US 2019/0315708 A1 · HETEROARYL PIPERIDINE ETHER ALLOSTERIC MODULATORS OF THE M4 MUSCARINIC ACETYLCHOLINE RECEPTOR

Abstract

The present invention is directed to heteroarylpiperidine ether compounds which are allosteric modulators of the M4 muscarinic acetylcholine receptor. The present invention is also directed to uses of the compounds described herein in the potential treatment or prevention of neurological and psychiatric disorders and diseases in which M4 muscarinic acetylcholine receptors are involved. The present invention is also directed to compositions comprising these compounds. The present invention is also directed to uses of these compositions in the potential prevention or treatment of such diseases in which M4 muscarinic acetylcholine receptors are involved.

A compound of the formula I:

wherein:
Y is selected from the group consisting of:
(1) N, and
(2) (CR11);
Z is selected from the group consisting of:
(1) N, and
(2) (CR10), with the proviso that if Y is N, then Z is (CR10);
R1 is selected from the group consisting of:
(1) —C1-6alkyl, which is unsubstituted or substituted with substituents selected from the group consisting of:
hydroxy, fluoro, —CN, —O—C1-6alkyl, and C3-6cycloalkyl, wherein the C1-6alkyl or C3-6cycloalkyl is unsubstituted or substituted with substituents selected from the group consisting of:
fluoro, cyano, CF3, C1-6alkyl or —O—C1-6alkyl;
(2) a phenyl, heteroaryl or heterocyclyl ring, wherein the phenyl, heteroaryl or heterocyclyl ring is substituted with one or more R1a, R1b and R1c, wherein R1a, R1b and R1c are independently selected from the group consisting of:
(a) hydrogen,
(b) halogen,
(c) C1-6alkyl, which is unsubstituted or substituted with substituents selected from the group consisting of:
hydroxyl, fluoro and —NH2,
(d) —O—C1-6alkyl, which is unsubstituted or substituted with substituents selected from the group consisting of:
fluoro and —NH2,
(e) C3-6cycloalkyl,
(f) —SO2—C1-6alkyl, and
(g) —CN;
R2 and R3 are independently selected from the group consisting of:
(1) hydrogen, and
(2) fluoro;
R7 is selected from the group consisting of:
(1) halogen,
(2) C1-6alkyl, which is unsubstituted or substituted with hydroxy, methoxy, fluoro or —(C═O)O—C1-6alkyl,
(3) —CN, and
(4) —(C═O)O—C1-6alkyl;
R8 is selected from the group consisting of:
(1) hydrogen,
(2) halogen,
(3) —C1-6alkyl, which is unsubstituted or substituted with substituents selected from the group consisting of:
hydroxy, methoxy, fluoro, —C(C═O)O—C1-6alkyl, —NH2, —NH(C1-6alkyl), —N(C1-6alkyl)2, —C(C═O)NH2, —C(C═O)OH, oxetanyl, phenyl, or pyridyl,
(4) —C2-4alkenyl,
(5) —C3-6cycloalkyl, which is unsubstituted or substituted with fluoro,
(6) a phenyl or heteroaryl ring, wherein the phenyl or heteroaryl ring is independently substituted with one or more R1a, R1b and R1c,
(7) —NH2, —NH(C1-6alkyl), or —N(C1-6alkyl)2, which is unsubstituted or substituted with fluoro, hydroxyl or pyridinyl,
(8) azetidinyl, furanyl, oxadiazolyl, pyrrolidinyl, or piperidinyl, which is unsubstituted or substituted with fluoro, or which is fused with oxetanyl, tetrahydrofuranyl, thiazolyl, or pyridinyl, which is unsubstituted or substituted with fluoro, and
(9) —CN;
each of R10 and R11 is independently selected from the group consisting of:
(1) hydrogen,
(2) halogen,
(3) hydroxy,
(4) —C1-6alkyl, which is unsubstituted or substituted with substituents selected from the group consisting of:
hydroxy, methoxy, or fluoro,
(5) —C2-4alkenyl,
(6) —O—C1-6alkyl, which is unsubstituted or substituted with substituents selected from the group consisting of:
methoxy or fluoro,
(7) —C3-6cycloalkyl, which is unsubstituted or substituted with fluoro,
(8) —(C═O)O—C1-6alkyl,
(9) —(C═O)NH2,
(10) —(C═O)—NH—C3-6cycloalkyl, which is unsubstituted or substituted with phenyl, pyridinyl, fluoro, chloro, —C1-6alkyl or —O—C1-6alkyl,
(11) —(C═O)—NH—C1-6alkyl, which is unsubstituted or substituted with benzodioxolyl, benzofuranyl, bicyclopentyl, imidazolyl, imidazolopyridinyl, indenyl, isothiazolyl, oxoisoindolinyl, oxopyrrolidinyl, phenyl, pyrrolidinonyl, pyrazolyl, pyridyl, pyridinyl, pyridazinyl, pyrimidinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, thiadiazolyl, thiazolyl, triazolyl, which is unsubstituted or substituted with fluoro, chloro, —CF3, —CN, —O—C1-6alkyl, phenyl, or pyridyl;
(12) —(C═O)—NH-heteroaryl or —(C═O)—NH-heterocyclyl, wherein the heteroaryl or heterocyclyl is selected from the group consisting of benzodioxolyl, benzofuranyl, bicyclopentyl, imidazolyl, imidazolopyridinyl, indenyl, isothiazolyl, oxoisoindolinyl, oxopyrrolidinyl, pyrrolidinonyl, pyrazolyl, pyridyl, pyridinyl, pyridazinyl, pyrimidinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, thiadiazolyl, thiazolyl, triazolyl, which is unsubstituted or substituted with fluoro, chloro, —CF3, —CN, —(SO2)—C1-6alkyl, —O—C1-6alkyl, phenyl, or pyridyl;
(13) —(C═O)—NH—O—C1-6alkyl,
(14) —(C═O)—NH—NH—C1-6alkyl,
(15) pyridyl,
(16) oxadiazolyl,
(17) —NH2,
(18) —NH—C1-6alkyl or —N(C1-6alkyl)2,which is unsubstituted or substituted with fluoro, hydroxyl, phenyl, or pyridyl,
(19) —CN,
(20) —S—C1-6alkyl, and
(21) —(SO2)—C1-6alkyl;
or a pharmaceutically acceptable salt thereof.

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Heteroaryl piperidine ether allosteric modulators of the m4 muscarinic acetylcholine receptor

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Heteroaryl piperidine ether allosteric modulators of the m4 muscarinic acetylcholine receptor

Life of this patent

Abstract

Claims22