Triazole compounds as T-type calcium channel blockers

Patent metadata

Field	Value
Publication number	US-10246426-B2
Application number	US-201515510980-A
Country	US
Kind code	B2
Filing date	Sep 14, 2015
Priority date	Sep 15, 2014
Publication date	Apr 2, 2019
Grant date	Apr 2, 2019

Abstract

The invention relates to compounds of formula (I)

wherein
X, Y, R 1 , R 2 , (R 4 ) n , and (R 5 ) m are as defined in the description, and to pharmaceutically acceptable salts of such compounds. These compounds are useful as calcium T-channel blockers.

First claim

The invention claimed is:

1. A compound of formula (I)

wherein
X represents a ring carbon or a ring nitrogen atom;
R 1 represents
(C 2-6 )alkyl;
(C 2-4 )alkyl mono-substituted with cyano, or (C 1-3 )alkoxy;
(C 1-4 )fluoroalkyl;
(C 1-3 )fluoroalkoxy;
pentafluoro-sulfanyl;
(C 3-6 )cycloalkyl-L 1 - wherein
said (C 3-6 )cycloalkyl optionally contains one ring oxygen atom; wherein said (C 3-6 )cycloalkyl is unsubstituted; or mono-substituted with fluoro, (C 1-3 )alkyl, (C 1-3 )alkoxy, hydroxy, cyano, or (C 1-3 )fluoroalkyl; or di-substituted with fluoro, or tri-substituted with two fluoro substituents and a (C 1-3 )alkyl substituent; and
the linker L 1 represents a direct bond, (C 1-2 )alkylene, oxygen, or (C 1-2 )alkylene-oxy;

5- or 6-membered heteroaryl, independently optionally mono-substituted with (C 1-3 )alkyl;
—NR 11 R 12 , wherein
R 11 and R 12 independently represent hydrogen, (C 1-3 )alkyl, (C 2-3 )fluoroalkyl, (C 3-6 )cycloalkyl, (C 3-6 )cycloalkyl mono- or di-substituted with fluoro, (C 3-6 )cycloalkyl-(C 1-3 )alkyl, (C 1-3 )alkoxy-(C 2-3 )alkyl;
or R 11 and R 12 , together with the nitrogen atom to which they are attached to, form a 4- to -6 membered ring which is optionally mono- or di-substituted with fluoro; a 2-oxo-pyrrolidinyl group; or a morpholinyl group;

and (R 4 ) n represents one or two optional substituents independently selected from (C 1-4 )alkyl, (C 1-4 )alkoxy, (C 1-3 )fluoroalkyl, (C 1-3 )fluoroalkoxy, halogen, and cyano;
or R 1 together with (R 4 ) n forms a non-aromatic 5- or 6-membered ring which is fused to the phenyl/pyridine ring; wherein said 5- or 6-membered ring optionally contains one or two heteroatoms independently selected from oxygen and nitrogen; wherein said fused 5- or 6-membered non-aromatic ring independently is optionally further mono-substituted with oxo; or di-, tri-, or tetra-substituted wherein one substituent is oxo and the remaining are (C 1-3 )alkyl;
or R 1 together with (R 4 ) n forms an aromatic 5- or 6-membered ring which is fused to the phenyl/pyridine ring; wherein said 5- or 6-membered ring optionally contains one or two nitrogen atoms, wherein said fused 5- or 6-membered aromatic ring independently is optionally further mono- or di-substituted wherein the substituents are independently selected from (C 1-4 )alkyl, (C 3-6 )cycloalkyl, (C 1 )fluoroalkyl, or cyano;

Y represents a ring carbon or a ring nitrogen atom; and
R 2 represents (C 1-4 )alkyl; (C 3-6 )cycloalkyl; (C 1-4 )alkoxy; (C 3-6 )cycloalkyl-oxy; (C 1-3 )fluoroalkyl; (C 1-3 )fluoroalkoxy; (C 1-3 )alkoxy-(C 2-3 )alkoxy; halogen; cyano; or —NR 21 R 22 , wherein R 21 and R 22 independently represent hydrogen, or (C 1-3 )alkyl, or R 21 and R 22 , together with the nitrogen atom to which they are attached to, form a 4- to -6 membered ring optionally mono- or di-substituted with fluoro, or a morpholinyl group;
and
(R 5 ) m represents one or two optional substituents independently selected from (C 1-4 )alkyl; (C 3-6 )cycloalkyl; (C 1-4 )alkoxy; halogen; cyano; (C 1-3 )fluoroalkyl; and (C 1-3 )fluoroalkoxy;
or a salt of such a compound.

2. A compound according to claim 1 , wherein X represents a ring carbon atom; or a salt of such a compound.

3. A compound according to claim 1 , wherein
R 1 represents
(C 2-6 )alkyl;
(C 2-4 )alkyl mono-substituted with cyano, or (C 1-3 )alkoxy;
(C 1-4 )fluoroalkyl;
(C 1-3 )fluoroalkoxy;
pentafluoro-sulfanyl;
(C 3-6 )cycloalkyl-L 1 - wherein
said (C 3-6 )cycloalkyl optionally contains one ring oxygen atom; wherein said (C 3-6 )cycloalkyl is unsubstituted, or mono-substituted with fluoro, (C 1-3 )alkyl, (C 1-3 )alkoxy, hydroxy, cyano, or (C 1-3 )fluoroalkyl, or di-substituted with fluoro, or tri-substituted with two fluoro substituents and a (C 1-3 )alkyl substituent; and
the linker L 1 represents a direct bond, (C 1-2 )alkylene, oxygen, or (C 1-2 )alkylene-oxy;

—NR 11 R 12 , wherein
R 11 and R 12 independently represent hydrogen, (C 1-3 )alkyl, (C 2-3 )fluoroalkyl, (C 3-6 )cycloalkyl, (C 3-6 )cycloalkyl mono- or di-substituted with fluoro, (C 3-6 )cycloalkyl-(C 1-3 )alkyl;
or R 11 and R 12 , together with the nitrogen atom to which they are attached to, form an azetidinyl or a pyrrolidinyl ring, both independently optionally mono- or di-substituted with fluoro;

and (R 4 ) n represents one optional substituent selected from (C 1-4 )alkyl, (C 1-4 )alkoxy, (C 1-3 )fluoroalkyl, (C 1-3 )fluoroalkoxy, halogen, and cyano;
or R 1 together with (R 4 ) n forms a non-aromatic 5- or 6-membered ring which is fused to the phenyl/pyridine ring to form a bicyclic ring system; wherein said bicyclic ring system is selected from 2,3-dihydro-benzooxazolyl, 3,4-dihydro-2H-benzo[1,4]oxazinyl, 2,3-dihydro-1H-indolyl, and 2,3-dihydro-benzofuranyl; wherein said non-aromatic 5- or 6-membered ring part of said bicyclic ring system independently is optionally further mono-substituted with oxo; or di-, tri-, or tetra-substituted wherein one substituent is oxo and the remaining are (C 1-3 )alkyl;
or R 1 together with (R 4 ) n forms an aromatic 5- or 6-membered ring which is fused to the phenyl/pyridine ring to form a bicyclic aromatic ring system selected from pyrazolo[3,4-b]pyridinyl, pyrrolo[2,3-b]pyridinyl, indolyl, indazolyl, quinoxalinyl, benzoimidazolyl, and quinolinyl; wherein said fused 5- or 6-membered aromatic ring part of said aromatic bicyclic ring system independently is optionally further mono- or di-substituted wherein the substituents are independently selected from (C 1-3 )alkyl, (C 3-6 )cycloalkyl, (C 1 )fluoroalkyl, or cyano;

or a salt of such a compound.

4. A compound according to claim 1 , wherein
R 1 represents
(C 2-6 )alkyl;
(C 1-4 )fluoroalkyl;
(C 1-3 )fluoroalkoxy;
(C 3-6 )cycloalkyl wherein
said (C 3-6 )cycloalkyl optionally contains one ring oxygen atom; wherein said (C 3-6 )cycloalkyl is mono-substituted with fluoro or (C 1-3 )fluoroalkyl, or di-substituted with fluoro; or

(C 3-6 )cycloalkyl-oxy- wherein
said (C 3-6 )cycloalkyl optionally contains one ring oxygen atom; wherein said (C 3-6 )cycloalkyl is unsubstituted, or di-substituted with fluoro;

and (R 4 ) n represents one optional substituent selected from (C 1-4 )alkyl, or halogen;

or a salt of such a compound.

5. A compound according to claim 1 , wherein the fragment

represents 4-isopropyl-phenyl, 4-dimethylamino-phenyl, 4-trifluoromethyl-phenyl, 4-tert.-butyl-phenyl, 4-(1-methoxy-ethyl)-phenyl, 4-(cyclopropyl-oxy)-phenyl, 4-(oxetan-3-yl)-phenyl, 4-(3-fluoro-oxetan-3-yl)-phenyl, 4-(cyclobutyl-oxy)-phenyl, 4-(3-methyl-oxetan-3-yl)-phenyl, 4-(1-cyano-cyclopropyl)-phenyl, 4-(1-cyano-1-methyl-ethyl)-phenyl, 4-(pentafluoro-sulfanyl)-phenyl, 3-methyl-4-(2,2,2-trifluoroethoxy)-phenyl, 4-(3-methoxy-oxetan-3-yl)-phenyl, 4-(oxetan-3-yl-methoxy)-phenyl, 4-(2-trifluoromethyl-cyclopropyl)-phenyl, 4-(1-trifluoromethyl-cyclopropyl)-phenyl, 4-((3-fluoro-oxetan-3-yl)-methoxy)-phenyl, 4-((3-methyl-oxetan-3-yl)-methoxy)-phenyl, 4-(3,3-difluoro-cyclobutyl-oxy)-phenyl, 4-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-phenyl, 4-((3,3-difluoro-cyclobutyl)-methoxy)-phenyl, 4-((3,3-difluoro-1-methyl-cyclobutyl)-methoxy)-phenyl; 2-(pyrrolidin-1-yl)-pyridin-5-yl, 2-(cyclopropyl(methyl)amino)-pyridin-5-yl, 2-(diethylamino)-pyridin-5-yl, 3-fluoro-2-(pyrrolidin-1-yl)-pyridin-5-yl, 2-((cyclopropylmethyl)-methyl-amino)-pyridin-5-yl, 2-(3,3-difluoro-pyrrolidin-1-yl)-pyridin-5-yl; 3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl, 1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl, 1-methyl-1H-pyrazolo[

Assignees

• Idorsia Pharmaceuticals Ltd

Inventors

• Bezencon Olivier
• Gatfield John
• Heidmann Bibia
• Siegrist Romain
• Stamm Simon

Classifications

• A61P43/00

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

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P35/00

  Antineoplastic agents · 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