Migrastatin analogs and uses thereof

1. A compound having one of the following structures:

or pharmaceutically acceptable salt thereof;

wherein R 1 and R 2 are hydrogen or lower alkyl;

R 3 , R 5 and R 6 are C 1-6 alkyl;

the bond is a single bond or a double bond;

R 4 is halogen, —OR 4A , —OC(═O)R 4A or —NR 4A R 4B ; wherein R 4A and R 4B are independently hydrogen; a nitrogen protecting group selected from a carbamate, an amide, a cyclic imide derivative, an N-alkyl amine, an N-aryl amine, an imine derivative or an enamine derivative or an oxygen protecting group selected from a substituted methyl ether, a substituted ethyl ether, a substituted benzyl ether, a silyl ether, an ester, a carbonate, a cyclic acetal or a ketal; or R 4A and R 4B , taken together with the nitrogen atom to which they are attached, form a C 3-20 heterocyclic or C 3-14 heteroaryl moiety; or R 4 , taken together with the carbon atom to which it is attached forms a moiety having the structure:

or R 4A and R 4B are independently a C 1-6 alkyl group optionally substituted with one or more of C 1-20 aliphatic; C 3-14 aryl; C 3-14 heteroaryl; C 1-20 alkylC 3-14 aryl; C 1-20 alkylC 3-14 heteroaryl, C 3-14 aryloxy; C 1-20 heteroalkoxy, C 3-14 heteroaryloxy; C 1-20 alkylthio; C 3-14 arylthio; heteroC 1-20 alkylthio; heteroC 3-14 arylthio; F; Cl; Br; I; —OH; —NO 2 ; —CN; —CF 3 ; —CH 2 CF 3 ; —CHC1 2 ; —CH 2 OH; —CH 2 CH 2 OH; —CH 2 NH 2 ; —CH 2 SO 2 CH 3 ; —C(O)R x ; —CO 2 (R x ); —CON(R x ) 2 ; —OC(O)R x ; —OCO 2 R x ; —OCON(R x ) 2 ; —N(R x ) 2 ; S(O) 2 R x ; —NR x (CO)R x wherein each occurrence of R x is independently C 1-20 aliphatic, heteroC 1-20 aliphatic, C 3-14 aryl, C 3-14 heteroaryl, C 1-20 alkylC 3-14 aryl or C 1-20 alkylC 3-14 heteroaryl;

X 1 is O, S, NR X1 or CR X1 R X2 ; wherein R X1 and R X2 are independently hydrogen, halogen, or a substituted or unsubstituted C 1-20 alkyl, heteroC 1-20 alkyl, cycloC 3-10 alkyl, heterocyclo C 3-10 alkyl, C 3-14 aryl or C 3-14 heteroaryl, or a nitrogen protecting group selected from a carbamate, an amide, a cyclic imide derivative, an N-alkyl amine, an N-aryl amine, an imine derivative or an enamine derivative;

Q is hydrogen, halogen, —CN, —S(O) 1-2 R Q1 , —NO 2 , —COR Q1 , —CO 2 R Q1 , —NR Q1 C(═O)R Q2 , —NR Q1 C(═O)OR Q2 , —CONR Q1 R Q2 , or a substituted or unsubstituted C 1-20 aliphatic, heteroC 1-20 aliphatic, C 3-20 alicyclic, heteroC 3-20 alicyclic, C 3-14 aryl or C 3-14 heteroaryl moiety, or —WR Q1 ; wherein W is independently O, S or NR Q3 and each occurrence of R Q1 , R Q2 and R Q3 is independently hydrogen, or a substituted or unsubstituted C 1-20 aliphatic, heteroC 1-20 aliphatic, C 3-20 alicyclic, heteroC 3-20 alicyclic, C 3-14 aryl or C 3-14 heteroaryl moiety;

Y 2 is hydrogen, or a substituted or unsubstituted C 1-20 alkyl, heteroC 1-20 alkyl, cyclo C 3-10 alkyl, heterocycloC 3-10 alkyl, C 3-14 aryl, or C 3-14 heteroaryl moiety; or —WR Y1 ;

W is O or NH; and

R Y1 and R Y2 are independently hydrogen, or a substituted or unsubstituted C 1-20 aliphatic, heteroC 1-20 aliphatic, C 3-20 alicyclic, heteroC 3-20 alicyclic, C 3-14 aryl or C 3-14 heteroaryl moiety;

wherein for the compound of formula (a), when X 1 is O and the bond is a double bond, Q is hydrogen, halogen, —CN, —S(O) 1-2 R Q1 , —NO 2 , —COR Q1 , —CO 2 R Q1 , —NR Q1 C(═O)R Q2 , —NR Q1 C(═O)OR Q2 , —CONR Q1 R Q2 , or —WR Q1 ; wherein W is independently O, S or NR Q3 and each occurrence of R Q1 , R Q2 and R Q3 is independently hydrogen, or a substituted or unsubstituted C 1-20 aliphatic, heteroC 1-20 aliphatic, C 3-20 alicyclic, heteroC 3-20 alicyclic, C 3-14 aryl or C 3-14 heteroaryl moiety.

2. The compound of claim 1 having one of the following structures:

or pharmaceutically acceptable salt thereof.

3. The compound of claim 2 , wherein the compound has the structure:

wherein n is 3; Y 2 and R Y1 are independently hydrogen or C 1-6 alkyl; R 7 is a substituted or unsubstituted, linear or branched, cyclic or acyclic C 1-6 alkyl moiety; R 8B is hydrogen or C 1-6 alkyl; and X, Y and Z are independently a bond, —O—, —S—, —C(═O)—, —NR Z1 —, —CHOR Z1 , —CHNR Z1 R Z2 , C═S, C═N(R Y1 ) or —CH(Hal); or a substituted or unsubstituted C 0-6 alkylidene or C 0-6 alkenylidene chain wherein up to two non-adjacent methylene units are independently optionally replaced by CO, CO 2 , COCO, CONR Z1 , OCONR Z1 , NR Z1 NR Z2 , NR Z1 NR Z2 CO, NR Z1 CO, NR Z1 CO 2 , NR Z1 CONR Z2 , SO, SO 2 , NR Z1 SO 2 , SO 2 NR Z1 , NR Z1 SO 2 NR Z2 , O, S, or NR Z1 ; wherein Hal is a halogen selected from F, Cl, Br and I; and each occurrence of R Z1 and R Z2 is independently hydrogen, C 1-20 alkyl, heteroC 1-20 alkyl, C 3-14 aryl, C 3-14 heteroaryl or C 1-20 acyl; or R Z1 and R Z2 , taken together with the nitrogen atom to which they are attached, form a heterocyclic or heteroaryl moiety;

or pharmaceutically acceptable salt thereof.

4. The compound of claim 2 , wherein the compound has the structure:

wherein n is 3; Y 2 and R Y1 are independently hydrogen or C 1-6 alkyl; R 7 is a substituted or unsubstituted, linear or branched, cyclic or acyclic C 1-6 alkyl moiety; R 8B is hydrogen or C 1-6 alkyl; and Y is —CHOR Y1 , —CHNR Y1 R Y2 , C═O, C═S, C═N(R Y1 ) or —CH(Hal); wherein Hal is a halogen selected from F, Cl, Br and I; and R Y1 and R Y2 are independently hydrogen, C 1-20 alkyl, heteroC 1-20 alkyl, C 3-14 aryl, C 3-14 heteroaryl or C 1-20 acyl, or R Y1 and R Y2 , taken together with the nitrogen atom to which they are attached, form a heterocyclic or heteroaryl moiety; or a pharmaceutically acceptable salt thereof.

5. The compound of claim 2 , wherein the compound has the structure:

wherein n is 3; Y 2 and R Y1 are independently hydrogen or C 1-6 alkyl; R 8B is hydrogen or C 1-6 alkyl; and R Y is hydrogen, halogen, —OR Y1 or —NR Y1 NR Y2 ; wherein R Y1 and R Y2 are independently hydrogen, C 1-20 alkyl, heteroC 1-20 alkyl, C 3-14 aryl, C 3-14 heteroaryl or C 1-20 acyl, or R Y1 and R Y2 , taken together with the nitrogen atom to which they are attached, form a heterocyclic or heteroaryl moiety;

or a pharmaceutically acceptable salt thereof.

6. The compound of claim 2 , wherein the compound has the structure:

wherein n is 3; Y 2 and R Y1 are independently hydrogen or C 1-6 alkyl; R 7 is a substituted or unsubstituted, linear or branched, cyclic or acyclic C 1-6 alkyl moiety; and R 8B is hydrogen or C 1-6 alkyl;

or a pharmaceutically acceptable salt thereof.

7. The compound of claim 1 , wherein the compound has the structure:

wherein n is 3; and Y 2 and R Y1 are independently hydrogen or C 1-6 alkyl;

or a pharmaceutically acceptable salt thereof.

8. The compound of claim 1 , wherein the compound has the structure:

wherein n is 3; and R Y1 and R Y2 are independently hydrogen or C 1-6 alkyl;

or a pharmaceutically acceptable salt thereof.

9. The compound of claim 2 , wherein the compound has one of the following structures:

W is O or NH;

R Y1 is hydrogen, or a substituted or unsubstituted C 1-20 aliphatic, heteroC 1-20 aliphatic, C 3-20 alicyclic, heteroC 3-20 alicyclic, C 3-14 aryl or C 3-14 heteroaryl moiety;

R 7 is a substituted or unsubstituted C 1-6 alkyl or heteroC 1-6 alkyl moiety;

R 8 is a substituted or unsubstituted C 1-20 alkyl, heteroC 1-20 alkyl, cycloC 3-20 alkyl, heterocycloC 3-20 alkyl, C 3-14 aryl or C 3-14 heteroaryl moiety; and Alk is a substituted or unsubstituted C 0-6 alkylidene or C 0-6 alkenylidene chain wherein up to two non-adjacent methylene units are independently optionally replaced by CO, CO 2 , COCO, CONR Z1 , OCONR Z1 , NR Z1 NR Z2 , NR Z1 NR Z2 CO, NR Z1 CO, NR Z1 CO 2 , NR Z1 CONR Z2 , SO, SO 2 , NR Z1 SO 2 , SO 2 NR Z1 , NR Z1 SO 2 NR Z2 , O, S, or NR Z1 ; wherein each occurrence of R Z1 and R Z2 is independently hydrogen, C 1-20 alkyl, heteroC 1-20 alkyl, C 3-14 aryl, C 3-14 heteroaryl or C 1-20 acyl; wherein for compounds of formula (a), when X 1 is O, the bond is a single bond;

or a pharmaceutically acceptable salt thereof.

10. The compound of claim 2 , wherein the compound has one of the following structures:

wherein Y 2 and R Y1 are independently hydrogen or C 1-6 alkyl;

or a pharmaceutically acceptable salt thereof.

11. The compound of claim 2 , wherein the compound has one of the following structures:

wherein Y 2 and R Y1 are independently hydrogen or C 1-6 alkyl; R 7 is a substituted or unsubstituted, linear or branched, cyclic or acyclic C 1-6 alkyl moiety; R 8B is hydrogen or C 1-6 alkyl; and X, Y and Z are independently a bond, —O—, —S—, —C(═O)—, —NR Z1 —, —CHOR Z1 , —CHNR Z1 R Z2 , C═S, N C═N(R Y1 ) or —CH(Hal); or a substituted or unsubstituted C 0-6 alkylidene or C 0-6 alkenylidene chain wherein up to two non-adjacent methylene units are independently optionally replaced by CO, CO 2 , COCO, CONR Z1 , OCONR Z1 , NR Z1 NR Z2 , NR Z1 NR Z2 CO, NR Z1 CO, NR Z1 CO 2 , NR Z1 CONR Z2 , SO, SO 2 , NR Z1 SO 2 , SO 2 NR Z1 , NR Z1 SO 2 NR Z2 , O, S, or NR Z1 ; wherein Hal is a halogen selected from F, Cl, Br and I; and each occurrence of R Z1 and R Z2 is independently hydrogen, C 1-20 alkyl, heteroC 1-20 alkyl, C 3-14 aryl, C 3-14 heteroaryl or C 1-20 acyl; or R Z1 and R Z2 , taken together with the nitrogen atom to which they are attached, form a C 3-20 heterocyclic or C 3-14 heteroaryl moiety;

or a pharmaceutically acceptable salt thereof.

12. The compound of claim 2 , wherein the compound has one of the following structures:

Y 2 and R Y1 are independently hydrogen or C 1-6 alkyl;

R 7 is a substituted or unsubstituted, linear or branched, cyclic or acyclic C 1-6 alkyl moiety;

R 8B is hydrogen or C 1-6 alkyl; and Y is —CHOR Y1 , —CHNR Y1 R Y2 , C═O, C═S, C═N(R Y1 ) or —CH(Hal); wherein Hal is a halogen selected from F, Cl, Br and I; and R Y1 and R Y2 are independently hydrogen, C 1-20 alkyl, heteroC 1-20 alkyl, C 3-14 aryl, C 3-14 heteroaryl or C 1-20 acyl, or R Y1 and R Y2 , taken together with the nitrogen atom to which they are attached, form a C 3-20 heterocyclic or C 3-14 heteroaryl moiety;

or a pharmaceutically acceptable salt thereof.

13. The compound of claim 2 , wherein the compound has one of the following structures:

wherein Y 2 and R Y1 are independently hydrogen or C 1-6 alkyl;

R 8B is hydrogen or C 1-6 alkyl; and RY is hydrogen, halogen, —OR Y1 or —NR Y1 NR Y2 ;

wherein R Y1 and R Y2 are independently hydrogen, C 1-20 alkyl, heteroC 1-20 alkyl, C 3-14 aryl, C 3-14 heteroaryl or C 1-20 acyl, or R Y1 and R Y2 , taken together with the nitrogen atom to which they are attached, form a C 3-20 heterocyclic or C 3-14 heteroaryl moiety;

or a pharmaceutically acceptable salt thereof.

14. The compound of claim 2 , wherein the compound has one of the following structures:

wherein Y 2 and R Y1 are independently hydrogen or C 1-6 alkyl;

R 7 is a substituted or unsubstituted, linear or branched, cyclic or acyclic C 1-6 alkyl moiety;

and R 8B is hydrogen or C 1-6 alkyl;

or a pharmaceutically acceptable salt thereof.

15. The compound of claim 1 , wherein the compound has one of the following structures:

wherein Y 2 and R Y1 are independently hydrogen or C 1-6 alkyl;

or a pharmaceutically acceptable salt thereof.

16. The compound of claim 1 , wherein the compound has one of the following structures:

and R Y1 and R Y2 are independently hydrogen or C 1-6 alkyl;

or a pharmaceutically acceptable salt thereof.

17. The compound of claim 1 , wherein R 1 and R 2 are each hydrogen.

18. The compound of claim 1 , wherein R 3 is C 1-6 alkyl.

19. The compound of claim 18 , wherein R 3 is methyl.

20. The compound of claim 1 , wherein R 5 and R 6 are each methyl;

R 4 is OH, OAc, NH 2 or halogen, or R 4 taken together with the carbon atom to which it is attached forms a moiety having the structure:

21. The compound according to any one of claim 3 or 11 , wherein R 7 is C 1-6 alkyl.

22. The compound according to claim 21 , wherein R 7 is methyl.

23. The compound according to claim 1 of formula (b) or (c) or the compound of formula (a) wherein when X 1 is O, the bond z, 900 is a single bond, wherein Q has the structure:

wherein R 7 is a substituted or unsubstituted, linear or branched, cyclic or acyclic C 1-6 alkyl moiety; R 8 is a substituted or unsubstituted C 3-20 carbocyclic, C 3-20 heterocyclic, C 3-14 aryl or C 3-14 heteroaryl moiety; and X, Y and Z are independently a bond, —O—, —S—, —C(═O)—, —NR Z1 —, —CHOR Z1 , —CHNR Z1 R Z2 , C═S, C═N(R Y1 ) OR —CH(Hal); or a substituted or unsubstituted C 0-6 alkylidene or C 0-6 alkenylidene chain where up to two non-adjacent methylene units are independently optionally replaced by CO, CO 2 , COCO, CONR Z1 , OCONR Z1 , NR Z1 NR Z2 , NR Z1 NR Z2 CO, NR Z1 CO, NR Z1 CO 2 , NR Z1 CONR Z2 , SO, SO 2 , NR Z1 SO 2 , SO 2 NR Z1 , NR Z1 SO 2 NR Z2 , O, S, or NR Z1 ; wherein Hal is a halogen selected from F, Cl, Br and I; and each occurrence of R Z1 and R Z2 is independently hydrogen, C 1-20 alkyl, heteroC 1-20 alkyl, C 3-14 aryl, C 3-14 heteroaryl or C 1-20 acyl; or R Z1 and R Z2 , taken together with the nitrogen atom to which they are attached, form a C 3-20 heterocyclic or C 3-14 heteroaryl moiety.

24. The compound according to claim 1 of formula (b) or (c) or the compound of formula (a) wherein when X 1 is O, the bond is a single bond, wherein Q has the structure:

wherein R 7 is a substituted or unsubstituted, linear or branched, cyclic or acyclic C 1-6 alkyl moiety; R 8 is a substituted or unsubstituted C 3-20 carbocyclic, C 3-20 heterocyclic, C 3-14 aryl or C 3-14 heteroaryl moiety; and R Y is hydrogen, halogen, —OR Y1 or —NR Y1 NR Y2 ; wherein R Y1 and R Y2 are independently hydrogen, C 1-20 alkyl, heteroC 1-20 alkyl, C 3-14 aryl, C 3-14 heteroaryl or C 1-20 acyl, or R Y1 and R Y2 , taken together with the nitrogen atom to which they are attached, form a C 3-20 heterocyclic or C 3-14 heteroaryl moiety.

25. The compound of any one of claim 9 , 20 , or 21 , wherein R 8 is one of:

wherein p is an integer from 0 to 5, as valency allows; q is 1 or 2, r is an integer from 1 to 6; each occurrence of R 8A is independently hydrogen, C 1-20 alkyl, heteroC 1-20 alkyl, C 3-14 aryl, C 3-14 heteroaryl, —(C 1-20 alkyl)C 3-14 aryl or —(C 1-20 alkyl)C 3-14 heteroaryl, —OR 8C , —SR 8C , —N(R 8C ) 2 , —SO 2 N(R 8C ) 2 , —(C═O)N(R 8C ) 2 , halogen, —CN, —NO 2 , —(C═O)OR 8C , —N(R 8C )(C═O)R 8D , wherein each occurrence of R 8C and R 8D is independently hydrogen, C 1-6 alkyl, C 1-6 heteroalkyl, C 3-14 aryl, C 3-14 heteroaryl, —(C 1-20 alkyl)C 1-20 aryl or —(C 1-20 alkyl)C 3-14 heteroaryl; and each occurrence of R 8B is independently hydrogen or C 1-6 alkyl.

26. The compound of claim 25 , wherein R 8 has the structure:

wherein R 8B is hydrogen or C 1-6 alkyl.

27. The compound of claim 2 or 9 , wherein Y 2 is C 1-6 alkyl and R Y1 is hydrogen or C 1-6 alkyl.

28. The compound of claim 2 or 9 , wherein R Y1 is H and Y 2 is CF 3 .

29. The compound of claim 16 , wherein R 4 is hydroxyl, C 1-6 alkoxy, acyloxy, amino or halogen, or R 4 taken together with the carbon atom to which it is attached forms a moiety having the structure:

wherein R Y1 and R Y2 are independently hydrogen, C 1-6 alkyl, C 3-14 aryl or C 3-14 heteroaryl.

30. The compound of claim 16 , wherein R 4 is OH, OAc, NH 2 or F, or R 4 taken together with the carbon atom to which it is attached forms a moiety having the structure:

31. The compound of claim 16 , wherein the stereocenter

has the following stereochemistry:

32. The compound of claim 16 , wherein the stereocenter

has the following stereochemistry:

33. The compound of claim 16 , wherein R 3 , R 5 and R 6 are each methyl and R 4 is OH, OAc, NH 2 or F, or R 4 taken together with the carbon atom to which it is attached forms a moiety having the structure:

and the stereocenter

has the following stereochemistry

34. The compound according to claim 1 , wherein the compound is selected from:

or a pharmaceutically acceptable salt thereof.

35. A compound having the formula

or pharmaceutically acceptable salt thereof.

36. A compound having the structure:

or pharmaceutically acceptable salt thereof;

wherein R 1 and R 2 are each independently hydrogen

R 3 , R 5 and R 6 are C 1-6 alkyl;

R 4 is halogen, —OR 4A , —OC(═O)R 4A or —NR 4A R 4B ; wherein R 4A and R 4B are independently hydrogen, or substituted or unsubstituted C 1-6 alkyl; a nitrogen protecting group selected from a carbamate, an amide, a cyclic imide derivative, an N-alkyl amine, an N-aryl amine, an imine derivative or an enamine derivative or an oxygen protecting group selected from a methyl ether, a substituted methyl ether, a substituted ethyl ether, a substituted benzyl ether, a silyl ether, an ester, a carbonate, a cyclic acetal or a ketal; or R 4A and R 4B , taken together with the nitrogen atom to which they are attached, form a C 3-20 heterocyclic or C 3-14 heteroaryl moiety; or R 4 , taken together with the carbon atom to which it is attached forms a moiety having the structure:

X 1 is O, S, NR X1 or CR X1 R X2 ; wherein R X1 and R X2 are independently hydrogen, halogen, or substituted or unsubstituted C 1-20 alkyl, heteroC 1-20 alkyl, cycloC 3-10 alkyl, heterocyclo C 3-10 alkyl, C 3-14 aryl or C 3-14 heteroaryl, or a nitrogen protecting group selected from a carbamate, an amide, a cyclic imide derivative, an N-alkyl amine, an N-aryl amine, an imine derivative or an enamine derivative; and

Y 1 and Y 2 are independently hydrogen, or a substituted or unsubstituted C 1-20 alkyl, heteroC 1-20 alkyl, cyclo C 3-10 alkyl, heterocycloC 3-10 alkyl, C 3-14 aryl, or C 3-14 heteroaryl moiety; or —WR Y1 ; wherein W is independently —O—, —S— or NR Y2 wherein each occurrence of R Y1 and R Y2 is independently hydrogen or an C 1-20 alkyl, heteroC 1-20 alkyl, cycloC 3-10 alkyl, heterocycloC 3-10 alkyl, C 3-14 aryl or C 3-14 heteroaryl moiety; or Y 1 and Y 2 together with the carbon atom to which they are attached form a moiety having the structure:

37. The compound of claim 36 having the structure:

wherein n is 3 ; and Y 1 and Y 2 are independently hydrogen, C 1-6 alkyl, or CF 3 .

38. The compound of claim 36 having the structure:

wherein Y 1 and Y 2 are independently hydrogen, C 1-6 alkyl, or CF 3 .

39. The compound of claim 37 or 38 , wherein R 5 and R 6 are each methyl.

40. The compound of claim 37 or 38 , wherein R 3 is lower alkyl.

41. The compound of claim 40 , wherein R 3 is methyl.

42. The compound of claim 37 or 38 , wherein R 4 is OH, OAc, NH 2 or halogen.

43. A pharmaceutical composition comprising:

a pharmaceutically acceptable carrier, adjuvant or vehicle; and

a compound according to any one of claim 1 , 34 , 35 , or 36 , or a pharmaceutically acceptable salt thereof.

44. The pharmaceutical composition of claim 43 , further comprising a cytotoxic agent.

45. The pharmaceutical composition of claim 44 , wherein the cytotoxic agent is an anticancer agent.

46. The pharmaceutical composition of claim 45 , wherein the anticancer agent is 12,13-desoxyepothilone B, (E)-9,10-dehydro-12,13-desoxyEpoB, 26-CF 3 -(E)-9,10-dehydro-12,13-desoxyEpoB, taxol, radicicol or TMC-95A/B.

47. The pharmaceutical composition of claim 43 , further comprising a palliative agent.