US 8,618,102 B2Granted

Bridged diazepan orexin receptor antagonists

AssigneeMerck Sharp & Dohme Corp.

InventorsPaul J. Coleman, Christopher D. Cox, Georgia B. McGaughey, Anthony J. Roecker, John D. Schreier

Life of this patent

Estimating the term…

Abstract

The present invention is directed to bridged diazepan compounds which are antagonists of orexin receptors, and which are useful in the treatment or prevention of neurological and psychiatric disorders and diseases in which orexin receptors are involved. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which orexin receptors are involved.

Claims12

Dependent claims

A compound of the formula I:

wherein:
X is selected from —SO2—, —(C═O)—, and —(C═S)—;
R1 is selected from the group consisting of:
(1) phenyl, where the phenyl is substituted with R1a, R1b and R1c,
(2) naphthyl, where the naphthyl is substituted with R1a, R1b and R1c, and
(3) heteroaryl, where the heteroaryl is substituted with R1a, R1b and R1c;
R2 is heteroaryl, where the heteroaryl is substituted with R2a, R2b and R2c;
R1a, R1b, R1c, R2a, R2b and R2c are independently selected from the group consisting of:
(1) hydrogen,
(2) halogen,
(3) hydroxyl,
(4) —(C═O)m—On—C1-6alkyl, where m is 0 or 1, n is 0 or 1 (wherein if m is 0 or n is 0, a bond is present) and where the alkyl is unsubstituted or substituted with one or more substituents selected from R13,
(5) —(C═O)m—On—C3-6cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one or more substituents selected from R13,
(6) —(C═O)m—C2-4alkenyl, where the alkenyl is unsubstituted or substituted with one or more substituents selected from R13,
(7) —(C═O)m—C2-4alkynyl, where the alkynyl is unsubstituted or substituted with one or more substituents selected from R13,
(8) —(C═O)m—On-phenyl or —(C═O)m—On-naphthyl, where the phenyl or naphthyl is unsubstituted or substituted with one or more substituents selected from R13,
(9) —(C═O)m—On-heterocycle, where the heterocycle is unsubstituted or substituted with one or more substituents selected from R13,
(10) —(C═O)m—NR10R11, wherein R10 and R11 are independently selected from the group consisting of:
(a) hydrogen,
(b) C1-6alkyl, which is unsubstituted or substituted with one or more substituents selected from R13,
(c) C3-6alkenyl, which is unsubstituted or substituted with one or more substituents selected from R13,
(d) cycloalkyl, which is unsubstituted or substituted with one or more substituents selected from R13,
(e) phenyl, which is unsubstituted or substituted with one or more substituents selected from R13, and
(f) heterocycle, which is unsubstituted or substituted with one or more substituents selected from R13,
(11) —S(O)2—NR10R11,
(12) —S(O)q—R12, where q is 0, 1 or 2 and where R12 is selected from the definitions of R10 and R11,
(13) —CO2H,
(14) —CN, and
(15) —NO2;
R13 is selected from the group consisting of:
(1) halogen,
(2) hydroxyl,
(3) —(C═O)m—On—C1-6alkyl, where the alkyl is unsubstituted or substituted with one or more substituents selected from R14,
(4) —On—(C1-3)perfluoroalkyl,
(5) —(C═O)m—On—C3-6cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one or more substituents selected from R14,
(6) —(C═O)m—C2-4alkenyl, where the alkenyl is unsubstituted or substituted with one or more substituents selected from R14,
(7) —(C═O)m—On-phenyl or —(C═O)m—On-naphthyl, where the phenyl or naphthyl is unsubstituted or substituted with one or more substituents selected from R14,
(8) —(C═O)m—On-heterocycle, where the heterocycle is unsubstituted or substituted with one or more substituents selected from R14,
(9) —CO2H,
(10) —CN, and
(11) —NO2;
R14 is selected from the group consisting of:
(1) hydroxyl,
(2) halogen,
(3) C1-6alkyl,
(4) —C3-6cycloalkyl,
(5) —O—C1-6alkyl,
(6) —O(C═O)—C1-6alkyl,
(7) —NH—C1-6alkyl,
(8) phenyl,
(9) heterocycle,
(10) —CO2H, and
(11) —CN;
or a pharmaceutically acceptable salt thereof.

51 more elements

A compound which is selected from the group consisting of:

2-{3-[5-Methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]-3,6-diazabicyclo[3.2.1]oct-6-yl}quinazoline;
(R,R)-2-{3-[5-Methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]-3,6-diazabicyclo[3.2.1]oct-6-yl}quinazoline;
(S,S)-2-{3-[5-Methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]-3,6-diazabicyclo[3.2.1]oct-6-yl}quinazoline;
6-Chloro-2-{3-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]-3,6-diazabicyclo[3.2.1]oct-6-yl}[1,3]oxazolo[5,4-b]pyridine;
6-Fluoro-2-{3-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]-3,6-diazabicyclo[3.2.1]oct-6-yl}quinazoline;
6-Fluoro-2-{3-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]-3,6-diazabicyclo[3.2.1]oct-6-yl}[1,3]oxazolo[5,4-b]pyridine;
2-[3-(2,6-Dimethoxybenzoyl)-3,6-diazabicyclo[3.2.1]oct-6-yl]quinazoline;
2-{3-[(2-Methyl-5-phenyl-1,3-thiazol-4-yl)carbonyl]-3,6-diazabicyclo[3.2.1]oct-6-yl}quinazoline;
2-[3-(Biphenyl-2-ylcarbonyl)-3,6-diazabicyclo[3.2.1]oct-6-yl]quinazoline;
2-{3-[2-Fluoro-6-(2H-1,2,3-triazol-2-yl)benzoyl]-3,6-diazabicyclo[3.2.1]oct-6-yl}quinazoline;
2-{3-[5-Fluoro-2-(2H-1,2,3-triazol-2-yl)benzoyl]-3,6-diazabicyclo[3.2.1]oct-6-yl}quinazoline;
2-{3-[5-Bromo-2-(2H-1,2,3-triazol-2-yl)benzoyl]-3,6-diazabicyclo[3.2.1]oct-6-yl}quinazoline;
2-{3-[2-(2H-1,2,3-Triazol-2-yl)benzoyl]-3,6-diazabicyclo[3.2.1]oct-6-yl}quinazoline;
3-[5-Methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]-6-(6-phenylpyrazin-2-yl)-3,6-diazabicyclo[3.2.1]octane;
3-[5-Methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]-6-(2-phenylpyrimidin-4-yl)-3,6-diazabicyclo[3.2.1]octane;
6-Chloro-2-{3-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]-3,6-diazabicyclo[3.2.1]oct-6-yl}-1,3-benzothiazole;
5-Chloro-2-{3-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]-3,6-diazabicyclo[3.2.1]oct-6-yl}-1,3-benzoxazole;
3-[5-Methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]-6-(4-phenylpyrimidin-2-yl)-3,6-diazabicyclo[3.2.1]octane;
6,7-Difluoro-2-{3-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]-3,6-diazabicyclo[3.2.1]oct-6-yl}quinoxaline;
2-{3-[5-Methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]-3,6-diazabicyclo[3.2.1]oct-6-yl}quinoxaline;
or a pharmaceutically acceptable salt thereof.

18 more elements

Dependencies are inferred from the claim text.

Facts

Application: 12/309,243Filed 13 Jul 2007 · us provisional application
Priority: 14 Jul 2006
Published: US 2009/0239843 A124 Sep 2009
Granted: 31 Dec 2013
Term ends: Not estimatedThe source records don’t support an estimate.

Classification8 codes

C07D 471/08
In which the condensed system contains two hetero rings: bridged systems
A61P 3/04
Drugs for disorders of the metabolism: anorexiants; Antiobesity agents
A61P 25/00
Drugs for disorders of the nervous system
A61P 25/20
Drugs for disorders of the nervous system: hypnotics; Sedatives

Family

Application60/831,178Us provisional application · filed 14 Jul 2006
US 2009/0239843 A1Pre-grant publication · published 24 Sep 2009
US 8,618,102 B2This patent

From the US filing history. Foreign family members aren’t listed.

Timeline

Citations

Open elsewhere

patentgrep

Loading patent…

Abstract

A compound of the formula I:

wherein:
X is selected from —SO2—, —(C═O)—, and —(C═S)—;
R1 is selected from the group consisting of:
(1) phenyl, where the phenyl is substituted with R1a, R1b and R1c,
(2) naphthyl, where the naphthyl is substituted with R1a, R1b and R1c, and
(3) heteroaryl, where the heteroaryl is substituted with R1a, R1b and R1c;
R2 is heteroaryl, where the heteroaryl is substituted with R2a, R2b and R2c;
R1a, R1b, R1c, R2a, R2b and R2c are independently selected from the group consisting of:
(1) hydrogen,
(2) halogen,
(3) hydroxyl,
(4) —(C═O)m—On—C1-6alkyl, where m is 0 or 1, n is 0 or 1 (wherein if m is 0 or n is 0, a bond is present) and where the alkyl is unsubstituted or substituted with one or more substituents selected from R13,
(5) —(C═O)m—On—C3-6cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one or more substituents selected from R13,
(6) —(C═O)m—C2-4alkenyl, where the alkenyl is unsubstituted or substituted with one or more substituents selected from R13,
(7) —(C═O)m—C2-4alkynyl, where the alkynyl is unsubstituted or substituted with one or more substituents selected from R13,
(8) —(C═O)m—On-phenyl or —(C═O)m—On-naphthyl, where the phenyl or naphthyl is unsubstituted or substituted with one or more substituents selected from R13,
(9) —(C═O)m—On-heterocycle, where the heterocycle is unsubstituted or substituted with one or more substituents selected from R13,
(10) —(C═O)m—NR10R11, wherein R10 and R11 are independently selected from the group consisting of:
(a) hydrogen,
(b) C1-6alkyl, which is unsubstituted or substituted with one or more substituents selected from R13,
(c) C3-6alkenyl, which is unsubstituted or substituted with one or more substituents selected from R13,
(d) cycloalkyl, which is unsubstituted or substituted with one or more substituents selected from R13,
(e) phenyl, which is unsubstituted or substituted with one or more substituents selected from R13, and
(f) heterocycle, which is unsubstituted or substituted with one or more substituents selected from R13,
(11) —S(O)2—NR10R11,
(12) —S(O)q—R12, where q is 0, 1 or 2 and where R12 is selected from the definitions of R10 and R11,
(13) —CO2H,
(14) —CN, and
(15) —NO2;
R13 is selected from the group consisting of:
(1) halogen,
(2) hydroxyl,
(3) —(C═O)m—On—C1-6alkyl, where the alkyl is unsubstituted or substituted with one or more substituents selected from R14,
(4) —On—(C1-3)perfluoroalkyl,
(5) —(C═O)m—On—C3-6cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one or more substituents selected from R14,
(6) —(C═O)m—C2-4alkenyl, where the alkenyl is unsubstituted or substituted with one or more substituents selected from R14,
(7) —(C═O)m—On-phenyl or —(C═O)m—On-naphthyl, where the phenyl or naphthyl is unsubstituted or substituted with one or more substituents selected from R14,
(8) —(C═O)m—On-heterocycle, where the heterocycle is unsubstituted or substituted with one or more substituents selected from R14,
(9) —CO2H,
(10) —CN, and
(11) —NO2;
R14 is selected from the group consisting of:
(1) hydroxyl,
(2) halogen,
(3) C1-6alkyl,
(4) —C3-6cycloalkyl,
(5) —O—C1-6alkyl,
(6) —O(C═O)—C1-6alkyl,
(7) —NH—C1-6alkyl,
(8) phenyl,
(9) heterocycle,
(10) —CO2H, and
(11) —CN;
or a pharmaceutically acceptable salt thereof.

51 more elements

Facts

Application

12/309,243Filed 13 Jul 2007 · us provisional application

Priority

14 Jul 2006

Published

US 2009/0239843 A124 Sep 2009

Granted

31 Dec 2013

Term ends

Not estimatedThe source records don’t support an estimate.

Classification8 codes

C07D 471/08
In which the condensed system contains two hetero rings: bridged systems
A61P 3/04
Drugs for disorders of the metabolism: anorexiants; Antiobesity agents
A61P 25/00
Drugs for disorders of the nervous system
A61P 25/20
Drugs for disorders of the nervous system: hypnotics; Sedatives