PDE9 Inhibitors with Imidazo Triazinone Backbone

Patent metadata

Field	Value
Publication number	US-2016213674-A1
Application number	US-201615089819-A
Country	US
Kind code	A1
Filing date	Apr 4, 2016
Priority date	Jan 26, 2012
Publication date	Jul 28, 2016
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 compound of formula (I) for use in 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 method of treating a subject suffering from a neurodegenerative disorder selected from the group consisting of Alzheimer's disease, mental retardation, cognitive impairments associated with schizophrenia (CIAS), attention-deficit/hyperactivity disorder, age-related cognitive decline, and substance-induced psychotic disorder; wherein said method comprises administering to said subject a therapeutically effective amount of a pharmaceutical composition comprising:
(A) 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, 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 or —CH 2 —;
provided that the compound is not:
(1) 2-[4-methyl-1-(2-pyridylmethyl) pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one;
(2) 2-[1-[(4-fluorophenyl)methyl]-4-methyl-pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one;
(3) 2-(1-benzyl-4-methyl-pyrrolidin-3-yl)-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one;
(4) 2-[4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one;
(5) 2-[1-[(6-methoxy-2-pyridyl)methyl]-4-methyl-pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one;
(6) 2-[(3S,4S)-1-benzyl-4-methyl-pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one;
(7) 2-[(3R,4R)-1-benzyl-4-methyl-pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one;
(8) 2-[(3R,4R)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one;
(9) 4-[3-methyl-4-(4-oxo-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-2-yl)pyrrolidin-1-yl]benzonitrile;
(10) 2-[(3S,4S)-1-[(4-fluorophenyl)methyl]-4-methyl-pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one;
(11) 2-[(3R,4R)-1-[(4-fluorophenyl)methyl]-4-methyl-pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one; or
(12) 2-[4-methyl-1-(pyrazin-2-ylmethyl) pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one;

and
(B) one or more pharmaceutically acceptable carriers, diluents or excipients.

2 . The method of claim 1 , wherein the neurodegenerative disorder is a substance-induced psychotic disorder and said substance-induced psychotic disorder is psychosis induced by: alcohol, an amphetamine, cannabis, cocaine, a hallucinogen, an inhalant, an opioid, or phencyclidine.

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

4 . The method of claim 1 , wherein said method comprises administering to said subject a therapeutically effective amount of a pharmaceutical composition comprising a compound, or a tautomer or pharmaceutically acceptable acid addition salt thereof; wherein said compound is selected from the group consisting of:
(1) 7-(4-fluorophenyl)-2-[4-methyl-1-[[6-(trifluoromethyl)-3-pyridyl-]methyl]pyrrolidin-3-yl]-3H-imidazo[5,1-f][1,2,4]triazin-4-one; (2) 2-[1-[(6-methoxy-3-pyridyl)methyl]-4-methyl-pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one; (3) 2-[4-methyl-1-[[4-(trifluoromethyl) phenyl]methyl]pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one; (4) 2-(1-benzyl-4-methyl-pyrrolidin-3-yl)-7-(3,6-dihydro-2H-pyran-4-yl)-3H-imidazo[5,1-f][1,2,4]triazin-4-one; (5) 7-(4-fluorophenyl)-2-[1-[(6-methoxy-3-pyridyl)methyl]-4-methyl-pyrrolidin-3-yl]-3H-imidazo[5,1-f][1,2,4]triazin-4-one; (6) 7-(4-fluorophenyl)-2-[4-methyl-1-(2-pyridylmethyl)pyrrolidin-3-yl]-3H-imidazo[5,1-f][1,2,4]triazin-4-one; (7) 2-(1-benzyl-4-methyl-pyrrolidin-3-yl)-7-(3-pyridyl)-3H-imidazo[5,1-f][1,2,4]triazin-4-one; (8) 2-[1-[(2,4-difluorophenyl)methyl]-4-methyl-pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one; (9) 2-(1-benzyl-4-methyl-pyrrolidin-3-yl)-7-[4-(trifluoromethoxy)phenyl]-3H-imidazo[5,1-f][1,2,4]triazin-4-one; (10) 7-(4-fluorophenyl)-2-[1-[(4-fluorophenyl)methyl]-4-methyl-pyrrolidin-3-yl]-3H-imidazo[5,1-f][1,2,4]triazin-4-one; (11) 2-(1-benzyl-4-methyl-pyrrolidin-3-yl)-7-(2,4-difluorophenyl)-3H-imidazo[5,1-f][1,2,4]triazin-4-one; (12) 2-[4-methyl-1-[[4-(trifluoromethoxy)phenyl]methyl]pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one; (13) 2-(1-benzyl-4-methyl-pyrrolidin-3-yl)-7-(4-pyridyl)-3H-imidazo[5,1-f][1,2,4]triazin-4-one; (14) 2-[[3-(4-methoxyphenyl)azetidin-1-yl]methyl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one; (15) 7-(4-fluorophenyl)-2-[[3-(4-methoxyphenyl)azetidin-1-yl]methyl]-3H-imidazo[5,1-f][1,2,4]triazin-4-one; (16) 7-(4-fluorophenyl)-2-[[3-(4-fluorophenyl)azetidin-1-yl]methyl]-3H-imidazo[5,1-f][1,2,4]triazin-4-one; (17) 2-[1-[(2-chloro-4-methoxy-phenyl)methyl]-4-methyl-pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one; (18) 2-[4-methyl-1-(quinoxalin-6-ylmethyl)pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]t

Assignees

• H Lundbeck As

Inventors

• Svenstrup Niels
• Simonsen Klaus Baek
• 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

• A61K31/53 Primary

  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

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• A61P25/00

  Drugs for disorders of the nervous system · CPC title