Pyridazinone compounds and their use as DAAO inhibitors

Patent metadata

Field	Value
Publication number	US-10463663-B2
Application number	US-201815899561-A
Country	US
Kind code	B2
Filing date	Feb 20, 2018
Priority date	Aug 22, 2011
Publication date	Nov 5, 2019
Grant date	Nov 5, 2019

Abstract

The present invention provides compounds of formula (I) and pharmaceutically acceptable salts thereof, wherein R 1 and R 2 are as defined in the specification, processes for their preparation, pharmaceutical compositions containing them and their use in therapy.

First claim

The invention claimed is:

1. A method of treating major depressive disorder or schizophrenia, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof,

wherein
R 1 is chosen from a hydrogen, a fluorine atom, and a trifluoromethyl group;
R 2 represents a group —X—Y—R 3 ;
X and Y each independently are chosen from a bond, an oxygen atom, —C(O), —S(O) n , —C(O)NR 4 , —S(O) 2 NR 4 , —NR 4 ,

and —CR 4 R 5 —, with the proviso that X and Y cannot both simultaneously represent a bond, and if X and Y are both not a bond, then at least one of X and Y represents —CR 4 R 5 —;
n is chosen from 0, 1 or 2;
each R 4 independently is chosen from a hydrogen atom, a C 1 -C 6 alkyl, and a C 1 -C 6 haloalkyl group;
each R 5 independently is chosen from a hydrogen atom, a C 1 -C 6 alkyl, C 1 -C 6 haloalkyl group, and ═CH—;
R 3 is chosen from a 3- to 10-membered saturated or unsaturated carbocyclic or heterocyclic ring system, wherein the ring system is unsubstituted or substituted by at least one substituent chosen from halogen, hydroxyl, cyano, oxo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 alkylthio, C 1 -C 6 alkylsulphinyl, C 1 -C 6 alkylsulphonyl, C 1 -C 6 alkylcarbonyl, C 1 -C 6 alkylcarbonyloxy, C 1 -C 6 alkoxycarbonyl, amino (—NH 2 ), —CON(R 6 ) 2 , C 1 -C 6 alkylamino, di-(C 1 -C 6 alkyl)amino, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkyloxy, C 3 -C 6 cycloalkylmethyl, —[O] p —(CH 2 ) q —O—R 7 and a 4- to 6-membered saturated or unsaturated heterocyclic ring, which is unsubstituted or substituted with at least one substituent chosen from C 1 -C 4 alkyl or C 1 -C 4 alkoxy;
each R 6 independently is a hydrogen atom or a C 1 -C 6 alkyl group;
p is chosen from 0 or 1;
q is chosen from 1, 2, 3 or 4; and
R 7 is chosen from a C 1 -C 6 alkyl group.

2. The method according to claim 1 , wherein R 1 is a hydrogen atom.

3. The method according to claim 1 , wherein Y is a bond or —CR 4 R 5 —.

4. The method according to claim 1 , wherein X is chosen from a —S(O) n , —NR 4 , —CHR 4 , and

and wherein Y is a bond or —CHR 4 .

5. The method according to claim 4 , wherein each R 4 is independently a hydrogen atom or a methyl group.

6. The method according to claim 1 , wherein R 3 is a ring system chosen from phenyl, pyridinyl, oxazolyl, pyrazinyl, cyclopropyl, cyclopentyl, cyclohexyl, tetrahydropyranyl, 2,3-dihydrobenzofuranyl, pyrimidinyl, imidazo[1,2-a]pyridinyl, pyrazolyl, thiazolyl, and piperidinyl; and wherein the ring system is unsubstituted or substituted.

7. The method according to claim 1 , wherein R 3 is a substituted or unsubstituted 3- to 6-membered saturated or unsaturated carbocyclic or heterocyclic ring system.

8. The method according to claim 7 , wherein R 3 is a 5- or 6-membered unsaturated carbocyclic or heterocyclic ring system, wherein the heterocyclic ring system comprises one or two ring heteroatoms independently chosen from nitrogen and oxygen; and
wherein the carbocyclic or heterocyclic ring system is unsubstituted or substituted by one, two, three or four substituents independently chosen from fluorine, chlorine, bromine, hydroxyl, cyano, oxo, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 1 -C 2 haloalkyl, C 1 -C 2 hydroxyalkyl, C 1 -C 4 alkoxy, C 1 -C 2 haloalkoxy, C 1 -C 4 alkylthio, C 1 -C 4 alkylsulphinyl, C 1 -C 4 alkylsulphonyl, C 1 -C 4 alkylcarbonyl, C 1 -C 4 alkylcarbonyloxy, C 1 -C 4 alkoxycarbonyl, amino, carboxamido, C 1 -C 4 alkylamino, di-(C 1 -C 4 alkyl)amino, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkyloxy, C 3 -C 6 cycloalkylmethyl, —[O] p —(CH 2 ) q —O—R 7 , and a 4- to 6-membered saturated or unsaturated heterocyclic ring unsubstituted or substituted by methyl or methoxy.

9. The method according to claim 7 , wherein the 3- to 6-membered saturated or unsaturated carbocyclic or heterocyclic ring system is unsubstituted or substituted by at least one substituent chosen from cyano, fluorine, chlorine, difluoromethyl, difluoromethoxy, trifluoromethyl, trifluoromethoxy, methyl, and methoxy.

10. The method according to claim 1 , wherein the compound of formula (I) is chosen from:
4-Hydroxy-6-(2-phenylethyl)pyridazin-3(2H)-one,
6-[2-(4-Fluorophenyl)ethyl]-4-hydroxypyridazin-3(2H)-one,
4-Hydroxy-6-{2-[5-(trifluoromethyl)pyridin-2-yl]ethyl}pyridazin-3(2H)-one,
6-[(4-Chlorobenzyl)sulfanyl]-4-hydroxypyridazin-3(2H)-one,
4-Hydroxy-6-{2-[6-(trifluoromethyl)pyridin-3-yl]ethyl}pyridazin-3(2H)-one,
6-[2-(3-Fluorophenyl)ethyl]-4-hydroxypyridazin-3(2H)-one,
6-[2-(2-Fluorophenyl)ethyl]-4-hydroxypyridazin-3(2H)-one,
6-[2-(3,5-Difluorophenyl)ethyl]-4-hydroxypyridazin-3(2H)-one,
6-[2-(3,4-Difluorophenyl)ethyl]-4-hydroxypyridazin-3(2H)-one,
4-Hydroxy-6-{2-[3-(trifluoromethoxy)phenyl]ethyl}pyridazin-3(2H)-one,
4-Hydroxy-6-{2-[3-(trifluoromethyl)phenyl]ethyl}pyridazin-3(2H)-one,
4-Hydroxy-6-{2-[5-(trifluoromethyl)pyridine-3-yl]ethyl}pyridazin-3(2H)-one,
6-(2-Cyclohexylethyl)-4-hydroxypyridazin-3(2H)-one,
6-(2-Cyclopropylethyl)-4-hydroxypyridazin-3(2H)-one,
6-(2-Cyclopentylethyl)-4-hydroxypyridazin-3(2H)-one,
4-Hydroxy-6-[2-(4-methoxycyclohexyl)ethyl]pyridazin-3(2H)-one,
6-[2-(2,4-Difluorophenyl)ethyl]-4-hydroxypyridazin-3(2H)-one,
6-{2-[3-(Difluoromethyl)phenyl]ethyl}-4-hydroxypyridazin-3(2H)-one,
6-Benzyl-4-hydroxypyridazin-3(2H)-one,
6-[2-(3-Chlorophenyl)ethyl]-4-hydroxypyridazin-3(2H)-one,
4-Hydroxy-6-(1-phenylcyclopropyl)pyridazin-3(2H)-one,
4-[2-(5-Hydroxy-6-oxo-1,6-dihydropyridazin-3-yl)ethyl]benzonitrile,
6-[2-(3-Fluoro-4-methylphenyl)ethyl]-4-hydroxypyridazin-3(2H)-one,
6-[2-(4-Fluoro-3-methylphenyl)ethyl]-4-hydroxypyridazin-3(2H)-one,
6-[2-(3,4-Dimethoxyphenyl)ethyl]-4-hydroxypyridazin-3(2H)-one,
4-Hydroxy-6-{2-[3-(trifluoromethoxy)phenyl]ethyl}pyridazin-3(2H)-one,
6-[2-(4-Chlorophenyl)ethyl]-4-hydroxypyridazin-3(2H)-one,
6-[2-(2-Chlorophenyl)ethyl]-4-hydroxypyridazin-3(2H)-one,
4-Hydroxy-6-{2-[2-(trifluoromethyl)phenyl]ethyl}pyridazin-3(2H)-one,
6-(4-(Difluoromethoxy)phenethyl)-4-hydroxypyridazin-3(2H)-one,
6-(4-(Trifluoromethoxy)phenethyl)-4-hydroxypyridazin-3(2H)-one,
6-(3-(Difluoromethoxy)phenethyl)-4-hydroxypyridazin-3(2H)-one,
6-[1-(4-Fluorophenyl)cyclopropyl]-4-hydroxypyridazin-3(2H)-one,
6-[1-(4-Fluorophenyl)ethyl]-4-hydroxypyridazin-3(2H)-one,
4-Hydroxy-6-{1-[3-(trifluoromethyl)phenyl]ethyl}pyridazin-3(2H)-one,
4-Hydroxy-6-{2-[4-(trifluoromethyl)phenyl]ethyl}pyridazin-3(2H)-one,
6-((Cyclopropylmethyl)(methyl)amino)-4-hydroxypyridazin-3(2H)-one,
6-((Cyclohexylmethyl)(methyl)amino)-4-hydroxypyridazin-3(2H)-one,
6-(3-Chlorobenzyl)-4-hydroxypyridazin-3(2H)-one,
6-(4-Chlorobenzyl)-4-hydroxypyridazin-3(2H)-one,
6-(Cyclohexylmethyl)-4-hydroxypyridazin-3(2H)-one,
6-(4-Fluorobenzyl)-4-hydroxypyridazin-3(2H)-one,
6-(2-Chloro-6-fluorobenzyl)-4-hydroxypyridazin-3(2H)-one,
6-(2-Chlorobenzyl)-4-hydroxypyridazin-3(2H)-one,
6-(3-Fluorobenzyl)-4-hydroxypyridazin-3(2H)-one,
6-(2-Fluorobenzyl)-4-hydroxypyridazin-3(2H)-one,
6-(4-Methylbenzyl)-4-hydroxypyridazin-3(2H)-one,
6-(3-Methylbenzyl)-4-hydroxypyridazin-3(2H)-one,
4-Hydroxy-6-(3-(trifluoromethyl)benzyl)pyridazin-3(2H)-one,
4-Hydroxy-6-{2-[5-(trifluoromethyl)pyridin-3-yl]ethyl}pyridazin-3(2H)-one,
4-Hydroxy-6-

Assignees

• Takeda Pharmaceuticals Co

Inventors

• Farnaby William
• Fieldhouse Charlotte
• Hazel Katherine
• Kerr Catrina
• Kinsella Natasha
• Livermore David
• Merchant Kevin
• Miller David

Classifications

• A61P43/00

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

• A61P29/02

  without antiinflammatory effect · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · 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

• A61P25/18

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