US 12,590,086 B2Granted

3-((1H-pyrazol-4-yl)methyl)-6′-(phenyl)-2H-(1,2′-bipyridin)-2-one derivatives and related compounds as GPR139 antagonists for use in a method of treatment of e.g. depression

AssigneeTakeda Pharmaceutical Company Limited

InventorsTomoaki Hasui, Satoshi Mikami, Toru Yamashita, Shinji Nakamura, Shinji Morimoto, Toshihiro Imaeda, Kazuaki Takami, Masaki Daini, Hiroyuki Kakei, Minoru Nakamura, Fumie Yamaguchi, Chunxiang Wang, Sachie Takashima, Makoto Kamata, Yuya Oguro, Shuhei Ikeda

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Abstract

The present invention refers to compounds of formula (I). The present invention also relates to compounds of formula (I) for use as G Protein coupled Receptor 139 (GPR139) antagonists in methods of medical treatment of e.g. depression, Alzheimer's disease, schizophrenia, drug addiction, sleep disorders, pain, and attention deficit hyperactivity disorder. Exemplary compounds are e.g. 3-((1H-pyrazol-4-yl)methyl)-6′-(phenyl)-2H-(1,2′-bipyridin)-2-one derivatives and related compounds. The present description discloses the synthesis and characterisation of exemplary compounds, pharmacological data thereof, as well as exemplary tablet formulations comprising the compounds of the invention (e.g. page 83 to page 110; examples 1 to 33; reference example 1; test examples 1 and 2; tables 1 to 4).

Claims27

Dependent claims

A compound of Formula (I)

or a pharmaceutically acceptable salt thereof, wherein:
R1 is
ring A1 is chosen from 6-membered aromatic rings optionally further substituted with 1 to 3 substituents chosen from:
(a) halogen atoms;
(b) cyano groups;
(c) optionally halogenated C1-6 alkyl groups;
(d) optionally halogenated C1-6 alkoxy groups;
and
(e) C3-10 cycloalkyl groups optionally substituted with 1 to 3 halogen atoms;
ring A2 is chosen from 5-membered monocyclic aromatic heterocyclic rings optionally further substituted with 1 to 3 substituents chosen from:
(a) halogen atoms;
(b) cyano groups;
(c) optionally halogenated C1-6 alkyl groups;
(d) optionally halogenated C1-6 alkoxy groups;
and
(e) C3-10 cycloalkyl groups;
ring B is chosen from pyridone rings optionally further substituted with 1 to 3 substituents chosen from halogen atoms and C1-6 alkyl groups;
R2 and R3 are each independently chosen from a hydrogen atom and C1-6 alkyl groups;
R4a and R4b are each independently chosen from substituents:
(1) C6-14 aryl groups optionally substituted with 1 to 3 halogen atoms;
(2) 3- to 14-membered non-aromatic heterocyclic groups optionally substituted with 1 to 3 substituents chosen from:
(a) halogen atoms;
and
(b) optionally halogenated C1-6 alkyl groups;
(3) mono- or di-C1-6 alkylamino groups optionally substituted with 1 to 3 C3-10 cycloalkyl groups optionally substituted with 1 to 3 halogen atoms;
and
(4) 3- to 14-membered non-aromatic heterocyclic oxy groups;
and
ring C is chosen from 5-membered monocyclic aromatic heterocyclic rings optionally further substituted with 1 to 3 substituents independently chosen from C1-6 alkyl groups.

26 more elements

A compound chosen from:

3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-6′-(4-fluorophenyl)-4′-(trifluoromethyl)-2H-[1,2′-bipyridin]-2-one;
3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-6′-(4-fluorophenyl)-2-oxo-4′-(trifluoromethyl)-2H-[1,2′-bipyridine]-3′-carbonitrile;
3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-6′-(4-fluorophenyl)-2-oxo-4′-(2,2,2-trifluoroethoxy)-2H-[1,2′-bipyridine]-3′-carbonitrile;
4′-(2,2-difluoroethoxy)-3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-6′-(4-fluorophenyl)-2-oxo-2H-[1,2′-bipyridine]-3′-carbonitrile;
3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-6′-(4-fluorophenyl)-6-methyl-2-oxo-4′-(trifluoromethyl)-2H-[1,2′-bipyridine]-3′-carbonitrile;
4′-(difluoromethyl)-3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-6′-(4-fluorophenyl)-2-oxo-2H-[1,2′-bipyridine]-3′-carbonitrile;
3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-3′-fluoro-6′-[(2R)-2-methylmorpholin-4-yl]-4′-(trifluoromethyl)-2H-[1,2′-bipyridin]-2-one;
3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-5′-methyl-6′-[(2R)-2-methylmorpholin-4-yl]-4′-(trifluoromethyl)-2H-[1,2′-bipyridin]-2-one;
3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-1-{2-fluoro-5-[(2R)-2-methylmorpholin-4-yl]-3-(trifluoromethyl)phenyl}pyridin-2 (1H)-one;
6′-[2-(difluoromethyl) morpholin-4-yl]-3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-3′-fluoro-4′-(trifluoromethyl)-2H-[1,2′-bipyridin]-2-one;
3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-3′-fluoro-4-methyl-6′-[(2R)-2-methylmorpholin-4-yl]-4′-(trifluoromethyl)-2H-[1,2′-bipyridin]-2-one;
3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-3′-fluoro-5-methyl-6′-[(2R)-2-methylmorpholin-4-yl]-4′-(trifluoromethyl)-2H-[1,2′-bipyridin]-2-one;
3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-3′-fluoro-6′-[(oxan-4-yl)oxy]-4′-(trifluoromethyl)-2H-[1,2′-bipyridin]-2-one;
3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-1-[4-{[(1-fluorocyclobutyl)methyl]amino}-6-(trifluoromethyl)pyrimidin-2-yl]pyridin-2 (1H)-one;
1-[4-{[(3,3-difluorocyclobutyl)methyl]amino}-6-(trifluoromethyl)pyrimidin-2-yl]-3-[(1-ethyl-1H-pyrazol-4-yl)methyl]pyridin-2 (1H)-one;
1-[4-{[(3,3-difluorocyclobutyl)methyl](methyl)amino}-6-(trifluoromethyl)pyrimidin-2-yl]-3-[(1-ethyl-1H-pyrazol-4-yl)methyl]pyridin-2 (1H)-one;
3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-1-[4 {[(1-fluorocyclobutyl)methyl](methyl)amino}-6-(trifluoromethyl)pyrimidin-2-yl]pyridin-2 (1H)-one;
1-{3-cyclopropyl-2-fluoro-5-[(2R)-2-methylmorpholin-4-yl]phenyl}-3-[(1-ethyl-1H-pyrazol-4-yl)methyl]pyridin-2 (1H)-one;
1-[3-cyclopropyl-5-(2,2-dimethylmorpholin-4-yl)-2-fluorophenyl]-3-[(1-ethyl-1H-pyrazol-4-yl)methyl]pyridin-2 (1H)-one;
1-{3-cyclopropyl-2-fluoro-5-[(oxan-4-yl)oxy]phenyl}-3-[(1-ethyl-1H-pyrazol-4-yl)methyl]pyridin-2 (1H)-one;
1-{3-bromo-2-fluoro-5-[(oxan-4-yl)oxy]phenyl}-3-[(1-ethyl-1H-pyrazol-4-yl)methyl]pyridin-2 (1H)-one;
3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-1-{2-fluoro-5-[(2R)-2-methylmorpholin-4-yl]-3-(trifluoromethoxy)phenyl}pyridin-2 (1H)-one;
1-{3-cyclopropyl-2-fluoro-5-[(2R)-2-methylmorpholin-4-yl]phenyl}-3-{[1-(propan-2-yl)-1H-pyrazol-4-yl]methyl}pyridin-2 (1H)-one;
1-{3-cyclopropyl-2-fluoro-5-[(2R)-2-methylmorpholin-4-yl]phenyl}-3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-4-fluoropyridin-2 (1H)-one;
3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-1-{2-fluoro-5-[(2R)-2-methylmorpholin-4-yl]-3-(propan-2-yl)phenyl}pyridin-2 (1H)-one;
3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-1-{2-fluoro-5-[(2R)-2-methylmorpholin-4-yl]-3-(2,2,2-trifluoroethyl)phenyl}pyridin-2 (1H)-one;
1-{3-cyclopropyl-5-[(2R)-2-methylmorpholin-4-yl]phenyl}-3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-6-methylpyridin-2 (1H)-one;
1-[3-(2,2-difluorocyclopropyl)-5-(4,4-difluoropiperidin-1-yl)-2-fluorophenyl]-3-[(1-ethyl-1H-pyrazol-4-yl)methyl]pyridin-2 (1H)-one;
1-{3-cyclopropyl-5-[(2R)-2-methylmorpholin-4-yl]phenyl}-3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-6-fluoropyridin-2 (1H)-one;
1-{3-cyclopropyl-2-fluoro-5-[(2R)-2-methylmorpholin-4-yl]phenyl}-3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-5-methylpyridin-2 (1H)-one;
and
1-{3-cyclopropyl-2-fluoro-5-[(2R)-2-methylmorpholin-4-yl]phenyl}-3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-4-methylpyridin-2 (1H)-one, or
a pharmaceutically acceptable salt of any of the foregoing.

30 more elements

Dependencies are inferred from the claim text.

Facts

Application: 17/999,514Filed 20 May 2021
Priority: JP 2020-09011122 May 2020
Published: US 2023/0357220 A19 Nov 2023
Granted: 31 Mar 2026
Term ends: Not estimatedThe source records don’t support an estimate.

Classification13 codes

C07D 413/14
Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms:…
A61P 25/00
Drugs for disorders of the nervous system
A61P 25/04
Drugs for disorders of the nervous system: centrally acting analgesics, e.g. opioids
A61P 25/18
Drugs for disorders of the nervous system: antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia