Polycyclic HERG activators

Patent metadata

Field	Value
Publication number	US-9255093-B2
Application number	US-201514688397-A
Country	US
Kind code	B2
Filing date	Apr 16, 2015
Priority date	Apr 17, 2014
Publication date	Feb 9, 2016
Grant date	Feb 9, 2016

Abstract

The present invention provides a compound of formula I, in which R 1 , R 2 , X and R 3 are defined in the Summary of the Invention, or a pharmaceutically acceptable salt thereof;

a method for manufacturing the compounds of the invention, and its therapeutic uses. The present invention further provides a combination of pharmacologically active agents and a pharmaceutical composition.

First claim

What is claimed is:

1. A compound, or salt thereof, of formula (I):

wherein
R 1 is selected from: CO 2 H or tetrazole and R 2 is selected from: H, halo, (C 1 -C 4 )alkyl or halo-substituted(C 1 -C 4 )alkyl, or R 1 is H and R 2 is CO 2 H or tetrazole;
X is selected from: H, halo, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, NR 8 R 9 , halo-substituted(C 1 -C 4 )alkyl, phenyl or a 5 to 6 membered heteroaryl containing 1 to 3 heteroatoms each independently selected from O, N, or S, where said phenyl or heteroaryl are optionally substituted with 1 to 2 substituents each independently selected from halo, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, halo-substituted(C 1 -C 4 )alkyl, hydroxy-substituted(C 1 -C 4 )alkyl, (C 1 -C 4 )alkylamino-substituted(C 1 -C 4 )alkyl, dimethylamino-substituted(C 1 -C 4 )alkyl;
R 8 is selected from: H, or (C 1 -C 4 )alkyl;
R 9 is selected from: H, or (C 1 -C 4 )alkyl;
R 3 is

where R 3a is selected from: H, (C 1 -C 4 )alkyl or halo-substituted(C 1 -C 4 )alkyl;
R 3b is selected from: H, (C 1 -C 4 )alkyl or taken together with R 3a forms a 3 to 7 membered saturated cycloalkyl or a 3 to 7 membered saturated heterocycle containing 1 to 2 heteroatoms selected from O, S or N;
R 3c is selected from: H or CH 3 ;
R 3d is selected from: H or CH 3 ;
R 4 is selected from:

wherein the dotted line indicates the point of attachment;
R 5 is selected from: H or CH 3 ;
R 6 is independently selected from: halo, nitrile, (C 1 -C 4 )alkyl, halo-substituted(C 1 -C 4 )alkyl, nitrile-substituted(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, halo-substituted(C 1 -C 4 )alkoxy, nitrile-substituted(C 1 -C 4 )alkoxy, (C 1 -C 4 )alkylene, N-acetyl, trifluouroacetyl, (C 1 -C 4 )alkylthio, halo-substituted thio, halo-substituted (C 1 -C 4 )alkylthio, (C 3 -C 6 )cycloalkyl, methylamino-substituted(C 1 -C 4 )alkyl, dimethylamino-substituted(C 1 -C 4 )alkyl, halo-substituted(C 1 -C 4 ) hydroxyalkyl, a 4 to 6 membered saturated heterocycle containing 1 to 2 heteroatoms selected from O, S or N, or a 5 to 6 membered heteroaryl containing 1 to 3 heteroatoms each independently selected from O, N, or S, where said heterocycle or heteroaryl are optionally substituted with 1 to 2 substituents each independently selected from (C 1 -C 4 )alkyl, halo, hydroxyl, amino or (C 1 -C 4 )alkoxy;
R 7 is selected from: H or halo;
n is 1, 2 or 3;
m is 0, 1 or 2;
or R 3c and R 4 taken together with the amine to which R 3c and R 4 are attached forms a fully saturated 4 to 7 membered heterocycle, where 1 to 2 of the ring carbons are each independently optionally replaced with a N or O, and said heterocycle is optionally substituted with 1 to 2 substituents each independently selected from (C 1 -C 4 )alkoxy, (C 1 -C 4 )alkyl, halo-substituted(C 1 -C 4 )alkyl, hydroxy(C 1 -C 4 )alkyl, cyclopropyl or oxo or a pharmaceutically acceptable salt thereof.

2. A compound, or salt thereof, according to claim 1 , wherein
R 1 is selected from: CO 2 H, or tetrazole;
R 2 is selected from: H, halo, (C 1 -C 4 )alkyl or halo-substituted(C 1 -C 4 )alkyl;
X is selected from: H, halo, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, NR 8 R 9 , halo-substituted(C 1 -C 4 )alkyl, phenyl or a 5 to 6 membered heteroaryl containing 1 to 3 heteroatoms each independently selected from O, N, or S, where said phenyl or heteroaryl are optionally substituted with 1 to 2 substituents each independently selected from halo, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, halo-substituted(C 1 -C 4 )alkyl, hydroxy-substituted(C 1 -C 4 )alkyl, (C 1 -C 4 )alkylamino-substituted(C 1 -C 4 )alkyl, dimethylamino-substituted(C 1 -C 4 )alkyl;
R 8 is selected from: H, or (C 1 -C 4 )alkyl;
R 9 is selected from: H, or (C 1 -C 4 )alkyl;
R 3 is

where R 3a is selected from: H, (C 1 -C 4 )alkyl or halo-substituted(C 1 -C 4 )alkyl;
R 3b is selected from: H, (C 1 -C 4 )alkyl or taken together with R 3a forms a 3 to 7 membered saturated cycloalkyl or a 3 to 7 membered saturated heterocycle containing 1 to 2 heteroatoms selected from O, S or N;
R 3c is selected from: H or CH 3 ;
R 3d is selected from: H or CH 3 ;
R 4 is selected from:

wherein the dotted line indicates the point of attachment;
R 5 is selected from: H or CH 3 ;
R 6 is independently selected from: halo, (C 1 -C 4 )alkyl, halo-substituted(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, halo-substituted(C 1 -C 4 )alkoxy, nitrile-substituted(C 1 -C 4 )alkoxy, (C 1 -C 4 )alkylene, N-acetyl, trifluouroacetyl, (C 1 -C 4 )alkylthio, halo-substituted thio, halo-substituted (C 1 -C 4 )alkylthio, (C 3 -C 6 )cycloalkyl, methylamino-substituted(C 1 -C 4 )alkyl, dimethylamino-substituted(C 1 -C 4 )alkyl, halo-substituted(C 1 -C 4 ) hydroxyalkyl, a 4 to 6 membered saturated heterocycle containing 1 to 2 heteroatoms selected from O, S or N, or a 5 to 6 membered heteroaryl containing 1 to 3 heteroatoms each independently selected from O, N, or S, where said heterocycle or heteroaryl are optionally substituted with 1 to 2 substituents each independently selected from (C 1 -C 4 )alkyl, halo, hydroxyl, amino or (C 1 -C 4 )alkoxy;
R 7 is selected from: H or halo;
n is 1, 2 or 3;
m is 0, 1, 2, 3 or 4;
or R 3c and R 4 taken together with the amine to which R 3c and R 4 are attached forms a fully saturated 4 to 7 membered heterocycle, where 1 to 2 of the ring carbons are each independently optionally replaced with a N or O, and said heterocycle is optionally substituted with 1 to 2 substituents each independently selected from (C 1 -C 4 )alkoxy, (C 1 -C 4 )alkyl, halo-substituted(C 1 -C 4 )alkyl, hydroxy(C 1 -C 4 )alkyl, cyclopropyl or oxo or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 , or a salt thereof, wherein the compound is of formula (II):

4. The compound of claim 1 , or a salt thereof, wherein the compound is of formula (III):

5. The compound of claim 1 , or a salt thereof, wherein the compound is of formula (IV):

6. The compound of claim 1 , or a salt thereof, wherein the compound is of formula (V):

7. The compound of claim 1 , or a salt thereof, wherein the compound is of formula (VI):

wherein,
R 2 is selected from: H, CH 3 or CF 3 ;
X is selected from: H, halo, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, halo-substituted(C 1 -C 4 )alkyl;
R 6 is independently selected from: halo, (C 1 -C 4 )alkyl, halo-substituted(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, halo-substituted(C 1 -C 4 )alkoxy; or a pharmaceutically acceptable salt thereof.

8. The compound of claim 1 , or a salt

Assignees

• Bebernitz Gregory Raymond
• Cody Emma
• Patel Tajesh
• Qian Ming
• Whitehead Lewis
• Zabawa Thomas
• Zecri Frederic
• Novartis Ag

Inventors

• Bebernitz Gregory Raymond
• Cody Emma
• Patel Tajesh
• Qian Ming
• Whitehead Lewis
• Zabawa Thomas
• Zecri Frederic

Classifications

• A61P9/06

  Antiarrhythmics · CPC title

• 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

• A61K31/5377

  not condensed and containing further heterocyclic rings, e.g. timolol · CPC title

• A61K31/343

  condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone · CPC title