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 - 57 . (canceled) 
     
     
         58 . A method of inhibiting TYK2, or a mutant thereof, in a biological sample comprising contacting the sample with a compound of formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         X is N or C(R 3 ); 
         R 1  is R, R D , or —OR; 
         R 2  is H, R C , —N(R)C(O)Cy 2 , —N(R)Cy 2 , —N(R)S(O) 2 Cy 2 , —OCy 2 , —SCy 2 , or Cy 2 ; 
         R 3  is H, halogen, or C 1-6  aliphatic; or 
         R 2  and R 3  are taken together with their intervening atoms to form a 4-7 membered partially unsaturated or aromatic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said ring is substituted with m instances of R 4 ; 
         each of Cy 1  and Cy 2  is independently 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 heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy 1  is substituted with n instances of R 5 ; and; wherein Cy 2  is substituted with p instances of R 6 ; 
         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 7 ) 2 —, —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 —; 
         each instance of R 4 , R 5 , R 6 , and R 7  is independently R A  or R B , and is substituted by q instances of R C ; 
         each instance of R A  is independently oxo, halogen, —CN, —NO 2 , —OR, —OR D , —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 , 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 , 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; 
         R D  is a C 1-4  aliphatic group wherein one or more hydrogens are replaced by deuterium; 
         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; and 
         each of m, n, p, and q is independently 0, 1, 2, 3, or 4. 
       
     
     
         59 . A method of inhibiting TYK2, or a mutant thereof, in a biological sample comprising contacting the sample with a compound of formula VIII: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         X is N or C(R 3 ); 
         Y is N or C(R 1 ); 
         R 1  is H, D, or halogen; 
         R, R D , or —OR; 
         R 2  is H, R C , —N(R)C(O)Cy 2 , —N(R)S(O) 2 Cy 2 , —N(R)Cy 2 , —OCy 2 , —SCy 2 , or Cy 2 ; 
         R 3  is H, halogen, or C 1-6  aliphatic; or 
         R 2  and R 3  are taken together with their intervening atoms to form a 4-7 membered partially unsaturated or aromatic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said ring is substituted with m instances of R 4 ; 
         each of Cy 1  and Cy 2  is independently 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 heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein Cy 1  is substituted with n instances of R 5 ; and; wherein Cy 2  is substituted with p instances of R 6 ; 
         Cy 3  is a 5-6 membered monocyclic partially unsaturated or heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein Cy 3  is substituted with r instances of R 8 ; 
         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 7 ) 2 —, —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—, —OC(O)N(R)—, —N(R)C(O)O—, —S—, —S(O)— or —S(O) 2 —; 
         each instance of R 4 , R 5 , R 6 , R 7  and R 8  is independently R A  or R B , and is substituted by q instances of R C ; 
         each instance of R A  is independently oxo, halogen, —CN, —NO 2 , —OR, —OR D , —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; 
         R D  is a C 1-4  aliphatic group wherein one or more hydrogens are replaced by deuterium; 
         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; and 
         each of m, n, p, q, and r is independently 0, 1, 2, 3, or 4. 
       
     
     
         60 . A method of inhibiting TYK2, or a mutant thereof, in a biological sample comprising contacting the sample with:
 (i) a compound of formula XVI:   
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         X is N or C(R X ); 
         one of Y 1 , Y 2 , Z 1 , and Z 2  is N, and the other three are C; 
         R 1  is D, R, R D , —NR 2 , —NRR D , —N(R D ) 2 , —N(R)C(O)NR 2 , —N(R)C(NR)NR 2 , —N(R)C(O)NRR D , —N(R)C(NR)NRR D , —OR, or —OR D ; 
         R 2  is H, R C , —N(R)C(O)Cy 2 , —N(R)S(O) 2 Cy 2 , —N(R)Cy 2 , —OCy 2 , —SCy 2 , or Cy 2 ; 
         R 3  is H, halogen, or C 1-6  aliphatic; or 
         R 2  and R 3  are taken together with their intervening atoms to form a 4-7 membered partially unsaturated or aromatic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said ring is substituted with m instances of R 4 ; 
         each of Cy 1  and Cy 2  is independently 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 heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy 1  is substituted with n instances of R 5 ; and; wherein Cy 2  is substituted with p instances of R 6 ; 
         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 7 ) 2 —, —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 —; 
         each instance of R 4 , R 5 , R 6 , and R 7  is independently R A  or R B , and is substituted by q instances of R C ; 
         each instance of R A  is independently oxo, halogen, —CN, —NO 2 , —OR, —OR D , —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; 
         R D  is a C 1-4  aliphatic group wherein one or more hydrogens are replaced by deuterium; 
         R X  is H, halogen, or C 1-6  aliphatic 
         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; and 
         each of m, n, p, and q is independently 0, 1, 2, 3, or 4; or 
         (ii) a compound of formula XVI′: 
       
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         Q is CH or N; 
         X is N or C(R X ); 
         one of Y 1 , Y 2 , Z 1 , and Z 2  is N, and the other three are C; 
         R 1  is D, R, R D , —NR 2 , —NRR D , —N(R D ) 2 , —N(R)C(O)NR 2 , —N(R)C(NR)NR 2 , —N(R)C(O)NRR D , —N(R)C(NR)NRR D , —OR, or —OR D ; 
         R 2  is H, R C , —N(R)C(O)Cy 2 , —N(R)S(O) 2 Cy 2 , —N(R)Cy 2 , —OCy 2 , —SCy 2 , or Cy 2 ; 
         R 3  is H, halogen, or C 1-6  aliphatic; or 
         R 2  and R 3  are taken together with their intervening atoms to form a 4-7 membered partially unsaturated or aromatic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said ring is substituted with m instances of R 4 ; 
         each of Cy 1  and Cy 2  is independently 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 heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy 1  is substituted with n instances of R 5 ; and; wherein Cy 2  is substituted with p instances of R 6 ; 
         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 7 ) 2 —, —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 —; 
         each instance of R 4 , R 5 , R 6 , and R 7  is independently R A  or R B , and is substituted by q instances of R C ; 
         each instance of R A  is independently oxo, halogen, —CN, —NO 2 , —OR, —OR D , —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; 
         R D  is a C 1-4  aliphatic group wherein one or more hydrogens are replaced by deuterium; 
         R X  is H, halogen, or C 1-6  aliphatic; 
         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; and 
         each of m, n, p, and q is independently 0, 1, 2, 3, or 4. 
       
     
     
         61 . A method of treating a TYK2-mediated disorder, disease, or condition in a patient comprising administering to said patient a compound of formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         X is N or C(R 3 ); 
         R 1  is R, R D , or —OR; 
         R 2  is H, R C , —N(R)C(O)Cy 2 , —N(R)Cy 2 , —N(R)S(O) 2 Cy 2 , —OCy 2 , —SCy 2 , or Cy 2 ; 
         R 3  is H, halogen, or C 1-6  aliphatic; or 
         R 2  and R 3  are taken together with their intervening atoms to form a 4-7 membered partially unsaturated or aromatic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said ring is substituted with m instances of R 4 ; 
         each of Cy 1  and Cy 2  is independently 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 heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy 1  is substituted with n instances of R 5 ; and; wherein Cy 2  is substituted with p instances of R 6 ; 
         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 7 ) 2 —, —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 —; 
         each instance of R 4 , R 5 , R 6 , and R 7  is independently R A  or R B , and is substituted by q instances of R C ; 
         each instance of R A  is independently oxo, halogen, —CN, —NO 2 , —OR, —OR D , —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 , 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 , 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; 
         R D  is a C 1-4  aliphatic group wherein one or more hydrogens are replaced by deuterium; 
         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; and 
         each of m, n, p, and q is independently 0, 1, 2, 3, or 4. 
       
     
     
         62 . A method of treating a TYK2-mediated disorder, disease, or condition in a patient comprising administering to said patient a compound of formula VIII: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         X is N or C(R 3 ); 
         Y is N or C(R 1 ); 
         R 1  is H, D, or halogen; 
         R, R D , or —OR; 
         R 2  is H, R C , —N(R)C(O)Cy 2 , —N(R)S(O) 2 Cy 2 , —N(R)Cy 2 , —OCy 2 , —SCy 2 , or Cy 2 ; 
         R 3  is H, halogen, or C 1-6  aliphatic; or 
         R 2  and R 3  are taken together with their intervening atoms to form a 4-7 membered partially unsaturated or aromatic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said ring is substituted with m instances of R 4 ; 
         each of Cy 1  and Cy 2  is independently 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 heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein Cy 1  is substituted with n instances of R 5 ; and; wherein Cy 2  is substituted with p instances of R 6 ; 
         Cy 3  is a 5-6 membered monocyclic partially unsaturated or heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein Cy 3  is substituted with r instances of R 8 ; 
         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 7 ) 2 —, —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—, —OC(O)N(R)—, —N(R)C(O)O—, —S—, —S(O)— or —S(O) 2 —; 
         each instance of R 4 , R 5 , R 6 , R 7  and R 8  is independently R A  or R B , and is substituted by q instances of R C ; 
         each instance of R A  is independently oxo, halogen, —CN, —NO 2 , —OR, —OR D , —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; 
         R D  is a C 1-4  aliphatic group wherein one or more hydrogens are replaced by deuterium; 
         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; and 
         each of m, n, p, q, and r is independently 0, 1, 2, 3, or 4. 
       
     
     
         63 . A method of treating a TYK2-mediated disorder, disease, or condition in a patient comprising administering to said patient:
 (i) a compound of formula XVI:   
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         X is N or C(R X ); 
         one of Y 1 , Y 2 , Z 1 , and Z 2  is N, and the other three are C; 
         R 1  is D, R, R D , —NR 2 , —NRR D , —N(R D ) 2 , —N(R)C(O)NR 2 , —N(R)C(NR)NR 2 , —N(R)C(O)NRR D , —N(R)C(NR)NRR D , —OR, or —OR D ; 
         R 2  is H, R C , —N(R)C(O)Cy 2 , —N(R)S(O) 2 Cy 2 , —N(R)Cy 2 , —OCy 2 , —SCy 2 , or Cy 2 ; 
         R 3  is H, halogen, or C 1-6  aliphatic; or 
         R 2  and R 3  are taken together with their intervening atoms to form a 4-7 membered partially unsaturated or aromatic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said ring is substituted with m instances of R 4 ; 
         each of Cy 1  and Cy 2  is independently 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 heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy 1  is substituted with n instances of R 5 ; and; wherein Cy 2  is substituted with p instances of R 6 ; 
         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 7 ) 2 —, —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 —; 
         each instance of R 4 , R 5 , R 6 , and R 7  is independently R A  or R B , and is substituted by q instances of R C ; 
         each instance of R A  is independently oxo, halogen, —CN, —NO 2 , —OR, —OR D , —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; 
         R D  is a C 1-4  aliphatic group wherein one or more hydrogens are replaced by deuterium; 
         R X  is H, halogen, or C 1-6  aliphatic; 
         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; and 
         each of m, n, p, and q is independently 0, 1, 2, 3, or 4; or 
         (ii) a compound of formula XVI′: 
       
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         Q is CH or N; 
         X is N or C(R X ); 
         one of Y 1 , Y 2 , Z 1 , and Z 2  is N, and the other three are C; 
         R 1  is D, R, R D , —NR 2 , —NRR D , —N(R D ) 2 , —N(R)C(O)NR 2 , —N(R)C(NR)NR 2 , —N(R)C(O)NRR D , —N(R)C(NR)NRR D , —OR, or —OR D ; 
         R 2  is H, R C , —N(R)C(O)Cy 2 , —N(R)S(O) 2 Cy 2 , —N(R)Cy 2 , —OCy 2 , —SCy 2 , or Cy 2 ; 
         R 3  is H, halogen, or C 1-6  aliphatic; or 
         R 2  and R 3  are taken together with their intervening atoms to form a 4-7 membered partially unsaturated or aromatic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said ring is substituted with m instances of R 4 ; 
         each of Cy 1  and Cy 2  is independently 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 heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy 1  is substituted with n instances of R 5 ; and; wherein Cy 2  is substituted with p instances of R 6 ; 
         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 7 ) 2 —, —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 —; 
         each instance of R 4 , R 5 , R 6 , and R 7  is independently R A  or R B , and is substituted by q instances of R C ; 
         each instance of R A  is independently oxo, halogen, —CN, —NO 2 , —OR, —OR D , —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; 
         R D  is a C 1-4  aliphatic group wherein one or more hydrogens are replaced by deuterium; 
         R X  is H, halogen, or C 1-6  aliphatic; 
         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; and 
         each of m, n, p, and q is independently 0, 1, 2, 3, or 4. 
       
     
     
         64 . The method of  claim 61 , wherein the TYK2-mediated disorder, disease, or condition is selected from an autoimmune disorder, an inflammatory disorder, a proliferative disorder, an endocrine disorder, a neurological disorder, and a disorder associated with transplantation. 
     
     
         65 . The method of  claim 61 , wherein the TYK2-mediated disorder, disease, or condition is selected from rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, type 1 diabetes, ankylosing spondylitis, systemic lupus erythematosus, multiple sclerosis, systemic sclerosis, psoriasis, Crohn's disease, ulcerative colitis, and inflammatory bowel disease. 
     
     
         66 . The method of  claim 61 , wherein the TYK2-mediated disorder, disease, or condition is a leukemia. 
     
     
         67 . The method of  claim 61 , wherein the TYK2-mediated disorder, disease, or condition is T-cell acute lymphoblastic leukemia (T-ALL). 
     
     
         68 . The method of  claim 61 , wherein the TYK2-mediated disorder, disease, or condition is a proliferative disorder associated with one or more activating mutations in TYK2. 
     
     
         69 . The method of  claim 61 , wherein the TYK2-mediated disorder, disease, or condition is transplant rejection or graft versus host disease. 
     
     
         70 . The method of  claim 61 , wherein the TYK2-mediated disorder, disease, or condition is polycystic ovary syndrome, Crouzon's syndrome, or type 1 diabetes. 
     
     
         71 . The method of  claim 61 , wherein the TYK2-mediated disorder, disease, or condition is Alzheimer's disease. 
     
     
         72 . The method of  claim 61 , wherein the TYK2-mediated disorder, disease, or condition is associated with type I interferon, IL-10, IL-12, or IL-23 signaling. 
     
     
         73 . The method of  claim 62 , wherein the TYK2-mediated disorder, disease, or condition is selected from an autoimmune disorder, an inflammatory disorder, a proliferative disorder, an endocrine disorder, a neurological disorder, and a disorder associated with transplantation. 
     
     
         74 . The method of  claim 62 , wherein the TYK2-mediated disorder, disease, or condition is selected from rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, type 1 diabetes, ankylosing spondylitis, systemic lupus erythematosus, multiple sclerosis, systemic sclerosis, psoriasis, Crohn's disease, ulcerative colitis, and inflammatory bowel disease. 
     
     
         75 . The method of  claim 62 , wherein the TYK2-mediated disorder, disease, or condition is a leukemia. 
     
     
         76 . The method of  claim 62 , wherein the TYK2-mediated disorder, disease, or condition is T-cell acute lymphoblastic leukemia (T-ALL). 
     
     
         77 . The method of  claim 62 , wherein the TYK2-mediated disorder, disease, or condition is a proliferative disorder associated with one or more activating mutations in TYK2. 
     
     
         78 . The method of  claim 62 , wherein the TYK2-mediated disorder, disease, or condition is transplant rejection or graft versus host disease. 
     
     
         79 . The method of  claim 62 , wherein the TYK2-mediated disorder, disease, or condition is polycystic ovary syndrome, Crouzon's syndrome, or type 1 diabetes. 
     
     
         80 . The method of  claim 62 , wherein the TYK2-mediated disorder, disease, or condition is Alzheimer's disease. 
     
     
         81 . The method of  claim 62 , wherein the TYK2-mediated disorder, disease, or condition is associated with type I interferon, IL-10, IL-12, or IL-23 signaling. 
     
     
         82 . The method of  claim 63 , wherein the TYK2-mediated disorder, disease, or condition is selected from an autoimmune disorder, an inflammatory disorder, a proliferative disorder, an endocrine disorder, a neurological disorder, and a disorder associated with transplantation. 
     
     
         83 . The method of  claim 63 , wherein the TYK2-mediated disorder, disease, or condition is selected from rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, type 1 diabetes, ankylosing spondylitis, systemic lupus erythematosus, multiple sclerosis, systemic sclerosis, psoriasis, Crohn's disease, ulcerative colitis, and inflammatory bowel disease. 
     
     
         84 . The method of  claim 63 , wherein the TYK2-mediated disorder, disease, or condition is a leukemia. 
     
     
         85 . The method of  claim 63 , wherein the TYK2-mediated disorder, disease, or condition is T-cell acute lymphoblastic leukemia (T-ALL). 
     
     
         86 . The method of  claim 63 , wherein the TYK2-mediated disorder, disease, or condition is a proliferative disorder associated with one or more activating mutations in TYK2. 
     
     
         87 . The method of  claim 63 , wherein the TYK2-mediated disorder, disease, or condition is transplant rejection or graft versus host disease. 
     
     
         88 . The method of  claim 63 , wherein the TYK2-mediated disorder, disease, or condition is polycystic ovary syndrome, Crouzon's syndrome, or type 1 diabetes. 
     
     
         89 . The method of  claim 63 , wherein the TYK2-mediated disorder, disease, or condition is Alzheimer's disease. 
     
     
         90 . The method of  claim 63 , wherein the TYK2-mediated disorder, disease, or condition is associated with type I interferon, IL-10, IL-12, or IL-23 signaling.