CN102746175B - 可用作plk1抑制剂的取代的嘧啶并二氮杂* - Google Patents

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Publication number

CN102746175B

CN102746175B CN201210030872.3A CN201210030872A CN102746175B CN 102746175 B CN102746175 B CN 102746175B CN 201210030872 A CN201210030872 A CN 201210030872A CN 102746175 B CN102746175 B CN 102746175B

Authority

CN

China

Prior art keywords

methyl

mol

tetrahydro

pyrimido

diazepine

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 abstract description 15
• 108010056274 polo-like kinase 1 Proteins 0.000 title abstract description 15
• 239000003112 inhibitor Substances 0.000 title abstract description 5
• OHXQYFCNXHGKPJ-UHFFFAOYSA-N 1h-pyrimido[5,4-c]diazepine Chemical class N1N=CC=CC2=NC=NC=C12 OHXQYFCNXHGKPJ-UHFFFAOYSA-N 0.000 title description 7
• UXNKBIRHIGVUMN-UHFFFAOYSA-N ethyl 3-(cyclopentylamino)-2,2-difluoropropanoate Chemical compound CCOC(=O)C(F)(F)CNC1CCCC1 UXNKBIRHIGVUMN-UHFFFAOYSA-N 0.000 claims description 4
• 239000000203 mixture Substances 0.000 abstract description 391
• 150000001875 compounds Chemical class 0.000 abstract description 38
• 206010028980 Neoplasm Diseases 0.000 abstract description 8
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 6
• 208000015914 Non-Hodgkin lymphomas Diseases 0.000 abstract description 3
• 210000000481 breast Anatomy 0.000 abstract description 3
• 210000001072 colon Anatomy 0.000 abstract description 3
• 201000010099 disease Diseases 0.000 abstract description 3
• 210000004072 lung Anatomy 0.000 abstract description 3
• 230000001613 neoplastic effect Effects 0.000 abstract description 3
• 208000026310 Breast neoplasm Diseases 0.000 abstract description 2
• 208000029742 colonic neoplasm Diseases 0.000 abstract description 2
• 238000009472 formulation Methods 0.000 abstract description 2
• 208000037841 lung tumor Diseases 0.000 abstract description 2
• 208000023958 prostate neoplasm Diseases 0.000 abstract description 2
• 208000035269 cancer or benign tumor Diseases 0.000 abstract 1
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 489
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 288
• -1 N-benzylpiperidinyl Chemical group 0.000 description 220
• 230000002829 reductive effect Effects 0.000 description 216
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 191
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 150
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 147
• 239000000243 solution Substances 0.000 description 130
• 238000010898 silica gel chromatography Methods 0.000 description 119
• 239000007787 solid Substances 0.000 description 115
• 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 99
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 94
• 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
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 78
• 238000000746 purification Methods 0.000 description 63
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 57
• 238000000034 method Methods 0.000 description 54
• 238000001914 filtration Methods 0.000 description 51
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 48
• 239000012044 organic layer Substances 0.000 description 43
• 238000002360 preparation method Methods 0.000 description 42
• 239000002244 precipitate Substances 0.000 description 40
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 39
• 239000001257 hydrogen Substances 0.000 description 38
• 229910052739 hydrogen Inorganic materials 0.000 description 38
• 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
• WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 35
• 239000012071 phase Substances 0.000 description 35
• ALOCUZOKRULSAA-UHFFFAOYSA-N 1-methylpiperidin-4-amine Chemical compound CN1CCC(N)CC1 ALOCUZOKRULSAA-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
• INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 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
• 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 32
• 239000003921 oil Substances 0.000 description 32
• 235000019198 oils Nutrition 0.000 description 32
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 28
• 238000001816 cooling Methods 0.000 description 28
• INUSQTPGSHFGHM-UHFFFAOYSA-N 2,4-dichloro-5-nitropyrimidine Chemical class [O-][N+](=O)C1=CN=C(Cl)N=C1Cl INUSQTPGSHFGHM-UHFFFAOYSA-N 0.000 description 27
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 27
• 235000015497 potassium bicarbonate Nutrition 0.000 description 27
• 229910000028 potassium bicarbonate Inorganic materials 0.000 description 27
• 239000011736 potassium bicarbonate Substances 0.000 description 27
• TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 27
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 26
• OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 26
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 25
• 239000000284 extract Substances 0.000 description 25
• 238000010992 reflux 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
• KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 24
• 239000012312 sodium hydride Substances 0.000 description 23
• 229910000104 sodium hydride Inorganic materials 0.000 description 23
• 239000000706 filtrate Substances 0.000 description 22
• 235000017557 sodium bicarbonate Nutrition 0.000 description 22
• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 22
• UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 21
• POXWDTQUDZUOGP-UHFFFAOYSA-N 1h-1,4-diazepine Chemical compound N1C=CC=NC=C1 POXWDTQUDZUOGP-UHFFFAOYSA-N 0.000 description 20
• 239000000843 powder Substances 0.000 description 20
• 239000008346 aqueous phase Substances 0.000 description 19
• 239000012074 organic phase Substances 0.000 description 19
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
• FWPIDFUJEMBDLS-UHFFFAOYSA-L tin(II) chloride dihydrate Chemical compound O.O.Cl[Sn]Cl FWPIDFUJEMBDLS-UHFFFAOYSA-L 0.000 description 18
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 17
• 239000012298 atmosphere Substances 0.000 description 16
• 239000003054 catalyst Substances 0.000 description 16
• KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 14
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 14
• 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
• 239000011541 reaction mixture Substances 0.000 description 14
• 239000012321 sodium triacetoxyborohydride Substances 0.000 description 14
• 239000000725 suspension Substances 0.000 description 14
• 239000000463 material Substances 0.000 description 13
• XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 12
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 12
• 238000003756 stirring Methods 0.000 description 12
• 238000005406 washing Methods 0.000 description 12
• VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 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
• 150000002431 hydrogen Chemical group 0.000 description 11
• 150000003839 salts Chemical class 0.000 description 11
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 10
• 235000011114 ammonium hydroxide Nutrition 0.000 description 10
• WBKFWQBXFREOFH-UHFFFAOYSA-N dichloromethane;ethyl acetate Chemical compound ClCCl.CCOC(C)=O WBKFWQBXFREOFH-UHFFFAOYSA-N 0.000 description 10
• 239000001632 sodium acetate Substances 0.000 description 10
• 235000017281 sodium acetate Nutrition 0.000 description 10
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-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 9
• VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 9
• 239000000908 ammonium hydroxide Substances 0.000 description 9
• 229910052799 carbon Inorganic materials 0.000 description 9
• 239000002904 solvent Substances 0.000 description 9
• ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 8
• 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
• 125000000217 alkyl group Chemical group 0.000 description 8
• 210000004027 cell Anatomy 0.000 description 8
• BGTOWKSIORTVQH-UHFFFAOYSA-N cyclopentanone Chemical compound O=C1CCCC1 BGTOWKSIORTVQH-UHFFFAOYSA-N 0.000 description 8
• 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 8
• SPWVRYZQLGQKGK-UHFFFAOYSA-N dichloromethane;hexane Chemical compound ClCCl.CCCCCC SPWVRYZQLGQKGK-UHFFFAOYSA-N 0.000 description 8
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 8
• 125000004484 1-methylpiperidin-4-yl group Chemical group CN1CCC(CC1)* 0.000 description 7
• 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 7
• 125000003118 aryl group Chemical group 0.000 description 7
• 239000012230 colorless oil Substances 0.000 description 7
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 7
• 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 7
• 239000012065 filter cake Substances 0.000 description 7
• 239000000543 intermediate Substances 0.000 description 7
• 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 description 6
• 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 6
• NISGSNTVMOOSJQ-UHFFFAOYSA-N cyclopentanamine Chemical compound NC1CCCC1 NISGSNTVMOOSJQ-UHFFFAOYSA-N 0.000 description 6
• FKRCODPIKNYEAC-UHFFFAOYSA-N ethyl propionate Chemical compound CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 description 6
• 150000002576 ketones Chemical class 0.000 description 6
• 239000004533 oil dispersion Substances 0.000 description 6
• 229920006395 saturated elastomer Polymers 0.000 description 6
• 229910000029 sodium carbonate Inorganic materials 0.000 description 6
• 238000001665 trituration Methods 0.000 description 6
• 210000004881 tumor cell Anatomy 0.000 description 6
• UXUSKEVDQGNTPV-UHFFFAOYSA-N 2-chloro-9-cyclopentyl-5,7,7-trimethyl-6,8-dihydropyrimido[4,5-b][1,4]diazepine Chemical compound ClC=1N=CC2=C(N(CC(CN2C)(C)C)C2CCCC2)N=1 UXUSKEVDQGNTPV-UHFFFAOYSA-N 0.000 description 5
• AWEBUXPVTLJUKN-UHFFFAOYSA-N 2-chloro-9-cyclopentyl-5-methylspiro[8h-pyrimido[4,5-b][1,4]diazepine-7,1'-cyclopropane]-6-one Chemical compound O=C1N(C)C2=CN=C(Cl)N=C2N(C2CCCC2)CC21CC2 AWEBUXPVTLJUKN-UHFFFAOYSA-N 0.000 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 description 5
• ZQNLYLZYBPNAFR-UHFFFAOYSA-N 4-[(9-cyclobutyl-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)CCN2C1CCC1 ZQNLYLZYBPNAFR-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
• LRJURAIIMHELTD-UHFFFAOYSA-N 4-[(9-cyclopentyl-5,7,7-trimethyl-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(C)(C)CN2C3CCCC3)C2=N1 LRJURAIIMHELTD-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
• JTWACDVQJZGGAG-UHFFFAOYSA-N 4-[(9-cyclopentyl-5,7-dimethyl-6-oxo-7,8-dihydropyrimido[4,5-b][1,4]diazepin-2-yl)amino]benzoic acid Chemical compound C12=NC(NC=3C=CC(=CC=3)C(O)=O)=NC=C2N(C)C(=O)C(C)CN1C1CCCC1 JTWACDVQJZGGAG-UHFFFAOYSA-N 0.000 description 5
• 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 description 5
• AIBZQRQRRXVKBQ-UHFFFAOYSA-N 4-[(9-cyclopentyl-5-methyl-6-oxo-7-propyl-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(CCC)CN1C1CCCC1 AIBZQRQRRXVKBQ-UHFFFAOYSA-N 0.000 description 5
• 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 description 5
• 239000005711 Benzoic acid Substances 0.000 description 5
• 239000002671 adjuvant Substances 0.000 description 5
• 239000012300 argon atmosphere Substances 0.000 description 5
• 238000006243 chemical reaction Methods 0.000 description 5
• PGGWSUSDGRDUFX-UHFFFAOYSA-N ethyl 3-(cyclopentylamino)propanoate Chemical compound CCOC(=O)CCNC1CCCC1 PGGWSUSDGRDUFX-UHFFFAOYSA-N 0.000 description 5
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 5
• CAVNRDHSIUXHAV-UHFFFAOYSA-N methyl 2-[(5-amino-2-chloropyrimidin-4-yl)-cyclopentylamino]cyclopentane-1-carboxylate Chemical class COC(=O)C1CCCC1N(C=1C(=CN=C(Cl)N=1)N)C1CCCC1 CAVNRDHSIUXHAV-UHFFFAOYSA-N 0.000 description 5
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 5
• FCOHNBLIUUJSGH-SSDOTTSWSA-N (r)-9-chloro-6-methyl-2,3,3a,4-tetrahydro-1h,6h-6,8,10,10b-tetraaza-benzo[e]azulen-5-one Chemical compound C1C(=O)N(C)C2=CN=C(Cl)N=C2N2CCC[C@@H]21 FCOHNBLIUUJSGH-SSDOTTSWSA-N 0.000 description 4
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