Tyk2 pseudokinase ligands

Abstract

Described herein are TYK2 pseudokinase ligands and methods of utilizing TYK2 pseudokinase ligands in the treatment of diseases, disorders or conditions. Also described herein are pharmaceutical compositions containing such compounds.

What is claimed is: 
     
         1 . A compound having the structure of Formula (I) or Formula (II): 
       
         
           
           
               
               
           
         
         wherein: 
       
       
         
           
           
               
               
           
         
         is C 3 -C 6 cycloalkyl, C 6 -C 10 aryl, C 2 -C 9 heterocycloalkyl, or C 2 -C 9 heteroaryl, wherein C 3 -C 6 cycloalkyl, C 6 -C 10 aryl, C 2 -C 9 heterocycloalkyl, or C 2 -C 9 heteroaryl is optionally substituted with 1, 2, 3, or 4 R 7 ; 
         X is —O—, —C(R 9 )(R 10 )—, —C(R 9 )(R 10 )—O—, —O—C(R 9 )(R 10 ), —C(O)—, —C(O)N(R 3 )—, —N(R 3 )C(O)—, or —N(R 17 )—; 
         L 1  is —C(O)N(R 3 )—, —N(R 3 )C(O)—, —C(R 9 )(R 10 )—O—, or —O—C(R 9 )(R 10 )—; 
         L 2  is —N(R 6 )—, —N(R 6 )CH 2 —, or —CH 2 N(R 6 )—; 
         each R 1  is independently selected from hydrogen, deuterium, C 1 -C 6 alkyl, and C 1 -C 6 deuteroalkyl; 
         each R 2  is independently selected from hydrogen, deuterium, C 1 -C 6 alkyl, and C 1 -C 6 deuteroalkyl; or R 1  and R 2  are combined to form a 3-, 4-, 5-, or 6-membered cycloalkyl ring or a 4-, 5-, or 6-membered heterocycloalkyl ring; 
         each R 3  is independently hydrogen or C 1 -C 6 alkyl; or R 2  and R 3  together with the atoms to which they are attached are combined to form a 5- or 6-membered heterocycloalkyl ring optionally substituted 1, 2, or 3 with groups selected from halogen, —OH, C 1 -C 6 alkyl, and —C 1 -C 6 alkyl-OH; 
         R 4  is selected from hydrogen, deuterium, C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl, and C 2 -C 9 heterocycloalkyl; 
         R 5  is selected from hydrogen, deuterium, C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl, and C 2 -C 9 heterocycloalkyl; 
         R 13  is hydrogen, deuterium, C 1 -C 6 alkyl, or C 1 -C 6 deuteroalkyl; or R 5  and R 13  together with the atoms to which they are attached are combined to form a 5- or 6-membered heterocycloalkyl ring or a 5- or 6-membered heteroaryl ring, wherein the 5- or 6-membered heterocycloalkyl ring or 5- or 6-membered heteroaryl ring is optionally substituted with 1, 2, or 3 groups selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, and C 1 -C 6 haloalkoxy; 
         R 6  is hydrogen or C 1 -C 6 alkyl; 
         each R 7  is independently selected from deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 heteroalkyl, oxo, —OR 11 , —N(R 11 ) 2 , —CN, —C(═O)R 12 , —C(═O)OR 11 , —C(═O)N(R 11 ) 2 , —NR 11 C(═O)R 12 , —NR 11 S(═O) 2 R 12 , —S(═O) 2 R 12 , and —S(═O) 2 N(R 11 ) 2 ; 
         each R 9  and each R 10  are independently selected from hydrogen, deuterium, C 1 -C 6 alkyl, and C 1 -C 6 deuteroalkyl; 
         each R 1  is independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, and phenyl, wherein phenyl is optionally substituted with 1, 2, or 3 groups selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 2 -C 9 heterocycloalkyl, C 2 -C 9 heteroaryl, —OR 14 , —N(R 14 ) 2 , —C(═O)OR 14 , and —C(═O)N(R 14 ) 2 ; 
         each R 12  is independently selected from C 1 -C 6 alkyl and C 1 -C 6 heteroalkyl; 
         each R 14  is independently selected from hydrogen, C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl; 
         R 17  is hydrogen or C 1 -C 6 alkyl; 
         R 18  is hydrogen, deuterium, halogen, C 1 -C 6 alkyl, or C 1 -C 6 deuteroalkyl; and 
         n is 1, 2, 3, or 4; 
         or a pharmaceutically acceptable salt or solvate thereof. 
       
     
     
         2 . The compound of  claim 1 , or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (I): 
       
         
           
           
               
               
           
         
       
     
     
         3 . The compound of  claim 1 , or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (II): 
       
         
           
           
               
               
           
         
       
     
     
         4 . The compound of any one of  claims 1 - 3 , or a pharmaceutically acceptable salt or solvate thereof, wherein 
       
         
           
           
               
               
           
         
       
       is C 6 -C 10 aryl optionally substituted with 1, 2, or 3 R 7 . 
     
     
         5 . The compound of  claim 4 , or a pharmaceutically acceptable salt or solvate thereof, wherein 
       
         
           
           
               
               
           
         
       
       is phenyl optionally substituted with 1, 2, or 3 R 7 . 
     
     
         6 . The compound of any one of  claims 1 - 3 , or a pharmaceutically acceptable salt or solvate thereof, wherein 
       
         
           
           
               
               
           
         
       
       is C 2 -C 9 heteroaryl optionally substituted with 1, 2, or 3 R 7 . 
     
     
         7 . The compound of  claim 6 , or a pharmaceutically acceptable salt or solvate thereof, wherein 
       
         
           
           
               
               
           
         
       
       is C 2 -C 9 heteroaryl selected from oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, triazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl, wherein oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, triazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl are optionally substituted with 1, 2, or 3 R 7 . 
     
     
         8 . The compound of any one of  claims 1 - 7 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 7  is selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, and —CN. 
     
     
         9 . The compound of  claim 7 , or a pharmaceutically acceptable salt or solvate thereof, wherein 
       
         
           
           
               
               
           
         
       
       is C 2 -C 9 heteroaryl selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         10 . The compound of any one of  claims 1 - 3 , or a pharmaceutically acceptable salt or solvate thereof, wherein 
       
         
           
           
               
               
           
         
       
       is C 2 -C 9 heterocycloalkyl optionally substituted with 1, 2, or 3 R 7 . 
     
     
         11 . The compound of any one of  claims 1 - 3 , or a pharmaceutically acceptable salt or solvate thereof, wherein 
       
         
           
           
               
               
           
         
       
       is C 3 -C 6 cycloalkyl optionally substituted with 1, 2, 3, or 4 R 7 . 
     
     
         12 . The compound of  claim 10  or  claim 11 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 7  is selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, and oxo. 
     
     
         13 . The compound of  claim 10 , or a pharmaceutically acceptable salt or solvate thereof, wherein 
       
         
           
           
               
               
           
         
       
       is C 2 -C 9 heterocycloalkyl selected from. 
       
         
           
           
               
               
           
         
       
     
     
         14 . The compound of any one of  claims 1 - 13 , or a pharmaceutically acceptable salt or solvate thereof, wherein L 1  is —C(O)N(R 3 )—. 
     
     
         15 . The compound of any one of  claims 1 - 13 , or a pharmaceutically acceptable salt or solvate thereof, wherein L 2  is —N(R 6 ). 
     
     
         16 . A compound having the structure of Formula (III) or Formula (IV): 
       
         
           
           
               
               
           
         
       
       wherein:
 X is —O— or —C(R 9 )(R 10 )—; 
 Y is ═N— or ═C(R 15 )—; 
 Z is ═N— or ═C(R 16 )—; 
 each R 1  is independently selected from hydrogen, deuterium, C 1 -C 6 alkyl, and C 1 -C 6 deuteroalkyl; 
 each R 2  is independently selected from hydrogen, deuterium, C 1 -C 6 alkyl, and C 1 -C 6 deuteroalkyl; 
 R 3  is hydrogen or C 1 -C 6 alkyl; 
 R 4  is selected from hydrogen, deuterium, C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl, and C 2 -C 9 heterocycloalkyl; 
 R 5  is selected from hydrogen, deuterium, C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl, and C 2 -C 9 heterocycloalkyl; 
 R 13  is hydrogen, deuterium, C 1 -C 6 alkyl, or C 1 -C 6 deuteroalkyl; or R 5  and R 13  together with the atoms to which they are attached are combined to form a 5- or 6-membered heterocycloalkyl ring or a 5- or 6-membered heteroaryl ring, wherein the 5- or 6-membered heterocycloalkyl ring or 5- or 6-membered heteroaryl ring is optionally substituted with 1, 2, or 3 groups selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, and C 1 -C 6 haloalkoxy; 
 R 6  is hydrogen or C 1 -C 6 alkyl; 
 R 7  and R 8  are independently selected from hydrogen, deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, —C 1 -C 6 alkyl-OH, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, C 2 -C 9 heterocycloalkyl, C 2 -C 9 heteroaryl, C 6 -C 10 aryl, —OR 11 , —N(R 11 ) 2 , —CN, —C(═O)R 12 , —C(═O)OR 11 , —C(═O)N(R 11 ) 2 , —NR 11 C(═O)R 11 , —NR 11 S(═O) 2 R 11 , —S(═O) 2 R 11 , and —S(═O) 2 N(R 11 ) 2 , wherein C 3 -C 6 cycloalkyl, C 2 -C 9 heterocycloalkyl, C 2 -C 9 heteroaryl, or C 6 -C 10 aryl are optionally substituted with 1, 2, or 3 groups selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, and C 1 -C 6 haloalkoxy; 
 R 9  and R 10  are independently selected from hydrogen, deuterium, C 1 -C 6 alkyl, and C 1 -C 6 deuteroalkyl; 
 each R 11  is independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, and phenyl, wherein phenyl is optionally substituted with 1, 2, or 3 groups selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 2 -C 9 heterocycloalkyl, C 2 -C 9 heteroaryl, —OR 14 , —N(R 14 ) 2 , —C(═O)OR 14 , and —C(═O)N(R 14 ) 2 ; 
 each R 11  is independently selected from C 1 -C 6 alkyl and C 1 -C 6 heteroalkyl; 
 each R 14  is independently selected from hydrogen, C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl; 
 R 15  and R 16  are independently selected from hydrogen, deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 heteroalkyl, —OR 11 , —N(R 11 ) 2 , —CN, —C(═O)R 11 , —C(═O)OR 11 , —C(═O)N(R 11 ) 2 , —NR 11 C(═O)R 12 , —NR 11 S(═O) 2 R 12 , —S(═O) 2 R 11 , and —S(═O) 2 N(R 11 ) 2 ; 
 R 18  is hydrogen, deuterium, halogen, C 1 -C 6 alkyl, or C 1 -C 6 deuteroalkyl; and 
 n is 1, 2, 3, or 4; 
 or a pharmaceutically acceptable salt or solvate thereof. 
 
     
     
         17 . The compound of  claim 16 , or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (III): 
       
         
           
           
               
               
           
         
       
     
     
         18 . The compound of  claim 16 , or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (IV): 
       
         
           
           
               
               
           
         
       
     
     
         19 . The compound of any one of  claims 16 - 18 , or a pharmaceutically acceptable salt or solvate thereof, wherein Y is ═C(R 15 )— and Z is ═C(R 16 )—. 
     
     
         20 . The compound of any one of  claims 16 - 18 , or a pharmaceutically acceptable salt or solvate thereof, wherein Y is ═N— and Z is ═C(R 16 )—. 
     
     
         21 . The compound of any one of  claims 16 - 20 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 16  is selected from hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, and —CN. 
     
     
         22 . The compound of any one of  claims 16 - 21 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 16  is selected from hydrogen, halogen, or C 1 -C 6 alkyl. 
     
     
         23 . The compound of any one of  claims 16 - 18 , or a pharmaceutically acceptable salt or solvate thereof, wherein Y is ═C(R 15 )— and Z is ═N—. 
     
     
         24 . The compound of any one of  claims 16 - 23 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 15  is selected from hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, and —CN. 
     
     
         25 . The compound of any one of  claims 16 - 24 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 15  is selected from hydrogen, halogen, or C 1 -C 6 alkyl. 
     
     
         26 . The compound of any one of  claims 16 - 18 , or a pharmaceutically acceptable salt or solvate thereof, wherein Y is ═N— and Z is ═N—. 
     
     
         27 . The compound of any one of  claims 16 - 26 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 7  and R 8  are independently selected from hydrogen, halogen, C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 2 -C 9 heteroaryl, —OR 11 , —N(R 11 ) 2 , —CN, —C(═O)OR 11 , —C(═O)N(R 11 ) 2 , —NR 11 C(═O)R 12 , —NR 11 S(═O) 2 R 12 , —S(═O) 2 R 12 , and —S(═O) 2 N(R 11 ) 2 , wherein C 2 -C 9 heteroaryl is optionally substituted with 1, 2, or 3 groups selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, and C 1 -C 6 haloalkoxy. 
     
     
         28 . The compound of any one of  claims 16 - 27 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 7  and R 8  are independently selected from hydrogen, halogen, C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, C 2 -C 9 heteroaryl, —OR 11 , —CN, —C(═O)N(R 11 ) 2 , and —NR 11 S(═O) 2 R 12 , wherein C 2 -C 9 heteroaryl is optionally substituted with 1 or 2 groups selected from halogen or C 1 -C 6 alkyl. 
     
     
         29 . The compound of any one of  claims 16 - 28 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 7  and R 8  are independently selected from hydrogen, halogen, and C 1 -C 6 alkyl. 
     
     
         30 . The compound of any one of  claims 1 - 29 , or a pharmaceutically acceptable salt or solvate thereof, wherein X is —O—. 
     
     
         31 . The compound of any one of  claims 1 - 29 , or a pharmaceutically acceptable salt or solvate thereof, wherein X is —C(R 9 )(R 10 )—. 
     
     
         32 . The compound of  claim 31 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 9  and R 10  are hydrogen. 
     
     
         33 . The compound of any one of  claims 1 - 32 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 4  and R 5  are independently selected from hydrogen and C 1 -C 6 alkyl. 
     
     
         34 . The compound of any one of  claims 1 - 33 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 4  is hydrogen and R 5  is C 1 -C 6 alkyl. 
     
     
         35 . The compound of any one of  claims 1 - 34 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 3  is hydrogen. 
     
     
         36 . The compound of any one of  claims 1 - 35 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 6  is hydrogen. 
     
     
         37 . The compound of any one of  claims 1 - 36 , or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1. 
     
     
         38 . The compound of any one of  claims 1 - 36 , or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2. 
     
     
         39 . The compound of any one of  claims 1 - 36 , or a pharmaceutically acceptable salt or solvate thereof, wherein n is 3. 
     
     
         40 . The compound of any one of  claims 1 - 39 , or a pharmaceutically acceptable salt or solvate thereof, wherein each R 1  is hydrogen. 
     
     
         41 . The compound of any one of  claims 1 - 40 , or a pharmaceutically acceptable salt or solvate thereof, wherein each R 2  is hydrogen. 
     
     
         42 . The compound of any one of  claims 1 - 41 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 18  is hydrogen. 
     
     
         43 . A compound selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or solvate thereof. 
       
     
     
         44 . A compound selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         pharmaceutically acceptable salt or solvate thereof. 
       
     
     
         45 . A compound selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or solvate thereof. 
       
     
     
         46 . A compound selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or solvate thereof. 
       
     
     
         47 . A compound selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or solvate thereof. 
     
     
         48 . A pharmaceutical composition comprising a compound of any one of  claims 1 - 47 , or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient. 
     
     
         49 . A method of treating an inflammatory or autoimmune disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of any one of  claims 1 - 47 , or a pharmaceutically acceptable salt or solvate thereof. 
     
     
         50 . The method of  claim 49 , wherein the disease is selected from rheumatoid arthritis, multiple sclerosis, psoriasis, lupus, intestinal bowel disease, Crohn's disease, ulcerative colitis, ankylosing spondylitis, vitiligo, and atopic dermatitis.