Tetrahydroquinoline amide M1 receptor positive allosteric modulators
View Patent ↗The present invention is directed to tetrahydroquinoline amide compounds of formula (I) (Formula should be inserted here) 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 1 is selected from the group consisting of
(1) —CH 2 —, or
(2) —O—;
R is a C 6-10 aryl or C 5-10 heterocyclyl group, said aryl or heterocyclyl group optionally substituted with 1 to 3 groups of R a ;
R a represents:
(a) halogen,
(b) hydroxy,
(c) —O—C 1-6 alkyl, said alkyl optionally substituted with 1 to 3 groups of halo;
(d) —C 1-6 alkyl, said alkyl optionally substituted with 1 to 3 groups of halo;
(e) cyano,
(f) —NR A R B ,
(g) t-butoxycarbonyl, —C(═O)—R C , —S(O) n —R C , C 5-10 heterocyclyl, and C 6-10 aryl, said heterocyclyl and aryl optionally substituted with 1 to 3 groups of R C ;
R A and R B are selected from the group consisting of
(i) hydrogen,
(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, and the carbocyclic is optionally substituted with one or more C 1-6 alkyl,
R C is selected from the group consisting of
(i) hydrogen,
(ii) —C 1-6 alkyl,
(iii) —O—C 1-6 alkyl,
(iv) CF 3 ,
(v) halogen,
(vi) cyano, and
n is 0, 1 or 2.
2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X 1 is —O—.
3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X 1 is —CH 2 —.
4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof wherein R is C 5-10 heterocyclyl optionally substituted with 1 to 3 groups of R a .
5. The compound of claim 4 or a pharmaceutically acceptable salt thereof, wherein the heterocyclyl is selected from the group consisting of optionally substituted pyridyl, quinolinyl, isoquinolinyl, quinolizinyl, quinoxalinyl, quinazolinyl, benzimidazolyl, oxanyl, pyranyl, and napthrindinyl.
6. The compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein R is optionally substituted pyridyl.
7. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the R a substituent on R is selected from the group consisting of halogen, hydroxy, —O—C 1-6 alkyl, said alkyl optionally substituted with 1 to 3 groups of halo; —C 1-6 alkyl, said alkyl optionally substituted with 1 to 3 groups of halo; t-butoxycarbonyl, —C(═O)—R C , —S(O) n —R C ; C 5-10 heterocyclyl, and C 6-10 aryl, said heterocyclyl and aryl optionally substituted with 1 to 3 groups of R c .
8. The compound of claim 7 or a pharmaceutically acceptable salt thereof, wherein R a is selected from the group consisting of chloro, fluoro, methoxy, pyridyl, phenyl, acetyl, and t-butoxycarbonyl, said pyridyl and phenyl optionally substituted with 1 to 3 groups of R c .
9. The compound of claim 1 of formula (I) represented by structural formula II:
or a pharmaceutically acceptable salt thereof, wherein N is a pyridyl.
10. The compound of claim 1 of formula I represented by structural formula III:
or a pharmaceutically acceptable salt thereof, wherein N is a pyridyl.
11. A compound of formula (I) of claim 1 which is:
Compound
Chirality
X
R
7
(1S, 2S)
CH
8
(1S, 2S)
CH
9
(1S, 2S)
CH
10
(1S, 2S)
CH
11
(1S, 2S)
CH
12
(3R, 4S)
O
13
(3R, 4S)
O
14
(3R, 4S)
O
15
(3R, 4S)
O
16
(3R, 4S)
O
17
(3R, 4S)
O
18
(3R, 4S)
O
19
(3R, 4S)
O
20
(3R, 4S)
O
21
(3R, 4S)
O
22
(3R, 4S)
O
23
(3R, 4S)
O
24
(3R, 4S)
O
1,5-Anhydro-3-[({4-[(6-chloropyridin-3-yl)methyl]-5,6,7,8-tetrahydroquinolin-2-yl}carbonyl)amino]-2,3-dideoxy-L-threo-pentitol,
N-[(1S,2S)-2-Hydroxycyclohexyl]-4-{[6-(methylsulfanyl)pyridin-3-yl]methyl}-5,6,7,8-tetrahydroquinoline-2-carboxamide,
1,5-Anhydro-2,3-dideoxy-3-[({4-[(6-methoxypyridin-3-yl)methyl]-5,6,7,8-tetrahydroquinolin-2-yl}carbonyl)amino]-L-threo-pentitol,
3-[{(4-[(1-Acetyl-1,2,3,6-tetrahydropyridin-4-yl)methyl]-5,6,7,8-tetrahydroquinolin-2-yl}carbonyl)amino]-1,5-anhydro-2,3-dideoxy-L-threo-pentitol,
1,5-Anhydro-2,3-dideoxy-3-{[(4-{[6-(1-methyl-1H-pyrazol-4-yl)pyridine-3-yl]methyl}-5,6,7,8-tetrahydroquinolin-2-yl)carbonyl]amino}-L-threo-pentitol,
1,5-Anhydro-2,3-dideoxy-3-{[(4-{[6-(pyrazin-2-yl)pyridine-3-yl]methyl}-5,6,7,8-tetrahydroquinolin-2-yl)carbonyl]amino}-L-threo-pentitol,
or a pharmaceutically acceptable salt thereof.
12. The compound according to claim 11 which is:
1,5-Anhydro-3-[({4-[(6-chloropyridin-3-yl)methyl]-5,6,7,8-tetrahydroquinolin-2-yl}carbonyl)amino]-2,3-dideoxy-L-threo-pentitol, N-[(1S,2S)-2-Hydroxycyclohexyl]-4-{[6-(methylsulfanyl)pyridin-3-yl]methyl}-5,6,7,8-tetrahydroquinoline-2-carboxamide,
1,5-Anhydro-2,3-dideoxy-3-[({4-[(6-methoxypyridin-3-yl)methyl]-5,6,7,8-tetrahydroquinolin-2-yl}carbonyl)amino]-L-threo-pentitol,
3-[{(4-[(1-Acetyl-1,2,3,6-tetrahydropyridin-4-yl)methyl]-5,6,7,8-tetrahydroquinolin-2-yl}carbonyl)amino]-1,5-anhydro-2,3-dideoxy-L-threo-pentitol,
1,5-Anhydro-2,3-dideoxy-3-{[(4-{[6-(1-methyl-1H-pyrazol-4-yl)pyridine-3-yl]methyl}-5,6,7,8-tetrahydroquinolin-2-yl)carbonyl]amino}-L-threo-pentitol,
1,5-Anhydro-2,3-dideoxy-3-{[(4-{[6-(pyrazin-2-yl)pyridine-3-yl]methyl}-5,6,7,8-tetrahydroquinolin-2-yl)carbonyl]amino}-L-threo-pentitol,
or a pharmaceutically acceptable salt thereof.
13. 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.
14. 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.