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)OR; —C(O)NHOR; or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said ring is substituted with m instances of R C ; 
         R 5  is hydrogen, or -L 1 -R 5A ; 
         R 6  is hydrogen, R A , or R B ; 
         or R 5  and R 6  are taken together with their intervening atoms to form a 4-7 membered partially unsaturated, or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said ring is substituted by R 5A  and n instances of R C ; 
         R 7  is hydrogen, halogen, —NH 2 , —NHR 7A , or —NHC(O)R 7A ; 
         or R 6  and R 7  are taken together with their intervening atoms to form a 4-7 membered partially unsaturated, or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said ring is substituted by p instances of R C ; 
         L 1  is a covalent bond or a C 1-4  bivalent saturated or unsaturated, straight or branched hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by —C(R 5B ) 2 —, —CH(R 5B )—, —N(R)—, —N(R)C(O)—, —C(O)N(R)—, —N(R)S(O) 2 —, —S(O) 2 N(R)—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —S(O)—, or —S(O) 2 —; 
         is R B , substituted by q instances of R C , wherein two R C  substituents on the same carbon are optionally taken together to form a 3-6 membered saturated or partially unsaturated spiro-fused heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or wherein two R C  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; 
         R 5A  and each instance of R 5B  are each independently R A  or R B , and are each substituted by r 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, wherein two optional substituents on the same carbon are optionally taken together to form a 3-6 membered saturated or partially unsaturated spiro-fused heterocyclic 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 m, n, p, q, and r is independently 0, 1, 2, 3, or 4. 
       
     
     
         2 . The compound of  claim 1  of one of formulas IV or X: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         3 . The compound of  claim 1  of formula I-a: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         4 . The compound of  claim 2  or  claim 3  of formulas IV-a or X-a: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         5 . The compound of  claim 4  wherein R 7  is —NH 2  or —NHR 7A , or a pharmaceutically acceptable salt thereof. 
     
     
         6 . The compound of  claim 5  of one of formulas IV-c or X-c: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         7 . (canceled) 
     
     
         8 . The compound of  claim 6  wherein is C 1-6  aliphatic. 
     
     
         9 . The compound of  claim 8  wherein R 7A  is methyl. 
     
     
         10 . (canceled) 
     
     
         11 . A pharmaceutical composition comprising a compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle. 
     
     
         12 - 32 . (canceled) 
     
     
         33 . The compound of  claim 1 , wherein R 3  is —C(O)OR. 
     
     
         34 . The compound of  claim 1 , wherein R 3  is —C(O)NHOR. 
     
     
         35 . The compound of  claim 1 , wherein R 3  is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said ring is substituted with m instances of R C . 
     
     
         36 . The compound of  claim 1  wherein R 5  is 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         37 . The compound of  claim 1 , wherein R 6  is methyl. 
     
     
         38 . The compound of  claim 1 , wherein R 7  is halogen 
     
     
         39 . The compound of  claim 1 , wherein R 7 —NHC(O)R 7A ; 
     
     
         40 . The compound of  claim 1 , wherein R 7  is —NHMe. 
     
     
         41 . The compound of  claim 1 , wherein R 7  is selected from 
       
         
           
           
               
               
           
         
       
     
     
         42 . The compound of  claim 1 , wherein R 7A  is selected from 
       
         
           
           
               
               
           
         
       
     
     
         43 . The compound of  claim 1 , wherein R C  is