Amide compounds as kinase inhibitors, compositions and methods of treatment

Abstract

The present disclosure relates to certain amides and heterocyclic compounds and uses of these amides and heterocyclic compounds to inhibit Rho-associated protein kinases and treat diseases including autoimmune disorders, graft versus host disease (GVHD), inflammation, cardiovascular disorders, central nervous system disorders, and neoplastic disorders.

1 - 20 . (canceled) 
     
     
         21 . A compound of Formula (I): 
       
         
           
           
               
               
           
         
       
       wherein:
 Z 1  is pyrazole optionally substituted with one or more of the following: halo, —OH, —CN, —COOR′, —OR′, —SR′, —OC(O)R′, —NHR′, —NR′R″, —NHC(O)R′, —NHC(O)NR′R″, —C(O)NR′R″, —NS(O) 2 R′, —S(O) 2 NR′R″, —S(O) 2 R′, guanidino, nitro, nitroso, —C1-C6 alkyl, aryl, or —C3-C7 cycloalkyl; 
 Z 2  is phenyl, pyridine, or pyrazole, wherein the phenyl, pyridine, or pyrazole is optionally substituted with, H, halo, —OH, —CN, —COOR′, —OR′, —OR′OR″, —O(CH 2 ) 2 NR′R″, —SR′, —OC(O)R′, —NHR′, —NR′R″, —NHC(O)R′, —NHC(O)NR′R″, —C(O)NR′R″, —NS(O) 2 R′, —S(O) 2 NR′R″, —S(O) 2 R′, guanidino, nitro, nitroso, —C1-C6 alkyl, aryl, —C3-C7 cycloalkyl, or a 3- to 10-membered heterocycle, and wherein the —C1-C6 alkyl, aryl, —C3-C7 cycloalkyl, or 3- to 10-membered heterocycle is optionally substituted with one or more of the following: halo, —OH, —CN, —COOR′, —OR′, —SR′, —OC(O)R′, —NHR′, —NR′R″, —NHC(O)R′, —NHC(O)NR′R″, —C(O)NR′R″, —NS(O) 2 R′, —S(O) 2 NR′R″, —S(O) 2 R′, guanidino, nitro, nitroso, —C1-C6 alkyl, aryl, or —C3-C7 cycloalkyl, and wherein the R′ or R″ are independently —H, methyl or ethyl; 
 R 1  is H, —C1-C6 alkyl or —C3-C7 cycloalkyl, wherein the —C1-C6 alkyl or —C3-C7 cycloalkyl is optionally substituted with one or more of the following: halo, —OH, —CN, —COOR′, —OR′, —SR′, —OC(O)R′, —NHR′, —NR′R″, —NHC(O)R′, —NHC(O)NR′R″, —C(O)NR′R″, —NS(O) 2 R′, —S(O) 2 NR′R″, or —S(O) 2 R′; 
 R is methyl; 
 X is a bond or —OR 4 , wherein R 4  is H, —C1-C6 alkyl or —C3-C7 cycloalkyl; 
 R 2  and R 3  are independently H, —C1-C6 alkyl, —C3-C7 cycloalkyl, aryl, C5-C10 membered heterocycle, 
 
       
         
           
           
               
               
           
         
       
       wherein
 the —C1-C6 alkyl, —C3-C7 cycloalkyl, aryl, C5-C10 membered heterocycle is optionally substituted with halo, —OH, —CN, —COOR′, —OR′, —SR′, —OC(O)R′, —NHR′, —NR′R″, —CNR′R″, —NHC(O)R′, —NHC(O)NR′R″, —C(O)NR′R″, —NS(O) 2 R′, —S(O) 2 NR′R″, —S(O) 2 R′, guanidino, nitro, nitroso, —C1-C6 alkyl, aryl, —C3-C7 cycloalkyl, or 3- to 11-membered heterocycle, wherein 
 the —C1-C6 alkyl, aryl, —C3-C7 cycloalkyl, or 3- to 11-membered heterocycle is optionally substituted with one or more of the following: halo, —OH, —CN, —COOR′, —CH 2 NR′R″, —OR′, —OR′R″, —SR′, —OC(O)R′, —NHR′, —NR′R″, —NHC(O)R′, —NHC(O)NR′R″, —C(O)NR′R″, —NS(O) 2 R′, —S(O) 2 NR′R″, —S(O) 2 R′, guanidino, nitro, nitroso, —C1-C6 alkyl, aryl, —C3-C7 cycloalkyl, and wherein 
 R 5  is —C1-C6 alkyl, —OCH 2 CH 2 —, —NR 6 CH 2 CH 2 —, —NC(O)CH 2 CH 2 —; R 6  is H, —C1-C6 alkyl or —C3-C7 cycloalkyl; and 
 R′ or R″ is independently —H or —C1-C6 alkyl, or R′ and R″ together, optionally attaching to N or O atom, form a 4- to 8-membered cyclic structure. 
 
     
     
         22 . The compound of  claim 21 , wherein Z 2  is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         23 . The compound of  claim 21 , wherein R 1  is H, unsubstituted methyl, methoxyethyl or dimethylaminoethyl. 
     
     
         24 . The compound of  claim 23 , wherein R 1  is H. 
     
     
         25 . The compound of  claim 24 , wherein R is methyl with R configuration. 
     
     
         26 . The compound of  claim 21 , wherein X is a bond. 
     
     
         27 . The compound of  claim 21 , wherein R 2  is H. 
     
     
         28 . The compound of  claim 27 , wherein R 3  is H, cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, cyclohexyl methyl, cyclopentyl methyl, cyclobutyl methyl, cyclopropyl methyl, phenyl, benzyl, pyrrolidine-3-yl, piperidine-4-yl, (pyrrolidine-3-yl)methyl, (piperidine-4-yl)methyl, 
       
         
           
           
               
               
           
         
       
       and wherein the cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, cyclohexyl methyl, cyclopentyl methyl, cyclobutyl methyl, cyclopropyl methyl phenyl, benzyl, pyrrolidine-3-yl, piperidine-4-yl, (pyrrolidine-3-yl)methyl or (piperidine-4-yl)methyl is optionally substituted with halo, —OH, —CN, —COOR′, —OR′, —SR′, —OC(O)R′, —NHR′, —NR′R″, —CNR′R″, —NHC(O)R′, —NHC(O)NR′R″, —C(O)NR′R″, —NS(O) 2 R′, —S(O) 2 NR′R″, —S(O) 2 R′, guanidino, nitro, nitroso, —C1-C6 alkyl, aryl, —C3-C7 cycloalkyl, or 3- to 11-membered heterocycle. 
     
     
         29 . The compound of  claim 27 , wherein R 3  is cyclopentyl or cyclohexyl. 
     
     
         30 . The compound of  claim 21 , wherein
 Z 2  is unsubstituted phenyl, unsubstituted pyridine, unsubstituted pyrazole, or phenyl substituted with halo, —OR′, —C1-C6 alkyl, —OR′OR″, —O(CH 2 ) 2 NR′R″, wherein the —C1-C6 alkyl is optionally substituted with one or more of —OR′ or NR′R″;   R 1  is H, unsubstituted methyl or dimethylamine;   X is a bond;   R 2  is H; and   R′ or R″ is independently —H, methyl or ethyl.   
     
     
         31 . The compound of  claim 21 , selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         32 . The compound of  claim 31 , consisting of 
       
         
           
           
               
               
           
         
       
     
     
         33 . A pharmaceutical composition, comprising the compound of  claim 21  and a pharmaceutically acceptable carrier. 
     
     
         34 . The pharmaceutical composition of  claim 33  for use in a method of inhibiting Rho-associated protein kinase activity in a subject. 
     
     
         35 . The method of  claim 34 , wherein the subject has a disease associated with Rho-associated protein kinase activity. 
     
     
         36 . The method of  claim 35 , wherein the disease associated with Rho-associated protein kinase activity is selected from the group consisting of: an arterial thrombotic disorder, cancer, a cardiovascular disease, a central nervous system disorder, glucose intolerance, a hematologic disease, a hematologic malignant neoplastic disorder, hyperinsulinemia, an infection, an inflammatory or autoimmune disease, insulin resistance, a metabolic syndrome, a neoplastic disease, a neurodegenerative disease, a neurodevelopmental disorder, an ocular disorder, osteoporosis, pulmonary arterial hypertension (PAH), type 2 diabetes, a vascular smooth muscle dysfunction, and combinations thereof. 
     
     
         37 . The method of  claim 36  wherein cancer is selected from the group consisting of: angioimmunoblastic T-cell lymphoma (AITL), breast cancer, cutaneous T-cell lymphoma (CTCL), hepatocellular cancer, gastric cancers, leukemia, lung cancer, lymphoma, multiple myeloma, ovarian cancer, pancreatic cancer, melanoma, amoeboid cancer cells, cancer characterized by amoeboid cancer cell migration, peripheral T-cell lymphoma (PTCL), prostate cancer, and renal cancer. 
     
     
         38 . The method of  claim 37 , wherein gastric cancer is RhoA-mutated gastric cancer. 
     
     
         39 . The method of  claim 35 , wherein the disease is selected from the group consisting of: gastric cancer, glaucoma, graft-versus-host disease (GVHD), melanoma, pancreatic cancer, primary myelofibrosis (MF), psoriasis, amoeboid cancer cells, cancer characterized by amoeboid cancer cell migration, liver fibrosis, and idiopathic pulmonary fibrosis. 
     
     
         40 . The method of  claim 35 , wherein the disease consists of RhoA-mutated gastric cancer, idiopathic pulmonary fibrosis, or both. 
     
     
         41 . The method of  claim 35 , wherein the disease is selected from the group consisting of: pulmonary arterial hypertension, amoeboid cancer cell, cancer characterized by amoeboid cancer cell migration, idiopathic pulmonary fibrosis, and primary myelofibrosis.