CN110590747B - Compound, preparation method, pharmaceutical composition and application thereof - Google Patents
Compound, preparation method, pharmaceutical composition and application thereof Download PDFInfo
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- CN110590747B CN110590747B CN201810601884.4A CN201810601884A CN110590747B CN 110590747 B CN110590747 B CN 110590747B CN 201810601884 A CN201810601884 A CN 201810601884A CN 110590747 B CN110590747 B CN 110590747B
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 186
- 238000002360 preparation method Methods 0.000 title claims abstract description 74
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 7
- 102100026810 Cyclin-dependent kinase 7 Human genes 0.000 claims abstract description 13
- 101000911952 Homo sapiens Cyclin-dependent kinase 7 Proteins 0.000 claims abstract description 13
- 150000003839 salts Chemical class 0.000 claims abstract description 13
- 229940043355 kinase inhibitor Drugs 0.000 claims abstract description 5
- 239000003757 phosphotransferase inhibitor Substances 0.000 claims abstract description 5
- 238000006243 chemical reaction Methods 0.000 claims description 142
- 229910052799 carbon Inorganic materials 0.000 claims description 49
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 46
- 239000002904 solvent Substances 0.000 claims description 27
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 25
- 125000000217 alkyl group Chemical group 0.000 claims description 19
- 238000000034 method Methods 0.000 claims description 16
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 13
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 11
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 8
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 8
- 238000010511 deprotection reaction Methods 0.000 claims description 8
- 229910052736 halogen Inorganic materials 0.000 claims description 8
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 7
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 7
- 125000000027 (C1-C10) alkoxy group Chemical group 0.000 claims description 6
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 6
- 239000003054 catalyst Substances 0.000 claims description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 229910052763 palladium Inorganic materials 0.000 claims description 5
- 125000004076 pyridyl group Chemical group 0.000 claims description 5
- 239000000126 substance Substances 0.000 claims description 5
- 125000006239 protecting group Chemical group 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical group [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000006650 (C2-C4) alkynyl group Chemical group 0.000 claims 2
- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims 1
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims 1
- 239000002671 adjuvant Substances 0.000 claims 1
- 125000003342 alkenyl group Chemical group 0.000 claims 1
- 125000000304 alkynyl group Chemical group 0.000 claims 1
- 230000002401 inhibitory effect Effects 0.000 abstract description 6
- 201000011510 cancer Diseases 0.000 abstract description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 161
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 89
- 239000000243 solution Substances 0.000 description 75
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 71
- 238000001035 drying Methods 0.000 description 60
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 56
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 56
- 229940126214 compound 3 Drugs 0.000 description 55
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 50
- 229910052938 sodium sulfate Inorganic materials 0.000 description 42
- 239000007787 solid Substances 0.000 description 42
- 229940125898 compound 5 Drugs 0.000 description 38
- 238000004809 thin layer chromatography Methods 0.000 description 38
- 239000007832 Na2SO4 Substances 0.000 description 37
- 229940125782 compound 2 Drugs 0.000 description 37
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 36
- 235000019439 ethyl acetate Nutrition 0.000 description 35
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 29
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 28
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 28
- 229920006395 saturated elastomer Polymers 0.000 description 25
- 238000005160 1H NMR spectroscopy Methods 0.000 description 24
- 239000012074 organic phase Substances 0.000 description 24
- 239000012071 phase Substances 0.000 description 24
- 229940125904 compound 1 Drugs 0.000 description 22
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 21
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 20
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 19
- 238000003756 stirring Methods 0.000 description 19
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 18
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 18
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 17
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 16
- 229910052786 argon Inorganic materials 0.000 description 14
- 238000002156 mixing Methods 0.000 description 14
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 13
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 13
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 13
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 13
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 12
- 238000004440 column chromatography Methods 0.000 description 12
- 239000000706 filtrate Substances 0.000 description 12
- -1 heterocycloalkyl radicals Chemical class 0.000 description 11
- 239000003921 oil Substances 0.000 description 11
- 238000005406 washing Methods 0.000 description 11
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 10
- SRVFFFJZQVENJC-IHRRRGAJSA-N aloxistatin Chemical compound CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](CC(C)C)C(=O)NCCC(C)C SRVFFFJZQVENJC-IHRRRGAJSA-N 0.000 description 10
- 125000005842 heteroatom Chemical group 0.000 description 10
- 229910000027 potassium carbonate Inorganic materials 0.000 description 10
- 238000002953 preparative HPLC Methods 0.000 description 10
- 125000003545 alkoxy group Chemical group 0.000 description 9
- 238000000605 extraction Methods 0.000 description 9
- 238000004293 19F NMR spectroscopy Methods 0.000 description 8
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 8
- 238000010791 quenching Methods 0.000 description 8
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 7
- 125000005428 anthryl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C3C(*)=C([H])C([H])=C([H])C3=C([H])C2=C1[H] 0.000 description 7
- 229910000024 caesium carbonate Inorganic materials 0.000 description 7
- 239000012043 crude product Substances 0.000 description 7
- 125000001624 naphthyl group Chemical group 0.000 description 7
- 125000005561 phenanthryl group Chemical group 0.000 description 7
- 230000000171 quenching effect Effects 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 6
- 239000007821 HATU Substances 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 6
- 239000012267 brine Substances 0.000 description 6
- 239000000284 extract Substances 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 238000010438 heat treatment Methods 0.000 description 6
- 125000001072 heteroaryl group Chemical group 0.000 description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 6
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 6
- 239000003960 organic solvent Substances 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- XSCHRSMBECNVNS-UHFFFAOYSA-N quinoxaline Chemical compound N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 description 6
- 239000008346 aqueous phase Substances 0.000 description 5
- 150000002367 halogens Chemical class 0.000 description 5
- 229910052760 oxygen Inorganic materials 0.000 description 5
- RWWYLEGWBNMMLJ-YSOARWBDSA-N remdesivir Chemical compound NC1=NC=NN2C1=CC=C2[C@]1([C@@H]([C@@H]([C@H](O1)CO[P@](=O)(OC1=CC=CC=C1)N[C@H](C(=O)OCC(CC)CC)C)O)O)C#N RWWYLEGWBNMMLJ-YSOARWBDSA-N 0.000 description 5
- 235000011152 sodium sulphate Nutrition 0.000 description 5
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- 238000006646 Dess-Martin oxidation reaction Methods 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 4
- YLEIFZAVNWDOBM-ZTNXSLBXSA-N ac1l9hc7 Chemical compound C([C@H]12)C[C@@H](C([C@@H](O)CC3)(C)C)[C@@]43C[C@@]14CC[C@@]1(C)[C@@]2(C)C[C@@H]2O[C@]3(O)[C@H](O)C(C)(C)O[C@@H]3[C@@H](C)[C@H]12 YLEIFZAVNWDOBM-ZTNXSLBXSA-N 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 description 4
- 238000007865 diluting Methods 0.000 description 4
- 238000010790 dilution Methods 0.000 description 4
- 239000012895 dilution Substances 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- 229910052717 sulfur Inorganic materials 0.000 description 4
- 229930192474 thiophene Natural products 0.000 description 4
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- 230000005526 G1 to G0 transition Effects 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 229940125773 compound 10 Drugs 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 229910052731 fluorine Inorganic materials 0.000 description 3
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 3
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 3
- 229910052740 iodine Inorganic materials 0.000 description 3
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
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- 229910052757 nitrogen Inorganic materials 0.000 description 3
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 3
- VIMMECPCYZXUCI-MIMFYIINSA-N (4s,6r)-6-[(1e)-4,4-bis(4-fluorophenyl)-3-(1-methyltetrazol-5-yl)buta-1,3-dienyl]-4-hydroxyoxan-2-one Chemical compound CN1N=NN=C1C(\C=C\[C@@H]1OC(=O)C[C@@H](O)C1)=C(C=1C=CC(F)=CC=1)C1=CC=C(F)C=C1 VIMMECPCYZXUCI-MIMFYIINSA-N 0.000 description 2
- LBUJPTNKIBCYBY-UHFFFAOYSA-N 1,2,3,4-tetrahydroquinoline Chemical compound C1=CC=C2CCCNC2=C1 LBUJPTNKIBCYBY-UHFFFAOYSA-N 0.000 description 2
- 125000005940 1,4-dioxanyl group Chemical group 0.000 description 2
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 description 2
- HBEDSQVIWPRPAY-UHFFFAOYSA-N 2,3-dihydrobenzofuran Chemical compound C1=CC=C2OCCC2=C1 HBEDSQVIWPRPAY-UHFFFAOYSA-N 0.000 description 2
- UJOBWOGCFQCDNV-UHFFFAOYSA-N 9H-carbazole Chemical compound C1=CC=C2C3=CC=CC=C3NC2=C1 UJOBWOGCFQCDNV-UHFFFAOYSA-N 0.000 description 2
- 125000006374 C2-C10 alkenyl group Chemical group 0.000 description 2
- 125000005865 C2-C10alkynyl group Chemical group 0.000 description 2
- 102100040428 Chitobiosyldiphosphodolichol beta-mannosyltransferase Human genes 0.000 description 2
- 102000003903 Cyclin-dependent kinases Human genes 0.000 description 2
- 108090000266 Cyclin-dependent kinases Proteins 0.000 description 2
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 2
- 101000891557 Homo sapiens Chitobiosyldiphosphodolichol beta-mannosyltransferase Proteins 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 2
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- 239000002253 acid Substances 0.000 description 2
- DZBUGLKDJFMEHC-UHFFFAOYSA-N acridine Chemical compound C1=CC=CC2=CC3=CC=CC=C3N=C21 DZBUGLKDJFMEHC-UHFFFAOYSA-N 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- 239000012964 benzotriazole Substances 0.000 description 2
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- 238000007796 conventional method Methods 0.000 description 2
- 125000004093 cyano group Chemical group *C#N 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 125000004852 dihydrofuranyl group Chemical group O1C(CC=C1)* 0.000 description 2
- 125000005047 dihydroimidazolyl group Chemical group N1(CNC=C1)* 0.000 description 2
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- 125000005049 dihydrooxadiazolyl group Chemical group O1N(NC=C1)* 0.000 description 2
- 125000005050 dihydrooxazolyl group Chemical group O1C(NC=C1)* 0.000 description 2
- 125000005051 dihydropyrazinyl group Chemical group N1(CC=NC=C1)* 0.000 description 2
- 125000005052 dihydropyrazolyl group Chemical group N1(NCC=C1)* 0.000 description 2
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- 125000005054 dihydropyrrolyl group Chemical group [H]C1=C([H])C([H])([H])C([H])([H])N1* 0.000 description 2
- 125000005056 dihydrothiazolyl group Chemical group S1C(NC=C1)* 0.000 description 2
- 125000005057 dihydrothienyl group Chemical group S1C(CC=C1)* 0.000 description 2
- 125000005058 dihydrotriazolyl group Chemical group N1(NNC=C1)* 0.000 description 2
- 230000008034 disappearance Effects 0.000 description 2
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- 239000007789 gas Substances 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 2
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- 125000002757 morpholinyl group Chemical group 0.000 description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
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- 239000000843 powder Substances 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
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- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 2
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- 150000003254 radicals Chemical class 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 238000009987 spinning Methods 0.000 description 2
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 2
- 238000010998 test method Methods 0.000 description 2
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 2
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 2
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 2
- 238000010792 warming Methods 0.000 description 2
- IRFSXVIRXMYULF-UHFFFAOYSA-N 1,2-dihydroquinoline Chemical compound C1=CC=C2C=CCNC2=C1 IRFSXVIRXMYULF-UHFFFAOYSA-N 0.000 description 1
- BCMCBBGGLRIHSE-UHFFFAOYSA-N 1,3-benzoxazole Chemical compound C1=CC=C2OC=NC2=C1 BCMCBBGGLRIHSE-UHFFFAOYSA-N 0.000 description 1
- WORJRXHJTUTINR-UHFFFAOYSA-N 1,4-dioxane;hydron;chloride Chemical compound Cl.C1COCCO1 WORJRXHJTUTINR-UHFFFAOYSA-N 0.000 description 1
- VMLKTERJLVWEJJ-UHFFFAOYSA-N 1,5-naphthyridine Chemical compound C1=CC=NC2=CC=CN=C21 VMLKTERJLVWEJJ-UHFFFAOYSA-N 0.000 description 1
- FLBAYUMRQUHISI-UHFFFAOYSA-N 1,8-naphthyridine Chemical compound N1=CC=CC2=CC=CN=C21 FLBAYUMRQUHISI-UHFFFAOYSA-N 0.000 description 1
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 1
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 1
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 description 1
- AWBOSXFRPFZLOP-UHFFFAOYSA-N 2,1,3-benzoxadiazole Chemical compound C1=CC=CC2=NON=C21 AWBOSXFRPFZLOP-UHFFFAOYSA-N 0.000 description 1
- HRCMXYXVAWHBTH-UHFFFAOYSA-N 2,3-dihydro-1,3-benzoxazole Chemical compound C1=CC=C2OCNC2=C1 HRCMXYXVAWHBTH-UHFFFAOYSA-N 0.000 description 1
- YJUFGFXVASPYFQ-UHFFFAOYSA-N 2,3-dihydro-1-benzothiophene Chemical compound C1=CC=C2SCCC2=C1 YJUFGFXVASPYFQ-UHFFFAOYSA-N 0.000 description 1
- BPXKZEMBEZGUAH-UHFFFAOYSA-N 2-(chloromethoxy)ethyl-trimethylsilane Chemical compound C[Si](C)(C)CCOCCl BPXKZEMBEZGUAH-UHFFFAOYSA-N 0.000 description 1
- UXGVMFHEKMGWMA-UHFFFAOYSA-N 2-benzofuran Chemical compound C1=CC=CC2=COC=C21 UXGVMFHEKMGWMA-UHFFFAOYSA-N 0.000 description 1
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 description 1
- BMIBJCFFZPYJHF-UHFFFAOYSA-N 2-methoxy-5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine Chemical compound COC1=NC=C(C)C=C1B1OC(C)(C)C(C)(C)O1 BMIBJCFFZPYJHF-UHFFFAOYSA-N 0.000 description 1
- VHMICKWLTGFITH-UHFFFAOYSA-N 2H-isoindole Chemical compound C1=CC=CC2=CNC=C21 VHMICKWLTGFITH-UHFFFAOYSA-N 0.000 description 1
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 229940125888 CDK7 inhibitor Drugs 0.000 description 1
- 108050006400 Cyclin Proteins 0.000 description 1
- 102000016736 Cyclin Human genes 0.000 description 1
- 102100030011 Endoribonuclease Human genes 0.000 description 1
- 101710199605 Endoribonuclease Proteins 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 229910010084 LiAlH4 Inorganic materials 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 1
- YNHIGQDRGKUECZ-UHFFFAOYSA-L PdCl2(PPh3)2 Substances [Cl-].[Cl-].[Pd+2].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-L 0.000 description 1
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- 101710113029 Serine/threonine-protein kinase Proteins 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000012300 argon atmosphere Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 125000002393 azetidinyl group Chemical group 0.000 description 1
- RFRXIWQYSOIBDI-UHFFFAOYSA-N benzarone Chemical compound CCC=1OC2=CC=CC=C2C=1C(=O)C1=CC=C(O)C=C1 RFRXIWQYSOIBDI-UHFFFAOYSA-N 0.000 description 1
- MXMZCLLIUQEKSN-UHFFFAOYSA-N benzimidazoline Chemical compound C1=CC=C2NCNC2=C1 MXMZCLLIUQEKSN-UHFFFAOYSA-N 0.000 description 1
- QRUDEWIWKLJBPS-UHFFFAOYSA-N benzotriazole Chemical compound C1=CC=C2N[N][N]C2=C1 QRUDEWIWKLJBPS-UHFFFAOYSA-N 0.000 description 1
- IPWKHHSGDUIRAH-UHFFFAOYSA-N bis(pinacolato)diboron Chemical compound O1C(C)(C)C(C)(C)OB1B1OC(C)(C)C(C)(C)O1 IPWKHHSGDUIRAH-UHFFFAOYSA-N 0.000 description 1
- UWTDFICHZKXYAC-UHFFFAOYSA-N boron;oxolane Chemical compound [B].C1CCOC1 UWTDFICHZKXYAC-UHFFFAOYSA-N 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 230000022131 cell cycle Effects 0.000 description 1
- WCZVZNOTHYJIEI-UHFFFAOYSA-N cinnoline Chemical compound N1=NC=CC2=CC=CC=C21 WCZVZNOTHYJIEI-UHFFFAOYSA-N 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 125000001070 dihydroindolyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- VFRSADQPWYCXDG-LEUCUCNGSA-N ethyl (2s,5s)-5-methylpyrrolidine-2-carboxylate;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.CCOC(=O)[C@@H]1CC[C@H](C)N1 VFRSADQPWYCXDG-LEUCUCNGSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- FFUAGWLWBBFQJT-UHFFFAOYSA-N hexamethyldisilazane Chemical compound C[Si](C)(C)N[Si](C)(C)C FFUAGWLWBBFQJT-UHFFFAOYSA-N 0.000 description 1
- USZLCYNVCCDPLQ-UHFFFAOYSA-N hydron;n-methoxymethanamine;chloride Chemical compound Cl.CNOC USZLCYNVCCDPLQ-UHFFFAOYSA-N 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 125000001967 indiganyl group Chemical group [H][In]([H])[*] 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 125000002510 isobutoxy group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])O* 0.000 description 1
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 1
- ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical compound C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 description 1
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- OBJNFLYHUXWUPF-IZZDOVSWSA-N n-[3-[[5-chloro-4-(1h-indol-3-yl)pyrimidin-2-yl]amino]phenyl]-4-[[(e)-4-(dimethylamino)but-2-enoyl]amino]benzamide Chemical compound C1=CC(NC(=O)/C=C/CN(C)C)=CC=C1C(=O)NC1=CC=CC(NC=2N=C(C(Cl)=CN=2)C=2C3=CC=CC=C3NC=2)=C1 OBJNFLYHUXWUPF-IZZDOVSWSA-N 0.000 description 1
- 125000006606 n-butoxy group Chemical group 0.000 description 1
- 125000003506 n-propoxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 description 1
- 125000005968 oxazolinyl 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
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 1
- 238000012746 preparative thin layer chromatography Methods 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000005412 pyrazyl group Chemical group 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical compound C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a compound, a preparation method, a pharmaceutical composition and application thereof. The compound I, stereoisomer or pharmaceutically acceptable salt thereof can be used as CDK7 kinase inhibitor, has high inhibitory activity, and can be used for treating various malignant tumors.
Description
Technical Field
The invention relates to a compound, a preparation method, a pharmaceutical composition and application thereof.
Background
Cyclin-dependent protein kinases (CDKs), a group of serine/threonine protein kinases, act as key regulators of the cell cycle in concert with cyclin. 20 CDK family members have been found in mammals. The CDK7 has been proved to have close relation with the occurrence and development of various malignant tumors, and the CDK7 inhibitor has the potential of treating various malignant tumors such as leukemia, breast cancer and the like.
Disclosure of Invention
The invention provides a compound, a preparation method, a pharmaceutical composition and application thereof. The compound can be used as a CDK7 kinase inhibitor, has high inhibitory activity and can be used for treating various malignant tumors.
The invention mainly solves the technical problems through the following technical scheme.
The invention provides a compound shown in a general formula I, a stereoisomer or pharmaceutically acceptable salt thereof,
wherein ring A is C3-C20Cycloalkyl (e.g. C)3-C6Cycloalkyl, preferably cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), C6-C20Aryl (e.g. C)6-C14Aryl, preferably phenyl, naphthyl, anthryl or phenanthryl), C1-C20Heteroaryl (e.g. C)1-C10Heteroaryl, preferably pyridineRadical) or C2-C20A heterocycloalkyl group;
ring B is C6-C20Aryl (e.g. C)6-C14Aryl, preferably phenyl, naphthyl, anthryl or phenanthryl), C3-C20Cycloalkyl (e.g. C)3-C6Cycloalkyl, preferably cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl) or C1-C20Heteroaryl (e.g. C)1-C10Heteroaryl, preferably pyridyl);
R1is H or C1-C10Alkyl (e.g. C)1-C4Alkyl, preferably methyl, ethyl, propyl or butyl);
R2is H, C1-C10Alkyl (e.g. C)1-C4Alkyl, preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl), C2-C10Alkenyl (e.g. C)2-C4Alkenyl, preferably
)、C2-C10Alkynyl (e.g. C)2-C4Alkynyl, preferably
)、C6-C20Aryl or C3-C20Cycloalkyl (e.g. C)3-C6Cycloalkyl, preferably cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl);
R3is H, C6-C20Aryl or C1-C20A heteroaryl group;
or, R2And R3Taken together with the atoms to which they are attached form a 5-7 membered heteroaryl, a 5-7 membered cycloalkyl or a 5-7 membered heterocycloalkyl; what is needed isThe 5-7 membered heteroaryl or the 5-7 membered heterocycloalkyl has a heteroatom selected from N, O and S, the number of heteroatoms being 1-4;
m is 0, 1 or 2;
R4at any position, each R4Independently of one another, halogen, C1-C10Alkyl, hydroxy, C1-C10Alkoxy, amino, nitro, cyano, or C substituted by halogen1-C10An alkyl group;
R5is composed of
Wherein n1 is 0 or 1; r5aAnd R5bIndependently is H or C1- C10An alkyl group; r5cIs H, halogen, C1-C10Alkyl radical, C1-C10Alkoxy, or substituted or unsubstituted C2-C20Heterocycloalkyl, said substituted C2-C20The substituent in the heterocycloalkyl group being C1-C10An alkyl group; said substituted or unsubstituted C2-C20Carbon atoms of heterocycloalkyl radicals with
Connecting;
q is 0, 1,2 or 3;
R6at any position, each R6Independently is halogen, substituted or unsubstituted C1-C10Alkyl, substituted or unsubstituted C1-C10Alkoxy, hydroxy, amino, nitro or cyano; said substituted C1- C10Alkyl or said substituted C1-C10Substituents in alkoxy are meant to be substituted by one or more (1-6, e.g. 1-3) of the following groups:
wherein each timeR isaEach RbAnd each RcIndependently is H or C1-C10Alkyl, or Ra、RbAnd the heteroatom attached thereto together form a 4-8 membered heterocyclic group, wherein 4-8 membered heterocyclic group means a 4-8 membered heterocyclic group having 1-4 heteroatoms selected from N, O and S (for example
)；
When R is5cIs H, halogen, C1-C10Alkyl or C1-C10When alkoxy, q is 1,2 or 3; each R6Independently is substituted C1-C10Alkyl or substituted C1-C10An alkoxy group;
L1is composed of
Or is absent; rlaAnd RlbIndependently H, C1-C10Alkyl or C substituted by halogen1-C10An alkyl group; or RlaAnd RlbTogether with the carbon atom to which they are attached form C3-C6A cycloalkyl group;
the alkyl group of (a),
The amino terminus of (a) is linked to the ring A; l is1Wherein, the carbon marked by the letter is S configuration chiral carbon, R configuration chiral carbon or achiral carbon;
L2is composed of
Or is absent;
wherein, said C1-C20Heteroaryl means a C having 1 to 4 heteroatoms selected from N, O and S1-C20A heteroaryl group; said C2-C20Heterocycloalkyl means a heteroatom selected from NO and S, C having 1 to 4 hetero atoms2-C20A heterocycloalkyl group.
In a preferred embodiment of the invention, in the compounds of the formula I, R5cWherein said substituted or unsubstituted C2-C20The heterocycloalkyl structure is preferably as follows:
wherein N is 1,2, 3, 4 or 5, and Z is C, O or N; when Z is O or N, R55Or R56Is absent; r51、 R52、R53、R54、R55And R56Independently is H or C1-C10An alkyl group.
In a preferred embodiment of the invention, in the compounds of the formula I, R5cPreferably substituted C2-C20A heterocycloalkyl group.
In a preferred embodiment of the invention, in the compounds of the formula I, R5cPreferably substituted C2-C20Heterocycloalkyl, said substituent preferably being C1-C10An alkyl group.
In a preferred embodiment of the invention, in the compounds of the formula I, R5cPreferably substituted C2-C20Heterocycloalkyl, the heteroatom being N, said substituent preferably being on N.
In a preferred embodiment of the invention, in the compounds of formula I, when R is5cIs substituted or unsubstituted C2-C20When it is heterocycloalkyl, said "C2-C20Heterocycloalkyl "is preferred
In a preferred embodiment of the invention, in the compounds of the formula I, R5cPreference is given to
(e.g. in
)、
(e.g. in
)、
(e.g. in
) Or
(e.g. in
). Wherein, the carbon marked by the letter is S configuration chiral carbon, R configuration chiral carbon or achiral carbon.
In a preferred embodiment of the invention, when R is6Is substituted C1-C10Alkyl or substituted C1-C10An alkoxy group; said substituted C1-C10Alkyl or said substituted C1-C10Substituents in alkoxy radicals
When the substitution is carried out,
in, RaAnd RbIs C1-C10An alkyl group; wherein R isaAnd RbThe same or different.
In a preferred embodiment of the invention, when L1Is composed of
(e.g. in
) When the current is over; rlaAnd RlbOne is H and the other is C1-C10An alkyl group; l is1In the formula (I), the carbon marked by the letter is S configuration chiral carbon, R configuration chiral carbon or achiral carbon.
In a preferred embodiment of the invention, when L1Is composed of
(e.g. in
) And R islaAnd RlbOne is H and the other is C1-C10When it is alkyl; l is1In (b), the carbon marked with a @isan R-configuration chiral carbon.
In a preferred embodiment of the invention, when L1Is composed of
(e.g. in
) When the current is over; rlaAnd RlbOne is H and the other is C1-C10An alkyl group; l is1In (b), the carbon marked with a ×, is an S-configuration chiral carbon.
In a preferred embodiment of the present invention, in the compound of formula I,
ring A is C6-C20Aryl (e.g. C)6-C14Aryl, preferably phenyl, naphthyl, anthryl or phenanthryl);
ring B is C6-C20Aryl (e.g. C)6-C14Aryl, preferably phenyl, naphthyl, anthryl or phenanthryl) or C1-C20Heteroaryl (e.g. C)1-C10Heteroaryl, preferably pyridyl);
R1is H;
R2is C1-C10Alkyl (e.g. C)1-C4Alkyl, preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl), C2-C10Alkenyl (e.g. C)2-C4Alkenyl, preferably
)、C2-C10Alkynyl (e.g. C)2-C4Alkynyl, preferably
) Or C3-C20Cycloalkyl (e.g. C)3-C6Cycloalkyl, preferably cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl);
R3is H;
m is 0;
R5is composed of
Wherein R is5cIs H, or substituted or unsubstituted C2-C20Heterocycloalkyl (e.g. phenyl)
Wherein, the carbon marked by the letter is S configuration chiral carbon, R configuration chiral carbon or achiral carbon);
q is 0 or 1; r6In any position, R6Is substituted C1-C10Alkyl or substituted C1-C10An alkoxy group; said substituted C1-C10Alkyl or said substituted C1-C10Substituents in alkoxy are meant to be substituted by one or more (1-6, e.g. 1-3) of the following groups:
wherein each R isaEach RbAnd each RcIndependently is H or C1-C10Alkyl, or Ra、RbAnd the heteroatom to which they are attached together form a 4-8 membered heterocyclic group (e.g.
)；
L1Is composed of
(e.g. in
)；RlaAnd RlbIndependently H, C1-C10Alkyl or C substituted by halogen1-C10An alkyl group; l is1Wherein, the carbon marked by the letter is S configuration chiral carbon, R configuration chiral carbon or achiral carbon;
L2is absent.
In a preferred embodiment of the present invention, in the compound of formula I,
ring A is C6-C20Aryl (e.g. C)6-C14Aryl, preferably phenyl, naphthyl, anthryl or phenanthryl);
ring B is C6-C20Aryl (e.g. C)6-C14Aryl, preferably phenyl, naphthyl, anthryl or phenanthryl) or C1-C20Heteroaryl (e.g. C)1-C10Heteroaryl, preferably pyridyl);
R1is H;
R2is C3-C20Cycloalkyl (e.g. C)3-C6Cycloalkyl, preferably cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl);
R3is H;
m is 0;
R5is composed of
Wherein R is5cIs substituted or unsubstituted C2-C20Heterocycloalkyl (e.g. phenyl)
Wherein, the carbon marked by the letter is S configuration chiral carbon, R configuration chiral carbon or achiral carbon);
q is 0;
L1is composed of
(e.g. in
)；RlaAnd RlbOne is H and the other is C1- C10An alkyl group; l is1Wherein, the carbon marked by the letter is S configuration chiral carbon, R configuration chiral carbon or achiral carbon;
L2is absent.
In a preferred embodiment of the present invention, the compound represented by the general formula I or a salt thereof is preferably any one of the following compounds: wherein, the carbon marked by the letter is S configuration chiral carbon, R configuration chiral carbon or achiral carbon;
a compound 11-1-P2 is prepared by chiral resolution of a compound 11-1-5 shown as follows by using an SFC device:
the resolution conditions and methods of the chiral resolution:
stationary phase (Column) chiral pak IC-H Daicel chemical Industries, Ltd,250 x 30mm i.d.,5 um; mobile phase A (Mobile phase A) Supercritical CO2Mobile phase B (mobile phase B) Ethanol (0.1% NH)3H2O); a: B60: 40at 50ml/min (flow rate); column Temperature 38 deg.C; nozle Pressure 100 Bar; nozle temp. 60 deg.C; evaporator temp. 20 deg.C; the temperature of the Trimmer Temp is 25 ℃; wave length is UV 220 nm; rt 6.08 min.
A compound 11-3-P2 is prepared by chiral resolution of a compound 11-3-5 shown as the following by SFC equipment;
the conditions and methods of the chiral resolution:
stationary phase (Column) chiral pak IC-H Daicel chemical Industries, Ltd,250 x 30mm i.d.,5 um; mobile phase A (Mobile phase A) Supercritical CO2Mobile phase B (mobile phase B) Ethanol (0.1% NH)3H2O); a: B60: 40at 50ml/min (flow rate); column Temperature 38 deg.C; nozle Pressure 100 Bar; nozle temp. 60 deg.C; evaporator temp. 20 deg.C; the temperature of the Trimmer Temp is 25 ℃; wave length is UV 220 nm; rt is 6.883 min.
The invention also provides a preparation method of the compound shown in the general formula I, which comprises the following steps: in a solvent, under the protection of gas and the action of alkali and a palladium catalyst, carrying out the reaction shown as the following on the compound shown as the general formula I-A and the compound shown as the general formula I-B;
wherein, the compound shown as the general formula I-AIn which X is halogen (e.g. F, Cl, Br or I) and M is
Wherein R isb1And Rb2Independently is hydroxy or C1-C10Alkoxy, or Rb1And Rb2Together with boron atoms (B) to form
L2Absent, the remaining individual letters and radical definitions are as previously described.
In the preparation method of the compound shown in the general formula I, the reaction method and conditions are conventional in the field. The following conditions are preferred in the present invention:
the solvent is preferably an organic solvent or a mixed solvent of an organic solvent and water. The organic solvent is preferably an ether solvent, such as 1, 4-dioxane. When the solvent is a mixed solvent of an organic solvent and water, the amounts of the organic solvent and water are not particularly limited as long as the reaction is not affected, and the volume ratio of the organic solvent to the water is preferably 5: 1. The amount of the solvent to be used is not particularly limited as long as the reaction proceeds.
The gas is preferably an inert gas such as argon.
The base may be a base conventional in the art for such reactions, preferably an inorganic strong base, such as cesium carbonate. The base may be used in an amount conventional for such reactions in the art, and its molar ratio to the compound of formula I-A is preferably 3: 1.
The palladium catalyst may be a palladium catalyst conventional for such reactions in the art, preferably Pd (dppf) Cl2. The palladium catalyst may be used in an amount conventional in such reactions in the art, and its molar ratio to the compound represented by formula I-A is preferably 0.1: 1.
The amount of the compound of formula I-A and the compound of formula I-B may be the amount conventionally used in such reactions in the art, and the molar ratio of the two is preferably 1: 1.2.
The temperature of the reaction may be a temperature conventional in the art for such reactions, preferably 100 ℃.
The progress of the reaction can be monitored by detection methods conventional in the art (e.g., TLC, GC, HNMR, or HPLC, etc.), preferably by detecting the disappearance of the compounds of formula I-A and formula I-B as the end point of the reaction. The reaction time is preferably 1.5 hours.
After the reaction is finished, the reaction can be treated by adopting a post-treatment method which is conventional in the field.
In a preferred embodiment of the invention, in the compounds of formula I, R is1When the compound is H, the compound can be prepared by the following method, wherein the method comprises the following steps: in a solvent, carrying out deprotection reaction on a compound shown as a general formula I-C as shown in the specification;
wherein R is1Is H, Q is an amino protecting group (e.g., Boc or SEM); the remaining letter and group definitions are as described above.
In the deprotection reaction, the solvent may be a solvent conventional in the art for such reactions, preferably a halogenated hydrocarbon solvent such as dichloromethane. The amount of the solvent to be used is not particularly limited as long as the reaction proceeds. The deprotection reaction is preferably carried out under the action of an acid. The acid is preferably an organic acid, such as trifluoroacetic acid. The temperature of the deprotection reaction may be a temperature conventional in the art for such reactions, preferably room temperature. The progress of the deprotection reaction can be monitored by detection methods conventional in the art (e.g., TLC, GC, HNMR, or HPLC, etc.), preferably as the end point of the reaction when the disappearance of the compound of formula I-C is detected. The reaction time is preferably 0.5 to 1 hour.
After the deprotection reaction is finished, the post-treatment method which is conventional in the field can be adopted for treatment. For example, spin-drying the solvent.
In the present invention, if the crude compound is obtained after the post-treatment, the crude compound can be separated and purified by conventional means such as preparative HPLC, preparative TLC or recrystallization.
In the deprotection reaction, when Q is an amino protecting group, and the amino protecting group can be removed under an acidic condition, the salt of the compound shown in the general formula I can be prepared. For example, when Q is Boc or SEM, it can be removed under the action of trifluoroacetic acid, and accordingly, the trifluoroacetate salt of the compound represented by the general formula I can be prepared.
In the invention, the compound shown in the general formula I can also be prepared into a compound shown in the general formula I, and the compound shown in the other general formula I can be obtained by peripheral modification by adopting a conventional method in the field.
The invention also provides a pharmaceutical composition which comprises the compound shown in the general formula I, a stereoisomer or pharmaceutically acceptable salt thereof and pharmaceutically acceptable auxiliary materials.
The invention also provides an application of the compound shown in the formula I, a stereoisomer or a pharmaceutically acceptable salt thereof in preparing CDK kinase inhibitors.
In the present invention, said C3-C20Cycloalkyl is preferably C3-C6Cycloalkyl radical, said C3-C6The cycloalkyl group is preferably a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group.
In the present invention, said C6-C20Aryl is preferably C6-C14Aryl is preferably phenyl, naphthyl, anthryl or phenanthryl.
In the present invention, said C1-C20The heteroaryl group is preferably selected from N, O and S, C having 1-4 heteroatoms1-C10A heteroaryl group. Said C1-C10Heteroaryl is preferably acridine, carbazole, cinnoline, carboline, quinoxaline, imidazole, pyrazole, pyrrole, indole, indoline, benzotriazole, benzimidazole, furan, thiophene, isothiazole, benzothiophene, dihydrobenzothiophene, benzofuran, isobenzofuran, benzoxazole, benzofurazan, benzopyrazole, quinoline, isoindole, isoquinoline, quinoxaline, imidazole, pyrazole, quinoline, indole, thiophene, quinoxaline, quinoline, thiophene, and mixtures thereof,Oxazole, oxadiazole, isoxazole, indole, pyrazine, pyridopyridine, tetrazolopyridine, pyridazine, pyridine, naphthyridine, pyrimidine, pyrrole, tetrazole, thiadiazole, thiazole, thiophene, triazole, quinazoline, tetrahydroquinoline, dihydrobenzimidazole, dihydrobenzofuran, dihydrobenzoxazole or dihydroquinoline.
In the present invention, said C2-C20The heterocycloalkyl group is preferably C with a heteroatom number of 1 to 4 selected from N, O and S2-C10A heterocycloalkyl group. Said C2-C10The heterocycloalkyl group is preferably an oxazolinyl, oxetanyl, pyranyl, tetrahydropyranyl, azetidinyl, 1, 4-dioxanyl, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, dihydrofuranyl, dihydroimidazolyl, dihydroindolyl, dihydroisoxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, tetrahydrofuranyl or tetrahydrothienyl group.
In the present invention, said C1-C10Alkyl is preferably C1-C4An alkyl group. Said C1-C4The alkyl group is preferably a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a tert-butyl group or an isobutyl group.
In the present invention, the 5-to 7-membered heteroaryl group is preferably a pyrrolyl group, a furyl group, a thienyl group, a pyrazyl group, an imidazolyl group, an oxazolyl group, a thiazolyl group, an isoxazolyl group, a pyridyl group, a pyridazinyl group, a pyrimidinyl group or a pyrazinyl group.
In the present invention, the 5-to 7-membered cycloalkyl group is preferably cyclopentyl, cyclohexyl or cycloheptyl.
In the present invention, the 5-to 7-membered heterocycloalkyl group is preferably a pyranyl group, a tetrahydropyranyl group, a tetrahydrofuranyl group, a piperidyl group, a 1, 4-dioxanyl group, a piperazinyl group, a piperidyl group, a pyrrolidinyl group, a morpholinyl group, a thiomorpholinyl group, a dihydrofuranyl group, a dihydroimidazolyl group, a dihydroisoxazolyl group, a dihydroisothiazolyl group, a dihydrooxadiazolyl group, a dihydrooxazolyl group, a dihydropyrazinyl group, a dihydropyrazolyl group, a dihydropyridinyl group, a dihydropyrimidinyl group, a dihydropyrrolyl group, a dihydrotetrazolyl group, a dihydrothiadiazolyl group, a dihydrothiazolyl group, a dihydrothienyl group, a dihydrotriazolyl group, a tetrahydrofuranyl group or a tetrahydrothienyl group.
In the present invention, the halogen is preferably F, Cl, Br or I.
In the present invention, said C1-C10Alkoxy is preferably C1-C4An alkoxy group. Said C1-C4The alkoxy group is preferably a methoxy group, an ethoxy group, a n-propoxy group, an isopropoxy group, a n-butoxy group, a tert-butoxy group or an isobutoxy group.
In the present invention, said C substituted by halogen1-C10In the alkyl group, the halogens are the same or different and are preferably F, Cl, Br or I. Said C substituted by halogen1-C10Alkyl is preferably C substituted by halogen1-C4Alkyl, for example trifluoromethyl.
In the present invention, said substituted or unsubstituted C2-C20In heterocycloalkyl radicals C2-C20Heterocycloalkyl groups are as defined above. R5cWherein said substituted or unsubstituted C2-C20The heterocycloalkyl structure is preferably as follows:
wherein Z is C or N, and when Z is N, R55Or R56Is absent; r51、 R52、R53、R54、R55And R56Independently is H or C1-C10An alkyl group; wherein C is1-C10Alkyl is as defined above.
The above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.
The reagents and starting materials used in the present invention are commercially available.
In the present invention, room temperature means 10 to 30 ℃.
The positive progress effects of the invention are as follows: the CDK7 kinase inhibitor has high inhibitory activity and can be used for treating various malignant tumors.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods in the following examples, in which specific conditions are not specified, were selected according to conventional methods and conditions, or according to the commercial instructions.
In the following examples, abbreviations are explained:
DCM: dichloromethane; boc2O: di-tert-butyl dicarbonate; PE: petroleum ether; EA: ethyl acetate; rf: a ratio shift value; Dess-Martin: dess-martin oxidizer; DMF: n, N-dimethylformamide; DIEA: n, N-diisopropylethylamine; ACN: acetonitrile; LiHMDS: bis-trimethylsilyl amido lithium; THF: tetrahydrofuran; a dioxane: 1, 4-dioxane; TFA: trifluoroacetic acid; MeOH: methanol; prep-TLC: preparing thin-layer chromatography; DCE: 1, 2-dichloroethane; room temperature: 10-30 ℃; rt: room temperature; HATU: 2- (7-benzotriazole oxide) -N, N, N ', N' -tetramethyluronium hexafluorophosphate; prep-HPLC: preparing a high-performance liquid phase; b is2Pin2: pinacol ester diborate; SEM: (trimethylsilyl) ethoxymethyl; boc: tert-butoxycarbonyl group.
In the following examples, room temperature means 10-30 ℃; overnight means 8-15 hours, e.g., 12 hours; eq means equivalent; solvent ratio such as PE/EA refers to the volume ratio.
Example 1
(1) Preparation of Compound 4b
Compound 4a (5.0g,49.5mmol,1.0eq) was dissolved in DCM (50mL) and Boc was added portionwise at 0 deg.C2O (11.75g,54.45mmol,1.1eq), 0.5h at 0 ℃ and TLC indicated complete reaction of the starting material. The reaction mixture was washed with saturated brine, dried over anhydrous sodium sulfate, and subjected to spin-drying to obtain compound 4b (8.5g, 85%)。TLC:PE/EA＝4/1，I2，Rf(Compound 4a) ═ 0.1, Rf(compound 4b) ═ 0.3.
(2) Preparation of Compound 4
Compound 4b (8.5g,42.3mmol,1.0eq) was dissolved in DCM (150mL), Dess-Martin (19.7g,46.5mmol,1.1eq) was added in portions at 0 ℃ and then reacted at 0 ℃ for 1h, after warming to room temperature for 1h, TLC showed the starting material was reacted. The reaction was poured slowly into saturated NaHCO3In the solution, the organic phase is separated and saturated Na is used for the organic phase2SO3The solution was washed with brine, dried over anhydrous sodium sulfate, and subjected to spin-drying to obtain compound 4(5.0g, 62%). TLC PE/EA 4/1, I2，Rf(Compound 4b) ═ 0.3, Rf(compound 4) ═ 0.4.
(3) Preparation of Compound 3
Will (COCl)2(9.85mL,114.79mmol,1.5eq) was added dropwise at room temperature to a solution of Compound 2(15.0 g,76.53mmol,1.0eq) in DCM (100mL), then 2 drops of DMF were added dropwise and reacted at room temperature for 2 h. The DCM was spun down and the residue was taken up three more times with DCM and spun dry. After the residue was dissolved in DCM, it was added slowly dropwise to a solution of compound 1(8.87g,51.27mmol,0.67eq) and DIEA (26.36g,204mmol,2.67eq) in ACN (60mL) at 0 deg.C, after the addition was complete, it was reacted at 0 deg.C for 1h and then allowed to warm to room temperature overnight. Most of the solvent was removed by evaporation, EA was added and dissolved, and the mixture was washed with saturated brine, dried over anhydrous sodium sulfate, and subjected to spin-drying to obtain compound 3(5.5g, 30%). TLC PE/EA 1/1, 254nm, Rf(Compound 1) ═ 0.7, Rf(compound 3) ═ 0.2.
(4) Preparation of Compound 5
LiHMDS (12.8mL,1M,12.8mmol,1.5eq) was added dropwise to a THF (30mL) solution of compound 3(3.0g, 8.54mmol,1.0eq) at-78 deg.C, the reaction was allowed to react at-78 deg.C for 1h, warmed to 0 deg.C for 1h, and then a THF solution of compound 4(2.5g,12.8mmol,1.5eq) was added dropwise to the system at 0 deg.C, allowed to react at 0 deg.C for 1h, and warmed to room temperature overnight. Saturated NH for reaction solution4After quenching with Cl solution, EA was added, washed with brine, dried over anhydrous sodium sulfate, and then applied to a column (PE/EA/DCM: 10/1/1-4/1/1), compound 5(2.0g, 59%) was obtained. TLC PE/EA 4/1, 254nm, Rf(Compound 3) ═ 0.2, Rf(compound 5) ═ 0.7.
(5) Preparation of Compound 11-2-7
Mixing compound 5(200mg,0.5mmol,1.0eq), compound 6(291mg,0.6mmol,1.2 eq), Cs2CO3(494mg,1.5mmol,3.0eq)，Pd(dppf)Cl2(37mg, 0.05mmol,0.1 eq) was added to the dioxane/H2In O (5mL/1mL), the mixture is heated to 100 ℃ under the protection of argon for reaction for 1.5h, and TLC shows that the reaction is finished. After the reaction was cooled to room temperature, EA (20mL) was added, washed with saturated brine, dried over anhydrous sodium sulfate, and then dried by spin-drying to obtain a crude product. The crude was dissolved in DCM (2mL), TFA (0.5mL) was added at RT and stirred for 1h at RT, and the reaction was monitored by LCMS. After the DCM was suspended, the residue was dissolved in water (10mL) and the organic phase was discarded after three back extractions of DCM. NaHCO for aqueous phase3The solid was adjusted to pH 7-8 and extracted three times with DCM. The organic phases were combined and dried over anhydrous sodium sulfate and the crude product obtained after spin drying was purified by prep-TLC (DCM/MeOH ═ 6/1 as developing solvent) to give compound 11-2-7(5mg, 2%).
TLC:DCM/MeOH)＝6/1，254nm，Rf(Compound 5) ═ 0.9, Rf(compound 11-2-7) ═ 0.3. LCMS, M +1 is 471.3.1H NMR(400MHz,CD3OD)δ8.57(d,J＝ 2.0Hz,1H),8.25(d,J＝8.8Hz,1H),8.03(dd,J＝8.6,2.4Hz,1H),7.66(s,1H), 7.52(d,J＝6.8Hz,1H),7.46-7.37(m,2H),6.99-6.94(m,1H),6.32(d,J＝15.3 Hz,1H),6.11(s,1H),3.91-3.88(m,1H),3.79-3.69(m,1H),3.10-2.99(m,1H), 2.93-2.91(m,1H),2.19-2.17(m,1H),2.06-2.00(m,2H),1.87-1.78(m,3H),1.55 (d,J＝7.0Hz,3H),1.00-0.82(m,4H),0.69-0.66(m,2H).
Example 2
(1) Preparation of Compound 2
TFA (1mL) was added to a solution of compound 5(350mg,0.88mmol,1.0eq) in DCM (5mL) at room temperature and reacted for 1h at room temperature, TLC indicated complete reaction. With saturated NaHCO3The pH of the solution was adjusted to about 7.5, the organic phase was separated, the aqueous phase was extracted with DCM (2 × 10mL), the organic phases were combined, dried over anhydrous sodium sulfate, and dried to give compound 2(260mg, 99%). TLC PE/EA 4/1, 254nm, Rf(compound 5) ═ 0.5, DCM/MeOH = 10/1, 254nm, Rf(compound 2) ═ 0.2.
(2) Preparation of Compound 3
Compound 2(260mg,0.88mmol,1.0eq) was dissolved in DCE (10mL) and HCHO (712mg, 37% wt in H) was added at room temperature2O,8.8mmol,10.0eq) and anhydrous MgSO4(1g) Stirred at room temperature for 5min, then NaBH (OAc)3(277mg,1.32mmol,1.5eq) was added to the reaction system in portions at 0 ℃ and reacted at 0 ℃ for 1h, then warmed to room temperature and reacted for 0.5h, TLC showed the reaction was complete. Filtration, cake washing with DCM, spin drying of the filtrate and column chromatography (DCM/MeOH-100/1-40/1) afforded compound 3(200mg, 73%). TLC DCM/MeOH-10/1, 254nm, Rf(Compound 2) ═ 0.2, Rf(compound 3) ═ 0.3.
(3) Preparation of Compound 11-1-5
Mixing compound 3(150mg,0.48mmol,1.0eq), compound 6(279mg,0.58mmol, 1.2eq) and Cs2CO3(470mg,1.45mmol,3.0eq) was dissolved in dioxane (10mL) and water (2mL), Pd (dppf) Cl was added2(35mg,0.048mmol,0.1eq), argon replacement, warming to 100 ℃ for 1.5h, TLC indicated complete reaction. After the reaction was cooled to room temperature, EA (20mL) was added, washed with saturated brine, dried over anhydrous sodium sulfate, and then spin-dried to obtain the crude product. The crude product was dissolved in DCM (2mL), TFA (0.5mL) was added at RT and stirred for 1h, and LC-MS monitored that the reaction was complete. The DCM was suspended dry and dissolved in water (10mL), and the organic phase was discarded after 3 back extractions with MTBE. NaHCO for aqueous phase3The solid was adjusted to pH 7-8 and extracted three times with DCM, the organic phases were combined and dried over anhydrous sodium sulphate and spun to give crude 200mg, 100mg of which was purified by prep-TLC (DCM/MeOH-6/1 as developing solvent) to give compound 11-1-5(25mg, 20%).
TLC:DCM/MeOH＝5/1，254nm，Rf(Compound 3) ═ 0.6, Rf(compound 11-1-5) ═ 0.3. LCMS M + 1-485.3.1H NMR(400MHz,DMSO-d6)δ12.03(s,1H), 10.76(s,1H),10.42(s,1H),8.63(d,J＝2.4Hz,1H),8.29(d,J＝8.8Hz,1H),8.08 (dd,J＝8.8,2.4Hz,1H),7.71(s,1H),7.57(d,J＝7.6Hz,1H),7.47-7.33(m,2H), 6.71-6.70(m,1H),6.46(d,J＝15.6Hz,1H),6.15(s,1H),3.97-3.86(m,1H),3.05 (s,1H),2.76(s,1H),2.22(s,3H),2.01(s,1H),1.86-1.67(m,3H),1.59(s,1H), 1.43(d,J＝6.8Hz,3H),1.24(s,1H),0.88(d,J＝8.4Hz,2H),0.62(d,J＝3.2Hz, 2H).
Example 3
(1) Preparation of Compound 4b-1
Compound 4a-1(5.0g,49.5mmol,1.0eq) was dissolved in DCM (50mL) and Boc was added portionwise at 0 deg.C2O (11.75g,54.45mmol,1.1eq), 0.5h at 0 ℃ and TLC showed the feed was complete. The reaction mixture was washed with saturated brine and sodium sulfateDrying, spin-drying and column chromatography (PE/EA-10/1) gave compound 4b-1(8.5g, 85%). TLC PE/EA 4/1, I2，Rf(Compound 4a-1) ═ 0.1, Rf(compound 4b-1) ═ 0.3.
(2) Preparation of Compound 4-1
Compound 4b-1(8.5g,42.3mmol,1.0eq) was dissolved in DCM (150mL) and Dess-Martin (19.7g,46.5mmol,1.1eq) was added in portions at 0 deg.C, reacted at 0 deg.C for 1h, then warmed to room temperature for 1h and TLC showed the starting material was reacted. The reaction was poured slowly into saturated NaHCO3Separating organic phase from the solution, and adding saturated Na2SO3The solution was washed, washed with brine, dried over sodium sulfate, spin-dried, and subjected to column chromatography (PE/EA ═ 10/1) to give compound 4-1(7.0g, 82%). TLC PE/EA 4/1, I2，Rf(Compound 4b-1) ═ 0.3, Rf(compound 4-1) ═ 0.4.
(3) Preparation of Compound 3
Will (COCl)2(6.6mL,76.5mmol,1.5eq) was added dropwise to a solution of Compound 2(10.0 g,51mmol,1.0eq) in DCM (80mL) at RT, then 2 drops of DMF were added dropwise and the reaction was carried out for 2-3h at RT. The DCM was spun off, taken up several times with DCM and then dissolved with DCM, and compound 1(5.92g,34.1mmol,0.67eq) and DIEA (17.6g, 136.2mmol,2.67eq) were added slowly dropwise to a solution of compound 1 (60mL) in acetonitrile at 0 deg.C, reacted for 1h at 0 deg.C and then allowed to warm to room temperature overnight. Most of the solvent was removed by evaporation, the residue was dissolved in EA, washed with saturated brine, dried over sodium sulfate, dried by spin-drying, and subjected to column chromatography (PE/EA ═ 3/1) to give compound 3(3.0g, 25%). TLC PE/EA 1/1, 254nm, Rf(Compound 1) ═ 0.7, Rf(compound 3) ═ 0.2.
(4) Preparation of Compound 5-1
LiHMDS (12.8mL,1M,12.8mmol,1.5eq) was added dropwise to a THF (30mL) solution of compound 3(3.0g, 8.54mmol,1.0eq) at-78 deg.C, the reaction was allowed to react at-78 deg.C for 1h, warmed to 0 deg.C for 1h, and then a THF solution of compound 4-1(2.5g,12.8mmol,1.5 eq) was added dropwise to the system at 0 deg.C for 1h, and then warmed to room temperature overnight. With saturated NH4The Cl solution was quenched, EA was added, washed with brine, dried over sodium sulfate, spun dry, and column filtered (PE/EA/DCM: 10/1/1, 4/1/1) to give compound 5-1(2.0g, 59%). TLC PE/EA 4/1, 254nm, Rf(Compound 3) ═ 0.2, Rf(compound 5-1) ═ 0.7.
(5) Preparation of Compound 11-4-7
Mixing 5-1(137mg,0.35mmol,1.0eq), 6(200mg,0.42mmol, 1.2eq), Cs2CO3(339mg,1.0mmol,3.0eq)，Pd(dppf)Cl2(20mg,0.03mmol, 0.08eq) was added to the dioxane/H2Reacting with O (5mL/1mL) under argon atmosphere at 120 deg.C for 2h, separating with EA and water, washing organic phase with water and saturated saline solution, drying with sodium sulfate, rotary evaporating to dry, adding 3N dioxane hydrochloride solution, stirring at room temperature for 1h, adding NaHCO3The reaction was dried by rotary drying to pH greater than 7, EA was added, the solid was filtered off, the EA was dried and purified by prep-TLC (DCM/MeOH ═ 7:1 as developing solvent) to give compound 11-4-7(10mg, yield: 6%).
TLC:DCM/MeOH)＝10/1，254nm，Rf(Compound 6) ═ 0.9, Rf(compound 11-4-7) ═ 0.3. LCMS M + 1-471.4.1H NMR(400MHz,DMSO-d6)δ12.02 (br s,1H),10.79(s,1H),10.40(s,1H),8.62(d,J＝2.0Hz,1H),8.27(d,J＝8.8 Hz,1H),8.07(dd,J＝8.8,2.4Hz,1H),7.70(s,1H),7.56(d,J＝7.6Hz,1H),7.44- 7.36(m,2H),6.88-6.83(m,1H),6.49(d,J＝15.2Hz,1H),6.12(s,1H),4.44(s, 1H),3.92-3.86(m,2H),3.08-2.92(m,2H),2.10-1.95(m,2H),1.86-1.73(m,2H), 1.60-1.52(m,1H),1.43(d,J＝6.8Hz,3H),0.88-0.85(m,2H),0.63-0.59(m,2H).
Example 4
(1) Preparation of Compound 2-a
TFA (1mL) was added to a solution of compound 5-1(350mg,0.88mmol,1.0eq) in DCM (5mL) at room temperature and reacted for 1h at room temperature. TLC showed complete reaction, saturated NaHCO3Adjusting pH of the solution to about 7.5, separating to obtain organic phase, extracting the aqueous phase with DCM (2X 10mL), mixing the organic phase with Na2SO4Drying and spin-drying gave compound 2-a (260mg, 99%). TLC PE/EA 4/1, 254nm, Rf(compound 5-1) ═ 0.5, DCM/MeOH = 10/1, 254nm, Rf(compound 2) ═ 0.2.
(2) Preparation of Compound 3
Compound 2-a (260mg,0.88mmol,1.0eq) was dissolved in DCE (10mL) and HCHO (712mg, 37% wt in H) was added at room temperature2O,8.8mmol,10.0eq) and anhydrous MgSO4(1g) Stirred at room temperature for 5min, then NaBH (OAc)3(277mg,1.32mmol,1.5eq) was added to the reaction system in portions at 0 ℃ and reacted at 0 ℃ for 1h, then warmed to room temperature and reacted for 0.5 h. TLC showed the reaction was complete, filtered, the filter cake was washed with DCM, the filtrate was spun dry and passed through a column (DCM/MeOH-100/1-40/1) to give compound 3-a (200mg, 73%). TLC DCM/MeOH-10/1, 254nm, Rf(Compound 2-a) ═ 0.2, Rf(compound 3-a) ═ 0.3.
(3) Preparation of Compound 11-3-5
Mixing the compound 3-a (200mg,0.64mmol,1.0eq), the compound 6(372mg,0.77mmol, 1.2eq) and Cs2CO3(631mg,1.93mmol,3.0eq) was dissolved in dioxane (10mL) in water (2mL) and Pd (dppf) Cl was added2(47mg,0.064mmol,0.1eq), argon replacement, heating to 100 ℃ for 1.5h, and TLC showed the reaction was complete. After the reaction was cooled to room temperature, EA (20mL) was added, washed with saturated brine and anhydrous Na2SO4Drying and spin-drying to obtain a crude product. The crude product was dissolved in DCM (2mL), TFA (0.5mL) was added at room temperature and stirred at room temperature for 1h, LC-MS monitored reaction completion, DCM was spin-dried, then it was dissolved in water (10mL), back-extracted with DCM 2-3 times, then NaHCO3The solid was adjusted to pH 8, extracted several times with DCM (8 × 10mL), the organic phases combined, anhydrous Na2SO4Drying and spin-drying gave the crude product which was purified by prep-TLC (DCM/MeOH ═ 6/1 as developing solvent) to give compound 11-3-5(35mg, 11%).
TLC:DCM/MeOH＝5/1，254nm，Rf(Compound 3-a) ═ 0.6, Rf(compound 11-3-5) ═ 0.3. LCMS M + 1-485.3.1H NMR(400MHz,DMSO-d6)δ12.02(s,1H), 10.80(s,1H),10.40(s,1H),8.63(d,J＝2.0Hz,1H),8.28(d,J＝8.8Hz,1H),8.08 (dd,J＝8.8,2.4Hz,1H),7.70(s,1H),7.57(d,J＝7.6Hz,1H),7.44-7.36(m,2H), 6.75-6.71(m,1H),6.50(d,J＝15.6Hz,1H),6.14(s,1H),3.93-3.91(m,1H),3.18 (br s,1H),2.34(br s,3H),2.06(br s,1H),1.84-1.78(m,3H),1.66(s,1H),1.43(d, J＝6.8Hz,3H),1.23(s,1H),0.88-0.86(m,2H),0.61-0.60(m,2H).
Example 5
(1) Preparation of Compound 2
LDA (2M in THF,315mL,0.63mol,3.0eq) was added dropwise to a solution of Compound 1(45.0g,0.21mol,1.0eq) in THF (500mL) at 0 deg.C under Ar protection. After the dropwise addition, the reaction is carried out for 30min at 0 ℃. Isoiodopropane (114g,0.67mol,3.2eq) was slowly added dropwise. Stirred at room temperature for 30 min. The reaction was quenched with hydrochloric acid. The reaction mixture was concentrated under reduced pressure to remove the solvent THF. The residue was extracted with EtOAc (3X 200mL), and the extracts were combined and washed with 2N HCl (2X 200 mL). The organic phase was extracted with 10% NaOH (2X 300mL) and the aqueous phases were combined and adjusted to pH 7 with hydrochloric acid. EtOAc (3X 500mL) extraction, combined extracts, washed with water (2X 500mL) and saturated brine (2X 500 mL). Dried over anhydrous sodium sulfate and spin-dried to give compound 2 as a pale yellow oil (45.0g, 84%).
(2) Preparation of Compound 4
Compound 2(2.3g,9.0mmol,2.0eq), compound 3(1.0g,4.5mmol,1.0eq), HATU (3.4g,9.0mmol,2.0eq) and DIEA (1.7g,13.4mmol,3.0eq) were dissolved in DMF (25 mL). The reaction was stirred at 60 ℃ for 16 h. Dilution with water, extraction with EtOAc, concentration of the extract under reduced pressure, and purification on silica gel (PE/EtOAc. 10/1) afforded compound 4(1.9g, 46%) as a colorless oil. TLC, PE/EtOAc 2:1, 254nm, Rf (compound 3) 0.1, and Rf (compound 4) 0.7.
(3) Preparation of Compound 5
Mixing compound 4(680mg,1.47mmol,1.0eq), B2Pin2(470mg,1.76mmol,1.2 eq), KOAc (432mg,4.41mmol,3.0eq) and Pd (dppf) Cl2(52mg,0.07mmol, 0.05eq) was added to dioxane (10 mL). Stirring and reacting for 6 hours at 100 ℃ under the protection of argon. The reaction was concentrated under reduced pressure and purified by column chromatography (PE/EtOAc 10:1) to give compound 5(674mg, 90%) as a colorless oil.
(4) Preparation of Compound 11-5
Mixing compound 5(140mg,0.27mmol,1.1eq), compound 6(78mg,0.25mmol, 1.0eq), Cs2CO3(313mg,0.82mmol,3.0eq)，Pd(dppf)Cl2(18mg,0.025mmol, 0.1eq) in dioxane/H2O (2mL/0.5 mL). Stirring and reacting for 2h at 100 ℃ under the protection of argon. The reaction was concentrated under reduced pressure, and the residue was diluted with EtOAc, washed with water and concentrated under reduced pressure. Obtained CH for solid2Cl2Dissolved (5mL), and TFA (1mL) was added dropwise. The reaction was stirred at room temperature for 1 h. Sat. NaHCO for reaction solution3Washing with anhydrous Na2SO4Drying, concentrating under reduced pressure, and purifying by crude prep-TLC (CH)2Cl2MeOH 10:1) purification followed by prep-HPLC (mobile phase: 0.1% TFA/H)2O/CH3CN) to give compound 11-5 as a white solid, TFA salt (5.7mg, 4%).
LCMS:M+1＝513.3。1H NMR(400MHz,DMSO-d6)δ11.05(s,1H),10.46 (s,1H),9.99(br,1H),8.65(d,J＝2.0Hz,1H),8.30(d,J＝8.4Hz,1H),8.12(dd, J＝8.8,2.4Hz,1H),7.70(s,1H),7.59(d,J＝7.6Hz,1H),7.45-7.37(m,2H), 6.85-6.79(m,1H),6.70(d,J＝15.2Hz,1H),6.13(s,1H),4.11-4.02(m,1H),3.73- 3.65(m,1H),3.37(d,J＝10.8Hz,1H),3.18-3.10(m,1H),2.83(d,J＝4.0Hz, 3H),2.44-2.37(m,1H),2.33-2.28(m,1H),2.13-1.77(m,4H),1.00(d,J＝6.4Hz, 3H),0.90-0.84(m,2H),0.69(d,J＝6.4Hz,3H),0.65-0.58(m,2H)；19F NMR(376 MHz,DMSO-d6):δ-74.05。
Example 6
Preparation of Compound 11-6
Intermediate compound 5(200mg,0.39mmol,1.0eq) of example 5, compound 2(122 mg,0.39mmol,1.0eq), K2CO3(163mg,1.18mmol,3.0eq) and Pd (dppf) Cl2(29mg,0.04mmol,0.1eq) in dioxane/H2O (2mL/0.5 mL). Stirring and reacting for 6h at 80 ℃ under the protection of argon. The reaction was concentrated under reduced pressure, the residue was diluted with EtOAc and washed with water and anhydrous Na2SO4Drying, and concentrating under reduced pressure. Obtained CH for solid2Cl2Dissolved (5mL), and TFA (1mL) was added dropwise. The reaction was stirred at room temperature for 1 h. Sat. NaHCO for reaction solution3Washing with anhydrous Na2SO4Drying, concentrating under reduced pressure, and purifying by pre-TLC (CH)2Cl2MeOH 10:1) purification followed by prep-HPLC (mobile phase: 0.1% TFA/H2O/CH3CN) to give compound 11-6 as a white solid, TFA salt (35.7mg, 15%).
LCMS:M+1＝513.4。1H NMR(400MHz,DMSO-d6)δ11.05(s,1H),10.47 (s,1H),10.01(br,1H),8.65(d,J＝2.0Hz,1H),8.30(d,J＝8.8Hz,1H),8.12(dd, J＝8.4,2.0Hz,1H),7.70(s,1H),7.59(d,J＝7.6Hz,1H),7.45-7.37(m,2H), 6.85-6.79(m,1H),6.70(d,J＝15.2Hz,1H),6.13(s,1H),4.11-4.02(m,1H),3.73- 3.65(m,1H),3.37(d,J＝10.8Hz,1H),3.18-3.09(m,1H),2.83(d,J＝4.4Hz, 3H),2.44-2.38(m,1H),2.33-2.27(m,1H),2.12-1.77(m,4H),1.00(d,J＝6.4Hz, 3H),0.90-0.85(m,2H),0.69(d,J＝6.8Hz,3H),0.65-0.59(m,2H)。19F NMR (376MHz,DMSO-d6):δ-74.39。
Example 7
(1) Preparation of Compound 2
Compound 1(540mg,1.82mmol,1.0eq) was dissolved in DCE (20 mL). Acetone (530mg,9.12mmol,5.0eq), NaBH (OAc) was added at room temperature3(773mg,3.65mmol, 2.0eq), anhydrous MgSO4(1.0g) and acetic acid (1 drop). The reaction was carried out at room temperature for 2 h. Filtering the reaction solution, concentrating the filtrate under reduced pressure, and purifying with Column (CH)2Cl2MeOH: 100:1 to 30:1) gave compound 2 as a brown oil (187 mg, 30%). TLC CH2Cl2:MeOH＝20:1，254nm，Rf(Compound 1) ═ 0.4, Rf(compound 2) ═ 0.5.
(2) Preparation of Compounds 11-7
Compound 2(100mg,0.30mmol,1.0eq), compound 3(142mg,0.30mmol, 1.0eq), K2CO3(123mg,0.89mmol,3.0eq) and Pd (dppf) Cl2(22mg,0.03mmol, 0.1eq) in dioxane/H2O (6.0mL/1.5 mL). Argon shieldThe reaction is stirred for 2 hours at the temperature of 80 ℃. The reaction solution was concentrated under reduced pressure, diluted with EtOAc, washed with water and dried over Na2SO4Drying, and concentrating under reduced pressure. The obtained solid is substituted by CH2Cl2Dissolved (5mL), and TFA (1mL) was added dropwise. The reaction was stirred at room temperature for 1 h. The reaction solution was concentrated under reduced pressure and the crude prep-HPLC (mobile phase: 0.1% TFA/H)2O/CH3CN) to give compound 11-7 as a white solid, TFA salt (19.91mg, 13%).
LCMS:M+1＝513.5。1H NMR(400MHz,DMSO-d6)δ10.70(s,1H),10.41 (s,1H),8.62(d,J＝2.0Hz,1H),8.27(d,J＝8.8Hz,1H),8.21(s,1H),8.08(dd,J ＝8.8,2.4Hz,1H),7.70(s,1H),7.56(d,J＝7.6Hz,1H),7.42(t,J＝7.6Hz,1H), 7.37(d,J＝7.6Hz,1H),6.77-6.71(m,1H),6.44(d,J＝15.6Hz,1H),6.12(s,1H), 3.93-3.88(m,1H),2.89-2.78(m,3H),2.54-2.51(m,1H),1.99-1.89(m,1H),1.85- 1.78(m,1H),1.74-1.67(m,2H),1.58-1.50(m,1H),1.43(d,J＝7.2Hz,3H),1.05 (d,J＝6.4Hz,3H),0.95(d,J＝6.4Hz,3H),0.90-0.85(m,2H),0.63-0.59(m,2H)。 19F NMR(376MHz,DMSO-d6):δ-73.41。
Example 8
(1) Preparation of Compound 2
Compound 1(351mg,1.19mmol,1.0eq) was dissolved in DCE (5 mL). Acetone (344mg,5.93mmol,5.0eq), NaBH (OAc) was added at room temperature3(502mg,2.37mmol, 2.0eq), anhydrous MgSO4(500mg) and acetic acid (1 drop). The reaction was carried out at room temperature for 2 h. Adding CH into the reaction solution2Cl2Diluting, washing with water, and removing anhydrous Na2SO4Drying, concentrating under reduced pressure, and purifying with Column (CH)2Cl2MeOH: 50:1 to 20:1) gave compound 2 as a brown oil (78mg, 19%). TLC CH2Cl2:MeOH＝20:1，254 nm，Rf(Compound 2) ═ 0.4, Rf(compound 3) ═ 0.5.
(2) Preparation of Compounds 11-8
Compound 2(78mg,0.23mmol,1.0eq), compound 3(111mg,0.23mmol, 1.0eq), K2CO3(96mg,0.69mmol,3.0 eq.) and Pd (dppf) Cl2(17mg,0.023mmol, 0.1eq) in dioxane/H2O (4mL/1 mL). Stirring and reacting for 2h at 80 ℃ under the protection of argon. Filtering the reaction solution to obtain filtrate CH2Cl2Diluting, washing with water, and removing anhydrous Na2SO4Drying, and concentrating under reduced pressure. Obtained CH for solid2Cl2Dissolved (5mL), and TFA (1mL) was added dropwise. The reaction was stirred at room temperature for 1 h. The reaction was concentrated under reduced pressure and the crude prep-HPLC (mobile phase: 0.1% TFA/H2O/CH3CN) to yield compound 11-8 as a yellow solid, TFA salt (25.88mg, 22%).
LCMS:M+1＝513.4。1H NMR(400MHz,DMSO-d6)δ11.00(s,1H),10.44 (s,1H),9.80(br,1H),8.65(d,J＝2.4Hz,1H),8.27(d,J＝8.4Hz,1H),8.11(dd, J＝8.8,2.4Hz,1H),7.70(s,1H),7.57(d,J＝7.6Hz,1H),7.45-7.37(m,2H), 6.91-6.85(m,1H),6.68(d,J＝15.2Hz,1H),6.12(s,1H),4.39-4.31(m,1H),3.94- 3.89(m,1H),3.59-3.54(m,1H),3.48-3.42(m,1H),3.31-3.22(m,1H),2.33-2.20 (m,1H),2.05-1.98(m,2H),1.93-1.78(m,2H),1.44(d,J＝6.8Hz,3H),1.30(dd, J＝16.4,6.4Hz,6H),0.89-0.86(m,2H),0.63-0.61(m,2H)。19F NMR(376MHz, DMSO-d6):δ-74.54。
Example 9
(1) Preparation of Compound 3
At room temperature (COCl)2(6.6g,52.32mmol,1.8eq) was added dropwise to CH of Compound 2(6.8g,34.88 mmol,1.2eq)2Cl2(50mL), 2 drops of DMF was added dropwise and the reaction was carried out at room temperature for 2 hours. CH (CH)2Cl2After removal of the residue by CH2Cl2(10mL) after dissolution was added slowly dropwise to a solution of compound 1(5.0g,29.07mmol,1.0eq) and DIEA (15.0g,116.27mmol,4.0eq) in MeCN (50mL) at 0 ℃. The dripping is finishedAfter the reaction is finished, the reaction is carried out for 5 hours at room temperature. The reaction was quenched with water. Adding CH2Cl2Diluted (100mL), washed with saturated brine (2 × 100mL), dried over anhydrous sodium sulfate, and spin-dried, followed by column chromatography (PE/EA: 5/1) to give compound 3(3.9g, 38%) as a yellow solid. TLC PE/EA 1/1, 254nm, Rf(Compound 1) ═ 0.7, Rf(compound 3) ═ 0.2.
(2) Preparation of Compound 5
Li HMDS (1M in THF,7.71mL,7.71mmol,1.5eq) was added dropwise to a solution of compound 3(1.8g,5.14mmol,1.0eq) in THF (20mL) at-78 deg.C under protection of Ar. The reaction solution reacts for 1h at-78 ℃, and then the temperature is raised to 0 ℃ for reaction for 1 h. A solution of Compound 4(1.5g,7.71mmol, 1.5eq) in THF (5mL) was added dropwise at 0 deg.C. The reaction was stirred at room temperature overnight. Saturated NH for reaction4And (4) quenching the Cl solution. EtOAc (30mL) was added, washed with saturated brine (2 × 30mL), dried over anhydrous sodium sulfate, and then applied to a column (PE/EA: 4/1-2/1) to give compound 5(1.2g, 59%) as a pale yellow solid. TLC PE/EA 4/1, 254nm, Rf(Compound 3) ═ 0.2, Rf(compound 5) ═ 0.7.
(3) Preparation of Compound 6
TFA (2mL) was added dropwise to CH of Compound 5(1.2g,3.04mmol) at room temperature2Cl2(10mL) in solution. The reaction was carried out at room temperature for 1 hour. The reaction was concentrated under reduced pressure, and the residue was diluted with water (20mL) and then with saturated NaHCO3The pH of the solution is adjusted to be about 9. CH (CH)2Cl2(3X 20mL) and the combined organic phases are dried over anhydrous Na2SO4And (5) drying and spin-drying. The resulting solid was washed with (PE: EtOAc ═ 1:1) to give compound 6(500mg, 56%) as a white solid.
(4) Preparation of Compound 7
Compound 6(200mg,0.68mmol,1.0eq) was dissolved in DCE (5 mL). Aq.37% (wt%) HCHO (550mg,6.78mmol,10.0eq) and anhydrous MgSO were added at room temperature4(300 mg). Stir at room temperature for 10 min. Addition of NaBH (OAc)3(215mg,1.05mmol,1.5eq) at room temperature for 2 h. Concentrating the reaction solution under reduced pressure, and purifying with Column (CH)2Cl2MeOH ═ 10:1) to give compound 7(150mg, 72%) as a pale yellow solid.
(5) Preparation of Compounds 11-9
Mixing compound 7(50mg,0.16mmol,1.0eq), compound 8(93mg,0.19mmol,1.2 eq) and K2CO3(67mg,0.49mmol,3.0eq) was dissolved in dioxane (5mL) and water (1 mL). Adding Pd (dppf) Cl2(12mg,0.02mmol,0.1 eq). Heating to 80 ℃ under the protection of argon and reacting for 2 hours. Saturated NH for reaction4And (4) quenching the Cl solution. Adding CH to the reaction solution2Cl2(20mL), saturated brine (2X 20mL), anhydrous Na2SO4And (5) drying and spin-drying. The resulting solid is dissolved in CH2Cl2To (5mL) was added TFA (1mL) dropwise. The reaction was stirred at room temperature for 1 h. The reaction was concentrated under reduced pressure, the residue was dissolved in water (10mL), and saturated NaHCO was added3The pH is adjusted to be approximately equal to 9. CH (CH)2Cl2(2X 20mL), the extracts were combined and extracted with anhydrous Na2SO4Drying, spin-drying, and passing through Column (CH)2Cl2MeOH ═ 5: 1). The solid obtained was then subjected to a C18 column (MeCN/H)2O) to yield the product 11-9 as a white solid (12mg, 15%).
LCMS:[M+1]＝484.4。1H NMR(400MHz,DMSO-d6)δ12.02(br,1H), 10.41(s,1H),10.32(br,1H),7.76(d,J＝8.4Hz,2H),7.65(s,1H),7.61(d,J＝ 8.4Hz,2H),7.50(d,J＝8.0Hz,1H),7.38(t,J＝8.0Hz,1H),7.31(d,J＝7.6Hz, 1H),6.75-6.69(m,1H),6.42(d,J＝13.6Hz,1H),6.13(s,1H),3.92-3.86(m,1H), 2.50-2.38(m,5H),2.17-2.07(m,2H),1.91-1.71(m,4H),1.42(d,J＝7.2Hz,3H), 0.89-0.85(m,2H),0.63-0.59(m,2H)。
Example 10
(1) Preparation of Compound 3
LiHMDS (1M in THF,7.71mL,7.71mmol,1.5eq) was added dropwise to a solution of compound 1(1.8g,5.14mmol,1.0eq) in THF (20mL) at-78 deg.C under protection of Ar. The reaction solution reacts for 1h at-78 ℃, and then the temperature is raised to 0 ℃ for reaction for 1 h. A solution of Compound 2(1.5g,7.71mmol, 1.5eq) in THF (5mL) was added dropwise at 0 deg.C. The reaction was stirred at room temperature overnight. Saturated NH for reaction4And (4) quenching the Cl solution. EtOAc (30mL) was added, washed with saturated brine (2 × 30mL), dried over anhydrous sodium sulfate, and then applied to a column (PE/EA: 4/1-2/1) to give compound 3(1.2g, 59%) as a pale yellow solid. TLC PE/EA 4/1, 254nm, Rf(Compound 1) ═ 0.2, Rf(compound 3) ═ 0.7.
(2) Preparation of Compound 4
TFA (2mL) was added dropwise to CH of Compound 3(1.2g,3.04mmol) at room temperature2Cl2(10mL) in solution. The reaction was carried out at room temperature for 1 hour. The reaction was concentrated under reduced pressure, and the residue was diluted with water (20mL) and then with saturated NaHCO3The pH of the solution is adjusted to be about 9. CH (CH)2Cl2(3X 20mL) and the combined organic phases are dried over anhydrous Na2SO4And (5) drying and spin-drying. The resulting solid was washed with (PE: EtOAc ═ 1:1) to give compound 4(600mg, 67%) as a white solid.
(3) Preparation of Compound 5
Compound 4(200mg,0.68mmol,1.0eq) was dissolved in DCE (5 mL). Aq.37% (wt%) HCHO (550mg,6.78mmol,10.0eq) and anhydrous MgSO were added at room temperature4(300 mg). Stir at room temperature for 10 min. Addition of NaBH (OAc)3(215mg,1.05mmol,1.5eq) at room temperature for 2 h. Concentrating the reaction solution under reduced pressure, and purifying with Column (CH)2Cl2MeOH ═ 10:1) to give compound 5(145mg, 69%) as a pale yellow solid.
(4) Preparation of Compounds 11-10
Mixing compound 5(75mg,0.24mmol,1.0eq), compound 6(140mg,0.29mmol, 1.2eq) and Cs2CO3(237mg,0.73mmol,3.0eq) was dissolved in dioxane (5mL) and water (1 mL). Adding Pd (dppf) Cl2(18mg,0.02mmol,0.1 eq). Heating to 100 ℃ under the protection of argon and reacting for 2 h. Saturated NH for reaction4And (4) quenching the Cl solution. Adding CH to the reaction solution2Cl2(20mL), washed with saturated brine (2X 20mL), anhydrous Na2SO4And (5) drying and spin-drying. The resulting solid is dissolved in CH2Cl2To (5mL) was added TFA (1mL) dropwise. The reaction was stirred at room temperature for 1 h. The reaction was concentrated under reduced pressure, the residue was dissolved in water (10mL), and saturated NaHCO was added3The pH is adjusted to be approximately equal to 9. CH (CH)2Cl2(2X 20mL) and the combined extracts were extracted with anhydrous Na2SO4Drying, spin-drying and then prep-TLC (CH)2Cl2MeOH ═ 10:1) purified to give the product 11-10(15mg, 13%) as a yellow solid.
LCMS:[M+1]＝484.4。1H NMR(400MHz,DMSO-d6)δ12.03(br,1H), 10.41(s,1H),10.28(br,1H),7.77(d,J＝8.8Hz,2H),7.65(s,1H),7.61(d,J＝ 8.8Hz,2H),7.50(d,J＝7.6Hz,1H),7.38(t,J＝7.6Hz,1H),7.32(d,J＝7.2Hz, 1H),6.72-6.66(m,1H),6.37(d,J＝15.2Hz,1H),6.13(s,1H),3.92-3.86(m,1H), 2.50-2.33(m,5H),2.10-1.96(m,2H),1.85-1.77(m,3H),1.67-1.60(m,1H),1.42 (d,J＝6.8Hz,3H),0.89-0.85(m,2H),0.63-0.59(m,2H)。
Example 11
(1) Preparation of Compound 3
Compound 1(768mg,2.48mmol,1.0eq), compound 2(1.47g,4.95mmol, 2.0eq), K2CO3(1.03g,7.44mmol,3.0 eq.) and Pd (dppf) Cl2(181mg,0.025mmol, 0.1eq) in dioxane/H2O (8mL/2 mL). Stirring and reacting for 16h at 80 ℃ under the protection of argon. The reaction was diluted with water (30mL) and extracted with EtOAc (3X 15 mL). Mixing the extractive solutions, anhydrous Na2SO4Drying, concentrating under reduced pressure, and purifying with Column (CH)2Cl2MeOH 50/1) yielded compound 3 as a yellow solid (630 mg, 65%).
(2) Preparation of Compound 4
To a solution of compound 3(120mg,0.31mmol,1.0eq) in MeOH (10mL) was added dropwise 1M aq naoh (0.91mL,0.91mmol,3.0 eq). The reaction was stirred at room temperature overnight. The reaction was concentrated under reduced pressure to remove solvent MeOH. Adjusting the pH of the residual solution to 2-3 with 1M aq. HCl, and then adding CH2Cl2MeOH (10/1,3X 10mL) extraction. The combined extracts were washed with saturated brine (10mL) and anhydrous Na2SO4Dried and concentrated under reduced pressure to give compound 4 as a yellow solid (100mg, 87%).
(3) Preparation of Compound 5
Compound 4(100mg,0.264mmol,1.0eq), compound 5(134mg,0.528mmol, 2.0eq), HATU (150mg,0.395mmol,1.5eq) and DIEA (102mg,0.791mmol, 3.0eq) were dissolved in DMF (10 mL). The reaction was stirred overnight at 50 ℃. Water was added for dilution and EtOAc extraction. Mixing the extractive solutions, washing with saturated saline, and adding anhydrous Na2SO4Drying and concentration under reduced pressure gave compound 5 as a yellow solid (150mg, 93%).
(4) Preparation of Compounds 11-13
To compound 6(150mg,0.24mmol,1.0eq) in CH2Cl2To the solution (3mL) was added TFA (3mL) dropwise. The reaction was stirred at room temperature overnight. The reaction was concentrated under reduced pressure and the crude prep-HPLC (mobile phase: 0.1% TFA/H2O/CH3CN) to give compound 11-13 as a pale yellow solid, TFA salt (32mg, 27%).
LCMS:M+1＝485.4。1H NMR(400MHz,DMSO-d6)δ11.03(s,1H),10.57 (s,1H),10.00(br,1H),8.67(d,J＝2.0Hz,1H),8.30(d,J＝8.8Hz,1H),8.12(dd, J＝8.4,2.4Hz,1H),7.72(s,1H),7.59(d,J＝7.6Hz,1H),7.46-7.39(m,2H), 6.85-6.79(m,1H),6.68(d,J＝15.2Hz,1H),6.55(s,1H),5.45(s,1H),5.04(s, 1H),4.11-4.03(m,1H),3.97-3.92(m,1H),3.71-3.66(m,1H),3.17-3.12(m,1H), 2.83(d,J＝3.6Hz,3H),2.36-2.27(m,1H),2.14-2.07(m,1H),2.03-1.94(m,1H), 1.98(s,3H),1.92-1.84(m,1H),1.46(d,J＝6.8Hz,3H)。19F NMR(376MHz, DMSO-d6):δ-74.30。
Example 12
(1) Preparation of Compound 2
To a solution of compound 1(25.0g,0.22mol,1.0eq) in THF (250mL) under Ar protection was added NaH (60%, 9.7g,0.24mol,1.1eq) in portions. After stirring at room temperature for 10min SEMCl (44.2g,0.27mol,1.2eq) was added dropwise. Stir at room temperature overnight. Saturated NH for reaction4And (4) quenching by using a Cl aqueous solution. The reaction was diluted with EtOAc, washed with water and anhydrous Na2SO4Drying, concentration under reduced pressure and column purification (PE/EtOAc ═ 5/1) gave compound 2(36.3g, 67%) as a white solid.
(2) Preparation of Compound 3
Compound 2(36.3g,149.6 mmol) at-78 deg.C under Ar protection1.0eq) in THF (400 mL) was added dropwise LDA (2M in THF,90mL,179.5mmol,1.2 eq). Stirring and reacting at-78 ℃ for 1h, and then dropwise adding I2(45.8g,179.5mmol,1.2eq) in THF. Stirred at room temperature for 2 h. Saturated Na for reaction2S2O3Aqueous solution and saturated NH4And (4) quenching by using a Cl aqueous solution. The reaction was diluted with EtOAc, washed with water and anhydrous Na2SO4Dried, concentrated under reduced pressure, and purified by column chromatography (PE/EtOAc: 10/1) to give compound 3(33.6g, 61%) as a yellow solid. TLC PE/EtOAc-5/1, 254nm, Rf(Compound 2) ═ 0.2, Rf(compound 3) ═ 0.5.
(3) Preparation of Compound 5
Compound 3(4.0g,10.83mmol,1.0eq), compound 4(1.82g,10.83mmol, 1.0eq), K2CO3(4.49g,32.5mmol,3.0eq)，Pd(dppf)Cl2(792mg,1.08mmol, 0.1eq) in dioxane/H2O (24mL/6 mL). Stirring and reacting for 3 hours at 80 ℃ under the protection of argon. The reaction was concentrated under reduced pressure, the residue was diluted with EtOAc, washed with water, concentrated under reduced pressure, and purified on silica gel (PE/EtOAc ═ 60/1) to give compound 5(2.5g, 83%) as a yellow oil. TLC PE/EtOAc-8/1, 254nm, Rf(Compound 3) ═ 0.4, Rf(compound 5) ═ 0.5.
(4) Preparation of Compound 6
Compound 5(2.03g,7.17mmol,1.0eq), reduced iron powder (4.0g,71.73mmol, 10.0eq) and ammonium chloride (7.67g,143.46mmol,20.0eq) were dissolved in ethanol (12mL) and water (6 mL). The reaction was stirred for 1h while heating to 70 ℃. Filtration and spin-drying of the filtrate gave compound 6 as a yellow oil (1.7g, 95%).
(5) Preparation of Compound 9
Compound 7(620mg,2.0mmol,1.0eq), compound 8(1.0g,3.6mmol,1.8 eq), K2CO3(828mg,6.0mmol,3.0eq) and Pd (dppf) Cl2(146mg,0.02mmol, 0.1eq) in dioxane/H2O (14mL/3 mL). Stirring and reacting for 16h at 80 ℃ under the protection of argon. The reaction was concentrated under reduced pressure, the residue was diluted with EtOAc and washed with water and anhydrous Na2SO4Drying, concentrating under reduced pressure, and purifying with Column (CH)2Cl2MeOH 200/1-20/1) gave compound 9 as a brown oil (310mg, 31%).
(6) Preparation of Compound 10
To a solution of compound 9(100mg,0.25mmol,1.0eq) in MeOH (2mL) was added dropwise a solution of NaOH (31mg,0.76mmol,3.0eq) in water (2 mL). The reaction was stirred at room temperature overnight. The reaction was concentrated under reduced pressure to remove solvent MeOH. The residue was adjusted to pH 5-6 with 2M aq. hcl and concentrated to give brown oil of compound 10 (crude, 96mg, 100%).
(7) Preparation of Compound 11
Compound 10(96mg,0.25mmol,1.0eq), compound 6(77mg,0.30mmol, 1.2eq), HATU (144mg,0.38mmol,1.5eq) and DIEA (98mg,0.76mmol,3.0 eq) were dissolved in DMF (2 mL). The reaction was stirred at room temperature overnight. Diluting with water, extracting with EtOAc, and extracting with anhydrous Na2SO4Drying and concentration under reduced pressure gave compound 11 as a brown oil (crude, 155mg, 100%).
(8) Preparation of Compounds 11-14
To compound 11(155mg,0.25mmol,1.0eq) in CH2Cl2To the solution (2mL) was added TFA (2mL) dropwise. The reaction was stirred at room temperature overnight. The reaction was concentrated under reduced pressure and the crude prep-HPLC (mobile phase: 0.1% TFA/H2O/CH3CN) to give compound 11-14 as an off-white solid, TFA salt (27.58 mg, 22%). LCMS M +1 ═ 485.4
1H NMR(400MHz,DMSO-d6)δ11.03(s,1H),10.56(s,1H),9.97(br,1H), 8.66(d,J＝2.0Hz,1H),8.28(d,J＝8.4Hz,1H),8.11(dd,J＝8.8,2.4Hz,1H), 7.72(s,1H),7.60(d,J＝7.6Hz,1H),7.46-7.38(m,2H),6.85-6.79(m,1H),6.70 (d,J＝15.2Hz,1H),6.55(s,1H),5.45(s,1H),5.03(s,1H),4.11-4.02(m,1H), 3.97-3.91(m,1H),3.19-3.10(m,1H),2.82(d,J＝4.4Hz,3H),2.71-2.66(m,1H), 2.33-2.29(m,1H),2.14-2.07(m,1H),2.03-1.98(m,1H),1.98(s,3H),1.94-1.86 (m,1H),1.46(d,J＝7.2Hz,3H).19F NMR(376MHz,DMSO-d6):δ-73.78.
Example 13
(1) Preparation of Compound 3
Compound 1(180mg,0.422mmol,1.0eq), compound 2(140mg,0.633mmol, 1.5eq), HATU (240mg,0.633mmol,1.5eq) and DIEA (163mg,1.266mmol, 3.0eq) were dissolved in DMF (6 mL). The reaction was stirred overnight at 50 ℃. Water was added for dilution and extracted with EtOAc (3X10 mL). Mixing the extractive solutions, washing with saturated saline, and adding anhydrous Na2SO4Dried and concentrated under reduced pressure to give compound 3(150mg, 53%) as a yellow solid.
(2) Preparation of Compounds 11-15
To compound 3(150mg,0.25mmol,1.0eq) in CH2Cl2To the solution (4mL) was added TFA (4mL) dropwise. The reaction was stirred at room temperature for 6 h. The reaction was concentrated under reduced pressure and the crude prep-HPLC (mobile phase: 0.1% TFA/H2O/CH3CN) purification to obtain a light yellow solid compound 11-15, TFSalt A (32mg, 27%).
LCMS:M+1＝469.4.1H NMR(400MHz,DMSO-d6)δ11.03(s,1H),10.72 (s,1H),9.94(br,1H),8.67(d,J＝2.4Hz,1H),8.28(d,J＝8.8Hz,1H),8.11(dd, J＝8.8,2.4Hz,1H),7.71(s,1H),7.58(d,J＝7.6Hz,1H),7.44(t,J＝7.6Hz,1H), 7.39(d,J＝7.6Hz,1H),6.85-6.79(m,1H),6.70(d,J＝15.2Hz,1H),6.63(s,1H), 4.50(s,1H),4.11-4.03(m,1H),3.97-3.91(m,1H),3.69-3.65(m,1H),3.19-3.10 (m,1H),2.83(d,J＝4.0Hz,3H),2.36～2.28(m,1H),2.14-2.07(m,1H),2.03-1.97 (m,1H),1.94-1.86(m,1H),1.46(d,J＝6.8Hz,3H).19F NMR(376MHz,DMSO- d6):δ-73.82.
Example 14
(1) Preparation of Compound 3
To a solution of compound 1(3.0g,8.12mmol,1.0eq), compound 2(1.2g,12.19mmol,1.5 eq) in THF (30mL) was added CuI (155mg,0.81mmol,0.1eq), PdCl2(PPh3)2(570mg,0.81mmol,0.1eq) and Et3N (3.3g,32.50mmol,4.0 eq). Stirring for 2h at room temperature under the protection of Ar. The reaction solution was diluted with EtOAc, washed with water and dried over Na2SO4Drying, concentration under reduced pressure and silica gel column purification (PE/EtOAc ═ 20/1) gave compound 3(1.9g, 69%) as a yellow oil. TLC PE/EtOAc-10/1, 254nm, Rf(Compound 1) ═ 0.2, Rf(compound 3) ═ 0.6.
(2) Preparation of Compound 4
To a solution of compound 3(1.9g,5.6mmol,1.0eq) in MeOH (30mL) was added K2CO3(1.2g,8.4mmol,1.5 eq). Stirred at room temperature for 2 h. Reaction solution CH2Cl2Dilution, filtration and concentration of the filtrate under reduced pressure gave compound 4 as a yellow oil (1.24g, 83%).
(3) Preparation of Compound 5
Compound 4(1.24g,4.64mmol,1.0eq), reduced iron powder (2.6g,46.4mmol,10.0 eq) and ammonium chloride (5.0g,92.8mmol,20.0eq) were dissolved in ethanol (20mL) and water (10 mL). The reaction was heated to 60 ℃ and stirred for 2 h. Filtration and spin-drying of the filtrate gave compound 5 as a yellow oil (1.0g, 91%).
(4) Preparation of Compounds 11-16
Compound 5(58mg,0.24mmol,1.2eq), compound 6(77mg,0.20mmol,1.0 eq), HATU (116mg,0.30mmol,1.5eq) and DIEA (79mg,0.61mmol,3.0eq) were dissolved in DMF (2 mL). The reaction was stirred overnight at 50 ℃. Diluting with water, extracting with EtOAc, and extracting with anhydrous Na2SO4Drying, and concentrating under reduced pressure. Residue plus CH2Cl2Dissolved (2mL), and TFA (2mL) was added dropwise. The reaction was stirred at room temperature overnight. The reaction was concentrated under reduced pressure and the crude prep-HPLC (mobile phase: 0.1% TFA/H2O/CH3CN) to yield compound 11-16 as a yellow solid, TFA salt (5.23mg, 4%).
LCMS:M+1＝469.4.1H NMR(400MHz,DMSO-d6)δ11.03(s,1H),10.72 (s,1H),10.04(br,1H),8.66(d,J＝2.4Hz,1H),8.28(d,J＝8.8Hz,1H),8.12(dd, J＝8.4,2.4Hz,1H),7.71(s,1H),7.59(d,J＝7.6Hz,1H),7.44(t,J＝7.6Hz,1H), 7.39(d,J＝7.6Hz,1H),6.87-6.81(m,1H),6.67(d,J＝15.2Hz,1H),6.63(s,1H), 4.50(s,1H),4.11-4.02(m,1H),3.71-3.64(m,1H),3.18-3.09(m,1H),2.82(d,J ＝4.8Hz,3H),2.70-2.66(m,1H),2.33-2.29(m,1H),2.12-2.05(m,1H),2.03-1.97 (m,1H),1.94-1.86(m,1H),1.46(d,J＝7.2Hz,3H).19F NMR(376MHz,DMSO- d6):δ-74.18.
Example 15
(1) Preparation of Compound 2b
Compound 2a (5.0g,21.8mmol,1.0eq) was dissolved in THF (60mL), the reaction was cooled to 0 deg.C, and BH3THF (26.2ml, 26.2mmol,1.2eq) was added to the reaction and allowed to warm to room temperature and stir for 2 h. Saturated NaHCO for reaction3Quench, EtOAc (2X 30mL) extraction, saturated brine wash, Na2SO4Drying and spin-drying to obtain compound 2b (4.8g, yield: 100%). TLC DCM/MeOH 10/1, I2，Rf(Compound 2a) ═ 0.2, Rf(compound 2b) ═ 0.4.
(2) Preparation of Compound 2
Dess-Matin (10.4g, 24.5mmol, 1.1eq) was added to Compound 2b (4.8g,22.3 mmol,1.0eq) in DCM (60 mL). The reaction was carried out at room temperature for 2 h. The reaction solution was poured into saturated NaHCO3Extracted with EtOAc (2 × 30 mL). The organic phases were combined, washed with brine and Na2SO4Drying, spin-drying and column chromatography (PE/EA-8/1) gave compound 2(3.9g, yield: 82%). TLC PE/EA 2/1, I2，Rf(Compound 2b) ═ 0.2, Rf(compound 2) ═ 0.4.
(3) Preparation of Compound 3
LiHMDS (1M in THF,1.5mL,1.5mmol,1.5eq) was added to Compound 1(352mg,1.0mmol,1.0eq) in THF (10mL) at-78 ℃. The reaction is carried out at minus 78 ℃ for 1h and at 0 ℃ for 1 h. A solution of compound 2(256mg,1.2mmol,1.2eq) in THF (3mL) was added to the reaction at 0 deg.C. The temperature is raised to room temperature and stirred for 2 h. Pouring the reaction solution into NH4In an aqueous Cl solution. EtOAc (3X 20mL) extraction, organic phase saturated brine wash, Na2SO4Dried, spun-dried and chromatographed (PE/EA/DCM-15/1/1) to give compound 3(280mg, yield: 68%). TLC, PE/EA is 1/1, 254nm，Rf(Compound 1) ═ 0.2, Rf(compound 3) ═ 0.6.
(4) Preparation of Compound 4
TFA (2mL) was added to Compound 3(440mg,1.08mmol,1.0eq) in DCM (5mL) and stirred at room temperature for 2 h. The solvent was spun off and the residue was dissolved in DCM. With saturated NaHCO3The solution was adjusted to pH 8. The organic phase was separated, washed with saturated brine and Na2SO4Drying and spin-drying to obtain compound 4(300mg, yield: 90%). TLC PE/EA 4/1, 254nm, Rf(compound 3) ═ 0.4, DCM/MeOH = 10/1, 254nm, Rf(compound 4) ═ 0.2.
(5) Preparation of Compound 5
Compound 4(300mg,0.97mmol,1.0eq), HCHO (37% in water, 728mg, 9.7mmol,10.0eq) and MgSO4(2g) Dissolve in DCE (10 mL). Stir at room temperature for 10 min. Reacting NaBH (OAc)3(310mg,1.46mmol,1.5eq) was added to the reaction in portions at 0 ℃. The reaction is carried out for 1h at the temperature of 0 ℃ and 0.5h at the room temperature. The reaction was filtered, the filtrate was dried by spinning, and the filtrate was purified by column chromatography (DCM/MeOH: 50/1) to give compound 5(200mg, yield: 63%). TLC DCM/MeOH-10/1, 254nm, Rf(Compound 4) ═ 0.2, Rf(compound 5) ═ 0.3.
(6) Preparation of Compound 7
Compound 5(200mg,0.62mmol,1.0eq), compound 6(481.39mg,1.24mmol, 2.0eq), K2CO3(257mg,1.86mmol,3.0eq) and Pd (dppf) Cl2(45mg,0.062mmol, 0.1eq) was dissolved in dioxane (10mL) and H2O (2 mL). Heating to 80 ℃ for reaction for 2 h. Will be reversedThe reaction solution was poured into EtOAc (20mL), washed with saturated brine, Na2SO4Dry, spin dry, and column pass (DCM/MeOH ═ 20/1) to give compound 7(60mg, yield: 32%). TLC DCM/MeOH-8/1, 254nm, Rf(Compound 5) ═ 0.4, Rf(compound 7) ═ 0.3.
(7) Preparation of Compounds 11-19
TFA (2mL) was added to Compound 7(90mg,0.15mmol,1.0eq) in DCM (5 mL). Stir at room temperature for 1 h. The solvent was spun off and the residue was dissolved in DCM. With saturated NaHCO3The solution was adjusted to pH 8. Separating the organic phase from Na2SO4And (5) drying and spin-drying. Crude prep-TLC (DCM/MeOH ═ 6/1) purified to give compounds 11-19(16mg, yield: 21%).
LCMS:M+1＝499.4.1H NMR(400MHz,DMSO-d6)δ12.10(br s,1H), 10.85(s,1H),10.49(s,1H),8.69(d,J＝2.0Hz,1H),8.35(d,J＝8.8Hz,1H), 8.16-8.13(m,1H),7.78(s,1H),7.63(d,J＝7.2Hz,1H),7.50-7.42(m,2H),6.83- 6.77(m,1H),6.52(d,J＝15.2Hz,1H),6.20(s,1H),4.00-3.95(m,1H),2.93(d,J ＝9.6Hz,1H),2.71(br s,1H),2.21(s,3H),2.11(br s,1H),1.84-1.24(m,13H), 0.88-0.86(m,2H),0.62-0.60(m,2H).
Example 16
(1) Preparation of Compound 2b
Compound 2a (5.0g,21.8mmol,1.0eq), N, O-dimethylhydroxylamine hydrochloride (2.6g, 26.2mmol,1.2eq), DIPEA (7.6mL,43.6mmol,1.5eq), EDCI (6.3g,32.7 mmol,1.5eq) and HOBT (5.3g,32.7mmol,1.5eq) were dissolved in DCM (50 mL). Stirred at room temperature for 3 h. Washing the reaction solution with water, washing with saturated brine, and Na2SO4Drying, spin-drying and column chromatography (PE/EA-5/1) gave compound 2b (5.3g, yield: 89%). TLC PE/EA 1/1, I2，Rf(Compound 2a) ═ 0.2, Rf(compound 2b) ═ 0.4.
(2) Preparation of Compound 2
Mixing LiAlH4(1.25g,33.0mmol,1.5eq) was added portionwise to compound 2b (6.0 g,22.0mmol,1.0eq) in THF (50mL) at 0 deg.C. The reaction is carried out for 1h at 0 ℃. The reaction solution was poured into ice water and filtered. The filtrate was extracted with EtOAc (3 × 100 mL). The organic phases were combined, washed with brine and Na2SO4Drying, spin-drying and column chromatography (PE/EA: 8/1) gave compound 2(4.4g, yield: 95%). TLC PE/EA 4/1, I2，Rf(Compound 2b) ═ 0.2, Rf(compound 2) ═ 0.4.
(3) Preparation of Compound 3
LiHMDS (1M in THF,2.13mL,2.13mmol,1.5eq) was added to compound 1(500mg,1.42mmol,1.0eq) in THF (10mL) at-78 ℃. The reaction is carried out at minus 78 ℃ for 1h and at 0 ℃ for 1 h. A solution of compound 2(455mg,2.13mmol,1.5eq) in THF (3mL) was added to the reaction at 0 ℃. The temperature is raised to room temperature and stirred for 2 h. Pouring the reaction solution into NH4In an aqueous Cl solution. EtOAc (3X 20mL) extraction, organic phase saturated brine wash, Na2SO4Dried, spun-dried and chromatographed (PE/EA/DCM-15/1/1) to give compound 3(400mg, yield: 70%). TLC PE/EA 1/1, 254nm, Rf(Compound 1) ═ 0.2, Rf(compound 3) ═ 0.6.
(4) Preparation of Compound 4
TFA (1mL) was added to Compound 3(400mg,0.975mmol,1.0eq) in DCM (3mL) and stirred at room temperature for 2 h. The solvent was spun off and the residue was dissolved in DCM. With saturated NaHCO3Adjusting the pH of the solution8. Separating the organic phase, washing with saturated brine, Na2SO4Drying and spin-drying gave Compound 4 (287mg, yield: 95%). TLC PE/EA 4/1, 254nm, Rf(compound 3) ═ 0.4; DCM/MeOH 10/1, 254nm, Rf(compound 4) ═ 0.2.
(5) Preparation of Compound 5
Compound 4(390mg,1.26mmol,1.0eq), HCHO (37% in water, 1.0g, 12.6mmol,10.0eq) and MgSO4(1.0g,8.33mmol,6.5eq) was dissolved in DCE (5 mL). Stir at room temperature for 10 min. Reacting NaBH (OAc)3(400mg,1.89mmol,1.5eq) was added to the reaction in portions at 0 ℃. The reaction is carried out for 1h at the temperature of 0 ℃ and 0.5h at the room temperature. The reaction was filtered, the filtrate was dried by spinning, and the filtrate was purified by column chromatography (DCM/MeOH-50/1) to give compound 5(260mg, yield: 63%). TLC DCM/MeOH-10/1, 254nm, Rf(Compound 4) ═ 0.2, Rf(compound 5) ═ 0.3.
(6) Preparation of Compound 7
Mixing compound 5(100mg,0.31mmol,1.0eq), compound 6(149mg,0.31mmol, 1.0eq), K2CO3(127mg,0.92mmol,3.0 eq.) and Pd (dppf) Cl2(25mg,0.031mmol, 0.1eq) in dioxane (10mL) and H2O (2 mL). Heating to 80 ℃ for reaction for 2 h. The reaction was poured into EtOAc (20mL), washed with saturated brine and Na2SO4Dry, spin dry, and column pass (DCM/MeOH ═ 20/1) to give compound 7(60mg, yield: 32%). TLC DCM/MeOH-8/1, 254nm, Rf(Compound 7) ═ 0.4, Rf(compound 5) ═ 0.3.
(7) Preparation of Compounds 11-20
TFA (0.5mL) was added to Compound 7(60mg,0.1mmol,1.0eq) in DCM (1 mL). Stir at room temperature for 1 h. The solvent was spun off and the residue was dissolved in DCM. With saturated NaHCO3The solution was adjusted to pH 8. Separating the organic phase from Na2SO4And (5) drying and spin-drying. The crude Prep-TLC (DCM/MeOH ═ 6/1) was purified to give compounds 11-20(13mg, yield: 26%).
LCMS:M+1＝499.4。1H NMR(400MHz,DMSO-d6)δ12.05(s,1H),10.83 (s,1H),10.43(s,1H),8.64(s,1H),8.29(d,J＝8.8Hz,1H),8.10-8.08(m,1H), 7.71(s,1H),7.58(d,J＝7.2Hz,1H),7.45-7.37(m,2H),6.74(d,J＝9.2Hz,1H), 6.49(d,J＝15.2Hz,1H),6.14(s,1H),3.92(d,J＝6.8Hz,1H),2.22(s,3H),1.84- 1.24(m,13H),0.88(d,J＝7.2Hz,2H),0.62(d,J＝3.2Hz,2H)。
Example 17
Chiral resolution of the compounds 11-1-5 of example 2 (300mg, 96% purity by LC-MS) was carried out using an SFC apparatus (resolution conditions and method: stationary phase (Column): ChiralPak IC-H Daicel chemical Industries, Ltd,250 x 30mm I.D.,5 um; mobile phase A:SupercrystallineCO-MS; (molecular phase A): chiral CO-S)2Mobile phase B (mobile phase B) Ethanol (0.1% NH)3H2O); a: B60: 40at 50ml/min (flow rate); column Temperature 38 deg.C; nozle Pressure 100 Bar; nozle temp. 60 deg.C; evaporator temp. 20 deg.C; the temperature of the Trimmer Temp is 25 ℃; wave length: UV 220nm) to give two yellow solids, Peak 1 and Peak 2.
Peak 1,11-1-P1
Yellow solid (Rt 5.05min,75.82mg, yield: 25%, solidified by1H NMR and LC-MS)；
LCMS:M+1＝485.4；
1H NMR(400MHz,DMSO-d6)δ12.03(s,1H),10.74(s,1H),10.42(s,1H), 8.62(d,J＝2.0Hz,1H),8.28(d,J＝8.4Hz,1H),8.07(dd,J＝8.8,2.4Hz,1H), 7.70(s,1H),7.57(d,J＝7.2Hz,1H),7.44-7.36(m,2H),6.72-6.66(m,1H),6.44 (d,J＝15.6Hz,1H),6.14(s,1H),3.92-3.89(m,1H),3.02-3.00(m,1H),2.73-2.71 (m,1H),2.22(s,3H),2.11-2.03(m,1H),1.98-1.97(m,1H),1.82-1.75(m,3H), 1.59-1.50(m,1H),1.42(d,J＝6.8Hz,3H),0.87(d,J＝8.4Hz,2H),0.62(d,J＝ 3.2Hz,2H).
Peak 2,11-1-P2
Yellow solid (Rt 6.08min,72.05mg, yield: 24%, solidified by1H NMR and LC-MS)
LCMS:M+1＝485.4
1H NMR(400MHz,DMSO-d6)δ12.03(s,1H),10.74(s,1H),10.42(s,1H), 8.62(d,J＝2.0Hz,1H),8.28(d,J＝8.4Hz,1H),8.07(dd,J＝8.8,2.4Hz,1H), 7.70(s,1H),7.57(d,J＝7.6Hz,1H),7.44-7.36(m,2H),6.72-6.66(m,1H),6.44 (d,J＝15.6Hz,1H),6.14(s,1H),3.93-3.89(m,1H),3.02-3.00(m,1H),2.73-2.69 (m,1H),2.22(s,3H),2.11-2.03(m,1H),1.98-1.97(m,1H),1.82-1.75(m,3H), 1.59-1.50(m,1H),1.42(d,J＝6.8Hz,3H),0.87(d,J＝8.4Hz,2H),0.62(d,J＝ 3.2Hz,2H).
Example 18
Chiral resolution of the compounds 11-3-5 of example 4(300mg, 95% purity by LC-MS) was carried out using an SFC apparatus (resolution conditions and method: Column: ChiralPak IC-H Daicel chemical Industries, Ltd, 250: 30mm I.D.,5 um; mobile phase A (Mobile phase A): Supercrystalline CO2Mobile phase B (mobile phase B) Ethanol (0.1% NH)3H2O); a: B60: 40at 50ml/min (flow rate); column Temperature 38 deg.C; nozle Pressure 100 Bar; nozle temp. 60 deg.C; evaporator temp. 20 deg.C; the temperature of the Trimmer Temp is 25 ℃; wave length: UV 220nm) to give two yellow solids, Peak 1 and Peak 2.
Peak 1,11-3-P1
Yellow solid(Rt＝5.719min,71.78mg,yield:24％,confirmed by 1H NMR and LC-MS)；
LCMS:M+1＝485.4；
1H NMR(400MHz,DMSO-d6)δ11.99(br s,1H),10.74(s,1H),10.45(s, 1H),8.62(d,J＝2.0Hz,1H),8.28(d,J＝8.4Hz,1H),8.07(dd,J＝8.8,2.4Hz, 1H),7.70(s,1H),7.56(d,J＝7.6Hz,1H),7.44-7.36(m,2H),6.72-6.66(m,1H), 6.44(d,J＝15.6Hz,1H),6.12(s,1H),3.93-3.91(m,1H),3.05-3.02(m,1H),2.75- 2.71(m,1H),2.20-2.13(m,4H),2.07-1.96(m,1H),1.83-1.70(m,3H),1.69-1.58 (m,1H),1.43(d,J＝6.8Hz,3H),0.88-0.86(m,2H),0.61-0.60(m,2H).
Peak 2,11-3-P2
Yellow solid(Rt＝6.883min,65.67mg,yield:22％,confirmed by 1H NMR and LC-MS)；
LCMS:M+1＝485.3；
1H NMR(400MHz,DMSO-d6)δ12.03(s,1H),10.74(s,1H),10.42(s,1H), 8.62(d,J＝2.4Hz,1H),8.28(d,J＝8.8Hz,1H),8.07(dd,J＝8.8,2.4Hz,1H), 7.70(s,1H),7.56(d,J＝7.6Hz,1H),7.44-7.36(m,2H),6.72-6.66(m,1H),6.44 (d,J＝15.6Hz,1H),6.14(s,1H),3.93-3.89(m,1H),3.05-3.00(m,1H),2.73-2.71 (m,1H),2.20-2.13(m,4H),2.00-1.97(m,1H),1.82-1.70(m,3H),1.69-1.58(m, 1H),1.43(d,J＝6.8Hz,3H),0.88-0.86(m,2H),0.61-0.60(m,2H).
Effect example 1
Test methods for CDK7 inhibitory activity refer to WO 2015058140.
CDK7 inhibition by compounds at 200nM and 10nM concentrations was determined using commercially available reagents such as CDK7/CyclinH/MAT1(Millipore, Cat. No. 14-476K, Lot. No. 1634571, His-CDK7+ GST-MAT1+ cyclinH) and CTD3 peptide (GL Biochem, Cat. No. 346885). The results are shown in Table 1.
TABLE 1 CDK7 inhibitory Activity
Effect example 2
Test methods for CDK7 inhibitory activity refer to WO 2015058140.
IC determination of CDK7 inhibition by the Compounds of examples 17 and 18 by CDK7 was determined using reagents such as commercially available CDK7/CyclinH/MAT1(Millipore, Cat. No. 14-476K, Lot. No. 1634571, His-CDK7+ GST-MAT1+ cyclinH) and CTD3 peptide (GL Biochem, Cat. No.346885)50. The results are given in the table below.
| Compound (I) | IC50(nM) |
| 11-1-P1 | 584 |
| 11-1-P2 | 13 |
| 11-3-P1 | 487 |
| 11-3-P2 | 8.1 |
Claims (7)
1. A compound shown in a general formula I, a stereoisomer or pharmaceutically acceptable salt thereof,
wherein the content of the first and second substances,
ring A is phenyl;
ring B is phenyl or pyridyl;
R1is H;
R2is C1-C4Alkyl radical, C2-C4Alkenyl radical, C2-C4Alkynyl or C3-C6A cycloalkyl group;
R3is H;
m is 0;
R5is composed of
Wherein n1 is 0; r5aAnd R5bIs H; r5cIs substituted or unsubstituted C2-C20Heterocycloalkyl, said substituted C2-C20The substituent in the heterocycloalkyl group being C1-C10Alkyl, said "C2-C20Heterocycloalkyl "is
Said substituted or unsubstituted C2-C20Carbon atoms of heterocycloalkyl radicals with
Connecting;
q is 0;
L1is composed of
RlaAnd RlbIndependently is H or C1-C10An alkyl group; l is1Wherein, the carbon marked by the letter is S configuration chiral carbon, R configuration chiral carbon or achiral carbon;
L2is absent.
2. The compound of formula I, a stereoisomer or pharmaceutically acceptable salt thereof according to claim 1, wherein, when R is2Is C1-C4When alkyl, said C1-C4Alkyl is methyl, ethyl, propyl or butyl;
and/or when R2Is C2-C4When alkenyl, said C2-C4Alkenyl is
And/or when R2Is C2-C4When it is alkynyl, said C2-C4Alkynyl is
And/or when R2Is C3-C6When there is a cycloalkyl group, said C3-C6Cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
3. The compound of formula I, a stereoisomer or pharmaceutically acceptable salt thereof according to claim 1, wherein R is5cIs composed of
And/or, L1Is composed of
4. A compound of formula I, a stereoisomer or pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein the compound of formula I or a salt thereof is any one of: the carbon marked by the letter is S configuration chiral carbon, R configuration chiral carbon or achiral carbon;
5. a process for producing a compound represented by the general formula I as claimed in claim 1, which comprises the following process (1) or process (2);
wherein the method (1) comprises the following steps: in a solvent, under the protection of gas and the action of alkali and a palladium catalyst, carrying out the reaction shown as the following on the compound shown as the general formula I-A and the compound shown as the general formula I-B;
wherein, in the compound shown in the general formula I-A, X is halogen, M is
Wherein R isb1And Rb2Independently is hydroxy or C1-C10Alkoxy, or Rb1And Rb2Together with boron atoms forming
L2Absent, each of the remaining letters and groups are as defined in claim 1;
method (2): in the compounds of the formula I, R1When the compound is H, the compound can be prepared by the following method, wherein the method comprises the following steps: in a solvent, carrying out deprotection reaction on a compound shown as a general formula I-C as shown in the specification;
wherein R is1Is H, Q is an amino protecting group; the remaining letter and group definitions are as defined in claim 1.
6. A pharmaceutical composition comprising a compound of formula I, a stereoisomer or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 4, and a pharmaceutically acceptable adjuvant.
7. Use of a compound of general formula I according to any one of claims 1 to 4, a stereoisomer or a pharmaceutically acceptable salt thereof in the preparation of a CDK7 kinase inhibitor.
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| CN108024970A (en) * | 2015-06-04 | 2018-05-11 | 奥瑞基尼探索技术有限公司 | The Hete rocyclic derivatives by substitution as CDK inhibitor |
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| CN108024970A (en) * | 2015-06-04 | 2018-05-11 | 奥瑞基尼探索技术有限公司 | The Hete rocyclic derivatives by substitution as CDK inhibitor |
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