US 10,329,289 B2 · 6,7-dihydro-5H-pyrrolo[3,4-B]pyridin-5-one allosteric modulators of the M4 muscarinic acetylcholine receptor

Abstract

The present invention is directed to 6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one 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 the group consisting of:
(1) hydrogen;
(2) —C1-6alkyl, which is unsubstituted or substituted with substituents selected from the group consisting of:
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 the group consisting of:
fluoro, cyano, CF3, C1-6alkyl 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 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, azetidinyl, fluoro, —OCH3, —OCH2CH2OCH3, —(C═O)—C1-6alkyl, —NH2, —NH(C1-6alkyl), and —N(C1-6alkyl)2,
(e) —O—C1-6alkyl, which is unsubstituted or substituted with substituents selected from the group consisting of:
hydroxy, cyclopropyl, cyclobutyl, cyclopentyl, azetidinyl, fluoro, —OCH3, —NH2, —NH(C1-6alkyl), —N(C1-6alkyl)2, and —NH(C═O)(C1-6alkyl),
(f) C3-6cycloalkyl, which is unsubstituted or substituted with substituents selected from the group consisting of:
C1-6alkyl, hydroxy, cyclopropyl, cyclobutyl, cyclopentyl, azetidinyl, fluoro, —OCH3, —NH2, —NH(C1-6alkyl), and —N(C1-6alkyl)2,
(g) —NH2,
(h) —NH(C1-6alkyl),
(i) —NH(C2-6alkyl)-OH,
(j) —N(C1-6alkyl)2,
(k) —SO2—C1-6alkyl,
(l) —(C═O)H,
(m) —(C═O)—C1-6alkyl,
(n) —(C═O)O—C1-6alkyl, and
(o) —CN;
R2 and R3 are independently selected from the group consisting of:
(1) hydrogen,
(2) fluoro,
(3) hydroxy, and
(4) —CH3;
R4 is hydrogen or methyl, and R6 is hydrogen or methyl, or R4 and R6 are joined together with a —(CH2)2— to form a bridged ring with the piperidine ring to which they are attached;
R5 is hydrogen, or where R2 is hydrogen, R3 and R5 may be joined together with a —(CH2)— to form a bridged ring with the piperidine ring to which they are attached;
R7 and R8 are independently 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, 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 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,
(4) —C(C═O)O—C1-6alkyl, and
(5) —P(O)(OH)2;
each of R10 and R11 is independently selected from the group consisting of:
(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 a pharmaceutically acceptable salt thereof;
with the proviso that the compound is other than:
2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-3-methyl-6,7-dihydro,5H-pyrrolo[3,4-b]pyridin-5-one;
3-((1-(3-methyl-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)piperidin-4-yl)oxy)benzonitrile;
3-methyl-2-(4-4((1-methyl-1H-indazol-5-yl)oxy)piperidin-1-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one;
3-methyl-2-(4-phenoxypiperidin-1-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one;
3-methyl-2-(4-((5-methylpyridin-3-yl)oxy)piperidin-1-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one;
2-(4-(isochroman-7-yloxy)piperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one;
3-methyl-2-(4-((1-methyl-1H-pyrazol-4-yl)oxy)piperidin-1-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]poyridin-5-one;
2-[4-(1,3-dihydro-2-benzofuran-5-yloxy)piperidin-1-yl]-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one;
3-methyl-2-(4-((1-methylcyclopropyl)methoxy)piperidin-1-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one;
2-(4-((2,3-dihydrobenzofuran-6-yl)oxy)piperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one;
2-(4-(isochroman-6-yloxy)piperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one;
2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-3,4-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one;
3,4-dimethyl-2-(4-((1-methylcyclopropyl)methoxy)piperidin-1-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one;
6-(2-hydroxyethyl)-3,4-dimethyl-2-(4-phenoxylpiperidin-1-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one;
6-(2-hydroxyethyl)-3,4-dimethyl-2-(4-((1-methycyclopropyl)methoxy)piperidin-1-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one;
or
2-(4-((1,3-dihydro-2-benzofuran-5-yl)oxy)piperidin-1-yl)-3,4-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one.

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6,7-dihydro-5H-pyrrolo[3,4-B]pyridin-5-one allosteric modulators of the M4 muscarinic acetylcholine receptor

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6,7-dihydro-5H-pyrrolo[3,4-B]pyridin-5-one allosteric modulators of the M4 muscarinic acetylcholine receptor

Life of this patent

Abstract

Claims20