Claims
- 1. A method for preparing a compound of formula I:
- 2. The method according to claim 1, wherein said compound of formula II is prepared by combining a compound of formula III with a compound of formula Rz1-Q-H in a suitable medium:
- 3. The method according to claim 2, wherein said compound of formula III is prepared by combining a compound of formula IV with a compound of formula Rz2-T-H in a suitable medium:
- 4. The method according to claim 1, wherein L3 is selected from halogen, optionally substituted arylsulfonyl, or optionally substituted alkylsulphonyl.
- 5. The method according to claim 4, wherein L3 is fluoro, chloro, bromo, iodo, paratoluenesulfonyl, methanesulfonyl, paranitrophenylsulfonyl, parabromophenylsulfonyl, or trifluoromethanesulfonate.
- 6. The method according to claim 5, wherein L3 is chloro or iodo.
- 7. The method according to claim 2, wherein L2 is halogen, optionally substituted arylsulfonyl, or optionally substituted alkylsulphonyl.
- 8. The method according to claim 7, wherein L2 is fluoro, chloro, bromo, iodo, paratoluenesulfonate, methanesulfonate, paranitrophenylsulfonyl, parabromophenylsulfonyl, or trifluoromethanesulfonate.
- 9. The method according to claim 8, wherein L2 is chloro or Iodo.
- 10. The method according to claim 3, wherein L1 is halogen, optionally substituted arylsulfonyl, or optionally substituted alkylsulphonyl.
- 11. The method according to claim 10, wherein L1 is optionally substituted alkylsulfonyl.
- 12. The method according to claim 11, wherein L1 is methanesulfonyl.
- 13. The method according to claim 1, wherein Q is N(R).
- 14. The method according to claim 1, wherein T is oxygen or sulfur.
- 15. The method according to claim 14, wherein T is sulfur.
- 16. The method according to claim 1, wherein Ry is —OR1 or —N(R1)2.
- 17. The method according to claim 16, wherein Ry is —N(R1)2, and wherein:
R1 is selected from R or a 3-7 membered monocyclic or an 8-10 membered bicyclic saturated, partially unsaturated, or fully unsaturated ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or:
each R1 is R such that the two R on the same nitrogen atom are taken together to form an optionally substituted 4-7 membered saturated ring having up to two additional heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein:
each R1 is optionally and independently substituted by up to four substituents selected from —R3, —OR3, —SR3, —CN, —NO2, oxo, halogen, —N(R3)2, —C(O)R3, —OC(O)R3, —CO2R3, —SO2R3, —SO2N(R3)2, —N(R3)SO2R3, —C(O)NR(R3), —C(O)N(R3)2, —OC(O)NR(R3), —OC(O)N(R3)2, —NR3C(O)R3, —NR3C(O)N(R3)2, or —NR3CO2(R3).
- 18. The method according to claim 17, wherein Ry is N(R1)2, wherein:
each R1 is independently selected from R, wherein R is hydrogen or an optionally substituted C1-4 aliphatic group.
- 19. The method according to claim 17, wherein Ry is N(R1)2 wherein:
each R1 is R such that the two R groups are taken together to form an optionally substituted 4-7 membered saturated ring having up to two additional heteroatoms independently selected from nitrogen, oxygen, or sulfur.
- 20. The method according to claim 19, wherein Ry is selected from pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, thiomorpholin-4-yl, piperazin-1-yl, diazepanyl, or tetrahydroisoquinolinyl, wherein each ring is optionally substituted with one or two groups independently selected from methyl, ethyl, methylsulfonyl, (CH2)2SO2CH3, cyclopropyl, CH2cyclopropyl, (CH2)2OH, CO2t-butyl, CH2phenyl, phenyl, NH2, NH(CH3), N(CH3)2, (CH2)2NH2, (CH2)2morpholin-4-yl, (CH2)2N(CH3)2, isopropyl, propyl, t-butyl, (CH2)2CN, or (CH2)2C(O)morpholin-4-yl.
- 21. The method according to claim 1, wherein Rz1 is a 3-7 membered monocyclic or an 8-10 membered bicyclic saturated, partially unsaturated, or fully unsaturated ring having 0-4 heteroatoms independently selected from oxygen, nitrogen or sulfur, wherein said ring is optionally and independently substituted by up to three substituents selected from —R3, —OR3, —SR3, —CN, —NO2, oxo, halogen, —N(R3)2, —C(O)R3, —OC(O)R3, —CO2R3, —SO2R3, —SO2N(R3)2, —N(R3)SO2R3, —C(O)NR(R3), —C(O)N(R3)2, —OC(O)NR(R3), —OC(O)N(R3)2, —NR3C(O)R3, —NR3C(O)N(R3)2, or —NR3CO2R3.
- 22. The method according to claim 21, wherein Rz1 is a 5-6 membered fully unsaturated ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is optionally and independently substituted by up to three substituents selected from —R3, —OR3, —SR3, —CN, —NO2, oxo, halogen, —N(R3)2, —C(O)R3, —OC(O)R3, —CO2R3, —SO2R3, —SO2N(R3)2, —N(R3)SO2R3, —C(O)NR(R3), —C(O)N(R3)2, —OC(O)NR(R3), —OC(O)N(R3)2, —NR3C(O)R3, —NR3C(O)N(R3)2, or —NR3CO2R3.
- 23. The method according to claim 22, wherein Rz1 is an optionally substituted ring selected from pyrazole or any one of the following 5-6 membered rings:
- 24. The method according to claim 23, wherein Rz1 is a pyrazole ring having up to two substituents independently selected from —N(R3)2, —OR3, or a C1-C4 aliphatic group.
- 25. The method according to claim 24, wherein Rz1 is a pyrazole optionally substituted with one substituent selected from methyl, ethyl, propyl, isopropyl, t-butyl, cyclopropyl, or phenyl.
- 26. The method according to claim 1, wherein Rz2 is an optionally substituted ring selected from a 5-6 membered monocyclic or an 8-10 membered bicyclic saturated, partially unsaturated, or fully unsaturated ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, wherein said ring is optionally substituted by up to three substituents independently selected from halogen, —CN, —NO2, —C(O)R3, —CO2R3, —C(O)NR(R3), —NR3C(O)R3, —N(R3)2, —N(R3)SO2R3, —NR3C(O)N(R3)2, or —NR3CO2R3.
- 27. The method according to claim 26, wherein:
Rz2 is selected from phenyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrazinyl, naphthyl, tetrahydronaphthyl, benzimidazolyl, benzthiazolyl, quinolinyl, quinazolinyl, benzodioxinyl, isobenzofuran, indanyl, indolyl, indolinyl, indazolyl, or isoquinolinyl, wherein:
Rz2 is optionally substituted with up to three substituents independently selected from —Cl, —Br, —F, —CN, —CF3, —COOH, —CONHMe, —CONHEt, —NH2, —NHAc, —NHSO2Me, —NHSO2Et, —NHSO2(n-propyl), —NHSO2(isopropyl), —NHCOEt, —NHCOCH2NHCH3, —NHCOCH2N(CO2t-Bu)CH3, —NHCOCH2N(CH3)2, —NHCOCH2CH2N(CH3)2, —NHCOCH2CH2CH2N(CH3)2, —NHCO(cyclopropyl), —NHCO(isopropyl), —NHCO(isobutyl), —NHCOCH2(morpholin-4-yl), —NHCOCH2CH2(morpholin-4-yl), —NHCOCH2CH2CH2(morpholin-4-yl), —NHCO2(t-butyl), —NH(cyclohexyl), —NHMe, —NMe2, —OH, —OMe, methyl, ethyl, cyclopropyl, isopropyl, or t-butyl.
- 28. The method according to claim 27, wherein Rz2 has one substituent selected from —NR3C(O)R3, wherein:
each R3 is independently selected from R or Ar, and wherein:
R is hydrogen or an optionally substituted C1-4 aliphatic group.
- 29. The method according to claim 1 wherein said suitable solvent is a protic solvent, a halogenated hydrocarbon, an ether, an aromatic hydrocarbon, a polar or a non-polar aprotic solvent, or any mixtures thereof.
- 30. The method according to claim 29, wherein said solvent is a C1-5 straight or branched alkyl alcohol, ether, or a polar or non-polar aprotic solvent.
- 31. The method according to claim 1 wherein said suitable base is selected from an organic amine, an alkaline earth metal carbonate, an alkaline earth metal hydride, or an alkaline earth metal hydroxide.
- 32. The method according to claim 31, wherein said suitable base is selected from a trialkyl amine, sodium carbonate, potassium carbonate, sodium hydride, potassium hydride, sodium hydroxide, or potassium hydroxide.
- 33. The method according to claim 1, wherein said method is used to prepare a compound selected from the following Table 1 and Table 2 compounds:
- 34. A compound of formula V:
- 35. The compound according to claim 34, wherein R5 is selected from hydrogen, methyl, ethyl, t-butyl, or isopropyl.
- 36. The compound according to claim 35, wherein R6 is selected from methyl, ethyl, or cyclopropyl.
- 37. The compound according to claim 36, wherein R7 is selected from methyl, ethyl, t-butyl, or cyclopropyl.
- 38. A compound selected from the following Table 1 compounds:
- 39. A compound selected from the following Table 3 compounds:
- 40. A composition comprising a compound according to claim 34, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
- 41. The composition according to claim 40, additionally comprising an anti-proliferative agent or a chemotherapeutic agent.
- 42. A method of inhibiting Aurora-1 in a biological sample, comprising contacting said sample with:
(a) a compound according to claim 34; or (b) a composition according to claim 40.
- 43. A method of inhibiting Aurora-2 in a biological sample, comprising contacting said sample with:
(a) a compound according to claim 34; or (b) a composition according to claim 40.
- 44. A method of inhibiting Aurora-3 in a biological sample, comprising contacting said sample with:
(a) a compound according to claim 34; or (b) a composition according to claim 40.
- 45. A method of inhibiting FLT-3 in a biological sample, comprising contacting said sample with:
(a) a compound according to claim 34; or (b) a composition according to claim 40.
- 46. A method of inhibiting Aurora-1 in a patient, comprising administering to said patient:
(a) a compound according to claim 34; or (b) a composition according to claim 40.
- 47. A method of inhibiting Aurora-2 in a patient, comprising administering to said patient:
(a) a compound according to claim 34; or (b) a composition according to claim 40.
- 48. A method of inhibiting Aurora-3 in a patient, comprising administering to said patient:
(a) a compound according to claim 34; or (b) a composition according to claim 40.
- 49. A method of inhibiting FLT-3 in a patient, comprising administering to said patient:
(a) a compound according to claim 34; or (b) a composition according to claim 40.
- 50. A method of inhibiting Aurora-1, Aurora-2, Aurora-3, and FLT-3 in a patient, comprising administering to said patient:
(a) a compound according to claim 34; or (b) a composition according to claim 40.
- 51. A method of treating cancer in a patient comprising the step of administering to said patient a composition according to claim 40.
- 52. The method according to claim 51 comprising the step of administering to said patient an additional chemotherapeutic or anti-proliferative agent.
- 53. The method according to claim 51, wherein said cancer is selected from melanoma, lymphoma, neuroblastoma, leukemia, or a cancer selected from colon, breast, lung, kidney, ovary, pancreatic, renal, CNS, cervical, prostate, or cancer of the gastric tract.
- 54. The method according to claim 51, wherein said cancer is selected from acute-myelogenous leukemia (AML), acute lymphocytic leukemia (ALL), mastocytosis or gastrointestinal stromal tumor (GIST).
- 55. A method of treating or lessening the severity of a cancer in a patient comprising the step of disrupting mitosis of the cancer cells by inhibiting Aurora protein kinase with a compound according to claim 34.
- 56. The method according to claim 55, comprising the step of administering to said patient a composition according to claim 40.
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority to U.S. Provisional Patent Application No. 60/390,658 filed Jun. 20, 2002 and U.S. Provisional Patent Application No. 60/411,609 filed Sep. 18, 2002, the contents of which are incorporated herein by reference.
Provisional Applications (2)
|
Number |
Date |
Country |
|
60390658 |
Jun 2002 |
US |
|
60411609 |
Sep 2002 |
US |