Quinolizidinone M1 receptor positive allosteric modulators
View Patent ↗The present invention is directed to spiropiperidine 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) cyano,
(2) —C(═O)—OR 4A ,
(3) —C(═O)—R 4A ,
(4) —OH, and
(5) phenyl;
R 2 is selected from the group consisting of
(1) —(CH 2 ) n -aryl, and
(2) heteroaryl,
wherein said aryl or heteroaryl moiety is optionally substituted with one or more
(a) halogen,
(b) hydroxy,
(c) —O—C 1-6 alkyl,
(d) —C 1-6 alkyl,
(e) —C 2-6 alkenyl
(f) —S(O) m —R 4A ,
(g) —C 2-6 alkynyl, and
(h) —N(R 4A R 4B );
R 3 is selected from the group consisting of
(1) hydrogen,
(2) —C 1-6 alkyl, and
(3) —CH 2 -aryl,
wherein said R 3 alkyl or aryl moiety is optionally substituted with one or more
(a) halogen,
(b) cyano, and
(c) —O—C 1-6 alkyl, wherein said alkyl is optionally substituted with one or more halo;
R 4A and R 4B are each independently selected from the group consisting of
(1) hydrogen,
(2) —C 1-6 alkyl,
(3) —(CH 2 ) n -aryl,
wherein said R 4A or R 4B alkyl or aryl moiety is optionally substituted with one or more
(a) halogen,
(b) cyano, and
(c) —O—C 1-6 alkyl, wherein said alkyl is optionally substituted with one or more halo;
R 6 is optionally present at one or more of the ring carbon atoms, and each R 6 is independently selected from the group consisting of
(1) halogen,
(2) —C 1-6 alkyl, and
(3) —(CH 2 ) n -aryl,
wherein said R 6 alkyl or aryl moiety is optionally substituted with one or more
(a) halogen,
(b) cyano, and
(c) —O—C 1-6 alkyl, wherein said alkyl is optionally substituted with one or more halo;
m is 0, 1 or 2;
n is 0, 1 or 2;
or a pharmaceutically acceptable salt thereof.
2. A compound of claim 1 , wherein R 1 is cyano.
3. A compound of claim 1 , wherein R 1 is selected from the group consisting of
(1) —C(═O)—OR 4A ,
(2) —C(═O)—R 4A ,
(3) —OH.
4. A compound of claim 1 , wherein R 4A and R 4B are each independently selected from C 1-6 alkyl.
5. A compound of claim 1 , wherein R 2 is pyridyl, and the pyridyl group is optionally substituted with one or more
(a) halogen,
(b) hydroxy,
(c) —O—C 1-6 alkyl
(d) —C 1-6 alkyl, and
(e) —C 2-6 alkenyl.
6. A compound of claim 5 , wherein the pyridyl is 2-pyridyl.
7. A compound of claim 1 , wherein R 2 is phenyl, optionally substituted with one or more
(a) halogen,
(b) hydroxy,
(c) —O—C 1-6 alkyl
(d) —C 1-6 alkyl, or
(e) —C 2-6 alkenyl.
8. A compound of claim 1 , wherein R 3 is hydrogen.
9. A compound of claim 1 , wherein R 6 is absent.
10. A compound of claim 1 , wherein R 6 is a halogen present at one ring carbon atom.
11. A compound of claim 1 , wherein the compound of formula (I) is a compound of formula (II):
wherein
R 2 is selected from the group consisting of
(1) —(CH 2 ) n -aryl, and
(2) heteroaryl,
wherein said aryl or heteroaryl moiety is optionally substituted with one or more
(a) halogen,
(b) hydroxy,
(c) —O—C 1-6 alkyl
(d) —C 1-6 alkyl,
(e) —C 2-6 alkenyl;
R 6 is optionally present at one or more of the ring carbon atoms, and each R 6 is independently selected from the group consisting of
(1) halogen,
(2) —C 1-6 alkyl, and
(3) —(CH 2 ) n -aryl,
wherein said R 6 alkyl or aryl moiety is optionally substituted with one or more
(a) halogen,
(b) cyano, and
(c) —O—C 1-6 alkyl, wherein said alkyl is optionally substituted with one or more halo; and
n is 0, 1 or 2;
or a pharmaceutically acceptable salt thereof.
12. A compound of claim 1 , wherein the compound of formula (I) is a compound of formula (III)
wherein
X is selected from the group consisting of
(1) CH, and
(2) N, and
R 5 is optionally present and is selected from the group consisting of
(1) halogen,
(2) hydroxy,
(3) —O—C 1-6 alkyl,
(4) —C 1-6 alkyl, and
(5) —C 2-6 alkenyl;
R 6 is optionally present at one or more of the ring carbon atoms, and each R 6 is independently selected from the group consisting of
(1) halogen,
(2) —C 1-6 alkyl, and
(3) —(CH 2 ) n -aryl,
wherein said R 6 alkyl or aryl moiety is optionally substituted with one or more
(a) halogen,
(b) cyano, and
(c) —O—C 1-6 alkyl, wherein said alkyl is optionally substituted with one or more halo; and
or a pharmaceutically acceptable salt thereof.
13. A compound of claim 12 , wherein X is N.
14. A compound of claim 1 , which is selected from the group consisting of
1-[(4-cyano-4-pyridin-2-ylpiperidin-1-yl)methyl]-4-oxo-4H-quinolizine-3-carboxylic acid;
1-{[4-cyano-4-(4-methylpyridin-2-yl)piperidin-1-yl]methyl}-4-oxo-4H-quinolizine-3-carboxylic acid;
1-{[4-cyano-4-(3-fluorophenyl)piperidin-1-yl]methyl}-4-oxo-4H-quinolizine-3-carboxylic acid;
1-[(4-cyano-4-pyridin-3-ylpiperidin-1-yl)methyl]-4-oxo-4H-quinolizine-3-carboxylic acid;
1-{[4-(3-bromopyridin-2-yl)-4-cyanopiperidin-1-yl]methyl}-4-oxo-4H-quinolizine-3-carboxylic acid;
1-{[4-cyano-4-(3-vinylpyridin-2-yl)piperidin-1-yl]methyl}-4-oxo-4H-quinolizine-3-carboxylic acid;
1-{[4-cyano-4-(5-vinylpyridin-2-yl)piperidine-1-yl]methyl}-4-oxo-4H-quinolizine-3-carboxylic acid; and
Sodium 1-[(4-cyano-4-pyridin-2-ylpiperidin-1-yl)methyl]-9-methyl-4-oxo-4H-quinolizine-3-carboxylate;
or a pharmaceutically acceptable salt thereof.
15. A compound of claim 1 , wherein R 3 is hydrogen, and R 1 and R 2 are defined as follows:
R 2
R 1
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
COCH 3
CO 2 CH 2 CH 3
OH
CN
CN
CN
CN
CN
or a pharmaceutically acceptable salt thereof.
16. 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.