Aryl and heteroaryl ether derivatives as liver X receptor beta agonists, compositions, and their use
In its many embodiments, the present invention provides certain substituted aryl and heteroaryl ether compounds of the Formula (I): and pharmaceutically acceptable salts thereof, wherein X, R 1 , R 2 , R 3 , L, R 4 , L 1 , Q, and R 5 are as defined herein. The novel compounds of the invention, and pharmaceutically acceptable compositions comprising a compound thereof, are useful as Liver X-β receptor (LXRβ) agonists, and may be useful for treating or preventing pathologies related thereto. Such pathologies include, but are not limited to, inflammatory diseases and diseases characterized by defects in cholesterol and lipid metabolism, such as Alzheimer's disease.
1. A compound having the structural Formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
X is CH or N;
R 1 is selected from H, methyl, and halogen;
R 2 is selected from H, Cl, cyano, cyclopropyl, —CH 3 , and —OCH 3 ;
R 4 is selected from H, Cl, and methyl;
-L- is a divalent moiety C(O)—;
R 3 is —N(R N1 )(R N2 ), wherein R N1 and R N2 are taken together with the nitrogen atom to which they are shown attached to form a 4-, 5-, or 6-membered fully saturated heterocyclic ring wherein said heterocyclic ring having 1, 2, or 3 ring heteroatoms selected from N, N-oxide, O, S, and S-oxide,
wherein said heterocyclic ring is unsubstituted or substituted with 1, 2, or 3 substituents independently selected from halogen, —OH, oxo, CN, —(C 1 -C 6 )alkyl, amino-substituted —(C 1 -C 6 )alkyl, —O—(C 1 -C 6 )alkyl, —(C 1 -C 6 )alkyl-OH, —(C 1 -C 6 )haloalkyl, —C(O)O—(C 1 -C 6 )alkyl, cyclopropyl, spirocyclopropyl, —CH 2 —NHC(O)O—(C 1 -C 6 )alkyl, —CH 2 —N(CH 3 )C(O)O—(C 1 -C 6 )alkyl, phenyl, benzyl, —NHC(O)-phenyl, heteroaryl, —(C 1 -C 4 )alkylheteroaryl, and heterocycloalkyl, wherein 1, 2, or 3 groups of said amino substituent on the amino-substituted —(C 1 -C 6 )alkyl is independently selected from —NH 2 , —N(C 1 -C 4 alkyl) 2 , and —NH(C 1 -C 4 alkyl);
-L 1 - is a divalent moiety selected from:
Q is a bond or a divalent moiety selected from —C(O)—, and —S(O) 2 —; and
R 5 is selected from:
1) —C(R 5A )(R 5B )(R 5C ), wherein:
R 5A is OH;
R 5B is —(C 1 -C 3 )fluoroalkyl; and
R 5C is selected from NH 2 , NHCH 3 , —(C 1 -C 6 )alkyl, —(C 1 -C 4 )fluoroalkyl, thiadiazolyl, thienyl, thiazolyl, ethenyl, ethynyl, phenyl, cyclopropyl, and cyclobutyl; wherein said phenyl is substituted with from 1-3 groups independently selected from halogen —(C 1 -C 6 )alkyl, and —(C 1 -C 6 )alkoxy; wherein said cyclopropyl or cyclobutyl is optionally substituted with —(C 1 -C 6 )alkyl;
2)
wherein n is an integer from 1 to 4;
wherein R 5D is selected from H, —(C 1 -C 6 )alkyl, —(C 1 -C 6 )haloalkyl, pyrimidinyl, phenyl, and said phenyl substituted with from 1 to 3 groups independently selected from OH, halogen, —(C 1 -C 6 )alkyl, and —O—(C 1 -C 6 )alkyl; and R 6 is H or CH 3 , —O—(C 1 -C 6 )alkyl; and
3) unsubstituted phenyl or phenyl substituted with 1, 2, or 3 groups independently selected from halogen, CN, —(C 1 -C 6 )alkyl, —(C 1 -C 6 )haloalkyl, and pyrrolidinyl.
2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X is N.
3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X is CH.
4. The compound of claim 3 , or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from H, methyl, F, and Cl.
5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein: Q is selected from a bond, and —C(O)—.
6. A compound or a pharmaceutically acceptable salt thereof, said compound selected from:
7. A pharmaceutical composition comprising a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.
8. A method for the treatment of Alzheimer's Disease, Neimann-Pick disease type C1, Parkinson's Disease, amyotrophic lateral sclerosis, stroke, age-related macular degeneration, schizophrenia, depression, cardiovascular disease, obesity, or diabetes, said method comprising administering an effective amount of a compound according to claim 1 to a patient in need thereof.