ROCK2 inhibitors

Abstract

The present disclosure relates to inhibitors of Rho-associated protein kinase (ROCK), pharmaceutical compositions containing the same, and uses thereof for the prevention or treatment of ROCK-mediated diseases. In particular, the ROCK inhibitors are selective for inhibiting ROCK2. JPEG2025539146000106.jpg73164

Description

[Technical Field]

[0001] The present disclosure relates to inhibitors of Rho-associated coiled-coil kinase (ROCK), pharmaceutical compositions containing the same, and uses thereof for the prevention or treatment of ROCK-mediated diseases. In particular, the ROCK inhibitors are selective for inhibiting ROCK2. [Background technology]

[0002] Rho-associated coiled-coil kinase (ROCK) is a serine / threonine kinase from the AGC (PKA, PKG, and PKC) kinase family and contains two isoforms, ROCK1 and ROCK2. The two isoforms are differentially expressed and regulated in specific tissues. For example, ROCK1 is ubiquitously expressed at relatively high levels, while ROCK2 is preferentially expressed in certain tissues, including the heart, brain, and skeletal muscle. ROCK is a target of the small GTPase Rho and is involved in diverse cellular activities achieved by phosphorylating downstream effector proteins (e.g., MLC, LIMK, ERM, MARCKS, CRMP-2, etc.). Studies have shown that various diseases (e.g., pulmonary fibrosis, cardiovascular and cerebrovascular diseases, neurological disorders, cancer, etc.) are related to ROCK-mediated pathways. Therefore, ROCK is considered an important target for novel drug development. Summary of the Invention

[0003] In one aspect, the present disclosure provides a compound of formula I: [ka] or a pharmaceutically acceptable salt thereof, wherein: X 1 is N or CH, X 2 is N or CH, X 3 is N or CR 3 and X 4 is N or CR4 and X 5 is selected from the group consisting of C, CH, and N; a is selected from 1 or 2; The dotted line represents an optional double bond; Each R 1 are independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, oxo, -CN, C1-C3 perfluoroalkyl, -OR 11 , and -NR 11 R 12 or selected from the group consisting of or alternatively, two R attached to the same carbon or to adjacent carbons 1 together form a 3-6 membered ring, which optionally contains 0-2 ring heteroatoms selected from O, S and N, and which is unsubstituted or optionally substituted with 1-3 substituents selected from halo, C-C alkyl, NH, OH, and O-C-C alkyl; b is selected from 0, 1, and 2; R 2 is selected from H, halo, C-C alkyl, NH, OH, and O-C-C alkyl; R 3 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoroalkyl, -OR 11 , -O-(C1-C6 alkyl)-OR 11 , -(C1-C6 alkyl)-OR 11 , -NR 11 R 12 , -O-(C1-C6 alkyl)-NR 11 R 12 , -(C1-C6 alkyl)-NR 11 R 12 , -NR 11 -(C1-C6 alkyl)-NR 11 R 12 , -NR 11 -(C1-C6 alkyl)-OR 11, -(C1-C6 alkyl) x -C(=O)R 11 , —O—(C1-C6 alkyl) x -C(=O)R 11 , -(C1-C6 alkyl) x -C(=O)OR 11 , -C(=O)-R 11 , -C(=O)OR 11 , -(C1-C6 alkyl) x -C(=O)NR 11 R 12 , -NR 11 -(C1-C6 alkyl) x -C(=O)R 11 , and -NR 11 -(C1-C6 alkyl) x -C(=O)OR 11 is selected from the group consisting of R 4 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoroalkyl, -OR 11 , -O-(C1-C6 alkyl)-OR 11 , -(C1-C6 alkyl)-OR 11 , -NR 11 R 12 , -O-(C1-C6 alkyl)-NR 11 R 12 , -(C1-C6 alkyl)-NR 11 R 12 , -NR 11 -(C1-C6 alkyl)-NR 11 R 12 , -NR 11 -(C1-C6 alkyl)-OR 11 , -(C1-C6 alkyl) x -C(=O)R 11 , —O—(C1-C6 alkyl) x -C(=O)R 11 , -(C1-C6 alkyl) x -C(=O)OR 11 , -C(=O)-R 11 , -C(=O)OR 11 , -(C1-C6 alkyl) x-C(=O)NR 11 R 12 , -NR 11 -(C1-C6 alkyl) x -C(=O)R 11 , and -NR 11 -(C1-C6 alkyl) x -C(=O)OR 11 is selected from the group consisting of Alternatively, R 3 and R 4 together form a 5- or 6-membered saturated or unsaturated fused ring, which may contain 0-2 ring heteroatoms selected from the group consisting of N, O, and S, and is unsubstituted or selected from C1-C6 alkyl, halo, -CN, -OH, oxo, -O-(C1-C6 alkyl), -O-(C1-C6 alkyl)-OH, -O-(C1-C6 alkyl)-O-(C1-C6 alkyl), -NR 11 R 12 , -O-(C1-C6 alkyl)-NR 11 R 12 , C1-C3 perfluoroalkyl, -NR 11 -(C1-C6 alkyl)NR 11 R 12 , and -NR 11 -(C1-C6 alkyl)-OR 11 and is substituted with 1 to 3 substituents selected from the group consisting of Each R 5 are independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoroalkyl, oxo, -OR 11 , -O-(C1-C6 alkyl)-OR 11 , -(C1-C6 alkyl)-OR 11 , -NR 11 R 12 , -O-(C1-C6 alkyl)-NR 11 R 12 , -(C1-C6 alkyl)-NR 11 R 12 , -NR 11 -(C1-C6 alkyl)-NR 11 R 12 , -NR 11-(C1-C6 alkyl)-OR 11 , -(C1-C6 alkyl) x -C(=O)R 11 , —O—(C1-C6 alkyl) x -C(=O)R 11 , -(C1-C6 alkyl) x -C(=O)OR 11 , -C(=O)-R 11 , -C(=O)OR 11 , -(C1-C6 alkyl) x -C(=O)NR 11 R 12 , -NR 11 -(C1-C6 alkyl) x -C(=O)R 11 , and -NR 11 -(C1-C6 alkyl) x -C(=O)OR 11 is selected from the group consisting of n is 0 to 3, R 6 and R 7 are independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoroalkyl, -OR 11 , -O-(C1-C6 alkyl)-OR 11 , -(C1-C6 alkyl)-OR 11 , -NR 11 R 12 , -O-(C1-C6 alkyl)-NR 11 R 12 , -O-(C1-C6 alkyl)-C(=O)NR 11 R 12 , -(C1-C6 alkyl)-NR 11 R 12 , -(C1-C6 alkyl)-C(=O)NR 11 R 12 , -NR 11 -(C1-C6 alkyl)-NR 11 R 12 , -NR 11 -(C1-C6 alkyl)-OR 11 , -(C1-C6 alkyl) x -C(=O)R 11, —O—(C1-C6 alkyl) x -C(=O)R 11 , -(C1-C6 alkyl) x -C(=O)OR 11 , -C(=O)-R 11 , -C(=O)OR 11 , -(C1-C6 alkyl) x -C(=O)NR 11 R 12 , -NR 11 -(C1-C6 alkyl) x -C(=O)R 11 , and -NR 11 -(C1-C6 alkyl) x -C(=O)OR 11 is selected from the group consisting of Alternatively, R 6 and R 7 together form a 5- or 6-membered saturated or unsaturated fused ring, which may contain 0-2 ring heteroatoms selected from the group consisting of N, O, and S, and is unsubstituted or selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C5-C 10 Aryl, C5-C 10 Heteroaryl, 3-10 membered heterocyclyl, -C1-C6 alkyl-(C3-C7 cycloalkyl), -C1-C6 alkyl-(C5-C 10 aryl), -C1-C6 alkyl-(C5-C 10 heteroaryl), -C1-C6 alkyl-(3-10 membered heterocyclyl), halo, -CN, -OH, oxo, -O-(C1-C6 alkyl), -O-(C1-C6 alkyl)-OH, -O-(C1-C6 alkyl)-O-(C1-C6 alkyl), -NR 11 R 12 , -O-(C1-C6 alkyl)-NR 11 R 12 , C1-C3 perfluoroalkyl, -NR 11 -(C1-C6 alkyl)NR 11 R 12 , -NR 11 -(C1-C6 alkyl)-OR 11 , and -C(=O)-N(R 8)(R 9 wherein each alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl is optionally substituted with 1 to 3 substituents selected from C1-C3 alkyl, C1-C3 perfluoroalkyl, oxo, halo, -CN, -OH, and NH2; R 8 and R 9 are each independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, 3- to 10-membered heterocyclyl, C6-C 10 Aryl, 5-14 membered heteroaryl, C 6-12 Aralkyl, -(C1-C6 alkyl)-OR 11 , -(C1-C6 alkyl)-NR 11 R 12 , -(C1-C6 alkyl) x -C(=O)R 11 , -(C1-C6 alkyl) x -C(=O)OR 11 , and -(C1-C6 alkyl) x -C(=O)NR 11 R 12 wherein each alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl is optionally substituted with 1 to 3 substituents selected from C1-C3 alkyl, C1-C3 perfluoroalkyl, oxo, halo, -CN, -OH, and NH2; Alternatively, R 8 and R 9 are taken together with the nitrogen to which they are attached to provide (i) a 4-6 membered heterocycle having 0-2 additional ring heteroatoms selected from N, O, and S, or (ii) a 5-10 membered heterobicyclic ring system having 0-3 additional ring heteroatoms selected from N, O, and S, wherein the heterocycle or bicyclic ring system is unsubstituted or substituted with halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, -CN, C1-C6 fluoroalkyl, C1-C3 perfluoroalkyl, -OR 11, oxo, -O-(C1-C6 alkyl)-OR 11 , -(C1-C6 alkyl)-OR 11 , -NR 11 R 12 , -O-(C1-C6 alkyl)-NR 11 R 12 , -(C1-C6 alkyl)-NR 11 R 12 , -NR 11 -(C1-C6 alkyl)-NR 11 R 12 , -NR 11 -(C1-C6 alkyl)-OR 11 , -(C1-C6 alkyl) x -C(=O)R 11 , —O—(C1-C6 alkyl) x -C(=O)R 11 , -(C1-C6 alkyl) x -C(=O)OR 11 , -C(=O)-R 11 , -C(=O)OR 11 , -(C1-C6 alkyl) x -C(=O)NR 11 R 12 , -NR 11 -(C1-C6 alkyl) x -C(=O)R 11 , and -NR 11 -(C1-C6 alkyl) x -C(=O)OR 11 and is substituted with 1 to 4 substituents selected from the group consisting of: each x is independently selected from 0 and 1; and Each R 11 and R 12 is independently selected from the group consisting of H and C1-C6 alkyl; or alternatively, R 11 and R 12when both are attached to the same nitrogen, combine to form a 4-7 membered heterocycle having 0-2 additional ring heteroatoms selected from the group consisting of N, O, and S, wherein the heterocycle is unsubstituted or substituted with 1-3 substituents selected from the group consisting of halo, C-C alkyl, C-C alkenyl, C-C alkynyl, C-C cycloalkyl, -CN, -NH, C-C perfluoroalkyl, -OH, -O-(C-C alkyl), and -(C-C alkyl)-OH.

[0004] In another aspect, the present disclosure provides a method for treating a ROCK2-mediated disease or disorder, the method comprising administering to a subject in need thereof an effective amount of a ROCK2 inhibitor provided herein, or a pharmaceutically acceptable salt thereof.

[0005] In embodiments provided in the present disclosure, the methods are used to treat a disease or disorder selected from the group consisting of a fibrotic disease, an inflammatory disease, an autoimmune disease, a cardiovascular disorder, a central nervous system disorder, a neoplastic disease, a metabolic syndrome, an eye disease, a kidney disease, a lung disease, a muscular dystrophy, a sickle cell disease, and a viral disease. [Brief explanation of the drawings]

[0006] [Figure 1] The structures and properties of compounds according to the present disclosure are shown. [Figure 2] Figure 1 shows that the compound of Example 6 inhibits IL-17 (A) and IL-21 (B) in human CD4+ T cells stimulated with conditions favoring Th17. [Figure 3] Figure 2 shows that selective ROCK2 inhibitors reduce profibrogenic gene expression in MRC-5 human fibroblasts pretreated with different doses of selective ROCK2 inhibitors (Compound A, Example 6, and KD025), dose-dependently downregulating TGF-β-induced α-SMA (A) and Col1A1 (B) gene expression as determined by PCR. [Figure 4]1 shows oral bioavailability evaluation (mean plasma concentration over time) in CD1 mice for the compound of Example 6. [Figure 5] 1 shows the efficacy of the compound of Example 6 in a mouse model of scleroderma. DETAILED DESCRIPTION OF THE INVENTION

[0007] The present invention will now be further described. In the following sections, different aspects of the present invention are provided. Each aspect presented may be combined with any other aspect(s), unless expressly indicated to the contrary. In particular, any feature indicated as being preferred or advantageous may be combined with any other feature(s) indicated as being preferred or advantageous.

[0008] The compounds, compositions and methods described herein provide selective inhibitors of Rho-associated coiled-coil kinase 2 (ROCK2) for use in the treatment of diseases or disorders, including fibrotic diseases, inflammatory diseases, autoimmune diseases, cardiovascular disorders, central nervous system disorders, neoplastic diseases, metabolic syndrome, eye diseases, renal diseases, pulmonary diseases, muscular dystrophies, sickle cell diseases, and viral diseases.

[0009] The compounds for use in the methods and compositions disclosed herein are ROCK inhibitors, and in particular, ROCK2-selective inhibitors. The compounds provide excellent inhibitory activity of ROCK (preferably ROCK2) and good selectivity (higher selectivity for ROCK2 over ROCK1). The compounds may further provide one or more of good physicochemical properties (e.g., solubility, physical and / or chemical stability), improved pharmacokinetic properties (e.g., improved bioavailability, adequate half-life and duration of action), improved permeability through the blood-brain barrier, and improved safety (low toxicity and / or fewer side effects, wide therapeutic window).

[0010] In one aspect, the present disclosure provides a compound of formula I: [ka] or a pharmaceutically acceptable salt thereof, wherein: X 1 is N or CH, X 2 is N or CH, X 3 is N or CR 3 and X 4 is N or CR 4 and X 5 is selected from the group consisting of C, CH, and N; a is selected from 1 or 2; The dotted line represents an optional double bond; Each R 1 are independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, oxo, -CN, C1-C3 perfluoroalkyl, -OR 11 , and -NR 11 R 12 or selected from the group consisting of or alternatively, two R attached to the same carbon or to adjacent carbons 1 together form a 3-6 membered ring, which optionally contains 0-2 ring heteroatoms selected from O, S and N, and which is unsubstituted or optionally substituted with 1-3 substituents selected from halo, C-C alkyl, NH, OH, and O-C-C alkyl; b is selected from 0, 1, and 2; R 2 is selected from H, halo, C-C alkyl, NH, OH, and O-C-C alkyl; R 3 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoroalkyl, -OR 11 , -O-(C1-C6 alkyl)-OR 11 , -(C1-C6 alkyl)-OR11 , -NR 11 R 12 , -O-(C1-C6 alkyl)-NR 11 R 12 , -(C1-C6 alkyl)-NR 11 R 12 , -NR 11 -(C1-C6 alkyl)-NR 11 R 12 , -NR 11 -(C1-C6 alkyl)-OR 11 , -(C1-C6 alkyl) x -C(=O)R 11 , —O—(C1-C6 alkyl) x -C(=O)R 11 , -(C1-C6 alkyl) x -C(=O)OR 11 , -C(=O)-R 11 , -C(=O)OR 11 , -(C1-C6 alkyl) x -C(=O)NR 11 R 12 , -NR 11 -(C1-C6 alkyl) x -C(=O)R 11 , and -NR 11 -(C1-C6 alkyl) x -C(=O)OR 11 is selected from the group consisting of R 4 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoroalkyl, -OR 11 , -O-(C1-C6 alkyl)-OR 11 , -(C1-C6 alkyl)-OR 11 , -NR 11 R 12 , -O-(C1-C6 alkyl)-NR 11 R 12 , -(C1-C6 alkyl)-NR 11 R 12 , -NR 11 -(C1-C6 alkyl)-NR 11 R 12 , -NR 11-(C1-C6 alkyl)-OR 11 , -(C1-C6 alkyl) x -C(=O)R 11 , —O—(C1-C6 alkyl) x -C(=O)R 11 , -(C1-C6 alkyl) x -C(=O)OR 11 , -C(=O)-R 11 , -C(=O)OR 11 , -(C1-C6 alkyl) x -C(=O)NR 11 R 12 , -NR 11 -(C1-C6 alkyl) x -C(=O)R 11 , and -NR 11 -(C1-C6 alkyl) x -C(=O)OR 11 is selected from the group consisting of Alternatively, R 3 and R 4 together form a 5- or 6-membered saturated or unsaturated fused ring, which may contain 0-2 ring heteroatoms selected from the group consisting of N, O, and S, and is unsubstituted or selected from C1-C6 alkyl, halo, -CN, -OH, oxo, -O-(C1-C6 alkyl), -O-(C1-C6 alkyl)-OH, -O-(C1-C6 alkyl)-O-(C1-C6 alkyl), -NR 11 R 12 , -O-(C1-C6 alkyl)-NR 11 R 12 , C1-C3 perfluoroalkyl, -NR 11 -(C1-C6 alkyl)NR 11 R 12 , and -NR 11 -(C1-C6 alkyl)-OR 11 and is substituted with 1 to 3 substituents selected from the group consisting of Each R 5 are independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoroalkyl, oxo, -OR 11 , -O-(C1-C6 alkyl)-OR11 , -(C1-C6 alkyl)-OR 11 , -NR 11 R 12 , -O-(C1-C6 alkyl)-NR 11 R 12 , -(C1-C6 alkyl)-NR 11 R 12 , -NR 11 -(C1-C6 alkyl)-NR 11 R 12 , -NR 11 -(C1-C6 alkyl)-OR 11 , -(C1-C6 alkyl) x -C(=O)R 11 , —O—(C1-C6 alkyl) x -C(=O)R 11 , -(C1-C6 alkyl) x -C(=O)OR 11 , -C(=O)-R 11 , -C(=O)OR 11 , -(C1-C6 alkyl) x -C(=O)NR 11 R 12 , -NR 11 -(C1-C6 alkyl) x -C(=O)R 11 , and -NR 11 -(C1-C6 alkyl) x -C(=O)OR 11 is selected from the group consisting of n is 0 to 3, Each R 6 are independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoroalkyl, -OR 11 , -O-(C1-C6 alkyl)-OR 11 , -(C1-C6 alkyl)-OR 11 , -NR 11 R 12 , -O-(C1-C6 alkyl)-NR 11 R 12 , -(C1-C6 alkyl)-NR 11 R 12 , -NR 11-(C1-C6 alkyl)-NR 11 R 12 , -NR 11 -(C1-C6 alkyl)-OR 11 , -(C1-C6 alkyl) x -C(=O)R 11 , —O—(C1-C6 alkyl) x -C(=O)R 11 , -(C1-C6 alkyl) x -C(=O)OR 11 , -C(=O)-R 11 , -C(=O)OR 11 , -(C1-C6 alkyl) x -C(=O)NR 11 R 12 , -NR 11 -(C1-C6 alkyl) x -C(=O)R 11 , and -NR 11 -(C1-C6 alkyl) x -C(=O)OR 11 selected from the group consisting of: Alternatively, R 6 and R 7 together form a 5- or 6-membered saturated or unsaturated fused ring, which may contain 0-2 ring heteroatoms selected from the group consisting of N, O, and S, and is unsubstituted or selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C5-C 10 Aryl, C5-C 10 Heteroaryl, 3-10 membered heterocyclyl, -C1-C6 alkyl-(C3-C7 cycloalkyl), -C1-C6 alkyl-(C5-C 10 aryl), -C1-C6 alkyl-(C5-C 10 heteroaryl), -C1-C6 alkyl-(3-10 membered heterocyclyl), halo, -CN, -OH, oxo, -O-(C1-C6 alkyl), -O-(C1-C6 alkyl)-OH, -O-(C1-C6 alkyl)-O-(C1-C6 alkyl), -NR 11 R 12 , -O-(C1-C6 alkyl)-NR 11 R 12, C1-C3 perfluoroalkyl, -NR 11 -(C1-C6 alkyl)NR 11 R 12 , -NR 11 -(C1-C6 alkyl)-OR 11 , and -C(=O)-N(R 8 )(R 9 wherein each alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl is optionally substituted with 1 to 3 substituents selected from C1-C3 alkyl, C1-C3 perfluoroalkyl, oxo, halo, -CN, -OH, and NH2; R 8 and R 9 are each independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, 3- to 10-membered heterocyclyl, C6-C 10 Aryl, 5-14 membered heteroaryl, C 6-12 Aralkyl, -(C1-C6 alkyl)-OR 11 , -(C1-C6 alkyl)-NR 11 R 12 , -(C1-C6 alkyl) x -C(=O)R 11 , -(C1-C6 alkyl) x -C(=O)OR 11 , and -(C1-C6 alkyl) x -C(=O)NR 11 R 12 wherein each alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl is optionally substituted with 1 to 3 substituents selected from C1-C3 alkyl, C1-C3 perfluoroalkyl, oxo, halo, -CN, -OH, and NH2; Alternatively, R 8 and R 9are taken together with the nitrogen to which they are attached to provide (i) a 4-6 membered heterocycle having 0-2 additional ring heteroatoms selected from N, O, and S, or (ii) a 5-10 membered heterobicyclic ring system having 0-3 additional ring heteroatoms selected from N, O, and S, wherein the heterocycle or bicyclic ring system is unsubstituted or substituted with halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, -CN, C1-C6 fluoroalkyl, C1-C3 perfluoroalkyl, -OR 11 , oxo, -O-(C1-C6 alkyl)-OR 11 , -(C1-C6 alkyl)-OR 11 , -NR 11 R 12 , -O-(C1-C6 alkyl)-NR 11 R 12 , -(C1-C6 alkyl)-NR 11 R 12 , -NR 11 -(C1-C6 alkyl)-NR 11 R 12 , -NR 11 -(C1-C6 alkyl)-OR 11 , -(C1-C6 alkyl) x -C(=O)R 11 , —O—(C1-C6 alkyl) x -C(=O)R 11 , -(C1-C6 alkyl) x -C(=O)OR 11 , -C(=O)-R 11 , -C(=O)OR 11 , -(C1-C6 alkyl) x -C(=O)NR 11 R 12 , -NR 11 -(C1-C6 alkyl) x -C(=O)R 11 , and -NR 11 -(C1-C6 alkyl) x -C(=O)OR 11 and is substituted with 1 to 4 substituents selected from the group consisting of: each x is independently selected from 0 and 1; and Each R 11 and R12 is independently selected from the group consisting of H and C1-C6 alkyl; or alternatively, R 11 and R 12 when both are attached to the same nitrogen, combine to form a 4-7 membered heterocycle having 0-2 additional ring heteroatoms selected from the group consisting of N, O, and S, wherein the heterocycle is unsubstituted or substituted with 1-3 substituents selected from the group consisting of halo, C-C alkyl, C-C alkenyl, C-C alkynyl, C-C cycloalkyl, -CN, -NH, C-C perfluoroalkyl, -OH, -O-(C-C alkyl), and -(C-C alkyl)-OH.

[0011] In some embodiments, the present disclosure provides a compound of formula II: [ka] or a pharmaceutically acceptable salt thereof, wherein: X 1 is N or CH, X 2 is N or CH, X 3 is N or CR 3 and X 4 is N or CR 4 and X 5 is selected from the group consisting of C, CH, and N; The dotted line represents an optional double bond; Each R 1 are independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, oxo, -CN, C1-C3 perfluoroalkyl, -OR 11 , and -NR 11 R 12 or selected from the group consisting of or alternatively, two R attached to the same carbon or to adjacent carbons 1together form a 3-6 membered ring, which optionally contains 0-2 ring heteroatoms selected from O, S and N, and which is unsubstituted or optionally substituted with 1-3 substituents selected from halo, C-C alkyl, NH, OH, and O-C-C alkyl; b is selected from 0, 1, and 2; R 3 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoroalkyl, -OR 11 , -O-(C1-C6 alkyl)-OR 11 , -(C1-C6 alkyl)-OR 11 , -NR 11 R 12 , -O-(C1-C6 alkyl)-NR 11 R 12 , -(C1-C6 alkyl)-NR 11 R 12 , -NR 11 -(C1-C6 alkyl)-NR 11 R 12 , -NR 11 -(C1-C6 alkyl)-OR 11 , -(C1-C6 alkyl) x -C(=O)R 11 , —O—(C1-C6 alkyl) x -C(=O)R 11 , -(C1-C6 alkyl) x -C(=O)OR 11 , -C(=O)-R 11 , -C(=O)OR 11 , -(C1-C6 alkyl) x -C(=O)NR 11 R 12 , -NR 11 -(C1-C6 alkyl) x -C(=O)R 11 , and -NR 11 -(C1-C6 alkyl) x -C(=O)OR 11 is selected from the group consisting of R 4is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoroalkyl, -OR 11 , -O-(C1-C6 alkyl)-OR 11 , -(C1-C6 alkyl)-OR 11 , -NR 11 R 12 , -O-(C1-C6 alkyl)-NR 11 R 12 , -(C1-C6 alkyl)-NR 11 R 12 , -NR 11 -(C1-C6 alkyl)-NR 11 R 12 , -NR 11 -(C1-C6 alkyl)-OR 11 , -(C1-C6 alkyl) x -C(=O)R 11 , —O—(C1-C6 alkyl) x -C(=O)R 11 , -(C1-C6 alkyl) x -C(=O)OR 11 , -C(=O)-R 11 , -C(=O)OR 11 , -(C1-C6 alkyl) x -C(=O)NR 11 R 12 , -NR 11 -(C1-C6 alkyl) x -C(=O)R 11 , and -NR 11 -(C1-C6 alkyl) x -C(=O)OR 11 is selected from the group consisting of Alternatively, R 3 and R 4 together form a 5- or 6-membered saturated or unsaturated fused ring, which may contain 0-2 ring heteroatoms selected from the group consisting of N, O, and S, and is unsubstituted or selected from C1-C6 alkyl, halo, -CN, -OH, oxo, -O-(C1-C6 alkyl), -O-(C1-C6 alkyl)-OH, -O-(C1-C6 alkyl)-O-(C1-C6 alkyl), -NR 11 R12 , -O-(C1-C6 alkyl)-NR 11 R 12 , C1-C3 perfluoroalkyl, -NR 11 -(C1-C6 alkyl)NR 11 R 12 , and -NR 11 -(C1-C6 alkyl)-OR 11 and is substituted with 1 to 3 substituents selected from the group consisting of Each R 5 are independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoroalkyl, oxo, -OR 11 , -O-(C1-C6 alkyl)-OR 11 , -(C1-C6 alkyl)-OR 11 , -NR 11 R 12 , -O-(C1-C6 alkyl)-NR 11 R 12 , -(C1-C6 alkyl)-NR 11 R 12 , -NR 11 -(C1-C6 alkyl)-NR 11 R 12 , -NR 11 -(C1-C6 alkyl)-OR 11 , -(C1-C6 alkyl) x -C(=O)R 11 , —O—(C1-C6 alkyl) x -C(=O)R 11 , -(C1-C6 alkyl) x -C(=O)OR 11 , -C(=O)-R 11 , -C(=O)OR 11 , -(C1-C6 alkyl) x -C(=O)NR 11 R 12 , -NR 11 -(C1-C6 alkyl) x -C(=O)R 11 , and -NR 11 -(C1-C6 alkyl) x -C(=O)OR 11 is selected from the group consisting of n is 0 to 3, X 6 is NR 10 , O and S; X 7 is selected from the group consisting of CH and N; R 8 and R 9 are each independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, 3- to 10-membered heterocyclyl, C6-C 10 Aryl, 5-14 membered heteroaryl, C 6-12 Aralkyl, -(C1-C6 alkyl)-OR 11 , -(C1-C6 alkyl)-NR 11 R 12 , -(C1-C6 alkyl) x -C(=O)R 11 , -(C1-C6 alkyl) x -C(=O)OR 11 , and -(C1-C6 alkyl) x -C(=O)NR 11 R 12 wherein each alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl is optionally substituted with 1 to 3 substituents selected from C1-C3 alkyl, C1-C3 perfluoroalkyl, oxo, halo, -CN, -OH, and NH2; Alternatively, R 8 and R 9 are taken together with the nitrogen to which they are attached to provide (i) a 4-6 membered heterocycle having 0-2 additional ring heteroatoms selected from N, O, and S, or (ii) a 5-10 membered heterobicyclic ring system having 0-3 additional ring heteroatoms selected from N, O, and S, wherein the heterocycle or bicyclic ring system is unsubstituted or substituted with halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, -CN, C1-C6 fluoroalkyl, C1-C3 perfluoroalkyl, -OR 11 , oxo, -O-(C1-C6 alkyl)-OR 11, -(C1-C6 alkyl)-OR 11 , -NR 11 R 12 , -O-(C1-C6 alkyl)-NR 11 R 12 , -(C1-C6 alkyl)-NR 11 R 12 , -NR 11 -(C1-C6 alkyl)-NR 11 R 12 , -NR 11 -(C1-C6 alkyl)-OR 11 , -(C1-C6 alkyl) x -C(=O)R 11 , —O—(C1-C6 alkyl) x -C(=O)R 11 , -(C1-C6 alkyl) x -C(=O)OR 11 , -C(=O)-R 11 , -C(=O)OR 11 , -(C1-C6 alkyl) x -C(=O)NR 11 R 12 , -NR 11 -(C1-C6 alkyl) x -C(=O)R 11 , and -NR 11 -(C1-C6 alkyl) x -C(=O)OR 11 and is substituted with 1 to 4 substituents selected from the group consisting of: R 10 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C5-C 10 Aryl, C5-C 10 Heteroaryl, 3-10 membered heterocyclyl, -C1-C6 alkyl-(C3-C7 cycloalkyl), -C1-C6 alkyl-(C5-C 10 aryl), -C1-C6 alkyl-(C5-C 10 heteroaryl), -C1-C6 alkyl-(3-10 membered heterocyclyl), -(C1-C6 alkyl)-NR 11 R 12 , -(C1-C6 alkyl)NR 11 R 12, -(C1-C6 alkyl)-OR 11 , and -C(=O)-N(R 11 )(R 12 wherein each alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl is optionally substituted with 1 to 3 substituents selected from C1-C3 alkyl, C1-C3 perfluoroalkyl, oxo, halo, -CN, -OH, and NH2; each x is independently selected from 0 and 1; and Each R 11 and R 12 is independently selected from the group consisting of H and C1-C6 alkyl; or alternatively, R 11 and R 12 when both are attached to the same nitrogen, combine to form a 4-7 membered heterocycle having 0-2 additional ring heteroatoms selected from the group consisting of N, O, and S, wherein the heterocycle is unsubstituted or substituted with 1-3 substituents selected from the group consisting of halo, C-C alkyl, C-C alkenyl, C-C alkynyl, C-C cycloalkyl, -CN, -NH, C-C perfluoroalkyl, -OH, -O-(C-C alkyl), and -(C-C alkyl)-OH.

[0012] In some embodiments, the present disclosure provides a compound of formula III: [ka] or a pharmaceutically acceptable salt thereof, wherein: X 2 is N or CH, X 3 is N or CR 3 and X 5 is selected from the group consisting of C, CH, and N; The dotted line represents an optional double bond; Each R 1are independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, oxo, -CN, C1-C3 perfluoroalkyl, -OR 11 , and -NR 11 R 12 or selected from the group consisting of or alternatively, two R attached to the same carbon or to adjacent carbons 1 together form a 3-6 membered ring, which optionally contains 0-2 ring heteroatoms selected from O, S and N, and which is unsubstituted or optionally substituted with 1-3 substituents selected from halo, C-C alkyl, NH, OH, and O-C-C alkyl; b is selected from 0, 1, and 2; R 3 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoroalkyl, -OR 11 , -O-(C1-C6 alkyl)-OR 11 , -(C1-C6 alkyl)-OR 11 , -NR 11 R 12 , -O-(C1-C6 alkyl)-NR 11 R 12 , -(C1-C6 alkyl)-NR 11 R 12 , -NR 11 -(C1-C6 alkyl)-NR 11 R 12 , -NR 11 -(C1-C6 alkyl)-OR 11 , -(C1-C6 alkyl) x -C(=O)R 11 , —O—(C1-C6 alkyl) x -C(=O)R 11 , -(C1-C6 alkyl) x -C(=O)OR 11 , -C(=O)-R 11 , -C(=O)OR 11 , -(C1-C6 alkyl) x -C(=O)NR11 R 12 , -NR 11 -(C1-C6 alkyl) x -C(=O)R 11 , and -NR 11 -(C1-C6 alkyl) x -C(=O)OR 11 is selected from the group consisting of R 4 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoroalkyl, -OR 11 , -O-(C1-C6 alkyl)-OR 11 , -(C1-C6 alkyl)-OR 11 , -NR 11 R 12 , -O-(C1-C6 alkyl)-NR 11 R 12 , -(C1-C6 alkyl)-NR 11 R 12 , -NR 11 -(C1-C6 alkyl)-NR 11 R 12 , -NR 11 -(C1-C6 alkyl)-OR 11 , -(C1-C6 alkyl) x -C(=O)R 11 , —O—(C1-C6 alkyl) x -C(=O)R 11 , -(C1-C6 alkyl) x -C(=O)OR 11 , -C(=O)-R 11 , -C(=O)OR 11 , -(C1-C6 alkyl) x -C(=O)NR 11 R 12 , -NR 11 -(C1-C6 alkyl) x -C(=O)R 11 , and -NR 11 -(C1-C6 alkyl) x -C(=O)OR 11 is selected from the group consisting of Alternatively, R 3 and R 4together form a 5- or 6-membered saturated or unsaturated fused ring, which may contain 0-2 ring heteroatoms selected from the group consisting of N, O, and S, and is unsubstituted or selected from C1-C6 alkyl, halo, -CN, -OH, oxo, -O-(C1-C6 alkyl), -O-(C1-C6 alkyl)-OH, -O-(C1-C6 alkyl)-O-(C1-C6 alkyl), -NR 11 R 12 , -O-(C1-C6 alkyl)-NR 11 R 12 , C1-C3 perfluoroalkyl, -NR 11 -(C1-C6 alkyl)NR 11 R 12 , and -NR 11 -(C1-C6 alkyl)-OR 11 and is substituted with 1 to 3 substituents selected from the group consisting of Each R 5 are independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoroalkyl, oxo, -OR 11 , -O-(C1-C6 alkyl)-OR 11 , -(C1-C6 alkyl)-OR 11 , -NR 11 R 12 , -O-(C1-C6 alkyl)-NR 11 R 12 , -(C1-C6 alkyl)-NR 11 R 12 , -NR 11 -(C1-C6 alkyl)-NR 11 R 12 , -NR 11 -(C1-C6 alkyl)-OR 11 , -(C1-C6 alkyl) x -C(=O)R 11 , —O—(C1-C6 alkyl) x -C(=O)R 11 , -(C1-C6 alkyl) x -C(=O)OR 11 , -C(=O)-R 11 , -C(=O)OR 11 , -(C1-C6 alkyl)x -C(=O)NR 11 R 12 , -NR 11 -(C1-C6 alkyl) x -C(=O)R 11 , and -NR 11 -(C1-C6 alkyl) x -C(=O)OR 11 is selected from the group consisting of n is 0 to 3, X 6 is NR 10 , O and S; X 7 is selected from the group consisting of CH and N; R 8 and R 9 are each independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, 3- to 10-membered heterocyclyl, C6-C 10 Aryl, 5-14 membered heteroaryl, C 6-12 Aralkyl, -(C1-C6 alkyl)-OR 11 , -(C1-C6 alkyl)-NR 11 R 12 , -(C1-C6 alkyl) x -C(=O)R 11 , -(C1-C6 alkyl) x -C(=O)OR 11 , and -(C1-C6 alkyl) x -C(=O)NR 11 R 12 wherein each alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl is optionally substituted with 1 to 3 substituents selected from C1-C3 alkyl, C1-C3 perfluoroalkyl, oxo, halo, -CN, -OH, and NH2; Alternatively, R 8 and R 9are taken together with the nitrogen to which they are attached to provide (i) a 4-6 membered heterocycle having 0-2 additional ring heteroatoms selected from N, O, and S, or (ii) a 5-10 membered heterobicyclic ring system having 0-3 additional ring heteroatoms selected from N, O, and S, wherein the heterocycle or bicyclic ring system is unsubstituted or substituted with halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, -CN, C1-C6 fluoroalkyl, C1-C3 perfluoroalkyl, -OR 11 , oxo, -O-(C1-C6 alkyl)-OR 11 , -(C1-C6 alkyl)-OR 11 , -NR 11 R 12 , -O-(C1-C6 alkyl)-NR 11 R 12 , -(C1-C6 alkyl)-NR 11 R 12 , -NR 11 -(C1-C6 alkyl)-NR 11 R 12 , -NR 11 -(C1-C6 alkyl)-OR 11 , -(C1-C6 alkyl) x -C(=O)R 11 , —O—(C1-C6 alkyl) x -C(=O)R 11 , -(C1-C6 alkyl) x -C(=O)OR 11 , -C(=O)-R 11 , -C(=O)OR 11 , -(C1-C6 alkyl) x -C(=O)NR 11 R 12 , -NR 11 -(C1-C6 alkyl) x -C(=O)R 11 , and -NR 11 -(C1-C6 alkyl) x -C(=O)OR 11 and is substituted with 1 to 4 substituents selected from the group consisting of: R 10is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C5-C 10 Aryl, C5-C 10 Heteroaryl, 3-10 membered heterocyclyl, -C1-C6 alkyl-(C3-C7 cycloalkyl), -C1-C6 alkyl-(C5-C 10 aryl), -C1-C6 alkyl-(C5-C 10 heteroaryl), -C1-C6 alkyl-(3-10 membered heterocyclyl), -(C1-C6 alkyl)-NR 11 R 12 , -(C1-C6 alkyl)NR 11 R 12 , -(C1-C6 alkyl)-OR 11 , and -C(=O)-N(R 11 )(R 12 wherein each alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl is optionally substituted with 1 to 3 substituents selected from C1-C3 alkyl, C1-C3 perfluoroalkyl, oxo, halo, -CN, -OH, and NH2; each x is independently selected from 0 and 1; and Each R 11 and R 12 is independently selected from the group consisting of H and C1-C6 alkyl; or alternatively, R 11 and R 12 when both are attached to the same nitrogen, combine to form a 4-7 membered heterocycle having 0-2 additional ring heteroatoms selected from the group consisting of N, O, and S, wherein the heterocycle is unsubstituted or substituted with 1-3 substituents selected from the group consisting of halo, C-C alkyl, C-C alkenyl, C-C alkynyl, C-C cycloalkyl, -CN, -NH, C-C perfluoroalkyl, -OH, -O-(C-C alkyl), and -(C-C alkyl)-OH.

[0013] In some embodiments, the present disclosure provides compounds of formula IV: [ka] or a pharmaceutically acceptable salt thereof, wherein: R 3 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoroalkyl, -OR 11 , -O-(C1-C6 alkyl)-OR 11 , -(C1-C6 alkyl)-OR 11 , -NR 11 R 12 , -O-(C1-C6 alkyl)-NR 11 R 12 , -(C1-C6 alkyl)-NR 11 R 12 , -NR 11 -(C1-C6 alkyl)-NR 11 R 12 , -NR 11 -(C1-C6 alkyl)-OR 11 , -(C1-C6 alkyl) x -C(=O)R 11 , —O—(C1-C6 alkyl) x -C(=O)R 11 , -(C1-C6 alkyl) x -C(=O)OR 11 , -C(=O)-R 11 , -C(=O)OR 11 , -(C1-C6 alkyl) x -C(=O)NR 11 R 12 , -NR 11 -(C1-C6 alkyl) x -C(=O)R 11 , and -NR 11 -(C1-C6 alkyl) x -C(=O)OR 11 is selected from the group consisting of R 4 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoroalkyl, -OR 11 , -O-(C1-C6 alkyl)-OR11 , -(C1-C6 alkyl)-OR 11 , -NR 11 R 12 , -O-(C1-C6 alkyl)-NR 11 R 12 , -(C1-C6 alkyl)-NR 11 R 12 , -NR 11 -(C1-C6 alkyl)-NR 11 R 12 , -NR 11 -(C1-C6 alkyl)-OR 11 , -(C1-C6 alkyl) x -C(=O)R 11 , —O—(C1-C6 alkyl) x -C(=O)R 11 , -(C1-C6 alkyl) x -C(=O)OR 11 , -C(=O)-R 11 , -C(=O)OR 11 , -(C1-C6 alkyl) x -C(=O)NR 11 R 12 , -NR 11 -(C1-C6 alkyl) x -C(=O)R 11 , and -NR 11 -(C1-C6 alkyl) x -C(=O)OR 11 is selected from the group consisting of Alternatively, R 3 and R 4 together form a 5- or 6-membered saturated or unsaturated fused ring, which may contain 0-2 ring heteroatoms selected from the group consisting of N, O, and S, and is unsubstituted or selected from C1-C6 alkyl, halo, -CN, -OH, oxo, -O-(C1-C6 alkyl), -O-(C1-C6 alkyl)-OH, -O-(C1-C6 alkyl)-O-(C1-C6 alkyl), -NR 11 R 12 , -O-(C1-C6 alkyl)-NR 11 R 12 , C1-C3 perfluoroalkyl, -NR 11 -(C1-C6 alkyl)NR11 R 12 , and -NR 11 -(C1-C6 alkyl)-OR 11 and is substituted with 1 to 3 substituents selected from the group consisting of X 6 is NR 10 , O and S; X 7 is selected from the group consisting of CH and N; R 8 and R 9 are each independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, 3- to 10-membered heterocyclyl, C6-C 10 Aryl, 5-14 membered heteroaryl, C 6-12 Aralkyl, -(C1-C6 alkyl)-OR 11 , -(C1-C6 alkyl)-NR 11 R 12 , -(C1-C6 alkyl) x -C(=O)R 11 , -(C1-C6 alkyl) x -C(=O)OR 11 , and -(C1-C6 alkyl) x -C(=O)NR 11 R 12 wherein each alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl is optionally substituted with 1 to 3 substituents selected from C1-C3 alkyl, C1-C3 perfluoroalkyl, oxo, halo, -CN, -OH, and NH2; Alternatively, R 8 and R 9are taken together with the nitrogen to which they are attached to provide (i) a 4-6 membered heterocycle having 0-2 additional ring heteroatoms selected from N, O, and S, or (ii) a 5-10 membered heterobicyclic ring system having 0-3 additional ring heteroatoms selected from N, O, and S, wherein the heterocycle or bicyclic ring system is unsubstituted or substituted with halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, -CN, C1-C6 fluoroalkyl, C1-C3 perfluoroalkyl, -OR 11 , oxo, -O-(C1-C6 alkyl)-OR 11 , -(C1-C6 alkyl)-OR 11 , -NR 11 R 12 , -O-(C1-C6 alkyl)-NR 11 R 12 , -(C1-C6 alkyl)-NR 11 R 12 , -NR 11 -(C1-C6 alkyl)-NR 11 R 12 , -NR 11 -(C1-C6 alkyl)-OR 11 , -(C1-C6 alkyl) x -C(=O)R 11 , —O—(C1-C6 alkyl) x -C(=O)R 11 , -(C1-C6 alkyl) x -C(=O)OR 11 , -C(=O)-R 11 , -C(=O)OR 11 , -(C1-C6 alkyl) x -C(=O)NR 11 R 12 , -NR 11 -(C1-C6 alkyl) x -C(=O)R 11 , and -NR 11 -(C1-C6 alkyl) x -C(=O)OR 11 and is substituted with 1 to 4 substituents selected from the group consisting of: R 10is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C5-C 10 Aryl, C5-C 10 Heteroaryl, 3-10 membered heterocyclyl, -C1-C6 alkyl-(C3-C7 cycloalkyl), -C1-C6 alkyl-(C5-C 10 aryl), -C1-C6 alkyl-(C5-C 10 heteroaryl), -C1-C6 alkyl-(3-10 membered heterocyclyl), -(C1-C6 alkyl)-NR 11 R 12 , -(C1-C6 alkyl)NR 11 R 12 , -(C1-C6 alkyl)-OR 11 , and -C(=O)-N(R 11 )(R 12 wherein each alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl is optionally substituted with 1 to 3 substituents selected from C1-C3 alkyl, C1-C3 perfluoroalkyl, oxo, halo, -CN, -OH, and NH2; each x is independently selected from 0 and 1; and Each R 11 and R 12 is independently selected from the group consisting of H and C1-C6 alkyl; or alternatively, R 11 and R 12 when both are attached to the same nitrogen, combine to form a 4-7 membered heterocycle having 0-2 additional ring heteroatoms selected from the group consisting of N, O, and S, wherein the heterocycle is unsubstituted or substituted with 1-3 substituents selected from the group consisting of halo, C-C alkyl, C-C alkenyl, C-C alkynyl, C-C cycloalkyl, -CN, -NH, C-C perfluoroalkyl, -OH, -O-(C-C alkyl), and -(C-C alkyl)-OH.

[0014] In some embodiments, the present disclosure provides a compound of formula V: [ka] or a pharmaceutically acceptable salt thereof, wherein: R 3 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoroalkyl, -OR 11 , -O-(C1-C6 alkyl)-OR 11 , -(C1-C6 alkyl)-OR 11 , -NR 11 R 12 , -O-(C1-C6 alkyl)-NR 11 R 12 , -(C1-C6 alkyl)-NR 11 R 12 , -NR 11 -(C1-C6 alkyl)-NR 11 R 12 , -NR 11 -(C1-C6 alkyl)-OR 11 , -(C1-C6 alkyl) x -C(=O)R 11 , —O—(C1-C6 alkyl) x -C(=O)R 11 , -(C1-C6 alkyl) x -C(=O)OR 11 , -C(=O)-R 11 , -C(=O)OR 11 , -(C1-C6 alkyl) x -C(=O)NR 11 R 12 , -NR 11 -(C1-C6 alkyl) x -C(=O)R 11 , and -NR 11 -(C1-C6 alkyl) x -C(=O)OR 11 is selected from the group consisting of R 4 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoroalkyl, -OR 11 , -O-(C1-C6 alkyl)-OR 11, -(C1-C6 alkyl)-OR 11 , -NR 11 R 12 , -O-(C1-C6 alkyl)-NR 11 R 12 , -(C1-C6 alkyl)-NR 11 R 12 , -NR 11 -(C1-C6 alkyl)-NR 11 R 12 , -NR 11 -(C1-C6 alkyl)-OR 11 , -(C1-C6 alkyl) x -C(=O)R 11 , —O—(C1-C6 alkyl) x -C(=O)R 11 , -(C1-C6 alkyl) x -C(=O)OR 11 , -C(=O)-R 11 , -C(=O)OR 11 , -(C1-C6 alkyl) x -C(=O)NR 11 R 12 , -NR 11 -(C1-C6 alkyl) x -C(=O)R 11 , and -NR 11 -(C1-C6 alkyl) x -C(=O)OR 11 is selected from the group consisting of Alternatively, R 3 and R 4 together form a 5- or 6-membered saturated or unsaturated fused ring, which may contain 0-2 ring heteroatoms selected from the group consisting of N, O, and S, and is unsubstituted or selected from C1-C6 alkyl, halo, -CN, -OH, oxo, -O-(C1-C6 alkyl), -O-(C1-C6 alkyl)-OH, -O-(C1-C6 alkyl)-O-(C1-C6 alkyl), -NR 11 R 12 , -O-(C1-C6 alkyl)-NR 11 R 12 , C1-C3 perfluoroalkyl, -NR 11 -(C1-C6 alkyl)NR 11 R12 , and -NR 11 -(C1-C6 alkyl)-OR 11 and is substituted with 1 to 3 substituents selected from the group consisting of R 8 and R 9 are each independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, 3- to 10-membered heterocyclyl, C6-C 10 Aryl, 5-14 membered heteroaryl, C 6-12 Aralkyl, -(C1-C6 alkyl)-OR 11 , -(C1-C6 alkyl)-NR 11 R 12 , -(C1-C6 alkyl) x -C(=O)R 11 , -(C1-C6 alkyl) x -C(=O)OR 11 , and -(C1-C6 alkyl) x -C(=O)NR 11 R 12 wherein each alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl is optionally substituted with 1 to 3 substituents selected from C1-C3 alkyl, C1-C3 perfluoroalkyl, oxo, halo, -CN, -OH, and NH2; Alternatively, R 8 and R 9 are taken together with the nitrogen to which they are attached to provide (i) a 4-6 membered heterocycle having 0-2 additional ring heteroatoms selected from N, O, and S, or (ii) a 5-10 membered heterobicyclic ring system having 0-3 additional ring heteroatoms selected from N, O, and S, wherein the heterocycle or bicyclic ring system is unsubstituted or substituted with halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, -CN, C1-C6 fluoroalkyl, C1-C3 perfluoroalkyl, -OR 11 , oxo, -O-(C1-C6 alkyl)-OR 11 , -(C1-C6 alkyl)-OR 11 , -NR 11 R12 , -O-(C1-C6 alkyl)-NR 11 R 12 , -(C1-C6 alkyl)-NR 11 R 12 , -NR 11 -(C1-C6 alkyl)-NR 11 R 12 , -NR 11 -(C1-C6 alkyl)-OR 11 , -(C1-C6 alkyl) x -C(=O)R 11 , —O—(C1-C6 alkyl) x -C(=O)R 11 , -(C1-C6 alkyl) x -C(=O)OR 11 , -C(=O)-R 11 , -C(=O)OR 11 , -(C1-C6 alkyl) x -C(=O)NR 11 R 12 , -NR 11 -(C1-C6 alkyl) x -C(=O)R 11 , and -NR 11 -(C1-C6 alkyl) x -C(=O)OR 11 and is substituted with 1 to 4 substituents selected from the group consisting of: R 10 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C5-C 10 Aryl, C5-C 10 Heteroaryl, 3-10 membered heterocyclyl, -C1-C6 alkyl-(C3-C7 cycloalkyl), -C1-C6 alkyl-(C5-C 10 aryl), -C1-C6 alkyl-(C5-C 10 heteroaryl), -C1-C6 alkyl-(3-10 membered heterocyclyl), -(C1-C6 alkyl)-NR 11 R 12 , -(C1-C6 alkyl)NR 11 R 12 , -(C1-C6 alkyl)-OR 11 , and -C(=O)-N(R 11)(R 12 wherein each alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl is optionally substituted with 1 to 3 substituents selected from C1-C3 alkyl, C1-C3 perfluoroalkyl, oxo, halo, -CN, -OH, and NH2; each x is independently selected from 0 and 1; and Each R 11 and R 12 is independently selected from the group consisting of H and C1-C6 alkyl; or alternatively, R 11 and R 12 when both are attached to the same nitrogen, combine to form a 4-7 membered heterocycle having 0-2 additional ring heteroatoms selected from the group consisting of N, O, and S, wherein the heterocycle is unsubstituted or substituted with 1-3 substituents selected from the group consisting of halo, C-C alkyl, C-C alkenyl, C-C alkynyl, C-C cycloalkyl, -CN, -NH, C-C perfluoroalkyl, -OH, -O-(C-C alkyl), and -(C-C alkyl)-OH.

[0015] In the above compound embodiments, R 3 is chosen to be H. R 4 may be selected from H, methyl, ethyl, halo, fluoromethyl, difluoromethyl, and trifluoromethyl. In some embodiments, R 3 and R 4 Both are H.

[0016] In the above compound embodiments, R 8 and R 9 may be independently selected from H, C1-C6 alkyl, and C3-C7 cycloalkyl, where each alkyl and cycloalkyl may be optionally substituted with 1 to 3 substituents selected from C1-C3 alkyl, C1-C3 perfluoroalkyl, and halo. 8 and R 9One of may be H and the other is selected from C1-C6 alkyl, and C3-C7 cycloalkyl, each alkyl and cycloalkyl optionally substituted with 1 to 3 substituents selected from C1-C3 alkyl, C1-C3 perfluoroalkyl and halo, especially fluoro.

[0017] In the above compound embodiments, R 8 and R 9 may together with the nitrogen to which they are attached provide a 4- or 5-membered heterocycle, which is unsubstituted or substituted with 1 to 4 substituents selected from the group consisting of C-C alkyl, C-C fluoroalkyl and halo, especially fluoro.

[0018] In the above compound embodiments, R 10 is selected from H and C1-C6 alkyl, in particular R 10 can be methyl.

[0019] In some embodiments, the present disclosure provides a compound of formula VI: [ka] or a pharmaceutically acceptable salt thereof, wherein: Each R 1 are independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, oxo, -CN, C1-C3 perfluoroalkyl, -OR 11 , and -NR 11 R 12 or selected from the group consisting of or alternatively, two R attached to the same carbon or to adjacent carbons 1 together form a 3-6 membered ring, which optionally contains 0-2 ring heteroatoms selected from O, S and N, and which is unsubstituted or optionally substituted with 1-3 substituents selected from halo, C-C alkyl, NH, OH, and O-C-C alkyl; b is selected from 0, 1, and 2; R 21 is selected from the group consisting of H, methyl, halo, fluoromethyl, difluoromethyl, and trifluoromethyl; R 41 is selected from the group consisting of H, methyl, ethyl, halo, fluoromethyl, difluoromethyl, and trifluoromethyl; R 81 is selected from the group consisting of H, C1-C6 alkyl, C3-C6 cycloalkyl, each alkyl or cycloalkyl optionally substituted with 1 to 3 substituents selected from halo, methyl, ethyl, fluoromethyl, difluoromethyl, and trifluoromethyl; R 91 is selected from the group consisting of H, C1-C6 alkyl, C3-C6 cycloalkyl, each alkyl or cycloalkyl optionally substituted with 1 to 3 substituents selected from halo, methyl, ethyl, fluoromethyl, difluoromethyl, and trifluoromethyl; Alternatively, R 81 and R 91 taken together with the nitrogen to which they are attached provide a 4-6 membered heterocycle, which is unsubstituted or substituted with 1 to 4 substituents selected from the group consisting of halo, methyl, ethyl, fluoromethyl, difluoromethyl, and trifluoromethyl; and R 101 is selected from the group consisting of H and methyl.

[0020] In some embodiments, the present disclosure provides a compound of formula VII: [ka] or a pharmaceutically acceptable salt thereof, wherein: R 21 is selected from the group consisting of H, methyl, halo, fluoromethyl, difluoromethyl, and trifluoromethyl; R 41is selected from the group consisting of H, methyl, ethyl, halo, fluoromethyl, difluoromethyl, and trifluoromethyl; R 81 is selected from the group consisting of H, C1-C6 alkyl, C3-C6 cycloalkyl, each alkyl or cycloalkyl optionally substituted with 1 to 3 substituents selected from halo, methyl, ethyl, fluoromethyl, difluoromethyl, and trifluoromethyl; R 91 is selected from the group consisting of H, C1-C6 alkyl, C3-C6 cycloalkyl, each alkyl or cycloalkyl optionally substituted with 1 to 3 substituents selected from halo, methyl, ethyl, fluoromethyl, difluoromethyl, and trifluoromethyl; Alternatively, R 81 and R 91 taken together with the nitrogen to which they are attached provide a 4-6 membered heterocycle, which is unsubstituted or substituted with 1 to 4 substituents selected from the group consisting of halo, methyl, ethyl, fluoromethyl, difluoromethyl, and trifluoromethyl; and R 101 is selected from the group consisting of H and methyl.

[0021] For each of the formulas for inhibitors of ROCK2 provided herein, the substructure: [ka] In the above, the dashed circle represents one or more optional double bonds. Thus, the substructure may be unsaturated, have a single double bond in any chemically permissible position, have two double bonds in chemically permissible positions, or be an aromatic ring system. As will be appreciated by those skilled in the art, the double bonds in such ring systems are not immediately adjacent. In embodiments, the substructure may include: [ka] In other embodiments, the moiety includes: [ka] Includes:

[0022] The term "heteroatom" as used herein means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, and sulfur.

[0023] The term "halogen" or "halo" refers to -F, -Cl, -Br or -I. Preferred halogens are -F, -Cl and -Br.

[0024] The term "hydroxyl" means --OH.

[0025] The term "oxo," as used herein, refers to an oxygen atom having a double bond to another atom, particularly to a carbon (ie, the substituent =O).

[0026] The term "alkyl" refers to the radical of saturated aliphatic groups, including straight-chain and branched-chain alkyl groups. Thus, C1-C6 alkyl includes methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, etc. Fluoroalkyl refers to an alkyl group in which one or more of the hydrogens has been replaced with -F. Perfluoroalkyl refers to an alkyl group in which each of the hydrogens has been replaced with -F.

[0027] The term "cycloalkyl" refers to a saturated carbocyclic group having 3 to 7 carbons in the ring. Cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0028] The term "alkenyl" refers to a straight-chain or branched hydrocarbyl having a double bond and 2 to 6 carbon atoms ("C2-C6 alkenyl"). Alkenyl includes vinyl, 1-propenyl, 2-propenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, 4-methyl-3-pentenyl, and the like. When a compound of the present disclosure contains an alkenyl group, the compound may exist as the E-form, the Z-form, or any mixture thereof.

[0029] The term "alkynyl" refers to a straight-chain or branched hydrocarbyl having a triple bond and two to six carbon atoms ("C2-C6 alkynyl"). Alkynyl includes ethynyl, propynyl, and the like.

[0030] As used herein, the term "aryl" includes 5- and 6-membered monocyclic aromatic groups that can contain zero to four heteroatoms, such as benzene, pyrene, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine. Aryl groups having heteroatoms within the ring structure may also be referred to as "aryl heterocycles," "heteroaromatics," or "heteroaryls." The term "aryl" also includes 7- to 14-membered polycyclic ring systems having two or more cyclic rings in which two or more carbons are shared by two adjacent rings (the rings are "fused rings"), where at least one of the rings is aromatic (including heteroaryl), and where, for example, the other cyclic rings can be fused cycloalkyl, cycloalkenyl, aryl, heteroaryl, and / or heterocyclic groups. Monocyclic heteroaryl groups can have 1 to 3 ring heteroatoms, and fused polycyclic heteroaryl groups can have 1 to 5 ring heteroatoms, the ring heteroatoms being selected from N, O and S.

[0031] The terms "heterocyclyl" and "heterocyclic group" refer to 3- to 10-membered ring structures, more preferably 5- or 6-membered rings, whose ring structures include one to four heteroatoms. Heterocycles can also be polycyclic. Examples of heterocyclic groups include thiophene, thianthrene, furan, pyran, isobenzofuran, chromene, xanthene, phenoxathiin, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, pyrimidine, phenanthroline, phenazine, phenarsazine, phenothiazine, furazan, phenoxazine, pyrrolidine, oxolane, thiolane, oxazole, piperidine, piperazine, morpholine, lactone, lactam, such as azetidinone and pyrrolidinone, sultam, sultone, and the like.

[0032] The term "aralkyl," as used herein, refers to a C1-C6 alkyl group (eg, an aromatic or heteroaromatic group) substituted with an aryl group.

[0033] As used herein, the definition of each designation, e.g., alkyl, m, n, R, etc., when it occurs more than once in any structure, is intended to be independent of its definition elsewhere in that structure.

[0034] It will be understood that "substituted," "substituted," or "substituted with" includes the implicit proviso that such substitution is consistent with the permissible valence of the substituted atom and substituent, and that the substitution results in a stable compound, e.g., one that does not spontaneously undergo transformation by rearrangement, cyclization, elimination, and the like.

[0035] Certain compounds provided in the present disclosure may exist in particular geometric or stereoisomeric forms. The present disclosure contemplates all such compounds as being within the scope of the present invention, including cis- and trans-isomers, R- and S-enantiomers, diastereomers, racemic mixtures thereof, and other mixtures thereof. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included in the present invention.

[0036] The term "pharmaceutically acceptable salts" refers to the relatively non-toxic, inorganic and organic acid addition salts, and inorganic and organic base addition salts, of the compounds disclosed herein.

[0037] As mentioned above, certain embodiments of ROCK2 inhibitors may contain basic functional groups such as amino, and can form pharmaceutically acceptable salts with pharmaceutically acceptable acids.These salts can be prepared in the system during the administration vehicle or dosage form manufacturing process, or can be prepared separately by reacting the purified free base form of the compound of the present invention with a suitable organic or inorganic acid, and isolating the salt thus formed during subsequent purification.Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate and laurylsulfonate, etc. (See, e.g., Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci. 66:1-19).

[0038] Pharmaceutically acceptable salts of the subject compounds include the conventional non-toxic salts or quaternary ammonium salts of the compounds, derived, for example, from non-toxic organic or inorganic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like, and salts prepared from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid (salicyclic acid), sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isothioic acid, and the like.

[0039] In other cases, the compounds provided herein may contain one or more acidic functional groups and therefore can form pharmaceutically acceptable salts with pharmaceutically acceptable bases. These salts can also be prepared in situ during the administration vehicle or dosage form manufacturing process, or separately by reacting the purified free acid form of the compound with a suitable base, such as a hydroxide, carbonate, or bicarbonate of a pharmaceutically acceptable metal cation, ammonia, or a pharmaceutically acceptable organic primary, secondary, or tertiary amine. Representative alkali or alkaline earth salts include lithium, sodium, potassium, calcium, magnesium, and aluminum salts. Representative organic amines useful for forming base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. (See, for example, Berge et al., supra.)

[0040] Treatment method The present disclosure provides a method for preventing or treating a ROCK2-mediated disease, comprising administering to a subject in need thereof an effective amount of a ROCK2 inhibitor disclosed herein, or a pharmaceutically acceptable salt thereof.

[0041] In some embodiments, the present disclosure provides a method of treating at least one disease or disorder selected from the group comprising fibrotic diseases, inflammatory diseases, and autoimmune diseases, comprising administering to a subject in need thereof a therapeutically effective amount of a compound or composition as defined herein.

[0042] In other embodiments, the present disclosure provides a method for the treatment of a cardiovascular disorder, a central nervous system disorder, a neoplastic disease, or metabolic syndrome, comprising administering to a subject in need thereof a therapeutically effective amount of a compound or composition as defined herein.

[0043] In some embodiments, the ROCK2-mediated disease is rheumatoid arthritis, systemic lupus erythematosus (SLE; lupus), psoriasis, psoriatic arthritis, multiple sclerosis, Crohn's disease, ulcerative colitis, atopic dermatitis, eczema, or an autoimmune disorder, including graft-versus-host disease (GVHD; acute and chronic), idiopathic pulmonary fibrosis, and scleroderma.

[0044] Other autoimmune disorders that may be treated according to the methods provided herein include acute disseminated encephalomyelitis (ADEM), acute necrotizing hemorrhagic leukoencephalitis, Addison's disease, alopecia areata, amyloidosis, ankylosing spondylitis, anti-GBM / anti-TBM nephritis, antiphospholipid syndrome (APS), autoimmune angioedema, autoimmune aplastic anemia, autoimmune autonomic neuropathy, autoimmune hepatitis, autoimmune hyperlipidemia, autoimmune immunodeficiency, autoimmune inner ear disease (AIED), autoimmune myocarditis, autoimmune oophoritis, autoimmune pancreatitis, autoimmune retinopathy, autoimmune thyroid disease, autoimmune Urticaria, axonal and neuronal neuropathy, Barrow's disease, Behçet's disease, bullous pemphigoid, cardiomyopathy, Castleman's disease, celiac disease, Chagas' disease, chronic inflammatory demyelinating polyneuropathy (CIDP), chronic relapsing multifocal osteomyelitis (CRMO), Churg-Strauss syndrome, Cogan's syndrome, Coxsackie myocarditis, CREST disease, demyelinating neuropathy, dermatitis herpetiformis, dermatomyositis, Devic's disease (neuromyelitis optica), discoid lupus erythematosus, Dressler's syndrome, eosinophilic esophagitis, eosinophilic fasciitis, erythema nodosum, Evans' syndrome, fibrosing alveolitis, giant cell Arteritis (temporal arteritis), giant cell myocarditis, glomerulonephritis, Goodpasture's syndrome, granulomatosis with polyangiitis (GPA), Graves' disease (known as Graves' disease in Japan), Guillain-Barré syndrome, Hashimoto's encephalitis, Hashimoto's thyroiditis, hemolytic anemia, Henoch-Schönlein purpura, hypogammaglobulinemia, idiopathic thrombocytopenic purpura (ITP), IgA nephropathy, IgG4-related sclerosing disease, immunoregulatory lipoproteins, inclusion body myositis, interstitial cystitis, juvenile arthritis, juvenile myositis, Kawasaki syndrome, Lambert-Eaton syndrome, leukocytoclastic vasculitis, lichen planus, lichen sclerosus, and woody nodules Meningitis, linear immunoglobulin A disease (LAD), Meniere's disease, microscopic polyangiitis, mixed connective tissue disease (MCTD), Mooren's ulcer, Much-Habermann disease, myasthenia gravis, myositis, neuromyelitis optica, neutropenia, ocular cicatricial pemphigoid, optic neuritis, relapsing rheumatism, streptococcal pediatric autoimmune neuropsychiatric disorders (PANDAS), paraneoplastic cerebellar degeneration, paroxysmal nocturnal hemoglobinuria (PNH), Parry-Romberg syndrome, Parsonage-Turner syndrome, pars planitis (peripheral uveitis), pemphigus, peripheral neuropathy, perivenous encephalomyelitis, pernicious anemia, POEMS syndrome,Polyarteritis nodosa, Autoimmune Polyglandular Syndrome (Types I, II, III), Polymyalgia Rheumatica, Polymyositis, Post-myocardial infarction Syndrome, Post-pericardiotomy Syndrome, Progestational Dermatitis, Primary Biliary Cirrhosis, Primary Sclerosing Cholangitis, Psoriatic Arthritis, Pyoderma Gangrenosum, Pure Red Cell Aplasia, Raynaud's Phenomenon, Reactive Arthritis, Reflex Sympathetic Dystrophy, Reiter's Syndrome, Relapsing Polychondritis, Retroperitoneal Fibrosis, Sarcoidosis, Schmidt's Syndrome, Scleritis, Sjögren's Syndrome, Sperm & Testicular Autoimmunity These include autoimmunity, stiff-person syndrome, subacute bacterial endocarditis (SBE), Susac syndrome, sympathetic ophthalmia, Takayasu's arteritis, temporal arteritis / giant cell arteritis, thrombocytopenic purpura (TTP), Tolosa-Hunt syndrome, transverse myelitis, undifferentiated connective tissue disease (UCTD), autoimmune type 1 diabetes, uveitis, vasculitis, vesicular-bullous dermatoses, vitiligo, and Wegener's granulomatosis (granulomatosis with polyangiitis; GPA).

[0045] Inflammatory disorders that can be treated by the methods provided herein include, but are not limited to, cardiovascular inflammation, pulmonary inflammation, renal inflammation, arteriosclerosis, and sepsis.

[0046] Fibrotic disorders that can be treated by the methods provided herein include idiopathic pulmonary fibrosis, renal fibrosis, kidney fibrosis, ocular fibrosis, cardiac fibrosis, NASH, scleroderma, systemic sclerosis, and liver cirrhosis.

[0047] In another embodiment, the present disclosure provides a method for the treatment of muscular dystrophy (Duchenne muscular dystrophy). In another embodiment, the present disclosure provides a method for the treatment of myotonic dystrophy.

[0048] In other embodiments, the ROCK2 inhibitors provided herein can be used to inhibit tumor cell growth and metastasis, as well as angiogenesis, and are useful for treating neoplastic diseases. Neoplastic diseases include any malignant growth or tumor caused by abnormal or uncontrolled cell division. Neoplastic diseases include lymphoma, carcinoma, leukemia, sarcoma, and blastoma. Non-limiting examples include squamous cell carcinoma, small cell lung cancer, pituitary cancer, esophageal cancer, astrocytoma, soft tissue sarcoma, non-small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, peritoneal cancer, hepatocellular carcinoma, gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, bladder cancer, liver cancer, hepatoma, breast cancer, colon cancer, colorectal cancer, endometrial or uterine cancer, salivary gland cancer, kidney cancer, liver cancer, prostate cancer, vulvar cancer, thyroid cancer, liver cancer, brain tumors, melanoma, and various types of head and neck cancer.

[0049] In other embodiments, the ROCK2 inhibitors provided herein may be used to treat cardiovascular disorders, including hypertension, cardiomyopathy, cardiac remodeling, atherosclerosis, restenosis, cardiac hypertrophy, cerebral ischemia, cerebral vasospasm, and erectile dysfunction.

[0050] In other embodiments, the ROCK2 inhibitors provided herein may be used to treat pulmonary disorders, including idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, and asthma.

[0051] In other embodiments, the ROCK2 inhibitors provided herein may be used to treat central nervous system disorders, including neuronal degeneration or spinal cord injury, traumatic brain injury, cerebral cavernous malformation, Huntington's disease, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), or multiple sclerosis.

[0052] In other embodiments, the present disclosure provides methods of treating kidney diseases, including polycystic kidney disease, renal fibrosis, and diabetic kidney disease.

[0053] In other embodiments, the ROCK2 inhibitors provided herein can be used to treat metabolic diseases, including insulin resistance, hyperinsulinemia, type 2 diabetes, obesity, metabolic syndrome, and glucose intolerance. ROCK2 inhibitors can be used to induce weight loss and / or limit weight gain. In one embodiment, ROCK2 inhibitors are used to reduce or prevent insulin resistance or restore insulin sensitivity.

[0054] In other embodiments, the ROCK2 inhibitors provided herein may be used to treat ocular disorders, including ocular hypertension, age-related macular degeneration (AMD; wet and dry), choroidal neovascularization (CNV), choroidal tumors, diabetic macular edema (DME), iris neovascularization, uveitis, glaucoma, primary open-angle glaucoma, acute angle-closure glaucoma, pigmentary glaucoma, congenital glaucoma, normal-tension glaucoma, secondary glaucoma, neovascular glaucoma, geographic atrophy, and retinitis of prematurity (ROP).

[0055] In another embodiment, the present disclosure provides a method of treating sickle cell disease.

[0056] In other embodiments, ROCK2 inhibitors provided herein can be used to treat (i.e., cure or reduce the severity of, etc.) viral infections, particularly coronavirus infections, e.g., SARS-CoV-1, SARS-CoV-2, and MERS-CoV, as well as to treat or prevent sequelae resulting from viral infections, including coronavirus infections, e.g., SARS-CoV-1, SARS-CoV-2, and MERS-CoV. In some embodiments, the viral infection is a SARS-CoV-1 infection. In some embodiments, the viral infection is a SARS-CoV-2 infection. In some embodiments, the infection is a MERS-CoV infection. In embodiments, the sequelae include one or more of the group consisting of fatigue, dyspnea (difficulty breathing), cough, arthralgia (pain in the joints), muscle pain, headache, chest pain, fever, palpitations, myocardial inflammation, ventricular dysfunction, stroke, pulmonary function abnormalities, fibrosis (e.g., pulmonary fibrosis), renal dysfunction, rash, alopecia, smell and / or taste disorders, sleep regulation disorders, cognitive changes, memory impairment, depression, anxiety, mood changes, and combinations thereof. In embodiments, the sequelae include inflammation and / or fibrosis.

[0057] Pharmaceutical Composition In one aspect, the present disclosure provides a pharmaceutically acceptable composition for use in treating a viral disease, the composition comprising a therapeutically effective amount of one or more of the ROCK2 inhibitors provided in the present disclosure formulated together with one or more pharmaceutically acceptable carriers. As described below, the pharmaceutical compositions of the present disclosure may be specially formulated for administration in solid or liquid form, including forms compatible with: (1) oral administration, e.g., drenches (aqueous or non-aqueous solutions, or suspensions), tablets, e.g., those intended for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; (2) parenteral administration, e.g., by subcutaneous, intramuscular, intravenous, or epidural injection, e.g., as a sterile solution or suspension, or sustained-release formulation; (3) topical application, e.g., as a cream, plaster, or controlled-release patch or spray applied to the skin; (4) vaginal or rectal administration, e.g., as a suppository, pessary, cream, or foam; (5) sublingual administration; (6) ocular administration; (7) transdermal administration; or (8) nasal administration.

[0058] The phrase "pharmaceutically acceptable" is used herein to refer to compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0059] As used herein, the phrase "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, manufacturing aid (e.g., lubricant, talc, magnesium, calcium, or zinc stearate, or stearic acid (steric acid)), solvent, or solvent encapsulating material, that is involved in carrying or transporting a compound of interest from one organ or body part to another. Each carrier must be compatible with the other ingredients of the formulation and not deleterious to the patient. Some examples of materials that can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethylcellulose, ethyl cellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository wax; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols, such as propanediol, sorbitan, sorbitol ... (11) polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) pH buffers; (21) polyesters, polycarbonates, and / or polyanhydrides; and (22) other non-toxic, compatible materials used in pharmaceutical formulations.

[0060] The compounds of the present disclosure can be formulated using conventional carriers and excipients, which may be selected in accordance with ordinary practice. Tablets may contain excipients, lubricants, fillers, binders, etc. Aqueous formulations may be prepared in sterile form and generally be isotonic if intended for delivery by other than oral administration. All formulations may optionally contain excipients, such as those listed in the "Handbook of Pharmaceutical Excipients" (1986). Excipients include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextran, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid, etc.

[0061] While it is possible for the ROCK2 inhibitors disclosed herein (referred to herein as "active ingredients") to be administered alone, it may be preferable to present them as pharmaceutical formulations. The formulations of the present disclosure, both for veterinary and human use, comprise at least one active ingredient, as provided above, along with one or more acceptable carriers therefor, and optionally other therapeutic ingredients, particularly additional therapeutic ingredients as described herein.

[0062] Formulations include those suitable for the routes of administration provided herein. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. General techniques and formulations can be found in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, Pa.). Such methods include the step of bringing into association the active ingredient with the carrier, which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[0063] Formulations of the present disclosure suitable for oral administration may be presented as discrete units each containing a predetermined amount of the active ingredient, such as capsules, cachets, or tablets; as a powder or granules; as a solution or suspension made in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be administered as a bolus, electuary, or paste.

[0064] Tablets can be made by compression or wet compression, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in a free-flowing form, such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surfactant, or dispersing agent. Molded tablets can be made by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent. Tablets can optionally be coated or scored, and are optionally formulated to provide a slow or controlled release of the active ingredient therefrom.

[0065] For infections of the eye or other external tissues, such as the mouth and skin, the formulations are preferably applied as topical solutions, ointments, or creams containing the active ingredient(s). The active ingredient may be present in an amount of, for example, 0.075-20% w / w (including active ingredient(s) in 0.1% w / w increments ranging from 0.1% to about 20%, e.g., 0.6% w / w, 0.7% w / w, etc.), preferably 0.2-15% w / w, and most preferably 0.5-10% w / w. When formulated into an ointment, the active ingredient may be used with either a paraffinic or water-miscible ointment base. Alternatively, the active ingredient may be formulated into a cream with an oil-in-water cream base.

[0066] If desired, the aqueous phase of the cream base may contain, for example, at least 30% w / w of a polyhydric alcohol, i.e., an alcohol having two or more hydroxyl groups, such as propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerol, and polyethylene glycol (including PEG 400), and mixtures thereof. Topical formulations may desirably include a compound that enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such skin penetration enhancers include dimethyl sulfoxide and related analogues.

[0067] The oil phase of the emulsion of the present disclosure can be composed of known ingredients in a known manner. The phase may simply contain an emulsifier (also known as an emulgent), but desirably contains a mixture of at least one emulsifier with a fat or oil, or both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier that acts as a stabilizer. It is also preferred to include both an oil and a fat. Taken together, the emulsifier(s), with or without stabilizer(s), constitutes the so-called emulsifying wax, and the wax, oil, and fat together constitute the so-called emulsifying ointment base, which forms the oily dispersed phase of the cream formulation.

[0068] Emulsifiers and emulsion stabilizers suitable for use in the formulations of the present disclosure include Tween® 60, Span® 80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl mono-stearate, and sodium lauryl sulfate. Additional emulsifiers and emulsion stabilizers suitable for use in the formulations of the present disclosure include Tween® 80.

[0069] The selection of suitable oils or fats for formulation is based on achieving the desired properties. Creams should preferably be non-greasy, non-staining, and washable products with a viscosity suitable for avoiding leakage from tubes or other containers. Linear or branched monobasic or dibasic alkyl esters, such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acid, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate, or a blend of branched esters known as crodamol CAP, may be used, the last three being the preferred esters. These may be used alone or in combination depending on the properties required. Alternatively, high-melting lipids, such as white soft paraffin and / or liquid paraffin, or other mineral oils, may be used.

[0070] Pharmaceutical formulations according to the present disclosure include, in addition to the combination of the present disclosure, one or more pharmaceutically acceptable carriers or excipients, and optionally other therapeutic agents. Pharmaceutical formulations containing the active ingredient can be in any form suitable for the intended method of administration. For example, when used for oral use, tablets, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups, or elixirs can be prepared. Compositions intended for oral use can be prepared according to any method known in the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents, such as sweeteners, flavoring agents, coloring agents, and preservatives, to provide a palatable preparation. Tablets containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients suitable for the manufacture of tablets are acceptable. These excipients may be, for example, inert diluents, such as calcium or sodium carbonate, lactose, calcium or sodium phosphate; granulating and disintegrating agents, such as corn starch or alginic acid; binders, such as starch, gelatin, or acacia gum; and lubricants, such as magnesium stearate, stearic acid, or talc. Tablets may be uncoated or may be coated by known techniques, including microencapsulation, to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action over a longer period. For example, a time-delay material, such as glyceryl monostearate or glyceryl distearate, alone or with a wax, may be employed.

[0071] Formulations for oral use may also be presented as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, such as starch, mannitol, calcium phosphate, or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin, or olive oil.

[0072] Aqueous suspensions of the present disclosure contain the active material mixed with excipients suitable for the manufacture of aqueous suspensions. Such excipients include suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, and gum acacia; dispersing or wetting agents such as naturally occurring phosphatides (e.g., lecithin), condensation products of alkylene oxides with fatty acids (e.g., polyoxyethylene stearates), condensation products of ethylene oxide with long-chain aliphatic alcohols (e.g., heptadecaethyleneoxycetanol), and condensation products of ethylene oxide with fatty acids and partial esters derived from hexitol anhydrides (e.g., polyethylene sorbitan monooleate). Aqueous suspensions may also contain one or more preservatives, for example, ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweeteners, such as sucrose or saccharin. Further non-limiting examples of suspending agents include cyclodextrins and Captisol (= sulfobutyl ether beta-cyclodextrin; SEB-beta-CD).

[0073] Oil suspensions can be prepared by suspending the active ingredient in vegetable oil, such as peanut oil, olive oil, sesame oil or coconut oil, or in mineral oil, such as liquid paraffin. Oral suspensions can contain thickening agents, such as beeswax, hard paraffin or cetyl alcohol. To provide a palatable oral preparation, sweeteners, such as those listed above, and flavoring agents can be added. These compositions can be preserved by adding antioxidants such as ascorbic acid.

[0074] Dispersible powders and granules of the present disclosure suitable for preparing an aqueous suspension by adding water provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those disclosed above. Additional excipients, such as sweeteners, flavoring agents, and coloring agents, may also be present.

[0075] The pharmaceutical compositions of the present disclosure may also be in the form of oil-in-water emulsions. The oil phase may be a vegetable oil, such as olive oil or peanut oil, or a mineral oil, such as liquid paraffin, or a mixture thereof. Suitable emulsifiers include naturally occurring gums, such as acacia gum and / or tragacanth gum, naturally occurring phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of these partial esters with ethylene oxide, such as polyoxyethylenesorbitan monooleate. Emulsions may also contain sweeteners and flavoring agents. Syrups and elixirs may be formulated with sweeteners, such as glycerol, sorbitol, or sucrose. Such formulations may also contain demulcents, preservatives, flavorings, or coloring agents.

[0076] The pharmaceutical compositions of the present disclosure may be in the form of a sterile injectable preparation, for example, an aqueous or oleaginous sterile injectable suspension. These suspensions may be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents mentioned above. Sterile injectable preparations may also be sterile injectable solutions made with non-toxic parenterally acceptable diluents or solvents, such as solutions made with 1,3-butanediol, or may be prepared as lyophilized powders. Among the acceptable vehicles and solvents that may be used are water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile fixed oils are conventionally used as solvents or suspending media. For this purpose, any bland, odorless fixed oil, including synthetic mono- or diglycerides, may be used. Additionally, fatty acids such as oleic acid may also be used in the preparation of injectables. Acceptable vehicles and solvents that may be used include water, Ringer's solution, isotonic sodium chloride solution, and hypertonic sodium chloride solution, among others.

[0077] The amount of active ingredient that can be combined with carrier materials to produce a single dosage form can vary depending on the host treated and the particular mode of administration. For example, a sustained-release formulation intended for oral administration to humans can contain approximately 1 to 1,000 mg of active ingredient, compounded with an appropriate and convenient amount of carrier material, which can vary from about 5% to about 95% (weight:weight) of the total composition. Pharmaceutical compositions can be prepared to provide easily measurable amounts for administration. For example, an aqueous solution intended for intravenous infusion can contain about 3 to 500 μg of active ingredient per milliliter of solution, so that infusion of a suitable volume can occur at a rate of about 30 mL / hour.

[0078] Formulations suitable for topical administration to the eye also include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient. The active ingredient may be present in such formulations in a concentration of 0.5 to 20%, conveniently 0.5 to 10%, especially about 1.5% w / w.

[0079] Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base, for example, gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.

[0080] Formulations for rectal administration may be presented as a suppository with a suitable base comprising, for example, cocoa butter or a salicylate.

[0081] Formulations suitable for pulmonary or nasal administration have particle sizes ranging from 0.1 to 500 microns, e.g., 0.5, 1, 30, or 35 microns, and are administered by rapid inhalation through the nasal passages or by inhalation through the mouth to reach the alveolar sacs. Suitable formulations include aqueous or oily solutions of the active ingredient. Formulations suitable for aerosol or dry powder administration can be prepared according to conventional methods and can be delivered with other therapeutic agents, e.g., compounds.

[0082] Formulations suitable for topical administration may be presented as suppositories, pessaries, tampons, creams, gels, pastes, foams or spray formulations containing, in addition to the active ingredient, such carriers as are known in the art to be appropriate.

[0083] Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostats, and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.

[0084] The formulations may be presented in unit-dose or multi-dose containers, for example, sealed ampoules and vials, and may be stored in a lyophilized condition (freeze-dried) requiring only the addition of a sterile liquid carrier, for example, water for injections. Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules, and tablets of the kind previously described. Preferred unit dosage formulations are those containing a daily dose or unit daily sub-dose, as herein above recited, or an appropriate fraction thereof, of the active ingredient.

[0085] The present disclosure further provides a veterinary composition comprising at least one active ingredient, as defined above, together with a veterinary carrier therefor.

[0086] A veterinary carrier is a material useful for the purpose of administering the composition, and may be a solid, liquid, or gaseous material that is otherwise inert or acceptable in the veterinary field and compatible with the active ingredient. These veterinary compositions may be administered orally, parenterally, or by any other desired route.

[0087] The compounds of the present disclosure are used to provide controlled-release pharmaceutical formulations ("controlled-release formulations") containing one or more compounds of the present disclosure as active ingredients, where release of the active ingredient is controlled and regulated to allow for less frequent administration or to improve the pharmacokinetic or toxicity profile of a given active ingredient.

[0088] The patient undergoing this treatment is any animal in need, including primates, particularly humans, as well as other mammals such as horses, cattle, pigs and sheep; and poultry and pets in general. [Example]

[0089] Example 1 Method A. Exemplification by the synthesis of 2-(3,3-difluoroazetidine-1-carbonyl)-1-methyl-6-{4-[3-(1H-pyrazol-4-yl)pyrrolidin-1-yl]pyrimidin-2-yl}-1H-indole (Example 6) [ka]

[0090] Step 1: Synthesis of Intermediate 1: 6-Bromo-2-(3,3-difluoroazetidine-1-carbonyl)-1H-indole

[0091] 6-Bromoindole-2-carboxylic acid (5.26 g, 21.91 mmol, 1.00 equiv) was dissolved in anhydrous DCM (25.0 mL). Oxalyl chloride (2.04 ml, 24.10 mmol, 1.10 equiv) was then added dropwise to the reaction mixture at 0° C., followed by the addition of a few drops of DMF. The mixture was stirred at 0° C. for 1 h, after which the cold bath was removed and stirring continued at room temperature for 3 h. TLC analysis indicated complete conversion of the starting material, and UPLC-MS analysis indicated the mass was consistent with the appropriate ester (sample quenched with MeOH). The reaction mixture was evaporated to dryness and co-evaporated twice with ACN. The resulting cream-colored powder was then redissolved in THF (25.0 mL) and transferred dropwise via syringe to a stirred, ice-cold solution of 3,3-difluoroazetidine hydrochloride (2.84 g, 21.91 mmol, 1.00 equiv.) and N,N-diisopropylethylamine (15.27 mL, 87.65 mmol, 4.00 equiv.) in DCM (25.0 mL). After 1 h at 0 °C, the cold bath was removed and the mixture was stirred at room temperature overnight. A solution of NaHCO3 was then added, and the DCM and THF mixture was removed in vacuo. The precipitate was collected by suction filtration, washed with water, and dried under high vacuum for 18 h to give 6-bromo-2-(3,3-difluoroazetidine-1-carbonyl)-1H-indole (6.5 g, 90% yield). 1 H NMR (400 MHz, DMSO-d6) δ 11.93 - 11.86 (m, 1H), 7.65 - 7.59 (m, 2H), 7.21 (dd, J = 8.6, 1.8 Hz, 1H), 6.95 (dd, J = 2.2, 0.9 Hz, 1H), 4.77 (m, J = 170.3 Hz, 4H). m / z: [M+H] - =314.8.

[0092] Step 2: Synthesis of 6-bromo-2-(3,3-difluoroazetidine-1-carbonyl)-1-methyl-1H-indole.

[0093] To a solution of 6-bromo-2-(3,3-difluoroazetidine-1-carbonyl)-1H-indole (1.20 g, 3.81 mmol, 1.00 equiv.) in anhydrous DMF (15.0 mL) was added NaH (0.12 g, 4.57 mmol, 1.20 equiv.) portionwise at 0 °C. The resulting mixture was stirred at the same temperature for 1 h. Then, methyl iodide (0.26 mL, 4.19 mmol, 1.10 equiv.) was added dropwise. Stirring was continued at 0 °C for 30 min and then at room temperature overnight. The progress of the reaction was monitored using TLC analysis (eluent: 10% MeOH-DCM). The reaction mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to give 6-bromo-2-(3,3-difluoroazetidine-1-carbonyl)-1-methyl-1H-indole (1.09 g, 70% yield), which was used in the next step without purification. 1 H NMR (400 MHz, DMSO-d6) δ 7.87 - 7.84 (m, 1H), 7.59 (d, J = 8.5 Hz, 1H), 7.25 (dd, J = 8.5, 1.7 Hz, 1H), 7.04 (d, J = 0.8 Hz, 1H), 5.04 - 4.38 (m, 4H), 3.93 (s, 3H). m / z: [M+H] + =330.75

[0094] Step 3: 2-(3,3-Difluoroazetidine-1-carbonyl)-1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (Intermediate 1).

[0095] 6-Bromo-2-(3,3-difluoroazetidine-1-carbonyl)-1-methyl-1H-indole (0.74 g, 2.25 mmol, 1.00 equiv.), bis(pinacolato)diboron (0.85 g, 3.37 mmol, 1.50 equiv.), and potassium acetate (0.66 g, 6.74 mmol, 3.00 equiv.) were dissolved in anhydrous dioxane (9.0 mL). The reaction mixture was purged with argon four times, after which 1,1'-bis(diphenylphosphino)-ferrocene-palladium(II) (0.05 g, 0.06 mmol, 0.03 equiv.) was added. The reaction mixture was placed in a preheated oil bath at 90 °C overnight. The reaction mixture was cooled to room temperature, filtered through a Celit pad, concentrated, and purified using flash column chromatography (0-10% MeOH in DCM, gradient elution) to give 2-(3,3-difluoroazetidine-1-carbonyl)-1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (Intermediate 1) (0.81 g, 89% yield). 1 H NMR (400 MHz, DMSO-d6) δ 7.83 (d, J = 0.9 Hz, 1H), 7.63 (dd, J = 8.0, 0.8 Hz, 1H), 7.42 (dd, J = 8.0, 0.9 Hz, 1H), 7.03 (d, J = 0.9 Hz, 1H), 4.70 (d, J = 105.5 Hz, 5H), 3.98 (s, 3H), 1.33 (s, 11H). m / z: [M+H] + =377.15.

[0096] Step 1': Synthesis of Intermediate 2: 3-(trifluoromethanesulfonyloxy)-2,5-dihydro-1H-pyrrole-1-carboxylate

[0097] To a stirred solution of 1-N-Cbz-3-pyrrolidinone (35.0 g, 159.642 mmol, 1.0 equiv) in anhydrous tetrahydrofuran (280 mL, 8.0 vol) cooled to −78°C, a 1.0 M solution of lithium bis(trimethylsilyl)amide in THF (167.62 mL, 167.62 mmol, 1.05 equiv) was added dropwise via syringe. After the addition was complete, the reaction mixture was stirred at 0°C for 40 minutes. The reaction mixture was then recooled to −78°C, and Comins reagent, i.e., 2-[N,N-bis(trifluoromethanesulfonyl)amino]-5-chloropyridine (75.22 g, 191.57 mmol, 1.20 equiv), was added. The reaction mixture was allowed to stir overnight at room temperature. After this time, complete conversion of the starting material was observed by TLC analysis (eluent: 30% EtOAc-hexane). The desired compound is UV inert and only visible after staining with Ce-Mo).

[0098] The reaction mixture was quenched with NaHCO and extracted with EtOAc. The organic layer was dried over NaSO, filtered, concentrated, and purified using CC (0-30% EtOAc in Hex, gradient elution) to give benzyl 3-(trifluoromethanesulfonyloxy)-2,5-dihydro-1H-pyrrole-1-carboxylate (19.08 g, 52.14 mmol, 33% yield). 1 H NMR (300 MHz, chloroform-d) δ 7.40 (d, J = 4.1 Hz, 5H), 5.78 (ddd, J = 16.4, 3.7, 1.9 Hz, 1H), 5.19 (d, J = 3.3 Hz, 2H), 4.39 - 4.25 (m, 4H).

[0099] Step 2': Benzyl 3-[1-(oxan-2-yl)-1H-pyrazol-4-yl]-2,5-dihydro-1H-pyrrole-1-carboxylate

[0100] A mixture of 1-(2-tetrahydropyranyl)-1H-pyrazole-4-boronic acid pinacol ester (15.95 g, 57.35 mmol, 1.1 equiv.), 3-(trifluoromethanesulfonyloxy)-2,5-dihydro-1H-pyrrole-1-carboxylate (19.08 g, 52.14 mmol, 1.0 equiv.), and anhydrous potassium carbonate (18.015 g, 130.35 mmol, 2.5 equiv.) was dissolved in anhydrous tetrahydrofuran (286.2 mL, 15.0 vol.) with a catalytic amount of water. The reaction mixture was purged with argon, and then tetrakis(triphenylphosphine)palladium (3.013 g, 2.607 mmol, 0.05 equiv.) was added. The reaction mixture was placed in a sealed vial and stirred at 100 °C overnight. TLC analysis indicated complete conversion of the starting material. The reaction mixture was dissolved in EtOAc, filtered through a Celit pad, and concentrated. The resulting material was redissolved in DCM on a short silica pad and washed with EtO (6.0 L). The filtrate was evaporated to give benzyl 3-[1-(oxan-2-yl)-1H-pyrazol-4-yl]-2,5-dihydro-1H-pyrrole-1-carboxylate (19.0 g, 51.61 mmol, 99% yield). 1 H NMR (400 MHz, DMSO-d6) δ 7.45 - 7.28 (m, 5H), 6.02 (dt, J = 11.3, 2.0 Hz, 1H), 5.36 (ddd, J = 9.8, 6.1, 2.3 Hz, 1H), 5.13 (d, J = 3.6 Hz, 2H), 4.42 - 4.30 (m, 2H), 4.29 - 4.17 (m, 2H), 3.94 (s, 3H), 3.67 - 3.56 (m, 1H), 2.15 - 2.00 (m, 1H), 1.97 - 1.85 (m, 2H), 1.76 - 1.60 (m, 1H), 1.54 (d, J = 8.6 Hz, 2H). m / z: [M+ACN+H] + =394.95.

[0101] Step 3': 1-(oxan-2-yl)-4-(pyrrolidin-3-yl)-1H-pyrazole

[0102] Benzyl 3-[1-(oxan-2-yl)-1H-pyrazol-4-yl]-2,5-dihydro-1H-pyrrole-1-carboxylate (19.0 g, 51.61 mmol, 1.0 equiv.) was dissolved in methanol (228.0 mL, 12.0 vol.). The flask was repeatedly evacuated and flushed with H2 gas (approximately 10 cycles) and then treated with 10% palladium on carbon (3.57 g, 33.546 mmol, 0.65 equiv.). The reaction was stirred overnight under a hydrogen atmosphere. After this time, complete conversion of the starting material was observed by TLC analysis (10% MeOH in DCM, compound UV inactive, stained with Ce-Mo). The catalyst was removed by filtration, and the filtrate was concentrated to give the crude product. The resulting material was purified on a short silica pad using gradient elution (20% to 100% MeOH in DCM+TEA) to give 1-(oxan-2-yl)-4-(pyrrolidin-3-yl)-1H-pyrazole (9.12 g, 40.386 mmol, 78% yield). 1 H NMR (400 MHz, DMSO-d6) δ 7.70 (s, 1H), 7.37 (s, 1H), 5.30 (dd, J = 10.2, 2.5 Hz, 1H), 3.95 - 3.87 (m, 1H), 3.65 - 3.56 (m, 1H), 3.19 - 3.11 (m, 1H), 3.03 (p, J = 7.8 Hz, 1H), 2.97 - 2.84 (m, 2H), 2.57 (ddd, J = 10.3, 7.7, 1.2 Hz, 1H), 2.06 (dddd, J = 14.7, 10.1, 7.5, 4.6Hz, 2H), 1.96 - 1.82 (m, 2H), 1.64 (dtt, J = 19.9, 7.7, 4.0 Hz, 2H), 1.56 - 1.47 (m, 2H).

[0103] Step 4': 2-chloro-4-{3-[1-(oxan-2-yl)-1H-pyrazol-4-yl]pyrrolidin-1-yl}pyrimidine

[0104] 1-(Oxan-2-yl)-4-(pyrrolidin-3-yl)-1H-pyrazole (0.6 g, 2.657 mmol, 1.0 equiv.) was dissolved in anhydrous acetonitrile (6.0 ml), and N,N-diisopropylethylamine (DIPEA) (0.694 ml, 3.985 mmol, 1.5 equiv.) was added dropwise. After 5 minutes of stirring, 2,4-dichloropyrimidine (0.396 g, 2.657 mmol, 1.0 equiv.) was added to the reaction mixture, and stirring was continued for 24 hours at room temperature in a sealed tube. UPLC-MS analysis then indicated the formation of two isomers. The reaction was quenched with water and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated to dryness. The resulting crude material was purified by FC using 10–70% iPrOH in Hex to give noF2 (2-chloro-4-{3-[1-(oxan-2-yl)-1H-pyrazol-4-yl]pyrrolidin-1-yl}pyrimidine (0.562 g, 1.599 mmol, 60% yield) as the major product fraction. 1 H NMR (300 MHz, DMSO-d6) δ 8.08 - 7.99 (m, 1H), 7.82 (s, 1H), 7.47 (s, 1H), 6.52 (d, J = 6.0 Hz, 1H), 5.37 - 5.28 (m, 1H), 3.90 (d, J = 11.8 Hz, 2H), 3.83 - 3.39 (m, 4H), 2.25 (d, J = 43.3 Hz, 1H), 2.02 (dd, J = 24.8, 14.7 Hz, 3H), 1.87 (d, J = 16.0 Hz, 2H), 1.74 - 1.58 (m, 1H), 1.58 - 1.41 (m, 2H). m / z: [M+H] + = 334.00.

[0105] Step 4: 2-(3,3-Difluoroazetidine-1-carbonyl)-1-methyl-6-(4-{3-[1-(oxan-2-yl)-1H-pyrazol-4-yl]pyrrolidin-1-yl}pyrimidin-2-yl)-1H-indole

[0106] A mixture of Intermediate 1 (0.079 g, 0.204 mmol, 1.2 equiv.), Intermediate 2 (0.071 g, 0.17 mmol, 1.0 equiv.), and sodium carbonate (0.054 g, 0.51 mmol, 3.0 equiv.) was dissolved in a mixture of dimethoxyethane (3.0 mL, 40 vol.) and water (1.0 mL, 8 vol.) and degassed with argon for 15 min. Tetrakis(triphenylphosphine)palladium (0.02 g, 0.017 mmol, 0.1 equiv.) was then added, and the reaction mixture was then heated under MW irradiation (110 °C, 2 h). The mixture was filtered through a pad of Celite, washed with EtOAc, and evaporated to dryness. The crude material was purified by FCC (0-5% MeOH in DCM) to give 2-(3,3-difluoroazetidine-1-carbonyl)-1-methyl-6-(4-{3-[1-(oxan-2-yl)-1H-pyrazol-4-yl]pyrrolidin-1-yl}pyrimidin-2-yl)-1H-indole (0.082 g, 0.135 mmol, 79%) as a pale yellow solid. m / z: [M+H] + =548.40.

[0107] Step 5: 2-(3,3-Difluoroazetidine-1-carbonyl)-1-methyl-6-{4-[3-(1H-pyrazol-4-yl)pyrrolidin-1-yl]pyrimidin-2-yl}-1H-indole

[0108] Reaction: To a solution of 2-(3,3-difluoroazetidine-1-carbonyl)-1-methyl-6-(4-{3-[1-(oxan-2-yl)-1H-pyrazol-4-yl]pyrrolidin-1-yl}pyrimidin-2-yl)-1H-indole (0.082 g, 0.135 mmol, 1.0 equiv) in anhydrous dioxane (0.82 ml, 10.0 vol) was added 4 M HCl in 1,4-dioxane (0.034 ml, 0.135 mmol, 1.0 equiv) dropwise and the mixture was stirred at room temperature overnight. The reaction mixture was evaporated to dryness and the residue was partitioned between DCM and a saturated solution of NaHCO3 and extracted twice with DCM. The combined organic phases were dried over sodium sulfate, filtered and evaporated to dryness. The crude material was triturated with ACN and then purified by preparative HPLC (C18 preparative column, ACN+0.1% FA, water+0.1% FA) to afford 2-(3,3-difluoroazetidine-1-carbonyl)-1-methyl-6-{4-[3-(1H-pyrazol-4-yl)pyrrolidin-1-yl]pyrimidin-2-yl}-1H-indole (0.016 g, 0.034 mmol, 25%) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 12.71 (s, 1H), 8.53 (s, 1H), 8.29 (d, J = 6.0 Hz, 1H), 8.27 - 8.17 (m, 1H), 7.68 (d, J = 8.5 Hz, 1H), 7.60 (s, 2H), 7.05 (s, 1H), 6.45 (d, J = 6.0 Hz, 1H), 5.05-4.48 (m, 4H), 4.22 (s, 1H), 4.02 (s, 3H), 3.48 (m, 4H), 2.37 (m, 1H), 2.04 (m, 1H). m / z: [M+H] + = 464.00.

[0109] Method A (Step 4') was used to obtain the compounds of Examples 64, 65, 67, and 68. Ar As reagents for the above, 2,4-dichloropyridine, 2,6-dichloropyridine, 3,5-dichloropyridazine and 2,6-dichloropyrazine were used, respectively.

[0110] Example 2 Method B. Exemplification by synthesis of the compound of Example 25. [ka]

[0111] Intermediate 2 is prepared in the same manner as in Method A.

[0112] Step 1: Synthesis of Intermediate 1: 6-Bromo-1H-indole-2-carboxylate

[0113] Thionyl chloride (6.051 mL, 83.314 mmol, 2.0 equiv.) was added dropwise to a solution of 6-bromoindole-2-carboxylic acid (10.0 g, 41.657 mmol, 1.0 equiv.) in methanol (200.0 mL, 20.0 vol.), and the resulting mixture was then refluxed for 5 h. The reaction mixture was evaporated to dryness, and the residue was dissolved in EtOAc and washed with water, a saturated solution of NaHCO3, and brine. The organic phase was dried over sodium sulfate, filtered, and evaporated to dryness to give methyl 6-bromo-1H-indole-2-carboxylate (9.2 g, 35.847 mmol, 86%) as a yellow solid. 1 H NMR (300 MHz, DMSO-d6) δ 12.08 (s, 1H), 7.67 - 7.58 (m, 2H), 7.22 (dd, J = 8.6, 1.8 Hz, 1H), 7.19 (dd, J = 2.2, 1.0 Hz, 1H), 3.88 (s, 3H).

[0114] Step 2: Synthesis of 6-bromo-1-methyl-1H-indole-2-carboxylate.

[0115] To a solution of 6-bromo-1H-indole-2-carboxylate (9.2 g, 35.847 mmol, 1.0 equiv) in anhydrous dimethylformamide (276.0 mL, 30.0 vol) was added sodium hydride (1.72 g, 43.016 mmol, 1.2 equiv) in portions at 0 °C, and the resulting mixture was stirred at 0–10 °C for 45 min. Methyl iodide (2.678 mL, 43.016 mmol, 1.2 equiv) was then added dropwise, and the mixture was stirred at room temperature over the weekend. The mixture was quenched with water, extracted with EtOAc, dried over sodium sulfate, filtered, and evaporated to dryness to give methyl 6-bromo-1-methyl-1H-indole-2-carboxylate (9.1 g, 32.244 mmol, 90%) as a yellow solid. 1 H NMR (300 MHz, DMSO-d6) δ 7.92 - 7.88 (m, 1H), 7.65 (d, J = 8.5 Hz, 1H), 7.30 - 7.24 (m, 2H), 4.01 (s, 3H), 3.86 (s, 3H).

[0116] Step 3: Synthesis of methyl 1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-2-carboxylate (Intermediate 1).

[0117] A solution of 6-bromo-1-methyl-1H-indole-2-carboxylate (9.1 g, 32.244 mmol, 1.0 equiv.), bis(pinacolato)diboron (10.645 g, 41.918 mmol, 1.3 equiv.), and potassium acetate (9.494 g, 96.733 mmol, 3.0 equiv.) in anhydrous 1,4-dioxane (182.0 mL, 20.0 vol.) was degassed with argon for 15 minutes and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride in dichloromethane (1.317 g, 1.612 mmol, 0.05 equiv.) was added. The reaction mixture was placed in a preheated oil bath at 100 °C overnight. The reaction mixture was cooled to room temperature, filtered through a Celit pad, washed with EtOAc, concentrated, and purified using flash column chromatography (0–5% MeOH in DCM, gradient elution) to afford 1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-2-carboxylate (8.19 g, 25.465 mmol, 79%) as a yellow solid. 1 H NMR (300 MHz, DMSO-d6) δ 7.87 (d, J = 1.1 Hz, 1H), 7.69 (dd, J = 8.1, 0.9 Hz, 1H), 7.43 (dd, J = 8.0, 0.9 Hz, 1H), 7.27 (d, J = 0.9 Hz, 1H), 4.06 (s, 3H), 3.87 (s, 3H), 1.33 (s, 12H). m / z: [M+H] + = 315.80.

[0118] Step 4: Synthesis of methyl 1-methyl-6-(4-{3-[1-(oxan-2-yl)-1H-pyrazol-4-yl]pyrrolidin-1-yl}pyrimidin-2-yl)-1H-indole-2-carboxylate.

[0119] A mixture of Intermediate 2 (4.56 g, 13.114 mmol, 1.0 equiv.), Intermediate 1 (4.724 g, 14.687 mmol, 1.12 equiv.), and sodium carbonate (4.17 g, 39.341 mmol, 3.0 equiv.) in dimethoxyethane (100 mL) / water (10 mL) was degassed for 15 minutes, and tetrakis(triphenylphosphine)palladium (0.758 g, 0.656 mmol, 0.05 equiv.) was added. The reaction mixture was placed in a preheated oil bath at 100 °C overnight. The reaction mixture was filtered through a pad of Celite, washed with EtOAc, evaporated to dryness, and purified using flash column chromatography (2-7% MeOH in DCM, gradient elution) to afford methyl 1-methyl-6-(4-{3-[1-(oxan-2-yl)-1H-pyrazol-4-yl]pyrrolidin-1-yl}pyrimidin-2-yl)-1H-indole-2-carboxylate (5.76 g, 11.246 mmol, 86%) as a yellow oil. 1 H NMR (400 MHz, DMSO-d6) δ 8.56 (s, 1H), 8.31 (d, J = 5.9 Hz, 1H), 8.23 ​​(dd, J = 8.4, 1.3 Hz, 1H), 7.86 (s, 1H), 7.74 (d, J = 8.4 Hz, 1H), 7.51 (s, 1H), 7.30 (d, J = 1.0 Hz, 1H), 6.47 (d, J = 6.0 Hz, 1H), 5.39 - 5.30 (m, 2H), 4.11 (s, 3H), 3.94 (s, 3H), 3.88 (s, 3H), 2.14 - 2.02 (m, 2H), 1.97 - 1.84 (m, 3H), 1.65 (d, J = 10.1 Hz, 1H), 1.53 (d, J = 8.3 Hz, 3H), 1.16 (s, 2H). m / z: [M+H] + =487.35.

[0120] Step 5: Synthesis of 1-methyl-6-(4-{3-[1-(oxan-2-yl)-1H-pyrazol-4-yl]pyrrolidin-1-yl}pyrimidin-2-yl)-1H-indole-2-carboxylic acid.

[0121] To a mixture of methyl 1-methyl-6-(4-{3-[1-(oxan-2-yl)-1H-pyrazol-4-yl]pyrrolidin-1-yl}pyrimidin-2-yl)-1H-indole-2-carboxylate (4.5 g, 8.786 mmol, 1.0 equiv) in dioxane (112.5 mL, 25.0 vol) / water (22.5 mL, 5.0 vol) was added lithium hydroxide monohydrate (1.659 g, 39.536 mmol, 4.5 equiv) and the mixture was stirred at room temperature overnight. The 1,4-dioxane was evaporated and the aqueous residue was washed twice with EtOAc. The aqueous phase was adjusted to pH = 6 and extracted with EtOAc. The combined organic phases were dried over Na2SO4, filtered, and concentrated. The crude compound was purified using FCC (100% EtOAc to remove UV-inactive impurities, followed by 20% MeOH in DCM with added acetic acid) to give 1-methyl-6-(4-{3-[1-(oxan-2-yl)-1H-pyrazol-4-yl]pyrrolidin-1-yl}pyrimidin-2-yl)-1H-indole-2-carboxylic acid (2.0 g, 4.232 mmol, 45%). 1 H NMR (300 MHz, DMSO-d6) δ 13.01 (s, 1H), 8.54 (s, 1H), 8.30 (d, J = 6.0 Hz, 1H), 8.21 (dd, J = 8.5, 1.3 Hz, 1H), 7.86 (s, 1H), 7.72 (d, J = 8.5 Hz, 1H), 7.51 (s, 1H), 7.24 (s, 1H), 6.46 (d, J = 6.0 Hz, 1H), 5.35 (dd, J = 10.1, 2.3 Hz, 1H), 4.10 (s, 3H), 3.92 (d, J = 12.1 Hz, 2H), 3.68 - 3.60 (m, 1H), 3.57 (s, 3H), 3.47 (s, 1H), 2.36 (s, 1H), 2.07 (td, J = 14.3, 13.4, 7.7 Hz, 2H), 1.89 (d, J = 13.5 Hz, 2H), 1.77 - 1.59 (m, 1H), 1.54 (d, J = 7.8 Hz, 2H). m / z: [M+H] - =470.95.

[0122] Step 6: Synthesis of N-(2,2-difluoroethyl)-1-methyl-6-(4-{3-[1-(oxan-2-yl)-1H-pyrazol-4-yl]pyrrolidin-1-yl}pyrimidin-2-yl)-1H-indole-2-carboxamide.

[0123] To a solution of 1-methyl-6-(4-{3-[1-(oxan-2-yl)-1H-pyrazol-4-yl]pyrrolidin-1-yl}pyrimidin-2-yl)-1H-indole-2-carboxylic acid (0.095 g, 0.181 mmol, 1.0 equiv.) in anhydrous dimethylformamide (1.43 mL, 15.0 vol.) was added HATU (0.083 g, 0.217 mmol, 1.2 equiv.), followed by N,N-diisopropylethylamine (DIPEA) (0.079 mL, 0.452 mmol, 2.5 equiv.) and 2,2-difluoroethanamine (17.6 mg, 0.217 mmol, 1.2 equiv.), and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc and washed with a saturated solution of NaHCO3 and brine. The organic phase was dried over sodium sulfate, filtered and evaporated to dryness to give N-(2,2-difluoroethyl)-1-methyl-6-(4-{3-[1-(oxan-2-yl)-1H-pyrazol-4-yl]pyrrolidin-1-yl}pyrimidin-2-yl)-1H-indole-2-carboxamide (0.065 g, 0.121 mmol, 64%). m / z: [M+H] + =536.40.

[0124] Step 7: Synthesis of N-(2,2-difluoroethyl)-1-methyl-6-(4-{3-[1-(oxan-2-yl)-1H-pyrazol-4-yl]pyrrolidin-1-yl}pyrimidin-2-yl)-1H-indole-2-carboxamide.

[0125] To a solution of N-(2,2-difluoroethyl)-1-methyl-6-(4-{3-[1-(oxan-2-yl)-1H-pyrazol-4-yl]pyrrolidin-1-yl}pyrimidin-2-yl)-1H-indole-2-carboxamide (0.065 g, 0.115 mmol, 1.0 equiv) in anhydrous dioxane (0.65 ml, 10.0 vol) was added 4 M HCl in 1,4-dioxane (0.144 ml, 0.576 mmol, 5.0 equiv) and the mixture was stirred at room temperature overnight. The mixture was evaporated to dryness. The residue was dissolved in EtOAc, washed twice with water, brine, dried over sodium sulfate, filtered, and evaporated to dryness. The crude product was purified by preparative HPLC (C-18 preparative column, 0.1% FA) to give N-(2,2-difluoroethyl)-1-methyl-6-{4-[3-(1H-pyrazol-4-yl)pyrrolidin-1-yl]pyrimidin-2-yl}-1H-indole-2-carboxamide (0.012 g, 0.026 mmol, 23%) as the formate salt. 1 H NMR (400 MHz, DMSO-d6) δ 12.74 (s, 1H), 8.93 (t, J = 6.0 Hz, 1H), 8.53 (s, 1H), 8.29 (d, J = 5.9 Hz, 1H), 8.21 (dd, J = 8.4, 1.4 Hz, 1H), 8.17 (s, 1H), 7.71 (d, J = 8.5 Hz, 1H), 7.60 (s, 2H), 7.19 (s, 1H), 6.45 (d, J = 6.0 Hz, 1H), 6.16 (tt, J = 55.9, 4.0 Hz, 2H), 4.22 (s, 1H), 4.07 (s, 3H), 4.03 - 3.76 (m, 2H), 3.76 - 3.62 (m, 3H), 3.48 (s, 4H), 2.37 (s, 1H), 2.05 (s, 2H). Formate. m / z: [M+H] + =452.15.

[0126] The deprotection step was also carried out using p-TsOH·H2O (2 equiv.) in MeOH at room temperature overnight.

[0127] Example 3 Method C. Synthetic illustration of the synthesis of intermediate 1' (for compounds of Example 17 and Example 56) [ka]

[0128] Step 1': Synthesis of Intermediate 1': 4-(3-bromophenyl)-1-methylpiperazin-2-one

[0129] Excess 1,3-dibromobenzene (2.48 g, 10.513 mmol, 4.0 equiv.) was added to a solution of 1-methylpiperazin-2-one (0.3 g, 2.628 mmol, 1.0 equiv.) and cesium carbonate (2.141 g, 6.57 mmol, 2.5 equiv.) in anhydrous toluene (3.0 mL, 10.0 vol.). The reaction mixture was degassed with argon. BINAP (2,2'-bis(diphenylphosphino)-1,1'-binaphthalene) (0.245 g, 0.394 mmol, 0.15 equiv.) and palladium(II) acetate (0.118 g, 0.526 mmol, 0.2 equiv.) were then added. The reaction mixture was placed in a sealed tube and stirred at 90 °C overnight. Afterwards, TLC analysis appeared to indicate some 1,3-dibromobenzene (an excess amount was added). The reaction mixture was filtered through a pad of Celit, washed with EtOAc, and concentrated. The resulting residue was treated with hexane and pentane, frozen, and sonicated. This was repeated several times until the pure product began to precipitate. The excess 1,3-dibromobenzene was removed. The compound was dried under high vacuum for 12 hours to give pure 4-(3-bromophenyl)-1-methylpiperazin-2-one (0.625 g, 2.322 mmol, 93%) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6) δ 7.17 (t, J = 8.1 Hz, 1H), 7.10 (t, J = 2.2 Hz, 1H), 6.96 - 6.91 (m, 2H), 3.79 (s, 2H), 3.52 (dd, J = 6.6, 4.2 Hz, 2H), 3.45 - 3.39 (m, 2H), 2.90 (s, 3H). m / z: [M+ACN] +=311.70.

[0130] The compound of Example 56 is prepared in the same manner using an excess of 1,4-dibromobenzene.

[0131] Step 2': Synthesis of 1-methyl-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperazin-2-one

[0132] 4-(3-Bromophenyl)-1-methylpiperazin-2-one (0.625 g, 2.16 mmol, 1.0 equiv) was dissolved in anhydrous dioxane (6.25 mL, 10.0 vol) and potassium acetate (0.636 g, 6.479 mmol, 3.0 equiv) was added, followed by bis(pinacolato)diboron (0.823 g, 3.239 mmol, 1.5 equiv). The reaction mixture was then purged with argon, and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride in dichloromethane (0.088 g, 0.108 mmol, 0.05 equiv) was added. The reaction mixture was placed in a sealed tube and stirred at 95 °C overnight. Complete conversion was observed after this time. The mixture was filtered through a pad of Celit, washed with EtOAc, and concentrated to dryness to give 1-methyl-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperazin-2-one (0.650 g, 94%), which was used in the next step without further purification. 1 (H NMR was not performed). m / z: [M+ACN] + =357.75.

[0133] Example 4 Method D. Synthesis of Intermediate 3': 3-(2-chloropyrimidin-4-yl)-1-[1-(oxan-2-yl)-1H-pyrazol-4-yl]-3-azabicyclo[3.1.0]hexane (for compound of Example 70) [ka]

[0134] Step 1': Synthesis of Intermediate 3: tert-butyl 1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

[0135] A 250 mL round-bottom flask containing anhydrous dichloromethane (62.5 mL, 25.0 vol) was placed under an inert atmosphere (Ar) and diethylzinc solution (67.753 mL, 67.753 mmol, 8.0 equiv.) was added. The flask was cooled to −40° C., and a solution of diiodomethane (36,293 g, 135,506 mmol, 16.0 equiv.) in anhydrous dichloromethane (25.0 mL, 10.0 vol.) was added over 40 minutes. The reaction was then allowed to stir at −40° C. for 1 hour. At −40° C., a solution of trifluoroacetic acid (7.725 g, 67.753 mmol, 8.0 equiv.) in anhydrous dichloromethane (25.0 mL, 10.0 vol.) was added dropwise over 20 minutes, and the mixture was then stirred at −15° C. for 1 hour. A solution of 1-Boc-2,5-dihydro-1H-pyrrole-3-boronic acid pinacol ester (2.5 g, 8.469 mmol, 1.0 equiv.) in anhydrous dichloromethane (25.0 mL, 10.0 vol.) was added dropwise, and the reaction mixture was allowed to stir at room temperature overnight. Over the course of the reaction, the BOC group was cleaved and had to be reattached. After stirring overnight, the crude reaction mixture was partially concentrated to one-quarter volume. Anhydrous tetrahydrofuran (37.5 mL, 2.5 vol.) was added, followed by d-tert-butyl dicarbonate (9.242 g, 42.346 mmol, 5.0 equiv.), anhydrous triethylamine (11.805 mL, 84.691 mmol, 10.0 equiv.), and DMAP (0.259 g, 2,117 mmol, 0.25 equiv.). After the mixture was stirred for an additional 3 h at room temperature, it was diluted with EtOAc and washed with a saturated solution of NaHCO, water, and extracted with brine. The organic layer was dried over NaSO, filtered, and concentrated to give the crude product, which was purified by FCC (0–30% EtOAc in hexanes) to give tert-butyl 1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (0.4 g, 1.281 mmol, 15%) as a yellow semisolid. 1H NMR (300 MHz, DMSO-d6) δ 3.45 (d, J = 10.7 Hz, 1H), 3.27 (d, J = 6.8 Hz, 3H), 1.60 (dt, J = 8.1, 4.3 Hz, 1H), 1.37 (s, 9H), 1.18 (s, 12H), 0.84 (dd, J = 7.6, 4.0 Hz, 1H), 0.32 (d, J = 4.6 Hz, 1H).

[0136] Step 2': 1-(trifluoro-λ 4 Synthesis of potassium benzyl (-boranyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

[0137] Tert-butyl-1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (0.4 g, 1.281 mmol, 1.0 equiv.) was dissolved in DCM (4.0 mL, 10.0 vol.) and TFA (1.752 g, 15.368 mmol, 12.0 equiv.) was added at room temperature. The reaction was stirred at room temperature until complete conversion of the starting material was observed by TLC analysis (approximately 3 h). The reaction was then concentrated in vacuo to give the crude material, which was dissolved in THF (6.0 mL, 20.0 vol.). The reaction was cooled to 0 °C, and 4-dimethylaminopyridine (0.015 g, 0.125 mmol, 0.1 equiv.), anhydrous triethylamine (1.045 mL, 7.499 mmol, 6.0 equiv.), and CbzCl (0.256 g, 1.5 mmol, 1.2 equiv.) were added. The reaction was stirred at 0 °C for 2 hours and then allowed to warm to room temperature overnight (18 hours). The reaction mixture was quenched with MeOH, diluted with EtOAc, and washed with water and brine. The organic layer was then dried over Na SO , filtered, and concentrated to give the crude product, 1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (0.4 g, 1.154 mmol), as a brown oil. The crude boronic ester was then dissolved in MeOH (4.88 ml, 15.0 vol), treated with KHF (0.513 g, 6.562 mmol, 7.0 equiv.), and stirred at reflux for 18 h. After cooling to room temperature, the reaction mixture was concentrated, and the resulting residue was slurried in 25% EtOAc in hexane for 15 min. The precipitate was collected by filtration and washed with 25% EtOAc in heptane (3 x 100 mL). The precipitate was then stirred in acetonitrile (10 mL) at 50 °C for 30 min, cooled to room temperature, and the solid was filtered off. The filtrate was evaporated to dryness and the potassium 1-(trifluoro-λ) methyl ... 4 Benzyl potassium (-boranyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (0.28 g, 0.849 mmol, 91%) was obtained. 1H NMR (300 MHz, DMSO-d6) δ 7.43 - 7.23 (m, 5H), 5.01 (s, 2H), 3.43 (dd, J = 13.7, 10.3 Hz, 1H), 3.29 - 3.16 (m, 3H), 1.05 - 0.93 (m, 1H), 0.39 (dd, J = 7.1, 3.0 Hz, 1H), -0.36 (s, 1H).

[0138] Step 3': Synthesis of benzyl 1-[1-(oxan-2-yl)-1H-pyrazol-4-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate

[0139] Potassium 1-(trifluoro-λ 4 A mixture of potassium benzyl (4-boranyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (0.16 g, 0.485 mmol, 1.0 equiv.), 4-bromo-1-(oxan-2-yl)-1H-pyrazole (0.112 g, 0.485 mmol, 1.0 equiv.), and cesium carbonate (0.474 g, 1.455 mmol, 3.0 equiv.) was dissolved in toluene (5.0 mL) and water (0.5 mL). The resulting mixture was degassed by bubbling N2 through the solution for 10 minutes, after which CatacXium® A Pd G3 catalyst (0.011 g, 0.0145 mmol, 0.05 equiv.) was added, and the mixture was degassed for an additional 5 minutes before heating at 90 °C for 18 hours. The reaction was cooled to room temperature, filtered through Celite, and eluted with EtOAc. The reaction was concentrated and purified by FCC (0-4% MeOH in DCM) to give benzyl 1-[1-(oxan-2-yl)-1H-pyrazol-4-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (0.14 g, 0.362 mmol, 75%). 1H NMR (300 MHz, DMSO-d6) δ 7.81 (s, 1H), 7.43 - 7.28 (m, 6H), 5.29 (d, J = 9.9 Hz, 1H), 5.07 (s, 2H), 3.89 (d, J = 11.7 Hz, 1H), 3.78 (t, J = 10.6 Hz, 1H), 3.56 (h, J = 9.5 Hz, 4H), 2.05 (q, J = 13.0, 11.8 Hz, 1H), 1.85 (d, J = 17.0 Hz, 2H), 1.75 - 1.58 (m, 2H), 1.52 (d, J = 7.6 Hz, 2H), 1.09 (s, 1H), 0.66 (t, J = 4.7 Hz, 1H).

[0140] Step 3': Synthesis of 1-[1-(oxan-2-yl)-1H-pyrazol-4-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate

[0141] Palladium on carbon (0.012 g, 0.109 mmol, 0.3 equiv) was added to a solution of benzyl 1-[1-(oxan-2-yl)-1H-pyrazol-4-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (0.14 g, 0.362 mmol, 1.0 equiv) in methanol (2.1 ml, 15.0 volumes), and the mixture was hydrogenated overnight. 1 Complete conversion was observed according to H NMR analysis. The mixture was filtered through a pad of Celite, washed with MeOH, and evaporated to dryness to give 1-[1-(oxan-2-yl)-1H-pyrazol-4-yl]-3-azabicyclo[3.1.0]hexane (0.08 g, 0.309 mmol, 85%). 1H NMR (300 MHz, DMSO-d6) δ 7.68 (s, 1H), 7.31 (s, 1H), 5.28 (dd, J = 10.0, 2.4 Hz, 1H), 3.89 (d, J = 11.8 Hz, 1H), 3.61 (d, J = 13.0 Hz, 1H), 3.01 - 2.71 (m, 3H), 2.25 (s, 1H), 2.13 - 1.98 (m, 1H), 1.98 - 1.80 (m, 2H), 1.74 - 1.57 (m, 1H), 1.57 - 1.37 (m, 3H), 1.24 (s, 1H), 0.84 (t, J = 4.5 Hz, 1H), 0.79 - 0.63 (m, 1H).

[0142] Step 4': Synthesis of 3-(2-chloropyrimidin-4-yl)-1-[1-(oxan-2-yl)-1H-pyrazol-4-yl]-3-azabicyclo[3.1.0]hexane

[0143] A mixture of 1-[1-(oxan-2-yl)-1H-pyrazol-4-yl]-3-azabicyclo[3.1.0]hexane (0.08 g, 0.309 mmol, 1.0 equiv.), 2,4-dichloropyrimidine (0.046 g, 0.309 mmol, 1.0 equiv.), and N,N-diisopropylethylamine (DIPEA) (0.081 mL, 0.463 mmol, 1.5 equiv.) in anhydrous acetonitrile (2.4 mL, 30.0 vol.) was stirred at room temperature overnight. The mixture was evaporated to dryness, and the residue was dissolved in EtOAc, washed twice with water, dried over sodium sulfate, filtered, and evaporated to dryness. The crude product was purified by FCC (0-6% MeOH in DCM) to give 3-(2-chloropyrimidin-4-yl)-1-[1-(oxan-2-yl)-1H-pyrazol-4-yl]-3-azabicyclo[3.1.0]hexane (0.065 g, 49%). 1H NMR (300 MHz, DMSO-d6) δ 8.06 (d, J = 6.0 Hz, 1H), 7.87 (d, J = 9.2 Hz, 1H), 7.46 (s, 1H), 6.54 (d, J = 6.0 Hz, 1H), 5.32 (d, J = 9.8 Hz, 1H), 3.90 (d, J = 12.0 Hz, 1H), 3.71 - 3.53 (m, 4H), 2.04 (d, J = 9.8 Hz, 1H), 1.87 (d, J = 16.5 Hz, 4H), 1.66 (dd, J = 10.6, 5.5 Hz, 1H), 1.53 (d, J = 7.3 Hz, 3H), 1.17 (s, 1H), 0.73 (t, J = 4.7 Hz, 1H).

[0144] Example 5 Method E. Synthesis of Intermediate 4: 2-chloro-4-{3-[5-methyl-1-(oxan-2-yl)-1H-pyrazol-4-yl]pyrrolidin-1-yl}pyrimidine (for compound of Example 66). [ka]

[0145] Step 1': Synthesis of 3-methyl-1-(oxan-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

[0146] A mixture of 3-methylpyrazole-4-boronic acid pinacol ester (4.2 g, 20.185 mmol, 1.0 equiv.), 3,4-dihydro-2H-pyran (2.025 mL, 1.867 g, 22.204 mmol, 1.1 equiv.), and p-toluenesulfonic acid (monohydrate) (0.767 g, 4.037 mmol, 0.2 equiv.) in anhydrous tetrahydrofuran (6.0 mL, 15.0 vol.) was refluxed for 40 h. The mixture was diluted with EtOAc, washed with water, saturated NaHCO solution, filtered, and evaporated to dryness. The crude material was purified by FCC (0-30% EtOAc in hexanes) to give 3-methyl-1-(oxan-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (4.0 g, 10.952 mmol, 54%) as a colorless oil. 1 H NMR (300 MHz, chloroform-d) δ 7.84 (s, 1H), 5.31 (dd, J = 9.7, 2.4 Hz, 1H), 4.18–3.98 (m, 1H), 3.69 (td, J = 11.1, 3.5 Hz, 1H), 2.42 (s, 3H), 2.22–1.95 (m, 3H), 1.82–1.53 (m, 3H), 1.31 (s, 12H).

[0147] Step 2': Synthesis of benzyl 3-[3-methyl-1-(oxan-2-yl)-1H-pyrazol-4-yl]-2,5-dihydro-1H-pyrrole-1-carboxylate

[0148] A mixture of benzyl 3-(trifluoromethanesulfonyloxy)pyrrolidine-1-carboxylate (3.66 g, 9.898 mmol, 1.0 equiv.), 3-methyl-1-(oxan-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (3.976 g, 10.887 mmol, 1.1 equiv.), and anhydrous potassium carbonate (3.42 g, 24.744 mmol, 2.5 equiv.) in anhydrous tetrahydrofuran (54.9 mL, 15.0 vol.) and water (14.64 mL, 4.0 vol.) was degassed with argon for 15 minutes, and tetrakis-(triphenylphosphine)palladium (0.543 g, 0.47 mmol, 0.048 equiv.) was added. The mixture was degassed for an additional 5 minutes and then heated at 90° C. for 15 hours. The mixture was filtered through a pad of Celite, washed with EtOAc, and evaporated to dryness. The crude material was purified by FCC (0-39% EtOAc in hexanes) to give benzyl 3-[3-methyl-1-(oxan-2-yl)-1H-pyrazol-4-yl]-2,5-dihydro-1H-pyrrole-1-carboxylate (2.2 g, 5.389 mmol, 54%). 1 H NMR (300 MHz, chloroform-d) δ 7.50–7.44 (m, 1H), 7.43–7.35 (m, 5H), 5.87–5.74 (m, 1H), 5.31 (s, 1H), 5.21 (s, 2H), 4.50–4.30 (m, 4H), 4.16–3.98 (m, 1H), 3.72 (d, J = 11.4 Hz, 1H), 2.40 (s, 3H), 2.15–1.95 (m, 3H), 1.79–1.57 (m, 3H).

[0149] Step 3': Synthesis of 3-methyl-1-(oxan-2-yl)-4-(pyrrolidin-3-yl)-1H-pyrazole

[0150] Palladium on carbon (0.172 g, 1.617 mmol, 0.3 equiv) was added to a solution of benzyl 3-[3-methyl-1-(oxan-2-yl)-1H-pyrazol-4-yl]-2,5-dihydro-1H-pyrrole-1-carboxylate (2.2 g, 5.389 mmol, 1.0 equiv) in methanol (44.0 ml, 20.0 vol), and the mixture was hydrogenated for 48 h. 1 Complete conversion of the starting material was observed according to H NMR. The mixture was filtered through a pad of Celite, washed with MeOH, and evaporated to dryness to give 3-methyl-1-(oxan-2-yl)-4-(pyrrolidin-3-yl)-1H-pyrazole (1.26 g, 4.819 mmol, 89%) as a yellow oil. 1 H NMR (300 MHz, DMSO-d6) δ 7.56 (s, 1H), 5.18 (dd, J = 10.3, 2.4 Hz, 1H), 3.87 (tq, J = 8.5, 5.3, 4.2 Hz, 1H), 3.65 - 3.51 (m, 2H), 3.09 (dt, J = 10.2, 6.5 Hz, 1H), 2.97 - 2.81 (m, 3H), 2.10 (s, 3H), 2.08 - 1.77 (m, 5H), 1.50 (tt, J = 10.8, 4.9 Hz, 4H).

[0151] Step 4': Synthesis of 2-chloro-4-{3-[5-methyl-1-(oxan-2-yl)-1H-pyrazol-4-yl]pyrrolidin-1-yl}pyrimidine

[0152] A mixture of 3-methyl-1-(oxan-2-yl)-4-(pyrrolidin-3-yl)-1H-pyrazole (0.145 g, 0.555 mmol, 1.0 equiv.), 2,4-dichloropyrimidine (0.083 g, 0.555 mmol, 1.0 equiv.), and N,N-diisopropylethylamine (DIPEA) (0.145 mL, 0.832 mmol, 1.5 equiv.) in anhydrous acetonitrile (1.45 mL, 10.0 vol.) was stirred at room temperature overnight. The ACN was evaporated, and the residue was dissolved in EtOAc, washed twice with water, dried over sodium sulfate, filtered, and evaporated to dryness. The crude material was purified by FCC (0-18% i-PrOH in hexanes) to give 2-chloro-4-{3-[3-methyl-1-(oxan-2-yl)-1H-pyrazol-4-yl]pyrrolidin-1-yl}pyrimidine (0.06 g, 0.155 mmol, 28%). 1 H NMR (300 MHz, DMSO-d6) δ 8.04 (t, J = 5.4 Hz, 1H), 7.69 (s, 1H), 6.53 (d, J = 6.0 Hz, 1H), 5.30 - 5.14 (m, 1H), 3.89 (d, J = 12.0 Hz, 2H), 3.76 (q, J = 9.3 Hz, 2H), 3.65 - 3.50 (m, 2H), 2.27 (s, 2H), 2.16 (s, 3H), 2.12 - 1.77 (m, 4H), 1.62 (d, J = 10.8 Hz, 1H), 1.57 - 1.43 (m, 3H).

[0153] Method E (Step 4') was used to obtain the compounds of Examples 69 and 71. Ar 3,5-Dichloropyridazine and 2,6-dichloropyrazine were used as reagents for the synthesis of 2,6-dichloropyrazine, respectively.

[0154] Example 6 [ka] Method A. 1H NMR (300 MHz, DMSO-d6) δ 12.71 (s, 1H), 8.53 (s, 1H), 8.29 (d, J = 6.0 Hz, 1H), 8.27 - 8.17 (m, 1H), 7.68 (d, J = 8.5 Hz, 1H), 7.60 (s, 2H), 7.05 (s, 1H), 6.45 (d, J = 6.0 Hz, 1H), 5.05-4.48 (m, 4H), 4.22 (s, 1H), 4.02 (s, 3H), 3.48 (m, 4H), 2.37 (m, 1H), 2.04 (m, 1H). m / z: [M+H] + = 464.22.

[0155] Example 7

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[0156] Example 8

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[0157] Example 9 [ka] Method A. 1 H NMR (300 MHz, DMSO-d6) δ 8.50 (s, 1H), 8.29 (d, J = 5.9 Hz, 1H), 8.25 - 8.16 (m, 2H), 7.66 (d, J = 8.4 Hz, 1H), 7.60 (s, 2H), 6.88 (s, 1H), 6.44 (d, J = 6.0 Hz, 1H), 4.27- 3.89 (m, 3H), 3.85 (m, 3H), 3.77 (m, 1H), 3.59-3.44 (m, 3H), 2.62 (d, J = 12.3 Hz, 3H), 2.36 (s, 1H), 2.04 (s, 1H). Some aliphatic signals overlapped with H2O. Formate. m / z: [M+H] + =442.27.

[0158] Example 10 [ka] Method A. 1H NMR (300 MHz, DMSO-d6) δ 8.96 (d, J = 8.8 Hz, 1H), 8.53 (s, 1H), 8.29 (d, J = 5.9 Hz, 1H), 8.26 - 8.19 (m, 2H), 7.72 (d, J = 8.5 Hz, 1H), 7.60 (s, 2H), 7.26 (s, 1H), 6.45 (d, J = 6.0 Hz, 1H), 4.86 (q, J = 7.9 Hz, 1H), 4.23 (s, 1H), 4.06 (s, 3H), 4.01-3.48 (m, 3H), 2.37 (s, 1H), 2.02 (s, 1H), 1.39 (d, J = 7.1 Hz, 3H). 2 のaliphatic CHプロトンがH2Oと Repeat していた.ギ sour rice. m / z: [M+H] + =484.22.

[0159] Example 11

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[0160] Example 12

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[0161] Example 13

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[0162] Example 14

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[0163] Example 15

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[0164] Example 16

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[0165] Example 17

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[0166] Example 18

Chemical formula

[0167] Example 19

Chemical formula

[0168] Example 20

Chemical formula

[0169] Example 21 [ka] Method A. 1 H NMR (400 MHz, DMSO-d6) δ 12.70 (s, 1H), 9.17 (t, J = 6.4 Hz, 1H), 8.54 (s, 1H), 8.30 (d, J = 5.9 Hz, 1H), 8.26 - 8.16 (m, 1H), 7.72 (d, J = 8.5 Hz, 1H), 7.61 (s, 2H), 7.25 (s, 1H), 6.45 (d, J = 6.0 Hz, 1H), 4.18 - 4.04 (m, 5H), 4.04 - 3.63 (m, 2H), 3.63-3.43 (m, 3H), 2.37 (s, 1H), 2.07 (d, J = 11.9 Hz, 1H). m / z: [M+H] + =470.24.

[0170] Example 22 [ka] Method A.1 H NMR (300 MHz, メタノール-d4) δ 8.46 (s, 1H), 8.24 (d, J = 6.1 Hz, 1H), 8.16 (d, J = 8.3 Hz, 1H), 7.71 (d, J = 8.4 Hz, 1H), 7.62 (s, 2H), 6.79 (s, 1H), 6.47 (d, J = 6.2 Hz, 1H), 5.50 (bs, 1H), 3.88 (s, iiii4H), 3.63 (d, J = 35.6 Hz, 3H), 3.18 (s, 3H), 2.48 (s, 1H), 2.18 (s, 1H), 1.56 (d, J = 7.1 Hz, 3H), 1.33 (d, J = 13.5 Hz, 1H). m / z: [M+H] + =498.23.

[0171] Example 23

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[0172] Example 24

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[0173] Example 25

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[0174] Example 26

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[0175] Example 27

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[0176] Example 28

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[0177] Example 29

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[0178] Example 30

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[0179] Example 31

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[0180] Example 32 [ka] Method A. 1 H NMR (400 MHz, DMSO-d6) δ 12.67 (s, 1H), 8.51 (s, 1H), 8.29 (d, J = 5.9 Hz, 1H), 8.21 (dd, J = 8.4, 1.4 Hz, 1H), 7.65 (d, J = 8.4 Hz, 2H), 7.51 (s, 1H), 6.71 (d, J = 0.9 Hz, 1H), 6.44 (d, J = 6.0 Hz, 1H), 4.10 (d, J = 96.8 Hz, 1H), 3.84 (s, 3H), 3.66 (s, 8H), 3.54 - 3.39 (m, 2H), 2.37 (bs, 1H), 2.06 (s, 1H). Two aliphatic CH protons overlapped with HO. m / z: [M+H] + =458.23.

[0181] Example 33 [ka] Method A. 1 H NMR (300 MHz, DMSO-d6) δ 8.74 (t, J = 5.9 Hz, 1H), 8.52 (s, 1H), 8.29 (d, J = 5.9 Hz, 1H), 8.25 (s, 1H), 8.20 (dd, J = 8.4, 1.4 Hz, 1H), 7.70 (d, J = 8.5 Hz, 1H), 7.60 (s, 2H), 7.14 (s, 1H), 6.45 (d, J = 6.0 Hz, 1H), 6.23 (td, J = 55.3, 3.9 Hz, 1H), 4.05 (s, 3H), 3.84 (d, J = 5.1 Hz, 2H), 2.52 (bs, 1H), 2.25 (bs, 1H), 2.02 (bs, 1H). Some of the aliphatic CH signals overlapped with HO. Formate. m / z: [M+H] + =514.24.

[0182] Example 34 [ka] Method A. 1 H NMR (300 MHz, DMSO-d6) δ 12.67 (s, 1H), 8.51 (s, 1H), 8.29 (d, J = 5.9 Hz, 1H), 8.21 (dd, J = 8.4, 1.3 Hz, 1H), 7.68 (d, J = 8.5 Hz, 1H), 7.60 (s, 2H), 6.92 (s, 1H), 6.44 (d, J = 6.0 Hz, 1H), 4.22 (s, 1H), 3.99 (s, 1H), 3.90 (s, 3H), 3.87 - 3.60 (m, 5H), 3.47 (s, 3H), 2.36 (s, 1H), 2.23 (s, 1H), 2.06 (dd, J = 13.0, 8.0 Hz, 2H). m / z: [M+H] + =510.28.

[0183] Example 35 [ka] Method A. 1 H NMR (300 MHz, DMSO-d6) δ 8.51 (s, 1H), 8.29 (d, J = 5.9 Hz, 1H), 8.22 - 8.15 (m, 2H), 7.68 (d, J = 8.4 Hz, 1H), 7.60 (s, 2H), 7.13 (s, 1H), 6.44 (d, J = 6.0 Hz, 1H), 4.11 (s, 3H), 2.36 (bs, 1H), 2.04 (bs, 1H). Some of the pyrrolidine CH signals overlapped with HO. Formate salt. m / z: [M+H] + =389.22.

[0184] Example 36 [ka] Method A. 1 H NMR (400 MHz, DMSO-d6) δ 8.54 (s, 1H), 8.30 (d, J = 5.9 Hz, 1H), 8.22 (dd, J = 8.4, 1.4 Hz, 1H), 8.16 (s, 1H), 7.70 (d, J = 8.5 Hz, 1H), 7.61 (s, 2H), 7.03 (s, 1H), 6.46 (d, J = 6.0 Hz, 1H), 5.12 (s, 1H), 4.53 (d, J = 7.6 Hz, 1H), 4.31 - 4.19 (m, 1H), 4.02 (s, 3H), 3.97-3.43 (m, 5H), 2.65 (s, 2H), 2.34 (d, J = 17.9 Hz, 2H), 2.05 (s, 1H). Formate salt. m / z: [M+H] + =496.24.

[0185] Example 37 [ka] Method A. 1H NMR (400 MHz, DMSO-d6) δ 12.68 (s, 1H), 8.52 (d, J = 12.1 Hz, 2H), 8.31 (d, J = 6.1 Hz, 1H), 8.17 (d, J = 8.5 Hz, 1H), 7.72 (d, J = 8.4 Hz, 1H), 7.61 (s, 2H), 7.17 (s, 1H), 6.51 (s, 1H), 4.30-4.19 (m, 1H), 4.04 (s, 3H), 3.93-3.64 (m, 2H) 3.59 (s, 2H), 3.54-3.41 (m, 2H), 3.29 (d, J = 6.4 Hz, 2H), 2.07 (s, 1H), 1.01 (s, 7H). m / z: [M+H] + =492.28.

[0186] Example 38

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[0187] Example 39

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[0188] Example 40 [ka] Method B. 1 H NMR (300 MHz, DMSO-d6) δ 8.76 (t, J = 6.4 Hz, 1H), 8.52 (s, 1H), 8.32 - 8.27 (m, 2H), 8.20 (dd, J = 8.5, 1.4 Hz, 1H), 7.69 (d, J = 8.4 Hz, 1H), 7.60 (s, 2H), 7.21 (s, 1H), 6.44 (d, J = 6.0 Hz, 1H), 4.22 (bs,1H), 4.05 (s, 3H), 3.93 (d, J = 1.4 Hz, 1H), 3.87 (d, J = 5.2 Hz, 1H), 3.71 - 3.66 (m, 2H), 3.62 (d, J = 6.6 Hz, 3H), 2.36 (bs, 1H), 2.07 (bs, 1H), 1.43 (d, J = 21.5 Hz, 3H). One aliphatic CH proton overlapped with HO. Formate. m / z: [M+H] + =496.43.

[0189] Example 41 [ka] Method B. 1 H NMR (300 MHz, DMSO-d6) δ 8.52 (s, 1H), 8.29 (d, J = 5.9 Hz, 1H), 8.21 (dd, J = 8.4, 1.4 Hz, 1H), 8.18 (s, 1H), 7.68 (d, J = 8.5 Hz, 1H), 7.60 (s, 2H), 6.97 (s, 1H), 6.45 (d, J = 6.0 Hz, 1H), 4.36 (d, J = 98.4 Hz, 5H), 4.02 (s, 3H), 2.37 (s, 2H), 2.09 (s, 1H), 1.63 (d, J = 22.0 Hz, 3H). 3 のaliphatic CHプロトンがH2Oと Repeat していた.ギ sour rice. LCMS (Method:m / z: [M+H] + =460.30.

[0190] Example 42

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[0191] Example 43

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[0192] Example 44

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[0193] Example 45

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[0194] Example 46 [ka] Method B. 1 H NMR (300 MHz, DMSO-d6) δ 12.67 (s, 1H), 8.52 (s, 1H), 8.29 (d, J = 5.9 Hz, 1H), 8.22 (dd, J = 8.4, 1.4 Hz, 1H), 7.68 (d, J = 8.4 Hz, 1H), 7.61 (s, 2H), 6.81 (d, J = 0.8 Hz, 1H), 6.45 (d, J = 6.0 Hz, 1H), 4.26 (s, 3H), 3.92 (t, J = 5.5 Hz, 2H), 3.85 (s, 4H), 3.44 (t, J = 5.4 Hz, 4H), 2.90 (s, 3H), 2.37 (s, 1H), 2.08 (s, 1H). One aliphatic CH proton overlapped with HO. m / z: [M+H] + =485.33.

[0195] Example 47 [ka] Method B. 1H NMR (400 MHz, DMSO-d6) δ 12.68 (s, 1H), 8.53 (s, 1H), 8.29 (d, J = 5.9 Hz, 1H), 8.22 (dd, J = 8.4, 1.3 Hz, 1H), 7.70 (d, J = 8.5 Hz, 2H), 7.50 (s, 1H), 7.01 (s, 1H), 6.45 (d, J = 6.0 Hz, 1H), 5.25 - 5.11 (m, 2H), 4.50 - 4.35 (m, 4H), 4.03 (s, 4H), 3.75 (d, J = 53.0 Hz, 1H), 3.64 - 3.56 (m, 1H), 3.48 (s, 2H), 2.77 (t, J = 7.5 Hz, 2H), 2.05 (s, 1H). m / z: [M+H] + =518.23.

[0196] Example 48

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[0197] Example 49

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[0198] Example 50

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[0199] Example 51

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[0200] Example 52

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[0201] Example 53

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[0202] Example 54

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[0203] Example 55

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[0204] Example 56

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[0205] Example 57

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[0206] Example 58

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[0207] Example 59 [ka] Method A. 1 H NMR (400 MHz, DMSO-d6) δ 13.49 (s, 1H), 12.68 (s, 1H), 8.67 (d, J = 60.3 Hz, 1H), 8.40 (d, J = 16.9 Hz, 1H), 8.29 (d, J = 5.9 Hz, 1H), 7.65 (dd, J = 82.3, 35.5 Hz, 3H), 6.46 (d, J = 6.0 Hz, 1H), 5.15 (t, J = 12.3 Hz, 2H), 4.60 (t, J = 12.3 Hz, 2H), 4.28 - 3.56 (m, 2H), 3.47 (s, 2H), 2.37 (s, 1H), 2.05 (s, 1H). One aliphatic CH proton overlapped with HO. m / z: [M+H] + =451.21.

[0208] Example 60 [ka] Method A. 1 H NMR (300 MHz, DMSO-d₆) δ 12.66 (s, 1H), 8.44 (s, 1H), 8.27 (d, J = 5.9 Hz, 1H), 8.14 (dd, J = 8.4, 1.4 Hz, 1H), 7.58 (d, J = 8.4 Hz, 2H), 7.43 (d, J = 3.0 Hz, 1H), 6.50–6.33 (m, 2H), 4.09 (d, J = 71.5 Hz, 1H), 3.72–3.43 (m, 3H), 3.86 (s, 3H), 2.36 (s, 1H), 2.08 (s, 1H). Two aliphatic CH protons overlapped with HO. m / z: [M+H] + =345.24.

[0209] Example 61

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[0210] Example 62

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[0211] Example 63 [ka] Method A. 1 H NMR (300 MHz, DMSO-d6) δ 11.89 (s, 1H), 8.55 (s, 1H), 8.28 (d, J = 5.5 Hz, 2H), 8.16 (dd, J = 8.5, 1.5 Hz, 1H), 7.67 (d, J = 8.5 Hz, 1H), 7.59 (s, 2H), 6.95 (d, J = 2.1 Hz, 1H), 6.43 (d, J = 6.0 Hz, 1H), 4.79 (d, J = 104.5 Hz, 4H), 4.19 (s, 1H), 4.06-3.71 (m, 3H), 2.37 (s, 1H), 2.05 (s, 1H). Formate. Some of the CH protons overlap with water. m / z: [M+H] + =450.20.

[0212] Example 64 [ka] Method A. 1H NMR (300 MHz, DMSO-d6) δ 12.66 (s, 1H), 8.26 - 8.18 (m, 2H), 7.88 (dd, J = 8.4, 1.4 Hz, 1H), 7.67 (d, J = 8.4 Hz, 1H), 7.59 (s, 2H), 7.09 (d, J = 2.2 Hz, 1H), 7.03 (s, 1H), 6.47 (dd, J = 5.8, 2.2 Hz, 1H), 4.87 (d, J = 95.6 Hz, 4H), 4.03 (s, 3H), 3.82 (dd, J = 9.6, 7.2 Hz, 1H), 3.64 - 3.53 (m, 1H), 3.46 (d, J = 8.5 Hz, 3H), 2.37 (d, J = 7.0 Hz, 1H), 2.13 - 1.97 (m, 1H). m / z: [M+H] + =463.19.

[0213] Example 65

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[0214] Example 66

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[0215] Example 67 [ka] Method A. 1 H NMR (300 MHz, DMSO-d6) δ 12.66 (s, 1H), 8.53 (s, 1H), 8.27 (s, 1H), 7.92 (d, J = 7.1 Hz, 2H), 7.76 - 7.43 (m, 3H), 7.05 (s, 1H), 4.69 (s, 4H), 4.03 (s, 3H), 3.78 (s, 1H), 2.38 (s, 1H), 2.06 (d, J = 7.9 Hz, 1H). Two of the CH protons overlap with water. One of the CH protons overlaps with Me at 4.03 ppm. m / z: [M+H] + =464.25.

[0216] Example 68 [ka] Method A. 1H NMR (300 MHz, DMSO-d6) δ 12.68 (s, 1H), 8.64 (d, J = 2.7 Hz, 1H), 8.30 (s, 1H), 7.98 - 7.91 (m, 1H), 7.73 (d, J = 8.5 Hz, 1H), 7.50 (s, 2H), 7.14 (d, J = 2.7 Hz, 1H), 7.06 (d, J = 0.8 Hz, 1H), 4.68 (s, 4H), 4.05 (s, 3H), 3.94 - 3.82 (m, 1H), 3.72-3.61 (m, 1H), 3.59-3.43 (m, 3H), 2.39 (s, 1H), 2.04 (dd, J = 20.7, 9.3 Hz, 1H). m / z: [M+H] + =464.23.

[0217] Example 69 [ka] Method E. 1 H NMR (300 MHz, DMSO-d6) δ 12.30 (s, 1H), 8.65 (d, J = 2.6 Hz, 1H), 8.31 (s, 1H), 7.95 (dd, J = 8.5, 1.4 Hz, 1H), 7.73 (d, J = 8.4 Hz, 1H), 7.40 (s, 1H), 7.15 (d, J = 2.7 Hz, 1H), 7.06 (s, 1H), 4.72 (bs, 4H), 4.05 (s, 3H), 3.88 (t, J = 8.4 Hz, 1H), 3.70 (t, J = 9.3 Hz, 1H), 3.59 - 3.46 (m, 1H), 3.40 (s, 1H), 2.35 (s, 1H), 2.23 (s, 3H), 2.03 (t, J = 10.3 Hz, 1H). One of the CH protons overlapped with water. m / z: [M+H] + =478.23.

[0218] Example 70 [ka] Method D. 1 H NMR (300 MHz, DMSO-d6) δ 12.67 (s, 1H), 8.53 (s, 1H), 8.31 (d, J = 5.9 Hz, 1H), 8.27 - 8.17 (m, 1H), 7.69 (d, J = 8.5 Hz, 2H), 7.56 (s, 1H), 7.05 (s, 1H), 6.48 (d, J = 6.0 Hz, 1H), 4.73 (bs, 4H), 4.02 (s, 3H), 3.80-3.55 (m, 3H), 1.90 - 1.80 (m, 1H), 1.21 (dd, J = 8.0, 5.0 Hz, 1H), 0.78 (t, J = 4.6 Hz, 1H). One of the CH protons overlapped with the Me group at 4.02 ppm. m / z: [M+H] + =476.20.

[0219] Example 71 [ka] Method E. 1 H NMR (300 MHz, DMSO-d6) δ 12.34 (d, J = 32.5 Hz, 1H), 8.54 (s, 1H), 8.28 (s, 1H), 7.92 (d, J = 10.3 Hz, 2H), 7.72 (d, J = 8.4 Hz, 1H), 7.47 (d, J = 45.5 Hz, 1H), 7.05 (s, 1H), 4.73 (bs, 4H), 4.09 - 3.94 (m, 4H, CH3, CH), 3.82 (t, J = 9.0 Hz, 1H), 3.59 (q, J = 9.3, 8.9 Hz, 1H), 3.36 (s, 2H),2.24 (s, 3H), 2.34 (s, 1H), 2.05 (d, J = 16.6 Hz, 1H). m / z: [M+H] + =478.20.

[0220] Comparative Example The structure of comparative compound A is shown below. [ka] This can be prepared according to the methods found in WO2019 / 001572.

[0221] Example 72 ADP-Glo ​​kinase assay (Promega). The ADP-Glo™ Kinase Assay is a luminescent ADP detection assay that allows for the measurement of kinase activity based on the amount of ADP produced during the kinase reaction. The kinase reaction is carried out in the presence of ATP, S6K substrate (KRRRLASLR), and ROCK kinase in an appropriate kinase reaction buffer (1x). At the end of the reaction, unconsumed ATP is depleted by the addition of ADP-Glo™ Reagent. Kinase Detection Reagent is then added to convert ADP to ATP, allowing newly synthesized ATP to be measured using a luciferase / luciferin reaction. Luminescence is proportional to ADP produced and, consequently, kinase activity. The ADP-Glo™ Kinase Assay was performed in a 384-well plate format as follows.

[0222] Kinase detection reagent preparation: The kinase detection buffer was thawed at room temperature (RT). If a precipitate was present, it was either dissolved by incubating the buffer at 37°C for 15 minutes with constant agitation or removed from the buffer by carefully pipetting the supernatant from the bottle. After both the kinase detection buffer and kinase detection substrate were equilibrated to room temperature, the entire amount of kinase detection buffer was transferred to the bottle containing the kinase detection substrate to redissolve the lyophilized substrate, followed by gentle mixing to obtain a homogenous solution.

[0223] Preparation of kinase reaction buffer: The kinase reaction buffer was freshly prepared before each experiment. The formulation of this buffer is shown in Table 1 below. [Table 1]

[0224] Preparation of ADP-Glo ​​reagent. Before performing the assay, three mixtures were prepared on ice: Mixture 1 - Contains ROCK1 or ROCK2 in kinase reaction buffer (1x) Mix 2 - Kinase reaction buffer (1x) containing S6K peptide Mix 3-kinase reaction buffer (1x) containing ATP

[0225] The final conditions for performing the ADP-Glo ​​kinase assay are shown in Table 2 below: Table 2. Final conditions for the ROCK ADP-Glo ​​kinase assay (concentrations in a final volume of 5 μL). [Table 2]

[0226] The reagent volume ratio in the assay was 1:1:2 kinase reactant to ADP-Glo™ reagent to kinase detection reagent. For a 384-well plate, the volumes were 5 μl kinase reactant, 5 μl ADP-Glo™ reagent, and 10 μl kinase detection reagent.

[0227] Construction of a standard curve for the conversion of ATP to ADP. To estimate the amount of ADP produced in the kinase reaction, standard curves were generated that represent the luminescence corresponding to the conversion of ATP to ADP based on the ATP concentration used in the kinase reaction. These conversion curves represent the amount of ATP and ADP obtainable in the reaction at a specific percentage of conversion, ranging from 100% conversion to approximately 0% conversion. The standards used to generate the ATP to ADP conversion curves were made by mixing appropriate volumes of ATP and ADP stock solutions.

[0228] Kinase inhibitor IC 50 Determining Values

[0229] Each plate contained a positive control (1 μM Compound A for ROCK2 and 1 μM RKI-1447 for ROCK1); vehicle control (1% DMSO); blank control (kinase reaction buffer (1x)); low control (substrate and ATP, no kinase) and autophosphorylation control (kinase and ATP, no substrate). Test compounds and reference compounds were diluted with 100% DMSO to obtain 10 mM stock solutions. Each compound was tested in duplicate in eight serial dilutions. The final concentration of DMSO in the reactions was 1% (max 50 nL).

[0230] 5 μl / well of kinase reaction buffer (1x) was dispensed into blank control wells. 2 μl / well of kinase reaction buffer (1x) was dispensed into no protein control (low control) wells and no substrate (autophosphorylation) wells. The plate was sealed with adhesive film and then briefly spun (1 min, 1000 rpm).

[0231] 2 μl / well of kinase (2.5x) solution was dispensed into the relevant wells of the assay plate. The plate was sealed with adhesive film and then briefly spun (1 min, 1000 rpm).

[0232] 2 μl / well of S6K substrate (2.5x) solution was dispensed into the relevant wells of the assay plate. The plate was sealed with adhesive film and then briefly spun (1 min, 1000 rpm).

[0233] 1 μl / well of ATP (5x) solution was dispensed into the appropriate wells of the assay plate. The final reaction volume was 15 μl. The plate was sealed with adhesive film and then briefly spun (1 min, 1000 rpm).

[0234] The plates were incubated at 25°C for 120 minutes with a shaking speed of 450 rpm.

[0235] After the incubation was complete, the kinase reaction was terminated, residual ATP was removed from the kinase reaction, and ADP was converted to ATP, which was measured in a luciferase / luciferin reaction. 5 μl of ADP-Glo™ Reagent was dispensed to stop the kinase reaction and deplete unconsumed ATP. The plate was sealed with adhesive film, then briefly spun (1 min, 1000 rpm), and incubated at 25° C. with a shaking speed of 450 rpm for 40 min.

[0236] 10 μl of kinase detection reagent was dispensed to convert ADP to ATP and to incorporate luciferase and luciferin to detect ATP. The plate was sealed with adhesive film, then briefly spun (1 min, 1000 rpm) and incubated at 25°C for 60 min with a shaking speed of 450 rpm.

[0237] After 5 minutes of dark acclimation, luminescence was measured using a PHERAstar FSX multimode plate reader (BMG Labtech).

[0238] Using GraphPad Prism 7.04 software, IC was calculated after scaling using a four-parameter model: log(inhibitor) vs. response with variable slope. 50 The parameters were calculated. [Table 3-1] [Table 3-2] [Table 3-3]

[0239] Example 73 Selective ROCK2 inhibition downregulates IL-17 and IL-21 secretion

[0240] Rho kinase (ROCK) is a member of the serine / threonine kinase family and is often studied for its role in cell morphology, motility, and shape through its effects on the cytoskeleton. Although the two ROCK isoforms, ROCK1 and ROCK2, share over 90% homology within their kinase domains, the functions of these proteins are non-overlapping and depend on the cell system in which ROCK is expressed and activated. Recent studies have demonstrated that ROCK2, but not ROCK1, regulates the pro-inflammatory IL-17-producing lineage of T cells, called Th17 cells, through a STAT3-dependent mechanism. Dysregulated activation of Th17 cells and STAT3 phosphorylation have been implicated in the pathogenesis of excessive inflammation and fibrotic pathologies. Furthermore, selective ROCK2 inhibition alters the balance between pro-inflammatory Th17 and immunosuppressive regulatory T cells (Tregs) by increasing STAT5 phosphorylation and IL-10 secretion. By using stimulatory antibodies against CD3 and CD28 (anti-CD3 / CD28) in combination with IL-1β and TGF-β (Th17-dominant conditions), we found that the novel selective ROCK2 inhibitor Example 6 strongly downregulated IL-17 and IL-21 secretion in Th17-dominant human CD4+ T cells in a dose-dependent manner with IC50s of 2046 nM and 1609 nM, respectively (Figure 2A and B).

[0241] FIG. 2 shows the effect of the compound of Example 6 on human CD4 T cells stimulated under conditions favoring Th17. + It inhibits IL-17 and IL-21 in T cells. + T cells were treated with the indicated doses of inhibitors and then stimulated with anti-CD3 / 28 mAb, IL-1β (50 ng / mL), and TGF-β (5 ng / mL) for 48 hours. Supernatants were analyzed for IL-17 and IL-21 by ELISA. One representative experiment out of three is shown. [Table 4] [Table 5]

[0242] Example 74 A selective ROCK2 inhibitor downregulates profibrogenic gene expression in fibroblasts

[0243] ROCK2 is activated by the small GTPase Rho in response to diverse profibrotic signals and regulates cytoskeletal dynamics, activation of various downstream intracellular targets, and expression of key profibrotic genes, such as fibronectin, smooth muscle actin (α-SMA), and collagen. Using MRC-5 human fibroblasts pretreated with different doses of selective ROCK2 inhibitors, Compound A, Example 6, and KD025 were found to dose-dependently downregulate and reduce TGF-β-induced α-SMA gene expression (determined by PCR) and collagen 1 (Col1a1) secretion (determined by ELISA) with IC50s ranging from 0.61 to 4.7 μM (Figure 3). These data further support the strong direct antifibrotic effects of selective ROCK2 inhibition.

[0244] Figure 3 shows that a selective ROCK2 inhibitor reduces profibrogenic gene expression and collagen 1 secretion in MRC-5 human fibroblasts. Human lung fibroblast MRC-5 cells were obtained from the American Type Culture Collection (ATCC) and cultured in MEM supplemented with 10% fetal bovine serum. Cells were seeded at 50,000 / mL / well in 24-well cell culture plates. The next day, cells were starved overnight in MEM containing 0.5% FBS. TGF-β1 (2.5 ng / mL) and various concentrations of Compound A, Example 6, or KD025 were applied to the cells for 48 hours. Cell mRNA was isolated, and αSMA mRNA expression was analyzed by RT-PCR. Collagen 1 secretion was determined by ELISA. A representative example of three different experiments is shown. [Table 6]

[0245] Example 75 To assess the bidirectional permeability of selected compounds, studies were performed using Caco-2 cell monolayers.

[0246] Incubations with Caco-2 cell monolayers were performed in duplicate. Test compounds Example 6 (5 μM), Example 66 (5 μM), Example 10 (5 μM), Example 70 (5 μM), and Example 27 (5 μM) or control compounds digoxin (10 μM) or metoprolol (10 μM) were added to a transport buffer containing Hank's balanced salt solution (HBSS) and 10 mM 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES), pH 7.4. These standard solutions were added to the appropriate donor wells of the apical or basal plate. Transport buffer containing DMSO was added to the appropriate receiver wells of the apical or basal plate. After 2 hours of incubation at 37°C, the cell plates were removed, and 50 μL samples from both the apical and basolateral sides were transferred to a new 96-well plate. Subsequently, 200 μL of acetonitrile containing internal standards (100 nM alprazolam, 200 nM caffeine, and 100 nM tolbutamide) was added to all samples to precipitate proteins, which were then analyzed by UPLC-MS / MS to determine the concentrations of test and control compounds. The concentration data were used to calculate the apical-to-basolateral apparent permeability (Papp) (P app(A→B) ), Papp in the basal to apical direction (P app(B→A) ), and the discharge ratio (P app(B→A) / P app(A→B) ) was calculated. Lucifer yellow was used as a marker to confirm the integrity of the cell monolayer after 2 hours of incubation.

[0247] Preparation of Caco-2 cells

[0248] 50 μL and 25 mL of cell culture medium were added to each well of the Transwell insert and reservoir, respectively, and then the HTS Transwell plate was incubated at 37°C and 5% CO for 1 hour before cells were seeded.

[0249] Caco-2 cells were diluted with culture medium to 6.86 x 10 cells / mL, and 50 μL of the cell suspension was dispensed into filter wells of a 96-well HTS Transwell plate. The cells were cultured in a cell culture incubator at 37°C, 5% CO2, and 95% relative humidity for 14–18 days. Cell culture medium was replaced every other day, beginning within 24 hours of initial seeding.

[0250] Assessment of cell monolayer integrity

[0251] The medium was removed from the reservoir and each Transwell insert and replaced with fresh, rewarmed medium.

[0252] Transepithelial electrical resistance (TEER) across the monolayer was measured using a Millicell Epithelial Volt-Ohm measurement system (Millipore, USA).

[0253] Once measurements were taken, the plates were returned to the incubator.

[0254] The TEER value was calculated according to the following equation: TEER measurement value (ohm) × membrane area (cm 2 ) = TEER value (ohm cm 2 )

[0255] The TEER value should be greater than 230 ohm·cm2, indicating a well-formed Caco-2 monolayer.

[0256] Preparation of solutions

[0257] Stock solutions of test compounds were prepared in DMSO at 1 mM and diluted with HBSS (10 mM HEPES, pH 7.4) to obtain 5 μM standard solutions. Stock solutions of control compounds were prepared in DMSO at 2 mM and diluted with HBSS (10 mM HEPES, pH 7.4) to obtain 10 μM standard solutions. Metoprolol and digoxin were used as control compounds.

[0258] Performing drug transport assays

[0259] The Caco-2 plates were removed from the incubator, the monolayers were washed twice with pre-warmed HBSS (10 mM HEPES, pH 7.4), and the plates were then incubated at 37°C for 30 minutes.

[0260] To determine the rate of drug transport from apical to basolateral, 125 μL of standard solution was added to the Transwell insert (apical compartment), and a 50 μL sample was immediately transferred from the apical compartment to a new 96-well plate containing 200 μL of acetonitrile containing IS (100 nM alprazolam, 200 nM caffeine, and 100 nM tolbutamide) and designated as the initial donor sample (AB). The wells were vortexed at 1000 rpm for 10 min. The receiver plate wells (basolateral compartment) were filled with 235 μL of transport buffer.

[0261] To determine the rate of drug transport in the basolateral-to-apical direction, 285 μL of standard solution was added to the receiver plate wells (basolateral compartment), and 50 μL of sample was immediately transferred from the basolateral compartment to a new 96-well plate containing 200 μL of acetonitrile containing IS (100 nM alprazolam, 200 nM caffeine, and 100 nM tolbutamide) as the initial donor sample (BA). The plate was vortexed at 1000 rpm for 10 minutes. The Transwell insert (apical compartment) was filled with 75 μL of transport buffer. The apical-to-basolateral and basolateral-to-apical transports should be performed simultaneously.

[0262] The plates were incubated at 37°C for 2 hours.

[0263] At the end of the incubation, 50 μL of sample from the donor side (apical compartment for Ap→Bl flow, and basolateral compartment for Bl→Ap flow) and the receiver side (basolateral compartment for Ap→Bl flow, and apical compartment for Bl→Ap flow) were transferred to wells of a new 96-well plate, followed by the addition of four volumes of IS (100 nM alprazolam, 200 nM caffeine, and 100 nM tolbutamide) in acetonitrile. The samples were vortexed for 10 min, and 50 μL of sample was transferred to wells of a new 96-well plate, followed by the addition of 50 μL of Hepes and 200 μL of IS. All samples were vortexed for 10 min and then centrifuged at 3,220 g for 40 min. A 150 μL aliquot of the supernatant was mixed with an appropriate volume of ultrapure water before LC-MS / MS analysis.

[0264] To determine Lucifer Yellow leakage after a 2-hour transport period, a Lucifer Yellow stock solution was prepared in DMSO and diluted with HBSS (10 mM HEPES, pH 7.4) to a final concentration of 100 μM. 100 μL of Lucifer Yellow solution was added to each Transwell insert (apical compartment), and the receiver plate wells (basolateral compartment) were filled with 300 μL of HBSS (10 mM HEPES, pH 7.4). The plates were incubated at 37°C for 30 minutes. Samples (80 μL) were removed directly from the apical and basolateral wells (using the basal access holes) and transferred to wells of a new 96-well plate. Lucifer Yellow fluorescence (to monitor monolayer integrity) signals were measured in a fluorescence plate reader at excitation of 480 nM and emission of 530 nM.

[0265] UPLC-MS / MS was used for sample analysis.

[0266] Data analysis

[0267] All calculations were performed using Microsoft Excel. Peak areas were determined from extracted ion chromatograms.

[0268] Calculate the apparent permeability (P) for drug transport assays using the following equation: app , cm / s × 10 -6 ) was calculated: P app =(dQ / dt) / (A×D0) [In the formula, P app is the apparent permeability (cm / s × 10 -6 ) and dQ / dt is the drug transport rate (pmol / sec), A is the membrane surface area (cm 2 ) and D0 is the initial donor concentration (nM; pmol / cm 3 ) is].

[0269] The following equation was used to determine the discharge ratio: Emission ratio=P app(B→A) / P app(A→B) [In the formula, P app(B→A) denotes the apparent permeability coefficient in the basal to apical direction. P app(A→B) denotes the apparent permeability coefficient in the apical to basal direction].

[0270] The recovery rate was determined using the following equation: Recovery rate (%) = ([drug] レシーバー ×V A +[Drugs] ドナー ×V D ) / ([Drugs] 初期、ドナー ×V D ) x 100 [In the formula, V A is the volume in the receiver well (unit: mL), V D is the volume in the donor well (unit: mL)].

[0271] The leakage rate of Lucifer Yellow (LY) from the monolayer was calculated using the following equation: LY leakage rate (%)=(I レシーバー ×0.3) / (I レシーバー ×0.3+I ドナー ×0.1)×100 [In the formula, Iレシーバー is the fluorescence intensity of the receiver well (0.3 mL). ドナー is the fluorescence intensity of the donor well (0.1 mL)].

[0272] Lucifer Yellow leakage should be less than 1.5% as determined by Transwell. app is qualitatively similar to that determined in the replicate Transwells, the monolayer is considered acceptable.

[0273] The results are summarized in Table 7 below: [Table 7]

[0274] Example 76 The purpose of this study was to evaluate the bidirectional permeability of selected compounds using MDCKII-MDR1 cell monolayers. The MDCKII-MDR1 assay is a cell-based tool for predicting blood-brain barrier permeability in vivo.

[0275] Incubations with MDCKII-MDR1 cell monolayers were performed in duplicate. Test compounds Compound A (1 μM), Example 6 (1 μM), Example 66 (1 μM), and Example 70 (1 μM) or control compounds digoxin (1 μM) or metoprolol (1 μM) were added to a transport buffer containing Hank's balanced salt solution (HBSS) and 10 mM 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES), pH 7.4. These standard solutions were added to the appropriate donor wells of the apical or basal plate. Transport buffer containing DMSO was added to the appropriate receiver wells of the apical or basal plate. After 2 hours of incubation at 37°C, the cell plates were removed, and 50 μL samples from both the apical and basolateral sides were transferred to a new 96-well plate. 200 μL of acetonitrile containing internal standards (100 nM alprazolam, 200 nM caffeine, 100 nM tolbutamide, and 200 nM labetalol) was then added to all samples to precipitate proteins, which were then analyzed by UPLC-MS / MS to determine the concentrations of test and control compounds. The concentration data were used to calculate the apparent apical-to-basolateral permeability (P app )(P app(A→B) ), Papp in the basal to apical direction (Papp(B→A)), and the efflux ratio (P app(B→A) / P app(A→B) ) was calculated. Lucifer yellow was used as a marker to confirm the integrity of the cell monolayer after 2 hours of incubation.

[0276] Preparation of monolayers

[0277] MDCK-MDR1 cell culture medium was prepared, consisting of Dulbecco's Modified Eagle Medium (DMEM) supplemented with 10% FBS and 1x penicillin-streptomycin mixture. 50 μL of cell culture medium was added to each well of a Transwell insert. The Transwell insert was removed from the reservoir, and 25 mL of medium was added to the reservoir tray. The plate(s) was incubated at 37°C and 5% CO2 for 1 hour, after which the plate(s) was ready for cell seeding.

[0278] Cells were cultured in T-75 flasks in a cell culture incubator set at 37°C, 5% CO2, and 95% relative humidity. Cells were allowed to reach 80-90% confluence before detachment and separation.

[0279] Cultured cells were rinsed in a T-75 flask with 5 mL of PBS, removed by aspiration, and 3 mL of trypsin / EDTA solution was added. The cells were incubated at 37°C for approximately 5 minutes or until the cells detached and floated. The trypsin / EDTA was inactivated by adding cell culture medium containing FBS.

[0280] The cell suspension was removed to a centrifuge tube and the cells were pelleted by centrifugation at 120 x g for 10 minutes. The cells were resuspended in cell culture medium at a density of 1.56 x 106 cells / mL.

[0281] 50 μL of the cell suspension was added to each well of the previously prepared Transwell plate(s). The cell number was 5.45×10 5 cells / cm 2 The plate(s) were incubated for 4-7 days. Medium changes were performed every other day, starting within 24 hours of initial seeding.

[0282] The procedure for medium change was as follows: The plate(s) were removed from the incubator and placed in the hood. Aspirate the medium from the reservoir and each Transwell insert. 100 μL of medium was added to each well of the Transwell insert and 25 mL of medium was added to the reservoir tray. The plate(s) were returned to the incubator.

[0283] Assessment of cell monolayer integrity

[0284] The medium was removed from the cell culture reservoir and each Transwell insert. 100 μL and 25 mL of pre-warmed cell culture medium were added to each Transwell insert and

[0285] The plate was then placed in a reservoir tray. The electrical resistance across the monolayer was measured using a Millicell Epithelial Volt-Ohm measurement system, and the electrical resistance was recorded for each well. After all wells were measured, the plate(s) was returned to the incubator.

[0286] The TEER of each well was calculated using the following equation: The TEER value of each well was 42 ohm cm 2 It should exceed TEER value (ohm cm 2 ) = TEER measurement value (ohm) × membrane area (cm 2 )

[0287] Transport assay procedure

[0288] The MDCK-MDR1 plate(s) were removed from the incubator and the monolayers were washed twice with pre-warmed HBSS (10 mM HEPES, pH 7.4). The plate(s) were then incubated at 37°C for 30 minutes.

[0289] Stock solutions of control and test compounds were diluted with DMSO to obtain 200 μM solutions, and then diluted with HBSS (10 mM HEPES, pH 7.4) to obtain 1 μM standard solutions. The final concentration of DMSO in the incubation system was 0.5%.

[0290] To determine the rate of drug transport from apical to basolateral, 125 μL of standard solution was added to the Transwell insert (apical compartment), and 50 μL of sample was immediately transferred from the apical compartment to a new 96-well plate containing 200 μL of acetonitrile containing IS (100 nM alprazolam, 200 nM caffeine, 200 nM labetalol, and 100 nM tolbutamide) as the initial donor sample (AB). The wells of the receiver plate (basolateral compartment) were filled with 235 μL of transport buffer.

[0291] To determine the rate of drug transport from basolateral to apical direction, 285 μL of standard solution was added to the receiver plate wells (basolateral compartment), and 50 μL of sample was immediately transferred from the basolateral compartment to a new 96-well plate containing 200 μL of acetonitrile containing IS (100 nM alprazolam, 200 nM caffeine, 200 nM labetalol, and 100 nM tolbutamide) as the initial donor sample (BA). The plate was vortexed at 1000 rpm for 10 min. The Transwell insert (apical compartment) was filled with 75 μL of transport buffer. The apical-to-basolateral and basolateral-to-apical transports should be performed simultaneously.

[0292] Incubate at 37°C for 2 hours. At the end of the transport period, 50 μL of sample was transferred from the donor side (apical compartment for Ap→B1 flow, and basolateral compartment for B1→Ap flow) and the receiver side (basolateral compartment for Ap→B1 flow, and apical compartment for B1→Ap flow) to a new 96-well plate. Four volumes of cold acetonitrile or cold methanol containing the appropriate internal standard (IS) was added to each well of the plate(s). Vortex for 5 minutes.

[0293] The samples were centrifuged at 3,220 g for 30 min. A 100 μL aliquot of the supernatant was mixed with an appropriate volume of ultrapure water (depending on the LC-MS / MS signal response and peak shape) before LC-MS / MS analysis.

[0294] To determine Lucifer Yellow leakage after a 2-hour transport period, a Lucifer Yellow stock solution was prepared in DMSO and diluted with HBSS (10 mM HEPES, pH 7.4) to a final concentration of 100 μM. 100 μL of Lucifer Yellow solution was added to each Transwell insert (apical compartment), and then the receiver plate wells (basolateral compartment) were filled with 300 μL of HBSS (10 mM HEPES, pH 7.4). The plates were incubated at 37°C for 30 minutes. 80 μL samples were removed directly from the apical and basolateral wells (using the basal access holes) and transferred to wells of a new 96-well plate. Lucifer Yellow fluorescence (to monitor monolayer integrity) signals were measured in a fluorescence plate reader at excitation of 480 nM and emission of 530 nM.

[0295] UPLC-MS / MS was used for sample analysis.

[0296] All calculations were performed using Microsoft Excel. Peak areas were determined from extracted ion chromatograms.

[0297] Apparent permeability coefficient (P app ) (units: centimeters / second) can be calculated for the MDCK-MDR1 drug transport assay using the following equation:

number

[0298] In the formula, V A is the volume in the receiver well (unit: mL) (0.235 mL for Ap → Bl flow and 0.075 mL for Bl → Ap flow), and area is the membrane surface area (0.143 cm for HTS Transwell-96 well permeation support). 2 ) and time is the total transport time (unit: seconds).

[0299] The following equation was used to determine the discharge ratio: Emission ratio=Papp(B→A) / P app(A→B) [In the formula, P app(B→A) denotes the apparent permeability coefficient in the basal to apical direction. P app(A→B) denotes the apparent permeability coefficient in the apical to basal direction].

[0300] The recovery rate was determined using the following equation: Recovery rate (%) = ([drug] アクセプター ×V A +[Drugs] ドナー ×V D ) / ([Drugs] 初期、ドナー ×V D ) x 100

[0301] In the formula, V A is the volume in the acceptor well (unit: mL) (0.235 mL for Ap → Bl flow, 0.075 mL for Bl → Ap flow), and V D is the volume in the donor well in mL (0.075 mL for Ap→Bl flow and 0.235 mL for Bl→Ap flow).

[0302] The leakage rate of Lucifer Yellow (LY) from the monolayer was calculated using the following equation: LY leakage%=([LY] アクセプター ) / ([LY] ドナー +[LY] アクセプター ) x 100

[0303] LY leakage should be less than approximately 1% to indicate a well-competent MDCK-MDR1 monolayer.

[0304] The functionality of the test system was confirmed using digoxin and metoprolol as positive and negative controls, respectively. Lucifer Yellow values ​​of less than 1.5% confirmed the integrity of the MDCKII-MDR1 cells during the experimental procedure. The results for the control compounds were within their respective historical ranges. Therefore, the acceptance criteria were met and the assay results for the compounds were considered acceptable. The permeability results for the compounds and control compounds are summarized in Table 8 below. [Table 8]

[0305] Example 77 The pharmacokinetics and brain permeability of the compound of Example 6 were studied after a single oral and a single intravenous administration to CD1 mice. The following conditions were used in the study: [Table 9]

[0306] Sample preparation

[0307] Plasma sample preparation: The desired concentration steps of the standard solutions were achieved by diluting the analyte stock solution with 50% aqueous acetonitrile. Five microliters of standard solution (1, 2, 10, 20, 100, 200, 1000, and 2000 ng / mL) were added to 10 μL of blank CD-1 male mouse plasma to achieve calibration standards ranging from 0.5 to 1000 ng / mL (0.5, 1, 5, 10, 50, 100, 500, and 1000 ng / mL) in a total volume of 15 μL. Four quality control samples of plasma were prepared independently from the samples used for the calibration curve: 1 ng / mL, 2 ng / mL, 50 ng / mL, and 800 ng / mL. These QC samples were prepared on the day of analysis using the same method as the calibration standards.

[0308] 15 μL of the standard, 15 μL of the QC sample, and 15 μL of the unknown sample (10 μL of plasma and 5 μL of blank solution) were each added to 150 μL of the IS mixture in acetonitrile to precipitate proteins. The samples were then vortexed for 30 seconds. After centrifugation at 4°C and 4000 rpm for 15 minutes, the supernatant was diluted 3-fold with water. 25 μL of the diluted supernatant was injected into the LC / MS / MS system for quantitative analysis.

[0309] Brain sample preparation: Brain samples were homogenized with water at a brain weight (g) to water volume (mL) ratio of 1:3. The desired concentration steps for the standard solutions were achieved by diluting the analyte stock solution with 50% aqueous acetonitrile. 15 μL of standard solution (1, 2, 10, 20, 100, 200, 1000, 2000 ng / mL) was added to 30 μL of blank CD1 male mouse brain homogenate to achieve calibration standards ranging from 0.5 to 1000 ng / mL (0.5, 1, 5, 10, 50, 100, 500, 1000 ng / mL) in a total volume of 45 μL. Four quality control samples of brain were prepared independently from the samples used for the calibration curve: 1 ng / mL, 2 ng / mL, 50 ng / mL, and 800 ng / mL. These QC samples were prepared on the day of analysis using the same method as the calibration standards.

[0310] 45 μL of the standard, 45 μL of the QC sample, and 45 μL of the unknown sample (30 μL of brain homogenate and 15 μL of blank solution) were each added to 150 μL of acetonitrile to precipitate proteins. The samples were then vortexed for 30 seconds. After centrifugation at 4°C and 4000 rpm for 15 minutes, the supernatant was diluted 3-fold with water. 15 μL of the diluted supernatant was injected into the LC / MS / MS system for quantitative analysis.

[0311] Example 78 The compound of Example 6 was tested in a mouse model of scleroderma.

[0312] Test animals: 9-11 week-old C57BL / 6 mice were obtained from an IACUC-approved laboratory animal supplier (Jackson Laboratory) and ear-tagged for identification purposes. From day -10 until the end of the study, animals were fed a Western Diet (Envigo, #120528). Animals were weighed twice weekly and monitored for clinical signs of pain or lameness. During disease induction, mice received supportive care as needed, including gel diet, cage time on a heating pad, and subcutaneous saline injections to maintain hydration.

[0313] Stimulation: On day -3, animals were randomized into treatment groups, and the backs of mice were shaved. On day 0, circles were drawn on the left and right sides of the animals' backs. The diameter of the circles was approximately 1 cm. On days 0-4 and 7-11, animals received two injections of bleomycin at 7.5 mg / kg / day, 100 μL injected SC on each day (2 days). Animals in the control group received two injections of 100 μL saline at the same time points. Needles were inserted around the circumference of the circle, and bleomycin was injected below the center of each circle. The insertion point was changed by quadrants each day. Circles were redrawn, and mice were shaved as needed throughout the study period.

[0314] Treatment: On day 7, animals from the treatment groups were re-stratified into 6 groups of 7-15 animals each, with the average weights being approximately the same in each group. From day 7 through day 20 (14 days of dosing), animals received the indicated doses of Compound A or Example 6 by oral gavage.

[0315] Formulation: Bleomycin (Hospira) was resuspended in saline to give mice 7.5 mg / kg / day in 200 μL. The vehicle was 0.4% MC (400 cp) and prepared weekly. Compound A and Example 6 were formulated in the vehicle solution and stored at 4° C. The salt correction for Compound A and Example 6 was 1.112 and 1, respectively.

[0316] PK: Half of the animals in each group were bled pre-dose and 4 hours post-dose on day 20. Blood was processed for serum and stored at -80°C.

[0317] End: Two skin patches were harvested from the mice using a 1 cm biopsy punch and weighed. One patch was frozen at -80°C for hydroxyproline analysis. The collagen content of the skin patches was determined by hydroxyproline assessment, and the results are shown in Figure 5.

Claims

1. Formula I: 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, X １ is N or CH, X ２ is N or CH, X ３ is N or CR ３ and X ４ is N or CR ４ and X ５ is selected from the group consisting of C, CH and N; a is selected from 1 or 2; The dotted line represents an optional double bond; Each R １ are independently H, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ７ Cycloalkyl, halo, oxo, -CN, C １ -C ３ Perfluoroalkyl, -OR １１ , and -NR １１ R １２ or selected from the group consisting of Or alternatively, two R １ are taken together to form a 3-6 membered ring, which may optionally contain 0-2 ring heteroatoms selected from O, S and N, and may be unsubstituted or optionally contains halo, C １ -C ３ Alkyl, NH ２ , OH, and O-C １ -C ３ It may be optionally substituted by 1 to 3 substituents selected from alkyl; b is selected from 0, 1, and 2; R ２ is H, halo, C １ -C ３ Alkyl, NH ２ , OH, and O-C １ -C ３ alkyl, R ３ is H, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ７ Cycloalkyl, halo, -CN, C １ -C ３ Perfluoroalkyl, -OR １１ , —O—(C １ -C ６ alkyl)-OR １１ , -(C １ -C ６ alkyl)-OR １１ , -NR １１ R １２ , —O—(C １ -C ６ alkyl)-NR １１ R １２ , -(C １ -C ６ alkyl)-NR １１ R １２ , -NR １１ -(C １ -C ６ alkyl)-NR １１ R １２ , -NR １１ -(C １ -C ６ alkyl)-OR １１ , -(C １ -C ６ alkyl) ｘ -C(=O)R １１ , —O—(C １ -C ６ alkyl) ｘ -C(=O)R １１ , -(C １ -C ６ alkyl) ｘ -C(=O)OR １１ , —C(═O)—R １１ , -C(=O)OR １１ , -(C １ -C ６ alkyl) ｘ -C(=O)NR １１ R １２ , -NR １１ -(C １ -C ６ alkyl) ｘ -C(=O)R １１ , and -NR １１ -(C １ -C ６ alkyl) ｘ -C(=O)OR １１ is selected from the group consisting of R ４ is H, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ７ Cycloalkyl, halo, -CN, C １ -C ３ Perfluoroalkyl, -OR １１ , —O—(C １ -C ６ alkyl)-OR １１ , -(C １ -C ６ alkyl)-OR １１ , -NR １１ R １２ , —O—(C １ -C ６ alkyl)-NR １１ R １２ , -(C １ -C ６ alkyl)-NR １１ R １２ , -NR １１ -(C １ -C ６ alkyl)-NR １１ R １２ , -NR １１ -(C １ -C ６ alkyl)-OR １１ , -(C １ -C ６ alkyl) ｘ -C(=O)R １１ , —O—(C １ -C ６ alkyl) ｘ -C(=O)R １１ , -(C １ -C ６ alkyl) ｘ -C(=O)OR １１ , —C(═O)—R １１ , -C(=O)OR １１ , -(C １ -C ６ alkyl) ｘ -C(=O)NR １１ R １２ , -NR １１ -(C １ -C ６ alkyl) ｘ -C(=O)R １１ , and -NR １１ -(C １ -C ６ alkyl) ｘ -C(=O)OR １１ is selected from the group consisting of Alternatively, R ３ and R ４ together form a 5- or 6-membered saturated or unsaturated fused ring, which may contain 0-2 ring heteroatoms selected from the group consisting of N, O, and S, and is unsubstituted or １ -C ６ Alkyl, halo, -CN, -OH, oxo, -O-(C １ -C ６ alkyl), —O—(C １ -C ６ alkyl)-OH, -O-(C １ -C ６ alkyl)-O-(C １ -C ６ alkyl), -NR １１ R １２ , —O—(C １ -C ６ alkyl)-NR １１ R １２ , C １ -C ３ Perfluoroalkyl, —NR １１ -(C １ -C ６ alkyl)NR １１ R １２ , and -NR １１ -(C １ -C ６ alkyl)-OR １１ and is substituted with 1 to 3 substituents selected from the group consisting of: Each R ５ are independently H, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ７ Cycloalkyl, halo, -CN, C １ -C ３ Perfluoroalkyl, oxo, -OR １１ , —O—(C １ -C ６ alkyl)-OR １１ , -(C １ -C ６ alkyl)-OR １１ , -NR １１ R １２ , —O—(C １ -C ６ alkyl)-NR １１ R １２ , -(C １ -C ６ alkyl)-NR １１ R １２ , -NR １１ -(C １ -C ６ alkyl)-NR １１ R １２ , -NR １１ -(C １ -C ６ alkyl)-OR １１ , -(C １ -C ６ alkyl) ｘ -C(=O)R １１ , —O—(C １ -C ６ alkyl) ｘ -C(=O)R １１ , -(C １ -C ６ alkyl) ｘ -C(=O)OR １１ , —C(═O)—R １１ , -C(=O)OR １１ , -(C １ -C ６ alkyl) ｘ -C(=O)NR １１ R １２ , -NR １１ -(C １ -C ６ alkyl) ｘ -C(=O)R １１ , and -NR １１ -(C １ -C ６ alkyl) ｘ -C(=O)OR １１ is selected from the group consisting of n is 0 to 3; R ６ and R ７ are independently H, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ７ Cycloalkyl, halo, -CN, C １ -C ３ Perfluoroalkyl, -OR １１ , —O—(C １ -C ６ alkyl)-OR １１ , -(C １ -C ６ alkyl)-OR １１ , -NR １１ R １２ , —O—(C １ -C ６ alkyl)-NR １１ R １２ , —O—(C １ -C ６ alkyl)-C(=O)NR １１ R １２ , -(C １ -C ６ alkyl)-NR １１ R １２ , -(C １ -C ６ alkyl)-C(=O)NR １１ R １２ , -NR １１ -(C １ -C ６ alkyl)-NR １１ R １２ , -NR １１ -(C １ -C ６ alkyl)-OR １１ , -(C １ -C ６ alkyl) ｘ -C(=O)R １１ , —O—(C １ -C ６ alkyl) ｘ -C(=O)R １１ , -(C １ -C ６ alkyl) ｘ -C(=O)OR １１ , —C(═O)—R １１ , -C(=O)OR １１ , -(C １ -C ６ alkyl) ｘ -C(=O)NR １１ R １２ , -NR １１ -(C １ -C ６ alkyl) ｘ -C(=O)R １１ , and -NR １１ -(C １ -C ６ alkyl) ｘ -C(=O)OR １１ or selected from the group consisting of Alternatively, R ６ and R ７ together form a 5- or 6-membered saturated or unsaturated fused ring, which may contain 0-2 ring heteroatoms selected from the group consisting of N, O, and S, and is unsubstituted or １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ７ Cycloalkyl, C ５ -C １０ Aryl, C ５ -C １０ Heteroaryl, 3- to 10-membered heterocyclyl, —C １ -C ６ Alkyl-(C ３ -C ７ cycloalkyl), -C １ -C ６ Alkyl-(C ５ -C １０ aryl), -C １ -C ６ Alkyl-(C ５ -C １０ heteroaryl), -C １ -C ６ Alkyl-(3- to 10-membered heterocyclyl), halo, —CN, —OH, oxo, —O—(C １ -C ６ alkyl), —O—(C １ -C ６ alkyl)-OH, -O-(C １ -C ６ alkyl)-O-(C １ -C ６ alkyl), -NR １１ R １２ , —O—(C １ -C ６ alkyl)-NR １１ R １２ , C １ -C ３ Perfluoroalkyl, —NR １１ -(C １ -C ６ alkyl)NR １１ R １２ , -NR １１ -(C １ -C ６ alkyl)-OR １１ and —C(═O)—N(R ８ ) (R ９ and each alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl is optionally substituted with 1 to 3 substituents selected from the group consisting of: １ -C ３ Alkyl, C １ -C ３ Perfluoroalkyl, oxo, halo, —CN, —OH, and NH ２ and optionally substituted with 1 to 3 substituents selected from R ８ and R ９ are each independently H, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ７ cycloalkyl, 3- to 10-membered heterocyclyl, C ６ -C １０ Aryl, 5- to 14-membered heteroaryl, C ６－１２ Aralkyl, -(C １ -C ６ alkyl)-OR １１ , -(C １ -C ６ alkyl)-NR １１ R １２ , -(C １ -C ６ alkyl) ｘ -C(=O)R １１ , -(C １ -C ６ alkyl) ｘ -C(=O)OR １１ , and -(C １ -C ６ alkyl) ｘ -C(=O)NR １１ R １２ and each alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl is optionally selected from the group consisting of: １ -C ３ Alkyl, C １ -C ３ Perfluoroalkyl, oxo, halo, —CN, —OH, and NH ２ and optionally substituted with 1 to 3 substituents selected from Alternatively, R ８ and R ９ taken together with the nitrogen to which they are attached provide (i) a 4-6 membered heterocycle having 0-2 additional ring heteroatoms selected from N, O and S, or (ii) a 5-10 membered heterobicyclic ring system having 0-3 additional ring heteroatoms selected from N, O and S, wherein said heterocycle or said bicyclic ring system is unsubstituted or is selected from halo, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ７ Cycloalkyl, -CN, C １ -C ６ Fluoroalkyl, C １ -C ３ Perfluoroalkyl, -OR １１ , oxo, —O—(C １ -C ６ alkyl)-OR １１ , -(C １ -C ６ alkyl)-OR １１ , -NR １１ R １２ , —O—(C １ -C ６ alkyl)-NR １１ R １２ , -(C １ -C ６ alkyl)-NR １１ R １２ , -NR １１ -(C １ -C ６ alkyl)-NR １１ R １２ , -NR １１ -(C １ -C ６ alkyl)-OR １１ , -(C １ -C ６ alkyl) ｘ -C(=O)R １１ , —O—(C １ -C ６ alkyl) ｘ -C(=O)R １１ , -(C １ -C ６ alkyl) ｘ -C(=O)OR １１ , —C(═O)—R １１ , -C(=O)OR １１ , -(C １ -C ６ alkyl) ｘ -C(=O)NR １１ R １２ , -NR １１ -(C １ -C ６ alkyl) ｘ -C(=O)R １１ , and -NR １１ -(C １ -C ６ alkyl) ｘ -C(=O)OR １１ and is substituted with 1 to 4 substituents selected from the group consisting of: each x is independently selected from 0 and 1; and Each R １１ and R １２ are independently H and C １ -C ６ alkyl; Or alternatively, R １１ and R １２ when both are attached to the same nitrogen, combine to form a 4-7 membered heterocycle having 0-2 additional ring heteroatoms selected from the group consisting of N, O and S, said heterocycle being unsubstituted or selected from halo, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ７ Cycloalkyl, —CN, —NH ２ , C １ -C ３ Perfluoroalkyl, —OH, —O—(C １ -C ６ alkyl), and -(C １ -C ６ or a pharmaceutically acceptable salt thereof, wherein:

2. Formula II: 【Chemistry 2】 2. The compound of claim 1, wherein: X １ is N or CH, X ２ is N or CH, X ３ is N or CR ３ and X ４ is N or CR ４ and X ５ is selected from the group consisting of C, CH and N; The dotted line represents an optional double bond; Each R １ are independently H, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ７ Cycloalkyl, halo, oxo, -CN, C １ -C ３ Perfluoroalkyl, -OR １１ , and -NR １１ R １２ or selected from the group consisting of Or alternatively, two R １ are taken together to form a 3-6 membered ring, which may optionally contain 0-2 ring heteroatoms selected from O, S and N, and may be unsubstituted or optionally contains halo, C １ -C ３ Alkyl, NH ２ , OH, and O-C １ -C ３ It may be optionally substituted by 1 to 3 substituents selected from alkyl; b is selected from 0, 1, and 2; R ３ is H, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ７ Cycloalkyl, halo, -CN, C １ -C ３ Perfluoroalkyl, -OR １１ , —O—(C １ -C ６ alkyl)-OR １１ , -(C １ -C ６ alkyl)-OR １１ , -NR １１ R １２ , —O—(C １ -C ６ alkyl)-NR １１ R １２ , -(C １ -C ６ alkyl)-NR １１ R １２ , -NR １１ -(C １ -C ６ alkyl)-NR １１ R １２ , -NR １１ -(C １ -C ６ alkyl)-OR １１ , -(C １ -C ６ alkyl) ｘ -C(=O)R １１ , —O—(C １ -C ６ alkyl) ｘ -C(=O)R １１ , -(C １ -C ６ alkyl) ｘ -C(=O)OR １１ , —C(═O)—R １１ , -C(=O)OR １１ , -(C １ -C ６ alkyl) ｘ -C(=O)NR １１ R １２ , -NR １１ -(C １ -C ６ alkyl) ｘ -C(=O)R １１ , and -NR １１ -(C １ -C ６ alkyl) ｘ -C(=O)OR １１ is selected from the group consisting of R ４ is H, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ７ Cycloalkyl, halo, -CN, C １ -C ３ Perfluoroalkyl, -OR １１ , —O—(C １ -C ６ alkyl)-OR １１ , -(C １ -C ６ alkyl)-OR １１ , -NR １１ R １２ , —O—(C １ -C ６ alkyl)-NR １１ R １２ , -(C １ -C ６ alkyl)-NR １１ R １２ , -NR １１ -(C １ -C ６ alkyl)-NR １１ R １２ , -NR １１ -(C １ -C ６ alkyl)-OR １１ , -(C １ -C ６ alkyl) ｘ -C(=O)R １１ , —O—(C １ -C ６ alkyl) ｘ -C(=O)R １１ , -(C １ -C ６ alkyl) ｘ -C(=O)OR １１ , —C(═O)—R １１ , -C(=O)OR １１ , -(C １ -C ６ alkyl) ｘ -C(=O)NR １１ R １２ , -NR １１ -(C １ -C ６ alkyl) ｘ -C(=O)R １１ , and -NR １１ -(C １ -C ６ alkyl) ｘ -C(=O)OR １１ is selected from the group consisting of Alternatively, R ３ and R ４ together form a 5- or 6-membered saturated or unsaturated fused ring, which may contain 0-2 ring heteroatoms selected from the group consisting of N, O, and S, and is unsubstituted or １ -C ６ Alkyl, halo, -CN, -OH, oxo, -O-(C １ -C ６ alkyl), —O—(C １ -C ６ alkyl)-OH, -O-(C １ -C ６ alkyl)-O-(C １ -C ６ alkyl), -NR １１ R １２ , —O—(C １ -C ６ alkyl)-NR １１ R １２ , C １ -C ３ Perfluoroalkyl, —NR １１ -(C １ -C ６ alkyl)NR １１ R １２ , and -NR １１ -(C １ -C ６ alkyl)-OR １１ and is substituted with 1 to 3 substituents selected from the group consisting of: Each R ５ are independently H, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ７ Cycloalkyl, halo, -CN, C １ -C ３ Perfluoroalkyl, oxo, -OR １１ , —O—(C １ -C ６ alkyl)-OR １１ , -(C １ -C ６ alkyl)-OR １１ , -NR １１ R １２ , —O—(C １ -C ６ alkyl)-NR １１ R １２ , -(C １ -C ６ alkyl)-NR １１ R １２ , -NR １１ -(C １ -C ６ alkyl)-NR １１ R １２ , -NR １１ -(C １ -C ６ alkyl)-OR １１ , -(C １ -C ６ alkyl) ｘ -C(=O)R １１ , —O—(C １ -C ６ alkyl) ｘ -C(=O)R １１ , -(C １ -C ６ alkyl) ｘ -C(=O)OR １１ , —C(═O)—R １１ , -C(=O)OR １１ , -(C １ -C ６ alkyl) ｘ -C(=O)NR １１ R １２ , -NR １１ -(C １ -C ６ alkyl) ｘ -C(=O)R １１ , and -NR １１ -(C １ -C ６ alkyl) ｘ -C(=O)OR １１ is selected from the group consisting of n is 0 to 3; X ６ is NR １０ , O and S; X ７ is selected from the group consisting of CH and N; R ８ and R ９ are each independently H, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ７ cycloalkyl, 3- to 10-membered heterocyclyl, C ６ -C １０ Aryl, 5- to 14-membered heteroaryl, C ６－１２ Aralkyl, -(C １ -C ６ alkyl)-OR １１ , -(C １ -C ６ alkyl)-NR １１ R １２ , -(C １ -C ６ alkyl) ｘ -C(=O)R １１ , -(C １ -C ６ alkyl) ｘ -C(=O)OR １１ , and -(C １ -C ６ alkyl) ｘ -C(=O)NR １１ R １２ and each alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl is optionally selected from the group consisting of: １ -C ３ Alkyl, C １ -C ３ Perfluoroalkyl, oxo, halo, —CN, —OH, and NH ２ and optionally substituted with 1 to 3 substituents selected from Alternatively, R ８ and R ９ taken together with the nitrogen to which they are attached provide (i) a 4-6 membered heterocycle having 0-2 additional ring heteroatoms selected from N, O and S, or (ii) a 5-10 membered heterobicyclic ring system having 0-3 additional ring heteroatoms selected from N, O and S, wherein said heterocycle or said bicyclic ring system is unsubstituted or is selected from halo, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ７ Cycloalkyl, -CN, C １ -C ６ Fluoroalkyl, C １ -C ３ Perfluoroalkyl, -OR １１ , oxo, —O—(C １ -C ６ alkyl)-OR １１ , -(C １ -C ６ alkyl)-OR １１ , -NR １１ R １２ , —O—(C １ -C ６ alkyl)-NR １１ R １２ , -(C １ -C ６ alkyl)-NR １１ R １２ , -NR １１ -(C １ -C ６ alkyl)-NR １１ R １２ , -NR １１ -(C １ -C ６ alkyl)-OR １１ , -(C １ -C ６ alkyl) ｘ -C(=O)R １１ , —O—(C １ -C ６ alkyl) ｘ -C(=O)R １１ , -(C １ -C ６ alkyl) ｘ -C(=O)OR １１ , —C(═O)—R １１ , -C(=O)OR １１ , -(C １ -C ６ alkyl) ｘ -C(=O)NR １１ R １２ , -NR １１ -(C １ -C ６ alkyl) ｘ -C(=O)R １１ , and -NR １１ -(C １ -C ６ alkyl) ｘ -C(=O)OR １１ and is substituted with 1 to 4 substituents selected from the group consisting of: R １０ is H, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ７ Cycloalkyl, C ５ -C １０ Aryl, C ５ -C １０ Heteroaryl, 3- to 10-membered heterocyclyl, —C １ -C ６ Alkyl-(C ３ -C ７ cycloalkyl), -C １ -C ６ Alkyl-(C ５ -C １０ aryl), -C １ -C ６ Alkyl-(C ５ -C １０ heteroaryl), -C １ -C ６ alkyl-(3- to 10-membered heterocyclyl), -(C １ -C ６ alkyl)-NR １１ R １２ , -(C １ -C ６ alkyl)NR １１ R １２ , -(C １ -C ６ alkyl)-OR １１ and —C(═O)—N(R １１ ) (R １２ and each alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl is optionally selected from the group consisting of C １ -C ３ Alkyl, C １ -C ３ Perfluoroalkyl, oxo, halo, —CN, —OH, and NH ２ and optionally substituted with 1 to 3 substituents selected from each x is independently selected from 0 and 1; and Each R １１ and R １２ are independently H and C １ -C ６ alkyl; Or alternatively, R １１ and R １２ when both are attached to the same nitrogen, combine to form a 4-7 membered heterocycle having 0-2 additional ring heteroatoms selected from the group consisting of N, O and S, the heterocycle being unsubstituted or selected from halo, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ７ Cycloalkyl, —CN, —NH ２ , C １ -C ３ Perfluoroalkyl, —OH, —O—(C １ -C ６ alkyl), and -(C １ -C ６ and substituted with 1 to 3 substituents selected from the group consisting of (alkyl)-OH.

3. Formula III: 【Transformation 3】 2. The compound of claim 1, wherein: X ２ is N or CH, X ３ is N or CR ３ and X ５ is selected from the group consisting of C, CH and N; The dotted line represents an optional double bond; Each R １ are independently H, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ７ Cycloalkyl, halo, oxo, -CN, C １ -C ３ Perfluoroalkyl, -OR １１ , and -NR １１ R １２ or selected from the group consisting of Or alternatively, two R １ are taken together to form a 3-6 membered ring, which may optionally contain 0-2 ring heteroatoms selected from O, S and N, and may be unsubstituted or optionally contains halo, C １ -C ３ Alkyl, NH ２ , OH, and O-C １ -C ３ It may be optionally substituted by 1 to 3 substituents selected from alkyl; b is selected from 0, 1, and 2; R ３ is H, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ７ Cycloalkyl, halo, -CN, C １ -C ３ Perfluoroalkyl, -OR １１ , —O—(C １ -C ６ alkyl)-OR １１ , -(C １ -C ６ alkyl)-OR １１ , -NR １１ R １２ , —O—(C １ -C ６ alkyl)-NR １１ R １２ , -(C １ -C ６ alkyl)-NR １１ R １２ , -NR １１ -(C １ -C ６ alkyl)-NR １１ R １２ , -NR １１ -(C １ -C ６ alkyl)-OR １１ , -(C １ -C ６ alkyl) ｘ -C(=O)R １１ , —O—(C １ -C ６ alkyl) ｘ -C(=O)R １１ , -(C １ -C ６ alkyl) ｘ -C(=O)OR １１ , —C(═O)—R １１ , -C(=O)OR １１ , -(C １ -C ６ alkyl) ｘ -C(=O)NR １１ R １２ , -NR １１ -(C １ -C ６ alkyl) ｘ -C(=O)R １１ , and -NR １１ -(C １ -C ６ alkyl) ｘ -C(=O)OR １１ is selected from the group consisting of R ４ is H, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ７ Cycloalkyl, halo, -CN, C １ -C ３ Perfluoroalkyl, -OR １１ , —O—(C １ -C ６ alkyl)-OR １１ , -(C １ -C ６ alkyl)-OR １１ , -NR １１ R １２ , —O—(C １ -C ６ alkyl)-NR １１ R １２ , -(C １ -C ６ alkyl)-NR １１ R １２ , -NR １１ -(C １ -C ６ alkyl)-NR １１ R １２ , -NR １１ -(C １ -C ６ alkyl)-OR １１ , -(C １ -C ６ alkyl) ｘ -C(=O)R １１ , —O—(C １ -C ６ alkyl) ｘ -C(=O)R １１ , -(C １ -C ６ alkyl) ｘ -C(=O)OR １１ , —C(═O)—R １１ , -C(=O)OR １１ , -(C １ -C ６ alkyl) ｘ -C(=O)NR １１ R １２ , -NR １１ -(C １ -C ６ alkyl) ｘ -C(=O)R １１ , and -NR １１ -(C １ -C ６ alkyl) ｘ -C(=O)OR １１ is selected from the group consisting of Alternatively, R ３ and R ４ together form a 5- or 6-membered saturated or unsaturated fused ring, which may contain 0-2 ring heteroatoms selected from the group consisting of N, O, and S, and is unsubstituted or １ -C ６ Alkyl, halo, -CN, -OH, oxo, -O-(C １ -C ６ alkyl), —O—(C １ -C ６ alkyl)-OH, -O-(C １ -C ６ alkyl)-O-(C １ -C ６ alkyl), -NR １１ R １２ , —O—(C １ -C ６ alkyl)-NR １１ R １２ , C １ -C ３ Perfluoroalkyl, —NR １１ -(C １ -C ６ alkyl)NR １１ R １２ , and -NR １１ -(C １ -C ６ alkyl)-OR １１ and is substituted with 1 to 3 substituents selected from the group consisting of: Each R ５ are independently H, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ７ Cycloalkyl, halo, -CN, C １ -C ３ Perfluoroalkyl, oxo, -OR １１ , —O—(C １ -C ６ alkyl)-OR １１ , -(C １ -C ６ alkyl)-OR １１ , -NR １１ R １２ , —O—(C １ -C ６ alkyl)-NR １１ R １２ , -(C １ -C ６ alkyl)-NR １１ R １２ , -NR １１ -(C １ -C ６ alkyl)-NR １１ R １２ , -NR １１ -(C １ -C ６ alkyl)-OR １１ , -(C １ -C ６ alkyl) ｘ -C(=O)R １１ , —O—(C １ -C ６ alkyl) ｘ -C(=O)R １１ , -(C １ -C ６ alkyl) ｘ -C(=O)OR １１ , —C(═O)—R １１ , -C(=O)OR １１ , -(C １ -C ６ alkyl) ｘ -C(=O)NR １１ R １２ , -NR １１ -(C １ -C ６ alkyl) ｘ -C(=O)R １１ , and -NR １１ -(C １ -C ６ alkyl) ｘ -C(=O)OR １１ is selected from the group consisting of n is 0 to 3; X ６ is NR １０ , O and S; X ７ is selected from the group consisting of CH and N; R ８ and R ９ are each independently H, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ７ cycloalkyl, 3- to 10-membered heterocyclyl, C ６ -C １０ Aryl, 5- to 14-membered heteroaryl, C ６－１２ Aralkyl, -(C １ -C ６ alkyl)-OR １１ , -(C １ -C ６ alkyl)-NR １１ R １２ , -(C １ -C ６ alkyl) ｘ -C(=O)R １１ , -(C １ -C ６ alkyl) ｘ -C(=O)OR １１ , and -(C １ -C ６ alkyl) ｘ -C(=O)NR １１ R １２ and each alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl is optionally selected from the group consisting of: １ -C ３ Alkyl, C １ -C ３ Perfluoroalkyl, oxo, halo, —CN, —OH, and NH ２ and optionally substituted with 1 to 3 substituents selected from Alternatively, R ８ and R ９ taken together with the nitrogen to which they are attached provide (i) a 4-6 membered heterocycle having 0-2 additional ring heteroatoms selected from N, O and S, or (ii) a 5-10 membered heterobicyclic ring system having 0-3 additional ring heteroatoms selected from N, O and S, wherein said heterocycle or said bicyclic ring system is unsubstituted or is selected from halo, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ７ Cycloalkyl, -CN, C １ -C ６ Fluoroalkyl, C １ -C ３ Perfluoroalkyl, -OR １１ , oxo, —O—(C １ -C ６ alkyl)-OR １１ , -(C １ -C ６ alkyl)-OR １１ , -NR １１ R １２ , —O—(C １ -C ６ alkyl)-NR １１ R １２ , -(C １ -C ６ alkyl)-NR １１ R １２ , -NR １１ -(C １ -C ６ alkyl)-NR １１ R １２ , -NR １１ -(C １ -C ６ alkyl)-OR １１ , -(C １ -C ６ alkyl) ｘ -C(=O)R １１ , —O—(C １ -C ６ alkyl) ｘ -C(=O)R １１ , -(C １ -C ６ alkyl) ｘ -C(=O)OR １１ , —C(═O)—R １１ , -C(=O)OR １１ , -(C １ -C ６ alkyl) ｘ -C(=O)NR １１ R １２ , -NR １１ -(C １ -C ６ alkyl) ｘ -C(=O)R １１ , and -NR １１ -(C １ -C ６ alkyl) ｘ -C(=O)OR １１ and is substituted with 1 to 4 substituents selected from the group consisting of: R １０ is H, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ７ Cycloalkyl, C ５ -C １０ Aryl, C ５ -C １０ Heteroaryl, 3- to 10-membered heterocyclyl, —C １ -C ６ Alkyl-(C ３ -C ７ cycloalkyl), -C １ -C ６ Alkyl-(C ５ -C １０ aryl), -C １ -C ６ Alkyl-(C ５ -C １０ heteroaryl), -C １ -C ６ alkyl-(3- to 10-membered heterocyclyl), -(C １ -C ６ alkyl)-NR １１ R １２ , -(C １ -C ６ alkyl)NR １１ R １２ , -(C １ -C ６ alkyl)-OR １１ and —C(═O)—N(R １１ ) (R １２ and each alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl is optionally selected from the group consisting of C １ -C ３ Alkyl, C １ -C ３ Perfluoroalkyl, oxo, halo, —CN, —OH, and NH ２ and optionally substituted with 1 to 3 substituents selected from each x is independently selected from 0 and 1; and Each R １１ and R １２ are independently H and C １ -C ６ alkyl; Or alternatively, R １１ and R １２ when both are attached to the same nitrogen, combine to form a 4-7 membered heterocycle having 0-2 additional ring heteroatoms selected from the group consisting of N, O and S, the heterocycle being unsubstituted or selected from halo, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ７ Cycloalkyl, —CN, —NH ２ , C １ -C ３ Perfluoroalkyl, —OH, —O—(C １ -C ６ alkyl), and -(C １ -C ６ and substituted with 1 to 3 substituents selected from the group consisting of (alkyl)-OH.

4. Formula IV: 【Chemistry 4】 2. The compound of claim 1, wherein: R ３ is H, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ７ Cycloalkyl, halo, -CN, C １ -C ３ Perfluoroalkyl, -OR １１ , —O—(C １ -C ６ alkyl)-OR １１ , -(C １ -C ６ alkyl)-OR １１ , -NR １１ R １２ , —O—(C １ -C ６ alkyl)-NR １１ R １２ , -(C １ -C ６ alkyl)-NR １１ R １２ , -NR １１ -(C １ -C ６ alkyl)-NR １１ R １２ , -NR １１ -(C １ -C ６ alkyl)-OR １１ , -(C １ -C ６ alkyl) ｘ -C(=O)R １１ , —O—(C １ -C ６ alkyl) ｘ -C(=O)R １１ , -(C １ -C ６ alkyl) ｘ -C(=O)OR １１ , —C(═O)—R １１ , -C(=O)OR １１ , -(C １ -C ６ alkyl) ｘ -C(=O)NR １１ R １２ , -NR １１ -(C １ -C ６ alkyl) ｘ -C(=O)R １１ , and -NR １１ -(C １ -C ６ alkyl) ｘ -C(=O)OR １１ is selected from the group consisting of R ４ is H, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ７ Cycloalkyl, halo, -CN, C １ -C ３ Perfluoroalkyl, -OR １１ , —O—(C １ -C ６ alkyl)-OR １１ , -(C １ -C ６ alkyl)-OR １１ , -NR １１ R １２ , —O—(C １ -C ６ alkyl)-NR １１ R １２ , -(C １ -C ６ alkyl)-NR １１ R １２ , -NR １１ -(C １ -C ６ alkyl)-NR １１ R １２ , -NR １１ -(C １ -C ６ alkyl)-OR １１ , -(C １ -C ６ alkyl) ｘ -C(=O)R １１ , —O—(C １ -C ６ alkyl) ｘ -C(=O)R １１ , -(C １ -C ６ alkyl) ｘ -C(=O)OR １１ , —C(═O)—R １１ , -C(=O)OR １１ , -(C １ -C ６ alkyl) ｘ -C(=O)NR １１ R １２ , -NR １１ -(C １ -C ６ alkyl) ｘ -C(=O)R １１ , and -NR １１ -(C １ -C ６ alkyl) ｘ -C(=O)OR １１ is selected from the group consisting of Alternatively, R ３ and R ４ together form a 5- or 6-membered saturated or unsaturated fused ring, which may contain 0-2 ring heteroatoms selected from the group consisting of N, O, and S, and is unsubstituted or １ -C ６ Alkyl, halo, -CN, -OH, oxo, -O-(C １ -C ６ alkyl), —O—(C １ -C ６ alkyl)-OH, -O-(C １ -C ６ alkyl)-O-(C １ -C ６ alkyl), -NR １１ R １２ , —O—(C １ -C ６ alkyl)-NR １１ R １２ , C １ -C ３ Perfluoroalkyl, —NR １１ -(C １ -C ６ alkyl)NR １１ R １２ , and -NR １１ -(C １ -C ６ alkyl)-OR １１ and is substituted with 1 to 3 substituents selected from the group consisting of: X ６ is NR １０ , O and S; X ７ is selected from the group consisting of CH and N; R ８ and R ９ are each independently H, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ７ cycloalkyl, 3- to 10-membered heterocyclyl, C ６ -C １０ Aryl, 5- to 14-membered heteroaryl, C ６－１２ Aralkyl, -(C １ -C ６ alkyl)-OR １１ , -(C １ -C ６ alkyl)-NR １１ R １２ , -(C １ -C ６ alkyl) ｘ -C(=O)R １１ , -(C １ -C ６ alkyl) ｘ -C(=O)OR １１ , and -(C １ -C ６ alkyl) ｘ -C(=O)NR １１ R １２ and each alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl is optionally selected from the group consisting of: １ -C ３ Alkyl, C １ -C ３ Perfluoroalkyl, oxo, halo, —CN, —OH, and NH ２ and optionally substituted with 1 to 3 substituents selected from Alternatively, R ８ and R ９ taken together with the nitrogen to which they are attached provide (i) a 4-6 membered heterocycle having 0-2 additional ring heteroatoms selected from N, O and S, or (ii) a 5-10 membered heterobicyclic ring system having 0-3 additional ring heteroatoms selected from N, O and S, wherein said heterocycle or said bicyclic ring system is unsubstituted or is selected from halo, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ７ Cycloalkyl, -CN, C １ -C ６ Fluoroalkyl, C １ -C ３ Perfluoroalkyl, -OR １１ , oxo, —O—(C １ -C ６ alkyl)-OR １１ , -(C １ -C ６ alkyl)-OR １１ , -NR １１ R １２ , —O—(C １ -C ６ alkyl)-NR １１ R １２ , -(C １ -C ６ alkyl)-NR １１ R １２ , -NR １１ -(C １ -C ６ alkyl)-NR １１ R １２ , -NR １１ -(C １ -C ６ alkyl)-OR １１ , -(C １ -C ６ alkyl) ｘ -C(=O)R １１ , —O—(C １ -C ６ alkyl) ｘ -C(=O)R １１ , -(C １ -C ６ alkyl) ｘ -C(=O)OR １１ , —C(═O)—R １１ , -C(=O)OR １１ , -(C １ -C ６ alkyl) ｘ -C(=O)NR １１ R １２ , -NR １１ -(C １ -C ６ alkyl) ｘ -C(=O)R １１ , and -NR １１ -(C １ -C ６ alkyl) ｘ -C(=O)OR １１ and is substituted with 1 to 4 substituents selected from the group consisting of: R １０ is H, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ７ Cycloalkyl, C ５ -C １０ Aryl, C ５ -C １０ Heteroaryl, 3- to 10-membered heterocyclyl, —C １ -C ６ Alkyl-(C ３ -C ７ cycloalkyl), -C １ -C ６ Alkyl-(C ５ -C １０ aryl), -C １ -C ６ Alkyl-(C ５ -C １０ heteroaryl), -C １ -C ６ alkyl-(3- to 10-membered heterocyclyl), -(C １ -C ６ alkyl)-NR １１ R １２ , -(C １ -C ６ alkyl)NR １１ R １２ , -(C １ -C ６ alkyl)-OR １１ and —C(═O)—N(R １１ ) (R １２ and each alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl is optionally selected from the group consisting of C １ -C ３ Alkyl, C １ -C ３ Perfluoroalkyl, oxo, halo, —CN, —OH, and NH ２ and optionally substituted with 1 to 3 substituents selected from each x is independently selected from 0 and 1; and Each R １１ and R １２ are independently H and C １ -C ６ alkyl; Or alternatively, R １１ and R １２ when both are attached to the same nitrogen, combine to form a 4-7 membered heterocycle having 0-2 additional ring heteroatoms selected from the group consisting of N, O and S, the heterocycle being unsubstituted or selected from halo, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ７ Cycloalkyl, —CN, —NH ２ , C １ -C ３ Perfluoroalkyl, —OH, —O—(C １ -C ６ alkyl), and -(C １ -C ６ and substituted with 1 to 3 substituents selected from the group consisting of (alkyl)-OH.

5. Formula V: 【Transformation 5】 2. The compound of claim 1, wherein: R ３ is H, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ７ Cycloalkyl, halo, -CN, C １ -C ３ Perfluoroalkyl, -OR １１ , —O—(C １ -C ６ alkyl)-OR １１ , -(C １ -C ６ alkyl)-OR １１ , -NR １１ R １２ , —O—(C １ -C ６ alkyl)-NR １１ R １２ , -(C １ -C ６ alkyl)-NR １１ R １２ , -NR １１ -(C １ -C ６ alkyl)-NR １１ R １２ , -NR １１ -(C １ -C ６ alkyl)-OR １１ , -(C １ -C ６ alkyl) ｘ -C(=O)R １１ , —O—(C １ -C ６ alkyl) ｘ -C(=O)R １１ , -(C １ -C ６ alkyl) ｘ -C(=O)OR １１ , —C(═O)—R １１ , -C(=O)OR １１ , -(C １ -C ６ alkyl) ｘ -C(=O)NR １１ R １２ , -NR １１ -(C １ -C ６ alkyl) ｘ -C(=O)R １１ , and -NR １１ -(C １ -C ６ alkyl) ｘ -C(=O)OR １１ is selected from the group consisting of R ４ is H, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ７ Cycloalkyl, halo, -CN, C １ -C ３ Perfluoroalkyl, -OR １１ , —O—(C １ -C ６ alkyl)-OR １１ , -(C １ -C ６ alkyl)-OR １１ , -NR １１ R １２ , —O—(C １ -C ６ alkyl)-NR １１ R １２ , -(C １ -C ６ alkyl)-NR １１ R １２ , -NR １１ -(C １ -C ６ alkyl)-NR １１ R １２ , -NR １１ -(C １ -C ６ alkyl)-OR １１ , -(C １ -C ６ alkyl) ｘ -C(=O)R １１ , —O—(C １ -C ６ alkyl) ｘ -C(=O)R １１ , -(C １ -C ６ alkyl) ｘ -C(=O)OR １１ , —C(═O)—R １１ , -C(=O)OR １１ , -(C １ -C ６ alkyl) ｘ -C(=O)NR １１ R １２ , -NR １１ -(C １ -C ６ alkyl) ｘ -C(=O)R １１ , and -NR １１ -(C １ -C ６ alkyl) ｘ -C(=O)OR １１ is selected from the group consisting of Alternatively, R ３ and R ４ together form a 5- or 6-membered saturated or unsaturated fused ring, which may contain 0-2 ring heteroatoms selected from the group consisting of N, O, and S, and is unsubstituted or １ -C ６ Alkyl, halo, -CN, -OH, oxo, -O-(C １ -C ６ alkyl), —O—(C １ -C ６ alkyl)-OH, -O-(C １ -C ６ alkyl)-O-(C １ -C ６ alkyl), -NR １１ R １２ , —O—(C １ -C ６ alkyl)-NR １１ R １２ , C １ -C ３ Perfluoroalkyl, —NR １１ -(C １ -C ６ alkyl)NR １１ R １２ , and -NR １１ -(C １ -C ６ alkyl)-OR １１ and is substituted with 1 to 3 substituents selected from the group consisting of: R ８ and R ９ are each independently H, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ７ cycloalkyl, 3- to 10-membered heterocyclyl, C ６ -C １０ Aryl, 5- to 14-membered heteroaryl, C ６－１２ Aralkyl, -(C １ -C ６ alkyl)-OR １１ , -(C １ -C ６ alkyl)-NR １１ R １２ , -(C １ -C ６ alkyl) ｘ -C(=O)R １１ , -(C １ -C ６ alkyl) ｘ -C(=O)OR １１ , and -(C １ -C ６ alkyl) ｘ -C(=O)NR １１ R １２ and each alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl is optionally selected from the group consisting of: １ -C ３ Alkyl, C １ -C ３ Perfluoroalkyl, oxo, halo, —CN, —OH, and NH ２ and optionally substituted with 1 to 3 substituents selected from Alternatively, R ８ and R ９ taken together with the nitrogen to which they are attached provide (i) a 4-6 membered heterocycle having 0-2 additional ring heteroatoms selected from N, O and S, or (ii) a 5-10 membered heterobicyclic ring system having 0-3 additional ring heteroatoms selected from N, O and S, wherein said heterocycle or said bicyclic ring system is unsubstituted or is selected from halo, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ７ Cycloalkyl, -CN, C １ -C ６ Fluoroalkyl, C １ -C ３ Perfluoroalkyl, -OR １１ , oxo, —O—(C １ -C ６ alkyl)-OR １１ , -(C １ -C ６ alkyl)-OR １１ , -NR １１ R １２ , —O—(C １ -C ６ alkyl)-NR １１ R １２ , -(C １ -C ６ alkyl)-NR １１ R １２ , -NR １１ -(C １ -C ６ alkyl)-NR １１ R １２ , -NR １１ -(C １ -C ６ alkyl)-OR １１ , -(C １ -C ６ alkyl) ｘ -C(=O)R １１ , —O—(C １ -C ６ alkyl) ｘ -C(=O)R １１ , -(C １ -C ６ alkyl) ｘ -C(=O)OR １１ , —C(═O)—R １１ , -C(=O)OR １１ , -(C １ -C ６ alkyl) ｘ -C(=O)NR １１ R １２ , -NR １１ -(C １ -C ６ alkyl) ｘ -C(=O)R １１ , and -NR １１ -(C １ -C ６ alkyl) ｘ -C(=O)OR １１ and is substituted with 1 to 4 substituents selected from the group consisting of: R １０ is H, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ７ Cycloalkyl, C ５ -C １０ Aryl, C ５ -C １０ Heteroaryl, 3- to 10-membered heterocyclyl, —C １ -C ６ Alkyl-(C ３ -C ７ cycloalkyl), -C １ -C ６ Alkyl-(C ５ -C １０ aryl), -C １ -C ６ Alkyl-(C ５ -C １０ heteroaryl), -C １ -C ６ alkyl-(3- to 10-membered heterocyclyl), -(C １ -C ６ alkyl)-NR １１ R １２ , -(C １ -C ６ alkyl)NR １１ R １２ , -(C １ -C ６ alkyl)-OR １１ and —C(═O)—N(R １１ ) (R １２ and each alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl is optionally selected from the group consisting of C １ -C ３ Alkyl, C １ -C ３ Perfluoroalkyl, oxo, halo, —CN, —OH, and NH ２ and optionally substituted with 1 to 3 substituents selected from each x is independently selected from 0 and 1; and Each R １１ and R １２ are independently H and C １ -C ６ alkyl; Or alternatively, R １１ and R １２ when both are attached to the same nitrogen, combine to form a 4-7 membered heterocycle having 0-2 additional ring heteroatoms selected from the group consisting of N, O and S, the heterocycle being unsubstituted or selected from halo, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ７ Cycloalkyl, —CN, —NH ２ , C １ -C ３ Perfluoroalkyl, —OH, —O—(C １ -C ６ alkyl), and -(C １ -C ６ and substituted with 1 to 3 substituents selected from the group consisting of (alkyl)-OH.

6. R ３ The compound of any one of claims 1 to 5, wherein is selected to be H.

7. R ４ The compound of any one of claims 1 to 6, wherein is selected from H, methyl, ethyl, halo, fluoromethyl, difluoromethyl and trifluoromethyl.

8. R ３ and R ４ The compound according to any one of claims 1 to 7, wherein each of

9. R ８ and R ９ However, independently, H, C １ -C ６ Alkyl, and C ３ -C ７ cycloalkyl, wherein each alkyl and cycloalkyl is optionally selected from C １ -C ３ Alkyl, C １ -C ３ A compound according to any one of claims 1 to 8, optionally substituted with 1 to 3 substituents selected from perfluoroalkyl and halo.

10. R ８ and R ９ One of the two is H and the other is C １ -C ６ Alkyl, and C ３ -C ７ cycloalkyl, wherein each alkyl and cycloalkyl is optionally selected from C １ -C ３ Alkyl, C １ -C ３ A compound according to any one of claims 1 to 9, optionally substituted with 1 to 3 substituents selected from perfluoroalkyl and halo, especially fluoro.

11. R ８ and R ９ together with the nitrogen to which they are attached to form a 4- or 5-membered heterocycle, said heterocycle being unsubstituted or １ -C ６ Alkyl, C １ -C ６ - A compound according to any one of claims 1 to 10, which is substituted with 1 to 4 substituents selected from the group consisting of fluoroalkyl and halo, in particular fluoro.

12. R １０ However, H and C １ -C ６ alkyl, in particular R １０ The compound of any one of claims 1 to 11, wherein may be methyl.

13. R １０ The compound according to any one of claims 1 to 11, wherein is methyl.

14. Formula VI: 【Transformation 6】 2. The compound of claim 1, wherein: Each R １ are independently H, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ７ Cycloalkyl, halo, oxo, -CN, C １ -C ３ Perfluoroalkyl, -OR １１ , and -NR １１ R １２ or selected from the group consisting of Or alternatively, two R １ are taken together to form a 3-6 membered ring, which may optionally contain 0-2 ring heteroatoms selected from O, S and N, and may be unsubstituted or optionally contains halo, C １ -C ３ Alkyl, NH ２ , OH, and O-C １ -C ３ It may be optionally substituted by 1 to 3 substituents selected from alkyl; b is selected from 0, 1, and 2; R ２１ is selected from the group consisting of H, methyl, halo, fluoromethyl, difluoromethyl and trifluoromethyl; R ４１ is selected from the group consisting of H, methyl, ethyl, halo, fluoromethyl, difluoromethyl and trifluoromethyl; R ８１ is H, C １ -C ６ Alkyl, C ３ -C ６ cycloalkyl, wherein each alkyl or cycloalkyl is optionally substituted with 1 to 3 substituents selected from halo, methyl, ethyl, fluoromethyl, difluoromethyl, and trifluoromethyl; R ９１ is H, C １ -C ６ Alkyl, C ３ -C ６ cycloalkyl, wherein each alkyl or cycloalkyl is optionally substituted with 1 to 3 substituents selected from halo, methyl, ethyl, fluoromethyl, difluoromethyl, and trifluoromethyl; Alternatively, R ８１ and R ９１ together with the nitrogen to which they are attached provide a 4-6 membered heterocycle, said heterocycle being unsubstituted or substituted with 1 to 4 substituents selected from the group consisting of halo, methyl, ethyl, fluoromethyl, difluoromethyl, and trifluoromethyl; and R １０１ is selected from the group consisting of H and methyl.

15. Formula VII: 【Transformation 7】 2. The compound of claim 1, wherein: R ２１ is selected from the group consisting of H, methyl, halo, fluoromethyl, difluoromethyl and trifluoromethyl; R ４１ is selected from the group consisting of H, methyl, ethyl, halo, fluoromethyl, difluoromethyl and trifluoromethyl; R ８１ is H, C １ -C ６ Alkyl, C ３ -C ６ cycloalkyl, wherein each alkyl or cycloalkyl is optionally substituted with 1 to 3 substituents selected from halo, methyl, ethyl, fluoromethyl, difluoromethyl, and trifluoromethyl; R ９１ is H, C １ -C ６ Alkyl, C ３ -C ６ cycloalkyl, wherein each alkyl or cycloalkyl is optionally substituted with 1 to 3 substituents selected from halo, methyl, ethyl, fluoromethyl, difluoromethyl, and trifluoromethyl; Alternatively, R ８１ and R ９１ together with the nitrogen to which they are attached provide a 4-6 membered heterocycle, said heterocycle being unsubstituted or substituted with 1 to 4 substituents selected from the group consisting of halo, methyl, ethyl, fluoromethyl, difluoromethyl, and trifluoromethyl; and R １０１ is selected from the group consisting of H and methyl.

16. The following structure: 【Transformation 8】 10. The compound of claim 1, wherein the compound is selected from the group consisting of:

17. formula: 【Chemistry 9】 or a pharmaceutically acceptable salt thereof.

18. A method for treating a disease or disorder mediated by ROCK2, comprising administering to a subject in need thereof an effective amount of a compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof.

19. 19. The method of claim 18, wherein the disease or disorder is selected from the group consisting of a fibrotic disease, an inflammatory disease, an autoimmune disease, a cardiovascular disorder, a central nervous system disorder, a neoplastic disease, a metabolic syndrome, an eye disease, a kidney disease, a lung disease, a muscular dystrophy, a sickle cell disease, and a viral disease.

20. 20. The method of claim 19, wherein the disease or disorder is selected from the group consisting of a fibrotic disease, an inflammatory disease, and an autoimmune disease.

21. 21. The method of claim 20, wherein the autoimmune disease is selected from the group consisting of rheumatoid arthritis, systemic lupus erythematosus (SLE; lupus), psoriasis, psoriatic arthritis, multiple sclerosis, Crohn's disease, ulcerative colitis, atopic dermatitis, eczema, or graft-versus-host disease (GVHD; acute and chronic), idiopathic pulmonary fibrosis, and scleroderma.

22. 20. The method of claim 19, wherein the disease or disorder is selected from the group consisting of a cardiovascular disorder, a central nervous system disorder, a neoplastic disease, or metabolic syndrome.

23. 21. The method of claim 20, wherein the inflammatory disease is selected from the group consisting of cardiovascular inflammation, pulmonary inflammation, renal inflammation, arteriosclerosis, and sepsis.

24. 21. The method of claim 20, wherein the fibrotic disorder is selected from the group consisting of idiopathic pulmonary fibrosis, renal fibrosis, kidney fibrosis, ocular fibrosis, cardiac fibrosis, NASH, scleroderma, systemic sclerosis, and liver cirrhosis.

25. 23. The method of claim 22, wherein the neoplastic disease is selected from the group consisting of ovarian cancer, breast cancer, and pancreatic cancer.

26. 23. The method of claim 22, wherein the cardiovascular disease is selected from the group consisting of hypertension, cardiomyopathy, cardiac remodeling, atherosclerosis, restenosis, cardiac hypertrophy, cerebral ischemia, cerebral vasospasm, and erectile dysfunction.

27. 20. The method of claim 19, wherein the pulmonary disease is selected from the group consisting of idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, and asthma.

28. 23. The method of claim 22, wherein the central nervous system disorder is selected from the group consisting of neuronal degeneration or spinal cord injury, traumatic brain injury, cerebral cavernous angioma, Huntington's disease, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), and multiple sclerosis.

29. 20. The method of claim 19, wherein the kidney disease is selected from the group consisting of polycystic kidney disease, renal fibrosis, and diabetic kidney disease.

30. 20. The method of claim 19, wherein the metabolic disorder is selected from the group consisting of insulin resistance, hyperinsulinemia, type 2 diabetes, obesity, metabolic syndrome, and glucose intolerance.

31. 20. The method of claim 19, wherein the ocular disease is selected from the group consisting of ocular hypertension, age-related macular degeneration (AMD; wet and dry forms), choroidal neovascularization (CNV), choroidal tumor, diabetic macular edema (DME), iris neovascularization, uveitis, glaucoma, primary open-angle glaucoma, acute angle-closure glaucoma, pigmentary glaucoma, congenital glaucoma, normal-tension glaucoma, secondary glaucoma, neovascular glaucoma, geographic atrophy, and retinitis of prematurity (ROP).

32. 19. The method of claim 18, wherein the disease is Duchenne muscular dystrophy.

33. 20. The method of claim 19, wherein the viral infection is a coronavirus infection, such as SARS-CoV-1, SARS-CoV-2, and MERS-CoV.

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