fibrosis

Abstract

The present invention relates to novel compounds and pharmaceutical compositions containing 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 in the treatment of cancer and fibrotic diseases.

Description

[Technical Field]

[0001] The present invention relates to novel compounds and pharmaceutical compositions containing 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 in the treatment of cancer and fibrotic diseases. [Background technology]

[0002] The discoidin domain receptors (DDRs), DDR1 and DDR2, are type 1 transmembrane receptor tyrosine kinases (RTKs) with collagen receptor functionality (Vogel et al., Mol. Cell, 1997). DDRs contain a characteristic collagen-binding discoidin domain in their N-terminal extracellular domains. These domains are followed by an extracellular juxtamembrane domain, a single transmembrane domain, a cytoplasmic juxtamembrane domain, and a catalytic kinase domain before a short C-terminal tail. Five isoforms of DDR1 (DRR1a-e) have been identified, resulting from alternative splicing of the cytoplasmic region. No additional isoforms of DDR2 have been identified. DDR1 and DDR2 have broad, but not completely, mutually exclusive expression profiles in epithelial cells and stroma, respectively. DDRs are activated by binding to collagens with broad specificity, but have clear preferences for certain collagen types. Once activated, DDRs are known to regulate cell adhesion, proliferation, and extracellular matrix remodeling. The DDR is upregulated in response to cellular activity and many forms of tissue injury, and as such, the DDR is recognized to be involved 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] Overexpression and / or activation of DDR1 and DDR2 are associated with multiple forms of cancer, as summarized in a recent review (Elkamhawy et al., Int. J. Mol. Sci., 2021). Studies have shown that elevated and / or mutated DDR expression levels are found in many cancer cell lines and primary tumor tissues, including those from lung, pancreas, prostate, breast, brain, ovary, and liver. DDR1 has been found to be a prognostic marker for non-small cell lung cancer (NSCLC) patients. Recent studies have shown that siRNA-mediated downregulation of DDR1 suppresses the malignant progression, 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. DDR1 involvement in glioblastoma cell invasion and epithelial-mesenchymal transition (EMT) has also been demonstrated. DDR1 expression was found in 50.5% of gastric cancer tissues. DDR1 has been found to control the growth of triple-negative breast cancer by regulating tumor-infiltrating CD4+ and CD8+ T cells. Strong evidence also indicates that DDR2 may be a potential biomarker and molecular target for various cancers. For example, overexpression of DDR2 has been reported to contribute to NSCLC, thyroid cancer, Hodgkin's lymphoma, nasopharyngeal carcinoma, prostate cancer, and head and neck squamous cell carcinoma. Studies have shown that DDR2 contributes to 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 essential role of wild-type DDR in cancer pathology and prognosis, various mutations in DDR1 and / or DDR2 have also been reported in many types of cancer cells, such as 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. DDR also plays a role in cancer growth by controlling how tumor cells interact with the surrounding collagen matrix. This role of DDR becomes even more prominent when considering its role as an extracellular matrix receptor.The extracellular matrix (ECM) provides structural properties to the tissue surrounding tumors and regulates cell proliferation, survival, migration, and invasion. The physiological interactions between tumor cells and the microenvironment represented by the extracellular matrix are disrupted in metastatic cancer. As a key component of the tumor extracellular matrix, type I collagen exhibits a dense and distorted structure in malignant cancers and is associated with tumorigenesis and metastasis. Therefore, the discovery of DDR as a collagen receptor represents a new target for controlling tumor progression.

[0004] The DDR also appears to play a central role in regulating inflammation and fibrosis. Regulation of fibrosis and inflammation has been demonstrated in several organs, including the lung and kidney. In the lung, DDR-1-deficient mice exhibit reduced bleomycin-induced lung injury (Vogel et al., Am. J. Respir. Crit. Care Med., 2006), and both DDR1 and DDR2 have been shown to be upregulated in patients with fibrotic lung disease (Bian et al., ERJ Open Res., 2016). In the kidney, DDR1 expression is elevated in patients with lupus nephritis and Goodpasture syndrome, as well as in mouse models of glomerulonephritis (Kerroch et al., FASEB Journal, 2012), and in the renal tubules of mice subjected to unilateral ureteral obstruction (UUO) (Guerrot et al., Am. J. Pathol., 2011). Several studies have shown that DDR1-deficient mice are protected from angiotensin II-mediated proteinuria, glomerular fibrosis, and inflammation, and have reduced collagen deposition, tubular macrophage infiltration, and pro-inflammatory cytokine levels after UUO treatment. Finally, COL3A3 KO mice (a mouse model of human Alport syndrome crossed with DDR1-null mice) have reduced renal fibrosis and attenuation as a result of reduced TGF-β-mediated signaling and reduced levels of the pro-inflammatory 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 inhibitory activity of DDR1 and / or DDR2 has been demonstrated to produce beneficial effects in mouse models of cancer and fibrotic disease (Richter et al., ACS Chem. Biol., 2019; Wang et al., J. Med. Chem., 2018; Zhu et al., J. Med. Chem., 2019). Such reports support the hypothesis that inhibitors of DDR kinase activity may be useful as therapeutic agents for the treatment of human cancer and fibrotic disease.

[0006] Furthermore, it is an object of certain embodiments of the present invention to provide novel compounds useful for treating diseases, such as cancer and fibrotic diseases. The compounds may be inhibitors of DDR1 and / or DDR2. It is an object of certain embodiments of the present invention to provide compounds having activity comparable to existing DDR1 and / or DDR2 inhibitors. It is an object of certain embodiments of the present invention to provide compounds having increased activity compared 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): [ka] (I) [In the formula, X 1 , X 2 and X 3 are each independently selected from carbon and nitrogen; X 1 , X 2 and X 3 at least two of are carbon; X 4 , X 5 , X 6 and X 7are each independently selected from carbon and nitrogen; X 4 , X 5 , X 6 and X 7 at least two of are carbon; R 1 may each occur independently as halo, nitro, cyano, or NR 9 R 10 , OR 11 , S.R. 9 , SO2NR 9 R 9 , SO2R 9 , CO2R 9 , C(O)R 9 ,CONR 9 R 9 , C1-C4-alkyl, NR 9 R 10 C1-C4-alkyl substituted with OR 11 C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and cyclopropyl substituted with; R 3 is independently selected from H and C1-C4-alkyl; R 4 are independently C1-C6-alkyl, C1-C6-haloalkyl, C0-C4-alkylene-R 4a Selected from;R 4a are independently selected from C3-C8-cycloalkyl, phenyl, 5-, 6-, 9- or 10-membered heteroaryl and 4- to 10-membered heterocycloalkyl; the heterocycloalkyl or heteroaryl group can be monocyclic or bicyclic; the cycloalkyl or heterocycloalkyl group can be substituted with one R 12 group and / or 1 to 4 R 13 group, and the phenyl or heteroaryl group is optionally substituted with one R 12 group and / or 1 to 3 R 14 optionally substituted with a group; Alternatively, R 3 and R 4together with the nitrogen atom to which they are attached form a 4- to 10-membered heterocycloalkyl group or a 5- or 9-membered heteroaryl group; the heterocycloalkyl or heteroaryl group can be monocyclic or bicyclic; and the heterocycloalkyl group is 12 group and / or 1 to 4 R 13 group, and the heteroaryl group is optionally substituted with one R 12 group and / or 1 to 3 R 14 optionally substituted with a group; R 5 is independently selected at each occurrence from H, halo and C-C-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 may each occur independently as halo, nitro, cyano, or NR 9 R 10 , OR 11 , S.R. 9 , SO2NR 9 R 9 , SO2R 9 , CO2R 9 , C(O)R 9 ,CONR 9 R 9 , C1-C4-alkyl, NR 9 R 10 C1-C4-alkyl substituted with OR 11 C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and cyclopropyl substituted with; R 7 may each occur independently as halo, nitro, cyano, or NR 9 R 10 , OR 11 , S.R. 9 , SO2NR 9 R 9 , SO2R 9 , CO2R 9 , C(O)R 9 ,CONR 9 R 9 , C1-C4-alkyl, NR9 R 10 C1-C4-alkyl substituted with OR 11 C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and cyclopropyl substituted with; R 8a are independently H, halo, nitro, cyano, NR 9 R 10 , OR 11 , S.R. 9 , SO2NR 9 R 9 , SO2R 9 , CO2R 9 , C(O)R 9 ,CONR 9 R 9 , C1-C4-alkyl, NR 9 R 10 C1-C4-alkyl substituted with OR 11 C1-C4-Alkyl, C2-C4-Alkenyl, C2-C4-Alkynyl, C1-C4-Haloalkyl and C0-C4-Alkylene-R 8c More selected; R 8b are independently H, C1-C4-alkyl, CONR 9 R 9 C1-C4-alkyl substituted with NR 9 R 10 C2-C4-alkyl substituted with OR 11 C2-C4-Alkyl, C3-C4-Alkenyl, C3-C4-Alkynyl, C1-C4-Haloalkyl and C0-C4-Alkylene-R 8c More selected; R 8c are independently selected from C3-C6-cycloalkyl and 3- to 7-membered heterocycloalkyl; the heterocycloalkyl group is bonded to the C0-C4-alkylene via a carbon atom in the heterocycloalkyl ring; the cycloalkyl or heterocycloalkyl group is bonded to the C0-C4-alkylene via a carbon atom in the heterocycloalkyl ring; 13 optionally substituted with a group; R 9is independently selected at each occurrence from H and C-C-alkyl; or two R 9 The groups, together with the nitrogen atom to which they are attached, may contain 0 to 4 R 13 forming a C5-C8-heterocycloalkyl group optionally substituted by a group; R 10 is independently selected at each occurrence from H, C-C-alkyl, C(O)-C-C-alkyl and S(O)-C-C-alkyl; or R 9 and R 10 together with the nitrogen atom to which they are attached, 0 to 4 R 13 forming a C5-C8-heterocycloalkyl group optionally substituted by a group; R 11 is independently selected at each occurrence from H, C-C-alkyl, C(O)-C-C-alkyl and C-C-haloalkyl; R 12 are independently selected from C3-C6-cycloalkyl, phenyl, 5- or 6-membered heteroaryl and 3- to 6-membered heterocycloalkyl; the cycloalkyl or heterocycloalkyl group is selected from 1 to 4 R 13 group, and the phenyl or heteroaryl group is optionally substituted with 1 to 3 R 14 optionally substituted with a group; R 13 independently at each occurrence, ═O, halo, nitro, cyano, NR 8 R 9 , OR 14 , S.R. 8 , SO2NR 8 R 8 , CO2R 8 , C(O)R 8 ,CONR 8 R 8 , C1-C4-alkyl, OR 11 C1-C4-alkyl substituted with NR 9 R 10 C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl, C6-C 10- selected from aryl and C3-C6-cycloalkyl; R 14 may each occur independently as halo, nitro, cyano, or NR 8 R 9 , OR 10 , S.R. 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, OR 11 C1-C4-alkyl substituted with NR 8 R 9 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; Any of the above alkyl, alkylene or cyclopropyl groups may, where chemically possible, be selected from halo, oxo, fluoro, nitro, cyano, NR a R b , OR a , S.R. a , CO2R a , C(O)R a ,CONR a R a , optionally substituted by 1 to 5 substituents each independently selected at each occurrence from the group consisting of C-C-alkyl, C-C-haloalkyl and cyclopropyl; R a is independently selected at each occurrence from H, C-C-alkyl and C-C-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. or a pharmaceutically acceptable salt thereof.

[0009] In one embodiment, the compound of Formula (I) may be represented by Formula (II): [ka] (II) wherein 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 defined above for compounds of formula (I).

[0010] In one embodiment, the compound of Formula (I) may be represented by Formula (III): [ka] (III) wherein 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 defined above for compounds of formula (I).

[0011] In one embodiment, the compound of Formula (I) has the formula (IV): [ka] (IV) wherein R 1 , R 3 , R 4 , R 5 , R 6 , R 7, R 8a , R 8b , m, n and p are as defined above for compounds of formula (I).

[0012] In one embodiment, the compound of Formula (I) has the formula (V): [ka] (V) wherein 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 defined above for compounds of formula (I).

[0013] In one embodiment, the compound of Formula (I) has the formula (VI): [ka] (VI) wherein 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 defined above for compounds of formula (I).

[0014] In one embodiment, the compound of Formula (I) has the formula (VII): [ka] (VII) wherein 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 defined above for compounds of formula (I).

[0015] In one embodiment, the compound of Formula (I) has the formula (VIII): [ka] (VIII) wherein 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 defined above for compounds of formula (I).

[0016] In one embodiment, the compound of Formula (I) has the formula (IX): [ka] (IX) wherein R 1 , R 3 , R 4 , R 6 , R 7 , R 8b , m, n and p are as defined above for compounds of formula (I).

[0017] In one embodiment, the compound of Formula (I) has the formula (X): [ka] (X) wherein R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8a , R 8b , m, and p are as described above for compounds of formula (I), and n is an integer selected from 0, 1, 2, and 3.

[0018] In one embodiment, the compound of formula (I) has formula (XI): [ka] (XI) wherein R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8a , R 8b , m, and p are as described above for compounds of formula (I), and n is an integer selected from 0, 1, 2, and 3.

[0019] In one embodiment, the compound of Formula (I) has the formula (XII): [ka] (XII) wherein R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8a , R 8b, m, and p are as described above for compounds of formula (I), and n is an integer selected from 0, 1, and 2.

[0020] The following embodiments apply to compounds represented by any of Formulas (I) to (XII). These embodiments are independent and interchangeable. Any one embodiment may be combined with any other embodiment, where chemically permissible. In other words, any feature described in the following embodiments may be combined (where chemically permissible) with features described in one or more other embodiments. In particular, where a compound is exemplified or illustrated herein, any two or more of the embodiments listed below, expressed at any level of generality, including that compound, may be combined to provide further embodiments that form part of the present disclosure.

[0021] X 1 can be carbon. 2 can be carbon. 3 can be carbon. 1 and X 2 can both be carbon. 2 and X 3 can both be carbon. 1 and X 3 can both be carbon. 1 , X 2 and X 3 may each be carbon.

[0022] X 1 , X 2 and X 3 Only one of X may be nitrogen. 1 can be nitrogen. 2 can be nitrogen. 3 may be nitrogen.

[0023] X 4 can be carbon. 5 can be carbon. 6 can be carbon. 7 can be carbon. 4and X 5 can both be carbon. 4 and X 6 can both be carbon. 4 and X 7 can both be carbon. 5 and X 6 can both be carbon. 5 and X 7 can both be carbon. 6 and X 7 can both be carbon. 4 , X 5 and X 6 Each X can be carbon. 4 , X 5 and X 7 Each X can be carbon. 4 , X 6 and X 7 Each X can be carbon. 5 , X 6 and X 7 Each X can be carbon. 4 , X 5 , X 6 and X 7 may each be carbon.

[0024] X 4 , X 5 , X 6 and X 7 At least one of X may be nitrogen. 4 , X 5 , X 6 and X 7 Only one of X can be nitrogen. 5 can be nitrogen. 4 can be nitrogen. 4 , X 5 , X 6 and X 7 Two of the X's may be nitrogen. 4 and X 5 Each X may be nitrogen. 4 and X 7 Each X may be nitrogen. 5 and X 7 Each X may be nitrogen.4 and X 6 may each be nitrogen.

[0025] 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.

[0026] R 1 independently at each occurrence, represent halo, nitro, cyano, OR 11 , C1-C4-alkyl, NR 9 R 10 C1-C4-alkyl substituted with OR 11 R may be selected from C-C-alkyl, C-C-haloalkyl and cyclopropyl substituted with R 1 independently at each occurrence, halo, OR 11 , N.R. 9 R 10 , cyano, C1-C4-alkyl and C1-C4-haloalkyl. R 1 independently at each occurrence, halo, OR 11 , C1-C4-alkyl, C1-C4-haloalkyl and cyclopropyl. 1 R at each occurrence may be independently selected from halo and C-C-alkyl. 1 R at each occurrence may independently be halo, e.g., fluoro. 1 may, independently at each occurrence, be C1-C4-alkyl, for example methyl.

[0027] X 1 does not have to be CH. X 1 is nitrogen, and R 1 m is at least 1 and X 1 is carbon and R 1 The base is X 1 m is 1 and X 1 is carbon and R 1 The base is X 1 Can be bonded to carbon. X 1 R attached to carbon 1Compounds containing the X group 1 R attached to carbon 1 In these embodiments, the compound exhibits increased activity compared to compounds lacking the X group. 1 R binds to 1 The group may be C1-C4-alkyl, for example methyl.

[0028] R 5 R at each occurrence may be independently selected from H, fluoro, and C-C-alkyl. 5 is independently selected at each occurrence from H, fluoro and C-C-alkyl, or two R 5 The groups and the carbon atoms to which they are attached may together form a C3-C6 cycloalkyl ring. 5 is independently selected at each occurrence from H 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. 5 may be independently selected at each occurrence from H and C1-C4-alkyl, such as methyl.

[0029] R 5 can be H at each occurrence. 5 R may be H in one occurrence and C-C-alkyl, e.g., methyl, in another occurrence. 5 At each occurrence, may be C1-C4-alkyl, for example methyl.

[0030] 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.

[0031] R 6 are independently halo, nitro, cyano, OR 11 , C1-C4-alkyl, NR 9 R 10 C1-C4-alkyl substituted with OR 11R may be selected from C-C-alkyl, C-C-haloalkyl and cyclopropyl substituted with R 6 independently, halo, OR 11 , C1-C4-alkyl, C1-C4-haloalkyl and cyclopropyl. 6 may be independently selected from halo and C-C-alkyl. When present, R 6 R can be halo, e.g., fluoro. 6 may be C1-C4-alkyl, for example methyl.

[0032] p may be selected from 0 and 1. p may be 0. p may be 1. p may be 2.

[0033] R 7 are independently halo, nitro, cyano, OR 11 , C1-C4-alkyl, NR 9 R 10 C1-C4-alkyl substituted with OR 11 R may be selected from C-C-alkyl, C-C-haloalkyl and cyclopropyl substituted with R 7 independently, halo, OR 11 , C1-C4-alkyl, C1-C4-haloalkyl and cyclopropyl. 7 may be independently selected from halo and C-C-alkyl. When present, R 7 R can be halo, e.g., fluoro. 7 may be C1-C4-alkyl, for example methyl.

[0034] R 8a can be H. R 8a is halo, C1-C4-alkyl, NR 9 R 10 C1-C4-alkyl substituted with OR 11 C1-C4-Alkyl, C1-C4-haloalkyl and C0-C4-alkylene-R substituted with 8c R 8amay be selected from H, halo, C-C-alkyl, C-C-haloalkyl and cyclopropyl. 8a may be selected from H, C-C-alkyl, C-C-haloalkyl and cyclopropyl. 8a may be selected from C1-C4-alkyl (e.g., methyl) and C1-C4-haloalkyl (e.g., CF3). 8a may be C1-C4-alkyl (e.g. methyl).

[0035] R 8b can be H. R 8b is C1-C4-alkyl, CONR 9 R 9 C1-C4-alkyl substituted with NR 9 R 10 C2-C4-alkyl substituted with OR 11 C2-C4-Alkyl, C1-C4-haloalkyl and C0-C4-alkylene-R substituted with 8c R 8b may be selected from H, C1-C4-alkyl and cyclopropyl. 8b may be C1-C4-alkyl (e.g. methyl).

[0036] R 8b are independently H, C1-C4-alkyl, NR 9 R 10 C2-C4-alkyl substituted with OR 11 C2-C4-Alkyl, C3-C4-Alkenyl, C3-C4-Alkynyl, C1-C4-Haloalkyl and C0-C4-Alkylene-R 8c It can be selected from the following.

[0037] R 8a H and R 8b R can be C1-C4-alkyl (e.g., methyl). 8a and R 8b can each be H. 8a and R 8b may each be C1-C4-alkyl (e.g., methyl).

[0038] R 9 may be independently selected at each occurrence from H and C1-C4-alkyl.

[0039] R 10 R may be independently selected at each occurrence from H, C-C-alkyl, C(O)-C-C-alkyl and S(O)-C-C-alkyl. 10 may be independently selected at each occurrence from H and C1-C4-alkyl.

[0040] R 11 R may be independently selected at each occurrence from H, C-C-alkyl and C-C-haloalkyl. 11 R may be independently selected at each occurrence from H and C-C-alkyl. 11 may, independently at each occurrence, be C1-C4-alkyl, for example methyl.

[0041] R 12 may be independently selected from 5- or 6-membered heteroaryl, and the heteroaryl group may be selected from 1 to 3 R 14 may be substituted with a group. R 12 may be independently selected from 5-membered heteroaryl, such as imidazole, and the heteroaryl group may be selected from 1 to 3 R 14 It may be substituted with a group.

[0042] R 13 represents independently at each occurrence oxo, fluoro, OR 11 , CO2R 9 , CO2NR 9 R 9 , C1-C4-alkyl, NR 9 R 10 C1-C4-alkyl substituted with OR 11 R may be selected from C-C-alkyl, C-C-haloalkyl and cyclopropyl substituted with R 13 independently at each occurrence, oxo, OR 11 , C1-C4-alkyl and cyclopropyl.13 R at each occurrence may be independently selected from oxo and C-C-alkyl. 13 may, independently at each occurrence, be C1-C4-alkyl, for example methyl.

[0043] R 14 independently at each occurrence, represent halo, nitro, cyano, OR 11 , C1-C4-alkyl, NR 8 R 9 C1-C4-alkyl substituted with OR 11 R may be selected from C-C-alkyl, C-C-haloalkyl and cyclopropyl substituted with R 14 independently at each occurrence, halo, OR 11 , C1-C4-alkyl, C1-C4-haloalkyl and cyclopropyl. 14 R at each occurrence may be independently selected from halo and C-C-alkyl. 14 R at each occurrence may independently be halo, e.g., fluoro. 14 may, independently at each occurrence, be C1-C4-alkyl, for example methyl.

[0044] It can be: R 3 But; R 4 are independently C1-C6-alkyl, C1-C6-haloalkyl, C0-C4-alkylene-R 4a Selected from;R 4a are independently selected from C3-C8-cycloalkyl, phenyl, 5-, 6-, 9- or 10-membered heteroaryl and 4- to 10-membered heterocycloalkyl; the heterocycloalkyl or heteroaryl group can be monocyclic or bicyclic; the cycloalkyl or heterocycloalkyl group can be substituted with one R 12 group and / or 1 to 4 R 13 group, and the phenyl or heteroaryl group is optionally substituted with one R 12 group and / or 1 to 3 R 14 optionally substituted with a group; Alternatively, R 3 and R 4 together with the nitrogen atom to which they are attached form a 4- to 10-membered heterocycloalkyl group or a 5- or 9-membered heteroaryl group; and the heterocycloalkyl group is 12 group and / or 1 to 4 R 13 group, and the heteroaryl group is optionally substituted with one R 12 group and / or 1 to 3 R 14 It may be substituted with a group.

[0045] It can be: R 3 But; R 4 are independently C1-C6-alkyl, C1-C6-haloalkyl, C0-C4-alkylene-R 4a Selected from;R 4a are independently selected from C3-C8-cycloalkyl, phenyl, 5-, 6-, 9- or 10-membered heteroaryl and 4- to 10-membered heterocycloalkyl; the heterocycloalkyl or heteroaryl group can be monocyclic or bicyclic; the cycloalkyl or heterocycloalkyl group can be selected from 1 to 4 R 13 group, and the phenyl or heteroaryl group is optionally substituted with 1 to 3 R 14 optionally substituted with a group; Alternatively, R 3 and R 4 together with the nitrogen atom to which they are attached form a 4- to 10-membered heterocycloalkyl group or a 5- or 9-membered heteroaryl group; and the heterocycloalkyl group is 13 group, and the heteroaryl group is optionally substituted with 1 to 3 R 14 It may be substituted with a group.

[0046] R 3 can be H.

[0047] R 4represents C1-C6-alkyl, C1-C6-haloalkyl and C0-C4-alkylene-R 4a It can be selected from the following.

[0048] R 4 may be selected from C-C-alkyl and C-C-haloalkyl. 4 R may be selected from C2-C3-alkyl and C2-C3-haloalkyl. 4 R can be C-C-haloalkyl. 4 R can be C-C-haloalkyl. 4 can be 2,2,2-trifluoroethyl.

[0049] Illustrative R 4 As a base, [ka] Examples include:

[0050] R 4 is C0-C4-alkylene-R 4a It can be. R 4 is CH2-R 4a It can be. R 4 is R 4a It could be.

[0051] R 4a may be independently selected from C3-C8-cycloalkyl, phenyl, 5-, 6-, 9- or 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl; the heterocycloalkyl or heteroaryl group may be monocyclic or bicyclic; the cycloalkyl or heterocycloalkyl group may be selected from 1 to 4 R 13 The phenyl or heteroaryl group may be substituted with 1 to 3 R 14 It may be substituted with a group.

[0052] R 4a may be selected from C3-C8-cycloalkyl and 4- to 10-membered heterocycloalkyl, and the cycloalkyl or heterocycloalkyl group may be selected from one R12 group and / or 1 to 4 R 13 may be substituted with a group. R 4a may be selected from C3-C8-cycloalkyl and 4- to 10-membered heterocycloalkyl, and the cycloalkyl or heterocycloalkyl group may be selected from 1 to 4 R 13 It may be substituted with a group.

[0053] R 4 may be selected from CH2-C3-C8-cycloalkyl and CH2-4 to 10-membered heterocycloalkyl, and the cycloalkyl or heterocycloalkyl group may be selected from one R 12 group and / or 1 to 4 R 13 may be substituted with a group. R 4 may be selected from CH2-C3-C8-cycloalkyl and CH2-4 to 10-membered heterocycloalkyl, and the cycloalkyl or heterocycloalkyl group may be selected from 1 to 4 R 13 It may be substituted with a group.

[0054] R 4 may be selected from C3-C8-cycloalkyl and 4- to 10-membered heterocycloalkyl, and the cycloalkyl or heterocycloalkyl group may be selected from one R 12 group and / or 1 to 4 R 13 may be substituted with a group. R 4 may be selected from C3-C8-cycloalkyl and 4- to 10-membered heterocycloalkyl, and the cycloalkyl or heterocycloalkyl group may be selected from 1 to 4 R 13 It may be substituted with a group.

[0055] Illustrative R 4 As a base, [ka] Examples include:

[0056] R 4amay be independently selected from phenyl and 5- or 6-membered heteroaryl; the phenyl or heteroaryl group may be selected from one R 12 group and / or 1 to 3 R 14 may be substituted with a group. R 4a may be independently selected from phenyl and 5- or 6-membered heteroaryl; the phenyl or heteroaryl group may be selected from 1 to 3 R 14 may be substituted with a group. R 4a may independently be phenyl; the phenyl group may be selected from one R 12 group and / or 1 to 3 R 14 may be substituted with a group. R 4a may independently be phenyl; the phenyl group may be selected from 1 to 3 R 14 may be substituted with a group. R 4a may independently be 5- or 6-membered heteroaryl; the heteroaryl group may be 12 group and / or 1 to 3 R 14 may be substituted with a group. R 4a may independently be a 5- or 6-membered heteroaryl; the heteroaryl group may be one to three R 14 It may be substituted with a group.

[0057] R 4 may be independently selected from CH2-phenyl or CH2-5 or 6 membered heteroaryl, and the phenyl or heteroaryl group is selected from one R 12 group and / or 1 to 3 R 14 may be substituted with a group. R 4 may be independently selected from CH2-phenyl or CH2-5 or 6-membered heteroaryl, and the phenyl or heteroaryl group may be selected from 1 to 3 R 14 may be substituted with a group. R 4 may independently be CH-phenyl, and the phenyl may be selected from one R 12 group and / or 1 to 3 R 14 may be substituted with a group. R 4 may independently be CH-phenyl, and the phenyl group may be selected from 1 to 3 R14 may be substituted with a group. R 4 may independently be CH or a 6-membered heteroaryl, and the heteroaryl group is 12 group and / or 1 to 3 R 14 may be substituted with a group. R 4 can independently be CH or a 6-membered heteroaryl, and the heteroaryl group is 14 It may be substituted with a group.

[0058] R 4 may be independently selected from phenyl or 5- or 6-membered heteroaryl, and the phenyl or heteroaryl group is selected from one R 12 group and / or 1 to 3 R 14 may be substituted with a group. R 4 may be independently selected from phenyl or 5- or 6-membered heteroaryl, and the phenyl or heteroaryl group may be selected from 1 to 3 R 14 may be substituted with a group. R 4 may independently be phenyl, and the phenyl group may be selected from one R 12 group and / or 1 to 3 R 14 may be substituted with a group. R 4 may independently be phenyl, and the phenyl group may be selected from 1 to 3 R 14 may be substituted with a group. R 4 may independently be a 5- or 6-membered heteroaryl, and the heteroaryl group is 12 group and / or 1 to 3 R 14 may be substituted with a group. R 4 can independently be a 5- or 6-membered heteroaryl, and the heteroaryl group is 14 It may be substituted with a group.

[0059] R 4 may be independently selected from phenyl or 6-membered heteroaryl, and the phenyl or 6-membered heteroaryl group may have one R at the meta position. 14 R 14 The group is OR11 R in the meta position may be selected from C1-C4-alkyl substituted with C1-C4-alkyl and C1-C4-haloalkyl. 14 The group is OR 11 The meta R may be C1-C4-alkyl substituted with, for example, —(CH3)2—OH. 14 The group may be C1-C4-haloalkyl, for example CF3.

[0060] R 4 R can be a six-membered heteroaryl group. 4 R can be phenyl. 4 is one R in the meta position 14 R may be a phenyl substituted with a group. 14 is R 14a An exemplary R 4 As a base, [ka] In the formula, R 14a But halo, nitro, cyano, NR 8 R 9 , OR 10 , S.R. 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, OR 11 C1-C4-alkyl substituted with NR 8 R 9 and cyclopropyl; z is an integer selected from 1 and 2.

[0061] Illustrative R 4 As a base, [ka] Examples include:

[0062] R 3 and R 4 may be taken together with the nitrogen atom to which they are attached to form a 4- to 10-membered heterocycloalkyl group or a 5- or 9-membered heteroaryl group; the heterocycloalkyl group may be provided by one R 12 group and / or 1 to 4 R 13 The heteroaryl group may be substituted with one R 12 group and / or 1 to 3 R 14 may be substituted with a group. R 3 and R 4 may be taken together with the nitrogen atom to which they are attached to form a 4- to 10-membered heterocycloalkyl group or a 5- or 9-membered heteroaryl group; the heterocycloalkyl group may be selected from 1 to 4 R 13 The heteroaryl group may be substituted with 1 to 3 R 14 It may be substituted with a group.

[0063] R 3 and R 4 may be taken together with the nitrogen atom to which they are attached to form a 5- or 9-membered heteroaryl group; a heteroaryl group may consist of one R 12 group and / or 1 to 3 R 14 may be substituted with a group. R 3 and R 4 may be taken together with the nitrogen atom to which they are attached to form a 5- or 9-membered heteroaryl group; the heteroaryl group may be comprised of 1 to 3 R 14 may be substituted with a group. R 3 and R 4 together with the nitrogen atom to which they are attached can form a 5-membered heteroaryl group; a heteroaryl group can be formed by one R 12 group and / or 1 to 3 R 14 may be substituted with a group. R 3 and R 4 together with the nitrogen atom to which they are attached can form a 5-membered heteroaryl group; the heteroaryl group can be formed by one to three R 14It may be substituted with a group.

[0064] Exemplary NR 3 R 4 As a base, [ka] Examples include:

[0065] R 3 and R 4 may be taken together with the nitrogen atom to which they are attached to form a 4- to 10-membered heterocycloalkyl group; the heterocycloalkyl group may be formed by one R 12 group and / or 1 to 4 R 13 may be substituted with a group. R 3 and R 4 may be taken together with the nitrogen atom to which they are attached to form a 4- to 10-membered heterocycloalkyl group; the heterocycloalkyl group may be comprised of 1 to 4 R 13 The heterocycloalkyl group may be a 7- to 10-membered bicyclic heterocycloalkyl group. The heterocyclic group may be a 7- to 10-membered bridged bicyclic heterocycloalkyl group. The heterocyclic group may be a monocyclic 4- to 7-membered heterocycloalkyl group. The heterocyclic group may be a monocyclic 5- to 6-membered heterocycloalkyl group. 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 heterocycloalkyl group referred to at this stage is a group consisting of one R 12 group and / or 1 to 4 R 13 The heterocycloalkyl group referred to in this step may be substituted with 1 to 4 R groups. 13 The heterocyclic group is pyrrolidine, and may be substituted with one R group at the 2-position. 13 The heterocyclic group is pyrrolidine and may be substituted with one R group at the 3-position. 13 The heterocyclic group may be substituted with a piperidine group, and may be substituted with one R group at the 2-position. 13The heterocyclic group may be substituted with a piperidine group, and may be substituted with one R group at the 3-position. 13 The heterocyclic group may be substituted with a piperidine group, and may be substituted with one R group at the 4-position. 13 The heterocyclic group may be morpholine and may be substituted with one R group at the 2-position. 13 The heterocyclic group may be substituted with a morpholine group and one R group at the 3-position. 13 R 13 The group is C1-C4-alkyl, OR 11 and C1-C4-haloalkyl, such as -CF3.

[0066] Exemplary NR 3 R 4 As a base, [ka] Examples include:

[0067] R 3 and R 4 is NR 3 R 4 may be selected to contain a CHF2 or CF3 group.

[0068] NR 3 R 4 is the expression [ka] [In the formula, a is an integer selected from 1 and 2; R 4b is selected from H and F at each occurrence; 4b The group is F; R 3a is 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 3aand one R 4c together with the carbon and nitrogen to which they are attached form a 4- to 6-membered heterocycloalkyl group. may have:

[0069] a can be 1. a can be 2.

[0070] NR 3 R 4 is the expression [ka] [In the formula, R 4b is selected from H and F at each occurrence; 4b The group is F; R 3a is independently selected from H and C1-C4-alkyl; R 4c is independently selected from H, C1-C4-alkyl and C4-C6-cycloalkyl; or R 3a and R 4c together with the carbon and nitrogen to which they are attached form a 4- to 6-membered heterocycloalkyl group. may have:

[0071] At least two R 4b The group can be F. Two R 4b The group is F and one R 4b The group can be H. Each R 4b The group can be F.

[0072] R 3a can be H.

[0073] R 3a is independently selected from H and C1-C4-alkyl; R 4c may be independently selected from H, C-C-alkyl and C-C-cycloalkyl. 3a is H;R 4cmay be independently selected from H, C1-C4-alkyl and C4-C6-cycloalkyl. The alkyl or cycloalkyl group may be unsubstituted.

[0074] R 4c R, at each occurrence, may be selected from C-C-alkyl and H. 4c may be H at each occurrence.

[0075] R 3a and R 4c R can, together with the carbon and nitrogen to which they are attached, form a 4- to 6-membered heterocycloalkyl group. 3a and R 4c R can, together with the carbon and nitrogen to which they are attached, form a 5-membered heterocycloalkyl group. 3a and R 4c together with the carbon and nitrogen to which they are attached can form a 6-membered heterocycloalkyl group. The heterocycloalkyl group can be unsubstituted.

[0076] The compound of formula (I) may be selected from: [ka] [ka] [ka] [ka] [ka] [ka]

[0077] The compound of formula (I) may be selected from: [ka] [ka] [ka]

[0078] The compound of formula (I) is [ka] It doesn't have to be.

[0079] In one aspect of the invention, there is provided a compound of the invention for use as a pharmaceutical.

[0080] According to another aspect, there is provided a compound of the present invention for use in treating a condition modulated by DDR1 and / or DDR2. A compound of any formula disclosed herein may be for use in treating a condition treatable by inhibition of DDR1 and / or DDR2.

[0081] In another aspect of the present invention, there is provided a compound of the present invention for use in the treatment of a disease or disorder selected from renal conditions, hepatic conditions, inflammatory conditions, cardiovascular conditions, acute and chronic organ transplant rejection, fibrotic diseases and cancer.

[0082] In one embodiment of the present invention, there is provided a method of treating a disease or disorder modulated by DDR1 and / or DDR2, the method comprising administering to a patient in need thereof a therapeutic amount of a compound of the present invention.

[0083] The method of treatment can be a method of treating a condition treatable by inhibition of DDR1 and / or DDR2.

[0084] The present invention also provides a method of treating a disease or disorder selected from a renal condition, a hepatic condition, an inflammatory condition, a cardiovascular condition, acute and chronic organ transplant rejection, a fibrotic disease, and cancer, the method comprising administering to a patient in need thereof a therapeutic amount of a compound of any of the formulas disclosed herein.

[0085] Renal conditions include acute kidney injury and chronic kidney disease with or without proteinuria, including end-stage renal disease (ESRD), including reduced creatinine clearance and reduced glomerular filtration rate, microalbuminuria, albuminuria and proteinuria, glomerulosclerosis with expansion of the plexiform mesangial matrix with or without significant cellular hyperplasia (particularly diabetic nephropathy and amyloidosis), focal thrombosis of glomerular capillaries (particularly thrombotic microangiopathy), global fibrinoid necrosis, ischemic lesions, malignant nephrosclerosis (e.g., ischemic regression, reduced renal blood flow and renal arteriopathy), swelling and proliferation of intracapillary (endothelial and mesangial) and / or extracapillary cells (crescents) as in glomerulonephritis entities, focal segmental glomerulosclerosis, IgA nephropathy, vasculitis / systemic disease, and acute and chronic kidney transplant rejection. Early and advanced Alport syndrome are also included in the renal conditions.

[0086] Inflammatory conditions include arthritis, osteoarthritis, multiple sclerosis, systemic lupus erythematosus, inflammatory bowel disease, abnormal elimination disorders, etc., as well as inflammatory airway diseases such as idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD) or chronic asthma. Further conditions of the respiratory system include iatrogenic drug-induced fibrosis, occupational and / or environmentally induced fibrosis, systemic diseases and other diffuse parenchymal lung diseases of various etiologies, including vasculitis, granulomatous diseases (sarcoidosis, hypersensitivity pneumonitis), collagen vascular diseases, radiation-induced fibrosis.

[0087] Vascular conditions include atherosclerosis, thrombotic vascular disease and thrombotic microangiopathy, proliferative arteriopathy (e.g., swollen myointimal cells and nodular thickening surrounded by a mucous extracellular matrix), atherosclerosis, decreased vascular compliance (e.g., stiffness, decreased ventricular compliance and decreased vascular compliance), endothelial dysfunction, and the like.

[0088] Cardiovascular conditions include acute coronary syndromes, coronary heart disease, myocardial infarction, arterial and pulmonary hypertension, cardiac arrhythmias such as atrial fibrillation, stroke and other vascular injuries.

[0089] Fibrotic diseases include, but are not limited to, myocardial and vascular fibrosis, renal fibrosis, hepatic fibrosis, pulmonary fibrosis, skin fibrosis, scleroderma and encapsulating peritonitis, systemic sclerosis, Alport syndrome, chronic kidney disease, NASH, interstitial lung disease, and systemic sclerosis.

[0090] In certain embodiments, the compound of the present invention is for use in the treatment of cancer or is used in the method of treating cancer.Examples include but are not limited to liver cancer, bladder cancer, hepatocellular carcinoma, squamous cell carcinoma of the lung, non-small cell lung cancer, adenocarcinoma of the lung, small cell lung cancer, various types of head and neck cancer, breast cancer, colon cancer, colorectal cancer, peritoneal cancer, hepatocellular carcinoma, gastrointestinal cancer, esophageal cancer, endometrial or uterine cancer, salivary gland cancer, squamous cell carcinoma, pituitary gland 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, cancer is selected from bladder cancer, pancreatic cancer, breast cancer, lung cancer, ovarian cancer and glioblastoma.

[0091] In another aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable excipient.

[0092] In one embodiment, the pharmaceutical composition may be a combination preparation comprising a further pharmaceutically active substance.

[0093] In one aspect of the invention, there is provided the use of a compound of the invention in the manufacture of a medicament for use in the treatment of any of the conditions disclosed herein. DETAILED DESCRIPTION OF THE INVENTION

[0094] The following are definitions of terms used in this application: Any term not defined herein has the ordinary meaning that one of ordinary skill in the art would understand that term.

[0095] The term "halo" refers to one of the halogens in Group 17 of the periodic table. In particular, the term refers to fluorine, chlorine, bromine, and iodine. Preferably, the term refers to chlorine or fluorine.

[0096] 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 straight or branched hydrocarbon chain containing 1, 2, 3, 4, 5, or 6 carbon atoms, e.g., methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, and n-hexyl. "Alkylene" groups can likewise be straight or branched and are divalent, i.e., bonded to the other position of the molecule at two points. Furthermore, an alkylene group can correspond, for example, to one of the alkyl groups listed in this paragraph. Alkyl and alkylene groups can be unsubstituted or substituted with one or more substituents.

[0097] The term "haloalkyl," independently at each occurrence, refers to a hydrocarbon chain substituted with at least one halogen atom selected from, for example, fluorine, chlorine, bromine, and iodine. For example, the term "C 1-6 "Haloalkyl" refers to a straight or branched straight or branched hydrocarbon chain containing 1, 2, 3, 4, 5, or 6 carbon atoms substituted with at least one halogen. The halogen atom can be located at any position on the hydrocarbon chain. For example, C 1-6Haloalkyl can refer to chloromethyl, fluoromethyl, trifluoromethyl, chloroethyl, such as 1-chloromethyl and 2-chloroethyl, trichloroethyl, such as 1,2,2-trichloroethyl, 2,2,2-trichloroethyl, fluoroethyl, such as 1-fluoromethyl and 2-fluoroethyl, trifluoroethyl, such as 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.

[0098] 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 may exist as an E or Z isomer. The double bond may be in any available position on the hydrocarbon chain. For example, "C 2-6 "Alkenyl" can be ethenyl, propenyl, butenyl, butadienyl, pentenyl, pentadienyl, hexenyl and hexadienyl.

[0099] The term "alkynyl" refers to a branched or straight hydrocarbon chain containing at least one triple bond. For example, the term "C 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 may be in any available position on the hydrocarbon chain. For example, "C 2-6 "Alkynyl" can be ethynyl, propynyl, butynyl, pentynyl and hexynyl.

[0100] The term "heteroalkyl" refers to a branched or straight-chain hydrocarbon chain containing at least one heteroatom selected from N, O, and S positioned between any carbon atoms in the chain or at any terminus of the chain. For example, the term "C 1-6"Heteroalkyl" refers to a branched or straight-chain hydrocarbon chain containing 1, 2, 3, 4, 5, or 6 carbon atoms and at least one heteroatom selected from N, O, and S, positioned between any carbon atoms in the chain or at a terminal end of the chain. For example, the hydrocarbon chain can contain one or two heteroatoms. 1-6 A heteroalkyl can be attached to the remainder of the molecule through a carbon or heteroatom. For example, "C 1-6 "Heteroalkyl" is C 1-6 N-Alkyl, C 1-6 N,N-alkyl, or C 1-6 It can be O-alkyl.

[0101] The term "heterocycle" refers to a saturated, unsaturated, or aromatic ring system containing at least one heteroatom selected from N, O, or S. A "heterocyclic" system can contain 1, 2, 3, or 4 heteroatoms, e.g., 1 or 2. A "heterocyclic" system can be a monocyclic or fused polycyclic ring system, e.g., bicyclic or tricyclic. A "heterocyclic" moiety can contain 3 to 14 carbon atoms, e.g., 3 to 8 carbon atoms for a monocyclic system, and 7 to 14 carbon atoms for a polycyclic system. "Heterocyclic" encompasses heterocycloalkyl, heterocycloalkenyl, and heteroaryl moieties. Examples of heterocyclic groups include oxirane, aziridine, azetidine, oxetane, tetrahydrofuran, pyrrolidine, imidazolidine, succinimide, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, piperidine, morpholine, thiomorpholine, piperazine, and tetrahydropyran. Heteroaryl includes groups such as pyridone and N-alkyl-pyridone.

[0102] 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 "Cycloalkyl" can be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

[0103] The term “C3-8 "Cycloalkenyl" refers to an unsaturated hydrocarbon ring system containing 3, 4, 5, 6, 7, or 8 carbon atoms that is not aromatic. The ring may contain more than one double bond, provided that the ring is not aromatic. For example, "C 3-8 "Cycloalkyl" can be cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadiene, cyclooctenyl and cycloatadienyl.

[0104] The term "heterocycloalkyl" refers to a saturated hydrocarbon ring system containing carbon atoms and at least one heteroatom in the ring selected from N, O, and S. For example, there can be 1, 2, or 3 heteroatoms, optionally 1 or 2. A "heterocycloalkyl" can be attached to the rest of the molecule through any carbon atom or heteroatom. A "heterocycloalkyl" can have one or more bonds, for example, 1 or 2 bonds, to the rest of the molecule, and these bonds can be through any of the atoms in the ring. For example, a "heterocycloalkyl" can be "C 3-8 The term "C" may be a heterocycloalkyl. 3-8 "Heterocycloalkyl" refers to a saturated hydrocarbon ring system containing 3, 4, 5, 6, 7, or 8 atoms, wherein at least one heteroatom in the ring is 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.

[0105] The term "aromatic," when applied to a substituent as a whole, means a monocyclic or polycyclic ring system having 4n+2 electrons in a conjugated pi system within the ring or ring system, where all atoms contributing to the conjugated pi system lie in the same plane.

[0106] The term "aryl" refers to an aromatic hydrocarbon ring system. The ring system has 4n+2 electrons in a conjugated π system, where all atoms contributing to the conjugated π system are on the same plane. For example, "aryl" can be phenyl and naphthyl. The aryl system itself can be substituted with other groups.

[0107] The term "heteroaryl" refers to an aromatic hydrocarbon ring system having at least one heteroatom selected from O, N, and S in a ring or fused ring system. The ring or ring system has 4n+2 electrons in a conjugated π system, where all atoms contributing to the conjugated π system are on the same plane. For example, "heteroaryl" can be imidazole, oxazole, isoxazole, thiazole, isothiazole, thien, furan, thianthrene, pyrrole, benzimidazole, pyrazole, pyrazine, pyridine, pyrimidine, and indole.

[0108] [ka] A bond terminating in a (-) indicates that the bond is connected to another atom not shown in the figure. A bond terminating within a ring structure and not at an atom of the ring structure indicates that the bond may be connected to any atom, if valence allows.

[0109] Bonds drawn as solid and dotted lines represent bonds that may be either single or double bonds, where chemically possible. For example, the bond drawn below may be a single or double bond. [ka]

[0110] When a moiety is substituted, it can be substituted at any position on the moiety, provided that it is chemically feasible and consistent with valence requirements. The moiety can be substituted with one or more substituents, for example, 1, 2, 3, or 4 substituents; optionally, 1 or 2 substituents on a group. When there are two or more substituents, the substituents can be the same or different.

[0111] Substituents are present only at chemically possible positions, and one skilled in the art can determine (experimentally or theoretically) without undue effort which substitutions are chemically possible and which substitutions are not possible.

[0112] Ortho, meta, and para substitution are terms well understood in the art. For the avoidance of doubt, "ortho" substitution refers to a substitution pattern in which, in the case of a single group (e.g., a fluoro group in the example below), adjacent carbons bear substituents; [ka] Other positions on the molecule are indicated by bonds ending in . [ka]

[0113] A "meta" substitution is a substitution pattern in which two substituents are one carbon away from each other, i.e., there is one carbon atom between the substituted carbons. In other words, the substituent is on a second atom away from an atom bearing another substituent. For example, the following group is meta-substituted: [ka]

[0114] "Para" substitution is a substitution pattern in which two substituents are two carbon atoms apart 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 an atom bearing another substituent. For example, the following group is para-substituted: [ka]

[0115] Throughout this specification, disclosure of compounds also encompasses pharmaceutically acceptable salts, solvates, and stereoisomers thereof.

[0116] If a compound has a stereocenter, both the (R) and (S) stereoisomers are contemplated by the present invention, and mixtures of stereoisomers or racemic mixtures are also contemplated by the present application. If a compound of the present invention has more than one stereoisomer, any combination of the (R) and (S) stereoisomers is contemplated. Combinations of the (R) and (S) stereoisomers may result in diastereomeric mixtures or single diastereoisomers. The compounds of the present invention may exist as a single stereoisomer or as a mixture of stereoisomers, such as racemic mixtures and other enantiomeric mixtures, and diastereomeric mixtures. If the mixture is a mixture of enantiomers, the enantiomeric excess may be any of those disclosed above. If the compound is a single stereoisomer, the compound may contain other diastereoisomers or enantiomers as impurities. Thus, a single stereoisomer does not necessarily have 100% enantiomeric excess (ee) or diastereomeric excess (de), but may have an ee or de of at least 85%, at least 60%, or less. For example, the ee or de can be 90% or greater, 90% or greater, 80% or greater, 70% or greater, 60% or greater, 50% or greater, 40% or greater, 30% or greater, 20% or greater, or 10% or greater.

[0117] 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. The present invention also contemplates solvates of the compounds. These may be hydrates or other solvate forms of the compounds.

[0118] Suitable acid addition salts are formed from acids which form non-toxic salts, examples of which include acetate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate / sulfate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hybenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, methionine, methylpropional ... Salts include nitrate, methylsulfate, naphthylate, 1,5-naphthalenedisulfonate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrogenphosphate, saccharate, stearate, succinate, tartrate, tosylate and trifluoroacetate.

[0119] Suitable base salts are formed from bases that form non-toxic salts. Examples include aluminum salt, arginine salt, benzathine salt, calcium salt, choline salt, diethylamine salt, diolamine salt, glycine salt, lysine salt, magnesium salt, meglumine salt, olamine salt, potassium salt, sodium salt, tromethamine salt, and zinc salt. Hemisalts of acids and bases, such as hemisulfate salts and hemicalcium salts, can also be formed. For a general review of suitable salts, see Stahl and Wermuth, "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" (Wiley-VCH, Weinheim, Germany, 2002).

[0120] Pharmaceutically acceptable salts of compounds of formula (I) may be prepared by one or more of three methods: (i) by reacting a compound of the invention with a desired acid or base; (ii) by removing an acid- or base-labile protecting group from a suitable precursor of a compound of the invention, or by ring-opening a suitable cyclic precursor, such as a lactone or lactam, with a desired acid or base; or (iii) By converting one salt of a compound of the invention into another salt by reaction with an appropriate acid or base or using a suitable ion exchange column.

[0121] All three reactions are typically carried out in solution. The resulting salts can be precipitated and recovered by filtration or by evaporation of the solvent. The degree of ionization in the resulting salts can vary from completely ionized to almost non-ionized.

[0122] The compound of the present invention can exist in both non-solvated and solvated form.The term "solvate" is used herein to describe the molecular complex that comprises the compound of the present invention and one or more stoichiometric amounts of pharmaceutically acceptable solvent molecules, such as ethanol.The term "hydrate" is used when the solvent is water.

[0123] In contrast to the solvates, the scope of the present invention includes complexes such as clathrates and drug-host inclusion complexes, in which the drug and host are present in stoichiometric or non-stoichiometric amounts. Also included are complexes of drugs 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).

[0124] Hereinafter all references to compounds of any formula include references to salts, solvates and complexes thereof and to solvates and complexes of salts thereof.

[0125] The compounds of the present invention include compounds of the various formulas defined herein (including all polymorphs and crystalline habits thereof), prodrugs thereof, and isomers (including optical isomers, geometric isomers, and tautomers) thereof as defined below, as well as isotopically labeled compounds of the present invention.

[0126] The present invention also includes all pharmaceutically acceptable isotopically labeled compounds of the present invention in which 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.

[0127] Examples of isotopes suitable for inclusion in compounds of the invention include hydrogen, e.g. 2 H and 3 H, carbon, e.g. 11 C. 13 C and 14 C, chlorine, e.g. 36 Cl, fluorine, e.g. 18 F, iodine, e.g. 123 I and 125 I, nitrogen, e.g. 13 N and 15 N, oxygen, e.g. 15 O. 17 O and 18 O, phosphorus, e.g. 32 P, and sulfur, e.g. 35 Examples include isotopes of S.

[0128] Certain isotopically labeled compounds, for example those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. The radioactive isotope tritium, i.e. 3 H, and carbon-14, i.e. 14 C is particularly useful for this purpose in view of its ease of incorporation and ready preparation of detection means.

[0129] Deuterium, i.e. 2Substitution with heavier isotopes, such as H, may offer therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and therefore may be preferable in some situations.

[0130] Before purification, the compounds of the present invention may exist as a mixture of enantiomers depending on the synthetic procedures used. Enantiomers can be separated by conventional techniques known in the art. Thus, the present invention encompasses individual enantiomers and mixtures thereof.

[0131] For some steps in the process for preparing the compounds of the present invention, it may be necessary to protect potentially reactive functional groups where reaction is not desired, and subsequently cleave the protecting group. In such cases, any suitable protecting radical may be used. In particular, protection and deprotection methods such as those described by TW GREENE (Protective Groups in Organic Synthesis, A. Wiley-Interscience Publication, 1981) or PJ Kocienski (Protecting groups, Georg Thieme Verlag, 1994) may be used. All of the above reactions and the preparation of novel starting materials used in the aforementioned methods are conventional, and suitable reagents and reaction conditions for their implementation or preparation, as well as procedures for isolating the desired products, are well known to those skilled in the art with reference to literature precedents and the examples and preparations herein.

[0132] Additionally, the compounds of the present invention and intermediates for their preparation may be purified according to various well-known methods, such as crystallization and chromatography.

[0133] One or more compounds of the invention may be combined with one or more pharmaceutical agents, such as anti-inflammatory agents, anti-fibrotic agents, chemotherapeutic agents, anti-cancer agents, immunosuppressants, anti-tumor vaccines, cytokine therapy, or tyrosine kinase inhibitors, for the treatment of conditions modulated by inhibition of the DDR, such as fibrotic diseases, autoimmune, inflammatory fibrotic conditions, inflammatory conditions, central nervous system disorders, or cancer.

[0134] The compounds for use in the method of treatment or treatment of renal conditions, hepatic conditions, inflammatory conditions, cardiovascular conditions, acute and chronic organ transplant rejection, fibrotic diseases and cancer as defined above may be applied as a sole therapy or may be in combination therapy with further active substances.

[0135] The compound is for use in the method or treatment of renal conditions, liver conditions, inflammatory conditions, cardiovascular conditions, acute and chronic organ transplant rejection, fibrotic diseases and cancer. The additional active substance can be one or more active substances used to treat the conditions treated by the compound of the present invention and the additional active substance. The additional active substance can include one or more of the following active substances: (i) steroids, such as corticosteroids, e.g., glucocorticoids and mineralocorticoids, e.g., alclometasone, alclometasone propionate, aldosterone, amcinonide, beclomethasone, beclomethasone propionate, betamethasone, betamethasone propionate, betamethasone sodium phosphate, betamethasone valerate, budesonide, clobetasone, clobetasone butyrate, clobetasol propionate, cloprendonol, cortisone, cortisone acetate, cortivazol, deoxycortone, desonide, desoximetasone, dexamethasone, dexamethasone sodium phosphate, dexamethasone isonicotinate ter, difluorocortolone, fluclorone, flumethasone, flunisolide, fluocinolone, fluocinolone acetonide, fluocinonide, fluocortin butyl, fluorocortisone, fluorocortolone, fluocortolone caproate, fluocortolone pivalate, fluorometholone, fluprednidene, fluprednidene acetate, flurandrenolone, fluticasone, fluticasone propionate, halcinonide, hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone aceponate, hydrocortisone buteprate, hydrocortisone valerate, icometasone, icometasone embutate, meprednisone, methylprednisolone, mometasone Paramethasone, mometasone furoate monohydrate, prednicarbate, prednisolone, prednisone, tixocortol, tixocortol pivalate, triamcinolone, triamcinolone acetonide, triamcinolone alcohol, and pharmaceutically acceptable derivatives of each. Combinations of steroids may be used, for example, a combination of two or more steroids mentioned in this paragraph; (ii) TNF inhibitors, such as etanercept; monoclonal antibodies (e.g., infliximab (Remicade), adalimumab (Humira), certolizumab pegol (Cimzia), golimumab (Simponi)); fusion proteins (e.g., etanercept (Enbrel)); and 5-HT 2Aagonists (e.g., 2,5-dimethoxy-4-iodoamphetamine, TCB-2, lysergic acid diethylamide (LSD), lysergic acid dimethylazetidide); (iii) anti-inflammatory drugs, such as nonsteroidal anti-inflammatory drugs; (iv) dihydrofolate reductase inhibitors / antifolates, such as methotrexate, trimethoprim, brodimoprim, tetroxoprim, iclaprim, pemetrexed, ralitrexed, and pralatrexate; and (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), casokinins, lactokines, and lactopeptides. (vi) Antifibrotic agents, such as 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), factor Xa inhibitors (e.g., apixaban, rivaroxaban), PGDH inhibitors, anti-αvβ6 monoclonal antibodies (e.g., BG00011), anti-CTGF monoclonal antibodies (e.g., FG-3019), PAR1 inhibitors, Nox4 inhibitors, and PAI-1 inhibitors.

[0136] Methods of treating cancer or compounds for use in the treatment may include, in addition to the compounds of the present invention, conventional surgery or radiation therapy or chemotherapy. Such chemotherapy may include one or more of the following categories of anti-tumor agents: (i) antiproliferative / antineoplastic agents and combinations thereof, such as alkylating agents (e.g., cisplatin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, uracil mustard, bendamustine, melphalan, chlorambucil, chlormethine, busulfan, temozolamide, nitrosoureas, ifosamide, melphalan, pipobroman, triethylene-melamine, triethylenethiazolinone, methylparaben ... opioids, carmustine, lomustine, streptozocin, and dacarbazine; antimetabolites (e.g., gemcitabine and antifolates, e.g., fluoropyrimidines, e.g., 5-fluorouracil and tegafur, raltitrexed, methotrexate, pemetrexed, cytosine arabinoside, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, pentostatin, and gemcitabine) vinorelbine and hydroxyurea); antibiotics (e.g., anthracyclines, such as adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin, and mithramycin); mitotic inhibitors (e.g., vinca alkaloids, such as vincristine, vinblastine, vindesine, and vinorelbine, and taxoids, such as taxol and taxotere, and polo kinase 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, ara-C, paclitaxel (taxol TM), nab-paclitaxel, docetaxel, mithramycin, deoxycoformycin, mitomycin-C, L-asparaginase, interferons (especially IFN-a), etoposide, and teniposide; (ii) Cytostatics, such as antiestrogens (e.g., tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene, and iodoxifene), antiandrogens (e.g., bicalutamide, flutamide, nilutamide, and cyproterone acetate), LHRH antagonists or agonists (e.g., goserelin, leuprorelin, and buserelin), progestogens (e.g., megestrol acetate), aromatase inhibitors (e.g., anastrozole, letrozole, vorazole, and exemestane), and 5α-reductase inhibitors, such as finasteride; and navelbene, CPT-II, anastrozole, letrazole, capecitabine, reloxafme, cyclophosphamide, ifosamide, and droloxafme; (iii) anti-invasive agents, such as dasatinib and bosutinib (SKI-606), and metalloproteinase inhibitors, inhibitors of urokinase plasminogen activator receptor function, or antibodies against heparanase; (iv) inhibitors of growth factor function: for example, growth factor antibodies and growth factor receptor antibodies, such as the anti-erbB2 antibody trastuzumab (Herceptin TM), the anti-EGFR antibody panitumumab, the anti-erbB1 antibody cetuximab, tyrosine kinase inhibitors, such as inhibitors of the epidermal growth factor family (e.g., EGFR family tyrosine kinase inhibitors, e.g., gefitinib, erlotinib, 6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)-quinazolin-4-amine (CI 1033), erbB2 tyrosine kinase inhibitors, e.g., lapatinib), and antibodies against costimulatory molecules, e.g., CTLA-4, 4-1BB and PD-1, or antibodies against cytokines (IL-10, TGF-β); inhibitors of the hepatocyte growth factor family; inhibitors of the insulin growth factor family; modulators of protein regulators of cell apoptosis (e.g., Bcl-2 inhibitors); inhibitors of the platelet-derived growth factor family, e.g., imatinib and / or nilotinib (AMN107); inhibitors of serine / threonine kinases (e.g., Ras / Raf signaling inhibitors, such as farnesyltransferase inhibitors, e.g., sorafenib, tipifarnib, and lonafarnib), inhibitors of cell signaling via 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; (v) Antiangiogenic agents, such as those that inhibit the effects of vascular endothelial growth factor, e.g., 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; (vi) gene therapy approaches, including approaches to replace abnormal genes such as, for example, abnormal p53 or abnormal BRCA1 or BRCA2; (vii) immunotherapeutic approaches, such as antibody therapies, such as alemtuzumab, rituximab, ibritumomab tiuxetan (Zevalin®) and ofatumumab; interferons, such as interferon alpha; interleukins, such as IL-2 (aldesleukin); interleukin inhibitors, such as IRAK4 inhibitors; cancer vaccines, such as preventative and therapeutic vaccines, for example HPV vaccines, such as Gardasil, Cervarix, Oncophage and Sipuleucel-T (Provenge); gp100; dendritic cell-based vaccines (e.g., Ad.p53 DC); and toll-like receptor modulators, such as TLR-7 or TLR-9 agonists; and (viii) Cytotoxic agents, such as fludarabine, cladribine, pentostatin, TM ); (ix) steroids, such as corticosteroids, for example glucocorticoids and mineralocorticoids, for example alclometasone, alclometasone propionate, aldosterone, amcinonide, beclomethasone, beclomethasone propionate, betamethasone, betamethasone propionate, betamethasone sodium phosphate, betamethasone valerate, budesonide, clobetasone, clobetasone butyrate, clobetasol propionate, cloprendonol, cortisone, cortisone acetate, cortivazol, deoxycortone, desonide, desoximetasone, dexamethasone, dexamethasone sodium phosphate, dexamethasone isonicotinate ter, difluorocortolone, fluclorone, flumethasone, flunisolide, fluocinolone, fluocinolone acetonide, fluocinonide, fluocortin butyl, fluorocortisone, fluorocortolone, fluocortolone caproate, fluocortolone pivalate, fluorometholone, fluprednidene, fluprednidene acetate, flurandrenolone, fluticasone, fluticasone propionate, halcinonide, hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone aceponate, hydrocortisone buteprate, hydrocortisone valerate, icometasone, icometasone embutate, meprednisone, methylprednisolone, mometasone Paramethasone, mometasone furoate monohydrate, prednicarbate, prednisolone, prednisone, tixocortol, tixocortol pivalate, triamcinolone, triamcinolone acetonide, triamcinolone alcohol, and pharmaceutically acceptable derivatives of each. Combinations of steroids may be used, for example, a combination of two or more steroids mentioned in this paragraph; (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); (xii) Chimeric antigen receptors, anticancer vaccines and arginase inhibitors.

[0137] Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate administration of the individual components of treatment. Such combination products utilize the compounds of this invention within the therapeutically effective dosage range set forth above and the other pharmaceutically active agent(s) within their approved dosage range.

[0138] The compound of the present invention can exist in a single crystalline form or a mixture of crystalline forms, or can be amorphous.Therefore, the compound of the present invention intended for pharmaceutical use can be administered as crystalline or amorphous product.They can be obtained as solid plug, powder or film by methods such as precipitation, crystallization, freeze-drying or spray-drying or evaporative drying.Microwave or radio frequency drying can be used for this purpose.

[0139] For the compounds of the present invention described above, the amount to be administered will naturally vary depending on the compound used, the mode of administration, the desired treatment, and the disorder being treated. For example, when the compounds of the present invention are administered orally, the daily dosage of the compounds of the present invention can range from 0.01 micrograms per kilogram of body weight (μg / kg) to 100 milligrams per kilogram of body weight (mg / kg).

[0140] The compound of the present invention or a pharmaceutically acceptable salt thereof may be used by itself, but is generally administered in the form of a pharmaceutical composition in which the compound of the present invention or a pharmaceutically acceptable salt thereof is combined with a pharmaceutically acceptable adjuvant, diluent or carrier. Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described, for example, in "Pharmaceuticals - The Science of Dosage Form Designs", ME Aulton, Churchill Livingstone, 1988.

[0141] Depending on the mode of administration of the compounds of the present invention, pharmaceutical compositions used to administer the compounds of the present invention preferably contain 0.05 to 99% w (weight percent) of the compounds of the present invention, more preferably 0.05 to 80% w of the compounds of the present invention, even more preferably 0.10 to 70% w of the compounds of the present invention, and even more preferably 0.10 to 50% w of the compounds of the present invention, all weight percentages being based on the total composition.

[0142] Pharmaceutical compositions may be administered locally (e.g., to the skin), for example, in the form of creams, gels, lotions, solutions, suspensions, or systemically, for example, by oral administration in the form of tablets, capsules, syrups, powders, or granules; or parenterally in the form of sterile solutions, suspensions, or emulsions for injection (including intravenous, subcutaneous, intramuscular, intravascular, or infusion); by rectal administration in the form of suppositories; or by inhalation in the form of an aerosol.

[0143] For oral administration, the compound of the present invention can be mixed with adjuvants or carriers such as lactose, saccharose, sorbitol, mannitol; starches such as potato starch, corn starch or amylopectin; cellulose derivatives; binders such as gelatin or polyvinylpyrrolidone; 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 above can be coated with concentrated sugar solution, which can contain, for example, gum arabic, gelatin, talc and titanium dioxide.Alternatively, tablets can be coated with suitable polymers dissolved in easily volatile organic solvents.

[0144] For the preparation of soft gelatin capsules, the compounds of the present invention can be mixed with, for example, vegetable oil or polyethylene glycol.Hard gelatin capsules can contain granules of the compounds using any of the additives mentioned above for tablets.Also, liquid or semi-solid forms of the compounds of the present invention can be filled into hard gelatin capsules.Liquid preparations for oral administration can be in the form of syrups or suspensions, for example, solutions containing the compounds of the present invention, with the balance being a mixture of sugar, ethanol, water, glycerol, and propylene glycol.If desired, such liquid preparations can contain colorants, flavors, sweeteners (e.g., saccharin), preservatives, and / or carboxymethylcellulose as a thickener, or other additives known to those skilled in the art.

[0145] For intravenous (parenteral) administration, the compounds of the present invention may be administered as a sterile aqueous or oily solution.

[0146] The size of a dose of a compound of the invention for therapeutic purposes will, of course, vary according to the nature and severity of the condition, the age and sex of the animal or patient, and the route of administration, in accordance with well-known principles of medicine.

[0147] Dosage levels, frequency of administration and duration of treatment of the compounds of the invention are expected to vary depending on the formulation and clinical indication, age and coexisting medical conditions of the patient.

[0148] Throughout this description and the claims, the words "comprise" and "contain" and variations thereof mean "including, but not limited to," and are not intended to (and do not) exclude other moieties, adjuncts, components, integers, or steps. Throughout this description and the claims, the singular encompasses the plural unless the context requires otherwise. In particular, where the indefinite article is used, it should be understood that the specification contemplates the plural as well as the singular, unless the context requires otherwise.

[0149] It should be understood that any feature, integer, property, compound, chemical moiety, or group described in connection with a particular aspect, embodiment, or example of the invention is applicable to any other aspect, embodiment, or example described herein, unless inconsistent. All features disclosed in this specification (including any accompanying claims, abstract, and drawings), and / or all steps of the disclosed methods or processes, may be combined in any combination, except combinations in which at least some of the features and / or steps are mutually exclusive. The invention is not limited to the details of the foregoing embodiments. The invention extends to any novel or any novel combination of features disclosed in this specification (including any accompanying claims, abstract, and drawings), or any novel or novel combination of steps of any disclosed methods or processes.

[0150] The reader's attention is drawn to all articles and documents related to this application that are filed contemporaneously or previously hereto and that are open to public inspection herewith, and the contents of all such articles and documents are incorporated herein by reference. [Example]

[0151] Compounds of the invention may be prepared according to or in analogy with general schemes 1 to 4. Alternatively, compounds of the invention may be prepared according to or in analogy with examples 1 to 105.

[0152] Examples and Synthesis (Experimental Procedure) Solvents, reagents, and starting materials were purchased from commercial suppliers and used as received unless otherwise noted. All reactions were performed at room temperature unless otherwise noted. Compound identity and purity were confirmed by LCMS UV analysis using a Waters Acquity SQ Detector 2 (ACQ-SQD2#LCA081). The diode array detector wavelength was set to acquire spectra at 254 nM, and MS was in positive and negative electrospray mode (m / z: 150–800). 2 μL aliquots were sequentially injected onto a guard column (0.2 μm × 2 mm filter) and a UPLC column (C18, 50 × 2.1 mm, <2 μm) maintained at 40 °C. Samples were eluted at a flow rate of 0.6 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) according to the gradients summarized in Table 1 below (Methods 1 and 2). Retention times (RT) are shown in minutes. The following methods were also used throughout the experimental section, with gradients detailed in Table 1. Method 3 used a Shimadzu 2020 series spectrometer equipped with a binary pump and a diode array detector (acquisition wavelengths of 214 and 254 nm), and MS was performed in positive and negative electrospray mode (m / z: 100-900). A 2 μL aliquot was injected onto an Agilent Poroshell 120 EC-C18 column (2.7 μm, 4.6 × 50 mm) maintained at 35°C and eluted at 1.0 ml / min with 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 used an Agilent Technologies 1290 Series spectrometer equipped with a binary pump and a diode array detector (acquisition wavelengths of 214 and 254 nm), and MS was performed in positive electrospray mode (m / z: 70–1000). Aliquots of 2 μL were injected onto an Agilent Eclipse Plus RRHD C18 column (1.8 μm, 3.0 × 50 mm) maintained at 40°C and eluted at 0.8 ml / min with a mobile phase consisting of A: 0.05% formic acid in water, B: 0.05% formic acid in ACN (v / v). [Table 1]

[0153] NMR was also used to characterize the final compounds. NMR spectra were obtained on a Bruker AVIII 400 Nanobay equipped with a 5 mm BBFO probe. Compound Rf values ​​were measured on silica thin-layer chromatography (TLC) plates, if desired. Compound purification was performed by flash column silica chromatography or preparative LCMS. LCMS purification was performed using a Waters 3100 mass detector equipped with a Waters 2489 UV / Vis detector in positive and negative electrospray mode (m / z: 150-800). XBridge NMR was performed 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) according to the gradient summarized in Table 1 below. TM The sample was eluted on a prep C18 5 μM OBD 19×100 mm column at a flow rate of 20 mL / min. [Table 2]

[0154] (General Routes and Schemes) [ka] General Scheme 1 Compounds of formula (I) can be prepared from intermediates represented by vi in ​​General Scheme 1. In step 1, an ortho-fluoronitroaryl compound undergoes a nucleophilic substitution reaction with an aryl or heteroaryl amine (where A represents a halogen, such as Cl, Br, or I, capable of participating in a metal-catalyzed cross-coupling reaction, e.g., a Suzuki or Stille reaction), in the presence of a base, e.g., sodium hydride, to give compounds of structure i. In step 2, the nitro group of i can be reduced with a transition metal catalyst in the presence of hydrogen gas or another hydrogen source, e.g., ammonium chloride, to give compounds of structure ii. In step 3, reaction with a carbonyl equivalent (e.g., CDI) gives cyclized products represented by iii. In step 4, the free NH of iii is reacted with an appropriate α-haloester (where A represents a halogen, e.g., Br, and OAlk represents an alkoxy group, e.g., ethoxide), followed by hydrolysis to the corresponding carboxylic acid using KOH or LiOH under basic conditions in step 5 to give compounds of structure v. In step 6, reaction with an appropriate amine using a carboxylic acid activating reagent such as HATU and a base such as DIPEA provides intermediates represented by vi.

[0155] [ka] General Scheme 2 Compounds of Formula I can be synthesized from intermediates of general structure vi by two routes, as described in General Scheme 2. According to Step 1a, vi (where A represents a halogen, e.g., Br, or another leaving group capable of participating in a metal-catalyzed cross-coupling reaction, e.g., triflate) undergoes transition metal-catalyzed cross-coupling with an azaindazole of structure ix (where B is a boronic acid, boronic ester, or stannyl group (trialkyltin) capable of participating in a Suzuki or Stille-type reaction with a compound of structure vi). As an example, A can be a boronic acid pinacol ester and B can be a bromide, and these groups undergo a Suzuki reaction catalyzed by Pd(dppf)Cl·DCM in the presence of KOAc in Step 1a to give compounds of Formula I. Alternatively, according to step 1, intermediates of structure vi can be converted to boronic esters or stannanes of formula vii by reaction with bis(pinacolato)diboron or tributyltin chloride, respectively, where B is boric acid, a borate ester, or a stannyl group (trialkyltin), which then undergo a Suzuki or Stille reaction in step 2 with an azaindazole of structure viii, where A is a halogen, such as Br, Cl, or I, to provide compounds of formula (I).

[0156] [ka] General Scheme 3 Compounds of formula (I) can also be obtained by rearranging the steps from General Schemes 1 and 2, as shown in General Scheme 3. The definitions of the groups A, B, and OAlk in the structures shown in General Scheme 3 are the same as those described for General Schemes 1 and 2. In step 1, intermediates of structure iv undergo a metal-catalyzed cross-coupling reaction, such as a Suzuki or Stille reaction, with a boronic ester or stannane derivative of an azaindazole represented by ix. In step 2, the cross-coupling product (xi) undergoes base-mediated ester hydrolysis as previously described, followed by amide coupling in step 3 to afford compounds of formula (I). Alternatively, the cross-coupling partners can be reversed by converting the halide or triflate iv to the corresponding boronic ester or stannane in step 1a, which is reacted with a haloazaindazole of structure viii in step 2b to afford intermediates of structure xi.

[0157] [ka] General Scheme 4 General Scheme 4 outlines an alternative route for preparing intermediates of structure iv, which can then be converted to intermediate vi (General Scheme 1), which can then be converted to compounds of Formula (I) by methods described in General Scheme 2. In Step 1, an 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 an appropriate α-haloester. In Step 3, the Boc protecting group of xv is removed using TFA, allowing for Chan-Lam-type coupling of xvi with an appropriate arylboronic acid in Step 4 using copper(II) acetate as a catalyst and air as the oxygen source to give intermediates of structure iv.

[0158] The azaindazole substituent R of the compound of formula I 8bIn General Schemes 2, 3, and 4, where R is H, steps 1a and 2 (General Scheme 2) and steps 1 and 1a (General Scheme 3) are 8b This can be done by using a 2-tetrahydropyran group as a protecting group at the R 8b A final deprotection step may be required to form compounds where is H. The deprotection step can be carried out by reaction with hydrogen chloride in an organic solvent such as 1,4-dioxane. Additionally, where experimental procedures are not described below for the synthesis of intermediates, the azaindazole derivatives depicted in general Schemes 1-4 were prepared by methods previously described in the open scientific literature.

[0159] (Synthesis of intermediates) Synthesis of Intermediate I-4, Ethyl 2-[3-(4-bromophenyl)-2-oxobenzimidazol-1-yl]acetate [ka] Scheme 1

[0160] Step A. Synthesis 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 (900 mg, 22.5 mmol) dispersed in mineral oil, and the reaction mixture was stirred at room temperature for 2 hours. A solution of (Boc)O (4.9 g, 22 mmol) in DMF (10 mL) was added dropwise. The reaction mixture was stirred at room temperature for 16 hours and then evaporated to dryness. The residue was diluted with ethyl acetate and washed with saturated aqueous NHCl (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 over NaSO 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): 1.73 min, m / z 233.2 [MH] - . 1 H NMR (400 MHz, DMSO-d6):δ 11.24 (s br , 1H), 7.64 (ddd, 0.5, 1.2, 8.0 Hz, 1H), 7.12 (dt, J = 1.2, 7.6 Hz, 1H), 7.05 (dt, J = 1.4, 7.8 Hz, 1H), 6.99 (ddd, J = 0.5, 1.4, 7.7 Hz, 1H), 1.59 (s, 9H) ppm.

[0161] Step B. Synthesis of Intermediate I-2, tert-butyl 3-(2-ethoxy-2-oxo-ethyl)-2-oxobenzimidazole-1-carboxylate: A mixture of CsCO (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 HO (60 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were dried over NaSO, and the solvent was removed in vacuo. The crude product was dry-loaded onto silica and purified by normal-phase flash chromatography (SiO, 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 (ES) + , Method 2): 1.90 min, m / z 321.1 [M+H] + . 1H NMR (400 MHz, CDCl3):δ 7.85 (dd, J = 1.7, 7.5 Hz, 1H), 7.18 (dt, J = 1.5, 7.6 Hz, 1H), 7.14 (dt, J = 1.6, 7.7 Hz), 6.85 (dd, J = 1.3, 7.7 Hz, 1H), 4.59 (s, 2H), 4.23 (q, J = 7.15, 2H), 1.67 (s, 9H), 1.26 (t, J = 7.14 Hz, 3H) ppm.

[0162] 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 hours. The reaction was quenched with saturated aqueous NaCO (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): 1.51 min, m / z 221.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6):δ 10.95 (s, 1H), 7.06 - 7.11 (m, 1H), 6.96 - 7.03 (m, 3H), 4.66 (s, 2H), 4.15 (q, J = 7.1 Hz, 2H), 1.21 (t, J = 7.1 Hz, 3H) ppm.

[0163] Step D. Synthesis of Intermediate I-4, Ethyl 2-[3-(4-bromophenyl)-2-oxobenzimidazol-1-yl]acetate: In a round-bottom flask equipped with a condenser open to air, 4-bromobenzeneboronic acid (4.1 g, 20 mmol), ethyl 2-(2-oxo-3H-benzimidazol-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 HO (50 mL) and saturated aqueous NHCl (50 mL). The aqueous layer was extracted with DCM (3 × 50 mL). The combined organic layers were dried over NaSO and concentrated in vacuo. The crude product was dry-loaded onto silica and purified by phase flash chromatography (25 g SiO, 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 (ES + , Method 2): 1.88 min, m / z 375.0 / 376.9 [M+H] + . 1 H NMR (400 MHz, DMSO-d6):δ 7.79 (td, J = 2.5, 9.6, 2H), 7.54 (td, J = 2.5, 9.6, 2H), 7.30 (d, J = 7.6 Hz, 1H), 7.07 - 7.20 (m, 3H), 4.82 (s, 2H), 4.19 (q, J = 7.1 Hz, 2H), 1.24 (t, J = 7.1 Hz, 3H) ppm.

[0164] 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 HO and slowly acidified to pH 2-3 by dropwise addition of 1 M HCl, giving 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): 1.63 min, m / z 346.9 / 348.9 [M+H] + . 1 H NMR (400 MHz, DMSO-d6):δ 13.19 (s, 1H), 7.78 (td, J = 2.5, 9.7 Hz, 2H), 7.54 (td, J = 2.6, 9.7, 2H), 7.29 (d br , J = 7.6 Hz, 1H), 7.06 - 7.18 (m, 3H), 4.69 (s, 2H) ppm.

[0165] Step F. Synthesis of Intermediate I-6, 2-[3-(4-bromophenyl)-2-oxobenzimidazol-1-yl]-N-(2,2,2-trifluoroethyl)acetamide: To a stirred solution of 2-[3-(4-bromophenyl)-2-oxobenzimidazol-1-yl]acetic acid (Intermediate I-5, 1.7 g, 4.9 mmol) and trifluoroethylamine (0.5 mL, 6 mmol) in DMF (30 mL), HATU (2.2 g, 6 mmol) and DIPEA (1.7 mL, 9.8 mmol) were added, and the mixture was stirred at room temperature for 2 hours. The mixture was poured into brine (50 mL) and DCM (50 mL). The layers were separated, the aqueous layer was extracted with DCM, and the combined organic layers were washed with saturated aqueous NH4Cl (3 × 30 mL) and brine, dried over Na2SO4, and concentrated in vacuo. The crude product was purified by flash chromatography (40 g SiO, 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): 1.86 min, m / z 428.0 / 429.9 [M+H] + . 1 H NMR (400 MHz, DMSO-d6):δ 8.97 (t, J = 6.3 Hz, 1H), 7.79 (td, J = 2.5, 9.6 Hz, 2H), 7.55 (td, J = 2.5, 9.6 Hz, 2H), 7.06 -7.17 (m, 4H), 4.66 (s, 2H), 3.97 (dq, J = 6.3, 9.8 Hz, 2H) ppm.

[0166] Intermediates synthesized following the same procedure as intermediate I-6 (Scheme 1), substituting 4-bromobenzeneboronic acid in step D and / or trifluoroethylamine in step F for the indicated building blocks, are listed in Table 3. [Table 3]

[0167] Synthesis of Intermediate I-11, 2-[3-(4-bromo-3-fluorophenyl)-2-oxobenzimidazol-1-yl]-N-(2,2,2-trifluoroethyl)acetamide [ka] Scheme 2

[0168] 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.HO (1.31 g, 31.2 mmol) in THF (10 mL) and HO (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 NaSO, 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): 4.10 min, m / z 193.15 [M+H] + . 1 H NMR (400 MHz, DMSO-d6):δ 10.93 (s, 1H), 7.12 (m c , 1H), 7.06 - 7.01 (m, 2H), 4.59 (s, 2H) ppm.

[0169] Step B. Synthesis of intermediate I-10, 2-(2-oxo-3H-benzimidazol-1-yl)-N-(2,2,2-trifluoroethyl)acetamide: A mixture of 2-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)acetic acid (I-9, 1.00 g, 5.20 mmol), 2,2,2-trifluoroethan-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 NaSO, and concentrated in vacuo to give 2-(2-oxo-3H-benzimidazol-1-yl)-N-(2,2,2-trifluoroethyl)acetamide (Intermediate I-10, 1.00 g, 3.66 mmol, 70% yield). LC-MS (ES + , Method 4): 0.66 min, m / z 274.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 10.90 (s, 1H), 8.90 (t, J = 6.2 Hz, 1H), 7.05 - 6.94 (m, 4H), 4.53 (s, 2H), 3.96 (dq, J = 6.3, 9.7 Hz, 2H) ppm.

[0170] 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 ethyl 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), NEt (445 mg, 4.40 mmol), and Cu(OAc) (533 mg, 2.93 mmol) in MeCN (12 mL) was stirred overnight at 25 °C under N. The reaction was concentrated to dryness, and the residue was taken up in EtOAc. The organic layer was washed with saturated aqueous NH4Cl (x2) and brine (x2), 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): 2.033 min, m / z 447.95 [M+H] + . 1 H NMR (400 MHz, DMSO-d6):δ 8.97 (t, J = 6.2 Hz, 1H), 7.95 (t, J = 8.3 Hz, 1H), 7.69 (dd, J = 2.4, 10.0 Hz, 1H), 7.45 (dd, J = 1.7, 8.6 Hz, 1H), 7.23 (d, J = 7.6 Hz, 1H), 7.21 - 7.09 (m, 3H), 4.68 (s, 2H), 3.99 (dq, J = 6.5, 9.8 Hz, 2H) ppm.

[0171] Intermediates synthesized following the same procedure as intermediate I-11 (Scheme 2), substituting (4-bromo-3-fluoro-phenyl)boronic acid for the building blocks described in Step C, are listed in Table 4. [Table 4]

[0172] Synthesis of Intermediate I-18, 2-[3-(4-bromophenyl)-4-methyl-2-oxobenzimidazol-1-yl]-N-(2,2,2-trifluoroethyl)acetamide [ka] Scheme 3

[0173] 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 dry DMF (150 mL) at 0 °C under N. The mixture was stirred at that temperature for 30 minutes, after which 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 NaSO, and concentrated in vacuo. The crude product was purified by flash chromatography (120 g SiO 2 , 1% EtOAc in petroleum ether) to give N-(4-bromophenyl)-2-methyl-6-nitro-aniline (Intermediate I-13, 39.4 g, 86 mmol, 49% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6):δ 8.03 (s, 1H), 7.70 (d, J = 8.3 Hz, 1H), 7.63 (t, J = 7.6 Hz, 1H), 7.54 (d, J = 7.7 Hz, 1H), 7.20 (d, J = 8.8 Hz, 2H), 6.43 (d, J = 8.7 Hz, 2H), 2.09 (s, 3H) ppm.

[0174] 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 NHCl (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): 1.86 min, m / z 277.0 [M+H] + .

[0175] Step C. Synthesis of Intermediate I-15, 3-(4-bromophenyl)-4-methyl-1H-benzimidazol-2-one: A mixture of N-(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 under a N atmosphere for 16 hours. The mixture was diluted with EtOAc (200 mL), washed with water (3 × 100 mL) and brine (100 mL), dried over NaSO, 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): 2.17 min, m / z 303.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6):δ 7.18 (s, 1H), 6.91 (d, J = 8.4 Hz, 2H), 6.55 (d, J = 8.6 Hz, 2H), 6.23 - 6.16 (m, 2H), 6.02 (d, J = 6.8 Hz, 1H), 1.07 (s, 3H) ppm.

[0176] 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 hours. 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 x 200 mL), and the combined organic layers were washed with brine (100 mL), dried over NaSO, and concentrated in vacuo to give ethyl 2-[3-(4-bromophenyl)-4-methyl-2-oxobenzimidazol-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): 2.65 min, m / z 389.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6):δ 7.76 (d, J = 8.6 Hz, 2H), 7.43 (d, J = 8.7 Hz, 2H), 7.13 (d, J = 7.7 Hz, 1H), 7.05 (t, J = 7.8 Hz, 1H), 6.89 (d, J = 7.8 Hz, 1H), 4.78 (s, 2H), 4.19 (q, J = 7.5 Hz, 2H), 1.85 (s, 3H), 1.24 (t, J = 7.5 Hz, 3H) ppm.

[0177] Step E. Synthesis 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·HO (97 mg, 2.32 mmol) in MeOH (2 mL), THF (2 mL), and HO (2 mL) was stirred at room temperature for 2 h. The reaction was treated with 6 M 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 NaSO, 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. UPLC-MS (ES + , Method 2): 2.09 min, m / z 361.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6):δ 7.75 (d, J = 8.6 Hz, 2H), 7.43 (d, J = 8.6 Hz, 2H), 7.12 (d, J = 7.8 Hz, 1H), 7.04 (t, J = 7.8 Hz, 1H), 6.86 (d, J = 7.6 Hz, 1H), 4.67 (s, 2H), 1.84 (s, 3H) ppm.

[0178] Step F. Synthesis of intermediate I-18, 2-[3-(4-bromophenyl)-4-methyl-2-oxobenzimidazol-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-trifluoroethan-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 under vacuum 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): 2.42 min, m / z 442.1 [M+H]. 1 H NMR (400 MHz, DMSO-d6):δ 8.94 (t, J = 6.2 Hz, 1H), 7.76 (d, J = 8.6 Hz, 2H), 7.43 (d, J = 8.6 Hz, 2H), 7.03 (t, J = 7.6 Hz, 1H), 6.99 (d, J = 7.2 Hz, 1H), 6.86 (d, J = 7.2 Hz, 1H), 4.63 (s, 2H), 3.95 (dq, J = 6.4, 16.2 Hz, 2H), 1.84 (s, 3H) ppm.

[0179] Intermediates synthesized following the same procedure as intermediate I-18 (Scheme 3), substituting 2-fluoro-1-methyl-3-nitrobenzene and 4-bromoaniline with the appropriate building blocks for Step A, or 2,2,2-trifluoroethan-1-amine with the appropriate building blocks for Step F, are listed in Table 5. [Table 5-1] [Table 5-2] [Table 5-3] [Table 6] [Table 7] [Table 8]

[0180] Analogous intermediates to intermediate I-16 (Scheme 3) were synthesized following the same synthetic route and procedure, replacing 2-fluoro-1-methyl-3-nitrobenzene and 4-bromoaniline in Step A with the appropriate building blocks. Such intermediates are shown in Table 6. [Table 9-1] [Table 9-2] [Table 9-3]

[0181] Intermediates synthesized according to the same procedure as intermediate iv-1 (Route 1), substituting the indicated building blocks for 3-(5-bromo-2-pyridyl)-4-methyl-1H-benzimidazol-2-one in Step D, and according to the same procedure as iv-4 (Route 4), substituting the indicated building blocks for ethyl 2-(2-oxo-3H-benzimidazol-1-yl)acetate in Step D, are listed in Table 6. [Table 10]

[0182] Synthesis of Intermediate I-31, 2-[3-[4-(1-methylpyrazolo[3,4-c]pyridin-4-yl)phenyl]-2-oxobenzimidazol-1-yl]acetic acid [ka] Scheme 4

[0183] Step A. Synthesis of Intermediate I-28, ethyl 2-[3-(4-bromophenyl)-2-oxobenzimidazol-1-yl]acetate: In a round-bottom flask equipped with a condenser open to air, 4-bromo-benzeneboronic acid (4.1 g, 20 mmol), ethyl 2-(2-oxo-3H-benzimidazol-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 HO (50 mL) and saturated aqueous NHCl (50 mL). The aqueous layer was extracted with DCM (3 × 50 mL). The combined organic layers were dried over NaSO and concentrated in vacuo. The crude product was dry-loaded onto silica and purified by flash chromatography (25 g SiO, 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 (ES + , Method 2): 1.88 min, m / z 375.0 / 376.9 [M+H] + . 1 H NMR (400 MHz, DMSO-d6):δ 7.79 (td, J = 2.5, 9.6, 2H), 7.54 (td, J = 2.5, 9.6, 2H), 7.30 (d, J = 7.6 Hz, 1H), 7.07 - 7.20 (m, 3H), 4.82 (s, 2H), 4.19 (q, J = 7.1 Hz, 2H), 1.24 (t, J = 7.1 Hz, 3H) ppm.

[0184] 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), Pd(dba) (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 N 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 organic layers were combined, dried over MgSO4, and concentrated in vacuo to give 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 (ES) + , Method 4): 4.55 min, m / z 423.3 [M+H] + .

[0185] Step C. Synthesis of Intermediate I-30, Ethyl 2-[3-[4-(1-methylpyrazolo[3,4-c]pyridin-4-yl)phenyl]-2-oxobenzimidazol-1-yl]acetate: Ethyl A degassed mixture of 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)Cl·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 N 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 (ES) + , Method 4): 1.533 min, m / z 428.15 [M+H] + . 1 H NMR (400 MHz, DMSO-d6):δ 9.24 (s, 1H), 8.52 (s, 1H), 8.44 (s, 1H), 8.05 (d, J = 8.4 Hz, 2H), 7.78 (d, J = 8.4 Hz, 2H), 7.34 (dd, J = 1.0, 7.5, 1H), 7.25 (dd, J = 1.0, 7.5 Hz, 1H), 7.20 (dt, J = 1.0, 7.5 Hz, 1H), 7.15 (dt, J = 1.0, 7.5 Hz, 1H), 4.87 (s, 2H), 4.27 (s, 3H), 4.22 (q, J = 7.1 Hz, 2H), 1.26 (t, J = 7.1 Hz, 3) ppm.

[0186] Step D. Synthesis 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 hours. The mixture was concentrated in vacuo, diluted with water, and extracted with ethyl acetate (×3). The combined organic layers were washed with brine, dried over NaSO, 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 (ES + , Method 4): 1.967 min, m / z 400.05 [M+H] + . 1 H NMR (400 MHz, DMSO-d6):δ 9.39 (s, 1H), 8.59 (s, 1H), 8.55 (s, 1H), 8.08 (d, J = 8.6 Hz, 2H), 7.81 (d, J = 8.6 Hz, 2H), 7.34 (d, J = 7.7 Hz, 1H), 7.25 (d, J = 7.7 Hz, 1H), 7.20 (t, J = 7.6 Hz, 1H), 7.15 (t, J = 7.6 Hz, 1H), 4.76 (s, 2H), 4.31 (s, 3H) ppm.

[0187] Synthesis of Intermediate I-34, 2-[4-methyl-3-[4-(1-methylpyrazolo[3,4-c]pyridin-4-yl)phenyl]-2-oxobenzimidazol-1-yl]acetic acid [ka] Scheme 5

[0188] Step A. Synthesis 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: Ethyl A mixture of 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 a N2 atmosphere overnight. The mixture was cooled to room temperature, filtered, concentrated in vacuo, and purified by flash chromatography (SiO, 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 (400 MHz, DMSO-d6):δ 7.84 (d, J = 8.2 Hz, 2H), 7.45 (d, J = 8.2 Hz, 2H), 7.12 (d, J = 7.8 Hz, 1H), 7.04 (t, J = 7.8 Hz, 1H), 6.86 (d, J = 7.8 Hz, 1H), 4.78 (s, 2H), 4.19 (q, J = 7.1 Hz, 2H), 1.81 (s, 3H), 1.35 (s, 12H), 1.24 (t, J = 7.1 Hz, 3H) ppm.

[0189] Step B. Synthesis of intermediate I-33, ethyl 2-[4-methyl-3-[4-(1-methylpyrazolo[3,4-c]pyridin-4-yl)phenyl]-2-oxobenzimidazol-1-yl]acetate: 4-bromo-1-methyl-1H-pyrazolo[3,4-c]pyridine (709 mg, 3.36 mmol), ethyl A mixture of 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 (Intermediate I-32, 2.2 g, 5.04 mmol), Pd(dppf)Cl (245 mg, 0.336 mmol), and KCO (1.39 g, 10.08 mmol) in degassed DMF (15 mL) was stirred at 80 °C under a N atmosphere overnight. The reaction was diluted with EtOAc (200 mL) and washed with water (50 mL × 3). The combined organic layer was washed with brine (100 mL) and dried over NaSO. The mixture was purified by column chromatography (SiO, 0-5% MeOH in DCM) to give ethyl 2-[4-methyl-3-[4-(1-methylpyrazolo[3,4-c]pyridin-4-yl)phenyl]-2-oxo-benzimidazol-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] + . 1 H NMR (400 MHz, DMSO-d6):δ 9.25 (s, 1H), 8.54 (s, 1H), 8.43 (s, 1H), 8.02 (d, J = 8.3 Hz, 2H), 7.64 (d, J = 8.3 Hz, 2H), 7.16 (d, J = 7.8 Hz, 1H), 7.07 (t, J = 7.8 Hz, 1H), 6.90 (d, J = 7.8 Hz, 1H), 4.82 (s, 2H), 4.21 (s, 3H), 4.21 (q, J = 7.1 Hz, 2H), 1.93 (s, 3H), 1.26 (t, J = 7.1 Hz, 3H) ppm.

[0190] Step C. Synthesis 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·HO (202.6 mg, 4.828 mmol) in MeOH (4 mL), THF (4 mL), and HO (4 mL) was stirred at room temperature for 2 hours. The reaction was treated with 1 M 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-benzimidazol-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] + . 1 H NMR (400 MHz, DMSO-d6):δ 9.26 (s, 1H), 8.55 (s, 1H), 8.44 (s, 1H), 8.02 (d, J = 8.3 Hz, 2H), 7.65 (d, J = 8.3 Hz, 2H), 7.16 (d, J = 7.8 Hz, 1H), 7.08 (t, J = 7.8 Hz, 1H), 6.90 (d, J = 7.8 Hz, 1H), 4.72 (s, 2H), 4.29 (s, 3H), 1.94 (s, 3H) ppm.

[0191] Intermediates synthesized following the same procedure as intermediate I-34 (Scheme 5), replacing 2-fluoro-1-methyl-3-nitrobenzene and 4-bromoaniline in Step A of Scheme 3 with the appropriate building blocks for Step A, are listed in Table 7. [Table 11-1] [Table 11-2] [Table 11-3] [Table 12]

[0192] Intermediates I-90 to I-95 were synthesized following the same procedure as intermediate I-95 (Scheme 13, step 6) and are shown in the table below. [Table 13]

[0193] Synthesis of tributyl-(1-methylpyrazolo[3,4-c]pyridin-4-yl)stannane (I-96) [ka] 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 product was purified by flash column chromatography eluting with EtOAc in petroleum ether to give ethyl tributyl-(1-methylpyrazolo[3,4-c]pyridin-4-yl)stannane (6.7 g, 15.9 mmol, 67% yield). LC-MS (ES-API, Aglient-LCMS-01-P2): 2.82 min, m / z 422.1 [M] + . [Table 14]

[0194] Synthesis of potassium trifluoro(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)borate (I-101) [ka] 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 equiv.) in dry THF (100 mL) was cooled to −78 °C, and nBuLi (1.5 equiv., 2.5 M in hexanes) was added dropwise while maintaining the temperature below −70 °C. The reaction mixture was then stirred at −78 °C for 30 min. The reaction was allowed to warm to 0 °C. KHF2 (6.0 equiv.) 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 hours 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].

[0195] (Example) Example 1: 2-[3-[4-(1-methylpyrazolo[3,4-c]pyridin-4-yl)phenyl]-2-oxobenzimidazol-1-yl]-N-(2,2,2-trifluoroethyl)acetamide [ka] Scheme 6

[0196] Step A. Synthesis 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: 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) was purged (3 × vacuum, 3 × N2). After the addition of Pd(dppf)Cl₂·DCM (570 mg, 0.7 mmol), the suspension was again purged (3× vacuum, 3× N₂) and heated to 95 °C under N₂. After 17 h, the mixture was filtered through filter paper. The filter paper was rinsed with EtOAc, and the filtrate was concentrated in vacuo and purified by flash chromatography (SiO₂, 25 g, EtOAc in petroleum ether, 5–95%) 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] + . 1 H NMR (400 MHz, CDCl3):δ 8.00 (d br , J = 8.3 Hz, 2H), 7.56 (d br , J = 8.3 Hz, 2H), 7.11 - 7.24 (m, 4H), 6.83 (t, J = 6.5 Hz, 1H), 4.64 (s, 2H), 3.90 (dq, J = 6.5, 8.9 Hz, 2H), 1.37 (s, 12H) ppm.

[0197] Step B. Example 1, Synthesis of 2-[3-[4-(1-methylpyrazolo[3,4-c]pyridin-4-yl)phenyl]-2-oxobenzimidazol-1-yl]-N-(2,2,2-trifluoroethyl)acetamide: 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 amide (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) was purged (3× vacuum, 3× N₂) and heated to 100 °C under N₂. After 16 h, the mixture was cooled to room temperature and purified by flash chromatography (SiO, 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): 3.07 min, m / z 481.6 [M+H] + . 1 H-NMR (400 MHz, DMSO-d6):δ 9.23 (s, 1H), 9.00 (t, J = 6.3 Hz, 1H), 8.51 (s, 1H), 8.43 (d, J = 0.8 Hz, 1H), 8.05 (td, J = 2.3, 9.0 Hz, 2H), 7.77 (td, J = 2.3, 9.0 Hz, 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, 9.9 Hz, 2H) ppm.

[0198] Table 8 lists examples synthesized according to the same procedure as in Example 1 (Scheme 6), replacing intermediate I-6 with the appropriate building blocks in Step A and 4-bromo-1-methyl-1H-pyrazolo[3,4-c]pyridine with the appropriate building blocks in Step B. [Table 15-1] [Table 15-2] [Table 15-3] [Table 15-4] [Table 15-5] [Table 15-6] [Table 15-7]

[0199] 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 [ka] Scheme 7 A solution of 2-[3-[4-(1-methylpyrazolo[3,4-c]pyridin-4-yl)phenyl]-2-oxo-benzimidazol-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 (x3), washed with brine (x3), dried over Na2SO4, concentrated in vacuo, and purified by prep-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:):1.533 min, m / z 495.10 [M+H] + . 1 H-NMR (400 MHz, DMSO-d6):δ 9.23 (s, 1H), 8.95 (d, J = 8.1 Hz, 1H), 8.52 (s, 1H), 8.44 (s, 1H), 8.05 (d, J = 7.9 Hz, 2H), 7.78 (d, J = 7.9 Hz, 2H), 7.28 - 7.08 (m, 4H), 4.72 - 4.59 (m, 3H), 4.30 (s, 3H), 1.32 (d, J = 6.6 Hz, 3H) ppm.

[0200] Table 9 lists examples synthesized following the same procedure as Example 17 (Scheme 7), substituting intermediate I-31, the amine coupling partner, and the coupling agents EDCI and HOBT with the appropriate building blocks and reagents. [Table 16-1] [Table 16-2]

Table 16-3

Table 16-4

Table 16-5

Table 16-6

Table 16-7

Table 16-8

Table 16-9

Table 16-10

Table 16-11

Table 16-12

Table 16-13

Table 16-14

Table 16-15

Table 16-16

Table 16-17

Table 16-18

[0201] 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 [ka] Scheme 8

[0202] 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)Cl (26 mg, 0.03 mmol), and KCO (147 mg, 1.06 mmol) in degassed 1,4-dioxane (5 mL) and degassed HO (0.5 mL) was stirred at 90 °C under a N atmosphere for 16 h. The mixture was diluted with water and extracted with EtOAc. The organic layer was dried over NaSO, 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): 1.06 min, m / z 551 [M+H] + .

[0203] Step B: Example 41, Synthesis of 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) and 4N HCl (4N HCl, 1.0 mL, 4.0 mmol) in MeOH (1.5 mL) was stirred at room temperature for 1 hour. The mixture was adjusted to pH > 7 with NaHCO (saturated aqueous solution), diluted with water, and extracted with EtOAc. The organic layer was dried over NaSO, 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): 3.68 min, m / z 467.25 [M+H] + . 1 H NMR (400 MHz, DMSO-d6):δ 13.88 (s, 1H), 9.06 (s, 1H), 8.96 (t, J = 6.3 Hz, 1H), 8.44 (s, 1H), 8.43 (s, 1H), 8.01 (d, J = 8.1 Hz, 2H), 7.73 (d, J = 8.1 Hz, 2H), 7.19 (d, J = 7.5 Hz, 1H), 7.16 - 7.03 (m, 3H), 4.66 (s, 2H), 3.95 (dq, J = 6.1, 9.6 Hz, 2H) ppm.

[0204] 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 [ka] Scheme 9

[0205] 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-(tributylstannyl)-1H-pyrazolo[3,4-c]pyridine (420 mg, 0.85 mmol), Pd(PPh) (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 a N 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): 1.44 min, m / z 565.0 [M+H] + .

[0206] 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 4 M HCl (1.5 mL in 1,4-dioxane) was stirred at room temperature for 1 hour. 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): 1.25 min, m / z 481.15 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.08 (s, 1H), 8.98 (t, J = 8.2 Hz, 1H), 8.45 (d, J = 6.3 Hz, 2H), 8.00 (d, J = 8.2 Hz, 2H), 7.62 (d, J = 8.2 Hz, 2H), 7.05-6.98 (m, 2H), 6.86 (d, J = 7.4 Hz, 1H), 4.65 (s, 2H), 3.99-3.95 (m, 2H), 1.90 (s, 3H) ppm.

[0207] Example 47: 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 [ka] Scheme 10

[0208] 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-pyrazin-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(PPh) (86 mg, 0.07 mmol), LiCl (94 mg, 2.22 mmol), and CuI (70 mg, 0.37 mmol) in toluene (10 mL) was stirred overnight at 100 °C under a N atmosphere. 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, concentrated in vacuo, and purified by silica gel column chromatography (100:1 DCM / MeOH to 50:1 DCM / MeOH) to afford 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 (220 mg, 65%) as a yellow solid. LC-MS (ES + , Method 4): 1.60 min, m / z,458.15 [M+H] + .

[0209] 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), LiOH (9.5 mg, 0.23 mmol), THF (3 mL), MeOH (3 mL), and HO (0.5 mL) was stirred at 25 °C for 2 h. The mixture was diluted with HO, and 10% HCl was added until a pH of 1–2 was reached. The resulting precipitate was isolated by filtration and analyzed by LC-MS (ES) to give 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, 85%) as a yellow solid. + , Method 3): 3.183 min, m / z 416.10 [M+H] + .

[0210] 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 silica gel chromatography (50 / 1 dichloromethane / methanol to 20:1 dichloromethane / methanol) to afford 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): 3.46 min, m / z 497.10 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.57 (d, J = 1.4 Hz, 1H), 9.35 (s, 1H), 9.15 (s, 1H), 9.11 (s, 1H), 9.01 (t, J = 6.3 Hz, 1H), 8.76 (s, 1H), 7.12 (t, J = 7.7 Hz, 1H), 7.05 (d, J = 7.8 Hz, 1H), 6.95 (d, J = 7.6 Hz, 1H), 4.69 (s, 2H), 4.28 (s, 3H), 4.03 -3.94F (m, 2H), 2.00 (s, 3H)ppm.

[0211] The following examples (Table 10) were prepared in a similar manner to Example 47 (Scheme 10), substituting I-37 in Step A or trifluoroethylamine in Step C with the appropriate building blocks as indicated in the table. [Table 17-1] [Table 17-2] [Table 17-3] [Table 17-4] [Table 17-5] [Table 17-6]

[0212] 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 [ka] Scheme 11

[0213] Step A: 2-[3-(5-bromopyrimidin-2-yl)-4-methyl-2-oxo-benzimidazol-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)acetate (600 mg, 1.54 mmol) and LiOH.HO (194 mg, 4.62 mmol) in HO / THF (8 mL) was stirred at room temperature for 2 hours. The mixture was concentrated in vacuo, and 1 M HCl was slowly added to adjust the pH to 3. The mixture was diluted with water (50 mL) and washed with EtOAc (100 mL × 3). The combined organic layers were washed with brine (50 mL), dried over NaSO, and concentrated to give 2-[3-(5-bromopyrimidin-2-yl)-4-methyl-2-oxo-benzimidazol-1-yl]acetic acid (440 mg, 79%) as a white solid. LC-MS (ES + , Method 4): 1.13 min, m / z 444 / 446 [M+H] + .

[0214] Step B: 2-[3-(5-Bromopyrimidin-2-yl)-4-methyl-2-oxo-benzimidazol-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-trifluoroethan-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 hours. The mixture was treated with water (50 mL) and filtered to give 2-[3-(5-bromopyrimidin-2-yl)-4-methyl-2-oxo-benzimidazol-1-yl]-N-(2,2,2-trifluoroethyl)acetamide (510 mg, 83%) as a white solid. LC-MS (ES+ , Method 4): 1.31 min, m / z 363 / 365 [M+H] + .

[0215] Step C: 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. 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-(tributylstannyl)-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 a 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-benzimidazol-1-yl]-N-(2,2,2-trifluoroethyl)acetamide as a white solid (Example 66) (10 mg, 8.9%). LC-MS (ES + , Method 3): 3.31 min, m / z 497.25 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 9.51 (s, 2H), 9.33 (s, 1H), 9.03 (t, J = 6.3 Hz, 1H), 8.68 (s, 1H), 8.58 (s, 1H), 7.09 (t, J = 7.8 Hz, 1H), 7.02 (d, J = 7.8 Hz, 1H), 6.92 (d, J = 7.6 Hz, 1H), 4.66 (s, 2H), 4.27 (s, 3H), 4.03-3.94 (m, 2H), 1.88 (s, 3H) ppm.

[0216] Example 68: 2-[4-methyl-2-oxo-3-[6-(1H-pyrazolo[3,4-c]pyridin-4-yl)-3-pyridyl]benzimidazol-1-yl]-N-[(1S)-2,2,2-trifluoro-1-methyl-ethyl]acetamide [ka] Scheme 12

[0217] Step A: Ethyl 2-[4-methyl-2-oxo-3-[6-(1-tetrahydropyran-2-ylpyrazolo[3,4-c]pyridin-4-yl)-3-pyridyl]benzimidazol-1-yl]acetate. A solution of ethyl 2-[3-(6-bromo-3-pyridyl)-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 N overnight. The mixture was diluted with EtOAc (8 mL) and washed with HO (10 mL × 3). The organic layers were washed with EtOAc (15 mL × 3), combined, dried over anhydrous NaSO, 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-pyridyl]benzimidazol-1-yl]acetate (160 mg, 24%) as a yellow solid. LC-MS (ES + , Method 3): 3.95 min, m / z 513.35 [M+H] + .

[0218] Step B: Ethyl 2-[4-methyl-2-oxo-3-[6-(1H-pyrazolo[3,4-c]pyridin-4-yl)-3-pyridyl]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-pyridyl]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 hours. The mixture was concentrated in vacuo and purified by silica gel column chromatography (20 / 1 petroleum ether / EtOAc to 1 / 3 petroleum ether / EtOAc) to give ethyl 2-[4-methyl-2-oxo-3-[6-(1H-pyrazolo[3,4-c]pyridin-4-yl)-3-pyridyl]benzimidazol-1-yl]acetate (130 mg, 96%). LC-MS (ES + , Method 3): 3.12 min, m / z 429.25 [M+H] + .

[0219] Step C: 2-[4-methyl-2-oxo-3-[6-(1H-pyrazolo[3,4-c]pyridin-4-yl)-3-pyridyl]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-pyridyl]benzimidazol-1-yl]acetate (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 HO (3 mL) and 10% HCl (3 mL) to pH 2-3. The mixture was diluted with water (5 mL × 3) and extracted with DCM (10 mL × 3). After drying over NaSO, 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-pyridyl]benzimidazol-1-yl]acetic acid (100 mg, 82%) as a yellow solid. LC-MS (ES +, Method 3): 2.72 min, m / z 401.25 [M+H] + .

[0220] Step D: 2-[4-Methyl-2-oxo-3-[6-(1H-pyrazolo[3,4-c]pyridin-4-yl)-3-pyridyl]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-pyridyl]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 hours. The mixture was diluted with EtOAc (15 mL) and washed with HO (3 mL × 3). The organic layers were combined and dried over anhydrous NaSO. 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-pyridyl]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): 3.13 min, m / z 496.30 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.16 (s, 1H), 8.95 (s, 1H), 8.91 - 8.85 (m, 2H), 8.79 (s, 1H), 8.40 (d, 1H), 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.

[0221] Example 93: 2-[4-methyl-3-[4-methyl-6-(1H-pyrazolo[3,4-c]pyridin-4-yl)-3-pyridyl]-2-oxo-benzimidazol-1-yl]-N-(2,2,2-trifluoroethyl)acetamide [ka] Example 93 was prepared in a manner analogous to Example 68 (Scheme 12), replacing I-38 with I-43 in Step A and (S)-2-amino-1,1,1-trifluoropropane hydrochloride with trifluoroethylamine in Step D. LC-MS (ES + , Method 3): 2.85 min, m / z 496.20 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 13.86 (s, 1H), 9.15 (s, 1H), 8.99 - 8.95 (m, 2H), 8.79 (d, J = 10.2 Hz, 2H), 8.32 (s, 1H), 7.05 (d, J = 4.5 Hz, 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.

[0222] Example 96: 2-[4-methyl-3-[3-methyl-5-(1-methylpyrazolo[3,4-c]pyridin-4-yl)pyrazin-2-yl]-2-oxo-benzimidazol-1-yl]-N-(2,2,2-trifluoroethyl)acetamide [ka] [ka] Scheme 13

[0223] 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 N for 15 min. 2-Fluoro-1-methyl-3-nitro-benzene (0.69 g, 1.2 equiv.) was added, and the resulting solution was continued to stir 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 product 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] + .

[0224] 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 / HO (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 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] + .

[0225] 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 under N for 2 h. The mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with water, brine, dried over NaSO, 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] + .

[0226] 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 equiv.) was added to I-81 (800 mg, 2.5 mmol) and KCO (2.0 equiv.) in acetone (10 mL). The reaction mixture was stirred for 12 h and then concentrated in vacuo. The crude was purified by flash column chromatography eluting with EtOAc in petroleum ether to give ethyl I-64 (817 mg, 79% yield). LC-MS (ES-API, Method 3): 3.85 min, m / z 405.10 [M] + .

[0227] 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): I-81 (450 mg, 1.11 mmol, 1.0 equiv), potassium A mixture of 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 / HO (10 mL, 3:1) was sparged with N2 three times and then warmed to 60 °C for 12 h. The mixture was then cooled to room temperature and water was added. The layers were partitioned. The aqueous layer was extracted with EtOAc. The combined organic extracts were washed with water and brine and concentrated under reduced pressure. The crude product 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)pyrazin-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] + .

[0228] 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 added slowly to adjust the pH to 3-4. The mixture was filtered, and 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] + .

[0229] 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): I-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 hours. The mixture was diluted with water (20 mL) and extracted with EoOAc. The combined organic phase was 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): 2.99 min, m / z 511.35 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 9.43 (s, 2H), 9.16 (s, 1H), 9.01 (m, 1H), 8.82 (s, 1H), 7.08 (d, J = 8.3 Hz, 2H), 6.90 (d, J = 7.1 Hz, 1H), 4.69 (d, J = 4.6 Hz, 2H), 4.28 (s, 3H), 4.03-3.96 (m, 2H), 2.64 (s, 3H), 1.81 (s, 3H) ppm.

[0230] Example 99: 2-[4-methyl-3-[5-methyl-6-(1H-pyrazolo[3,4-c]pyridin-4-yl)-3-pyridyl]-2-oxo-benzimidazol-1-yl]-N-(2,2,2-trifluoroethyl)acetamide [ka] Example 99 was prepared in a manner analogous to Example 68 (Scheme 12), replacing I-38 with I-65 in Step A and (S)-2-amino-1,1,1-trifluoropropane hydrochloride with trifluoroethylamine in Step D. LC-MS (ES + , Method 3): 2.78 min, m / z 496.30 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.62 (s, 1H), 8.99 (m, 1H), 8.75 (d, J = 2.3 Hz, 1H), 8.67 (s, 1H), 8.50 (s, 1H), 8.08 (d, J = 2.3 Hz, 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.

[0231] Example 100: 2-[4-methyl-3-[6-methyl-5-(1-methylpyrazolo[3,4-c]pyridin-4-yl)pyrazin-2-yl]-2-oxo-benzimidazol-1-yl]-N-(2,2,2-trifluoroethyl)acetamide [ka] Example 100 was prepared in a manner analogous to Example 68 (Scheme 12), replacing I-38 with I-66 in Step A and (S)-2-amino-1,1,1-trifluoropropane hydrochloride with trifluoroethylamine in Step D. LC-MS (ES + , Method 4): 1.53 min, m / z 511.15 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 9.35 (s, 1H), 9.01 (t, J = 6.3 Hz, 1H), 8.96 (s, 1H), 8.57 (s, 1H), 8.21 (s, 1H), 7.12 (m, 1H), 7.05 (d, J = 7.7 Hz, 1H), 6.96 (d, J = 7.5 Hz, 1H), 4.68 (s, 2H), 4.27 (s, 3H), 4.03 - 3.94 (m, 2H), 2.62 (s, 3H), 2.01 (s, 3H) ppm.

[0232] Example 69: 2-[4-methyl-2-oxo-3-[5-(1H-pyrazolo[3,4-c]pyridin-4-yl)-2-pyridyl]benzimidazol-1-yl]-N-[(1S)-2,2,2-trifluoro-1-methyl-ethyl]acetamide [ka] Scheme 14

[0233] Steps A to C are the same as those described for Example 47 in Scheme 10. In Step A, tributyl-(1-methylpyrazolo[3,4-c]pyridin-4-yl)stannane is replaced with tributyl-(1-tetrahydropyran-2-ylpyrazolo[3,4-c]pyridin-4-yl)stannane. In Step C, trifluoroethylamine is replaced with (2S)-amino-1,1,1-trifluoropropane.

[0234] Step D: 2-[4-methyl-2-oxo-3-[5-(1H-pyrazolo[3,4-c]pyridin-4-yl)-2-pyridyl]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-pyridyl]benzimidazol-1-yl]-N-[(1S)-2,2,2-trifluoro-1-methyl-ethyl]acetamide (50 mg, 0.09 mmol) in methanol (2 mL) and 4 M HCl in 1,4-dioxane (1 mL) was stirred at 25 ° C. for 2 hours. 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-pyridyl]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): 1.25 min, m / z 496.15 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 13.92 (s, 1H), 9.15 (s, 1H), 9.09 (s, 1H), 8.95 (d, J = 8.8 Hz, 1H), 8.54 (d, J = 18.3 Hz, 3H), 7.82 (d, J = 8.2 Hz, 1H), 7.07 (m, 1H), 7.00 (d, J = 7.8 Hz, 1H), 6.90 (d, J = 7.7 Hz, 1H), 4.64 (s, 3H), 1.93 (s, 3H), 1.30 (d, J = 7.0 Hz, 3H) ppm.

[0235] 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-pyridyl]benzimidazol-2-one [ka] Example 70 was prepared in a manner analogous to Example 69 (Scheme 13). (2S)-amino-1,1,1-trifluoropropane was replaced with (2S)-2-(trifluoromethyl)morpholine in Step C. LC-MS (ES + , Method 3): 3.02 min, m / z 538.30 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ δ 9.49 (s, 1H), 9.15 (d, J = 2.4 Hz, 1H), 8.76 (d, J = 29.7 Hz, 2H), 8.59 (dd, J = 8.3, 2.4 Hz, 1H), 7.85 (d, J = 8.2 Hz, 1H), 7.08 (d, J = 8.3 Hz, 2H), 6.92 - 6.88 (m, 1H), 5.07 (q, J = 27.8, 17.3 Hz, 1H), 4.91 - 4.82 (m, 1H), 4.43 (s, 1H), 4.28 (s, 1H), 4.14 (d, J = 13.2 Hz, 1H), 4.06 (d, J = 13.3 Hz, 1H), 4.00 (s, 1H), 3.39 (s, 1H), 2.92 (d, J = 13.6 Hz, 1H), 1.95 (s, 3H) ppm.

[0236] 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-pyridyl]benzimidazol-2-one [ka] Example 71 was prepared in a manner similar to Example 69 (Scheme 13). (2S)-amino-1,1,1-trifluoropropane was replaced with (2R)-2-(trifluoromethyl)morpholine in Step C. LC-MS (ES + , Method 3): 3.25 min, m / z 538.30 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 13.96 (s, 1H), 9.15 (s, 1H), 9.10 (d, J = 2.5 Hz, 1H), 8.57 (s, 1H), 8.54 - 8.51 (m, 2H), 7.80 (d, J = 8.2 Hz, 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.

[0237] Example 72: 2-[4-methyl-2-oxo-3-[5-(1H-pyrazolo[3,4-c]pyridin-4-yl)-2-pyridyl]benzimidazol-1-yl]-N-(2,2,2-trifluoroethyl)acetamide [ka] Example 72 was prepared in a manner similar to Example 69 (Scheme 13). (2S)-amino-1,1,1-trifluoropropane was replaced with trifluoroethylamine in Step C. LC-MS (ES + , Method 3): 3.05 min, m / z 482.25 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.15 (s, 1H), 9.09 (d, J = 2.4 Hz, 1H), 9.05 (m, 1H), 8.56 (s, 1H), 8.53 (m, J = 8.6 Hz, 2H), 7.82 (d, J = 8.2 Hz, 1H), 7.07 (t, J = 7.7 Hz, 1H), 7.01 (d, J = 7.7 Hz, 1H), 6.90 (d, J = 7.4 Hz, 1H), 4.67 (s, 2H), 3.98 (m, J = 7.2 Hz, 2H), 1.94 (s, 3H) ppm.

[0238] 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 [ka] Example 73 was prepared in a manner similar to Example 69 (Scheme 13). Intermediate I-39 in Step A was replaced with ethyl 2-[3-(5-bromopyrimidin-2-yl)-4-methyl-2-oxo-benzimidazol-1-yl]acetate (Intermediate I-45). LC-MS (ES + , Method 3): 2.95 min, m / z 497.20 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.52 (s, 2H), 9.20 (s, 1H), 8.62 (d, J = 12.0 Hz, 2H), 7.09 (m, 1H), 7.02 (d, J = 12.0 Hz ,1H), 6.91 (d, J = 8.0 Hz, 1H), 4.63 (m, 3H), 1.88 (s, 3H), 1.30 (d, J = 8.0 Hz, 3H) ppm.

[0239] Example 94: 2-[4-methyl-3-[2-methyl-6-(1H-pyrazolo[3,4-c]pyridin-4-yl)-3-pyridyl]-2-oxo-benzimidazol-1-yl]-N-(2,2,2-trifluoroethyl)acetamide [ka] Example 94 was prepared in a manner similar to Example 69 (Scheme 13). Intermediate I-39 in Step A was replaced with ethyl 2-[3-(5-bromopyrimidin-2-yl)-4-methyl-2-oxo-benzimidazol-1-yl]acetate (Intermediate I-63), and (S)-2-amino-1,1,1-trifluoropropane was substituted for trifluoroethylamine in Step C. LC-MS (ES + , Method 4): 1.24 min, m / z 496.20 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.67 (s, 1H), 9.25 (s, 1H), 9.10-9.02 (m, 2H), 8.40 (d, J = 8.0 Hz, 1H), 8.13 (d, J = 8.0 Hz, 1H),7.06 (d, J = 4.0 Hz, 2H), 6.87 (m, 1H), 4.69 (s, 2H), 4.03-3.93 (m, 2H), 2.48 (s, 3H), 1.82 (s, 3H) ppm.

[0240] 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 [ka] Example 98 was prepared in a manner similar to Example 69 (Scheme 13). Intermediate I-39 in Step A was replaced with ethyl 2-[3-(5-bromopyrimidin-2-yl)-4-methyl-2-oxo-benzimidazol-1-yl]acetate (Intermediate I-45), and (S)-2-amino-1,1,1-trifluoropropane was replaced with (R)-2-amino-1,1,1-trifluoropropane in Step C. LC-MS (ES + , Method 3): 2.95 min, m / z 497.20 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 9.52 (s, 2H), 9.20 (s, 1H), 8.62 (d, J = 12.0 Hz, 2H), 7.09 (m, 1H), 7.02 (d, J = 12.0 Hz ,1H), 6.91 (d, J = 8.0 Hz, 1H), 4.63 (m, 3H), 1.88 (s, 3H), 1.30 (d, J = 8.0 Hz, 3H) ppm.

[0241] 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 [ka] Scheme 15

[0242] Step A: 2-Bromo-N-(2-methyl-6-nitrophenyl)pyrimidin-5-amine. A solution of NaH (1.53 g, 38.13 mmol) in DMF (20 mL) was stirred at 0 °C under N for 5 minutes, after which 2-bromopyrimidin-5-amine (2.95 g, 19.07 mmol) in DMF (10 mL) was slowly added and stirred for 0.5 hours. 2-Fluoro-1-methyl-3-nitrobenzene (3.30 g, 19.07 mmol) was slowly added, and the mixture was stirred for 16 hours. 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 NaSO, and concentrated in vacuo to give 2-bromo-N-(2-methyl-6-nitrophenyl)pyrimidin-5-amine (1.8 g, 25%). LC-MS (ES) + , Method 3): 3.86 min, m / z 309 / 311 [M+H] + . 1 H NMR (400 MHz, 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.

[0243] Step B: N-(2-methyl-6-nitrophenyl)-2-(1-methylpyrazolo[3,4-c]pyridin-4-yl)pyrimidin-5-amine. A solution of 2-bromo-N-(2-methyl-6-nitrophenyl)pyrimidin-5-amine (100 mg, 0.32 mmol), tributyl-(1-methylpyrazolo[3,4-c]pyridin-4-yl)stannane (164 mg, 0.38 mmol), Pd(PPh) (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 at 120 °C under N overnight. The mixture was diluted with EtOAc (30 mL) and washed with HO (15 mL × 3). The organic layers were washed with EtOAc (5 mL x 3), combined, dried over anhydrous NaSO, 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): 3.25 min, m / z 362.0 [M+H] + . 1 H NMR (400 MHz, 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.

[0244] 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-nitrophenyl)-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 hour. The mixture was diluted with water and EtOAc, the phases were separated, and the combined organic layers were washed with brine (20 mL), extracted with ethyl acetate (30 mL), dried over Na2SO4, and 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 (400 MHz, 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.

[0245] Step D: 4-Methyl-3-[2-(1-methylpyrazolo[3,4-c]pyridin-4-yl)pyrimidin-5-yl]-1H-benzimidazol-2-one. A solution of 4-methyl-N-[2-(1-methylpyrazolo[3,4-c]pyridin-4-yl)pyrimidin-5-yl]benzene-1,2-diamine (35 mg, 0.11 mmol), CDI (85.7 mg, 0.52 mmol) in DMF (0.3 mL) was stirred at 100 °C under N overnight. The mixture was diluted with EtOAc (3 mL) and washed with HO (5 mL × 3). The organic layers were washed with EtOAc (5 mL x 3), combined, dried over anhydrous NaSO, 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): 3.117 min, m / z 358.0 [M+H] + .

[0246] 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 CsCO (54.75 mg, 0.16 mmol) in MeCN (5 mL) was stirred at 50 °C for 2 h. The mixture was quenched with HO (3 mL), and the mixture was extracted with EtOAc (8 mL × 3). The organic layers were combined and washed with HO (8 mL × 3), followed by NaCl (aq.) (5 mL × 3). The organic layer was dried over anhydrous NaSO and then concentrated to give ethyl 2-[4-methyl-3-[2-(1-methylpyrazolo[3,4-c]pyridin-4-yl)pyrimidin-5-yl]-2-oxo-benzimidazol-1-yl]acetate (20 mg, 54%) as a yellow solid. LC-MS (ES) + , Method 3): 3.583 min, m / z 444.25 [M+H] + .

[0247] 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.HO (8.53 mg, 0.20 mmol) in THF (1.5 mL), MeOH (1.5 mL), and HO (1 mL) was stirred at 25 °C for 2 h. The mixture was diluted with HO (5 mL) and 10% HCl (3 mL) to pH 2-3. The mixture was diluted with water (10 mL x 3) and extracted with DCM (10 mL x 3). After drying over Na2SO4, filtration, and concentration in vacuo, 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, 61%) was obtained as a white solid. LC-MS (ES + , Method 3): 2.817 min, m / z 416.0 [M+H] + .

[0248] 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 HO (2 mL x 3). The organic layers were washed with EtOAc (5 mL x 3), combined, dried over anhydrous NaSO, 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): 3.42 min, m / z 497.20 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.39 (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 = 7.2 Hz, 1H), 4.69 (s, 2H), 4.28 (s, 3H), 4.04 - 3.96 (m, 2H), 2.01 (s, 3H) ppm.

[0249] Example 91: 2-[3-[6-(1-methylpyrazolo[3,4-c]pyridin-4-yl)-3-pyridyl]-2-oxo-benzimidazol-1-yl]-N-(2,2,2-trifluoroethyl)acetamide [ka] Scheme 16 Example 91 was prepared from intermediate I-62 using a Stille coupling with 1-methyl-4-(tributylstannyl)-1H-pyrazolo[3,4-c]pyridine under the conditions described in Scheme 11, Step C. LC-MS (ES + , Method 4): 1.47 min, m / z 482.20 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.28 (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.

[0250] Example 92: 2-[3-[6-(1,3-dimethylpyrazolo[3,4-c]pyridin-4-yl)-3-pyridyl]-4-methyl-2-oxo-benzimidazol-1-yl]-N-(2,2,2-trifluoroethyl)acetamide [ka] Scheme 17

[0251] Step A: 2-[3-(6-Bromo-3-pyridyl)-4-methyl-2-oxo-benzimidazol-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 hours. The mixture was concentrated in vacuo, and the pH was adjusted to 3 by the slow addition of 1 M HCl. The mixture was diluted with water (50 mL) and washed with EtOAc (100 mL × 3). The combined organic layers were washed with brine (50 mL), dried over NaSO, and concentrated to give 2-[3-(6-bromo-3-pyridyl)-4-methyl-2-oxo-benzimidazol-1-yl]acetic acid (380 mg, 82%) as a white solid. LC-MS (ES + , Method 4): 1.66 min, m / z 361.9 / 363.9 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 13.19 (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.

[0252] Step B: 2-[3-(6-Bromo-3-pyridyl)-4-methyl-2-oxo-benzimidazol-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 hours. The mixture was treated with water (50 mL) and filtered to give 2-[3-(6-bromo-3-pyridyl)-4-methyl-2-oxo-benzimidazol-1-yl]-N-(2,2,2-trifluoroethyl)acetamide (400 mg, 86%) as a white solid. LC-MS (ES + , Method 4): 1.38 min, m / z 442.7 / 444.6 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.98 (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.

[0253] Step C: 2-[3-[6-(1,3-dimethylpyrazolo[3,4-c]pyridin-4-yl)-3-pyridyl]-4-methyl-2-oxo-benzimidazol-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-(tributylstannyl)-1H-pyrazolo[3,4-c]pyridine (115 mg, 0.27 mmol), Pd(PPh) (26 mg, 0.023 mmol), CuI (24 mg, 0.11 mmol), and LiCl (29 mg, 0.68 mmol) in toluene (3 mL) was stirred at 110 °C under N overnight. The mixture was filtered and concentrated. The crude was purified by preparative TLC (DCM / MeOH, 20:1) to give 2-[3-[6-(1,3-dimethylpyrazolo[3,4-c]pyridin-4-yl)-3-pyridyl]-4-methyl-2-oxo-benzimidazol-1-yl]-N-(2,2,2-trifluoroethyl)acetamide (Example 92) (20.4 mg, 15%) as an off-white solid. LC-MS (ES + , Method 3): 3.28 min, m / z 496.10 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.29 (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.

[0254] Example 102: 2-[4-methyl-3-[5-methyl-6-(3-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-3-pyridyl]-2-oxo-benzimidazol-1-yl]-N-(2,2,2-trifluoroethyl)acetamide [ka] Scheme 18

[0255] Step A: 2-[4-methyl-3-[5-methyl-6-(3-methyl-1-tetrahydropyran-2-yl-pyrazolo[3,4-c]pyridin-4-yl)-3-pyridyl]-2-oxo-benzimidazol-1-yl]acetic acid. A solution of ethyl 2-[3-(6-bromo-5-methyl-3-pyridyl)-4-methyl-2-oxo-benzimidazol-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(PPh) (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-pyridyl]-2-oxo-benzimidazol-1-yl]acetic acid as a yellow oil (180 mg) which was used without further purification. LC-MS (ES + , Method 3): 3.10 min, m / z 513.3 [M+H] + .

[0256] Step B: 2-[4-methyl-3-[5-methyl-6-(3-methyl-1-tetrahydropyran-2-yl-pyrazolo[3,4-c]pyridin-4-yl)-3-pyridyl]-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-pyridyl]-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 hours. The mixture was partitioned between water and EtOAc, the phases were separated, and the organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure to give the 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-pyridyl]-2-oxo-benzimidazol-1-yl]-N-(2,2,2-trifluoroethyl)acetamide (10 mg, 59%) as a yellow solid. LC-MS (ES) + , Method 3): 3.98 min, m / z 594 [M+H] + .

[0257] Step C: 2-[4-methyl-3-[5-methyl-6-(3-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-3-pyridyl]-2-oxo-benzimidazol-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-pyridyl]-2-oxo-benzimidazol-1-yl]-N-(2,2,2-trifluoroethyl)acetamide (10 mg, 0.02 mmol) in DCM (1 mL) was added 4 M HCl in dioxane (0.5 mL, 0.02 mmol) at 25 ° C., and the mixture was stirred for 3 hours. 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-pyridyl]-2-oxo-benzimidazol-1-yl]-N-(2,2,2-trifluoroethyl)acetamide (2 mg, 18%) as a white solid. LC-MS (ES + , Method 3): 2.783 min, m / z 510.30 [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 9.09 (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 = 9.3 Hz, 2H), 2.31 (s, 3H), 2.14 (s, 3H), 2.07 (s, 3H) ppm.

[0258] Example 103: 2-[4-methyl-3-[2-methyl-6-(3-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-3-pyridyl]-2-oxo-benzimidazol-1-yl]-N-(2,2,2-trifluoroethyl)acetamide [ka] Example 103 was prepared analogously to Example 102 (Scheme 17) by replacing intermediate I-65 with intermediate I-63 in Step A. LC-MS (ES + , Method 4): 1.12 min, m / z 510.20 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.55 (s, 1H), 9.04 (s, 1H), 8.58 (s, 1H), 8.13 (d, J = 8.0 Hz, 1H), 7.93 (d, J = 8.0 Hz, 1H),7.06 (d, J = 4.0 Hz, 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.

[0259] Example 104: 2-[4-methyl-3-[3-methyl-5-(3-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)pyrazin-2-yl]-2-oxo-benzimidazol-1-yl]-N-(2,2,2-trifluoroethyl)acetamide [ka] Example 104 was prepared analogously to Example 102 (Scheme 17) by replacing intermediate I-65 with intermediate I-64 in Step A. LC-MS (ES + , Method 3): 2.95 min, m / z 511.30 [M+H] + . 1 H NMR (400 MHz, MeOD-d4) δ 9.11 (s, 1H), 8.96 (s, 1H), 8.49 (m, 1H), 7.16 (m, 1H), 7.05 (d, J = 7.9 Hz, 1H), 6.98 (d, J = 7.7 Hz, 1H), 4.78 (s, 2H), 4.01 (dd, J = 9.4, 5.7 Hz, 2H), 2.69 (s, 3H), 2.50 (s, 3H), 1.91 (s, 3H) ppm.

[0260] Example 105: 2-[4-methyl-3-[6-methyl-5-(3-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)pyrazin-2-yl]-2-oxo-benzimidazol-1-yl]-N-(2,2,2-trifluoroethyl)acetamide [ka] Example 105 was prepared analogously to Example 102 (Scheme 17) by replacing intermediate I-65 with intermediate I-66 in Step A. LC-MS (ES + , Method 3): 2.91 min, m / z 511.35 [M+H] + . 1 H NMR (400 MHz, MeOD-d4) δ 9.59 (s, 1H), 9.07 (s, 1H), 8.57 (s, 1H), 7.21 (t, J = 7.8 Hz, 1H), 7.05 (d, J = 4.0 Hz, 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.

[0261] Examples 106-115 were prepared in a similar manner to Example 75 (Scheme 15). [Table 18-1] [Table 18-2]

[0262] (Biochemical assays for DDR1 and DDR2) The binding ability of compounds 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 compounds in a 384-well plate in a volume of 5 μL. After 30 minutes of incubation at room temperature, 2.5 μL 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) was added to the plate. After 60 minutes of incubation at room temperature, time-resolved fluorescence was measured using a BMG Labtech PHERAstar plate reader. DMSO (1%) and reference compound (1 μM) were used to obtain the maximum and minimum assay signals, respectively. Data were analyzed using a four-parameter logistic model to obtain IC 50 Values ​​were calculated and at least two independent replicates were performed for each compound.

[0263] (bioactivity value) The following table shows the pICs of the above examples for DDR1 and DDR2 kinases: 50 Values ​​are shown (A:pIC 50 >8;B:8≥pIC 50 >7;C:7≥pIC 50 >6;D:pIC 50 ≤6; ND: not determined). [Table 19-1] [Table 19-2]

Claims

1. Formula (I): 【Chemical 1】 (I) [In the formula, X 1 , X 2 and X 3 are each independently selected from carbon and nitrogen; X 1 , X 2 and X 3 at least two of are carbon; X 4 , X 5 , X 6 and X 7 are each independently selected from carbon and nitrogen; X 4 , X 5 , X 6 and X 7 at least two of are carbon; R 1 may each occur independently as halo, nitro, cyano, or NR 9 R 10 , OR 11 , S.R. 9 , SO 2 NR 9 R 9 , SO 2 R 9 , CO 2 R 9 , C(O)R 9 ,CONR 9 R 9 , C 1 -C 4 -Alkyl, NR 9 R 10 C replaced with 1 -C 4 -Alkyl, OR 11 C replaced with 1 -C 4 -Alkyl, C 2 -C 4 -Alkenyl, C 2 -C 4 -alkynyl, C 1 -C 4 - selected from haloalkyl and cyclopropyl; R 3 but independently, H and C 1 -C 4 - selected from alkyl; R 4 But independently, C 1 -C 6 -Alkyl, C 1 -C 6 -haloalkyl, C 0 -C 4 -Alkylene-R 4a Selected from: R 4a But independently, C 3 -C 8 - selected from cycloalkyl, phenyl, 5-, 6-, 9-, or 10-membered heteroaryl and 4- to 10-membered heterocycloalkyl; the heterocycloalkyl or heteroaryl group may be monocyclic or bicyclic; the cycloalkyl or heterocycloalkyl group is selected from one R 12 group and / or 1 to 4 R 13 group, and the phenyl or heteroaryl group is optionally substituted with one R 12 group and / or 1 to 3 R 14 optionally substituted with a group; Alternatively, R 3 and R 4 together with the nitrogen atom to which they are attached form a 4- to 10-membered heterocycloalkyl group or a 5- or 9-membered heteroaryl group; the heterocycloalkyl or heteroaryl group may be monocyclic or bicyclic; the heterocycloalkyl group may be substituted with one R 12 group and / or 1 to 4 R 13 group, and the heteroaryl group is optionally substituted with one R 12 group and / or 1 to 3 R 14 optionally substituted with a group; R 5 but independently in each occurrence H, halo and C 1 -C 4 -alkyl, or two R 5 The groups and the carbon atoms to which they are attached together form C 3 -C 6 may form a cycloalkyl ring; R 6 may each occur independently as halo, nitro, cyano, or NR 9 R 10 , OR 11 , S.R. 9 , SO 2 NR 9 R 9 , SO 2 R 9 , CO 2 R 9 , C(O)R 9 ,CONR 9 R 9 , C 1 -C 4 -Alkyl, NR 9 R 10 C replaced with 1 -C 4 -Alkyl, OR 11 C replaced with 1 -C 4 -Alkyl, C 2 -C 4 -Alkenyl, C 2 -C 4 -alkynyl, C 1 -C 4 - selected from haloalkyl and cyclopropyl; R 7 may each occur independently as halo, nitro, cyano, or NR 9 R 10 , OR 11 , S.R. 9 , SO 2 NR 9 R 9 , SO 2 R 9 , CO 2 R 9 , C(O)R 9 ,CONR 9 R 9 , C 1 -C 4 -Alkyl, NR 9 R 10 C replaced with 1 -C 4 -Alkyl, OR 11 C replaced with 1 -C 4 -Alkyl, C 2 -C 4 -Alkenyl, C 2 -C 4 -alkynyl, C 1 -C 4 - selected from haloalkyl and cyclopropyl; R 8a are independently H, halo, nitro, cyano, NR 9 R 10 , OR 11 , S.R. 9 , SO 2 NR 9 R 9 , SO 2 R 9 , CO 2 R 9 , C(O)R 9 ,CONR 9 R 9 , C 1 -C 4 -Alkyl, NR 9 R 10 C replaced with 1 -C 4 -Alkyl, OR 11 C replaced with 1 -C 4 -Alkyl, C 2 -C 4 -Alkenyl, C 2 -C 4 -alkynyl, C 1 -C 4 -haloalkyl and C 0 -C 4 -Alkylene-R 8c Selected from: R 8b However, independently, H, C 1 -C 4 -Alkyl, CONR 9 R 9 C replaced with 1 -C 4 -Alkyl, NR 9 R 10 C replaced with 2 -C 4 -Alkyl, OR 11 C replaced with 2 -C 4 -Alkyl, C 3 -C 4 -Alkenyl, C 3 -C 4 -alkynyl, C 1 -C 4 -haloalkyl and C 0 -C 4 -Alkylene-R 8c Selected from: R 8c But independently, C 3 -C 6 -cycloalkyl and 3- to 7-membered heterocycloalkyl; wherein the heterocycloalkyl group is joined to C via a carbon atom in the heterocycloalkyl ring. 0 -C 4 -alkylene; the cycloalkyl or heterocycloalkyl group is 13 optionally substituted with a group; R 9 but independently at each occurrence, H and C 1 -C 4 -alkyl; or two R 9 The groups, together with the nitrogen atoms to which they are attached, may be 0 to 4 R 13 C optionally substituted with a group 5 -C 8 - forming a heterocycloalkyl group; R 10 However, independently at each occurrence, H, C 1 -C 4 -Alkyl, C(O)-C 1 -C 4 -Alkyl and S(O) 2 -C 1 -C 4 -alkyl; or R 9 and R 10 together with the nitrogen atom to which they are attached, 0 to 4 R 13 C optionally substituted with a group 5 -C 8 - forming a heterocycloalkyl group; R 11 However, independently at each occurrence, H, C 1 -C 4 -Alkyl, C(O)-C 1 -C 4 -Alkyl and C 1 -C 4 -haloalkyl; R 12 But independently, C 3 -C 6 -cycloalkyl, phenyl, 5- or 6-membered heteroaryl, and 3- to 6-membered heterocycloalkyl; wherein the cycloalkyl or heterocycloalkyl group is selected from 1 to 4 R 13 groups, and the phenyl or heteroaryl group is optionally substituted with 1 to 3 R 14 optionally substituted with a group; R 13 independently at each occurrence, ═O, halo, nitro, cyano, NR 8 R 9 , OR 14 , S.R. 8 , SO 2 NR 8 R 8 , CO 2 R 8 , C(O)R 8 ,CONR 8 R 8 , C 1 -C 4 -Alkyl, OR 11 C replaced with 1 -C 4 -Alkyl, NR 9 R 10 C replaced with 1 -C 4 -Alkyl, C 2 -C 4 -Alkenyl, C 2 -C 4 -alkynyl, C 1 -C 4 -haloalkyl, C 6 -C 10 -aryl and C 3 -C 6 -cycloalkyl; R 14 may each occur independently as halo, nitro, cyano, or NR 8 R 9 , OR 10 , S.R. 8 , SO 2 R 8 , SO 2 NR 8 R 8 , CO 2 R 8 , C(O)R 8 ,CONR 8 R 8 , C 1 -C 4 -Alkyl, C 2 -C 4 -Alkenyl, C 2 -C 4 -alkynyl, C 1 -C 4 -haloalkyl, OR 11 C replaced with 1 -C 4 -Alkyl, NR 8 R 9 C replaced with 1 -C 4 - selected from 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; Any of the above alkyl, alkylene or cyclopropyl groups may, where chemically possible, be selected from halo, oxo, fluoro, nitro, cyano, NR a R b , OR a , S.R. a , CO 2 R a , C(O)R a ,CONR a R a , C 1 -C 4 -Alkyl, C 1 -C 4 -optionally substituted with 1 to 5 substituents each independently selected at each occurrence from the group consisting of haloalkyl and cyclopropyl; R a However, independently at each occurrence, H, C 1 -C 4 -Alkyl and C 1 -C 4 -haloalkyl; and R b However, independently at each occurrence, H, C 1 -C 4 -Alkyl, C(O)-C 1 -C 4 -Alkyl and S(O) 2 -C 1 -C 4 -alkyl] or a pharmaceutically acceptable salt thereof.

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

3. m is at least 1 and X 1 is carbon and R 1 The group is X 1 10. The compound of claim 1, wherein the carbon atom is bonded to the compound.

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

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

6. R 5 The compound of any one of claims 1 to 5, wherein each occurrence is H.

7. R 6 C 1 -C 4 7. The compound according to claim 1, wherein -alkyl.

8. R 8a The compound of any one of claims 1 to 7, wherein is H.

9. R 8b is H and C 1 -C 4 9. The compound according to claim 1, wherein the aryl group is selected from the group consisting of aryl, ...

10. X 1 , X 2 and X 3 10. The compound of claim 1, wherein each is carbon.

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

12. X 4 , X 5 , X 6 and X 7 11. The compound according to any one of claims 1 to 10, wherein at least one of is nitrogen.

13. NR 3 R 4 But, the formula 【Chemistry 2】 [In the formula, a is an integer selected from 1 and 2; R 4b is selected from H and F at each occurrence; and 4b The group is F; R 3a but independently, H and C 1 -C 4 - selected from alkyl; R 4c However, independently at each occurrence, H, C 1 -C 4 -Alkyl and C 4 -C 6 -cycloalkyl; or R 3a and one R 4c together with the carbon and nitrogen to which they are attached form a 4- to 6-membered heterocycloalkyl group.

13. The compound of any one of claims 1 to 12, having the formula:

14. 14. The compound of claim 13, wherein a is 1.

15. At least two R 4b 15. The compound of claim 13 or 14, wherein the group is F.

16. R 3a The compound of any one of claims 13 to 15, wherein is H.

17. R 4c is H and C 1 -C 4 17. The compound according to any one of claims 13 to 16, wherein the aryl group is selected from -alkyl.

18. R 3a and R 4c together with the carbon and nitrogen to which they are attached form a 4-6 membered heterocycloalkyl group.

19. R 3 is H and R 4 C 1 -C 6 -Alkyl, C 1 -C 6 -haloalkyl and C 0 -C 4 -Alkylene-R 4a The compound according to any one of claims 1 to 12, selected from:

20. R 4 C 1 -C 6 -Alkyl and C 1 -C 6 15. The compound of claim 14, wherein the alkyl is selected from the group consisting of -haloalkyl.

21. R 4 C 0 -C 4 -Alkylene-R 4a 15. The compound of claim 14, wherein:

22. R 4 R 4a 17. The compound of claim 16, wherein:

23. R 4a But C 3 -C 8 -cycloalkyl and 4- to 10-membered heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl group is selected from 1 to 4 R 13 18. The compound of claim 16 or 17, optionally substituted with a group.

24. R 4a are independently selected from phenyl and 5- or 6-membered heteroaryl; and the phenyl or heteroaryl group is selected from one R 12 group and / or 1 to 3 R 14 18. The compound of claim 16 or 17, optionally substituted with a group.

25. R 3 and R 4 together with the nitrogen atom to which they are attached, form 1 to 4 R 13 The compound according to any one of claims 1 to 12, which forms a monocyclic 4- to 7-membered heterocycloalkyl group optionally substituted with a group.

26. the below described: 【Chemistry 3】 【Chemistry 4】 【Chemistry 5】 【Chemistry 6】 【Chemistry 7】 【Chemistry 8】 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. 27. A compound according to any one of claims 1 to 26 for use in treating a disease or disorder selected from renal conditions, hepatic conditions, inflammatory conditions, cardiovascular conditions, acute and chronic organ transplant rejection, fibrotic diseases and cancer.

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