Fibrosis

Abstract

The present invention relates to a novel compound and a pharmaceutical composition comprising the novel compound.More specifically, the present invention relates to a compound useful as an inhibitor of discoidin domain receptor 1 (DDR1) and discoidin domain receptor 2 (DDR2).The compound is particularly useful for the treatment of cancer and fibrotic diseases.

Description

[Technical field]

[0001] The present invention relates to novel compounds and pharmaceutical compositions comprising said 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 the N-terminal extracellular domain. These domains are preceded 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 alternative 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 with clear preferences for certain types of collagen. Upon activation, DDRs are known to regulate cell adhesion, proliferation and extracellular matrix remodeling. It has been recognized that the DDR is upregulated in response to cellular activity and many forms of tissue injury, and such DDR is 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] As summarized in a recent review (Elkamhawy et al, Int. J. Mol. Sci., 2021), overexpression and / or activation of DDR1 and DDR2 are associated with various forms of cancer. Studies have shown that elevated and / or mutated DDR expression levels are found in many cancer cell lines and primary tumor tissues, including lung, pancreas, prostate, breast, brain, ovary, and liver. DDR1 was found to be a prognostic marker for patients with non-small cell lung cancer (NSCLC). A recent study found that siRNA-mediated downregulation of DDR1 suppressed the malignant transformation, migration, invasion, and survival of melanoma cells. It was also found that DDR1 protein is expressed in 63% of serous ovarian cancer tissues, but not in normal ovarian surface epithelium. It was also demonstrated that DDR1 is involved in the invasion and epithelial-mesenchymal transition (EMT) of glioblastoma cells. DDR1 expression was found in 50.5% of gastric cancer tissues. DDR1 was found to control the growth of triple-negative breast cancer by regulating tumor-infiltrating CD4+ and CD8+ T cells. There is also strong evidence that DDR2 may be a potential biomarker and molecular target for various cancers. For example, overexpression of DDR2 has been reported to contribute to NSCLC, thyroid cancer, Hodgkin lymphoma, nasopharyngeal carcinoma, prostate cancer, and head and neck squamous cell carcinoma. Studies have shown that DDR2 contributes to breast cancer metastasis by stabilizing SNAIL1 protein. DDR2 has also been shown to be a favorable independent predictor of primary breast cancer recurrence and outcome. In addition to the important 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, for example, G1486T (DDR1) and A496S (DDR1) in lung cancer, N502S (DDR1), A533S (DDR1) and A803V (DDR1) in acute myeloid leukemia (AML), and S768R (DDR2) in squamous cell carcinoma. DDR also plays a role in cancer growth by controlling how tumor cells interact with the surrounding collagen matrix. This role of DDR becomes more prominent when considering its role as an extracellular matrix receptor.The extracellular matrix (ECM) not only controls cell proliferation, survival, migration and invasion, but also provides structural properties to the tissue surrounding the tumor. In metastatic cancer, the physiological interactions between tumor cells and the microenvironment represented by the extracellular matrix are disrupted. Type I collagen, a major component of the tumor extracellular matrix, exhibits a dense and distorted structure in malignant cancers, which is related to tumor formation and metastasis. Therefore, the discovery of DDR as a collagen receptor represents a new target in controlling tumor progression.

[0004] 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 show 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 diseases (Bian et al, ERJ Open Res., 2016). In the kidney, DDR1 expression is elevated in patients with lupus nephritis and Goodpasture's syndrome, in mouse models of glomerulonephritis (Kerroch et al, FASEB journal, 2012), and in the renal tubules of mice with unilateral ureteral obstruction (UUO) (Guerrot et al, Am. J. Pathol., 2011). Several studies have demonstrated that DDR1 null mice are protected from angiotensin II-mediated proteinuria, glomerular fibrosis and inflammation, and exhibit reduced collagen deposition, tubular macrophage infiltration and 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 inflammation as a result of reduced TGF-β-mediated signaling and reduced levels of the proinflammatory cytokine IL-6 (Dorison, Cell Adhesion and Migration, 2018).

[0005] Small molecule inhibitors of DDR1 and DDR2 kinase activity have been disclosed in the prior art, and 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 would be beneficial as therapeutic agents for human cancer and fibrotic disease.

[0006] Furthermore, it is an object of certain embodiments of the present invention to provide novel compounds useful for the treatment of 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 relative to existing DDR1 and / or DDR2 inhibitors.

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

[0008] The present invention relates to a compound represented by formula (I) [ka] [In the formula, Z 1 and Z 2 are respectively, -CR 8a - and -NR 8b -, where Z 1 and Z 2 One is -CR 8a - and the other is -NR 8b - where Z 1 and Z 2 The ring containing is a pyrazole; X 1Independently, CR 7a and N; X 2 , X 3 and X 4 are each independently selected from carbon and nitrogen, 2 , X 3 and X 4 at least one of is carbon; R 1 is independently represented by 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 by OR 11 C-C-alkyl, C-C-alkenyl, C-C-alkynyl, C-C-haloalkyl and cyclopropyl, substituted by; R 2 is independently selected at each occurrence from H, fluoro, C-C-alkyl, C-C-haloalkyl and cyclopropyl; or two R 2 the groups and the carbon atoms to which they are attached together form a C3-C6-cycloalkyl ring; 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 where R 4aare independently selected from C-C-cycloalkyl, phenyl, 5-, 6-, 9- or 10-membered heteroaryl and 4-10-membered heterocycloalkyl; wherein said heterocycloalkyl or heteroaryl groups may be monocyclic or bicyclic; wherein said cycloalkyl or heterocycloalkyl groups may optionally be joined by a single R 12 group and / or 1 to 4 R 13 groups, said phenyl or heteroaryl groups being optionally substituted by a single R 12 group and / or 1 to 3 R 14 may be substituted by a group; Or, R 3 and R 4 together with the nitrogen atom to which they are attached form a 4-10 membered heterocycloalkyl group or a 5- or 9-membered heteroaryl group; wherein said heterocycloalkyl or heteroaryl group may be monocyclic or bicyclic; and wherein said heterocycloalkyl group optionally comprises a single R 12 group and / or 1 to 4 R 13 groups, the heteroaryl group optionally being substituted by a single R 12 group and / or 1 to 3 R 14 optionally substituted by groups; 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 is independently selected from H, C-C-alkyl, C-C-haloalkyl and cyclopropyl; R 7 and R 7a are each independently H, halo, nitro, cyano, or NR 9 R 10 , OR 11 , S.R. 9 , SO2NR 9 R 9 , SO2R9 , CO2R 9 , C(O)R 9 ,CONR 9 R 9 , C1-C4-alkyl, NR 9 R 10 C1-C4-alkyl substituted by OR 11 C-C-alkyl, C-C-alkenyl, C-C-alkynyl, C-C-haloalkyl and cyclopropyl, substituted by; 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 by OR 11 C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and C0-C4-alkylene-R 8c Selected from; R 8b are independently H, C1-C4-alkyl, NR 9 R 10 C2-C4-alkyl substituted by OR 11 C2-C4-alkyl, C3-C4-alkenyl, C3-C4-alkynyl, C1-C4-haloalkyl and C0-C4-alkylene-R 8c Selected from; R 8care independently selected from C-C-cycloalkyl and 3-7 membered heterocycloalkyl; wherein said heterocycloalkyl group is bonded to the C-C-alkylene via a carbon atom of the heterocycloalkyl ring; wherein said cycloalkyl or heterocycloalkyl group is optionally selected from 1 to 4 R 13 may be substituted by a group; R 9 is independently selected from H and C1-C4-alkyl at each occurrence; or two R 9 The groups, together with the nitrogen atom to which they are attached, optionally 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, optionally 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 is independently selected from C-C-cycloalkyl, phenyl, 5- or 6-membered heteroaryl and 3-6-membered heterocycloalkyl; wherein said cycloalkyl or heterocycloalkyl group is optionally selected from 1 to 4 R 13 groups, and the phenyl or heteroaryl group is optionally substituted with 1 to 3 R 14 may be substituted by a group; R 13 is independently represented at each occurrence by ═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 by NR 9 R 10 C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl, C6-C 10 -aryl and C3-C6-cycloalkyl; R 14 is independently represented by 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 by NR 8 R 9 C1-C4-alkyl and cyclopropyl, substituted by; m is an integer selected from 0, 1, 2 and 3; wherein any of said alkyl, alkylene or cyclopropyl groups are optionally, if chemically possible, selected independently at each occurrence 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 , C1-C4-alkyl, C1-C4-haloalkyl and cyclopropyl; ais independently selected at each occurrence from H, C-C-alkyl and C-C-haloalkyl; 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. and pharma- ceutically acceptable salts thereof.

[0009] In certain embodiments, the compound of Formula (I) has the formula (II): [ka] [In the formula, Z 1 , Z 2 , X 1 , X 2 , X 3 , X 4 , R 1 , R 3 , R 4 , R 5 , R 6 , R 7 and m is as described above for compounds of formula (I). It is a compound of the formula:

[0010] In certain embodiments, the compound of Formula (I) has the formula (III): [ka] [In the formula, Z 1 , Z 2 , X 1 , X 2 , X 3 , X 4 , R 1 , R 3 , R 4 , R 7 and m is as described above for compounds of formula (I). It is a compound of the formula:

[0011] In certain embodiments, the compound of Formula (I) has the formula (IV): [ka] [In the formula, X 1 , X 2 , X 3 , X 4 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8a , R 8b , m and n are as described above for compounds of formula (I). It is a compound of the formula:

[0012] In certain embodiments, the compound of formula (I) has the formula (V): [ka] [In the formula, X 1 , X 2 , X 3 , X 4 , R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8a , R 8b and m is as described above for compounds of formula (I). It is a compound of the formula:

[0013] In certain embodiments, the compound of Formula (I) has the formula (VI): [ka] [In the formula, Z 1 , Z 2 , X 1 , X 2 , X 3 , X 4 , R 1 , R 3 , R 4 , R 7 , R 8a , R 8b and m is as described above for compounds of formula (I). It is a compound of the formula:

[0014] In certain embodiments, the compound of Formula (I) has the formula (VII): [ka] [In the formula, X 1 , X 2 , X 3 , X 4 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8b , m and n are as described above for compounds of formula (I). It is a compound of the formula:

[0015] In certain embodiments, the compound of Formula (I) has the formula (VIII): [ka] [In the formula, X 1 , X 2 , X 3 , X 4 , R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8b and m is as described above for compounds of formula (I). It is a compound of the formula:

[0016] In certain embodiments, the compound of Formula (I) has the formula (IX): [ka] [In the formula, X 1 , X 2 , X 3 , X 4 , R 1 , R 3 , R 4 , R 7 , R 8band m is as described above for compounds of formula (I). It is a compound of the formula:

[0017] In certain embodiments, the compound of Formula (I) has the formula (X): [ka] [where, X 1 , X 2 , X 3 , X 4 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8a , R 8b , m and n are as described above for compounds of formula (I). It is a compound of the formula:

[0018] In certain embodiments, the compound of Formula (I) has the formula (XI): [ka] [where, X 1 , X 2 , X 3 , X 4 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8a , m and n are as described above for compounds of formula (I). It is a compound of the formula:

[0019] In certain embodiments, the compound of Formula (I) has the formula (XII): [ka] [where, X 1 , X 2 , X 3 , X 4 , R1 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8a and m is as described above for compounds of formula (I). It is a compound of the formula:

[0020] In certain embodiments, the compound of Formula (I) has the formula (XIII): [ka] [where, X 1 , X 2 , X 3 , X 4 , R 1 , R 3 , R 4 , R 7 , R 8a and m is as described above for compounds of formula (I). It is a compound of the formula:

[0021] In certain embodiments, the compound of Formula (I) has the formula (XIV): [ka] [In the formula, Z 1 , Z 2 , X 1 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and m is as described above for compounds of formula (I). It is a compound of the formula:

[0022] In certain embodiments, the compound of Formula (I) has the formula (XV): [ka] [where, X 1 , R 1 , R 2 , R3 , R 4 , R 5 , R 6 , R 7 , R 8a , R 8b , m and n are as described above for compounds of formula (I). It is a compound of the formula:

[0023] In certain embodiments, the compound of Formula (I) has the formula (XVI): [ka] [In the formula, X 1 , X 2 , X 3 , X 4 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8a , R 8b , m and n are as described above for compounds of formula (I). It is a compound of the formula:

[0024] In certain embodiments, the compound of Formula (I) has the formula (XVII): [ka] [In the formula, Z 1 , Z 2 , X 1 , X 2 , X 3 , X 4 , R 1 , R 5 , R 6 , R 7 and m are as described above for compounds of formula (I); R 4b is selected, for each occurrence, from H and F; where at least two R 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. It is a compound of the formula:

[0025] In certain embodiments, the compound of Formula (I) has the formula (XVIII): [ka] [In the formula, X 1 , R 1 , R 2 , R 5 , R 6 , R 7 , R 8a , R 8b and m are as described above for compounds of formula (I); R 3a , R 4b and R 4c is as described above for formula (XVII). It is a compound of the formula:

[0026] In certain embodiments, the compound of Formula (I) has the formula (XIX): [ka] [In the formula, X 1 , R 1 , R 2 , R 5 , R 6 , R 7 , R 8a , R 8b and m are as described above for compounds of formula (I); R 3a , R 4b and R 4c is as described above for formula (XVII). It is a compound of the formula:

[0027] In some embodiments, the compound of Formula (I) has the formula (XX): [ka] [where, X 1 , R 6 , R 7 , R 8a and R 8b is as described above for compounds of formula (I); R 3a , R 4b and R 4c is as described above for formula (XVII). It is a compound of the formula:

[0028] In certain embodiments, the compound of Formula (I) has the formula (XXI): [ka] [In the formula, Z 1 , Z 2 , X 1 , R 1 , R 3 , R 4 , R 5 , R 6 , R 7 and m is as described above for compounds of formula (I). It is a compound of the formula:

[0029] The following embodiments apply to any of the compounds of formula (I)-(XXI). These embodiments are independent and interchangeable. Any one embodiment can be combined with any other embodiment, if chemically permissible. In other words, any feature described in the following embodiments can be combined with one or more features described in other embodiments, if chemically permissible. In particular, if 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, can be combined to provide further embodiments that form part of the present disclosure.

[0030] Z 1 is NR8b and Z 2 may be CH, or Z 1 is CR 8a and Z 2 may be NH.

[0031] Z 1 is NR 8b and Z 2 is CR 8a Z 1 is NR 8b and Z 2 may be CH. 1 may be NMe, and Z 2 is CR 8a Z 1 may be NMe, and Z 2 may be CH.

[0032] Z 1 is CR 8a and Z 2 is NR 8b Z 1 is CR 8a and Z 2 may be NH.

[0033] X 1 may be N. 1 is CR 7a may be also possible.

[0034] X 2 may be carbon. 3 may be carbon. 4 may be carbon. 2 and X 3 may both be carbon. 3 and X 4 may both be carbon. 2 and X 4 may both be carbon. 2 , X 3 and X4 may each be carbon.

[0035] X 2 , X 3 and X 4 Up to one of X may be nitrogen. 2 , X 3 and X 4 One of X may be nitrogen. 2 may be nitrogen. 3 may be nitrogen. 4 may be nitrogen. 2 may be prime, and X 3 may be carbon, and X 4 may be carbon.

[0036] m may be 0.

[0037] m may be 1. When m is 1, a single R 1 The group is NR 6 When m is 1, a single R 1 The group may be located para to NR6. When m is 1, a single R 1 The group may be located para to NR6.

[0038] m may be 2.

[0039] R 1 is independently selected for each occurrence as halo, nitro, cyano, OR 11 , C1-C4-alkyl, NR 9 R 10 C1-C4-alkyl substituted by OR 11 R may be selected from C1-C4-alkyl, C1-C4-haloalkyl and cyclopropyl, each of which is substituted by R 1 are, for each occurrence independently, halo, OR 11 , C1-C4-alkyl, C1-C4-haloalkyl and cyclopropyl. 1may be independently selected at each occurrence from halo and C-C-alkyl. 1 R may, independently at each occurrence, be halo, e.g., fluoro. 1 may be, independently at each occurrence, C1-C4-alkyl, e.g., methyl. 1 may be H.

[0040] m may be 1, and a single R 1 The group is F and NR 6 It may be located ortho to the amino acid.

[0041] m may be 0, R 2 may be H for each occurrence, and R 5 may be H for each occurrence.

[0042] R 2 is independently H, fluoro, nitro, cyano, OR 11 , C1-C4-alkyl, NR 9 R 10 C1-C4-alkyl substituted by OR 11 R may be selected from C1-C4-alkyl, C1-C4-haloalkyl and cyclopropyl, each of which is substituted by R 2 are independently H, fluoro, and OR for each occurrence. 11 , C1-C4-alkyl, C1-C4-haloalkyl and cyclopropyl. 2 may be independently selected at each occurrence from H, fluoro and C-C-alkyl. 2 R may be independently selected at each occurrence from fluoro and C-C-alkyl. 2 may be independently selected at each occurrence from H and C-C-alkyl. 2 may be H for each occurrence. R 2 Each occurrence of R may be fluoro. 2 Each occurrence of R may be C1-C4-alkyl, e.g. methyl. 2The groups and the carbon atoms attached to them may together form a C3-C6-cycloalkyl ring, for example cyclopropyl.

[0043] R 5 may be independently selected at each occurrence from H, fluoro and C-C-alkyl. 5 may be 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 may be independently selected at each occurrence from H 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 may be independently selected at each occurrence from H and C1-C4-alkyl, for example methyl.

[0044] R 5 may be H for each occurrence. R 5 may be H in one occurrence and C-C-alkyl, e.g., methyl, in the other occurrence. 5 Each occurrence may be C1-C4-alkyl, e.g. methyl.

[0045] R 6 may be H. 6 may be C1-C4-alkyl, for example methyl.

[0046] R 7 may be H. 7 are independently halo, nitro, cyano, OR 11 , C1-C4-alkyl, NR 9 R 10 C1-C4-alkyl substituted by OR 11 R may be selected from C1-C4-alkyl, C1-C4-haloalkyl and cyclopropyl, each of which is substituted by R7 independently, halo, OR 11 , C1-C4-alkyl, C1-C4-haloalkyl and cyclopropyl. 7 may be independently selected from halo and C-C-alkyl. 7 When present, R may be halo, e.g. fluoro. 7 may be C1-C4-alkyl, for example methyl.

[0047] R 7a may be H. 7a are independently halo, nitro, cyano, OR 11 , CO2R 9 ,CONR 9 R 9 , C1-C4-alkyl, NR 9 R 10 C1-C4-alkyl substituted by OR 11 R may be selected from C1-C4-alkyl, C1-C4-haloalkyl and cyclopropyl, each of which is substituted by R 7a independently, halo, OR 11 , C1-C4-alkyl, C1-C4-haloalkyl and cyclopropyl.

[0048] R 7 may be H, and X 1 may be N. 7 may be H, and X 1 is CR 7a R 7 may be H, and X 1 R may be CH. 7 may be H, and X 1 is CR 7a where R 7a are independently halo, nitro, cyano, OR 11 , CO2R 9 ,CONR 9 R 9 , C1-C4-alkyl, NR 9 R10 C1-C4-alkyl substituted by OR 11 C1-C4-alkyl, C1-C4-haloalkyl and cyclopropyl, substituted by

[0049] R 8a may be H. 8a is halo, C1-C4-alkyl, NR 9 R 10 C1-C4-alkyl substituted by OR 11 C1-C4-alkyl, C1-C4-haloalkyl and C0-C4-alkylene-R 8c R 8a may 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). 8a may be halo, e.g., F.

[0050] R 8b may be H. 8b is C1-C4-alkyl, NR 9 R 10 C2-C4-alkyl substituted by OR 11 C2-C4-alkyl, C1-C4-haloalkyl and C0-C4-alkylene-R 8c R 8b may be selected from H, C1-C4-alkyl and cyclopropyl. R 8b may be C1-C4-alkyl (e.g. methyl).

[0051] R 8b are independently H, C1-C4-alkyl, NR9 R 10 C2-C4-alkyl substituted by OR 11 C2-C4-alkyl, C3-C4-alkenyl, C3-C4-alkynyl, C1-C4-haloalkyl and C0-C4-alkylene-R 8c is selected from.

[0052] R 8a may be H, and R 8b R may be C1-C4-alkyl (e.g., methyl). 8a may be C1-C4-alkyl (e.g. methyl), and R 8b R may be C1-C4-alkyl (e.g., methyl). 8a and R 8b may both be methyl.

[0053] R 9 may be independently selected at each occurrence from H and C1-C4-alkyl.

[0054] R 10 may be independently selected at each occurrence from H, C-C-alkyl, C(O)-C-C-alkyl and S(O)-C-C-alkyl. R 10 may be independently selected at each occurrence from H and C1-C4-alkyl.

[0055] R 11 may be independently selected at each occurrence from H, C-C-alkyl and C-C-haloalkyl. 11 may be independently selected at each occurrence from H and C-C-alkyl. 11 may, independently at each occurrence, be C1-C4-alkyl, e.g. methyl.

[0056] R 12 may be independently selected from 5- or 6-membered heteroaryl, where the heteroaryl group is optionally selected from 1 to 3 R 14R 12 may be independently selected from 5-membered heteroaryl, such as imidazole, where the heteroaryl group is optionally selected from 1 to 3 R 14 It may be substituted by groups.

[0057] R 13 is independently selected for each occurrence from oxo, fluoro, OR 11 , CO2R 9 , CO2NR 9 R 9 , C1-C4-alkyl, NR 9 R 10 C1-C4-alkyl substituted by OR 11 R may be selected from C1-C4-alkyl, C1-C4-haloalkyl and cyclopropyl, each of which is substituted by R 13 is independently for each occurrence oxo, OR 11 , C1-C4-alkyl and cyclopropyl. 13 R may be independently selected at each occurrence from oxo and C-C-alkyl. 13 may be independently selected at each occurrence from C1-C4-alkyl, for example methyl.

[0058] R 14 is independently selected for each occurrence as halo, nitro, cyano, OR 11 , C1-C4-alkyl, NR 8 R 9 C1-C4-alkyl substituted by OR 11 R may be selected from C1-C4-alkyl, C1-C4-haloalkyl and cyclopropyl, each of which is substituted by R 14 are, for each occurrence independently, halo, OR 11 , C1-C4-alkyl, C1-C4-haloalkyl and cyclopropyl. 14 may be independently selected at each occurrence from halo and C-C-alkyl. 14R may be independently selected at each occurrence from halo, e.g., fluoro. 14 may be independently selected at each occurrence from C1-C4-alkyl, for example methyl.

[0059] R 3 may be H; and R 4 are independently C1-C6-alkyl, C1-C6-haloalkyl, C0-C4-alkylene-R 4a where R 4a may be independently selected from C-C-cycloalkyl, phenyl, 5-, 6-, 9- or 10-membered heteroaryl and 4-10-membered heterocycloalkyl; wherein said heterocycloalkyl or heteroaryl groups may be monocyclic or bicyclic; said cycloalkyl or heterocycloalkyl groups may optionally be joined by a single R 12 group and / or 1 to 4 R 13 groups, said phenyl or heteroaryl groups being optionally substituted by a single R 12 Basic and / or 1-3 R 14 may be substituted by a group; or, R 3 and R 4 may be taken together with the nitrogen atom to which they are attached to form a 4-10 membered heterocycloalkyl group or a 5- or 9-membered heteroaryl group; wherein said heterocycloalkyl group may optionally be joined by a single R 12 group and / or 1 to 4 R 13 groups, the heteroaryl group optionally being substituted by a single R 12 group and / or 1 to 3 R 14 It may be substituted by groups.

[0060] R 3 may be H; and R 4are independently C1-C6-alkyl, C1-C6-haloalkyl, C0-C4-alkylene-R 4a where R 4a may be independently selected from C3-C8-cycloalkyl, phenyl, 5-, 6-, 9- or 10-membered heteroaryl and 4-10-membered heterocycloalkyl; wherein said heterocycloalkyl or heteroaryl group may be monocyclic or bicyclic; said cycloalkyl or heterocycloalkyl group may optionally be selected from 1 to 4 R 13 groups, and the phenyl or heteroaryl group is optionally substituted with 1 to 3 R 14 may be substituted by a group; Or, R 3 and R 4 may be taken together with the nitrogen atom to which they are attached to form a 4-10 membered heterocycloalkyl group or a 5- or 9-membered heteroaryl group, wherein said heterocycloalkyl group optionally comprises 1 to 4 R 13 The heteroaryl group may be optionally substituted with 1 to 3 R 14 It may be substituted by groups.

[0061] R 3 may be H.

[0062] R 4 is C1-C6-alkyl, C1-C6-haloalkyl and C0-C4-alkylene-R 4a may be selected from 。

[0063] R 4 may be selected from C-C-alkyl and C-C-haloalkyl. 4 may be selected from C2-C3-alkyl and C2-C3-haloalkyl. 4 R may be C1-C4-haloalkyl. 4 R may be C2-C3-haloalkyl. 4 may be 2,2,2-trifluoroethyl.

[0064] Example R 4 The base is [ka] Includes.

[0065] R 4 is C0-C4-alkylene-R 4a R 4 CH2-R 4a R 4 is R 4a may be also possible.

[0066] R 4a may be independently selected from C-C-cycloalkyl, phenyl, 5-, 6-, 9- or 10-membered heteroaryl, 4-10-membered heterocycloalkyl, where said heterocycloalkyl or heteroaryl group may be monocyclic or bicyclic; where said cycloalkyl or heterocycloalkyl group may optionally be selected from 1 to 4 R 13 groups, and the phenyl or heteroaryl group is optionally substituted with 1 to 3 R 14 It may be substituted by a group.

[0067] R 4a may be selected from C-C-cycloalkyl and 4-10 membered heterocycloalkyl, wherein said cycloalkyl or heterocycloalkyl group may optionally be selected from a single R 12 group and / or 1 to 4 R 13 R 4a may be selected from C-C-cycloalkyl and 4-10 membered heterocycloalkyl, wherein said cycloalkyl or heterocycloalkyl group may optionally be selected from 1 to 4 R 13 It may be substituted by groups.

[0068] R 4may be selected from CH2-C3-C8-cycloalkyl and CH2-4-10-membered heterocycloalkyl, wherein said cycloalkyl or heterocycloalkyl group may optionally be selected from a single R 12 group and / or 1 to 4 R 13 may be substituted by groups. 4 may be selected from CH2-C3-C8-cycloalkyl and CH2-4-10-membered heterocycloalkyl, wherein said cycloalkyl or heterocycloalkyl group may optionally be selected from 1 to 4 R 13 It may be substituted by groups.

[0069] R 4 may be selected from C-C-cycloalkyl and 4-10 membered heterocycloalkyl, wherein said cycloalkyl or heterocycloalkyl group may optionally be selected from a single R 12 group and / or 1 to 4 R 13 R 4 may be selected from C-C-cycloalkyl and 4-10 membered heterocycloalkyl, wherein said cycloalkyl or heterocycloalkyl group may optionally be selected from 1 to 4 R 13 It may be substituted by groups.

[0070] R as an example 4 The base is [ka] Includes.

[0071] R 4a may be independently selected from phenyl and 5- or 6-membered heteroaryl; wherein said phenyl or heteroaryl group is optionally joined to a single R 12 group and / or 1 to 3 R 14 R 4a may be independently selected from phenyl and 5- or 6-membered heteroaryl; wherein said phenyl or heteroaryl group is optionally selected from 1 to 3 R14 R 4a may independently be phenyl; wherein the phenyl group is optionally selected from a single R 12 group and / or 1 to 3 R 14 R 4a may independently be phenyl; wherein the phenyl group is optionally selected from 1 to 3 R 14 R 4a may independently be a 5- or 6-membered heteroaryl; wherein the heteroaryl group is optionally joined to a single R 12 group and / or 1 to 3 R 14 R 4a may independently be a 5- or 6-membered heteroaryl; wherein the heteroaryl group optionally comprises 1 to 3 R 14 It may be substituted by groups.

[0072] R 4 may be independently selected from CH2-phenyl or CH2-5- or 6-membered heteroaryl, wherein said phenyl or heteroaryl group is optionally joined by a single R 12 group and / or 1 to 3 R 14 R 4 may be independently selected from CH2-phenyl or CH2-5- or 6-membered heteroaryl, wherein said phenyl or heteroaryl group is optionally joined by 1 to 3 R 14 R 4 may independently be CH-phenyl, wherein said phenyl is optionally joined to a single R 12 group and / or 1 to 3 R 14 R 4 may independently be CH-phenyl, where the phenyl group is optionally joined to one to three R 14 R 4may independently be CH-5 or 6 membered heteroaryl, where the heteroaryl group is optionally joined to a single R 12 group and / or 1 to 3 R 14 R 4 may independently be CH-5 or 6 membered heteroaryl, where the heteroaryl group is optionally joined to one or more of R 14 It may be substituted by groups.

[0073] R 4 may be independently selected from phenyl or 5- or 6-membered heteroaryl, wherein said phenyl or heteroaryl group is optionally joined to a single R 12 group and / or 1 to 3 R 14 R 4 may be independently selected from phenyl or 5- or 6-membered heteroaryl, wherein said phenyl or heteroaryl group is optionally joined by 1 to 3 R 14 R 4 may independently be phenyl, where the phenyl group is optionally joined to a single R 12 group and / or 1 to 3 R 14 R 4 may independently be phenyl, where the phenyl group is optionally selected from 1 to 3 R 14 R 4 may independently be a 5- or 6-membered heteroaryl, wherein the heteroaryl group is optionally joined to a single R 12 group and / or 1 to 3 R 14 R 4 may independently be a 5- or 6-membered heteroaryl, where the heteroaryl group optionally contains 1 to 3 R 14 It may be substituted by groups.

[0074] R 4may be independently selected from phenyl or 6-membered heteroaryl, wherein said phenyl or 6-membered heteroaryl group is provided with one R 14 R 14 The group is OR 11 R in the meta position may be selected from C1-C4-alkyl, C1-C4-alkyl and C1-C4-haloalkyl substituted by 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.

[0075] R 4 R may be a six-membered heteroaryl group. 4 R may be phenyl. 4 is one R at the meta position 14 R may be a phenyl group substituted with 14 is R 14a As an example, R 4 The base is [ka] [In the formula, R 14a are 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 by NR 8 R 9 and cyclopropyl, substituted by; where z is an integer selected from 1 and 2. Includes.

[0076] Example R 4 The base is [ka] Includes

[0077] R 3 and R 4 may be taken together with the nitrogen atom to which they are attached to form a 4-10 membered heterocycloalkyl group or a 5- or 9-membered heteroaryl group; wherein said heterocycloalkyl group may optionally be joined by a single R 12 group and / or 1 to 4 R 13 group, wherein the heteroaryl group is optionally substituted with a single R 12 group and / or 1 to 3 R 14 R 3 and R 4 may be taken together with the nitrogen atom to which they are attached to form a 4-10 membered heterocycloalkyl group or a 5- or 9-membered heteroaryl group, wherein said heterocycloalkyl group optionally comprises 1 to 4 R 13 group, wherein the heteroaryl group is optionally substituted with 1 to 3 R 14 It may be substituted by groups.

[0078] 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; where the heteroaryl group is optionally comprised of a single R 12 group and / or 1 to 3 R 14 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, wherein said heteroaryl group optionally comprises 1 to 3 R 14 R3 and R 4 may be taken together with the nitrogen atom to which they are attached to form a 5-membered heteroaryl group; where the heteroaryl group is optionally composed of a single R 12 group and / or 1 to 3 R 14 R 3 and R 4 may be taken together with the nitrogen atom to which they are attached to form a 5-membered heteroaryl group, wherein said heteroaryl group optionally comprises 1 to 3 R 14 It may be substituted by groups.

[0079] NR as an example 3 R 4 The base is [ka] Includes.

[0080] R 3 and R 4 may be taken together with the nitrogen atom to which they are attached to form a 4-10 membered heterocycloalkyl group; said heterocycloalkyl group may optionally be joined by a single R 12 group and / or 1 to 4 R 13 R 3 and R 4 may be taken together with the nitrogen atom to which they are attached to form a 4-10 membered heterocycloalkyl group; said heterocycloalkyl group may optionally be selected from 1 to 4 R 13The heterocycloalkyl group may be substituted by a 7-10 membered bicyclic heterocycloalkyl group. The heterocyclic group may be a 7-10 membered bridged bicyclic heterocycloalkyl group. The heterocyclic group may be a monocyclic 4-7 membered heterocycloalkyl group. The heterocyclic group may be a monocyclic 5-6 membered heterocycloalkyl group. The heterocyclic group may be a pyrrolidine. The heterocyclic group may be a piperidine. The heterocyclic group may be a morpholine. The heterocyclic group may be a piperazine. For the avoidance of doubt, the heterocycloalkyl groups referred to in this paragraph may optionally be substituted with a single R 12 group and / or 1 to 4 R 13 The heterocycloalkyl groups referred to in this paragraph may be optionally substituted with 1 to 4 R 13 The heterocyclic group may be pyrrolidine and may be substituted with one R 13 The heterocyclic group may be pyrrolidine and may be substituted with one R 13 The heterocyclic group may be piperidine and may be substituted with one R 13 The heterocyclic group may be piperidine and may be substituted with one R 13 The heterocyclic group may be piperidine and may be substituted with one R 13 The heterocyclic group may be morpholine and may be substituted with one R 13 The heterocyclic group may be morpholine and may be substituted with one R 13 R 13 The group is C1-C4-alkyl, OR 11 R may be selected from C1-C4-alkyl (e.g., -(CH3)2-OH), and C1-C4-haloalkyl (e.g., -CF3), substituted by 13The group may be C1-C4-haloalkyl, for example -CHF2 or -CF3.

[0081] NR as an example 3 R 4 The base is [ka] Includes.

[0082] R 3 and R 4 is NR 3 R 4 may be selected to include a CHF2 group or a CF3 group.

[0083] NR 3 R 4 is the expression: [ka] [In the formula, R 4b is selected, for each occurrence, from H and F; where at least one R 4b The group is F; R 3a is independently selected from H and C-C-alkyl; R 4c is independently selected from H, C-C-alkyl and C-C-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.

[0043]

[0084] At least two R 4b The group may be F. Two R 4b The group may be F, and one R 4b The group may be H. R 4b Each group may be F.

[0085] R 3a may be independently selected from H and C-C-alkyl; R4c may be independently selected from H, C-C-alkyl and C-C-cycloalkyl. 3a may be H; R 4c may be independently selected from H, C1-C4-alkyl and C4-C6-cycloalkyl. Said alkyl or cycloalkyl groups may be unsubstituted.

[0086] R 3a and R 4c R may be taken together with the carbon and nitrogen to which they are attached to form a 4-6 membered heterocycloalkyl group. 3a and R 4c may be taken together with the carbon and nitrogen to which they are attached to form a 5-membered heterocycloalkyl group, which may be unsubstituted.

[0087] The compound of formula (I) [ka] [ka] [ka] [ka] [ka] [ka] may be selected from:

[0088] The compound of formula (I) [ka] [ka] [ka] [ka] [ka] may be selected from:

[0089] In one aspect of the invention there is provided a compound of the invention for use as a pharmaceutical.

[0090] In another aspect, there is provided a compound of the invention for use in treating a condition modulated by DDR1 and / or DDR2. The compounds of any formula disclosed herein may be for use in treating a condition treatable by inhibition of DDR1 and / or DDR2.

[0091] In another aspect of the invention, there is provided a compound of the invention for use in the treatment of a disease or disorder selected from kidney disease, liver disease, inflammatory conditions, vascular conditions, acute and chronic organ transplant rejection, fibrotic diseases and cancer.

[0092] In one embodiment of the present invention, a method of treating a disease or disorder regulated by DDR1 and / or DDR2 is provided, comprising administering to a patient in need thereof a therapeutic amount of a compound of the present invention.

[0093] The method of treating may be a method of treating a condition treatable by inhibition of DDR1 and / or DDR2.

[0094] The present invention also provides a method of treating a disease or disorder selected from kidney disease, liver disease, inflammatory conditions, vascular conditions, acute and chronic organ transplant rejection, fibrotic diseases and cancer, comprising administering to a patient in need thereof a therapeutic amount of a compound of any of the formulae disclosed herein.

[0095] Kidney disease includes acute kidney injury and chronic kidney disease with or without proteinuria, including end stage renal disease (ESRD). These include reduced creatinine clearance and reduced glomerular filtration rate, microalbuminuria, albuminuria and proteinuria, glomerulosclerosis with expansion of the plexiform mesangial matrix with or without significant hypercellularity (particularly diabetic nephropathy and amyloidosis), focal thrombosis of the glomerular capillaries (particularly thrombotic microangiopathy), global fibrinoid necrosis, ischemic lesions, malignant nephrosclerosis (such as ischemic regression, reduced renal blood flow and renal arteriopathy), swelling and proliferation of intracapillary cells (endothelial cells, mesangial cells) and / or extracapillary cells (crescent cells) as seen in glomerulonephritis, focal segmental glomerular sclerosis, IgA nephropathy, vasculitis / systemic disease, acute and chronic renal transplant rejection. Renal diseases include early Alport syndrome and advanced Alport syndrome.

[0096] 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, such as vasculitis, granulomatous diseases (sarcoidosis, hypersensitivity pneumonitis), collagen vascular diseases, radiation-induced fibrosis, etc.

[0097] Vascular conditions include atherosclerosis, thrombotic vascular disease and thrombotic microangiopathy, proliferative arteriopathy (such as enlarged myointimal cells and nodular hyperplasia surrounded by a mucinous extracellular matrix), atherosclerosis, reduced vascular compliance (such as sclerosis, reduced ventricular compliance and reduced vascular compliance), endothelial dysfunction, and the like.

[0098] Vascular 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.

[0099] Fibrotic diseases include, but are not limited to, myocardial fibrosis, vascular fibrosis, renal fibrosis, hepatic fibrosis, pulmonary fibrosis, skin fibrosis, scleroderma, encapsulating peritonitis, systemic sclerosis, Alport syndrome, chronic kidney disease, NASH, interstitial lung disease, and systemic sclerosis.

[0100] In certain embodiments, the compounds of the invention are used in the treatment or method of treating cancer. Examples include, but are not limited to, liver cancer, bladder cancer, hepatoma, squamous carcinoma of the lung, non-small cell lung cancer, adenocarcinoma of the lung, small cell lung cancer, various types of head and cervix cancer, breast cancer, colon cancer, colorectal cancer, peritoneal cancer, hepatocellular carcinoma, gastrointestinal cancer, esophageal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, squamous cell carcinoma, pituitary cancer, astrocytoma, soft tissue sarcoma, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, kidney cancer, liver cancer, prostate cancer, vulvar cancer, thyroid cancer, hepatic carcinoma, brain cancer, endometrial cancer, testicular cancer, cholangiocarcinoma, gallbladder cancer, carcinoma, gastric cancer and melanoma. In certain embodiments, the cancer is selected from bladder cancer, pancreatic cancer, breast cancer, lung cancer, ovarian cancer and glioblastoma.

[0101] In another aspect of the invention, there is provided a pharmaceutical composition comprising a compound of the invention and a pharma- ceutically acceptable excipient.

[0102] In certain embodiments, the pharmaceutical composition may be a combination product that includes an additional pharma- ceutical active agent.

[0103] 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.

[0104] Detailed Description Below are definitions of terms used in this application. Terms not defined herein take on the ordinary meaning that one of ordinary skill in the art would understand such terms.

[0105] The term "halo" refers to one of the halogens of 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.

[0106] The term "alkyl" means a straight or branched hydrocarbon chain. For example, the term "C 1-6 "Alkyl" means a 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 may likewise be straight or branched and are divalent, i.e., bonded to the rest of the molecule at two positions. Furthermore, the alkylene group may correspond, for example, to one of the alkyl groups listed in this paragraph. Alkyl and alkylene groups may be unsubstituted or substituted by one or more substituents.

[0107] The term "haloalkyl" refers, independently at each occurrence, 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" means a straight or branched hydrocarbon chain containing 1, 2, 3, 4, 5, or 6 carbon atoms substituted with at least one halogen. The halogen atom may be located at any position on the hydrocarbon chain. For example, C 1-6Haloalkyl can mean chloromethyl, fluoromethyl, trifluoromethyl, chloroethyl, e.g. 1-chloromethyl and 2-chloroethyl, trichloroethyl, e.g. 1,2,2-trichloroethyl, 2,2,2-trichloroethyl, fluoroethyl, e.g. 1-fluoromethyl and 2-fluoroethyl, trifluoroethyl, e.g. 1,2,2-trifluoroethyl and 2,2,2-trifluoroethyl, chloropropyl, trichloropropyl, fluoropropyl, trifluoropropyl. The term "fluoroalkyl" means a hydrocarbon chain substituted with at least one fluorine atom.

[0108] 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" means 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 be present as an E or Z isomer. The double bond may be in any position on the hydrocarbon chain. For example, "C 2-6 "Alkenyl" may be ethenyl, propenyl, butenyl, butadienyl, pentenyl, pentadienyl, hexenyl and hexadienyl.

[0109] The term "alkynyl" refers to a branched or straight chain hydrocarbon chain containing at least one triple bond. For example, the term "C 2-6 "Alkynyl" means a branched or straight chain hydrocarbon chain containing at least one triple bond and having 2, 3, 4, 5 or 6 carbon atoms. The triple bond may be at any position on the hydrocarbon chain. For example, "C 2-6 "Alkynyl" may be ethynyl, propynyl, butynyl, pentynyl and hexynyl.

[0110] The term "heteroalkyl" refers to a branched or straight-chained hydrocarbon chain containing at least one heteroatom selected from N, O and S positioned between any carbon in the chain or at the end of the chain. For example, the term "C1-6 "Heteroalkyl" means 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 located between any carbon in the chain or at the end of the chain. For example, the hydrocarbon chain may contain one or two heteroatoms. 1-6 A heteroalkyl may 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 may be O-alkyl.

[0111] The term "heterocycle" refers to a saturated, unsaturated or aromatic ring system containing at least one heteroatom selected from N, O or S. A "heterocycle" system may contain 1, 2, 3 or 4 heteroatoms, e.g., 1 or 2 heteroatoms. A "heterocyclic" system may be a monocyclic or fused polycyclic ring system, e.g., bicyclic or tricyclic. A "heterocyclic" moiety may contain 3 to 14 carbon atoms, e.g., 3 to 8 carbon atoms in a monocyclic system and 7 to 14 carbon atoms in a polycyclic system. "Heterocycle" encompasses heterocycloalkyl, heterocycloalkenyl and heteroaryl moieties. For example, the heterocyclic group can be 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-alkylpyridone.

[0112] The term “C 3-8 "Cycloalkyl" means a saturated hydrocarbon ring system containing 3, 4, 5, 6, 7, or 8 carbon atoms. For example, "C 3-8"Cycloalkyl" may be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

[0113] The term “C 3-8 "Cycloalkenyl" means a non-aromatic unsaturated hydrocarbon ring system containing 3, 4, 5, 6, 7 or 8 carbon atoms. If the ring system is not aromatic, the ring may contain more than one double bond. For example, "C 3-8 "Cycloalkyl" can be cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadiene, cyclooctenyl and cycloatadienyl.

[0114] The term "heterocycloalkyl" refers to a saturated hydrocarbon ring system containing carbon atoms and at least one heteroatom selected from N, O and S in the ring. For example, there may be 1, 2 or 3 heteroatoms, and optionally there may be 1 or 2. A "heterocycloalkyl" may be bonded to the rest of the molecule through any carbon atom or heteroatom. A "heterocycloalkyl" may have one or more bonds, for example 1 or 2 bonds, to the rest of the molecule: these bonds may be through any atom of the ring. For example, a "heterocycloalkyl" is a "C 3-8 The term "C heterocycloalkyl" may also be used. 3-8 "Heterocycloalkyl" is a saturated hydrocarbon ring system containing 3, 4, 5, 6, 7, or 8 atoms, at least one of which is a heteroatom in the ring selected from N, O, and S. "Heterocycloalkyl" may be oxirane, aziridine, azetidine, oxetane, tetrahydrofuran, pyrrolidine, imidazolidine, succinimide, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, piperidine, morpholine, thiomorpholine, piperazine, and tetrahydropyran.

[0115] The term "aromatic" when applied to a substituent group 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.

[0116] The term "aryl" refers to an aromatic hydrocarbon ring system. The ring system has 4n+2 electrons in a conjugated π system within the ring with all atoms contributing to the conjugated π system being on the same plane. For example, "aryl" can be phenyl and naphthyl. The aryl system itself can be substituted by other groups.

[0117] The term "heteroaryl" refers to an aromatic hydrocarbon ring system having at least one heteroatom selected from O, N and S in a single ring or in fused rings. The ring or ring system has 4n+2 electrons in a conjugated π-system with all atoms contributing to the conjugated π-system being in the same plane. For example, a "heteroaryl" can be imidazole, oxazole, isoxazole, thiazole, isothiazole, thien, furan, thianthrene, pyrrole, benzimidazole, pyrazole, pyrazine, pyridine, pyrimidine and indole.

[0118] [ka] A bond that terminates in indicates that it is attached to another atom not shown in the structure. A bond that terminates inside a ring structure and does not terminate at an atom of the ring structure indicates that the bond may be attached to any atom in the ring structure allowed by valences.

[0119] Bonds drawn with solid and dotted lines indicate bonds that may be either single or double bonds where chemically possible. For example, the bond drawn below may be either a single bond or a double bond. [ka]

[0120] When a moiety is substituted, it may be substituted at any point on the moiety which is chemically possible and consistent with valence requirements. The moiety may be substituted with one or more substituents, e.g., 1, 2, 3, or 4 substituents; a group may have one or two substituents. When there are two or more substituents, the substituents may be the same or different.

[0121] Substituents are present only where chemically possible, and one skilled in the art can determine (experimentally or theoretically) without undue effort which substitutions are chemically possible and which are not.

[0122] Ortho, meta and para substitution are terms well understood in the art. For the avoidance of doubt, "ortho" substitution means that adjacent carbons are substituted (either a simple group such as the fluoro group in the example below, or [ka] The substitution pattern has the bond between the two groups (the other part of the molecule shown at the bond end). [ka]

[0123] A "meta" substitution is a substitution pattern in which two substituents are on carbons that are separated from each other by one carbon, i.e., there is a single carbon atom between the substituted carbons. In other words, there is a substituent on a second atom separated from an atom that has another substituent. For example, the following group is meta substituted: [ka]

[0124] "Para" substitution is a substitution pattern in which two substituents are on carbons that are separated from each other by two carbons, i.e., there are two carbon atoms between the substituted carbons. In other words, there is a substituent on an atom that is a third away from an atom that has another substituent. For example, the following group is para substituted: [ka]

[0125] Throughout this specification, disclosure of compounds also encompasses the pharma- ceutically acceptable salts, solvates and stereoisomers thereof.

[0126] In the case where a compound has a stereocenter, both the (R) and (S) stereoisomers are contemplated by the present invention, as well as mixtures of stereoisomers or racemic mixtures. In the case where a compound of the present invention has more than one stereoisomer, any combination of the (R) and (S) stereoisomers is contemplated. The combination of the (R) and (S) stereoisomers may result in a diastereomeric mixture or a single diastereoisomer. The compound of the present invention may exist as a single stereoisomer, or may be a mixture of stereoisomers, such as a racemic mixture, a mixture of other enantiomers, and a diastereomeric mixture. In the case where the mixture is a mixture of enantiomers, the enantiomeric excess may be any of those disclosed above. In the case where the compound is a single stereoisomer, the compound may also contain other diastereoisomers or enantiomers as impurities. Thus, a single stereoisomer does not necessarily have an enantiomeric excess (ee) or diastereomeric excess (de) of 100%, but may have an ee or de of at least 85%, at least 60% or less. For example, ee or de can be 90% or more, 90% or more, 80% or more, 70% or more, 60% or more, 50% or more, 40% or more, 30% or more, 20% or more, or 10% or more.

[0127] The present invention contemplates pharma- ceutically acceptable salts of the compounds of the present invention. These may include acid addition salts and base salts of the compounds. These may be acid addition salts and base salts of the compounds. In addition, the present invention contemplates solvates of the compounds. These may be hydrates or other solvate forms of the compounds.

[0128] Suitable acid addition salts are formed from acids which form non-toxic salts, for example, 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. These include: doyate, isethionate, lactate, malate, maleate, malonate, mesylate, methyl sulfate, naphthylate, 1,5-naphthalenedisulfonate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, saccharate, stearate, succinate, tartrate, tosylate and trifluoroacetate.

[0129] Suitable base salts are formed from bases which form non-toxic salts. Examples include aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts. Hemi-salts of acids and bases may also be formed, such as hemisulfate and hemicalcium salts. For a review of suitable salts, see "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

[0130] 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 the desired acid or base; or (iii) by converting a salt of a compound of the invention into another salt by reaction with an appropriate acid or base or by using an appropriate ion exchange column.

[0131] All three reactions are typically carried out in solution. The resulting salt precipitates and is collected by filtration or recovered by evaporation of the solvent. The degree of ionization in the resulting salts can vary from completely ionized to almost non-ionized.

[0132] The compounds of the present invention can exist in both non-solvated and solvated forms.The term "solvate" is used herein to indicate a molecular complex that comprises the compounds of the present invention and a stoichiometric amount of one or more pharma-ceutically acceptable solvent molecules, such as ethanol.The term "hydrate" is adopted when said solvent is water.

[0133] The scope of the present invention includes complexes such as clathrates, drug-host inclusion complexes, etc., in which the drug and host are present in stoichiometric or non-stoichiometric amounts, in contrast to the aforementioned solvates. 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).

[0134] Hereinafter all references to compounds of any formula include references to salts, solvates and complexes thereof and to solvates and complexes of salts thereof.

[0135] The compounds of the present invention include compounds of the several formulas defined herein (including all polymorphs and crystal habits thereof), prodrugs, and isomers thereof (including optical isomers, geometric isomers and tautomers) as defined below, as well as isotopically labeled compounds of the present invention.

[0136] The present invention also includes all pharma- ceutically 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.

[0137] Examples of isotopes suitable for inclusion in the compounds of the present 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, for example 35 Examples include S.

[0138] 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 ease of detection.

[0139] Deuterium, i.e. 2 Substitution with heavier isotopes, such as H, may confer certain therapeutic advantages resulting from greater metabolic stability, for example increased half-life in vivo or reduced dosage requirements and therefore may be preferred in some circumstances.

[0140] The compound of the present invention before purification may exist as a mixture of enantiomers depending on the synthetic procedure used. Enantiomers can be separated by conventional techniques known in the art. Therefore, the present invention covers individual enantiomers and their mixtures.

[0141] In some steps of the process for preparing the compounds of the present invention, it may be necessary to protect potentially reactive functional groups that are not desired to react, and then to cleave said protecting groups. In such cases, any suitable protecting radical can be used. In particular, the protection and deprotection methods described by TW GREENE (Protective Groups in Organic Synthesis, A. Wiley- Interscience Publication, 1981) or PJ Kocienski (Protecting groups, Georg Thieme Verlag, 1994) can be used. The above reactions and preparation of new starting materials used in the preceding methods are all conventional, and the appropriate reagents and reaction conditions for their implementation or preparation, as well as the procedures for isolating the desired products, will be known to those skilled in the art by reference to the literature precedents and the examples and preparations herein.

[0142] Additionally, the compounds of the present invention and intermediates for preparing them can be purified according to various well-known methods, such as, for example, crystallization or chromatography.

[0143] 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 ROCK, such as fibrotic diseases, autoimmune diseases, inflammatory fibrotic conditions, inflammatory conditions, central nervous system disorders, or cancer.

[0144] The treatment methods or compounds for use in the treatment of kidney disease, liver disease, inflammatory conditions, vascular conditions, acute and chronic organ transplant rejection, fibrotic diseases and cancer defined herein may be applied as a monotherapy or as a combination therapy with an additional active agent.

[0145] The treatment method or compound for use in the treatment of kidney disease, liver disease, inflammatory conditions, vascular conditions, acute and chronic organ transplant rejection, fibrotic diseases and cancer. The additional active agent may be one or more active agents used to treat the condition treated by the compound of the present invention and the additional active agent. The additional active agent may include one or more of the following active agents: (i) Steroids, such as corticosteroids (including glucocorticoids and mineralocorticoids), such as alclomethasone, alclomethasone dipropionate, aldosterone, amcinonide, beclomethasone, beclomethasone dipropionate, betamethasone, betamethasone dipropionate, betamethasone sodium phosphate, betamethasone valerate, budesonide, clobetasone, clobetasone butyrate, clobetasone difluorocortolone, flucloxolone, flumethasone, flunisolide, fluocinolone, fluocinolone acetonide, fluocinonide, fluocinonide, fluocortin butyl, fluoxetine ... orocortisone, 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, icomethasone, icomethasone embutate, meprednisone, methylprednisolone, mometasone paramethasone, mometasone furoate monohydrate, prednicarbate, prednisolone, prednisone, tixocortol, tixocortol pivalate, triamcinolone, triamcinolone acetonide, triamcinolone alcohol and their pharma- ceutically acceptable derivatives. Combinations of steroids may be used, for example a combination of two or more of the 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 2A Agonists (e.g., 2,5-dimethoxy-4-iodoamphetamine, TCB-2, lysergic acid diethylamide (LSD), lysergic acid dimethylazetidide); (iii) anti-inflammatory drugs, such as non-steroidal anti-inflammatory drugs; (iv) dihydrofolate reductase inhibitors / antifolates, such as methotrexate, trimethoprim, brodimoprim, tetroxoprim, iclaprim, pemetrexed, ralitrexed, and pralatrexate; and (v) Immunosuppressants such as cyclosporines, tacrolimus, sirolimus spimecrolimus, angiotensin II inhibitors (e.g. valsartan, telmisartan, losartan, irbesatan, azilsartan, olmesartan, candesartan, eprosartan) and ACE inhibitors such as sulfhydryl-containing agents (e.g. captopril, zofenopril), dicarboxylate-containing agents (e.g. enalapril, ramipril, quinapril, perindopril, lisinopril, benazepril, imidapril, zofenopril, trandolapril), phosphate-containing agents (e.g. fosinopril), casokinin, lactokinin, and lactotripeptides. (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) 15PGDH inhibitors, anti-αvβ6 monoclonal antibodies (e.g. BG00011), anti-CTGF monoclonal antibodies (e.g. FG-3019), PAR1 inhibitors, Nox4 inhibitors and PAI-1 inhibitors.

[0146] The methods of treating cancer or compounds for use in treating cancer 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, triethylene triethylenethiophoporamine, carmustine, lomustine, stroptozocin and dacarbazine; antimetabolites (e.g. gemcitabine and antifolates such as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, pemetrexed, cytosine arabinoside, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine , fludarabine phosphate, pentostatin, and gemcitabine 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 taxatate). and polo kinase inhibitors; proteasome inhibitors, such as carfilzomib and bortezomib; interferon therapy; and topoisomerase inhibitors (such as the epipodophyllotoxins etoposide and teniposide, amsacrine, topotecan, mitoxantrone and camptothecin); bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, ara-C, paclitaxel (taxol TM ), formycin, docetaxel, mithramycin, deoxy-co-formycin, mitomycin-C, L-asparaginase, interferons (especially IFN-a), etoposide, and teniposide; (ii) Cytostatics, such as antiestrogens (e.g. tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene and idoxifene), 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 ( such as anastrozole, letrozole, borazole and exemestane) and inhibitors of 5*-reductase such as finasteride; and navelbene, CPT-ll, anastrozole, letrazole, capecitabine, reloxafme, cyclophosphamide, ifosamide, and droloxafine; (iii) anti-invasive agents, such as dasatinib and bosutinib (SKI-606), and metalloproteinase inhibitors, urokinase plasminogen activator receptor function inhibitors, or antibodies against heparanase; (iv) Growth factor function inhibitors: For example, such inhibitors include growth factor antibodies and growth factor receptor antibodies, such as the anti-erbB2 antibody trastuzumab [Herceptin TM], anti-EGFR antibody panitumumab, anti-erbB1 antibody cetuximab, tyrosine kinase inhibitors, such as epidermal growth factor family inhibitors (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-lBB and PD-l) or antibodies against cytokines (IL-I0, TGF-beta); hepatocyte growth factor family inhibitors; insulin growth factor family inhibitors; modulators of protein regulators of cell apoptosis (e.g. Bcl-2 inhibitors); platelet-derived growth factor family inhibitors, e.g. imatinib and / or nilotinib (AMN107); serine / threonine kinase inhibitors (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 action of vascular endothelial growth factor), such as the anti-vascular endothelial growth factor antibody bevacizumab (Avastin) TM );thalidomide;lenalidomide;and, for example, VEGF receptor tyrosine kinase inhibitors, such as vandetanib, vatalanib, sunitinib, axitinib and pazopanib; (vi) gene therapy approaches (including, for example, approaches to replace abnormal genes such as abnormal p53 or abnormal BRCA1 or BRCA2); (vii) immunotherapy approaches (including, for example, antibody therapy approaches), 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 (including preventative and therapeutic vaccines, such as 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 (including glucocorticoids and mineralocorticoids), for example alclometasone, alclometasone dipropionate, aldosterone, amcinonide, beclomethasone, beclomethasone dipropionate, betamethasone, betamethasone dipropionate, betamethasone sodium phosphate, betamethasone valerate, budesonide, clobetasone, clobetasone butyrate, clobetasol phosphate. lopionate, cloprednol, cortisone, cortisone acetate, cortivazol, deoxycortone, desonide, desoxymethasone, dexamethasone, dexamethasone sodium phosphate, dexamethasone isonicotinate, difluorocortolone, fluclorolone, 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, icomethasone, icomethasone embutate, meprednisone, methylprednisolone, mometasone paramethasone, mometasone furoate monohydrate, prednicarbate, prednisolone, prednisone, tixocortol, tixocortol pivalate, triamcinolone, triamcinolone acetonide, triamcinolone alcohol and pharma- ceutically acceptable derivatives of each of these. A combination of steroids is used, for example a combination of two or more of the 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.

[0147] Such combination treatment may be achieved by simultaneous, sequential or separate administration of the individual components of the treatment. Such combination products will use the compounds of this invention within the therapeutically effective dosage ranges described herein and the other pharmacologic active agent within its approved dosage range.

[0148] The compounds of the present invention may exist in single crystalline form, in a mixture of crystalline forms, or may be amorphous.Therefore, the compounds of the present invention intended for pharmaceutical use may be administered as crystalline or amorphous products.They may be obtained as solid plugs, powders, or films by methods such as precipitation, crystallization, freeze-drying, spray drying, evaporative drying, etc.For this purpose, microwave drying or radio frequency drying may be used.

[0149] For the compounds of the present invention described above, the dosage administered will of course vary depending on the compound employed, the mode of administration, the treatment desired and the disorder indicated. For example, when the compounds of the present invention are administered orally, the daily dosage of the compounds of the present invention may be in the range of 0.01 micrograms per kilogram of body weight (μg / kg) to 100 milligrams per kilogram of body weight (mg / kg).

[0150] The compound of the present invention or its pharmaceutically acceptable salt can be used alone, but is generally administered in the form of a pharmaceutical composition in which the compound of the present invention or its pharmaceutically acceptable salt is associated 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, 198.

[0151] Depending on the mode of administration of the compound of the present invention, the pharmaceutical composition used to administer the compound of the present invention preferably contains 0.05-99% w (weight percent) of the compound of the present invention, more preferably 0.05-80% w of the compound of the present invention, even more preferably 0.10-70% w of the compound of the present invention, and even more preferably 0.10-50% w of the compound of the present invention, all weight percentages being based on the total composition.

[0152] The pharmaceutical compositions may be administered topically (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 a sterile solution, suspension or emulsion for injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion); rectally in the form of a suppository; or by inhalation in the form of an aerosol.

[0153] For oral administration, the compound of the present invention is 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 cores prepared as described above may be coated with a concentrated sugar solution, including, for example, gum arabic, gelatin, talcum and titanium dioxide. Alternatively, tablets may be coated with a suitable polymer dissolved in a readily volatile organic solvent.

[0154] For preparation of soft gelatin capsules, the compound of the present invention may be mixed with, for example, vegetable oil or polyethylene glycol. Hard gelatin capsules may contain granules of the compound using any of the excipients mentioned above for tablets. Liquid or semi-solid preparations of the compound of the present invention may also be filled into hard gelatin capsules. Liquid preparations for oral application may be in the form of syrups or suspensions, for example, solutions containing the compound of the present invention, the balance being sugar and a mixture of ethanol, water, glycerol and propylene glycol. Optionally, such liquid preparations may contain coloring agents, flavoring agents, sweeteners (such as saccharin), carboxymethylcellulose as preservatives and / or thickeners, or other excipients known to those skilled in the art.

[0155] For intravenous (parenteral) administration, the compounds of the present invention may be administered as sterile aqueous or oily solutions.

[0156] The size of a therapeutic dose of the compounds of the invention will naturally vary according to well-known principles of medicine, depending on the nature and severity of the condition, the age and sex of the animal or patient, and the route of administration.

[0157] Dose levels, frequency of administration and duration of treatment of the compounds of the invention are expected to vary depending on the formulation, clinical indication, age, and comorbid conditions of the patient.

[0158] Throughout the description and claims of this specification, 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, additives, components, integers, or steps. Throughout the description and claims of this specification, the singular includes the plural, unless the context requires otherwise. In particular, when the indefinite article is used, the specification is understood to contemplate the plural as well as the singular, unless the context requires otherwise.

[0159] It is 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 also applicable to other aspects, embodiments or examples described herein, except where inconsistent therewith. All of the features disclosed in this specification (including the accompanying claims, abstract and drawings), and / or all of the steps of any method or process so disclosed, may be combined in any combination, except combinations in which at least some of such features and / or steps are mutually exclusive. The invention is not limited to the details of the foregoing embodiments. The invention extends to any novel one, or any novel combination, of the features disclosed in this specification (including the accompanying claims, abstract and drawings), or any novel one, or any novel combination of the steps of any method or process so disclosed.

[0160] The reader is directed to all papers and documents relating to this application that have been filed contemporaneously or prior to this application and that are in the public domain herewith, the contents of all such papers and documents being incorporated herein by reference.

[0161] Compounds of the invention can be prepared according to or analogous to general schemes 1-4 and examples 1-14.

[0162] Examples and Synthesis Experimental procedure Solvents, reagents and starting materials were purchased from commercial suppliers and used as received unless otherwise stated. All reactions were performed at room temperature unless otherwise stated. Compound identity and purity were confirmed by LCMS. Retention times RT were reported in minutes. The following methods were used wherever described throughout the experimental section, with gradients detailed in Table 1. Method 1 utilized a Shimadzu 2020 series spectrometer equipped with a binary pump and a diode array detector (capture wavelengths 214 and 254 nm), with MS in positive and negative electrospray mode. Aliquots of 2 μL were 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 / water (v / v), B: 0.05% formic acid / ACN (v / v). Method 2 utilized an Agilent Technologies 1290 Series spectrometer equipped with a binary pump and a diode 254 array detector (capture wavelengths 214 and 254 nm) with the MS in positive electrospray mode. A 2 μL aliquot was injected onto an Agilent Eclipse Plus RRHD C18, (3.0×50 mm) column maintained at 40° C. and eluted at 0.8 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).

[0163] [Table 1]

[0164] 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. In some cases, the Rf values ​​of the compounds were measured on silica thin layer chromatography (TLC) plates.

[0165] Purification of compounds was performed by flash column chromatography on silica or preparative LCMS. LCMS purification was performed using a Waters 3100 mass detector with a Waters 2489 UV / Vis detector in positive and negative electrospray mode (m / z: 150-800). Samples were analyzed using XBridge TM A prep C18 5 μM OBD 19×100 mm column was used, eluting at a flow rate of 20 mL / min with 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) following the gradient outlined in Table 2 below. [Table 2]

[0166] General synthesis route Examples conforming to formula (I) can be prepared by one or more of the synthetic routes described in the following general schemes 1-4. Starting materials and reagents used in the routes described in general schemes 1-4 are either commercially available or prepared using procedures described in the chemical literature, identified using typical chemical structure and reaction search tools. The order of steps may be altered. Where reactive groups are present, such as amines or alcohols, the reactivity of these groups can be masked, if necessary, using suitable protecting groups, such as carbamates, tosylates, hemiaminals, acteals and esters.

[0167] [ka]

[0168] General Scheme 1 General Scheme 1 (where X a In step B, lactam (GI-1) is N-alkylated with an α-haloester such as ethyl bromoacetate in the presence of a base such as triethylamine or cesium carbonate in an organic solvent such as acetonitrile or MeCN (Z is a halogen, typically a bromide, but can also be a chloride or iodide) to give intermediate GI-2. The ester group of GI-2 can be hydrolyzed in step B using LiOH in MeOH, THG and water, and the resulting acid can be reacted in step 3 with a suitable amine in the presence of an activating agent such as HATU to form an amide bond to give amides shown as GI-3. In step D, GI-3 is subjected to a transition metal catalyzed amination such as the Buchwald-Hartwig reaction with a suitable aminoindazole derivative (GI-4) to give examples of formula (I). Z 1 or Z 2 In the case where is NH, the corresponding NH in GI-4 can be protected with a suitable group such as THP or tosyl to facilitate step D. In such cases, a further deprotection step (typically using TFA or HCl) is required to finally prepare the example of formula (I).

[0169] [ka]

[0170] General Scheme 2 General Scheme 2 is a variation of General Scheme 1, in which the N-alkylated lactam GI-2 is subjected in Step A to amination via a Buchwald-Hartwig reaction with an appropriate aminoindazole derivative (GI-4) to give an alkyl ester (typically ethyl or t-butyl) of formula GI-5. Steps B and C show ester hydrolysis and amide formation in a similar manner to General Scheme 1 to provide examples of formula (I). Also, Z 1 or Z 2When is NH, the corresponding NH in GI-4 can be protected with a suitable group such as THP or tosyl to facilitate step A. In these cases, an additional deprotection step (typically using TFA or HCl) is required to ultimately prepare examples of formula (I).

[0171] [ka]

[0172] General Scheme 3 According to General Scheme 3, N-alkylated lactam GI-2 (wherein X a is a halogen, typically a bromide) is converted to an aminolactam of formula GI-6. Step A involves a transition metal catalyzed amination such as a Buchwald-Hartwig reaction with a suitable amine bearing an acid labile protecting group (PG), e.g., t-butyl carbamate, and step B is the removal of the protecting group using HCl or TFA in an organic solvent such as DCM or MeOH. GI-6 can then be subjected to a second transition metal catalyzed amination (step C) such as a Buchwald-Hartwig reaction with a halogen-containing indazole derivative (GI-7) in the presence of a palladium catalyst such as Pd2(dba)3, a ligand such as xantphos, and a base such as cesium carbonate in 1,4-dioxane as a solvent, and then GI-5 can be subjected to hydrolysis and amide formation in steps C and D as previously described in steps B and C of general schemes 1 and 2. As previously described, in the examples of formula (I), Z 1 or Z 2 When is NH, the corresponding NH in GI-7 can be protected with a suitable group such as THP or tosyl to facilitate step C. In such cases, an additional final deprotection step (typically using TFA or HCl) is required to finally prepare the example of formula (I).

[0173] [ka]

[0174] General Scheme 4 General Scheme 4 is a variant of General Scheme 3. In steps A and B, GI-3 (described in General Scheme 1) is subjected to an amination equivalent to that described in steps A and B of General Scheme 3 to give GI-8, which is then reacted in step C with GI-7 under the conditions described in step C of General Scheme 3 to give the examples of formula (I). As mentioned above, Z in the examples of formula (I) 1 or Z 2 When is NH, the corresponding NH in GI-7 can be protected with a suitable group such as THP or tosyl to facilitate step C. In such cases, an additional deprotection step (typically using TFA or HCl) is required to finally prepare the example of formula (I).

[0175] [ka]

[0176] General Scheme 5 Intermediates of structure GI-1, if not commercially available, can be prepared using the methodology outlined in general Scheme 5. An appropriately substituted aryl or heteroaryl ethyl ester, shown as GI-1a (where X a is a halogen, typically a bromide), is subjected in step A to halogenation with NBS in the presence of a radical initiator such as benzoyl peroxide using CCl4 as solvent, and then cyclized in step B with concentrated aqueous ammonia.

[0177] [ka]

[0178] General Scheme 6 Alternatively, structure GI-I (wherein one R 2The intermediate of formula (I) (wherein R is not H) can be prepared according to General Scheme 6. GI-1c is subjected to the same steps A and B as described in General Scheme 5 to give GI-1e. GI-1e is then alkylated in step C in the presence of a base such as NaHMDS and an appropriate alkyl iodide or bromide in THF as solvent. 2 If the groups are not equivalent and are not H, repeat step C with the appropriate alkyl iodide or bromide to form a second R 2 Obtain the base.

[0179] If the haloindazoles of formula GI-7 are not commercially available or described in the chemical literature, they can be prepared by methods similar to those reported in the literature (Gaikwad et al. Eur. J. Med. Chem., 90, 2015, p707-731). General schemes 7 and 8 illustrate the methods used herein.

[0180] [ka]

[0181] General Scheme 7 General Scheme 7 includes a compound of formula (I) 1 is CR8a, and Z 2 The preparation of the haloindazoles (GI-7b and GI-7(i)) used in the synthesis of examples of the formula GI-7a (typically, halogen X is NH) is described in step A. a The appropriate ortho-fluorocarbonyl heteroaryl halide of (wherein is a bromide) was reacted with hydrazine hydrate in iPrOH at 80° C. In step B, a protecting group was optionally incorporated to negate the reactivity of the free NH group in the subsequent steps. The protecting group used was either the THP group, which was incorporated using 3,4-dihydropyran with catalytic para-TsOH in THF at 50° C., or the tosyl group, which was incorporated using tosyl chloride and triethylamine in DCM at room temperature.

[0182] Formula (I) [wherein, Z 2 is CR 8a and Z 1 The haloindazoles (GI-7d and GI-7(ii)) used in the synthesis of examples of [wherein is NH] were prepared in an identical manner starting from isomeric fluorocarbonylheteroaryl halides of formula GI-7c as shown in general Scheme 8.

[0183] [ka]

[0184] General Scheme 8 Aminoindazoles of formula GI-4, if not commercially available or described in the chemical literature, can be prepared by methods analogous to those reported in the literature. General Schemes 9 and 10 show the methods used.

[0185] [ka]

[0186] General Scheme 9 General Scheme 9 includes a compound of formula (I) 1 is CR 8a and Z 2 The preparation of aminoindazoles (GI-4(i) and GI-4(ii)) used in the synthesis of examples of the formula GI-7a (typically halogen X is not NH) is described in step A. a is bromide) in iPrOH at 80 °C with an appropriate ortho-fluorocarbonyl heteroaryl halide, 8a(corresponding to ) to give the haloindazole of formula GI-4a. In step B, the haloindazole GI-4a is subjected to Buchwald-Hartwig amination with t-butyl carbamate catalyzed by Pd2(dba)3 and Xantphos (or equivalent catalytic system) in the presence of a base such as cesium carbonate in a solvent such as 1,4-dioxane. GI-4b can be Boc-deprotected in step C using HCl in dioxane or TFA with or without a co-solvent such as DCM to give the aminoindazole of formula GI-4(i). Finally, R 6 If not H, then R 6 , in MeOH, with the appropriate aldehyde (R 6 by reductive amination with R 6 X a (where X a can be introduced by alkylation with 1,2-diamino-2,3-diphenyl-1,4-diphenyl-2,5-diphenyl-1,6-diphenyl-2,7-diphenyl-1,8-diphenyl-2,9-diphenyl-1,8-diphenyl-2,10-diphenyl-1,9-diphenyl-2,10 ...

[0187] Formula (I) [wherein, Z 2 is CR 8a and Z 1 The aminoindazoles (GI-4(iii) and GI-4(iv)) used in the synthesis of examples of [wherein is not NH] were prepared in an identical manner starting from isomeric fluorocarbonylheteroaryl halides of formula GI-7c as shown in general Scheme 10.

[0188] [ka]

[0189] General Scheme 10 Synthesis of intermediates In the following Scheme 1, the synthesis of some intermediates common to certain examples is described and synthetic approaches that may be adopted to prepare other examples by selecting appropriately functionalized building blocks in place of one or more of them in Scheme 1, as detailed in the description of the preparation of the individual examples.

[0190] [ka]

[0191] Scheme 1 Process A. Synthesis of intermediate I-1 (tert-butyl 7-bromo-1-oxo-isoindoline-2-carboxylate) A mixture of 7-bromoisoindolin-1-one (1.0 g, 4.7 mmol), Boc2O (1.5 g, 7.1 mmol) and DMAP (57 mg, 0.47 mmol) in MeCN (20 mL) was stirred at room temperature for 16 h. The mixture was concentrated under reduced pressure and purified by normal phase chromatography (25 g column, 10-50% EtOAc in petrol) to give tert-butyl 7-bromo-1-oxo-isoindoline-2-carboxylate (intermediate I-1, 1.4 g, 4.5 mmol, 95% yield) as a white solid. UPLC-MS (ES + , Method 1): 4.05 minutes, m / z 256.0 / 258.0 [M-tBu+H] + . 1 H NMR (400 MHz, DMSO-d6) δ (ppm) 7.75 (d, J=7.2 Hz, 1H), 7.71 - 7.60 (m, 2H), 4.78 (s, 2H), 1.57 (s, 9H).

[0192] Process B. Synthesis of intermediate I-2 (tert-butyl 7-[(1-methylindazol-5-yl)amino]-1-oxo-isoindoline-2-carboxylate) A mixture of tert-butyl 7-bromo-1-oxo-isoindoline-2-carboxylate (intermediate I-1, 1.0 g, 3.2 mmol), 1-methyl-1H-indazol-5-amine (519 mg, 3.5 mmol), Pd2(dba)3 (293 mg, 0.32 mmol), Xantphos (185 mg, 0.32 mmol) and Cs2CO3 (2.1 g, 6.4 mmol) in 1,4-dioxane (20 mL) was heated to 100 °C and stirred for 16 h. The mixture was allowed to cool to room temperature, concentrated under reduced pressure, and purified by normal phase chromatography (25 g column, 5-20% EtOAc in petrol) to give tert-butyl 7-[(1-methylindazol-5-yl)amino]-1-oxo-isoindoline-2-carboxylate (Intermediate I-2, 1.0 g, 2.6 mmol, 82% yield) as an off-white solid. UPLC-MS (ES + , Method 1): 4.39 minutes, m / z 379.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ (ppm) 8.68 (s, 1H), 8.02 (s, 1H), 7.72 - 7.68 (m, 2H), 7.45 (t, J=8.3 Hz, 1H), 7.37 (dd, J=1.7, 8.9 Hz, 1H), 6.98 (d, J=8.3 Hz, 1H), 6.87 (d, J=7.2 Hz, 1H), 4.77 (s, 2H), 4.08 (s, 3H), 1.57 (s, 9H).

[0193] Process C. Synthesis of intermediate I-3 (7-[(1-methylindazol-5-yl)amino]isoindolin-1-one) 7-[(1-methylindazol-5-yl)amino]-1-oxo-isoindoline-2-carboxylate (intermediate I-2, 150 mg, 0.39 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (0.5 mL) was added and the mixture was stirred at room temperature for 2 h, then concentrated under reduced pressure to give crude 7-[(1-methylindazol-5-yl)amino]isoindolin-1-one (intermediate I-3, 100 mg, 0.36 mmol, 92% yield), which was used in the next step without further purification. UPLC-MS (ES + , Method 2): 1.50 min, m / z 279.2 [M+H] + .

[0194] Process D. Synthesis of intermediate I-4 (ethyl 2-[7-[(1-methylindazol-5-yl)amino]-1-oxo-isoindolin-2-yl]acetate) A mixture of 7-[(1-methylindazol-5-yl)amino]isoindolin-1-one (Intermediate I-3, 418 mg, 1.5 mmol), ethyl 2-bromoacetate (276 mg, 1.6 mmol) and Cs2CO3 (978 mg, 3.0 mmol) in MeCN (20 mL) was heated to 50 °C and stirred for 16 h. The mixture was concentrated under reduced pressure and purified by normal phase chromatography (12 g column, 10% to 35% EtOAc in petrol) to give ethyl 2-[7-[(1-methylindazol-5-yl)amino]-1-oxo-isoindolin-2-yl]acetate (Intermediate I-4, 428 mg, 78% yield) as an off-white solid. UPLC-MS (ES + ,Method 1): 4.39 minutes, m / z 379.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ (ppm) 8.62 (s, 1H), 8.02 (s, 1H), 7.71 - 7.69 (m, 2H), 7.42 (t, J=7.8 Hz, 1H), 7.37 (dd, J=1.8, 8.9 Hz, 1H), 7.05 (d, J=8.2 Hz, 1H), 6.93 (d, J=7.2 Hz, 1H), 4.54 (s, 2H), 4.41 (s, 2H), 4.22 (q, J=7.1 Hz, 2H), 4.10 (s, 3H), 1.28 (t, J=7.0 Hz, 3H).

[0195] Process E. Synthesis of intermediate I-5 (2-[7-[(1-methylindazol-5-yl)amino]-1-oxo-isoindolin-2-yl]acetic acid) To a solution of ethyl 2-[7-[(1-methylindazol-5-yl)amino]-1-oxo-isoindolin-2-yl]acetate (428 mg, 1.2 mmol) in THF (8 mL) and MeOH (5 mL) was added a solution of LiOH monohydrate (247 mg, 5.9 mmol) and the mixture was stirred at room temperature for 16 h. The mixture was acidified with 10% aqueous HCl to pH 6 and the resulting precipitate was collected by filtration, dissolved in MeOH and concentrated under reduced pressure to give 2-[7-[(1-methylindazol-5-yl)amino]-1-oxo-isoindolin-2-yl]acetic acid (Intermediate I-5, 300 mg, 0.89 mmol, 76% yield) as a white solid. UPLC-MS (ES + , Method 1): 3.48 minutes, m / z 337.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ (ppm) 8.62 (s, 1H), 8.00 (s, 1H), 7.70 - 7.66 (m, 2H), 7.42 - 7.33 (m, 2H), 7.03 (d, J=9.2 Hz, 1H), 6.90 (d, J=7.3 Hz, 1H), 4.51 (s, 2H), 4.29 (s, 2H), 4.07 (s, 3H).

[0196] Process F. Synthesis of intermediate I-6 (ethyl 2-(7-bromo-1-oxo-isoindolin-2-yl)acetate) A solution of 7-bromoisoindolin-1-one (400 mg, 1.9 mmol), ethyl 2-bromoacetate (472 mg, 2.8 mmol) and Cs2CO3 (1.8 g, 5.6 mmol) in MeCN (10 mL) was stirred at room temperature for 2 h. The mixture was diluted with water (50 mL), dichloromethane (50 mL) was added and the phases were separated. The aqueous phase was extracted three times with dichloromethane and the organic phases were combined, dried over Na2SO4 and concentrated under reduced pressure to give ethyl 2-(7-bromo-1-oxo-isoindolin-2-yl)acetate (intermediate I-6, 465 mg, 1.6 mmol, 83% yield) as an off-white solid. UPLC-MS (ES + , Method 2): 0.95 min, m / z 285.5 [M+H] + - Me ester (samples transesterified in MeOH) 1 H NMR (400 MHz, CDCl3) δ (ppm) 7.62 (d, J=6.0 Hz, 1H), 7.43 - 7.36 (m, 2H), 4.50 (s, 2H), 4.40 (s, 2H), 4.24 (q, J=6.9 Hz, 2H), 1.31 (t, J=7.0 Hz, 3H).

[0197] Process G. Synthesis of intermediate I-7 (2-(7-bromo-1-oxo-isoindolin-2-yl)acetic acid) To a solution of ethyl 2-(7-bromo-1-oxo-isoindolin-2-yl)acetate (intermediate I-6, 465 mg, 1.6 mmol) in THF (2 mL) and MeOH (2 mL) was added a solution of LiOH monohydrate (197 mg, 4.7 mmol) in water (2 mL) and the solution was stirred at room temperature for 2 h. The mixture was acidified with 1 M HCl to pH 5-6 and the resulting precipitate was collected by filtration, dissolved in MeOH and concentrated under reduced pressure to give crude 2-(7-bromo-1-oxo-isoindolin-2-yl)acetic acid (intermediate I-7, 421 mg, quantitative yield), which was used in the next step without further purification. UPLC-MS (ES + , Method 2): 0.72 min, m / z 269.7 / 271.5 [M+H] + .

[0198] Process H. Synthesis of intermediate I-8 (2-(7-bromo-1-oxo-isoindolin-2-yl)-N-(2,2,2-trifluoroethyl)acetamide) A mixture of 2-(7-bromo-1-oxo-isoindolin-2-yl)acetic acid (420 mg, 1.6 mmol), trifluoroethylamine (186 mg, 1.9 mmol), EDCI (292 mg, 1.9 mmol), HOBT (24 mg, 1.9 mmol) and DIPEA (0 mg, 4.7 mmol) in DMF (5 mL) was stirred at room temperature overnight. The mixture was diluted with water (50 mL), dichloromethane (100 mL) was added and the phases were separated. The aqueous phase was extracted with dichloromethane (2x100 mL) and the organic phases were combined, dried over Na2SO4 and concentrated under reduced pressure to give 2-(7-bromo-1-oxo-isoindolin-2-yl)-N-(2,2,2-trifluoroethyl)acetamide (intermediate I-8, 400 mg, 73% yield) as an off-white solid. UPLC-MS (ES + , Method 2): 1.30 minutes, m / z 350.9 / 352.9 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ (ppm) 8.81 (t, J=6.2 Hz, 1H), 7.71 - 7.61 (m, 2H), 7.58 - 7.52 (m, 1H), 4.50 (s, 2H), 4.28 (s, 2H), 4.00 - 3.90 (m, 2H).

[0199] Process I. Synthesis of intermediate I-13 (tert-butyl 4-bromo-1,1-dimethyl-3-oxo-isoindoline-2-carboxylate) A solution of tert-butyl 7-bromo-1-oxo-isoindoline-2-carboxylate (Intermediate I-1, 500 mg, 1.6 mmol) in THF (5 mL) was cooled to 0° C. and NaHMDS (2 M in THF, 2.4 mL, 4.8 mmol) was added. The mixture was stirred at 0° C. for 30 min, then methyl iodide (0.3 mL, 4.8 mmol) was added dropwise. The mixture was slowly warmed to room temperature, concentrated under reduced pressure, and purified by normal phase chromatography (25 g column, 10% EtOAc in petrol) to give tert-butyl 4-bromo-1,1-dimethyl-3-oxo-isoindoline-2-carboxylate (Intermediate I-13, 380 mg, 70% yield) as a clear oil. UPLC-MS (ES + , Method 2): 2.10 minutes, m / z 284.0 / 286.0 [M-tBu+H] + .

[0200] Process J. Synthesis of intermediate I-18 (tert-butyl 4-bromo-1-methyl-3-oxo-isoindoline-2-carboxylate) A solution of tert-butyl 7-bromo-1-oxo-isoindoline-2-carboxylate (Intermediate I-1, 500 mg, 1.6 mmol) in THF (10 mL) was stirred at -60 °C under N2 for 5 min, then KHMDS (1.6 mL, 1.6 mmol) was added dropwise and the mixture was stirred for 1 h. MeI (159 mg, 1.12 mmol) in THF (10 mL) was added dropwise and the mixture was stirred for 2 h. The mixture was warmed to room temperature, concentrated under reduced pressure, and purified by prep-TLC to give tert-butyl 4-bromo-1-methyl-3-oxo-isoindoline-2-carboxylate (Intermediate I-18, 229 mg, 0.7 mmol, 43% yield) as a clear oil. UPLC-MS (ES + , Method 1): 4.25 minutes, m / z 270.0 / 272.0 [M-tBu+H] + . 1 H NMR (400 MHz, DMSO-d6) δ (ppm) 7.83 - 7.69 (m, 3H), 5.14 (q, J=6.4 Hz, 1H), 1.66 - 1.62 (m, 12H).

[0201] Process K. Synthesis of intermediate I-19 (ethyl 2-[7-[(3-methyl-1-tetrahydropyran-2-yl-indazol-6-yl)amino]-1-oxo-isoindolin-2-yl]acetate) A degassed solution of 3-methyl-1-tetrahydropyran-2-yl-indazol-6-amine (6 g, 26 mmol), Cs2CO3 (13 g, 39 mmol), Xantphos (3 g, 5.2 mmol), Pd2(dba)3 (4.8 g, 5.2 mmol) and ethyl 2-(7-bromo-1-oxo-isoindolin-2-yl)acetate (7.7 g, 26 mmol) in 1,4-dioxane (50 mL) was stirred at 100 °C for 16 h. The mixture was concentrated under reduced pressure and purified by normal phase chromatography (hexane:EtOAc=3:1) to give ethyl 2-[7-[(3-methyl-1-tetrahydropyran-2-yl-indazol-6-yl)amino]-1-oxo-isoindolin-2-yl]acetate (Intermediate I-19, 6.2 g, 14 mmol, 53% yield) as an off-white solid. UPLC-MS (ES + , Method 1): 4.32 minutes, m / z 449.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ (ppm) 8.90 (s, 1H), 7.67 (d, J=8.4 Hz, 1H), 7.54 - 7.43 (m, 2H), 7.32 (d, J=8.2 Hz, 1H), 7.09 (d, J=8.2 Hz, 1H), 6.99 (d, J=7.1 Hz, 1H), 5.79 - 5.70 (m, 1H), 4.52 (s, 2H), 4.39 (s, 2H), 4.19 (q, J=7.0 Hz, 2H), 3.93 - 3.83 (m, 1H), 3.78 - 3.69 (m, 1H), 2.47 (s, 3H), 2.44 - 2.33 (m, 1H), 2.08 - 1.99 (m, 2H), 1.96 - 1.89 (m, 1H), 1.81 - 1.67 (m, 1H), 1.62 - 1.52 (m, 2H), 1.25 (t, J=7.0 Hz, 3H).

[0202] Process L.Synthesis of intermediate I-20 (ethyl 2-[7-[(3-methyl-1H-indazol-6-yl)amino]-1-oxo-isoindolin-2-yl]acetate) A solution of ethyl 2-[7-[(3-methyl-1-tetrahydropyran-2-yl-indazol-6-yl)amino]-1-oxo-isoindolin-2-yl]acetate (Intermediate I-19, 6 g, 13 mmol) in trifluoroacetic acid (30 mL) was stirred under microwave irradiation at 80° C. for 2 h. The mixture was concentrated under reduced pressure and purified by reverse phase chromatography (MeCN:water=60:40) to give ethyl 2-[7-[(3-methyl-1H-indazol-6-yl)amino]-1-oxo-isoindolin-2-yl]acetate (Intermediate I-20, 1.8 g, 4.9 mmol, 37% yield) as an off-white solid. UPLC-MS (ES + , Method 1): 3.65 minutes, m / z 365.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ (ppm) 12.41 (s, 1H), 8.81 (s, 1H), 7.66 (d, J=8.9 Hz, 1H), 7.47 (t, J=7.8 Hz, 1H), 7.33 (s, 1H), 7.29 (d, J=8.4 Hz, 1H), 7.00 - 6.96 (m, 2H), 4.52 (s, 2H), 4.38 (s, 2H), 4.18 (q, J=7.1 Hz, 2H), 2.47 (s, 3H), 1.25 (t, J=7.1 Hz, 3H).

[0203] Table 3 shows intermediates constructed in a manner similar to I-2 (tert-butyl 7-[(1-methylindazol-5-yl)amino]-1-oxo-isoindoline-2-carboxylate) (Step B, Scheme 1) by replacing tert-butyl 7-bromo-1-oxo-isoindoline-2-carboxylate (intermediate I-1) or 1-methyl-1H-indazol-5-amine with the appropriate building blocks. [Table 3]

[0204] Table 4 shows intermediates synthesized in a manner similar to I-3 (7-[(1-methylindazol-5-yl)amino]isoindolin-1-one) (Step C, Scheme 1) by replacing 7-[(1-methylindazol-5-yl)amino]-1-oxo-isoindoline-2-carboxylate with the appropriate building block. This intermediate was used in the next step without further purification. [Table 4]

[0205] Table 5 shows intermediates that were synthesized in a manner similar to I-4 (ethyl 2-[7-[(1-methylindazol-5-yl)amino]-1-oxo-isoindolin-2-yl]acetate (Step D, Scheme 1) by replacing 7-[(1-methylindazol-5-yl)amino]isoindolin-1-one with the appropriate building block. [Table 5]

[0206] Table 6 shows intermediates that were synthesized in a manner similar to I-5 (2-[7-[(1-methylindazol-5-yl)amino]-1-oxo-isoindolin-2-yl]acetic acid) (Step E, Scheme 1) by replacing ethyl 2-[7-[(1-methylindazol-5-yl)amino]-1-oxo-isoindolin-2-yl]acetate with the appropriate building blocks. [Table 6-1] [Table 6-2]

[0207] Table 7 shows intermediates prepared from intermediate I-6 (ethyl 2-(7-bromo-1-oxo-isoindolin-2-yl)acetate) in a manner similar to intermediate I-19 (ethyl 2-[7-[(3-methyl-1-tetrahydropyran-2-yl-indazol-6-yl)amino]-1-oxo-isoindolin-2-yl]acetate) (Step K, Scheme 1) by replacing 3-methyl-1-tetrahydropyran-2-yl-indazol-6-amine with the appropriate building blocks. [Table 7]

[0208] Further intermediates used in the preparation of the examples were derived from intermediate I-6 according to Scheme 2 below.

[0209] [ka]

[0210] Scheme 2 Step A. Intermediate I-29 (Ethyl 2-[7-(tert-butoxycarbonylamino)-1-oxo-isoindolin-2-yl]acetate). A mixture of ethyl 2-(7-bromo-1-oxoisoindolin-2-yl)acetate (4 g, 13.417 mol), tert-butyl carbamate (3.14 g, 26.8 mol), Pd2(dba)3 (1.3 g, 1.34 mol, 0.1 eq), Xantphos (775 mg, 1.34 mol) and Cs2CO3 (8.72 g, 26.8 mol) in 1,4-dioxane (30 mL) was stirred at 100 °C under N2 overnight. The mixture was concentrated under vacuum and purified by silica gel column chromatography (pet. ether / EtOAc, 30 / 1 to pet. ether / EtOAc, 20 / 1, v / v) to give ethyl 2-[7-(tert-butoxycarbonylamino)-1-oxo-isoindolin-2-yl]acetate (I-29) (2.73 g, 60.8% yield) as a colorless oil. UPLC-MS (ES +, Method 1): 4.38 minutes, m / z 334.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ (ppm) 9.42 (s, 1H), 8.02-8.00 (m, 1H), 7.57-7.53 (m, 1H), 7.21-7.19 (m, 1H), 4.51 (s, 2H), 4.35, (s, 2H), 4.15 (q, J = 7.3 Hz, 2H), 1.49 (s, 9H), 1.21 (t, J = 7.3 Hz, 3H).

[0211] Step B. Intermediate I-30 (Ethyl 2-(7-amino-1-oxo-isoindolin-2-yl)acetate). A mixture of ethyl 2-[7-(tert-butoxycarbonylamino)-1-oxo-isoindolin-2-yl]acetate (I-29) (500 mg, 1.5 mmol) in DCM (5 mL) and 4M HCl in dioxane (3 mL) was stirred at room temperature for 2 h. The reaction was concentrated to give ethyl 2-(7-amino-1-oxo-isoindolin-2-yl)acetate (I-30) (530 mg, 90% yield) as a crude solid, which was used without further purification. UPLC-MS (ES + , Method 2): 1.00 min, m / z 235.1 [M+H] + .

[0212] Step C. Intermediate I-31 (Ethyl 2-[7-[[4-fluoro-3-methyl-1-(p-tolylsulfonyl)indazol-6-yl]amino]-1-oxo-isoindolin-2-yl]acetate). A solution of 6-bromo-4-fluoro-3-methyl-1-(p-tolylsulfonyl)indazole (410 mg, 1.07 mmol), ethyl 2-(7-amino-1-oxo-isoindolin-2-yl)acetate (I-30) (276 mg, 1.181 mmol), Cs2CO3 (700 mg, 2.14 mmol), Xantphos (124 mg, 0.22 mmol) and Pd2(dba)3 (98 mg, 0.11 mmol) in 1,4-dioxane (5.0 mL) was stirred at 100 °C under N2 overnight. The mixture was diluted with EtOAc (10 mL) and washed with HO (10 mLx3). The organic phases were washed with EtOAc (20 mLx3), combined, dried over anhydrous NaSO and concentrated to give a yellow solid analyzed as ethyl 2-[7-[[4-fluoro-3-methyl-1-(p-tolylsulfonyl)indazol-6-yl]amino]-1-oxo-isoindolin-2-yl]acetate (I-31) (400 mg, 69% yield), which was used without further purification. UPLC-MS (ES + , Method 1): 4.62 minutes, m / z 537.0 [M+H] + .

[0213] Step D. Intermediate I-32 (2-[7-[(4-fluoro-3-methyl-1H-indazol-6-yl)amino]-1-oxo-isoindolin-2-yl]acetic acid). A mixture of ethyl 2-[7-[[4-fluoro-3-methyl-1-(p-tolylsulfonyl)indazol-6-yl]amino]-1-oxo-isoindolin-2-yl]acetate (I-31) (400 mg, 0.75 mmol) and LiOH.H2O (93.8 mg, 2.23 mmol) in THF (3 mL), MeOH (3 mL) and H2O (2 mL) was stirred at 25 °C overnight. The mixture was diluted with H2O (10 mL) and 10% HCl in water (25 mL) was added to reach pH 2-3. The mixture was further diluted with water (20 mLx3) and extracted with DCM (30 mLx3). After drying over Na2SO4, the mixture was filtered and concentrated under reduced pressure to give 2-[7-[(4-fluoro-3-methyl-1H-indazol-6-yl)amino]-1-oxo-isoindolin-2-yl]acetic acid (I-32) (200 mg, 76% yield) as a white solid. UPLC-MS (ES + , Method 1): 3.52 min, m / z 355.0 [M+H] + .

[0214] Intermediate I-33 (2-[7-[(3-methyl-1H-pyrazolo[4,3-b]pyridin-6-yl)amino]-1-oxo-isoindolin-2-yl]acetic acid) [ka]

[0215] Intermediate I-33 was prepared following a synthetic route similar to that used for I-32 (Scheme 2). In step C, 6-bromo-4-fluoro-3-methyl-1-(p-tolylsulfonyl)indazole was replaced with 6-bromo-3-methyl-1-(p-tolylsulfonyl)pyrazolo[4,3-b]pyridine. UPLC-MS (ES + , Method 1): 2.88 minutes, m / z 338.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ (ppm) 8.49 (s, 1H), 7.81 - 7.78 (m, 2H), 7.48 - 7.09 (m, 6H), 4.51 (s, 2H), 4.23 (s, 2H), 2.30 (s, 3H).

[0216] Intermediate I-34 (2-[1-oxo-7-[(1-tetrahydropyran-2-ylpyrazolo[3,4-b]pyridin-5-yl)amino]isoindolin-2-yl]acetic acid) [ka]

[0217] Intermediate I-34 was prepared following a synthetic route similar to that used for I-32 (Scheme 2). In step C, 6-bromo-4-fluoro-3-methyl-1-(p-tolylsulfonyl)indazole was replaced with 1-tetrahydropyran-2-ylpyrazolo[3,4-b]pyridin-5-amine. UPLC-MS (ES + , Method 2): 1.22 minutes, m / z 408.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ (ppm) 8.67 (s, 1H), 8.54 (s, 1H), 8.20 (s, 1H), 8.15 (s, 1H), 7.39 - 7.34 (m, 1H), 6.96 - 6.91 (m, 2H), 6.02 - 5.99 (m, 1H), 4.49 (s, 2H), 4.24 (s, 2H), 3.97 - 3.94 (m, 1H), 3.73 - 3.71 (m, 1H), 2.25 - 1.57 (m, 6H).

[0218] Intermediate I-35 (2-[7-[(3-isopropyl-1H-indazol-6-yl)amino]-1-oxo-isoindolin-2-yl]acetic acid) [ka]

[0219] Intermediate I-35 was prepared in a manner similar to intermediate I-32 (Scheme 2). In step C, 6-bromo-4-fluoro-3-methyl-1-(p-tolylsulfonyl)indazole was replaced with 6-bromo-3-isopropyl-1-(p-tolylsulfonyl)indazole.

[0220] Intermediate I-36 (2-[7-(1H-indazol-6-ylamino)-1-oxo-isoindolin-2-yl]acetic acid) [ka]

[0221] Intermediate I-36 was prepared in a manner similar to intermediate I-32 (Scheme 2). In step C, 6-bromo-4-fluoro-3-methyl-1-(p-tolylsulfonyl)indazole was replaced with 6-bromo-1-tetrahydropyran-2-yl-indazole. UPLC-MS (ES + , Method 1): 3.23 min, m / z, 323.1 [M+H] + .

[0222] Intermediate I-37 (2-[7-[(3-cyano-1-tetrahydropyran-2-yl-indazol-5-yl)amino]-1-oxo-isoindolin-2-yl]acetic acid) [ka]

[0223] Intermediate I-37 was prepared in a manner similar to intermediate I-32 (Scheme 2). In step C, 6-bromo-4-fluoro-3-methyl-1-(p-tolylsulfonyl)indazole was replaced with 5-bromo-1-tetrahydropyran-2-yl-indazole-3-carbonitrile. UPLC-MS (ES +, Method 1): 4.11 min, m / z, 432.2 [M+H] + .

[0224] Intermediate I-38 (2-[7-[(3-fluoro-1H-indazol-5-yl)amino]-1-oxo-isoindolin-2-yl]acetic acid) [ka]

[0225] Intermediate I-38 was prepared in a manner similar to intermediate I-32 (Scheme 2). In step C, 6-bromo-4-fluoro-3-methyl-1-(p-tolylsulfonyl)indazole was replaced with 5-bromo-3-fluoro-1-(p-tolylsulfonyl)indazole. UPLC-MS (ES + , Method 1): 3.45 minutes, m / z, 351.1 [M+H] + .

[0226] Intermediate I-39 (2-[1-oxo-7-(1H-pyrazolo[4,3-b]pyridin-5-ylamino)isoindolin-2-yl]acetic acid) [ka]

[0227] Intermediate I-39 was prepared in a manner similar to intermediate I-32 (Scheme 2). In step C, 6-bromo-4-fluoro-3-methyl-1-(p-tolylsulfonyl)indazole was replaced with 5-bromo-1-tetrahydropyran-2-yl-pyrazolo[4,3-b]pyridine. UPLC-MS (ES + , Method 2): 0.71 min, m / z, 323.6 [M+H] + .

[0228] Intermediate I-40 (2-[7-[(1-methylpyrazolo[4,3-b]pyridin-5-yl)amino]-1-oxo-isoindolin-2-yl]acetic acid) [ka]

[0229] Intermediate I-40 was prepared in a manner similar to intermediate I-32 (Scheme 2). In step C, 6-bromo-4-fluoro-3-methyl-1-(p-tolylsulfonyl)indazole was replaced with 5-bromo-1-methyl-pyrazolo[4,3-b]pyridine. UPLC-MS (ES + , Method 1): 3.58 minutes, m / z 338.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ (ppm) 9.82 (s, 1H), 8.78 (d, J = 8.3 Hz, 1H), 8.15 - 7.96 (m, 2H), 7.63 - 7.51 (m, 1H), 7.05 (dd, J = 26.4, 8.2 Hz, 2H), 4.52 (s, 2H), 4.41 (s, 2H), 4.04 (s, 3H), 3.70 (s, 3H).

[0230] Intermediate I-42 (2-[7-[(1-methylpyrazolo[3,4-b]pyridin-5-yl)amino]-1-oxo-isoindolin-2-yl]acetic acid) [ka]

[0231] Intermediate I-42 was prepared in a manner similar to intermediate I-32 (Scheme 2). In step C, 6-bromo-4-fluoro-3-methyl-1-(p-tolylsulfonyl)indazole was replaced with 5-bromo-1N-methylpyrazolo[3,4-b]pyridine. UPLC-MS (ES + , Method 1): 3.51 minutes, m / z 338.2 [M+H] + .

[0232] Intermediate I-47 (2-[7-[(3-methyl-1H-pyrazolo[4,3-b]pyridin-6-yl)amino]-1-oxo-isoindolin-2-yl]acetic acid) [ka]

[0233] Intermediate I-47 was prepared in a manner similar to intermediate I-32 (Scheme 2). In step C, 6-bromo-4-fluoro-3-methyl-1-(p-tolylsulfonyl)indazole was replaced with 6-bromo-3-methyl-1-(p-tolylsulfonyl)pyrazolo[4,3-b]pyridine. UPLC-MS (ES + , Method 1): 2.91 min, m / z 338.2 [M+H] + .

[0234] Intermediate I-43 (7-Bromo-2-[2-oxo-2-[(2S)-(trifluoromethyl)pyrrolidin-1-yl]ethyl]isoindolin-1-one) [ka]

[0235] Intermediate I-43 was prepared in an analogous manner to intermediate I-8 (Scheme 1), substituting (2S)-(trifluoromethyl)pyrrolidine for trifluoroethylamine in step H. UPLC-MS (ES + , Method 1): 3.72 minutes, m / z, 391.0 / 393.0 [M+H] + .

[0236] Intermediate I-44 (2-(7-bromo-1-oxo-isoindolin-2-yl)-N-[(1S)-2,2,2-trifluoro-1-methyl-ethyl]acetamide) [ka]

[0237] Intermediate I-44 was prepared in an analogous manner to intermediate I-8 (Scheme 1), substituting (2S)-amino-1,1,1-trifluoropropane hydrochloride for trifluoroethylamine in step H. UPLC-MS (ES + , Method 1): 3.52 minutes, m / z, 365.1 / 367.1 [M+H] + .

[0238] Further examples can be prepared from intermediates I-48 and I-49, the syntheses of which are described in Scheme 3 and in the methods below.

[0239] [ka]

[0240] Scheme 3 Step A. Ethyl 2-bromo-4-(bromomethyl)pyridine-3-carboxylate. A mixture of ethyl 2-bromo-4-methyl-pyridine-3-carboxylate (2 g, 8.19 mmol), NBS (2.92 g, 16.38 mmol), benzoyl peroxide (396 mg, 1.63 mmol) in CCl4 (20 mL) was stirred at 90 °C under N2 overnight. The mixture was diluted with water (100 mL), extracted with EtOAc (100 mL x 3), and dried over Na2CO3. The mixture was purified by silica gel chromatography (pet. ether / EtOAc, 100 / 1 to pet. ether / EtOAc, 50 / 1) to give ethyl 2-bromo-4-(bromomethyl)pyridine-3-carboxylate (1.14 g, 21% yield). UPLC-MS (ES + , Method 1): 3.98 minutes, m / z 323.9 [M+H] + .

[0241] Step B. 4-Bromo-1,2-dihydropyrrolo[3,4-c]pyridin-3-one. A mixture of ethyl 2-bromo-4-(bromomethyl)pyridine-3-carboxylate (1.14 g, 1.76 mmol) and concentrated ammonium hydroxide (6 mL) in THF (10 mL) was stirred at 25° C. under N2. The mixture was partitioned between DCM and water, and the organic phases were combined, dried over Na2SO4, concentrated and then purified by silica gel chromatography (pet. ether / EtOAc, 5:1 to pet. ether / EtOAc, 1:2) to give 4-bromo-1,2-dihydropyrrolo[3,4-c]pyridin-3-one (320 mg, 43% yield) as a yellow solid. UPLC-MS (ES + , Method 1): 1.34 minutes, m / z 213.1 [M+H] + .

[0242] Step C. tert-Butyl 2-(4-bromo-3-oxo-1H-pyrrolo[3,4-c]pyridin-2-yl)acetate. A mixture of 4-bromo-1,2-dihydropyrrolo[3,4-c]pyridin-3-one (200 mg, 0.94 mmol), Cs2CO3 (610 mg, 1.88 mmol), tert-butyl bromoacetate (274 mg, 1.41 mmol) in THF (5 mL) was stirred at 50° C. for 2 h. The mixture was diluted with water (20 mL), extracted with EtOAc (15 mL×3), and dried over Na2CO3. The mixture was purified by silica gel chromatography (pet. ether / EtOAc, 1 / 2) to give tert-butyl 2-(4-bromo-3-oxo-1H-pyrrolo[3,4-c]pyridin-2-yl)acetate (130 mg, 42% yield) as a brown solid. UPLC-MS (ES + , Method 1): 3.48 minutes, m / z 329.1 [M+H] + .

[0243] Step D. tert-Butyl 2-[4-[(1-methylindazol-5-yl)amino]-3-oxo-1H-pyrrolo[3,4-c]pyridin-2-yl]acetate (Intermediate I-48). A mixture of tert-butyl 2-(4-bromo-3-oxo-1H-pyrrolo[3,4-c]pyridin-2-yl)acetate (200 mg, 0.61 mmol), 1-methyl-1H-indazol-5-amine (89.9 mg, 0.61 mmol), Pd2(dba)3 (55.9 mg, 0.061 mmol), Xantphos (35.3 mg, 0.061 mmol) and Cs2CO3 (397 mg, 1.22 mmol) in 1,4-dioxane (3 mL) was stirred at 100° C. under N2 overnight. The mixture was diluted with saturated NH4Cl (20 mL) and extracted with EtOAc (30 mL×3). The mixture was concentrated in vacuo and purified by silica gel chromatography (DCM methanol, 20 / 1) to afford tert-butyl 2-[4-[(1-methylindazol-5-yl)amino]-3-oxo-1H-pyrrolo[3,4-c]pyridin-2-yl]acetate (I-48) (50 mg, 21%) as a white solid. UPLC-MS (ES + , Method 1): 3.82 min, m / z 394.2 [M+H] + .

[0244] Step E. 2-[4-[(1-methylindazol-5-yl)amino]-3-oxo-1H-pyrrolo[3,4-c]pyridin-2-yl]acetic acid (Intermediate I-49). A mixture of tert-butyl 2-[4-[(1-methylindazol-5-yl)amino]-3-oxo-1H-pyrrolo[3,4-c]pyridin-2-yl]acetate (I-48) (40 mg, 0.1017 mmol, 1.0 eq) and TFA (1 mL) in DCM (2 mL) was stirred at 25° C. for 4 h. The mixture was concentrated in vacuo to give 2-[4-[(1-methylindazol-5-yl)amino]-3-oxo-1H-pyrrolo[3,4-c]pyridin-2-yl]acetic acid (Intermediate I-49) (40 mg) as a brown solid containing residual TFA, which was used without further purification. UPLC-MS (ES+ , Method 1): 2.55 minutes, m / z 338.2 [M+H] + .

[0245] Synthesis of Examples Example 1 (2-[7-[(1-methylindazol-5-yl)amino]-1-oxo-isoindolin-2-yl]-N-(2,2,2-trifluoroethyl)acetamide) [ka]

[0246] A mixture of 2-[7-[(1-methylindazol-5-yl)amino]-1-oxo-isoindolin-2-yl]acetic acid (Intermediate I-5, 60 mg, 0.18 mmol), trifluoroethylamine (27 mg, 0.27 mmol), T3P (170 mg, 0.3 mmol) and DIPEA (69 mg, 0.53 mmol) in dichloromethane (2 mL) was stirred at room temperature for 16 h. The mixture was concentrated under reduced pressure and purified by prep LCMS to give 2-[7-[(1-methylindazol-5-yl)amino]-1-oxo-isoindolin-2-yl]-N-(2,2,2-trifluoroethyl)acetamide (Example 1, 12 mg, 16% yield) as a yellow solid. UPLC-MS (ES + , Method 1): 3.74 min, m / z 418.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ (ppm) 8.88 (t, J=6.4 Hz, 1H), 8.68 (s, 1H), 8.05 (s, 1H), 7.75 - 7.71 (m, 2H), 7.46 - 7.37 (m, 2H), 7.07 (d, J=8.3 Hz, 1H), 6.94 (d, J=7.3 Hz, 1H), 4.54 (s, 2H), 4.32 (s, 2H), 4.12 (s, 3H), 4.02 (dq, J=6.6, 9.7 Hz, 2H).

[0247] Table 8 lists examples synthesized according to the same procedure as in Example 1, substituting 2-[7-[(1-methylindazol-5-yl)amino]-1-oxo-isoindolin-2-yl]acetic acid (Intermediate I-5) and / or trifluoroethylamine with the appropriate building blocks.

[0248] [Table 8-1] [Table 8-2] [Table 8-3]

Table 8-4

Table 8-5

Table 8-6

Table 8-7

Table 8-8

Table 8-9

Table 8-10

Table 8-11

Table 8-12

Table 8-13

Table 8-14

Table 8-15

Table 8-16

Table 8-17

Table 8-18

Table 8-19

Table 8-20

[0249] Example 6 (2-[7-[(3-methyl-1H-indazol-6-yl)amino]-1-oxo-isoindolin-2-yl]-N-(2,2,2-trifluoroethyl)acetamide) [ka]

[0250] A mixture of 2-(7-bromo-1-oxo-isoindolin-2-yl)-N-(2,2,2-trifluoroethyl)acetamide (intermediate I-8, 50 mg, 0.14 mmol), 3-methyl-1H-indazol-6-amine (25 mg, 0.17 mmol), Pd2(dba)3 (13 mg, 0.014 mmol), t-BuBrettphos (14 mg, 0.028 mmol), K2CO3 (40 mg, 0.28 mmol) and AcOH (4.2 mg, 0.07 mmol) in t-BuOH (2 mL) was heated to 110 °C and stirred for 16 h. The mixture was concentrated under reduced pressure and the crude product was purified by prep-HPLC to give 2-[7-[(3-methyl-1H-indazol-6-yl)amino]-1-oxo-isoindolin-2-yl]-N-(2,2,2-trifluoroethyl)acetamide (Example 6, 6.5 mg, 11% yield) as a white solid.

[0251] UPLC-MS (ES + , Method 2): 1.58 minutes, m / z 418.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ (ppm) 12.36 (s, 1H), 8.83-8.79 (m, 2H), 7.64 (d, J = 8.0 Hz, 1H), 7.44 (t, J = 8.0 Hz, 1H), 7.31 (s, 1H), 7.27 (d, J = 8.0 Hz, 1H), 6.95 (d, J = 8.0 Hz, 2H), 4.48 (s, 2H), 4.25 (s, 2H), 3.99-3.90 (m, 2H), 2.45 (s, 3H).

[0252] Example 78 (2-[7-[methyl-(3-methyl-1H-indazol-6-yl)amino]-1-oxo-isoindolin-2-yl]-N-(2,2,2-trifluoroethyl)acetamide)

[0253] [ka]

[0254] Scheme 3 Step A. In a manner similar to Scheme 6, 2-(7-bromo-1-oxo-isoindolin-2-yl)-N-(2,2,2-trifluoroethyl)acetamide (Intermediate I-8) was reacted with N,3-dimethyl-1-tetrahydropyran-2-yl-indazol-6-amine to give 2-[7-[methyl-(3-methyl-1-tetrahydropyran-2-yl-indazol-6-yl)amino]-1-oxo-isoindolin-2-yl]-N-(2,2,2-trifluoroethyl)acetamide. UPLC-MS (ES + , Method 1): 3.81 min, m / z 516.3 [M+H] + .

[0255] Step B. 2-[7-[methyl-(3-methyl-1-tetrahydropyran-2-yl-indazol-6-yl)amino]-1-oxo-isoindolin-2-yl]-N-(2,2,2-trifluoroethyl)acetamide (200 mg, 0.39 mmol) was dissolved in DCM (6 mL) and TFA (2 mL) and stirred at room temperature for 30 min. The solvent was removed under reduced pressure to leave a residue which was purified by prep-HPLC to give 2-[7-[methyl-(3-methyl-1H-indazol-6-yl)amino]-1-oxo-isoindolin-2-yl]-N-(2,2,2-trifluoroethyl)acetamide (21 mg, 13% yield) as a yellow solid. UPLC-MS (ES + , Method 1): 3.35 minutes, m / z 432.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ (ppm) 12.12 (s, 1H), 8.79 (t,J= 6.4 Hz, 1H), 7.58 (t,J= 7.7 Hz, 1H), 7.43 (d,J= 7.4 Hz, 1H), 7.38 (d,J= 8.8 Hz, 1H), 7.21 (d,J= 7.9 Hz, 1H), 6.65 (d,J= 2.0 Hz, 1H), 6.50 (dd,J= 8.8, 2.0 Hz, 1H), 4.53 (s, 2H), 4.22 (s, 2H), 3.99 - 3.89 (m, 2H), 3.33 (s, 3H), 2.40 (s, 3H).

[0256] Table 9 lists examples that were synthesized following the same procedure as in Example 6, but replacing 3-methyl-1H-indazol-6-amine and I-8 with the appropriate building blocks. When a THP-protected building block was coupled with intermediate I-8 or analogues (as indicated in the table), a final THP deprotection step was required to obtain the corresponding examples. THP deprotection was carried out under standard conditions, for example as described in Scheme 78. [Table 9-1] [Table 9-2] [Table 9-3] [Table 9-4] [Table 9-5] [Table 9-6] [Table 9-7]

[0257] Example 10 (N-[3-(1-hydroxy-1-methyl-ethyl)phenyl]-2-[7-[(1-methylindazol-5-yl)amino]-1-oxo-isoindolin-2-yl]acetamide)

[0258] [ka]

[0259] Scheme 4 Process A. The intermediate (N-(3-acetylphenyl)-2-[7-[(1-methylindazol-5-yl)amino]-1-oxo-isoindolin-2-yl]acetamide) was synthesized according to a similar procedure to Example 1 using 3-aminoacetophenone as a coupling partner with intermediate I-5. The compound was obtained as a white solid (40 mg, 0.09 mmol, 37% yield from 80 mg of intermediate I-5). UPLC-MS (ES + , Method 1): 3.82 min, m / z 454.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ (ppm) 10.45 (s, 1H), 8.64 (s, 1H), 8.21 (s, 1H), 7.99 (s, 1H), 7.87 (d, J=8.0 Hz, 1H), 7.73 - 7.65 (m, 3H), 7.51 (t, J=7.9 Hz, 1H), 7.39 (t, J=7.8 Hz, 1H), 7.34 (dd, J=1.8, 8.9 Hz, 1H), 7.03 (d, J=8.3 Hz, 1H), 6.91 (d, J=7.4 Hz, 1H), 4.57 (s, 2H), 4.42 (s, 2H), 4.06 (s, 3H), 2.58 (s, 3H).

[0260] Process B.N-[3-(1-hydroxy-1-methyl-ethyl)phenyl]-2-[7-[(1-methylindazol-5-yl)amino]-1-oxo-isoindolin-2-yl]acetamide (Example 10). A solution of N-(3-acetylphenyl)-2-[7-[(1-methylindazol-5-yl)amino]-1-oxo-isoindolin-2-yl]acetamide (40 mg, 0.09 mmol) in THF (1 mL) was cooled to 0° C. and methylmagnesium bromide (1 M in THF, 3.5 mmol, 3.5 mL) was added dropwise. The mixture was stirred at 0° C. for 2 h. Saturated NH4Cl (5 mL) and EtOAc (5 mL) were added, the phases were separated, and the aqueous phase was extracted with EtOAc (3×5 mL). The organic phases were combined, dried over Na2SO4, and concentrated under reduced pressure. Purification by prep HPLC afforded N-[3-(1-hydroxy-1-methyl-ethyl)phenyl]-2-[7-[(1-methylindazol-5-yl)amino]-1-oxo-isoindolin-2-yl]acetamide (5 mg, 0.1 mmol, 13% yield) as an off-white solid. UPLC-MS (ES + , Method 1): 3.69 min, m / z 452.3 [M-H2O+H] + . 1 H NMR (400 MHz, DMSO-d6) δ (ppm) 10.18 (s, 1H), 8.65 (s, 1H), 8.00 (s, 1H), 7.72 - 7.65 (m, 3H), 7.50 (d, J=8.2 Hz, 1H), 7.39 (t, J=7.6 Hz, 1H), 7.34 (d, J=10.2 Hz, 1H), 7.25 (t, J=7.9 Hz, 1H), 7.17 (d, J=7.8 Hz, 1H), 7.03 (d, J=8.3 Hz, 1H), 6.90 (d, J=7.4 Hz, 1H), 5.01 (s, 1H), 4.56 (s, 2H), 4.38 (s, 2H), 4.07 (s, 3H), 1.43 (s, 6H).

[0261] Example 25 (2-[7-[(3-methyl-1H-indazol-6-yl)amino]-1-oxo-isoindolin-2-yl]-N-[3-(trifluoromethyl)phenyl]acetamide)

[0262] [ka]

[0263] Scheme 5 Process A. The intermediate (2-[7-[(3-methyl-1-tetrahydropyran-2-yl-indazol-6-yl)amino]-1-oxo-isoindolin-2-yl]-N-[3-(trifluoromethyl)phenyl]acetamide) was synthesized according to the same procedure as in Example 1, using 3-(trifluoromethyl)aniline as a coupling partner with intermediate I-25. The compound was obtained as an off-white solid (60 mg, 0.1 mmol, 24% yield from 150 mg of intermediate I-25). UPLC-MS (ES + , Method 1): 4.52 min, m / z 564.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ (ppm) 10.58 (s, 1H), 8.95 (s, 1H), 8.13 (s, 1H), 7.81 (d, J=8.3 Hz, 1H), 7.68 (d, J=8.7 Hz, 1H), 7.60 (t, J=7.9 Hz, 1H), 7.51 - 7.48 (m, 2H), 7.45 (d, J=7.6 Hz, 1H), 7.33 (d, J=7.9 Hz, 1H), 7.10 (d, J=7.2 Hz, 1H), 7.01 (d, J=7.1 Hz, 1H), 5.75 - 5.72 (m, 1H), 4.59 (s, 2H), 4.44 (s, 2H), 3.90 - 3.87 (m, 1H), 3.76 - 3.69 (m, 1H), 2.47 (s, 3H), 2.45 - 2.34 (m, 2H), 1.96 - 1.92 (m, 1H), 1.80 - 1.70 (m, 1H), 1.59 - 1.53 (m, 2H).

[0264] Step B. 2-[7-[(3-methyl-1H-indazol-6-yl)amino]-1-oxo-isoindolin-2-yl]-N-[3-(trifluoromethyl)phenyl]acetamide (Example 25). To a solution of 2-[7-[(3-methyl-1-tetrahydropyran-2-yl-indazol-6-yl)amino]-1-oxo-isoindolin-2-yl]-N-[3-(trifluoromethyl)phenyl]acetamide (60 mg, 0.1 mmol) in DCM (3 mL) was added TFA (2.5 mL) dropwise. The mixture was stirred at room temperature for 2 h, then concentrated under reduced pressure and purified by prep-HPLC to give 2-[7-[(3-methyl-1H-indazol-6-yl)amino]-1-oxo-isoindolin-2-yl]-N-[3-(trifluoromethyl)phenyl]acetamide (Example 25, 13 mg, 0.03 mmol, 25% yield) as a yellow solid. UPLC-MS (ES + , Method 1): 4.05 minutes, m / z 480.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ (ppm) 12.37 (s, 1H), 10.55 (s, 1H), 8.84 (s, 1H), 8.10 (s, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.57 (t, 1H), 7.46 (d, J = 8.6 Hz, 1H), 7.43 (s, 1H), 7.32 (s, 1H), 7.29 (s, 1H), 6.97 (s, 1H), 4.56 (s, 2H), 4.41 (s, 2H), 2.45 (s, 3H).

[0265] Example 51 (7-[(1-methylpyrazolo[3,4-b]pyridin-5-yl)amino]-2-[2-oxo-2-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethyl]isoindolin-1-one)

[0266] [ka]

[0267] Scheme 6 Step A. Intermediate I-28 (2-[7-[(1-methylpyrazolo[3,4-b]pyridin-5-yl)amino]-1-oxo-isoindolin-2-yl]acetic acid). A mixture of ethyl 2-(7-((1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)amino)-1-oxoisoindolin-2-yl)acetate (I-27) (1.12 g, 3.067 mmol, 1.0 eq) and LiOH.HO (386 mg, 9.2 mmol) in HO / THF / MeOH (1:1:1, 18 mL) was stirred at room temperature for 2 h. The reaction was diluted with water (200 mL) and washed with DCM (100 mL x 3). The aqueous phase was adjusted to pH 3 by slow addition of 1 M HCl. The mixture was washed with DCM (200 mL×3) and concentrated to give I-28 (2-[7-[(1-methylpyrazolo[3,4-b]pyridin-5-yl)amino]-1-oxo-isoindolin-2-yl]acetic acid) as a yellow solid (960 mg, 93% yield). UPLC-MS (ES + , Method 2): 0.82 min, m / z 338.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ (ppm) 8.62 (s, 1H), 8.52 (d, J = 5.9Hz, 1H), 8.17 (d, J = 5.9Hz, 1H), 8.08 (s, 1H), 7.38 - 7.34 (m, 1H), 6.91 (d, J = 6.9Hz, 2H), 4.27 (s, 2H), 4.06 (s, 3H).

[0268] Step B. 7-[(1-methylpyrazolo[3,4-b]pyridin-5-yl)amino]-2-[2-oxo-2-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethyl]isoindolin-1-one (Example 51). A mixture of 2-(7-((1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)amino)-1-oxoisoindolin-2-yl)acetic acid (I-28) (237 mg, 0.70 mmol), (S)-2-(trifluoromethyl)pyrrolidine (195.48 mg, 1.40 mmol), HATU (400.7 mg, 1.05 mmol) and DIEA (272.39 mg, 2.10 mmol) in DMF (8 mL) was stirred at room temperature overnight. The mixture was diluted with 40 mL of water and extracted with ethyl acetate (10 mL x 5). The organic solution was washed with brine (25 mL x 3), dried over Na2SO4, and concentrated under vacuum. The crude product was purified by prep-TLC (DCM / MeOH = 20 / 1, v / v). Methanol (2 mL) was added to the product and filtered, and the solid was concentrated and dried to give 7-[(1-methylpyrazolo[3,4-b]pyridin-5-yl)amino]-2-[2-oxo-2-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethyl]isoindolin-1-one (Example 51) (140 mg, 43.4%. Yield) as a yellow solid. UPLC-MS (ES + , Method 2): 1.70 min, m / z, 459.15 [M+H]. 1H NMR (400 MHz, DMSO-d6) δ (ppm) 8.63 (s, 1H), 8.53 (d, J = 2.4 Hz, 1H), 8.17 (d, J = 2.4 Hz, 1H), 8.08 (s, 1H), 7.36 (t, J = 7.8 Hz, 1H), 6.91 (d, J = 7.8 Hz, 2H), 5.08 - 4.40 (m, 5H), 4.07 (s, 3H), 3.71 - 3.63 (m, 2H), 2.16 - 1.90 (m, 4H).

[0269] Table 10 lists examples synthesized from I-28 following the same procedure as in Step B of Example 51 (Scheme 6), substituting the appropriate building block for (S)-2-(trifluoromethyl)pyrrolidine. [Table 10-1] [Table 10-2] [Table 10-3] [Table 10-4]

[0270] Example 73 (2-[1-oxo-7-(1H-pyrazolo[3,4-b]pyridin-5-ylamino)isoindolin-2-yl]-N-[(1S)-2,2,2-trifluoro-1-methyl-ethyl]acetamide)

[0271] [ka]

[0272] Scheme 7 Step A. 2-[1-oxo-7-[(1-tetrahydropyran-2-ylpyrazolo[3,4-b]pyridin-5-yl)amino]isoindolin-2-yl]-N-[(1S)-2,2,2-trifluoro-1-methyl-ethyl]acetamide. A mixture of 2-(1-oxo-7-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)amino)isoindolin-2-yl)acetic acid (80 mg, 0.19 mmol), (1S)-1,1,1-trifluoropropan-2-amine hydrochloride (44 mg, 0.29 mmol), HATU (110 mg, 0.29 mmol) and DIPEA (101 mg, 0.78 mmol) in DMF (2 mL) was stirred at room temperature overnight. The reaction was diluted with EtOAc (100 mL) and washed with water (50 mL×3) and brine, then dried over sodium sulfate. The crude product was purified by silica gel flash column chromatography (DCM to DCM:MeOH, 50:1) and the desired fractions were concentrated to give 2-[1-oxo-7-[(1-tetrahydropyran-2-ylpyrazolo[3,4-b]pyridin-5-yl)amino]isoindolin-2-yl]-N-[(1S)-2,2,2-trifluoro-1-methyl-ethyl]acetamide as a yellow solid (35 mg, 35% yield). UPLC-MS (ES + , Method 2): 2.04 min, m / z 503 [M+H] + .

[0273] Step B. 2-[1-oxo-7-(1H-pyrazolo[3,4-b]pyridin-5-ylamino)isoindolin-2-yl]-N-[(1S)-2,2,2-trifluoro-1-methyl-ethyl]acetamide (Example 73). A mixture of 2-[1-oxo-7-[(1-tetrahydropyran-2-ylpyrazolo[3,4-b]pyridin-5-yl)amino]isoindolin-2-yl]-N-[(1S)-2,2,2-trifluoro-1-methyl-ethyl]acetamide (35 mg, 0.07 mmol) in HCl, 1,4-dioxane solution (4 M, 1 mL) and DCM (1 mL) and MeOH (1 mL) was stirred at room temperature for 1 h. The mixture was concentrated to give 2-[1-oxo-7-(1H-pyrazolo[3,4-b]pyridin-5-ylamino)isoindolin-2-yl]-N-[(1S)-2,2,2-trifluoro-1-methyl-ethyl]acetamide (Example 73) (29 mg, 92% yield) as a yellow solid. UPLC-MS (ES + , Method 2): 1.29 min, m / z, 419.05 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ (ppm) 8.74 (d,J= 8.9 Hz, 1H), 8.47 (d,J= 2.4 Hz, 1H), 8.16 (d,J= 2.4 Hz, 1H), 8.09 (s, 1H), 7.35 (t,J= 7.8 Hz, 1H), 6.90 (d,J= 7.9 Hz, 2H), 4.62 (h,J= 7.7 Hz, 1H), 4.48 (s, 2H), 4.29 - 4.18 (m, 2H), 1.27 (d,J= 6.9 Hz, 3H).

[0274] The examples in Table 11 were prepared from intermediate I-34 in a procedure analogous to Example 73 (Scheme 7), substituting the appropriate building block for (1S)-1,1,1-trifluoropropan-2-amine hydrochloride in Step A. [Table 11-1] [Table 11-2]

[0275] Example 79 (2-[1,1-difluoro-4-[(1-methylindazol-5-yl)amino]-3-oxo-isoindolin-2-yl]-N-(2,2,2-trifluoroethyl)acetamide)

[0276] [ka]

[0277] Scheme 8 Step A. 4-Bromoisoindoline-1,3-dione. A solution of 3-bromophthalic anhydride (1.1 g, 4.84 mmol) in formamide (4 mL) was stirred at 200° C. for 2 hr. The resulting suspension was slurried with water to give 4-bromoisoindoline-1,3-dione (1.0 g, 91% yield) as a white solid after filtration and drying under suction. UPLC-MS (ES + , Method 1): 3.25 minutes, m / z, 224.00 [MH] + .

[0278] Step B. Ethyl 2-(4-bromo-1,3-dioxo-isoindolin-2-yl)acetate. A solution of 4-bromoisoindoline-1,3-dione (1.0 g, 4.42 mmol), ethyl bromoacetate (886 mg, 5.3 mmol) and cesium carbonate (2.16 g, 6.6 mmol) in MeCN (10 mL) was stirred at 50° C. for 2 h. The mixture was filtered, the filter cake washed with MeCN, and the organic phases combined, concentrated in vacuo and slurried with cold ether to give ethyl 2-(4-bromo-1,3-dioxo-isoindolin-2-yl)acetate (1.0 g, 72% yield) as an off-white semi-solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm) 8.07 - 8.05 (d, J = 8 Hz, 1H), 7.95 - 7.93 (d, J = 8 Hz, 1H), 7.80 - 7.76 (t, J = 8 Hz, 1H), 4.42 (s, 2H), 4.19 - 4.14 (q, J = 7 Hz 2H), 1.23 - 1.19 (t, J = 7 Hz 3H).

[0279] Step C. Ethyl 2-(4-bromo-3-oxo-1-thioxo-isoindolin-2-yl)acetate. A mixture of ethyl 2-(4-bromo-1,3-dioxo-isoindolin-2-yl)acetate (360 mg, 1.15 mmol) and Lawesson's reagent (513 mg, 1.28 mmol) was added to toluene (10 mL) and heated to reflux for 14 hr. After cooling to room temperature, the toluene was removed under reduced pressure and the resulting residue was purified by silica gel flash column chromatography (loaded in DCM and eluted with 10:1 hexanes / EtOAc) to give ethyl 2-(4-bromo-3-oxo-1-thioxo-isoindolin-2-yl)acetate (250 mg, 66% yield) as a yellow solid. 1 H NMR (400 MHz, CDCl3) δ (ppm) 7.98 - 7.96 (d, J = 8 Hz, 1H), 7.86 - 7.84 (d, J = 8 Hz, 1H), 7.58 - 7.54 (t, J = 8 Hz, 1H), 4.79 (s, 2H), 4.25 - 4.20 (q, J = 7 Hz 2H), 1.30 - 1.26 (t, J = 7 Hz 3H).

[0280] Step D. Ethyl 2-(4-bromo-1,1-difluoro-3-oxo-isoindolin-2-yl)acetate. A mixture of ethyl 2-(4-bromo-3-oxo-1-thioxo-isoindolin-2-yl)acetate (190 mg, 0.58 mmol), NBS (515 mg, 2.89 mmol) and n-BuNHF (3.5 g, 5.8 mmol) in DCM (10 mL) was stirred at room temperature for 14 hr. The mixture was filtered and concentrated to an oily residue, which was purified by preparative TLC in 10:1 hexane / EtOAc to give ethyl 2-(4-bromo-1,1-difluoro-3-oxo-isoindolin-2-yl)acetate (80 mg, 39% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ (ppm) 7.86 - 7.84 (d, J = 8 Hz, 1H), 7.71 - 7.69 (d, J = 8 Hz, 1H), 7.60 - 7.66 (t, J = 8 Hz, 1H), 4.3 (s, 2H), 4.26 - 4.21 (q, J = 7 Hz 2H), 1.23 - 1.19 (t, J = 7 Hz 3H).

[0281] Step E. 2-(4-Bromo-1,1-difluoro-3-oxo-isoindolin-2-yl)acetic acid. A solution of LiOH.HO (57.8 mg, 1.37 mmol) in water (2 mL) was added to a mixture of ethyl 2-(4-bromo-1,1-difluoro-3-oxo-isoindolin-2-yl)acetate (230 mg, 0.69 mmol) in 1:1 MeOH / THF (6 mL) and the resulting mixture was stirred at 25° C. for 2 hr. The mixture was concentrated and the residue was diluted with water (2 mL) and the pH was adjusted to 2 with 2N HCl, then filtered and the solid was dried to give 2-(4-Bromo-1,1-difluoro-3-oxo-isoindolin-2-yl)acetic acid (100 mg, 46% yield) as a white solid. UPLC-MS (ES + , Method 1): 3.50 minutes, m / z, 303.9 / 305.9 [MH] + .

[0282] Step F. 2-(4-Bromo-1,1-difluoro-3-oxo-isoindolin-2-yl)-N-(2,2,2-trifluoroethyl)acetamide. A solution of 2-(4-bromo-1,1-difluoro-3-oxo-isoindolin-2-yl)acetic acid (80 mg, 0.29 mmol), 2,2,2-trifluoroethan-1-amine (38.8 mg, 0.39 mmol), DIEA (168 mg, 1.30 mmol) and T3P (297 mg, 0.39 mmol) in DCM (1 mL) was stirred at room temperature for 16 h. The mixture was concentrated to an oily residue and purified by prep-TLC to give 2-(4-bromo-1,1-difluoro-3-oxo-isoindolin-2-yl)-N-(2,2,2-trifluoroethyl)acetamide (38.6 mg, 38% yield) as a white solid. UPLC-MS (ES + , Method 1): 3.51 min, m / z, 386.6 / 388.6 [M+H] + .

[0283] Step G. 2-[1,1-difluoro-4-[(1-methylindazol-5-yl)amino]-3-oxo-isoindolin-2-yl]-N-(2,2,2-trifluoroethyl)acetamide (Example 79). A solution of 2-(4-bromo-1,1-difluoro-3-oxo-isoindolin-2-yl)-N-(2,2,2-trifluoroethyl)acetamide (80 mg, 0.2 mmol), cesium carbonate (101 mg, 0.31 mmol), Xantphos (11.9 mg, 0.02 mmol), bis(dibenzylideneacetone)palladium(0) (18.9 g, 0.02 mmol), 1-methyl-1H-indazol-5-amine (30.4 mg, 0.2 mmol) in 1,4-dioxane (2 mL) was stirred at 100° C. for 16 h. The mixture was concentrated under reduced pressure and purified by prep-HPLC to give 2-[1,1-difluoro-4-[(1-methylindazol-5-yl)amino]-3-oxo-isoindolin-2-yl]-N-(2,2,2-trifluoroethyl)acetamide (Example 79) (21 mg, 22% yield) as a yellow solid. UPLC-MS (ES +, Method 1): 3.75 min, m / z, 454.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ (ppm) 8.86 (t,J= 6.4 Hz, 1H), 8.32 (s, 1H), 8.01 (s, 1H), 7.68 (dd,J = 5.4, 3.4 Hz, 2H), 7.52 (t,J = 7.9 Hz, 1H), 7.36 (dd,J = 8.9, 1.9 Hz, 1H), 7.15 - 7.08 (m, 2H), 4.22 (s, 2H), 4.06 (s, 3H), 4.02 - 3.90 (m, 2H).

[0284] Example 80 (2-[7-[(3-isopropyl-1H-indazol-6-yl)amino]-1-oxo-isoindolin-2-yl]-N-(2,2,2-trifluoroethyl)acetamide) [ka]

[0285] A mixture of 2-(7-((3-isopropyl-1H-indazol-6-yl)amino)-1-oxoisoindolin-2-yl)acetic acid (15 mg, 0.04 mmol), 2,2,2-trifluoroethan-1-amine (6.12 mg, 0.06 mmol), HATU (23.5 mg, 0.06 mmol,) and DIPEA (16 mg, 0.12 mmol) in DMF (1 mL) was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and purified by preparative TLC (DCM:MeOH=20:1) to give 2-[7-[(3-isopropyl-1H-indazol-6-yl)amino]-1-oxo-isoindolin-2-yl]-N-(2,2,2-trifluoroethyl)acetamide (2.2 mg, 12% yield) as a white solid. UPLC-MS (ES + , Method 2): 1.66 min, m / z, 446.1 [M+H] + . 1H NMR (400 MHz, Acetonitrile-d3) δ (ppm) 10.59 (s, 1H), 8.84 (s, 1H), 7.72 (d,J = 8.6 Hz, 1H), 7.45 - 7.41 (m, 1H), 7.40 (t,J = 1.7 Hz, 1H), 7.34-7.31 (m, 1H), 7.16 - 7.11 (m, 1H), 7.00 (dd,J = 8.7, 1.8 Hz, 1H), 6.92 (d,J = 8.0 Hz, 1H), 4.45 (s, 2H), 4.22 (s, 2H), 3.90 (qd,J = 9.5, 6.5 Hz, 2H), 3.36 (p,J = 7.0 Hz, 1H), 1.40 (d,J = 8.0 Hz, 6H).

[0286] Example 81 (2-[7-(1H-indazol-6-ylamino)-1-oxo-isoindolin-2-yl]-N-(2,2,2-trifluoroethyl)acetamide) [ka]

[0287] A solution of intermediate I-36 (90 mg, 0.27 mmol), trifluoroethylamine (33.19 mg, 0.33 mmol), T3P (133.27 mg, 0.41 mmol) and DIEA (180 mg, 1.39 mmol) in DCM (1.0 mL) was stirred at 25 °C for 2 h. The mixture was diluted with EtOAc (5 mL) and washed with HO (5 mL x 3). The organic phases were washed with EtOAc (10 mL x 3), combined, dried over anhydrous Na2SO4 and concentrated to give a yellow solid, which was purified by prep-TLC (DCM:MeOH = 20:1) to give 2-[7-(1H-indazol-6-ylamino)-1-oxo-isoindolin-2-yl]-N-(2,2,2-trifluoroethyl)acetamide (5.1 mg, 5% yield) as a white solid. UPLC-MS (ES + , Method 1): 3.35 min, m / z, 404.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ (ppm) 12.81 (s, 1H), 8.84 (t,J = 5.2 Hz, 2H), 7.97 (s, 1H), 7.71 (d,J = 8.5 Hz, 1H), 7.46 - 7.40 (m, 2H), 7.29 (d,J = 8.3 Hz, 1H), 7.00 - 6.95 (m, 2H), 4.48 (s, 2H), 4.25 (s, 2H), 3.99 - 3.90 (m, 2H).

[0288] Example 82 (5-[[3-oxo-2-[2-oxo-2-[(2S)-(trifluoromethyl)pyrrolidin-1-yl]ethyl]isoindolin-4-yl]amino]-1H-indazole-3-carbonitrile) [ka]

[0289] Example 82 was prepared from intermediate I-37 in a manner analogous to that used for Example 25 (Scheme 5), substituting I-37 for I-25 and substituting (2S)-trifluoromethylpyrrolidine for 3-(trifluoromethyl)aniline in Step A. UPLC-MS (ES + , Method 1): 3.98 min, m / z, 469.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ (ppm) 14.29 (s, 1H), 8.84 (s, 1H), 7.75 (d,J = 8.9 Hz, 1H), 7.68 (d,J = 1.9 Hz, 1H), 747 - 7.43 (m, 2H), 7.23 (d,J = 8.3 Hz, 1H), 6.97 (d,J = 7.4 Hz, 1H), 4.78 - 4.57 (m, 1H), 4.51 - 4.37 (m, 4H), 3.67 (d,J = 8.2 Hz, 2H), 2.14 - 1.99 (m, 3H).

[0290] Example 83 (7-[(3-fluoro-1H-indazol-5-yl)amino]-2-[2-oxo-2-[(2S)-(trifluoromethyl)pyrrolidin-1-yl]ethyl]isoindolin-1-one) [ka]

[0291] Example 83 was prepared in an analogous manner to Example 81, substituting I-38 for I-36 and (2S)-(trifluoromethyl)pyrrolidine for trifluoroethylamine. UPLC-MS (ES + , Method 1): 4.02 min, m / z, 462.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ (ppm) 12.50 (s, 1H), 8.64 (s, 1H), 7.55 (d, J = 1.9 Hz, 1H), 7.50 (dd, J = 8.9, 2.3 Hz, 1H), 7.41 - 7.33 (m, 2H), 7.04 (d, J = 8.2 Hz, 1H), 6.90 (d, J = 7.3 Hz, 1H), 4.81 - 4.70 (m, 1H), 4.51 - 4.35 (m, 4H), 3.67 (d, J = 8.6 Hz, 2H), 2.13 - 1.93 (m, 4H).

[0292] Example 84 (2-[2-oxo-2-[(2S)-(trifluoromethyl)pyrrolidin-1-yl]ethyl]-7-(1H-pyrazolo[4,3-b]pyridin-5-ylamino)isoindolin-1-one) [ka]

[0293] Example 83 was prepared in a similar manner to Example 81, substituting I-39 for I-38. UPLC-MS (ES+ , Method 1): 3.57 min, m / z, 445.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ (ppm) 13.2 (bs, 1H), 9.86 (s, 1H), 8.79 - 8.77 (m, 1H), 8.13 - 7.92 (m, 2H), 7.59 - 7.51 (m, 1H), 7.09 - 6.92 (m, 2H), 4.81 - 4.70 (m, 1H), 4.54 - 4.39 (m, 4H), 3.71 - 3.63 (m, 2H), 2.12 - 1.96 (m, 4H).

[0294] Example 86 (5-[methyl-[3-oxo-2-[2-oxo-2-[(2S)-(trifluoromethyl)pyrrolidin-1-yl]ethyl]isoindolin-4-yl]amino]-1H-indazole-3-carbonitrile)

[0295] [ka]

[0296] Scheme 9 Step A. 2-[7-[(3-cyano-1-tetrahydropyran-2-yl-indazol-5-yl)-methyl-amino]-1-oxo-isoindolin-2-yl]acetic acid. A mixture of ethyl 2-[7-[(3-cyano-1-tetrahydropyran-2-yl-indazol-5-yl)-methyl-amino]-1-oxo-isoindolin-2-yl]acetate (90 mg, 0.19 mol), LiOH (15.95 mg, 0.38 mmol), THF (2 mL), MeOH (2 mL) and HO (0.5 mL) was stirred at 25° C. for 2 h. The mixture was diluted with H2O and 10% HCl to achieve pH 1-2 and concentrated in vacuo to give 2-[7-[(3-cyano-1-tetrahydropyran-2-yl-indazol-5-yl)-methyl-amino]-1-oxo-isoindolin-2-yl]acetic acid (100 mg, quantitative yield) as a white solid. UPLC-MS (ES + , Method 1): 4.11 minutes, m / z 465.2 [M+H] + .

[0297] Step B. 5-[methyl-[3-oxo-2-[2-oxo-2-[(2S)-(trifluoromethyl)pyrrolidin-1-yl]ethyl]isoindolin-4-yl]amino]-1-tetrahydropyran-2-yl-indazole-3-carbonitrile. A mixture of 2-[7-[(3-cyano-1-tetrahydropyran-2-yl-indazol-5-yl)-methyl-amino]-1-oxo-isoindolin-2-yl]acetic acid (80 mg, 0.17 mmol), (2S)-trifluoromethylpyrrolidine (37.47 mg, 0.26 mmol), HATU (81.9 mg, 0.21 mmol) and DIEA (69.5 mg, 0.53 mmol) in DMF (1 mL) was stirred at 25° C. overnight. The mixture was slurried with water (20 mL) and the solid was dried under vacuum to give 5-[methyl-[3-oxo-2-[2-oxo-2-[(2S)-(trifluoromethyl)pyrrolidin-1-yl]ethyl]isoindolin-4-yl]amino]-1-tetrahydropyran-2-yl-indazole-3-carbonitrile (100 mg, 97% yield) as a yellow solid. UPLC-MS (ES + , Method 1): 4.35 minutes, m / z 567.2 [M+H] + .

[0298] Step C. 5-[methyl-[3-oxo-2-[2-oxo-2-[(2S)-(trifluoromethyl)pyrrolidin-1-yl]ethyl]isoindolin-4-yl]amino]-1H-indazole-3-carbonitrile (Example 86). A mixture of 5-[methyl-[3-oxo-2-[2-oxo-2-[(2S)-(trifluoromethyl)pyrrolidin-1-yl]ethyl]isoindolin-4-yl]amino]-1-tetrahydropyran-2-yl-indazole-3-carbonitrile (100 mg, 0.17 mmol,) and 4N HCl-dioxane (1.5 mL) in DCM (1 mL) was stirred at 25° C. for 2 h. The mixture was diluted with water (10 mL), extracted with EtOAc (10 mL×3), and dried over Na2CO3. The mixture was purified by preparative TLC (Pet. Ether / EtOAc=1 / 1) to give 5-[methyl-[3-oxo-2-[2-oxo-2-[(2S)-(trifluoromethyl)pyrrolidin-1-yl]ethyl]isoindolin-4-yl]amino]-1H-indazole-3-carbonitrile (Example 86) (25 mg, 85% yield) as a yellow solid. UPLC-MS (ES + , Method 1): 3.85 min, m / z 483.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ (ppm) 14.06 (s, 1H), 7.60 (t,J = 7.7 Hz, 1H), 7.48 - 7.43 (m, 2H), 7.20 (d,J = 7.9 Hz, 1H), 7.00 - 6.99 (m, 1H), 6.91 (dd,J = 9.2, 2.3 Hz, 1H), 5.02 - 4.68 (m, 1H), 4.49 - 4.31 (m, 4H), 3.66 - 3.56 (m, 2H), 3.35 (s, 3H), 2.07 - 1.97 (m, 4H).

[0299] Example 91 (2-[7-[(4-chloro-3-methyl-1H-indazol-6-yl)amino]-1-oxo-isoindolin-2-yl]-N-(2,2,2-trifluoroethyl)acetamide)

[0300] [ka]

[0301] Scheme 10 Step A. 2-(7-amino-1-oxo-isoindolin-2-yl)acetic acid (Intermediate I-45). A solution of ethyl 2-(7-amino-1-oxoisoindolin-2-yl)acetate (200 mg, 0.85 mmol) and LiOH (93.14 mg, 2.27 mmol) in THF (3 mL) and HO (1 mL) was stirred at 25 °C for 2 h. The mixture was neutralized with dilute HCl, then extracted with EtOAc (15 mL x 3), dried over anhydrous NaSO, and concentrated in vacuo to give 2-(7-amino-1-oxo-isoindolin-2-yl)acetic acid (150 mg, 85% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ (ppm) 12.83 (s, 1H), 7.21 (dd,J= 8.1, 7.3 Hz, 1H), 6.67 - 6.61 (m, 1H), 6.61 - 6.54 (m, 1H), 6.03 (s, 2H), 4.36 (s, 2H), 4.18 (s, 2H).

[0302] Step B. 2-(7-amino-1-oxo-isoindolin-2-yl)-N-(2,2,2-trifluoroethyl)acetamide (Intermediate I-46). A mixture of 2-(7-amino-1-oxoisoindolin-2-yl)acetic acid (150 mg, 0.72 mol), HATU (414 mg, 1.09 mmol) and DIPEA (279 mg, 2.18 mmol) in DMF (2 mL) was stirred at 25° C. for 30 min, after which 2,2,2-trifluoroethan-1-amine (79 mg, 0.80 mol) was added and the mixture was stirred at room temperature for 2 h. The mixture was diluted with water (15 mL) and extracted with EtOAc (20 mL×3). The organic phases were combined, washed with brine (50 mL), dried over Na2SO4, concentrated under vacuum and purified by silica gel column chromatography (pet. ether / EtOAc, 5 / 1 to pet. ether / EtOAc, 1 / 1) to give 2-(7-amino-1-oxo-isoindolin-2-yl)-N-(2,2,2-trifluoroethyl)acetamide (110 mg, 53% yield) as a clear oil. UPLC-MS (ES + , Method 1): 3.12 minutes, m / z, 288.2 [M+H] + 1 H NMR (400 MHz, DMSO-d6) δ (ppm) 8.75 (t,J = 6.4 Hz, 1H), 7.21 (t,J= 7.7 Hz, 1H), 6.60 (dd,J = 24.5, 7.7 Hz, 2H), 6.03 (s, 2H), 4.35 (s, 2H), 4.16 (s, 2H), 3.91 (tt,J = 9.9, 4.9 Hz, 2H).

[0303] Step C. 2-[7-[[4-chloro-3-methyl-1-(p-tolylsulfonyl)indazol-6-yl]amino]-1-oxo-isoindolin-2-yl]-N-(2,2,2-trifluoroethyl)acetamide. A mixture of 6-bromo-4-chloro-3-methyl-1-tosyl-1H-indazole (130 mg, 0.32 mol), 2-(7-amino-1-oxoisoindolin-2-yl)-N-(2,2,2-trifluoroethyl)acetamide (93 mg, 0.32 mol), t-BuBrettphos (31.5 mg, 0.065 mmol), Pd2(dba)3 (29.7 mg, 0.032 mol, 0.1), K2CO3 (8 mg, 0.65 mmol) in t-BuOH (2 mL) and AcOH (0.5 mL) was irradiated in a microwave at 100° C. for 2 h. The mixture was diluted with water (5 mL) and extracted with EtOAc (20 mL×3). The organic phases were combined, washed with brine (20 mL), dried over Na2SO4, concentrated in vacuo and purified by silica gel column chromatography (DCM / MeOH, 100 / 1 to DCM / MeOH, 50 / 1) to give 2-[7-[[4-chloro-3-methyl-1-(p-tolylsulfonyl)indazol-6-yl]amino]-1-oxo-isoindolin-2-yl]-N-(2,2,2-trifluoroethyl)acetamide (55 mg 28% yield) as a yellow solid. UPLC-MS (ES + , Method 2): 2.15 minutes, m / z, 607.1 [M+H] +

[0304] Step D. 2-[7-[(4-chloro-3-methyl-1H-indazol-6-yl)amino]-1-oxo-isoindolin-2-yl]-N-(2,2,2-trifluoroethyl)acetamide (Example 91). A solution of ethyl 2-(7-amino-1-oxoisoindolin-2-yl)acetate (50 mg, 0.082 mmol) and LiOH (20 mg, 0.41 mmol) in THF (3 mL) and HO (1 mL) was stirred at 50 °C for 2 h. The mixture was adjusted to pH 7.0 with dilute HCl, then concentrated and the crude material was purified by preparative HPLC to give 2-[7-[(4-chloro-3-methyl-1H-indazol-6-yl)amino]-1-oxo-isoindolin-2-yl]-N-(2,2,2-trifluoroethyl)acetamide (3.3 mg, 37% yield) as a yellow solid. UPLC-MS (ES + , Method 1): 3.85 minutes, m / z,452.20 [M+H] + 1 H NMR (400 MHz, DMSO-d6) δ (ppm) 12.63 (s, 1H), 8.89 - 8.71 (m, 2H), 7.47 (t,J= 7.8 Hz, 1H), 7.32 - 7.25 (m, 2H), 7.07 - 6.96 (m, 2H), 4.49 (s, 2H), 4.25 (s, 2H), 3.99 - 3.89 (m, 2H), 2.60 (s, 3H).

[0305] Example 93 (2-[7-[(7-fluoro-1-methyl-indazol-5-yl)amino]-1-oxo-isoindolin-2-yl]-N-(2,2,2-trifluoroethyl)acetamide) [ka]

[0306] 5-Bromo-7-fluoro-1-methyl-indazole (70 mg, 0.30 mmol), 2-(7-amino-1-oxo-isoindolin-2-yl)-N-(2,2,2-trifluoroethyl)acetamide (97 mg, 0.33 mmol), Cs2CO3 (199 mg, 0.61 mmol), Xantphos (35.3 mg, 0.061 mmol) and Pd2(dba)3 (28 mg, 0.031 mmol) in 1,4-dioxane (2.0 mL) were stirred at 100 °C under N2 overnight. The mixture was diluted with EtOAc (5 mL) and washed with H2O (5 mL x 3). The organic phases were washed with EtOAc (10 mL x 3), combined, dried over anhydrous Na2SO4 and concentrated to give a yellow solid. This was purified by preparative TLC to give 2-[7-[(7-fluoro-1-methyl-indazol-5-yl)amino]-1-oxo-isoindolin-2-yl]-N-(2,2,2-trifluoroethyl)acetamide (21 mg, 16% yield) as a yellow solid. UPLC-MS (ES + , Method 1): 3.89 min, m / z, 436.2 [M+H] + 1 H NMR (400 MHz, DMSO-d6) δ (ppm) 8.81 (t, J = 6.3 Hz, 1H), 8.63 (s, 1H), 8.03 (d, J = 2.4 Hz, 1H), 7.49 (d, J = 1.6 Hz, 1H), 7.39 (t, J = 7.9 Hz, 1H), 7.21 (dd, J = 13.2, 1.7 Hz, 1H), 7.09 (d, J = 8.2 Hz, 1H), 6.92 (d, J = 7.4 Hz, 1H), 4.47 (s, 2H), 4.24 (s, 2H), 4.16 (s, 3H), 3.99 - 3.90 (m, 2H). UPLC-MS (ES + , Method 1): 3.89 min, m / z, 436.2 [M+H] +

[0307] Example 96 (7-[(7-fluoro-1-methyl-indazol-5-yl)amino]-2-[2-oxo-2-(2S)-(trifluoromethyl)pyrrolidin-1-yl]ethyl]isoindolin-1-one)

[0308] [ka]

[0309] Scheme 11 Steps A and B. Intermediate I-47 (7-amino-2-[2-oxo-2-[(2S)-(trifluoromethyl)pyrrolidin-1-yl]ethyl]isoindolin-1-one) was prepared starting from I-43 instead of I-6 using the same procedure as outlined in Scheme 2 for intermediate I-30. UPLC-MS (ES + , Method 1): 3.45 minutes, m / z, 328.2 [M+H] +

[0310] Step C. 7-[(7-Fluoro-1-methyl-indazol-5-yl)amino]-2-[2-oxo-2-[(2S)-(trifluoromethyl)pyrrolidin-1-yl]ethyl]isoindolin-1-one (Example 96). A solution of 5-bromo-7-fluoro-1-methyl-indazole (60 mg, 0.26 mmol), -amino-2-[2-oxo-2-[(2S)-(trifluoromethyl)pyrrolidin-1-yl]ethyl]isoindolin-1-one (94.3 mg, 0.28 mmol), Cs2CO3 (172.22 mg, 0.52 mmol), Xantphos (30.58 mg, 0.052 mmol) and Pd2(dba)3 (24.20 mg, 0.026 mmol) in 1,4-dioxane (1.0 mL) was stirred at 100 °C under N2 overnight. The mixture was diluted with EtOAc (10 mL) and washed with H2O (8 mL x 3). The organic phases were washed with EtOAc (10 mL x 3), combined, dried over anhydrous Na2SO4 and concentrated to give a yellow solid. The mixture was purified by preparative TLC to give 7-[(7-fluoro-1-methyl-indazol-5-yl)amino]-2-[2-oxo-2-[(2S)-(trifluoromethyl)pyrrolidin-1-yl]ethyl]isoindolin-1-one (16 mg, 21% yield) as a yellow solid. UPLC-MS (ES + , Method 1): 4.18 minutes, m / z 476.3 [M+H] + 1 H NMR (400 MHz, DMSO-d6) δ (ppm) 8.64 (s, 1H), 8.03 (d,J= 2.4 Hz, 1H), 7.49 (d,J= 1.6 Hz, 1H), 7.39 (t,J= 7.8 Hz, 1H), 7.21 (dd,J= 13.3, 1.7 Hz, 1H), 7.09 (d,J= 8.2 Hz, 1H), 6.92 (d,J= 7.4 Hz, 1H), 5.08 - 4.72 (m, 1H), 4.60 - 4.36 (m, 4H), 4.16 (s, 3H), 3.70 - 3.63 (m, 2H), 2.07 - 2.00 (m, 4H).

[0311] Example 101 (2-[7-[(1,3-dimethylpyrazolo[3,4-b]pyridin-5-yl)amino]-1-oxo-isoindolin-2-yl]-N-(2,2,2-trifluoroethyl)acetamide) [ka]

[0312] A mixture of 2-(7-amino-1-oxoisoindolin-2-yl)-N-(2,2,2-trifluoroethyl)acetamide (I-46) (80 mg, 0.28 mmol), 5-bromo-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine (75 mg, 0.33 mmol), Pd2dba3 (25.6 mg, 0.028 mmol), Xantphos (32.4 mg, 0.056 mmol), Cs2CO3 (274 mg, 0.84 mmol) in 1,4-dioxane (3 mL) was stirred at 110° C. under N2 atmosphere overnight. The reaction was diluted with EtOAc (100 mL) and washed with water (50 ml×3). The organic phases were combined and washed with brine (30 mL) and Na2SO4, then concentrated and purified by silica gel chromatography (EtOAc / pet. ether, 1 / 1) to give 2-[7-[(1,3-dimethylpyrazolo[3,4-b]pyridin-5-yl)amino]-1-oxo-isoindolin-2-yl]-N-(2,2,2-trifluoroethyl)acetamide (20 mg, 16% yield) as a white solid. UPLC-MS (ES + , Method 1): 1.56 min, m / z 433.1 [M+H] + 1 H NMR (400 MHz, DMSO-d6) δ (ppm) 8.81 (t,J= 6.3 Hz, 1H), 8.58 (s, 1H), 8.48 (d,J= 2.4 Hz, 1H), 8.13 (d,J= 2.4 Hz, 1H), 7.35 (t,J= 7.9 Hz, 1H), 6.92 - 6.86 (m, 2H), 4.48 (s, 2H), 4.25 (s, 2H), 3.98 - 3.90 (m, 5H), 2.48 (s, 3H).

[0313] Example 102 (7-[(1,3-dimethylpyrazolo[3,4-b]pyridin-5-yl)amino]-2-[2-oxo[(2S)-(trifluoromethyl)pyrrolidin-1-yl]ethyl]isoindolin-1-one) [ka]

[0314] Intermediate I-50 (7-amino-2-[2-oxo-2-[(2S)-(trifluoromethyl)pyrrolidin-1-yl]ethyl]isoindolin-1-one) was prepared in an analogous manner to I-46 (Scheme 10) by replacing 2,2,2-trifluoroethan-1-amine with (2S)-(trifluoromethyl)pyrrolidine in step B. UPLC-MS (ES + , Method 1): 3.45 minutes, m / z 328.2 [M+H] +

[0315] 7-[(1,3-Dimethylpyrazolo[3,4-b]pyridin-5-yl)amino]-2-[2-oxo-2-[(2S)-(trifluoromethyl)pyrrolidin-1-yl]ethyl]isoindolin-1-one (Example 102) was prepared using the same method as Example 101, replacing I-46 with I-50. UPLC-MS (ES + , Method 1): 1.76 minutes, m / z 473.2 [M+H] + 1H NMR (400 MHz, DMSO-d6) δ (ppm) 8.55 (s, 1H), 8.46 (d, J = 2.4 Hz, 1H), 8.02 (d, J = 2.3 Hz, 1H), 7.33 (t, J = 7.8 Hz, 1H), 6.88 (dd, J = 11.9, 7.9 Hz, 2H), 5.36 - 4.31 (m, 5H), 4.00 (s, 3H), 3.70-3.60 (m, 2H), 2.49 (s, 3H), 2.12 - 2.09 (m, 4H).

[0316] Example 105 (N-methyl-2-[7-[(3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)amino]-1-oxo-isoindolin-2-yl]-N-(2,2,2-trifluoroethyl)acetamide)

[0317] [ka]

[0318] Scheme 12 Step A. 2-(7-amino-1-oxo-isoindolin-2-yl)acetic acid. A mixture of ethyl 2-[7-(tert-butoxycarbonylamino)-1-oxo-isoindolin-2-yl]acetate (6 g, 17.94 mmol) in DCM (10 mL) and HCl in dioxane (4 M) (18 mL, 179.44 mmol) was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure to give 2-(7-amino-1-oxo-isoindolin-2-yl)acetic acid hydrochloride as a yellow solid (4.5 g, quantitative yield). UPLC-MS (ES + , Method 2): 1.13 minutes, m / z 235.1 [M+H].

[0319] Step B. 2-(7-amino-1-oxo-isoindolin-2-yl)-N-methyl-N-(2,2,2-trifluoroethyl)acetamide. A solution of 2-(7-amino-1-oxo-isoindolin-2-yl)acetic acid (400 mg, 1.94 mmol), HATU (1.1 g, 2.91 mmol), DIEA (1.01 mL, 5.82 mmol) and 2,2,2-trifluoro-N-methyl-ethanamine hydrochloride (0.26 mL, 2.13 mmol) in DCM (5 mL) was stirred at 25° C. for 5 h. The mixture was purified by reverse-phase column chromatography on C-18 modified silica gel eluted with MeCN and water with 0.1% TFA as additive to give 2-(7-amino-1-oxo-isoindolin-2-yl)-N-methyl-N-(2,2,2-trifluoroethyl)acetamide as a white solid (340 mg, 58% yield). UPLC-MS (ES + , Method 1): 3.34 minutes, m / z 302.2 [M+H].

[0320] Step C. N-Methyl-2-[7-[(3-methyl-1-tetrahydropyran-2-yl-pyrazolo[3,4-b]pyridin-5-yl)amino]-1-oxo-isoindolin-2-yl]-N-(2,2,2-trifluoroethyl)acetamide. A solution of 2-(7-amino-1-oxo-isoindolin-2-yl)-N-methyl-N-(2,2,2-trifluoroethyl)acetamide (60 mg, 0.2 mmol), 5-bromo-3-methyl-1-tetrahydropyran-2-yl-pyrazolo[3,4-b]pyridine (71 mg, 0.24 mmol), K2CO3 (55 mg, 0.4 mmol), Pd2(dba)3 (18 mg, 0.02 mmol) and t-BuBrettphos (19 mg, 0.04 mmol) in t-butanol (1 mL) was stirred in a sealed tube at 110° C. for 2 h. The mixture was filtered through Celite and the filter cake was washed with DCM. The organics were combined, dried over Na2SO4 and concentrated to give an oily residue which was purified by preparative TLC eluting with DCM in MeOH (20:1) to give N-methyl-2-[7-[(3-methyl-1-tetrahydropyran-2-yl-pyrazolo[3,4-b]pyridin-5-yl)amino]-1-oxo-isoindolin-2-yl]-N-(2,2,2-trifluoroethyl)acetamide as a yellow solid (35 mg, 34% yield). UPLC-MS (ES + , Method 1): 4.08 minutes, m / z 517.4 [M+H].

[0321] Step D. N-Methyl-2-[7-[(3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)amino]-1-oxo-isoindolin-2-yl]-N-(2,2,2-trifluoroethyl)acetamide (Example 105). To a solution of N-methyl-2-[7-[(3-methyl-1-tetrahydropyran-2-yl-pyrazolo[3,4-b]pyridin-5-yl)amino]-1-oxo-isoindolin-2-yl]-N-(2,2,2-trifluoroethyl)acetamide (35 mg, 0.07 mmol) in DCM (1 mL) was added 4M HCl in dioxane (0.5 mL). The mixture was stirred at 25° C. for 2 hr. The mixture was concentrated and purified by preparative-TLC (DCM and MeOH 20:1) to give a yellow solid (23 mg, 80% yield) analyzed as N-methyl-2-[7-[(3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)amino]-1-oxo-isoindolin-2-yl]-N-(2,2,2-trifluoroethyl)acetamide (Example 105). UPLC-MS (ES + , Method 1): 3.45 minutes, m / z 433.3 [M+H]. 1 H NMR (400 MHz, DMSO-d6) δ (ppm) 13.19 (s, 1H), 8.56 (d, J = 2.8 Hz, 1H), 8.43 (d, J = 2.4 Hz, 1H), 8.13 (d, J = 2.5 Hz, 1H), 7.35 (t, J = 7.8 Hz, 1H), 6.92 - 6.85 (m, 2H), 4.51 (d, J = 20.5 Hz, 2H), 4.44 (d, J = 2.7 Hz, 2H), 4.20 (q, J = 9.8 Hz, 2H), 3.19 (s, 3H), 2.48 (s, 3H).

[0322] Biochemical Assay Methods for DDR1 and DDR2 The ability of compounds to bind to DDR1 and DDR2 was quantified using the LanthaScreen Eu kinase binding assay. Recombinant human DDR1 (2.5 nM; aa440-876 with GST tag) and DDR2 (1.75 nM; aa427-855 with 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 and a volume of 5 uL. After 30 min incubation at room temperature, 2.5 uL of Eu-anti-GST antibody (diluted to 1 nM in assay buffer) + kinase tracer 178 (diluted to 5 nM for DDR1 and 10 nM for DDR2 in assay buffer) was added to the plate. After 60 min incubation at room temperature, time-resolved fluorescence was measured on a BMG Labtech PHERAstar plate reader. DMSO (1%) and reference compound (1 μM) were used to generate Max and Min assay signals, respectively. Data were analyzed using a four-parameter logistic model to determine IC 50 Values ​​were calculated and replicated at least twice independently for each compound.

[0323] Biological activity value The following table shows the pICs of the above examples against DDR1 and DDR2 kinases: 50 Values ​​are shown (A: pIC50>8; B: 8≧pIC50>7; C: 7≧pIC50>6; D: pIC50≦6; ND: not determined). [Table 12-1] [Table 12-2] [Table 12-3]

Claims

1. Formula (I) 【Chemistry 1】 [In the formula, Z 1 and Z 2 are -CR 8a - and -NR 8b - where Z 1 and Z 2 One of them is -CR 8a - and the other is -NR 8b - where Z 1 and Z 2 The ring containing is a pyrazole; X 1 is independently 7a and N; X 2 , X 3 and X 4 are each independently selected from carbon and nitrogen, 2 , X 3 and X 4 at least one of which is carbon; R 1 independently for each occurrence: 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 is replaced by 1 -C 4 -Alkyl, OR 11 C is replaced by 1 -C 4 -Alkyl, C 2 -C 4 -Alkenyl, C 2 -C 4 -alkynyl, C 1 -C 4 - selected from haloalkyl and cyclopropyl; R 2 are independently H, fluoro, and C for each occurrence. 1 -C 4 -Alkyl, C 1 -C 4 -haloalkyl and cyclopropyl; or two R 2 The groups and the carbon atoms to which they are attached together form C 3 -C 6 - forming a cycloalkyl ring; R 3 are independently H and C 1 -C 4 - selected from alkyl; R 4 independently, C 1 -C 6 -Alkyl, C 1 -C 6 -haloalkyl, C 0 -C 4 -Alkylene-R 4a where R is selected from 4a independently, C 3 -C 8 - selected from cycloalkyl, phenyl, 5-, 6-, 9-, or 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl; wherein said heterocycloalkyl or heteroaryl group may be monocyclic or bicyclic; and wherein said cycloalkyl or heterocycloalkyl group optionally comprises a single R 12 group and / or 1 to 4 R 13 group, and the phenyl or heteroaryl group may optionally be substituted with a single R 12 group and / or 1 to 3 R 14 optionally substituted by groups; 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; wherein said heterocycloalkyl or heteroaryl group may be monocyclic or bicyclic; and wherein said heterocycloalkyl group optionally contains a single R 12 group and / or 1 to 4 R 13 The heteroaryl group may optionally be substituted by a single R 12 group and / or 1 to 3 R 14 optionally substituted by groups; R 5 are independently for 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 are independently H, C 1 -C 4 -Alkyl, C 1 -C 4 - selected from haloalkyl and cyclopropyl; R 7 and R 7a are each independently H, 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 is replaced by 1 -C 4 -Alkyl, OR 11 C is replaced by 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 is replaced by 1 -C 4 -Alkyl, OR 11 C is replaced by 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 are independently H, C 1 -C 4 -Alkyl, NR 9 R 10 C is replaced by 2 -C 4 -Alkyl, OR 11 C is replaced by 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 independently, C 3 -C 6 -cycloalkyl and 3- to 7-membered heterocycloalkyl; wherein said heterocycloalkyl group is C through a carbon atom of the heterocycloalkyl ring. 0 -C 4 -alkylene; wherein said cycloalkyl or heterocycloalkyl group is optionally linked to 1 to 4 R 13 optionally substituted by groups; R 9 independently for each occurrence, H and C 1 -C 4 -alkyl; or two R 9 The groups, together with the nitrogen atom to which they are attached, optionally contain 0 to 4 R 13 C optionally substituted by a group 5 -C 8 -forming a heterocycloalkyl group; R 10 independently for 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, optionally 0 to 4 R 13 C optionally substituted by a group 5 -C 8 -forming a heterocycloalkyl group; R 11 independently for each occurrence, H, C 1 -C 4 -Alkyl, C(O)-C 1 -C 4 -Alkyl and C 1 -C 4 -haloalkyl; R 12 independently, C 3 -C 6 -cycloalkyl, phenyl, 5- or 6-membered heteroaryl, and 3- to 6-membered heterocycloalkyl; wherein said cycloalkyl or heterocycloalkyl group optionally has 1 to 4 R 13 groups, and the phenyl or heteroaryl group may optionally be substituted by 1 to 3 R 14 optionally substituted by groups; R 13 independently for 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 is replaced by 1 -C 4 -Alkyl, NR 9 R 10 C is replaced by 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 independently for each occurrence: halo, nitro, cyano, 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 is replaced by 1 -C 4 --Alkyl, NR 8 R 9 C is replaced by 1 -C 4 - selected from alkyl and cyclopropyl; m is an integer selected from 0, 1, 2 and 3; wherein any of said alkyl, alkylene or cyclopropyl groups may optionally, where chemically possible, be selected from the group consisting of 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 -haloalkyl and cyclopropyl; a independently for each occurrence, H, C 1 -C 4 -Alkyl and C 1 -C 4 -haloalkyl; R b independently for 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. Z 1 NR 8b and Z 2 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:

3. Z 1 is CR 8a and Z 2 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:

4. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein m is 0.

5. R 2 But independently for each occurrence, C 1 -C 4 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R is selected from -alkyl and H.

6. R 5 is H at each occurrence, or a pharmaceutically acceptable salt thereof.

7. R 6 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein

8. R 7 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein

9. X 1 or a pharmaceutically acceptable salt thereof.

10. X 1 is CR 7a 2. The compound of claim 1, wherein:

11. R 7a 11. The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein:

12. R 7a but independently halo, nitro, cyano, OR 11 , CO 2 R 9 ,CONR 9 R 9 , C 1 -C 4 -Alkyl, NR 9 R 10 C is replaced by 1 -C 4 -Alkyl, OR 11 C is replaced by 1 -C 4 -Alkyl, C 1 -C 4 12. The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein: - is selected from haloalkyl and cyclopropyl.

13. X 2 , X 3 and X 4 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein each is carbon.

14. 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 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, selected from:

15. R 4 But C 1 -C 6 -Alkyl and C 1 -C 6 15. The compound of claim 14, or a pharmaceutically acceptable salt thereof, wherein the aryl group is selected from -haloalkyl.

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

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

18. R 4a But C 3 -C 8 -cycloalkyl and 4-10 membered heterocycloalkyl, wherein said cycloalkyl or heterocycloalkyl group optionally has 1 to 4 R 13 17. The compound of claim 16, or a pharmaceutically acceptable salt thereof, optionally substituted by a group.

19. R 4a are independently selected from phenyl and 5-6 membered heteroaryl; wherein said phenyl or heteroaryl group is optionally joined to a single R 12 group and / or 1 to 3 R 14 17. The compound of claim 16, or a pharmaceutically acceptable salt thereof, optionally substituted by a group.

20. R 3 and R 4 together with the nitrogen atom to which they are attached, optionally 1 to 4 R 13 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, which forms a monocyclic 4- to 7-membered heterocycloalkyl group optionally substituted by a group.

21. NR 3 R 4 But the formula: 【Chemistry 2】 [In the formula, R 4b is selected, for each occurrence, from H and F; where at least one R 4b The group is F; R 3a are independently H and C 1 -C 4 - selected from alkyl; R 4c are independently H, C 1 -C 4 -Alkyl and C 4 -C 6 -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.

2. The compound of claim 1, wherein:

22. The compound of formula (I) 【Transformation 3】 【Chemistry 4】 【Transformation 5】 【Transformation 6】 【Transformation 7】 【Transformation 8】 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, selected from:

23. 23. A pharmaceutical formulation comprising a compound according to any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

24. A pharmaceutical comprising the compound according to any one of claims 1 to 22 or a pharmaceutically acceptable salt thereof.

25. 23. A medicament for treating a disease or disorder selected from kidney disease, liver disease, inflammatory conditions, vascular conditions, acute and chronic organ transplant rejection, fibrotic diseases and cancer, comprising a compound of any one of claims 1 to 22 or a pharmaceutically acceptable salt thereof.

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