Small molecules for the modulation of MCL-1 and methods of modulating cell death, cell division, cell differentiation and methods of treating disorders
This invention relates to compounds which selectively bind to the survival protein MCL-1 with high affinity and selectivity, pharmaceutical compositions containing such compounds and the use of those compounds or compositions for modulating MCL-1 activity and for treating hyperproliferative disorders, angiogenesis disorders, cell cycle regulation disorders, autophagy regulation disorders, inflammatory disorders, and/or infectious disorders and/or for enhancing cellular engraftment and/or wound repair, as a sole agent or in combination with other active ingredients.
1. A pharmaceutical composition comprising:
a pharmaceutically acceptable diluent or carrier; and
a compound of formula (J) or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof:
wherein
R 22 is substituted or unsubstituted aryl, wherein R 22 , when substituted, is substituted by hydroxyl or halogen;
R 23 is C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 1 -C 6 alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl, wherein R 23 , when substituted, is substituted by Z;
R 24 is C 1 -C 8 alkyl, C 2 -C 8 alkynyl, C 1 -C 6 alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl, wherein R 24 , when substituted, is substituted by Z; and
each Z, independently, is halogen, hydroxyl, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 1 -C 6 alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl;
provided that the compound is not
2. The composition of claim 1 , wherein R 22 is hydroxylphenyl, dihydroxylphenyl, trihydroxylphenyl or iodophenyl.
3. The composition of claim 1 , wherein R 23 is C 1 -C 8 alkyl, aryl, heteroaryl or heterocycloalkyl, in which each of C 1 -C 8 alkyl, aryl, heteroaryl and heterocycloalkyl is unsubstituted or substituted by Z.
4. The composition of claim 3 , wherein R 23 is C 1 -C 8 alkyl; unsubstituted heteroaryl; benzoxazinonyl; or aryl substituted by halogen, C 1 -C 8 alkyl or C 1 -C 6 alkoxy.
5. The composition of claim 4 , wherein R 23 is methyl, thienyl, furyl, fluorophenyl, dichlorophenyl, dimethylphenyl, difluoromethoxyphenyl, or benzoxazinonyl.
6. The composition of claim 1 , wherein R 24 is C 1 -C 8 alkyl, aryl, or cycloalkyl, in which each of C 1 -C 8 alkyl, aryl, and cycloalkyl is unsubstituted or substituted by Z.
7. The composition of claim 6 , wherein R 24 is C 1 -C 8 alkyl, C 1 -C 8 alkyl substituted by phenyl, aryl substituted by halogen, or cycloalkyl.
8. The composition of claim 7 , wherein R 24 is methyl, ethyl, isopropyl, benzyl, cyclohexyl or fluorophenyl.
9. A pharmaceutical composition, comprising:
or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof; and
a pharmaceutically acceptable diluent or carrier.
10. A method for modulating apoptotic cell death in a cell, comprising contacting the cell with the composition of claim 9 , thereby regulating apoptotic cell death in said cell.
11. A method for modulating metabolism in a cell, comprising contacting the cell with the composition of claim 9 , thereby regulating energy production and consumption to effect cell viability in said cell.
12. A method of treating the hyperproliferative disorder in a mammal, comprising administering to a mammal in need thereof, a therapeutically effective amount of the composition of claim 9 .
13. The method of claim 12 , wherein the hyperproliferative disorder is cancer.
14. A method for modulating apoptotic cell death in a cell, comprising contacting the cell with the composition of claim 1 , thereby regulating apoptotic cell death in said cell.
15. A method for modulating metabolism in a cell, comprising contacting the cell with the composition of claim 1 , thereby regulating energy production and consumption to effect cell viability in said cell.
16. A method of treating a hyperproliferative disorder in a mammal, comprising administering to the mammal in need thereof, a therapeutically effective amount of the composition of claim 1 .
17. The method of claim 16 , wherein the hyperproliferative disorder is cancer.