Pyrazolo [4,3-C] cinnolin-3-one M1 receptor positive allosteric modulators
View Patent ↗The present invention is directed to pyrazolo[4,3-c]cinnolin-3-one compounds of 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.
1. A compound of formula (I):
or a pharmaceutically acceptable salt thereof, wherein
—X═Y— is selected from the group consisting of:
(2) —CH═N—, or
(3) —N═CH—
R 1 is selected from the group consisting of
(1) aryl,
(2) a heteroaryl group which is a cyclic or polycyclic group, having from five to twelve ring atoms, said ring atoms selected from C, O, N or S, at least one of which is O, N or S,
(3) a heterocyclic group, which is a non-aromatic cyclic or polycyclic group having from three to twelve ring atoms selected from C, O, N or S, at least one of which is O, N or S,
(4) —C 1-6 alkyl,
(5) —C 3-8 cycloalkyl,
(6) —C 2-6 alkenyl
wherein said aryl, heteroaryl, heterocyclic, alkyl, alkenyl and cycloalkyl R 1 moiety is optionally substituted with one or more
(a) halogen,
(b) hydroxy,
(c) —O—C 1-6 alkyl,
(d) —C 1-6 alkyl, and
(e) cyano;
R 2 is selected from the group consisting of
(1) aryl,
(2) a heteroaryl group which is a cyclic or polycyclic group, having from five to twelve ring atoms, said ring atoms selected from C, O, N or S, at least one of which is O, N or S, or
(3) halogen,
wherein said aryl or heteroaryl R 2 moiety is optionally substituted with one or more
(a) halogen,
(b) hydroxy,
(c) —O—C 1-6 alkyl,
(d) —C 1-6 alkyl,
(e) —CN,
(f) —NR A R B ,
(g) —NH(C═O)—C 1-6 alkyl,
wherein R A and R B are selected from the group consisting of
(i) hydrogen, or
(ii) —C 1-6 alkyl,
or R A and R B 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;
R 3 is optionally present at one or more of the fused phenyl ring carbons, and each R 3 is selected from the group consisting of
(1) —C 1-6 alkyl,
(2) halogen,
(3) cyano, and
(4) —O—C 1-6 alkyl,
wherein any alkyl R 3 moiety is optionally substituted with one or more halo.
2. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is phenyl which is optionally substituted by one or more
(a) halogen,
(b) hydroxy,
(c) —O—C 1-6 alkyl,
(d) —C 1-6 alkyl, and
(e) cyano.
3. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is heteroaryl, which is optionally substituted by one or more
(a) halogen (for example fluoro, chloro or bromo),
(b) hydroxy,
(c) —O—C 1-6 alkyl,
(d) —C 1-6 alkyl, and
(e) cyano.
4. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is heterocyclic, which is optionally substituted by one or more
(a) hydroxy, or
(b) —C 1-6 alkyl.
5. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is cycloalkyl, alkyl or alkenyl, each of which are optionally substituted by one or more
(a) hydroxy, or
(b) halogen.
6. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is phenyl, which is optionally substituted with one or more
(a) halogen,
(b) hydroxy,
(c) —O—C 1-6 alkyl,
(d) —C 1-6 alkyl,
(e) —CN,
(f) —NR A R B ,
(g) —NH(C═O)—C 1-6 alkyl,
wherein R A and R B are selected from the group consisting of
(i) hydrogen, or
(ii) —C 1-6 alkyl,
or R A and R B 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.
7. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is heteroaryl, which is optionally substituted with one or more
(a) halogen,
(b) hydroxy,
(c) —O—C 1-6 alkyl,
(d) —C 1-6 alkyl,
(e) —CN,
(f) —NR A R B ,
(g) —NH(C═O)—C 1-6 alkyl,
wherein R A and R B are selected from the group consisting of
(i) hydrogen, or
(ii) —C 1-6 alkyl,
or R A and R B 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.
8. A compound of claim 1 , which is selected from the group consisting of
2-(2-Methylphenyl)-5-{[6-(1H-pyrazol-1-yl)pyridine-3-yl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]cinnolin-3-one;
2-(2-Methylphenyl)-5-{[6-(1-methyl-1H-pyrazol-4-yl)pyridine-3-yl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]cinnolin-3-one;
(±)-6-Chloro-2-(trans-2-hydroxycyclohexyl)-5[(6′-methyl-2,3′-bipyridin-5-yl)methyl]-2,5-dihydro-3H-pyrazolo[4,3-c]cinnolin-3-one;
(±)-6-Chloro-2-(trans-2-hydroxycyclohexyl)-5[(6-methylpyridin-3-yl)methyl]-2,5-dihydro-3H-pyrazolo[4,3-c]cinnolin-3-one;
2-(2-Methylphenyl)-5-{[6-(morpholin-4-yl)pyridine-3-yl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]cinnolin-3-one;
2-(2-Methylphenyl)-5-{[6-(1,3-thiazol-4-yl)pyridin-3-yl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]cinnolin-3-one;
2-(2,3-Dimethylphenyl)-5-{[6-(1,3-thiazol-4-yl)pyridin-3-yl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]cinnolin-3-one;
2-(6-Fluoro-2-methylpyridin-3-yl)-5-{[6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]cinnolin-3-one;
(±)-2-(trans-2-Hydroxycyclohexyl)-5-{[6-(1,3-thiazol-4-yl)pyridin-3-yl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]cinnolin-3-one;
2-(2-Methylphenyl)-5-[4-(6-methylpyridin-3-yl)benzyl]-2,5-dihydro-3H-pyrazolo[4,3-c]cinnolin-3-one;
2-(2,3-Dimethylphenyl)-5-[(6′-methyl-2,3′-bipyridin-5-yl)methyl]-2,5-dihydro-3H-pyrazolo[4,3-c]cinnolin-3-one;
2-(2,3-Dimethylphenyl)-5-[(6′-methyl-2,3′-bipyridin-5-yl)methyl]-2,5-dihydro-3H-pyrazolo[4,3-c]cinnolin-3-one;
or a pharmaceutically acceptable salt thereof.
9. The compound of claim 1 , wherein the compound of formula (I) is a compound of formula (III):
or a pharmaceutically acceptable salt thereof.
10. A compound of claim 9 , or a pharmaceutically acceptable salt thereof, wherein the compound of formula (III) is a compound of formula (IIIA)
wherein R 7 is methyl and R 2 is selected from the group consisting of
11. A compound of claim 9 , or a pharmaceutically acceptable salt thereof, wherein the compound of formula (III) is a compound of formula (IIIB)
and each R 7 is methyl, and R 2 is selected from the group consisting of
12. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (IV):
wherein R 7 is optionally present at one or more of the phenyl ring carbon atoms, and each R 7 is selected from the group consisting of
(1) halogen,
(2) hydroxy,
(3) —O—C 1-6 alkyl,
(4) —C 1-6 alkyl, and
(5) cyano.
13. A pharmaceutical composition comprising a therapeutically effective amount of a compound of any of claims 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.