WO2022143779A1 - Alkenyl-containing compound and application thereof - Google Patents
Alkenyl-containing compound and application thereof Download PDFInfo
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- WO2022143779A1 WO2022143779A1 PCT/CN2021/142527 CN2021142527W WO2022143779A1 WO 2022143779 A1 WO2022143779 A1 WO 2022143779A1 CN 2021142527 W CN2021142527 W CN 2021142527W WO 2022143779 A1 WO2022143779 A1 WO 2022143779A1
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 293
- 125000003342 alkenyl group Chemical group 0.000 title abstract description 3
- 150000003839 salts Chemical class 0.000 claims abstract description 33
- 229910052757 nitrogen Inorganic materials 0.000 claims description 20
- 125000000217 alkyl group Chemical group 0.000 claims description 16
- 125000003545 alkoxy group Chemical group 0.000 claims description 15
- 229910052739 hydrogen Inorganic materials 0.000 claims description 14
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 12
- 229910052799 carbon Inorganic materials 0.000 claims description 11
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 11
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 125000004076 pyridyl group Chemical group 0.000 claims description 6
- 229910052760 oxygen Inorganic materials 0.000 claims description 5
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 5
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 238000006243 chemical reaction Methods 0.000 description 346
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 289
- 239000000243 solution Substances 0.000 description 221
- 235000019439 ethyl acetate Nutrition 0.000 description 97
- 239000012074 organic phase Substances 0.000 description 81
- 238000003786 synthesis reaction Methods 0.000 description 68
- 230000015572 biosynthetic process Effects 0.000 description 67
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 62
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 62
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 62
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 62
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 56
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 50
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- 108700002148 exportin 1 Proteins 0.000 description 25
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 24
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- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 22
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 description 20
- DLYUQMMRRRQYAE-UHFFFAOYSA-N tetraphosphorus decaoxide Chemical compound O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 20
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 18
- 102100029095 Exportin-1 Human genes 0.000 description 17
- 101100485284 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) CRM1 gene Proteins 0.000 description 16
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 16
- 101150094313 XPO1 gene Proteins 0.000 description 16
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- 238000012360 testing method Methods 0.000 description 14
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- 230000030147 nuclear export Effects 0.000 description 13
- DEVSOMFAQLZNKR-RJRFIUFISA-N (z)-3-[3-[3,5-bis(trifluoromethyl)phenyl]-1,2,4-triazol-1-yl]-n'-pyrazin-2-ylprop-2-enehydrazide Chemical compound FC(F)(F)C1=CC(C(F)(F)F)=CC(C2=NN(\C=C/C(=O)NNC=3N=CC=NC=3)C=N2)=C1 DEVSOMFAQLZNKR-RJRFIUFISA-N 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 125000001424 substituent group Chemical group 0.000 description 12
- 238000002953 preparative HPLC Methods 0.000 description 11
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- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 10
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- 229910000029 sodium carbonate Inorganic materials 0.000 description 8
- 230000004083 survival effect Effects 0.000 description 8
- 241000699670 Mus sp. Species 0.000 description 7
- 125000004432 carbon atom Chemical group C* 0.000 description 7
- 239000006285 cell suspension Substances 0.000 description 7
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- 238000000034 method Methods 0.000 description 7
- 102000004169 proteins and genes Human genes 0.000 description 7
- 108090000623 proteins and genes Proteins 0.000 description 7
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 6
- 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 6
- 125000004429 atom Chemical group 0.000 description 6
- 125000000524 functional group Chemical group 0.000 description 6
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 6
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
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- 125000005647 linker group Chemical group 0.000 description 5
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- 238000000926 separation method Methods 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- FWBHETKCLVMNFS-UHFFFAOYSA-N 4',6-Diamino-2-phenylindol Chemical compound C1=CC(C(=N)N)=CC=C1C1=CC2=CC=C(C(N)=N)C=C2N1 FWBHETKCLVMNFS-UHFFFAOYSA-N 0.000 description 4
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- 206010025323 Lymphomas Diseases 0.000 description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
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- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 4
- 230000001404 mediated effect Effects 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
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- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 4
- 210000004940 nucleus Anatomy 0.000 description 4
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 4
- 229910052938 sodium sulfate Inorganic materials 0.000 description 4
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 4
- 235000011152 sodium sulphate Nutrition 0.000 description 4
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- 210000004881 tumor cell Anatomy 0.000 description 4
- 125000006555 (C3-C5) cycloalkyl group Chemical group 0.000 description 3
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 3
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- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
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- 125000002962 imidazol-1-yl group Chemical group [*]N1C([H])=NC([H])=C1[H] 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
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- XMBWDFGMSWQBCA-YPZZEJLDSA-N iodane Chemical compound [125IH] XMBWDFGMSWQBCA-YPZZEJLDSA-N 0.000 description 1
- 229940044173 iodine-125 Drugs 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000000155 isotopic effect Effects 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 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 1
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- DHRRIBDTHFBPNG-UHFFFAOYSA-L magnesium dichloride hexahydrate Chemical compound O.O.O.O.O.O.[Mg+2].[Cl-].[Cl-] DHRRIBDTHFBPNG-UHFFFAOYSA-L 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 238000013227 male C57BL/6J mice Methods 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
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- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 1
- 125000001434 methanylylidene group Chemical group [H]C#[*] 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
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- 230000004048 modification Effects 0.000 description 1
- RIVIDPPYRINTTH-UHFFFAOYSA-N n-ethylpropan-2-amine Chemical compound CCNC(C)C RIVIDPPYRINTTH-UHFFFAOYSA-N 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
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
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- 230000003000 nontoxic effect Effects 0.000 description 1
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- 150000007524 organic acids Chemical class 0.000 description 1
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- 239000003960 organic solvent Substances 0.000 description 1
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- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
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- PNJWIWWMYCMZRO-UHFFFAOYSA-N pent‐4‐en‐2‐one Natural products CC(=O)CC=C PNJWIWWMYCMZRO-UHFFFAOYSA-N 0.000 description 1
- 230000008823 permeabilization Effects 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- YOPKGUUNMWGPCZ-UHFFFAOYSA-N phosphoric acid;propane Chemical compound CCC.OP(O)(O)=O YOPKGUUNMWGPCZ-UHFFFAOYSA-N 0.000 description 1
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- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000004323 potassium nitrate Substances 0.000 description 1
- 235000010333 potassium nitrate Nutrition 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 230000008569 process Effects 0.000 description 1
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- 230000001737 promoting effect Effects 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- GRJJQCWNZGRKAU-UHFFFAOYSA-N pyridin-1-ium;fluoride Chemical compound F.C1=CC=NC=C1 GRJJQCWNZGRKAU-UHFFFAOYSA-N 0.000 description 1
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 description 1
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
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- 238000005215 recombination Methods 0.000 description 1
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- 238000004467 single crystal X-ray diffraction Methods 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 125000003003 spiro group Chemical group 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 238000003419 tautomerization reaction Methods 0.000 description 1
- ISIJQEHRDSCQIU-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNCC1 ISIJQEHRDSCQIU-UHFFFAOYSA-N 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
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
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- 125000001425 triazolyl group Chemical group 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
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- 241000701161 unidentified adenovirus Species 0.000 description 1
- 241000712461 unidentified influenza virus Species 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
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- 229940051021 yellow-fever virus Drugs 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4965—Non-condensed pyrazines
- A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
-
- 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
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
-
- 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
- C07D401/02—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 two hetero rings
- C07D401/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
-
- 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
- C07D403/06—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 carbon chain containing only aliphatic carbon atoms
Definitions
- the present invention relates to a class of alkenyl-containing compounds and applications thereof, in particular to a compound represented by formula (I) or a pharmaceutically acceptable salt thereof.
- XPO1 protein is a component of the Golgi apparatus and one of the nuclear transport receptors.
- XPO1 and RanGTP can interact with the nucleus with a hydrophobic nuclear export signal (Nuclear Export Signal, NES).
- the cargo protein binds to form a stable nuclear export transport complex, and through the action of XPO1 and nucleoporin, after passing through the central channel of the nuclear pore complex and entering the cytoplasm, under the action of RanGAP, the RanGTP bound to XPO1 is hydrolyzed to RanGDP, The depolymerization of the nuclear export transport complex releases the cargo monocytogenes.
- XPO1 is responsible for the nuclear export of more than 240 proteins. These include a large number of tumor suppressor proteins, such as P53, P73, and FOXO1; growth regulatory proteins, such as I ⁇ B, Rb1, P21, P27, BRCA1, and APC; anti-apoptotic proteins, such as NPM, survivin, and AP-1, etc. . Under normal physiological conditions, in the absence of DNA damage or other oncogenic stress, the nuclear export of these proteins avoids their own hyperactivation in the nucleus. In certain tumors, over-expressed XPO1 will cause excessive nuclear export of these proteins, reduce the effective concentration in the nucleus and cause functional disorders, thereby inhibiting the apoptosis process of tumor cells and promoting the occurrence and development of tumors.
- tumor suppressor proteins such as P53, P73, and FOXO1
- growth regulatory proteins such as I ⁇ B, Rb1, P21, P27, BRCA1, and APC
- anti-apoptotic proteins such as NPM,
- XPO1 protein is highly expressed in a variety of solid tumors and hematological tumors, such as ovarian cancer, cervical cancer, pancreatic cancer, liver cancer, osteosarcoma, glioblastoma, lung cancer, multiple myeloma, lymphoma, leukemia, etc. . And high expression of XPO1 is often associated with poor tumor prognosis. Studies have also shown that XPO1 protein can inhibit the nuclear export of I ⁇ B, inhibit the NF- ⁇ B pathway, and inhibit the occurrence and development of KRAS mutant tumors. Different subtypes of KRAS mutant cell lines are sensitive to XPO1 inhibitors.
- XPO1-mediated nuclear export is required for the life cycle of some viruses, such as human immunodeficiency virus (HIV), adenovirus, influenza virus (H1N1, H5N1), hepatitis B virus (HBV), hepatitis C virus (HCV), human papilloma virus (HPV), respiratory syncytial virus (RSV), dengue virus, SARS coronavirus, yellow fever virus, West Nile virus, herpes simplex virus (HSV) and cytomegalovirus ( CMV) and others rely on the nuclear transport function of XPO1 to complete assembly and maturation.
- viruses such as human immunodeficiency virus (HIV), adenovirus, influenza virus (H1N1, H5N1), hepatitis B virus (HBV), hepatitis C virus (HCV), human papilloma virus (HPV), respiratory syncytial virus (RSV), dengue virus, SARS coronavirus, yellow fever virus, West Nile virus
- LMB Leptomycin B
- KPT-330 Selinexor
- Karyopharm Therapeutic is the first marketed XPO1 inhibitor developed by Karyopharm Therapeutic and is currently approved for the treatment of relapsed, refractory multiple myeloma and diffuse large B-cell lymphoma.
- Clinical trials for other indications such as glioblastoma, endometrioma, and non-small cell lung cancer are also underway.
- XPO1 inhibitors bring a new mechanism of drug options.
- the currently listed XPO1 inhibitor Selinexor still has disadvantages such as poor metabolism and poor safety.
- the present invention is devoted to developing a new class of XPO1 inhibitors with high activity, better metabolic properties and safer for the treatment of various tumors including hematological tumors and solid tumors.
- the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
- L is selected from single bond, NR 4 and O;
- R 1 , R 2 and R 3 are each independently selected from H, F, Cl, Br, I, C 1-3 alkyl and C 1-3 alkoxy, said C 1-3 alkyl and C 1-3 3 alkoxy is optionally substituted with 1, 2 or 3 R a ;
- R 1 and R 2 together with the bond to which they are attached form a C 3-5 cycloalkenyl group optionally substituted with 1, 2 or 3 R b ;
- R4 is independently selected from H and CH3 ;
- X 1 and X 2 are each independently selected from CR c and N, and X 1 and X 2 are not simultaneously selected from N;
- Ring B is selected from phenyl, 5-6 membered heteroaryl and The phenyl group, 5-6 membered heteroaryl group and optionally substituted with 1, 2 or 3 Rd ;
- n 0, 1 and 2;
- Ra and Rc are each independently selected from H, F, Cl, Br, I and CH3 ;
- R b and R d are each independently selected from F, Cl, Br, I, C 1-3 alkyl and C 1-3 alkoxy, and said C 1-3 alkyl and C 1-3 alkoxy are any is replaced by 1, 2 or 3 Rs;
- R is independently selected from F, Cl, Br and I.
- the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
- L is selected from single bond, NR 4 and O;
- R 1 , R 2 and R 3 are each independently selected from H, F, Cl, Br, I, C 1-3 alkyl and C 1-3 alkoxy, said C 1-3 alkyl and C 1-3 3 alkoxy is optionally substituted with 1, 2 or 3 R a ;
- R 1 and R 2 together with the bond to which they are attached constitute a C 3-5 cycloalkylalkenyl group optionally substituted with 1, 2 or 3 R b ;
- X 1 and X 2 are each independently selected from CR c and N, and X 1 and X 2 are not simultaneously selected from N;
- Ring B is selected from phenyl, 5-6 membered heteroaryl and The 5-6-membered heteroaryl and optionally substituted with 1, 2 or 3 Rd ;
- n 0, 1 and 2;
- Ra and Rc are independently selected from H, F, Cl, Br and I;
- R b and R d are each independently selected from F, Cl, Br, I, C 1-3 alkyl and C 1-3 alkoxy, and said C 1-3 alkyl and C 1-3 alkoxy are any is replaced by 1, 2 or 3 Rs;
- R is independently selected from F, Cl, Br and I.
- R b and R d are independently selected from F, Cl, Br, I, CH 3 and OCH 3 , and said CH 3 and OCH 3 are optionally substituted with 1, 2 or 3 Rs , and other variables are as defined in the present invention.
- R b and R d are independently selected from F, Cl, CH 3 , CH 2 F, CHF 2 , CF 3 and OCH 3 , and other variables are as defined in the present invention.
- R 1 , R 2 and R 3 are independently selected from H, F, Cl, Br, I, CH 3 , CH 2 CH 3 and OCH 3 , the CH 3 , CH 2 CH 3 and OCH3 are optionally substituted with 1, 2 or 3 R a , other variables are as defined in the present invention.
- R 1 , R 2 and R 3 are each independently selected from H, F, Cl, Br, I, CH 3 , CH 2 F, CHF 2 , CF 3 , CH 2 CH 3 and OCH 3.
- Other variables are as defined in the present invention.
- R 1 and R 2 and the bond to which they are attached together form a cyclopentenyl group, which is optionally substituted with 1, 2 or 3 R b , and other variables are as defined in the present invention definition.
- the above-mentioned L is selected from a single bond, NH and O, and other variables are as defined in the present invention.
- the above-mentioned ring B is selected from phenyl, pyridyl, pyrazinyl and The phenyl, pyridyl, pyrazinyl and Optionally substituted with 1, 2 or 3 Rd , other variables are as defined herein.
- the above-mentioned ring B is selected from phenyl, Other variables are as defined in the present invention.
- the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from the group consisting of
- R 1 , R 2 , R 3 , R d and L are as defined in the present invention.
- the present invention also provides a compound represented by the following formula or a pharmaceutically acceptable salt thereof,
- salts refers to salts of the compounds of the present invention, prepared from compounds with specific substituents discovered by the present invention and relatively non-toxic acids or bases.
- base addition salts can be obtained by contacting the neutral forms of such compounds with a sufficient amount of base in neat solution or in a suitable inert solvent.
- Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts or similar salts.
- acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in neat solution or in a suitable inert solvent.
- Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts including, for example, acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-toluenesulfonic, citric, tartaric, and methanesulfonic acids; also include salts of amino acids such as arginine, etc. , and salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain both basic and acidic functional groups and thus can be converted into either base
- the pharmaceutically acceptable salts of the present invention can be synthesized from the acid or base containing parent compound by conventional chemical methods. Generally, such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of the two.
- the compounds provided herein also exist in prodrug forms.
- Prodrugs of the compounds described herein are readily chemically altered under physiological conditions to convert to the compounds of the present invention.
- prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an in vivo environment.
- the compounds of the present invention may exist in specific geometric or stereoisomeric forms.
- the present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)-isomers, (L)-isomers, and racemic and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which belong to within the scope of the present invention.
- Additional asymmetric carbon atoms may be present in substituents such as alkyl. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.
- enantiomers or “optical isomers” refer to stereoisomers that are mirror images of each other.
- cis-trans isomer or “geometric isomer” result from the inability to rotate freely due to double bonds or single bonds to ring carbon atoms.
- diastereomer refers to a stereoisomer in which the molecule has two or more chiral centers and the molecules are in a non-mirror-image relationship.
- tautomer or “tautomeric form” refers to isomers of different functional groups that are in dynamic equilibrium and are rapidly interconverted at room temperature.
- a chemical equilibrium of tautomers can be achieved if tautomers are possible (eg, in solution).
- proton tautomers also called prototropic tautomers
- prototropic tautomers include interconversions by migration of protons, such as keto-enol isomerization and imine-ene Amine isomerization.
- Valence tautomers include interconversions by recombination of some bonding electrons.
- keto-enol tautomerization is the interconversion between two tautomers, pentane-2,4-dione and 4-hydroxypent-3-en-2-one.
- the terms “enriched in one isomer”, “enriched in isomers”, “enriched in one enantiomer” or “enriched in one enantiomer” refer to one of the isomers or pairs
- the enantiomer content is less than 100%, and the isomer or enantiomer content is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or Greater than or equal to 96%, or greater than or equal to 97%, or greater than or equal to 98%, or greater than or equal to 99%, or greater than or equal to 99.5%, or greater than or equal to 99.6%, or greater than or equal to 99.7%, or greater than or equal to 99.8%, or greater than or equal to 99.9%.
- isomeric excess or “enantiomeric excess” refer to the difference between two isomers or relative percentages of two enantiomers. For example, if the content of one isomer or enantiomer is 90% and the content of the other isomer or enantiomer is 10%, the isomer or enantiomeric excess (ee value) is 80% .
- Optically active (R)- and (S)-isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting mixture of diastereomers is separated and the auxiliary group is cleaved to provide pure desired enantiomer.
- a diastereomeric salt is formed with an appropriate optically active acid or base, followed by conventional methods known in the art
- the diastereoisomers were resolved and the pure enantiomers recovered.
- separation of enantiomers and diastereomers is usually accomplished by the use of chromatography employing a chiral stationary phase, optionally in combination with chemical derivatization (eg, from amines to amino groups) formate).
- the compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound.
- compounds can be labeled with radioisotopes, such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C).
- deuterated drugs can be formed by replacing hydrogen with deuterium, and the bonds formed by deuterium and carbon are stronger than those formed by ordinary hydrogen and carbon. Compared with non-deuterated drugs, deuterated drugs can reduce toxic side effects and increase drug stability. , enhance the efficacy, prolong the biological half-life of drugs and other advantages. All transformations of the isotopic composition of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.
- substituted means that any one or more hydrogen atoms on a specified atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence of the specified atom is normal and the substituted compound is stable.
- oxygen it means that two hydrogen atoms are substituted. Oxygen substitution does not occur on aromatic groups.
- optionally substituted means that it may or may not be substituted, and unless otherwise specified, the type and number of substituents may be arbitrary on a chemically achievable basis.
- any variable eg, R
- its definition in each case is independent.
- the group may optionally be substituted with up to two Rs, with independent options for R in each case.
- combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
- linking group When the number of a linking group is 0, such as -(CRR) 0 -, it means that the linking group is a single bond.
- substituents When a substituent is vacant, it means that the substituent does not exist. For example, when X in AX is vacant, it means that the structure is actually A.
- substituents do not indicate through which atom it is attached to the substituted group, such substituents may be bonded through any of its atoms, for example, pyridyl as a substituent may be through any one of the pyridine rings. The carbon atom is attached to the substituted group.
- the listed linking group does not indicate its direction of attachment, the direction of attachment is arbitrary, for example, The linking group L in the middle is -MW-, at this time -MW- can connect ring A and ring B in the same direction as the reading order from left to right. It is also possible to connect ring A and ring B in the opposite direction to the reading order from left to right. Combinations of the linking groups, substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
- C 1-3 alkyl is used to denote a straight or branched chain saturated hydrocarbon group consisting of 1 to 3 carbon atoms.
- the C 1-3 alkyl group includes C 1-2 and C 2-3 alkyl groups, etc.; it can be monovalent (eg methyl), divalent (eg methylene) or multivalent (eg methine) .
- Examples of C1-3 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.
- C1-3alkoxy refers to those alkyl groups containing 1 to 3 carbon atoms attached to the remainder of the molecule through an oxygen atom.
- the C 1-3 alkoxy group includes C 1-2 , C 2-3 , C 3 and C 2 alkoxy and the like.
- Examples of C 1-3 alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.
- C 3-5 cycloalkyl means a saturated cyclic hydrocarbon group consisting of 3 to 5 carbon atoms, which is a monocyclic ring system, said C 3-5 cycloalkyl including C 3 -4 and C 4-5 cycloalkyl, etc.; it may be monovalent, divalent or polyvalent.
- Examples of C3-5 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and the like.
- C 3-5 cycloalkenyl means a partially unsaturated cyclic hydrocarbon group consisting of 3 to 5 carbon atoms containing at least one carbon-carbon double bond, including monocyclic and bicyclic rings system, wherein the bicyclic ring system includes spiro, paracyclic and bridged rings, any ring of this system is non-aromatic.
- the C 3-5 cycloalkenyl includes C 3-5 or C 4-5 cycloalkenyl and the like; it may be monovalent, divalent or multivalent. Examples of C 3-5 cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, and the like.
- the terms “5-6 membered heteroaryl ring” and “5-6 membered heteroaryl” are used interchangeably in the present invention, and the term “5-6 membered heteroaryl” means from 5 to 6 ring atoms It is composed of a monocyclic group with a conjugated ⁇ electron system, wherein 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms. Where the nitrogen atom is optionally quaternized, the nitrogen and sulfur heteroatoms may be optionally oxidized (ie, NO and S(O) p , p is 1 or 2).
- a 5-6 membered heteroaryl group can be attached to the remainder of the molecule through a heteroatom or a carbon atom.
- the 5-6 membered heteroaryl groups include 5- and 6-membered heteroaryl groups.
- Examples of the 5-6 membered heteroaryl include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrrolyl, etc.) azolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5- oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1, 2,4
- Cn-n+m or Cn - Cn+m includes any particular instance of n to n+ m carbons, eg C1-12 includes C1 , C2 , C3, C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , and C 12 , also including any range from n to n+ m , eg C 1-12 includes C 1-3 , C 1-6 , C 1-9 , C 3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12 , and C 9-12 , etc.; in the same way, n yuan to n +m-membered means that the number of atoms in the ring is from n to n+m, for example, 3-12-membered ring includes 3-membered ring, 4-membered ring, 5-membered ring, 6-membered ring, 7-membered ring, 8-membere
- the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments enumerated below, embodiments formed in combination with other chemical synthesis methods, and those well known to those skilled in the art Equivalent to alternatives, preferred embodiments include, but are not limited to, the embodiments of the present invention.
- the structure of the compound of the present invention can be confirmed by conventional methods well known to those skilled in the art. If the present invention relates to the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art. For example, single crystal X-ray diffraction method (SXRD), the cultured single crystal is collected by Bruker D8 venture diffractometer, the light source is CuK ⁇ radiation, and the scanning mode is: After scanning and collecting relevant data, the crystal structure was further analyzed by the direct method (Shelxs97), and the absolute configuration could be confirmed.
- SXRD single crystal X-ray diffraction method
- the cultured single crystal is collected by Bruker D8 venture diffractometer
- the light source is CuK ⁇ radiation
- the scanning mode is: After scanning and collecting relevant data, the crystal structure was further analyzed by the direct method (Shelxs97), and the absolute configuration could be confirmed.
- the solvent used in the present invention is commercially available.
- the present invention adopts the following abbreviations: aq represents water; eq represents equivalent, equivalent; DCM represents dichloromethane; PE represents petroleum ether; DMF represents N,N-dimethylformamide; DMSO represents dimethyl sulfoxide; EtOAc stands for ethyl acetate; EtOH stands for ethanol; MeOH stands for methanol; CBz stands for benzyloxycarbonyl, which is an amine protecting group; BOC stands for tert-butoxycarbonyl, which is an amine protecting group; HOAc stands for acetic acid; rt stands for room temperature; O/N stands for overnight; THF for tetrahydrofuran; Boc 2 O for di-tert-butyl dicarbonate; TFA for trifluoroacetic acid; DIPEA for diisopropylethylamine.
- the compound of the present invention has excellent in vitro anti-proliferative activity, life-extending activity and no obvious drug side effects; the compound of the present invention has excellent pharmacokinetic properties.
- step 1
- reaction solution After adding sodium iodide (22.92 g, 152.91 mmol) and acetic acid (100 mL) to a pre-dried reaction flask, the reaction solution was heated to 70°C. After the sodium iodide (22.92 g, 152.91 mmol) was completely dissolved, compound ST-1-1 (10 g, 101.94 mmol) was added to the reaction solution. After the addition was completed, the reaction was continued at 70°C for 12 hours. After completion of the reaction, the reaction solution was lowered to 25°C, and methyl tert-butyl ether (150 mL) and water (100 mL) were added.
- the aqueous phase was extracted with methyl tert-butyl ether (40 mL*3), and the organic phase was collected.
- the organic phase was washed with 10% aqueous sodium thiosulfate solution (30 mL), then with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to obtain compound ST-1.
- reaction solution was adjusted to 10 with aqueous sodium hydroxide solution (1M), the reaction solution was extracted with ethyl acetate (10mL*3), the organic phase was collected, and the organic phase was washed with saturated brine (20mL). The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain crude product.
- the crude product was subjected to preparative high performance liquid chromatography (chromatographic column: Phenomenex Gemini-NX 80*40mm*3 ⁇ m; mobile phase: [water (0.05% NH 3 H 2 O+10 mM NH 4 HCO 3 )-ACN]; B (acetonitrile)% : 40%-70%, 8min) to separate compound 3.
- reaction solution 4-2 (27.27 g, 91.80 mmol) and dioxane (270 mL) were added to a pre-dried single-neck flask, then sodium hydroxide (2 M, 103.49 mL) was added, and the mixture was stirred at 25° C. for 20 hours.
- the reaction solution 4-3 was obtained, which was directly used in the next reaction without purification.
- Phosphorus oxychloride (266.04 g, 1.74 mol) was added to the pre-dried reaction flask, followed by compound 8-3 (15.8 g, 74.82 mmol). Nitrogen was replaced three times, and the mixture was stirred at 100°C for 16 hours. After the reaction was completed, the reaction solution was slowly added dropwise to water (200 mL) to quench, the pH was adjusted to 10 with saturated aqueous sodium carbonate solution, the reaction solution was extracted with ethyl acetate (200 mL*2), the organic phase was collected, saturated brine (200 mL) Washed, dried over anhydrous sodium sulfate, and concentrated.
- the compounds of the present invention have excellent in vitro antiproliferative activity.
- human lymphoma TMD8 cell SCID mouse systemic model the life-extending activity of the test substance administered alone was evaluated.
- human lymphoma TMD8 cells were used to establish a systemic model of SCID mice by tail vein inoculation, and the antitumor effects of Selinexor and compound 6 alone were evaluated.
- the test substance Selinexor and the compound of the present invention were both dissolved in the vehicle of 1% poloxamer 188+1% polyvinylpyrrolidone and administered orally three times a week, and continued to be administered until the end of the experiment (oral administration, once every other day ⁇ 3 /week, 15mg/kg day 0-8 + 10mg/kg day 9-37).
- TMD8 cells were cultured in RPMI-1640 medium containing 10% FBS, maintained in a 37°C saturated humidity incubator with 5% CO 2 . TMD8 cells in logarithmic growth phase were collected, resuspended in PBS, and the cell concentration was adjusted to 5 ⁇ 10 7 /mL. Under sterile conditions, 0.2 mL of cell suspension was inoculated into mice via tail vein, and the final concentration of inoculation was 10 ⁇ 10 6 /0.2 mL PBS/mouse. 18 days after inoculation, animals were randomly divided into groups according to body weight, so that the difference in body weight of each group was less than 10% of the mean.
- the median survival time (Median Survival Time, MST) calculation formula is: when the cumulative survival rate is 50%, the corresponding survival time (the day of group administration is recorded as day 0), the specific value is determined by GraphPad Prism 6 software (San Diego , CA, USA) is calculated;
- the relative life extension rate (%T/CMST) was calculated as: TMST/CMST ⁇ 100%, where TMST was the MST of the treatment group, and CMST was the MST of the negative control group;
- the relative life extension rate of compound 6 was 150%, while that of Selinexor was 133.33%.
- the survival rate was 0%, while the survival rate of the compound 6 group was 50%.
- the purpose of this experiment was to study the pharmacokinetics of the test article in the plasma of male C57BL/6J mice after intravenous and oral administration.
- Animals were randomly divided into two groups with 2 males in each group.
- the compounds are formulated into the indicated formulations, either as clear solutions for intravenous injection or as clear or homogeneous suspensions for oral formulations.
- Whole blood samples were collected from jugular vein puncture or saphenous vein at 5, 15, 30 minutes, 1, 2, 4, 6, and 8 hours post-dose.
- the whole blood sample was added to a centrifuge tube containing anticoagulant, centrifuged at 3000g for 15 min at 4°C, and the supernatant plasma was quickly frozen on dry ice, and then stored in a -70 ⁇ 10°C refrigerator until LC-MS/MS analysis.
- Plasma drug concentration data for compounds were processed in a non-compartmental model using WinNonlin TM Version 6.3.0 (Pharsight, Mountain View, CA) pharmacokinetic software.
- the following pharmacokinetic parameters were calculated using the log-linear trapezoidal method: plasma clearance (CL), volume of distribution (Vd), elimination half-life (T 1/2 ), mean residence time of drug in the body from 0 to terminal time points (MRT 0-last ), the mean residence time of the drug in the body from 0 o’clock to infinity (MRT 0-inf ), the area under the time-plasma concentration curve from 0 o’clock to the terminal time point (AUC 0-last ), 0 o’clock to infinity Area under the time-plasma concentration curve (AUCo -inf ) and bioavailability (F).
- CL plasma clearance
- Vd volume of distribution
- T 1/2 elimination half-life
- MRT 0-last mean residence time of drug in the body from 0 to terminal time points
- MRT 0-inf mean residence time of the drug in the body from 0 o’clock to infinity
- AUC 0-last the area under the time-plasma concentration curve from 0 o’clock to the terminal
- the compounds of the present invention have excellent pharmacokinetic properties.
- Corning pipette plating 100uL (100 microliters) per well, cell density 32k/well. Incubate for 2-3 hours in a post-CO 2 incubator at 37°C. Dispense the prepared compound into the corresponding cell plate with a pipette, 100uL per well, and incubate at 37°C for 2 hours. Remove the cell plate from the incubator, discard the medium, and fix it with 4% paraformaldehyde for 20 min at room temperature. The fixative was discarded and washed three times with phosphate buffered saline (PBS), 5 min/time. 0.3% Triton X-100 at room temperature for 20min.
- PBS phosphate buffered saline
- the permeabilization fluid was discarded and washed three times with phosphate buffered saline (PBS), 5 min/time.
- Block with 5% BSA solution Bovine Serum Albumin, BSA
- Alexa Fluor 594 fluorescent Anti-iKB alpha antibody incubation 1:400 dilution, incubate overnight at 4 °C.
- Discard the antibody solution Wash 3 times with phosphate buffered saline (PBS), 5 min/time. Dilute at 1:2000, incubate at room temperature for 20 min, DAPI (4', 6-diamidino-2-phenylindole (4', 6-diamidino-2 -phenylindole).
- the Operetta instrument takes pictures and analyzes the data.
- the compounds of the present invention have good CRM1-mediated nuclear export inhibitory ability.
Abstract
An alkenyl-containing compound represented by formula I or a pharmaceutically acceptable salt thereof.
Description
本申请主张如下优先权This application claims the following priority
CN202011607611.4,申请日:2020年12月29日。CN202011607611.4, application date: December 29, 2020.
本发明涉及一类含烯基类化合物及其应用,具体涉及式(I)所示化合物或其药学上可接受的盐。The present invention relates to a class of alkenyl-containing compounds and applications thereof, in particular to a compound represented by formula (I) or a pharmaceutically acceptable salt thereof.
细胞内特定蛋白的正确定位对细胞发挥正常功能尤为重要,而蛋白的核内外转运在稳定和平衡细胞的正常发育中起到了重要的作用。其中,蛋白的核输出依赖于核输出蛋白(Exportin 1,XPO1)也叫作染色体区域稳定蛋白1(Chromosome region maintenance 1,CRM1)。XPO1蛋白是高尔基体的组成部分,也是核转运受体之一,作为一个泛素化的出核转运受体,XPO1和RanGTP能够与核内带有疏水性出核信号(Nuclear Export Signal,NES)的货物蛋白结合,形成稳定的出核转运复合体,并通过XPO1与核孔蛋白的作用,穿越核孔复合体中央通道进入细胞质后,在RanGAP的作用下,与XPO1结合的RanGTP水解成为RanGDP,出核转运复合体解聚后释放出货物单白。The correct localization of specific proteins in cells is particularly important for the normal function of cells, and the transport of proteins to and from the nucleus plays an important role in stabilizing and balancing the normal development of cells. Among them, the nuclear export of the protein depends on the nuclear export protein (Exportin 1, XPO1), also known as Chromosome region maintenance 1 (CRM1). XPO1 protein is a component of the Golgi apparatus and one of the nuclear transport receptors. As a ubiquitinated nuclear export transport receptor, XPO1 and RanGTP can interact with the nucleus with a hydrophobic nuclear export signal (Nuclear Export Signal, NES). The cargo protein binds to form a stable nuclear export transport complex, and through the action of XPO1 and nucleoporin, after passing through the central channel of the nuclear pore complex and entering the cytoplasm, under the action of RanGAP, the RanGTP bound to XPO1 is hydrolyzed to RanGDP, The depolymerization of the nuclear export transport complex releases the cargo monocytogenes.
XPO1作为karyopherin-β家族最重要的核受体之一,负责超过240种蛋白的出核转运。其中包括了大量的抑癌基因蛋白,如P53、P73和FOXO1等;生长调节蛋白,如IκB、Rb1、P21、P27、BRCA1和APC等;抗凋亡蛋白,如NPM、survivin和AP-1等。在正常生理条件,没有DNA损伤或其他致癌应激时,上述蛋白的核输出转运避免了自身在核内的过度激活。而在特定肿瘤中,过量表达的XPO1会使这些蛋白过度核输出,降低核内的有效浓度及发生功能紊乱,从而抑制肿瘤细胞的凋亡进程,促进肿瘤的发生发展。As one of the most important nuclear receptors of the karyopherin-β family, XPO1 is responsible for the nuclear export of more than 240 proteins. These include a large number of tumor suppressor proteins, such as P53, P73, and FOXO1; growth regulatory proteins, such as IκB, Rb1, P21, P27, BRCA1, and APC; anti-apoptotic proteins, such as NPM, survivin, and AP-1, etc. . Under normal physiological conditions, in the absence of DNA damage or other oncogenic stress, the nuclear export of these proteins avoids their own hyperactivation in the nucleus. In certain tumors, over-expressed XPO1 will cause excessive nuclear export of these proteins, reduce the effective concentration in the nucleus and cause functional disorders, thereby inhibiting the apoptosis process of tumor cells and promoting the occurrence and development of tumors.
已有研究表明XPO1蛋白在多种实体瘤以及血液瘤中高表达,如卵巢癌、宫颈癌、胰腺癌、肝癌、骨肉瘤、胶质母细胞瘤、肺癌、多发性骨髓瘤、淋巴瘤、白血病等。并且XPO1的高表达常与肿瘤的不良预后相关。也有研究表明XPO1蛋白可以通过抑制IκB的核输出,抑制NF-κB通路,抑制KRAS突变肿瘤的发生和发展,不同亚型的KRAS突变的细胞株对XPO1抑制剂敏感。Studies have shown that XPO1 protein is highly expressed in a variety of solid tumors and hematological tumors, such as ovarian cancer, cervical cancer, pancreatic cancer, liver cancer, osteosarcoma, glioblastoma, lung cancer, multiple myeloma, lymphoma, leukemia, etc. . And high expression of XPO1 is often associated with poor tumor prognosis. Studies have also shown that XPO1 protein can inhibit the nuclear export of IκB, inhibit the NF-κB pathway, and inhibit the occurrence and development of KRAS mutant tumors. Different subtypes of KRAS mutant cell lines are sensitive to XPO1 inhibitors.
此外,XPO1介导的出核转运对于一些病毒的生命周期是需要的,如人免疫缺陷病毒(HIV)、腺病毒、流感病毒(H1N1、H5N1)、乙型肝炎病毒(HBV)、丙型肝炎病毒(HCV)、人乳头状瘤病毒(HPV)、呼吸道合胞体病毒(RSV)、登革热病毒、SARS冠状病毒、黄热病病毒、西尼罗河病毒、单纯性疱疹病毒(HSV)和巨细胞病毒(CMV)等依赖于XPO1的核转运功能完成组装和成熟。In addition, XPO1-mediated nuclear export is required for the life cycle of some viruses, such as human immunodeficiency virus (HIV), adenovirus, influenza virus (H1N1, H5N1), hepatitis B virus (HBV), hepatitis C virus (HCV), human papilloma virus (HPV), respiratory syncytial virus (RSV), dengue virus, SARS coronavirus, yellow fever virus, West Nile virus, herpes simplex virus (HSV) and cytomegalovirus ( CMV) and others rely on the nuclear transport function of XPO1 to complete assembly and maturation.
早期对XPO1抑制剂的研究主要集中在天然产物XPO1抑制剂Leptomycin B(LMB)。LMB本身对于肿瘤细胞具有非常高的毒性,但是对于动物和人的耐受性差,由于其过强的毒性导致临床I期试验终止。KPT-330(Selinexor)是Karyopharm Therapeutic公司研发的第一个上市的XPO1抑制剂,目前已获批用于治疗复发、难治多发性骨髓瘤和弥漫性大B细胞淋巴瘤。其他适应症如胶质母细胞瘤、子宫内膜瘤、非小 细胞肺癌等临床试验也正在开展中。Early research on XPO1 inhibitors focused on the natural product XPO1 inhibitor Leptomycin B (LMB). LMB itself has very high toxicity to tumor cells, but it is poorly tolerated in animals and humans, and the clinical phase I trial was terminated due to its excessive toxicity. KPT-330 (Selinexor) is the first marketed XPO1 inhibitor developed by Karyopharm Therapeutic and is currently approved for the treatment of relapsed, refractory multiple myeloma and diffuse large B-cell lymphoma. Clinical trials for other indications such as glioblastoma, endometrioma, and non-small cell lung cancer are also underway.
XPO1抑制剂带来了全新机制的用药选择,然而目前上市的XPO1抑制剂Selinexor仍存在代谢性质不佳,安全性较差等缺点。本发明致力于发展一类新的具有高活性、代谢性质更佳和更安全的XPO1抑制剂,用于治疗包括血液瘤和实体瘤等多种肿瘤。XPO1 inhibitors bring a new mechanism of drug options. However, the currently listed XPO1 inhibitor Selinexor still has disadvantages such as poor metabolism and poor safety. The present invention is devoted to developing a new class of XPO1 inhibitors with high activity, better metabolic properties and safer for the treatment of various tumors including hematological tumors and solid tumors.
发明内容SUMMARY OF THE INVENTION
本发明提供了式(I)所示化合物或其药学上可接受的盐,The present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
其中,in,
L选自单键、NR
4和O;
L is selected from single bond, NR 4 and O;
R
1、R
2和R
3分别独立地选自H、F、Cl、Br、I、C
1-3烷基和C
1-3烷氧基,所述C
1-3烷基和C
1-3烷氧基任选被1、2或3个R
a取代;
R 1 , R 2 and R 3 are each independently selected from H, F, Cl, Br, I, C 1-3 alkyl and C 1-3 alkoxy, said C 1-3 alkyl and C 1-3 3 alkoxy is optionally substituted with 1, 2 or 3 R a ;
或者,R
1和R
2与它们相连的键共同构成C
3-5环烯基,所述C
3-5环烯基任选被1、2或3个R
b取代;
Alternatively, R 1 and R 2 together with the bond to which they are attached form a C 3-5 cycloalkenyl group optionally substituted with 1, 2 or 3 R b ;
R
4独立地选自H和CH
3;
R4 is independently selected from H and CH3 ;
X
1和X
2分别独立地选自CR
c和N,且X
1和X
2不同时选自N;
X 1 and X 2 are each independently selected from CR c and N, and X 1 and X 2 are not simultaneously selected from N;
环B选自苯基、5~6元杂芳基和
所述苯基、5~6元杂芳基和
任选被1、2或3个R
d取代;
Ring B is selected from phenyl, 5-6 membered heteroaryl and The phenyl group, 5-6 membered heteroaryl group and optionally substituted with 1, 2 or 3 Rd ;
m选自0、1和2;m is selected from 0, 1 and 2;
R
a和R
c分别独立地选自H、F、Cl、Br、I和CH
3;
Ra and Rc are each independently selected from H, F, Cl, Br, I and CH3 ;
R
b和R
d分别独立地选自F、Cl、Br、I、C
1-3烷基和C
1-3烷氧基,所述C
1-3烷基和C
1-3烷氧基任选被1、2或3个R取代;
R b and R d are each independently selected from F, Cl, Br, I, C 1-3 alkyl and C 1-3 alkoxy, and said C 1-3 alkyl and C 1-3 alkoxy are any is replaced by 1, 2 or 3 Rs;
R独立地选自F、Cl、Br和I。R is independently selected from F, Cl, Br and I.
本发明提供了式(I)所示化合物或其药学上可接受的盐,The present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
其中,in,
L选自单键、NR
4和O;
L is selected from single bond, NR 4 and O;
R
1、R
2和R
3分别独立地选自H、F、Cl、Br、I、C
1-3烷基和C
1-3烷氧基,所述C
1-3烷基和C
1-3烷氧基任选被1、2或3个R
a取代;
R 1 , R 2 and R 3 are each independently selected from H, F, Cl, Br, I, C 1-3 alkyl and C 1-3 alkoxy, said C 1-3 alkyl and C 1-3 3 alkoxy is optionally substituted with 1, 2 or 3 R a ;
或者,R
1和R
2与它们相连的键共同构成C
3-5环烷烯基,所述C
3-5环烷烯基任选被1、2或3个R
b取代;R
4独立地选自H和CH
3;
Alternatively, R 1 and R 2 together with the bond to which they are attached constitute a C 3-5 cycloalkylalkenyl group optionally substituted with 1, 2 or 3 R b ; R 4 independently selected from H and CH3 ;
X
1和X
2分别独立地选自CR
c和N,且X
1和X
2不同时选自N;
X 1 and X 2 are each independently selected from CR c and N, and X 1 and X 2 are not simultaneously selected from N;
环B选自苯基、5~6元杂芳基和
所述5~6元杂芳基和
任选被1、2或3个R
d取代;
Ring B is selected from phenyl, 5-6 membered heteroaryl and The 5-6-membered heteroaryl and optionally substituted with 1, 2 or 3 Rd ;
m选自0、1和2;m is selected from 0, 1 and 2;
R
a和R
c独立地选自H、F、Cl、Br和I;
Ra and Rc are independently selected from H, F, Cl, Br and I;
R
b和R
d分别独立地选自F、Cl、Br、I、C
1-3烷基和C
1-3烷氧基,所述C
1-3烷基和C
1-3烷氧基任选被1、2或3个R取代;
R b and R d are each independently selected from F, Cl, Br, I, C 1-3 alkyl and C 1-3 alkoxy, and said C 1-3 alkyl and C 1-3 alkoxy are any is replaced by 1, 2 or 3 Rs;
R独立地选自F、Cl、Br和I。R is independently selected from F, Cl, Br and I.
本发明的一些方案中,上述R
b和R
d分别独立地选自F、Cl、Br、I、CH
3和OCH
3,所述CH
3和OCH
3任选被1、2或3个R取代,其他变量如本发明所定义。
In some embodiments of the present invention, the above R b and R d are independently selected from F, Cl, Br, I, CH 3 and OCH 3 , and said CH 3 and OCH 3 are optionally substituted with 1, 2 or 3 Rs , and other variables are as defined in the present invention.
本发明的一些方案中,上述R
b和R
d分别独立地选自F、Cl、CH
3、CH
2F、CHF
2、CF
3和OCH
3,其他变量如本发明所定义。
In some embodiments of the present invention, the above R b and R d are independently selected from F, Cl, CH 3 , CH 2 F, CHF 2 , CF 3 and OCH 3 , and other variables are as defined in the present invention.
本发明的一些方案中,上述R
1、R
2和R
3分别独立地选自H、F、Cl、Br、I、CH
3、CH
2CH
3和OCH
3,所述CH
3、CH
2CH
3和OCH
3任选被1、2或3个R
a取代,其他变量如本发明所定义。
In some embodiments of the present invention, the above R 1 , R 2 and R 3 are independently selected from H, F, Cl, Br, I, CH 3 , CH 2 CH 3 and OCH 3 , the CH 3 , CH 2 CH 3 and OCH3 are optionally substituted with 1, 2 or 3 R a , other variables are as defined in the present invention.
本发明的一些方案中,上述R
1、R
2和R
3分别独立地选自H、F、Cl、Br、I、CH
3、CH
2F、CHF
2、CF
3、CH
2CH
3和OCH
3,其他变量如本发明所定义。
In some aspects of the present invention, the above R 1 , R 2 and R 3 are each independently selected from H, F, Cl, Br, I, CH 3 , CH 2 F, CHF 2 , CF 3 , CH 2 CH 3 and OCH 3. Other variables are as defined in the present invention.
本发明的一些方案中,上述R
1和R
2与它们相连的键共同构成环戊烯基,所述环戊烯基任选被1、2或3个R
b取代,其他变量如本发明所定义。
In some embodiments of the present invention, the above R 1 and R 2 and the bond to which they are attached together form a cyclopentenyl group, which is optionally substituted with 1, 2 or 3 R b , and other variables are as defined in the present invention definition.
本发明的一些方案中,上述R
1和R
2与它们相连的键共同构成
其他变量如本发明所定义。
In some aspects of the present invention, the above-mentioned R 1 and R 2 and the bonds to which they are attached together form Other variables are as defined in the present invention.
本发明的一些方案中,上述L选自单键、NH和O,其他变量如本发明所定义。In some embodiments of the present invention, the above-mentioned L is selected from a single bond, NH and O, and other variables are as defined in the present invention.
本发明的一些方案中,上述环B选自苯基、吡啶基、吡嗪基和
所述苯基、吡啶基、吡嗪基和
任选被1、2或3个R
d取代,其他变量如本发明所定义。
In some embodiments of the present invention, the above-mentioned ring B is selected from phenyl, pyridyl, pyrazinyl and The phenyl, pyridyl, pyrazinyl and Optionally substituted with 1, 2 or 3 Rd , other variables are as defined herein.
本发明的一些方案中,上述环B选自苯基、
其他变量如本发明所定义。
In some aspects of the present invention, the above-mentioned ring B is selected from phenyl, Other variables are as defined in the present invention.
本发明的一些方案中,上述结构单元
选自
其他变量如本发明所定义。
In some aspects of the present invention, the above-mentioned structural units selected from Other variables are as defined in the present invention.
本发明的一些方案中,上述结构单元
选自
其他变量如本发明所定义。
In some aspects of the present invention, the above-mentioned structural units selected from Other variables are as defined in the present invention.
本发明还有一些方案是由上述各变量任意组合而来。There are still some solutions of the present invention which are obtained by any combination of the above variables.
本发明的一些方案中,上述化合物或其药学上可接受的盐,其选自In some aspects of the present invention, the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from the group consisting of
其中,in,
R
1、R
2、R
3、R
d和L如本发明所定义。
R 1 , R 2 , R 3 , R d and L are as defined in the present invention.
本发明还提供了下式所示化合物或其药学上可接受的盐,The present invention also provides a compound represented by the following formula or a pharmaceutically acceptable salt thereof,
定义和说明Definition and Explanation
除非另有说明,本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的,而应该按照普通的含义去理解。当本文中出现商品名时,意在指代其对应的商品或其活性成分。这里所采用的术语“药学上可接受的”,是针对那些化合物、材料、组合物和/或剂型而言,它们在可靠的医学判断的范围之内,适用于与人类和动物的组织接触使用,而没有 过多的毒性、刺激性、过敏性反应或其它问题或并发症,与合理的利益/风险比相称。Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered indeterminate or unclear without specific definitions, but should be understood in its ordinary meaning. When a trade name appears herein, it is intended to refer to its corresponding commercial product or its active ingredient. As used herein, the term "pharmaceutically acceptable" refers to those compounds, materials, compositions and/or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissue , without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.
术语“药学上可接受的盐”是指本发明化合物的盐,由本发明发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本发明的化合物中含有相对酸性的功能团时,可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物的中性形式接触的方式获得碱加成盐。药学上可接受的碱加成盐包括钠、钾、钙、铵、有机氨或镁盐或类似的盐。当本发明的化合物中含有相对碱性的官能团时,可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物的中性形式接触的方式获得酸加成盐。药学上可接受的酸加成盐的实例包括无机酸盐,所述无机酸包括例如盐酸、氢溴酸、硝酸、碳酸,碳酸氢根,磷酸、磷酸一氢根、磷酸二氢根、硫酸、硫酸氢根、氢碘酸、亚磷酸等;以及有机酸盐,所述有机酸包括如乙酸、丙酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸和甲磺酸等类似的酸;还包括氨基酸(如精氨酸等)的盐,以及如葡糖醛酸等有机酸的盐。本发明的某些特定的化合物含有碱性和酸性的官能团,从而可以被转换成任一碱或酸加成盐。The term "pharmaceutically acceptable salts" refers to salts of the compounds of the present invention, prepared from compounds with specific substituents discovered by the present invention and relatively non-toxic acids or bases. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral forms of such compounds with a sufficient amount of base in neat solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts or similar salts. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in neat solution or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts including, for example, acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-toluenesulfonic, citric, tartaric, and methanesulfonic acids; also include salts of amino acids such as arginine, etc. , and salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain both basic and acidic functional groups and thus can be converted into either base or acid addition salts.
本发明的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下,这样的盐的制备方法是:在水或有机溶剂或两者的混合物中,经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。The pharmaceutically acceptable salts of the present invention can be synthesized from the acid or base containing parent compound by conventional chemical methods. Generally, such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of the two.
除了盐的形式,本发明所提供的化合物还存在前药形式。本文所描述的化合物的前药容易地在生理条件下发生化学变化从而转化成本发明的化合物。此外,前体药物可以在体内环境中通过化学或生化方法被转换到本发明的化合物。In addition to salt forms, the compounds provided herein also exist in prodrug forms. Prodrugs of the compounds described herein are readily chemically altered under physiological conditions to convert to the compounds of the present invention. Furthermore, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an in vivo environment.
本发明的某些化合物可以以非溶剂化形式或者溶剂化形式存在,包括水合物形式。一般而言,溶剂化形式与非溶剂化的形式相当,都包含在本发明的范围之内。Certain compounds of the present invention may exist in unsolvated as well as solvated forms, including hydrated forms. In general, solvated and unsolvated forms are equivalent and are intended to be included within the scope of the present invention.
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物,包括顺式和反式异构体、(-)-和(+)-对对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体,及其外消旋混合物和其他混合物,例如对映异构体或非对映体富集的混合物,所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物,均包括在本发明的范围之内。The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)-isomers, (L)-isomers, and racemic and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which belong to within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.
除非另有说明,术语“对映异构体”或者“旋光异构体”是指互为镜像关系的立体异构体。Unless otherwise indicated, the terms "enantiomers" or "optical isomers" refer to stereoisomers that are mirror images of each other.
除非另有说明,术语“顺反异构体”或者“几何异构体”系由因双键或者成环碳原子单键不能自由旋转而引起。Unless otherwise specified, the terms "cis-trans isomer" or "geometric isomer" result from the inability to rotate freely due to double bonds or single bonds to ring carbon atoms.
除非另有说明,术语“非对映异构体”是指分子具有两个或多个手性中心,并且分子间为非镜像的关系的立体异构体。Unless otherwise indicated, the term "diastereomer" refers to a stereoisomer in which the molecule has two or more chiral centers and the molecules are in a non-mirror-image relationship.
除非另有说明,“(D)”或者“(+)”表示右旋,“(L)”或者“(-)”表示左旋,“(DL)”或者“(±)”表示外消旋。Unless otherwise specified, "(D)" or "(+)" means dextrorotatory, "(L)" or "(-)" means levorotatory, and "(DL)" or "(±)" means racemic.
除非另有说明,用楔形实线键
和楔形虚线键
表示一个立体中心的绝对构型,用直形实线键
和直形虚线键
表示立体中心的相对构型,用波浪线
表示楔形实线键
或楔形虚线键
或用波浪线
表示直形实线键
和直形虚线键
Use solid wedge keys unless otherwise specified and wedge-dotted keys Indicate the absolute configuration of a stereocenter, using a straight solid key and straight dashed keys Indicate the relative configuration of the stereocenter, with a wavy line Represents a solid wedge key or wedge-dotted key or with wavy lines Represents a straight solid key and straight dashed keys
本发明的化合物可以存在特定的。除非另有说明,术语“互变异构体”或“互变异构体形式”是指在室温下,不同官能团异构体处于动态平衡,并能很快的相互转化。若互变异构体是可能的(如在溶液中),则可以达到互变异构体的化学平衡。例如,质子互变异构体(proton tautomer)(也称质子转移互变异构体(prototropic tautomer))包括通过质子迁移来进行的互相转化,如酮-烯醇异构化和亚胺-烯胺异构化。价键异构体(valence tautomer)包括一些成键电子的重组来进行的相互转化。其中酮-烯醇互变异构化的具体实例是戊烷-2,4-二酮与4-羟基戊-3-烯-2-酮两个互变异构体之间的互变。The compounds of the present invention may exist in particular. Unless otherwise specified, the term "tautomer" or "tautomeric form" refers to isomers of different functional groups that are in dynamic equilibrium and are rapidly interconverted at room temperature. A chemical equilibrium of tautomers can be achieved if tautomers are possible (eg, in solution). For example, proton tautomers (also called prototropic tautomers) include interconversions by migration of protons, such as keto-enol isomerization and imine-ene Amine isomerization. Valence tautomers include interconversions by recombination of some bonding electrons. A specific example of keto-enol tautomerization is the interconversion between two tautomers, pentane-2,4-dione and 4-hydroxypent-3-en-2-one.
除非另有说明,术语“富含一种异构体”、“异构体富集”、“富含一种对映体”或者“对映体富集”指其中一种异构体或对映体的含量小于100%,并且,该异构体或对映体的含量大于等于60%,或者大于等于70%,或者大于等于80%,或者大于等于90%,或者大于等于95%,或者大于等于96%,或者大于等于97%,或者大于等于98%,或者大于等于99%,或者大于等于99.5%,或者大于等于99.6%,或者大于等于99.7%,或者大于等于99.8%,或者大于等于99.9%。Unless otherwise indicated, the terms "enriched in one isomer", "enriched in isomers", "enriched in one enantiomer" or "enriched in one enantiomer" refer to one of the isomers or pairs The enantiomer content is less than 100%, and the isomer or enantiomer content is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or Greater than or equal to 96%, or greater than or equal to 97%, or greater than or equal to 98%, or greater than or equal to 99%, or greater than or equal to 99.5%, or greater than or equal to 99.6%, or greater than or equal to 99.7%, or greater than or equal to 99.8%, or greater than or equal to 99.9%.
除非另有说明,术语“异构体过量”或“对映体过量”指两种异构体或两种对映体相对百分数之间的差值。例如,其中一种异构体或对映体的含量为90%,另一种异构体或对映体的含量为10%,则异构体或对映体过量(ee值)为80%。Unless otherwise indicated, the terms "isomeric excess" or "enantiomeric excess" refer to the difference between two isomers or relative percentages of two enantiomers. For example, if the content of one isomer or enantiomer is 90% and the content of the other isomer or enantiomer is 10%, the isomer or enantiomeric excess (ee value) is 80% .
可以通过的手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体以及D和L异构体。如果想得到本发明某化合物的一种对映体,可以通过不对称合成或者具有手性助剂的衍生作用来制备,其中将所得非对映体混合物分离,并且辅助基团裂开以提供纯的所需对映异构体。或者,当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时,与适当的光学活性的酸或碱形成非对映异构体的盐,然后通过本领域所公知的常规方法进行非对映异构体拆分,然后回收得到纯的对映体。此外,对映异构体和非对映异构体的分离通常是通过使用色谱法完成的,所述色谱法采用手性固定相,并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如,可用放射性同位素标记化合物,比如氚(
3H),碘-125(
125I)或C-14(
14C)。又例如,可用重氢取代氢形成氘代药物,氘与碳构成的键比普通氢与碳构成的键更坚固,相比于未氘化药物,氘代药物有降低毒副作用、增加药物稳定性、增强疗效、延长药物生物半衰期等优势。本发明的化合物的所有同位素组成的变换,无论放射性与否,都包括在本发明的范围之内。
Optically active (R)- and (S)-isomers, as well as D and L isomers, can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting mixture of diastereomers is separated and the auxiliary group is cleaved to provide pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a diastereomeric salt is formed with an appropriate optically active acid or base, followed by conventional methods known in the art The diastereoisomers were resolved and the pure enantiomers recovered. In addition, separation of enantiomers and diastereomers is usually accomplished by the use of chromatography employing a chiral stationary phase, optionally in combination with chemical derivatization (eg, from amines to amino groups) formate). The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound. For example, compounds can be labeled with radioisotopes, such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C). For another example, deuterated drugs can be formed by replacing hydrogen with deuterium, and the bonds formed by deuterium and carbon are stronger than those formed by ordinary hydrogen and carbon. Compared with non-deuterated drugs, deuterated drugs can reduce toxic side effects and increase drug stability. , enhance the efficacy, prolong the biological half-life of drugs and other advantages. All transformations of the isotopic composition of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.
术语“任选”或“任选地”指的是随后描述的事件或状况可能但不是必需出现的,并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。The terms "optional" or "optionally" mean that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. .
术语“被取代的”是指特定原子上的任意一个或多个氢原子被取代基取代,取代基可以包括重氢和氢的 变体,只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为氧(即=O)时,意味着两个氢原子被取代。氧取代不会发生在芳香基上。术语“任选被取代的”是指可以被取代,也可以不被取代,除非另有规定,取代基的种类和数目在化学上可以实现的基础上可以是任意的。The term "substituted" means that any one or more hydrogen atoms on a specified atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence of the specified atom is normal and the substituted compound is stable. When the substituent is oxygen (ie =O), it means that two hydrogen atoms are substituted. Oxygen substitution does not occur on aromatic groups. The term "optionally substituted" means that it may or may not be substituted, and unless otherwise specified, the type and number of substituents may be arbitrary on a chemically achievable basis.
当任何变量(例如R)在化合物的组成或结构中出现一次以上时,其在每一种情况下的定义都是独立的。因此,例如,如果一个基团被0-2个R所取代,则所述基团可以任选地至多被两个R所取代,并且每种情况下的R都有独立的选项。此外,取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。When any variable (eg, R) occurs more than once in the composition or structure of a compound, its definition in each case is independent. Thus, for example, if a group is substituted with 0-2 Rs, the group may optionally be substituted with up to two Rs, with independent options for R in each case. Furthermore, combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
当一个连接基团的数量为0时,比如-(CRR)
0-,表示该连接基团为单键。
When the number of a linking group is 0, such as -(CRR) 0 -, it means that the linking group is a single bond.
当其中一个变量选自单键时,表示其连接的两个基团直接相连,比如A-L-Z中L代表单键时表示该结构实际上是A-Z。When one of the variables is selected from a single bond, it means that the two groups connected to it are directly connected, for example, when L in A-L-Z represents a single bond, it means that the structure is actually A-Z.
当一个取代基为空缺时,表示该取代基是不存在的,比如A-X中X为空缺时表示该结构实际上是A。当所列举的取代基中没有指明其通过哪一个原子连接到被取代的基团上时,这种取代基可以通过其任何原子相键合,例如,吡啶基作为取代基可以通过吡啶环上任意一个碳原子连接到被取代的基团上。当所列举的连接基团没有指明其连接方向,其连接方向是任意的,例如,
中连接基团L为-M-W-,此时-M-W-既可以按与从左往右的读取顺序相同的方向连接环A和环B构成
也可以按照与从左往右的读取顺序相反的方向连接环A和环B构成
所述连接基团、取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
When a substituent is vacant, it means that the substituent does not exist. For example, when X in AX is vacant, it means that the structure is actually A. When the listed substituents do not indicate through which atom it is attached to the substituted group, such substituents may be bonded through any of its atoms, for example, pyridyl as a substituent may be through any one of the pyridine rings. The carbon atom is attached to the substituted group. When the listed linking group does not indicate its direction of attachment, the direction of attachment is arbitrary, for example, The linking group L in the middle is -MW-, at this time -MW- can connect ring A and ring B in the same direction as the reading order from left to right. It is also possible to connect ring A and ring B in the opposite direction to the reading order from left to right. Combinations of the linking groups, substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
除非另有规定,术语“C
1-3烷基”用于表示直链或支链的由1至3个碳原子组成的饱和碳氢基团。所述C
1-3烷基包括C
1-2和C
2-3烷基等;其可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。C
1-
3烷基的实例包括但不限于甲基(Me)、乙基(Et)、丙基(包括n-丙基和异丙基)等。
Unless otherwise specified, the term "C 1-3 alkyl" is used to denote a straight or branched chain saturated hydrocarbon group consisting of 1 to 3 carbon atoms. The C 1-3 alkyl group includes C 1-2 and C 2-3 alkyl groups, etc.; it can be monovalent (eg methyl), divalent (eg methylene) or multivalent (eg methine) . Examples of C1-3 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.
除非另有规定,术语“C
1-3烷氧基”表示通过一个氧原子连接到分子的其余部分的那些包含1至3个碳原子的烷基基团。所述C
1-3烷氧基包括C
1-2、C
2-3、C
3和C
2烷氧基等。C
1-3烷氧基的实例包括但不限于甲氧基、乙氧基、丙氧基(包括正丙氧基和异丙氧基)等。
Unless otherwise specified, the term " C1-3alkoxy " refers to those alkyl groups containing 1 to 3 carbon atoms attached to the remainder of the molecule through an oxygen atom. The C 1-3 alkoxy group includes C 1-2 , C 2-3 , C 3 and C 2 alkoxy and the like. Examples of C 1-3 alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.
除非另有规定,“C
3-5环烷基”表示由3至5个碳原子组成的饱和环状碳氢基团,其为单环体系,所述C
3-5环烷基包括C
3-4和C
4-5环烷基等;其可以是一价、二价或者多价。C
3-5环烷基的实例包括,但不限于,环丙基、环丁基、环戊基等。
Unless otherwise specified, "C 3-5 cycloalkyl" means a saturated cyclic hydrocarbon group consisting of 3 to 5 carbon atoms, which is a monocyclic ring system, said C 3-5 cycloalkyl including C 3 -4 and C 4-5 cycloalkyl, etc.; it may be monovalent, divalent or polyvalent. Examples of C3-5 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and the like.
除非另有规定,“C
3-5环烯基”表示包含至少一个碳-碳双键的由3至5个碳原子组成的部分不饱和的环 状碳氢基团,其包括单环和双环体系,其中双环体系包括螺环、并环和桥环,此体系的任意环都是非芳香性的。所述C
3-5环烯基包括C
3-5或C
4-5环烯基等;其可以是一价、二价或者多价。C
3-5环烯基的实例包括但不限于,环丙烯基、环丁烯基、环戊烯基、环戊二烯基等。
Unless otherwise specified, "C 3-5 cycloalkenyl" means a partially unsaturated cyclic hydrocarbon group consisting of 3 to 5 carbon atoms containing at least one carbon-carbon double bond, including monocyclic and bicyclic rings system, wherein the bicyclic ring system includes spiro, paracyclic and bridged rings, any ring of this system is non-aromatic. The C 3-5 cycloalkenyl includes C 3-5 or C 4-5 cycloalkenyl and the like; it may be monovalent, divalent or multivalent. Examples of C 3-5 cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, and the like.
除非另有规定,本发明术语“5-6元杂芳环”和“5-6元杂芳基”可以互换使用,术语“5-6元杂芳基”表示由5至6个环原子组成的具有共轭π电子体系的单环基团,其1、2、3或4个环原子为独立选自O、S和N的杂原子,其余为碳原子。其中氮原子任选地被季铵化,氮和硫杂原子可任选被氧化(即NO和S(O)
p,p是1或2)。5-6元杂芳基可通过杂原子或碳原子连接到分子的其余部分。所述5-6元杂芳基包括5元和6元杂芳基。所述5-6元杂芳基的实例包括但不限于吡咯基(包括N-吡咯基、2-吡咯基和3-吡咯基等)、吡唑基(包括2-吡唑基和3-吡唑基等)、咪唑基(包括N-咪唑基、2-咪唑基、4-咪唑基和5-咪唑基等)、噁唑基(包括2-噁唑基、4-噁唑基和5-噁唑基等)、三唑基(1H-1,2,3-三唑基、2H-1,2,3-三唑基、1H-1,2,4-三唑基和4H-1,2,4-三唑基等)、四唑基、异噁唑基(3-异噁唑基、4-异噁唑基和5-异噁唑基等)、噻唑基(包括2-噻唑基、4-噻唑基和5-噻唑基等)、呋喃基(包括2-呋喃基和3-呋喃基等)、噻吩基(包括2-噻吩基和3-噻吩基等)、吡啶基(包括2-吡啶基、3-吡啶基和4-吡啶基等)、吡嗪基或嘧啶基(包括2-嘧啶基和4-嘧啶基等)。
Unless otherwise specified, the terms "5-6 membered heteroaryl ring" and "5-6 membered heteroaryl" are used interchangeably in the present invention, and the term "5-6 membered heteroaryl" means from 5 to 6 ring atoms It is composed of a monocyclic group with a conjugated π electron system, wherein 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms. Where the nitrogen atom is optionally quaternized, the nitrogen and sulfur heteroatoms may be optionally oxidized (ie, NO and S(O) p , p is 1 or 2). A 5-6 membered heteroaryl group can be attached to the remainder of the molecule through a heteroatom or a carbon atom. The 5-6 membered heteroaryl groups include 5- and 6-membered heteroaryl groups. Examples of the 5-6 membered heteroaryl include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrrolyl, etc.) azolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5- oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1, 2,4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl and 5-isoxazolyl, etc.), thiazolyl (including 2-thiazolyl , 4-thiazolyl and 5-thiazolyl, etc.), furyl (including 2-furyl and 3-furyl, etc.), thienyl (including 2-thienyl and 3-thienyl, etc.), pyridyl (including 2- -pyridyl, 3-pyridyl and 4-pyridyl, etc.), pyrazinyl or pyrimidinyl (including 2-pyrimidinyl and 4-pyrimidinyl, etc.).
除非另有规定,C
n-n+m或C
n-C
n+m包括n至n+m个碳的任何一种具体情况,例如C
1-12包括C
1、C
2、C
3、C
4、C
5、C
6、C
7、C
8、C
9、C
10、C
11、和C
12,也包括n至n+m中的任何一个范围,例如C
1-12包括C
1-
3、C
1-6、C
1-9、C
3-6、C
3-9、C
3-12、C
6-9、C
6-12、和C
9-12等;同理,n元至n+m元表示环上原子数为n至n+m个,例如3-12元环包括3元环、4元环、5元环、6元环、7元环、8元环、9元环、10元环、11元环、和12元环,也包括n至n+m中的任何一个范围,例如3-12元环包括3-6元环、3-9元环、5-6元环、5-7元环、6-7元环、6-8元环、和6-10元环等。
Unless otherwise specified, Cn-n+m or Cn - Cn+m includes any particular instance of n to n+ m carbons, eg C1-12 includes C1 , C2 , C3, C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , and C 12 , also including any range from n to n+ m , eg C 1-12 includes C 1-3 , C 1-6 , C 1-9 , C 3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12 , and C 9-12 , etc.; in the same way, n yuan to n +m-membered means that the number of atoms in the ring is from n to n+m, for example, 3-12-membered ring includes 3-membered ring, 4-membered ring, 5-membered ring, 6-membered ring, 7-membered ring, 8-membered ring, 9-membered ring , 10-membered ring, 11-membered ring, and 12-membered ring, also including any one range from n to n+m, for example, 3-12-membered ring includes 3-6 membered ring, 3-9 membered ring, 5-6 membered ring ring, 5-7 membered ring, 6-7 membered ring, 6-8 membered ring, and 6-10 membered ring, etc.
本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备,包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式,优选的实施方式包括但不限于本发明的实施例。The compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments enumerated below, embodiments formed in combination with other chemical synthesis methods, and those well known to those skilled in the art Equivalent to alternatives, preferred embodiments include, but are not limited to, the embodiments of the present invention.
本发明的化合物可以通过本领域技术人员所熟知的常规方法来确认结构,如果本发明涉及化合物的绝对构型,则该绝对构型可以通过本领域常规技术手段予以确证。例如单晶X射线衍射法(SXRD),把培养出的单晶用Bruker D8 venture衍射仪收集衍射强度数据,光源为CuKα辐射,扫描方式:
扫描,收集相关数据后,进一步采用直接法(Shelxs97)解析晶体结构,便可以确证绝对构型。
The structure of the compound of the present invention can be confirmed by conventional methods well known to those skilled in the art. If the present invention relates to the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art. For example, single crystal X-ray diffraction method (SXRD), the cultured single crystal is collected by Bruker D8 venture diffractometer, the light source is CuKα radiation, and the scanning mode is: After scanning and collecting relevant data, the crystal structure was further analyzed by the direct method (Shelxs97), and the absolute configuration could be confirmed.
本发明所使用的溶剂可经市售获得。本发明采用下述缩略词:aq代表水;eq代表当量、等量;DCM代表二氯甲烷;PE代表石油醚;DMF代表N,N-二甲基甲酰胺;DMSO代表二甲亚砜;EtOAc代表乙酸乙酯;EtOH代表乙醇;MeOH代表甲醇;CBz代表苄氧羰基,是一种胺保护基团;BOC代表叔丁氧羰基是一种胺保护基团;HOAc代表乙酸;r.t.代表室温;O/N代表过夜;THF代表四氢呋喃;Boc
2O代表二-叔丁基二碳酸酯;TFA代表三氟乙酸;DIPEA代表二异丙基乙基胺。
The solvent used in the present invention is commercially available. The present invention adopts the following abbreviations: aq represents water; eq represents equivalent, equivalent; DCM represents dichloromethane; PE represents petroleum ether; DMF represents N,N-dimethylformamide; DMSO represents dimethyl sulfoxide; EtOAc stands for ethyl acetate; EtOH stands for ethanol; MeOH stands for methanol; CBz stands for benzyloxycarbonyl, which is an amine protecting group; BOC stands for tert-butoxycarbonyl, which is an amine protecting group; HOAc stands for acetic acid; rt stands for room temperature; O/N stands for overnight; THF for tetrahydrofuran; Boc 2 O for di-tert-butyl dicarbonate; TFA for trifluoroacetic acid; DIPEA for diisopropylethylamine.
化合物依据本领域常规命名原则或者使用
软件命名,市售化合物采用供应商目录名称。
Compounds are named according to conventional nomenclature in the art or are used Software naming, commercially available compounds use supplier catalog names.
技术效果technical effect
本发明化合物具有优异的体外抗增殖活性,生命延长活性且没有明显的药物毒副作用;本发明化合物具有优异的药代动力学性质。The compound of the present invention has excellent in vitro anti-proliferative activity, life-extending activity and no obvious drug side effects; the compound of the present invention has excellent pharmacokinetic properties.
下面通过实施例对本发明进行详细描述,但并不意味着对本发明任何不利限制。本文已经详细地描述了本发明,其中也公开了其具体实施例方式,对本领域的技术人员而言,在不脱离本发明精神和范围的情况下针对本发明具体实施方式进行各种变化和改进将是显而易见的。The present invention will be described in detail by the following examples, but it does not mean any unfavorable limitation of the present invention. The present invention has been described in detail herein, and specific embodiments thereof have also been disclosed. For those skilled in the art, various changes and modifications can be made to the specific embodiments of the present invention without departing from the spirit and scope of the invention. will be obvious.
参考例1:ST-1Reference example 1: ST-1
合成路线:synthetic route:
步骤1:step 1:
在预先干燥的反应瓶中加入碘化钠(22.92g,152.91mmol)和乙酸(100mL)后将反应液加热至70℃。待碘化钠(22.92g,152.91mmol)全部溶解完,向反应液中加入化合物ST-1-1(10g,101.94mmol)。加毕后,在70℃下继续反应12小时。反应完毕后,反应液降至25℃,加入甲基叔丁基醚(150mL)和水(100mL)。水相用甲基叔丁基醚(40mL*3)萃取,收集有机相。用氢氧化钠(3M,aq)中和有机相至pH=7。再用10%的硫代硫酸钠水溶液(30mL)洗涤有机相,之后用饱和食盐水(50mL)洗涤,无水硫酸钠干燥,浓缩得到化合物ST-1。After adding sodium iodide (22.92 g, 152.91 mmol) and acetic acid (100 mL) to a pre-dried reaction flask, the reaction solution was heated to 70°C. After the sodium iodide (22.92 g, 152.91 mmol) was completely dissolved, compound ST-1-1 (10 g, 101.94 mmol) was added to the reaction solution. After the addition was completed, the reaction was continued at 70°C for 12 hours. After completion of the reaction, the reaction solution was lowered to 25°C, and methyl tert-butyl ether (150 mL) and water (100 mL) were added. The aqueous phase was extracted with methyl tert-butyl ether (40 mL*3), and the organic phase was collected. The organic phase was neutralized to pH=7 with sodium hydroxide (3M, aq). The organic phase was washed with 10% aqueous sodium thiosulfate solution (30 mL), then with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to obtain compound ST-1.
1H NMR(400MHz,CDCl
3)δppm 1.15-1.29(m,3H),4.12(br dd,J=13.43,6.40Hz,2H),6.70-6.89(m,1H),7.35(dt,J=8.60,4.11Hz,1H)。
1 H NMR (400 MHz, CDCl 3 ) δppm 1.15-1.29 (m, 3H), 4.12 (br dd, J=13.43, 6.40 Hz, 2H), 6.70-6.89 (m, 1H), 7.35 (dt, J=8.60 , 4.11Hz, 1H).
参考例2:ST-2Reference example 2: ST-2
合成路线:synthetic route:
步骤1:化合物ST-2的合成Step 1: Synthesis of Compound ST-2
在预先干燥的反应瓶中加入化合物ST-2-1(0.5g,1.32mmol)和四氢呋喃(10mL),将反应液冷却至0℃,滴加氢氧化锂(165.97mg,3.96mmol)和水(10mL)的混合液,反应液在0℃搅拌3小时。反应完成后,向反应液加入水(10mL)和乙酸乙酯(10mL),用盐酸水溶液(3M)调节pH到3,分液,有机相用无水硫酸钠干燥,浓缩得到化合物ST-2。Compound ST-2-1 (0.5 g, 1.32 mmol) and tetrahydrofuran (10 mL) were added to the pre-dried reaction flask, the reaction solution was cooled to 0 °C, and lithium hydroxide (165.97 mg, 3.96 mmol) and water ( 10 mL), the reaction solution was stirred at 0 °C for 3 hours. After the reaction was completed, water (10 mL) and ethyl acetate (10 mL) were added to the reaction solution, the pH was adjusted to 3 with aqueous hydrochloric acid (3M), the layers were separated, the organic phase was dried over anhydrous sodium sulfate, and concentrated to obtain compound ST-2.
1H NMR(400MHz,CDCl
3)δppm 9.66(s,1H),8.55(s,2H),7.91(s,1H),7.30-7.26(m,1H),5.83-5.80(m,1H)。
1 H NMR (400 MHz, CDCl 3 ) δ ppm 9.66 (s, 1H), 8.55 (s, 2H), 7.91 (s, 1H), 7.30-7.26 (m, 1H), 5.83-5.80 (m, 1H).
实施例1Example 1
合成路线:synthetic route:
步骤1:化合物1-3的合成Step 1: Synthesis of Compounds 1-3
置换氮气3次,氮气条件,-78℃下在预先干燥的反应瓶中加入四氢呋喃(25mL)和二异丙基氨基锂(2M,10.30mL),后将化合物1-1(1g,10.30mmol)溶于四氢呋喃(2mL)中滴加进反应液中。加毕后,在-78℃下反应1小时。之后将化合物1-2(2.49g,10.30mmol)溶于四氢呋喃(3mL)滴加进反应液中。加毕后,将反应液移至25℃下继续搅拌反应15小时。反应完成后,加入饱和氯化铵水溶液(15mL),后用乙酸乙酯(20mL*3)萃取反应液,收集有机相后用饱和食盐水(25mL)洗涤有机相,再用无水硫酸钠干燥有机相,浓缩得到化合物1-3,直接用于下一步反应。MS-ESI m/z:339.9[M+H]
+。
Nitrogen was replaced 3 times. Under nitrogen conditions, tetrahydrofuran (25 mL) and lithium diisopropylamide (2M, 10.30 mL) were added to the pre-dried reaction flask at -78°C, and then compound 1-1 (1 g, 10.30 mmol) was added. It was dissolved in tetrahydrofuran (2 mL) and added dropwise to the reaction solution. After the addition was completed, the reaction was carried out at -78°C for 1 hour. Then, compound 1-2 (2.49 g, 10.30 mmol) was dissolved in tetrahydrofuran (3 mL) and added dropwise to the reaction solution. After the addition was completed, the reaction solution was moved to 25° C. to continue stirring and reacting for 15 hours. After the reaction was completed, saturated aqueous ammonium chloride solution (15 mL) was added, the reaction solution was extracted with ethyl acetate (20 mL*3), the organic phase was collected, washed with saturated brine (25 mL), and dried over anhydrous sodium sulfate. The organic phase was concentrated to obtain compound 1-3, which was directly used in the next reaction. MS-ESI m/z: 339.9 [M+H] + .
步骤2:化合物1-4的合成Step 2: Synthesis of Compounds 1-4
在预先干燥的反应瓶中加入化合物1-3(1g,2.95mmol)和二氯甲烷(10mL),后将戴斯-马丁氧化剂(2.50g,5.90mmol)溶于二氯甲烷(10mL)中,加至反应液中,后在25℃下反应2小时。向反应液中加入饱和硫代 硫酸钠水溶液(20mL),用二氯甲烷(20mL*3)萃取反应液,再用饱和食盐水(30mL)洗涤有机相,用无水硫酸钠干燥有机相浓缩得化合物1-4。MS-ESI m/z:337.9[M+H]
+。
Compound 1-3 (1 g, 2.95 mmol) and dichloromethane (10 mL) were added to a pre-dried reaction flask, then Dess-Martin oxidant (2.50 g, 5.90 mmol) was dissolved in dichloromethane (10 mL), It was added to the reaction solution, and then reacted at 25°C for 2 hours. Saturated aqueous sodium thiosulfate solution (20 mL) was added to the reaction solution, the reaction solution was extracted with dichloromethane (20 mL*3), the organic phase was washed with saturated brine (30 mL), and the organic phase was dried with anhydrous sodium sulfate and concentrated to obtain Compounds 1-4. MS-ESI m/z: 337.9 [M+H] + .
步骤3:化合物1-5的合成Step 3: Synthesis of Compounds 1-5
25℃下,在预先干燥的反应瓶中加入化合物1-4(1.67g,4.95mmol)和乙醇(10mL),加入水合肼(644.62mg,6.44mmol)和三乙胺(651.50mg,6.44mmol),并搅拌反应4小时。向反应液中加入乙酸乙酯(40mL),用饱和碳酸氢钠水溶液(20mL*2)洗涤反应液,收集有机相,再用饱和食盐水(30mL)洗涤有机相,用无水硫酸钠干燥有机相,浓缩反应液得到粗品。粗品经柱层析(石油醚:乙酸乙酯=1:1)纯化得化合物1-5。MS-ESI m/z:331.9[M+H]
+。
At 25°C, compound 1-4 (1.67 g, 4.95 mmol) and ethanol (10 mL) were added to a pre-dried reaction flask, and hydrazine hydrate (644.62 mg, 6.44 mmol) and triethylamine (651.50 mg, 6.44 mmol) were added. , and the reaction was stirred for 4 hours. Ethyl acetate (40 mL) was added to the reaction solution, the reaction solution was washed with saturated aqueous sodium bicarbonate solution (20 mL*2), the organic phase was collected, and the organic phase was washed with saturated brine (30 mL), and the organic phase was dried over anhydrous sodium sulfate. phase, and the reaction solution was concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate=1:1) to obtain compound 1-5. MS-ESI m/z: 331.9 [M+H] + .
步骤4:化合物1-6的合成Step 4: Synthesis of Compounds 1-6
在预先干燥的反应瓶中加入化合物1-5(16mg,48.31μmol)和N,N-二甲基甲酰胺(1mL),后加入三乙烯二胺(10.84mg,96.62μmol)搅拌0.5小时。之后将化合物ST-1(6.1mg,26.99μmol)滴加至反应液中,25℃下反应20小时。浓缩反应液得到化合物1-6,粗产品无需直接用于下一步。MS-ESI m/z:430.0[M+H]
+。
Compound 1-5 (16 mg, 48.31 μmol) and N,N-dimethylformamide (1 mL) were added to a pre-dried reaction flask, and then triethylenediamine (10.84 mg, 96.62 μmol) was added and stirred for 0.5 hour. Then, compound ST-1 (6.1 mg, 26.99 μmol) was added dropwise to the reaction solution, and the reaction was carried out at 25° C. for 20 hours. The reaction solution was concentrated to obtain compound 1-6, and the crude product was not directly used in the next step. MS-ESI m/z: 430.0 [M+H] + .
步骤5:化合物1-7的合成Step 5: Synthesis of Compounds 1-7
在预先干燥的反应瓶中加入化合物1-6(20.7mg,48.22μmol)和四氢呋喃(1mL),后将氢氧化锂(5.77mg,241.08μmol,5eq)溶于水(1mL)后滴加至反应液中,在25℃下反应3小时。加入氢氧化钠水溶液(1M)至pH=10,后加入乙酸乙酯(15mL),再用pH=10的氢氧化钠水溶液(10mL*3)萃取反应液,收集水相,之后用浓盐酸调节水相pH至1。再用乙酸乙酯(15mL*3)萃取pH=1的水溶液,收集有机相,用饱和食盐水(20mL)洗涤有机相,用无水硫酸钠干燥,浓缩得到化合物1-7。MS-ESI m/z:401.9[M+H]
+。
Compound 1-6 (20.7 mg, 48.22 μmol) and tetrahydrofuran (1 mL) were added to a pre-dried reaction flask, and lithium hydroxide (5.77 mg, 241.08 μmol, 5 eq) was dissolved in water (1 mL) and added dropwise to the reaction. The solution was reacted at 25°C for 3 hours. Add sodium hydroxide aqueous solution (1M) to pH=10, then add ethyl acetate (15 mL), then extract the reaction solution with sodium hydroxide aqueous solution (10 mL*3) of pH=10, collect the aqueous phase, and then adjust with concentrated hydrochloric acid The pH of the aqueous phase was 1. The pH=1 aqueous solution was extracted with ethyl acetate (15 mL*3), the organic phase was collected, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to obtain compound 1-7. MS-ESI m/z: 401.9 [M+H] + .
步骤6:化合物1的合成Step 6: Synthesis of Compound 1
在预先干燥的反应瓶中加入化合物1-7(10mg,24.92μmol),乙酸乙酯(1mL)和四氢呋喃(1mL),降低温度至-60℃,之后加入1-8(3.29mg,29.91μmol),丙烷磷酸酐50%乙酸乙酯溶液(31.72mg,49.84μmol)并滴加N,N-二异丙基乙胺(12.88mg,99.69μmol)。加毕后,将反应液升至25℃,继续反应16小时。反应完成后,浓缩反应液,经制备高效液相色谱(色谱柱:Phenomenex Gemini-NX 80*40mm*3μm;流动相:[水(0.05%NH
3H
2O+10mM NH
4HCO
3)-ACN];B(乙腈)%:30%-60%,8min)分离得到化合物1。
Compound 1-7 (10 mg, 24.92 μmol), ethyl acetate (1 mL) and tetrahydrofuran (1 mL) were added to a pre-dried reaction flask, the temperature was lowered to -60°C, and then 1-8 (3.29 mg, 29.91 μmol) was added , propane phosphoric anhydride 50% ethyl acetate solution (31.72 mg, 49.84 μmol) and N,N-diisopropylethylamine (12.88 mg, 99.69 μmol) was added dropwise. After the addition, the reaction solution was raised to 25°C, and the reaction was continued for 16 hours. After the reaction was completed, the reaction solution was concentrated, and subjected to preparative high performance liquid chromatography (chromatographic column: Phenomenex Gemini-NX 80*40mm*3 μm; mobile phase: [water (0.05% NH 3 H 2 O+10mM NH 4 HCO 3 )-ACN] ]; B (acetonitrile)%: 30%-60%, 8 min) was isolated to obtain compound 1.
1H NMR(400MHz,CD
3OD)δppm 6.11(d,J=10.04Hz,1H),7.81(d,J=2.76Hz,1H),7.85(d,J=10.04Hz,1H),7.99(dd,J=2.76,1.51Hz,1H),8.06(s,1H),8.09(d,J=1.51Hz,1H),8.11(d,J=5.52Hz,1H),8.50(s,2H),8.52(d,J=5.77Hz,1H),9.27(s,1H)。
1 H NMR (400 MHz, CD 3 OD) δppm 6.11 (d, J=10.04 Hz, 1H), 7.81 (d, J=2.76 Hz, 1H), 7.85 (d, J=10.04 Hz, 1H), 7.99 (dd , J=2.76, 1.51Hz, 1H), 8.06(s, 1H), 8.09(d, J=1.51Hz, 1H), 8.11(d, J=5.52Hz, 1H), 8.50(s, 2H), 8.52 (d, J=5.77 Hz, 1H), 9.27 (s, 1H).
实施例2Example 2
合成路线:synthetic route:
步骤1:化合物2-3的合成Step 1: Synthesis of Compounds 2-3
置换氮气3次,氮气条件,-78℃下在预先干燥的反应瓶中加入四氢呋喃(25mL)和二异丙基氨基锂(2M,8.81mL),后将化合物2-1(1g,8.81mmol)溶于四氢呋喃(2mL)滴加进反应液中,在-78℃下反应1小时。之后在-78℃下,将化合物1-2(4.26g,17.61mmol)溶于四氢呋喃(3mL)滴加进反应液中。加毕后,将反应液移至25℃下继续搅拌反应15小时。反应完成后,加入饱和氯化铵水溶液(15mL),用乙酸乙酯(20mL*3)萃取反应液,收集有机相,用饱和食盐水(25mL)洗涤有机相,再用无水硫酸钠干燥有机相,浓缩得化合物2-3。MS-ESI m/z:355.9[M+H]
+。
The nitrogen was replaced 3 times. Under nitrogen conditions, tetrahydrofuran (25 mL) and lithium diisopropylamide (2M, 8.81 mL) were added to the pre-dried reaction flask at -78°C, and compound 2-1 (1 g, 8.81 mmol) was added to the reaction flask. The solution was dissolved in tetrahydrofuran (2 mL) and added dropwise to the reaction solution, and the mixture was reacted at -78°C for 1 hour. Then, compound 1-2 (4.26 g, 17.61 mmol) dissolved in tetrahydrofuran (3 mL) was added dropwise to the reaction solution at -78°C. After the addition was completed, the reaction solution was moved to 25° C. to continue stirring and reacting for 15 hours. After the reaction was completed, saturated aqueous ammonium chloride solution (15 mL) was added, the reaction solution was extracted with ethyl acetate (20 mL*3), the organic phase was collected, washed with saturated brine (25 mL), and dried over anhydrous sodium sulfate. phase, and concentrated to obtain compound 2-3. MS-ESI m/z: 355.9 [M+H] + .
步骤2:化合物2-4的合成Step 2: Synthesis of Compounds 2-4
在预先干燥的反应瓶中加入化合物2-3(1g,2.81mmol)和二氯甲烷(10mL),后将戴斯-马丁氧化剂(2.39g,5.62mmol)溶于二氯甲烷(10mL)中,加至反应液中,后在25℃下反应2小时。反应完成后向反应液中加入饱和硫代硫酸钠水溶液(20mL),用二氯甲烷(20*3)萃取反应液,再用饱和食盐水(30mL)洗涤有机相,用无水硫酸钠干燥有机相,浓缩得化合物2-4,直接用于下一步反应。MS-ESI m/z:353.9[M+H]
+。
Compound 2-3 (1 g, 2.81 mmol) and dichloromethane (10 mL) were added to a pre-dried reaction flask, and Dess-Martin oxidant (2.39 g, 5.62 mmol) was dissolved in dichloromethane (10 mL), It was added to the reaction solution, and then reacted at 25°C for 2 hours. After the reaction was completed, saturated aqueous sodium thiosulfate solution (20 mL) was added to the reaction solution, the reaction solution was extracted with dichloromethane (20*3), the organic phase was washed with saturated brine (30 mL), and the organic phase was dried with anhydrous sodium sulfate. phase, and concentrated to obtain compound 2-4, which was directly used in the next reaction. MS-ESI m/z: 353.9 [M+H] + .
步骤3:化合物2-5的合成Step 3: Synthesis of Compounds 2-5
在预先干燥的反应瓶中加入化合物2-4(2g,5.66mmol)和乙醇(10mL),后加入水合肼(736.08mg,7.35mmol)和三乙胺(743.94mg,7.35mmol)。将反应液置于80℃下,加热回流反应4小时。反应完成后,向反应液中加入乙酸乙酯(40mL),用饱和碳酸氢钠水溶液(20mL*2)洗涤反应液,收集有机相,再用饱和食 盐水(30mL)洗涤有机相,用无水硫酸钠干燥有机相,浓缩后柱层析(石油醚/乙酸乙酯=3:1)分离得化合物2-5。MS-ESI m/z:331.9[M+H]
+。
Compound 2-4 (2 g, 5.66 mmol) and ethanol (10 mL) were added to a pre-dried reaction flask, followed by hydrazine hydrate (736.08 mg, 7.35 mmol) and triethylamine (743.94 mg, 7.35 mmol). The reaction solution was placed at 80°C and heated under reflux for 4 hours. After the reaction was completed, ethyl acetate (40 mL) was added to the reaction solution, the reaction solution was washed with saturated aqueous sodium bicarbonate solution (20 mL*2), the organic phase was collected, and the organic phase was washed with saturated brine (30 mL), and anhydrous The organic phase was dried over sodium sulfate, concentrated and separated by column chromatography (petroleum ether/ethyl acetate=3:1) to obtain compound 2-5. MS-ESI m/z: 331.9 [M+H] + .
步骤4:化合物2-6的合成Step 4: Synthesis of Compounds 2-6
在预先干燥的反应瓶中加入化合物2-5(50mg,150.96μmol,1eq)和N,N-二甲基甲酰胺(1mL)中,加入三乙烯二胺(33.87mg,301.92μmol)后搅拌0.5小时。之后滴加化合物ST-1(19.0mg,84.07μmol)至反应液中,在25℃下搅拌反应20小时。浓缩反应液得化合物2-6,直接用于下一步反应。MS-ESI m/z:430.0[M+H]
+。
Compound 2-5 (50 mg, 150.96 μmol, 1 eq) and N,N-dimethylformamide (1 mL) were added to a pre-dried reaction flask, triethylenediamine (33.87 mg, 301.92 μmol) was added, and the mixture was stirred for 0.5 Hour. Then, compound ST-1 (19.0 mg, 84.07 μmol) was added dropwise to the reaction solution, and the reaction was stirred at 25° C. for 20 hours. The reaction solution was concentrated to obtain compound 2-6, which was directly used in the next reaction. MS-ESI m/z: 430.0 [M+H] + .
步骤5:化合物2-7的合成Step 5: Synthesis of Compounds 2-7
在预先干燥的反应瓶中加入化合物2-6(64.8mg,150.94μmol)和四氢呋喃(1mL)。之后将氢氧化锂(18.07mg,754.69μmol)溶于水(1mL)中滴加至反应液中,在25℃下反应4小时。反应完成后,加入氢氧化钠水溶液(1M)至pH=10,后加入乙酸乙酯(15mL),再用pH=10的氢氧化钠水溶液(10mL*3)萃取反应液,收集水相,之后用浓盐酸调节水相pH至1。再用乙酸乙酯(15mL*3)萃取水相,收集有机相,用饱和食盐水(20mL)洗涤有机相,无水硫酸钠干燥,浓缩得化合物2-7。MS-ESI m/z:401.9[M+H]
+。
Compound 2-6 (64.8 mg, 150.94 μmol) and tetrahydrofuran (1 mL) were added to a pre-dried reaction vial. Then, lithium hydroxide (18.07 mg, 754.69 μmol) was dissolved in water (1 mL) and added dropwise to the reaction solution, and the reaction was carried out at 25° C. for 4 hours. After the completion of the reaction, an aqueous sodium hydroxide solution (1M) was added to pH=10, and then ethyl acetate (15 mL) was added. The reaction solution was extracted with an aqueous sodium hydroxide solution (10 mL*3) at pH=10, and the aqueous phase was collected. The pH of the aqueous phase was adjusted to 1 with concentrated hydrochloric acid. The aqueous phase was then extracted with ethyl acetate (15 mL*3), the organic phase was collected, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to obtain compound 2-7. MS-ESI m/z: 401.9 [M+H] + .
步骤6:化合物2的合成Step 6: Synthesis of Compound 2
在预先干燥的反应瓶中加入化合物2-7(60mg,149.53μmol),乙酸乙酯(1mL)和四氢呋喃(1mL)中,降低反应液温度至-60℃,之后加入化合物1-8(19.8mg,179.81μmol)和丙烷磷酸酐50%乙酸乙酯溶液(190.31mg,299.06μmol),再滴加N,N-二异丙基乙胺(77.30mg,598.11μmol)。将反应液升温至25℃,继续反应16小时。反应完成后,加入氢氧化钠水溶液(1M)调节pH至10,后用乙酸乙酯(10mL*3)萃取反应液,收集有机相,用饱和食盐水(20mL)洗涤有机相,最后用无水硫酸钠干燥,浓缩得到粗品。粗品经制备高效液相色谱(色谱柱:Phenomenex Gemini-NX 80*40mm*3μm;流动相:[水(0.05%NH
3H
2O+10mM NH
4HCO
3)-ACN];B(乙腈)%:27%-57%,8min)分离得到化合物2。
Compound 2-7 (60 mg, 149.53 μmol), ethyl acetate (1 mL) and tetrahydrofuran (1 mL) were added to a pre-dried reaction flask, the temperature of the reaction solution was lowered to -60°C, and then compound 1-8 (19.8 mg) was added. , 179.81 μmol) and propane phosphoric anhydride 50% ethyl acetate solution (190.31 mg, 299.06 μmol), and then N,N-diisopropylethylamine (77.30 mg, 598.11 μmol) was added dropwise. The temperature of the reaction solution was raised to 25°C, and the reaction was continued for 16 hours. After the completion of the reaction, sodium hydroxide aqueous solution (1M) was added to adjust the pH to 10, then the reaction solution was extracted with ethyl acetate (10mL*3), the organic phase was collected, washed with saturated brine (20mL), and finally with anhydrous Dry over sodium sulfate and concentrate to give crude product. The crude product was subjected to preparative high performance liquid chromatography (chromatographic column: Phenomenex Gemini-NX 80*40mm*3 μm; mobile phase: [water (0.05% NH 3 H 2 O+10 mM NH 4 HCO 3 )-ACN]; B (acetonitrile)% : 27%-57%, 8 min) to obtain compound 2.
1H NMR(400MHz,CD
3OD)δppm 6.09(d,J=10.04Hz,1H),7.73(d,J=10.04Hz,1H),7.82(d,J=2.76Hz,1H),7.86(dd,J=6.27,1.00Hz,1H),7.99(dd,J=2.76,1.51Hz,1H),8.07-8.12(m,2H),8.53(s,2H),8.57(d,J=6.27Hz,1H),9.39(s,1H)。
1 H NMR (400 MHz, CD 3 OD) δppm 6.09 (d, J=10.04 Hz, 1H), 7.73 (d, J=10.04 Hz, 1H), 7.82 (d, J=2.76 Hz, 1H), 7.86 (dd ,J=6.27,1.00Hz,1H),7.99(dd,J=2.76,1.51Hz,1H),8.07-8.12(m,2H),8.53(s,2H),8.57(d,J=6.27Hz, 1H), 9.39(s, 1H).
实施例3Example 3
合成路线:synthetic route:
步骤1:化合物3-3的合成Step 1: Synthesis of Compounds 3-3
在预先干燥的反应瓶中加入化合物3-1(50mg,252.50μmol),化合物3-2(130.3mg,505.18μmol),[1,1'-双(二苯基膦基)二茂铁]二氯化钯(27.71mg,37.87μmol)和磷酸钾(160.79mg,757.50μmol)溶于1,4-二氧六环(4mL)和水(0.5mL)中,置换3次氮气,置于100℃下反应12小时。反应完成后,浓缩反应液得到粗品,粗品经柱层析(石油醚:乙酸乙酯=3:1)分离得化合物3-3。MS-ESI m/z:331.9[M+H]
+。
Compound 3-1 (50 mg, 252.50 μmol), compound 3-2 (130.3 mg, 505.18 μmol), [1,1′-bis(diphenylphosphino)ferrocene]di Palladium chloride (27.71 mg, 37.87 μmol) and potassium phosphate (160.79 mg, 757.50 μmol) were dissolved in 1,4-dioxane (4 mL) and water (0.5 mL), replaced with nitrogen three times, and placed at 100°C The reaction was continued for 12 hours. After the reaction was completed, the reaction solution was concentrated to obtain a crude product, and the crude product was separated by column chromatography (petroleum ether:ethyl acetate=3:1) to obtain compound 3-3. MS-ESI m/z: 331.9 [M+H] + .
步骤2:化合物3-4的合成Step 2: Synthesis of Compounds 3-4
在预先干燥的反应瓶中加入化合物3-3(50mg,150.96μmol)和N,N-二甲基甲酰胺(1mL),后加入三乙烯二胺(33.87mg,301.92μmol)搅拌0.5小时。之后滴加化合物ST-1(19mg,84.07μmol)至反应液中,在25℃下反应20小时。反应完成后,浓缩反应液得到化合物3-4,直接用于下一步反应。MS-ESI m/z:430.0[M+H]
+。
Compound 3-3 (50 mg, 150.96 μmol) and N,N-dimethylformamide (1 mL) were added to a pre-dried reaction flask, and then triethylenediamine (33.87 mg, 301.92 μmol) was added and stirred for 0.5 hour. Then, compound ST-1 (19 mg, 84.07 μmol) was added dropwise to the reaction solution, and the reaction was carried out at 25° C. for 20 hours. After the reaction was completed, the reaction solution was concentrated to obtain compound 3-4, which was directly used in the next reaction. MS-ESI m/z: 430.0 [M+H] + .
步骤3:化合物3-5的合成Step 3: Synthesis of Compounds 3-5
在预先干燥的反应瓶中加入化合物3-4(64.8mg,150.94μmol)和四氢呋喃(1mL)。后将氢氧化锂(18.07mg,754.69μmol)溶于水(1mL)中滴加至反应液中,在25℃下反应4小时。反应完成后,加入氢氧化钠水溶液(1M)至pH=10,后加入乙酸乙酯(15mL),再用pH=10的氢氧化钠水溶液(10mL*3)萃取反应液,收集水相,之后用浓盐酸调节水相pH至1。再用乙酸乙酯(15mL*3)萃取水相,收集有机相,用饱和食盐水(20mL)洗涤有机相,用无水硫酸钠干燥,浓缩得化合物3-5。MS-ESI m/z:401.9[M+H]
+。
Compound 3-4 (64.8 mg, 150.94 μmol) and tetrahydrofuran (1 mL) were added to a pre-dried reaction vial. Then, lithium hydroxide (18.07 mg, 754.69 μmol) was dissolved in water (1 mL) and added dropwise to the reaction solution, and the reaction was carried out at 25° C. for 4 hours. After the completion of the reaction, an aqueous sodium hydroxide solution (1M) was added to pH=10, and then ethyl acetate (15 mL) was added. The reaction solution was extracted with an aqueous sodium hydroxide solution (10 mL*3) at pH=10, and the aqueous phase was collected. The pH of the aqueous phase was adjusted to 1 with concentrated hydrochloric acid. The aqueous phase was then extracted with ethyl acetate (15 mL*3), the organic phase was collected, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to obtain compound 3-5. MS-ESI m/z: 401.9 [M+H] + .
步骤4:化合物3的合成Step 4: Synthesis of Compound 3
在预先干燥的反应瓶中加入化合物3-5(20mg,49.84μmol),乙酸乙酯(1mL)和四氢呋喃(1mL),降低反应温度至-60℃,之后加入化合物1-8(6.59mg,59.81μmol)和丙烷磷酸酐50%乙酸乙酯溶液(63.44mg,99.69μmol),再滴加N,N-二异丙基乙胺(25.77mg,199.37μmol)。将反应液温度升至25℃,继续反应16小时。反应完成后,用氢氧化钠水溶液(1M)调节反应液pH至10,再用乙酸乙酯(10mL*3)萃取反应液,收集有机相,用饱和食盐水(20mL)洗涤有机相,最后用无水硫酸钠干燥有机相,浓缩得到粗品。粗品经制备 高效液相色谱(色谱柱:Phenomenex Gemini-NX 80*40mm*3μm;流动相:[水(0.05%NH
3H
2O+10mM NH
4HCO
3)-ACN];B(乙腈)%:40%-70%,8min)分离得化合物3。
Compound 3-5 (20 mg, 49.84 μmol), ethyl acetate (1 mL) and tetrahydrofuran (1 mL) were added to a pre-dried reaction flask, the reaction temperature was lowered to -60°C, and then compound 1-8 (6.59 mg, 59.81 μmol) and propane phosphoric anhydride 50% ethyl acetate solution (63.44 mg, 99.69 μmol), and N,N-diisopropylethylamine (25.77 mg, 199.37 μmol) was added dropwise. The temperature of the reaction solution was raised to 25°C, and the reaction was continued for 16 hours. After the reaction was completed, the pH of the reaction solution was adjusted to 10 with aqueous sodium hydroxide solution (1M), the reaction solution was extracted with ethyl acetate (10mL*3), the organic phase was collected, and the organic phase was washed with saturated brine (20mL). The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain crude product. The crude product was subjected to preparative high performance liquid chromatography (chromatographic column: Phenomenex Gemini-NX 80*40mm*3 μm; mobile phase: [water (0.05% NH 3 H 2 O+10 mM NH 4 HCO 3 )-ACN]; B (acetonitrile)% : 40%-70%, 8min) to separate compound 3.
1H NMR(400MHz,CD
3OD)δppm 6.01(d,J=10.29Hz,1H),7.58(dd,J=8.53,4.52Hz,1H),7.72(d,J=10.29Hz,1H),7.85(d,J=2.76Hz,1H),7.98(s,1H),8.00-8.03(m,1H),8.12(d,J=1.25Hz,1H),8.25(dd,J=8.66,1.13Hz,1H),8.81(dd,J=4.52,1.25Hz,1H),9.07-9.12(m,1H),9.09(s,1H)。
1 H NMR (400 MHz, CD 3 OD) δppm 6.01 (d, J=10.29 Hz, 1H), 7.58 (dd, J=8.53, 4.52 Hz, 1H), 7.72 (d, J=10.29 Hz, 1H), 7.85 (d,J=2.76Hz,1H),7.98(s,1H),8.00-8.03(m,1H),8.12(d,J=1.25Hz,1H),8.25(dd,J=8.66,1.13Hz, 1H), 8.81 (dd, J=4.52, 1.25Hz, 1H), 9.07-9.12 (m, 1H), 9.09 (s, 1H).
实施例4Example 4
合成路线:synthetic route:
步骤1:化合物4-2的合成Step 1: Synthesis of Compound 4-2
在预先干燥的三口瓶中加入化合物4-1(21g,96.25mmol)和四氯化碳(525mL),然后加入N-溴代丁二酰亚胺(27.41g,154.01mmol)和偶氮二异丁腈(31.61g,192.51mmol),升高反应温度至80℃,搅拌72小时。反应完成后,减压浓缩溶剂至干后加入水(400mL),用二氯甲烷(150mL*3)萃取反应液,收集有机 相,饱和食盐水(400mL)洗涤,无水硫酸钠干燥,浓缩,柱层析(石油醚:乙酸乙酯=10:1)纯化,得化合物4-2。
1H NMR(400MHz,CDCl
3)δppm 8.06(d,1H),7.83(d,1H),7.49(t,1H),5.11(s,2H),3.998(s,3H)。
In a pre-dried three-necked flask, compound 4-1 (21 g, 96.25 mmol) and carbon tetrachloride (525 mL) were added, followed by N-bromosuccinimide (27.41 g, 154.01 mmol) and azodiiso Butyronitrile (31.61 g, 192.51 mmol), raise the reaction temperature to 80°C and stir for 72 hours. After the reaction was completed, the solvent was concentrated under reduced pressure to dryness, water (400 mL) was added, the reaction solution was extracted with dichloromethane (150 mL*3), the organic phase was collected, washed with saturated brine (400 mL), dried over anhydrous sodium sulfate, and concentrated. Column chromatography (petroleum ether:ethyl acetate=10:1) was purified to obtain compound 4-2. 1 H NMR (400 MHz, CDCl 3 ) δ ppm 8.06 (d, 1H), 7.83 (d, 1H), 7.49 (t, 1H), 5.11 (s, 2H), 3.998 (s, 3H).
步骤2:化合物4-3的合成Step 2: Synthesis of Compounds 4-3
在预先干燥的单口瓶中加入4-2(27.27g,91.80mmol)和二氧六环(270mL),然后加入氢氧化钠(2M,103.49mL),25℃搅拌20小时。得到4-3反应液,不纯化,直接用于下一步反应。4-2 (27.27 g, 91.80 mmol) and dioxane (270 mL) were added to a pre-dried single-neck flask, then sodium hydroxide (2 M, 103.49 mL) was added, and the mixture was stirred at 25° C. for 20 hours. The reaction solution 4-3 was obtained, which was directly used in the next reaction without purification.
步骤3:化合物4-4的合成Step 3: Synthesis of Compounds 4-4
向上述4-3反应液中加入H
2SO
4(47.56g,484.94mmol),加料时控制反应温度不超过50℃,后自然降温至25℃搅拌64小时。反应完成后,向反应液中加入水(200mL),用乙酸乙酯(80mL*3)萃取反应液,收集有机相,饱和食盐水(100mL)洗涤,无水硫酸钠干燥,浓缩,柱层析(石油醚:乙酸乙酯=10:1)分离。得到化合物4-4。
1H NMR(400MHz,CDCl
3)δppm 8.13(d,1H),7.95(d,1H),7.72(t,1H),5.48(s,2H)。
H 2 SO 4 (47.56 g, 484.94 mmol) was added to the above reaction solution 4-3, the reaction temperature was controlled not to exceed 50° C. during the addition, and then the temperature was naturally cooled to 25° C. and stirred for 64 hours. After the reaction was completed, water (200 mL) was added to the reaction solution, the reaction solution was extracted with ethyl acetate (80 mL*3), the organic phase was collected, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography. (Petroleum ether:ethyl acetate=10:1) separation. Compound 4-4 is obtained. 1 H NMR (400 MHz, CDCl 3 ) δ ppm 8.13 (d, 1H), 7.95 (d, 1H), 7.72 (t, 1H), 5.48 (s, 2H).
步骤4:化合物4-5的合成Step 4: Synthesis of Compounds 4-5
在预先干燥的单口瓶中加入化合物4-4(5g,24.74mmol)和硫酸(50mL),然后加入硝酸钾(2.63g,25.97mmol),100℃搅拌16小时。反应完成后,向反应液中加入冰水(50mL)搅拌5min后将其倒入乙酸乙酯(100mL)中,分液,收集有机相,用饱和食盐水(100mL)洗涤,无水硫酸钠干燥,浓缩,柱层析(石油醚:乙酸乙酯=4:1)分离。得到化合物4-5。
1H NMR(400MHz,CDCl
3)δppm 8.94(s,1H),8.81(s,1H),5.59(s,2H)。
Compound 4-4 (5 g, 24.74 mmol) and sulfuric acid (50 mL) were added to a pre-dried single-necked flask, then potassium nitrate (2.63 g, 25.97 mmol) was added, and the mixture was stirred at 100° C. for 16 hours. After the completion of the reaction, add ice water (50 mL) to the reaction solution, stir for 5 min, pour it into ethyl acetate (100 mL), separate the layers, collect the organic phase, wash with saturated brine (100 mL), and dry over anhydrous sodium sulfate. , concentrated and separated by column chromatography (petroleum ether:ethyl acetate=4:1). Compound 4-5 is obtained. 1 H NMR (400 MHz, CDCl 3 ) δ ppm 8.94 (s, 1H), 8.81 (s, 1H), 5.59 (s, 2H).
步骤5:化合物4-6的合成Step 5: Synthesis of Compounds 4-6
在氢化瓶中加入化合物4-5(2.25g,9.10mmol)和MeOH(50mL),然后加入钯/碳(1g,10%纯度),氢气置换三次,25℃,50psi搅拌4小时。反应液过滤,滤液浓缩,柱层析(石油醚:乙酸乙酯=1:1)分离。得到化合物4-6。
1H NMR(400MHz,CDCl
3)δppm 7.29(s,1H),7.17(s,1H),5.34(s,2H),4.18(br,2H)。
Compound 4-5 (2.25 g, 9.10 mmol) and MeOH (50 mL) were added to a hydrogenation bottle, then palladium/carbon (1 g, 10% purity) was added, hydrogen was replaced three times, and the mixture was stirred at 25° C., 50 psi for 4 hours. The reaction solution was filtered, and the filtrate was concentrated and separated by column chromatography (petroleum ether:ethyl acetate=1:1). Compound 4-6 is obtained. 1 H NMR (400 MHz, CDCl 3 ) δ ppm 7.29 (s, 1H), 7.17 (s, 1H), 5.34 (s, 2H), 4.18 (br, 2H).
步骤6:化合物4-7的合成Step 6: Synthesis of Compounds 4-7
在预先干燥的单口瓶中加入化合物4-6(1.78g,8.20mmol),氢溴酸(7mL)和水(7mL),降温至0℃后缓慢加入亚硝酸钠(593.85mg,8.61mmol)和水(7mL)的混合溶液,搅拌20min后加入氢溴酸(7mL)和溴化亚铜(1.47g,10.25mmol)的混合溶液,油浴加热80℃搅拌20min。反应完成后,向反应液中加入水(10mL),用二氯甲烷(20mL*3)萃取反应液,收集有机相,饱和食盐水(20mL)洗涤,无水硫酸钠干燥,浓缩,柱层析(石油醚:乙酸乙酯=5:1)纯化,得到化合物4-7。
1H NMR(400MHz,CDCl
3)δppm 8.24(s,1H),8.04(s,1H),5.42(s,2H)。
Compound 4-6 (1.78 g, 8.20 mmol), hydrobromic acid (7 mL) and water (7 mL) were added to a pre-dried single-necked flask, and the temperature was lowered to 0 °C, and sodium nitrite (593.85 mg, 8.61 mmol) and sodium nitrite (593.85 mg, 8.61 mmol) and The mixed solution of water (7 mL) was stirred for 20 min, and then a mixed solution of hydrobromic acid (7 mL) and cuprous bromide (1.47 g, 10.25 mmol) was added, and the mixture was heated in an oil bath at 80 °C and stirred for 20 min. After the reaction was completed, water (10 mL) was added to the reaction solution, the reaction solution was extracted with dichloromethane (20 mL*3), the organic phase was collected, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography. (Petroleum ether:ethyl acetate=5:1) to obtain compound 4-7. 1 H NMR (400 MHz, CDCl 3 ) δ ppm 8.24 (s, 1H), 8.04 (s, 1H), 5.42 (s, 2H).
步骤7:化合物4-8的合成Step 7: Synthesis of Compounds 4-8
在预先干燥的单口瓶中加入化合物4-7(400mg,1.42mmol),氰化锌(200.57mg,1.71mmol),四(三苯基膦)钯(246.72mg,213.50μmol)和N-甲基吡咯烷酮(4mL),微波130℃搅拌30min。反应完成后,向反应液中加入水(50mL),用乙酸乙酯(50mL*3)萃取反应液,收集有机相,饱和食盐水(50mL)洗涤,无水 硫酸钠干燥,浓缩。柱层析(石油醚:乙酸乙酯=2:1)分离得到化合物4-8。
1H NMR(400MHz,CDCl
3)δppm 8.20(s,1H),8.41(s,1H),5.55(s,2H)。
Compound 4-7 (400 mg, 1.42 mmol), zinc cyanide (200.57 mg, 1.71 mmol), tetrakis(triphenylphosphine) palladium (246.72 mg, 213.50 μmol) and N-methyl cyanide were added to a pre-dried single-necked bottle Pyrrolidone (4 mL) was microwaved at 130°C and stirred for 30 min. After the reaction was completed, water (50 mL) was added to the reaction solution, the reaction solution was extracted with ethyl acetate (50 mL*3), the organic phase was collected, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated. Column chromatography (petroleum ether:ethyl acetate=2:1) isolated compound 4-8. 1 H NMR (400 MHz, CDCl 3 ) δ ppm 8.20 (s, 1H), 8.41 (s, 1H), 5.55 (s, 2H).
步骤8:化合物4-9的合成Step 8: Synthesis of Compounds 4-9
在预先干燥的单口瓶中加入化合物4-8(874mg,3.85mmol)和N,N-二甲基甲酰胺(5mL),然后依次加入硫氢化钠(570.08mg,7.70mmol)和六水氯化镁(860.51mg,4.23mmol),加毕后,25℃搅拌3小时。反应完成后,向反应液中加入水(100mL),用乙酸乙酯(80mL*3)萃取反应液,收集有机相,饱和食盐水(50mL)洗涤,无水硫酸钠干燥,浓缩得到粗品。粗品经柱层析(石油醚:乙酸乙酯=1:1)分离得到化合物4-9。
1H NMR(400MHz,CDCl
3)δppm 8.61(s,1H),8.44(s,1H),7.75(br,1H),7.45(br,1H),5.51(s,2H)。
Compound 4-8 (874 mg, 3.85 mmol) and N,N-dimethylformamide (5 mL) were added to a pre-dried single-necked flask, followed by sodium hydrosulfide (570.08 mg, 7.70 mmol) and magnesium chloride hexahydrate ( 860.51 mg, 4.23 mmol), after the addition was completed, the mixture was stirred at 25°C for 3 hours. After the reaction was completed, water (100 mL) was added to the reaction solution, the reaction solution was extracted with ethyl acetate (80 mL*3), the organic phase was collected, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was separated by column chromatography (petroleum ether:ethyl acetate=1:1) to obtain compound 4-9. 1 H NMR (400 MHz, CDCl 3 ) δ ppm 8.61 (s, 1H), 8.44 (s, 1H), 7.75 (br, 1H), 7.45 (br, 1H), 5.51 (s, 2H).
步骤9:化合物4-10的合成Step 9: Synthesis of Compounds 4-10
在预先干燥的三口瓶中加入化合物4-9(1.14g,4.36mmol,1eq)和N,N-二甲基甲酰胺(10mL),然后加入水合肼(445.85mg,8.73mmol),25℃搅拌1小时。然后滴加甲酸(10mL),滴加完毕后升温至90℃搅拌1小时。反应完成后,反应液降温至室温,加入水(100mL)和乙酸乙酯(100mL),分液,有机相用1M稀盐酸(30mL)洗涤,分液,有机相用饱和碳酸钠水溶液(10mL)洗涤,分液,有机相用饱和食盐水(50mL*2)洗涤,分液,有机相无水硫酸钠干燥,水泵40℃减压浓缩,柱层析(石油醚:乙酸乙酯=1:1)分离得到化合物4-10。
1H NMR(400MHz,CDCl
3)δppm 9.08(s,1H),8.79(s,1H),8.42(s,1H),5.55(s,2H)。
Compound 4-9 (1.14g, 4.36mmol, 1eq) and N,N-dimethylformamide (10mL) were added to a pre-dried three-necked flask, followed by hydrazine hydrate (445.85mg, 8.73mmol), and stirred at 25°C 1 hour. Then, formic acid (10 mL) was added dropwise, and the temperature was raised to 90° C. and stirred for 1 hour after the dropwise addition. After the reaction was completed, the reaction solution was cooled to room temperature, water (100 mL) and ethyl acetate (100 mL) were added, and the layers were separated. The organic phase was washed with 1M dilute hydrochloric acid (30 mL), and the layers were separated. The organic phase was washed with saturated aqueous sodium carbonate solution (10 mL). Washing, separation, the organic phase was washed with saturated brine (50mL*2), the layers were separated, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure at 40°C with a water pump, and subjected to column chromatography (petroleum ether:ethyl acetate=1:1 ) was isolated to give compound 4-10. 1 H NMR (400 MHz, CDCl 3 ) δ ppm 9.08 (s, 1H), 8.79 (s, 1H), 8.42 (s, 1H), 5.55 (s, 2H).
步骤10:化合物4-11的合成Step 10: Synthesis of Compounds 4-11
在预先干燥的单口瓶中加入化合物4-10(570mg,2.12mmol),N,N-二甲基甲酰胺(6mL),三乙烯二胺(475.05mg,4.24mmol),冰浴降温至0℃后滴加化合物ST-1(550.38mg,2.44mmol),滴加完毕后缓慢至25℃搅拌2小时。反应完成后,向反应液中加入乙酸乙酯(20mL)和饱和食盐水(20mL),分液后有机相用1M稀盐酸(20mL)洗涤,分液后有机相用饱和碳酸钠水溶液(20mL)洗涤,分液,有机相无水硫酸钠干燥,浓缩,柱层析(石油醚:乙酸乙酯=1:1)分离得到化合物4-11。MS-ESI m/z:368.2[M+H]
+。
Compound 4-10 (570 mg, 2.12 mmol), N,N-dimethylformamide (6 mL), triethylenediamine (475.05 mg, 4.24 mmol) were added to a pre-dried single-necked bottle, and the temperature was cooled to 0°C in an ice bath. After that, compound ST-1 (550.38 mg, 2.44 mmol) was added dropwise, and after the dropwise addition was completed, it was slowly stirred at 25° C. for 2 hours. After the reaction was completed, ethyl acetate (20 mL) and saturated brine (20 mL) were added to the reaction solution, the organic phase was washed with 1M dilute hydrochloric acid (20 mL) after separation, and the organic phase was washed with saturated aqueous sodium carbonate solution (20 mL) after separation. Washed, separated, the organic phase was dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (petroleum ether:ethyl acetate=1:1) to obtain compound 4-11. MS-ESI m/z: 368.2 [M+H] + .
步骤11:化合物4-12的合成Step 11: Synthesis of Compounds 4-12
在预先干燥的单口瓶中加入化合物4-11(100mg,272.27μmol)和四氢呋喃(1mL),冰浴降温至0℃后加入氢氧化锂(57.13mg,1.36mmol)和水(1mL)的溶液,0℃搅拌2小时。反应完成后,向反应液中加入1M稀盐酸调pH<3,加乙酸乙酯(5mL)和水(5mL)分液,收集有机相,饱和食盐水(5mL)洗涤,无水硫酸钠干燥,浓缩,没有纯化。得到化合物4-12,直接用于下一步反应。Compound 4-11 (100 mg, 272.27 μmol) and tetrahydrofuran (1 mL) were added to a pre-dried single-necked bottle, and a solution of lithium hydroxide (57.13 mg, 1.36 mmol) and water (1 mL) was added after cooling to 0 °C in an ice bath, Stir at 0°C for 2 hours. After the reaction was completed, 1M dilute hydrochloric acid was added to the reaction solution to adjust pH<3, ethyl acetate (5 mL) and water (5 mL) were added to separate the layers, the organic phase was collected, washed with saturated brine (5 mL), and dried over anhydrous sodium sulfate. Concentrated without purification. Compound 4-12 was obtained, which was directly used in the next reaction.
步骤12:化合物4的合成Step 12: Synthesis of Compound 4
在预先干燥的单口瓶中加入化合物4-12(30mg,88.44μmol)和四氢呋喃(1mL),EtOAc(1mL),然后冰浴降温至0℃后加入1-8(11.69mg,106.12μmol),丙烷磷酸酐50%乙酸乙酯溶液(56.28mg,176.87μmol),N,N-二异丙基乙胺(45.72mg,353.75μmol),升温至25℃搅拌3小时。反应完成后,向反应液中加入水(10mL),用二氯甲烷(30mL*3)萃取反应液,收集有机相,饱和食盐水(20mL)洗涤,无水硫酸钠干燥,浓 缩得到粗品。粗品经制备高效液相色谱(色谱柱:Phenomenex Gemini-NX C18 75*30mm*3μm;流动相:[水(10mM NH
4HCO
3)-ACN];B(乙腈)%:20%-50%,10.5min)分离得到化合物4。
Compound 4-12 (30 mg, 88.44 μmol), tetrahydrofuran (1 mL), EtOAc (1 mL) were added to a pre-dried single-necked flask, then cooled to 0°C in an ice bath, and then added 1-8 (11.69 mg, 106.12 μmol), propane Phosphoric anhydride 50% ethyl acetate solution (56.28 mg, 176.87 μmol), N,N-diisopropylethylamine (45.72 mg, 353.75 μmol), warmed to 25° C. and stirred for 3 hours. After the reaction was completed, water (10 mL) was added to the reaction solution, the reaction solution was extracted with dichloromethane (30 mL*3), the organic phase was collected, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was subjected to preparative high performance liquid chromatography (chromatographic column: Phenomenex Gemini-NX C18 75*30mm*3μm; mobile phase: [water (10mM NH 4 HCO 3 )-ACN]; B (acetonitrile)%: 20%-50%, 10.5 min) to separate compound 4.
1H NMR(400MHz,CD
3OD)δppm 9.56(s,1H),8.76(s,1H),8.69(s,1H),8.10(s,1H),8.09(m,1H),7.93(s,1H),7.46(d,J=10.8Hz,1H),6.06(d,J=10.8Hz,1H),5.61(s,2H)。
1 H NMR (400MHz, CD 3 OD) δppm 9.56(s, 1H), 8.76(s, 1H), 8.69(s, 1H), 8.10(s, 1H), 8.09(m, 1H), 7.93(s, 1H), 7.46 (d, J=10.8Hz, 1H), 6.06 (d, J=10.8Hz, 1H), 5.61 (s, 2H).
实施例5Example 5
合成路线:synthetic route:
步骤1:化合物5-2的合成Step 1: Synthesis of Compound 5-2
在预先干燥过的反应瓶中加入丙烯酸乙酯(22.82g,227.98mmol),化合物5-1(50g,142.49mmol,1eq),四丁基氯化铵(39.60g,142.49mmol),碳酸钾(39.39g,284.98mmol,2eq)和N,N-二甲基甲酰胺(500mL),将醋酸钯(1.60g,7.12mmol)加入反应瓶中,氮气保护下,反应液在25℃搅拌60小时。反应完成后,反应液浓缩,粗品通过柱层析(石油醚:乙酸乙酯=1:1)纯化得化合物5-2。MS-ESI m/z:324.1[M+H]
+。
In the pre-dried reaction flask was added ethyl acrylate (22.82g, 227.98mmol), compound 5-1 (50g, 142.49mmol, 1eq), tetrabutylammonium chloride (39.60g, 142.49mmol), potassium carbonate ( 39.39g, 284.98mmol, 2eq) and N,N-dimethylformamide (500mL), palladium acetate (1.60g, 7.12mmol) was added to the reaction flask, and the reaction solution was stirred at 25°C for 60 hours under nitrogen protection. After the reaction was completed, the reaction solution was concentrated, and the crude product was purified by column chromatography (petroleum ether:ethyl acetate=1:1) to obtain compound 5-2. MS-ESI m/z: 324.1 [M+H] + .
步骤2:化合物5-3的合成Step 2: Synthesis of Compounds 5-3
在预先干燥的反应瓶中加入化合物5-2(22g,68.09mmol),4-甲基苯磺酰肼(38.04g,204.27mmol),乙酸 钠(22.34g,272.36mmol,4eq),四氢呋喃(220mL)和水(80mL),反应液在80℃搅拌12小时。反应完成后,在反应液中加入水(500mL),用乙酸乙酯(250mL*3)萃取反应液,收集有机相,用饱和食盐水(500mL)洗涤有机相,无水硫酸钠干燥,过滤,浓缩。粗品通过柱层析(石油醚:乙酸乙酯=1:1)分离得到化合物5-3。MS-ESI m/z:326.1[M+H]
+。
Compound 5-2 (22g, 68.09mmol), 4-methylbenzenesulfonylhydrazide (38.04g, 204.27mmol), sodium acetate (22.34g, 272.36mmol, 4eq), tetrahydrofuran (220mL) were added to a pre-dried reaction flask ) and water (80 mL), and the reaction solution was stirred at 80°C for 12 hours. After the reaction was completed, water (500 mL) was added to the reaction solution, the reaction solution was extracted with ethyl acetate (250 mL*3), the organic phase was collected, washed with saturated brine (500 mL), dried over anhydrous sodium sulfate, filtered, concentrate. The crude product was separated by column chromatography (petroleum ether:ethyl acetate=1:1) to obtain compound 5-3. MS-ESI m/z: 326.1 [M+H] + .
步骤3:化合物5-4的合成Step 3: Synthesis of Compounds 5-4
在预先干燥过的反应瓶中加入化合物5-3(21g,64.59mmol),氢氧化钠水溶液(2M,64.59mL)和乙醇(42mL)。氮气保护下,反应液在25℃下搅拌2小时。反应完成后,反应液中缓慢加入浓盐酸(12M),调节pH至3,加入水(250mL),用乙酸乙酯(150mL*3)萃取反应液,收集有机相,饱和食盐水(100mL)洗涤有机相,用无水硫酸钠干燥,浓缩。得到化合物5-4。MS-ESI m/z:298.0[M+H]
+。
Compound 5-3 (21 g, 64.59 mmol), aqueous sodium hydroxide solution (2 M, 64.59 mL) and ethanol (42 mL) were added to a pre-dried reaction flask. Under nitrogen protection, the reaction solution was stirred at 25°C for 2 hours. After the reaction was completed, concentrated hydrochloric acid (12M) was slowly added to the reaction solution, pH was adjusted to 3, water (250 mL) was added, the reaction solution was extracted with ethyl acetate (150 mL*3), the organic phase was collected, and washed with saturated brine (100 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated. Compound 5-4 is obtained. MS-ESI m/z: 298.0 [M+H] + .
步骤4:化合物5-5的合成Step 4: Synthesis of Compounds 5-5
在预先干燥的反应瓶中加入氯磺酸(50.99g,437.61mmol),冷却至0℃,将化合物5-4(13g,43.76mmol)加入到反应液中,反应在25℃搅拌12小时。反应完成后,反应液缓慢加入到冰水(250mL)中搅拌10分钟,后用乙酸乙酯(150mL*3)萃取反应液,收集有机相,饱和食盐水(200mL)洗涤,有机相用无水硫酸钠干燥,浓缩。粗品通过柱层析(石油醚:乙酸乙酯=1:1)分离得到化合物5-5。MS-ESI m/z:280.0[M+H]
+。
Chlorosulfonic acid (50.99 g, 437.61 mmol) was added to the pre-dried reaction flask, cooled to 0 °C, compound 5-4 (13 g, 43.76 mmol) was added to the reaction solution, and the reaction was stirred at 25 °C for 12 hours. After the reaction was completed, the reaction solution was slowly added to ice water (250 mL) and stirred for 10 minutes, then the reaction solution was extracted with ethyl acetate (150 mL*3), the organic phase was collected, washed with saturated brine (200 mL), and the organic phase was washed with anhydrous Dry over sodium sulfate and concentrate. The crude product was separated by column chromatography (petroleum ether:ethyl acetate=1:1) to obtain compound 5-5. MS-ESI m/z: 280.0 [M+H] + .
步骤5:化合物5-6的合成Step 5: Synthesis of Compounds 5-6
在预先干燥的反应瓶中加入1,2-乙二硫醇(2.90g,30.75mmol),化合物5-5(7.8g,27.95mmol),甲苯(80mL)和对甲苯磺酸(962.67mg,5.59mmol),反应液在120℃搅拌12小时。反应完成后,反应液中加入水(100mL),用乙酸乙酯(150mL*3)萃取反应液,收集有机相,饱和食盐水(80mL)洗涤,有机相用无水硫酸钠干燥,浓缩。粗品通过柱层析(石油醚:乙酸乙酯=10:1)分离目标产物,得到化合物5-6。MS-ESI m/z:356.2[M+H]
+。
To a pre-dried reaction flask was added 1,2-ethanedithiol (2.90 g, 30.75 mmol), compound 5-5 (7.8 g, 27.95 mmol), toluene (80 mL) and p-toluenesulfonic acid (962.67 mg, 5.59 mmol), the reaction solution was stirred at 120 °C for 12 hours. After the reaction was completed, water (100 mL) was added to the reaction solution, the reaction solution was extracted with ethyl acetate (150 mL*3), the organic phase was collected, washed with saturated brine (80 mL), and the organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was separated by column chromatography (petroleum ether:ethyl acetate=10:1) to obtain compound 5-6. MS-ESI m/z: 356.2 [M+H] + .
步骤6:化合物5-7的合成Step 6: Synthesis of Compounds 5-7
在预先干燥的反应瓶中加入二溴海因(11.27g,39.41mmol,4eq)和二氯甲烷(40mL),反应液冷却至-70℃,滴加吡啶氢氟酸盐(7.81g,78.82mmol),滴加过程中温度维持在-65℃以下,加毕后在-70℃搅拌1小时,然后在-70℃加入化合物5-6(3.5g,9.85mmol)的二氯甲烷(4mL)溶液,反应液在-70℃搅拌4小时,25℃搅拌12小时。反应完成后,反应液中加入饱和碳酸钠水溶液(100mL),饱和亚硫酸钠水溶液(100mL)和二氯甲烷(100mL),分液,饱和食盐水(100mL)洗涤有机相,有机相用无水硫酸钠干燥,浓缩得到化合物5-7。MS-ESI m/z:380.9[M+H]
+。
Dibromohydantoin (11.27g, 39.41mmol, 4eq) and dichloromethane (40mL) were added to the pre-dried reaction flask, the reaction solution was cooled to -70°C, and pyridine hydrofluoride (7.81g, 78.82mmol) was added dropwise. ), the temperature was maintained below -65°C during the dropwise addition, and after the addition was completed, the mixture was stirred at -70°C for 1 hour, and then a solution of compound 5-6 (3.5g, 9.85mmol) in dichloromethane (4mL) was added at -70°C , the reaction solution was stirred at -70°C for 4 hours and at 25°C for 12 hours. After the reaction was completed, saturated aqueous sodium carbonate solution (100 mL), saturated aqueous sodium sulfite solution (100 mL) and dichloromethane (100 mL) were added to the reaction solution, the layers were separated, and the organic phase was washed with saturated brine (100 mL), and the organic phase was washed with anhydrous sodium sulfate. Dry and concentrate to give compound 5-7. MS-ESI m/z: 380.9 [M+H] + .
步骤7:化合物5-8的合成Step 7: Synthesis of Compounds 5-8
在预先干燥的反应瓶中加入化合物5-7(3.4g,8.95mmol)和二氯甲烷(20mL),在25℃将1,8-二氮杂二环十一碳-7-烯(2.18g,14.32mmol)滴加到反应液中,反应液在25℃搅拌12小时。反应完成后,反应液中加入盐酸水溶液(2M,50mL),用二氯甲烷(25mL*2)萃取反应液,收集有机相,饱和食盐水(20mL)洗涤, 有机相用无水硫酸钠干燥,浓缩。粗品通过柱层析(石油醚:乙酸乙酯=10:1)分离得到化合物5-8。MS-ESI m/z:300.0[M+H]
+。
Compound 5-7 (3.4 g, 8.95 mmol) and dichloromethane (20 mL) were added to a pre-dried reaction flask, and 1,8-diazabicycloundec-7-ene (2.18 g) was added at 25°C. , 14.32 mmol) was added dropwise to the reaction solution, and the reaction solution was stirred at 25° C. for 12 hours. After the reaction was completed, aqueous hydrochloric acid (2M, 50mL) was added to the reaction solution, the reaction solution was extracted with dichloromethane (25mL*2), the organic phase was collected, washed with saturated brine (20mL), and the organic phase was dried with anhydrous sodium sulfate, concentrate. The crude product was separated by column chromatography (petroleum ether:ethyl acetate=10:1) to obtain compound 5-8. MS-ESI m/z: 300.0 [M+H] + .
步骤8:化合物5-9的合成Step 8: Synthesis of Compounds 5-9
在预先干燥的反应瓶中加入化合物5-8(1.6g,5.35mmol),邻硝基苯磺酰氯(2.37g,10.70mmol)和乙腈(20mL),冷却至0℃,水合肼(1.07g,21.40mmol)加入反应液中,反应液在55℃搅拌12小时。反应完成后,反应液中加入水(50mL),用乙酸乙酯(25mL*2)萃取反应液,收集有机相,饱和食盐水(50mL)洗涤,用无水硫酸钠干燥有机相,浓缩。粗品通过柱层析(石油醚:乙酸乙酯=1:1)分离得到化合物5-9。MS-ESI m/z:302.0[M+H]
+。
Compound 5-8 (1.6 g, 5.35 mmol), o-nitrobenzenesulfonyl chloride (2.37 g, 10.70 mmol) and acetonitrile (20 mL) were added to a pre-dried reaction flask, cooled to 0° C., hydrazine hydrate (1.07 g, 21.40 mmol) was added to the reaction solution, and the reaction solution was stirred at 55° C. for 12 hours. After the reaction was completed, water (50 mL) was added to the reaction solution, the reaction solution was extracted with ethyl acetate (25 mL*2), the organic phase was collected, washed with saturated brine (50 mL), and the organic phase was dried with anhydrous sodium sulfate and concentrated. The crude product was separated by column chromatography (petroleum ether:ethyl acetate=1:1) to obtain compound 5-9. MS-ESI m/z: 302.0 [M+H] + .
步骤9:化合物5-10的合成Step 9: Synthesis of Compounds 5-10
在预先干燥过的反应瓶中加入化合物5-9(0.1g,332.17μmol),氰化锌(39.01mg,332.17μmol),三(二亚苄基丙酮)二钯(0)(30.42mg,33.22μmol),1,1'-双(二苯基膦)二茂铁(36.83mg,66.43μmol)和N,N-二甲基甲酰胺(1mL),氮气保护下,在130℃微波反应0.5小时。反应完成后,反应液浓缩。粗品通过制备薄层色谱硅胶板(石油醚:乙酸乙酯=10:1)分离得到化合物5-10。MS-ESI m/z:248.1[M+H]
+。
Compound 5-9 (0.1 g, 332.17 μmol), zinc cyanide (39.01 mg, 332.17 μmol), tris(dibenzylideneacetone)dipalladium(0) (30.42 mg, 33.22 μmol) were added to the pre-dried reaction flask μmol), 1,1'-bis(diphenylphosphino)ferrocene (36.83 mg, 66.43 μmol) and N,N-dimethylformamide (1 mL), under nitrogen protection, microwave reaction at 130 °C for 0.5 h . After the reaction was completed, the reaction solution was concentrated. The crude product was separated by preparative thin layer chromatography on silica gel plate (petroleum ether:ethyl acetate=10:1) to obtain compound 5-10. MS-ESI m/z: 248.1 [M+H] + .
步骤10:化合物5-11的合成Step 10: Synthesis of Compounds 5-11
在预先干燥的反应瓶中加入化合物5-10(0.46g,1.86mmol)和N,N-二甲基甲酰胺(5mL),再依次加入硫氢化钠(306.86mg,3.72mmol),氯化镁六水合物(416.21mg,2.05mmol,1.1eq),反应液在25℃搅拌2小时。反应完成后,反应液中加入水(10mL),用乙酸乙酯(20mL*3)萃取反应液,收集有机相,饱和食盐水(50mL)洗涤,无水硫酸钠干燥有机相,浓缩。粗品通过制备板(石油醚:乙酸乙酯=3:1)分离得到化合物5-11。MS-ESI m/z:282.2[M+H]
+。
Compound 5-10 (0.46g, 1.86mmol) and N,N-dimethylformamide (5mL) were added to the pre-dried reaction flask, followed by sodium hydrosulfide (306.86mg, 3.72mmol), magnesium chloride hexahydrate Compound (416.21 mg, 2.05 mmol, 1.1 eq), the reaction solution was stirred at 25°C for 2 hours. After the reaction was completed, water (10 mL) was added to the reaction solution, the reaction solution was extracted with ethyl acetate (20 mL*3), the organic phase was collected, washed with saturated brine (50 mL), and the organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was isolated by preparative plate (petroleum ether:ethyl acetate=3:1) to obtain compound 5-11. MS-ESI m/z: 282.2[M+H] + .
步骤11:化合物5-12的合成Step 11: Synthesis of Compounds 5-12
在预先干燥的反应瓶中加入化合物5-11(0.6g,2.13mmol)和N,N-二甲基甲酰胺(3mL),然后加入水合肼(217.95mg,4.27mmol),25℃搅拌30分钟,然后加入甲酸(3mL),滴加完毕后,反应液在90℃搅拌16小时。反应完成后,反应液直接浓缩得到化合物5-12。MS-ESI m/z:290.2[M+H]
+。
Compound 5-11 (0.6 g, 2.13 mmol) and N,N-dimethylformamide (3 mL) were added to a pre-dried reaction flask, followed by hydrazine hydrate (217.95 mg, 4.27 mmol), and stirred at 25°C for 30 minutes , and then formic acid (3 mL) was added. After the dropwise addition, the reaction solution was stirred at 90° C. for 16 hours. After completion of the reaction, the reaction solution was directly concentrated to obtain compound 5-12. MS-ESI m/z: 290.2 [M+H] + .
步骤12:化合物5-13的合成Step 12: Synthesis of Compounds 5-13
在预先干燥的反应瓶中加入化合物5-12(1.15g,3.98mmol),三乙烯二胺(892.10mg,7.95mmol)和N,N-二甲基甲酰胺(7mL),将反应液冷却至0℃,将化合物ST-1(1.26g,5.57mmol)滴加入反应液中,反应液在20℃搅拌12小时。反应完成后,反应液中加入水(20mL),用乙酸乙酯(30mL*3)萃取反应液,收集有机相,饱和食盐水(50mL)洗涤,有机相用无水硫酸钠干燥,浓缩。粗品通过柱层析(石油醚:乙酸乙酯=1:1)分离得到化合物5-13。MS-ESI m/z:388.3[M+H]
+。
Compound 5-12 (1.15 g, 3.98 mmol), triethylenediamine (892.10 mg, 7.95 mmol) and N,N-dimethylformamide (7 mL) were added to the pre-dried reaction flask, and the reaction solution was cooled to At 0°C, compound ST-1 (1.26 g, 5.57 mmol) was added dropwise to the reaction solution, and the reaction solution was stirred at 20°C for 12 hours. After the reaction was completed, water (20 mL) was added to the reaction solution, the reaction solution was extracted with ethyl acetate (30 mL*3), the organic phase was collected, washed with saturated brine (50 mL), and the organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was separated by column chromatography (petroleum ether:ethyl acetate=1:1) to obtain compound 5-13. MS-ESI m/z: 388.3 [M+H] + .
步骤13:化合物5-14的合成Step 13: Synthesis of Compounds 5-14
在预先干燥的反应瓶中加入化合物5-13(0.12g,309.83μmol),四氢呋喃(3mL)和水(3mL),反应冷却至 0℃,将氢氧化锂(39.01mg,929.50μmol)加入反应瓶中,反应液在0℃搅拌3小时。反应完成后,向反应液中加入盐酸水溶液(3M)调节pH至4,用乙酸乙酯(30mL*3)萃取反应液,收集有机相,饱和食盐水(20mL)洗涤,有机相用无水硫酸钠干燥,浓缩得到化合物5-14。
1H NMR(400MHz,CD
3OD)δppm 9.53(s,1H),8.52-8.43(m,2H),7.41(d,J=10.52Hz,1H),5.90(d,J=10.52Hz,1H),3.30-3.28(m,2H),3.27-2.69(m,2H)。
Compound 5-13 (0.12 g, 309.83 μmol), tetrahydrofuran (3 mL) and water (3 mL) were added to the pre-dried reaction flask, the reaction was cooled to 0°C, and lithium hydroxide (39.01 mg, 929.50 μmol) was added to the reaction flask , the reaction solution was stirred at 0 °C for 3 hours. After the completion of the reaction, aqueous hydrochloric acid (3M) was added to the reaction solution to adjust pH to 4, the reaction solution was extracted with ethyl acetate (30mL*3), the organic phase was collected, washed with saturated brine (20mL), and the organic phase was washed with anhydrous sulfuric acid. Dry over sodium and concentrate to give compound 5-14. 1 H NMR (400MHz, CD 3 OD) δppm 9.53 (s, 1H), 8.52-8.43 (m, 2H), 7.41 (d, J=10.52Hz, 1H), 5.90 (d, J=10.52Hz, 1H) , 3.30-3.28 (m, 2H), 3.27-2.69 (m, 2H).
步骤14:化合物5的合成Step 14: Synthesis of Compound 5
在预先干燥的反应瓶中加入化合物5-14(0.05g,139.18μmol),四氢呋喃(1mL)和乙酸乙酯(1mL),将反应液降至0℃,将1-8(18.39mg,167.01μmol),丙烷磷酸酐50%乙酸乙酯溶液(88.57mg,278.36μmol),N,N-二异丙基乙胺(71.95mg,556.71μmol)依次加入到反应瓶中,在0℃搅拌3小时。反应完成后,反应液中加入水(10mL),用乙酸乙酯(30mL*3)萃取反应液,收集有机相,饱和食盐水(20mL)洗涤,有机相用无水硫酸钠干燥,浓缩。粗品通过制备高效液相色谱(色谱柱:Phenomenex Gemini-NX C18 75*30mm*3μm;流动相:[水(10mM NH
4HCO
3)-ACN];B(乙腈)%:27%-57%,10.5min)分离得到化合物5。
Compound 5-14 (0.05 g, 139.18 μmol), tetrahydrofuran (1 mL) and ethyl acetate (1 mL) were added to a pre-dried reaction flask, the reaction solution was lowered to 0°C, and 1-8 (18.39 mg, 167.01 μmol) was added. ), propane phosphoric anhydride 50% ethyl acetate solution (88.57mg, 278.36μmol), N,N-diisopropylethylamine (71.95mg, 556.71μmol) were sequentially added to the reaction flask and stirred at 0°C for 3 hours. After the reaction was completed, water (10 mL) was added to the reaction solution, the reaction solution was extracted with ethyl acetate (30 mL*3), the organic phase was collected, washed with saturated brine (20 mL), and the organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by preparative high performance liquid chromatography (chromatographic column: Phenomenex Gemini-NX C18 75*30mm*3μm; mobile phase: [water (10mM NH 4 HCO 3 )-ACN]; B (acetonitrile)%: 27%-57%, 10.5 min) to separate compound 5.
1H NMR(400MHz,CD
3OD)δppm 9.57(s,1H),8.49(s,1H),8.43(s,1H),8.14-8.08(m,2H),7.93(d,J=2.64Hz,1H),7.44(d,J=10.52Hz,1H),6.02(d,J=10.52Hz,1H),3.30-3.27(m,2H),2.80-2.68(m,2H)。
1 H NMR (400MHz, CD 3 OD) δppm 9.57(s, 1H), 8.49(s, 1H), 8.43(s, 1H), 8.14-8.08(m, 2H), 7.93(d, J=2.64Hz, 1H), 7.44 (d, J=10.52Hz, 1H), 6.02 (d, J=10.52Hz, 1H), 3.30-3.27 (m, 2H), 2.80-2.68 (m, 2H).
实施例6Example 6
合成路线:synthetic route:
步骤1:化合物3的合成Step 1: Synthesis of Compound 3
将化合物6-1(0.5g,2.05mmol)溶于水(3mL)中,后加入浓盐酸(204.00mg,2.13mmol),之后将化合物6-2(333.58mg,2.25mmol)溶于水(2mL)中加至反应液中,在20℃下搅拌10min,析出固体。反应液过滤,用水(30mL)洗涤滤饼,得化合物6-3。Compound 6-1 (0.5 g, 2.05 mmol) was dissolved in water (3 mL), concentrated hydrochloric acid (204.00 mg, 2.13 mmol) was added, and compound 6-2 (333.58 mg, 2.25 mmol) was dissolved in water (2 mL). ) was added to the reaction solution, stirred at 20° C. for 10 min, and a solid was precipitated. The reaction solution was filtered, and the filter cake was washed with water (30 mL) to obtain compound 6-3.
1H NMR(400MHz,DMSO-d
6)δppm 7.24(s,1H),7.51(s,1H),7.64(s,2H),11.70(s,1H)。
1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.24 (s, 1H), 7.51 (s, 1H), 7.64 (s, 2H), 11.70 (s, 1H).
步骤2:化合物6-4的合成Step 2: Synthesis of Compounds 6-4
将化合物6-3(300mg,999.48μmol)溶于甲苯(5mL)中,加入三乙胺(101.14mg,999.48μmol)和叠氮磷酸二苯酯(275.06mg,999.48μmol)后,缓慢升温至115℃,回流反应2小时。反应完成后,将反应液倒入到氢氧化钾水溶液(10%纯度,10mL)中,后用氢氧化钾水溶液(10%,10mL*2)萃取反应液,收集水相后用浓盐酸调节水相pH至3左右,有固体析出,过滤得到化合物6-4,不纯化直接用于下一步反应。Compound 6-3 (300 mg, 999.48 μmol) was dissolved in toluene (5 mL), triethylamine (101.14 mg, 999.48 μmol) and diphenylphosphonium azide (275.06 mg, 999.48 μmol) were added, and the temperature was slowly raised to 115 ℃, the reaction was refluxed for 2 hours. After the reaction was completed, the reaction solution was poured into an aqueous potassium hydroxide solution (10% purity, 10 mL), and the reaction solution was extracted with an aqueous potassium hydroxide solution (10%, 10 mL*2), and the aqueous phase was collected and adjusted with concentrated hydrochloric acid. The pH of the phase was about 3, and a solid was precipitated, and the compound 6-4 was obtained by filtration, which was directly used in the next reaction without purification.
步骤3:化合物6-5的合成Step 3: Synthesis of Compounds 6-5
将化合物6-4(100mg,336.52μmol)溶于N,N-二甲基甲酰胺(3mL)中,加入三乙烯二胺(75.50mg,673.04μmol)在15℃下搅拌反应0.5小时,后加入化合物ST-1(46.09mg,203.93μmol)反应16小时。反应完成后,反应液中加入水(20mL),用乙酸乙酯(20mL*3)萃取反应液,收集有机相,饱和食盐水(30mL)洗涤有机相,无水硫酸钠干燥,浓缩。经制备薄层色谱硅胶板(石油醚:乙酸乙酯=6:1)分离得化合物6-5。MS-ESI m/z:396.0[M+H]
+。
Compound 6-4 (100 mg, 336.52 μmol) was dissolved in N,N-dimethylformamide (3 mL), triethylenediamine (75.50 mg, 673.04 μmol) was added, and the reaction was stirred at 15 ° C for 0.5 hours, and then added Compound ST-1 (46.09 mg, 203.93 μmol) was reacted for 16 hours. After the reaction was completed, water (20 mL) was added to the reaction solution, the reaction solution was extracted with ethyl acetate (20 mL*3), the organic phase was collected, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated. Compound 6-5 was isolated by preparative thin layer chromatography on silica gel plate (petroleum ether:ethyl acetate=6:1). MS-ESI m/z: 396.0 [M+H] + .
步骤4:化合物6-6的合成Step 4: Synthesis of Compounds 6-6
将化合物6-5(110mg,278.30μmol)溶于四氢呋喃(9mL)和水(9mL)中,0℃下加入氢氧化锂(23.33mg,974.05μmol)后在20℃下反应2小时。反应完成后,反应液用浓盐酸调节pH至3,后用乙酸乙酯(30mL*3)萃取反应液,收集有机相,饱和食盐水(40mL)洗涤有机相,无水硫酸钠干燥,浓缩得化合物6-6。MS-ESI m/z:367.8[M+H]
+。
Compound 6-5 (110 mg, 278.30 μmol) was dissolved in tetrahydrofuran (9 mL) and water (9 mL), and lithium hydroxide (23.33 mg, 974.05 μmol) was added at 0° C. and reacted at 20° C. for 2 hours. After the reaction was completed, the pH of the reaction solution was adjusted to 3 with concentrated hydrochloric acid, and then the reaction solution was extracted with ethyl acetate (30 mL*3), the organic phase was collected, washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, and concentrated to obtain Compounds 6-6. MS-ESI m/z: 367.8 [M+H] + .
步骤5:化合物6的合成Step 5: Synthesis of Compound 6
将化合物6-5(50mg,136.16μmol)溶于乙酸乙酯(3mL)和四氢呋喃(3mL)中,降低反应液温度至-60℃,之后加入1-8(17.99mg,163.40μmol),丙烷磷酸酐50%乙酸乙酯溶液(86.65mg,272.33μmol)并滴加N,N-二异丙基乙胺(70.39mg,544.66μmol),后在20℃下继续反应21小时。反应完成后,反应液浓缩得到粗品,粗品经制备高效液相色谱(色谱柱:Phenomenex Gemini-NX 80*40mm*3μm;流动相:[水(0.05%NH
3H
2O+10mM NH
4HCO
3)-ACN];B(乙腈)%:40%-64%,8min)纯化得到化合物6。
Compound 6-5 (50 mg, 136.16 μmol) was dissolved in ethyl acetate (3 mL) and tetrahydrofuran (3 mL), the temperature of the reaction solution was lowered to -60°C, and then 1-8 (17.99 mg, 163.40 μmol), propane phosphoric acid was added. Anhydride 50% ethyl acetate solution (86.65 mg, 272.33 μmol) and N,N-diisopropylethylamine (70.39 mg, 544.66 μmol) were added dropwise, and the reaction was continued at 20° C. for 21 hours. After the reaction was completed, the reaction solution was concentrated to obtain a crude product, which was subjected to preparative high performance liquid chromatography (chromatographic column: Phenomenex Gemini-NX 80*40mm*3 μm; mobile phase: [water (0.05% NH 3 H 2 O+10 mM NH 4 HCO 3 ) . )-ACN]; B (acetonitrile) %: 40%-64%, 8 min) was purified to give compound 6.
1H NMR(400MHz,DMSO-d
6)δppm 5.96(d,J=10.38Hz,1H),6.90(d,J=10.51Hz,1H),7.94(d,J=2.75Hz,1H),8.05(s,1H),8.07(d,J=2.50Hz,1H),8.10(s,1H),8.49(s,2H),9.13(s,1H)。
1 H NMR (400 MHz, DMSO-d 6 ) δppm 5.96 (d, J=10.38 Hz, 1H), 6.90 (d, J=10.51 Hz, 1H), 7.94 (d, J=2.75 Hz, 1H), 8.05 ( s, 1H), 8.07 (d, J=2.50Hz, 1H), 8.10 (s, 1H), 8.49 (s, 2H), 9.13 (s, 1H).
实施例7Example 7
合成路线:synthetic route:
步骤1:化合物7-2的合成Step 1: Synthesis of Compound 7-2
在预先干燥的反应瓶中加入化合物7-1(2g,10.10mmol),三乙烯二胺(2.27g,20.20mmol)和N,N-二甲基甲酰胺(30mL),反应液冷却至0℃加入化合物ST-1(3.20g,14.14mmol),反应液在20摄氏度搅拌12小时。反应完成后,反应液浓缩,柱层析(石油醚:乙酸乙酯=1:1)分离得化合物7-2。
1H NMR(400MHz,CDCl
3)δppm 9.27(s,1H),8.67(s,1H),7.92(s,1H),7.05(d,J=10.32Hz,1H),5.87(d,J=10.32Hz,1H),4.29-4.24(q,2H),1.34-1.30(t,3H)。
Compound 7-1 (2g, 10.10mmol), triethylenediamine (2.27g, 20.20mmol) and N,N-dimethylformamide (30mL) were added to the pre-dried reaction flask, and the reaction solution was cooled to 0°C Compound ST-1 (3.20 g, 14.14 mmol) was added, and the reaction solution was stirred at 20 degrees Celsius for 12 hours. After the completion of the reaction, the reaction solution was concentrated, and the compound 7-2 was isolated by column chromatography (petroleum ether:ethyl acetate=1:1). 1 H NMR (400MHz, CDCl 3 ) δppm 9.27 (s, 1H), 8.67 (s, 1H), 7.92 (s, 1H), 7.05 (d, J=10.32 Hz, 1H), 5.87 (d, J=10.32 Hz, 1H), 4.29-4.24 (q, 2H), 1.34-1.30 (t, 3H).
步骤2:化合物7-3的合成Step 2: Synthesis of Compound 7-3
在预先干燥的反应瓶中加入化合物7-2(0.383g,1.29mmol),3,5-二三氟甲基苯硼酸(500.40mg,1.94mmol),四氢呋喃(10mL),水(3mL),[1,1'-双(二苯基膦基)二茂铁]二氯化钯(211.25mg,258.68μmol)和碳酸钠(274.17mg,2.59mmol),氮气保护下在40℃搅拌2小时。反应完成后,反应液浓缩,柱层析(石油醚:乙酸乙酯=1:1)得到化合物7-3。
1H NMR(400MHz,CDCl
3)δppm 9.69(s,1H),8.65(s,1H),8.31(s,1H),8.06(s,2H),7.94(s,1H),7.73(d,J=10.32Hz,1H),5.84(d,J=10.32Hz,1H),4.30(q,J=7.2Hz,2H),1.36(t,J=7.2Hz,3H)。
In a pre-dried reaction flask was added compound 7-2 (0.383 g, 1.29 mmol), 3,5-ditrifluoromethylbenzeneboronic acid (500.40 mg, 1.94 mmol), tetrahydrofuran (10 mL), water (3 mL), [ 1,1'-Bis(diphenylphosphino)ferrocene]palladium dichloride (211.25 mg, 258.68 μmol) and sodium carbonate (274.17 mg, 2.59 mmol) were stirred at 40° C. for 2 hours under nitrogen protection. After the completion of the reaction, the reaction solution was concentrated and subjected to column chromatography (petroleum ether:ethyl acetate=1:1) to obtain compound 7-3. 1 H NMR (400MHz, CDCl 3 ) δppm 9.69(s, 1H), 8.65(s, 1H), 8.31(s, 1H), 8.06(s, 2H), 7.94(s, 1H), 7.73(d, J = 10.32 Hz, 1H), 5.84 (d, J=10.32 Hz, 1H), 4.30 (q, J=7.2 Hz, 2H), 1.36 (t, J=7.2 Hz, 3H).
步骤3:化合物7-4的合成Step 3: Synthesis of Compounds 7-4
在预先干燥的反应瓶中加入化合物7-3(0.3g,698.79μmol),四氢呋喃(6mL),将反应液冷却至0℃,将氢氧化锂(87.96mg,2.10mmol)和水(2mL)的混合液滴加到反应瓶中,反应液在0℃搅拌1小时。反应完成后,将2M盐酸水溶液滴加入反应液中,调节pH至3,用乙酸乙酯(10mL*3)萃取反应液,收集有机相,饱和食盐水(10mL)洗涤,无水硫酸钠干燥,浓缩得化合物7-4。
1H NMR(400MHz,CD
3OD)δppm 9.49(s,1H),8.79(s,1H),8.46(s,1H),8.30(s,2H),8.02(s,1H),7.71(d,J=10.32Hz,1H),5.95(d,J=10.32Hz,1H)。
Compound 7-3 (0.3 g, 698.79 μmol), tetrahydrofuran (6 mL) were added to a pre-dried reaction flask, the reaction solution was cooled to 0°C, and a mixture of lithium hydroxide (87.96 mg, 2.10 mmol) and water (2 mL) was added. The mixture was added dropwise to the reaction flask, and the reaction solution was stirred at 0° C. for 1 hour. After the completion of the reaction, 2M aqueous hydrochloric acid was added dropwise to the reaction solution, adjusted to pH 3, the reaction solution was extracted with ethyl acetate (10 mL*3), the organic phase was collected, washed with saturated brine (10 mL), and dried over anhydrous sodium sulfate, Concentrate to obtain compound 7-4. 1 H NMR (400MHz, CD 3 OD) δppm 9.49(s, 1H), 8.79(s, 1H), 8.46(s, 1H), 8.30(s, 2H), 8.02(s, 1H), 7.71(d, J=10.32Hz, 1H), 5.95 (d, J=10.32Hz, 1H).
步骤4:化合物7的合成Step 4: Synthesis of Compound 7
在预先干燥的反应瓶中加入化合物7-4(0.1g,249.21μmol),四氢呋喃(2mL)/乙酸乙酯(2mL),反应液冷却至0℃,将1-8(32.93mg,299.06μmol),N,N-二异丙基乙胺(128.83mg,996.85μmol),丙烷磷酸酐50%乙 酸乙酯溶液(317.18mg,498.43μmol)加入反应液中,反应在0℃搅拌3小时。反应完成后,反应液中加入水(20mL),用乙酸乙酯(20mL*3)萃取反应液,收集有机相,饱和食盐水(30mL)洗涤有机相,无水硫酸钠干燥,浓缩得到粗品。粗品经制备高效液相色谱(色谱柱:Phenomenex Gemini-NX C18 75*30mm*3μm;流动相:[水(10mM NH
4HCO
3)-ACN];B(乙腈)%:35%-55%,8min)分离纯化得化合物7。
1H NMR(400MHz,DMSO-d
6)δppm 10.47(s,1H),9.40(s,1H),9.09(s,1H),8.95(s,1H),8.74(s,1H),8.51(s,2H),8.15-8.13(m,2H),8.09(s,1H),7.95(s,1H),7.67(d,J=10.32Hz,1H),6.10(d,J=10.32Hz,1H)。
Compound 7-4 (0.1 g, 249.21 μmol), tetrahydrofuran (2 mL)/ethyl acetate (2 mL) was added to the pre-dried reaction flask, the reaction solution was cooled to 0°C, and 1-8 (32.93 mg, 299.06 μmol) was added to the reaction flask. , N,N-diisopropylethylamine (128.83 mg, 996.85 μmol), propane phosphoric anhydride 50% ethyl acetate solution (317.18 mg, 498.43 μmol) were added to the reaction solution, and the reaction was stirred at 0° C. for 3 hours. After the reaction was completed, water (20 mL) was added to the reaction solution, the reaction solution was extracted with ethyl acetate (20 mL*3), the organic phase was collected, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was subjected to preparative high performance liquid chromatography (chromatographic column: Phenomenex Gemini-NX C18 75*30mm*3μm; mobile phase: [water (10mM NH 4 HCO 3 )-ACN]; B (acetonitrile)%: 35%-55%, 8min) to separate and purify compound 7. 1 H NMR (400MHz, DMSO-d 6 ) δppm 10.47(s, 1H), 9.40(s, 1H), 9.09(s, 1H), 8.95(s, 1H), 8.74(s, 1H), 8.51(s ,2H),8.15-8.13(m,2H),8.09(s,1H),7.95(s,1H),7.67(d,J=10.32Hz,1H),6.10(d,J=10.32Hz,1H) .
实施例8Example 8
合成路线:synthetic route:
步骤1:化合物8-2的合成Step 1: Synthesis of Compound 8-2
在预先干燥的反应瓶中加入化合物8-1(20g,119.68mmol),硫酸(23.48g,239.35mmol)和甲醇(237.54g,7.41mol,80℃加热回流19小时。反应完成后,向反应液中加饱和碳酸钠水溶液调pH至10,二氯甲烷(500mL*2)萃取反应液,收集有机相,饱和食盐水(200mL)洗涤,无水硫酸钠干燥,浓缩得到化合物8-2。
1H NMR(400MHz,CDCl
3)δppm 9.07(s,1H),8.84(d,J=4.8Hz,1H),7.50(d,J=4.8Hz,1H),3.95-3.94(m,6H)。
Compound 8-1 (20 g, 119.68 mmol), sulfuric acid (23.48 g, 239.35 mmol) and methanol (237.54 g, 7.41 mol, 80° C. were heated to reflux for 19 hours at 80° C. after the reaction was completed. After the reaction was completed, the reaction solution was added to the reaction solution. Saturated aqueous sodium carbonate solution was added to adjust the pH to 10, the reaction solution was extracted with dichloromethane (500 mL*2), the organic phase was collected, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and concentrated to obtain compound 8-2. 1 H NMR (400 MHz, CDCl3 ) δ ppm 9.07 (s, 1H), 8.84 (d, J=4.8 Hz, 1H), 7.50 (d, J=4.8 Hz, 1H), 3.95-3.94 (m, 6H).
步骤2:化合物8-3的合成Step 2: Synthesis of Compound 8-3
在预先干燥的反应瓶中加入化合物8-2(16g,81.98mmol),二氯甲烷(80mL),降温到0℃,缓慢加入间氯过氧苯甲酸(33.29g,163.96mmol),加毕后缓慢升温至20℃,搅拌6小时。反应完成后,向反应液中加饱和亚硫酸钠水溶液(400mL)至淀粉碘化钾试纸不显蓝色,加饱和碳酸钠水溶液调pH至10。用二氯甲烷(400mL*2)萃取,收集有机相,饱和食盐水(200mL)洗涤,无水硫酸钠干燥,浓缩得到化合物8-3。
1H NMR (400MHz,CDCl
3)δppm 8.34(s,1H),8.25(dd,J=6.8,2.0Hz,1H),7.70(d,J=6.8Hz,1H),3.95(s,3H),3.92(s,3H)。
Compound 8-2 (16 g, 81.98 mmol) and dichloromethane (80 mL) were added to the pre-dried reaction flask, the temperature was lowered to 0° C., and m-chloroperoxybenzoic acid (33.29 g, 163.96 mmol) was slowly added. The temperature was gradually raised to 20°C and stirred for 6 hours. After the completion of the reaction, add saturated aqueous sodium sulfite solution (400 mL) to the reaction solution until the starch potassium iodide test paper does not appear blue, and add saturated aqueous sodium carbonate solution to adjust the pH to 10. Extract with dichloromethane (400 mL*2), collect the organic phase, wash with saturated brine (200 mL), dry over anhydrous sodium sulfate, and concentrate to obtain compound 8-3. 1 H NMR (400MHz, CDCl 3 ) δppm 8.34 (s, 1H), 8.25 (dd, J=6.8, 2.0 Hz, 1H), 7.70 (d, J=6.8 Hz, 1H), 3.95 (s, 3H), 3.92(s, 3H).
步骤3:化合物8-4的合成Step 3: Synthesis of Compounds 8-4
在预先干燥的反应瓶中加入三氯氧磷(266.04g,1.74mol),后加入化合物8-3(15.8g,74.82mmol)。氮气置换三次,100℃搅拌16小时。反应完成后,反应液缓慢滴加入水(200mL)中淬灭,用饱和碳酸钠水溶液调pH至10,用乙酸乙酯(200mL*2)萃取反应液,收集有机相,饱和食盐水(200mL)洗涤,无水硫酸钠干燥,浓缩。粗品经柱层析(石油醚:乙酸乙酯=3:1)分离得到化合物8-4。
1H NMR(400MHz,CDCl
3)δppm 8.87(s,1H),7.51(s,1H),3.95(s,3H),3.94(s,3H)。
Phosphorus oxychloride (266.04 g, 1.74 mol) was added to the pre-dried reaction flask, followed by compound 8-3 (15.8 g, 74.82 mmol). Nitrogen was replaced three times, and the mixture was stirred at 100°C for 16 hours. After the reaction was completed, the reaction solution was slowly added dropwise to water (200 mL) to quench, the pH was adjusted to 10 with saturated aqueous sodium carbonate solution, the reaction solution was extracted with ethyl acetate (200 mL*2), the organic phase was collected, saturated brine (200 mL) Washed, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by column chromatography (petroleum ether:ethyl acetate=3:1) to obtain compound 8-4. 1 H NMR (400 MHz, CDCl 3 ) δ ppm 8.87 (s, 1H), 7.51 (s, 1H), 3.95 (s, 3H), 3.94 (s, 3H).
步骤4:化合物8-5的合成Step 4: Synthesis of Compounds 8-5
在预先干燥的反应瓶中加入化合物8-4(3.3g,14.37mmol),无水甲醇(16.5mL)与无水四氢呋喃(33mL)。氮气保护下降低反应液温度至0℃,分批加入硼氢化钠(2.80g,74.08mmol)。0℃下搅拌2小时。反应完成后,反应液中加入盐酸水溶液(1M)调pH至6左右,加入饱和碳酸钠水溶液调pH至11,减压浓缩,加入二氯甲烷(100mL),甲醇(10mL)。过滤,滤液减压浓缩得到化合物8-5。
1H NMR(400MHz,CD
3OD)δppm 8.01(s,1H),7.15(s,1H),4.75(s,2H),4.63(s,2H)。
Compound 8-4 (3.3 g, 14.37 mmol), anhydrous methanol (16.5 mL) and anhydrous tetrahydrofuran (33 mL) were added to a pre-dried reaction flask. The temperature of the reaction solution was lowered to 0°C under nitrogen protection, and sodium borohydride (2.80 g, 74.08 mmol) was added in portions. Stir at 0°C for 2 hours. After the reaction was completed, aqueous hydrochloric acid (1M) was added to the reaction solution to adjust pH to about 6, saturated aqueous sodium carbonate solution was added to adjust pH to 11, concentrated under reduced pressure, dichloromethane (100 mL) and methanol (10 mL) were added. After filtration, the filtrate was concentrated under reduced pressure to obtain compound 8-5. 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.01 (s, 1H), 7.15 (s, 1H), 4.75 (s, 2H), 4.63 (s, 2H).
步骤5:化合物8-6的合成Step 5: Synthesis of Compounds 8-6
在预先干燥的反应瓶中加入化合物8-5(900mg,5.18mmol),二氯甲烷(36mL),然后加入二氧化锰(2.25g,25.92mmol)。-5~0℃下加入三乙基硅烷(2.71g,23.33mmol),15min内滴加三氟乙酸(8.87g,77.77mmol),-5~0℃下搅拌1小时。20℃下搅拌16小时。反应完成后,向反应液中加入甲醇(5mL),过滤,滤液减压浓缩。柱层析(石油醚:乙酸乙酯=3:1)分离得到化合物8-6。
1H NMR(400MHz,MeOD)δppm 8.29(s,1H),7.42(s,1H),5.09(s,2H),5.06(s,2H)。
To a pre-dried reaction flask was added compound 8-5 (900 mg, 5.18 mmol), dichloromethane (36 mL), followed by manganese dioxide (2.25 g, 25.92 mmol). Triethylsilane (2.71 g, 23.33 mmol) was added at -5 to 0 °C, trifluoroacetic acid (8.87 g, 77.77 mmol) was added dropwise within 15 min, and the mixture was stirred at -5 to 0 °C for 1 hour. Stir at 20°C for 16 hours. After the reaction was completed, methanol (5 mL) was added to the reaction solution, filtered, and the filtrate was concentrated under reduced pressure. Column chromatography (petroleum ether:ethyl acetate=3:1) isolated compound 8-6. 1 H NMR (400 MHz, MeOD) δ ppm 8.29 (s, 1H), 7.42 (s, 1H), 5.09 (s, 2H), 5.06 (s, 2H).
步骤6:化合物8-7的合成Step 6: Synthesis of Compounds 8-7
在预先干燥的反应瓶中加入化合物8-6(0.15g,964.13μmol),水合肼(492.49mg,9.64mmol),反应液在120℃搅拌6小时。反应完成后,反应液直接浓缩得到化合物8-7,不纯化直接用于下一步反应。Compound 8-6 (0.15 g, 964.13 μmol) and hydrazine hydrate (492.49 mg, 9.64 mmol) were added to the pre-dried reaction flask, and the reaction solution was stirred at 120° C. for 6 hours. After the completion of the reaction, the reaction solution was directly concentrated to obtain compound 8-7, which was directly used in the next reaction without purification.
步骤7:化合物8的合成Step 7: Synthesis of Compound 8
在预先干燥的反应瓶中加入化合物ST-2(0.1g,284.74μmol),8-7(129.13mg,854.21μmol),四氢呋喃(0.5mL),乙酸乙酯(0.5mL),N,N-二异丙基乙胺(73.60mg,569.47μmol),丙烷磷酸酐50%乙酸乙酯溶液(271.79mg,427.10μmol),反应液在0℃下搅拌1小时。反应完成后,向反应液中加入水(5mL),用乙酸乙酯(10mL*3)萃取反应液,收集有机相,饱和食盐水(10mL)洗涤,无水硫酸钠干燥,浓缩。粗品经制备高效液相色谱(色谱柱:Waters Xbridge BEH C18 100*30mm*10μm;流动相:[水(10mM NH
4HCO
3)-ACN];B(乙腈)%:30%-50%,8min)分离得到化合物8。
1H NMR(400MHz,CD
3OD)δppm 9.60(s,1H),8.61(s,2H),8.06-8.00(m,2H),7.45(d,J=10.8Hz,1H),6.71(s,1H),6.06(d,J=10.0Hz,1H),4.99(s,2H),4.89(s,2H)。
Compound ST-2 (0.1 g, 284.74 μmol), 8-7 (129.13 mg, 854.21 μmol), tetrahydrofuran (0.5 mL), ethyl acetate (0.5 mL), N,N-dihydrofuran were added to the pre-dried reaction flask. Isopropylethylamine (73.60 mg, 569.47 μmol), propane phosphoric anhydride 50% ethyl acetate solution (271.79 mg, 427.10 μmol), the reaction solution was stirred at 0° C. for 1 hour. After the reaction was completed, water (5 mL) was added to the reaction solution, the reaction solution was extracted with ethyl acetate (10 mL*3), the organic phase was collected, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was subjected to preparative high performance liquid chromatography (chromatographic column: Waters Xbridge BEH C18 100*30mm*10μm; mobile phase: [water (10mM NH 4 HCO 3 )-ACN]; B (acetonitrile)%: 30%-50%, 8min ) was isolated to give compound 8. 1 H NMR (400MHz, CD 3 OD) δppm 9.60(s, 1H), 8.61(s, 2H), 8.06-8.00(m, 2H), 7.45(d, J=10.8Hz, 1H), 6.71(s, 1H), 6.06(d, J=10.0Hz, 1H), 4.99(s, 2H), 4.89(s, 2H).
实施例9Example 9
合成路线:synthetic route:
步骤1:化合物9-3的合成Step 1: Synthesis of Compounds 9-3
在预先干燥的反应瓶中加入化合物6-1(2g,8.19mmol),乙醇(10mL),将化合物9-2(1.13g,12.86mmol)和水(10mL)的混合液加入反应瓶中,反应液在20℃搅拌0.5小时。反应完成后,反应液中加入水(20mL),用乙酸乙酯(40mL*3)萃取反应液,收集有机相,饱和食盐水(30mL)洗涤有机相,无水硫酸钠干燥,浓缩。得化合物9-3。MS-ESI m/z:313.0[M-H]
+。
Compound 6-1 (2 g, 8.19 mmol), ethanol (10 mL) were added to the pre-dried reaction flask, and a mixture of compound 9-2 (1.13 g, 12.86 mmol) and water (10 mL) was added to the reaction flask, and the reaction was carried out. The solution was stirred at 20°C for 0.5 hours. After the reaction was completed, water (20 mL) was added to the reaction solution, the reaction solution was extracted with ethyl acetate (40 mL*3), the organic phase was collected, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated. Compound 9-3 was obtained. MS-ESI m/z: 313.0 [MH] + .
步骤2:化合物9-4的合成Step 2: Synthesis of Compounds 9-4
在预先干燥的反应瓶中加入化合物9-3(2.5g,7.96mmol),甲苯(20mL),加入三乙胺(805.17mg,7.96mmol),叠氮磷酸二苯酯(2.19g,7.96mmol,1.72mL),反应液在110℃搅拌16小时。反应完成后,反应液中加入水(100mL),用乙酸乙酯(80mL*3)萃取反应液,收集有机相,饱和食盐水(60mL)洗涤有机相,无水硫酸钠干燥,浓缩。粗品中加入乙醇(20mL),搅拌10分钟,过滤,收集滤饼,得到化合物9-4,不纯化直接用于下一步反应。Compound 9-3 (2.5 g, 7.96 mmol), toluene (20 mL), triethylamine (805.17 mg, 7.96 mmol), diphenylphosphoryl azide (2.19 g, 7.96 mmol) were added to the pre-dried reaction flask, 1.72 mL), the reaction solution was stirred at 110 °C for 16 hours. After the reaction was completed, water (100 mL) was added to the reaction solution, the reaction solution was extracted with ethyl acetate (80 mL*3), the organic phase was collected, washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, and concentrated. Ethanol (20 mL) was added to the crude product, stirred for 10 minutes, filtered, and the filter cake was collected to obtain compound 9-4, which was directly used in the next reaction without purification.
步骤3:化合物9-5的合成Step 3: Synthesis of Compounds 9-5
在预先干燥的反应瓶中加入化合物9-4(1.55g,4.98mmol),三乙烯二胺(1.12g,9.96mmol),N,N-二甲基甲酰胺(15mL),将反应液冷却至0℃,将化合物ST-1(1.69g,7.47mmol)加入反应液中,反应液在0℃搅拌6小时。反应完成后,反应液中加入水(20mL),用乙酸乙酯(40mL*3)萃取反应液,收集有机相,饱和食盐水(30mL)洗涤有机相,无水硫酸钠干燥,浓缩。柱层析(石油醚:乙酸乙酯=1:1)分离得化合物9-5。MS- ESI m/z:410.0[M+H]
+。
Compound 9-4 (1.55 g, 4.98 mmol), triethylenediamine (1.12 g, 9.96 mmol), N,N-dimethylformamide (15 mL) were added to the pre-dried reaction flask, and the reaction solution was cooled to At 0°C, compound ST-1 (1.69 g, 7.47 mmol) was added to the reaction solution, and the reaction solution was stirred at 0°C for 6 hours. After the reaction was completed, water (20 mL) was added to the reaction solution, the reaction solution was extracted with ethyl acetate (40 mL*3), the organic phase was collected, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated. Compound 9-5 was isolated by column chromatography (petroleum ether:ethyl acetate=1:1). MS-ESI m/z: 410.0 [M+H] + .
步骤4:化合物9-6的合成Step 4: Synthesis of Compounds 9-6
在预先干燥的反应瓶中加入化合物9-5(0.11g,268.76μmol),四氢呋喃(3mL),将反应液冷却至0℃,将氢氧化锂(33.83mg,806.29μmol)和水(3mL)在0℃滴加入反应瓶中,反应液在0℃搅拌1小时。反应完成后,将1M盐酸滴加入反应瓶中,调节pH至4-5,用乙酸乙酯(40mL*3)萃取反应液,收集有机相,饱和食盐水(30mL)洗涤有机相,无水硫酸钠干燥,浓缩得化合物9-6,不纯化直接用于下一步反应。MS-ESI m/z:382.0[M+H]
+。
Compound 9-5 (0.11 g, 268.76 μmol), tetrahydrofuran (3 mL) were added to the pre-dried reaction flask, the reaction solution was cooled to 0°C, and lithium hydroxide (33.83 mg, 806.29 μmol) and water (3 mL) were mixed in It was added dropwise to the reaction flask at 0°C, and the reaction solution was stirred at 0°C for 1 hour. After the reaction was completed, 1M hydrochloric acid was added dropwise to the reaction flask, the pH was adjusted to 4-5, the reaction solution was extracted with ethyl acetate (40mL*3), the organic phase was collected, the organic phase was washed with saturated brine (30mL), and anhydrous sulfuric acid was used to wash the organic phase. It was dried over sodium and concentrated to obtain compound 9-6, which was used in the next reaction without purification. MS-ESI m/z: 382.0 [M+H] + .
步骤5:化合物9的合成Step 5: Synthesis of Compound 9
在预先干燥的反应瓶中加入化合物9-6(0.09g,236.08μmol),四氢呋喃(1mL),乙酸乙酯(1mL),N,N-二异丙基乙胺(122.05mg,944.31μmol),丙烷磷酸酐50%乙酸乙酯溶液(300.46mg,472.16μmol),1-8(31.20mg,283.29μmol)依次加入反应瓶中,反应液在0℃搅拌1小时。反应完成后,反应液中加入水(20mL),用乙酸乙酯(40mL*3)萃取反应液,收集有机相,饱和食盐水(30mL)洗涤有机相,无水硫酸钠干燥,浓缩。粗品经制备高效液相色谱(色谱柱:Phenomenex Gemini-NX 80*40mm*3μm;流动相:[water(10mM NH
4HCO
3)-ACN];B(乙腈)%:20%-50%,8min)分离得化合物9。
1H NMR(400MHz,CD
3OD)δppm 2.34(s,3H),6.39(d,J=8.91Hz,1H),6.78(d,J=8.91Hz,1H),7.78(s,1H),7.90(d,J=2.89Hz,1H),8.03(dd,J=2.70,1.44Hz,1H),8.14(d,J=1.38Hz,1H),8.54(s,2H)。
Compound 9-6 (0.09 g, 236.08 μmol), tetrahydrofuran (1 mL), ethyl acetate (1 mL), N,N-diisopropylethylamine (122.05 mg, 944.31 μmol) were added to a pre-dried reaction flask, Propane phosphoric anhydride 50% ethyl acetate solution (300.46 mg, 472.16 μmol), 1-8 (31.20 mg, 283.29 μmol) were sequentially added to the reaction flask, and the reaction solution was stirred at 0° C. for 1 hour. After the reaction was completed, water (20 mL) was added to the reaction solution, the reaction solution was extracted with ethyl acetate (40 mL*3), the organic phase was collected, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was subjected to preparative high performance liquid chromatography (chromatographic column: Phenomenex Gemini-NX 80*40mm*3μm; mobile phase: [water(10mM NH 4 HCO 3 )-ACN]; B (acetonitrile)%: 20%-50%, 8min ) to isolate compound 9. 1 H NMR (400 MHz, CD 3 OD) δppm 2.34 (s, 3H), 6.39 (d, J=8.91 Hz, 1H), 6.78 (d, J=8.91 Hz, 1H), 7.78 (s, 1H), 7.90 (d, J=2.89 Hz, 1H), 8.03 (dd, J=2.70, 1.44 Hz, 1H), 8.14 (d, J=1.38 Hz, 1H), 8.54 (s, 2H).
实施例10Example 10
合成路线:synthetic route:
步骤1:化合物10-3的合成Step 1: Synthesis of Compound 10-3
在预先干燥的反应瓶中加入化合物10-2(1.5g,16.65mmol)和化合物10-1(35.64g,240.49mmol),氮气保护下在88℃搅拌16小时。反应液浓缩。粗品中加石油醚(5mL),乙酸乙酯(10mL),搅拌10分钟,过滤,收集滤液,浓缩得化合物10-3,不纯化直接用于下一步反应。Compound 10-2 (1.5 g, 16.65 mmol) and compound 10-1 (35.64 g, 240.49 mmol) were added to the pre-dried reaction flask, and the mixture was stirred at 88° C. for 16 hours under nitrogen protection. The reaction solution was concentrated. Petroleum ether (5 mL) and ethyl acetate (10 mL) were added to the crude product, stirred for 10 minutes, filtered, and the filtrate was collected and concentrated to obtain compound 10-3, which was directly used in the next reaction without purification.
步骤2:化合物10-5的合成Step 2: Synthesis of Compound 10-5
在预先干燥的反应瓶中加入化合物10-3(956.77mg,6.55mmol),10-4(0.5g,2.18mmol,337.84μL),乙醇(10mL),在50℃搅拌36小时。反应完成后,反应液浓缩得化合物10-5,不纯化直接用于下一步反应。MS-ESI m/z:330.0[M+H]
+。
Compound 10-3 (956.77 mg, 6.55 mmol), 10-4 (0.5 g, 2.18 mmol, 337.84 μL), ethanol (10 mL) were added to a pre-dried reaction flask, and the mixture was stirred at 50° C. for 36 hours. After the reaction was completed, the reaction solution was concentrated to obtain compound 10-5, which was directly used in the next reaction without purification. MS-ESI m/z: 330.0 [M+H] + .
步骤3:化合物10-6的合成Step 3: Synthesis of Compound 10-6
在预先干燥的反应瓶中加入化合物10-5(0.7g,2.13mmol),乙醇(10mL),甲醇钠(8.51mmol),在75℃搅拌4小时。反应完成后,反应液中加入水(10mL),反应液浓缩得到混悬液,用乙酸乙酯(40mL*3)萃取反应液,收集有机相,饱和食盐水(30mL)洗涤有机相,无水硫酸钠干燥,浓缩。粗品通过柱层析(石油醚:乙酸乙酯=1:1)分离得化合物10-6。MS-ESI m/z:298.1[M+H]
+。
Compound 10-5 (0.7 g, 2.13 mmol), ethanol (10 mL), and sodium methoxide (8.51 mmol) were added to a pre-dried reaction flask, and the mixture was stirred at 75° C. for 4 hours. After the reaction was completed, water (10 mL) was added to the reaction solution, the reaction solution was concentrated to obtain a suspension, the reaction solution was extracted with ethyl acetate (40 mL*3), the organic phase was collected, and the organic phase was washed with saturated brine (30 mL), and anhydrous Dry over sodium sulfate and concentrate. The crude product was separated by column chromatography (petroleum ether:ethyl acetate=1:1) to obtain compound 10-6. MS-ESI m/z: 298.1 [M+H] + .
步骤4:化合物10-7的合成Step 4: Synthesis of Compound 10-7
在预先干燥的反应瓶中加入化合物10-6(0.25g,841.31μmol),N,N-二甲基甲酰胺(2mL),三乙烯二胺(188.74mg,1.68mmol),将化合物ST-1(228.17mg,1.01mmol)在0℃缓慢加入反应瓶中,0℃搅拌6小时。反应完成后,反应液中加入水(20mL),用乙酸乙酯(40mL*3)萃取反应液,收集有机相,饱和食盐水(30mL)洗涤有机相,无水硫酸钠干燥,浓缩。粗品通过prep-TLC(石油醚:乙酸乙酯=3:1)分离纯化得化合物10-7。MS-ESI m/z:396.0[M+H]
+。
Compound 10-6 (0.25 g, 841.31 μmol), N,N-dimethylformamide (2 mL), triethylenediamine (188.74 mg, 1.68 mmol) were added to the pre-dried reaction flask, compound ST-1 (228.17 mg, 1.01 mmol) was slowly added to the reaction flask at 0°C, and stirred at 0°C for 6 hours. After the reaction was completed, water (20 mL) was added to the reaction solution, the reaction solution was extracted with ethyl acetate (40 mL*3), the organic phase was collected, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was separated and purified by prep-TLC (petroleum ether:ethyl acetate=3:1) to obtain compound 10-7. MS-ESI m/z: 396.0 [M+H] + .
步骤5:化合物10-8的合成Step 5: Synthesis of Compound 10-8
在预先干燥的反应瓶中加入化合物10-7(0.1g,253.00μmol),四氢呋喃(3mL),将反应液冷却至0℃,将氢氧化锂(31.85mg,759.00μmol)和水(3mL)的混合液在0℃滴加入反应液中,在0℃搅拌1小时。反应完成后,反应液中加入1M盐酸水溶液调节pH至4-5,反应液中加入水(20mL),用乙酸乙酯(40mL*3)萃取反应液,收集有机相,饱和食盐水(30mL)洗涤有机相,无水硫酸钠干燥,浓缩,得化合物10-8,不做纯化直接用于下一步反应。MS-ESI m/z:368.0[M+H]
+。
Compound 10-7 (0.1 g, 253.00 μmol), tetrahydrofuran (3 mL) were added to a pre-dried reaction flask, the reaction solution was cooled to 0°C, and a mixture of lithium hydroxide (31.85 mg, 759.00 μmol) and water (3 mL) was added. The mixed solution was added dropwise to the reaction solution at 0°C, followed by stirring at 0°C for 1 hour. After the reaction was completed, 1M aqueous hydrochloric acid was added to the reaction solution to adjust the pH to 4-5, water (20mL) was added to the reaction solution, the reaction solution was extracted with ethyl acetate (40mL*3), the organic phase was collected, saturated brine (30mL) The organic phase was washed, dried over anhydrous sodium sulfate, and concentrated to obtain compound 10-8, which was directly used in the next reaction without purification. MS-ESI m/z: 368.0 [M+H] + .
步骤6:化合物10的合成Step 6: Synthesis of Compound 10
在预先干燥的反应瓶中加入化合物10-8(0.1g,272.33μmol),N,N-二甲基甲酰胺(2mL),将反应液冷却至0℃,依次加入N,N-二异丙基乙胺(105.59mg,816.99μmol),丙烷磷酸酐50%乙酸乙酯溶液(259.95mg,408.50μmol),1-8(44.98mg,408.50μmol),在0℃搅拌1小时。反应完成后,反应液中加入水(20mL),用乙酸乙酯(40mL*3)萃取反应液,收集有机相,饱和食盐水(30mL)洗涤有机相,无水硫酸钠干燥,浓缩。粗品经制备高效液相色谱(色谱柱:Waters Xbridge BEH C18 100*30mm*10μm;流动相:[水(10mM NH
4HCO
3)-ACN];B(乙腈)%:20%-50%,8min)分离得化合物10。
Compound 10-8 (0.1 g, 272.33 μmol) and N,N-dimethylformamide (2 mL) were added to the pre-dried reaction flask, the reaction solution was cooled to 0°C, and N,N-diisopropyl was added in sequence Ethylamine (105.59 mg, 816.99 μmol), propane phosphoric anhydride 50% in ethyl acetate (259.95 mg, 408.50 μmol), 1-8 (44.98 mg, 408.50 μmol), stirred at 0° C. for 1 hour. After the reaction was completed, water (20 mL) was added to the reaction solution, the reaction solution was extracted with ethyl acetate (40 mL*3), the organic phase was collected, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was subjected to preparative high performance liquid chromatography (chromatographic column: Waters Xbridge BEH C18 100*30mm*10μm; mobile phase: [water (10mM NH 4 HCO 3 )-ACN]; B (acetonitrile)%: 20%-50%, 8min ) to isolate compound 10.
1H NMR(400MHz,CD
3OD)δppm 5.78(d,J=10.29Hz,1H),7.06(d,J=10.29Hz,1H),7.95(d,J=2.76Hz,1H),8.03(s,1H),8.10(dd,J=2.70,1.44Hz,1H),8.34(d,J=1.38Hz,1H),8.43(s,2H),8.68(s,1H)。
1 H NMR (400MHz, CD 3 OD) δppm 5.78 (d, J=10.29 Hz, 1H), 7.06 (d, J=10.29 Hz, 1H), 7.95 (d, J=2.76 Hz, 1H), 8.03 (s , 1H), 8.10 (dd, J=2.70, 1.44Hz, 1H), 8.34 (d, J=1.38Hz, 1H), 8.43 (s, 2H), 8.68 (s, 1H).
实施例11Example 11
合成路线:synthetic route:
步骤1:化合物11-2的合成Step 1: Synthesis of Compound 11-2
氮气条件下,向预先干燥好的反应瓶中加入化合物11-1(500mg,4.42mmol)和N,N-二甲基甲酰胺(20mL)后,0℃下加入氢化钠(265.00mg,6.63mmol),搅拌20分钟后,加入二苯基膦酰羟胺(1.55g,6.65mmol),升高反应温度至25℃,反应16小时。反应液过滤,滤液浓缩得粗产品化合物11-2,不纯化直接用于下一步反应。MS-ESI m/z:129.2[M+H]
+。
Under nitrogen, compound 11-1 (500 mg, 4.42 mmol) and N,N-dimethylformamide (20 mL) were added to the pre-dried reaction flask, and then sodium hydride (265.00 mg, 6.63 mmol) was added at 0°C. ), after stirring for 20 minutes, diphenylphosphonamide (1.55 g, 6.65 mmol) was added, the reaction temperature was raised to 25° C., and the reaction was carried out for 16 hours. The reaction solution was filtered, and the filtrate was concentrated to obtain the crude product compound 11-2, which was directly used in the next reaction without purification. MS-ESI m/z: 129.2 [M+H] + .
步骤2:化合物11的合成Step 2: Synthesis of Compound 11
向预先干燥好的反应瓶中加入化合物6-6(100mg,272.33μmol),乙酸乙酯(3mL)和四氢呋喃(3mL),后降低反应液温度至-60℃,之后加入化合物11-2(53mg,413.65μmol),丙烷磷酸酐50%乙酸乙酯溶液(171.20mg,538.06μmol)并滴加N,N-二异丙基乙胺(140.98mg,1.09mmol),后在20℃下继续反应16小时。反应完成后,反应液浓缩得粗品。粗品经制备高效液相色谱(Welch Xtimate C18 100*40mm*3μm;流动相:[水(0.075%TFA)-ACN];B(乙腈)%:50%-80%,8min)分离得到化合物11。Compound 6-6 (100 mg, 272.33 μmol), ethyl acetate (3 mL) and tetrahydrofuran (3 mL) were added to the pre-dried reaction flask, and then the temperature of the reaction solution was lowered to -60°C, and then compound 11-2 (53 mg) was added. , 413.65 μmol), propane phosphoric anhydride 50% ethyl acetate solution (171.20 mg, 538.06 μmol) and N,N-diisopropylethylamine (140.98 mg, 1.09 mmol) was added dropwise, and the reaction was continued at 20 ° C for 16 Hour. After the reaction was completed, the reaction solution was concentrated to obtain a crude product. The crude product was separated by preparative high performance liquid chromatography (Welch Xtimate C18 100*40mm*3μm; mobile phase: [water (0.075% TFA)-ACN]; B (acetonitrile)%: 50%-80%, 8min) to obtain compound 11.
1H NMR(400MHz,DMSO-d
6)δppm 3.83(s,3H)4.13(s,2H)5.31(s,1H)5.89(d,J=10.29Hz,1H)6.91(d,J=10.29Hz,1H)8.06(s,1H)8.49(s,2H)9.09(s,1H)10.59(s,1H)。
1 H NMR (400MHz, DMSO-d 6 )δppm 3.83(s,3H)4.13(s,2H)5.31(s,1H)5.89(d,J=10.29Hz,1H)6.91(d,J=10.29Hz, 1H) 8.06(s, 1H) 8.49(s, 2H) 9.09(s, 1H) 10.59(s, 1H).
实验例1:肿瘤细胞抗增殖活性(IC
50)测试
Experimental Example 1: Anti-proliferative activity (IC 50 ) test of tumor cells
1.把对数生长期的肿瘤(前列腺癌22Rv1)细胞悬液接种于96孔培养板;每孔4000个细胞,每孔加入90μL细胞悬液,37℃,5%CO
2培养箱中培养48小时。待细胞贴壁后,分别加入适当浓度的受试化合物和阳性对照药物,配置八种不同浓度的样品,以空白对照组为阴性对照组,在培养箱中培养72小时。然后每孔加入50μL的CellTiter-Glo工作液,用铝箔纸包裹细胞板以避光。将培养板在轨道摇床上振摇2分钟以诱导细胞裂解,培养板在室温放置10分钟以稳定发光信号。EnVision读板器上检测发光信号,计算抑制率。
1. Inoculate the tumor (prostate cancer 22Rv1) cell suspension in the logarithmic growth phase in a 96-well culture plate; 4000 cells per well, add 90 μL of cell suspension to each well, and culture 48 in a 37°C, 5% CO 2 incubator. Hour. After the cells adhered, appropriate concentrations of the test compound and positive control drug were added to prepare eight samples of different concentrations. The blank control group was used as the negative control group, and the cells were incubated in an incubator for 72 hours. Then add 50 μL of CellTiter-Glo working solution to each well, and wrap the cell plate with aluminum foil to protect from light. The plates were shaken on an orbital shaker for 2 minutes to induce cell lysis, and the plates were left at room temperature for 10 minutes to stabilize the luminescent signal. The luminescent signal was detected on the EnVision plate reader and the inhibition rate was calculated.
2.把对数生长期的肿瘤(大B细胞淋巴瘤Toledo和多发性骨髓瘤MM1.S)细胞悬液分别接种于384孔培养板;每孔3000个细胞,每孔加入40μL细胞悬液,37℃,5%CO
2培养箱中培养24小时。待细胞贴壁后,分别加入适当浓度的受试化合物和阳性对照药物,配置十种不同浓度的样品,以空白对照组为阴性对照组,在培养箱中培养120小时。然后根据CTG检测方法计算抑制率。
2. Inoculate the cell suspensions of the tumors in the logarithmic growth phase (large B-cell lymphoma Toledo and multiple myeloma MM1.S) in a 384-well culture plate; 3000 cells per well, 40 μL of cell suspension are added to each well, Incubate for 24 hours in a 37°C, 5% CO 2 incubator. After the cells adhered, appropriate concentrations of the test compound and positive control drug were added to prepare ten samples of different concentrations. The blank control group was used as the negative control group, and the cells were incubated in an incubator for 120 hours. The inhibition rate was then calculated according to the CTG detection method.
3.把对数生长期的肿瘤(大B细胞淋巴瘤TMD8)细胞悬液接种于96孔培养板;每孔1.5*10
4个细胞,每孔加入75μL细胞悬液,37℃,5%CO
2培养箱中培养24小时。待细胞贴壁后,分别加入适当浓度的受试化合物和阳性对照药物,配置九种不同浓度的样品,以空白对照组为阴性对照组,在培养箱中培养72小时。然后根据CTG检测方法计算抑制率。
3. Inoculate the tumor (large B-cell lymphoma TMD8) cell suspension in logarithmic growth phase in a 96-well culture plate; 1.5*10 4 cells per well, add 75 μL of cell suspension to each well, 37°C, 5% CO 2 in an incubator for 24 hours. After the cells adhered to the wall, appropriate concentrations of the test compound and positive control drug were added to prepare nine samples of different concentrations, and the blank control group was used as the negative control group, and incubated in an incubator for 72 hours. The inhibition rate was then calculated according to the CTG detection method.
实验结果:见表1。Experimental results: see Table 1.
表1:本发明化合物体外肿瘤细胞抗增殖活性测试结果Table 1: In vitro tumor cell antiproliferative activity test results of the compounds of the present invention
供试品testing sample | 22Rv1(μM)22Rv1(μM) | Toledo(μM)Toledo(μM) | MM1.S(μM)MM1.S(μM) | TMD8(μM)TMD8(μM) |
化合物6Compound 6 | 0.0770.077 | 0.0490.049 | 0.0260.026 | 0.0730.073 |
化合物11Compound 11 | 0.0130.013 | 0.0100.010 | 0.0040.004 | 0.0050.005 |
SelinexorSelinexor | 0.0720.072 | 0.0840.084 | 0.0400.040 | 0.1410.141 |
结论:本发明化合物具有优异的体外抗增殖活性。Conclusion: The compounds of the present invention have excellent in vitro antiproliferative activity.
实验例2:体内研究Experimental Example 2: In vivo study
人淋巴瘤TMD8细胞SCID小鼠系统性模型:Human lymphoma TMD8 cell SCID mouse systemic model:
使用人淋巴瘤TMD8细胞SCID小鼠系统性模型,对受试物单独给药的生命延长活性进行评价。本研究使用人淋巴瘤TMD8细胞,尾静脉接种建立SCID小鼠系统性模型,对Selinexor和化合物6单独给药的抗肿瘤作用进行评价。受试物Selinexor和本发明化合物均溶于1%泊洛沙姆188+1%聚乙烯吡咯烷酮的溶媒中每周3次口服给药,持续给药至实验结束(口服给药,隔日一次×3/周,15mg/kg第0-8天+10mg/kg第9-37天)。Using the human lymphoma TMD8 cell SCID mouse systemic model, the life-extending activity of the test substance administered alone was evaluated. In this study, human lymphoma TMD8 cells were used to establish a systemic model of SCID mice by tail vein inoculation, and the antitumor effects of Selinexor and compound 6 alone were evaluated. The test substance Selinexor and the compound of the present invention were both dissolved in the vehicle of 1% poloxamer 188+1% polyvinylpyrrolidone and administered orally three times a week, and continued to be administered until the end of the experiment (oral administration, once every other day × 3 /week, 15mg/kg day 0-8 + 10mg/kg day 9-37).
TMD8细胞培养于含10%FBS的RPMI-1640培养基,维持在5%CO
2的37℃饱和湿度培养箱中。收集对数生长期TMD8细胞,重悬于PBS中,调整细胞浓度至5×10
7/mL。在无菌条件下,尾静脉接种0.2mL细胞悬液至小鼠体内,接种终浓度为10×10
6/0.2mL PBS/小鼠。接种后18天,将动物按体重随机分组, 使各组动物体重差异差异小于均值的10%。
TMD8 cells were cultured in RPMI-1640 medium containing 10% FBS, maintained in a 37°C saturated humidity incubator with 5% CO 2 . TMD8 cells in logarithmic growth phase were collected, resuspended in PBS, and the cell concentration was adjusted to 5×10 7 /mL. Under sterile conditions, 0.2 mL of cell suspension was inoculated into mice via tail vein, and the final concentration of inoculation was 10×10 6 /0.2 mL PBS/mouse. 18 days after inoculation, animals were randomly divided into groups according to body weight, so that the difference in body weight of each group was less than 10% of the mean.
根据动物福利相关规定,实验期间如果个别实验动物符合以下任一条件,该动物将从实验组中移除并施以安乐死。1、动物体重与第0天相比下降超过20%(BWL≥20%);2、动物出现严重不良反应,如失明、瘫痪等。个别动物到达动物福利终点,进行最后一次称量后施以CO
2安乐死。同组中的剩余动物继续给药观察,直至到达动物福利终点或实验终点。
According to relevant regulations on animal welfare, if an individual experimental animal meets any of the following conditions during the experiment, the animal will be removed from the experimental group and euthanized. 1. The body weight of the animals decreased by more than 20% compared with the 0th day (BWL≥20%); 2. The animals had serious adverse reactions, such as blindness, paralysis, etc. Individual animals reached the animal welfare endpoint and were euthanized with CO 2 after their final weighing. The remaining animals in the same group continue to be administered and observed until the animal welfare endpoint or experimental endpoint is reached.
评价指标:Evaluation indicators:
中位生存时间(Median Survival Time,MST)计算公式为:累积生存率为50%时,所对应的生存时间(分组给药当天记为第0天),具体数值由GraphPad Prism 6软件(San Diego,CA,USA)计算得出;The median survival time (Median Survival Time, MST) calculation formula is: when the cumulative survival rate is 50%, the corresponding survival time (the day of group administration is recorded as day 0), the specific value is determined by GraphPad Prism 6 software (San Diego , CA, USA) is calculated;
相对生命延长率(%T/CMST)计算公式为:TMST/CMST×100%,其中TMST为治疗组MST,CMST为阴性对照组MST;The relative life extension rate (%T/CMST) was calculated as: TMST/CMST×100%, where TMST was the MST of the treatment group, and CMST was the MST of the negative control group;
以相对生命延长率%T/CMST评价实验的治疗效果时,评价标准以125%为界,当%T/CMST≥125%并经统计学分析P<0.05时,视为有生命延长活性,反之则无。药物相关动物死亡数超过20%,则认为该药物剂量具有严重毒性。When the relative life extension rate %T/CMST was used to evaluate the therapeutic effect of the experiment, the evaluation standard was 125%. When the %T/CMST≥125% and the statistical analysis P<0.05, it was regarded as having life extension activity, and vice versa. No. A drug-related dose of more than 20% of animals was considered to be severely toxic.
实验结果:Experimental results:
如表2中所示,化合物6的相对生命延长率为150%,而Selinexor的相对生命延长率为133.33%。当溶媒组小鼠全部死亡时(第25天),Selinexor组小鼠也全部死亡,生存率为0%,而化合物6组的生存率为50%。As shown in Table 2, the relative life extension rate of compound 6 was 150%, while that of Selinexor was 133.33%. When all the mice in the vehicle group died (day 25), all the mice in the Selinexor group also died, and the survival rate was 0%, while the survival rate of the compound 6 group was 50%.
表2:TMD8系统模型药效研究结果Table 2: Results of the efficacy study of the TMD8 system model
化合物compound | MST(天)MST(day) | %T/CMST(%)%T/CMST(%) | 生存率(%,第25天)Survival rate (%, day 25) |
溶媒组vehicle group | 1818 | // | 00 |
SelinexorSelinexor | 24*twenty four* | 133.33133.33 | 00 |
化合物6Compound 6 | 27*27* | 150150 | 5050 |
*:P<0.05相对于溶媒组*:P<0.05 vs vehicle group
结论:综合评估Selinexor组和化合物6组的相对生命延长率和第25天(溶媒组动物全部死亡)的小鼠生存率,化合物6在该模型中初步展现出优于Selinexor的生命延长活性,且没有明显的药物毒副作用。Conclusion: The relative life extension rate of Selinexor group and compound 6 group and the survival rate of mice on day 25 (all animals in vehicle group died) were comprehensively evaluated. Compound 6 preliminarily showed better life extension activity than Selinexor in this model, and No obvious drug side effects.
实施例3:化合物在小鼠体内药代动力学评价Example 3: Pharmacokinetic evaluation of compounds in mice
实验目的:Purpose:
本实验旨在研究供试品静脉注射和口服给药后在雄性C57BL/6J小鼠血浆中的药代动力学情况。The purpose of this experiment was to study the pharmacokinetics of the test article in the plasma of male C57BL/6J mice after intravenous and oral administration.
实验方法:experimental method:
将动物随机分为两组,每组2只雄性。将化合物配制为指定制剂,静脉注射制剂为澄清溶液,口服制剂可以为澄清或者均一混悬液。Animals were randomly divided into two groups with 2 males in each group. The compounds are formulated into the indicated formulations, either as clear solutions for intravenous injection or as clear or homogeneous suspensions for oral formulations.
动物在给药后5、15、30分钟、1、2、4、6、8小时从颈静脉穿刺或者隐静脉采集全血样品。将全血样品加入含有抗凝剂的离心管中,4℃,3000g离心15min,取上清血浆于干冰上快速冷冻,然后保存在-70±10℃冰箱中直到进行LC-MS/MS分析。Whole blood samples were collected from jugular vein puncture or saphenous vein at 5, 15, 30 minutes, 1, 2, 4, 6, and 8 hours post-dose. The whole blood sample was added to a centrifuge tube containing anticoagulant, centrifuged at 3000g for 15 min at 4°C, and the supernatant plasma was quickly frozen on dry ice, and then stored in a -70±10°C refrigerator until LC-MS/MS analysis.
数据处理:data processing:
使用WinNonlin
TMVersion 6.3.0(Pharsight,Mountain View,CA)药动学软件,以非房室模型对化合物的血浆药物浓度数据进行处理。达峰浓度(C
max)和达峰时间(T
max)以及可定量末时间,从血药浓度-时间图中直接获得。
Plasma drug concentration data for compounds were processed in a non-compartmental model using WinNonlin ™ Version 6.3.0 (Pharsight, Mountain View, CA) pharmacokinetic software. The peak concentration (C max ) and time to peak (T max ), as well as the end time of quantification, were obtained directly from the plasma concentration-time plot.
使用对数线性梯形法计算下列药代动力学参数:血浆清除率(CL),分布容积(Vd),消除相半衰期(T
1/2),0点到末端时间点药物在体内的平均滞留时间(MRT
0-last),0点到无限时间药物在体内的平均滞留时间(MRT
0-inf),0点到末端时间点时间-血浆浓度曲线下面积(AUC
0-last),0点到无限时间-血浆浓度曲线下面积(AUC
0-inf)和生物利用度(F)。
The following pharmacokinetic parameters were calculated using the log-linear trapezoidal method: plasma clearance (CL), volume of distribution (Vd), elimination half-life (T 1/2 ), mean residence time of drug in the body from 0 to terminal time points (MRT 0-last ), the mean residence time of the drug in the body from 0 o’clock to infinity (MRT 0-inf ), the area under the time-plasma concentration curve from 0 o’clock to the terminal time point (AUC 0-last ), 0 o’clock to infinity Area under the time-plasma concentration curve (AUCo -inf ) and bioavailability (F).
实验结果:Experimental results:
表3:化合物小鼠静脉注射给药(1mg/kg)药代动力学参数Table 3: Pharmacokinetic parameters of compound mice administered intravenously (1 mg/kg)
供试品testing sample | 清除率(mL/min/kg)Clearance (mL/min/kg) | T 1/2(小时) T 1/2 (hour) | 浓度积分AUC(nM.hr)Concentration integral AUC (nM.hr) | Vdss(L/kg)Vdss(L/kg) |
SelinexorSelinexor | 15.615.6 | 1.681.68 | 23322332 | 2.252.25 |
化合物6Compound 6 | 6.706.70 | 3.143.14 | 54275427 | 1.801.80 |
化合物11Compound 11 | 10.310.3 | 2.922.92 | 34053405 | 2.442.44 |
表4:化合物小鼠口服给药(2mg/kg)药代动力学参数Table 4: Compound mice orally administered (2 mg/kg) pharmacokinetic parameters
供试品testing sample | C max(nM) Cmax (nM) | T max(小时) T max (hours) | 浓度积分AUC(nM.hr)Concentration integral AUC (nM.hr) | 生物利用度F(%)Bioavailability F(%) |
SelinexorSelinexor | 374374 | 1.501.50 | 21372137 | 45.845.8 |
化合物6Compound 6 | 597597 | 2.002.00 | 44554455 | 41.041.0 |
化合物11Compound 11 | 671671 | 3.003.00 | 59655965 | 87%87% |
结论:本发明化合物具有优异的药代动力学性质。Conclusion: The compounds of the present invention have excellent pharmacokinetic properties.
实施例4:化合物核输出抑制活性测试Example 4: Compound nuclear export inhibitory activity test
使用293T细胞测试化合物对CRM1介导的核输出能力。Compounds were tested for CRM1-mediated nuclear export ability using 293T cells.
Corning移液器铺板,100uL(100微升)每孔,细胞密度为32k/well。后置CO
2培养箱37℃孵育2-3小时。用移液枪将配置好的化合物分配到对应细胞板中,每孔100uL,37℃孵育2小时。将细胞板从培养箱中取出,弃掉培养基,用4%多聚甲醛室温固定20min。弃掉固定液,用磷酸缓冲液(PBS)洗3次,5min/次。0.3%Triton X-100室温作用20min。弃掉透膜液,用磷酸缓冲液(PBS)洗3次,5min/次。5%BSA溶液(牛血清白蛋白(Bovine Serum Albumin,BSA)室温封闭1h(小时)。Alexa Fluor 594荧光Anti-iKB alpha抗体 孵育:1:400稀释,4℃下过夜孵育。弃掉抗体溶液,用磷酸缓冲液(PBS)洗3次,5min/次。1:2000稀释,室温孵育20min,DAPI(4',6-二脒基-2-苯基吲哚(4',6-diamidino-2-phenylindole))。弃掉DAPI溶液,用磷酸缓冲液(PBS)洗3次,5min/次。Operetta仪器拍照分析数据。
Corning pipette plating, 100uL (100 microliters) per well, cell density 32k/well. Incubate for 2-3 hours in a post-CO 2 incubator at 37°C. Dispense the prepared compound into the corresponding cell plate with a pipette, 100uL per well, and incubate at 37°C for 2 hours. Remove the cell plate from the incubator, discard the medium, and fix it with 4% paraformaldehyde for 20 min at room temperature. The fixative was discarded and washed three times with phosphate buffered saline (PBS), 5 min/time. 0.3% Triton X-100 at room temperature for 20min. The permeabilization fluid was discarded and washed three times with phosphate buffered saline (PBS), 5 min/time. Block with 5% BSA solution (Bovine Serum Albumin, BSA) at room temperature for 1 h (hour). Alexa Fluor 594 fluorescent Anti-iKB alpha antibody incubation: 1:400 dilution, incubate overnight at 4 °C. Discard the antibody solution, Wash 3 times with phosphate buffered saline (PBS), 5 min/time. Dilute at 1:2000, incubate at room temperature for 20 min, DAPI (4', 6-diamidino-2-phenylindole (4', 6-diamidino-2 -phenylindole). Discard the DAPI solution and wash with phosphate buffered saline (PBS) for 3 times, 5 min/time. The Operetta instrument takes pictures and analyzes the data.
表5:化合物对CRM1介导的核输出抑制能力Table 5: Compounds' ability to inhibit CRM1-mediated nuclear export
供试品testing sample | EC 50(nM) EC50 (nM) |
化合物6Compound 6 | 4545 |
化合物11Compound 11 | 6565 |
结论:本发明化合物具有较好的CRM1介导的核输出抑制能力。Conclusion: The compounds of the present invention have good CRM1-mediated nuclear export inhibitory ability.
Claims (13)
- 式(I)所示化合物或其药学上可接受的盐,A compound represented by formula (I) or a pharmaceutically acceptable salt thereof,其中,in,L选自单键、NR 4和O; L is selected from single bond, NR 4 and O;R 1、R 2和R 3分别独立地选自H、F、Cl、Br、I、C 1-3烷基和C 1-3烷氧基,所述C 1-3烷基和C 1-3烷氧基任选被1、2或3个R a取代; R 1 , R 2 and R 3 are each independently selected from H, F, Cl, Br, I, C 1-3 alkyl and C 1-3 alkoxy, said C 1-3 alkyl and C 1-3 3 alkoxy is optionally substituted with 1, 2 or 3 R a ;或者,R 1和R 2与它们相连的键共同构成C 3-5环烯基,所述C 3-5环烯基任选被1、2或3个R b取代; Alternatively, R 1 and R 2 together with the bond to which they are attached form a C 3-5 cycloalkenyl group optionally substituted with 1, 2 or 3 R b ;R 4独立地选自H和CH 3; R4 is independently selected from H and CH3 ;X 1和X 2分别独立地选自CR c和N,且X 1和X 2不同时选自N; X 1 and X 2 are each independently selected from CR c and N, and X 1 and X 2 are not simultaneously selected from N;环B选自苯基、5~6元杂芳基和 所述苯基、5~6元杂芳基和 任选被1、2或3个R d取代;m选自0、1和2; Ring B is selected from phenyl, 5-6 membered heteroaryl and The phenyl group, 5-6 membered heteroaryl group and optionally substituted with 1, 2 or 3 R d ; m is selected from 0, 1 and 2;R a和R c分别独立地选自H、F、Cl、Br、I和CH 3; Ra and Rc are each independently selected from H, F, Cl, Br, I and CH3 ;R b和R d分别独立地选自F、Cl、Br、I、C 1-3烷基和C 1-3烷氧基,所述C 1-3烷基和C 1-3烷氧基任选被1、2或3个R取代; R b and R d are each independently selected from F, Cl, Br, I, C 1-3 alkyl and C 1-3 alkoxy, and said C 1-3 alkyl and C 1-3 alkoxy are any is replaced by 1, 2 or 3 Rs;R独立地选自F、Cl、Br和I。R is independently selected from F, Cl, Br and I.
- 根据权利要求1所述化合物或其药学上可接受的盐,其中,R b和R d分别独立地选自F、Cl、Br、I、CH 3和OCH 3,所述CH 3和OCH 3任选被1、2或3个R取代。 The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R b and R d are independently selected from F, Cl, Br, I, CH 3 and OCH 3 , wherein CH 3 and OCH 3 are either Option is substituted with 1, 2 or 3 Rs.
- 根据权利要求2所述化合物或其药学上可接受的盐,其中,R b和R d分别独立地选自F、Cl、CH 3、CH 2F、CHF 2、CF 3和OCH 3。 The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein R b and R d are each independently selected from F, Cl, CH 3 , CH 2 F, CHF 2 , CF 3 and OCH 3 .
- 根据权利要求1所述化合物或其药学上可接受的盐,其中,R 1、R 2和R 3分别独立地选自H、F、Cl、Br、I、CH 3、CH 2CH 3和OCH 3,所述CH 3、CH 2CH 3和OCH 3任选被1、2或3个R a取代。 The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 and R 3 are each independently selected from H, F, Cl, Br, I, CH 3 , CH 2 CH 3 and OCH 3 , the CH3 , CH2CH3 and OCH3 are optionally substituted with 1, 2 or 3 Ra .
- 根据权利要求4所述化合物或其药学上可接受的盐,其中,R 1、R 2和R 3分别独立地选自H、F、Cl、Br、I、CH 3、CH 2F、CHF 2、CF 3、CH 2CH 3和OCH 3。 The compound of claim 4 or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 and R 3 are each independently selected from H, F, Cl, Br, I, CH 3 , CH 2 F, CHF 2 , CF 3 , CH 2 CH 3 and OCH 3 .
- 根据权利要求1所述化合物或其药学上可接受的盐,其中,R 1和R 2与它们相连的键共同构成环戊烯基,所述环戊烯基任选被1、2或3个R b取代。 The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 together with the bond to which they are attached form a cyclopentenyl group optionally formed by 1, 2 or 3 R b substituted.
- 根据权利要求1所述化合物或其药学上可接受的盐,其中,L选自单键、NH和O。The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein L is selected from a single bond, NH and O.
- 根据权利要求1所述化合物或其药学上可接受的盐,其中,环B选自苯基、吡啶基、吡嗪基和 所述苯基、吡啶基、吡嗪基和 任选被1、2或3个R d取代。 The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Ring B is selected from the group consisting of phenyl, pyridyl, pyrazinyl and The phenyl, pyridyl, pyrazinyl and Optionally substituted with 1, 2 or 3 Rd .
- 根据权利要求1~8任意一项所述化合物或其药学上可接受的盐,其化合物选自The compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of其中,in,R 1、R 2、R 3、R d和L如权利要求1~8任意一项所定义。 R 1 , R 2 , R 3 , R d and L are as defined in any one of claims 1 to 8 .
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