US 2013/0210804 A1 · TRICYCLIC MGLUR5 RECEPTOR MODULATORS

Abstract

The present invention is directed to tricyclic compounds which are positive allosteric modulators of metabotropic glutamate receptors, particularly the mGluR5 receptor, and which are useful in the treatment or prevention of neurological and psychiatric disorders associated with glutamate dysfunction and diseases in which metabotropic glutamate receptors are involved. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which metabotropic glutamate receptors are involved.

A compound of the formula I:

wherein:
A is selected from the group consisting of phenyl, naphthyl and heteroaryl;
X is selected from N, O, S and C(R8),
Y is selected from N, O, S and C(R8),
wherein X is N and Y is O, to form a oxadiazole ring, or
X is O and Y is N, to form a oxadiazole ring, or
X is C(R8) and Y is S to form a thiazole ring, or
X is S and Y is C(R8) to form a thiazole ring, or
X is C(R8) and Y is N to form an imidazole ring, or
X is N and Y is C(R8) to form an imidazole ring, or
X is C(R8) and Y is O to form an oxazole ring, or
X is O and Y is C(R8) to form an oxazole ring, or
X is N and Y is N to form a triazole ring;
Q is selected from C and N,
V is selected from C and N,
K is —CH2—,
Z is selected from —CH2—, —CH(CH3)—, —CHF—, —CF2—, —CH(OH)—, —O—, —S—, —S(O)—, —NH—, and —N(CH3)—, or
K is —CH(OH)— and Z is —CH(OH)—, or
K and Z taken together form —CH═CH—, or
K and Z taken together form a cyclopropyl ring;
R1a, R1b and R1c may be absent if the valency of A does not permit such substitution and are independently selected from the group consisting of:
(1) hydrogen,
(2) halogen,
(3) hydroxyl,
(4) —(C═O)m—On—C1-6alkyl, where m is 0 or 1, n is 0 or 1 (wherein if m is 0 or n is 0, a bond is present) and where the alkyl is unsubstituted or substituted with one or more substituents selected from R13,
(5) —(C═O)m—On—C3-6cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one or more substituents selected from R13,
(6) —(C═O)m—C2-4alkenyl, where the alkenyl is unsubstituted or substituted with one or more substituents selected from R13,
(7) —(C═O)m—C2-4alkynyl, where the alkynyl is unsubstituted or substituted with one or more substituents selected from R13,
(8) —(C═O)m—On-phenyl or —(C═O)m—On-napthyl, where the phenyl or naphthyl is unsubstituted or substituted with one or more substituents selected from R13,
(9) —(C═O)m—On-heteroaryl, where the heteraryl is unsubstituted or substituted with one or more substituents selected from R13,
(10) —(C═O)m—NR10R11, wherein R10 and R11 are independently selected from the group consisting of:
(a) hydrogen,
(b) C1-6alkyl, which is unsubstituted or substituted with R14,
(c) C3-6alkenyl, which is unsubstituted or substituted with R14,
(d) C3-6alkynyl, which is unsubstituted or substituted with R14,
(e) C3-6cycloalkyl which is unsubstituted or substituted with R14,
(f) phenyl, which is unsubstituted or substituted with R14, and
(g) heteroaryl, which is unsubstituted or substituted with R14,
(11) —S(O)2—NR10R11,
(12) —S(O)q—R12, where q is 0, 1 or 2 and where R12 is selected from the definitions of R10 and R11,
(13) —CO2H,
(14) —CN, and
(15) —NO2;
R2a, R2b and R2c are independently selected from the group consisting of:
(1) hydrogen,
(2) halogen,
(3) hydroxyl,
(4) —(C═O)m—On—C1-6alkyl, where the alkyl is unsubstituted or substituted with one or more substituents selected from R13,
(5) —(C═O)m—On—C3-6cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one or more substituents selected from R13,
(6) —(C═O)m—C2-4alkenyl, where the alkenyl is unsubstituted or substituted with one or more substituents selected from R13,
(7) —(C═O)m—C2-4alkynyl, where the alkynyl is unsubstituted or substituted with one or more substituents selected from R13,
(8) —(C═O)m—On-phenyl or —(C═O)m—On-napthyl, where the phenyl or naphthyl is unsubstituted or substituted with one or more substituents selected from R13,
(9) —(C═O)m—On-heteroaryl, where the heteroaryl is unsubstituted or substituted with one or more substituents selected from R13,
(10) —(C═O)m—NR10R11,
(11) —S(O)2—NR10R11,
(12) —S(O)q—R12,
(13) —CO2H,
(14) —CN, and
(15) —NO2;
R8 is selected from the group consisting of:
(1) hydrogen,
(2) halogen,
(3) C1-6alkyl, which is unsubstituted or substituted with R13,
(4) C3-6alkenyl, which is unsubstituted or substituted with R13,
(5) C3-6alkynyl, which is unsubstituted or substituted with R13,
(6) C3-6cycloalkyl which is unsubstituted or substituted with R13,
(7) phenyl, which is unsubstituted or substituted with R13, and
(6) heteroaryl, which is unsubstituted or substituted with R13,
R13 is selected from the group consisting of:
(1) halogen,
(2) hydroxyl,
(3) —(C═O)m—On—C1-6alkyl, where the alkyl is unsubstituted or substituted with one or more substituents selected from R14,
(4) —On—(C1-3)perfluoroalkyl,
(5) —(C═O)m—On—C3-6cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one or more substituents selected from R14,
(6) —(C═O)m—C2-4alkenyl, where the alkenyl is unsubstituted or substituted with one or more substituents selected from R14,
(7) —(C═O)m—C2-4alkynyl, where the alkynyl is unsubstituted or substituted with one or more substituents selected from R14,
(8) —(C═O)m—On-phenyl or —(C═O)m—On-napthyl, where the phenyl or naphthyl is unsubstituted or substituted with one or more substituents selected from R14,
(9) —(C═O)m—On-heteroaryl, where the heteroaryl is unsubstituted or substituted with one or more substituents selected from R14,
(10) —(C═O)m—NR10R11,
(11) —S(O)2—NR10R11,
(12) —S(O)q—R12,
(13) —CO2H,
(14) —CN, and
(15) —NO2;
R14 is selected from the group consisting of:
(1) hydroxyl,
(2) halogen,
(3) C1-6alkyl,
(4) —C3-6cycloalkyl,
(5) —O—C1-6 alkyl,
(6) —O(C═O)—C1-6alkyl,
(7) —NH—C1-6 alkyl,
(8) phenyl,
(9) heteroaryl,
(10) —CO2H, and
(11) —CN;
or a pharmaceutically acceptable salt thereof.

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Tricyclic mglur5 receptor modulators

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Tricyclic mglur5 receptor modulators

Life of this patent

Abstract

Claims17