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: 
         X and Y are ═N—; 
         Ring A is phenyl; a 5-6 membered partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-12 membered partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered bicyclic heteroaryl ring having 2-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 
         each of R 1  and R 1′  is independently hydrogen, —R 2 , halogen, —CN, —NO 2 , —OR, —SR, —NR 2 , —S(O) 2 R, —S(O) 2 NR 2 , —S(O)R, —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 , or —N(R)S(O) 2 R; or 
         R 1  and R 1′  are taken together with their intervening atoms to form an optionally substituted 3-7 membered spiro-fused ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 
         each R 2  is independently an optionally substituted group selected from C 1-6  aliphatic, phenyl, a 4-7 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; 
         R 3  is C 2-6  aliphatic or Cy′; wherein R 3  is substituted with n instances of R 8 ; 
         R 5  is halogen, —CN, —NO 2 , —OR, —SR, —NR 2 , —S(O) 2 R, —S(O) 2 NR 2 , —S(O)R, —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)S(O) 2 R, and Cy 2 ; wherein R 5  is substituted with p instances of R 9 ; or 
         when Ring A is partially unsaturated, L 1 R 5 , taken together, may also be absent; 
         each of Cy 1  and Cy 2  is independently phenyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 6-12 membered bicyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 
         each instance of R 7  and R 8  is independently oxo, —R 2 , halogen, —CN, —NO 2 , —OR, —SR, —NR 2 , —S(O) 2 R, —S(O) 2 NR 2 , —S(O)R, —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 , or —N(R)S(O) 2 R; 
         each instance of R 9  is independently oxo, C 1-6  hydroxyaliphatic, —R 2 , halogen, —CN, —NO 2 , —OR, —SR, —NR 2 , —S(O) 2 R, —S(O) 2 NR 2 , —S(O)R, —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 , or —N(R)S(O) 2 R; 
         L 1  is a covalent bond or a C 1-6  bivalent saturated or unsaturated, straight or branched hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by —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 —; 
         m is 0-2; 
         n is 0-4; 
         p is 0-3; and 
         each R is independently hydrogen, or an optionally substituted group selected from C 1-6  aliphatic, phenyl, a 4-7 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. 
       
     
     
         2 . The compound of  claim 1  of formula II: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof 
       
     
     
         3 . (canceled) 
     
     
         4 . The compound of  claim 1  of one of formulas VI-a, VI-b, VI-c, VI-d, VI-e, VI-f, VI-g, VI-h, VI-i, VI-j, VI-k, VI-l, VI-m, VI-n, VI-o, VI-p, VI-q, VI-r, VI-s, VI-t, VI-v, VI-x, VI-y, VI-z, or VI-aa: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         5 . The compound of  claim 1 , wherein L 1  is a covalent bond. 
     
     
         6 . The compound of  claim 1  wherein L 1  is —C(O)—. 
     
     
         7 . The compound of  claim 1 , wherein R 3  is Cy 1 . 
     
     
         8 . The compound of  claim 1 , wherein R 3  is one of the following: 
       
         
           
           
               
               
           
         
       
     
     
         9 . The compound of  claim 1  wherein R 3 (R 8 ) n , taken together, is one of the following: 
       
         
           
           
               
               
           
         
       
     
     
         10 . The compound of  claim 1  wherein R 5  is Cy 2 . 
     
     
         11 . The compound of  claim 1 , wherein R 5  is one of the following: 
       
         
           
           
               
               
           
         
       
     
     
         12 . The compound of  claim 1  wherein R 5 (R 9 ) p , taken together, is one of the following: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         13 . The compound of  claim 1  wherein at least one R 8  is halogen, —CN, or hydroxymethyl. 
     
     
         14 . The compound of  claim 1  wherein Ring A is a 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 
     
     
         15 . The compound of  claim 14 , wherein Ring A is pyrazolyl. 
     
     
         16 . The compound of  claim 1  of formula VIII-c: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         17 . The compound of  claim 16 , wherein n is 2-3. 
     
     
         18 . (canceled) 
     
     
         19 . A pharmaceutical composition comprising a compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle. 
     
     
         20 . (canceled) 
     
     
         21 . A method of treating a TYK2-mediated disorder, disease, or condition in a patient comprising administering to the patient the compound of  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
         22 . The method of  claim 21  wherein the disorder is selected from an autoimmune disorder, an inflammatory disorder, a proliferative disorder, an endocrine disorder, a neurological disorder, or a disorder associated with transplantation. 
     
     
         23 - 41 . (canceled)