PDE9 Inhibitors with Imidazo Triazinone Backbone

Patent metadata

Field	Value
Publication number	US-2017081333-A1
Application number	US-201615358168-A
Country	US
Kind code	A1
Filing date	Nov 22, 2016
Priority date	Jan 26, 2012
Publication date	Mar 23, 2017
Grant date	—

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

1 . A compound having the structure (I):

or a tautomer or pharmaceutically acceptable acid addition salt of said compound;
wherein R2 is cyclized with either R1 or R3,
wherein R1, R2 and R3 are:
R1, when cyclized with R2, is:

wherein R6 is selected from the group consisting of H, —CH 3 , —C 2 H 5 , and —C 3 H 7 ,
wherein * denotes the cyclization point, and

R1, when not cyclized, is selected from the group consisting of:
H and

wherein R6 is selected from the group consisting of H, —CH 3 , —C 2 H 5 , and —C 3 H 7 ;

R2 is selected from the group consisting of:

wherein R7 and R11 independently are selected from the group consisting of H, —CH 3 , —C 2 H 5 , and —C 3 H 7 ;
wherein * denotes the cyclization point; and

R3, when cyclized with R2, is:

wherein * denotes the cyclization point, and
wherein R8 is selected from the group consisting of H,
C 1 -C 6 alkyl, branched C 3 -C 6 alkyl, C 3 -C 6 cycloalkyl,
C 6 -C 10 aryl, substituted C 6 -C 10 aryl, C 3 -C 9 heteroaryl,
substituted C 3 -C 9 heteroaryl, C 1 -C 6 alkoxy, branched C 3 -C 6 alkoxy, C 3 -C 6 cycloalkoxy, C 6 -C 10 aryloxy,
substituted C 6 -C 10 aryloxy, C 3 -C 9 heteroaryloxy, and
substituted C 3 -C 9 heteroaryloxy; and

R3, when not cyclized, is:

wherein:
R9 is selected from the group consisting of H, —CH 3 , and —C 2 H 5 ; and
R10 is selected from the group consisting of C 6 -C 10 aryl, substituted C 6 -C 10 aryl, C 3 -C 9 heteroaryl, and substituted
C 3 -C 9 heteroaryl;

R4 is selected from the group consisting of C 6 -C 10 aryl,
substituted C 6 -C 10 aryl, C 3 -C 9 heteroaryl, substituted C 3 -C 9 heteroaryl, C 3 -C 6 heterocyclyl, substituted C 3 -C 6 heterocyclyl, C 3 -C 6 cycloalkyl, and substituted C 3 -C 6 cycloalkyl;
R5 is selected from the group consisting of hydrogen, F, Cl, CN, —CH 3 , —C 2 H 5 , —C 3 H 7 , and —CF 3 ;
A is absent,

and tautomers and pharmaceutically acceptable acid addition salts thereof.

2 . The compound of claim 1 , wherein the one or more heteroaryls of R4, R8 and R10 independently of each other comprise one or two nitrogen.

3 . The compound of claim 1 , wherein said compound is selected from the group consisting of:
(1) 2-[[3-(4-methoxyphenyl)azetidin-1-yl]methyl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one

(2) 7-(4-fluorophenyl)-2-[[3-(4-methoxyphenyl)azetidin-1-yl]methyl]-3H-imidazo[5,1-f][1,2,4]triazin-4-one

(3) 7-(4-fluorophenyl)-2-[[3-(4-fluorophenyl)azetidin-1-yl]methyl]-3H-imidazo[5,1-f][1,2,4]triazin-4-one

(4) 2-[[3-(4-fluorophenyl)azetidin-1-yl]methyl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one

(5) 2-[[3-(4-fluorophenoxy)azetidin-1-yl]methyl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one

(6) 2-[[3-[(4-fluorophenyl)methoxy]azetidin-1-yl]methyl]-7-tetrahydropyran-4-yl-3H-imidazo[5, 1-f][1,2,4]triazin-4-one

(7) 2-[[3-(2,6-difluorophenoxy)azetidin-1-yl]methyl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one

(8) 7-tetrahydropyran-4-yl-2-[[3-[4-(trifluoromethoxy)phenoxy]azetidin-1-yl]methyl]-3H-imidazo[5,1-f][1,2,4]triazin-4-one

(9) 2-[[3-(4-dimethylaminophenyl)azetidin-1-yl]methyl]-7-tetrahydropyran-4-yl-3H-imidazo[5, 1-f][1,2,4]triazin-4-one

(10) 2-[(3-phenoxyazetidin-1-yl)methyl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one

(11) 2-[1-[3-(4-methoxyphenyl)azetidin-1-yl]ethyl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one

(12) 2-[1-[3-(4-fluorophenyl)azetidin-1-yl]ethyl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one

(13) 2-[(3-phenylazetidin-1-yl)methyl]-7-tetrahydropyran-4-yl-3H-imidazol[5,1-f][1,2,4]triazin-4-one

(14) 2-[[3-(4-methylphenoxy)azetidin-1-yl]methyl]-7-tetrahydropyran-4-yl-3H-imidazo[5, 1-f][1,2,4]triazin-4-one

(15) 2-[[3-(2-pyridyl)azetidin-1-yl]methyl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one

(16) 2-[[3-(4-isopropylphenoxy)azetidin-1-yl]methyl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one

(17) 7-tetrahydropyran-4-yl-2-[[3-[5-(trifluoromethyl)-2-pyridyl]azetidin-1-yl]methyl]-3H-imidazo[5,1-f][1,2,4]triazin-4-one

(18) 2-[[3-(3-pyridyloxy)azetidin-1-yl]methyl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one

(19) 2-[(1R)-1-[3-(4-methoxyphenyl)azetidin-1-yl]ethyl]-7-tetrahydropyran-4-yl-3H-imidazo[5, 1-f][1,2,4]triazin-4-one

(20) 2-[1-[3-(4-fluorophenoxy)azetidin-1-yl]ethyl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one

(21) 2-[1-[3-(4-hydroxyphenyl)azetidin-1-yl]ethyl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one

(22) 2-[1-[3-(4-methylphenoxy)azetid

Assignees

• H Lundbeck As

Inventors

• Svenstrup Niels
• Simonsen Klaus Baiek
• Rasmussen Lars Kyhn
• Juhl Karsten
• Langgård Morten
• Wen Kate
• Wang Yazhou

Classifications

• A61P31/18

  for HIV · 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

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• A61K31/53

  having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine (melarsoprol A61K31/555 {; with four nitrogen atoms A61K31/495}) · CPC title

• A61P25/00

  Drugs for disorders of the nervous system · CPC title