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1. (WO2009151589) DIAZACARBAZOLES AND METHODS OF USE
ملاحظة: نص مبني على عمليات التَعرف الضوئي على الحروف. الرجاء إستخدام صيغ PDF لقيمتها القانونية

We claim:

1. A compound of formula (I), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), or (I-h), or a solvate, hydrate, or salt thereof:


X is CR2 or N; Y is CR4 or N; Z is CR7a or N; W is CR8a or N; provided that (i) Z and W are not both N at the same time and (ii) X and Y are not both N at the same time; R2 is H, halo, CN, CF3, -OCF3, OH, -NO2, Ci-C5 alkyl, -0(Ci-C5 alkyl), -S(C-C5 alkyl), or

N(R22)2;

R3 is H, halo, -O-R9, -N(R22)-R9, -S(O)P-R9, or R9; p is O, 1 or 2; R4 is H, halo, CN, CF3, -OCF3, OH, -NO2, -(CR14R15)nC(=Y')ORπ,

-(CR14R15)nC(=Y')NR' 1R12, -(CR14R15)nNRπR12, -(CR14R^)nOR1 ', -(CR14R1 ^(O^R1 ',

-(CR14R15)nNR12C(=Y')R11, -(CR14R15)nNR12C(=Y')ORπ, -(CR14R15)nNR12C(=Y')NRπR12, -(CR14R15)nNR12SO2R11, -(CR14R15)nOC(=Y')R11, -(CR14R15)nOC(=Y')NRI IR12, -(CR14R15)nS(O)2NRπR12, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one to four R13 groups; each n is independently 0-5;

R5 is H, CN, CF3, OH, -(CR14R15)nC(=Y')ORu, -(CR14Rls)nC(=Y')NRπR12,

-(CR14R15)nNR12C(=Y')Ru, -(CR14R15^NR11R12, -(CR14R15)nORπ, -(CR14R15)nS(O)pRu, -(CR14R15)nNR12C(=Y')OR11, -(CR14R15)nNR12C(=Y')NR11R12, -(CR14R15)nNR12SO2R11, -(CR14R15)nOC(=Y')Rπ, -(CR14R15)nOC(=Y')NRπR12, -(CR14R15)nS(O)2NRπR12, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl wherein the said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one to four R13 groups;

R6 is H, CN, -CF3, -OCF3, halo, -CC=V)OR1 \ -C(=Y')NRUR12, -OR11, -OC(=Y')RU, -NR11R12, -NR12C(=Y')RU, -NR12C(=Y')NRπR12, -NR12S(O)qRπ, -SR11, -S(O)R11, -S(O)2R11, -0C(=Y')NRuR12, -S(O)2NR11R12, -S(O)2(OR11), -SC(=Y')RU, -SC(=Y')ORπ, -SC(=Y')NRπR12, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted by one to four R13 groups;

R7a is H, halo, -CN, -OH, -NO2, -0(Ci -C3 alkyl), or Ci-C4 alkyl, wherein each said alkyl is optionally substituted with one to three groups selected from halo, N(R22)2 or OR22;

R7b is H, -OH, -CN, -0(Ci-C3 alkyl), or Ci-C4 alkyl, wherein each said alkyl is optionally substituted with one to three groups selected from halo, N(R22)2 or OR22;

R8a is H, halo, -CN, -NO2, -N(R22)2, -OH, -O(C,-C3 alkyl), or Ci-C3 alkyl, wherein each said alkyl is optionally substituted with one to three halo groups;

R8b is H, -OH, -CN, -0(Ci-C3 alkyl), or Ci-C3 alkyl, wherein each said alkyl is optionally substituted with one to three halo groups; each R9 is independently alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein each member of R is independently substituted with one to three R10 groups; each R10 is independently H, CN, -CF3, -OCF3, -NO2, halo, R11, -OR1 1, -NRI2C(=Y')Rπ,

-NR12C(=NR12)Rπ, -NR12S(COqR1 1, -SR11, -NR11R12, oxo, -C(=Y')ORπ, -C(=Y')NRπR12, -S(O)qRπ, -NR12CC=V)OR1 \ -NR12C(=Y')NRUR12, -OC(=Y')Rπ, -OC(=Y')NRπR12, or

-S(O)2NR11R12; each q independently is 1 or 2; R11 and R12 are independently H, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one to four

R13 groups, wherein two geminal R13 groups are optionally taken together with the atom to which they are attached to form a 3-6 membered ring having additional 0-2 heteroatoms selected from O, S, and N, said ring being optionally substituted with one to four R18 groups; R11 and R12 are optionally taken together with the attached N atom to form a 4-7 membered ring having additional 0-2 heteroatoms selected from O, S, and N, said ring being optionally substituted with one to four R13 groups; each R13 is independently halo, CN, CF3, -OCF3, -NO2, oxo, -(CR14R15)nC(=Y')R16,

-(CR14R15)nC(=Y')OR16, -(CR14R15)πC(=Y')NR16R17, -( CR14R15)nNR16R17,

-(CR14R15)n0R16, -(CR14R15)nSR16, -(CR14R15)nNR16C(=Y')R17,

-(CR14R15)nNR16C(=Y')OR17, -(CR14R15)nNR17C(=Y')NR16R17, -(CR14R15)nNR17SO2R16,

-(CR14R15)nOC(=Y')R16, -(CR14R15)nOC(=Y')NR16R17, -(CR14R15)nS(O)R16,

-(CR14R15)nS(O)2R16, -(CR14R15)nS(O)2NR16R17, or R16; R14 and R15 are independently selected from H, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one to four R18 groups; R16 and R17 are independently H, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one to four

R18 groups; R16 and R17 are optionally taken together with the attached N atom to form a 5-6 membered ring having additional 0-2 heteroatoms selected from O, S, and N, said ring being optionally substituted with one to four R18 groups; each R18 is independently H, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, CN, CF3,

-OCF3, -NO2, oxo, -(CR19R20)n C(=Y')R23, -(CR19R20)nC(=Y')OR23, -(CR19R20),,

C(=Y')NR23R24, -(CR19R20)nNR23R24, -(CR19R20)nOR23, -(CR19R20)n-SR23, -(CR19R20)n

NR24C(=Y')R23, -(CR19R20)n NR24C(=Y')OR23, -(CR19R20)nNR22C(=Y')NR23R24, -(CR19R20)nNR24SO2R23, -(CR19R20)nOC(=Y')R23, -(CR19R20),, OC(=Y')NR23R24, -(CR19R20)nS(O)R23, -(CR19R20)nS(O)2R23, or -(CR1V)nS(O)2NR23R24, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one to four R21 groups;

R19 and R20 are independently H, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one to four R25 groups;

R23 and R24 are independently H, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one to four R21 groups;

R23 and R24 are optionally taken together with the attached N atom to form a 5-6 membered ring having additional 0-2 heteroatoms selected from O, S, and N, said ring being optionally substituted with one to four R21 groups; each R21 is independently H, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, CN, CF3, -OCF3, -NO2, oxo, -C(=Y')R25, -C(=Y')OR25, -C(=Y')NR25R26, -NR25R26, -OR25, -SR25, -NR26C(=Y')R25, -NR26C(=Y')OR25, -NR22C(=Y')NR25R26, -NR26SO2R25, -OC(=Y')R25, -OC(=Y')NR25R26, -S(O)R25, -S(O)2R25, or -S(O)2NR25R26, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one to four R25 groups; each R25 and R26 is independently H, alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one to four groups selected from halo, -CN, -OCF3, -CF3, -NO2, -Ci-C6 alkyl, -OH, oxo, -SH, -0(Ci-C6 alkyl), -S(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), -N(Ci-C6 alkyl)2, -SO2(C1-C6 alkyl), -CO2H, -CO2(C1-C6 alkyl), -C(O)NH2, -C(O)NH(C]-C6 alkyl), -C(O)N(C1-C6 alkyl)2, -N(C]-C6 alkyl)C(O)(Ci-C6 alkyl), -NHC(O)(Ci-C6 alkyl), -NHSO2(C]-C6 alkyl), -N(Ci-C6 alkyl)SO2(Ci-C6 alkyl), -SO2NH2, -SO2NH(C1-C6 alkyl), -SO2N(C-C6 alkyl)2, -OC(O)NH2, -OC(O)NH(C]-C6 alkyl), -OC(O)N(C]-C6 alkyl)2, -NHC(O)NH(C1-C6 alkyl), -NHC(O)N(Ci-C6 alkyl)2, -N(Ci-C6 alkyl)C(O)NH(C,-C6 alkyl), -N(Ci-C6 alkyl)C(O)N(Ci-C6 alkyl)2, -NHC(O)NH(C]-C6 alkyl), -NHC(O)N(Ci-C6 alkyl)2, -NHC(O)O(Ci-C6 alkyl), and -N(C1-C6 alkyl)C(O)O(C,-C6 alkyl);

R25 and R26 are optionally taken together with the attached N atom to form a 5-6 membered ring having additional 0-2 heteroatoms selected from O, S, and N, said ring being optionally substituted with one to four groups selected from halo, -CN, -OCF3, -CF3, -NO2, -CpC6 alkyl, -OH, oxo, -SH, -0(C1-C6 alkyl), -S(Ci-C6 alkyl), -NH2, -NH(C1-C6 alkyl), -N(C1- C6 alkyl)2, -SO2(Ci-C6 alkyl), -CO2H, -CO2(Ci-C6 alkyl), -C(O)NH2, -C(O)NH(Ci-C6 alkyl), -C(O)N(C-C6 alkyl)2, -N(C1-C6 alkyl)C(O)(Ci-C6 alkyl), -NHC(O)(Ci-C6 alkyl), -NHSO2(C1-C6 alkyl), -N(CpC6 alkyl)SO2(C,-C6 alkyl), -SO2NH2, -SO2NH(Ci-C6 alkyl), -SO2N(Ci-C6 alkyl)2, -OC(O)NH2, -OC(O)NH(Ci-C6 alkyl), -OC(O)N(Ci-C6 alkyl)2, -NHC(O)NH(Ci-C6 alkyl), -NHC(O)N(C]-C6 alkyl)2, -N(Ci-C6 alkyl)C(O)NH(C,-C6 alkyl), -N(Ci-C6 alkyl)C(O)N(Ci-C6 alkyl)2, -NHC(O)NH(Ci-C6 alkyl), -NHC(O)N(Ci-C6 alkyl)2, -NHC(O)O(Ci-C6 alkyl), and -N(CpC6 alkyl)C(O)O(C,-C6 alkyl);

Y' is independently O, NR22, or S; and each R22 is independently H or C1-C5 alkyl.

2. The compound of claim 1 wherein X is CR2.

3. The compound of claim 2 wherein R2 is H.

4. The compound of claim 2 or 3 wherein Y is CR4.

5. The compound of claim 4 wherein R4 is H.

6. The compound of claim 4 or 5 wherein Z is CR7a.

7. The compound of claim 6 wherein R7a is H.

8. The compound of claim 4 or 5 wherein Z is N.

9. The compound of any one of claims 6-8 wherein W is CR8a.

10. The compound of claim 9 wherein R8a is H.

11. The compound of claim 9 or 10 wherein R3 is Br.

12. The compound of claim 9 or 10 wherein R3 is R9.

13. The compound of claim 12 wherein R9 is C2-C3 alkynyl, C6 aryl, or 5-6 membered monocyclic or 8-10 membered bicyclic heteroaryl having 1 to 2 ring atoms selected from N, O and S; and wherein each member of R9 is independently substituted with one to two R10 groups.

14. The compound of claim 13 wherein R9 is propynyl, phenyl, pyrazolyl, pyridyl, pyrimidinyl, thienyl, furanyl, imidazolyl, or benzothienyl, wherein each member of R9 is independently substituted with one to two R10 groups.

15. The compound of claim 14 wherein R9 is phenyl substituted with one to two R10 groups.

16. The compound of claim 14 or 15 wherein R10 is halo, R1 ', -OR1 1, CN, -CF3, -OCF3, -NR12C(=O)RU, -NR12S(O)C1R1 ', -SR11, -NR11R12, -Q=O)NR11R12, -S(O)qRn, or -S(O)2NR11R12, wherein R11 and R12 are optionally taken together with the attached N atom to form a 4-7 membered ring having additional 0-2 heteroatoms selected from O, S, and N, said ring being optionally substituted with one to four R13 groups.

17. The compound of claim 16 wherein R10 is R1 ' .

18. The compound of claim 17 wherein R11 is Ci-C6 alkyl, or 5-6 membered monocyclic or 8-10 membered bicyclic heterocyclyl having 1 to 2 heteroatoms selected from N and O, wherein said alkyl and heterocyclyl are optionally substituted with one to four R13 groups, wherein two geminal R13 groups are optionally taken together with the atom to which they are attached to form a six-membered ring having 0-2 heteroatom selected from O, S, and N, said ring being optionally substituted with one to four R18 groups.

19. The compound of claim 18 wherein R11 is Ci-C6 alkyl, wherein alkyl is optionally substituted with one to two R13 groups and wherein each R13 is independently halo, CN, CF3, -OCF3, oxo, -(CR14R15)nC(O)OR16, -(CR14R15)nC(O)NR16R17, -( CR14R15)nNR16R17, -(CR14R15)nOR16, -(CR14R15)nNR16C(O)R17, -(CR14R15)nS(O)2NR16R17, or R16.

20. The compound of claim 18 wherein R11 is 5-6 membered monocyclic or 8-10 membered bicyclic heterocyclyl having 1 to 2 heteroatoms selected from N and O, wherein said alkyl and heterocyclyl are optionally substituted with one to two R13 groups and wherein each R13 is independently halo, CN, CF3, -OCF3, oxo, -(CR14R15)nC(O)OR16,

-(CR14R15)nC(O)NR16R17, -( CR14R15)nNR16R17, -(CR14R15)nOR16, -(CR14R15)nNR16C(O)R17, -(CR14R15X1S(O)2NR16R17, or R16.

21. The compound of claim 16 wherein R1 ° is -OR1 ' .

22. The compound of claim 21 wherein R11 is H, Ci-C4 alkyl, or 5-6 membered monocyclic or 8-10 membered bicyclic heterocyclyl having 1 to 2 nitrogen atoms, wherein said alkyl or heterocyclyl is optionally substituted with one to two R13 groups, wherein each R13 is independently halo, CN, CF3, -OCF3, oxo, -(CR14R15)nC(O)OR16, -(CR14R1^nC(O)NR16R17, -( CR14R15)nNR16R17, -(CR14Rls)n0R16, -(CR14R15)nNR16C(O)R17, -(CR14R15)nS(O)2NR16R17, or R 16

23. The compound of any one of claims 11-22 wherein R5 is H.

24. The compound of any one of claims 11-22 wherein R5 is


25. The compound of claim 23 wherein R6 is CN, halo, -C(O)NR1 1R12, -OR11, -NR11R12, -NR12C(O)R11, Ci-C3 alkyl, C3-C6 cycloalkyl, 5-6 membered heterocyclyl having 1 to 2 heteroatoms, Ce aryl, or 5-6 membered heteroaryl having 1 to 2 heteroatoms; wherein said alkyl is substituted with one to two R13 groups except H; and said cycloalkyl, aryl, heterocyclyl or heteroaryl is optionally substituted by one to two R13 groups; wherein heteroatoms are selected from N, O and S; wherein each R12 is H or Ci-C3 alkyl and each R11 is independently H or Ci-C3 alkyl optionally substituted by one to two R13 groups.

26. The compound of claim 25 wherein R 6 is CN.

27. The compound of claim 25 wherein R6 is pyridyl, or pyrazolyl optionally substituted with methyl.

28. The title compounds of EXAMPLES 1-25.

29. A pharmaceutical composition comprising a compound of any one of claims 1-28 and a pharmaceutically acceptable carrier.

30. The pharmaceutical composition of claim 29, further comprising a second chemotherapeutic agent.

31. The pharmaceutical composition of claim 30, wherein said second chemotherapeutic agent is a DNA damaging agent.

32. A method of inhibiting abnormal cell growth or treating a hyperproliferative disorder in a mammal comprising administering to said mammal a therapeutically effective amount of a pharmaceutical composition of any one of claims 29-31.

33. The method of treating cancer in a mammal comprising administering to said mammal a therapeutically effective amount of a pharmaceutical composition of any one of claims 29-31.

34. The method of claim 33, wherein cancer is selected from breast cancer, colorectal cancer, ovarian cancer, non-small cell lung cancer, malignant brain tumors, sarcomas, melanoma, lymphoma, myelomas and leukemia.

35. The method of any one of claims 32-34, wherein said second chemotherapeutic agent is administered to said mammal sequentially or consecutively.