Pyrazole compounds and their use as T-type calcium channel blockers

Patent metadata

Field	Value
Publication number	US-10065929-B2
Application number	US-201715847611-A
Country	US
Kind code	B2
Filing date	Dec 19, 2017
Priority date	Jun 3, 2014
Publication date	Sep 4, 2018
Grant date	Sep 4, 2018

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 method of decreasing burst firing discharges in a neuronal cell by blocking calcium T-channels; said method comprising the administration to a subject in need thereof of 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 substituent selected from (C 1-3 )alkyl and cyano; 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, form a 4- to- 6 membered ring 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 3-6 )cycloalkyl, (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 (C 1-3 )alkyl; di-substituted with (C 1-3 )alkyl; 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 1-3 )alkyl, (C 3-6 )cycloalkyl, (C 1 )fluoroalkyl, or cyano;
or R 1 represents methyl, or halogen; and (R 4 ) n represents one substituent selected from (C 1-3 )fluoroalkoxy which is attached to the phenyl/pyridinyl ring in ortho- or meta-position to the point of attachment of the —CH 2 —CO—NH— group;

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, 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 pharmaceutically acceptable salt of such a compound.

2. A method according to claim 1 , said method comprising the administration to a subject in need thereof of a compound of Formula (I), wherein X represents a ring carbon atom; or a pharmaceutically acceptable salt of such a compound.

3. A method according to claim 1 , said method comprising the administration to a subject in need thereof of a compound of Formula (I), 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 1-33 )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 selected from oxadiazolyl, pyrazinyl, pyrimidinyl, and pyridinyl; wherein said heteroaryl independently is optionally mono-substituted with (C 1-3 )alkyl; or
—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, form an azetidinyl or a pyrrolidinyl ring, both independently optionally mono- or di-substituted with fluoro; or a 2-oxo-pyrrolidinyl group;

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-benzoxazolyl, 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 pyrrolo[2,3-b]pyridinyl, indolyl, indazolyl, quinoxalinyl, benzimidazolyl, 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 R 1 represents methyl, or halogen; and (R 4 ) n represents one substituent selected from (C 1-3 )fluoroalkoxy which is attached to the phenyl/pyridinyl ring in ortho- or meta-position to the point of attachment of the —CH 2 —CO—NH— group;

or a pharmaceutically acceptable salt of such a compound.

4. A method according to claim 2 , said method comprising the administration to a subject in need thereof of a compound of Formula (I), 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 pharmaceutically acceptable salt of such a compound.

5. A method acco

Assignees

• Idorsia Pharmaceuticals Ltd

Inventors

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

Classifications

• A61P43/00

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

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P29/00

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