Inhibitors of ROCK2

Abstract

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

Description

[Technical field]

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

[0002] Rho-associated coiled-coil kinase (ROCK) is a serine / threonine kinase from the AGC (PKA, PKG, and PKC) kinase family, which includes 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, whereas ROCK2 is preferentially expressed in certain tissues, including heart, brain, and skeletal muscle. ROCK is a target of the small GTPase Rho and is involved in diverse cellular activities that are accomplished by phosphorylating downstream effector proteins (e.g., MLC, LIMK, ERM, MARCKS, CRMP-2, etc.). Studies have shown that various diseases (e.g., pulmonary fibrosis, cardio- and cerebrovascular diseases, neurological diseases, cancer, etc.) are involved in ROCK-mediated pathways. Therefore, ROCK is considered an important target for the development of novel drugs. Summary of the Invention

[0003] In one aspect, the disclosure provides an inhibitor of ROCK2 having formula I: [ka] [During the ceremony, R 1 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 , -NR11 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; R 2 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 selected from the group consisting of; Or, R 1 and R 2 are unsubstituted, optionally containing 0-2 ring heteroatoms selected from the group consisting of N, O, and S, or 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 forming a 5- or 6-membered saturated or unsaturated fused ring substituted with 1 to 3 substituents selected from the group consisting of: X 4 is N or CH; R 3 and R 4 are each independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, 3- to 10-membered heterocyclyl, C6-C 10Aryl, 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 selected from the group consisting of; Or, R 3 and R 4 are taken together with the nitrogen to which they are attached to form (i) a 4-6 membered heterocyclic ring 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 heterocyclic ring or heterobicyclic ring system is unsubstituted or is selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, 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: The dotted line represents an optional double bond; 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 selected from the group consisting of; n is 0 to 3; X 1 CR 6 and N; X 2 is CHR 6 , N.R. 7 , O and S; X 3 is selected from the group consisting of C, CH, and N; 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; Each R 7 are independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, -(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 selected from the group consisting of; each x is independently selected from 0 and 1; Each R 11 and R 12 is independently selected from the group consisting of H and C1-C6 alkyl; Or, R 11 and R 12 when both are attached to the same nitrogen, they together form a 4-7 membered heterocyclic ring having 0-2 additional ring heteroatoms selected from the group consisting of N, O, and S, and which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, -CN, -NH2, C1-C3 perfluoroalkyl, -OH, -O-(C1-C6 alkyl), and -(C1-C6 alkyl)-OH. or a pharma- ceutically acceptable salt thereof.

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

[0005] In embodiments provided in the present disclosure, the method is 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 renal disease, a pulmonary disease, a muscular dystrophy, a sickle cell disease, and a viral disease. [Brief description of the drawings]

[0006] [Figure 1] The structures and properties of compounds according to the present disclosure are shown. [Diagram 2] AB show that the compounds of Example 1 (2A) and Example 2 (2B) inhibit IL-17 in human CD4+ T cells stimulated under Th17-biased conditions. [Diagram 3] FIG. 1 shows that the compounds of Examples 1 and 2 downregulate STAT3 phosphorylation induced by Th17-biased activation in human CD4+ T cells. [Figure 4] 1 shows that the compounds of Examples 1 and 2 down-regulate pCofilin in human CD4+ T cells. [Diagram 5] FIG. 1 shows that the compounds of Examples 1 and 2 reduce the expression of pro-fibrotic genes in human lung fibroblast MRC-5 cells. [Figure 6] FIG. 1 shows that the compounds of Examples 1 and 2 down-regulate the secretion of type 1 collagen in human lung fibroblast MRC-5 cells. [Figure 7] Figure 2 shows that the compounds of Examples 1 and 2 downregulate adipogenesis in human adipocytes. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0007] The present invention will now be further described. In the following passages, 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 ROCK (preferably ROCK2) inhibitory activity and good selectivity (higher selectivity for ROCK2 than for ROCK1). The compounds may additionally provide one or more of good physicochemical properties (e.g., solubility, physical and / or chemical stability), improved pharmacokinetic properties (e.g., improved bioavailability, suitable half-life and duration of action), and improved safety (low toxicity and / or fewer side effects, broad therapeutic window). In particular, the ROCK2 inhibitors provided herein may exhibit improved solubility and / or improved bioavailability when orally administered.

[0010] In one aspect, the disclosure provides an inhibitor of ROCK2 having formula I: [ka] [During the ceremony, R 1is 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; R 2 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 R12 , -(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; Or, R 1 and R 2 are unsubstituted, optionally containing 0-2 ring heteroatoms selected from the group consisting of N, O, and S, or 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 forming a 5- or 6-membered saturated or unsaturated fused ring substituted with 1 to 3 substituents selected from the group consisting of: X4 is N or CH; R 3 and R 4 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 selected from the group consisting of; Or, R 3 and R 4 are taken together with the nitrogen to which they are attached to form (i) a 4-6 membered heterocyclic ring 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 heterocyclic ring or heterobicyclic ring system is unsubstituted or is selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, 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 , -NR11 -(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: The dotted line represents an optional double bond; 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 selected from the group consisting of; n is 0 to 3; X 1 CR 6 and N; X 2 is CHR 6 , N.R. 7 , O and S; X 3 is selected from the group consisting of C, CH, and N; 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; Each R 7 are independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, -(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 selected from the group consisting of; each x is independently selected from 0 and 1; Each R 11 and R 12 is independently selected from the group consisting of H and C1-C6 alkyl; Or, R 11 and R 12 when both are attached to the same nitrogen, they together form a 4-7 membered heterocyclic ring having 0-2 additional ring heteroatoms selected from the group consisting of N, O, and S, and which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, -CN, -NH2, C1-C3 perfluoroalkyl, -OH, -O-(C1-C6 alkyl), and -(C1-C6 alkyl)-OH. or a pharma- ceutically acceptable salt thereof.

[0011] In some embodiments, the present disclosure provides an inhibitor of ROCK2 having formula II: [ka] [During the ceremony, R 1 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 selected from the group consisting of; R 2is 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; Or, R 1 and R 2 are unsubstituted, optionally containing 0-2 ring heteroatoms selected from the group consisting of N, O, and S, or 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)-NR11 R 12 , C1-C3 perfluoroalkyl, -NR 11 -(C1-C6 alkyl)NR 11 R 12 , and -NR 11 -(C1-C6 alkyl)-OR 11 forming a 5- or 6-membered saturated or unsaturated fused ring substituted with 1 to 3 substituents selected from the group consisting of: R 3 and R 4 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 selected from the group consisting of; Or, R 3 and R 4 are taken together with the nitrogen to which they are attached to form (i) a 4-6 membered heterocyclic ring 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 heterocyclic ring or heterobicyclic ring system is unsubstituted or is selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoroalkyl, -OR 11 , oxo, -O-(C1-C6 alkyl)-OR 11 , -(C1-C6 alkyl)-OR 11 , -NR11 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: The dotted line represents an optional double bond; 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 R12 , -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; n is 0 to 3; X 1 CR 6 and N; X 2 is CHR 6 , N.R. 7 , O and S; X 3 is selected from the group consisting of C, CH, and N; 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 R12 , -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; Each R 7 are independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, -(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 selected from the group consisting of; each x is independently selected from 0 and 1; Each R 11 and R 12 is independently selected from the group consisting of H and C1-C6 alkyl; Or, R 11 and R 12when both are attached to the same nitrogen, they together form a 4-7 membered heterocyclic ring having 0-2 additional ring heteroatoms selected from the group consisting of N, O, and S, and which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, -CN, -NH2, C1-C3 perfluoroalkyl, -OH, -O-(C1-C6 alkyl), and -(C1-C6 alkyl)-OH. or a pharma- ceutically acceptable salt thereof.

[0012] In some embodiments, the disclosure provides an inhibitor of ROCK2 having formula IIa: [ka] [During the ceremony, R 3 and R 4 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 selected from the group consisting of; Or, R 3 and R 4are taken together with the nitrogen to which they are attached to form (i) a 4-6 membered heterocyclic ring 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 heterocyclic ring or heterobicyclic ring system is unsubstituted or is selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, 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 substituted with 1 to 4 substituents selected from the group consisting of: The dotted line represents an optional double bond; X 1 CR 6 and N; X 2 is CHR 6 , N.R. 7 , O and S; X 3 is selected from the group consisting of C, CH, and N; 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; Each R 7are independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, -(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 selected from the group consisting of; each x is independently selected from 0 and 1; Each R 11 and R 12 is independently selected from the group consisting of H and C1-C6 alkyl; Or, R 11 and R 12 when both are attached to the same nitrogen, they together form a 4-7 membered heterocyclic ring having 0-2 additional ring heteroatoms selected from the group consisting of N, O, and S, and which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, -CN, -NH2, C1-C3 perfluoroalkyl, -OH, -O-(C1-C6 alkyl), and -(C1-C6 alkyl)-OH. or a pharma- ceutically acceptable salt thereof.

[0013] In some embodiments, the present disclosure provides an inhibitor of ROCK2 having formula III: [ka] [During the ceremony, R 1 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 selected from the group consisting of; R 2 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)-NR11 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; Or, R 1 and R 2 are unsubstituted, optionally containing 0-2 ring heteroatoms selected from the group consisting of N, O, and S, or 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 forming a 5- or 6-membered saturated or unsaturated fused ring substituted with 1 to 3 substituents selected from the group consisting of: R 3 and R 4are 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 selected from the group consisting of; Or, R 3 and R 4 are taken together with the nitrogen to which they are attached to form (i) a 4-6 membered heterocyclic ring 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 heterocyclic ring or heterobicyclic ring system is unsubstituted or is selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, 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: The dotted line represents an optional double bond; 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 selected from the group consisting of; n is 0 to 3; X 1 CR 6 and N; X 2 is CHR 6 , N.R. 7 , O and S; X 3 is selected from the group consisting of C, CH, and N; 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; Each R 7 are independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, -(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 selected from the group consisting of; each x is independently selected from 0 and 1; Each R 11 and R 12 is independently selected from the group consisting of H and C1-C6 alkyl; Or, R 11 and R 12 when both are attached to the same nitrogen, they together form a 4-7 membered heterocyclic ring having 0-2 additional ring heteroatoms selected from the group consisting of N, O, and S, and which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, -CN, -NH2, C1-C3 perfluoroalkyl, -OH, -O-(C1-C6 alkyl), and -(C1-C6 alkyl)-OH. or a pharma- ceutically acceptable salt thereof.

[0014] In some embodiments, the present disclosure provides an inhibitor of ROCK2 having formula IIIa: [ka] [During the ceremony, R 3 and R 4 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 selected from the group consisting of; Or, R 3 and R 4 are taken together with the nitrogen to which they are attached to form (i) a 4-6 membered heterocyclic ring 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 heterocyclic ring or heterobicyclic ring system is unsubstituted or is selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, 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)-NR11 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: The dotted line represents an optional double bond; X 1 CR 6 and N; X 2 is CHR 6 , N.R. 7 , O and S; X 3 is selected from the group consisting of C, CH, and N; 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; Each R 7 are independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, -(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 selected from the group consisting of; each x is independently selected from 0 and 1; Each R 11 and R 12 is independently selected from the group consisting of H and C1-C6 alkyl; Or, R 11 and R12 when both are attached to the same nitrogen, they together form a 4-7 membered heterocyclic ring having 0-2 additional ring heteroatoms selected from the group consisting of N, O, and S, and which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, -CN, -NH2, C1-C3 perfluoroalkyl, -OH, -O-(C1-C6 alkyl), and -(C1-C6 alkyl)-OH. or a pharma- ceutically acceptable salt thereof.

[0015] In each of the formulas for inhibitors of ROCK2 provided herein, the substructure: [ka] The dashed circle in represents one or more optional double bonds. Thus, the substructure may be unsaturated, have one 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 of skill in the art, the double bonds in such ring systems are not directly adjacent (i.e., they do not share a carbon atom). In embodiments, the substructure may include: [ka] In other embodiments, the moiety includes: [ka] Includes:

[0016] The term "heteroatom" as used herein means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen and sulfur.

[0017] The term "halogen" or "halo" refers to -F, -Cl, -Br, or -I. Preferred halogens are -F, -Cl, and -Br.

[0018] The term "hydroxyl" means --OH.

[0019] 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).

[0020] 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, and the like.

[0021] The term "cycloalkyl" refers to a saturated carbocyclic group having from 3 to 7 carbons in the ring. Cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0022] The term "alkenyl" refers to a straight 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.

[0023] The term "alkynyl" refers to a straight or branched chain hydrocarbyl having a triple bond and 2 to 6 carbon atoms ("C2-C6 alkynyl"). Alkynyl includes ethynyl, propynyl, and the like.

[0024] The term "aryl" as used herein includes 5- and 6-membered monocyclic aromatic groups that may contain 0-4 heteroatoms, such as benzene, pyrene, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine. Aryl groups having heteroatoms in 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 may 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.

[0025] 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.

[0026] The term "aralkyl," as used herein, refers to a C1-C6 alkyl group substituted with an aryl group (e.g., an aromatic or heteroaromatic group).

[0027] As used herein, the definition of each designation, e.g., alkyl, m, n, R, etc., when it occurs more than one time in any structure, is intended to be independent of its definition elsewhere in that structure.

[0028] It will be understood that "substituted," "substitution," 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.

[0029] Certain compounds provided in the present disclosure may exist in specific 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 a substituent, such as an alkyl group. All such isomers and mixtures thereof are included in the present invention.

[0030] 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.

[0031] As shown 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-situ during administration vehicle or dosage form manufacturing process, or can be prepared separately by reacting purified free base form of the compound of the present invention with 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, napthylate, mesylate, glucoheptonate, lactobionate, and laurylsulfonate. (See, e.g., Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci. 66:1-19).

[0032] 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.

[0033] In other cases, the compounds provided in the present disclosure may contain one or more acidic functional groups, and therefore can form pharma- ceutically acceptable salts with pharma-ceutically acceptable bases. These salts can also be prepared in situ during the administration vehicle or dosage form manufacturing process, or can be prepared separately by reacting the purified free acid form of the compound with a suitable base, such as a hydroxide, carbonate or bicarbonate of a pharma-ceutically acceptable metal cation, ammonia, or a pharma-ceutically 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).

[0034] The ROCK2 inhibitors provided herein may exhibit improved solubility and / or improved bioavailability when administered orally. For example, the compounds of Example 1 and Example 2 exhibit kinetic solubility of 2.2 μg / ml and 2.69 μg / ml, respectively, which is significantly improved compared to Comparative Compound A, which has a kinetic solubility of less than 1.9 μg / ml.

[0035] Treatment method The present disclosure provides a method for preventing or treating a disease mediated by ROCK2, comprising administering to a subject in need thereof an effective amount of a ROCK2 inhibitor disclosed herein, or a pharma- ceutically acceptable salt thereof.

[0036] In some embodiments, the present disclosure provides a method of treatment of 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.

[0037] In other embodiments, the present disclosure provides a method of treating 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.

[0038] In some embodiments, the ROCK2-mediated disease is an autoimmune disease, including 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.

[0039] 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, and autoimmune psoriasis. Eruptions, axonal and neuronal neuropathies, 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, 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, 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, ligneous conjunctivitis, linear IgA disease (LAD), Meniere's disease , microscopic polyangiitis, mixed connective tissue disease (MCTD), Mooren's ulcer, Mukka-Habermann disease, myasthenia gravis, myositis, neuromyelitis optica, neutropenia, ocular cicatricial pemphigoid, optic neuritis, relapsing rheumatism, streptococcal childhood 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, polyglandular autoimmune syndrome (type I,II, III), rheumatic polymyalgia, polymyositis, post-myocardial infarction syndrome, post-pericardiotomy syndrome, progesterone 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, Sjogren's syndrome, spermatozoa These include testicular 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 osteomyelitis, undifferentiated connective tissue disease (UCTD), autoimmune diabetes mellitus type 1, uveitis, vasculitis, bullous dermatoses, vitiligo, and Wegener's granulomatosis (granulomatosis with polyangiitis; GPA).

[0040] 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.

[0041] 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.

[0042] 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.

[0043] 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 lymphomas, carcinomas, leukemias, sarcomas, and blastomas. 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.

[0044] 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.

[0045] 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.

[0046] 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.

[0047] In other embodiments, the present disclosure provides methods of treatment of kidney disease, including polycystic kidney disease, renal fibrosis, and diabetic kidney disease.

[0048] 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 cause weight loss and / or limit weight gain. In one embodiment, ROCK2 inhibitors are used to reduce or prevent insulin resistance or restore insulin sensitivity.

[0049] 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).

[0050] In another embodiment, the disclosure provides a method of treating sickle cell disease.

[0051] In other embodiments, ROCK2 inhibitors provided herein may be used to treat (i.e., cure or reduce the severity of) 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.

[0052] Pharmaceutical Compositions In one aspect, the present disclosure provides a pharma- ceutically 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 pharma- ceutically 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., 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, ointment, 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) ophthalmic administration; (7) transdermal administration; or (8) nasal administration.

[0053] The phrase "pharmacologically 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.

[0054] As used herein, the phrase "pharmacologically acceptable carrier" refers to a pharma- ceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, manufacturing aid (e.g., lubricants, talc, magnesium, calcium, or zinc stearate, or steric acid), solvent, or solvent encapsulating material, 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 which may serve as pharma- ceutically 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, ethylcellulose, 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 protease, glyceryl stearate, 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 buffer solutions; (21) polyesters, polycarbonates, and / or polyanhydrides; and (22) other non-toxic, compatible substances used in pharmaceutical formulations.

[0055] The compounds of the present disclosure can be formulated using conventional carriers and excipients, which may be selected in accordance with normal practice. Tablets may contain excipients, lubricants, fillers, binders, and the like. Aqueous formulations may be prepared in sterile form and generally be isotonic if intended for delivery other than oral administration. All formulations may optionally contain excipients, such as those shown 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, and the like.

[0056] While it is possible for the ROCK2 inhibitors disclosed herein (herein referred to 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, contain, in addition to at least one active ingredient as provided above, one or more acceptable carriers therefor, and optionally other therapeutic ingredients, particularly further therapeutic ingredients as described herein.

[0057] The formulations include those suitable for the administration route provided herein. The formulations may conveniently be provided 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 combining the active ingredient with the carrier corresponding to 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.

[0058] Formulations of the present disclosure suitable for oral administration may be presented as separate units, such as capsules, cachets or tablets, each containing a predetermined amount of the active ingredient; 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.

[0059] 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 powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active agent or dispersing agent. Molded tablets can be made by molding in a suitable machine a mixture of powdered active ingredient moistened with an inert liquid diluent. Tablets can be optionally coated or stamped, and are optionally formulated to provide a slow or controlled release of the active ingredient therefrom.

[0060] For infections of the eye or other external tissues, such as the mouth and skin, the formulation is preferably applied as a topical solution, ointment or cream 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 the range of 0.1% w / w to 20% in increments of 0.1% w / w, such as 0.6% w / w, 0.7% w / w, etc.), preferably 0.2-15% w / w, most preferably 0.5-10% w / w. When formulated into an ointment, the active ingredient may be used with an ointment base that is either paraffinic or water-miscible. Alternatively, the active ingredient may be formulated into a cream with an oil-in-water cream base.

[0061] 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 contain a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such skin penetration enhancers include dimethylsulfoxide and related analogues.

[0062] 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 emulgent), but desirably contains a mixture of at least one emulsifier with a fat or oil, or both fat and oil. It preferably contains a hydrophilic emulsifier together with a lipophilic emulsifier that acts as a stabilizer. It is also preferred to contain both an oil and a fat. Taken together, the emulsifier(s) with or without stabilizer(s) constitute the so-called emulsifying wax, which together with oil and fat constitute the so-called emulsifying ointment base that forms the oily dispersed phase of cream formulations.

[0063] 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 monostearate, and sodium lauryl sulfate. Additional emulsifiers and emulsion stabilizers suitable for use in the formulations of the present disclosure include Tween® 80.

[0064] The choice of oil or fat suitable for formulation is based on providing the desired properties. Creams should preferably be non-oily, non-staining, washable products with suitable viscosity to avoid leakage from tubes or other containers. Linear or branched monobasic or dibasic alkyl esters may be used, 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 mixture of branched esters known as crodamole CAP, the last three being the preferred esters. These may be used alone or in combination, depending on the properties required. Alternatively, high melting point lipids, such as white soft paraffin and / or liquid paraffin, or other mineral oils, may be used.

[0065] A pharmaceutical formulation according to the present disclosure includes, in addition to the combination according to the present disclosure, one or more pharma- ceutically acceptable carriers or excipients, and optionally other therapeutic agents. The pharmaceutical formulation containing the active ingredient may 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 may be prepared. Compositions intended for oral use may 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 pharma- ceutically 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 gum acacia; and lubricants such as magnesium stearate, stearic acid or talc. The 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 of time. For example, a time-delay material such as glyceryl monostearate or glyceryl distearate may be used alone or with a wax.

[0066] 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.

[0067] The aqueous suspension of the present disclosure contains the active material in admixture 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, and 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), condensation products of ethylene oxide with fatty acids and partial esters derived from hexitol anhydrides (e.g., polyoxyethylene sorbitan monooleate). The aqueous suspension may also contain one or more preservatives, such as ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin. Further non-limiting examples of suspending agents include cyclodextrin and Captisol (=sulfobutyl ether beta-cyclodextrin; SEB-beta-CD).

[0068] Oil suspensions can be formulated 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. In order to provide a palatable oral preparation, sweeteners, such as those listed above, and flavoring agents can be added. These compositions can be preserved by the addition of an antioxidant, such as ascorbic acid.

[0069] Dispersible powders and granules of the present disclosure suitable for preparing aqueous suspension by adding water provide active ingredient in admixture with dispersing or wetting agent, suspending agent, and one or more preservatives.Suitable dispersing or wetting agent and suspending agent are exemplified by those disclosed above.Additional excipients, such as sweeteners, flavoring agents and coloring agents, can also be present.

[0070] The pharmaceutical composition of the present disclosure may also be in the form of an oil-in-water emulsion. 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 emulsifying agents include naturally occurring gums, such as gum acacia and / or gum tragacanth, naturally occurring phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and the condensation products of these partial esters with ethylene oxide, such as polyoxyethylenesorbitan monooleate. The emulsion 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 a demulcent, a preservative, a flavoring agent or a coloring agent.

[0071] The pharmaceutical compositions of the present disclosure may be in the form of a sterile injectable preparation, for example, a sterile injectable suspension, aqueous or oleaginous. This suspension may be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents mentioned above. The sterile injectable preparation may also be a sterile injectable solution made with a non-toxic parenterally acceptable diluent or solvent, for example, a solution made with 1,3-butanediol, or may be prepared as a lyophilized powder. Acceptable vehicles and solvents that may be used include, among others, water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils may be conventionally used as a solvent or suspending medium. For this purpose, any bland, odorless fixed oil may be used, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid may be used in the preparation of injectables as well. Acceptable vehicles and solvents that may be used include, among others, water, Ringer's solution, isotonic sodium chloride solution, and hypertonic sodium chloride solution.

[0072] The amount of active ingredient that can be combined with carrier materials to produce a single dosage form can vary depending on the host being treated and the particular mode of administration. For example, a sustained release formulation intended for oral administration to humans can contain approximately 1-1000 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 3-500 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.

[0073] Formulations suitable for topical administration to the eye also include eye drops in which 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.

[0074] Formulations suitable for topical administration in the mouth include lozenges which contain the active ingredient in a flavored base, usually sucrose and acacia or tragacanth; pastilles which contain the active ingredient in an inert base, for example, gelatin and glycerin, or sucrose and acacia, and mouthwashes which contain the active ingredient in a suitable liquid carrier.

[0075] Formulations for rectal administration may be presented as a suppository with a suitable base comprising, for example, cocoa butter or a salicylate.

[0076] Formulations suitable for pulmonary or nasal administration have particle sizes ranging from 0.1 to 500 microns, e.g., 0.5, 1, 30, 35 microns, which are administered by rapid inhalation through the nasal passages, or 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.

[0077] 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.

[0078] 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.

[0079] The formulations may be presented in unit-dose or multi-dose containers, for example, sealed ampoules and vials, and stored in a lyophilized condition (freeze-dried) requiring only the addition of a sterile liquid carrier, for example, water for injection. 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 hereinbefore recited, or an appropriate fraction thereof, of the active ingredient.

[0080] The present disclosure further provides a veterinary composition comprising at least one active ingredient, as defined above, together with a veterinary carrier therefor.

[0081] A veterinary carrier is a material useful for the purpose of administering the composition, which 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.

[0082] 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 less frequent administration or to improve the pharmacokinetic or toxicity profile of a given active ingredient.

[0083] The patient undergoing this treatment may be 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. EXAMPLES

[0084] Example 1 Method A. Illustrated by the synthesis of 2-[2-(3,3-difluoroazetidine-1-carbonyl)-1-methyl-1H-indol-6-yl]-N-[4-(1H-imidazol-5-yl)phenyl]pyrimidin-4-amine. [ka]

[0085] Step 1: Synthesis of Intermediate 1: 6-Bromo-2-(3,3-difluoroazetidine-1-carbonyl)-1H-indole

[0086] 6-Bromoindole-2-carboxylic acid (5.26 g, 21.91 mmol, 1.00 equiv) was dissolved in anhydrous DCM (25.0 mL) and then oxalyl chloride (2.04 ml, 24.10 mmol, 1.10 equiv) was added dropwise to the reaction mixture at 0° C., followed by a few drops of DMF. The mixture was stirred at 0° C. for 1 h, then the cold bath was removed and stirring was continued at room temperature for 3 h. TLC analysis showed complete conversion of starting material and UPLC-MS analysis showed mass consistency with the appropriate ester (sample was quenched with MeOH). The reaction mixture was evaporated to dryness and coevaporated twice with ACN. The resulting cream powder was then redissolved in THF (25.0 mL) and transferred dropwise via syringe into 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 stirred overnight at room temperature. A solution of NaHCO3 was then added and the mixture of DCM and THF was removed in vacuo. The precipitate was collected by vacuum 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 (400MHz, DMSO-d6) δ11.93-11.86(m,1H),7.65-7.59(m,2H),7.21(dd,J=8.6,1.8Hz,1H),6.95(dd,J=2.2,0.9Hz,1H),4.77(m,J=170.3Hz,4H). UPLC-MS,m / z:[M+H]=314.8

[0087] Step 2: Synthesis of 6-bromo-2-(3,3-difluoroazetidine-1-carbonyl)-1-methyl-1H-indole.

[0088] 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 was 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 (400MHz, DMSO-d6) δ7.87-7.84(m,1H),7.59(d,J=8.5Hz,1H),7.25(dd,J=8.5,1.7Hz,1H),7.04(d,J=0.8Hz,1H),5.04-4.38(m,4H),3.93(s,3H). UPLC-MS,m / z:[M+H] + =330.75

[0089] 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).

[0090] 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 90° C. oil bath 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(400MHz,DMSO-d6)δ7.83(d,J=0.9Hz,1H),7.63(dd,J=8.0,0.8Hz,1H),7.42(dd,J=8. 0,0.9Hz,1H),7.03(d,J=0.9Hz,1H),4.70(d,J=105.5Hz,5H),3.98(s,3H),1.33(s,11H). UPLC-MS,m / z:[M+H] + =377.15.

[0091] Step 4: Synthesis of Intermediate 2: 2-chloro-N-[4-(1H-imidazol-5-yl)phenyl]pyrimidin-4-amine

[0092] To a solution of 4-(1H-imidazol-5-yl)aniline (0.89 g, 5.60 mmol, 1.00 equiv.) in ethanol (9.0 mL) was added N,N-diisopropylethylamine (DIPEA) (1.46 mL, 8.38 mmol, 1.50 equiv.) and the reaction mixture was stirred at room temperature for 15 min. Then 2,4-dichloropyrimidine (0.83 g, 5.6 mmol, 1.00 equiv.) was added and the reaction mixture was allowed to stir for 24 h. It was filtered. The resulting solid cake was redissolved in boiling ethanol, filtered again, and dried under high vacuum to give 2-chloro-N-[4-(1H-imidazol-5-yl)phenyl]pyrimidin-4-amine (0.89 g, 56% yield). 1 H NMR(300MHz,DMSO-d6)δ12.90(s,1H),10.15(s,1H),8.14(d,J=5.9Hz,1H),8.03(s,2H),7.60(d,J=2.4Hz,4H),6.78(d,J=5.9Hz,1H). UPLC-MS,m / z:[M+H] + =271.95.

[0093] Step 5: 2-[2-(3,3-difluoroazetidine-1-carbonyl)-1-methyl-1H-indol-6-yl]-N-[4-(1H-imidazol-5-yl)phenyl]pyrimidin-4-amine.

[0094] A mixture of intermediate 1 (0.20 g, 0.49 mmol, 1.40 equiv.), intermediate 2 (0.10 g, 0.35 mmol, 1.00 equiv.), and sodium carbonate (0.07 g, 0.70 mmol, 2.00 equiv.) was dissolved in a mixture of dimethoxyethane (6.0 mL) and water (2.0 mL) and degassed with argon for 15 min. Tetrakis(triphenylphosphine)palladium (0.024 g, 0.021 mmol, 0.06 equiv.) was then added and the reaction mixture was stirred at 110° C. in a microwave reactor. The progress of the reaction was monitored using UPLC-MS analysis and complete conversion of the starting material was obtained after 4 h of stirring. After cooling, the mixture was diluted with EtOAc and filtered through a Celit pad. The filtrate was concentrated in vacuo and purified by HPLC (mobile phase: HO+0.1% FA, ACN+0.1% FA column C18 prep) to give the compound 2-[2-(3,3-difluoroazetidine-1-carbonyl)-1-methyl-1H-indol-6-yl]-N-[4-(1H-imidazol-5-yl)phenyl]pyrimidin-4-amine formate (0.060 g, 35%) as a yellow foam. 1 H NMR(400MHz,DMSO-d6)δ9.69(s,1H),8.56(s,1H),8.41(d,J=5.8Hz,1H),8.28(d,J=7.2Hz,2H),8.21(dd,J=8.5,1.4Hz,1H),7.81(s,4H ),7.75(d,J=8.5Hz,1H),7.71(d,J=1.1Hz,1H),7.55(s,1H),7.08(s,1H),6.73(d,J=5.8Hz,1H),4.73(d,J=111.7Hz,4H),4.05(s,3H). LCMS,m / z:[M+H] + =486.41.

[0095] Example 2 Method B - exemplified by 2-[2-(3,3-difluoroazetidine-1-carbonyl)-1-methyl-1H-indol-6-yl]-N-[4-(1H-1,2,3-triazol-4-yl)phenyl]pyrimidin-4-amine. [ka]

[0096] Step 1': Synthesis of Intermediate 2': 1-(azidomethyl)-4-methoxybenzene

[0097] A mixture of 4-methoxybenzyl chloride (2.00 g, 12.77 mmol, 1.00 equiv) and sodium azide (0.99 g, 15.32 mmol, 1.20 equiv) in anhydrous dimethylsulfoxide (20.0 mL) was stirred at room temperature overnight. The reaction progress was monitored by TLC analysis (eluent: 9:1 DCM:MeOH). The mixture was partitioned between water and EtOAc. The aqueous phase was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and evaporated to dryness to give 1-(azidomethyl)-4-methoxybenzene (1.98 g, 94%) as a yellowish liquid.

[0098] Step 2': Synthesis of 4-{1-[(4-methoxyphenyl)methyl]-1H-1,2,3-triazol-4-yl}aniline

[0099] To a mixture of 1-(azidomethyl)-4-methoxybenzene (1.98 g, 12.013 mmol, 1.0 equiv.) and 4-ethynylaniline (1.40 g, 12.00 mmol, 1.00 equiv.) in anhydrous dimethylsulfoxide (29.70 mL), copper(II) sulfate pentahydrate (0.60 g, 2.40 mmol, 0.20 equiv.) was added, followed by sodium ascorbate (0.92 g, 4.80 mmol, 0.40 equiv.), and the resulting mixture was stirred at room temperature for 2 h. UPLC-MS analysis showed complete conversion of the starting material. The mixture was poured into cold water. The precipitated solid was filtered, washed with water, and dried to give 4-{1-[(4-methoxyphenyl)methyl]-1H-1,2,3-triazol-4-yl}aniline (2.5 g, 73%) as a yellow solid. 1H NMR(300MHz,DMSO-d6)δ8.26(s,1H),7.48(d,J=8.0Hz,2H),7.37-7.23(m,2H),7 .00-6.87(m,2H),6.58(d,J=8.0Hz,2H),5.49(s,2H),5.19(s,2H),3.74(s,3H). UPLC-MS,m / z:[M+H] + =281.10.

[0100] Step 3': Synthesis of 2-chloro-N-(4-{1-[(4-methoxyphenyl)methyl]-1H-1,2,3-triazol-4-yl}phenyl)pyrimidin-4-amine

[0101] To a solution of 4-{2-[(4-methoxyphenyl)methyl]-2H-1,2,3-triazol-4-yl}aniline (2.50 g, 8.83 mmol, 1.00 equiv.) in ethanol (15.0 mL), N,N-diisopropyl-ethylamine (DIPEA) (1.999 mL, 11.48 mmol, 1.30 equiv.) was added and the reaction mixture was stirred at room temperature for 15 min. Then, 2,4-dichloropyrimidine (1.31 g, 8.83 mmol, 1.00 equiv.) was added and the reaction mixture was left to stir at 90° C. overnight. It was evaporated to dryness. The crude was purified by FCC (0-5% MeOH in DCM) to give 2-chloro-N-(4-{1-[(4-methoxyphenyl)methyl]-1H-1,2,3-triazol-4-yl}phenyl)pyrimidin-4-amine (1.43 g, 40%) as a yellow solid. 1 H NMR(300MHz,DMSO-d6)δ10.13(s,1H),8.52(s,1H),8.18(d,J=5.9Hz,1H),7.83(d,J=8.6Hz,2H),7.66(d, J=8.3Hz,2H),7.34(d,J=8.4Hz,2H),7.01-6.91(m,2H),6.79(d,J=5.9Hz,1H),5.56(s,2H),3.74(s,3H). UPLC-MS,m / z:[M+H] - =392.10.

[0102] Step 4': 2-[2-(3,3-difluoroazetidine-1-carbonyl)-1-methyl-1H-indol-6-yl]-N-(4-{1-[(4-methoxyphenyl)methyl]-1H-1,2,3-triazol-4-yl}phenyl)pyrimidin-4-amine.

[0103] A mixture of intermediate 1 (0.35 g, 0.42 mmol, 1.10 equiv.), intermediate 2' (0.25 g, 0.38 mmol, 1.00 equiv.), and sodium carbonate (0.12 g, 1.14 mmol, 3.00 equiv.) was dissolved in a mixture of dimethoxyethane (6.0 mL) and water (2.0 mL) and degassed with argon for 10 min. Tetrakis(triphenylphosphine)palladium (0.04 g, 0.04 mmol, 0.10 equiv.) was then added and the reaction mixture was stirred at 110 °C in a microwave reactor. The progress of the reaction was monitored using UPLC-MS analysis and complete conversion of the starting material was obtained after 4 h of stirring. After cooling, the mixture was diluted with EtOAc and filtered through a Celit pad. The filtrate was concentrated to dryness to give crude compound 2-[2-(3,3-difluoroazetidine-1-carbonyl)-1-methyl-1H-indol-6-yl]-N-(4-{1-[(4-methoxyphenyl)methyl]-1H-1,2,3-triazol-4-yl}phenyl)pyrimidin-4-amine (0.2 g), which was used in the next step without further purification. UPLC-MS, m / z: [M=H] + =607.10. 1 H NMR analysis was not performed.

[0104] Step 5': 2-[2-(3,3-difluoroazetidine-1-carbonyl)-1-methyl-1H-indol-6-yl]-N-[4-(1H-1,2,3-triazol-4-yl)phenyl]pyrimidin-4-amine.

[0105] 2-[2-(3,3-Difluoroazetidine-1-carbonyl)-1-methyl-1H-indol-6-yl]-N-(4-{2-[(4-methoxyphenyl)methyl]-2H-1,2,3-triazol-4-yl}phenyl)pyrimidin-4-amine (0.20 g, 0.20 mmol, 1.00 equiv) was dissolved in trifluoroacetic acid (1.06 mL, 13.85 mmol, 70.00 equiv) and the reaction mixture was stirred overnight at 100° C. No further partial conversion was observed. The reaction mixture was evaporated to dryness and purified using preparative HPLC (mobile phase: ACN+0.1% FA, HO+0.1% FA, column C18 prep) to give 2-[2-(3,3-difluoroazetidine-1-carbonyl)-1-methyl-1H-indol-6-yl]-N-[4-(1H-1,2,3-triazol-4-yl)phenyl]pyrimidin-4-amine (0.025 g, 26%). 1 H NMR(400MHz,DMSO-d6)δ9.89(s,1H),8.57(s,1H),8.44(d,J=5.9Hz,1H),8.32(d,J=16.4Hz,2H),8.21(d,J=8.6Hz ,1H),7.93(q,J=8.6Hz,4H),7.76(d,J=8.6Hz,1H),7.09(s,1H),6.78(d,J=5.8Hz,1H),4.86(s,4H),4.06(s,3H). LCMS,m / z:[M=H] + =487.18.

[0106] Example 3 Method C. Exemplify by the synthesis of 2-[2-(3,3-difluoroazetidine-1-carbonyl)-4H,5H,6H,7H-thieno[2,3-c]pyridin-6-yl]-N-[4-(1H-imidazol-4-yl)phenyl]pyrimidin-4-amine (Ex.3) and 2-[2-(3,3-difluoroazetidine-1-carbonyl)-4H,5H,6H,7H-thieno[2,3-c]pyridin-6-yl]-N-[4-(1H-1,2,3-triazol-4-yl)phenyl]pyrimidin-4-amine (Ex.3'). [ka]

[0107] Step 1 and Step 2: Synthesis of Intermediate 1: 3,3-Difluoro-1-{4H,5H,6H,7H-thieno[2,3-c]pyridine-2-carbonyl}azetidine

[0108] 6-[(tert-butoxy)carbonyl]-4H,5H,6H,7H-thieno[2,3-c]pyridine-2-carboxylic acid (0.20 g, 0.70 mmol, 1.00 equiv) was dissolved in DMF (5 mL) and then DIPEA (0.50 mL, 2.83 mmol, 4.00 equiv) was added to the reaction mixture followed by HATU (0.32 g, 0.84 mmol, 1.20 equiv). The reaction mixture was stirred at room temperature for 15 min and 3,3-difluoroazetidine hydrochloride (0.11 g, 0.85 mmol, 1.20 equiv) was added. The reaction mixture was allowed to stir overnight at room temperature. The reaction mixture was quenched by the addition of water and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to give tert-butyl 2-(3,3-difluoroazetidine-1-carbonyl)-4H,5H,6H,7H-thieno[2,3-c]pyridine-6-carboxylate, [M+ACN] + =358.90. The crude material was used in the next step without further purification. To the resulting residue was added 2M HCl in dioxane (2.00 mL, 8.20 mmol, 11.00 equiv.) and the mixture was stirred at room temperature for 12 h. The solvent was evaporated to dryness and the resulting HCl salt of 3,3-difluoro-1-{4H,5H,6H,7H-thieno[2,3-c]pyridine-2-carbonyl}azetidine (0.25 g) was used as is for the next step. UPLC-MS, m / z: [M+ACN] + =299.80.

[0109] Step 3: Synthesis of 2-[2-(3,3-difluoroazetidine-1-carbonyl)-4H,5H,6H,7H-thieno[2,3-c]pyridin-6-yl]-N-[4-(1H-imidazol-5-yl)phenyl]pyrimidin-4-amine.

[0110] To a solution of intermediate 1 (0.17 g, 0.33 mmol, 1.00 equiv) in acetonitrile (5.0 mL), N,N-diisopropylethylamine (DIPEA) (0.23 mL, 1.33 mmol, 4.00 equiv) was added and the reaction mixture was stirred at room temperature for 15 min. Then intermediate 2 (0.10 g, 0.33 mmol, 1.00 equiv) was added and the reaction mixture was left stirring at 95 °C overnight. Low conversion of starting material was observed (by UPLC-MS analysis). Cs2CO3 (0.21 g, 0.66 mmol, 2.00 equiv) was added to the reaction mixture and stirring was continued for another 12 h at the same temperature. Then the reaction mixture was quenched with water and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, concentrated and purified by preparative HPLC (mobile phase: ACN+0.1% FA, HO+0.1% FA column C18 prep) to give 2-[2-(3,3-difluoroazetidine-1-carbonyl)-4H,5H,6H,7H-thieno[2,3-c]pyridin-6-yl]-N-[4-(1H-imidazol-5-yl)phenyl]pyrimidin-4-amine (0.003 g, 2%). 1 H NMR(400MHz,DMSO-d6)δ9.37(s,1H),8.42(s,5H),7.97(d,J=5.7Hz,1H),7.67(dd,J=26.6,10.4Hz,6 H),7.51(s,1H),7.34(s,1H),6.11(d,J=5.7Hz,1H),4.98(s,2H),4.04(t,J=5.8Hz,3H),2.75(s,3H). LCMS,m / z:[M+H] + =493.85.

[0111] Step 4: 2-[2-(3,3-difluoroazetidine-1-carbonyl)-4H,5H,6H,7H-thieno[2,3-c]pyridin-6-yl]-N-[4-(1H-1,2,3-triazol-4-yl)phenyl]pyrimidin-4-amine.

[0112] 2-[2-(3,3-Difluoroazetidine-1-carbonyl)-4H,5H,6H,7H-thieno[2,3-c]pyridin-6-yl]-N-(4-{1-[(4-methoxyphenyl)methyl]-1H-1,2,3-triazol-4-yl}phenyl)pyrimidin-4-amine (0.20 g, 0.20 mmol, 1.00 equiv) was dissolved in trifluoroacetic acid (1.06 mL, 13.85 mmol, 70.00 equiv) and the reaction mixture was stirred overnight at 100° C. No further partial conversion was observed. The reaction mixture was evaporated to dryness and purified using preparative HPLC (mobile phase: ACN+0.1% FA, HO+0.1% FA, column C18 prep) to give 22-[2-(3,3-difluoroazetidine-1-carbonyl)-4H,5H,6H,7H-thieno[2,3-c]pyridin-6-yl]-N-[4-(1H-1,2,3-triazol-4-yl)phenyl]pyrimidin-4-amine (0.025 g, 26%). 1 H NMR(400MHz,DMSO-d6)δ9.50(s,1H),8.35(s,1H),8.27(s,1H),8.00(d,J=5.7Hz,1H),7.83(d,J=8.7Hz,2H),7.75(d,J= 8.7Hz,2H),7.34(s,1H),6.13(d,J=5.7Hz,1H),4.99(s,2H),4.67(s,4H),4.05(t,J=5.7Hz,2H),2.76(d,J=6.0Hz,2H). Formate. LCMS,m / z:[M+H]+=495.11.

[0113] Example 4 (Method A) [ka]

[0114] 1H NMR(300MHz,DMSO-d6)δ12.51(s,1H),9.71(s,1H),8.47(s,1H),8.40(d,J=5.9Hz,1H),8.20(dd,J=8.4,1.3Hz,1H),8.14(s,1H),7.81(d,J=2.6 Hz,5H),7.75(d,J=8.4Hz,1H),7.55(s,1H),7.09(s,1H),6.71(d,J=5.9 Hz, 1H), 5.52 (s, 2H), 4.69 (d, J=89.6Hz, 4H), 3.18 (s, 3H), 2.86 (s, 3H). Formate. LCMS,m / z:[M+H] + =557.33.

[0115] Example 5 (Method A) [ka]

[0116] 1 H NMR (400MHz, DMSO-d6) δ 9.66(s,1H), 8.55(s,1H), 8.40(d,J=5.8Hz,1H), 8.19(dd,J=8.4,1.4Hz,1H), 8.16(s,1H), 7.80(s,4H), 7.73(d,J=8.4Hz,1H), 7.70(d,J=1.1Hz,1H), 7.51(s,1H), 7.00(s,1H), 6.71(d,J=5.9Hz,1H), 4.87-4.37(m,6H), 2.14(s,6H). The two aliphatic protons CH2 were overlapped with H2O. Formate salt. LCMS, m / z: [M+H] + =543.23.

[0117] Example 6 (Method A) [ka]

[0118] 1H NMR(400MHz,DMSO-d6)δ9.70(s,1H),8.64(s,1H),8.41(d,J=5.8Hz,1H),8.27(s,1H),8.21(dd,J=8.4,1.3Hz,1H),7.82(d,J=4.9Hz,4H ),7.75(d,J=8.4Hz,1H),7.70(d,J=1.0Hz,1H),7.49(s,1H),7.12(s,1H),6.73(d,J=5.8Hz,1H),5.02-4.41(m,10H),3.62-3.52(m,1H).ギ sour rice. LCMS,m / z:[M+H] + =542.14.

[0119] Example 7 (Method A)

change

[0120] 1 H NMR(300MHz,DMSO-d6)δ9.68(s,1H),8.54(s,1H),8.40(d,J=5.9Hz,1H),8.24-8.14(m,2H),7.87-7.77(m,4H),7.74(d,J=8 .4Hz,1H),7.70(s,1H),7.53(s,1H),7.02(s,1H),6.72(d,J=5.9Hz,1H),4.31-3.96(m,4H),3.95(s,3H),3.91-3.71(m,2H).ギ sour rice. LCMS,m / z:[M+H] + =500.39.

[0121] Example 8 (Method A)

change

[0122] 1H NMR(400MHz,DMSO-d6)δ9.73(s,1H),9.10(d,J=8.8Hz,1H),8.56(s,1H),8.41(d,J=5 .8Hz,1H),8.33(s,4H),8.20(dd,J=8.4,1.3Hz,1H),7.87-7.75(m,5H),7.71(d,J=1. 0Hz,1H),7.50(s,1H),7.23(s,1H),6.73(d,J=5.8Hz,1H),4.87(dt,J=15.3,7.7Hz,1 H),4.72(t,J=6.9Hz,2H),2.60(t,J=6.8Hz,2H),2.16(s,6H),1.40(d,J=7.0Hz,3H).ギ acid salt (1:4). LCMS,m / z:[M+H] + =563.23.

[0123] Example 9 (Method A)

change

[0124] 1 H NMR(300MHz,DMSO-d6)δ9.70(s,1H),8.99(d,J=8.9Hz,1H),8.56(s,1H),8.41(d,J=5.8Hz,1H),8.31(s,2H),8.20(dd,J=8.4,1.3Hz,1H),7.8 6-7.75(m,4H),7.70(d,J=1.1Hz,1H),7.53(s,1H),7.30(s,1H),6.73( d,J=5.9Hz,1H),4.99-4.80(m,1H),4.09(s,3H),1.40(d,J=7.1Hz,3H).ギ sour rice. LCMS,m / z:[M+H] + =506.18.

[0125] Example 10 (Method A)

change

[0126] 1H NMR(400MHz,DMSO-d6)δ12.12(s,1H),9.70(s,1H),9.06(d,J=8.9Hz,1H),8.63(s,1H),8. 42(d,J=5.8Hz,1H),8.21(d,J=8.7Hz,1H),7.88-7.76(m,5H),7.71(s,1H),7.52(s,1H),7 .32(s,1H),6.73(d,J=5.9Hz,1H),5.00(dt,J=15.4,7.5Hz,2H),4.95-4.84(m,1H),4.61( dt,J=7.9,6.1Hz,2H),4.46(t,J=6.1Hz,2H),3.51(p,J=7.0Hz,1H),1.40(d,J=7.0Hz,3H). LCMS,m / z:[M+H] + =562.51.

[0127] Example 11 (Method A)

change

[0128] 1 H NMR(400MHz,DMSO-d6)δ12.11(s,1H),9.69(s,1H),8.61(s,1H),8.41(d,J=5.8Hz, 1H),8.20(dd,J=8.4,1.3Hz,1H),7.82(s,4H),7.74(d,J=8.5Hz,1H),7.71(d,J=1.1 Hz,1H),7.52(s,1H),7.04(s,1H),6.72(d,J=5.8Hz,1H),4.81(d,J=7.4Hz,2H),4. 62(dd,J=7.8,6.1Hz,2H),4.42(s,2H),3.98(dd,J=84.9,48.3Hz,4H),3.47(s,2H). 1つのプロトンCHは、H2Oと Repeatしていた. LCMS,m / z:[M+H] + =556.14.

[0129] Example 12 (Method A)

change

[0130] 1 H NMR(400MHz,DMSO-d6)δ9.68(s,1H),8.53(s,1H),8.40(d,J=5.8Hz,1H),8.3 0(s,3H),8.18(dd,J=8.4,1.4Hz,1H),7.84-7.77(m,4H),7.72(d,J=8.4Hz,1H ),7.70(d,J=1.1Hz,1H),7.52(s,1H),6.90(s,1H),6.72(d,J=5.9Hz,1H),3.9 3(s,3H),3.66(t,J=6.3Hz,2H),3.55(t,J=6.6Hz,2H),1.91(d,J=8.3Hz,4H).ギ acid salt (1:3). LCMS,m / z:[M+H] + =464.39.

[0131] Example 13 (Method A)

change

[0132] 1 H NMR(400MHz,DMSO-d6)δ9.70(s,1H),8.57(s,1H),8.42(d,J=5.8Hz,1H),8.21(dd,J=8.5,1.4Hz,1H),8.14(s,1H),7.87-7.7 3(m,5H),7.55(s,1H),7.06(s,1H),6.73(d,J=5.9Hz,1H),4.66(s,2H),4.20(s,2H),4.00(s,2H),3.80(s,2H),3.05(s,2H). 6つのaliphatic プロトン2×CH3は, DMSO-d6とrepeated していた. LCMS,m / z:[M+H] + =557.20.

[0133] Example 14 (Method A)

change

[0134] 1H NMR(400MHz,DMSO-d6)δ9.75(s,1H),8.58(s,1H),8.44-8.39(m,2H),8.28(s,2H),7.91(d,J=8.3Hz,1H),7.80(q,J=8 .6Hz,4H),7.70(d,J=1.1Hz,1H),7.66(d,J=1.0Hz,1H),7.55(s,1H),6.77(d,J=5.9Hz,1H),5.12(s,2H),4.56(s,2H). Formate (1:2). LCMS,m / z:[M+H] + =473.29.

[0135] Example 15 (Method B) [ka]

[0136] 1 H NMR (300MHz, DMSO-d6) δ 9.82(s,1H), 8.56(s,1H), 8.44(d,J=5.8Hz,1H), 8.28(s,1H), 8.20(dd,J=8.4,1.3Hz,1H), 8.14(s,1H), 7.97-7.87(m,4H), 7.74(d,J=8.4Hz,1H), 7.01(s,1H), 6.75(d,J=5.8Hz,1H), 4.64(t,J=6.0Hz,6H), 2.17(s,6H). The two aliphatic protons CH2 were overlapped with DMSO. Formate salt. LCMS, m / z: [M+H] + =544.38.

[0137] Example 16 (Method B) [ka]

[0138] 1H NMR(400MHz,DMSO-d6)δ9.84(s,1H),8.53(s,1H),8.44(s,1H),8.40(s,3H),8.30(s,1H),8.19(dd,J=8.4,1.4Hz,1H),7.93(q,J=8 .7Hz,4H),7.73(d,J=8.4Hz,1H),6.91(s,1H),6.76(d,J=5.8Hz,1H),3.94(s,3H),3.67(s,2H),3.54(d,J=6.9Hz,2H),1.90(s,4H). Formate (1:3). LCMS,m / z:[M+H] + =465.37.

[0139] Example 17 (Method B) [ka]

[0140] 1 H NMR (400MHz, DMSO-d6) δ 9.84(s,1H), 8.55(s,1H), 8.44(d,J=5.8Hz,1H), 8.35(s,1H), 8.30(s,1H), 8.20(dd,J=8.4,1.4Hz,1H), 7.93(q,J=8.8Hz,4H), 7.75(d,J=8.5Hz,1H), 7.02(s,1H), 6.76(d,J=5.8Hz,1H), 4.20(s,2H), 3.95(s,4H), 3.81(s,1H). The two aliphatic protons CH2 were overlapped with H2O. Formate salt. LCMS, m / z: [M+H] + =501.20.

[0141] Example 18 (Method B) [ka]

[0142] 1H NMR (400MHz, DMSO-d6) δ 9.81(s,1H), 8.55(s,1H), 8.44(d,J=5.8Hz,1H), 8.26(s,1H), 8.19(dd,J=8.4,1.3Hz,1H), 8.14(s,1H), 7.92(q,J=8.7Hz,4H), 7.74(d,J=8.4Hz,1H), 6.97(d,J=3.2Hz,1H), 6.75(d,J=5.8Hz,1H), 4.57(s,2H), 4.14(s,2H), 3.96(s,2H), 3.78(s,2H), 2.19(s,6H). The two aliphatic protons CH2 were overlapped with DMSO-d6. Formate salt. LCMS, m / z: [M+H] + =558.16.

[0143] Example 19 (Method B) [ka]

[0144] 1 H NMR(400MHz,DMSO-d6)δ9.91(s,1H),8.58(s,1H),8.46(d,J=5.8Hz,1H),8.42(dd,J=8.2,1.4Hz,1H),8.39(s ,1H),8.32(s,1H),7.96-7.88(m,5H),7.67(d,J=1.0Hz,1H),6.81(d,J=5.9Hz,1H),5.12(s,2H),4.56(s,2H). Formate. LCMS,m / z:[M+H] + =474.20.

[0145] Example 20 (Method B) [ka]

[0146] 1H NMR(400MHz,DMSO-d6)δ12.14(s,1H),9.74(s,1H),8.98(d,J=1.4Hz,1H),8.46(dd,J=8.5,1.5Hz,1H),8.43(d,J=5.9Hz,1H),8.08(d, J=8.5Hz,1H),8.01(s,1H),7.79(s,4H),7.71(d,J=1.1Hz,1H),7.59(d,J=20.2Hz,1H),6.77(d,J=5.9Hz,1H),4.85(d,J=199.8Hz,4H). The acid residue contains している. LCMS,m / z:[M+H] + =489.10.

[0147] Example 21 (Method B)

change

[0148] 1 H NMR (400MHz, DMSO-d6) δ13.60(d,J=36.6Hz,1H),9.72(s,1H),8.68(d,J=34.4Hz,1H),8.50-8.33(m,2H),8.20(d,J=3.9Hz, 2H),7.81(s,5H),7.71(d,J=1.1Hz,1H),7.53(s,1H),6.73(d,J=5.8Hz,1H),5.16(d,J=13.0Hz,2H),4.62(t,J=12.3Hz,2H).ギ sour rice. LCMS,m / z:[M+H] + =472.88.

[0149] Example 22 (Method B)

change

[0150] 1H NMR (400MHz, DMSO-d6) δ13.65(s,1H),9.85(s,1H),8.67(s,1H),8.44(d,J=5.8Hz,1H),8.37(s,2H),8.30(s,1 H),7.93(s,4H),7.81(d,J=12.2Hz,1H),6.77(d,J=5.8Hz,1H),5.18(t,J=12.3Hz,2H),4.62(t,J=12.2Hz,2H). LCMS,m / z:[M+H] + =474.25.

[0151] Example 23 (Method C)

change

[0152] 1 H NMR (400MHz, DMSO-d6) δ9.34 (s, 1H), 8.17 (s, 2H), 7.97 (d, J = 5.7 Hz, 1H), 7.76-7.67 (m, 3H), 7.63 (d, J = 8.4 Hz, 2H), 7.50 (s, 1H), 7.38 (s, 1H), 6.10 (d, J = 5.7 Hz, 1H), 4.96 (s, 2H), 4.12 (s, 1H), 4.04 (t, J = 5.8 Hz, 4H), 3.77 (s, 2H), 2.75 (s, 2H). Hydroxyethyl acetate (1:2). LCMS, m / z: [M+H] + =520.11.

[0153] Example 24 (Method C)

change

[0154] 1H NMR(400MHz,DMSO-d6)δ9.49(s,1H),8.32(s,2H),8.27(s,1H),8.00(d,J=5.7Hz,1H),7.88-7.80(m,2H),7.75(d,J=8.7Hz,2H ),7.38(s,1H),6.13(d,J=5.7Hz,1H),4.97(s,2H),4.12(s,1H),4.05(t,J=5.9Hz,4H),3.77(s,2H),2.76(s,3H),2.61(s,1H). Formate (1:2). LCMS,m / z:[M+H] + =521.09.

[0155] Example 25 (Method C) [ka]

[0156] 1 H NMR(400MHz,DMSO-d6)δ12.12(s,1H),i9.34(s,1H),8.28(s,2H),7.97(d,J=5.6Hz,1H),7.73(s,2H),7.68(d,J=1.1Hz,1H),7.63(d,J=7.9 Hz,2H),7.54(s,1H),7.42(s,1H),6.10(d,J=5.7Hz,1H),4.97(s,2H),4.21(bs,1H),4.04(t,J=5.8Hz,3H),3.96-3.69(m,4H),2.76(s,2H). Formate (1:2). LCMS,m / z:[M+H] + =508.42.

[0157] Comparative Example The structure of comparative compound A is shown below. [ka] This can be prepared according to the methods found in WO2019 / 001572.

[0158] Example 26 ADP-Glo ​​Kinase Assay (Promega). The ADP-Glo™ Kinase Assay is a luminescent ADP detection assay that allows the measurement of kinase activity based on the amount of ADP generated 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). Once the reaction is complete, 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 generated and therefore to kinase activity. The ADP-Glo™ Kinase Assay was performed in a 384-well plate format as follows.

[0159] Preparation of Kinase Detection Reagent: 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 swirling or removed from the buffer by carefully aspirating the supernatant from the bottle with a pipette. After both the Kinase Detection Buffer and Kinase Detection Substrate were equilibrated to room temperature, the lyophilized substrate was reconstituted by transferring the entire volume of Kinase Detection Buffer to the bottle containing the Kinase Detection Substrate, followed by gentle mixing to obtain a homogenous solution.

[0160] Preparation of kinase reaction buffer: The kinase reaction buffer was freshly prepared before each experiment. The composition of this buffer is shown in Table 1 below. [Table 1]

[0161] Preparation of ADP-Glo ​​Reagent. Before performing the assay, prepare three mixtures on ice: Mixture 1 - Contains ROCK1 or ROCK2 in kinase reaction buffer (1x) Mixture 2 - Kinase reaction buffer (1x) containing S6K peptide Mixture 3-kinase reaction buffer (1x) containing ATP

[0162] The final conditions for performing the ADP-Glo ​​kinase assay are set forth in Table 2 below: [Table 2]

[0163] The ratio of reagent volumes in the assay was 1:1:2 kinase reactant to ADP-Glo™ Reagent to kinase detection reagent. In a 384-well plate, the volumes were 5 μl kinase reactant, 5 μl ADP-Glo™ Reagent, and 10 μl kinase detection reagent.

[0164] Generation of standard curves for ATP to ADP conversion. 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 that can be obtained in the reaction at a specific conversion percentage ranging from 100% conversion to 0% conversion. The standards used to generate the ATP to ADP conversion curves are made by mixing appropriate volumes of ATP and ADP stock solutions.

[0165] Determination of IC50 values ​​of kinase inhibitors

[0166] Each plate contained positive controls (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 and reference compounds were diluted in 100% DMSO to obtain 10 mM stock solutions. Each compound was tested in duplicate in 8 serial dilutions. The final concentration of DMSO in the reactions was 1% (max 50 nL).

[0167] 5 μl / well of kinase reaction buffer (1×) was dispensed into blank control wells. 2 μl / well of kinase reaction buffer (1×) was dispensed into no protein control (low control) and no substrate (autophosphorylation) wells. Plates were sealed with cling film and then briefly spun (1 min, 1000 rpm).

[0168] 2 μl / well of kinase (2.5x) solution was dispensed into the relevant wells of the assay plate. The plate was sealed with cling film and then spun briefly (1 min, 1000 rpm).

[0169] 2 μl / well of S6K substrate (2.5x) solution was dispensed into the relevant wells of the assay plate. The plate was sealed with cling film and then spun briefly (1 min, 1000 rpm).

[0170] 1 μl / well of ATP (5x) solution was dispensed into the relevant wells of the assay plate. The final reaction volume was 15 μl. The plate was sealed with cling film and then spun briefly (1 min, 1000 rpm).

[0171] The plates were incubated at 25° C. for 120 minutes with a shaking speed of 450 rpm.

[0172] After the incubation was completed, the kinase reaction was terminated, residual ATP was depleted from the kinase reaction, and ADP was converted to ATP, which was measured in the luciferase / luciferin reaction. 5 μl of ADP-Glo™ Reagent was dispensed to stop the kinase reaction and to deplete unconsumed ATP. The plate was sealed with cling film, then briefly spun (1 min, 1000 rpm) and incubated at 25° C. with a shaking speed of 450 rpm for 40 min.

[0173] 10 μl of kinase detection reagent was dispensed to convert ADP to ATP and to introduce luciferase and luciferin to detect ATP. Plates were sealed with cling film, then briefly spun (1 min, 1000 rpm) and incubated at 25° C. for 60 min with a shaking speed of 450 rpm.

[0174] After 5 min of dark acclimation, luminescence was measured using a PHERAstar FSX multimode plate reader (BMG Labtech).

[0175] After normalization, GraphPad Prism 7.04 software was used to calculate IC using a four-parameter model: log(inhibitor) vs. response-variable slope. 50 The parameters were calculated. [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5]

[0176] Example 28 Selective ROCK2 inhibition downregulates IL-17 secretion via a pSTAT3-dependent mechanism

[0177] Rho kinases (ROCKs) are members of the serine / threonine kinase family that are often studied for their role in cell morphology, motility, and shape through their effects on the cytoskeleton. Although the two isoforms of ROCK, ROCK1 and ROCK2, share over 90% homology within their kinase domains, the functions of these proteins are not redundant and depend on the cell system in which ROCK is expressed and activated. Recent studies have demonstrated that ROCK2, but not ROCK1, regulates the proinflammatory 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. Selective ROCK2 inhibition also shifts the balance between proinflammatory Th17 and immunosuppressive regulatory T cells (Tregs) by enhancing STAT5 phosphorylation and IL-10 secretion.

[0178] By using stimulatory antibodies against CD3 and CD28 (anti-CD3 / CD28) in combination with IL-1β and TGF-β (Th17 biased conditions), we found that novel selective ROCK2 inhibitors, such as the compounds of Examples 1 and 2, robustly down-regulated IL-17 secretion in Th17 biased human CD4+ T cells in a dose-dependent manner with EC50s of 838 nM and 764 nM, respectively (see Figures 2A and 2B). + T cells were treated with the indicated doses of ROCK2 inhibitor and then stimulated with anti-CD3 / 28 mAb, IL-1β (50 ng / mL) and TGF-β (5 ng / mL) for 48 h. Supernatants were analyzed for IL-17 by ELISA. One representative of three different experiments is shown.

[0179] The induction and expression of IL-17 and other proinflammatory cytokines has been shown to depend on the activation and phosphorylation of certain transcription factors, including STAT3. +Treatment of T cells resulted in a dose-dependent attenuation of STAT3 phosphorylation (Figure 3), consistent with the ability of the compounds of Examples 1 and 2 to downregulate IL-17 secretion and pCofilin (a classical downstream ROCK target) under the same stimulation conditions (Figure 4). + 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 2 h. Cell lysates were prepared and analyzed by Western blot. One representative of three different experiments is shown.

[0180] Example 27 A selective ROCK2 inhibitor downregulates the expression of profibrotic genes in fibroblasts

[0181] ROCK is activated by the small GTPase Rho in response to various 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 3 (Col3A1). By using MRC-5 human fibroblasts pretreated with different dosages of selective ROCK2 inhibitors, we found that both compounds of Example 1 and Example 2 dose-dependently down-regulated TGF-β-induced fibronectin, α-SMA and Col3A1 gene expression as determined by PCR (Figure 5), and Col1A protein production in the supernatant as measured by ELISA (Figure 6). These data further support that selective ROCK2 inhibition has a direct and robust antifibrotic effect.

[0182] In these studies, 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. Cells were exposed to TGF-β1 (2.5 ng / mL) and various concentrations of the compounds of Examples 1 and 2 for 48 hours. Cellular mRNA was isolated and mRNA expression of the indicated genes (fibronectin, αSMA and col3A) was analyzed by RT-PCR (Figure 5). Secreted procollagen 1a (Col1A1) in the supernatant was measured by ELISA (Figure 6).

[0183] Example 28 A selective ROCK2 inhibitor potently downregulates differentiation in human adipocytes

[0184] Adipogenesis is a complex, multi-step process that develops from precursor stem cells to fat-synthesizing and fat-storing adipocytes. Dysregulation of adipocyte function has been shown to be involved in the pathogenesis of a wide variety of metabolic diseases, including type 2 diabetes and obesity. ROCK has been implicated in regulating adipocyte differentiation, but its isoform-specific contribution to adipogenesis and other metabolic pathways has not been fully elucidated. Recent data demonstrated that KD025, a selective ROCK2 inhibitor, downregulated adipocyte differentiation in both mouse 3T3-L1 preadipocytes and human adipose-derived stem cells by reducing the expression of key adipogenic / lipogenic genes, such as PPARg, C / EBPa, and Glut4. By using primary human adipocytes, we found that novel selective ROCK2 inhibitors Ex.1 and Ex.2 downregulated adipogenesis in a dose-dependent manner (Figure 7), further supporting the possibility of countering metabolism by targeting ROCK2 in cells. In this study, human subcutaneous adipocytes were grown to confluence and then induced to differentiate with an adipogenic cocktail (0.1 μM dexamethasone, 1 μM insulin, 200 μM indomethacin, 250 μM isobutylmethylxanthine (IBMX)) in the presence of the indicated concentrations of Ex.1 or Ex.2 for 10 days. Differentiated cells were stained with Oil Red, which was extracted with isopropanol, and measured by absorbance at 492 nM.

Claims

1. Compounds having formula I: 【Chemistry 1】 [During the ceremony, R １１ , １２ 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 Selected from the group consisting of; R ２ 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 Selected from the group consisting of; Alternatively, R １ and R ２ Together, It may contain 0 to 2 ring heteroatoms selected from the group consisting of N, O, and S, or it may be unsubstituted or C 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 A 5-membered or 6-membered saturated or unsaturated condensed ring substituted with 1 to 3 substituents selected from the group consisting of the following: It forms; X ４ is N or CH; R ３ and R ４ These are H and C, which are independent of each other. １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C ３ -C ７ Cycloalkyl, 3-10 membered heterocyclyl, C ６ -C １０ Aryl, 5-14 member heteroaryl, C ６－１２ Aralkil, - (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 Selected from the group consisting of; Alternatively, R ３ and R ４ Together with the nitrogen to which they are bound, (i) A heterocyclic ring having 4 to 6 members, wherein the heterocyclic ring has 0 to 2 additional ring heteroatoms selected from N, O, and S, or (ii) A heterobicyclic ring system having 5 to 10 members, wherein the heterobicyclic ring system has 0 to 3 additional ring heteroatoms selected from N, O, and S. It forms a complex ring or a complex bicyclic ring system, and the complex ring or the complex bicyclic ring system is unsubstituted or halo, C １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C ３ -C ７ Cycloalkyl, halo, -CN, 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 It is substituted with 1 to 4 substituents selected from the group consisting of; The dotted line represents an optional double bond; Each R ５ These are H and C, independently. １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, 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 Selected from the group consisting of; n is between 0 and 3; X １ CR ６ Selected from the group consisting of and N; X ２ CHR ６ , NR ７ Selected from the group consisting of O and S; X ３ It is selected from the group consisting of C, CH, and N; Each R ６ These are H and C, independently. １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, 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 Selected from the group consisting of; Each R ７ These are H and C, independently. １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C ３ -C ７ Cycloalkyl, -(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 Selected from the group consisting of; Each x is independently selected from 0 and 1; Each R １１ and R １２ H and C are independent of each other. １ -C ６ Selected from the group consisting of alkyl groups; Alternatively, R １１ and R １２ When both are bonded to the same nitrogen, they come together. A 4- to 7-membered heterocyclic ring having 0 to 2 additional ring heteroatoms selected from the group consisting of N, O, and S, and being unsubstituted or halo, C １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, 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 The heterocyclic ring is substituted with 1 to 3 substituents selected from the group consisting of alkyl)-OH. [forming] or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1, having formula II: 【Chemistry 2】 [During the ceremony, R １ H, C １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, 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 Selected from the group consisting of; R ２ H, C １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, 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 Selected from the group consisting of; Alternatively, R １ and R ２ Together, It may contain 0 to 2 ring heteroatoms selected from the group consisting of N, O, and S, or it may be unsubstituted or C 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 A 5-membered or 6-membered saturated or unsaturated condensed ring substituted with 1 to 3 substituents selected from the group consisting of the following: It forms; R ３ and R ４ These are H and C, which are independent of each other. １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C ３ -C ７ Cycloalkyl, 3-10 membered heterocyclyl, C ６ -C １０ Aryl, 5-14 member heteroaryl, C ６－１２ Aralkil, - (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 Selected from the group consisting of; Alternatively, R ３ and R ４ Together with the nitrogen to which they are bound, (i) A 4-6 membered heterocyclic ring having 0-2 additional ring heteroatoms selected from N, O, and S, or (ii) A heterobicyclic ring system having 5 to 10 members, wherein the heterobicyclic ring system has 0 to 3 additional ring heteroatoms selected from N, O, and S. It forms a complex ring or a complex bicyclic ring system, and the complex ring or the complex bicyclic ring system is unsubstituted or halo, C １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C ３ -C ７ Cycloalkyl, halo, -CN, 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 It is substituted with 1 to 4 substituents selected from the group consisting of; The dotted line represents an optional double bond; Each R ５ These are H and C, independently. １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, 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 Selected from the group consisting of; n is between 0 and 3; X １ CR ６ Selected from the group consisting of and N; X ２ CHR ６ , NR ７ Selected from the group consisting of O and S; X ３ It is selected from the group consisting of C, CH, and N; Each R ６ These are H and C, independently. １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, 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 Selected from the group consisting of; Each R ７ These are H and C, independently. １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C ３ -C ７ Cycloalkyl, -(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 Selected from the group consisting of; Each x is independently selected from 0 and 1; Each R １１ and R １２ H and C are independent of each other. １ -C ６ Selected from the group consisting of alkyl groups; Alternatively, R １１ and R １２ When both are bonded to the same nitrogen, they come together. A 4- to 7-membered heterocyclic ring having 0 to 2 additional ring heteroatoms selected from the group consisting of N, O, and S, and being unsubstituted or halo, C １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, 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 The heterocyclic ring is substituted with 1 to 3 substituents selected from the group consisting of alkyl)-OH. [forming] or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 1, having formula IIa: 【Transformation 3】 [During the ceremony, R ３ and R ４ 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 selected from the group consisting of; Alternatively, R ３ and R ４ Together with the nitrogen to which they are bound, (i) A heterocyclic ring having 4 to 6 members, wherein the heterocyclic ring has 0 to 2 additional ring heteroatoms selected from N, O, and S, or (ii) A heterobicyclic ring system having 5 to 10 members, wherein the heterobicyclic ring system has 0 to 3 additional ring heteroatoms selected from N, O, and S. is formed; the heterocyclic ring or the hetero-bicyclic ring system is unsubstituted or is halo, 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 , oxo, -O-(C １ -C ６ alkyl)-OR １１ , -(C １ -C ６ alkyl)-OR １１ , -NR １１ R[[ID=3۷]] １２ , -O-(C １ -C ６ alkyl)-NR １１ R １２ , -(C １ -C ６ alkyl)-NR １１ R<000096۱>, -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<00009८3>[[ID=१८]], -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 It is substituted with 1 to 4 substituents selected from the group consisting of; The dotted line represents an optional double bond; X １ CR ６ Selected from the group consisting of and N; X ２ CHR ６ , NR ７ Selected from the group consisting of O and S; X ３ It is selected from the group consisting of C, CH, and N; Each R ６ These are H and C, independently. １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, 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 Selected from the group consisting of; Each R ７ These are H and C, independently. １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C ３ -C ７ Cycloalkyl, -(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 Selected from the group consisting of; Each x is independently selected from 0 and 1; Each R １１ and R １２ H and C are independent of each other. １ -C ６ Selected from the group consisting of alkyl groups; Alternatively, R １１ and R １２ When both are bonded to the same nitrogen, they come together. A 4- to 7-membered heterocyclic ring having 0 to 2 additional ring heteroatoms selected from the group consisting of N, O, and S, and being unsubstituted or halo, C １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, 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 The heterocyclic ring is substituted with 1 to 3 substituents selected from the group consisting of alkyl)-OH. [forming] or a pharmaceutically acceptable salt thereof.

4. The compound according to claim 1, having formula III: 【Chemistry 4】 [During the ceremony, R １ H, C １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, 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 Selected from the group consisting of; R ２ H, C １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, 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 Selected from the group consisting of; Alternatively, R １ and R ２ Together, It may contain 0 to 2 ring heteroatoms selected from the group consisting of N, O, and S, or it may be unsubstituted or C 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 A 5-membered or 6-membered saturated or unsaturated condensed ring substituted with 1 to 3 substituents selected from the group consisting of the following: It forms; R ３ and R ４ These are H and C, which are independent of each other. １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C ３ -C ７ Cycloalkyl, 3-10 membered heterocyclyl, C ６ -C １０ Aryl, 5-14 member heteroaryl, C ６－１２ Aralkil, - (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 Selected from the group consisting of; Alternatively, R ３ and R ４ Together with the nitrogen to which they are bound, (i) A heterocyclic ring having 4 to 6 members, wherein the heterocyclic ring has 0 to 2 additional ring heteroatoms selected from N, O, and S, or (ii) A heterobicyclic ring system having 5 to 10 members, wherein the heterobicyclic ring system has 0 to 3 additional ring heteroatoms selected from N, O, and S. It forms a complex ring or a complex bicyclic ring system, and the complex ring or the complex bicyclic ring system is unsubstituted or halo, C １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C ３ -C ７ Cycloalkyl, halo, -CN, 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 It is substituted with 1 to 4 substituents selected from the group consisting of; The dotted line represents an optional double bond; Each R ５ These are H and C, independently. １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, 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 Selected from the group consisting of; n is between 0 and 3; X １ CR ６ Selected from the group consisting of and N; X ２ CHR ６ , NR ７ Selected from the group consisting of O and S; X ３ It is selected from the group consisting of C, CH, and N; Each R ６ These are H and C, independently. １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, 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 Selected from the group consisting of; Each R ７ These are H and C, independently. １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C ３ -C ７ Cycloalkyl, -(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 Selected from the group consisting of; Each x is independently selected from 0 and 1; Each R １１ and R １２ H and C are independent of each other. １ -C ６ Selected from the group consisting of alkyl groups; Alternatively, R １１ and R １２ When both are bonded to the same nitrogen, they come together. A 4- to 7-membered heterocyclic ring having 0 to 2 additional ring heteroatoms selected from the group consisting of N, O, and S, and being unsubstituted or halo, C １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, 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 The heterocyclic ring is substituted with 1 to 3 substituents selected from the group consisting of alkyl)-OH. [forming] or a pharmaceutically acceptable salt thereof.

5. The compound according to claim 1, having formula IIIa: 【Transformation 5】 [During the ceremony, R ３ and R ４ These are H and C, which are independent of each other. １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C ３ -C ７ Cycloalkyl, 3-10 membered heterocyclyl, C ６ -C １０ Aryl, 5-14 member heteroaryl, C ６－１２ Aralkil, - (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 Selected from the group consisting of; Alternatively, R ３ and R ４ Together with the nitrogen to which they are bound, (i) A heterocyclic ring having 4 to 6 members, wherein the heterocyclic ring has 0 to 2 additional ring heteroatoms selected from N, O, and S, or (ii) A heterobicyclic ring system having 5 to 10 members, wherein the heterobicyclic ring system has 0 to 3 additional ring heteroatoms selected from N, O, and S. It forms a complex ring or a complex bicyclic ring system, and the complex ring or the complex bicyclic ring system is unsubstituted or halo, C １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C ３ -C ７ Cycloalkyl, halo, -CN, 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 It is substituted with 1 to 4 substituents selected from the group consisting of; The dotted line represents an optional double bond; X １ CR ６ Selected from the group consisting of and N; X ２ CHR ６ , NR ７ Selected from the group consisting of O and S; X ３ It is selected from the group consisting of C, CH, and N; Each R ６ These are H and C, independently. １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, 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 Selected from the group consisting of; Each R ７ These are H and C, independently. １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C ３ -C ７ Cycloalkyl, -(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 Selected from the group consisting of; Each x is independently selected from 0 and 1; Each R １１ and R １２ H and C are independent of each other. １ -C ６ Selected from the group consisting of alkyl groups; Alternatively, R １１ and R １２ When both are bonded to the same nitrogen, they come together. A 4- to 7-membered heterocyclic ring having 0 to 2 additional ring heteroatoms selected from the group consisting of N, O, and S, and being unsubstituted or halo, C １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, 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 The heterocyclic ring is substituted with 1 to 3 substituents selected from the group consisting of alkyl)-OH. [forming] or a pharmaceutically acceptable salt thereof.

6. formula: 【Transformation 6】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof, having 2-[2-(3,3-difluoroazetidine-1-carbonyl)-1-methyl-1H-indole-6-yl]-N-[4-(1H-imidazole-5-yl)phenyl]pyrimidine-4-amine].

7. formula: 【Transformation 7】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof, having 2-[2-(3,3-difluoroazetidine-1-carbonyl)-1-methyl-1H-indole-6-yl]-N-[4-(1H-1,2,3-triazole-4-yl)phenyl]pyrimidine-4-amine].

8. A pharmaceutical composition for the treatment of a disease or disorder mediated by ROCK2, comprising an effective amount of any compound according to claim 1 to 7 or a pharmaceutically acceptable salt thereof.

9. The pharmaceutical composition according to claim 8, wherein the disease or disorder is selected from the group consisting of fibrous diseases, inflammatory diseases, autoimmune diseases, cardiovascular disorders, central nervous system disorders, neoplasms, metabolic syndromes, eye diseases, kidney diseases, lung diseases, muscular dystrophy, sickle cell disease, and viral diseases.

10. The pharmaceutical composition according to claim 9, wherein the disease or disorder is selected from the group consisting of fibrous diseases, inflammatory diseases, and autoimmune diseases.

11. The pharmaceutical composition according to claim 10, 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.

12. The pharmaceutical composition according to claim 9, wherein the disease or disorder is selected from the group consisting of cardiovascular disorders, central nervous system disorders, neoplasms, or metabolic syndromes.

13. The pharmaceutical composition according to claim 10, wherein the inflammatory disorder is selected from the group consisting of cardiovascular inflammation, pneumonia, nephritis, arteriosclerosis, and sepsis.

14. The pharmaceutical composition according to claim 10, wherein the fibrous disorder is selected from the group consisting of idiopathic pulmonary fibrosis, renal fibrosis, kidney fibrosis, ophthalmic fibrosis, cardiac fibrosis, NASH, scleroderma, systemic scleroderma, and liver cirrhosis.

15. The pharmaceutical composition according to claim 12, wherein the neoplastic disease is selected from the group consisting of ovarian cancer, breast cancer, and pancreatic cancer.

16. The pharmaceutical composition according to claim 12, 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.

17. The pharmaceutical composition according to claim 9, wherein the lung disease is selected from the group consisting of idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, and asthma.

18. The pharmaceutical composition according to claim 9, wherein the central nervous system disorder is selected from the group consisting of neuronal degeneration or spinal cord injury, traumatic brain injury, cavernous vascular malformation, Huntington's disease, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), and multiple sclerosis.

19. The pharmaceutical composition according to claim 9, wherein the kidney disease is selected from the group consisting of polycystic kidney disease, renal fibrosis, and diabetic kidney disease.

20. The pharmaceutical composition according to claim 9, wherein the metabolic disease is selected from the group consisting of insulin resistance, hyperinsulinemia, type 2 diabetes, obesity, metabolic syndrome, and glucose intolerance.

21. The pharmaceutical composition according to claim 9, wherein the eye disease is selected from the group consisting of ocular hypertension, age-related macular degeneration (AMD; wet and dry types), choroidal neovascularization (CNV), choroidal tumor, diabetic macular edema (DME), iris neovascularization, uveitis, glaucoma, primary open-angle glaucoma, acute closed-angle glaucoma, pigmentary glaucoma, congenital glaucoma, normal-tension glaucoma, secondary glaucoma, neovascular glaucoma, geographic atrophy, and retinitis of prematurity (ROP).

22. The pharmaceutical composition according to claim 9, wherein the disease is Duchenne muscular dystrophy.

23. The pharmaceutical composition according to claim 9, wherein the viral infection is a coronavirus infection such as SARS-CoV-1, SARS-CoV-2, and MERS-CoV.

Images