JP5087640B2 - Ｐｌｋ１阻害剤として有用な置換ピリミドジアゼピン - Google Patents

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Publication number

JP5087640B2

JP5087640B2 JP2009553997A JP2009553997A JP5087640B2 JP 5087640 B2 JP5087640 B2 JP 5087640B2 JP 2009553997 A JP2009553997 A JP 2009553997A JP 2009553997 A JP2009553997 A JP 2009553997A JP 5087640 B2 JP5087640 B2 JP 5087640B2

Authority

JP

Japan

Prior art keywords

mole

methyl

tetrahydro

pyrimido

rac

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.)

Expired - Fee Related

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• 102100031463 Serine/threonine-protein kinase PLK1 Human genes 0.000 title description 12
• 108010056274 polo-like kinase 1 Proteins 0.000 title description 11
• 239000003112 inhibitor Substances 0.000 title description 3
• OHXQYFCNXHGKPJ-UHFFFAOYSA-N 1h-pyrimido[5,4-c]diazepine Chemical class N1N=CC=CC2=NC=NC=C12 OHXQYFCNXHGKPJ-UHFFFAOYSA-N 0.000 title 1
• 150000001875 compounds Chemical class 0.000 claims description 39
• 150000003839 salts Chemical class 0.000 claims description 13
• 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 10
• DQJHTCZROXSXEZ-UHFFFAOYSA-N 4-[(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-8h-pyrimido[4,5-b][1,4]diazepin-2-yl)amino]-3-methoxybenzoic acid Chemical compound COC1=CC(C(O)=O)=CC=C1NC1=NC=C(N(C)C(=O)C(F)(F)CN2C3CCCC3)C2=N1 DQJHTCZROXSXEZ-UHFFFAOYSA-N 0.000 claims description 5
• 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 5
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
• 239000008194 pharmaceutical composition Substances 0.000 claims 3
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 513
• 239000000203 mixture Substances 0.000 description 371
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 288
• 230000002829 reductive effect Effects 0.000 description 219
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 192
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 153
• 239000000243 solution Substances 0.000 description 142
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 138
• -1 PLK1 Proteins 0.000 description 121
• 239000007787 solid Substances 0.000 description 115
• 238000010898 silica gel chromatography Methods 0.000 description 112
• 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 97
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 94
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 92
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 84
• 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
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 80
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 78
• 238000000746 purification Methods 0.000 description 52
• 238000001914 filtration Methods 0.000 description 51
• 239000012044 organic layer Substances 0.000 description 51
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 48
• CVLAEJNQNKXNNN-UHFFFAOYSA-N diazepin-4-one Chemical compound O=C1C=CC=NN=C1 CVLAEJNQNKXNNN-UHFFFAOYSA-N 0.000 description 44
• 239000002244 precipitate Substances 0.000 description 40
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 39
• PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical compound O.CC#N PBCJIPOGFJYBJE-UHFFFAOYSA-N 0.000 description 37
• OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 37
• ALOCUZOKRULSAA-UHFFFAOYSA-N 1-methylpiperidin-4-amine Chemical compound CN1CCC(N)CC1 ALOCUZOKRULSAA-UHFFFAOYSA-N 0.000 description 35
• 239000003921 oil Substances 0.000 description 35
• 235000019198 oils Nutrition 0.000 description 35
• WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 34
• INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 34
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 33
• OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 33
• 239000012071 phase Substances 0.000 description 33
• KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 32
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 32
• 239000001257 hydrogen Substances 0.000 description 32
• 229910052739 hydrogen Inorganic materials 0.000 description 32
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 31
• 229910000028 potassium bicarbonate Inorganic materials 0.000 description 28
• 235000015497 potassium bicarbonate Nutrition 0.000 description 28
• 239000011736 potassium bicarbonate Substances 0.000 description 28
• TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 28
• 238000010992 reflux Methods 0.000 description 27
• JXYPNRIYAMXJSE-UHFFFAOYSA-N 1,4-diazepin-6-one Chemical compound O=C1C=NC=CN=C1 JXYPNRIYAMXJSE-UHFFFAOYSA-N 0.000 description 26
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 26
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 26
• 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 26
• 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 26
• 238000001816 cooling Methods 0.000 description 25
• 239000000284 extract Substances 0.000 description 25
• 238000000034 method Methods 0.000 description 25
• JNFGLYJROFAOQP-UHFFFAOYSA-N 4-amino-3-methoxybenzoic acid Chemical compound COC1=CC(C(O)=O)=CC=C1N JNFGLYJROFAOQP-UHFFFAOYSA-N 0.000 description 24
• KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 24
• 239000012312 sodium hydride Substances 0.000 description 24
• 229910000104 sodium hydride Inorganic materials 0.000 description 24
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 23
• 239000000706 filtrate Substances 0.000 description 23
• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 23
• 235000017557 sodium bicarbonate Nutrition 0.000 description 23
• INUSQTPGSHFGHM-UHFFFAOYSA-N 2,4-dichloro-5-nitropyrimidine Chemical compound [O-][N+](=O)C1=CN=C(Cl)N=C1Cl INUSQTPGSHFGHM-UHFFFAOYSA-N 0.000 description 22
• 239000008346 aqueous phase Substances 0.000 description 21
• PNGLEYLFMHGIQO-UHFFFAOYSA-M sodium;3-(n-ethyl-3-methoxyanilino)-2-hydroxypropane-1-sulfonate;dihydrate Chemical compound O.O.[Na+].[O-]S(=O)(=O)CC(O)CN(CC)C1=CC=CC(OC)=C1 PNGLEYLFMHGIQO-UHFFFAOYSA-M 0.000 description 20
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
• 239000012074 organic phase Substances 0.000 description 18
• 239000000843 powder Substances 0.000 description 18
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 18
• 239000003054 catalyst Substances 0.000 description 17
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 17
• 239000012298 atmosphere Substances 0.000 description 15
• FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 14
• CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 14
• 238000006243 chemical reaction Methods 0.000 description 14
• 239000011541 reaction mixture Substances 0.000 description 14
• VFBAFXHFFOATDK-UHFFFAOYSA-N 4-[(9-cyclopentyl-5,7-dimethyl-6-oxo-7,8-dihydropyrimido[4,5-b][1,4]diazepin-2-yl)amino]-3-methoxybenzoic acid Chemical compound COC1=CC(C(O)=O)=CC=C1NC1=NC=C(N(C)C(=O)C(C)CN2C3CCCC3)C2=N1 VFBAFXHFFOATDK-UHFFFAOYSA-N 0.000 description 13
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 13
• 125000000217 alkyl group Chemical group 0.000 description 13
• 239000000463 material Substances 0.000 description 13
• 238000003756 stirring Methods 0.000 description 13
• 239000000725 suspension Substances 0.000 description 13
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 13
• XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 12
• KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 12
• 239000012321 sodium triacetoxyborohydride Substances 0.000 description 12
• 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 description 11
• 235000011114 ammonium hydroxide Nutrition 0.000 description 11
• FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 11
• 229910000024 caesium carbonate Inorganic materials 0.000 description 11
• UHCROXCVKZSKQH-UHFFFAOYSA-N 4-[(9-cyclohexyl-6-oxo-7,8-dihydro-5h-pyrimido[4,5-b][1,4]diazepin-2-yl)amino]-3-methoxybenzoic acid Chemical compound COC1=CC(C(O)=O)=CC=C1NC1=NC=C(NC(=O)CCN2C3CCCCC3)C2=N1 UHCROXCVKZSKQH-UHFFFAOYSA-N 0.000 description 10
• XBYFLVPPIOYEJF-UHFFFAOYSA-N 4-amino-3-methoxy-n-(1-methylpiperidin-4-yl)benzamide Chemical compound C1=C(N)C(OC)=CC(C(=O)NC2CCN(C)CC2)=C1 XBYFLVPPIOYEJF-UHFFFAOYSA-N 0.000 description 10
• VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 10
• 239000005711 Benzoic acid Substances 0.000 description 10
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 10
• VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 10
• 239000002253 acid Substances 0.000 description 10
• 239000000908 ammonium hydroxide Substances 0.000 description 10
• WBKFWQBXFREOFH-UHFFFAOYSA-N dichloromethane;ethyl acetate Chemical compound ClCCl.CCOC(C)=O WBKFWQBXFREOFH-UHFFFAOYSA-N 0.000 description 10
• 239000002904 solvent Substances 0.000 description 10
• YJBKVPRVZAQTPY-UHFFFAOYSA-J tetrachlorostannane;dihydrate Chemical compound O.O.Cl[Sn](Cl)(Cl)Cl YJBKVPRVZAQTPY-UHFFFAOYSA-J 0.000 description 10
• 238000010792 warming Methods 0.000 description 10
• 239000001632 sodium acetate Substances 0.000 description 9
• 235000017281 sodium acetate Nutrition 0.000 description 9
• FGUUSXIOTUKUDN-IBGZPJMESA-N C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 Chemical compound C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 FGUUSXIOTUKUDN-IBGZPJMESA-N 0.000 description 8
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 8
• 229910052799 carbon Inorganic materials 0.000 description 8
• 210000004027 cell Anatomy 0.000 description 8
• SPWVRYZQLGQKGK-UHFFFAOYSA-N dichloromethane;hexane Chemical compound ClCCl.CCCCCC SPWVRYZQLGQKGK-UHFFFAOYSA-N 0.000 description 8
• 150000002431 hydrogen Chemical class 0.000 description 8
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 8
• 0 *C(*)(C(*)(*)N)C(O*)=C Chemical compound *C(*)(C(*)(*)N)C(O*)=C 0.000 description 7
• ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 7
• 125000003118 aryl group Chemical group 0.000 description 7
• 238000009835 boiling Methods 0.000 description 7
• 239000012230 colorless oil Substances 0.000 description 7
• BGTOWKSIORTVQH-UHFFFAOYSA-N cyclopentanone Chemical compound O=C1CCCC1 BGTOWKSIORTVQH-UHFFFAOYSA-N 0.000 description 7
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 7
• 239000000543 intermediate Substances 0.000 description 7
• XQSNXLDLKOJJOU-UHFFFAOYSA-N pyrimido[5,4-c]diazepin-3-one Chemical compound N1=NC(=O)C=CC2=NC=NC=C21 XQSNXLDLKOJJOU-UHFFFAOYSA-N 0.000 description 7
• 125000004484 1-methylpiperidin-4-yl group Chemical group CN1CCC(CC1)* 0.000 description 6
• 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 description 6
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
• 239000002671 adjuvant Substances 0.000 description 6
• 125000003545 alkoxy group Chemical group 0.000 description 6
• NISGSNTVMOOSJQ-UHFFFAOYSA-N cyclopentanamine Chemical compound NC1CCCC1 NISGSNTVMOOSJQ-UHFFFAOYSA-N 0.000 description 6
• LHDCHYVFWKPLQZ-UHFFFAOYSA-N ethyl 3-[(2-chloro-5-nitropyrimidin-4-yl)-cyclopentylamino]propanoate Chemical compound N=1C(Cl)=NC=C([N+]([O-])=O)C=1N(CCC(=O)OCC)C1CCCC1 LHDCHYVFWKPLQZ-UHFFFAOYSA-N 0.000 description 6
• 239000012065 filter cake Substances 0.000 description 6
• 229910000029 sodium carbonate Inorganic materials 0.000 description 6
• ITHXIBFJDSOAJB-UHFFFAOYSA-N 13-chloro-2-cyclopentyl-2,9,12,14-tetrazatricyclo[8.4.0.03,7]tetradeca-1(14),10,12-trien-8-one Chemical compound C12=NC(Cl)=NC=C2NC(=O)C2CCCC2N1C1CCCC1 ITHXIBFJDSOAJB-UHFFFAOYSA-N 0.000 description 5
• 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 description 5
• 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 description 5
• 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 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 description 5
• QGMRUXZRDZDXQB-UHFFFAOYSA-N 4-[(9-cyclopentyl-5,7-dimethyl-6-oxo-7,8-dihydropyrimido[4,5-b][1,4]diazepin-2-yl)amino]-3-methylbenzoic acid Chemical compound C12=NC(NC=3C(=CC(=CC=3)C(O)=O)C)=NC=C2N(C)C(=O)C(C)CN1C1CCCC1 QGMRUXZRDZDXQB-UHFFFAOYSA-N 0.000 description 5
• YFERVAVZCUFSOD-UHFFFAOYSA-N 4-[(9-cyclopentyl-5,7-dimethyl-6-oxo-7,8-dihydropyrimido[4,5-b][1,4]diazepin-2-yl)amino]-n-(1-methylpiperidin-4-yl)benzamide Chemical compound C12=NC(NC=3C=CC(=CC=3)C(=O)NC3CCN(C)CC3)=NC=C2N(C)C(=O)C(C)CN1C1CCCC1 YFERVAVZCUFSOD-UHFFFAOYSA-N 0.000 description 5
• NCBDNLPHIWOJDM-UHFFFAOYSA-N 4-[(9-cyclopentyl-5,8-dimethyl-6-oxo-7,8-dihydropyrimido[4,5-b][1,4]diazepin-2-yl)amino]-3-methoxybenzoic acid Chemical compound COC1=CC(C(O)=O)=CC=C1NC1=NC=C(N(C)C(=O)CC(C)N2C3CCCC3)C2=N1 NCBDNLPHIWOJDM-UHFFFAOYSA-N 0.000 description 5
• SDIZMNBKDHPNAT-UHFFFAOYSA-N 4-[(9-cyclopentyl-7-ethyl-5-methyl-6-oxo-7,8-dihydropyrimido[4,5-b][1,4]diazepin-2-yl)amino]-3-methoxybenzoic acid Chemical compound C12=NC(NC=3C(=CC(=CC=3)C(O)=O)OC)=NC=C2N(C)C(=O)C(CC)CN1C1CCCC1 SDIZMNBKDHPNAT-UHFFFAOYSA-N 0.000 description 5
• XZUXWJPIZPSABN-UHFFFAOYSA-N CC=CC=CC=CCC(CCCCC)=O Chemical compound CC=CC=CC=CCC(CCCCC)=O XZUXWJPIZPSABN-UHFFFAOYSA-N 0.000 description 5
• 206010028980 Neoplasm Diseases 0.000 description 5
• 239000012300 argon atmosphere Substances 0.000 description 5
• 230000015572 biosynthetic process Effects 0.000 description 5
• PGGWSUSDGRDUFX-UHFFFAOYSA-N ethyl 3-(cyclopentylamino)propanoate Chemical compound CCOC(=O)CCNC1CCCC1 PGGWSUSDGRDUFX-UHFFFAOYSA-N 0.000 description 5
• UFPCXHAIIFQMSN-UHFFFAOYSA-N ethyl 3-[(2-chloro-5-nitropyrimidin-4-yl)-cyclopentylamino]butanoate Chemical compound N=1C(Cl)=NC=C([N+]([O-])=O)C=1N(C(C)CC(=O)OCC)C1CCCC1 UFPCXHAIIFQMSN-UHFFFAOYSA-N 0.000 description 5
• 125000001153 fluoro group Chemical group F* 0.000 description 5
• 239000007788 liquid Substances 0.000 description 5
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 5
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