Claims for Patent: 10,183,931

Summary for Patent: 10,183,931

Title:	Rho kinase inhibitors
Abstract:	The invention relates to inhibitors of ROCK1 and/or ROCK2. Also provided are methods of treating diseases and disorders involving inhibiting ROCK1 and/or ROCK2.
Inventor(s):	Masha Poyurovsky, Ji-In Kim, Kevin liu, Alexandra Zanin-Zhorov
Assignee:	Kadmon Corp LLC
Application Number:	US15/809,460
Patent Claims:	1. A method for the treatment of an autoimmune disorder selected from rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus (SLE), psoriasis, Crohn's disease, atopic dermatitis, eczema, and graft-versus-host disease (GVHD), in a human subject by administering a therapeutically effective amount of a compound of the formula XXXI: or a pharmaceutically acceptable salt thereof, wherein: R1 is selected from the group consisting of —O—(CH2)rCO2R12, —O—(CH2)y, —C(═O)NR13R14, —O—(CH2)y, -heteroaryl, —O—(CH2)y, -cycloalkyl, —O—C(═O)—(CH2)y, —NR13R14, —O—(CH2)z—NR13R14, —NH—C(═O)—(CH2)y, —NR13R14, —NH—C(═O)—X—R15, —NH—(CH2)y, —NR13R14; R12 is selected from the group consisting of C1-C6 alkyl, —(C1-C6 alkyl)-O—(C1-C6 alkyl), —(C1-C6 alkyl)-NR16R17, —(C1-C6 alkyl)-C(═O)NR16R17, —(C1-C6 alkyl)-O—(C1-C6 alkyl)-O—(C1-C6 alkyl), aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted at one or more carbon atoms by from 1 to 3 substituents independently selected from halo, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; R13 and R14 are independently selected from the group consisting of H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, —(C1-C6 alkyl)-O—(C1-C6 alkyl), —(C1-C6 alkyl)-NR16R17, —(C1-C6 alkyl)-C(═O)NR16R17, aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; or R13 and R14 may be taken together to form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C3-C7 cycloalkyl, oxo, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; X is selected from a covalent bond, O, NH, and C1-C6 alkyl; R15 is selected from the group consisting of heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl, or R15 is selected from —(C1-C6 alkyl)-O—(C1-C6 alkyl), —(C1-C6 alkyl)-NR16R17, —CO2R18, —O—(CH2)x—CO2R18, and —C(═O)NR16R17; R16 and R17 are independently selected from the group consisting of H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, —(C1-C6 alkyl)-O—(C1-C6 alkyl), aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; or R16 and R17 may be taken together to form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, oxo, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; R18 is selected from the group consisting of H, aryl, aralkyl, heteroaryl, C1-C6 alkyl, —(C1-C6 alkyl)-O—(C1-C6 alkyl), —(C1-C6 alkyl)-NR16R17, —(C1-C6 alkyl)-O—(C1-C6 alkyl)-O—(C1-C6 alkyl), each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoroalkyl; x is selected from 0 to 6; y is selected from 0 to 6; z is selected from 2 to 6; each R2 is independently selected from the group consisting of lower alkyl, CN, halo, hydroxy, lower alkoxy, amino, and perfluoro lower alkyl; each R3 is independently selected from the group consisting of lower alkyl, CN, halo, hydroxy, lower alkoxy, amino, and perfluoro lower alkyl; R4 is selected from H, —(CH2)a—NR43R44, —Y—R42, —O—(CH2)a—CO2R42, —O—(CH2)a—C(═O)NR43R44, —O—(CH2)a-heteroaryl, —O—(CH2)a-cycloalkyl, —O—C(═O)—(CH2)a—NR43R44, —O—(CH2)c—N43R44, —NH—C(═)—(CH2)a—NR43R44, —NH—C(═O)—Y—R45, —NH—C(═O)—(CH2)a—NR43R44; R42 is selected from the group consisting of C1-C6 alkyl, —(C1-C6 alkyl)-O—(C1-C6 alkyl), —(C1-C6 alkyl)-NR46R47, —(C1-C6 alkyl)-C(═O)N46R47, —(C1-C6 alkyl)-O—(C1-C6 alkyl)-O—(C1-C6 alkyl), each of which may be optionally substituted at one or more carbon atoms by from 1 to 3 substituents independently selected from halo, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; R43 and R44 are independently selected from the group consisting of H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, —(C1-C6 alkyl)-O—(C1-C6 alkyl), —(C1-C6 alkyl)-NR46R47, —(C1-C6 alkyl)-C(═O)NR46R47, aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; or R43 and R44 may be taken together to form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, oxo, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; Y is selected from a covalent bond, O, NH, and C1-C6 alkyl; R45 is selected from the group consisting of H, aryl, —(C1-C6 alkyl)-O—(C1-C6 alkyl), —(C1-C6 alkyl)-NR46R47, —CO2R48, —O—(CH2)6—CO2R48, and —C(═O)NR46R47, R46 and R47 independently selected from the group consisting of H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, —(C1-C6 alkyl)-O—(C1-C6 alkyl), aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; or R46 and R47 may be taken together to form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, oxo, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; R48 is selected from the group consisting of H, aryl, aralkyl, heteroaryl, C1-C6 alkyl, —(C1-C6 alkyl)-O—(C1-C6 alkyl), —(C1-C6 alkyl)-NR46R47, —(C1-C6 alkyl)-O—(C1-C6 alkyl)-O—(C1-C6 alkyl), each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoroalkyl; a is selected from 0 to 6; b is selected from 0 to 6; c is selected from 2 to 6; R5 is selected from the group consisting of H, C1-C6 alkyl, —(CH2)d—C(═O)—NR53R54, —C(═O)—(CH2)d—NR53R54, —C(═O)—X—R55, and —C(═O)—(CH2)d—NR53R54; R53 and R54 are independently selected from the group consisting of H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, —(C1-C6 alkyl)-O—(C1-C6 alkyl), —(C1-C6 alkyl)-NR56R57, —(C1-C6 alkyl)-C(═O)NR56R57, aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; or R53 and R54 may be taken together to form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C3-C7 cycloalkyl, oxo, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; R55 is selected from the group consisting of H, aryl, —(C1-C6 alkyl)-O—(C1-C6 alkyl), —(C1-C6 alkyl)-NR56R57, —CO2R58, —O—(CH2)e—CO2R58, and —C(═O)NR56R57, R56 and R57 independently selected from the group consisting of H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, —(C1-C6 alkyl)-O—(C1-C6 alkyl), aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; or R56 and R57 may be taken together to form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, oxo, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; R58 is selected from the group consisting of H, aryl, aralkyl, heteroaryl, C1-C6 alkyl, —(C1-C6 alkyl)-O—(C1-C6 alkyl), —(C1-C6 alkyl)-NR56R57, —(C1-C6 alkyl)-O—(C1-C6 alkyl)-O—(C1-C6 alkyl), each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoroalkyl; d is selected from 0 to 6; e is selected from 0 to 6; R6 is selected from the group consisting of H, C1-C6 alkyl, —(CH2)r—C(═O)—NR63R64, —C(═O)—(CH2)r—NR63R64, —C(═O)—X—R65, and —C(═O)—(CH2)r—NR63R64; R63 and R64 are independently selected from the group consisting of H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, —(C1-C6 alkyl)-O—(C1-C6 alkyl), —(C1-C6 alkyl)-NR66R67, —(C1-C6 alkyl)-C(═O)NR66R67, aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; or R63 and R64 may be taken together to form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C3-C7 cycloalkyl, oxo, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; R65 is selected from the group consisting of H, aryl, —(C1-C6 alkyl)-O—(C1-C6 alkyl), —(C1-C6 alkyl)-NR66R67, —CO2R, —O—(CH2), —CO2RbS, and —C(═O)NR66R67, R66 and R67 independently selected from the group consisting of H, C1-C5 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, —(C1-C6 alkyl)-O—(C1-C6 alkyl), aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; or R66 and R67 may be taken together to form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, oxo, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; R68 is selected from the group consisting of H, aryl, aralkyl, heteroaryl, C1-C6 alkyl, —(C1-C6 alkyl)-O—(C1-C6 alkyl), —(C1-C6 alkyl)-NR66R67, —(C1-C6 alkyl)-O—(C1-C6 alkyl)-O—(C1-C6 alkyl), each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoroalkyl; r is selected from 0 to 6; s is selected from 0 to 6; n is selected from 0 to 4; m is selected from 0 to 3; and p is selected from 0 and 1. 2. The method according to claim 1, wherein the compound has the formula XXXII: or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, n and m are as for the compound of the formula XXXI. 3. The method according to claim 1, wherein the compound has the formula XXXIV: or a pharmaceutically acceptable salt thereof, wherein: R13 and R14 are independently selected from the group consisting of H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, —(C1-C6 alkyl)-O—(C1-C6 alkyl), —(C1-C6 alkyl)-NR16R17, —(C1-C6 alkyl)-C(═O)NR16R17, aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; or R13 and R14 may be taken together to form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C3-C7 cycloalkyl, oxo, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; X is selected from a covalent bond, O, NH, and C1-C6 alkyl; R16 and R17 are independently selected from the group consisting of H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, —(C1-C6 alkyl)-O—(C1-C6 alkyl), aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; or R16 and R17 may be taken together to form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, oxo, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; each R2 is independently selected from the group consisting of lower alkyl, CN, halo, hydroxy, lower alkoxy, amino, and perfluoro lower alkyl; each R3 is independently selected from the group consisting of lower alkyl, CN, halo, hydroxy, lower alkoxy, amino, and perfluoro lower alkyl; n is selected from 0 to 4; and m is selected from 0 to 3. 4. The method according to claim 1, wherein the compound has formula XXXIVa: or a pharmaceutically acceptable salt thereof, wherein: R13 and R14 are independently selected from the group consisting of H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, —(C1-C6 alkyl)-O—(C1-C6 alkyl), —(C1-C6 alkyl)-NR16R17, —(C1-C6 alkyl)-C(═O)NR16R17, aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; or R13 and R14 may be taken together to form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, oxo, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; R16 and R17 are independently selected from the group consisting of H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, —(C1-C6 alkyl)-O—(C1-C6 alkyl), aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; or R16 and R17 may be taken together to form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, oxo, hydroxy, amino, cyano and C1-C3 perfluoro alkyl. 5. The method according to claim 1, wherein the compound has of the formula: or a pharmaceutically acceptable salt thereof. 6. The method according to claim 1, wherein autoimmune disorder is psoriasis. 7. The method according to claim 1, wherein autoimmune disorder is graft-versus-host disease (GVHD). 8. The method according to claim 5, wherein autoimmune disorder is psoriasis. 9. The method according to claim 5, wherein autoimmune disorder is graft-versus-host disease (GVHD).