US2021101895A1PendingUtilityA1
Liver x receptor (lxr) modulators for the treatment of dermal diseases, disorders and conditions
Est. expiryMar 2, 2032(~5.6 yrs left)· nominal 20-yr term from priority
Inventors:Raju Mohan
A61K 31/4155C07D 403/04C07D 231/12C07D 413/04C07D 231/16C07D 409/04C07D 405/04C07D 417/04A61P 17/16A61P 17/04A61P 17/00A61P 17/06A61P 43/00A61P 17/02
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Claims
Abstract
Described herein are liver X receptor (LXR) modulators and methods of utilizing LXR modulators in the treatment of dermal diseases, disorders or conditions. Also described herein are pharmaceutical compositions containg such compounds.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A compound having the structure of Formula (A):
wherein:
X is —O— or —S—;
A and B are each nitrogen, wherein A and B are bonded together to form a five-membered heteroaryl ring;
L 1 and L 2 are each independently a bond, C 1 -C 6 alkyl, or C 1 -C 6 heteroalkyl;
R 1 is hydrogen, halogen, —CF 3 , —OR 8 , —N(R 8 ) 2 , —C(═O)R 8 , —C(═O)OR 8 , —C(═O)N(R 8 ) 2 , —C(═N—OH)R 8 , —C(═S)N(R 8 ) 2 , or —C(═O)OCH 2 SCH 3 ;
R 2 is —OR 9 , —N(R 9 ) 2 , —C(═O)R 9 , —C(═O)OR 9 , —C(═O)N(R 9 ) 2 , —NR 10 C(═O)R 9 , —C(═N—OH)R 9 , —C(═S)N(R 9 ) 2 , —C(═O)OCH 2 SCH 3 , C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
R 3 is hydrogen, halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;
R 4 is aryl or heteroaryl; wherein aryl or heteroaryl is substituted with at least one R 11 ;
each R 8 , each R 9 , and each R 10 are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, —C 1 -C 6 alkyl-aryl, aryl, or heteroaryl;
R 11 is independently halogen, nitro, —OR 10 , —N(R 10 ) 2 , —CN, —C(═O)R 10 , —C(═O)OR 10 , —C(═O)N(R 10 ) 2 , —NR 10 C(═O)R 10 , NR 10 SO 2 R 10 , —SOR 10 , —SO 2 R 10 , —SO 2 N(R 10 ) 2 , —C(═O)OCH 2 SCH 3 , C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, —C 1 -C 6 alkyl-aryl, optionally substituted aryl, or optionally substituted heteroaryl;
or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof.
2 . The compound of claim 1 wherein R 4 is aryl.
3 . The compound of claim 2 wherein R 1 is —C(═O)OR 8 and R 8 is C 1 -C 6 alkyl.
4 . The compound of claim 3 wherein L 2 is a bond.
5 . The compound of claim 4 wherein R 2 is optionally substituted aryl.
6 . The compound of claim 5 wherein R 2 is optionally substituted phenyl.
7 . The compound of claim 6 wherein R 3 is hydrogen.
8 . The compound of claim 3 wherein L 2 is C 1 -C 6 alkyl.
9 . The compound of claim 8 wherein R 2 is —OR 9 , —N(R 9 ) 2 , optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl.
10 . The compound of claim 9 wherein R 3 is hydrogen.
11 . The compound of claim 2 wherein R 1 is —CF 3 .
12 . The compound of claim 11 wherein L 2 is C 1 -C 6 alkyl.
13 . The compound of claim 12 wherein R 2 is —C(═O)OR 9 and R 9 is C 1 -C 6 alkyl.
14 . The compound of claim 13 wherein R 3 is hydrogen.
15 . The compound of claim 14 wherein R 4 is phenyl; wherein phenyl is substituted with one R 11 .
16 . The compound of claim 15 wherein R 11 is —SO 2 R 10 and R 10 is C 1 -C 6 alkyl.
17 . A compound having the structure of Formula (E):
wherein:
A and B are each nitrogen, wherein A and B are bonded together to form a five-membered heteroaryl ring;
L 1 is a bond, C 1 -C 6 alkyl, or C 1 -C 6 heteroalkyl;
L 2 is C 1 -C 6 alkyl or C 1 -C 6 heteroalkyl;
R 1 is hydrogen, halogen, —CF 3 , —OR 8 , —N(R 8 ) 2 , —C(═O)R 8 , —C(═O)OR 8 , —C(═O)N(R 8 ) 2 , —C(═N—OH)R 8 , —C(═S)N(R 8 ) 2 , —C(═CH 2 )CH 3 , or —C(═O)OCH 2 SCH 3 ;
R 2 is —C(═O)OR 9 , —C(═O)N(R 9 ) 2 , —NR 10 C(═O)R 9 , —C(═N—OH)R 9 , —C(═S)N(R 9 ) 2 , or —C(═O)OCH 2 SCH 3 ;
R 3 is hydrogen, halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;
R 4 is aryl or heteroaryl; wherein aryl or heteroaryl is substituted with at least one R 11 ;
each R 8 , each R 9 , and each R 10 are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, —C 1 -C 6 alkyl-aryl, aryl, or heteroaryl;
R 11 is independently halogen, nitro, —OR 10 , —N(R 10 ) 2 , —CN, —C(═O)R 10 , —C(═O)N(R 10 ) 2 , —NR 10 C(═O)R 10 , NR 10 SO 2 R 10 , —SO 2 R 10 , —SO 2 N(R 10 ) 2 , —C(═O)OCH 2 SCH 3 , C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, —C 1 -C 6 alkyl-aryl, optionally substituted aryl, or optionally substituted heteroaryl;
or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof.
18 . The compound of claim 17 wherein R 4 is aryl.
19 . The compound of claim 18 wherein R 2 is —C(═O)OR 9 ; and R 9 is C 1 -C 6 alkyl or C 1 -C 6 heteroalkyl.
20 . The compound of claim 19 wherein L 2 is C 1 -C 6 alkyl.
21 . The compound of claim 20 wherein L 2 is —CH 2 —.
22 . The compound of claim 21 wherein L 1 is a bond.
23 . The compound of claim 22 wherein R 1 is —CF 3 , —C(═O)R 8 , —C(═O)OR 8 , —C(═O)N(R 8 ) 2 , or —C(═CH 2 )CH 3 .
24 . The compound of claim 23 wherein R 4 is phenyl; wherein phenyl is substituted with one R 11 .
25 . The compound of claim 24 wherein R 11 is —SO 2 R 10 and R 10 is C 1 -C 6 alkyl.
26 . A compound having the structure of Formula (F):
wherein:
X is —S—;
A and B are each nitrogen, wherein A and B are bonded together to form a five-membered heteroaryl ring;
L 1 is a bond, C 1 -C 6 alkyl, or C 1 -C 6 heteroalkyl;
L 2 is C 1 -C 6 alkyl or C 1 -C 6 heteroalkyl;
R 1 is hydrogen, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, —CF 3 , —OR 8 , —N(R 8 ) 2 , —C(═O)R 8 , —C(═O)OR 8 , —C(═O)N(R 8 ) 2 , —C(═N—OH)R 8 , —C(═S)N(R 8 ) 2 , —C(═CH 2 )CH 3 , or —C(═O)OCH 2 SCH 3 ;
R 2 is —C(═C)OR 13 , —NR 10 C(═C)R 9 , —C(═N—OH)R 9 , —C(═S)N(R 9 ) 2 , or —C(═O)OCH 2 SR 15 ;
R 3 is hydrogen, halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;
R 4 is aryl or heteroaryl; wherein aryl or heteroaryl is substituted with at least one R 11 ;
each R 8 , each R 9 , and each R 10 are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, —C 1 -C 6 alkyl-aryl, aryl, or heteroaryl;
R 11 is independently halogen, nitro, —OR 10 , —N(R 10 ) 2 , —CN, —C(═O)R 10 , —C(═O)OR 10 , —C(═O)N(R 10 ) 2 , —NR 10 C(═O)R 10 , NR 10 SO 2 R 10 , —SOR 10 , —SO 2 R 14 , —SO 2 N(R 10 ) 2 , —C(═O)OCH 2 SCH 3 , optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 8 cycloalkyl, C 1 -C 6 haloalkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted —C 1 -C 6 alkyl-aryl, optionally substituted aryl, or optionally substituted heteroaryl;
R 13 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, —C 1 -C 6 alkyl-aryl, aryl, or heteroaryl;
R 10 is C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, —C 1 -C 6 alkyl-aryl, aryl, or heteroaryl;
R 15 is C 1 -C 6 alkyl;
or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof.
27 . The compound of claim 26 wherein R 2 is —(C═O)OR 13 and R 13 is C 2 -C 6 alkyl, C 1 -C 6 heteroalkyl, —C 1 -C 6 alkyl-aryl, aryl, or heteroaryl.
28 . The compound of claim 27 wherein R 13 is C 2 -C 6 alkyl or C 1 -C 6 heteroalkyl.
29 . The compound of claim 28 wherein R 4 is phenyl.
30 . The compound of claim 29 wherein R 4 is substituted with at least two R 11 .
31 . The compound of claim 30 wherein R 11 is independently halogen, —SO 2 R 14 , —NR 10 SO 2 R 10 , or —SO 2 N(R 10 ) 2 .
32 . The compound of claim 29 wherein R 4 is substituted with one R 11 and R 11 is —SO 2 R 14 .
33 . The compound of claim 32 wherein R 14 is C 1 -C 6 alkyl.
34 . The compound of claim 32 wherein R 14 is C 2 -C 6 alkyl, C 1 -C 6 heteroalkyl, —C 1 -C 6 alkyl-aryl, aryl, or heteroaryl.
35 . The compound of claim 34 wherein R 14 is C 2 -C 6 alkyl.
36 . The compound of claim 35 wherein L 2 is C 1 -C 6 alkyl.
37 . The compound of claim 36 wherein L 2 is —CH 2 —.
38 . The compound of claim 37 wherein L 1 is a bond.
39 . The compound of claim 38 wherein R 1 is hydrogen, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, —OR 8 , —N(R 8 ) 2 , —C(═O)R 8 , —C(═O)OR 8 , —C(═O)N(R 8 ) 2 , —C(═N—OH)R 8 , —C(═S)N(R 8 ) 2 , —C(═CH 2 )CH 3 , or —C(═O)OCH 2 SCH 3 .
40 . The compound of claim 39 wherein R 1 is C 1 -C 6 alkyl, or —C(═CH 2 )CH 3 .
41 . A compound selected from:
or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof.
42 . A compound selected from:
or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof.
43 . A pharmaceutical composition comprising a pharmaceutically acceptable diluent, excipient or binder, and a compound of any one of claim 1 , 17 , or 26 ; or a pharmaceutically acceptable salt, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof.
44 . A method of treating a disease, disorder or condition in a mammal that would benefit from LXR modulation comprising administering to the mammal a compound or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof according to any one of claim 1 , 17 , or 26 .
45 . A method of modulating LXR activity comprising contacting LXR, or portion thereof, with the compound or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof according to any one of claim 1 , 17 , or 26 .
46 . The method of claim 45 , wherein the disease, disorder or condition in a mammal is a dermal disease, disorder or condition selected from skin aging, scarring, psoriasis, dermatitis, eczema, urticaria, rosacea, burns, and acne.Cited by (0)
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