Heteroaryl inhibitors of pad4

Abstract

The present invention provides compounds useful as inhibitors of PAD4, compositions thereof, and methods of treating PAD4-related disorders.

We claim: 
     
         1 . A compound of formula III-a, III-b, III-c, III-d, III-e, III-f, III-g, III-h, IV-a, IV-b, IV-c, IV-d, IV-e, IV-f, IV-g or IV-h: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         R 1  is hydrogen or an optionally substituted group selected from aliphatic, phenyl, a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 4-7 membered monocyclic saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
         R 2  is hydrogen or optionally substituted C 1-6-  aliphatic; 
         R 3  is hydrogen or Ring A; 
         Ring A is an optionally substituted ring selected from a 3-7 membered monocyclic saturated or partially unsaturated carbocyclic ring, phenyl, a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 4-7 membered monocyclic saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
         R 4  is R or —C(O)OR; 
         each R is independently hydrogen or C 1-6  aliphatic optionally substituted with 1-3 fluorine atoms; 
         R 5  is hydrogen or CN, or:
 R 5  and R 4  are taken together with their intervening atoms to form a triazole ring; or 
 R 5  and R 3  are taken together with their intervening atoms to form a triazole ring; and 
 
         provided that said compound of the formulae is other than a compound selected from I-69, I-76 or I-114 and those depicted in Table 2. 
       
     
     
         2 . The compound according to  claim 1 , wherein R 1  is —S(CH 3 ), 
       
         
           
           
               
               
           
         
       
     
     
         3 . The compound according to  claim 1 , wherein R 2  is H, methyl, ethyl, 
       
         
           
           
               
               
           
         
       
     
     
         4 . The compound according to  claim 1 , wherein R 3  is selected from H, 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         5 . The compound according to  claim 1 , wherein R 4  is H, CH 3  or —C(O)OR. 
     
     
         6 . The compound according to  claim 1 , wherein R 5  is hydrogen or CN, or: R 5  and R 4  are taken together with their intervening atoms to form a triazole ring; or R 5  and R 3  are taken together with their intervening atoms to form a triazole ring. 
     
     
         7 . The compound according to  claim 1 , wherein said compound is selected from those set forth in Table 1, or a pharmaceutically acceptable salt thereof. 
     
     
         8 . A pharmaceutically acceptable composition comprising the compound according to  claim 1 , and a pharmaceutically acceptable carrier, adjuvant, or vehicle. 
     
     
         9 . The composition according to  claim 8 , in combination with an additional therapeutic agent. 
     
     
         10 . A method of treating a PAD4-mediated disease, disorder, or condition in a subject in need thereof comprising the step of administering to said subject a pharmaceutical composition of  claim 8 . 
     
     
         11 . The method according to  claim 10 , wherein the PAD4-mediated disease, disorder, or condition is selected from rheumatoid arthritis, vasculitis, systemic lupus erythematosus, ulcerative colitis, cancer, cystic fibrosis, asthma, cutaneous lupus erythematosis, and psoriasis.