US 10,945,771 B2 · Azabicyclo[4.1.0]heptane allosteric modulators of the M4 muscarinic acetylcholine receptor

Abstract

The present invention is directed to azabicyclo[4.1.0]heptane 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:
R1 is selected from:
(1) hydrogen;
(2) —C1-6alkyl, which is unsubstituted or substituted with substituents selected from:
hydroxy, fluoro, —CN, —O—C1-6alkyl, C3-6cycloalkyl, bicycle[1.1.1]pentane, tetrahydrofuranyl, phenyl, pyridyl, oxazolyl, —NH2, —NH(—C1-6alkyl), —N—C1-6alkyl)2, and —N(C═O)—C1-6alkyl, wherein the C1-6alkyl or C3-6cycloalkyl is unsubstituted or substituted with substituents selected from:
fluoro, cyano, CF3, C1-6 alkyl or —O—C1-6alkyl;
(3) 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:
(a) hydrogen,
(b) hydroxy,
(c) halogen,
(d) C1-6alkyl, which is unsubstituted or substituted with substituents selected from:
hydroxy, cyclopropyl, cyclobutyl, cyclopentyl, azetidinyl, fluoro, —OCH3, —OCH2CH2OCH3, —(C═O)—C1-6 alkyl, —NH2, —NH(C1-6alkyl), —N(C1-6 alkyl)2, and —N(C3-6cycloalkyl),
(e) —O—C1-6alkyl, which is unsubstituted or substituted with substituents selected from:
hydroxy, cyclopropyl, cyclobutyl, cyclopentyl, azetidinyl, fluoro, —OCH3, —NH2, —NH(C1-6alkyl), —N(C1-6alkyl)2, —N(C3-6cycloalkyl), and —NH(C═O)(C1-6alkyl),
(f) C3-6cycloalkyl, which is unsubstituted or substituted with substituents selected from:
C1-6alkyl, hydroxy, cyclopropyl, cyclobutyl, cyclopentyl, azetidinyl, fluoro, —OCH3, —NH2, —NH(C1-6alkyl), —N(C1-6alkyl)2, and —N(C3-6 cycloalkyl),
(g) —NH2,
(h) —NH(C1-6 alkyl),
(i) —NH(C2-6alkyl)-OH,
(j) —N(C1-6alkyl)2,
(k) —N(C3-6cycloalkyl),
(l) —SO2—C1-6alkyl,
(m) —(C═O)H,
(n) —(C═O)—C1-6alkyl,
(o) —(C═O)O—C1-6alkyl, and
(p) —CN;
R2 and R3 are independently selected from:
(1) hydrogen,
(2) fluoro,
(3) hydroxy, and
(4) —CH3;
R4 is hydrogen or methyl;
R7 and R8 are independently selected from:
(1) hydrogen,
(2) C1-6alkyl, which is unsubstituted or substituted with substituents selected from:
hydroxy, fluoro, and —OCH3,
(3) —CH═CH2,
(4) cyclopropyl,
(5) -fluoro,
(6) -chloro,
(7) -bromo,
(8) —CN,
(9) —(C═O)H, and
(10) —(C═O)O—C1-6alkyl;
R9 is selected from:
(1) hydrogen,
(2) —C1-6alkyl, which is unsubstituted or substituted with substituents selected from:
hydroxy, methoxy, fluoro, —C(C═O)O—C1-6alkyl, —CN, —NH2, —NH(C1-6alkyl), —N(C1-6alkyl)2, —C(C═O)NH2, —C(C═O)OH, —SO2C1-6alkyl, oxetanyl, or pyridyl;
(3) —C3-6cycloalkyl, which is unsubstituted or substituted with substituents selected from:
hydroxy, and C1-6alkyl-hydroxy,
(4) oxetanyl,
(6) tetrahydrofuranyl, and
(6) —C(C═O)O—C1-6alkyl;
each of R10 and R11 is independently selected from:
(1) hydrogen,
(2) —OH,
(3) —CH3,
(4) —CH2OH,
(5) —CH2CH2OH, and
(6) —C(CH3)2OH,
or R10 and R11 taken together form a cyclopropyl group, a=CH2 group or a keto group,
or R9 and R10 taken together form a piperidine, piperazine or morpholine ring, which is unsubstituted or substituted with substituents selected from:
hydroxy, methoxy, and —C1-6alkyl;
or a pharmaceutically acceptable salt thereof.

61 more elements

Azabicyclo[4.1.0]heptane allosteric modulators of the M4 muscarinic acetylcholine receptor

Life of this patent

Azabicyclo[4.1.0]heptane allosteric modulators of the M4 muscarinic acetylcholine receptor

Life of this patent

Abstract

Claims18