Tlr7/8 antagonists and uses thereof

Abstract

or pharmaceutically acceptable compositions thereof, is useful to as a TLR7/8 antagonist.

1 . A compound of formula I, 
       
         
           
           
               
               
           
         
         Ring A is aryl or heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each of which is optionally substituted; 
         Ring B is heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each of which is optionally substituted; 
         R 1  is —H, —CH 3 —, —CF 3 —, —CN, —F, —Cl, —OCH 3 , or —OCF 3 ; 
         each R 2  is independently —H, —R, halogen, -haloalkyl, —OR, —SR, —CN, —NO 2 , —SO 2 R, —SOR, —C(O)R, —CO 2 R, —C(O)N(R) 2 , —NRC(O)R, —NRC(O)N(R) 2 , —NRSO 2 R, or —N(R) 2 ; 
         each R 3  is independently —H, —R, halogen, -haloalkyl, —OR, —SR, —CN, —NO 2 , —SO 2 R, —SOR, —C(O)R, —CO 2 R, —C(O)N(R) 2 , —NRC(O)R, —NRC(O)N(R) 2 , —NRSO 2 R, or —N(R) 2 ; 
         X is C(R 4 ) 2 ; 
         Y is C(R) 2 ; 
         each R 4  is independently —H, —R, halogen, -haloalkyl, —OR, —SR, —CN, —NO 2 , —SO 2 R, —SOR, —C(O)R, —CO 2 R, —C(O)N(R) 2 , —C(NH)R, —C(NH)NR 2 , —NRC(O)R, —NRC(O)N(R) 2 , —NRSO 2 R, or —N(R) 2 ; 
         each R 5  is independently —H, —R, halogen, -haloalkyl, —OR, —SR, —CN, —NO 2 , —SO R, —SOR, —C(O)R, —CO 2 R, —C(O)N(R) 2 , —NRC(O)R, —NRC(O)N(R) 2 , —NRSO 2 R, or —N(R) 2 ; 
         each R is independently hydrogen, C 1-6  aliphatic, C 3-10  aryl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each of which is optionally substituted; or 
         two R groups on the same atom are taken together with the atom to which they are attached to form a C 3-10  aryl a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each of which is optionally substituted; 
         k is 1 or 2; 
         n is 0, 1, or 2; 
         p is 0, 1, or 2; 
         r is 0, 1, or 2; and 
         t is 0, 1, or 2. 
       
     
     
         2 . The compound of  claim 1 , wherein Ring A is C 6  aryl or a 6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. 
     
     
         3 . The compound of  claim 2 , wherein Ring A is phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or triazinyl. 
     
     
         4 . The compound of  claim 3 , wherein Ring A is 
       
         
           
           
               
               
           
         
       
     
     
         5 . The compound of  claim 1 , wherein Ring B is a 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. 
     
     
         6 . The compound of  claim 5 , wherein Ring B is 
       
         
           
           
               
               
           
         
       
     
     
         7 - 8 . (canceled) 
     
     
         9 . The compound of  claim 1 , wherein each R 4  is independently C 1-6  aliphatic, —C(O)R, —C(NH)NR 2 , —NRC(O)R, —N(R) 2 ; or 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each of which is optionally substituted. 
     
     
         10 . The compound of  claim 9 , wherein each R 4  is independently 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         11 . The compound of  claim 1 , wherein each R 5  is independently C 1-6  aliphatic, C 3-10  aryl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each of which is optionally substituted. 
     
     
         12 . The compound of  claim 11 , wherein each R 5  is independently methyl, ethyl, ethyl, propyl, i-propyl, butyl, s-butyl, t-butyl, straight or branched pentyl, or straight or branched hexyl; each of which is optionally substituted. 
     
     
         13 . The compound of  claim 1 , of formula I-a, 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         14 . The compound of  claim 1 , of formula I-b, 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         15 . The compound of  claim 1 , selected from the group consisting of compounds shown in the following Table 
       
         
           
                 
                 
               
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   Compound 120 
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   Compound 121 
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   Compound 122 
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   Compound 123 
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   Compound 124 
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   Compound 125 
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   Compound 126 
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   Compound 127 
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   Compound 128 
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   Compound 129 
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   Compound 130 
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   Compound 131 
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   Compound 132 
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   Compound 133 
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   Compound 134 
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   Compound 135 
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   Compound 136 
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   Compound 137 
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   Compound 138 
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   Compound 139 
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   Compound 140 
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   Compound 141 
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   Compound 142 
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   Compound 143 
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   Compound 144 
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   Compound 145 
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   Compound 146 
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   Compound 147 
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   Compound 148 
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   Compound 149 
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   Compound 150 
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   Compound 151 
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   Compound 152 
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   Compound 153 
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   Compound 154 
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   Compound 155 
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   Compound 156 
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   Compound 157 
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   Compound 158 
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   Compound 159 
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   Compound 160 
                 
                     
                 
             
                
               
               
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         16 . A pharmaceutical composition, comprising:
 the compound of  claim 1 , and a pharmaceutically acceptable adjuvant, carrier, or vehicle.   
     
     
         17 . A method for inhibiting TLR7/8, or a mutant thereof, activity in a patient or in a biological sample, comprising:
 administering to said patient or contacting said biological sample with the compound of  claim 1  or a physiologically acceptable salt thereof.   
     
     
         18 . A method for treating a TLR7/8-mediated disorder in a patient in need thereof, comprising:
 administering to said patient the compound of  claim 1  or a physiologically acceptable salt thereof.   
     
     
         19 . The method of  claim 18 , wherein the disorder is selected from Rheumatoid Arthritis, Psoriatic arthritis, Osteoarthritis, Systemic Lupus Erythematosus, Lupus nephritis, Ankylosing Spondylitis, Osteoporosis, Systemic sclerosis, Multiple Sclerosis, Psoriasis, Type I diabetes, Type II diabetes, Inflammatory Bowel Disease (Crohn's Disease and Ulcerative Colitis), Hyperimmunoglobulinemia D and periodic fever syndrome, Cryopyrin-associated periodic syndromes, Schnitzler's syndrome, Systemic juvenile idiopathic arthritis, Adult's onset Still's disease, Gout, Pseudogout, SAPHO syndrome, Castleman's disease, Sepsis, Stroke, Atherosclerosis, Celiac disease, DIRA (Deficiency of IL-1 Receptor Antagonist), Alzheimer's disease, Parkinson's disease, Sjoren's disease, polymyositis, dermatomyositis, and Cancer. 
     
     
         20 . A method for treating cancer in a subject, comprising:
 administering to said subject the compound of  claim 1  or a physiologically acceptable salt thereof.