Heterocyclic quinolizine derived M1 receptor positive allosteric modulators
AssigneeMerck Sharp & Dohme Corp.
InventorsDouglas C. Beshore, Scott D. Kuduk
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Abstract
The present invention is directed to novel 3-oxo-2,3-dihydropyrazolo[4,3-c]quinolizine derived compounds of generic formula (I) or a pharmaceutically acceptable salt thereof, 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.
Claims14
A compound of formula (I):
- and pharmaceutically acceptable salts thereof, wherein
- R1 represents —NR2R3, or a nitrogen containing C5-10 heterocyclyl;
- wherein said heterocyclyl is optionally substituted with one or more of Ra;
- R2 and R3 independently represent
- (a) hydroxy,
- (b) —O—C1-6 alkyl, said alkyl optionally substituted with 1 to 3 groups of Ra;
- (c) —C1-6 alkyl, said alkyl optionally substituted with 1 to 3 groups of Ra;
- (d) -hydrogen;
- Ra represents:
- (a) halogen,
- (b) hydroxy,
- (c) —O—C1-6 alkyl, said alkyl optionally substituted with 1 to 3 groups of halo;
- (d) —C1-6 alkyl, said alkyl optionally substituted with 1 to 3 groups of halo;
- (e) cyano,
- (f) —NRARB, wherein RA and RB are selected from the group consisting of
- (i) hydrogen,
- (ii) —C1-6 alkyl,
- or RA and RB are linked together with the nitrogen to which they are both attached to form a 2-6 membered carbocyclic ring, wherein one or two of the ring carbon atoms is replaced by a nitrogen, oxygen or sulfur, and the carbocyclic is optionally substituted with one or more C1-6 alkyl,
- (g) represents —C(═O)—RC, —S(O)n—RC;
- C5-10 heterocyclyl, and C6-10 aryl, said heterocyclyl and aryl optionally substituted with 1 to 3 groups of RC;
- and wherein RC is selected from the group consisting of
- (i) hydrogen,
- (ii) —C1-6 alkyl,
- (iii) —O—C1-6 alkyl,
- (iv) CF3,
- (v) halogen,
- (vi) cyano,
- n is 0, 1 or 2.
A compound which is:
- 1-{[2-(2-fluorophenyl)-3-oxo-2,3-dihydropyrazolo[4,3-c]quinolizin-5-yl]methyl}-4-(4-methylpyridin-2-yl)piperidine-4-carbonitrile;
- 2-(2-fluorophenyl)-5-{[4-(1-methyl-1H-pyrazol-4-yl)-3-oxopiperazin-1-yl]methyl}pyrazolo[4,3-c]quinolizin-3(2H)-one;
- 2-(2-fluorophenyl)-5-{[1-(pyridin-4-yl)-3,4-dihydroisoquinolin-2(1H)-yl]methyl}pyrazolo[4,3-c]quinolizin-3(2H)-one,
- 1-{[2-(2-fluorophenyl)-3-oxo-2,3-dihydropyrazolo[4,3-c]quinolizin-5-yl]methyl}-4-(4-methoxypyridin-2-yl)piperidine-4-carbonitrile,
- 2-(2-fluorophenyl)-5-({4-[4-(trifluoromethyl)phenyl]piperidin-1-yl]methyl)pyrazolo[4,3-yl)pyrazolo[4,3-c]quinolizin-3(2H)-one,
- 1-{[2-(2-fluorophenyl)-3-oxo-2,3-dihydropyrazolo[4,3-c]quinolizin-5-yl]methyl}-4-phenylpiperidine-4-carbonitrile,
- 4-(4-{[2-(2-fluorophenyl)-3-oxo-2,3-dihydropyrazolo[4,3-c]quinolizin-5-yl]methyl}piperazin-1-yl)benzonitrile,
- 2-(2-fluorophenyl)-5-{[4-(1-methyl-1H-pyrazol-4-yl)piperazin-1-yl]methyl}pyrazolo[4,3-c]quinolizin-3(2H)-one,
- 5-[(4,4-difluoropiperidin-1-yl)methyl]-2-(2-fluorophenyl)pyrazolo[4,3-c]quinolizin-3 (2H)-one,
- 4-fluoro-1-{[2-(2-fluorophenyl)-3-oxo-2,3-dihydropyrazolo[4,3-c]quinolizin-5-yl]methyl}piperidine-4-carbonitrile,
- and pharmaceutically acceptable salts thereof.
Dependencies are inferred from the claim text.