US 11,230,556 B2 · 6,5-fused heteroaryl piperidine ether allosteric modulators of the M4 muscarinic acetylcholine receptor

Abstract

The present invention is directed to 6,5-fused 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:
K is N or C—R8;
Q is N or C;
X is selected from the group consisting of:
(1) ═N—,
(2) —(NR9)—,
(3) —C═O—,
(4) ═(CR10)—, and
(5) —(CHR10—;
Y is selected from the group consisting of:
(1) —O—,
(2) ═N—,
(3) —(NR9)—,
(4) —C═O—, and
(5) —(CR11R12)—;
Z is selected from the group consisting of:
(1) —(NR9)—,
(2) —C═O—,
(3) ═(CR12)—,
(4) —(CHR12)—, and
(5) —(SO2)—;
with the proviso that if X is —(CHR10)—, Y is —(NR9)—, and Z is —(C═O)—, then Q is —N—;
R1 is selected from the group consisting of:
benzodioxolyl, benzoimidazolyl, benzoxazolyl, benzooxazinone, benzooxazolone, benzothiazolyl, chromanyl, cyclopentapyridinyl, dihydrobenzo[1,4]dioxinyl, dihydrobenzofuranyl, dihydrobenzo[1,4]oxazinyl, dihydrofuropyridinyl, dihydroisobenzofuranyl, dihydroisoquinolinone, dihydropyranopyridinyl, dihydroimidazopyridine, dihydropyrido[1,4]oxazinyl, dihydroquinolinone, indazolyl, indanyl, indolyl, isochromanone, isobenzofuranone, isochromanyl, isoindolinyl, isoxazolyl, oxoisoindolinyl, phenyl, pyrazolopyridinyl, pyrazolyl, pyridyl, pyrrolopyridinyl, pyrimidinyl, quinolinone, quinolinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, and tetrahydropyranyl, which group is substituted with one or more R1a, R1b and R1c, wherein R1aR1b and R1c are independently selected from the group consisting of:
(a) hydrogen,
(b) hydroxy,
(c) halogen,
(d) C1-6alkyl, which is unsubstituted or substituted with substituents selected from the group consisting of:
hydroxy, cyclopropyl, cyclobutyl, cyclopentyl, fluoro, and —OCH3,
(e) —O—C1-6alkyl, which is unsubstituted or substituted with substituents selected from the group consisting of:
hydroxy, cyclopropyl, cyclobutyl, cyclopentyl, fluoro, and —OCH3,
(f) C3-6cycloalkyl, which is unsubstituted or substituted with substituents selected from the group consisting of:
hydroxy, cyclopropyl, cyclobutyl, cyclopentyl, fluoro, and —OCH3, and
(p) —CN;
R2 and R3 are independently selected from the group consisting of:
(1) hydrogen,
(2) fluoro,
(3) hydroxy, and
(4) —CH3;
R7 and R8 are independently selected from the group consisting of:
(1) hydrogen,
(2) C1-6alkyl,
(5) -fluoro, and
(6) -chloro;
R9 is selected from the group consisting of:
(1) hydrogen,
(2) —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, or pyridyl,
(3) —C3-6cycloalkyl, which is unsubstituted or substituted with fluoro,
(4) —C═O—C1-6alkyl, which is unsubstituted or substituted with substituents selected from the group consisting of:
hydroxy, methoxy, ethoxy, fluoro, azetidinyl, oxetanyl, or —C3-6cycloalkyl which is unsubstituted or substituted with fluoro, pyrrolyl, imidazolyl, —NH2, —NH(C1-6alkyl), or —N(C1-6alkyl)2,
(4) —(C═O)O—C1-6alkyl,
(5) —(SO2)—C1-6alkyl, and
(6) —(SO2)—C3-6cycloalkyl,
and when Y is —(NR9)—and X is —(CHR10)—, X and Y may be joined together with —CH2OCH2CH2—to form a morpholinyl ring, or with —CH2NHCH2CH2—to form a piperazinyl ring;
each of R10, R11 and R12 is independently selected from the group consisting of:
(1) hydrogen,
(2) fluoro,
(3) —OH,
(3) —CH3,
(4) —CF3,
(5) —CH2OH,
(6) —CH2CH2OH, and
(7) —C(CH3)2OH;
or a pharmaceutically acceptable salt thereof.

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6,5-fused heteroaryl piperidine ether allosteric modulators of the M4 muscarinic acetylcholine receptor

Life of this patent

6,5-fused heteroaryl piperidine ether allosteric modulators of the M4 muscarinic acetylcholine receptor

Life of this patent

Abstract

Claims11