7-deazapurine modulators of histone methyltransferase, and methods of use thereof

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

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 22a is aryl, heteroaryl, aralkyl, heteroaralkyl, fused bicyclyl, biaryl, aryloxyaryl, heteroaryloxyaryl, aryloxyheteroaryl or heteroaryloxyheteroaryl;

R 22b is hydrogen or alkyl;

R 24 is hydrogen or alkyl;

R 25a , R 25b , R 25c , and R 25d independently are -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, haloalkyl, 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, haloalkyl, 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 C 3 -C 5 cycloalkyl, optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of cyano, lower alkoxy and halo;

R 7b is hydrogen, lower alkyl, lower haloalkyl, cyano, halo, lower alkoxy, or C 3 -C 5 cycloalkyl, optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of cyano, lower alkoxy and halo; and

R 7c is hydrogen, lower alkyl, lower haloalkyl, cyano, halo, lower alkoxy, or C 3 -C 5 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 R 2 is

4. The compound of claim 3 , wherein Y is —NH—, —N(alkyl)-, —O—, or —CH 2 —.

5. The compound of claim 3 , wherein R 22a is aryl or aralkyl.

6. The compound of claim 3 , wherein R 22a is substituted phenyl or substituted benzyl.

7. The compound of claim 3 , wherein R 22a is

8. The compound of claim 3 , wherein R 22b is hydrogen, or methyl.

9. The compound of claim 3 , wherein R 1 is hydrogen, or alkyl selected from a group consisting of —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CH 2 CH(CH 3 ) 2 and —CH 2 CH 2 CH(CH 3 ) 2 .

10. The compound of claim 1 , wherein A is

11. The compound of claim 1 , wherein R 3 is hydroxyl or hydrogen.

12. The compound of claim 1 , wherein R 4 is hydroxyl or hydrogen.

13. The compound of claim 1 , wherein R 41 is hydrogen or methyl.

14. The compound of claim 1 , wherein Z is hydrogen or

wherein R 5a and R 5b are hydrogen.

15. The compound of claim 1 , wherein R 7a is hydrogen or lower alkyl, R 7b is hydrogen or lower alkyl, and R 7c is hydrogen or lower alkyl.

16. A compound, or a pharmaceutically acceptable salt, hydrate, enantiomer or stereoisomer thereof, is selected from the group consisting of

17. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt, hydrate, enantiomer or stereoisomer thereof; and a pharmaceutically acceptable diluent or carrier.

18. A kit or packaged pharmaceutical comprising a compound of claim 1 , and instructions for use thereof.

19. A method of treating or preventing a disorder in which DOT1-mediated protein methylation plays a part, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1 .

20. The method of claim 19 , wherein the disorder is cancer or a neurological disorder.