6-AMINOPYRIDIN-3-YL THIAZOLES AS MODULATORS OF RORyT

Abstract

The present invention comprises compounds of Formula I. wherein: A 1 , A 2 , A 3 , A 4 , A 5 , R 1 , and R 2 are defined in the specification. The invention also comprises a method of treating or ameliorating a syndrome, disorder or disease, wherein the syndrome, disorder or disease is rheumatoid arthritis or psoriasis. The invention also comprises a method of modulating RORγt activity in a mammal by administration of a therapeutically effective amount of at least one compound of Formula I.

We claim: 
     
         1 . A compound of Formula I. 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is H, —C (1-3) alkyl, —CHF 2 , —CF 3 , —CN, —OCH 3 , —OCH 2 CH 3 , cyclopropyl, OCF 3 , or OCHF 2 ; 
         R 2  is H, F, —CHF 2 , —CF 3 , —CN, —OCH 3 , —OCHF 2 , or OCF 3 ; provided that R 2  may not be H if R 1  is H; 
         A 1  and A 2  are taken together with their attached nitrogen to form 
       
       
         
           
           
               
               
           
         
         A 3  is H, —C (1-6) alkyl, 
       
       
         
           
           
               
               
           
         
       
       —SO 2 CH(CH 3 ) 2 , —SO 2 CH 3 , 
       
         
           
           
               
               
           
         
       
       wherein said —C (1-6) alkyl is optionally substituted with one —NH 2  group, one or two —OH groups, and may be additionally substituted with up to six fluorine atoms;
 A 4  is —H, or —CH 3 ; 
 A 5  is —C (4-6) cycloalkyl, —C (1-6) alkyl, 
 
       
         
           
           
               
               
           
         
       
       wherein said —C (1-6) alkyl and —C (4-6) cycloalkyl are optionally substituted with up to three fluorine atoms; and said —C (1-6) alkyl is independently optionally substituted with one cyclobutyl, or up to two cyclopropyl groups;
 and pharmaceutically acceptable salts thereof. 
 
     
     
         2 . The compound of  claim 1  wherein:
 A 5  is —C (4-6) cycloalkyl, —C (3-6) alkyl, 
 
       
         
           
           
               
               
           
         
       
       wherein said —C (3-6) alkyl and —C (4-6) cycloalkyl are optionally substituted with up to three fluorine atoms;
 and pharmaceutically acceptable salts thereof. 
 
     
     
         3 . The compound of  claim 2  wherein:
 R 1  is H, —C (1-3) alkyl, —CHF 2 , —CF 3 , —CN, —OCH 3 , —OCH 2 CH 3 , or cyclopropyl; 
 R 2  is H, F, —CHF 2 , —CF 3 , —CN, —OCH 3 , or —OCHF 2 ; provided that R 2  may not be H if R 1  is H; 
 and pharmaceutically acceptable salts thereof. 
 
     
     
         4 . The compound of  claim 3  selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         and pharmaceutically acceptable salts thereof. 
       
     
     
         5 . The compound of  claim 3  selected from the group consisting of: 
       
         
           
           
               
               
           
         
         and pharmaceutically acceptable salts thereof. 
       
     
     
         6 . The compound of  claim 3  selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         and pharmaceutically acceptable salts thereof. 
       
     
     
         7 . The compound of  claim 3  selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         8 . A pharmaceutical composition, comprising a compound of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         9 . A method for treating or ameliorating a RORγt mediated inflammatory syndrome, disorder or disease selected from the group consisting of: inflammatory bowel diseases, rheumatoid arthritis, psoriasis, chronic obstructive pulmonary disorder, psoriatic arthritis, ankylosing spondylitis, neutrophilic asthma, steroid resistant asthma, multiple sclerosis, and systemic lupus erythematosus, comprising administering to a subject in need thereof an effective amount of a compound of  claim 1 . 
     
     
         10 . A method for treating or ameliorating a RORγt mediated inflammatory syndrome, disorder or disease selected from the group consisting of: depression and metabolic syndrome, comprising administering to a subject in need thereof an effective amount of a compound of  claim 1 . 
     
     
         11 . The method of  claim 9 , wherein the disease is psoriasis. 
     
     
         12 . The method of  claim 9 , wherein the disease is rheumatoid arthritis. 
     
     
         13 . The method of  claim 9 , wherein the inflammatory bowel disease is ulcerative colitis. 
     
     
         14 . The method of  claim 9 , wherein the inflammatory bowel disease is Crohn's disease. 
     
     
         15 . The method of  claim 9 , wherein the disease is multiple sclerosis. 
     
     
         16 . The method of  claim 9 , wherein the disease is neutrophilic asthma. 
     
     
         17 . The method of  claim 9 , wherein the disease is steroid resistant asthma. 
     
     
         18 . The method of  claim 9 , wherein the disease is psoriatic arthritis. 
     
     
         19 . The method of  claim 9 , wherein the disease is ankylosing spondylitis. 
     
     
         20 . The method of  claim 9 , wherein the disease is systemic lupus erythematosus. 
     
     
         21 . The method of  claim 9 , wherein the disease is chronic obstructive pulmonary disorder. 
     
     
         22 . The method of  claim 10 , wherein the disease is depression. 
     
     
         23 . The method of  claim 10 , wherein the disease is metabolic syndrome. 
     
     
         24 . A method of inhibiting production of interleukin-17, comprising administering to a subject in need thereof an effective amount of a compound of  claim 1 .