CN113637017B - Compound containing dihydropterin structure, its preparation method and application - Google Patents
Compound containing dihydropterin structure, its preparation method and application Download PDFInfo
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- CN113637017B CN113637017B CN202110927335.8A CN202110927335A CN113637017B CN 113637017 B CN113637017 B CN 113637017B CN 202110927335 A CN202110927335 A CN 202110927335A CN 113637017 B CN113637017 B CN 113637017B
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- compound
- mmol
- dihydropterin
- acid
- methyl
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 152
- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- PXZWKVIXSKSCFR-UHFFFAOYSA-N 7,8-dihydropterin Chemical group N1=CCNC2=C1C(=O)N=C(N)N2 PXZWKVIXSKSCFR-UHFFFAOYSA-N 0.000 title claims abstract description 15
- -1 dihydropterin compound Chemical class 0.000 claims abstract description 61
- 102100023712 Poly [ADP-ribose] polymerase 1 Human genes 0.000 claims abstract description 36
- 108010064218 Poly (ADP-Ribose) Polymerase-1 Proteins 0.000 claims abstract description 28
- 239000003112 inhibitor Substances 0.000 claims abstract description 22
- 108091005625 BRD4 Proteins 0.000 claims abstract description 21
- 102100029895 Bromodomain-containing protein 4 Human genes 0.000 claims abstract description 21
- 150000003839 salts Chemical class 0.000 claims abstract description 15
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 9
- 239000003937 drug carrier Substances 0.000 claims abstract description 3
- 238000000034 method Methods 0.000 claims description 46
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 28
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 11
- 239000002253 acid Substances 0.000 claims description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 6
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 6
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 6
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 4
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 3
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 3
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 3
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 2
- KSEBMYQBYZTDHS-HWKANZROSA-M (E)-Ferulic acid Natural products COC1=CC(\C=C\C([O-])=O)=CC=C1O KSEBMYQBYZTDHS-HWKANZROSA-M 0.000 claims description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims description 2
- 229940092714 benzenesulfonic acid Drugs 0.000 claims description 2
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 claims description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 claims description 2
- 235000015165 citric acid Nutrition 0.000 claims description 2
- 229940079593 drug Drugs 0.000 claims description 2
- KSEBMYQBYZTDHS-HWKANZROSA-N ferulic acid Chemical compound COC1=CC(\C=C\C(O)=O)=CC=C1O KSEBMYQBYZTDHS-HWKANZROSA-N 0.000 claims description 2
- 229940114124 ferulic acid Drugs 0.000 claims description 2
- KSEBMYQBYZTDHS-UHFFFAOYSA-N ferulic acid Natural products COC1=CC(C=CC(O)=O)=CC=C1O KSEBMYQBYZTDHS-UHFFFAOYSA-N 0.000 claims description 2
- 235000001785 ferulic acid Nutrition 0.000 claims description 2
- 229910000042 hydrogen bromide Inorganic materials 0.000 claims description 2
- 239000004310 lactic acid Substances 0.000 claims description 2
- 235000014655 lactic acid Nutrition 0.000 claims description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 2
- 239000011976 maleic acid Substances 0.000 claims description 2
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 2
- 235000006408 oxalic acid Nutrition 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 235000011007 phosphoric acid Nutrition 0.000 claims description 2
- 229940107700 pyruvic acid Drugs 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- 238000001308 synthesis method Methods 0.000 claims description 2
- 239000011975 tartaric acid Substances 0.000 claims description 2
- 235000002906 tartaric acid Nutrition 0.000 claims description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 2
- QURCVMIEKCOAJU-UHFFFAOYSA-N trans-isoferulic acid Natural products COC1=CC=C(C=CC(O)=O)C=C1O QURCVMIEKCOAJU-UHFFFAOYSA-N 0.000 claims description 2
- 239000000203 mixture Substances 0.000 abstract description 8
- 206010006187 Breast cancer Diseases 0.000 abstract description 3
- 208000026310 Breast neoplasm Diseases 0.000 abstract description 3
- 206010061902 Pancreatic neoplasm Diseases 0.000 abstract description 2
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 abstract description 2
- 201000002528 pancreatic cancer Diseases 0.000 abstract description 2
- 208000008443 pancreatic carcinoma Diseases 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 159
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 68
- 230000015572 biosynthetic process Effects 0.000 description 67
- 238000003786 synthesis reaction Methods 0.000 description 67
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 66
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 64
- 239000007787 solid Substances 0.000 description 49
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 42
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 38
- CXNIUSPIQKWYAI-UHFFFAOYSA-N xantphos Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 description 38
- 238000006243 chemical reaction Methods 0.000 description 37
- 239000007858 starting material Substances 0.000 description 37
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 35
- ZBNZAJFNDPPMDT-UHFFFAOYSA-N 1h-imidazole-5-carboxamide Chemical compound NC(=O)C1=CNC=N1 ZBNZAJFNDPPMDT-UHFFFAOYSA-N 0.000 description 34
- 239000003208 petroleum Substances 0.000 description 34
- 238000004440 column chromatography Methods 0.000 description 33
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 30
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 30
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 28
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 28
- 239000007821 HATU Substances 0.000 description 27
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 27
- 229910000024 caesium carbonate Inorganic materials 0.000 description 27
- 239000002904 solvent Substances 0.000 description 27
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 26
- 238000000746 purification Methods 0.000 description 25
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 24
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 22
- NAWJZCSEYBQUGY-UHFFFAOYSA-N 2,3-diaminobenzamide Chemical compound NC(=O)C1=CC=CC(N)=C1N NAWJZCSEYBQUGY-UHFFFAOYSA-N 0.000 description 20
- 239000000243 solution Substances 0.000 description 20
- 239000007788 liquid Substances 0.000 description 19
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 19
- 229910000027 potassium carbonate Inorganic materials 0.000 description 19
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical group [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 16
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 16
- 230000000694 effects Effects 0.000 description 16
- 239000012312 sodium hydride Substances 0.000 description 16
- 229910000104 sodium hydride Inorganic materials 0.000 description 16
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 15
- 239000003054 catalyst Substances 0.000 description 15
- 230000005764 inhibitory process Effects 0.000 description 14
- 229910000029 sodium carbonate Inorganic materials 0.000 description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 13
- 239000012046 mixed solvent Substances 0.000 description 13
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 13
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 description 12
- OFRMASLPWOMYHN-UHFFFAOYSA-N 1-[3-methoxy-4-[[6-(2-propan-2-ylsulfonylanilino)-7H-purin-2-yl]amino]phenyl]piperidin-4-ol Chemical group COc1cc(ccc1Nc1nc(Nc2ccccc2S(=O)(=O)C(C)C)c2[nH]cnc2n1)N1CCC(O)CC1 OFRMASLPWOMYHN-UHFFFAOYSA-N 0.000 description 12
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 12
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 12
- 210000004027 cell Anatomy 0.000 description 12
- BGRWYRAHAFMIBJ-UHFFFAOYSA-N diisopropylcarbodiimide Natural products CC(C)NC(=O)NC(C)C BGRWYRAHAFMIBJ-UHFFFAOYSA-N 0.000 description 12
- 239000002994 raw material Substances 0.000 description 12
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 229960000583 acetic acid Drugs 0.000 description 9
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical group [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 8
- 101710179684 Poly [ADP-ribose] polymerase Proteins 0.000 description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 8
- 239000011230 binding agent Substances 0.000 description 8
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- 101100132433 Arabidopsis thaliana VIII-1 gene Proteins 0.000 description 7
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- 239000003795 chemical substances by application Substances 0.000 description 7
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 7
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- 238000000967 suction filtration Methods 0.000 description 7
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 6
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- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 6
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 6
- 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 5
- LWRSYTXEQUUTKW-UHFFFAOYSA-N DMB Natural products COC1=CC=C(C=O)C(OC)=C1 LWRSYTXEQUUTKW-UHFFFAOYSA-N 0.000 description 5
- 229920000776 Poly(Adenosine diphosphate-ribose) polymerase Polymers 0.000 description 5
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- 239000003638 chemical reducing agent Substances 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 239000002609 medium Substances 0.000 description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- TXUICONDJPYNPY-UHFFFAOYSA-N (1,10,13-trimethyl-3-oxo-4,5,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-17-yl) heptanoate Chemical compound C1CC2CC(=O)C=C(C)C2(C)C2C1C1CCC(OC(=O)CCCCCC)C1(C)CC2 TXUICONDJPYNPY-UHFFFAOYSA-N 0.000 description 4
- 101001053401 Arabidopsis thaliana Acid beta-fructofuranosidase 3, vacuolar Proteins 0.000 description 4
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- 229910021626 Tin(II) chloride Inorganic materials 0.000 description 4
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 description 4
- 238000003556 assay Methods 0.000 description 4
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- UQLDLKMNUJERMK-UHFFFAOYSA-L di(octadecanoyloxy)lead Chemical compound [Pb+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O UQLDLKMNUJERMK-UHFFFAOYSA-L 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 4
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- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 description 3
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 3
- 101100459319 Arabidopsis thaliana VIII-2 gene Proteins 0.000 description 3
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- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 3
- 108020004414 DNA Proteins 0.000 description 3
- 108010033040 Histones Proteins 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 3
- 239000004305 biphenyl Substances 0.000 description 3
- NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 description 3
- YNHIGQDRGKUECZ-UHFFFAOYSA-N dichloropalladium;triphenylphosphanium Chemical compound Cl[Pd]Cl.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-N 0.000 description 3
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention discloses a compound with a dihydropterin structure in a general formula (I), a preparation method and application thereof. The invention also discloses a composition containing the dihydropterin compound or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, and application of the composition in preparing PARP-1 and BRD4 double-target inhibitors. The compound of the invention can be used for treating tumors such as breast cancer, pancreatic cancer and the like.
Description
Technical Field
The invention relates to pharmaceutical chemistry, in particular to a PARP-1 and BRD4 double-target inhibitor containing dihydropterin structure, a preparation method thereof and application thereof in treating tumors.
Technical Field
The primary mechanism of action of PARP-1 inhibitors is synthetic lethality, so that the effect of using PARP-1 inhibitors to treat tumor cells with deletion or mutation of homologous recombination genes is best, for example, when using PARP-1 inhibitors to block single-stranded DNA damage repair of BRCA1/2 mutant tumor cells, synthetic lethality can be formed, and finally cell death is caused. There are currently 6 PARP-1 inhibitors approved for sale, which are Olaparib (Olaparib), lu Kapa ni (rupaparib), nilaparib (nirapparib), tazopanib (talazopanib), fluzopanib (fluzopanib) and pamipril (Pamiparib), respectively. In addition, there are a number of PARP-1 inhibitors in the clinical research stage. However, with the deep research and the subsequent release of clinical test results, the PARP-1 inhibitor is found to have good curative effects on triple negative breast cancer and ovarian cancer with partial BRCA gene mutation only when being singly used; in addition, long-term use of PARP-1 inhibitors is faced with resistance problems. These problems limit the clinical use of PARP-1 inhibitors and are also critical scientific problems to be solved in the PARP inhibitor field. BRD4 protein is one of the members of the terminal Bromodomain family (BET), which is located in the nucleus and contains a Bromodomain (Bromodomain, brD) capable of recognizing acetylated histones, which plays a role in the recruitment of transcription factors, the enrichment and mediator complex assembly in the vicinity of promoters and enhancers, and in the key physiological processes of cells such as oncogenes, pro-inflammatory cytokines or transcription prolongation of chemokines, and which abnormalities can affect the occurrence and progression of a variety of diseases such as cancer and inflammation, and also the cardiovascular and central nervous system, and is a potential drug target. Currently, a number of BRD4 inhibitors have been introduced into clinical studies, such as ABBV-075, CPI-0610, and the like. In addition, BRD4 proteins have been found to regulate DNA damage repair in a number of ways. The use of PARP-1 inhibitors in combination with BRD4 inhibitors has shown significant synergy in PARP inhibitor-insensitive or PARP inhibitor-resistant tumor cell lines, but such combination has a number of disadvantages, such as poorly controlled dosing, non-uniform pharmacokinetic properties, susceptibility to drug-drug interactions and side effects therefrom.
Disclosure of Invention
The invention aims to: the invention aims to provide a compound containing a dihydropterin structure.
It is another object of the present invention to provide specific methods for the preparation of such compounds and their pharmaceutical use as dual-target inhibitors of PARP-1 and BRD 4.
The technical scheme is as follows: the invention discloses a compound containing dihydropterin structure shown in a general formula (I) or pharmaceutically acceptable salt thereof:
wherein: r is R 1 Represents a C1-C6 alkyl group;
R 2 represents a C1-C6 alkyl group, a C3-C6 cycloalkyl group,Wherein: x represents O, S or NH; y is Y 1 、Y 2 、Y 3 、Y 4 、Y 5 And Y 6 Each represents N or CH; r is R 4 Represents H, F, cl, br,CH 3 、CF 3 、OCH 3 、OCF 3 、OH、NH 2 、NHCOCH 3 Or CN, R 4 May be mono-or polysubstituted;
R 3 represents hydrogen, C1-C4 alkyl;
a representsWherein: r is R 5 Represents a linear alkoxy group of H, C to C6 or a cycloalkoxy group of C3 to C6, R 5 May be mono-or polysubstituted; r is R 6 Represents H or CH 3 ；R 7 Representative H, F, cl, br, CH 3 、CF 3 、OCH 3 、OCF 3 Or CN.
Wherein R is 1 Preferably represent H, CH 3 Or CH (CH) 2 CH 3 ；R 1 More preferably represents CH 3 Or CH (CH) 2 CH 3 。
R 2 Preferably represents R 2 More preferably represents->
R 3 Preferably represents H or CH 3 ；R 3 More preferably represents CH 3 。
A preferably representsWherein: r is R 6 Represents H or CH 3 ；R 8 Representative H, OCH 3 、OCH 2 CH 3 、OCH(CH 3 ) 2 Or->A more preferably represents->
The pharmaceutically acceptable salts are acid addition salts of the compounds of formula (I) with: hydrogen chloride, hydrogen bromide, sulfuric acid, carbonic acid, oxalic acid, citric acid, succinic acid, tartaric acid, phosphoric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or ferulic acid.
Use of a compound comprising a dihydropterin structure or a pharmaceutically acceptable salt thereof for the preparation of a dual-target inhibitor of PARP-1 and BRD4 for the treatment of a tumor.
The compounds (I) of the present invention are classified into the types of I-A, I-B, I-C, I-D, I-E and I-F, and their synthesis methods are described below, respectively:
when A isR 2 Is->R 3 In the case of H, the compound (I-A) of the present invention can be prepared by the following method:
wherein R is 1 And R is 8 R is as defined above 2 Is cyclopentyl.
Preparing a compound III by reacting the compound II with cyclopentanone, wherein the reducing agent is selected from sodium borohydride, sodium triacetoxyborohydride and sodium cyanoborohydride; the base is selected from triethylamine, pyridine, N-Diisopropylethylamine (DIPEA), 4-Dimethylaminopyridine (DMAP), potassium carbonate, sodium carbonate, cesium carbonate or sodium acetate, preferably sodium acetate; the solvent is selected from dichloromethane, tetrahydrofuran, 1, 4-dioxane, ethyl acetate, N-dimethylformamide or a mixed solvent of any two, preferably dichloromethane.
Preparing a compound IV by reacting the compound III with 2, 4-dichloro-5-nitropyrimidine, wherein the acid-binding agent is selected from triethylamine, N-diisopropylethylamine, sodium carbonate, potassium carbonate or cesium carbonate, preferably potassium carbonate; the solvent is selected from dichloromethane, tetrahydrofuran, 1, 4-dioxane, acetone, ethyl acetate, N-dimethylformamide or mixed solvent of any two, preferably acetone.
Preparing a compound V from the compound IV through reduction and cyclization, wherein the reducing agent is selected from iron powder, zinc powder or stannous chloride, and preferably iron powder; the solvent is selected from methanol, ethanol, tetrahydrofuran, 1, 4-dioxane, N-dimethylformamide, acetic acid, hydrochloric acid or a mixed solvent of any two, preferably acetic acid.
Preparing a compound VI by reacting a compound V with methyl iodide, wherein the base is selected from sodium hydride, potassium carbonate, sodium carbonate or cesium carbonate, preferably sodium hydride; the solvent is selected from dichloromethane, tetrahydrofuran, 1, 4-dioxane, N-dimethylformamide or mixed solvent of any two, preferably N, N-dimethylformamide.
Preparation of Compound VIII by reaction of Compound VI with Compound VII the catalyst used is selected from the group consisting of [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (Pd (dppf) Cl) 2 ) Tetrakis (triphenylphosphine) palladium (Pd (PPh) 3 ) 4 ) Bis (triphenylphosphine) palladium dichloride (Pd (PPh) 3 ) 2 Cl 2 ) Tris (dibenzylideneacetone) dipalladium (Pd) 2 (dba) 3 ) Or palladium acetate (Pd (OAc) 2 ) Preferably Pd 2 (dba) 3 The method comprises the steps of carrying out a first treatment on the surface of the The ligand used is selected from triphenylphosphine, 2-dicyclohexylphosphine-2 ',4',6' -triisopropylbiphenyl (X-Phos), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (Xantphos) or 2- (dicyclohexylphosphine) -3, 6-dimethoxy-2 ' -4' -6' -tri-I-propyl-11 ' -biphenyl (Brett-Phos), preferably Xantphos; the base used is selected from sodium hydroxide, potassium hydroxide, cesium carbonate, potassium carbonate or sodium carbonate, preferably cesium carbonate; the solvent is selected from tetrahydrofuran, 1, 4-dioxane, toluene or a mixed solvent of any two, preferably 1, 4-dioxane.
Compound IX is prepared from compound VIII by hydrolysis, the base used being selected from lithium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, preferably sodium hydroxide.
The preparation of compound I-A from the reaction of compound IX with 2, 3-diaminobenzamide using a condensing agent selected from Carbonyl Diimidazole (CDI), dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), 1- (3-dimethylaminopropyl) -3-Ethylcarbodiimide (EDCI), 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea Hexafluorophosphate (HATU) or benzotriazol-1-yl-oxy-tripyrrolidinylphosphine hexafluorophosphate (PyBOP), preferably HATU; the acid binding agent is selected from N, N-diisopropylethylamine or triethylamine, preferably N, N-diisopropylethylamine.
When A isR 2 To remove->Other than radicals R 3 In the case of H, the compound (I-A) of the present invention can be prepared by the following method:
wherein R is 1 And R is 8 R is as defined above 2 DMB is 2, 4-dimethoxybenzyl except cyclopentyl, which is defined as before.
Preparing a compound X by reacting the compound II with 2, 4-dimethoxy benzaldehyde, wherein the reducing agent is selected from sodium borohydride, sodium triacetoxyborohydride and sodium cyanoborohydride; the base is selected from triethylamine, pyridine, N-diisopropylethylamine, 4-dimethylaminopyridine, potassium carbonate, sodium carbonate, cesium carbonate or sodium acetate, preferably sodium acetate; the solvent is selected from dichloromethane, tetrahydrofuran, 1, 4-dioxane, ethyl acetate, N-dimethylformamide or a mixed solvent of any two, preferably dichloromethane.
Preparing a compound XI by reacting the compound X with a compound 2, 4-dichloro-5-nitropyrimidine, wherein the acid-binding agent is selected from triethylamine, N-diisopropylethylamine, sodium carbonate, potassium carbonate or cesium carbonate, preferably potassium carbonate; the solvent is selected from dichloromethane, tetrahydrofuran, 1, 4-dioxane, acetone, ethyl acetate, N-dimethylformamide or mixed solvent of any two, preferably acetone.
Preparing a compound XII from the compound XI through reduction and cyclization, wherein the reducing agent is selected from iron powder, zinc powder or stannous chloride, preferably iron powder; the solvent is selected from methanol, ethanol, tetrahydrofuran, 1, 4-dioxane, N-dimethylformamide, acetic acid, hydrochloric acid or a mixed solvent of any two, preferably acetic acid.
Preparing a compound XIII from the reaction of the compound XII with methyl iodide, wherein the base is selected from sodium hydride, potassium carbonate, sodium carbonate or cesium carbonate, preferably sodium hydride; the solvent is selected from dichloromethane, tetrahydrofuran, 1, 4-dioxane, N-dimethylformamide or mixed solvent of any two, preferably N, N-dimethylformamide.
The compound XIV is prepared by removing DMB protecting group from compound XIII, wherein the deprotection agent is trifluoroacetic acid, organic solution of HCl, organic solution of p-toluenesulfonic acid, DDQ, preferably trifluoroacetic acid.
Compound VI is prepared by substitution of compound XIV with XV using a base selected from sodium hydride, potassium carbonate, sodium carbonate or cesium carbonate, preferably sodium hydride.
Compound VI is reacted with VII to produce compound VIII, compound VIII is hydrolyzed to produce compound IX, and compound IX is reacted with 2, 3-diaminobenzamide to produce the target compound I-A, with the corresponding reaction conditions being the same as before.
When A isR 3 In the case of C1-C6 alkyl or C3-C6 cycloalkyl, the compound (I-B) of the present invention can be prepared by the following method:
wherein R is 1 、R 2 、R 3 And R is 8 Is as defined above.
From the reaction of the compounds VIII and XVI, the base used is selected from sodium hydride, potassium carbonate, sodium carbonate or cesium carbonate, preferably sodium hydride; the solvent is selected from dichloromethane, tetrahydrofuran, 1, 4-dioxane, N-dimethylformamide or mixed solvent of any two, preferably N, N-dimethylformamide.
Compound XVIII is prepared from compound XVII by hydrolysis, the base used being selected from lithium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, preferably sodium hydroxide.
The compound I-B is prepared by reacting a compound XVIII with 2, 3-diaminobenzamide, the condensing agent used being selected from Carbonyl Diimidazole (CDI), dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), 1- (3-dimethylaminopropyl) -3-Ethylcarbodiimide (EDCI), 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea Hexafluorophosphate (HATU) or benzotriazol-1-yl-oxy-tripyrrolidinylphosphine hexafluorophosphate (PyBOP), preferably HATU; the acid binding agent is selected from N, N-diisopropylethylamine or triethylamine, preferably N, N-diisopropylethylamine.
When A isR 3 In the case of H, the compound (I-C) of the present invention can be prepared by the following method:
wherein R is 1 、R 2 And R is 8 Is as defined above.
Preparation of compound I-C from the reaction of compound IX with 2- (aminomethyl) -1H-benzo [ d ] imidazole-4-carboxamide the condensing agent used is selected from Carbonyldiimidazole (CDI), dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), 1- (3-dimethylaminopropyl) -3-Ethylcarbodiimide (EDCI), 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU) or benzotriazol-1-yl-oxy-tripyrrolidinylphosphine hexafluorophosphate (PyBOP), preferably HATU; the acid binding agent is selected from N, N-diisopropylethylamine or triethylamine, preferably N, N-diisopropylethylamine.
When A isR 3 In the case of H, the compound (I-D) of the present invention can be prepared by the following method:
wherein R is 1 、R 2 And R is 6 Is as defined above.
Preparation of Compound XX by reaction of Compounds VI and XIX with a catalyst selected from the group consisting of [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (Pd (dppf) Cl) 2 ) Tetrakis (triphenylphosphine) palladium (Pd (PPh) 3 ) 4 ) Bis (triphenylphosphine) palladium dichloride (Pd (PPh) 3 ) 2 Cl 2 ) Tris (dibenzylideneacetone) dipalladium (Pd) 2 (dba) 3 ) Or palladium acetate (Pd (OAc) 2 ) Preferably Pd 2 (dba) 3 The method comprises the steps of carrying out a first treatment on the surface of the The ligand used is selected from triphenylphosphine, 2-dicyclohexylphosphine-2 ',4',6' -triisopropylbiphenyl (X-Phos), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (Xantphos) or 2- (dicyclohexylphosphine) -3, 6-dimethoxy-2 ' -4' -6' -tri-I-propyl-11 ' -biphenyl (Brett-Phos), preferably Xantphos; the base used is selected from sodium hydroxide, potassium hydroxide, cesium carbonate, potassium carbonate or sodium carbonate, preferably cesium carbonate; the solvent is selected from tetrahydrofuran, 1, 4-dioxane, toluene or a mixed solvent of any two, preferably 1, 4-dioxane.
Compound XXI is prepared from compound XX by hydrolysis, and the base used is selected from lithium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, preferably sodium hydroxide.
Preparation of compound I-D from the reaction of compound XXI with 2, 3-diaminobenzamide using a condensing agent selected from Carbonyl Diimidazole (CDI), dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), 1- (3-dimethylaminopropyl) -3-Ethylcarbodiimide (EDCI), 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea Hexafluorophosphate (HATU) or benzotriazol-1-yl-oxy-tripyrrolidinylphosphine hexafluorophosphate (PyBOP), preferably HATU; the acid binding agent is selected from N, N-diisopropylethylamine or triethylamine, preferably N, N-diisopropylethylamine.
When A isR 3 In the case of H, the compounds (I-E) according to the invention can be prepared by the following method:
wherein R is 1 、R 2 And R is 6 Is as defined above.
Preparation of compound I-E from the reaction of compound XXI with 2- (aminomethyl) -1H-benzo [ d ] imidazole-4-carboxamide, using a condensing agent selected from Carbonyl Diimidazole (CDI), dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), 1- (3-dimethylaminopropyl) -3-Ethylcarbodiimide (EDCI), 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea Hexafluorophosphate (HATU) or benzotriazol-1-yl-oxy-tripyrrolidinylphosphine hexafluorophosphate (PyBOP), preferably HATU; the acid binding agent is selected from N, N-diisopropylethylamine or triethylamine, preferably N, N-diisopropylethylamine.
When A isR 3 In the case of H, the compound (I-F) of the present invention can be prepared by the following method:
wherein R is 1 And R is 2 Is as defined above.
Preparation of compound XXIII from reaction of compound XXII with 2, 3-diaminobenzamide using a condensing agent selected from Carbonyl Diimidazole (CDI), dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), 1- (3-dimethylaminopropyl) -3-Ethylcarbodiimide (EDCI), 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea Hexafluorophosphate (HATU) or benzotriazol-1-yl-oxy-tripyrrolidinylphosphine hexafluorophosphate (PyBOP), preferably HATU; the acid binding agent is selected from N, N-diisopropylethylamine or triethylamine, preferably N, N-diisopropylethylamine.
Preparing a compound XXIV from the compound XXIII through a reduction reaction, wherein the reducing agent is selected from iron powder, zinc powder, stannous chloride or hydrogen, and preferably stannous chloride; the solvent is selected from methanol, ethanol, tetrahydrofuran, 1, 4-dioxane, acetic acid, hydrochloric acid or mixed solvent of any two, preferably ethanol.
Preparation of Compounds I-F from the reaction of Compound XXIV with Compound VI with a catalyst selected from the group consisting of [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (Pd (dppf) Cl) 2 ) Tetrakis (triphenylphosphine) palladium (Pd (PPh) 3 ) 4 ) Bis (triphenylphosphine) palladium dichloride (Pd (PPh) 3 ) 2 Cl 2 ) Tris (dibenzylideneacetone) dipalladium (Pd) 2 (dba) 3 ) Or palladium acetate (Pd (OAc) 2 ) Preferably Pd 2 (dba) 3 The method comprises the steps of carrying out a first treatment on the surface of the The ligand used is selected from triphenylphosphine, 2-dicyclohexylphosphine-2 ',4',6' -triisopropylbiphenyl (X-Phos), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (Xantphos) or 2- (dicyclohexylphosphine) -3, 6-dimethoxy-2 ' -4' -6' -tri-I-propyl-11 ' -biphenyl (Brett-Phos), preferably Xantphos; the base used is selected from sodium hydroxide, potassium hydroxide, cesium carbonate, potassium carbonate or sodium carbonate, preferably cesium carbonate; the solvent is selected from tetrahydrofuran, 1, 4-dioxane, toluene or a mixed solvent of any two, preferably 1, 4-dioxane.
The invention also discloses a pharmaceutical composition, the compound can be added with pharmaceutically acceptable carriers to prepare common pharmaceutical preparations, such as tablets, capsules, syrup, suspending agents and injection, and common pharmaceutical auxiliary materials such as spice, sweetener, liquid or solid filler or diluent and the like can be added.
The application of the compound with the general formula (I) and the hydrate, solvate or crystal thereof in preparing PARP-1 and BRD4 double-target inhibitor medicaments is also within the protection scope of the invention.
Further, the PARP-1 and BRD4 dual-target inhibitor can be used for treating tumors.
Pharmacological experiments show that the compound disclosed by the invention can have good inhibition effect on PARP-1 and BRD4, and can be used for preparing medicines for treating diseases such as leukemia, breast cancer, ovarian cancer, pancreatic cancer and the like. The study shows that the combined use of the PARP-1 inhibitor and the BRD4 inhibitor has remarkable effect on treating cancers such as breast cancer and the like, so that the development of the PARP-1 and BRD4 double-target inhibitor has great practical significance and potential application prospect.
The beneficial effects are that: compared with the prior art, the invention has the following remarkable advantages:
the single active ingredient can play a double inhibition role on PARP-1 and BRD4, reduce the dosage of the medicine, improve the treatment effect, reduce the drug resistance and reduce the toxic and side effects; the dual inhibition effect on PARP-1 and BRD4 is obvious, and the IC of each target point 50 Values of no more than 1.0. Mu.M; the application is wide, and the medicine taking the medicine as an active ingredient can be used for treating various cancers or tumors related to PARP-1 and/or BRD 4.
Detailed Description
Example 1
(R) -2- (4- ((8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5, 6,7, 8-dihydropterin-2-yl) amino) -3-methoxyphenyl) -1H-benzo [ d ]]Imidazole-4-carboxamide (I-a-1:R 1 ＝CH 2 CH 3 ,/>R 3 synthesis of =h)
Synthesis of methyl (R) -2- (cyclopentylamino) butyrate (III-1)
In a 50mL three-necked flask, methyl D-2-aminobutyrate hydrochloride (II-1, 1.48g,9.70 mmol) was added, suspended in 20mL methylene chloride, and sodium acetate (0.7) was added0g,8.49 mmol), cyclopentanone (0.75 mL,8.49 mmol), and NaBH (AcO) was added in portions with stirring under ice-bath conditions 3 (2.70 g,12.74 mmol) was transferred to room temperature and stirred. After about 12h, after TLC (petroleum ether: ethyl acetate=4:1) detection (ninhydrin color development) detects complete reaction of the starting materials, saturated NaHCO is added 3 The solution was extracted with dichloromethane (15 mL. Times.3) until no bubbles evolved, the dichloromethane phase was retained and washed with 20mL saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered off with suction, and the filtrate concentrated to give 0.85g as a brown oily liquid in 47.3% yield. 1 H NMR(300MHz,Chloroform-d)δ(ppm):3.74(s,3H),3.23(t,J＝6.6Hz,1H),2.98(p,J＝6.6Hz,1H),2.23-2.15(m,1H),1.87-1.47(m,8H),1.39-1.24(m,2H),0.93(t,J＝7.5Hz,3H).
Synthesis of methyl (R) -2- ((2-chloro-5-nitropyrimidin-4-yl) (cyclopentyl) amino) butyrate (IV-1)
In a 25mL eggplant bottle, compound III-1 (0.62 g,3.35 mmol) was added, and after 12mL of acetone was dissolved and clarified, anhydrous potassium carbonate (0.46 g,3.35 mmol) was added, 2, 4-dichloro-5-nitropyrimidine (0.69 g,3.55 mmol) was added under ice bath conditions, and the reaction was transferred to room temperature, stirred for about 12 hours, and after TLC (petroleum ether: ethyl acetate=8:1) detected that the starting material was substantially completely reacted, water was added, extracted with ethyl acetate (15 mL. Times.3), the ethyl acetate phase was dried over anhydrous sodium sulfate, suction filtration, and column chromatography (petroleum ether: ethyl acetate=25:1) was used after concentration of the filtrate to purify a yellow oily liquid, yield: 62.3%. 1 H NMR(300MHz,Chloroform-d)δ(ppm):8.66(s,1H),3.76(s,3H),3.55(t,J＝8.0Hz,1H),2.49-2.33(m,1H),2.29-1.41(m,10H),1.05(t,J＝7.5Hz,3H).
Synthesis of (R) -2-chloro-8-cyclopentyl-7-ethyl-7, 8-dihydropterin-6 (5H) -one (V-1)
In a 25mL three-necked flask, IV-1 (0.58 g,1.69 mmol) was added, dissolved in 8mL acetic acid, heated to 80℃and reduced iron powder (0.28 g,5.07 mmol) was added thereto, and the reaction was continued at 80 ℃. After the TLC (petroleum ether: ethyl acetate=4:1) detects that the raw material is basically reacted completely, water is added, extraction is performed with ethyl acetate (15 mL×3), the ethyl acetate phase is dried with anhydrous sodium sulfate, suction filtration is performed, the filtrate is concentrated, the residue is purified with column chromatography (petroleum ether: ethyl acetate=2:1), 0.24g of white solid is obtained,yield: 50.6%, m.p.174-175 ℃. 1 H NMR(300MHz,Chloroform-d)δ(ppm):9.27(s,1H),7.70(s,1H),4.34(m,1H),4.23(dd,J＝7.4,3.5Hz,1H),2.23-1.55(m,10H),0.96(t,J＝7.5Hz,3H).
Synthesis of (R) -2-chloro-8-cyclopentyl-7-ethyl-5-methyl-7, 8-dihydropterin-6 (5H) -one (VI-1)
In a 25mL three-necked flask, V-1 (0.23 g,0.82 mmol) was dissolved in 5mL DMF, cooled in an ice bath, methyl iodide (0.08 mL,1.23 mmol) was added, 60% sodium hydride (0.05 g,1.23 mmol) was added in portions, a small amount of bubbles were generated, the ice bath was stopped, and the mixture was transferred to room temperature and stirred. After detecting the complete reaction of the raw materials by TLC (petroleum ether: ethyl acetate=8:1) for about 3 hours, adding 20mL of water, extracting by using ethyl acetate (15 mL multiplied by 3), drying an ethyl acetate phase by using anhydrous sodium sulfate, carrying out suction filtration, concentrating filtrate, and purifying by column chromatography (petroleum ether: ethyl acetate=80:1), thus obtaining 0.19g of white solid with the yield of 78.5 percent and m.p.101-102 ℃. 1 H NMR(300MHz,Chloroform-d)δ(ppm):7.66(s,1H),4.34(m,1H),4.25(dd,J＝3.6,7.5Hz,1H),3.32(s,3H),2.13-1.54(m,10H),0.86(t,J＝7.5Hz,3H).
Synthesis of methyl (R) -4- ((8-cyclopentyl-7-ethyl-5-methyl-6-oxo 5,6,7, 8-dihydropterin-2-yl) amino) -3-methoxybenzoate (VIII-1)
In a 25mL three-necked flask, VI-1 (0.39 g,1.32 mmol), methyl 4-amino-3-methoxybenzoate (VII-1, 0.30g,1.65 mmol), cesium carbonate (0.65 g,1.98 mmol), xantphos (0.15 g,0.26 mmol) were added sequentially, suspended in 6mL 1, 4-dioxane, and the mixture was evacuated to N 2 After three bubbling times, pd was added 2 (dba) 3 (0.12 g,0.13 mmol), and N was introduced by vacuum 2 Bubbling three times in N 2 Heating to reflux under protection. After the reaction is performed for about 10 hours and the TLC (petroleum ether: ethyl acetate=2:1) detects that the raw materials are completely reacted, the reaction is cooled to room temperature, ethyl acetate is added, the reaction is filtered by suction through kieselguhr, and the reaction is purified by column chromatography (petroleum ether: ethyl acetate=2:1), so that 0.48g of pale yellow oily liquid is obtained, and the yield is: 85.4%. 1 H NMR(300MHz,Chloroform-d)δ(ppm):8.58(d,J＝8.6Hz,1H),7.80(s,1H),7.74-7.68(m,2H),7.56(s,1H),4.53(t,J＝8.0Hz,1H),4.29-4.22(m,1H),4.00(s,3H),3.93(s,3H),3.35(s,3H),2.26-1.45(m,10H),0.90(t,J＝7.5Hz,3H).
Synthesis of (R) -4- ((8-cyclopentyl-7-ethyl-5-methyl-6-oxo 5,6,7, 8-dihydropyridin-2-yl) amino) -3-methoxybenzoic acid (IX-1)
In a 25mL single-necked flask, VIII-1 (0.25 g,0.59 mmol) was dissolved in 4mL of methanol to clarify the solution, and after 10mL of 1M NaOH was added thereto, the reaction solution turned white and milky, and the temperature was raised to 70℃and stirred. After about 4 hours of reaction, TLC (petroleum ether: ethyl acetate=1:2) detected complete reaction of the starting materials. After extraction with ethyl acetate, the aqueous phase was retained, ph=2 was adjusted with 2M hydrochloric acid, a large amount of white solid was precipitated, extracted with ethyl acetate (15 ml×3), the ethyl acetate phase was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to give 0.16g of white solid, yield: 66.2%, m.p.249-250 ℃. The next reaction was directly carried out without purification. 1 H NMR(300MHz,DMSO-d 6 )δ(ppm):12.84(s,1H),8.50(d,J＝8.5Hz,1H),7.86(s,1H),7.69(s,1H),7.57(dd,J＝8.4,1.8Hz,1H),7.49(d,J＝1.8Hz,1H),4.35(p,J＝8.2Hz,1H),4.28-4.21(m,1H),3.94(s,3H),3.25(s,3H),2.08-1.15(m,10H),0.76(t,J＝7.4Hz,3H).
Synthesis of (R) -2- (4- ((8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5, 6,7, 8-dihydropterin-2-yl) amino) -3-methoxyphenyl) -1H-benzo [ d ] imidazole-4-carboxamide (I-A-1)
In a 50mL three-necked flask, compound IX-1 (0.20 g,0.49 mmol), 2, 3-diaminobenzamide (0.07 g,0.49 mmol), HATU (0.20 g,0.53 mmol) were added in sequence, DIPEA (0.17 mL,0.97 mmol) was added in portions, 5mL DMF was dissolved and clarified, reaction was performed at room temperature for about 10 hours, after TLC (dichloromethane: methanol=20:1) detected that the starting material was completely reacted, poured into 50mL of water, a large amount of solid was precipitated, after suction filtration and drying, the solid was dissolved in 8mL of glacial acetic acid, reacted at 120℃for about 4 hours, after TLC (dichloromethane: methanol=20:1) detected that the starting material was completely reacted, the reaction was stopped, 50mL of water was added dropwise, a large amount of solid was precipitated, extracted with ethyl acetate (15 mL×3), dried over anhydrous sodium sulfate, suction filtration, and column chromatography (dichloromethane: methanol=50:1) was purified to obtain a yellow solid of 0.09g, yield: 34.3%, m.p.198-200 ℃. 1 H NMR(300MHz,DMSO-d 6 )δ(ppm):13.22(s,1H),9.37(s,1H),8.53(d,J＝8.3Hz,1H),7.90-7.80(m,4H),7.81-7.66(m,3H),7.31(t,J＝7.7Hz,1H),4.44-4.30(m,1H),4.30-4.21(m,1H),4.04(s,3H),3.26(s,3H),2.10-1.51(m,10H),0.78(t,J＝7.4Hz,3H).
Example 2
(R) -2- (4- ((8-cyclopentyl-5, 7-dimethyl-6-oxo-5, 6,7, 8-dihydropterin-2-yl) amino) -3-methoxyphenyl) -1H-benzo [ d ]]Imidazole-4-carboxamide (I-a-2:R 1 ＝CH 3 ,/>R 3 synthesis of =h)
Synthesis of cyclopentyl-D-alanine methyl ester (III-2)
With D-alanine methyl ester hydrochloride (II-2, 1.00g,11.22 mmol), sodium acetate (0.73 g,8.95 mmol), cyclopentanone (0.79 mL,8.49 mmol), naBH (AcO) 3 (2.84 g,12.74 mmol) was used as a starting material, and the same procedure as III-1 was followed to give 0.88g of a brown oily liquid in 45.8% yield. 1 H NMR(300MHz,Chloroform-d)δ(ppm):3.75(s,3H),3.42(q,J＝7.0Hz,1H),3.02(p,J＝6.8Hz,1H),2.23-2.14(m,1H),2.01-1.36(m,8H),1.31(d,J＝7.0Hz,3H).
Synthesis of N- (2-chloro-5-nitropyrimidin-4-yl) -N-cyclopentyl-D-alanine methyl ester (IV-2)
Using Compound III-2 (2.00 g,11.68 mmol), anhydrous potassium carbonate (1.61 g,11.91 mmol) and 2, 4-dichloro-5-nitropyrimidine (2.37 g,11.91 mmol) as raw materials, the same procedure as IV-1 was followed, and column chromatography (petroleum ether: ethyl acetate=25:1) gave 1.87g of yellow solid with a yield of 48.6% and a temperature of m.p.125-126 ℃. 1 H NMR(300MHz,Chloroform-d)δ(ppm):8.62(s,1H),3.76(s,3H),3.65-3.54(m,1H),2.28-2.08(m,1H),2.02-1.45(m,8H),1.25(d,J＝6.8Hz,3H).
Synthesis of (R) -2-chloro-8-cyclopentyl-7-methyl-7, 8-dihydropterin-6 (5H) -one (V-2)
IV-2 (1.86 g,5.66 mmol) and reduced iron powder (0.95 g,16.98 mmol) are used as raw materials, the operation is the same as V-1, and column chromatography (petroleum ether: ethyl acetate=2:1) is used for purification, so that 1.21g of white solid is obtained, the yield is 76.1%, and the m.p. 197-198 ℃. 1 H NMR(300MHz,Chloroform-d)δ(ppm):9.46(s,1H),7.78(s,1H),4.49(m,1H),4.32(q,J＝6.8Hz,1H),2.20-1.64(m,8H),1.48(d,J＝6.8Hz,3H).
Synthesis of (R) -2-chloro-8-cyclopentyl-5, 7-dimethyl-7, 8-dihydropterin-6 (5H) -one (VI-2)
V-2 (1.00 g,3.56 mmol), methyl iodide (0.33 ml,5.34 mmol) and 60% sodium hydride (0.21 g,5.34 mmol) are used as raw materials, the operation is the same as VI-1, and column chromatography (petroleum ether: ethyl acetate=2:1) is used for purification, so that 0.84g of white solid is obtained, the yield is 84.0%, and m.p.99-100 ℃. 1 H NMR(300MHz,Chloroform-d)δ(ppm):7.75(s,1H),4.49(m,1H),4.38(q,J＝6.7Hz,1H),3.36(s,3H),2.16-1.65(m,8H),1.40(d,J＝6.8Hz).
Synthesis of methyl (R) -4- ((8-cyclopentyl-5, 7-dimethyl-6-oxo-5, 6,7, 8-dihydropterin-2-yl) amino) -3-methoxybenzoate (VIII-2)
Starting from compound VI-2 (0.50 g,1.78 mmol), methyl 4-amino-3-methoxybenzoate (VII-1, 0.37g,2.04 mmol), cesium carbonate (0.87 g,2.67 mmol), xantphos (0.21 g,0.36 mmol), pd 2 (dba) 3 (0.16 g,0.18 mmol) as catalyst, dioxane as solvent, and column chromatography (petroleum ether: ethyl acetate=2:1) purification to give 0.55g of pale yellow oily paste with a yield of 72.6%, m.p. 225-227 ℃. 1 H NMR(300MHz,Chloroform-d)δ(ppm):8.53(d,J＝8.5Hz,1H),8.16(m,1H),7.76-7.69(m,2H),7.59(d,J＝1.8Hz,1H),4.68-4.55(m,1H),4.40(q,J＝6.8Hz,1H),4.03(s,3H),3.95(s,3H),3.36(s,3H),2.30-1.68(m,8H),1.41(d,J＝6.8Hz,3H).
Synthesis of (R) -4- ((8-cyclopentyl-5, 7-dimethyl-6-oxo-5, 6,7, 8-dihydropterin-2-yl) amino) -3-methoxybenzoic acid (IX-2)
Using compound VIII-2 (0.35 g,0.82 mmol) as a starting material, the same operation as IX-1 gave 0.31g of a white solid with a yield of 91.5% and a m.p.171-172 ℃. 1 H NMR(300MHz,DMSO-d 6 )δ(ppm):12.32(s,1H),8.53(d,J＝8.5Hz,1H),7.93(s,1H),7.74(s,1H),7.60(dd,J＝8.4,1.8Hz,1H),7.52(d,J＝1.8Hz,1H),4.52-4.39(m,1H),4.39-4.31(m,1H),3.97(s,3H),3.26(s,3H),2.09-1.56(m,8H),1.26(d,J＝6.7Hz,3H).
Synthesis of (R) -2- (4- ((8-cyclopentyl-5, 7-dimethyl-6-oxo-5, 6,7, 8-dihydropterin-2-yl) amino) -3-methoxyphenyl) -1H-benzo [ d ] imidazole-4-carboxamide (I-A-2)
Using compound IX-2 (0.34 g,0.83 mmol), 2, 3-diaminobenzamide (0.13 g,0.83 mmol), HATU (0.31 g,0.83 mmol) and DIPEA (0.29 ml,1.66 mmol) as starting materials, the same procedure was followed as for I-A-1 to give 0.14g of a yellow solid with a yield of 32.0% and m.p.265-267 ℃. 1 H NMR(300MHz,DMSO-d 6 )δ(ppm):13.23(s,1H),9.39(s,1H),8.57(d,J＝8.9Hz,1H),7.92(s,1H),7.89-7.81(m,3H),7.79-7.65(m,3H),7.32(t,J＝7.8Hz,1H),4.45(p,J＝8.3Hz,1H),4.34(q,J＝6.7Hz,1H),4.04(s,3H),3.25(s,3H),2.13-1.54(m,8H),1.25(d,J＝6.8Hz,3H).
Example 3
(R) -2- (4- ((8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5, 6,7, 8-dihydropterin-2-yl) amino) phenyl) -1H-benzo [ d]Imidazole-4-carboxamide (I-a-3:R 1 ＝CH 2 CH 3 ,/>R 3 ＝H)
synthesis of methyl (R) -4- ((8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5, 6,7, 8-dihydropterin-2-yl) amino) benzoate (VIII-3)
Starting from compound VI-1 (0.10 g,0.34 mmol), methyl para-aminobenzoate (VII-2, 0.09g,0.37 mmol), cesium carbonate (0.16 g,0.50 mmol), xantphos (0.04 g,0.07 mmol), pd 2 (dba) 3 (0.03 g,0.07 mmol) as catalyst, dioxane as solvent, and column chromatography (dichloromethane: methanol=45:1) was performed in the same manner as VIII-1 to obtain 0.12g of a yellow solid, yield: 85.29%.
Synthesis of (R) -4- ((8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5, 6,7, 8-dihydropterin-2-yl) amino) benzoic acid (IX-3)
Using compound VIII-3 (0.33 g,0.82 mmol) as a starting material, the same procedure as IX-1 gave 0.28g of a white solid in 86.3% yield.
Synthesis of (R) -2- (4- ((8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5, 6,7, 8-dihydropterin-2-yl) amino) phenyl) -1H-benzo [ d ] imidazole-4-carboxamide (I-A-3)
Using compound IX-3 (0.33 g,0.83 mmol), 2, 3-diaminobenzamide (0.13 g,0.83 mmol), HATU (0.31 g,0.83 mmol) and DIPEA (0.29 ml,1.66 mmol) as starting materials, the same procedure was followed as for I-A-1 to give 0.14g of a yellow solid with a yield of 32.0% m.p. >300℃。 1 H NMR(300MHz,DMSO-d 6 )δ(ppm):13.19(s,1H),9.49(s,1H),9.44(s,1H),8.15(d,J＝8.5Hz,2H),7.99(d,J＝8.5Hz,2H),7.91(s,1H),7.87(d,J＝7.6Hz,1H),7.79(s,1H),7.72(d,J＝7.9Hz,1H),7.33(t,J＝7.8Hz,1H),4.56-4.42(m,1H),4.31-4.24(m,1H),3.30(s,3H),2.19-1.58(m,10H),0.81(t,J＝7.4Hz,3H).
Example 4
(R) -2- (4- ((8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5, 6,7, 8-dihydropterin-2-yl) amino) -3-ethoxyphenyl) -1H-benzo [ d ]]Imidazole-4-carboxamide (I-a-4:R 1 ＝CH 2 CH 3 ,/> R 3 ＝H)
synthesis of methyl (R) -4- ((8-cyclopentyl-7-ethyl-5-methyl-6-oxo 5,6,7, 8-dihydropterin-2-yl) amino) -3-ethoxybenzoate (VIII-4)
Starting from compound VI-1 (0.25 g,0.85 mmol), methyl 4-amino-3-ethoxybenzoate (VII-3, 0.19g,0.98 mmol), cesium carbonate (0.41 g,1.28 mmol), xantphos (0.10 g,0.17 mmol), pd 2 (dba) 3 (0.08 g,0.09 mmol) as catalyst, dioxane as solvent, and column chromatography (petroleum ether: ethyl acetate=2:1) purification gave 0.24g of pale yellow oily paste with a yield of 62.2%. 1 H NMR(300MHz,DMSO-d 6 )δ(ppm):8.55(d,J＝8.5Hz,1H),7.88(s,1H),7.72(s,1H),7.61(dd,J＝8.5,1.8Hz,1H),7.50(d,J＝1.9Hz,1H),4.33-4.28(m,1H),4.28-4.22(m,1H),4.05(q,J＝7.1Hz,2H),3.84(s,3H),3.28(s,3H),2.04-1.54(m,10H),1.20(t,J＝7.1Hz,3H),0.78(t,J＝7.4Hz,3H).
Synthesis of (R) -4- ((8-cyclopentyl-7-ethyl-5-methyl-6-oxo 5,6,7, 8-dihydropyridin-2-yl) amino) -3-ethoxybenzoic acid (IX-4):
using compound VIII-4 (0.24 g,0.53 mmol) as a starting material, the same procedure as IX-1 gave 0.16g of a white solid in 68.7% yield, m.p.276-277 ℃. 1 H NMR(300MHz,DMSO-d 6 )δ(ppm):12.79(s,1H),8.50(d,J＝8.5Hz,1H),7.86(s,1H),7.67(s,1H),7.56(dd,J＝8.5,1.8Hz,1H),7.48(d,J＝1.8Hz,1H),4.33-4.27(m,1H),4.28-4.24(m,1H),4.19(q,J＝7.0Hz,2H),3.26(s,3H),2.06-1.51(m,10H),1.43(t,J＝6.9Hz,3H),0.76(t,J＝7.4Hz,3H).
Synthesis of (R) -2- (4- ((8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5, 6,7, 8-dihydropterin-2-yl) amino) -3-ethoxyphenyl) -1H-benzo [ d ] imidazole-4-carboxamide (I-A-4)
Using compound IX-4 (0.17 g,0.39 mmol), 2, 3-diaminobenzamide (0.06 g,0.39 mmol), HATU (0.15 g,0.39 mmol) and DIPEA (0.14 ml,0.77 mmol) as starting materials, the same procedure was followed as for I-A-1 to give 0.10g of a yellow solid with a yield of 46.5% and a temperature of m.p.234-236 ℃. 1 H NMR(300MHz,DMSO-d 6 )δ(ppm):13.22(s,1H),9.38(s,1H),8.54(d,J＝8.5Hz,1H),8.02-7.80(m,4H),7.79-7.61(m,3H),7.31(t,J＝7.8Hz,1H),4.38-4.17(m,4H),3.27(s,3H),2.10-1.57(m,10H),1.49(t,J＝7.0Hz,3H),0.77(t,J＝7.4Hz,3H).
Example 5
(R) -2- (4- ((8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5, 6,7, 8-dihydropyridin-2-yl) amino) -3-isopropoxyphenyl) -1H-benzo [ d ]]Imidazole-4-carboxamide (I-a-5:R 1 ＝CH 2 CH 3 ,R 3 ＝H)
synthesis of methyl (R) -4- ((8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5, 6,7, 8-dihydropterin-2-yl) amino) methyl) -3-isopropoxybenzoate (VIII-5)
Starting from compound VI-1 (0.25 g,0.85 mmol), methyl 4-amino-3-isopropoxybenzoate (VII-4, 0.20g,0.98 mmol), cesium carbonate (0.41 g,1.28 mmol), xantphos (0.10 g,0.17 mmol), pd 2 (dba) 3 (0.08 g,0.08 mmol) as catalyst, dioxane as solvent, and column chromatography (petroleum ether: ethyl acetate=2:1) purification gave 0.26g of pale yellow oily paste with a yield of 65.4%. 1 H NMR(300MHz,DMSO-d 6 )δ(ppm):8.57(d,J＝8.6Hz,1H),7.87(s,1H),7.70(s,1H),7.60(dd,J＝8.5,1.8Hz,1H),7.53(d,J＝1.8Hz,1H),4.78(p,J＝6.0Hz,1H),4.34-4.29(m,1H),4.29-4.21(m,1H),3.84(s,3H),3.27(s,3H),2.02(s,10H),1.38(d,J＝6.0Hz,6H),0.78(t,J＝7.4Hz,3H).
Synthesis of (R) -4- ((8-cyclopentyl-7-ethyl-5-methyl-6-oxo 5,6,7, 8-dihydropyridin-2-yl) amino) -3-isopropoxybenzoic acid (IX-5)
Using compound VIII-5 (0.25 g,0.53 mmol) as a starting material, the same procedure as IX-1 gave 0.23g of a white solid with a yield of 94.9% and a m.p.250-251 ℃. 1 H NMR(300MHz,DMSO-d 6 )δ(ppm):12.69(s,1H),8.52(d,J＝8.5Hz,1H),7.85(s,1H),7.65(s,1H),7.56(dd,J＝8.5,1.8Hz,1H),7.50(d,J＝1.8Hz,1H),4.74(p,J＝6.0Hz,1H),4.31-4.25(m,1H),4.24-4.16(m,1H),3.25(s,3H),2.06-1.52(m,10H),1.36(d,J＝6.0Hz,6H),0.76(t,J＝7.4Hz,3H).
Synthesis of (R) -2- (4- ((8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5, 6,7, 8-dihydropyridin-2-yl) amino) -3-isopropoxyphenyl) -1H-benzo [ d ] imidazole-4-carboxamide (I-A-5)
Using compound IX-5 (0.24 g,0.53 mmol), 2, 3-diaminobenzamide (0.08 g,0.53 mmol), HATU (0.20 g,0.53 mmol) and DIPEA (0.18 ml,1.06 mmol) as raw materials, the same procedure as for I-A-1 gave 0.15g of pale yellow solid with a yield of 49.8% and m.p.240-242 ℃. 1 H NMR(300MHz,DMSO-d 6 )δ(ppm):13.22(s,1H),9.41(d,J＝3.3Hz,1H),8.61(d,J＝8.4Hz,1H),7.92-7.84(m,4H),7.77(d,J＝3.3Hz,1H),7.74(d,J＝8.4Hz,1H),7.68(s,1H),,7.34(t,J＝7.8Hz,1H),4.88(p,J＝5.9Hz,1H),4.36-4.21(m,2H),3.29(s,3H),2.11-1.58(m,10H),1.45(d,J＝6.0Hz,6H),0.79(t,J＝7.4Hz,3H).
Example 6
(R) -2- (4- ((8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5, 6,7, 8-dihydropterin-2-yl) amino) -3- (cyclopentyloxy) phenyl) -1H-benzo [ d ]]Imidazole-4-carboxamide (I-a-6:R 1 ＝CH 2 CH 3 ,R 3 ＝H)
synthesis of methyl (R) -4- ((8-cyclopentyl-7-ethyl-5-methyl-6-oxo 5,6,7, 8-dihydropterin-2-yl) amino) -3- (cyclopentyloxy) benzoate (VIII-6)
Starting from compound VI-1 (0.25 g,0.85 mmol), methyl 4-amino-3-cyclopentyloxy benzoate (VII-5, 0.23g,0.98 mmol), cesium carbonate (0.41 g,1.28 mmol), xantphos (0.10 g,0.17 mmol), pd 2 (dba) 3 (0.08 g,0.08 mmol) as catalyst, dioxane as solvent, and column chromatography (petroleum ether: ethyl acetate=2:1) purification to give pale yellow oily paste liquid 0.32g, yield 76.3%. 1 H NMR(300MHz,DMSO-d 6 )δ(ppm):8.57(d,J＝8.5Hz,1H),7.87(s,1H),7.65(s,1H),7.61(dd,J＝8.5,1.8Hz,1H),7.52(d,J＝1.9Hz,1H),5.07-5.00(m,1H),4.35-4.26(m,1H),4.24-4.10(m,1H),3.85(s,3H),3.27(s,3H),2.12-1.51(m,18H),0.77(t,J＝7.4Hz,3H).
Synthesis of (R) -4- ((8-cyclopentyl-7-ethyl-5-methyl-6-oxo 5,6,7, 8-dihydropterin-2-yl) amino) -3- (cyclopentyloxy) benzoic acid (IX-6)
Using compound VIII-6 (0.30 g,0.61 mmol) as a starting material, the same operation as IX-1 gave 0.17g of a white solid with a yield of 58.3%, m.p.251-252 ℃. 1 H NMR(300MHz,DMSO-d 6 )δ(ppm):12.60(s,1H),8.50(d,J＝8.5Hz,1H),7.84(s,1H),7.64(s,1H),7.56(dd,J＝8.5,1.8Hz,1H),7.49(d,J＝1.8Hz,1H),5.05-4.95(m,1H),4.33-4.25(m,1H),4.15(p,J＝8.3Hz,1H),3.25(s,3H),2.11-1.47(m,18H),0.75(t,J＝7.4Hz,3H).
Synthesis of (R) -2- (4- ((8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5, 6,7, 8-dihydropterin-2-yl) amino) -3-) cyclopentyloxy) phenyl) -1H-benzo [ d ] imidazole-4-carboxamide (I-A-6)
Using compound IX-6 (0.23 g,0.48 mmol), 2, 3-diaminobenzamide (0.07 g,0.48 mmol), HATU (0.18 g,0.48 mmol) and DIPEA (0.17 ml,0.96 mmol) as starting materials, the same procedure was followed as for I-A-1 to give 0.1g of a yellow solid with a yield of 35.0% and a temperature of m.p.232-234 ℃. 1 H NMR(300MHz,DMSO-d 6 )δ(ppm):13.20(s,1H),9.41(d,J＝3.5Hz,1H),8.58(d,J＝9.0Hz,1H),7.89-7.80(m,4H),7.75(d,J＝3.5Hz,1H),7.71(d,J＝8.0Hz,1H),7.60(s,1H),7.32(t,J＝7.8Hz,1H),5.15-5.05(m,1H),4.31-4.24(m,1H),4.18(p,J＝8.3Hz,1H),3.26(s,3H),2.15-1.45(m,18H),0.75(t,J＝7.4Hz,3H).
Example 7
(R) -2- (4- ((8- (2, 4-dimethoxybenzyl) -7-ethyl-5-methyl-6-oxo-5, 6,7, 8-dihydropterin-2-yl) amino) -3-methoxyphenyl) -1H-benzo [ d ]]Imidazole-4-carboxamide (I-a-7:R 1 ＝CH 2 CH 3 ,/>R 3 ＝H)
synthesis of methyl (R) -2- ((2, 4-dimethoxybenzyl) amino) butyrate (X-1)
As compounds D-2-aminobutyric acid methyl ester hydrochloride (II-1, 1.48g,9.70 mmol), sodium acetate (0.70 g,8.49 mmol), 2, 4-dimethoxybenzaldehyde (1.41 g,8.49 mmol), naBH (AcO) 3 (2.70 g,12.74 mmol) was used as a starting material and purified by column chromatography (petroleum ether: ethyl acetate=20:1) using III-1 to give 1.18g as a pale yellow oily liquid in 45.3% yield. 1 H NMR(300MHz,Chloroform-d)δ(ppm):7.15(d,J＝8.8Hz,1H),6.47-6.38(m,2H),3.83(s,3H),3.81(s,3H),3.70(d,J＝7.5Hz,2H),3.68(s,3H),3.23(t,J＝6.5Hz,1H),2.02(s,1H),1.77-1.61(m,2H),0.93(t,J＝7.4Hz,3H).
Synthesis of methyl (R) -2- ((2-chloro-5-nitropyrimidin-4-yl) (2, 4-dimethoxybenzyl) amino) butyrate (XI-1)
With compound X-1 (0.95 g,3.55 mmol), anhydrous potassium carbonate (0.49 g, 3) 55 mmol), 2, 4-dichloro-5-nitropyrimidine (0.69 g,3.62 mmol) as starting material, was purified by column chromatography (petroleum ether: ethyl acetate=20:1) to give 0.93g of a yellow oily liquid in 65.5% yield. 1 H NMR(300MHz,Chloroform-d)δ(ppm):8.67(s,1H),7.06(d,J＝9.0Hz,1H),6.44-6.37(m,2H),4.51-4.45(m,1H),4.44(d,J＝5.8Hz,2H),3.81(s,3H),3.73(s,3H),3.64(s,3H),2.11-1.97(m,2H),1.07(t,J＝7.5Hz,3H).
Synthesis of (R) -2-chloro-8- (2, 4-dimethoxybenzyl) -7-ethyl-7, 8-dihydropterin-6 (5H) -one (XII-1)
XI-1 (0.67 g,1.58 mmol) and reduced iron powder (0.26 g,4.74 mmol) are used as raw materials, the operation is the same as V-1, and column chromatography (petroleum ether: ethyl acetate=2:1) is used for purification, so that 0.32g of white solid is obtained, the yield is 55.8%, and the temperature is m.p.112-113 ℃. 1 H NMR(300MHz,DMSO-d 6 )δ(ppm):10.90(s,1H),7.58(s,1H),7.19(d,J＝8.3Hz,1H),6.58(d,J＝2.4Hz,1H),6.49(dd,J＝8.3,2.4Hz,1H),5.11(d,J＝14.9Hz,1H),4.18(d,J＝14.9Hz,1H),4.06-3.97(m,1H),3.76(s,3H),3.74(s,3H),1.88-1.73(m,2H),0.76(t,J＝7.4Hz,3H).
Synthesis of (R) -2-chloro-8- (2, 4-dimethoxybenzyl) -7-ethyl-5-methyl-7, 8-dihydropterin-6 (5H) -one (XIII-1)
Using XII-1 (1.55 g,4.27 mmol), methyl iodide (0.40 ml,6.41 mmol) and 60% sodium hydride (0.25 g,6.41 mmol) as raw materials, the same procedure as VI-1 was followed, and column chromatography (petroleum ether: ethyl acetate=2:1) was used to purify 1.30g of a white solid, the yield was 80.7%, and the temperature of m.p.125-126 ℃. 1 H NMR(300MHz,DMSO-d 6 )δ(ppm):7.89(s,1H),7.21(d,J＝8.3Hz,1H),6.59(d,J＝2.4Hz,1H),6.50(dd,J＝8.3,2.4Hz,1H),5.12(d,J＝14.9Hz,1H),4.21(d,J＝14.9Hz,1H),4.14(t,J＝5.1Hz,1H),3.77(s,3H),3.75(s,3H),3.24(s,3H),1.86-1.74(m,2H),0.74(t,J＝7.4Hz,3H).
Synthesis of methyl (R) -4- ((8- (2, 4-dimethoxybenzyl) -7-ethyl-5-methyl-6-oxo-5, 6,7, 8-dihydropterin-2-yl) amino) -3-methoxybenzoate (VIII-7)
Starting from compound XIII-1 (0.25 g,0.66 mmol), methyl 4-amino-3-methoxybenzoate (VII-1, 0.14g,0.76 mmol), cesium carbonate (0.32 g,0.99 mmol), xantphos (0.08 g,0.13 mmol), pd 2 (dba) 3 (0.06 g,0.07 mmol) as catalyst, dioxane as solvent, and column chromatography (petroleum ether: ethyl acetate=2:1) purification to obtain pale yellow oily paste liquid 0.33g, yield 95.9%. 1 H NMR(300MHz,DMSO-d 6 )δ(ppm):8.47(d,J＝8.5Hz,1H),7.90(s,1H),7.81(s,1H),7.56(dd,J＝8.5,1.8Hz,1H),7.51(d,J＝1.8Hz,1H),7.21(d,J＝8.4Hz,1H),6.65(d,J＝2.4Hz,1H),6.51(dd,J＝8.4,2.4Hz,1H),5.28(d,J＝15.1Hz,1H),4.26(d,J＝15.1Hz,1H),4.14(t,J＝5.2Hz,1H),3.98(s,3H),3.86(s,3H),3.84(s,3H),3.78(s,3H),3.30(s,3H),1.91-1.77(m,2H),0.80(t,J＝7.4Hz,3H).
Synthesis of (R) -4- ((8- (2, 4-dimethoxybenzyl) -7-ethyl-5-methyl-6-oxo-5, 6,7, 8-dihydropterin-2-yl) amino) -3-methoxybenzoic acid (IX-7)
Using compound VIII-7 (0.33 g,0.63 mmol) as a starting material, the same operation as IX-1 gave 0.24g of a white solid with a yield of 75.1% and a m.p.248-249 ℃. 1 H NMR(300MHz,DMSO-d 6 )δ(ppm):12.64(s,1H),8.39(d,J＝8.3Hz,1H),7.86(s,1H),7.72(s,1H),7.54-7.44(m,2H),7.17(d,J＝8.4Hz,1H),6.61(d,J＝2.4Hz,1H),6.48(dd,J＝8.4,2.4Hz,1H),5.25(d,J＝15.1Hz,1H),4.22(d,J＝15.1Hz,1H),4.10(t,J＝5.2Hz,1H),3.93(s,3H),3.80(s,3H),3.74(s,3H),3.26(s,3H),1.86-1.74(m,2H),0.76(t,J＝7.4Hz,3H).
Synthesis of (R) -2- (4- ((8- (2, 4-dimethoxybenzyl) -7-ethyl-5-methyl-6-oxo-5, 6,7, 8-dihydropterin-2-yl) amino) -3-methoxyphenyl) -1H-benzo [ d ] imidazole-4-carboxamide (I-A-7)
Using compound IX-7 (0.24 g,0.47 mmol), 2, 3-diaminobenzamide (0.07 g,0.47 mmol), HATU (0.18 g,0.47 mmol) and DIPEA (0.16 ml,0.94 mmol) as starting materials, the same procedure was followed as for I-A-1 to give 0.08g of a yellow solid with a yield of 27.2% and m.p.266-268 ℃. 1 H NMR(300MHz,DMSO-d 6 )δ(ppm):13.22(s,1H),9.43(s,1H),8.45(d,J＝8.5Hz,1H),7.90-7.82(m,3H),7.81-7.74(m,3H),7.74-7.67(m,1H),7.32(t,J＝7.8Hz,1H),7.19(d,J＝8.3Hz,1H),6.64(d,J＝2.4Hz,1H),6.49(dd,J＝8.4,2.4Hz,1H),5.28(d,J＝15.2Hz,1H),4.25(d,J＝15.1Hz,1H),4.11(t,J＝5.2Hz,1H),4.03(s,3H),3.83(s,3H),3.74(s,3H),3.27(s,3H),1.88-1.75(m,2H),0.78(t,J＝7.4Hz,3H).
Example 8
(R) -2- (4- ((7-ethyl-5-methyl-8- ((5-methylthiophene-2-yl) methyl) -6) oxo-5, 6,7, 8-dihydropterin-2-acyl) amino) -3-methoxyphenyl) -1H-benzo [ d ]]Imidazole-4-carboxamide (I-a-8:R 1 ＝CH 2 CH 3 ,/>R 3 ＝H)
synthesis of (R) -2-chloro-7-ethyl-5-methyl-7, 8-dihydropterin-6 (5H) -one (XIV-1)
XIII-1 (0.55 g,1.46 mmol) was dissolved in 7mL of trifluoroacetic acid in a 25mL single-necked flask and the mixture was stirred at 80℃for 3 hours to obtain a pink solid, and after TLC (petroleum ether: ethyl acetate=1:1) had detected that the starting material had reacted completely, the solvent was removed under reduced pressure and purified by column chromatography (petroleum ether: ethyl acetate=1:1) to obtain 0.22g of a white solid in 66.5% yield. 1 H NMR(400MHz,DMSO-d 6 )δ(ppm):8.62(s,1H),7.80(s,1H),4.28(td,J＝4.9,1.9Hz,1H),3.21(s,3H),1.91-1.64(m,2H),0.83(t,J＝7.4Hz,3H).
Synthesis of (R) -2-chloro-7-ethyl-5-methyl-8- ((5-methylthiophene-2-yl) methyl) -7, 8-dihydropterin-6 (5H) -one (VI-3)
In a 25mL single necked flask, XIV-1 (0.21 g,0.93 mmol) and 2-bromomethyl-5-methylthiophene (XV-1, 0.26g,1.39 mmol) were dissolved in 6mL DMF, 60% sodium hydride (0.07 g,1.67 mmol) was added under ice bath conditions and transferred to room temperature and stirred. After 3h, TLC (petroleum ether: ethyl acetate=2:1) detected that the starting material was completely reacted. After the reaction, 25mL of water was added, the mixture was extracted with ethyl acetate (15 mL. Times.3), the ethyl acetate phase was washed with saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography (petroleum ether: ethyl acetate=4:1) after suction filtration to give 0.24g of a pale yellow solid, yield: 76.6%, m.p.159-160 ℃. 1 H NMR(300MHz,DMSO-d 6 )δ(ppm):7.91(s,1H),6.98(d,J＝3.5Hz,1H),6.66(d,J＝3.1Hz,1H),5.11(d,J＝15.4Hz,1H),4.61(d,J＝15.4Hz,1H),4.37-4.23(m,1H),3.24(s,3H),2.38(s,3H),1.87-1.72(m,2H),0.65(t,J＝7.4Hz,3H).
Synthesis of methyl (R) -4- ((7-ethyl-5-methyl-8- ((5-methylthiophene-2-yl) methyl) -6-oxo-5, 6,7, 8-dihydropterin-2-yl) amino) -3-methoxybenzoate (VIII-8)
Starting from compound VI-3 (0.40 g,1.19 mmol), compound VII-1 (0.25 g,1.36 mmol), cesium carbonate (0.59 g,1.78 mmol), xantphos (0.14 g,0.24 mmol), pd 2 (dba) 3 (0.11 g,0.12 mmol) as catalyst, dioxane as solvent, and column chromatography (petroleum ether: ethyl acetate=2:1) purification was carried out in the same manner as VIII-1 to obtain 0.49g of pale yellow oily paste liquid, yield: 85.5%. 1 H NMR(300MHz,DMSO-d 6 )δ(ppm):8.57(d,J＝8.5Hz,1H),7.89(s,1H),7.81(s,1H),7.59(dd,J＝8.4,1.8Hz,1H),7.50(d,J＝1.9Hz,1H),6.98(d,J＝3.3Hz,1H),6.66(d,J＝3.3Hz,1H),5.28(d,J＝15.4Hz,1H),4.58(d,J＝15.4Hz,1H),4.24(t,J＝4.9Hz,1H),3.96(s,3H),3.83(s,3H),3.25(s,3H),2.36(s,3H),1.88-1.72(m,2H),0.70(t,J＝7.4Hz,3H).
Synthesis of (R) -4- ((7-ethyl-5-methyl-8- ((5-methylthiophene-2-yl) methyl) -6-oxo-5, 6,7, 8-dihydropterin-2-yl) amino) -3-methoxybenzoic acid (IX-8)
Using compound VIII-8 (0.49 g,1.02 mmol) as a starting material, the same operation as IX-1 gave 0.43g of a pale yellow solid with a yield of 90.2% and a m.p.236-237 ℃. 1 H NMR(300MHz,DMSO-d 6 )δ(ppm):12.68(s,1H),8.54(d,J＝8.4Hz,1H),7.95(s,1H),7.92(s,1H),7.60(d,J＝8.6Hz,1H),7.53(s,1H),7.01(d,J＝3.4Hz,1H),6.69(d,J＝3.3Hz,1H),5.31(d,J＝15.3Hz,1H),4.63(d,J＝15.4Hz,1H),4.30(t,J＝4.9Hz,1H),3.99(s,3H),3.28(s,3H),2.40(s,3H),1.91-1.78(m,2H),0.73(t,J＝7.3Hz,3H).
Synthesis of (R) -2- (4- ((7-ethyl-5-methyl-8- ((5-methylthiophene-2-yl) methyl) -6) oxo-5, 6,7, 8-dihydropterin-2-acyl) amino) -3-methoxyphenyl) -1H-benzo [ d ] imidazole-4-carboxamide (I-A-8)
Using compound IX-8 (0.43 g,0.94 mmol), 2, 3-diaminobenzamide (0.14 g,0.94 mmol), HATU (0.18 g,0.94 mmol) and DIPEA (0.33 ml,0.96 mmol) as starting materials, the same procedure was followed as for I-A-1 to give 0.15g of a yellow solid with a yield of 27.3% and m.p.201-203 ℃. 1 H NMR(300MHz,DMSO-d 6 )δ(ppm):13.23(s,1H),9.40(s,1H),8.61(d,J＝8.7Hz,1H),7.97-7.78(m,5H),7.78-7.67(m,2H),7.32(t,J＝7.8Hz,1H),7.00(d,J＝3.4Hz,1H),6.67(d,J＝2.8Hz,1H),5.32(d,J＝15.4Hz,1H),4.61(d,J＝15.4Hz,1H),4.25(t,J＝4.9Hz,1H),4.05(s,3H),3.26(s,3H),2.37(s,3H),1.88-1.74(m,2H),0.71(t,J＝7.3Hz,3H).
Example 9
(R) -2- (4- ((8-benzyl-7-ethyl-5-methyl-6-oxo-5, 6,7, 8-dihydropterin-2-yl) amino) -3-methoxyphenyl) -1H-benzo [ d ] ]Imidazole-4-carboxamide (I-a-9:R 1 ＝CH 2 CH 3 ,/>R 3 ＝H)
synthesis of (R) -8-benzyl-2-chloro-7-ethyl-5-methyl-7, 8-dihydropterin-6 (5H) -one (VI-4)
Using XIV-1 (0.21 g,0.93 mmol), benzyl bromide (XV-2, 0.24g,1.39 mmol) and 60% sodium hydride (0.07 g,1.67 mmol) as starting materials, the same procedure was followed as for VI-3, and purification by column chromatography (petroleum ether: ethyl acetate=4:1) afforded 0.22g of a white solid in 74.6% yield. 1 H NMR(400MHz,DMSO-d 6 )δ(ppm):7.93(s,1H),7.40-7.23(m,5H),5.23(d,J＝15.3Hz,1H),4.42(d,J＝15.3Hz,1H),4.21(t,J＝4.9Hz,1H),3.26(s,3H),1.86-1.75(m,2H),0.70(t,J＝7.4Hz,3H).
Synthesis of methyl (R) -4- ((8-benzyl-7-ethyl-5-methyl-6-oxo 5,6,7, 8-dihydropterin-2-yl) amino) -3-methoxybenzoate (VIII-9)
Starting from compound VI-4 (0.22 g,0.69 mmol), compound VII-1 (0.15 g,0.79 mmol), cesium carbonate (0.34 g,1.04 mmol), xantphos (0.08 g,0.14 mmol), pd 2 (dba) 3 (0.06 g,0.07 mmol) as catalyst, dioxane as solvent, and column chromatography (petroleum ether: ethyl acetate=2:1) purification to obtain pale yellow oily paste liquid 0.26g, yield: 81.2%, m.p. 157-158 ℃. 1 H NMR(300MHz,DMSO-d 6 )δ(ppm):8.43(d,J＝8.5Hz,1H),7.94(s,1H),7.82(s,1H),7.55(d,J＝8.7Hz,1H),7.50(s,1H),7.44-7.30(m,5H),5.38(d,J＝15.5Hz,1H),4.47(d,J＝15.5Hz,1H),4.21(t,J＝5.0Hz,1H),3.96(s,3H),3.86(s,3H),3.32(s,3H),1.91-1.77(m,2H),0.78(t,J＝7.4Hz,3H).
Synthesis of (R) -4- ((8-benzyl-7-ethyl-5-methyl-6-oxo 5,6,7, 8-dihydropyridin-2-yl) amino) -3-methoxybenzoic acid (IX-9)
Using compound VIII-9 (0.26 g,0.56 mmol) as a starting material, the same operation as IX-1 gave 0.23g of a white solid in 91.6% yield, m.p.175-176 ℃. 1 H NMR(300MHz,DMSO-d 6 )δ(ppm):12.33(s,1H),8.38(d,J＝8.3Hz,1H),7.92(s,1H),7.77(s,1H),7.50(d,J＝8.4Hz,2H),7.42-7.31(m,5H),5.37(d,J＝15.6Hz,1H),4.46(d,J＝15.5Hz,1H),4.20(t,J＝5.0Hz,1H),3.95(s,3H),3.31(s,3H),1.88-1.78(m,2H),0.77(t,J＝7.4Hz,3H).
Synthesis of (R) -2- (4- ((8-benzyl-7-ethyl-5-methyl-6-oxo-5, 6,7, 8-dihydropterin-2-yl) amino) -3-methoxyphenyl) -1H-benzo [ d ] imidazole-4-carboxamide (I-A-9)
Using compound IX-9 (0.23 g,0.51 mmol), 2, 3-diaminobenzamide (0.08 g,0.51 mmol), HATU (0.2 g,0.51 mmol) and DIPEA (0.18 ml,1.03 mmol) as starting materials, the same procedure was followed as for I-A-1 to give 0.08g of a yellow solid with a yield of 27.8% and a m.p.205-207 ℃. 1 H NMR(300MHz,DMSO-d 6 )δ(ppm):13.23(s,1H),9.42(s,1H),8.47(d,J＝8.5Hz,1H),7.93(s,1H),7.92-7.82(m,2H),7.80(d,J＝6.6Hz,3H),7.74(dd,J＝7.9,1.0Hz,1H),7.48-7.29(m,6H),5.42(d,J＝15.2Hz,1H),4.47(d,J＝15.4Hz,1H),4.19(t,J＝5.0Hz,1H),4.05(s,3H),3.32(s,3H),1.91-1.78(m,2H),0.78(t,J＝7.4Hz,3H).
Example 10
(R) -2- (4- ((7-ethyl-5-methyl-6-oxo-8- (3- (trifluoromethyl) benzyl) -5,6,7, 8-dihydropterin-2-yl) amino) -3-methoxyphenyl) -1H-benzo [ d]Imidazole-4-carboxamide (I-a-10:R 1 ＝CH 2 CH 3 ,/>R 3 ＝H)
synthesis of (R) -2-chloro-7-ethyl-5-methyl-8- (3- (trifluoromethyl) benzyl) -7, 8-dihydropterin-6 (5H) -one (VI-5)
Using compound XIV-1 (0.21 g,0.93 mmol), 3-trifluoromethyl bromobenzyl (XV-3, 0.24g,1.39 mmol) and 60% sodium hydride (0.07 g,1.67 mmol) as raw materials, the same procedure as VI-3 was followed, and column chromatography (petroleum ether: ethyl acetate=4:1) was performed to obtain a pale yellow solid (0.25 g, yield: 69.9%, m.p.106-107 ℃). 1 H NMR(300MHz,DMSO-d 6 )δ(ppm):7.93(s,1H),7.82(s,1H),7.73-7.54(m,3H),5.18(d,J＝15.5Hz,1H),4.58(d,J＝15.5Hz,1H),4.37(dd,J＝5.7,4.0Hz,1H),3.27(s,3H),1.87-1.71(m,2H),0.70(t,J＝7.4Hz,3H).
Synthesis of methyl (R) -4- ((7-ethyl-5-methyl-6-oxo-8- (3- (trifluoromethyl) benzyl)) -5,6,7, 8-dihydropterin-2-yl) amino) -3-methoxybenzoate (VIII-10)
Starting from compound VI-5 (0.46 g,1.19 mmol), compound VII-1 (0.25 g,1.36 mmol), cesium carbonate (0.59 g,1.78 mmol), xantphos (0.14 g,0.24 mmol), pd 2 (dba) 3 (0.11 g,0.12 mmol) as catalyst, dioxane as solvent, and column chromatography (petroleum ether: ethyl acetate=2:1) purification to obtain pale yellow oily paste liquid 0.51g, yield 80.3%, m.p. 177-178 ℃. 1 H NMR(300MHz,DMSO-d 6 )δ(ppm):8.34(d,J＝8.5Hz,1H),7.93(s,1H),7.84(s,1H),7.79(s,1H),7.71-7.42(m,5H),5.31(d,J＝15.8Hz,1H),4.63(d,J＝15.8Hz,1H),4.34(s,1H),3.95(s,3H),3.84(s,3H),3.38(s,3H),1.94-1.73(m,2H),0.78(t,J＝7.0Hz,3H).
Synthesis of (R) -4- ((7-ethyl-5-methyl-6-oxo-8) (3- (trifluoromethyl) benzyl) -5,6,7, 8-dihydropterin-2-yl) amino) -3-methoxybenzoic acid (IX-10)
Using compound VIII-10 (0.36 g,0.68 mmol) as a starting material, the same operation as IX-1 gave 0.30g of a white solid with a yield of 85.6%, m.p.233-234 ℃. 1 H NMR(300MHz,DMSO-d 6 )δ(ppm):12.24(s,1H),8.30(d,J＝8.9Hz,1H),7.92(s,1H),7.83(s,1H),7.76(s,1H),7.72-7.55(m,3H),7.51-7.43(m,2H),5.31(d,J＝15.8Hz,1H),4.62(d,J＝15.9Hz,1H),4.33(t,J＝5.0Hz,1H),3.93(s,3H),3.31(s,3H),1.88-1.72(m,2H),0.77(t,J＝7.4Hz,3H).
Synthesis of (R) -2- (4- ((7-ethyl-5-methyl-6-oxo-8- (3- (trifluoromethyl) benzyl) -5,6,7, 8-dihydropterin-2-yl) amino) -3-methoxyphenyl) -1H-benzo [ d ] imidazole-4-carboxamide (I-A-10)
Using compound IX-10 (0.37 g,0.72 mmol), 2, 3-diaminobenzamide (0.11 g,0.72 mmol), HATU (0.27 g,0.72 mmol) and DIPEA (0.25 ml,1.44 mmol) as starting materials, the same procedure was followed as for I-A-1 to give 0.14g of a yellow solid with a yield of 30.8% and m.p.176-178 ℃. 1 H NMR(300MHz,DMSO-d 6 )δ(ppm):13.20(s,1H),9.40(s,1H),8.40(d,J＝8.5Hz,1H),8.03-7.49(m,11H),7.32(t,J＝7.8Hz,1H),5.33(d,J＝15.7Hz,1H),4.61(d,J＝15.7Hz,1H),4.29(t,J＝5.0Hz,1H),4.01(s,3H),3.30(s,3H),1.90-1.70(m,2H),0.75(t,J＝7.4Hz,3H).
Example 11
(R) -2- (4- ((8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5, 6,7, 8-dihydropterin-2-yl) (methyl) amino) -3-methoxyphenyl) -1H-benzo [ d ]]Imidazole-4-carboxamide (I-B-1:R 1 ＝CH 2 CH 3 ,
R 3 ＝CH 3 ) Is synthesized by (a)
Synthesis of methyl (R) -4- ((8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5, 6,7, 8-dihydropterin-2-yl) (methyl) amino) -3-methoxybenzoate (XVII-1)
Using compound VIII-1 (0.20 g,0.47 mmol), methyl iodide (XVI-1, 0.04ml,0.70 mmol) and 60% sodium hydride (0.03 g,0.70 mmol) as starting materials, the same procedure as VI-1 was followed, and purification by column chromatography (petroleum ether: ethyl acetate=1:1) gave 0.19g of a yellow oily liquid in 91.9% yield. 1 H NMR(300MHz,Chloroform-d)δ(ppm):7.73(dd,J＝8.1,1.9Hz,1H),7.67(d,J＝1.8Hz,1H),7.65(s,1H),7.33(d,J＝8.1Hz,1H),4.22-4.12(m,2H),3.98(s,3H),3.88(s,3H),3.48(s,3H),3.32(s,3H),2.00-1.26(m,10H),0.86(t,J＝7.5Hz,3H).
Synthesis of (R) -4- ((8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5, 6,7, 8-dihydropterin-2-yl) (methyl) amino) -3-methoxybenzoic acid (XVIII-1)
Starting with compound XVII-1 (0.19 g,0.42 mmol), operating as IX-1, the purification gives 0.15g of yellow oily liquid, yield: 81.2%. 1 H NMR(300MHz,DMSO-d 6 )δ(ppm):12.74(s,1H),7.66-7.56(m,2H),7.52(s,1H),7.43(d,J＝8.0Hz,1H),4.36-4.26(m,2H),3.79(s,3H),3.73-3.59(m,1H),3.37(s,3H),3.21(s,3H),1.90-1.06(m,10H),0.70(t,J＝7.3Hz,3H).
Synthesis of (R) -2- (4- ((8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5, 6,7, 8-dihydropterin-2-yl) (methyl) amino) -3-methoxyphenyl) -1H-benzo [ d ] imidazole-4-carboxamide (I-B-1)
Using compound XVIII-1 (0.18 g,0.34 mmol), 2, 3-diaminobenzamide (0.05 g,0.35 mmol), HATU (0.13 g,0.34 mmol) and DIPEA (0.12 ml,0.68 mmol) as starting materials, the same procedure was followed as for I-A-1 to give 0.06g of a yellow solid with a yield of 31.8% and a m.p.230-232 ℃. 1 H NMR(300MHz,DMSO-d 6 )δ(ppm):13.39(s,1H),9.37(s,1H),7.93-7.85(m,3H),7.81-7.74(m,2H),7.71(s,1H),7.42(d,J＝7.9Hz,1H),7.37(t,J＝7.8Hz,1H),4.17-4.09(m,1H),3.86(s,3H),3.68-3.54(m,1H),3.33(s,3H),3.21(s,3H),1.93-1.06(m,10H),0.71(t,J＝7.4Hz,3H).
Example 12
(R) -2- (4- ((8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5, 6,7, 8-dihydropterin-2-yl) (methyl) amino) -3-methoxyphenyl) -1H-benzo [ d ]]Imidazole-4-carboxamide (I-B-2:R 1 ＝CH 3 ,/> R 3 ＝CH 3 ) Is synthesized by (a)
Synthesis of methyl (R) -4- ((8-cyclopentyl-5, 7-dimethyl-6-oxo-5, 6,7, 8-dihydropterin-2-yl) (methyl) amino) -3-methoxybenzoate (XVII-2)
Using compound VIII-2 (0.20 g,0.47 mmol), methyl iodide (XVI-1, 0.04ml,0.70 mmol) and 60% sodium hydride (0.03 g,0.70 mmol) as starting materials, the same procedure as XVII-1 was followed, and purification by column chromatography (petroleum ether: ethyl acetate=1:1) gave 0.19g of a yellow oily liquid in 91.9% yield. 1 H NMR(300MHz,Chloroform-d)δ(ppm):7.68(dd,J＝8.1,1.8Hz,1H),7.65(s,1H),7.64(d,J＝1.8Hz,1H),7.29(d,J＝8.1Hz,1H),4.21(q,J＝6.8Hz,1H),4.17-4.13(m,1H),3.94(s,3H),3.85(s,3H),3.42(s,3H),3.26(s,3H),1.83-1.35(m,8H),1.31(d,J＝6.8Hz,3H).
Synthesis of (R) -4- ((8-cyclopentyl-5, 7-dimethyl-6-oxo-5, 6,7, 8-dihydropterin-2-yl) (methyl) amino) -3-methoxybenzoic acid (XVIII-2)
Starting with compound XVII-2 (0.19 g,0.43 mmol) as IX-1, the purification gives 0.17g of a yellow oily liquid in yield: 92.8%. 1 H NMR(300MHz,DMSO-d 6 )δ(ppm):12.20(s,1H),7.76(s,1H),7.62-7.55(m,2H),7.35(d,J＝7.9Hz,1H),4.20(q,J＝6.9Hz,1H),3.78(s,3H),3.74-3.63(m,1H),3.31(s,3H),3.20(s,3H),1.97-1.54(m,8H),1.19(d,J＝6.8Hz,3H).
Synthesis of (R) -2- (4- ((8-cyclopentyl-5, 7-dimethyl-6-oxo-5, 6,7, 8-dihydropterin-2-yl) (methyl) amino) -3-methoxyphenyl) -1H-benzo [ d ] imidazole-4-carboxamide (I-B-2)
Using compound XVIII-2 (0.18 g,0.42 mmol), 2, 3-diaminobenzamide (0.06 g,0.43 mmol), HATU (0.16 g,0.42 mmol) and DIPEA (0.15 ml,0.85 mmol) as starting materials, the same procedure was followed as for I-A-1 to give 0.06g of a yellow solid with a yield of 17.6% and a m.p.194-196 ℃. 1 H NMR(300MHz,DMSO-d 6 )δ(ppm):13.40(s,1H),9.37(s,1H),8.0-7.84(m,3H),7.82-7.66(m,3H),7.45-7.32(m,2H),4.17(q,J＝6.9Hz,1H),3.87(s,3H),3.77-3.58(m,1H),3.34(s,3H),3.19(s,3H),1.87-1.23(m,8H),1.18(d,J＝6.8Hz,3H).
Example 13
(R) -2- ((4- ((8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5, 6,7, 8-dihydropyridin-2-yl) amino) -3-methoxybenzamide) methyl) -1H-benzo [ d ]]Imidazole-4-carboxamide (I-C-1:R 1 ＝CH 2 CH 3 ,/>R 3 ＝H)
synthesis of (R) -2- ((4- ((8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5, 6,7, 8-dihydropyridin-2-yl) amino) -3-methoxybenzamide) methyl) -1H-benzo [ d ] imidazole-4-carboxamide (I-C-1)
In a 25mL single-necked flask, compound IX-1 (0.15 g,0.36 mmol), 2- (aminomethyl) -1H-benzo [ d ] was added sequentially ]Imidazole-4-carboxamide (0.06 g,0.33 mmol), HATU (0.14 g,0.36 mmol) and DIPEA (0.11 mL,0.66 mmol) are added in portions, 5mL of LDMF is dissolved and clarified, the reaction is carried out at room temperature for about 10 hours, 50mL of water is slowly added dropwise after TLC (dichloromethane: methanol=10:1) detects that the raw materials are completely reacted, a large amount of solid is separated out from the reaction liquid, suction filtration and drying are carried out, and column chromatography (dichloromethane: methanol=50:1) is carried out for purification, thus obtaining 0.11g of white solid with the yield of 50.6% and the temperature of m.p.208-210 ℃. 1 H NMR(300MHz,DMSO-d 6 )δ(ppm):12.76(s,1H),9.27(s,1H),9.16(s,1H),8.48(d,J＝8.7Hz,1H),7.86(s,1H),7.85-7.76(m,1H),7.76-7.54(m,5H),7.28(s,1H),4.77(d,J＝5.4Hz,2H),4.39-4.31(m,1H),4.22-4.28(m,1H),3.95(s,3H),3.25(s,3H),2.09-1.50(m,10H),0.76(t,J＝7.4Hz,3H).
Example 14
(R) -2- (4- ((8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5, 6,7, 8-dihydropterin-2-yl) amino) -3-methoxybenzyl) -1H-benzo [ d ]]Imidazole-4-carboxamide (I-D-1:R 1 ＝CH 2 CH 3 ,/> R 3 synthesis of =h)
Synthesis of methyl (R) -2- (4- ((8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5, 6,7, 8-dihydropterin-2-yl) amino) -3-methoxyphenyl) acetate (XX-1)
Using Compound VI-1 (0.12 g,0.41 mmol), methyl 2- (4-amino-3-methoxyphenyl) acetate (XIX-1, 0.10g,0.51 mmol), cesium carbonate (0.20 g,0.61 mmol), xantphos (0.05 g,0.08 mmol) as a starting material, palladium acetate (0.01 g,0.04 mmol) as a catalyst, the same procedure as VIII-1 was followed, and purification gave 0.11g of a yellow oily liquid in 59.6% yield. 1 H NMR(300MHz,DMSO-d 6 )δ(ppm):8.14(d,J＝8.4Hz,1H),7.78(s,1H),7.44(s,1H),6.92(d,J＝1.5Hz,1H),6.80(dd,J＝8.4Hz,1.5Hz,1H),4.27-4.17(m,2H),3.84(s,3H),3.62(m,5H)3.23(s,3H),2.05-1.35(m,10H),0.76(t,J＝7.4Hz,3H).
Synthesis of (R) -2- (4- ((8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5, 6,7, 8-dihydropterin-2-yl) amino) -3-methoxyphenyl) acetic acid (XXI-1)
Starting with compound XX-1 (0.11 g,0.24 mmol), operating with IX-1, purification gives 0.08g of a white solid, yield: 75.2%. 1 H NMR(300MHz,DMSO-d 6 )δ(ppm):12.5(s,1H),9.35(s,1H),7.68(s,1H),7.53(d,J＝8.1Hz,1H),7.04(d,J＝1.7Hz,1H),6.89(dd,J＝8.1Hz,1.7Hz,1H),4.47-4.41(m,1H),4.09-3.97(m,1H),3.80(s,3H),3.58(s,2H),3.20(s,3H),2.00-1.65(m,10H),0.74(t,J＝7.3Hz,3H).
Synthesis of (R) -2- (4- ((8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5, 6,7, 8-dihydropterin-2-yl) amino) -3-methoxybenzyl) -1H-benzo [ D ] imidazole-4-carboxamide (I-D-1)
Using compound XXI-1 (0.19 g,0.43 mmol), 2, 3-diaminobenzamide (0.06 g,0.43 mmol), HTAU (0.18 g,0.47 mmol), DIPEA (0.15 ml,0.86 mmol) as a starting material, the same procedure as for I-A-1 was followed by column chromatography purification (dichloromethane: methanol=50:1) to give 0.1g of a white solid with a yield of 41.7%, m.p.167-169 ℃. 1 H NMR(300MHz,DMSO-d 6 )δ(ppm):12.71(s,1H),9.32(s,1H),8.14(d,J＝8.3Hz,1H),7.83-7.73(m,2H),7.72-7.59(m,2H),7.47(s,1H),7.27(s,1H),7.10(s,1H),6.91(d,J＝8.2Hz,1H),4.29-4.16(m,4H),3.85(s,3H),3.22(s,3H),2.02-1.20(m,10H),0.75(t,J＝7.0Hz,3H).
Example 15
2- (1- (4- (((R) -8-cyclopentyl-7)-ethyl-5-methyl-6-oxo-5, 6,7, 8-dihydropterin-2-yl) amino) -3-methoxyphenyl) ethyl) -1H-benzo [ d]Imidazole-4-carboxamide (I-D-2:R 1 ＝CH 2 CH 3 ,/>R 3 ＝H)/>
synthesis of methyl 2- (4- ((R) -8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5, 6,7, 8-dihydropterin-2-yl) amino) -3-methoxyphenyl) propanoate (XX-2)
Starting from compound VI-1 (0.20 g,0.68 mmol), methyl 2- (4-amino-3-methoxyphenyl) propionate (XIX-2, 0.16g,0.78 mmol), cesium carbonate (0.33 g,1.02 mmol), xantphos (0.08 g,0.13 mmol), pd 2 (dba) 3 (0.06 g,0.07 mmol) as catalyst, dioxane as solvent, and column chromatography (petroleum ether: ethyl acetate=2:1) purification was carried out in the same manner as in VIII-1 to obtain 0.14g of pale yellow oily liquid, yield: 39.1%. 1 H NMR(300MHz,Chloroform-d)δ(ppm):8.26(d,J＝8.2Hz,1H),7.73(s,1H),7.34(s,1H),6.97-6.88(m,2H),4.40-4.34(m,1H),4.22-4.13(m,1H),3.88(s,3H),3.76-3.69(m,4H),3.28(s,3H),1.95-1.51(m,10H),1.25(d,J＝7.2Hz,3H),0.85(t,J＝7.4Hz,3H).
Synthesis of 2- (4- (((R) -8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5, 6,7, 8-dihydropterin-2-yl) amino) -3-methoxyphenyl) propionic acid (XXI-2)
Starting with compound XX-2 (0.12 g,0.26 mmol), operating with IX-1, purification gives 0.10g of a yellow oily liquid, yield: 84.6%. 1 H NMR(300MHz,Chloroform-d)δ(ppm):13.74(s,1H),9.13(s,1H),7.64(s,1H),7.50(d,J＝8.1Hz,1H),6.99-6.83(m,2H),4.45-4.32(m,1H),4.22-4.11(m,1H),3.89-3.66(m,4H),3.44-3.23(s,3H),2.00-1.65(m,10H),1.30(d,J＝7.2Hz,3H),0.74(t,J＝7.3Hz,3H).
Synthesis of 2- (1- (4- (((R) -8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5, 6,7, 8-dihydropterin-2-yl) amino) -3-methoxyphenyl) ethyl) -1H-benzo [ D ] imidazole-4-carboxamide (I-D-2)
Using compound XXI-2 (0.10 g,0.22 mmol), 2, 3-diaminobenzamide (0.03 g,0.22 mmol), HATU (0.08 g,0.22 mmol) and DIPEA (0.08 ml,0.44 mmol) as raw materials, the same procedure was followed as for I-A-1 to give 0.05g of a yellow solid with a yield of 40.0% and a m.p.174-176 ℃. 1 H NMR(300MHz,DMSO-d 6 )δ(ppm):12.66(s,1H),9.39(s,1H),8.09(d,J＝8.2Hz,1H),7.80(dd,J＝7.6,1.1Hz,1H),7.77-7.68(m,2H),7.61(dd,J＝8.0,1.1Hz,1H),7.47(s,1H),7.26(t,J＝7.8Hz,1H),7.10(s,1H),6.89(d,J＝8.4Hz,1H),4.44(q,J＝7.0Hz,1H),4.30-4.12(m,2H),3.85(s,3H),3.22(s,3H),2.02-1.35(m,13H),0.74(t,J＝7.4Hz,3H).
Example 16
(R) -2- (4- ((8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5, 6,7, 8-dihydropterin-2-yl) amino) -3-methoxybenzyl) -1H-benzo [ d ]]Imidazole-4-carboxamide (I-E-1:R 1 ＝CH 2 CH 3 ,R 3 synthesis of =h)
As compound XXI-1 (0.10 g,0.23 mmol), 2- (aminomethyl) -1H-benzo [ d ]]Imidazole-4-carboxamide (0.04 g,0.23 mmol), HTAU (0.10 g,0.25 mmol), DIPEA (0.08 ml,0.45 mmol) were used as starting material, the same procedure as for I-C-1 was followed, and column chromatography purification gave 0.09g of white solid with a yield of 64.8%, m.p.203-205 ℃. 1 H NMR(300MHz,DMSO-d 6 )δ(ppm):12.76(s,1H),9.22(s,1H),8.72(s,1H),8.07(d,J＝8.6Hz,1H),7.86-7.75(m,2H),7.75-7.62(m,2H),7.54(s,1H),7.28(t,J＝7.4Hz,1H),6.96(s,1H),6.84(d,J＝8.0Hz,1H),4.57(d,J＝5.6Hz,2H),4.27(t,J＝8.3Hz,1H),4.23-4.17(m,1H),3.81(s,3H),3.50(s,2H),3.23(s,3H),2.01-1.46(m,10H),0.76(t,J＝7.4Hz,3H).
Example 17
(R) -2- (3- ((8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5, 6,7, 8-dihydropterin-2-yl) amino) phenyl) -1H-benzo [ d]Imidazole-4-carboxamide (I-F-1:R 1 ＝CH 2 CH 3 ,/>R 3 synthesis of =h)
Synthesis of 2- (3-nitrophenyl) -1H-benzo [ d ] imidazole-4-carboxamide (XXIII-1)
Using m-nitrobenzoic acid (XXII-1, 0.15g,0.9 mmol), 2, 3-diaminobenzamide (0.13 g,0.85 mmol), HATU (0.34 g,0.90 mmol) and DIPEA (0.30 ml,1.7 mmol) as starting materials, the same procedure was followed as for I-A-1 to give 0.22g of a yellow solid with a yield of 86.7% and m.p.>300℃。 1 H NMR(300MHz,DMSO-d 6 )δ(ppm):13.83(s,1H),9.27(s,1H),9.09(t,J＝2.0Hz,1H),8.74(d,J＝7.6Hz,1H),8.42(dd,J＝8.3,1.6Hz,1H),7.98-7.91(m,2H),7.90(s,1H),7.83(dd,J＝8.0,1.1Hz,1H),7.44(t,J＝7.8Hz,1H).
Synthesis of 2- (3-aminophenyl) -1H-benzo [ d ] imidazole-4-carboxamide (XXIV-1)
In a 50mL single-necked flask, compound XXIII-1 (0.22 g,0.78 mmol) was suspended in absolute ethanol, heated to 75deg.C and refluxed, stannous chloride dihydrate (1.60 g,7.1 mmol) was added in portions, and the solution gradually turned yellow and clear during the reaction. After 5h, TLC (dichloromethane: methanol=15:1) detected complete reaction of the starting material, stopped heating and cooled to room temperature. Most of the solvent was distilled off under reduced pressure, 30mL of water was added, ethyl acetate (15 mL. Times.3) was extracted, the ethyl acetate phase was washed with saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography (dichloromethane: methanol=50:1) to give 0.17g of a white solid with a yield of 86.4% and an m.p.250 to 251 ℃. 1 H NMR(300MHz,DMSO-d 6 )δ(ppm):13.22(s,1H),9.40(s,1H),7.95-7.79(m,2H),7.70(dd,J＝8.0,1.2Hz,1H),7.47(t,J＝2.0Hz,1H),7.38-7.28(m,2H),7.22(t,J＝7.8Hz,1H),6.74(dd,J＝8.0,1.4Hz,1H),5.44(s,2H).
Synthesis of (R) -2- (3- ((8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5, 6,7, 8-dihydropterin-2-yl) amino) phenyl) -1H-benzo [ d ] imidazole-4-carboxamide (I-F-1)
Starting from compound XXIV-1 (0.08 g,0.27 mmol), compound VI-1 (0.07 g,0.30 mmol), cesium carbonate (0.13 g,0.40 mmol) and Xantphos (0.03 g,0.05 mmol)，Pd 2 (dba) 3 (0.02 g,0.03 mmol) as catalyst, dioxane as solvent, and column chromatography (dichloromethane: methanol=45:1) purification to give 0.10g of yellow flaky solid with yield: 72.6%, m.p. 180-182 ℃. 1 H NMR(300MHz,DMSO-d 6 )δ(ppm):13.35(s,1H),9.46(s,1H),9.35(s,1H),8.72(s,1H),7.97-7.88(m,3H),7.85(d,J＝8.6Hz,1H),7.76(d,J＝8.2Hz,1H),7.72(d,J＝7.8Hz,1H),7.49(t,J＝7.9Hz,1H),7.38(t,J＝7.8Hz,1H),4.53-4.38(m,1H),4.30-4.20(m,1H),2.08-1.18(m,10H),0.82(t,J＝7.4Hz,3H).
Example 18
PARP-1 and BRD4 inhibitory activity of some compounds of the invention were tested and the results were as follows:
(1) PARP-1 inhibition Activity assay
Experimental reagent: bovine serum albumin was purchased from Biyundian, histone and NAD + Dithiothreitol is purchased from source leaves, activated DNA (CGGAATTCCG) is prepared in gold Studies, PARP protein and TMB developing solution are purchased from Yiqiao Shenzhou, pADPr antibody is purchased from santacruz company, anti-mouse IgG-HRP-linked antibody is purchased from CST company, high-adsorption ELISA plate is purchased from corning company, blocking solution is PBS solution of 1% BSA, PARP buffer is 0.05M Tris-HCl 0.1M NaCl solution, and reaction buffer is prepared from 10mM NAD + (15μL)、1M DTT(15μL)、2M MgCl 2 (15. Mu.L), 10. Mu.g/. Mu.L of activated DNA (15. Mu.L), DMSO (150. Mu.L), PARP buffer (7.5 mL), each of which was self-prepared by the laboratory.
The experimental method comprises the following steps: a. coating: 100. Mu.L of histone PBS solution (20. Mu.g/mL) was added to each well and incubated overnight at 4℃in a refrigerator. The plates were decanted and washed 2 times with PBST. b. Closing: 200. Mu.L of blocking solution was added to each well and incubated for 2 hours at room temperature. Pouring out, washing the plate 2 times by PBST, and washing the plate 1 time by PARP buffer. c. The reaction: mu.L of reaction buffer with or without compound and 50. Mu.L of PARP protein (0.2. Mu.g/mL in PARP buffer) were added sequentially to each well. No compound was added to the negative control and no PARP protein was added to the blank control. The reaction was carried out at room temperature for 45 minutes. Pouring out and washing the plate for 2 times. d. Incubating primary antibody: mu.L pADPr antibody (1:1500) was added to each well and incubated for 1 hour at room temperature. The plates were decanted and washed 2 times with PBST. e. Incubating the secondary antibody: mu.L of anti-mouse IgG-HR was added per wellP (1:2000), incubated at room temperature for 30 minutes. The plates were decanted and washed 4 times with PBST. f. Color development: 100. Mu.L of TMB color development solution was added to each well, and the reaction was carried out in the dark for about 15 minutes (color was observed), and 50. Mu.L of 2M H was added to each well 2 SO 4 The reaction was terminated. The absorbance at 450nm was read by a microplate reader.
(2) BRD4 (1, 2) inhibition activity assay: experimental reagent: BRD4 (D1, D2) protein was purchased from BPS, (+) -JQ1 from MCE, peptide from GLChina, DMSO from Sigma, optiPlate-384 well plate from PerkinElmer.
The experimental method comprises the following steps: a. 1 XAssay buffer was prepared. b. Preparing a compound concentration gradient: test compound concentrations were 1 μm, 2-fold diluted, 6 concentrations, and multiplex well test was set. (+) -JQ1 test concentrations were 10. Mu.M starting, 10 concentrations were diluted 3-fold, and duplicate wells were set for each concentration. The solution was diluted in a 384 well Source plate in a gradient to a corresponding 1000-fold final concentration, and then transferred with Echo550 to a 384 well reaction plate for assay. Transfer of 20nL of 100% DMSO in Max wells and transfer of 20nL of (+) -JQ1 at maximum concentration in Min wells. c. A4X protein solution was prepared from the 1X reaction solution. d. A4X polypeptide solution was prepared from the 1X reaction solution. e. mu.L of a 4 Xprotein solution was added to each well, and the mixture was centrifuged at 1000rpm for 1min and incubated at room temperature for 15 min. f. mu.L of 4 Xpolypeptide solution was added to each well of the reaction plate, and the mixture was centrifuged at 1000rpm for 1min. g. 10. Mu.L of the test solution was added, centrifuged at 1000rpm for 60 seconds, and after gentle shaking and mixing, incubated at room temperature for 60 minutes. h. The EnVision reading was used and the dose-response curve fitted: the log value of the concentration is taken as an X axis, the percent inhibition rate is taken as a Y axis, and a log (inhibitor) vs. response-Variable slope fit quantitative response curve of analysis software GraphPad Prism 5 is adopted, so that the IC of the compound on protein binding inhibition is obtained 50 Values. Then, the IC of the compound is calculated by treatment with Graphpad Prism 5 software 50 。
(3) Experimental results: the results of in vitro PARP-1 and BRD4 inhibition activity screening of some compounds of the present invention are shown in Table 1.IC (integrated circuit) 50 0.001-0.25 mu M (including 0.25 mu M) (recorded as: ++). IC (integrated circuit) 50 0.25-0.5 mu M (including 0.5 mu M) (recorded as: ++); IC (integrated circuit) 50 0.5-1.0 mu M (including 1.0 mu M) (denoted as: +).
Table 1 inhibition of PARP-1, BRD4 by partial Compounds
The results in Table 1 show that the compounds of the invention have certain inhibition activity on PARP-1 and BRD4, wherein the compounds I-A-1, I-A-2, I-B-1, I-B-2 and I-D-2 have higher inhibition activity on PARP-1 and BRD 4.
Example 19
In vitro anti-tumor activity experiments and results of partial compounds of the invention are as follows:
(1) In vitro antitumor Activity test: cell culture conditions: MDA-MB-231 cells, THP-1 cells and HCT-116 cells were subcultured with L15 medium, RPMI-1640 medium and Mc coy's 5A medium containing 10% serum, respectively, and when the cells were in the logarithmic growth phase, the passages were: taking THP-1 as an example, the old medium was removed by centrifugation, the centrifuged cells were washed 2 times with 6mLPBS, PBS was removed, and the cells were resuspended in RPMI-1640 complete medium and cultured in dishes for 3 days with a single change of fluid.
MTT experiment: a. the cells in logarithmic growth phase were grown at 5X 10 3 Cells/wells were seeded in 96-well plates at 37℃in 5% CO 2 Culturing under the condition until all the materials are attached. b. The compound stock solution was diluted to the corresponding concentration with complete medium, 100 μl of the compound dilution was added to the first column of each compound, and after mixing well, the application was performed in a sesquidilution method, and incubation was continued for 72h. c. 10. Mu.L MTT was added to each well, after 4h incubation, the broth was removed, 150. Mu.L/well DMSO was added, and after shaking until the pellet was completely dissolved, it was read at 570nm using an ELISA reader. d.Graphpad prism 8.3.0 calculation IC 50 。
(2) Experimental results: in vitro antitumor activity assays were performed on some of the compounds of the present invention and the results are shown in Table 2.IC (integrated circuit) 50 0.01-0.5 mu M (including 0.5 mu M) (recorded as: ++). IC (integrated circuit) 50 0.5-1.0 mu M (including 1.0 mu M) (noted as: ++). IC (integrated circuit) 50 1.0-2.0 mu M (including 2.0 mu M) (recorded as: ++); IC (integrated circuit) 50 2.0-20.0 mu M (expressed as: +).
Table 2 inhibition Activity of some of the Compounds against tumor cells
The results in Table 2 show that the compound of the invention has certain inhibition activity on the growth activities of leukemia cells THP-1, colon cancer cells HCT116 and triple negative breast cancer MDA-MB-231, wherein the proliferation inhibition effects of the compounds I-A-1, I-A-2 and I-A-3 on three cells are higher.
Claims (9)
1. A dihydropterin structure-containing compound of the general formula (I):
（I）
wherein:
R 1 represents a C1-C6 alkyl group;
R 2 represents a C1-C6 alkyl group, a C3-C6 cycloalkyl group,、/>Wherein: x represents O, S or NH; y is Y 1 、Y 2 、Y 3 、Y 4 、Y 5 And Y 6 Each represents N or CH; r is R 4 Representative H, F, cl, br, CH 3 、CF 3 、OCH 3 、OCF 3 、OH、NH 2 、NHCOCH 3 Or CN, R 4 May be mono-or polysubstituted;
R 3 represents hydrogen, C1-C4 alkyl;
said A represents、/>、/>、/>Or->Wherein: r is R 6 Represents H or CH 3 ；R 8 Representative H, OCH 3 、OCH 2 CH 3 、OCH(CH 3 ) 2 Or->。
2. The dihydropterin structure-containing compound of the general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 1 Representative H, CH 3 Or CH (CH) 2 CH 3 。
3. The dihydropterin structure-containing compound of the general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 2 Representative of、/>、/>、/>、/>、Or->。
4. The dihydropterin structure-containing compound of the general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 3 Represents H or CH 3 。
5. The dihydropterin structure-containing compound of the general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 1 Represents CH 3 Or CH (CH) 2 CH 3 ，R 2 Representative of，R 3 Represents CH 3 A represents- >。
6. The dihydropterin structure-containing compound of general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein the pharmaceutically acceptable salt is an acid addition salt of the compound of general formula (I) of claim 1 with: hydrogen chloride, hydrogen bromide, sulfuric acid, carbonic acid, oxalic acid, citric acid, succinic acid, tartaric acid, phosphoric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or ferulic acid.
7. A pharmaceutical composition comprising a compound of formula (I) according to claims 1-5 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
8. Use of a compound containing a dihydropterin structure of general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5 for the preparation of a dual-target inhibitor drug of PARP-1 and BRD4 for the treatment of tumors.
9. A process for the preparation of a dihydropterin structure-containing compound of general formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, comprising the steps of:
the compounds (I) are classified into I-A, I-B, I-C, I-D, I-E and I-F, and the synthesis methods are described below, respectively:
when A is，R 2 Is- >，R 3 In the case of H, the compound (I-A) can be prepared by the following method:
wherein R is 1 And R is 8 Is defined in claim 1, R 2 Is cyclopentyl;
when A is，R 2 To remove->Other than radicals R 3 In the case of H, the compound (I-A) can be prepared by the following method:
wherein R is 1 And R is 8 Is defined in claim 1, R 2 Except for cyclopentyl, which is defined as in claim 1, dmb is 2, 4-dimethoxybenzyl;
when A is，R 3 When the compound is C1-C6 alkyl or C3-C6 cycloalkyl, the compound (I-B) can be prepared by the following method:
wherein R is 1 、R 2 、R 3 And R is 8 Is as defined in claim 1;
when A is，R 3 In the case of H, the compound (I-C) can be prepared by the following method:
wherein R is 1 、R 2 And R is 8 Is as defined in claim 1;
when A is，R 3 In the case of H, the compound (I-D) can be prepared by the following method:
wherein R is 1 、R 2 And R is 6 Is as defined in claim 1;
when A is，R 3 In the case of H, the compound (I-E) can be prepared by the following method:
wherein R is 1 、R 2 And R is 6 Is as defined in claim 1;
when A is，R 3 In the case of H, the compound (I-F) can be prepared by the following method:
wherein R is 1 And R is 2 Is as defined in claim 1.
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| CN202110927335.8A CN113637017B (en) | 2021-08-12 | 2021-08-12 | Compound containing dihydropterin structure, its preparation method and application |
| PCT/CN2022/103284 WO2023016134A1 (en) | 2021-08-12 | 2022-07-01 | Compound containing tetrahydropterin structure, and preparation method therefor and use thereof |
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| CN1551881A (en) * | 2001-09-04 | 2004-12-01 | ���ָ��Ӣ��ķ�������Ϲ�˾ | Dihydropteridinones, processes for preparing them and their use as pharmaceutical compositions |
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| CN113637017B (en) * | 2021-08-12 | 2024-03-26 | 中国药科大学 | Compound containing dihydropterin structure, its preparation method and application |
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