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.

1 . (canceled) 
     
     
         2 . (canceled) 
     
     
         3 . (canceled) 
     
     
         4 . A compound of formula IV: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         each of X and Y is independently ═C(R 6 )—, ═N—, or ═N + (→O − )—, provided that X and Y are not simultaneously ═C(R 6 )—; 
         Ring A is phenyl; a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-6 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 4-6 membered saturated or partially unsaturated carbocyclic ring; wherein Ring A is substituted with m instances of R 7 ; 
         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 a group selected from C 1-6  alkyl, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, 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 R 3  is substituted with n instances of R 8 ; 
         R 4  is hydrogen or optionally substituted C 1-6  aliphatic; or
 R 4  and one instance of R 7  are taken together with their intervening atoms to form a 5-6 membered partially unsaturated or aromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; 
 
         R 5  is a group selected from 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, phenyl, a 3-14 membered saturated or partially unsaturated heterocyclic ring having 1-4 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 R 5  is substituted with p instances of R 9 ; 
         R 6  is 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; 
         each instance of R 7 , R 8 , R 10 , and R 11  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 —C(R 10 ) 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 —; or
 L 1  and one instance of R 7  are taken together with their intervening atoms to form a 5-10 membered partially unsaturated or aromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, sulfur, and boron; wherein said ring is substituted by q instances of R 11 ; and R 5  is attached to any position of the ring formed by L 1  and R 7 ; 
 
         m is 0-4; 
         n is 0-4; 
         p is 0-6; 
         q is 0-4; 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. 
 
       
     
     
         5 . The compound of  claim 4 , wherein Ring A is phenyl, pyridin-2-yl, pyridine-3-yl, or pyrazol-4-yl. 
     
     
         6 . The compound of  claim 4 , wherein Ring A is pyridin-2-yl. 
     
     
         7 . The compound of nm  claim 4 , wherein X is ═C(R 6 )—; and Y is ═N—. 
     
     
         8 . The compound of nm  claim 4 , wherein R 6  is hydrogen. 
     
     
         9 . The compound of nm  claim 4 , wherein L 1  is —CH 2 C(O)—, —C(O)—, or a covalent bond. 
     
     
         10 . The compound of  claim 9 , wherein L 1  is —C(O)—. 
     
     
         11 . The compound of  claim 9 , wherein L 1  is a covalent bond. 
     
     
         12 . The compound of  claim 4 , wherein R 3  is phenyl, pyrrolidinyl, or piperidinyl. 
     
     
         13 . The compound of nm  claim 4 , wherein R 3  is phenyl. 
     
     
         14 . The compound of  claim 4 , wherein n is 2, and at least one R 8  is fluoro. 
     
     
         15 . A compound of  claim 4  selected from those depicted in Table 1 of the specification, or a pharmaceutically acceptable salt thereof. 
     
     
         16 . A pharmaceutical composition comprising a compound of  claim 4 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle. 
     
     
         17 . A method of inhibiting TYK2 in a biological sample comprising contacting the sample with the compound of  claim 4 , or a pharmaceutically acceptable salt thereof. 
     
     
         18 . A method of treating an TYK2-mediated disorder, disease, or condition in a patient comprising administering to said patient the pharmaceutical composition of  claim 16 . 
     
     
         19 . The method of  claim 18  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. 
     
     
         20 . The method of  claim 19  wherein the disorder is an autoimmune disorder. 
     
     
         21 . The method of  claim 20  wherein the autoimmune disorder is selected from type 1 diabetes, systemic lupus erythematosus, multiple sclerosis, systemic sclerosis, psoriasis, Crohn's disease, ulcerative colitis, and inflammatory bowel disease. 
     
     
         22 . The method of  claim 19  wherein the disorder is an inflammatory disorder. 
     
     
         23 . The method of  claim 22  wherein the inflammatory disorder is selected from rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, psoriasis, Crohn's disease, ulcerative colitis, and inflammatory bowel disease. 
     
     
         24 . The method of  claim 19  wherein the disorder is a proliferative disorder. 
     
     
         25 . The method of  claim 24  wherein the proliferative disorder is a hematological cancer. 
     
     
         26 . The method of  claim 24  wherein the proliferative disorder is a leukemia. 
     
     
         27 . The method of  claim 26  wherein the leukemia is a T-cell leukemia. 
     
     
         28 . The method of  claim 27  wherein the T-cell leukemia is T-cell acute lymphoblastic leukemia (T-ALL). 
     
     
         29 . The method of  claim 24  wherein the proliferative disorder is associated with one or more activating mutations in TYK2. 
     
     
         30 . The method of  claim 19  wherein the disorder is associated with transplantation. 
     
     
         31 . The method of  claim 30  wherein the disorder is transplant rejection or graft versus host disease. 
     
     
         32 . The method of  claim 19  wherein the disorder is an endocrine disorder. 
     
     
         33 . The method of  claim 32  wherein the endocrine disorder is polycystic ovary syndrome, Crouzon's syndrome, or type 1 diabetes. 
     
     
         34 . The method of  claim 19  wherein the disorder is a neurological disorder. 
     
     
         35 . The method of  claim 34  wherein the neurological disorder is Alzheimer's disease. 
     
     
         36 . The method of  claim 18  wherein the disorder is associated with type I interferon, IL-10, IL-12, or IL-23 signaling.