DDR1 and DDR2 inhibitors having dihydrobenzimidazolone nucleus

Abstract

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

Description

Technical Field

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

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

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

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

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

[0006] In addition, certain embodiments of the present invention aim to provide novel compounds for treating diseases such as cancer and fibrotic diseases. These compounds may be inhibitors of DDR1 and / or DDR2. Certain embodiments of the present invention aim to provide compounds having activity comparable to that of existing DDR1 and / or DDR2 inhibitors. Certain embodiments of the present invention aim to provide compounds having enhanced activity relative to existing DDR1 and / or DDR2 inhibitors.

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

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

[0009]

[0010] in

[0011] X 1 、X 2 and X 3 are each independently selected from carbon and nitrogen, wherein X 1 、X 2 and X 3 At least two of them are carbon;

[0012] X 4 、X 5 、X 6 and X 7 are each independently selected from carbon and nitrogen, wherein X 4 、X 5 、X 6 and X 7 At least two of them are carbon;

[0013] X 8 、X 9 、X 10 and X 11 are each independently selected from carbon and nitrogen, wherein X 8 、X 9 、X 10 and X 11 At least two of them are carbon;

[0014] R 1 is independently selected at each occurrence from the group consisting of: halogen, nitro, cyano, NR 9 R 10 , OR 11 SR 9 、SO2NR 9 R 9 、SO2R 9 、CO2R 9 、C(O)R 9 、CONR 9 R 9 、C1-C4-alkyl、NR 9 R 10 Substituted C1-C4-alkyl, 11 substituted C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and cyclopropyl;

[0015] R 3independently selected from H and C1-C4-alkyl;

[0016] R 4 independently selected from C1-C6-alkyl, C1-C6-haloalkyl, C0-C4-alkylene-R 4a ; where R 4a independently selected from the group consisting of C3-C8-cycloalkyl, phenyl, 5-, 6-, 9- or 10-membered heteroaryl and 4- to 10-membered heterocycloalkyl; wherein the heterocycloalkyl or heteroaryl may be monocyclic or bicyclic; wherein the cycloalkyl or heterocycloalkyl is optionally substituted by a single R 12 group and / or 1 to 4 R 13 and wherein the phenyl or heteroaryl is optionally substituted with a single R 12 group and / or 1 to 3 R 14 group substitution;

[0017] or R 3 and R 4 Together with the nitrogen atom to which they are attached, they form a 4- to 10-membered heterocycloalkyl or a 5- or 9-membered heteroaryl; wherein the heterocycloalkyl or heteroaryl may be monocyclic or bicyclic; wherein the heterocycloalkyl is optionally substituted by a single R 12 group and / or 1 to 4 R 13 and wherein the heteroaryl group is optionally substituted with a single R 12 group and / or 1 to 3 R 14 group substitution;

[0018] R 5 is independently selected at each occurrence from H, halogen and C1-C4-alkyl, or two R 5 The groups and the carbon atoms to which they are attached may together form a C3-C6-cycloalkyl ring;

[0019] R 6 is independently selected at each occurrence from the group consisting of: halogen, nitro, cyano, NR 9 R 10 , OR 11 SR 9 、SO2NR 9 R 9 、SO2R 9 、CO2R 9 、C(O)R 9 、CONR 9 R 9 、C1-C4-alkyl、NR 9 R 10 Substituted C1-C4-alkyl, 11 substituted C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and cyclopropyl;

[0020] R 7 is independently selected at each occurrence from the group consisting of: halogen, nitro, cyano, NR 9 R 10 , OR 11 SR 9 、SO2NR 9 R 9 、SO2R 9 、CO2R 9 、C(O)R 9 、CONR 9 R 9 、C1-C4-alkyl、NR 9 R 10 Substituted C1-C4-alkyl, 11 substituted C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and cyclopropyl;

[0021] R 8a Independently selected from the following: H, halogen, nitro, cyano, NR 9 R 10 , OR 11 SR 9 、SO2NR 9 R 9 、SO2R 9 、CO2R 9 、C(O)R 9 、CONR 9 R 9 、C1-C4-alkyl、NR 9 R 10 Substituted C1-C4-alkyl, 11 Substituted C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and C0-C4-alkylene-R 8c ;

[0022] R 8c independently selected from C3-C6-cycloalkyl and 3 to 7 membered heterocycloalkyl; wherein the heterocycloalkyl is attached to the C0-C4-alkylene via a carbon atom in the heterocycloalkyl ring; wherein the cycloalkyl or heterocycloalkyl is optionally substituted by 1 to 4 R 13 group substitution;

[0023] R 9 are independently selected at each occurrence from H and C1-C4-alkyl; or two R 9 The groups together with the nitrogen atom to which they are attached form an optionally substituted group consisting of 0 to 4 R 15 a C5-C8 heterocycloalkyl group substituted with a group;

[0024] R 9a is independently selected at each occurrence from H and C1-C4-alkyl;

[0025] R 10 is independently selected at each occurrence from H, C1-C4-alkyl, C(O)-C1-C4-alkyl and S(O)2-C1-C4-alkyl; or R 9 and R 10 Together with the nitrogen atom to which they are attached, they form a 15 a C5-C8 heterocycloalkyl group substituted with a group;

[0026] R 11 is independently selected at each occurrence from H, C1-C4-alkyl, C(O)-C1-C4-alkyl and C1-C4-haloalkyl;

[0027] R 12 independently selected from C3-C6-cycloalkyl, phenyl, 5- or 6-membered heteroaryl and 3- to 6-membered heterocycloalkyl; wherein the cycloalkyl or heterocycloalkyl is optionally substituted by 1 to 4 R 13 wherein the phenyl or heteroaryl group is optionally substituted with 1 to 3 R 14 group substitution;

[0028] R 13 is independently selected at each occurrence from the group consisting of: =O, halogen, nitro, cyano, NR 9 R 10 , OR 11 SR 9 、SO2NR 9 R 9 、CO2R 9 、C(O)R 9 、CONR 9 R 10 、C1-C4-alkyl、OR 11 Substituted C1-C4-alkyl, NR 9 R 10 Substituted C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl, C6-C 10 -aryl and C3-C6-cycloalkyl;

[0029] R 14 is independently selected at each occurrence from the group consisting of: halogen, nitro, cyano, NR 9 R 10 , OR 11 SR 9 、SO2R 9 、SO2NR 9R 10 、CO2R 9 、C(O)R 9 、CONR 9 R 9 , C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl, 11 Substituted C1-C4-alkyl, NR 9 R 10 Substituted C1-C4-alkyl and cyclopropyl;

[0030] R 15 is independently selected at each occurrence from the group consisting of: =O, halogen, nitro, cyano, NR 9a R 10 , OR 11 SR 9 、SO2NR 9a R 9 、CO2R 9 、C(O)R 9 、CONR 9a R 10 、C1-C4-alkyl、OR 11 Substituted C1-C4-alkyl, NR 9a R 10 Substituted C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl, C6-C 10 -aryl and C3-C6-cycloalkyl;

[0031] m is an integer selected from 0, 1, 2, 3 and 4;

[0032] n is an integer selected from 0, 1, 2, 3 and 4;

[0033] p is an integer selected from 0, 1, 2, 3 and 4;

[0034] wherein any of the above alkyl, alkylene or cyclopropyl groups is optionally substituted, where chemically possible, with 1 to 5 substituents, each of which is independently selected at each occurrence from the group consisting of halogen, oxo, fluoro, nitro, cyano, NR a R b , OR a SR a 、CO2R a 、C(O)R a 、CONR a R a , C1-C4-alkyl, C1-C4-haloalkyl and cyclopropyl; wherein R ais independently selected at each occurrence from H, C1-C4-alkyl and C1-C4-haloalkyl; and R b is independently selected at each occurrence from H, C1-C4-alkyl, C(O)-C1-C4-alkyl and S(O)2-C1-C4-alkyl.

[0035] The present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof:

[0036] in

[0037] X 1 、X 2 and X 3 are each independently selected from carbon and nitrogen, wherein X 1 、X 2 and X 3 At least two of them are carbon;

[0038] X 4 、X 5 、X 6 and X 7 are each independently selected from carbon and nitrogen, wherein X 4 、X 5 、X 6 and X 7 At least two of them are carbon;

[0039] X 8 、X 9 、X 10 and X 11 are each independently selected from carbon and nitrogen, wherein X 8 、X 9 、X 10 and X 11 At least two of them are carbon;

[0040] R 1 is independently selected at each occurrence from the group consisting of: halogen, nitro, cyano, NR 9 R 10 , OR 11 SR 9 、SO2NR 9 R 9 、SO2R 9 、CO2R 9 、C(O)R 9 、CONR 9 R 9 、C1-C4-alkyl、NR 9 R 10 Substituted C1-C4-alkyl, 11substituted C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and cyclopropyl;

[0041] R 3 independently selected from H and C1-C4-alkyl;

[0042] R 4 independently selected from C1-C6-alkyl, C1-C6-haloalkyl, C0-C4-alkylene-R 4a ; where R 4a independently selected from the group consisting of C3-C8-cycloalkyl, phenyl, 5-, 6-, 9- or 10-membered heteroaryl and 4- to 10-membered heterocycloalkyl; wherein the heterocycloalkyl or heteroaryl may be monocyclic or bicyclic; wherein the cycloalkyl or heterocycloalkyl is optionally substituted by a single R 12 group and / or 1 to 4 R 13 and wherein the phenyl or heteroaryl is optionally substituted with a single R 12 group and / or 1 to 3 R 14 group substitution;

[0043] or R 3 and R 4 Together with the nitrogen atom to which they are attached, they form a 4- to 10-membered heterocycloalkyl or a 5- or 9-membered heteroaryl; wherein the heterocycloalkyl or heteroaryl may be monocyclic or bicyclic; wherein the heterocycloalkyl is optionally substituted by a single R 12 group and / or 1 to 4 R 13 and wherein the heteroaryl group is optionally substituted with a single R 12 group and / or 1 to 3 R 14 group substitution;

[0044] R 5 is independently selected at each occurrence from H, halogen and C1-C4-alkyl, or two R 5 The groups and the carbon atoms to which they are attached may together form a C3-C6 cycloalkyl ring;

[0045] R 6 is independently selected at each occurrence from the group consisting of: halogen, nitro, cyano, NR 9 R 10 , OR 11 SR 9 、SO2NR 9 R 9 、SO2R 9 、CO2R 9 、C(O)R 9 、CONR 9 R 9 、C1-C4-alkyl、NR 9 R10 Substituted C1-C4-alkyl, 11 substituted C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and cyclopropyl;

[0046] R 7 is independently selected at each occurrence from the group consisting of: halogen, nitro, cyano, NR 9 R 10 , OR 11 SR 9 、SO2NR 9 R 9 、SO2R 9 、CO2R 9 、C(O)R 9 、CONR 9 R 9 、C1-C4-alkyl、NR 9 R 10 Substituted C1-C4-alkyl, 11 substituted C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and cyclopropyl;

[0047] R 8a Independently selected from the following: H, halogen, nitro, cyano, NR 9 R 10 , OR 11 SR 9 、SO2NR 9 R 9 、SO2R 9 、CO2R 9 、C(O)R 9 、CONR 9 R 9 、C1-C4-alkyl、NR 9 R 10 Substituted C1-C4-alkyl, 11 Substituted C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and C0-C4-alkylene-R 8c ;

[0048] R 8c independently selected from C3-C6-cycloalkyl and 3 to 7 membered heterocycloalkyl; wherein the heterocycloalkyl is attached to the C0-C4-alkylene via a carbon atom in the heterocycloalkyl ring; wherein the cycloalkyl or heterocycloalkyl is optionally substituted by 1 to 4 R 13 group substitution;

[0049] R 9are independently selected at each occurrence from H and C1-C4-alkyl; or two R 9 The groups together with the nitrogen atom to which they are attached form an optionally substituted group consisting of 0 to 4 R 13 a C5-C8 heterocycloalkyl group substituted with a group;

[0050] R 10 is independently selected at each occurrence from H, C1-C4-alkyl, C(O)-C1-C4-alkyl and S(O)2-C1-C4-alkyl; or R 9 and R 10 Together with the nitrogen atom to which they are attached, they form a 13 a C5-C8 heterocycloalkyl group substituted with a group;

[0051] R 11 is independently selected at each occurrence from H, C1-C4-alkyl, C(O)-C1-C4-alkyl and C1-C4-haloalkyl;

[0052] R 12 independently selected from C3-C6-cycloalkyl, phenyl, 5- or 6-membered heteroaryl and 3- to 6-membered heterocycloalkyl; wherein the cycloalkyl or heterocycloalkyl is optionally substituted by 1 to 4 R 13 wherein the phenyl or heteroaryl group is optionally substituted with 1 to 3 R 14 group substitution;

[0053] R 13 is independently selected at each occurrence from the group consisting of: =O, halogen, nitro, cyano, NR 8 R 9 , OR 14 SR 8 、SO2NR 8 R 8 、CO2R 8 、C(O)R 8 、CONR 8 R 8 、C1-C4-alkyl、OR 11 Substituted C1-C4-alkyl, NR 9 R 10 Substituted C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl, C6-C 10 -aryl and C3-C6-cycloalkyl;

[0054] R 14 is independently selected at each occurrence from the group consisting of: halogen, nitro, cyano, NR 8 R 9 , OR 10 SR 8、SO2R 8 、SO2NR 8 R 8 、CO2R 8 、C(O)R 8 、CONR 8 R 8 , C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl, 11 Substituted C1-C4-alkyl, NR 8 R 9 Substituted C1-C4-alkyl and cyclopropyl;

[0055] m is an integer selected from 0, 1, 2, 3 and 4;

[0056] n is an integer selected from 0, 1, 2, 3 and 4;

[0057] p is an integer selected from 0, 1, 2, 3 and 4;

[0058] wherein any of the above alkyl, alkylene or cyclopropyl groups is optionally substituted, where chemically possible, with 1 to 5 substituents, each of which is independently selected at each occurrence from the group consisting of halogen, oxo, fluoro, nitro, cyano, NR a R b , OR a SR a 、CO2R a 、C(O)R a 、CONR a R a , C1-C4-alkyl, C1-C4-haloalkyl and cyclopropyl; wherein R a is independently selected at each occurrence from H, C1-C4-alkyl and C1-C4-haloalkyl; and R b is independently selected at each occurrence from H, C1-C4-alkyl, C(O)-C1-C4-alkyl and S(O)2-C1-C4-alkyl.

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

[0060]

[0061] where X 4 、X 5 、X 6 、X 7 、R 1 、R 3 、R 4 、R 5 、R 6 、R7 、R 8a , m, n and p are as described above for the compounds of formula (I) or (Ia).

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

[0063]

[0064] where X 1 、X 2 、X 3 、R 1 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8a , m, n and p are as described above for the compounds of formula (I) or (Ia).

[0065] In one embodiment, the compound of formula (I) or (Ia) is a compound of formula (IV):

[0066]

[0067] where R 1 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8a , m, n and p are as described above for the compounds of formula (I) or (Ia).

[0068] In one embodiment, the compound of formula (I) or (Ia) is a compound of formula (V):

[0069]

[0070] where X 1 、X 2 、X 3 、X 4 、X 5 、X 6 、X 7 、R 1 、R 3 、R 4 、R 6 、R 7 、R 8a , m, n and p are as described above for the compounds of formula (I) or (Ia).

[0071] In one embodiment, the compound of formula (I) or (Ia) is a compound of formula (VI):

[0072]

[0073] where X 1 、X 2 、X 3 、X 4 、X 5 、X 6 、X 7 、R 1 、R 3 、R 4 、R 5 、R 6 、R 7 , m, n and p are as described above for the compound of formula (I).

[0074] In one embodiment, the compound of formula (I) or (Ia) is a compound of formula (VII):

[0075]

[0076] where X 1 、X 2 、X 3 、X 4 、X 5 、X 6 、X 7 、R 1 、R 3 、R 4 、R 6 、R 7 , m, n and p are as described above for the compounds of formula (I) or (Ia).

[0077] In one embodiment, the compound of formula (I) or (Ia) is a compound of formula (VIII):

[0078]

[0079] where X 4 、X 5 、X 6 、X 7 、R 1 、R 3 、R 4 、R 6 、R 7 , m, n and p are as described above for the compounds of formula (I) or (Ia).

[0080] In one embodiment, the compound of formula (I) or (Ia) is a compound of formula (IX):

[0081]

[0082] where R 1 、R 3 、R 4 、R 6 、R 7 , m, n and p are as described above for the compounds of formula (I) or (Ia).

[0083] In one embodiment, the compound of formula (I) or (Ia) is a compound of formula (X):

[0084]

[0085] where X 4 、X 5 、X 6 、X 7 、X 8 、X 9 、X 10 、X 11 、R 1 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8a , m, n and p are as described above for the compounds of formula (I) or (Ia).

[0086] In one embodiment, the compound of formula (I) or (Ia) is a compound of formula (XI):

[0087]

[0088] where X 1 、X 2 、X 3 、X 8 、X 9 、X 10 、X 11 、R 1 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8a , m, n and p are as described above for the compounds of formula (I) or (Ia).

[0089] In one embodiment, the compound of formula (I) or (Ia) is a compound of formula (XII):

[0090]

[0091] where X 1 、X 2 、X 3 、X 4 、X 5 、X 6 、X 7 、X 8 、X 9 、X 10 、X 11 、R 1 、R 3 、R 4 、R 6 、R 7 、R 8a , m, n and p are as described above for the compounds of formula (I) or (Ia).

[0092] In one embodiment, the compound of formula (I) or (Ia) is a compound of formula (XIIIa) or (XIIIb):

[0093]

[0094] where R 1 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8a , m, n and p are as described above for the compounds of formula (I) or (Ia).

[0095] In one embodiment, the compound of formula (I) or (Ia) is a compound of formula (XIVa) or (XIVb) or (XIVc) or (XIVd):

[0096]

[0097] where R 1 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8a , m, n and p are as described above for the compounds of formula (I) or (Ia).

[0098] In one embodiment, the compound of formula (I) is a compound of formula (XVa) or (XVb) or (XVc) or (XVd):

[0099]

[0100] where X 4 、X 5 、X6 、X 7 、R 1 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8a , m, n and p are as described above for the compounds of formula (I) or (Ia).

[0101] In one embodiment, the compound of formula (I) or (Ia) is a compound of formula (XVI):

[0102]

[0103] where X 4 、X 5 、X 6 、X 7 、X 8 、X 9 、X 10 、X 11 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8a , n and p are as described above for compounds of formula (I) or (Ia); and wherein R 1a Selected from the following: halogen, nitro, cyano, NR 9 R 10 , OR 11 SR 9 、SO2NR 9 R 9 、SO2R 9 、CO2R 9 、C(O)R 9 、CONR 9 R 9 and C1-C4-alkyl. 1a It may be C1-C4-alkyl, for example methyl.

[0104] In one embodiment, the compound of formula (I) or (Ia) is a compound of formula (XVII):

[0105]

[0106] where R 1 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8a, m, n and p are as described above for the compounds of formula (I) or (Ia).

[0107] In one embodiment, the compound of formula (I) or (Ia) is a compound of formula (XVIII):

[0108]

[0109] where X 5 、X 7 、X 8 、X 9 、X 10 、X 11 、R 3 、R 4 、R 6 、R 7 、R 8a , n and p are as described above for compounds of formula (I) or (Ia); and wherein R 1a Selected from the following: halogen, nitro, cyano, NR 9 R 10 , OR 11 SR 9 、SO2NR 9 R 9 、SO2R 9 、CO2R 9 、C(O)R 9 、CONR 9 R 9 and C1-C4-alkyl. 1a It may be C1-C4-alkyl, for example methyl.

[0110] The following embodiments are applicable to compounds of any formula (I)-(XVIII). These embodiments are independent and interchangeable. Where chemically permitted, any one embodiment can be combined with any other embodiment. In other words, any feature described in the following embodiments can (where chemically permitted) be combined with the feature described in one or more other embodiments. In particular, in the case of illustrating or illustrating a compound in this specification, any two or more of the embodiments listed below that comprise the compound expressed with any general level can be combined to provide another embodiment forming a part of this disclosure.

[0111] Can be X 1 It is carbon. 2 It is carbon. It can be X 3 It is carbon. It can be X 1 and X 2 All are carbon. It can be X 2 and X 3 All are carbon. It can be X1 and X 3 All are carbon. It can be X 1 、X 2 and X 3 Each is carbon.

[0112] Can be X 1 、X 2 and X 3 The only one in is nitrogen. It can be X 1 is nitrogen. It can be X 2 It is nitrogen. It can be X 3 It's nitrogen.

[0113] Can be X 4 It is carbon. It can be X 5 It is carbon. It can be X 6 It is carbon. It can be X 7 It is carbon. It can be X 4 and X 5 All are carbon. It can be X 4 and X 6 All are carbon. It can be X 4 and X 7 All are carbon. It can be X 5 and X 6 All are carbon. It can be X 5 and X 7 All are carbon. It can be X 6 and X 7 All are carbon. It can be X 4 、X 5 and X 6 Each is carbon. It can be X 4 、X 5 and X 7 Each is carbon. It can be X 4 、X 6 and X 7 Each is carbon. It can be X 5 、X 6 and X 7 Each is carbon. It can be X 4 、X 5 、X 6 and X 7 Each is carbon.

[0114] Can be X 4 、X 5 、X 6 and X 7 At least one of is nitrogen. It can be X 4 、X 5 、X 6 and X 7 The only one in is nitrogen. It can be X5 It is nitrogen. It can be X 4 It is nitrogen. It can be X 4 、X 5 、X 6 and X 7 Two of them are nitrogen. It can be X 4 and X 5 Each is nitrogen. It can be X 4 and X 7 Each is nitrogen. It can be X 5 and X 7 Each is nitrogen. It can be X 4 and X 6 Each is nitrogen.

[0115] Can be X 8 It is carbon. It can be X 9 It is carbon. It can be X 10 It is carbon. It can be X 11 It is carbon. It can be X 8 、X 9 、X 10 and X 11 Each is carbon.

[0116] Can be X 8 、X 9 、X 10 and X 11 The only one in is nitrogen. It can be X 8 It is nitrogen. It can be X 9 It is nitrogen. It can be X 10 It is nitrogen. It can be X 11 It's nitrogen.

[0117] m can be 0. m can be 1. m can be 2. m can be 3. m can be 4.

[0118] R 1 Each occurrence may be independently selected from the following: halogen, nitro, cyano, OR 11 、C1-C4-alkyl、NR 9 R 10 Substituted C1-C4-alkyl, 11 Substituted C1-C4-alkyl, C1-C4-haloalkyl and cyclopropyl. 1 may be independently selected at each occurrence from halogen, OR 11 NR 9 R 10 , cyano, C1-C4-alkyl and C1-C4-haloalkyl. 1 may be independently selected at each occurrence from halogen, OR 11, C1-C4-alkyl, C1-C4-haloalkyl and cyclopropyl. 1 R at each occurrence may be independently selected from halogen and C1-C4-alkyl. 1 R may independently at each occurrence be halogen, such as fluorine. 1 Each occurrence may independently be C1-C4-alkyl, for example methyl.

[0119] It can be that m is at least 1, X 1 is carbon, R 1 Group attached to X 1 On carbon. It can be m is 1, X 1 is carbon, R 1 Group attached to X 1 On carbon.

[0120] R 5 R may be independently selected at each occurrence from H, fluorine and C1-C4-alkyl. 5 may be independently selected at each occurrence from H, fluorine and C1-C4-alkyl, or two R 5 The groups and the carbon atoms to which they are attached may together form a C3-C6 cycloalkyl ring. 5 Each occurrence may be independently selected from H and C1-C4-alkyl, or two R 5 The groups and the carbon atoms to which they are attached may together form a C3-C6 cycloalkyl ring. 5 may be independently selected at each occurrence from H and C1-C4-alkyl, such as methyl.

[0121] It can be R 5 In each case it is H. It can be R 5 In one occurrence it is H and in the other occurrences it is C1-C4-alkyl, such as methyl. It can be R 5 is C1-C4-alkyl at each occurrence, for example methyl.

[0122] n can be 0. n can be 1. n can be 2. n can be 3. n can be 4.

[0123] R 6 Can be independently selected from the following: halogen, nitro, cyano, OR 11 、C1-C4-alkyl、NR 9 R 10 Substituted C1-C4-alkyl, 11 Substituted C1-C4-alkyl, C1-C4-haloalkyl and cyclopropyl. 6 can be independently selected from halogen, OR 11 , C1-C4-alkyl, C1-C4-haloalkyl and cyclopropyl.6 may be independently selected from halogen and C1-C4-alkyl. 6 It may be a halogen, such as fluorine. 6 It may be C1-C4-alkyl, for example methyl.

[0124] p can be 0. p can be 1. p can be 2. p can be 3. p can be 4.

[0125] R 7 Can be independently selected from the following: halogen, nitro, cyano, OR 11 、C1-C4-alkyl、NR 9 R 10 Substituted C1-C4-alkyl, 11 Substituted C1-C4-alkyl, C1-C4-haloalkyl and cyclopropyl. 7 can be independently selected from halogen, OR 11 , C1-C4-alkyl, C1-C4-haloalkyl and cyclopropyl. 7 may be independently selected from halogen and C1-C4-alkyl. 7 It may be a halogen, such as fluorine. 7 It may be C1-C4-alkyl, for example methyl.

[0126] R 8a It can be H. R 8a Can be selected from the following: halogen, C1-C4-alkyl, NR 9 R 10 Substituted C1-C4-alkyl, 11 Substituted C1-C4-alkyl, C1-C4-haloalkyl and C0-C4-alkylene-R 8c . R 8a R may be selected from H, halogen, C1-C4-alkyl, C1-C4-haloalkyl and cyclopropyl. 8a R may be selected from H, C1-C4-alkyl, C1-C4-haloalkyl and cyclopropyl. 8a R may be selected from C1-C4-alkyl (eg methyl) and C1-C4-haloalkyl (eg CF3). 8a It may be C1-C4-alkyl (eg methyl).

[0127] R 8c may be independently selected from C3-C6-cycloalkyl and 3 to 7 membered heterocycloalkyl; wherein the heterocycloalkyl is attached to the C0-C4-alkylene via a carbon atom in the heterocycloalkyl ring; wherein the cycloalkyl or heterocycloalkyl is optionally substituted by 1 to 4 R 13 Group substitution.

[0128] It can be R9 is independently selected at each occurrence from H and C1-C4-alkyl.

[0129] It can be R 10 is independently selected at each occurrence from H, C1-C4-alkyl, C(O)-C1-C4-alkyl and S(O)2-C1-C4-alkyl. 10 is independently selected at each occurrence from H and C1-C4-alkyl.

[0130] It can be R 11 is independently selected at each occurrence from H, C1-C4-alkyl and C1-C4-haloalkyl. 11 is independently selected at each occurrence from H and C1-C4-alkyl. 11 is independently at each occurrence C1-C4-alkyl, for example methyl.

[0131] R 12 may be independently selected from 5 or 6 membered heteroaryl, wherein the heteroaryl is optionally substituted by 1 to 3 R 14 Group substitution. 12 can be independently selected from 5-membered heteroaryl, such as imidazole, wherein the heteroaryl is optionally substituted by 1 to 3 R 14 Group substitution.

[0132] R 13 Each occurrence may be independently selected from the following: oxo, fluoro, OR 11 、CO2R 9 、CO2NR 9 R 9 、C1-C4-alkyl、NR 9 R 10 Substituted C1-C4-alkyl, 11 Substituted C1-C4-alkyl, C1-C4-haloalkyl and cyclopropyl. 13 Each occurrence may be independently selected from oxo, OR 11 , C1-C4-alkyl and cyclopropyl. 13 R at each occurrence may be independently selected from oxo and C1-C4-alkyl. 13 Each occurrence may independently be C1-C4-alkyl, for example methyl.

[0133] R 14 Each occurrence may be independently selected from the following: halogen, nitro, cyano, OR 11 、C1-C4-alkyl、NR 8 R 9 Substituted C1-C4-alkyl, 11Substituted C1-C4-alkyl, C1-C4-haloalkyl and cyclopropyl. 14 Each occurrence may be independently selected from the following: halogen, nitro, cyano, OR 11 、C1-C4-alkyl、NR 9 R 10 Substituted C1-C4-alkyl, 11 Substituted C1-C4-alkyl, C1-C4-haloalkyl and cyclopropyl. 14 may be independently selected at each occurrence from halogen, OR 11 , C1-C4-alkyl, C1-C4-haloalkyl and cyclopropyl. 14 R at each occurrence may be independently selected from halogen and C1-C4-alkyl. 14 R may independently at each occurrence be halogen, such as fluorine. 14 Each occurrence may independently be C1-C4-alkyl, for example methyl.

[0134] It can be:

[0135] R 3 is H; and

[0136] R 4 independently selected from C1-C6-alkyl, C1-C6-haloalkyl, C0-C4-alkylene-R 4a ; where R 4a independently selected from the group consisting of C3-C8-cycloalkyl, phenyl, 5-, 6-, 9- or 10-membered heteroaryl and 4- to 10-membered heterocycloalkyl; wherein the heterocycloalkyl or heteroaryl may be monocyclic or bicyclic; wherein the cycloalkyl or heterocycloalkyl is optionally substituted by a single R 12 group and / or 1 to 4 R 13 and wherein the phenyl or heteroaryl is optionally substituted with a single R 12 group and / or 1 to 3 R 14 group substitution;

[0137] or R 3 and R 4 Together with the nitrogen atom to which they are attached, they form a 4- to 10-membered heterocycloalkyl or a 5- or 9-membered heteroaryl; wherein the heterocycloalkyl is optionally substituted by a single R 12 group and / or 1 to 4 R 13 and wherein the heteroaryl group is optionally substituted with a single R 12 group and / or 1 to 3 R 14 Group substitution.

[0138] It can be:

[0139] R 3 is H; and

[0140] R 4 independently selected from C1-C6-alkyl, C1-C6-haloalkyl, C0-C4-alkylene-R 4a ; where R 4a independently selected from the group consisting of C3-C8-cycloalkyl, phenyl, 5-, 6-, 9- or 10-membered heteroaryl and 4- to 10-membered heterocycloalkyl; wherein the heterocycloalkyl or heteroaryl may be monocyclic or bicyclic; wherein the cycloalkyl or heterocycloalkyl is optionally substituted by 1 to 4 R 13 wherein the phenyl or heteroaryl group is optionally substituted with 1 to 3 R 14 group substitution;

[0141] or R 3 and R 4 Together with the nitrogen atom to which they are attached, they form a 4- to 10-membered heterocycloalkyl or a 5- or 9-membered heteroaryl; wherein the heterocycloalkyl is optionally substituted by 1 to 4 R 13 and wherein the heteroaryl group is optionally substituted with 1 to 3 R 14 Group substitution.

[0142] It can be R 3 It’s H.

[0143] It can be R 4 is selected from C1-C6-alkyl, C1-C6-haloalkyl and C0-C4-alkylene-R 4a .

[0144] It can be R 4 is selected from C1-C6-alkyl and C1-C6-haloalkyl. 4 is selected from C2-C3-alkyl and C2-C3-haloalkyl. 4 Is C1-C4-haloalkyl. It can be R 4 Is a C2-C3-haloalkyl group. It can be R 4 It is 2,2,2-trifluoroethyl.

[0145] Illustrative R 4 Groups include:

[0146]

[0147] It can be R 4 is C0-C4-alkylene-R 4a . It can be R 4 It is CH2-R 4a . It can be R 4 It is R 4a .

[0148] It can be R4a independently selected from C3-C8-cycloalkyl, phenyl, 5-, 6-, 9- or 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, wherein the heterocycloalkyl or heteroaryl may be monocyclic or bicyclic; wherein the cycloalkyl or heterocycloalkyl is optionally substituted by 1 to 4 R 13 wherein the phenyl or heteroaryl group is optionally substituted with 1 to 3 R 14 Group substitution.

[0149] It can be R 4a is selected from C3-C8-cycloalkyl and 4 to 10 membered heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally substituted by a single R 12 group and / or 1 to 4 R 13 Group substitution. It can be R 4a is selected from C3-C8-cycloalkyl and 4 to 10 membered heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally substituted by 1 to 4 R 13 Group substitution.

[0150] It can be R 4 is selected from CH2-C3-C8-cycloalkyl and CH2-4 to 10-membered heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally substituted by a single R 12 group and / or 1 to 4 R 13 Group substitution. It can be R 4 is selected from CH2-C3-C8-cycloalkyl and CH2-4 to 10-membered heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally substituted by 1 to 4 R 13 Group substitution.

[0151] It can be R 4 is selected from C3-C8-cycloalkyl and 4 to 10 membered heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally substituted by a single R 12 group and / or 1 to 4 R 13 Group substitution. It can be R 4 is selected from C3-C8-cycloalkyl and 4 to 10 membered heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally substituted by 1 to 4 R 13 Group substitution.

[0152] Illustrative R 4 Groups include:

[0153]

[0154] It can be R 4a independently selected from: phenyl and 5 or 6 membered heteroaryl; wherein said phenyl or heteroaryl is optionally substituted by a single R 12 group and / or 1 to 3 R 14 Group substitution. It can be R 4aindependently selected from: phenyl and 5 or 6 membered heteroaryl; wherein the phenyl or heteroaryl is optionally substituted by 1 to 3 R 14 Group substitution. It can be R 4a is independently phenyl; wherein the phenyl is optionally substituted by a single R 12 group and / or 1 to 3 R 14 Group substitution. It can be R 4a is independently phenyl; wherein the phenyl group is optionally substituted by 1 to 3 R 14 Group substitution. It can be R 4a are independently 5- or 6-membered heteroaryl; wherein the heteroaryl is optionally substituted by a single R 12 group and / or 1 to 3 R 14 Group substitution. It can be R 4a is independently a 5- or 6-membered heteroaryl; wherein the heteroaryl is optionally substituted by 1 to 3 R 14 Group substitution.

[0155] It can be R 4 independently selected from CH2-phenyl and CH2-5 or 6 membered heteroaryl, wherein said phenyl or heteroaryl is optionally substituted by a single R 12 group and / or 1 to 3 R 14 Group substitution. It can be R 4 independently selected from CH2-phenyl and CH2-5 or 6 membered heteroaryl, wherein the phenyl or heteroaryl is optionally substituted by 1 to 3 R 14 Group substitution. It can be R 4 is independently CH2-phenyl, wherein the phenyl group is optionally substituted by a single R 12 group and / or 1 to 3 R 14 Group substitution. It can be R 4 is independently CH2-phenyl, wherein the phenyl group is optionally substituted by 1 to 3 R 14 Group substitution. It can be R 4 is independently CH2-5 or 6 membered heteroaryl, wherein said heteroaryl is optionally substituted by a single R 12 group and / or 1 to 3 R 14 Group substitution. It can be R 4 is independently CH2-5 or 6 membered heteroaryl, wherein said heteroaryl is optionally substituted by 1 to 3 R 14 Group substitution.

[0156] It can be R 4 are independently selected from phenyl or 5 or 6 membered heteroaryl, wherein said phenyl or heteroaryl is optionally substituted by a single R 12 group and / or 1 to 3 R 14 Group substitution. It can be R 4are independently selected from phenyl or 5 or 6 membered heteroaryl, wherein the phenyl or heteroaryl is optionally substituted by 1 to 3 R 14 Group substitution. It can be R 4 is independently phenyl, wherein the phenyl group is optionally substituted by a single R 12 group and / or 1 to 3 R 14 Group substitution. It can be R 4 is independently phenyl, wherein the phenyl group is optionally substituted by 1 to 3 R 14 Group substitution. It can be R 4 is independently a 5- or 6-membered heteroaryl, wherein said heteroaryl is optionally substituted with a single R 12 group and / or 1 to 3 R 14 Group substitution. It can be R 4 is independently a 5- or 6-membered heteroaryl, wherein the heteroaryl is optionally substituted by 1 to 3 R 14 Group substitution.

[0157] It can be R 4 are independently selected from phenyl or 6-membered heteroaryl, wherein the phenyl or 6-membered heteroaryl is replaced by 1 R 14 Group substitution. It can be R 14 The group is selected from OR 11 Substituted C1-C4-alkyl, C1-C4-alkyl and C1-C4-haloalkyl. R 14 The group is OR 11 Substituted C1-C4-alkyl, for example -(CH3)2-OH. R can be in the meta position 14 The group is C1-C4-haloalkyl, for example CF3.

[0158] It can be R 4 Is a 6-membered heteroaryl group. It can be R 4 is phenyl. It can be R 4 It is in the meta position by 1 R 14 Phenyl substituted with a group. It can be R 14 It is R 14a . Illustrative R 4 Groups include:

[0159]

[0160] where R 14a Selected from the following: halogen, nitro, cyano, NR 8 R 9 , OR 10 SR 8 、SO2R 8 、SO2NR 8 R 8 、CO2R 8、C(O)R 8 、CONR 8 R 8 , C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl, 11 Substituted C1-C4-alkyl, NR 8 R 9 Substituted C1-C4-alkyl and cyclopropyl;

[0161] And wherein z is an integer selected from 1 and 2.

[0162] It can be R 4 Is a 6-membered heteroaryl group. It can be R 4 is phenyl. It can be R 4 It is in the meta position by 1 R 14 Phenyl substituted with a group. It can be R 14 It is R 14a . Illustrative R 4 Groups include:

[0163]

[0164] where R 14a Selected from the following: halogen, nitro, cyano, NR 9 R 10 , OR 11 SR 9 、SO2R 9 、SO2NR 9 R 9 、CO2R 9 、C(O)R 9 、CONR 9 R 9 , C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl, 11 Substituted C1-C4-alkyl, NR 9 R 10 substituted C1-C4-alkyl and cyclopropyl; and wherein z is an integer selected from 1 and 2.

[0165] Illustrative R 4 Groups include:

[0166]

[0167]

[0168] It can be R 3 and R 4Together with the nitrogen atom to which they are attached, they form a 4- to 10-membered heterocycloalkyl or a 5- or 9-membered heteroaryl; wherein the heterocycloalkyl is optionally substituted by a single R 12 group and / or 1 to 4 R 13 and wherein the heteroaryl group is optionally substituted with a single R 12 group and / or 1 to 3 R 14 Group substitution. It can be R 3 and R 4 Together with the nitrogen atom to which they are attached, they form a 4- to 10-membered heterocycloalkyl or a 5- or 9-membered heteroaryl; wherein the heterocycloalkyl is optionally substituted by 1 to 4 R 13 and wherein the heteroaryl group is optionally substituted with 1 to 3 R 14 Group substitution.

[0169] It can be R 3 and R 4 Together with the nitrogen atom to which they are attached, they form a 5- or 9-membered heteroaryl group; wherein the heteroaryl group is optionally substituted by a single R 12 group and / or 1 to 3 R 14 Group substitution. It can be R 3 and R 4 Together with the nitrogen atom to which they are attached, they form a 5- or 9-membered heteroaryl group; wherein the heteroaryl group is optionally substituted by 1 to 3 R 14 Group substitution. It can be R 3 and R 4 Together with the nitrogen atom to which they are attached, they form a 5-membered heteroaryl; wherein the heteroaryl is optionally substituted by a single R 12 group and / or 1 to 3 R 14 Group substitution. It can be R 3 and R 4 Together with the nitrogen atom to which they are attached, they form a 5-membered heteroaryl group; wherein the heteroaryl group is optionally substituted by 1 to 3 R 14 Group substitution.

[0170] Illustrative NR 3 R 4 Groups include:

[0171]

[0172] It can be R 3 and R 4 Together with the nitrogen atom to which they are attached, they form a 4- to 10-membered heterocycloalkyl group; wherein said heterocycloalkyl group is optionally substituted by a single R 12 group and / or 1 to 4 R 13 Group substitution. It can be R 3 and R 4Together with the nitrogen atom to which they are attached, they form a 4- to 10-membered heterocycloalkyl group; wherein said heterocycloalkyl group is optionally substituted by 1 to 4 R 13 The heterocyclic group may be 7 to 10-membered bicyclic heterocyclic alkyl. The heterocyclic group may be 7 to 10-membered bridged bicyclic heterocyclic alkyl. The heterocyclic group may be a monocyclic 4 to 7-membered heterocyclic alkyl. The heterocyclic group may be a monocyclic 5 to 6-membered heterocyclic alkyl. The heterocyclic group may be pyrrolidine. The heterocyclic group may be piperidine. The heterocyclic group may be morpholine. The heterocyclic group may be piperazine. For clarity, the heterocyclic group mentioned in this paragraph is optionally replaced by a single R 12 group and / or 1 to 4 R 13 The heterocycloalkyl mentioned in this paragraph may be optionally substituted with 1 to 4 R 13 The heterocyclic group may be pyrrolidine, and is replaced by an R at the 2 position. 13 The heterocyclic group may be pyrrolidine, and is replaced by one R at the 3 position. 13 The heterocyclic group may be piperidine, and is replaced by an R at the 2 position. 13 The heterocyclic group may be piperidine, and the 3-position is replaced by one R 13 The heterocyclic group may be piperidine, and is replaced by an R at the 4 position. 13 The heterocyclic group may be morpholine, and is replaced by an R at the 2 position. 13 The heterocyclic group may be morpholine, and is replaced by one R at the 3 position. 13 Group substitution. It can be R 13 The group is selected from C1-C4-alkyl, 11 Substituted C1-C4-alkyl (eg -(CH3)2-OH) and C1-C4-haloalkyl (eg -CF3).

[0173] Illustrative NR 3 R 4 Groups include:

[0174]

[0175]

[0176] You can choose R 3 and R 4 Make NR 3 R 4 Contains a CHF2 group or a CF3 group.

[0177] It can be NR 3 R 4 With formula wherein a is an integer selected from 1 and 2;

[0178] R 4b is selected from H and F at each occurrence; wherein at least one R 4b The group is F;

[0179] R 3a independently selected from H and C1-C4-alkyl;

[0180] R 4c is independently selected at each occurrence from H, C1-C4-alkyl and C4-C6-cycloalkyl; or

[0181] R 3a and a single R 4c Together with the carbon and nitrogen to which they are attached they form a 4- to 6-membered heterocycloalkyl.

[0182] a can be 1. a can be 2.

[0183] It can be NR 3 R 4 With formula where R 4b is selected from H and F at each occurrence; wherein at least one R 4b The group is F;

[0184] R 3a independently selected from H and C1-C4-alkyl;

[0185] R 4c independently selected from H, C1-C4-alkyl and C4-C6-cycloalkyl; or

[0186] R 3a and R 4c Together with the carbon and nitrogen to which they are attached they form a 4- to 6-membered heterocycloalkyl.

[0187] There can be at least two R 4b The group is F. There can be two R 4b The group is F, one R 4b The group is H. Each R 4b The groups are all F.

[0188] It can be R 3a It’s H.

[0189] It can be R 3a are independently selected from H and C1-C4-alkyl; and R 4c is independently selected from H, C1-C4-alkyl and C4-C6-cycloalkyl. 3a is H; and R 4cis independently selected from H, C1-C4-alkyl and C4-C6-cycloalkyl. The alkyl or cycloalkyl may be unsubstituted.

[0190] It can be R 4c is selected at each occurrence from C1-C4-alkyl and H. It may be R 4c It is H at every occurrence.

[0191] It can be R 3a and R 4c Together with the carbon and nitrogen to which they are attached, they form a 4- to 6-membered heterocycloalkyl group. 3a and R 4c Together with the carbon and nitrogen to which they are attached, they form a 5-membered heterocycloalkyl group. 3a and R 4c Together with the carbon and nitrogen to which they are attached, they form a 6-membered heterocycloalkyl. The heterocycloalkyl may be unsubstituted.

[0192] The compound of formula (I) may be selected from the following:

[0193]

[0194]

[0195]

[0196] The compound of formula (I) may be selected from the following:

[0197]

[0198]

[0199]

[0200]

[0201] In one aspect of the present invention there is provided a compound of the present invention for use as a medicament.

[0202] According to another aspect, compounds of the invention are provided for use in treating conditions modulated by DDR1 and / or DDR2.Compounds of any of the formulae disclosed herein are useful in treating conditions treatable by inhibition of DDR1 and / or DDR2.

[0203] 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 the group consisting of renal conditions, liver conditions, inflammatory conditions, cardiovascular conditions, acute and chronic organ transplant rejection, fibrotic diseases and cancer.

[0204] In one aspect of the present invention, there is provided a method of treating a disease or condition modulated by DDR1 and / or DDR2, wherein the method comprises administering to a patient in need thereof a therapeutic amount of a compound of the present invention.

[0205] The therapeutic method may be a method of treating a condition treatable by inhibition of DDR1 and / or DDR2.

[0206] The present invention also provides a method of treating a disease or disorder selected from the group consisting of renal conditions, liver conditions, inflammatory conditions, cardiovascular conditions, acute and chronic organ transplant rejection, fibrotic diseases, and cancer, wherein the method comprises administering to a patient in need thereof a therapeutic amount of a compound of any formula disclosed herein.

[0207] The kidney condition includes acute kidney injury and with or without the chronic kidney disease of proteinuria, including end-stage renal disease (ESRD).This includes creatinine clearance reduction and glomerular filtration rate reduction, microalbuminuria, albuminuria and proteinuria, with or without the glomerular sclerosis (particularly diabetic nephropathy and amyloidosis) of the reticular mesangial matrix expansion with obvious excessive cells, the focal thrombosis (particularly thrombotic microangiopathy) of glomerular capillaries, overall fibrinoid necrosis, ischemic lesions, malignant nephrosclerosis (such as ischemic retraction, renal blood flow reduction and renal artery disease), (endothelium and mesangium) capillary and / or the swelling and proliferation of capillary extracellular cells (crescents), such as glomerulonephritis entity, focal segmental glomerulosclerosis, IgA nephropathy, vasculitis / systemic disease and acute and chronic renal transplant rejection.Alport syndrome in early and late stages is also included in the kidney condition.

[0208] Inflammatory conditions include arthritis, osteoarthritis, multiple sclerosis, systemic lupus erythematosus, inflammatory bowel disease, abnormal emptying disorders, and inflammatory airway diseases such as idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD), or chronic asthma. Other conditions of the respiratory system include other diffuse lung parenchymal diseases of different etiologies, including iatrogenic drug-induced fibrosis, occupational and / or environmentally induced fibrosis, systemic diseases, and vasculitis, granulomatous diseases (sarcoidosis, hypersensitivity pneumonitis), collagen vascular diseases, and radiation-induced fibrosis.

[0209] Vascular conditions include atherosclerosis, thrombotic vascular disease and thrombotic microangiopathy, proliferative arteriopathy (e.g., swollen myoendothelial cells surrounded by a mucinous extracellular matrix and nodular thickening), atherosclerosis, decreased vascular compliance (e.g., stiffness, decreased ventricular compliance, and decreased vascular compliance), endothelial dysfunction, etc.

[0210] Cardiovascular conditions include acute coronary syndrome, coronary heart disease, myocardial infarction, arterial and pulmonary hypertension, arrhythmias such as atrial fibrillation, stroke and other vascular injuries.

[0211] Fibrotic diseases include, but are not limited to, myocardial and vascular fibrosis, renal fibrosis, hepatic fibrosis, pulmonary fibrosis, cutaneous fibrosis, scleroderma and encapsulating peritonitis, systemic sclerosis, Alport syndrome, chronic kidney disease, NASH, interstitial lung disease, and systemic sclerosis.

[0212] In certain embodiments, the compounds of the present invention are used to treat cancer or in a method for treating cancer. Examples include, but are not limited to, liver cancer, bladder cancer, hepatoma, squamous cell carcinoma of the lung, non-small cell lung cancer, adenocarcinoma of the lung, small cell lung cancer, various head and neck cancers, breast cancer, colon cancer, colorectal cancer, peritoneal cancer, hepatocellular carcinoma, gastrointestinal cancer, esophageal cancer, endometrial cancer or uterine cancer, salivary gland cancer, squamous cell carcinoma, pituitary cancer, astrocytoma, soft tissue sarcoma, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, kidney cancer, liver cancer, prostate cancer, vulvar cancer, thyroid cancer, liver cancer, brain cancer, endometrial cancer, testicular cancer, bile duct cancer, gallbladder cancer, gastric cancer, and melanoma. In certain embodiments, the cancer is selected from bladder cancer, pancreatic cancer, breast cancer, lung cancer, ovarian cancer, and glioblastoma.

[0213] In another aspect of the present invention, a pharmaceutical composition is provided, wherein the composition comprises a compound of the present invention and a pharmaceutically acceptable excipient.

[0214] In one embodiment, the pharmaceutical composition may be a combination product comprising an additional pharmaceutically active agent.

[0215] In one aspect of the present invention there is provided the use of a compound of the present invention in the preparation of a medicament for the treatment of any of the conditions disclosed herein.

[0216] The invention may also be defined by the following numbered clauses:

[0217] 1. A compound of formula (I) or a pharmaceutically acceptable salt thereof:

[0218] in

[0219] X 1 、X 2 and X 3 are each independently selected from carbon and nitrogen, wherein X 1 、X 2 and X 3 At least two of them are carbon;

[0220] X 4 、X 5、X 6 and X 7 are each independently selected from carbon and nitrogen, wherein X 4 、X 5 、X 6 and X 7 At least two of them are carbon;

[0221] X 8 、X 9 、X 10 and X 11 are each independently selected from carbon and nitrogen, wherein X 8 、X 9 、X 10 and X 11 At least two of them are carbon;

[0222] R 1 is independently selected at each occurrence from the group consisting of: halogen, nitro, cyano, NR 9 R 10 , OR 11 SR 9 、SO2NR 9 R 9 、SO2R 9 、CO2R 9 、C(O)R 9 、CONR 9 R 9 、C1-C4-alkyl、NR 9 R 10 Substituted C1-C4-alkyl, 11 substituted C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and cyclopropyl;

[0223] R 3 independently selected from H and C1-C4-alkyl;

[0224] R 4 independently selected from C1-C6-alkyl, C1-C6-haloalkyl, C0-C4-alkylene-R 4a ; where R 4a independently selected from the group consisting of C3-C8-cycloalkyl, phenyl, 5-, 6-, 9- or 10-membered heteroaryl and 4- to 10-membered heterocycloalkyl; wherein the heterocycloalkyl or heteroaryl may be monocyclic or bicyclic; wherein the cycloalkyl or heterocycloalkyl is optionally substituted by a single R 12 group and / or 1 to 4 R 13 and wherein the phenyl or heteroaryl is optionally substituted with a single R 12 group and / or 1 to 3 R 14 group substitution;

[0225] or R 3 and R 4 Together with the nitrogen atom to which they are attached, they form a 4- to 10-membered heterocycloalkyl or a 5- or 9-membered heteroaryl; wherein the heterocycloalkyl or heteroaryl may be monocyclic or bicyclic; wherein the heterocycloalkyl is optionally substituted by a single R 12 group and / or 1 to 4 R 13 and wherein the heteroaryl group is optionally substituted with a single R 12 group and / or 1 to 3 R 14 group substitution;

[0226] R 5 is independently selected at each occurrence from H, halogen and C1-C4-alkyl, or two R 5 The groups and the carbon atoms to which they are attached may together form a C3-C6-cycloalkyl ring;

[0227] R 6 is independently selected at each occurrence from the group consisting of: halogen, nitro, cyano, NR 9 R 10 , OR 11 SR 9 、SO2NR 9 R 9 、SO2R 9 、CO2R 9 、C(O)R 9 、CONR 9 R 9 、C1-C4-alkyl、NR 9 R 10 Substituted C1-C4-alkyl, 11 substituted C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and cyclopropyl;

[0228] R 7 is independently selected at each occurrence from the group consisting of: halogen, nitro, cyano, NR 9 R 10 , OR 11 SR 9 、SO2NR 9 R 9 、SO2R 9 、CO2R 9 、C(O)R 9 、CONR 9 R 9 、C1-C4-alkyl、NR 9 R 10 Substituted C1-C4-alkyl, 11substituted C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and cyclopropyl;

[0229] R 8a Independently selected from the following: H, halogen, nitro, cyano, NR 9 R 10 , OR 11 SR 9 、SO2NR 9 R 9 、SO2R 9 、CO2R 9 、C(O)R 9 、CONR 9 R 9 、C1-C4-alkyl、NR 9 R 10 Substituted C1-C4-alkyl, 11 Substituted C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and C0-C4-alkylene-R 8c ;

[0230] R 8c independently selected from C3-C6-cycloalkyl and 3 to 7 membered heterocycloalkyl; wherein the heterocycloalkyl is attached to the C0-C4-alkylene via a carbon atom in the heterocycloalkyl ring; wherein the cycloalkyl or heterocycloalkyl is optionally substituted by 1 to 4 R 13 group substitution;

[0231] R 9 are independently selected at each occurrence from H and C1-C4-alkyl; or two R 9 The groups together with the nitrogen atom to which they are attached form an optionally substituted group consisting of 0 to 4 R 13 a C5-C8 heterocycloalkyl group substituted with a group;

[0232] R 10 is independently selected at each occurrence from H, C1-C4-alkyl, C(O)-C1-C4-alkyl and S(O)2-C1-C4-alkyl; or R 9 and R 10 Together with the nitrogen atom to which they are attached, they form a 13 a C5-C8 heterocycloalkyl group substituted with a group;

[0233] R 11 is independently selected at each occurrence from H, C1-C4-alkyl, C(O)-C1-C4-alkyl and C1-C4-haloalkyl;

[0234] R 12independently selected from C3-C6-cycloalkyl, phenyl, 5- or 6-membered heteroaryl and 3- to 6-membered heterocycloalkyl; wherein the cycloalkyl or heterocycloalkyl is optionally substituted by 1 to 4 R 13 wherein the phenyl or heteroaryl group is optionally substituted with 1 to 3 R 14 group substitution;

[0235] R 13 is independently selected at each occurrence from the group consisting of: =O, halogen, nitro, cyano, NR 8 R 9 , OR 14 SR 8 、SO2NR 8 R 8 、CO2R 8 、C(O)R 8 、CONR 8 R 8 、C1-C4-alkyl、OR 11 Substituted C1-C4-alkyl, NR 9 R 10 Substituted C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl, C6-C 10 -aryl and C3-C6-cycloalkyl;

[0236] R 14 is independently selected at each occurrence from the group consisting of: halogen, nitro, cyano, NR 8 R 9 , OR 10 SR 8 、SO2R 8 、SO2NR 8 R 8 、CO2R 8 、C(O)R 8 、CONR 8 R 8 , C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl, 11 Substituted C1-C4-alkyl, NR 8 R 9 Substituted C1-C4-alkyl and cyclopropyl;

[0237] m is an integer selected from 0, 1, 2, 3 and 4;

[0238] n is an integer selected from 0, 1, 2, 3 and 4;

[0239] p is an integer selected from 0, 1, 2, 3 and 4;

[0240] wherein any of the above alkyl, alkylene or cyclopropyl groups is optionally substituted, where chemically possible, with 1 to 5 substituents, each of which is independently selected at each occurrence from the group consisting of halogen, oxo, fluoro, nitro, cyano, NR a R b , OR a SR a 、CO2R a 、C(O)R a 、CONR a R a , C1-C4-alkyl, C1-C4-haloalkyl and cyclopropyl; wherein R a is independently selected at each occurrence from H, C1-C4-alkyl and C1-C4-haloalkyl; and R b is independently selected at each occurrence from H, C1-C4-alkyl, C(O)-C1-C4-alkyl and S(O)2-C1-C4-alkyl.

[0241] 2. The compound of clause 1, wherein m is 0 or 1.

[0242] 3. The compound of clause 1, wherein m is at least 1, X 1 is carbon, R 1 Group attached to X 1 On carbon.

[0243] 4. The compound of any one of clauses 1 to 3, wherein n is 0 or 1.

[0244] 5. The compound of any one of clauses 1 to 4, wherein p is 0 or 1.

[0245] 6. The compound of any one of clauses 1 to 5, wherein R 5 It is H at every occurrence.

[0246] 7. The compound of any one of clauses 1 to 6, wherein R 8a is selected from H and C1-C4-alkyl.

[0247] 8. The compound of any one of clauses 1 to 7, wherein X 1 、X 2 and X 3 Each is carbon.

[0248] 9. The compound of any one of clauses 1 to 8, wherein X 8 、X 9 、X 10 and X 11 Each is carbon.

[0249] 10. The compound of any one of clauses 1 to 9, wherein X 4 、X5 、X 6 and X 7 Each is carbon.

[0250] 11. The compound of any one of clauses 1 to 9, wherein X 4 、X 5 、X 6 and X 7 At least one of them is nitrogen.

[0251] 12. The compound of any one of clauses 1 to 11, wherein NR 3 R 4 With formula in

[0252] a is an integer selected from 1 and 2;

[0253] R 4b is selected from H and F at each occurrence; wherein at least one R 4b The group is F;

[0254] R 3a independently selected from H and C1-C4-alkyl;

[0255] R 4c is independently selected at each occurrence from H, C1-C4-alkyl and C4-C6-cycloalkyl; or R 3a and a single R 4c Together with the carbon and nitrogen to which they are attached they form a 4- to 6-membered heterocycloalkyl.

[0256] 13. The compound of clause 12, wherein a is 1.

[0257] 14. The compound of clause 12 or 13, wherein at least two R 4b The group is F.

[0258] 15. The compound of any one of clauses 12 to 14, wherein R 3a It’s H.

[0259] 16. The compound of any one of clauses 12 to 15, wherein R 4c is selected from H and C1-C4-alkyl.

[0260] 17. The compound of any one of clauses 12 to 14, wherein R 3a and R 4c Together with the carbon and nitrogen to which they are attached they form a 4- to 6-membered heterocycloalkyl.

[0261] 18. The compound of clause 1, wherein the compound of formula (I) is selected from the group consisting of:

[0262]

[0263]

[0264]

[0265] 19. A pharmaceutical formulation comprising a compound according to any one of clauses 1 to 18 and a pharmaceutically acceptable excipient.

[0266] 20. A compound according to any one of clauses 1 to 18 for use as a medicament.

[0267] 21. A compound according to any one of clauses 1 to 18 for use in treating a disease or disorder selected from the group consisting of renal conditions, liver conditions, inflammatory conditions, cardiovascular conditions, acute and chronic organ transplant rejection, fibrotic diseases and cancer. DETAILED DESCRIPTION

[0268] The following are definitions of terms used in this application. Any term not defined herein has the same meaning as commonly understood by a skilled artisan.

[0269] The term "halogen" refers to a halogen from Group 17 of the Periodic Table of the Elements. In particular, the term refers to fluorine, chlorine, bromine and iodine. Preferably, the term refers to chlorine or fluorine.

[0270] The term "alkyl" refers to a straight or branched hydrocarbon chain. For example, the term "C 1-6 "Alkyl" refers to a straight or branched hydrocarbon chain containing 1, 2, 3, 4, 5 or 6 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl and n-hexyl. An "alkylene" group can likewise be straight or branched and is divalent, i.e., it is attached to the rest of the molecule at two positions. Furthermore, an alkylene group can, for example, correspond to one of those alkyl groups listed in this paragraph. Alkyl and alkylene groups can be unsubstituted or substituted with one or more substituents.

[0271] The term "haloalkyl" refers to a hydrocarbon chain substituted with at least one halogen atom, independently selected at each occurrence from, for example, fluorine, chlorine, bromine, and iodine. For example, the term "C 1-6 "Haloalkyl" refers to a straight or branched hydrocarbon chain containing 1, 2, 3, 4, 5 or 6 carbon atoms substituted by at least one halogen. The halogen atom may be present at any position on the hydrocarbon chain. For example, C 1-6Haloalkyl may refer to chloromethyl, fluoromethyl, trifluoromethyl, chloroethyl (e.g., 1-chloromethyl and 2-chloroethyl), trichloroethyl (e.g., 1,2,2-trichloroethyl, 2,2,2-trichloroethyl), fluoroethyl (e.g., 1-fluoromethyl and 2-fluoroethyl), trifluoroethyl (e.g., 1,2,2-trifluoroethyl and 2,2,2-trifluoroethyl), chloropropyl, trichloropropyl, fluoropropyl, trifluoropropyl. The term "fluoroalkyl" refers to a hydrocarbon chain substituted with at least one fluorine atom.

[0272] The term "alkenyl" refers to a branched or straight hydrocarbon chain containing at least one double bond. For example, the term "C 2-6 "Alkenyl" refers to a branched or straight hydrocarbon chain containing at least one double bond and having 2, 3, 4, 5 or 6 carbon atoms. The double bond can exist as E or Z isomers. The double bond can be in any possible position of the hydrocarbon chain. For example, "C 2-6 The term "alkenyl" may include ethenyl, propenyl, butenyl, butadienyl, pentenyl, pentadienyl, hexenyl and hexadienyl.

[0273] The term "alkynyl" refers to a branched or straight hydrocarbon chain containing at least one triple bond. For example, the term "C 2-6 "Alkynyl" refers to a branched or straight hydrocarbon chain containing at least one triple bond and having 2, 3, 4, 5 or 6 carbon atoms. The triple bond can be in any possible position of the hydrocarbon chain. For example, "C 2-6 The term "alkynyl" may include ethynyl, propynyl, butynyl, pentynyl and hexynyl.

[0274] The term "heteroalkyl" refers to a branched or straight hydrocarbon chain containing at least one heteroatom selected from N, O and S between any carbon atoms in the chain or at the end of the chain. 1-6 "Heteroalkyl" refers to a branched or straight hydrocarbon chain containing 1, 2, 3, 4, 5 or 6 carbon atoms and at least one heteroatom selected from N, O and S and located between any carbon atoms in the chain or at the end of the chain. For example, the hydrocarbon chain may contain one or two heteroatoms. 1-6 A heteroalkyl group can be bonded to the rest of the molecule through a carbon or heteroatom. For example, a "C 1-6 "Heteroalkyl" can be C 1-6 N-alkyl, C 1-6 N,N-alkyl or C 1-6 O-alkyl.

[0275] The term "heterocycle" refers to a saturated, unsaturated, or aromatic ring system containing at least one heteroatom selected from N, O, or S. A "heterocycle" system can contain 1, 2, 3, or 4 heteroatoms, for example, 1 or 2. A "heterocycle" system can be a monocyclic or fused polycyclic ring system, for example, a bicyclic or tricyclic ring system. The "heterocycle" moiety can contain 3 to 14 carbon atoms, for example, 3 to 8 carbon atoms in a monocyclic system and 7 to 14 carbon atoms in a polycyclic system. A "heterocycle" includes heterocycloalkyl, heterocycloalkenyl, and heteroaryl moieties. For example, a heterocyclic group can be: oxirane, aziridine, azetidine, oxetane, tetrahydrofuran, pyrrolidine, imidazolidine, succinimide, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, piperidine, morpholine, thiomorpholine, piperazine, and tetrahydropyran. Heteroaryl groups include groups such as pyridone and N-alkyl-pyridone.

[0276] The term "C 3-8 "Cycloalkyl" refers to a saturated hydrocarbon ring system containing 3, 4, 5, 6, 7 or 8 carbon atoms. For example, "C 3-8 The "cycloalkyl" group may include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

[0277] The term "C 3-8 "Cycloalkenyl" refers to a non-aromatic, unsaturated hydrocarbon ring system containing 3, 4, 5, 6, 7 or 8 carbon atoms. The ring may contain more than one double bond, provided that the ring system is not aromatic. For example, "C 3-8 The "cycloalkyl" may be cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, cyclooctenyl and cycloatadienyl.

[0278] The term "heterocycloalkyl" refers to a saturated hydrocarbon ring system containing carbon atoms and at least one heteroatom selected from N, O and S in the ring. For example, there may be 1, 2 or 3 heteroatoms, optionally 1 or 2. "Heterocycloalkyl" can be bonded to the rest of the molecule through any carbon atom or heteroatom. "Heterocycloalkyl" can have one or more, for example one or two, bonds to the rest of the molecule: these bonds can be through any atom in the ring. For example, "heterocycloalkyl" can be "C 3-8 Heterocycloalkyl". The term "C 3-8 "Heterocycloalkyl" refers to a saturated hydrocarbon ring system containing 3, 4, 5, 6, 7 or 8 atoms, wherein at least one atom in the ring is a heteroatom selected from N, O and S. "Heterocycloalkyl" can be oxirane, aziridine, azetidine, oxetane, tetrahydrofuran, pyrrolidine, imidazolidine, succinimide, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, piperidine, morpholine, thiomorpholine, piperazine and tetrahydropyran.

[0279] The term "aromatic" when applied to a substituent as a whole refers to a monocyclic or polycyclic ring system having 4n+2 electrons in a conjugated π system within the ring or ring system, wherein all atoms contributing to the conjugated π system are in the same plane.

[0280] The term "aryl" refers to an aromatic hydrocarbon ring system. This ring system has 4n+2 electrons in a conjugated π system within the ring, where all atoms contributing to the conjugated π system are in the same plane. Examples of "aryl" include phenyl and naphthyl. Aryl systems themselves may be substituted with other groups.

[0281] The term "heteroaryl" refers to an aromatic hydrocarbon ring system having at least one heteroatom selected from O, N, and S in a monocyclic or fused ring system. The ring or ring system has 4n+2 electrons in a conjugated π system, wherein all atoms contributing to the conjugated π system are in the same plane. For example, "heteroaryl" can be imidazole, oxazole, isoxazole, thiazole, isothiazole, thiophene, furan, thianthrene, pyrrole, benzimidazole, pyrazole, pyrazine, pyridine, pyrimidine, and indole.

[0282] by A bond ending in a cyclic structure indicates that the bond is to another atom not shown in the structure. A bond that ends inside a cyclic structure and does not terminate at an atom in the ring structure indicates that the bond may be attached to any atom in the ring structure, as valence permits.

[0283] Where chemically possible, bonds drawn as solid and dashed lines represent bonds that can be either single or double bonds. For example, the bond drawn below can be either a single bond or a double bond.

[0284]

[0285] Where a moiety is substituted, it may be substituted at any point on the moiety where chemically possible and consistent with valence requirements. The moiety may be substituted with one or more substituents, for example 1, 2, 3 or 4 substituents; optionally, there may be 1 or 2 substituents on a group. Where there are two or more substituents, these substituents may be the same or different.

[0286] Substituents are present only at positions where they are chemically possible, and one skilled in the art can readily determine (either experimentally or theoretically) which substitutions are chemically possible and which are not.

[0287] Ortho, meta, and para substitution are terms well known in the art. For clarity, "ortho" substitution is a substitution pattern in which adjacent carbons have substituents, whether simple groups, such as the fluorine group in the example below, or other parts of the molecule, such as The key at the end is shown.

[0288]

[0289] "Meta" substitution is a substitution pattern in which the two substituents are on carbons that are one carbon away from each other, i.e., there is a single carbon atom between the substituted carbons. In other words, there is a substituent on the second atom away from the atom with the other substituent. For example, the following groups are meta-substituted:

[0290]

[0291] "Para" substitution is a substitution pattern in which the two substituents are on carbons two carbons away from each other, meaning there are two carbon atoms between the substituted carbons. In other words, there is a substituent on a third atom away from the atom bearing the other substituent. For example, the following groups are para-substituted:

[0292]

[0293] Throughout the specification, disclosure of compounds also includes pharmaceutically acceptable salts, solvates and stereoisomers thereof.

[0294] In the case of a compound having a stereocenter, the present invention contemplates (R) and (S) stereoisomers, and similarly, mixtures of stereoisomers or racemic mixtures are accomplished by the present application. In the case of a compound of the present invention having two or more stereocenters, any combination of (R) and (S) stereoisomers can be contemplated. The combination of (R) and (S) stereoisomers can produce a diastereomeric mixture or a single diastereoisomer. The compounds of the present invention can exist in the form of a single stereoisomer, or can be a mixture of stereoisomers, such as a racemic mixture and other enantiomeric mixtures, and a diastereomeric mixture. In the case where the mixture is a mixture of enantiomers, the enantiomeric excess can be any one disclosed above. In the case where the compound is a single stereoisomer, these compounds may still contain other diastereomers or enantiomers as impurities. Thus, a single stereoisomer does not necessarily have an enantiomeric excess (ee) or diastereomeric excess (de) of 100%, but may have an ee or de of about at least 85%, at least 60%, or less. For example, the ee or de may be 90% or more, 90% or more, 80% or more, 70% or more, 60% or more, 50% or more, 40% or more, 30% or more, 20% or more, or 10% or more.

[0295] The present invention contemplates pharmaceutically acceptable salts of the compounds of the present invention. These salts may include acid addition salts and base salts of the compounds. These salts may be acid addition salts and base salts of the compounds. In addition, the present invention contemplates solvates of the compounds. These solvates may be hydrates or other solvated forms of the compounds.

[0296] Suitable acid addition salts are formed from acids that form non-toxic salts. Examples include acetate, aspartate, benzoate, benzenesulfonate, bicarbonate / carbonate, bisulfate / sulfate, borate, camphorsulfonate, citrate, edisylate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, methanesulfonate, methylsulfate, naphthoate (naphthylate), 1,5-naphthalenedisulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrogenphosphate, sucrose, stearate, succinate, tartrate, toluenesulfonate, and trifluoroacetate.

[0297] Suitable alkali salts are formed from bases that form non-toxic salts. Examples include aluminum salts, arginine salts, benzathine penicillin salts, calcium salts, choline salts, diethylamine salts, diethanolamine salts, glycine salts, lysine salts, magnesium salts, meglumine salts, ethanolamine salts, potassium salts, sodium salts, tromethamine salts, and zinc salts. Hemisalts of acids and bases, such as hemisulphates and hemicalcium salts, can also be formed. For a review of suitable salts, see "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

[0298] Pharmaceutically acceptable salts of compounds of formula (I) can be prepared by one or more of the following three methods:

[0299] (i) by reacting a compound of the present invention with a desired acid or base;

[0300] (ii) by removing an acid- or base-labile protecting group from a suitable precursor of the compound of the invention, or by ring-opening a suitable cyclic precursor (e.g., a lactone or lactam), using the desired acid or base; or

[0301] (iii) converting one salt of a compound of the present invention into another salt by reaction with a suitable acid or base or by passing through a suitable ion exchange column.

[0302] All three reactions are typically performed in solution. The resulting salt can precipitate and be collected by filtration, or it can be recovered by evaporating the solvent. The degree of ionization of the resulting salt can range from completely ionized to almost non-ionized.

[0303] The compounds of the present invention may exist in unsolvated and solvated forms. The term "solvate" is used herein to describe a molecular complex comprising a compound of the present invention and a stoichiometric amount of one or more pharmaceutically acceptable solvent molecules (e.g., ethanol). When the solvent is water, the term "hydrate" is used.

[0304] Included within the scope of the present invention are complexes, such as clathrates, drug-host inclusion complexes, in which, in contrast to the solvates described above, the drug and host are present in stoichiometric or non-stoichiometric amounts. Also included are drug complexes containing two or more organic and / or inorganic components, which may be in stoichiometric or non-stoichiometric amounts. The resulting complexes may be ionized, partially ionized, or non-ionized. For a review of such complexes, see Haleblian, J Pharm Sci, 64(8), 1269-1288 (August 1975).

[0305] Hereinafter, all references to compounds of any formula include references to salts, solvates and complexes thereof, and to solvates and complexes of their salts.

[0306] The compounds of the present invention include compounds of the numerous formulae as defined herein, including all polymorphs and crystal habits thereof, prodrugs and isomers (including optical isomers, geometric isomers and tautomers) thereof as defined below, and isotopically labeled compounds of the present invention.

[0307] The present invention also includes all pharmaceutically acceptable isotopically labeled compounds of the present invention, wherein one or more atoms are replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number most commonly found in nature.

[0308] Examples of suitable isotopes for inclusion in the compounds of the present invention include isotopes of hydrogen (e.g. 2 H and 3 H), carbon isotopes (such as 11 C. 13 C and 14 C), isotopes of chlorine (such as 36 Cl), fluorine isotopes (such as 18 F), iodine isotopes (such as 123 I and 125I), nitrogen isotopes (such as 13 N and 15 N), oxygen isotopes (such as 15 O. 17 O and 18 O), phosphorus isotopes (such as 32 P) and sulfur isotopes (such as 35 S).

[0309] Certain isotopically labeled compounds, for example compounds incorporating radioactive isotopes, are useful in drug and / or substrate tissue distribution studies. 3 H) and carbon-14 (i.e. 14 C) are particularly suitable for this purpose because they are easy to incorporate and have readily available means of detection.

[0310] Using heavier isotopes such as deuterium (i.e. 2 H) substitutions may offer certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and thus may be preferred in some circumstances.

[0311] Before purification, the compounds of the present invention may exist as mixtures of enantiomers, depending on the synthetic method used. Enantiomers may be separated by conventional techniques known in the art. Therefore, the present invention encompasses single enantiomers and mixtures thereof.

[0312] For some steps of the method for preparing the compounds of this invention, it may be necessary to protect the potential reactive functional groups that do not wish to react, and therefore the blocking group described in the cracking. In such a case, any compatible protected free radical can be used. Especially, the method for protection and deprotection can be used, as described in TWGREENE (Protective Groups in Organic Synthesis, A.Wiley-Interscience Publication, 1981) or PJKocienski (Protecting groups, Georg Thieme Verlag, 1994). The preparation of all the above-mentioned reactions and the new raw materials used in the aforementioned method is conventional, and reference precedents and examples related thereto and preparation are known to those skilled in the art for the suitable reagents and reaction conditions and the program for separating the required product to realize their performance or preparation.

[0313] Furthermore, the compounds of the present invention and the intermediates used in their preparation can be purified according to various well-known methods, such as crystallization or chromatography.

[0314] One or more compounds of the invention can be combined with one or more agents, such as anti-inflammatory agents, anti-fibrotic agents, chemotherapeutic agents, anti-cancer agents, immunosuppressive agents, anti-tumor vaccines, cytokine therapy, or tyrosine kinase inhibitors, for the treatment of conditions modulated by inhibition of ROCK, such as fibrotic diseases, autoimmunity, inflammatory fibrotic conditions, inflammatory conditions, central nervous system disorders, or cancer.

[0315] The treatment methods or compounds defined above for the treatment of renal conditions, liver conditions, inflammatory conditions, cardiovascular conditions, acute and chronic organ transplant rejection, fibrotic diseases and cancer may be applied as monotherapy or as combination therapy in combination with additional active agents.

[0316] Therapeutic methods or compounds for treating renal conditions, liver conditions, inflammatory conditions, cardiovascular conditions, acute and chronic organ transplant rejection, fibrotic diseases, and cancer. The additional active agent can be one or more active agents for treating the conditions treated by the compounds of the invention and the additional active agent. The additional active agent can include one or more of the following active agents:

[0317] (i) Steroids, such as corticosteroids, including glucocorticoids and mineralocorticoids, for example, alclomethasone, alclomethasone dipropionate, aldosterone, amcinonide, beclomethasone, beclomethasone dipropionate, betamethasone, betamethasone dipropionate, betamethasone sodium phosphate, betamethasone valerate, budesonide, clobetasone, clobetasone butyrate, clobetasol propionate, cloprednisolone, cortisone, cortisone acetate, cortivazole, deoxycorticosterone, desonide, desoximetasone, dexamethasone, dexamethasone sodium phosphate, dexamethasone isonicotinate, diflucortolone, fluclorololone, flumethasone, flunisolide, fluocinolone acetonide, fluocinolone acetate, fluocinolone butyl, fluocinolone acetonide steroids, such as fluocinolone, fluocinolone, fluocinolone hexanoate, fluocinolone pivalate, fluorometholone, fluprednidene, fluprednisolone acetate, flurandrenolide, fluticasone, fluticasone propionate, halcinonide, hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone acetate propionate, hydrocortisone propionate butyrate, hydrocortisone valerate, icomethasone, icomethasone acetate butyrate, methylprednisolone, methylprednisolone, mometasone, paramethasone, mometasone furoate monohydrate, prednicasone, prednisolone, prednisone, tixocortol, tixocortol pivalate, triamcinolone acetonide, triamcinolone acetonide acetate, triamcinolone acetonide alcohol, and their respective pharmaceutically acceptable derivatives. Combinations of steroids may be used, such as combinations of two or more of the steroids mentioned in this paragraph;

[0318] (ii) TNF inhibitors, such as etanercept; monoclonal antibodies (e.g., infliximab (Remicade), adalimumab (Humira), cetrimonium (Cimzia), golimumab (Simponi)); fusion proteins (e.g., etanercept (Enbrel)); and 5-HT 2A agonists (e.g., 2,5-dimethoxy-4-iodoamphetamine, TCB-2, lysergic acid diethylamide (LSD), lysergic acid dimethylazetidine);

[0319] (iii) anti-inflammatory drugs, such as nonsteroidal anti-inflammatory drugs;

[0320] (iv) dihydrofolate reductase inhibitors / antifolates, such as methotrexate, trimethoprim, bromoprim, tetraoxaprine, iclaprim, pemetrexed, ralitrexed, and pralatrexate; and

[0321] (v) Immunosuppressants, such as cyclosporine, tacrolimus, sirolimus, pimecrolimus, angiotensin II inhibitors (e.g., valsartan, telmisartan, losartan, irbesartan, azilsartan, olmesartan, candesartan, eprosartan) and ACE inhibitors, such as sulfhydryl-containing agents (e.g., captopril, zofenopril), dicarboxylate-containing agents (e.g., enalapril, ramipril, quinapril, perindopril, lisinopril, benazepril, imidapril, zofenopril, trandolapril), phosphate-containing agents (e.g., fosinopril), casokinin, lactokinin and lactotripeptide.

[0322] (vi) anti-fibrotic 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 etexilate), factor Xa inhibitors (e.g., apixaban, rivaroxaban), 15PGDH inhibitors, anti-αvβ6 monoclonal antibodies (e.g., BG00011), anti-CTGF monoclonal antibodies (FG-3019), PAR1 inhibitors, Nox4 inhibitors, and PAI-1 inhibitors.

[0323] In addition to the compounds of the present invention, the treatment methods or compounds for treating cancer may also include conventional surgery or radiotherapy or chemotherapy. Such chemotherapy may include one or more of the following classes of anti-tumor agents:

[0324] (i) antiproliferative / antineoplastic drugs and combinations thereof, such as alkylating agents (e.g., cisplatin, oxaliplatin, carboplatin, cyclophosphamide, mechlorethamine, uracil mechlorethamine, bendamustine, melphalan, chlorambucil, mechlorethamine, busulfan, temozolomide, nitrosoureas, ifosfamide, melphalan, pipobroman, triethylene-melamine, triethylenethiophoporamine, carmustine, lomustine, streptozocin, and dacarbazine); antimetabolites (e.g., gemcitabine and antifolates such as fluoropyrimidines (e.g., 5-fluorouracil and tegafur), raltitrexed, methotrexate, pemetrexed, cytosine arabinoside, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate); , pentostatin, gemcitabine, and hydroxyurea); antibiotics (e.g., anthracyclines such as doxorubicin, bleomycin, doxorubicin, daunorubicin, epirubicin, idarubicin, mitomycin-C, dactinomycin, and mithramycin); antimitotics (e.g., vinca alkaloids such as vincristine, vinblastine, vindesine, and vinorelbine, and taxanes such as paclitaxel and taxotere, and multikinase inhibitors); proteasome inhibitors such as carfilzomib and bortezomib; interferon therapy; and topoisomerase inhibitors (e.g., epipodophyllotoxins such as etoposide and teniposide, amsacrine, topotecan, mitoxantrone, and camptothecin); bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, cytarabine, paclitaxel (Taxol TM ), albumin-bound paclitaxel (nabpaclitaxel), docetaxel, mithramycin, deoxyco-formycin, mitomycin-C, L-asparaginase, interferon (especially IFN-a), etoposide, and teniposide;

[0325] (ii) cytostatic agents, such as antiestrogens (e.g., tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene, and iodoxyfene), antiandrogens (e.g., bicalutamide, flutamide, nilutamide, and cyproterone acetate), LHRH antagonists or LHRH agonists (e.g., goserelin, leuprorelin, and buserelin), progestins (e.g., megestrol acetate), aromatase inhibitors (e.g., anastrozole, letrozole, vorazole, and exemestane), and 5α-reductase inhibitors, such as finasteride; and navelbene, CPT-11, anastrozole, letrozole, capecitabine, raloxifene, cyclophosphamide, ifosfamide, and droloxafine;

[0326] (iii) anti-invasive agents, such as dasatinib and bosutinib (SKI-606), as well as metalloproteinase inhibitors, inhibitors of urokinase plasminogen activator receptor function, or heparanase antibodies;

[0327] (iv) Inhibitors of growth factor function: For example, such inhibitors include growth factor antibodies and growth factor receptor antibodies, such as the anti-erbB2 antibody trastuzumab [Herceptin TM ], anti-EGFR antibody panitumumab, anti-erbB1 antibody cetuximab, tyrosine kinase inhibitors, such as inhibitors of the epidermal growth factor family (e.g., EGFR family tyrosine kinase inhibitors, such as gefitinib, erlotinib, 6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)-quinazolin-4-amine (CI 1033), erbB2 tyrosine kinase inhibitors, such as lapatinib) and antibodies to costimulatory molecules (such as CTLA-4, 4-1BB and PD-1), or antibodies to cytokines (IL-10, TGF-β); inhibitors of the hepatocyte growth factor family; inhibitors of the insulin growth factor family; modulators of apoptosis protein regulators (e.g., Bcl-2 inhibitors); inhibitors of the platelet-derived growth factor family, such as imatinib and / or nilotinib (AMN107); inhibitors of serine / threonine kinases (e.g. Ras / Raf signaling inhibitors, such as farnesyl transferase inhibitors, for example, sorafenib, tipifarnib, and lonafarnib), inhibitors of cell signaling through MEK and / or AKT kinases, c-kit inhibitors, abl kinase inhibitors, PI3 kinase inhibitors, Plt3 kinase inhibitors, CSF-1R kinase inhibitors, IGF receptor, kinase inhibitors; Aurora kinase inhibitors and cyclin-dependent kinase inhibitors, for example, CDK2 and / or CDK4 inhibitors; and CCR2, CCR4, or CCR6 modulators;

[0328] (v) Anti-angiogenic agents, such as those that inhibit the action of vascular endothelial growth factor, such as the anti-vascular endothelial growth factor antibody bevacizumab (Avastin TM ); thalidomide; lenalidomide; and, for example, VEGF receptor tyrosine kinase inhibitors such as vandetanib, vatalanib, sunitinib, axitinib, and pazopanib;

[0329] (vi) gene therapy approaches, including, for example, approaches to replace abnormal genes such as abnormal p53 or abnormal BRCA1 or BRCA2;

[0330] (vii) Immunotherapy approaches, including, for example, antibody therapies such as alemtuzumab, rituximab, ibritumomab and ofatumumab; interferons, such as interferon alpha; interleukins, such as IL-2 (aldesleukin); interleukin inhibitors, such as IRAK4 inhibitors; cancer vaccines, including prophylactic and therapeutic vaccines, such as HPV vaccines, such as Gardasil, Cervarix, Oncophage, and Sipuleucel-T (Provenge); gp100; dendritic cell-based vaccines (such as Ad.p53 DC); and toll-like receptor modulators, such as TLR-7 or TLR-9 agonists; and

[0331] (viii) Cytotoxic agents such as fludarabine, cladribine, pentostatin, TM );

[0332] (ix) Steroids, such as corticosteroids, including glucocorticoids and mineralocorticoids, for example, alclomethasone, alclomethasone dipropionate, aldosterone, amcinonide, beclomethasone, beclomethasone dipropionate, betamethasone, betamethasone dipropionate, betamethasone sodium phosphate, betamethasone valerate, budesonide, clobetasone, clobetasone butyrate, clobetasol propionate, cloprednisolone, cortisone, cortisone acetate, cortivazole, deoxycorticosterone, desonide, desoximetasone, dexamethasone, dexamethasone sodium phosphate, dexamethasone isonicotinate, diflucortolone, fluclorololone, flumethasone, flunisolide, fluocinolone acetonide, fluocinolone acetate, fluocinolone butyl, fluocinolone butyl, fluocinolone acetonide Flucortolone, flucortolone hexanoate, flucortolone pivalate, fluorometholone, fluprednidine, fluprednisolone acetate, flurandrenolide, fluticasone, fluticasone propionate, halcinonide, hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone acetate propionate, hydrocortisone propionate butyrate, hydrocortisone valerate, icomethasone, icomethasone acetate butyrate, methylprednisolone, methylprednisolone, mometasone, paramethasone, mometasone furoate monohydrate, prednicasone, prednisolone, prednisone, tixocortol, tixocortol pivalate, triamcinolone acetonide, triamcinolone acetonide acetate, triamcinolone acetonide alcohol, and pharmaceutically acceptable derivatives thereof. Combinations of steroids may be used, such as combinations of two or more of the steroids mentioned in this paragraph;

[0333] (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);

[0334] (xii) Chimeric antigen receptors, anticancer vaccines and arginase inhibitors.

[0335] Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate administration of the individual components of the treatment.Such combination products employ the compounds of this invention within the therapeutically effective dosage range described above and the other pharmaceutically active agent within its approved dosage range.

[0336] The compounds of the present invention may exist as a mixture of single crystal forms or crystalline forms, or they may be amorphous. Therefore, the compounds of the present invention intended for pharmaceutical use may be administered as crystallized or amorphous products. They may be obtained, for example, by precipitation, crystallization, freeze drying, spray drying, or evaporative drying, for example, as solid plugs, powders, or films. Microwave or radio frequency drying may be used for this purpose.

[0337] For the above-mentioned compounds of the present invention, the dosage will certainly vary with the compound used, mode of administration, desired treatment and indicated disease. For example, if the compound of the present invention is administered orally, the daily dosage of the compound of the present invention can be in the range of 0.01 micrograms per kilogram of body weight (μg / kg) to 100 milligrams per kilogram of body weight (mg / kg).

[0338] The compounds of the present invention or their pharmaceutically acceptable salts can be used alone, but are generally administered in the form of pharmaceutical compositions in which the compounds of the present invention or their pharmaceutically acceptable salts are combined with a pharmaceutically acceptable adjuvant, diluent, or carrier. Conventional procedures for selecting and preparing suitable pharmaceutical formulations are described, for example, in "Pharmaceuticals - The Science of Dosage Form Designs", ME Aulton, Churchill Livingstone, 1988.

[0339] Depending on the mode of administration of the compound of the present invention, the pharmaceutical composition for administering the compound of the present invention will preferably contain 0.05 to 99% w (weight percentage) of the compound of the present invention, more preferably 0.05 to 80% w of the compound of the present invention, still more preferably 0.10 to 70% w of the compound of the present invention, and even more preferably 0.10 to 50% w of the compound of the present invention, all weight percentages being based on the total composition.

[0340] The pharmaceutical composition can be administered topically (e.g., to the skin) in the form of, for example, a cream, gel, lotion, solution, suspension, or systemically, for example, orally in the form of tablets, capsules, syrups, powders, or granules; or parenterally (including intravenously, subcutaneously, intramuscularly, intravascularly, or by infusion) in the form of a sterile injectable solution, suspension, or emulsion; rectally in the form of a suppository; or inhaled in the form of an aerosol.

[0341] For oral administration, the compounds of the present invention can be mixed with an adjuvant or carrier, such as lactose, sucrose, sorbitol, mannitol; starches such as potato starch, corn starch, or pullulan; cellulose derivatives; binders such as gelatin or polyvinyl pyrrolidone; and / or lubricants such as magnesium stearate, calcium stearate, polyethylene glycol, wax, paraffin, etc., and then compressed into tablets. If coated tablets are desired, the core tablets prepared as described above can be coated with a concentrated sugar solution, which can contain, for example, gum arabic, gelatin, talc, and titanium dioxide. Alternatively, the tablets can be coated with a suitable polymer dissolved in a volatile organic solvent.

[0342] In order to prepare soft gelatin capsules, the compound of the present invention can be mixed with, for example, vegetable oil or polyethylene glycol. Hard gelatin capsules can contain compound particles prepared using the above-mentioned excipients for tablets. In addition, the liquid or semisolid preparations of the compounds of this invention can be filled into hard gelatin capsules. Liquid preparations for oral use can be in the form of syrup or suspension, for example, a solution containing the compounds of this invention, and the remainder is a mixture of sugar and ethanol, water, glycerol and propylene glycol. Optionally, such liquid preparations can contain coloring agents, flavorings, sweeteners (such as saccharin), preservatives and / or carboxymethyl cellulose as thickeners or other excipients well known to those skilled in the art.

[0343] For intravenous (parenteral) administration, the compounds of the present invention may be administered as sterile aqueous or oily solutions.

[0344] According to well-known medical principles, the size of the dose of the compounds of the present invention for therapeutic purposes will naturally vary depending on the nature and severity of the condition, the age and sex of the animal or patient and the route of administration.

[0345] Dosage levels, dosing frequency, and duration of treatment with the compounds of the invention are expected to vary depending on the formulation and the clinical indication, age, and comorbid medical conditions of the patient.

[0346] Throughout the description and claims of this specification, the words "comprise" and "include" and their variations mean "including but not limited to", and they are not intended to (and do not) exclude other parts, additives, components, integers or steps. Throughout the description and claims of this specification, the singular encompasses the plural unless the context requires otherwise. In particular, where the indefinite article is used, the specification should be understood as contemplating plurality as well as singularity, unless the context requires otherwise.

[0347] Features, integers, characteristics, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein unless incompatible therewith. All features disclosed in this specification (including any accompanying claims, abstract and drawings), and / or all steps of any method or process so disclosed, may be combined in any combination, except combinations in which at least some of such features and / or steps are mutually exclusive. The invention is not limited to the details of any foregoing embodiments. The invention extends to any novel one or any novel combination of features of the features disclosed in this specification (including any accompanying claims, abstract and drawings), or to any novel one or any novel combination of steps of any method or process so disclosed.

[0348] The reader's attention is directed to all papers and documents filed concurrently with or prior to this specification in connection with this application, which papers and documents are open to the public with this specification, and the contents of all such papers and documents are incorporated herein by reference.

[0349] The compounds of the present invention can be prepared according to or in analogy to General Schemes 1-4 and Examples 1 to 65.

[0350] Experimental procedures

[0351] Unless otherwise stated, solvents, reagents, and raw materials were purchased from commercial suppliers and used as received. Unless otherwise stated, all reactions were performed at room temperature. Compounds were identified and their purity confirmed by LCMS UV using a Waters Acquity SQ detector 2 (ACQ-SQD2#LCA081). The diode array detector wavelength was set to acquire spectra at a wavelength of 254 nM, and the MS was in positive and negative electrospray mode (m / z: 150-800). 2 μL aliquots were injected sequentially onto a guard column (0.2 μm × 2 mm filter) and a UPLC column (C18, 50 × 2.1 mm, <2 μm) and maintained at 40°C. The sample was eluted at a flow rate of 0.6 mL / min using a mobile phase system consisting of A (0.1% (v / v) formic acid in water) and B (0.1% (v / v) formic acid in acetonitrile) according to the gradient listed in Table 1 below (Methods 1 and 2). Retention time RT is in minutes. The following methods were also used when described throughout the experimental sections, with gradients detailed in Table 1. Method 3 utilized a Shimadzu 2020 series spectrometer equipped with a binary pump and a diode array detector (collection wavelengths of 214 and 254 nm), with the MS in positive and negative electrospray modes (m / z: 100-900). A 2 μL aliquot was injected onto an Agilent Poroshell 120EC-C18 column (2.7 μm, 4.6 × 50 mm), maintained at 35°C, and eluted at 1.0 mL / min using a mobile phase consisting of: A: 0.05% formic acid in water (v / v), B: 0.05% formic acid in ACN (v / v). Method 4 utilized an Agilent Technologies 1290 series spectrometer equipped with a binary pump and a diode array detector (collection wavelengths of 214 and 254 nm), with the MS in positive electrospray mode (m / z: 70-1000). A 2 μL aliquot was injected onto an Agilent Eclipse Plus RRHDC18 (1.8 μm, 3.0×50 mm) column, maintained at 40° C., and eluted at 0.8 mL / min using a mobile phase consisting of: A: 0.05% formic acid in water (v / v), B: 0.05% formic acid in ACN (v / v).

[0352] Table 1

[0353]

[0354]

[0355] NMR was also used to characterize the final compounds. NMR spectra were obtained on a Bruker AVIII 400 Nanobay with a 5 mm BBFO probe. Optionally, the Rf values ​​of the compounds were measured on silica gel thin layer chromatography (TLC) plates.

[0356] Compounds were purified by silica gel flash column chromatography or preparative LCMS. LCMS purification was performed using a Waters 3100 mass spectrometer in positive and negative electrospray modes (m / z: 150-800) and a Waters 2489 UV / Vis detector. TM The sample was eluted on a preparative C18 5μM OBD 19×100mm column at a flow rate of 20 mL / min using a mobile phase system consisting of A (0.1% (v / v) formic acid in water) and B (0.1% (v / v) formic acid in acetonitrile).

[0357] Table 2

[0358] Time (min) ％A ％B 0 90 10 1.5 90 10 11.7 5 95 13.7 5 95 14 90 90 15 90 90

[0359] General routes and plans

[0360] General plan 1

[0361]

[0362] Note: STEP = step, same below

[0363] Compounds of formula (I) can be prepared from the intermediates represented by vi in ​​General Scheme 1. In step 1, an o-fluoronitroaryl compound is reacted with an aryl or heteroaryl amine (wherein A represents a halogen capable of participating in metal-mediated cross-coupling reactions such as Suzuki or Stille reactions, such as Cl, Br or I) in the presence of a base such as sodium hydride to undergo a nucleophilic substitution reaction to obtain a compound of structure i. In step 2, the nitro group of i can be reduced by transition metal catalysis in the presence of hydrogen, or using an alternative hydrogen source such as ammonium chloride to produce a compound of structure ii. In step 3, reaction with a carbonyl equivalent (e.g., CDI) yields a cyclized product represented by iii. In step 4, the free NH of iii is reacted with a suitable α-haloester, wherein A is a halogen such as Br and OAlk represents an alkoxy group such as ethoxide, which is subsequently hydrolyzed to the corresponding carboxylic acid with KOH or LiOH under alkaline conditions in step 5 to obtain a compound of structure v. In step 6, reaction with a suitable amine using a carboxylic acid activating reagent such as HATU and a base such as DIPEA affords the intermediate represented by vi.

[0364] General Scheme 2

[0365]

[0366] Compounds of Formula I can be synthesized from intermediates represented by general structure vi via two routes described in General Scheme 2. According to Step 1a, vi (wherein A represents a halogen such as Br, or another leaving group capable of participating in a metal-catalyzed cross-coupling reaction such as triflate) undergoes a transition metal-catalyzed cross-coupling with an azaimidazole of structure xxi, where B is a boronic acid, boronic ester, or stannyl (trialkyltin) capable of participating in a Suzuki or Stille-type reaction with compounds of structure vi. As an example, A can be a pinacol boronic acid ester and B can be a bromide, and these groups undergo a Suzuki reaction catalyzed by Pd(dppf)Cl2·DCM in the presence of KOAc in Step 1a to provide compounds of Formula I. Alternatively, according to step 1, the intermediate of structure vi can be converted to the boronate or stannane of formula vii by reaction with bis(pinacolato)diboron or tributyltin chloride (wherein B is boronic acid, boronate or stannyl(trialkyltin)), respectively, and in step 2, a subsequent Suzuki or Stille reaction with an azaimidazole of structure xx, where A is a halogen such as Br, Cl or I, to provide a compound of formula (I).

[0367] General Scheme 3

[0368]

[0369] Compounds of formula (I) can also be obtained by reordering the steps of General Schemes 1 and 2 as described in General Scheme 3. The definitions of the groups A, B and OAlk in the structure shown in General Scheme 3 are the same as those described in General Schemes 1 and 2. In step 1, the intermediate of structure iv is subjected to a metal-catalyzed cross-coupling reaction, such as a Suzuki or Stille reaction with a boronic ester or stannane derivative of a heteroaryl group xxi. In step 2, the cross-coupling product (xi) is subjected to a base-mediated ester hydrolysis as described above, followed by an amide coupling in step 3 to provide the compound of formula (I). Alternatively, the cross-coupling partner can be reversed by converting the halide or triflate iv to the corresponding boronic ester or stannane in step 1a and reacting it with a haloazaindazole of structure xx in step 2b to provide the intermediate of structure xi.

[0370] General Scheme 4

[0371]

[0372] Synthesis of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine

[0373]

[0374] Isopropylmagnesium bromide (21 mL, 20.5 mmol, 1 M solution in THF) was added dropwise to a stirred solution of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5.72 g, 30.73 mmol) and 3-iodopyrazolo[1,5-a]pyridine (5.0 g, 20.49 mmol) in THF (50 mL) under N2 at 5°C over a period of 10 min. The resulting solution was stirred at 5°C for 2 h and then concentrated under reduced pressure. The residue was diluted with DCM (10 mL) and the suspension was filtered through a pad of silica gel eluting with EtOAc (10 mL) and evaporated to give the crude product which was purified by flash chromatography eluting with 0-20% EtOAc / heptane to give 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine (320 mg, 6%).

[0375] LCMS (ES+, method 3): 4.12 min, m / z 245.2 [M+H] +

[0376] Synthesis of N-(4-bromo-2-methylphenyl)-2-methyl-6-nitroaniline

[0377]

[0378] To a solution of 4-bromo-2-methylaniline (200 mg, 1.08 mmol, 1.0 equiv) in DMF (2 mL) was added a solution of 2-fluoro-1-methyl-3-nitrobenzene (200 mg, 1.29 mmol, 1.2 equiv) in DMF (2 mL) at 0°C under N2. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was filtered and purified by reverse phase chromatography to give N-(4-bromo-2-methylphenyl)-2-methyl-6-nitroaniline (120 mg, 35%).

[0379] LCMS (ES + , Method 3):4.60min,m / z,321.1[M] +

[0380] In Table 3 are described intermediates synthesized following the same procedure as intermediate i-1 (Scheme 6) replacing 4-bromo-2-methylaniline and 2-fluoro-1-methyl-3-nitrobenzene with the described building blocks.

[0381] Table 3

[0382]

[0383]

[0384]

[0385] Synthesis of N2-(4-bromo-2-methylphenyl)-3-methylbenzene-1,2-diamine

[0386]

[0387] A solution of N-(4-bromo-2-methylphenyl)-2-methyl-6-nitroaniline (12.0 g, 37.4 mmol), NHCl (9.99 g, 187 mmol) and iron (10.4 g, 187 mmol) in ethanol and water (30 mL, 2:1, v / v) was stirred at 80° C. for 2 h. The reaction mixture was concentrated in vacuo and purified by flash chromatography (petroleum ether / EtOAc 5:1 to 3:1) to give N-(4-bromo-2-methylphenyl)-3-methylbenzene-1,2-diamine (8.00 g, 44%) as a yellow solid.

[0388] LCMS (ES + , Method 3): 4.22min, m / z 291.2 / 293.2[M] + / [M+2] +

[0389] In Table 4, intermediates synthesized following the same procedure as intermediate ii-1 (Scheme 7) are described, wherein the described building blocks are substituted for N-(4-bromo-2-methylphenyl)-2-methyl-6-nitroaniline.

[0390] Table 4

[0391]

[0392]

[0393] Synthesis of 3-(4-bromo-2-methylphenyl)-4-methyl-1H-benzimidazol-2-one

[0394]

[0395] By N2-(4-bromo-2-methylphenyl)-3-methylbenzene-1,2-diamine (8.00g, 27.5mmol) and CDI (13.4g, 82.4mmol) in DMF (20mL) stir 16h at 100 ℃.The reaction mixture is diluted with water (20mL), extracted with EtOAc (5mL x 3).The combined organic phase is washed with salt water, dried over Na2SO4 and concentrated in vacuo.The crude material is purified by flash chromatography (petroleum ether / EtOAc 5:1 to 3:1) to obtain 3-(4-bromo-2-methylphenyl)-4-methyl-1H-benzimidazol-2-one (8.00g, 64%) as a yellow solid.

[0396] LCMS (ES + , Method 3): 2.47 min, m / z 317.1 / 319.1 [M] + / [M+2] +

[0397] Intermediates synthesized following the same procedure as intermediate iii-1 (Scheme 8) are described in Table 5, wherein the described building blocks are substituted for N2-(4-bromo-2-methylphenyl)-3-methylbenzene-1,2-diamine.

[0398] Table 5

[0399]

[0400]

[0401] Synthesis of ethyl 2-(3-(4-bromophenyl)-2-oxo-benzimidazol-1-yl)acetate

[0402]

[0403] Step A: Synthesis of xiv-1: To a solution of 2-hydroxybenzimidazole (500 mg, 3.73 mmol) in DMF (10 mL) was added sodium hydride (150 mg, 3.75 mmol, 60% dispersion in mineral oil), and the reaction mixture was stirred at room temperature for 1.5 h. A solution of di-tert-butyl dicarbonate (814 mg, 3.73 mmol) in DMF (5 mL) was added dropwise. The reaction mixture was stirred at room temperature for 4 h and then evaporated to dryness. The residue was diluted with ethyl acetate and saturated NH4Cl aqueous solution. The phases were separated and the aqueous phase was extracted with ethyl acetate. The organic phase was washed with brine, then passed through a phase separator filter paper, and evaporated to dryness to give tert-butyl 2-oxo-3H-benzimidazole-1-carboxylate (870 mg, 3.71 mmol, 100% yield) as an off-white solid.

[0404] UPLCMS(ES+ , Method 2): 1.55 min, m / z 233.1 [M+H] +

[0405] Step B: synthesis xv-1: a mixture of cesium carbonate (181mg, 0.55mmol), ethyl bromoacetate (0.05mL, 0.47mmol) and 2-oxo-3H-benzoimidazole-1-carboxylic acid tert-butyl ester (100mg, 0.43mmol) in MeCN (2.5mL) is heated at 80 ℃ for 2h. The reaction mixture is evaporated to dryness, and the residue is suspended in water. The aqueous phase is extracted four times with ethyl acetate. The organic phase is washed with salt water, passed through a phase separation filter paper, and evaporated to dryness. By flash column chromatography (4g posts, eluent is 0-25% ethyl acetate in petroleum ether) purification of residue, 3-(2-ethoxy-2-oxo-ethyl)-2-oxo-benzoimidazole-1-carboxylic acid tert-butyl ester (100mg, 0.31mmol, 73% yield) is obtained as a colorless oil.

[0406] UPLCMS(ES + , Method 2): 1.79 min, m / z 343.0 [M+Na] +

[0407] Step C: Synthesis of xvi-1: tert-Butyl 3-(2-ethoxy-2-oxo-ethyl)-2-oxo-benzimidazole-1-carboxylate (1.14 g, 3.56 mmol) was dissolved in DCM (25 mL) and trifluoroacetic acid (2.73 mL, 35.59 mmol) was added. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was evaporated to dryness and co-evaporated with toluene to give ethyl 2-(2-oxo-3H-benzimidazol-1-yl)acetate (700 mg, 3.18 mmol, 89% yield) as a white solid.

[0408] UPLCMS(ES + , Method 2): 1.32 min, m / z 221.1 [M+H] +

[0409] 1H NMR (400MHz, DMSO-d6) δ10.95 (s, 1H), 7.11-7.07 (m, 1H), 7.01-7.00 (m, 3H), 4.66 (s, 2H), 4.15 (q, J = 7.1Hz, 2H), 1.21 (t, J = 7.1Hz, 3H) ppm.

[0410] Step D: Synthesis of iv-4: 4-bromo-phenylboronic acid (911 mg, 4.54 mmol), ethyl 2-(2-oxo-3H-benzimidazol-1-yl)acetate (500 mg, 2.27 mmol) and copper (II) acetate (824 mg, 4.54 mmol) were mixed in DCM (15 mL) and triethylamine (0.95 mL, 6.81 mmol) was added. The reaction mixture was exposed to air and stirred overnight at room temperature. The reaction mixture was diluted with dichloromethane and water. The phases were separated and the aqueous phase was extracted with dichloromethane. The organic phase was washed with salt water, passed through a phase separator, and evaporated to dryness. The residue was purified by flash column chromatography, eluted with 0-25% EtOAc solution in petroleum ether to give ethyl 2-[3-(4-bromophenyl)-2-oxo-benzimidazol-1-yl]acetate (364 mg, 0.97 mmol, 43% yield) as a white solid.

[0411] UPLCMS(ES + , Method 2): 1.88 min, m / z 375.0 / 377.0 [M] + / [M+2] +

[0412] Synthesis of ethyl 2-(3-(4-bromo-2-methylphenyl)-4-methyl-2-oxo-benzimidazol-1-yl)acetate

[0413]

[0414] A solution of 3-(4-bromo-2-methylphenyl)-4-methyl-1H-benzimidazol-2-one (8.00 g, 25.2 mmol), ethyl bromoacetate (4.2 mL, 37.8 mmol) and CsCO (16.4 g, 50.4 mmol) in MeCN (20 mL) was stirred at 50° C. for 2 h. The reaction mixture was concentrated in vacuo and purified by flash chromatography (petroleum ether / EtOAc 5:1 to 3:1) to give ethyl 2-(3-(4-bromo-2-methylphenyl)-4-methyl-2-oxo-benzimidazol-1-yl)acetate (7.00 g, 58%) as a yellow solid.

[0415] LCMS (ES + , Method 3): 4.15min, m / z 403.1 / 405.1[M] + / [M+2] +

[0416] In Table 6 are described intermediates synthesized following the same procedure as intermediate iv-1 (Scheme 10) whereby 3-(4-bromo-2-methylphenyl)-4-methyl-1H-benzimidazol-2-one was replaced by the described building blocks.

[0417] Table 6

[0418]

[0419]

[0420]

[0421] Synthesis of ethyl 2-(4-methyl-3-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,3,2-dioxaborolan-2-yl)phenyl)-2-oxo-benzimidazol-1-yl)acetate

[0422]

[0423] A solution of 3-(4-bromo-2-methylphenyl)-4-methyl-1H-benzimidazol-2-one (1.00 g, 2.48 mmol), bis(pinacolato)diboron (0.94 g, 3.72 mmol), potassium acetate (0.49 g, 4.96 mmol), Pd2(dba)3 (0.45 g, 0.5000 mmol) and xantphos (0.24 g, 0.50 mmol) in THF (2 mL) was stirred at 70°C for 16 h. The reaction mixture was concentrated in vacuo and purified by flash chromatography (petroleum ether / EtOAc 5:1 to 3:1) to give ethyl 2-(4-methyl-3-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,3,2-dioxaborolan-2-yl)phenyl)-2-oxo-benzimidazol-1-yl)acetate (1.00 g, 72%) as a red solid.

[0424] LCMS (ES + , Method 3): 4.45 min, m / z 451.4 [M+H] +

[0425] In Table 7, intermediates synthesized following the same procedure as intermediate x-1 (Scheme 11) are described, wherein the described building blocks are substituted for 3-(4-bromo-2-methylphenyl)-4-methyl-1H-benzimidazol-2-one.

[0426] Table 7

[0427]

[0428]

[0429] Synthesis of 2-[3-(6-bromo-2-methyl-3-pyridyl)-4-methyl-2-oxo-benzimidazol-1-yl]acetic acid

[0430]

[0431] A mixture of ethyl 2-[3-(6-bromo-2-methyl-3-pyridinyl)-4-methyl-2-oxo-benzimidazol-1-yl]acetate (5 g, 12.37 mmol) and lithium hydroxide monohydrate (1037.9 mg, 24.74 mmol) in THF (8 mL) and water (8 mL) was stirred at 25° C. for 1 h. The mixture was adjusted to pH 3 and extracted with DCM (15 mL×3). The combined organic layers were washed with brine (50 mL), dried over Na SO and concentrated in vacuo to afford 2-[3-(6-bromo-2-methyl-3-pyridinyl)-4-methyl-2-oxo-benzimidazol-1-yl]acetic acid (4.6 g, 12.23 mmol, 99% yield) as a yellow solid.

[0432] LCMS (ES+, method 3): 3.22 min, m / z 378.2 [M+2] +

[0433] Intermediates synthesized according to the same procedure as intermediate v-2 (Scheme 12) are described in Table 8, wherein the described building blocks are used instead of ethyl 2-[3-(6-bromo-2-methyl-3-pyridinyl)-4-methyl-2-oxo-benzoimidazol-1-yl]acetate.

[0434] Table 8

[0435]

[0436]

[0437]

[0438] Synthesis of 2-[3-(6-bromo-4-methyl-3-pyridyl)-4-methyl-2-oxo-benzimidazol-1-yl]-N-(2,2,2-trifluoroethyl)acetamide

[0439]

[0440] A solution of 2-[3-(6-bromo-4-methyl-3-pyridinyl)-4-methyl-2-oxo-benzimidazol-1-yl]acetic acid (4.80 g, 12.8 mmol), trifluoroethylamine (1.22 mL, 15.3 mmol), HATU (5.82 g, 15.3 mmol) and DIEA (4.95 g, 38.3 mmol) in DMF (2 mL) was stirred at 25 ° C for 2 h. Water was added to the mixture. The reaction mixture was filtered and the solid was washed with water to give 2-[3-(6-bromo-4-methyl-3-pyridinyl)-4-methyl-2-oxo-benzimidazol-1-yl]-N-(2,2,2-trifluoroethyl)acetamide (5.60 g, 12.2 mmol, 96% yield). LCMS (ES+, Method 3): 3.45 min, m / z 459.3 [M+2] +

[0441] Intermediates synthesized according to the same procedure as intermediate vi-1 (Scheme 13) are described in Table 9, wherein 2-[3-(6-bromo-4-methyl-3-pyridinyl)-4-methyl-2-oxo-benzimidazol-1-yl]acetic acid and trifluoroethylamine were replaced by the described building blocks.

[0442] Table 9

[0443]

[0444]

[0445]

[0446]

[0447] Synthesis of 2-[4-methyl-2-oxo-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]benzimidazol-1-yl]-N-(2,2,2-trifluoroethyl)acetamide

[0448] A solution of 2-[3-(4-bromophenyl)-4-methyl-2-oxo-benzimidazol-1-yl]-N-(2,2,2-trifluoroethyl)acetamide (5.00 g, 11.34 mmol), bis(pinacolato)diboron (5.74 g, 22.61 mmol), KOAc (3.33 g, 33.92 mmol), XPhos (1.08 g, 2.26 mmol, 2.27 equiv) and Pd2(dba)3 (2.07 g, 2.26 mmol) in THF (35 mL) was stirred at 70°C under N2 overnight. The mixture was concentrated in vacuo and purified by silica gel column (petroleum ether / EtOAc 10:1 to petroleum ether / EtOAc 1:1, v / v) to give 2-[4-methyl-2-oxo-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]benzimidazol-1-yl]-N-(2,2,2-trifluoroethyl)acetamide (5.0 g, 10.22 mmol, 90.4% yield).

[0449] LCMS (ES+, method 3): 4.32 min, m / z 490.0 [M+H]+

[0450] In Table 10, intermediates synthesized following the same procedure as intermediate vii-1 (Scheme 14) are described, wherein the described building blocks are substituted for 2-[3-(4-bromophenyl)-4-methyl-2-oxo-benzimidazole-1-

[0451] 1-[[(2,2,2-trifluoroethyl)acetamide]-N-(2,2,2-trifluoroethyl)acetamide.

[0452] Synthetic borate esters

[0453] Table 10

[0454]

[0455]

[0456] Procedure A: Synthesis of ethyl 2-(4-methyl-3-(2-methyl-4-pyrazolo[1,5-a]pyrazin-3-yl-phenyl)-2-oxo-benzimidazol-1-yl)acetate

[0457]

[0458] A solution of ethyl 2-(4-methyl-3-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-oxo-benzimidazol-1-yl)acetate (280 mg, 0.620 mmol), 3-bromopyrazolo[1,5-a]pyrazine (148 mg, 0.750 mmol), Pd(dppf)Cl2.DCM (50.0 mg, 0.620 mmol) and Na2CO3 (132 mg, 1.24 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL) was stirred under nitrogen at 90° C. for 16 h. The reaction mixture was diluted with water (200 mL) and extracted with EtOAc (100 mL×3). The combined organic layers were dried over NaSO, concentrated in vacuo and purified by flash chromatography (pure DCM to DCM / MeOH 80:1) to give ethyl 2-(4-methyl-3-(2-methyl-4-pyrazolo[1,5-a]pyrazin-3-yl-phenyl)-2-oxo-benzoimidazol-1-yl)acetate (155 mg, 56%) as a yellow solid. LCMS (ES+, Method 4): 2.12 min, m / z 442.1 [M+H] +

[0459] Procedure B: Synthesis of ethyl 2-(4-methyl)-2-oxo-3-(5-pyrazolo[1-5-a]pyridin-3-yl)pyrazin-2-yl)benzimidazol-1-yl)acetate

[0460]

[0461] A solution of ethyl 2-(3-(5-bromopyrazin-2-yl)-4-methyl-2-oxo-benzimidazol-1-yl)acetate (120 mg, 0.307 mmol, 1.0 equiv), 3-(4,4,5,5-tetramethyl-1,3-2-dioxaborolan-2-yl)pyrazolo[1-5-a]pyridine (82.4 mg, 0.337 mol, 1.1 equiv), Pd(dppf)Cl2 (24.8 mg, 0.0307 mmol, 0.1 equiv), Na2CO3 (65.0 mg, 0.614 mmol, 2.0 equiv) in 1,4-dioxane (5 mL) and water (0.5 mL) was stirred under nitrogen at 100° C. for 16 h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL x 3). The reaction mixture was concentrated in vacuo and purified by flash chromatography (petroleum ether / EtOAc 10:1 to 2:1) to give ethyl 2-(4-methyl)-2-oxo-3-(5-pyrazolo[1-5-a]pyridin-3-yl)pyrazin-2-yl)benzimidazol-1-yl)acetate (170 mg, 97%) as a yellow solid.

[0462] LCMS (ES + , Method 3): 4.18 min, m / z 429.2 [M+H] +

[0463] Procedure C: Synthesis of ethyl 2-(4-methyl-2-oxo-3-(2-pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-5-yl)benzimidazol-1-yl)acetate

[0464]

[0465] Step A: Synthesis of xvii-1: A mixture of 2-bromo-N-(2-methyl-6-nitro-phenyl)pyrimidin-5-amine (intermediate i-6, 3.14 g, 10.16 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine (2.98 g, 12.19 mmol), K2CO3 (4.21 g, 30.47 mmol) and Pd(dppf)Cl2.DCM (823.4 mg, 1.02 mmol) in 1,4-dioxane (60 mL) and water (6 mL) was stirred at 90°C under N2 for 16 h. The mixture was filtered and concentrated under reduced pressure. The product was purified by column chromatography on silica gel (petroleum ether).

[0466] / EtOAc=3 / 1 ~ DCM / MeOH=100 / 1, v / v) to give N-(2-methyl-6-nitro-phenyl)-2-pyrazolo[1,5-a]pyridin-3-yl-pyrimidin-5-amine (2.6 g, 7.51 mmol, 74% yield) as a yellow solid.

[0467] LC-MS(ES + , Method 4):1.61min,m / z,347.1[M+H] +

[0468] Step B: Synthesis of xviii-1: A mixture of N-(2-methyl-6-nitro-phenyl)-2-pyrazolo[1,5-a]pyridin-3-yl-pyrimidin-5-amine (1.23 g, 3.55 mmol), iron (0.99 g, 17.76 mmol) and NH4Cl (1.90 g, 35.51 mmol) in ethanol (30 mL) and water (10 mL) was stirred at N2, 80 ° C for 1 h. The mixture was filtered and concentrated in vacuo. The residue was diluted with water (50 mL) and extracted with EtOAc (25 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4 and concentrated under reduced pressure. Purification by silica gel column (DCM / MeOH=50 / 1, v / v) gave 3-methyl-N2-(2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-5-yl)benzene-1,2-diamine (770 mg, 2.43 mmol, 69% yield) as an off-white solid. LC-MS (ES + , Method 3):1.60min,m / z,317.2[M+H] +

[0469] Step C: Synthesis of xix-1: A mixture of 3-methyl-N2-(2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-5-yl)benzene-1,2-diamine (770 mg, 2.43 mmol) and CDI (1.18 g, 7.30 mmol) in DMF (20 mL) was stirred under N2 at 100°C overnight. The mixture was diluted with water (50 mL) and extracted with EtOAc (25 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4 and concentrated in vacuo to give the crude product, which was purified by silica gel column (DCM / MeOH=50 / 1, v / v) to give 4-methyl-3-(2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-5-yl)-1H-benzimidazol-2-one (786 mg, 2.30 mmol, 94% yield) as an off-white solid.

[0470] LC-MS(ES + , Method 3):1.59min,m / z,343.2[M+H] +

[0471] Step D: Synthesis of xi-3: A solution of 4-methyl-3-(2-pyrazolo[1,5-a]pyridin-3-ylpyridin-5-yl)-1H-benzimidazol-2-one (1.57 g, 4.59 mmol), Cs2CO3 (2.99 g, 9.17 mmol) and ethyl bromoacetate (0.76 mL, 6.88 mmol) in MeCN (20 mL) was stirred at room temperature for 16 h. The reaction mixture was filtered, concentrated in vacuo and purified by flash chromatography (petroleum ether / EtOAc 1:1) to give ethyl 2-(4-methyl-2-oxo-3-(2-pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-5-yl)benzimidazol-1-yl)acetate (1.58 g, 80%) as a yellow solid.

[0472] LCMS (ES + , Method 4): 2.02 min, m / z 429.2 [M+H] +

[0473] Intermediates synthesized following the same procedure as intermediate xi-1 (Schemes 15-17) are described in Table 11, wherein the described building blocks are substituted for 3-(4-bromo-2-methylphenyl)-4-methyl-1H-benzimidazol-2-one.

[0474] Table 11

[0475]

[0476]

[0477]

[0478] Synthesis of 2-(4-methyl-3-(2-methyl-4-pyrazolo[1,5-a]pyrazin-3-yl-phenyl)-2-oxo-benzimidazol-1-yl)acetic acid

[0479]

[0480] Procedure D: A solution of ethyl 2-(4-methyl-3-(2-methyl-4-pyrazolo[1,5-a]pyrazin-3-yl-phenyl)-2-oxo-benzimidazol-1-yl)acetate (155 mg, 0.350 mmol), LiOH.HO (44.2 mg, 1.05 mmol) in THF (1.5 mL) and water (1.5 mL) was stirred at 25° C. for 1 h. The reaction mixture was acidified to pH 5 with 1 M HCl and filtered to give 2-(4-methyl-3-(2-methyl-4-pyrazolo[1,5-a]pyrazin-3-yl-phenyl)-2-oxo-benzimidazol-1-yl)acetic acid (60.0 mg, 41%) as a grey solid.

[0481] LCMS (ES+, method 4): 1.61 min, m / z 414.2 [M+H] +

[0482] Intermediates synthesized following the same procedure as intermediate xii-1 (Scheme 18) are described in Table 12, wherein the described building blocks were substituted for 3-(4-bromo-2-methylphenyl)-4-methyl-1H-benzimidazol-2-one.

[0483] Table 12

[0484]

[0485]

[0486]

[0487] Synthesis of the final compound

[0488]

[0489] Note: Method = method, Example = example, the same below

[0490] Plan 19

[0491] Method A: Example 1: A solution of 2-[2-oxo-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]benzimidazol-1-yl]-N-(2,2,2-trifluoroethyl)acetamide (80.0 mg, 0.170 mmol), potassium acetate (49.6 mg, 0.510 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride dichloromethane complex (41.2 mg, 0.0500 mmol) and 3-bromo-pyrazolo[1,5-a]pyridine (99.5 mg, 0.510 mmol) in 1,4-dioxane (2.1 mL) and water (0.4 mL) was purged (3 times vacuum, 3 times N2) and heated to 95° C. After 2.5 h, the mixture was cooled to room temperature and filtered. The solid was rinsed with EtOAc. The filtrate was reduced in vacuo and purified by flash chromatography (0-100% EtOAc in petroleum ether, then 0-20% MeOH in DCM) and heated to 400°C. i Recrystallization from PrOH / petroleum ether gave 2-[2-oxo-3-(4-pyrazolo[1,5-a]pyridin-3-ylphenyl)benzimidazol-1-yl]-N-(2,2,2-trifluoroethyl)acetamide (6.0 mg, 8%) as an off-white solid. UPLCMS (ES + , method 1): 3.88 min, m / z 466.6 [M+H]+

[0492] 1H NMR(400MHz,DMSO-d6)δ9.03-8.87(m,1H),8.82-8.67(m,1H),8.48(s,1H),8.11-8.04(m,1H),7.96-8.88(m,2H) ,7.69-7.60(m,2H),7.43-7.37(m,1H),7.09-7.18(m,4H),7.04-6.97(m,1H),4.69(s,2H),4.09-3.89(m,2H)ppm

[0493]

[0494] Method B: Example 18: A solution of 2-[3-(5-bromo-2-pyridinyl)-4-methyl-2-oxo-benzoimidazol-1-yl]-N-(2,2,2-trifluoroethyl)acetamide (100 mg, 0.226 mmol, 1.0 equiv), 3-(4,4,5,5-tetramethyl-1,3-2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine (66.1 mg, 0.271 mmol, 1.2 equiv), Na2CO3 (47.8 mg, 0.451 mmol, 2.0 equiv) and Pd(dppf)Cl2 (18.3 mg, 0.0226 mmol, 0.1 equiv) in 1,4-dioxane (1.0 mL) and H2O (0.1 mL) was stirred under N2 at 100°C overnight. The reaction mixture was diluted with EtOAc (3 mL). The layers were separated and the aqueous layer was extracted with EtOAc (10 mL x 3). The combined organic layers were washed with water (5 mL x 3), dried over anhydrous Na2SO4 and concentrated in vacuo. The crude product was purified by preparative HPLC to give 2-[4-methyl-2-oxo-3-(5-pyrazolo[1,5-a]pyridin-3-yl-2-pyridinyl)benzimidazol-1-yl]-N-(2,2,2-trifluoroethyl)acetamide (21.8 mg, 20%) as a yellow solid. LCMS (ES+, Method 3): 3.72 min, m / z 481.2 [M+H] +

[0495] 1H NMR (400MHz, DMSO-d6) δ9.00-8.96(m,2H),8.81(d,J=7.0Hz,1H),8.61(s,1H),8.38-8.36(m,1H),8.13(d,J=9.0Hz,1H),7.68(d,J=8.2Hz ,1H),7.43-7.42(m,1H),7.06-7.02(m,2H),6.99(d,J=7.7Hz,1H),6.87(d,J=7.5Hz,1H),4.64(s,2H),4.02-3.93(m,2H),1.89(s,3H)ppm

[0496]

[0497] Method C: Example 29: A solution of 2-[4-methyl-2-oxo-3-(6-pyrazolo[1,5-a]pyridin-3-yl-3-pyridinyl)benzimidazol-1-yl]acetic acid (35.0 mg, 0.0900 mmol), (3S)-3-(trifluoromethyl)morpholine hydrochloride (20.2 mg, 0.110 mmol), CMPI (49.3 mg, 0.190 mmol) and triethylamine (26.6 mg, 0.260 mmol) in THF (1.5 mL) was stirred at 75°C for 2 h. The reaction mixture was filtered and purified by p-TLC (DCM / MeOH=20 / 1) to give 4-methyl-1-[2-oxo-2-[rac-(3S)-3-(trifluoromethyl)morpholin-4-yl]ethyl]-3-(6-pyrazolo[1,5-a]pyridin-3-yl-3-pyridinyl)benzimidazol-2-one (17.9 mg, 21%) as a white solid.

[0498] LCMS (ES+, method 3): 1.81 min, m / z 537.2 [M+H] +

[0499] 1H NMR (400MHz, DMSO-d6) δ8.82-8.80(m,2H),8.68(d,J=2.6Hz,1H),8.60(d,J=9.0Hz,1H),8.08(d,J=8.5Hz,1H),7.94-7.91(m,1H),7.49-7.4 5(m,1H),7.09-7.00(m,3H),6.89-6.85(m,1H),5.19-4.70(m,3H),4. 20-4.11(m,1H),3.95-3.87(m,2H),3.71-3.46(m,3H),1.93(s,3H)ppm

[0500]

[0501] Method D: Example 14: A mixture of 2-[2-oxo-3-(4-pyrazolo[1,5-a]pyridin-3-ylphenyl)benzimidazol-1-yl]acetic acid (70.0 mg, 0.175 mmol, 1.0 equiv), (2S)-2-(difluoromethyl)pyrrolidine (24.3 mg, 0.200 mmol, 1.1 equiv), HATU (83.1 mg, 0.219 mmol, 1.5 equiv) and DIPEA (117 mg, 0.911 mmol, 5.0 equiv) in DMF (1 mL) was stirred at 25 °C overnight. The reaction mixture was concentrated in vacuo and purified by P-HPLC to give 1-[2-oxo-2-[rac-(2S)-2-(difluoromethyl)pyrrolidin-1-yl]ethyl]-3-(4-pyrazolo[1,5-a]pyridin-3-ylphenyl)benzimidazol-2-one (7.3 mg, 8%) as a white solid.

[0502] LCMS (ES+, method 3): 4.45 min, m / z 488.2 [M+H] +

[0503] 1H NMR(400MHz, DMSO-d6)δ8.78(d,J=7.0Hz,1H),8.47(s,1H),8.07(d,J=9.0Hz, 1H),7.91(d,J=8.5Hz,2H),7.62(d,J=8.3Hz,2H),7.40-7.36(m,1H),7.21(d, J=8.8Hz,1H),7.16-7.09(m,3H),7.01-6.98(m,1H),6.34-6.05(m,1H),5.05- 4.77(m,2H),4.28(d,J=24.7Hz,1H),3.74-3.70(m,2H),2.04-1.97(m,4H)ppm

[0504] Table 13

[0505]

[0506]

[0507]

[0508]

[0509]

[0510]

[0511]

[0512]

[0513]

[0514]

[0515]

[0516]

[0517]

[0518]

[0519]

[0520]

[0521]

[0522]

[0523]

[0524]

[0525]

[0526]

[0527]

[0528]

[0529]

[0530]

[0531]

[0532]

[0533]

[0534]

[0535]

[0536]

[0537] DDR1 and DDR2 binding assay

[0538] The ability of the compounds to bind to DDR1 and DDR2 was quantified using the LanthaScreen Eu kinase binding assay. Recombinant human DDR1 (2.5 nM; aa440-876 containing a GST tag) and DDR2 (1.75 nM; aa427-855 containing a GST tag) were diluted in assay buffer (50 mM HEPES pH 7.3, 10 mM MgCl2, 1 mM EGTA, and 0.01% Tween) in a 5 uL volume in a 384-well plate with various concentrations of compound. After incubation at room temperature for 30 minutes, 2.5 μL of Eu-anti-GST antibody (diluted to 1 nM in assay buffer) plus kinase tracer 178 (diluted to 5 nM for DDR1 and 10 nM for DDR2 in assay buffer) were added to the plate. After incubation at room temperature for 60 minutes, time-resolved fluorescence was measured on a BMG Labtech PHERAstar plate reader. DMSO (1%) and reference compound (1 μM) were used to generate the maximum and minimum assay signals, respectively. Data were analyzed using a four-parameter logistic model to calculate the IC 50 At least two independent replicates were performed for each compound.

[0539] Biological activity value

[0540] The following table (Table 14) shows the pIC values ​​of the above examples for DDR1 and DDR2 kinases. 50 Value (A: pIC 50 >8; B: 8 ≥ pIC 50 >7; C: 7 ≥ pIC 50 >6;D:pIC 50 ≤6; ND: not determined).

[0541] Table 11

[0542]

[0543]

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof: in X 1 、X 2 and X 3 are each independently selected from carbon and nitrogen, wherein X 1 、X 2 and X 3 At least two of them are carbon; X 4 、X 5 、X 6 and X 7 are each independently selected from carbon and nitrogen, wherein X 4 、X 5 、X 6 and X 7 At least two of them are carbon; X 8 、X 9 、X 10 and X 11 are each independently selected from carbon and nitrogen, wherein X 8 、X 9 、X 10 and X 11 At least two of them are carbon; R 1 is independently selected at each occurrence from the group consisting of: halogen, nitro, cyano, NR 9 R 10 , OR 11 SR 9 、SO2NR 9 R 9 、SO2R 9 、CO2R 9 、C(O)R 9 、CONR 9 R 9 、C1-C4-alkyl、NR 9 R 10 Substituted C1-C4-alkyl, 11 substituted C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and cyclopropyl; R 3 independently selected from H and C1-C4-alkyl; R 4 independently selected from C1-C6-alkyl, C1-C6-haloalkyl, C0-C4-alkylene-R 4a ; where R 4a independently selected from the group consisting of C3-C8-cycloalkyl, phenyl, 5-, 6-, 9- or 10-membered heteroaryl and 4- to 10-membered heterocycloalkyl; wherein the heterocycloalkyl or heteroaryl may be monocyclic or bicyclic; wherein the cycloalkyl or heterocycloalkyl is optionally substituted by a single R 12 group and / or 1 to 4 R 13 and wherein the phenyl or heteroaryl is optionally substituted with a single R 12 group and / or 1 to 3 R 14 group substitution; or R 3 and R 4 Together with the nitrogen atom to which they are attached, they form a 4- to 10-membered heterocycloalkyl or a 5- or 9-membered heteroaryl; wherein the heterocycloalkyl or heteroaryl may be monocyclic or bicyclic; wherein the heterocycloalkyl is optionally substituted by a single R 12 group and / or 1 to 4 R 13 and wherein the heteroaryl group is optionally substituted with a single R 12 group and / or 1 to 3 R 14 group substitution; R 5 is independently selected at each occurrence from H, halogen and C1-C4-alkyl, or two R 5 The groups and the carbon atoms to which they are attached may together form a C3-C6 cycloalkyl ring; R 6 is independently selected at each occurrence from the group consisting of: halogen, nitro, cyano, NR 9 R 10 , OR 11 SR 9 、SO2NR 9 R 9 、SO2R 9 、CO2R 9 、C(O)R 9 、CONR 9 R 9 、C1-C4-alkyl、NR 9 R 10 Substituted C1-C4-alkyl, 11 substituted C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and cyclopropyl; R 7 is independently selected at each occurrence from the group consisting of: halogen, nitro, cyano, NR 9 R 10 , OR 11 SR 9 、SO2NR 9 R 9 、SO2R 9 、CO2R 9 、C(O)R 9 、CONR 9 R 9 、C1-C4-alkyl、NR 9 R 10 Substituted C1-C4-alkyl, 11 substituted C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and cyclopropyl; R 8a Independently selected from the following: H, halogen, nitro, cyano, NR 9 R 10 , OR 11 SR 9 、SO2NR 9 R 9 、SO2R 9 、CO2R 9 、C(O)R 9 、CONR 9 R 9 、C1-C4-alkyl、NR 9 R 10 Substituted C1-C4-alkyl, 11 Substituted C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and C0-C4-alkylene-R 8c ; R 8c independently selected from C3-C6-cycloalkyl and 3 to 7 membered heterocycloalkyl; wherein the heterocycloalkyl is attached to the C0-C4-alkylene via a carbon atom in the heterocycloalkyl ring; wherein the cycloalkyl or heterocycloalkyl is optionally substituted by 1 to 4 R 13 group substitution; R 9 are independently selected at each occurrence from H and C1-C4-alkyl; or two R 9 The groups together with the nitrogen atom to which they are attached form an optionally substituted group consisting of 0 to 4 R 15 a C5-C8 heterocycloalkyl group substituted with a group; R 9a is independently selected at each occurrence from H and C1-C4-alkyl; R 10 is independently selected at each occurrence from H, C1-C4-alkyl, C(O)-C1-C4-alkyl and S(O)2-C1-C4-alkyl; or R 9 and R 10 Together with the nitrogen atom to which they are attached, they form a 15 a C5-C8 heterocycloalkyl group substituted with a group; R 11 is independently selected at each occurrence from H, C1-C4-alkyl, C(O)-C1-C4-alkyl and C1-C4-haloalkyl; R 12 independently selected from C3-C6-cycloalkyl, phenyl, 5- or 6-membered heteroaryl and 3- to 6-membered heterocycloalkyl; wherein the cycloalkyl or heterocycloalkyl is optionally substituted by 1 to 4 R 13 wherein the phenyl or heteroaryl group is optionally substituted with 1 to 3 R 14 group substitution; R 13 is independently selected at each occurrence from the group consisting of: =O, halogen, nitro, cyano, NR 9 R 10 , OR 11 SR 9 、SO2NR 9 R 9 、CO2R 9 、C(O)R 9 、CONR 9 R 10 、C1-C4-alkyl、OR 11 Substituted C1-C4-alkyl, NR 9 R 10 Substituted C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl, C6-C 10 -aryl and C3-C6-cycloalkyl; R 14 is independently selected at each occurrence from the group consisting of: halogen, nitro, cyano, NR 9 R 10 , OR 11 SR 9 、SO2R 9 、SO2NR 9 R 10 、CO2R 9 、C(O)R 9 、CONR 9 R 9 , C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl, 11 Substituted C1-C4-alkyl, NR 9 R 10 Substituted C1-C4-alkyl and cyclopropyl; R 15 is independently selected at each occurrence from the group consisting of: =O, halogen, nitro, cyano, NR 9a R 10 , OR 11 SR 9 、SO2NR 9a R 9 、CO2R 9 、C(O)R 9 、CONR 9a R 10 、C1-C4-alkyl、OR 11 Substituted C1-C4-alkyl, NR 9a R 10 Substituted C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl, C6-C 10 -aryl and C3-C6-cycloalkyl; m is an integer selected from 0, 1, 2, 3 and 4; n is an integer selected from 0, 1, 2, 3 and 4; p is an integer selected from 0, 1, 2, 3 and 4; wherein any of the above alkyl, alkylene or cyclopropyl groups is optionally substituted, where chemically possible, with 1 to 5 substituents, each of which is independently selected at each occurrence from the group consisting of halogen, oxo, fluoro, nitro, cyano, NR a R b , OR a SR a 、CO2R a 、C(O)R a 、CONR a R a , C1-C4-alkyl, C1-C4-haloalkyl and cyclopropyl; wherein R a is independently selected at each occurrence from H, C1-C4-alkyl and C1-C4-haloalkyl; and R b is independently selected at each occurrence from H, C1-C4-alkyl, C(O)-C1-C4-alkyl and S(O)2-C1-C4-alkyl.

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

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

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

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

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

7. A compound according to any one of claims 1 to 6, wherein R 8a is selected from H and C1-C4-alkyl.

8. A compound according to any one of claims 1 to 7, wherein X 1 、X 2 and X 3 Each is carbon.

9. The compound according to any one of claims 1 to 8, wherein X 8 、X 9 、X 10 and X 11 Each is carbon.

10. The compound according to any one of claims 1 to 9, wherein X 4 、X 5 、X 6 and X 7 Each is carbon.

11. The compound according to any one of claims 1 to 9, wherein X 4 、X 5 、X 6 and X 7 At least one of them is nitrogen.

12. A compound according to any one of claims 1 to 11, wherein NR 3 R 4 With formula in a is an integer selected from 1 and 2; R 4b is selected from H and F at each occurrence; wherein at least one R 4b The group is F; R 3a independently selected from H and C1-C4-alkyl; R 4c is independently selected at each occurrence from H, C1-C4-alkyl and C4-C6-cycloalkyl; or R 3a and a single R 4c Together with the carbon and nitrogen to which they are attached they form a 4- to 6-membered heterocycloalkyl.

13. The compound according to claim 12, wherein a is 1.

14. The compound according to claim 12 or 13, wherein at least two R 4b The group is F.

15. A compound according to any one of claims 12 to 14, wherein R 3a It’s H.

16. A compound according to any one of claims 12 to 15, wherein R 4c is selected from H and C1-C4-alkyl.

17. A compound according to any one of claims 12 to 14, wherein R 3a and R 4c Together with the carbon and nitrogen to which they are attached they form a 4- to 6-membered heterocycloalkyl.

18. The compound according to claim 1, wherein the compound of formula (I) is selected from the group consisting of:

19. A pharmaceutical formulation comprising a compound according to any one of claims 1 to 18 and a pharmaceutically acceptable excipient.

20. A compound according to any one of claims 1 to 18 for use as a medicament.

21. A compound according to any one of claims 1 to 18 for use in treating a disease or disorder selected from the group consisting of renal conditions, liver conditions, inflammatory conditions, cardiovascular conditions, acute and chronic organ transplant rejection, fibrotic diseases and cancer.

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