WO2023011573A1 - 芳香乙炔类衍生物及其制备方法和用途 - Google Patents
芳香乙炔类衍生物及其制备方法和用途 Download PDFInfo
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- WO2023011573A1 WO2023011573A1 PCT/CN2022/110172 CN2022110172W WO2023011573A1 WO 2023011573 A1 WO2023011573 A1 WO 2023011573A1 CN 2022110172 W CN2022110172 W CN 2022110172W WO 2023011573 A1 WO2023011573 A1 WO 2023011573A1
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- WIPO (PCT)
- Prior art keywords
- phenyl
- methyl
- ethynyl
- pyrimidin
- bis
- Prior art date
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- -1 Aromatic acetylene derivative Chemical class 0.000 title claims abstract description 413
- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- 150000003839 salts Chemical class 0.000 claims abstract description 37
- 239000003814 drug Substances 0.000 claims abstract description 17
- 125000001424 substituent group Chemical group 0.000 claims abstract description 16
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 14
- 150000001875 compounds Chemical class 0.000 claims description 73
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 65
- 125000000623 heterocyclic group Chemical group 0.000 claims description 64
- 125000003118 aryl group Chemical group 0.000 claims description 60
- 125000000217 alkyl group Chemical group 0.000 claims description 59
- 125000001072 heteroaryl group Chemical group 0.000 claims description 55
- 125000003545 alkoxy group Chemical group 0.000 claims description 39
- 229910052736 halogen Inorganic materials 0.000 claims description 36
- 150000002367 halogens Chemical class 0.000 claims description 35
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 28
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 25
- 241000894006 Bacteria Species 0.000 claims description 19
- 229910005965 SO 2 Inorganic materials 0.000 claims description 19
- 125000004429 atom Chemical group 0.000 claims description 14
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 11
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 11
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 11
- 229910052799 carbon Inorganic materials 0.000 claims description 10
- 229910052760 oxygen Inorganic materials 0.000 claims description 10
- 125000001188 haloalkyl group Chemical group 0.000 claims description 9
- 229910052757 nitrogen Inorganic materials 0.000 claims description 9
- 241000607768 Shigella Species 0.000 claims description 8
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 8
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 8
- 241000588724 Escherichia coli Species 0.000 claims description 7
- 241000589517 Pseudomonas aeruginosa Species 0.000 claims description 7
- 201000010099 disease Diseases 0.000 claims description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 7
- 230000001404 mediated effect Effects 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 7
- 239000000203 mixture Substances 0.000 claims description 7
- 208000035143 Bacterial infection Diseases 0.000 claims description 6
- 208000022362 bacterial infectious disease Diseases 0.000 claims description 6
- 150000007942 carboxylates Chemical group 0.000 claims description 5
- 239000003112 inhibitor Substances 0.000 claims description 5
- 229910052717 sulfur Inorganic materials 0.000 claims description 5
- 241000589291 Acinetobacter Species 0.000 claims description 4
- 241000588832 Bordetella pertussis Species 0.000 claims description 4
- 241000589562 Brucella Species 0.000 claims description 4
- 241000588747 Klebsiella pneumoniae Species 0.000 claims description 4
- 241000589242 Legionella pneumophila Species 0.000 claims description 4
- 241000606860 Pasteurella Species 0.000 claims description 4
- 241000588769 Proteus <enterobacteria> Species 0.000 claims description 4
- 241000293871 Salmonella enterica subsp. enterica serovar Typhi Species 0.000 claims description 4
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 4
- 229940115932 legionella pneumophila Drugs 0.000 claims description 4
- 241000607626 Vibrio cholerae Species 0.000 claims description 3
- 150000005840 aryl radicals Chemical class 0.000 claims description 3
- 238000005859 coupling reaction Methods 0.000 claims description 3
- 229940118696 vibrio cholerae Drugs 0.000 claims description 3
- 125000002373 5 membered heterocyclic group Chemical group 0.000 claims description 2
- 125000006163 5-membered heteroaryl group Chemical group 0.000 claims description 2
- 241000588650 Neisseria meningitidis Species 0.000 claims description 2
- 230000009471 action Effects 0.000 claims description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 2
- 239000003054 catalyst Substances 0.000 claims description 2
- 150000001924 cycloalkanes Chemical class 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 125000006239 protecting group Chemical group 0.000 claims description 2
- 150000003254 radicals Chemical class 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- 229940123346 LpxC inhibitor Drugs 0.000 abstract description 2
- 229940124597 therapeutic agent Drugs 0.000 abstract description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 222
- 238000006243 chemical reaction Methods 0.000 description 184
- 239000000243 solution Substances 0.000 description 183
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 170
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 117
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 105
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 94
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 93
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 77
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 73
- 239000003480 eluent Substances 0.000 description 73
- 239000012074 organic phase Substances 0.000 description 73
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 70
- 238000010898 silica gel chromatography Methods 0.000 description 58
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 48
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 46
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 46
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 40
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 36
- FAQYAMRNWDIXMY-UHFFFAOYSA-N trichloroborane Chemical compound ClB(Cl)Cl FAQYAMRNWDIXMY-UHFFFAOYSA-N 0.000 description 35
- 238000010791 quenching Methods 0.000 description 32
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 31
- 239000007791 liquid phase Substances 0.000 description 31
- 239000012071 phase Substances 0.000 description 29
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 28
- YAMHXTCMCPHKLN-UHFFFAOYSA-N imidazolidin-2-one Chemical compound O=C1NCCN1 YAMHXTCMCPHKLN-UHFFFAOYSA-N 0.000 description 25
- 239000012141 concentrate Substances 0.000 description 23
- 238000000746 purification Methods 0.000 description 22
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 21
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 21
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 21
- 238000003756 stirring Methods 0.000 description 21
- 238000000926 separation method Methods 0.000 description 19
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 18
- 239000005457 ice water Substances 0.000 description 18
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 17
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 16
- 238000004262 preparative liquid chromatography Methods 0.000 description 16
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 15
- 238000005481 NMR spectroscopy Methods 0.000 description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- 125000002619 bicyclic group Chemical group 0.000 description 15
- 229920006395 saturated elastomer Polymers 0.000 description 15
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 10
- 125000003367 polycyclic group Chemical group 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- 235000017557 sodium bicarbonate Nutrition 0.000 description 10
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 10
- DNCYBUMDUBHIJZ-UHFFFAOYSA-N 1h-pyrimidin-6-one Chemical compound O=C1C=CN=CN1 DNCYBUMDUBHIJZ-UHFFFAOYSA-N 0.000 description 9
- 239000008346 aqueous phase Substances 0.000 description 9
- 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 9
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- 238000012360 testing method Methods 0.000 description 9
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- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 7
- YQKWBFZGLGMZCT-UHFFFAOYSA-N (4-ethynylphenyl)-morpholin-4-ylmethanone Chemical compound C=1C=C(C#C)C=CC=1C(=O)N1CCOCC1 YQKWBFZGLGMZCT-UHFFFAOYSA-N 0.000 description 6
- OZKXSTLYLNSXRE-UHFFFAOYSA-N 4-[(4-ethynylphenyl)methyl]morpholine Chemical compound C1=CC(C#C)=CC=C1CN1CCOCC1 OZKXSTLYLNSXRE-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- 241000699670 Mus sp. Species 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 125000002950 monocyclic group Chemical group 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 description 6
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- LULBEMRHRASDFM-UHFFFAOYSA-N 4-(iodomethyl)-5,6-bis(phenylmethoxy)pyrimidine Chemical compound C(C1=CC=CC=C1)OC1=NC=NC(=C1OCC1=CC=CC=C1)CI LULBEMRHRASDFM-UHFFFAOYSA-N 0.000 description 5
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- NVYLBKHPSREQBQ-WEVVVXLNSA-N (ne)-n-[(4-iodophenyl)methylidene]hydroxylamine Chemical compound O\N=C\C1=CC=C(I)C=C1 NVYLBKHPSREQBQ-WEVVVXLNSA-N 0.000 description 4
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- AZLBARIKNQPUJP-UHFFFAOYSA-N 4-[(4-ethynylphenyl)methyl]-1,4-thiazinane 1,1-dioxide Chemical compound C(#C)C1=CC=C(C=C1)CN1CCS(CC1)(=O)=O AZLBARIKNQPUJP-UHFFFAOYSA-N 0.000 description 4
- SJXHLZCPDZPBPW-UHFFFAOYSA-N 4-ethynylbenzoic acid Chemical compound OC(=O)C1=CC=C(C#C)C=C1 SJXHLZCPDZPBPW-UHFFFAOYSA-N 0.000 description 4
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- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 4
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- VALZSZJVEFACEZ-UHFFFAOYSA-N azetidine-3-carboxamide Chemical compound NC(=O)C1CNC1 VALZSZJVEFACEZ-UHFFFAOYSA-N 0.000 description 4
- 230000001580 bacterial effect Effects 0.000 description 4
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical compound ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 125000005842 heteroatom Chemical group 0.000 description 4
- 208000015181 infectious disease Diseases 0.000 description 4
- 238000010253 intravenous injection Methods 0.000 description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 4
- GZQKNULLWNGMCW-PWQABINMSA-N lipid A (E. coli) Chemical compound O1[C@H](CO)[C@@H](OP(O)(O)=O)[C@H](OC(=O)C[C@@H](CCCCCCCCCCC)OC(=O)CCCCCCCCCCCCC)[C@@H](NC(=O)C[C@@H](CCCCCCCCCCC)OC(=O)CCCCCCCCCCC)[C@@H]1OC[C@@H]1[C@@H](O)[C@H](OC(=O)C[C@H](O)CCCCCCCCCCC)[C@@H](NC(=O)C[C@H](O)CCCCCCCCCCC)[C@@H](OP(O)(O)=O)O1 GZQKNULLWNGMCW-PWQABINMSA-N 0.000 description 4
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- NSZBSAHNAGOSAW-UHFFFAOYSA-N 2-[4-[(1,1-dioxo-1,4-thiazinan-4-yl)methyl]phenyl]ethynyl-trimethylsilane Chemical compound C[Si](C)(C)C#CC1=CC=C(CN2CCS(CC2)(=O)=O)C=C1 NSZBSAHNAGOSAW-UHFFFAOYSA-N 0.000 description 3
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 3
- HQQVXVKQOPZRBJ-UHFFFAOYSA-N 3,3a,4,5,6,6a-hexahydro-1h-furo[3,4-c]pyrrole Chemical compound C1OCC2CNCC21 HQQVXVKQOPZRBJ-UHFFFAOYSA-N 0.000 description 3
- IWSNHXBESGDQMF-UHFFFAOYSA-N 3-amino-3-(4-iodophenyl)propanoic acid Chemical compound OC(=O)CC(N)C1=CC=C(I)C=C1 IWSNHXBESGDQMF-UHFFFAOYSA-N 0.000 description 3
- NRDZZGZIDVLPNN-UHFFFAOYSA-N 4-(4-iodophenyl)pyrrolidin-2-one Chemical compound C1=CC(I)=CC=C1C1CC(=O)NC1 NRDZZGZIDVLPNN-UHFFFAOYSA-N 0.000 description 3
- BFIZGNKQOJSJAA-UHFFFAOYSA-N 4-[(5-ethynylpyridin-2-yl)methyl]morpholine Chemical compound N1=CC(C#C)=CC=C1CN1CCOCC1 BFIZGNKQOJSJAA-UHFFFAOYSA-N 0.000 description 3
- NIEBHDXUIJSHSL-UHFFFAOYSA-N 4-iodobenzaldehyde Chemical compound IC1=CC=C(C=O)C=C1 NIEBHDXUIJSHSL-UHFFFAOYSA-N 0.000 description 3
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- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
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- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 3
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- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
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- 239000011698 potassium fluoride Substances 0.000 description 3
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- 238000011160 research Methods 0.000 description 3
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- 125000000524 functional group Chemical group 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000003304 gavage Methods 0.000 description 1
- BEBCJVAWIBVWNZ-UHFFFAOYSA-N glycinamide Chemical compound NCC(N)=O BEBCJVAWIBVWNZ-UHFFFAOYSA-N 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 210000004347 intestinal mucosa Anatomy 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 238000000752 ionisation method Methods 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 210000002429 large intestine Anatomy 0.000 description 1
- 229920006008 lipopolysaccharide Polymers 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229940050176 methyl chloride Drugs 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 238000005142 microbroth dilution method Methods 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- LAIZPRYFQUWUBN-UHFFFAOYSA-L nickel chloride hexahydrate Chemical compound O.O.O.O.O.O.[Cl-].[Cl-].[Ni+2] LAIZPRYFQUWUBN-UHFFFAOYSA-L 0.000 description 1
- QMMRZOWCJAIUJA-UHFFFAOYSA-L nickel dichloride Chemical compound Cl[Ni]Cl QMMRZOWCJAIUJA-UHFFFAOYSA-L 0.000 description 1
- 239000012038 nucleophile Substances 0.000 description 1
- 229920001778 nylon Polymers 0.000 description 1
- 238000003305 oral gavage Methods 0.000 description 1
- 239000005416 organic matter Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 125000003566 oxetanyl group Chemical group 0.000 description 1
- MIPHRQMEIYLZFZ-UHFFFAOYSA-N oxolan-3-amine Chemical compound NC1CCOC1 MIPHRQMEIYLZFZ-UHFFFAOYSA-N 0.000 description 1
- 125000005476 oxopyrrolidinyl group Chemical group 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- ZOUWOGOTHLRRLS-UHFFFAOYSA-N palladium;phosphane Chemical compound P.[Pd] ZOUWOGOTHLRRLS-UHFFFAOYSA-N 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- GJVFBWCTGUSGDD-UHFFFAOYSA-L pentamethonium bromide Chemical compound [Br-].[Br-].C[N+](C)(C)CCCCC[N+](C)(C)C GJVFBWCTGUSGDD-UHFFFAOYSA-L 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- RPGWZZNNEUHDAQ-UHFFFAOYSA-N phenylphosphine Chemical compound PC1=CC=CC=C1 RPGWZZNNEUHDAQ-UHFFFAOYSA-N 0.000 description 1
- IWELDVXSEVIIGI-UHFFFAOYSA-N piperazin-2-one Chemical compound O=C1CNCCN1 IWELDVXSEVIIGI-UHFFFAOYSA-N 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- HDOWRFHMPULYOA-UHFFFAOYSA-N piperidin-4-ol Chemical compound OC1CCNCC1 HDOWRFHMPULYOA-UHFFFAOYSA-N 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- JHHZLHWJQPUNKB-UHFFFAOYSA-N pyrrolidin-3-ol Chemical compound OC1CCNC1 JHHZLHWJQPUNKB-UHFFFAOYSA-N 0.000 description 1
- LMBZZTJQNYGICT-UHFFFAOYSA-N pyrrolidine-3-carbonitrile;hydrochloride Chemical compound Cl.N#CC1CCNC1 LMBZZTJQNYGICT-UHFFFAOYSA-N 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000000611 regression analysis Methods 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000036303 septic shock Effects 0.000 description 1
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 1
- 239000012064 sodium phosphate buffer Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 125000005415 substituted alkoxy group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000004149 thio group Chemical group *S* 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- CWMFRHBXRUITQE-UHFFFAOYSA-N trimethylsilylacetylene Chemical compound C[Si](C)(C)C#C CWMFRHBXRUITQE-UHFFFAOYSA-N 0.000 description 1
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- 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
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Definitions
- the invention relates to an aromatic acetylene derivative, a preparation method thereof, a pharmaceutical composition containing the derivative and the use of the aromatic acetylene derivative or the pharmaceutical composition as a therapeutic agent, especially as an LPXC inhibitor.
- UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase is a Zn2 + -dependent metalloenzyme that is the first step in lipid A synthesis
- Lipid A is an important component of the outer membrane of Gram-negative bacteria, which can anchor lipopolysaccharide on the outer membrane of the cell and maintain the integrity of its own cells. At the same time, it acts as a hydrophobic external barrier, preventing external factors such as antibiotics from entering cells, and protecting bacteria from damage.
- lipid A is also the active component of bacterial endotoxin, which enters the blood through the intestinal mucosa, activates the immune response of the human body, and even causes severe septic shock, which is also the cause of pathogenic infection caused by Gram-negative bacteria. Therefore, by inhibiting LPXC, the biosynthesis of lipid A of Gram-negative bacteria can be inhibited, thereby effectively controlling the infection of Gram-negative bacteria.
- LPXC structure and characteristics of LPXC
- the structures of these three different sources of LPXC are highly similar, all contain two domains, and the active region is located at the junction of the two domains.
- Each domain contains an ⁇ -helix and a ⁇ -sheet, and the ⁇ -sheet sandwiches the ⁇ -helix, forming a sandwich structure of " ⁇ - ⁇ - ⁇ - ⁇ ".
- amino acid sequences of these two domains are slightly different, they have the same spatial structure.
- each structural domain has a corresponding insertion region, which is composed of ⁇ -sheets and forms different functional regions.
- LPXC has high homology in Gram-negative bacteria and has no common sequence with various mammalian enzyme systems. From a biological point of view, due to its unique advantages of broad-spectrum and low toxicity, it can inhibit The target of LPXC will be an ideal direction for the research of antibacterial drugs.
- the present invention provides a kind of aromatic acetylene derivative shown in a kind of general formula (I) or its stereoisomer, tautomer or its pharmaceutically acceptable salt:
- X and Y are each independently selected from C or N, and X and Y are not N at the same time;
- Ring A is selected from 4-6 membered heteroaryl or 4-6 membered heterocyclic group, preferably 5-membered heteroaryl or 5-membered heterocyclic group;
- L 1 is selected from a single bond or -CH 2 -;
- R 1 is the same or different, each independently selected from -G 1 -R 4 ;
- R 2 are the same or different, each independently selected from hydroxyl, cyano, halogen, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, cycloalkyl , heterocyclyl, aryl or heteroaryl are optionally further substituted by one or more substituents selected from halogen, hydroxyl, cyano or alkoxy;
- R 3 are the same or different, each independently selected from hydroxyl, cyano, halogen, alkyl, cycloalkyl, heterocyclyl, alkoxy or -C(O)R 5 , wherein the alkyl, cycloalkane
- one or more substituents selected from halogen, hydroxy, cyano, alkoxy, -C(O)OR 5 or -C(O)NR 6 R 7 replaced by
- R 4 is selected from cyano, halogen, alkyl, hydroxyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(O)R 5 , -C(O)OR 5 , - OC(O)R 5 , -NR 6 R 7 , -C(O)NR 6 R 7 , -SO 2 NR 6 R 7 or -NR 6 C(O)R 7 , wherein the alkoxy, alkane
- the radical, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more RA ;
- RA is selected from halogen, hydroxy, amino, hydroxyalkyl, alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(O)R 5 , -C(O)OR 5.
- alkyl , cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally further selected from one or more of halogen, hydroxy, amino, haloalkyl, hydroxyalkyl, alkoxy, alkyl, cycloalkyl, hetero Cyclic group, aryl group, heteroaryl group, -C(O)R 5 , -C(O)OR 5 , -OC(O)R 5 , -NR 6 R 7 , -C(O)NR 6 R 7 , Substituents of -SO 2 NR 6 R 7 or -NR 6 C(O)R 7 ;
- R 8 , R 9 and R 10 are each independently selected from a hydrogen atom, alkyl, amino, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl , aryl or heteroaryl are optionally further replaced by one or more selected from hydroxyl, halogen, nitro, amino, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl , carboxyl or carboxylate substituents;
- n 0, 1, 2 or 3;
- n 0, 1 or 2, preferably n is 0;
- p 0, 1 or 2.
- a compound described in general formula (I) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof which is a compound described in general formula (II) Or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof:
- ring A, R 1 -R 3 , L 1 , m, n and p are defined as described in general formula (I).
- a compound described in general formula (II) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof which is a compound described in general formula (III) Or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof:
- RA is selected from haloalkyl, hydroxyalkyl, alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxyl, wherein said alkyl, cycloalkyl, heterocyclyl, Aryl and heteroaryl are optionally further substituted by carboxyl;
- q 0, 1 or 2;
- Ring A, G 1 , R 2 , R 3 , L 1 , n and p are as defined in general formula (I).
- the compound described in general formula (I) is selected from:
- the present invention provides a pharmaceutical composition, which contains an effective dose of the compound described in general formula (I), (II) or (III) or its stereoisomers, tautomers body or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
- the present invention provides a compound described in general formula (I), (II) or (III) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or its pharmaceutical composition in the preparation of LPXC Use in inhibitors.
- the present invention also provides a compound described in general formula (I), (II) or (III) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or its pharmaceutical composition
- the disease mediated by LPXC is preferably a bacterial infection caused by Gram-negative bacteria
- the disease mediated by LPXC is selected from the group consisting of Escherichia coli, green Pseudomonas, Proteus, Shigella, Klebsiella pneumoniae, Brucella, Salmonella typhi, Acinetobacter, Yersinia, Legionella pneumophila, Bordetella pertussis, Shigella, Pasteurella, Cholera Bacterial infection caused by gram-negative bacteria such as Vibrio and meningitidis.
- the present invention further provides a compound described in general formula (I, (II) or (III) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or its pharmaceutical composition in the preparation of therapeutic Use in medicine for bacterial infections caused by Gram-negative bacteria.
- the present invention provides a compound described in general formula (I), (II) or (III) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or its pharmaceutical composition in the preparation of large intestine Bacillus, Pseudomonas aeruginosa, Proteus, Shigella, Klebsiella pneumoniae, Brucella, Salmonella typhi, Acinetobacter, Yersinia, Legionella pneumophila, Bordetella pertussis, Shigella, Pasteurella
- Bacillus Pseudomonas aeruginosa, Proteus, Shigella, Klebsiella pneumoniae, Brucella, Salmonella typhi, Acinetobacter, Yersinia, Legionella pneumophila, Bordetella pertussis, Shigella, Pasteurella
- the application in the medicine of the bacterial infection caused by gram-negative bacteria such as genus, vibrio cholerae, meningoc
- the present invention also provides a method for treating diseases mediated by LPXC, comprising administering the compound described in general formula (I), (II) or (III) or its stereoisomer, mutual variants or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof.
- the disease mediated by LPXC is a bacterial infection caused by Gram-negative bacteria; more preferably, the Gram-negative bacteria are selected from the group consisting of Escherichia coli, Pseudomonas aeruginosa, Proteus, Shigella, and Klebsiella pneumoniae , Brucella, Salmonella typhi, Acinetobacter, Yersinia, Legionella pneumophila, Bordetella pertussis, Shigella, Pasteurella, Vibrio cholerae, Neisseria meningitidis.
- the Gram-negative bacteria are selected from the group consisting of Escherichia coli, Pseudomonas aeruginosa, Proteus, Shigella, and Klebsiella pneumoniae , Brucella, Salmonella typhi, Acinetobacter, Yersinia, Legionella pneumophila, Bordetella pertussis, Shigella, Pasteurella, Vibrio
- Alkyl when used as a group or a part of a group refers to a C 1 -C 20 straight chain or branched aliphatic hydrocarbon group. It is preferably a C 1 -C 10 alkyl group, more preferably a C 1 -C 6 alkyl group or a C 1 -C 4 alkyl group.
- alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-di Methylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1 -Ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethyl Butyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl wait.
- Alkyl groups can be substituted or unsubstituted.
- Cycloalkyl means a non-aromatic cyclic alkyl group in which one or more of the atoms forming the ring is a carbon atom, including monocyclic, polycyclic, fused, bridged and spiro rings, preferably having 3 to 7 members Monocyclic or 7-10 membered bicyclic or tricyclic.
- Examples of “cycloalkyl” include, but are not limited to, cyclopropyl, cyclopentyl, cyclobutyl. Cycloalkyl groups can be substituted or unsubstituted. Preference is given to C 3 -C 7 cycloalkyl, C 3 -C 6 cycloalkyl or C 5 -C 7 cycloalkyl.
- “Spirocycloalkyl” refers to a polycyclic group with 5 to 18 members, two or more ring structures, and one carbon atom (called a spiro atom) shared between the single rings.
- the ring contains one or more Aromatic systems with double bonds, but none of the rings have fully conjugated ⁇ electrons. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan.
- the spiro cycloalkyl group is divided into single spiro, double spiro or polyspiro cycloalkyl, preferably single spiro and double spiro cycloalkyl, preferably 4-membered/5-membered, 4-membered Yuan/6 yuan, 5 yuan/5 yuan or 5 yuan/6 yuan.
- spirocycloalkyl include, but are not limited to: spiro[4.5]decyl, spiro[4.4]nonyl, spiro[3.5]nonyl, spiro[2.4]heptyl.
- “Fused cycloalkyl” refers to a 5- to 18-membered, all-carbon polycyclic group containing two or more ring structures sharing a pair of carbon atoms with each other, and one or more rings may contain one or more double bonds, Aromatic systems where none of the rings have fully conjugated pi-electrons, preferably 6 to 12, more preferably 7 to 10 membered. According to the number of rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic condensed cycloalkyl groups, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicycloalkyl groups.
- fused cycloalkyl include, but are not limited to: bicyclo[3.1.0]hexyl, bicyclo[3.2.0]hept-1-enyl, bicyclo[3.2.0]heptyl, Decalinyl or tetrahydrophenanthrenyl.
- “Bridged cycloalkyl” refers to a 5- to 18-membered, full-carbon polycyclic group that contains two or more ring structures and shares two carbon atoms that are not directly connected to each other.
- One or more rings may contain one or more Aromatic systems with multiple double bonds but none of the rings having fully conjugated pi electrons are preferably 6 to 12 membered, more preferably 7 to 10 membered. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan.
- bridged cycloalkyl include, but are not limited to: (1s,4s)-bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, (1s,5s)-bis Cycloo[3.3.1]nonyl, bicyclo[2.2.2]octyl, (1r,5r)-bicyclo[3.3.2]decyl.
- a heteroatom such as oxygen, nitrogen or S(O) r (where r is selected from 0, 1 or 2), etc.
- a 5 to 7 membered monocyclic ring or a 7 to 10 membered bicyclic or tricyclic ring which may contain 1, 2 or 3 members selected from nitrogen, oxygen and/or S(O) r (wherein r is selected from 0, 1 or 2 ) atoms.
- heterocyclyl examples include, but are not limited to, morpholinyl, oxetanyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydropyranyl, 1,1-dioxo-thiomorpholinyl , piperidinyl, 2-oxo-piperidinyl, pyrrolidinyl, 2-oxo-pyrrolidinyl, piperazin-2-one, 8-oxa-3-aza-bicyclo[3.2.1] Octyl, piperazinyl, hexahydropyrimidine,
- a heterocyclyl group can be substituted or unsubstituted.
- “Spiroheterocyclic group” refers to a polycyclic group with 5 to 18 members, two or more ring structures, and one atom shared between the single rings.
- it is 6 to 14 yuan, more preferably 7 to 10 yuan.
- the spirocycloalkyl group can be divided into single spiroheterocyclyl, double spiroheterocyclyl or polyspiroheterocyclyl, preferably single spiroheterocyclyl and double spiroheterocyclyl. More preferably, it is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospiro heterocyclic group.
- spiroheterocyclyl include, but are not limited to: 1,7-dioxaspiro[4.5]decyl, 2-oxa-7-azaspiro[4.4]nonyl, 7-oxaspiro[4.4]nonyl, Heteraspiro[3.5]nonyl, 5-oxaspiro[2.4]heptyl.
- bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic groups.
- fused heterocyclyl include, but are not limited to: octahydropyrrolo[3,4-c]pyrrolyl, octahydro-1H-isoindolyl, 3-azabicyclo[3.1. 0]hexyl, octahydrobenzo[b][1,4]dioxine,
- it is 6 to 14 yuan, more preferably 7 to 10 yuan.
- bridged heterocyclyl include, but are not limited to: 2-azabicyclo[2.2.1]heptyl, 2-azabicyclo[2.2.2]octyl, 2-azabicyclo[2.2.2]octyl, Cyclo[3.3.2]decyl.
- Aryl means a carbocyclic aromatic system containing one or two rings, wherein the rings may be joined together in a fused fashion.
- aryl includes monocyclic or bicyclic aryl groups, such as phenyl, naphthyl, tetrahydronaphthyl aromatic groups. Preferred aryl groups are C 6 -C 10 aryl groups, more preferred aryl groups are phenyl and naphthyl, most preferably naphthyl.
- Aryl groups can be substituted or unsubstituted.
- Heteroaryl refers to an aromatic 5 to 6 membered monocyclic ring or 8 to 10 membered bicyclic ring, which may contain 1 to 4 atoms selected from nitrogen, oxygen and/or sulfur.
- Preferred heteroaryl groups are C 6 -C 10 heteroaryl groups containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur.
- heteroaryl examples include, but are not limited to, furyl, pyridyl, 2-oxo-1,2-dihydropyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl , oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, benzo Dioxolyl, benzothienyl, benzimidazolyl, indolyl, isoindolyl, 1,3-dioxo-isoindolyl, quinolinyl, indazolyl, benzo Isothiazolyl, benzoxazolyl, benzisoxazolyl, isothiazolyl, 1H-1,2,
- Alkoxy refers to a group of (alkyl-O-). Wherein, alkyl refers to relevant definitions herein. C 1 -C 6 or C 1 -C 4 alkoxy is preferred. Examples include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, and the like.
- Niro refers to a -NO2 group.
- Haldroxy means an -OH group.
- Halogen refers to fluorine, chlorine, bromine and iodine.
- Amino refers to -NH2 .
- Cyano refers to -CN.
- Benzyl means -CH2 -phenyl.
- Carboxy refers to -C(O)OH.
- Carboxylate group refers to -C(O)O-alkyl or -C(O)O-cycloalkyl, wherein the definitions of alkyl and cycloalkyl are as above.
- Hydroalkyl means a hydroxy-substituted alkyl group, wherein alkyl is as defined above.
- Aminoalkyl means an amino-substituted alkyl group, wherein alkyl is as defined above.
- Haloalkyl means a halogen substituted alkyl wherein alkyl is as defined above.
- Haloalkoxy means a halogen substituted alkoxy group, wherein alkoxy group is as defined above.
- DMSO dimethylsulfoxide
- THP refers to 2-tetrahydropyranyl
- TFA trifluoroacetic acid
- Ts refers to p-toluenesulfonyl.
- leaving group an atom or functional group that is separated from a larger molecule in a chemical reaction, is a term used in nucleophilic substitution reactions and elimination reactions.
- the reactant attacked by the nucleophile is called the substrate, and the atom or atomic group that breaks off with a pair of electrons from the substrate molecule is called the leaving group.
- Groups that are easy to accept electrons and have strong ability to bear negative charges are good leaving groups. The smaller the pKa of the conjugate acid of the leaving group, the easier it is for the leaving group to detach from other molecules.
- Common leaving groups include, but are not limited to, halogens, methanesulfonyl, -OTs, or -OH.
- Substituted means that one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms are independently substituted by the corresponding number of substituents. It goes without saying that substituents are only in their possible chemical positions and that a person skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when bonded to a carbon atom with an unsaturated (eg, ethylenic) bond.
- R 8 , R 9 and R 10 are each independently selected from a hydrogen atom, alkyl, amino, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl , aryl or heteroaryl are optionally further replaced by one or more selected from hydroxyl, halogen, nitro, amino, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl , Carboxyl or carboxylate substituents are substituted.
- “Pharmaceutically acceptable salt” refers to certain salts of the above compounds that can maintain their original biological activity and are suitable for medical use.
- the pharmaceutically acceptable salt of the compound represented by the general formula (I) may be a metal salt or an amine salt with a suitable acid.
- “Pharmaceutical composition” means a mixture containing one or more compounds described herein, or a physiologically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as a physiologically acceptable carrier.
- the purpose of the pharmaceutical composition is to promote the administration to the organism, facilitate the absorption of the active ingredient and thus exert biological activity.
- the present invention provides a preparation method of a compound of general formula (I) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, said method comprising:
- the compound of general formula (I-a) and the compound of (I-b) undergo a coupling reaction under the action of a catalyst, and optionally further remove the protecting group to obtain the compound of general formula (I);
- X is selected from halogen
- Ring A, X, Y, R 1 to R 3 , L 1 , n, m and p are as defined in general formula (I).
- the mass spectrum is measured by LC/MS instrument, and the ionization method can be ESI or APCI.
- the thin-layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate.
- the specification of the silica gel plate used in thin-layer chromatography (TLC) is 0.15mm-0.2mm, and the specification of thin-layer chromatography separation and purification products is 0.4mm. ⁇ 0.5mm.
- CD 3 OD deuterated methanol.
- the argon atmosphere means that the reaction bottle is connected to an argon balloon with a volume of about 1 L.
- the solution in the reaction refers to an aqueous solution.
- the compound was purified by silica gel column chromatography eluent system and thin layer chromatography, wherein the eluent system was selected from: A: petroleum ether and ethyl acetate system; B: dichloromethane and methanol system; C: two Chloromethane and ethyl acetate system; the volume ratio of the solvent varies according to the polarity of the compound, and can also be adjusted by adding a small amount of acidic or alkaline reagents, such as acetic acid or triethylamine.
- A petroleum ether and ethyl acetate system
- B dichloromethane and methanol system
- C two Chloromethane and ethyl acetate system
- the volume ratio of the solvent varies according to the polarity of the compound, and can also be adjusted by adding a small amount of acidic or alkaline reagents, such as acetic acid or triethylamine.
- 4,5-bis(benzyloxy)-6-vinylpyrimidine 1d (1.1 g, 3.46 mmol, self-produced according to patent WO2020061375) and triethylamine (699.25 mg, 6.91 mmol, 957.87 ⁇ L) were dissolved in N, N-Dimethylformamide (14.04 mL), slowly dropwise added (Z)-N-hydroxy-4-iodobenzimidoyl chloride 1c (972.54 mg, 3.46 mmol) in N,N-dimethylformamide solution (10 mL), react at room temperature for 6 hours.
- the di Bis(trichloromethyl)carbonate (2.58g, 8.70mmol) was added to the methyl chloride (80mL) solution, and reacted at low temperature for 20 minutes, then rose to room temperature and reacted overnight.
- Di-tert-butyl dicarbonate (5.51g, 25.25mmol) was added to 50mL of dioxane in 3-amino-3-(4-iodophenyl)propionic acid 4b (4.9g, 16.83mmol), and then 50mL of Saturated sodium bicarbonate solution, stirred overnight at room temperature.
- the reaction liquid Add 20mL of water, extract with ethyl acetate (20mL ⁇ 3), wash with saturated sodium chloride solution (20mL), dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure, and the obtained residue is purified by silica gel column chromatography ( Eluent: System A) to obtain 3-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-5-(4-((4-(morpholine-4-carbonyl) Phenyl)ethynyl)phenyl)-2-oxoimidazoline-1-carboxylic acid tert-butyl ester 4f (60 mg), yield: 49.66%.
- Potassium phosphate (6.50g, 30.60mmol), bis(triphenylphosphine)palladium dichloride (859.18mg, 1.22mmol), 4,5-dibenzyloxy-6-chloropyrimidine 5a (2.0g, 6.12mmol , self-made according to patent WO2020102572) and 2-allyl-4,4,5,5-tetramethyl-1,3,2-dioxaborane (4.11g, 24.48mmol) were sequentially added to tetrahydrofuran (20mL ) and water (4 mL), the argon gas was replaced three times, heated to 90° C., and reacted for 20 hours.
- 4-ethynylbenzoic acid 17a (1g, 6.84mmol) and morpholine 17b (3.58g, 41.06mmol) were added to 5mL of dichloromethane, and 1-(3-dimethylaminopropyl)-3-ethyl Carbodiimide hydrochloride (2.10g, 10.95mmol), react overnight at room temperature.
- reaction solution was extracted with dichloromethane (30ml ⁇ 2), the water layer was separated, and the combined organic phase was washed with saturated sodium chloride solution (30mL ⁇ 2) successively, dried over anhydrous sodium sulfate, filtered, and reduced pressure After concentration, the obtained residue was purified by silica gel column chromatography (eluent: system A) to obtain (4-ethynylphenyl)(morpholinyl)methanone 17c (600 mg, 40.74% yield).
- reaction solution was extracted with ethyl acetate (30mlx2), and the water layer was separated. The combined organic phase was washed with saturated sodium chloride solution (30mLx2) successively, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
- reaction solution was extracted with ethyl acetate (30ml ⁇ 2), the water layer was separated, and the combined organic phases were successively washed with saturated sodium chloride solution (30mL ⁇ 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain The residue was purified by silica gel column chromatography (eluent: System A and System B) to give 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-(4 -Iodophenyl)-4-methylpyrrolidin-2-one 20 g (130 mg, 214.71 ⁇ mol, 47.19% yield).
- reaction solution was extracted with ethyl acetate (30ml ⁇ 2), the water layer was separated, the combined organic phase was washed with saturated sodium chloride solution (30mL ⁇ 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain The residue was purified by silica gel column chromatography (eluent: system B) to obtain 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-methyl-4- (4-((4-(morpholinemethyl)phenyl)ethynyl)phenyl)pyrrolidin-2-one 20j (50 mg, 73.66 ⁇ mol, 55.75% yield).
- reaction solution was concentrated under reduced pressure, 30 mL of saturated sodium bicarbonate solution was added to the residue, extracted with ethyl acetate (30 mL ⁇ 3), the combined organic phases were successively washed with saturated sodium chloride solution (20 mL), and dried over anhydrous sodium sulfate , filtered, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: eluent: system B) to obtain 1-((5,6-bis(benzyloxy)pyrimidine-4- yl)methyl)-4-(4-iodophenyl)imidazolin-2-one 21d (1 g, 1.69 mmol, 77.93% yield).
- reaction solution was quenched by adding 20 mL of ice water, extracted with ethyl acetate (20 mL ⁇ 3), the combined organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain The residue was purified by silica gel column chromatography (eluent: system A) to give 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-(4-iodo Phenyl)-3-isopropylimidazolin-2-one 21e (450 mg, 709.21 ⁇ mol, 42.02% yield).
- reaction solution was extracted with ethyl acetate (30mL ⁇ 2), the water layer was separated, the combined organic phase was washed with saturated sodium chloride solution (30mL ⁇ 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain The residue was purified by silica gel column chromatography (eluent: system B) to give 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-(4-(( 4-(((1,1-dioxotetrahydrothiophen-3-yl)amino)methyl)phenyl)ethynyl)phenyl)-3-isopropylimidazolin-2-one 21k (50mg, 66.14 ⁇ mol, 93.26% yield).
- 4-(2-Trimethylsilylethynyl)benzaldehyde 22a (400 mg, 1.98 mmol) was dissolved in 1,2-dichloroethane (15 mL), and thiomorpholine 1,1-dioxide was added sequentially 22b (534.53mg, 3.95mmol) and acetic acid (1.25mL) were reacted at room temperature for 30 minutes, then sodium triacetoxyborohydride (1.26g, 5.93mmol) was added at 0°C, and reacted at room temperature for two hours.
- reaction solution was extracted with ethyl acetate (30ml ⁇ 2), the water layer was separated, the combined organic phase was washed with saturated sodium chloride solution (30mL ⁇ 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain The residue was purified by silica gel column chromatography (eluent: eluent: system B) to obtain 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-( 4-((4-((1,1-thiomorpholine dioxide)methyl)phenyl)ethynyl)phenyl)-3-isopropylimidazolin-2-one 22e (26mg, 34.40 ⁇ mol, 48.50% yield).
- 4-(2-Trimethylsilylethynyl)benzaldehyde 22a (400mg, 1.98mmol) was dissolved in 1,2-dichloroethane (20mL), and hexahydro-1H-furo[3,4 -c] Pyrrole 23a (335.57 mg, 2.97 mmol) and acetic acid (1.25 mL) were reacted at room temperature for 2 hours, then sodium triacetoxyborohydride (1.26 g, 5.93 mmol) was added and reacted at room temperature for 2 hours.
- reaction solution was extracted with ethyl acetate (30ml ⁇ 2), the water layer was separated, the combined organic phase was washed with saturated sodium chloride solution (30mL ⁇ 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain The residue was purified by silica gel column chromatography (eluent: system A) to obtain 5-(4-ethynylbenzyl)hexahydro-1H-furo[3,4-c]pyrrole 23c (311mg, 1.37mmol ,89.08% yield).
- reaction solution was extracted with ethyl acetate (30ml ⁇ 2), the water layer was separated, the combined organic phase was washed with saturated sodium chloride solution (30mL ⁇ 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain The residue was purified by silica gel column chromatography (eluent: system B) to obtain 4-((4-(1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)- 3-Isopropyl-2-oxoimidazolin-4-yl)phenyl)ethynyl)benzaldehyde 24b (230 mg, 361.22 ⁇ mol, 76.40% yield).
- reaction solution was extracted with ethyl acetate (30ml ⁇ 2), the water layer was separated, the combined organic phase was washed with saturated sodium chloride solution (30mL ⁇ 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain The residue was purified by silica gel column chromatography (eluent: system B) to obtain 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-isopropyl-4 -(4-((6-(morpholinomethyl)pyridin-3-yl)ethynyl)phenyl)imidazolin-2-one 25d (55 mg, 77.59 ⁇ mol, 98.46% yield).
- Example 1-36 According to the synthesis method of Example 1-36, the following compounds were prepared, including:
- reaction was heated to 70°C and stirred for 5 hours. After the reaction was complete, the reaction solution was extracted with ethyl acetate (30ml ⁇ 2), the water layer was separated, and the combined organic phase was washed with saturated sodium chloride solution (30mL ⁇ 2) successively.
- reaction solution was extracted with ethyl acetate (30ml ⁇ 2), the water layer was separated, the combined organic phase was washed with saturated sodium chloride solution (30mL ⁇ 2), dried over anhydrous sodium sulfate, filtered, and reduced pressure Concentrate, and the obtained residue is purified by silica gel column chromatography (eluent: system A) to obtain 2-(4-ethynylphenoxy)ethan-1-ol 89d (120 mg, 739.90 ⁇ mol, 73.48% yield) .
- reaction was heated to 70°C and stirred for 5 hours. After the reaction was complete, the reaction solution was extracted with ethyl acetate (30ml ⁇ 2), the water layer was separated, and the combined organic phase was washed with saturated sodium chloride solution (30mL ⁇ 2) successively.
- 4-ethynyl benzoic acid 90a 500mg, 3.42mmol
- 3-methoxy azacycline hydrochloride 90b 845.62mg, 6.84mmol
- 1-(3 -Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride 1.05g, 5.47mmol
- 4-dimethylaminopyridine 41.80mg, 342.13 ⁇ mol
- reaction solution was extracted with dichloromethane (30ml ⁇ 2), the water layer was separated, the combined organic phase was washed with saturated sodium chloride solution (30mL ⁇ 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue Further separation and purification by silica gel column chromatography (eluent: system C) gave (4-ethynylphenyl)(3-methoxyazetidin-1-yl)methanone 90c (500mg, 2.32mmol, 67.90% yield).
- reaction solution was extracted with ethyl acetate (30mL ⁇ 2), the water layer was separated, the combined organic phase was washed with saturated sodium chloride solution (30mL ⁇ 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue Further separation and purification by silica gel column chromatography (eluent: system B) to obtain 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-isopropyl-4 -(4-((4-(3-methoxyazetidine-1-carbonyl)phenyl)ethynyl)phenyl)imidazolin-2-one 90d (35mg, 48.49 ⁇ mol, 51.28% yield) .
- 4-ethynylbenzoic acid 90a 150mg, 1.03mmol
- thiomorpholine 1-oxide hydrochloride 36a 255.61mg, 1.64mmol
- 1-(3-di Methylaminopropyl)-3-ethylcarbodiimide hydrochloride 314.82mg, 1.64mmol
- 4-dimethylaminopyridine (12.54mg, 102.64 ⁇ mol
- reaction solution was extracted with dichloromethane (30ml ⁇ 2), the water layer was separated, the combined organic phase was washed with saturated sodium chloride solution (30mL ⁇ 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue Further separation and purification by silica gel column chromatography (eluent: system A) gave (4-ethynylphenyl)(1-oxythiomorpholine)methanone 91a (100 mg, 404.35 ⁇ mol, 39.39% yield).
- reaction was warmed to 70°C and stirred for 5 hours.
- the reaction solution was extracted with ethyl acetate (30ml ⁇ 2), the water layer was separated, the combined organic phase was washed with saturated sodium chloride solution (30mL ⁇ 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain The residue was further separated and purified by silica gel column chromatography (eluent: system B) to obtain 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-isopropyl- 4-(4-((4-(1-Oxothiomorpholine-4-carbonyl)phenyl)ethynyl)phenyl)imidazolin-2-one 91b (30 mg, 39.79 ⁇ mol, 50.50% yield).
- reaction solution was extracted with dichloromethane (30ml ⁇ 2), the water layer was separated, the combined organic phase was washed with saturated sodium chloride solution (30mL ⁇ 2), dried over anhydrous sodium sulfate, filtered, and reduced pressure Concentration, the obtained residue was further separated and purified by silica gel column chromatography (eluent: system C) to obtain N-(4-ethynylbenzyl)-2-hydroxyacetamide 92c (300mg, 1.59mmol, 44.30% yield ).
- N-(4-((4-(1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-isopropyl-2-oxoimidazoline-4- yl)phenyl)ethynyl)benzyl)-2-hydroxyacetamide 92d (20mg, 28.74 ⁇ mol) was added to 1.5mL dichloromethane, boron trichloride (0.8mL) was added, and the reaction was carried out at room temperature for 1 hour.
- reaction solution was extracted with dichloromethane (30ml ⁇ 2), the water layer was separated, and the combined organic phase was washed successively with saturated sodium chloride solution (30mL ⁇ 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain The residue was further separated and purified by silica gel column chromatography (eluent: system A) to obtain 4-ethynyl-N-(2-methoxyethyl)benzamide 93b (360mg, 1.77mmol, 51.77% yield ).
- Example 1-93 According to the synthesis method of Example 1-93, the following compounds were prepared, including:
- Test example 1 compound of the present invention is to LpxC enzymatic activity inhibitory assay
- the following method is used to determine the inhibitory degree of the compounds of the present invention to the enzymatic activity of recombinant Pseudomonas aeruginosa LpxC under in vitro conditions.
- test compound was first dissolved in DMSO to prepare a 10 mM stock solution.
- the reaction was carried out in a 96-well microwell plate.
- 20 ⁇ L of recombinant Pseudomonas aeruginosa LpxC purchased from Signalway Antibody, catalog number AP74647-2 was added to the wells with a final concentration of 5 nM; 5 ⁇ L of the test compound was added, and the compound was diluted 4 times.
- the concentration range is 0.61-10000nM; add 5 ⁇ L LpxC substrate UDP-3-O-(R-3-hydroxydecanoyl)-GlcNAc (purchased from Biosynth Carbosynth, product number is mu75071), the final concentration of the substrate is 10 ⁇ M , and incubated at 25°C for 120 minutes.
- Example 15 Compound number IC 50 /nM Example 7 42.45 Example 9 13.12 Example 10 22.99 Example 11 8.00 Example 13 15.72 Example 15 33.17 Example 16 24.69 Example 17 23.17 Example 22 36.1 Example 23 32.08 Example 24 20.58
- the compound of the present invention has an inhibitory IC50 of less than 100nM on the enzyme activity of recombinant Pseudomonas aeruginosa LpxC, and has a significant inhibitory effect on the enzyme activity of LpxC.
- Test example 2 the antibacterial activity evaluation of the compound of the present invention
- test compound was dissolved in DMSO to prepare a 12.8 mg/mL stock solution, and then DMSO was used to prepare 11 double-diluted 100 ⁇ high-concentration working solutions (the final concentration of the system was 64 ⁇ g/mL-0.06 ⁇ g/mL).
- the minimum drug concentration for cell growth is the minimum inhibitory concentration (MIC) of the compound, as shown in Table 2 below.
- the compound of the present invention has good inhibitory effect on K. pneumoniae (K.Pneumoniae ATCC13883) and Escherichia coli (E.coli ATCC 25922).
- ND means not determined.
- the LC/MS/MS method was used to determine the compound 13 of the present invention administered to the mice intravenously or intragastrically, and to measure the drug concentration in plasma at different times, and to study the pharmacological effects of the compound of the present invention in mice. Kinetic features.
- ICR mice male, 29.0-33.8 g, were purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd.
- Intravenous injection group Weigh an appropriate amount of medicine, add 10% HP- ⁇ -CD aqueous solution, vortex, and sonicate for 60 minutes. Add 10 ⁇ L of 1M HCl, vortex, mix well, pH 3.5-4.0, filter with (Rephile, Nylon, 0.45 ⁇ m) to obtain a colorless solution, and prepare the final concentration of 0.2 mg/mL;
- Oral gavage group Weigh an appropriate amount of medicine, add 10% Solutol HS15-20% HP- ⁇ -CD, vortex, and sonicate for 30 minutes to obtain a colorless solution, and prepare a final concentration of 0.5 mg/kg.
- ICR mice each compound to be tested was divided into intravenous injection group (nine in each group) and gavage group (nine in each group), orbital intravenous injection administration (administration dose 1mg/kg, give Drug volume 5mL/kg) and intragastric administration (administration dose 5mg/kg, administration volume 10mL/kg), take food 4 hours after administration.
Abstract
本发明涉及一种芳香乙炔类衍生物、其制备方法及含有该衍生物的药物组合物在医药上的应用。具体而言,本发明涉及一种通式(I)所示的芳香乙炔类衍生物、其制备方法及其可药用的盐,以及它们作为治疗剂,特别是LPXC抑制剂的用途,其中通式(I)中的各取代基的定义与说明书中的定义相同。
Description
本申请要求以下中国专利申请的优先权:1)于2021年8月5日提交到中国国家知识产权局、申请号为202110893756.3、发明名称为“芳香乙炔类衍生物及其制备方法和用途”的中国专利申请;2)于2022年5月30日提交到中国国家知识产权局、申请号为202210596714.8、发明名称为“芳香乙炔类衍生物及其制备方法和用途”的中国专利申请;3)于2022年6月29日提交到中国国家知识产权局、申请号为202210756227.3、发明名称为“芳香乙炔类衍生物及其制备方法和用途”的中国专利申请。上述中国专利申请的全部内容均通过引用结合在本申请中。
本发明涉及一种芳香乙炔类衍生物、其制备方法、含有该衍生物的药物组合物以及所述芳香乙炔类衍生物或药物组合物作为治疗剂特别是作为LPXC抑制剂的用途。
二十世纪三十年代至六十年代是抗生素发展的黄金时期,此后抗生素类药物在全世界范围内广泛使用,但是细菌耐药性问题也相继出现,耐药菌已经成为威胁人类健康的重大问题。而多重耐药革兰氏阴性菌是发生感染的主要病原体之一,目前临床上用来治疗多重耐药革兰氏阴性菌感染的药物严重匮乏,仍然采用毒性较大的药物。近几年,细菌耐药性虽然一直是国际医药界的热门话题,但是研发速度进展缓慢,国内外进入临床研究的化合物寥寥无几,因此,找到一种新型的革兰氏阴性菌抗菌药物是亟需解决的重要问题。
UDP-3-O-(R-3-羟基肉豆蔻酰基)-N-乙酰葡糖胺脱乙酰酶(LPXC)是一种依赖Zn
2+的金属酶,它是合成类脂A的第一步限速酶,而类脂A则是革兰氏阴性菌细胞外膜的重要组成成分,可以将脂多糖锚定在细胞外膜上,保持自身细胞的完整性。同时作为疏水性的外部屏障,阻碍抗生素等外部因子进入细胞,保护细菌免受侵害。另外,类脂A也是细菌内毒素的活性成分,通过肠粘膜入血,激活人体的免疫反应,甚至造成严重的败血性休克,这也是革兰氏阴性菌引起病原性感染的原因。因此,通过对LPXC的抑制,可以抑制革兰氏阴性菌类脂A的生物合成,从而有效控制革兰氏阴性菌的感染。
目前对LPXC的结构和特性的进一步认知大多通过对大肠杆菌、铜绿假单胞菌和超嗜热菌的LPXC晶体分离纯化和解析鉴定得到。这三种不同来源的LPXC结构高度相似,都含有两个结构域,活性区位于2个结构域的交界处。每个结构域包含α螺旋和β折叠,β折叠包夹着α螺旋,形成“β-α-α-β”的夹心结构。尽管这两个结构域的氨基酸序列有些许差别,但具有相同的空间结构。另外,每个结构域都有与之相应的***区,由β折叠构成,形成不同的功能区域。研究表明,LPXC在革兰氏阴性菌具有较高的同源性,与哺乳动物各种酶系没有共同的序列,从生物学角度来看,由于其广谱性和低毒性的独特优势,抑制LPXC这一靶点将会是研究抑菌药物的一个理想方向。
现在关于LPXC的抑制剂还没有药物上市。虽然LPXC抑制剂的研究和应用已取得一定的进展,但是仍远未能满足人们的治疗需要,其提高的空间仍然巨大,仍有必要继续研究和开发新的LPXC抑制剂。
发明内容
针对上述的技术问题,本发明提供一种通式(I)所示的一种芳香乙炔类衍生物或其立体异构体、互变异构体或其可药用的盐:
其中:
X和Y各自独立地选自C或N,且X、Y不同时为N;
环A选自4元~6元杂芳基或4元~6元杂环基,优选为5元杂芳基或5元杂环基;
L
1选自单键或-CH
2-;
R
1相同或不同,各自独立地选自-G
1-R
4;
G
1选自单键、-CH
2-或-C(=O)-;
R
2相同或不同,各自独立地选自羟基、氰基、卤素、烷基、烷氧基、环烷基、杂环基、芳基或杂芳基,其中所述的烷基、环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自卤素、羟基、氰基或烷氧基的取代基所取代;
R
3相同或不同,各自独立地选自羟基、氰基、卤素、烷基、环烷基、杂环基、烷氧基或-C(O)R
5,其中所述的烷基、环烷基、杂环基或烷氧基任选进一步被一个或多个选自卤素、羟基、氰基、烷氧基、-C(O)OR
5或-C(O)NR
6R
7的取代基所取代;
R
4选自氰基、卤素、烷基、羟基、烷氧基、环烷基、杂环基、芳基、杂芳基、-C(O)R
5、-C(O)OR
5、-OC(O)R
5、-NR
6R
7、-C(O)NR
6R
7、-SO
2NR
6R
7或-NR
6C(O)R
7,其中所述的烷氧基、烷基、环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个R
A所取代;
R
A选自卤素、羟基、氨基、羟烷基、烷氧基、烷基、环烷基、杂环基、芳基、杂芳基、-C(O)R
5、-C(O)OR
5、-OC(O)R
5、-NR
6R
7、-C(O)NR
6R
7、-SO
2NR
6R
7或-NR
6C(O)R
7,其中所述的烷基、环烷基、杂环基、芳基、杂芳基任选进一步被一个或多个选自卤素、羟基、氨基、卤代烷基、羟烷基、烷氧基、烷基、环烷基、杂环基、芳基、杂芳基、-C(O)R
5、-C(O)OR
5、-OC(O)R
5、-NR
6R
7、-C(O)NR
6R
7、-SO
2NR
6R
7或-NR
6C(O)R
7的取代基取代;
R
5选自氢原子、烷基、环烷基、杂环基、芳基或杂芳基,其中所述的烷基、环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自羟基、卤素、硝基、氰基、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基、杂环基、芳基、杂芳基、=O、-C(O)R
8、-C(O)OR
8、 -OC(O)R
8、-NR
9R
10、-C(O)NR
9R
10、-SO
2NR
9R
10或-NR
9C(O)R
10的取代基所取代;
R
6和R
7各自独立地选自氢原子、羟基、卤素、烷基、烷氧基、环烷基、杂环基、芳基或杂芳基,其中所述的烷基、烷氧基、环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自羟基、卤素、硝基、氰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、=O、-C(O)R
8、-C(O)OR
8、-OC(O)R
8、-NR
9R
10、-C(O)NR
9R
10、-SO
2NR
9R
10或-NR
9C(O)R
10的取代基所取代;
或者,R
6和R
7与其所连接的原子一起形成一个4~8元杂环基,其中所述4~8元杂环基内含有一个或多个N、O、S或SO
2,并且所述的4~8元杂环基任选进一步被一个或多个选自羟基、卤素、硝基、氰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、=O、-C(O)R
8、-C(O)OR
8、-OC(O)R
8、-NR
9R
10、-C(O)NR
9R
10、-SO
2NR
9R
10或-NR
9C(O)R
10的取代基所取代;
R
8、R
9和R
10各自独立地选自氢原子、烷基、氨基、环烷基、杂环基、芳基或杂芳基,其中所述的烷基、环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自羟基、卤素、硝基、氨基、氰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、羧基或羧酸酯基的取代基所取代;
m为0、1、2或3;
n为0、1或2,n优选为0;且
p为0、1或2。
根据本发明的优选方案,提供一种通式(I)所述的化合物或其立体异构体、互变异构体或其可药用的盐,其为通式(II)所述的化合物或其立体异构体、互变异构体或其可药用的盐:
其中:环A、R
1~R
3、L
1、m、n和p的定义如通式(I)中所述。
根据本发明的优选方案,提供一种通式(II)所述的化合物或其立体异构体、互变异构体或其可药用的盐,其为通式(III)所述的化合物或其立体异构体、互变异构体或其可药用的盐:
其中:
R
A选自卤代烷基、羟烷基、烷氧基、烷基、环烷基、杂环基、芳基、杂芳基、羧基,其中所述的烷基、环烷基、杂环基、芳基、杂芳基任选进一步被羧基取代;
q为0、1或2;
环A、G
1、R
2、R
3、L
1、n和p的定义如通式(I)中所述。
根据本发明的优选方案,提供一种通式(I)、(II)或(III)所述的化合物或其立体异构体、互变异构体或其可药用的盐,其中环A选自:
根据本发明的优选方案,提供一种通式(I)、(II)或(III)所述的化合物或其立体异构体、互变异构体或其可药用的盐,其中
根据本发明的优选方案,提供一种通式(I)或(II)所述的化合物或其立体异构体、互变异构体或其可药用的盐,其中
根据本发明的优选方案,提供一种通式(I)、(II)或(III)所述的化合物或其立体异构体、互变异构体或其可药用的盐,其中n选自0。
根据本发明的优选方案,提供一种通式(I)、(II)或(III)所述的化合物或其立体异构体、互变异构体或其可药用的盐,其中L
1选自-CH
2-。
在本发明的优选方案中,通式(I)所述的化合物选自:
或其立体异构体、互变异构体或其可药用的盐。
注:如果在画出的结构和给出的该结构的名称之间有差异,则画出的结构将给予更大的权重。
更进一步,本发明提供一种药物组合物,所述的药物组合物含有有效剂量的通式(I)、(II)或(III)所述的化合物或其立体异构体、互变异构体或其可药用的盐,以及可药用的载体。
本发明提供一种通式(I)、(II)或(III)所述的化合物或其立体异构体、互变异构体或其可药用的盐,或其药物组合物在制备LPXC抑制剂中的用途。
本发明还提供一种通式(I)、(II)或(III)所述的化合物或其立体异构体、互变异构体或其可药用的盐,或其药物组合物在制备治疗由LPXC介导的疾病的药物中的用途,其中所述的由LPXC介导的疾病优选革兰氏阴性菌导致的细菌感染;其中所述的由LPXC介导的疾病选自大肠杆菌、绿脓杆菌、变形杆菌、痢疾杆菌、肺炎杆菌、布氏杆菌、伤寒杆菌、不动杆菌属、耶尔森菌属、嗜肺军团菌、百日咳杆菌、志贺菌属、巴斯德菌属、霍乱弧菌、脑膜炎双球菌等革兰氏阴性菌引起的细菌感染。
本发明进一步提供一种通式(I、(II)或(III)所述的化合物或其立体异构体、互变异构体或其可药用的盐,或其药物组合物在制备治疗革兰氏阴性菌导致的细菌感染的药物中的用途。
本发明提供一种通式(I)、(II)或(III)所述的化合物或其立体异构体、互变异构体或其可药用的盐,或其药物组合物在制备大肠杆菌、绿脓杆菌、变形杆菌、痢疾杆菌、肺炎杆菌、布氏杆菌、伤寒杆菌、不动杆菌属、耶尔森菌属、嗜肺军团菌、百日咳杆菌、志贺菌属、巴斯德菌属、霍乱弧菌、脑膜炎双球菌等革兰氏阴性菌引起的细菌感染的药物中的用途。
本发明还提供了一种治疗由LPXC介导的疾病的方法,包括向有此需要的对象给予通式(I)、(II)或(III)所述的化合物或其立体异构体、互变异构体或其可药用的盐,或其药物组合物。优选地,所述由LPXC介导的疾病为革兰氏阴性菌导致的细菌感染;更优选地,所述革兰氏阴性菌选自大肠杆菌、绿脓杆菌、变形杆菌、痢疾杆菌、肺炎杆菌、布氏杆菌、伤寒杆菌、不动杆菌属、耶尔森菌属、嗜肺军团菌、百日咳杆菌、志贺菌属、巴斯德菌属、霍乱弧菌、脑膜炎双球菌。
发明的详细说明
除非有相反陈述,否则本发明在说明书和权利要求书中所使用的部分术语定义如下:
“烷基”当作一基团或一基团的一部分时是指包括C
1-C
20直链或者带有支链的脂肪烃基团。优选为C
1-C
10烷基,更优选为C
1-C
6烷基或C
1-C
4烷基。烷基基团的实施例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基等。烷基可以是取代或未取代的。
“环烷基”是指非芳香性环状烷基,其中一个或多个成环的原子是碳原子,包括单环、多环、稠环、桥环和螺环,优选具有3至7元单环或7至10元双环或三环。“环烷基”的实例包括但不限于环丙基、环戊基、环丁基。环烷基可以是取代或未取代的。优选C
3-C
7环烷基、C
3-C
6环烷基或C
5-C
7环烷基。
“螺环烷基”指5至18元,两个或两个以上环状结构,且单环之间彼此共用一个碳原子 (称螺原子)的多环基团,环内含有1个或多个双键,但没有一个环具有完全共轭的π电子的芳香***。优选为6至14元,更优选为7至10元。根据环与环之间共用螺原子的数目将螺环烷基分为单螺、双螺或多螺环烷基,优选为单螺和双螺环烷基,优选为4元/5元、4元/6元、5元/5元或5元/6元。“螺环烷基”的非限制性实施例包括但不限于:螺[4.5]癸基、螺[4.4]壬基、螺[3.5]壬基、螺[2.4]庚基。
“稠环烷基”指5至18元,含有两个或两个以上环状结构彼此公用一对碳原子的全碳多环基团,一个或多个环可以含有一个或多个双键,但没有一个环具有完全共轭的π电子的芳香***,优选为6至12元,更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠环烷基,优选为双环或三环,更优选为5元/5元或5元/6元双环烷基。“稠环烷基”的非限制性实施例包括但不限于:二环[3.1.0]己基、二环[3.2.0]庚-1-烯基、二环[3.2.0]庚基、十氢化萘基或十四氢菲基。
“桥环烷基”指5至18元,含有两个或两个以上环状结构,彼此共用两个不直接相连接碳原子的全碳多环基团,一个或多个环可以含有一个或多个双键,但没有一个环具有完全共轭的π电子的芳香***,优选为6至12元,更优选为7至10元。优选为6至14元,更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环桥环烷基,优选为双环、三环或四环,更有选为双环或三环。“桥环烷基”的非限制性实施例包括但不限于:(1s,4s)-二环[2.2.1]庚基、二环[3.2.1]辛基、(1s,5s)-二环o[3.3.1]壬基、二环[2.2.2]辛基、(1r,5r)-二环[3.3.2]癸基。
“杂环基”、“杂环烷基”、“杂环”或“杂环的”在本申请中可交换使用,都是指非芳香性杂环基,其中一个或多个成环的原子是杂原子,如氧、氮或S(O)
r(其中r选自0、1或2)等,且所述的环原子任选包括-C(=O)-,包括单环、多环、稠环、桥环和螺环。优选具有5至7元单环或7至10元双环或三环,其可以包含1,2或3个选自氮、氧和/或S(O)
r(其中r选自0、1或2)中的原子。“杂环基”的实例包括但不限于吗啉基、氧杂环丁烷基、硫代吗啉基、四氢呋喃基、四氢吡喃基、1,1-二氧代-硫代吗啉基、哌啶基、2-氧代-哌啶基、吡咯烷基、2-氧代-吡咯烷基、哌嗪-2-酮、8-氧杂-3-氮杂-双环[3.2.1]辛基、哌嗪基、六氢嘧啶、
杂环基可以是取代或未取代的。
“螺杂环基”指5至18元,两个或两个以上环状结构,且单环之间彼此共用一个原子的多环基团,环内含有1个或多个双键,但没有一个环具有完全共轭的π电子的芳香***,其中一个或多个环原子选自氮、氧、C(=O)或S(O)
r(其中r选自0、1或2)的杂原子,其余环原子为碳。优选为6至14元,更优选为7至10元。根据环与环之间共用螺原子的数目将螺环烷基分为单螺杂环基、双螺杂环基或多螺杂环基,优选为单螺杂环基和双螺杂环基。更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺杂环基。“螺杂环基”的非限制性实施例包括但不限于:1,7-二氧杂螺[4.5]癸基、2-氧杂-7-氮杂螺[4.4]壬基、7-氧杂螺[3.5]壬基、5-氧杂螺[2.4]庚基。
“稠杂环基”指含有两个或两个以上环状结构彼此共用一对原子的多环基团,一个或多个环可以含有一个或多个双键,但没有一个环具有完全共轭的π电子的芳香***,其中一个或多个环原子选自氮、氧、C(=O)或S(O)
r(其中r选自0、1或2)的杂原子,其余环原子为碳。优选为6至14元,更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠杂环基,优选为双环或三环,更优选为5元/5元或5元/6元双环稠杂环基。“稠杂环基”的非限制性实施例包括但不限于:八氢吡咯并[3,4-c]吡咯基、八氢-1H-异吲哚基,3-氮杂二环[3.1.0]己基,八氢苯并[b][1,4]二噁英(dioxine),
“桥杂环基”指5至14元,5至18元,含有两个或两个以上环状结构,彼此共用两个不直接相连接的原子的多环基团,一个或多个环可以含有一个或多个双键,但没有一个环具有完全共轭的π电子的芳香***,其中一个或多个环原子选自氮、氧、C(=O)或S(O)
r(其中r选自0、1或2)的杂原子,其余环原子为碳。优选为6至14元,更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环桥杂环基,优选为双环、三环或四环,更有选为双环或三环。“桥杂环基”的非限制性实施例包括但不限于:2-氮杂二环[2.2.1]庚基,2-氮杂二环[2.2.2]辛基、2-氮杂二环[3.3.2]癸基。
“芳基”是指含有一个或者两个环的碳环芳香***,其中所述环可以以稠合的方式连接在一起。术语“芳基”包括单环或双环的芳基,比如苯基、萘基、四氢萘基的芳香基团。优选芳基为C
6-C
10芳基,更优选芳基为苯基和萘基,最优选为萘基。芳基可以是取代或未取代的。
“杂芳基”是指芳香族5至6元单环或8至10元双环,其可以包含1至4个选自氮、氧 和/或硫中的原子。优选的杂芳基为C
6-C
10杂芳基,其中包含1至3个选自氮、氧和硫的杂原子。“杂芳基”的实施例包括但不限于呋喃基、吡啶基、2-氧代-1,2-二氢吡啶基、哒嗪基、嘧啶基、吡嗪基、噻吩基、异噁唑基、噁唑基、噁二唑基、咪唑基、吡咯基、吡唑基、***基、四氮唑基、噻唑基、异噻唑基、1,2,3-噻二唑基、苯并间二氧杂环戊烯基、苯并噻吩基、苯并咪唑基、吲哚基、异吲哚基、1,3-二氧代-异吲哚基、喹啉基、吲唑基,苯并异噻唑基,苯并噁唑基,苯并异噁唑基,异噻唑基、1H-1,2,4-***基、4H-1,2,4-***基、吡啶基、嘧啶基、吡嗪-2(1H)-酮基、嘧啶-4(3H)-酮基、哒嗪-3(2H)-酮基、1H-吲哚基、1H-苯并[d]咪唑基、1H-吡咯并[2,3-c]吡啶基、3H-咪唑并[4,5-c]吡啶基、异喹啉基、喹唑啉基、2H-异吲哚基、呋喃[3,2-b]吡啶基、呋喃[2,3-c]吡啶基、噻吩并[2,3-c]吡啶基、苯并呋喃基、苯并[b]噻吩基、1H-吡咯并[3,2-b]吡啶基、2H-吡咯并[3,4-c]吡啶基。杂芳基可以是取代或未取代的。
“烷氧基”是指(烷基-O-)的基团。其中,烷基见本文有关定义。C
1-C
6或C
1-C
4的烷氧基为优先选择。其实例包括,但不限于:甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基等。
“硝基”指-NO
2基团。
“羟基”指-OH基团。
“卤素”是指氟、氯、溴和碘。
“氨基”指-NH
2。
“氰基”指-CN。
“苄基”指-CH
2-苯基。
“羧基”指-C(O)OH。
“羧酸酯基”指-C(O)O-烷基或-C(O)O-环烷基,其中烷基、环烷基的定义如上所述。
“羟烷基”指羟基取代的烷基,其中烷基的定义如上所述。
“氨烷基”指氨基取代的烷基,其中烷基的定义如上所述。
“卤代烷基”指卤素取代的烷基,其中烷基的定义如上所述。
“卤代烷氧基”指卤素取代的烷氧基,其中烷氧基的定义如上所述。
“DMSO”指二甲基亚砜。
“BOC”指叔丁氧基羰基。
“Bn”指苄基。
“THP”指2-四氢吡喃基。
“TFA”指三氟醋酸。
“Ts”指对甲苯磺酰基。
“离去基团(leaving group)”,或称离去基,在化学反应中从一较大分子中脱离的原子或官能基,是亲核取代反应与消除反应中应用的术语。在亲核取代反应中,被亲核试剂进攻 的反应物称为底物(substrate),而从底物分子中带着一对电子断裂出去的原子或原子团称为离去基团。易接受电子、承受负电荷能力强的基团是好的离去基团。当离去基团共轭酸的pKa越小,离去基团越容易从其他分子中脱离。原因是因为当其共轭酸的pKa越小,相应离去基团不需和其他原子结合,以阴离子(或电中性离去基团)的形式存在的趋势也就增强。常见的离去基团包括但不限于卤素、甲磺酰基、-OTs或-OH。
“取代的”指基团中的一个或多个氢原子,优选为最多5个,更优选为1~3个氢原子彼此独立地被相应数目的取代基取代。不言而喻,取代基仅处在它们的可能的化学位置,本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如,具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。
本说明书所述的“取代”或“取代的”,如无特别指出,均是指基团可被一个或多个选自以下的基团取代:烷基、烷氧基、烷硫基、烷基氨基、卤素、疏基、羟基、硝基、氰基、环烷基、杂环基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氨基、卤代烷基、羟烷基、羧基、羧酸酯基、=O、-C(O)R
5、-C(O)OR
5、-OC(O)R
5、-NR
6R
7、-C(O)NR
6R
7、-SO
2NR
6R
7或-NR
6C(O)R
7;
R
5选自氢原子、烷基、环烷基、杂环基、芳基或杂芳基,其中所述的烷基、环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自羟基、卤素、硝基、氰基、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基、杂环基、芳基、杂芳基、=O、-C(O)R
8、-C(O)OR
8、-OC(O)R
8、-NR
9R
10、-C(O)NR
9R
10、-SO
2NR
9R
10或-NR
9C(O)R
10的取代基所取代;
R
6和R
7各自独立地选自氢原子、羟基、卤素、烷基、烷氧基、环烷基、杂环基、芳基或杂芳基,其中所述的烷基、烷氧基、环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自羟基、卤素、硝基、氰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、=O、-C(O)R
8、-C(O)OR
8、-OC(O)R
8、-NR
9R
10、-C(O)NR
9R
10、-SO
2NR
9R
10或-NR
9C(O)R
10的取代基所取代;
或者,R
6和R
7与其所连接的原子一起形成一个4~8元杂环基,其中所述4~8元杂环基内含有一个或多个N、O、S或SO
2,并且所述的4~8元杂环基任选进一步被一个或多个选自羟基、卤素、硝基、氰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、=O、-C(O)R
8、-C(O)OR
8、-OC(O)R
8、-NR
9R
10、-C(O)NR
9R
10、-SO
2NR
9R
10或-NR
9C(O)R
10的取代基所取代;
R
8、R
9和R
10各自独立地选自氢原子、烷基、氨基、环烷基、杂环基、芳基或杂芳基,其中所述的烷基、环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自羟基、卤素、硝基、氨基、氰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、羧基或羧酸酯基的取代基所取代。
“可药用的盐”是指上述化合物能保持原有生物活性并且适合于医药用途的某些盐类。通式(I)所表示的化合物的可药用的盐可以为金属盐、与合适的酸形成的胺盐。
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上可药用的盐或前体药物与其他化学组分的混合物,以及其他组分例如生理学可药用的载体。药物组合物的目的是促进对生物体的给药,利于活性成分的吸收进而发挥生物活性。
本发明化合物的合成方法
为了完成本发明的目的,本发明采用如下技术方案:
本发明提供了一种通式(I)化合物或其立体异构体、互变异构体或其可药用的盐的制备方法,所述方法包括:
通式(I-a)化合物与(I-b)化合物与在催化剂作用下发生偶联反应,任选进一步脱去保护基,得到通式(I)化合物;
其中:
X
1选自卤素;
环A、X、Y、R
1~R
3、L
1、n、m和p的定义如通式(I)中所述。
以下结合实施例用于进一步描述本发明,但这些实施例并非限制着本发明的范围。
实施例
实施例给出了式(I)所表示的代表性化合物的制备及相关结构鉴定数据。必须说明,下述实施例是用于说明本发明而不是对本发明的限制。
1H NMR图谱是用Bruker仪器(400MHz)测定而得,化学位移用ppm表示。使用四甲基硅烷内标准(0.00ppm)。
1H NMR的表示方法:s=单峰,d=双重峰,t=三重峰,m=多重峰,br=变宽的,dd=双重峰的双重峰,dt=三重峰的双重峰。若提供偶合常数时,其单位为Hz。
质谱是用LC/MS仪测定得到,离子化方式可为ESI或APCI。
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板,薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm~0.2mm,薄层层析分离纯化产品采用的规格是0.4mm~0.5mm。
柱层析一般使用烟台黄海硅胶200~300目硅胶为载体。
在下列实施例中,除非另有指明,所有温度为摄氏温度,除非另有指明,各种起始原料和试剂来自市售或者是根据已知的方法合成,市售原料和试剂均不经进一步纯化直接使用,除非另有指明,市售厂家包括但不限于Aldrich Chemical Company,ABCR GmbH & Co.KG,Acros Organics,广赞化工科技有限公司和景颜化工科技有限公司等处购买。
CD
3OD:氘代甲醇。
CDCl
3:氘代氯仿。
DMSO-d
6:氘代二甲基亚砜。
氩气氛是指反应瓶连接一个约1L容积的氩气气球。
实施例中无特殊说明,反应中的溶液是指水溶液。
对化合物进行纯化,采用硅胶柱层析洗脱剂体系和薄层色谱法,其中洗脱剂体系选自:A:石油醚和乙酸乙酯体系;B:二氯甲烷和甲醇体系;C:二氯甲烷和乙酸乙酯体系;其中溶剂的体积比根据化合物的极性不同而不同,也可以加入少量的酸性或碱性试剂进行调节,如醋酸或三乙胺等。
实施例1
5-羟基-6-(3-(4-((4-(吗啉甲基)苯基)乙炔基)苯基)-4,5-二氢异噁唑-5-基)嘧啶-4(3H)-酮
第一步
(E)-4-碘苯甲醛肟
将盐酸羟胺(5.99g,86.20mmol)、碳酸钾(11.9g,86.20mmol)、4-碘苯甲醛1a(10g,43.10mmol)和水(80mL)依次加入到乙醇中(80mL),室温反应过夜。反应结束后,以乙酸乙酯(100mL×3)萃取,合并有机相,减压浓缩,得到的残留物通过硅胶柱层析纯化(洗脱剂:A体系),得到(E)-4-碘苯甲醛肟1b(8g),产率:75.14%。
MS m/z(ESI):247.8[M+1]
+
第二步
(Z)-N-羟基-4-碘代苯并亚胺酰氯
将(E)-4-碘苯甲醛肟1b(1g,4.05mmol)溶于N,N-二甲基甲酰胺中(10mL),慢慢加入氯代丁二酰亚胺(594.59mg,4.45mmol),室温搅拌反应过夜。反应完全后,得到(Z)-N-羟基-4-碘代苯并亚胺酰氯1c,反应液未经纯化,直接用于下一步反应。
第三步
5-(5,6-双(苄氧基)嘧啶-4-基)-3-(4-碘苯基)-4,5-二氢异噁唑
将4,5-双(苄氧基)-6-乙烯基嘧啶1d(1.1g,3.46mmol,根据专利WO2020061375自制而得)和三乙胺(699.25mg,6.91mmol,957.87μL)溶于N,N-二甲基甲酰胺(14.04mL),缓慢滴加(Z)-N-羟基-4-碘代苯并亚胺酰氯1c(972.54mg,3.46mmol)的N,N-二甲基甲酰胺溶液(10mL),室温反应6小时。反应完全后,加水淬灭反应,乙酸乙酯(50mL×3)萃取,合并有机相,减压浓缩,得到的残留物通过硅胶柱层析纯化(洗脱剂:A体系),得到5-(5,6-双(苄氧基)嘧啶-4-基)-3-(4-碘苯基)-4,5-二氢异噁唑1e(1.4g),产率:71.92%。
MS m/z(ESI):563.8[M+1]
+
第四步
4-(4-((4-(5-(5,6-双(苄氧基))嘧啶-4-基)-4,5-二氢异噁唑-3-基)苯基)乙炔基)苄基)吗啉
将5-(5,6-双(苄氧基)嘧啶-4-基)-3-(4-碘苯基)-4,5-二氢异噁唑1e(0.8g,1.42mmol)、4-(4-乙炔基苄基)吗啉1f(285.79mg,1.42mmol)、双(三苯基膦)二氯化钯(199.34mg,284.00μmol)、碘化亚铜(54.09mg,284.00μmol)和三乙胺(431.07mg,4.26mmol)溶于N,N-二甲基甲酰胺(6mL),置换氩气三次,室温搅拌过夜。反应完全后,加水淬灭反应,乙酸乙酯(20ml×3)萃取,合并有机相,减压浓缩,得到的残留物通过硅胶柱层析纯化(洗脱剂:B体系),得到4-(4-((4-(5-(5,6-双(苄氧基))嘧啶-4-基)-4,5-二氢异噁唑-3-基)苯基)乙炔基)苄基)吗啉1g(0.85g),产率:94.01%。
MS m/z(ESI):637.0[M+1]
+
第五步
5-羟基-6-(3-(4-((4-(吗啉甲基)苯基)乙炔基)苯基)-4,5-二氢异噁唑-5-基)嘧啶-4(3H)-酮
将4-(4-((4-(5-(5,6-双(苄氧基))嘧啶-4-基)-4,5-二氢异噁唑-3-基)苯基)乙炔基)苄基)吗啉1g(0.2g,314.10μmol)溶于二氯甲烷(2mL),缓慢滴加三氯化硼(1.84g,15.71mmol,5mL),加热至30℃,反应6小时。反应结束后,冰浴下加适量甲醇淬灭。减压过滤,制备液相色谱分离(分离柱AKZONOBEL Kromasil;250×21.2mm I.D.;5μm,20mL/min;流动相A:0.05%TFA+H
2O,流动相B:CH
3CN),得到5-羟基-6-(3-(4-((4-(吗啉甲基)苯基)乙炔基)苯基)-4,5-二氢异噁唑-5-基)嘧啶-4(3H)-酮1(25mg),产率:13.67%。
MS m/z(ESI):457.2[M+1]
+
实施例2
3-((5-羟基-6-氧代-1,6-二氢嘧啶-4-基)甲基)-5-(4-((4-(吗啉甲基)苯基)乙炔基)苯基)噁唑烷-2-酮2
第一步
2-氨基-1-(4-溴苯基)乙-1-醇
向2-氨基-1-(4-溴苯基)乙-1-酮盐酸盐2a(5g,17.42mmol)的四氢呋喃(100mL)溶液中加入硼氢化钠(1.98g,52.27mmol),然后加入乙醇(50mL),室温反应2小时,反应结束后,反应液中加入30mL水,乙酸乙酯(40mL×3)萃取,饱和氯化钠溶液(20mL)洗涤,有机相以无水硫酸钠干燥,过滤,减压浓缩,得到2-氨基-1-(4-溴苯基)乙-1-醇2b(3.76g),产率:100%,未经纯化,直接进行下一步反应。
MS m/z(ESI):216.0[M+1]
+
第二步
5-(4-溴苯基)噁唑烷-2-酮
在零下78℃条件下,向2-氨基-1-(4-溴苯基)乙-1-醇2b(3.76g,17.40mmol)和三乙胺(3.52g,34.80mmol,4.84mL)的二氯甲烷(80mL)溶液中,加入双(三氯甲基)碳酸酯(2.58g,8.70mmol),低温反应20分钟,升至室温反应过夜。反应液中加入20mL水,以二氯甲 烷(60mL×3)萃取,饱和氯化钠溶液(30mL)洗涤,有机相以无水硫酸钠干燥,过滤,减压浓缩,得到的残留物通过硅胶柱层析纯化(洗脱剂:B体系),得到5-(4-溴苯基)噁唑烷-2-酮2c(2.62g),产率:62.2%。
MS m/z(ESI):242.0[M+1]
+
第三步
3-((5,6-双(苄氧基)嘧啶-4-基)甲基)-5-(4-溴苯基)噁唑烷-2-酮
将碳酸钾(856.43mg,6.20mmol)加入5-(4-溴苯基)噁唑烷-2-酮2c(500mg,2.07mmol)和4,5-双(苄氧基)-6-(碘甲基)嘧啶2d(892.83mg,2.07mmol,根据专利WO 2020061375自制而得)的乙腈中(40mL),加热至回流,反应6小时,反应结束后,反应液中加入20mL水,乙酸乙酯(20mL×3)萃取,饱和氯化钠溶液(20mL)洗涤,有机相以无水硫酸钠干燥,过滤,减压浓缩,得到的残留物通过硅胶柱层析纯化(洗脱剂:A体系),得到3-((5,6-双(苄氧基)嘧啶-4-基)甲基)-5-(4-溴苯基)噁唑烷-2-酮2e(0.94g),产率:83.29%。
MS m/z(ESI):546.1[M+1]
+
第四步
3-((5,6-双(苄氧基)嘧啶-4-基)甲基)-5-(4-((4-(吗啉甲基)苯基)乙炔基)苯基)噁唑烷-2-酮
将3-((5,6-双(苄氧基)嘧啶-4-基)甲基)-5-(4-溴苯基)噁唑烷-2-酮2e(910mg,1.67mmol)、4-(4-乙炔基苄基)吗啉1f(435.74mg,2.17mmol)、双(三苯基膦)二氯化钯(58.45mg,83.27μmol)、四丁基溴化铵(536.88mg,1.67mmol)和哌啶(425.43mg,5.00mmol)加入到水中(20mL),氩气置换三次,加热至85℃,反应4小时。反应结束后,反应液中加入乙酸乙酯(30mL×3)萃取,饱和氯化钠溶液(20mL)洗涤,有机相以无水硫酸钠干燥,过滤,减压浓缩,得到的残留物通过硅胶柱层析纯化(洗脱剂:A体系),得到3-((5,6-双(苄氧基)嘧啶-4-基)甲基)-5-(4-((4-(吗啉甲基)苯基)乙炔基)苯基)噁唑烷-2-酮2f(0.835g),产率:75.2%。
MS m/z(ESI):667.3[M+1]
+
第五步
3-((5-羟基-6-氧代-1,6-二氢嘧啶-4-基)甲基)-5-(4-((4-(吗啉甲基)苯基)乙炔基)苯基)噁唑烷-2-酮
冰水浴条件下,将三氯化硼(8mL)加入3-((5,6-双(苄氧基)嘧啶-4-基)甲基)-5-(4-((4-(吗啉甲基)苯基)乙炔基)苯基)噁唑烷-2-酮2f(860mg,1.29mmol)的二氯甲烷中(3mL),缓慢升温至35℃,反应5小时,反应结束后,甲醇淬灭反应,反应液减压浓缩,制备液相分离(分离柱AKZONOBEL Kromasil;250×21.2mm I.D.;5μm,20mL/min;流动相A:0.05%TFA+H
2O,流动相B:CH
3CN),得到3-((5-羟基-6-氧代-1,6-二氢嘧啶-4-基)甲基)-5-(4-((4-(吗啉甲基)苯基)乙炔基)苯基)噁唑烷-2-酮2(100mg),产率:12.34%。
MS m/z(ESI):487.2[M+1]
+
1H NMR(400MHz,DMSO-d
6)δ10.17(s,1H),9.66(s,1H),7.80(s,1H),7.68(d,J=7.9Hz,2H),7.63(d,J=8.2Hz,2H),7.57(d,J=7.9Hz,2H),7.52(d,J=8.1Hz,2H),5.62(dd,J=8.8, 7.0Hz,1H),4.38(s,2H),4.32(s,2H),3.99(t,J=8.9Hz,3H),3.65(s,2H),3.43(dd,J=8.8,7.0Hz,1H),3.26(s,2H),3.13(s,2H).
实施例3
3-((5-羟基-6-氧代-1,6-二氢嘧啶-4-基)甲基)-5-(4-((4-(吗啉-4-羰基)苯基)乙炔基)苯基)噁唑啉-2-酮
第一步
3-((5,6-双(苄氧基)嘧啶-4-基)甲基)-5-(4-(((4-(吗啉-4-羰基)苯基)乙炔基)苯基)噁唑烷-2-酮
将3-((5,6-双(苄氧基)嘧啶-4-基)甲基)-5-(4-溴苯基)噁唑烷-2-酮2e(130mg,237.92μmol)、(4-乙炔基苯基)(吗啉代)甲酮3a(51.21mg,237.92μmol)、双(三苯基膦)二氯化钯(8.35mg,11.90μmol)、四丁基溴化铵(76.70mg,237.92μmol)和哌啶(60.78mg,713.75μmol)加到水中(3mL),氩气置换三次,加热至85℃,反应4小时。反应结束后,反应液中加入乙酸乙酯(20mL×3)萃取,饱和氯化钠溶液(20mL)洗涤,有机相以无水硫酸钠干燥,过滤,减压浓缩,得到的残留物通过硅胶柱层析纯化(洗脱剂:A体系),得到3-((5,6-双(苄氧基)嘧啶-4-基)甲基)-5-(4-(((4-(吗啉-4-羰基)苯基)乙炔基)苯基)噁唑烷-2-酮3b(130mg),产率:80.27%。
MS m/z(ESI):681.3[M+1]
+
第二步
3-((5-羟基-6-氧代-1,6-二氢嘧啶-4-基)甲基)-5-(4-((4-(吗啉-4-羰基)苯基)乙炔基)苯基)噁唑啉-2-酮
冰水浴条件下,将三氯化硼(1.5mL)滴加入3-((5,6-双(苄氧基)嘧啶-4-基)甲基)-5-(4-(((4-(吗啉-4-羰基)苯基)乙炔基)苯基)噁唑烷-2-酮3b(130mg,190.97μmol)的二氯 甲烷中(2mL),加热至35℃,反应5小时,反应结束后,甲醇淬灭反应,反应液减压浓缩,制备液相分离(分离柱AKZONOBEL Kromasil;250×21.2mm I.D.;5μm,20mL/min;流动相A:0.05%TFA+H
2O,流动相B:CH
3CN),得到3-((5-羟基-6-氧代-1,6-二氢嘧啶-4-基)甲基)-5-(4-((4-(吗啉-4-羰基)苯基)乙炔基)苯基)噁唑啉-2-酮3(11.97mg),产率:9.96%。
MS m/z(ESI):501.2[M+1]
+
1H NMR(400MHz,DMSO-d
6)δ9.14-9.51(m,4H),8.44(dd,J=5.2,1.7Hz,1H),8.14(s,4H),7.20(dd,J=16.8,11.0Hz,1H),6.62(dd,J=16.9,1.7Hz,1H),5.92(dd,J=10.8,1.8Hz,1H),5.09(d,J=7.5Hz,2H),4.95(t,J=7.5Hz,2H),4.88(t,J=7.6Hz,1H),3.91(t,J=6.7Hz,1H),3.64(s,1H),3.52(d,J=6.1Hz,1H),3.45(s,1H),3.32(s,1H),3.29(d,J=7.3Hz,2H).
实施例4
5-羟基-6-((4-(4-((4-(吗啉-4-羰基)苯基)乙炔基)苯基)-2-氧代咪唑啉-1-基)甲基)嘧啶-4(3H)-酮
第一步
(E)-3-(4-碘苯基)丙烯酸
将4-碘苯甲醛1a(10g,43.10mmol)、丙二酸(5.38g,51.72mmol)和醋酸铵(6.64g,86.20mmol)加到乙醇中(10mL),回流反应6小时,冷却至室温,反应结束后,过滤,滤饼用乙醇和正己烷40mL各洗一次,滤饼干燥,得到(E)-3-(4-碘苯基)丙烯酸4a(9.8g),产率:82.97%。
MS m/z(ESI):275.0[M+1]
+
第二步
3-氨基-3-(4-碘苯基)丙酸
将(E)-3-(4-碘苯基)丙烯酸4a(6g,21.89mmol)、醋酸铵(5.06g,65.68mmol)和乙醇(50mL)加入压力管中,加热回流,反应6小时,反应结束后,冷却至室温过滤,滤饼用乙醇和正己烷40mL各洗一次,滤饼干燥,得到3-氨基-3-(4-碘苯基)丙酸4b(5g),产率:78.16%。MS m/z(ESI):292.0[M+1]
+
第三步
3-((叔丁氧羰基)氨基)-3-(4-碘苯基)丙酸
将二碳酸二叔丁酯(5.51g,25.25mmol)加入3-氨基-3-(4-碘苯基)丙酸4b(4.9g,16.83mmol)的50mL二氧六环中,再加入50mL的饱和碳酸氢钠溶液,室温搅拌过夜。反应结束后,过滤,滤饼用正己烷50mL洗两次,滤液用柠檬酸溶液酸化,乙酸乙酯(40mL×3)萃取,饱和氯化钠溶液(20mL)洗涤,有机相以无水硫酸钠干燥,过滤,减压浓缩,得到3-((叔丁氧羰基)氨基)-3-(4-碘苯基)丙酸4c(4.85g),产率:73.65%,未经纯化,直接进行下一步反应。
MS m/z(ESI):414.0[M+23]
+
第四步
5-(4-碘苯基)-2-氧代咪唑啉-1-甲酸叔丁酯
将3-((叔丁氧羰基)氨基)-3-(4-碘苯基)丙酸4c(1g,2.56mmol)、叠氮磷酸二苯酯(844.17mg,3.07mmol)和三乙胺(646.66mg,6.39mmol)加到甲苯中(25mL),室温搅拌30分钟。加热至80℃,反应4小时,反应结束后,反应液中加入20mL水,乙酸乙酯(20mL×3)萃取,饱和氯化钠溶液(20mL)洗涤,有机相以无水硫酸钠干燥,过滤,减压浓缩,得到5-(4-碘苯基)-2-氧代咪唑啉-1-甲酸叔丁酯4d(992mg),产率:99.97%,未经纯化,直接进行下一步反应。
MS m/z(ESI):333.0[M-55]
+
第五步
3-((5,6-双(苄氧基)嘧啶-4-基)甲基)-5-(4-碘苯基)-2-氧代咪唑啉-1-甲酸叔丁酯
将5-(4-碘苯基)-2-氧代咪唑啉-1-甲酸叔丁酯4d(800mg,2.06mmol)、4,5-双(苄氧基)-6-(碘甲基)嘧啶2d(890.79mg,2.06mmol)、碳酸钾(854.47mg,6.18mmol)加到乙腈中 (5mL),加热至90℃,反应10小时,反应结束后,反应液中加入20mL水,乙酸乙酯(20mL×3)萃取,饱和氯化钠溶液(20mL)洗涤,有机相以无水硫酸钠干燥,过滤,减压浓缩,得到的残留物通过硅胶柱层析纯化(洗脱剂:A体系),得到3-((5,6-双(苄氧基)嘧啶-4-基)甲基)-5-(4-碘苯基)-2-氧代咪唑啉-1-甲酸叔丁酯4e(510mg),产率:35.73%。
MS m/z(ESI):637.1[M-55]
+
第六步
3-((5,6-双(苄氧基)嘧啶-4-基)甲基)-5-(4-((4-(吗啉-4-羰基)苯基)乙炔基)苯基)-2-氧代咪唑啉-1-甲酸叔丁酯
将3-((5,6-双(苄氧基)嘧啶-4-基)甲基)-5-(4-碘苯基)-2-氧代咪唑啉-1-甲酸叔丁酯4e(100mg,154.91μmol)、(4-乙炔基苯基)(吗啉代)甲酮3a(33.34mg,154.91μmol)、双(三苯基膦)二氯化钯(5.44mg,7.75μmol)、四丁基溴化铵(49.94mg,154.91μmol)和哌啶(39.57mg,464.73μmol)加到水中(2mL),氩气置换三次,加热至85℃,反应4小时,反应结束后,反应液中加入20mL水,乙酸乙酯(20mL×3)萃取,饱和氯化钠溶液(20mL)洗涤,有机相以无水硫酸钠干燥,过滤,减压浓缩,得到的残留物通过硅胶柱层析纯化(洗脱剂:A体系),得到3-((5,6-双(苄氧基)嘧啶-4-基)甲基)-5-(4-((4-(吗啉-4-羰基)苯基)乙炔基)苯基)-2-氧代咪唑啉-1-甲酸叔丁酯4f(60mg),产率:49.66%。
MS m/z(ESI):780.5[M+1]
+
第七步
5-羟基-6-((4-(4-((4-(吗啉-4-羰基)苯基)乙炔基)苯基)-2-氧代咪唑啉-1-基)甲基)嘧啶-4(3H)-酮
将三氯化硼(1mL)加入3-((5,6-双(苄氧基)嘧啶-4-基)甲基)-5-(4-((4-(吗啉-4-羰基)苯基)乙炔基)苯基)-2-氧代咪唑啉-1-甲酸叔丁酯4f(60mg,76.94μmol)的二氯甲烷中(1mL),加热至35℃,反应6小时,反应结束后,甲醇淬灭反应,反应液减压浓缩,制备液相分离(分离柱AKZONOBEL Kromasil;250×21.2mm I.D.;5μm,20mL/min;流动相A:0.05%TFA+H
2O,流动相B:CH
3CN),得到5-羟基-6-((4-(4-((4-(吗啉-4-羰基)苯基)乙炔基)苯基)-2-氧代咪唑啉-1-基)甲基)嘧啶-4(3H)-酮4(8.58mg),产率:17.78%。
MS m/z(ESI):500.2[M+1]
+
1H NMR(400MHz,DMSO-d
6)δ12.65(s,1H),9.31-9.76(m,1H),7.78(s,1H),7.59(dd,J=18.8,8.0Hz,4H),7.45(dd,J=12.0,8.0Hz,4H),7.10(d,J=14.3Hz,1H),4.72(t,J=8.1Hz,1H),4.19(d,J=6.7Hz,2H),3.80(s,1H),3.63(s,8H),3.09(s,1H).
实施例5
5-羟基-6-((3-(4-((4-(吗啉甲基)苯基)乙炔基)苯基)-4,5-二氢异噁唑-5-基)甲基)嘧啶-4(3H)-酮
实施例6
5-羟基-6-((3-(4-((4-(吗啉甲基)苯基)乙炔基)苯基)-4,5-二氢异噁唑-4-基)甲基)嘧啶-4(3H)-酮
第一步
4-烯丙基-5,6-双(苄氧基)嘧啶
将磷酸钾(6.50g,30.60mmol)、双(三苯基磷)二氯化钯(859.18mg,1.22mmol)、4,5-二苄氧基-6-氯嘧啶5a(2.0g,6.12mmol,根据专利WO2020102572自制而得)和2-烯丙基-4,4,5,5-四甲基-1,3,2-二恶硼烷(4.11g,24.48mmol)依次加入到四氢呋喃(20mL)与水(4mL)的混合溶液中,置换氩气三次,加热至90℃,反应20小时。反应完全后,加入水(10mL),用乙酸乙酯萃取(10mL×3),合并的有机相用饱和食盐水洗涤,无水硫酸钠干燥,减压浓缩,得到的残留物通过硅胶柱层析纯化(洗脱剂:A体系),得到4-烯丙基-5,6-双(苄氧基)嘧啶5b(250mg),产率:21.6%。
MS m/z(ESI):333.1[M+1]
+
第二步
5-((5,6-双(苄氧基)嘧啶-4-基)甲基)-3-(4-碘苯基)-4,5-二氢异噁唑5c
4-((5,6-双(苄氧基)嘧啶-4-基)甲基)-3-(4-碘苯基)-4,5-二氢异噁唑5d
将吡啶(24.02mg,303.60μmol)、(E)-4-碘苯甲醛肟1b(250mg,1.01mmol)和4-烯丙基-5,6-双(苄氧基)嘧啶5b(504.58mg,1.52mmol)依次加入到氯仿(5mL)溶液中,冰水浴冷却下,缓慢滴加次氯酸钠溶液(1.61g,3.04mmol),然后升温至室温,搅拌3小时。反应完全后,加入水(10mL),用乙酸乙酯萃取(10mL×3),合并的有机相用饱和食盐水洗涤,无水硫酸钠干燥,减压浓缩,得到的残留物通过硅胶柱层析纯化(洗脱剂:A体系),得到5-((5,6-双(苄氧基)嘧啶-4-基)甲基)-3-(4-碘苯基)-4,5-二氢异噁唑5c和4-((5,6-双(苄氧基)嘧啶-4-基)甲基)-3-(4-碘苯基)-4,5-二氢异噁唑5d的混合物(470mg),产率:80.4%。
MS m/z(ESI):578.1[M+1]
+
第三步
4-(4-((4-(5-((5,6-双(苄氧基)嘧啶-4-基)甲基)-4,5-二氢异噁唑-3-基)苯基)乙炔基)苄基)吗啉5e
4-(4-((4-(4-((5,6-双(苄氧基)嘧啶-4-基)甲基)-4,5-二氢异噁唑-3-基)苯基)乙炔基)苄基)吗啉5f
将上述5-((5,6-双(苄氧基)嘧啶-4-基)甲基)-3-(4-碘苯基)-4,5-二氢异噁唑5c和4-((5,6-双(苄氧基)嘧啶-4-基)甲基)-3-(4-碘苯基)-4,5-二氢异噁唑5d的混合物(470mg,813.98μmol)、4-(4-乙炔基苄基)吗啉1f(163.82mg,813.98μmol)、氯化烯丙基钯二聚物(29.78mg,81.40μmol)、1,4-二氮杂双环辛烷(182.61mg,1.63mmol)和三叔丁基膦(16.47mg,81.40μmol)加入到乙腈(10mL)溶液中,置换氩气三次,室温反应20小时。反应完全后,加入水(10mL)。用乙酸乙酯萃取(10mL×3),合并的有机相用饱和食盐水洗涤,无水硫酸钠干燥,减压浓缩,得到的残留物通过硅胶柱层析纯化(洗脱剂:A体系),得到4-(4-((4-(5-((5,6-双(苄氧基)嘧啶-4-基)甲基)-4,5-二氢异噁唑-3-基)苯基)乙炔基)苄基)吗啉5e(210mg)和4-(4-((4-(4-((5,6-双(苄氧基)嘧啶-4-基)甲基)-4,5-二氢异噁唑-3-基)苯基)乙炔基)苄基)吗啉5f(110mg),产率分别是39.6%和20.8%。
MS m/z(ESI):651.2[M+1]
+
MS m/z(ESI):651.0[M+1]
+
第四步
5-羟基-6-((3-(4-((4-(吗啉代甲基)苯基)乙炔基)苯基)-4,5-二氢异噁唑-5-基)甲基)嘧啶-4(3H)-酮
将4-(4-((4-(5-((5,6-双(苄氧基)嘧啶-4-基)甲基)-4,5-二氢异噁唑-3-基)苯基)乙炔基)苄基)吗啉5e(100mg,153.67μmol)溶于二氯甲烷(2mL)溶液中,冰水浴冷却下,缓慢滴加1M的三氯化硼二氯甲烷溶液(2mL),然后升至室温,搅拌20小时。反应完全后,加入甲醇淬灭(2mL),减压浓缩,制备液相分离(分离柱AKZONOBEL Kromasil;250×21.2mm I.D.;5μm,20mL/min;流动相A:0.05%TFA+H
2O,流动相B:CH
3CN),得到5-羟基-6-((3-(4-((4-(吗啉代甲基)苯基)乙炔基)苯基)-4,5-二氢异噁唑-5-基)甲基)嘧啶-4(3H)-酮5(6.7mg),产率:18.5%。
MS m/z(ESI):470.8[M+1]
+
第五步
5-羟基-6-((3-(4-((4-(吗啉甲基)苯基)乙炔基)苯基)-4,5-二氢异噁唑-4-基)甲基)嘧啶-4(3H)-酮
将4-(4-((4-(4-((5,6-双(苄氧基)嘧啶-4-基)甲基)-4,5-二氢异噁唑-3-基)苯基)乙炔基)苄基)吗啉5f(110mg,169μmol)加入到二氯甲烷(2mL)溶液中,冰水浴冷却下,缓慢滴加1M的三氯化硼二氯甲烷溶液(2mL),然后升至室温,搅拌20小时。反应完全后,加入甲醇淬灭(2mL),减压浓缩,制备液相分离(分离柱AKZONOBEL Kromasil;250×21.2mm I.D.;5μm,20mL/min;流动相A:0.05%TFA+H
2O,流动相B:CH
3CN),得到5-羟基-6-((3-(4-((4-(吗啉代甲基)苯基)乙炔基)苯基)-4,5-二氢异噁唑-4-基)甲基)嘧啶-4(3H)-酮6(27mg),产率:27.2%。
MS m/z(ESI):471.1[M+1]
+
实施例7
5-羟基-6-((4-(4-((4-(吗啉甲基)苯基)乙炔基)苯基)-2-氧代吡咯烷-1-基)甲基)嘧啶-4(3H)-酮
第一步
(E)-3-(4-碘苯基)丙烯酸甲酯
零摄氏度条件的氩气气氛下,向叔丁醇钾(2.90g,25.86mmol)的四氢呋喃中(50mL)慢慢滴加2-(乙氧基(丙基)磷酰基)乙酸甲酯7a(5.43g,25.86mmol),反应30分钟,加入4-碘苯甲醛1a(5g,21.55mmol)的四氢呋喃溶液(10mL)。升至室温,搅拌3小时。反应结束后,加水(30mL)淬灭反应,乙酸乙酯(30mL×3)萃取,合并有机相,饱和食盐水洗涤,无水硫酸钠干燥,过滤,减压浓缩,得到(E)-3-(4-碘苯基)丙烯酸甲酯7b(6g),产率:96.65%,未经纯化,直接进行下一步反应。
MS m/z(ESI):288.6[M+1]
+
第二步
3-(4-碘苯基)-4-硝基丁酸甲酯
在零下10℃,向硝基甲烷(15mL)中加入1,8-二氮杂双环[5.4.0]十一碳-7-烯(1.59g,10.41mmol),加入(E)-3-(4-碘苯基)丙烯酸甲酯7b(3g,10.41mmol),搅拌1小时,慢慢升至室温,搅拌5小时。反应结束后,加水(10mL)淬灭反应,用稀盐酸溶液酸化体系,乙酸乙酯(30mL×3)萃取,合并有机相,饱和食盐水洗涤,无水硫酸钠干燥,过滤,减压浓缩,得到的残留物通过硅胶柱层析纯化(洗脱剂:A体系),得到3-(4-碘苯基)-4-硝基丁酸甲酯7c(3.1g),产率:85.27%。
1H NMR(400MHz,DMSO-d
6)δ7.62-7.72(m,2H),7.12-7.19(m,2H),4.96(dd,J=13.3,5.9Hz,1H),4.85(dd,J=13.3,9.5Hz,1H),3.77(ddd,J=9.1,6.0,3.0Hz,1H),3.52(s,3H),2.82(dd,J=16.3,6.3Hz,1H),2.71(dd,J=16.3,8.6Hz,1H).
第三步
4-(4-碘苯基)吡咯烷-2-酮
将3-(4-碘苯基)-4-硝基丁酸甲酯7c(500mg,1.43mmol)加入到甲醇(10mL),加入氯化镍(92.80mg,716.08μmol),反应5分钟后,加入硼氢化钠(108.36mg,2.86mmol),室温反应过夜。零摄氏度条件下加入饱和氯化铵水溶液,随后加入乙酸乙酯(30mL×2)萃取,分去水层,合并的有机相依次以饱和氯化钠溶液(30mL×2)洗涤,无水硫酸钠干燥,过滤,减压浓缩,得到的残留物通过硅胶柱层析纯化(洗脱剂:A体系),得到4-(4-碘苯基)吡咯烷-2-酮7d(200mg),产率:48.64%。
MS m/z(ESI):287.9[M+1]
+
第四步
1-((5,6-双(苄氧基)嘧啶-4-基)甲基)-4-(4-碘苯基)吡咯烷-2-酮
将4-(4-碘苯基)吡咯烷-2-酮7d(184mg,640.90μmol)和4,5-双(苄氧基)-6-(碘甲基)嘧啶2d(277.03mg,640.90μmol)加入到乙腈(5mL)中,再加入碳酸铯(835.27mg,2.56mmol),加热至100℃,反应4小时。反应液以乙酸乙酯(30mL×2)萃取,分去水层,合并的有机相依次以饱和氯化钠溶液(30mL×2)洗涤,无水硫酸钠干燥,过滤,减压浓缩,得到的残留物通过硅胶柱层析纯化(洗脱剂:B体系),得到1-((5,6-双(苄氧基)嘧啶-4-基)甲基)-4-(4-碘苯基)吡咯烷-2-酮7e(110mg),产率:29.02%。
MS m/z(ESI):591.8[M+1]
+
第五步
1-((5,6-双(苄氧基)嘧啶-4-基)甲基)-4-(4-((4-(吗啉甲基)苯基)乙炔基)苯基)吡咯烷-2-酮
室温下,向1-((5,6-双(苄氧基)嘧啶-4-基)甲基)-4-(4-碘苯基)吡咯烷-2-酮7e(100mg,169.08μmol)的水溶液中(2mL)加入双(三苯基膦)二氯化钯(4.75mg,6.76μmol)、四丁基溴化铵(54.51mg,169.08μmol)和哌啶(43.19mg,507.24μmol)。反应升温至70℃,搅拌5小时。反应液以乙酸乙酯(30mL×2)萃取,分去水层,合并的有机相依次以饱和氯化钠溶液(30mL×2)洗涤,无水硫酸钠干燥,过滤,减压浓缩,得到的残留物通过硅胶柱层析纯化(洗脱剂:B体系),得到1-((5,6-双(苄氧基)嘧啶-4-基)甲基)-4-(4-((4-(吗啉甲基)苯基)乙炔基)苯基)吡咯烷-2-酮7f(60mg),产率:53.38%。
MS m/z(ESI):665.0[M+1]
+
第六步
5-羟基-6-((4-(4-((4-(吗啉甲基)苯基)乙炔基)苯基)-2-氧代吡咯烷-1-基)甲基)嘧啶-4(3H)-酮
冰水浴条件下,将三氯化硼(1mL)滴加入1-((5,6-双(苄氧基)嘧啶-4-基)甲基)-4-(4-((4-(吗啉甲基)苯基)乙炔基)苯基)吡咯烷-2-酮7f(60mg,90.25μmol)的二氯甲烷中(2mL),室温反应2小时,反应完全后,加入甲醇淬灭(2mL),减压浓缩,制备液相分离(分离柱AKZONOBEL Kromasil;250×21.2mm I.D.;5μm,20mL/min;流动相A:0.05%TFA+H
2O,流动相B:CH
3CN),得到5-羟基-6-((4-(4-((4-(吗啉甲基)苯基)乙炔基)苯基)-2-氧代吡咯烷-1-基)甲基)嘧啶-4(3H)-酮7(13mg),产率:22.47%。
MS m/z(ESI):485.2[M+1]
+
1H NMR(400MHz,DMSO-d
6)δ10.22(s,1H),9.57(s,1H),7.77(s,1H),7.66(d,J=7.9Hz,2H),7.54(dd,J=14.6,8.0Hz,4H),7.39(d,J=8.0Hz,2H),4.37(q,J=9.0,8.6Hz,4H),3.96(s,2H),3.74(t,J=8.8Hz,2H),3.60-3.65(m,2H),3.29-3.33(m,1H),3.06-3.26(m,4H),2.75(dd,J=16.5,9.0Hz,1H),2.38(dd,J=16.5,8.1Hz,1H).
实施例8
5-羟基-6-((4-(4-((4-(吗啉甲基)苯基)乙炔基)苯基)-2-氧代咪唑啉-1-基)甲基)嘧啶-4(3H)-酮
第一步
3-((5,6-双(苄氧基)嘧啶-4-基)甲基)-5-(4-((4-(吗啉甲基)苯基)乙炔基)苯基)-2-氧代咪唑啉-1-甲酸叔丁酯
将3-((5,6-双(苄氧基)嘧啶-4-基)甲基)-5-(4-碘苯基)-2-氧代咪唑啉-1-甲酸叔丁酯4e(1g,1.44mmol)、4-(4-乙炔基苄基)吗啉1f(311.77mg,1.55mmol)、双(三苯基膦)二氯化钯(54.37mg,77.45μmol)、四丁基溴化铵(499.38mg,1.55mmol)和哌啶(395.71mg,4.65mmol)加到水(2mL)中,氩气置换三次,加热至85℃,反应4小时,反应液中加入20mL水,用乙酸乙酯(20mL×3)萃取,饱和氯化钠溶液(20mL)洗涤,有机相以无水硫酸钠干燥,过滤,减压浓缩,得到的残留物通过硅胶柱层析纯化(洗脱剂:A体系),得到3-((5,6-双(苄氧基)嘧啶-4-基)甲基)-5-(4-((4-(吗啉甲基)苯基)乙炔基)苯基)-2-氧代咪唑啉-1-甲酸叔丁酯8a(660mg),产率:55.63%。
MS m/z(ESI):766.4[M+1]
+
第二步
5-羟基-6-((4-(4-((4-(吗啉甲基)苯基)乙炔基)苯基)-2-氧代咪唑啉-1-基)甲基)嘧啶-4(3H)-酮
冰水浴条件下,将三氯化硼(0.5mL)和3-((5,6-双(苄氧基)嘧啶-4-基)甲基)-5-(4-((4-(吗啉甲基)苯基)乙炔基)苯基)-2-氧代咪唑啉-1-甲酸叔丁酯8a(60mg,78.34μmol)的二氯甲烷(1mL)溶液中,缓慢升至室温,反应过夜。反应完全后,加入甲醇淬灭(2mL),减压浓缩,制备液相分离(分离柱AKZONOBEL Kromasil;250×21.2mm I.D.;5μm,20mL/min;流动相A:0.05%TFA+H
2O,流动相B:CH
3CN),得到5-羟基-6-((4-(4-((4-(吗啉甲基)苯基)乙炔基)苯基)-2-氧代咪唑啉-1-基)甲基)嘧啶-4(3H)-酮8(11.54mg),产率:23.78%。
MS m/z(ESI):486.2[M+1]
+
1H NMR(400MHz,DMSO-d
6)δ10.64(s,1H),9.57(s,1H),7.83(s,1H),7.71(d,J=8.0Hz,2H),7.57-7.69(m,4H),7.49(d,J=8.1Hz,2H),7.14(s,1H),4.79(t,J=8.1Hz,1H),4.44(s,2H),4.25(d,J=9.6Hz,2H),3.86(s,2H),3.77(s,2H),3.23-3.44(m,3H),3.04-3.24(m,3H).
实施例9
5-羟基-6-((3-(2-氟乙基)-4-(4-((4-(吗啉甲基)苯基)乙炔基)苯基)-2-氧代咪唑啉-1-基)甲基)嘧啶-4(3H)-酮
第一步
1-((5,6-双(苄氧基)嘧啶-4-基)甲基)-4-(4-((4-(吗啉甲基)苯基)乙炔基)苯基)咪唑啉-2-酮
将盐酸(457.00mg,12.53mmol)加入3-((5,6-双(苄氧基)嘧啶-4-基)甲基)-5-(4-((4-(吗啉甲基)苯基)乙炔基)苯基)-2-氧代咪唑啉-1-甲酸叔丁酯8a(480mg,626.72μmol)的乙酸乙酯(4mL)溶液中,室温搅拌4小时,反应结束后,反应液减压浓缩,加入20mL饱和碳酸氢钠溶液,用乙酸乙酯(20mL×3)萃取,饱和氯化钠溶液(20mL)洗涤,有机相以无水硫酸钠干燥,过滤,减压浓缩,得到的残留物通过硅胶柱层析纯化(洗脱剂:B体系),得到1-((5,6-双(苄氧基)嘧啶-4-基)甲基)-4-(4-((4-(吗啉甲基)苯基)乙炔基)苯基)咪唑啉-2-酮9a(200mg),产率:47.93%。
MS m/z(ESI):666.3[M+1]
+
第二步
1-((5,6-双(苄氧基)嘧啶-4-基)甲基)-3-(2-氟乙基)-4-(4-(((4-(吗啉甲基)苯基)乙炔基)苯基)咪唑啉-2-酮
冰水浴条件下,向1-((5,6-双(苄氧基)嘧啶-4-基)甲基)-4-(4-((4-(吗啉甲基)苯基)乙炔基)苯基)咪唑啉-2-酮9a(80mg,120.16μmol)的N,N-二甲基甲酰胺(2mL)溶液中加入氢化钠(6.25mg,144.19μmol,60%purity),搅拌20分钟,再加入1-氟-2-碘乙烷(25.08mg,144.19 μmol),室温搅拌2小时,反应结束后,反应液中加入20mL冰水淬灭,用乙酸乙酯(20mL×3)萃取,饱和氯化钠溶液(20mL)洗涤,有机相以无水硫酸钠干燥,过滤,减压浓缩,得到1-((5,6-双(苄氧基)嘧啶-4-基)甲基)-3-(2-氟乙基)-4-(4-(((4-(吗啉甲基)苯基)乙炔基)苯基)咪唑啉-2-酮9b(85mg),产率:99.38%,未经纯化,直接进行下一步反应。
MS m/z(ESI):712.3[M+1]
+
第三步
5-羟基-6-((3-(2-氟乙基)-4-(4-((4-(吗啉甲基)苯基)乙炔基)苯基)-2-氧代咪唑啉-1-基)甲基)嘧啶-4(3H)-酮
冰水浴条件下,将三氯化硼(1mL)加入1-((5,6-双(苄氧基)嘧啶-4-基)甲基)-3-(2-氟乙基)-4-(4-(((4-(吗啉甲基)苯基)乙炔基)苯基)咪唑啉-2-酮9b(85mg,119.41μmol)的二氯甲烷(1mL)溶液,室温反应5小时,反应完全后,加入甲醇淬灭(2mL),减压浓缩,制备液相分离(分离柱AKZONOBEL Kromasil;250×21.2mm I.D.;5μm,20mL/min;流动相A:0.05%TFA+H
2O,流动相B:CH
3CN),得到5-羟基-6-((3-(2-氟乙基)-4-(4-((4-(吗啉甲基)苯基)乙炔基)苯基)-2-氧代咪唑啉-1-基)甲基)嘧啶-4(3H)-酮9(4.4mg),产率:5.51%。
MS m/z(ESI):532.2[M+1]
+
1H NMR(400MHz,DMSO-d
6)δ10.30(s,1H),9.51(s,1H),7.78(s,1H),7.66(d,J=7.9Hz,2H),7.52-7.63(m,4H),7.46(d,J=8.0Hz,2H),4.77(dd,J=9.1,7.0Hz,1H),4.21-4.50(m,6H),3.95(s,2H),3.77(t,J=9.0Hz,2H),3.67(s,2H),3.22(s,2H),3.13(dd,J=8.9,6.9Hz,3H),2.91(dddd,J=25.0,15.0,6.4,3.5Hz,1H).
实施例10
5-羟基-6-((3-甲基-4-(4-((4-(吗啉甲基)苯基)乙炔基)苯基)-2-氧代咪唑啉-1-基)甲基)嘧啶-4(3H)-酮
第一步
1-((5,6-双(苄氧基)嘧啶-4-基)甲基)-3-甲基-4-(4-((4-(吗啉甲基)苯基)乙炔基)苯基)咪唑啉-2-酮
冰水浴条件下,向1-((5,6-双(苄氧基)嘧啶-4-基)甲基)-4-(4-((4-(吗啉甲基)苯基)乙炔基) 苯基)咪唑啉-2-酮9a(80mg,120.16μmol)的N,N-二甲基甲酰胺(2mL)溶液中,加入氢化钠(6.25mg,144.19μmol,60%purity),搅拌20分钟,再加入碘甲烷(20.47mg,144.19μmol),室温搅拌2小时,反应结束后,反应液中加入20mL冰水淬灭,用乙酸乙酯(20mL×3)萃取,饱和氯化钠溶液(20mL)洗涤,有机相以无水硫酸钠干燥,过滤,减压浓缩,得到1-((5,6-双(苄氧基)嘧啶-4-基)甲基)-3-甲基-4-(4-((4-(吗啉甲基)苯基)乙炔基)苯基)咪唑啉-2-酮10a(81mg),产率:99.16%,未经纯化,直接进行下一步反应。
MS m/z(ESI):680.3[M+1]
+
第二步
5-羟基-6-((3-甲基-4-(4-((4-(吗啉甲基)苯基)乙炔基)苯基)-2-氧代咪唑啉-1-基)甲基)嘧啶-4(3H)-酮
冰水浴条件下,将三氯化硼(1mL)加入1-((5,6-双(苄氧基)嘧啶-4-基)甲基)-3-甲基-4-(4-((4-(吗啉甲基)苯基)乙炔基)苯基)咪唑啉-2-酮10a(81mg,119.15μmol)的二氯甲烷(1mL)溶液中,室温反应过夜。反应完全后,加入甲醇淬灭(2mL),减压浓缩,制备液相分离(分离柱AKZONOBEL Kromasil;250×21.2mm I.D.;5μm,20mL/min;流动相A:0.05%TFA+H
2O,流动相B:CH
3CN),得到5-羟基-6-((3-甲基-4-(4-((4-(吗啉甲基)苯基)乙炔基)苯基)-2-氧代咪唑啉-1-基)甲基)嘧啶-4(3H)-酮10(4.38mg),产率:5.87%。
MS m/z(ESI):500.2[M+1]
+
1H NMR(400MHz,DMSO-d
6)δ10.52(s,1H),9.51(s,1H),7.79(s,1H),7.66(d,J=8.0Hz,2H),7.60(p,J=4.9,4.4Hz,4H),7.44(d,J=8.0Hz,2H),4.53(t,J=8.4Hz,1H),4.39(s,2H),4.25(s,2H),3.83-4.15(m,4H),3.72(s,1H),3.70(s,3H),3.20(d,J=23.5Hz,4H),3.06(t,J=8.3Hz,1H).
实施例11
5-羟基-6-((3-异丙基-4-(4-((4-(吗啉甲基)苯基)乙炔基)苯基)-2-氧代咪唑啉-1-基)甲基)嘧啶-4(3H)-酮
第一步
1-((5,6-双(苄氧基)嘧啶-4-基)甲基)-3-异丙基-4-(4-((4-(吗啉甲基)苯基)乙炔基)苯基)咪唑啉-2-酮
冰水浴条件下,向1-((5,6-双(苄氧基)嘧啶-4-基)甲基)-4-(4-((4-(吗啉甲基)苯基)乙炔基)苯基)咪唑啉-2-酮9a(70mg,105.14μmol)的N,N-二甲基甲酰胺(2mL)溶液中加入氢化钠(5.47mg,126.17μmol,60%purity),冰浴下搅拌20分钟,再加入2-碘丙烷(19.66mg,115.65μmol),室温搅拌2小时,反应结束后,向反应液中加入20mL冰水淬灭,用乙酸乙酯(20mL×3)萃取,饱和氯化钠溶液(20mL)洗涤,有机相以无水硫酸钠干燥,过滤,减压浓缩,得到1-((5,6-双(苄氧基)嘧啶-4-基)甲基)-3-异丙基-4-(4-((4-(吗啉甲基)苯基)乙炔基)苯基)咪唑啉-2-酮11a(74mg),产率:99.43%,未经纯化,直接进行下一步反应。
MS m/z(ESI):708.3[M+1]
+
第二步
5-羟基-6-((3-异丙基-4-(4-((4-(吗啉甲基)苯基)乙炔基)苯基)-2-氧代咪唑啉-1-基)甲基)嘧啶-4(3H)-酮
冰水浴条件下,将三氯化硼(1.5mL)加入1-((5,6-双(苄氧基)嘧啶-4-基)甲基)-3-异丙基-4-(4-((4-(吗啉甲基)苯基)乙炔基)苯基)咪唑啉-2-酮11a(74mg,104.54μmol)的二氯甲烷(1mL)溶液中,室温反应过夜,反应完全后,加入甲醇淬灭(2mL),减压浓缩,制备液相分离(分离柱AKZONOBEL Kromasil;250×21.2mm I.D.;5μm,20mL/min;流动相A:0.05%TFA+H
2O,流动相B:CH
3CN),得到5-羟基-6-((3-异丙基-4-(4-((4-(吗啉甲基)苯基)乙炔基)苯基)-2-氧代咪唑啉-1-基)甲基)嘧啶-4(3H)-酮11(1.36mg),产率:1.95%。
MS m/z(ESI):528.2[M+1]
+
1H NMR(400MHz,Methanol-d
4)δ7.79(s,1H),7.65(d,J=8.0Hz,2H),7.52-7.59(m,4H),7.49(d,J=8.3Hz,2H),4.93-4.94(m,1H),4.79(q,J=2.3Hz,1H),4.35-4.43(m,3H),4.05(s,2H),3.77-3.89(m,2H),3.75(d,J=14.2Hz,2H),3.36(d,J=9.6Hz,2H),3.24(dd,J=15.7,6.0Hz,2H),3.17-3.21(m,1H),1.23(d,J=6.8Hz,3H),0.89(d,J=6.8Hz,3H).
实施例12
5-羟基-6-((3-(2-羟乙基)-4-(4-((4-(吗啉甲基)苯基)乙炔基)苯基)-2-氧代咪唑啉-1-基)甲基)嘧啶-4(3H)-酮
第一步
1-((5-(苄氧基)-6-羟基嘧啶-4-基)甲基)-3-(2-羟基乙基)-4-(4-((4-(吗啉甲基)苯基)乙炔基)苯基)咪唑啉-2-酮
将碳酸铯(101.0mg,310.0μmol)和1-((5,6-双(苄氧基)嘧啶-4-基)甲基)-4-(4-((4-(吗啉甲基)苯基)乙炔基)苯基)咪唑啉-2-酮9a(70mg,105.14μmol)加到N,N-二甲基甲酰胺(2mL)中,再加入2-碘乙醇(19.89mg,115.65μmol),加热至120℃,反应3小时,反应结束后,用乙酸乙酯(20mL×3)萃取,分别用水(20mL)和饱和氯化钠溶液(20mL)洗涤,有机相以无水硫酸钠干燥,过滤,减压浓缩,得到1-((5-(苄氧基)-6-羟基嘧啶-4-基)甲基)-3-(2-羟基乙基)-4-(4-((4-(吗啉甲基)苯基)乙炔基)苯基)咪唑啉-2-酮12a(65mg),产率:99.76%,未经纯化,直接进行下一步反应。
MS m/z(ESI):620.3[M+1]
+
第二步
5-羟基-6-((3-(2-羟乙基)-4-(4-((4-(吗啉甲基)苯基)乙炔基)苯基)-2-氧代咪唑啉-1-基)甲基)嘧啶-4(3H)-酮
冰水浴条件下,将三氯化硼(1.5mL)加入1-((5-(苄氧基)-6-羟基嘧啶-4-基)甲基)-3-(2-羟基乙基)-4-(4-((4-(吗啉甲基)苯基)乙炔基)苯基)咪唑啉-2-酮12a(20mg,32.27μmol)的二氯甲烷(1mL)中,室温反应5小时,反应完全后,加入甲醇淬灭(2mL),减压浓缩,制备液相分离(分离柱AKZONOBEL Kromasil;250×21.2mm I.D.;5μm,20mL/min;流动相A:0.05%TFA+H
2O,流动相B:CH
3CN),得到5-羟基-6-((3-(2-羟乙基)-4-(4-((4-(吗啉甲基)苯基)乙炔基)苯基)-2-氧代咪唑啉-1-基)甲基)嘧啶-4(3H)-酮12(9.53mg),产率:43.49%。
MS m/z(ESI):530.2[M+1]
+
1H NMR(400MHz,Methanol-d
4)δ7.76(s,1H),7.65(d,J=7.9Hz,2H),7.54(dd,J=8.2,3.7Hz,4H),7.41-7.47(m,2H),4.95-4.92(m,2H),4.39(d,J=2.4Hz,4H),3.99-4.15(m,3H),3.92(t,J=9.1Hz,2H),3.66-3.82(m,3H),3.37(s,2H),3.20-3.29(m,3H).
实施例13和实施例14
(R)-5-hydroxy-6-((3-isopropyl-4-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-2-oxoimidazolidin-1-yl)methyl)pyrimidin-4(3H)-one 13
(R)-5-羟基-6-((3-异丙基-4-(4-((4-(吗啉甲基)苯基)乙炔基)苯基)-2-氧代咪唑啉-1-基)甲基)嘧啶-4(3H)-酮13
(S)-5-hydroxy-6-((3-isopropyl-4-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-2-oxoimidaz olidin-1-yl)methyl)pyrimidin-4(3H)-one 14
(S)-5-羟基-6-((3-异丙基-4-(4-((4-(吗啉甲基)苯基)乙炔基)苯基)-2-氧代咪唑啉-1-基)甲基)嘧啶-4(3H)-酮14
第一步
将5-羟基-6-((3-异丙基-4-(4-((4-(吗啉甲基)苯基)乙炔基)苯基)-2-氧代咪唑啉-1-基)甲基)嘧啶-4(3H)-酮11(412mg)通过制备型超临界流体色谱仪(型号:MGⅡpreparative SFC(SFC-14),色谱柱:ChiralCel OX(250×30mm I.D.,10μm),流动相:A相为CO
2,B相为Ethanol(0.1%NH
3H
2O),梯度:B相40%,流速:80mL/min,背压:100bar,柱温:38℃)进行分离纯化,分离的馏分通过旋转蒸发器在浴温40℃下除去溶剂,得到(R)-5-羟基-6-((3-异丙基-4-(4-((4-(吗啉甲基)苯基)乙炔基)苯基)-2-氧代咪唑啉-1-基)甲基)嘧啶-4(3H)-酮13(114mg,215μmol,27.6%yield)和(S)-5-羟基-6-((3-异丙基-4-(4-((4-(吗啉甲基)苯基)乙炔基)苯基)-2-氧代咪唑啉-1-基)甲基)嘧啶-4(3H)-酮14(122mg,28.6%yield)。
13MS m/z(ESI):528.0[M+1]
+
1H NMR(400MHz,DMSO-d
6)δ7.78(s,1H),7.64–7.41(m,6H),7.36(d,J=8.0Hz,2H),4.70(dd,J=9.2,7.2Hz,1H),4.26(d,J=15.6Hz,1H),4.19(d,J=15.2Hz,1H),3.74–3.66(m,2H),3.59–3.57(m,4H),3.49(s,2H),3.04(t,J=8.0Hz,1H),2.35(t,J=4.7Hz,4H),1.13(d,J=6.8Hz,3H),0.77(d,J=7.2Hz,3H).
14MS m/z(ESI):528.0[M+1]
+
实施例15
5-hydroxy-6-((3-isopropyl-2-oxo-4-(4-((4-(((tetrahydrofuran-3-yl)amino)methyl)phenyl)ethynyl)phenyl)imidazolidin-1-yl)methyl)pyrimidin-4(3H)-one
5-羟基-6-((3-异丙基-2-氧代-4-(4-((4-(((四氢呋喃-3-基)氨基)甲基)苯基)乙炔基)苯基)咪唑啉-1-基)甲基)嘧啶基-4(3H)-酮
第一步
1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-isopropyl-4-(4-((4-(((tetrahydrofuran-3-yl)amino)methyl)phenyl)ethynyl)phenyl)imidazolidin-2-one
1-((5,6-二(苄氧基)嘧啶-4-基)甲基)-3-异丙基-4-(4-((4-(((四氢呋喃-3-基)氨基)甲基)苯基)乙炔基)苯基)咪唑啉-2-酮
将4-((4-(1-((5,6-二(苄氧基)嘧啶-4-基)甲基)-3-异丙基-2-氧代咪唑啉-4-基)苯基)乙炔基)苯甲醛4e(50mg,78.53μmol),四氢呋喃-3-胺15b(13.68mg,157.05μmol)溶于1,2-二氯乙烷(5mL),再加入乙酸(0.2mL),搅拌30分钟,加入醋酸硼氢化钠(49.93mg,235.58μmol),室温下持续搅拌12小时。加入饱和碳酸氢钠水溶液15mL淬灭,再加入二氯甲烷(30mL)和水(15mL),分液,水相用二氯甲烷萃取(30mL×2),合并的有机相以饱和氯化钠溶液(30mL×2)洗涤,无水硫酸钠干燥,过滤,减压浓缩至干,残留物经制备液相色谱纯化得到1-((5,6-二(苄氧基)嘧啶-4-基)甲基)-3-异丙基-4-(4-((4-(((四氢呋喃-3-基)氨基)甲基)苯基)乙炔基)苯基)咪唑啉-2-酮15c(40mg,71.96%yield)。
MS m/z(ESI):708.0[M+1]
+
第二步
5-hydroxy-6-((3-isopropyl-2-oxo-4-(4-((4-(((tetrahydrofuran-3-yl)amino)methyl)phenyl)ethynyl)phenyl)imidazolidin-1-yl)methyl)pyrimidin-4(3H)-one
5-羟基-6-((3-异丙基-2-氧代-4-(4-((4-(((四氢呋喃-3-基)氨基)甲基)苯基)乙炔基)苯基)咪唑啉-1-基)甲基)嘧啶基-4(3H)-酮
冰浴条件下,将三氯化硼(0.4mL)滴加入1-((5,6-二(苄氧基)嘧啶-4-基)甲基)-3-异丙 基-4-(4-((4-(((四氢呋喃-3-基)氨基)甲基)苯基)乙炔基)苯基)咪唑啉-2-酮15c(40mg,56.51μmol)的二氯甲烷(1mL)溶液,室温反应2小时,甲醇淬灭反应。制备液相色谱纯化,得到5-羟基-6-((3-异丙基-2-氧代-4-(4-((4-(((四氢呋喃-3-基)氨基)甲基)苯基)乙炔基)苯基)咪唑啉-1-基)甲基)嘧啶基-4(3H)-酮15(6mg,15.14%yield,91.5%purity)。
MS m/z(ESI):528.0[M+1]
+
实施例16
5-hydroxy-6-((3-isopropyl-4-(4-((4-((3-methoxyazetidin-1-yl)methyl)phenyl)ethynyl)phenyl)-2-oxoimidazolidin-1-yl)methyl)pyrimidin-4(3H)-one
5-羟基-6-((3-异丙基-4-(4-((4-((3-甲氧基吖丁啶-1-基)甲基)苯基)乙炔基)苯基)-2-氧代咪唑啉-1-基)甲基)嘧啶基4(3H)-酮
第一步
3-methoxy-1-(4-((trimethylsilyl)ethynyl)benzyl)azetidine
3-甲氧基-1-(4-((三甲基硅基)乙炔基)苄基)吖丁啶
4-(2-三甲基硅基乙炔基)苯甲醛16a(400mg,1.98mmol)溶于1,2-二氯乙烷(10mL)溶液后,加入3-甲氧基吖丁啶盐酸盐16b(488.65mg,3.95mmol,和醋酸(1.2mL),室温反应30分钟后,加入0℃下加入三乙酰氧基硼氢化钠(1.26g,5.93mmol),室温反应2小时。反应液加入50mL饱和碳酸氢钠溶液,二氯甲烷(100ml)萃取,有机相用无水硫酸钠干燥,减压浓缩,残留物通过硅胶柱层析进一步分离纯化(洗脱剂:体系A),得到3-甲氧基-1-(4-((三甲基硅基)乙炔基)苄基)吖丁啶16c(400mg,73.99%yield)。
MS m/z(ESI):274.0[M+1]
+
第二步
1-(4-ethynylbenzyl)-3-methoxyazetidine
1-(4-乙炔基苄基)-3-甲氧基吖丁啶
将3-甲氧基-1-(4-((三甲基硅基)乙炔基)苄基)吖丁啶16c(400mg,1.46mmol)加入到甲醇(10mL)中,加入氟化钾(339.96mg,5.85mmol),室温反应4小时。反应完成,减压浓缩,得到的残留物用硅胶柱层析法(洗脱剂:体系A)纯化,得到1-(4-乙炔基苄基)-3-3-甲氧基吖丁啶16d(280mg,95.10%yield)。
MS m/z(ESI):202.0[M+1]
+
第三步
1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-isopropyl-4-(4-((4-((3-methoxyazetidin-1-yl)methyl)phenyl)ethynyl)phenyl)imidazolidin-2-one
1-((5,6-二(苄氧基)嘧啶基-4-基)甲基)-3-异丙基-4-(4-((4-((3-甲氧基吖丁啶基-1-基)甲基)苯基)乙炔基)苯基)咪唑啉-2-酮
室温下,向1-((5,6-二(苄氧基)嘧啶基-4-基)甲基)-4-(4-碘苯基)-3-异丙基咪唑啉-2-酮16e(55mg,86.68μmol)和1-(4-乙炔基苄基)-3-3-甲氧基吖丁啶16d(34.9mg,173μmol)的水(1mL)溶液中,依次加入双(三苯基膦)氯化钯(2.43mg,3.47μmol)、四丁基溴化铵(27.94mg,86.68μmol)和哌啶(22.14mg,260.04μmol),升温至70℃搅拌5小时。反应液以乙酸乙酯(30mlx2)萃取,分去水层,合并的有机相依次以饱和氯化钠溶液(30mL×2)洗涤,无水硫酸钠干燥,过滤,减压浓缩,得到的残留物用硅胶柱层析法(洗脱剂:体系B)纯化,得到1-((5,6-二(苄氧基)嘧啶基-4-基)甲基)-3-异丙基-4-(4-((4-((3-甲氧基吖丁啶基-1-基)甲基)苯基)乙炔基)苯基)咪唑啉-2-酮16f(29mg,47.26%yield)。
MS m/z(ESI):708.4[M+1]
+
第四步
5-hydroxy-6-((3-isopropyl-4-(4-((4-((3-methoxyazetidin-1-yl)methyl)phenyl)ethynyl)phenyl)-2-oxoimidazolidin-1-yl)methyl)pyrimidin-4(3H)-one
5-羟基-6-((3-异丙基-4-(4-((4-((3-甲氧基吖丁啶-1-基)甲基)苯基)乙炔基)苯基)-2-氧代咪唑啉-1-基)甲基)嘧啶基4(3H)-酮
冰浴条件下,将三氯化硼(0.8mL)滴加入1-((5,6-二(苄氧基)嘧啶基-4-基)甲基)-3-异丙基-4-(4-((4-((3-甲氧基吖丁啶基-1-基)甲基)苯基)乙炔基)苯基)咪唑啉-2-酮16f(29mg,40.97μmol)的二氯甲烷(2mL)溶液,室温反应2小时,甲醇淬灭,制备液相色谱分离纯化,得到5-羟基-6-((3-异丙基-4-(4-((4-((3-甲氧基吖丁啶-1-基)甲基)苯基)乙炔基)苯基)-2-氧代咪唑啉-1-基)甲基)嘧啶基4(3H)-酮16(2mg,7.55%yield,99.26%purity)。
MS m/z(ESI):528.3[M+1]
+
实施例17
5-hydroxy-6-((3-isopropyl-4-(4-((4-(morpholine-4-carbonyl)phenyl)ethynyl)phenyl)-2-oxoimidazolidin-1-yl)methyl)pyrimidin-4(3H)-one
5-羟基-6-((3-异丙基-4-(4-((4-(***啉-4-羰基)苯基)乙炔基)苯基)-2-氧代咪唑啉-1-基)甲基)嘧啶基4(3H)-酮
第一步
(4-ethynylphenyl)(morpholino)methanone
(4-乙炔基苯基)(吗啉基)甲酮
将4-乙炔基苯甲酸17a(1g,6.84mmol)和吗啉17b(3.58g,41.06mmol)加入到5mL二氯甲烷中,加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(2.10g,10.95mmol),室温反应过夜。反应完全后,反应液以二氯甲烷(30ml×2)萃取,分去水层,合并的有机相依次以饱和氯化钠溶液(30mL×2)洗涤,无水硫酸钠干燥,过滤,减压浓缩,得到的残留物用硅胶柱层析法(洗脱剂:体系A)纯化,得到(4-乙炔基苯基)(吗啉基)甲酮17c(600mg,40.74%yield)。
MS m/z(ESI):216.2[M+1]
+
第二步
1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-isopropyl-4-(4-((4-(morpholine-4-carbonyl)phenyl)ethynyl)phenyl)imidazolidin-2-one
1-((5,6-二(苄氧基)嘧啶基-4-基)甲基)-3-异丙基-4-(4-((4-(吗啉-4-羰基)苯基)乙炔基)苯基)咪唑啉-2-酮
室温下,向1-((5,6-二(苄氧基)嘧啶-4-基)甲基)-4-(4-碘苯基)-3-异丙基咪唑啉-2-酮17d和(4-乙炔基苯基)(吗啉基)甲酮17c(67.85mg,315.21μmol)的1.5mL水溶液中加入双(三苯基膦)氯化钯(4.42mg,6.30μmol)、四丁基溴化铵(50.81mg,157.60μmol)和哌啶(40.26mg,472.81μmol),反应升温至70℃搅拌5小时。反应完全后,反应液用乙酸乙酯(30mlx2)萃取,分去水层,合并的有机相依次以饱和氯化钠溶液(30mL×2)洗涤,无水硫酸钠干燥,过滤,减压浓缩,得到的残留物用硅胶柱层析法(洗脱剂:体系B)纯化,得到1-((5,6-二(苄氧基)嘧啶基-4-基)甲基)-3-异丙基-4-(4-((4-(吗啉-4-羰基)苯基)乙炔基)苯基)咪唑啉-2-酮17e(100mg,87.90%yield)。
MS m/z(ESI):722.0[M+1]
+
第三步
5-hydroxy-6-((3-isopropyl-4-(4-((4-(morpholine-4-carbonyl)phenyl)ethynyl)phenyl)-2-oxoimidazolidin-1-yl)methyl)pyrimidin-4(3H)-one
5-羟基-6-((3-异丙基-4-(4-((4-(吗啉-4-羰基)苯基)乙炔基)苯基)-2-氧代咪唑啉-1-基)甲基)嘧啶基4(3H)-酮
1-((5,6-二(苄氧基)嘧啶基-4-基)甲基)-3-异丙基-4-(4-((4-(吗啉-4-羰基)苯基)乙炔基)苯基)咪唑啉-2-酮17e(99.86mg,138.35μmol)加入到二氯甲烷(5mL)中,加入三氯化硼(2mL),室温反应1小时。反应完全,减压浓缩,制备液相分离纯化,得到5-羟基-6-((3-异丙基-4-(4-((4-(吗啉-4-羰基)苯基)乙炔基)苯基)-2-氧代咪唑啉-1-基)甲基)嘧啶基4(3H)-酮17(23mg,24.57%yield,96.88%purity)。
MS m/z(ESI):542.3[M+1]
+
实施例20
5-hydroxy-6-((4-methyl-4-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-2-oxopyrrolidin-1-yl)methyl)pyrimidin-4(3H)-one
5-羟基-6-((4-甲基-4-(4-((4-(吗啉甲基)苯基)乙炔基)苯基)-2-氧代吡咯烷-1-基)甲基)嘧啶基-4(3H)-酮
第一步
methyl(E)-3-(4-iodophenyl)but-2-enoate
(E)-3-(4-碘代苯基)丁-2-烯酸甲酯
在0℃下,向氢化钠(1.32g,30.48mmol,60%purity)的四氢呋喃(60mL)溶液中缓慢滴加2-(乙氧基磷酰基)乙酸甲酯20b(6.11g,33.53mmol),升至室温,滴加1-(4-碘代苯基)乙酮20a(5g,20.32mmol)的四氢呋喃(20mL)溶液,室温反应16小时,LC-MS检测反应完全。将反应液中加60mL水淬灭反应,乙酸乙酯(30mL×3)萃取,合并的有机相依次用饱和食盐水洗涤,无水硫酸钠干燥,减压下浓缩,得到的残留物用硅胶柱层析法(洗脱剂:体系A)纯化,得到(E)-3-(4-碘代苯基)丁-2-烯酸甲酯20c(2.8g,9.27mmol,45.61%yield)。
MS m/z(ESI):303.0[M+1]
+
第二步
methyl 3-(4-iodophenyl)-3-methyl-4-nitrobutanoate
3-(4-碘代苯基)-3-甲基-4-硝基丁酸甲酯
向(E)-3-(4-碘代苯基)丁-2-烯酸甲酯20c(1.7g,5.63mmol)的硝基甲烷(20mL)中,滴加四丁基氟化铵(1M,5.63mL),在100℃反应过夜,LC-MS检测反应完全。将反应液在减压下浓缩,加入12mL乙酸乙酯,用1M盐酸溶液酸化体系。用乙酸乙酯萃取(30mL×3),合并的有机相依次用饱和食盐水洗涤,无水硫酸钠干燥,过滤,得到的残留物通过硅胶柱层析进一步分离纯化(洗脱剂:体系A),得到3-(4-碘代苯基)-3-甲基-4-硝基丁酸甲酯20d(800mg,2.20mmol,39.15%yield)。
MS m/z(ESI):361.8[M-1]
+
第三步
4-(4-iodophenyl)-4-methylpyrrolidin-2-one
4-(4-碘代苯基)-4-甲基吡咯烷-2-酮
将3-(4-碘代苯基)-3-甲基-4-硝基丁酸甲酯20d(100mg,275.37μmol)加入到1mL甲醇中,加入氯化镍(II)六水合物(17.84mg,137.69μmol),反应5分钟后,0℃下加入硼氢化钠(20.83mg,550.74μmol),室温反应过夜。0℃条件下加入饱和氯化铵溶液,随后加入二氯甲烷(30mlx2)萃取,分去水层,合并的有机相依次通过饱和氯化钠溶液(30mL×2)洗涤,无水硫酸钠干燥,过滤,减压浓缩,得到的残留物用硅胶柱层析法(洗脱剂:体系A)纯化,得到4-(4-碘代苯基)-4-甲基吡咯烷-2-酮20e(40mg,132.84μmol,48.24%yield)。
MS m/z(ESI):301.8[M+1]
+
第四步
1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-(4-iodophenyl)-4-methylpyrrolidin-2-one
1-((5,6-双(苄氧基)嘧啶-4-基)甲基)-4-(4-碘代苯基)-4-甲基吡咯烷-2-酮
将4-(4-碘代苯基)-4-甲基吡咯烷-2-酮20e(137mg,454.96μmol)加入到5mL乙腈中,依次加入4,5-二苄氧基-6-(碘甲基)嘧啶20f(196.66mg,454.96μmol)和碳酸铯(370.59mg,1.14mmol),将反应液升至90℃反应4小时。反应液以乙酸乙酯萃取(30ml×2),分去水层,合并的有机相依次通过饱和氯化钠溶液洗涤(30mL×2),无水硫酸钠干燥,过滤,减压浓缩,得到的残留物用硅胶柱层析法(洗脱剂:体系A和体系B)纯化,得到1-((5,6-双(苄氧基)嘧啶-4-基)甲基)-4-(4-碘代苯基)-4-甲基吡咯烷-2-酮20g(130mg,214.71μmol,47.19%yield)。
MS m/z(ESI):606.1[M+1]
+
第五步
1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-methyl-4-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)pyrrolidin-2-one
1-((5,6-双(苄氧基)嘧啶-4-基)甲基)-4-甲基-4-(4-((4-(吗啉甲基)苯基)乙炔基)苯基)吡咯烷-2-酮
室温下,向1-((5,6-双(苄氧基)嘧啶-4-基)甲基)-4-(4-碘代苯基)-4-甲基吡咯烷-2-酮20g(80mg,132.13μmol)和4-(4-乙炔基苄基)吗啉20h(26.6mg,132μmol)的1mL水溶液中,依次加入双三苯基膦二氯化钯(3.71mg,5.29μmol)四丁基溴化铵(42.59mg,132.13μmol)、哌啶(33.75mg,396.39μmol)。反应升温至70℃搅拌5小时。反应液以乙酸乙酯萃取(30ml×2),分去水层,合并的有机相依次以饱和氯化钠溶液洗涤(30mL×2),无水硫酸钠干燥,过滤,减压浓缩,得到的残留物用硅胶柱层析法(洗脱剂:体系B)纯化,得到1-((5,6-双(苄氧基)嘧啶-4-基)甲基)-4-甲基-4-(4-((4-(吗啉甲基)苯基)乙炔基)苯基)吡咯烷-2-酮20j(50mg,73.66μmol,55.75%yield)。
MS m/z(ESI):679.0[M+1]
+
第六步
5-hydroxy-6-((4-methyl-4-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-2-oxopyrrolidin-1-yl)methyl)pyrimidin-4(3H)-one
5-羟基-6-((4-甲基-4-(4-((4-(吗啉甲基)苯基)乙炔基)苯基)-2-氧代吡咯烷-1-基)甲基)嘧啶基-4(3H)-酮
冰浴条件下,将三氯化硼(0.8mL)滴加入1-((5,6-双(苄氧基)嘧啶-4-基)甲基)-4-甲基-4-(4-((4-(吗啉甲基)苯基)乙炔基)苯基)吡咯烷-2-酮20j(50mg,73.66μmol)的2mL二氯甲烷溶液,室温反应2小时,甲醇淬灭,减压浓缩,残留物通过制备液相分离纯化,得到5-羟基-6-((4-甲基-4-(4-((4-(吗啉甲基)苯基)乙炔基)苯基)-2-氧代吡咯烷-1-基)甲基)嘧啶基-4(3H)-酮20(10mg,15.12μmol,20.52%yield,92.6%)
MS m/z(ESI):499.2[M+1]
+
实施例21
6-((4-(4-((4-(((1,1-dioxidotetrahydrothiophen-3-yl)amino)methyl)phenyl)ethynyl)phenyl)-3-isopropyl-2-oxoimidazolidin-1-yl)methyl)-5-hydroxypyrimidin-4(3H)-one
6-((4-(4-((4-(((1,1-二氧化四氢噻吩-3-基)氨基)甲基)苯基)乙炔基)苯基)-3-异丙基-2-氧代咪唑啉-1-基)甲基)-5-羟基嘧啶基-4(3H)-酮
第一步
tert-butyl
3-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-5-(4-iodophenyl)-2-oxoimidazolidine-1-carboxylate
3-((5,6-双(苄氧基)嘧啶-4-基)甲基)-5-(4-碘苯基)-2-氧代咪唑啉-1-羧酸叔丁酯
将5-(4-碘苯基)-2-氧代咪唑啉-1-羧酸叔丁酯21a(4.2g,10.82mmol)、4,5-二苄氧基-6-(碘甲基)嘧啶21b(4.68g,10.82mmol)、碳酸钾(4.49g,32.46mmol)加入70mL乙腈中,反应液加热至98℃回流过夜,监测反应完全。反应液中加入水(20mL),乙酸乙酯萃取(30mL×3),合并的有机相依次以饱和氯化钠溶液洗涤(20mL),无水硫酸钠干燥,过滤,减压浓缩,得到的残留物用硅胶柱层析法(洗脱剂:体系A)纯化,得到3-((5,6-双(苄氧基)嘧啶-4-基)甲基)-5-(4-碘苯基)-2-氧代咪唑啉-1-羧酸叔丁酯21c(3g,4.33mmol,40.04%yield)。
MS m/z(ESI):592.8[M-100+H]
第二步
1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-(4-iodophenyl)imidazolidin-2-one
1-((5,6-双(苄氧基)嘧啶-4-基)甲基)-4-(4-碘代苯基)咪唑啉-2-酮
冰浴下,将1,4-二氧六环的盐酸溶液(4M,10.83mL)滴入3-((5,6-双(苄氧基)嘧啶-4-基)甲基)-5-(4-碘苯基)-2-氧代咪唑啉-1-羧酸叔丁酯21c(1.5g,2.17mmol)的1,4-二氧六环(20mL)溶液,撤去冰浴,室温反应1小时,监测反应完全。反应液在减压下浓缩,残留物中加入30mL饱和碳酸氢钠溶液,乙酸乙酯萃取(30mL×3),合并的有机相依次以饱和氯化钠溶液洗涤(20mL),无水硫酸钠干燥,过滤,减压浓缩,得到的残留物用硅胶柱层析法(洗脱剂:洗脱剂:体系B)纯化,得到1-((5,6-双(苄氧基)嘧啶-4-基)甲基)-4-(4-碘代苯基)咪唑啉-2-酮21d(1g,1.69mmol,77.93%yield)。
MS m/z(ESI):592.8[M+1]
+
第三步
1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-(4-iodophenyl)-3-isopropylimidazolidin-2-one
1-((5,6-双(苄氧基)嘧啶-4-基)甲基)-4-(4-碘代苯基)-3-异丙基咪唑啉-2-酮
氩气氛下,冰浴下,1-((5,6-双(苄氧基)嘧啶-4-基)甲基)-4-(4-碘代苯基)咪唑啉-2-酮21d(1g,1.69mmol)的N,N-二甲基甲酰胺(30mL)溶液中加入氢化钠(146.35mg,3.38mmol,60%purity),冰浴下搅拌20分钟后,加入2-碘丙烷(573.88mg,3.38mmol,336.98μL),室温搅拌2小时,监测反应完全。反应液中加入20mL冰水淬灭,乙酸乙酯萃取(20mL×3),合并的有机相依次以饱和氯化钠溶液洗涤(20mL),无水硫酸钠干燥,过滤,减压浓缩,得到的残留物用硅胶柱层析法(洗脱剂:体系A)纯化,得到1-((5,6-双(苄氧基)嘧啶-4-基)甲基)-4-(4-碘代苯基)-3-异丙基咪唑啉-2-酮21e(450mg,709.21μmol,42.02%yield)。
MS m/z(ESI):634.8[M+1]
第四步
3-((4-((trimethylsilyl)ethynyl)benzyl)amino)tetrahydrothiophene 1,1-dioxide
3-((4-((三甲基硅基)乙炔基)苯基)氨基)四氢噻吩1,1-二氧化物
4-(2-三甲基硅基乙炔基)苯甲醛21f(400mg,1.98mmol)溶于1,2-二氯乙烷(20L)后加入1,1-二氧代四氢噻吩-3-胺盐酸盐21g(678.70mg,3.95mmol)和醋酸(1.25mL),室温反应30分钟后,0℃下加入三乙酰氧基硼氢化钠(1.26g,5.93mmol),室温反应2小时。反应液加入50mL饱和碳酸氢钠溶液,二氯甲烷萃取(100ml),合并的有机相无水硫酸钠干燥,过滤,减压浓缩,得到的残留物通过硅胶柱层析进一步分离纯化(洗脱剂:体系B),得到3-((4-((三甲基硅基)乙炔基)苯基)氨基)四氢噻吩1,1-二氧化物21h(290mg,902.00μmol,45.62%yield)。
MS m/z(ESI):321.9[M+1]
+
第五步
3-((4-ethynylbenzyl)amino)tetrahydrothiophene 1,1-dioxide
3-((4-乙炔基苄基)氨基)四氢噻吩1,1-二氧化物
3-((4-((三甲基硅基)乙炔基)苯基)氨基)四氢噻吩1,1-二氧化物21h(280mg,870.89μmol)的30mL甲醇溶液中加入氟化钾(202.40mg,3.48mmol),室温反应4小时。反应液以乙酸乙酯萃取(30ml×2),分去水层,合并的有机相依次以饱和氯化钠溶液洗涤(30mL×2),无水硫酸钠干燥,过滤,减压浓缩,得到的残留物用硅胶柱层析法(洗脱剂:体系B)纯化,得到3-((4-乙炔基苄基)氨基)四氢噻吩1,1-二氧化物21j(180mg,721.94μmol,82.90%yield)。
MS m/z(ESI):250.0[M+1]
+
第六步
1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-(4-((4-(((1,1-dioxidotetrahydrothiophen-3-yl)amino)methyl)phenyl)ethynyl)phenyl)-3-isopropylimidazolidin-2-one
1-((5,6-双(苄氧基)嘧啶-4-基)甲基)-4-(4-((4-(((1,1-二氧代四氢噻吩-3-基)氨基)甲基)苯基)乙炔基)苯基)-3-异丙基咪唑啉-2-酮
室温下,1-((5,6-双(苄氧基)嘧啶-4-基)甲基)-4-(4-碘代苯基)-3-异丙基咪唑啉-2-酮21e(45mg,70.92μmol)和3-((4-乙炔基苄基)氨基)四氢噻吩1,1-二氧化物21j(21.22mg,85.11μmol)的水(1mL)溶液中,依次加入双三苯基膦二氯化钯(1.99mg,2.84μmol),四丁基溴化铵(22.86mg,70.92μmol)和哌啶(18.12mg,212.76μmol),反应升温至70℃搅拌5小时。反应液以乙酸乙酯萃取(30mL×2),分去水层,合并的有机相依次以饱和氯化钠溶液洗涤(30mL×2),无水硫酸钠干燥,过滤,减压浓缩,得到的残留物用硅胶柱层析法(洗脱剂:体系B)纯化,得到1-((5,6-双(苄氧基)嘧啶-4-基)甲基)-4-(4-((4-(((1,1-二氧代四氢噻吩-3-基)氨基)甲基)苯基)乙炔基)苯基)-3-异丙基咪唑啉-2-酮21k(50mg,66.14μmol,93.26%yield)。
MS m/z(ESI):755.9[M+1]
+
第七步
6-((4-(4-((4-(((1,1-dioxidotetrahydrothiophen-3-yl)amino)methyl)phenyl)ethynyl)phenyl)-3-isopropyl-2-oxoimidazolidin-1-yl)methyl)-5-hydroxypyrimidin-4(3H)-one
6-((4-(4-((4-(((1,1-二氧化四氢噻吩-3-基)氨基)甲基)苯基)乙炔基)苯基)-3-异丙基-2-氧代咪唑啉-1-基)甲基)-5-羟基嘧啶基-4(3H)-酮
冰浴下,将三氯化硼(0.8mL)滴加入1-((5,6-双(苄氧基)嘧啶-4-基)甲基)-4-(4-((4-(((1,1-二氧代四氢噻吩-3-基)氨基)甲基)苯基)乙炔基)苯基)-3-异丙基咪唑啉-2-酮21k(60mg,79.37μmol)的二氯甲烷(2mL)溶液,室温反应2小时,甲醇淬灭,减压浓缩,残留物通过制备液相分离纯化,得到6-((4-(4-((4-(((1,1-二氧化四氢噻吩-3-基)氨基)甲基)苯基)乙炔基)苯基)-3-异丙基-2-氧代咪唑啉-1-基)甲基)-5-羟基嘧啶基-4(3H)-酮21(2mg,2.81μmol,3.54%yield)。
MS m/z(ESI):575.9[M+1]
+
实施例22
6-((4-(4-((4-((1,1-dioxidothiomorpholino)methyl)phenyl)ethynyl)phenyl)-3-isopropyl-2-oxoimidazolidin-1-yl)methyl)-5-hydroxypyrimidin-4(3H)-one
6-((4-(4-((4-((1,1-二氧化硫代吗啉)甲基)苯基)乙炔基)苯基)-3-异丙基-2-氧代咪唑啉-1-基)甲基)-5-羟基嘧啶基-4(3H)-酮
第一步
4-(4-((trimethylsilyl)ethynyl)benzyl)thiomorpholine 1,1-dioxide
4-(4-((三甲基硅基)乙炔基)苄基)硫代吗啉1,1-二氧化物
4-(2-三甲基硅基乙炔基)苯甲醛22a(400mg,1.98mmol)溶于1,2-二氯乙烷(15mL)中,依次加入硫代吗啉1,1-二氧化物22b(534.53mg,3.95mmol)和醋酸(1.25mL),室温反应30分钟后,0℃下加入三乙酰氧基硼氢化钠(1.26g,5.93mmol),室温反应两小时。反应液加入50mL饱和碳酸氢钠溶液,二氯甲烷萃取(100ml),有机相依次通过无水硫酸钠干燥,过滤,减压浓缩,得到的残留物通过硅胶柱层析进一步分离纯化(洗脱剂:体系A),得到4-(4-((三甲基硅基)乙炔基)苄基)硫代吗啉1,1-二氧化物22c(157mg,488.32μmol,24.70%yield)
MS m/z(ESI):321.9[M+1]
+
第二步
4-(4-ethynylbenzyl)thiomorpholine 1,1-dioxide
4-(4-乙炔基苄基)硫代吗啉1,1-二氧化物
将4-(4-((三甲基硅基)乙炔基)苄基)硫代吗啉1,1-二氧化物22c(157mg,488.32μmol)加入到甲醇(5mL)中,加入氟化钾(113.49mg,1.95mmol),室温反应4小时。反应完成,减压浓缩,得到的残留物用硅胶柱层析法(洗脱剂:洗脱剂:体系A)纯化,得到4-(4-乙炔基苄基)硫代吗啉1,1-二氧化物22d(90mg,360.97μmol,73.92%yield)。
MS m/z(ESI):249.9[M+1]
+
第三步
1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-(4-((4-((1,1-dioxidothiomorpholino)methyl)phenyl)ethynyl)phenyl)-3-isopropylimidazolidin-2-one
1-((5,6-双(苄氧基)嘧啶-4-基)甲基)-4-(4-((4-((1,1-二氧化硫代吗啉)甲基)苯基)乙炔基)苯基)-3-异丙基咪唑啉-2-酮
室温下,1-((5,6-双(苄氧基)嘧啶-4-基)甲基)-4-(4-碘代苯基)-3-异丙基咪唑啉-2-酮21e(45mg,70.92μmo)和4-(4-乙炔基苄基)硫代吗啉1,1-二氧化物22d(21.22mg,85.11μmol)的水(1mL)溶液中,依次加入双三苯基膦二氯化钯(1.99mg,2.84μmol)、四丁基溴化铵(22.86mg,70.92μmol)和哌啶(18.12mg,212.76μmol),升温至70℃搅拌5小时。反应液以乙酸乙酯萃取(30ml×2),分去水层,合并的有机相依次以饱和氯化钠溶液洗涤(30mL×2),无水硫酸钠干燥,过滤,减压浓缩,得到的残留物用硅胶柱层析法(洗脱剂:洗脱剂:体系B)纯化,得到1-((5,6-双(苄氧基)嘧啶-4-基)甲基)-4-(4-((4-((1,1-二氧化硫代吗啉)甲基)苯基)乙炔基)苯基)-3-异丙基咪唑啉-2-酮22e(26mg,34.40μmol,48.50%yield)。
MS m/z(ESI):755.9[M+1]
+
第四步
6-((4-(4-((4-((1,1-dioxidothiomorpholino)methyl)phenyl)ethynyl)phenyl)-3-isopropyl-2-oxoimidazolidin-1-yl)methyl)-5-hydroxypyrimidin-4(3H)-one
6-((4-(4-((4-((1,1-二氧化硫代吗啉)甲基)苯基)乙炔基)苯基)-3-异丙基-2-氧代咪唑啉-1-基)甲基)-5-羟基嘧啶基-4(3H)-酮
冰浴下,在1-((5,6-双(苄氧基)嘧啶-4-基)甲基)-4-(4-((4-((1,1-二氧化硫代吗啉)甲基)苯基)乙炔基)苯基)-3-异丙基咪唑啉-2-酮22e(26mg,34.40μmol)的二氯甲烷(1mL)溶液中滴加三氯化硼(0.4mL),室温反应2小时,甲醇淬灭,减压浓缩,残留物通过制备液相分离纯化,得到6-((4-(4-((4-((1,1-二氧化硫代吗啉)甲基)苯基)乙炔基)苯基)-3-异丙基-2-氧代咪唑啉-1-基)甲基)-5-羟基嘧啶基-4(3H)-酮22(3mg,4.11μmol,11.96%yield)。
MS m/z(ESI):575.9[M+1]
+
实施例23
5-hydroxy-6-((3-isopropyl-2-oxo-4-(4-((4-((tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)methyl)phenyl)ethynyl)phenyl)imidazolidin-1-yl)methyl)pyrimidin-4(3H)-one
5-羟基-6-((3-异丙基-2-氧代-4-(4-((4-((四氢-1H-呋喃[3,4-c]吡咯-5(3H)-基)甲基)苯基)乙炔基)苯基)咪唑啉-1-基)甲基)嘧啶基-4(3H)-酮
第一步
5-(4-((trimethylsilyl)ethynyl)benzyl)hexahydro-1H-furo[3,4-c]pyrrole
5-(4-((三甲基硅基)乙炔基l)苄基)六氢-1H-呋喃并[3,4-c]吡咯
将4-(2-三甲基硅基乙炔基)苯甲醛22a(400mg,1.98mmol)溶于1,2-二氯乙烷(20mL),依次加入六氢-1H-呋喃并[3,4-c]吡咯23a(335.57mg,2.97mmol)和醋酸(1.25mL),室温反应2小时后,加入三乙酰氧基硼氢化钠(1.26g,5.93mmol),室温反应2小时。反应液加入50mL饱和碳酸氢钠溶液,二氯甲烷萃取(100mL),有机相依次通过无水硫酸钠干燥, 过滤,减压浓缩,得到的残留物通过硅胶柱层析进一步分离纯化(洗脱剂:体系B),得到5-(4-((三甲基硅基)乙炔基)苄基)六氢-1H-呋喃并[3,4-c]吡咯23b(460mg,1.54mmol,77.69%yield)。
MS m/z(ESI):300.0[M+1]
+
第二步
5-(4-ethynylbenzyl)hexahydro-1H-furo[3,4-c]pyrrole
5-(4-乙炔基苄基)六氢-1H-呋喃并[3,4-c]吡咯
5-(4-((三甲基硅基)乙炔基)苄基)六氢-1H-呋喃并[3,4-c]吡咯23b(460mg,1.54mmol)的甲醇(20mL)溶液中加入氟化钾(356.96mg,6.14mmol),室温反应4小时。反应液以乙酸乙酯萃取(30ml×2),分去水层,合并的有机相依次以饱和氯化钠溶液洗涤(30mL×2),无水硫酸钠干燥,过滤,减压浓缩,得到的残留物用硅胶柱层析法(洗脱剂:体系A)纯化,得到5-(4-乙炔基苄基)六氢-1H-呋喃并[3,4-c]吡咯23c(311mg,1.37mmol,89.08%yield)。
MS m/z(ESI):228.0[M+1]
+
第三步
1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-isopropyl-4-(4-((4-((tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)methyl)phenyl)ethynyl)phenyl)imidazolidin-2-one
1-((5,6-双(苄氧基)嘧啶-4-基)甲基)-3-异丙基-4-(4-((4-((四氢-1H-呋喃并[3,4-c]吡咯-5(3H)-基)甲基)苯基)乙炔基)苯基)咪唑啉-2-酮
室温下,1-((5,6-双(苄氧基)嘧啶-4-基)甲基)-4-(4-碘代苯基)-3-异丙基咪唑啉-2-酮21e(45.81mg,72.20μmol)和和5-(4-乙炔基苄基)六氢-1H-呋喃并[3,4-c]吡咯23c(19.7mg,87μmol)的水(1mL)溶液中,依次加入双三苯基膦二氯化钯(2.03mg,2.89μmol)、四丁基溴化铵(23.27mg,72.20μmol)和哌啶(18.44mg,216.59μmol)。反应升温至70℃搅拌5小时。反应液以乙酸乙酯萃取(30ml×2),分去水层,合并的有机相依次以饱和氯化钠溶液洗涤(30mL×2),无水硫酸钠干燥,过滤,减压浓缩,得到的残留物用硅胶柱层析法(洗脱剂:体系B)纯化,得到1-((5,6-双(苄氧基)嘧啶-4-基)甲基)-3-异丙基-4-(4-((4-((四氢-1H-呋喃并[3,4-c]吡咯-5(3H)-基)甲基)苯基)乙炔基)苯基)咪唑啉-2-酮23d(45mg,61.32μmol,84.93%yield)。
MS m/z(ESI):734.0[M+1]
+
第四步
5-hydroxy-6-((3-isopropyl-2-oxo-4-(4-((4-((tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)methyl)phenyl)ethynyl)phenyl)imidazolidin-1-yl)methyl)pyrimidin-4(3H)-one
5-羟基-6-((3-异丙基-2-氧代-4-(4-((4-((四氢-1H-呋喃[3,4-c]吡咯-5(3H)-基)甲基)苯基)乙炔基)苯基)咪唑啉-1-基)甲基)嘧啶基-4(3H)-酮
冰浴下,将1-((5,6-双(苄氧基)嘧啶-4-基)甲基)-3-异丙基-4-(4-((4-((四氢-1H-呋喃并[3,4-c]吡咯-5(3H)-基)甲基)苯基)乙炔基)苯基)咪唑啉-2-酮23d(45mg,61.32μmol)的二氯甲烷(1mL)溶液中滴加三氯化硼(0.4mL),室温反应2小时,甲醇淬灭,减压浓缩,残留物通过 制备液相分离纯化,得到5-羟基-6-((3-异丙基-2-氧代-4-(4-((4-((四氢-1H-呋喃[3,4-c]吡咯-5(3H)-基)甲基)苯基)乙炔基)苯基)咪唑啉-1-基)甲基)嘧啶基-4(3H)-酮23(5mg,7.38μmol,12.04%yield)。
MS m/z(ESI):554.0[M+1]
+
实施例24
5-hydroxy-6-((4-(4-((4-((4-hydroxypiperidin-1-yl)methyl)phenyl)ethynyl)phenyl)-3-isopropyl-2-oxoimidazolidin-1-yl)methyl)pyrimidin-4(3H)-one
5-羟基-6-((4-(4-((4-((4-羟基哌啶-1-基)甲基)苯基)乙炔基)苯基)-3-异丙基-2-氧代咪唑啉-1-基)甲基)嘧啶基-4(3H)-酮
第一步
4-((4-(1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-isopropyl-2-oxoimidazolidin-4-yl)phenyl)ethynyl)benzaldehyde
4-((4-(1-((5,6-双(苄氧基)嘧啶-4-基)甲基)-3-异丙基-2-氧代咪唑啉-4-基)苯基)乙炔基)苯甲醛
室温下,向1-((5,6-双(苄氧基)嘧啶-4-基)甲基)-4-(4-碘代苯基)咪唑啉-2-酮21d(300mg,472.81μmol)和4-乙炔基苯甲醛24a(73.8mg,567μmol)的水(1mL)溶液中,依次加入双三苯基膦二氯化钯13.27mg,18.91μmol),四丁基溴化铵(152.42mg,472.81μmol)和哌啶(120.78mg,1.42mmol),反应升温至70℃搅拌5小时。反应液以乙酸乙酯萃取(30ml×2),分去水层,合并的有机相依次以饱和氯化钠溶液洗涤(30mL×2),无水硫酸钠干燥,过滤,减压浓缩,得到的残留物用硅胶柱层析法(洗脱剂:体系B)纯化,得到4-((4-(1-((5,6-双(苄氧基)嘧啶-4-基)甲基)-3-异丙基-2-氧代咪唑啉-4-基)苯基)乙炔基)苯甲醛24b(230mg,361.22μmol,76.40%yield)。
MS m/z(ESI):637.3[M+1]
+
第二步
1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-(4-((4-((4-hydroxypiperidin-1-yl)methyl)phenyl)ethynyl)phenyl)-3-isopropylimidazolidin-2-one
1-((5,6-双(苄氧基)嘧啶-4-基)甲基)-4-(4-((4-((4-羟基哌啶基-1-基)甲基)苯基)乙炔基)苯基)-3-异丙基咪唑啉-2-酮
将4-((4-(1-((5,6-双(苄氧基)嘧啶-4-基)甲基)-3-异丙基-2-氧代咪唑啉-4-基)苯基)乙炔基)苯甲醛24b(50mg,78.53μmol),哌啶-4-醇(15.89mg,157.05μmol)溶于5mL 1,2-二氯乙烷中,加入乙酸(0.2mL),搅拌30分钟,加入醋酸硼氢化钠(49.93mg,235.58μmol),室温下持续搅拌12小时。加入饱和碳酸氢钠水溶液15mL淬灭,再加入二氯甲烷(30mL)和水(15mL),分液,水相用二氯甲烷萃取(30mL×2),合并的有机相以饱和氯化钠溶液洗涤(30mL×2),无水硫酸钠干燥,过滤,减压浓缩,得到的残留物用硅胶柱层析法(洗脱剂:体系B)纯化,得到1-((5,6-双(苄氧基)嘧啶-4-基)甲基)-4-(4-((4-((4-羟基哌啶基-1-基)甲基)苯基)乙炔基)苯基)-3-异丙基咪唑啉-2-酮24c(20mg,27.71μmol,35.28%yield)。
MS m/z(ESI):722.0[M+1]
+
第三步
5-hydroxy-6-((4-(4-((4-((4-hydroxypiperidin-1-yl)methyl)phenyl)ethynyl)phenyl)-3-isopropyl-2-oxoimidazolidin-1-yl)methyl)pyrimidin-4(3H)-one
5-羟基-6-((4-(4-((4-((4-羟基哌啶-1-基)甲基)苯基)乙炔基)苯基)-3-异丙基-2-氧代咪唑啉-1-基)甲基)嘧啶基-4(3H)-酮
冰浴下,1-((5,6-双(苄氧基)嘧啶-4-基)甲基)-4-(4-((4-((4-羟基哌啶基-1-基)甲基)苯基)乙炔基)苯基)-3-异丙基咪唑啉-2-酮24c(20mg,27.71μmol)的二氯甲烷(2mL)溶液中,滴加三氯化硼(0.8mL),室温反应2小时,甲醇淬灭,减压浓缩,残留物通过制备液相分离纯化,得到5-羟基-6-((4-(4-((4-((4-羟基哌啶-1-基)甲基)苯基)乙炔基)苯基)-3-异丙基-2-氧代咪唑啉-1-基)甲基)嘧啶基-4(3H)-酮24(1mg,1.41μmol,5.08%yield)。
MS m/z(ESI):542.0[M+1]
+
实施例25
5-hydroxy-6-((3-isopropyl-4-(4-((6-(morpholinomethyl)pyridin-3-yl)ethynyl)phenyl)-2-oxoimidazolidin-1-yl)methyl)pyrimidin-4(3H)-one
5-羟基-6-((3-异丙基-4-(4-((6-(吗啉甲基)吡啶-3-基)乙炔基)苯基)-2-氧代咪唑啉-1-基)甲基)嘧啶基-4(3H)-酮
第一步
4-((5-ethynylpyridin-2-yl)methyl)morpholine
4-((5-乙炔基吡啶-2-基)甲基)吗啉
将5-乙炔基吡啶-2-甲醛25a(200mg,1.53mmol)溶于1,2-二氯乙烷(3mL)中,依次加入吗啉25b(398.62mg,4.58mmol)、乙酸(0.2mL)和醋酸硼氢化钠(969.75mg,4.58mmol),室温反应4小时。在0℃加水淬灭反应,以二氯甲烷萃取(30ml×2),分去水层,合并的有机相依次以饱和氯化钠溶液洗涤(30mL×2),无水硫酸钠干燥,过滤,减压浓缩,得到的残留物用硅胶柱层析法(洗脱剂:体系A)纯化,得到4-((5-乙炔基吡啶-2-基)甲基)吗啉25c(170mg,840.54μmol,55.11%yield)。
MS m/z(ESI):203.1[M+1]
+
第二步
1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-isopropyl-4-(4-((6-(morpholinomethyl)pyridin-3-yl)ethynyl)phenyl)imidazolidin-2-one
1-((5,6-双(苄氧基)嘧啶-4-基)甲基)-3-异丙基-4-(4-((6-(吗啉甲基)吡啶-3-基)乙炔基)苯基)咪唑啉-2-酮
室温下,将1-((5,6-双(苄氧基)嘧啶-4-基)甲基)-4-(4-碘代苯基)-3-异丙基咪唑啉-2-酮21e(50mg,78.80μmol)和4-((5-乙炔基吡啶-2-基)甲基)吗啉25c(19.13mg,94.56μmol)的水(1mL)溶液中,依次加入双三苯基膦二氯化钯(2.21mg,3.15μmol)、四丁基溴化铵(25.40mg,78.80μmol)和哌啶(20.13mg,236.40μmol),反应升温至70℃搅拌5小时。反应液以乙酸乙酯萃取(30ml×2),分去水层,合并的有机相依次以饱和氯化钠溶液洗涤(30mL×2),无水硫酸钠干燥,过滤,减压浓缩,得到的残留物用硅胶柱层析法(洗脱剂:体系B)纯化,得到1-((5,6-双(苄氧基)嘧啶-4-基)甲基)-3-异丙基-4-(4-((6-(吗啉甲基)吡啶-3-基)乙炔基)苯基)咪唑啉-2-酮25d(55mg,77.59μmol,98.46%yield)。
MS m/z(ESI):709.3[M+1]
+
第三步
5-hydroxy-6-((3-isopropyl-4-(4-((6-(morpholinomethyl)pyridin-3-yl)ethynyl)phenyl)-2-oxoimidazolidin-1-yl)methyl)pyrimidin-4(3H)-one
5-羟基-6-((3-异丙基-4-(4-((6-(吗啉甲基)吡啶-3-基)乙炔基)苯基)-2-氧代咪唑啉-1-基)甲基) 嘧啶基-4(3H)-酮
冰浴下,1-((5,6-双(苄氧基)嘧啶-4-基)甲基)-3-异丙基-4-(4-((6-(吗啉甲基)吡啶-3-基)乙炔基)苯基)咪唑啉-2-酮25d(50mg,70.54μmol)的二氯甲烷(2mL)溶液中滴加三氯化硼(0.8mL),室温反应2小时,甲醇淬灭,减压浓缩,残留物通过制备液相分离纯化,得到5-羟基-6-((3-异丙基-4-(4-((6-(吗啉甲基)吡啶-3-基)乙炔基)苯基)-2-氧代咪唑啉-1-基)甲基)嘧啶基-4(3H)-酮25(10mg,14.83μmol,21.03%yield)。
MS m/z(ESI):529.0[M+1]
+
实施例26
6-((3-cyclopropyl-4-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-2-oxoimidazolidin-1-yl)methyl)-5-hydroxypyrimidin-4(3H)-one
6-((3-环丙基-4-(4-((4-(吗啉甲基)苯基)乙炔基)苯基)-2-氧代咪唑啉-1-基)甲基)-5-羟基嘧啶基-4(3H)-酮
第一步
tert-butyl
3-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-5-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-2-oxoimidazolidine-1-carboxylate
3-((5,6-双(苄氧基)嘧啶-4-基)甲基)-5-(4-((4-(吗啉甲基)苯基)乙炔基)苯基)-2-氧代咪唑啉-1-羧酸叔丁酯
氩气氛下,将3-((5,6-双(苄氧基)嘧啶-4-基)甲基)-5-(4-碘苯基)-2-氧代咪唑啉-1-羧酸叔丁酯21c(4g,5.78mmol),4-(4-乙炔基苄基)吗啉26a(1.39g,6.93mmol),双三苯基膦二氯化钯(203mg,289μmol),四丁基溴化铵(1.86g,5.78mmol)和哌啶(1.48g,17.33mmol)加入 到50mL水中,升至75℃反应5小时。反应完全后,加入水(20mL),乙酸乙酯萃取(40mL×3),合并有机相依次用饱和氯化钠溶液洗涤(20mL),无水硫酸钠干燥,过滤,减压浓缩,得到的残留物用硅胶柱层析法(洗脱剂:体系A)纯化,得到3-((5,6-双(苄氧基)嘧啶-4-基)甲基)-5-(4-((4-(吗啉甲基)苯基)乙炔基)苯基)-2-氧代咪唑啉-1-羧酸叔丁酯26b(3g,3.92mmol,67.8%yield)。
MS m/z(ESI):766.5[M+1]
+
第二步
1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)imidazolidin-2-one
1-((5,6-双(苄氧基)嘧啶-4-基)甲基)-4-(4-((4-(吗啉甲基)苯基)乙炔基)苯基)咪唑啉-2-酮
冰浴下,将浓盐酸(3.0mL)加入到3-((5,6-双(苄氧基)嘧啶-4-基)甲基)-5-(4-((4-(吗啉甲基)苯基)乙炔基)苯基)-2-氧代咪唑啉-1-羧酸叔丁酯26b(3g,3.92mmol)的30mL 1,4-二氧六环溶液中,室温下反应2小时。反应完全后,加入饱和碳酸氢钠溶液至碱性,减压浓缩除去有机溶剂,乙酸乙酯萃取(40mL×3),合并有机依次用饱和氯化钠溶液(20mL)洗涤,无水硫酸钠干燥,过滤,减压浓缩,得到的残留物用硅胶柱层析法(洗脱剂:体系B)纯化,得到1-((5,6-双(苄氧基)嘧啶-4-基)甲基)-4-(4-((4-(吗啉甲基)苯基)乙炔基)苯基)咪唑啉-2-酮26c(2.34g,3.51mmol,89.7%yield)。
MS m/z(ESI):666.3[M+1]
+
第三步
1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-cyclopropyl-4-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)imidazolidin-2-one
1-((5,6-双(苄氧基)嘧啶-4-基)甲基)-3-环丙基-4-(4-((4-(吗啉甲基)苯基)乙炔基)苯基)咪唑啉-2-酮
1-((5,6-双(苄氧基)嘧啶-4-基)甲基)-4-(4-((4-(吗啉甲基)苯基)乙炔基)苯基)咪唑啉-2-酮26c(200mg,300μmol)的四氢呋喃(1.5mL)溶液中加入环丙基硼酸(77.4mg,901μmol)、醋酸铜(164mg,901μmol),加热至80℃反应过夜。反应完全后,加入乙酸乙酯(50mL),过滤,滤液用饱和氯化钠溶液洗涤(20mL),无水硫酸钠干燥,过滤,减压浓缩,得到的残留物用硅胶柱层析法(洗脱剂:体系A)纯化,得到1-((5,6-双(苄氧基)嘧啶-4-基)甲基)-3-环丙基-4-(4-((4-(吗啉甲基)苯基)乙炔基)苯基)咪唑啉-2-酮26d(40mg,56.7μmol,18.9%yield)。
MS m/z(ESI):706.3[M+1]
+
第四步
6-((3-cyclopropyl-4-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-2-oxoimidazolidin-1-yl)methyl)-5-hydroxypyrimidin-4(3H)-one
6-((3-环丙基-4-(4-((4-(吗啉甲基)苯基)乙炔基)苯基)-2-氧代咪唑啉-1-基)甲基)-5-羟基嘧啶 基-4(3H)-酮
冰浴下,1-((5,6-双(苄氧基)嘧啶-4-基)甲基)-3-环丙基-4-(4-((4-(吗啉甲基)苯基)乙炔基)苯基)咪唑啉-2-酮26d(60mg,85μmol)的二氯甲烷(1.2mL)溶液中滴加三氯化硼(2.5mL),室温下反应5小时。反应完全后,加入甲醇淬灭,减压浓缩,残留物通过制备液相色谱分离纯化,得到6-((3-环丙基-4-(4-((4-(吗啉甲基)苯基)乙炔基)苯基)-2-氧代咪唑啉-1-基)甲基)-5-羟基嘧啶基-4(3H)-酮26(11.7mg,18.3μmol,21.5%yield)。
MS m/z(ESI):526.2[M+1]
+
实施例27
2-(3-((5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)methyl)-5-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-2-oxoimidazolidin-1-yl)acetonitrile
2-(3-((5-羟基-6-氧代-1,6-二氢嘧啶-4-基)甲基)-5-(4-((4-(吗啉甲基)苯基)乙炔基)苯基)-2-氧代咪唑啉-1-基)乙腈
第一步
2-(3-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-5-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-2-oxoimidazolidin-1-yl)acetonitrile
2-(3-((5,6-双(苄氧基)嘧啶-4-基)甲基)-5-(4-((4-(吗啉甲基)苯基)乙炔基)苯基)-2-氧代咪唑啉-1-基)乙腈
冰浴下,氩气氛下,1-((5,6-双(苄氧基)嘧啶-4-基)甲基)-4-(4-((4-(吗啉甲基)苯基)乙炔基)苯基)咪唑啉-2-酮26h(620mg,931μmol)的10mL N,N-二甲基甲酰胺溶液中加入氢化钠(121mg,2.79mmol,60%purity),升至室温反应20分钟,加入2-氯乙腈(211mg,2.79mmol),继续反应3小时。反应完全后,加入水(20mL)淬灭反应。用乙酸乙酯萃取(30mL×3),合 并的有机相依次用饱和氯化钠溶液洗涤(20mL),无水硫酸钠干燥,过滤,减压浓缩,得到的残留物用硅胶柱层析法(洗脱剂:体系A)纯化,得到2-(3-((5,6-双(苄氧基)嘧啶-4-基)甲基)-5-(4-((4-(吗啉甲基)苯基)乙炔基)苯基)-2-氧代咪唑啉-1-基)乙腈27a(270mg,383μmol,41.1%yield)
MS m/z(ESI):705.3[M+1]
+
第二步
2-(3-((5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)methyl)-5-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-2-oxoimidazolidin-1-yl)acetonitrile
2-(3-((5-羟基-6-氧代-1,6-二氢嘧啶-4-基)甲基)-5-(4-((4-(吗啉甲基)苯基)乙炔基)苯基)-2-氧代咪唑啉-1-基)乙腈
室温下,将三氯化硼(3mL)加入2-(3-((5,6-双(苄氧基)嘧啶-4-基)甲基)-5-(4-((4-(吗啉甲基)苯基)乙炔基)苯基)-2-氧代咪唑啉-1-基)乙腈27a(130mg,184μmol)的1.2mL二氯甲烷溶液中,搅拌5小时。反应完全后,加入少量冰水淬灭反应,浓缩,残留物通过制备液相色谱分离纯化,得到2-(3-((5-羟基-6-氧代-1,6-二氢嘧啶-4-基)甲基)-5-(4-((4-(吗啉甲基)苯基)乙炔基)苯基)-2-氧代咪唑啉-1-基)乙腈27(31.5mg,49.0μmol,26.6%yield)。
MS m/z(ESI):525.3[M+1]
+
实施例28
2-(3-((5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)methyl)-5-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-2-oxoimidazolidin-1-yl)acetamide
2-(3-((5-羟基-6-氧代-1,6-二氢嘧啶-4-基)甲基)-5-(4-((4-(吗啉甲基)苯基)乙炔基)苯基)-2-氧代咪唑啉-1-基)乙酰胺
冰浴下,将氢氧化钾(3.21mg,57.2μmol)加入至2-(3-((5-羟基-6-氧代-1,6-二氢嘧啶-4-基)甲基)-5-(4-((4-(吗啉甲基)苯基)乙炔基)苯基)-2-氧代咪唑啉-1-基)乙腈27(15mg,28.6μmol)的二甲基亚砜(1mL)溶液中,滴加双氧水(30%,0.5mL),升至室温反应1小时。反应完全后,用1M盐酸调至中性,减压浓缩,残留物通过通过制备液相色谱分离纯化,得到2-(3-((5-羟基-6-氧代-1,6-二氢嘧啶-4-基)甲基)-5-(4-((4-(吗啉甲基)苯基)乙炔基)苯基)-2- 氧代咪唑啉-1-基)乙酰胺28(13.0mg,19.0μmol,66.5%yield)
MS m/z(ESI):543.2[M+1]
+
实施例29
6-((3-(2,2-difluoroethyl)-4-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-2-oxoimidazolidin-1-yl)methyl)-5-hydroxypyrimidin-4(3H)-one
6-((3-(2,2-二氟乙基)-4-(4-((4-(吗啉甲基)苯基)乙炔基)苯基)-2-氧代咪唑啉-1-基)甲基)-5-羟基嘧啶基-4(3H)-酮
第一步
1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-(2,2-difluoroethyl)-4-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)imidazolidin-2-one
1-((5,6-双(苄氧基)嘧啶-4-基)甲基)-3-(2,2-二氟乙基)-4-(4-((4-(吗啉甲基)苯基)乙炔基)苯基)咪唑啉-2-酮
冰浴下,氩气氛下,将氢化钠(7.81mg,180μmol,60%purity)加入至1-((5,6-双(苄氧基)嘧啶-4-基)甲基)-4-(4-((4-(吗啉甲基)苯基)乙炔基)苯基)咪唑啉-2-酮26h(80mg,120μmol)的N,N-二甲基甲酰胺(2mL)溶液中,搅拌10分钟后,加入三氟甲磺酸(2,2-二氟乙酯)(51.5mg,240μmol),继续反应2小时。反应完全后,加入水(20mL),用乙酸乙酯萃取(20mL×3),合并有机相,用饱和氯化钠溶液(20mL)洗涤,无水硫酸钠干燥,过滤,减压浓缩,得到的残留物用硅胶柱层析法(洗脱剂:体系A)纯化,得到1-((5,6-双(苄氧基)嘧啶-4-基)甲基)-3-(2,2-二氟乙基)-4-(4-((4-(吗啉甲基)苯基)乙炔基)苯基)咪唑啉-2-酮29a(80mg,110μmol,91.2%yield)
MS m/z(ESI):730.3[M+1]
+
第二步
6-((3-(2,2-difluoroethyl)-4-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-2-oxoimidazolidin-1-yl)methyl)-5-hydroxypyrimidin-4(3H)-one
6-((3-(2,2-二氟乙基)-4-(4-((4-(吗啉甲基)苯基)乙炔基)苯基)-2-氧代咪唑啉-1-基)甲基)-5-羟基嘧啶基-4(3H)-酮
将三氯化硼(3mL)加入至1-((5,6-双(苄氧基)嘧啶-4-基)甲基)-3-(2,2-二氟乙基)-4-(4-((4-(吗啉甲基)苯基)乙炔基)苯基)咪唑啉-2-酮29a(100mg,137μmol)的1.5mL二氯甲烷溶液中,室温下反应过夜。反应完全后,加入甲醇淬灭反应,减压浓缩,残留物通过制备液相色谱分离纯化,得到6-((3-(2,2-二氟乙基)-4-(4-((4-(吗啉甲基)苯基)乙炔基)苯基)-2-氧代咪唑啉-1-基)甲基)-5-羟基嘧啶基-4(3H)-酮29(34.8mg,50.3μmol,36.7%yield)。MS m/z(ESI):550.3[M+1]
+
实施例30
5-hydroxy-6-((4-(4-((4-(((2-hydroxyethyl)amino)methyl)phenyl)ethynyl)phenyl)-3-isopropyl-2-oxoimidazolidin-1-yl)methyl)pyrimidin-4(3H)-one
5-羟基-6-((4-(4-((4-(((2-羟基乙基)氨基)甲基)苯基)乙炔基)苯基)-3-异丙基-2-氧代咪唑啉-1-基)甲基)嘧啶基-4(3H)-酮
第一步
1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-(4-((4-(((2-hydroxyethyl)amino)methyl)phenyl)ethynyl)phenyl)-3-isopropylimidazolidin-2-one
1-((5,6-双(苄氧基)嘧啶-4-基)甲基)-4-(4-((4-(((2-羟基乙基)氨基)甲基)苯基)乙炔基)苯基)-3- 异丙基咪唑啉-2-酮
将4-((4-(1-((5,6-双(苄氧基)嘧啶-4-基)甲基)-3-异丙基-2-氧代咪唑啉-4-基)苯基)乙炔基)苯甲醛24g(62mg,97.37μmol)和2-氨基乙醇30a(11.90mg,194.74μmol)溶于3mL 1,2-二氯乙烷中,加入乙酸(1mL),室温搅拌30分钟,加入三乙酰基硼氢化钠(41.27mg,194.74μmol),室温搅拌12小时。反应完全后,加入饱和碳酸氢钠水溶液15mL淬灭,用二氯甲烷萃取(30mL×2),合并的有机相依次以饱和氯化钠溶液洗涤(30mL×2),无水硫酸钠干燥,过滤,减压浓缩,得到的残留物经制备液相色谱纯化(洗脱剂:体系B),得到1-((5,6-双(苄氧基)嘧啶-4-基)甲基)-4-(4-((4-(((2-羟基乙基)氨基)甲基)苯基)乙炔基)苯基)-3-异丙基咪唑啉-2-酮30b(25mg,36.67μmol,37.66%yield)。
MS m/z(ESI):682.0[M+1]
+
第二步
5-hydroxy-6-((4-(4-((4-(((2-hydroxyethyl)amino)methyl)phenyl)ethynyl)phenyl)-3-isopropyl-2-oxoimidazolidin-1-yl)methyl)pyrimidin-4(3H)-one
5-羟基-6-((4-(4-((4-(((2-羟基乙基)氨基)甲基)苯基)乙炔基)苯基)-3-异丙基-2-氧代咪唑啉-1-基)甲基)嘧啶基-4(3H)-酮
将1-((5,6-双(苄氧基)嘧啶-4-基)甲基)-4-(4-((4-(((2-羟基乙基)氨基)甲基)苯基)乙炔基)苯基)-3-异丙基咪唑啉-2-酮30b(25mg,36.67μmol)加入到2mL二氯甲烷中,加入三氯化硼(0.8mL),室温反应2小时。反应完全后,减压浓缩,残留物通过制备液相分离纯化,得到5-羟基-6-((4-(4-((4-(((2-羟基乙基)氨基)甲基)苯基)乙炔基)苯基)-3-异丙基-2-氧代咪唑啉-1-基)甲基)嘧啶基-4(3H)-酮30(7mg,10.81μmol,29.48%yield)。
MS m/z(ESI):502.0[M+1]
+
实施例31
2-((4-((4-(1-((5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)methyl)-3-isopropyl-2-oxoimidazolidin-4-yl)phenyl)ethynyl)benzyl)amino)acetamide
2-((4-((4-(1-((5-羟基-6-氧代-1,6-二氢嘧啶-4-基)甲基)-3-异丙基-2-氧代咪唑啉-4-基)苯基)乙炔基)苄基)氨基)乙酰胺
第一步
2-((4-((4-(1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-isopropyl-2-oxoimidazolidin-4-yl)phenyl)ethynyl)benzyl)amino)acetamide
2-((4-((4-(1-((5,6-双(苄氧基)嘧啶-4-基)甲基)-3-异丙基-2-氧代咪唑啉-4-基)苯基)乙炔基)苄基)氨基)乙酰胺
将4-((4-(1-((5,6-双(苄氧基)嘧啶-4-基)甲基)-3-异丙基-2-氧代咪唑啉-4-基)苯基)乙炔基)苯甲醛24g(73mg,114.65μmol)和2-氨基乙酰胺31a(16.99mg,229.29μmol)溶于2mL 1,2-二氯乙烷中,再加入乙酸(0.5mL),室温搅拌30分钟,加入三乙酰基硼氢化钠(48.60mg,229.29μmol),室温下持续搅拌12小时。反应完全后,加入饱和碳酸氢钠水溶液15mL淬灭,再加入二氯甲烷(30mL)和水(15mL),分液,水相用二氯甲烷萃取(30mL×2),合并的有机相以饱和氯化钠溶液洗涤(30mL×2),无水硫酸钠干燥,过滤,减压浓缩,得到的残留物通过制备液相色谱纯化(洗脱剂:体系B),得到2-((4-((4-(1-((5,6-双(苄氧基)嘧啶-4-基)甲基)-3-异丙基-2-氧代咪唑啉-4-基)苯基)乙炔基)苄基)氨基)乙酰胺31b(50mg,71.96μmol,62.77%yield)。
MS m/z(ESI):695.4[M+1]
+
第二步
2-((4-((4-(1-((5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)methyl)-3-isopropyl-2-oxoimidazolidin-4-yl)phenyl)ethynyl)benzyl)amino)acetamide
2-((4-((4-(1-((5-羟基-6-氧代-1,6-二氢嘧啶-4-基)甲基)-3-异丙基-2-氧代咪唑啉-4-基)苯基)乙炔基)苄基)氨基)乙酰胺
将2-((4-((4-(1-((5,6-双(苄氧基)嘧啶-4-基)甲基)-3-异丙基-2-氧代咪唑啉-4-基)苯基)乙炔基)苄基)氨基)乙酰胺31b(50mg,71.96μmol)加入2mL二氯甲烷中,加入三氯化硼(0.8mL),室温反应1小时。反应完全后,减压浓缩,残留物通过制备液相分离纯化,得到2-((4-((4-(1-((5-羟基-6-氧代-1,6-二氢嘧啶-4-基)甲基)-3-异丙基-2-氧代咪唑啉-4-基)苯基)乙炔基)苄基)氨基)乙酰胺31(16mg,24.53μmol,34.09%yield)。
MS m/z(ESI):515.0[M+1]
+
实施例32
5-hydroxy-6-((4-(4-((4-((3-hydroxypyrrolidin-1-yl)methyl)phenyl)ethynyl)phenyl)-3-isopropyl-2-oxoimidazolidin-1-yl)methyl)pyrimidin-4(3H)-one
5-羟基-6-((4-(4-((4-((3-羟基吡咯烷-1-基)甲基)苯基)乙炔基)苯基)-3-异丙基-2-氧代咪唑啉-1-基)甲基)嘧啶-4(3H)-酮
第一步
1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-(4-((4-((3-hydroxypyrrolidin-1-yl)methyl)phenyl)ethynyl)phenyl)-3-isopropylimidazolidin-2-one
1-((5,6-双(苄氧基)嘧啶-4-基)甲基)-4-(4-((4-((3-羟基吡咯烷-1-基)甲基)苯基)乙炔基)苯基)-3-异丙基咪唑啉-2-酮
将4-((4-(1-((5,6-双(苄氧基)嘧啶-4-基)甲基)-3-异丙基-2-氧代咪唑啉-4-基)苯基)乙炔基)苯甲醛24g(50mg,78.53μmol)和吡咯烷-3-醇32a(13.68mg,157.05μmol)溶于1mL 1,2-二氯乙烷中,再加入乙酸(0.2mL),搅拌30分钟,加入三乙酰基硼氢化钠(33.29mg,157.05μmol),室温下持续搅拌12小时。反应完全后,加入饱和碳酸氢钠水溶液15mL淬灭,再加入二氯甲烷(30mL)和水(15mL),分液,水相用二氯甲烷萃取(30mL×2),合并的有机相以饱和氯化钠溶液洗涤(30mL×2),无水硫酸钠干燥,过滤,减压浓缩,残留物经制备液相色谱纯化(洗脱剂:体系A),得到1-((5,6-双(苄氧基)嘧啶-4-基)甲基)-4-(4-((4-((3-羟基吡咯烷-1-基)甲基)苯基)乙炔基)苯基)-3-异丙基咪唑啉-2-酮32b(40mg,56.51μmol,71.96%yield)。
MS m/z(ESI):708.5[M+1]
+
第二步
5-hydroxy-6-((4-(4-((4-((3-hydroxypyrrolidin-1-yl)methyl)phenyl)ethynyl)phenyl)-3-isopropyl-2-oxoimidazolidin-1-yl)methyl)pyrimidin-4(3H)-one
5-羟基-6-((4-(4-((4-((3-羟基吡咯烷-1-基)甲基)苯基)乙炔基)苯基)-3-异丙基-2-氧代咪唑啉-1-基)甲基)嘧啶-4(3H)-酮
将1-((5,6-双(苄氧基)嘧啶-4-基)甲基)-4-(4-((4-((3-羟基吡咯烷-1-基)甲基)苯基)乙炔基)苯基)-3-异丙基咪唑啉-2-酮32b(40mg,56.51μmol)加入2mL二氯甲烷中,加入三氯化硼(0.8mL),室温反应1小时。反应完全后,减压浓缩,残留物通过制备液相分离纯化,得到5-羟基-6-((4-(4-((4-((3-羟基吡咯烷-1-基)甲基)苯基)乙炔基)苯基)-3-异丙基-2-氧代咪唑啉-1-基)甲基)嘧啶-4(3H)-酮32(9.78mg,15.20μmol,26.91%yield)。
MS m/z(ESI):528.0[M+1]
+
实施例33
5-hydroxy-6-((4-(4-((4-(((3-hydroxycyclobutyl)amino)methyl)phenyl)ethynyl)phenyl)-3-isopropyl-2-oxoimidazolidin-1-yl)methyl)pyrimidin-4(3H)-one
5-羟基-6-((4-(4-((4-(((3-羟基环丁基)氨基)甲基)苯基)乙炔基)苯基)-3-异丙基-2-氧代咪唑啉-1-基)甲基)嘧啶基-4(3H)-酮
第一步
1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-(4-((4-(((3-hydroxycyclobutyl)amino)methyl)phenyl)ethynyl)phenyl)-3-isopropylimidazolidin-2-one
1-((5,6-双(苄氧基)嘧啶-4-基)甲基)-4-(4-((4-(((3-羟基环丁基)氨基)甲基)苯基)乙炔基)苯基)-3-异丙基咪唑啉-2-酮
将4-((4-(1-((5,6-双(苄氧基)嘧啶-4-基)甲基)-3-异丙基-2-氧代咪唑啉-4-基)苯基)乙炔基)苯甲醛24g(50mg,78.53μmol)和3-氨基环丁烷-1-醇盐酸盐33a(19.41mg,157.05μmol)溶于1mL 1,2-二氯乙烷中,加入乙酸(0.2mL),搅拌30分钟,加入三乙酰基硼氢化钠(33.29mg,157.05μmol),室温下持续搅拌12小时。反应完全后,加入饱和碳酸氢钠水溶液15mL 淬灭,加入二氯甲烷(30mL)和水(15mL),分液,水相用二氯甲烷萃取(30mL×2),合并的有机相以饱和氯化钠溶液洗涤(30mL×2),无水硫酸钠干燥,过滤,减压浓缩,得到的残留物通过制备液相色谱纯化(洗脱剂:体系B),得到1-((5,6-双(苄氧基)嘧啶-4-基)甲基)-4-(4-((4-(((3-羟基环丁基)氨基)甲基)苯基)乙炔基)苯基)-3-异丙基咪唑啉-2-酮33b(20mg,28.25μmol,35.98%yield)。
MS m/z(ESI):708.0[M+1]
+
第二步
5-hydroxy-6-((4-(4-((4-(((3-hydroxycyclobutyl)amino)methyl)phenyl)ethynyl)phenyl)-3-isopropyl-2-oxoimidazolidin-1-yl)methyl)pyrimidin-4(3H)-one
5-羟基-6-((4-(4-((4-(((3-羟基环丁基)氨基)甲基)苯基)乙炔基)苯基)-3-异丙基-2-氧代咪唑啉-1-基)甲基)嘧啶基-4(3H)-酮
将1-((5,6-双(苄氧基)嘧啶-4-基)甲基)-4-(4-((4-(((3-羟基环丁基)氨基)甲基)苯基l)乙炔基)苯基)-3-异丙基咪唑啉-2-酮33b(20mg,28.25μmol)加入到2mL二氯甲烷中,加入三氯化硼(0.8mL),室温反应1小时。反应完全后,减压浓缩,残留物通过制备液相分离纯化,得到5-羟基-6-((4-(4-((4-(((3-羟基环丁基)氨基)甲基)苯基)乙炔基)苯基)-3-异丙基-2-氧代咪唑啉-1-基)甲基)嘧啶基-4(3H)-酮33(11mg,17.08μmol,60.45%yield)。
MS m/z(ESI):528.0[M+1]
+
实施例34
1-(4-((4-(1-((5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)methyl)-3-isopropyl-2-oxoimidazolidin-4-yl)phenyl)ethynyl)benzyl)azetidine-3-carbonitrile
1-(4-((4-(1-((5-羟基-6-氧代-1,6-二氢嘧啶-4-基)甲基)-3-异丙基-2-氧代咪唑啉-4-基)苯基)乙炔基)苄基)氮杂环丁烷-3-腈
第一步
1-(4-((4-(1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-isopropyl-2-oxoimidazolidin-4-yl)phenyl)ethynyl)benzyl)azetidine-3-carbonitrile
1-(4-((4-(1-((5,6-双(苄氧基)嘧啶-4-基)甲基)-3-异丙基-2-氧代咪唑啉-4-基)苯基)乙炔基)苄基) 氮杂环丁烷-3-腈
将4-((4-(1-((5,6-双(苄氧基)嘧啶-4-基)甲基)-3-异丙基-2-氧代咪唑啉-4-基)苯基)乙炔基)苯甲醛24g(43mg,67.53μmol)和氮杂环丁烷-3-腈盐酸盐34a(12.01mg,101.30μmol)溶于1,2-二氯乙烷(999.73μL)中,加入乙酸(4.06mg,67.53μmol,3.86μL),搅拌30分钟,加入三乙酰基硼氢化钠(28.63mg,135.06μmol),室温下持续搅拌12小时。反应完全后,加入饱和碳酸氢钠水溶液15mL淬灭,再加入二氯甲烷(30mL)和水(15mL),分液,水相用二氯甲烷萃取(30mL×2),合并的有机相以饱和氯化钠溶液洗涤(30mL×2),无水硫酸钠干燥,过滤,减压浓缩,残留物经制备液相色谱纯化(洗脱剂:体系B),得到1-(4-((4-(1-((5,6-双(苄氧基)嘧啶-4-基)甲基)-3-异丙基-2-氧代咪唑啉-4-基)苯基)乙炔基)苄基)氮杂环丁烷-3-腈34b(26mg,36.99μmol,54.78%yield)。
MS m/z(ESI):703.3[M+1]
+
第二步
1-(4-((4-(1-((5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)methyl)-3-isopropyl-2-oxoimidazolidin-4-yl)phenyl)ethynyl)benzyl)azetidine-3-carbonitrile
1-(4-((4-(1-((5-羟基-6-氧代-1,6-二氢嘧啶-4-基)甲基)-3-异丙基-2-氧代咪唑啉-4-基)苯基)乙炔基)苄基)氮杂环丁烷-3-腈
将1-(4-((4-(1-((5,6-双(苄氧基)嘧啶-4-基)甲基)-3-异丙基-2-氧代咪唑啉-4-基)苯基)乙炔基)苄基)氮杂环丁烷-3-腈34b(26mg,36.99μmol)加入到2.5mL二氯甲烷中,加入三氯化硼(0.1mL),室温反应1小时。反应完全后,加入甲醇淬灭,减压浓缩,残留物通过制备液相分离纯化,得到1-(4-((4-(1-((5-羟基-6-氧代-1,6-二氢嘧啶-4-基)甲基)-3-异丙基-2-氧代咪唑啉-4-基)苯基)乙炔基)苄基)氮杂环丁烷-3-腈34(6.8mg,10.62μmol,28.70%yield)。
MS m/z(ESI):523.4[M+1]
+
实施例35
1-(4-((4-(1-((5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)methyl)-3-isopropyl-2-oxoimidazolidin-4-yl)phenyl)ethynyl)benzyl)pyrrolidine-3-carbonitrile
1-(4-((4-(1-((5-羟基-6-氧代-1,6-二氢嘧啶-4-基)甲基)-3-异丙基-2-氧代咪唑啉-4-基)苯基)乙炔基)苄基)吡咯烷-3-腈
第一步
1-(4-((4-(1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-isopropyl-2-oxoimidazolidin-4-yl)phenyl)ethynyl)benzyl)pyrrolidine-3-carbonitrile
1-(4-((4-(1-((5,6-双(苄氧基)嘧啶-4-基)甲基)-3-异丙基-2-氧代咪唑啉-4-基)苯基)乙炔基)苄基)吡咯烷-3-腈
将4-((4-(1-((5,6-双(苄氧基)嘧啶-4-基)甲基)-3-异丙基-2-氧代咪唑啉-4-基)苯基)乙炔基)苯甲醛24g(40mg,62.82μmol)和吡咯烷-3-腈盐酸盐35a(9.06mg,68.32μmol)溶于1mL 1,2-二氯乙烷中,加入乙酸(3.77mg,62.82μmol,3.59μL),搅拌30分钟,加入三乙酰基硼氢化钠(26.63mg,125.64μmol),室温下持续搅拌12小时。反应完全后,加入饱和碳酸氢钠水溶液15mL淬灭,再加入二氯甲烷(30mL)和水(15mL),分液,水相用二氯甲烷萃取(30mL×2),合并的有机相以饱和氯化钠溶液洗涤(30mL×2),无水硫酸钠干燥,过滤,减压浓缩,残留物经制备液相色谱纯化(洗脱剂:体系B),得到1-(4-((4-(1-((5,6-双(苄氧基)嘧啶-4-基)甲基)-3-异丙基-2-氧代咪唑啉-4-基)苯基)乙炔基)苄基)吡咯烷-3-腈35b(40mg,55.80μmol,88.82%yield)。
MS m/z(ESI):717.4[M+1]
+
第二步
1-(4-((4-(1-((5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)methyl)-3-isopropyl-2-oxoimidazolidin-4-yl)phenyl)ethynyl)benzyl)pyrrolidine-3-carbonitrile
1-(4-((4-(1-((5-羟基-6-氧代-1,6-二氢嘧啶-4-基)甲基)-3-异丙基-2-氧代咪唑啉-4-基)苯基)乙炔基)苄基)吡咯烷-3-腈
将1-(4-((4-(1-((5,6-双(苄氧基)嘧啶-4-基)甲基)-3-异丙基-2-氧代咪唑啉-4-基)苯基)乙炔基)苄基)吡咯烷-3-腈35b(40mg,55.80μmol)加入到2mL二氯甲烷中,加入三氯化硼(0.5mL),室温反应1小时。反应完全后,加入甲醇淬灭,减压浓缩,残留物通过制备液相分离纯化,得到1-(4-((4-(1-((5-羟基-6-氧代-1,6-二氢嘧啶-4-基)甲基)-3-异丙基-2-氧代咪唑啉-4-基)苯基)乙炔基)苄基)吡咯烷-3-腈35(8mg,12.10μmol,21.69%yield)。
MS m/z(ESI):537.0[M+1]
+
实施例36
5-hydroxy-6-((3-isopropyl-4-(4-((4-((1-oxidothiomorpholino)methyl)phenyl)ethynyl)phenyl)-2-oxoimidazolidin-1-yl)methyl)pyrimidin-4(3H)-one
5-羟基-6-((3-异丙基-4-(4-((4-((1-氧化硫代吗啉)甲基)苯基)乙炔基)苯基)-2-氧代咪唑啉-1-基)甲基)嘧啶基-4(3H)-酮
第一步
1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-isopropyl-4-(4-((4-((1-oxidothiomorpholino)methyl)phenyl)ethynyl)phenyl)imidazolidin-2-one
1-((5,6-双(苄氧基)嘧啶-4-基)甲基)-3-异丙基-4-(4-((4-((1-氧化硫代吗啉)甲基)苯基)乙炔基)苯基)咪唑啉-2-酮
将4-((4-(1-((5,6-双(苄氧基)嘧啶-4-基)甲基)-3-异丙基-2-氧代咪唑啉-4-基)苯基)乙炔基)苯甲醛24g(40mg,62.82μmol)和硫代吗啉1-氧化物36a(14.67mg,94.23μmol)溶于1mL1,2-二氯乙烷中,加入乙酸(3.77mg,62.82μmol,3.59μL),搅拌30分钟,加入三乙酰基硼氢化钠(26.63mg,125.64μmol),室温下持续搅拌12小时。反应完全后,加入饱和碳酸氢钠水溶液15mL淬灭,加入二氯甲烷(30mL)和水(15mL),分液,水相用二氯甲烷萃取(30mL×2),合并的有机相以饱和氯化钠溶液洗涤(30mL×2),无水硫酸钠干燥,过滤,减压浓缩,残留物经制备液相色谱纯化(洗脱剂:体系B),得到1-((5,6-双(苄氧基)嘧啶-4-基)甲基)-3-异丙基-4-(4-((4-((1-氧化硫代吗啉)甲基)苯基)乙炔基)苯基)咪唑啉-2-酮36b(20mg,27.03μmol,43.03%yield)。
MS m/z(ESI):740.0[M+1]
+
第二步
5-hydroxy-6-((3-isopropyl-4-(4-((4-((1-oxidothiomorpholino)methyl)phenyl)ethynyl)phenyl)-2-oxoimidazolidin-1-yl)methyl)pyrimidin-4(3H)-one
5-羟基-6-((3-异丙基-4-(4-((4-((1-氧化硫代吗啉)甲基)苯基)乙炔基)苯基)-2-氧代咪唑啉-1-基)甲基)嘧啶基-4(3H)-酮
将1-((5,6-双(苄氧基)嘧啶-4-基)甲基)-3-异丙基-4-(4-((4-((1-氧化硫代吗啉)甲基)苯基)乙炔基)苯基)咪唑啉-2-酮36b(20mg,27.03μmol)加入到2mL二氯甲烷中,加入三氯化硼(0.5mL),室温反应1小时。反应完全后,加入甲醇淬灭,减压浓缩,残留物通过制备液 相分离纯化,得到5-羟基-6-((3-异丙基-4-(4-((4-((1-氧化硫代吗啉)甲基)苯基)乙炔基)苯基)-2-氧代咪唑啉-1-基)甲基)嘧啶基-4(3H)-酮36(4mg,5.90μmol,21.83%yield)。
MS m/z(ESI):560.0[M+1]
+
根据实施例1-36的合成方法,制备如下的化合物,包括:
实施例88
1-((5-((4-(1-((5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)methyl)-3-isopropyl-2-oxoimidazolidin-4-yl)phenyl)ethynyl)pyridin-2-yl)methyl)azetidine-3-carboxamide
1-((5-((4-(1-((5-羟基-6-氧代-1,6-二羟基嘧啶-4-基)甲基)-3-异丙基-2-氧代咪唑啉-4-基)苯基)乙炔基)吡啶-2-基)甲基)氮杂环丁烷-3-甲酰胺
第一步
1-(4-ethynylbenzyl)azetidine-3-carboxamide
1-(4-乙炔基苯基)氮杂环丁烷-3-甲酰胺
将4-乙炔基苯甲醛88a(200mg,1.54mmol)和氮杂环丁烷-3-甲酰胺盐酸盐88b(307.72mg,2.25mmol)溶于1,2-二氯乙烷(2.00mL),加入乙酸(92.28mg,1.54mmol,87.89μL),搅拌30分钟,加入三乙酰基硼氢化钠(651.41mg,3.07mmol),室温下持续搅拌12小时。反应完全后,反应液中依次加入饱和碳酸氢钠水溶液15mL淬灭,加入二氯甲烷(30mL)和水(15mL),分液,水相用二氯甲烷萃取(30mL×2),合并的有机相以饱和氯化钠溶液洗涤(30mL×2),无水硫酸钠干燥,过滤,减压浓缩至干,残留物经制备液相色谱纯化(洗脱剂:体系B),得到1-(4-乙炔基苯基)氮杂环丁烷-3-甲酰胺88c(100mg,466.72μmol,30.37%yield)。
MS m/z(ESI):214.9[M+1]
第二步
1-(4-((4-(1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-isopropyl-2-oxoimidazolidin-4-yl)phenyl)ethynyl)benzyl)azetidine-3-carboxamide
1-(4-((4-(1-((5,6-双(苄氧基)嘧啶-4-基)甲基)-3-异丙基-2-氧代咪唑啉-4-基)甲基)乙炔基)苄基)氮杂环丁烷-3-甲酰胺
室温下,向1-((5,6-双(苄氧基)嘧啶-4-基)甲基)-4-(4-碘代苯基)-3-异丙基咪唑啉-2-酮21e(50mg,78.80μmol)和1-(4-乙炔基苯基)氮杂环丁烷-3-甲酰胺88c(33.77mg,157.60μmol)的水(2mL)溶液中加入双三苯基膦二氯化钯(2.21mg,3.15μmol),四丁基溴化铵(25.40mg, 78.80μmol)和哌啶(20.13mg,236.40μmol)。反应升温至70℃搅拌5小时,反应完全后,反应液以乙酸乙酯萃取(30ml×2),分去水层,合并的有机相依次以饱和氯化钠溶液洗涤(30mL×2),无水硫酸钠干燥,过滤,减压浓缩,得到的残留物用硅胶柱层析法(洗脱剂:体系B)纯化,得到1-(4-((4-(1-((5,6-双(苄氧基)嘧啶-4-基)甲基)-3-异丙基-2-氧代咪唑啉-4-基)甲基)乙炔基)苄基)氮杂环丁烷-3-甲酰胺88d(30mg,41.62μmol,52.81%yield)。
MS m/z(ESI):721.0[M+1]
第三步
1-((5-((4-(1-((5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)methyl)-3-isopropyl-2-oxoimidazolidin-4-yl)phenyl)ethynyl)pyridin-2-yl)methyl)azetidine-3-carboxamide
1-((5-((4-(1-((5-羟基-6-氧代-1,6-二羟基嘧啶-4-基)甲基)-3-异丙基-2-氧代咪唑啉-4-基)苯基)乙炔基)吡啶-2-基)甲基)氮杂环丁烷-3-甲酰胺
将1-(4-((4-(1-((5,6-双(苄氧基)嘧啶-4-基)甲基)-3-异丙基-2-氧代咪唑啉-4-基)甲基)乙炔基)苄基)氮杂环丁烷-3-甲酰胺88d(30mg,41.62μmol)加入到2mL二氯甲烷中,随后加入三氯化硼(0.8mL),室温反应1小时。反应完全后,加入甲醇淬灭,减压浓缩,残留物通过制备液相进一步分离纯化,得到1-((5-((4-(1-((5-羟基-6-氧代-1,6-二羟基嘧啶-4-基)甲基)-3-异丙基-2-氧代咪唑啉-4-基)苯基)乙炔基)吡啶-2-基)甲基)氮杂环丁烷-3-甲酰胺88(7mg,9.88μmol,23.75%yield)。
MS m/z(ESI):541.3[M+1]
实施例89
5-hydroxy-6-((4-(4-((4-(2-hydroxyethoxy)phenyl)ethynyl)phenyl)-3-isopropyl-2-oxoimidazolidin-1-yl)methyl)pyrimidin-4(3H)-one
5-羟基-6-((4-(4-((4-(2-羟基乙氧基)苯基)乙炔基)苯基)-3-异丙基-2-氧代咪唑啉-1-基)甲基)嘧啶-4(3H)-酮
第一步
2-(4-((trimethylsilyl)ethynyl)phenoxy)ethan-1-ol
2-(4-((三甲基硅基)乙炔基)苯氧基)乙-1-醇
室温下,向2-(4-溴苯氧基)乙醇89a(600mg,2.76mmol)和乙炔基(三甲基)硅烷89b(298.65mg,3.04mmol,429.71μL)的三乙胺(10.29mL)溶液中加入碘化亚铜(52.64mg,276.42μmol)和双三苯基膦二氯化钯(194.02mg,276.42μmol)。室温搅拌过夜,反应完全后,反应液以乙酸乙酯萃取(30ml×2),分去水层,合并的有机相依次以饱和氯化钠溶液洗涤(30mL×2),无水硫酸钠干燥,过滤,减压浓缩,得到的残留物用硅胶柱层析法(洗脱剂:体系B)纯化,得到2-(4-((三甲基硅基)乙炔基)苯氧基)乙-1-醇89c(250mg,1.07mmol,38.59%yield)。
MS m/z(ESI):235.1[M+1]
第二步
2-(4-ethynylphenoxy)ethan-1-ol
2-(4-乙炔基苯氧基)乙-1-醇
将2-(4-((三甲基硅基)乙炔基)苯氧基)乙-1-醇89c(236mg,1.01mmol)加入到甲醇中,加入碳酸钾(417.52mg,3.02mmol),室温反应1小时。反应完全后,反应液以乙酸乙酯萃取(30ml×2),分去水层,合并的有机相依次以饱和氯化钠溶液洗涤(30mL×2),无水硫酸钠干燥,过滤,减压浓缩,得到的残留物用硅胶柱层析法(洗脱剂:体系A)纯化,得到2-(4-乙炔基苯氧基)乙-1-醇89d(120mg,739.90μmol,73.48%yield)。
MS m/z(ESI):163.0[M+1]
第三步
1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-(4-((4-(2-hydroxyethoxy)phenyl)ethynyl)phenyl)-3-isopropylimidazolidin-2-one
1-((5,6-双(苄氧基)嘧啶-4-基)甲基)-4-(4-((4-(2-羟乙基)苯基)乙炔基)苯基)-3-异丙基咪唑啉-2-酮
室温下,向1-((5,6-双(苄氧基)嘧啶-4-基)甲基)-4-(4-碘代苯基)-3-异丙基咪唑啉-2-酮21e (60mg,94.56μmol)2-(4-乙炔基苯氧基)乙-1-醇89d(30.67mg,189.12μmol)的水(2mL)溶液中加入双三苯基膦二氯化钯(2.65mg,3.78μmol),四丁基溴化铵(30.48mg,94.56μmol)和哌啶(24.16mg,283.69μmol)。反应升温至70℃搅拌5小时,反应完全后,反应液以乙酸乙酯萃取(30ml×2),分去水层,合并的有机相依次以饱和氯化钠溶液洗涤(30mL×2),无水硫酸钠干燥,过滤,减压浓缩,得到的残留物用硅胶柱层析法(洗脱剂:体系B)纯化,得到1-((5,6-双(苄氧基)嘧啶-4-基)甲基)-4-(4-((4-(2-羟乙基)苯基)乙炔基)苯基)-3-异丙基咪唑啉-2-酮89e(30mg,44.86μmol,47.44%yield)。
MS m/z(ESI):669.3[M+1]
第四步
5-hydroxy-6-((4-(4-((4-(2-hydroxyethoxy)phenyl)ethynyl)phenyl)-3-isopropyl-2-oxoimidazolidin-1-yl)methyl)pyrimidin-4(3H)-one
5-羟基-6-((4-(4-((4-(2-羟基乙氧基)苯基)乙炔基)苯基)-3-异丙基-2-氧代咪唑啉-1-基)甲基)嘧啶-4(3H)-酮
将1-((5,6-双(苄氧基)嘧啶-4-基)甲基)-4-(4-((4-(2-羟乙基)苯基)乙炔基)苯基)-3-异丙基咪唑啉-2-酮89e(30mg,44.86μmol)加入到2mL二氯甲烷中,加入三氯化硼(0.5mL),室温反应1小时。反应完全后,加入甲醇淬灭,减压浓缩,残留物通过制备液相进一步分离纯化,得到5-羟基-6-((4-(4-((4-(2-羟基乙氧基)苯基)乙炔基)苯基)-3-异丙基-2-氧代咪唑啉-1-基)甲基)嘧啶-4(3H)-酮89(4mg,6.48μmol,14.44%yield)。
MS m/z(ESI):488.9[M+1]
1H NMR(400MHz,DMSO)δ12.60(s,1H),9.48(s,1H),7.79(s,1H),7.60–7.40(m,6H),6.99(d,J=8.4Hz,2H),4.69(t,J=8.2Hz,1H),4.26(d,J=15.6Hz,1H),4.19(d,J=15.6Hz,1H),4.02(t,J=4.8Hz,2H),3.73–3.67(m,4H),3.04(t,J=8.0Hz,1H),1.13(d,J=6.8Hz,3H),0.77(d,J=6.4Hz,3H).
实施例90
5-hydroxy-6-((3-isopropyl-4-(4-((4-(3-methoxyazetidine-1-carbonyl)phenyl)ethynyl)phenyl)-2-oxoimidazolidin-1-yl)methyl)pyrimidin-4(3H)-one
5-羟基-6-((3-异丙基-4-(4-((4-(3-甲氧基氮杂环丁烷-1-羰基)苯基)乙炔基)苯基)-2-氧代咪唑啉-1-基)甲基)嘧啶-4(3H)-酮
第一步
(4-ethynylphenyl)(3-methoxyazetidin-1-yl)methanone
(4-乙炔基苯基)(3-甲氧基氮杂环丁-1-基)甲酮
将4-乙炔基苯甲酸90a(500mg,3.42mmol)和3-甲氧基氮杂环订完盐酸盐90b(845.62mg,6.84mmol)加入到5mL二氯甲烷中,依次加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(1.05g,5.47mmol),4-二甲氨基吡啶(41.80mg,342.13μmol),室温反应过夜。反应液用二氯甲烷萃取(30ml×2),分去水层,合并的有机相依次以饱和氯化钠溶液洗涤(30mL×2),无水硫酸钠干燥,过滤,减压浓缩,残留物用硅胶柱层析进一步分离纯化(洗脱剂:体系C),得到(4-乙炔基苯基)(3-甲氧基氮杂环丁-1-基)甲酮90c(500mg,2.32mmol,67.90%yield)。
MS m/z(ESI):216.2[M+1]
+
第二步
1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-isopropyl-4-(4-((4-(3-methoxyazetidine-1-carbonyl)phenyl)ethynyl)phenyl)imidazolidin-2-one
1-((5,6-双(苄氧基)嘧啶-4-基)甲基)-3-异丙基-4-(4-((4-(3-甲氧基氮杂环丁烷-1-羰基)苯基)乙炔基)苯基)咪唑啉-2-酮
室温下,向1-((5,6-双(苄氧基)嘧啶-4-基)甲基)-4-(4-碘代苯基)-3-异丙基咪唑啉-2-酮21e(60mg,94.56μmol)和(4-乙炔基苯基)(3-甲氧基氮杂环丁-1-基)甲酮90c(40.71mg,189.12μmol)的水(1.5mL)溶液中,依次加入双三苯基膦二氯化钯(2.65mg,3.78μmol),四丁基溴化铵(30.48mg,94.56μmol)和哌啶(24.16mg,283.69μmol),反应升温至70℃搅拌5小时。反应液以乙酸乙酯萃取(30mL×2),分去水层,合并的有机相依次以饱和氯化钠溶液洗涤(30mL×2),无水硫酸钠干燥,过滤,减压浓缩,残留物用硅胶柱层析进一步分离纯化(洗脱剂:体系B)纯化,得到1-((5,6-双(苄氧基)嘧啶-4-基)甲基)-3-异丙基-4-(4-((4-(3-甲氧基氮杂环丁烷-1-羰基)苯基)乙炔基)苯基)咪唑啉-2-酮90d(35mg,48.49μmol,51.28%yield)。
MS m/z(ESI):722.0[M+1]
+
第三步
5-hydroxy-6-((3-isopropyl-4-(4-((4-(3-methoxyazetidine-1-carbonyl)phenyl)ethynyl)phenyl)-2-o xoimidazolidin-1-yl)methyl)pyrimidin-4(3H)-one
5-羟基-6-((3-异丙基-4-(4-((4-(3-甲氧基氮杂环丁烷-1-羰基)苯基)乙炔基)苯基)-2-氧代咪唑啉-1-基)甲基)嘧啶-4(3H)-酮
将1-((5,6-双(苄氧基)嘧啶-4-基)甲基)-3-异丙基-4-(4-((4-(3-甲氧基氮杂环丁烷-1-羰基)苯基)乙炔基)苯基)咪唑啉-2-酮90d(35mg,48.49μmol)加入2mL二氯甲烷中,加入三氯化硼(0.5mL),室温反应1小时。反应完全后,加入甲醇淬灭,减压浓缩,残留物通过制备液相进一步分离纯化,得到5-羟基-6-((3-异丙基-4-(4-((4-(3-甲氧基氮杂环丁烷-1-羰基)苯基)乙炔基)苯基)-2-氧代咪唑啉-1-基)甲基)嘧啶-4(3H)-酮90(6mg,8.40μmol,17.33%yield)。
MS m/z(ESI):542.3[M+1]
+
1H NMR(400MHz,DMSO)δ12.59(br,1H),9.50(s,1H),7.79(s,1H),7.68(d,J=8.3Hz,2H),7.61(d,J=8.4Hz,2H),7.58(d,J=8.4Hz,2H),7.52(d,J=8.4Hz,2H),4.71(dd,J=9.2,7.2Hz,1H),4.45(dt,J=6.4,3.3Hz,1H),4.29–4.12(m,5H),3.85(q,J=7.1Hz,1H),3.74-3.67(m,2H),3.22(s,3H),3.04(t,J=8.0Hz,1H),1.13(d,J=6.8Hz,3H),0.78(d,J=6.8Hz,3H).
实施例91
5-hydroxy-6-((3-isopropyl-4-(4-((4-(1-oxidothiomorpholine-4-carbonyl)phenyl)ethynyl)phenyl)-2-oxoimidazolidin-1-yl)methyl)pyrimidin-4(3H)-one
5-羟基-6-((3-异丙基-4-(4-((4-(1-氧化硫代吗啉-4-羰基)苯基)乙炔基)苯基)-2-氧代咪唑啉-1-基)甲基)嘧啶-4(3H)-酮
第一步
(4-ethynylphenyl)(1-oxidothiomorpholino)methanone
(4-乙炔基苯基)(1-氧化硫代吗啉)甲酮
将4-乙炔基苯甲酸90a(150mg,1.03mmol)和硫代吗啉1-氧化物盐酸盐36a(255.61mg,1.64mmol)加入到1mL二氯甲烷中,依次加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(314.82mg,1.64mmol)和4-二甲氨基吡啶(12.54mg,102.64μmol),室温反应过夜。反应液以二氯甲烷萃取(30ml×2),分去水层,合并的有机相依次以饱和氯化钠溶液洗涤(30mL×2),无水硫酸钠干燥,过滤,减压浓缩,残留物用硅胶柱层析进一步分离纯化(洗脱剂:体系A)纯化,得到(4-乙炔基苯基)(1-氧化硫代吗啉)甲酮91a(100mg,404.35μmol,39.39%yield)。
MS m/z(ESI):247.9[M+1]
+
第二步
1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-isopropyl-4-(4-((4-(1-oxidothiomorpholine-4-carbonyl)phenyl)ethynyl)phenyl)imidazolidin-2-one
1-((5,6-双(苄氧基)嘧啶-4-基)甲基)-3-异丙基-4-(4-((4-(1-氧化硫代吗啉-4-羰基)苯基)乙炔基)苯基)咪唑啉-2-酮
室温下,1-((5,6-双(苄氧基)嘧啶-4-基)甲基)-4-(4-碘代苯基)-3-异丙基咪唑啉-2-酮21e(50mg,78.80μmol)和(4-乙炔基苯基)(1-氧化硫代吗啉)甲酮91a(38.98mg,157.60μmol)的水(1.5mL)溶液中,依次加入双三苯基膦二氯化钯(2.21mg,3.15μmol),四丁基溴化铵(25.40mg,78.80μmol)和哌啶(20.13mg,236.40μmol)。反应升温至70℃搅拌5小时。反应液以乙酸乙酯萃取(30ml×2),分去水层,合并的有机相依次以饱和氯化钠溶液洗涤(30mL×2),无水硫酸钠干燥,过滤,减压浓缩,得到的残留物硅胶柱层析进一步分离纯化(洗脱剂:体系B)纯化,得到1-((5,6-双(苄氧基)嘧啶-4-基)甲基)-3-异丙基-4-(4-((4-(1-氧化硫代吗啉-4-羰基)苯基)乙炔基)苯基)咪唑啉-2-酮91b(30mg,39.79μmol,50.50%yield)。
MS m/z(ESI):754.9[M+1]
+
第三步
5-hydroxy-6-((3-isopropyl-4-(4-((4-(1-oxidothiomorpholine-4-carbonyl)phenyl)ethynyl)phenyl)-2-oxoimidazolidin-1-yl)methyl)pyrimidin-4(3H)-one
5-羟基-6-((3-异丙基-4-(4-((4-(1-氧化硫代吗啉-4-羰基)苯基)乙炔基)苯基)-2-氧代咪唑啉-1-基)甲基)嘧啶-4(3H)-酮
将1-((5,6-双(苄氧基)嘧啶-4-基)甲基)-3-异丙基-4-(4-((4-(1-氧化硫代吗啉-4-羰基)苯基)乙炔基)苯基)咪唑啉-2-酮91b(30mg,39.79μmol)加入到2mL二氯甲烷中,加入三氯化硼(0.8mL),室温反应1小时。反应完全后,加入甲醇淬灭,减压浓缩,残留物通过制备液相进一步分离纯化,得到5-羟基-6-((3-异丙基-4-(4-((4-(1-氧化硫代吗啉-4-羰基)苯基)乙炔基)苯基)-2-氧代咪唑啉-1-基)甲基)嘧啶-4(3H)-酮91(8mg,11.57μmol,29.08%yield)。
MS m/z(ESI):574.2[M+1]
+
实施例92
2-hydroxy-N-(4-((4-(1-((5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)methyl)-3-isopropyl-2-oxoimidazolidin-4-yl)phenyl)ethynyl)benzyl)acetamide
2-羟基-N-(4-((4-(1-((5-羟基-6-氧代-1,6-二氢嘧啶-4-基)甲基)-3-异丙基-2-氧代咪唑啉-4-基)苯基)乙炔基)苄基)乙酰胺
N-(4-ethynylbenzyl)-2-hydroxyacetamide
N-(4-乙炔基苄基)-2-羟基乙酰胺
将(4-乙炔基苯基)甲胺92a(600mg,3.58mmol,S02)和2-羟基乙酸92b(326.64mg,4.30mmol)加入到2mL二氯甲烷中,依次加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(1.10g,5.73mmol),4-二甲氨基吡啶(43.73mg,357.92μmol),室温反应过夜。反应完全后,反应液以二氯甲烷萃取(30ml×2),分去水层,合并的有机相依次以饱和氯化钠溶液洗涤(30mL×2),无水硫酸钠干燥,过滤,减压浓缩,得到的残留物硅胶柱层析进一步分离纯化(洗脱剂:体系C)纯化,得到N-(4-乙炔基苄基)-2-羟基乙酰胺92c(300mg,1.59mmol,44.30%yield)。
MS m/z(ESI):190.2[M+1]
+
第二步
N-(4-((4-(1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-isopropyl-2-oxoimidazolidin-4-yl)phenyl)ethynyl)benzyl)-2-hydroxyacetamide
N-(4-((4-(1-((5,6-双(苄氧基)嘧啶-4-基)甲基)-3-异丙基-2-氧代咪唑啉-4-基)苯基)乙炔基)苄基)-2-羟基乙酰胺
室温下,向1-((5,6-双(苄氧基)嘧啶-4-基)甲基)-4-(4-碘代苯基)-3-异丙基咪唑啉-2-酮21e(60mg,94.56μmol)和N-(4-乙炔基苄基)-2-羟基乙酰胺92c(35.78mg,189.12μmol)的水(1mL)溶液中,依次加入双三苯基膦二氯化钯(2.65mg,3.78μmol),四丁基溴化铵(30.48mg, 94.56μmol)和哌啶(24.16mg,283.69μmol),反应升温至70℃搅拌5小时。反应液以乙酸乙酯萃取(30ml×2),分去水层,合并的有机相依次以饱和氯化钠溶液洗涤(30mL×2),无水硫酸钠干燥,过滤,减压浓缩,得到的残留物硅胶柱层析进一步分离纯化(洗脱剂:体系B)纯化,得到N-(4-((4-(1-((5,6-双(苄氧基)嘧啶-4-基)甲基)-3-异丙基-2-氧代咪唑啉-4-基)苯基)乙炔基)苄基)-2-羟基乙酰胺92d(30mg,43.12μmol,45.60%yield)。
MS m/z(ESI):696.3[M+1]
+
第三步
2-hydroxy-N-(4-((4-(1-((5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)methyl)-3-isopropyl-2-oxoimidazolidin-4-yl)phenyl)ethynyl)benzyl)acetamide
2-羟基-N-(4-((4-(1-((5-羟基-6-氧代-1,6-二氢嘧啶-4-基)甲基)-3-异丙基-2-氧代咪唑啉-4-基)苯基)乙炔基)苄基)乙酰胺
将N-(4-((4-(1-((5,6-双(苄氧基)嘧啶-4-基)甲基)-3-异丙基-2-氧代咪唑啉-4-基)苯基)乙炔基)苄基)-2-羟基乙酰胺92d(20mg,28.74μmol)加入到1.5mL二氯甲烷中,加入三氯化硼(0.8mL),室温反应1小时。反应完全后,加入甲醇淬灭,减压浓缩,残留物通过制备液相进一步分离纯化,得到2-羟基-N-(4-((4-(1-((5-羟基-6-氧代-1,6-二氢嘧啶-4-基)甲基)-3-异丙基-2-氧代咪唑啉-4-基)苯基)乙炔基)苄基)乙酰胺92(8mg,12.03μmol,41.86%yield)。
MS m/z(ESI):516.0[M+1]
+
1H NMR(400MHz,DMSO)δ12.57(br,1H),9.48(s,1H),8.37(t,J=6.4Hz,1H),7.79(s,1H),7.59–7.45(m,6H),7.31(d,J=8.4Hz,2H),4.70(dd,J=9.2,7.2Hz,1H),4.33(d,J=6.3Hz,2H),4.26(d,J=15.6Hz,1H),4.18(d,J=15.6Hz,1H),3.87(s,2H),3.74-3.67(m,4H),3.04(t,J=8.0Hz,1H),1.13(d,J=6.8Hz,3H),0.77(d,J=6.8Hz,3H).
实施例93
4-((4-(1-((5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)methyl)-3-isopropyl-2-oxoimidazolidin-4-yl)phenyl)ethynyl)-N-(2-methoxyethyl)benzamide
4-((4-(1-((5-羟基-6-氧代-1,6-二氢嘧啶-4-基)甲基)-3-异丙基-2-氧代咪唑啉-4-基)苯基)乙炔基)-N-(2-甲氧基乙基)苯甲酰胺
第一步
4-ethynyl-N-(2-methoxyethyl)benzamide
4-乙炔基-N-(2-甲氧基乙基)苯甲酰胺
将4-乙炔基苯甲酸90a(500mg,3.42mmol)和甲氧基乙胺93a(513.95mg,6.84mmol)加入到2mL二氯甲烷中,依次加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(655.87mg,3.42mmol)和4-二甲氨基吡啶(41.80mg,342.13μmol),室温反应过夜。反应液以二氯甲烷萃取(30ml×2),分去水层,合并的有机相依次以饱和氯化钠溶液)洗涤(30mL×2),无水硫酸钠干燥,过滤,减压浓缩,得到的残留物硅胶柱层析进一步分离纯化(洗脱剂:体系A)纯化,得到4-乙炔基-N-(2-甲氧基乙基)苯甲酰胺93b(360mg,1.77mmol,51.77%yield)。
MS m/z(ESI):204.2[M+1]
+
第二步
4-((4-(1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-isopropyl-2-oxoimidazolidin-4-yl)phenyl)ethynyl)-N-(2-methoxyethyl)benzamide
4-((4-(1-((5,6-双(苄氧基)嘧啶-4-基)甲基)-3-异丙基-2-氧代咪唑啉-4-基)苯基)乙炔基)-N-(2-甲氧基乙基)苯甲酰胺
室温下,1-((5,6-双(苄氧基)嘧啶-4-基)甲基)-4-(4-碘代苯基)-3-异丙基咪唑啉-2-酮21e(60mg,94.56μmol)和4-乙炔基-N-(2-甲氧基乙基)苯甲酰胺93b(38.44mg,189.12μmol)的水(1mL)溶液中,依次加入双三苯基膦二氯化钯(2.65mg,3.78μmol),四丁基溴化铵(30.48mg,94.56μmol)和哌啶(24.16mg,283.69μmol),反应升温至70℃搅拌5小时。反应液以乙酸乙酯萃取(30mL×2),分去水层,合并的有机相依次以饱和氯化钠溶液洗涤(30mL×2),无水硫酸钠干燥,过滤,减压浓缩,残留物用硅胶柱层析法(洗脱剂:体系B)纯化,得到4-((4-(1-((5,6-双(苄氧基)嘧啶-4-基)甲基)-3-异丙基-2-氧代咪唑啉-4-基)苯基)乙炔基)-N-(2-甲氧基乙基)苯甲酰胺93d(40mg,56.35μmol,59.59%yield)。
MS m/z(ESI):710.3[M+1]
+
第三步
4-((4-(1-((5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)methyl)-3-isopropyl-2-oxoimidazolidin-4-yl)phenyl)ethynyl)-N-(2-methoxyethyl)benzamide
4-((4-(1-((5-羟基-6-氧代-1,6-二氢嘧啶-4-基)甲基)-3-异丙基-2-氧代咪唑啉-4-基)苯基)乙炔基)-N-(2-甲氧基乙基)苯甲酰胺
将4-((4-(1-((5,6-双(苄氧基)嘧啶-4-基)甲基)-3-异丙基-2-氧代咪唑啉-4-基)苯基)乙炔基)-N-(2-甲氧基乙基)苯甲酰胺93d(40mg,56.35μmol)加入到2mL二氯甲烷中,加入三氯化硼(0.8mL),室温反应1小时。反应完全后,加入甲醇淬灭,减压浓缩,残留物通过制备液相进一步分离纯化,得到4-((4-(1-((5-羟基-6-氧代-1,6-二氢嘧啶-4-基)甲基)-3-异丙基-2-氧代咪唑啉-4-基)苯基)乙炔基)-N-(2-甲氧基乙基)苯甲酰胺93(1.82mg,2.68μmol,4.75%yield)。
MS m/z(ESI):530.2[M+1]
+
1H NMR(400MHz,DMSO)δ9.61(br,1H),8.65(s,1H),7.92-7.89(m,3H),7.64(d,J=8.0,2H),7.58(d,J=8.0Hz,2H),7.52(d,J=8.0Hz,2H),4.71(t,J=8.0,1H),4.24(d,J=15.6Hz,,1H),4.22(d,J=15.6Hz,,1H),3.72-3.67(m,2H),3.47–3.42(m,4H),3.27(s,3H),3.05(t,J=8.0Hz,1H),1.13(d,J=6.8Hz,3H),0.78(d,J=6.4Hz,3H).
根据实施例1-93的合成方法,制备如下的化合物,包括:
生物学评价
测试例1、本发明化合物对LpxC酶学活性抑制测定
以下方法用于测定本发明化合物在体外条件下对重组Pseudomonas aeruginosa LpxC酶学活性的抑制程度。
将实验流程简述如下:受试化合物首先溶解于DMSO中制备为10mM贮存液。反应在96孔微孔板中进行,首先向孔中加入20μL重组Pseudomonas aeruginosa LpxC(购自Signalway Antibody,货号为AP74647-2),终浓度分别为5nM;加入5μL待测化合物,化合物进行4倍稀释,8个浓度点,浓度范围为0.61-10000nM;加入5μL LpxC底物UDP-3-O-(R-3-hydroxydecanoyl)-GlcNAc(购自Biosynth Carbosynth,货号为mu75071),底物终浓度为10μM,于25℃孵育120分钟。随后向反应体系中加入20μL的2.0mg/mL fluorescamine(购自Sigma-Aldrich,货号为F9015,溶剂为1:1dimethylformamide/acetonitrile),混匀,反应10分钟;最后加入50μL的200mM磷酸钠缓冲液(pH 8.0)终止反应,使用微量板读数仪(BMG)进行读数,激发波长和发射波长分别为390nm和495nm。通过与对照组(0.1%DMSO)的荧光强度比值进行比较,计算化合物在各浓度下的百分比抑制率,并通过GraphPad Prism 5软件以化合物浓度对数值-抑制率进行非线性回归分析,获得化合物的IC
50值,具体如下表1所示。
表1 本发明化合物对LpxC酶学活性抑制结果
化合物编号 | IC 50/nM |
实施例7 | 42.45 |
实施例9 | 13.12 |
实施例10 | 22.99 |
实施例11 | 8.00 |
实施例13 | 15.72 |
实施例15 | 33.17 |
实施例16 | 24.69 |
实施例17 | 23.17 |
实施例22 | 36.1 |
实施例23 | 32.08 |
实施例24 | 20.58 |
实施例25 | 28.88 |
实施例26 | 9.55 |
实施例27 | 15.84 |
实施例28 | 35.53 |
实施例31 | 37.4 |
实施例36 | 52.02 |
实施例88 | 14.92 |
实施例90 | 19.99 |
实施例92 | 55.43 |
实施例93 | 60.9 |
结论:本发明化合物对重组Pseudomonas aeruginosa LpxC酶活性抑制的IC
50均小于100nM,对于LpxC酶活性具有显著抑制作用。
测试例2、本发明化合物抗菌活性评价
体外最低抑菌浓度(minimum inhibitory concentration,MIC)测定按照CLSI的指南开展,使用微量肉汤稀释法进行测试。
将实验流程简述如下:受试化合物溶解于DMSO中制备为12.8mg/mL贮存液,而后使用DMSO配置成11个两倍稀释的100×高浓度工作液(体系终浓度为64μg/mL-0.06μg/mL)。将-80℃甘油冻存的菌株(K.Pneumoniae ATCC13883和E.coli ATCC 25922)接到固体琼脂培养基,放置培养箱35℃培养18~24h,完成菌株准备工作,而后收集适量固体平板培养物重悬于生理盐水,混匀,用浊度仪将菌悬液浊度调节至合适的浊度,约含1×10
8cfu/mL细菌,然后将调好浊度的菌悬液用测试培养基稀释至细菌浓度为5×10
5cfu/ml,完成接种液制备。将198μL的接种液接种于96孔板中,随后加入2μL的化合物的100×高浓度工作液,之后将96孔板置于35℃培养18~24h,培养后,通过肉眼观察测试板,完全抑制菌体生长的最低药物浓度为该化合物的最低抑菌浓度(MIC),具体如下表2所示。
表2 本发明化合物的抗菌活性测试结果
结论:本发明化合物对于肺炎杆菌(K.Pneumoniae ATCC13883)和大肠杆菌(E.coli ATCC 25922)均具有较好的抑制作用。
备注:ND表示未测定。
测试例3 本发明化合物ICR小鼠药代动力学研究
1、实验目的
以ICR小鼠为受试动物,采用LC/MS/MS法测定小鼠静脉注射或灌胃给予本发明化合物13,测定其不同时刻血浆中的药物浓度,研究本发明化合物在小鼠体内的药代动力学特征。
2、实验方案
2.1实验药品与动物;
实施例13化合物;
ICR小鼠,雄性,29.0~33.8g,购买于北京维通利华实验动物技术有限公司。
2.2药物配制
静脉注射组:称取适量药物,加入10%HP-β-CD水溶液,涡旋,超声60分钟。加入10μL的1M HCl,涡旋,混匀,pH 3.5-4.0,使用(Rephile,Nylon,0.45μm)过滤,得无色溶液,配置最终配置浓度为0.2mg/mL;
口服灌胃组:称取适量药物,加入10%Solutol HS15-20%HP-β-CD,涡旋,超声30分钟,得到无色溶液,配置最终配置浓度为0.5mg/kg。
2.3给药
ICR小鼠,每个待测化合物分为静脉注射组(每组9只)和灌胃组(每组9只),禁食过夜后分别眼眶静脉注射给药(给药剂量1mg/kg,给药体积5mL/kg)和灌胃给药(给药剂量5mg/kg,给药体积10mL/kg),给药4小时后进食。
3、操作
于给药前和给药后0.083小时、0.25小时、0.5小时、1小时、2小时、4小时、8小时、12小时和24小时经颈眼眶采约0.1mL血液,全血样品置于含EDTA-K2的抗凝管中。血液样本采集后置于冰上,离心分离血浆(离心条件:1500g,10分钟)。收集的血浆分析前存放于–40~–20℃。
用LC-MS/MS测定不同化合物静脉注射和灌胃给药后小鼠血浆中待测化合物含量。
4、药代动力学参数结果
本发明的化合物药代动力学参数如表3所示。
表3 本发明化合物的药代动力学参数结果
结论:本发明实施例13化合物的血药浓度和曲线下面积较高,且生物利用度较高,具有较好的药代动力学性质。
Claims (14)
- 一种通式(I)所示的化合物或其立体异构体、互变异构体或其可药用的盐:其中:X和Y各自独立地选自C或N,且X、Y不同时为N;环A选自4元~6元杂芳基或4元~6元杂环基,优选为5元杂芳基或5元杂环基;L 1选自单键或-CH 2-;R 1相同或不同,各自独立地选自-G 1-R 4;G 1选自单键、-CH 2-或-C(=O)-;R 2相同或不同,各自独立地选自羟基、氰基、卤素、烷基、烷氧基、环烷基、杂环基、芳基或杂芳基,其中所述的烷基、环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个卤素、羟基、氰基或烷氧基的取代基所取代;R 3相同或不同,各自独立地选自羟基、氰基、卤素、烷基、环烷基、杂环基、烷氧基或-C(O)R 5,其中所述的烷基、环烷基、杂环基或烷氧基任选进一步被一个或多个选自卤素、羟基、氰基、烷氧基、-C(O)OR 5或-C(O)NR 6R 7的取代基所取代;R 4选自氰基、卤素、烷基、羟基、烷氧基、环烷基、杂环基、芳基、杂芳基、-C(O)R 5、-C(O)OR 5、-OC(O)R 5、-NR 6R 7、-C(O)NR 6R 7、-SO 2NR 6R 7或-NR 6C(O)R 7,其中所述的烷氧基、烷基、环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个R A所取代;R A选自卤素、羟基、氨基、羟烷基、烷氧基、烷基、环烷基、杂环基、芳基、杂芳基、-C(O)R 5、-C(O)OR 5、-OC(O)R 5、-NR 6R 7、-C(O)NR 6R 7、-SO 2NR 6R 7或-NR 6C(O)R 7的取代基所取代,其中所述的烷基、环烷基、杂环基、芳基、杂芳基任选进一步被一个或多个选自卤素、羟基、氨基、卤代烷基、羟烷基、烷氧基、烷基、环烷基、杂环基、芳基、杂芳基、-C(O)R 5、-C(O)OR 5、-OC(O)R 5、-NR 6R 7、-C(O)NR 6R 7、-SO 2NR 6R 7或-NR 6C(O)R 7的取代基取代;R 5选自氢原子、烷基、环烷基、杂环基、芳基或杂芳基,其中所述的烷基、环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自羟基、卤素、硝基、氰基、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基、杂环基、芳基、杂芳基、=O、-C(O)R 8、-C(O)OR 8、-OC(O)R 8、-NR 9R 10、-C(O)NR 9R 10、-SO 2NR 9R 10或-NR 9C(O)R 10的取代基所取代;R 6和R 7各自独立地选自氢原子、羟基、卤素、烷基、烷氧基、环烷基、杂环基、芳基 或杂芳基,其中所述的烷基、烷氧基、环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自羟基、卤素、硝基、氰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、=O、-C(O)R 8、-C(O)OR 8、-OC(O)R 8、-NR 9R 10、-C(O)NR 9R 10、-SO 2NR 9R 10或-NR 9C(O)R 10的取代基所取代;或者,R 6和R 7与它们相连接的原子一起形成一个4~8元杂环基,其中4~8元杂环基内含有一个或多个N、O、S或SO 2,并且所述的4~8元杂环基任选进一步被一个或多个选自羟基、卤素、硝基、氰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、=O、-C(O)R 8、-C(O)OR 8、-OC(O)R 8、-NR 9R 10、-C(O)NR 9R 10、-SO 2NR 9R 10或-NR 9C(O)R 10的取代基所取代;R 8、R 9和R 10各自独立地选自氢原子、烷基、氨基、环烷基、杂环基、芳基或杂芳基,其中所述的烷基、环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自羟基、卤素、硝基、氨基、氰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、羧基或羧酸酯基的取代基所取代;m为0,1,2或3;n为0,1或2;n优选为0;且p为0、1或2。
- 根据权利要求1~3任一项所述的化合物或其立体异构体、互变异构体或其可药用的盐,其中n选自0。
- 根据权利要求1~3任一项所述的化合物或其立体异构体、互变异构体或其可药用的盐,其中L 1选自-CH 2-。
- 一种药物组合物,所述的药物组合物含有有效剂量的根据权利要求1~9中任何一项所述的化合物或其立体异构体、互变异构体或其可药用的盐,及可药用的载体、赋形剂或它们的组合物。
- 根据权利要求1~9中任何一项所述的化合物或其立体异构体、互变异构体或其可药用的盐,或根据权利要求11所述的药物组合物在制备LPXC抑制剂中的用途。
- 根据权利要求1~9中任何一项所述的化合物或其立体异构体、互变异构体或其可药用的盐,或根据权利要求11所述的药物组合物在制备治疗由LPXC介导的疾病的药物中的用途,其中所述的由LPXC介导的疾病选自革兰氏阴性菌导致的细菌感染。
- 根据权利要求13所述的用途,其中所述的革兰氏阴性菌选自大肠杆菌、绿脓杆菌、变形杆菌、痢疾杆菌、肺炎杆菌、布氏杆菌、伤寒杆菌、不动杆菌属、耶尔森菌属、嗜肺军团菌、百日咳杆菌、志贺菌属、巴斯德菌属、霍乱弧菌、脑膜炎双球菌。
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WO2024083177A1 (zh) * | 2022-10-21 | 2024-04-25 | 浙江海正药业股份有限公司 | 芳香乙炔类衍生物、制备方法和其医药上的用途 |
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