TWI619713B - 用於激酶調節的化合物和方法及其適應症 - Google Patents
用於激酶調節的化合物和方法及其適應症 Download PDFInfo
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- TWI619713B TWI619713B TW104127657A TW104127657A TWI619713B TW I619713 B TWI619713 B TW I619713B TW 104127657 A TW104127657 A TW 104127657A TW 104127657 A TW104127657 A TW 104127657A TW I619713 B TWI619713 B TW I619713B
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 664
- 238000000034 method Methods 0.000 title abstract description 4
- 108091000080 Phosphotransferase Proteins 0.000 title description 7
- 102000020233 phosphotransferase Human genes 0.000 title description 7
- 230000033228 biological regulation Effects 0.000 title description 2
- 150000003839 salts Chemical class 0.000 claims abstract description 62
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 12
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- 238000004519 manufacturing process Methods 0.000 claims 1
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- 101100335081 Mus musculus Flt3 gene Proteins 0.000 abstract description 5
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- 101150117329 NTRK3 gene Proteins 0.000 abstract description 5
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- 238000009472 formulation Methods 0.000 abstract description 3
- 239000000203 mixture Substances 0.000 abstract description 3
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- 125000001153 fluoro group Chemical group F* 0.000 description 412
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- 125000003545 alkoxy group Chemical group 0.000 description 389
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 351
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 323
- 125000000753 cycloalkyl group Chemical group 0.000 description 273
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 253
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- 229910052801 chlorine Inorganic materials 0.000 description 253
- 150000002431 hydrogen Chemical class 0.000 description 194
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 99
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 99
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 97
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- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 89
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- 229910052794 bromium Inorganic materials 0.000 description 66
- 239000012453 solvate Substances 0.000 description 52
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 45
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 44
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 40
- 125000005055 alkyl alkoxy group Chemical group 0.000 description 36
- 229910052757 nitrogen Inorganic materials 0.000 description 36
- 150000001721 carbon Chemical group 0.000 description 34
- 125000004433 nitrogen atom Chemical group N* 0.000 description 34
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 description 33
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 33
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- 239000002585 base Substances 0.000 description 24
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 23
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 23
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- LZTOGEVTAZHIFX-UHFFFAOYSA-N 5-chloro-3-iodo-1h-pyrrolo[2,3-b]pyridine Chemical compound ClC1=CN=C2NC=C(I)C2=C1 LZTOGEVTAZHIFX-UHFFFAOYSA-N 0.000 description 21
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 14
- IUCJMVBFZDHPDX-UHFFFAOYSA-N tretamine Chemical compound C1CN1C1=NC(N2CC2)=NC(N2CC2)=N1 IUCJMVBFZDHPDX-UHFFFAOYSA-N 0.000 description 14
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 13
- 150000001335 aliphatic alkanes Chemical group 0.000 description 13
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 12
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- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 9
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- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
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- 125000005885 heterocycloalkylalkyl group Chemical group 0.000 description 2
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- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 2
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
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- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000000000 cycloalkoxy group Chemical group 0.000 description 1
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- 125000004850 cyclobutylmethyl group Chemical group C1(CCC1)C* 0.000 description 1
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000004851 cyclopentylmethyl group Chemical group C1(CCCC1)C* 0.000 description 1
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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