Ror modulators and their uses

Abstract

The invention relates to ROR modulators; compositions comprising an effective amount of a ROR modulator; and methods for treating or preventing diseases associated with ROR.

1 . A compound of the Formula I: 
       
         
           
           
               
               
           
         
         wherein 
         A is aryl or heteroaryl, optionally substituted with C1-C4 alkyl, halogen, OH, CN, or N(R 4 ) 2 ; 
         R 1  is absent, H, OH, halogen, N(R 4 ) 2 , or C1-C4 alkyl optionally substituted with halogen, OH, O-alkyl, CN, or N(R 4 ) 2 ; 
         R 2  and R 3  are independently selected from H, halogen or C1-C4 alkyl optionally substituted with halogen, OH, CN, or N(R 4 ) 2 , or R 2  and R 3 , taken together may form a 4-7 membered saturated or unsaturated ring, optionally incorporating 0-3 N, O, or S atoms; wherein the 4-7 membered ring is optionally substituted with C1-C4 alkyl, halogen, OH, carbonyl, CN, halogen, or N(R 4 ) 2 , or R 2  and R 3 , can be taken together to form a carbonyl; 
         each R 4  is independently H, alkyl, or aryl, or two R 4  can be taken together to form a 4-7 membered ring, optionally incorporating 0-3 N, O, S atoms; wherein the 4-7 membered ring is optionally substituted with C1-C4 alkyl, halogen, OH, CN, halogen, or N(R 4 ) 2 ; 
         R 5  is independently H or alkyl, or both R 5  can be taken together to form a carbonyl; 
         R 7  and R 8  are independently H or alkyl optionally substituted with C1-C4 alkyl, halogen, OH, CN, or N(R 4 ) 2 ; 
         n is 0 or 1; 
         p is 1 or 2; and 
         wherein the symbol   indicates a single or double bond; 
         or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, or tautomer thereof. 
       
     
     
         2 . The compound of  claim 1 , wherein A is aryl. 
     
     
         3 . The compound of  claim 2 , wherein A is phenyl. 
     
     
         4 . The compound of  claim 1 , wherein R 2  and R 3  are taken together to form a ring selected from the group consisting of pyrrolidine, pyrrole, pyrazole, imidazole, furan, tetrahydrofuran, piperidine, pyridine, pyrimidine, oxazole, isothiazole, and thiazole. 
     
     
         5 . The compound of  claim 4 , wherein the ring is pyrrolidine. 
     
     
         6 . The compound of  claim 4 , wherein the ring is tetrahydrofuran. 
     
     
         7 . The compound of  claim 1 , wherein R 2  and R 3  are taken together to form a carbonyl group. 
     
     
         8 . The compound of  claim 1 , wherein R 7  is H and R 8  is H or CH 3 . 
     
     
         9 . The compound of  claim 1 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         10 . A compound of formula Ia: 
       
         
           
           
               
               
           
         
         wherein 
         A is aryl or heteroaryl optionally substituted with C1-C4 alkyl, halogen, OH, CN, or N(R 4 ) 2 ; 
         R 1  is absent, H, OH, halogen, N(R 4 ) 2 , or C1-C4 alkyl optionally substituted with halogen, OH, O-alkyl, CN, or N(R 4 ) 2 ; 
         R 2  and R 3  are independently selected from H, halogen or C1-C4 alkyl optionally substituted with halogen, OH, CN, or N(R 4 ) 2 , or R 2  and R 3 , taken together may form a 4-7 membered saturated or unsaturated ring, optionally incorporating 0-3 N, O, or S atoms; wherein the 4-7 membered ring is optionally substituted with C1-C4 alkyl, halogen, OH, carbonyl, CN, halogen, or N(R 4 ) 2 , or R 2  and R 3 , can be taken together to form a carbonyl; 
         each R 4  is independently H, alkyl, or aryl, or two R 4  can be taken together to form a 4-7 membered ring, optionally incorporating 0-3 N, O, S atoms; wherein the 4-7 membered ring is optionally substituted with C1-C4 alkyl, halogen, OH, CN, halogen, or N(R 4 ) 2 ; 
         R 7  and R 8  are independently H or alkyl optionally substituted with C1-C4 alkyl, halogen, OH, CN, or N(R 4 ) 2 ; and 
         p is 1 or 2; 
         or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, or tautomer thereof. 
       
     
     
         11 . The compound of  claim 10 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         12 . A compound of formula Ib: 
       
         
           
           
               
               
           
         
         wherein 
         A is aryl or heteroaryl, optionally substituted with C1-C4 alkyl, halogen, OH, CN, or N(R 4 ) 2 ; 
         R 1  is absent, H, OH, halogen, N(R 4 ) 2 , or C1-C4 alkyl optionally substituted with halogen, OH, O-alkyl, CN, or N(R 4 ) 2 ; 
         R 2  and R 3  are independently selected from H, halogen or C1-C4 alkyl optionally substituted with halogen, OH, CN, or N(R 4 ) 2 , or R 2  and R 3 , taken together may form a 4-7 membered saturated or unsaturated ring, optionally incorporating 0-3 N, O, or S atoms; wherein the 4-7 membered ring is optionally substituted with C1-C4 alkyl, halogen, OH, carbonyl, CN, halogen, or N(R 4 ) 2 , or R 2  and R 3 , can be taken together to form a carbonyl; 
         each R 4  is independently H, alkyl, or aryl, or two R 4  can be taken together to form a 4-7 membered ring, optionally incorporating 0-3 N, O, S atoms; wherein the 4-7 membered ring is optionally substituted with C1-C4 alkyl, halogen, OH, CN, halogen, or N(R 4 ) 2 ; 
         R 7  and R 8  are independently H or alkyl optionally substituted with C1-C4 alkyl, halogen, OH, CN, or N(R 4 ) 2 ; and 
         p is 1 or 2; 
         or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, or tautomer thereof. 
       
     
     
         13 . The compound of  claim 12 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         14 . A compound of formula Ic: 
       
         
           
           
               
               
           
         
       
       wherein
 A is aryl or heteroaryl, optionally substituted with C1-C4 alkyl, halogen, OH, CN, or N(R 4 ) 2 ; 
 R 1  is absent, H, OH, halogen, N(R 4 ) 2 , or C1-C4 alkyl optionally substituted with halogen, OH, O-alkyl, CN, or N(R 4 ) 2 ; 
 R 2  and R 3  are independently selected from H, halogen or C1-C4 alkyl optionally substituted with halogen, OH, CN, or N(R 4 ) 2 , or R 2  and R 3 , taken together may form a 4-7 membered saturated or unsaturated ring, optionally incorporating 0-3 N, O, or S atoms; wherein the 4-7 membered ring is optionally substituted with C1-C4 alkyl, halogen, OH, carbonyl, CN, halogen, or N(R 4 ) 2 , or R 2  and R 3 , can be taken together to form a carbonyl; 
 each R 4  is independently H, alkyl, or aryl, or two R 4  can be taken together to form a 4-7 membered ring, optionally incorporating 0-3 N, O, S atoms; wherein the 4-7 membered ring is optionally substituted with C1-C4 alkyl, halogen, OH, CN, halogen, or N(R 4 ) 2 ; 
 R 7  and R 8  are independently H or alkyl optionally substituted with C1-C4 alkyl, halogen, OH, CN, or N(R 4 ) 2 ; and 
 p is 1 or 2; 
 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, or tautomer thereof. 
 
     
     
         15 . The compound of  claim 14 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         16 . A compound of formula Id: 
       
         
           
           
               
               
           
         
         wherein 
         A is aryl or heteroaryl, optionally substituted with C1-C4 alkyl, halogen, OH, CN, or N(R 4 ) 2 ; 
         R 1  is absent, H, OH, halogen, N(R 4 ) 2 , or C1-C4 alkyl optionally substituted with halogen, OH, O-alkyl, CN, or N(R 4 ) 2 ; 
         R 2  and R 3  are independently selected from H, halogen or C1-C4 alkyl optionally substituted with halogen, OH, CN, or N(R 4 ) 2 , or R 2  and R 3 , taken together may form a 4-7 membered saturated or unsaturated ring, optionally incorporating 0-3 N, O, or S atoms; wherein the 4-7 membered ring is optionally substituted with C1-C4 alkyl, halogen, OH, carbonyl, CN, halogen, or N(R 4 ) 2 , or R 2  and R 3 , can be taken together to form a carbonyl; 
         each R 4  is independently H, alkyl, or aryl, or two R 4  can be taken together to form a 4-7 membered ring, optionally incorporating 0-3 N, O, S atoms; wherein the 4-7 membered ring is optionally substituted with C1-C4 alkyl, halogen, OH, CN, halogen, or N(R 4 ) 2 ; 
         p is 1 or 2; 
         Y is NR 7 R 8 —C(O)—; 
         R 7  and R 8  are independently H or alkyl optionally substituted with C1-C4 alkyl, halogen, OH, CN, or N(R 4 ) 2 ; and 
         wherein the symbol   indicates a single or double bond; 
         or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, or tautomer thereof. 
       
     
     
         17 . A pharmaceutical composition comprising a compound of  claim 1  or  14  and a pharmaceutically acceptable carrier. 
     
     
         18 . A method of treating any disease mediated by Retinoic Acid Receptor-Related Orphan Receptor (ROR)α and/or RORγ, said method comprising administering an effective amount of a compound of  claim 1  or  14  to a patient in need thereof. 
     
     
         19 . The method of  claim 18 , wherein the disease is selected from the group consisting of angina pectoris, myocardial infarction, atherosclerosis, cystic fibrosis, gastritis, autoimmune myositis, giant cell arteritis, Wegener's granulomatosis, asthma, chronic obstructive pulmonary disease, rheumatoid arthritis, juvenile rheumatoid arthritis, allergen-induced lung inflammation, allergy, psoriasis, psoriatic arthritis, colitis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, Sjogren's syndrome, dry eye, optic neuritis, neuromyelitis optica, myasthenia gravis, Guillain-Barre syndrome, Graves disease, multiple sclerosis, autoimmune uveitis, ankylosing spondylitis, organ transplant rejection, polymyalgia rheumatic, systemic lupus erythematosus, cutaneous lupus, lupus nephritis, glomerulonephritis, diabetes mellitus type 1, pulmonary inflammation, macular degeneration, obesity, non-alcoholic fatty liver disease, steatohepatitis, insulin resistance, diabetes mellitus type 2, glucose intolerance, and metabolic syndrome.