Salicylate inhibitors of MELK and methods of use
Provided herein are small molecule inhibitors of maternal embryonic leucine zipper kinase (MELK) having the structure of formula (I), wherein X and R 1 -R 3 are defined in the specification. The compounds are useful for treating cancer and other conditions or diseases associated with aberrant MELK expression. Also provided herein are pharmaceutical compositions comprising a compound of formula (I) and a pharmaceutically acceptable carrier. The invention also provides methods of treating cancers associated with over-expression of MELK.
1. A compound represented by formula (I) or a pharmaceutically acceptable salt thereof:
wherein:
R 1 represents substituted or unsubstituted pyrrolyl, pyrazolyl, indazolyl, indolyl, isoquinolinyl, pyrimidinyl, isoxazolyl, oxazolyl, pyridazinyl, pyrazinyl, benzimidazolyl, benzimidazolonyl, benzothiazolonyl, quinolinyl, quinzolinyl, or quinoxalinyl;
R 2 represents substituted or unsubstituted aryl, heteroaryl, aralkyl, or heteroaralkyl;
R 3 represents substituted or unsubstituted alkyl, cycloalkyl, (cycloalkyl)alkyl, aralkyl, heteroarylalkyl, heterocycloalkyl, or (heterocycloalkyl)alkyl, wherein the substituted or unsubstituted alkyl comprises a tertiary or quaternary carbon; and
X represents NH;
provided that when R 2 represents substituted or unsubstituted aryl, then R 3 is not aralkyl.
2. The compound of claim 1 , wherein R 3 represents substituted or unsubstituted cycloalkyl, (cycloalkyl)alkyl, aralkyl, heteroarylalkyl, heterocycloalkyl, or (heterocycloalkyl)alkyl.
3. The compound of claim 1 , wherein R 3 is isopropyl, benzyl, cyclohexyl, cyclohexylmethyl, (3-pyridinyl)methyl, or 2,3-dihydro-1H-inden-2-yl.
4. The compound of claim 1 , wherein R 1 is optionally substituted by one or more substituents selected from (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkyl, halo, —OH, (C 1 -C 6 )haloalkoxyl, —SH, —S((C 1 -C 6 )alkyl), (C 1 -C 6 )hydroxyalkyl, and —CF 3 .
5. The compound of claim 1 , wherein R 2 represents substituted or unsubstituted aryl or heteroaryl.
6. The compound of claim 1 , wherein R 2 represents substituted or unsubstituted 2-pyridinyl, 3-pyridinyl, or 4-pyridinyl.
7. The compound of claim 1 , wherein R 2 represents
wherein m and n are integers, each independently selected from 0 and 1.
8. The compound of claim 1 , wherein R 2 represents substituted or unsubstituted heteroaryl, aralkyl, or heteroaralkyl.
9. The compound of claim 1 , wherein R 3 represents substituted or unsubstituted cycloalkyl, (cycloalkyl)alkyl, heteroarylalkyl, heterocycloalkyl, or (heterocycloalkyl)alkyl.
10. The compound of claim 1 , wherein R 2 represents substituted or unsubstituted heteroaryl, aralkyl, or heteroaralkyl; and R 3 represents substituted or unsubstituted cycloalkyl, (cycloalkyl)alkyl, heteroarylalkyl, heterocycloalkyl, or (heterocycloalkyl)alkyl.
11. The compound of claim 1 , represented by any of the following structural formulae:
12. A compound, or a pharmaceutically acceptable salt thereof, represented by any of the following structural formulae:
or
13. A pharmaceutical composition comprising a compound of claim 1 , and a pharmaceutically acceptable carrier.