RU2591191C2 - Трициклические пирроло производные, способ их получения и их применение в качестве ингибиторов киназы - Google Patents

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Publication number

RU2591191C2

RU2591191C2 RU2013139353/04A RU2013139353A RU2591191C2 RU 2591191 C2 RU2591191 C2 RU 2591191C2 RU 2013139353/04 A RU2013139353/04 A RU 2013139353/04A RU 2013139353 A RU2013139353 A RU 2013139353A RU 2591191 C2 RU2591191 C2 RU 2591191C2

Authority

RU

Russia

Prior art keywords

methyl

formula

pyrrolo

carboxamide

compound

Prior art date

2011-01-26

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• 150000003233 pyrroles Chemical class 0.000 title abstract description 3
• 229940043355 kinase inhibitor Drugs 0.000 title description 5
• 239000003757 phosphotransferase inhibitor Substances 0.000 title description 5
• 238000004519 manufacturing process Methods 0.000 title description 4
• 150000001875 compounds Chemical class 0.000 claims abstract description 316
• -1 C1-C6alkoxy Chemical group 0.000 claims abstract description 136
• 238000000034 method Methods 0.000 claims abstract description 124
• 239000001257 hydrogen Substances 0.000 claims abstract description 73
• 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 73
• 125000003118 aryl group Chemical group 0.000 claims abstract description 42
• 150000002431 hydrogen Chemical class 0.000 claims abstract description 33
• 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 31
• 101000659223 Homo sapiens Dual specificity protein kinase TTK Proteins 0.000 claims abstract description 29
• 150000003839 salts Chemical class 0.000 claims abstract description 29
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 26
• 101001019502 Homo sapiens Alpha-L-iduronidase Proteins 0.000 claims abstract description 25
• 101000678466 Homo sapiens 40S ribosomal protein S27 Proteins 0.000 claims abstract description 24
• 230000000694 effects Effects 0.000 claims abstract description 21
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 20
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 20
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 20
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 18
• 102000001253 Protein Kinase Human genes 0.000 claims abstract description 17
• 108060006633 protein kinase Proteins 0.000 claims abstract description 17
• 201000010099 disease Diseases 0.000 claims abstract description 15
• 101100297651 Mus musculus Pim2 gene Proteins 0.000 claims abstract description 13
• 125000005843 halogen group Chemical group 0.000 claims abstract description 10
• 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 9
• 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 9
• 101001001642 Xenopus laevis Serine/threonine-protein kinase pim-3 Proteins 0.000 claims abstract description 8
• 125000005842 heteroatom Chemical group 0.000 claims abstract description 6
• 208000032839 leukemia Diseases 0.000 claims abstract description 6
• 208000026310 Breast neoplasm Diseases 0.000 claims abstract description 5
• 206010006187 Breast cancer Diseases 0.000 claims abstract description 4
• 206010033128 Ovarian cancer Diseases 0.000 claims abstract description 3
• 206010061535 Ovarian neoplasm Diseases 0.000 claims abstract description 3
• 206010035226 Plasma cell myeloma Diseases 0.000 claims abstract description 3
• 201000001441 melanoma Diseases 0.000 claims abstract description 3
• 201000000050 myeloid neoplasm Diseases 0.000 claims abstract description 3
• 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims abstract 2
• 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims abstract 2
• 206010009944 Colon cancer Diseases 0.000 claims abstract 2
• 208000029742 colonic neoplasm Diseases 0.000 claims abstract 2
• 238000006243 chemical reaction Methods 0.000 claims description 162
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical class CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 110
• 239000002904 solvent Substances 0.000 claims description 45
• 206010028980 Neoplasm Diseases 0.000 claims description 38
• 125000005415 substituted alkoxy group Chemical group 0.000 claims description 23
• 201000011510 cancer Diseases 0.000 claims description 20
• 239000003112 inhibitor Substances 0.000 claims description 14
• 230000002401 inhibitory effect Effects 0.000 claims description 14
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 12
• 230000002378 acidificating effect Effects 0.000 claims description 8
• 230000003993 interaction Effects 0.000 claims description 8
• 239000008194 pharmaceutical composition Substances 0.000 claims description 8
• 108090000623 proteins and genes Proteins 0.000 claims description 8
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 6
• 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 6
• 102000004169 proteins and genes Human genes 0.000 claims description 6
• 238000000338 in vitro Methods 0.000 claims description 5
• JPYAEEZHLANFOV-UHFFFAOYSA-N 2-(4-bromo-2-methoxyanilino)-n-(2,6-diethylphenyl)-9-methyl-5,6-dihydropyrrolo[3,2-h]quinazoline-7-carboxamide Chemical compound CCC1=CC=CC(CC)=C1NC(=O)C1=CN(C)C(C2=N3)=C1CCC2=CN=C3NC1=CC=C(Br)C=C1OC JPYAEEZHLANFOV-UHFFFAOYSA-N 0.000 claims description 4
• ZWVHBACWMIHSNL-UHFFFAOYSA-N 2-methylsulfanyl-9-piperidin-4-ylpyrrolo[3,2-h]quinazoline-7-carboxamide Chemical compound C1=2C3=NC(SC)=NC=C3C=CC=2C(C(N)=O)=CN1C1CCNCC1 ZWVHBACWMIHSNL-UHFFFAOYSA-N 0.000 claims description 4
• XHEYSFJJPSXTHP-UHFFFAOYSA-N 2-methylsulfanyl-9h-pyrrolo[3,2-h]quinazoline-7-carboxamide Chemical compound C12=NC(SC)=NC=C2C=CC2=C1NC=C2C(N)=O XHEYSFJJPSXTHP-UHFFFAOYSA-N 0.000 claims description 4
• RDPVTOHYFXEMBO-UHFFFAOYSA-N 5h-pyrrolo[3,2-h]quinazoline-7-carboxamide Chemical compound N1=CN=C2C3=NC=C(C(=O)N)C3=CCC2=C1 RDPVTOHYFXEMBO-UHFFFAOYSA-N 0.000 claims description 4
• KGKDUDXNIIDOCV-UHFFFAOYSA-N 8-methyl-2-methylsulfanyl-6,9-dihydro-5h-pyrrolo[3,2-h]quinazoline-7-carboxamide Chemical compound C12=NC(SC)=NC=C2CCC2=C1NC(C)=C2C(N)=O KGKDUDXNIIDOCV-UHFFFAOYSA-N 0.000 claims description 4
• PSFMCOGQKUBLKM-UHFFFAOYSA-N 8-methyl-2-methylsulfanyl-9-propan-2-ylpyrrolo[3,2-h]quinazoline-7-carboxamide Chemical compound C12=NC(SC)=NC=C2C=CC2=C1N(C(C)C)C(C)=C2C(N)=O PSFMCOGQKUBLKM-UHFFFAOYSA-N 0.000 claims description 4
• UKHAILBNXALNFF-UHFFFAOYSA-N 8-methyl-2-methylsulfanyl-9h-pyrrolo[3,2-h]quinazoline-7-carboxamide Chemical compound C12=NC(SC)=NC=C2C=CC2=C1NC(C)=C2C(N)=O UKHAILBNXALNFF-UHFFFAOYSA-N 0.000 claims description 4
• IJFXPCHHRYCYMT-UHFFFAOYSA-N 9-(2-hydroxyethyl)-2-methylsulfanyl-5,6-dihydropyrrolo[3,2-h]quinazoline-7-carboxamide Chemical compound C12=NC(SC)=NC=C2CCC2=C1N(CCO)C=C2C(N)=O IJFXPCHHRYCYMT-UHFFFAOYSA-N 0.000 claims description 4
• LVYDNZIZBIQXIS-UHFFFAOYSA-N 9-(2-hydroxyethyl)-8-methyl-2-methylsulfanylpyrrolo[3,2-h]quinazoline-7-carboxamide Chemical compound C12=NC(SC)=NC=C2C=CC2=C1N(CCO)C(C)=C2C(N)=O LVYDNZIZBIQXIS-UHFFFAOYSA-N 0.000 claims description 4
• FRANNCVVJFQWOT-TXEJJXNPSA-N C1=2C3=NC(SC)=NC=C3C=CC=2C(C(N)=O)=CN1[C@@H]1CC[C@H](N)CC1 Chemical compound C1=2C3=NC(SC)=NC=C3C=CC=2C(C(N)=O)=CN1[C@@H]1CC[C@H](N)CC1 FRANNCVVJFQWOT-TXEJJXNPSA-N 0.000 claims description 4
• 230000007062 hydrolysis Effects 0.000 claims description 4
• 238000006460 hydrolysis reaction Methods 0.000 claims description 4
• ZXOFAHRGRROAQR-UHFFFAOYSA-N 1-(isocyanomethylsulfonyl)-2-methylbenzene Chemical compound CC1=CC=CC=C1S(=O)(=O)C[N+]#[C-] ZXOFAHRGRROAQR-UHFFFAOYSA-N 0.000 claims description 3
• CQNXJSHIMDAHNX-UHFFFAOYSA-N 2-(dimethylamino)-8-methyl-6,9-dihydro-5h-pyrrolo[3,2-h]quinazoline-7-carboxamide Chemical compound C12=NC(N(C)C)=NC=C2CCC2=C1NC(C)=C2C(N)=O CQNXJSHIMDAHNX-UHFFFAOYSA-N 0.000 claims description 3
• NKTVIWIDORBNHH-UHFFFAOYSA-N 2-(dimethylamino)-8-methyl-9h-pyrrolo[3,2-h]quinazoline-7-carboxamide Chemical compound C12=NC(N(C)C)=NC=C2C=CC2=C1NC(C)=C2C(N)=O NKTVIWIDORBNHH-UHFFFAOYSA-N 0.000 claims description 3
• RJGLNSNPZNKTGL-UHFFFAOYSA-N 2-[2-methoxy-4-(4-methylpiperazin-1-yl)anilino]-8,9-dimethyl-5,6-dihydropyrrolo[3,2-h]quinazoline-7-carboxamide Chemical compound C=1C=C(NC=2N=C3C=4N(C)C(C)=C(C(N)=O)C=4CCC3=CN=2)C(OC)=CC=1N1CCN(C)CC1 RJGLNSNPZNKTGL-UHFFFAOYSA-N 0.000 claims description 3
• CCYINSRXXFXUST-UHFFFAOYSA-N 2-methyl-6,9-dihydro-5h-pyrrolo[3,2-h]quinazoline-7-carboxamide Chemical compound C12=NC(C)=NC=C2CCC2=C1NC=C2C(N)=O CCYINSRXXFXUST-UHFFFAOYSA-N 0.000 claims description 3
• YQUFJQISWIFZLH-UHFFFAOYSA-N 2-methylsulfanyl-6,9-dihydro-5h-pyrrolo[3,2-h]quinazoline-7-carboxamide Chemical compound C12=NC(SC)=NC=C2CCC2=C1NC=C2C(N)=O YQUFJQISWIFZLH-UHFFFAOYSA-N 0.000 claims description 3
• 125000004195 4-methylpiperazin-1-yl group Chemical group [H]C([H])([H])N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 3
• DGFIPMBMVVDMPR-UHFFFAOYSA-N 8-methyl-2-methylsulfanyl-9-propan-2-yl-5,6-dihydropyrrolo[3,2-h]quinazoline-7-carboxamide Chemical compound C12=NC(SC)=NC=C2CCC2=C1N(C(C)C)C(C)=C2C(N)=O DGFIPMBMVVDMPR-UHFFFAOYSA-N 0.000 claims description 3
• MNTKEWDJIACGNK-UHFFFAOYSA-N 9-(2-hydroxyethyl)-8-methyl-2-methylsulfanyl-5,6-dihydropyrrolo[3,2-h]quinazoline-7-carboxamide Chemical compound C12=NC(SC)=NC=C2CCC2=C1N(CCO)C(C)=C2C(N)=O MNTKEWDJIACGNK-UHFFFAOYSA-N 0.000 claims description 3
• QRUJSWHITUPGKU-UHFFFAOYSA-N 9-(azepan-3-yl)-2-methylsulfanylpyrrolo[3,2-h]quinazoline-7-carboxamide;hydrochloride Chemical compound Cl.C1=2C3=NC(SC)=NC=C3C=CC=2C(C(N)=O)=CN1C1CCCCNC1 QRUJSWHITUPGKU-UHFFFAOYSA-N 0.000 claims description 3
• JYHABUQXZXZOLO-UHFFFAOYSA-N 9-ethyl-2-methylsulfanylpyrrolo[3,2-h]quinazoline-7-carboxamide Chemical compound C1=NC(SC)=NC2=C3N(CC)C=C(C(N)=O)C3=CC=C21 JYHABUQXZXZOLO-UHFFFAOYSA-N 0.000 claims description 3
• UECMCGVVQAQYOJ-UHFFFAOYSA-N 9-methyl-2-methylsulfanylpyrrolo[3,2-h]quinazoline-7-carboxamide Chemical compound C12=NC(SC)=NC=C2C=CC2=C1N(C)C=C2C(N)=O UECMCGVVQAQYOJ-UHFFFAOYSA-N 0.000 claims description 3
• BRAYMNJVFKIQLD-TXEJJXNPSA-N C1=2C3=NC(SC)=NC=C3CCC=2C(C(N)=O)=CN1[C@@H]1CC[C@H](N)CC1 Chemical compound C1=2C3=NC(SC)=NC=C3CCC=2C(C(N)=O)=CN1[C@@H]1CC[C@H](N)CC1 BRAYMNJVFKIQLD-TXEJJXNPSA-N 0.000 claims description 3
• 230000008482 dysregulation Effects 0.000 claims description 3
• 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 claims description 3
• CNSGSATYYDDERW-UHFFFAOYSA-N n-(2,6-diethylphenyl)-2-[2-methoxy-4-(4-methylpiperazin-1-yl)anilino]-10-methyl-6,7-dihydro-5h-pyrrolo[4,5]cyclohepta[1,2-d]pyrimidine-8-carboxamide Chemical compound CCC1=CC=CC(CC)=C1NC(=O)C1=CN(C)C(C2=N3)=C1CCCC2=CN=C3NC1=CC=C(N2CCN(C)CC2)C=C1OC CNSGSATYYDDERW-UHFFFAOYSA-N 0.000 claims description 3
• ISJSUWAGGVIHDZ-UHFFFAOYSA-N n-(2,6-diethylphenyl)-2-[2-methoxy-4-(4-methylpiperazin-1-yl)anilino]-8,9-dimethyl-5,6-dihydropyrrolo[3,2-h]quinazoline-7-carboxamide Chemical compound CCC1=CC=CC(CC)=C1NC(=O)C1=C(C)N(C)C(C2=N3)=C1CCC2=CN=C3NC1=CC=C(N2CCN(C)CC2)C=C1OC ISJSUWAGGVIHDZ-UHFFFAOYSA-N 0.000 claims description 3
• OPNNOTYFOGVNGH-UHFFFAOYSA-N n-(2,6-diethylphenyl)-2-[2-methoxy-4-(4-methylpiperazin-1-yl)anilino]-9-methyl-5,6-dihydropyrrolo[3,2-h]quinazoline-7-carboxamide Chemical compound CCC1=CC=CC(CC)=C1NC(=O)C1=CN(C)C(C2=N3)=C1CCC2=CN=C3NC1=CC=C(N2CCN(C)CC2)C=C1OC OPNNOTYFOGVNGH-UHFFFAOYSA-N 0.000 claims description 3
• SWZFCGQEKUXWPZ-UHFFFAOYSA-N n-(2,6-diethylphenyl)-2-[2-methoxy-4-(4-pyrrolidin-1-ylpiperidin-1-yl)anilino]-8,9-dimethyl-5,6-dihydropyrrolo[3,2-h]quinazoline-7-carboxamide Chemical compound CCC1=CC=CC(CC)=C1NC(=O)C1=C(C)N(C)C(C2=N3)=C1CCC2=CN=C3NC1=CC=C(N2CCC(CC2)N2CCCC2)C=C1OC SWZFCGQEKUXWPZ-UHFFFAOYSA-N 0.000 claims description 3
• HRLWNUGLIWNXQQ-UHFFFAOYSA-N n-(2,6-diethylphenyl)-2-[2-methoxy-4-(4-pyrrolidin-1-ylpiperidin-1-yl)anilino]-9-methyl-5,6-dihydropyrrolo[3,2-h]quinazoline-7-carboxamide Chemical compound CCC1=CC=CC(CC)=C1NC(=O)C1=CN(C)C(C2=N3)=C1CCC2=CN=C3NC1=CC=C(N2CCC(CC2)N2CCCC2)C=C1OC HRLWNUGLIWNXQQ-UHFFFAOYSA-N 0.000 claims description 3
• ILEDQKOHCPIFFS-UHFFFAOYSA-N n-(2,6-diethylphenyl)-2-[4-[3-(dimethylamino)propyl-methylamino]-2-methoxyanilino]-9-methyl-5,6-dihydropyrrolo[3,2-h]quinazoline-7-carboxamide Chemical compound CCC1=CC=CC(CC)=C1NC(=O)C1=CN(C)C(C2=N3)=C1CCC2=CN=C3NC1=CC=C(N(C)CCCN(C)C)C=C1OC ILEDQKOHCPIFFS-UHFFFAOYSA-N 0.000 claims description 3
• PTUKZCQTLIICLP-UHFFFAOYSA-N n-(2,6-diethylphenyl)-2-[4-[4-(dimethylamino)piperidin-1-yl]-2-methoxyanilino]-9-methyl-5,6-dihydropyrrolo[3,2-h]quinazoline-7-carboxamide Chemical compound CCC1=CC=CC(CC)=C1NC(=O)C1=CN(C)C(C2=N3)=C1CCC2=CN=C3NC1=CC=C(N2CCC(CC2)N(C)C)C=C1OC PTUKZCQTLIICLP-UHFFFAOYSA-N 0.000 claims description 3
• 125000001424 substituent group Chemical group 0.000 claims description 3
• WVXCGDMQTJXDKL-UHFFFAOYSA-N 2-(4-bromo-2-methoxyanilino)-n-(2,6-diethylphenyl)-10-methyl-6,7-dihydro-5h-pyrrolo[4,5]cyclohepta[1,2-d]pyrimidine-8-carboxamide Chemical compound CCC1=CC=CC(CC)=C1NC(=O)C1=CN(C)C(C2=N3)=C1CCCC2=CN=C3NC1=CC=C(Br)C=C1OC WVXCGDMQTJXDKL-UHFFFAOYSA-N 0.000 claims description 2
• SNFGHOGDCXZSGY-UHFFFAOYSA-N 2-(4-bromo-2-methoxyanilino)-n-(2,6-diethylphenyl)-8,9-dimethyl-5,6-dihydropyrrolo[3,2-h]quinazoline-7-carboxamide Chemical compound CCC1=CC=CC(CC)=C1NC(=O)C1=C(C)N(C)C(C2=N3)=C1CCC2=CN=C3NC1=CC=C(Br)C=C1OC SNFGHOGDCXZSGY-UHFFFAOYSA-N 0.000 claims description 2
• HCUXMELTHAQYDN-MUUNZHRXSA-N 2-(4-bromo-2-methoxyanilino)-n-[(1s)-2-(1,3-dioxoisoindol-2-yl)-1-phenylethyl]-9-methyl-5,6-dihydropyrrolo[3,2-h]quinazoline-7-carboxamide Chemical compound COC1=CC(Br)=CC=C1NC1=NC=C(CCC2=C3N(C)C=C2C(=O)N[C@H](CN2C(C4=CC=CC=C4C2=O)=O)C=2C=CC=CC=2)C3=N1 HCUXMELTHAQYDN-MUUNZHRXSA-N 0.000 claims description 2
• QZODUKPIHBQCBB-UHFFFAOYSA-N 2-methylsulfanyl-9-piperidin-4-yl-5,6-dihydropyrrolo[3,2-h]quinazoline-7-carboxamide Chemical compound C1=2C3=NC(SC)=NC=C3CCC=2C(C(N)=O)=CN1C1CCNCC1 QZODUKPIHBQCBB-UHFFFAOYSA-N 0.000 claims description 2
• 230000002152 alkylating effect Effects 0.000 claims description 2
• 239000003085 diluting agent Substances 0.000 claims description 2
• 239000003937 drug carrier Substances 0.000 claims description 2
• RSPVCUOYQUFMQA-UHFFFAOYSA-N n-(2,6-diethylphenyl)-2-[2-methoxy-4-(4-pyrrolidin-1-ylpiperidin-1-yl)anilino]-10-methyl-6,7-dihydro-5h-pyrrolo[4,5]cyclohepta[1,2-d]pyrimidine-8-carboxamide Chemical compound CCC1=CC=CC(CC)=C1NC(=O)C1=CN(C)C(C2=N3)=C1CCCC2=CN=C3NC1=CC=C(N2CCC(CC2)N2CCCC2)C=C1OC RSPVCUOYQUFMQA-UHFFFAOYSA-N 0.000 claims description 2
• LYFDXTJJPSDFMS-UHFFFAOYSA-N n-(2,6-diethylphenyl)-2-[4-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methoxyanilino]-9-methyl-5,6-dihydropyrrolo[3,2-h]quinazoline-7-carboxamide Chemical compound CCC1=CC=CC(CC)=C1NC(=O)C1=CN(C)C(C2=N3)=C1CCC2=CN=C3NC1=CC=C(N2CCN(CCO)CC2)C=C1OC LYFDXTJJPSDFMS-UHFFFAOYSA-N 0.000 claims description 2
• ACLQSKDWSJHJCN-UHFFFAOYSA-N n-(2,6-diethylphenyl)-2-[4-[4-(dimethylamino)piperidin-1-yl]-2-methoxyanilino]-10-methyl-6,7-dihydro-5h-pyrrolo[4,5]cyclohepta[1,2-d]pyrimidine-8-carboxamide Chemical compound CCC1=CC=CC(CC)=C1NC(=O)C1=CN(C)C(C2=N3)=C1CCCC2=CN=C3NC1=CC=C(N2CCC(CC2)N(C)C)C=C1OC ACLQSKDWSJHJCN-UHFFFAOYSA-N 0.000 claims description 2
• SWEYDUSNJPBSGO-UHFFFAOYSA-N n-(2,6-diethylphenyl)-2-[4-[4-(dimethylamino)piperidin-1-yl]-2-methoxyanilino]-8,9-dimethyl-5,6-dihydropyrrolo[3,2-h]quinazoline-7-carboxamide Chemical compound CCC1=CC=CC(CC)=C1NC(=O)C1=C(C)N(C)C(C2=N3)=C1CCC2=CN=C3NC1=CC=C(N2CCC(CC2)N(C)C)C=C1OC SWEYDUSNJPBSGO-UHFFFAOYSA-N 0.000 claims description 2
• 210000000496 pancreas Anatomy 0.000 claims description 2
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
• TYHCBIKGTCZFTK-UHFFFAOYSA-N quinazoline-7-carboxamide Chemical compound C1=NC=NC2=CC(C(=O)N)=CC=C21 TYHCBIKGTCZFTK-UHFFFAOYSA-N 0.000 claims description 2
• 238000007363 ring formation reaction Methods 0.000 claims description 2
• 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims 1
• 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 claims 1
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract description 11
• 230000033228 biological regulation Effects 0.000 abstract description 8
• 239000000126 substance Substances 0.000 abstract description 7
• 230000001771 impaired effect Effects 0.000 abstract description 5
• 206010061902 Pancreatic neoplasm Diseases 0.000 abstract 1
• 208000015486 malignant pancreatic neoplasm Diseases 0.000 abstract 1
• 201000002528 pancreatic cancer Diseases 0.000 abstract 1
• 208000008443 pancreatic carcinoma Diseases 0.000 abstract 1
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 127
• 238000005481 NMR spectroscopy Methods 0.000 description 105
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 84
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 77
• 238000004128 high performance liquid chromatography Methods 0.000 description 65
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 53
• 239000000203 mixture Substances 0.000 description 48
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 47
• 238000004896 high resolution mass spectrometry Methods 0.000 description 40
• 230000014759 maintenance of location Effects 0.000 description 40
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 39
• 210000004027 cell Anatomy 0.000 description 38
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 38
• 239000000243 solution Substances 0.000 description 37
• 239000007787 solid Substances 0.000 description 35
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 33
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 31
• 239000011734 sodium Substances 0.000 description 29
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 27
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 27
• 230000009466 transformation Effects 0.000 description 26
• 102100036109 Dual specificity protein kinase TTK Human genes 0.000 description 25
• 239000011347 resin Substances 0.000 description 25
• 229920005989 resin Polymers 0.000 description 25
• 238000011282 treatment Methods 0.000 description 23
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
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