HETEROARYL LINKED QUINOLINYL MODULATORS OF RORyt

Abstract

The present invention comprises compounds of Formula I. wherein: R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 R 8 , and R 9 are defined in the specification. The invention also comprises a method of treating or ameliorating a syndrome, disorder or disease, wherein said 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 claim 1.

What is claimed is: 
     
         1 . A method for treating or ameliorating a RORγt mediated inflammatory syndrome, disorder or disease comprising administering to a subject in need thereof an effective amount of a compound of Formula I 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is azetidinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, pyridyl, pyridyl N-oxide, pyrazinyl, pyrimidinyl, pyridazyl, piperidinyl, tetrahydropyranyl, phenyl, oxazolyl, isoxazolyl, thiophenyl, benzoxazolyl, or quinolinyl; wherein said piperidinyl, pyridyl, pyridyl N-oxide, imidazolyl, phenyl, thiophenyl, benzoxazolyl, and pyrazolyl are optionally substituted with SO 2 CH 3 , C(O)CH 3 , C(O)NH 2 , CH 3 , CH 2 CH 3 , CF 3 , Cl, F, —CN, OCH 3 , N(CH 3 ) 2 , —(CH 2 ) 3 OCH 3 , SCH 3 , OH, CO 2 H, CO 2 C(CH 3 ) 3 , or OCH 2 OCH 3 ; and optionally substituted with up to two additional substituents independently selected from the group consisting of Cl, OCH 3 , and CH 3 ; and wherein said triazolyl, oxazolyl, isoxazolyl, and thiazolyl are optionally substituted with one or two CH 3  groups; and wherein said azetidinyl is optionally substituted with CO 2 C(CH 3 ) 3 , C(O)NH 2 , CH 3 , SO 2 CH 3 , or C(O)CH 3 ; 
 R 2  is 1-methyl-1,2,3-triazolyl, pyridyl, pyridyl-N-oxide, 1-methyl pyrazol-4-yl, pyrimidin-5-yl, pyridazyl, pyrazin-2-yl, oxazolyl, isoxazolyl, N-acetyl-azetidin-3-yl, N-methylsulfonyl-azetidin-3-yl, N-Boc-azetidin-3-yl, N-methyl-azetidin-3-yl, N-acetamidyl-azetidin-3-yl, N-acetyl piperidinyl, 1-H-piperidinyl, N-Boc-piperidinyl, N—C (1-2) alkyl-piperidinyl, thiazol-5-yl, 1-(3-methoxypropyl)-imidazol-5-yl, or 1-C (1-2) alkyl imidazol-5-yl; wherein said 1-C (1-2) alkyl imidazol-5-yl is optionally substituted with up to two additional CH 3  groups, or one substituent selected from the group consisting of SCH 3 , and Cl; and said pyridyl, and pyridyl-N-oxide are optionally substituted with up to two substituents independently selected from the group consisting of C(O)NH 2 , —CN, OCH 3 , CF 3 , Cl, and CH 3 ; and said thiazol-5-yl, oxazolyl, and isoxazolyl are optionally substituted with up to two CH 3  groups; and said 1-methyl pyrazol-4-yl is optionally substituted with up to two additional CH 3  groups; 
 R 3  is H, OH, OCH 3 , NHCH 3 , N(CH 3 ) 2  or NH 2 ; 
 R 4  is H, or F; 
 R 5  is H, Cl, —CN, CF 3 , SCH 3 , OC (1-3) alkyl, OH, C (1-4) alkyl, N(CH 3 )OCH 3 , NH(C (1-2) alkyl), N(C (1-2) alkyl) 2 , NH-cyclopropyl, OCHF 2 , 4-hydroxy-piperidinyl, azetidin-1-yl, or fur-2-yl; 
 R 6  is —O-phenyl, —NHphenyl, —N(C (1-3) alkyl)phenyl, —N(CO 2 C(CH 3 ) 3 )phenyl, —O-pyridyl, —NHpyridyl, —N(C (1-3) alkyl)pyridyl, or —N(CO 2 C(CH 3 ) 3 )pyridyl wherein said phenyl portions thereof or said pyridyl portions thereof are optionally substituted with OCF 3 , SO 2 CH 3 , CF 3 , CHF 2 , imidazol-1-yl, pyrazol-1-yl, 1,2,4-triazol-1-yl, CH 3 , OCH 3 , Cl, F, or —CN; 
 R 7  is H, Cl, —CN, C (1-4) alkyl, OCH 2 CF 3 , OCH 2 CH 2 OCH 3 , CF 3 , SCH 3 , SO 2 CH 3 , OCHF 2 , NA 1 A 2 , C(O)NHCH 3 , N(CH 3 )CH 2 CH 2 NA 1 A 2 , OCH 2 CH 2 NA 1 A 2 , OC (1-3) alkyl, OCH 2 -(1-methyl)-imidazol-2-yl, imidazol-2-yl, fur-2-yl, pyrazol-4-yl, pyrid-3-yl, or pyrimidin-5-yl; thiophen-3-yl, 1-methyl-indazol-5-yl, 1-methyl-indazol-6-yl, phenyl, or 
 
       
         
           
           
               
               
           
         
          wherein said imidazolyl or pyrazolyl can be optionally substituted with a CH 3  group; 
         A 1  is H or C (1-4) alkyl; 
         A 2  is H, C (1-4) alkyl, cyclopropyl, C (1-4) alkylOC (1-4) alkyl, C (1-4) alkylOH, C(O)C (1-2) alkyl, or OCH 3 ; or A 1  and A 2  may be taken together with their attached nitrogen to form a ring selected from the group consisting of: 
       
       
         
           
           
               
               
           
         
         R a  is H, F, OC (1-3) alkyl, or OH; 
         R b  is CH 3 , or phenyl; 
         R 8  is H, CH 3 , OCH 3 , or F; 
         R 9  is H, or F; 
       
       and pharmaceutically acceptable salts thereof. 
     
     
         2 . The method of  claim 1 , wherein the disease is 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. 
     
     
         3 . The method of  claim 2 , wherein the disease is psoriasis. 
     
     
         4 . The method of  claim 2 , wherein the disease is rheumatoid arthritis. 
     
     
         5 . The method of  claim 2 , wherein the inflammatory bowel disease is ulcerative colitis. 
     
     
         6 . The method of  claim 2 , wherein the inflammatory bowel disease is Crohn's disease. 
     
     
         7 . The method of  claim 2 , wherein the disease is multiple sclerosis. 
     
     
         8 . The method of  claim 2 , wherein the disease is neutrophilic asthma. 
     
     
         9 . The method of  claim 2 , wherein the disease is steroid resistant asthma. 
     
     
         10 . The method of  claim 2 , wherein the disease is psoriatic arthritis. 
     
     
         11 . The method of  claim 2 , wherein the disease is ankylosing spondylitis. 
     
     
         12 . The method of  claim 2 , wherein the disease is systemic lupus erythematosus. 
     
     
         13 . The method of  claim 2 , wherein the disease is chronic obstructive pulmonary disorder. 
     
     
         14 . A method of treating or ameliorating a syndrome, disorder or disease, in a subject in need thereof comprising administering to the subject an effective amount of a compound of  claim 1  or composition or medicament thereof in a combination therapy with one or more anti-inflammatory agents, or immunosuppressive agents, wherein said syndrome, disorder or disease is selected from the group consisting of: rheumatoid arthritis, and psoriasis. 
     
     
         15 . A method of  claim 1  wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       and pharmaceutically acceptable salts thereof. 
     
     
         16 . The method of  claim 15 , wherein the disease is 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. 
     
     
         17 . The method of  claim 16 , wherein the disease is psoriasis. 
     
     
         18 . The method of  claim 16 , wherein the disease is rheumatoid arthritis. 
     
     
         19 . The method of  claim 16 , wherein the inflammatory bowel disease is ulcerative colitis. 
     
     
         20 . The method of  claim 16 , wherein the inflammatory bowel disease is Crohn's disease. 
     
     
         21 . The method of  claim 16 , wherein the disease is multiple sclerosis. 
     
     
         22 . The method of  claim 16 , wherein the disease is neutrophilic asthma. 
     
     
         23 . The method of  claim 16 , wherein the disease is steroid resistant asthma. 
     
     
         24 . The method of  claim 16 , wherein the disease is psoriatic arthritis. 
     
     
         25 . The method of  claim 16 , wherein the disease is ankylosing spondylitis. 
     
     
         26 . The method of  claim 16 , wherein the disease is systemic lupus erythematosus. 
     
     
         27 . The method of  claim 16 , wherein the disease is chronic obstructive pulmonary disorder. 
     
     
         28 . A method of treating or ameliorating a syndrome, disorder or disease, in a subject in need thereof comprising administering to the subject an effective amount of a compound of  claim 15  or composition or medicament thereof in a combination therapy with one or more anti-inflammatory agents, or immunosuppressive agents, wherein said syndrome, disorder or disease is selected from the group consisting of: rheumatoid arthritis, and psoriasis.