PHENYL AND PYRIDINYL SUBSTITUTED IMIDAZOLES AS MODULATORS OF RORgT

Abstract

The present invention comprises compounds of Formula I. wherein: R 1 , R 2 , R 3 , R 4 , R 5 , R a , R b , Q 1 , and Q 2 are defined in the specification. The invention also comprises a method of treating or ameliorating a ROR-γ-t mediated syndrome, disorder or disease, including wherein the syndrome, disorder or disease is selected from the group consisting of rheumatoid arthritis, psoriatic arthritis, and 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 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 Formula I 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is —C (1-4)  alkyl, —NH 2 , —NHC (1-4)  alkyl, —N(C (1-4)  alkyl) 2 , —NHC(O)NH 2 , NHC(O)C (1-4)  alkyl, —NHC(O)H, or —NHC(O)NHC (1-4)  alkyl; 
 R 2  is H, —OH, or —NH 2 ; 
 R 3  is —H, —OH, —CN, —NH 2 , —CONH 2 , —CO 2 H, —CO 2 C (1-4)  alkyl, —CH 2 OH, —CH 2 NH 2 , —CH 2 CN, —NHC (1-4)  alkyl, or —CONHC (1-4)  alkyl; 
 R 4  is —H, —Cl, —C (1-4)  alkyl, —F, —CN, —C(O)NH 2 , or 
 
       
         
           
           
               
               
           
         
       
       wherein said —C (1-4)  alkyl is optionally substituted with up to six fluorine atoms;
 R 5  is —C (1-4)  alkyl, wherein said —C (1-4)  alkyl is optionally substituted with —CN, —OH, —OCH 3 , —OCF 3 , or up to six fluorine atoms; 
 Q 1  is N or CR c ; 
 Q 2  is N or CH; provided that Q 2  is not N if Q 1  is N; 
 R a  is —F, —Cl, —OCD 3 , —CN, —OC (1-3)  alkyl, or —C (1-3)  alkyl, wherein said —C (1-3)  alkyl and said OC (1-3)  alkyl are optionally substituted with up to three fluorine atoms; 
 R b  is —NA 1 A 2 , —C (3-6)  alkyl, or —OC (1-3)  alkyl, wherein said —C (3-6)  alkyl is optionally substituted with —OH or oxo, and the —C (3-6)  alkyl may additionally be substituted with up to six fluorine atoms, and said —OC (1-3)  alkyl is optionally substituted with up to three fluorine atoms; 
 R c  is —H, —OCH 3 , —F, —CH 3 , —CF 3 , —OCF 3 , or —Cl; 
 A 1  is —C (2-3)  alkyl, wherein said —C (2-3)  alkyl is optionally substituted with up to six fluorine atoms; 
 A 2  is H, or A 1  and A 2  are taken together with their attached nitrogen to form 
 
       
         
           
           
               
               
           
         
       
       and pharmaceutically acceptable salts thereof. 
     
     
         2 . The method of  claim 1 , wherein the disease is selected from the group consisting of: depression and metabolic syndrome. 
     
     
         3 . The method of  claim 1 , wherein the disease is psoriasis. 
     
     
         4 . The method of  claim 1 , wherein the disease is rheumatoid arthritis. 
     
     
         5 . The method of  claim 1 , wherein the inflammatory bowel disease is ulcerative colitis. 
     
     
         6 . The method of  claim 1 , wherein the inflammatory bowel disease is Crohn's disease. 
     
     
         7 . The method of  claim 1 , wherein the disease is multiple sclerosis. 
     
     
         8 . The method of  claim 1 , wherein the disease is neutrophilic asthma. 
     
     
         9 . The method of  claim 1 , wherein the disease is steroid resistant asthma. 
     
     
         10 . The method of  claim 1 , wherein the disease is psoriatic arthritis. 
     
     
         11 . The method of  claim 1 , wherein the disease is ankylosing spondylitis. 
     
     
         12 . The method of  claim 1 , wherein the disease is systemic lupus erythematosus. 
     
     
         13 . The method of  claim 1 , wherein the disease is chronic obstructive pulmonary disorder. 
     
     
         14 . The method of  claim 2 , wherein the disease is depression. 
     
     
         15 . The method of  claim 2 , wherein the disease is metabolic syndrome. 
     
     
         16 . A method of inhibiting production of interleukin-17, comprising administering to a subject in need thereof an effective amount of a compound of Formula I 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is —C (1-4)  alkyl, —NH 2 , —NHC (1-4)  alkyl, —N(C (1-4)  alkyl) 2 , —NHC(O)NH 2 , NHC(O)C (1-4)  alkyl, —NHC(O)H, or —NHC(O)NHC (1-4)  alkyl; 
 R 2  is H, —OH, or —NH 2 ; 
 R 3  is —H, —OH, —CN, —NH 2 , —CONH 2 , —CO 2 H, —CO 2 C (1-4)  alkyl, —CH 2 OH, —CH 2 NH 2 , —CH 2 CN, —NHC (1-4)  alkyl, or —CONHC (1-4)  alkyl; 
 R 4  is —H, —Cl, —C (1-4)  alkyl, —F, —CN, —C(O)NH 2 , or 
 
       
         
           
           
               
               
           
         
       
       wherein said —C (1-4)  alkyl is optionally substituted with up to six fluorine atoms;
 R 5  is —C (1-4)  alkyl, wherein said —C (1-4)  alkyl is optionally substituted with —CN, —OH, —OCH 3 , —OCF 3 , or up to six fluorine atoms; 
 Q 1  is N or CR c ; 
 Q 2  is N or CH; provided that Q 2  is not N if Q 1  is N; 
 R a  is —F, —Cl, —OCD 3 , —CN, —OC (1-3)  alkyl, or —C (1-3)  alkyl, wherein said —C (1-3)  alkyl and said OC (1-3)  alkyl are optionally substituted with up to three fluorine atoms; 
 R b  is —NA 1 A 2 , —C (3-6)  alkyl, or —OC (1-3)  alkyl, wherein said —C (3-6)  alkyl is optionally substituted with —OH or oxo, and the —C (3-6)  alkyl may additionally be substituted with up to six fluorine atoms, and said —OC (1-3)  alkyl is optionally substituted with up to three fluorine atoms; 
 R is —H, —OCH 3 , —F, —CH 3 , —CF 3 , —OCF 3 , or —Cl; 
 A 1  is —C (2-3)  alkyl, wherein said —C (2-3)  alkyl is optionally substituted with up to six fluorine atoms; 
 A 2  is H, or A 1  and A 2  are taken together with their attached nitrogen to form 
 
       
         
           
           
               
               
           
         
       
       and pharmaceutically acceptable salts thereof.