US 8,940,898 B2Granted

Piperidinyl alkyne orexin receptor antagonists

AssigneeMerck Sharp & Dohme Corp.

InventorsScott D. Kuduk, Jason W. Skudlarek

Life of this patent

Estimating the term…

Abstract

The present invention is directed to piperidinyl alkyne compounds which are antagonists of orexin receptors. The present invention is also directed to uses of the piperidinyl alkyne compounds described herein in the treatment or prevention of neurological and psychiatric disorders and diseases in which orexin receptors are involved. The present invention is also directed to pharmaceutical compositions comprising these compounds. The present invention is also directed to uses of these pharmaceutical compositions in the prevention or treatment of such diseases in which orexin receptors are involved.

Claims16

Dependent claims

A compound of the formula I:

wherein:
the alkyne group is attached to either the 2- or the 3-position of the piperidine;
A is selected from the group consisting of phenyl, naphthyl, and mono- and bicyclic heteroaryl;
B is selected from the group consisting of phenyl, naphthyl, and mono- and bicyclic heteroaryl;
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 napthyl is unsubstituted or substituted with one or more substituents selected from R13,
(9) —(C═O)m—On-heterocycle, where the heterocycle 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) C1-6 alkyl, 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) heterocycle, 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 may be absent if the valency of B 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 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 napthyl is unsubstituted or substituted with one or more substituents selected from R13,
(9) —(C═O)m—On-heterocycle, where the heterocycle 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;
R3 is C1-6alkyl or C3-6cycloalkyl, which is unsubstituted or substituted with one or more substituents selected from 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 napthyl is unsubstituted or substituted with one or more substituents selected from R14,
(9) —(C═O)m—On-heterocycle, where the heterocycle 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—C1-6alkyl,
(6) —O(C═O)—C1-6allyl,
(7) —NH—C1-6alkyl,
(8) phenyl,
(9) heterocycle,
(10) —CO2H, and
(11) —CN;
or a pharmaceutically acceptable salt thereof.

70 more elements

A compound which is selected from the group consisting of:

[(2R,5R)-2-methyl-5-(pyridin-2-ylethynyl)piperidin-1-yl][2-(2H-1,2,3-triazol-2-yl)phenyl]methanone;
2-{[(3S,6R)-6-methyl-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]ethynyl}pyridine;
4-{[(3S,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]ethynyl}pyridine;
3-{[(3S,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]ethynyl}pyridine;
3-{[(3S,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]ethynyl}pyridin-2-ol;
3-{[(3S,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]ethynyl}pyridin-4-ol;
(2-{[(3S,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]ethynyl} phenyl)methanol;
(5-{[(3S,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]ethynyl}pyridin-2-yl)methanol;
(6-{[(3S,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]ethynyl}pyridin-3-yl)methanol;
(6-{[(3S,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]ethynyl}pyridin-2-yl)methanol;
(2-{[(3S,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]ethynyl}pyridin-4-yl)methanol;
(5-[(3S,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl piperidin-3-yl]ethynyl}pyridin-3-yl)methanol;
(4-{[(3S,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]ethynyl}pyridin-2-yl)methanol;
{(2R,5S)-5-[(5-fluoropyridin-2-yl)ethynyl]-2-methylpiperidin-1-yl}[5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone;
[5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl][2-(phenylethynyl)piperidin-1-yl]methanone;
1-{[5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}-2-(phenylethynyl)piperidine;
5-fluoro-2-[(1-{[5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-2-yl)ethynyl]pyridine;
2-[(4-fluorophenyl)ethynyl]-1-{[5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidine;
2-[(1-{[5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-2-yl)ethynyl]quinoline;
3-[(1-{[5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-2-yl)ethynyl]quinoline;
1-{[5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}-2-(naphthalen-2-ylethynyl)piperidine;
(2-methyl-5-phenyl-1,3-thiazol-4-yl)[2-(phenylethynyl)piperidin-1-yl]methanone;
1-[(2-methyl-5-phenyl-1,3-thiazol-4-yl)carbonyl]-2-(phenylethynyl)piperidine;
1-[(2-methyl-5-phenyl-1,3-thiazol-4-yl)carbonyl]-2-(naphthalen-2-ylethynyl)piperidine;
5-fluoro-2-({1-[(2-methyl-5-phenyl-1,3-thiazol-4-yl)carbonyl]piperidin-2-yl}ethynyl)pyridine;
2-[(4-fluorophenyl)ethynyl]-1-[(2-methyl-5-phenyl-1,3-thiazol-4-yl)carbonyl]piperidine;
2-({1-[(2-methyl-5-phenyl-1,3-thiazol-4-yl)carbonyl]piperidin-2-yl}ethynyl)quinoline;
3-({1-[(2-methyl-5-phenyl-1,3-thiazol-4-yl)carbonyl]piperidin-2-yl}ethynyl)isoquinoline;
and
3-({1-[(2-methyl-5-phenyl-1,3-thiazol-4-yl)carbonyl]piperidin-2-yl}ethynyl)quinoline;
or a pharmaceutically acceptable salt thereof.

28 more elements

Dependencies are inferred from the claim text.

Facts

Application: 14/354,454Filed 19 Oct 2012 · us provisional application
Priority: 25 Oct 2011
Published: US 2014/0243368 A128 Aug 2014
Granted: 27 Jan 2015
Term ends: Not estimatedThe source records don’t support an estimate.

Classification8 codes

C07D 401/10
Containing two hetero rings: linked by a carbon chain containing aromatic rings
A61P 25/00
Drugs for disorders of the nervous system
C07D 401/12
Containing two hetero rings: linked by a chain containing hetero atoms as chain links
C07D 401/14
Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a…:…

Family

Application61/551,166Us provisional application · filed 25 Oct 2011
US 2014/0243368 A1Pre-grant publication · published 28 Aug 2014
US 8,940,898 B2This patent

From the US filing history. Foreign family members aren’t listed.

Timeline

Citations

Open elsewhere

patentgrep

Loading patent…

Abstract

A compound of the formula I:

wherein:
the alkyne group is attached to either the 2- or the 3-position of the piperidine;
A is selected from the group consisting of phenyl, naphthyl, and mono- and bicyclic heteroaryl;
B is selected from the group consisting of phenyl, naphthyl, and mono- and bicyclic heteroaryl;
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 napthyl is unsubstituted or substituted with one or more substituents selected from R13,
(9) —(C═O)m—On-heterocycle, where the heterocycle 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) C1-6 alkyl, 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) heterocycle, 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 may be absent if the valency of B 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 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 napthyl is unsubstituted or substituted with one or more substituents selected from R13,
(9) —(C═O)m—On-heterocycle, where the heterocycle 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;
R3 is C1-6alkyl or C3-6cycloalkyl, which is unsubstituted or substituted with one or more substituents selected from 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 napthyl is unsubstituted or substituted with one or more substituents selected from R14,
(9) —(C═O)m—On-heterocycle, where the heterocycle 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—C1-6alkyl,
(6) —O(C═O)—C1-6allyl,
(7) —NH—C1-6alkyl,
(8) phenyl,
(9) heterocycle,
(10) —CO2H, and
(11) —CN;
or a pharmaceutically acceptable salt thereof.

70 more elements

Facts

Application

14/354,454Filed 19 Oct 2012 · us provisional application

Priority

25 Oct 2011

Published

US 2014/0243368 A128 Aug 2014

Granted

27 Jan 2015

Term ends

Not estimatedThe source records don’t support an estimate.

Classification8 codes

C07D 401/10
Containing two hetero rings: linked by a carbon chain containing aromatic rings
A61P 25/00
Drugs for disorders of the nervous system
C07D 401/12
Containing two hetero rings: linked by a chain containing hetero atoms as chain links
C07D 401/14
Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a…:…