyridin-5-yl)amino]-1-oxo-isoindolin-2-yl]acetate (50 mg, 0.11 mmol) and LiOH (9.5 mg, 0.23 mmol), THF (3 mL), MeOH (3 mL) and H2O (0.5 mL) was stirred at 25°C for 2 h. The mixture was diluted with H2O and 10% HCl was added until pH reached 1-2. The resulting precipitate was isolated by filtration and analyzed to be 2-[4-methyl-3-[5-(1-methylpyrazolo[3,4-c]pyridin-4-yl)pyrazin-2-yl]-2-oxo-benzoimidazol-1-yl]acetic acid (40 mg, 85%) as a yellow solid. LC-MS (ES + , method 3):3.183min,m / z,416.10[M+H] +

[0420] Step C: 2-[4-methyl-3-[5-(1-methylpyrazolo[3,4-c]pyridin-4-yl)pyrazin-2-yl]-2-oxo-benzimidazol-1-yl]-N-(2,2,2-trifluoroethyl)acetamide. A mixture of 2-[4-methyl-3-[5-(1-methylpyrazolo[3,4-c]pyridin-4-yl)pyrazin-2-yl]-2-oxo-benzimidazol-1-yl]acetic acid (40 mg, 0.096 mmol), trifluoroethylamine (14 mg, 0.14 mmol), HATU (44 mg, 0.12 mmol) and DIEA (62.11 mg, 0.48 mmol) in DMF (5 mL) was stirred at 25 °C overnight. The mixture was purified by flash column chromatography on silica gel (dichloromethane / methanol, 50 / 1 to dichloromethane / methanol, 20:1) to give 2-[4-methyl-3-[5-(1-methylpyrazolo[3,4-c]pyridin-4-yl)pyrazin-2-yl]-2-oxo-benzimidazol-1-yl]-N-(2,2,2-trifluoroethyl)acetamide (Example 47) (9.2 mg, 19.2%) as a white solid. LC-MS (ES + , method 3):3.46min,m / z,497.10[M+H] + . 1H NMR (400MHz, DMSO-d6) δ9.57(d,J=1.4Hz,1H),9.35(s,1H),9.15(s,1H),9.11(s,1H),9.01(t,J=6.3Hz,1H),8.76(s,1H),7.12 (t,J=7.7Hz,1H),7.05(d,J=7.8Hz,1H),6.95(d,J=7.6Hz,1H),4.69(s,2H),4.28(s,3H),4.03–3.94F(m,2H),2.00(s,3H)ppm.

[0421] The following examples (Table 10) were prepared by a procedure analogous to Example 47 (Scheme 10) by substituting the appropriate building blocks described in the table for I-37 in Step A or trifluoroethylamine in Step C.

[0422] Table 10

[0423]

[0424]

[0425]

[0426]

[0427]

[0428]

[0429]

[0430]

[0431] Example 66: 2-[4-methyl-3-[5-(1-methylpyrazolo[3,4-c]pyridin-4-yl)pyrimidin-2-yl]-2-oxo-benzimidazol-1-yl]-N-(2,2,2-trifluoroethyl)acetamide

[0432]

[0433] Solution 11

[0434] Step A:2-[3-(5-bromopyrimidin-2-yl)-4-methyl-2-oxo-benzoimidazol-1-yl]acetic acid. A mixture of ethyl 2-(3-(5-bromopyrimidin-2-yl)-4-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)acetic acid (600 mg, 1.54 mmol) and LiOH.H2O (194 mg, 4.62 mmol) in H2O / THF (8 mL) was stirred at room temperature for 2 h. The mixture was concentrated under vacuum and the pH was adjusted to 3 by slowly adding 1M HCl. The mixture was diluted with water (50 mL) and washed with EtOAc (100 ml x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4 and concentrated to give 2-[3-(5-bromopyrimidin-2-yl)-4-methyl-2-oxo-benzoimidazol-1-yl]acetic acid (440 mg, 79%) as a white solid.

[0435] LC-MS(ES + , Method 4):1.13min,m / z,444 / 446[M+H] + .

[0436] Step B : 2-[3-(5-bromopyrimidin-2-yl)-4-methyl-2-oxo-benzoimidazol-1-yl]-N-(2,2,2-trifluoroethyl)acetamide. A mixture of 2-(3-(5-bromopyrimidin-2-yl)-4-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)acetic acid (500 mg, 1.38 mmol), 2,2,2-trifluoroethane-1-amine (205 mg, 2.07 mmol), HATU (787 mg, 2.07 mmol) and DIPEA (535 mg, 4.14 mmol) in DMF (5 mL) was stirred at room temperature for 2 h. The mixture was treated with water (50 ml) and filtered to give 2-[3-(5-bromopyrimidin-2-yl)-4-methyl-2-oxo-benzoimidazol-1-yl]-N-(2,2,2-trifluoroethyl)acetamide (510 mg, 83%) as a white solid. LC-MS (ES + , Method 4):1.31min,m / z,363 / 365[M+H] + .

[0437] Step C: 2-[4-methyl-3-[5-(1-methylpyrazolo[3,4-c]pyridin-4-yl)pyrimidin-2-yl]-2-oxo-benzoimidazol-1-yl]-N-(2,2,2-trifluoroethyl)acetamide. A mixture of 2-(3-(5-bromopyrimidin-2-yl)-4-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(2,2,2-trifluoroethyl)acetamide (100 mg, 0.23 mmol), 1-methyl-4-(tributyltinyl)-1H-pyrazolo[3,4-c]pyridine (115 mg, 0.27 mmol), Pd(PPh3)4 (26 mg, 0.023 mmol), CuI (24 mg, 0.11 mmol), and LiCl (29 mg, 0.68 mmol) in toluene (4 ml) was stirred at 120°C under N2 atmosphere overnight. The reaction was filtered and purified by preparative TLC (DCM / MeOH, 20:1) to give 2-[4-methyl-3-[5-(1-methylpyrazolo[3,4-c]pyridin-4-yl)pyrimidin-2-yl]-2-oxo-benzoimidazol-1-yl]-N-(2,2,2-trifluoroethyl)acetamide as a white solid (Example 66) (10 mg, 8.9%). LC-MS (ES + , Method 3):3.31min,m / z,497.25[M+H] + .1H NMR (400MHz, DMSO-d6) δ9.51(s,2H),9.33(s,1H),9.03(t,J=6.3Hz,1H),8.68(s,1H),8.58(s,1H),7.09(t,J=7.8H z,1H),7.02(d,J=7.8Hz,1H),6.92(d,J=7.6Hz,1H),4.66(s,2H),4.27(s,3H),4.03-3.94(m,2H),1.88(s,3H)ppm.

[0438] Example 68: 2-[4-methyl-2-oxo-3-[6-(1H-pyrazolo[3,4-c]pyridin-4-yl)-3-pyridinyl]benzimidazol-1-yl]-N-[(1S)-2,2,2-trifluoro-1-methyl-ethyl]acetamide

[0439]

[0440] Solution 12

[0441] Step A:Ethyl 2-[4-methyl-2-oxo-3-[6-(1-tetrahydropyran-2-ylpyrazolo[3,4-c]pyridin-4-yl)-3-pyridinyl]benzimidazol-1-yl]acetate. A solution of ethyl 2-[3-(6-bromo-3-pyridinyl)-4-methyl-2-oxo-benzimidazol-1-yl]acetate (Intermediate I-38) (500 mg, 1.28 mmol), tributyl-(1-tetrahydropyran-2-ylpyrazolo[3,4-c]pyridin-4-yl)stannane (756 mg, 1.54 mmol), tetrakis(triphenylphosphine)palladium(0) (148.57 mg, 0.13 mmol), lithium chloride (162 mg, 3.84 mmol) and CuI (122 mg, 0.64 mmol) in toluene (3 mL) was stirred at 110 °C under N2 overnight. The mixture was diluted with EtOAc (8 mL) and washed with H2O (10 mL×3). The organic layer was washed with EtOAc (15 mL×3), combined, dried over anhydrous Na2SO4, and purified by preparative TLC to give ethyl 2-[4-methyl-2-oxo-3-[6-(1-tetrahydropyran-2-ylpyrazolo[3,4-c]pyridin-4-yl)-3-pyridinyl]benzimidazol-1-yl]acetate (160 mg, 24%) as a yellow solid. LC-MS (ES + , Method 3): 3.95min, m / z, 513.35 [M+H] +

[0442] Step B: Ethyl 2-[4-methyl-2-oxo-3-[6-(1H-pyrazolo[3,4-c]pyridin-4-yl)-3-pyridinyl]benzimidazol-1-yl]acetate. A solution of ethyl 2-[4-methyl-2-oxo-3-[6-(1-tetrahydropyran-2-ylpyrazolo[3,4-c]pyridin-4-yl)-3-pyridinyl]benzimidazol-1-yl]acetate (160 mg, 0.31 mmol), hydrochloric acid (4N in dioxane) (3 mL, 0.01 mmol) in DCM (1.0 mL) was stirred at room temperature for 2 h. The mixture was concentrated under vacuum and purified by silica gel column chromatography (petroleum ether / EtOAc, 20 / 1 to petroleum ether / EtOAc, 1 / 3) to give ethyl 2-[4-methyl-2-oxo-3-[6-(1H-pyrazolo[3,4-c]pyridin-4-yl)-3-pyridinyl]benzimidazol-1-yl]acetate (130 mg, 96%). LC-MS (ES + , Method 3):3.12min,m / z,429.25[M+H] +

[0443] Step C:2-[4-methyl-2-oxo-3-[6-(1H-pyrazolo[3,4-c]pyridin-4-yl)-3-pyridinyl]benzimidazol-1-yl]acetic acid. A mixture of ethyl 2-[4-methyl-2-oxo-3-[6-(1H-pyrazolo[3,4-c]pyridin-4-yl)-3-pyridinyl]benzimidazol-1-yl]acetic acid (130 mg, 0.3 mmol) and lithium hydroxide monohydrate (38.19 mg, 0.91 mmol) in THF (3 mL), methanol (3 mL) and water (1 mL) was stirred at room temperature for 2 h. The mixture was diluted with H2O (3 mL), and 10% HCl (3 mL) was added to bring the pH to 2-3. The mixture was diluted with water (5 mL×3) and extracted with DCM (10 mL×3). After drying over Na2SO4, the mixture was filtered and concentrated in vacuo to give 2-[4-methyl-2-oxo-3-[6-(1H-pyrazolo[3,4-c]pyridin-4-yl)-3-pyridinyl]benzimidazol-1-yl]acetic acid (100 mg, 82%) as a yellow solid. LC-MS (ES + , Method 3):2.72min,m / z,401.25[M+H] +

[0444] Step D: 2-[4-Methyl-2-oxo-3-[6-(1H-pyrazolo[3,4-c]pyridin-4-yl)-3-pyridinyl]benzimidazol-1-yl]-N-[(1S)-2,2,2-trifluoro-1-methyl-ethyl]acetamide A solution of 2-[4-methyl-2-oxo-3-[6-(1H-pyrazolo[3,4-c]pyridin-4-yl)-3-pyridinyl]benzimidazol-1-yl]acetic acid (100 mg, 0.25 mmol), (2S)-2-amino-1,1,1-trifluoropropane hydrochloride (33.89 mg, 0.3 mmol), HATU (113.96 mg, 0.3 mmol) and DIEA (96.83 mg, 0.75 mmol) in DMF (10 mL) was stirred at room temperature for 2 h. The mixture was diluted with EtOAc (15 mL) and washed with H2O (3 mL×3). The organic layers were combined and dried over anhydrous Na2SO4. The mixture was purified by reverse phase column chromatography to give 2-[4-methyl-2-oxo-3-[6-(1H-pyrazolo[3,4-c]pyridin-4-yl)-3-pyridinyl]benzimidazol-1-yl]-N-[(1S)-2,2,2-trifluoro-1-methyl-ethyl]acetamide (49.7 mg, 40%) as an off-white solid. LC-MS (ES + , Method 3): 3.13min, m / z, 496.30 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ9.16(s,1H),8.95(s,1H),8.91–8.85(m,2H),8.79(s,1H),8.40(d,1 H),8.11(m,1H),7.09–7.01(m,2H),6.89(d,1H),4.60(m,3H),1.96(s,3H),1.30(d,3H)ppm.

[0445] Example 93: 2-[4-methyl-3-[4-methyl-6-(1H-pyrazolo[3,4-c]pyridin-4-yl)-3-pyridinyl]-2-oxo-benzoimidazol-1-yl]-N-(2,2,2-trifluoroethyl)acetamide

[0446]

[0447] Example 93 was prepared in a manner analogous to Example 68 (Scheme 12) substituting 1-43 for 1-38 in Step A and trifluoroethylamine for (S)-2-amino-1,1,1-trifluoropropane hydrochloride in Step D.

[0448] LC-MS(ES + , Method 3): 2.85min, m / z 496.20 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ13.86(s,1H),9.15(s,1H),8.99–8.95(m,2H),8.79(d,J=10.2Hz,2H),8.32(s,1H ),7.05(d,J=4.5Hz,2H),6.87(m,1H),4.73–4.64(m,2H),4.04–3.94(m,2H),2.23(s,3H),1.84(s,3H)ppm.

[0449] Example 96: 2-[4-methyl-3-[3-methyl-5-(1-methylpyrazolo[3,4-c]pyridin-4-yl)pyrazin-2-yl]-2-oxo-benzoimidazol-1-yl]-N-(2,2,2-trifluoroethyl)acetamide

[0450]

[0451] Solution 13

[0452] Step 1: Synthesis of 5-bromo-3-methyl-N-(2-methyl-6-nitro-phenyl)pyrazin-2-amine (I-71): NaOH (0.45 g, 3.0 equiv) was added to a solution of 5-bromo-3-methyl-pyrazin-2-amine (0.90 g, 3.72 mmol, 1.0 equiv) in DMSO (10 mL), and the resulting mixture was stirred at 25 °C under N2 for 15 min. 2-Fluoro-1-methyl-3-nitro-benzene (0.69 g, 1.2 equiv) was added and the resulting solution was kept stirring for 2 h. The mixture was diluted with water (20 mL) and extracted with EtOAc (×3). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated in vacuo. The crude material was purified by flash column chromatography eluting with EtOAc in petroleum ether to give I-71 (1.23 g, 78% yield). LC-MS (ES-API, method 3): 3.88 min, m / z, 325.2 [M+2] + .

[0453] Step 2: Synthesis of N2-(5-bromo-3-methyl-pyrazin-2-yl)-3-methyl-benzene-1,2-diamine (I-76): Iron (622 mg, 6.0 equiv) was added to a mixture of I-71 (600 mg, 1.85 mmol), NH4Cl (6.0 equiv) in EtOH / H2O (2:1, 6 mL) at 50 °C and the reaction was stirred for 2 h. The mixture was filtered and concentrated in vacuo. The crude material was purified by flash column chromatography eluting with EtOAc in petroleum ether to give I-76 (418 mg, 77% yield). LC-MS (ES-API, Method 3): 3.05 min, m / z, 295.2 [M+2] +

[0454] Step 3: Synthesis of 3-(5-bromo-3-methyl-pyrazin-2-yl)-4-methyl-1H-benzimidazol-2-one (I-81): A mixture of I-76 (500 mg, 1.7 mmol) and CDI (553 mg, 2 equiv.) in EtOAc (5 mL, 10 V) was stirred at 55 ° C. and N2 for 2 h. The mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated in vacuo to give I-81 (439 mg, 81% yield). LC-MS (ES-API, Method 3): 3.38 min, m / z, 321.2 [M+2] +

[0455] Step 4: Synthesis of ethyl 2-(3-(5-bromo-3-methylpyrazin-2-yl)-4-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)acetate (I-64): Ethyl bromoacetate (1.2 eq.) was added to a mixture of I-81 (800 mg, 2.5 mmol) and K2CO3 (2.0 eq.) in acetone (10 mL). The reaction mixture was stirred for 12 h and then concentrated in vacuo. The crude material was purified by flash column chromatography eluting with EtOAc in petroleum ether to afford ethyl I-64 (817 mg, 79% yield). LC-MS (ES-API, Method 3): 3.85 min, m / z, 405.10 [M] +

[0456] Step 5: Synthesis of ethyl 2-(4-methyl-3-(3-methyl-5-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)pyrazin-2-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)acetate (I-89): A mixture of I-81 (450 mg, 1.11 mmol, 1.0 equiv), potassium trifluoro(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)borate (560 mg, 48% assay, 1.0 equiv), K2CO3 (306 mg, 2.0 equiv) and Pd(dppf)Cl2 (41 mg, 0.05 equiv) in THF / H2O (10 mL, 3:1) was backfilled three times with N2 and then heated to 60°C for 12 h. The mixture was then cooled to room temperature and water was added. The layers were separated. The aqueous layer was extracted with EtOAc. The combined organic extracts were washed with water and brine and concentrated under reduced pressure. The crude material was purified by flash column chromatography eluting with EtOAc in petroleum ether to give ethyl 2-(4-methyl-3-(3-methyl-5-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)pyrazine-2-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)acetate (425 mg, 83% yield). LC-MS (ES-API, Method 3): 2.98 min, m / z, 443.35 [M+H] +

[0457] Step 6: Synthesis of 2-(4-methyl-3-(3-methyl-5-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)pyrazin-2-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)acetic acid (I-95): A solution of NaOH (78 mg, 2.0 equiv) in water (5 mL) was added to a solution of I-89 (450 mg, 0.98 mmol) in THF. The resulting mixture was stirred at 25 °C for 2 h. 3 M aqueous HCl was slowly added to adjust the pH to 3 to 4. The mixture was filtered, the solid was collected, and dried under vacuum at 55 °C to give I-95 (382 mg, 80% yield). LC-MS (ES-API, Method 3): 2.88 min, m / z, 430.30 [M+H] +

[0458] Step 7: Synthesis of 2-(4-methyl-3-(3-methyl-5-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)pyrazin-2-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(2,2,2-trifluoroethyl)acetamide (Example 96): 1-95 (100 mg, 0.23 mmol), DIEA (181 mg, 1.4 mmol), trifluoroethylamine (0.03 mL, 0.35 mmol) and HATU (106 mg, 0.28 mmol) in DMF (3 mL) were stirred at 25 °C for 2 h. The mixture was diluted with water (20 mL) and extracted with EoOAc. The combined organic phases were washed with brine, dried over sodium sulfate and concentrated in vacuo. Further purification by flash column chromatography eluting with MeOH in DCM gave Example 96 (65 mg, 55% yield). LC-MS (ES-API, method 3): 2.99min, m / z, 511.35[M+H]+.1H NMR(400MHz,DMSO-d6)δ9.43(s,2H),9.16(s,1H),9.01(m,1H),8.82(s,1H),7.08(d,J=8.3Hz,2H),6.9 0(d,J=7.1Hz,1H),4.69(d,J=4.6Hz,2H),4.28(s,3H),4.03-3.96(m,2H),2.64(s,3H),1.81(s,3H)ppm.

[0459] Example 99: 2-[4-methyl-3-[5-methyl-6-(1H-pyrazolo[3,4-c]pyridin-4-yl)-3-pyridinyl]-2-oxo-benzoimidazol-1-yl]-N-(2,2,2-trifluoroethyl)acetamide

[0460]

[0461] Example 99 was prepared in a manner similar to Example 68 (Scheme 12), substituting I-65 for I-38 in Step A and trifluoroethylamine for (S)-2-amino-1,1,1-trifluoropropane hydrochloride in Step D. LC-MS (ES + , Method 3): 2.78min, m / z 496.30 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.62 (s, 1H), 8.99 (m, 1H), 8.75 (d, J = 2.3Hz, 1H), 8.67 (s, 1H), 8.50 (s, 1H), 8.08 (d, J = 2.3Hz, 1H),7.12–7.01(m,2H),6.94–6.86(m,1H),4.68(s,2H),4.04–3.94(m,2H),3.57(s,3H),2.46(s,3H),1.97(s,3H)ppm.

[0462] Example 100: 2-[4-methyl-3-[6-methyl-5-(1-methylpyrazolo[3,4-c]pyridin-4-yl)pyrazin-2-yl]-2-oxo-benzoimidazol-1-yl]-N-(2,2,2-trifluoroethyl)acetamide

[0463]

[0464] Example 100 was prepared in a manner analogous to Example 68 (Scheme 12) substituting 1-66 for 1-38 in Step A and trifluoroethylamine for (S)-2-amino-1,1,1-trifluoropropane hydrochloride in Step D.

[0465] LC-MS(ES + , method 4): 1.53min, m / z 511.15[M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.35 (s, 1H), 9.01 (t, J = 6.3Hz, 1H), 8.96 (s, 1H), 8.57 (s, 1H), 8.21 (s, 1H), 7.12 (m, 1H), 7.0 5(d,J=7.7Hz,1H),6.96(d,J=7.5Hz,1H),4.68(s,2H),4.27(s,3H),4.03–3.94(m,2H),2.62(s,3H),2.01(s,3H)ppm.

[0466] Example 69: 2-[4-methyl-2-oxo-3-[5-(1H-pyrazolo[3,4-c]pyridin-4-yl)-2-pyridinyl]benzimidazol-1-yl]-N-[(1S)-2,2,2-trifluoro-1-methyl-ethyl]acetamide

[0467]

[0468] Solution 14

[0469] Steps A to C are similar to Steps A to C described in Example 47 in Scheme 10. In Step A, tributyl-(1-tetrahydropyran-2-ylpyrazolo[3,4-c]pyridin-4-yl)stannane is substituted for tributyl-(1-methylpyrazolo[3,4-c]pyridin-4-yl)stannane. In Step C, (2S)-amino-1,1,1-trifluoropropane is substituted for trifluoroethylamine.

[0470] Step D: 2-[4-Methyl-2-oxo-3-[5-(1H-pyrazolo[3,4-c]pyridin-4-yl)-2-pyridinyl]benzimidazol-1-yl]-N-[(1S)-2,2,2-trifluoro-1-methyl-ethyl]acetamide A solution of 2-[4-methyl-2-oxo-3-[5-(1-tetrahydropyran-2-ylpyrazolo[3,4-c]pyridin-4-yl)-2-pyridinyl]benzimidazol-1-yl]-N-[(1S)-2,2,2-trifluoro-1-methyl-ethyl]acetamide (50 mg, 0.09 mmol) in methanol (2 mL) and 4M HCl in 1,4-dioxane (1 mL) were stirred at 25°C for 2 h. The reaction mixture was concentrated and purified by preparative TLC (DCM / MeOH, 30:1) to give 2-[4-methyl-2-oxo-3-[5-(1H-pyrazolo[3,4-c]pyridin-4-yl)-2-pyridinyl]benzimidazol-1-yl]-N-[(1S)-2,2,2-trifluoro-1-methyl-ethyl]acetamide (19.7 mg, 47%) as a yellow solid. LC-MS (ES) + , method 4): 1.25min, m / z 496.15[M+H] + . 1H NMR (400MHz, DMSO-d6) δ13.92(s,1H),9.15(s,1H),9.09(s,1H),8.95(d,J=8.8Hz,1H),8.54(d,J=18.3Hz,3H),7.82(d,J= 8.2Hz,1H),7.07(m,1H),7.00(d,J=7.8Hz,1H),6.90(d,J=7.7Hz,1H),4.64(s,3H),1.93(s,3H),1.30(d,J=7.0Hz,3H)ppm.

[0471] Example 70: 4-methyl-1-[2-oxo-2-[(2S)-2-(trifluoromethyl)morpholin-4-yl]ethyl]-3-[5-(1H-pyrazolo[3,4-c]pyridin-4-yl)-2-pyridinyl]benzimidazol-2-one

[0472]

[0473] Example 70 was prepared in analogy to Example 69 (Scheme 13). In Step C, (2S)-2-(trifluoromethyl)morpholine was used instead of (2S)-amino-1,1,1-trifluoropropane. LC-MS (ES + , method 3): 3.02min, m / z 538.30[M+H] + . 1 H NMR(400MHz, DMSO-d6)δδ9.49(s,1H),9.15(d,J=2.4Hz,1H),8.76(d,J=29.7Hz,2H),8.59(d d,J=8.3,2.4Hz,1H),7.85(d,J=8.2Hz,1H),7.08(d,J=8.3Hz,2H),6.92–6.88(m,1H),5.07( q,J=27.8,17.3Hz,1H),4.91–4.82(m,1H),4.43(s,1H),4.28(s,1H),4.14(d,J=13.2Hz,1H) ,4.06(d,J=13.3Hz,1H),4.00(s,1H),3.39(s,1H),2.92(d,J=13.6Hz,1H),1.95(s,3H)ppm.

[0474] Example 71: 4-methyl-1-[2-oxo-2-[(2R)-2-(trifluoromethyl)morpholin-4-yl]ethyl]-3-[5-(1H-pyrazolo[3,4-c]pyridin-4-yl)-2-pyridinyl]benzimidazol-2-one

[0475]

[0476] Example 71 was prepared in analogy to Example 69 (Scheme 13). In Step C, (2R)-2-(trifluoromethyl)morpholine was used instead of (2S)-amino-1,1,1-trifluoropropane. LC-MS (ES + , Method 3): 3.25min, m / z 538.30 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ13.96 (s, 1H), 9.15 (s, 1H), 9.10 (d, J = 2.5Hz, 1H), 8.57 (s,1H),8.54–8.51(m,2H),7.80(d,J=8.2Hz,1H),7.08–7.06(m,2H),6.90–6.88 (m,1H),5.12–5.01(m,1H),4.90–4.83(m,1H),4.43–4.16(m,2H),4.13–3.97(m ,2H),3.79–3.55(m,1H),3.45–3.35(m,1H),2.96–2.86(m,1H),1.93(s,3H)ppm.

[0477] Example 72: 2-[4-methyl-2-oxo-3-[5-(1H-pyrazolo[3,4-c]pyridin-4-yl)-2-pyridinyl]benzimidazol-1-yl]-N-(2,2,2-trifluoroethyl)acetamide

[0478]

[0479] Example 72 was prepared in a manner analogous to Example 69 (Scheme 13). In step C, trifluoroethylamine was used instead of (2S)-amino-1,1,1-trifluoropropane. LC-MS (ES + , method 3): 3.05min, m / z 482.25[M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.15(s,1H),9.09(d,J=2.4Hz,1H),9.05(m,1H),8.56(s,1H),8.53(m,J=8.6Hz,2H),7.82(d,J=8.2Hz ,1H),7.07(t,J=7.7Hz,1H),7.01(d,J=7.7Hz,1H),6.90(d,J=7.4Hz,1H),4.67(s,2H),3.98(m,J=7.2Hz,2H),1.94(s,3H)ppm.

[0480] Example 73: 2-[4-methyl-2-oxo-3-[5-(1H-pyrazolo[3,4-c]pyridin-4-yl)pyrimidin-2-yl]benzimidazol-1-yl]-N-[(1S)-2,2,2-trifluoro-1-methyl-ethyl]acetamide

[0481]

[0482] Example 73 was prepared in a similar manner to Example 69 (Scheme 13). 2-[3-(5-bromopyrimidin-2-yl)-4-methyl-2-oxo-benzoimidazol-1-yl]acetic acid ethyl ester (Intermediate I-45) was substituted for Intermediate I-39 in Step A. LC-MS (ES + , Method 3): 2.95min, m / z 497.20 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.52 (s, 2H), 9.20 (s, 1H), 8.62 (d, J = 12.0Hz, 2H), 7.09 (m, 1H), 7.02 ( d,J=12.0Hz,1H),6.91(d,J=8.0Hz,1H),4.63(m,3H),1.88(s,3H),1.30(d,J=8.0Hz,3H)ppm.

[0483] Example 94: 2-[4-methyl-3-[2-methyl-6-(1H-pyrazolo[3,4-c]pyridin-4-yl)-3-pyridinyl]-2-oxo-benzoimidazol-1-yl]-N-(2,2,2-trifluoroethyl)acetamide

[0484]

[0485] Example 94 was prepared in a manner similar to Example 69 (Scheme 13). 2-[3-(5-bromopyrimidin-2-yl)-4-methyl-2-oxo-benzoimidazol-1-yl]ethyl acetate (Intermediate I-63) was substituted for Intermediate I-39 in Step A, and trifluoroethylamine was substituted for (S)-2-amino-1,1,1-trifluoropropane in Step C. LC-MS (ES + , method 4): 1.24min, m / z 496.20 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ9.67(s,1H),9.25(s,1H),9.10-9.02(m,2H),8.40(d,J=8.0Hz,1H),8.13(d,J=8.0 Hz,1H),7.06(d,J=4.0Hz,2H),6.87(m,1H),4.69(s,2H),4.03-3.93(m,2H),2.48(s,3H),1.82(s,3H)ppm.

[0486] Example 98: 2-[4-methyl-2-oxo-3-[5-(1H-pyrazolo[3,4-c]pyridin-4-yl)pyrimidin-2-yl]benzimidazol-1-yl]-N-[(1R)-2,2,2-trifluoro-1-methyl-ethyl]acetamide

[0487]

[0488] Example 98 was prepared in a manner similar to Example 69 (Scheme 13). 2-[3-(5-bromopyrimidin-2-yl)-4-methyl-2-oxo-benzoimidazol-1-yl]ethyl acetate (Intermediate I-45) was substituted for Intermediate I-39 in Step A, and (R)-2-amino-1,1,1-trifluoropropane was substituted for (S)-2-amino-1,1,1-trifluoropropane in Step C. LC-MS (ES + , Method 3): 2.95min, m / z 497.20 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.52 (s, 2H), 9.20 (s, 1H), 8.62 (d, J = 12.0Hz, 2H), 7.09 (m, 1H), 7.02 ( d,J=12.0Hz,1H),6.91(d,J=8.0Hz,1H),4.63(m,3H),1.88(s,3H),1.30(d,J=8.0Hz,3H)ppm.

[0489] Example 75: 2-[4-methyl-3-[2-(1-methylpyrazolo[3,4-c]pyridin-4-yl)pyrimidin-5-yl]-2-oxo-benzimidazol-1-yl]-N-(2,2,2-trifluoroethyl)acetamide

[0490]

[0491] Solution 15

[0492] Step A:2-Bromo-N-(2-methyl-6-nitro-phenyl)pyrimidin-5-amine. A solution of NaH (1.53 g, 38.13 mmol) in DMF (20 mL) was stirred at 0°C and N2 for 5 min, then 2-bromopyrimidin-5-amine (2.95 g, 19.07 mmol) in DMF (10 mL) was slowly added and stirred for 0.5 h. 2-Fluoro-1-methyl-3-nitrobenzene (3.30 g, 19.07 mmol) was slowly added, and the mixture was stirred for 16 h. The mixture was diluted with water (50 mL) and extracted with EtOAc (200 mL×3). The combined organic layers were washed with brine (200 mL), dried over Na2SO4 and concentrated in vacuo to give 2-bromo-N-(2-methyl-6-nitro-phenyl)pyrimidin-5-amine (1.8 g, 25%). LC-MS (ES + , Method 3): 3.86min, m / z 309 / 311 [M+H] + . 1 H NMR (400MHz, DMSO-d6)8.51(s,1H),7.96(s,2H),7.85(m,1H),7.68(m,1H),7.40(m,1H),2.21(s,3H)ppm.

[0493] Step B :N-(2-methyl-6-nitro-phenyl)-2-(1-methylpyrazolo[3,4-c]pyridin-4-yl)pyrimidin-5-amine. A solution of 2-bromo-N-(2-methyl-6-nitro-phenyl)pyrimidin-5-amine (100 mg, 0.32 mmol), tributyl-(1-methylpyrazolo[3,4-c]pyridin-4-yl)stannane (164 mg, 0.38 mmol), Pd(PPh3)4 (37 mg, 0.032 mmol), LiCl (41 mg, 0.95 mmol) and CuI (34 mg, 0.16 mmol) in toluene (1.0 mL) was stirred overnight at 120° C. under N2. The mixture was diluted with EtOAc (30 mL) and washed with H2O (15 mL×3). The organic layer was washed with EtOAc (5 mL x 3), combined, dried over anhydrous Na2SO4 and concentrated to give a yellow solid, which was purified by preparative TLC to give N-(2-methyl-6-nitro-phenyl)-2-(1-methylpyrazolo[3,4-c]pyridin-4-yl)pyrimidin-5-amine (30 mg, 26%) as a yellow solid. LC-MS (ES + , Method 3): 3.25min, m / z, 362.0 [M+H] + . 1H NMR(400MHz,DMSO-d6)9.24–9.16(m,2H),8.76(s,1H),8.62(s,1H),8.29(s ,2H),7.81(d,1H),7.75(d,1H),7.46(m,1H),4.24(s,3H),2.27(s,3H)ppm.

[0494] Step C: 3-Methyl-N2-[2-(1-methylpyrazolo[3,4-c]pyridin-4-yl)pyrimidin-5-yl]benzene-1,2-diamine. A solution of N-(2-methyl-6-nitro-phenyl)-2-(1-methylpyrazolo[3,4-c]pyridin-4-yl)pyrimidin-5-amine (20 mg, 0.06 mmol) and palladium (2.94 mg, 0.03 mmol) in IPA (2 mL) was stirred at 50 °C for 1 h. The mixture was diluted with water and EtOAc, the phases were separated, the combined organic layers were washed with brine (20 mL), extracted with ethyl acetate (30 mL), and dried over Na2SO4, concentrated in vacuo to give the crude product, which was purified by preparative TLC (petroleum ether / EtOAc, 1 / 1) to give 3-methyl-N2-[2-(1-methylpyrazolo[3,4-c]pyridin-4-yl)pyrimidin-5-yl]benzene-1,2-diamine (10 mg, 54%) as a brown oil. 1 H NMR (400MHz, DMSO-d6)9.11(s,1H),9.03(s,1H),8.76(s,1H),8.62(s,1H),8.29(s,2H),7.90–7.33(m,4H),4.24(s,3H),2.24(s,3H)ppm.

[0495] Step D: 4-Methyl-3-[2-(1-methylpyrazolo[3,4-c]pyridin-4-yl)pyrimidin-5-yl]-1H-benzimidazol-2-one. A solution of methyl-N2-[2-(1-methylpyrazolo[3,4-c]pyridin-4-yl)pyrimidin-5-yl]benzene-1,2-diamine (35 mg, 0.11 mmol) and CDI (85.7 mg, 0.52 mmol) in DMF (0.3 mL) was stirred at 100° C. under N2 overnight. The mixture was diluted with EtOAc (3 mL) and washed with H2O (5 mL×3). The organic layer was washed with EtOAc (5 mL×3), combined, dried over anhydrous Na2SO4 and concentrated to give a yellow solid, which was purified by preparative TLC to give 4-methyl-3-[2-(1-methylpyrazolo[3,4-c]pyridin-4-yl)pyrimidin-5-yl]-1H-benzimidazol-2-one (30 mg, 79%). LC-MS (ES +, method 3):3.117min,m / z,358.0[M+H] +

[0496] Step E: Ethyl 2-[4-methyl-3-[2-(1-methylpyrazolo[3,4-c]pyridin-4-yl)pyrimidin-5-yl]-2-oxo-benzimidazol-1-yl]acetate. A solution of 4-methyl-3-[2-(1-methylpyrazolo[3,4-c]pyridin-4-yl)pyrimidin-5-yl]-1H-benzimidazol-2-one (30 mg, 0.08 mmol), ethyl bromoacetate (21.05 mg, 0.12 mmol) and Cs2CO3 (54.75 mg, 0.16 mmol) in MeCN (5 mL) was stirred at 50° C. for 2 h. The mixture was quenched with H2O (3 mL) and extracted with EtOAc (8 mL×3). The organic layers were combined, washed with H2O (8 mL x 3), then washed with NaCl (aqueous solution) (5 mL x 3), and the organic phase was dried over anhydrous Na2SO4 before concentration to give ethyl 2-[4-methyl-3-[2-(1-methylpyrazolo[3,4-c]pyridin-4-yl)pyrimidin-5-yl]-2-oxo-benzoimidazol-1-yl]acetate (20 mg, 54%) as a yellow solid. LC-MS (ES + , Method 3):3.583min,m / z,444.25[M+H] +

[0497] Step F: 2-[4-methyl-3-[2-(1-methylpyrazolo[3,4-c]pyridin-4-yl)pyrimidin-5-yl]-2-oxo-benzimidazol-1-yl]acetic acid. A mixture of ethyl 2-[4-methyl-3-[2-(1-methylpyrazolo[3,4-c]pyridin-4-yl)pyrimidin-5-yl]-2-oxo-benzimidazol-1-yl]acetate (30 mg, 0.06 mmol) and LiOH.H2O (8.53 mg, 0.20 mmol) in THF (1.5 mL), MeOH (1.5 mL) and H2O (1 mL) was stirred at 25°C for 2 h. The mixture was diluted with H2O (5 mL), and 10% HCl (3 mL) was added to bring the pH to 2-3. The mixture was diluted with water (10 mL×3) and extracted with DCM (10 mL×3). After drying over Na2SO4, filtration and concentration in vacuo afforded 2-[4-methyl-3-[2-(1-methylpyrazolo[3,4-c]pyridin-4-yl)pyrimidin-5-yl]-2-oxo-benzoimidazol-1-yl]acetic acid (17 mg, 61%) as a white solid. LC-MS (ES + , method 3):2.817min,m / z,416.0[M+H]+

[0498] Step G: 2-[4-methyl-3-[2-(1-methylpyrazolo[3,4-c]pyridin-4-yl)pyrimidin-5-yl]-2-oxo-benzimidazol-1-yl]-N-(2,2,2-trifluoroethyl)acetamide (Example 75). A solution of 2-[4-methyl-3-[2-(1-methylpyrazolo[3,4-c]pyridin-4-yl)pyrimidin-5-yl]-2-oxo-benzimidazol-1-yl]acetic acid (17 mg, 0.041 mmol), trifluoroethylamine (6.08 mg, 0.061 mmol), HATU (23.34 mg, 0.061 mmol) and DIEA (26.44 mg, 0.20 mmol) in DMF (0.5 mL) was stirred at 25° C. overnight. The mixture was diluted with EtOAc (5 mL) and washed with H2O (2 mL×3). The organic layer was washed with EtOAc (5 mL x 3), combined, dried over anhydrous Na2SO4 and concentrated to give a yellow solid, which was purified by preparative TLC to give 2-[4-methyl-3-[2-(1-methylpyrazolo[3,4-c]pyridin-4-yl)pyrimidin-5-yl]-2-oxo-benzimidazol-1-yl]-N-(2,2,2-trifluoroethyl)acetamide (Example 75) (2.0 mg, 10%) as a white solid. LC-MS (ES + , method 3): 3.42min, m / z, 497.20 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ9.39(s,1H),9.33(s,1H),9.21(s,2H),9.06(m,1H),8.86(s,1H),7.11–7 .05(m,2H),6.93(d,J=7.2Hz,1H),4.69(s,2H),4.28(s,3H),4.04–3.96(m,2H),2.01(s,3H)ppm.

[0499] Example 91: 2-[3-[6-(1-methylpyrazolo[3,4-c]pyridin-4-yl)-3-pyridinyl]-2-oxo-benzoimidazol-1-yl]-N-(2,2,2-trifluoroethyl)acetamide

[0500]

[0501] Scheme 16

[0502] Example 91 was prepared from intermediate 1-62 using Stille coupling with 1-methyl-4-(tributyltinyl)-1H-pyrazolo[3,4-c]pyridine under the conditions described in step C of Scheme 11. LC-MS (ES + , Method 4):1.47min,m / z,482.20[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ9.28(s,1H),9.05(s,1H),9.03–8.96(m,2H),8.75(s,1H),8. 42(d,1H),8.22(d,1H),7.30–7.12(m,4H),4.71(s,2H),4.26(s,3H),2.24(m,2H)ppm.

[0503] Example 92: 2-[3-[6-(1,3-dimethylpyrazolo[3,4-c]pyridin-4-yl)-3-pyridinyl]-4-methyl-2-oxo-benzoimidazol-1-yl]-N-(2,2,2-trifluoroethyl)acetamide

[0504]

[0505] Solution 17

[0506] Step A: 2-[3-(6-bromo-3-pyridinyl)-4-methyl-2-oxo-benzoimidazol-1-yl]acetic acid. A mixture of ethyl 2-(3-(6-bromopyridin-3-yl)-4-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)acetate (I-38) (500 mg, 1.29 mmol) and LiOH.HO (162 mg, 3.86 mmol) in HO / THF (5 mL / 5 mL) was stirred at room temperature for 2 h. The mixture was concentrated under vacuum and the pH was adjusted to 3 by slowly adding 1 M HCl. The mixture was diluted with water (50 mL) and washed with EtOAc (100 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4 and concentrated to give 2-[3-(6-bromo-3-pyridinyl)-4-methyl-2-oxo-benzoimidazol-1-yl]acetic acid (380 mg, 82%) as a white solid. LC-MS (ES + , method 4):1.66min,m / z,361.9 / 363.9[M+H] + . 1H NMR (400MHz, DMSO-d6) δ13.19(bs,1H),8.56(s,1H),7.95(d,1H),7.84(d,1H),7.12–7.06(m,2H0,6.88(d,1H),4.67(s,2H),1.87(s,3H)ppm.

[0507] Step B: 2-[3-(6-Bromo-3-pyridinyl)-4-methyl-2-oxo-benzoimidazol-1-yl]-N-(2,2,2-trifluoroethyl)acetamide A mixture of 2-(3-(6-bromopyridin-3-yl)-4-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)acetic acid (380 mg, 1.05 mmol), 2,2,2-trifluoroethan-1-amine (156 mg, 1.58 mmol), HATU (600.7 mg, 1.58 mmol) and DIPEA (408.4 mg, 3.16 mmol) in DMF (5 mL) was stirred at room temperature for 2 h. The mixture was treated with water (50 ml) and filtered to give 2-[3-(6-bromo-3-pyridinyl)-4-methyl-2-oxo-benzoimidazol-1-yl]-N-(2,2,2-trifluoroethyl)acetamide (400 mg, 86%) as a white solid. LC-MS (ES + , method 4): 1.38min, m / z 442.7 / 444.6 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.98(m,1H0,8.55(S,1H),7.94–7.85(m,2H),7.07–7.01(m,2H),6.88(d,1H),4.63(s,2H),2.39(m,2H),1.87(s,3H)ppm.

[0508] Step C: 2-[3-[6-(1,3-dimethylpyrazolo[3,4-c]pyridin-4-yl)-3-pyridinyl]-4-methyl-2-oxo-benzoimidazol-1-yl]-N-(2,2,2-trifluoroethyl)acetamide. A mixture of 2-(3-(6-bromopyridin-3-yl)-4-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(2,2,2-trifluoroethyl)acetamide (100 mg, 0.23 mmol), 5-bromo-3-methyl-1-tosyl-1H-pyrazolo[4,3-b]pyridine, 1-methyl-4-(tributyltinyl)-1H-pyrazolo[3,4-c]pyridine (115 mg, 0.27 mmol), Pd(PPh3)4 (26 mg, 0.023 mmol), CuI (24 mg, 0.11 mmol), LiCl (29 mg, 0.68 mmol) in toluene (3 ml) was stirred at 110° C. under N2 overnight. The mixture was filtered and concentrated. The crude product was purified by preparative TLC (DCM / MeOH, 20:1) to give 2-[3-[6-(1,3-dimethylpyrazolo[3,4-c]pyridin-4-yl)-3-pyridinyl]-4-methyl-2-oxo-benzoimidazol-1-yl]-N-(2,2,2-trifluoroethyl)acetamide (Example 92) (20.4 mg, 15%) as an off-white solid. LC-MS (ES) + , method 3): 3.28min, m / z 496.10 [M+H] + . 1 HNMR(400MHz,DMSO-d6)δ9.29(s,1H),8.98-8.94(m,2H),8.90(d,J=2.4 Hz,1H),8.74(s,1H),8.40(d,J=8.5 Hz,1H),8.10(dd,J=8.4,2.5 Hz,1H),7.08–7.02(m,2H),6.89(d,J=7.1 Hz,1H),4.67(s,2H),4.26(s,3H),4.03-3.94(m,2H),1.94(s,3H)ppm.

[0509] Example 102: 2-[4-methyl-3-[5-methyl-6-(3-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-3-pyridinyl]-2-oxo-benzoimidazol-1-yl]-N-(2,2,2-trifluoroethyl)acetamide

[0510]

[0511] Scheme 18

[0512] Step A:2-[4-methyl-3-[5-methyl-6-(3-methyl-1-tetrahydropyran-2-yl-pyrazolo[3,4-c]pyridin-4-yl)-3-pyridinyl]-2-oxo-benzoimidazol-1-yl]acetic acid. A solution of ethyl 2-[3-(6-bromo-5-methyl-3-pyridinyl)-4-methyl-2-oxo-benzoimidazol-1-yl]acetate (I-65) (150 mg, 0.37 mmol), tributyl-(3-methyl-1-tetrahydropyran-2-yl-pyrazolo[3,4-c]pyridin-4-yl)stannane (375 mg, 0.74 mmol), LiCl (47 mg, 1.1 mmol), CuI (39 mg, 0.19 mmol) and Pd(PPh3)4 (86 mg, 0.07 mmol) in xylene (5 mL) was stirred at 130 °C overnight. The mixture was cooled to room temperature, filtered through celite and concentrated in vacuo to give crude 2-[4-methyl-3-[5-methyl-6-(3-methyl-1-tetrahydropyran-2-yl-pyrazolo[3,4-c]pyridin-4-yl)-3-pyridinyl]-2-oxo-benzoimidazol-1-yl]acetic acid (180 mg) as a yellow oil which was used without further purification. LC-MS (ES) + , Method 3):3.10 min, m / z 513.3[M+H] + .

[0513] Step B: 2-[4-Methyl-3-[5-methyl-6-(3-methyl-1-tetrahydropyran-2-yl-pyrazolo[3,4-c]pyridin-4-yl)-3-pyridinyl]-2-oxo-benzimidazol-1-yl]-N-(2,2,2-trifluoroethyl)acetamide. A solution of 2-[4-methyl-3-[5-methyl-6-(3-methyl-1-tetrahydropyran-2-yl-pyrazolo[3,4-c]pyridin-4-yl)-3-pyridinyl]-2-oxo-benzimidazol-1-yl]acetic acid (15 mg, 0.03 mmol), DIEA (11 mg, 0.09 mmol) and HATU (17 mg, 0.04 mmol) in DMF (0.5 mL) was stirred at 25 °C for 3 h. The mixture was partitioned between water and EtOAc, the phases were separated, the organics were dried over Na2SO4, filtered and concentrated under reduced pressure to give a crude product, which was purified by preparative TLC (DCM / MeOH, 30:1) to give 2-[4-methyl-3-[5-methyl-6-(3-methyl-1-tetrahydropyran-2-yl-pyrazolo[3,4-c]pyridin-4-yl)-3-pyridinyl]-2-oxo-benzoimidazol-1-yl]-N-(2,2,2-trifluoroethyl)acetamide (10 mg, 59%) as a yellow solid. LC-MS (ES +, Method 3): 3.98min m / z, 594[M+H] + .

[0514] Step C: 2-[4-methyl-3-[5-methyl-6-(3-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-3-pyridinyl]-2-oxo-benzoimidazol-1-yl]-N-(2,2,2-trifluoroethyl)acetamide. To a solution of 2-[4-methyl-3-[5-methyl-6-(3-methyl-1-tetrahydropyran-2-yl-pyrazolo[3,4-c]pyridin-4-yl)-3-pyridinyl]-2-oxo-benzoimidazol-1-yl]-N-(2,2,2-trifluoroethyl)acetamide (10 mg, 0.02 mmol) in DCM (1 mL) was added 4M HCl in dioxane (0.5 mL, 0.02 mmol) at 25°C and the mixture was stirred for 3 h. The mixture was concentrated and purified by preparative TLC (DCM / MeOH, 30 / 1) to give 2-[4-methyl-3-[5-methyl-6-(3-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-3-pyridinyl]-2-oxo-benzoimidazol-1-yl]-N-(2,2,2-trifluoroethyl)acetamide (2 mg, 18%) as a white solid. LC-MS (ES) + , Method 3): 2.783min, m / z 510.30[M+H] + . 1 H NMR(400MHz, Methanol-d4)δ9.09(s,1H),8.72–8.69(m,1H),8.22(s,1H),8.10–8.07(m,1H),7. 17–6.96(m,4H),4.78(s,2H),4.01(q,J=9.3Hz,2H),2.31(s,3H),2.14(s,3H),2.07(s,3H)ppm.

[0515] Example 103: 2-[4-methyl-3-[2-methyl-6-(3-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-3-pyridinyl]-2-oxo-benzoimidazol-1-yl]-N-(2,2,2-trifluoroethyl)acetamide

[0516]

[0517] Example 103 was prepared in a similar manner to Example 102 (Scheme 17) by substituting Intermediate 1-63 for Intermediate 1-65 in Step A. LC-MS (ES + , method 4): 1.12min, m / z 510.20[M+H] +. 1 H NMR (400MHz, DMSO-d6) δ9.55(s,1H),9.04(s,1H),8.58(s,1H),8.13(d,J=8.0Hz,1H),7.93(d,J=8.0Hz,1H), 7.06(d,J=4.0Hz,2H),6.89(brs,1H),4.69(s,2H),3.99(brs,2H),2.44(s,3H),2.39(s,3H),1.83(s,3H)ppm.

[0518] Example 104: 2-[4-methyl-3-[3-methyl-5-(3-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)pyrazin-2-yl]-2-oxo-benzoimidazol-1-yl]-N-(2,2,2-trifluoroethyl)acetamide

[0519]

[0520] Example 104 was prepared in a similar manner to Example 102 (Scheme 17) by substituting Intermediate 1-64 for Intermediate 1-65 in Step A. LC-MS (ES + , Method 3): 2.95min, m / z 511.30 [M+H] + . 1 H NMR(400MHz,MeOD-d4)δ9.11(s,1H),8.96(s,1H),8.49(m,1H),7.16(m,1H),7.05(d,J=7.9Hz,1H),6.9 8(d,J=7.7Hz,1H),4.78(s,2H),4.01(dd,J=9.4,5.7Hz,2H),2.69(s,3H),2.50(s,3H),1.91(s,3H)ppm.

[0521] Example 105: 2-[4-methyl-3-[6-methyl-5-(3-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)pyrazin-2-yl]-2-oxo-benzoimidazol-1-yl]-N-(2,2,2-trifluoroethyl)acetamide

[0522]

[0523] Example 105 was prepared in a similar manner to Example 102 (Scheme 17) by substituting Intermediate 1-66 for Intermediate 1-65 in Step A. LC-MS (ES + , Method 3): 2.91min, m / z 511.35[M+H] + . 1H NMR (400MHz, MeOD-d4) δ9.59(s,1H),9.07(s,1H),8.57(s,1H),7.21(t,J=7.8Hz,1H),7.05(d,J=4 .0Hz,2H),4.80(s,2H),4.05–3.98(m,2H),3.38(s,2H),2.59(s,3H),2.29(s,3H),2.14(s,3H)ppm.

[0524] Examples 106 to 115 were prepared in analogy to Example 75 (Scheme 15).

[0525]

[0526]

[0527]

[0528] Biochemical assays for DDR1 and DDR2

[0529] The ability of compounds to bind to DDR1 and DDR2 was quantified using the LanthaScreen Eu kinase binding assay. Recombinant human DDR1 (2.5 nM; aa440-876 containing a GST tag) and DDR2 (1.75 nM; aa427-855 containing a GST tag) were diluted in assay buffer (50 mM HEPES pH 7.3, 10 mM MgCl2, 1 mM EGTA, and 0.01% Tween) with various concentrations of compound in a 5 uL volume in a 384-well plate. After incubation for 30 minutes at room temperature, 2.5 uL of Eu-anti-GST antibody (diluted to 1 nM in assay buffer) plus kinase tracer 178 (diluted to 5 nM for DDR1 and 10 nM for DDR2 in assay buffer) were added to the plate. After incubation for 60 minutes at room temperature, time-resolved fluorescence was measured on a BMG Labtech PHERAstar plate reader. DMSO (1%) and reference compound (1 μM) were used to generate the maximum and minimum assay signals, respectively. The data were analyzed using a four-parameter logistic model to calculate the IC 50 At least two independent replicates were performed for each compound.

[0530] Biological activity value

[0531] The following table shows the pIC values ​​of the above examples for DDR1 and DDR2 kinases. 50 Value (A: pIC 50 >8; B: 8 ≥ pIC 50 >7; C: 7 ≥ pIC 50 >6; D: pIC50 ≤6; ND: not determined).

[0532] Table 11

[0533]

[0534]

[0535]

[0536]

[0537]

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof: in X 1 , X 2 and X 3 Each independently selected from carbon and nitrogen, wherein X 1 , X 2 and X 3 At least two of them are carbon; X 4 , X 5 , X 6 and X 7 Each independently selected from carbon and nitrogen, wherein X 4 , X 5 , X 6 and X 7 At least two of them are carbon; R 1 is independently selected at each occurrence from halogen, nitro, cyano, NR 9 R 10 , OR 11 , SR 9 、SO2NR 9 R 9 、SO2R 9 、CO2R 9 、C(O)R 9 ,CONR 9 R 9 、C1-C4-alkyl、NR 9 R 10 Substituted C1-C4-alkyl, 11 substituted C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and cyclopropyl; R 3 independently selected from H and C1-C4-alkyl; R 4 independently selected from C1-C6-alkyl, C1-C6-haloalkyl, C0-C4-alkylene-R 4a ; where R 4a independently selected from: C3-C8-cycloalkyl, phenyl, 5, 6, 9 or 10-membered heteroaryl and 4 to 10-membered heterocycloalkyl; wherein the heterocycloalkyl or heteroaryl may be monocyclic or bicyclic; wherein the cycloalkyl or heterocycloalkyl is optionally substituted by a single R 12 group and / or 1 to 4 R 13 wherein the phenyl or heteroaryl group is optionally substituted by a single R 12 group and / or 1 to 3 R 14 Group substitution; or R 3 and R 4 Together with the nitrogen atom to which they are attached, they form a 4- to 10-membered heterocycloalkyl or a 5- or 9-membered heteroaryl; wherein the heterocycloalkyl or heteroaryl may be monocyclic or bicyclic; wherein the heterocycloalkyl is optionally substituted by a single R 12 group and / or 1 to 4 R 13 wherein the heteroaryl group is optionally substituted by a single R 12 group and / or 1 to 3 R 14 Group substitution; R 5 are independently selected at each occurrence from H, halogen and C1-C4-alkyl, or two R 5 The groups and the carbon atoms to which they are attached may together form a C3-C6-cycloalkyl ring; R 6 is independently selected at each occurrence from halogen, nitro, cyano, NR 9 R 10 , OR 11 , SR 9 、SO2NR 9 R 9 、SO2R 9 、CO2R 9 、C(O)R 9 ,CONR 9 R 9 、C1-C4-alkyl、NR 9 R 10 Substituted C1-C4-alkyl, 11 substituted C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and cyclopropyl; R 7 is independently selected at each occurrence from halogen, nitro, cyano, NR 9 R 10 , OR 11 , SR 9 、SO2NR 9 R 9 、SO2R 9 、CO2R 9 、C(O)R 9 ,CONR 9 R 9 、C1-C4-alkyl、NR 9 R 10 Substituted C1-C4-alkyl, 11 substituted C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and cyclopropyl; R 8a are independently selected from H, halogen, nitro, cyano, NR 9 R 10 , OR 11 , SR 9 、SO2NR 9 R 9 、SO2R 9 、CO2R 9 、C(O)R 9 ,CONR 9 R 9 、C1-C4-alkyl、NR 9 R 10 Substituted C1-C4-alkyl, 11 Substituted C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and C0-C4-alkylene-R 8c ; R 8b independently selected from H, C1-C4-alkyl, 9 R 9 Substituted C1-C4-alkyl, NR 9 R 10 Substituted C2-C4-alkyl, 11 Substituted C2-C4-alkyl, C3-C4-alkenyl, C3-C4-alkynyl, C1-C4-haloalkyl and C0-C4-alkylene-R 8c ; R 8c independently selected from C3-C6-cycloalkyl and 3 to 7 membered heterocycloalkyl; wherein the heterocycloalkyl is attached to the C0-C4-alkylene via a carbon atom in the heterocycloalkyl ring; wherein the cycloalkyl or heterocycloalkyl is optionally substituted by 1 to 4 R 13 Group substitution; R 9 are independently selected at each occurrence from H and C1-C4-alkyl; or two R 9 The groups together with the nitrogen atom to which they are attached form an optionally substituted group consisting of 0 to 4 R 13 C5-C8 heterocycloalkyl substituted with a group; R 10 is independently selected at each occurrence from H, C1-C4-alkyl, C(O)-C1-C4-alkyl and S(O)2-C1-C4-alkyl; or R 9 and R 10 Together with the nitrogen atom to which they are attached, they form an optionally substituted 0 to 4 R 13 C5-C8 heterocycloalkyl substituted with a group; R 11 is independently selected at each occurrence from H, C1-C4-alkyl, C(O)-C1-C4-alkyl and C1-C4-haloalkyl; R 12 independently selected from C3-C6-cycloalkyl, phenyl, 5- or 6-membered heteroaryl and 3- to 6-membered heterocycloalkyl; wherein the cycloalkyl or heterocycloalkyl is optionally substituted by 1 to 4 R 13 wherein the phenyl or heteroaryl group is optionally substituted by 1 to 3 R 14 Group substitution; R 13 is independently selected at each occurrence from =O, halogen, nitro, cyano, NR 8 R 9 , OR 14 , SR 8 、SO2NR 8 R 8 、CO2R 8 、C(O)R 8 ,CONR 8 R 8 , C1-C4-alkyl, OR 11 Substituted C1-C4-alkyl, NR 9 R 10 Substituted C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl, C6-C 10 - aryl and C3-C6-cycloalkyl; R 14 is independently selected at each occurrence from halogen, nitro, cyano, NR 8 R 9 , OR 10 , SR 8 、SO2R 8 、SO2NR 8 R 8 、CO2R 8 、C(O)R 8 ,CONR 8 R 8 , C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl, 11 Substituted C1-C4-alkyl, NR 8 R 9 Substituted C1-C4-alkyl and cyclopropyl; m is an integer selected from 0, 1, 2, 3 and 4; n is an integer selected from 0, 1, 2, 3 and 4; p is an integer selected from 0, 1 and 2; wherein any of the above alkyl, alkylene or cyclopropyl groups is optionally substituted, where chemically possible, by 1 to 5 substituents, each of which is independently selected at each occurrence from the group consisting of halogen, oxo, fluoro, nitro, cyano, NR a R b , OR a , SR a 、CO2R a 、C(O)R a ,CONR a R a , C1-C4-alkyl, C1-C4-haloalkyl and cyclopropyl; wherein R a is independently selected at each occurrence from H, C1-C4-alkyl and C1-C4-haloalkyl; and R b is independently selected at each occurrence from H, C1-C4-alkyl, C(O)-C1-C4-alkyl and S(O)2-C1-C4-alkyl.

2. The compound according to claim 1, wherein m is 0 or 1.

3. The compound according to claim 1, wherein m is at least 1, X 1 is carbon, and R 1 Group connected to X 1 On carbon.

4. The compound according to any one of claims 1 to 3, wherein n is 0 or 1.

5. The compound according to any one of claims 1 to 4, wherein p is 0.

6. A compound according to any one of claims 1 to 5, wherein R 5 It is H at every occurrence.

7. A compound according to any one of claims 1 to 6, wherein R 6 At each occurrence it is C1-C4-alkyl.

8. A compound according to any one of claims 1 to 7, wherein R 8a It's H.

9. A compound according to any one of claims 1 to 8, wherein R 8b is selected from H and C1-C4-alkyl.

10. A compound according to any one of claims 1 to 9, wherein X 1 , X 2 and X 3 Each is carbon.

11. A compound according to any one of claims 1 to 10, wherein X 4 , X 5 , X 6 and X 7 Each is carbon.

12. A compound according to any one of claims 1 to 10, wherein X 4 , X 5 , X6 and X 7 At least one of them is nitrogen.

13. A compound according to any one of claims 1 to 12, wherein NR 3 R 4 With formula in a is an integer selected from 1 and 2; R 4b is selected from H and F at each occurrence; wherein at least one R 4b The group is F; R 3a independently selected from H and C1-C4-alkyl; R 4c is independently selected at each occurrence from H, C1-C4-alkyl and C4-C6-cycloalkyl; or R 3a and a single R 4c Together with the carbon and nitrogen to which they are attached they form a 4- to 6-membered heterocycloalkyl.

14. The compound according to claim 13, wherein a is 1.

15. The compound according to claim 13 or 14, wherein at least two R 4b The group is F.

16. A compound according to any one of claims 13 to 15, wherein R 3a It's H.

17. A compound according to any one of claims 13 to 16, wherein R 4c is selected from H and C1-C4-alkyl.

18. A compound according to any one of claims 13 to 15, wherein R 3a and R 4c Together with the carbon and nitrogen to which they are attached they form a 4- to 6-membered heterocycloalkyl.

19. A compound according to any one of claims 1 to 12, wherein R 3 Yes H, R 4 is selected from C1-C6-alkyl, C1-C6-haloalkyl and C0-C4-alkylene-R 4a .

20. The compound according to claim 14, wherein R 4 is selected from C1-C6-alkyl and C1-C6-haloalkyl.

21. The compound according to claim 14, wherein R 4 is C0-C4-alkylene-R 4a .

22. The compound according to claim 16, wherein R 4 YesR 4a .

23. The compound according to claim 16 or 17, wherein R 4a is selected from C3-C8-cycloalkyl and 4- to 10-membered heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally substituted by 1 to 4 R 13 Group substitution.

24. The compound according to claim 16 or 17, wherein R 4a independently selected from: phenyl and 5 or 6 membered heteroaryl; wherein the phenyl or heteroaryl is optionally substituted by a single R 12 group and / or 1 to 3 R 14 Group substitution.

25. A compound according to any one of claims 1 to 12, wherein R 3 and R 4 Together with the nitrogen atom to which they are attached, they form a monocyclic 4- to 7-membered heterocycloalkyl group, which may be optionally substituted by 1 to 4 R 13 Group substitution.

26. A compound of formula (I) selected from:

27. A pharmaceutical formulation comprising a compound according to any one of claims 1 to 26 and a pharmaceutically acceptable excipient.

28. A compound according to any one of claims 1 to 26 for use as a medicament.

29. A compound according to any one of claims 1 to 26 for use in treating a disease or disorder selected from the group consisting of renal conditions, liver conditions, inflammatory conditions, cardiovascular conditions, acute and chronic organ transplant rejection, fibrotic diseases and cancer.

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