Fused heteroaryl derivatives as orexin receptor antagonists

Patent metadata

Field	Value
Publication number	US-10526336-B2
Application number	US-201515535315-A
Country	US
Kind code	B2
Filing date	Dec 18, 2015
Priority date	Dec 23, 2014
Publication date	Jan 7, 2020
Grant date	Jan 7, 2020

Abstract

The present invention is directed to fused heteroaryl derivative compounds which are antagonists of orexin receptors. The present invention is also directed to uses of the compounds described herein in the potential treatment or prevention of neurological and psychiatric disorders and diseases in which orexin receptors are involved. The present invention is also directed to pharmaceutical compositions comprising these compounds. The present invention is also directed to uses of these pharmaceutical compositions in the prevention or treatment of such diseases in which orexin receptors are involved.

First claim

What is claimed is:

1. A compound of the formula I:

wherein:
A is selected from the group consisting of phenyl, naphthyl and heteroaryl;
B is selected from the group consisting of:

Y is O, S or NH;
each of R 1a , R 1b and R 1c is independently selected from the group consisting of:
(1) hydrogen,
(2) halogen,
(3) hydroxyl,
(4) —(CH 2 ) s -(C═O) m —O n —C 1-6 alkyl, and where the alkyl is unsubstituted or substituted with one or more substituents selected from R 4 ,
(5) —(CH 2 ) s -(C═O) m —O n —C 3-6 cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one or more substituents selected from R 4 ,
(6) —(CH 2 ) s -(C═O) m —C 2-4 alkenyl, where the alkenyl is unsubstituted or substituted with one or more substituents selected from R 4 ,
(7) —(CH 2 ) s -(C═O) m —C 2-4 alkynyl, where the alkynyl is unsubstituted or substituted with one or more substituents selected from R 4 ,
(8) —(CH 2 ) s -(C═O) m —O n -phenyl or —(CH 2 ) s -(C═O) m —O n -naphthyl, where the phenyl or naphthyl is unsubstituted or substituted with one or more substituents selected from R 4 ,
(9) —(CH 2 ) s -(C═O) m —O n —X, wherein X is heterocyclyl or heteroaryl, wherein the heterocyclyl or heteroaryl is unsubstituted or substituted with one or more substituents selected from R 4 ,
(10) —(CH 2 ) s -(C═O) m —NR 10 R 11 ,
(11) —(CH 2 ) s -S(O) 2 —NR 10 OR 11 ,
(12) —(CH 2 ) s -S(O) q —R 12 , where q is 0, 1 or 2 and where R 12 is selected from the definitions of R 10 and R 11 ,
(13) —CO 2 H,
(14) —CN, and
(15) —NO 2 ;
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
s is independently 0, 1, 2 or 3;

R 3 is selected from hydrogen, C 1-6 alkyl and C 3-6 cycloalkyl, wherein the alkyl or cycloalkyl is unsubstituted or substituted with one or more substituents selected from R 4 ;
R 4 is independently selected from the group consisting of:
(1) hydroxyl,
(2) halogen,
(3) C 1-6 alkyl,
(4) —C 3-6 cycloalkyl,
(5) —O—C 1-6 alkyl,
(6) —O(C═O)—C 1-6 alkyl,
(7) —NH 2 ,
(7) —NH—C 1-6 alkyl,
(8) —NO 2 ,
(9) phenyl,
(10) heterocyclyl,
(11) —CO 2 H, and
(12) —CN;

R 5 is independently selected from the group consisting of:
hydrogen, halogen, OH, NH 2 , CN, C 1 -C 6 alkylOR 6 , —O(C═O)—C 1-6 alkyl, —(C═O)—NR 6 2 , C 1-6 alkyl, C 1-6 alkenyl, C 3 -C 8 cycloalkyl, wherein the alkyl, alkenyl or cycloalkyl is optionally substituted with one or more moieties selected from the group consisting of halogen, OH and NH 2 ;

R 6 is independently hydrogen or C 1-6 alkyl;
R 10 and R 11 are independently selected from the group consisting of:
(a) hydrogen,
(b) C 1-6 alkyl, which is unsubstituted or substituted with R 4 ,
(c) C 3-6 alkenyl, which is unsubstituted or substituted with R 4 ,
(d) C 3-6 alkynyl, which is unsubstituted or substituted with R 4 ,
(e) C 3-6 cycloalkyl which is unsubstituted or substituted with R 4 ,
(f) phenyl, which is unsubstituted or substituted with R 4 , and
(g) heterocyclyl, which is unsubstituted or substituted with R 4 ,

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, of the formula Ia:

wherein
A is selected from the group consisting of phenyl, thienyl, pyridyl and pyrimidinyl;
Y is O, S or NH;
R 1a and R 1b are both H, R 1c is selected from the group consisting of:
(1) hydrogen,
(2) halogen,
(3) hydroxyl,
(4) —(CH 2 ) s -(C═O) m —O n —C 1-6 alkyl, and where the alkyl is unsubstituted or substituted with one or more substituents selected from R 4 ,
(5) —(CH 2 ) s -O n —C 3-6 cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one or more substituents selected from R 4 ,
(6) -phenyl, where the phenyl is unsubstituted or substituted with one or more substituents selected from R 4 ,
(7) -heteroaryl selected from the group consisting of triazolyl, pyrimidinyl, tetrazolyl, pyrazolyl and pyridinyl, where the heteroaryl is unsubstituted or substituted with one or more substituents selected from R 4 ,
(8) —(CH 2 ) s -S(O) q —R 12 , where q is 0, 1 or 2 and where R 12 is selected from
(a) C 1-6 alkyl, which is unsubstituted or substituted with R 4 ,
(b) C 3-6 alkenyl, which is unsubstituted or substituted with R 4 ,
(c) C 3-6 alkynyl, which is unsubstituted or substituted with R 4 ,
n is 0 or 1, m is 0 or 1, (wherein if m is 0 or n is 0, a bond is present)

s is independently 0, 1, 2 or 3;

R 3 is selected from hydrogen or C 1-6 alkyl, which is unsubstituted or substituted with one or more substituents selected from R 4 ;
R 4 is independently selected from the group consisting of:
(1) hydroxyl,
(2) halogen,
(3) C 1-6 alkyl,
(4) —NH 2 ,
(5) —NH—C 1-6 alkyl,
(6) —NO 2 , and
(7) —CN;

R 5 is independently selected from the group consisting of:
hydrogen, halogen, OH, NH 2 , CN, C 1 -C 6 alkylOR 6 , and C 1-6 alkyl, wherein the alkyl is optionally substituted with one or more moieties selected from the group consisting of halogen, OH and NH 2 ;

R 6 is hydrogen or C 1-6 alkyl;
or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein
B is:

4. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein R 3 is methyl.

5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, of the formula Ib:

6. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein R 5 is selected from the group consisting of: halogen, CN, methyl, fluoro-methyl, difluoro-methyl, and trifluoro-methyl.

7. A compound which is selected from the group consisting of:
(2-(2H-1,2,3-triazol-2-yl)phenyl)((2R,5R)-5-(imidazo[1,2-a]pyrazin-8-yloxy)-2-methylpiperidin-1-yl)methanone;
((2R,5R)-5-(imidazo[1,2-a]pyrazin-8-yloxy)-2-methylpiperidin-1-yl)(2-((methylsulfonyl)methyl)phenyl)methanone;
((2R,5R)-5-(imidazo[1,2-a]pyrazin-8-yloxy)-2-methylpiperidin-1-yl)(2-(2,2,2-trifluoroethyl)phenyl)methanone;
((2R,5R)-5-(imidazo[1,2-a]pyrazin-8-yloxy)-2-methylpiperidin-1-yl)(2-propylphenyl)methanone;
(2-(2H-1,2,3-triazol-2-yl)phenyl)((2R,5R)-5-(imidazo[1,2-a]pyrazin-8-ylthio)-2-methylpiperidin-1-yl)methanone;
(2-(2H-1,2,3-triazol-2-yl)phenyl)((2R,5R)-2-methyl-5-((2-methylimidazo[1,2-a]pyrazin-8-yl)oxy)piperidin-1-yl)methanone;
(2-(2H-1,2,3-triazol-2-yl)thiophen-3-yl)((2R,5R)-2-methyl-5-((2-methylimidazo[1,2-a]pyrazin-8-yl)oxy)piperidin-1-yl)methanone;
(4-(2H-1,2,3-triazol-2-yl)thiophen-3-yl)((2R,5R)-2-methyl-5-((2-methylimidazo[1,2-a]pyrazin-8-yl)oxy)piperidin-1-yl)methanone;
1-(2-((2R,5R)-2-methyl-5-((2-methylimidazo[1,2-a]pyrazin-8-yl)oxy)piperidine-1-carbonyl)phenyl)cyclopropanecarbonitrile;
(4-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)((2R,5R)-2-methyl-5-((2-methylimidazo[1,2-a]pyrazin-8-yl)oxy)piperidin-1-yl)methanone;
(2-(2H-tetrazol-2-yl)phenyl)((2R,5R)-2-methyl-5-((2-methylimidazo[1,2-a]pyrazin-8-yl)oxy)piperidin-1-yl)methanone;
((2R,5R)-2-methyl-5-((2-methylimidazo[1,2-a]pyrazin-8-yl)oxy)piperidin-1-yl)(2-((methylsulfonyl)methyl)phenyl)methanone;
((2R,5R)-2-methyl-5-((2-meth

Assignees

• Merck Sharp & Dohme

Inventors

• Kuduk Scott D
• Liverton Nigel
• Beshore Douglas C
• Meng Na
• Luo Yunfu

Classifications

• C07D498/02

  in which the condensed system contains two hetero rings · CPC title

• A61P3/04

  Anorexiants; Antiobesity agents · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title

• C07D498/04

  Ortho-condensed systems · CPC title