Heterocyclic-fused pyrazolo[4,3-
View Patent ↗The present invention is directed to heterocyclic fused pyrazole[4,3-c]pyridine-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):
wherein ring A is saturated or unsaturated, and is formed from 3 or 4 ring atoms, selected from the group consisting of S, O, CH, CH 2 , N and NH, wherein one or more of the ring atoms is optionally substituted by one or more R 1 ,
R 1 is optionally present at one or more of the ring A atoms, and each R 1 is selected from the group consisting of
(1) halogen,
(2) —C 1-6 alkyl,
(3) —OC 1-6 alkyl, or
(4) hydroxy,
wherein the alkyl R 1 moiety is optionally substituted with one or more
(a) halogen,
(b) hydroxy,
(c) —O—C 1-6 alkyl, or
(d) —C 2-8 alkenyl,
R 2 is optionally present at one or more of the ring carbon atoms, and each R 2 is selected from the group consisting of
(1) halogen,
(2) —C 1-6 alkyl,
(3) —OC 1-6 alkyl, or
(4) hydroxy,
R 3 is selected from the group consisting of (1) —C 2-6 alkyl,
(2) —C 6-10 aryl, or
(3) heteroaryl, which is an aromatic cyclic group, having from five to twelve ring atoms, the ring atoms selected from C, O, N, N→O or S, at least one of which is O, N, N→O or S,
wherein the alkyl, aryl or heteroaryl moiety is optionally substituted with one or more
(a) halogen,
(b) hydroxy,
(c) —C 1-6 alkyl,
(d) —O—C 1-6 alkyl,
(e) —C 3-8 cycloalkyl, or
(f) —C 6-10 aryl,
or R 2 and R 3 together form a chain of 3 or 4 ring atoms, selected from the group consisting of S, CH, CH 2 , N and NH, wherein one or more of the ring atoms is optionally substituted by one or more
(a) halogen,
(b) —C 1-6 alkyl, or
(c) —OC 1-6 alkyl;
R 4 is optionally present at one or more of the ring carbon atoms, and each R 4 is selected from the group consisting of
(1) halogen,
(2) —C 1-6 alkyl,
(3) —OC 1-6 alkyl, or
(4) hydroxy; and
X is CH;
or a pharmaceutically acceptable salt thereof.
2. A compound of claim 1 , wherein A forms one of the following rings:
3. A compound of claim 1 wherein R 2 is optionally present at one of the ring carbon atoms, and R 2 is selected from the group consisting of
(1) halogen,
(2) —C 1-6 alkyl, or
(3) —OC 1-6 alkyl.
4. A compound of claim 1 wherein R 4 is present at one of the ring carbon atoms, and is selected from the group consisting of
(1) halogen, or
(2) —C 1-6 alkyl.
5. A compound of claim 1 wherein R 3 is selected from the group consisting of
(1) —C 6-10 aryl, or
(2) heteroaryl having from five to twelve ring atoms, the ring atoms selected from C, O, N, N→O or S, at least one of which is O, N, N→O or S,
wherein the aryl or heteroaryl moiety is optionally substituted with one or more
(a) halogen,
(b) hydroxy, or
(c) —C 1-6 alkyl.
6. A compound of claim 5 , wherein R 3 is imidazolyl or phenyl.
7. A compound of claim 1 , wherein the compound of formula (I) is a compound of formula (II)
and pharmaceutically acceptable salts thereof.
8. A compound of claim 7 , wherein A forms one of the following rings:
9. A compound of claim 7 , wherein R 2 is optionally present at one of the ring carbon atoms, and R 2 is selected from the group consisting of
(1) halogen,
(2) —C 1-6 alkyl, or
(3) —OC 1-6 alkyl.
10. A compound of claim 7 , wherein R 4 is present at one of the ring carbon atoms, and is selected from the group consisting of
(1) halogen, or
(2) —C 1-6 alkyl.
11. A compound of claim 1 , which is selected from the group consisting of:
2-(2-Fluorophenyl)-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]-1,5-naphthyridin-3-one;
2-(2-Fluorophenyl)-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]-1,8-naphthyridin-3-one;
2-(2-Fluorophenyl)-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]-1,8-naphthyridin-3-one;
2-(2-Fluorophenyl)-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]-1,7-naphthyridin-3-one;
2-(2-Fluorophenyl)-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]-1,6-naphthyridin-3-one;
2-(2-Methylphenyl)-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[3′,4′:4,5]-pyrido[2,3-b]pyrazin-3-one;
2-(2-Fluorophenyl)-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-5,6,7,8-tetrahydrocyclopenta[b]pyrazolo[3,4-c]pyridine-3(2H)-one;
2-(2-Fluorophenyl)-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5,6,7,8,9-hexahydro-3H-pyrazolo[3,4-d]pyridine-3(2H)-one;
(±)-2-(2-Fluorophenyl)-9-(prop-2-en-1-yloxy)-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5,6,7,8,9-hexahydro-3H-pyrazolo[4,3-c]quinolin-3-one;
(±)-2-(2-Fluorophenyl)-9-hydroxy-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5,6,7,8,9-hexahydro-3H-pyrazolo[4,3-c]quinolin-3-one;
2-(2-Fluorophenyl)-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-d]thieno[3,2-b]pyridin-3-one;
2-(2-Methylphenyl)-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[3,4-d]thieno[3,2-b]pyridin-3-one;
2-(2-Fluorophenyl)-5-[(1-methyl- 1 H-indazol-5-yl)methyl]-2,5-dihydro-3H-pyrazolo[4,3-d]thieno[3,2-b]pyridin-3-one;
or a pharmaceutically acceptable salt thereof.
12. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
13. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 11 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.