Modulators of RHO-associated protein kinase (ROCK)

Abstract

The present invention relates to novel compounds and pharmaceutical compositions comprising said novel compounds. More specifically, the present invention relates to compounds useful as modulators of RHO-associated protein kinase (ROCK), such as ROCK1 and / or ROCK2 inhibitors. The present invention also relates to methods for preparing said compounds, the use of said compounds and methods of treatment using said compounds. The compounds of the present invention can therefore be used to treat ROCK-mediated diseases.

Description

[Technical field]

[0001] The present invention relates to novel compounds and pharmaceutical compositions comprising said novel compounds. More specifically, the present invention relates to compounds useful as modulators of RHO-associated protein kinase (ROCK), such as ROCK1 and / or ROCK2 inhibitors. The present invention also relates to methods for preparing said compounds, the use of said compounds and methods of treatment using said compounds. The compounds of the present invention can therefore be used to treat ROCK-mediated diseases. [Background technology]

[0002] Rho-associated coiled-coil kinases (ROCKs) are members of the AGC family of serine / threonine kinases involved in many aspects of cell signaling [Lock et al. 2012]. Two isoforms of ROCKs, highly conserved across mammalian species, are known to exist as ROCK1 and ROCK2. Their amino acid sequences share 65% homology and their kinase domains 92% homology. Furthermore, they contain a long coiled-coil domain, a PH domain and a Rho-binding domain, suggesting that they are activated by Rho GTPases, such as RhoA, which link several classes of cell surface receptors to internal kinase signaling. ROCK1 and ROCK2 have been shown to bind and phosphorylate a number of matrix proteins involved in processes such as migration, profibrotic cytokine production, cell adhesion and proliferation, although the majority of studies have been associated with actin cytoskeleton reorganization [Surma et al. 2014]. The best-characterized ROCK substrate is myosin phosphatase target subunit 1 (MYPT1), a regulatory subunit of myosin phosphatase. MYPT1 neutralizes myosin light chain (MLC) kinase activity, thus reducing smooth muscle cell contraction. ROCK phosphorylates and deactivates MYPT1, which in turn leads to mLC kinase phosphorylation, activation and actomyosin contraction [Feng et al. 1999; Velasco et al. 2002]. When administered systemically, pan-ROCK inhibitors result in vasodilation, hyperemia and hypotension, limiting their use as therapeutic agents in the setting of fibrosis and most other diseases [Kast et al. 2007]. ROCK is also known to phosphorylate LIM-kinases (LIMK1 and LIMK2), which in turn phosphorylates cofilin, leading to an increase in cellular actin filaments [Maekawa et al. 1999]. Many additional substrates have been identified, some of which have been suggested to be more specifically phosphorylated by ROCK1 or ROCK2 [Hartmann et al. 2015].ROCK isoforms are differentially expressed in various tissues, with ROCK1 predominating in kidney, liver, lung, and testis, whereas ROCK2 is predominantly expressed in brain and muscle tissues [Nakagawa et al 1996]. Isoform expression can be altered during disease, with ROCK2 often being increased in expression relative to ROCK1; taken together, all these data strongly suggest that ROCK1 and ROCK2 have overlapping and distinct functions in homeostasis and disease.

[0003] Both ROCK1 and ROCK2 are involved in multiple profibrotic processes, and pan-ROCK inhibitors can potently suppress TGFβ-stimulated myofibroblast activation, chemokine-driven fibroblast migration, and EMT in response to profibrotic mediators such as lysophosphatidic acid (LPA) and endothelin [Sakai et al 2016]. The specific roles of ROCK isoforms in disease are currently largely unknown, although both independent and overlapping roles have been suggested. Studies using haplozygous knockout mice (ROCK2+ / -) in which one allele of ROCK2 has been ablated (reducing ROCK2 expression) have shown that multiple aspects of the disease can be attenuated. Knipe et al (Knipe R Pharmacol Rev. 2015;67(1): 103-17; Knipe R Am J Respir Cell Mol Biol. 2018 Apr;58(4): 471-481) showed that both ROCK1+ / - and ROCK2+ / - mice were protected in a bleomycin-induced pulmonary fibrosis model of IPF. More recent studies have focused on both ROCK2+ / - and ROCK2 haplozygous mice in which one allele of ROCK2 is mutated to a kinase-active death configuration, thus reducing signaling but not ROCK2 expression [Wei et al 2020]. In both models, knockout mice were significantly protected from weight gain when fed a high-fat diet and showed some resistance to obesity-induced type 2 diabetes and hepatic steatosis. The results were similar to a study conducted by Soliman et al. (2016) in which ROCK2+ / - mice also exhibited type 2 diabetic insulin resistance when fed a high-fat diet. Previous studies investigating ROCK2 in the context of nutritional deficiency also demonstrated a role for ROCK2 in atherosclerosis. Low-density lipoprotein receptor-deficient (LDLr- / -) mice develop atherosclerosis when fed a high-cholesterol diet.Bone marrow-specific deletion of ROCK2 in these mice resulted in a dramatic reduction in atherosclerotic lesions and reduced inflammatory cytokines in macrophages, suggesting that ROCK2 may have a prominent role in macrophage-derived adipose foam cell formation, a key pathogenic promoter of atherosclerosis [Zhou et al., 2012]. ROCK2 may also have a role in the often fatal thrombosis observed in atherosclerosis. LDLr- / - mice with platelet-specific knockout of ROCK2 showed a marked reduction in circulating thrombi when fed a high cholesterol diet [Sladojevic et al., 2017]. Furthermore, tissue-specific knockout of ROCK2 has also shown protection in human disease models. Deletion of ROCK2 in cardiac-specific fibroblasts reduced both cardiac hypertrophy and fibrosis and improved cardiac function in an angiotensin II-infused model of heart failure [Shimizu et al., 2017]. A similar protection was also observed in the same model when ROCK2 was specifically reduced in cardiomyocytes [Okamoto et al 2013]. Collectively, the knockout data indicate that ROCK2 is not only involved in fibrosis but also in several deleterious processes leading to fibrosis and tissue remodeling, making ROCK2 a nodal point for disease progression.

[0004] ROCK also has a prominent role in central nervous system (CNS) pathology. For example, ROCK signaling has been shown to be elevated in serum, spleen, brain, and spinal cord of multiple sclerosis (MS) patients compared to healthy individuals. Dysregulation of autophagy contributes to the development of misfolded tau aggregates in early Alzheimer's disease (AD). When inhibited, ROCK2 expressed in excitatory neurons can induce the autophagy pathway, and ROCK2 inhibition may be a therapeutic approach for AD. Summary of the Invention [Problem to be solved by the invention]

[0005] It is further an object of certain embodiments of the invention to provide novel treatments, such as treatments for diabetes, inflammation, Alzheimer's, muscular dystrophy, hypertension, fibrosis, cancer, central nervous system pathologies and other conditions in which ROCK1 and / or ROCK2 are implicated, in particular, it is an object of certain embodiments of the invention to provide compounds that have activity equivalent to existing ROCK therapies.

[0006] It is an object of certain embodiments of the present invention to provide compounds that exhibit reduced cytotoxicity or increased solubility compared to prior art compounds and existing treatments.

[0007] It is another object of certain embodiments of the present invention to provide compounds that have a convenient pharmacokinetic profile and a suitable duration of action after administration. It is a further object of certain embodiments of the present invention to provide compounds where one or more metabolic fragments or fragments of the drug after absorption are GRAS (Generally Regarded as Safe).

[0008] Certain embodiments of the present invention meet some or all of the above objectives. [Means for solving the problem]

[0009] Brief description of the invention The present invention relates to a compound of formula (I): [ka] [During the ceremony, X 1 and X 2 are each independently selected from carbon and nitrogen; 1 and X 2 at least one of is carbon; X 3 is selected from carbon and nitrogen; R 1 and R 2 each independently represents H, halo, nitro, cyano, or NR 8 R 9 , OR 10 , S.R. 8 , SO2R8 , 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, NR 8 R 9 C1-C4-alkyl substituted with OR 10 and cyclopropyl, substituted with; R 3 are independently C1-C4-alkyl, C1-C4-haloalkyl, C0-C3-alkylene-R 3a and C2-C4-alkylene-R 3b where R 3a is independently selected at each occurrence from cyclopropyl and azetidinyl, and the cyclopropyl or azetidinyl group is optionally selected from 1 to 4 R 11 group; where R 3b is NR in each case independently 8 R 9 , OR 10 and S.R. 8 Selected from; R 4 and R 12 each occurrence independently represents halo, nitro, cyano, NR 8 R 9 , OR 10 , S.R. 8 , SO2R 8 , SO2NR 8 R 8 , CO2R 8 , C(O)R 8 ,CONR 8 R 8 , C.R. 8 R 8 NR 8 R 9 , C.R. 8 R 8 OR 8 , C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and cyclopropyl; R 5 is independent of CONR 8 R 8 , unsubstituted phenyl, 1 to 4 R 11 and phenyl and 4-10 membered heterocyclyl substituted with a group, wherein the heterocyclyl group may be monocyclic or bicyclic, and wherein any ring of the heterocyclyl group may be saturated, unsaturated, or partially unsaturated; and wherein any saturated or partially unsaturated ring may optionally be substituted with one R 13 group and / or 1 to 4 R 11 group, wherein any unsaturated ring is optionally substituted with one R 13 group and / or 1 to 3 R 12 is substituted with a group; R 6 is independently H, halo, C1-C4-alkyl, NR 8 R 9 C1-C4-alkyl substituted with OR 10 or two R selected from C1-C4-alkyl and cyclopropyl substituted with 6 the groups and the carbon atoms to which they are attached may together form a C3-C6 cycloalkyl ring; R 7 and R 8 are each independently selected from H, C-C-alkyl and C-C-haloalkyl; R 9 is independently selected at each occurrence from H, C-C-alkyl, C(O)-C-C-alkyl and S(O)-C-C-alkyl; or R 8 and R 9 may optionally be 0 to 4 R 11 forming a C5-C8-heterocycloalkyl group substituted with a group; R 10 is independently selected at each occurrence from H, C-C-alkyl, C(O)-C-C-alkyl and C-C-haloalkyl; R 11 represents independently at each occurrence: ═O, halo, nitro, cyano, NR 8 R9 , OR 14 , S.R. 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 and cyclopropyl; R 13 are independently C3-C6-cycloalkyl, 3- to 6-membered heterocycloalkyl, CR 8 R 8 NR 8 R 9 and C.R. 8 R 8 OR 8 where R 13 When is cycloalkyl or heterocycloalkyl, R 13 is optionally 1 to 4 R 11 is substituted with a group; R 14 is independently selected at each occurrence from H, C-C-alkyl; C-C-haloalkyl and C(O)-C-C-alkyl; and m is an integer selected from 0, 1, 2, 3, and 4; wherein any of the alkyl or cycloalkyl (e.g. cyclopropyl) groups may in each case optionally be halo, oxo, nitro, cyano, NR a R b , OR a , S.R. a , CO2R a , C(O)R a ,CONR a R a and wherein R is substituted with 1 to 5 substituents independently selected from the group consisting of a is independently selected at each occurrence from H, C-C-alkyl, and C-C-haloalkyl; and R b is independently selected at each occurrence from H, C1-C4-alkyl, C(O)-C1-C4-alkyl and S(O)2-C1-C4-alkyl. and pharma- ceutically acceptable salts thereof.

[0010] In certain embodiments, the compound of Formula (I) has the formula (II): [ka] [In the formula, X 1 , X 2 , R 2 , R 3 , R 4 , R 5 , R 6 and m is as defined above for compounds of formula (I). It is a compound of the formula:

[0011] In certain embodiments, the compound of Formula (I) has the formula (III): [ka] [In the formula, R 2 , R 3 , R 4 , R 5 , R 6 and m is as defined above for compounds of formula (I). It is a compound of the formula:

[0012] In certain embodiments, the compound of Formula (I) has the formula (IV): [ka] [In the formula, R 2 , R 3 , R 4 , R 5 , R 6 and m is as defined above for compounds of formula (I). It is a compound of the formula:

[0013] In certain embodiments, the compound of Formula (I) has the formula (V): [ka] [In the formula, R 2, R 3 , R 4 , R 5 , R 6 and m is as defined above for compounds of formula (I). It is a compound of the formula:

[0014] In certain embodiments, the compound of Formula (I) has the formula (VI): [ka] [In the formula, R 2 , R 3 , R 4 , R 6 , R 12 and m is as defined above for compounds of formula (I). It is a compound of the formula:

[0015] In certain embodiments, the compound of Formula (I) has the formula (VII): [ka] [In the formula, R 2 , R 3 , R 4 , R 6 , R 12 and m is as defined above for compounds of formula (I). It is a compound of the formula:

[0016] The following embodiments apply to any compound of formula (I)-(VII). These embodiments are independent and interchangeable. Any one embodiment may be combined with any other embodiment, if scientifically possible. In other words, any of the features described in the following embodiments may be combined with the features described in one or more other embodiments (if chemically possible). In particular, when a compound is exemplified or illustrated herein, any two or more of the following embodiments, expressed at a general level including that compound, may be combined to provide further embodiments that form part of the present invention.

[0017] X 1 is carbon and X 2may be nitrogen. 1 is nitrogen and X 2 X may be carbon. 1 CR 4a and X 2 is nitrogen; where R 4a are independently halo, nitro, cyano, OR 10 , C1-C4-alkyl and C1-C4-haloalkyl and cyclopropyl. X 1 is nitrogen and X 2 R 4a where R 4a are independently halo, nitro, cyano, OR 10 , C1-C4-alkyl and C1-C4-haloalkyl and cyclopropyl.

[0018] X 3 X may be carbon. 3 may be nitrogen.

[0019] R 1 If exists, then X 3 For the avoidance of doubt, this embodiment may be one in which X 3 is carbon.

[0020] R 1 and R 2 each independently represents H, halo, nitro, cyano, OR 10 , H selected from C1-C4-alkyl, C1-C4-haloalkyl and cyclopropyl, halo, nitro, cyano, OR 10 , C1-C4-alkyl, C1-C4-haloalkyl and cyclopropyl.

[0021] R 1 are independently H, halo, nitro, cyano, OR 10 , C1-C4-alkyl and C1-C4-haloalkyl and cyclopropyl. 1may be independently selected from H, fluoro, C1-C3-alkyl, such as methyl, C1-C3-fluoroalkyl and cyclopropyl. 1 may be H.

[0022] R 2 are independently H, halo, nitro, cyano, OR 10 , C1-C4-alkyl, C1-C4-haloalkyl and cyclopropyl. 2 may be independently selected from H, fluoro, C-C-alkyl, C-C-fluoroalkyl and cyclopropyl. 2 R may be H. 2 may be independently selected from fluoro, C1-C3-alkyl, C1-C3-fluoroalkyl and cyclopropyl. 2 R may be independently halo, e.g., fluoro. 2 may be independently C1-C3-alkyl, for example methyl.

[0023] R 3 may be independently selected from C1-C4-alkyl and cyclopropyl. 3 may be C1-C4-alkyl, for example methyl or ethyl.

[0024] m may be 0. m may be selected from 1 and 2. m may be 1.

[0025] R 4 each occurrence independently represents halo, nitro, cyano, OR 10 , C1-C4-alkyl, C1-C4-haloalkyl, CR 8 R 8 NR 8 R 9 , C.R. 8 R 8 OR 8 and cyclopropyl. 4 each occurrence independently represents halo, nitro, cyano, OR 10, C1-C4-alkyl, C1-C4-haloalkyl, CR 8 R 8 NR 8 R 9 , C.R. 8 R 8 OR 8 and cyclopropyl. 4 R may be independently selected at each occurrence from fluoro, C-C-alkyl, C-C-fluoroalkyl, and cyclopropyl. 4 R may be independently selected at each occurrence from fluoro, C-C-alkyl, C-C-fluoroalkyl, and cyclopropyl. 4 R can be independently at each occurrence halo, e.g., fluoro. 4 may be independently in each occurrence C1-C3-alkyl, for example methyl.

[0026] m is 1, and R 4 may be C1-C3-alkyl, e.g., methyl. 4 The group is R 5 Alternatively, one R 4 The group is R 5 It may be meta to the group.

[0027] R 5 Independently CONR 8 R 8 , unsubstituted phenyl, 1 to 4 R 11 and phenyl and 4-10 membered heterocyclyl substituted with a group, wherein the heterocyclyl group may be monocyclic or bicyclic, and wherein any ring of the heterocyclyl group may be saturated, unsaturated, or partially unsaturated; and wherein any saturated or partially unsaturated ring may optionally be substituted with one R 13 group and / or 1 to 4 R 11 group, where any unsaturated ring is substituted with one R 13 group and / or 1 to 3 R 12 is substituted with a group.

[0028] R 5may independently be a 5- or 6-membered monocyclic heterocyclyl, where the heterocyclyl group may be saturated, unsaturated, or partially unsaturated; and where any saturated or partially unsaturated ring may optionally be joined by one R 13 group and / or 1 to 4 R 11 group, where any unsaturated ring is substituted with one R 13 group and / or 1 to 3 R 12 It is substituted with the R group. 5 may independently be a 5- or 6-membered monocyclic heterocyclyl, where the heterocyclyl group may be saturated, unsaturated, or partially unsaturated; and where any saturated or partially unsaturated ring may optionally be joined by one R 13 group and / or 1 to 4 R 11 group, wherein any unsaturated ring is optionally substituted with one R 13 group and / or 1 to 3 R 12 It is substituted with the R group. 5 independently optionally one R 13 group and / or 1 to 3 R 12 R may be a 5- or 6-membered monocyclic heteroaryl substituted with a group. 5 independently optionally one R 13 group and / or 1 to 3 R 12 R may be a 5-membered monocyclic heteroaryl substituted with a group. 5 independently optionally one R 13 group and / or 1 to 3 R 12 R may be a 6-membered monocyclic heteroaryl substituted with a group. 5 independently optionally one R 13 group and / or 1 to 3 R 12 R may be a 5-membered monocyclic heteroaryl substituted with a group. 5 The group may contain nitrogen in the ring system. 5 Optionally, one R 13 group and / or 1 to 3 R 12 R may be selected from imidazole and pyridine substituted with a R group. 5 Optionally, one R 13 group and / or 1 to 3 R12 It may be an imidazole substituted with a R group. 5 Optionally, one R 13 group and / or 1 to 3 R 12 It may be a pyridine substituted with a group.

[0029] R 5 are independently selected from 4- to 10-membered heterocyclyl, where the heterocyclyl group may be monocyclic or bicyclic, and where any ring of the heterocyclyl group may be saturated, unsaturated, or partially unsaturated; and where any saturated or partially unsaturated ring may optionally be joined by one R 13 group and / or 1 to 4 R 11 group, where any unsaturated ring is substituted with one R 13 group and / or 1 to 3 R 12 It is substituted with the R group. 5 are independently selected from 4- to 10-membered heterocyclyl, where the heterocyclyl group may be monocyclic or bicyclic, and where any ring of the heterocyclyl group may be saturated, unsaturated, or partially unsaturated; and where any saturated or partially unsaturated ring may optionally be joined by one R 13 group and / or 1 to 4 R 11 group, wherein any unsaturated ring is optionally substituted with one R 13 group and / or 1 to 3 R 12 is substituted with a group.

[0030] R 5 are independently selected from 4-10 membered heterocyclyl, where the heterocyclyl group may be monocyclic or bicyclic, and where any ring of the heterocyclyl group may be saturated, unsaturated, or partially unsaturated; and where any saturated or partially unsaturated ring may optionally contain 1-4 R 11 group, where any unsaturated ring is substituted with 1 to 3 R 12 It is substituted with the R group. 5are independently selected from 4-10 membered heterocyclyl, where the heterocyclyl group may be monocyclic or bicyclic, and where any ring of the heterocyclyl group may be saturated, unsaturated, or partially unsaturated; and where any saturated or partially unsaturated ring may optionally contain 1-4 R 11 group, wherein any unsaturated ring is optionally substituted with 1 to 3 R 12 is substituted with a group.

[0031] R 5 may independently be a 5- or 6-membered monocyclic heterocyclyl, where the heterocyclyl group may be saturated, unsaturated or partially unsaturated; and where any saturated or partially unsaturated ring may optionally contain 1 to 4 R 11 group, where any unsaturated ring is substituted with 1 to 3 R 12 It is substituted with the R group. 5 may independently be a 5- or 6-membered monocyclic heterocyclyl, where the heterocyclyl group may be saturated, unsaturated or partially unsaturated; and where any saturated or partially unsaturated ring may optionally contain 1 to 4 R 11 group, wherein any unsaturated ring is optionally substituted with 1 to 3 R 12 It is substituted with the R group. 5 independently, optionally, 1 to 3 R 12 R may be a 5- or 6-membered monocyclic heteroaryl substituted with a group. 5 independently, optionally, 1 to 3 R 12 R may be a 5-membered monocyclic heteroaryl substituted with a group. 5 independently, optionally, 1 to 3 R 12 R may be a 6-membered monocyclic heteroaryl substituted with a group. 5 independently, optionally, 1 to 3 R 12 R may be a 5-membered monocyclic heteroaryl substituted with a group. 5 The group may contain nitrogen in the ring system. 5 and optionally 1 to 3 R 12 R may be selected from imidazole and pyridine substituted with a R group. 5 and optionally 1 to 3 R12 It may be an imidazole substituted with a R group. 5 and optionally 1 to 3 R 12 It may be a pyridine substituted with a group.

[0032] R 5 R can be unsubstituted phenyl. 5 1 to 4 R 11 R may be a phenyl substituted with a phenyl group. 5 R 11 R may be a phenyl substituted with a phenyl group. 5 can be phenyl substituted with cyclopropyl.

[0033] R 5 The structure is [ka] (wherein x1 is independently an integer selected from 0, 1 and 2). x1 may be 0.

[0034] R 5 The structure is [ka] wherein x2 is an integer independently selected from 0 and 1; and R 12a are independently selected from H and C1-C4-alkyl. x2 may be 0. R 12a may be C1-C4-alkyl, for example methyl.

[0035] R 5 The structure is [ka] [In the formula, R 12b is independently selected from halo, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and cyclopropyl; and x1 is independently an integer selected from 0, 1 and 2. x1 may be 0. R 12b may be selected from C1-C4-cycloalkyl and cyclopropyl.

[0036] R 5 The structure is [ka] [In the formula, R 12d and R 12c each independently represents H, halo, nitro, cyano, OR 10 H, halo, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl, CR 8 R 8 NR 8 R 9 , C.R. 8 R 8 OR 8 and cyclopropyl; and R 12a are independently selected from H, C1-C4-alkyl and cyclopropyl. R 12a R can be C1-C4-alkyl, e.g., methyl. 12d can be H. R 12d may be selected from C1-C4-cycloalkyl and cyclopropyl. 12c can be H. R 12c may be selected from C1-C4-cycloalkyl and cyclopropyl.

[0037] R 5 The structure is [ka] [In the formula, R 12b are independently halo, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl, CR 8 R 8 NR 8 R 9 , C.R. 8 R8 OR 8 and cyclopropyl; and R 12f and R 12e are each independently selected from H, halo, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and cyclopropyl. R 12f can be H. R 12e can be H. R 12e may be selected from C1-C4-cycloalkyl and cyclopropyl. 12b may be selected from C1-C4-cycloalkyl and cyclopropyl.

[0038] R 5 The structure is [ka] [In the formula, R 12g is selected from H, C1-C4-alkyl, C1-C4-haloalkyl and cyclopropyl. R 12g may be C1-C4-haloalkyl, for example trifluoroethyl.

[0039] R 5 The structure is [ka] [In the formula, R 12g is selected from H, C1-C4-alkyl, C1-C4-haloalkyl and cyclopropyl. R 12g may be C1-C4-haloalkyl, for example trifluoroethyl.

[0040] R 5 The structure is [ka] wherein y is an integer independently selected from 0 and 1; and x3 is an integer independently selected from 0, 1, 2, and 3. x3 may be 0. x3 may be 1. y may be 0. y may be 1.

[0041] R 5 The structure is [ka] wherein y is an integer independently selected from 0 and 1; and x3 is an integer independently selected from 0, 1, 2, and 3. x3 may be 0. x3 may be 1. y may be 0. y may be 1.

[0042] R 5 The structure is [ka] wherein y is an integer independently selected from 0 and 1; and x3 is an integer independently selected from 0, 1, 2, and 3. x3 may be 0. x3 may be 1. y may be 0. y may be 1.

[0043] R 5 The structure is [ka] (wherein x4 is independently an integer selected from 0, 1 and 2). x4 may be 0. x4 may be 1.

[0044] R 5 The structure is [ka] (wherein x4 is independently an integer selected from 0, 1 and 2). x4 may be 0. x4 may be 1.

[0045] R 5 The structure is [ka] may have:

[0046] R 5 The structure is [ka] may have:

[0047] R 5 The structure is [ka] [In the formula, R 11a are independently selected from H, C1-C4-alkyl, C1-C4-haloalkyl and cyclopropyl. R 11a R can be C1-C4-alkyl, e.g., methyl. 11a can be C1-C4-haloalkyl.

[0048] R 5 The structure is [ka] [In the formula, R 11b are independently selected from H, C1-C4-alkyl, C1-C4-haloalkyl and cyclopropyl. R 11b may be C1-C4-haloalkyl, for example trifluoroethyl or trifluoropropyl.

[0049] R 5 The structure is [ka] wherein y is an integer independently selected from 0 and 1; and x3 is an integer independently selected from 0, 1, 2, and 3. x3 may be 0. x3 may be 1. y may be 0. y may be 1. R 13 can be cyclopropyl.

[0050] R 5 The structure is [ka] [In the formula, R 12h are independently selected from H, C1-C4-alkyl, C1-C4-haloalkyl and cyclopropyl. R 12h can be cyclopropyl.

[0051] R 12 each occurrence independently represents halo, nitro, cyano, OR 10 , C1-C4-alkyl and C1-C4-haloalkyl and cyclopropyl. R 12 R may be independently selected at each occurrence from fluoro, C-C-alkyl, C-C-fluoroalkyl, and cyclopropyl. 12 R may be independently selected at each occurrence from fluoro, C-C-alkyl, C-C-fluoroalkyl, and cyclopropyl. 12 R may be independently selected at each occurrence from C-C-alkyl, e.g., methyl and cyclopropyl. 12 R can be independently at each occurrence halo, e.g., fluoro. 12 may be independently in each occurrence C1-C3-alkyl, for example methyl.

[0052] R 13 can be C3-C6-cycloalkyl. R 13 CR 8 R 8 NR 8 R 9 It can be. R 13 CR 8 R 8 OR 8 It can be. R 13can be a 3- to 6-membered heterocycloalkyl. 13 can be C3-C4-cycloalkyl. R 13 R can be a 4-membered heterocycloalkyl. 13 R may be selected from oxetane, azetidine, cyclopropyl and cyclobutyl. 13 R can be cyclopropyl. 13 may be C1-C4-alkyl, for example methyl.

[0053] Example R 5 The base is: [ka] Includes.

[0054] Further illustrative examples R 5 The base is: [ka] Includes.

[0055] Further illustrative examples R 5 The basis is [ka] Includes.

[0056] Further illustrative examples R 5 The basis is [ka] Includes.

[0057] 2 R's 6 The R groups and the carbon atoms to which they are attached may together form a C3-C6 cycloalkyl ring. 6 The groups and the carbon atom to which they are attached may join together to form a cyclopropyl ring.

[0058] R 6R may be independently selected at each occurrence from H, fluoro, C-C-alkyl, and cyclopropyl. 6 R may be independently selected at each occurrence from H and C-C-alkyl. 6 can be H in each case. R 6 may in each case be C1-C4-alkyl, for example Me. 6 group is H and one R 6 The group may be C1-C4-alkyl, for example Me.

[0059] R 7 can be H. R 7 may be C1-C4-alkyl, for example methyl.

[0060] The compound of formula (I) may be selected from: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[0061] In certain embodiments, compounds of the invention are provided that have a ROCK2 binding affinity within category +++ or ++++ as defined elsewhere herein. In certain embodiments, a ROCK2 binding affinity IC of < 3 μM 50 In one embodiment, compounds of the invention are provided that have a ROCK2 binding affinity IC value of <0.3 μM. 50 Optionally, the binding activity is determined using the assay for ROCK2 inhibition defined in the Examples.

[0062] In one aspect of the invention there is provided a compound of the invention for use as a pharmaceutical.

[0063] According to another aspect, the present invention provides a pharmaceutical formulation comprising a compound of the present invention and a pharma- ceutically acceptable excipient.

[0064] In some embodiments, the pharmaceutical composition may be a combination product that includes an additional pharma- ceutical active agent, which may be, for example, an anti-inflammatory agent, an anti-fibrotic agent, a chemotherapeutic agent, an anti-cancer agent, an immunosuppressant, an anti-tumor vaccine, a cytokine therapy, or a tyrosine kinase inhibitor.

[0065] According to another embodiment, the compounds of the present invention are provided for use in treating conditions regulated by ROCK1 and / or ROCK2. Usually, conditions regulated by ROCK (it should be noted that ROCK means either or both ROCK1 and ROCK2) are conditions that can be treated by inhibiting ROCK using the compounds of the present invention. Compounds of any formula disclosed herein can be for use in treating conditions treatable by inhibiting ROCK. As mentioned above, ROCK signaling is involved in several conditions.

[0066] In another aspect of the invention there is provided a compound of the invention for use in the treatment of a disease or disorder selected from a fibrotic disease, an autoimmune disease, a muscular dystrophy, an inflammatory condition, a central nervous system disorder or cancer.

[0067] In certain embodiments of the present invention, methods are provided for treating a disease or disorder regulated by ROCK1 and / or ROCK2, comprising administering to a patient in need thereof a therapeutic amount of a compound of the present invention.

[0068] The method of treatment may be a method of treating a condition treatable by inhibition of ROCK1 and / or ROCK2.

[0069] The present invention also provides a method of treating a disease or disorder selected from a fibrotic disease, an autoimmune, an inflammatory-fibrotic condition, an inflammatory condition, a central nervous system disorder, or cancer, comprising administering to a patient in need thereof a therapeutic amount of a compound of any of the formulas disclosed herein.

[0070] The disease or disorder may be selected from sarcoidosis, sclerosis, primary sclerosing cholangitis, sclerosing cholangitis, dermatitis, atopic dermatitis, Still's disease, chronic obstructive pulmonary disease, Guillain-Barré disease, Graves' disease, Addison's disease, Raynaud's phenomenon or autoimmune hepatitis, arthritis, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, degenerative arthritis, polymyalgia rheumatica, ankylosing spondylitis, reactive arthritis, gout, pseudogout, inflammatory joint disease, systemic lupus erythematosus, polymyositis and fibromyalgia. Further types of arthritis include Achilles tendinitis, achondroplasia, acrohypertrophic arthropathy, adhesive capsulitis, adult-onset Still's disease, anserine bursitis, avascular necrosis, Behcet's syndrome, biceps tendinitis, Blount's disease, brucellosis, bursitis, calcaneal bursitis, calcium pyrophosphate dihydrate deposition disease (CPPD), crystal deposition disease, Caplan's syndrome, carpal tunnel syndrome, cavernous vascular malformation, chondrocalcinosis, chondromalacia patellar, chronic synovitis, chronic recurrent multiple osteoarthritis, and chronic osteochondritis. Myelitis, Churg-Strauss syndrome, Cogan syndrome, corticosteroid-induced osteoporosis, costosternal syndrome, CREST syndrome, cryoglobulinemia, degenerative joint disease, dermatomyositis, diabetic digital sclerosis, generalized idiopathic osteoarthritis (DISH), discitis, discoid lupus erythematosus, drug-induced lupus, Duchenne muscular dystrophy, Dupuytren's contracture, Ehlers-Danlos syndrome, endometriosis, enteropathic arthritis, epicondylitis, erosive inflammatory Osteoarthropathy, exercise-induced compartment syndrome, Fabry disease, familial Mediterranean fever, Farber lipogranulomatosis, Felty syndrome, fifth disease, flat feet, foreign body synovitis, Freiberg disease, fungal arthritis, Gaucher disease, giant cell arteritis, gonococcal arthritis, Goodpasture syndrome, granulomatous arteritis, joint bleeding, hemochromatosis, Henoch-Scholein purpura, Hepatitis B surface antigen disease, hip dysplasia, Hurler syndrome, hypermobility syndrome, hypersensitivity vasculitis, hypertrophy Osteoarthropathy, immune complex disease, impingement syndrome, Jaccoud's arthropathy, juvenile ankylosing spondylitis, juvenile dermatomyositis, juvenile rheumatoid arthritis, Kawasaki disease, Kienböck's disease, Legg-Calve-Perthes disease, Lesch-Nyhan syndrome, linear scleroderma, lipoid cutaneous arthritis, Löfgren's syndrome, Lyme disease, malignant synovial sarcoma, Marfan syndrome, synovial fold syndrome, metastatic carcinomatous arthritis, mixed connective tissue disease (MCTD), mixed cryoglobulinemia, mucopolysaccharidoses,Multicentric reticulohistiocytosis, multiple epiphyseal dysplasia, mycoplasmal arthritis, myofascial pain syndrome, neonatal lupus, neuropathic arthropathy, nodular panniculitis, malformation of the tissues, olecranon bursitis, Osgood-Schlatter disease, osteoarthropathy, osteochondromatosis, osteogenesis imperfecta, osteomalacia, osteomyelitis, osteonecrosis, osteoporosis, overlap syndrome, hypertrophic dermoperiostosis, Paget's disease of bone, relapsing rheumatism, patellofemoral pain syndrome, Pellegrini-Steeda syndrome, pigmented villonodular synovitis, piriformis syndrome, plantar fasciitis, polyarteritis nodosa, polymyalgia rheumatica, polymyositis, popliteal cyst, posterior tibial tendonitis, Pott's disease, prepatellar bursitis, prosthetic joint infection, pseudoxanthoma elasticum, psoriatic arthritis, Raynaud's phenomenon, reactive arthritis / Reiter's syndrome, reflex sympathetic dystrophy syndrome, relapsing polychondritis, retrocalcaneal bursitis, rheumatic fever, rheumatoid vasculitis, rotator cuff tendinitis, sacroiliac Inflammation, Salmonella osteomyelitis, Sarcoidosis, Lead gout, Scheuermann's osteochondritis, Scleroderma, Septic arthritis, Seronegative arthritis, Shigella arthritis, Shoulder-hand syndrome, Sickle cell arthropathy, Sjogren's syndrome, Slipped capital femoral epiphysis, Spinal stenosis, Spondylolysis, Staphylococcal arthritis, Stickler syndrome, Subacute cutaneous lupus, Sweet's syndrome, Sydenham's chorea, Syphilitic arthritis, Systemic lupus erythematosus (SLE), Takayasu's arteritis, Tarsal tunnel Syndrome, tennis elbow, Tietze's syndrome, transient osteoporosis, traumatic arthritis, trochanteric bursitis, tuberculous arthritis, ulcerative colitis arthritis, undifferentiated connective tissue syndrome (UCTS), urticarial vasculitis, viral arthritis, Wegener's granulomatosis, Whipple's disease, Wilson's disease, Yersinia arthritis and conditions involving angiogenesis and / or inflammation including atherosclerosis, rheumatoid arthritis (RA), hemangiomas, angiofibromas and psoriasis. Other non-limiting examples of neovascular diseases include retinopathy of prematurity (retrolental fibroplasia), corneal graft rejection, corneal neovascularization associated with refractive surgery complications, corneal neovascularization associated with contact lens complications, corneal neovascularization associated with pterygium and recurrent pterygium, corneal ulcer disease and non-specific ocular surface disease, insulin-dependent diabetes mellitus, multiple sclerosis, myasthenia gravis, Chlorphus' disease, autoimmune nephritis, primary biliary cirrhosis, acute pancreatitis, allograft rejection, allergic inflammation, contact dermatitis and delayed hypersensitivity reactions, inflammatory bowel disease, septic shock, osteoporosis,These include osteoarthritis, cognitive deficits induced by neuronal inflammation, Osler-Weber syndrome, restenosis and fungal, parasitic and viral infections, including cytomegalovirus infection.

[0071] Any of the conditions listed above as treatable by ROCK1 and / or ROCK2 inhibition may be treated with the compounds of the invention or by methods involving administration of the compounds of the invention or by medicaments manufactured through the beneficial use of the compounds of the invention.

[0072] In certain embodiments, the disease or disorder is idiopathic pulmonary fibrosis (IPF); systemic sclerosis (SSC); interstitial lung disease (ILD); type 1 and type 2 diabetes; diabetic nephropathy; nonalcoholic steatohepatitis (NASH); nonalcoholic fatty liver disease (NAFLD); hypertension, atherosclerosis, restenosis, stroke, heart failure, coronary vasospasm, cerebral vasospasm, peripheral circulatory disorders, peripheral arterial occlusive disease, ischemia / reperfusion injury, pulmonary hypertension and angina, erectile dysfunction, fibroid lung, fibroid liver and fibroid kidney, glaucoma, ocular hypertension, retinopathy, rheumatoid arthritis, psoriasis, psoriatic arthritis, Sjogren's syndrome, asthma, adult respiratory distress syndrome, chronic obstructive pulmonary disease (COPD), SLE, cGVHD, inflammatory bowel disease, intestinal stenosis, neuronal degeneration or neuropathies. The cancer may be selected from disorders involving physical injury of tissue, Huntington's disease, Parkinson's disease, Alzheimer's, amyotrophic lateral sclerosis (ALS), multiple sclerosis, liver cancer, bladder cancer, hepatocellular carcinoma, lung squamous cell carcinoma, non-small cell lung cancer, lung adenocarcinoma, small cell lung cancer, various types of head and neck cancer, breast cancer, colon cancer, colorectal cancer, peritoneal cancer, hepatocellular carcinoma, gastrointestinal cancer, esophageal cancer, endometrial or uterine cancer, salivary gland cancer, squamous cell carcinoma, pituitary cancer, astrocytoma, soft tissue sarcoma, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, kidney cancer, liver cancer, prostate cancer, vulvar cancer, thyroid cancer, liver cancer, brain cancer, endometrial cancer, testicular cancer, cholangiocarcinoma, gallbladder cancer, gastric cancer and melanoma, wherein the method comprises administering to a patient in need thereof a therapeutic amount of a compound of any formula disclosed herein.

[0073] In certain embodiments, the disease or disorder is selected from idiopathic pulmonary fibrosis (IPF); systemic sclerosis (SSC); interstitial lung disease (ILD); type 1 and type 2 diabetes; diabetic nephropathy; nonalcoholic steatohepatitis (NASH); nonalcoholic fatty liver disease (NAFLD); hypertension, atherosclerosis, restenosis, stroke, heart failure, coronary vasospasm, cerebral vasospasm, peripheral circulatory disorders, peripheral arterial occlusive disease, ischemia / reperfusion injury, pulmonary hypertension and angina pectoris and erectile dysfunction, fibroid lung, fibroid liver and fibroid kidney.

[0074] In certain embodiments, the disease or disorder is selected from glaucoma, ocular hypertension, retinopathy, rheumatoid arthritis, psoriasis, psoriatic arthritis, Sjogren's syndrome, asthma, adult respiratory distress syndrome, chronic obstructive pulmonary disease (COPD), SLE and cGVHD, inflammatory bowel disease and intestinal stenosis.

[0075] In some embodiments, the compounds of the present invention are used for or in the method of treating central nervous system disorders.Such disorders involve neuronal degeneration or physical injury of neural tissue, including but not limited to Huntington's disease, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS) or multiple sclerosis.

[0076] In some embodiments, the compound of the present invention is used for or in the treatment of cancer.Examples include but are not limited to liver cancer, bladder cancer, hepatocellular carcinoma, lung squamous cell carcinoma, non-small cell lung cancer, lung adenocarcinoma, small cell lung cancer, various types of head and neck cancer, breast cancer, colon cancer, colorectal cancer, peritoneal cancer, hepatocellular carcinoma, digestive tract cancer, esophageal cancer, endometrial or uterine cancer, salivary gland cancer, squamous cell carcinoma, pituitary cancer, astrocytoma, soft tissue sarcoma, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, kidney cancer, liver cancer, prostate cancer, vulvar cancer, thyroid cancer, liver cancer, brain cancer, endometrial cancer, testicular cancer, cholangiocarcinoma, gallbladder cancer, gastric cancer and melanoma.

[0077] In another aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of the present invention and a pharma- ceutically acceptable excipient.

[0078] In certain embodiments, the pharmaceutical composition may be a combination product that includes an additional pharma- ceutical active agent, which may be as described elsewhere herein.

[0079] In certain embodiments of the invention there is provided the use of a compound of the invention in the manufacture of a medicament for use in the treatment of any of the conditions disclosed herein. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0080] Detailed Description Below are definitions of terms used in this specification. Any terms not defined herein are to be taken as having the ordinary meaning as one of ordinary skill in the art would understand that term.

[0081] The term "halo" refers to the halogens of group 17 of the periodic table. In particular, the term refers to fluorine, chlorine, bromine and iodine. Preferably, the term refers to chlorine or fluorine.

[0082] The term "alkyl" refers to a straight or branched hydrocarbon chain. For example, the term "C 1-6 "Alkyl" refers to a straight or branched hydrocarbon chain containing 1, 2, 3, 4, 5, or 6 carbon atoms, e.g., methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, and n-hexyl. "Alkylene" groups may likewise be straight or branched and are divalent, i.e., bonded to the rest of the molecule at two points. Additionally, alkylene groups may correspond, for example, to the alkyl groups listed in this paragraph. Alkyl and alkylene groups may be unsubstituted or substituted with one or more substituents.

[0083] The term "haloalkyl" refers to a hydrocarbon chain substituted with at least one halogen atom, independently at each occurrence selected from, for example, fluorine, chlorine, bromine, and iodine. For example, the term "C 1-6"Haloalkyl" refers to a straight or branched hydrocarbon chain containing 1, 2, 3, 4, 5, or 6 carbon atoms substituted with at least one halogen. The halogen atom may be located at any position on the hydrocarbon chain. For example, C 1-6 Haloalkyl can refer to chloromethyl, fluoromethyl, trifluoromethyl, chloroethyl, e.g., 1-chloromethyl and 2-chloroethyl, trichloroethyl, e.g., 1,2,2-trichloroethyl, 2,2,2-trichloroethyl, fluoroethyl, e.g., 1-fluoromethyl and 2-fluoroethyl, trifluoroethyl, e.g., 1,2,2-trifluoroethyl and 2,2,2-trifluoroethyl, chloropropyl, trichloropropyl, fluoropropyl, trifluoropropyl. The term "fluoroalkyl" refers to a hydrocarbon chain substituted with at least one fluorine atom.

[0084] The term "alkenyl" refers to a branched or straight-chain hydrocarbon chain containing at least one double bond. For example, the term "C 2-6 "Alkenyl" refers to a branched or straight hydrocarbon chain containing at least one double bond and having 2, 3, 4, 5 or 6 carbon atoms. The double bond may be present as an E or Z isomer. Any possible position of the double bonded hydrocarbon chain may be present. For example, "C 2-6 "Alkenyl" can be ethenyl, propenyl, butenyl, butadienyl, pentenyl, pentadienyl, hexenyl and hexadienyl.

[0085] The term "alkynyl" refers to a branched or straight-chain hydrocarbon chain containing at least one triple bond. For example, the term "C 2-6 "Alkynyl" refers to a branched or straight chain hydrocarbon chain containing at least one triple bond and having 2, 3, 4, 5 or 6 carbon atoms. Any position of the triple bond may be present in the hydrocarbon chain. For example, "C 2-6 Alkynyl" can be ethynyl, propynyl, butynyl, pentynyl and hexynyl.

[0086] The term "heteroalkyl" refers to a branched or straight-chained hydrocarbon chain that may contain at least one heteroatom selected from N, O, and S positioned between any carbon within the chain or at the end of the chain. For example, the term "C 1-6 "Heteroalkyl" refers to a branched or straight chain hydrocarbon chain containing 1, 2, 3, 4, 5, or 6 carbon atoms and containing at least one heteroatom selected from N, O, and S, positioned between any carbons in the chain or at the end of the chain. For example, the hydrocarbon chain can contain one or two heteroatoms. 1-6 A heteroalkyl can be attached to the remainder of the molecule through a carbon or heteroatom. For example, "C 1-6 Heteroalkyl" is C 1-6 N-Alkyl, C 1-6 N,N-alkyl or C 1-6 It can be O-alkyl.

[0087] The term "heterocycle" refers to a saturated, unsaturated or aromatic ring system containing at least one heteroatom selected from N, O or S. A "heterocyclic" system may contain 1, 2, 3 or 4, e.g. 1 or 2, heteroatoms. A "heterocyclic" system may be a monocyclic or fused polycyclic ring system, e.g. bicyclic or tricyclic. A "heterocyclic" moiety may contain 3 to 14 carbon atoms, e.g. 3 to 8 carbon atoms in a monocyclic system and 7 to 14 carbon atoms in a polycyclic system. "Heterocyclic" encompasses heterocycloalkyl, heterocycloalkenyl and heteroaryl moieties. For example, the heterocyclic group can be oxirane, aziridine, azetidine, oxetane, tetrahydrofuran, pyrrolidine, imidazolidine, succinimide, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, piperidine, morpholine, thiomorpholine, piperazine, and tetrahydropyran. Heterocyclyl can include groups such as pyridone and N-alkyl-pyridone.

[0088] The term “C 3-8 "Cycloalkyl" refers to a saturated hydrocarbon ring system containing 3, 4, 5, 6, 7, or 8 carbon atoms. For example, "C3-8 "Cycloalkyl" can be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

[0089] The term “C 3-8 "Cycloalkenyl" refers to an unsaturated hydrocarbon ring system containing 3, 4, 5, 6, 7, or 8 carbon atoms that is not aromatic. The ring may contain more than one double bond as long as the ring system is not aromatic. For example, "C 3-8 "Cycloalkyl" can be cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadiene, cyclooctenyl and cycloatadienyl.

[0090] The term "heterocycloalkyl" refers to a saturated hydrocarbon ring system containing carbon atoms and at least one heteroatom selected from N, O and S in the ring. For example, there can be 1, 2 or 3, optionally 1 or 2 heteroatoms. A "heterocycloalkyl" can be attached to the rest of the molecule through any carbon atom or heteroatom. A "heterocycloalkyl" can have one or more, for example 1 or 2 bonds to the rest of the molecule: these bonds can be through any of the atoms of the ring. For example, a "heterocycloalkyl" can be "C 3-8 The term "C" may be a heterocycloalkyl. 3-8 "Heterocycloalkyl" refers to a saturated hydrocarbon ring system containing 3, 4, 5, 6, 7, or 8 atoms, with at least one of the atoms in the ring being a heteroatom selected from N, O, and S. "Heterocycloalkyl" can be oxirane, aziridine, azetidine, oxetane, tetrahydrofuran, pyrrolidine, imidazolidine, succinimide, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, piperidine, morpholine, thiomorpholine, piperazine, and tetrahydropyran.

[0091] The term "aromatic," when applied to a substituent, refers to a monocyclic or polycyclic ring system having 4n+2 electrons of a conjugated pi system within the ring or ring system as a whole, where all atoms contributing to the conjugated pi system lie in the same plane.

[0092] The term "aryl" refers to an aromatic hydrocarbon ring system. The ring system has 4n+2 electrons of a conjugated pi system within the ring, where all atoms contributing to the conjugated pi system are in the same plane. For example, "aryl" can be phenyl and naphthyl. The aryl system itself can be substituted with other groups.

[0093] The term "heteroaryl" refers to an aromatic hydrocarbon ring system having at least one heteroatom selected from O, N and S in a single ring or fused ring system. The ring or ring system has 4n+2 electrons in a conjugated π system, where all atoms contributing to the conjugated π system are in the same plane. For example, a "heteroaryl" can be imidazole, oxazole, isoxazole, thiazole, isothiazole, thien, furan, thianthrene, pyrrole, benzimidazole, pyrazole, pyrazine, pyridine, pyrimidine and indole.

[0094] [ka] A bond ending in means that the bond is attached to another atom not shown in the structure. A bond that ends within a ring structure and does not end at an atom of the ring structure indicates that the bond may be attached to any atom, if allowed by valences.

[0095] Bonds depicted as solid and dotted lines represent bonds that may be single or double bonds, if chemically possible. For example, the following bond may be a single or double bond: [ka]

[0096] If a moiety is substituted, it may be substituted at any point on the moiety, provided that it is chemically feasible and consistent with the valence requirements of the atom. A moiety may be substituted with one or more substituents, for example, 1, 2, 3 or 4 substituents; optionally, a group may have 1 or 2 substituents. When there are two or more substituents, the substituents may be the same or different.

[0097] Substituents are present only at positions where they are chemically possible, and one skilled in the art can determine (experimentally or theoretically) without undue effort which substitutions are chemically possible and which are not.

[0098] Ortho, meta and para substitutions are terms well understood in the art. For the avoidance of doubt, "ortho" substitution refers to a simple group, such as the fluoro group in the example below or [ka] Any other part of a molecule indicated by a bond ending in is a substitution pattern in which adjacent carbons bear substituents. [ka]

[0099] A "meta" substitution is a substitution pattern in which there are two substituents on carbons that are one carbon away from each other, i.e., there is one carbon atom between the substituted carbons. In other words, one substituent is on the second atom from the atom that bears the other substituent. For example, the following group is meta substituted: [ka]

[0100] "Para" substitution is a substitution pattern in which there are two substituents on carbons that are two carbon atoms apart from each other, i.e., there are two carbon atoms between the substituted carbons. In other words, one substituent is on the third atom from the atom that bears the other substituent. For example, the following group is para substituted: [ka]

[0101] Throughout this description, the disclosure of the compounds also encompasses their pharma- ceutically acceptable salts, solvates, and stereoisomers. When the compounds have a stereocenter, both (R) and (S) stereoisomers are contemplated by the present invention, and equal mixtures of stereoisomers or racemic mixtures are contemplated by the present application. When the compounds of the present invention have more than one stereocenter, any combination of (R) and (S) stereoisomers is contemplated. The combination of (R) and (S) stereoisomers may result in a diastereomeric mixture or a single diastereoisomer. The compounds of the present invention can exist as a single stereoisomer or can be a mixture of stereoisomers, such as a racemic mixture and other enantiomeric and diastereomeric mixtures. When the mixture is a mixture of enantiomers, the enantiomeric excess can be any of those described above. When the compounds are single stereoisomers, the compounds may still contain other diastereoisomers or enantiomers as impurities. Thus, a single stereoisomer may not necessarily have 100% enantiomeric excess (ee) or diastereomeric excess (de), but rather may have an ee or de of about at least 85%, at least 60% or less, For example, the ee or de may be 90% or more, 90% or more, 80% or more, 70% or more, 60% or more, 50% or more, 40% or more, 30% or more, 20% or more, or 10% or more.

[0102] The present invention contemplates pharma- ceutically acceptable salts of the compounds of the present invention. These may include the acid addition and base salts of the compounds. These may be the acid addition and base salts of the compounds. In addition, the present invention contemplates the solvates of the compounds. These may be hydrates or other solvated forms of the compounds.

[0103] Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include acetate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate / sulfate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hybenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 1,5-naphthalenedisulfonate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrogenphosphate, saccharate, stearate, succinate, tartrate, tosylate and trifluoroacetate.

[0104] Suitable base salts are formed from bases which form non-toxic salts. Examples include aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts. Hemisalts of acids and bases can also be formed, such as hemisulfate and hemicalcium salts. For a review of suitable salts, see "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

[0105] Pharmaceutically acceptable salts of compounds of formula (I) may be prepared by one or more of three methods: (i) reacting a compound of the invention with a desired acid or base; (ii) removal of acid- or base-labile protecting groups from suitable precursors of the compounds of the invention using a desired acid or base or a ring-opening reaction of suitable cyclic precursors, such as lactones or lactams; or (iii) Conversion of one salt of a compound of the invention to another salt by reaction with an appropriate acid or base or by means of a suitable ion exchange column.

[0106] All three reactions are typically carried out in solution. The resulting salt may precipitate and be collected by filtration or may be recovered by solvent evaporation. The degree of ionization in the resulting salt may vary from completely ionized to nearly non-ionized.

[0107] The compounds of the present invention can exist in unsolvated and solvated forms.The term "solvate" is used herein to refer to a molecular complex that comprises the compounds of the present invention and a stoichiometric amount of one or more pharma-ceutically acceptable solvent molecules, such as ethanol.The term "hydrate" is used when the solvent is water.

[0108] In contrast to the solvates, the scope of the present invention includes complexes such as clathrates, drug-host inclusion complexes, in which the drug and host are present in stoichiometric or non-stoichiometric amounts. Also included are complexes of drugs that contain two or more organic and / or inorganic components, which may be in stoichiometric or non-stoichiometric amounts. The resulting complexes may be ionized, partially ionized, or non-ionized. For a review of such complexes, see J Pharm Sci, 64 (8), 1269-1288 by Haleblian (August 1975).

[0109] Hereinafter, any reference to a compound of any formula includes reference to salts, solvates and complexes thereof and to solvates and complexes of salts thereof.

[0110] The compounds of the present invention include compounds of the several formulas defined herein, including all polymorphs and crystal habits thereof, as defined below, prodrugs thereof, and isomers (including optical, geometric and tautomeric isomers) and isotopically labeled compounds of the present invention.

[0111] The present invention also includes all pharma- ceutically acceptable isotopically labeled compounds of the present invention in which one or more atoms are replaced by an atom having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number most commonly found in nature.

[0112] Examples of isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, e.g. 2 H and 3 H, isotopes of carbon, e.g. 11 C. 13 C and 14 C, an isotope of chlorine, e.g. 36 Cl, an isotope of fluorine, e.g. 18 F, an isotope of iodine, e.g. 123 I and 125 I, an isotope of nitrogen, e.g. 13 N and 15 N, isotopes of oxygen, e.g. 15 O. 17 O and 18 O, isotopes of phosphorus, e.g. 32 P and sulfur isotopes, e.g. 35 Contains S.

[0113] Certain isotopically labeled compounds, for example those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. The radioactive isotope tritium, i.e. 3 H and carbon-14, i.e. 14 C is particularly useful for this purpose in view of its ease of incorporation and ready means of detection.

[0114] Deuterium, i.e. 2 Substitution with heavier isotopes, such as H, may offer certain therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and therefore may be preferable in certain circumstances.

[0115] Before purification, the compounds of the present invention may exist as a mixture of enantiomers, depending on the synthesis method used. Enantiomers may be separated by conventional techniques known in the art. Thus, the present invention may include individual enantiomers as well as mixtures thereof.

[0116] In some steps of the preparation process of the compounds of the present invention, it may be necessary to protect potentially reactive functional groups that are not desired to react, and then to remove the protecting group. In such cases, any compatible protecting group may be used. In particular, the protection and deprotection methods described by TW GREENE (Protective Groups in Organic Synthesis, A. Wiley- Interscience Publication, 1981) or PJ Kocienski (Protecting groups, Georg Thieme Verlag, 1994) may be used. All the above reactions and preparation of new starting materials used in the above-mentioned methods are conventional, and suitable reagents and reaction conditions for carrying out or preparing, as well as methods for isolating the desired products, are well known to those skilled in the art, with reference to the prior art and the examples and preparations herein.

[0117] Additionally, the compounds of the present invention and the intermediates for their preparation may be purified by a variety of well-known methods, such as, for example, crystallization or chromatography.

[0118] One or more compounds of the invention may be combined with one or more agents, such as anti-inflammatory agents, anti-fibrotic agents, chemotherapeutic agents, anti-cancer agents, immunosuppressants, anti-tumor vaccines, cytokine therapy, or tyrosine kinase inhibitors, for the treatment of conditions modulated by ROCK inhibition, such as fibrotic diseases, autoimmune, inflammatory-fibrotic conditions, inflammatory conditions, central nervous system disorders, or cancer.

[0119] The method of treatment or the compounds for use in the treatment of fibrotic diseases, autoimmune, inflammatory-fibrotic conditions, inflammatory conditions, central nervous system disorders or cancer as defined above may be applied as monotherapy or as combination therapy with additional active agents.

[0120] The method of treatment or compound for use in treating fibrotic diseases, autoimmune, inflammatory-fibrotic conditions, inflammatory conditions, central nervous system disorders, may include an additional active agent in addition to the compound of the present invention. The additional active agent may be one or more active agents used to treat the condition treated by the compound of the present invention and the additional active agent. The additional active agent may include one or more of the following active agents: (i) Glucocorticoids and mineralocorticoids, such as aclomethasone, aclomethasone dipropionate, aldosterone, amcinonide, beclomethasone, beclomethasone dipropionate, betamethasone, betamethasone dipropionate, betamethasone sodium phosphate, betamethasone valerate, budesonide, clobetasone, clobetasone butyrate, clobetasol propionate, cloprendol, cortisone, cortisone acetate, cortivazol, deoxycortone, desonide, desoxymethasone, dexamethasone, dexamethasone sodium phosphate, dexamethasone isonicotinate, difluorocortolone, fluclorolone, flumethasone, flunisolide, fluocinolone, fluocinolone acetonide, fluocinonide, fluocortin butyl, fluorocortisone, fluoro Steroids such as corticosteroids, including cortolone, flucortolone caproate, flucortolone pivalate, fluorometholone, fluprednidene, fluprednidene acetate, flurandrenolone, fluticasone, fluticasone propionate, halcinonide, hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone aceponate, hydrocortisone butyrate propionate, hydrocortisone valerate, icometasone, icometasone embutate, meprednisone, methylprednisolone, mometasone paramethasone, mometasone furoate monohydrate, prednicarbate, prednisolone, prednisone, tixocortol, tixocortol pivalate, triamcinolone, triamcinolone acetonide, triamcinolone alcohol, and their respective pharma- ceutically acceptable derivatives. Combinations of steroids may be used, such as combinations of two or more of the steroids described in this paragraph; (ii) TNF inhibitors, such as etanercept; monoclonal antibodies (e.g., infliximab (Remicade), adalimumab (Humira), certolizumab pegol (Cimzia), golimumab (Simponi)); fusion proteins (e.g., etanercept (Enbrel)); and 5-HT 2A agonists (e.g., 2,5-dimethoxy-4-iodoamphetamine, TCB-2, lysergic acid diethylamide (LSD), lysergic acid dimethylazetidide); (iii) anti-inflammatory drugs, such as non-steroidal anti-inflammatory drugs; (iv) dihydrofolate reductase inhibitors / antifolates, such as methotrexate, trimethoprim, prodimoprim, tetroxoprim, iclaprim, pemetrexed, raltitrexed, and pralatrexate; and (v) Immunosuppressants such as cyclosporines, tacrolimus, sirolimus spimecrolimus, angiotensin II inhibitors (e.g. valsartan, telmisartan, losartan, irbesartan, azilsartan, olmesartan, candesartan, eprosartan) and ACE inhibitors such as sulfhydryl-containing agents (e.g. captopril, zofenopril), dicarboxylic acid-containing agents (e.g. enalapril, ramipril, quinapril, perindopril, lisinopril, benazepril, imidapril, zofenopril, trandolapril), phosphate-containing agents (e.g. fosinopril), casokinins, lactokines and lactotripeptides; (vi) anti-fibrotic agents, such as: pirfenidone, nintedanib, anti-CTGF monoclonal antibodies (e.g. pamrevlumab), anti-αvβ6 monoclonal antibodies (e.g. PLN-74809), anti-IL-13 monoclonal antibodies (e.g. tralokinumab, QAX576, lebrikizumab), simtuzumab, 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, PAR1 inhibitors, Nox4 inhibitors and PAI-1 inhibitors; (vii) CNS therapy, for example: levodopa, dopamine agonists, apomorphine, glutamate antagonists, anticholinergics, COMT inhibitors, MAO-B inhibitors, riluzole (Rilutek), tetrabenazine (Xenazine), haloperidol (Haldol), chlorpromazine, risperidone (Risperdal), quetiapine (Seroquel), amantadine, levetiracetam (Keppra), clonazepam (Klonopin), donepezil (Amande), Recept), galantamine (Razadine), rivastigmine (Exelon), memantine (Ebixa, Axula), aducanumab, ocrelizumab, interferon beta-1a (Avonex, Rebif), peg-interferon beta-1a (Pregridy), teriflunomide (Aubagio), fingolimod (Gilenya), mitoxantrone (Novantrone), dimethyl fumarate (Tecfidera), and natalizumab (Tysabri).

[0121] Methods of treating or compounds for use in treating cancer, sarcoma, melanoma, skin cancer, blood tumors, lymphoma, carcinoma, leukemia, and central nervous system disorders may include, in addition to the compounds of the present invention, conventional surgery or radiation therapy or chemotherapy. Such chemotherapy may include one or more of the following categories of anti-tumor agents: (i) Antiproliferative / antineoplastic drugs and combinations thereof, such as alkylating agents (e.g. cisplatin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, uracil mustard, bendamustine, melphalan, chlorambucil, chlormethine, busulfan, temozolamide, nitrosoureas, ifosamide, melphalan, pipobroman, triethylene-melamine, triethylenethiophosphoramine, carmustine, lomustine, streptozocin, and dacarbazine); antimetabolites (e.g. gemcitabine and antifolates, such as fluoropyrimidines, e.g. 5-fluorouracil and tegafur, raltitrexed, methotrexate, pemetrexed, cytosine arabinoside, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, pentostatin, and gemcitabine, and hydrazine); roxyurea; antibiotics (e.g. anthracyclines such as adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin); mitotic inhibitors (e.g. vinca alkaloids such as vincristine, vinblastine, vindesine and vinorelbine and taxoids such as taxol and taxotere and polo kinase inhibitors); proteasome inhibitors such as carfilzomib and bortezomib; interferon therapy; and topoisomerase inhibitors (e.g. epipodophyllotoxins such as etoposide and teniposide, amsacrine, topotecan, mitoxantrone and camptothecin); bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, ara-C, paclitaxel (taxol TM ), nab-paclitaxel, docetaxel, mithramycin, deoxycoformycin, mitomycin-C, L-asparaginase, interferons (especially IFN-a), etoposide and teniposide; (ii) Cytostatics, such as antiestrogens (e.g. tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene and idoxifene), antiandrogens (e.g. bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or agonists (e.g. goserelin, leuprorelin and buserelin), progestogens (e.g. megestrol acetate), aromatase inhibitors (e.g. anastrozole, letrozole, borazole and exemestane) and 5α-reductase inhibitors, such as finasteride; and navelbine, CPT-ll, anastrozole, letrozole, capecitabine, reloxafam, cyclophosphamide, ifosamide and droloxafine; (iii) anti-invasive agents, such as dasatinib and bosutinib (SKI-606) and metalloproteinase inhibitors, urokinase plasminogen activator receptor function inhibitors or antibodies against heparanase; (iv) Growth factor function inhibitors: For example, such inhibitors include growth factor antibodies and growth factor receptor antibodies, such as the anti-erbB2 antibody trastuzumab [Herceptin TM], anti-EGFR antibody panitumumab, anti-erbB1 antibody cetuximab, tyrosine kinase inhibitors such as epidermal growth factor family inhibitors (e.g. EGFR family tyrosine kinase inhibitors, e.g. gefitinib, erlotinib, 6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)-quinazolin-4-amine (CI 1033), erbB2 tyrosine kinase inhibitors, e.g. lapatinib) and antibodies against costimulatory molecules, e.g. CTLA-4, 4-lBB and PD-1 or antibodies against cytokines (IL-I0, TGF-beta); hepatocyte growth factor family inhibitors; insulin growth factor family inhibitors; modulators of cell apoptosis protein regulators (e.g. Bcl-2 inhibitors); platelet-derived growth factor family inhibitors, e.g. imatinib and / or nilotinib (AMN107); serine / threonine kinase inhibitors (e.g. Ras / R af signaling inhibitors, such as farnesyltransferase inhibitors, e.g. sorafenib, tipifarnib and lonafarnib), inhibitors of cell signaling via MEK and / or AKT kinases, c-kit inhibitors, abl kinase inhibitors, PI3 kinase inhibitors, Plt3 kinase inhibitors, CSF-1R kinase inhibitors, IGF receptor, kinase inhibitors; Aurora kinase inhibitors and cyclin dependent kinase inhibitors, e.g. CDK2 and / or CDK4 inhibitors; and CCR2, CCR4 or CCR6 modulators; (v) Antiangiogenic agents, such as those that inhibit the action of vascular endothelial growth factor, e.g., the anti-vascular endothelial growth factor antibody bevacizumab (Avastin TM );thalidomide;lenalidomide;and, for example, VEGF receptor tyrosine kinase inhibitors, such as vandetanib, vatalanib, sunitinib, axitinib and pazopanib; (vi) gene therapy approaches, including, for example, replacement of an abnormal gene, such as an abnormal p53 or an abnormal BRCA1 or BRCA2; (vii) immunotherapies, including, for example, antibody therapies, such as alemtuzumab, rituximab, ibritumomab tiuxetan (Zevalin®) and ofatumumab; interferons, such as interferon alpha; interleukins, such as IL-2 (aldesleukin); interleukin inhibitors, such as IRAK4 inhibitors; cancer vaccines, including preventative and treatment vaccines, such as HPV vaccines, e.g., Gardasil, Cervarix, Oncophage and Sipuleucel-T (Provenge); gp100; dendritic cell-based vaccines (e.g., Ad.p53 DC); and toll-like receptor modulators, such as TLR-7 or TLR-9 agonists; and (viii) Cytotoxic agents, such as fludarabine (Fludara), cladribine, pentostatin (Nipent), TM ); (ix) steroids, such as glucocorticoids and mineralocorticoids, for example aclomethasone, aclomethasone dipropionate, aldosterone, amcinonide, beclomethasone, beclomethasone dipropionate, betamethasone, betamethasone dipropionate, betamethasone sodium phosphate, betamethasone valerate, budesonide, clobetasone, clobetasone butyrate, clobetasol propionate, cloprendol, cortisone, cortisone acetate, cortivazol, deoxycortone, desonide, desoxymethasone, dexamethasone, dexamethasone sodium phosphate, dexamethasone isonicotinate, difluorocortolone, fluclorolone, flumethasone, flunisolide, fluocinolone, fluocinolone acetonide, fluocinonide, fluocortin butyl, fluoro Corticosteroids including cortisone, fluorocortolone, flucortolone caproate, flucortolone pivalate, fluorometholone, fluprednidene, fluprednidene acetate, flurandrenolone, fluticasone, fluticasone propionate, halcinonide, hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone aceponate, hydrocortisone butyrate propionate, hydrocortisone valerate, icometasone, icometasone embutate, meprednisone, methylprednisolone, mometasone paramethasone, mometasone furoate monohydrate, prednicarbate, prednisolone, prednisone, tixocortol, tixocortol pivalate, triamcinolone, triamcinolone acetonide, triamcinolone alcohol and their respective pharma- ceutically acceptable derivatives. Combinations of steroids may be used, such as combinations of two or more of the steroids described in this paragraph; (x) targeted therapies, such as PI3Kd inhibitors, e.g., idelalisib and perifosine; PD-1, PD-L1, PD-L2 and CTL4-A modulators, antibodies and vaccines; other IDO inhibitors (e.g., indoximod); anti-PD-1 monoclonal antibodies (e.g., MK-3475 and nivolumab); anti-PD-L1 monoclonal antibodies (e.g., MEDI-4736 and RG-7446); anti-PD-L2 monoclonal antibodies; and anti-CTLA-4 antibodies (e.g., ipilimumab); (xii) Chimeric antigen receptors, anticancer vaccines and arginase inhibitors.

[0122] Such combination treatment may be achieved by way of simultaneous, sequential or separate administration of the individual components of the treatment.Such combination products employ the compounds of this invention within the therapeutically effective dosage range noted above and the other pharmacologic active agent within its approved dosage range.

[0123] The compounds of the present invention may exist in a single crystalline form or a mixture of crystalline forms or may be amorphous. Thus, the compounds of the present invention intended as pharmaceuticals may be administered as crystalline or amorphous products. They may be obtained, for example, in solid plugs, powders or films by methods such as precipitation, crystallization, freeze-drying or spray-drying or evaporative drying. Microwave or radio frequency drying may be used for this purpose.

[0124] The dosage of the compound of the present invention will vary depending on the compound used, the administration method, the desired treatment and the disorder to be treated. For example, if the compound of the present invention is administered orally, the daily dosage of the compound of the present invention may be in the range of 0.01 microgram / kilogram body weight (μg / kg) to 100 milligram / kilogram body weight (mg / kg).

[0125] The compound of the present invention or its pharmaceutically acceptable salt may be used by itself, but generally it is administered in the form of a pharmaceutical composition in which the compound of the present invention or its pharmaceutically acceptable salt is combined with a pharmaceutically acceptable adjuvant, diluent or carrier. The selection and preparation of suitable pharmaceutical preparations are described, for example, in "Pharmaceuticals - The Science of Dosage Form Designs", ME Aulton, Churchill Livingstone, 1988.

[0126] Depending on the method of administration of the compounds of the present invention, the pharmaceutical composition used to administer the compounds of the present invention preferably contains 0.05-99% w (weight percent) of the compound of the present invention, more preferably 0.05-80% w of the compound of the present invention, even more preferably 0.10-70% w of the compound of the present invention, and even more preferably 0.10-50% w of the compound of the present invention, all weight percentages being based on the total composition.

[0127] The pharmaceutical compositions may be administered topically (e.g., to the skin) in the form of, for example, creams, gels, lotions, solutions, suspensions, or orally in the form of, for example, tablets, capsules, syrups, powders or granules; parenterally (including intravenously, subcutaneously, intramuscularly, intravascularly or by infusion) in the form of a sterile solution, suspension or emulsion for injection; rectally in the form of a suppository; or systemically by inhalation in the form of an aerosol.

[0128] For oral administration, the compound of the present invention can be mixed with adjuvants or carriers such as lactose, saccharose, sorbitol, mannitol; starches such as potato starch, corn starch or amylopectin; cellulose derivatives; binders such as gelatin or polyvinylpyrrolidone; and / or lubricants such as magnesium stearate, calcium stearate, polyethylene glycol, wax, paraffin, etc., and then compressed into tablets.If coated tablets are required, the cores prepared as above can be coated with a concentrated sugar solution, which can contain, for example, gum arabic, gelatin, talc and titanium dioxide.Alternatively, tablets can be coated with a suitable polymer dissolved in a readily volatile organic solvent.

[0129] For the preparation of soft gelatin capsules, the compound of the present invention may be mixed with, for example, vegetable oil or polyethylene glycol. Hard gelatin capsules may contain granules of the compound using the additives mentioned above for tablets. Also, liquid or semi-solid preparations of the compound of the present invention may be filled into hard gelatin capsules. Liquid preparations for oral application may be in the form of syrups or suspensions, for example, solutions containing the compound of the present invention, the balance being a mixture of sugar and ethanol, water, glycerol and propylene glycol. If desired, such liquid preparations may contain coloring agents, flavoring agents, sweeteners (e.g. saccharin), carboxymethylcellulose as preservatives and / or thickeners, or other additives known to those skilled in the art.

[0130] For intravenous (parenteral) administration, the compounds of the present invention may be administered in the form of a sterile aqueous or oily solution.

[0131] The amount of the compounds of the invention administered for therapeutic purposes will naturally vary depending on the nature and severity of the condition, the age and sex of the animal or patient and the route of administration, in accordance with well-known principles of medicine.

[0132] The dosage, frequency of administration and duration of treatment of the compounds of the invention are expected to vary depending on the formulation and clinical indication, age and coexisting medical conditions of the patient.

[0133] Throughout this specification and the claims, the terms "comprise" and "include" and variations thereof mean "including, but not limited to," and do not (and do not) intend to exclude other moieties, additives, components, integers, or steps. Throughout this specification and the claims, the singular includes the plural unless the context requires otherwise. In particular, when using the indefinite article, the description should be interpreted as contemplating both the plural and the singular, unless the context requires otherwise.

[0134] Any feature, integer, characteristic, compound, chemical moiety or group described in connection with a particular aspect, embodiment or example of the invention should be construed as applicable to any other aspect, embodiment or example described herein, unless incompatible. All of the features disclosed herein (including any accompanying claims, abstract and drawings) and / or all of the steps of any method or procedure so disclosed may be combined in any combination, except combinations in which at least some of such features and / or steps are mutually exclusive. The invention is not limited to the details of any of the aforementioned embodiments. The invention extends to any novel or any novel combination of features disclosed herein (including any accompanying claims, abstract and drawings) or any novel or any novel combination of steps of any method or procedure so disclosed.

[0135] The reader is directed to all articles and documents submitted contemporaneously or prior to this application and published herewith, the contents of all such articles and documents being incorporated herein by reference.

[0136] Compounds of the invention may be prepared according to or analogously to general Schemes 1 and 2 and Examples 1-132. EXAMPLES

[0137] Examples and Synthesis As used herein, the following terms have the following meanings: "Ac" refers to acetyl; "ADP" refers to adenosine diphosphate; "ATP" refers to adenosine triphosphate; "Boc" refers to tert-butoxycarbonyl; "dba" refers to dibenzylideneacetone; "d" refers to doublet; "DCE" refers to 1,2-dichloroethane; "DCM" refers to dichloromethane; "DIPEA" refers to N,N-diisopropylethylamine; "DMAP" refers to 4-(dimethylamino)-1,2-tetrahydrofuran; "DMF" refers to N,N-dimethylformamide; "DMSO" refers to dimethylsulfoxide; "dppf" refers to 1,1'-bis(diphenylphosphino)ferrocene; "DTT" refers to dithiothreitol; "EDC" refers to N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide; "EDTA" refers to ethylenediaminetetra-acetic acid; "ES-API" refers to electrospray atmospheric pressure ionization; "ESI " refers to electrospray ionization; "Et" refers to ethyl; "EtOAc" refers to ethyl acetate; "HATU" refers to 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate; "HEPES" refers to (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid); "HOBt" refers to 1-hydroxybenzotriazole hydrate; "HPLC" refers to high performance liquid chromatography. "IPA" refers to 2-propanol; "J" refers to coupling constant; "LCMS" or "LC-MS" refers to liquid chromatography / mass spectrometry; "LiHMDS" refers to lithium bis(trimethylsilyl)amide; "m" refers to multiplet; "Me" refers to methyl; "MIM" refers to monoisotopic mass; "min" refers to minutes; "MS" refers to mass spectrometry; "NMR" refers to nuclear magnetic resonance; "Pet. Ether" refers to petroleum ether; "PG" refers to protecting group; "PTSA" refers to p-toluenesulfonic acid monohydrate; "q" refers to quartet; "quint" refers to quintet; "Rf" refers to retention factor; "RT" refers to retention time; "rt" refers to room temperature; "s" refers to singlet; "SCX" refers to strong cation exchange; "SEM" refers to 2-(trimethylsilyl)ethoxymethyl; "t" refers to triplet; "TBME" refers to tert-butyl methyl ether; "TEA" refers to triethylamine; "TFA" refers to trifluoroacetic acid; "TFE" refers to trifluoroethanol; "THF" refers to tetrahydrofuran; "THP" refers to tetrahydropyran; "TLC" refers to thin layer chromatography; "TMS" refers to tetramethylsilane; "UPLC" refers to ultra-performance liquid chromatography; "UV" refers to ultraviolet; "XantPhos" refers to 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; and "XPhos" refers to 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl.

[0138] Solvents, reagents and starting materials were purchased from commercial sources and used as received unless otherwise stated. All reactions were performed at rt unless otherwise stated. Compound characterization and purity checks were performed by LCMS UV using a Waters Acquity SQ Detector 2 (ACQ-SQD2#LCA081). The diode array detector wavelength was 254 nM and MS was performed in positive and negative electrospray mode (m / z: 150-800). 2 μL volumes were injected consecutively onto a guard column (0.2 μm×2 mm filter) and a UPLC column (C18, 50×2.1 mm, <2 μm) maintained at 40° C. Samples were eluted at a flow rate of 0.6 mL / min using a mobile phase system consisting of A (0.1% (v / v) formic acid in water) and B (0.1% (v / v) formic acid in acetonitrile) following the following gradient: Retention times RT are given in minutes. [Table 1]

[0139] Compound characterization was also performed by LCMS UV using: Method C LC: Agilent Technologies 1290 Series Binary Pump Diode Array Detector Column: Agilent Eclipse Plus RRHD C18, 1.8 μm, 3.0 × 50 mm Column temperature: 40℃ Acquisition wavelength: 214nm, 254nm Mobile phase: A: 0.05% formic acid in water (v / v), B: 0.05% formic acid in MeCN (v / v) Runtime: 3.0 minutes Flow rate: 0.8mL / min gradient: [Table 2] MS:G6120A, quadrupole LC / MS Ion source: ESI Signal: Yang TIC: 70-1000 m / z Fragmenter: 60 Threshold: 5 Gain: 1 Drying gas flow: 10L / min Nebulizer pressure: 35psi

[0140] Method D LC: Agilent Technologies 1290 Series Binary Pump Diode Array Detector Column: Agilent Eclipse Plus RRHD C18, 1.8 μm, 3.0 × 50 mm Column temperature: 40℃ Acquisition wavelength: 214nm, 254nm Mobile phase: A: 0.05% formic acid in water (v / v), B: 0.05% formic acid in MeCN (v / v) Runtime: 3.0 minutes Flow rate: 0.8mL / min gradient: [Table 3] MS: G6120A, quadrupole LC / MS Ion source: ESI Signal: Yang TIC: 70-1000 m / z Fragmenter: 60 Threshold: 5 Gain: 1 Drying gas flow: 10L / min Nebulizer pressure: 35psi

[0141] Method E LC: Agilent Technologies 1290 Series Binary Pump Diode array detector. Column: Agilent Eclipse Plus RRHD C18, 1.8 μm, 3.0 × 50 mm Column temperature: 40℃ Acquisition wavelength: 214nm, 254nm Mobile phase: A: 0.05% formic acid in water (v / v), B: 0.05% formic acid in MeCN (v / v) Runtime: 3.0 minutes Flow rate: 0.8mL / min gradient: [Table 4] MS: G6120A, quadrupole LC / MS Ion source: ESI Signal: Yang TIC: 70-1000 m / z Fragmenter: 60 Threshold: 5 Gain: 1 Drying gas flow: 10L / min Nebulizer pressure: 35psi

[0142] Method F LC: Shimadzu 2020 series Binary Pump Diode Array Detector Column: Agilent Poroshell 120 EC-C18, 2.7 μm, 4.6 × 50 mm Column temperature: 35℃ Acquisition wavelength: 214nm, 254nm Mobile phase: A: 0.05% formic acid in water (v / v), B: 0.05% formic acid in ACN (v / v) Runtime: 5.0 minutes Flow rate: 1.0mL / min gradient: [Table 5] MS: Ion source: ESI Signals: Positive and Negative TIC: 100-900 m / z Fragmenter: 60 Threshold: 5 Gain: 1 Drying gas: 20L / min Atomization gas: 1.5L / min

[0143] Method G LC: Shimadzu 2020 series Binary Pump Diode Array Detector Column: Agilent Poroshell 120 EC-C18, 2.7 μm, 4.6 × 50 mm Column temperature: 35℃ Acquisition wavelength: 214nm, 254nm Mobile phase: A: 0.05% formic acid in water (v / v), B: 0.05% formic acid in ACN (v / v) Runtime: 5.0 minutes Flow rate: 1.0mL / min gradient: [Table 6] MS: Ion source: ESI Signals: Positive and Negative TIC: 100-900 m / z Fragmenter: 60 Threshold: 5 Gain: 1 Drying gas: 20L / min Atomization gas: 1.5L / min

[0144] Method H LC: Shimadzu LC-20XR series Binary Pump Diode Array Detector Column: Waters ACQUITY UPLC HSS C18, 1.8 μm, 3.0 x 50 mm Column temperature: 25℃ Acquisition wavelength: 214nm, 254nm Mobile phase: A: 0.05% formic acid in water (v / v), B: 0.05% formic acid in ACN (v / v) Runtime: 3.0 minutes Flow rate: 0.5mL / min gradient: [Table 7] MS:2020, Quadrupole LC / MS, Ion source: API-ESI TIC: 100-900 m / z Drying gas flow: 15L / min Nebulizer pressure: 1.5L / min Drying gas temperature: 250℃ Vcap: 4500V.

[0145] Method I LC: Shimadzu 2020 series Binary Pump Diode Array Detector Column: Agilent Poroshell 120 EC-C18, 2.7 μm, 4.6 × 50 mm Column temperature: 35℃ Acquisition wavelength: 214nm, 254nm Mobile phase: A: 0.05% formic acid in water (v / v), B: 0.05% formic acid in ACN (v / v) Runtime: 5.0 minutes Flow rate: 1.0mL / min gradient: [Table 8] MS: Ion source: ESI Signals: Positive and Negative TIC: 100-900 m / z Fragmenter: 60 Threshold: 5 Gain: 1 Drying gas: 20L / min Atomization gas: 1.5L / min

[0146] Method J LC: Shimadzu LC-20XR series Binary Pump Diode Array Detector Column: Waters ACQUITY UPLC HSS C18, 1.8 μm, 3.0 x 50 mm Column temperature: 25℃ Acquisition wavelength: 214nm, 254nm Mobile phase: A: 0.05% formic acid in water (v / v), B: 0.05% formic acid in MeCN (v / v) Runtime: 3.0 minutes Flow rate: 0.6mL / min gradient: [Table 9] MS:2020, Quadrupole LC / MS Ion source: API-ESI TIC: 100-900 m / z Drying gas flow: 15L / min Nebulizer pressure: 1.5L / min Drying gas temperature: 250℃ Vcap: 4500V

[0147] Method K LC: Shimadzu LC-20XR series Binary Pump Diode Array Detector Column: Waters ACQUITY UPLC HSS C18, 1.8 μm, 3.0 x 50 mm column Column temperature: 25℃ Acquisition wavelength: 214nm, 254nm Mobile phase: A: 0.05% formic acid in water (v / v), B: 0.05% formic acid in MeCN (v / v) Runtime: 3.0 minutes Flow rate: 0.6mL / min gradient: [Table 10] MS:2020, Quadrupole LC / MS Ion source: API-ESI TIC: 100-900 m / z Drying gas flow: 15L / min Nebulizer pressure: 1.5L / min Drying gas temperature: 250℃ Vcap: 4500V

[0148] Method L LC: Agilent Technologies 1290 Series Binary Pump Diode Array Detector Column: Agilent Poroshell 120 EC-C18, 2.7 μm, 4.6 × 50 mm Column temperature: 35℃ Acquisition wavelength: 214nm, 254nm Mobile phase: A: 0.05% formic acid in water (v / v), B: 0.05% formic acid in MeCN (v / v) Runtime: 5.0 minutes Flow rate: 1.0mL / min gradient: [Table 11] MS:G6120A, quadrupole LC / MS Ion source: ESI Signals: Positive and Negative TIC: 70-1000 m / z Fragmenter: 60 Threshold: 5 Gain: 1 Drying gas flow: 10L / min Nebulizer pressure: 35psi

[0149] Method M LC: Agilent Technologies 1290 Series Binary Pump Diode Array Detector Column: Agilent Poroshell 120 EC-C18, 2.7 μm, 4.6 × 50 mm Column temperature: 35℃ Acquisition wavelength: 214nm, 254nm Mobile phase: A: 0.05% formic acid in water (v / v), B: 0.05% formic acid in MeCN (v / v) Runtime: 5.0 minutes Flow rate: 1.0mL / min gradient: [Table 12] MS:G6120A, quadrupole LC / MS Ion source: ESI Signals: Positive and Negative TIC: 70-1000 m / z Fragmenter: 60 Threshold: 5 Gain: 1 Drying gas flow: 10L / min Nebulizer pressure: 35psi

[0150] Method N LC: Agilent Technologies 1290 Series Binary Pump Diode Array Detector Column: Agilent Poroshell 120 EC-C18, 2.7 μm, 4.6 × 50 mm Column temperature: 35℃ Acquisition wavelength: 214nm, 254nm Mobile phase: A: 0.05% formic acid in water (v / v), B: 0.05% formic acid in ACN (v / v) Runtime: 5.0 minutes Flow rate: 1.0mL / min gradient: [Table 13] MS: G6120A, quadrupole LC / MS Ion source: ESI Signal: Yang TIC: 70-1000 m / z Fragmenter: 60 Threshold: 5 Gain: 1 Drying gas flow: 10L / min Nebulizer pressure: 35psi

[0151] Method O LC: Shimadzu LC-20XR series Binary Pump Diode Array Detector Column: Waters ACQUITY UPLC HSS C18, 1.8 μm, 3.0 x 50 mm column Column temperature: 25℃ Acquisition wavelength: 214nm, 254nm Mobile phase: A: 0.05% formic acid in water (v / v), B: 0.05% formic acid in MeCN (v / v) Runtime: 3.0 minutes Flow rate: 0.6mL / min gradient: [Table 14] MS:2020, Quadrupole LC / MS Ion source: API-ESI TIC: 100-900 m / z Drying gas flow: 15L / min Nebulizer pressure: 1.5L / min Drying gas temperature: 250℃ Vcap: 4500V.

[0152] Method P LC: Shimadzu LC-20AD series Binary Pump Diode Array Detector Column: Waters Sunfire, 3.5 μm, 4.6 x 50 mm column Column temperature: 25℃ Acquisition wavelength: 214nm, 254nm Mobile phase: A: 0.05% formic acid in water (v / v), B: 0.05% formic acid in MeCN (v / v) Runtime: 5.0 minutes Flow rate: 1mL / min gradient: [Table 15] MS:2020, Quadrupole LC / MS Ion source: API-ESI TIC: 100~900m / Drying gas flow: 15L / min, Nebulizer pressure: 1.5L / min Drying gas temperature: 250℃ Vcap: 4500V.

[0153] Method Q LC: Shimadzu LC-20AD series Binary Pump Diode Array Detector Column: Waters Sunfire, 3.5 μm, 4.6 x 50 mm column Column temperature: 25℃ Acquisition wavelength: 214nm, 254nm Mobile phase: A: 0.05% formic acid in water (v / v), B: 0.05% formic acid in MeCN (v / v) Runtime: 5.0 minutes Flow rate: 1mL / min gradient: [Table 16] MS:2020, Quadrupole LC / MS Ion source: API-ESI TIC: 100-900 m / z Drying gas flow: 15L / min Nebulizer pressure: 1.5L / min Drying gas temperature: 250℃ Vcap: 4500V.

[0154] Method R LC: Agilent Technologies 1290 Series Binary Pump Diode Array Detector Column: Agilent EclipsePlus RRHD C18, 1.8 μm, 3.0 × 50 mm Column temperature: 25℃ Acquisition wavelength: 214nm, 254nm Mobile phase: 0.05% formic acid in water (v / v), B: 0.05% formic acid in ACN (v / v) Flow rate: 0.8mL / min gradient: [Table 17] MS: G6120A, quadrupole LC / MS, ion source: API-ES TIC: 70-1000 m / z Fragmenter: 70 Drying gas flow: 12L / min Nebulizer pressure: 36psi Drying gas temperature: 350℃ Vcap: 3000V.

[0155] Method S LC: Shimadzu 2020 series Binary Pump Diode Array Detector Column: Agilent Poroshell 120 EC-C18, 2.7 μm, 4.6 × 50 mm Column temperature: 35℃ Acquisition wavelength: 214nm, 254nm Mobile phase: A: 0.05% formic acid in water (v / v), B: 0.05% formic acid in ACN (v / v) Runtime: 5.0 minutes Flow rate: 1.0mL / min gradient: [Table 18] MS: Ion source: ESI Signal: Positive / Negative TIC: 100-900 m / z Fragmenter: 60 Threshold: 5 Gain: 1 Drying gas: 20L / min Atomization gas: 1.5L / min

[0156] NMR was also used to characterize the final compounds. 1 H NMR spectra were obtained at rt on a Bruker AVI 500 with a 5 mm Dual or 5 mm QNP probe with Z gradient, a Bruker DRX500 with a 5 mm QNP probe with Z gradient or a Bruker AVIII 400 Nanobay with a 5 mm BBFO probe unless otherwise stated. Chemical shifts are given in ppm and referenced to TMS (0.00 ppm), DMSO-d6 (2.50 ppm), CDCl3 (7.26 ppm) or MeOD-d4 (3.31 ppm). NH or OH signals that exchange with deuterated solvents are not given.

[0157] If desired, compound Rf values ​​were measured on silica thin layer chromatography (TLC) plates.

[0158] Compound purification was performed by flash column silica chromatography or preparative LCMS. LCMS purification was performed using a Waters 3100 Mass detector and a Waters 2489 UV / Vis detector in positive and negative electrospray mode (m / z: 150-800). Samples were run at a flow rate of 20 mL / min on an XBridge TM The elution was performed on a prep C18 5 μM OBD 19×100 mm column with a mobile phase system consisting of A (0.1% (v / v) formic acid in water) and B (0.1% (v / v) formic acid in acetonitrile) according to the gradient shown in the table below. [Table 19]

[0159] Compound characterization was also performed by analytical supercritical fluid chromatography (SFC) using a Waters UPC2 analytical SFC (SFC-H). A volume of 10 μL was injected onto an HPLC column (cellulose-2, 150×4.6 mm ID, 3 μm) at RT controlled at 35° C. Samples were eluted under isocratic elution (50% phase B) with a mobile phase system consisting of CO2 in A and methanol in B (0.05% DEA, V / V) at a flow rate of 2.0 mL / min.

[0160] Compound purification was also performed by preparative supercritical fluid chromatography (SFC). SFC purification was performed using a MG II preparative SFC (SFC-13). Samples were eluted under isocratic elution (50% phase B) with a mobile phase system consisting of A CO2 and B methanol (0.1% NH3H2O) on cellulose-2, 250 x 30 mm ID, 10 μm particle size at a flow rate of 80 mL / min. [Table 20]

[0161] HPLC purity method (Agilent 17 minutes) [Table 21]

[0162] General Scheme 1 [ka]

[0163] General Scheme 2 [ka]

[0164] General synthesis of intermediates 1 and 2: [ka] Intermediate 1: 3,5-Dibromo-1-methyl-1,2,4-triazole [ka] To a solution of 3,5-dibromo-1H-1,2,4-triazole (10.0 g, 44.1 mmol) in DMF (75 mL) and potassium carbonate (12.2 g, 88.2 mmol, 2.0 equiv) was added iodomethane (3.02 mL, 48.5 mmol, 1.1 equiv) in one portion. This caused a strong exotherm from 17° C. to 38° C. after 1 min. The reaction mixture was stirred overnight, diluted with 150 mL of EtOAc, and then filtered to remove most of the inorganics. The solvent was removed under reduced pressure and the resulting yellow oily solid was partitioned between EtOAc (250 mL) and water (100 mL) and the aqueous was washed with EtOAc (150 mL). The combined organics were washed with brine (50 mL), dried over magnesium sulfate, filtered and the was removed under reduced pressure to give 3,5-dibromo-1-methyl-1,2,4-triazole (6.2 g, 25.8 mmol, 58% yield) as a yellow solid. UPLC-MS (ES +, Method A): 1.79 min, m / z 241.7 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 3.83 (3H).

[0165] Intermediate 2: 3,5-Dibromo-1-ethyl-1,2,4-triazole [ka] Following the method described for Intermediate 1, a solution of 3,5-dibromo-1H-1,2,4-triazole (60 g, 266.88 mmol, 1.0 equiv), iodoethane (45.36 g, 293.52 mmol, 1.1 equiv) and KCO (73.2 g, 533.64 mmol, 2.0 equiv) in DMF (216 mL) gave, after workup, 3,5-dibromo-1-ethyl-1,2,4-triazole (59 g, 231.45 mmol, 88%). LC-MS (ES-API, Method N): 1.58 min, m / z, 254.1 [M] + . 1 H NMR (400 MHz, DMSO-d6) δ 4.18 (q, J = 7.2 Hz, 2H), 1.36 (t, J = 7.2 Hz, 3H).

[0166] Intermediate 3: 5-Amino-3,3-dimethyl-isoindolin-1-one [ka] [ka] Step 1: tert-Butyl 5-bromo-1-oxo-isoindoline-2-carboxylate A mixture of 5-bromo-2,3-dihydroisoindol-1-one (1 g, 4.72 mmol), di-tert-butyl dicarbonate (1.23 g, 5.66 mmol, 1.2 equiv), triethylamine (0.79 mL, 5.67 mmol, 1.2 equiv) and 4-dimethylaminopyridine DMAP (28.8 mg, 0.24 mmol, 0.05 equiv) in DCM (47 mL) was stirred overnight at 25° C. The mixture was concentrated and the residue was purified by flash chromatography eluting with 0-40% EtOAc in petroleum ether and concentrated under reduced pressure to give tert-butyl 5-bromo-1-oxo-isoindoline-2-carboxylate (1.40 g, 4.49 mmol, 95% yield) as a white solid. UPLC-MS (ES + , Method A): 1.79 min, m / z 255.9 [M-tBu] + 1 H NMR (400 MHz, CDCl3) δ 7.79-7.75 (1H, m), 7.66-7.61 (2H, m), 4.73 (2H, s), 1.60 (9H, s).

[0167] Step 2: tert-Butyl 6-bromo-1,1-dimethyl-3-oxo-isoindoline-2-carboxylate To a solution of tert-butyl 5-bromo-1-oxo-isoindoline-2-carboxylate (1000 mg, 3.2 mmol) in anhydrous THF (11 mL) at -20 °C under N2, sodium bis(trimethylsilyl)amide (2.0 M in THF, 4.8 mL, 9.6 mmol, 3.0 equiv) was added slowly while maintaining the reaction mixture below -20 °C. After stirring for 30 min, iodomethane (606.42 μL, 9.74 mmol, 3.0 equiv) was then added and the mixture was allowed to slowly warm to room temperature and stirred overnight. Methanol (1 mL) was carefully added and the mixture was concentrated under reduced pressure. The crude material was purified by flash column chromatography eluting with 0-30% EtOAc in petroleum ether to afford tert-butyl 6-bromo-1,1-dimethyl-3-oxo-isoindoline-2-carboxylate (770 mg, 2.26 mmol, 71% yield) as a pale yellow solid. UPLC-MS (ES + , Method A): 1.94 min, m / z 284.0 [M-tBu] +

[0168] Step 3: tert-Butyl 6-(tert-butoxycarbonylamino)-1,1-dimethyl-3-oxo-isoindoline-2-carboxylate A solution of a mixture of tert-butyl 6-bromo-1,1-dimethyl-3-oxoisoindoline-2-carboxylate (757 mg, 2.23 mmol, 1.0 equiv), tert-butyl carbamate (521 mg, 4.45 mmol, 2.0 equiv), Cs2CO3 (2.17 g, 6.675 mmol, 3.0 equiv), XantPhos (257 mg, 0.445 mmol, 0.2 equiv) and Pd(OAc)2 (50 mg, 0.2225 mmol, 0.1 equiv) in toluene (10 mL) was stirred at 110 °C under N2 overnight, cooled and concentrated under reduced pressure. Further purification by flash column chromatography eluting with 25% EtOAc in petroleum ether afforded tert-butyl 6-(tert-butoxycarbonylamino)-1,1-dimethyl-3-oxo-isoindoline-2-carboxylate (704 mg, 1.87 mmol, 84% yield). LC-MS (ES-API, Method D): 2.736 min, m / z 321.1 [M+H-tBu] + .

[0169] Step 4: 5-Amino-3,3-dimethyl-isoindolin-1-one A solution of tert-butyl 6-((tert-butoxycarbonyl)amino)-1,1-dimethyl-3-oxoisoindoline-2-carboxylate (704 mg, 1.87 mmol, 1.0 equiv) in 4 M hydrogen chloride in 1,4-dioxane (7 mL) was stirred at room temperature overnight. The mixture was diluted with aqueous NaHCO3 (15 mL) and extracted with EtOAc (8 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, and concentrated under reduced pressure to give 5-amino-3,3-dimethyl-isoindolin-1-one (220 mg, 1.25 mmol, 67% yield) as a yellow solid. LCMS (ES-API, Method D): 0.17 min, m / z 177.1 [M+H] + 1 H NMR (400 MHz, DMSO-d6) δ 8.00 (s, 1H), 7.23 (d, J = 8.9 Hz, 1H), 6.58-6.53 (m, 2H), 5.72 (s, 2H), 1.36 (s, 6H)

[0170] Intermediate 4: 5'-Aminospiro[cyclopropane-1,3'-isoindolin]-1'-one [ka] [ka] Step 1: 4-Bromo-2-(dibromomethyl)benzonitrile A solution of 4-bromo-2-methylbenzonitrile (100 g, 510 mmol, 1.0 equiv.), NBS (261 g, 1530 mmol, 2.0 equiv.) and BPO (12.36 g, 51 mmol, 0.1 equiv.) in CCl4 (1500 mL) was stirred at 85° C. overnight under N2 atmosphere. The reaction mixture was filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography eluting with EtOAc / petroleum ether (100:1) to give 4-bromo-2-(dibromomethyl)benzonitrile (133.5 g, 339 mmol, 66% yield). 1 H NMR (400 MHz, DMSO-d6) δ 8.09-8.06 (m, 1H), 7.98-7.93 (m, 1H), 7.89-7.84 (m, 1H), 7.42 (s, 1H).

[0171] Step 2: 4-Bromo-2-formyl-benzonitrile A solution of 4-bromo-2-(dibromomethyl)benzonitrile (124.3 g, 354 mmol, 1.0 equiv) and AgNO3 (150 g, 888 mmol, 3.0 equiv) in MeCN / H2O (200 mL / 80 mL) was stirred at 80 °C overnight, filtered, and concentrated. The crude material was purified by flash column chromatography (eluted with 0-5% EtOAc in petroleum ether) to give 4-bromo-2-formyl-benzonitrile (46 g, 219 mmol, 62% yield). 1 H NMR (400MHz, DMSO-d6) δ 10.09 (s, 1H), 8.37-8.35 (d, J = 2.1 Hz, 1H), 8.18-8.14 (dd, J = 8.1, 2.1 Hz, 1H), 8.07-8.02 (d, J = 8.4 Hz, 1H).

[0172] Step 3: 5-Bromo-3-methylene-isoindolin-1-one To a solution of iodo-trimethyl-oxo-lambda^{6}-sulfane (10.66 g, 48.45 mmol, 1.2 equiv) in dry DMSO (50 mL) and dry THF (30 mL), NaH (1.93 g, 48.45 mmol, 1.2 equiv) was added at 0° C. and stirred for 30 min, then a solution of 4-bromo-2-formylbenzonitrile (8.48 g, 40.38 mmol, 1.0 equiv) in dry DMSO (50 mL) and dry THF (30 mL) was added at 0° C. and stirred for 10 min. The mixture was quenched with saturated NH4Cl and extracted with EtOAc (150 mL×3). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated to give crude 5-bromo-3-methylene-isoindolin-1-one (7.35 g, 32.81 mmol, 81% yield), which was used in the next step without further purification. LCMS (ES-API, Method D): 1.64 min, m / z 224 / 226 [M] + / [M+2] + .

[0173] Step 4: 5'-Bromospiro[cyclopropane-1,3'-isoindolin]-1'-one To a solution of 5-bromo-3-methyleneisoindolin-1-one (1.0 g, 4.46 mmol) in DCM (25 mL) was added diethylzinc (27 mL, 27 mmol) at 0° C. under nitrogen. After stirring for 15 min, diiodomethane (4.5 mL, 54 mmol) and diethylzinc (27 mL, 27 mmol) were added at 0° C. After stirring for 5 min, additional diiodomethane (4.5 mL, 54 mmol) was added. The reaction mixture was then stirred at rt overnight, quenched with saturated aqueous NH4Cl, and extracted with DCM (100 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. Further purification by flash column chromatography eluting with DCM / MeOH (50:1) afforded 5'-bromospiro[cyclopropane-1,3'-isoindolin]-1'-one (480 mg, 2.02 mmol, 45% yield). LCMS (ES-API, Method C): 0.74 min, m / z 237.9 / 239.9 [M] + / [M+2]+ .

[0174] Step 5: tert-Butyl N-(1'-oxospiro[cyclopropane-1,3'-isoindoline]-5'-yl)carbamate To a solution of 5'-bromospiro[cyclopropane-1,3'-isoindolin]-1'-one (400 mg, 1.68 mmol, 1.0 equiv) and tert-butyl carbamate (394 mg, 3.36 mmol, 2.0 equiv) in toluene (20 mL) was added Pd(OAc)2 (38 mg, 0.168 mmol, 0.1 equiv) and Cs2CO3 (1.64 g, 5.04 mmol, 3.0 equiv) and Xant-Phos (194 mg, 0.336 mmol, 0.2 equiv). The mixture was then stirred at 110 °C under nitrogen overnight. The crude material was purified by flash column chromatography eluting with EtOAc / petroleum ether (2:1) to give tert-butyl N-(1'-oxospiro[cyclopropane-1,3'-isoindolin]-5'-yl)carbamate (220 mg, 0.80 mmol, 48% yield). LC-MS (ES-API, Method J): 0.62 min, m / z, 275.10 [M+H] + .

[0175] Step 6: 5'-aminospiro[cyclopropane-1,3'-isoindolin]-1'-one A mixture of tert-butyl N-(1'-oxospiro[cyclopropane-1,3'-isoindolin]-5'-yl)carbamate (1.6 g, 5.83 mmol, 1.0 equiv) and TFA (10 mL, 5.83 mmol, 1.0 equiv) in DCM was stirred at room temperature under N2 for 1 h. The pH of the mixture was adjusted to pH 8 with NaHCO3. The mixture was diluted with water (50 mL) and extracted with CHCl3 / iPrOH (3:1, 20 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude material was purified by flash column chromatography to give 5'-aminospiro[cyclopropane-1,3'-isoindolin]-1'-one (770 mg, 4.42 mmol, 76% yield). LC-MS (ES-API, Method K): 0.40 min, m / z,175.1 [M+H] + .

[0176] Intermediate 5: 5-Amino-3-methyl-isoindolin-1-one [ka] [ka] Step 1: 5-Bromo-3-methyl-isoindolin-1-one To a solution of 5-bromo-3-methyleneisoindolin-1-one (11 g, 49.1 mmol, 1.0 equiv) in dioxane (275 mL) and EtOH (275 mL) was added (PPh3)3RhCl (2.27, 2.45 mmol, 0.05 equiv) and the mixture was stirred at 50 °C under H2 atmosphere overnight. The mixture was concentrated under reduced pressure. The crude material was purified by flash column chromatography eluting with EtOAc in petroleum ether (20:1 to 3:1) to give 5-bromo-3-methyl-isoindolin-1-one (9.1 g, 40.25 mmol, 82% yield). LCMS (ES-API, Method D): 1.42 min, m / z 226.0 [M+H] + .

[0177] Step 2: tert-Butyl N-(3-methyl-1-oxo-isoindolin-5-yl)carbamate To a solution of 5-bromo-3-methylisoindolin-1-one (6.8 g, 30.1 mmol) and tert-butyl carbamate (7.05 g, 60.2 mmol, 2.0 equiv) in toluene (200 mL) was added Pd(OAc)2 (675 mg, 3.0 mmol, 0.1 equiv) and Cs2CO3 (29.4 g, 90.2 mmol, 3.0 equiv) and XantPhos (3.5 g, 6.0 mmol, 0.2 equiv) and the mixture was stirred at 110 °C under nitrogen overnight. The mixture was cooled and concentrated under reduced pressure. The crude material was purified by flash column chromatography eluting with EtOAc in petroleum ether (50:1 to 20:1) to give tert-butyl N-(3-methyl-1-oxo-isoindolin-5-yl)carbamate. LCMS (ES-API, Method D): 1.61 min, m / z 263.2 [M+H] + .

[0178] Step 3: 5-Amino-3-methyl-isoindolin-1-one To a solution of tert-butyl N-(3-methyl-1-oxoisoindolin-5-yl)carbamate (2.3 g, 8.76 mmol, 1.0 equiv) in MeOH (2 mL) was added 4 M HCl in 1,4-dioxane (6 mL). The mixture was stirred at rt overnight, adjusted to pH=8 with saturated sodium bicarbonate solution, and extracted with EtOAc (30 mL×5). The combined organic layers were washed with brine and dried over Na2SO4 to give 5-amino-3-methyl-isoindolin-1-one (1.28 g, 6.30 mmol, 72% yield). LCMS (ES-API, Method C): 0.32 min, m / z 163.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.99 (s, 1H), 7.28 (d, J = 9.1 Hz, 1H), 6.62-6.58 (m, 2H), 5.73 (s, 2H), 4.42 (q, J = 6.2 Hz, 1H), 1.30 (d, J = 6.6Hz, 3H).

[0179] Intermediate 6: 5-Amino-3,6-dimethylisoindolin-1-one [ka] [ka] Step 1a: (E)-N-(1-(3-bromo-4-methylphenyl)ethylidene)-2-methylpropane-2-sulfinamide Titanium ethoxide (148 g, 422.4 mmol, 1.5 equiv.) was added to a solution of 1-(3-bromo-4-methylphenyl)ethan-1-one (30 g, 140.8 mmol, 1.0 equiv.) and 2-methylpropane-2-sulfinamide (34 g, 281.6 mmol, 2.0 equiv.) in dry THF (600 mL), and the mixture was heated at 80° C. under N2 atmosphere overnight and then cooled to room temperature. The mixture was used directly in the next step without further treatment. LC-MS (ES-API, Method C): 1.95 min, m / z 316.0 / 318.0 [M] + / [M+2] + .

[0180] Step 1b: N-(1-(3-bromo-4-methylphenyl)ethyl)-2-methylpropane-2-sulfinamide NaBH4 (15.96 g, 422.4 mmol, 1.5 equiv.) was added to the crude mixture (E)-N-(1-(3-bromo-4-methylphenyl)ethylidene)-2-methylpropane-2-sulfinamide in THF at 0 °C under N2 atmosphere, then warmed to rt and stirred overnight. The mixture was quenched with MeOH (250 mL), diluted with NaHCO3 (sat. aq., 600 mL) and extracted with EtOAc (200 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4 and concentrated under reduced pressure to give crude N-(1-(3-bromo-4-methylphenyl)ethyl)-2-methylpropane-2-sulfinamide (37.6 g, 118 mmol, 84% for 2 steps) as a yellow solid, which was used directly in the next step without further purification. LC-MS (ES-API, Method C): 1.72 min, m / z 318.1 / 320.1 [M] + / [M+2] + .

[0181] Step 2: 1-(3-bromo-4-methylphenyl)ethan-1-amine To a solution of N-(1-(3-bromo-4-methylphenyl)ethyl)-2-methylpropane-2-sulfinamide (44 g, 138.25 mmol) in MeOH (38 mL) was added a solution of HCl in 1,4-dioxane (4 M, 38 mL). The reaction mixture was stirred at room temperature overnight, adjusted to pH 8 with saturated sodium bicarbonate solution at 0° C., extracted with EtOAc (300 mL×5), washed with brine, dried over Na2SO4, and concentrated to give crude 1-(3-bromo-4-methylphenyl)ethan-1-amine (assumed quantitative) as a yellow solid, which was used directly in the next step. 1 H NMR (400 MHz, CDCl3) δ 7.78 (s, 1H), 7.48-7.42 (m, 2H), 4.19-4.12 (m, 1H), 3.95-3.90 (m, 2H), 2.50 (s, 3H), 1.45-1.39 (d, J = 6.6 Hz, 3H).

[0182] Step 3: N-(1-(3-bromo-4-methylphenyl)ethyl)picolinamide A solution of 1-(3-bromo-4-methylphenyl)ethan-1-amine (25 g, 116.8 mmol, 1.0 equiv), picolinic acid (14.4 g, 116.8 mmol, 1.0 equiv), HATU (53.3 g, 140.1 mmol, 1.2 equiv) and DIEA (45.3 g, 350.3 mmol, 3.0 equiv) in DMF (250 mL) was stirred at room temperature overnight, diluted with water (1,000 mL) and extracted with EtOAc (200 mL x 3). The combined organic layers were washed with brine (200 mL), dried over Na2SO4 and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with 12.5% ​​EtOAc in petroleum ether to give crude N-(1-(3-bromo-4-methylphenyl)ethyl)picolinamide (37.3 g, 116.8 mmol, 62% yield over 4 steps) as a light yellow solid. LC-MS (ES-API, Method C): 1.75 min, m / z 319.1 / 321.1 [M] + / [M+2] + .

[0183] Step 4: 5-Bromo-3,6-dimethylisoindolin-1-one A solution of N-(1-(3-bromo-4-methylphenyl)ethyl)picolinamide (5.0 g, 1.0 equiv.), Co(OAc)2·4H2O (2.3 g, 0.6 equiv.), Ag2CO3 (25.9 g, 6.0 equiv.), PivOH (9.6 g, 6.0 equiv.) and DEAD (16.4 g, 6.0 equiv.) in TFE (10 V) was heated in a sealed tube at 120 °C for 16 h. The reaction mixture was then filtered through Celite and washed twice with EtOAc (5 V). Water (20 V) was added to the filtrate. The layers were separated and the organic layer was extracted twice with EtOAc (10 V). The combined organic layers were washed with brine (10 V), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column silica gel chromatography eluting with 5-35% EtOAc in n-heptane to give 5-bromo-3,6-dimethylisoindolin-1-one (2.4 g, 58% yield) as a yellow solid. LC-MS (ES-API, Method D): 1.71 min, m / z= 240.0 / 242.0 [M] + / [M+2] +

[0184] Step 5: tert-Butyl N-(3,6-dimethyl-1-oxoisoindolin-5-yl)carbamate A solution of 5-bromo-3,6-dimethyl-isoindolin-1-one (4.0 g, 16.8 mmol, 1.0 equiv), tert-butyl carbamate (3.91 g, 33.6 mmol, 2.0 equiv), Cs2CO3 (16.32 g, 50.4 mmol, 3.0 equiv), Xant-Phos (1.93 g, 3.36 mmol, 0.2 equiv) and Pd(OAc)2 (374 mg, 1.68 mmol, 0.1 equiv) in toluene (255 mL) was heated at 110 °C under N2 overnight. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with 2-5% MeOH in DCM to give tert-butyl (3,6-dimethyl-1-oxoisoindolin-5-yl)carbamate (3.46 g, 12.52 mmol, 75% yield) as a yellow solid. LC-MS (ES-API, Method D): 1.74 min, m / z 277.2 [M+H] + .

[0185] Step 6: 5-Amino-3,6-dimethylisoindolin-1-one A mixture of tert-butyl N-(3,6-dimethyl-1-oxoisoindolin-5-yl)carbamate (3.16 g, 11.4 mmol, 1 equiv.), MeOH (3 mL) and 4 M HCl in 1,4-dioxane (9 mL, 3 equiv.) was stirred at 25° C. overnight. The reaction was repeated using tert-butyl (3,6-dimethyl-1-oxoisoindolin-5-yl)carbamate (300 mg, 1.1 mmol), and the mixture was combined, diluted with saturated aqueous NaHCO3 (50 mL), and extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, and then concentrated under reduced pressure to give crude 5-amino-3,6-dimethylisoindolin-1-one (2.75 g, estimated quantitative) as a yellow solid. LC-MS (ES-API, Method D): 0.39 min, m / z 177.1 [M+H]+ . 1 H NMR (400 MHz, DMSO-d6) δ 7.92 (s, 1H), 7.16 (s, 1H), 6.62 (s, 1H), 5.43 (s, 2H), 4.38 (q, J = 6.6 Hz, 1H), 2.08 (s, 3H), 1.26 (d, J = 6.6Hz, 3H).

[0186] Intermediate 7: 5-Amino-6-fluoro-3-methylisoindolin-1-one [ka] Step 1: (E)-N-(1-(3-bromo-4-fluorophenyl)ethylidene)-2-methylpropane-2-sulfonamide Titanium ethoxide (43.7 g, 124 mmol, 3.0 equiv.) was added to a solution of 1-(3-bromo-4-fluorophenyl)ethan-1-one (9 g, 41.4 mmol, 1.0 equiv.) and 2-methylpropane-2-sulfinamide (9.9 g, 82.8 mmol, 2 equiv.) in THF (160 mL), and the mixture was heated at 80° C. under N2 atmosphere overnight and then cooled to room temperature. The mixture was used directly in the next step without further treatment. LC-MS (ES-API, Method C): 1.57 min, m / z 322.1 [M+2] +

[0187] Step 2: N-(1-(3-bromo-4-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide NaBH4 (4.7 g, 0.1 mol) was added to the mixture from the previous step at 0 °C under N2 atmosphere, then warmed to rt and stirred overnight. The reaction was quenched with MeOH (120 mL), diluted with NaHCO3 (sat. aq., 300 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4 and concentrated under reduced pressure to give crude N-(1-(3-bromo-4-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (12.9 g, 40.0 mmol) as a light yellow solid, which was used directly in the next step without further purification. LC-MS (ES-API, Method C): 1.32 min, m / z 322.1 [M] + 1 H NMR (400 MHz, DMSO-d6) δ 7.76 (dd, J = 2.1, 6.8 Hz, 1H), 7.48-7.43 (m, 1H), 7.34 (t, J = 8.6 Hz, 1H), 5.76 (d, J = 8.0 Hz, 1H), 4.45-4.37 (m, 1H), 1.39 (d, J = 7.2 Hz, 3H), 1.13 (s, 9H)

[0188] Step 3: 1-(3-bromo-4-fluorophenyl)ethan-1-amine HCl (4M in 1,4-dioxane, 20 mL) was added to a solution of N-[1-(3-bromo-4-fluoro-phenyl)ethyl]-2-methyl-propane-2-sulfinamide (11.92 g, 37.0 mmol) in MeOH (20 mL) and the mixture was stirred at room temperature overnight. The mixture was diluted with NaHCO3 (saturated aqueous, 100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4 and concentrated under reduced pressure to give crude 1-(3-bromo-4-fluorophenyl)ethan-1-amine (8.74 g) as an orange oil, which was used in the next step without further purification. LC-MS (ES-API, Method C): 0.35 min, m / z= 218.0 / 220.0 [M] + / [M+2]+ 1 H NMR (400 MHz, DMSO-d6) δ 7.68 (dd, J = 1.7, 6.9 Hz, 1H), 7.40-7.34 (m, 1H), 7.26 (t, J = 8.7 Hz, 1H), 4.04-3.95 (m, 1H), 1.21 (d, J = 6.6Hz, 3H)

[0189] Step 4: N-[1-(3-bromo-4-fluoro-phenyl)ethyl]pyridine-2-carboxamide A solution of 1-(3-bromo-4-fluoro-phenyl)ethanamine (8.74 g, 40.1 mmol), picolinic acid (5.43 g, 44.1 mmol), HATU (18.26 g, 48.1 mmol) and DIPEA (15.59 g, 120.3 mmol) in DMF (100 mL) was stirred at room temperature overnight. The mixture was diluted with water (1,000 mL), extracted with EtOAc (100 mL×3), and the combined organic layers were washed with brine (50 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with 5% MeOH in DCM to give N-[1-(3-bromo-4-fluoro-phenyl)ethyl]pyridine-2-carboxamide (9.3 g, 69% yield over 4 steps) as a light yellow solid. LC-MS (ES-API, Method C): 1.61 min, m / z= 323.0 / 325.0 [M+H] + 1 H NMR (400 MHz, DMSO-d6) δ 9.20 (d, J = 8.5 Hz, 1H), 8.69 (d, J =4.7 Hz, 1H), 8.03-7.98 (m, 2H), 7.80 (dd, J = 2.1, 6.9 Hz, 1H), 7.66-7.61 (m, 1H), 7.52-7.46 (m, 1H), 7.33 (t, J = 8.8 Hz, 1H), 5.23-5.14 (m, 1H), 1.53 (d, J = 7.9 Hz, 3H)

[0190] Step 5: 5-Bromo-6-fluoro-3-methylisoindolin-1-one A solution of N-[1-(3-bromo-4-fluoro-phenyl)ethyl]pyridine-2-carboxamide (5.0 g, 1.0 equiv.), Co(OAc)2(H2O)4 (2.3 g, 0.6 equiv.), Ag2CO3 (25.6 g, 6.0 equiv.), pivalic acid (9.5 g, 6.0 equiv.) and DEAD (16.2 g, 6.0 equiv.) in 2,2,2-trifluoroethanol (10 V) was heated at 120° C. in a sealed tube for 16 h. The reaction mixture was then filtered through Celite and washed twice with EtOAc (5 V). Water (20 V) was added to the filtrate. The layers were separated and the organic layer was extracted twice with EtOAc (10 V). The combined organic layers were washed with brine (10 V), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column silica gel chromatography eluting with 5-30% EtOAc in n-heptane to give 5-bromo-6-fluoro-3-methylisoindolin-1-one (2.1 g, 49% yield) as a light yellow solid. LC-MS (ES-API, Method C): 0.69 min, m / z= 244.0 / 246.0 [M] + / [M+2] + 1 H NMR (400 MHz, DMSO-d6) δ 8.87 (s, 1H), 8.04 (d, J = 6.1 Hz, 1H), 7.57 (d, J = 7.7 Hz, 1H), 4.64 (q, J = 6.9 Hz, 1H), 1.38 (d, J = 6.4 Hz, 3H)

[0191] Step 6: tert-Butyl N-(6-fluoro-3-methyl-1-oxoisoindolin-5-yl)carbamate A solution of 5-bromo-6-fluoro-3-methyl-isoindolin-1-one (2.5 g, 10.2 mmol), tert-butyl carbamate (2.4 g, 20.4 mmol), Pd(OAc)2 (230 mg, 1.02 mmol), XantPhos (1.2 g, 2.04 mmol) and Cs2CO3 (10 g, 30.6 mmol) in toluene (80 mL) was heated at 110° C. under N2 overnight. The mixture was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel eluting with 2% MeOH in DCM to give tert-butyl (6-fluoro-3-methyl-1-oxoisoindolin-5-yl)carbamate (1.58 g, 60% for two steps) as an orange solid. LC-MS (ES-API, Method D): 1.77 min, m / z= 281.1 [M+H] + 1 H NMR (400 MHz, DMSO-d6) δ 9.27 (s, 1H), 8.65 (s, 1H), 7.94 (d, J = 6.8 Hz, 1H), 7.44-7.41 (m, 1H), 4.60 (q, J = 6.4 Hz, 1H), 1.50 (s, 9H), 1.35 (d, J = 7.1 Hz, 3H)

[0192] Step 7: 5-Amino-6-fluoro-3-methylisoindolin-1-one A mixture of tert-butyl N-(6-fluoro-3-methyl-1-oxo-isoindolin-5-yl)carbamate (1.58 g, 5.6 mmol), MeOH (3 mL) and 4 M HCl in 1,4-dioxane (9 mL) was stirred at 25° C. overnight. The mixture was diluted with NaHCO3 (saturated aqueous, 100 mL), extracted with CHCl3 / iPrOH (3:1, v / v, 60 mL×3) and the combined organic layers were washed with brine (20 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was slurried with EtOAc (6 mL) and collected by filtration to give 5-amino-6-fluoro-3-methylisoindolin-1-one (500 mg, 49%) as a brown solid. LC-MS (ES-API, Method C): 0.42 min, m / z= 181.1 [M+H] + 1 H NMR (400 MHz, DMSO-d6) δ 8.17 (s, 1H), 7.15 (d, J = 10.4 Hz, 1H), 6.79 (d, J = 7.6 Hz, 1H), 5.76 (s, 2H), 4.43 (q, J = 6.8 Hz, 1H), 1.27 (d, J = 6.8 Hz, 3H)

[0193] Compounds prepared in a similar manner to that described above are shown in the table below. [Table 22]

[0194] [ka]

[0195] Intermediate 9: 5-[(5-bromo-2-ethyl-1,2,4-triazol-3-yl)amino]isoindolin-1-one [ka] A solution of 5-aminoisoindolin-1-one (4.3 g, 29.02 mmol, 1.0 equiv), 3,5-dibromo-1-ethyl-1H-1,2,4-triazole (7.77 g, 30.47 mmol, 1.05 equiv) and NaHMDS (15.97 g, 87.07 mmol, 3.0 equiv) in DMF (80 mL) was stirred at -30 °C for ½ h and at rt under N2 overnight. The mixture was diluted with NH4Cl (300 mL) and extracted with EtOAc (200 mL). The combined organic layers were washed with brine (200 mL), dried over Na2SO4 and concentrated under reduced pressure to give 5-[(5-bromo-2-ethyl-1,2,4-triazol-3-yl)amino]isoindolin-1-one (5.5 g, 17.07 mmol, 59%). LC-MS (ES-API, Method D): 1.20 min, m / z= 322.1 / 324.0 [M] + / [M+2] + 1 H NMR (400 MHz, DMSO-d6) δ 9.51 (s, 1H), 8.32 (s, 1H), 7.83 (s, 1H), 7.65-7.57 (m, 2H), 4.37 (s, 2H), 4.21-4.16 (m, 2H), 1.34 (t, J = 7.0Hz, 3H)

[0196] Intermediate 10: 5-[(5-bromo-2-ethyl-1,2,4-triazol-3-yl)amino]-3,6-dimethyl-isoindolin-1-one [ka] To a solution of 5-amino-3,6-dimethylisoindolin-1-one (5.5 g, 31.21 mmol) and 3,5-dibromo-1-ethyl-1H-1,2,4-triazole (7.96 mg, 31.21 mmol) in dry DMF (75 mL) was added NaHMDS (2 M in THF, 46.8 mL, 93.6 mmol). The mixture was incubated at -20 °C under N2 for 15 min. The mixture was then allowed to continue reaction at rt under N2 overnight. The mixture was diluted with water (800 mL) at 0 °C, extracted with EtOAc (200 mL × 5), washed with brine, dried over Na2SO4 and concentrated under reduced pressure to give crude 5-[(5-bromo-2-ethyl-1,2,4-triazol-3-yl)amino]-3,6-dimethyl-isoindolin-1-one as a yellow solid (5.45 g, 80% purity). LC-MS (ES-API, Method D): 1.33 min, m / z= 350.1 / 352.1 [M] + / [M+2] + 1H NMR (400 MHz, DMSO-d6) δ 8.48 (s, 1H), 8.45 (s, 1H), 7.49 (s, 1H), 7.42 (s, 1H), 4.58 (q, J = 6.5 Hz, 1H), 4.09 (q, J = 7.5 Hz, 2H), 2.31 (s, 3H), 1.38-1.32 (m, 6H)

[0197] Intermediate 11: 5-[(5-bromo-2-ethyl-1,2,4-triazol-3-yl)amino]-3-methyl-isoindolin-1-one [ka] To a solution of 5-amino-3-methylisoindolin-1-one (1.28 g, 7.88 mmol) and 3,5-dibromo-1-ethyl-1H-1,2,4-triazole (2.00 g, 7.88 mmol) in dry DMF (16 mL) was added NaHMDS (2 M in THF, 11.8 mL, 23.6 mmol). The mixture was stirred at -20 °C with N2 for 15 min and then returned to rt with N2 overnight. The mixture was concentrated and the residue was purified by flash column chromatography (SiO2) eluting with MeOH in DCM (70:1 to 30:1) to give 5-[(5-bromo-2-ethyl-1,2,4-triazol-3-yl)amino]-3-methyl-isoindolin-1-one (1.98 g, 5.89 mmol, 75%) as a light yellow solid. LCMS (ES-API, Method D): 1.27 min, m / z= 336.1 / 338.1 [M] + / [M+2] + 1 H NMR (400 MHz, DMSO-d6) δ 9.47 (s, 1H), 8.42 (s, 1H), 7.69 (s, 1H), 7.64-7.56 (m, 2H), 4.62 (q, J = 6.7 Hz, 1H), 4.16 (q, J = 6.9 Hz, 2H), 1.38-1.33 (m, 6H)

[0198] Intermediate 12: 5-[(5-bromo-2-ethyl-1,2,4-triazol-3-yl)amino]-6-fluoro-isoindolin-1-one [ka] To a solution of 5-amino-6-fluoro-isoindolin-1-one (73 mg, 0.44 mmol, 1.0 equiv.) and 3,5-dibromo-1-ethyl-1H-1,2,4-triazole (118 mg, 0.46 mmol) in DMF (3 mL), NaHMDS (2 M in THF, 0.7 mL, 1.4 mmol) was added at -30 °C under N2, warmed to rt and stirred overnight. The mixture was diluted with saturated NH4Cl (50 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, and concentrated under reduced pressure to give 5-[(5-bromo-2-ethyl-1,2,4-triazol-3-yl)amino]-6-fluoro-isoindolin-1-one as an orange solid (0.14 g, 0.421 mmol, 93%). LC-MS (ES-API, Method D): 1.14 min, m / z= 340.1 / 342.1 [M] + / [M+2] +

[0199] Intermediate 13: 5-[(5-bromo-2-ethyl-1,2,4-triazol-3-yl)amino]-6-fluoro-3-methyl-isoindolin-1-one [ka] To a solution of 5-amino-6-fluoro-3-methyl-isoindolin-1-one (100 mg, 0.56 mmol, 1.0 equiv.) and 3,5-dibromo-1-ethyl-1H-1,2,4-triazole (148 mg, 0.58 mmol) in DMF (5 mL) was added NaHMDS (2 M in THF, 0.83 mL, 1.7 mmol) at -30 °C under N2, warmed to rt and stirred overnight. The mixture was diluted with saturated NH4Cl (50 mL), extracted with EtOAc (10 mL x 3), and the combined organic layers were washed with brine (10 mL), dried over Na2SO4, and concentrated under reduced pressure to give 5-[(5-bromo-2-ethyl-1,2,4-triazol-3-yl)amino]-6-fluoro-3-methyl-isoindolin-1-one (0.17 g, 0.50 mmol, 90%). LC-MS (ES-API, Method D): 1.33 min, m / z= 354.1 / 356.1 [M] + / [M+2] + 1 H NMR (400 MHz, DMSO-d6) δ 9.26 (s, 1H), 8.70 (s, 1H), 7.84 (d, J = 7.6 Hz, 1H), 7.55 (d, J = 10.1 Hz, 1H), 4.71 (q, J = 6.4 Hz, 1H), 4.23 (q, J = 7.5 Hz, 2H), 1.47-1.40 (m, 6H)

[0200] Compounds prepared in a similar manner to that described above are shown in Table 2 below. [Table 23] [Table 24]

[0201] General method Intermediate 18: 5-Methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyridine [ka] Step 1: 4-(5-methylpyridin-2-yl)phenol A solution of 2-bromo-5-methylpyridine (3.0 g, 17.4 mmol), (4-hydroxyphenyl)boronic acid (2.89 g, 20.9 mmol), Pd(dppf)Cl2DCM (1.42 g, 1.74 mmol) and K2CO3 (3.62 g, 26.1 mmol) in 1,4-dioxane / HO (90 mL / 10 mL) was stirred at 100 °C under N2 atmosphere overnight. The mixture was cooled to room temperature and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with 50% EtOAc in petroleum ether to give 4-(5-methylpyridin-2-yl)phenol (1.44 g, 45%) as an off-white solid. LC-MS (ES-API, Method C): 0.40 min, m / z= 185.1 [M+H] + 1 H NMR (400 MHz, DMSO-d6) δ 9.67 (s, 1H), 8.44 (s, 1H), 7.91 (d, J = 9.4 Hz, 2H), 7.74 (d, J = 7.8 Hz, 1H), 7.63 (dd, J = 2.1, 8.0 Hz, 1H), 6.86 (d, J = 8.6 Hz, 2H), 2.33 (s, 3H)

[0202] Step 2: 4-(5-methylpyridin-2-yl)phenyl trifluoromethanesulfonate To a mixture of 4-(5-methylpyridin-2-yl)phenol (1.34 g, 7.2 mmol) and TEA (2.2 g, 21.6 mmol) in DCM (30 mL) was slowly added trifluoromethanesulfonic anhydride (3.1 g, 11.0 mmol) at 0° C. The resulting mixture was stirred at 0° C. for 0.5 h and then at rt under N2 atmosphere overnight. The mixture was diluted with water (100 mL) and extracted with DCM (20 mL×3). The combined organic layers were washed with brine (80 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by column silica gel chromatography eluting with 25% EtOAc in petroleum ether to give 4-(5-methylpyridin-2-yl)phenyl trifluoromethanesulfonate (1.94 g, 85%) as a brown oil. LC-MS (ES-API, Method C): 2.00 min, m / z= 318.1 [M+H] + 1 H NMR (400 MHz, DMSO-d6) δ 8.55 (s, 1H), 8.25 (d, J = 9.0 Hz, 2H), 7.95 (d, J = 8.2 Hz, 1H), 7.76 (dd, J = 1.8, 8.0 Hz, 1H), 7.61 (d, J = 8.9 Hz, 2H), 2.37 (s, 3H)

[0203] Step 3: 5-Methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyridine A mixture of 4-(5-methylpyridin-2-yl)phenyl trifluoromethanesulfonate (1.7 g, 5.4 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (2.72 g, 10.7 mmol), Pd(dppf)Cl2DCM (438 mg, 0.54 mmol) and potassium acetate (1.58 g, 16.2 mmol) in 1,4-dioxane (75 mL) was stirred at 90 °C under N2 atmosphere overnight. The mixture was concentrated under reduced pressure and the crude material was purified by column chromatography on silica gel eluting with 25% EtOAc in petroleum ether to give 5-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyridine (1.8 g, assumed quantitative) as a brown solid which was used in the next step without further purification. LC-MS (ES-API, Method C): 1.70 min, m / z= 296.2 [M+H] + 1 H NMR (400 MHz, DMSO-d6) δ 8.51 (d, J = 1.6 Hz, 1H), 8.07 (d, J = 8.4 Hz, 2H), 7.88 (d, J = 8.0 Hz, 1H), 7.77 (d, J = 8.0 Hz, 2H), 7.71-7.69 (m, 1H), 2.34 (s, 3H), 1.31 (s, 12H)

[0204] Intermediate 19: 2-Methyl-5-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyridine [ka] Step 1: 3-Methyl-4-(6-methyl-3-pyridyl)phenol A solution of 5-bromo-2-methylpyridine (1.89 g, 10.99 mmol), (4-hydroxy-2-methylphenyl)boronic acid (2 g, 13.16 mmol), K2CO3 (2.3 g, 16.44 mmol) and Pd(dppf)Cl2.DCM (897 mg, 1.10 mmol) in 1,4-dioxane / H2O (45 mL / 5 mL) was stirred at 100 °C under N2 atmosphere overnight. The mixture was cooled to room temperature and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with 1-2.5% MeOH in DCM to give 3-methyl-4-(6-methyl-3-pyridyl)phenol (1.16 g, 53%) as a yellow solid. LC-MS (ES-API, Method D: ) 0.33 min, m / z= 200.1 [M+H] + 1 H NMR (400 MHz, DMSO-d6) δ 9.42 (s, 1H), 8.35 (d, J = 2.0 Hz, 1H), 7.60 (dd, J = 2.3, 7.8 Hz, 1H), 7.27 (d, J = 7.9 Hz, 1H), 7.02 (d, J = 8.5 Hz, 1H), 6.72-6.70 (m, 1H), 6.69-6.66 (m, 1H), 2.49 (s, 3H), 2.15 (s, 3H)

[0205] Step 2: [3-methyl-4-(6-methyl-3-pyridyl)phenyl]trifluoromethanesulfonate To a mixture of 3-methyl-4-(6-methylpyridin-3-yl)phenol (1.1 g, 5.52 mmol) and TEA (1.67 g, 16.56 mmol) in dry DCM (15 mL) was slowly added trifluoromethanesulfonic anhydride (2.3 g, 8.15 mmol) at 0° C. The resulting mixture was stirred at 0° C. for 0.5 h and then at room temperature overnight under N2 atmosphere. The mixture was diluted with water (30 mL) and extracted with DCM (15 mL×2). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by column silica gel chromatography eluting with 10% EtOAc in petroleum ether to give [3-methyl-4-(6-methyl-3-pyridyl)phenyl]trifluoromethanesulfonate (716 mg, 39%) as a yellow oil. LC-MS (ES-API, Method C): 1.09 min, m / z= 332.1 [M+H] + 1 H NMR (400 MHz, DMSO-d6) δ 8.44 (d, J = 1.8 Hz, 1H), 7.72 (dd, J = 2.5, 8.0 Hz, 1H), 7.49 (s, 1H), 7.42-7.39 (m, 2H), 7.34 (d, J = 7.8 Hz, 1H), 2.52 (s, 3H), 2.28 (s, 3H)

[0206] Step 3: 2-Methyl-5-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyridine A mixture of 3-methyl-4-(6-methylpyridin-3-yl)phenyl trifluoromethanesulfonate (705 mg, 2.12 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.08 g, 4.25 mmol), Pd(dppf)Cl2.DCM (173 mg, 0.212 mmol) and potassium acetate (626 mg, 6.38 mmol) in 1,4-dioxane (25 mL) was stirred at 90° C. under N2 atmosphere overnight. The mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with 10-25% EtOAc in petroleum ether to give 2-methyl-5-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyridine (707 mg, assumed quantitative) as a light yellow oil. LC-MS (ES-API, Method C): 0.24 min, m / z= 228.1 (boronic acid), 0.93 min, m / z= 310.2 [M+H] + 1 H NMR (400 MHz, DMSO-d6) δ 8.41 (d, J = 2.3 Hz, 1H), 7.67 (dd, J = 8.0, 2.4 Hz, 1H), 7.62 (s, 1H), 7.56 (d, J = 7.5 Hz, 1H), 7.33 (d, J = 8.0 Hz, 1H), 7.23 (d, J = 7.5 Hz, 1H), 2.52 (s, 3H), 2.24 (s, 3H), 1.31 (s, 12H)

[0207] Intermediate 20: 5-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-(trifluoromethyl)pyridine [ka] Step 1: [4-[2-(trifluoromethyl)pyridin-4-yl]phenol [ka] To a solution of trifluoromethyl-5-bromo-2-pyridine (5.0 g, 22.1 mmol) and 4-hydroxybenzeneboronic acid (3.36 g, 24.3 mmol) in 1,4-dioxane (110 mL) was added a solution of K2CO3 (9.17 g, 66.4 mmol) in water (33 mL) and the mixture was degassed with N2 for 10 min. [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride DCM complex (1.81 g, 2.21 mmol) was then added and the mixture was heated at 80 °C overnight. After cooling to rt, the mixture was concentrated under reduced pressure and EtOAc (200 mL) was added. The mixture was filtered through Celite and washed thoroughly with EtOAc. The filtrate was washed with water and brine (50 mL each), dried (Na2SO4), filtered and then concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO2) eluting with EtOAc in petroleum ether (0-40%) to afford 4-[6-(trifluoromethyl)-3-pyridyl]phenol (5.13 g, 97%) as an off-white solid. UPLC-MS (ES + , Method A): 1.57 min, m / z= 240.2 [M+H] + 1 H NMR (400MHz, DMSO-d6) δ 9.85 (s, 1H), 9.02 (d, J = 2.1 Hz, 1H), 8.26 (dd, J = 8.2, 2.1 Hz, 1H), 7.91 (d, J = 8.2 Hz, 1H), 7.69-7.64 (m, 2H), 6.94-6.90 (m, 2H)

[0208] Step 2: [4-[6-(trifluoromethyl)-3-pyridyl]phenyl]trifluoromethanesulfonate [ka] To a solution of 4-[6-(trifluoromethyl)-3-pyridyl]phenol (4.6 g, 19.2 mmol) in anhydrous pyridine (48 mL) under N2 was added K2CO3 (2.66 g, 19.2 mmol) followed by N-phenylbis-trifluoromethanesulfonimide (6.87 g, 19.2 mmol) in portions. The mixture was stirred at 25 °C for 3 days. The mixture was reduced in vacuum and the residue partitioned between saturated aqueous (Na2CO3) solution (50 mL) and EtOAc (100 mL). The aqueous layer was extracted with EtOAc (50 mL). The combined organic phases were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by silica chromatography eluting with EtOAc in petroleum ether (0-30%) to give [4-[6-(trifluoromethyl)-3-pyridyl]phenyl]trifluoromethanesulfonate (6.27 g, 88%) as a colorless oil that solidified on standing. UPLC-MS (ES + , Method A): 2.01 min, m / z= 372.1 [M+H] + 1 H NMR (400MHz, DMSO-d6) δ 9.13 (d, J = 2.0 Hz, 1H), 8.42 (dd, J = 8.1, 2.0 Hz, 1H), 8.05-8.00 (m, 3H), 7.72-7.67 (m, 2H)

[0209] Step 3: 5-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-(trifluoromethyl)pyridine [ka] A solution of [4-[6-(trifluoromethyl)-3-pyridyl]phenyl]trifluoromethanesulfonate (6.27 g, 16.9 mmol), bis(pinacolato)diboron (6.44 g, 25.4 mmol) and KOAc (4.98 g, 50.7 mmol) in 1,4-dioxane (80 mL) was degassed with N2 for 10 min, then [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride DCM complex (1.38 g, 1.69 mmol) was added and the mixture was heated at 80° C. for 2 h. After cooling to rt, the mixture was filtered through Celite and washed with EtOAc. The filtrate was reduced in vacuo and the residue was purified by flash column chromatography (SiO2) eluting with 0–100% DCM in petroleum ether to give 5-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-(trifluoromethyl)-pyridine (5.59 g, 16.0 mmol, 95%) as a white solid. UPLC-MS (ES + , Method A): 2.15 minutes, m / z= 350.0 [M+H] + 1 H NMR (400MHz, DMSO-d6) δ 9.11 (d, J = 2.1 Hz, 1H), 8.39 (dd, J = 8.2, 2.1 Hz, 1H), 8.00 (d, J = 8.2 Hz, 1H), 7.87-7.81 (m, 4H), 1.32 (s, 12H)

[0210] Intermediate 21: 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-(trifluoromethyl)pyridine [ka] Step 1: 4-[2-(trifluoromethyl)-4-pyridyl]phenol [ka] 4-Bromo-2-(trifluoromethyl)pyridine (9.5 g, 42.0 mmol), K2CO3 (17.5 g, 127 mmol) and 4-hydroxybenzeneboronic acid (6.38 g, 46.3 mmol) were combined in 1,4-dioxane (100 mL) and water (20 mL). The reaction mixture was degassed with N2 for 10 min, then [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride DCM complex (3.43 g, 4.2 mmol) was added and the reaction mixture was heated at 80 °C for 1 h. After cooling to rt, the reaction mixture was concentrated under reduced pressure. The residue was diluted with EtOAc, filtered through Celite and then evaporated to dryness under reduced pressure. The residue was purified by flash column chromatography (SiO2) eluting with EtOAc in petroleum ether (0-40%) to give 4-[2-(trifluoromethyl)-4-pyridyl]phenol (9.19 g, 38.4 mmol, 91%) as a grey solid. UPLC-MS (ES + , Method A): 1.59 min, m / z= 240.1 [M+H] + 1 H NMR (400 MHz, DMSO-d6) δ 10.00 (s, 1H), 8.73 (d, J =5.5 Hz, 1H), 8.08 (d, J =1.2 Hz, 1H), 7.96 (dd, J = 1.2, 5.5 Hz, 1H), 7.83-7.79 (m, 2H), 6.94- 6.90 (m, 2H)

[0211] Step 2: [4-[2-(trifluoromethyl)-4-pyridyl]phenyl]trifluoromethanesulfonate [ka] Trifluoromethanesulfonic anhydride (7.11 mL, 42.2 mmol) was added to a solution of 4-[2-(trifluoromethyl)-4-pyridyl]phenol (9.19 g, 38.4 mmol) and TEA (7.43 mL, 50 mmol) in DCM (200 mL) at 0 °C under N2. The reaction mixture was warmed to rt and after 30 min the reaction was poured into water. The organic layer was separated, washed with saturated aqueous NaHCO3, saturated aqueous NH4Cl, dried (Na2SO4), filtered and concentrated under reduced pressure to give [4-[2-(trifluoromethyl)-4-pyridyl]phenyl]trifluoromethanesulfonate (13.46 g, 36.3 mmol, 94%) as a yellow oil. UPLC-MS (ES+, method A): 2.01 min, m / z= 372.2 [M+H] + 1 H NMR (400 MHz, CDCl3) δ 8.82 (d, J = 5.2Hz, 1H), 7.88-7.86 (m, 1H), 7.77-7.73 (m, 2H), 7.69-7.66 (m, 1H), 7.48-7.44 (m, 2H)

[0212] Step 3: 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-(trifluoromethyl)pyridine [ka] [4-[2-(trifluoromethyl)-4-pyridyl]phenyl]trifluoromethanesulfonate (13.46 g, 36.3 mmol), bis(pinacolato)diboron (13.8 g, 54.4 mmol) and KOAc (10.7 g, 109 mmol) were combined in 1,4-dioxane (90 mL) and the reaction mixture was degassed with N2. [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride DCM complex (2.96 g, 3.63 mmol) was added and the mixture was heated at 80 °C for 2 h. After cooling to rt, the mixture was filtered through Celite and then washed with EtOAc. After evaporation of the solvent, the residue was purified by flash column chromatography (SiO2) eluting with EtOAc in petroleum ether (0–100%) to give 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-(trifluoromethyl)pyridine (12.6 g, 36.1 mmol, 99%) as a colorless oil. UPLC-MS (ES + , Method A): 2.15 minutes, m / z= 350.0 [M+H] + 1 H NMR (400 MHz, CDCl3) δ 8.78 (d, J = 4.4 Hz, 1H), 7.95 (d, J = 8.4Hz, 2H), 7.92-7.90 (m, 1H), 7.72-7.70 (m, 1H), 7.66 (d, J = 8.4Hz, 2H), 1.38 (s, 12H)

[0213] Compounds prepared in a similar manner to that described above are shown in Table 3 below. [Table 25] [Table 26] [Table 27] [Table 28] [Table 29] [Table 30] [Table 31]

[0214] Intermediate 57: 4-Methyl-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]imidazole [ka] Step 1: 1-(4-bromoanilino)propan-2-one [ka] KI (1.59 g, 9.6 mmol) and K2CO3 (1.45 g, 10.5 mmol) were added to a solution of 4-bromoaniline (1.5 g, 8.7 mmol) in DMF (17.4 mL) under N2, the reaction mixture was stirred for 5 min at 20 °C, after which chloroacetone (1.56 mL, 19.6 mmol) was added. The reaction mixture was then stirred at 20 °C for 1 h. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between EtOAc and water. The two phases were separated and the water was re-extracted with EtOAc. The organic extracts were combined, washed with brine and filtered through phase separation filter paper. The crude material was purified by flash column chromatography (silica) eluting with EtOAc in petroleum ether (0-60%) to give 1-(4-bromoanilino)propan-2-one (701 mg, 3.07 mmol, 35% yield) as a yellow solid. UPLC-MS (ES + , Method A): 1.62 min, m / z= 227.9 / 229.8 [M] + / [M+2] + 1H NMR (400 MHz, CDCl3) δ 7.30-7.22 (m, 2H), 6.50-6.44 (m, 2H), 4.61 (br s, 1H), 3.97 (d, J = 4.4 Hz, 2H), 2.26 (s, 3H)

[0215] Step 2: N-acetonyl-N-(4-bromophenyl)formamide [ka] Formic acid (2.5 mL, 66.4 mmol) and acetic anhydride (6.3 mL, 66.4 mmol) were heated at 60° C. for 15 min. The solution was then cooled at 0° C. and 1-(4-bromoanilino)propan-2-one (0.13 mL, 3.07 mmol) was added. The mixture was heated at 60° C. for 1 h. The reaction mixture was cooled at rt and concentrated under reduced pressure. The residue was partitioned into EtOAc and saturated aqueous NaHCO3 was added. The two phases were separated and the aqueous phase was re-extracted with EtOAc. The combined organic extracts were washed with brine, filtered through phase separation paper and concentrated under reduced pressure to give N-acetonyl-N-(4-bromophenyl)formamide (676 mg, 2.64 mmol, 86% yield) as a yellow oil. UPLC-MS (ES + , Method A): 1.43 min, m / z= 255.9 / 257.8 [M] + / [M+2] + 1 H NMR (400 MHz, CDCl3) δ 8.46 (s, 1H), 7.57-7.50 (m, 2H), 7.10-7.02 (m, 2H), 4.52 (s, 2H), 2.22 (s, 3H)

[0216] Step 3: 1-(4-bromophenyl)-4-methyl-imidazole [ka] TEA (0.37 mL, 2.64 mmol) and NHOAc (2.04 g, 26.4 mmol) were added successively to a suspension of N-acetonyl-N-(4-bromophenyl)formamide (676 mg, 2.64 mmol) in 1-butanol (13 mL). The vial was sealed and the mixture was heated at 150 °C for 45 min. The reaction mixture was cooled to rt and then concentrated under reduced pressure. The residue was partitioned between EtOAc and water. The two phases were separated and the aqueous phase was re-extracted with EtOAc. The combined organic extracts were washed with brine, filtered through a phase separation filter paper and then concentrated under reduced pressure. The crude material was purified by flash column chromatography (silica) eluting with EtOAc in petroleum ether (0-100%) to give 1-(4-bromophenyl)-4-methyl-imidazole (351 mg, 1.48 mmol, 56% yield) as a yellow solid. UPLC-MS (ES + , Method A): 1.12 min, m / z= 236.9 / 238.8 [M] + / [M+2] + 1 H NMR (400 MHz, CDCl3) δ 7.76 (d, J = 1.3 Hz, 1H), 7.62-7.56 (m, 2H), 7.27-7.21 (m, 2H), 6.98-6.96 (m, 1H), 2.29 (d, J = 1.0 Hz, 3H)

[0217] Step 4: 4-Methyl-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]imidazole [ka] 1-(4-Bromophenyl)-4-methyl-imidazole (351 mg, 1.48 mmol), bis(pinacolato)diboron (564 mg, 2.22 mmol) and KOAc (436 mg, 4.44 mmol) were combined in 1,4-dioxane (15 mL). The reaction mixture was degassed with N2, then [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride DCM complex (60 mg, 0.07 mmol) was added. The reaction mixture was heated at 100°C overnight. After cooling to rt, the reaction mixture was filtered through Celite and washed with EtOAc. The filtrate was concentrated under reduced pressure and the crude material was purified by flash column chromatography (silica) eluting with EtOAc in petroleum ether (0-100%) to give 4-methyl-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]imidazole (189 mg, 0.66 mmol, 45% yield) as a brown oil. UPLC-MS (ES + , Method A): 1.36 min, m / z- 284.9 [M+H] + 1 H NMR (400 MHz, CDCl3) δ 7.92-7.86 (m, 2H), 7.81 (d, J = 1.4 Hz, 1H), 7.39-7.32 (m, 2H), 7.05-7.04 (m, 1H), 2.30 (d, J = 1.0 Hz, 3H), 1.36 (s, 12H)

[0218] Intermediate 58: 4-Cyclopropyl-1-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]imidazole [ka] Step 1: 2-(4-Bromo-2-methyl-anilino)-1-cyclopropyl-ethanone [ka] K2CO3 (446 mg, 3.2 mmol) and KI (491 mg, 3.0 mmol) were added to a solution of 4-bromo-2-methylaniline (500 mg, 2.7 mmol) in DMF (5.0 mL) under N2, the reaction mixture was stirred for 5 min at 20 °C, after which 2-bromo-1-cyclopropylethanone (0.59 mL, 6.05 mmol) was added. The reaction mixture was then stirred at 20 °C for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between EtOAc and water. The two phases were separated and the water was re-extracted with EtOAc. The organic extracts were combined, washed with brine and filtered through phase separation filter paper. The crude material was purified by flash column chromatography (silica) eluting with EtOAc in petroleum ether (0-60%) to give 2-(4-bromo-2-methyl-anilino)-1-cyclopropyl-ethanone (405 mg, 1.5 mmol, 56% yield) as a brown oil. UPLC-MS (ES + , Method A): 1.90 minutes, m / z- 267.9 / 269.9 [M] + / [M+2] + 1 H NMR (400 MHz, CDCl3) δ 7.21 (dd, J = 8.3, 2.5 Hz, 1H), 7.18-7.16 (m, 1H), 6.36 (d, J = 8.4Hz, 1H), 4.60 (br s, 1H), 4.17 (s, 2H), 2.17 (s, 3H), 2.05-1.98 (m, 1H), 1.20-1.15 (m, 2H), 1.05-0.99 (m, 2H)

[0219] Step 2: N-(4-bromo-2-methyl-phenyl)-N-(2-cyclopropyl-2-oxo-ethyl)formamide [ka] Formic acid (1.23 mL, 32.6 mmol) and acetic anhydride (3.1 mL, 32.6 mmol) were heated at 60° C. for 15 min. The solution was then cooled at 0° C. and 2-(4-bromo-2-methyl-anilino)-1-cyclopropyl-ethanone (0.13 mL, 1.51 mmol) was added. The mixture was heated at 60° C. for 1 h. The reaction mixture was cooled at rt and concentrated under reduced pressure. The residue was partitioned between EtOAc and saturated aqueous NaHCO3. The two phases were separated and the aqueous phase was re-extracted with EtOAc. The combined organic extracts were washed with brine, filtered through phase separation paper and concentrated under reduced pressure to give N-(4-bromo-2-methyl-phenyl)-N-(2-cyclopropyl-2-oxo-ethyl)formamide (423 mg, 1.43 mmol, 95% yield) as a yellow oil. UPLC-MS (ES + , Method A): 1.67 min, m / z= 295.9 / 297.9 [M] + / [M+2] + 1 H NMR (400 MHz, CDCl3) δ 8.18 (s, 1H), 7.44 (d, J = 2.0 Hz, 1H), 7.38-7.34 (m, 1H), 7.23 (d, J = 8.4 Hz, 1H), 4.58 (s, 2H), 2.29 (s, 3H), 1.97-1.90 (m, 1H), 1.13-1.08 (m, 2H), 0.99-0.93 (m, 2H)

[0220] Step 3: 1-(4-bromo-2-methylphenyl)-4-cyclopropyl-imidazole [ka] TEA (0.2 mL, 1.43 mmol) and NHOAc (1.1 g, 14.3 mmol) were added successively to a suspension of N-(4-bromo-2-methyl-phenyl)-N-(2-cyclopropyl-2-oxo-ethyl)formamide (423 mg, 1.43 mmol) in 1-butanol (7 mL). The vial was sealed and the mixture was heated at 150° C. for 45 min. The reaction mixture was cooled at rt and concentrated under reduced pressure. The residue was partitioned between EtOAc and water. The two phases were separated and the aqueous phase was re-extracted with EtOAc. The combined organic extracts were washed with brine, filtered through phase separation paper and concentrated under reduced pressure. The crude material was purified by flash column chromatography (silica) eluting with EtOAc in petroleum ether (0-50%) to give 1-(4-bromo-2-methyl-phenyl)-4-cyclopropyl-imidazole (129 mg, 0.47 mmol, 33% yield) as a yellow oil. UPLC-MS (ES + , Method A): 1.32 minutes, m / z- 277.0 / 278.9 [M] + / [M+2] + 1 H NMR (400 MHz, CDCl3) δ 7.47 (d, J = 2.0 Hz, 1H), 7.42-7.38 (m, 2H), 7.07 (d, J = 8.3 Hz, 1H), 6.75 (d, J = 1.3 Hz, 1H), 2.18 (s, 3H), 1.94-1.86 (m, 1H), 0.92-0.85 (m, 2H), 0.84-0.79 (m, 2H)

[0221] Step 4: 4-Cyclopropyl-1-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]imidazole [ka] 1-(4-Bromophenyl)-4-cyclopropyl-imidazole (129 mg, 0.47 mmol), bis(pinacolato)diboron (196 mg, 0.77 mmol) and KOAc (151 mg, 1.54 mmol) were combined in 1,4-dioxane (5 mL). The reaction mixture was degassed with N2, then [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride DCM complex (21 mg, 0.03 mmol) was added. The reaction mixture was heated at 100 °C overnight. Cooled to rt, the reaction mixture was filtered through Celite and washed thoroughly with EtOAc. The filtrate was concentrated under reduced pressure. The crude material was purified by flash column chromatography (silica) eluting with EtOAc in petroleum ether (0-100%) to give 4-cyclopropyl-1-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]imidazole (quantitative) as a brown oil. UPLC-MS (ES + , Method A): 1.52 minutes, m / z- 325.0 [M+H] + 1 H NMR (400 MHz, CDCl3) δ 7.76 (d, J = 1.4 Hz, 1H), 7.70 (d, J = 7.8 Hz, 1H), 7.44 (d, J = 1.4 Hz, 1H), 7.20 (d, J = 7.8 Hz, 1H), 6.79 (d, J = 1.3 Hz, 1H), 2.23 (s, 3H), 1.94-1.87 (m, 1H), 1.36 (s, 12H), 0.91-0.85 (m, 2H), 0.84-0.80 (m, 2H)

[0222] Intermediate 59: 4-Cyclopropyl-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]imidazole [ka] Step 1: 2-(4-Bromoanilino)-1-cyclopropyl-ethanone [ka] KI (3.4 g, 20.5 mmol) and K2CO3 (3.09 g, 22.4 mmol) were added to a solution of 4-bromoaniline (3.21 g, 18.7 mmol) in DMF (34 mL). The reaction was stirred for 5 min at 20 °C under N2 and 2-bromo-1-cyclopropylethanone (4.1 mL, 41.9 mmol) was added. The reaction mixture was stirred at 20 °C for 1 h. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between EtOAc and water and the two phases were separated. The aqueous layer was re-extracted with EtOAc. The organic extracts were combined, washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (silica) eluting with EtOAc in petroleum ether (0-60%) to give 2-(4-bromoanilino)-1-cyclopropyl-ethanone (4.28 g, 16.8 mmol, 90% yield) as a yellow solid. UPLC-MS (ES + , Method A): 1.80 min, m / z= 253.9 / 255.9 [M] + / [M+2] + 1 H NMR (400 MHz, CDCl3) δ 7.27 (d, J = 8.9 Hz, 2H), 6.49 (d, J = 8.9 Hz, 2H), 4.67 (s, 1H), 4.13 (s, 2H), 2.03-1.96 (m, 1H), 1.18-1.13 (m, 2H), 1.03-0.98 (m, 2H)

[0223] Step 2: N-(4-bromophenyl)-N-(2-cyclopropyl-2-oxo-ethyl)formamide [ka] Formic acid (13.7 mL, 364 mmol) and acetic anhydride (34 mL, 364 mmol) were heated at 60° C. for 15 min. The solution was then cooled at 0° C. and 2-(4-bromoanilino)-1-cyclopropyl-ethanone (4.28 g, 16.8 mmol) was added. The mixture was heated at 60° C. for 1 h. The reaction mixture was cooled at rt and concentrated under reduced pressure. The residue was partitioned between EtOAc and saturated aqueous NaHCO3. The two phases were separated and the aqueous phase was re-extracted with EtOAc. The combined organic extracts were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure to give N-(4-bromophenyl)-N-(2-cyclopropyl-2-oxo-ethyl)formamide (4.75 g, 16.8 mmol, 99% yield) as a yellow oil. UPLC-MS (ES + , Method A): 1.57 min, m / z= 281.9 / 283.9 [M] + / [M+2] + 1 H NMR (400 MHz, CDCl3) δ 8.47 (s, 1H), 7.51 (d, J = 8.8 Hz, 2H), 7.06 (d, J = 8.8 Hz, 2H), 4.70 (s, 2H), 2.02-1.94 (m, 1H), 1.15-1.10 (m, 2H), 1.01-0.95 (m, 2H)

[0224] Step 3: 1-(4-bromophenyl)-4-cyclopropyl-imidazole [ka] A solution of N-(4-bromophenyl)-N-(2-cyclopropyl-2-oxo-ethyl)formamide (4.75 g, 16.8 mmol) in 1-butanol (40 mL), TEA (2.35 mL, 16.9 mmol) and NHOAc (13.0 g, 168 mmol) were added in four equal portions to four microwave vials. The vials were sealed and the mixture was irradiated at 150 °C for 1.5 h. The reaction mixtures were combined and concentrated under reduced pressure. The residue was partitioned between EtOAc and water. The organic layer was washed with brine, dried (NaSO), filtered and concentrated. The crude material was purified by flash column chromatography (silica) eluting with EtOAc in petroleum ether (0-50%) to give 1-(4-bromophenyl)-4-cyclopropyl-imidazole (2.35 g, 8.93 mmol, 53% yield) as a yellow solid. UPLC-MS (ES + , Method A): 1.21 min, m / z= 262.9 / 264.9 [M] + / [M+2] + 1 H NMR (400 MHz, CDCl3) δ 7.71 (d, J = 1.2 Hz, 1H), 7.58 (d, J = 8.8 Hz, 2H), 7.26 (d, J = 8.8 Hz, 2H), 7.00 (d, 1H, J = 1.2Hz, 1H), 1.96-1.88 (m, 1H), 0.94-081 (m, 4H)

[0225] Step 4: 4-Cyclopropyl-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]imidazole [ka] 1-(4-Bromophenyl)-4-cyclopropyl-imidazole (2.35 g, 8.9 mmol), bis(pinacolato)diboron (2.49 g, 9.8 mmol) and KOAc (1.75 g, 17.9 mmol) were combined in 1,4-dioxane (50 mL) and the mixture was degassed with N2 for 10 min. [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride DCM complex (729 mg, 0.89 mmol) was added and the reaction mixture was heated at 90 °C for 2 h. After cooling to rt, the mixture was filtered through Celite and washed with EtOAc. The filtrate was concentrated under reduced pressure and the residue was purified by flash column chromatography (silica) eluting with EtOAc in petroleum ether (0–100%) to give 4-cyclopropyl-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]imidazole (1.8 g, 5.8 mmol, 65% yield) as a colorless oil. UPLC-MS (ES + , Method A): 1.45 minutes, m / z- 311.0 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.89 (d, J = 8.4Hz, 2H), 7.84-7.82 (m, 1H), 7.35 (d, J = 8.4Hz, 2H), 7.06-7.05 (m, 1H), 1.96-1.89 (m, 1H), 1.36 (s, 12H), 0.93-0.82 (m, 4H)

[0226] Intermediate 60: 4-Cyclopropyl-1-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]imidazole Step 1: 1-(3-bromophenyl)-4-cyclopropyl-imidazole [ka] A mixture of 4-cyclopropyl-1H-imidazole (573 mg, 5.3 mmol), 1-bromo-3-iodo-benzene (2.25 g, 7.95 mmol), trans-1,2-diaminocyclohexane (363 mg, 3.18 mmol), CuI (303 mg, 1.59 mmol), and Cs2CO3 (5.18 g, 15.9 mmol) in diethylene glycol dimethyl ether (5 mL) was degassed and the mixture was stirred at 90° C. for 18 h under N2. The mixture was diluted with water (100 mL) and extracted with EtOAc (250 mL). The organic layer was concentrated under reduced pressure and the residue was purified by flash column chromatography (silica) eluting with 0.5% concentrated NH4OH in MeOH in DCM (5%) to give 1-(3-bromophenyl)-4-cyclopropyl-imidazole (700 mg, 2.66 mmol, 50% yield) as a dark green solid. LC-MS (ES-API, Method D): 0.88 min, m / z= 263.0 / 265.0 [M] + / [M+2] +

[0227] Step 2: 4-Cyclopropyl-1-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]imidazole [ka] Pd2(dba)3 (61 mg, 0.066 mmol) was added to a solution of 1-(3-bromophenyl)-4-cyclopropyl-imidazole (350 mg, 1.33 mmol), bis(pinacolato)diboron (507 mg, 2.0 mmol), KOAc (392 mg, 3.99 mmol) and XPhos (63 mg, 0.13 mmol) in THF (10 mL) and the mixture was stirred at 75 °C under N2 for 18 h. The mixture was concentrated under reduced pressure and purified by reverse phase column chromatography (C18 silica, 40-60 μm, 0-100% water / MeCN containing 0.1% TFA) to give 4-cyclopropyl-1-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]imidazole (400 mg, 1.29 mmol, 97% yield) as a yellow oil. LC-MS (ES-API, Method D): 1.18 min, m / z= 311.2 [M+H] + .

[0228] Intermediate 61: 2,5-Dimethyl-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]imidazole [ka] Step 1: N-prop-2-ynylacetamide [ka] To a solution of prop-2-yn-1-amine (2.0 g, 36.3 mmol) and NEt3 (11 g, 109 mmol) in DCM (50 mL) was added acetyl chloride (2.8 mL, 40 mmol) at 0 °C. The mixture was stirred overnight at rt under N2 and allowed to warm. The mixture was concentrated under reduced pressure and purified by flash column chromatography (silica) eluting with EtOAc in petroleum ether (35%) to give N-prop-2-ynylacetamide (3.3 g, 34 mmol, 94% yield). 1 H NMR (400 MHz, DMSO-d6) δ 8.26, (s, 1H), 3.82 (dd, J = 5.6, 2.4 Hz, 2H), 3.07 (s, 1H);1.81, (s, 3H)

[0229] Step 2: 1-(4-bromophenyl)-2,5-dimethyl-imidazole [ka] To a solution of N-(prop-2-yn-1-yl)acetamide (300 mg, 3.09 mmol) and 4-bromoaniline (797 mg, 4.64 mmol) in toluene (3 mL) was added zinc trifluoromethanesulfonate (56 mg, 0.15 mmol). The mixture was sealed in a vial and heated at 140° C. under N2 in a microwave for 1 h. The mixture was concentrated under reduced pressure and purified by flash column chromatography (silica) eluting with MeOH in DCM (5%) to give 1-(4-bromophenyl)-2,5-dimethyl-imidazole (490 mg, 1.95 mmol, 63% yield). LCMS (ES-API, Method C): 0.31 min, m / z= 251.0 / 253.0 [M] + / [M+2] +

[0230] Step 3: 2,5-Dimethyl-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]imidazole [ka] Pd2dba3 (160 mg, 0.18 mmol) and XPhos (167 mg, 0.35 mmol) were added to a solution of 1-(4-bromophenyl)-2,5-dimethyl-1H-imidazole (440 mg, 1.75 mmol), bis(pinacolato)diboron (890 mg, 3.5 mmol) and KOAc (516 mg, 5.25 mmol) in THF (10 mL). The mixture was heated at 75 °C for 18 h under N2. The mixture was filtered, concentrated under reduced pressure, and purified by reverse phase column (C18 spherical 40-60 μm 100A 40 g) chromatography to give 2,5-dimethyl-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]imidazole (450 mg, 1.51 mmol, 86% yield). LC-MS (ES-API, Method D): 1.16 min, m / z= 299.1 [M+H] +

[0231] Intermediate 62:2,4-Dimethyl-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]imidazole [ka] Step 1: 1-(4-bromophenyl)-2,4-dimethyl-imidazole [ka] CuI (606 mg, 3.18 mmol) and (+ / -)-trans-1,2-diaminocyclohexane (727 mg, 6.4 mmol) were added to a solution of 1-bromo-4-iodobenzene (3.0 g, 10.6 mmol), 2,5-dimethyl-1H-imidazole (2.04 g, 21.2 mmol) and Cs2CO3 (10.4 g, 31.8 mmol) in diethylene glycol dimethyl ether (10 mL). The mixture was degassed with N2 for 10 min. The vial was then sealed and heated at 150 °C for 18 h. The mixture was extracted with EtOAc, concentrated under reduced pressure and purified by flash column chromatography (silica) eluting with MeOH in DCM (2%) to give 1-(4-bromophenyl)-2,4-dimethyl-imidazole (470 mg, 1.87 mmol, 17% yield) as an orange oil. LCMS (ES-API, Method C): 0.30 min, m / z= 251.0 / 253.0 [M] + / [M+2] +

[0232] Step 2: 2,4-Dimethyl-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]imidazole [ka] Pd2dba3 (157 mg, 0.17 mmol) and XPhos (163 mg, 0.34 mmol) were added to a solution of 1-(4-bromophenyl)-2,4-dimethyl-1H-imidazole (430 mg, 1.7 mmol), 4,4,5,5-tetramethyl-2-(3,3,4,4-tetramethylboron-1-yl)-1,3,2-dioxaborolane (870 mg, 3.4 mmol) and KOAc (504 mg, 5.1 mmol) in THF (10 mL). The mixture was heated at 75 °C for 18 h under N2. The mixture was filtered, concentrated under reduced pressure, and purified on a reverse phase column (C18 spherical 40-60 μm 100A 40 g; eluent: MeCN / water; gradient: 0-30%) to give 2,4-dimethyl-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]imidazole (300 mg, 1.0 mmol, 59% yield). LCMS (ES-API, Method D): 1.12 min, m / z= 299.1 [M+H] +

[0233] Intermediate 63: 2,4,5-trimethyl-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]imidazole [ka] Step 1: 1-(4-bromophenyl)-2,4,5-trimethyl-imidazole [ka] Butane-2,3-dione (1.0 g, 11.6 mmol) was added to a solution of acetaldehyde (512 mg, 11.6 mmol), 4-bromoaniline (999 mg, 5.8 mmol) and NHOAc (895 mg, 11.6 mmol) in MeOH (4.6 mL). The reaction was heated and stirred at 80° C. for 18 h. The reaction mixture was extracted with toluene and the solvent was removed under reduced pressure. The crude product was purified by flash column chromatography (silica) eluting with EtOAc in petroleum ether (50%) to give 1-(4-bromophenyl)-2,4,5-trimethyl-imidazole (400 mg, 1.51 mmol, 26% yield). LCMS (ES -API, Agilent, Method C) 0.38 min, m / z= 265.0 / 267.0 [M] + / [M+2] +

[0234] Step 2: 4,5-trimethyl-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]imidazole [ka] Pd2(dba)3 (121 mg, 0.13 mmol) and XPhos (126 mg, 0.27 mmol) were added to a solution of 1-(4-bromophenyl)-2,4,5-trimethyl-imidazole (350 mg, 1.33 mmol), bis(pinacolato)diboron (525 mg, 1.99 mmol) and KOAc (390 mg, 3.98 mmol) in THF (15 mL). The solution was heated and stirred at 75 °C for 18 h. The mixture was filtered and the solvent was removed under reduced pressure. The residue was purified by reverse phase chromatography (C18) eluting with a MeCN / water gradient 0-100% to give 2,4,5-trimethyl-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]imidazole (334 mg, 1.07 mmol, 81% yield). LCMS (ES -API, Method D): 0.35 min, m / z= 231.0 [M+H] +(boronic acid) & 1.18 min, m / z= 313.2 [M+H] + (boronic ester)

[0235] Intermediate 64: 4-Ethyl-5-methyl-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]imidazole [ka] Step 1: 2-(4-bromoanilino)pentan-3-one [ka] LiBr (4.17 g, 48.0 mmol) was added to a solution of 4-bromoaniline (5.5 g, 32.0 mmol), 2-bromopentan-3-one (5.84 g, 35.4 mmol) and NaHCO3 (5.41 g, 64.4 mmol) in EtOH (60 mL). The mixture was heated at 90 °C for 18 h under N2. The mixture was purified by flash column chromatography (silica) eluting with EtOAc in petroleum ether (20%) to give 2-(4-bromoanilino)pentan-3-one (7.6 g, 29.7 mmol, 93% yield) as an orange solid. LCMS (ES-API, Method D): 2.36 min, m / z= 256.0 / 258.0 [M] + / [M+2] +

[0236] Step 2: N-(4-bromophenyl)-N-(1-methyl-2-oxo-butyl)formamide [ka] Acetic anhydride (40 mL) was added to a solution of 2-((4-bromophenyl)amino)pentan-3-one (7.6 g, 29.7 mmol) in formic acid (120 mL) at 0° C. The mixture was stirred at rt for 2 h. The mixture was extracted with EtOAc (3×100 mL) and the combined organic layers were washed with saturated aqueous NaHCO3 and saturated brine, dried (Na2SO4) and concentrated under reduced pressure to give N-(4-bromophenyl)-N-(1-methyl-2-oxo-butyl)formamide (7.7 g, 27.0 mmol, 92% yield) as an orange oil. LCMS (ES-API, Method D): 2.00 min, m / z= 283.9 / 285.9 [M] + / [M+2] +

[0237] Step 3: 1-(4-bromophenyl)-4-ethyl-5-methyl-imidazole [ka] NHOAc (2.71 g, 35.2 mmol) was added to a solution of N-(4-bromophenyl)-N-(3-oxopentan-2-yl)formamide (2.0 g, 7.0 mmol) in acetic acid (glacial) (20 mL). The mixture was heated at 130° C. for 1 h under N. The reaction mixture was extracted with EtOAc (3×150 mL) and the combined organic layers were washed with saturated aqueous NaHCO, brine, dried (NaSO) and concentrated under reduced pressure and purified by flash column chromatography (silica) eluting with MeOH in DCM (5%) to give 1-(4-bromophenyl)-4-ethyl-5-methyl-imidazole (1.7 g, 6.4 mmol, 91% yield) as an orange solid. LCMS (ES-API, Method D): 0.87 min, m / z= 265.0 / 266.9 [M] + / [M+2] +

[0238] Step 4: 4-Ethyl-5-methyl-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]imidazole [ka] Pd2dba3 (173 mg, 0.19 mmol) and XPhos (180 mg, 0.38 mmol) were added to a solution of 1-(4-bromophenyl)-4-ethyl-5-methyl-1H-imidazole (500 mg, 1.89 mmol), 4,4,5,5-tetramethyl-2-(3,3,4,4-tetramethylboron-1-yl)-1,3,2-dioxaborolane (958 mg, 3.78 mmol) and KOAc (555 mg, 5.7 mmol) in THF (10 mL). The mixture was heated at 75 °C for 18 h under N2. The mixture was filtered, the solvent removed under reduced pressure, and purified by reverse phase chromatography (C18 spherical 40-60 μm 100A 40 g) to give 4-ethyl-5-methyl-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]imidazole (450 mg, 1.44 mmol, 76% yield) as an orange solid. LCMS (ES-API, Method D): 1.34 min, m / z= 313.2 [M+H] +

[0239] Intermediate 65: 4-Cyclopropyl-1-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]imidazole [ka] [ka] Step 1: 2-(4-Bromo-2-fluoro-anilino)-1-cyclopropyl-ethanone To a solution of 4-bromo-2-fluoroaniline (3.0 g, 15.8 mmol) in EtOH (60 ml), 2-bromo-1-cyclopropylethan-1-one (2.83 g, 17.4 mmol), LiBr (2.06 g, 23.7 mmol) and NaHCO3 (2.65 g, 31.6 mmol) was added and the mixture was stirred overnight under nitrogen at 80° C. The mixture was concentrated and purified by flash column chromatography (petroleum ether / EtOAc=10 / 1) to give 2-(4-bromo-2-fluoro-anilino)-1-cyclopropyl-ethanone (2.78 g, 10.21 mmol, 65%). LCMS (ES-API, Method C): 1.62 min, m / z= 272 / 274 [M] + / [M+2] +

[0240] Step 2: N-(4-bromo-2-fluoro-phenyl)-N-(2-cyclopropyl-2-oxo-ethyl)formamide To a solution of 2-((4-bromo-2-fluorophenyl)amino)-1-cyclopropylethan-1-one (2.72 g, 10 mmol) in formic acid (21 mL) was added acetic anhydride (7 mL) and the mixture was stirred at rt overnight. The mixture was concentrated, adjusted to pH=9 with NaHCO3, extracted with EtOAc, washed with brine, dried over Na2SO4, and concentrated to give N-(4-bromo-2-fluoro-phenyl)-N-(2-cyclopropyl-2-oxo-ethyl)formamide (2.74 g, 9.13 mmol, 91%). LCMS (ES-API, Method C): 1.22 min, m / z= 300 / 302 [M] + / [M+2] +

[0241] Step 3: 1-(4-bromo-2-fluoro-phenyl)-4-cyclopropyl-imidazole To a solution of N-(4-bromo-2-fluorophenyl)-N-(2-cyclopropyl-2-oxoethyl)formamide (2.56 g, 8.5 mmol) in acetic acid (64 mL) was added NHOAc (3.29 g, 42.5 mmol) and the mixture was stirred at 130° C. under nitrogen overnight. The mixture was concentrated, adjusted to pH=9 with NaHCO, extracted with EtOAc, washed with brine, dried over NaSO, concentrated and purified by flash column chromatography (DCM / MeOH=20 / 1) to give 1-(4-bromo-2-fluoro-phenyl)-4-cyclopropyl-imidazole (0.95 g, 3.38 mmol, 40%). LCMS (ES-API, Method C): 0.40 min, m / z= 281 / 283 [M] + / [M+2] +

[0242] Step 4: 4-Cyclopropyl-1-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]imidazole To a solution of 1-(4-bromo-2-fluorophenyl)-4-cyclopropyl-1H-imidazole (900 mg, 3.2 mmol) in THF (50 mL) was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.63 g, 6.4 mmol), Pd2dba3 (360 mg, 0.32 mmol) and XPhos (378 mg, 0.64 mmol) and KOAc (1.08 g, 9.6 mmol) and the mixture was stirred at 75 °C under nitrogen overnight. The mixture was concentrated and purified by reverse phase chromatography (30% MeCN in water) to give 4-cyclopropyl-1-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]imidazole (0.63 g, 1.92 mmol, 60%). LCMS (ES-API, Method D): 0.29 min, m / z= 247.1 [M+H] + Boronic Acids

[0243] Intermediate 66:2-(4-cyclopropyl-1H-imidazol-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile [ka] [ka] Step 1: 2-(4-Bromo-2-iodo-anilino)-1-cyclopropyl-ethanone To a solution of 4-bromo-2-iodoaniline (16.5 g, 55.57 mmol, 1.0 equiv) in EtOH (80 mL) was added 2-bromo-1-cyclopropylethan-1-one (9.9 g, 61.12 mmol, 1.1 equiv), LiBr (9.31 g, 83.36 mmol, 1.5 equiv) and NaHCO3 (7.26 g, 111.14 mmol, 2.0 equiv). The reaction mixture was stirred at 80 °C under N2 overnight. The solution was concentrated and purified by flash column chromatography to give 2-(4-bromo-2-iodo-anilino)-1-cyclopropyl-ethanone (21.3 g, 56.0 mmol, 100%). LC-MS (ES-API, Method C): 2.27 min, m / z= 380.0 / 381.9 [M] + / [M+2] +

[0244] Step 2: N-(4-bromo-2-iodo-phenyl)-N-(2-cyclopropyl-2-oxo-ethyl)formamide To the stirring 2-((4-bromo-2-iodophenyl)amino)-1-cyclopropylethan-1-one (19 g, 50.13 mmol, 1.0 equiv) at 0 °C under N2 was added acetic anhydride (28.8 mL) and formic acid (86.3 mL) and the reaction mixture was warmed to rt overnight. The solution was concentrated, basified to pH 9, and diluted with water (1000 mL). The aqueous phase was extracted with EtOAc (300 mL x 4) and concentrated. The crude was purified by flash column chromatography (petroleum ether / EtOAc = 100:1 to 20:1) to give N-(4-bromo-2-iodo-phenyl)-N-(2-cyclopropyl-2-oxo-ethyl)formamide (23.0 g, 56.36 mmol, assumed quantitative). LC-MS (ES-API, Method D): 2.39 min, m / z= 407.9 / 409.9 [M] + / [M+2] +

[0245] Step 3: 1-(4-bromo-2-iodo-phenyl)-4-cyclopropyl-imidazole To a solution of N-(4-bromo-2-iodophenyl)-N-(2-cyclopropyl-2-oxo-ethyl)formamide (21.0 g, 51.47 mmol, 1.0 equiv) in acetic acid (20 mL) was added NHOAc (1.87 g, 24.52 mmol, 5.0 equiv). The reaction mixture was stirred at 130 °C under N overnight. The solution was concentrated and basified to pH 9. The crude was purified by flash column chromatography (DCM / MeOH 100:1 to 30:1) to give 1-(4-bromo-2-iodo-phenyl)-4-cyclopropyl-imidazole (5.5 g, 14.14 mmol, 25%). 1 H NMR (400 MHz, DMSO-d6) δ 8.18 (d, J = 2.1 Hz, 1H), 7.68 (dd, J = 2.2, 8.3 Hz, 1H), 7.58 (s, 1H), 7.31 (d, J = 8.2 Hz, 1H), 7.03 (s, 1H), 1.86-1.78 (m, 1H), 0.80-0.73 (m, 2H), 0.69-0.64 (m, 2H)

[0246] Step 4: 5-Bromo-2-(4-cyclopropylimidazol-1-yl)benzonitrile A solution of 1-(4-bromo-2-iodophenyl)-4-cyclopropyl-1H-imidazole (1.0 g, 2.57 mmol) and CuCN (4.6 g, 51.41 mmol) in NMP (10 mL) was stirred with N2 at 100° C. overnight. The mixture was diluted with water (100 mL), extracted with EtOAc (20 mL×10), washed with brine, dried over Na2SO4, concentrated and purified by flash column chromatography (petroleum ether / EtOAc=6 / 1) to give 5-bromo-2-(4-cyclopropylimidazol-1-yl)benzonitrile (0.23 g, 0.79 mmol, 31%). LC-MS (ES-API, Method K): 1.07 min, m / z= 288.00 [M] + / [M+2] +

[0247] Step 5: 2-(4-cyclopropyl-1H-imidazol-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile A solution of 5-bromo-2-(4-cyclopropyl-1H-imidazol-1-yl)benzonitrile (1.3 g, 4.51 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (11.46 g, 45.12 mmol), XPhos (2.15 g, 4.51 mmol), KOAc (1.33 g, 13.55 mmol) and Pd2(dba)3 (826.3 mg, 0.90 mmol) in THF (180 mL) was stirred overnight under N2 at 75 °C. The mixture was concentrated and purified by flash column chromatography (petroleum ether / EtOAc 2:1) to give [3-cyano-4-(4-cyclopropylimidazol-1-yl)phenyl]boronic acid. 1H NMR (400 MHz, DMSO-d6) δ 8.15 (s, 1H), 8.08 (d, J = 8.4 Hz, 1H), 8.03 (s, 1H), 7.73 (d, J = 7.6 Hz, 1H), 7.46 (s, 1H), 1.97-1.89 (m, 1H), 1.38 (s, 12H), 0.91-0.84 (m, 2H), 0.79-0.75 (m, 2H)

[0248] Compounds prepared in a similar manner to the above are shown in Table 4 below. [Table 32]

[0249] General synthesis method for intermediates 71-74 A method for the preparation of intermediate 71 is shown below. Further intermediates prepared in an analogous manner from commercially available bromophenols are shown in Table 5. [ka] Intermediate 71: 2-Cyclopropyl-1-methyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]imidazole [ka] Step 1: 4-(2-cyclopropyl-1-methyl-imidazol-4-yl)phenol To a solution of 4-bromo-2-cyclopropyl-1-methyl-1H-imidazole (20 g, 0.1 mol) in 1,4-dioxane (470 mL) and water (53 mL) was added (4-hydroxyphenyl)boronic acid (17.81 g, 0.12 mol), Pd(dppf)Cl2CH2Cl2 (8.13 g, 0.01 mol) and K2CO3 (20.63 g, 0.15 mol) and the mixture was stirred at 100° C. under nitrogen overnight. The mixture was concentrated and purified by column chromatography (petroleum ether / EtOAc 2:1) to give 4-(2-cyclopropyl-1-methyl-imidazol-4-yl)phenol (19.86 g, 92.69 mmol, 93%). LCMS (ES-API, Method C): 0.32 min, m / z= 215.2 [M+H] + 1 H NMR (400 MHz, DMSO-d6) δ 9.27 (s, 1H), 7.48 (d, J = 8.5 Hz, 2H), 7.26 (s, 1H), 6.73 (d, J = 8.7 Hz, 2H), 3.67 (s, 3H), 2.01-1.94 (m, 1H), 0.96-0.85 (m, 4H)

[0250] Step 2: [4-(2-cyclopropyl-1-methyl-imidazol-4-yl)phenyl]trifluoromethanesulfonate To a solution of 4-(2-cyclopropyl-1-methyl-1H-imidazol-4-yl)phenol (19.86 g, 92.691 mmol) in DCM, TfO (23.4 mL, 139.04 mmol) and TEA (38.6 mL, 278.07 mmol) were added at 0° C. and then left at room temperature overnight. The mixture was concentrated and purified by flash column chromatography (petroleum ether / EtOAc 4:1) to give [4-(2-cyclopropyl-1-methyl-imidazol-4-yl)phenyl]trifluoromethanesulfonate (13.0 g, 37.54 mmol, 41%). LCMS (ES-API, Method D): 1.23 min, m / z= 347.0 [M+H] + 1 H NMR (400 MHz, DMSO-d6) δ 7.82 (d, J = 9.0 Hz, 2H), 7.60 (s, 1H), 7.43 (d, J = 8.9 Hz, 2H), 3.71 (s, 3H), 2.04-1.96 (m, 1H), 0.98-0.93 (m, 2H), 0.91-0.86 (m, 2H)

[0251] Step 3: 2-Cyclopropyl-1-methyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]imidazole To a solution of 4-(2-cyclopropyl-1-methyl-1H-imidazol-4-yl)phenyl trifluoromethanesulfonate (13.56 g, 39.2 mmol) in dioxane (90 mL) was added bis(pinacolato)diboron (19.89 g, 78.3 mmol), Pd(dppf)Cl2CH2Cl2 (3.2 g, 3.9 mmol) and KOAc (11.53 g, 117 mmol) and the mixture was stirred overnight under nitrogen at 90° C. The mixture was concentrated and purified by column (petroleum ether / EtOAc 2:1, v / v) to give 2-cyclopropyl-1-methyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]imidazole (17.8 g, 54.9 mmol, 100%).

[0252] [Table 33]

[0253] General synthesis of intermediates 76-82 A method for preparing intermediate 76 is shown below. Additional intermediates prepared in an analogous manner from commercially available bromophenols are shown in Table 6.

[0254] Intermediate 76: 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-(2,2,2-trifluoro-1-methyl-ethyl)piperidine [ka] Step 1: (2,2,2-trifluoro-1-methyl-ethyl) trifluoromethanesulfonate To a solution of 1,1,1-trifluoro-2-propanol (1.0 g, 8.77 mmol) and pyridine (1.06 mL, 13.15 mmol) in DCM (10 mL) was added trifluoromethanesulfonic anhydride (1.77 mL, 10.52 mmol) under nitrogen atmosphere at 0° C. and stirred at rt overnight. The crude reaction mixture was used directly in the next step without purification.

[0255] Step 2: 4-(4-bromophenyl)-1-(2,2,2-trifluoro-1-methyl-ethyl)piperidine To a solution of 4-(4-bromophenyl)piperidine (500 mg, 2.08 mmol) and TEA (1.16 mL, 8.32 mmol) in THF (20 mL) was added (2,2,2-trifluoro-1-methyl-ethyl)trifluoromethanesulfonate as crude solution from the previous step at rt and stirred overnight at 60° C. The mixture was concentrated and purified by flash column chromatography (petroleum ether / EtOAc 50:1) to give 4-(4-bromophenyl)-1-(2,2,2-trifluoro-1-methyl-ethyl)piperidine (120 mg, 17%) as a white oil. LCMS (ES-API, Method C): 2.59 min, m / z= 336.0 / 338.0 [M] + / [M+2] + 1 H NMR (400 MHz, DMSO-d6) d 7.48 (d, J = 8.8 Hz, 2H), 7.23 (d, J = 8.6 Hz, 2H), 3.54-3.45 (m, 1H), 2.99 (t, J = 13.0 Hz, 2H), 2.60 (t, J = 10.7 Hz, 1H), 2.51-2.45 (m, 1H), 1.80-1.70 (m, 2H), 1.62-1.52 (m, 2H), 1.20 (d, J = 6.9 Hz, 3H).

[0256] Step 3: 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-(2,2,2-trifluoro-1-methyl-ethyl)piperidine To a solution of 4-(4-bromophenyl)-1-(2,2,2-trifluoro-1-methyl-ethyl)piperidine (320 mg, 0.95 mmol) in THF (15 mL) was added bis(pinacolato)diboron (483 mg, 1.90 mmol), Pd2(dba)3 (87.17 mg, 0.10 mmol), XPhos (90.75 mg, 0.19 mmol) and KOAc (280 mg, 2.86 mmol). The mixture was stirred at 70° C. under nitrogen overnight. The mixture was concentrated and purified by flash column chromatography (petroleum ether / EtOAc 40:1) to give 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-(2,2,2-trifluoro-1-methyl-ethyl)piperidine. LCMS (ES-API, Method C): 2.89 min, m / z= 384.3 [M+H] +

[0257] [Table 34] [Table 35] [Table 36]

[0258] The above intermediate 93 and analogs were prepared according to the following schemes and methods: [ka] 4-(4-bromophenyl)-1-(2,2,2-trifluoroethyl)pyrazole A solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole (1.00 g, 3.62 mmol), 1,4-dibromobenzene (1.7 mg, 7.25 mmol), Pd(dppf)Cl2DCM (296 mg, 0.36 mmol) and K2CO3 (751 mg, 5.43 mmol) in 1,4-dioxane (90 mL) and water (10 mL) was stirred overnight under inert atmosphere at 80° C. The mixture was concentrated and purified by column chromatography eluting with petroleum ether / EtOAc (10:1) to give 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-(2,2,2-trifluoroethyl)pyrazole (530 mg). LC-MS (Method C): 1.60 min, m / z 304.9 [M+H] +

[0259] 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-(2,2,2-trifluoroethyl)pyrazole A solution of 4-(4-bromophenyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole (480 mg, 1.57 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (799 mg, 3.15 mmol), KOAc (463 mg, 4.72 mmol), Pd2(dba)3 (144 mg, 0.16 mmol) and X-PhOS (150 mg, 0.31 mmol) in THF (20 mL) was stirred at 75 °C with N2 overnight. Further purification by flash column chromatography eluting with DCM / MeOH (20:1) afforded 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-(2,2,2-trifluoroethyl)pyrazole (presumed quantitative). LC-MS (Method C): 1.87 min, m / z 353.2 [M+H] +

[0260]

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

Table 50

Table 51

Table 52

Table 53

Table 54

Table 55

Table 56

Table 57

Table 58

Table 59

Table 60

Table 61

Table 62

Table 63

Table 64

Table 65

Table 66

Table 67

Table 68

Table 69

Table 70

Table 71

Table 72

[0261] Compound 145 and analogs were prepared according to the following methods. [ka] A mixture of 5-((3-(4-(1-benzyl-6-methyl-1,2,5,6-tetrahydropyridin-3-yl)-3-methylphenyl)-1-ethyl-1H-1,2,4-triazol-5-yl)amino)-3,6-dimethylisoindolin-1-one (180 mg, 0.329 mmol, 1.0 equiv.) in IPA (27 mL), Pd / C (180 mg), Pd(OH)2 (180 mg) and acetic acid (1.97 mg, 0.0329, 0.1 equiv.) was stirred at 80° C. under H2 (0.4 MPa) overnight. The mixture was concentrated under reduced pressure to give the crude material which was purified by filtration to give the crude product. Further purification by preparative HPLC gave 5-[[2-ethyl-5-[3-methyl-4-(6-methyl-3-piperidyl)phenyl]-1,2,4-triazol-3-yl]amino]-3,6-dimethyl-isoindolin-1-one (20 mg, 0.0436 mmol). LC-MS (ES-API, Method G): 0.833 min, m / z, 459.30 [M+H]+(%). 1 H NMR (400 MHz, DMSO-d6) δ 8.36 (s, 1H), 8.18 (s, 1H), 7.74 (d, J = 8.4 Hz, 1H), 7.69 (d, J = 4.7 Hz, 2H), 7.47 - 7.43 (m, 2H), 7.23 (d, J = 8.0 Hz, 1H), 4.53 (q, J = 6.7 Hz, 1H), 4.12 (q, J = 7.2 Hz, 2H), 3.00 - 2.86 (m, 2H), 2.82 - 2.74 (m, 1H), 2.61 - 2.54 (m, 1H), 2.34 (s, 3H), 2.32 (s, 3H), 1.83 - 1.74(m, 1H), 1.71 - 1.57 (m, 2H), 1.37 (t, J = 7.2 Hz, 3H), 1.31 (d, J = 6.6 Hz, 3H),1.23 - 1.16 (m, 1H), 1.12 (d, J = 6.6 Hz, 2H), 1.02 (d, J = 6.2 Hz, 1H).

[0262] ROCK2 binding activity: Assays for ROCK2 inhibition were performed using the protein construct N-terminal 6His-tagged ROCK2 catalytic domain 11-552 (Dundee University, UK). Protein was purified from a baculovirus expression system. Long S6 peptide (KEAKEKRQEQIAKRRRLSSLRASTSKSGGSQK) was used as substrate. Kinase reactions were performed in 96-well plates (black, half area) in a 15 μl volume using 1.25 nM constitutively active ROCK2 kinase, 100 μM long S6 peptide, 20 μM ATP and DMSO solutions of test compounds (or DMSO only as control). The final concentration of DMSO was ≦1%. The assay buffer was 50 mM HEPES pH 7.5 supplemented with 0.2 mM EDTA, 10 mM magnesium acetate, 0.01% Tween-20, 1 mM DTT and 0.01% BSA. Test compounds were pre-incubated with ROCK2 kinase for 1 h, after which ATP and long S6 peptide were added. After a further 1 h incubation, ADP production was measured using the ADP-Glo ​​Kinase Assay (Promega) according to the manufacturer's instructions. Luminescence was measured on a PHERAstar FS (BMG Labtech). The concentration of test compound required for 50% inhibition of ADP production (IC 50 ) was calculated using a four-parameter logistic function with Dotmatics software.

[0263] Table 8 shows the ROCK2 or ROCK1 binding activity as determined in the above assay for compounds of a particular formula, relative to the compound's ROCK2 or ROCK1 IC 50 The values ​​are categorized as "+", "++", "+++" and "++++". The "+" category indicates a ROCK2 or ROCK1 IC of >10 μM 50 The category "++" represents compounds with a ROCK2 or ROCK1 IC value between 10 and 3 μM. 50 The category "+++" represents compounds with a ROCK2 or ROCK1 IC value between 3 and 0.3 μM. 50 The category "++++" represents compounds with a ROCK2 or ROCK1 IC value of <0.3 μM.50 represents a compound having a value.

[0264] [Table 82] [Table 83]

[0265] Throughout this specification and the claims, the terms "comprise" and "include" and variations thereof mean "including, but not limited to," and do not (and do not) intend to exclude other moieties, additives, components, integers, or steps. Throughout this specification and the claims, the singular includes the plural unless the context requires otherwise. In particular, when using the indefinite article, the description should be interpreted as contemplating both the plural and the singular, unless the context requires otherwise.

[0266] Any feature, integer, characteristic, compound, chemical moiety or group described in connection with a particular aspect, embodiment or example of the invention should be construed as applicable to any other aspect, embodiment or example described herein, unless incompatible. All of the features disclosed herein (including any accompanying claims, abstract and drawings) and / or all of the steps of any method or procedure so disclosed may be combined in any combination, except combinations in which at least some of such features and / or steps are mutually exclusive. The invention is not limited to the details of any of the aforementioned embodiments. The invention extends to any novel or any novel combination of features disclosed herein (including any accompanying claims, abstract and drawings) or any novel or any novel combination of steps of any method or procedure so disclosed.

[0267] The reader is directed to all articles and documents submitted contemporaneously or prior to this application and published herewith, the contents of all such articles and documents being incorporated herein by reference.

Claims

1. Formula (I): 【Chemistry 1】 [During the ceremony, X １ and X ２ are each independently selected from carbon and nitrogen; １ and X ２ at least one of is carbon; X ３ is selected from carbon and nitrogen; R １ and R ２ are each independently H, halo, nitro, cyano, NR ８ R ９ , OR １０ , S.R. ８ , S.O. ２ R ８ , S.O. ２ NR ８ R ８ , CO ２ R ８ , C(O)R ８ , C.O.R. ８ R ８ , C １ -C ４ -Alkyl, C ２ -C ４ -alkenyl, C ２ -C ４ -alkynyl, C １ -C ４ -haloalkyl, NR ８ R ９ C substituted with １ -C ４ -Alkyl, OR １０ C substituted with １ -C ４ - selected from alkyl and cyclopropyl; R ３ is independently C １ -C ４ -Alkyl, C １ -C ４ -haloalkyl, C ０ -C ３ -Alkylene-R ３ａ and C ２ -C ４ -Alkylene-R ３ｂ wherein R ３ａ is independently selected at each occurrence from cyclopropyl and azetidinyl, and the cyclopropyl or azetidinyl group is optionally selected from 1 to 4 R １１ group; where R ３ｂ is independently in each case NR ８ R ９ , OR １０ and S.R. ８ Selected from: R ４ and R １２ each occurrence independently represents halo, nitro, cyano, NR ８ R ９ , OR １０ , S.R. ８ , S.O. ２ R ８ , S.O. ２ NR ８ R ８ , CO ２ R ８ , C(O)R ８ , C.O.R. ８ R ８ , C.R. ８ R ８ NR ８ R ９ , C.R. ８ R ８ OR ８ , C １ -C ４ -Alkyl, C ２ -C ４ -alkenyl, C ２ -C ４ -alkynyl, C １ -C ４ - selected from haloalkyl and cyclopropyl; R ５ is independently CONR ８ R ８ , unsubstituted phenyl, 1 to 4 R １１ and phenyl and 4- to 10-membered heterocyclyl substituted with a group, wherein the heterocyclyl group may be monocyclic or bicyclic, and wherein any ring of the heterocyclyl group may be saturated, unsaturated, or partially unsaturated; and wherein any saturated or partially unsaturated ring optionally contains one R １３ group and / or 1 to 4 R １１ group, wherein any unsaturated ring is optionally substituted with one R １３ group and / or 1 to 3 R １２ substituted with a group; R ６ is independently in each occurrence H, halo, C １ -C ４ -Alkyl, NR ８ R ９ C substituted with １ -C ４ -Alkyl, OR １０ C substituted with １ -C ４ - alkyl and cyclopropyl, or two R ６ The groups and the carbon atoms to which they are attached together form C ３ -C ６ may form a cycloalkyl ring; R ７ and R ８ are each independently H, C １ -C ４ -Alkyl and C １ -C ４ -haloalkyl; R ９ is independently in each case H, C １ -C ４ -alkyl, C(O)-C １ -C ４ -Alkyl and S(O) ２ -C １ -C ４ -alkyl; or R ８ and R ９ optionally, together with the nitrogen atom to which they are attached, 0 to 4 R １１ C substituted with a group ５ -C ８ - forms a heterocycloalkyl group; R １０ is independently in each case H, C １ -C ４ -alkyl, C(O)-C １ -C ４ -Alkyl and C １ -C ４ -haloalkyl; R １１ is independently, at each occurrence, ═O, halo, nitro, cyano, NR ８ R ９ , OR １４ , S.R. ８ , S.O. ２ NR ８ R ８ , CO ２ R ８ , C(O)R ８ , C.O.R. ８ R ８ , C １ -C ４ -Alkyl, C ２ -C ４ -alkenyl, C ２ -C ４ -alkynyl, C １ -C ４ - selected from haloalkyl and cyclopropyl; R １３ is independently C ３ -C ６ -cycloalkyl, 3- to 6-membered heterocycloalkyl, CR ８ R ８ NR ８ R ９ and C.R. ８ R ８ OR ８ wherein R １３ When is cycloalkyl or heterocycloalkyl, R １３ optionally 1 to 4 R １１ substituted with a group; R １４ is independently in each case H, C １ -C ４ - alkyl; C １ -C ４ -haloalkyl and C(O)-C １ -C ４ - alkyl; and m is an integer selected from 0, 1, 2, 3 and 4; wherein any of the alkyl or cycloalkyl (e.g., cyclopropyl) groups may in each case optionally be halo, oxo, nitro, cyano, NR ａ R ｂ , OR ａ , S.R. ａ , CO ２ R ａ , C(O)R ａ , C.O.R. ａ R ａ and is substituted with 1 to 5 substituents independently selected from the group consisting of: ａ is independently in each case H, C １ -C ４ -Alkyl and C １ -C ４ -haloalkyl; and R ｂ is independently in each case H, C １ -C ４ -alkyl, C(O)-C １ -C ４ -Alkyl and S(O) ２ -C １ -C ４ -alkyl. or a pharmaceutically acceptable salt thereof.

2. X ３ is CR １ 2. The compound of claim 1, wherein:

3. R １ 3. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein:

4. R ２ are independently H, fluoro, C １ -C ３ -Alkyl, C １ -C ３ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein - is selected from fluoroalkyl and cyclopropyl.

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

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

7. R ３ became independent and became C １ -C ４ 2. The compound of claim 1, wherein the aryl group is selected from alkyl and cyclopropyl.

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

9. R ４ is C １ -C ３ 9. The compound of claim 8, or a pharmaceutically acceptable salt thereof, wherein - is selected from alkyl and cyclopropyl.

10. R ５ optionally one R １３ group and / or 1 to 3 R １２ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, which is an imidazole substituted with a group.

11. R ５ optionally one R １３ group and / or 1 to 3 R １２ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, which is a pyridine substituted with a group.

12. R ５ The structure: 【Chemistry 2】 12. The compound of claim 11, or a pharmaceutically acceptable salt thereof, having the formula: wherein x4 is independently an integer selected from 0, 1 and 2.

13. R ５ The structure 【Transformation 3】 12. The compound of claim 11, or a pharmaceutically acceptable salt thereof, having the formula: wherein x4 is independently an integer selected from 0, 1 and 2.

14. R ６ independently at each occurrence H and C １ -C ４ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the aryl group is selected from the group consisting of aryl, ...

15. Two R's ６ The groups and the carbon atoms to which they are attached together form C ３ -C ６ 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, which forms a cycloalkyl ring.

16. A compound of formula (I) or a pharmaceutically acceptable salt thereof selected from: 【Chemistry 4】 【Transformation 5】 【Transformation 6】 【Transformation 7】 【Transformation 8】 【Chemistry 9】 【Chemistry 10】 【Chemistry 11】 【Chemistry 12】 【Chemistry 13】 【Chemistry 14】

17. 17. A pharmaceutical formulation comprising a compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

18. 18. The pharmaceutical formulation of claim 17 for use in the treatment of a disease or disorder selected from a fibrotic disease, an autoimmune, an inflammatory-fibrotic condition, an inflammatory condition, a central nervous system disorder or cancer.

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