Aminobenzoquinazolinone M1 receptor positive allosteric modulators
View Patent ↗The present invention is directed to aminobenzoquinazolinone 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. Compound of formula (I):
wherein X and Y are selected from the group consisting of
(1) CH 2 , or
(2) O,
provided that if one of X or Y is O, then the other is CH 2 ;
Z is selected from the group consisting of
(1) N, or
(2) —CR 5 ,
Q 1 , Q 2 , Q 3 and Q 4 are each selected from the group consisting of
(1) N, or
(2) CR 3 ,
wherein if one of Q 1 , Q 2 , Q 3 or Q 4 is N, then the others are each CR 3 ;
R 1 is selected from the group consisting of
(1) halogen, or
(2) hydroxyl;
R 2 is optionally present at one or more of the ring carbon atoms, and is selected from the group consisting of
(1) halogen,
(2) ═O,
(3) —C 1-6 alkyl,
(4) CN,
(5) —C 6-10 aryl, and
(6) heteroaryl, which is an aromatic cyclic or polycyclic group, having from five to twelve ring atoms, said ring atoms selected from C, O, N, N→O, C(═O) or S, at least one of which is O, N, N→O or S,
wherein said alkyl, aryl or heteroaryl R 2 group is optionally substituted with one or more
(a) halogen,
(b) —C 1-6 alkyl,
(c) —C 3-8 cycloalkyl,
(d) —NR 7 R 8 ,
(e) —O—C 1-6 alkyl,
(f) C 6-10 aryl,
(g) CN, or
(h) hydroxyl;
R 3 is selected from the group consisting of
(1) hydrogen,
(2) halogen,
(3) —C 1-6 alkyl, or
(4) —O—C 1-6 alkyl;
R 4 is selected from the group consisting of
(1) —C 1-6 alkyl,
(2) —C 6-10 aryl,
(3) heteroaryl group, wherein the heteroaryl is an aromatic cyclic or polycyclic group, having from five to twelve ring atoms, said ring atoms selected from C, O, N, N→O, C(═O) or S, at least one of which is O, N, N→O or S,
wherein said alkyl, aryl or heteroaryl R 4 group is optionally substituted with one or more
(a) halogen,
(b) hydroxy,
(c) —CN,
(d) —O—C 1-6 alkyl, optionally substituted with halogen,
(e) —C 1-6 alkyl, optionally substituted with halogen
(f) —C 6-10 aryl, or
(g) heteroaryl group, wherein the heteroaryl is an aromatic cyclic or polycyclic group, having from five to twelve ring atoms, said ring atoms selected from C, O, N, N→O, C(═O) or S, at least one of which is O, N, N→O or S,
or R 2 and R 4 are linked together to form a fused aryl or heteroaryl group having from five to twelve ring atoms, said ring atoms selected from C, O, N, N→O, C(═O) or S, wherein the aryl or heteroaryl ring is optionally substituted with one or more
(a) halogen,
(b) hydroxy,
(c) —CN,
(d) —O—C 1-6 alkyl, optionally substituted with halogen,
(e) —C 1-6 alkyl, optionally substituted with halogen
(f) —C 6-10 aryl, or
(g) heteroaryl group, wherein the heteroaryl is an aromatic cyclic or polycyclic group, having from five to twelve ring atoms, said ring atoms selected from C, O, N, N→O, C(═O) or S, at least one of which is O, N,N O or S;
R 5 is selected from the group consisting of
(1) hydrogen,
(2) halogen, or
(3) CN,
R 7 and R 8 are selected from the group consisting of
(1) hydrogen, or
(2) —C 1-6 alkyl,
or R 7 and R 8 are linked together with the nitrogen to which they are attached to form a 4-6 membered carbocyclic ring, wherein one or two of the ring carbon atoms is optionally replaced by a nitrogen, oxygen or sulfur, and the ring is optionally substituted with one or more C 1-6 alkyl;
or a pharmaceutically acceptable salt thereof.
2. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X and Y are both CH 2 .
3. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X is CH 2 and Y is O.
4. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each of Q 1 , Q 2 , Q 3 and Q 4 is CR 3 and R 3 is hydrogen.
5. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each of Q 2 is N, and each of Q 1 , Q 3 and Q 4 is CR 3 and R 3 is hydrogen.
6. A compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 is hydroxyl.
7. A compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 is halogen.
8. A compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 and R 4 are linked together to form a fused aryl or heteroaryl group having from five to twelve ring atoms, said ring atoms selected from C, O, N, N→O, C(═O) or S.
9. A compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 4 is a heteroaryl group, wherein the heteroaryl is an aromatic cyclic or polycyclic group, having from five to twelve ring atoms, said ring atoms selected from C, O, N, N→O, C(═O) or S, at least one of which is O, N, N→O or S.
10. A compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 4 is phenyl.
11. A compound of claim 1 , wherein the compound of formula (I) is a compound of formula (II):
or a pharmaceutically acceptable salt thereof, wherein X, Y, R 2 , and R 4 are as defined in claim 1 .
12. A compound of claim 11 , or a pharmaceutically acceptable salt thereof, wherein X and Y are both CH 2 .
13. A compound of claim 11 or a pharmaceutically acceptable salt thereof, wherein R 4 is a heteroaryl group, wherein the heteroaryl is an aromatic cyclic or polycyclic group, having from five to twelve ring atoms, said ring atoms selected from C, O, N, N→O, C(═O) or S, at least one of which is O, N, N→O or S.
14. A compound of claim 1 , wherein the compound of formula (I) is a compound of formula (III):
or a pharmaceutically acceptable salt thereof, wherein R 4 is defined in claim 1 .
15. A compound of claim 14 , or a pharmaceutically acceptable salt thereof, wherein X and Y are both CH 2 .
16. A compound of claim 1 , which is selected from the group consisting of
rac-1-({3-[(1R,2R)-2-Hydroxycyclohexyl]-4-oxo-3,4-dihydrobenzo[h]quinazolin-6-yl}methyl)-4-pyridin-2-ylpiperidine-4-carbonitrile;
1-({3-[(1S,2S)-2-Hydroxycyclohexyl]-4-oxo-3,4-dihydrobenzo[h]quinazolin-6-yl}methyl)-4-pyridin-2-ylpiperidine-4-carbonitrile;
1-({3-[3R,4S]-3-Hydroxytetrahydro-2H-pyran-4-yl]-4-oxo-3,4-dihydrobenzo[h]quinazolin-6-yl}methyl)-4-pyridin-2-ylpiperidine-4-carbonitrile;
1-({3-[(1S,2S)-2-Hydroxycyclohexyl]-4-oxo-3,4-dihydrobenzo[h]quinazolin-6-yl}methyl)-4-pyridin-2-ylpiperidine-4-carbonitrile 1-oxide;
1-({3-[(1S,2S)-2-Hydroxycyclohexyl]-4-oxo-3,4-dihydropyrido[3,4-h]quinazolin-6-yl}methyl)-4-(4-methylpyridin-2-yl)piperidine-4-carbonitrile;
3-[(1S,2S)-2-Hydroxycyclohexyl]-6-{[4-(3-thienyl)piperazin-1-yl]methyl}benzo[h]quinazolin-4(3H)-one;
rac-3-[(1R,2R)-2-Hydroxycyclohexyl]-6-{[4-(1-methyl-1H-pyrazol-4-yl)-3-oxopiperazin-1-yl]methyl}benzo[h]quinazolin-4(3H)-one;
1-({3-[(1S,2S)-2-Hydroxycyclohexyl]-4-oxo-3,4-dihydrobenzo[h]quinazolin-6-yl}methyl)-4-methylpiperidine-4-carbonitrile;
6-[(4-Fluoro-4-pyridin-2-ylpiperidin-1-yl)methyl]-3-[(1S,2S)-2-hydroxycyclohexyl]benzo[h]quinazolin-4(3H)-one;
or a pharmaceutically acceptable salt thereof.
17. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (IIA)
wherein R 9 is selected from the group consisting of
Chirality
R 9
racemic
racemic
racemic
racemic
racemic
racemic
racemic
racemic
racemic
racemic
racemic
racemic
(1S, 2S)
(1S, 2S)
(1S, 2S)
(1S, 2S)
(1S, 2S)
(1S, 2S)
(1S, 2S)
(1S, 2S)
(1S, 2S)
(1S, 2S)
(1S, 2S)
(1S, 2S)
(1S, 2S)
(1S, 2S)
(1S, 2S)
(1S, 2S)
(1S, 2S)
(1S, 2S)
(1S, 2S)
(1S, 2S)
(1S, 2S)
(1S, 2S)
N/A
18. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (IIB)
wherein R 9 is selected from the group consisting of
Chirality
R 9
(3R, 4S)
(3R, 4S)
(3R, 4S)
(3R, 4S)
(3R, 4S)
(3R, 4S)
(3R, 4S)
19. A compound of claim 1 , wherein the compound of formula (I) is a compound of formula
wherein R 10 is
or a pharmaceutically acceptable salt thereof.
20. 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.
21. A pharmaceutical composition for the treatment of a disease or disorder mediated by the muscarinic M1 receptor, wherein said disease or disorder is selected from the group consisting of Alzheimer's disease, schizophrenia, pain or sleep disorders, comprising a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
22. A method of treating a disease or disorder mediated by the muscarinic M1 receptor, wherein said disease or disorder is selected from the group consisting of Alzheimer's disease, schizophrenia, pain or sleep disorders in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.