IP Library › Granted Patent US 10,308,620

Granted Patent B2

US 10,308,620 · App. 15/580,632 · Granted Jun 4, 2019

Muscarinic M1 receptor positive allosteric modulators

Inventors: Ramakrishna Nirogi (Hyderabad, IN); Abdul Rasheed Mohammed (Hyderabad, IN); Anil Karbhari Shinde (Hyderabad, IN); Shankar Reddy Gagginapally (Hyderabad, IN); Venkateswarlu Jasti (Hyderabad, IN)

Assignee: SUVEN LIFE SCIENCES LIMITED

C07D265/36 A61P25/18 A61P25/28 C07D279/16 C07D413/06 C07D413/12 C07D413/14 C07D417/06 C07D498/04

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Quick Facts

Patent No.: US 10,308,620
App. No.: 15/580,632
Granted: Jun 4, 2019
Kind: B2

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USPTO Patent Center↗ Full Patent PDF↗

Abstract

The present invention relates to compound of formula (I), or stereoisomers and pharmaceutically acceptable salts as muscarinic M1 receptor positive allosteric modulators. This invention also relates to methods of preparing such compounds and pharmaceutical compositions comprising such compounds. The compounds of this invention are useful in the treatment of various disorders that are related to muscarinic M1 receptor.

Claims (253)

1. A compound of formula (I),

wherein:

A 1 and A 2 are each independently represents CH, CF or N;

W is O, S, S(O) or S(O) 2 ;

R 1 is

R 2 is

wherein * represents point of attachment;

R 3 is OH, F, NH 2 or H;

R 4 at each occurrence is independently selected from halogen, —O—CH 3 ; —S—CH 3 , —N(CH 3 ) 2 , —CH 3 , —CF 3 , —CHF 2 , —CH 2 F, —OH, —CN, phenyl, pyridyl and hydrogen; wherein phenyl and pyridyl are optionally substituted with one or more substituents selected from the group consisting of halogen or CH 3 ;

X is CH 2 , O or NH; and

a is 0 or 1; and b is 1 or 2;

or an isotopic form, a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof.

2. The compound of formula (I) as claimed in claim 1 , wherein:

W is O;

A 1 and A 2 are CH;

R 1 is

and

R 2 is

3. The compound of formula (I) as claimed in claim 1 , wherein:

W is S;

A 1 and A 2 are CH;

R 1 is

and

R 2 is

4. The compound of formula (I) as claimed in claim 1 , wherein:

W is O;

A 1 and A 2 are CH;

R 1 is

R 2 is

and

X is CH 2 .

5. The compound of formula (I) as claimed in claim 1 , wherein:

W is S;

A 1 and A 2 are CH;

R 1 is

R 2 is

and

X is CH 2 .

6. The compound according to claim 1 , wherein the compound is selected from the group consisting of:

N-(cis-1S, 2S-2-Hydroxycyclohexyl)-4-(2-fluorobenzyl)-4H-benzo[1,4]oxazine-2-carboxamide;

N-(cis-1S, 2S-2-Hydroxycyclohexyl)-8-fluoro-4-(2-fluorobenzyl)-4H-benzo[1,4]oxazine-2-carboxamide;

N-(cis-1S, 2S-2-Hydroxycyclohexyl)-4-{2-fluorobenzyl}-4H-pyrido[3,2-b][1,4]oxazine-2-carboxamide;

N-(cis-1S, 2S-2-Hydroxycyclohexyl)-4-benzyl-4H-benzo[1,4]oxazine-2-carboxamide;

N-(cis-1S, 2S-2-Hydroxycyclohexyl)-4-(4-methoxybenzyl)-4H-benzo[1,4]oxazine-2-carboxamide;

N-(2-Hydroxy-2-methylpropyl)-4-(4-methoxybenzyl)-4H-benzo[1,4]oxazine-2-carboxamide;

N-(cis-1S, 2S-2-Hydroxycyclohexyl)-4-(3-fluorobenzyl)-4H-benzo[1,4]oxazine-2-carboxamide;

N-(2-Hydroxy-2-methylpropyl)-4-(3-fluorobenzyl)-4H-benzo[1,4]oxazine-2-carboxamide;

N-(cis-1S, 2S-2-Hydroxycyclohexyl)-4-(3-methoxybenzyl)-4H-benzo[1,4]oxazine-2-carboxamide;

N-(2-Hydroxy-2-methylpropyl)-4-(3-methoxybenzyl)-4H-benzo[1,4]oxazine-2-carboxamide;

N-(cis-1S, 2S-2-Hydroxycyclohexyl)-4-(2-methoxypyridin-4-ylmethyl)-4H-benzo[1,4]oxazine-2-carboxamide;

N-(2-Hydroxy-2-methylpropyl)-4-(2-methoxypyridin-4-yl methyl)-4H-benzo[1,4]oxazine-2-carboxamide;

N-(cis-1S, 2S-2-Hydroxycyclohexyl)-4-(4-fluorobenzyl)-4H-benzo[1,4]oxazine-2-carboxamide;

N-(2-Hydroxy-2-methylpropyl)-4-(4-fluorobenzyl)-4H-benzo[1,4]oxazine-2-carboxamide;

N-(cis-1S, 2S-2-Hydroxycyclohexyl)-4-(2-methoxy pyridin-5-ylmethyl)-4H-benzo[1,4]oxazine-2-carboxamide;

N-(2-Hydroxy-2-methylpropyl)-4-(2-methoxypyridin-5-ylmethyl)-4H-benzo[1,4]oxazine-2-carboxamide;

N-(cis-1S, 2S-2-Hydroxycyclohexyl)-4-(3-trifluoromethylbenzyl)-4H-benzo[1,4]oxazine-2-carboxamide;

N-(cis-1S, 2S-2-Hydroxycyclohexyl)-4-(2,3-difluoro benzyl)-4H-benzo[1,4]oxazine-2-carboxamide;

N-(cis-1S, 2S-2-Hydroxycyclohexyl)-4-(3,4-difluoro benzyl)-4H-benzo[1,4]oxazine-2-carboxamide;

N-(3-Hydroxytetrahydrpyran-4-yl)-4-(2,3-difluoro benzyl)-4H-benzo[1,4]oxazine-2-carboxamide;

N-(cis-1S, 2S-2-Hydroxycyclohexyl)-4-(2-chloropyridin-5-ylmethyl)-4H-benzo[1,4]oxazine-2-carboxamide;

N-(cis-1S, 2S-2-Hydroxycyclohexyl)-4-(pyridin-3-ylmethyl)-4H-benzo[1,4]oxazine-2-carboxamide;

N-(cis-1S, 2S-2-Hydroxycyclohexyl)-4-(pyridin-4-ylmethyl)-4H-benzo[1,4]oxazine-2-carboxamide;

N-(cis-1S, 2S-2-Hydroxycyclohexyl)-4-(2-chloropyridin-4-ylmethyl)-4H-benzo[1,4]oxazine-2-carboxamide;

N-(cis-1S, 2S-2-Hydroxycyclohexyl)-4-(pyridin-2-ylmethyl)-4H-benzo[1,4]oxazine-2-carboxamide;

N-(cis-1S, 2S-2-Hydroxycyclohexyl)-4-(3,4-dichloro benzyl)-4H-benzo[1,4]oxazine-2-carboxamide;

N-(cis-1S, 2S-2-Hydroxycyclohexyl)-4-(2-methylpyridin-3-ylmethyl)-4H-benzo[1,4]oxazine-2-carboxamide;

N-(cis-1S, 2S-2-Hydroxycyclohexyl)-4-(2,4-dichlorobenzyl)-4H-benzo[1,4]oxazine-2-carboxamide;

N-(cis-1S, 2S-2-Hydroxycyclohexyl)-8-fluoro-4-(2,3-difluorobenzyl)-4H-benzo[1,4]oxazine-2-carboxamide;

N-(cis-1S, 2S-2-Hydroxycyclohexyl)-4-benzyl-4H-pyrido[3,2-b][1,4]oxazine-2-carboxamide;

N-(cis-1S, 2S-2-Hydroxycyclohexyl)-1-Benzyl-1H-pyrido[2,3-b][1,4]oxazine-3-carboxamide;

N-(cis-1S, 2S-2-Hydroxycyclohexyl)-1-{2,3-difluorobenzyl}-1H-pyrido[2,3-b][1,4]oxazine-3-carboxamide;

N-(cis-1S, 2S-2-Hydroxycyclohexyl)-4-(2,3-difluorobenzyl)-4H-pyrido[3,2-b][1,4]oxazine-2-carboxamide;

N-(cis-1S, 2S-2-Hydroxycyclohexyl)-4-(3-fluoropyridin-4-ylmethyl)-4H-benzo[1,4]oxazine-2-carboxamide;

N-(cis-1S, 2S-2-Hydroxycyclohexyl)-4-(4-fluorobenzyl)-4H-pyrido[3,2-b][1,4]oxazine-2-carboxamide;

N-(cis-1S, 2S-2-Hydroxycyclohexyl)-1-(3-fluorobenzyl)-1H-pyrido[2,3-b][1,4]oxazine-3-carboxamide;

N-(cis-1S, 2S-2-Hydroxycyclohexyl)-4-(2-trifluoromethylbenzyl)-4H-benzo[1,4]oxazine-2-carboxamide;

N-(cis-1S, 2S-2-Hydroxycyclohexyl)-4-(2-chlorobenzyl)-8-fluoro-4H-benzo[1,4]oxazine-2-carboxamide;

N-(trans-1R,2R-2-Hydroxycyclopentyl)-4-(2,3-difluorobenzyl)-4H-benzo[1,4]oxazine-2-carboxamide;

N-(trans-1R,2R-2-Hydroxycyclopentyl)-4-(2-fluorobenzyl)-4H-benzo[1,4]oxazine-2-carboxamide;

N-(cis-1S, 2S-2-Hydroxycyclohexyl)-4-(2-chlorobenzyl)-4H-benzo[1,4]oxazine-2-carboxamide;

N-(trans-1R, 2R-2-Hydroxycyclopentyl)-4-(2,3-difluorobenzyl)-8-fluoro-4H-benzo[1,4]oxazine-2-carboxamide;

N-(2-Hydroxymethylphenyl)-4-(2-fluorobenzyl)-4H-benzo[1,4]oxazine-2-carboxamide;

N-(2-Hydroxymethylphenyl)-4-(2,3-difluorobenzyl)-8-fluoro-4H-benzo[1,4]oxazine-2-carboxamide;

N-(2-Hydroxymethylphenyl)-4-(2,3-difluorobenzyl)-4H-benzo[1,4]oxazine-2-carboxamide;

N-(2-Hydroxymethylphenyl)-4-(2-fluorobenzyl)-8-fluoro-4H-benzo[1,4]oxazine-2-carboxamide;

N-(1-Hydroxymethyl-2-methylpropyl)-8-fluoro-4-(2-fluorobenzyl)-4H-benzo[1,4]oxazine-2-carboxamide;

N-(cis-1S, 2S-2-Hydroxycyclohexyl)-4-benzyl-8-fluoro-4H-benzo[1,4]oxazine-2-carboxamide;

N-(cis-1R, 2R-2-Hydroxycyclohexyl)-4-{2-fluorobenzyl}-4H-benzo[1,4]oxazine-2-carboxamide;

N-(cis-1R, 2R-2-Hydroxycyclohexyl)-4-{2-fluorobenzyl}-8-fluoro-4H-benzo[1,4]oxazine-2-carboxamide;

N-(cis-1S, 2S-2-Hydroxycyclohexyl)-4-{3-fluorobenzyl}-8-fluoro-4H-benzo[1,4]oxazine-2-carboxamide;

N-(cis-1S, 2S-2-Hydroxycyclohexyl)-4-(2-phenylpyridin-4-ylmethyl)-4H-benzo[1,4]oxazine-2-carboxamide;

N-(cis-1S, 2S-2-Hydroxycyclohexyl)-8-fluoro-4-(2-phenylpyridin-4-ylmethyl)-4H-benzo[1,4]oxazine-2-carboxamide;

N-(cis-1S, 2S-2-Hydroxycyclohexyl)-4-(2-chloropyridin-4-ylmethyl)-8-fluoro-4H-benzo[1,4]oxazine-2-carboxamide;

N-(cis-1S, 2S-2-Hydroxycyclohexyl)-4-(2-fluorobenzyl)-5-fluoro-4H-benzo[1,4]oxazine-2-carboxamide;

N-(cis-1S, 2S-2-Hydroxycyclohexyl)-4-(pyridine-2-ylmethyl)-5-fluoro-4H-benzo[1,4]oxazine-2-carboxamide;

N-(cis-1S, 2S-2-Hydroxycyclohexyl)-4-(pyridine-4-ylmethyl)-8-fluoro-4H-benzo[1,4]oxazine-2-carboxamide;

N-(cis-1S, 2S-2-Hydroxycyclohexyl)-4-(6′-Fluoro-5′-methyl-[2,3′]bipyridinyl-4-ylmethyl)-4H-benzo[1,4]oxazine-2-carboxamide;

N-(cis-1S, 2S-2-Hydroxycyclohexyl)-4-[2-(1-methyl-1H-pyrazol-3-yl)-pyridin-4-ylmethyl]-4H-benzo[1,4]oxazine-2-carboxamide;

N-(cis-1S, 2S-2-Hydroxycyclohexyl)-4-(1-methyl-1H-pyrazol-3-ylmethyl)-4H-benzo[1,4]oxazine-2-carboxamide;

N-(cis-1S, 2S-2-Hydroxycyclohexyl)-4-(2-fluorobenzyl)-5,8-difluoro-4H-benzo[1,4]oxazine-2-carboxamide;

N-(cis-1S, 2S-2-Hydroxycyclohexyl)-8-fluoro-4-(3-fluoropyridin-4-ylmethyl)-4H-benzo[1,4]oxazine-2-carboxamide;

N-(cis-1S, 2S-2-Hydroxycyclohexyl)-8-fluoro-4-(2-methylpyridin-4-ylmethyl)-4H-benzo[1,4]oxazine-2-carboxamide;

N-(cis-1S, 2S-2-Hydroxycyclohexyl)-8-fluoro-4-(2-methylpyridin-5-ylmethyl)-4H-benzo[1,4]oxazine-2-carboxamide;

N-(cis-1S, 2S-2-Hydroxycyclohexyl)-4-(2-methylpyridin-4-ylmethyl)-4H-benzo[1,4]oxazine-2-carboxamide;

N-(cis-1S, 2S-2-Hydroxycyclohexyl)-4-(2-methylpyridin-5-ylmethyl)-4H-benzo[1,4]oxazine-2-carboxamide;

N-(cis-1S, 2S-2-Hydroxycyclohexyl)-5,8-difluoro-4-(pyridin-4-ylmethyl)-4H-benzo[1,4]oxazine-2-carboxamide;

N-(3-Hydroxytetrahydropyran-4-yl)-4-(3-fluorobenzyl)-4H-benzo[1,4]oxazine-2-carboxamide;

N-(3-Hydroxytetrahydropyran-4-yl)-4-(4-fluorobenzyl)-8-fluoro-4H-benzo[1,4]oxazine-2-carboxamide;

N-(3-Hydroxytetrahydropyran-4-yl)-4-(3-trifluoromethylbenzyl)-4H-benzo[1,4]oxazine-2-carboxamide;

N-(3-Hydroxytetrahydropyran-4-yl)-4-(2-methoxypyridin-5-ylmethyl)-4H-benzo[1,4]oxazine-2-carboxamide;

N-(3-Hydroxytetrahydropyran-4-yl)-4-(pyridin-4-ylmethyl)-8-fluoro-4H-benzo[1,4]oxazine-2-carboxamide;

N-(3-Fluoropiperidin-4-yl)-4-(2-fluorobenzyl)-8-fluoro-4H-benzo[1,4]oxazine-2-carboxamide;

N-(3-Fluoropiperidin-4-yl)-4-(2,3-difluorobenzyl)-8-fluoro-4H-benzo[1,4]oxazine-2-carboxamide;

N-(3-Hydroxypiperidin-4-yl)-4-(2,3-difluorobenzyl)-8-fluoro-4H-benzo[1,4]oxazine-2-carboxamide;

N-(3-Hydroxypiperidin-4-yl)-4-(2-fluorobenzyl)-4H-benzo[1,4]oxazine-2-carboxamide;

N-(cis-1S, 2S-2-hydroxy cyclohexyl)-4-(2,3-difluorobenzyl)-4H-benzo[1,4]thiazine-2-carboxamide;

N-(cis-1S, 2S-2-Hydroxycyclohexyl)-4-(3-fluorobenzyl)-4H-benzo[1,4]thiazine-2-carboxamide;

N-(cis-1S, 2S-2-Hydroxycyclohexyl)-4-benzyl-4H-benzo[1,4]thiazine-2-carboxamide;

N-(cis-1S, 2S-2-Hydroxycyclohexyl)-4-{4-methoxybenzyl}-4H-benzo[1,4]thiazine-2-carboxamide;

N-(cis-1S, 2S-2-Hydroxycyclohexyl)-4-{4-fluorobenzyl}-4H-benzo[1,4]thiazine-2-carboxamide;

N-(cis-1S, 2S-2-Hydroxycyclohexyl)-4-{pyridin-4-yl-methyl}-4H-benzo[1,4]thiazine-2-carboxamide;

N-(cis-1S, 2S-2-Hydroxycyclohexyl)-4-{2-chloropyridin-5-yl-methyl}-4H-benzo[1,4]thiazine-2-carboxamide;

N-(cis-1S, 2S-2-Hydroxycyclohexyl)-4-{pyridin-2-yl-methyl}-4H-benzo[1,4]thiazine-2-carboxamide;

N-(cis-1S, 2S-2-Hydroxycyclohexyl)-4-(2,3-difluorobenzyl)-1-oxo-4H-benzo[1,4]thiazine-2-carboxamide;

N-(cis-1S, 2S-2-Hydroxycyclohexyl)-4-benzyl-1-oxo-4H-benzo[1,4]thiazine-2-carboxamide;

N-(cis-1S, 2S-2-Hydroxycyclohexyl)-4-{3-fluorobenzyl}-1-oxo-4H-benzo[1,4]thiazine-2-carboxamide;

N-(cis-1S, 2S-2-Hydroxycyclohexyl)-4-{pyridin-2-yl-methyl}-1-oxo-4H-benzo[1,4]thiazine-2-carboxamide;

N-(cis-1S, 2S-2-Hydroxycyclohexyl)-4-{2-chloropyridin-5-yl-methyl}-1-oxo-4H-benzo[1,4]thiazine-2-carboxamide;

N-(3-Hydroxypiperidin-4-yl)-4-(4-fluorobenzyl)-8-fluoro-4H-benzo[1,4]oxazine-2-carboxamide;

N-(3-Hydroxypiperidin-4-yl)-4-(4-fluorobenzyl)-4H-benzo[1,4]oxazine-2-carboxamide;

N-(3-Hydroxypiperidin-4-yl)-4-(2,3-difluorobenzyl)-4H-benzo[1,4]oxazine-2-carboxamide; and

N-(3-Hydroxypiperidin-4-yl)-4-(2-fluorobenzyl)-8-fluoro-4H-benzo[1,4]oxazine-2-carboxamide;

or a pharmaceutically acceptable salt thereof.

7. The compound according to claim 6 , wherein the pharmaceutically acceptable salt is selected from the group consisting of:

N-(3-Fluoropiperidin-4-yl)-4-(2-fluorobenzyl)-8-fluoro-4H-benzo[1,4]oxazine-2-carboxamide hydrochloride;

N-(3-Fluoropiperidin-4-yl)-4-(2,3-difluorobenzyl)-8-fluoro-4H-benzo[1,4]oxazine-2-carboxamide hydrochloride;

N-(3-Hydroxypiperidin-4-yl)-4-(2,3-difluorobenzyl)-8-fluoro-4H-benzo[1,4]oxazine-2-carboxamide trifluoroacetate;

N-(3-Hydroxypiperidin-4-yl)-4-(2-fluorobenzyl)-4H-benzo[1,4]oxazine-2-carboxamide trifluoroacetate;

N-(3-Hydroxypiperidin-4-yl)-4-(4-fluorobenzyl)-8-fluoro-4H-benzo[1,4]oxazine-2-carboxamide trifluoroacetate;

N-(3-Hydroxypiperidin-4-yl)-4-(4-fluorobenzyl)-4H-benzo[1,4]oxazine-2-carboxamide trifluoroacetate;

N-(3-Hydroxypiperidin-4-yl)-4-(2,3-difluorobenzy)-4H-benzo[1,4]oxazine-2-carboxamide trifluoroacetate; and

N-(3-Hydroxypiperidin-4-yl)-4-(2-fluorobenzy)-8-fluoro-4H-benzo[1,4]oxazine-2-carboxamide trifluoroacetate.

8. A pharmaceutical composition comprising a compound according to claim 1 , and pharmaceutically acceptable excipients or carriers.

9. A method for treating a disorder related to muscarinic M1 receptor selected from the group consisting of Alzheimer's disease, schizophrenia, cognitive disorders, pain, and sleep disorders, comprising administering to a patient in need thereof a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, according to claim 1 .

10. The method according to claim 9 , wherein the compound is selected from the group consisting of: