US2023348478A1PendingUtilityA1
Tyk2 pseudokinase ligands
Est. expiryNov 8, 2039(~13.3 yrs left)· nominal 20-yr term from priority
C07D 487/04C07D 519/00A61P 29/00A61P 37/00A61K 31/519A61K 31/538C07D 498/18C07D 487/18
69
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Claims
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.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A compound having the structure of Formula (I′):
wherein:
X is N or C(R 6 );
Y is C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 9 heterocycloalkyl, C 6 -C 10 aryl, C 2 -C 9 heteroaryl, or
R 7 wherein C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 9 heterocycloalkyl, C 6 -C 10 aryl, or C 2 -C 9 heteroaryl are optionally substituted by 1, 2, 3, or 4 R 7 ;
L 1 is a bond, —O—, —C(O)—, —N(R 9 )—, —N(R 9 )CH 2 —, or —CH 2 N(R 9 )—;
R 1 is C 3 -C 6 cycloalkyl substituted by 1, 2, or 3 R 13 ;
R 2 , R 3 , and R 4 are independently selected from hydrogen, deuterium, C 1 -C 6 alkyl, and C 1 -C 6 deuteroalkyl;
R 5 is hydrogen or C 1 -C 6 alkyl;
each R 6 is independently selected from hydrogen, deuterium, C 1 -C 6 alkyl, and C 1 -C 6 deuteroalkyl;
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 haloalkoxy, C 1 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl, C 2 -C 9 heterocycloalkyl, C 6 -C 10 aryl, C 2 -C 9 heteroaryl, oxo, —OR 10 , —N(R 10 ) 2 , —CN, —C(═O)R 11 , —C(═O)OR 10 , —C(═O)N(R 10 ) 2 , —NR 10 C(═O)R 11 , —NR 10 S(═O) 2 R 11 , —S(═O) 2 R 11 , and —S(═O) 2 N(R 10 ) 2 , wherein C 3 -C 6 cycloalkyl, C 2 -C 9 heterocycloalkyl, C 6 -C 10 aryl, C 2 -C 9 heteroaryl 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, C 1 -C 6 haloalkoxy, C 2 -C 9 heterocycloalkyl, C 2 -C 9 heteroaryl, —OR 12 , —N(R 12 ) 2 , —C(═O)OR 12 , and —C(═O)N(R 12 ) 2 ; or two R 7 are combined to form a 5-, 6-, or 7-membered heterocycloalkyl ring or a 4-, 5-, or 6-membered cycloalkyl ring;
R 8 is hydrogen, deuterium, halogen, C 1 -C 6 alkyl, or C 1 -C 6 deuteroalkyl;
R 9 is hydrogen or C 1 -C 6 alkyl;
each R 10 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 12 , —N(R 12 ) 2 , —C(═O)OR 12 , and —C(═O)N(R 2 ) 2 ;
each R 1 is independently selected from C 1 -C 6 alkyl and C 1 -C 6 heteroalkyl;
each R 12 is independently selected from hydrogen, C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl;
each R 13 is independently selected from 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 haloalkoxy, C 1 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl, C 2 -C 9 heterocycloalkyl, C 6 -C 10 aryl, C 2 -C 9 heteroaryl, oxo, —OR 10 , —N(R 10 ) 2 , —CN, —C(═O)R 11 , —C(═O)OR 10 , —C(═O)N(R 10 ) 2 , —NR 10 C(═O)R 11 , —NR 10 S(═O) 2 R 11 , —S(═O) 2 R 11 , and —S(═O) 2 N(R 10 ) 2 , wherein C 3 -C 6 cycloalkyl, C 2 -C 9 heterocycloalkyl, C 6 -C 10 aryl, C 2 -C 9 heteroaryl 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, C 1 -C 6 haloalkoxy, C 2 -C 9 heterocycloalkyl, C 2 -C 9 heteroaryl, —OR 12 , —N(R 12 ) 2 , —C(═O)OR 12 , and —C(═O)N(R 12 ) 2 ; and
n is 0, 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, wherein Y is C 6 -C 10 aryl optionally substituted with 1, 2, or 3 R 7 .
3 . The compound of claim 1 or claim 2 , or a pharmaceutically acceptable salt or solvate thereof, wherein Y is phenyl optionally substituted with 1, 2, or 3 R 7 .
4 . The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein Y is C 2 -C 9 heteroaryl optionally substituted with 1, 2, or 3 R 7 .
5 . The compound of claim 4 , or a pharmaceutically acceptable salt or solvate thereof, wherein Y 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 .
6 . The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein Y is
7 . The compound of claim 6 , or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0, 1, or 2.
8 . The compound of any one of claims 1 - 7 , or a pharmaceutically acceptable salt or solvate thereof, wherein each R 7 is independently selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 alkoxy.
9 . The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein Y is
10 . The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein Y is
11 . The compound of any one of claims 1 - 10 , or a pharmaceutically acceptable salt or solvate thereof, wherein each R 13 is independently selected from halogen, —OH, —CN, C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, and oxo.
12 . The compound of any one of claims 1 - 11 , or a pharmaceutically acceptable salt or solvate thereof, wherein each R 13 is independently selected from halogen, —OH, and —CN.
13 . The compound of any one of claims 1 - 12 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is cyclopropyl substituted by 1 R 13 .
14 . The compound of any one of claims 1 - 12 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is cyclobutyl substituted by 1 or 2 R 13 .
15 . The compound of any one of claims 1 - 11 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is
16 . The compound of any one of claims 1 - 15 , or a pharmaceutically acceptable salt or solvate thereof, wherein L 1 is a bond.
17 . The compound of any one of claims 1 - 15 , or a pharmaceutically acceptable salt or solvate thereof, wherein L 1 is —N(H)—.
18 . The compound of any one of claims 1 - 17 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 and R 4 are independently selected from hydrogen and C 1 -C 6 alkyl.
19 . The compound of any one of claims 1 - 18 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is hydrogen and R 4 is C 1 -C 6 alkyl.
20 . The compound of any one of claims 1 - 18 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is hydrogen and R 4 is C 1 -C 6 deuteroalkyl.
21 . The compound of any one of claims 1 - 20 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 6 is hydrogen.
22 . The compound of any one of claims 1 - 21 , or a pharmaceutically acceptable salt or solvate thereof, wherein each R 8 is hydrogen.
23 . The compound of any one of claims 1 - 22 , or a pharmaceutically acceptable salt or solvate thereof, wherein each R 2 is hydrogen.
24 . The compound of any one of claims 1 - 23 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 5 is hydrogen.
25 . The compound of any one of claims 1 - 24 , or a pharmaceutically acceptable salt or solvate thereof, wherein X is N.
26 . The compound of any one of claims 1 - 24 , or a pharmaceutically acceptable salt or solvate thereof, wherein X is C(R 6 ).
27 . The compound of any one of claims 1 - 24 , or a pharmaceutically acceptable salt or solvate thereof, wherein X is C(H).
28 . A compound selected from:
or a pharmaceutically acceptable salt or solvate thereof.
29 . A compound selected from:
or a pharmaceutically acceptable salt or solvate thereof.
30 . A compound having the structure of Formula (I) or Formula (II):
wherein:
X is N or C(R 6 );
Y is C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 9 heterocycloalkyl, C 6 -C 10 aryl, C 2 -C 9 heteroaryl, or
w herein C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 9 heterocycloalkyl, C 6 -C 10 aryl, or C 2 -C 9 heteroaryl are optionally substituted by 1, 2, 3, or 4 R 7 ;
L 1 is a bond, —O—, —C(O)—, —N(R 9 )—, —N(R 9 )CH 2 —, or —CH 2 N(R 9 )—;
R 1 is selected from hydrogen, deuterium, C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, C 3 -C 6 cycloalkyl, —C 1 -C 6 alkyl-C 3 -C 6 cycloalkyl, C 2 -C 9 heterocycloalkyl, and C 2 -C 9 heteroaryl, wherein C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, —C 1 -C 6 alkyl-C 3 -C 6 cycloalkyl, C 2 -C 9 heterocycloalkyl, or C 2 -C 9 heteroaryl are optionally substituted by 1, 2, or 3 R 7 ;
R 2 , R 3 , and R 4 are independently selected from hydrogen, deuterium, C 1 -C 6 alkyl, and C 1 -C 6 deuteroalkyl;
R 5 is hydrogen or C 1 -C 6 alkyl;
each R 6 is independently selected from hydrogen, deuterium, C 1 -C 6 alkyl, and C 1 -C 6 deuteroalkyl;
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 haloalkoxy, C 1 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl, C 2 -C 9 heterocycloalkyl, C 6 -C 10 aryl, C 2 -C 9 heteroaryl, oxo, —OR 10 , —N(R 10 ) 2 , —CN, —C(═O)R 11 , —C(═O)OR 10 , —C(═O)N(R 10 ) 2 , —NR 10 C(═O)R 11 , —NR 10 S(═O) 2 R 11 , —S(═O) 2 R 11 , and —S(═O) 2 N(R 10 ) 2 , wherein C 3 -C 6 cycloalkyl, C 2 -C 9 heterocycloalkyl, C 6 -C 10 aryl, C 2 -C 9 heteroaryl 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, C 1 -C 6 haloalkoxy, C 2 -C 9 heterocycloalkyl, C 2 -C 9 heteroaryl, —OR 12 , —N(R 12 ) 2 , —C(═O)OR 12 , and —C(═O)N(R 12 ) 2 ; or two R 7 are combined to form a 5-, 6-, or 7-membered heterocycloalkyl ring or a 4-, 5-, or 6-membered cycloalkyl ring;
R 8 is hydrogen, deuterium, halogen, C 1 -C 6 alkyl, or C 1 -C 6 deuteroalkyl;
R 9 is hydrogen or C 1 -C 6 alkyl;
each R 10 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 12 , —N(R 12 ) 2 , —C(═O)OR 12 , and —C(═O)N(R 2 ) 2 ;
each R 11 is independently selected from C 1 -C 6 alkyl and C 1 -C 6 heteroalkyl;
each R 12 is independently selected from hydrogen, C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl; and
n is 0, 1, 2, 3, or 4;
or a pharmaceutically acceptable salt or solvate thereof.
31 . The compound of claim 30 , or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (I):
32 . The compound of claim 30 , or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (II):
33 . The compound of any one of claims 30 - 32 , or a pharmaceutically acceptable salt or solvate thereof, wherein Y is C 6 -C 10 aryl optionally substituted with 1, 2, or 3 R 7 .
34 . The compound of claim 33 , or a pharmaceutically acceptable salt or solvate thereof, wherein Y is phenyl optionally substituted with 1, 2, or 3 R 7 .
35 . The compound of any one of claims 30 - 34 , or a pharmaceutically acceptable salt or solvate thereof, wherein Y is C 2 -C 9 heteroaryl optionally substituted with 1, 2, or 3 R 7 .
36 . The compound of claim 35 , or a pharmaceutically acceptable salt or solvate thereof, wherein Y 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 .
37 . The compound of an one of claims 30 - 32 , or a pharmaceutically acceptable salt or solvate thereof, wherein Y is
38 . The compound of claim 37 , or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0, 1, or 2.
39 . The compound of any one of claims 30 - 38 , or a pharmaceutically acceptable salt or solvate thereof, wherein each R 7 is independently selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 alkoxy.
40 . The compound of any-one of claims 30 - 32 , or a pharmaceutically acceptable salt or solvate thereof, wherein Y is
41 . The compound of any one of claims 30 - 32 , or a pharmaceutically acceptable salt or solvate thereof, wherein Y is
42 . The compound of any one of claims 30 - 41 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, C 3 -C 6 cycloalkyl, —C 1 -C 6 alkyl-C 3 -C 6 cycloalkyl, C 2 -C 9 heterocycloalkyl, and C 2 -C 9 heteroaryl, wherein C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, —C 1 -C 6 alkyl-C 3 -C 6 cycloalkyl, C 2 -C 9 heterocycloalkyl, or C 2 -C 9 heteroaryl are optionally substituted by 1, 2, or 3 R 7 .
43 . The compound of any one of claims 30 - 42 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is hydrogen.
44 . The compound of any one of claims 30 - 42 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is C 1 -C 6 alkyl optionally substituted by 1, 2, or 3 R 7 .
45 . The compound of claim 44 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is unsubstituted C 1 -C 6 alkyl.
46 . The compound of any one of claims 30 - 42 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is C 3 -C 6 cycloalkyl optionally substituted by 1, 2, or 3 R 7 .
47 . The compound of claim 46 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is unsubstituted C 3 -C 6 cycloalkyl.
48 . The compound of any one of claims 30 - 42 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is C 2 -C 9 heterocycloalkyl optionally substituted by 1, 2, or 3 R 7 .
49 . The compound of any one of claims 30 - 42 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is C 2 -C 9 heteroaryl optionally substituted by 1, 2, or 3 R 7 .
50 . The compound of any one of claims 30 - 49 , or a pharmaceutically acceptable salt or solvate thereof, wherein L 1 is a bond.
51 . The compound of any one of claims 30 - 49 , or a pharmaceutically acceptable salt or solvate thereof, wherein L 1 is —N(H)—.
52 . The compound of any one of claims 30 - 51 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 and R 4 are independently selected from hydrogen and C 1 -C 6 alkyl.
53 . The compound of any one of claims 30 - 52 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is hydrogen and R 4 is C 1 -C 6 alkyl.
54 . The compound of any one of claims 30 - 52 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is hydrogen and R 4 is C 1 -C 6 deuteroalkyl.
55 . The compound of any one of claims 30 - 54 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 6 is hydrogen.
56 . The compound of any one of claims 30 - 55 , or a pharmaceutically acceptable salt or solvate thereof, wherein each R 8 is hydrogen.
57 . The compound of any one of claims 30 - 56 , or a pharmaceutically acceptable salt or solvate thereof, wherein each R 2 is hydrogen.
58 . The compound of any one of claims 30 - 57 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 5 is hydrogen.
59 . The compound of any one of claims 30 - 58 , or a pharmaceutically acceptable salt or solvate thereof, wherein X is N.
60 . The compound of any one of claims 30 - 58 , or a pharmaceutically acceptable salt or solvate thereof, wherein X is C(R 6 ).
61 . The compound of any one of claims 30 - 58 , or a pharmaceutically acceptable salt or solvate thereof, wherein X is C(H).
62 . A compound selected from:
or a pharmaceutically acceptable salt or solvate thereof.
63 . A compound selected from:
or a pharmaceutically acceptable salt or solvate thereof.
64 . A pharmaceutical composition comprising a compound of any one of claims 1 - 63 , or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.
65 . 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 - 63 , or a pharmaceutically acceptable salt or solvate thereof.
66 . The method of claim 65 , 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.Join the waitlist — get patent alerts
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