DDR1 and DDR2 inhibitors with a dihydrobenzimidazolone core

Abstract

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

Description

[Technical Field]

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

[0002] The discoidin domain receptors (DDRs), DDR1 and DDR2, are type 1 transmembrane receptor tyrosine kinases (RTKs) with collagen receptor functionality (Vogel et al., Mol. Cell, 1997). DDRs contain a characteristic collagen-binding discoidin domain in their N-terminal extracellular domains. These domains are followed by an extracellular juxtamembrane domain, a single transmembrane domain, a cytoplasmic juxtamembrane domain, and a catalytic kinase domain followed by a short C-terminal tail. Five isoforms of DDR1 (DRR1a-e) have been identified, resulting from alternative splicing of the cytoplasmic region. No additional isoforms of DDR2 have been identified. DDR1 and DDR2 have broad, but not completely, mutually exclusive expression profiles in epithelial cells and stroma, respectively. DDRs are activated by binding to collagens with broad specificity, but have clear preferences for certain collagen types. When activated, DDRs are known to regulate cell adhesion, proliferation, and extracellular matrix remodeling. The DDR is upregulated in response to cellular activity and many forms of tissue injury, and as such, the DDR is recognized to be involved in diseases, including cancer, atherosclerosis, and diseases characterized by fibrosis and inflammation. Inhibitors of DDR kinase activity may be beneficial as therapeutic agents in these disease areas.

[0003] Overexpression and / or activation of DDR1 and DDR2 are associated with multiple forms of cancer, as summarized in a recent review (Elkamhawy et al., Int. J. Mol. Sci., 2021). Studies have shown that elevated and / or mutated DDR expression levels are found in many cancer cell lines and primary tumor tissues, including those from lung, pancreas, prostate, breast, brain, ovary, and liver. DDR1 has been found to be a prognostic marker for non-small cell lung cancer (NSCLC) patients. Recent studies have shown that siRNA-mediated downregulation of DDR1 suppresses the malignant progression, migration, invasion, and survival of melanoma cells. DDR1 protein was also found to be expressed in 63% of serous ovarian cancer tissues but not in normal ovarian surface epithelium. DDR1 involvement in glioblastoma cell invasion and epithelial-mesenchymal transition (EMT) has also been demonstrated. DDR1 expression was found in 50.5% of gastric cancer tissues. DDR1 has been found to control the growth of triple-negative breast cancer by regulating tumor-infiltrating CD4+ and CD8+ T cells. Strong evidence also indicates that DDR2 may be a potential biomarker and molecular target for various cancers. For example, overexpression of DDR2 has been reported to contribute to NSCLC, thyroid cancer, Hodgkin's lymphoma, nasopharyngeal carcinoma, prostate cancer, and head and neck squamous cell carcinoma. Studies have shown that DDR2 contributes to breast cancer metastasis by stabilizing the SNAIL1 protein. DDR2 has also been shown to be a favorable independent predictor of recurrence and outcome in primary breast cancer. In addition to the essential role of wild-type DDR in cancer pathology and prognosis, various mutations in DDR1 and / or DDR2 have also been reported in many types of cancer cells, such as G1486T (DDR1) and A496S (DDR1) in lung cancer, N502S (DDR1), A533S (DDR1) and A803V (DDR1) in acute myeloid leukemia (AML), and S768R (DDR2) in squamous cell carcinoma. DDR also plays a role in cancer growth by controlling how tumor cells interact with the surrounding collagen matrix. This role of DDR becomes even more prominent when considering its role as an extracellular matrix receptor.The extracellular matrix (ECM) provides structural properties to the tissue surrounding tumors and regulates cell proliferation, survival, migration, and invasion. The physiological interactions between tumor cells and the microenvironment represented by the extracellular matrix are disrupted in metastatic cancer. As a key component of the tumor extracellular matrix, type I collagen exhibits a dense and distorted structure in malignant cancers and is associated with tumorigenesis and metastasis. Therefore, the discovery of DDR as a collagen receptor represents a new target for controlling tumor progression.

[0004] The DDR also appears to play a central role in regulating inflammation and fibrosis. Regulation of fibrosis and inflammation has been demonstrated in several organs, including the lung and kidney. In the lung, DDR-1-deficient mice exhibit reduced bleomycin-induced lung injury (Vogel et al., Am. J. Respir. Crit. Care Med., 2006), and both DDR1 and DDR2 have been shown to be upregulated in patients with fibrotic lung disease (Bian et al., ERJ Open Res., 2016). In the kidney, DDR1 expression is elevated in patients with lupus nephritis and Goodpasture syndrome, as well as in mouse models of glomerulonephritis (Kerroch et al., FASEB Journal, 2012), and in the renal tubules of mice subjected to unilateral ureteral obstruction (UUO) (Guerrot et al., Am. J. Pathol., 2011). Several studies have shown that DDR1-deficient mice are protected from angiotensin II-mediated proteinuria, glomerular fibrosis, and inflammation, and have reduced collagen deposition, tubular macrophage infiltration, and pro-inflammatory cytokine levels after UUO treatment. Finally, COL3A3 KO mice (a mouse model of human Alport syndrome crossed with DDR1-null mice) have reduced renal fibrosis and attenuation as a result of reduced TGF-β-mediated signaling and reduced levels of the pro-inflammatory cytokine IL-6 (Dorison, Cell Adhesion and Migration, 2018).

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

[0006] Furthermore, it is an object of certain embodiments of the present invention to provide novel compounds useful for treating diseases, such as cancer and fibrotic diseases. The compounds may be inhibitors of DDR1 and / or DDR2. It is an object of certain embodiments of the present invention to provide compounds having activity comparable to existing DDR1 and / or DDR2 inhibitors. It is an object of certain embodiments of the present invention to provide compounds having increased activity compared to existing DDR1 and / or DDR2 inhibitors.

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

[0008] The present invention relates to a compound of formula (Ia): [ka] (Ia) [In the formula, X 1 , X 2 and X 3 are each independently selected from carbon and nitrogen; X 1 , X 2 and X 3 at least two of are carbon; X 4 , X 5 , X 6 and X 7are each independently selected from carbon and nitrogen; X 4 , X 5 , X 6 and X 7 at least two of are carbon; X 8 , X 9 , X 10 and X 11 are each independently selected from carbon and nitrogen; X 8 , X 9 , X 10 and X 11 at least two of are carbon; R 1 each occurrence independently represents halo, nitro, cyano, NR 9 R 10 , OR 11 , S.R. 9 , SO2NR 9 R 9 , SO2R 9 , CO2R 9 , C(O)R 9 ,CONR 9 R 9 , C1-C4-alkyl, NR 9 R 10 C1-C4-alkyl substituted by OR 11 C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and cyclopropyl, substituted by; R 3 is independently selected from H and C1-C4-alkyl; R 4 are independently C1-C6-alkyl, C1-C6-haloalkyl, C0-C4-alkylene-R 4a Selected from;R 4a are independently selected from C3-C8-cycloalkyl, phenyl, 5-, 6-, 9- or 10-membered heteroaryl and 4- to 10-membered heterocycloalkyl; the heterocycloalkyl or heteroaryl group can be monocyclic or bicyclic; the cycloalkyl or heterocycloalkyl group can be selected from one R 12 group and / or 1 to 4 R 13The phenyl or heteroaryl group may be optionally substituted by one R 12 group and / or 1 to 3 R 14 optionally substituted by groups; Alternatively, R 3 and R 4 together with the nitrogen atom to which they are both attached form a 4- to 10-membered heterocycloalkyl group or a 5- or 9-membered heteroaryl group; the heterocycloalkyl or heteroaryl group can be monocyclic or bicyclic; the heterocycloalkyl group can be a 4- to 10-membered heterocycloalkyl group or a 5- or 9-membered heteroaryl group ... 12 group and / or 1 to 4 R 13 The heteroaryl group may be optionally substituted by one R 12 group and / or 1 to 3 R 14 optionally substituted by groups; R 5 is, at each occurrence, independently selected from H, halo and C-C-alkyl, or two R 5 the groups and the carbon atoms to which they are attached, taken together, form a C3-C6 cycloalkyl ring; R 6 each occurrence independently represents halo, nitro, cyano, NR 9 R 10 , OR 11 , S.R. 9 , SO2NR 9 R 9 , SO2R 9 , CO2R 9 , C(O)R 9 ,CONR 9 R 9 , C1-C4-alkyl, NR 9 R 10 C1-C4-alkyl substituted by OR 11 C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and cyclopropyl, substituted by; R 7 each occurrence independently represents halo, nitro, cyano, NR 9R 10 , OR 11 , S.R. 9 , SO2NR 9 R 9 , SO2R 9 , CO2R 9 , C(O)R 9 ,CONR 9 R 9 , C1-C4-alkyl, NR 9 R 10 C1-C4-alkyl substituted by OR 11 C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and cyclopropyl, substituted by; R 8a are independently H, halo, nitro, cyano, NR 9 R 10 , OR 11 , S.R. 9 , SO2NR 9 R 9 , SO2R 9 , CO2R 9 , C(O)R 9 ,CONR 9 R 9 , C1-C4-alkyl, NR 9 R 10 C1-C4-alkyl substituted by OR 11 C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and C0-C4-alkylene-R 8c Selected from; R 8c are independently selected from C3-C6-cycloalkyl and 3- to 7-membered heterocycloalkyl; the heterocycloalkyl group is bonded to the C0-C4-alkylene via a carbon atom in the heterocycloalkyl ring; the cycloalkyl or heterocycloalkyl group is bonded to the C0-C4-alkylene via a carbon atom in the heterocycloalkyl ring; 13 optionally substituted by groups; R 9 is, at each occurrence, independently selected from H and C-C-alkyl; or two R 9The groups, together with the nitrogen atom to which they are attached, can consist of 0 to 4 R 15 forming a C5-C8-heterocycloalkyl group, which may be optionally substituted by a group; R 9a is independently selected at each occurrence from H and C1-C4-alkyl; R 10 is, at each occurrence, independently selected from H, C-C-alkyl, C(O)-C-C-alkyl and S(O)-C-C-alkyl; or R 9 and R 10 together with the nitrogen atom to which they are attached, form 0 to 4 R 15 forming a C5-C8-heterocycloalkyl group, which may be optionally substituted by a group; R 11 is, at each occurrence, independently selected from H, C-C-alkyl, C(O)-C-C-alkyl and C-C-haloalkyl; R 12 are independently selected from C3-C6-cycloalkyl, phenyl, 5- or 6-membered heteroaryl and 3- to 6-membered heterocycloalkyl; said cycloalkyl or heterocycloalkyl group may be selected from 1 to 4 R 13 The phenyl or heteroaryl group may be optionally substituted by 1 to 3 R 14 optionally substituted by groups; R 13 each occurrence independently represents ═O, halo, nitro, cyano, NR 9 R 10 , OR 11 , S.R. 9 , SO2NR 9 R 9 , CO2R 9 , C(O)R 9 ,CONR 9 R 10 , C1-C4-alkyl, OR 11 C1-C4-alkyl substituted by NR 9 R 10C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl, C6-C 10 - selected from aryl and C3-C6-cycloalkyl; R 14 each occurrence independently represents halo, nitro, cyano, NR 9 R 10 , OR 11 , S.R. 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, OR 11 C1-C4- alkyl, NR 9 R 10 C1-C4-alkyl and cyclopropyl substituted by; R 15 each occurrence independently represents ═O, halo, nitro, cyano, NR 9a R 10 , OR 11 , S.R. 9 , SO2NR 9a R 9 , CO2R 9 , C(O)R 9 ,CONR 9a R 10 , C1-C4-alkyl, OR 11 C1-C4-alkyl substituted by NR 9a R 10 C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl, C6-C 10 - selected from 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; Any of the above alkyl, alkylene or cyclopropyl groups may, where chemically possible, be selected from halo, oxo, fluoro, nitro, cyano, NR a R b , OR a , S.R. a , CO2R a , C(O)R a ,CONR a R a , optionally substituted by 1 to 5 substituents each independently selected, at each occurrence, from the group consisting of C-C-alkyl, C-C-haloalkyl and cyclopropyl; R a is, at each occurrence, independently selected from H, C-C-alkyl and C-C-haloalkyl; R b is, each occurrence independently, selected from H, C1-C4-alkyl, C(O)-C1-C4-alkyl and S(O)2-C1-C4-alkyl. or a pharmaceutically acceptable salt thereof.

[0009] The present invention relates to a compound of formula (I): [ka] (I) [In the formula, X 1 , X 2 and X 3 are each independently selected from carbon and nitrogen; X 1 , X 2 and X 3 at least two of are carbon; X 4 , X 5 , X 6 and X 7 are each independently selected from carbon and nitrogen; X 4 , X 5 , X 6 and X 7 at least two of are carbon; X 8 , X 9, X 10 and X 11 are each independently selected from carbon and nitrogen; X 8 , X 9 , X 10 and X 11 at least two of are carbon; R 1 each occurrence independently represents halo, nitro, cyano, NR 9 R 10 , OR 11 , S.R. 9 , SO2NR 9 R 9 , SO2R 9 , CO2R 9 , C(O)R 9 ,CONR 9 R 9 , C1-C4-alkyl, NR 9 R 10 C1-C4-alkyl substituted by OR 11 C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and cyclopropyl, substituted by; R 3 is independently selected from H and C1-C4-alkyl; R 4 are independently C1-C6-alkyl, C1-C6-haloalkyl, C0-C4-alkylene-R 4a Selected from;R 4a are independently selected from C3-C8-cycloalkyl, phenyl, 5-, 6-, 9- or 10-membered heteroaryl and 4- to 10-membered heterocycloalkyl; the heterocycloalkyl or heteroaryl group can be monocyclic or bicyclic; the cycloalkyl or heterocycloalkyl group can be selected from one R 12 group and / or 1 to 4 R 13 The phenyl or heteroaryl group may be optionally substituted by one R 12 group and / or 1 to 3 R 14 optionally substituted by groups; Alternatively, R 3 and R4 together with the nitrogen atom to which they are both attached form a 4- to 10-membered heterocycloalkyl group or a 5- or 9-membered heteroaryl group; the heterocycloalkyl or heteroaryl group may be monocyclic or bicyclic; the heterocycloalkyl group may be a 4- to 10-membered heterocycloalkyl group or a 5- or 9-membered heteroaryl group ... 12 group and / or 1 to 4 R 13 The heteroaryl group may be optionally substituted by one R 12 group and / or 1 to 3 R 14 optionally substituted by groups; R 5 is, at each occurrence, independently selected from H, halo and C-C-alkyl, or two R 5 The groups and the carbon atoms to which they are attached may together form a C3-C6 cycloalkyl ring; R 6 each occurrence independently represents halo, nitro, cyano, NR 9 R 10 , OR 11 , S.R. 9 , SO2NR 9 R 9 , SO2R 9 , CO2R 9 , C(O)R 9 ,CONR 9 R 9 , C1-C4-alkyl, NR 9 R 10 C1-C4-alkyl substituted by OR 11 C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and cyclopropyl, substituted by; R 7 each occurrence independently represents halo, nitro, cyano, NR 9 R 10 , OR 11 , S.R. 9 , SO2NR 9 R 9 , SO2R 9 , CO2R 9 , C(O)R 9 ,CONR9 R 9 , C1-C4-alkyl, NR 9 R 10 C1-C4-alkyl substituted by OR 11 C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and cyclopropyl, substituted by; R 8a are independently H, halo, nitro, cyano, NR 9 R 10 , OR 11 , S.R. 9 , SO2NR 9 R 9 , SO2R 9 , CO2R 9 , C(O)R 9 ,CONR 9 R 9 , C1-C4-alkyl, NR 9 R 10 C1-C4-alkyl substituted by OR 11 C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and C0-C4-alkylene-R 8c Selected from; R 8c are independently selected from C3-C6-cycloalkyl and 3- to 7-membered heterocycloalkyl; the heterocycloalkyl group is bonded to the C0-C4-alkylene via a carbon atom in the heterocycloalkyl ring; the cycloalkyl or heterocycloalkyl group is bonded to the C0-C4-alkylene via a carbon atom in the heterocycloalkyl ring; 13 optionally substituted by groups; R 9 is, at each occurrence, independently selected from H and C-C-alkyl; or two R 9 The groups, together with the nitrogen atom to which they are attached, can consist of 0 to 4 R 13 forming a C5-C8-heterocycloalkyl group, which may be optionally substituted by a group; R 10is, at each occurrence, independently selected from H, C-C-alkyl, C(O)-C-C-alkyl and S(O)-C-C-alkyl; or R 9 and R 10 together with the nitrogen atom to which they are attached, form 0 to 4 R 13 forming a C5-C8-heterocycloalkyl group, which may be optionally substituted by a group; R 11 is, at each occurrence, independently selected from H, C-C-alkyl, C(O)-C-C-alkyl and C-C-haloalkyl; R 12 are independently selected from C3-C6-cycloalkyl, phenyl, 5- or 6-membered heteroaryl and 3- to 6-membered heterocycloalkyl; the cycloalkyl or heterocycloalkyl group is selected from 1 to 4 R 13 The phenyl or heteroaryl group may be optionally substituted by 1 to 3 R 14 optionally substituted by groups; R 13 each occurrence independently represents ═O, halo, nitro, cyano, NR 8 R 9 , OR 14 , S.R. 8 , SO2NR 8 R 8 , CO2R 8 , C(O)R 8 ,CONR 8 R 8 , C1-C4-alkyl, OR 11 C1-C4-alkyl substituted by NR 9 R 10 C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl, C6-C 10 - selected from aryl and C3-C6-cycloalkyl; R 14 each occurrence independently represents halo, nitro, cyano, NR 8 R 9 , OR 10 , S.R.8 , SO2R 8 , SO2NR 8 R 8 , CO2R 8 , C(O)R 8 ,CONR 8 R 8 , C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl, OR 11 C1-C4- alkyl, NR 8 R 9 C1-C4-alkyl and cyclopropyl substituted by; 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; Any of the above alkyl, alkylene or cyclopropyl groups may, where chemically possible, be selected from halo, oxo, fluoro, nitro, cyano, NR a R b , OR a , S.R. a , CO2R a , C(O)R a ,CONR a R a , optionally substituted by 1 to 5 substituents each independently selected, at each occurrence, from the group consisting of C-C-alkyl, C-C-haloalkyl and cyclopropyl; R a is, at each occurrence, independently selected from H, C-C-alkyl and C-C-haloalkyl; R b is, each occurrence independently, selected from H, C1-C4-alkyl, C(O)-C1-C4-alkyl and S(O)2-C1-C4-alkyl. or a pharmaceutically acceptable salt thereof.

[0010] In one embodiment, the compound of Formula (I) or (Ia) has the formula (II): [ka] (II) [where, X 4 , X 5 , X 6 , X 7 , R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8a , m, n and p are as defined above for compounds of formula (I) or (Ia). is a compound of

[0011] In one embodiment, the compound of Formula (I) or (Ia) has the formula (III): [ka] (III) [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 defined above for compounds of formula (I) or (Ia). is a compound of

[0012] In one embodiment, the compound of Formula (I) or (Ia) has the formula (IV): [ka] (IV) [In the formula, R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8a , m, n and p are as defined above for compounds of formula (I) or (Ia). is a compound of

[0013] In one embodiment, the compound of Formula (I) or (Ia) has the formula (V): [ka] (V) [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 defined above for compounds of formula (I) or (Ia). is a compound of

[0014] In one embodiment, the compound of Formula (I) or (Ia) has the formula (VI): [ka] (VI) [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 defined above for compounds of formula (I). is a compound of

[0015] In one embodiment, the compound of Formula (I) or (Ia) has the formula (VII): [ka] (VII) [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 defined above for compounds of formula (I) or (Ia). is a compound of

[0016] In one embodiment, the compound of Formula (I) or (Ia) has the formula (VIII): [ka] (VIII) [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 defined above for compounds of formula (I) or (Ia). is a compound of

[0017] In one embodiment, the compound of Formula (I) or (Ia) has the formula (IX): [ka] (IX) [In the formula, R 1 , R 3 , R 4 , R 6 , R 7 , m, n and p are as defined above for compounds of formula (I) or (Ia). is a compound of

[0018] In one embodiment, the compound of Formula (I) or (Ia) has the formula (X): [ka] (X) [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 defined above for compounds of formula (I) or (Ia). is a compound of

[0019] In one embodiment, the compound of Formula (I) or (Ia) has the formula (XI): [ka] (XI) [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 defined above for compounds of formula (I) or (Ia). is a compound of

[0020] In one embodiment, the compound of Formula (I) or (Ia) has the formula (XII): [ka] (XII) [where, X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X8 , X 9 , X 10 , X 11 , R 1 , R 3 , R 4 , R 6 , R 7 , R 8a , m, n and p are as defined above for compounds of formula (I) or (Ia). is a compound of

[0021] In one embodiment, the compound of Formula (I) or (Ia) has the formula (XIIIa) or (XIIIb): [ka] [In the formula, R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8a , m, n and p are as defined above for compounds of formula (I) or (Ia). is a compound of

[0022] In one embodiment, the compound of Formula (I) or (Ia) has the formula (XIVa) or (XIVb) or (XIVc) or (XIVd): [ka] [In the formula, R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8a , m, n and p are as defined above for compounds of formula (I) or (Ia). is a compound of

[0023] In one embodiment, the compound of Formula (I) or (Ia) has Formula (XVa) or (XVb) or (XVc) or (XVd): [ka] [where, X 4 , X 5 , X 6 , X 7 , R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8a , m, n and p are as defined above for compounds of formula (I) or (Ia). is a compound of

[0024] In one embodiment, the compound of Formula (I) or (Ia) has the formula (XVI): [ka] (XVI) [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); R 1a are halo, nitro, cyano, NR 9 R 10 , OR 11 , S.R. 9 , SO2NR 9 R 9 , SO2R 9 , CO2R 9 , C(O)R 9 ,CONR 9 R 9 and C1-C4-alkyl] It is a compound of R 1a may be C1-C4-alkyl, for example methyl.

[0025] In one embodiment, the compound of Formula (I) or (Ia) is (XVII): [ka] (XVII) [In the formula, R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8a , m, n and p are as defined above for compounds of formula (I) or (Ia). is a compound of

[0026] In one embodiment, the compound of Formula (I) or (Ia) is (XVIII): [ka] (XVIII) [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); R 1a are halo, nitro, cyano, NR 9 R 10 , OR 11 , S.R. 9 , SO2NR 9 R 9 , SO2R 9 , CO2R 9 , C(O)R 9 ,CONR 9 R 9 and C1-C4-alkyl. 1a may be C1-C4-alkyl, for example methyl.

[0027] The following embodiments apply to any compound of Formula (I)-(XVIII). These embodiments are independent and interchangeable. Any one embodiment may be combined with any other embodiment, where chemically permissible. In other words, any feature described in the following embodiments may be combined (where chemically permissible) with features described in one or more other embodiments. In particular, where a compound is exemplified or illustrated herein, any two or more of the embodiments listed below, expressed at any level of generality, including that compound, may be combined to provide further embodiments that form part of the present disclosure.

[0028] X 1 can be carbon. 2 can be carbon. 3 can be carbon. 1 and X 2 can both be carbon. 2 and X 3 can both be carbon. 1 and X 3 can both be carbon. 1 , X 2 and X 3 may each be carbon.

[0029] X 1 , X 2 and X 3 Only one of X can be nitrogen. 1 can be nitrogen. 2 can be nitrogen. 3 may be nitrogen.

[0030] X 4 can be carbon. 5 can be carbon. 6 can be carbon. 7 can be carbon. 4 and X 5 can both be carbon. 4 and X 6 can both be carbon. 4 and X7 can both be carbon. 5 and X 6 can both be carbon. 5 and X 7 can both be carbon. 6 and X 7 can both be carbon. 4 , X 5 and X 6 Each of X can be carbon. 4 , X 5 and X 7 Each of X can be carbon. 4 , X 6 and X 7 Each of X can be carbon. 5 , X 6 and X 7 Each of X can be carbon. 4 , X 5 , X 6 and X 7 may each be carbon.

[0031] X 4 , X 5 , X 6 and X 7 At least one of X may be nitrogen. 4 , X 5 , X 6 and X 7 Only one of X can be nitrogen. 5 can be nitrogen. 4 can be nitrogen. 4 , X 5 , X 6 and X 7 Two of the X's may be nitrogen. 4 and X 5 Each X may be nitrogen. 4 and X 7 Each X may be nitrogen. 5 and X 7 Each X may be nitrogen. 4 and X 6 may each be nitrogen.

[0032] X 8can be carbon. 9 can be carbon. 10 can be carbon. 11 can be carbon. 8 , X 9 , X 10 and X 11 may each be carbon.

[0033] X 8 , X 9 , X 10 and X 11 Only one of X can be nitrogen. 8 can be nitrogen. 9 can be nitrogen. 10 can be nitrogen. 11 may be nitrogen.

[0034] m can be 0. m can be 1. m can be 2. m can be 3. m can be 4.

[0035] R 1 each occurrence independently represents halo, nitro, cyano, OR 11 , C1-C4-alkyl, NR 9 R 10 C1-C4-alkyl substituted by OR 11 R may be selected from C-C-alkyl, C-C-haloalkyl and cyclopropyl substituted by 1 each occurrence independently represents halo, OR 11 , N.R. 9 R 10 , cyano, C1-C4-alkyl and C1-C4-haloalkyl. R 1 each occurrence independently represents halo, OR 11 , C1-C4-alkyl, C1-C4-haloalkyl and cyclopropyl. 1 R, at each occurrence, may be independently selected from halo and C-C-alkyl. 1 R, at each occurrence, may independently be halo, e.g., fluoro. 1may independently at each occurrence be C1-C4-alkyl, for example methyl.

[0036] m must be at least 1 and X 1 can be carbon and R 1 The base is X 1 m can be 1 and X 1 can be carbon and R 1 The base is X 1 It can be attached to carbon.

[0037] R 5 R may be independently selected from H, fluoro, and C-C-alkyl at each occurrence. 5 is, at each occurrence, independently selected from H, fluoro and C-C-alkyl, or two R 5 The groups and the carbon atoms to which they are attached may together form a C3-C6 cycloalkyl ring. 5 is, at each occurrence, independently selected from H and C-C-alkyl, or two R 5 The groups and the carbon atoms to which they are attached may, together, form a C3-C6 cycloalkyl ring. 5 may be independently selected at each occurrence from H and C1-C4-alkyl, such as methyl.

[0038] R 5 Each occurrence may be H. 5 R may be H in one occurrence and C-C-alkyl, e.g., methyl, in another occurrence. 5 Each occurrence may be C1-C4-alkyl, for example methyl.

[0039] n can be 0. n can be 1. n can be 2. n can be 3. n can be 4.

[0040] R 6 are independently halo, nitro, cyano, OR 11 , C1-C4-alkyl, NR 9R 10 C1-C4-alkyl substituted by OR 11 R may be selected from C-C-alkyl, C-C-haloalkyl and cyclopropyl substituted by 6 independently, halo, OR 11 , C1-C4-alkyl, C1-C4-haloalkyl and cyclopropyl. 6 may be independently selected from halo and C-C-alkyl. When present, R 6 R can be halo, e.g., fluoro. 6 may be C1-C4-alkyl, for example methyl.

[0041] p can be 0. p can be 1. p can be 2. p can be 3. p can be 4.

[0042] R 7 are independently halo, nitro, cyano, OR 11 , C1-C4-alkyl, NR 9 R 10 C1-C4-alkyl substituted by OR 11 R may be selected from C-C-alkyl, C-C-haloalkyl and cyclopropyl substituted by 7 independently, halo, OR 11 , C1-C4-alkyl, C1-C4-haloalkyl and cyclopropyl. 7 may be independently selected from halo and C-C-alkyl. When present, R 7 R can be halo, e.g., fluoro. 7 may be C1-C4-alkyl, for example methyl.

[0043] R 8a can be H. R 8a is halo, C1-C4-alkyl, NR 9 R 10 C1-C4-alkyl substituted by OR 11C-C-alkyl, C-C-haloalkyl and C-C-alkylene-R 8c R 8a R may be selected from halo, C-C-alkyl, C-C-haloalkyl and cyclopropyl. 8a may be selected from C-C-alkyl, C-C-haloalkyl and cyclopropyl. 8a may be selected from C1-C4-alkyl (e.g., methyl) and C1-C4-haloalkyl (e.g., CF3). 8a may be C1-C4-alkyl (e.g. methyl).

[0044] R 8c may be independently selected from C3-C6-cycloalkyl and 3- to 7-membered heterocycloalkyl; the heterocycloalkyl group is bonded to the C0-C4-alkylene via a carbon atom in the heterocycloalkyl ring; the cycloalkyl or heterocycloalkyl group may be bonded to the C0-C4-alkylene via a carbon atom in the heterocycloalkyl ring; 13 It may be optionally substituted by groups.

[0045] R 9 may be independently selected from H and C1-C4-alkyl at each occurrence.

[0046] R 10 R, at each occurrence, may be independently selected from H, C-C-alkyl, C(O)-C-C-alkyl and S(O)-C-C-alkyl. 10 may be independently selected from H and C1-C4-alkyl at each occurrence.

[0047] R 11 R, at each occurrence, may be independently selected from H, C-C-alkyl and C-C-haloalkyl. 11 R may be independently selected from H and C-C-alkyl at each occurrence. 11 may independently at each occurrence be C1-C4-alkyl, for example methyl.

[0048] R 12 may independently be a 5- or 6-membered heteroaryl, and the heteroaryl group may be a 5- or 6-membered heteroaryl group ... 14 R 12 may be independently selected from 5-membered heteroaryl, such as imidazole, and the heteroaryl group may be selected from 1 to 3 R 14 It may be optionally substituted by groups.

[0049] R 13 each occurrence independently represents oxo, fluoro, OR 11 , CO2R 9 , CO2NR 9 R 9 , C1-C4-alkyl, NR 9 R 10 C1-C4-alkyl substituted by OR 11 R may be selected from C-C-alkyl, C-C-haloalkyl and cyclopropyl substituted by 13 is independently, at each occurrence, oxo, OR 11 , C1-C4-alkyl and cyclopropyl. 13 R may be independently selected from oxo and C-C-alkyl at each occurrence. 13 may independently at each occurrence be C1-C4-alkyl, for example methyl.

[0050] R 14 each occurrence independently represents halo, nitro, cyano, OR 11 , C1-C4-alkyl, NR 8 R 9 C1-C4-alkyl substituted by OR 11 R may be selected from C-C-alkyl, C-C-haloalkyl and cyclopropyl substituted by 14 each occurrence independently represents halo, nitro, cyano, OR 11 , C1-C4-alkyl, NR 9 R10 C1-C4-alkyl substituted by OR 11 R may be selected from C-C-alkyl, C-C-haloalkyl and cyclopropyl substituted by 14 each occurrence independently represents halo, OR 11 , C1-C4-alkyl, C1-C4-haloalkyl and cyclopropyl. 14 R, at each occurrence, may be independently selected from halo and C-C-alkyl. 14 R, at each occurrence, may independently be halo, e.g., fluoro. 14 may independently at each occurrence be C1-C4-alkyl, for example methyl.

[0051] It can be: R 3 But H; R 4 are independently C1-C6-alkyl, C1-C6-haloalkyl, C0-C4-alkylene-R 4a Selected from;R 4a are independently selected from C3-C8-cycloalkyl, phenyl, 5-, 6-, 9- or 10-membered heteroaryl and 4- to 10-membered heterocycloalkyl; the heterocycloalkyl or heteroaryl group can be monocyclic or bicyclic; the cycloalkyl or heterocycloalkyl group can be substituted with one R 12 group and / or 1 to 4 R 13 group, and the phenyl or heteroaryl group is optionally substituted by one R 12 group and / or 1 to 3 R 14 optionally substituted by groups; Alternatively, R 3 and R 4 together with the nitrogen atom to which they are both attached form a 4- to 10-membered heterocycloalkyl group or a 5- or 9-membered heteroaryl group; and the heterocycloalkyl group is 12 group and / or 1 to 4 R 13The heteroaryl group may be optionally substituted by one R 12 group and / or 1 to 3 R 14 It may be optionally substituted by groups.

[0052] It can be: R 3 But H; R 4 are independently C1-C6-alkyl, C1-C6-haloalkyl, C0-C4-alkylene-R 4a Selected from;R 4a are independently selected from C3-C8-cycloalkyl, phenyl, 5-, 6-, 9- or 10-membered heteroaryl and 4- to 10-membered heterocycloalkyl; the heterocycloalkyl or heteroaryl group can be monocyclic or bicyclic; the cycloalkyl or heterocycloalkyl group is selected from 1 to 4 R 13 and the phenyl or heteroaryl group is optionally substituted by 1 to 3 R 14 optionally substituted by groups; Alternatively, R 3 and R 4 together with the nitrogen atom to which they are both attached form a 4- to 10-membered heterocycloalkyl group or a 5- or 9-membered heteroaryl group; and the heterocycloalkyl group is 13 and the heteroaryl group is optionally substituted by 1 to 3 R 14 It may be optionally substituted by groups.

[0053] R 3 can be H.

[0054] R 4 represents C1-C6-alkyl, C1-C6-haloalkyl and C0-C4-alkylene-R 4a may be selected from 。

[0055] R 4R may be selected from C-C-alkyl and C-C-haloalkyl. 4 R may be selected from C2-C3-alkyl and C2-C3-haloalkyl. 4 R can be C-C-haloalkyl. 4 R can be C-C-haloalkyl. 4 can be 2,2,2-trifluoroethyl.

[0056] Illustrative R 4 As a base, [ka] Examples include:

[0057] R 4 is C0-C4-alkylene-R 4a It can be. R 4 is CH2-R 4a It can be. R 4 is R 4a It could be.

[0058] R 4a may be independently selected from C3-C8-cycloalkyl, phenyl, 5-, 6-, 9- or 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, wherein the heterocycloalkyl or heteroaryl group may be monocyclic or bicyclic; the cycloalkyl or heterocycloalkyl group may be selected from 1 to 4 R 13 The phenyl or heteroaryl group may be optionally substituted by 1 to 3 R 14 It may be optionally substituted by groups.

[0059] R 4a may be selected from C3-C8-cycloalkyl and 4- to 10-membered heterocycloalkyl, and the cycloalkyl or heterocycloalkyl group may be selected from one R 12 group and / or 1 to 4 R 13 R 4amay be selected from C3-C8-cycloalkyl and 4- to 10-membered heterocycloalkyl, and the cycloalkyl or heterocycloalkyl group may be selected from 1 to 4 R 13 It may be optionally substituted by groups.

[0060] R 4 may be selected from CH2-C3-C8-cycloalkyl and CH2-4 to 10-membered heterocycloalkyl, and the cycloalkyl or heterocycloalkyl group may be selected from one R 12 group and / or 1 to 4 R 13 R 4 may be selected from CH2-C3-C8-cycloalkyl and CH2-4 to 10-membered heterocycloalkyl, and the cycloalkyl or heterocycloalkyl group may be selected from 1 to 4 R 13 It may be optionally substituted by groups.

[0061] R 4 may be selected from C3-C8-cycloalkyl and 4- to 10-membered heterocycloalkyl, and the cycloalkyl or heterocycloalkyl group may be selected from one R 12 group and / or 1 to 4 R 13 R 4 may be selected from C3-C8-cycloalkyl and 4- to 10-membered heterocycloalkyl, and the cycloalkyl or heterocycloalkyl group may be selected from 1 to 4 R 13 It may be optionally substituted by groups.

[0062] Illustrative R 4 As a base, [ka] Examples include:

[0063] R 4a may be independently selected from phenyl and 5- or 6-membered heteroaryl; the phenyl or heteroaryl group may be selected from one R 12group and / or 1 to 3 R 14 R 4a may be independently selected from phenyl and 5- or 6-membered heteroaryl; the phenyl or heteroaryl group may be selected from 1 to 3 R 14 R 4a may independently be phenyl; the phenyl group may be selected from one R 12 group and / or 1 to 3 R 14 R 4a may independently be phenyl; the phenyl group may be selected from 1 to 3 R 14 R 4a may independently be a 5- or 6-membered heteroaryl; the heteroaryl group may be a 5- or 6-membered heteroaryl; 12 group and / or 1 to 3 R 14 R 4a may independently be a 5- or 6-membered heteroaryl; the heteroaryl group may be a 5- or 6-membered heteroaryl; 14 It may be optionally substituted by groups.

[0064] R 4 may independently be CH2-phenyl or CH2-5- or 6-membered heteroaryl, and the phenyl or heteroaryl group is selected from the group consisting of one R 12 group and / or 1 to 3 R 14 R 4 may independently be CH2-phenyl or CH2-5- or 6-membered heteroaryl, and the phenyl or heteroaryl group may be selected from 1 to 3 R 14 R 4 may independently be CH-phenyl, and the phenyl may be selected from one R 12 group and / or 1 to 3 R 14 R 4 may independently be CH-phenyl, and the phenyl group may be selected from 1 to 3 R 14R 4 CH can independently be a 5- or 6-membered heteroaryl, and the heteroaryl group is selected from one R 12 group and / or 1 to 3 R 14 R 4 CH can independently be a 5- or 6-membered heteroaryl, and the heteroaryl group is selected from 1 to 3 R 14 It may be optionally substituted by groups.

[0065] R 4 may be independently selected from phenyl or 5- or 6-membered heteroaryl, and the phenyl or heteroaryl group is selected from one R 12 group and / or 1 to 3 R 14 R 4 may be independently selected from phenyl or 5- or 6-membered heteroaryl, and the phenyl or heteroaryl group may be selected from 1 to 3 R 14 R 4 may independently be phenyl, and the phenyl group may be selected from one R 12 group and / or 1 to 3 R 14 R 4 may independently be phenyl, and the phenyl group may be selected from 1 to 3 R 14 R 4 may independently be a 5- or 6-membered heteroaryl, and the heteroaryl group is 12 group and / or 1 to 3 R 14 R 4 may independently be a 5- or 6-membered heteroaryl, and the heteroaryl group may be a 5- or 6-membered heteroaryl group ... 14 It may be optionally substituted by groups.

[0066] R 4may be independently selected from phenyl or 6-membered heteroaryl, and the phenyl or 6-membered heteroaryl group is provided with one R at the meta position. 14 substituted by the R group. 14 The group is OR 11 The meta R may be selected from C-C-alkyl, C-C-alkyl and C-C-haloalkyl substituted by 14 The group is OR 11 The meta R may be C-C-alkyl substituted with, for example, —(CH)—OH. 14 The group may be C1-C4-haloalkyl, for example CF3.

[0067] R 4 R can be a six-membered heteroaryl group. 4 R can be phenyl. 4 is one R at the meta position 14 It may be phenyl substituted by a group. R 14 is R 14a An exemplary R 4 As a base, [ka] [In the formula, R 14a are halo, nitro, cyano, NR 8 R 9 , OR 10 , S.R. 8 , SO2R 8 , SO2NR 8 R 8 , CO2R 8 , C(O)R 8 ,CONR 8 R 8 , C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl, OR 11 C1-C4-alkyl substituted by NR 8 R 9 and cyclopropyl, substituted by: Examples include:

[0068] R 4 R can be a six-membered heteroaryl group. 4 R can be phenyl. 4 is one R at the meta position 14 It may be phenyl substituted by a group. R 14 is R 14a An exemplary R 4 As a base, [ka] [In the formula, R 14a are halo, nitro, cyano, NR 9 R 10 , OR 11 , S.R. 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, OR 11 C1-C4-alkyl substituted by NR 9 R 10 and cyclopropyl, substituted by: Examples include:

[0069] Illustrative R 4 As a base, [ka] Examples include:

[0070] R 3 and R 4 may be taken together with the nitrogen atom to which they are both attached to form a 4- to 10-membered heterocycloalkyl group or a 5- or 9-membered heteroaryl group; the heterocycloalkyl group may be taken together with one R 12 group and / or 1 to 4 R13 The heteroaryl group may be optionally substituted by one R 12 group and / or 1 to 3 R 14 R 3 and R 4 may be taken together with the nitrogen atom to which they are both attached to form a 4- to 10-membered heterocycloalkyl group or a 5- or 9-membered heteroaryl group; the heterocycloalkyl group may be selected from 1 to 4 R 13 The heteroaryl group may be optionally substituted by 1 to 3 R 14 It may be optionally substituted by groups.

[0071] R 3 and R 4 can be taken together with the nitrogen atom to which they are both attached to form a 5- or 9-membered heteroaryl group; a heteroaryl group can be formed by one R 12 group and / or 1 to 3 R 14 R 3 and R 4 can be taken together with the nitrogen atom to which they are both attached to form a 5- or 9-membered heteroaryl group; the heteroaryl group can be comprised of 1 to 3 R 14 R 3 and R 4 can be taken together with the nitrogen atom to which they are both attached to form a 5-membered heteroaryl group; a heteroaryl group can be formed by one R 12 group and / or 1 to 3 R 14 R 3 and R 4 can be taken together with the nitrogen atom to which they are both attached to form a 5-membered heteroaryl group; the heteroaryl group can be composed of 1 to 3 R 14 It may be optionally substituted by groups.

[0072] Exemplary NR 3 R 4 As a base, [ka] Examples include:

[0073] R 3 and R 4 may be taken together with the nitrogen atom to which they are both attached to form a 4- to 10-membered heterocycloalkyl group; the heterocycloalkyl group may be formed by one R 12 group and / or 1 to 4 R 13 R 3 and R 4 may be taken together with the nitrogen atom to which they are both attached to form a 4- to 10-membered heterocycloalkyl group; the heterocycloalkyl group may be comprised of 1 to 4 R 13 The heterocycloalkyl group may be optionally substituted by a group. The heterocycloalkyl group may be a 7- to 10-membered bicyclic heterocycloalkyl group. The heterocyclic group may be a 7- to 10-membered bridged bicyclic heterocycloalkyl group. The heterocyclic group may be a monocyclic 4- to 7-membered heterocycloalkyl group. The heterocyclic group may be a monocyclic 5- to 6-membered heterocycloalkyl group. The heterocyclic group may be pyrrolidine. The heterocyclic group may be piperidine. The heterocyclic group may be morpholine. The heterocyclic group may be piperazine. For the avoidance of doubt, the heterocycloalkyl group referred to at this stage is a group consisting of one R 12 group and / or 1 to 4 R 13 The heterocycloalkyl group referred to in this step may be optionally substituted by 1 to 4 R groups. 13 The heterocyclic group may be pyrrolidine, optionally substituted with one R 13 The heterocyclic group may be pyrrolidine, substituted with one R group at the 3-position. 13 The heterocyclic group may be piperidine and may be substituted with one R group at the 2-position. 13 The heterocyclic group may be piperidine and may be substituted with one R group at the 3-position. 13The heterocyclic group may be piperidine and may be substituted with one R group at the 4-position. 13 The heterocyclic group may be morpholine and may be substituted with one R group at the 2-position. 13 The heterocyclic group may be morpholine and may be substituted with one R group at the 3-position. 13 may be substituted by a group. 13 The group is C1-C4-alkyl, OR 11 may be selected from C1-C4-alkyl substituted by, for example -(CH3)2-OH, and C1-C4-haloalkyl, for example -CF3.

[0074] Exemplary NR 3 R 4 As a base, [ka] Examples include:

[0075] R 3 and R 4 is NR 3 R 4 may be selected to contain a CHF2 or CF3 group.

[0076] NR 3 R 4 is the expression: [ka] [In the formula, a is an integer selected from 1 and 2; R 4b each, if present, is selected from H and F; at least one R 4b The group is F; R 3a is independently selected from H and C1-C4-alkyl; R 4c is independently selected at each occurrence from H, C1-C4-alkyl and C4-C6-cycloalkyl; or R 3a and one R 4ctogether with the carbon and nitrogen to which they are attached form a 4- to 6-membered heterocycloalkyl group. may have:

[0077] a can be 1. a can be 2.

[0078] NR 3 R 4 is the expression: [ka] [In the formula, R 4b each, if present, is selected from H and F; at least one R 4b The group is F; R 3a is independently selected from H and C1-C4-alkyl; R 4c are independently selected from H, C1-C4-alkyl and C4-C6-cycloalkyl; or R 3a and R 4c together with the carbon and nitrogen to which they are attached form a 4- to 6-membered heterocycloalkyl group. may have:

[0079] At least two R 4b The group can be F. Two R 4b The group can be F and one R 4b The group can be H. Each R 4b The group can be F.

[0080] R 3a can be H.

[0081] R 3a is independently selected from H and C1-C4-alkyl; R 4c may be independently selected from H, C-C-alkyl and C-C-cycloalkyl. 3a can be H;R 4cmay be independently selected from H, C1-C4-alkyl and C4-C6-cycloalkyl. The alkyl or cycloalkyl group may be unsubstituted.

[0082] R 4c R, when present, may be selected from C-C-alkyl (e.g., methyl) and H. 4c Each occurrence may be H.

[0083] R 3a and R 4c R can be taken together with the carbon and nitrogen to which they are attached to form a 4- to 6-membered heterocycloalkyl group. 3a and R 4c R may, together with the carbon and nitrogen to which they are attached, form a 5-membered heterocycloalkyl group. 3a and R 4c can be taken together with the carbon and nitrogen to which they are attached to form a 6-membered heterocycloalkyl group, which can be unsubstituted.

[0084] The compound of formula (I) [ka] [ka] [ka] may be selected from:

[0085] The compound of formula (I) [ka] [ka] [ka] [ka] [ka] [ka] may be selected from:

[0086] In one aspect of the invention, there is provided a compound of the invention for use as a pharmaceutical.

[0087] According to another aspect, there is provided a compound of the present invention for use in treating a condition regulated by DDR1 and / or DDR2. The compound of any formula disclosed herein may be for use in treating a condition treatable by a disorder of DDR1 and / or DDR2.

[0088] In another aspect of the present invention, there is provided a compound of the present invention for use in the treatment of a disease or disorder selected from a renal condition, a hepatic condition, an inflammatory condition, a cardiovascular condition, acute and chronic organ transplant rejection, a fibrotic disease and cancer.

[0089] In one embodiment of the present invention, there is provided a method of treating a disease or disorder modulated by DDR1 and / or DDR2, the method comprising administering to a patient in need thereof a therapeutic amount of a compound of the present invention.

[0090] The method of treatment can be a method of treating a condition treatable by inhibition of DDR1 and / or DDR2.

[0091] The present invention also provides a method of treating a disease or disorder selected from a renal condition, a hepatic condition, an inflammatory condition, a cardiovascular condition, acute and chronic organ transplant rejection, a fibrotic disease, and cancer, the method comprising administering to a patient in need thereof a therapeutic amount of a compound of any of the formulas disclosed herein.

[0092] Renal conditions include acute kidney injury and chronic kidney disease with or without proteinuria, including end-stage renal disease (ESRD), including reduced creatinine clearance and reduced glomerular filtration rate, microalbuminuria, albuminuria and proteinuria, glomerulosclerosis with expansion of the plexiform mesangial matrix with or without significant cellular hyperplasia (particularly diabetic nephropathy and amyloidosis), focal thrombosis of glomerular capillaries (particularly thrombotic microangiopathy), global fibrinoid necrosis, ischemic lesions, malignant nephrosclerosis (e.g., ischemic regression, reduced renal blood flow and renal arteriopathy), swelling and proliferation of intracapillary (endothelial and mesangial) and / or extracapillary cells (crescents) as in glomerulonephritis entities, focal segmental glomerulosclerosis, IgA nephropathy, vasculitis / systemic disease, and acute and chronic kidney graft rejection. Early and advanced Alport syndrome are also included in the renal conditions.

[0093] Inflammatory conditions include arthritis, osteoarthritis, multiple sclerosis, systemic lupus erythematosus, inflammatory bowel disease, abnormal elimination disorders, etc., as well as inflammatory airway diseases such as idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD) or chronic asthma. Further conditions of the respiratory system include iatrogenic drug-induced fibrosis, occupational and / or environmentally induced fibrosis, systemic diseases and other diffuse parenchymal lung diseases of various etiologies, including vasculitis, granulomatous diseases (sarcoidosis, hypersensitivity pneumonitis), collagen vascular diseases, radiation-induced fibrosis.

[0094] Vascular conditions include atherosclerosis, thrombotic vascular disease and thrombotic microangiopathy, proliferative arteriopathy (e.g., swollen myointimal cells and nodular thickening surrounded by a mucous extracellular matrix), atherosclerosis, decreased vascular compliance (e.g., stiffness, decreased ventricular compliance and decreased vascular compliance), endothelial dysfunction, and the like.

[0095] Cardiovascular conditions include acute coronary syndromes, coronary heart disease, myocardial infarction, arterial and pulmonary hypertension, cardiac arrhythmias such as atrial fibrillation, stroke and other vascular injuries.

[0096] Fibrotic diseases include, but are not limited to, myocardial and vascular fibrosis, renal fibrosis, hepatic fibrosis, pulmonary fibrosis, skin fibrosis, scleroderma and encapsulating peritonitis, systemic sclerosis, Alport syndrome, chronic kidney disease, NASH, interstitial lung disease, and systemic sclerosis.

[0097] In certain embodiments, the compound of the present invention is for use in the treatment of cancer or is used in the method of treating cancer.Examples include but are not limited to liver cancer, bladder cancer, hepatocellular carcinoma, squamous cell carcinoma of the lung, non-small cell lung cancer, adenocarcinoma of the lung, small cell lung cancer, various types of head and neck cancer, breast cancer, colon cancer, colorectal cancer, peritoneal cancer, hepatocellular carcinoma, digestive cancer, esophageal cancer, endometrial 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, cancer is selected from bladder cancer, pancreatic cancer, breast cancer, lung cancer, ovarian cancer and glioblastoma.

[0098] In another aspect of the present invention, there is provided a composition comprising a compound of the present invention and a pharmaceutically acceptable excipient.

[0099] In one embodiment, the pharmaceutical composition may be a combination preparation further comprising a pharmaceutically active substance.

[0100] In one aspect of the invention, there is provided the use of a compound of the invention in the manufacture of a medicament for use in the treatment of any of the conditions disclosed herein.

[0101] The present invention can also be defined according to the following numbered clauses: 1. Formula (I): [ka] (I) [In the formula, X 1 , X 2 and X 3are each independently selected from carbon and nitrogen; X 1 , X 2 and X 3 at least two of are carbon; X 4 , X 5 , X 6 and X 7 are each independently selected from carbon and nitrogen; X 4 , X 5 , X 6 and X 7 at least two of are carbon; X 8 , X 9 , X 10 and X 11 are each independently selected from carbon and nitrogen; X 8 , X 9 , X 10 and X 11 at least two of are carbon; R 1 each occurrence independently represents halo, nitro, cyano, NR 9 R 10 , OR 11 , S.R. 9 , SO2NR 9 R 9 , SO2R 9 , CO2R 9 , C(O)R 9 ,CONR 9 R 9 , C1-C4-alkyl, NR 9 R 10 C1-C4-alkyl substituted by OR 11 C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and cyclopropyl, substituted by; R 3 is independently selected from H and C1-C4-alkyl; R 4 are independently C1-C6-alkyl, C1-C6-haloalkyl, C0-C4-alkylene-R 4a Selected from;R 4aare independently selected from C3-C8-cycloalkyl, phenyl, 5-, 6-, 9- or 10-membered heteroaryl and 4- to 10-membered heterocycloalkyl; the heterocycloalkyl or heteroaryl group can be monocyclic or bicyclic; the cycloalkyl or heterocycloalkyl group can be selected from one R 12 group and / or 1 to 4 R 13 The phenyl or heteroaryl group may be optionally substituted by one R 12 group and / or 1 to 3 R 14 optionally substituted by groups; Alternatively, R 3 and R 4 together with the nitrogen atom to which they are both attached form a 4- to 10-membered heterocycloalkyl group or a 5- or 9-membered heteroaryl group; the heterocycloalkyl or heteroaryl group can be monocyclic or bicyclic; the heterocycloalkyl group can be a 4- to 10-membered heterocycloalkyl group or a 5- or 9-membered heteroaryl group ... 12 group and / or 1 to 4 R 13 The heteroaryl group may be optionally substituted by one R 12 group and / or 1 to 3 R 14 optionally substituted by groups; R 5 is, at each occurrence, independently selected from H, halo and C-C-alkyl, or two R 5 the groups and the carbon atoms to which they are attached together form a C3-C6 cycloalkyl ring; R 6 each occurrence independently represents halo, nitro, cyano, NR 9 R 10 , OR 11 , S.R. 9 , SO2NR 9 R 9 , SO2R 9 , CO2R 9 , C(O)R 9 ,CONR 9 R 9 , C1-C4-alkyl, NR 9 R 10C1-C4-alkyl substituted by OR 11 C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and cyclopropyl, substituted by; R 7 each occurrence independently represents halo, nitro, cyano, NR 9 R 10 , OR 11 , S.R. 9 , SO2NR 9 R 9 , SO2R 9 , CO2R 9 , C(O)R 9 ,CONR 9 R 9 , C1-C4-alkyl, NR 9 R 10 C1-C4-alkyl substituted by OR 11 C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and cyclopropyl, substituted by; R 8a are independently H, halo, nitro, cyano, NR 9 R 10 , OR 11 , S.R. 9 , SO2NR 9 R 9 , SO2R 9 , CO2R 9 , C(O)R 9 ,CONR 9 R 9 , C1-C4-alkyl, NR 9 R 10 C1-C4-alkyl substituted by OR 11 C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and C0-C4-alkylene-R 8c Selected from; R 8care independently selected from C3-C6-cycloalkyl and 3- to 7-membered heterocycloalkyl; the heterocycloalkyl group is bonded to the C0-C4-alkylene via a carbon atom in the heterocycloalkyl ring; the cycloalkyl or heterocycloalkyl group is bonded to the C0-C4-alkylene via a carbon atom in the heterocycloalkyl ring; 13 optionally substituted by groups; R 9 is, at each occurrence, independently selected from H and C-C-alkyl; or two R 9 The groups, together with the nitrogen atom to which they are attached, can consist of 0 to 4 R 13 forming a C5-C8-heterocycloalkyl group, which may be optionally substituted by a group; R 10 is, at each occurrence, independently selected from H, C-C-alkyl, C(O)-C-C-alkyl and S(O)-C-C-alkyl; or R 9 and R 10 together with the nitrogen atom to which they are attached, form 0 to 4 R 13 forming a C5-C8-heterocycloalkyl group, which may be optionally substituted by a group; R 11 is, at each occurrence, independently selected from H, C-C-alkyl, C(O)-C-C-alkyl and C-C-haloalkyl; R 12 teeth 、 independently selected from C3-C6-cycloalkyl, phenyl, 5- or 6-membered heteroaryl and 3- to 6-membered heterocycloalkyl; said cycloalkyl or heterocycloalkyl group may be selected from 1 to 4 R 13 The phenyl or heteroaryl group may be optionally substituted by 1 to 3 R 14 optionally substituted by groups; R 13 each occurrence independently represents ═O, halo, nitro, cyano, NR 8 R 9 , OR 14 , S.R. 8 , SO2NR 8R 8 , CO2R 8 , C(O)R 8 ,CONR 8 R 8 , C1-C4-alkyl, OR 11 C1-C4-alkyl substituted by NR 9 R 10 C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl, C6-C 10 - selected from aryl and C3-C6-cycloalkyl; R 14 each occurrence independently represents halo, nitro, cyano, NR 8 R 9 , OR 10 , S.R. 8 , SO2R 8 , SO2NR 8 R 8 , CO2R 8 , C(O)R 8 ,CONR 8 R 8 , C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl, OR 11 C1-C4- alkyl, NR 8 R 9 C1-C4-alkyl and cyclopropyl substituted by; 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; Any of the above alkyl, alkylene or cyclopropyl groups may, where chemically possible, be selected from halo, oxo, fluoro, nitro, cyano, NR a R b , OR a , S.R. a , CO2R a , C(O)R a ,CONR a R a, optionally substituted by 1 to 5 substituents each independently selected, at each occurrence, from the group consisting of C-C-alkyl, C-C-haloalkyl and cyclopropyl; R a is, at each occurrence, independently selected from H, C-C-alkyl and C-C-haloalkyl; and R b is, each occurrence independently, selected from H, C1-C4-alkyl, C(O)-C1-C4-alkyl and S(O)2-C1-C4-alkyl. or a pharmaceutically acceptable salt thereof. 2. The compound according to item 1, wherein m is 0 or 1. 3. m is at least 1 and X 1 is carbon and R 1 The group is X 1 Item 1. The compound according to item 1, wherein the carbon atom is bonded to the compound. 4. The compound according to any one of items 1 to 3, wherein n is 0 or 1. 5. The compound according to any one of items 1 to 4, wherein p is 0 or 1. 6. R 5 and each, when present, is H. The compound according to any one of items 1 to 5. 7. R 8a is selected from H and C1-C4-alkyl. 8. X 1 , X 2 and X 3 and each represent a carbon atom. 9. X 8 , X 9 , X 10 and X 11 and each represent a carbon atom. 10. X 4 , X 5 , X 6 and X 7 and each represent a carbon atom. 11. X 4 , X 5 , X6 and X 7 Item 10. The compound according to any one of items 1 to 9, wherein at least one of is nitrogen. 12. NR 3 R 4 but, has the expression [ka] [In the formula, a is an integer selected from 1 and 2; R 4b each, if present, is selected from H and F; at least one R 4b The group is F; R 3a is independently selected from H and C1-C4-alkyl; R 4c is independently, at each occurrence, selected from H, C1-C4-alkyl and C4-C6-cycloalkyl; or R 3a and one R 4c together with the carbon and nitrogen to which they are attached form a 4- to 6-membered heterocycloalkyl group. Item 12. The compound according to any one of items 1 to 11, having the following structure: 13. The compound according to item 12, wherein a is 1. 14. At least two R's 4b Item 14. The compound according to item 12 or 13, wherein the group is F. 15. R 3a 15. The compound according to any one of items 12 to 14, wherein is H. 16. R 4c 16. The compound according to any one of items 12 to 15, wherein is selected from H and C1-C4-alkyl. 17. R 3a and R 4c together with the carbon and nitrogen to which they are attached form a 4- to 6-membered heterocycloalkyl group. 18. The compound of formula (I) [ka] [ka] [ka] The compound according to item 1, selected from: 19. A pharmaceutical formulation comprising the compound according to any one of items 1 to 18 and a pharmaceutically acceptable excipient. 20. The compound according to any one of items 1 to 18 for use as a pharmaceutical. 21. For use in the treatment of a disease or disorder selected from a renal condition, a hepatic condition, an inflammatory condition, a cardiovascular condition, acute and chronic organ transplant rejection, fibrotic disease and cancer.

[0102] Detailed Description The following are definitions of terms used in this application: Any term not defined herein has the ordinary meaning that one of ordinary skill in the art would understand that term.

[0103] The term "halo" refers to one of the halogens in Group 17 of the periodic table. In particular, the term refers to fluorine, chlorine, bromine, and iodine. Preferably, the term refers to chlorine or fluorine.

[0104] 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, e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, and n-hexyl. "Alkylene" groups can likewise be straight or branched and are divalent, i.e., bonded to the other position of the molecule at two positions. Furthermore, an alkylene group can correspond, for example, to one of the alkyl groups listed in this paragraph. Alkyl and alkylene groups can be unsubstituted or substituted with one or more substituents.

[0105] The term "haloalkyl" refers to a hydrocarbon chain substituted with at least one halogen atom, each occurring independently selected from, for example, fluorine, chlorine, bromine, and iodine. For example, the term "C 1-6 "Haloalkyl" refers to a straight or branched straight or branched hydrocarbon chain containing 1, 2, 3, 4, 5, or 6 carbon atoms substituted with at least one halogen. The halogen atom can be located at any position on the hydrocarbon chain. For example, C 1-6 Haloalkyl can refer to chloromethyl, fluoromethyl, trifluoromethyl, chloroethyl, such as 1-chloromethyl and 2-chloroethyl, trichloroethyl, such as 1,2,2-trichloroethyl, 2,2,2-trichloroethyl, fluoroethyl, such as 1-fluoromethyl and 2-fluoroethyl, trifluoroethyl, such as 1,2,2-trifluoroethyl and 2,2,2-trifluoroethyl, chloropropyl, trichloropropyl, fluoropropyl, trifluoropropyl. The term "fluoroalkyl" refers to a hydrocarbon chain substituted with at least one fluorine atom.

[0106] The term "alkenyl" refers to a branched or straight hydrocarbon chain containing at least one double bond. For example, the term "C 2-6 "Alkenyl" refers to a branched or straight hydrocarbon chain containing at least one double bond and having 2, 3, 4, 5, or 6 carbon atoms. The double bond may exist as an E or Z isomer. The double bond may be in any available position on the hydrocarbon chain. For example, "C 2-6 "Alkenyl" can be ethenyl, propenyl, butenyl, butadienyl, pentenyl, pentadienyl, hexenyl and hexadienyl.

[0107] The term "alkynyl" refers to a branched or straight hydrocarbon chain containing at least one triple bond. For example, the term "C 2-6 "Alkynyl" refers to a branched or straight hydrocarbon chain containing at least one triple bond and having 2, 3, 4, 5, or 6 carbon atoms. The triple bond may be in any available position on the hydrocarbon chain. For example, "C2-6 "Alkynyl" can be ethynyl, propynyl, butynyl, pentynyl and hexynyl.

[0108] The term "heteroalkyl" refers to a branched or straight-chain hydrocarbon chain containing at least one heteroatom selected from N, O, and S positioned between any carbon atoms in the chain or at any terminus of the chain. For example, the term "C 1-6 "Heteroalkyl" refers to a branched or straight-chain hydrocarbon chain containing 1, 2, 3, 4, 5, or 6 carbon atoms and at least one heteroatom selected from N, O, and S, positioned between any carbon atoms in the chain or at a terminal end of the chain. For example, the hydrocarbon chain can contain one or two heteroatoms. 1-6 A heteroalkyl can be attached to the remainder of the molecule through a carbon or heteroatom. For example, "C 1-6 "Heteroalkyl" is C 1-6 N-Alkyl, C 1-6 N,N-alkyl, or C 1-6 It can be O-alkyl.

[0109] The term "heterocycle" refers to a saturated, unsaturated, or aromatic ring system containing at least one heteroatom selected from N, O, or S. A "heterocyclic" system can contain 1, 2, 3, or 4 heteroatoms, e.g., 1 or 2. A "heterocyclic" system can be a monocyclic or fused polycyclic ring system, e.g., bicyclic or tricyclic. A "heterocyclic" moiety can contain 3 to 14 carbon atoms, e.g., 3 to 8 carbon atoms for a monocyclic system, and 7 to 14 carbon atoms for a polycyclic system. "Heterocyclic" encompasses heterocycloalkyl, heterocycloalkenyl, and heteroaryl moieties. Examples of heterocyclic groups include oxirane, aziridine, azetidine, oxetane, tetrahydrofuran, pyrrolidine, imidazolidine, succinimide, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, piperidine, morpholine, thiomorpholine, piperazine, and tetrahydropyran. Heteroaryl includes groups such as pyridone and N-alkyl-pyridone.

[0110] The term “C 3-8 "Cycloalkyl" refers to a saturated hydrocarbon ring system containing 3, 4, 5, 6, 7, or 8 carbon atoms. For example, "C 3-8 "Cycloalkyl" can be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

[0111] The term “C 3-8 "Cycloalkenyl" refers to an unsaturated hydrocarbon ring system containing 3, 4, 5, 6, 7, or 8 carbon atoms that is not aromatic. The ring may contain more than one double bond, provided that the ring is not aromatic. For example, "C 3-8 "Cycloalkyl" can be cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadiene, cyclooctenyl and cycloatadienyl.

[0112] The term "heterocycloalkyl" refers to a saturated hydrocarbon ring system containing carbon atoms and at least one heteroatom in the ring selected from N, O, and S. For example, there can be 1, 2, or 3 heteroatoms, optionally 1 or 2. A "heterocycloalkyl" can be attached to the rest of the molecule through any carbon atom or heteroatom. A "heterocycloalkyl" can have one or more bonds, for example, 1 or 2 bonds, to the rest of the molecule, and these bonds can be through any of the atoms in the ring. For example, a "heterocycloalkyl" can be "C 3-8 The term "C" may be a heterocycloalkyl. 3-8"Heterocycloalkyl" refers to a saturated hydrocarbon ring system containing 3, 4, 5, 6, 7, or 8 atoms, wherein at least one heteroatom in the ring is selected from N, O, and S. "Heterocycloalkyl" can be oxirane, aziridine, azetidine, oxetane, tetrahydrofuran, pyrrolidine, imidazolidine, succinimide, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, piperidine, morpholine, thiomorpholine, piperazine, and tetrahydropyran.

[0113] The term "aromatic," when applied to a substituent as a whole, means a monocyclic or polycyclic ring system having 4n+2 electrons in a conjugated pi system within the ring or ring system, where all atoms contributing to the conjugated pi system lie in the same plane.

[0114] The term "aryl" refers to an aromatic hydrocarbon ring system. The ring system has 4n+2 electrons in a conjugated π system, where all atoms contributing to the conjugated π system are on the same plane. For example, "aryl" can be phenyl and naphthyl. The aryl system itself can be substituted with other groups.

[0115] The term "heteroaryl" refers to an aromatic hydrocarbon ring system having at least one heteroatom selected from O, N, and S in a ring or fused ring system. The ring or ring system has 4n+2 electrons in a conjugated π system, where all atoms contributing to the conjugated π system are on the same plane. For example, "heteroaryl" can be imidazole, oxazole, isoxazole, thiazole, isothiazole, thien, furan, thianthrene, pyrrole, benzimidazole, pyrazole, pyrazine, pyridine, pyrimidine, and indole.

[0116] [ka] A bond terminating in a (-) indicates that the bond is connected to another atom not shown in the figure. A bond terminating within a ring structure and not at an atom of the ring structure indicates that the bond may be connected to any atom, if valence allows.

[0117] Bonds drawn as solid and dotted lines represent bonds that may be either single or double bonds, where chemically possible. For example, the bond drawn below may be a single or double bond. [ka]

[0118] When a moiety is substituted, it can be substituted at any position on the moiety, provided that it is chemically feasible and consistent with valence requirements. The moiety can be substituted with one or more substituents, for example, 1, 2, 3, or 4 substituents; optionally, 1 or 2 substituents on a group. When there are two or more substituents, the substituents can be the same or different.

[0119] Substituents are present only at chemically possible positions, and one skilled in the art can determine (experimentally or theoretically) without undue effort which substitutions are chemically possible and which substitutions are not possible.

[0120] Ortho, meta, and para substitution are terms well understood in the art. For the avoidance of doubt, "ortho" substitution refers to a substitution pattern in which, in the case of a single group (e.g., a fluoro group in the example below), adjacent carbons bear substituents; [ka] Other positions on the molecule are indicated by bonds ending in . [ka]

[0121] A "meta" substitution is a substitution pattern in which two substituents are one carbon away from each other, i.e., there is one carbon atom between the substituted carbons. In other words, the substituent is on a second atom away from an atom bearing another substituent. For example, the following group is meta-substituted: [ka]

[0122] "Para" substitution is a substitution pattern in which two substituents are two carbon atoms apart from each other, i.e., there are two carbon atoms between the substituted carbons. In other words, there is a substituent on a third atom away from an atom bearing another substituent. For example, the following group is para-substituted: [ka]

[0123] Throughout this specification, disclosure of compounds also encompasses pharmaceutically acceptable salts, solvates, and stereoisomers thereof.

[0124] If a compound has a stereocenter, both the (R) and (S) stereoisomers are contemplated by the present invention, and mixtures of stereoisomers or racemic mixtures are also contemplated by the present application. If a compound of the present invention has more than one stereoisomer, any combination of the (R) and (S) stereoisomers is contemplated. Combinations of the (R) and (S) stereoisomers may result in diastereomeric mixtures or single diastereoisomers. The compounds of the present invention may exist as a single stereoisomer or as a mixture of stereoisomers, such as racemic mixtures and other enantiomeric mixtures, and diastereomeric mixtures. If the mixture is a mixture of enantiomers, the enantiomeric excess may be any of those disclosed above. If the compound is a single stereoisomer, the compound may contain other diastereoisomers or enantiomers as impurities. Thus, a single stereoisomer does not necessarily have 100% enantiomeric excess (ee) or diastereomeric excess (de), but may have an ee or de of at least 85%, at least 60%, or less. For example, the ee or de can be 90% or greater, 90% or greater, 80% or greater, 70% or greater, 60% or greater, 50% or greater, 40% or greater, 30% or greater, 20% or greater, or 10% or greater.

[0125] The present invention contemplates pharmaceutically acceptable salts of the compounds of the present invention. These may include acid addition salts and base salts of the compounds. These may be acid addition salts and base salts of the compounds. The present invention also contemplates solvates of the compounds. These may be hydrates or other solvate forms of the compounds.

[0126] Suitable acid addition salts are formed from acids which form non-toxic salts, examples of which include acetate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate / sulfate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hybenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, methionine, methylpropional ... Salts include nitrate, methylsulfate, naphthylate, 1,5-naphthalenedisulfonate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrogenphosphate, saccharate, stearate, succinate, tartrate, tosylate and trifluoroacetate.

[0127] Suitable base salts are formed from bases that form non-toxic salts. Examples include aluminum salt, arginine salt, benzathine salt, calcium salt, choline salt, diethylamine salt, diolamine salt, glycine salt, lysine salt, magnesium salt, meglumine salt, olamine salt, potassium salt, sodium salt, tromethamine salt, and zinc salt. Hemisalts of acids and bases, such as hemisulfate salts and hemicalcium salts, can also be formed. For a general review of suitable salts, see Stahl and Wermuth, "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" (Wiley-VCH, Weinheim, Germany, 2002).

[0128] Pharmaceutically acceptable salts of compounds of formula (I) may be prepared by one or more of three methods: (i) by reacting a compound of the invention with a desired acid or base; (ii) by removing an acid- or base-labile protecting group from a suitable precursor of a compound of the invention, or by ring-opening a suitable cyclic precursor, such as a lactone or lactam, with a desired acid or base; or (iii) By converting one salt of a compound of the invention into another salt by reaction with an appropriate acid or base or using a suitable ion exchange column.

[0129] All three reactions are typically carried out in solution. The resulting salts can be precipitated and recovered by filtration or by evaporation of the solvent. The degree of ionization in the resulting salts can vary from completely ionized to almost non-ionized.

[0130] The compound of the present invention can exist in both non-solvated and solvated form.The term "solvate" is used herein to describe the molecular complex that comprises the compound of the present invention and one or more stoichiometric amounts of pharmaceutically acceptable solvent molecules, such as ethanol.The term "hydrate" is used when the solvent is water.

[0131] In contrast to the solvates, the scope of the present invention includes complexes such as clathrates and drug-host inclusion complexes, in which the drug and host are present in stoichiometric or non-stoichiometric amounts. Also included are complexes of drugs containing two or more organic and / or inorganic components, which may be in stoichiometric or non-stoichiometric amounts. The resulting complexes may be ionized, partially ionized, or non-ionized. For a review of such complexes, see Haleblian, J Pharm Sci, 64 (8), 1269-1288 (August 1975).

[0132] Hereinafter all references to compounds of any formula include references to salts, solvates and complexes thereof and to solvates and complexes of salts thereof.

[0133] The compounds of the present invention include compounds of the various formulas defined herein (including all polymorphs and crystalline habits thereof), prodrugs thereof, and isomers (including optical isomers, geometric isomers, and tautomers) thereof as defined below, as well as isotopically labeled compounds of the present invention.

[0134] The present invention also includes all pharmaceutically acceptable isotopically labeled compounds of the present invention in which one or more atoms are replaced by an atom having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number most commonly found in nature.

[0135] Examples of isotopes suitable for inclusion in compounds of the invention include hydrogen, e.g. 2 H and 3 H, carbon, e.g. 11 C. 13 C and 14 C, chlorine, e.g. 36 Cl, fluorine, e.g. 18 F, iodine, e.g. 123 I and 125 I, nitrogen, e.g. 13 N and 15 N, oxygen, e.g. 15 O. 17 O and 18 O, phosphorus, e.g. 32 P, and sulfur, e.g. 35 Examples include isotopes of S.

[0136] Certain isotopically labeled compounds, for example those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. The radioactive isotope tritium, i.e. 3 H, and carbon-14, i.e. 14 C is particularly useful for this purpose in view of its ease of incorporation and ready preparation of detection means.

[0137] Deuterium, i.e. 2Substitution with heavier isotopes, such as H, may offer therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and therefore may be preferable in some situations.

[0138] Before purification, the compounds of the present invention may exist as a mixture of enantiomers depending on the synthetic procedures used. Enantiomers can be separated by conventional techniques known in the art. Thus, the present invention encompasses individual enantiomers and mixtures thereof.

[0139] For some steps in the process for preparing the compounds of the present invention, it may be necessary to protect potentially reactive functional groups where reaction is not desired, and subsequently cleave the protecting group. In such cases, any suitable protecting radical may be used. In particular, protection and deprotection methods such as those described by T.W. GREENE (Protective Groups in Organic Synthesis, A. Wiley-Interscience Publication, 1981) or P.J. Kocienski (Protecting Groups, Georg Thieme Verlag, 1994) may be used. All of the above reactions and the preparation of novel starting materials used in the aforementioned methods are conventional, and suitable reagents and reaction conditions for their implementation or preparation, as well as procedures for isolating the desired products, are well known to those skilled in the art with reference to literature precedents and the examples and preparations herein.

[0140] Additionally, the compounds of the present invention and intermediates for their preparation may be purified according to various well-known methods, such as crystallization and chromatography.

[0141] One or more compounds of the invention may be combined with one or more pharmaceutical agents, such as anti-inflammatory agents, anti-fibrotic agents, chemotherapeutic agents, anti-cancer agents, immunosuppressants, anti-tumor vaccines, cytokine therapy, or tyrosine kinase inhibitors, for the treatment of conditions modulated by inhibition of the DDR, such as fibrotic diseases, autoimmune, inflammatory fibrotic conditions, inflammatory conditions, central nervous system disorders, or cancer.

[0142] The compounds for use in the method of treatment or treatment of renal conditions, hepatic conditions, inflammatory conditions, cardiovascular conditions, acute and chronic organ transplant rejection, fibrotic diseases and cancer as defined above may be applied as a sole therapy or may be in combination therapy with further active substances.

[0143] The compound is for use in the method or treatment of renal conditions, liver conditions, inflammatory conditions, cardiovascular conditions, acute and chronic organ transplant rejection, fibrotic diseases and cancer. The additional active substance can be one or more active substances used to treat the conditions treated by the compound of the present invention and the additional active substance. The additional active substance can include one or more of the following active substances: (i) steroids, such as corticosteroids, e.g., glucocorticoids and mineralocorticoids, e.g., alclometasone, alclometasone propionate, aldosterone, amcinonide, beclomethasone, beclomethasone propionate, betamethasone, betamethasone propionate, betamethasone sodium phosphate, betamethasone valerate, budesonide, clobetasone, clobetasone butyrate, clobetasol propionate, cloprendonol, cortisone, cortisone acetate, cortivazol, deoxycortone, desonide, desoximetasone, dexamethasone, dexamethasone sodium phosphate, dexamethasone isonicotinate ter, difluorocortolone, fluclorone, flumethasone, flunisolide, fluocinolone, fluocinolone acetonide, fluocinonide, fluocortin butyl, fluorocortisone, fluorocortolone, fluocortolone caproate, fluocortolone pivalate, fluorometholone, fluprednidene, fluprednidene acetate, flurandrenolone, fluticasone, fluticasone propionate, halcinonide, hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone aceponate, hydrocortisone buteprate, hydrocortisone valerate, icometasone, icometasone embutate, meprednisone, methylprednisolone, mometasone Paramethasone, mometasone furoate monohydrate, prednicarbate, prednisolone, prednisone, tixocortol, tixocortol pivalate, triamcinolone, triamcinolone acetonide, triamcinolone alcohol, and pharmaceutically acceptable derivatives of each. Combinations of steroids may be used, for example, a combination of two or more steroids mentioned in this paragraph; (ii) TNF inhibitors, such as etanercept; monoclonal antibodies (e.g., infliximab (Remicade), adalimumab (Humira), certolizumab pegol (Cimzia), golimumab (Simponi)); fusion proteins (e.g., etanercept (Enbrel)); and 5-HT 2Aagonists (e.g., 2,5-dimethoxy-4-iodoamphetamine, TCB-2, lysergic acid diethylamide (LSD), lysergic acid dimethylazetidide); (iii) anti-inflammatory drugs, such as nonsteroidal anti-inflammatory drugs; (iv) dihydrofolate reductase inhibitors / antifolates, such as methotrexate, trimethoprim, brodimoprim, tetroxoprim, iclaprim, pemetrexed, ralitrexed, and pralatrexate; and (v) Immunosuppressants such as cyclosporine, tacrolimus, sirolimus pimecrolimus, angiotensin II inhibitors (e.g., valsartan, telmisartan, losartan, irbesartan, azilsartan, olmesartan, candesartan, eprosartan) and ACE inhibitors such as sulfhydryl-containing agents (e.g., captopril, zofenopril), dicarboxylate-containing agents (e.g., enalapril, ramipril, quinapril, perindopril, lisinopril, benazepril, imidapril, zofenopril, trandolapril), phosphate-containing agents (e.g., fosinopril), casokinins, lactokines, and lactopeptides. (vi) Antifibrotic agents, such as pirfenidone, nintedanib, anti-IL-13 monoclonal antibodies (e.g., tralokinumab, QAX576, lebrikizumab), simtuzumab, FG-3019, lysophosphatidic acid receptor antagonists (e.g., BMS-986020, AM966), LOXL2 inhibitors, BET bromodomain inhibitors (e.g., JQ1), HDAC inhibitors (e.g., vorinostat), thrombin inhibitors (e.g., dabigatran), factor Xa inhibitors (e.g., apixaban, rivaroxaban), PGDH inhibitors, anti-αvβ6 monoclonal antibodies (e.g., BG00011), anti-CTGF monoclonal antibodies (e.g., FG-3019), PAR1 inhibitors, Nox4 inhibitors, and PAI-1 inhibitors.

[0144] Methods of treating cancer or compounds for use in the treatment may include, in addition to the compounds of the present invention, conventional surgery or radiation therapy or chemotherapy. Such chemotherapy may include one or more of the following categories of anti-tumor agents: (i) antiproliferative / antineoplastic agents and combinations thereof, such as alkylating agents (e.g., cisplatin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, uracil mustard, bendamustine, melphalan, chlorambucil, chlormethine, busulfan, temozolamide, nitrosoureas, ifosamide, melphalan, pipobroman, triethylene-melamine, triethylenethiazolinone, methylparaben ... opioids, carmustine, lomustine, streptozocin, and dacarbazine; antimetabolites (e.g., gemcitabine and antifolates, e.g., fluoropyrimidines, e.g., 5-fluorouracil and tegafur, raltitrexed, methotrexate, pemetrexed, cytosine arabinoside, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, pentostatin, and gemcitabine) vinorelbine and hydroxyurea); antibiotics (e.g., anthracyclines, such as adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin, and mithramycin); mitotic inhibitors (e.g., vinca alkaloids, such as vincristine, vinblastine, vindesine, and vinorelbine, and taxoids, such as taxol and taxotere, and polo kinase inhibitors); proteasome inhibitors, such as carfilzomib and bortezomib; interferon therapy; and topoisomerase inhibitors (e.g., epipodophyllotoxins, such as etoposide and teniposide, amsacrine, topotecan, mitoxantrone, and camptothecin); bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, ara-C, paclitaxel (taxol TM), nab-paclitaxel, docetaxel, mithramycin, deoxycoformycin, mitomycin-C, L-asparaginase, interferons (especially IFN-a), etoposide, and teniposide; (ii) Cytostatics, such as antiestrogens (e.g., tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene, and iodoxifene), antiandrogens (e.g., bicalutamide, flutamide, nilutamide, and cyproterone acetate), LHRH antagonists or agonists (e.g., goserelin, leuprorelin, and buserelin), progestogens (e.g., megestrol acetate), aromatase inhibitors (e.g., anastrozole, letrozole, vorazole, and exemestane), and 5α-reductase inhibitors, such as finasteride; and navelbene, CPT-II, anastrozole, letrazole, capecitabine, reloxafme, cyclophosphamide, ifosamide, and droloxafme; (iii) anti-invasive agents, such as dasatinib and bosutinib (SKI-606), and metalloproteinase inhibitors, inhibitors of urokinase plasminogen activator receptor function, or antibodies against heparanase; (iv) inhibitors of growth factor function: for example, growth factor antibodies and growth factor receptor antibodies, such as the anti-erbB2 antibody trastuzumab (Herceptin TM), the anti-EGFR antibody panitumumab, the anti-erbB1 antibody cetuximab, tyrosine kinase inhibitors, such as inhibitors of the epidermal growth factor family (e.g., EGFR family tyrosine kinase inhibitors, e.g., gefitinib, erlotinib, 6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)-quinazolin-4-amine (CI 1033), erbB2 tyrosine kinase inhibitors, e.g., lapatinib), and antibodies against costimulatory molecules, e.g., CTLA-4, 4-1BB and PD-1, or antibodies against cytokines (IL-10, TGF-β); inhibitors of the hepatocyte growth factor family; inhibitors of the insulin growth factor family; modulators of protein regulators of cell apoptosis (e.g., Bcl-2 inhibitors); inhibitors of the platelet-derived growth factor family, e.g., imatinib and / or nilotinib (AMN107); inhibitors of serine / threonine kinases (e.g., Ras / Raf signaling inhibitors, such as farnesyltransferase inhibitors, e.g., sorafenib, tipifarnib, and lonafarnib), inhibitors of cell signaling via MEK and / or AKT kinases, c-kit inhibitors, abl kinase inhibitors, PI3 kinase inhibitors, Plt3 kinase inhibitors, CSF-1R kinase inhibitors, IGF receptor kinase inhibitors; Aurora kinase inhibitors and cyclin-dependent kinase inhibitors, e.g., CDK2 and / or CDK4 inhibitors; and CCR2, CCR4, or CCR6 modulators; (v) Antiangiogenic agents, such as those that inhibit the effects of vascular endothelial growth factor, e.g., the anti-vascular endothelial growth factor antibody bevacizumab (Avastin TM ); thalidomide; lenalidomide; and for example, VEGF receptor tyrosine kinase inhibitors, such as vandetanib, vatalanib, sunitinib, axitinib, and pazopanib; (vi) gene therapy approaches, including approaches to replace abnormal genes such as, for example, abnormal p53 or abnormal BRCA1 or BRCA2; (vii) immunotherapeutic approaches, such as antibody therapies, such as alemtuzumab, rituximab, ibritumomab tiuxetan (Zevalin®) and ofatumumab; interferons, such as interferon alpha; interleukins, such as IL-2 (aldesleukin); interleukin inhibitors, such as IRAK4 inhibitors; cancer vaccines, such as preventative and therapeutic vaccines, for example HPV vaccines, such as Gardasil, Cervarix, Oncophage and Sipuleucel-T (Provenge); gp100; dendritic cell-based vaccines (e.g., Ad.p53 DC); and toll-like receptor modulators, such as TLR-7 or TLR-9 agonists; and (viii) Cytotoxic agents, such as fludarabine, cladribine, pentostatin, TM ); (ix) steroids, such as corticosteroids, for example glucocorticoids and mineralocorticoids, for example alclometasone, alclometasone propionate, aldosterone, amcinonide, beclomethasone, beclomethasone propionate, betamethasone, betamethasone propionate, betamethasone sodium phosphate, betamethasone valerate, budesonide, clobetasone, clobetasone butyrate, clobetasol propionate, cloprendonol, cortisone, cortisone acetate, cortivazol, deoxycortone, desonide, desoximetasone, dexamethasone, dexamethasone sodium phosphate, dexamethasone isonicotinate ter, difluorocortolone, fluclorone, flumethasone, flunisolide, fluocinolone, fluocinolone acetonide, fluocinonide, fluocortin butyl, fluorocortisone, fluorocortolone, fluocortolone caproate, fluocortolone pivalate, fluorometholone, fluprednidene, fluprednidene acetate, flurandrenolone, fluticasone, fluticasone propionate, halcinonide, hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone aceponate, hydrocortisone buteprate, hydrocortisone valerate, icometasone, icometasone embutate, meprednisone, methylprednisolone, mometasone Paramethasone, mometasone furoate monohydrate, prednicarbate, prednisolone, prednisone, tixocortol, tixocortol pivalate, triamcinolone, triamcinolone acetonide, triamcinolone alcohol, and pharmaceutically acceptable derivatives of each. Combinations of steroids may be used, for example, a combination of two or more steroids mentioned in this paragraph; (x) targeted therapies, such as PI3Kd inhibitors, e.g., idelalisib and perifosine; PD-1, PD-L1, PD-L2 and CTL4-A modulators, antibodies and vaccines; other IDO inhibitors (e.g., indoximod); anti-PD-1 monoclonal antibodies (e.g., MK-3475 and nivolumab); anti-PD-L1 monoclonal antibodies (e.g., MEDI-4736 and RG-7446); anti-PD-L2 monoclonal antibodies; and anti-CTLA-4 antibodies (e.g., ipilimumab); (xii) Chimeric antigen receptors, anticancer vaccines and arginase inhibitors.

[0145] Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate administration of the individual components of treatment. Such combination products utilize the compounds of this invention within the therapeutically effective dosage range set forth above and the other pharmaceutically active agent(s) within their approved dosage range.

[0146] The compound of the present invention can exist in a single crystalline form or a mixture of crystalline forms, or can be amorphous.Therefore, the compound of the present invention intended for pharmaceutical use can be administered as crystalline or amorphous product.They can be obtained as solid plug, powder or film by methods such as precipitation, crystallization, freeze-drying or spray-drying or evaporative drying.Microwave or radio frequency drying can be used for this purpose.

[0147] For the compounds of the present invention described above, the amount to be administered will naturally vary depending on the compound used, the mode of administration, the desired treatment, and the disorder being treated. For example, when the compounds of the present invention are administered orally, the daily dosage of the compounds of the present invention can range from 0.01 micrograms per kilogram of body weight (μg / kg) to 100 milligrams per kilogram of body weight (mg / kg).

[0148] The compound of the present invention or a pharmaceutically acceptable salt thereof may be used by itself, but is generally administered in the form of a pharmaceutical composition in which the compound of the present invention or a pharmaceutically acceptable salt thereof is combined with a pharmaceutically acceptable adjuvant, diluent or carrier. Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described, for example, in "Pharmaceuticals - The Science of Dosage Form Designs", ME Aulton, Churchill Livingstone, 1988.

[0149] Depending on the mode of administration of the compounds of the present invention, pharmaceutical compositions used to administer the compounds of the present invention preferably contain 0.05 to 99% w (weight percent) of the compounds of the present invention, more preferably 0.05 to 80% w of the compounds of the present invention, even more preferably 0.10 to 70% w of the compounds of the present invention, and even more preferably 0.10 to 50% w of the compounds of the present invention, all weight percentages being based on the total composition.

[0150] Pharmaceutical compositions may be administered locally (e.g., to the skin), for example, in the form of creams, gels, lotions, solutions, suspensions, or systemically, for example, by oral administration in the form of tablets, capsules, syrups, powders, or granules; or parenterally in the form of sterile solutions, suspensions, or emulsions for injection (including intravenous, subcutaneous, intramuscular, intravascular, or infusion); by rectal administration in the form of suppositories; or by inhalation in the form of an aerosol.

[0151] For oral administration, the compound of the present invention can be mixed with adjuvants or carriers such as lactose, saccharose, sorbitol, mannitol; starches such as potato starch, corn starch or amylopectin; cellulose derivatives; binders such as gelatin or polyvinylpyrrolidone; and / or lubricants such as magnesium stearate, calcium stearate, polyethylene glycol, wax, paraffin, etc., and then compressed into tablets.If coated tablets are required, the core prepared as above can be coated with concentrated sugar solution, which can contain, for example, gum arabic, gelatin, talc and titanium dioxide.Alternatively, tablets can be coated with suitable polymers dissolved in easily volatile organic solvents.

[0152] For the preparation of soft gelatin capsules, the compounds of the present invention can be mixed with, for example, vegetable oil or polyethylene glycol.Hard gelatin capsules can contain granules of the compounds using any of the additives mentioned above for tablets.Also, liquid or semi-solid forms of the compounds of the present invention can be filled into hard gelatin capsules.Liquid preparations for oral administration can be in the form of syrups or suspensions, for example, solutions containing the compounds of the present invention, with the balance being a mixture of sugar, ethanol, water, glycerol, and propylene glycol.If desired, such liquid preparations can contain colorants, flavors, sweeteners (e.g., saccharin), preservatives, and / or carboxymethylcellulose as a thickener, or other additives known to those skilled in the art.

[0153] For intravenous (parenteral) administration, the compounds of the present invention may be administered as a sterile aqueous or oily solution.

[0154] The size of a dose of a compound of the invention for therapeutic purposes will, of course, vary according to the nature and severity of the condition, the age and sex of the animal or patient, and the route of administration, in accordance with well-known principles of medicine.

[0155] Dosage levels, frequency of administration and duration of treatment of the compounds of the invention are expected to vary depending on the formulation and clinical indication, age and coexisting medical conditions of the patient.

[0156] Throughout this description and the claims, the words "comprise" and "contain" and variations thereof mean "including, but not limited to," and are not intended to (and do not) exclude other moieties, adjuncts, components, integers, or steps. Throughout this description and the claims, the singular encompasses the plural unless the context requires otherwise. In particular, where the indefinite article is used, it should be understood that the specification contemplates the plural as well as the singular, unless the context requires otherwise.

[0157] It should be understood that any feature, integer, property, compound, chemical moiety, or group described in connection with a particular aspect, embodiment, or example of the invention is applicable to any other aspect, embodiment, or example described herein, unless inconsistent. All features disclosed in this specification (including any accompanying claims, abstract, and drawings), and / or all steps of the disclosed methods or processes, may be combined in any combination, except combinations in which at least some of the features and / or steps are mutually exclusive. The invention is not limited to the details of the foregoing embodiments. The invention extends to any novel or any novel combination of features disclosed in this specification (including any accompanying claims, abstract, and drawings), or any novel or novel combination of steps of any disclosed methods or processes.

[0158] The reader's attention is drawn to all articles and documents related to this application that are filed contemporaneously or previously hereto and that are open to public inspection herewith, and the contents of all such articles and documents are incorporated herein by reference.

[0159] Compounds of the present invention may be prepared according to or in analogy with general Schemes 1-4 and Examples 1-65.

[0160] (Experimental Procedure) Solvents, reagents, and starting materials were purchased from commercial suppliers and used as received unless otherwise noted. All reactions were performed at room temperature unless otherwise noted. Compound identity and purity were confirmed by LCMS UV analysis using a Waters Acquity SQ Detector 2 (ACQ-SQD2#LCA081). The diode array detector wavelength was set to acquire spectra at 254 nM, and MS was in positive and negative electrospray mode (m / z: 150–800). 2 μL aliquots were sequentially injected onto a guard column (0.2 μm × 2 mm filter) and a UPLC column (C18, 50 × 2.1 mm, <2 μm) maintained at 40 °C. Samples were eluted at a flow rate of 0.6 mL / min using a mobile phase system consisting of A (0.1% (v / v) formic acid in water) and B (0.1% (v / v) formic acid in acetonitrile) according to the gradients summarized in Table 1 below (Methods 1 and 2). Retention times (RT) are shown in minutes. The following methods were also used throughout the experimental section, with gradients detailed in Table 1. Method 3 used a Shimadzu 2020 series spectrometer equipped with a binary pump and a diode array detector (acquisition wavelengths of 214 and 254 nm), and MS was performed in positive and negative electrospray mode (m / z: 100-900). A 2 μL aliquot was injected onto an Agilent Poroshell 120 EC-C18 column (2.7 μm, 4.6 × 50 mm) maintained at 35°C and eluted at 1.0 ml / min with a mobile phase consisting of A: 0.05% formic acid in water (v / v), B: 0.05% formic acid in ACN (v / v). Method 4 used an Agilent Technologies 1290 Series spectrometer equipped with a binary pump and a diode array detector (acquisition wavelengths of 214 and 254 nm), and MS was performed in positive electrospray mode (m / z: 70–1000). Aliquots of 2 μL were injected onto an Agilent Eclipse Plus RRHD C18 column (1.8 μm, 3.0 × 50 mm) maintained at 40°C and eluted at 0.8 ml / min with a mobile phase consisting of A: 0.05% formic acid in water, B: 0.05% formic acid in ACN (v / v).

[0161] [Table 1]

[0162] NMR was also used to characterize the final compounds. NMR spectra were obtained on a Bruker AVIII 400 Nanobay equipped with a 5 mm BBFO probe. In some cases, the Rf values ​​of the compounds were measured on silica thin-layer chromatography (TLC) plates.

[0163] Compound purification was performed by flash column silica chromatography or preparative LCMS. LCMS purification was performed using a Waters 3100 Mass Detector equipped with a Waters 2489 UV / Vis Detector in positive and negative electrospray mode (m / z: 150-800). XBridge was used with a mobile phase system consisting of A (0.1% (v / v) formic acid in water) and B (0.1% (v / v) formic acid in acetonitrile) according to the gradient summarized in Table 2 below. TM The sample was eluted on a prep C18 5 μM OBD 19×100 mm column at a flow rate of 20 mL / min.

[0164] [Table 2]

[0165] General Routes and Schemes [ka] Compounds of formula (I) can be prepared from intermediates represented by vi in ​​General Scheme 1. In step 1, an ortho-fluoronitroaryl compound undergoes a nucleophilic substitution reaction with an aryl or heteroaryl amine (where A represents a halogen, such as Cl, Br, or I, capable of participating in a metal-catalyzed cross-coupling reaction, e.g., a Suzuki or Stille reaction), in the presence of a base, e.g., sodium hydride, to give compounds of structure i. In step 2, the nitro group of i can be reduced with a transition metal catalyst in the presence of hydrogen gas or another hydrogen source, e.g., ammonium chloride, to give compounds of structure ii. In step 3, reaction with a carbonyl equivalent (e.g., CDI) gives cyclized products represented by iii. In step 4, the free NH of iii is reacted with an appropriate α-haloester (where A represents a halogen, e.g., Br, and OAlk represents an alkoxy group, e.g., ethoxide), followed by hydrolysis to the corresponding carboxylic acid using KOH or LiOH under basic conditions in step 5 to give compounds of structure v. In step 6, reaction with an appropriate amine using a carboxylic acid activating reagent such as HATU and a base such as DIPEA provides intermediates represented by vi.

[0166] General Scheme 2 [ka] Compounds of Formula I can be synthesized from intermediates of general structure vi via two routes, as described in General Scheme 2. According to Step 1a, vi (where A represents a halogen, e.g., Br, or another leaving group capable of participating in a metal-catalyzed cross-coupling reaction, e.g., triflate) undergoes a transition metal-catalyzed cross-coupling with an azaindazole of structure xxi (where B is a boronic acid, boronic ester, or stannyl group (trialkyltin) capable of participating in a Suzuki or Stille-type reaction with a compound of structure vi). As an example, A can be a boronic acid pinacol ester and B can be a bromide, and these groups undergo a Suzuki reaction catalyzed by Pd(dppf)Cl·DCM in the presence of KOAc in Step 1a to give compounds of Formula I. Alternatively, according to step 1, intermediates of structure vi can be converted to boronic esters or stannanes of formula vii by reaction with bis(pinacolato)diboron or tributyltin chloride, respectively, where B is boric acid, a borate ester, or a stannyl group (trialkyltin), which then undergo a Suzuki or Stille reaction in step 2 with an azaindazole of structure xx, where A is a halogen, such as Br, Cl, or I, to provide compounds of formula (I).

[0167] General Scheme 3 [ka] Compounds of formula (I) can also be obtained by rearranging the steps from General Schemes 1 and 2, as shown in General Scheme 3. The definitions of the groups A, B, and OAlk in the structures shown in General Scheme 3 are the same as those described for General Schemes 1 and 2. In step 1, intermediates of structure iv undergo a metal-catalyzed cross-coupling reaction, such as a Suzuki or Stille reaction, with a boronic ester or stannane derivative of heteroaryl xxi. In step 2, the cross-coupling product (xi) undergoes base-mediated ester hydrolysis as previously described, followed by amide coupling in step 3 to obtain compounds of formula (I). Alternatively, the cross-coupling partners can be reversed by converting the halide or triflate iv to the corresponding boronic ester or stannane in step 1a, which is reacted with a haloazaindazole of structure xx in step 2b to obtain intermediates of structure xi.

[0168] General Scheme 4 [ka]

[0169] Synthesis of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine [ka] Scheme 5 Isopropylmagnesium bromide (21 mL, 20.5 mmol, 1 M solution in THF) was added dropwise over 10 minutes 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) at 5° C. under N. The resulting solution was stirred at 5° C. for 2 hours and then concentrated under reduced pressure. The residue was diluted with DCM (10 mL) and the suspension was filtered through a silica gel pad, eluting with EtOAc (10 mL) and evaporated to give the crude product, which was purified via 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%). LCMS (ES+, method 3): 4.12 min, m / z 245.2 [M+H] +

[0170] Synthesis of N-(4-bromo-2-methylphenyl)-2-methyl-6-nitroaniline [ka] Scheme 6 To a solution of 4-bromo-2-methylaniline (200 mg, 1.08 mmol, 1.0 eq) in DMF (2 mL) at 0 °C under N was added a solution of 2-fluoro-1-methyl-3-nitrobenzene (200 mg, 1.29 mmol, 1.2 eq) in DMF (2 mL). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was filtered and purified via reverse phase chromatography to give N-(4-bromo-2-methylphenyl)-2-methyl-6-nitroaniline (120 mg, 35%). LCMS (ES + , Method 3): 4.60 min, m / z, 321.1 [M] +

[0171] Intermediates synthesized following the same procedure as intermediate i-1 (Scheme 6), substituting 4-bromo-2-methylaniline and 2-fluoro-1-methyl-3-nitrobenzene for the listed building blocks, are listed in Table 3. [Table 3-1] [Table 3-2]

[0172] Synthesis of N2-(4-bromo-2-methylphenyl)-3-methylbenzene-1,2-diamine [ka] Scheme 7 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) were stirred for 2 h at 80° C. The reaction mixture was concentrated under reduced pressure and purified via 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. LCMS (ES + , Method 3): 4.22 minutes, m / z 291.2 / 293.2 [M] + / [M+2] +

[0173] Intermediates synthesized according to the same procedure as intermediate ii-1 (Scheme 7), substituting N-(4-bromo-2-methylphenyl)-2-methyl-6-nitroaniline for the indicated building blocks, are listed in Table 4. [Table 4-1] [Table 4-2]

[0174] Synthesis of 3-(4-bromo-2-methylphenyl)-4-methyl-1H-benzimidazol-2-one [ka] Scheme 8 A solution of N2-(4-bromo-2-methylphenyl)-3-methylbenzene-1,2-diamine (8.00 g, 27.5 mmol) and CDI (13.4 g, 82.4 mmol) in DMF (20 mL) was stirred at 100 °C for 16 h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (5 mL × 3). The organic phases were combined, washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude material was purified via flash chromatography (petroleum ether / EtOAc 5:1 to 3:1) to give 3-(4-bromo-2-methylphenyl)-4-methyl-1H-benzimidazol-2-one (8.00 g, 64%) as a yellow solid. LCMS (ES + , Method 3): 2.47 minutes, m / z 317.1 / 319.1 [M] + / [M+2] +

[0175] Table 5 lists intermediates synthesized following the same procedure as intermediate iii-1 (Scheme 8), substituting N2-(4-bromo-2-methylphenyl)-3-methylbenzene-1,2-diamine for the indicated building blocks. [Table 5-1] [Table 5-2]

[0176] Synthesis of ethyl 2-(3-(4-bromophenyl)-2-oxo-benzimidazol-1-yl)acetate [ka] Scheme 9

[0177] 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 aqueous NH4Cl. 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 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. UPLCMS (ES + , Method 2): 1.55 minutes, m / z 233.1 [M+H] +

[0178] Step B: Synthesis of xv-1: A mixture of cesium carbonate (181 mg, 0.55 mmol), ethyl bromoacetate (0.05 mL, 0.47 mmol), and tert-butyl 2-oxo-3H-benzimidazole-1-carboxylate (100 mg, 0.43 mmol) in MeCN (2.5 mL) was heated at 80 °C for 2 h. The reaction mixture was evaporated to dryness, and the residue was suspended in water. The aqueous phase was extracted four times with ethyl acetate. The organic phase was washed with brine, passed through a phase-separating filter paper, and evaporated to dryness. The residue was purified by flash column chromatography (4 g cartridge, eluent: ethyl acetate in petroleum ether 0-25%) to give tert-butyl 3-(2-ethoxy-2-oxo-ethyl)-2-oxo-benzimidazole-1-carboxylate (100 mg, 0.31 mmol, 73% yield) as a colorless oil. UPLCMS (ES + , Method 2): 1.79 min, m / z 343.0 [M+Na] +

[0179] 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 hours. 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. UPLCMS (ES + , Method 2): 1.32 minutes, m / z 221.1 [M+H] + 1H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 7.11 - 7.07 (m, 1H), 7.01 - 7.00 (m, 3H), 4.66 (s, 2H), 4.15 (q, J = 7.1 Hz, 2H), 1.21 (t, J = 7.1 Hz, 3H) ppm.

[0180] Step D: Synthesis of iv-4: 4-Bromo-benzeneboronic 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 stirred at room temperature in the open air overnight. 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 brine, passed through a phase separator, and evaporated to dryness. The residue was purified by flash column chromatography eluting with 0-25% EtOAc in pet. 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. UPLCMS (ES + , Method 2): 1.88 minutes, m / z 375.0 / 377.0 [M]+ / [M+2] +

[0181] Synthesis of 2-(3-(4-bromo-2-methylphenyl)-4-methyl-2-oxo-benzimidazol-1-yl) acetate [ka] Scheme 10 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 for 2 h at 50° C. The reaction mixture was concentrated under reduced pressure and purified via flash chromatography (petroleum ether / EtOAc 5:1 to 3:1) to afford ethyl 2-(3-(4-bromo-2-methylphenyl)-4-methyl-2-oxo-benzimidazol-1-yl)acetate (7.00 g, 58%) as a yellow solid. LCMS (ES + , Method 3): 4.15 minutes, m / z 403.1 / 405.1 [M] + / [M+2] + Table 6 lists intermediates synthesized following the same procedure as intermediate iv-1 (Scheme 10), substituting 3-(4-bromo-2-methylphenyl)-4-methyl-1H-benzimidazol-2-one for the indicated building blocks. [Table 6-1] [Table 6-2] [Table 6-3]

[0182] 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 [ka] Scheme 11 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), Pd(dba) (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 under reduced pressure and purified via flash chromatography (petroleum ether / EtOAc 5:1 to 3:1) to afford 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. LCMS (ES + , Method 3): 4.45 minutes, m / z 451.4 [M+H] +

[0183] Table 7 lists intermediates synthesized according to the same procedure as intermediate x-1 (Scheme 11), substituting 3-(4-bromo-2-methylphenyl)-4-methyl-1H-benzimidazol-2-one for the components indicated. [Table 7]

[0184] Synthesis of 2-[3-(6-bromo-2-methyl-3-pyridyl)-4-methyl-2-oxo-benzimidazol-1-yl]acetic acid [ka] Scheme 12 A mixture of ethyl 2-[3-(6-bromo-2-methyl-3-pyridyl)-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 organic layers were combined, washed with brine (50 mL), dried over Na SO , and concentrated in vacuo to give 2-[3-(6-bromo-2-methyl-3-pyridyl)-4-methyl-2-oxo-benzimidazol-1-yl]acetic acid (4.6 g, 12.23 mmol, 99% yield) as a yellow solid. LCMS (ES+, Method 3): 3.22 min, m / z 378.2 [M+2] +

[0185] Table 8 lists intermediates synthesized according to the same procedure as intermediate v-2 (Scheme 12), substituting ethyl 2-[3-(6-bromo-2-methyl-3-pyridyl)-4-methyl-2-oxo-benzimidazol-1-yl]acetate for the listed building blocks. [Table 8]

[0186] Synthesis of 2-[3-(6-bromo-4-methyl-3-pyridyl)-4-methyl-2-oxo-benzimidazol-1-yl]-N-(2,2,2-trifluoroethyl)acetamide [ka] Scheme 13 A solution of 2-[3-(6-bromo-4-methyl-3-pyridyl)-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-pyridyl)-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] +

[0187] Table 9 lists intermediates synthesized according to the same procedure as intermediate vi-1 (Scheme 13), substituting 2-[3-(6-bromo-4-methyl-3-pyridyl)-4-methyl-2-oxo-benzimidazol-1-yl]acetic acid and trifluoroethylamine for the listed components. [Table 9-1] [Table 9-2] [Table 9-3]

[0188] [ka] Scheme 14 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 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 eq) and Pd(dba) (2.07 g, 2.26 mmol) in THF (35 mL) was stirred at 70 °C under N overnight. The mixture was concentrated in vacuo and purified by silica gel column (Pet. ether / EtOAc 10:1 to Pet. 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). LCMS (ES+, method 3): 4.32 min, m / z 490.0 [M+H]+

[0189] Intermediates synthesized according to the same procedure as intermediate vii-1 (Scheme 14), substituting 2-[3-(4-bromophenyl)-4-methyl-2-oxo-benzimidazol-1-yl]-N-(2,2,2-trifluoroethyl)acetamide for the indicated building blocks, are listed in Table 10. Synthesis of Boronic Esters [Table 10]

[0190] 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 [ka] Scheme 15 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)Cl.DCM (50.0 mg, 0.620 mmol), and NaCO (132 mg, 1.24 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL) was stirred at 90 °C under nitrogen for 16 h. The reaction mixture was diluted with water (200 mL) and extracted with EtOAc (100 mL × 3). The organic layers were combined, dried over Na2SO4, concentrated under reduced pressure and purified via 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-benzimidazol-1-yl)acetate (155 mg, 56%) as a yellow solid. LCMS (ES+, Method 4): 2.12 min, m / z 442.1 [M+H] +

[0191] Step B: Synthesis of ethyl 2-(4-methyl)-2-2-oxo-3-(5-pyrazolo[1-5-a]pyridin-3-yl)pyrazin-2-yl)benzimidazol-1-yl)acetate [ka] Scheme 16 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 eq), 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 eq), Pd(dppf)Cl (24.8 mg, 0.0307 mmol, 0.1 eq), and NaCO (65.0 mg, 0.614 mmol, 2.0 eq) in 1,4-dioxane (5 mL) and water (0.5 mL) was stirred at 100 °C under nitrogen for 16 h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL × 3). The reaction mixture was concentrated under reduced pressure and purified via flash chromatography (petroleum ether / EtOAc 10:1 to 2:1) to afford ethyl 2-(4-methyl)-2-2-oxo-3-(5-pyrazolo[1-5-a]pyridin-3-yl)pyrazin-2-yl)benzimidazol-1-yl)acetate (170 mg, 97%) as a yellow solid. LCMS (ES + , Method 3): 4.18 minutes, m / z 429.2 [M+H] +

[0192] 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 [ka] Scheme 17

[0193] Step A: Synthesis of xvii-1: A mixture of 2-bromo-N-(2-methyl-6-nitrophenyl)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), KCO (4.21 g, 30.47 mmol), and Pd(dppf)Cl.DCM (823.4 mg, 1.02 mmol) in 1,4-dioxane (60 mL) and water (6 mL) was stirred at 90 °C under N for 16 h. The mixture was filtered and concentrated under reduced pressure. Purification by silica gel column (Pet. ether / EtOAc = 3 / 1 to DCM / MeOH = 100 / 1, v / v) gave 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. LC-MS (ES + , Method 4): 1.61 min, m / z, 347.1 [M+H] +

[0194] 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 80 °C under N2 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 × 3). The organic layers were combined, 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): 1.60 min, m / z, 317.2 [M+H] +

[0195] 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 at 100 °C under N2 overnight. The mixture was diluted with water (50 mL) and extracted with EtOAc (25 mL × 3). The organic layers were combined, washed with brine (100 mL), dried over NaSO, and concentrated in vacuo to give the crude material, 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. LC-MS (ES + , Method 3): 1.59 min, m / z, 343.2 [M+H] +

[0196] Step D: Synthesis of xi-3: A solution of 4-methyl-3-(2-pyrazolo[1,5-a]pyridin-3-ylpyrmidin-5-yl)-1H-benzimidazol-2-one (1.57 g, 4.59 mmol), CsCO (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 under reduced pressure, and purified via flash chromatography (petroleum ether / EtOAc 1:1) to afford 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. LCMS (ES + , Method 4): 2.02 minutes, m / z 429.2 [M+H] +

[0197] Intermediates synthesized according to the same procedure as intermediate xi-1 (Schemes 15-17), substituting 3-(4-bromo-2-methylphenyl)-4-methyl-1H-benzimidazol-2-one for the components listed, are listed in Table 11. [Table 11-1] [Table 11-2] [Table 11-3]

[0198] Synthesis of 2-(4-methyl-3-(2-methyl-4-pyrazolo[1,5-a]pyrazin-3-yl-phenyl)-2-oxo-benzimidazol-1-yl)acetic acid [ka] Scheme 18

[0199] 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 gray solid. LCMS (ES+, method 4): 1.61 min, m / z 414.2 [M+H] +

[0200] Table 12 lists intermediates synthesized following the same procedure as intermediate xii-1 (Scheme 18), substituting 3-(4-bromo-2-methylphenyl)-4-methyl-1H-benzimidazol-2-one for the indicated building blocks. [Table 12-1] [Table 12-2] [Table 12-3]

[0201] Synthesis of the final compound [ka] Scheme 19

[0202] 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×vacuum, 3×N2) and heated to 95° C. After 2.5 hours, the mixture was cooled to room temperature and filtered. The solids were rinsed with EtOAc. The filtrate was reduced in vacuo and purified via flash chromatography (0-100% EtOAc in petroleum ether, then 0-20% MeOH in DCM) and heated. iRecrystallization 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 minutes, m / z 466.6 [M+H] + 1H NMR (400 MHz, DMSO-d6) δ 9.03 - 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

[0203] [ka] Scheme 20 Method B: Example 18: A solution of 2-[3-(5-bromo-2-pyridyl)-4-methyl-2-oxo-benzimidazol-1-yl]-N-(2,2,2-trifluoroethyl)acetamide (100 mg, 0.226 mmol, 1.0 eq), 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 eq), NaCO (47.8 mg, 0.451 mmol, 2.0 eq) and Pd(dppf)Cl (18.3 mg, 0.0226 mmol, 0.1 eq) in 1,4-dioxane (1.0 mL) and HO (0.1 mL) was stirred at 100 °C under N overnight. The reaction mixture was diluted with EtOAc (3 mL). The layers were separated, and the aqueous phase was extracted with EtOAc (10 mL × 3). The organic layers were combined, washed with water (5 mL × 3), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by prep-HPLC to give 2-[4-methyl-2-oxo-3-(5-pyrazolo[1,5-a]pyridin-3-yl-2-pyridyl)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] + 1H NMR (400 MHz, DMSO-d6) δ 9.00 - 8.96 (m, 2H), 8.81 (d, J = 7.0 Hz, 1H), 8.61 (s, 1H), 8.38 - 8.36 (m, 1H), 8.13 (d, J = 9.0 Hz, 1H), 7.68 (d, J = 8.2 Hz, 1H), 7.43 - 7.42 (m, 1H), 7.06 - 7.02 (m, 2H), 6.99 (d, J = 7.7 Hz, 1H), 6.87 (d, J = 7.5 Hz, 1H), 4.64 (s, 2H), 4.02 - 3.93 (m, 2H), 1.89 (s, 3H) ppm

[0204] [ka] Scheme 21 Method C: Example 29: A solution of 2-[4-methyl-2-oxo-3-(6-pyrazolo[1,5-a]pyridin-3-yl-3-pyridyl)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-pyridyl)benzimidazol-2-one (17.9 mg, 21%) as a white solid. LCMS (ES+, method 3): 1.81 min, m / z 537.2 [M+H] + 1H NMR (400 MHz, DMSO-d6) δ 8.82 - 8.80 (m, 2H), 8.68 (d, J = 2.6 Hz, 1H), 8.60 (d, J = 9.0 Hz, 1H), 8.08 (d, J = 8.5 Hz, 1H), 7.94 - 7.91 (m, 1H), 7.49 - 7.45 (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

[0205] [ka] Scheme 22 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 eq), (2S)-2-(difluoromethyl)pyrrolidine (24.3 mg, 0.200 mmol, 1.1 eq), HATU (83.1 mg, 0.219 mmol, 1.5 eq) and DIPEA (117 mg, 0.911 mmol, 5.0 eq) 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. LCMS (ES+, method 3): 4.45 min, m / z 488.2 [M+H] + 1H NMR (400 MHz, DMSO-d6) δ 8.78 (d, J = 7.0 Hz, 1H), 8.47 (s, 1H), 8.07 (d, J = 9.0 Hz, 1H), 7.91 (d, J = 8.5 Hz, 2H), 7.62 (d, J = 8.3 Hz, 2H), 7.40 - 7.36 (m, 1H), 7.21 (d, J = 8.8 Hz, 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 = 24.7 Hz, 1H), 3.74 - 3.70 (m, 2H), 2.04 - 1.97 (m, 4H) ppm [Table 13-1] [Table 13-2] [Table 13-3] [Table 13-4] [Table 13-5] [Table 13-6] [Table 13-7] [Table 13-8] [Table 13-9] [Table 13-10] [Table 13-11] [Table 13-12] [Table 13-13] [Table 13-14] [Table 13-15]

[0206] (Biochemical assays for DDR1 and DDR2) The binding ability of compounds to DDR1 and DDR2 was quantified using the LanthaScreen Eu kinase binding assay. Recombinant human DDR1 (2.5 nM; aa440-876 containing a GST tag) and DDR2 (1.75 nM; aa427-855 containing a GST tag) were diluted in assay buffer (50 mM HEPES pH 7.3, 10 mM MgCl2, 1 mM EGTA, and 0.01% Tween) with various concentrations of compounds in a 384-well plate in a volume of 5 μL. After 30 minutes of incubation at room temperature, 2.5 μL of Eu-anti-GST antibody (diluted to 1 nM in assay buffer) plus Kinase Tracer 178 (diluted to 5 nM for DDR1 and 10 nM for DDR2 in assay buffer) was added to the plate. After 60 minutes of incubation at room temperature, time-resolved fluorescence was measured using a BMG Labtech PHERAstar plate reader. DMSO (1%) and reference compound (1 μM) were used to obtain the maximum and minimum assay signals, respectively. Data were analyzed using a four-parameter logistic model to obtain IC 50 Values ​​were calculated and at least two independent replicates were performed for each compound.

[0207] (bioactivity value) The following table (Table 14) shows the pICs of the above examples against DDR1 and DDR2 kinases. 50 Values ​​are shown (A:pIC 50 >8;B:8≥pIC 50 >7;C:7≥pIC 50 >6;D:pIC 50 ≦6; ND: Not determined) [Table 14]

Claims

1. Formula (I): 【Chemistry 1】 (I) [During the ceremony X 1 , X 2 and X 3 are each independently selected from carbon and nitrogen; X 1 , X 2 and X 3 at least two of are carbon; X 4 , X 5 , X 6 and X 7 are each independently selected from carbon and nitrogen; X 4 , X 5 , X 6 and X 7 at least two of are carbon; X 8 , X 9 , X 10 and X 11 are each independently selected from carbon and nitrogen; X 8 , X 9 , X 10 and X 11 at least two of are carbon; R 1 each occurrence independently represents halo, nitro, cyano, NR 9 R 10 , OR 11 , S.R. 9 , SO 2 NR 9 R 9 , SO 2 R 9 , CO 2 R 9 , C(O)R 9 ,CONR 9 R 9 , C 1 -C 4 Alkyl, NR 9 R 10 C is replaced by 1 -C 4 -Alkyl, OR 11 C is replaced by 1 -C 4 Alkyl, C 2 -C 4 Alkenyl, C 2 -C 4 Alkynyl, C 1 -C 4 selected from haloalkyl and cyclopropyl; R 3 are independently H and C 1 -C 4 alkyl; R 4 independently, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 0 -C 4 Alkylene-R 4a Selected from: R 4a independently, C 3 -C 8 cycloalkyl, phenyl, 5-, 6-, 9-, or 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl; the heterocycloalkyl or heteroaryl group may be monocyclic or bicyclic; and the cycloalkyl or heterocycloalkyl group may be selected from one R 12 group and / or 1 to 4 R 13 The phenyl or heteroaryl group may be optionally substituted by one R 12 group and / or 1 to 3 R 14 optionally substituted by groups; Alternatively, R 3 and R 4 together with the nitrogen atom to which they are both attached form a 4- to 10-membered heterocycloalkyl group or a 5- or 9-membered heteroaryl group; the heterocycloalkyl or heteroaryl group can be monocyclic or bicyclic; the heterocycloalkyl group can be a 4- to 10-membered heterocycloalkyl group or a 5- or 9-membered heteroaryl group ... 12 group and / or 1 to 4 R 13 The heteroaryl group may be optionally substituted by one R 12 group and / or 1 to 3 R 14 optionally substituted by groups; R 5 each occurrence independently represents H, halo, and C 1 -C 4 -alkyl, or two R 5 The groups and the carbon atoms to which they are attached together form C 3 -C 6 forming a cycloalkyl ring; R 6 each occurrence independently represents halo, nitro, cyano, NR 9 R 10 , OR 11 , S.R. 9 , SO 2 NR 9 R 9 , SO 2 R 9 , CO 2 R 9 , C(O)R 9 ,CONR 9 R 9 , C 1 -C 4 -Alkyl, NR 9 R 10 C is replaced by 1 -C 4 -Alkyl, OR 11 C is replaced by 1 -C 4 -Alkyl, C 2 -C 4 -Alkenyl, C 2 -C 4 -alkynyl, C 1 -C 4 - selected from haloalkyl and cyclopropyl; R 7 each occurrence independently represents halo, nitro, cyano, NR 9 R 10 , OR 11 , S.R. 9 , SO 2 NR 9 R 9 , SO 2 R 9 , CO 2 R 9 , C(O)R 9 ,CONR 9 R 9 , C 1 -C 4 -Alkyl, NR 9 R 10 C is replaced by 1 -C 4 -Alkyl 0 , OR 11 C is replaced by 1 -C 4 -Alkyl, C 2 -C 4 -Alkenyl, C 2 -C 4 -alkynyl, C 1 -C 4 - selected from haloalkyl and cyclopropyl; R 8a are independently H, halo, nitro, cyano, NR 9 R 10 , OR 11 , S.R. 9 , SO 2 NR 9 R 9 , SO 2 R 9 , CO 2 R 9 , C(O)R 9 ,CONR 9 R 9 , C 1 -C 4 -Alkyl, NR 9 R 10 C is replaced by 1 -C 4 -Alkyl, OR 11 C is replaced by 1 -C 4 -Alkyl, C 2 -C 4 -Alkenyl, C 2 -C 4 -alkynyl, C 1 -C 4 -haloalkyl and C 0 -C 4 -Alkylene-R 8c Selected from: R 8c independently, C 3 -C 6 -cycloalkyl and 3- to 7-membered heterocycloalkyl; the heterocycloalkyl group is joined to C via a carbon atom in the heterocycloalkyl ring. 0 -C 4 -alkylene; the cycloalkyl or heterocycloalkyl group is 13 optionally substituted by groups; R 9 each, if present, independently represents H and C 1 -C 4 -alkyl; or two R 9 The groups, together with the nitrogen atom to which they are attached, can consist of 0 to 4 R 15 C optionally substituted by a group 5 -C 8 - forming a heterocycloalkyl group; R 9a each, if present, independently represents H and C 1 -C 4 - alkyl; R 10 are each independently, when present, H, C 1 -C 4 -Alkyl, C(O)-C 1 -C 4 -Alkyl and S(O) 2 -C 1 -C 4 -alkyl; or R 9 and R 10 together with the nitrogen atom to which they are attached, form 0 to 4 R 15 C optionally substituted by a group 5 -C 8 - forming a heterocycloalkyl group; R 11 are each independently, when present, H, C 1 -C 4 -Alkyl, C(O)-C 1 -C 4 -Alkyl and C 1 -C 4 -haloalkyl; R 12 independently, C 3 -C 6 -cycloalkyl, phenyl, 5- or 6-membered heteroaryl, and 3- to 6-membered heterocycloalkyl; said cycloalkyl or heterocycloalkyl group is selected from 1 to 4 R 13 The phenyl or heteroaryl group may be optionally substituted by one to three R 14 optionally substituted by groups; R 13 each occurrence independently represents ═O, halo, nitro, cyano, NR 9 R 10 , OR 11 , S.R. 9 , SO 2 NR 9 R 9 , CO 2 R 9 , C(O)R 9 ,CONR 9 R 10 , C 1 -C 4 -Alkyl, OR 11 C is replaced by 1 -C 4 -Alkyl, NR 9 R 10 C is replaced by 1 -C 4 -Alkyl, C 2 -C 4 -Alkenyl, C 2 -C 4 -alkynyl, C 1 -C 4 -haloalkyl, C 6 -C 10 -aryl and C 3 -C 6 -cycloalkyl; R 14 each occurrence independently represents halo, nitro, cyano, NR 9 R 10 , OR 11 , S.R. 9 , SO 2 R 9 , SO 2 NR 9 R 10 , CO 2 R 9 , C(O)R 9 ,CONR 9 R 9 , C 1 -C 4 -Alkyl, C 2 -C 4 -Alkenyl, C 2 -C 4 -alkynyl, C 1 -C 4 -haloalkyl, OR 11 C is replaced by 1 -C 4 -Alkyl, NR 9 R 10 C is replaced by 1 -C 4 - selected from alkyl and cyclopropyl; R 15 each occurrence independently represents ═O, halo, nitro, cyano, NR 9a R 10 , OR 11 , S.R. 9 , SO 2 NR 9a R 9 , CO 2 R 9 , C(O)R 9 ,CONR 9a R 10 , C 1 -C 4 -Alkyl, OR 11 C is replaced by 1 -C 4 -Alkyl, NR 9a R 10 C is replaced by 1 -C 4 -Alkyl, C 2 -C 4 -Alkenyl, C 2 -C 4 -alkynyl, C 1 -C 4 -haloalkyl, C 6 -C 10 -aryl and C 3 -C 6 -cycloalkyl; 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; Any of the above alkyl, alkylene or cyclopropyl groups may, where chemically possible, be selected from halo, oxo, fluoro, nitro, cyano, NR a R b , OR a , S.R. a , CO 2 R a , C(O)R a ,CONR a R a , C 1 -C 4 -Alkyl, C 1 -C 4 -optionally substituted with 1 to 5 substituents, each independently at each occurrence, selected from the group consisting of haloalkyl and cyclopropyl; R a are each independently, when present, H, C 1 -C 4 -Alkyl and C 1 -C 4 -haloalkyl; and R b are each independently, when present, H, C 1 -C 4 -Alkyl, C(O)-C 1 -C 4 -Alkyl and S(O) 2 -C 1 -C 4 -alkyl]. or a pharmaceutically acceptable salt thereof.

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

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

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

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

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

7. R 8a But H and C 1 -C 4 7. The compound according to claim 1, wherein the aryl group is selected from the group consisting of aryl, ... and aryl.

8. X 1 , X 2 and X 3 The compound of any one of claims 1 to 7, wherein each is carbon.

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

10. X 4 , X 5 , X 6 and X 7 10. The compound of claim 1, wherein each is carbon.

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

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

12. The compound of any one of claims 1 to 11, having the formula:

13. 13. The compound of claim 12, wherein a is 1.

14. At least two R 4b 14. The compound of claim 12 or claim 13, wherein the group is F.

15. R 3a The compound of any one of claims 12 to 14, wherein is H.

16. R 4c But H and C 1 -C 4 16. The compound according to any one of claims 12 to 15, wherein the alkyl is selected from the group consisting of -alkyl.

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

18. The compound of formula (I) 【Transformation 3】 【Chemistry 4】 【Transformation 5】 2. The compound of claim 1, selected from:

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

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