Bicyclic heterocycle derivatives for the treatment of pulmonary arterial hypertension

Patent metadata

Field	Value
Publication number	US-9751876-B2
Application number	US-201414511044-A
Country	US
Kind code	B2
Filing date	Oct 9, 2014
Priority date	Sep 1, 2011
Publication date	Sep 5, 2017
Grant date	Sep 5, 2017

Abstract

Bicyclic heterocyclic derivatives of formula I useful in inhibiting PDGF receptor mediated biological activity.

wherein A is

and R 1 , R 1a , R 2 , R 3 , R 4 , R 5 , R 6 and X are as defined herein.

First claim

The invention claimed is:

1. A method for treating a disease or disorder mediated by the PDGF receptor, wherein the method comprises administering to a subject in need thereof a compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:
A is

R 1 is C 1 -C 4 alkyl; C 1 -C 4 alkoxy optionally substituted by one or more halogen atoms; CN; or halogen;
R 1a is H, halogen, C 1 -C 4 alkyl or C 1 -C 4 haloalkyl;
X is N or CH;
R 2 is H; C 1 -C 8 alkyl optionally substituted by one or more OH, —NR 9 R 11 or C 1 -C 4 alkoxy; C 1 -C 8 haloalkyl; C 2 -C 8 alkynyl substituted by one or more halogen, OH, —NR 9 R 11 or C 1 -C 4 alkoxy; C 3 -C 10 cycloalkyl; —(C 1 -C 4 alkyl)-C 3 -C 8 cycloalkyl; C 1 -C 8 alkoxy optionally substituted by one or more halogen, —NR 9 R 11 or OH; OH; CN; halogen; —(C 0 -C 4 alkyl)-NR 9 R 11 ; —(C 0 -C 4 alkyl)-CO 2 R 15 ; —(C 0 -C 4 alkyl)-C(O)NR 9 R 11 ; —(C 0 -C 4 alkyl)-C 6 -C 14 aryl; or —(C 0 -C 4 alkyl)-3 to 14 membered heterocyclyl; wherein the cycloalkyl, —(C 0 -C 4 alkyl)-C 6 -C 14 aryl and —(C 0 -C 4 alkyl)-3 to 14 membered heterocyclyl are each optionally substituted by one or more Z a substituents;
R 3 is H; C 1 -C 8 alkyl optionally substituted by one or more OH, —NR 9 R 11 or C 1 -C 4 alkoxy; C 1 -C 8 haloalkyl; C 2 -C 8 alkynyl substituted by one or more halogen, OH, —NR 9 R 11 , or C 1 -C 4 alkoxy; C 3 -C 10 cycloalkyl; —(C 1 -C 4 alkyl)-C 3 -C 8 cycloalkyl; C 1 -C 8 alkoxy optionally substituted by one or more halogen, —NR 9 R 11 or OH; OH; CN; halogen; —(C 0 -C 4 alkyl)-NR 9 R 11 ; —(C 0 -C 4 alkyl)-CO 2 R 15 ; —(C 0 -C 4 alkyl)-C(O)NR 9 R 11 ; —(C 0 -C 4 alkyl)-C 6 -C 14 aryl; or —(C 0 -C 4 alkyl)-3 to 14 membered heterocyclyl; wherein the cycloalkyl, —(C 0 -C 4 alkyl)-C 6 -C 14 aryl and —(C 0 -C 4 alkyl)-3 to 14 heterocyclyl are each optionally substituted by one or more Z a substituents;
each Z a is independently OH; (C 0 -C 4 alkyl)-C 6 aryl; O—C 6 aryl; C 1 -C 4 alkyl optionally substituted by one or more OH, CN or —NR 19a R 21a ; C 1 -C 4 haloalkyl; C 1 -C 4 alkoxy optionally substituted by one or more OH, —CO 2 R 19a , —NR 19a R 21a or C 1 -C 4 alkoxy; —NR 18a C(O)R 21a ; —C(O)NR 19a R 21a ; —NR 18a C(O)NR 19a R 21a ; NR 19a R 21a ; —(C 0 -C 4 alkyl)-C(O)OR 18a ; —(C 0 -C 4 alkyl)-C(O)R 19a ; oxo; CN; NO 2 ; halogen; —(C 0 -C 4 alkyl)-4 to 6 membered heterocyclyl; or —O-(4 to 6 membered heterocyclyl); wherein the (C 0 -C 4 alkyl)-C 6 aryl, O—C 6 aryl, —(C 0 -C 4 alkyl)-4 to 6 membered heterocyclyl and —O-(4 to 6 membered heterocyclyl) are each optionally substituted by OH, halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl or C 1 -C 4 alkoxy optionally substituted by one or more halogens;
R 4 is H;
R 5 is H, C 1 -C 4 alkyl or C 1 -C 4 haloalkyl;
R 6 is selected from C 1 -C 8 alkyl optionally substituted by one or more C 1 -C 4 alkoxy or —NR 19 R 21 ; C 1 -C 8 haloalkyl; —(C 0 -C 4 alkyl)-C 3 -C 8 cycloalkyl; C 1 -C 8 alkoxy optionally substituted by one or more halogen atoms; —NR 19 R 21 ; —(C 0 -C 4 alkyl)-C 6 -C 14 aryl; and —(C 0 -C 4 alkyl)-3 to 14 membered heterocyclyl; wherein the —(C 0 -C 4 alkyl)-C 3 -C 8 cycloalkyl, —(C 0 -C 4 alkyl)-C 6 -C 14 aryl and —(C 0 -C 4 alkyl)-3 to 14 heterocyclyl are each optionally substituted by one or more Z substituents;
each Z is independently selected from (C 0 -C 4 alkyl)-C 6 aryl; O—C 6 aryl; C 1 -C 6 alkyl optionally substituted by one or more C 1 -C 6 alkoxy, CN or —NR 19 R 21 ; C 1 -C 6 haloalkyl; C 1 -C 6 alkoxy optionally substituted by one or more —NR 19 R 21 or C 1 -C 4 alkoxy; —NR 19 R 21 ; (C 0 -C 4 C 4 alkyl)-C(O)R 19 ; CN; halogen and (C 0 -C 4 alkyl)-4 to 6 membered heterocyclyl; and wherein the aryl and heterocyclyl are each optionally substituted by one or more halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl and C 1 -C 6 alkoxy optionally substituted by one or more halogens;

R 9 and R 11 are each independently selected from H; C 1 -C 6 alkyl optionally substituted by one or more C 1 -C 4 alkoxy or OH; C 1 -C 6 haloalkyl; —(C 0 -C 1 alkyl)-C 3 -C 6 cycloalkyl; (C 0 -C 4 alkyl)-C 6 -C 14 aryl optionally substituted by one or more groups selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy and halogen; and (C 0 -C 4 alkyl)-3- to 14-membered heterocyclyl optionally substituted by one or more groups selected from halogen, oxo, C 1 -C 6 alkyl and C(O)C 1 -C 6 alkyl; or
R 9 and R 11 together with the nitrogen atom to which they are attached form a 5- to 10-membered heterocyclyl, which heterocyclyl includes 0 to 3 further heteroatoms selected from N, O and S, the heterocyclyl being optionally substituted by one or more substituents selected from OH; halogen; phenyl, 5- to 10-membered heterocyclyl; C 1 -C 6 alkyl; C 1 -C 6 haloalkyl; C 1 -C 6 alkoxy optionally substituted by one or more OH or C 1 -C 4 alkoxy; and C(O)OC 1 -C 6 alkyl; wherein the phenyl and heterocyclyl substituent groups are themselves optionally substituted by C 1 -C 6 alkyl, C 1 -C 6 haloalkyl or C 1 -C 6 alkoxy;
R 15 is selected from H; C 1 -C 8 alkyl; C 1 -C 8 haloalkyl; C 3 -C 10 cycloalkyl; (—C 1 -C 4 alkyl)-C 3 -C 8 cycloalkyl; —(C 0 -C 4 alkyl)-C 6 -C i4 aryl and —(C 0 -C 4 alkyl)-3 to 14 membered heterocyclyl group; wherein the C 3 -C 10 cycloalkyl, (—C 1 -C 4 alkyl)-C 3 -C 8 cycloalkyl, —(C 0 -C 4 alkyl)-C 6 -C 14 aryl and —(C 0 -C 4 alkyl)-3 to 14 membered heterocyclyl groups are each optionally substituted by one or more Z substituents;
R 18a is independently H or C 1 -C 6 alkyl;
R 19a and R 21a are each independently H; C 1 -C 6 alkyl optionally substituted by one or more C 1 -C 4 alkoxy, —NR 22 R 23 ′, or OH; C 1 -C 6 haloalkyl; —(C 0 -C 1 alkyl)-C 3 -C 6 cycloalkyl; —(C 0 -C 4 alkyl)- C 6 -C 14 aryl optionally substituted by one or more groups selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy and halogen; or —(C 0 -C 4 alkyl)-3- to 14-membered heterocyclyl optionally substituted by one or more groups selected from halogen, oxo, C 1 -C 6 alkyl and C(O)C 1 -C 6 alkyl; or
R 19a and R 21a together with the nitrogen atom to which they attached form a 5- to 10-membered heterocyclyl, which heterocyclyl includes 0 to 3 further heteroatoms selected from N, O and S, the heterocyclyl being optionally substituted by one or more substituents selected from OH; halogen; phenyl; 5- to 10-membered heterocyclyl; C 1 -C 6 alkyl; C 1 -C 6 haloalkyl; C 1 -C 6 alkoxy optionally substituted by one or more OH or C 1 -C 4 alkoxy; and C(O)OC 1 -C 6 alkyl; wherein the phenyl and heterocyclyl substituent groups are themselves optionally substituted by C 1 -C 6 alkyl, C 1 -C 6 haloalkyl or C 1 -C 6 alkoxy;
R 18 is independently H or C 1 -C 6 alkyl;
R 19 and R 21 are each independently C 1 -C 6 alkyl optionally substituted by one or more C 1 -C 4 alkoxy; C 1 -C 6 haloalkyl; —(C 0 -C 1 alkyl)-C 3 -C 6 cycloalkyl; —(C 0 -C 4 alkyl)-C 6 -C 14 aryl optionally substituted by one or more groups selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy and halogen; or —(C 0 -C 4 alkyl)-3- to 14-membered heterocyclyl, optionally substituted by one or more groups selected from halogen, C 1 -C 6 alkyl and —C(O)C 1 -C 6 alkyl; or
R 19 and R 21 together with the nitrogen atom to which they attached form a 5- to 10-membered heterocyclyl, which heterocyclyl includes 0 to 3 further heteroatoms selected from N, O and S, the heterocyclyl being optionally substituted by one or more substituents selected from halogen; phenyl; 5- to 10-membered heterocyclyl; C 1 -C 6 alkyl; C 1 -C 6 haloalkyl;

Assignees

• Novartis Ag

Inventors

• Bruce Ian
• Chamoin Sylvie
• Collingwood Stephen Paul
• Furet Pascal
• Furminger Vikki
• Janus Diana
• Lewis Sarah
• Loren Jon Christopher
• Molteni Valentina
• Saunders Alex Michael
• Shaw Duncan
• Sviridenko Lilya
• Thomson Christopher
• West Ryan
• Yeh Vince

Classifications

• A61P43/00

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

• A61P9/12

  Antihypertensives · CPC title

• A61P11/00

  Drugs for disorders of the respiratory system · CPC title

• A61K31/444

  containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone · CPC title

• C07D471/04 Primary

  Ortho-condensed systems · CPC title