Pyrazine-based tubulin inhibitors

1. A tubulin inhibitor of the formula I:

wherein:

R 1 is H, C 1-6 alkyl, C 1-6 alkylNR 5 R 6 , C 1-6 alkylNR 5 COR 6 , C 1-6 alkylNR 5 SO 2 R 6 , C 1-6 alkylCO 2 R 5 , C 1-6 alkylCONR 5 R 6 , where R 5 and R 6 are each independently H, C 1-4 alkyl, aryl, hetaryl, C 1-4 alkylaryl, C 1-4 alkylhetaryl or may be joined to form a 3-8 membered ring optionally containing an atom selected from O, S, NR 7 and R 7 is selected from H, C 1-4 alkyl;

R 2 and R 3 are each independently halogen, C 1-4 alkyl, OH, OC 1-4 alkyl, CF 3 , OCF 3 , CN, C 1-4 alkylNR 8 R 9 , OC 1-4 alkylNR 8 R 9 , OCONR 8 R 9 , NR 8 R 9 , NR 8 COR 9 , NR 10 CONR 8 R 9 , NR 8 SO 2 R 9 , COOR 8 , CONR 8 R 9 ; wherein R 8 , R 9 and R 10 are each independently H, C 1-4 alkyl, C 1-4 alkyl cycloalkyl, or may be joined to form a 3-8 membered ring optionally containing an atom selected from O, S, NR 11 ; wherein R 11 is H, C 1-11 alkyl or CF 3 ;

alternatively, R 2 and R 3 , when located on adjacent carbon atoms, may be joined to form the ring system

where R 22 is H, C 1-4 alkyl, or CF 3 ;

Q is C 1-4 alkylene;

W is C 2-4 alkyl or C 2-6 alkenyl, where C 2-4 alkyl or C 2-6 alkenyl may be optionally substituted with C 1-4 alkyl, OH, OC 1-4 alkyl, NR 15 R 16 ; wherein R 15 , and R 16 are each independently H, C 1-4 alkyl, C 1-4 alkyl cycloalkyl, C 1-4 alkyl cyclohetalkyl, aryl, hetaryl, or may be joined to form a 3-8 membered ring optionally containing an atom selected from O, S, NR 17 wherein R 17 is H or C 1-4 alkyl;

A is aryl, or hetaryl each optionally substituted with 0-3 substituents independently selected from halogen, C 1-4 alkyl, CF 3 , aryl, hetaryl, OCF 3 , OC 1-4 alkyl, OC 2-5 alkylNR 18 R 19 , Oaryl, Ohetaryl, CO 2 R 18 , CONR 18 R 19 , NR 18 R 19 , C 1-4 alkylNR 18 R 19 , NR 20 C 1-4 alkylNR 18 R 19 , NR 18 COR 19 , NR 20 CONR 18 R 19 , NR 18 SO 2 R 19 ; wherein R 18 , R 19 are each independently H, C 1-4 alkyl, C 1-4 alkyl cyclohetalkyl, aryl, hetaryl, C 1-4 alkyl aryl, C 1-4 alkyl hetaryl, or may be joined to form a 3-8 membered ring optionally containing an atom selected from O, S, NR 21 ; wherein R 20 and R 21 are independently H or C 1-4 alkyl; and

Z is H or C 1-4 alkyl,

or a tubulin inhibitor of the formula

or pharmaceutically acceptable prodrugs, salts or stereoisomers thereof,

wherein prodrugs are esters of a free carboxy or hydroxy group or amides of a free amino group.

2. A tubulin inhibitor according to claim 1 wherein W is C 2-4 alkyl or C 2-4 alkylamino which is a mixture of the compound that possesses S chirality at the chiral carbon bearing W, and the compound that possesses R chirality at said carbon.

3. A tubulin inhibitor according to claim 2 wherein the mixture comprises at least 70% of the compound that possesses S chirality at said carbon.

4. A tubulin inhibitor according to claim 3 wherein the compound comprises at least 80% of the compound that possesses S chirality at said carbon.

5. A tubulin inhibitor according to claim 3 wherein the compound comprises at least 90% of the compound that possesses S chirality at said carbon.

6. A tubulin inhibitor according to claim 3 wherein the compound comprises at least 95% of the compound that possesses S chirality at said carbon.

7. A tubulin inhibitor according to claim 3 wherein the compound comprises at least 99% of the compound that possesses S chirality at said carbon.

and the pharmaceutically acceptable salts and stereoisomers thereof.

8. A composition comprising a carrier and at least one tubulin inhibitor of claim 1 .

9. A method of modulating microtubule polymerization in a cell wherein said method comprises administering a tubulin inhibitor according to claim 1 .

10. A tubulin inhibitor of the formula II:

or pharmaceutically acceptable prodrugs, salts or stereoisomers thereof, wherein:

R 1 is H, C 1-6 alkyl, C 1-6 alkylNR 5 R 6 , where R 5 and R 6 are each independently H or C 1-4 alkyl, or may be joined to form a 3-8 membered ring optionally containing an atom selected from O, S, NR 7 wherein R 7 is H or C 1-4 alkyl;

A is aryl or hetaryl each optionally substituted with 0-3 substituents independently selected from halogen, C 1-4 alkyl, CF 3 , aryl, hetaryl, OCF 3 , OC 1-4 alkyl, OC 2-5 alkylNR 18 R 19 , Oaryl, Ohetaryl, CO 2 R 18 , CONR 18 R 19 , NR 18 R 19 , C 1-4 alkylNR 18 R 19 , NR 20 C 1-4 alkylNR 18 R 19 , NR 18 COR 19 , NR 20 CONR 18 R 19 , NR 18 SO 2 R 19 , where R 18 and R 19 are each independently H, C 1-4 alkyl, C 1-4 alkylcyclohetalkyl, aryl, hetaryl, C 1-4 alkylaryl, C 1-4 alkylhetaryl, or may be joined to form a 3-8 membered ring optionally containing an atom selected from O, S or NR 21 ; R 20 is H or C 1-4 alkyl; wherein R 21 is H or C 1-4 alkyl;

R 2 is 1-2 substituents independently selected from halogen, C 1-4 alkyl, OH, OC 1-4 alkyl, CF 3 , OCF 3 , CN, C 1-4 alkylNR 8 R 9 , OC 1-4 alkylNR 8 R 9 , CO 2 R 8 , CONR 8 R 9 , NR 8 R 9 , NR 8 COR 9 , NR 10 CONR 8 R 9 , NR 8 SO 2 R 9 ; wherein R 8 , R 9 and R 10 are each independently H or C 1-4 alkyl;

Y is H, OH, NR 12 R 13 ; and R 12 , wherein R 13 are each independently H or C 1-4 alkyl, or may be joined to form a 3-6 membered ring optionally containing an atom selected from O, S, NR 14 wherein R 14 is H or C 1-4 alkyl;

n is 0, 1, 2, 3 or 4;

with the proviso that if R 2 represents 2 substituents, n is 0 and Y is H; and

if R 2 represents one substituent and n is 0, Y cannot be H;

W is C 2-4 alkyl or C 2-6 alkenyl, where C 2-4 alkyl or C 2-6 alkenyl may be optionally substituted with C 1 -alkyl, OH, OC 1-4 alkyl or NR 15 R 16 ; wherein R 15 and R 16 are each independently H, C 1-4 alkyl, C 1-4 alkylcycloalkyl, C 1-4 alkylcyclohetalkyl, aryl or hetaryl, or may be joined to form a 3-8 membered ring optionally containing an atom selected from O, S or NR 17 ; wherein R 17 is selected from H or C 1-4 alkyl;

wherein prodrugs are esters of a free carboxy or hydroxy group or amides of a free amino group.

11. A composition comprising a carrier and at least one tubulin inhibitor of claim 10 .

12. A method of modulating microtubule polymerization in a cell wherein said method comprises administering a tubulin inhibitor according to claim 10 .

13. A tubulin inhibitor selected from the group consisting of:

14. A composition comprising a carrier and at least one tubulin inhibitor of claim 13 .

15. A method of modulating microtubule polymerization in a cell wherein said method comprises administering a tubulin inhibitor according to claim 13 .