Pyridoquinazolinone M1 receptor positive allosteric modulators
View Patent ↗The present invention is directed to quinolinone-pyrazolone 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 R 1 is selected from the group consisting of
(1) —C 6-10 aryl, or
(2) heteroaryl, wherein the heteroaryl is an aromatic cyclic 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 each aryl or heteroaryl is optionally substituted with one or more R 2 group;
R 2 is selected from the group consisting of
(1) halogen,
(2) —C 1-6 alkyl,
(3) —C 2-8 alkenyl,
(4) —O—C 1-6 alkyl,
(5) —S—C 1-6 alkyl,
(6) —C(═O)—(O) n —R 4 ,
(7) —C 6-10 aryl,
(8) 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,
(9) —NR 5 R 6 ,
wherein said alkyl, alkenyl, 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
wherein said alkyl, cycloalkyl or aryl is optionally substituted with one or more
(i) halogen,
(ii) hydroxyl,
(iii) —NR 9 R 10 ;
X and Y are selected from the group consisting of
(1) CH 2 , or
(2) O,
wherein one of X or Y is O, then the other is CH 2 ;
Q 1 , Q 2 , Q 3 and Q 4 are each selected from the group consisting of
(1) N, or
(2) CR 3 ,
provided that one of Q 1 , Q 2 , Q 3 or Q 4 is N and the others are each CR 3 ;
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) hydrogen,
(2) —C 1-6 alkyl,
(3) —C 3-8 cycloalkyl,
(4) —C 2-6 alkenyl,
(5) —C 0-2 alkyl-C 6-10 aryl,
(6) —C 0-2 alkyl-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, alkenyl, aryl or heteroaryl R 7 group is optionally substituted with one or more
(a) halogen,
(b) hydroxy,
(c) —O—C 1-6 alkyl,
(d) —C 1-6 alkyl, optionally substituted with halogen;
R 5 and R 6 , or R 7 and R 8 , or R 9 and R 10 are each independently selected from the group consisting of
(1) hydrogen,
(2) —C 1-6 alkyl,
(3) —C 3-8 cycloalkyl, or
(4) —C 6-10 aryl,
wherein said alkyl, cycloalkyl or aryl is optionally substituted with one or more
(a) halogen,
(b) —C 1-6 alkyl,
(c) —C 3-8 cycloalkyl,
(d) —O—C 1-6 alkyl,
(e) —C 6-10 aryl,
(f) heteroaryl, which is an aromatic cyclic or polycyclic cyclic, having from five to twelve ring atoms, said ring atoms selected from C, O, N, N→O, C(═O), SO 2 or S, at least one of which is O, N, N→O, SO 2 or S,
or R 5 and R 6 , or R 7 and R 8 , or R 9 and R 10 are linked together with the nitrogen to which they are both attached to form a 4-8 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
(a) halogen,
(b) —C 1-6 alkyl,
(c) —O—C 1-6 alkyl, or
(d) —C 6-10 aryl,
n is 0 or 1;
or a pharmaceutically acceptable salt thereof.
2. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is phenyl, wherein the phenyl is substituted by one R 2 group, which is para to the methylene group that binds the phenyl to the core, and each R 2 is selected from the group consisting of
(1) halogen,
(2) —C 1-6 alkyl,
(3) —C 2-8 alkenyl,
(4) —O—C 1-6 alkyl,
(5) —S—C 1-6 alkyl,
(7) —C 6-10 aryl (typically, phenyl), or
(8) 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,
(9) —NR 5 R 6 ,
wherein said alkyl, alkenyl, aryl or heteroaryl R 2 group is optionally substituted as described above.
3. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is heteroaryl, wherein the heteroaryl is an aromatic cyclic 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.
4. A compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Q 2 is N, and each of Q 1 , Q 3 and Q 4 is CR 3 .
5. A compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Q 4 is N, and each of Q 1 , Q 2 and Q 3 is CR 3 .
6. A compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein X and Y are both CH 2 .
7. A compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein X is CH 2 and Y is O.
8. A compound of claim 1 , wherein the compound of formula (I) is a compound of formula (II)
or a pharmaceutically acceptable salt thereof, wherein Y, R 2 , Q 1 , Q 2 , Q 3 and Q 4 are as defined in claim 1 .
9. A compound of claim 8 , or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from the group consisting of
(1) halogen,
(2) —C 1-6 alkyl,
(3) —C 2-8 alkenyl,
(4) —O—C 1-6 alkyl,
(5) —S—C 1-6 alkyl, or
(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, alkenyl, aryl or heteroaryl R 2 group is optionally substituted as described above.
10. A compound of claim 1 , wherein the compound of formula (I) is a compound of formula (III):
or a pharmaceutically acceptable salt thereof, wherein Y, R 2 , Q 1 , Q 2 , Q 3 and Q 4 are as defined in claim 1 .
11. A compound of claim 10 , or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from the group consisting of
(1) halogen,
(2) —C 1-6 alkyl,
(3) —C 2-8 alkenyl,
(4) —O—C 1-6 alkyl,
(5) —S—C 1-6 alkyl, or
(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.
12. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (IV)
or a pharmaceutically acceptable salt thereof, wherein Y and R 1 are as described in claim 1 .
13. A compound of claim 1 , which is selected from the group consisting of
6-[(6-Chloropyridin-3-yl)methyl]-3-[(1S,2S)-2-hydroxycyclohexyl]pyrido[3,4-h]quinazolin-4(3H)-one;
6-[(6-Chloropyridin-3-yl)methyl]-3-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]pyrido[3,4-h]quinazolin-4(3H)-one;
3-[(1S,2S)-2-Hydroxycyclohexyl]-6-[(6-methylpyridin-3-yl)methyl]pyrido[3,4-h]quinazolin-4(3H)-one;
3-[(1S,2S)-2-Hydroxycyclohexyl]-6-[(6-methoxypyridin-3-yl)methyl]pyrido[3,4-h]quinazolin-4(3H)-one;
3-[(1S,2S)-2-Hydroxycyclohexyl]-6-{[6-(methylthio)pyridine-3-yl]methyl}pyrido[3,4-h]quinazolin-4(3H)-one;
3-[(1S,2S)-2-Hydroxycyclohexyl]-6-{[6-(1H-pyrazol-1-yl)pyridine-3-yl]methyl}pyrido[2,3-h]quinazolin-4(3H)-one;
3-[(1S,2S)-2-Hydroxycyclohexyl]-6-{[6-(1-methyl-1H-pyrazol-4-yl)pyridine-3-yl]methyl}pyrido[3,4-h]quinazolin-4(3H)-one;
3-[(1S,2S)-2-Hydroxycyclohexyl]-6-[(6-pyrazin-2-ylpyridin-3-yl)methyl]pyrido[3,4-h]quinazolin-4(3H)-one;
4-({3-[(1S,2S)-2-Hydroxycyclohexyl]-4-oxo-3,4-dihydropyrido[3,4-h]quinazolin-6-yl}methyl)benzaldehyde;
3-[(1S,2S)-2-Hydroxycyclohexyl]-6-[4-(1-hydroxyethyl)benzyl]pyrido[3,4-h]quinazolin-4(3H)-one;
3-[(1S,2S)-2-Hydroxycyclohexyl]-6-[4-(1-hydroxypropyl)benzyl]pyrido[3,4-h]quinazolin-4(3H)-one;
3-[(1S,2S)-2-Hydroxycyclohexyl]-6-(4-morpholin-4-ylbenzyl)pyrido[3,4-h]quinazolin-4(3H)-one; and
3-[(3S,4S)-4-Hydroxytetrahydro-2H-pyran-3-yl]-6-[(2-methylpyridin-4-yl)methyl]pyrido[2,3-h]quinazolin-4(3H)-one;
or a pharmaceutically acceptable salt thereof.
14. A compound of claim 1 , which is a compound of formula (IA)
wherein R 1 is selected from the group consisting of
or a pharmaceutically acceptable salt thereof.
15. A compound of claim 1 , which is a compound of Formula (IB),
wherein R 11 , Q 5 and Q 6 are grouped as follows:
Q 5
Q 6
R 11
N
N
CH
!! EMBED
CH
CH
CH
CH
H
CH
H
CH
Cl
CH
Br
CH
Br
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
OMe
CH
OMe
CH
Me
CH
Me
CH
F
CH
F
CH
or a pharmaceutically acceptable salt thereof.
16. A compound of claim 1 , which is a compound of Formula (IC)
wherein Q 5 and R 11 are grouped as follows:
Q 5
R 11
OMe
OMe
Me
Me
F
F
or a pharmaceutically acceptable salt thereof.
17. A compound of claim 1 , which is a compound of Formula (ID), wherein R 11 , Q 5 and Q 6 are grouped as follows:
Q 5
Q 6
R 11
N
Cl
N
Me
N
N
N
N
N
Cl
N
Me
CH
F
CH
Cl
CH
OMe
N
SMe
CH
Br
N
N
N
Et
N
N
OMe
N
or a pharmaceutically acceptable salt thereof.
18. A compound of claim 1 , wherein the compound of formula (I) is a compound of formula (IE):
wherein R is selected from the group consisting of
or a pharmaceutically acceptable salt thereof.
19. 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.