Compounds and methods for inhibiting histone demethylases

Patent metadata

Field	Value
Publication number	US-9802941-B2
Application number	US-201514836397-A
Country	US
Kind code	B2
Filing date	Aug 26, 2015
Priority date	Aug 27, 2014
Publication date	Oct 31, 2017
Grant date	Oct 31, 2017

Abstract

The present application relates to compounds being of Formula (I), (II), (III), (IV), (V), (VI), (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), and (IIIg). Compounds of Formula (I) have the structure:

wherein Q, R 1 , R 18 , R 19 , M, A and Y are as defined herein. The compounds of the application can modulate the activity of histone demethylases (HDMEs), and can be useful for the prevention and/or treatment of diseases in which genomic dysregulation is involved in the pathogenesis, e.g., cancer.

First claim

The invention claimed is:

1. A compound being of Formula (I):

wherein:
Q is selected from CO 2 H, CO 2 R 20 , —CH═NR 12 , —W, —CH 2 NHR 13 , —CH═O and —CH(OR 17 ) 2 ;
M is CH or N;
A is selected from —C(R 2 ) 2 C(O)—, —C(R 2 ) 2 C(R 2 ) 2 C(O)—, C 3-10 alkyl, —Z—C 3-10 cycloalkylene, —Z-heterocyclylene, —Z-heteroarylene and —Z-arylene, wherein the C 3-10 alkyl, —Z-cycloalkylene, —Z-heterocyclylene, —Z-heteroarylene and —Z-arylene are optionally substituted with one or more R 3 , or A and Y form a C 3-10 cycloalkyl or heterocyclic ring;
Y is selected from —H, —NR 6 R 7 , —OR 7 , C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-10 cycloalkyl, heterocyclyl, heteroaryl and aryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, heteroaryl and aryl are optionally substituted with one or more R 3 ;
R 1 is selected from —H, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, and C 3-10 cycloalkyl, wherein the alkyl, alkenyl, alkynyl and cycloalkyl are optionally substituted with one or more substituents selected from —OH, aryl, C 1-6 alkoxy, heteroaryl, aryloxy, heteroaryloxy, —NR 6 R 7 , —F and C 3-6 cycloalkyl; or R 1 , together with A-Y and the nitrogen atom to which it is attached, forms a nitrogen-containing heterocyclic ring optionally substituted with one or more substituents independently selected from C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, and C 3-10 cycloalkyl, wherein the alkyl, alkenyl, alkynyl and cycloalkyl are optionally substituted with one or more substituents independently selected from —OH, aryl, C 1-6 alkoxy, heteroaryl, aryloxy, heteroaryloxy, —NR 6 R 7 , —F and C 3-6 cycloalkyl; or R 1 and R 18 , together with the atoms to which they are attached, form a nitrogen-containing heterocyclic ring optionally substituted with one or more substituents independently selected from C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, and C 3-10 cycloalkyl, wherein the alkyl, alkenyl, alkynyl and cycloalkyl are optionally substituted with one or more substituents independently selected from —OH, aryl, C 1-6 alkoxy, heteroaryl, aryloxy, heteroaryloxy, —NR 6 R 7 , —F and C 3-6 cycloalkyl;
Each R 2 is independently selected from —H, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, and C 3-10 cycloalkyl, wherein the alkyl, alkenyl, alkynyl and cycloalkyl are optionally substituted with one or more substituents independently selected from —OH, aryl, C 1-6 alkoxy, heteroaryl, aryloxy, heteroaryloxy, —F, C 3-6 cycloalkyl, —Z-heterocyclyl, —Z-aryl, —Z-heteroaryl, —Z—NR 6 R 7 , —Z—C(═O)—NR 6 R 7 , —Z—NR 6 —C(═O)—R 7 , —Z—C(═O)—R 7 , —Z—OR 7 , halogen, —Z—SR 7 , —Z—SOR 7 , —Z—SO 2 R 7 , —Z—SO 2 NR 6 R 7 and —Z—COOR 7 ; or two R 2 substituents on adjacent carbon atoms, together with the carbon atoms to which they are attached, form a C 4-10 cycloalkyl or heterocyclic ring; or two R 2 substituents on the same carbon atom, together with the carbon atom to which they are attached, form a C 3-10 cycloalkyl or heterocyclic ring; or R 2 and Y, together with the carbon atoms to which they are attached, form a C 4-10 cycloalkyl or heterocyclic ring;
each R 3 is independently selected from C 1-6 alkyl, C 1-4 fluoroalkyl, C 1-4 hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, —Z-heterocyclyl, —Z-aryl, —Z-heteroaryl, —Z—NR 6 R 7 , —Z—C(═O)—NR 6 R 7 , —Z—NR 6 —C(═O)—R 7 , —Z—C(═O)—R 7 , —Z—OR 7 , halogen, —Z—SR 7 , —Z—SOR 7 , —Z—SO 2 R 7 , —Z—SO 2 NR 6 R 7 and —Z—COOR 7 , wherein the heterocyclyl is optionally substituted with one or more R 4 , and wherein the heteroaryl and aryl are optionally substituted with one or more R 5 ; or two R 3 on the same carbon atom may, together with the carbon atom to which they are attached, form a C 3-10 cycloalkyl or heterocyclic ring;
Z is selected from a single bond, C 1-4 alkylene, heterocyclylene and C 3-6 cycloalkylene;
each R 4 is independently selected from C 1-6 alkyl, C 1-4 fluoroalkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, C 3-10 cycloalkyl, —Z—NR 6 R 7 , —Z—C(═O)—NR 6 R 7 , —Z—NR 6 —C(═O)—R 7 , —Z—C(═O)—R 7 , —Z—C(═O)—H, —OR 7 , halogen, —SR 7 , —SOR 7 , —SO 2 R 7 , —SO 2 NR 6 R 7 , and —COOR 7 ;
each R 5 is independently selected from C 1-6 alkyl, C 1-4 fluoroalkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, —CN, —F, —Cl, —Br, —Z—NR 6 R 7 , —Z—C(═O)—NR 6 R 7 , —Z—NR 6 —C(═O)—R 7 , —Z—C(═O)—R 7 , —Z—C(═O)—H, —SR 7 , —SOR 7 , —SO 2 R 7 , —SO 2 NR 6 R 7 , and —COOR 7 ;
each R 6 and R 7 is independently selected from —H, C 1-8 alkyl, C 1-4 fluoroalkyl, C 1-4 hydroxyalkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-10 cycloalkyl, —Z-heterocyclyl, —Z-heteroaryl and —Z-aryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, heteroaryl and aryl are optionally substituted with one or more R 8 ; or R 6 and R 7 may, together with the N-atom to which they are attached, form a heterocyclic ring optionally substituted with one or more R 8 ;
each R 8 is independently selected from C 1-6 alkyl, C 1-4 fluoroalkyl, C 1-4 hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, —Z-heterocyclyl, —Z-heteroaryl, —Z-aryl, —Z—NR 10 R 11 , —Z—C(═O)—NR 10 R 11 , —Z—OR 9 , halogen, —CN, —Z—SR 9 , —Z—SOR 9 , —Z—SO 2 R 9 and —Z—COOR 9 , wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, heteroaryl and aryl are optionally substituted with one or more substituents independently selected from C 1-4 alkyl, C 1-4 fluoroalkyl, C 1-4 hydroxyalkyl, C 3-6 cycloalkyl, —Z-heterocyclyl, —Z-heteroaryl, —Z-aryl, —Z—NR 10 R 11 , —Z—C(═O)—NR 10 R 11 , —Z—OR 9 , halogen, —CN, —Z—SR 9 , —Z—SOR 9 , —Z—SO 2 R 9 and —Z—COOR 9 ; wherein the heterocyclyl is optionally substituted with one or more R 4 and wherein the heteroaryl and aryl are optionally substituted with one or more R 5 ;
each R 9 is independently selected from —H, C 1-8 alkyl, C 1-4 fluoroalkyl, C 1-4 hydroxyalkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-10 cycloalkyl, —Z-heterocyclyl, —Z-aryl, and —Z-heteroaryl, wherein the heterocyclyl is optionally substituted with one or more R 4 and wherein the heteroaryl and aryl are optionally substituted with one or more R 5 ;
each of R 10 and R 11 is independently selected from —H, C 1-6 alkyl, C 1-4 fluoroalkyl, C 1-4 hydroxyalkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-10 cycloalkyl, heterocyclyl, heteroaryl, and C 6-14 aryl, wherein the heterocyclyl is optionally substituted with one or more R 4 and wherein the heteroaryl and aryl are optionally substituted with one or more R 5 ; or R 10 and R 11 may, together with the N-atom to which they are attached, form a 5- to 7-membered heterocyclic ring optionally substituted with one or more R 4 ;
when Q is —CH═NR 12 , R 12 is selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, —Z-heterocyclyl, —Z-aryl, —Z-heteroaryl, —Z—NR 6 R 7 , —Z—C(═O)—NR 6 R 7 , —Z—NR 6 —C(═O)—R 7 , —Z—C(═O)—R 7 , —Z—OR 7 , —Z—SR 7 , —Z—SOR 7 , —Z—SO 2 R 7 and —Z—COOR 7 , wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, heteroaryl and aryl are optionally substituted with one or more R 3 ;
when Q is —CH 2 NHR 13 , R 13 is selected from —H, —C(O)R 7 , —C(O)C(O)R 7 , —C(O)C(O)OR 7 , C 1-8 alkyl, C 1-4 fluoroalkyl, C 1-4 hydroxyalkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-10 cycloalkyl, —Z—heterocyclyl, and —Z-monocyclic-heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, and heteroaryl are optionally substituted with one or more R 8 ; or R 13 is —CR 14 R 15 NR 6 R 7 , —CR 14 R 15 CN, or —CR 14 R 15 OR 7 , wherein each R 14 and R 15 is independently selected from —H, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-10 cycloalkyl, heterocyclyl, heteroaryl, and C 6-14 aryl,

Assignees

• Gilead Sciences Inc

Inventors

• Boesen Thomas
• Labelle Marc
• Yang Ying
• Saraswat Neerja
• Dudekula Dastagiri
• Cook Cyril John
• Vakiti Ramkrishna Reddy
• Zhang Rui
• Ullah Farman

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

• A61P35/00

  Antineoplastic agents · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61P27/06

  Antiglaucoma agents or miotics · CPC title