Substituted imidazo [1,5-a]pyrazines as PDE9 inhibitors

Patent metadata

Field	Value
Publication number	US-9643970-B2
Application number	US-201214434308-A
Country	US
Kind code	B2
Filing date	Oct 9, 2012
Priority date	Oct 10, 2011
Publication date	May 9, 2017
Grant date	May 9, 2017

Abstract

This invention is directed to compounds, which are PDE9 enzyme inhibitors. The invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention and a pharmaceutically acceptable carrier. The present invention also provides processes for the preparation of the compounds of formula (I)

The present invention further provides a method of treating a subject suffering from a neurodegenerative disorder comprising administering to the subject a therapeutically effective amount of a compound of formula (I). The present invention further provides a method of treating a subject suffering from a psychiatric disorder comprising administering to the subject a therapeutically effective amount of a compound of formula (I).

First claim

The invention claimed is:

1. A compound having the structure (I):

and a tautomer or a pharmaceutically acceptable acid addition salt thereof,
wherein:
A is absent or —CH 2 —;
R1 is cyclized with R2 or R3 is cyclized with R2;
R1 is selected from the group consisting of —H and —CH 2 R7,
wherein:
R7 is selected from the group consisting of —H, —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 and —CH(CH 3 ) 2 ; or

R1, when cyclized with R2, is

wherein:
R7 is selected from the group consisting of —H, —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 and —CH(CH 3 ) 2 ; and
* is the cyclization point;

R2 is selected from the group consisting of:

wherein:
R8 is selected from the group consisting of —H, —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 and —CH(CH 3 ) 2 ;
R12 is selected from the group consisting of —H, —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 and —CH(CH 3 ) 2 ; and
* is the cyclization point;

R3 is —CH(R10)(R11),
wherein:
R10 is selected from the group consisting of —H, —CH 3 and —CH 2 CH 3 ; and
R11 is selected from the group consisting of optionally substituted C 6 -C 10 aryl and optionally substituted C 3 -C 9 heteroaryl;
wherein the substituents for C 6 -C 10 aryl and C 3 -C 9 heteroaryl are independently selected from the group consisting of —F, —Cl, —CN, —CF 3 , —OCF 3 , —OCH 3 , —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —N(CH 3 ) 2 and cyclopropyl; or

R3, when cyclized with R2, is

wherein:
R9 is selected from the group consisting of —H, —C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 6 -C 10 aryl, substituted phenyl, optionally substituted C 3 -C 9 heteroaryl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkoxy, optionally substituted C 6 -C 10 aryloxy and optionally substituted C 3 -C 9 heteroaryloxy; and
* is the cyclization point;
wherein the substituents for phenyl, C 3 -C 9 heteroaryl, C 6 -C 10 aryloxy and C 3 -C 9 heteroaryloxy are independently selected from the group consisting of —F, —Cl, —CN, —CF 3 , —OCF 3 , —OCH 3 , —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —N(CH 3 ) 2 and cyclopropyl;

R4 is selected from the group consisting of —H, —F, —Cl, —CN, —CF 3 , —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 and —CH(CH 3 ) 2 ;
R5 is selected from the group consisting of optionally substituted C 6 -C 10 aryl, optionally substituted C 3 -C 9 heteroaryl, optionally substituted C 3 -C 6 heterocyclyl and optionally substituted C 3 -C 6 cycloalkyl;
wherein the substituents for C 6 -C 10 aryl, C 3 -C 9 heteroaryl, C 3 -C 6 heterocyclyl and C 3 -C 6 cycloalkyl are independently selected from the group consisting of —F, —Cl, —CN, —CF 3 , —OCF 3 , —OCH 3 , —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —N(CH 3 ) 2 and cyclopropyl; and

R6 is selected from the group consisting of —H, —F, —Cl, —CN, —CF 3 , —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 and —CH(CH 3 ) 2 .

2. The compound of claim 1 , wherein R9 is selected from the group consisting of branched C 3 -C 6 alkyl and branched C 3 -C 6 alkoxy.

3. The compound of claim 1 , wherein the C 3 -C 9 heteroaryl of R5, the C 3 -C 9 heteroaryl of R9 and the C 3 -C 9 heteroaryl of R11 each independently comprise one or two nitrogen atoms.

4. The compound of claim 1 , wherein the compound is selected from the group consisting of:
(1) 3-(4-fluorophenyl)-6-[1-(3-methoxyazetidin-1-yl)ethyl]-7H-imidazo[1,5-a]pyrazin-8-one,
(2) 6-[1-(cyclohexylmethylamino)ethyl]-3-phenyl-7H-imidazo[1,5-a]pyrazin-8-one,
(3) 6-[(3-methoxyazetidin-1-yl)methyl]-3-phenyl-7H-imidazo[1,5-a]pyrazin-8-one,
(4) 3-phenyl-6-[(3-pyrazin-2-yloxyazetidin-1-yl)methyl]-7H-imidazo[1,5-a]pyrazin-8-one,
(5) 3-phenyl-6-[(3-pyrimidin-2-yloxyazetidin-1-yl)methyl]-7H-imidazo[1,5-a]pyrazin-8-one,
(6) 6-[[3-[(6-fluoro-2-pyridyl)oxy]azetidin-1-yl]methyl]-3-phenyl-7H-imidazo[1,5-a]pyrazin-8-one,
(7) 3-phenyl-6-[1-(3-pyrimidin-2-yloxyazetidin-1-yl)ethyl]-7H-imidazo[1,5-a]pyrazin-8-one,
(8) 3-phenyl-6-[(3-phenylazetidin-1-yl)methyl]-7H-imidazo[1,5-a]pyrazin-8-one,
(9) 6-[[benzyl(methyl)amino]methyl]-3-phenyl-7H-imidazo[1,5-a]pyrazin-8-one,
(10) methyl 1-benzyl-4-(8-oxo-3-phenyl-7H-imidazo[1,5-a]pyrazin-6-yl)pyrrolidine-3-carboxylate,
(11) 6-[[3-(4-ethylphenyl)azetidin-1-yl]methyl]-3-phenyl-7H-imidazo[1,5-a]pyrazin-8-one,
(12) 6-[1-[3-(4-fluorophenyl)azetidin-1-yl]propyl]-3-phenyl-7H-imidazo[1,5-a]pyrazin-8-one,
(13) 3-phenyl-6-[(3-quinoxalin-2-yloxyazetidin-1-yl)methyl]-7H-imidazo[1,5-a]pyrazin-8-one,
(14) 6-[[3-(4,6-dimethylpyrimidin-2-yl)oxyazetidin-1-yl]methyl]-3-phenyl-7H-imidazo[1,5-a]pyrazin-8-one,
(15) 3-phenyl-6-[1-(3-pyrazin-2-yloxyazetidin-1-yl)ethyl]-7H-imidazo[1,5-a]pyrazin-8-one,
(16) 6-[[3-(3-fluorophenoxy)azetidin-1-yl]methyl]-3-phenyl-7H-imidazo[1,5-a]pyrazin-8-one,
(17) 6-[(3-anilinopyrrolidin-1-yl)methyl]-3-phenyl-7H-imidazo[1,5-a]pyrazin-8-one,
(18) 3-phenyl-6-[1-(3-phenylazetidin-1-yl)ethyl]-7H-imidazo[1,5-a]pyrazin-8-one,
(19) 6-[[3-(4-fluorophenyl)azetidin-1-yl]methyl]-3-phenyl-7H-imidazo[1,5-a]pyrazin-8-one,
(20) 6-[1-(3-methoxyazetidin-1-yl)ethyl]-3-phenyl-7H-imidazo[1,5-a]pyrazin-8-one,
(21) 6-[(3-phenoxyazetidin-1-yl)methyl]-3-phenyl-7H-imidazo[1,5-a]pyrazin-8-one,
(22) 6-[(3-methoxyazetidin-1-yl)-phenyl-methyl]-3-phenyl-7H-imidazo[1,5-a]pyrazin-8-one,
(23) 6-[[3-(4-fluorophenoxy)azetidin-1-yl]methyl]-3-phenyl-7H-imidazo[1,5-a]pyrazin-8-one,
(24) 6-[1-[3-(3-fluorophenoxy)azetidin-1-yl]ethyl]-3-phenyl-7H-imidazo[1,5-a]pyrazin-8-one,
(25) 6-[1-(3-phenoxyazetidin-1-yl)ethyl]-3-phenyl-7H-imidazo[1,5-a]pyrazin-8-one,
(26) 6-[1-[3-(4-fluorophenoxy)azetidin-1-yl]ethyl]-3-phenyl-7H-imidazo[1,5-a]pyrazin-8-one,
(27) 6-[1-[3-[(6-fluoro-2-pyridyl)oxy]azetidin-1-yl]ethyl]-3-phenyl-7H-imidazo[1,5-a]pyrazin-8-one,
(28) 6-[1-[3-(4-fluorophenyl)azetidin-1-yl]ethyl]-3-phenyl-7H-imidazo[1,5-a]pyrazin-8-one,
(29) 6-[1-[3-(4-methyl-2-pyridyl)azetidin-1-yl]ethyl]-3-phenyl-7H-imidazo[1,5-a]pyrazin-8-one,
(30) 6-[1-[3-(4-ethylphenyl)azetidin-1-yl]ethyl]-3-phenyl-7H-imidazo[1,5-a]pyrazin-8-one,
(31) 6-(1-benzyl-4-methyl-pyrrolidin-3-yl)-3-phenyl-7H-imidazo[1,5-a]pyrazin-8-one,
(32) 6-[1-[3-(2-fluorophenoxy)azetidin-1-yl]ethyl]-3-phenyl-7H-imidazo[1,5-a]pyrazin-8-one,
(33) 6-[[3-(2-fluorophenoxy)azetidin-1-yl]methyl]-3-phenyl-7H-imidazo[1,5-a]pyrazin-8-one,
(34) 6-[1-[3-(4-methoxyphenyl)azetidin-1-yl]ethyl]-3-phenyl-7H-imidazo[1,5-a]pyrazin-8-one,
(35) 4-[1-[(8-oxo-3-phenyl-7H-imidazo[1,5-a]pyrazin-6-yl)methyl]azetidin-3-yl]benzonitrile,
(36) 3-phenyl-6-[1-(3-pyrimidin-2-ylazetidin-1-yl)ethyl]-7H-imidazo[1,5-a]pyrazin-8-one,
(37) 3-phenyl-6-[[3-(2-pyridyl)azetidin-1-yl]methyl]-7H-imidazo[1,5-a]pyrazin-8-one,
(38) 4-[1-[1-(8-oxo-3-phenyl-7h-imidazo[1,5-a]pyrazin-6-yl)ethyl]azetidin-3-yl]benzonitrile,
(39) 3-cyclopentyl-6-[(3-pyrimidin-2-yloxyazetidin-1-yl)methyl]-7H-imidazo[1,5-a]pyrazin-8-one,
(40) 3-cyclopentyl-6-[1-[3-(4-fluorophenyl)azetidin-1-yl]ethyl]-7H-imidazo[1,5-a]pyrazin-8-one,
(41) 3-cyclopentyl-6-[[3-(4-methoxyphenyl)azetidin-1-yl]methyl]-7H-imidazo[1,5-a]pyrazin-8-one,
(42) 3-cyclopentyl-6-[1-(3-pyrimidin-2-yloxyazetidin-1-yl)ethyl]-7H-imidazo[1,5-a]pyrazin-8-one,
(43) 6-[4-methyl-1-(2-pyridylmethyl)pyrrolidin-3-yl]-3-phenyl-7H-imidazo[1,5-a]pyrazin-8-one,
(44) 6-[[3-(4-fluorophenyl) azetidin-1-yl]methyl]-3-tetrahydropyran-4-yl-7H-imidazo[1,5-a]pyrazin-8-one,
(45) 6-[(3-benzyloxyazetidin-1

Assignees

• H Lundbeck As
• H Lundbeck As

Inventors

• Svenstrup Niels
• Simonsen Klaus Baek
• Rasmussen Lars Kyhn
• Juhl Karsten
• Langgard Morten
• Wen Kate
• Wang Yazhou

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P25/32

  Alcohol-abuse · CPC title

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title

• A61P25/30

  for treating abuse or dependence · CPC title

• A61P25/18

  Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia · CPC title