US2021269406A1PendingUtilityA1
Liver x receptor (lxr) modulators
Est. expirySep 4, 2033(~7.1 yrs left)· nominal 20-yr term from priority
Inventors:Raju Mohan
A61P 17/00C07D 231/14C07D 231/12A61P 43/00A61P 1/18A61P 27/02A61P 35/00A61K 31/415A61P 35/04A61K 45/06A61K 31/4164A61P 17/06A61P 31/18C07D 233/64A61P 31/04C07D 409/14A61P 25/16A61P 3/10A61P 1/04A61P 29/00A61P 25/00C07D 413/04A61P 9/10A61P 25/28A61P 3/00A61P 3/06A61P 1/16A61P 1/00A61P 31/00A61K 31/422A61K 31/4152C07D 233/10C07D 409/04
71
PatentIndex Score
0
Cited by
0
References
0
Claims
Abstract
Described herein are liver X receptor (LXR) modulators and methods of utilizing LXR modulators in the treatment of LXR-associated 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 of Formula (IA):
or a pharmaceutically acceptable salt thereof, wherein:
L 1 is a bond, C 1 -C 6 alkyl, or C 1 -C 6 heteroalkyl;
R 1 is —OR 9 , —N(R 9 ) 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 haloalkyl, C 2 -C 9 heterocycloalkyl, —C(═O)R 8 , or —C(═O)N(R 9 ) 2 ;
R 2 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 8 cycloalkyl, or —C 1 -C 6 alkyl-C 3 -C 8 cycloalkyl;
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 5 is independently halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;
R 8 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 haloalkyl, —C 1 -C 6 alkyl-aryl, aryl, or heteroaryl;
each R 9 is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, —C 1 -C 6 alkyl-aryl, aryl, or heteroaryl;
each R 10 is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, —C 1 -C 6 alkyl-aryl, aryl, or heteroaryl;
each 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 , optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted 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; and
n is 0-4.
2 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein L 1 is a bond.
3 . The compound of any one of claims 1 - 2 , or a pharmaceutically acceptable salt thereof, wherein R 1 is C 1 -C 6 alkyl.
4 . The compound of any one of claims 1 - 2 , or a pharmaceutically acceptable salt thereof, wherein R 1 is C 2 -C 6 alkenyl.
5 . The compound of any one of claims 1 - 2 , or a pharmaceutically acceptable salt thereof, wherein R 1 is C 1 -C 6 haloalkyl.
6 . The compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein R 1 is —CF 3 .
7 . The compound of any one of claims 1 - 2 , or a pharmaceutically acceptable salt thereof, wherein R 1 is —C(═O)N(R 9 ) 2 .
8 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein L 1 is C 1 -C 6 alkyl; and R 1 is —OH.
9 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein -L 1 -R 1 is —C(═CH 2 )CH 3 , isopropyl, —C(═O)NHCH 2 CF 3 , —CF 3 , or —C(CH 3 ) 2 OH.
10 . The compound of any one of claims 1 - 9 , or a pharmaceutically acceptable salt thereof, wherein R 2 is C 1 -C 6 alkyl.
11 . The compound of claim 10 , or a pharmaceutically acceptable salt thereof, wherein R 2 is isobutyl.
12 . The compound of claim 10 , or a pharmaceutically acceptable salt thereof, wherein R 2 is sec-butyl.
13 . The compound of any one of claims 1 - 9 , or a pharmaceutically acceptable salt thereof, wherein R 2 is C 3 -C 8 cycloalkyl.
14 . The compound of any one of claims 1 - 9 , or a pharmaceutically acceptable salt thereof, wherein R 2 is —C 1 -C 6 alkyl-C 3 -C 8 cycloalkyl.
15 . The compound of any one of claims 1 - 9 , or a pharmaceutically acceptable salt thereof, wherein R 2 is isobutyl, sec-butyl, cyclohexyl, —CH 2 -cyclohexyl, or —CH 2 -cyclopropyl.
16 . The compound of any one of claims 1 - 15 , or a pharmaceutically acceptable salt thereof, wherein R 3 is hydrogen.
17 . The compound of any one of claims 1 - 16 , or a pharmaceutically acceptable salt thereof, wherein “optionally substituted” means optionally substituted by 1, 2, 3, or 4 substituents independently selected from halo, cyano, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, hydoxy, C 1 -C 4 alkoxy, C 1 -C 4 haloalkyl, C 1 -C 4 haloalkoxy, amino, C 1 -C 4 alkylamino, and di(C 1 -C 4 alkyl)amino.
18 . The compound of any one of claims 1 - 17 , or a pharmaceutically acceptable salt thereof, wherein n is 0.
19 . The compound of any one of claims 1 - 18 , or a pharmaceutically acceptable salt thereof, wherein R 4 is phenyl, which is substituted with at least one R 11 .
20 . The compound of any one of claims 1 - 19 , or a pharmaceutically acceptable salt thereof, wherein at least one R 11 is —NR 10 SO 2 R 10 , —SOR 10 , —SO 2 R 10 , or —SO 2 N(R 10 ) 2 .
21 . The compound of any one of claims 1 - 19 , or a pharmaceutically acceptable salt thereof, wherein at least one R 11 is —SO 2 R 10 .
22 . The compound of any one of claims 20 - 21 , or a pharmaceutically acceptable salt thereof, wherein each R 10 is independently C 1 -C 6 alkyl.
23 . The compound of any one of claims 1 - 18 , or a pharmaceutically acceptable salt thereof, wherein R 4 is phenyl substituted with one R 11 , wherein R 11 is —SO 2 R 10 and R 10 is C 1 -C 6 alkyl; or R 4 is phenyl substituted with two R 11 , and one R 11 is —SO 2 R 10 ; and one R 11 is optionally substituted C 1 -C 6 alkyl.
24 . The compound of any one of claims 1 - 18 , or a pharmaceutically acceptable salt thereof, wherein R 4 is phenyl substituted with two R 11 , wherein one R 11 is —SO 2 CH 3 and one R 11 is —CH 2 OH.
25 . The compound of any one of claims 1 - 18 , or a pharmaceutically acceptable salt thereof, wherein R 4 is phenyl substituted with one R 11 , wherein R 11 is —SO 2 R 10 and R 10 is C 1 -C 6 alkyl.
26 . The compound of any one of claims 1 - 18 , wherein the compound is a compound of Formula (IB):
wherein:
R 11a is —NR 10 SO 2 R 10 , —SOR 10 , —SO 2 R 10 , or —SO 2 N(R 10 ) 2 ; and
m is 0 or 1;
or a pharmaceutically acceptable salt thereof.
27 . The compound of any one of claims 1 - 18 , wherein the compound is a compound of Formula (IC):
wherein m is 0 or 1;
or a pharmaceutically acceptable salt thereof.
28 . The compound of claim 1 or 27 , or a pharmaceutically acceptable salt thereof, wherein:
L 1 is a bond or C 1 -C 6 alkyl;
R 1 is —OR 9 , —C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 haloalkyl, or —C(═O)N(R 9 ) 2 ;
R 2 is C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, or —C 1 -C 6 alkyl-C 3 -C 8 cycloalkyl;
R 3 is hydrogen;
R 4 is phenyl substituted with at least one R 11 ;
each R 11 is independently —NR 10 SO 2 R 10 , —SOR 10 , —SO 2 R 10 , —SO 2 N(R 10 ) 2 , or C 1 -C 6 alkyl, wherein said C 1 -C 6 alkyl is optionally substituted by 1 hydoxy;
provided that at least one R 11 is —NR 10 SO 2 R 10 , —SOR 10 , —SO 2 R 10 , or —SO 2 N(R 10 ) 2 ,
each R 10 is independently C 1 -C 6 alkyl; and
each R 9 is independently hydrogen or C 1 -C 6 haloalkyl; and
n is 0.
29 . The compound of claim 1 or 27 , or a pharmaceutically acceptable salt thereof, wherein:
L 1 is a bond or C 1 -C 6 alkyl;
R 1 is —OR 9 , —C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 haloalkyl, or —C(═O)N(R 9 ) 2 ;
R 2 is C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, or —C 1 -C 6 alkyl-C 3 -C 8 cycloalkyl;
R 3 is hydrogen;
R 4 is phenyl substituted with one R 11 , wherein R 11 is —SO 2 R 10 and R 10 is C 1 -C 6 alkyl; or
R 4 is phenyl substituted with two R 11 , wherein one R 11 is —SO 2 R 10 and one R 11 is optionally substituted C 1 -C 6 alkyl;
each R 9 is independently hydrogen or C 1 -C 6 haloalkyl; and
n is 0.
30 . The compound of claim 1 or 27 , or a pharmaceutically acceptable salt thereof, wherein:
-L 1 -R 1 is —C(═CH 2 )CH 3 , isopropyl, —C(═O)NHCH 2 CF 3 , —CF 3 , or —C(CH 3 ) 2 OH;
R 2 is isobutyl, sec-butyl, cyclohexyl, —CH 2 -cyclohexyl, or —CH 2 -cyclopropyl;
R 3 is hydrogen;
R 4 is phenyl substituted with two R 11 , wherein one R 11 is —SO 2 CH 3 and one R 11 is —CH2OH; or R 4 is phenyl substituted with one R 11 , wherein R 11 is —SO 2 R 10 and R 10 is CH 3 ; and
n is 0.
31 . The compound of claim 1 , selected from:
or a pharmaceutically acceptable salt thereof.
32 . The compound of claim 1 , selected from:
or a pharmaceutically acceptable salt thereof.
33 . A compound of Formula (II):
or a pharmaceutically acceptable salt thereof, wherein:
X is —O—, —S—, or —C(R 6 )═C(R 6 )—;
L 1 is a bond, C 1 -C 6 alkyl, or C 1 -C 6 heteroalkyl;
R 1 is —OR 9 , —N(R 9 ) 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 haloalkyl, C 2 -C 9 heterocycloalkyl, —C(═O)R 8 , or —C(═O)N(R 9 ) 2 ;
R 2 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 8 cycloalkyl, or —C 1 -C 6 alkyl-C 3 -C 8 cycloalkyl;
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 5 is independently halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;
each R 6 is independently hydrogen, halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;
R 8 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 haloalkyl, —C 1 -C 6 alkyl-aryl, aryl, or heteroaryl;
each R 9 is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, —C 1 -C 6 alkyl-aryl, aryl, or heteroaryl;
each R 10 is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, —C 1 -C 6 alkyl-aryl, aryl, or heteroaryl;
each 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 10 R 10 , —SOR 10 , —SO 2 R 10 , —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, optionally substituted 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; and
n is 0-2.
34 . The compound of claim 33 , or a pharmaceutically acceptable salt thereof, wherein X is —S—.
35 . The compound of claim 33 , or a pharmaceutically acceptable salt thereof, wherein X is —CH═CH—.
36 . The compound of claim 35 , or a pharmaceutically acceptable salt thereof, wherein L 1 is a bond; and R 1 is C 1 -C 6 alkyl.
37 . The compound of claim 35 , or a pharmaceutically acceptable salt thereof, wherein L 1 is a bond and R 1 is C 1 -C 6 haloalkyl.
38 . The compound of claim 35 , or a pharmaceutically acceptable salt thereof, wherein -L 1 -R 1 is C 1 -C 6 alkyl, C 1 -C 6 alkyl-OH, or C 1 -C 6 haloalkyl.
39 . The compound of claim 35 , or a pharmaceutically acceptable salt thereof, wherein -L 1 -R 1 is selected from CF 3 or —C(CH 3 ) 2 OH.
40 . The compound of any one of claims 35 - 39 , or a pharmaceutically acceptable salt thereof, wherein R 2 is C 1 -C 6 alkyl.
41 . The compound of any one of claims 35 - 39 , or a pharmaceutically acceptable salt thereof, wherein R 2 is isobutyl.
42 . The compound of any one of claims 35 - 41 , or a pharmaceutically acceptable salt thereof, wherein R 3 is hydrogen.
43 . The compound of any one of claims 35 - 42 , or a pharmaceutically acceptable salt thereof, wherein n is 0.
44 . The compound of any one of claims 35 - 43 , or a pharmaceutically acceptable salt thereof, wherein R 4 is phenyl; wherein said phenyl is substituted with at least one R 11 .
45 . The compound of any one of claims 35 - 44 , or a pharmaceutically acceptable salt thereof, wherein at least one R 11 is —NR 10 SO 2 R 10 , —SOR 10 , —SO 2 R 10 , or —SO 2 N(R 10 ) 2 .
46 . The compound of any one of claims 35 - 44 , or a pharmaceutically acceptable salt thereof, wherein at least one R 11 is —SO 2 R 10 .
47 . The compound of claim 45 or 46 , or a pharmaceutically acceptable salt thereof, wherein each R 10 is independently C 1 -C 6 alkyl.
48 . The compound of claim 45 or 46 , or a pharmaceutically acceptable salt thereof, wherein each R 10 is methyl.
49 . The compound of any one of claims 35 - 43 , or a pharmaceutically acceptable salt thereof, wherein R 4 is phenyl substituted with one R 11 , wherein R 11 is —SO 2 R 10 and R 10 is C 1 -C 6 alkyl; or R 4 is phenyl substituted with two R 11 , and one R 11 is —SO 2 R 10 and one R 11 is optionally substituted C 1 -C 6 alkyl.
50 . The compound of any one of claims 35 - 43 , or a pharmaceutically acceptable salt thereof, wherein R 4 is phenyl substituted with two R 11 , wherein one R 11 is —SO 2 CH 3 and one R 11 is —CH 2 OH.
51 . The compound of any one of claims 35 - 43 , or a pharmaceutically acceptable salt thereof, wherein R 4 is phenyl substituted with one R 11 , wherein R 11 is —SO 2 R 10 and R 10 is C 1 -C 6 alkyl.
52 . The compound of any one of claims 35 - 51 , or a pharmaceutically acceptable salt thereof, wherein “optionally substituted” means optionally substituted by 1, 2, 3, or 4 substituents independently selected from halo, cyano, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, hydoxy, C 1 -C 4 alkoxy, C 1 -C 4 haloalkyl, C 1 -C 4 haloalkoxy, amino, C 1 -C 4 alkylamino, and di(C 1 -C 4 alkyl)amino.
53 . The compound of any one of claims 35 - 43 , wherein the compound is a compound of Formula (IIA):
wherein:
R 11a is —NR 10 SO 2 R 10 , —SOR 10 , —SO 2 R 10 , or —SO 2 N(R 10 ) 2 ; and
m is 0 or 1;
or a pharmaceutically acceptable salt thereof.
54 . The compound of any one of claims 35 - 43 , wherein the compound is a compound of Formula (IIB):
wherein m is 0 or 1;
or a pharmaceutically acceptable salt thereof.
55 . The compound of claim 35 , or a pharmaceutically acceptable salt thereof, wherein:
X is —CH═CH—; -L 1 -R 1 is C 1 -C 6 alkyl, C 1 -C 6 alkyl-OH, or C 1 -C 6 haloalkyl; R 2 is C 1 -C 6 alkyl; R 3 is hydrogen; R 4 is phenyl; wherein said phenyl is substituted with at least one R 11 ; each R 11 is independently —NR 10 SO 2 R 10 , —SOR 10 , —SO 2 R 10 , —SO 2 N(R 10 ) 2 , or C 1 -C 6 alkyl, wherein said C 1 -C 6 alkyl is optionally substituted by 1 hydoxy; provided that at least one R 11 is —NR 10 SO 2 R 10 , —SOR 10 , —SO 2 R 10 , or —SO 2 N(R 10 ) 2 , each R 10 is independently C 1 -C 6 alkyl; and n is 0.
56 . The compound of claim 35 , or a pharmaceutically acceptable salt thereof, wherein:
X is —CH═CH—; -L 1 -R 1 is C 1 -C 6 alkyl, C 1 -C 6 alkyl-OH, or C 1 -C 6 haloalkyl; R 2 is C 1 -C 6 alkyl; R 3 is hydrogen; R 4 is phenyl; wherein said phenyl is substituted with at least one R 11 ; wherein each R 11 is independently —SO 2 R 10 , or C 1 -C 6 alkyl, wherein said C 1 -C 6 alkyl is optionally substituted by 1 hydoxy; provided that at least one R 11 is —SO 2 R 10 , each R 10 is independently C 1 -C 6 alkyl; and n is 0.
57 . The compound of claim 35 , selected from:
or a pharmaceutically acceptable salt thereof.
58 . The compound of claim 34 , selected from:
or a pharmaceutically acceptable salt thereof.
59 . A compound selected from:
or a pharmaceutically acceptable salt thereof.
60 . A pharmaceutical composition comprising a compound according to any one of claims 1 - 59 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
61 . 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 according to any one of claims 1 - 59 , or a pharmaceutically acceptable salt thereof.
62 . The method of claim 61 , wherein the disease, disorder or condition in a mammal is increased lipid levels, increased cholesterol levels, low HDL-cholesterol, high LDL-cholesterol, atherosclerotic diseases, diabetes, non-insulin dependent diabetes mellitus, metabolic syndrome, dyslipidemia, sepsis, inflammatory diseases, infectious diseases, skin diseases, colitis, pancreatitis, cholestasis of the liver, fibrosis of the liver, psoriasis, Alzheimer's disease, Parkinson's disease, impaired/improvable cognitive function, HIV, cancer including metastatic cancer and metastatic melanoma, acute macular degeneration, and age related forms of macular degeneration (wet and dry forms).
63 . The method of claim 61 , wherein the disease, disorder or condition is cancer.
64 . The method of claim 63 , wherein the cancer is malignant melanoma.
65 . The method of claim 63 , wherein ApoE levels are reduced in said cancer.
66 . The method of claim 62 , further comprising administering a second therapeutic agent.
67 . The method of claim 66 , wherein the second therapeutic agent is a BRAF inhibitor.
68 . The method of claim 67 , wherein the BRAF inhibitor is selected from PDC-4032, GSK2118436, and PLX-3603.
69 . The method of claim 66 , wherein the second therapeutic agent is sunitinib malate, sorafenib tosylate, imatinib mesylate, or nilotinib hydrochloride monohydrate; or a combination thereof.
70 . The method of any one of claims 61 - 69 , wherein the mammal is a human.
71 . The method of claim 61 , wherein the disease, disorder or condition is Alzheimer's disease.
72 . The method of claim 61 , wherein the disease, disorder or condition is Parkinson's disease.
73 . A method of modulating LXR activity comprising contacting LXR, or portion thereof, with a compound according to any one of claims 1 - 59 , or a pharmaceutically acceptable salt thereof.Cited by (0)
No later patents cite this yet.
References (0)
No backward citations on record.