Modulators of histone methyltransferase, and methods of use thereof

Patent metadata

Field	Value
Publication number	US-9029343-B2
Application number	US-201113991321-A
Country	US
Kind code	B2
Filing date	Dec 5, 2011
Priority date	Dec 3, 2010
Publication date	May 12, 2015
Grant date	May 12, 2015

Abstract

Disclosed are compounds, pharmaceutical compositions containing the compounds, and the uses of the compounds and compositions as modulators of histone methyltransferases, and for treating diseases influenced by modulation of histone methyltransferase activity.

First claim

We claim:

1. A compound of formula I:

or a pharmaceutically acceptable salt, hydrate, enantiomer or stereoisomer thereof, wherein independently for each occurrence,
X is

R 1 is hydrogen, alkyl, cycloalkyl, alkylcycloalkyl, alkylaryl, haloalkyl, formyl, heterocyclyl, heterocyclylalkyl,

 or (C 2 -C 4 )alkyl substituted with

R 10 is hydrogen or alkyl;
R 11a is hydrogen, alkyl, or alkyl-cycloalkyl;
R 11b is hydrogen or alkyl; or taken together with R 11a and the nitrogen to which it is attached forms a 4- to 8-membered heterocyclyl comprising 0 or 1 additional heteroatoms;
R 13 is hydrogen, alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl or silyl;
R 14 is hydrogen, alkyl, aryl, heteroaryl, aralkyl or heteroaralkyl;
R 15 is alkyl, cycloalkyl or cycloalkylalkyl;
R 20 is hydrogen, alkyl, cycloalkyl or cycloalkylalkyl;
A is

R 2 is

Y is —NH—, —N(alkyl)-, —O—, or —CR 6 2 —;
R 22a is aryl, heteroaryl, aralkyl, heteroaralkyl, fused bicyclyl, biaryl, aryloxyaryl, heteroaryloxyaryl, aryloxyheteroaryl or heteroaryloxyheteroaryl, each of which is unsubstituted or substituted;
R 22b is hydrogen or alkyl;
R 24 is hydrogen or alkyl;
R 25a , R 25b , R 25c , R 25d are each independently -M 2 -T 2 , in which M 2 is a bond, SO 2 , SO, S, CO, CO 2 , O, O—C 1 -C 4 alkyl linker, C 1 -C 4 alkyl linker, NH, or N(R t ), R t being C 1 -C 6 alkyl, and T 2 is H, halo, or R S4 , R S4 being C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 8-membered heterocycloalkyl, or 5 to 10-membered heteroaryl, and each of O—C 1 -C 4 alkyl linker, C 1 -C 4 alkyl linker, R t , and R S4 being optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, carboxyl, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxyl, amino, mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 6-membered heterocycloalkyl, and 5 to 6-membered heteroaryl;
R 3 is hydrogen, halogen, hydroxy, alkyloxy, aralkyloxy, alkylcarbonyloxy or silyloxy;
R 4 is hydrogen, halogen, hydroxy, alkyloxy, aralkyloxy, alkylcarbonyloxy or silyloxy;
R 41 is hydrogen, alkyl or alkynyl;
Z is hydrogen or

R 5a is hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, biaryl, alkenylalkyl, alkynylalkyl, carbocyclylalkyl, heterocyclylalkyl, aralkyl, heteroaralkyl, alkylcarbonylaminoalkyl, arylcarbonylaminoalkyl, aralkylcarbonylaminoalkyl, arylsulfonylaminoalkyl, alkylthioalkyl, aralkylthioalkyl or heteroaralkylthioalkyl; or alkyl substituted with 1, 2 or 3 substituents independently selected from the group consisting of hydroxy, halo, carboxy, alkyoxy, aryloxy, aralkyloxy, nitro, amino, amido, aryl and heteroaryl;
R 5b is hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, biaryl, alkenylalkyl, alkynylalkyl, carbocyclylalkyl, heterocyclylalkyl, aralkyl, heteroaralkyl, alkylcarbonylaminoalkyl, arylcarbonylaminoalkyl, aralkylcarbonylaminoalkyl, arylsulfonylaminoalkyl, alkylthioalkyl, aralkylthioalkyl or heteroaralkylthioalkyl; or alkyl substituted with 1, 2 or 3 substituents independently selected from the group consisting of hydroxy, halo, carboxy, alkyoxy, aryloxy, aralkyloxy, nitro, amino, amido, aryl and heteroaryl; or taken together with R 5a and the nitrogen to which it is attached forms a 4- to 8-membered heterocyclyl comprising 0 or 1 additional heteroatoms;
each R 6 independently is hydrogen, alkyl or halo; or two geminal R 6 taken together are ethylene, propylene or butylene;
R 7a is hydrogen, lower alkyl, lower haloalkyl, cyano, halo, lower alkoxy, or C3-C5 cycloalkyl, optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of cyano, lower alkoxy and halo; and
R 7b is hydrogen, lower alkyl, lower haloalkyl, cyano, halo, lower alkoxy, or C3-C5 cycloalkyl, optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of cyano, lower alkoxy and halo.

2. The compound of claim 1 , wherein X is

3. The compound of claim 1 , wherein X is

4. A compound of formula I:

or a pharmaceutically acceptable salt, hydrate, enantiomer or stereoisomer thereof, wherein independently for each occurrence,
X is

R 1 is hydrogen, alkyl, cycloalkyl, alkylcycloalkyl, alkylaryl, haloalkyl, formyl, heterocyclyl, heterocyclylalkyl,

or (C 1 -C 4 )alkyl substituted with

except that when X is

R 1 is not

R 10 is hydrogen or alkyl;
R 11a is hydrogen, alkyl, or alkyl-cycloalkyl;
R 11b is hydrogen or alkyl; or taken together with R 11a and the nitrogen to which it is attached forms a 4- to 8-membered heterocyclyl comprising 0 or 1 additional heteroatoms;
R 13 is hydrogen, alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl or silyl;
R 14 is hydrogen, alkyl, aryl, heteroaryl, aralkyl or heteroaralkyl;
R 15 is alkyl, cycloalkyl or cycloalkylalkyl;
R 20 is hydrogen, alkyl, cycloalkyl or cycloalkylalkyl;
A is

R 2 is

Y is —NH—, —N(alkyl)-, —O—, or —CR 6 2 —;
R 24 is hydrogen or alkyl;
R 25a , R 25b , R 25c , R 25d are each independently -M 2 -T 2 , in which M 2 is a bond, SO 2 , SO, S, CO, CO 2 , O, O—C 1 -C 4 alkyl linker, C 1 -C 4 alkyl linker, NH, or N(R t ), R t being C 1 -C 6 alkyl, and T 2 is H, halo, or R S4 , R S4 being C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 8-membered heterocycloalkyl, or 5 to 10-membered heteroaryl, and each of O—C 1 -C 4 alkyl linker, C 1 -C 4 alkyl linker, R t , and R S4 being optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, carboxyl, cyano, C 1 -C 6 alkyl, C 2 -C 6

Assignees

• Chesworth Richard
• Kuntz Kevin W
• Olhava Edward J
• Patane Michael A
• Epizyme Inc

Inventors

• Chesworth Richard
• Kuntz Kevin W
• Olhava Edward J
• Patane Michael A

Classifications

• C07H19/167

  with ribosyl as the saccharide radical · CPC title

• C07H19/16 Primary

  Purine radicals · CPC title

• C07D473/34

  attached in position 6, e.g. adenine · CPC title

• A61P35/00

  Antineoplastic agents · CPC title