IP Library › Granted Patent US 9,284,312

Granted Patent B2

US 9,284,312 · App. 14/117,178 · Granted Mar 15, 2016

N-methyl tetrahydroquinoline M1 receptor positive allosteric modulators

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Quick Facts

Patent No.: US 9,284,312
App. No.: 14/117,178
Granted: Mar 15, 2016
Kind: B2

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Abstract

The present invention is directed to N-methyl tetrahydroquinoline 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.

Claims (150)

1. A compound of formula (I):

and pharmaceutically acceptable salts thereof, wherein

--- represents a bond which can be absent or present,

Y is selected from the group consisting of

(1) a C 5-10 heterocycle group, said heterocycle optionally substituted with 1 to 3 groups of R 1 , and

(2) C 6-10 aryl group, said aryl optionally substituted with 1 to 3 groups of R 1 ,

X and X 1 are independently selected from —CH 2 and —O—;

R 1 is selected from the group consisting of

(1) hydrogen,

(2) C 6-10 aryl,

(3) C 5-10 heterocycle,

(4) (CH 2 ) n halogen,

(5) —CN,

(6) —O—C 1-6 alkyl,

(7) —C 1-6 alkyl,

(8) —C 2-6 alkenyl

(9) —S(═O) n —R 2 ,

(10) —(C(O)O) m NR 3A R 3B ,

(11) —OH,

(12) -oxo,

(13) —C(═O)—(O) m —R 4 ,

(14) CF 3 ,

wherein said aryl, heterocycle, alkyl and alkenyl moiety is optionally substituted with one to three of

(a) halogen,

(b) hydroxy,

(d) —C 1-6 alkyl,

(e) —C(═O)—(O) m —R 4 ,

(f) —N(R 3A R 3B ),

(g) —S(═O) n —R 5 , or

(h) C 5-10 heteroaryl, which is optionally substituted with 1 to 3 groups of C 1-6 alkyl,

R 2 , R 4 , and R 5 are independently selected from the group consisting of

(1) hydrogen,

(2) —C 1-6 alkyl,

(3) —C 2-6 alkenyl, and

(3) —(CH 2 ) n -aryl,

(4) —N(R 1 ) 2

wherein said R 2 , R 4 and R 5 alkyl or aryl moiety is optionally substituted with one or more

(a) halogen,

(b) cyano, and

R 3A and R 3B are selected from the group consisting of

(1) hydrogen,

(2) —C 1-6 alkyl,

(3) —C 3-6 cycloalkyl,

(4) —C(═O)—O—R 4 ,

(5) —S(O) 2 —R 4 ,

or R 3A and R 3B 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 optionally replaced by a nitrogen, oxygen or sulfur;

m is 0 or 1; and

n is 0, 1 or 2.

2. The compound according to claim 1 wherein --- is a bond.

3. The compound according to claim 1 wherein X and X 1 are CH 2 .

4. The compound according to claim 1 wherein X is O and X 1 is CH 2 .

5. The compound according to claim 1 wherein X is CH 2 and X 1 is O.

6. The compound according to claim 1 wherein Y is C 6-10 aryl, optionally substituted with 1 to 3 groups of R 1 selected from the group consisting of C 6-10 aryl, C 5-10 heterocycle, OH, (CH 2 ) n halogen, —CN, CF 3 , —O—C 1-6 alkyl, —C 1-6 alkyl, —SC 1-6 alkyl, and —C(O)ONR 3A R 3B , said aryl, heterocycle optionally substituted with 1 to 3 groups of C 1-6 alkyl.

7. The compound according to claim 1 wherein Y is C 5-10 heterocycle, optionally substituted with 1 to 3 groups of R 1 selected from the group consisting of C 6-10 aryl, C 5-10 heterocycle, OH, (CH 2 ) n halogen, —CN, CF 3 , —O—C 1-6 alkyl, —C 1-6 alkyl, —SC 1-6 alkyl, and —C(O)ONR 3A R 3B , said aryl, heterocycle optionally substituted with 1 to 3 groups of C 1-6 alkyl.

8. The compound according to claim 6 wherein Y is optionally substituted phenyl, and X and X 1 are CH 2 .

9. The compound according to claim 6 wherein Y is optionally substituted phenyl and X is O and X 1 is CH 2 .

10. The compound according to claim 6 wherein Y is optionally substituted phenyl and X is CH 2 and X 1 is O.

11. The compound according to claim 7 wherein Y is optionally substituted pyridyl, and X and X 1 are CH 2 .

12. The compound according to claim 7 wherein Y is optionally substituted pyridyl and X is O and X 1 is CH 2 .

13. The compound according to claim 7 wherein Y is optionally substituted pyridyl and X is CH 2 and X 1 is O.

14. The compound according to claim 1 represented by structural formulas (Ia):

and pharmaceutically acceptable salts thereof, wherein X, X 1 and Y are as previously described.

15. The compound according to claim 1 represented by structural formula (Ib):

16. A compound of formula (I) of claim 1 which is

6-[(6-Chloropyridin-3-yl)methyl]-3-[(1S,2S)-2-hydroxycyclohexyl]-10-methyl-9,10-dihydropyrido[3,2-h]quinazolin-4(3H)-one;

6-[(6-Chloropyridin-3-yl)methyl]-3-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]-10-methyl-9,10-dihydropyrido[3,2-h]quinazolin-4(3H)-one;

3-[(1S,2S)-2-Hydroxycyclohexyl]-10-methyl-6-{[-(methylthio)-pyridin-3-yl]methyl}-9,10-dihydropyrido[3,2-h]quinazolin-4(3H)-one;

3-[(1S,2S)-2-Hydroxycyclohexyl]-6-[(6-methoxypyridin-3-yl)methyl]-10-methyl-9,10-dihydropyrido[3,2-h]quinazolin-4(3H)-one;

3-[(1S,2S)-2-Hydroxycyclohexyl]-10-methyl-6-(pyridine-3-ylmethyl)-9,10-dihydropyrido[3,2-h]quinazolin-4(3H)-one;

3-[(1S,2S)-2-Hydroxycyclohexyl]-10-methyl-6-{[6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl]methyl}-9,10-dihydropyrido[3,2-h]quinazolin-4(3H)-one;

6-(4-Hydroxybenzyl)-3-[(1S,2S)-2-hydroxycyclohexyl]-10-methyl-9,10-dihydropyrido[3,2-h]quinazolin-4(3H)-one;

4-({3-[(1S,2S)-2-Hydroxycyclohexyl]-10-methyl-4-oxo-3,4,9,10-tetrahydropyrido[3,2-h]quinazolin-6-yl}methyl)phenyl dimethylcarbamate;

3-[(1S,2S)-2-Hydroxycyclohexyl]-6-[(2-methoxypyridin-4-yl)methyl]-10-methyl-9,10-dihydropyrido[3,2-h]quinazolin-4(3H)-one;

6-[(6-Chloropyridin-3-yl)methyl]-3-[(1S,2S)-2-hydroxycyclohexyl]-10-methyl-7,8,9,10-tetrahydropyrido[3,2-h]quinazolin-4(3H)-one;

3[(1S,2S)-2-hydroxycyclohexyl]-6-(4-methoxybenzyl)-10-methyl-9,10-dihydropyrido[3,2-h]quinazolin-4(3H)-one,

1,5-anhydro-2,3-dideoxy-3-[6-(4-methoxybenzyl)-10-methyl-4-oxo-9,10-dihydropyrido[3,2-h]quinazolin-3(4H)-yl]-L-threo-pentitol,

4-({3-[(1S,2S)-2-hydroxycyclohexyl]-10-methyl-4-oxo-3,4,9,10-tetrahydropyrido[3,2-h]quinazolin-6-yl}methyl)phenyl ethyl(methyl)carbamate,

3-[(1S,2S)-2-hydroxycyclohexyl]-6-(3-methoxybenzyl)-10-methyl-9,10-dihydropyrido[3,2-h]quinazolin-4(3H)-one,

1,5-anhydro-2,3-dideoxy-3-[6-(3-methoxybenzyl)-10-methyl-4-oxo-9,10-dihydropyrido[3,2-h]quinazolin-3(4H)-yl]-L-threo-pentitol,

6-(3-hydroxybenzyl)-3-[(1S,2S)-2-hydroxycyclohexyl]-10-methyl-9,10-dihydropyrido[3,2-h]quinazolin-4(3H)-one,

3-({3-[(1S,2S)-2-hydroxycyclohexyl]-10-methyl-4-oxo-3,4,9,10-tetrahydropyrido[3,2-h]quinazolin-6-yl}methyl)phenyl dimethylcarbamate,

3-({3-[(1S,2S)-2-hydroxycyclohexyl]-10-methyl-4-oxo-3,4,9,10-tetrahydropyrido[3,2-h]quinazolin-6-yl}methyl)phenyl ethyl(methyl)carbamate,

3-[4-({3-[(1S,2S)-2-hydroxycyclohexyl]-4-oxo-3,4-dihydrobenzo[h]quinazolin-6-yl}methyl)pyridin-2-yl]phenyl dimethylcarbamate,

3-[4-({3-[(1S,2S)-2-hydroxycyclohexyl]-4-oxo-3,4-dihydrobenzo[h]quinazolin-6-yl}methyl)pyridin-2-yl]phenyl ethyl(methyl)carbamate,

3-[(1S,2S)-2-hydroxycyclohexyl]-10-methyl-6-(4-methylbenzyl)-9,10-dihydropyrido[3,2-h]quinazolin-4(3H)-one,

1,5-anhydro-2,3-dideoxy-3-[10-methyl-6-(4-methylbenzyl)-4-oxo-9,10-dihydropyrido[3,2-h]quinazolin-3(4H)-yl]-L-threo-pentitol,

6-(3-fluorobenzyl)-3-[(1S,2S)-2-hydroxycyclohexyl]-10-methyl-9,10-dihydropyrido[3,2-h]quinazolin-4(3H)-one,

3-[(1S,2S)-2-hydroxycyclohexyl]-10-methyl-6-(3-methylbenzyl)-9,10-dihydropyrido[3,2-h]quinazolin-4(3H)-one,

6-(3-chlorobenzyl)-3-[(1S,2S)-2-hydroxycyclohexyl]-10-methyl-9,10-dihydropyrido[3,2-h]quinazolin-4(3H)-one,

6-(3,4-difluorobenzyl)-3-[(1S,2S)-2-hydroxycyclohexyl]-10-methyl-9,10-dihydropyrido[3,2-h]quinazolin-4(3H)-one,

6-(3,5-difluorobenzyl)-3-[(1S,2S)-2-hydroxycyclohexyl]-10-methyl-9,10-dihydropyrido[3,2-h]quinazolin-4(3H)-one,

3-[(1S,2S)-2-hydroxycyclohexyl]-10-methyl-6-[3-(trifluoromethyl)benzyl]-9,10-dihydropyrido[3,2-h]quinazolin-4(3H)-one,

3-[(1S,2S)-2-hydroxycyclohexyl]-10-methyl-6-[4-(trifluoromethyl)benzyl]-9,10-dihydropyrido[3,2-h]quinazolin-4(3H)-one,

1,5-anhydro-2,3-dideoxy-3-{10-methyl-4-oxo-6-[4-(trifluoromethyl)benzyl]-9,10-dihydropyrido[3,2-h]quinazolin-3(4H)-yl}-L-threo-pentitol,

1,5-anhydro-2,3-dideoxy-3-[6-(4-fluorobenzyl)-10-methyl-4-oxo-9,10-dihydropyrido[3,2-h]quinazolin-3(4H)-yl]-L-threo-pentitol,

6-(4-chlorobenzyl)-3-[(1S,2S)-2-hydroxycyclohexyl]-10-methyl-(9,10-dihydropyrido[3,2-h]quinazolin-4(3H)-one,

4-({3-[(1S,2S)-2-hydroxycyclohexyl]-10-methyl-4-oxo-3,4,9,10-tetrahydropyrido[3,2-h]quinazolin-6-yl}methyl)benzonitrile,

3-({3-[(1S,2S)-2-hydroxycyclohexyl]-10-methyl-4-oxo-3,4,9,10-tetrahydropyrido[3,2-h]quinazolin-6-yl}methyl)benzonitrile,

1,5-anhydro-2,3-dideoxy-3-[10-methyl-6-{[6-(methylsulfanyl)pyridin-3-yl]methyl}-4-oxo-9,10-dihydropyrido[3,2-h]quinazolin-3(4H)-yl]-L-threo-pentitol,

1,5-anhydro-2,3-dideoxy-3-{6-[(6-methoxypyridin-3-yl)methyl]-10-methyl-4-oxo-9,10-dihydropyrido[3,2-h]quinazolin-3(4H)-yl}-L-threo-pentitol,

1,5-anhydro-2,3-dideoxy-3-[10-methyl-4-oxo-6-(pyridin-3-ylmethyl)-9,10-dihydropyrido[3,2-h]quinazolin-3(4H)-yl]-L-threo-pentitol,

6-[(6-fluoropyridin-3-yl)methyl]-3-[(1S,2S)-2-hydroxycyclohexyl]-10-methyl-9,10-dihydropyrido[3,2-h]quinazolin-4(3H)-one,

3-[(1S,2S)-2-hydroxycyclohexyl]-10-methyl-6-{[6-(trifluoromethyl)pyridin-3-yl]methyl}-9,10-dihydropyrido[3,2-h]quinazolin-4(3H)-one,

6-[(2-fluoropyridin-4-yl)methyl]-3-[(1S,2S)-2-hydroxycyclohexyl]-10-methyl-9,10-dihydropyrido[3,2-h]quinazolin-4(3H)-one,

3-[(1S,2S)-2-hydroxycyclohexyl]-10-methyl-6-{[2-(trifluoromethyl)pyridin-4-yl]methyl}-9,10-dihydropyrido[3,2-h]quinazolin-4(3H)-one,

1,5-anhydro-3-{6-[(2-chloropyridin-4-yl)methyl]-10-methyl-4-oxo-9,10-dihydropyrido[3,2-h]quinazolin-3(4H)-yl}-2,3-dideoxy-L-threo-pentitol,

1,5-anhydro-2,3-dideoxy-3-{6-[(2-methoxypyridin-4-yl)methyl]-10-methyl-4-oxo-9,10-dihydropyrido[3,2-h]quinazolin-3(4H)-yl}-L-threo-pentitol,

1,5-anhydro-2,3-dideoxy-3-{6-[(2-fluoropyridin-4-yl)methyl]-10-methyl-4-oxo-9,10-dihydropyrido[3,2-h]quinazolin-3(4H)-yl}-L-threo-pentitol,

3-[(1S,2S)-2-hydroxycyclohexyl]-10-methyl-6-{[2-(methylsulfanyl)pyridin-4-yl]methyl}-9,10-dihydropyrido[3,2-h]quinazolin-4(3H)-one,

3-[(1S,2S)-2-hydroxycyclohexyl]-10-methyl-6-(quinolin-4-ylmethyl)-9,10-dihydropyrido[3,2-h]quinazolin-4(3H)-one,

3-[(1S,2S)-2-hydroxycyclohexyl]-6-(4-methoxybenzyl)-10-methyl-9,10-dihydropyrido[3,2-h]quinazolin-4(3H)-one,

1,5-anhydro-2,3-dideoxy-3-[6-(4-methoxybenzyl)-10-methyl-4-oxo-9,10-dihydropyrido[3,2-h]quinazolin-3 (4H)-yl]-L-threo-pentitol,