Phenyl and pyridopyrazole derivatives as inhibitors of DDR1

Abstract

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

[0002] Discoidin domain receptors (DDR) DDR1 and DDR2 are type 1 transmembrane receptor tyrosine kinases (RTKs) with collagen receptor function (Vogel et al, Mol. Cell, 1997). DDR possesses a characteristic collagen-binding discoidin domain in its N-terminal extracellular domain. These domains are preceded by a short C-terminal tail by a peri-extracellular domain, a single transmembrane domain, a cytoplasmic co-membrane domain, and a catalytic kinase domain. Five isoforms of DDR1 (DDR1a-e) have been identified, arising from alternative splicing of the cytoplasmic domain. No other isoforms of DDR2 have been identified. DDR1 and DDR2 have broadly (but not completely) mutually exclusive expression profiles in epithelial cells and stroma, respectively. DDR is activated by binding to collagen, exhibiting broad specificity but preferring specific collagen types. Once activated, DDR is known to regulate cell adhesion, proliferation, and extracellular matrix remodeling. DDR is recognized as being upregulated in response to cellular activity and many forms of tissue injury, and such DDR is involved in diseases including cancer and atherosclerosis, as well as diseases characterized by fibrosis and inflammation. Inhibitors of DDR kinase activity may be useful as therapeutic agents in these disease areas.

[0003] As summarized in a recent review (Elkamhawy et al, Int. J. Mol. Sci., 2021), overexpression and / or activation of DDR1 and DDR2 are associated with various forms of cancer. Studies have shown that elevated DDR expression levels and mutations are found not only in primary tumor tissues such as lung, pancreas, prostate, breast, brain, ovary, and liver, but also in many cancer cell lines. DDR1 has been found to be a prognostic marker for non-small cell lung cancer (NSCLC). Recent studies have demonstrated that siRNA-mediated downregulation of DDR1 suppresses malignancy, migration, invasion, and survival of melanoma cells. The DDR1 protein was also found to be expressed in 63% of serous ovarian cancer tissue, but not in normal ovarian surface epithelium. DDR1 has also been shown to be involved in glioblastoma cell invasion and epithelial-mesenchymal transition (EMT). DDR1 expression was found in 50.5% of gastric cancer tissue. DDR1 has been found to regulate the proliferation of triple-negative breast cancer by modulating tumor-infiltrating CD4+ and CD8+ T cells. There is also strong evidence suggesting that DDR2 may be a potential biomarker and molecular target for various cancers. For example, DDR2 overexpression has been reported to be associated with NSCLC, thyroid cancer, Hodgkin lymphoma, nasopharyngeal carcinoma, prostate cancer, and head and neck squamous cell carcinoma. Studies have shown that DDR2 is involved in 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. For example, G1486T(DDR1) and A496S(DDR1) are found in lung cancer, N502S(DDR1), A533S(DDR1), and A803V(DDR1) in acute myeloid leukemia (AML), and S768R(DDR2) in squamous cell carcinoma. DDRs also play a role in cancer growth by regulating how tumor cells interact with the surrounding collagen matrix. This role of DDRs becomes even more pronounced when considering their role as extracellular matrix receptors.The extracellular matrix (ECM) not only controls cell proliferation, survival, migration, and invasion, but also gives structural properties to the tissue surrounding the tumor. In metastatic cancer, the physiological interaction between tumor cells and the microenvironment, represented by the extracellular matrix, is disrupted. Type I collagen, a major component of the tumor extracellular matrix, exhibits a dense and distorted structure in malignant cancers and is involved in tumorigenesis and metastasis. Therefore, the discovery of DDR as a collagen receptor represents a new target in controlling tumor progression.

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

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

[0006] Furthermore, it is an object of certain embodiments of the present invention to provide novel compounds useful for the treatment of diseases such as cancer and fibrotic diseases. This compound may be an inhibitor of DDR1 and / or DDR2. It is an object of certain embodiments of the present invention to provide a compound having an activity comparable to that of existing DDR1 and / or DDR2 inhibitors. An object of certain embodiments of the present invention is to provide a compound having increased activity against existing DDR1 and / or DDR2 inhibitors.

[0007] Certain embodiments of the present invention meet some or all of the above objects. Detailed Description of the Invention

[0008] The present invention relates to formula (I):

Chemical formula

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

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

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

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

[0013] In an embodiment, the compound of formula (I) is a compound of formula (VI): [Chemical formula] (wherein Z 1 , Z 2 , X 1 , R 1 , R 3 , R 4 , R 7 , R 8a , R 8b and m are as described above for the compound of formula (I)) is a compound of.

[0014] In an embodiment, the compound of formula (I) is a compound of formula (VII): [Chemical formula] (wherein X 1 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8b , m and n are as described above for the compound of formula (I)) is a compound of.

[0015] In an embodiment, the compound of formula (I) is a compound of formula (VIII): [Chemical formula] (wherein X 1 , R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8b and m are as described above for the compound of formula (I)) is a compound of.

[0016] In an embodiment, the compound of formula (I) is of formula (IX): [Chemical formula] (wherein X 1 , R 1 , R 3 , R 4 , R 7 , R 8b and m are as described above for the compound of formula (I)) is a compound of.

[0017] In an embodiment, the compound of formula (I) is of formula (X): [Chemical formula] (wherein X 1 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8a , R 8b , m and n are as described above for the compound of formula (I)) is a compound of.

[0018] In an embodiment, the compound of formula (I) is of formula (XI): [Chemical formula] (wherein X 1 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8a , m and n are as described above for the compound of formula (I)) is a compound of.

[0019] In an embodiment, the compound of formula (I) is of formula (XII):<000093​​ (In the formula, X 1 , R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8a (and m are as described above for the compound of formula (I)) It is a compound of [the compound].

[0020] In this embodiment, the compound of formula (I) is formula (XIII): [ka] (In the formula, X 1 , R 1 , R 3 , R 4 , R 7 , R 8a (and m are as described above for the compound of formula (I)) It is a compound of [the compound].

[0021] In this embodiment, the compound of formula (I) is formula (XIV): [ka] [In the formula, Z 1 , Z 2 , X 1 , R 1 , R 7 And m are as described above for the compound of formula (I); R 4b Each is selected from H and F, and at least two R 4b The base is F; R 3a These are independently selected from H and C1-C4-alkyl groups; R 4c These are independently selected from H, C1-C4-alkyl and C4-C6-cycloalkyl; or R 3a and R 4ctogether with the carbon and nitrogen to which they are attached to form a 4- to 6-membered heterocycloalkyl group is a compound of

[0022] In an embodiment, the compound of formula (I) is of formula (XV): [Chemical formula] [wherein X 1 , R 1 , R 5 , R 6 , R 7 , R 8b and m are as described above for the compound of formula (I); here, R 3a , R 4b and R 4c are as described above for formula (XIV)] is a compound of

[0023] The following embodiments apply to any of the compounds of formulas (I) to (XV). These embodiments are independent and interchangeable. If chemically acceptable, any one embodiment may be combined with other embodiments. In other words, any of the features described in the following embodiments can be combined with the features described in one or more other embodiments (if chemically acceptable). In particular, if a compound is exemplified or illustrated herein, any two or more of the following embodiments, expressed at any level of generality, that include that compound may be combined to provide further embodiments that form part of the present disclosure.

[0024] Z 1 is NR 8b and Z 2 is CH; or Z 1 is CR 8a and Z 2 is NH, in either case.

[0025] Z 1 is NR 8b and Z2 CR 8a It is fine. Z 1 NR 8b And Z 2 It may be CH. 1 NMe is Z 2 CR 8a It is fine. Z 1 NMe is Z 2 CH may also be used.

[0026] Z 1 CR 8a And Z 2 NR 8b It is fine. Z 1 CR 8a And Z 2 It may also be NH.

[0027] X 1 There may be N of them. 1 CR 7a That's fine.

[0028] m can be 0.

[0029] m may be 1. If m is 1, a single R 1 The basis is, NR 6 It may be located ortho to the given point. If m is 1, a single R 1 The base is NR 6 It may be located in parallel with respect to m. If m is 1, a single R 1 The base is NR 6 It may be located parallel to it.

[0030] m may also be 2.

[0031] R 1 is halo, nitro, cyano, OR 11 , C1-C4-alkyl, NR 9 R 10 C1-C4 alkyl, OR substituted with 11C1-C4-alkyl, C1-C4-haloalkyl, and cyclopropyl substituted with R can be independently selected. 1 These are, independently, Halo, OR 11 , can be selected from C1-C4-alkyl, C1-C4-haloalkyl, and cyclopropyl. 1 Each of these can be independently selected from halo and C1-C4-alkyl. 1 Each of these can be independently a halo, for example, a fluorocarbon. 1 Each of these may independently be a C1-C4 alkyl group, for example, methyl.

[0032] m may be 1, and one R 1 The base is F, and NR 6 It is located in the ortho position relative to the other position.

[0033] n may be 0.

[0034] n may be 1, or it may be 2.

[0035] R 2 These are, independently, Halo, Nitro, Cyano, and OR. 11 , C1-C4-alkyl, NR 9 R 10 C1-C4 alkyl, OR substituted with 11 C1-C4-alkyl, C1-C4-haloalkyl, and cyclopropyl substituted with R can be selected. 2 These are, independently, Halo, OR 11 , can be selected from C1-C4-alkyl, C1-C4-haloalkyl, and cyclopropyl. 2 Each of these can be independently selected from halo and C1-C4-alkyl. 2 Each of these can be a halo, for example, a fluorocarbon. 2 Each of these may independently be a C1-C4 alkyl group, for example, methyl.

[0036] R 5Each of these can be independently selected from H, fluoro, and C1-C4-alkyl. 5 Each of these is independently selected from H, fluoro, and C1-C4-alkyl, or two R 5 The groups and the carbon atoms bonded to them may together form a C3-C6 cycloalkyl ring. 5 Each of these is independently selected from H and C1-C4-alkyl, or two R 5 The carbon atoms to which the group is bonded may come together to form a C3-C6 cycloalkyl ring. 5 Each of these can be independently selected from H and C1-C4-alkyl groups, such as methyl.

[0037] R 5 However, each could be H, or R 5 Each of these may be H on one side and a C1-C4-alkyl group, such as methyl. 5 Each of these may be a C1-C4 alkyl group, for example, methyl.

[0038] R 6 H may also be used. 6 This may be a C1-C4 alkyl group, for example, methyl.

[0039] R 7 is halo, nitro, cyano, OR 11 , C1-C4-alkyl, NR 9 R 10 C1-C4 alkyl, OR substituted with 11 R may be independently selected from C1-C4-alkyl, C1-C4-haloalkyl, and cyclopropyl substituted with R. 7 Independently, Halo, OR 11 , can be selected from C1-C4-alkyl, C1-C4-haloalkyl, and cyclopropyl. 7 R can be independently selected from halo and C1-C4 alkyl. If present, 7 This may be a halo, for example, a fluorocarbon. 7This may be a C1-C4 alkyl group, for example, methyl.

[0040] R 7a H may also be used. 7a is halo, nitro, cyano, OR 11 CO2R 9 CONR 9 R 9 , C1-C4-alkyl, NR 9 R 10 C1-C4 alkyl, OR substituted with 11 The substituted C1-C4-alkyl, C1-C4-haloalkyl, and cyclopropyl groups may be independently selected. 7a Hello, OR 11 These can be independently selected from C1-C4-alkyl, C1-C4-haloalkyl, and cyclopropyl.

[0041] R 7 H is X 1 R may be N. 7 H is X 1 CR 7a It is also acceptable. 7 H is X 1 CH may also be used. 7 H is X 1 CR 7a This is fine, and here R 7a is halo, nitro, cyano, OR 11 CO2R 9 CONR 9 R 9 , C1-C4-alkyl, NR 9 R 10 C1-C4 alkyl, OR substituted with 11 The following are independently selected from C1-C4-alkyl, C1-C4-haloalkyl, and cyclopropyl substituted with .

[0042] R 8a H may also be used. 8a This is halo, C1-C4-alkyl, NR 9 R 10 C1-C4 alkyl, OR substituted with11 C1-C4-alkyl, C1-C4-haloalkyl and C0-C4-alkylene-R substituted with 8c You may choose from R. 8a R may be selected from H, halo, C1-C4-alkyl, C1-C4-haloalkyl, and cyclopropyl. 8a R may be selected from H, C1-C4-alkyl, C1-C4-haloalkyl, and cyclopropyl. 8a This may be selected from C1-C4-alkyl (e.g., methyl) and C1-C4-haloalkyl (e.g., CF3). 8a This may be a C1-C4 alkyl group (for example, methyl).

[0043] R 8b R may be H. 8b C1-C4-alkyl, NR 9 R 10 C2-C4 alkyl, OR substituted with 11 Substituted C2-C4-alkyl, C1-C4-haloalkyl and C0-C4-alkylene-R 8c You may choose from the following: R 8b R may be selected from H, C1-C4-alkyl, and cyclopropyl. 8b This may be a C1-C4 alkyl group (for example, methyl).

[0044] R 8b These are independently H, C1-C4-alkyl, NR 9 R 10 C2-C4 alkyl, OR substituted with 11 C2-C4-alkyl, C3-C4-alkenyl, C3-C4-alkynyl, C1-C4-haloalkyl and C0-C4-alkylene-R substituted with 8c Selected from.

[0045] R 8a H is R 8b It may also be a C1-C4 alkyl group (for example, methyl).

[0046] R9 Each of these may be independently selected from H and C1-C4-alkyl groups.

[0047] R 10 Each of these may be independently selected from H, C1-C4-alkyl, C(O)-C1-C4-alkyl, and S(O)2-C1-C4-alkyl.

[0048] R 11 Each of these may be independently selected from H, C1-C4-alkyl, and C1-C4-haloalkyl. 11 Each of these may be independently selected from H and C1-C4-alkyl. 11 Each of these is independently a C1-C4 alkyl group, such as methyl.

[0049] R 12 The heteroaryl group may be independently selected from a 5-membered or 6-membered heteroaryl group, wherein the heteroaryl group comprises 1 to 3 R 14 The base may be substituted as desired. 12 The heteroaryl group may be independently selected from a 5-membered heteroaryl group, such as imidazole, and the heteroaryl group may consist of 1 to 3 R 14 The base may be replaced as desired.

[0050] R 13 These are, independently, oxo, fluoro, and OR. 11 CO2R 9 CO2NR 9 R 9 , C1-C4-alkyl, NR 9 R 10 C1-C4 alkyl, OR substituted with 11 R may be selected from C1-C4-alkyl, C1-C4-haloalkyl, and cyclopropyl substituted with R. 13 These are, independently, oxo, OR 11 , can be selected from C1-C4 alkyl and cyclopropyl. 13 Each of these can be independently selected from oxo and C1-C4-alkyl groups. 13Each of these may independently be a C1-C4 alkyl group, for example, methyl.

[0051] R 14 These are, independently, Halo, Nitro, Cyano, and OR. 11 , C1-C4-alkyl, NR 8 R 9 C1-C4 alkyl, OR substituted with 11 C1-C4-alkyl, C1-C4-haloalkyl, and cyclopropyl substituted with R can be selected. 14 These are, independently, Halo, OR 11 , can be selected from C1-C4-alkyl, C1-C4-haloalkyl, and cyclopropyl. 14 Each of these can be independently selected from halo and C1-C4-alkyl. 14 Each of these can be a halo, for example, a fluorocarbon. 14 Each of these may independently be a C1-C4 alkyl group, for example, methyl.

[0052] R 3 H is; R 4 These are C1-C6-alkyl, C1-C6-haloalkyl, and C0-C4-alkylene-R 4a Selected independently of; here, R 4a The group is independently selected from C3-C8-cycloalkyl, phenyl, 5-membered, 6-membered, 9-membered or 10-membered heteroaryl and 4- to 10-membered heterocycloalkyl groups; the heterocycloalkyl or heteroaryl group may be monocyclic or bicyclic; the cycloalkyl or heterocycloalkyl group may have one R 12 Base and / or 1 to 4 R 13 The group may be optionally substituted with a group, and the phenyl group or heteroaryl group may be one R 12 Base and / or 1-3 R 14 The base may be replaced as desired; or, R 3 and R 4These, together with the nitrogen atom to which they are bonded, form a 4- to 10-membered heterocycloalkyl group or a 5- or 9-membered heteroaryl group; the heterocycloalkyl group has one R 12 Base and / or 1 to 4 R 13 The group may be substituted as desired; the heteroaryl group may have one R 12 Base and / or 1-3 R 14 The base may be replaced as desired.

[0053] R 3 H is; R 4 These are C1-C6-alkyl, C1-C6-haloalkyl, and C0-C4-alkylene-R 4a Selected independently of; here, R 4a The group is independently selected from C3-C8-cycloalkyl, phenyl, 5-membered, 6-membered, 9-membered or 10-membered heteroaryl and 4- to 10-membered heterocycloalkyl groups; the heterocycloalkyl or heteroaryl group may be monocyclic or bicyclic; the cycloalkyl or heterocycloalkyl group may have 1 to 4 R 13 The phenyl group or heteroaryl group, which may be optionally substituted with a group, has 1 to 3 R 14 The base may be replaced as desired; or, R 3 and R 4 These, together with the nitrogen atom to which they are bonded, form a 4- to 10-membered heterocycloalkyl group or a 5- or 9-membered heteroaryl group; the heterocycloalkyl group has 1 to 4 R 13 The group may be substituted as desired; the heteroaryl group may have 1 to 3 R 14 The base may be replaced as desired.

[0054] R 3 H may also be used.

[0055] R 4 These include C1-C6-alkyl, C1-C6-haloalkyl, and C0-C4-alkylene-R4a You may choose from the following.

[0056] R 4 This may be selected from C1-C6-alkyl and C1-C6-haloalkyl. 4 This may be selected from C2-C3-alkyl and C2-C3-haloalkyl. 4 It may also be a C1-C4-haloalkyl group. 4 It may also be a C2-C3-haloalkyl group. 4 This may be 2,2,2-trifluoroethyl.

[0057] R 4 Examples of the basis include the following: [ka]

[0058] R 4 is C0-C4-alkylene-R 4a It is also acceptable. 4 CH2-R 4a It is also acceptable. 4 R 4a That's fine.

[0059] R 4a The group is independently selected from C3-C8-cycloalkyl, phenyl, 5-membered, 6-membered, 9-membered or 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl, wherein the heterocycloalkyl or heteroaryl group may be monocyclic or bicyclic; the cycloalkyl or heterocycloalkyl group may have 1 to 4 R 13 The group may be optionally substituted with a group, and the phenyl group or heteroaryl group may have 1 to 3 R 14 The base may be replaced as desired.

[0060] R 4a The R is selected from C3-C8-cycloalkyl and 4- to 10-membered heterocycloalkyl groups, and the cycloalkyl or heterocycloalkyl group has one R12 Base and / or 1 to 4 R 13 The base may be substituted as desired. 4a The cycloalkyl group is selected from C3-C8-cycloalkyl groups and 4- to 10-membered heterocycloalkyl groups, and the cycloalkyl group or heterocycloalkyl group has 1 to 4 R groups. 13 The base may be replaced as desired.

[0061] R 4 The cycloalkyl group is selected from CH2-C3-C8-cycloalkyl groups and CH2-4-membered to 10-membered heterocycloalkyl groups, and the cycloalkyl group or heterocycloalkyl group has one R 12 Base and / or 1 to 4 R 13 The base may be substituted as desired. 4 The cycloalkyl group is selected from CH2-C3-C8-cycloalkyl groups and CH2-4 to 10-membered heterocycloalkyl groups, and the cycloalkyl group or heterocycloalkyl group has 1 to 4 R groups. 13 The base may be replaced as desired.

[0062] R 4 The R is selected from C3-C8-cycloalkyl and 4- to 10-membered heterocycloalkyl groups, and the cycloalkyl or heterocycloalkyl group has one R 12 Base and / or 1 to 4 R 13 The base may be substituted as desired. 4 The cycloalkyl group is selected from C3-C8-cycloalkyl groups and 4- to 10-membered heterocycloalkyl groups, and the cycloalkyl group or heterocycloalkyl group has 1 to 4 R groups. 13 The base may be replaced as desired.

[0063] R 4 Examples of the basis include the following: [ka]

[0064] R 4aThe phenyl group or heteroaryl group is independently selected from phenyl and 5-membered or 6-membered heteroaryl groups; the phenyl group or heteroaryl group is one R 12 Base and / or 1-3 R 14 The base may be substituted as desired. 4a However, these may be independently selected from phenyl and 5-membered or 6-membered heteroaryl groups; the phenyl or heteroaryl group may have 1 to 3 R 14 The base may be substituted as desired. 4a is independently phenyl; the phenyl group is one R 12 Base and / or 1-3 R 14 The base may be substituted as desired. 4a This may independently be phenyl; the phenyl group may have 1 to 3 R 14 The base may be substituted as desired. 4a The heteroaryl group is independently a 5-membered or 6-membered heteroaryl group; the heteroaryl group is one R 12 Base and / or 1-3 R 14 The base may be substituted as desired. 4a The group is independently a 5-membered or 6-membered heteroaryl group; the heteroaryl group comprises 1 to 3 R 14 The base may be replaced as desired.

[0065] R 4 The phenyl group or heteroaryl group is independently selected from CH2-phenyl or CH2-5-membered or 6-membered heteroaryl, and the phenyl group or heteroaryl group has one R 12 Base and / or 1 to 3 R 14 The base may be substituted as desired. 4 The phenyl group or the heteroaryl group is independently selected from CH2-phenyl or CH2-5-membered or 6-membered heteroaryl groups, and the phenyl group or the heteroaryl group has 1 to 3 R 14 The base may be substituted as desired. 4 This is independently CH2-phenyl, and the phenyl is one R 12 Base and / or 1-3 R 14The base may be substituted as desired. 4 Each is independently CH2-phenyl, and the phenyl group has 1 to 3 R 14 The base may be substituted as desired. 4 Each is independently a CH2-5 membered or 6 membered heteroaryl group, and the heteroaryl group has one R 12 Base and / or 1-3 R 14 The base may be substituted as desired. 4 Each is independently a CH2-5 membered or 6 membered heteroaryl group, and the heteroaryl group has 1 to 3 R 14 The base may be replaced as desired.

[0066] R 4 The group is independently selected from phenyl or a 5- or 6-membered heteroaryl group, and the phenyl or heteroaryl group has one R 12 Base and / or 1 to 3 R 14 The base may be substituted as desired. 4 The group is independently selected from phenyl or a 5- or 6-membered heteroaryl group, and the phenyl or heteroaryl group has 1 to 3 R 14 The base may be substituted as desired. 4 It is independently phenyl, and the phenyl group has one R 12 Base and / or 1-3 R 14 The base may be substituted as desired. 4 Independently, the phenyl group has 1 to 3 R 14 The group may be a phenyl group which may be optionally substituted. 4 Each is independently a 5-membered or 6-membered heteroaryl group, wherein the heteroaryl group has one R 12 Base and / or 1-3 R 14 The base may be substituted as desired. 4 Each is independently a 5-membered or 6-membered heteroaryl group, wherein the heteroaryl group has 1 to 3 R 14 The base may be replaced as desired.

[0067] R4 The group is independently selected from phenyl or a 6-membered heteroaryl group, and the phenyl or 6-membered heteroaryl group has one R 14 The base may be substituted at the meta position. 14 The base is OR 11 The R at the meta position may be selected from C1-C4-alkyl, C1-C4-alkyl, and C1-C4-haloalkyl groups. 14 The base is OR 11 (For example, a C1-C4 alkyl group substituted with -(CH3)2-OH). R at the meta position. 14 The group may be a C1-C4 haloalkyl group, for example, CF3.

[0068] R 4 R may be a 6-membered heteroaryl group. 4 R may be phenyl. 4 This is one R 14 It may also be a phenyl compound substituted at the meta position with a group. 14 R 14a It is also acceptable. 4 Examples of the basis include the following: [ka] (In the formula, R 14a Halo, Nitro, Cyano, NR 8 R 9 , OR 10 , SR 8 SO2R 8 SO2NR 8 R 8 CO2R 8 , C(O)R 8 CONR 8 R 8 , C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl, OR 11 C1-C4 alkyl, NR substituted with 8 R 9 Selected from C1-C4 alkyl and cyclopropyl groups substituted with (where z is an integer selected from 1 and 2).

[0069] R 4 Examples of the basis include the following: [ka]

[0070] R 3 and R 4 These, together with the nitrogen atom to which they are bonded, form a 4- to 10-membered heterocycloalkyl group, or a 5- or 9-membered heteroaryl group; the heterocycloalkyl group has one R 12 Base and / or 1 to 4 R 13 The group may be optionally substituted with a heteroaryl group, and the heteroaryl group may be one R 12 Base and / or 1-3 R 14 The base may be substituted as desired. 3 and R 4 These, together with the nitrogen atom to which they are bonded, form a 4- to 10-membered heterocycloalkyl group, or a 5- or 9-membered heteroaryl group; the heterocycloalkyl group has 1 to 4 R 13 The heteroaryl group may be substituted as desired, and the heteroaryl group may have 1 to 3 R 14 The base may be replaced as desired.

[0071] R 3 and R 4 These, together with the nitrogen atom to which they are bonded, form a 5-membered or 9-membered heteroaryl group; the heteroaryl group has one R 12 Base and / or 1-3 R 14 The base may be substituted as desired. 3 and R 4 These, together with the nitrogen atom to which they are bonded, form a 5-membered or 9-membered heteroaryl group; the heteroaryl group has 1 to 3 R 14 The base may be substituted as desired. 3 and R 4These may, together with the nitrogen atom to which they are bonded, form a 5-membered heteroaryl group; where the heteroaryl group is one R 12 Base and / or 1-3 R 14 The base may be substituted as desired. 3 and R 4 These may, together with the nitrogen atom to which they are bonded, form a 5-membered heteroaryl group; the heteroaryl group may have 1 to 3 R 14 The base may be replaced as desired.

[0072] NR 3 R 4 Examples of the basis include the following: [ka]

[0073] R 3 and R 4 These may, together with the nitrogen atom to which they are bonded, form a 4- to 10-membered heterocycloalkyl group; the heterocycloalkyl group may have one R 12 Base and / or 1 to 4 R 13 The base may be substituted as desired. 3 and R 4 These, together with the nitrogen atom to which they are bonded, form a 4- to 10-membered heterocycloalkyl group; the heterocycloalkyl group has 1 to 4 R 13The heterocycloalkyl group may be optionally substituted with a R group. The heterocyclic 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. To avoid misunderstanding, heterocycloalkyl groups referred to in this paragraph have one R group. 12 Base and / or 1 to 4 R 13 The group may be optionally substituted with R. The heterocycloalkyl groups referred to in this paragraph have 1 to 4 R groups. 13 The group may be substituted as desired. The heterocyclic group is pyrrolidine, and one R 13 The group may be substituted at the 2nd position. The heterocyclic group is pyrrolidine, and one R 13 The group may be substituted at the 3rd position. The heterocyclic group is piperidine, and one R 13 The group may be substituted at the 2nd position. The heterocyclic group is piperidine, and one R 13 The group may be substituted at the 3rd position. The heterocyclic group is piperidine, and one R 13 The group may be substituted at position 4. The heterocyclic group is morpholine, and one R 13 The group may be substituted at position 2. The heterocyclic group is morpholine, and one R 13 In some cases, the third position is substituted in the base. 13 The group is C1-C4-alkyl, OR 11 A C1-C4-alkyl (e.g., -(CH3)2-OH) and a C1-C4-haloalkyl (e.g., -CF3) substituted with R may be selected. 13 The group may be a C1-C4 haloalkyl group (e.g., -CHF2 or -CF3).

[0074] NR 3 R 4Examples of the basis include the following: [ka]

[0075] R 3 and R 4 , NR 3 R 4 The group may be selected to contain either two -CHF groups or three CF groups.

[0076] NR 3 R 4 The formula is: [ka] (In the formula, R 4b Each is selected from H and F; at least one R 4b The base is F; R 3a Each is independently selected from H and C1-C4-alkyl; R 4c Each is independently selected from H, C1-C4-alkyl and C4-C6-cycloalkyl; or R 3a and R 4c (These, together with the carbon and nitrogen atoms to which they are bonded, form 4- to 6-membered heterocycloalkyl groups.) They may have it.

[0077] At least two R 4b The base may be F. Two R 4b The base is F, and one R 4b The base may be H. 4b The base may be F.

[0078] R 3a R is independently selected from H and C1-C4-alkyl groups; 4c R may be independently selected from H, C1-C4-alkyl, and C4-C6-cycloalkyl. 3a H is; R4c The alkyl group may be independently selected from H, C1-C4-alkyl, and C4-C6-cycloalkyl groups. The alkyl group or cycloalkyl group may be unsubstituted.

[0079] R 3a and R 4c These may, together with the carbon and nitrogen atoms to which they are bonded, form a 4- to 6-membered heterocycloalkyl group. 3a and R 4c These may, together with the carbon and nitrogen atoms to which they are bonded, form a five-membered heterocycloalkyl group. The heterocycloalkyl group may be unsubstituted.

[0080] The compound of formula (I) can be selected from the following: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[0081] In one aspect of the present invention, a compound of the present invention is provided for use as a pharmaceutical.

[0082] In another embodiment, compounds of the present invention are provided for use in the treatment of diseases regulated by DDR1 and / or DDR2. Compounds of any formula disclosed herein may be used for use in the treatment of diseases treatable by inhibition of DDR1 and / or DDR2.

[0083] In another embodiment of the present invention, compounds of the present invention are provided for use in the treatment of a disease or disorder selected from kidney disease, liver disease, inflammatory disease, cardiovascular disease, acute and chronic organ transplant rejection, fibrous disease, and cancer.

[0084] One aspect of the present invention provides a method for treating a disease or disorder regulated by DDR1 and / or DDR2, the method comprising administering a therapeutic dose of the compound of the present invention to a patient in need of treatment.

[0085] The treatment method may also be a method of treating a condition that can be treated by inhibiting DDR1 and / or DDR2.

[0086] The present invention also provides a method for treating a disease or disorder selected from kidney disease, liver disease, inflammatory disease, cardiovascular disease, acute and chronic organ transplant rejection, fibrotic disease, and cancer, comprising administering a therapeutic dose of any compound of any formula disclosed herein to a patient in need of treatment.

[0087] Kidney diseases include acute kidney injury, as well as chronic kidney diseases, regardless of the presence or absence of proteinuria, including end-stage renal disease (ESRD). These include decreased creatinine clearance and decreased glomerular filtration rate, microalbuminuria, albuminuria and proteinuria, glomerulosclerosis with or without marked hypercellularity of the reticular mesangial matrix (especially diabetic nephropathy and amyloidosis), focal thrombosis of glomerular capillaries (especially thrombotic microangiopathy), systemic fibrinoid necrosis, ischemic lesions, malignant nephrosclerosis (e.g., ischemic regression, decreased renal blood flow and renal arteriovenous disease), swelling and proliferation of intracapillary cells (endothelial and mesangial) and / or extracapillary cells (crescent cells) such as glomerulonephritis, focal segmental glomerulosclerosis, IgA nephropathy, vasculitis / systemic diseases, and acute and chronic kidney transplant rejection. Early and advanced Alport syndrome are also included in kidney diseases.

[0088] Inflammatory diseases include arthritis, osteoarthritis, multiple sclerosis, systemic lupus erythematosus, inflammatory bowel disease, and impaired elimination, 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 other diffuse parenchymal lung diseases with various etiologies, such as ectopic drug-induced fibrosis, occupational and / or environmentally induced fibrosis, systemic diseases and vasculitis, granulomatous diseases (sarcoidosis, hypersensitivity pneumonitis), collagen vascular diseases, and radiation-induced fibrosis.

[0089] Vascular diseases include atherosclerosis, thrombotic vascular disease and thrombotic microangiopathy, proliferative artery disease (e.g., swelling and nodular thickening of endomysial cells surrounded by a mucinous extracellular matrix), atherosclerosis, decreased vascular compliance (e.g., rigidity, decreased ventricular compliance and decreased vascular compliance), and endothelial dysfunction.

[0090] Cardiovascular diseases include acute coronary syndrome, coronary heart disease, myocardial infarction, arterial and pulmonary hypertension, cardiac arrhythmias such as atrial fibrillation, stroke, and other vascular injuries.

[0091] Fibrotic diseases include, but are not limited to, cardiomyopathy and vascular fibrosis, renal fibrosis, hepatic fibrosis, pulmonary fibrosis, cutaneous fibrosis, scleroderma and encapsulated peritonitis, systemic sclerosis, Alport syndrome, chronic kidney disease, NASH, interstitial lung disease, and systemic sclerosis.

[0092] In certain embodiments, the compounds of the present invention are used in the treatment of cancer or in methods for treating cancer. Examples include, but are not limited to, liver cancer, bladder cancer, hepatic cancer, squamous cell carcinoma of the lung, non-small cell lung cancer, adenocarcinoma of the lung, small cell lung cancer, various types of head and neck cancer, breast cancer, colon cancer, colorectal cancer, peritoneal cancer, hepatocellular carcinoma, gastrointestinal cancer, esophageal cancer, endometrial cancer or uterine cancer, salivary gland cancer, squamous cell carcinoma, pituitary cancer, astrocytoma, soft tissue sarcoma, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, kidney cancer, liver cancer, prostate cancer, vulvar cancer, thyroid cancer, liver cancer, brain tumor, endometrial cancer, testicular cancer, bile duct cancer, gallbladder cancer, gastric cancer, and melanoma. In certain embodiments, the cancer is selected from bladder cancer, pancreatic cancer, breast cancer, lung cancer, ovarian cancer, and glioblastoma.

[0093] In another aspect of the present invention, a pharmaceutical composition is provided, the composition comprising the compound of the present invention and a pharmaceutically acceptable excipient.

[0094] In one embodiment, the pharmaceutical composition may be a combination product containing additional pharmaceutically active agents.

[0095] In one aspect of the present invention, the use of the compounds of the present invention in the manufacture of pharmaceuticals for use in the treatment of any condition disclosed herein is provided.

[0096] The following are definitions of terms used in this application. Terms not defined herein are given in the ordinary sense that a person skilled in the art would understand them to mean.

[0097] The term "halo" refers to one of the halogens in Group 17 of the periodic table. Specifically, this term refers to fluorine, chlorine, bromine, and iodine. Preferably, this term refers to chlorine or fluorine.

[0098] The term "alkyl" refers to a linear or branched hydrocarbon chain. For example, the term "C 1-6"Alkyl" refers to a linear or branched hydrocarbon chain containing 1, 2, 3, 4, 5, or 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, and n-hexyl. Similarly, an "alkylene group" may be linear or branched and may have two bonding sites with the rest of the molecule. Furthermore, an alkylene group may correspond, for example, to one of the alkyl groups listed in this paragraph. Alkyl and alkylene groups may be unsubstituted or substituted with one or more substituents.

[0099] The term "haloalkyl" refers to a hydrocarbon chain substituted with at least one halogen atom, each independently selected, such as fluorine, chlorine, bromine, and iodine. For example, the term "C 1-6 "Haloalkyl" refers to a linear or branched hydrocarbon chain containing 1, 2, 3, 4, 5, or 6 carbon atoms substituted with at least one halogen. The halogen atom may be located at any position on the hydrocarbon chain. For example, C 1-6 Haloalkyl refers to chloromethyl, fluoromethyl, trifluoromethyl, chloroethyl (e.g., 1-chloromethyl and 2-chloroethyl), trichloroethyl (e.g., 1,2,2-trichloroethyl, 2,2,2-trichloroethyl), fluoroethyl (e.g., 1-fluoromethyl and 2-fluoroethyl), trifluoroethyl (e.g., 1,2,2-trifluoroethyl and 2,2,2-trifluoroethyl), chloropropyl, trichloropropyl, fluoropropyl, and trifluoropropyl. The term "fluoroalkyl" refers to a hydrocarbon chain substituted with at least one fluorine atom.

[0100] The term "alkenyl" refers to a branched or straight hydrocarbon chain containing at least one double bond. For example, "C 2-6The term "alkenyl" refers to a branched or straight hydrocarbon chain having at least one double bond and containing two, three, four, five, or six carbon atoms. The double bond may exist as an E isomer or a Z isomer. The double bond may be at any possible position in the hydrocarbon chain. For example, "C 2-6 "Alkenyl" may be etenyl, propenyl, butenyl, butadienyl, pentenyl, pentadienyl, hexenyl, and hexadienyl.

[0101] The term "alkynyl" refers to a branched or straight hydrocarbon chain containing at least one triple bond. For example, "C 2-6 The term "alkynyl" refers to a branched or straight hydrocarbon chain having two, three, four, five, or six carbon atoms and containing at least one triple bond. The triple bond may be at any possible position in the hydrocarbon chain. For example, "C 2-6 "Alkinyl" may be ethinyl, propynyl, butynyl, pentynyl, and hexynyl.

[0102] The term "heteroalkyl" refers to a branched or straight-chain hydrocarbon chain that contains at least one heteroatom selected from N, O, and S, located between any carbon atoms in the chain or at the end of the chain. For example, "C 1-6 The term "heteroalkyl" refers to a branched or straight hydrocarbon chain containing one, two, three, four, five, or six carbon atoms and at least one heteroatom selected from N, O, and S, positioned between the carbon atoms in the chain or at the ends of the chain. For example, a hydrocarbon chain may contain one or two heteroatoms. 1-6 Heteroalkyl groups can be bonded to the rest of the molecule via carbon or heteroatoms. For example, "C 1-6 "Heteroalkyl" is C 1-6 N-alkyl, C 1-6 N,N-alkyl or C 1-6 It may be an O-alkyl group.

[0103] The term “heterocyclic” refers to a saturated, unsaturated, or aromatic cyclic system containing at least one heteroatom selected from N, O, or S. A “heterocyclic” system may contain one, two, three, or four heteroatoms, for example, one or two. A “heterocyclic” system may be monocyclic or a fused polycyclic system, such as a bicyclic or tricyclic system. A “heterocyclic” moiety may contain 3 to 14 carbon atoms, for example, 3 to 8 carbon atoms in a monocyclic system and 7 to 14 carbon atoms in a polycyclic system. A “heterocyclic” system includes heterocycloalkyl, heterocycloalkenyl, and heteroaryl moies. For example, heterocyclic groups may include: oxirane, aziridine, azetidine, oxetane, tetrahydrofuran, pyrrolidine, imidazolidine, succinimide, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, piperidine, morpholine, thiomorpholine, piperazine, and tetrahydropyran. Heteroaryl groups include pyridone and N-alkylpyridone.

[0104] "C 3-8 The term "cycloalkyl" refers to a saturated hydrocarbon ring system containing 3, 4, 5, 6, 7, or 8 carbon atoms. For example, "C 3-8 "Cycloalkyl" may be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0105] The term “C 3-8 A "cycloalkenyl" refers to a non-aromatic, unsaturated hydrocarbon ring system containing 3, 4, 5, 6, 7, or 8 carbon atoms. If the ring system is non-aromatic, the ring may contain two or more double bonds. For example, "C 3-8 "Cycloalkyl" may be cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadiene, cyclooctenyl, and cycloatadienyl.

[0106] The term "heterocycloalkyl" refers to a saturated hydrocarbon ring system comprising a carbon atom and at least one heteroatom selected from N, O, and S within the ring. For example, there may be one, two, or three heteroatoms, and optionally one or two heteroatoms. A "heterocycloalkyl" can be bonded to the rest of the molecule via the carbon atom or heteroatoms. A "heterocycloalkyl" may have one or more, for example, one or two bonds to the rest of the molecule, and these bonds may be via any atom in the ring. For example, a "heterocycloalkyl" is a "C 3-8 The term "heterocycloalkyl" is also acceptable. 3-8 "Heterocycloalkyl" refers to a saturated hydrocarbon ring system containing 3, 4, 5, 6, 7, or 8 atoms, where at least one atom is a heteroatom in the ring selected from N, O, and S. Examples of "heterocycloalkyl" include oxiran, aziridine, azetidine, oxetane, tetrahydrofuran, pyrrolidine, imidazolidine, succinimide, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, piperidine, morpholine, thiomorpholine, piperazine, and tetrahydropyran.

[0107] The term "aromatic," when applied to substituents as a whole, refers to a monocyclic or polycyclic system in which all atoms contributing to the π-conjugated system are coplanar, or in which the π-conjugated system within the ring or ring system has 4n+2 electrons.

[0108] The term "aryl" refers to an aromatic hydrocarbon ring system. The ring system has 4n+2 electrons in its π-conjugated system, and all atoms contributing to the π-conjugated system are coplanar. For example, "aryl" may be phenyl or naphthyl. The aryl system itself may be substituted with other groups.

[0109] The term "heteroaryl" refers to an aromatic hydrocarbon ring system having at least one heteroatom selected from O, N, and S within a monocyclic or fused ring system. The ring or ring system has 4n+2 electrons in the π-conjugated system, and all atoms contributing to the π-conjugated system are coplanar. For example, "heteroaryl" may be imidazole, oxazole, isoxazole, thiazole, isothiazole, thien, furan, thiantrene, pyrrole, benzimidazole, pyrazole, pyrazine, pyridine, pyrimidine, and indole.

[0110] [ka] Bonds ending with a dot indicate that the bond will bond with another atom not shown in the structure. Bonds that terminate within a cyclic structure and not on an atom in the cyclic structure indicate that the bond can bond with any atom in the cyclic structure, provided that the valence allows it.

[0111] Solid and dotted lines represent bonds that can be either single or double bonds, if chemically possible. For example, the following bonds: [ka] These can be single or double bonds.

[0112] If a portion is substituted, it is chemically possible, and the substitution may occur at a position that satisfies the valence requirements. This portion may be substituted with one or more substituents, for example, one, two, three, or four substituents, and optionally, one or two substituents may be present on a single group. If there are two or more substituents, the substituents may be the same or different.

[0113] Substituents exist only at positions where they are chemically possible, and a person skilled in the art can determine whether a substitution is chemically possible or not (experimentally or theoretically) without excessive effort.

[0114] Ortho, meta, and para substitutions are well understood terms in the art. Without a doubt, an "ortho" substitution is a substitution pattern where an adjacent carbon atom has a substituent, such as a simple group, e.g., the fluoro group in the following example. [ka] ,or [ka] It is the remaining part of the molecule, indicated by a bond ending in -.

[0115] A "meta" substitution is a substitution pattern in which two substituents lie on carbons that have one carbon removed from each other, i.e., there is one carbon atom between the substituted carbons. In other words, the substituents lie on the second-to-last atom from the atom with the other substituent. For example, the following groups are meta substitutions.

[0116] A "para" substitution is a substitution pattern in which two substituents are located on carbon atoms that have been removed from each other; that is, there are two carbon atoms between the substituted carbon atoms. In other words, the substituents are located on the third atom away from the atom with the other substituent. For example, the following groups are para substitutions.

[0117] Throughout this specification, the disclosure of compounds also includes their pharmaceutically acceptable salts, solvates, and stereoisomers.

[0118] If a compound has a stereocenter, both (R) and (S) stereoisomers are intended by the present invention, and equal amounts of the stereoisomers or a racemic mixture are encompassed by this application. If a compound of the present invention has two or more stereocenters, any combination of the (R) and (S) stereoisomers is intended. The combination of the (R) and (S) stereoisomers may be a diastereomer mixture or a single diastereomer. The compound of the present invention may exist as a single stereoisomer, or as a mixture of stereoisomers, e.g., a racemic mixture and a mixture of other enantiomers, as well as a mixture of diastereomers. If the mixture is a mixture of enantiomers, the enantiomer excess may be any of those disclosed above. If the compound is a single stereoisomer, the compound may contain other diastereomers or enantiomers as impurities. Therefore, a single stereoisomer does not necessarily have to have a 100% enantiomer excess (ee) or diastereomer excess (de), but may have an ee or de of approximately 85% or more, approximately 60% or more, or less. For example, the ee or de may be 90% or more, 90% or more, 80% or more, 70% or more, 60% or more, 50% or more, 40% or more, 30% or more, 20% or more, or 10% or more.

[0119] The present invention aims to provide pharmaceutically acceptable salts of the compounds of the present invention. These may include acid addition salts and basic salts of the compounds. These may be acid addition salts and basic salts of the compounds. Furthermore, the present invention aims to provide solvates of the compounds. These may be hydrates or other solvated forms of the compounds.

[0120] A suitable acid addition salt is formed from an acid that forms a non-toxic salt. Examples include acetate, aspartate, benzoate, besilate, bicarbonate / carbonate, bisulfate / sulfate, borate, cansilate, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronic acid, hexafluorophosphate, hibenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, mesilate, methylsulfate, naphthylate, 1,5-naphthalenedisulfonate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, saccharinate, stearate, succinate, tartrate, tosylate, and trifluoroacetate.

[0121] Suitable basic salts are formed from bases that form non-toxic salts. Examples include aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine, and zinc salts. Hemi salts of acids and bases, such as hemisulfate and hemicalcium salt, may also be formed. For a review of suitable salts, see Stahl and Wermuth, "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" (Wiley-VCH, Weinheim, Germany, 2002).

[0122] Medicinally acceptable salts of the compound of formula (I) can be obtained in the following three ways: (i) By reacting the compound of the present invention with a desired acid or base; (ii) by removing an acid- or base-unstable protecting group from a suitable precursor of the compound of the present invention, or by ring-opening a suitable cyclic precursor, such as a lactone or lactam, using a desired acid or base; or (iii) By converting one salt of the compound of the present invention to another salt by reaction with a suitable acid or base, or by a suitable ion exchange column, It can be manufactured by one or more of the following.

[0123] All three reactions typically occur in solution. The resulting salts precipitate and are collected by filtration or by evaporation of the solvent. The degree of ionization of the resulting salts can vary from fully ionized to almost unionized.

[0124] The compounds of the present invention may exist in both non-solvated and solvated forms. The term "solvated" is used herein to refer to a molecular complex comprising the compound of the present invention and one or more pharmaceutically acceptable solvent molecules, such as ethanol, in stoichiometric amounts. The term "hydrated" is used when the solvent is water.

[0125] The scope of the present invention includes complexes such as clathrates and drug-host inclusion complexes, where, in contrast to the solvates described above, the drug and host are present in stoichiometric or non-stoichiometric amounts. It also includes drug complexes comprising two or more organic and / or inorganic components, which may be present in stoichiometric or non-stoichiometric amounts. The resulting complexes may be ionized, partially ionized, or unionized. For a review of such complexes, see J Pharm Sci, 64 (8), 1269-1288 by Haleblian (August 1975).

[0126] The following descriptions of any compound of any of the formulas include descriptions of their salts, solvates, and complexes, as well as descriptions of the solvates and complexes of their salts.

[0127] The compounds of the present invention include compounds of numerous formulas as defined herein, their polymorphs and crystal habits, their prodrugs and isomers (including optical, geometric and tautomeristic isomers) as defined below, and all isotopically labeled compounds of the present invention.

[0128] The present invention also includes all pharmaceutically acceptable isotope-labeled compounds of the present invention in which one or more atoms have the same atomic number but have an atomic mass or mass number different from the most common and naturally occurring atomic mass or mass number.

[0129] Suitable isotopes included in the compound of the present invention include, for example, 2 H and 3 Hydrogen isotopes such as H, 11 C, 13 C and 14 Isotopes of carbon such as C, 36 Chlorine isotopes such as Cl, 18 Fluorine isotopes such as F, 123 I and 125 Iodine isotopes such as I 13 N and 15 Nitrogen isotopes such as N, 15 O, 17 O and 18 Oxygen isotopes such as O, 32 Phosphorus isotopes such as P, 35 Examples include sulfur isotopes such as S. If there are any gifts, please accept them and write the name of the giver on a tag.

[0130] Compounds labeled with specific isotopes, such as those incorporating radioactive isotopes, are useful in studies of the tissue distribution of drugs and / or substrates. Radioactive isotopes such as tritium, i.e. 3 H, and carbon 14, i.e. 14C is particularly useful for this purpose in terms of the ease of their incorporation and the ease of detection means.

[0131] Deuterium, that is 2 Substitution with heavier isotopes, such as 1H, may result in certain therapeutic benefits stemming from greater metabolic stability, such as an increased half-life in vivo or a reduced required dose, and therefore may be preferable in some situations.

[0132] Prior to purification, the compounds of the present invention may exist as a mixture of enantiomers, depending on the synthesis method used. These enantiomers can be separated by conventional techniques known in the art. Therefore, the present invention comprises individual enantiomers and mixtures thereof.

[0133] In some steps of the method for producing the compounds of the present invention, it may be necessary to protect potentially reactive functional groups that are not to be reacted, and then to cleave the protecting groups. In such cases, a suitable protecting group can be used. In particular, methods for protection and deprotection can be found, for example, those by TW GREENE (Protective Groups in Organic Synthesis, A. Wiley-Interscience Publication, 1981) or PJ Kocienski (Protecting groups, Georg Thieme Verlag, 1994). All of the above reactions, and the preparation of the novel starting materials used in the aforementioned methods, are conventional, and suitable reagents and reaction conditions for their implementation or production, as well as methods for isolating the desired products, will be well known to those skilled in the art by referring to the prior art, the examples and production examples herein.

[0134] Furthermore, the compounds of the present invention and their production intermediates can be purified according to various well-known methods, such as crystallization or chromatography.

[0135] One or more compounds of the present invention may be used in combination with one or more agents (e.g., anti-inflammatory agents, anti-fibrotic agents, chemotherapeutic agents, anticancer agents, immunosuppressants, antitumor vaccines, cytokine therapy agents, or tyrosine kinase inhibitors) for the treatment of diseases regulated by inhibition of ROCK (e.g., fibrous diseases, autoimmune diseases, inflammatory fibrous diseases, inflammatory diseases, central nervous system diseases, or cancer).

[0136] The methods or compounds for use in the treatment of renal disease, hepatic disease, inflammatory disease, cardiovascular disease, acute and chronic organ transplant rejection, fibrous disease, and cancer, as defined herein, may be applied as monotherapy or in combination with additional activators.

[0137] A therapeutic method or compound for use in the treatment of kidney disease, liver disease, inflammatory disease, cardiovascular disease, acute and chronic organ transplant rejection, fibrous disease, and cancer may include additional activators in addition to the compound of the present invention. The additional activators may be one or more activators used to treat the condition treated by the compound of the present invention and the additional activators. Examples of additional activators include one or more of the following: (i) Steroids: For example, corticosteroids such as glucocorticoids and mineralocorticoids, such as acromethasone, acromethasone dipropionate, aldosterone, amcinonide, beclomethasone, beclomethasone dipropionate, betamethasone dipropionate, betamethasone sodium phosphate, betamethasone valerate, budesonide, clobetazone, clobetazone butyrate, clobetasol propionate, cloprednol, cortisone, cortisone acetate, cortibazole, deoxycorton, desonide, desoxymethasone, dexamethasone, dexamethasone sodium phosphate, dexamethasone isonicotinate, difluorocortolone, fluchlorolone, flumethasone, flunisolide, fluocinolone, fluocinolone acetonide, fluocinonide, fluocinolone Rutin butyl, fluorocortisone, fluorocortolone, fluocortolone caproate, fluocortolone pivalate, fluorometholone, flupredniden, fluprednidenone acetate, flulandrenolone, fluticasone, fluticasone propionate, halcinonide, hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone aceponate, hydrocortisone buteplat, hydrocortisone valerate, icometasone, icometasone embutate, meprednisone, methylprednisolone, mometasone, parametasone, mometasone furoate monohydrate, prednicarbate, prednisolone, prednisone, thixocortol, thixocortol pivalate, triamcinolone, triamcinolone acetonide, triamcinolone alcohol, and their pharmaceutically acceptable derivatives. Combinations of steroids, for example, combinations of two or more steroids described in this paragraph may be used; (ii) TNF inhibitors: e.g., 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: for example, nonsteroidal anti-inflammatory drugs; (iv) Dihydrofolate reductase inhibitors / folate antagonists: e.g., methotrexate, trimethoprim, brodimoprim, tetroxoprim, ikuraprim, pemetrexed, laritrexed and pralatrexate; and, (v) Immunosuppressants: for example, cyclosporine, tacrolimus, sirolimus, pimecrolimus, angiotensin II inhibitors (e.g., valsartan, telmisartan, losartan, irbesatan, azilsartan, olmesartan, candesartan, eprosartan) and ACE inhibitors, for example, sulfhydryl-containing agents (e.g., captopril, zofenopril), dicarboxylate-containing agents (e.g., enalapril, ramipril, quinapril, perindopril, lisinopril, benazepril, imidapril, zofenopril, trandolapril), phosphate-containing agents (e.g., fosinopril), casokinin, lactokinin and lactotripeptides. (vi) Antifibrotic agents: e.g., pirfenidone, nintedanib, anti-IL-13 monoclonal antibodies (e.g., tralokinumab, QAX576, lebrikizumab), simtuzumab, FG-3019, lysophosphatidic acid receptor antagonists (e.g., BMS-986020, AM966), LOXL2 inhibitors, BET bromodomain inhibitors (e.g., JQ1), HDAC inhibitors (e.g., vorinostat), thrombin inhibitors (e.g., dabigatran), factor Xa inhibitors (e.g., apixaban, rivaroxaban), 15PGDH inhibitors, anti-αvβ6 monoclonal antibodies (e.g., BG00011), anti-CTGF monoclonal antibodies (e.g., FG-3019), PAR1 inhibitors, Nox4 inhibitors, and PAI-1 inhibitors.

[0138] A method for treating cancer, or a compound for use in the treatment of cancer, may include, in addition to the compounds of the present invention, conventional surgery, radiotherapy, or chemotherapy. Such chemotherapy may include one or more antitumor agents from the following categories: (i) Antiproliferative / antinomatal agents and combinations thereof: for example, alkylating agents (e.g., cisplatin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, uracil mustard, bendamustine, melphalan, chlorambucil, chlormethine, busulfan, temozolamide, nitrosourea, ifosamide, melphalan, pipobromane, triethylene-melamine, triethylenethiophosphoramine, carmustine, lomustine, stroptozosin, etc.) (e.g., dacarbazine); antimetabolites (e.g., gemcitabine, and folate antagonists, e.g., fluoropyrimidines such as 5-fluorouracil and tegafur, larcitrexed, methotrexate, pemetrexed, cytosine arabinoside, phloxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, pentostatin, gemcitabine and hydroxyurea); antibiotics (e.g., adriamycin, bleomycin, doxorubicin, daunomycin, Anthracyclines such as epirubicin, idarubicin, mitomycin-C, dactinomycin, and mitramycin; mitotic inhibitors (e.g., vinca alkaloids such as vincristine, vinblastine, vindesine, and vinorelbine, as well as taxoids such as taxol and taxotere, and polokinase inhibitors); proteasome inhibitors, e.g., carfilzomib and bortezomib; interferon therapies; and topoisomerase inhibitors (e.g., etopo Epipodophyllotoxin such as cyd and teniposide, amsacrin, topotecan, mitoxantrone and camptothecin; bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, ara-C, paclitaxel (Taxol®), nab-paclitaxel, docetaxel, mitramycin, deoxycoformycin, mitomycin-C, L-asparaginase, interferon (especially IFN-a), etoposide and teniposide; (ii) Cell proliferation inhibitors: for example, anti-estrogens (e.g., tamoxifen, fulvestrant, toremifene, raloxifene, doroxifene, iodoxifene), anti-androgens (e.g., bicalutamide, flutamide, nilutamide, and cyproterone acetate), LHRH antagonists or LHRH agonists (e.g., goserelin, leuprorelin, and buserelin), progestogens (e.g., megestrol acetate), aromatase inhibitors (e.g., anastrozole, letrozole, borazole, and exemestane), and 5α-reductase inhibitors, for example, finasteride; navelben, CPT-II, anastrazole, letrazole, capecitabine, reloxafum, cyclophosphamide, ifosamide, and doroxafine; (iii) Anti-invasive agents: for example, dasatinib and bosutinib (SKI-606), and metalloproteinase inhibitors, inhibitors of urokinase-type plasminogen activator receptor function, or antibodies against heparanase; (iv) Growth factor function inhibitors: For example, such inhibitors include growth factor antibodies and growth factor receptor antibodies, e.g., anti-erbB2 antibody trastuzumab [Herceptin™], anti-EGFR antibody panitumumab, anti-erbB1 antibody cetuximab, tyrosine kinase inhibitors, e.g., inhibitors of the epidermal growth factor family (e.g., EGFR family tyrosine kinase inhibitors, e.g., gefitinib, erlotinib, 6-acrylamide-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)-quinazoline-4-amine (CI 1033), erbB2 tyrosine kinase inhibitors such as lapatinib, antibodies against co-stimulatory molecules such as CTLA-4, 4-IBB and PD-1, or antibodies against cytokines (IL-I0, 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 such as imatinib and / or nilotinib (AMN107); inhibitors of serine / threonine kinases (e.g., farnesiac Cell transferase inhibitors (such as sorafenib, tipifarnib, and ronafarnib, which are Ras / Raf signaling inhibitors), cell signaling inhibitors mediated by 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; cyclin-dependent kinase inhibitors such as aurora kinase inhibitors and CDK2 and / or CDK4 inhibitors; and CCR2, CCR4, or CCR6 modulators; (v) Anti-angiogenic agents: for example, those that inhibit the action of vascular endothelial growth factor, such as the anti-vascular endothelial growth factor antibody bevacizumab (Avastin®); thalidomide; lenalidomide; and VEGF receptor tyrosine kinase inhibitors such as vandetanib, batalanib, sunitinib, axitinib, and pazopanib; (vi) Gene therapy approaches: for example, approaches that replace abnormal genes such as p53 abnormalities or BRCA1 or BRCA2 abnormalities; (vii) Immunotherapy approaches: for example, antibody therapies such as alemtuzumab, rituximab, ibritumomab, uxetan (Zevalin®) and ofatumumab; interferons such as interferon-alpha; interleukins such as IL-2 (aldesleukin); interleukin inhibitors, for example, IRAK4 inhibitors; cancer vaccines, including prophylactic and therapeutic vaccines such as HPV vaccines, for example, Gardasil, Cervarix, Oncophage and Cipleucel-T (Provenge); gp100; dendritic cell vaccines (Ad.p53 DC, etc.); Toll-like receptor modulators, for example, TLR-7 or TLR-9 agonists; and, (viii) Cytotoxic drugs: e.g., fludarivine (Fuldara), cladribine, pentostatin (Nipent®); (ix) Steroids: For example, corticosteroids such as glucocorticoids and mineralocorticoids, such as acromethasone, acromethasone dipropionate, aldosterone, amcinonide, beclomethasone, beclomethasone dipropionate, betamethasone dipropionate, betamethasone sodium phosphate, betamethasone valerate, budesonide, clobetazone, clobetazone butyrate, clobetasol propionate, cloprednol, cortisone, cortisone acetate, cortibazole, deoxycorton, desonide, desoxymethasone, dexamethasone, dexamethasone sodium phosphate, dexamethasone isonicotinate, difluorocortolone, fluchlorolone, flumethasone, flunisolide, fluocinolone, fluocinolone acetonide, fluocinonide, fluocinolone Rutin butyl, fluorocortisone, fluorocortolone, fluocortolone caproate, fluocortolone pivalate, fluorometholone, flupredniden, fluprednidenone acetate, flulandrenolone, fluticasone, fluticasone propionate, halcinonide, hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone aceponate, hydrocortisone buteplat, hydrocortisone valerate, icometasone, icometasone embutate, meprednisone, methylprednisolone, mometasone, parametasone, mometasone furoate monohydrate, prednicarbate, prednisolone, prednisone, thixocortol, thixocortol pivalate, triamcinolone, triamcinolone acetonide, triamcinolone alcohol, and their pharmaceutically acceptable derivatives. Combinations of steroids, for example, combinations of two or more steroids described in this paragraph may be used; (x) Targeted therapies: e.g., PI3Kd inhibitors, e.g., idelalisib and perifosin; 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, anti-cancer vaccines, and arginase inhibitors.

[0139] Such combination therapy may be performed by simultaneous, sequential, or separate administration of the individual therapeutic components. Such combination agents utilize the compounds of the present invention within the range of therapeutically effective doses described herein and other pharmaceutically active agents within the range of approved doses.

[0140] The compounds of the present invention may exist in a single crystalline form or a mixture of crystalline forms, or they may be amorphous. Therefore, for pharmaceutical use, the compounds of the present invention can be administered as crystalline or amorphous products. They can be obtained as solid plugs, powders, or films by methods such as precipitation, crystallization, freeze-drying, spray-drying, or evaporation-drying. For this purpose, microwave or high-frequency drying may be used.

[0141] The dosage of the above-mentioned compounds of the present invention will, of course, vary depending on the compound used, the method of administration, the therapeutic purpose, and the disease to be treated. For example, when the compounds of the present invention are administered orally, the daily dose of the compounds of the present invention may range from 0.01 micrograms (μg / kg) per kilogram of body weight to 100 milligrams (mg / kg) per kilogram of body weight.

[0142] The compounds of the present invention or their pharmaceutically acceptable salts may be used on their own, but are typically administered in the form of pharmaceutical compositions in which the compounds of the present invention or their pharmaceutically acceptable salts are combined with pharmaceutically acceptable excipients, diluents, or carriers. Conventional methods for selecting and manufacturing appropriate pharmaceutical formulations are described, for example, in "Pharmaceuticals - The Science of Dosage Form Designs", ME Aulton, Churchill Livingstone, 1988.

[0143] Depending on the method of administering the compound of the present invention, the pharmaceutical composition used to administer the compound of the present invention preferably contains 0.05 to 99% by weight of the compound of the present invention, more preferably 0.05 to 80% by weight of the compound of the present invention, even more preferably 0.10 to 70% by weight of the compound of the present invention, and even more preferably 0.10 to 50% by weight of the compound of the present invention, all weight percentages are based on the total amount of the composition.

[0144] Pharmaceutical compositions can be administered topically (e.g., on the skin) in the form of, for example, creams, gels, lotions, solutions, or suspensions, or systemically by oral administration in the form of, for example, tablets, capsules, syrups, powders, or granules; or by parenteral administration in the form of sterile solutions, suspensions, or emulsions for injection (such as intravenous, subcutaneous, intramuscular, intravascular, or intravenous infusion); by rectal administration in the form of suppositories; or by inhalation in the form of aerosols.

[0145] For oral administration, the compounds of the present invention may be mixed with excipients or carriers, such as lactose, saccharose, sorbitol, mannitol; starches, such as potato starch, corn starch, or amylopectin; cellulose derivatives; binders, such as gelatin or polyvinylpyrrolidone; and / or lubricants, such as magnesium stearate, calcium stearate, polyethylene glycol, wax, paraffin, etc., and then compressed into tablets. If coated tablets are required, the cores prepared as described above may be coated with a concentrated sugar solution, which may contain, for example, gum arabic, gelatin, talcum, and titanium dioxide. Alternatively, the tablets may be coated with a suitable polymer dissolved in a volatile organic solvent.

[0146] For the manufacture of soft gelatin capsules, the compounds of the present invention may be mixed with, for example, vegetable oil or polyethylene glycol. Hard gelatin capsules may contain granules of the compounds using any of the above-mentioned excipients for tablets. Liquid or semi-solid formulations of the compounds of the present invention can also be filled into hard gelatin capsules. Liquid formulations for oral administration may be in the form of syrup or suspension and may be, for example, a solution containing the compounds of the present invention, with the remainder being sugar, and a mixture of ethanol, water, glycerol, and propylene glycol. Optionally, such liquid formulations may contain carboxymethylcellulose as a coloring agent, flavoring agent, sweetener (such as saccharin), preservative, and / or thickener, or other excipients known to those skilled in the art.

[0147] For intravenous (parenteral) administration, the compounds of the present invention may be administered as sterile aqueous or oily solutions.

[0148] The size of the therapeutic dose of the compound of the present invention will naturally vary according to well-known principles of pharmacopoeia, depending on the nature and severity of the disease, the age and sex of the animal or patient, and the route of administration.

[0149] The dosage level, frequency of administration, and duration of treatment of the compound of the present invention will naturally vary depending on the prescription and the patient's clinical signs, age, and comorbidities.

[0150] Throughout this specification and in the claims, the words “comprise” and “contain,” and their variations thereto, mean “including, but not limited to,” and are not intended (and are not intended) to exclude other parts, additives, ingredients, integers, or steps. Throughout this specification and in the claims, unless the context makes otherwise, the singular form includes the plural form. In particular, where the indefinite article is used, this specification is understood to intend both the singular and plural forms unless the context makes otherwise.

[0151] Features, integers, properties, compounds, chemical parts, or groups described in connection with specific aspects, embodiments, or examples of the present invention should be understood to be applicable to other aspects, embodiments, or examples described herein, unless they are incompatible. All features and / or all steps of the disclosed methods or processes disclosed herein (including the appended claims, abstract, and drawings) can be combined in any combination, except for at least some combinations in which such features and / or steps mutually exclude each other. The present invention is not limited to the details of the embodiments described above. The present invention extends to novel features or combinations of novel features of the features disclosed herein (including the appended claims, abstract, and drawings), or to novel steps or combinations of novel steps of the disclosed methods or processes.

[0152] The reader's attention is directed to all papers and documents filed concurrently with or prior to this application and made publicly available herein, and all the contents of such papers and documents are incorporated herein by reference.

[0153] The compounds of the present invention can be produced by following general schemes 1 to 11 and examples 1 to 104, or by similar methods.

[0154] Examples and Synthesis Examples Experimental method The solvents, reagents, and starting materials used were commercially available and, unless otherwise specified, were used as obtained. All reactions were carried out at room temperature unless otherwise specified. The identity and purity of the compounds were confirmed by LCMS UV using a Waters Acquity SQ Detector 2 (ACQ-SQD2#LCA081). The diode array detector was set to obtain a wavelength of 254 nm, and the MS was performed in positive and negative electrospray mode (m / z: 150-800). Two μl aliquots were injected sequentially into a guard column (0.2 μm x 2 mm filter) and a ULC column (C18, 50 x 2.1 mm, <2 μm), and maintained at 40°C. Samples were eluted at a flow rate of 0.6 mL / min using mobile phase systems 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 outlined in Table 1 below (Methods 1 and 2). Retention times (RT) are reported in minutes. The following methods were also used when described in the Experiments section, and the gradients are listed in Table 1. In Method 3, a Shimadzu 2020 series spectrometer equipped with a binary pump and diode array detector (capture wavelengths 214 nm and 254 nm) was used, and MS was performed in positive and negative electrospray modes (m / z: 100-900). 2 μL aliquots were injected into 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 using the following mobile phases: A: 0.05% formic acid aqueous solution (v / v) and B: 0.05% ACN formate (v / v). In Method 4, an Agilent Technologies 1290 series spectrometer equipped with a binary pump and diode array detector (capture wavelengths 214 nm and 254 nm) was used, and MS was performed in positive electrospray mode (m / z: 70-1000).Two μL aliquots were injected into an Agilent Eclipse Plus RRHD C18 (1.8 μm, 3.0 × 50 mm) column and eluted at 0.8 ml / min while held at 40°C: A: 0.05% formic acid / water (v / v) and B: 0.05% formic acid / ACN (v / v).

[0155] [Table 1]

[0156] NMR was also used to characterize the final compounds. NMR spectra were obtained using a Bruker AVIII 400 Nanobay equipped with a 5 mm BBFO probe. Rf values ​​of the compounds were measured on silica thin-layer chromatography (TLC) plates as appropriate.

[0157] The compounds were purified by flash column chromatography on silica or preparative LC-MS. LC-MS purification was performed using a Waters 3100 mass detector and a Waters 2489 UV / Vis detector in positive and negative electrospray modes (m / z: 150-800). Samples were eluted at a flow rate of 20 mL / min using an XBridge™ prep C18 5 μM OBD 19x100 mm column with mobile phases A (0.1% (v / v) formic acid aqueous solution) and B (0.1% (v / v) formic acid acetonitrile) according to the gradient outlined in Table 2 below. [Table 2]

[0158] Synthesis of intermediates The following Scheme 1 describes the synthesis of several intermediates common to a particular example and shows a synthesis method that can be used to produce other examples by selecting other appropriately functionalized building blocks instead of one or more building blocks in Scheme 1, as detailed in the production descriptions of the individual examples. [ka]

[0159] Project A. Synthesis of intermediate I-1, 8-bromo-2H-isoquinoline-1-one To a solution of 8-bromoisoquinoline (5.0 g, 24 mmol) in dichloromethane (60 mL), m-CPBA (8.1 g, 36 mmol) was gradually added over 5 minutes at 0°C. The mixture was heated to rt and stirred for 4 hours. The reaction mixture was quenched by adding saturated Na2S2O3 aqueous solution, and the layers were separated. The organic layers were washed with saturated NaHCO3 aqueous solution, and the combined aqueous layers were extracted three times with dichloromethane. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to obtain a crude N-oxide intermediate as a yellow solid.

[0160] N-oxide was dissolved in acetic anhydride (45.6 mL, 483 mmol) and heated to 140°C, stirring for 3 hours. The mixture was cooled to room temperature, concentrated under reduced pressure to obtain a brown oily substance, which was dissolved in methanol (20 mL). Saturated aqueous NaHCO3 solution (20 mL, 365 mmol) was added, and the mixture was stirred overnight under rot, concentrated under reduced pressure, and cooled to 0°C. 2M HCl was added dropwise to adjust the pH to 3, stirring was stopped, and the mixture was allowed to stand for 30 minutes. The resulting brown solid was recovered by filtration, dissolved in methanol, and concentrated under reduced pressure to obtain 8-bromo-2H-isoquinoline-1-one (intermediate I-1, 5.4 g, 24 mmol, 99% yield) as a brown solid. UPLC-MS (ES + , Method 2):1.34 min, m / z 223.9 / 225.8 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.28 (s, 1H), 7.69 (d, J=7.7 Hz, 1H), 7.64 (d, J=7.9 Hz, 1H), 7.49 (t, J=7.8 Hz, 1H), 7.19 (t, J=6.5 Hz, 1H), 6.54 (d, J=7.0 Hz, 1H).

[0161] Project B. Synthesis of intermediate I-2,2-(8-bromo-1-oxo-2-isoquinolyl)-N-(2,2,2-trifluoroethyl)acetamide To a solution of 8-bromo-2H-isoquinoline-1-one (intermediate I-1, 2.8 g, 13 mmol) in dichloromethane (25 mL), Cs2CO3 (10.2 g, 31 mmol) and 2-chloro-N-(2,2,2-trifluoroethyl)acetamide (2.4 g, 14 mmol) were added, and the mixture was stirred overnight at rt. ELISA was added, the mixture was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by normal-phase chromatography (25 g column, 0-5% methanol / dichloromethane) to obtain 2-(8-bromo-1-oxo-2-isoquinolyl)-N-(2,2,2-trifluoroethyl)acetamide (intermediate I-2, 1.1 g, 3 mmol, 24% yield) as an orange solid. UPLC-MS (ES + , Method 2):1.60 min, m / z 363.0 / 364.9 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.91 (t, J=6.5 Hz, 1H), 7.74 (dd, J=1.3, 7.8 Hz, 1H), 7.67 (dd, J=1.1, 8.0 Hz, 1H), 7.53 (t, J=7.8 Hz, 1H), 7.49 (d, J=7.3 Hz, 1H), 6.63 (d, J=7.4 Hz, 1H), 4.64 (s, 2H), 3.97 (q, J=5.5 Hz, 2H).

[0162] Projects C and D. Synthesis of intermediate I-3, 2-(8-amino-1-oxo-2-isoquinolyl)-N-(2,2,2-trifluoroethyl)acetamide Project C. A solution of 2-(8-bromo-1-oxo-2-isoquinolyl)-N-(2,2,2-trifluoroethyl)acetamide (intermediate I-2, 1.4 g, 3.9 mmol), tert-butylcarbamate (677 mg, 5.8 mmol), and Cs2CO3 (2.5 g, 7.7 mmol) / 1,4-dioxane (30 mL) was degassed with N2 for 10 minutes. Tris(dibenzylideneacetone)dipalladium(0) (177 mg, 0.19 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (223 mg, 0.39 mmol) were added, the vial was sealed, and the mixture was heated at 100°C and stirred overnight. The mixture was filtered through a Celite pad, washed with MeOH, and concentrated under reduced pressure. The crude product was purified by normal-phase chromatography (25 g column, 55-70% ethyl acetate / petroleum) to obtain the carbamate intermediate tert-butyl N-[1-oxo-2-[2-oxo-2-(2,2,2-trifluoroethylamino)ethyl]-8-isoquinolyl]carbamate (1.5 g, 3.6 mmol, 94% yield) as a yellow solid. UPLC-MS (ES + , Method 2):1.86 min, m / z 400.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.08 (s, 1H), 8.93 (t, J=6.4 Hz, 1H), 8.28 (d, J=7.3 Hz, 1H), 7.65 (t, J=8.1 Hz, 1H), 7.46 (d, J=7.3 Hz, 1H), 7.25 (d, J=7.0 Hz, 1H), 6.68 (d, J=7.4 Hz, 1H), 4.69 (s, 2H), 4.01 - 3.96 (m, 2H), 1.49 (s, 9H).

[0163] Project D. To a solution of tert-butyl N-[1-oxo-2-[2-oxo-2-(2,2,2-trifluoroethylamino)ethyl]-8-isoquinolyl]carbamate (1.6 g, 4 mmol) in acetonitrile (20 mL) and dichloromethane (10 mL), HCl (4 M, 4 mL, 16 mmol in dioxane) was added dropwise, and the mixture was stirred overnight at room temperature. The mixture was concentrated under reduced pressure, and the crude product was purified using an SCX cartridge (10 g, washed with methanol, then washed with 7 M ammonia / methanol). The basic fraction was concentrated under reduced pressure to obtain 2-(8-amino-1-oxo-2-isoquinolyl)-N-(2,2,2-trifluoroethyl)acetamide (intermediate I-3, 580 mg, 2 mmol, 48% yield) as a brown solid. UPLC-MS (ES + (Short-term acidification): 1.36 min, m / z 300.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.84 (t, J=6.3 Hz, 1H), 7.30 - 7.19 (m, 4H), 6.60 - 6.56 (m, 2H), 6.36 (d, J=7.7 Hz, 1H), 4.56 (s, 2H), 3.96 (dq, J=6.3, 9.8 Hz, 2H).

[0164] Project E. Synthesis of intermediate I-4, ethyl 2-(8-bromo-1-oxo-2-isoquinolyl)acetate To a solution of 8-bromo-2H-isoquinoline-1-one (intermediate I-1, 2.5 g, 11 mmol) in dichloromethane (25 mL), ethyl bromo (2.5 mL, 22 mmol) and Cs2CO3 (9.1 g, 28 mmol) were added, and the mixture was stirred overnight at room temperature. Water was added to separate the layers, and the aqueous layer was extracted three times with dichloromethane. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by normal-phase chromatography (25 g column, 0-5% methanol / dichloromethane) to obtain ethyl 2-(8-bromo-1-oxo-2-isoquinolyl)acetate (intermediate I-4, 2.6 g, 8.4 mmol, 76% yield) as an orange solid. UPLC-MS (ES + (Short-term acidity): 1.66 min, m / z 310.0 / 311.9 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.76 (dd, J=1.2, 7.7 Hz, 1H), 7.68 (dd, J=1.1, 8.0 Hz, 1H), 7.57 - 7.52 (m, 2H), 6.67 (d, J=7.4 Hz, 1H), 4.72 (s, 2H), 4.13 (q, J=7.1 Hz, 2H), 1.20 (t, J=7.1 Hz, 3H).

[0165] Project F. Synthesis of intermediate I-5,2-(8-bromo-1-oxo-2-isoquinolyl)acetic acid Ethyl 2-(8-bromo-1-oxo-2-isoquinolyl)acetate (intermediate I-4, 5.5 g, 16 mmol) was suspended in THF (30 mL) and methanol (20 mL), and a solution of lithium hydroxide (561 mg, 23 mmol) / water (10 mL) was added. The mixture was stirred at rt for 2 hours, and then concentrated under reduced pressure. The aqueous solution was acidified to pH 4 with 2 M hydrochloric acid. The resulting precipitate was collected by filtration, dissolved in MeOH, and concentrated under reduced pressure to obtain 2-(8-bromo-1-oxo-2-isoquinolyl)acetic acid (intermediate I-5, 4.0 g, 14 mmol, 91% yield) as a light brown solid. UPLC-MS (ES + (Short-term acidity): 1.34 min, m / z 283.9 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 13.01 (s, 1H), 7.75 (dd, J=1.2, 7.7 Hz, 1H), 7.67 (dd, J=1.1, 7.9 Hz, 1H), 7.56 - 7.51 (m, 2H), 6.64 (d, J=7.4 Hz, 1H), 4.63 (s, 2H).

[0166] Project G. Synthesis of intermediate I-2,2-(8-bromo-1-oxo-2-isoquinolyl)-N-(2,2,2-trifluoroethyl)acetamide HATU (1.56 g, 4.1 mmol) was added to a solution of 2-(8-bromo-1-oxo-2-isoquinolyl)acetic acid (intermediate I-5, 770 mg, 2.7 mmol), N,N-diisopropylethylamine (0.95 mL, 5.5 mmol), and trifluoroethylamine (0.33 mL, 4.1 mmol) / dichloromethane (25 mL), and DMF (5 mL), and the mixture was stirred overnight at room temperature. The mixture was diluted with DCM and water. The aqueous layer was extracted three times with dichloromethane. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by normal-phase chromatography (40 g column, 0-5% methanol in dichloromethane) to obtain 2-(8-bromo-1-oxo-2-isoquinolyl)-N-(2,2,2-trifluoroethyl)acetamide (intermediate I-2, 503 mg, 1.4 mmol, 51% yield) as an off-white solid. For characterization, see step B.

[0167] Engineering HおよびI. Synthesis of intermediate I-6,2-[8-[(1-methylindazole-5-yl)amino]-1-oxo-2-isoquinolyl]acetic acid Project H.Ethyl 2-(8-bromo-1-oxo-2-isoquinolyl)acetate (intermediate I-4, 940 mg, 2.4 mmol) was suspended in toluene (12 mL). 1-Methyl-1h-indazole-5-amine (480 mg, 3.3 mmol) and Cs2CO3 (663 mg, 1.8 mmol, yield 73) (1.5 g, 4.5 mmol) were added, and the mixture was degassed over N2 for 5 minutes. Then, 4,5-bis(diphenylphosphin)-9,9-dimethylxanthene (167 mg, 0.3 mmol) and tris(dibenzylideneacetone)dipalladium (0) (138 mg, 0.15 mmol) were added, the reaction vial was sealed, and heated at 110°C overnight. The mixture was cooled and partitioned between dichloromethane and water. The aqueous phase was extracted three times with dichloromethane, the combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by normal-phase chromatography (25 g column, eluted with 20-90% siRNA / petroleum) to obtain the intermediate ethyl ester ethyl 2-[8-[(1-methylindazole-5-yl)amino]-1-oxo-2-isoquinolyl]acetate (663 mg, 1.8 mmol, yield 73%) as a brown solid. UPLC-MS (ES + (Short-term acidity): 1.83 min, m / z 377.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.88 (s, 1H), 7.99 (d, J=0.9 Hz, 1H), 7.70 - 7.66 (m, 2H), 7.40 (t, J=7.9 Hz, 1H), 7.40 (d, J=7.3 Hz, 1H), 7.32 (dd, J=2.0, 8.9 Hz, 1H), 6.88 (d, J=8.6 Hz, 1H), 6.83 (d, J=7.3 Hz, 1H), 6.57 (d, J=7.4 Hz, 1H), 4.75 (s, 2H), 4.18 (q, J=7.1 Hz, 2H), 4.06 (s, 3H), 1.24 (t, J=7.1 Hz, 3H).

[0168] Project H. Ethyl 2-[8-[(1-methylindazole-5-yl)amino]-1-oxo-2-isoquinolyl]acetate (660 mg, 1.5 mmol) was dissolved in THF (5 mL) and methanol (4 mL), and a solution of lithium hydroxide (74 mg, 3.1 mmol) / water (3 mL) was added. The mixture was stirred at room temperature for 1.5 hours, then concentrated under reduced pressure and acidified to pH 4 with 1 M hydrochloric acid. The resulting precipitate was collected by filtration, washed with water, and dissolved in methanol. The product was concentrated under reduced pressure to obtain 2-[8-[(1-methylindazole-5-yl)amino]-1-oxo-2-isoquinolyl]acetic acid (intermediate I-6, 482 mg, 1.4 mmol, 90% yield) as a yellow solid. UPLC-MS (ES + (Short-term acidity): 1.60 min, m / z 349.1 [M+H] + . 1 1H NMR (400 MHz, DMSO-d6): δ 11.00 (s, 1H), 7.99 (d, J=0.8 Hz, 1H), 7.69 - 7.65 (m, 2H), 7.41 - 7.35 (m, 2H), 7.32 (dd, J=2.1, 8.6 Hz, 1H), 6.88 (d, J=8.3 Hz, 1H), 6.82 (d, J=7.1 Hz, 1H), 6.53 (d, J=7.3 Hz, 1H), 4.61 (s, 2H), 4.06 (s, 3H) (no OH peak observed).

[0169] Table 2 describes intermediates synthesized by replacing 8-bromoisoquinoline with appropriate building blocks in a manner similar to that of 8-bromo-2H-isoquinoline-1-one in I-1. [Table 3]

[0170] Table 3 describes intermediates synthesized by replacing 2-trifluoroethylamine with appropriate building blocks in a manner similar to that of 2-(8-bromo-1-oxo-2-isoquinolyl)-N-(2,2,2-trifluoroethyl)acetamide (via step G, scheme 1) in I-2. [Table 4]

[0171] The intermediates in Table 4 can be produced from the intermediates in Table 3 using the methods described in steps C and D of Scheme 1. [Table 5]

[0172] Table 5 lists intermediates prepared by replacing 1-methyl-1H-indazole-5-amine in step H with an appropriate building block, in a method similar to I-4 to I-6 of Scheme 1. [Table 6] [Table 7] Table 5

[0173] Synthesis of methylated aniline indazole Methylated indazole 1 (MI1) [ka] Project A. A solution of 5-bromo-1-methyl-1H-indazole (900 mg, 4.3 mmol), methanamine (2M in THF, 795 mg, 25.6 mmol), Cs2CO3 (2.8 g, 8.5 mmol), and t-Buxphos-Pd-G3 (338 mg, 0.43 mmol) in dioxane (20 mL) was stirred overnight at 100°C under N2. The mixture was concentrated and purified by normal-phase chromatography (25 g column, 10-50% siRNA / petroleum ether), followed by reverse-phase chromatography (12 g column, 25% MeCN in water) to obtain N,1-dimethylindazole-5-amine as a yellow solid (MI1, 67 mg, 0.42 mmol, 10% yield). UPLCMS (Method 4): 0.550 min, m / z, 162.2 [M+H]. 1 H NMR (400 MHz, DMSO-d6) δ 7.75 (s, 1H), 7.39 (d, J=8.9 Hz, 1H), 6.87 (dd, J=2.1, 8.9 Hz, 1H), 6.59 (d, J=1.8 Hz, 1H), 5.49 - 5.42 (m, 1H), 3.97 (s, 3H), 2.72 (d, J=5.2 Hz, 3H).

[0174] Methylated indazole 2 (MI2) [ka]

[0175] Project A. A mixture of 3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-6-amine (1 g, 4.32 mmol), sodium methoxide (2.34 g, 43 mmol), and formaldehyde (195 mg, 6.5 mmol) in MeOH (15 mL) was stirred at room temperature for 16 hours. NaBH4 (327 mg, 8.65 mmol) was added to the mixture and stirred for 4 hours. After completion, the reaction solution was diluted with water (10 mL) and extracted with ELISA (3 × 50 mL). The combined extracts were washed with brine (3 × 10 mL), dried on Na2SO4, and evaporated. The residue was purified by column chromatography (0-100% siRNA in gasoline) to obtain N,3-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-6-amine (MI2, 0.42 g, 1.7 mmol, yield 40%) as a white solid. UPLCMS (Method 3): 3.35 min, m / z, 246.3 [M+H]. 1 H NMR (400 MHz, CDCl3) δ 7.38 (d, J=8.6 Hz, 1H), 6.50 (d, J=8.7 Hz, 1H), 6.47 (s, 1H), 5.55 (dd, J=1.9, 10.0 Hz, 1H), 4.13 - 4.07 (m, 1H), 3.97 - 3.97 (m, 1H), 3.80 - 3.73 (m, 1H), 2.93 (s, 3H), 2.67 - 2.57 (m, 1H), 2.50 (s, 3H), 2.20 - 2.15 (m, 1H), 2.06 - 2.01 (m, 1H), 1.83 - 1.64 (m, 3H).

[0176] Methylated indazole 3 (MI3) [ka]

[0177] Project A.A solution of 5-bromo-7-fluoro-1-tetrahydropyran-2-yl-indazole (650 mg, 2.2 mmol), NH2-Boc (509 mg, 4.4 mmol), Cs2CO3 (1.42 g, 4.4 mmol), Xantphos (403.0 mg, 0.44 mmol), and Pd2(dba)3 (255 mg, 0.44 mmol) in 1,4-dioxane (7 mL) was stirred overnight at 100°C under N2. The mixed solution was filtered through a Celite pad, washed with ethyl acetate, and concentrated under vacuum to obtain tert-butyl N-(7-fluoro-1-tetrahydropyran-2-yl-indazole-5-yl)carbamate (500 mg, 1.5 mmol, yield 69) as a brown solid, which was used in the next step without further purification. UPLCMS (ES + , Method 3):4.37 min, m / z 336.2 [M+H] + .

[0178] Project B. A solution of tert-butyl N-(7-fluoro-1-tetrahydropyran-2-ylindazole-5-yl)carbamate (50 mg, 0.15 mmol) and LiAlH4 (0.8 mL, 0.76 mmol) in THF (5 mL) was stirred overnight at 60°C. Water (3 mL) was added, and NaOH (10% aqueous solution) was added until the pH reached 11. The mixed solution was further diluted with water, extracted with DCM, the organic matter was dried (Na2SO4), filtered, and concentrated to obtain 7-fluoro-N-methyl-1-tetrahydropyran-2-ylindazole-5-amine (30 mg, 81%) as a white solid. UPLCMS (ES + , Method 3):3.28 min, m / z 250.0 [M+H] + . [Examples]

[0179] Example 1, 2-[8-(1H-indazole-5-ylamino)-1-oxo-2-isoquinolyl]-N-(2,2,2-trifluoroethyl)acetamide [ka]

[0180] Project A. 2-(8-amino-1-oxo-2-isoquinolyl)-N-(2,2,2-trifluoroethyl)acetamide (intermediate I-3, 50 mg, 0.17 mmol), 5-bromo-1-tetrahydropyran-2-yl-pyrazolo[3,4-b]pyridine (52 mg, 0.18 mmol), tris(dibenzylideneacetone)dipalladium(0) (8 mg, 0.01 mmol), tbubrettphos (8 mg, 0.02 mmol), potassium carbonate (46 mg, 0.33 mmol), and acetic acid (5 μL, 0.08 mmol) were dissolved in tert-butanol (2 mL), the vial was sealed and degassed, and the mixture was stirred overnight at 110°C. The mixture was cooled to room temperature, filtered through a Celite pad, washed with siRNA, concentrated under reduced pressure, and purified by normal-phase chromatography (12 g column, 0-5% methanol in dichloromethane) to obtain the THP-protected intermediate 2-[1-oxo-8-[(1-tetrahydropyran-2-ylindazole-5-yl)amino]-2-isoquinolyl]-N-(2,2,2-trifluoroethyl)acetamide (61 mg, 0.12 mmol, yield 73) as an orange solid. UPLC-MS (ES + , Method 2):1.85 min, m / z 500.3 [M+H] + 1H NMR (400 MHz, DMSO-d6) δ 8.91 (t, J=6.4 Hz, 1H), 8.06 (s, 1H), 7.76 (d, J=8.7 Hz, 1H), 7.68 (d, J=1.8 Hz, 1H), 7.41 - 7.32 (m, 3H), 6.90 (d, J=8.2 Hz, 1H), 6.84 (d, J=7.8 Hz, 1H), 6.54 (d, J=7.4 Hz, 1H), 5.85 (dd, J=2.6, 9.6 Hz, 1H), 4.67 (s, 2H), 3.99 (qd, J=5.5, 9.6 Hz, 2H), 3.93 - 3.88 (m, 1H), 3.77 - 3.72 (m, 2H), 2.07 - 1.97 (m, 2H), 1.79 - 1.74 (m, 2H), 1.63 - 1.57 (m, 2H).

[0181] Project B. To a solution of 2-[1-oxo-8-[(1-tetrahydropyran-2-ylindazole-5-yl)amino]-2-isoquinolyl]-N-(2,2,2-trifluoroethyl)acetamide (60 mg, 0.12 mmol) in methanol (1 mL) and acetonitrile (1 mL), HCl (4 M in dioxane, 0.3 mL, 1.2 mmol) was added dropwise, and the mixture was stirred overnight. The mixture was concentrated under vacuum, purified by reverse-phase chromatography (4 g column, 10-60% MeCN in water, 0.1% formic acid), and dried overnight under vacuum to obtain 2-[8-(1H-indazole-5-ylamino)-1-oxo-2-isoquinolyl]-N-(2,2,2-trifluoroethyl)acetamide (12 mg, 0.03 mmol, yield 24) as a yellow solid. UPLC-MS (ES + , Method 1):3.54 min, m / z 416.1 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 13.07 (s, 1H), 10.92 (s, 1H), 8.91 (t, J=6.3 Hz, 1H), 8.02 (s, 1H), 7.66 (d, J=1.4 Hz, 1H), 7.58 (d, J=8.8 Hz, 1H), 7.40 - 7.34 (m, 2H), 7.27 (dd, J=1.9, 8.8 Hz, 1H), 6.87 (d, J=7.8 Hz, 1H), 6.81 (d, J=7.1 Hz, 1H), 6.53 (d, J=7.4 Hz, 1H), 4.66 (s, 2H), 3.98 (dq, J=6.6, 9.7 Hz, 2H).

[0182] Table 6 shows example compounds synthesized by following the same procedure as in Example 1 (Scheme 5), but replacing 5-bromo-1-tetrahydropyran-2-yl-pyrazolo[3,4-b]pyridine in step A with an appropriate building block, and, if necessary, replacing I-3 with an appropriate aniline intermediate.

[0183] [Table 8] [Table 9] [Table 10]

[0184] [Table 11] [Table 12] [Table 13] Table 6

[0185] Example 3, 2-[8-[(1-methylindazole-5-yl)amino]-1-oxo-2-isoquinolyl]-N-(2,2,2-trifluoroethyl)acetamide [ka]

[0186] Project A. 2-(8-amino-1-oxo-2-isoquinolyl)-N-(2,2,2-trifluoroethyl)acetamide (intermediate I-3, 50 mg, 0.17 mmol), 5-bromo-1-methyl-1H-indazole (39 mg, 0.18 mmol), tris(dibenzylideneacetone)dipalladium (0) (8 mg, 0.01 mmol), tbubrettphos (8 mg, 0.02 mmol), potassium carbonate (46 mg, 0.33 mmol), and acetic acid (glacial acetic acid) (5 μL, 0.08 mmol) were dissolved in tert-butanol (2 mL). The vial was sealed and degassed, and the mixed solution was stirred overnight at 110°C. The mixed solution was cooled to room temperature, filtered through a Celite pad, washed with ethyl acetate, concentrated under reduced pressure, purified by reverse-phase chromatography (12 g column, 35-60% acetonitrile / water, 0.1% formic acid), and dried overnight under vacuum to obtain 2-[8-[(1-methylindazole-5-yl)amino]-1-oxo-2-isoquinolyl]-N-(2,2,2-trifluoroethyl)acetamide (32 mg, 0.07 mmol, 44% yield) as a yellow solid. UPLC-MS (ES + , Method 1):3.88 min, m / z 430.2 [M+H] + (100%). 1H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 8.92 (t, J=6.2 Hz, 1H), 7.99 (d, J=0.9 Hz, 1H), 7.67 (d, J=8.9 Hz, 1H), 7.65 (d, J=1.9 Hz, 1H), 7.38 (t, J=8.0 Hz, 1H), 7.36 (d, J=7.3 Hz, 1H), 7.31 (dd, J=2.0, 8.9 Hz, 1H), 6.87 (dd, J=0.9, 8.4 Hz, 1H), 6.82 (dd, J=0.9, 7.7 Hz, 1H), 6.53 (d, J=7.4 Hz, 1H), 4.67 (s, 2H), 4.06 (s, 3H), 3.98 (q, J=5.4 Hz, 2H).

[0187] Table 7 shows example compounds synthesized by following the same procedure as in Example 3 (Scheme 6), but replacing 5-bromo-1-methyl-1H-indazole in step A with an appropriate building block, and, where necessary, replacing I-3 with I-9. [Table 14] [Table 15] [Table 16] [Table 17] 1 For example, if a different HPLC and mass spectrometry method is used, it will be shown in the individual examples. Table 7

[0188] Example 52, 2-[8-[(7-chloro-1H-indazole-5-yl)amino]-1-oxo-2-isoquinolyl]-N-(2,2,2-trifluoroethyl)acetamide [ka]

[0189] Project A. 2-(8-bromo-1-oxo-2-isoquinolyl)-N-(2,2,2-trifluoroethyl)acetamide (intermediate I-2, 50 mg, 0.14 mmol), Cs2CO3 (90 mg, 0.28 mmol), and 7-chloro-1-tetrahydropyran-2-ylindazole-5-amine (42 mg, 0.17 mmol) were dissolved in toluene (2 mL). After degassing the vial with N2 for 10 minutes, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (8 mg, 0.01 mmol) and tris(dibenzylideneacetone)dipalladium(0) (6.3 mg, 0.01 mmol) were added, the vial was sealed, and the mixture was heated to 110°C and stirred overnight. The mixture was filtered through a Celite pad, washed with methanol, and concentrated under vacuum. The crude product was purified by reverse-phase chromatography (12 g column, 20-70% acetonitrile in water, 0.1% formic acid) to obtain the THP-protected intermediate 2-[8-[(7-chloro-1-tetrahydropyran-2-ylindazole-5-yl)amino]-1-oxo-2-isoquinolyl]-N-(2,2,2-trifluoroethyl)acetamide (36 mg, 0.07 mmol, 49% yield) as a yellow solid. UPLC-MS (ES + , Method 2):2.07 min, m / z 534.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 11.02 (s, 1H), 8.92 (t, J=6.3 Hz, 1H), 8.17 (s, 1H), 7.83 - 7.80 (m, 1H), 7.72 (d, J=1.7 Hz, 1H), 7.42 - 7.35 (m, 2H), 6.97 (d, J=8.3 Hz, 1H), 6.89 (d, J=7.1 Hz, 1H), 6.56 (d, J=7.4 Hz, 1H), 6.24 (dd, J=2.0, 10.1 Hz, 1H), 4.67 (s, 2H), 4.00 - 3.91 (m, 3H), 3.75 - 3.68 (m, 1H), 2.13 - 2.10 (m, 1H), 2.06 - 2.03 (m, 1H), 1.81 - 1.72 (m, 2H), 1.59 - 1.54 (m, 2H).

[0190] Project B. To a solution of 2-[8-[(7-chloro-1-tetrahydropyran-2-ylindazole-5-yl)amino]-1-oxo-2-isoquinolyl]-N-(2,2,2-trifluoroethyl)acetamide (36 mg, 0.07 mmol) in acetonitrile (1 mL) and methanol (1 mL), hydrochloric acid (4 M in dioxane, 0.08 mL, 0.34 mmol) was added, and the mixture was stirred overnight at rt. The mixture was concentrated under reduced pressure, and the crude product was purified by reverse-phase chromatography (12 g column, 20-60% acetonitrile / water, 0.1% formic acid). The mixture was dried overnight under vacuum to obtain 2-[8-[(7-chloro-1H-indazole-5-yl)amino]-1-oxo-2-isoquinolyl]-N-(2,2,2-trifluoroethyl)acetamide (7.5 mg, 0.02 mmol, yield 25%) as a light brown solid. UPLC-MS (ES + , Method 1):3.72 min, m / z 450.0 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 13.59 (s, 1H), 10.95 (s, 1H), 8.92 (t, J=6.4 Hz, 1H), 8.15 (s, 1H), 7.67 (s, 1H), 7.44 - 7.35 (m, 3H), 6.88 (t, J=8.5 Hz, 2H), 6.55 (d, J=7.4 Hz, 1H), 4.67 (s, 2H), 3.98 (q, J=5.4 Hz, 2H).

[0191] Table 8 shows example compounds synthesized by following the same procedure as in Example 52 (Scheme 7), but replacing 7-chloro-1-tetrahydropyran-2-yl-indazole-5-amine in step A with an appropriate building block, and, where necessary, replacing I-2 with I-8. [Table 18] [Table 19] [Table 20] Table 8

[0192] Example 88, 2-[8-[methyl-(1-methylindazole-5-yl)amino]-1-oxo-2-isoquinolyl]-N-(2,2,2-trifluoroethyl)acetamide [ka] Project A.A mixed solution of N,1-dimethyl-1H-indazole-5-amine (MI1, 67 mg, 0.42 mmol), 2-(8-bromo-1-oxoisoquinoline-2(1H)-yl)-N-(2,2,2-trifluoroethyl)acetamide (intermediate I-2, 150 mg, 0.42 mmol), Pd2(dba)3 (38 mg, 0.042 mmol), Xantphos (24 mg, 0.042 mmol), and Cs2CO3 (243 mg, 0.75 mmol) in toluene (2 mL) was stirred overnight under N2 at 110°C. The mixed solution was concentrated under reduced pressure and purified by reverse-phase prep-HPLC to obtain 2-[8-[methyl-(1-methylindazole-5-yl)amino]-1-oxo-2-isoquinolyl]-N-(2,2,2-trifluoroethyl)acetamide (25 mg, 0.056 mmol, 14% yield) as a white solid. LC-MS (Method 3): 3.650 min, m / z, 444.3 [M+H]. 1 H NMR (400 MHz, DMSO) δ 8.79 (t, J=6.7 Hz, 1H), 7.81 (s, 1H), 7.67 (t, J=7.8 Hz, 1H), 7.52 (d, J=7.2 Hz, 1H), 7.43 (d, J=7.4 Hz, 1H), 7.33 (d, J=9.2 Hz, 1H), 7.21 (d, J=7.7 Hz, 1H), 6.86 (d, J=2.0 Hz, 1H), 6.69 (dd, J=2.1, 9.1 Hz, 1H), 6.61 (d, J=7.4 Hz, 1H), 4.55 (s, 2H), 3.96 (s, 3H), 3.94 - 3.86 (m, 2H), 3.19 (s, 3H).

[0193] Table 9 shows example compounds synthesized by following the same procedure as Example 88 (Scheme 8), but replacing N,1-dimethyl-1H-indazole-5-amine in step A with a suitable aniline building block. [Table 21] [Table 22]

[0194] Example 9, N-isobutyl-2-[8-[(1-methylindazole-5-yl)amino]-1-oxo-2-isoquinolyl]acetamide [Table 23]

[0195] Project A. HATU (49 mg, 0.13 mmol) was added to a solution of 2-[8-[(1-methylindazole-5-yl)amino]-1-oxo-2-isoquinolyl]acetic acid (intermediate I-6, 30 mg, 0.09 mmol), isobutylamine (0.01 mL, 0.1 mmol), and N,N-diisopropylethylamine (0.03 mL, 0.17 mmol) in DMF (2 mL), and the mixture was stirred overnight at room temperature. The mixture was partitioned between ethyl acetate and water to separate the layers. The organic layer was washed with brine, and the combined aqueous layer was extracted twice with ethyl acetate, dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by normal-phase chromatography (4 g column, 70-100% siRNA / petroleum ether) to obtain N-isobutyl-2-[8-[(1-methylindazole-5-yl)amino]-1-oxo-2-isoquinolyl]acetamide (10 mg, 0.025 mmol, yield 29) as a white solid. UPLC-MS (ES + , Method 1):4.05 min, m / z 404.3 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 8.16 (t, J=5.7 Hz, 1H), 7.99 (d, J=0.9 Hz, 1H), 7.68 (d, J=8.9 Hz, 1H), 7.65 (d, J=1.9 Hz, 1H), 7.38 (t, J=8.1 Hz, 1H), 7.34 - 7.30 (m, 2H), 6.87 (d, J=8.3 Hz, 1H), 6.81 (d, J=7.0 Hz, 1H), 6.51 (d, J=7.4 Hz, 1H), 4.57 (s, 2H), 4.06 (s, 3H), 2.94 (t, J=6.3 Hz, 2H), 1.75 - 1.68 (m, 1H), 0.87 (d, J=6.7 Hz, 6H).

[0196] Table 10 shows example compounds synthesized by following the same procedure as in Example 9 (Scheme 9), but by replacing 7-isobutylamine in step A with an appropriate amine building block, or by replacing I-3 with I-13. [Table 24] [Table 25] [Table 26] [Table 27] TIFF0007884586000078.tif240156 [Table 28] [Table 29] [Table 30] Table 31 Table 32 Table 33 Table 34 Table 35 Table 36 Table 37 Table 38 Table 39 Table 40 Table 41 Table 42 Table 43 Table 44 Table 45 Table 46 [Table 47] [Table 48] [Table 49] 1 For example, if other HPLC and mass spectrometry methods were used, these are shown in the individual examples. Table 10

[0197] Example 27. 2-[1-oxo-8-(1H-pyrazolo[3,4-b]pyridine-5-ylamino)-2-isoquinolyl]-N-[(1S)-2,2,2-trifluoro-1-methyl-ethyl]acetamide [ka] Project A. 2-[1-oxo-8-[(1-tetrahydropyran-2-ylpyrazolo[3,4-b]pyridine-5-yl)amino]-2-isoquinolyl]acetic acid (intermediate I-12, 50 mg, 0.12 mmol), (S)-2-amino-1,1,1-trifluoropropane hydrochloride (20 mg, 0.13 mmol), and N,N-diisopropylethylamine (0.05 mL, 0.3 mmol) in DMF (2 mL) were mixed with HATU (68 mg, 0.18 mmol), and the mixture was stirred overnight at room temperature. The mixture was diluted with ethyl acetate, washed three times with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by normal-phase chromatography (12 g column, 10-90% ethyl acetate / petroleum ether) to obtain 2-[1-oxo-8-[(1-tetrahydropyran-2-ylpyrazolo[3,4-b]pyridine-5-yl)amino]-2-isoquinolyl]-N-[(1S)-2,2,2-trifluoro-1-methyl-ethyl]acetamide (50 mg, 0.1 mmol, 82% yield) as a brown solid. UPLC-MS (ES +, Method 2):1.89 min, m / z 515.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 8.84 (d, J=8.8 Hz, 1H), 8.53 (d, J=2.4 Hz, 1H), 8.22 (d, J=2.3 Hz, 1H), 8.18 (s, 1H), 7.42 - 7.36 (m, 2H), 6.89 (d, J=7.2 Hz, 1H), 6.82 (d, J=7.5 Hz, 1H), 6.56 (d, J=7.4 Hz, 1H), 6.02 (dd, J=2.2, 10.4 Hz, 1H), 4.69 - 4.62 (m, 3H), 3.98 - 3.93 (m, 1H), 3.71 - 3.70 (m, 1H), 2.08 - 2.04 (m, 1H), 1.98 - 1.91 (m, 2H), 1.83 - 1.76 (m, 2H), 1.66 - 1.56 (m, 3H).

[0198] Project B. To a solution of 2-[1-oxo-8-[(1-tetrahydropyran-2-ylpyrazolo[3,4-b]pyridine-5-yl)amino]-2-isoquinolyl]-N-[(1S)-2,2,2-trifluoro-1-methyl-ethyl]acetamide (50 mg, 0.1 mmol) / acetonitrile (2 mL), HCl (4 M in dioxane, 0.12 mL, 0.5 mmol) was added, and the mixed solution was stirred overnight at room temperature. The mixed solution was concentrated under reduced pressure, purified by reverse-phase chromatography (12 g column, 20-60% acetonitrile / water, 0.1% formic acid), and vacuum-dried overnight to obtain 2-[1-oxo-8-(1H-pyrazolo[3,4-b]pyridine-5-ylamino)-2-isoquinolyl]-N-[(1S)-2,2,2-trifluoro-1-methyl-ethyl]acetamide (22 mg, 0.05 mmol, 53% yield) as a pale yellow solid. UPLC-MS (ES + , Method 1):3.70 min, m / z 431.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 13.67 (s, 1H), 10.94 (s, 1H), 8.84 (d, J=8.8 Hz, 1H), 8.46 (d, J=2.4 Hz, 1H), 8.18 (d, J=2.3 Hz, 1H), 8.11 (s, 1H), 7.42 - 7.35 (m, 2H), 6.87 (d, J=7.6 Hz, 1H), 6.78 (d, J=8.3 Hz, 1H), 6.55 (d, J=7.4 Hz, 1H), 4.72 - 4.57 (m, 3H), 1.29 (d, J=7.0 Hz, 3H).

[0199] Table 11 shows example compounds synthesized by following the same procedure as in Example 27 (Scheme 10), but replacing (S)-2-amino-1,1,1-trifluoropropane hydrochloride in step A with a suitable amine building block.

[0200] [Table 50] [Table 51] 1 For example, if other HPLC and mass spectrometry methods were used, these are shown in the individual examples. Table 11

[0201] Example 38, N-[3-(1-hydroxy-1-methyl-ethyl)phenyl]-2-[8-[(1-methylindazole-5-yl)amino]-1-oxo-2-isoquinolyl]acetamide [ka] Project A.A solution of N-(3-acetylphenyl)-2-[8-[(1-methylindazole-5-yl)amino]-1-oxo-2-isoquinolyl]acetamide (30 mg, 0.06 mmol) / THF (2 mL) was cooled to 0°C under N2, and bromo(methyl)magnesium (1 M, 0.14 mL, 0.14 mmol in THF) was added dropwise. The mixture was stirred at 0°C for 2 hours. The reaction was quenched by adding MeOH (1 mL), and the solution was warmed to room temperature and concentrated under reduced pressure. The crude product was purified by reverse-phase chromatography (12 g column, 20-60% acetonitrile / water, 0.1% formic acid) and dried overnight under vacuum to obtain N-[3-(1-hydroxy-1-methyl-ethyl)phenyl]-2-[8-[(1-methylindazole-5-yl)amino]-1-oxo-2-isoquinolyl]acetamide (10 mg, 0.021 mmol, 32% yield) as an off-white solid. UPLC-MS (ES + , Method 1):4.20 min, m / z 482.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 10.33 (s, 1H), 7.97 (s, 1H), 7.71 (s, 1H), 7.68 - 7.64 (m, 2H), 7.48 (d, J=8.2 Hz, 1H), 7.42 - 7.37 (m, 2H), 7.31 (d, J=10.4 Hz, 1H), 7.24 (t, J=7.9 Hz, 1H), 7.15 (d, J=8.5 Hz, 1H), 6.88 (d, J=8.3 Hz, 1H), 6.84 (d, J=7.7 Hz, 1H), 6.56 (d, J=7.3 Hz, 1H), 5.01 (s, 1H), 4.78 (s, 2H), 4.05 (s, 3H), 1.40 (s, 6H).

[0202] Table 12 shows example compounds synthesized by following the same procedure as in Example 38 (Scheme 11), but replacing N-(3-acetylphenyl)-2-[8-[(1-methylindazole-5-yl)amino]-1-oxo-2-isoquinolyl]acetamide in step A with an appropriate corresponding ketone or ester example compound. [Table 52] [Table 53] [Table 54] [Table 55] [Table 56] 1 For example, if other HPLC and mass spectrometry methods were used, these are shown in the individual examples. Table 12

[0203] Example 47. 2-[6-fluoro-8-[(1-methylindazole-5-yl)amino]-1-oxo-2-isoquinolyl]-N-(2,2,2-trifluoroethyl)acetamide [ka]

[0204] Project A. To a solution of 8-bromo-6-fluoroisoquinoline (1.0 g, 4.4 mmol) in dichloromethane (25 mL), m-chloroperbenzoic acid (1.53 g, 8.9 mmol) was added at 0°C, and the mixture was stirred for 4 hours while slowly warming to rt. The reaction was quenched with saturated aqueous Na2S2O3, the layers were separated, the organic layers were washed with saturated aqueous NaHCO3, and the combined aqueous layers were extracted with dichloromethane. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to obtain the intermediate N-oxide as a pale orange solid. N-oxide was dissolved in acetic anhydride (20 mL, 212 mmol), the mixture was heated to 140°C and stirred for 3 hours, then cooled to room temperature and concentrated under reduced pressure. The resulting brown oil was dissolved in methanol (20 mL) and saturated NaHCO3 aqueous solution (20 mL, 88 mmol) was added. The mixture was stirred overnight at room temperature, concentrated under reduced pressure, and neutralized by adding 2M HCl dropwise until the pH reached 6. The resulting brown solid was collected by filtration, dissolved in methanol, and concentrated under reduced pressure to obtain 8-bromo-6-fluoro-2H-isoquinoline-1-one (963 mg, 4.0 mmol, yield 90%) as a brown solid. UPLC-MS (ES + , Method 2):1.62 min, m / z 241.8 / 243.8 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.34 (s, 1H), 7.64 (dd, J=2.6, 8.6 Hz, 1H), 7.55 (dd, J=2.6, 9.4 Hz, 1H), 7.25 (app t, J=6.5 Hz, 1H), 6.54 (dd, J=1.3, 7.1 Hz, 1H).

[0205] Project B. To a solution of 8-bromo-6-fluoro-2H-isoquinoline-1-one (963 mg, 4.0 mmol) / dichloromethane (15 mL), ethyl bromo (0.9 mL, 8.0 mmol) and Cs2CO3 (3.25 g, 10.0 mmol) were added, and the mixture was stirred overnight at room temperature. Water was added to separate the layers, the aqueous layer was extracted with dichloromethane, the combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by normal-phase chromatography (25 g column, 10-90% toluene / gasoline) to obtain ethyl 2-(8-bromo-6-fluoro-1-oxo-2-isoquinolyl) (1.1 g, 3.35 mmol, 84% yield) as an orange solid. UPLC-MS (ES + , Method 2):1.82 min, m / z 328.0 / 329.9 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.73 (dd, J=2.6, 8.6 Hz, 1H), 7.60 - 7.56 (m, 2H), 6.66 (d, J=7.4 Hz, 1H), 4.71 (s, 2H), 4.17 (q, J=7.1 Hz, 2H), 1.23 (t, J=7.1 Hz, 3H).

[0206] Project C. A mixture of ethyl 2-(8-bromo-6-fluoro-1-oxo-2-isoquinolyl)acetate (500 mg, 1.5 mmol) / methanol (4 mL) was mixed with a solution of lithium hydroxide (109 mg, 4.6 mmol) / water (4 mL), and the mixture was stirred overnight at room temperature. The mixture was concentrated under reduced pressure, and then neutralized by adding 2 M HCl dropwise until the pH was 4. The resulting precipitate was collected by filtration, dissolved in methanol, and concentrated under reduced pressure to obtain 2-(8-bromo-6-fluoro-1-oxo-2-isoquinolyl)acetic acid (445 mg, 1.5 mmol, 97% yield) as a pale yellow solid. UPLC-MS (ES +, Method 2):1.57 min, m / z 299.9 / 301.9 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 13.03 (s, 1H), 7.72 (dd, J=2.6, 8.6 Hz, 1H), 7.59 - 7.55 (m, 2H), 6.63 (d, J=7.4 Hz, 1H), 4.63 (s, 2H).

[0207] Project D. HATU (846 mg, 2.2 mmol) was added to a solution of 2-(8-bromo-6-fluoro-1-oxo-2-isoquinolyl)acetic acid (445 mg, 1.5 mmol), trifluoroethylamine (220 mg, 2.2 mmol), N,N-diisopropylethylamine (0.5 mL, 3.0 mmol), and trifluoroethylamine (0.18 mL, 2.2 mmol) in dichloromethane (10 mL). The mixture was stirred overnight at room temperature. Water was added to separate the layers, the organic layers were washed with brine, and the combined aqueous layers were extracted with dichloromethane. The organic layers were combined, dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by normal-phase chromatography (12 g column, 10-100% ethyl acetate / petroleum ether) to obtain 2-(8-bromo-6-fluoro-1-oxo-2-isoquinolyl)-N-(2,2,2-trifluoroethyl)acetamide (434 mg, 1.1 mmol, 77% yield) as a pale orange solid. UPLC-MS (ES + , Method 2):1.73 min, m / z 381.0 / 382.9 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.91 (t, J=6.2 Hz, 1H), 7.70 (dd, J=2.6, 8.6 Hz, 1H), 7.58 - 7.53 (m, 2H), 6.62 (d, J=7.4 Hz, 1H), 4.63 (s, 2H), 3.97 (dq, J=6.4, 9.8 Hz, 2H).

[0208] Project E. 2-(8-bromo-6-fluoro-1-oxo-2-isoquinolyl)-N-(2,2,2-trifluoroethyl)acetamide (50 mg, 0.12 mmol), 1-methyl-1h-indazole-5-amine (21 mg, 0.14 mmol), tris(dibenzylideneacetone)dipalladium (0) (5.4 mg, 0.01 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (6.7 mg, 0.01 mmol), and Cs2CO3 (77 mg, 0.24 mmol) were dissolved in toluene (2 mL). The vial was sealed and degassed, and the mixture was stirred overnight at 110°C. The mixture was concentrated under reduced pressure and purified by normal-phase chromatography (12 g column, 10-100% ethyl ethyl in gasoline). The purified product was triturated with isopropanol and dried overnight under vacuum to obtain 2-[6-fluoro-8-[(1-methylindazole-5-yl)amino]-1-oxo-2-isoquinolyl]-N-(2,2,2-trifluoroethyl)acetamide (30 mg, 0.067 mmol, 57% yield) as a white solid. UPLC-MS (ES + , Method 1):4.32 min, m / z 448.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.13 (s, 1H), 8.93 (t, J=6.3 Hz, 1H), 8.02 (s, 1H), 7.74 - 7.68 (m, 2H), 7.43 (d, J=7.3 Hz, 1H), 7.34 (dd, J=1.7, 8.8 Hz, 1H), 6.63 (dd, J=2.1, 9.4 Hz, 1H), 6.54 (d, J=7.4 Hz, 1H), 6.45 (dd, J=2.1, 12.4 Hz, 1H), 4.67 (s, 2H), 4.07 (s, 3H), 3.98 (dq, J=6.4, 9.7 Hz, 2H).

[0209] The following example compounds (Table 13) were prepared according to the route described in Scheme 12 for Example 47, by replacing 8-bromo-6-fluoroisoquinoline in step A with a suitable fluorinated 8-bromoisoquinoline starting material, and / or replacing trifluoroethylamine in step D with a suitable amine building block, or replacing 1-methyl-1h-indazole-5-amine in step E with a suitable aniline building block. [Table 57] [Table 58] [Table 59]

[0210] Example 51. 2-[8-[(1-methylindazole-5-yl)amino]-1-oxo-2-isoquinolyl]-N-(2,2,2-trifluoroethyl)propanamide [ka] Project A. To a solution of 8-bromo-2H-isoquinoline-1-one (intermediate I-1, 250 mg, 1.1 mmol) in DMF (5 mL), ethyl 2-bromopropionate (0.2 mL, 1.7 mmol) and Cs2CO3 (727 mg, 2.2 mmol) were added, and the mixture was stirred overnight at room temperature. The mixture was diluted with ethyl ammonium compounds, washed three times with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by normal-phase chromatography (25 g column, 10-90% ethyl ammonium compounds / petroleum ether) to obtain ethyl 2-(8-bromo-1-oxo-2-isoquinolyl)propanoate (155 mg, 0.48 mmol, 43% yield) as a yellow oil. UPLC-MS (ES + , Method 2):1.83 min, m / z 324.0 / 325.9 [M+H]+ . 1 H NMR (400 MHz, DMSO-d6) δ 7.75 (dd, J=1.2, 7.7 Hz, 1H), 7.68 (dd, J=1.1, 8.0 Hz, 1H), 7.57 - 7.52 (m, 2H), 6.69 (d, J=7.5 Hz, 1H), 5.21 (q, J=7.2 Hz, 1H), 4.18 - 4.08 (m, 2H), 1.58 (d, J=7.2 Hz, 3H), 1.16 (t, J=7.1 Hz, 3H).

[0211] Project B. A mixture of ethyl 2-(8-bromo-1-oxo-2-isoquinolyl)propanoate (155 mg, 0.48 mmol) / methanol (3 mL) was mixed with a solution of lithium hydroxide (34 mg, 1.4 mmol) / water (3 mL), and the mixture was stirred overnight under rot. The mixture was concentrated under reduced pressure, and then neutralized by adding 2 M HCl dropwise until the pH was 4. The resulting precipitate was collected by filtration, dissolved in methanol, and concentrated under reduced pressure to obtain 2-(8-bromo-1-oxo-2-isoquinolyl)propanoate (145 mg, 0.48 mmol, 100% yield) as a white solid. UPLC-MS (ES + , Method 2):1.56 min, m / z 295.9 / 297.9 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.91 (s, 1H), 7.75 (d, J=7.8 Hz, 1H), 7.67 (d, J=7.0 Hz, 1H), 7.56 - 7.51 (m, 2H), 6.66 (d, J=7.4 Hz, 1H), 5.20 (q, J=7.3 Hz, 1H), 1.57 (d, J=7.4 Hz, 3H).

[0212] Project C. To a solution of 2-(8-bromo-1-oxo-2-isoquinolyl)propanoic acid (145 mg, 0.48 mmol), N,N-diisopropylethylamine (0.17 mL, 0.98 mmol), and trifluoroethylamine (0.06 mL, 0.73 mmol) in DMF (3 mL), HATU (279 mg, 0.73 mmol) was added, and the mixture was stirred overnight at room temperature. The mixture was diluted with ethyl acetate, washed three times with brine, dried over Na₂SO₄, and reduced in pressure. The crude product was purified by normal-phase chromatography (12 g column, 10-90% ethyl acetate / petroleum ether) to obtain 2-(8-bromo-1-oxo-2-isoquinolyl)-N-(2,2,2-trifluoroethyl)propanamide (149 mg, 0.39 mmol, yield 81%) as a pale yellow solid. UPLC-MS (ES + , Method 2):1.71 min, m / z 377.0 / 378.9 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.90 (t, J=6.2 Hz, 1H), 7.74 (dd, J=1.2, 7.7 Hz, 1H), 7.67 (dd, J=1.2, 8.1 Hz, 1H), 7.53 (t, J=7.8 Hz, 1H), 7.49 (d, J=7.5 Hz, 1H), 6.66 (d, J=7.6 Hz, 1H), 5.45 (q, J=7.3 Hz, 1H), 3.98 - 3.89 (m, 2H), 1.55 (d, J=7.3 Hz, 3H).

[0213] Project D.2-(8-bromo-1-oxo-2-isoquinolyl)-N-(2,2,2-trifluoroethyl)propanamide (50 mg, 0.13 mmol), 1-methyl-1h-indazole-5-amine (21 mg, 0.15 mmol), tris(dibenzylideneacetone)dipalladium (0) (6.1 mg, 0.01 mmol), 4,5-bis(diphenylphosphin)-9,9-dimethylxanthene (7.7 mg, 0.01 mmol), and Cs2CO3 (86 mg, 0.27 mmol) were dissolved in toluene (2 mL). The vial was sealed and degassed, and the mixture was stirred overnight at 110°C. The mixture was filtered through a Celite pad, washed with methanol, and concentrated under reduced pressure. The crude product was purified by reverse-phase chromatography (12 g column, 25-65% acetonitrile / water, 0.1% formic acid), and then dried overnight under vacuum to obtain 2-[8-[(1-methylindazole-5-yl)amino]-1-oxo-2-isoquinolyl]-N-(2,2,2-trifluoroethyl)propanamide (39 mg, 0.09 mmol, yield 66) as a white solid. UPLC-MS (ES + , Method 1):4.44 min, m / z 444.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 8.89 (t, J=6.4 Hz, 1H), 7.99 (s, 1H), 7.70 - 7.64 (m, 2H), 7.41 - 7.34 (m, 2H), 7.31 (dd, J=1.9, 8.8 Hz, 1H), 6.86 (d, J=8.3 Hz, 1H), 6.82 (d, J=7.3 Hz, 1H), 6.57 (d, J=7.6 Hz, 1H), 5.49 (q, J=7.3 Hz, 1H), 4.06 (s, 3H), 4.02 - 3.87 (m, 2H), 1.58 (d, J = 7.3 Hz, 3H).

[0214] The following examples (Table 14) were prepared according to the route described in Scheme 13 as Example 51, by replacing ethyl 2-bromopropionate in step A with a suitable electrophilic starting material. [Table 60]

[0215] Example 8, 2-[5-methyl-8-[(1-methylindazole-5-yl)amino]-1-oxo-2-isoquinolyl]-N-(2,2,2-trifluoroethyl)acetamide [ka]

[0216] Project A To a solution of 5-bromo-8-nitro-2H-isoquinoline-1-one (160 mg, 0.6 mmol) / DMF (10 mL), ethyl bromo (0.13 mL, 1.2 mmol) and Cs2CO3 (484 mg, 1.5 mmol) were added, and the mixture was heated to 90°C and stirred overnight. The mixture was cooled to rt, diluted with ethyl ethyl ethyl ethyl ethyl ethyl ethyl ethyl ethyl ethyl ethyl ethyl ethyl ethyl ethyl ethyl ethyl ethyl ethyl ethyl ethyl ethyl ethyl ethyl hydroxyl hydroxyl ethyl ethyl ethyl hydroxyl ethyl ethyl hydroxyl ethyl ethyl ethyl ethyl ethyl hydroxyl ethyl ethyl ethyl hydroxyl ethyl ethyl hydroxyl ethyl ethyl ethyl ethyl ethyl hydroxyl ethyl hydroxyl ethyl ethyl ethyl ethyl ethyl ethyl ethyl ethyl ethyl ethyl ethyl ethyl hydroxyl UPLC-MS (ES + , Method 2):1.68 min, m / z 355.0 / 357.0 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 8.28 (d, J=8.2 Hz, 1H), 7.82 (d, J=7.7 Hz, 1H), 7.78 (d, J=8.3 Hz, 1H), 6.95 (d, J=7.7 Hz, 1H), 4.82 (s, 2H), 4.17 (q, J=7.1 Hz, 2H), 1.22 (t, J=7.1 Hz, 3H).

[0217] Project B. Methylboronic acid (0.08 mL, 2.8 mmol), K2CO3 (584 mg, 4.2 mmol), and ethyl 2-(5-bromo-8-nitro-1-oxo-2-isoquinolyl) acetate (500 mg, 1.4 mmol) were dissolved in 1,4-dioxane (6 mL) and water (1 mL). This solution was degassed, and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride dichloromethane complex (115 mg, 0.14 mmol) was added. The mixture was stirred at 110°C for 4 hours. The mixture was cooled to rt, diluted with methanol, quenched with 2 M hydrochloric acid, filtered through a methanol-washed Celite pad, and concentrated under reduced pressure. Ether and water were added, the layers were separated, and the organic layers were washed with brine. The combined aqueous layers were extracted with Ether. The organic layers were combined, dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by normal-phase chromatography (25 g column, 0-5% methanol / dichloromethane) to obtain ethyl 2-(5-methyl-8-nitro-1-oxo-2-isoquinolyl) acetate (191 mg, 0.66 mmol, 47% yield) as a yellow solid. UPLC-MS (ES + , Method 2):1.59 min, m / z 291.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 7.74 (d, J=8.1 Hz, 1H), 7.70 (d, J=7.7 Hz, 1H), 7.67 (d, J=7.7 Hz, 1H), 6.86 (d, J=7.6 Hz, 1H), 4.79 (s, 2H), 4.16 (q, J=7.5 Hz, 2H), 2.57 (s, 3H), 1.21 (t, J=7.1 Hz, 3H).

[0218] Project C. A mixture of ethyl 2-(5-methyl-8-nitro-1-oxo-2-isoquinolyl)acetate (191 mg, 0.7 mmol) in methanol (4 mL) and THF (2 mL) was mixed with a solution of lithium hydroxide (47 mg, 2.0 mmol) / water (2 mL), and the mixture was stirred overnight at room temperature. The mixture was concentrated under reduced pressure, and then neutralized by adding 2 M HCl dropwise until the pH reached 4. The resulting precipitate was collected by filtration, dissolved in methanol, and concentrated under reduced pressure to obtain 2-(5-methyl-8-nitro-1-oxo-2-isoquinolyl)acetic acid (145 mg, 0.55 mmol, 84% yield) as a yellow solid. UPLC-MS (ES + , Method 2):1.37 min, m / z 263.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 13.12 (s, 1H), 7.75 - 7.65 (m, 3H), 6.83 (d, J=7.6 Hz, 1H), 4.70 (s, 2H), 2.57 (s, 3H).

[0219] Project D.HATU (315 mg, 0.83 mmol) was added to a solution of 2-(5-methyl-8-nitro-1-oxo-2-isoquinolyl)acetic acid (145 mg, 0.55 mmol), N,N-diisopropylethylamine (0.2 mL, 1.1 mmol), and trifluoroethylamine (0.07 mL, 0.83 mmol) in dichloromethane (8 mL). The mixture was stirred overnight at room temperature. The mixture was diluted with dichloromethane, water was added, and the layers were separated. The aqueous layer was extracted with dichloromethane, the combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by normal-phase chromatography (25 g column, 0-5% methanol / dichloromethane) to obtain 2-(5-methyl-8-nitro-1-oxo-2-isoquinolyl)-N-(2,2,2-trifluoroethyl)acetamide (190 mg, 0.55 mmol, 100% yield) as a pale yellow solid. UPLC-MS (ES + , Method 2):1.55 min, m / z 344.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.94 (t, J=6.2 Hz, 1H), 7.72 (d, J=7.8 Hz, 1H), 7.68 - 7.62 (m, 2H), 6.81 (d, J=7.6 Hz, 1H), 4.70 (s, 2H), 3.97 (dq, J=6.4, 9.7 Hz, 2H), 2.56 (s, 3H).

[0220] Project E.A solution of 2-(5-methyl-8-nitro-1-oxo-2-isoquinolyl)-N-(2,2,2-trifluoroethyl)acetamide (190 mg, 0.55 mmol) / methanol (8 mL) was purged with 3 cycles of vac / N2. After adding palladium (10 wt% / carbon, 29 mg, 0.03 mmol), three more vac / N2 cycles were performed, and the mixture was placed under an H2 atmosphere (3 x H2 / vac cycles) and stirred at rt for 1 hour. The mixture was filtered through a Celite pad washed with methanol, concentrated under reduced pressure, and purified by SCX column elution, first with methanol, and then with 7 M ammonia / methanol. The basic layer was concentrated under reduced pressure to obtain 2-(8-amino-5-methyl-1-oxo-2-isoquinolyl)-N-(2,2,2-trifluoroethyl)acetamide (143 mg, 0.46 mmol, 82% yield) as a brown solid. UPLC-MS (ES + , Method 2):1.47 min, m / z 314.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.84 (t, J=5.6 Hz, 1H), 7.28 (d, J=7.6 Hz, 1H), 7.16 (d, J=8.2 Hz, 1H), 7.03 (br s, 2H), 6.51 (d, J=7.8 Hz, 1H), 6.43 (d, J=7.6 Hz, 1H), 4.58 (s, 2H), 4.00 - 3.92 (m, 2H), 2.24 (s, 3H).

[0221] Project F. 2-(8-amino-5-methyl-1-oxo-2-isoquinolyl)-N-(2,2,2-trifluoroethyl)acetamide (40 mg, 0.13 mmol), tbubrettphos (6 mg, 0.01 mmol), K2CO3 (35 mg, 0.26 mmol), acetic acid (glacial acetic acid) (5 μL, 0.06 mmol), and 5-bromo-1-methyl-1H-indazole (30 mg, 0.14 mmol) were dissolved in tert-butanol (2 mL). The mixture was degassed, tris(dibenzylideneacetone)dipalladium (0) (6 mg, 0.01 mmol) was added, the vial was sealed, and the mixture was stirred overnight at 110°C. The mixture was filtered through a Celite pad, washed with methanol, and then concentrated under reduced pressure. The crude product was purified by reverse-phase chromatography (12 g column, 20-60% acetonitrile and 0.1% formic acid in water), dried overnight under vacuum, and 2-[5-methyl-8-[(1-methylindazole-5-yl)amino]-1-oxo-2-isoquinolyl]-N-(2,2,2-trifluoroethyl)acetamide (34 mg, 0.08 mmol, yield 60%) was obtained as a pale yellow solid. UPLC-MS (ES + , Method 1):4.07 min, m / z 444.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.88 (s, 1H), 8.91 (t, J=6.4 Hz, 1H), 7.97 (d, J=0.9 Hz, 1H), 7.65 (d, J=8.8 Hz, 1H), 7.62 (d, J=2.0 Hz, 1H), 7.44 (d, J=7.6 Hz, 1H), 7.31 - 7.26 (m, 2H), 6.85 (d, J=8.3 Hz, 1H), 6.59 (d, J=7.6 Hz, 1H), 4.68 (s, 2H), 4.05 (s, 3H), 3.98 (dq, J=6.4, 9.7 Hz, 2H), 2.32 (s, 3H).

[0222] Example 125, 1-methyl-5-[[1-oxo-2-[2-oxo-2-(2,2,2-trifluoroethylamino)ethyl]-8-isoquinolyl]amino]indazole-7-carboxamide [ka] Project A. A mixed solution of 2-(8-((7-cyano-1-methyl-1H-indazole-5-yl)amino)-1-oxoisoquinoline-2(1H)-yl)-N-(2,2,2-trifluoroethyl)acetamide (Example 119, 8 mg, 0.018 mol) and K2CO3 (0.5 mg, 0.0035 mmol) in water (0.5 mL) and DMSO (0.5 mL) was stirred at 150°C for 0.5 hours under microwave irradiation. The mixed solution was purified by prep-HPLC to obtain 1-methyl-5-[[1-oxo-2-[2-oxo-2-(2,2,2-trifluoroethylamino)ethyl]-8-isoquinolyl]amino]indazole-7-carboxamide (Example 125, 2.3 mg, 0.005 mmol, 28% yield) as a yellow solid. UPLC-MS (ES + , Method 3):3.35 min, m / z 473.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.04 (s, 1H), 8.91 (t, J=6.2 Hz, 1H), 8.20 (s, 1H), 8.08 (s, 1H), 7.79 (s, 1H), 7.69 (s, 1H), 7.47 - 7.36 (m, 3H), 7.01 (d, J=8.3 Hz, 1H), 6.88 (d, J=7.6 Hz, 1H), 6.56 (d, J=7.4 Hz, 1H), 4.69 (s, 2H), 4.09 (s, 3H), 4.03 - 3.93 (m, 2H).

[0223] The following examples (Table 15) were prepared according to the route described in Scheme 15 of Example 125, by replacing 2-(8-((7-cyano-1-methyl-1H-indazole-5-yl)amino)-1-oxoisoquinoline-2(1H)-yl)-N-(2,2,2-trifluoroethyl)acetamide in step A with a suitable cyano starting material. [Table 61]

[0224] DDR1 およびDDR2 biochemical method The binding ability of the compounds to DDR1 and DDR2 was quantified using the LanthaScreen Eu Kinase binding assay. Recombinant human DDR1 (2.5 nM; GST tagged aa440-876) and DDR2 (1.75 nM; GST tagged aa427-855) were diluted in assay buffer (50 mM HEPES pH 7.3, 10 mM MgCl2, 1 mM EGTA, and 0.01% Tween), and various concentrations of the compounds were placed in a 384-well plate to a volume of 5 μL. After incubation at room temperature for 30 minutes, 2.5 μL of Eu-anti-GST antibody (diluted to 1 nM using assay buffer) and Kinase TRacer 178 (diluted in assay buffer to 5 nM for DDR1 and 10 nM for DDR2) were added to the plate. After incubation at room temperature for 60 minutes, time-resolved fluorescence was measured using a BMG Labtech PHERastar plate reader. Max and Min assay signals were generated using DMSO (1%) and a reference compound (1 μM), respectively. Data were analyzed using a four-parameter logistic model, with at least two independent replicate tests performed for each compound. IC50 was also calculated. 50 The value was calculated.

[0225] biochemical activity value The following table shows the pIC values ​​of the above examples for DDR1 and DDR2 kinases. 50 The value is shown (A: pIC 50 >8;B:8≧pIC50 >7;C:7≧pIC 50 >6;D:pIC 50 ≦6; ND: undecided). Table 62 Table 63 Table 64 Table 65 Table 66 Table 67 Table 68

Claims

1. Equation (I): 【Chemistry 1】 [In the formula, Z 1 and Z 2 are each -CR 8a - and -NR 8b - selected from, where Z 1 and Z 2 one of is -CR 8a - and the other is -NR 8b -; where Z 1 and Z 2 The ring containing is pyrazole; X 1 CR is independent. 7a and selected from N; R 1 and R 2 These are, independently, Halo, Nitro, Cyano, and NR. 9 R 10 , OR 11 , SR 9 , SO 2 NR 9 R 9 , SO 2 R 9 CO 2 R 9 , C(O)R 9 CONR 9 R 9 , C 1 -C 4 -Alkyl, NR 9 R 10 C replaced by 1 -C 4 -alkyl, OR 11 C replaced by 1 -C 4 -alkyl, C 2 -C 4 -Alkenil, C 2 -C 4 -Alkinyl, C 1 -C 4 - Selected from haloalkyl and cyclopropyl; R 3 H and C are independent of each other. 1 -C 4 -Selected from alkyl; R 4 C 1 -C 6 -alkyl, C 1 -C 6 -Haloalkyl, C 0 -C 4 -Alkilen-R 4a Selected independently of; where R 4a C 3 -C 8 - Independently selected from cycloalkyl, phenyl, 5-membered, 6-membered, 9-membered or 10-membered heteroaryl and 4-membered to 10-membered heterocycloalkyl groups; the heterocycloalkyl or heteroaryl group may be monocyclic or bicyclic; the cycloalkyl or heterocycloalkyl group may have one R 12 Base and / or 1 to 4 R 13 The group may be optionally substituted with a group, and the phenyl group or heteroaryl group may be one R 12 Base and / or 1 to 3 R 14 The base may be replaced as desired; or R 3 and R 4 These, together with the nitrogen atom to which they are bonded, form a 4- to 10-membered heterocycloalkyl group or a 5- or 9-membered heteroaryl group; the heterocycloalkyl group or heteroaryl group may be monocyclic or bicyclic; the heterocycloalkyl group may have one R 12 Base and / or 1 to 4 R 13 The group may be optionally substituted with a group; the heteroaryl group is one R 12 Base and / or 1 to 3 R 14 The base may be replaced as desired; R 5 These are H, Halo, and C, each independently. 1 -C 4 - Selected from alkyl, or two R 5 The group and the carbon atoms to which they are bonded together, C 3 -C 6 A cycloalkyl ring may be formed; R 6 H and C are independent of each other. 1 -C 4 -alkyl, C 1 -C 4 - Selected from haloalkyl and cyclopropyl; R 7 and R 7a are each independently H, halo, nitro, cyano, NR 9 R 10 、OR 11 、SR 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 substituted C 1 -C 4 -alkyl, OR 11 substituted C 1 -C 4 -alkyl, C 2 -C 4 -alkenyl, C 2 -C 4 -alkynyl, C 1 -C 4 -haloalkyl and cyclopropyl; R 8a These are independently H, halo, nitro, cyano, and NR. 9 R 10 , OR 11 , SR 9 , SO 2 NR 9 R 9 , SO 2 R 9 CO 2 R 9 , C(O)R 9 CONR 9 R 9 , C 1 -C 4 -Alkyl, NR 9 R 10 C replaced by 1 -C 4 -alkyl, OR 11 C replaced by 1 -C 4 -alkyl, C 2 -C 4 -Alkenil, C 2 -C 4 -Alkinyl, C 1 -C 4 -Haloalkyl and C 0 -C 4 -Alkilen-R 8c Selected from; R 8b H and C are independent of each other. 1 -C 4 -Alkyl, NR 9 R 10 C replaced by 2 -C 4 -alkyl, OR 11 C replaced by 2 -C 4 -alkyl, C 3 -C 4 -Alkenil, C 3 -C 4 -Alkinyl, C 1 -C 4 -Haloalkyl and C 0 -C 4 -Alkilen-R 8c Selected from; R 8c Independently, C 3 -C 6 - Selected from cycloalkyl and 3-membered to 7-membered heterocycloalkyl; the heterocycloalkyl group is C via the carbon atoms of the heterocycloalkyl ring. 0 -C 4 -Bonded to an alkylene; the cycloalkyl group or heterocycloalkyl group has 1 to 4 R 13 The base may be replaced as desired; R 9 H and C are independent of each other. 1 -C 4 - Selected from alkyl groups; or two R groups 9 The groups, together with the nitrogen atoms to which they are bonded, form 0 to 4 R groups. 13 C may be substituted as desired in the base. 5 -C 8 -Forms heterocycloalkyl groups; R 10 These are H and C, which are independent of each other. 1 -C 4 -alkyl, C(O)-C 1 -C 4 -Alkyl and S(O) 2 -C 1 -C 4 - Selected from alkyl; or R 9 and R 10 Together with the nitrogen atom to which they are bonded, they form 0 to 4 R 13 C may be substituted as desired in the base. 5 -C 8 -Forms heterocycloalkyl groups; R 11 These are H and C, which are independent of each other. 1 -C 4 -alkyl, C(O)-C 1 -C 4 -Alkyl and C 1 -C 4 - Selected from haloalkyl; R 12 Independently, C 3 -C 6 -Selected from cycloalkyl, phenyl, 5-membered or 6-membered heteroaryl and 3- to 6-membered heterocycloalkyl; the cycloalkyl or heterocycloalkyl group has 1 to 4 R 13 The group may be substituted with a group as desired, and the phenyl group or heteroaryl group may have 1 to 3 R 14 The base may be replaced as desired; R 13 These are, independently, =O, halo, nitro, cyano, NR 8 R 9 , OR 14 , SR 8 , SO 2 NR 8 R 8 CO 2 R 8 , C(O)R 8 CONR 8 R 8 , C 1 -C 4 -alkyl, OR 11 C replaced by 1 -C 4 -Alkyl, NR 9 R 10 C replaced by 1 -C 4 -alkyl, C 2 -C 4 -Alkenil, C 2 -C 4 -Alkinyl, C 1 -C 4 -Haloalkyl, C 6 -C 10 -Aryl and C 3 -C 6 - Selected from cycloalkyl; R 14 Halo, Nitro, Cyano, NR 8 R 9 , OR 10 , SR 8 , SO 2 R 8 , SO 2 NR 8 R 8 CO 2 R 8 , C(O)R 8 CONR 8 R 8 , C 1 -C 4 -alkyl, C 2 -C 4 -Alkenil, C 2 -C 4 -Alkinyl, C 1 -C 4 - Haloalkyl, OR 11 C replaced by 1 -C 4 -Alkyl, NR 8 R 9 C replaced by 1 -C 4 - Independently selected from alkyl and cyclopropyl; m is an integer selected from 0, 1, 2, and 3; n is an integer selected from 0, 1, and 2; Here, any of the alkyl group, alkylene group, or cyclopropyl group is, where chemically possible, independently a halo, oxo, fluoro, nitro, cyano, or NR group. a R b , OR a , SR a CO 2 R a , C(O)R a CONR a R a , C 1 -C 4 -alkyl, C 1 -C 4 - May optionally be substituted with 1 to 5 substituents selected from the group consisting of haloalkyl and cyclopropyl; where R a These are H and C, which are independent of each other. 1 -C 4 -Alkyl and C 1 -C 4 - Selected from haloalkyl; R b These are H and C, which are independent of each other. 1 -C 4 -alkyl, C(O)-C 1 -C 4 -Alkyl and S(O) 2 -C 1 -C 4 - Selected from alkyl groups] Compounds of or pharmaceutically acceptable salts thereof.

2. Z 1 NR 8b Z 2 The compound according to claim 1, wherein is CH.

3. Z 1 CR 8a Z 2 The compound according to claim 1, wherein is NH.

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

5. The compound according to claim 1, wherein m is 1.

6. One R 1 The base is F, and NR 6 The compound according to claim 5, which is in the ortho position relative to the original compound.

7. The compound according to claim 1, wherein n is 0.

8. R 5 The compound according to claim 1, wherein each of the atoms is H.

9. R 6 The compound according to claim 1, wherein H is present.

10. R 7 The compound according to claim 1, wherein H is present.

11. X 1 The compound according to claim 1, wherein N is present.

12. X 1 However, CR 7a The compound according to claim 1.

13. R 7a The compound according to claim 12, wherein H is present.

14. R 7a However, halo, nitro, cyano, OR 11 CO 2 R 9 CONR 9 R 9 , C 1 -C 4 -Alkyl, NR 9 R 10 C replaced by 1 -C 4 -alkyl, OR 11 C replaced by 1 -C 4 -alkyl, C 1 -C 4 - The compound according to claim 12, independently selected from haloalkyl and cyclopropyl.

15. R 3 H is R 4 C 1 -C 6 -alkyl, C 1 -C 6 -Haloalkyl and C 0 -C 4 -Alkilen-R 4a A compound according to claim 1, selected from the following.

16. R 4 However, C 1 -C 6 -Alkyl and C 1 -C 6 - A compound according to claim 15, selected from haloalkyls.

17. R 4 However, C 0 -C 4 -Alkilen-R 4a The compound according to claim 15.

18. R 4 However, R 4a The compound according to claim 17.

19. R 4a However, C 3 -C 8 - Selected from cycloalkyl and 4-membered to 10-membered heterocycloalkyl groups, wherein the cycloalkyl group or heterocycloalkyl group has 1 to 4 R 13 The compound according to claim 17, which may be optionally substituted with a base.

20. R 4a However, C 3 -C 8 - Selected from cycloalkyl and 4-membered to 10-membered heterocycloalkyl groups, wherein the cycloalkyl group or heterocycloalkyl group has 1 to 4 R 13 The compound according to claim 18, which may be optionally substituted with a base.

21. R 4a However, independently selected from phenyl and 5-membered or 6-membered heteroaryl groups; the phenyl group or heteroaryl group is one R 12 Base and / or 1 to 3 R 14 The compound according to claim 17, which may be optionally substituted with a base.

22. R 4a However, independently selected from phenyl and 5-membered or 6-membered heteroaryl groups; the phenyl group or heteroaryl group is one R 12 Base and / or 1 to 3 R 14 The compound according to claim 18, which may be optionally substituted with a base.

23. R 3 and R 4 However, together with the nitrogen atom to which they are bonded, they form 1 to 4 R atoms. 13 The compound according to claim 1, wherein the base forms a monocyclic 4- to 7-membered heterocycloalkyl group which may be optionally substituted.

24. NR 3 R 4 However, the formula is: 【Chemistry 2】 [In the formula, R 4b is selected from H and F; at least two R 4b The base is F; R 3a H and C are independent of each other. 1 -C 4 -Selected from alkyl; R 4c H and C are independent of each other. 1 -C 4 -Alkyl and C 4 -C 6 - Selected from cycloalkyl; or R 3a and R 4c These, together with the carbon and nitrogen atoms to which they are bonded, form 4- to 6-membered heterocycloalkyl groups. The compound according to claim 1, having the following characteristics.

25. The compounds of formula (I) are as follows: 【Transformation 3】 【Chemistry 4】 【Transformation 5】 【Transformation 6】 【Transformation 7】 【Transformation 8】 【Chemistry 9】 【Chemistry 10】 【Chemistry 11】 【Chemistry 12】 【Chemistry 13】 【Chemistry 14】 【Chemistry 15】 【Chemistry 16】 【Chemistry 17】 [Chemistry 18] A compound selected from among them.

26. A pharmaceutical composition comprising a compound according to any one of claims 1 to 25 and a pharmaceutically acceptable excipient.

27. The pharmaceutical composition according to claim 26 for the treatment of a disease or disorder selected from kidney disease, liver disease, inflammatory disease, cardiovascular disease, acute and chronic organ transplant rejection, fibrous disease, and cancer.

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