Amino-quinolines as kinase inhibitors

Abstract

Disclosed are compounds having the formula: wherein R 1 , R 2 , R 3 and Z are as defined herein, and methods of making and using the same.

What is claimed is: 
     
         1 . A method of treating a disease mediated by RIP2 kinase comprising administering a therapeutically effective amount of a compound according to Formula (I) or a salt thereof, or a hydrate thereof, 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is H, —SO 2 (C 1 -C 4 alkyl), —CO(C 1 -C 4 alkyl), or (C 1 -C 4 alkyl); 
         R 2  is —SOR a  or —SO 2 R a , wherein R a  is an optionally substituted (C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, 4-7 membered heterocycloalkyl, aryl, or heteroaryl group, wherein:
 said (C 1 -C 6 )alkyl is optionally substituted by one or two groups each independently selected from the group consisting of cyano, hydroxyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxy(C 2 -C 6 )alkoxy, —CO 2 H, —CO 2 (C 1 -C 4 )alkyl, —SO 2 (C 1 -C 4  alkyl), —CONH 2 , —CONH(C 1 -C 4  alkyl), —CON(C 1 -C 4 alkyl)(C 1 -C 4 alkyl), —SO 2 NH 2 , —SO 2 NH(C 1 -C 4 alkyl), —SO 2 N(C 1 -C 4  alkyl)(C 1 -C 4  alkyl), amino, (C 1 -C 4  alkyl)amino-, (C 1 -C 4  alkyl)(C 1 -C 4  alkyl)amino-, C 3 -C 7 cycloalkyl, phenyl, 5-6 membered heteroaryl, 9-10 membered heteroaryl, 4-7 membered heterocycloalkyl and (phenyl)(C 1 -C 4  alkyl)amino-, wherein said C 3 -C 7 cycloalkyl, phenyl, (phenyl)(C 1 -C 4  alkyl)amino-, 5-6 membered heteroaryl, 9-10 membered heteroaryl or 4-7 membered heterocycloalkyl is optionally substituted by 1-3 groups each independently selected from the group consisting of halogen, —CF 3 , (C 1 -C 4 )alkyl, hydroxy(C 1 -C 4 )alkyl and (C 1 -C 4 )alkoxy, 
 said (C 3 -C 7 )cycloalkyl or 4-7 membered heterocycloalkyl is optionally substituted by 1-3 groups each independently selected from the group consisting of halogen, —CF 3 , hydroxyl, amino, (C 1 -C 4 )alkyl, phenyl(C 1 -C 4 )alkyl-, hydroxy(C 1 -C 4 )alkyl-, oxo, and (C 1 -C 4 )alkoxy, and 
 said aryl or heteroaryl is optionally substituted by 1-3 groups each independently selected from the group consisting of halogen, —CF 3 , hydroxyl, amino, (C 1 -C 4 )alkyl, phenyl(C 1 -C 4 )alkyl-, hydroxy(C 1 -C 4 )alkyl- and (C 1 -C 4 )alkoxy, 
 and wherein said heteroaryl is a 5-6 membered heteroaryl or a 9-10 membered heteroaryl, and any of said 4-7 membered heterocycloalkyl contains one heteroatom selected from the group consisting of N, O and S, any of said 5-6 membered heteroaryl contains one heteroatom selected from the group consisting of N, O and S and optionally further containing one or two nitrogen atoms, and any of said 9-10 membered heteroaryl contains one heteroatom selected from the group consisting of N, O and S and optionally further containing 1, 2 or 3 nitrogen atoms; 
 R 3  is halogen, hydroxy, (C 1 -C 4 )alkoxy-, halo(C 1 -C 4 )alkyl-, halo(C 1 -C 4 )alkoxy-, (C 1 -C 4 )alkoxy(C 1 -C 6 )alkyl-, halo(C 1 -C 4 )alkoxy(C 1 -C 6 )alkyl-, (C 1 -C 4 )alkoxy(C 2 -C 6 )alkoxy-, halo(C 1 -C 4 )alkoxy(C 2 -C 6 )alkoxy-, hydroxy(C 1 -C 4 )alkyl-, hydroxy(C 2 -C 6 )alkoxy-, cyano(C 1 -C 4 )alkyl-, cyano(C 2 -C 6 )alkoxy-, or (C 3 -C 6 )cycloalkoxy-, wherein the halo(C 1 -C 4 )alkyl-, halo(C 1 -C 4 )alkoxy-, halo(C 1 -C 4 )alkoxy(C 1 -C 6 )alkyl-, or halo(C 1 -C 4 )alkoxy(C 2 -C 6 )alkoxy- contains 2 or 3 halo atoms and wherein the (C 3 -C 6 )cycloalkyl moiety of the (C 3 -C 6 )cycloalkoxy- group, is optionally substituted by a group selected from the group consisting of cyano, halo, hydroxyl, (C 1 -C 6 )alkoxy and (C 1 -C 4 )alkoxy(C 2 -C 6 )alkoxy; 
 
       
       
         
           
           
               
               
           
         
         
           Z is pyrazolyl, having the formula: wherein: 
           R 12  is methyl or trifluoromethyl; 
           R 13  is H, methyl, or trifluoromethyl; 
           R 14  is H or (C 1 -C 3 )alkyl; or 
           R 12  and R 13 , taken together with the atoms to which they are attached, form a 6 membered carbocyclic ring or heterocyclic ring substituted by R 15  and R 16 , wherein the heterocyclic ring contains 1 nitrogen atom; 
           wherein R 15  and R 16  are each independently selected from the group consisting of H, halogen, cyano, (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, phenoxy, phenyl(C 1 -C 4 )alkoxy, hydroxyl, hydroxy(C 1 -C 4 )alkyl-, and aminocarbonyl, wherein the phenyl moiety of said phenoxy or phenyl(C 1 -C 4 )alkoxy is optionally substituted by 1-3 substituents each independently selected from the group consisting of halogen, —CF 3 , (C 1 -C 4 )alkyl and (C 1 -C 4 )alkoxy, 
           to a human in need thereof, wherein the disease is selected from uveitis, dermatitis, acute lung injury, type 2 diabetes mellitus, arthritis, rheumatoid arthritis, ulcerative colitis, Crohn's disease, early-onset inflammatory bowel disease, extraintestinal inflammatory bowel disease, prevention of ischemia reperfusion injury in solid organ transplant, non-alcohol steatohepatitis, autoimmune hepatitis, asthma, systemic lupus erythematosus, multiple sclerosis, sarcoidosis, Blau syndrome/early-onset sarcoidosis, Wegner's granulomatosis, and interstitial pulmonary disease. 
         
       
     
     
         2 . The method according to  claim 1 , wherein the disease is selected from uveitis, Blau Syndrome, early-onset sarcoidosis, ulcerative colitis, Crohn's disease, Wegener's granulamatosis and sarcoidosis. 
     
     
         3 . The method according to  claim 1 , wherein the disease is Crohn's disease. 
     
     
         4 . The method according to  claim 1 , wherein the disease is ulcerative colitis. 
     
     
         5 . The method according to  claim 1 , wherein the disease is Blau syndrome. 
     
     
         6 . The method according to  claim 1 , wherein the disease is rheumatoid arthritis. 
     
     
         7 . The method according to  claim 1 , wherein the compound is a pharmaceutically acceptable salt of said compound. 
     
     
         8 . The method according to  claim 1 , wherein R′ is H. 
     
     
         9 . The method according to  claim 1 , wherein R 2  is —SO 2 R a . 
     
     
         10 . The method according to  claim 1 , wherein the compound is: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof.