Tricyclic kinase inhibitors of MELK and methods of use
Provided herein are tricyclic small molecule inhibitors of maternal embryonic leucine zipper kinase (MELK). 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 tricyclic compound of the invention 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 (IV) or a pharmaceutically acceptable salt thereof:
wherein:
Z represents O, S, NH, or N(alkyl);
—X—Y— represents —CR 3 ═CR 4 — or —CHR 3 —CHR 4 —;
R 1 , independently for each occurrence, represents aryl, substituted by at least three occurrences of substituent R x ;
R x , independently for each occurrence, is selected from the group consisting of halo, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkenyl, (C 1 -C 6 )alkynyl, (C 1 -C 6 )haloalkyl, aryl, —OH, (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )alkoxyl, (C 1 -C 6 )haloalkoxyl, —SH, —S((C 1 -C 6 )alkyl), (C 1 -C 6 )hydroxyalkyl, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, —CN, —CF 3 , —NO 2 , —NH 2 , —NH(R 6 ), —N(R 6 ) 2 , (C 1 -C 6 )alkyl substituted by —N(R 6 ) 2 , —C(O)NH 2 , —C(O)NH(R 6 ), —C(O)N(R 6 ) 2 , —N(H)C(O)(R 6 ), —N(R 6 )C(O)(R 6 ), —S(O) 2 NH 2 , —S(O) 2 NH(R 6 ), —S(O) 2 N(R 6 ) 2 , —N(H)S(O) 2 (R 6 ), and —N(R 6 )S(O) 2 (R 6 );
wherein at least one occurrence of R x is OH;
R 2 represents aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, or heterocycloalkylalkyl, optionally substituted by one or more occurrences of substituent R 5 ;
R 3 and R 4 are each independently selected from the group consisting of H, alkyl, aralkyl, and aryl;
R 5 , independently for each occurrence, is selected from the group consisting of substituted or unsubstituted alkyl, alkenyl, alkynyl, halo, haloalkyl, alkoxyl, amino, aminoalkyl, hydroxy, hydroxyalkyl, aryl, aryloxy, arylalkoxy, heteroaryl, heteroaryloxy, heteroarylalkoxy, cyano, nitro, cycloalkyl, and heterocycloalkyl;
R 6 , independently for each occurrence, is selected from the group consisting of (C 1 -C 6 )alkyl, aryl, and aryl(C 1 -C 6 )alkyl, or, for —N(R 6 ) 2 , —C(O)N(R 6 ) 2 , and —S(O) 2 N(R 6 ) 2 , or two occurrences of R 6 , together with the nitrogen atom to which they are attached can be taken together to form an optionally substituted ring;
W represents N, CH, or CR 1 ; and
m is an integer from 1-3.
2. The compound of claim 1 , wherein —X—Y— is —CH═CH—.
3. The compound of claim 1 , represented by formula (IVa):
4. The compound of claim 1 , wherein R 2 is substituted by one or more occurrences of substituent R 5 , wherein at least one occurrence of R 5 is amino or aminoalkyl.
5. The compound of claim 1 , represented by formula (V),
wherein:
A represents 1,4-cyclohexanediyl, 1,3-cyclohexanediyl, 1,2-cyclohexanediyl, 1,4-phenylene, 1,4-cycloheptanediyl, 1,3-cycloheptanediyl, 1,3-cyclooctanediyl, 1,4-cyclooctanediyl, 1,5-cyclooctanediyl;
B represents (C 1 -C 6 )alkylene or a bond; and
R 9 and R 10 are each independently selected from the group consisting of H, (C 1 -C 6 )alkyl, aryl, and aryl(C 1 -C 6 )alkyl, or, R 9 and R 10 , together with the nitrogen atom to which they are attached can be taken together to form an optionally substituted heterocyclic ring.
6. The compound of claim 1 , represented by any one of the following formulae:
7. A method of treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1 .
8. The method of claim 7 , wherein the cancer is associated with overexpression of MELK.
9. A method of inhibiting maternal embryonic leucine zipper kinase (MELK), comprising contacting MELK with an amount of a compound of claim 1 effective to inhibit MELK.
10. A method for treating or preventing a condition associated with aberrant maternal embryonic leucine zipper kinase (MELK), comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1 .
11. A method for decreasing the rate of mitosis in a cancer cell, comprising contacting a cancer cell with an amount of a compound of claim 1 effective to decrease the rate of mitosis of the cancer cell.
12. A pharmaceutical composition comprising a compound of claim 1 , and a pharmaceutically acceptable carrier.
13. The compound of claim 1 , wherein Z is O.
14. The compound of claim 1 , wherein W is N.
15. The compound of claim 1 , wherein W is CH.
16. The compound of claim 1 , wherein each occurrence of R x is independently selected from the group consisting of (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 .
17. The compound of claim 1 , wherein each occurrence of R x is independently selected from the group consisting of (C 1 -C 6 )haloalkyl, halo, —OH, (C 1 -C 6 )hydroxyalkyl, and —CF 3 .
18. The compound of claim 1 , wherein R 1 represents
19. The compound of claim 1 , wherein m is 1.
20. The compound of claim 3 , wherein R 2 represents aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, or heterocycloalkylalkyl, optionally substituted by one or more occurrences of substituent R 5 ;
wherein R 5 , independently for each occurrence, is selected from the group consisting of substituted or unsubstituted alkyl, halo, haloalkyl, amino, aminoalkyl, heteroaryl, heteroaryloxy, and heterocycloalkyl.