Inhibitors of histone demethylases

Patent metadata

Field	Value
Publication number	US-9650339-B2
Application number	US-201414381556-A
Country	US
Kind code	B2
Filing date	Feb 26, 2014
Priority date	Feb 27, 2013
Publication date	May 16, 2017
Grant date	May 16, 2017

Abstract

Compounds of the form

In which Q is selected from —CH═NR 12 , —W, —CH 2 NHR 13 , —CH═O and —CH(OR 17 ) 2 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 and formulations and methods of use of such compounds.

First claim

The invention claimed is:

1. A compound of the Formula (I)

wherein
Q is selected from —CH═NR 12 , —W, —CH 2 NHR 13 , and —CH═O;
A is selected from —CH 2 C(O)—, C 1-8 alkylene, and C 2-8 alkenylene, which C 1-8 alkylene and C 2-8 alkenylene may optionally be substituted with one or more R 3 ;
Y is selected from —NR 6 R 7 , —OR 7 , C 1-8 alkyl, C 3-10 cycloalkyl, heterocyclyl, and aryl, which C 1-8 alkyl, C 3-10 cycloalkyl, heterocyclyl, and aryl may optionally be substituted with one or more R 3 ;
R 1 is selected from —H and C 1-8 alkyl;
each R 3 is independently selected from C 1-6 alkyl, C 1-4 hydroxyalkyl, C 3-10 cycloalkyl, —Z-heterocyclyl, —Z-aryl, NR 6 R 7 , —Z—OR 7 , halogen, and —Z—SR 7 , wherein any aryl may be substituted with one or more R 5 ;
each Z is independently selected from a single bond and C 1-4 alkylene;
each R 5 is independently selected from C 1-6 alkyl and C 1-4 alkoxy;
each of R 6 and R 7 is independently selected from —H, C 1-8 alkyl, C 1-4 fluoroalkyl, C 1-4 perfluoroalkyl, C 2-8 alkynyl, C 3-10 cycloalkyl, —Z-heterocyclyl, and —Z-aryl, which C 1-8 alkyl, heterocyclyl, and aryl may optionally be substituted with one or more independently selected R 8 ; or, alternatively, R 6 and R 7 may together with the N-atom to which they are attached form an N-heterocyclic ring optionally substituted with one or more independently selected R 8 ;
each R 8 is independently selected from C 1-6 alkyl, C 3-10 cycloalkyl, —Z-heterocyclyl, —Z-aryl, —Z—NR 10 R 11 , halogen, and —CN, which C 3-10 cycloalkyl, heterocyclyl, and aryl may optionally be substituted with one or more selected from C 1-4 alkyl, —Z—NR 10 R 11 , —Z—OR 9 , halogen, and —Z—SOR 9 ;
each R 9 is independently selected C 1-8 alkyl; and
each of R 10 and R 11 is independently selected C 1-6 alkyl, or, alternatively, R 10 and R 11 may together with the N-atom to which they are attached form an N-heterocyclic ring;
with the proviso that Y is not H when A is —CH 2 —;
when Q is —CH═NR 12 , R 12 is selected from C 1-10 alkyl, C 3-10 cycloalkyl, —Z-aryl, —Z—NR 6 R 7 , and —Z—OR 7 , which C 1-10 alkyl, C 3-10 cycloalkyl, and aryl may optionally be substituted with one or more R 3 ;
when Q is —CH 2 NHR 13 , R 13 is selected from hydrogen, —C(O)R 7 , —C(O)C(O)OR 7 , C 1-8 alkyl, and C 3-10 cycloalkyl, which C 1-8 alkyl may optionally be substituted with one or more independently selected R 8 , with the proviso that C 1-8 alkyl is not substituted with —Z-aryl;
when Q is W, W is selected from an 1,3-diaza-C 5-7 -cycloalk-2-yl group which is N-substituted with R 16 and optionally further substituted with one or more R 3 ; a 1,3-thiaza-C 5-7 -cycloalk-2-yl group which is N-substituted with R 16 and optionally further substituted with one or more R 3 ; and an 1,3-oxaza-C 5-7 -cycloalk-2-yl group which is N-substituted with R 16 and optionally further substituted with one or more R 3 wherein in all three instances two R 3 's on the same carbon atom may together form a spiro group;
R 16 is selected from hydrogen and —C(O)R 7 ; and
each aryl is phenyl and each heterocyclyl comprises 1 or 2 nitrogen atoms and 4 or 5 total ring atoms;
or an isomer or a mixture of isomers thereof, or a pharmaceutically acceptable salt, or solvate thereof.

2. A compound according to claim 1 , wherein A is selected from —CHR 2 C(O)— and C 1-8 alkylene.

3. A compound according to claim 1 , wherein Y is —NR 6 R 7 .

4. A compound according to claim 3 , wherein A is —CHR 2 C(O)—.

5. A compound according to claim 4 , wherein A is —CH 2 C(O)—.

6. A compound according to claim 2 , wherein Y is

wherein n is from 1 to 3 and each of R 6 , R 10 and R 11 independently is as defined in claim 1 .

7. A compound according to claim 6 , wherein Y is

wherein n is from 1 to 3 and each of R 10 and R 11 independently is as defined in claim 1 .

8. A compound according to claim 6 , wherein Y is

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

9. A compound according to claim 1 , wherein Y is selected from heterocyclyl and aryl, each of which may be optionally substituted with one or more R 3 .

10. A compound according to claim 1 , wherein R 13 is H.

11. A compound according to claim 1 , wherein Q is of the formula

wherein R 18 and R 19 are hydrogen, or together form a 1,3-diaza-C 5-7 -cycloalk-2-yl group which is N-substituted with R 16 and optionally further substituted with one or more R 3 ; a 1,3-thiaza-C 5-7 -cycloalk-2-yl group which is N-substituted with R 16 and optionally further substituted with one or more R 3 ; an 1,3-oxaza-C 5-7 -cycloalk-2-yl group which is N-substituted with R 16 and optionally further substituted with one or more R 3 , wherein in all three instances two R 3 's on the same carbon atom may together form a spiro group.

12. A compound selected from
N-{[2-({[4-(diethylamino)butyl]amino}methyl)pyridin-4-yl]methyl}-2,2,2-trifluoroacetamide;
[2-({[4-(dimethylamino)butyl]amino}methyl)pyridin-4-yl]methanamine;
[2-({[3-(dimethylamino)propyl]amino}methyl)pyridin-4-yl]methanamine;
2-({[4-(aminomethyl)pyridin-2-yl]methyl}amino)-N-[2-(dimethylamino)ethyl]-N-ethylacetamide;
[2-({[4-(diethylamino)butyl]amino}methyl)pyridin-4-yl]methanamine;
N-[4-(diethylamino)butyl]-2,2,2-trifluoro-N-({4-[(trifluoroacetamido)methyl]pyridin-2-yl}methyl)acetamide;
[2-({[4-(azetidin-1-yl)butyl]amino}methyl)pyridin-4-yl]methanamine;
[2-({[5-(dimethylamino)pentyl]amino}methyl)pyridin-4-yl]methanamine;
2-({[4-(aminomethyl)pyridin-2-yl]methyl}amino)-N-{1-[(2-methoxyphenyl)methyl]piperidin-4-yl}acetamide;
N-{[2-({[4-(dimethylamino)butyl]amino}methyl)pyridin-4-yl]methyl}cyclopropanamine;
N-{[2-({[3-(2-methylpiperidin-1-yl)propyl]amino}methyl)pyridin-4-yl]methyl}cyclopropanamine;
N-({2-[(propylamino)methyl]pyridin-4-yl}methyl)cyclopropanamine;
2-{[(4-{[(cyanomethyl)amino]methyl}pyridin-2-yl)methyl]amino}-N,N-dimethylacetamide;
2-{[(4-{[(2-fluoroethyl)amino]methyl}pyridin-2-yl)methyl]amino}-N,N-dimethylacetamide;
2-({[4-({[2-(dimethylamino)ethyl]amino}methyl)pyridin-2-yl]methyl}amino)-N,N-dimethylacetamide;
{[(2S)-1-benzylpyrrolidin-2-yl]methyl}[(4-{[(cyclopropylmethyl)amino]methyl}pyridin-2-yl)methyl]amine;
benzyl(methyl) {3-[({4-[(methylamino)methyl]pyridin-2-yl}methyl)amino]propyl}amine;
benzyl[3-({[4-({[2-(dimethylamino)ethyl]amino}methyl)pyridin-2-yl]methyl}amino)propyl]methylamine;
benzyl(3-{[(4-{[(2-methoxyethyl)amino]methyl}pyridin-2-yl)methyl]amino}propyl)methylamine;
2-[({4-[(cyclopropylamino)methyl]pyridin-2-yl}methyl)amino]-N-{1-[(2-methoxyphenyl)methyl]piperidin-4-yl}acetamide;
2-cyclopropyl-2-({[2-({[2-(dimethylamino)ethyl]amino}methyl)pyridin-4-yl]methyl}amino)acetonitrile;
2-({[2-({[3-(dimethylamino)propyl]amino}methyl)pyridin-4-yl]methyl}amino)propanenitrile;
2-[({2-[({4-[benzyl(cyclopropyl)amino]butyl}amino)methyl]pyridin-4-yl}methyl)amino]acetonitrile;
2-[2-({[3-(dimethylamino)propyl]amino}methyl)pyridin-4-yl]-2-(methylamino)acetonitrile;

Assignees

• Gilead Sciences Inc

Inventors

• Labelle Marc
• Boesen Thomas
• Khan Qasim
• Vakiti Ramkrishna Reddy
• Sharma Utpal
• Yang Ying
• Mehrotra Mukund
• Saraswat Neerja
• Ullah Farman

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61P43/00

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

• C07D213/48

  Aldehydo radicals · CPC title

• A61K31/454

  containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone · CPC title