Inhibitors of histone demethylases

Patent metadata

Field	Value
Publication number	US-10189787-B2
Application number	US-201414472059-A
Country	US
Kind code	B2
Filing date	Aug 28, 2014
Priority date	Oct 2, 2012
Publication date	Jan 29, 2019
Grant date	Jan 29, 2019

Abstract

The present application discloses compounds capable of modulating the activity of histone demethylases (HDMEs), which are useful for prevention and/or treatment of diseases in which genomic dysregulation is involved in the pathogenesis, such as e.g. cancer. The present application also discloses pharmaceutical compositions comprising said compounds and the use of such compounds as a medicament. The compounds take the form

First claim

The invention claimed is:

1. A compound of Formula (I)

wherein
A is —CH 2 C(O)—;
Y is —NR 6 R 7 ; p 1 R 1 is —H;
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, —N(R 10 ) 2 , carbamoyl, and —OH;
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, carbamoyl and —OH;
each of 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 alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, heteroaryl and aryl may optionally be substituted with one or more independently selected 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 alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, heteroaryl and aryl may optionally be substituted with one or more 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 any heterocyclyl may be further substituted with one or more R 4 as defined above, and wherein any heteroaryl and any aryl may be further substituted with one or more R 5 as defined above;
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 any heterocyclyl may be substituted with one or more R 4 as defined above, and wherein any heteroaryl and any aryl may be substituted with one or more R 5 as defined above; and
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 aryl, wherein any heterocyclyl may be substituted with one or more R 4 as defined above, and wherein any heteroaryl and any aryl may be substituted with one or more R 5 as defined above;
or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein Y is

wherein n is from 1 to 3.

3. The compound of claim 1 , wherein Y is

wherein n is from 1 to 3 and each m independently is from 0 to 2.

4. The compound of claim 1 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

5. The pharmaceutically acceptable salt of the compound of claim 1 , wherein the pharmaceutically acceptable salt is selected from succinic, maleic, acetic, fumaric, citric, tartaric, benzoic, trifluoroacetic, malic, lactic, formic, propionic, glycolic, gluconic, camphorsulfuric, isothionic, mucic, gentisic, isonicotinic, saccharic, glucuronic, furoic, glutamic, ascorbic, anthranilic, salicylic, phenylacetic, mandelic, embonic (pamoic), ethanesulfonic, pantothenic, stearic, sulfinilic, alginic, galacturonic, benzenesulfonic, p-toluenesulfonic, oxalic, methanesulfonic and naphthalenesulfonic acid salt.

6. A pharmaceutical composition comprising a compound of claim 1 and one or more pharmaceutically acceptable excipients, diluents or carriers.

7. The pharmaceutical composition according to claim 6 , further comprising one or more active substances.

8. The pharmaceutically acceptable salt of claim 5 , wherein the pharmaceutically acceptable salt is the oxalic acid salt.

Assignees

• Gilead Sciences Inc

Inventors

• Labelle Marc
• Boesen Thomas
• Mehrotra Mukund
• Khan Qasim
• Ullah Farman

Classifications

• A61P43/00

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

• A61P35/00

  Antineoplastic agents · CPC title

• C07D401/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• A61K31/4545

  containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine · CPC title

• A61K31/44

  Non condensed pyridines; Hydrogenated derivatives thereof · CPC title