CA2680757A1 - Substituted pyrimidodiazepines useful as plk1 inhibitors - Google Patents

Info

Publication number

CA2680757A1

CA2680757A1 CA002680757A CA2680757A CA2680757A1 CA 2680757 A1 CA2680757 A1 CA 2680757A1 CA 002680757 A CA002680757 A CA 002680757A CA 2680757 A CA2680757 A CA 2680757A CA 2680757 A1 CA2680757 A1 CA 2680757A1

Authority

CA

Canada

Prior art keywords

methyl

tetrahydro

pyrimido

diazepin

mole

Prior art date

2007-03-22

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

• Espacenet
• Global Dossier
• CIPO
• Discuss

• 239000003112 inhibitor Substances 0.000 title abstract description 4
• OHXQYFCNXHGKPJ-UHFFFAOYSA-N 1h-pyrimido[5,4-c]diazepine Chemical class N1N=CC=CC2=NC=NC=C12 OHXQYFCNXHGKPJ-UHFFFAOYSA-N 0.000 title 1
• 101150073897 plk1 gene Proteins 0.000 title 1
• 239000000203 mixture Substances 0.000 claims abstract description 398
• 150000001875 compounds Chemical class 0.000 claims abstract description 63
• 206010028980 Neoplasm Diseases 0.000 claims abstract description 10
• 210000000481 breast Anatomy 0.000 claims abstract description 5
• 210000001072 colon Anatomy 0.000 claims abstract description 5
• 210000004072 lung Anatomy 0.000 claims abstract description 5
• 208000026310 Breast neoplasm Diseases 0.000 claims abstract description 4
• 208000029742 colonic neoplasm Diseases 0.000 claims abstract description 4
• 208000037841 lung tumor Diseases 0.000 claims abstract description 4
• 208000023958 prostate neoplasm Diseases 0.000 claims abstract description 4
• -1 benzy Chemical group 0.000 claims description 147
• 238000000034 method Methods 0.000 claims description 56
• 239000001257 hydrogen Substances 0.000 claims description 47
• 229910052739 hydrogen Inorganic materials 0.000 claims description 47
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 28
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 26
• 150000002431 hydrogen Chemical class 0.000 claims description 18
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 16
• 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 14
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 14
• 150000003839 salts Chemical class 0.000 claims description 13
• 229910052799 carbon Inorganic materials 0.000 claims description 12
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 11
• 125000000217 alkyl group Chemical group 0.000 claims description 10
• 125000003118 aryl group Chemical group 0.000 claims description 9
• 125000001153 fluoro group Chemical group F* 0.000 claims description 8
• 239000000543 intermediate Substances 0.000 claims description 8
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 8
• 125000004484 1-methylpiperidin-4-yl group Chemical group CN1CCC(CC1)* 0.000 claims description 7
• HGIQFVGANLZKQU-UHFFFAOYSA-N 4-[(9-cyclopentyl-5,7-dimethyl-6-oxo-7,8-dihydropyrimido[4,5-b][1,4]diazepin-2-yl)amino]-3-methoxy-n-(1-methylpiperidin-4-yl)benzamide Chemical compound COC1=CC(C(=O)NC2CCN(C)CC2)=CC=C1NC(N=C12)=NC=C1N(C)C(=O)C(C)CN2C1CCCC1 HGIQFVGANLZKQU-UHFFFAOYSA-N 0.000 claims description 7
• LDHSQRGRCOVYGS-UHFFFAOYSA-N 4-[(9-cyclopentyl-5,7-dimethyl-6-oxo-7,8-dihydropyrimido[4,5-b][1,4]diazepin-2-yl)amino]-3-methyl-n-(1-methylpiperidin-4-yl)benzamide Chemical compound C12=NC(NC=3C(=CC(=CC=3)C(=O)NC3CCN(C)CC3)C)=NC=C2N(C)C(=O)C(C)CN1C1CCCC1 LDHSQRGRCOVYGS-UHFFFAOYSA-N 0.000 claims description 7
• 229910052757 nitrogen Chemical group 0.000 claims description 7
• IBPQWZCJXXORJW-UHFFFAOYSA-N 3-methoxy-4-[[5-methyl-9-(2-methylcyclopentyl)-6-oxo-7,8-dihydropyrimido[4,5-b][1,4]diazepin-2-yl]amino]-n-(1-methylpiperidin-4-yl)benzamide Chemical compound COC1=CC(C(=O)NC2CCN(C)CC2)=CC=C1NC(N=C12)=NC=C1N(C)C(=O)CCN2C1CCCC1C IBPQWZCJXXORJW-UHFFFAOYSA-N 0.000 claims description 6
• FLRQYXWPTPXTGU-UHFFFAOYSA-N 4-[(9-cyclopentyl-5-methyl-6-oxospiro[8h-pyrimido[4,5-b][1,4]diazepine-7,1'-cyclopropane]-2-yl)amino]-3-methyl-n-(1-methylpiperidin-4-yl)benzamide Chemical compound C1CN(C)CCC1NC(=O)C(C=C1C)=CC=C1NC1=NC=C(N(C)C(=O)C2(CC2)CN2C3CCCC3)C2=N1 FLRQYXWPTPXTGU-UHFFFAOYSA-N 0.000 claims description 6
• 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 6
• 125000001072 heteroaryl group Chemical group 0.000 claims description 6
• JHFJRUYFTIYHQW-UHFFFAOYSA-N n-(1-benzylpiperidin-4-yl)-4-[(9-cyclopentyl-5,7-dimethyl-6-oxo-7,8-dihydropyrimido[4,5-b][1,4]diazepin-2-yl)amino]-3-methoxybenzamide Chemical compound COC1=CC(C(=O)NC2CCN(CC=3C=CC=CC=3)CC2)=CC=C1NC(N=C12)=NC=C1N(C)C(=O)C(C)CN2C1CCCC1 JHFJRUYFTIYHQW-UHFFFAOYSA-N 0.000 claims description 6
• IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 6
• IBXXOMFMJDLCMA-UHFFFAOYSA-N 4-[(9-cyclohexyl-5,7-dimethyl-6-oxo-7,8-dihydropyrimido[4,5-b][1,4]diazepin-2-yl)amino]-3-methoxy-n-(1-methylpiperidin-4-yl)benzamide Chemical compound COC1=CC(C(=O)NC2CCN(C)CC2)=CC=C1NC(N=C12)=NC=C1N(C)C(=O)C(C)CN2C1CCCCC1 IBXXOMFMJDLCMA-UHFFFAOYSA-N 0.000 claims description 5
• CTYOHHYDHUKUIO-UHFFFAOYSA-N 4-[(9-cyclopentyl-5,7,7-trimethyl-6-oxo-8h-pyrimido[4,5-b][1,4]diazepin-2-yl)amino]-3-methoxy-n-(1-methylpiperidin-4-yl)benzamide Chemical compound COC1=CC(C(=O)NC2CCN(C)CC2)=CC=C1NC(N=C12)=NC=C1N(C)C(=O)C(C)(C)CN2C1CCCC1 CTYOHHYDHUKUIO-UHFFFAOYSA-N 0.000 claims description 5
• OIQXOUFTLOIJOI-UHFFFAOYSA-N 4-[(9-cyclopentyl-5,7,7-trimethyl-6-oxo-8h-pyrimido[4,5-b][1,4]diazepin-2-yl)amino]-n-(1-methylpiperidin-4-yl)benzamide Chemical compound C1CN(C)CCC1NC(=O)C(C=C1)=CC=C1NC1=NC=C(N(C)C(=O)C(C)(C)CN2C3CCCC3)C2=N1 OIQXOUFTLOIJOI-UHFFFAOYSA-N 0.000 claims description 5
• XQDKWJLCKMUHOU-UHFFFAOYSA-N 4-[(9-cyclopentyl-5-methyl-6-oxospiro[8h-pyrimido[4,5-b][1,4]diazepine-7,1'-cyclopropane]-2-yl)amino]-n-(1-methylpiperidin-4-yl)benzamide Chemical compound C1CN(C)CCC1NC(=O)C(C=C1)=CC=C1NC1=NC=C(N(C)C(=O)C2(CC2)CN2C3CCCC3)C2=N1 XQDKWJLCKMUHOU-UHFFFAOYSA-N 0.000 claims description 5
• NDCVIXPHNRQVDK-UHFFFAOYSA-N 4-[(9-cyclopentyl-5-methyl-6-oxospiro[8h-pyrimido[4,5-b][1,4]diazepine-7,1'-cyclopropane]-2-yl)amino]-n-(oxan-4-yl)benzamide Chemical compound N1=C2N(C3CCCC3)CC3(CC3)C(=O)N(C)C2=CN=C1NC(C=C1)=CC=C1C(=O)NC1CCOCC1 NDCVIXPHNRQVDK-UHFFFAOYSA-N 0.000 claims description 5
• 150000001412 amines Chemical class 0.000 claims description 5
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
• 125000000623 heterocyclic group Chemical group 0.000 claims description 5
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
• FQTWOSYKQWEEME-UHFFFAOYSA-N 3-methoxy-4-[(5-methyl-6-oxo-9-propan-2-yl-7,8-dihydropyrimido[4,5-b][1,4]diazepin-2-yl)amino]-n-(1-methylpiperidin-4-yl)benzamide Chemical compound C=1C=C(NC=2N=C3N(C(C)C)CCC(=O)N(C)C3=CN=2)C(OC)=CC=1C(=O)NC1CCN(C)CC1 FQTWOSYKQWEEME-UHFFFAOYSA-N 0.000 claims description 4
• ZCIPNEIFSXLQBB-UHFFFAOYSA-N 4-[(5,7-dimethyl-6-oxo-9-prop-2-enyl-7,8-dihydropyrimido[4,5-b][1,4]diazepin-2-yl)amino]-3-methoxy-n-(1-methylpiperidin-4-yl)benzamide Chemical compound C=1C=C(NC=2N=C3N(CC=C)CC(C)C(=O)N(C)C3=CN=2)C(OC)=CC=1C(=O)NC1CCN(C)CC1 ZCIPNEIFSXLQBB-UHFFFAOYSA-N 0.000 claims description 4
• AIPYUAKSIHTKGZ-UHFFFAOYSA-N 4-[(9-butyl-5-methyl-6-oxo-7,8-dihydropyrimido[4,5-b][1,4]diazepin-2-yl)amino]-3-methoxy-n-(1-methylpiperidin-4-yl)benzamide Chemical compound N1=C2N(CCCC)CCC(=O)N(C)C2=CN=C1NC(C(=C1)OC)=CC=C1C(=O)NC1CCN(C)CC1 AIPYUAKSIHTKGZ-UHFFFAOYSA-N 0.000 claims description 4
• PQAUSXLMLXRHEX-UHFFFAOYSA-N 4-[(9-cyclobutyl-5-methyl-6-oxo-7,8-dihydropyrimido[4,5-b][1,4]diazepin-2-yl)amino]-n-(3-imidazol-1-ylpropyl)-3-methoxybenzamide Chemical compound COC1=CC(C(=O)NCCCN2C=NC=C2)=CC=C1NC(N=C12)=NC=C1N(C)C(=O)CCN2C1CCC1 PQAUSXLMLXRHEX-UHFFFAOYSA-N 0.000 claims description 4
• LRDRLMCOSRRVKE-UHFFFAOYSA-N 4-[(9-cyclohexyl-5-methyl-6-oxo-7,8-dihydropyrimido[4,5-b][1,4]diazepin-2-yl)amino]-3-methoxy-n-(1-methylpiperidin-4-yl)benzamide Chemical compound COC1=CC(C(=O)NC2CCN(C)CC2)=CC=C1NC(N=C12)=NC=C1N(C)C(=O)CCN2C1CCCCC1 LRDRLMCOSRRVKE-UHFFFAOYSA-N 0.000 claims description 4
• UGRZMDBZHXAOEC-UHFFFAOYSA-N 4-[(9-cyclopentyl-5,7,7-trimethyl-6-oxo-8h-pyrimido[4,5-b][1,4]diazepin-2-yl)amino]-3-methyl-n-(1-methylpiperidin-4-yl)benzamide Chemical compound C1CN(C)CCC1NC(=O)C(C=C1C)=CC=C1NC1=NC=C(N(C)C(=O)C(C)(C)CN2C3CCCC3)C2=N1 UGRZMDBZHXAOEC-UHFFFAOYSA-N 0.000 claims description 4
• QKFBHYASVVSNKQ-UHFFFAOYSA-N 4-[(9-cyclopentyl-7-ethyl-5-methyl-6-oxo-7,8-dihydropyrimido[4,5-b][1,4]diazepin-2-yl)amino]-3-methoxy-n-(1-methylpiperidin-4-yl)benzamide Chemical compound C12=NC(NC=3C(=CC(=CC=3)C(=O)NC3CCN(C)CC3)OC)=NC=C2N(C)C(=O)C(CC)CN1C1CCCC1 QKFBHYASVVSNKQ-UHFFFAOYSA-N 0.000 claims description 4
• 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 4
• 125000005842 heteroatom Chemical group 0.000 claims description 4
• 238000004519 manufacturing process Methods 0.000 claims description 4
• QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 4
• 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 3
• POPZPBUUJSINMT-UHFFFAOYSA-N 4-[(9-cyclobutyl-5,7-dimethyl-6-oxo-7,8-dihydropyrimido[4,5-b][1,4]diazepin-2-yl)amino]-3-methoxy-n-(1-methylpiperidin-4-yl)benzamide Chemical compound COC1=CC(C(=O)NC2CCN(C)CC2)=CC=C1NC(N=C12)=NC=C1N(C)C(=O)C(C)CN2C1CCC1 POPZPBUUJSINMT-UHFFFAOYSA-N 0.000 claims description 3
• JFRNFMQDZRWAQB-UHFFFAOYSA-N 4-[(9-cyclopentyl-5-methyl-6-oxo-7,8-dihydropyrimido[4,5-b][1,4]diazepin-2-yl)amino]-3-methoxy-n-(1-methylpiperidin-4-yl)benzamide Chemical compound COC1=CC(C(=O)NC2CCN(C)CC2)=CC=C1NC(N=C12)=NC=C1N(C)C(=O)CCN2C1CCCC1 JFRNFMQDZRWAQB-UHFFFAOYSA-N 0.000 claims description 3
• DEKOFLRRNDPZDQ-UHFFFAOYSA-N 4-[(9-cyclopentyl-5-methyl-6-oxospiro[8h-pyrimido[4,5-b][1,4]diazepine-7,1'-cyclopropane]-2-yl)amino]-3-methoxy-n-(1-methylpiperidin-4-yl)benzamide Chemical compound COC1=CC(C(=O)NC2CCN(C)CC2)=CC=C1NC(N=C1N(C2CCCC2)C2)=NC=C1N(C)C(=O)C12CC1 DEKOFLRRNDPZDQ-UHFFFAOYSA-N 0.000 claims description 3
• 201000011510 cancer Diseases 0.000 claims description 3
• 125000001309 chloro group Chemical group Cl* 0.000 claims description 3
• 239000003814 drug Substances 0.000 claims description 3
• 229910052736 halogen Inorganic materials 0.000 claims description 3
• 150000002367 halogens Chemical class 0.000 claims description 3
• 229910052760 oxygen Inorganic materials 0.000 claims description 3
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
• 230000008569 process Effects 0.000 claims description 3
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
• 125000001424 substituent group Chemical group 0.000 claims description 3
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 2
• 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 2
• DJNZZLZKAXGMMC-UHFFFAOYSA-N 4-[(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-8h-pyrimido[4,5-b][1,4]diazepin-2-yl)amino]-3-methoxy-n-(1-methylpiperidin-4-yl)benzamide Chemical compound COC1=CC(C(=O)NC2CCN(C)CC2)=CC=C1NC(N=C12)=NC=C1N(C)C(=O)C(F)(F)CN2C1CCCC1 DJNZZLZKAXGMMC-UHFFFAOYSA-N 0.000 claims description 2
• GAWIXWVDTYZWAW-UHFFFAOYSA-N C[CH]O Chemical group C[CH]O GAWIXWVDTYZWAW-UHFFFAOYSA-N 0.000 claims description 2
• 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 2
• 125000001246 bromo group Chemical group Br* 0.000 claims description 2
• 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 2
• 125000002346 iodo group Chemical group I* 0.000 claims description 2
• 125000003386 piperidinyl group Chemical group 0.000 claims description 2
• 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 2
• 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 2
• 229920002554 vinyl polymer Polymers 0.000 claims description 2
• 102100031463 Serine/threonine-protein kinase PLK1 Human genes 0.000 abstract description 12
• 108010056274 polo-like kinase 1 Proteins 0.000 abstract description 11
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 7
• 230000000771 oncological effect Effects 0.000 abstract description 4
• 208000015914 Non-Hodgkin lymphomas Diseases 0.000 abstract description 3
• 201000010099 disease Diseases 0.000 abstract description 3
• 230000002062 proliferating effect Effects 0.000 abstract description 3
• 238000009472 formulation Methods 0.000 abstract description 2
• XEKOWRVHYACXOJ-UHFFFAOYSA-N ethyl acetate Substances CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 535
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 298
• 230000002829 reductive effect Effects 0.000 description 217
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 193
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 156
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• 239000000243 solution Substances 0.000 description 146
• 239000007787 solid Substances 0.000 description 117
• 238000010898 silica gel chromatography Methods 0.000 description 116
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 107
• 239000010410 layer Substances 0.000 description 102
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 94
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• 239000012267 brine Substances 0.000 description 82
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 82
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 81
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• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 48
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• KYSGSGFXDCAVQB-UHFFFAOYSA-N 2-chloro-9-cyclopentyl-5,7-dimethyl-7,8-dihydropyrimido[4,5-b][1,4]diazepin-6-one Chemical compound C12=NC(Cl)=NC=C2N(C)C(=O)C(C)CN1C1CCCC1 KYSGSGFXDCAVQB-UHFFFAOYSA-N 0.000 description 40
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• FWPIDFUJEMBDLS-UHFFFAOYSA-L tin(II) chloride dihydrate Chemical compound O.O.Cl[Sn]Cl FWPIDFUJEMBDLS-UHFFFAOYSA-L 0.000 description 18
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