TWI732083B - 苯并咪唑衍生物、其藥物組合物及其應用 - Google Patents

Info

Publication number

TWI732083B

TWI732083B TW106145306A TW106145306A TWI732083B TW I732083 B TWI732083 B TW I732083B TW 106145306 A TW106145306 A TW 106145306A TW 106145306 A TW106145306 A TW 106145306A TW I732083 B TWI732083 B TW I732083B

Authority

TW

Taiwan

Prior art keywords

fluoro

methyl

pyridin

pyrimidin

compound

Prior art date

2016-12-22

Links

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• 239000008194 pharmaceutical composition Substances 0.000 title claims description 34
• 125000003785 benzimidazolyl group Chemical class N1=C(NC2=C1C=CC=C2)* 0.000 title description 2
• 150000001875 compounds Chemical class 0.000 claims abstract description 192
• -1 benzimidazole compound Chemical class 0.000 claims abstract description 31
• 206010028980 Neoplasm Diseases 0.000 claims abstract description 26
• 108010025464 Cyclin-Dependent Kinase 4 Proteins 0.000 claims abstract description 13
• 102100036252 Cyclin-dependent kinase 4 Human genes 0.000 claims abstract description 13
• 108010025468 Cyclin-Dependent Kinase 6 Proteins 0.000 claims abstract description 10
• 102100026804 Cyclin-dependent kinase 6 Human genes 0.000 claims abstract description 10
• OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Natural products OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 81
• 150000003839 salts Chemical class 0.000 claims description 42
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 33
• LJXQPZWIHJMPQQ-UHFFFAOYSA-N pyrimidin-2-amine Chemical compound NC1=NC=CC=N1 LJXQPZWIHJMPQQ-UHFFFAOYSA-N 0.000 claims description 32
• 239000003814 drug Substances 0.000 claims description 27
• 229940079593 drug Drugs 0.000 claims description 25
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 23
• 238000002360 preparation method Methods 0.000 claims description 20
• 210000004027 cell Anatomy 0.000 claims description 15
• 201000011510 cancer Diseases 0.000 claims description 11
• 229910052736 halogen Inorganic materials 0.000 claims description 11
• 150000002367 halogens Chemical class 0.000 claims description 11
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 10
• 229940043378 cyclin-dependent kinase inhibitor Drugs 0.000 claims description 8
• 229910052739 hydrogen Inorganic materials 0.000 claims description 8
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 8
• 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 claims description 8
• 239000001257 hydrogen Substances 0.000 claims description 7
• 239000000460 chlorine Substances 0.000 claims description 6
• 229910052801 chlorine Inorganic materials 0.000 claims description 6
• 229910052731 fluorine Inorganic materials 0.000 claims description 6
• 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 5
• ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 5
• PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 5
• 239000011737 fluorine Substances 0.000 claims description 5
• NVHXMNNCHAFIHX-UHFFFAOYSA-N pyridazin-3-amine Chemical compound NC1=CC=C=N[N]1 NVHXMNNCHAFIHX-UHFFFAOYSA-N 0.000 claims description 5
• 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 4
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• 208000025205 Mantle-Cell Lymphoma Diseases 0.000 claims description 4
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• 125000004575 3-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 3
• 208000003174 Brain Neoplasms Diseases 0.000 claims description 3
• 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 3
• 208000034578 Multiple myelomas Diseases 0.000 claims description 3
• XOJPAVACYRFOBK-UHFFFAOYSA-N N-[5-[(4-ethylpiperazin-1-yl)methyl]pyridin-2-yl]-5-fluoro-4-(6-fluoro-1-methyl-1,2,3,4-tetrahydropyrido[1,2-a]benzimidazol-8-yl)pyrimidin-2-amine Chemical compound C(C)N1CCN(CC1)CC=1C=CC(=NC=1)NC1=NC=C(C(=N1)C1=CC2=C(N=C3N2C(CCC3)C)C(=C1)F)F XOJPAVACYRFOBK-UHFFFAOYSA-N 0.000 claims description 3
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• 206010035226 Plasma cell myeloma Diseases 0.000 claims description 3
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• 201000001275 rectum cancer Diseases 0.000 claims description 3
• PFIWFAQPXJTVMJ-UHFFFAOYSA-N 4-(6-fluoro-1-methyl-1,2,3,4-tetrahydropyrido[1,2-a]benzimidazol-8-yl)-N-[5-(4-methylpiperazin-1-yl)pyridin-2-yl]pyrimidin-2-amine Chemical compound FC1=CC(=CC2=C1N=C1N2C(CCC1)C)C1=NC(=NC=C1)NC1=NC=C(C=C1)N1CCN(CC1)C PFIWFAQPXJTVMJ-UHFFFAOYSA-N 0.000 claims description 2
• PARKZPSTBUFKQV-UHFFFAOYSA-N 5-fluoro-4-(6-fluoro-1-methyl-1,2,3,4-tetrahydropyrido[1,2-a]benzimidazol-8-yl)-N-[5-(4-methylpiperazin-1-yl)pyridin-2-yl]pyrimidin-2-amine Chemical compound FC=1C(=NC(=NC=1)NC1=NC=C(C=C1)N1CCN(CC1)C)C1=CC2=C(N=C3N2C(CCC3)C)C(=C1)F PARKZPSTBUFKQV-UHFFFAOYSA-N 0.000 claims description 2
• UHYVUSGJRCYGIS-UHFFFAOYSA-N 5-fluoro-4-(6-fluoro-1-methyl-1,2,3,4-tetrahydropyrido[1,2-a]benzimidazol-8-yl)-N-[5-[(4-methylpiperazin-1-yl)methyl]pyrimidin-2-yl]pyrimidin-2-amine Chemical compound FC=1C(=NC(=NC=1)NC1=NC=C(C=N1)CN1CCN(CC1)C)C1=CC2=C(N=C3N2C(CCC3)C)C(=C1)F UHYVUSGJRCYGIS-UHFFFAOYSA-N 0.000 claims description 2
• 208000000461 Esophageal Neoplasms Diseases 0.000 claims description 2
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
• 239000002875 cyclin dependent kinase inhibitor Substances 0.000 claims description 2
• 201000004101 esophageal cancer Diseases 0.000 claims description 2
• 201000001441 melanoma Diseases 0.000 claims description 2
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims 3
• RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims 3
• MBWCGVALSPOFFA-UHFFFAOYSA-N 1-[[6-[[5-fluoro-4-(9-fluoro-4-methyl-3,4-dihydro-1H-[1,4]oxazino[4,3-a]benzimidazol-7-yl)pyrimidin-2-yl]amino]pyridin-3-yl]methyl]-3-methylpyrrolidin-3-ol Chemical compound FC=1C(=NC(=NC=1)NC1=CC=C(C=N1)CN1CC(CC1)(O)C)C1=CC2=C(N=C3COCC(N32)C)C(=C1)F MBWCGVALSPOFFA-UHFFFAOYSA-N 0.000 claims 1
• JQTMGOLZSBTZMS-UHFFFAOYSA-N 4-methylpiperazine-1-carbaldehyde Chemical compound CN1CCN(C=O)CC1 JQTMGOLZSBTZMS-UHFFFAOYSA-N 0.000 claims 1
• LYDUVXJJOQDXDQ-UHFFFAOYSA-N 5-chloro-N-[5-[(4-ethylpiperazin-1-yl)methyl]pyridin-2-yl]-4-(6-fluoro-1-methyl-1,2,3,4-tetrahydropyrido[1,2-a]benzimidazol-8-yl)pyrimidin-2-amine Chemical compound CCN1CCN(Cc2ccc(Nc3ncc(Cl)c(n3)-c3cc(F)c4nc5CCCC(C)n5c4c3)nc2)CC1 LYDUVXJJOQDXDQ-UHFFFAOYSA-N 0.000 claims 1
• WEHOAOIWDMWUCL-UHFFFAOYSA-N CC1CCCC2=NC3=C(N12)C=C(C=C3F)C4=NC(=NC=C4F)NC5=NC=C(C=C5)N6CC=C(C=C6)N(C)C Chemical compound CC1CCCC2=NC3=C(N12)C=C(C=C3F)C4=NC(=NC=C4F)NC5=NC=C(C=C5)N6CC=C(C=C6)N(C)C WEHOAOIWDMWUCL-UHFFFAOYSA-N 0.000 claims 1
• ZPZMQKYMPFGUAF-UHFFFAOYSA-N N-[5-[(4-ethylpiperazin-1-yl)methyl]pyridin-2-yl]-4-(6-fluoro-1-methyl-1,2,3,4,4a,5-hexahydropyrido[1,2-a]benzimidazol-8-yl)-5-methylpyrimidin-2-amine Chemical compound C(C)N1CCN(CC1)CC=1C=CC(=NC=1)NC1=NC=C(C(=N1)C1=CC2=C(NC3N2C(CCC3)C)C(=C1)F)C ZPZMQKYMPFGUAF-UHFFFAOYSA-N 0.000 claims 1
• 230000005484 gravity Effects 0.000 claims 1
• 150000002431 hydrogen Chemical class 0.000 claims 1
• CKJNUZNMWOVDFN-UHFFFAOYSA-N methanone Chemical compound O=[CH-] CKJNUZNMWOVDFN-UHFFFAOYSA-N 0.000 claims 1
• 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims 1
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