CA2517291A1 - Ortho-substituted aryl and heteroaryl tie-2 modulators and methods of use - Google Patents
Ortho-substituted aryl and heteroaryl tie-2 modulators and methods of use Download PDFInfo
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Abstract
The present invention provides compounds for modulating protein kinase enzymatic activity for modulating cellular activities such as proliferation, differentiation, programmed cell death, migration and chemoinvasion. Compounds of the invention inhibit, regulate and/or modulate kinases, particularly Tie-2. Methods of using the compounds and pharmaceutical compositions thereof to treat kinase-dependent diseases and conditions are also an aspect of the invention.
Claims (50)
1. A compound for modulating kinase activity of Formula I, or a pharmaceutically acceptable salt, hydrate, or prodrug thereof, wherein, Ar is a five- to six-membered aromatic ring system containing between one and three heteroatoms, said five- to six-membered aromatic ring system substituted with -X and -Y-L-Z, in an ortho relationship to each other, and said five- to six-membered aromatic ring system optionally substituted with up to four R1;
each R1 is independently selected from -H, halogen, -CN, -NO2, -OR3, -N(R3)R3, -s(O)O-2R3' -SO2N(R3)R3, -CO2R3, -C(O)N(R3)R3, -N(R3)SO2R3, -N(R3)C(O)R3, -N(R3)CO2R3, -C(O)R3, -OC(O)R3, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted lower arylalkyl, optionally substituted heterocyclyl, and optionally substituted lower heterocyclylalkyl;
optionally two of R1, together with the atoms to which they are attached, form a first ring system fused with Ar, said first ring system substituted with zero to three additional of R1;
X is selected from the following six formulae:
wherein, W is selected from -C(R2)(R2)-, -N(R4)-, -S(O)0-2-, and -O-;
n = 1 or 2;
p=0 or 1;
q is 1 to 3;
M is -OR3 or -N(R3)R4;
each R2 is independently selected from -H, halogen, oxo, -CN, -NH2, -NO2, -OR3, -N(R3)R3, -N(R3)R5, -S(O)0-2R3, -SO2N(R3)R3, -CO2R3, -C(O)N(R3)R3, -N(R3)SO2R3, -N(R3)C(O)R3, -N(R3)CO2R3, -N(R3)C(O)N(R3)R3, -C(O)R3, -OC(O)R3, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted lower arylalkyl, optionally substituted heterocyclyl, and optionally substituted lower heterocyclylalkyl;
two of R2, together with the atoms to which they are attached, can form an optionally substituted three- to seven-membered ring system;
each R3 is independently selected from -H, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted lower arylalkyl, optionally substituted heterocyclyl, and optionally substituted lower heterocyclylalkyl; or two of R3, when taken together with a common nitrogen to which they are attached, form an optionally substituted five- to seven-membered heterocyclyl ring, said optionally substituted five- to seven-membered heterocyclyl ring optionally containing at least one additional heteroatom selected from N, O, S, and P;
each R4 is independently selected from R3, -SO2R3, -SO2N(R3)R3, -CO2R3, -C(O)N(R3)R3, and -C(O)R3;
Y is selected from -CH2-, -O-, -S(O)0-2-, -N(R3)-, and absent;
L is selected from -(CH2)1-3-, -(CH2)1-3N(R3)-, -(CH2)1-3O-, -(CH2)1-3S(O)0-2-and absent;
each of the aforementioned methylenes optionally substituted;
Z is a five- to seven-membered ring system or -R3, said five- to seven-membered ring system optionally substituted with zero to four of R5; and R5 is selected from -H, halogen, -CN, oxo, -NO2, -OR3, -N(R3)R4, -S(O)0-2R3, -SO2N(R3)R3, -CO2R3, -C(O)N(R3)R, -N(R3)SO2R3, -N(R3)C(O)R3, -N(R3)CO2R3, -C(O)R3, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted lower arylalkyl, optionally substituted heterocyclyl, and optionally substituted lower heterocyclylalkyl; and optionally two of R5, together with the atoms to which they are attached, form a second ring system fused with said five- to seven-membered ring system, said second ring system substituted with zero to four of R5.
each R1 is independently selected from -H, halogen, -CN, -NO2, -OR3, -N(R3)R3, -s(O)O-2R3' -SO2N(R3)R3, -CO2R3, -C(O)N(R3)R3, -N(R3)SO2R3, -N(R3)C(O)R3, -N(R3)CO2R3, -C(O)R3, -OC(O)R3, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted lower arylalkyl, optionally substituted heterocyclyl, and optionally substituted lower heterocyclylalkyl;
optionally two of R1, together with the atoms to which they are attached, form a first ring system fused with Ar, said first ring system substituted with zero to three additional of R1;
X is selected from the following six formulae:
wherein, W is selected from -C(R2)(R2)-, -N(R4)-, -S(O)0-2-, and -O-;
n = 1 or 2;
p=0 or 1;
q is 1 to 3;
M is -OR3 or -N(R3)R4;
each R2 is independently selected from -H, halogen, oxo, -CN, -NH2, -NO2, -OR3, -N(R3)R3, -N(R3)R5, -S(O)0-2R3, -SO2N(R3)R3, -CO2R3, -C(O)N(R3)R3, -N(R3)SO2R3, -N(R3)C(O)R3, -N(R3)CO2R3, -N(R3)C(O)N(R3)R3, -C(O)R3, -OC(O)R3, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted lower arylalkyl, optionally substituted heterocyclyl, and optionally substituted lower heterocyclylalkyl;
two of R2, together with the atoms to which they are attached, can form an optionally substituted three- to seven-membered ring system;
each R3 is independently selected from -H, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted lower arylalkyl, optionally substituted heterocyclyl, and optionally substituted lower heterocyclylalkyl; or two of R3, when taken together with a common nitrogen to which they are attached, form an optionally substituted five- to seven-membered heterocyclyl ring, said optionally substituted five- to seven-membered heterocyclyl ring optionally containing at least one additional heteroatom selected from N, O, S, and P;
each R4 is independently selected from R3, -SO2R3, -SO2N(R3)R3, -CO2R3, -C(O)N(R3)R3, and -C(O)R3;
Y is selected from -CH2-, -O-, -S(O)0-2-, -N(R3)-, and absent;
L is selected from -(CH2)1-3-, -(CH2)1-3N(R3)-, -(CH2)1-3O-, -(CH2)1-3S(O)0-2-and absent;
each of the aforementioned methylenes optionally substituted;
Z is a five- to seven-membered ring system or -R3, said five- to seven-membered ring system optionally substituted with zero to four of R5; and R5 is selected from -H, halogen, -CN, oxo, -NO2, -OR3, -N(R3)R4, -S(O)0-2R3, -SO2N(R3)R3, -CO2R3, -C(O)N(R3)R, -N(R3)SO2R3, -N(R3)C(O)R3, -N(R3)CO2R3, -C(O)R3, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted lower arylalkyl, optionally substituted heterocyclyl, and optionally substituted lower heterocyclylalkyl; and optionally two of R5, together with the atoms to which they are attached, form a second ring system fused with said five- to seven-membered ring system, said second ring system substituted with zero to four of R5.
2. The compound according to claim 1, of formula II, wherein, A and E are each independently N or -C(R1)-; and G is selected from -S(O)0-2-, and -C(R1)=C(R1)-.
3. The compound according to claim 2, wherein Ar is selected from the following formulae.
4. The compound according to claim 3, wherein -Y-L-Z is selected from the following formulae, wherein g is zero to two; D is selected from -C(R5)(R5)-, -O-, -S(O)0-2-, and -N(R4)-; Q is =N- or -C(R5)-, T is selected from absent, -N(R3)-, -S- and -O-; and each methylene between Y and T is optionally substituted; provided that when both Y and T are heteroatoms then g must be two.
5. The compound according to claim 4, wherein Y is -O- or optionally substituted -CH2-.
6. The compound according to claim 5, wherein X is selected from the following formulae.
7. The compound according to claim 6, wherein R4a is selected from -SO2R3, -SO2N(R3)R4, -CO2R3, -C(O)N(R3)R4, and -C(O)R3.
8. The compound according to claim 7, wherein each R2 is independently selected from -H or optionally substituted lower alkyl.
9. The compound according to claim 8, wherein each R2 is independently selected from -H, haloalkyl, -C1-6alkyl-N(R3)R3, -C1-6alkyl-OR3, -C1-6alkyl-CO2R3, and -C1-6alkyl-C(O)N(R3)R3.
10. The compound according to claim 9, wherein R4a is -C(O)N(R3)R3 or-C(O)R3.
11. The compound according to claim 10, wherein -Y-L-Z is selected from the following formulae, wherein Y, T, and g are as described above.
12. The compound according to claim 11, wherein g is one or two.
13. The compound according to claim 12, wherein each R5 is independently selected from -H, halogen, -CN, -NH2, -NO2, -OR3, -N(R3)R4, -S(O)0-2R3, -SO2N(R3)R3, -CO2R3, -C(O)N(R3)R3, -N(R3)SO2R3, -N(R3)C(O)R3, -N(R3)CO2R3, -C(O)R3, and optionally substituted lower alkyl.
14. The compound according to claim 13, wherein -Y-L-Z is selected from the following formulae.
15. The compound according to claim 14, having formula III, wherein J is N or CH, and B is =N- or =C(R5)-.
16. The compound according to claim 15, wherein R3a is selected from optionally substituted aryl, optionally substituted lower arylalkyl, optionally substituted heterocyclyl, and optionally substituted lower heterocyclylalkyl.
17. The compound according to claim 16, wherein R3a is selected from optionally substituted aryl and optionally substituted heteroaryl.
18. The compound according to claim 17, wherein R3a is optionally substituted phenyl.
19. The compound according to claim 18, wherein said optionally substituted phenyl is substituted with at least one of halogen, -CN, -CF3, -NH2, -NO2, -OR3, -N(R3)R3, -S(O)0-2R3, -SO2N(R3)R3, -CO2R3, -C(O)N(R3)R3, -N(R3)SO2R3, -N(R3)C(O)R3, -N(R3)CO2R3, -C(O)R3, optionally substituted lower alkyl, and optionally substituted aryl.
20. The compound according to claim 19, wherein said optionally substituted phenyl group is substituted with at least one trifluoromethyl group.
21. The compound according to claim 20, wherein said optionally substituted phenyl group is substituted with at least two trifluoromethyl groups
22. The compound according to claim 19, wherein said optionally substituted phenyl group is substituted with at least one lower alkyl group.
23. The compound according to claim 19, wherein R3b is -H.
24. The compound according to claim 23, wherein R4b is selected from R3, -H, -CO2R3, -C(O)N(R3)R4, and -C(O)R3.
25. The compound according to claim 24, wherein Ar is according to the formula below.
26. The compound according to claim 24, wherein Ar is according to the formula below.
27. The compound according to claim 24, wherein Ar is according to the formula below.
28. The compound according to claim 24, wherein Ar is according to the formula below.
29. The compound according to claim 24, wherein Ar is according to the formula below.
30. A compound for modulating kinase activity of Formula IV, or a pharmaceutically acceptable salt, hydrate, or prodrug thereof, wherein, Ar is selected from the following formulae:
each R1 is independently selected from -H, halogen, -CN, -NO2, -OR3, -N(R3)R3, -S(O)0-2R3, -SO2N(R3)R3, -CO2R3, -C(O)N(R3)R3, -N(R3)SO2R3, -N(R3)C(O)R3, -N(R3)CO2R3, -C(O)R3, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted lower arylalkyl, optionally substituted heterocyclyl, and optionally substituted lower heterocyclylalkyl;
optionally two of R1, together with the atoms to which they are attached, form a first ring system fused with Ar, said first ring system substituted with zero to three additional of R1;
each R2 is independently selected from -H, halogen, oxo, -CN, -NH2, -NO2, -OR3, -N(R3)R3, -N(R3)R5, -S(O)0-2R3, -SO2N(R3)R3, -CO2R3, -C(O)N(R3)R3, -N(R3)SO2R3, -N(R3)C(O)R3, -N(R3)CO2R3, -N(R3)C(O)N(R3)R3, -C(O)R3, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted lower arylalkyl, optionally substituted heterocyclyl, and optionally substituted lower heterocyclylalkyl;
two of R2, together with the atoms to which they are attached, can form an optionally substituted three- to seven-membered ring system;
each R3 is independently selected from -H, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted lower arylalkyl, optionally substituted heterocyclyl, and optionally substituted lower heterocyclylalkyl; or two of R3, when taken together with a common nitrogen to which they are attached, form an optionally substituted five- to seven-membered heterocyclyl ring, said optionally substituted five- to seven-membered heterocyclyl ring optionally containing at least one additional heteroatom selected from N, O, S, and P;
each R4 is independently selected from R3, -SO2R3, -S02N(R3)R3, -CO2R3, -C(O)N(R3)R3, and -C(O)R3;
Y is selected from optionally substituted -CH2-, -O-, -S-, and -N(R3)-;
L is selected from optionally substituted -CH2-, -O-, -S-, -N(R3)- and absent;
provided that Y and L are not both heteroatoms;
B is =N- or =C(H)-;
at each instance, R5 and R6 are independently selected from -H, halogen, -CN, -NO2, -OR3, -N(R3)R4, -S(O)0-2R3, -SO2N(R3)R3, -CO2R3, -C(O)N(R3)R, -N(R3)SO2R3, -N(R3)C(O)R3, -N(R3)CO2R3, -C(O)R3, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted lower arylalkyl, optionally substituted heterocyclyl, and optionally substituted lower heterocyclylalkyl; and optionally two of R5, together with the atoms to which they are attached, form a ring system fused with the ring containing B according to formula IV, said ring system substituted with zero to two additional of R5.
each R1 is independently selected from -H, halogen, -CN, -NO2, -OR3, -N(R3)R3, -S(O)0-2R3, -SO2N(R3)R3, -CO2R3, -C(O)N(R3)R3, -N(R3)SO2R3, -N(R3)C(O)R3, -N(R3)CO2R3, -C(O)R3, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted lower arylalkyl, optionally substituted heterocyclyl, and optionally substituted lower heterocyclylalkyl;
optionally two of R1, together with the atoms to which they are attached, form a first ring system fused with Ar, said first ring system substituted with zero to three additional of R1;
each R2 is independently selected from -H, halogen, oxo, -CN, -NH2, -NO2, -OR3, -N(R3)R3, -N(R3)R5, -S(O)0-2R3, -SO2N(R3)R3, -CO2R3, -C(O)N(R3)R3, -N(R3)SO2R3, -N(R3)C(O)R3, -N(R3)CO2R3, -N(R3)C(O)N(R3)R3, -C(O)R3, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted lower arylalkyl, optionally substituted heterocyclyl, and optionally substituted lower heterocyclylalkyl;
two of R2, together with the atoms to which they are attached, can form an optionally substituted three- to seven-membered ring system;
each R3 is independently selected from -H, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted lower arylalkyl, optionally substituted heterocyclyl, and optionally substituted lower heterocyclylalkyl; or two of R3, when taken together with a common nitrogen to which they are attached, form an optionally substituted five- to seven-membered heterocyclyl ring, said optionally substituted five- to seven-membered heterocyclyl ring optionally containing at least one additional heteroatom selected from N, O, S, and P;
each R4 is independently selected from R3, -SO2R3, -S02N(R3)R3, -CO2R3, -C(O)N(R3)R3, and -C(O)R3;
Y is selected from optionally substituted -CH2-, -O-, -S-, and -N(R3)-;
L is selected from optionally substituted -CH2-, -O-, -S-, -N(R3)- and absent;
provided that Y and L are not both heteroatoms;
B is =N- or =C(H)-;
at each instance, R5 and R6 are independently selected from -H, halogen, -CN, -NO2, -OR3, -N(R3)R4, -S(O)0-2R3, -SO2N(R3)R3, -CO2R3, -C(O)N(R3)R, -N(R3)SO2R3, -N(R3)C(O)R3, -N(R3)CO2R3, -C(O)R3, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted lower arylalkyl, optionally substituted heterocyclyl, and optionally substituted lower heterocyclylalkyl; and optionally two of R5, together with the atoms to which they are attached, form a ring system fused with the ring containing B according to formula IV, said ring system substituted with zero to two additional of R5.
31. The compound according to claim 30, wherein Y is -O- and L is optionally substituted -CH2-.
32. The compound according to claim 31, wherein at least one of R6 is optionally substituted lower alkyl.
33. The compound according to claim 32, wherein said at least one optionally substituted lower alkyl is meta- to the piperazine urea function as depicted in formula IV.
34. The compound according to claim 33, wherein R4a is selected from R3, -H, -CO2R3, -C(O)N(R3)R4, and -C(O)R3.
35. The compound according to claim 34, wherein R4a is selected from -H, -CO2R3, -C(O)N(R3)R4, and -C(O)R3.
36. The compound according to claim 35, wherein -Y-L- is -OCH2-.
37. The compound according to claim 36, wherein Ar is according to the formula below.
38. The compound according to claim 36, wherein Ar is according to the formula below.
39. The compound according to claim 36, wherein Ar is according to the formula below.
40. The compound according to claim 36, wherein Ar is according to the formula below.
41. The compound according to claim 36, wherein Ar is according to the formula below.
42. The compound according to claim 1, selected from Table 4.
19~
19~
43. A pharmaceutical composition comprising the compound according to any one of claims 1 - 42 and a pharmaceutically acceptable carrier.
44. A metabolite of the compound or the pharmaceutical composition according to any one of claims 1 - 43.
45. A method of modulating the in vivo activity of a kinase, the method comprising administering to a subject an effective amount of a composition comprising at least one of the compound according to any of claims 1 - 42 and the pharmaceutical composition according to claim 43.
46. The method according to claim 45, wherein the kinase is Tie-2.
47. The method according to claim 46, wherein modulating the in vivo activity of Tie-2 comprises inhibition of Tie-2.
48. A method of treating diseases or disorders associated with uncontrolled, abnormal, and/or unwanted cellular activities, the method comprising administering, to a mammal in need thereof, a therapeutically effective amount of a composition comprising at least one of the compound according to any of claims 1 - 42 and the pharmaceutical composition according to claim 43.
49. A method of screening for modulator of a Tie-2 kinase, the method comprising combining either a composition comprising at least one of the compound according to any of claims 1 - 42 and the pharmaceutical composition according to claim 43, and at least one candidate agent and determining the effect of the candidate agent on the activity of said kinase.
50. A method of inhibiting proliferative activity in a cell, the method comprising administering to said cell an effective amount of at least one of the compound according to any of claims 1 - 42 and the pharmaceutical composition according to claim 43.
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US45656503P | 2003-03-19 | 2003-03-19 | |
US60/456,565 | 2003-03-19 | ||
PCT/US2004/008579 WO2004083235A2 (en) | 2003-03-19 | 2004-03-19 | Tie-2 modulators and methods of use |
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CA2517291C CA2517291C (en) | 2012-05-08 |
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US (1) | US8013156B2 (en) |
EP (1) | EP1608373A4 (en) |
JP (1) | JP4960085B2 (en) |
AU (1) | AU2004221812B2 (en) |
CA (1) | CA2517291C (en) |
WO (1) | WO2004083235A2 (en) |
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AU2013211455B2 (en) * | 2005-09-19 | 2017-12-07 | Neuronascent, Inc. | Methods and compositions for stimulating neurogenesis and inhibiting neuronal degeneration |
KR101158568B1 (en) | 2005-09-19 | 2012-07-02 | 뉴로내슨트, 아이엔씨. | Methods and compositions for stimulating neurogenesis and inhibiting neuronal degeneration |
EP2076499B1 (en) * | 2006-10-04 | 2010-05-12 | F.Hoffmann-La Roche Ag | Pyrazine-2-carboxamide derivatives as cb2 receptor modulators |
EP2307456B1 (en) | 2008-06-27 | 2014-10-15 | Amgen Inc. | Ang-2 inhibition to treat multiple sclerosis |
GB0818241D0 (en) | 2008-10-06 | 2008-11-12 | Cancer Res Technology | Compounds and their use |
EP2387563B2 (en) | 2009-01-16 | 2022-04-27 | Exelixis, Inc. | Malate salt of n- (4- { [ 6, 7-bis (methyloxy) quinolin-4-yl]oxy}phenyl-n' - (4 -fluorophenyl) cyclopropane-1,1-dicarboxamide, and crystalline forms thereof for the treatment of cancer |
UY33198A (en) * | 2010-01-26 | 2011-08-31 | Boehringer Ingelheim Int | 5-ALQUINIL-PYRIMIDINS. |
WO2012061337A1 (en) | 2010-11-02 | 2012-05-10 | Exelixis, Inc. | Fgfr2 modulators |
CN105636945B (en) | 2013-10-14 | 2017-11-17 | 卫材R&D管理有限公司 | The quinoline compound selectively substituted |
SI3057964T1 (en) | 2013-10-14 | 2020-03-31 | Eisai R&D Management Co., Ltd. | Selectively substituted quinoline compounds |
TWI704145B (en) | 2015-06-05 | 2020-09-11 | 芬蘭商奧利安公司 | New pharmaceutical compounds |
WO2024035627A1 (en) * | 2022-08-08 | 2024-02-15 | Ajax Therapeutics, Inc. | Heterocyclic amide and urea compounds as jak2 inhibitors |
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- 2004-03-19 AU AU2004221812A patent/AU2004221812B2/en not_active Ceased
- 2004-03-19 CA CA2517291A patent/CA2517291C/en not_active Expired - Fee Related
- 2004-03-19 US US10/549,300 patent/US8013156B2/en not_active Expired - Fee Related
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AU2004221812B2 (en) | 2010-02-18 |
US20070275952A1 (en) | 2007-11-29 |
EP1608373A4 (en) | 2010-09-29 |
WO2004083235A2 (en) | 2004-09-30 |
WO2004083235A3 (en) | 2005-03-03 |
AU2004221812A1 (en) | 2004-09-30 |
JP4960085B2 (en) | 2012-06-27 |
JP2006524682A (en) | 2006-11-02 |
EP1608373A2 (en) | 2005-12-28 |
CA2517291C (en) | 2012-05-08 |
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