Indazole and indole derivatives as inhibitors of retinoic acid related orphan receptor gamma (ror gamma) for the treatment of immune-related diseases

Abstract

The present invention provides compounds of formula (I), wherein A 1 , A 2 , Z 1 , Z 2 , Z 3 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , n, p and q are as defined herein. In certain embodiments, the compounds of the invention are RORγt antagonists. In other embodiments, the compounds of the invention are useful in the treatment and/or prevention of inflammatory and autoimmune conditions.

1 . A compound of formula (I): 
       
         
           
           
               
               
           
         
         wherein: 
         Z 1  is N; 
         Z 2  and Z 3  are each CH; 
         A 1  is phenyl or pyridyl; 
         R 1  is H or C 1-6  alkyl optionally substituted with one or more substituents selected from the group consisting of halo, OH, and phenyl, wherein the phenyl groups is optionally substituted with 1 to 3 substituents selected from the group consisting of OH, CN, NO 2 , halo, C 1-4  alkyl, and C 1-4  haloalkyl; 
         each R 2  is independently selected from the group consisting of halo, CN, NO 2 , OR 11 , NR 11 R 12 , and C 1-6  alkyl optionally substituted with one or more substituents selected from the group consisting of phenyl, halo, CN, NO 2 , OR 11 , and NR 11 R 12 ;
 wherein each R 11  and R 12  is independently selected from the group consisting of hydrogen, C 1-4  alkyl optionally substituted with one or more halo substituents, and C 3-8  cycloalkyl optionally substituted with one or more halo substituents; 
 
         n is 0, 1, 2, 3, and 4; 
         A 2  is phenyl or pyridyl; 
         each R 3  is independently selected from the group consisting of halo, CN, NO 2 , OH, OR 13 , NR 13 R 14 , C 1-6  alkyl, C 2-6  alkenyl, C 3-8  cycloalkyl, and C 5-7  heterocyclyl, wherein the alkyl, alkenyl, cycloalkyl, or heterocyclyl is independently optionally substituted with one or more substituents selected from the group consisting of phenyl, halo, CN, NO 2 , OH, OR 13 , and NR 13 R 14 ;
 wherein each R 13  and R 14  is independently selected from the group consisting of hydrogen, C 1-4  alkyl, C 3-8  cycloalkyl, and C 5-7  heterocyclyl, any of which is optionally substituted with one or more substituents selected from the group consisting of halo, C 1-4  alkoxy, and oxo, or R 13  and R 14  together with the nitrogen atom to which they are attached optionally form a 4-7 membered heterocyclic ring optionally containing one or more further heteroatoms selected from the group consisting of N, O, and S and optionally substituted with one or more substituents selected from the group consisting of halo, C 1-4  alkoxy and oxo; 
 
         p is 0, 1, 2, 3, 4, and 5; 
         each R 4  is independently the group consisting of R 15  and C 1-4  alkyl optionally substituted with one or more R 15 ;
 wherein R 15  is independently selected from the group consisting of halo, CN, NO 2 , OR 16 , C(═O)R 16 , C(═O)OR 16 , C(═O)NR 16 R 17 , SR 16 , S(═O)R 16 , SO 2 R 16 , NR 16 R 17 , and NR 18 C(═O)R 16 ; 
 wherein each R 16  and R 17  is independently selected from the group consisting of hydrogen, C 1-6  alkyl optionally substituted with one or more halo substituents, C 3-8  cycloalkyl, optionally substituted with one or more halo substituents, and C 5-7  heterocyclyl optionally substituted with one or more halo substituents; and 
 wherein R 18  is H or C 14  alkyl; 
 
         q is 0, 1, or 2; 
         each of R 5  and R 6  is H, or R 5  and R 6  together may form ═O when:
 A 1  is pyridyl; or 
 A 2  is pyridyl; or 
 R 3  is other than halogen, C 1-6  alkyl optionally substituted with halo or C 3-8  cycloalkyl; or 
 R 2  is other than halo or OH; 
 
         or a pharmaceutically or veterinarily acceptable salt, solvate, stereoisomer, or hydrate thereof or a deuterated or tritiated variant thereof. 
       
     
     
         2 - 3 . (canceled) 
     
     
         4 . The compound of  claim 1 , wherein in the A 1  ring the group C(═O)OR 1  is positioned at the meta or para position of the ring relative to the remainder of the molecule. 
     
     
         5 . The compound of  claim 4  wherein:
 A 1  is phenyl and the group C(═O)OR 1  is at the 4-position of the ring; or 
 A 1  is 2-pyridyl and the C(═O)OR 1  group is at the 5-position of the pyridyl ring; or 
 A 1  is 3-pyridyl and the C(═O)OR 1  group is at the 6-position of the pyridyl ring. 
 
     
     
         6 . The compound of  claim 1 , wherein A 2  is phenyl or 4-pyridyl. 
     
     
         7 . The compound of  claim 1 , which is a compound of formula (IA), in which both A 1  and A 2  are phenyl: 
       
         
           
           
               
               
           
         
         wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , Z 1 , Z 2 , Z 3 , n, and q are as defined in  claim 1 . 
       
     
     
         8 . The compound of  claim 1 , wherein R 1  is H, C 1-6  alkyl or benzyl. 
     
     
         9 . The compound of  claim 1 , wherein n is 0, 1, or 2 and R 2 , when present is chloro, fluoro, methyl, or trifluoromethyl; or wherein n is 0, 1, or 2 and R 2 , when present, is OH. 
     
     
         10 . The compound of  claim 1 , wherein n is 0 or 1. 
     
     
         11 . The compound of  claim 1 , wherein each R 3  is independently selected from the group consisting of halo, CN, NO 2 , OH, NR 12 R 13  and C 1-4  alkyl optionally substituted with one or more substituents selected from the group consisting of phenyl, halo, CN, NO 2 , OH, and NR 12 R 13 ;
 wherein each R 12  and R 13  is independently selected from the group consisting of hydrogen, C 1-2  alkyl optionally substituted with one or more halo substituents, and C 3-7  cycloalkyl optionally substituted with one or more halo substituents.   
     
     
         12 . The compound of  claim 1 , wherein p is 2, one of the R 3  groups is halo and the other is trifluoromethyl. 
     
     
         13 . The compound of  claim 1 , wherein:
 A 1  is phenyl and A 2  is phenyl, p is 2, and the substituents R 3  are positioned at the 2- and 6-positions of the phenyl ring; or   A 1  is phenyl and A 2  is 4-pyridyl, p is 2, and the substituents R 3  are positioned at the 2- and 6-positions of the pyridyl ring; or   A 1  is 2-pyridyl wherein the C(═O)OR 1  group is at the 5-position of the pyridyl ring or 3 pyridyl wherein the C(═O)OR 1  group is at the 6-position of the pyridine ring; and A 2  is phenyl, p is 2, and the substituents R 3  are positioned at the 2- and 6-positions of the phenyl ring.   
     
     
         14 . The compound of  claim 1 , wherein R 4  is chloro or fluoro and q is 1; or wherein q is 0 and R 4  is not present. 
     
     
         15 . (canceled) 
     
     
         16 . A compound of  claim 1 , which is selected from the group consisting of:
 5-[3-(2,6-dichlorobenzoyl)indazol-1-yl]pyridine-2-carboxylic acid (Compound 15);   6-[3-(2,6-dichlorobenzoyl)indazol-1-yl]pyridine-3-carboxylic acid (Compound 16);   6-[3-[(2,6-dichlorophenyl)methyl]indazol-1-yl]pyridine-3-carboxylic acid (Compound 17);   4-[3-[[2-chloro-6-(trifluoromethyl)phenyl]methyl]indazol-1-yl]benzoic acid (Compound 18);   5-[3-[2-chloro-6-(trifluoromethyl)benzoyl]indazol-1-yl]pyridine-2-carboxylic acid (Compound 25);   6-[3-[2-chloro-6-(trifluoromethyl)benzoyl]indazol-1-yl]pyridine-3-carboxylic acid (Compound 26);   6-(3-{[2-chloro-6-(trifluoromethyl)phenyl]methyl}indazol-1-yl)pyridine-3-carboxylic acid (Compound 30);   5-(3-{[2-chloro-6-(trifluoromethyl)phenyl]methyl}indazol-1-yl)pyridine-2-carboxylic acid (Compound 33);   6-{3-[2-chloro-6-(trifluoromethyl)benzoyl]-7-fluoroindazol-1-yl}pyridine-3-carboxylic acid (Compound 35);   C 1-6  alkyl and benzyl esters thereof; and any pharmaceutically or veterinarily acceptable salts or free acids, solvates, hydrates, any deuterated or tritiated variants thereof, and stereoisomers thereof.   
     
     
         17 - 20 . (canceled) 
     
     
         21 . A method of treating an inflammatory or autoimmune disease, the method comprising administering to a patient in need of such treatment an effective amount of at least one compound of  claim 1 . 
     
     
         22 . The method of  claim 22 , wherein the inflammatory or autoimmune disease is selected from the group consisting of asthma, chronic obstructive pulmonary disease (COPD), bronchitis, an allergic disease, cystic fibrosis, lung allograft rejection, multiple sclerosis, rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, systemic lupus erythematosus, psoriasis, Hashimoto's disease, pancreatitis, autoimmune diabetes, autoimmune ocular disease, ulcerative colitis, Crohn's disease, inflammatory bowel disease (IBD), Sjorgen's syndrome, Behcet's disease, optic neuritis, type I diabetes, neuromyelitis optica, myasthenia gravis, uveitis, Guillain-Barre syndrome, psoriatic arthritis, Graves' disease, and scleritis. 
     
     
         23 . A pharmaceutical or veterinary composition comprising at least one compound of  claim 1  and a pharmaceutically or veterinarily acceptable excipient or carrier. 
     
     
         24 . The composition of  claim 23 , further comprising an additional active agent for the treatment of a disease or condition selected from the group consisting of asthma, chronic obstructive pulmonary disease (COPD), bronchitis, an allergic disease, cystic fibrosis, lung allograft rejection, multiple sclerosis, rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, systemic lupus erythematosus, psoriasis, Hashimoto's disease, pancreatitis, autoimmune diabetes, autoimmune ocular disease, ulcerative colitis, Crohn's disease, inflammatory bowel disease (IBD), Sjorgen's syndrome, Behcet's disease, optic neuritis, type I diabetes, neuromyelitis optica, myasthenia gravis, uveitis, Guillain-Barre syndrome, psoriatic arthritis, Graves' disease, and scleritis. 
     
     
         25 . (canceled)