Cyanopyridine derivatives as liver X receptor beta agonists, compositions, and their use
In its many embodiments, the present invention provides substituted cyanopyridine containing compounds of the Formula (I): and acceptable salts thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , X, Y, Q, and the moiety 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:
the moiety
is a divalent moiety selected from the group consisting of
Y is selected from the group consisting of C(H), C(F), C(Cl), and N,
R 1 is selected from the group consisting of halogen, CN, OH, —(C 3 -C 6 )cycloalkyl, —(C 1- C 4 )alkyl, —(C 1 -C 4 )haloalkyl, and —(C 1 -C 4 )alkoxy;
R 2 is selected from the group consisting of H and halogen;
R 3 is a moiety selected from the group consisting of:
—C(O)N(R N1 )(R N2 ),
wherein R N1 and R N2 are each independently selected from the group consisting of H, —NH2, —NH(C 1 -C 4 alkyl), —N(C 1 -C 4 alkyl) 2 , —(C 1- C 4 alkyl), —(C 2- C 6 )alkenyl, —(C 1- C 4 )alkoxy, —(C 3- C 6 )cycloalkyl, —CH 2 (C 3- C 6 )cycloalkyl, phenyl, —(C 1 -C 4 )alkylphenyl, heterocycloalkyl, —(C 1 -C 4 )alkylheterocycloalkyl, heteroaryl, and —(C 1 -C 4 )alkylheteroaryl,
wherein said —(C 1 -C 4 )alkyl, —(C 1 -C 4 )alkoxy, phenyl, —(C 3 -C 6 )cycloalkyl, heterocycloalkyl, and heteroaryl portions of said R N1 and R N2 are unsubstituted or substituted with one, two, or three groups independently selected from the group consisting of OH, CN, halogen, —NH 2 , —N(C 1 -C 4 alkyl) 2 , —NH(C 1 -C 4 alkyl), —(C 1 -C 4 )alkoxy, optionally substituted phenyl, and optionally substituted heteroaryl, wherein said optional substituents on said phenyl are 1 to 3 groups independently selected from OH, CN, —(C 1 -C 4 )alkyl, —(C 1 -C 4 )alkoxy, and wherein said optional substituents on said heteroaryl are 1 to 3 groups independently selected from —(C 1 -C 4 )alkyl, and —(C 1 -C 4 )alkoxyl, or, alternatively, R N1 and R N2 , together with the nitrogen atom to which they are shown attached, form a 4-, 5-, or 6-membered heteroaryl or partially unsaturated or fully saturated heterocyclic ring comprising (including said nitrogen atom) 1, 2, or 3 ring heteroatoms independently selected from the group consisting of N, O, and S, wherein said heterocyclic ring is unsubstituted or substituted with one, two, or three substitutents independently selected from the group consisting of halo, OH, CN, —(C 1 -C 4 )alkyl, amino-substituted —(C 1 -C 4 )alkyl, wherein said amino is one, two, or three groups independently selected from the group consisting of —NH 2 , —N(C 1 -C 4 alkyl) 2 , and —NH(C 1 -C 4 alkyl), —(C 1 -C 4 )haloalkyl, —(C 1 -C 4 )alkyl-OH, phenyl, benzyl, heteroaryl, and —(C 1 -C 4 )alkylheteroaryl;
R 4 is selected from the group consisting of H, —CN, halogen, —(C 1 -C 4 )alkyl, —(C 2 -C 4 )alkenyl, and —(C 2 -C 4 )alkynyl, wherein said —(C 1 -C 4 )alkyl is optionally substituted with hydroxyl;
Q is selected from the group consisting of —S(O) 2 —, —C(O)—, —C(O)O—, and —C(O)C(O)—; and
R 5 is selected from the group consisting of
—(C 1 -C 8 )alkyl, —(C 1 -C 8 )haloalkyl, —C(OH)(R 5A ) 2 , —C(OCH 3 )(R 5A ) 2 , phenyl, —(C 1 -C 4 )alkyl-phenyl, cycloalkyl, —(C 1 -C 4 )alkyl-cycloalkyl, heterocycloalkyl, —(C 1- C 4 )alkylheterocycloalkyl, heteroaryl, and —(C 1 -C 4 )alkyl-heteroaryl,
wherein each said phenyl, cycloalkyl, and heteroaryl portion of R 5 is unsubstituted or substituted with one, two, or three groups independently selected from the group consisting of halogen, CN, —(C 1 -C 6 )alkyl, —(C 1 -C 4 )haloalkyl, —O(C 1 -C 6 )alkyl, —O(C 1 -C 4 )haloalkyl, phenyl, and
wherein each R 5A is independently selected from the group consisting of —(C 1 -C 8 )alkyl, —(C 1 -C 8 )haloalkyl, phenyl, —(C 1 -C 4 )alkyl-phenyl, and cycloalkyl, wherein said phenyl and said cycloalkyl portion of R 5A is unsubstituted or substituted with one, two, or three groups independently selected from the group consisting of halogen, CN, —(C 1 -C 6 )alkyl, —(C 1 -C 4 )haloalkyl, —O(C 1 -C 6 )alkyl, and —O(C 1 -C 4 )haloalkyl.
2. The compound of claim 1 , wherein:
Y is selected from the group consisting of CH, C(F), C(Cl); and
the moiety
is selected from the group consisting of
3. The compound of claim 1 , wherein:
Y is selected from the group consisting of CH, C(F), C(Cl); and
the moiety
is selected from the group consisting of
4. The compound according to claim 1 , wherein:
Y is selected from the group consisting of CH, C(F), C(Cl); and
the moiety
5. The compound of claim 1 , wherein:
Y is N; and
the moiety
is selected from the group consisting of
6. The compound according to claim 1 , wherein:
Y is N; and
the moiety
is selected from the group consisting of
7. The compound according to claim 1 , wherein:
Y is N; and
the moiety
8. The compound according to claim 1 , wherein:
R N1 is selected from the group consisting of H, CH 3 , and cyclopropyl; and
R N2 is selected from the group consisting of —NH2, —NH(C 1 -C 4 alkyl), —N(C 1 -C 4 alkyl) 2 , —(C 1 -C 4 )alkyl, —(C 1 -C 4 )alkenyl, —(C 1 -C 4 )alkoxyl, and heterocycloalkyl, wherein said —(C 1 -C 4 )alkyl of R N2 is unsubstituted or substituted with from 1 to 3 groups independently selected from CN, OH, optionally substituted phenyl, and optionally substituted heteroaryl, wherein said optional substituents on said phenyl are 1 to 3 groups independently selected from OH, CN, —(C 1 -C 4 )alkyl, —(C 1 -C 4 )alkoxyl, and wherein said optional substituents on said heteroaryl are 1 to 3 groups independently selected from —(C 1 -C 4 )alkyl, and —(C 1 -C 4 )alkoxyl.
9. The compound according to claim 1 , wherein:
R N1 and R N2 , together with the nitrogen atom to which they are shown attached, form a 4-, 5-, or 6-membered heteroaryl or partially unsaturated or fully saturated heterocyclic ring comprising (including said nitrogen atom) 1, 2 or 3 ring heteroatoms independently selected from the group consisting of N, O, and S, wherein said heteroaryl and said heterocyclic ring is unsubstituted or substituted with one, two, or three substitutents independently selected from the group consisting of halo, OH, CN, —(C 1 -C 4 )alkyl, amino-substituted —(C 1 -C 4 )alkyl, wherein said amino is one, two, or three groups independently selected from the group consisting of —NH 2 , —N(C 1 -C 4 alkyl) 2 , and —NH(C 1 -C 4 alkyl), —(C 1 -C 4 )haloalkyl, —(C 1 -C 4 )alkyl-OH, phenyl, benzyl, heteroaryl, and —(C 1 -C 4 )alkylheteroaryl.
10. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein said compound is selected from the group consisting of:
11. A pharmaceutical composition comprising a compound according to claim 1 , a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.
12. 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.
13. The method of claim 12 , wherein said treatment is Alzheimer's disease.