AU2001292670A1 - Pyrazole compounds useful as protein kinase inhibitors - Google Patents
Pyrazole compounds useful as protein kinase inhibitorsInfo
- Publication number
- AU2001292670A1 AU2001292670A1 AU2001292670A AU9267001A AU2001292670A1 AU 2001292670 A1 AU2001292670 A1 AU 2001292670A1 AU 2001292670 A AU2001292670 A AU 2001292670A AU 9267001 A AU9267001 A AU 9267001A AU 2001292670 A1 AU2001292670 A1 AU 2001292670A1
- Authority
- AU
- Australia
- Prior art keywords
- ring
- optionally substituted
- aliphatic
- halo
- phenyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 239000003909 protein kinase inhibitor Substances 0.000 title description 11
- 229940045988 antineoplastic drug protein kinase inhibitors Drugs 0.000 title description 6
- 150000003217 pyrazoles Chemical class 0.000 title 1
- 238000000034 method Methods 0.000 claims description 423
- 125000001931 aliphatic group Chemical group 0.000 claims description 340
- 150000001875 compounds Chemical class 0.000 claims description 287
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 206
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 201
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 197
- 125000001424 substituent group Chemical group 0.000 claims description 172
- 125000000217 alkyl group Chemical group 0.000 claims description 154
- 229910052739 hydrogen Inorganic materials 0.000 claims description 141
- 239000001257 hydrogen Substances 0.000 claims description 140
- 239000000203 mixture Substances 0.000 claims description 140
- 229910052757 nitrogen Inorganic materials 0.000 claims description 140
- 125000000623 heterocyclic group Chemical group 0.000 claims description 135
- 125000001072 heteroaryl group Chemical group 0.000 claims description 115
- 125000001475 halogen functional group Chemical group 0.000 claims description 107
- 125000005843 halogen group Chemical group 0.000 claims description 102
- 125000003118 aryl group Chemical group 0.000 claims description 98
- 125000004429 atom Chemical group 0.000 claims description 97
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 96
- 201000010099 disease Diseases 0.000 claims description 90
- 108010014905 Glycogen Synthase Kinase 3 Proteins 0.000 claims description 87
- 125000004076 pyridyl group Chemical group 0.000 claims description 87
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 82
- 125000001624 naphthyl group Chemical group 0.000 claims description 81
- 238000011282 treatment Methods 0.000 claims description 76
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims description 63
- 230000002401 inhibitory effect Effects 0.000 claims description 62
- 125000005605 benzo group Chemical group 0.000 claims description 56
- 230000000694 effects Effects 0.000 claims description 54
- 125000003386 piperidinyl group Chemical group 0.000 claims description 51
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 51
- 239000005441 aurora Substances 0.000 claims description 49
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 47
- 239000003112 inhibitor Substances 0.000 claims description 43
- 125000002619 bicyclic group Chemical group 0.000 claims description 40
- 125000004193 piperazinyl group Chemical group 0.000 claims description 40
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 38
- 229910052799 carbon Inorganic materials 0.000 claims description 38
- 125000005842 heteroatom Chemical group 0.000 claims description 38
- 229910052760 oxygen Inorganic materials 0.000 claims description 38
- 239000001301 oxygen Substances 0.000 claims description 38
- 125000006413 ring segment Chemical group 0.000 claims description 38
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 38
- 125000004607 1,2,3,4-tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 claims description 37
- 125000002757 morpholinyl group Chemical group 0.000 claims description 37
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 36
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- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 34
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 34
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 33
- 229910052717 sulfur Inorganic materials 0.000 claims description 33
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 32
- 201000011510 cancer Diseases 0.000 claims description 32
- 239000011593 sulfur Chemical group 0.000 claims description 32
- 125000004605 1,2,3,4-tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 claims description 30
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 29
- 239000012472 biological sample Substances 0.000 claims description 28
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 28
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 26
- 125000002950 monocyclic group Chemical group 0.000 claims description 26
- 150000002431 hydrogen Chemical class 0.000 claims description 24
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 23
- 229910052736 halogen Inorganic materials 0.000 claims description 22
- 206010012601 diabetes mellitus Diseases 0.000 claims description 21
- 125000001188 haloalkyl group Chemical group 0.000 claims description 21
- 125000001544 thienyl group Chemical group 0.000 claims description 21
- 125000003725 azepanyl group Chemical group 0.000 claims description 19
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- 125000004452 carbocyclyl group Chemical group 0.000 claims description 14
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- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 12
- 230000026731 phosphorylation Effects 0.000 claims description 12
- 238000006366 phosphorylation reaction Methods 0.000 claims description 12
- 125000004530 1,2,4-triazinyl group Chemical group N1=NC(=NC=C1)* 0.000 claims description 11
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 11
- 125000001118 alkylidene group Chemical group 0.000 claims description 11
- 239000003814 drug Substances 0.000 claims description 11
- 239000008103 glucose Substances 0.000 claims description 11
- 238000004519 manufacturing process Methods 0.000 claims description 11
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 11
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 11
- 201000000980 schizophrenia Diseases 0.000 claims description 11
- 230000002708 enhancing effect Effects 0.000 claims description 10
- 125000006161 haloaliphatic group Chemical group 0.000 claims description 9
- 125000004043 oxo group Chemical group O=* 0.000 claims description 9
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 8
- 229940124597 therapeutic agent Drugs 0.000 claims description 7
- 102000002254 Glycogen Synthase Kinase 3 Human genes 0.000 claims 4
- -1 heat shock factor-1 Proteins 0.000 description 274
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 136
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 93
- 102000001267 GSK3 Human genes 0.000 description 85
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 73
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 68
- 201000006417 multiple sclerosis Diseases 0.000 description 65
- 238000000524 positive electrospray ionisation mass spectrometry Methods 0.000 description 50
- 239000007787 solid Substances 0.000 description 46
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 43
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 41
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 41
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 38
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 38
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 38
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 36
- 101100439046 Caenorhabditis elegans cdk-2 gene Proteins 0.000 description 34
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 33
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 33
- 229910001868 water Inorganic materials 0.000 description 31
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 29
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 28
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- 238000005160 1H NMR spectroscopy Methods 0.000 description 26
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 description 26
- 238000002451 electron ionisation mass spectrometry Methods 0.000 description 26
- 239000008194 pharmaceutical composition Substances 0.000 description 26
- 125000003226 pyrazolyl group Chemical group 0.000 description 26
- 239000000243 solution Substances 0.000 description 25
- 230000001404 mediated effect Effects 0.000 description 24
- 239000002904 solvent Substances 0.000 description 20
- 125000004663 dialkyl amino group Chemical group 0.000 description 19
- 125000004473 dialkylaminocarbonyl group Chemical group 0.000 description 17
- 235000002639 sodium chloride Nutrition 0.000 description 17
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 16
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 16
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- OCBFFGCSTGGPSQ-UHFFFAOYSA-N [CH2]CC Chemical compound [CH2]CC OCBFFGCSTGGPSQ-UHFFFAOYSA-N 0.000 description 14
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 14
- 230000005764 inhibitory process Effects 0.000 description 14
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- 125000003282 alkyl amino group Chemical group 0.000 description 13
- 238000000746 purification Methods 0.000 description 13
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 12
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PCT/US2001/028793 WO2002022605A1 (en) | 2000-09-15 | 2001-09-14 | Pyrazole compounds useful as protein kinase inhibitors |
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AU2001296875A Abandoned AU2001296875A1 (en) | 2000-09-15 | 2001-09-14 | Triazole compounds useful as protein kinase inhibitors |
AU2001296871A Abandoned AU2001296871A1 (en) | 2000-09-15 | 2001-09-14 | Pyrazole compounds useful as protein kinase inhibitors |
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- 2001-09-14 MX MXPA03002294A patent/MXPA03002294A/es active IP Right Grant
- 2001-09-14 DE DE60119749T patent/DE60119749T2/de not_active Expired - Lifetime
- 2001-09-14 IL IL15474701A patent/IL154747A0/xx unknown
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- 2001-09-14 HU HU0401819A patent/HUP0401819A3/hu unknown
- 2001-09-14 AU AU2001291013A patent/AU2001291013A1/en not_active Abandoned
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- 2001-09-14 CN CNB018174272A patent/CN100355750C/zh not_active Expired - Fee Related
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2003
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- 2003-03-14 NO NO20031189A patent/NO326850B1/no not_active IP Right Cessation
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2006
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2008
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN109826608A (zh) * | 2019-04-08 | 2019-05-31 | 中国科学院地质与地球物理研究所 | 一种分段压裂装置 |
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