Induction of apoptosis in cancer cells

1. A compound having formula (I):

wherein R 1 is adamantyl, bicyclooctyl, bicyclooctenyl, aza-bicyclooctyl, or aza-bicyclooctenyl;

wherein the R 1 groups are optionally substituted with one or more C 1-10 alkyl groups;

R 2 is hydroxy, —SH, amino, —CN, (C 1-10 alkyl)NH—, (C 1-10 alkyl) 2 N—, —COOR 14 , —C(═O)R 14 , —C(═O)N(R 14 ) 2 , —N(R 14 )C(═O)R 14 , —P(O)(OR 14 ) 2 (phosphonic acid), —S(O) 2 OR 14 (sulfonic acid), —S(O) 2 N(R 14 ) 2 (sulfonamide), —N—C(NH)—N(R 14 ) 2 (guanidino), (hydroxy)C 1-10 alkylene-, (C 1-10 alkyl)—C(O)—, —C(O)—NHOR 14 (hydroxamic acid), or oxime;

R 3 is hydrogen, C 1-10 alkyl, hydroxy, amino, (C 1-10 alkyl)NH—, (C 1-10 alkyl) 2 N—, —COOR 14 (carboxylic acid), —P(O)(OR 14 ) 2 (phosphonic acid), —S(O) 2 OR 14 (sulfonic acid), —S(O) 2 N(R 14 ) 2 (sulfonamide), —N—C(NH)—N(R 15 ) 2 (guanidino), (hydroxy)C 1-10 alkylene, (C 1-10 alkyl)—C(O)—, —C(O)—NHOR 14 (hydroxamic acid), carbonyl oxime, fluoro, chloro, bromo, iodo, —CF 3 or nitro; or R 1 and R 3 taken together with the ring to which they are attached can form a polycyclic group which can be fully saturated, partially saturated or aromatic;

R 4 is

wherein each R 5 is independently hydroxy, C 1-10 alkyl, C 1-10 alkoxy, amino, (C 1-10 alkyl)NH—, (C 1-10 alkyl) 2 N—, (amino)C 1-10 alkyleneoxy)—, (acetamido)alkoxy, (C 1-10 )mercapto, (hydroxy)C 1-10 alkylene-, halo, halo(C 1-10 )alkyl, (C 1-10 alkoxy)-C 1-10 alkylene-, nitro, acetamido, phenyl, or substituted phenyl;

R 6 is hydrogen, hydroxy, C 1-10 alkyl, C 1-10 alkoxy, amino, (C 1-10 alkyl)NH—, (C 1-10 alkyl) 2 N—, (amino)C 1-10 alkyleneoxy)-, (acetamido)alkoxy, (C 1-10 alkyl)mercapto, (hydroxy)C 1-10 alkylene-, halo, halo(C 1-10 )alkyl, (C 1-10 alkoxy)C 1-10 alkylene-, nitro, acetamido, phenyl, or substituted phenyl;

R 9 is —COOR 14 , —P(O)(OR 14 ) 2 , —S(O) 2 OR 14 , —C(O)—NHOR 14 , thiazolidenedione, tropolone, tetrazole, nitro, —(CH 2 ) j OR 15 , or —N—C(NH)—N(R 15 ) 2 ;

R 12 is —C(R 16 )═C(R 16 )(R 9 ), aryl-R 9 , or 2-cyclopropyl-R 9 , where each R 16 is independently hydrogen or fluorine;

R 14 is hydrogen, (C 1-25 )alkyl or aryl;

R 15 is hydrogen, (C 1-10 alkyl)—C(O)—, or(aryl)—C(O)—;

j is from 1 to 10; and n is 0, 1, 2, or 3;

wherein any alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, polycycloalkyl, polycycloalkenyl, heterocycloalkyl, polyheterocycloalkyl, heterocycloalkenyl, polyheterocycloalkenyl, aryl, or heteroaryl group of R 1 , R 2 , R 3 , R 5 , and R 6 is optionally substituted with one or more, such as 1, 2, 3, or 4, substituents independently selected from oxo(═O), halo, —OH, —CN, —NO 2 , —CF 3 , —OCF 3 , —S(O) 0-2 C 1-6 alkyl, C 1-8 alkyl, C 1-8 alkoxy, C 1-8 alkyl-NR a R b , phenyl, C 1-8 alkanoyl, —NR a R b , —C(═O)NR a R b , or —SO 2 NNR a R b ;

wherein each R a and R b is independently hydrogen, C 1-6 alkyl, C 1-6 alkanoyl, C 1-6 alkoxycarbonyl, aryl, (aryl)C 1-8 alkylene-, arylcarbonyl, or aryloxycarbonyl; or R a and R b together with the nitrogen to which they are attached form a pyrrolidino, piperidino, morpholino, or thiomorpholino ring; or

a pharmaceutical acceptable salt thereof.

2. The compound of claim 1 wherein R 1 is adamantyl.

3. The compound of claim 1 wherein R 2 is hydroxy, —COOR 14 , —C(═O)CH 3 , or —SH.

4. The compound of claim 3 wherein R 2 is hydroxy.

5. The compound of claim 1 wherein R 3 is hydrogen, methyl, ethyl, chloro, bromo, fluoro, or —CF 3 .

6. The compound of claim 5 wherein R 3 is hydrogen, or methyl.

7. The compound of claim 1 wherein R 4 is

8. The compound of claim 7 wherein R 5 and R 6 are independently hydrogen, methyl, ethyl, methoxy, ethoxy, chloro, bromo, fluoro, —CF 3 , —O—(CH 2 ) 3 —NH 2 , or —O—(CH 2 ) 3 —NH—C(═O)CH 3 .

9. The compound of claim 8 wherein R 5 and R 6 are independently hydrogen, methyl, methoxy, ethoxy, chloro, bromo, fluoro, —CF 3 , —O—(CH 2 ) 3 —NH 2 or —O—(CH 2 ) 3 —NH—C(═O)CH 3 .

10. The compound of claim 9 wherein R 5 and R 6 are independently hydrogen, methyl, chloro, bromo, or fluoro, —CF 3 , —O—(CH 2 ) 3 —NH 2 or —O—(CH 2 ) 3 —NH—C(═O)CH 3 .

11. The compound of claim 10 wherein one of R 5 and R 6 is hydrogen and the other is methyl, chloro, bromo, —CF 3 , —O—(CH 2 ) 3 —NH 2 , or —O—(CH 2 ) 3 —NH—C(═O)CH 3 .

12. The compound of claim 1 wherein R 9 is —COOR 14 , —P(O)(OR 14 ) 2 , —S(O) 2 OR 14 , or —C(O)—NHOR 14 .

13. The compound of claim 12 wherein R 9 is —COOR 14 .

14. The compound of claim 1 wherein R 12 is —C(H)═C(H)(R 9 ), or aryl-R 9 .

15. The A compound of claim 1 wherein having the formula (II):

wherein R 1 is adamantyl, bicyclooctyl, bicyclooctenyl, aza-bicyclooctyl, or aza-bicyclooctenyl;

wherein R 2 is —OH, R 4 is

R 12 is —C(H)═C(H)—C(═O)OR 14 where R 14 is hydrogen or ethyl; and R 5 and R 6 are independently hydrogen, is methyl, methoxy, chloro, or fluoro and R 6 is hydrogen, methyl, methoxy, chloro, or fluoro.

16. The compound of claim 15 wherein R 12 is the E-isomer.

17. The compound of claim 1 wherein R 3 is —CF 3 .

18. The A compound of claim 15 having the formula:

or a plmrmaceutically acceptable salt thereof.

19. The A compound of claim 15 having the formula:

or a pharmaceutically acceptable salt thereof.

20. The compound of claim 15 having the formula:

or a pharmaceutically acceptable salt thereof.

21. The A compound of claim 15 having the formula:

or a pharmaceutically acceptable salt thereof.

22. A method of treating cancer in a mammal comprising contacting the cancer cells with a compound of claim 1 , effective to reduce the viability of the cancerous cells, wherein the cancer is lung cancer, breast cancer, prostate cancer, or leukemia.

23. The method of claim 22 wherein the leukemia is acute lymphocytic leukemia, acute myelogenous leukemia, or chronic myelogenous leukemia.

24. A method for inducing apoptosis, inducing caspase activity, or inducing cell death in a mammal comprising contacting target cells with a compound of claim 1 , effective to induce apoptosis, induce caspase activity, or induce cell death to the target cells, wherein the target cells are lung cancer, breast cancer, prostate cancer, or leukemia cells.

25. The compound of claim 1 wherein R 6 is methyl, chloro, bromo, trifluoromethyl, —O—(CH 2 ) 3 —NH 2 , —OR or —O—(CH 2 ) 3 —NHC(═O)CH 3 wherein R of —OR is hydrogen or C 1 -C 10 alkyl.

26. The compound of claim 1 wherein n is 0.

27. The compound of claim 26 wherein R 1 is adamantyl.

28. The compound of claim 26 wherein R 2 is hydroxy, —COOR 14 , —C(═O)CH 3 , or —SH.

29. The compound of claim 28 wherein R 2 is hydroxy.

30. The compound of claim 26 wherein R 3 is hydrogen, methyl, ethyl, chloro, bromo, fluoro, or —CF 3 .

31. The compound of claim 26 wherein R 6 is methyl, ethyl, methoxy, ethoxy, chloro, bromo, fluoro, —CF 3 , —O—(CH 2 ) 3 —NH 2 , or —O—(CH 2 ) 3 —NH—C(═O)CH 3 .

32. The compound of claim 31 wherein R 6 is methyl, methoxy, ethoxy, chloro, bromo, fluoro, —CF 3 , —O—(CH 2 ) 3 —NH 2 or —O—CH 2 ) 3 —NH—C(═O)CH 3 .

33. The compound of claim 32 wherein R 6 is methyl, chloro, bromo, fluoro, —CF 3 , —O—(CH 2 ) 3 —NH 2 or —O—(CH 2 ) 3 —NH—C(═O)CH 3 .

34. The compound of claim 33 wherein R 6 is methyl, chloro, bromo, —CF 3 , —O—(CH 2 ) 3 —NH 2 or —O—(CH 2 ) 3 —NH—C(═O)CH 3 .