Tyk2 inhibitors and uses thereof

Abstract

The present invention provides compounds, compositions thereof, and methods of using the same for the inhibition of TYK2, and the treatment of TYK2-mediated disorders.

We claim: 
     
         1 . A compound of formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         R 3  is —C(O)NH 2 ; —C(O)NHR 3A ; or —C(O)N(R 3A ) 2 ; 
         R 5  is -L 1 -R 5A ; 
         R 6  is hydrogen, R A , or R B ; 
         R 7  is hydrogen, halogen, —NH 2 , —NHR 7A , or —NHC(O)R 7A ; 
         L 1  is —N(R); 
         R 3A  is a 5-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 5-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted by q instances of R C ; 
         R 5A  is R A  or R B , and is substituted by r instances of R C ; 
         R 7A  is R B , and is substituted by q instances of R C ; 
         each instance of R A  is independently oxo, halogen, —CN, —NO 2 , —OR, —SR, —NR 2 , —S(O) 2 R, —S(O) 2 NR 2 , —S(O)R, —S(O)NR 2 , —C(O)R, —C(O)OR, —C(O)NR 2 , —C(O)N(R)OR, —OC(O)R, —OC(O)NR 2 , —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR 2 , —N(R)C(NR)NR 2 , —N(R)S(O) 2 NR 2 , or —N(R)S(O) 2 R; 
         each instance of R B  is independently C 1-6  aliphatic; phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 
         each instance of R C  is independently oxo, halogen, —CN, —NO 2 , —OR, —SR, —NR 2 , —S(O) 2 R, —S(O) 2 NR 2 , —S(O)R, —S(O)NR 2 , —C(O)R, —C(O)OR, —C(O)NR 2 , —C(O)N(R)OR, —OC(O)R, —OC(O)NR 2 , —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR 2 , —N(R)C(NR)NR 2 , —N(R)S(O) 2 NR 2 , or —N(R)S(O) 2 R or an optionally substituted group selected from C 1-6  aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or wherein two optional substituents on adjacent carbons are optionally taken together to form a 3-6 membered saturated or partially unsaturated fused heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 
         each R is independently hydrogen, or an optionally substituted group selected from C 1-6  aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two R groups on the same nitrogen are taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur; 
         wherein each hydrogen bound to carbon can be optionally and independently replaced by deuterium; and
 each instance of q and r is independently 0, 1, 2, 3, or 4. 
 
       
     
     
         2 - 32 . (canceled) 
     
     
         33 . The compound of  claim 1 , of formula VII, IX, or XVI: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         34 . The compound of  claim 33 , wherein —N(R)— in L 1  is —N(H)—. 
     
     
         35 . The compound of  claim 34 , wherein R 6  is hydrogen. 
     
     
         36 . The compound of  claim 35 , wherein R 7  is —NHR 7A . 
     
     
         37 . The compound of  claim 36 , wherein R 7A  is C 1-6  aliphatic. 
     
     
         38 . The compound of  claim 37 , wherein R 7A  is methyl. 
     
     
         39 . The compound of  claim 38 , wherein R 3  is —C(O)NHR 3A . 
     
     
         40 . The compound of  claim 39 , wherein R 3A  is a pyrrolidinyl ring substituted by q instances of R C . 
     
     
         41 . The compound of  claim 40 , wherein the r instances of R C  are selected from the group consisting of methyl, 
       
         
           
           
               
               
           
         
       
     
     
         42 . The compound of formula VII of  claim 40 , wherein r is 2 and the two R C  groups on R 5A  are on adjacent atoms and form a 3-6 membered saturated or partially unsaturated fused heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 
     
     
         43 . A pharmaceutical composition comprising a compound of  claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.