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Paramétrages

Paramétrages

1. WO2005063258 - CONJUGUES DE PHOSPHONATE INHIBANT LA KINASE

Note: Texte fondé sur des processus automatiques de reconnaissance optique de caractères. Seule la version PDF a une valeur juridique

Claims

We claim:

1. A compound comprising one or more phosphonates and a substructure of formula I:


wherein L1 and L2 are -N- or -CRa-; and

Ra is hydrogen, alkyl, substituted alkyl, aryl or substituted aryl;

or a pharmaceutically acceptable salt thereo.

2. The compound of claim 1 that comprises a substructure of the formula:


wherein:

L1 and L2 are independently -N-, or -CRa-, provided that only one of L1 or L2 is a nitrogen atom;

Ra is hydrogen, alkyl, aryl or substituted aryl;

R20 is hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl aryl, cycloalkyl, substituted aryl, or -NRbRc;

Rb and Rc are independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, or aralkyl;

R21 is hydrogen, alkyl, cycloalkyl, substituted cycloalkyl, substituted alkyl, aryl, substituted aryl, aralkyl, or substituted aralkyl; and

R22 and R23 are independently hydrogen, alkyl, substituted aryl, or aralkyl.

3. The compound of claim 1 that comprises a substructure of formula II:


.

4. The compound of claim 1 that comprises a substructure of formula Ilia, IVa or Va:




5. The compound of claim 1 having formula 1, 2, 3, or 4:





wherein:

A0 is A1;

A1 is:


;

A3 is:


;

Y1 is independently O, S, N(Rx), N(ORx), or N(N(Rx)( Rx));

Y2 is independently a bond, O, N(Rx), N(ORx), N(N(Rx)( Rx)), or -S(O)M2-; and when Y2 joins two phosphorous atoms Y2 can also be C(R2)(R2);

Rx is independently H, R2, W3, a protecting group, or the formula:


;

Ry is independently H, W3, R2 or a protecting group;

R2 is independently H, R3 or R4 wherein each R4 is independently substituted with 0 to 3 R3 groups;

R3 is R3a, R3b, R3c or R3d, provided that when R3 is bound to a heteroatom, then R3 is R3c or R3d:

R3a is F, Cl, Br, I, -CN, N3 or -NO2;

R3b is Y1;

R3c is -Rx, -N(Rx)(Rx), -SRx, -S(O)Rx, -S(O)2Rx, -S(O)(ORx), -S(O)2(ORx), -OC(Y1)Rx, -OC(Y1)ORx, -OC(Y1)(N(Rx)(Rx)), -SC(Y1)Rx, -SC(Y1)ORx, -SC(Y1)(N(Rx)(Rx)), -N(Rx)C(Y1)Rx, -N(Rx)C(Y1)ORx, or -N(Rx)C(Y1)(N(Rx)(Rx)) ;

R3d is -C(Y1)Rx, -C(Y1)ORx or -C(Y1)(N(Rx)(Rx));

R4 is an alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms, or alkynyl of 2 to 18 carbon atoms;

R5 is R4 wherein each R4 is substituted with 0 to 3 R3 groups;

W3 is W4 or W5;

W4 is R5, -C(Y1)R5, -C(Y1)W5, -SO2R5, or -SO2W5;

W5 is carbocycle or heterocycle wherein W5 is independently substituted with 0 to 3 R2 groups;

W6 is W3 independently substituted with 1, 2, or 3 A3 groups;

M2 is 0, 1 or 2;

M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

M12b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

M1a, M1c, and M1d are independently 0 or 1;

M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

L1 and L2 are independently -N-, or -CRa-, provided that only one of L1 or L2 is a nitrogen atom;

Ra is hydrogen, alkyl, aryl or substituted aryl;

R20 is hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl aryl, cycloalkyl, substituted aryl, or -NRbRc;

Rb and Rc are independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, or aralkyl;

R21 is hydrogen, alkyl, cycloalkyl, substituted cycloalkyl, substituted alkyl, aryl, substituted aryl, aralkyl, or substituted aralkyl; and

R22 and R23 are independently hydrogen, alkyl, substituted aryl, or aralkyl.

6. The compound of claim 5 wherein A1 is of the formula:


.

7. The compound of claim 5 wherein A1 is of the formula:


.

8. The compound of claim 5 wherein A is of the formula


.

9. The compound of claim 5 wherein A1 is of the formula:


;

10. The compound of claim 5 wherein A1 is of the formula:
;

and W5a is a carbocycle or a heterocycle where W5a is independently substituted with 0 or 1 R2 groups.

11. The compound of claim 5 wherein M12a is 1.

12. The compound of claim 5 wherein A1 is of the formula:


.

13. The compound of claim 5 wherein A1 is of the formula:


.

14. The compound of claim 5 wherein A1 is of the formula:


;

W5a is a carbocycle independently substituted with 0 or 1 R2 groups;

15. The compound of claim 5 wherein A1 is of the formula:


Y2b is O or N(R2); and

M12d is 1, 2, 3, 4, 5, 6, 7 or 8.

16. The compound of claim 5 wherein A1 is of the formula:


;

W5a is a carbocycle independently substituted with 0 or 1 R2 groups;

17. The compound of claim 5 wherein A1 is of the formula:


;

W5a is a carbocycle or heterocycle where W5a is independently substituted with 0 or 1 R2 groups.

18. The compound of claim 5 wherein A1 is of the formula:


Y2b is O orN(R2);and

M12dis1,2, 3,4, 5, 6, 7 or 8.

19. The compound of any one of claims 5-18 wherein A3 is of the formula:


.

20. The compound of any one of claims 5-18 wherein A3 is of the formula:


.

21. The compound of any one of claims 5-18 wherein A3 is of the formula:
;

Y1ais O or S;and

Y2a is O, N(Rx) or S.

22. The compound of any one of claims 5-18 wherein A 3 is of the formula:


; and Y2b is O or N(Rx).

23. The compound of any one of claims 5-18 wherein A3 is of the formula:


;

R1 is independently H or alkyl of 1 to 18 carbon atoms;

Y2b is Oor N(Rx);and

M12dis1,2, 3,4, 5, 6, 7 or 8.

24. The compound of any one of claims 5-18 wherein A3 is of the formula:
;

Y2bisOorN(Rx);and

M12d is 1,2, 3, 4, 5, 6, 7 or 8.

25. The compound of claim 24 wherein M12d is 1.

26. The compound of any one of claims 5-18 wherein A3 is of the formula:


.

27. The compound of any one of claims 5-18 wherein A3 is of the formula:


28. The compound of claim 27 wherein W5 is a carbocycle.

29. The compound of any one of claims 5-18 wherein A3 is of the formula:


30. The compound of claim 29 wherein W5 is phenyl.

31. The compound of claim 30 wherein M 12b is 1.

32. The compound of any one of claims 5-18 wherein A3 is of the formula:


; Y1a is O or S; and

Y2a is O, N(Rx) or S.

33. The compound of any one of claims 5-18 wherein A3 is of the formula:


; and Y2b is O or N(Rx).

34. The compound of any one of claims 5-18 wherein A3 is of the formula:


;

R1 is independently H or alkyl of 1 to 18 carbon atoms;

Y2b is O or N(Rx); and

M12d is 1, 2, 3, 4, 5, 6, 7 or 8.

35. The compound of claim 34 wherein R1 is H.

36. The compound of claim 34 wherein M12d is 1.

37. The compound of any one of claims 5-18 wherein A3 is of the formula:


wherein the phenyl carbocycle is substituted with 0, 1, 2, or 3 R2 groups.

38. The compound of any one of claims 5-18 wherein A3 is of the formula:
.

wherein R1 is independently H or alkyl of 1 to 18 carbon atoms.

39. The compound of any one of claims 5-18 wherein A 3 is of the formula:


.

40. The compound of any one of claims 5-18 wherein A3 is of the formula:


.

41. The compound of any one of claims 5-18 wherein A 3 is of the formula:
.

42. The compound of any one of claims 5-18 wherein A3 is of the formula:


;

Y1a is O or S; and

Y2a is O, N(R2) or S.

43. The compound of any one of claims 5-18 wherein A3 is of the formula:


;

Y1a is O or S;

Y2b is O or N(R2); and

Y2c is O, N(Ry) or S.

44. The compound of any one of claims 5-18 wherein A3 is of the formula:

R1 is independently H or alkyl of 1 to 18 carbon atoms;

Y1a is O or S;

Y2b is O or N(R2);

Y2d is O or N(Ry);and

M12d is 1,2, 3, 4, 5, 6, 7 or 8.

45. The compound of any one of claims 5-18 wherein A 3 is of the formula:


;

Y2b is O or N(R2);and

M12d is 1,2, 3, 4, 5, 6, 7 or 8.

46. The compound of any one of claims 5-18 wherein A3 is of the formula:


and Y2b isOorN(R2).

47. The compound of any one of claims 5-18 wherein A3 is of the formula:


.

48. The compound of any one of claims 5-18 wherein A3 is of the formula:


;

49. The compound of any one of claims 5-18 wherein A3 is of the formula:


; Y1a is O or S; and

Y2a is O, N(R2) or S.

50. The compound of any one of claims 5-18 wherein A3 is of the formula:
;

Y1a is O or S;

Y2bis O or N(R2);and

Y2c is O, N(Ry) or S.

51. The compound of any one of claims 5-18 wherein A3 is of the formula:


R1 is independently H or alkyl of 1 to 18 carbon atoms;

Y1a is O or S;

Y2b is O or N(R2);

Y2d is O or N(Ry);and

M12d is 1, 2, 3, 4, 5, 6, 7 or 8.

52. The compound of any one of claims 5-18 wherein A3 is of the formula:


;

Y2b isOor N(R2);and

M12d is 1,2, 3, 4, 5, 6, 7 or 8.

53. The compound of any one of claims 5-18 wherein A3 is of the formula:


aαd Y2bis O or N(R2).

54. The compound of claim 5 wherein A0 is of the formula:


wherein each R is independently (C1-C6)alkyl.

55. The compound of claim 2 wherein:

Ra is hydrogen, or substituted aryl;

R20 is hydrogen, cycloalkyl, or -NRbRc;

Rb is hydrogen, and Rc is substituted alkyl, or substituted aryl;

R21 is hydrogen, alkyl, substituted cycloalkyl, or substituted aralkyl;

R22 is hydrogen, or alkyl; and

R23 is hydrogen, substituted aryl, substituted cycloalkyl, or aralkyl.

56. The compound of any one of claims 1 -55 which inhibits a

serine/threonine kinase, tyrosine kinase, Bcr-Abl kinase, cyclin-dependent kinase, Flt3 tyrosine kinase, MAP Erk kinase, JAK3 kinase, VEGF receptor kinase, PDGF receptor tyrosine kinase, protein kinase C, insulin receptor tyrosine kinase, and/or an EGF receptor tyrosine kinase.

57. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound as described in any one of claims 1-55.

58. A unit dosage form comprising a compound as described in any one of claims 1-55 and a pharmaceutically acceptable excipient.

59. A method for inhibiting a kinase in vitro or in vivo comprising contacting a sample in need of such treatment with a compound as described in any one of claims 1-55.

60. The method of claim 59 wherein the contacting is in vivo.

61. A method of inhibiting a kinase in an animal, comprising administering a compound as described in any one of claims 1-55 to the animal.

62. The method of claim 61 wherein the compound is formulated with a pharmaceutically acceptable carrier.

63. The method of claim 62 wherein the formulation further comprises a second active ingredient.

64. The method of any one of claims 59-63 wherein the kinase is a serine/threonine kinase, tyrosine kinase, Bcr-Abl kinase, cyclin-dependent kinase, Flt3 tyrosine kinase, MAP Erk kinase, JAK3 kinase, NEGF receptor kinase, PDGF receptor tyrosine kinase, protein kinase C, insulin receptor tyrosine kinase, and/or an EGF receptor tyrosine kinase.

65. A method of treating cancer in an animal in need of such treatment comprising administering an effective amount of a compound as described in any one of claims 1-55 to the animal.

66. A compound as described in any one of claims 1-55 for use in medical therapy.

67. The use of a compound as described in any one of claims 1 -55 to prepare a medicament for inhibiting a kinase in an animal.

68. The use of claim 67 wherein the kinase is a serine/threonine kinase, tyrosine kinase, Bcr-Abl kinase, cyclin-dependent kinase, Flt3 tyrosine kinase, MAP Erk kinase, JAK3 kinase, VEGF receptor kinase, PDGF receptor tyrosine kinase, protein kinase C, insulin receptor tyrosine kinase, and/or an EGF receptor tyrosine kinase.

69. The use of a compound as described in any one of claims 1 -55 to prepare a medicament for treating cancer in an animal.

70. A method for preparing a compound as described in the schemes and examples herein.

71. A method for preparing a pharmaceutical composition, comprising combining a pharmaceutically acceptable excipient and a compound as described in any one of claims 1-55.