Dimeric IAP inhibitors

1. A compound of formula (I):

wherein

R 1 a and R 1 b are independently H or optionally substituted hydroxyl, alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

R 2 a, and R 2 b are independently H or optionally substituted alkyl, cycloalkyl, or heterocycloalkyl;

R 3 a, and R 3 b are independently H or optionally substituted alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

both R 5 a and R 6 a, and R 5 b and R 6 b, are carbon atoms linked by a covalent bond or by an optionally-substituted alkylene or alkenylene group of 1 to 8 carbon atoms where one to three carbon atoms can be replaced by N, O, S(O) n , or C═O;

R 17 a and R 17 b are independently —OH, lower alkoxy, or lower alkyl;

R 7 a, R 7 b, R 8 a, R 8 b are independently H or optionally substituted hydroxyl, alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or R 7 a and R 8 a, or R 7 b and R 8 b, or both, can be linked by an optionally-substituted alkylene or alkenylene group of 3 to 8 carbon atoms where one to three carbon atoms can be replaced by N, O, S(O) n , or C═O;

each n can be the same or different and is 0, 1, or 2;

Xa is —O—, —N(La—R 10 a)-, —S—, optionally-substituted —C(La—R 10 a)=CH—, —C(O)—O—, —C(O)—N(La—R 10 a)-, —N═C(La—R 10 a)-;

Xb is —O—, —N(Lb-R 10 b)-, —S—, optionally-substituted —C(Lb-R 10 b)=CH—, —C(O)—O—, —C(O)—N(Lb-R 10 b)-, —N═C(Lb-R 10 b)-;

La and Lb are independently a covalent bond or C 1 —C 4 alkylene;

Wa, Wb, R 10 a, and R 10 b are defined in paragraphs (a) through (c), which follow:

(a) when Wa and Wb together are a Linker, then Xa or Xb are independently —O—, —S—, or —C(O)—O—; R 10 a and R 10 b, respectively, are absent; or

(b) when Wa and Wb together are a Linker; Xa is —N(La—R 10 a)-, —C(La—R 10 a)=CH—, —N═C(La—R 10 a)-, or —C(O)—N(La—R 10 a)- ; Xb is —N(Lb-R 10 b)-, —C(Lb-R 10 b)=CH—,—N═C(Lb-R 10 b)-, or —C(O)—N(Lb-R 10 b)-; R 10 a and R 10 b are independently H or optionally substituted hydroxyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or

(c) when Wa and Wb together are a Linker; Xa is —N(La—R 10 a)-, —C(La—R 10 a)=CH—, —N═C(La—R 10 a)-, or —C(O)—N(La—R 10 a)-; Xb is —N(Lb-R 10 b)-, —C(Lb-R 10 b)=CH—, —N═C(Lb-R 10 b)-, or —C(O)—N(Lb-R 10 b)-; R 10 a and R 10 b together are a Linker;

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein R 3 a, R 4 a, R 3 b, and R 4 b are independently H, methyl, ethyl, isopropyl, isobutyl, sec-butyl, tert-butyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, optionally-substituted with hydroxyl, mercapto, sulfonyl, alkylsulfonyl, halogen, pseudohalogen, amino, carboxyl, alkyl, haloalky, pseudohaloalkyl, alkoxy, or alkylthio.

3. The compound of claim 1 wherein R 2 a and R 2 b are independently H, methyl, fluoromethyl, difluoromethyl, ethyl, fluoroethyl, hydroxyethyl, or cycloalkyl.

4. The compound of claim 1 wherein R 1 a and R 1 b are independently H, methyl, allyl, propargyl, ethyl, hydroxyethyl, cycloalkyl, or cycloalkylmethyl.

5. The compound of claim 1 wherein R 3 a, and R 3 b are independently optionally substituted lower alkyl or C 3 -C 8 cycloalkyl wherein the optional substituents are hydroxy or lower alkoxy.

6. The compound of claim 1 wherein Wa and Wb together are a covalent bond or optionally substituted alkylene, cycloalkyl, or aryl, of 2 to 20 carbon atoms where one or more carbon atoms can be replaced with N, O, or S(O) n ; and Xa and Xb are independently —O—, —S—, or —C(O)—O—.

7. The compound of claim 1 wherein Wa and Wb together are a covalent bond or optionally substituted alkylene, cycloalkyl, or aryl, of 2 to 20 carbon atoms where one or more carbon atoms can be replaced with N, O, or S(O) n ; Xa is —N(La—R 10 a)-, —C(La—R 10 a)=CH—, or —C(O)—N(La—R 10 a)-; Xb is —N(Lb-R 10 b)—, —C(Lb-R 10 b)=CH—, or —C(O)—N(La—R 10 a)-; Xb is —N(Lb-R 10 b)-; —C(Lb-R 10 b)=CH—, or —C(O)—N(Lb-R 10 b)-; R 10 a and R 10 b are independently H or optionally substituted hydroxyl, alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl.

8. The compound of claim 1 wherein Wa and Wb together are a covalent bond or optionally substituted alkylene, cycloalkyl, or aryl, of 2 to 20 carbon atoms where one or more carbon atoms can be replaced with N, O, or S(O) n ; Xa is —N(La—R 10 a)-, —C(La—R 10 a)=CH—, or —C(O)—N(La—R 10 a)-; Xb is —N(Lb-R 10 b)-,—C(Lb-R 10 b)=CH—, or —C(O)—N(Lb-R 10 b)—; R 10 a and R 10 b together are an optionally-substituted alkylene, cycloalkyl, or aryl of 2 to 20 carbon atoms where one or more carbon atoms can be replaced with N, O, or S(O) n .

9. The compound of claim 1 wherein Wa and Wb are not covalently bound, and Wa and Wb are independently H, Cl, Br, F, CN, COOH, or optionally substituted hydroxyl, alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Xa is —N(La—R 10 a)-, —C(La—R 10 a)=CH—, or —C(O)—N(La—R 10 a)-; Xb is —N(Lb-R 10 b)-,—C(Lb-R 10 b)=CH—, or —C(O)—N(Lb-R 10 b)-; R 10 a and R 10 b together are an optionally-substituted alkylene, cycloalkyl, or aryl of 2 to 20 carbon atoms where one or more carbon atoms can be replaced with N, O, or S(O) n .

10. The compound of claim 1 wherein Wa and Wb are not covalently bound, Wa is H, Cl, Br, F, CN, COOH, or optionally substituted hydroxyl, alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Xa is —N(La—R 10 a)-, —C(La—R 10 a)=CH—, or —C(O)—N(La—R 10 a)-; Xb is —O—, —N(Lb-R 10 b)-, —S—,—C(Lb-R 10 b)=CH—, —C(O)—O—, —C(O)—N(Lb-R 10 b)-; and R 10 b is H or optionally-substituted alkyl; and Wb and R 10 a together are a covalent bond or optionally substituted alkylene, cycloalkyl, or aryl, of 2 to 20 carbon atoms where one or more carbon atoms can be replaced with N, O, or S(O) n .

11. The compound of claim 1 wherein Wa and Wb are not covalently bound, Wb is H, Cl, Br, F, CN, COOH, or optionally substituted hydroxyl, alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Xb is —N(Lb-R 10 b)-, —C(Lb-R 10 b)=CH—, or —C(O)—N(Lb-R 10 b)-; Xa is —O—, —N(La—R 10 a)-, —S—, —C(La—R 10 a)=CH—, —C(O)—O—, —C(O)—N(La—R 10 a)-; and R 10 a is H or optionally-substituted alkyl; and Wa and R 10 b together are a covalent bond or optionally substituted alkylene, cycloalkyl, or aryl, of 2 to 20 carbon atoms where one or more carbon atoms can be replaced with N, O, or S(O) n .

12. The compound of claim 1 wherein Z 1 a and Z 1 b are both N and Z 2 a and Z 2 b are both C and wherein R 3 a and R 4 a, and R 3 b and R 4 b, are each carbon and are linked by a covalent bond or by an optionally-substituted alkylene or alkenylene group of 1 to 8 carbon atoms where one to three carbon atoms can be replaced by N, O, S(O) n , or C═O.

13. The compound of claim 1 wherein R 10 a and R 10 b are not heterocycloalkyl or heteroaryl.

14. The compound of claim 1 having formula (II):

wherein

Xa is —N—, —C═C(R 16 a)-, —N═C— or —C(O)N—;

Xb is —N—, —C═C(R 16 b)-, —N═C— or —C(O)N—;

La and Lb are independently a covalent bond or C 1 -C 4 alkylene;

Ya is —C—, —N—, or —N + —; such that,

When Ya is —C—then R 10 a, R 11 a, R 12 a, R 13 a, R 14 a, R 15 a, and R 16 a are, independently, —H, halogen, or optionally substituted alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, hydroxyl, alkoxy, polyalkylether, amino, alkylamino, dialkylamino, alkoxyalkyl, sulfonate, aryloxy, heteroaryloxy, acyl, acetyl, carboxylate, sulfonate, sulfone, imine, or oxime; provided that when Xa is —N—or —C(O)—N—, —L 1 —R 10 a is bound to the —N— atom; and, when Xa is —C═C(R 16 a)- or —N═C—, —L 1 —R 10 a is bound to the —C═atom; and

When Ya is —N— or —N + —, then R11 a is absent or —O—, and R 10 a, R 11a , R 13 a, R 14 a, R 15 a, and R 16 a are, independently, —H, halogen, or optionally substituted alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, hydroxyl, alkoxy, polyalkylether, amino, alkylamino, dialkylamino, alkoxyalkyl, sulfonate, aryloxy, heteroaryloxy, acyl, acetyl, carboxylate, sulfonate, sulfone, imine, or oxime; provided that when X is —N— or —C(O)—N—, —L 1 —R 10a is bound to the —N—atom; and, when X is —C═C(R 16 a)- or —N═C—, —L 1 —R 10 a is bound to the —C═ atom;

Yb is —C—, —N—, or —N + —; such that,

When Yb is —C— then R 10 b, R 11 b, R 12 b, R 13 b, R 14 b, R 15 b, and R 16 b are, independently, —H, halogen, or optionally substituted alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, hydroxyl, alkoxy, polyalkylether, amino, alkylamino, dialkylamino, alkoxyalkyl, sulfonate, aryloxy, heteroaryloxy, acyl, acetyl, carboxylate, sulfonate, sulfone, imine, or oxime; provided that when Xb is —N— or —C(O)—N—, —L 1 —R 10 b is bound to the —N— atom; and, when Xb is —C═C(R 16 b)- or —N═C—, —L 1 —R 10 b is bound to the —C═ atom; and

when Yb is —N— or —N + —, then R 11 b is absent or —O—, and R 10 b, R 12 b, R 13 b, R 14 b, R 15 b, and R 16 b are, independently, —H, halogen, or optionally substituted alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, hydroxyl, alkoxy, polyalkylether, amino, alkylamino, dialkylamino, alkoxyalkyl, sulfonate, aryloxy, heteroaryloxy, acyl, acetyl, carboxylate, sulfonate, sulfone, imine, or oxime; provided that when Xb is —N— or —C(O)—N—, —L 1 —R 10 b is bound to the —N— atom; and, when Xb is —C═C(R 16 b)- or —N═C—, —L 1 —R 10 b is bound to the —C═atom.

15. The compound of claim 14 wherein (i) R 5 a and R 6 a, and R 5 b and R 6 b, are each carbon and are linked by a covalent bond or by an optionally-substituted alkylene or alkenylene group of 1 to 8 carbon atoms where one to three carbon atoms can be replaced by N, O, S(O) n , or C═O.

16. The compound of claim 14 wherein R 3 a and R 4 a, and R 3 b and R 4 b, are carbon atoms and are linked by a covalent bond or by an optionally-substituted alkylene or alkenylene group of 1 to 3 carbon atoms of which one or more can be replaced by N, O, S(O) n , or C═O.

17. The compound of claim 14 wherein

R 4 a and R 3 a or R 4 b and R 3 b, or both, are linked by an alkylene or alkenylene group of 1 to 3 atoms;

R 2 a and R 2 b are independently selected from methyl, fluoromethyl, difluoromethyl, ethyl, fluoroethyl, and cycloalkyl;

Wa and Wb together are a covalent bond or optionally substituted alkylene, cycloalkyl, or aryl, of 2 to 20 carbon atoms where one or more carbon atoms can be replaced with N, O, or S(O) n ; and Xa and Xb are independently —O—, —S—, or —C(O)—; or

Wa and Wb together are a covalent bond or optionally substituted alkylene, cycloalkyl, or aryl, of 2 to 20 carbon atoms where one or more carbon atoms can be replaced with N, O, or S(O) n ; Xa is —N(La—R 10 a)-, —C(La—R 10 a)=CH—, or —C(O)—N(La—R 10 a)-; Xb is —N(Lb-R 10 b)-, —C(Lb-R 10 b)=CH—, or —C(O)—N(Lb-R 10 b)-; R 10 a and R 10 b are independently H or optionally substituted hydroxyl, alkyl, cycloalkyl, heterocycloalkyl, aryl, or, heteroaryl.

18. The compound of claim 14 wherein R 10 a and R 10 b are not optionally substituted 5-, 6-, or 7-membered heterocycloalkyl or heteroaryl.

19. The compound of claim 1 having formula (IV), or a pharmaceutically acceptable salt thereof:

wherein —La—R 10 a-Wb- is a covalent bond.

20. The compound of claim 1 that is selected from compounds A through M, as follows:

Com-

R13a/

R12a/

R11a/

pound

R1a

R2a

R3a

R17a

R17b

R3b

R2b

R1b

R13b

R12b

R11b

A

Me

S-Me

S-(2R-

S-

S-

S-(2R-

S-Me

Me

H

F

H

MeCHOMe)

OH

OH

MeCHOMe)

B

Me

S-

S-(2R-

S-

S-

S-(2R-

S-

Me

H

F

H

CH 2 OH

MeCHOMe)

OH

OH

MeCHOMe)

CH 2 OH

C

Me

S-Me

S-tBu

S-

S-

S-tBu

S-Me

Me

H

F

H

OH

OH

D

Me

S-Et

S-tBu

S-

S-

S-tBu

S-Et

Me

H

F

H

OH

OH

E

Et

S-Me

S-(2R-

S-

S-

S-(2R-

S-Me

Et

H

F

H

MeCHOMe)

OH

OH

MeCHOMe)

F

Me

S-Et

S-(2R-

S-

S-

S-(2R-

S-Et

Me

H

F

H

MeCHOMe)

OH

OH

MeCHOMe)

G

Me

S-Me

S-(2R-

S-

S-

S-(2R-

S-Me

Me

H

F

H

MeCHOMe)

OMe

OMe

MeCHOMe)

H

Me

S-Et

S-(2R-

S-

S-

S-(2R-

S-Et

Me

H

F

H

MeCHOMe)

OMe

OMe

MeCHOMe)

I

Me

S-Me

S-tBu

S-

S-

S-tBu

S-Me

Me

H

F

H

OMe

OMe

J

Me

S-Et

S-tBu

S-

S-

S-tBu

S-Et

Me

H

F

H

OMe

OMe

K

Et

S-Me

S-(2R-

S-

S-

S-(2R-

S-Me

Et

H

F

H

MeCHOMe)

OMe

OMe

MeCHOMe)

L

Et

S-Me

S-tBu

S-

S-

S-tBu

S-Me

Et

H

F

H

OMe

OMe

M

Me

S-Me

S-(2R-

S-

S-Me

S-(2R-

S-Me

Me

H

F

H

MeCHOMe)

Me

MeCHOMe)

21. The compound of claim 1 having the formula

wherein R 1 a, R 1 b, R 2 a, R 2 b, R 3 a, and R 3 b are independently lower alkyl, lower alkoxy, lower alkanol, or C 3 -C 6 cycloalkyl; R 17 a and R 17 b are independently —OH, lower alkoxy or lower alkyl; R 11 a, R 11 b, R 12 a, R 12 b, R 13 a, R 13 b, R 14 a, and R 14 b are independently —H or halogen.

22. A method for inducing apoptosis in a cell comprising contacting the cell with a compound of claim 1 in an amount sufficient to induce apoptosis in the cell.

23. The method of claim 22 , wherein said cell is neoplastic.

24. The method of claim 22 , wherein said cell overexpresses an inhibitor of caspase.

25. The method of claim 22 , wherein the inhibitor inhibits activation or activity of one or more of a caspase selected from caspase-3, caspase-7 and caspase-9.

26. A method of stimulating apoptosis in a cell comprising contacting the cell with a compound of claim 1 in an amount sufficient to stimulate apoptosis in the cell.

27. The method of claim 26 , wherein said cells are cancer cells.

28. A method of enhancing apoptosis of pathogenic cells in vivo in an individual comprising administering to the individual a therapeutically effective amount of a compound of claim 1 .

29. The method of claim 28 further comprising administering a second therapy selected from radiation, chemotherapy, immunotherapy, photodynamic therapy and combinations thereof.

30. A method of treating a disease associated with the overexpression of IAP in an individual comprising administering to said individual an effective amount of a compound of claim 1 .

31. A method of treating cancer comprising administering a therapeutically effective amount of a compound of claim 1 .

32. A pharmaceutical composition comprising: a compound selected from a compound of claim 1 and a pharmaceutically acceptable excipient.

33. The composition of claim 32 further comprising a second chemotherapeutic agent.

34. The composition of claim 33 , wherein said second chemotherapeutic agent is selected from alkylating agents, plant alkaloids, antitumor antibiotics, antimetabolites, topoisomerase inhibitors and combinations thereof.

35. The composition of claim 34 , wherein said chemotherapeutic agent is selected from altretamine, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cyclophosphomide, dacarbazine, hexamethylmelamine, ifosfamide, lomustine, melphalan, mechlorethamine, oxaliplatin, procarbazine, streptozocin, temozolomide, thiotepa, uramustine, docetaxel, etoposide, irinotecan, paclitaxel, tenisopide, topotecan, vincristine, vinblastine, vindesine, vinorelbine, bleomycin, dactinomycin, daunorubicin, epirubicin, hydroxyurea, idarubicin, mitomycin, mitoxantrone, plicamycin, azathioprine, capecitabine, cladribine, cytarabine, fludarabine, fluorouracil, floxuridine, gemcitabine, mercaptopurine, methotrexate, nelarabine, pemetrexed, pentostatin, thioguanine, camptothecan, irinotecan, topotecan, BNP 1350, SN 38, 9-amino-camptothecan, lurtotecan, gimatecan, diflomotecan, an anthracycline, anthraquinone, podophyllotoxin, doxorubicin, epirubicin, idarubicin, nemorubicin, mitoxantrone, loxoxantrone, etoposide, teniposide and combinations thereof

36. The compound of claim 1 wherein Xa is —N(La—R 10 a)-, —C(La—R 10 a)=CH—, —N═C(La—R 10 a)-, or —C(O)—N(La—R 10 a)-; Xb is —N(Lb-R 10 b)-, —C(Lb-R 10 b)=CH—, —N═C(Lb-R 10 b)-, or —C(O)—N(Lb-R 10 b)-; R 10 a and R 10 b are independently H or optionally substituted hydroxyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl.

37. The compound of claim 21 wherein R11a, R11b, R13a, R13b, R18a, and R18b are —H and R12a and R12b are halogen.

38. The compound of claim 37 wherein R1a and R1b are lower alkyl and R2a and R2b are lower alkyl or lower alkanol.

39. The compound of claim 1 having the formula

or a pharmaceutically acceptable salt thereof.

40. The compound of claim 39 or a pharmaceutically acceptable salt thereof wherein

R 1 a and R 1 b are independently H, methyl, allyl, propargyl, ethyl, hydroxyethyl, cycloalkyl, or cycloalkylmethyl;

R 2 a and R 2 b are independently H, methyl, fluoromethyl, difluoromethyl, ethyl, fluoroethyl, hydroxyethyl, or cycloalkyl;

R 3 a, and R 3 b are independently optionally substituted lower alkyl or C 3 -C 8 cycloalkyl wherein the optional substituents are hydroxy or lower alkoxy;

Wa and Wb together are a covalent bond or optionally substituted alkylene, cycloalkyl, or aryl, of 2 to 20 carbon atoms where one or more carbon atoms can be replaced with N, O, or S(O) n ;

R 17 a and R 17 b are independently —OH, lower alkoxy or lower alkyl; and

R 11 a, R 11 b, R 12 a, R 12 b, R 13 a, R 13 b, R 14 a, and R 14 b are independently H or halogen.