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US 8,940,765 B2Granted
N-linked quinolineamide M1 receptor positive allosteric modulators
AssigneeMerck Sharp & Dohme Corp.
InventorsScott D. Kuduk, Christina Ng DiMarco, Zhi-Qiang Yang
Life of this patent
Estimating the term…
Abstract
The present invention is directed to N-linked quinoline amide compounds of general formula (I) which are M1 receptor positive allosteric modulators and that are useful in the treatment of diseases in which the M1 receptor is involved, such as Alzheimer's disease, schizophrenia, pain or sleep disorders. The invention is also directed to pharmaceutical compositions comprising the compounds, and to the use of the compounds and compositions in the treatment of diseases mediated by the M1 receptor.
Claims15
A compound of formula (I):
- and pharmaceutically acceptable salts thereof, wherein
- X═Y═CH2, X═O and Y═CH2, or X═CH2 and Y═O;
- each R is selected from the group consisting of
- (1) hydrogen,
- (2) C6-10aryl,
- (3) C5-10 heterocycle, optionally substituted with 1 to 3 groups of Ra,
- (4) —C1-6 alkyl, optionally substituted with 1 to 3 groups of Ra,
- (5) —C2-6 alkenyl, optionally substituted with 1 to 3 groups of Ra,
- (6) —S(═O)n—R1,
- (7) —OH,
- (8) or R and R can be linked together with the nitrogen to which they are both attached to form a 3-6membered saturated heterocyclic ring, wherein one or two of the ring carbon atoms are optionally replaced by a nitrogen, oxygen or sulfur;
- wherein said saturated 25 heterocyclic ring is optionally susbstituted with 1 to 3 groups of Ra,
- Ra and Ra1 are independently selected from the group consisting of:
- (1) hydroxyl,
- (2) halogen,
- (3) C1-6alkyl,
- (4) C6-10aryl, which is unsubstituted or substituted with 1 to 3 groups of Rb,
- (5) (CH2)nheterocyclyl, which is unsubstituted or substituted with 1 to 3 groups of Rb, and
- (6) —CN,
- Rb is selected from the group consisting of:
- (1) hydroxyl,
- (2) halogen,
- (3) C1-6alkyl, and
- (4) C1-4haloalkyl,
- R1 is selected from the group consisting of:
- (1) hydrogen,
- (2) —C1-6 alkyl,
- (3) —C2-6 alkenyl, and
- (4) —N(R1)2
- n is 0-4.
27 more elements
A compound which is
- 4-[(4-cyano-4-pyridin-2-ylpiperidin-1-yl)methyl]-N-[(1S,2S)-2-hydroxycyclohexyl]quinoline-2-carboxamide,
- N-[(1S,2S)-2-hydroxycyclohexyl]-4-{[4-(1-methyl-1H-pyrazole-4-yl)piperzin-1-yl]methyl}quinoline-2-,
- 4-{[4-cyano-4-(4-methylpyridin-2-yl)piperidin-1-yl]methyl}-N-[(1S,2S)-2-hydroxycyclohexyl]quinoline-2-carboxamide,
- 4-[(4-cyano-4-phenylpiperidin-1-yl)methyl]-N-[(1S,2S)-2-hydroxycyclohexyl]quinoline-2-carbozamide,
- 4-{[4-cyano-4-(2-fluorophenyl)piperidin-1-yl]methyl}-N-[(1S,2S)-2-hydroxycyclohexyl]quinoline-2-carboxamide,
- 4-{[4-(2-chlorophenyl)-4-cyanopiperidin-1-yl]methyl}-N-[(1S,2S)-2-hydroxycyclohexyl]quinoline-2-carboxamide,
- 4-{[4-cyano-4-(2-methylphenyl)piperidin-1-yl]methyl}-N-[(1S,2S)-2-hydroxycyclohexyl]quinoline-2-carboxamide,
- 1,5-anhydro-3-{[(4-{[4-cyano-4-(4-methylpyridin-2-yl)piperidin-1-yl]methyl}quinoline-2-yl)carbonyl]amino}-2,3-dideoxy-L-threo-penitol,
- 4-[(4-cyano-4-pyridin-3-ylpiperidin-1-yl)methyl]-N-[(1S,2S)-2-hydroxycyclohexyl]quinoline-2-carboxamide,
- 4-[(4-cyano-4-pyridin-4-ylpiperidin-1-yl)methyl]-N-[(1S,2S)-2-hydroxycyclohexyl]quinoline-2-carboxamide,
- 8-fluoro-4-[(4-fluoro-[(4-phenylpiperidin-1-yl)methyl]-N-(1S,2S)-2-hydroxycyclohexyl]quinoline-2-carboxamide,
- 1,5-anhydro-2,3-dideoxy-3-[({8-fluoro-4-[(4-fluoro-4-phenylpiperidin-1-yl)methyl]quinoline-2-yl}carbonyl)amino]-L-threo-penitol,
- 8-fluro-N-[(1S,2S)-2-hydroxycyclohexyl]-4-{[4-(1-methyl-1H-pyrazol-4-yl)piperazin-1-yl]methyl}quinoline-2-carboxamide,
- 4-[(4-cyano-4-pyrazin-2-ylpiperidin-1-yl)methyl]8-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]quinoline-2-carboxamide,
- 4-[(4-cyano-4-pyrimidin-4-ylpiperidin-1-yl)methyl]8-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]quinoline-2-carboxamide,
- 8-fluoro-4-[(4-fluoro-4-pyridin-2-ylpiperidin-1-yl)methyl]-N-[(1S,2S)-2-hydroxycyclohexyl]quinline-2-carboxamide,
- 4-[(4-cyano-4-pyridazin-4-ylpiperidin-1-yl)methyl]-8-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]quinoline-2-carboxamide,
- 4-(3′,6′-dihydro-2,4′-bipyridin-1′(2′H)-ylmethyl)-8-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]quinoline-2-carboxamide,
- 8-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]-4-({5-[4-(trifluoromethyl)phenyl]piperidin-1-yl}methyl)quinoline-2-carboxamide,
- 8-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]-4-[(4-pyridin-4-ylpiperidin-1-yl)methyl]quinoline-2-carboxamide,
- 8-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]-4-[(4-phenylpiperidin-1-yl)methyl]quinoline-2-carboxamide,
- 4-[(4-cyano-4-ylpiperidin-1-yl)methyl]-8-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]quinoline-2-carboxamide,
- 8-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]-4-[(4-pyridin-3-ylpiperidin-1-yl)methyl]quinoline-2-carboxamide,
- 4-[(4-cyano-3-ylpiperidin-1-yl)methyl]-8-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]quinoline-2-carboxamide,
- 8-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]-4-[(4-pyridin-2-ylpiperidin-1-yl)methyl]quinoline-2-carboxamide,
- 4-[(4-cyano-4-fluoropiperidin-1-yl)methyl]-8-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]quinoline-2-carboxamide,
- 4-[(4-cyano-4-fluoropiperidin-1-yl)methyl]-5,8-difluoro-N-[(1S,2S)-2-hydroxycyclohexyl]quinoline-2-carboxamide,
- 4-{[4-cyano-4-(4-methylpyridin-2-yl]methyl}-8-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]quinoline-2-carboxamide,
- 4-{[4-cyano-4-(4-methylpyridin-2-yl]methyl}-5,8-difluoro-N-[(1S,2S)-2-hydroxycyclohexyl]quinoline-2-carboxamide,
- 4-{[4-(4-chloropyridin-2-yl)-4-fluoropiperidin-1-yl]methyl}-8-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]quinoline-2-carboxamide,
- 8-fluoro-4-{[4-fluoro-4-(4-methylpyridin-2-yl)piperidin-1-yl]methyl}-N-[(1S,2S)-2-hydroxycyclohexyl]quinoline-2-carboxamide,
- and pharmaceutically acceptable salts thereof.
29 more elements
Dependencies are inferred from the claim text.