HUE034460T2 - Substituted tetrahydrocarbazole and carbazole carboxamide compounds useful as kinase inhibitors - Google Patents

Info

Publication number

HUE034460T2

HUE034460T2 HUE14740094A HUE14740094A HUE034460T2 HU E034460 T2 HUE034460 T2 HU E034460T2 HU E14740094 A HUE14740094 A HU E14740094A HU E14740094 A HUE14740094 A HU E14740094A HU E034460 T2 HUE034460 T2 HU E034460T2

Authority

HU

Hungary

Prior art keywords

mmol

formula

bromo

chloro

compounds

Prior art date

2013-06-25

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• 150000001875 compounds Chemical class 0.000 claims description 461
• -1 2-hydroxypropyl Chemical group 0.000 claims description 56
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 44
• 238000011282 treatment Methods 0.000 claims description 40
• 239000000463 material Substances 0.000 claims description 37
• ZMXDDKWLCZADIW-UHFFFAOYSA-N dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 35
• 201000010099 disease Diseases 0.000 claims description 31
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 22
• 239000000126 substance Substances 0.000 claims description 18
• 229910052801 chlorine Inorganic materials 0.000 claims description 17
• 229910052731 fluorine Inorganic materials 0.000 claims description 15
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 13
• GFHHIWFKWFBNRU-UHFFFAOYSA-N 9h-carbazole-1-carboxamide Chemical compound C12=CC=CC=C2NC2=C1C=CC=C2C(=O)N GFHHIWFKWFBNRU-UHFFFAOYSA-N 0.000 claims description 5
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
• 238000002560 therapeutic procedure Methods 0.000 claims description 5
• UJOBWOGCFQCDNV-UHFFFAOYSA-N Carbazole Natural products C1=CC=C2C3=CC=CC=C3NC2=C1 UJOBWOGCFQCDNV-UHFFFAOYSA-N 0.000 claims description 3
• 150000003857 carboxamides Chemical class 0.000 claims description 3
• 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 2
• HSCXNTXDIJELNZ-UHFFFAOYSA-N 1,2-dihydroquinoline-3,4-dione Chemical compound C1=CC=C2C(=O)C(=O)CNC2=C1 HSCXNTXDIJELNZ-UHFFFAOYSA-N 0.000 claims 1
• 208000017667 Chronic Disease Diseases 0.000 claims 1
• 235000010799 Cucumis sativus var sativus Nutrition 0.000 claims 1
• 244000299906 Cucumis sativus var. sativus Species 0.000 claims 1
• BXDZOYLPNAIDOC-UHFFFAOYSA-N N-[5-[(5-tert-butyl-1,3-oxazol-2-yl)methylsulfanyl]-1,3-thiazol-2-yl]-1-[2-[2-[2-[2-[2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]ethoxy]ethoxy]ethoxy]ethylamino]-2-oxoethyl]piperidine-4-carboxamide Chemical compound CC(C)(C)c1cnc(CSc2cnc(NC(=O)C3CCN(CC(=O)NCCOCCOCCOCCNc4cccc5C(=O)N(C6CCC(=O)NC6=O)C(=O)c45)CC3)s2)o1 BXDZOYLPNAIDOC-UHFFFAOYSA-N 0.000 claims 1
• 125000001309 chloro group Chemical group Cl* 0.000 claims 1
• 238000013329 compounding Methods 0.000 claims 1
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• 210000003038 endothelium Anatomy 0.000 claims 1
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• 230000000977 initiatory effect Effects 0.000 claims 1
• 125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims 1
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• 230000001172 regenerating effect Effects 0.000 claims 1
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims 1
• 239000000203 mixture Chemical class 0.000 description 554
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• 235000019439 ethyl acetate Nutrition 0.000 description 167
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• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 152
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• IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 104
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• HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 52
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• KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 46
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• 239000002244 precipitate Substances 0.000 description 42
• SDQJTWBNWQABLE-UHFFFAOYSA-N 1h-quinazoline-2,4-dione Chemical group C1=CC=C2C(=O)NC(=O)NC2=C1 SDQJTWBNWQABLE-UHFFFAOYSA-N 0.000 description 38
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 38
• 238000006243 chemical reaction Methods 0.000 description 37
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• 238000002347 injection Methods 0.000 description 36
• 239000007924 injection Substances 0.000 description 36
• 229910000024 caesium carbonate Inorganic materials 0.000 description 35
• 239000010410 layer Substances 0.000 description 33
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• 239000008194 pharmaceutical composition Substances 0.000 description 32
• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 31
• 239000012044 organic layer Substances 0.000 description 30
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 29
• 239000013078 crystal Chemical group 0.000 description 27
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 25
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical class CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 25
• XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 24
• IACTUCOOIHQLNN-UHFFFAOYSA-N CC(C)(O)c1ccc2c(c1)[nH]c1c(cc(Cl)c(Br)c21)C(N)=O Chemical compound CC(C)(O)c1ccc2c(c1)[nH]c1c(cc(Cl)c(Br)c21)C(N)=O IACTUCOOIHQLNN-UHFFFAOYSA-N 0.000 description 24
• 238000000746 purification Methods 0.000 description 24
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 22
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 21
• 230000000694 effects Effects 0.000 description 21
• 235000011056 potassium acetate Nutrition 0.000 description 21
• IPWKHHSGDUIRAH-UHFFFAOYSA-N bis(pinacolato)diboron Chemical compound O1C(C)(C)C(C)(C)OB1B1OC(C)(C)C(C)(C)O1 IPWKHHSGDUIRAH-UHFFFAOYSA-N 0.000 description 18
• NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 18
• 239000012453 solvate Substances 0.000 description 18
• IILVSKMKMOJHMA-UHFFFAOYSA-N 3-bromo-2-methylaniline Chemical compound CC1=C(N)C=CC=C1Br IILVSKMKMOJHMA-UHFFFAOYSA-N 0.000 description 17
• VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 17
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