Mitotic kinesin inhibitors
The present invention relates to compounds that are useful for treating cellular proliferative diseases, for treating disorders mediated, at least in part, by KSP, and for inhibiting KSP. The invention also related to pharmaceutical compositions comprising such compounds, methods of treating cancer by the administration of such compositions, and processes for the preparation of the compounds. Compounds of the invention have the following formula:
1. A compound of the formula:
wherein:
m is 0, 1, 2, or 3;
p is 1,2,3 or 4;
R 3 is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, and heterocyclyl;
R 5 is selected from the group consisting of hydrogen, alkyl, aryl, heterocyclyl, alkoxycarbonyl, aryloxycarbonyl, heterocyclyloxycarbonyl, aminocarbonyl, alkylcarbonyl, arylcarbonyl, heterocyclylcarbonyl, alkylsulfonyl, arylsulfonyl, and heterocyclylsulfonyl
R 8 is selected from the group consisting of unsubstituted alkyl, substituted alkyl, aryl, and heterocyclyl;
R 10 and R 11 are independently selected from the group consisting of hydrogen and C 1 to C 4 alkyl;
wherein, said compound inhibits kinesin spindle protein with an IC 50 value of less than or equal to 25 μM;
or pharmaceutically acceptable salts or stereoisomers thereof.
2. The compound of claim 1 wherein when R 3 is alkyl, then alkyl is selected from the group consisting of —CH(CH 3 ) 2 , —CH(CH 3 )(CH 2 CH 3 ), —CH(CH 2 CH 3 ) 2 , —C(CH 3 ) 3 , —C(CH 2 CH 3 ) 3 , —CH 2 CH(CH 3 ) 2 , —CH 2 CH(CH 3 )(CH 2 CH 3 ), —CH 2 CH(CH 2 CH 3 ) 2 , —CH 2 C(CH 3 ) 3 , —CH 2 C(CH 2 CH 3 ) 3 , —CH(CH 3 )CH(CH 3 )(CH 2 CH 3 ), —CH 2 CH 2 CH(CH 3 ) 2 , —CH 2 CH 2 CH(CH 3 )(CH 2 CH 3 ), —CH 2 CH 2 CH(CH 2 CH 3 ) 2 , —CH 2 CH 2 C(CH 3 ) 3 , —CH 2 CH 2 C(CH 2 CH 3 ), —CH(CH 3 )CH 2 CH(CH 3 ) 2 , —CH(CH 3 )CH(CH 3 )CH(CH 3 ) 2 , and —CH(CH 2 CH 3 )CH(CH 3 )CH(CH 3 )(CH 2 CH 3 ).
3. The compound of claim 1 , wherein R 10 and R 11 are hydrogen.
4. The compound of claim 1 , wherein one of R 10 or R 11 is hydrogen and other is alkyl.
5. The compound of claim 1 , wherein one of R 10 or R 11 is hydrogen and other is ethyl or methyl.
6. The compound of claim 1 , wherein the IC 50 value of the compound is less than or equal to 10 μM.
7. The compound of claim 1 , wherein the IC 50 value of the compound is less than or equal to 1 μM.
8. The compound of claim 1 , wherein R 3 is selected from the group consisting of ethyl, isopropyl, cyclopropyl, phenyl, thienyl, and pyridinyl.
9. The compound of claim 8 , wherein R 3 is ethyl or isopropyl.
10. The compound of claim 1 , wherein R 5 is arylcarbonyl or heterocyclylcarbonyl.
11. The compound of claim 10 , wherein R 5 is selected from the group consisting of benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-methylbenzoyl, 4-trifluoromethylbenzoyl, and 3-fluoro-4-methylbenzoyl.
12. The compound of claim 11 , wherein R 5 is selected from the group consisting of 4-bromobenzoyl, 4-methylbenzoyl and 3-fluoro-4-methylbenzoyl.
13. The compound of claim 1 , wherein R 8 is unsubstituted alkyl or substituted alkyl.
14. The compound of claim 13 , wherein R 8 is methyl.
15. The compound of claim 1 , wherein m is 0 or 1.
16. The compound of claim 1 , wherein p is 3.
17. A compound selected from the group consisting of:
N-(3-aminopropyl)-N-[1-(3-benzyl-4-oxo-6,7,8 ,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-2-yl)propyl]-4-bromobenzamide;
N-(3-aminopropyl)-N-[1-(3-benzyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-2-yl)-2-methylpropyl]-4-methylbenzamide;
N-(3-aminopropyl)-N-[1-(3-benzyl-8-methyl-4-oxo-6,7,8,9-tetrahydro-4H-Pyrido[1,2-a]pyrimidin-2-yl)propyl]-4-methylbenzamide;
N-(3-aminopropyl)-N-[1-(3-benzyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-2-yl)-2-methylpropyl]-3-fluoro-4-methylbenzamide;
N-(3-ethylaminopropyl)-N-[1-(3-benzyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-2-yl)-2-methylpropyl]-4-methylbenzamide;
N-(3-ethylaminopropyl)-N-[1-(3-benzyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-2-yl)-2-methylpropyl]-3-fluoro-4-methylbenzamide; and
N-(3-methylaminopropyl)-N-[1-(3-benzyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-2-yl)-2-methylpropyl]-4-methylbenzamide.
18. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier.