WO2022161443A1 - 嘧啶并吡喃类化合物 - Google Patents
嘧啶并吡喃类化合物 Download PDFInfo
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- WO2022161443A1 WO2022161443A1 PCT/CN2022/074390 CN2022074390W WO2022161443A1 WO 2022161443 A1 WO2022161443 A1 WO 2022161443A1 CN 2022074390 W CN2022074390 W CN 2022074390W WO 2022161443 A1 WO2022161443 A1 WO 2022161443A1
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- Prior art keywords
- compound
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- ethyl acetate
- reaction solution
- mmol
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- -1 Pyrimidopyran compound Chemical class 0.000 title claims abstract description 74
- 150000001875 compounds Chemical class 0.000 claims abstract description 468
- 150000003839 salts Chemical class 0.000 claims abstract description 47
- 238000002360 preparation method Methods 0.000 claims description 115
- 125000000217 alkyl group Chemical group 0.000 claims description 36
- 229910052731 fluorine Inorganic materials 0.000 claims description 34
- 229910052794 bromium Inorganic materials 0.000 claims description 33
- 229910052801 chlorine Inorganic materials 0.000 claims description 33
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 25
- 229910052739 hydrogen Inorganic materials 0.000 claims description 25
- 229910052740 iodine Inorganic materials 0.000 claims description 25
- 229910052799 carbon Inorganic materials 0.000 claims description 24
- 125000006555 (C3-C5) cycloalkyl group Chemical group 0.000 claims description 22
- 125000003545 alkoxy group Chemical group 0.000 claims description 17
- 125000003118 aryl group Chemical group 0.000 claims description 17
- 102200006539 rs121913529 Human genes 0.000 claims description 16
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 14
- 125000000304 alkynyl group Chemical group 0.000 claims description 13
- 239000003814 drug Substances 0.000 claims description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 12
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 10
- 125000001624 naphthyl group Chemical group 0.000 claims description 10
- 125000001041 indolyl group Chemical group 0.000 claims description 9
- 230000035772 mutation Effects 0.000 claims description 9
- 125000003342 alkenyl group Chemical group 0.000 claims description 8
- 125000004366 heterocycloalkenyl group Chemical group 0.000 claims description 8
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 claims description 8
- 238000006467 substitution reaction Methods 0.000 claims description 8
- 125000003554 tetrahydropyrrolyl group Chemical group 0.000 claims description 8
- 125000004605 1,2,3,4-tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 claims description 7
- 125000004076 pyridyl group Chemical group 0.000 claims description 6
- 150000001336 alkenes Chemical class 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 201000010099 disease Diseases 0.000 claims description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 claims description 2
- UWYZHKAOTLEWKK-UHFFFAOYSA-N 1,2,3,4-tetrahydroisoquinoline Chemical compound C1=CC=C2CNCCC2=C1 UWYZHKAOTLEWKK-UHFFFAOYSA-N 0.000 claims 2
- 125000005843 halogen group Chemical group 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 573
- 239000000243 solution Substances 0.000 description 300
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 275
- 238000006243 chemical reaction Methods 0.000 description 268
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 242
- 239000000543 intermediate Substances 0.000 description 159
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 152
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Substances CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 144
- 239000012043 crude product Substances 0.000 description 131
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 125
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 122
- 239000003208 petroleum Substances 0.000 description 112
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 107
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 104
- 239000012074 organic phase Substances 0.000 description 89
- 238000003786 synthesis reaction Methods 0.000 description 89
- 230000015572 biosynthetic process Effects 0.000 description 88
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 81
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 78
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 74
- 238000003756 stirring Methods 0.000 description 72
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 72
- 229910052757 nitrogen Inorganic materials 0.000 description 69
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 59
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 59
- 239000003960 organic solvent Substances 0.000 description 58
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 56
- 210000004027 cell Anatomy 0.000 description 55
- 239000003480 eluent Substances 0.000 description 53
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 50
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 44
- 238000005481 NMR spectroscopy Methods 0.000 description 44
- 239000012071 phase Substances 0.000 description 43
- 238000000926 separation method Methods 0.000 description 43
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 37
- 239000000203 mixture Substances 0.000 description 37
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 36
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 36
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 35
- 239000002904 solvent Substances 0.000 description 33
- 239000000706 filtrate Substances 0.000 description 28
- 238000010898 silica gel chromatography Methods 0.000 description 27
- 239000008346 aqueous phase Substances 0.000 description 26
- 238000000746 purification Methods 0.000 description 26
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 25
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 24
- 206010028980 Neoplasm Diseases 0.000 description 23
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 21
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
- 238000004440 column chromatography Methods 0.000 description 21
- 238000004128 high performance liquid chromatography Methods 0.000 description 19
- 238000010791 quenching Methods 0.000 description 19
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 18
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 18
- 238000012360 testing method Methods 0.000 description 17
- 238000004809 thin layer chromatography Methods 0.000 description 17
- 102100030708 GTPase KRas Human genes 0.000 description 16
- 101000584612 Homo sapiens GTPase KRas Proteins 0.000 description 16
- 230000005764 inhibitory process Effects 0.000 description 16
- 238000002474 experimental method Methods 0.000 description 15
- 238000002953 preparative HPLC Methods 0.000 description 15
- 239000002994 raw material Substances 0.000 description 15
- 239000011734 sodium Substances 0.000 description 15
- 125000004429 atom Chemical group 0.000 description 14
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 14
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 13
- 125000004432 carbon atom Chemical group C* 0.000 description 13
- 229940125904 compound 1 Drugs 0.000 description 13
- 239000005457 ice water Substances 0.000 description 13
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 13
- 235000017557 sodium bicarbonate Nutrition 0.000 description 13
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 12
- 229910000029 sodium carbonate Inorganic materials 0.000 description 12
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 12
- 239000002253 acid Substances 0.000 description 11
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- 230000002401 inhibitory effect Effects 0.000 description 11
- 238000000034 method Methods 0.000 description 11
- 229920006395 saturated elastomer Polymers 0.000 description 11
- ZSXGLVDWWRXATF-UHFFFAOYSA-N N,N-dimethylformamide dimethyl acetal Chemical compound COC(OC)N(C)C ZSXGLVDWWRXATF-UHFFFAOYSA-N 0.000 description 10
- 239000012065 filter cake Substances 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- 239000000126 substance Substances 0.000 description 10
- 229910015900 BF3 Inorganic materials 0.000 description 9
- 229910002092 carbon dioxide Inorganic materials 0.000 description 9
- 238000001816 cooling Methods 0.000 description 9
- 238000001914 filtration Methods 0.000 description 9
- 150000004675 formic acid derivatives Chemical class 0.000 description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 9
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 9
- RKMGAJGJIURJSJ-UHFFFAOYSA-N 2,2,6,6-tetramethylpiperidine Chemical compound CC1(C)CCCC(C)(C)N1 RKMGAJGJIURJSJ-UHFFFAOYSA-N 0.000 description 8
- 241000282414 Homo sapiens Species 0.000 description 8
- 125000005842 heteroatom Chemical group 0.000 description 8
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 8
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 7
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 7
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 7
- WRQNANDWMGAFTP-UHFFFAOYSA-N Methylacetoacetic acid Chemical compound COC(=O)CC(C)=O WRQNANDWMGAFTP-UHFFFAOYSA-N 0.000 description 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 7
- 239000001569 carbon dioxide Substances 0.000 description 7
- 239000013592 cell lysate Substances 0.000 description 7
- 238000010790 dilution Methods 0.000 description 7
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- 229940079593 drug Drugs 0.000 description 7
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- 238000011534 incubation Methods 0.000 description 7
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 7
- 125000006413 ring segment Chemical group 0.000 description 7
- 229910000104 sodium hydride Inorganic materials 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- 125000001424 substituent group Chemical group 0.000 description 7
- 239000006228 supernatant Substances 0.000 description 7
- SFHYNDMGZXWXBU-LIMNOBDPSA-N 6-amino-2-[[(e)-(3-formylphenyl)methylideneamino]carbamoylamino]-1,3-dioxobenzo[de]isoquinoline-5,8-disulfonic acid Chemical compound O=C1C(C2=3)=CC(S(O)(=O)=O)=CC=3C(N)=C(S(O)(=O)=O)C=C2C(=O)N1NC(=O)N\N=C\C1=CC=CC(C=O)=C1 SFHYNDMGZXWXBU-LIMNOBDPSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 6
- 241000699670 Mus sp. Species 0.000 description 6
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
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- NNBBQNFHCVVQHZ-UHFFFAOYSA-N methyl carbamimidothioate;sulfuric acid Chemical compound CSC(N)=N.OS(O)(=O)=O NNBBQNFHCVVQHZ-UHFFFAOYSA-N 0.000 description 6
- 229910052760 oxygen Inorganic materials 0.000 description 6
- 239000012312 sodium hydride Substances 0.000 description 6
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 5
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 5
- 206010009944 Colon cancer Diseases 0.000 description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 5
- 235000019270 ammonium chloride Nutrition 0.000 description 5
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 5
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- 125000000753 cycloalkyl group Chemical group 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 239000012091 fetal bovine serum Substances 0.000 description 5
- QGWNDRXFNXRZMB-UHFFFAOYSA-N guanidine diphosphate Natural products C1=2NC(N)=NC(=O)C=2N=CN1C1OC(COP(O)(=O)OP(O)(O)=O)C(O)C1O QGWNDRXFNXRZMB-UHFFFAOYSA-N 0.000 description 5
- 238000002868 homogeneous time resolved fluorescence Methods 0.000 description 5
- 239000001257 hydrogen Substances 0.000 description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 5
- 125000005647 linker group Chemical group 0.000 description 5
- 239000012046 mixed solvent Substances 0.000 description 5
- XONPDZSGENTBNJ-UHFFFAOYSA-N molecular hydrogen;sodium Chemical compound [Na].[H][H] XONPDZSGENTBNJ-UHFFFAOYSA-N 0.000 description 5
- 125000002950 monocyclic group Chemical group 0.000 description 5
- 125000004433 nitrogen atom Chemical group N* 0.000 description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 description 5
- MOHYOXXOKFQHDC-UHFFFAOYSA-N 1-(chloromethyl)-4-methoxybenzene Chemical compound COC1=CC=C(CCl)C=C1 MOHYOXXOKFQHDC-UHFFFAOYSA-N 0.000 description 4
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 4
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- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 4
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 4
- LQZMLBORDGWNPD-UHFFFAOYSA-N N-iodosuccinimide Substances IN1C(=O)CCC1=O LQZMLBORDGWNPD-UHFFFAOYSA-N 0.000 description 4
- 108010059447 Son of Sevenless Proteins Proteins 0.000 description 4
- 102000005588 Son of Sevenless Proteins Human genes 0.000 description 4
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 4
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- 238000012054 celltiter-glo Methods 0.000 description 4
- 208000029742 colonic neoplasm Diseases 0.000 description 4
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- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 4
- 125000004122 cyclic group Chemical group 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
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- 230000000694 effects Effects 0.000 description 4
- VFRSADQPWYCXDG-LEUCUCNGSA-N ethyl (2s,5s)-5-methylpyrrolidine-2-carboxylate;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.CCOC(=O)[C@@H]1CC[C@H](C)N1 VFRSADQPWYCXDG-LEUCUCNGSA-N 0.000 description 4
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- IVDFJHOHABJVEH-UHFFFAOYSA-N pinacol Chemical compound CC(C)(O)C(C)(C)O IVDFJHOHABJVEH-UHFFFAOYSA-N 0.000 description 4
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- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 4
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- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 3
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 3
- WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 description 3
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- 238000007789 sealing Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 238000004467 single crystal X-ray diffraction Methods 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- NXQKSXLFSAEQCZ-SFHVURJKSA-N sotorasib Chemical compound FC1=CC2=C(N(C(N=C2N2[C@H](CN(CC2)C(C=C)=O)C)=O)C=2C(=NC=CC=2C)C(C)C)N=C1C1=C(C=CC=C1O)F NXQKSXLFSAEQCZ-SFHVURJKSA-N 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 230000037351 starvation Effects 0.000 description 1
- 230000003068 static effect Effects 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- GZCRRIHWUXGPOV-UHFFFAOYSA-N terbium atom Chemical compound [Tb] GZCRRIHWUXGPOV-UHFFFAOYSA-N 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
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 238000002877 time resolved fluorescence resonance energy transfer Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 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
- 238000000844 transformation Methods 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- QIWRFOJWQSSRJZ-UHFFFAOYSA-N tributyl(ethenyl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)C=C QIWRFOJWQSSRJZ-UHFFFAOYSA-N 0.000 description 1
- PIILXFBHQILWPS-UHFFFAOYSA-N tributyltin Chemical class CCCC[Sn](CCCC)CCCC PIILXFBHQILWPS-UHFFFAOYSA-N 0.000 description 1
- ZMANZCXQSJIPKH-UHFFFAOYSA-O triethylammonium ion Chemical compound CC[NH+](CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-O 0.000 description 1
- CWMFRHBXRUITQE-UHFFFAOYSA-N trimethylsilylacetylene Chemical group C[Si](C)(C)C#C CWMFRHBXRUITQE-UHFFFAOYSA-N 0.000 description 1
- 239000001226 triphosphate Substances 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 230000005751 tumor progression Effects 0.000 description 1
- 238000011144 upstream manufacturing Methods 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 229960005080 warfarin Drugs 0.000 description 1
- PJVWKTKQMONHTI-UHFFFAOYSA-N warfarin Chemical compound OC=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 PJVWKTKQMONHTI-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
-
- 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
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with 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
Definitions
- the present invention relates to a class of pyrimidopyran compounds, in particular to a compound represented by formula (III) and a pharmaceutically acceptable salt thereof.
- RAS oncogene mutations are the most common activating mutations in human cancers, occurring in 30% of human tumors.
- the RAS gene family includes three subtypes (KRAS, HRAS, and NRAS), of which 85% of RAS-driven cancers are caused by mutations in the KRAS subtype.
- KRAS mutations are commonly found in solid tumors such as lung adenocarcinoma, pancreatic ductal carcinoma, and colorectal cancer. In KRAS-mutant tumors, 80% of oncogenic mutations occurred at codon 12, with the most common mutations including: p.G12D (41%), p.G12V (28%), and p.G12C (14%).
- KRAS is a murine sarcoma virus oncogene and an important member of the RAS protein.
- KRAS is like a molecular switch, which can control the path of regulating cell growth when it is normal; after KRAS gene mutation, it can independently transmit growth and proliferation signals to downstream pathways independently of upstream growth factor receptor signals, resulting in uncontrolled cell growth and tumor progression.
- whether the KRAS gene has mutation is also an important indicator of tumor prognosis.
- KRAS G12C small molecules that directly target KRAS mutations are mainly concentrated in the field of KRAS G12C .
- Amgen's AMG510 and Mirati Therapeutics' MRTX849 have shown good therapeutic effects on KRAS G12C- mutated tumor patients in clinical studies. But so far, no KRAS G12D small molecule has entered the clinical research stage, and KRAS G12D- mutated tumor patients have not benefited from precision medicine.
- the present invention provides a compound represented by formula (III) or a pharmaceutically acceptable salt thereof,
- T 1 is selected from CR 7 R 8 , NR 9 and O;
- T 2 is selected from CH and N;
- L 1 is selected from -CH 2 - and a bond
- R 1 , R 2 , R 3 , R 4 and R 5 are each independently selected from H and C 1-3 alkyl optionally substituted with 1 , 2 or 3 Ra ;
- R 6 is selected from C 6-10 aryl and 5-10 membered heteroaryl, the C 6-10 aryl and 5-10 membered heteroaryl are optionally surrounded by 1, 2, 3, 4 or 5 R b replace;
- R 7 and R 8 are each independently selected from H, CH 3 and NH 2 ;
- R 9 is selected from H and CH 3 ;
- R 10 is selected from 4-8 membered heterocycloalkyl and The 4-8 membered heterocycloalkyl and optionally substituted with 1, 2 or 3 R c ;
- R 11 and R 12 are each independently selected from H, C 1-3 alkyl and C 3-5 cycloalkyl, said C 1-3 alkyl and C 3-5 cycloalkyl being optionally 3 halogen substitutions;
- Structural units selected from 5-6 membered heterocycloalkenyl
- Structural units is selected from C 3-5 cycloalkyl
- Structural units selected from 4-5 membered heterocycloalkyl
- n is selected from 0, 1 or 2;
- n is selected from 0, 1 or 2;
- p is selected from 1 or 2;
- q is selected from 1, 2 or 3;
- r is selected from 1 or 2;
- s is selected from 1, 2 or 3;
- each R a is independently selected from F, Cl, Br and I;
- Each R is independently selected from F, Cl, Br and I.
- the R 1 , R 2 , R 3 , R 4 and R 5 are each independently selected from H, CH 3 , CH 2 CH 3 and CH(CH 3 ) 2 , the CH 3 , CH 2 CH 3 and CH(CH 3 ) 2 are optionally substituted with 1, 2 or 3 Ra , other variables are as defined herein.
- said R 1 , R 2 , R 3 , R 4 and R 5 are independently selected from H and CH 3 , and other variables are as defined herein.
- the R 6 is selected from phenyl, pyridyl, naphthyl, indolyl and indazolyl, and said phenyl, pyridyl, naphthyl, indolyl and indazolyl are any Optionally substituted with 1, 2, 3, 4 or 5 R b , other variables are as defined in the present invention.
- the R 6 is selected from Other variables are as defined in the present invention.
- each R c is independently selected from H, F, Cl, Br, OH, CN, CH 3 , CH 2 CH 3 , CH 2 CF 3 , OCH 3 , OCF 3 and Other variables are as defined in the present invention.
- the R 10 is selected from tetrahydropyrrolyl, hexahydro-1H-pyrrolizinyl and 1,2,3,4-tetrahydroisoquinolinyl, the tetrahydropyrrolyl , hexahydro-1H-pyrrolizinyl and 1,2,3,4-tetrahydroisoquinolinyl are optionally substituted with 1, 2 or 3 R c and other variables are as defined herein.
- the R 10 is selected from Other variables are as defined in the present invention.
- the R 10 is selected from Other variables are as defined in the present invention.
- said R 11 and R 12 are independently selected from H and CH 3 , respectively, and other variables are as defined in the present invention.
- the present invention provides a compound represented by formula (III) or a pharmaceutically acceptable salt thereof,
- T 1 is selected from CR 7 R 8 , NR 9 and O;
- T 2 is selected from CH and N;
- L 1 is selected from -CH 2 - and a bond
- R 1 , R 2 , R 3 , R 4 and R 5 are each independently selected from H and C 1-3 alkyl optionally substituted with 1 , 2 or 3 Ra ;
- R 6 is selected from C 6-10 aryl and 5-10 membered heteroaryl, the C 6-10 aryl and 5-10 membered heteroaryl are optionally surrounded by 1, 2, 3, 4 or 5 R b replace;
- R 7 and R 8 are each independently selected from H, CH 3 and NH 2 ;
- R 9 is selected from H and CH 3 ;
- R 10 is selected from 4-8 membered heterocycloalkyl and The 4-8 membered heterocycloalkyl and optionally substituted with 1, 2 or 3 R c ;
- R 11 and R 12 are each independently selected from H, C 1-3 alkyl and C 3-5 cycloalkyl, said C 1-3 alkyl and C 3-5 cycloalkyl being optionally 3 halogen substitutions;
- Structural units selected from 5-6 membered heterocycloalkenyl
- Structural units is selected from C 3-5 cycloalkyl
- Structural units selected from 4-5 membered heterocycloalkyl
- n is selected from 0, 1 or 2;
- n is selected from 0, 1 or 2;
- p is selected from 1 or 2;
- q is selected from 1, 2 or 3;
- r is selected from 1 or 2;
- s is selected from 1, 2 or 3;
- each R a is independently selected from F, Cl, Br and I;
- Each R b is independently selected from F, Cl, Br, I, OH, NH 2 , CN, C 1-3 alkyl, C 1-3 alkoxy, C 2-3 alkynyl, C 2-3 alkene and C 3-5 cycloalkyl, the C 1-3 alkyl, C 1-3 alkoxy, C 2-3 alkynyl, C 2-3 alkenyl and C 3-5 cycloalkyl are optional replaced by 1, 2 or 3 Rs;
- Each R c is independently selected from H, F, Cl, Br, OH, CN, C 1-3 alkyl, C 1-3 alkoxy and -C 1-3 alkyl-O-CO-C 1- 3 alkylamino; each R is independently selected from F, Cl and Br;
- the R 1 , R 2 , R 3 , R 4 and R 5 are each independently selected from H, CH 3 , CH 2 CH 3 and CH(CH 3 ) 2 , the CH 3 , CH 2 CH 3 and CH(CH 3 ) 2 are optionally substituted with 1, 2 or 3 Ra , other variables are as defined herein.
- said R 1 , R 2 , R 3 , R 4 and R 5 are independently selected from H and CH 3 , and other variables are as defined herein.
- each R b is independently selected from F, OH, NH 2 , CH 3 , CF 3 , CH 2 CH 3 and -C ⁇ CH, and other variables are as defined herein.
- said R 6 is selected from phenyl, naphthyl, indolyl and indazolyl, and said phenyl, naphthyl, indolyl and indazolyl are optionally substituted by 1, 2, 3, 4 or 5 R b substitutions and other variables are as defined in the present invention.
- the R 6 is selected from Other variables are as defined in the present invention.
- each R c is independently selected from H, F, Cl, Br, OH, CN, CH 3 , CH 2 CH 3 , CH 2 CF 3 , OCH 3 , OCF 3 and Other variables are as defined in the present invention.
- the R 10 is selected from tetrahydropyrrolyl, hexahydro-1H-pyrrolizinyl and 1,2,3,4-tetrahydroisoquinolinyl, the tetrahydropyrrolyl , hexahydro-1H-pyrrolizinyl and 1,2,3,4-tetrahydroisoquinolinyl are optionally substituted with 1, 2 or 3 R c and other variables are as defined herein.
- the R 10 is selected from Other variables are as defined in the present invention.
- said R 11 and R 12 are independently selected from H and CH 3 , respectively, and other variables are as defined in the present invention.
- the present invention provides a compound represented by formula (II) or a pharmaceutically acceptable salt thereof,
- T 1 is selected from CR 7 R 8 , NR 9 and O;
- T 2 is selected from CH and N;
- L 1 is selected from -CH 2 - and a bond
- R 1 , R 2 , R 3 , R 4 and R 5 are each independently selected from H and C 1-3 alkyl optionally substituted with 1 , 2 or 3 Ra ;
- R 6 is selected from C 6-10 aryl and 5-10 membered heteroaryl, the C 6-10 aryl and 5-10 membered heteroaryl are optionally surrounded by 1, 2, 3, 4 or 5 R b replace;
- R 7 and R 8 are each independently selected from H, CH 3 and NH 2 ;
- R 9 is selected from H and CH 3 ;
- R 10 is selected from 4-8 membered heterocycloalkyl and The 4-8 membered heterocycloalkyl and optionally substituted with 1, 2 or 3 R c ;
- Structural units selected from 5-6 membered heterocycloalkenyl
- Structural units is selected from C 3-5 membered cycloalkyl
- Structural units selected from 4-5 membered heterocycloalkyl
- n is selected from 0, 1 or 2;
- n is selected from 0, 1 or 2;
- p is selected from 1 or 2;
- q is selected from 1, 2 or 3;
- r is selected from 1 or 2;
- s is selected from 1, 2 or 3;
- each R a is independently selected from F, Cl, Br and I;
- Each R b is independently selected from F, Cl, Br, I, OH, NH 2 , CN, C 1-3 alkyl, C 1-3 alkoxy, C 2-3 alkynyl, C 2-3 alkene and C 3-5 cycloalkyl, the C 1-3 alkyl, C 1-3 alkoxy, C 2-3 alkynyl, C 2-3 alkenyl and C 3-5 cycloalkyl are optional replaced by 1, 2 or 3 Rs;
- Each R c is independently selected from H, F, Cl, Br, OH, CN, C 1-3 alkyl, C 1-3 alkoxy and -C 1-3 alkyl-O-CO-C 1- 3 alkylamino;
- each R is independently selected from F, Cl and Br;
- the R 1 , R 2 , R 3 , R 4 and R 5 are each independently selected from H, CH 3 , CH 2 CH 3 and CH(CH 3 ) 2 , the CH 3 , CH 2 CH 3 and CH(CH 3 ) 2 are optionally substituted with 1, 2 or 3 Ra , other variables are as defined herein.
- said R 1 , R 2 , R 3 , R 4 and R 5 are independently selected from H and CH 3 , and other variables are as defined herein.
- each R b is independently selected from F, OH, NH 2 , CH 3 , CF 3 , CH 2 CH 3 and -C ⁇ CH, and other variables are as defined herein.
- said R 6 is selected from phenyl, naphthyl, indolyl and indazolyl, and said phenyl, naphthyl, indolyl and indazolyl are optionally substituted by 1, 2, 3, 4 or 5 R b substitutions and other variables are as defined in the present invention.
- the R 6 is selected from Other variables are as defined in the present invention.
- each R c is independently selected from H, F, Cl, Br, OH, CN, CH 3 , CH 2 CH 3 , CH 2 CF 3 , OCH 3 , OCF 3 and Other variables are as defined in the present invention.
- the R 10 is selected from tetrahydropyrrolyl, hexahydro-1H-pyrrolizinyl and 1,2,3,4-tetrahydroisoquinolinyl, the tetrahydropyrrolyl , hexahydro-1H-pyrrolizinyl and 1,2,3,4-tetrahydroisoquinolinyl are optionally substituted with 1, 2 or 3 R c and other variables are as defined herein.
- the R 10 is selected from Other variables are as defined in the present invention.
- the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
- T 1 is selected from CR 7 R 8 and NR 9 ;
- T when is selected from single bond, T is selected from CH and N;
- R 1 , R 2 , R 3 , R 4 and R 5 are each independently selected from H and C 1-3 alkyl optionally substituted with 1 , 2 or 3 Ra ;
- R is selected from phenyl and naphthyl optionally substituted with 1 , 2 , 3, 4 or 5 R;
- R 7 and R 8 are each independently selected from H, CH 3 and NH 2 ;
- R 9 is selected from H and CH 3 ;
- R 1 and R 2 form a ring with the attached atom to make the building block form
- R 1 and R 4 form a ring with the attached atom to make the building block form
- R4 and R5 form a ring with the attached atom to make the building block form
- R 2 and R 7 form tetrahydropyrrolidinyl with the attached atom
- R 2 and R 3 form a C 3-5 membered cycloalkyl with the attached atom;
- R 7 and R 8 form a 4-5 membered heterocycloalkyl with the attached atom
- n is selected from 0, 1 or 2;
- n is selected from 0, 1 or 2;
- p is selected from 1 or 2;
- q is selected from 1, 2 or 3;
- r is selected from 1 or 2;
- s is selected from 1, 2 or 3;
- each R a is independently selected from F, Cl, Br and I;
- Each R b is independently selected from F, Cl, Br, I, OH, NH2 , CN, CH3 , CF3 , and OCH3 .
- the R 1 , R 2 , R 3 , R 4 and R 5 are each independently selected from H, CH 3 , CH 2 CH 3 and CH(CH 3 ) 2 , the CH 3 , CH 2 CH 3 and CH(CH 3 ) 2 are optionally substituted with 1, 2 or 3 Ra , other variables are as defined herein.
- the R 1 , R 2 , R 3 , R 4 and R 5 are independently selected from H and CH 3 , respectively, and other variables are as defined herein.
- the R 2 and R 7 form with the attached atoms
- Other variables are as defined in the present invention.
- the R 2 and R 3 form with the attached atoms
- Other variables are as defined in the present invention.
- the R7 and R8 form with the attached atom
- Other variables are as defined in the present invention.
- the R 6 is selected from Other variables are as defined in the present invention.
- the compound or a pharmaceutically acceptable salt thereof is selected from,
- T 2 , R 6 , R 11 and R 12 are as defined in the present invention.
- the compound or a pharmaceutically acceptable salt thereof is selected from,
- T 2 , R 6 , R 11 and R 12 are as defined in the present invention.
- the compound or a pharmaceutically acceptable salt thereof is selected from,
- z is selected from 0, 1, 2, 3, 4 and 5;
- T 2 , R b , R 11 and R 12 are as defined in the present invention.
- the compound or a pharmaceutically acceptable salt thereof is selected from,
- each R is independently selected from F, Cl, Br and I;
- T 2 , R 11 and R 12 are as defined in the present invention.
- the group is optionally substituted with 1, 2, 3, 4 or 5 R, other variables are as defined in the present invention.
- the compound or a pharmaceutically acceptable salt thereof is selected from,
- T 2 , R b1 , R b2 , R b3 , R b4 , R b5 , R b6 , R b7 , R 11 and R 12 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,
- the compound, or a pharmaceutically acceptable salt thereof is selected from,
- the compound, or a pharmaceutically acceptable salt thereof is selected from,
- the present invention also provides the use of the above-mentioned compound or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating diseases related to KRAS G12D mutation.
- the present invention also provides the use of the above compound or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of tumor-related diseases.
- the compound of the invention has good inhibitory effect on KRAS G12D mutant enzymes, can effectively inhibit p-ERK, has good cell proliferation inhibitory activity on KRAS G12D mutant cells, can effectively inhibit tumor growth in vivo, and has good drug resistance.
- the compounds of the present invention have a moderate to high degree of plasma binding and have good pharmacokinetic properties.
- 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.
- 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 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 amine or magnesium salts or similar salts.
- acid addition salts can be obtained by contacting 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 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 mixtures thereof and other mixtures, such as enantiomerically or diastereomerically enriched mixtures, all of which belong to this within the scope of the 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.
- 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.
- 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.
- any one or more sites in the group can be linked to other groups by chemical bonds.
- connection method of the chemical bond is not located, and there is an H atom at the linkable site, when the chemical bond is connected, the number of H atoms at the site will be correspondingly reduced with the number of chemical bonds connected to the corresponding valence. the group.
- the chemical bond connecting the site to other groups can be represented by straight solid line bonds straight dotted key or wavy lines express.
- a straight solid bond in -OCH 3 indicates that it is connected to other groups through the oxygen atom in this group;
- the straight dashed bond in the group indicates that it is connected to other groups through the two ends of the nitrogen atom in the group;
- the wavy line in the phenyl group indicates that it is connected to other groups through the 1 and 2 carbon atoms in the phenyl group;
- 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 1-3 alkylamino refers to those alkyl groups containing 1 to 3 carbon atoms attached to the remainder of the molecule through an amino group.
- the C 1-3 alkylamino groups include C 1-2 , C 3 and C 2 alkylamino groups and the like.
- Examples of C 1-3 alkylamino include, but are not limited to, -NHCH 3 , -N(CH 3 ) 2 , -NHCH 2 CH 3 , -N(CH 3 )CH 2 CH 3 , -NHCH 2 CH 2 CH 3 , - NHCH 2 (CH 3 ) 2 and the like.
- C 2-3 alkenyl is used to denote a straight or branched chain hydrocarbon group consisting of 2 to 3 carbon atoms containing at least one carbon-carbon double bond, a carbon-carbon double bond can be located anywhere in the group.
- the C 2-3 alkenyl group includes C 3 and C 2 alkenyl groups; the C 2-3 alkenyl group may be monovalent, divalent or multivalent. Examples of C 2-3 alkenyl groups include, but are not limited to, vinyl, propenyl, and the like.
- C 2-3 alkynyl is used to denote a straight or branched chain hydrocarbon group consisting of 2 to 3 carbon atoms containing at least one carbon-carbon triple bond, a carbon-carbon triple bond can be located anywhere in the group. It can be monovalent, bivalent or multivalent.
- the C 2-3 alkynyl groups include C 3 and C 2 alkynyl groups. Examples of C2-3alkynyl groups include, but are not limited to, ethynyl, propynyl, and the like.
- the term "4-5 membered heterocycloalkyl” by itself or in combination with other terms denotes a saturated monocyclic group consisting of 4 to 5 ring atoms, 1, 2, 3 or 4 ring atoms, respectively are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms, where the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (ie, NO and S(O) p , p is 1 or 2). Furthermore, with respect to the "4-5 membered heterocycloalkyl", a heteroatom may occupy the position of attachment of the heterocycloalkyl to the remainder of the molecule.
- the 4-5 membered heterocycloalkyl includes 4 and 5 membered heterocycloalkyl.
- Examples of 4-5 membered heterocycloalkyl include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl ( Including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.) or tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.) 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 6-10 aryl ring and “C 6-10 aryl group” can be used interchangeably in the present invention
- C 6-10 aryl ring” or C 6-10 aryl group means by A cyclic hydrocarbon group composed of 6 to 10 carbon atoms with a conjugated ⁇ -electron system, which may be a monocyclic, fused bicyclic or fused tricyclic system, wherein each ring is aromatic. It may be monovalent, divalent or polyvalent, and C6-10 aryl groups include C6-9 , C9 , C10 and C6 aryl groups and the like. Examples of C6-10 aryl groups include, but are not limited to, phenyl, naphthyl (including 1-naphthyl and 2-naphthyl, and the like).
- 5-10-membered heteroaryl ring and “5-10-membered heteroaryl” can be used interchangeably in the present invention, and the term “5-10-membered heteroaryl” refers to a ring consisting of 5 to 10 rings.
- a cyclic group composed of atoms 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. It can be a monocyclic, fused bicyclic or fused tricyclic ring system, wherein each ring is aromatic.
- the nitrogen and sulfur heteroatoms may be optionally oxidized (ie, NO and S(O) p , p is 1 or 2).
- a 5-10 membered heteroaryl group can be attached to the rest of the molecule through a heteroatom or a carbon atom.
- the 5-10-membered heteroaryl groups include 10-membered, 9-membered, 9-10-membered, 5-8-membered, 5-7-membered, 5-6-membered, 5-membered, and 6-membered heteroaryl groups, and the like.
- Examples of the 5-10 membered heteroaryl group 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 (
- the term "4-8 membered heterocycloalkyl" by itself or in combination with other terms denotes a saturated cyclic group consisting of 4 to 8 ring atoms, respectively, of which 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms, where the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (ie, NO and S(O) p , p is 1 or 2). It includes monocyclic and bicyclic ring systems, wherein bicyclic ring systems include spiro, paracyclic and bridged rings.
- a heteroatom may occupy the position of attachment of the heterocycloalkyl to the remainder of the molecule.
- the 4-8 membered heterocycloalkyl includes 4-6 membered, 5-6 membered, 4 membered, 5 membered and 6 membered heterocycloalkyl and the like.
- 4-8 membered heterocycloalkyl examples include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl ( Including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2- piperidinyl and 3-piperidyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), Dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl,
- the term "5-6 membered heterocycloalkenyl" by itself or in combination with other terms respectively denotes a partially unsaturated cyclic group consisting of 5 to 6 ring atoms containing at least one carbon-carbon double bond , whose 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may optionally be Oxidation (ie NO and S(O) p , p is 1 or 2).
- bicyclic ring systems include spiro, paracyclic and bridged rings, any ring of this system is non-aromatic.
- a heteroatom may occupy the position of attachment of the heterocycloalkenyl to the rest of the molecule.
- the 5-6 membered heterocyclenyl includes 5-membered and 6-membered heterocyclenyl and the like. Examples of 5-6 membered heterocycloalkenyl include but are not limited to
- 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: hr stands for hour; LDA stands for lithium diisopropylamide; B 2 Pin 2 stands for pinacol diboronate; Pd(dppf)Cl 2 .
- CH 2 Cl 2 stands for [1,1 '-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex; DIPEA stands for N,N-diisopropylethylamine; NBS stands for N-bromosuccinimide; NIS represents N-iodosuccinimide; PdCl 2 (PPh 3 ) 2 represents bistriphenylphosphonium palladium dichloride; CuI represents cuprous iodide; Et 3 N represents triethylamine; K 4 FeCN 6 represents bismuth Potassium ferricyanide; n-BuLi for n-butyllithium; PhNTf 2 for N-phenylbis(trifluoromethanesulfonyl)imide; Pd(dppf)Cl 2 for [1,1'-bis(diphenyl) phosphine)ferrocene]palladium dichloride.
- DIPEA stands for N,N-
- 2,2,6,6-Tetramethylpiperidine (31.31 g, 221.65 mmol, 37.63 mL) was added to anhydrous tetrahydrofuran (300 mL), cooled to -5 °C, n-butyllithium (2.5M, 94.57mL), react at -5 ⁇ 0°C for 15 minutes, cool down to -60°C, add a solution of compound A1-2 (27g, 73.88mmol) in tetrahydrofuran (60mL), react at -60°C for 0.5 hours, quickly add N,N- Dimethylformamide (108.00 g, 1.48 mol, 113.69 mL), the reaction solution was further stirred at -60°C for 10 minutes.
- reaction solution was stirred at 0 °C for 0.5 hours, n-butyllithium (2.5M, 11.70 mL) was added dropwise, the reaction solution was stirred under this condition for 0.5 hours, cooled to -60 °C, and compound A1- 5 (4.5 g, 9.75 mmol) in tetrahydrofuran (20 mL), the reaction solution was stirred at -60 °C for 0.5 h.
- the aqueous phase was extracted with dichloromethane (50 mL*2), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure.
- the solution of intermediate 7-3 obtained in step 2 was dissolved in dichloromethane (10 mL), and diisopropylethylamine (177.26 mg, 1.37 mmol, 238.90 ⁇ L) and di-tert-butyl dicarbonate ( 149.67 mg, 685.78 ⁇ mol, 157.55 ⁇ L), and the reaction solution was continuously stirred at this temperature for 18 hours.
- compound 7-4 (50.06 mg, 60.91 ⁇ mol) was dissolved in methanol (5 mL), potassium monoperoxysulfate (37.44 mg, 60.91 ⁇ mol) was added, and the reaction solution was stirred at this temperature for 1 hour .
- compound 1-2A (7.42 mg, 46.60 ⁇ mol) was dissolved in anhydrous tetrahydrofuran (1 mL), sodium tert-butoxide (4.48 mg, 46.60 ⁇ mol) was added, and the reaction solution was stirred at this temperature for 30 minutes.
- Compound 7-5 (30.04 mg, 35.85 ⁇ mol) was added, and the reaction solution was continued to stir at this temperature for 1 hour.
- compound 8-4 (2.43 g, 7.31 mmol) was dissolved in dichloromethane (15 mL), and N,N-dimethylformamide dimethylacetal (871.27 mg, 7.31 mmol, 971.31 ⁇ L) was added. ), the reaction solution was stirred at this temperature for 2 hours. Then, the reaction solution was cooled to 0° C., boron trifluoride ether (1.04 g, 7.31 mmol, 902.37 ⁇ L) was added, and the reaction solution was continuously stirred for 1 hour.
- compound 8-6 (1.14 g, 3.31 mmol) and 2-methylthiourea (1.87 g, 9.93 mmol) were added to ethanol (20 mL), and sodium carbonate (1.05 g, 9.93 mmol) was added to react The temperature of the liquid was raised to 60°C and stirring was continued for 15 hours.
- compound 8-7 (1.34 g, 3.49 mmol) was dissolved in N,N-dimethylformamide (20 mL), and N,N diisopropylethylamine (1.35 g, 10.47 mmol, 1.82 ⁇ L) and N-phenylbistrifluoromethanesulfonimide (1.87 g, 5.24 mmol), and the reaction was stirred at this temperature for 3 hours.
- the reaction solution was diluted with ethyl acetate (100 mL), washed with water (20 mL*2) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure.
- compound 9-9 (855 mg, 1.33 mmol) was dissolved in N,N-dimethylformamide (10 mL), and N,N diisopropylethylamine (515.68 mg, 3.99 mmol, 694.99 mmol) was added. ⁇ L) and N-phenylbistrifluoromethanesulfonimide (570.17 mg, 1.60 mmol), and the reaction was stirred at this temperature for a further 3 hours. The reaction solution was diluted with ethyl acetate (50 mL), washed with water (15 mL*4), dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure.
- compound 1-2A (101.56 mg, 637.96 ⁇ mol) was dissolved in anhydrous tetrahydrofuran (2 mL), sodium tert-butoxide (40.87 mg, 425.31 ⁇ mol) was added, and the reaction solution was stirred for 1 hour at this temperature , compound 9-12 (185 mg, 212.65 ⁇ mol) was added, and the reaction solution was continued to stir at this temperature for 1 hour.
- compound A1-7 (518 mg, 881.62 ⁇ mol) was dissolved in anhydrous tetrahydrofuran (2 mL), the reaction solution was cooled to -78 °C, dimethyl copper lithium (0.5 M, 5.29 mL) was added dropwise, and the reaction solution was Stirring was continued at this temperature for 0.5 hour.
- compound 1-2A (47.21 mg, 296.56 ⁇ mol) was dissolved in anhydrous tetrahydrofuran (1 mL), sodium tert-butoxide (19.00 mg, 197.71 ⁇ mol) was added, and the reaction solution was stirred at this temperature for 1 hour , Compound 10-5 (86.00 mg, 98.85) was added, and the reaction solution was continued to stir at this temperature for 1 hour.
- Dissolve 11-1 (10g, 44.39mmol, 1eq) in THF (100mL), add LDA (2M, 24.41mL, 1.1eq) dropwise at -78°C, continue stirring for 0.5hr after the dropwise addition, and then dropwise add 11-2A (18.30 g, 46.61 mmol, 1.05 eq) in THF (50 mL), stirred for 0.5 hr and at room temperature for 0.5 hr.
- Step 7 Preparation of the hydrochloride salt of compound 11A and the hydrochloride salt of compound 11B
- Trifluoroacetic acid (5 mL) was added to a solution of 11-7 (500 mg, 535.31 ⁇ mol, 1 eq) in dichloromethane (5 mL), and the system was stirred at 20 °C for 1 hour.
- Xtimate C18 150*40mm*5 ⁇ m; mobile phase: [water (0.05% hydrochloric acid)-acetonitrile]; (acetonitrile)%: 10%-30%, 10min) to separate the hydrochloric acid salt of compound 11A and the hydrochloric acid of compound 11B Salt, MS m/z 594.1 [M+H] + .
- raw material A1-4 (5 g, 10.59 mmol) and copper powder (3.36 g, 52.93 mmol) were added to a 100-milliliter jar, followed by DMSO (40 mL) and pentafluoroiodoethane (5.21 g, 21.17 mmol) ), heated to 120°C and stirred for 12 hours after sealing. 50 ml of saturated brine and 200 ml of methyl tert-butyl ether were added to the reaction solution, stirred for 10 minutes, filtered, and the aqueous phase was removed by static separation.
- reaction solution was slowly added to 50 ml of saturated aqueous ammonium chloride solution to quench, and 100 ml of methyl tert-butyl ether was added and stirred for 5 minutes, the aqueous phase was removed, the organic phase was concentrated under reduced pressure, and the residue was purified by column machine (eluent). : 10-20% ethyl acetate/petroleum ether) to give compound 12-2.
- MS m/z 628.2 [M+H] + .
- Step 10 Preparation of Formate Salt of Compound 12, Compound 12A and Compound 12B
- Trifluoroacetic acid (0.5 mL) was added to a solution of raw material 12-9 (0.1 g, 101.52 ⁇ mol) in dichloromethane (1.5 mL) at room temperature of 25 °C, followed by stirring for 4 hours.
- the reaction solution was directly concentrated under reduced pressure, and the residue was subjected to Preparative HPLC purification (chromatographic column: Phenomenex Luna C18 75*30mm*3 ⁇ m; mobile phase: [water (0.025% formic acid)-acetonitrile]; (acetonitrile)%: 1%-35%, 8min) to obtain the formate salt of 12 .
- Trifluoroacetic acid (5mL) was added to 13-8 (0.6g, 692.02 ⁇ mol, 1eq), the system was stirred at 55°C for 5 hours, the reaction solution was spin-dried, and separated by preparative HPLC (chromatographic column: Phenomenex C18 150*40mm *5 ⁇ m; mobile phase: [water (0.05% hydrochloric acid)-acetonitrile]; (acetonitrile) %: 1%-30%, 10 min) to obtain the hydrochloride salt of compound 13.
- Trifluoroacetic acid (1 mL) was added to 15-3 (40 mg, 1 eq), the system was stirred at 55° C. for 2 hours, the reaction solution was spun dry, and passed through preparative HPLC (chromatographic column: Xtimate C18 150*40mm*5 ⁇ m; mobile phase : [water (0.05% hydrochloric acid)-acetonitrile]; (acetonitrile) %: 1%-30%, 10 min) to obtain the hydrochloride of compound 15. MS m/z: 605.0 [M+H] + .
- Trifluoroacetic acid (5 mL) was added to 16-3 (0.3 g, 302.14 ⁇ mol, 1 eq), the system was stirred at 55° C. for 5 hours, the reaction solution was spun dry, and passed through preparative HPLC (chromatographic column: Xtimate C18 150*40mm* 5 ⁇ m; mobile phase: [water (0.05% hydrochloric acid)-acetonitrile]; (acetonitrile)%: 1%-30%, 10 min) separation to obtain the hydrochloride of compound 16. MS m/z: 653.3 [M+H] + .
- 17-1 (0.4 g, 427.21 ⁇ mol, 1 eq) was weighed, DCM (10 mL) and m-CPBA (86.73 mg, 427.21 ⁇ mol, 85% content, 1 eq) were added, and the reaction was carried out at 25° C. for 1 hr. Sodium bicarbonate was added to quench, extracted with DCM, dried over anhydrous sodium sulfate, and spin-dried to obtain 17-2, which was directly put into the next step. MS m/z: 952.4 [M+H] + .
- Trifluoroacetic acid (6mL) was added to 17-3 (0.3g, 302.14 ⁇ mol, 1eq), the system was stirred at 25°C for 5 hours, the reaction solution was spun dry, and passed through a preparative HPLC column: Xtimate C18 150*40mm*5 ⁇ m ; mobile phase: [water (0.025% formic acid)-acetonitrile]; (acetonitrile)%: 17%-57%, 8 min) separation to obtain the formate salt of compound 17-4. MS m/z: 707.4 [M+H] + .
- Trifluoroacetic acid (5 mL) was added to 18-3 (60 mg, 108.77 ⁇ mol, 1 eq), the system was stirred at 50°C for 2 hours, the reaction solution was spun dry, and separated by acid HPLC (chromatographic column: Xtimate C18 150*40mm* 5 ⁇ m; mobile phase: [water (0.05% hydrochloric acid)-acetonitrile]; (acetonitrile)%: 1%-30%, 10min), and then basic separation (chromatographic column: Phenomenex C18 80*40mm*3 ⁇ m; mobile phase: [ Water (0.5% ammonia water)-acetonitrile]; (acetonitrile)%: 40%-70%, 8 min) to give compound 18. MS m/z: 552.3 [M+H] + .
- 19-1 (0.07 g, 89.52 ⁇ mol, 1 eq) was weighed, DCM (10 mL) was added, m-CPBA (18.17 mg, 89.52 ⁇ mol, 85% content, 1 eq) was added, and the reaction was carried out at 25° C. for 1 hr. Sodium bicarbonate was added to quench, extracted with DCM, dried over anhydrous sodium sulfate, and spin-dried to obtain 19-2, which was directly put into the next step. MS m/z: 798.3 [M+H] + .
- Trifluoroacetic acid (3 mL) was added to 19-3 (50 mg, 55.99 ⁇ mol, 1 eq), the system was stirred at 55°C for 5 hours, the reaction solution was spun dry, and separated by acidic HPLC (chromatographic column: Xtimate C18 150*40mm*5 ⁇ m ; Mobile phase: [water (0.05% hydrochloric acid)-acetonitrile]; (acetonitrile)%: 1%-30%, 10 min) to obtain the hydrochloride of compound 19. MS m/z: 553.3 [M+H] + .
- reaction solution was poured into 1 L of water, 500 mL of methyl tert-butyl ether was added and stirred, the organic phase was collected after separation, and the aqueous phase was extracted with methyl tert-butyl ether (500 mL*2).
- the organic phases were combined, washed with saturated brine (1 L ⁇ 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
- 400 mL of petroleum ether was added to the crude product, slurried for 2 hours, filtered, and the filter cake was rinsed with petroleum ether (100 mL*2), and then spin-dried to obtain compound 20-2.
- MS m/z 430.0 [M+H] + .
- 2,2,6,6-Tetramethylpiperidine (39.39g, 278.87mmol, 47.34mL, 3eq) was added to anhydrous tetrahydrofuran (400mL), cooled to -10°C, replaced with nitrogen three times, and dropped under nitrogen protection
- Add n-butyllithium (2.5M, 111.55mL, 3eq)
- react at -10°C for 10 minutes then cool down to -60°C
- dropwise add compound 20-2 (40g, 92.96mmol, 1eq) in anhydrous tetrahydrofuran (100mL)
- N,N-dimethylformamide (67.94g, 929.56mmol, 71.52mL, 10eq) was rapidly added, and the reaction was continued for 10 minutes.
- reaction solution was filtered through celite, and the filter cake was rinsed with methyl tert-butyl ether (300 mL*4), washed with 1 L of water, washed with 1 L of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain Compound 20-4.
- Dissolve 1-2A (77.10mg, 484.31 ⁇ mol, 2.5eq) in tetrahydrofuran (3mL), cool down to -15°C, then add sodium tert-butoxide (37.24mg, 387.45 ⁇ mol, 2eq), continue stirring at -15°C for 0.5hr Then, a solution of compound 20-11 (160 mg, 193.73 ⁇ mol, 1 eq) in tetrahydrofuran (1 mL) was added, and stirring was continued for 1 hr.
- Step 12 Synthesis of the hydrochloride salt of compound 20, compound 20A and compound 20B
- compound 21-1 (20g, 137.40mmol, 1eq), N,N-dimethylformamide (200mL), potassium iodide (22.81g, 137.40mmol, 1eq), anhydrous potassium carbonate ( 47.47g, 343.50mmol, 2.5eq), p-methoxybenzyl chloride (44.11g, 281.67mmol, 38.36mL, 2.05eq) was added under stirring, then the temperature was raised to 65°C and stirred for 4hr. The algae was filtered, the filter cake was rinsed with 200 mL of methyl tert-butyl ether, and then 200 mL of water was added to the filtrate for extraction.
- 2,2,6,6-Tetramethylpiperidine (43.93g, 311.00mmol, 52.80mL, 4eq) was dissolved in tetrahydrofuran (300mL), then cooled to -5°C, n-butyllithium (2.5M, 124.40 mL, 4eq), stirred for 0.5hr, then cooled to -60°C, added compound 21-2 (30g, 77.75mmol, 1eq) in tetrahydrofuran (30mL), stirred for 0.5hr, and then added N,N-dimethylformamide (113.66g, 1.55moL, 119.64mL, 20eq), continue stirring for 0.5hr.
- 2,2,6,6-Tetramethylpiperidine (81.22g, 574.98mmol, 97.62mL, 4eq) was added to anhydrous tetrahydrofuran (500mL), cooled to -5°C, and n-butyllithium (2.5°C) was added dropwise.
- MS m/z 745.3 [M+H] + .
- reaction solution was spin-dried, 15 mL of water and 80 mL of ethyl acetate were added to the residue, and the pH was adjusted to 6-7 with 2M hydrochloric acid, the organic phase was separated, the aqueous phase was extracted with ethyl acetate (50 mL ⁇ 3), and the organic phases were combined, Dry with anhydrous sodium sulfate, remove the drying agent by filtration, and concentrate the filtrate to obtain crude compound 24-4.
- MS m/z 670.2 [M+H] + .
- Compound 29-4 (20g, 48.47mmol, 1eq) was added to anhydrous tetrahydrofuran (200mL) and water (50mL), cooled to 0°C, and sodium periodate (31.10g, 145.42mmol, 8.06mL, 3eq) was added. and osmium tetroxide (1.5g, 5.90mmol, 306.12 ⁇ L, 1.22e-1eq), slowly warmed to 18°C, and reacted for 1 hour.
- reaction solution was added to 300 mL of 10% sodium thiosulfate solution, extracted with ethyl acetate (100 mL*2), washed with 500 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated.
- control compound stock solution 1 mM
- concentration of the test compound stock solution 10 mM.
- the compound of the present invention has a significant inhibitory effect on KRAS G12D enzyme.
- AGS cells were seeded in a transparent 96-well cell culture plate, 80 ⁇ L of cell suspension per well, each well containing 10,000 cells, the cell plate was placed in a carbon dioxide incubator, and incubated at 37 degrees overnight;
- the compound of the present invention has a significant inhibitory effect on p-ERK in AGS cells.
- GP2D cells were seeded in a transparent 96-well cell culture plate, 80 ⁇ L of cell suspension per well, each well containing 8000 cells, the cell plate was placed in a carbon dioxide incubator, and incubated at 37 degrees overnight;
- the hydrochloride salt of compound 11A 3.4 The hydrochloride salt of compound 11B 75.9 Formate salt of compound 12 20.9 The hydrochloride salt of compound 14 5.2 Compound 15 hydrochloride 8.4 The hydrochloride salt of compound 16 2.9 Compound 17 27.1 Compound 18 66.4 The hydrochloride salt of compound 19 17.5 Compound 20B 1.3 The hydrochloride salt of compound 21 2.6 The hydrochloride salt of compound 22 2.7 Formate salt of compound 23 23.4 The hydrochloride salt of compound 25 96.4 The hydrochloride salt of compound 26 18.8 The hydrochloride salt of compound 27 118.3
- the compound of the present invention has a significant inhibitory effect on p-ERK in GP2D cells.
- PANC0403 cells were purchased from Nanjing Kebai; RPMI-1640 medium was purchased from Biological Industries; fetal bovine serum was purchased from Biosera; Advanced Phospho-ERK1/2 (THR202/TYR204) KIT was purchased from Cisbio.
- the KIT composition of Advanced Phospho-ERK1/2 (THR202/TYR204) is shown in Table 5.
- PANC0403 cells were seeded in a transparent 96-well cell culture plate, 80 ⁇ L of cell suspension per well, each well containing 10,000 PANC0403 cells, the cell plate was placed in a carbon dioxide incubator, and incubated at 37 degrees overnight;
- the compound to be tested was diluted with 100% DMSO to 2mM as the first concentration, and then 5-fold diluted with a pipette to the eighth concentration, i.e., diluted from 2mM to 25.6nM.
- the IC50 value can be obtained by curve fitting with four parameters (log(inhibitor) vs.response- in GraphPad Prism -Variable slope mode derived).
- Min well negative control well reads 0.5% DMSO cell well cell lysate
- the compound of the present invention has a significant inhibitory effect on p-ERK in PANC0403 cells.
- RPMI 1640 DMEM
- PBS Phosphate Buffered Saline
- FBS Fetal Bovine Serum
- Antibiotic-antimycotic Antibiotic-Antifungal
- L-glutamine L-Glutamine
- DMSO Dimethyl Sulfoxide
- the tumor cell lines were cultured in a 37°C, 5% CO2 incubator according to the culture conditions indicated in the culture method. Periodically passaged, cells in logarithmic growth phase were taken for plating.
- the plates were incubated overnight in an incubator at 37°C, 5% CO2 , and 100% relative humidity.
- the solution in the ULA plate was then transferred to a black bottom plate (#655090) and left at room temperature for 25 minutes to stabilize the luminescent signal.
- Luminescent signals were detected on a 2104 EnVision plate reader.
- IR(%) (1 ⁇ (RLU compound ⁇ RLU blank control)/(RLU vehicle control ⁇ RLU blank control)*100%.
- the inhibition rates of different concentrations of compounds were calculated in Excel, and then GraphPad Prism software was used to make inhibition curves and calculate related parameters, including minimum inhibition rate, maximum inhibition rate and IC 50 .
- the compound of the present invention has the inhibitory effect on KRAS G12D cell mutation.
- Plasma samples with a compound concentration of 2 ⁇ M were prepared from the plasma of the above five species respectively, placed in a 96-well rapid equilibrium dialysis device, and dialyzed against phosphate buffer solution at 37 ⁇ 1 °C for 4 h. Warfarin was used as the control compound in this experiment.
- the concentrations of analytes in plasma and dialysis buffer were determined by LC-MS/MS method.
- the unbound rate (%) of the hydrochloride salt of Compound 1 at the test concentration of 2 ⁇ M is shown in Table 10 below.
- the recovery rate (%) of compound 1 in the dialysis device was 82.4-109.5, which met the requirements for recovery rate and stability in this experiment.
- the compounds of the present invention showed better free state concentrations in the plasma of the above five species.
- Test compounds were mixed with 5% DMSO + 95% (10% HP- ⁇ -CD) in water, vortexed and sonicated to prepare 0.5 mg/mL clear solution (intravenous) or 3 mg/mL clear solution (oral), microporous After filtration through the filter membrane, it is ready for use.
- Male SD mice aged 7 to 10 weeks were selected, and the candidate compound solution was administered intravenously at a dose of about 2 mg/kg.
- Candidate compound solutions are administered orally at a dose of approximately 30 mg/kg.
- Whole blood was collected for a certain period of time, plasma was prepared, drug concentration was analyzed by LC-MS/MS method, and pharmacokinetic parameters were calculated by Phoenix WinNonlin software (Pharsight, USA).
- the compounds of the present invention have good oral bioavailability.
- GP2D cell subcutaneous xenograft tumor Balb/c nude mouse model 0.2 mL (2 ⁇ 10 6 ) GP2D cells (plus Matrigel, volume ratio of 1:1) were subcutaneously inoculated into each mouse On the right back, when the average tumor volume reached 149mm 3 , group administration was started, with 6 mice in each group. On the day of the experiment, the animals were given the corresponding drugs according to the groups.
- the first group G1 was set as a negative control group, which was given 5% DMSO+95% (10% HP- ⁇ -CD) by gavage alone, the second group G2- the fourth group G4 was given the hydrochloride of compound 1, and the dosage was And the scheme is shown in Table 13.
- PO oral
- QD means once a day
- BID means once a day.
- the body weight and tumor size of the animals were measured twice a week, while the clinical symptoms of the animals were observed and recorded every day, and the last weighed animal body weight was referenced for each administration.
- the hydrochloride of compound 1 has a significant inhibitory effect on the xenograft tumor of human colon cancer GP2D mice.
- the second group G2 (3mg/kg, PO, BID) on the 20th day, the tumor volume inhibition rate TGI (%) was 19.4%;
- the third group G3 (10mg/kg, PO, BID) and the fourth group G4 (30mg/kg, PO, BID) on the 20th day, the tumor volume inhibition rate TGI (%) were 53.9 % and 83.7%; the detailed results are shown in Table 14.
- N/A means not detected.
Abstract
涉及一类嘧啶并吡喃类化合物，具体公开了式(III)所示化合物及其药学上可接受的盐。
Description
本发明主张如下优先权：
CN202110139674.X，申请日：2021年02月01日；
CN202110258547.1，申请日：2021年03月09日；
CN202110706033.8，申请日：2021年06月24日；
CN202210070174.X，申请日：2022年01月20日。
本发明涉及一类嘧啶并吡喃类化合物，具体涉及式(III)所示化合物及其药学上可接受的盐。
RAS癌基因突变是人类癌症中最常见的激活突变，发生在30％的人类肿瘤中。RAS基因家族包括三个亚型(KRAS、HRAS和NRAS)，其中85％的RAS驱动的癌症是由KRAS亚型突变引起的。KRAS突变常见于实体肿瘤中，如：肺腺癌、胰腺导管癌和结直肠癌等。在KRAS突变肿瘤中，80％的致癌突变发生在密码子12上，最常见的突变包括：p.G12D(41％)、p.G12V(28％)和p.G12C(14％)。
KRAS是一种鼠类肉瘤病毒癌基因，是RAS蛋白中的重要一员。KRAS好像分子开关，当正常时能控制调控细胞生长的路径；KRAS基因突变后，可以不依赖于上游生长因子受体信号，独立向下游通路传输生长和增殖信号，造成不受控制的细胞生长和肿瘤进展。同时KRAS基因是否有突变，也是肿瘤预后的一个重要指标。
目前，直接靶向KRAS突变的小分子主要集中在KRAS
G12C领域。其中，Amgen公司的AMG510和和Mirati Therapeutics的MRTX849在临床研究中，对KRAS
G12C突变的肿瘤患者都展现出了良好的治疗效果。但至今还没有KRAS
G12D小分子进入临床研究阶段，KRAS
G12D突变的肿瘤患者也还没有从精准医疗中获益。
发明内容
本发明提供了式(III)所示化合物或其药学上可接受的盐，
结构单元
选自
T
1选自CR
7R
8、NR
9和O；
T
2选自CH和N；
L
1选自-CH
2-和键；
R
1、R
2、R
3、R
4和R
5分别独立地选自H和C
1-3烷基，所述C
1-3烷基任选被1、2或3个R
a取代；
R
6选自C
6-10芳基和5-10元杂芳基，所述C
6-10芳基和5-10元杂芳基任选被1、2、3、4或5个R
b取代；
R
7和R
8分别独立地选自H、CH
3和NH
2；
R
9选自H和CH
3；
R
10选自4-8元杂环烷基和
所述4-8元杂环烷基和
任选被1、2或3个R
c取代；
R
11和R
12分别独立地选自H、C
1-3烷基和C
3-5环烷基，所述C
1-3烷基和C
3-5环烷基任选被1、2或3个卤素取代；
结构单元
选自5-6元杂环烯基；
结构单元
选自C
3-5环烷基；
结构单元
选自4-5元杂环烷基；
m选自0、1或2；
n选自0、1或2；
p选自1或2；
q选自1、2或3；
r选自1或2；
s选自1、2或3；
各R
a分别独立地选自F、Cl、Br和I；
各R
b分别独立地选自F、Cl、Br、I、OH、NH
2、CN、C
1-3烷基、C
1-3烷氧基、C
2-3炔基、C
2-3烯基、-C(＝O)C
1-
3烷基和C
3-5环烷基，所述C
1-3烷基、C
1-3烷氧基、C
2-3炔基、C
2-3烯基、-C(＝O)C
1-3烷基和C
3-5环烷基任选被1、2、3、4或5个R取代；
各R
c分别独立地选自H、F、Cl、Br、I、OH、CN、C
1-3烷基、C
1-3烷氧基和-C
1-3烷基-O-C(＝O)-C
1-3烷氨基；
各R分别独立地选自F、Cl、Br和I。
在本发明的一些方案中，所述R
1、R
2、R
3、R
4和R
5分别独立地选自H、CH
3、CH
2CH
3和CH(CH
3)
2，所述CH
3、CH
2CH
3和CH(CH
3)
2任选被1、2或3个R
a取代，其他变量如本发明所定义。
在本发明的一些方案中，所述R
1、R
2、R
3、R
4和R
5分别独立地选自H和CH
3，其他变量如本发明所定义。
在本发明的一些方案中，所述结构单元
选自
其他变量如本发明所定义。
在本发明的一些方案中，所述结构单元
选自
其他变量如本发明所定义。
在本发明的一些方案中，所述各R
b分别独立地选自F、Cl、Br、I、OH、NH
2、CN、CH
3、CH
2CH
3、OCH
3、OCH
2CH
3、-CH＝CH
2、-CH
2-CH＝CH
2、-C≡CH、-C(＝O)CH
3和环丙基，所述CH
3、CH
2CH
3、OCH
3、 OCH
2CH
3、-CH＝CH
2、-CH
2-CH＝CH
2、-C≡CH、-C(＝O)CH
3和环丙基任选被1、2、3、4或5个R取代，其他变量如本发明所定义。
在本发明的一些方案中，所述各R
b分别独立地选自F、Cl、Br、I、OH、NH
2、CN、CH
3、CF
3、CH
2CH
3、CF
2CF
3、-CH＝CH
2、-C≡CH、-C(＝O)CH
3和环丙基，其他变量如本发明所定义。
在本发明的一些方案中，所述R
6选自苯基、吡啶基、萘基、吲哚基和吲唑基，所述苯基、吡啶基、萘基、吲哚基和吲唑基任选被1、2、3、4或5个R
b取代，其他变量如本发明所定义。
在本发明的一些方案中，所述R
6选自
其他变量如本发明所定义。
在本发明的一些方案中，所述各R
c分别独立地选自H、F、Cl、Br、OH、CN、CH
3、CH
2CH
3、CH
2CF
3、OCH
3、OCF
3和
其他变量如本发明所定义。
在本发明的一些方案中，所述R
10选自四氢吡咯基、六氢-1H-吡咯里嗪基和1,2,3,4-四氢异喹啉基，所述四氢吡咯基、六氢-1H-吡咯里嗪基和1,2,3,4-四氢异喹啉基任选被1、2或3个R
c取代，其他变量如本发明所定义。
在本发明的一些方案中，所述R
10选自
其他变量如本发明所定义。
在本发明的一些方案中，所述R
10选自
其他变量如本发明所定义。
在本发明的一些方案中，所述R
11和R
12分别独立地选自H和CH
3，其他变量如本发明所定义。
本发明提供了式(III)所示化合物或其药学上可接受的盐，
结构单元
选自
T
1选自CR
7R
8、NR
9和O；
T
2选自CH和N；
L
1选自-CH
2-和键；
R
1、R
2、R
3、R
4和R
5分别独立地选自H和C
1-3烷基，所述C
1-3烷基任选被1、2或3个R
a取代；
R
6选自C
6-10芳基和5-10元杂芳基，所述C
6-10芳基和5-10元杂芳基任选被1、2、3、4或5个R
b取代；
R
7和R
8分别独立地选自H、CH
3和NH
2；
R
9选自H和CH
3；
R
10选自4-8元杂环烷基和
所述4-8元杂环烷基和
任选被1、2或3个R
c取代；
R
11和R
12分别独立地选自H、C
1-3烷基和C
3-5环烷基，所述C
1-3烷基和C
3-5环烷基任选被1、2或3个卤素取代；
结构单元
选自5-6元杂环烯基；
结构单元
选自C
3-5环烷基；
结构单元
选自4-5元杂环烷基；
m选自0、1或2；
n选自0、1或2；
p选自1或2；
q选自1、2或3；
r选自1或2；
s选自1、2或3；
各R
a分别独立地选自F、Cl、Br和I；
各R
b分别独立地选自F、Cl、Br、I、OH、NH
2、CN、C
1-3烷基、C
1-3烷氧基、C
2-3炔基、C
2-3烯基和C
3-5环烷基，所述C
1-3烷基、C
1-3烷氧基、C
2-3炔基、C
2-3烯基和C
3-5环烷基任选被1、2或3个R取代；
各R
c分别独立地选自H、F、Cl、Br、OH、CN、C
1-3烷基、C
1-3烷氧基和-C
1-3烷基-O-CO-C
1-3烷氨基；各R分别独立地选自F、Cl和Br；
在本发明的一些方案中，所述R
1、R
2、R
3、R
4和R
5分别独立地选自H、CH
3、CH
2CH
3和CH(CH
3)
2，所述CH
3、CH
2CH
3和CH(CH
3)
2任选被1、2或3个R
a取代，其他变量如本发明所定义。
在本发明的一些方案中，所述R
1、R
2、R
3、R
4和R
5分别独立地选自H和CH
3，其他变量如本发明所定义。
在本发明的一些方案中，所述结构单元
选自
其他变量如本发明所定义。
在本发明的一些方案中，所述结构单元
选自
其他变量如本发明所定义。
在本发明的一些方案中，所述各R
b分别独立地选自F、Cl、Br、I、OH、NH
2、CN、CH
3、CH
2CH
3、OCH
3、OCH
2CH
3、-CH＝CH
2、-CH
2-CH＝CH
2和-C≡CH，所述CH
3、CH
2CH
3、OCH
3、OCH
2CH
3、-CH＝CH
2、-CH
2-CH＝CH
2和-C≡CH任选被1、2或3个R取代，其他变量如本发明所定义。
在本发明的一些方案中，所述各R
b分别独立地选自F、OH、NH
2、CH
3、CF
3、CH
2CH
3和-C≡CH，其他变量如本发明所定义。
在本发明的一些方案中，所述R
6选自苯基、萘基、吲哚基和吲唑基，所述苯基、萘基、吲哚基和吲唑基任选被1、2、3、4或5个R
b取代，其他变量如本发明所定义。
在本发明的一些方案中，所述R
6选自
其他变量如本发明所定义。
在本发明的一些方案中，所述各R
c分别独立地选自H、F、Cl、Br、OH、CN、CH
3、CH
2CH
3、CH
2CF
3、OCH
3、OCF
3和
其他变量如本发明所定义。
在本发明的一些方案中，所述R
10选自四氢吡咯基、六氢-1H-吡咯里嗪基和1,2,3,4-四氢异喹啉基，所述四氢吡咯基、六氢-1H-吡咯里嗪基和1,2,3,4-四氢异喹啉基任选被1、2或3个R
c取代，其他变量如本发明所定义。
在本发明的一些方案中，所述R
10选自
其他变量如本发明所定义。
在本发明的一些方案中，所述R
11和R
12分别独立地选自H和CH
3，其他变量如本发明所定义。
本发明提供了式(II)所示化合物或其药学上可接受的盐，
结构单元
选自
T
1选自CR
7R
8、NR
9和O；
T
2选自CH和N；
L
1选自-CH
2-和键；
R
1、R
2、R
3、R
4和R
5分别独立地选自H和C
1-3烷基，所述C
1-3烷基任选被1、2或3个R
a取代；
R
6选自C
6-10芳基和5-10元杂芳基，所述C
6-10芳基和5-10元杂芳基任选被1、2、3、4或5个R
b取代；
R
7和R
8分别独立地选自H、CH
3和NH
2；
R
9选自H和CH
3；
R
10选自4-8元杂环烷基和
所述4-8元杂环烷基和
任选被1、2或3个R
c取代；
结构单元
选自5-6元杂环烯基；
结构单元
选自C
3-5元环烷基；
结构单元
选自4-5元杂环烷基；
m选自0、1或2；
n选自0、1或2；
p选自1或2；
q选自1、2或3；
r选自1或2；
s选自1、2或3；
各R
a分别独立地选自F、Cl、Br和I；
各R
b分别独立地选自F、Cl、Br、I、OH、NH
2、CN、C
1-3烷基、C
1-3烷氧基、C
2-3炔基、C
2-3烯基和C
3-5环烷基，所述C
1-3烷基、C
1-3烷氧基、C
2-3炔基、C
2-3烯基和C
3-5环烷基任选被1、2或3个R取代；
各R
c分别独立地选自H、F、Cl、Br、OH、CN、C
1-3烷基、C
1-3烷氧基和-C
1-3烷基-O-CO-C
1-3烷氨基；
各R分别独立地选自F、Cl和Br；
在本发明的一些方案中，所述R
1、R
2、R
3、R
4和R
5分别独立地选自H、CH
3、CH
2CH
3和CH(CH
3)
2，所述CH
3、CH
2CH
3和CH(CH
3)
2任选被1、2或3个R
a取代，其他变量如本发明所定义。
在本发明的一些方案中，所述R
1、R
2、R
3、R
4和R
5分别独立地选自H和CH
3，其他变量如本发明所定义。
在本发明的一些方案中，所述结构单元
选自
其他变量如本发明所定义。
在本发明的一些方案中，所述结构单元
选自
其他变量如本发明所定义。
在本发明的一些方案中，所述各R
b分别独立地选自F、Cl、Br、I、OH、NH
2、CN、CH
3、CH
2CH
3、OCH
3、OCH
2CH
3、-CH＝CH
2、-CH
2-CH＝CH
2和-C≡CH，所述CH
3、CH
2CH
3、OCH
3、OCH
2CH
3、-CH＝CH
2、-CH
2-CH＝CH
2和-C≡CH任选被1、2或3个R取代，其他变量如本发明所定义。
在本发明的一些方案中，所述各R
b分别独立地选自F、OH、NH
2、CH
3、CF
3、CH
2CH
3和-C≡CH，其他变量如本发明所定义。
在本发明的一些方案中，所述R
6选自苯基、萘基、吲哚基和吲唑基，所述苯基、萘基、吲哚基和吲唑基任选被1、2、3、4或5个R
b取代，其他变量如本发明所定义。
在本发明的一些方案中，所述R
6选自
其他变量如本发明所定义。
在本发明的一些方案中，所述各R
c分别独立地选自H、F、Cl、Br、OH、CN、CH
3、CH
2CH
3、CH
2CF
3、OCH
3、OCF
3和
其他变量如本发明所定义。
在本发明的一些方案中，所述R
10选自四氢吡咯基、六氢-1H-吡咯里嗪基和1,2,3,4-四氢异喹啉基，所述四氢吡咯基、六氢-1H-吡咯里嗪基和1,2,3,4-四氢异喹啉基任选被1、2或3个R
c取代，其他变量如本发明所定义。
在本发明的一些方案中，所述R
10选自
其他变量如本发明所定义。
本发明提供了式(I)所示化合物或其药学上可接受的盐，
T
1选自CR
7R
8和NR
9；
当
选自单键，T
2选自CH和N；
当
选自双键，T
2选自C；
R
1、R
2、R
3、R
4和R
5分别独立地选自H和C
1-3烷基，所述C
1-3烷基任选被1、2或3个R
a取代；
R
6选自苯基和萘基，所述苯基和萘基任选被1、2、3、4或5个R
b取代；
R
7和R
8分别独立地选自H、CH
3和NH
2；
R
9选自H和CH
3；
或者，R
1和R
2与相连的原子成环使结构单元
形成
或者，R
1和R
4与相连的原子成环使结构单元
形成
或者，R
4和R
5与相连的原子成环使结构单元
形成
或者，R
2和R
7与相连的原子形成四氢吡咯烷基；
或者，R
2和R
3与相连的原子形成C
3-5元环烷基；
或者，R
7和R
8与相连的原子形成4-5元杂环烷基；
m选自0、1或2；
n选自0、1或2；
p选自1或2；
q选自1、2或3；
r选自1或2；
s选自1、2或3；
各R
a分别独立地选自F、Cl、Br和I；
各R
b分别独立地选自F、Cl、Br、I、OH、NH
2、CN、CH
3、CF
3和OCH
3。
在本发明的一些方案中，所述R
1、R
2、R
3、R
4和R
5分别独立地选自H、CH
3、CH
2CH
3和CH(CH
3)
2，所述CH
3、CH
2CH
3和CH(CH
3)
2任选被1、2或3个R
a取代，其他变量如本发明所定义。
在本发明的一些方案中，所述R
1、R
2、R
3、R
4和R
5分别独立地选自H和CH
3，其他变量如本发明所定义。
在本发明的一些方案中，所述结构单元
选自
其他变量如本发明所定义。
在本发明的一些方案中，所述结构单元
选自
其他变量如本发明所定义。
在本发明的一些方案中，所述结构单元
选自
其他变量如本发明所定义。
在本发明的一些方案中，所述R
2和R
7与相连的原子形成
其他变量如本发明所定义。
在本发明的一些方案中，所述R
2和R
3与相连的原子形成
其他变量如本发明所定义。
在本发明的一些方案中，所述R
7和R
8与相连的原子形成
其他变量如本发明所定义。
在本发明的一些方案中，所述结构单元
选自
在本发明的一些方案中，所述结构单元
选自
其他变量如本发明所定义。
在本发明的一些方案中，所述R
6选自
其他变量如本发明所定义。
在本发明的一些方案中，所述化合物或其药学上可接受的盐，其化合物选自，
其中，
T
2、R
6、R
11和R
12如本发明所定义。
在本发明的一些方案中，所述化合物或其药学上可接受的盐，其化合物选自，
其中，
T
2、R
6、R
11和R
12如本发明所定义。
在本发明的一些方案中，所述化合物或其药学上可接受的盐，其化合物选自，
其中，
z选自0、1、2、3、4和5；
T
2、R
b、R
11和R
12如本发明所定义。
在本发明的一些方案中，所述化合物或其药学上可接受的盐，其化合物选自，
其中，
R
b1、R
b2、R
b3、R
b4、R
b5、R
b6和R
b7分别独立地选自H、F、Cl、Br、I、OH、NH
2、CN、C
1-3烷基、C
1-3烷氧基、C
2-3炔基、C
2-3烯基、-C(＝O)C
1-3烷基和C
3-5环烷基，所述C
1-3烷基、C
1-3烷氧基、C
2-3炔基、C
2-3烯基、-C(＝O)C
1-3烷基和C
3-5环烷基任选被1、2、3、4或5个R取代；
各R分别独立地选自F、Cl、Br和I；
T
2、R
11和R
12如本发明所定义。
在本发明的一些方案中，所述R
b1、R
b2、R
b3、R
b4、R
b5、R
b6和R
b7分别独立地选自H、F、Cl、Br、I、OH、NH
2、CN、CH
3、CH
2CH
3、OCH
3、OCH
2CH
3、-CH＝CH
2、-CH
2-CH＝CH
2、-C≡CH、-C(＝O)CH
3和环丙基，所述CH
3、CH
2CH
3、OCH
3、OCH
2CH
3、-CH＝CH
2、-CH
2-CH＝CH
2、-C≡CH、-C(＝O)CH
3和环丙基任选被1、2、3、4或5个R取代，其他变量如本发明所定义。
在本发明的一些方案中，所述R
b1、R
b2、R
b3、R
b4、R
b5、R
b6和R
b7分别独立地选自H、F、Cl、Br、I、OH、NH
2、CN、CH
3、CHF
2、CH
2F、CF
3、CH
2CH
3、CH
2CF
3、CF
2CF
3、OCH
3、OCF
3、-CH＝CH
2、-C≡CH、-C(＝O)CH
3、-C(＝O)CF
3、和环丙基，其他变量如本发明所定义。
在本发明的一些方案中，所述R
b1、R
b2、R
b3、R
b4、R
b5、R
b6和R
b7分别独立地选自H、F、Cl、Br、I、OH、NH
2、CN、CH
3、CF
3、CH
2CH
3、CF
2CF
3、-CH＝CH
2、-C≡CH、-C(＝O)CH
3和环丙基，其他变量如本发明所定义。
在本发明的一些方案中，所述化合物或其药学上可接受的盐，其化合物选自，
其中，
T
2、R
b1、R
b2、R
b3、R
b4、R
b5、R
b6、R
b7、R
11和R
12如本发明所定义。
本发明还有一些方案是由上述变量任意组合而来。
本发明还提供了下式所示化合物或其药学上可接受的盐，
在本发明的一些方案中，所述化合物或其药学上可接受的盐，其选自，
在本发明的一些方案中，所述化合物或其药学上可接受的盐，其选自，
本发明还提供了上述化合物或其药学上可接受的盐在制备治疗与KRAS
G12D突变相关疾病的药物中的应用。
本发明还提供了上述化合物或其药学上可接受的盐在制备治疗与肿瘤相关疾病的药物中的应用。
技术效果
本发明化合物对KRAS
G12D突变的酶有良好的抑制作用，可有效抑制p-ERK，对KRAS
G12D突变的细胞具有良好的细胞增殖抑制活性，可有效抑制体内肿瘤生长，且耐药性佳。本发明化合物具有中等到高程度的血浆结合率，有较好的药代动力学性质。
相关定义
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。
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、有机胺或镁盐或类似的盐。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。
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。
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。
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。
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。
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。
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。
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。
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。
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。
除非另有规定，当某一基团具有一个或多个可连接位点时，该基团的任意一个或多个位点可以通过化学键与其他基团相连。当该化学键的连接方式是不定位的，且可连接位点存在H原子时，则连接化学键时，该位点的H原子的个数会随所连接化学键的个数而对应减少变成相应价数的基团。所述位点与其他基团连接的化学键可以用直形实线键
直形虚线键
或波浪线
表示。例如-OCH
3中的直形实线键表示通过该基团中的氧原子与其他基团相连；
中的直形虚线键表示通过该基团中的氮原子的两端与其他基团相连；
中的波浪线表示通过该苯基基团中的1和2位碳原子与其他基团相连；
表示该哌啶基上的任意可连接位点可以通过1个化学键与其他基团相连，至少包括
这4种连接方式，即使-N-上画出了H原子，但是
仍包括
这种连接方式的基团，只是在连接1个化学键时，该位点的的H会对应减少1个变成相应的一价哌啶基。
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
或直形虚线键
如
表示
代表
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。
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。
除非另有规定，术语“C
1-3烷氨基”表示通过氨基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烷氨基包括C
1-2、C
3和C
2烷氨基等。C
1-3烷氨基的实例包括但不限于-NHCH
3、-N(CH
3)
2、-NHCH
2CH
3、-N(CH
3)CH
2CH
3、-NHCH
2CH
2CH
3、-NHCH
2(CH
3)
2等。
除非另有规定，“C
2-3烯基”用于表示直链或支链的包含至少一个碳-碳双键的由2至3个碳原子组成的碳氢基团，碳-碳双键可以位于该基团的任何位置上。所述C
2-3烯基包括C
3和C
2烯基；所述C
2-3烯基可以是一价、二价或者多价。C
2-3烯基的实例包括但不限于乙烯基、丙烯基等。
除非另有规定，“C
2-3炔基”用于表示直链或支链的包含至少一个碳-碳三键的由2至3个碳原子组成的碳氢基团，碳-碳三键可以位于该基团的任何位置上。其可以是一价、二价或者多价。所述C
2-3炔基包括C
3和C
2炔基。C
2-3炔基的实例包括但不限于乙炔基、丙炔基等。
除非另有规定，术语“4-5元杂环烷基”本身或者与其他术语联合分别表示由4至5个环原子组成的饱和单环基团，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)。此外，就该“4-5元杂环烷基”而言，杂原子可以占据杂环烷基与分子其余部分的连接位置。所述4-5元杂环烷基包括4元和5元杂环烷基。4-5元杂环烷基的实例包括但不限于氮杂环丁基、氧杂环丁基、硫杂环丁基、吡咯烷基、吡唑烷基、咪唑烷基、四氢噻吩基(包括四氢噻吩-2-基和四氢噻吩-3-基等)或四氢呋喃基(包括四氢呋喃-2-基等)等。
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。
除非另有规定，本发明术语“C
6-10芳环”和“C
6-10芳基”可以互换使用，术语“C
6-10芳环”或“C
6-10芳基”表示由6至10个碳原子组成的具有共轭π电子体系的环状碳氢基团，它可以是单环、稠合双环或稠合三环体系，其中各个环均为芳香性的。其可以是一价、二价或者多价，C
6-10芳基包括C
6-9、C
9、C
10和C
6芳基等。C
6-10芳基的实例包括但不限于苯基、萘基(包括1-萘基和2-萘基等)。
除非另有规定，本发明术语“5-10元杂芳环”和“5-10元杂芳基”可以互换使用，术语“5-10元杂芳基”是表示由5至10个环原子组成的具有共轭π电子体系的环状基团，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。其可以是单环、稠合双环或稠合三环体系，其中各个环均为芳香性的。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)。5-10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5-10元杂芳基包括10元、9元、9-10元、5-8元、5-7元、5-6元、5元和6元杂芳基等。所述5-10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)、***基(1H-1,2,3-***基、2H-1,2,3-***基、1H-1,2,4-***基和4H-1,2,4-***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、嘧啶基(包括2-嘧啶基和4-嘧啶基等)、苯并噻唑基(包括5-苯并噻唑基等)、嘌呤基、苯并咪唑基(包括2-苯并咪唑基等)、苯并噁唑基、吲哚基(包括5-吲哚基等)、异喹啉基(包括1-异喹啉基和5-异喹啉基等)、喹喔啉基(包 括2-喹喔啉基和5-喹喔啉基等)或喹啉基(包括3-喹啉基和6-喹啉基等)。
除非另有规定，术语“4-8元杂环烷基”本身或者与其他术语联合分别表示由4至8个环原子组成的饱和环状基团，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)。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。此外，就该“4-8元杂环烷基”而言，杂原子可以占据杂环烷基与分子其余部分的连接位置。所述4-8元杂环烷基包括4-6元、5-6元、4元、5元和6元杂环烷基等。4-8元杂环烷基的实例包括但不限于氮杂环丁基、氧杂环丁基、硫杂环丁基、吡咯烷基、吡唑烷基、咪唑烷基、四氢噻吩基(包括四氢噻吩-2-基和四氢噻吩-3-基等)、四氢呋喃基(包括四氢呋喃-2-基等)、四氢吡喃基、哌啶基(包括1-哌啶基、2-哌啶基和3-哌啶基等)、哌嗪基(包括1-哌嗪基和2-哌嗪基等)、吗啉基(包括3-吗啉基和4-吗啉基等)、二噁烷基、二噻烷基、异噁唑烷基、异噻唑烷基、1,2-噁嗪基、1,2-噻嗪基、六氢哒嗪基、高哌嗪基、高哌啶基或二氧杂环庚烷基等。
除非另有规定，术语“5-6元杂环烯基”本身或者与其他术语联合分别表示包含至少一个碳-碳双键的由5至6个环原子组成的部分不饱和的环状基团，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)。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。此外，就该“5-6元杂环烯基”而言，杂原子可以占据杂环烯基与分子其余部分的连接位置。所述5-6元杂环烯基包括5元和6元杂环烯基等。5-6元杂环烯基的实例包括但不限于
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。
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。
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。
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：hr代表小时；LDA代表二异丙基氨基锂； B
2Pin
2代表联硼酸频那醇酯；Pd(dppf)Cl
2
.CH
2Cl
2代表[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物；DIPEA代表N,N-二异丙基乙胺；NBS代表N-溴代丁二酰亚胺；NIS代表N-碘代丁二酰亚胺；PdCl
2(PPh
3)
2代表双三苯基磷二氯化钯；CuI代表碘化亚铜；Et
3N代表三乙胺；K
4FeCN
6代表亚铁***；n-BuLi代表正丁基锂；PhNTf
2代表N-苯基双(三氟甲烷磺酰)亚胺；Pd(dppf)Cl
2代表[1,1'-双(二苯基膦)二茂铁]二氯化钯。
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。
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。
参考例1
步骤1：化合物A1-2的合成
在干燥的2L三口瓶中，将氢化钠(39.12g,978.08mmol,60％)加入到N,N-二甲基甲酰胺(510mL)中，反应体系为非均相灰色，降温至0℃，氮气保护下滴加化合物A1-1(51g,407.53mmol)的N,N-二甲基甲酰胺(200mL)溶液，继续在0℃反应0.5小时，加入对甲氧基氯苄(140.41g,896.57mmol,122.10mL)，缓慢升温至20℃，并在氮气保护下继续搅拌7.5小时。将反应液缓慢加入到200mL饱和氯化铵中，用甲基叔丁基醚(200mL*2)萃取，合并后的有机相用200mL饱和食盐水洗涤，无水硫酸钠干燥，过滤， 减压除去有机溶剂，所得粗品经硅胶柱层析(洗脱剂：石油醚:乙酸乙酯＝100:0～10:1)分离纯化，得到化合物A1-2。
1H NMR(400MHz,CDCl
3)δ:7.23-7.18(m,4H),6.91-6.87(m,1H),6.82-6.76(m,4H),6.65-6.59(m,2H),4.20(s,4H),3.79(s,6H),2.19(s,3H)。MS m/z:366.1[M+H]
+。
步骤2：化合物A1-3的合成
将2,2,6,6-四甲基哌啶(31.31g,221.65mmol,37.63mL)加入到无水四氢呋喃(300mL)中，降温至-5℃，滴加正丁基锂(2.5M,94.57mL)，-5～0℃反应15分钟，降温至-60℃，加入化合物A1-2(27g,73.88mmol)的四氢呋喃(60mL)溶液，-60℃反应0.5小时，快速加入N,N-二甲基甲酰胺(108.00g,1.48mol,113.69mL)，反应液在-60℃继续搅拌10分钟。向反应液中加入400mL饱和氯化铵，用甲基叔丁基醚(200mL*2)萃取，合并后的有机相用200mL饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压除去有机溶剂，所得粗产物经混合溶剂(石油醚：甲基叔丁基醚＝5:1，70mL)打浆0.5小时，过滤，滤饼干燥，滤液浓缩后经硅胶柱层析(洗脱剂：石油醚：乙酸乙酯＝100:0～10:1)分离纯化，合并滤饼和柱层析得到化合物A1-3。
1H NMR(400MHz,CDCl
3)δ:10.43-10.35(m,1H),7.21-7.18(m,5H),6.92-6.81(m,5H),4.25(s,4H),3.80(s,6H),2.23(s,3H)。MS m/z:394.2[M+H]
+。
步骤3：化合物A1-4的合成
将化合物A1-3(17.8g,45.24mmol)加入到N,N-二甲基甲酰胺(170mL)中，加入溴代丁二酰亚胺(8.05g,45.24mmol)，反应液在20℃下继续搅拌20分钟。将反应液加入到300mL的水中，用甲基叔丁基醚(150mL*2)萃取，合并后的有机相用饱和食盐水(100mL*2)洗涤，无水硫酸钠干燥，过滤，减压除去有机溶剂，所得粗产物经混合溶剂(乙酸乙酯：甲基叔丁基醚＝1:1，50mL)打浆0.5小时，过滤，将滤饼干燥，得到化合物A1-4。
1H NMR(400MHz,CDCl
3)δ:10.39(s,1H),7.17(d,J＝8.8Hz,4H),6.89(d,J＝8.8Hz,1H),6.85-6.82(m,4H),4.22(s,4H),3.79(s,6H),2.28(s,3H)。MS m/z:472.1[M+H]
+，474.1[M+3H]
+。
步骤4：化合物A1-5的合成
将化合物A1-4(19.3g,40.86mmol)加入到N,N-二甲基甲酰胺(190mL)中，反应液在氮气下加入碘化亚铜(15.56g,81.72mmol)和氟磺酰基二氟乙酸甲酯(39.25g,204.30mmol,25.99mL)，反应液升温至100℃继续搅拌1小时。冷却，反应液经硅藻土过滤，滤液加入到300mL的水中，用甲基叔丁基醚(150mL*2)萃取，合并后的有机相用饱和食盐水(200mL*2)洗涤，无水硫酸钠干燥，过滤，减压除去有机溶剂，所得粗产物经硅胶柱层析(洗脱剂：石油醚：乙酸乙酯＝100:0-10:1)分离纯化，得到化合物A1-5。
1H NMR(400MHz,CDCl
3)δ:10.37(q,J＝4.0Hz,1H),7.18-7.11(m,4H),6.89-6.82(m,4H),6.73(d,J＝8.8Hz,1H),4.36(s,4H),3.81(s,6H),2.37-2.29(m,3H)。MS m/z:484.0[M+Na]
+。
步骤5：化合物A1-6的合成
将无水四氢呋喃(50mL)和氢化钠(1.17g,29.26mmol,60％)加入到干燥的三口烧瓶中，降温至0℃，氮气保护下滴加乙酰乙酸甲酯(3.40g,29.26mmol,3.15mL)，反应液在0℃下继续搅拌0.5小时，滴加正丁基锂(2.5M,11.70mL)，反应液在该条件下继续搅拌0.5小时，降温至-60℃，滴加化合物A1-5(4.5g,9.75mmol)的四氢呋喃(20mL)溶液，反应液在-60℃继续搅拌0.5小时。向反应液中加入100mL饱和氯化铵溶液，用乙酸乙酯30mL的萃取，有机相用80mL饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压除去有机溶剂，所得粗品经硅胶柱层析(洗脱剂：石油醚：乙酸乙酯＝100:0-3:1)分离纯化，得到化合物A1-6。
1H NMR(400MHz,CDCl
3)δ:7.18-7.15(m,4H),6.90-6.78(m,4H),6.61(d,J＝8.8Hz,1H),5.72-5.57 (m,1H),4.31(m,4H),3.81(s,6H)，3.76(s,3H),3.56(s,2H),3.50-3.38(m,1H),2.98-2.93(m,1H),2.38-2.26(m,3H)。MS m/z:578.1[M+H]
+。
步骤6：化合物A1-7的合成
将化合物A1-6(3g,5.19mmol)加入到无水二氯甲烷(30mL)中，加入N,N-二甲基甲酰胺二甲基缩醛(742.74mg,6.23mmol,828.02μL)，反应液在20℃搅拌16小时。加入三氟化硼***(884.66mg,6.23mmol,769.27μL)，在20℃下继续搅拌1小时。将反应液加入到20mL饱和碳酸氢钠溶液中，分液，水相用20mL二氯甲烷萃取，合并后的有机相用无水硫酸钠干燥，过滤，减压除去有机溶剂，所得粗品经硅胶柱层析(洗脱剂：石油醚：乙酸乙酯＝100:0-3:1)分离纯化，得到化合物A1-7。
1H NMR(400MHz,CDCl
3)δ:8.43(d,J＝0.8Hz,1H),7.21-7.10(m,4H),6.91-6.81(m,4H),6.70(d,J＝8.8Hz,1H),5.93(dd,J＝3.2,14.8Hz,1H),4.35(s,4H),3.8(s,3H)，3.81(s,6H),3.38-3.29(m,1H),2.68(dd,J＝3.6,16.8Hz,1H),2.39-2.24(m,3H)。MS m/z:588.2[M+H]
+。
步骤7：化合物A1-8的合成
将化合物A1-7(2.1g,3.57mmol)加入到无水四氢呋喃(21mL)中，降温至-60℃，氮气保护下，加入三仲丁基硼氢化锂(1M,4.29mL)，反应液在-60℃继续搅拌0.5小时。将反应液加入到30mL的饱和氯化铵中，分液，乙酸乙酯(30mL*2)萃取，合并后的有机相用20mL饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压除去有机溶剂，所得粗品经硅胶柱层析(洗脱剂：石油醚：乙酸乙酯＝100:0＝3:1)分离纯化，得到化合物A1-8。
1H NMR(400MHz,CDCl
3)δ:7.167-7.14(m,4H),6.87-6.83(m，4H),6.63(d,J＝8.8Hz,1H),5.05-5.00(m,1H),4.61-4.58(m,1H),4.42-4.24(m,5H),3.85-3.73(m,10H)，3.13-3.05(m,1H),2.47-2.38(m,1H),2.35-2.31(m,3H)。MS m/z:590.1[M+H]
+。
步骤8：化合物A1-9的合成
将化合物A1-8(1.27g,2.15mmol)加入到乙醇(15mL)和水(3mL)中，加入碳酸氢钠(3.62g,43.08mmol,1.68mL)和甲基异硫脲硫酸盐(4.05g,21.54mmol)，反应液在50℃条件下继续搅拌4小时。将反应液加入到40mL水中，用乙酸乙酯(20mL*2)萃取，合并后的有机相用饱和食盐水(20mL*2)洗涤，无水硫酸钠干燥，过滤，减压除去有机溶剂，所得粗品经硅胶柱层析(洗脱剂：石油醚：乙酸乙酯＝100：0-1:1)分离纯化，得到化合物A1-9。
1H NMR(400MHz,CDCl
3)δ:7.22-7.14(m,4H),6.91-6.82(m,4H),6.65(dd,J＝8.4Hz 1H),5.12-5.08(m,1H),4.97-4.91(m,1H),4.67-4.57(m,1H),4.45-4.22(m,4H),3.88-3.74(m,6H),3.43-3.35(m,1H),2.77-2.72(m,1H),2.59(m,3H),2.40-2.31(m,3H)。MS m/z:630.2[M+H]
+。
步骤9：化合物A1和A2的合成
将化合物A1-9(51g,81.00mmol)溶于二氯甲烷(500mL)中，加入N,N二异丙基乙胺(31.40g,242.99mmol,42.32mL)，降温至0～10℃，将三氟甲磺酸酐(34.28g,121.49mmol,20.05mL)缓慢加入到反应液中，在此温度下反应15分钟。反应液倒入饱和氯化铵水溶液(400mL)，分液，水相用二氯甲烷(50mL*2)萃取，合并后的有机相用无水硫酸钠干燥，过滤，减压除去有机溶剂，所得粗品经混合溶剂(石油醚：甲基叔丁基醚＝20:1，100mL)打浆，过滤，滤饼干燥，得到A1-10。取20g A1-10经超临界液相色谱(SFC)分离纯化(柱子:DAICEL CHIRALPAK IG(250mm*50mm,10μm)；流动相:A(CO
2)和B(0.1％NH
3H
2O EtOH)；梯度:EtOH％:11％-11％,8min)。得到A1(柱子：Chiralpak IG-3,3μm，0.46cm id×5cm L；流动相：A(CO
2)和B(EtOH，含0.1％异丙胺)；梯度：B％＝5～50％，3min；流速:3.4mL/min；波 长:220nm；压力:1800psi,Rt＝0.924min,MS:m/z(ESI):762.0[M+H]
+，旋光：
浓度：0.1682g/100mL。)和A2(柱子：Chiralpak IG-3,3μm，0.46cm id×5cm L；流动相：A(CO
2)和B(EtOH，含0.1％异丙胺)；梯度：B％＝5～50％，3min；流速:3.4mL/min；波长:220nm；压力:1800psi,Rt＝1.073min,手性纯度：99.99％，MS:m/z(ESI):762.0[M+H]
+,旋光：
浓度：0.3476g/100mL)。
1H NMR(400MHz,CDCl
3)δ:7.03-7.14(m,4H),6.73-6.82(m,4H),6.57(d,J＝8.4,1H)5.08(d,J＝9.6,1H),4.92(d,J＝15.6,1H),4.67(d,J＝15.6,1H),4.24(q,J＝10,4H),3.719(s,6H)3.42-3.59(m,1H),2.87-3.04(m,1H),2.47(s,3H),2.19-2.35(m,3H)。
实施例1
步骤1:中间体1-1的制备
将化合物A2(80mg,105.02μmol)和化合物1-A1(26.75mg,126.03μmol)溶于N,N-二甲基甲酰胺(2mL)中，加入二异丙基乙胺(40.72mg,315.07μmol,54.88μL)，反应液升温至100℃下继续搅拌1小时。冷却，减压除去有机溶剂，所得粗产物经薄层层析制备板(展开剂：石油醚：乙酸乙酯＝2:1)分离纯化，得到化合物1-1。MS m/z＝824.3[M+H]
+.
步骤2:中间体1-2的制备
将化合物1-1(70mg,84.96μmol)溶于二氯甲烷(2mL)中，加入间氯过氧苯甲酸(34.50mg,169.92μmol,85％含量)，反应液在20℃下继续搅拌3小时。减压除去有机溶剂，所得粗产物经薄层层析制备板(展开剂：二氯甲烷：甲醇＝10:1)分离纯化，得到化合物1-2。MS m/z＝856.2[M+H]
+.
步骤3:中间体1-3的制备
冰水浴条件下，将化合物1-2A(12.09mg,75.94μmol)溶于无水甲苯(1mL)中，加入叔丁醇钠(7.30mg,75.94μmol)，反应液继续搅拌30分钟，加入化合物1-2(50mg,58.42μmol)的甲苯(1mL)溶液，反应液在冰水浴下继续搅拌2小时。减压除去有机溶剂，所得粗产物经薄层层析制备板(展开剂：二氯甲烷：甲醇＝10:1)分离纯化，得到化合物1-3。MS m/z＝935.3[M+H]
+.
步骤4:化合物1的盐酸盐制备
将化合物1-3(40mg,42.78μmol)溶于无水二氯甲烷(2mL)中，加入三氟乙酸(1mL)，反应液在20℃下继续搅拌2小时。减压除去溶剂，所得粗产物通过高效液相色谱法(柱子:Phenomenex Synergi C18150*30mm*4μm；流动相:[水(0.05％盐酸)-乙腈]；(乙腈)％:15％-45％,9分钟)分离纯化，得到化合物1的盐酸盐。
1H NMR(400MHz,CD
3OD)δ:6.86-6.84(d,J＝8.0Hz,1H),5.66-5.53(m,1H),5.27-5.25(m,1H),5.01-4.98(m,1H),4.84-4.77(m,2H),4.30-4.17(m,2H),4.12-3.82(m,5H),3.61-3.58(m,1H),3.51-3.38(m,2H),3.08-3.03(m,1H),2.80-2.47(m,7H),2.44-1.98(m,10H).MS m/z＝595.6[M+H]
+.
实施例2
步骤1:中间体2-1的制备
将化合物A2(80mg,105.02μmol)和化合物2-A1(27.07mg,136.53μmol)溶于N,N-二甲基甲酰胺(1.2mL)中，加入二异丙基乙胺(33.93mg,262.56μmol,45.73μL)，反应液升温至100℃下继续搅拌1小时。冷却，减压除去有机溶剂，所得粗产物经薄层层析制备板(展开剂：石油醚：乙酸乙酯＝3:1)分离纯化，得到化合物2-1。MS m/z＝810.1[M+H]
+.
步骤2:中间体2-2的制备
将化合物2-1(73mg,90.13μmol)溶于二氯甲烷(1mL)中，加入间氯过氧苯甲酸(36.60mg,180.27μmol,85％含量)，反应液在20℃下继续搅拌15小时。减压除去有机溶剂，所得粗产物经薄层层析制备板(展开剂：石油醚：乙酸乙酯＝1:1)分离纯化，得到化合物2-2。MS m/z＝842.0[M+H]
+.
步骤3:中间体2-3的制备
15℃条件下，将化合物1-2A(20.80mg,130.66μmol)溶于无水四氢呋喃(1mL)中，加入叔丁醇钠(12.56mg,130.66μmol)，反应液继续搅拌30分钟，加入化合物2-2(55mg,65.33μmol)，反应液在该温度下继续搅拌1小时。减压除去有机溶剂，所得粗产物经薄层层析制备板(展开剂：二氯甲烷：甲醇＝10:1)分离纯化，得到化合物2-3。MS m/z＝921.4[M+H]
+.
步骤4:化合物2的盐酸盐制备
将化合物2-3(42mg,45.60μmol)溶于无水二氯甲烷(0.5mL)中，加入三氟乙酸(0.25mL)，反应液在15℃下继续搅拌2小时。减压除去溶剂，所得粗产物通过高效液相色谱法(柱子:Phenomenex Synergi C18 150*30mm*4μm；流动相:[水(0.05％盐酸)-乙腈]；(乙腈)％:12％-42％,9分钟)分离纯化，得到化合物2的盐酸盐。MS m/z＝581.6[M+H]
+.
实施例3
步骤1:中间体3-1的制备
将化合物A2(80mg,105.02μmol)和化合物3-1A(24.99mg,126.03μmol)溶于N,N-二甲基甲酰胺(1.2mL)中，加入二异丙基乙胺(40.72mg,315.07μmol,54.88μL)，反应液升温至100℃下继续搅拌1小时。冷却，减压除去有机溶剂，所得粗产物经薄层层析制备板(展开剂：石油醚：乙酸乙酯＝2:1)分离纯化，得到化合物3-1。MS m/z＝810.2[M+H]
+.
步骤2:中间体3-2的制备
将化合物3-1(67mg,82.73μmol)溶于二氯甲烷(1mL)中，加入间氯过氧苯甲酸(33.59mg,165.45μmol,85％含量)，反应液在20℃下继续搅拌5小时。减压除去有机溶剂，所得粗产物经薄层层析制备板(展开剂：石油醚：乙酸乙酯＝1:1)分离纯化，得到化合物3-2。MS m/z＝842.4[M+H]
+.
步骤3:中间体3-3的制备
15℃条件下，将化合物1-2A(15.13mg,95.02μmol)溶于无水四氢呋喃(1mL)中，加入叔丁醇钠(9.13mg,95.02μmol)，反应液继续搅拌30分钟，加入化合物3-2(40mg,47.51μmol)，反应液在该温度下继续搅拌1小时。减压除去有机溶剂，所得粗产物经薄层层析制备板(展开剂：二氯甲烷：甲醇＝10:1)分离纯化，得到化合物3-3。MS m/z＝921.4[M+H]
+.
步骤4:化合物3的盐酸盐制备
将化合物3-3(20mg,21.72μmol)溶于无水二氯甲烷(0.5mL)中，加入三氟乙酸(0.25mL)，反应液在15℃下继续搅拌2小时。减压除去溶剂，所得粗产物通过高效液相色谱法(柱子:Phenomenex Synergi C18 150*30mm*4μm；流动相:[水(0.05％盐酸)-乙腈]；(乙腈)％:12％-42％,9分钟)分离纯化，得到化合物3的盐酸盐。MS m/z＝581.6[M+H]
+.
实施例5
步骤1:中间体5-1的制备
将化合物A2(80mg,105.02μmol)和化合物5-1A(22.30mg,105.02μmol)溶于N,N-二甲基甲酰胺(1mL)中，加入二异丙基乙胺(40.72mg,315.07μmol,54.88μL)，反应液升温至100℃下继续搅拌1小时。冷却，减压除去有机溶剂，所得粗产物经薄层层析制备板(展开剂：石油醚：乙酸乙酯＝5:1)分离纯化，得到化合物5-1。MS m/z＝824.3[M+H]
+.
步骤2:中间体5-2的制备
将化合物5-1(60mg,72.82μmol)溶于二氯甲烷(2mL)中，加入间氯过氧苯甲酸(29.57mg,145.64μmol,85％含量)，反应液在20℃下继续搅拌16小时。减压除去有机溶剂，所得粗产物经薄层层析制备板(展开剂：石油醚：乙酸乙酯＝1:1)分离纯化，得到化合物5-2。MS m/z＝856.3[M+H]
+.
步骤3:中间体5-3的制备
将化合物1-2A(12.09mg,75.94μmol)溶于无水四氢呋喃(1mL)中，加入叔丁醇钠(7.30mg,75.94μmol)，反应液在20℃继续搅拌30分钟，加入化合物5-2(50mg,58.42μmol)，反应液在该温度下继续搅拌1小时。减压除去有机溶剂，所得粗产物经薄层层析制备板(展开剂：二氯甲烷：甲醇＝10:1)分离纯化，得到化合物5-3。MS m/z＝935.3[M+H]
+.
步骤4:化合物5的盐酸盐制备
将化合物5-3(22mg,23.53μmol)溶于无水二氯甲烷(1.4mL)中，加入三氟乙酸(0.7mL)，反应液在20℃下继续搅拌1小时。减压除去溶剂，所得粗产物通过高效液相色谱法(柱子:Phenomenex Synergi C18 150*30mm*4μm；流动相:[水(0.05％盐酸)-乙腈]；(乙腈)％:20％-50％,9分钟)分离纯化，得到化合物5的盐酸盐。
1H NMR(400MHz,CD
3OD)δ:6.86-6.84(d,J＝8.4Hz,1H),5.69-5.51(m,1H),5.27-5.25(m,1H),5.09-5.04(m,2H),5.00-4.94(m,4H),4.81-4.78(m,1H),3.97-3.88(m,3H),3.72-3.68(m,1H),3.53-3.38 (m,5H),3.05-3.01(m,1H),2.66-2.63(m,2H),2.52-2.45(m,1H),2.42-2.15(m,10H).MS m/z:595.1[M+H]
+.
实施例6
步骤1:中间体6-1的制备
将化合物A2(80mg,105.02μmol)和化合物6-1A(22.30mg,105.02μmol)溶于N,N-二甲基甲酰胺(1mL)中，加入二异丙基乙胺(40.72mg,315.07μmol,54.88μL)，反应液升温至100℃下继续搅拌1小时。冷却，减压除去有机溶剂，所得粗产物经薄层层析制备板(展开剂：石油醚：乙酸乙酯＝5:1)分离纯化，得到化合物6-1。MS m/z＝824.5[M+H]
+.
步骤2:中间体6-2的制备
将化合物6-1(70mg,84.96μmol)溶于二氯甲烷(1.5mL)中，加入间氯过氧苯甲酸(34.50mg,169.92μmol,85％含量)，反应液在15℃下继续搅拌6小时。减压除去有机溶剂，所得粗产物经薄层层析制备板(展开剂：石油醚：乙酸乙酯＝1:1)分离纯化，得到化合物6-2。MS m/z＝856.4[M+H]
+.
步骤3:中间体6-3的制备
将化合物1-2A(12.09mg,75.94μmol)溶于无水四氢呋喃(1mL)中，加入叔丁醇钠(7.30mg,75.94μmol)，反应液在15℃继续搅拌30分钟，加入化合物6-2(50mg,58.42μmol)的无水四氢呋喃(0.2mL)溶液，反应液在该温度下继续搅拌1.5小时。减压除去有机溶剂，所得粗产物经薄层层析制备板(展开剂：石油醚：乙酸乙酯＝1:1)分离纯化，得到化合物6-3。MS m/z＝935.6[M+H]
+.
步骤4:化合物6的盐酸盐制备
将化合物6-3(36mg,38.50μmol)溶于无水二氯甲烷(1.0mL)中，加入三氟乙酸(0.5mL)，反应液在15℃下继续搅拌2小时。减压除去溶剂，所得粗产物通过高效液相色谱法(柱子:Phenomenex Synergi C18 150*30mm*4μm；流动相:[水(0.05％盐酸)-乙腈]；(乙腈)％:15％-45％,9分钟)分离纯化，得到化合物6的盐酸盐。MS m/z:595.6[M+H]
+.
实施例7
步骤1:中间体7-2的制备
在20℃下，将化合物7-1(160mg,487.14μmol)溶于二氯甲烷(2mL)中，加入三氟乙酸(2mL)，反应液在该温度下继续搅拌18小时。减压除去有机溶剂，得到粗产物7-2，该化合物不经进一步纯化直接用于下一步反应。
步骤2:中间体7-3的制备
将化合物A2(350.00mg,459.48μmol)和化合物7-2(50.62mg,459.48μmol)溶于N,N-二甲基甲酰胺(2mL)中，加入二异丙基乙胺(178.15mg,1.38mmol,240.10μL)，反应液升温至100℃继续搅拌1小时。冷却，得到化合物7-3的溶液，该溶液不经进一步纯化直接用于下一步反应。MS m/z:722.1[M+H]
+。
步骤3:中间体7-4的制备
在20℃下，将步骤2所得中间体7-3溶液溶于二氯甲烷(10mL)中，加入二异丙基乙胺(177.26mg,1.37mmol,238.90μL)和二碳酸二叔丁酯(149.67mg,685.78μmol,157.55μL)，反应液在该温度下继续搅拌18小时。减压除去有机溶剂，所得粗产物经硅胶柱层析(洗脱剂：乙酸乙酯/石油醚＝0～15％)分离纯化，得到化合物7-4。
1H NMR(400MHz,CD
3OD)δ:7.17-7.14(d,J＝8.8Hz,4H),6.86-6.84(d,J＝8.8Hz,4H),6.64-6.62(d,J＝8.0Hz,1H),6.26-6.20(m,2H),5.20-5.16(m,1H),4.73-4.61(m,4H),4.35-4.29(m,4H),3.81(s,6H),3.35-2.81(m,6H),2.51(s,3H),2.35(s,3H),1.52(s,9H).MS m/z:822.3[M+H]
+。
步骤4:中间体7-5的制备
在20℃下，将化合物7-4(50.06mg,60.91μmol)溶于甲醇(5mL)中，加入单过氧硫酸氢钾(37.44mg,60.91μmol)，反应液在该温度下继续搅拌1小时。减压除去有机溶剂，所得粗产物经薄层层析制备板(展开剂：石油醚：乙酸乙酯＝1：1)分离纯化，得到化合物7-5。MS m/z:838.3[M+H]
+.
步骤5:中间体7-6的制备
在20℃下，将化合物1-2A(7.42mg,46.60μmol)溶于无水四氢呋喃(1mL)中，加入叔丁醇钠(4.48mg,46.60μmol)，反应液在该温度下继续搅拌30分钟，加入化合物7-5(30.04mg,35.85μmol)，反应液在该温度下继续搅拌1小时。减压除去有机溶剂，所得粗产物经薄层层析制备板(展开剂：二氯甲烷：甲 醇＝10:1)分离纯化，得到化合物7-6。MS m/z＝933.5[M+H]
+。
步骤6:化合物7的盐酸盐制备
在20℃下，将化合物7-6(25mg,26.79μmol)溶于无水二氯甲烷(1.0mL)中，加入三氟乙酸(1mL)，反应液在该温度下继续搅拌1小时。减压除去溶剂，所得粗产物通过高效液相色谱法(柱子:Xtimate C18150*40mm*5μm；流动相:[水(0.05％盐酸)-乙腈]；(乙腈)％:1％-30％,10分钟)分离纯化，得到化合物7的盐酸盐。MS m/z:593.5[M+H]
+.
实施例8
步骤1:中间体8-2的制备
冰水浴条件下，将氢化钠(2.33g,58.28mmol,60％含量)悬浮于无水四氢呋喃(120mL)中，加入化合物8-1(10g,44.83mmol)，反应液在该温度下继续搅拌1小时，然后冷却到-78℃，滴加正丁基锂(2.5M,30.48mL)，反应液搅拌1小时，最后加入N,N-二甲基甲酰胺(16.38g,224.15mmol,17.25mL)，所得反应液搅拌0.5小时。用2M盐酸水溶液(10mL)淬灭，然后用乙酸乙酯(50mL*3)萃取，合并有机相，减压除去有机溶剂，所得粗品经硅胶柱层析(洗脱剂：乙酸乙酯/石油醚＝0～30％)分离纯化，得到化合物8-2。
1H NMR(400MHz,CDCl
3)δ:10.42(s,1H),9.10–9.06(m,1H),7.76-7.75(m,1H),7.67-7.66(m,1H),7.59-7.57(m,2H),7.46-7.45(m,1H),5.64(brs,1H)。
步骤2:中间体8-3的制备
冰水浴条件下，将化合物8-2(3.0g,17.42mmol)溶于无水二氯甲烷(50mL)中，加入二异丙基乙胺(6.76g,52.27mmol,9.10mL)和氯甲醚(2.10g,26.14mmol,1.99mL)，所得反应液继续搅拌2小时。减压除去有机溶剂，残留物溶于乙酸乙酯(100mL)中，用水(10mL*3)和饱和食盐水(10mL)洗涤，减压除去有机溶剂，所得粗品经硅胶柱层析(洗脱剂：乙酸乙酯/石油醚＝0～10％)分离纯化，得到化合物8- 3。
1H NMR(400MHz,CDCl
3)δ:10.40(s,1H),9.14-9.11(m,1H),7.82-7.80(m,1H),7.78-7.77(m,1H),7.69-7.67(m,1H),7.57-7.55(m,2H),5.36(s,2H),3.55(s,3H)。
步骤3:中间体8-4的制备
氮气保护下，将氢化钠(414.37mg,10.36mmol,60％含量)悬浮于无水四氢呋喃(8mL)中，混合液冷却到0℃，滴加乙酰乙酸甲酯(1.20g,10.36mmol,1.11mL)，反应液继续搅拌30分钟，滴加正丁基锂(2.5M,4.14mL)，继续搅拌反应30分钟，将反应液冷却到-78℃，滴加化合物8-3(1.12g,5.18mmol)的无水四氢呋喃(2mL)溶液，反应液在该温度下继续搅拌1小时。将反应液用水(20mL)淬灭，用乙酸乙酯(80mL*3)萃取，合并后的有机相用无水硫酸钠干燥，减压除去有机溶剂，所得粗产物经硅胶柱层析(洗脱剂：乙酸乙酯/石油醚＝0～75％)分离纯化，得到化合物8-4。
1H NMR(400MHz,CDCl
3)δ:7.90-7.88(m,1H),7.79-7.77(m,1H),7.49-7.35(m,4H),5.98-5.95(m,1H),5.32(s,2H),3.78(s,3H),3.56(s,2H),3.53(s,3H),3.15-3.01(m,3H).MS m/z:350.2[M+H
2O]
+。
步骤4:中间体8-5的制备
在18℃下，将化合物8-4(2.43g,7.31mmol)溶于二氯甲烷(15mL)中，加入N,N-二甲基甲酰胺二甲缩醛(871.27mg,7.31mmol,971.31μL)，反应液在该温度下继续搅拌2小时。然后将反应液冷却到0℃，加入三氟化硼***(1.04g,7.31mmol,902.37μL)，反应液继续搅拌1小时。减压除去有机溶剂，所得粗品加入乙酸乙酯(100mL)，用水(20mL)，饱和碳酸氢钠水溶液(20mL)和饱和食盐水(10mL)洗涤，减压除去有机溶剂，所得粗品经硅胶柱层析(洗脱剂：乙酸乙酯/石油醚＝0～35％)分离纯化，得到化合物8-5。
1H NMR(400MHz,CDCl
3)δ:8.54(s,1H),7.79-7.77(m,2H),7.49-7.35(m,4H),6.30-6.26(m,1H),5.32(s,2H),3.87(s,3H),3.56(s,3H),3.15-3.01(m,2H).MS m/z:343.2[M+H]
+。
步骤5:中间体8-6的制备
氮气保护下，将化合物8-5(1.42g,4.15mmol)溶于无水四氢呋喃(15mL)中，反应液冷却到-78℃，滴加三仲丁基硼氢化锂(1M,4.15mL)，反应液在该温度下继续搅拌1小时。将反应液用水(1mL)淬灭，用乙酸乙酯(80mL)稀释，有机相用水(20mL)和饱和食盐水(20mL)洗涤，无水硫酸钠干燥，减压除去有机溶剂，所得粗产物经硅胶柱层析(洗脱剂：乙酸乙酯/石油醚＝0～15％)分离纯化，得到化合物8-6。MS m/z:367.1[M+Na]
+。
步骤6:中间体8-7的制备
氮气保护下，将化合物8-6(1.14g,3.31mmol)和2-甲基硫脲(1.87g,9.93mmol)加入到乙醇(20mL)中，加入碳酸钠(1.05g,9.93mmol)，反应液升温至60℃继续搅拌15小时。减压除去有机溶剂，残留物中加入水(15mL)和乙酸乙酯(100mL)，用6M盐酸水溶液调节pH至5-6，分液，有机相用饱和食盐水(20mL)洗涤，减压除去有机溶剂，得到粗品化合物8-7，该化合物不经进一步纯化直接用于下一步反应。MS m/z:385.1[M+H]
+。
步骤7:中间体8-8的制备
在16℃下，将化合物8-7(1.34g,3.49mmol)溶于N,N-二甲基甲酰胺(20mL)中，加入N,N二异丙基乙胺(1.35g,10.47mmol,1.82μμL)和N-苯基双三氟甲烷磺酸亚胺(1.87g,5.24mmol)，反应液在该温度下继续搅拌3小时。反应液用乙酸乙酯(100mL)稀释，用水(20mL*2)和饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，减压除去有机溶剂，所得粗品经硅胶柱层析(洗脱剂：乙酸乙酯/石油醚＝0～10％) 分离纯化，得到化合物8-8。
1H NMR(400MHz,CDCl3)δ:7.92-7.90(m,1H),7.82-7.80(m,1H),7.49-7.46(m,1H),7.43-7.35(m,3H),5.50-5.47(m,1H),5.32(s,2H),5.06-5.02(m,1H),4.94-4.90(m,1H),3.54(s,3H),3.40-3.22(m,2H),2.55(s,3H).MS m/z:517.0[M+H]
+。
步骤8:中间体8-9的制备
将化合物8-8(300mg,580.82μmol)和化合物1-1A(160.29mg,755.07μmol)溶于N,N-二甲基甲酰胺(3mL)中，加入二异丙基乙胺(225.20mg,1.74mmol,303.51μL)，反应液升温至100℃继续搅拌1小时。冷却，减压除去有机溶剂，所得粗产物经硅胶柱层析(洗脱剂：乙酸乙酯/石油醚＝0～25％)分离纯化，得到化合物8-9。
1H NMR(400MHz,CDCl
3)δ:7.98-7.96(m,1H),7.80-7.78(m,1H),7.49-7.36(m,4H),5.50-5.47(m,1H),5.31(s,2H),4.92-4.89(m,1H),4.78-4.75(m,1H),4.36-4.30(m,2H),3.97-3.78(m,1H),3.58-3.30(m,6H),3.19-3.12(m,2H),2.53(s,3H),1.78-1.46(m,13H).MS m/z:579.8[M+H]
+。
步骤9:中间体8-10的制备
在15℃下，将化合物8-9(270mg,466.55μmol)溶于二氯甲烷(2.5mL)中，加入间氯过氧苯甲酸(189.44mg,933.09μmol,85％含量)，反应液在该温度下继续搅拌18小时。减压除去有机溶剂，所得粗产物经硅胶柱层析(洗脱剂：乙酸乙酯/石油醚＝0～60％)分离纯化，得到化合物8-10。MS m/z＝611.2[M+H]
+。
步骤10:中间体8-11的制备
在15℃下，将化合物1-2A(125.13mg,785.96μmol)溶于无水四氢呋喃(2mL)中，加入叔丁醇钠(75.53mg,785.96μmol)，反应液在该温度下继续搅拌1小时，加入化合物8-10(240mg,392.98μmol)，反应液在该温度下继续搅拌0.5小时。减压除去有机溶剂，所得粗产物经硅胶柱层析(洗脱剂：甲醇/二氯甲烷＝0～4％)分离纯化，得到化合物8-11。MS m/z＝690.3[M+H]
+。
步骤11:化合物8的盐酸盐制备
在18℃下，将化合物8-11(53mg,76.83μmol)溶于氯化氢的二氧六环溶液中(2mL，4M)，反应液在该温度下继续搅拌30分钟。减压除去溶剂，所得粗产物通过高效液相色谱法(柱子:Phenomenex Synergi C18 150*30mm*4μm；流动相:[水(0.05％盐酸)-乙腈]；(乙腈)％:9％-39％,9分钟)分离纯化，得到化合物8的盐酸盐。
1H NMR(400MHz,D
2O)δ:7.95-7.93(m,1H),7.76-7.74(m,1H),7.48-7.36(m,2H),7.22-7.20(m,2H),5.95-5.47(m,2H),4.96-4.93(m,1H),4.66-4.53(m,4H),4.20-4.17(m,2H),3.87-3.68(m,6H),3.48-3.38(m,2H),3.17-3.15(m,2H),2.60-2.37(m,2H),2.28-2.23(m,3H),2.08-2.03(m,4H),1.88-1.85(m,1H).MS m/z＝546.3[M+H]
+。
实施例9
步骤1:中间体9-6的制备
氮气保护下，将氢化钠(346.70mg,8.67mmol,60％含量)悬浮于无水四氢呋喃(10mL)中，混合液冷却到0℃，滴加丙酰乙酸甲酯(1.13g,8.67mmol,1.07mL)，反应液继续搅拌30分钟，滴加正丁基锂(2.5M,3.47mL)，继续搅拌反应30分钟，将反应液冷却到-78℃，滴加化合物A1-5(2.0g,4.33mmol)的无水四氢呋喃(10mL)溶液，反应液在该温度下继续搅拌1.5小时。将反应液用0.5M盐酸水溶液(20mL)淬灭，分液，水相用乙酸乙酯(50mL*2)萃取，合并后的有机相用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，减压除去有机溶剂，所得粗产物经硅胶柱层析(洗脱剂：乙酸乙酯/石油醚＝0～35％)分离纯化，得到化合物9-6。MS m/z:614.5[M+Na]
+。
步骤2:中间体9-7的制备
在20℃下，将化合物9-6(2.0g,3.38mmol)溶于二氯甲烷(10mL)中，加入N,N-二甲基甲酰胺二甲缩醛(1.21g,10.14mmol,1.35mL)，反应液在该温度下继续搅拌18小时。减压除去有机溶剂，所得粗品经硅胶柱层析(洗脱剂：乙酸乙酯/石油醚＝0～35％)分离纯化，得到化合物9-7。MS m/z:602.2[M+H]
+。
步骤3:中间体9-8的制备
氮气保护下，将化合物9-7(750mg,1.25mmol)溶于无水四氢呋喃(20mL)中，反应液冷却到-78℃，滴加三仲丁基硼氢化锂(1M,1.25mL)，反应液在该温度下继续搅拌1小时。将反应液用0.5M盐酸水溶液(5mL)淬灭，用乙酸乙酯(100mL)萃取，有机相用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，减压除去有机溶剂，所得粗产物经硅胶柱层析(洗脱剂：乙酸乙酯/石油醚＝0～20％)分离纯化，得到化合物9-8。MS m/z:604.2[M+H]
+。
步骤4:中间体9-9的制备
氮气保护下，将化合物9-8(750mg,1.24mmol)和2-甲基硫脲(701.63mg,3.73mmol)加入到乙醇(10mL)中，加入碳酸钠(263.39mg,2.49mmol)，反应液升温至60℃继续搅拌15小时。减压除去有机溶剂，残留物中加入水(10mL)，用2M盐酸水溶液调节pH至5-6，乙酸乙酯萃取(30mL*3)，合并后的有机相用饱和食盐水(10mL)洗涤，减压除去有机溶剂，得到粗品化合物9-9，该化合物不经进一步纯化直接用于下一步反应。MS m/z:666.4[M+Na]
+。
步骤5:中间体9-10的制备
在20℃下，将化合物9-9(855mg,1.33mmol)溶于N,N-二甲基甲酰胺(10mL)中，加入N,N二异丙基乙胺(515.68mg,3.99mmol,694.99μL)和N-苯基双三氟甲烷磺酸亚胺(570.17mg,1.60mmol)，反应液在该温度下继续搅拌3小时。反应液用乙酸乙酯(50mL)稀释，用水(15mL*4)洗涤，无水硫酸钠干燥，过滤，减压除去有机溶剂，所得粗品经硅胶柱层析(洗脱剂：乙酸乙酯/石油醚＝0～15％)分离纯化，得到化合物9-10。MS m/z:776.1[M+H]
+。
步骤6:中间体9-11的制备
将化合物9-10(240mg,309.38μmol)和化合物1-1A(78.81mg,371.25μmol)溶于N,N-二甲基甲酰胺(2mL)中，加入二异丙基乙胺(119.95mg,928.13μmol,161.66μL)，反应液升温至100℃继续搅拌1小时。冷却，减压除去有机溶剂，所得粗产物经硅胶柱层析(洗脱剂：乙酸乙酯/石油醚＝0～45％)分离纯化，得到化合物9-11。MS m/z:838.5[M+H]
+。
步骤7:中间体9-12的制备
在20℃下，将化合物9-11(260mg,310.28μmol)溶于二氯甲烷(2mL)中，加入间氯过氧苯甲酸(3125.98mg,620.55μmol,85％含量)，反应液在该温度下继续搅拌15小时。减压除去有机溶剂，所得粗产物经硅胶柱层析(洗脱剂：乙酸乙酯/石油醚＝0～25％)分离纯化得到化合物9-12。MS m/z＝870.3[M+H]
+。
步骤8:中间体9-13的制备
在20℃下，将化合物1-2A(101.56mg,637.96μmol)溶于无水四氢呋喃(2mL)中，加入叔丁醇钠(40.87mg,425.31μmol)，反应液在该温度下继续搅拌1小时，加入化合物9-12(185mg,212.65μmol)，反应液在该温度下继续搅拌1小时。减压除去有机溶剂，所得粗产物经硅胶柱层析(洗脱剂：乙酸乙酯/石油醚＝0～65％)分离纯化，得到化合物9-13。MS m/z＝949.3[M+H]
+。
步骤9:化合物9的制备
在20℃下，将化合物9-13(151mg,159.11μmol)溶于三氟乙酸(1.2mL)，反应液在该温度下继续搅拌1小时。减压除去溶剂，所得粗产物通过高效液相色谱法(柱子:Phenomenex C18 80*40mm*3μm；流动相:[水(0.5％氨水)-乙腈]；(乙腈)％:47％-77％,8分钟)分离纯化，得到化合物9。
1H NMR(400MHz,CD
3OD)δ:6.74-6.72(d,J＝8.8Hz,1H),5.38-5.24(m,1H),4.64-4.60(m,2H),4.20-4.10(m,2H),3.59-3.37(m,6H),3.26-3.03(m,5H),2.40-2.37(m,3H),2.28-1.68(m,11H),1.21-1.17(m,3H).MS m/z＝609.3[M+H]
+。
实施例10
步骤1:中间体10-1的制备
氮气保护下，将化合物A1-7(518mg,881.62μmol)溶于无水四氢呋喃(2mL)中，反应液冷却到-78℃，滴加二甲基铜锂(0.5M,5.29mL)，反应液在该温度下继续搅拌0.5小时。将反应液加入水(10mL)和乙酸乙酯(50mL)，过滤，分液，水相用乙酸乙酯(20mL*3)萃取，合并有机相，减压除去有机溶剂，所得粗产物经硅胶柱层析(洗脱剂：乙酸乙酯/石油醚＝0～20％)分离纯化，得到化合物10-1。
1H NMR(400MHz,CDCl
3)δ:7.17-7.14(m,4H),6.87-6.83(m,4H),6.63-6.61(d,J＝7.2Hz,1H),5.42-5.39(m,1H),4.86-4.84(m,1H),4.38-4.24(m,5H),3.80-3.73(m,9H)，3.13-3.05(m,1H),2.41-2.38(m,4H),1.48-1.37(m,3H)。MS m/z:604.2[M+H]
+。
步骤2:中间体10-2的制备
氮气保护下，将化合物10-1(488mg,808.48μmol)和2-甲基硫脲(456.53mg,2.43mmol)加入到乙醇(5mL)中，加入碳酸钠(171.38mg,1.62mmol)，反应液升温至60℃继续搅拌32小时。减压除去有机溶剂，残留物中加入水(20mL)，用2M盐酸水溶液调节pH至5-6，乙酸乙酯(100mL*3)萃取，合并后的有机相用无水硫酸钠干燥，减压除去有机溶剂，得到粗品化合物10-2，该化合物不经进一步纯化直接用于下一步反应。MS m/z:644.3[M+H]
+。
步骤3:中间体10-3的制备
在20℃下，将化合物10-2(502mg,779.88μmol)溶于N,N-二甲基甲酰胺(5mL)中，加入N,N二异丙基乙胺(302.38mg,2.34mmol,407.52μL)和N-苯基双三氟甲烷磺酸亚胺(417.92mg,1.17mmol)，反应液在该温度下继续搅拌2小时。减压除去有机溶剂，所得粗品经硅胶柱层析(洗脱剂：乙酸乙酯/石油醚＝0～20％)分离纯化，得到化合物10-3。MS m/z:776.1[M+H]
+。
步骤4:中间体10-4的制备
将化合物10-3(185mg,238.48μmol)和化合物1-1A(65.81mg,310.02μmol)溶于N,N-二甲基甲酰胺(1.5mL)中，加入二异丙基乙胺(92.46mg,715.43μmol,124.62μL)，反应液升温至100℃继续搅拌1小时。冷却，减压除去有机溶剂，所得粗产物经硅胶柱层析(洗脱剂：乙酸乙酯/石油醚＝0～30％)分离纯化，得到化合物10-4。MS m/z:838.8[M+H]
+。
步骤5:中间体10-5的制备
在20℃下，将化合物10-4(105.00mg,125.30μmol)溶于二氯甲烷(2mL)中，加入间氯过氧苯甲酸(50.88mg,250.61μmol,85％含量)，反应液在该温度下继续搅拌1.5小时。减压除去有机溶剂，所得粗产物经硅胶柱层析(洗脱剂：乙酸乙酯/石油醚＝0～35％)分离纯化，得到化合物10-5。MS m/z＝870.3[M+H]
+。
步骤6:中间体10-6的制备
在20℃下，将化合物1-2A(47.21mg,296.56μmol)溶于无水四氢呋喃(1mL)中，加入叔丁醇钠(19.00mg,197.71μmol)，反应液在该温度下继续搅拌1小时，加入化合物10-5(86.00mg,98.85)，反应液在该温度下继续搅拌1小时。减压除去有机溶剂，所得粗品加入饱和食盐水(1mL)和乙酸乙酯(5mL)，分液，减压除去有机溶剂，粗产物经硅胶柱层析(洗脱剂：甲醇/二氯甲烷＝0～4％)分离纯化，得到化合物10-6。MS m/z＝949.5[M+H]
+。
步骤7:化合物10的甲酸盐制备
在20℃下，将化合物10-6(75.00mg,79.03μmol)溶于三氟乙酸(1.5mL)中，反应液在该温度下继续搅拌30分钟。减压除去溶剂，所得粗产物通过高效液相色谱法(柱子:Phenomenex C18 150*40mm*5μm；流动相:[水(0.025％甲酸)-乙腈]；(乙腈)％:5％-35％,10分钟)分离纯化，得到化合物10的甲酸盐。
1H NMR(400MHz,CD
3OD)δ:8.51(s,1H),6.72-6.70(d,J＝8.4Hz,1H),5.51-5.31(m,3H),4.36-4.19(m,4H),4.10-4.07(m,2H),3.71-3.40(m,4H),3.21-3.18(m,2H),2.82-2.70(m,1H),2.51-1.98(m,15H),1.51-1.47(m,3H)。MS m/z＝609.6[M+H]
+。
实施例11
步骤1:中间体11-2的制备
将11-1(10g,44.39mmol,1eq)溶于THF(100mL)中，-78℃下滴加LDA(2M,24.41mL,1.1eq)，滴毕继续搅拌0.5hr，接着滴加11-2A(18.30g,46.61mmol,1.05eq)的THF(50mL)溶液，搅拌0.5hr，室温下搅拌0.5hr。加入饱和氯化铵溶液淬灭反应，用乙酸乙酯萃取(500mL*2)，合并萃取后的有机相，用1L饱和食盐水洗涤，用无水硫酸钠干燥，过滤，旋干。通过柱层析(洗脱剂：10％乙酸乙酯/石油醚)分离得到11-2。
步骤2:中间体11-3的制备
将11-2(15.2g,42.54mmol,1eq)，B
2Pin
2(12.96g,51.04mmol,1.2eq)，Pd(dppf)Cl
2
.CH
2Cl
2(3.47g,4.25mmol,0.1eq)和KOAc(12.52g,127.61mmol,3eq)溶于1,4-二氧六环(130mL)中，氮气保护下在90℃反应16hr。冷至室温，过硅藻土，通过柱层析分离(洗脱剂：10％乙酸乙酯/石油醚)得到11-3。
步骤3:中间体11-4的制备
向A2(3.3g,4.33mmol)和11-3(2.18g,6.50mmol)的1,4-二氧六环(30mL)和水(1mL)的混合溶液中加入碳酸钠(1.38g,13.00mmol和1,1-双(二苯基磷)二茂铁氯化钯(530.68mg,649.84μmol)，用氮气置换三次，体系在90℃下搅拌加热12小时。过滤，将滤液旋干，通过柱层析(洗脱剂：10～20％乙酸乙酯/石油醚)分离得到11-4。MS m/z:821.4[M+H]
+。
步骤4:中间体11-5的制备
向11-4(530mg,645.61μmol)的二氯甲烷(50mL)溶液中加入间氯过氧苯甲酸(131.07mg,645.61 μmol)，体系在20℃下搅拌0.5小时。反应液依次用30mL饱和碳酸氢钠溶液和30mL饱和食盐水洗涤，用无水硫酸钠干燥，过滤，旋干。通过柱层析(洗脱剂：20～60％乙酸乙酯/石油醚)分离得到11-5。MS m/z:859.3[M+Na]
+。
步骤5:中间体11-6的制备
20℃下，向1-2A(164.35mg,1.03mmol)的四氢呋喃(15mL)，溶液中加入叔丁醇钠(99.21mg,1.03mmol)，体系在该温度下搅拌0.5小时，接着加入11-5(720.00mg,860.29μmol)，继续搅拌0.5小时。将反应液用80mL乙酸乙酯稀释，用30mL饱和食盐水洗涤，用无水硫酸钠干燥，过滤，旋干通过柱层析(洗脱剂：0～5％甲醇/二氯甲烷)分离得到11-6。MS m/z:932.4[M+H]
+。
步骤6:中间体11-7的制备
将化合物11-6((620mg,665.22μmol)的乙醇(40mL)溶液中加入氢氧化钯(467.12mg,3.33mmol)，体系在50℃下氢气压力为50psi下反应15小时，过滤，将滤液旋干得到11-7。MS m/z:934.4[M+H]
+。
步骤7:化合物11A的盐酸盐和化合物11B的盐酸盐的制备
向11-7(500mg,535.31μmol,1eq)的二氯甲烷(5mL)溶液中加入三氟乙酸(5mL)，体系在20℃下搅拌1小时，将反应液旋干，通过制备HPLC(色谱柱:Xtimate C18 150*40mm*5μm；流动相:[水(0.05％盐酸)-乙腈]；(乙腈)％:10％-30％,10min)分离得到化合物11A的盐酸盐和化合物11B的盐酸盐,MS m/z＝594.1[M+H]
+。其中11A的盐酸盐:
1H NMR(400MHz,CD
3OD)δ＝7.02(d,J＝8.0Hz,1H),5.71-5.52(m,1H),5.26-5.16(m,2H),4.98-4.92(m,1H),4.78-4.67(m,2H),4.18(br s,2H),4.05-3.87(m,3H),3.58-3.44(m,2H),3.30-3.23(m,1H),3.02-2.93(m,1H),2.83-2.58(m,2H),2.54-2.38(m,8H),2.36-2.17(m,5H),2.04-1.86(m,2H)。11B的盐酸盐:
1H NMR(400MHz,CD
3OD)δ＝6.95(d,J＝8.4Hz,1H),5.73-5.50(m,1H),5.31-5.17(m,2H),5.05-4.95(m,1H),4.80-4.60(m,2H),4.23-3.85(m,5H),3.59-3.35(m,3H),3.05-2.69(m,2H),2.66-2.35(m,10H),2.33-1.91(m,6H)。
实施例12
步骤1:中间体12-1的制备
氮气保护下，向100毫升闷罐中加入原料A1-4(5g,10.59mmol)和铜粉(3.36g,52.93mmol)，随后加入DMSO(40mL)和五氟碘乙烷(5.21g,21.17mmol)，密封完毕后加热到120℃搅拌12小时。向反应液中加入50毫升饱和食盐水和200毫升甲基叔丁基醚，搅拌10分钟，过滤，静止分液除去水相，有机相减压浓缩残余物经过过柱机(洗脱剂：5％乙酸乙酯/石油醚)，纯化得到化合物12-1。MS m/z＝512.1[M+H]
+。
步骤2:中间体12-2的制备
冰水浴0℃氮气保护下，向四氢呋喃(50mL)中加入氢化钠(1.56g,39.10mmol,60％含量)，搅拌15分钟后滴加乙酰乙酸乙酯(4.54g,39.10mmol)，继续搅拌15分钟后滴加正丁基锂(2.5M,15.64mL)，搅拌30分钟，滴加原料12-1(4g,7.82mmol)的四氢呋喃(10mL)溶液，得到的混合物自然升至室温25℃搅拌1小时。反应液中缓慢加入50毫升饱和氯化铵水溶液中淬灭，加100毫升甲基叔丁基醚搅拌5分钟，除去水相，有机相减压浓缩，残余物经过过柱机纯化(洗脱剂：10-20％乙酸乙酯/石油醚)，得到化合物12-2。MS m/z＝628.2[M+H]
+。
步骤3:中间体12-3的制备
室温25℃氮气保护下，向原料12-2(1.6g,2.55mmol)的二氯甲烷(20mL)溶液中滴加DMF-DMA(486.09mg,4.08mmol)，搅拌1小时，随后反应瓶置于冰水浴中降温至0℃，加入三氟化硼***(542.77mg,3.82mmol)，搅拌1小时。向反应液中加入20毫升饱和碳酸氢钠水溶液和30毫升二氯甲烷搅拌5分钟，除去水相，有机相减压浓缩残余物经过过柱机纯化(洗脱剂：10-30％乙酸乙酯/石油醚)，得到化合物12-3。MS m/z＝638.1[M+H]
+。
步骤4:中间体12-4的制备
干冰-乙酸乙酯浴-60℃氮气保护下，向原料12-3的四氢呋喃(15mL)溶液中滴加三仲丁基硼氢化锂(1M,1.73mL)，得到的混合物搅拌60分钟。向反应液中加入2毫升0.5M HCl水溶液，20毫升饱和食盐水和50毫升乙酸乙酯搅拌10分钟，除去水相，有机相减压浓缩，残余物经过过柱机纯化(洗脱剂：30％乙酸乙酯/石油醚)，得到化合物12-4。MS m/z＝640.2[M+H]
+。
步骤5:中间体12-5的制备
向原料12-4(1g,1.56mmol)和S-甲基异硫脲硫酸盐(1.31g,4.69mmol)的乙醇(15mL)溶液中加入碳酸钠(331.43mg,3.13mmol)，得到的混合物加热到45℃搅拌12小时。反应液减压浓缩除去大部分乙醇，向残余物中加入10毫升0.5M稀盐酸和30毫升2-甲基四氢呋喃搅拌10分钟，除去水相，有机相减压浓缩残余物经过过柱机纯化(洗脱剂：10-30％乙酸乙酯/石油醚)，得到化合物12-5。MS m/z＝680.1[M+H]
+。
步骤6:中间体12-6的制备
冰水浴0℃氮气保护下，向原料12-5(0.6g,882.78μmol)的二氯甲烷(10mL)溶液中加入DIPEA(228.19mg,1.77mmol)，随后滴加三氟甲磺酸酐(373.60mg,1.32mmol,218.48μL)，搅拌1小时。向反应液中加入20毫升二氯甲烷稀释，随后加入20毫升饱和氯化铵水溶液搅拌10分钟，除去水相，有机相减压浓缩，得到化合物12-6。MS m/z＝812.0[M+H]
+。
步骤7:中间体12-7的制备
室温25℃氮气保护下，向原料12-6(0.75g,923.95μmol)的DMF(10mL)溶液中加入DIPEA(358.24mg,2.77mmol)和1-1A(235.37mg,1.11mmol)，加热到50℃搅拌30分钟。向反应液中加入20毫升水和30毫升乙酸乙酯搅拌10分钟，除去水相，有机相减压浓缩，残余物经过过柱机纯化(洗脱剂：10-20％乙酸乙酯/石油醚)，得到化合物12-7。MS m/z＝874.2[M+H]
+。
步骤8:中间体12-8的制备
冰水浴0℃氮气保护下，向原料12-7(0.32g,366.16μmol)的二氯甲烷(5mL)溶液中加入间氯过氧苯甲酸(81.77mg,402.77μmol,85％含量)搅拌2小时。向反应液中加入20毫升二氯甲烷稀释，随后加入10毫升饱和碳酸氢钠水溶液和10毫升饱和Na
2SO
3溶液搅拌10分钟(经淀粉碘化钾试纸检测)，除去水相，有机相减压浓缩。残余物经过过柱机纯化(洗脱剂：10-30％乙酸乙酯/石油醚)，得到化合物12-8。MS m/z＝890.2[M+H]
+。
步骤9:中间体12-9的制备
冰水浴0℃氮气保护下，向原料1-2A(85.87mg,539.36μmol)的四氢呋喃(5mL)溶液中加入叔丁醇钠(69.11mg,719.15μmol)，搅拌30分钟后加入原料12-8(0.32g,359.57μmol)，得到的混合物搅拌1小时。向反应液中加入10毫升饱和氯化铵水溶液和20毫升乙酸乙酯搅拌10分钟，除去水相，有机相减压浓缩。残余物经过过柱机纯化(洗脱剂：10％甲醇/二氯甲烷)，得到化合物12-9。MS m/z＝985.3[M+H]
+。
步骤10:化合物12的的甲酸盐、化合物12A和化合物12B的制备
室温25℃下，向原料12-9(0.1g,101.52μmol)的二氯甲烷(1.5mL)溶液中加入三氟乙酸(0.5mL)，搅拌4小时，反应液直接减压浓缩，残余物经过制备HPLC纯化(色谱柱:Phenomenex Luna C18 75*30mm*3μm；流动相:[水(0.025％甲酸)-乙腈]；(乙腈)％:1％-35％,8min)分离得到12的甲酸盐。再进行手性分离(色谱柱:DAICEL CHIRALPAK AD(250mm*30mm,10μm)；流动相:[0.1％NH
3H
2O MeOH]；(甲醇)％:40％-40％,10min)，得化合物12A(Rt＝3.473min)和化合物12B(Rt＝4.102min)。
化合物12A：
1H NMR(400MHz,CD
3OD)δ＝6.74(d,J＝8.6Hz,1H),5.40-5.20(m,1H),5.16-5.06(m,1H),4.76-4.54(m,3H),4.20-4.05(m,3H),3.65(br s,2H),3.59-3.51(m,1H),3.49-3.39(m,1H),3.27-3.16(m,3H),3.12-2.97(m,2H),2.84(br dd,J＝3.2,17.7Hz,1H),2.36(br dd,J＝2.7,6.9Hz,5H),2.16-1.68(m,8H)。MS m/z＝645.3[M+H]
+。
化合物12B：
1H NMR(400MHz,CD
3OD)δ＝6.74(d,J＝8.6Hz,1H),5.40-5.18(m,1H),5.10(br dd,J ＝3.9,10.8Hz,1H),4.74-4.49(m,3H),4.21-4.08(m,2H),4.04(d,J＝10.3Hz,1H),3.56-3.37(m,4H),3.29-3.13(m,4H),3.07-2.93(m,2H),2.83(br dd,J＝3.1,16.9Hz,1H),2.40-2.15(m,5H),2.14-1.63(m,9H)。MS m/z＝645.3[M+H]
+。
实施例13
步骤1:中间体13-1的制备
-5℃下，将钠氢(10.17g,254.16mmol,60％含量)慢慢分批加入到四氢呋喃(500mL)中，用氮气置换三次，加完后，然后慢慢加入乙酰乙酸甲酯(29.51g,254.16mmol)，体系在该温度下反应10min，接着滴加正丁基锂(2.5M,101.66mL)，滴完后继续搅拌10min，冷却到-10℃，继续滴加A1-3(50g,127.08mmol)的四氢呋喃(100mL)溶液，滴完后继续反应10min。加入400mL饱和氯化铵溶液淬灭反应，用乙酸乙酯萃取(500mL*2)，合并萃取后的有机相，用1L饱和食盐水洗涤，用无水硫酸钠干燥，过滤，旋干。通过柱层析(洗脱剂：15-40％乙酸乙酯/石油醚)分离得到13-1。
步骤2:中间体13-2的制备
向13-1(58.5g,114.80mmol)的二氯甲烷(350mL)溶液中加入二甲基甲酰胺二甲基缩醛(21.89g,183.69mmol)，体系在25℃下反应1小时，冷却到0℃，慢慢滴入三氟化硼***(24.44g,172.21mmol)，继续反应15min，向体系中加入350mL饱和碳酸氢钠溶液，用二氯甲烷(300mL*2)萃取，合并萃取后的有机相，用500mL饱和食盐水洗涤，用无水硫酸钠干燥，过滤，旋干，通过柱层析(洗脱剂：15～40％乙酸乙酯/石油醚)分离得到13-2。MS m/z:520.3[M+H]
+。
步骤3:中间体13-3的制备
-60℃下，向13-2(42.5g,81.80mmol)的四氢呋喃(500mL)溶液中滴入三仲丁基硼氢化锂(1M,89.98mL)，体系在该温度下反应10min。将反应液倒入1L 1N的盐酸溶液中，用乙酸乙酯(1L*2)萃取，合并萃取后的有机相，用饱和食盐水洗涤(1.5L)用无水硫酸钠干燥，过滤，旋干通过柱层析(洗脱剂：0～10％乙酸乙酯/石油醚)分离得到13-3。MS m/z:522.3[M+H]
+。
步骤4:中间体13-4的制备
向13-3(28.5g,54.64mmol)和甲基异硫脲硫酸盐(45.63g,163.93mmol)的乙醇(400mL)溶液中加入碳酸钠(11.58g,109.28mmol,2eq)，体系在50℃下搅拌加热18小时。减压浓缩除去大部分乙醇，向体系中加入400mL水和400mL乙酸乙酯，用1N的盐酸调节至pH＝4，分离出有机相，水相用乙酸乙酯(400mL)萃取，合并萃取后的有机相。用500mL饱和食盐水洗涤，有机相中有很多不溶固体，将固体滤出，抽干得13-4。
1H NMR(400MHz,DMSO-d
6)δ＝7.20(d,J＝8.4Hz,4H),6.88-6.80(m,5H),6.73(br d,J＝6.4Hz,1H),4.90(dd,J＝4.0,10.0Hz,1H),4.68-4.41(m,2H),4.15(s,4H),3.71(s,6H),2.80-2.64(m,2H),2.47(s,3H),2.14(s,3H)。MS m/z:562.2[M+H]
+。
步骤5:中间体13-5的制备
向13-4(24.5g,43.62mmol,1eq)的N,N-二甲基甲酰胺(300mL)溶液中加入二异丙基乙胺(16.91g,130.86mmol)，接着加入N-苯基三氟甲基磺酰胺(18.70g,52.34mmol)，体系在20℃下搅拌0.5小时，将反应液用1.5L乙酸乙酯稀释，依次用水(800mL*2)和饱和食盐水(1L)洗涤，用无水硫酸钠干燥，过滤，旋干。通过柱层析(洗脱剂：0～10％乙酸乙酯/石油醚)分离得到13-5。MS m/z:694.1[M+H]
+。
步骤6:中间体13-6的制备
向13-5(21.5g,30.99mmol)的N’N-二甲基甲酰胺(150mL)溶液中加入1-1A(7.24g,34.09mmol)，体系在90℃下加热1小时，将反应液旋干，通过柱层析(洗脱剂：5～20％乙酸乙酯/石油醚)分离得到13-6。
1H NMR(400MHz,CDCl
3)δ7.19(d,J＝8.8Hz,4H),6.88-6.79(m,5H),6.63(d,J＝8.0Hz,1H),5.12(dd,J＝4.0,10.8Hz,1H),4.88-4.70(m,2H),4.42-4.25(m,2H),4.20(s,4H),3.81(s,6H),3.48-3.42(m,2H),3.18-2.92(m,4H),2.53(s,3H),2.21(s,3H),2.03-1.89(m,3H),1.75-1.65(m,1H),1.52(s,9H)。MS m/z:756.4[M+H]
+。
步骤7:中间体13-7的制备
称取13-6(1g,1.32mmol,1eq)，加入DCM(30mL)和m-CPBA(268.57mg,1.32mmol,85％含量,1eq)，在25℃反应1hr。加入碳酸氢钠淬灭，DCM萃取，无水硫酸钠干燥，旋干得到13-7，直接投下一步。
步骤8:中间体13-8的制备
20℃下，向1-2A(404.09mg,2.54mmol,2eq)的甲苯(50mL)溶液中加入叔丁醇钠(10mg,0.103mmol)，接着加入13-7(979.69mg,1.27mmol,1eq)，在120℃反应15hr。降到室温，加水淬灭，乙酸乙酯萃取，无水硫酸钠干燥，旋干。通过柱层析(洗脱剂：0～5％甲醇/二氯甲烷)分离得到13-8。MS m/z:867.3[M+H]
+。
步骤9:化合物13的盐酸盐制备
向13-8(0.6g,692.02μmol,1eq)中加入三氟乙酸(5mL)，体系在55℃下搅拌5小时，将反应液旋干，通过制备HPLC分离(色谱柱:Phenomenex C18 150*40mm*5μm；流动相:[水(0.05％盐酸)-乙腈]；(乙腈)％:1％-30％,10min)，得到化合物13的盐酸盐。
1H NMR(400MHz,CD
3OD)δ7.57-7.50(m,1H),7.40-7.30(m,1H),5.74-5.55(m,1H),5.33-5.23(m,1H),5.21-5.11(m,1H),4.84-4.76(m,2H),4.34-4.22(m,2H),4.17 -3.83(m,5H),3.71-3.61(m,1H),3.53-3.42(m,1H),3.36-3.22(m,3H),3.17-3.04(m,1H),2.85-2.47(m,3H),2.01-2.43(m,10H)。MS m/z:527.2[M+H]
+。
实施例14
步骤1：中间体14-1的合成
将化合物13-6(200mg,264.57μmol,1eq)溶解于N,N-二甲基甲酰胺(3mL)中，然后加入N-氯代丁二酰亚胺(45.93mg,343.94μmol,1.3eq)，所得反应液25℃搅拌反应15小时。反应液直接用高效液相色谱分离，分离条件：(色谱柱:Welch Xtimate C18 100*40mm*3μm；流动相:[水(0.025％三氟乙酸)-乙腈]；乙腈％:50％-80％,8min)，得到化合物14-1的三氟乙酸盐。MS m/z＝790.4[M+H]
+。
步骤2：中间体14-2的合成
将化合物14-1的三氟乙酸盐(123mg)溶解于无水二氯甲烷(2mL)中，然后加入间氯过氧苯甲酸(31.59mg)，所得反应液15℃搅拌反应15小时。将反应液旋干得到粗品，粗品过柱纯化(甲醇/二氯甲烷＝0～3％)得到14-2。MS m/z＝806.2[M+H]
+。
步骤3：中间体14-3的合成
将化合物1-2A(37.96mg,238.47μmol,3eq)，叔丁醇钠(15.28mg,158.98μmol,2eq)和化合物14-2(64.1mg,79.49μmol,1eq)加入到甲苯(2mL)中，于15℃搅拌反应4小时，将反应液用30mL乙酸乙酯稀释，然后用水5mL和饱和食盐水5mL洗涤，有机相旋干得到粗品，粗品过柱纯化(甲醇/二氯甲烷＝0～5％)得到化合物14-3。MS m/z＝901.3[M+H]
+。
步骤4：化合物14的盐酸盐合成
将化合物14-3(67mg,74.32μmol,1eq)加入到三氟乙酸(2mL)中，25℃搅拌反应4小时。将反应液旋干，残留物中加入碳酸钠300mg和乙酸乙酯5mL搅拌20分钟，过滤，滤液减压除去溶剂得到粗品。粗品 高效液相色谱制备分离(分离条件：色谱柱:Xtimate C18 150*40mm*5μm；流动相:[水(0.05％盐酸)-乙腈]；(乙腈)％:1％-30％,10min)得到化合物14的盐酸盐，MS m/z＝561.2[M+H]
+。
实施例15
步骤1:中间体15-1的制备
称取13-6(2.00g,2.64mmol,1eq)，加入DMF(50mL)和NBS(940.54mg,5.28mmol,2eq)，加毕于25℃反应4hr。加入碳酸氢钠淬灭，乙酸乙酯萃取，无水硫酸钠干燥，旋干。通过柱层析(洗脱剂：5～20％乙酸乙酯/石油醚)分离得到15-1。MS m/z:834.2[M+H]
+。
步骤2:中间体15-2的制备
称取15-1(1g,1.32mmol,1eq)，加入DCM(30mL)和m-CPBA(268.57mg,1.32mmol,85％含量,1eq)，于25℃反应1hr。加入碳酸氢钠淬灭，DCM萃取，无水硫酸钠干燥，旋干得到15-2，直接投下一步。
步骤3:中间体15-3的制备
20℃下，向1-2A(16mg,0.103mmol)的四氢呋喃(15mL)，溶液中加入叔丁醇钠(10mg,0.103mmol)，体系在该温度下搅拌0.5小时，接着加入15-2(73mg,86μmol)，继续搅拌0.5小时。将反应液用10mL乙酸乙酯稀释，用10mL饱和食盐水洗涤，用无水硫酸钠干燥，过滤，旋干通过柱层析(洗脱剂：0～5％甲醇/二氯甲烷)分离得到15-3。MS m/z:946.8[M+H]
+。
步骤4:化合物15的盐酸盐制备
向15-3(40mg,1eq)中加入三氟乙酸(1mL)，体系在55℃下搅拌2小时，将反应液旋干，通过制备HPLC(色谱柱:Xtimate C18 150*40mm*5μm；流动相:[水(0.05％盐酸)-乙腈]；(乙腈)％:1％-30％,10min)，得到化合物15的盐酸盐。MS m/z:605.0[M+H]
+。
实施例16
步骤1:中间体16-1的制备
称取13-6(1g,1.32mmol,1eq)，加入DMF(25mL)，NIS(892.85mg,3.97mmol,3eq)。25℃反应5hr。加水淬灭，乙酸乙酯萃取，水洗，干燥。通过柱层析(洗脱剂：5～20％乙酸乙酯/石油醚)分离得到16-1。MS m/z:882.2[M+H]
+。
步骤2:中间体16-2的制备
称取16-1(0.6g,680.40μmol,1eq)，加入DCM(30mL)和m-CPBA(138.14mg,680.40μmol,85％含量,1eq)，于25℃反应1hr。加入碳酸氢钠淬灭，DCM萃取，无水硫酸钠干燥，旋干得到16-2，直接投下一步。
步骤3:中间体16-3的制备
20℃下，向1-2A(132.99mg,835.34μmol,1.5eq)的四氢呋喃(50mL)溶液中加入叔丁醇钠(80.28mg,835.34μmol,1.5eq)，接着加入16-2(0.5g,556.90μmol,1eq)，加毕于25℃反应15hr。加水淬灭，乙酸乙酯萃取，无水硫酸钠干燥，旋干。通过柱层析(洗脱剂：0～5％甲醇/二氯甲烷)分离得到16-3。MS m/z:993.2[M+H]
+。
步骤4:化合物16的盐酸盐制备
向16-3(0.3g,302.14μmol,1eq)中加入三氟乙酸(5mL)，体系在55℃下搅拌5小时，将反应液旋干，通过制备HPLC(色谱柱:Xtimate C18 150*40mm*5μm；流动相:[水(0.05％盐酸)-乙腈]；(乙腈)％:1％-30％,10min)分离，得到化合物16的盐酸盐。MS m/z:653.3[M+H]
+。
实施例17
步骤1:中间体17-1的制备
称取16-1(0.8g,907.20μmol,1eq)，加入PdCl
2(PPh
3)
2(127.35mg,181.44μmol,0.2eq)，CuI(51.83mg,272.16μmol,0.3eq)，EtOH(20mL)，Et
3N(229.50mg,2.27mmol,315.68μL,2.5eq)，三甲基硅基乙炔(330.91mg,1.81mmol,407.07μL,2eq)。抽换氮气3次，80℃反应5hr。过硅藻土，旋干，通过柱层析(洗脱剂：5～20％乙酸乙酯/石油醚)分离得到17-1。MS m/z:936.4[M+H]
+。
步骤2:中间体17-2的制备
称取17-1(0.4g,427.21μmol,1eq)，加入DCM(10mL)和m-CPBA(86.73mg,427.21μmol,85％含量,1eq)，加毕于25℃反应1hr。加入碳酸氢钠淬灭，DCM萃取，无水硫酸钠干燥，旋干得到17-2，直接投下一步。MS m/z:952.4[M+H]
+。
步骤3:中间体17-3的制备
20℃下，向1-2A(100.31mg,630.05μmol,1.5eq)的四氢呋喃(5mL)溶液中加入叔丁醇钠(60.55mg,630.05μmol,1.5eq)，接着加入17-2(0.4g,420.04μmol,1eq)，加毕25℃反应15hr。加水淬灭，乙酸乙酯萃取，无水硫酸钠干燥，旋干。得到17-3。MS m/z:1047.5[M+H]
+。
步骤4:中间体17-4的甲酸盐制备
向17-3(0.3g,302.14μmol,1eq)中加入三氟乙酸(6mL)，体系在25℃下搅拌5小时，将反应液旋干，通过制备HPLC色谱柱:Xtimate C18 150*40mm*5μm；流动相:[水(0.025％甲酸)-乙腈]；(乙腈)％:17％-57％,8min)分离，得到化合物17-4的甲酸盐。MS m/z:707.4[M+H]
+。
步骤5:化合物17的制备
称取17-4的甲酸盐(30mg)，加入THF(2mL)，四甲基氟化铵(11.86mg,127.30μmol,3eq)，60℃反应4hr。直接旋干，通过HPLC分离(色谱柱:Phenomenex C18 80*40mm*3μm；流动相:[水(0.5％氨水)-乙腈]；(乙腈)％:43％-73％,8min)，得化合物17。MS m/z:551.2[M+H]
+。
实施例18
步骤1:中间体18-1的制备
称取16-1(0.4g,453.60μmol,1eq)，加入K
4FeCN
6(36.76mg,99.79μmol,0.22eq)，Na
2CO
3(48.08mg,453.60μmol,1eq)，Pd(OAc)
2(20.37mg,90.72μmol,0.2eq)，DMAc(5mL)。抽换氮气3次，120℃反应15hr。加水淬灭，乙酸乙酯萃取，干燥，旋干。通过柱层析(洗脱剂：5～20％乙酸乙酯/石油醚)分离得到18-1。MS m/z:781.2[M+H]
+。
步骤2:中间体18-2的制备
称取18-1(100mg,128.05μmol,1eq)，加入DCM(10mL)和m-CPBA(26.00mg,128.05μmol,85％含量,1eq)，加毕于25℃反应1hr。加入碳酸氢钠淬灭，DCM萃取，无水硫酸钠干燥，旋干得到18-2，直接投下一步。MS m/z:797.2[M+H]
+。
步骤3:中间体18-3的制备
20℃下，向1-2A(27.97mg,175.67μmol,2eq)的甲苯(5mL)溶液中加入叔丁醇钠(10.97mg,114.19μmol,1.3eq)，接着加入18-2(70mg,87.84μmol,1eq)，加毕于120℃反应5hr。加水淬灭，乙酸乙酯萃取，无水硫酸钠干燥，旋干，得到18-3。MS m/z:892.4[M+H]
+。
步骤4:化合物18的制备
向18-3(60mg,108.77μmol,1eq)中加入三氟乙酸(5mL)，体系在50℃下搅拌2小时，将反应液旋干，先酸性HPLC分离(色谱柱:Xtimate C18 150*40mm*5μm；流动相:[水(0.05％盐酸)-乙腈]；(乙腈)％:1％-30％,10min)，再碱性分离(色谱柱:Phenomenex C18 80*40mm*3μm；流动相:[水(0.5％氨水)-乙腈]；(乙腈)％:40％-70％,8min)得到化合物18。MS m/z:552.3[M+H]
+。
实施例19
步骤1:中间体19-1的制备
称取16-1(0.1g,113.40μmol,1eq)，加入Pd(dppf)Cl
2(16.60mg,22.68μmol,0.2eq)，1,4-二氧六环(5mL)，H
2O(1mL)，乙烯基硼酸频哪酯((26.20mg,170.10μmol,28.85μL,1.5eq)，K
2CO
3(23.51mg,170.10μmol,1.5eq)。抽换氮气3次，95℃反应15hr。直接旋干。通过柱层析(洗脱剂：5～20％乙酸乙酯/石油醚)分离得到19-1。MS m/z:782.3[M+H]
+。
步骤2:中间体19-2的制备
称取19-1(0.07g,89.52μmol,1eq)，加入DCM(10mL)，加入m-CPBA(18.17mg,89.52μmol,85％含量,1eq)，加毕于25℃反应1hr。加入碳酸氢钠淬灭，DCM萃取，无水硫酸钠干燥，旋干得到19-2，直接投下一步。MS m/z:798.3[M+H]
+。
步骤3:中间体19-3的制备
20℃下，向1-2A(19.95mg,125.32μmol,2eq)的甲苯(5mL)溶液中加入叔丁醇钠(9.03mg,93.99μmol,1.5eq)，接着加入19-2(0.05g,62.66μmol,1eq)，加毕于120℃反应5hr。加水淬灭，乙酸乙酯萃取，无水硫酸钠干燥，旋干，得到19-3。MS m/z:893.3[M+H]
+。
步骤4:化合物19的盐酸盐制备
向19-3(50mg,55.99μmol,1eq)中加入三氟乙酸(3mL)，体系在55℃下搅拌5小时，将反应液旋干，酸性HPLC分离(色谱柱:Xtimate C18 150*40mm*5μm；流动相:[水(0.05％盐酸)-乙腈]；(乙腈)％:1％-30％,10min)，得到化合物19的盐酸盐。MS m/z:553.3[M+H]
+。
实施例20
步骤1：中间体20-2的合成
将化合物20-1(85g,447.34mmol,1eq)、碳酸钾(154.57g,1.12mol,2.5eq)和碘化钾(74.26g,447.34mmol,1eq)加入到N-甲基吡咯烷酮(850mL)中，缓慢滴加入对甲氧基氯苄(143.62g,917.04mmol,124.89mL,2.05eq)，体系缓慢放热至30℃，明显产气，反应1小时。将反应液倒入1L水中，再加入500mL甲基叔丁基醚搅拌，分液后收集有机相，水相用甲基叔丁基醚萃取(500mL*2)。合并有机相，饱和食盐水洗涤(1Lx 2)，无水硫酸钠干燥，减压浓缩。向粗品中加入400mL石油醚，打浆2小时，过滤，将滤饼利用石油醚(100mL*2)淋洗后，旋干得到化合物20-2。MS m/z＝430.0[M+H]
+。
步骤2：中间体20-3的合成
将2,2,6,6-四甲基哌啶(39.39g,278.87mmol,47.34mL,3eq)加入到无水四氢呋喃(400mL)中，降温至-10℃，氮气置换三次，氮气保护下滴加正丁基锂(2.5M,111.55mL,3eq)，-10℃反应10分钟后，降温至-60℃，滴加入化合物20-2(40g,92.96mmol,1eq)的无水四氢呋喃(100mL)溶液，反应0.5小时后，快速加入N,N-二甲基甲酰胺(67.94g,929.56mmol,71.52mL,10eq)，反应10分钟。将反应液加入到500mL的饱和氯化铵中，用乙酸乙酯(200mL*2)萃取，合并有机相，500mL的饱和食盐水洗涤，无水硫酸钠干燥过滤后浓缩，粗品混合溶剂(石油醚：甲基叔丁基醚＝5:1)100mL打浆16小时，过滤，将滤饼淋洗(石油醚：甲基叔丁基醚＝5:1，50mL*2)后，旋干，得到化合物20-3，
1H NMR(400MHz,CDCl
3)δ＝10.35(s,1H),7.24-7.13(m,5H),6.90-6.77(m,5H),4.24(s,4H),3.79(s,6H)。MS m/z＝458.0[M+H]
+。
步骤3：中间体20-4的合成
将化合物20-3(42g,91.64mmol,1eq)加入到N,N-二甲基甲酰胺(210mL)中，氮气置换三次，氮气保护下加入碘化亚铜(3.49g,18.33mmol,0.2eq)，升温至80℃，滴加入氟磺酰二氟乙酸甲酯(52.82g,274.92mmol,34.98mL,3eq)，升温至100℃，反应1小时。将反应液垫硅藻土过滤，滤饼用甲基叔丁基醚(300mL*4)淋洗后，用1L的水洗涤，1L的饱和食盐水洗涤，无水硫酸钠干燥过滤后浓缩，得到化合物20-4。
1H NMR(400MHz,CDCl
3)δ＝10.44(s,1H),7.34(d,J＝8.4Hz,1H),7.17(d,J＝8.0Hz,4H),6.97(t,J＝8.4Hz,1H),6.86(d,J＝8.4Hz,4H),4.39(s,4H),3.80(s,6H)，MS m/z＝448.0[M+H]
+。
步骤4：中间体20-5的合成
将钠氢(1.27g,31.85mmol,60％含量,2.5eq)溶于四氢呋喃(60mL)，氮气置换两次，然后降温至0℃，加入乙酰乙酸甲酯(3.70g,31.85mmol,3.42mL,2.5eq)，搅拌10min，然后加入正丁基锂(2.5M,12.74mL,2.5eq)，继续搅拌10min.降温-15℃，加入化合物20-4(5.7g,12.74mmol,1eq)的四氢呋喃(5mL)，继续搅拌30min。向反应液中加入100mL饱和氯化铵，乙酸乙酯萃取(100mL*2)，合并有机相，无水硫酸钠干燥，过滤浓缩，柱纯化(石油醚：乙酸乙酯＝10：1)得化合物20-5。MS m/z＝586.2[M+Na
+。
步骤5：中间体20-6的合成
将化合物20-5(6g,10.39mmol,1eq)溶于二氯甲烷(60mL)，然后加入N,N-二甲基甲酰胺二甲基缩醛(2.48g,20.78mmol,2.76mL,2eq)，25℃搅拌12hr，然后降温至0℃，加入三氟化硼***复合物(2.65g,18.70mmol,2.31mL,1.8eq)，25℃搅拌1hr。将滤液缓慢倒入50mL饱和氯化铵溶液中，用乙酸乙酯(50mL*2)萃取，有机相用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩。过柱纯化(石油醚：乙酸乙酯＝10：1)得化合物20-6。MS m/z＝596.1[M+Na]
+。
步骤6：中间体20-7的合成
将化合物20-6(4.2g,7.32mmol,1eq)溶于四氢呋喃(40mL)，降温至-65℃，然后加入三仲丁基硼氢化理(1M,8.79mL,1.2eq)，继续搅拌0.5hr。加水淬灭，将反应体系缓慢倒入10mL饱和氯化铵溶液中，用乙酸乙酯(10mL*2)萃取，有机相用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩。得化合物20-7。MS m/z＝576.2[M+H]
+。
步骤7：中间体20-8的合成
将化合物20-7(2g,3.47mmol,1eq)，S-甲基异硫脲硫酸盐(4.84g,17.37mmol,5eq)溶于乙醇(40mL)，水(5mL)，然后加入碳酸钠(1.29g,12.16mmol,3.5eq)，50℃继续搅拌16hr。向反应液中加入50mL水，用乙酸乙酯(40mL*2)萃取，有机相用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓 缩。得化合物20-8。MS m/z＝616.1[M+H]
+。
步骤8：中间体20-9的合成
将化合物20-8(2.25g,3.65mmol,1eq)，N,N-二异丙基乙胺(2.83g,21.93mmol,3.82mL,6eq)溶于二氯甲烷(20mL)，降温至0℃，然后加入三氟甲磺酸酐(4.64g,16.45mmol,2.71mL,4.5eq)，0℃继续搅拌0.5hr。将反应液用饱和氯化铵(20mL)洗，饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤滤液减压浓缩。过柱纯化(石油醚：乙酸乙酯＝10：1)，化合物20-9。MS m/z＝748.1[M+H]
+。
步骤9：中间体20-10的合成
将化合物20-9(0.35g,468.10μmol,1eq)、N,N-二异丙基乙胺(302.50mg,2.34mmol,407.68μL,5eq)溶于N,N-二甲基甲酰胺(3mL)，然后加入1-1A(248.43mg,1.17mmol,2.5eq)，50℃继续搅拌0.5hr。向反应液中加入25mL乙酸乙酯，饱和氯化铵(25mL)洗，饱和食盐水洗(25mL*2)，无水硫酸钠干燥，过滤浓缩。过柱纯化(石油醚：乙酸乙酯＝10：1)，得化合物20-10。
1H NMR(400MHz,CDCl
3)δ7.24-7.27(m,1H),7.14-7.17(m,4H),6.81-6.84(m,5H),5.13-5.16(m,1H),4.37-4.26(m,6H),3.89-3.79(m,8H),3.46-3.39(m,3H),2.97-3.07(m,2H),2.52(s,3H),1.93-1.99(m,3H),1.64-1.68(m,2H),1.50(s,9H)。MS m/z＝810.3[M+H]
+。
步骤10：中间体20-11的合成
将化合物20-10(300mg,370.41μmol,1eq)溶于二氯甲烷(3mL)，然后加入间氯过氧苯甲酸(97.76mg,481.54μmol,85％含量,1.3eq)，15℃继续搅拌0.5hr。将反应液用20mL二氯甲烷稀释，5％硫代硫酸钠洗(10mL)，饱和碳酸氢钠洗(10mL)，饱和食盐水(10mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩。过柱纯化(石油醚：乙酸乙酯＝5：1)，得化合物20-11。MS m/z＝826.3[M+H]
+。
步骤11：中间体20-12的合成
将1-2A(77.10mg,484.31μmol,2.5eq)溶于四氢呋喃(3mL)，降温至-15℃，然后加入叔丁醇钠(37.24mg,387.45μmol,2eq)，-15℃继续搅拌0.5hr，然后加入化合物20-11(160mg,193.73μmol,1eq)的四氢呋喃(1mL)溶液，继续搅拌1hr。将滤液缓慢倒入20mL饱和氯化铵溶液中，用乙酸乙酯(15mL*2)萃取，有机相用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩。过柱纯化(二氯甲烷：甲醇＝50：1)，得化合物20-12。MS m/z＝921.4[M+H]
+。
步骤12：化合物20的盐酸盐、化合物20A和化合物20B的合成
将化合物20-12(0.11g,119.43μmol,1eq)溶于二氯甲烷(4mL)，然后加入三氟乙酸(1.36g,11.94mmol,884.31μL,100eq)，15℃搅拌5hr，将滤液缓慢倒入10mL水中，分液，水相用饱和碳酸氢钠调pH＝9，乙酸乙酯萃取(15mL*2)，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩。进行pre-HPLC分离(色谱柱:Phenomenex Luna 80*30mm*3μm；流动相:[水(0.05％盐酸)-乙腈]；(乙腈)％:5％-25％,8min)，得化合物20的盐酸盐。再进行手性分离(色谱柱:DAICEL CHIRALCEL OD(250mm*30mm,10μm)；流动相:[0.1％氨水乙醇]；(乙醇)％:40％-40％,12min)，得化合物20A(Rt＝3.920)和化合物20B(Rt＝4.275)。
化合物20A：
1H NMR(400MHz,CDCl
3)δ7.27-7.29(m,2H),6.75-6.79(m,1H),5.12-5.33(m,2H),4.75-4.79(m,2H),3.88-4.10(m,5H),2.96-3.58(m,12H),2.15-2.28(m,3H),1.87-1.96(m,5H)。MS m/z＝581.2[M+H]
+。
化合物20B：
1H NMR(400MHz,CDCl
3)δ＝7.30-7.27(m,1H),6.77(t,J＝8.4Hz,1H),5.34-5.17(m,1H),5.15-5.07(m,1H),4.80-4.71(m,2H),4.17-4.06(m,3H),3.97-3.86(m,2H),3.59(s,2H),3.49-3.08(m,6H),3.06-2.89(m,3H),2.31-2.10(m,3H),2.06-1.65(m,7H)，MS m/z＝581.2[M+H]
+。
实施例21
步骤1：中间体21-2的合成
向预先干燥的反应瓶中加入化合物21-1(20g,137.40mmoL,1eq)，N,N-二甲基甲酰胺(200mL)，碘化钾(22.81g,137.40mmoL,1eq)，无水碳酸钾(47.47g,343.50mmoL,2.5eq)，搅拌下加入对甲氧基氯苄(44.11g,281.67mmoL,38.36mL,2.05eq)，然后升温至65℃搅拌4hr，反应液降温至室温，然后垫硅藻土过滤，200mL甲基叔丁基醚淋洗滤饼，然后滤液加入200mL水，萃取，水相用乙酸乙酯(100mL*2)萃取，然后合并有机相，饱和食盐水(200mL*3)洗涤，无水硫酸钠干燥，过滤，浓缩，得到粗品，粗品用50mL石油醚打浆48hr，过滤，收集滤饼，干燥得到产品，得到化合物21-2，直接用于下一步，
1H NMR(400MHz,DMSO-d
6)δ＝7.18-7.17(m,5H),6.85-6.82(m,6H),4.24(s,4H),3.74-3.71(m,6H)。MS m/z＝386.1[M+H]
+。
步骤2：中间体21-3的合成
将2,2,6,6-四甲基哌啶(43.93g,311.00mmoL,52.80mL,4eq)溶于四氢呋喃(300mL)，然后降温至-5℃，加入正丁基锂(2.5M,124.40mL,4eq)，搅拌0.5hr，然后降温至-60℃，加入化合物21-2(30g,77.75mmoL,1eq)的四氢呋喃(30mL)，搅拌0.5hr，然后加入N,N-二甲基甲酰胺(113.66g,1.55moL,119.64mL,20eq)， 继续搅拌0.5hr。向反应液加入200mL饱和氯化铵。乙酸乙酯萃取(200mL)，分液，饱和食盐水洗100mL，无水硫酸钠干燥过滤浓缩。过柱纯化(石油醚：乙酸乙酯＝10：1)，得化合物21-3。
步骤3：中间体21-4的合成
将钠氢(6.38g,159.47mmol,60％含量,2.2eq)溶于四氢呋喃(300mL)，N
2置换两次，然后降温至0℃，加入乙酰乙酸甲酯(18.52g,159.47mmol,17.15mL,2.2eq)，搅拌10min，然后加入正丁基锂(2.5M,63.79mL,2.2eq)，继续搅拌10min，降温-15℃，加入化合物21-3(30g,72.49mmol,1eq)的四氢呋喃(50mL)，继续搅拌30min。向反应液中加入100mL饱和氯化铵，乙酸乙酯萃取(100mL*2)，合并有机相，无水硫酸钠干燥，过滤浓缩。过柱纯化(石油醚：乙酸乙酯＝10：1)，得化合物21-4。MS m/z＝530.2[M+H]
+。
步骤4：中间体21-5的合成
将化合物21-4(20g,37.74mmoL,1eq)溶于无水二氯(50mL)中，氮气保护下加入N,N-二甲基甲酰胺二甲基缩醛(5.40g,45.28mmoL,6.02mL,1.2eq)，25℃反应16hr，加入三氟化硼***(6.43g,45.28mmoL,5.59mL,1.2eq)，20℃反应1hr，将反应液加入50mL饱和碳酸氢钠溶液中，用二氯甲烷(20mL*2)萃取分液，合并有机相，用30mL饱和食盐水洗涤后，无水硫酸钠干燥过滤后浓缩。粗品过柱纯化(石油醚:乙酸乙酯＝10:1-1:1)得到化合物21-5。
1H NMR(400MHz,CDCl
3)δ＝8.45(s,1H),7.14(m,4H),7.00-6.69(m,6H),5.80(m,1H),4.27-4.10(m,5H),3.79(m,1H),3.94-3.66(m,8H),2.98-2.73(m,1H)。MS m/z＝540.2[M+H]
+。
步骤5：中间体21-6的合成
将化合物21-5(12g,22.22mmoL,1eq)加入无水四氢呋喃(30mL)中，在氮气保护下加入三仲丁基硼氢化锂(11.83g,62.22mmoL,13.60mL,2.8eq)，-60℃反应1hr，将反应液加入40mL水中，用乙酸乙酯(20mL*2)萃取，合并有机相，再用20mL饱和食盐水洗涤，无水硫酸钠干燥后浓缩，粗品过柱纯化(石油醚：乙酸乙酯＝100:0＝3:1)，得到化合物21-6。MS m/z＝542.2[M+H]
+。
步骤6：中间体21-7的合成
将化合物21-6(5.5g,10.15mmoL,1eq)加入到乙醇(15mL)和水(3mL)中，加入碳酸氢钠(2.15g,20.30mmoL,2eq)和甲基异硫脲硫酸盐(2.74g,30.44mmoL,3eq)，45-50℃反应16hr，反应液用水(20mL)和乙酸乙酯(20mL*2)萃取，合并有机相用饱和食盐水(20mL*2)洗涤，无水硫酸钠干燥后浓缩，粗品直接投试下一步，得到化合物21-7。MS m/z＝582.2[M+H]
+。
步骤7：中间体21-8的合成
将化合物21-7(6g,8.04mmoL,1eq)加入到无水二氯甲烷(20mL)中，0℃加入N,N-二异丙基乙胺(3.12g,24.12mmoL,4.20mL,3eq)，降温到0-10℃，将三氟甲磺酸酐(4.08g,14.47mmoL,2.39mL,1.8eq)缓慢滴加，0℃反应0.5hr，将反应液加入到20mL饱和氯化铵中，用无水二氯甲烷(10mL*2)萃取，合并有机相，用20mL饱和食盐水洗涤，无水硫酸钠干燥过滤后浓缩，粗品过柱纯化(石油醚：乙酸乙酯＝1:0-0:1)得到化合物21-8。MS m/z＝714.1[M+H]
+。
步骤8：中间体21-9的盐酸盐合成
将化合物21-8(0.8g,1.12mmoL,1eq)，化合物1-1A(475.62mg,2.24mmoL,2eq)，DIPEA(434.33mg,3.36mmoL,585.35μL,3eq)加入到N,N-二甲基甲酰胺(5mL)中，50℃反应1hr。将反应液加入饱和氯化 铵(20mL)中，用乙酸乙酯(20mL*2)萃取，合并有机相，再用20mL饱和食盐水洗涤，无水硫酸钠干燥后浓缩，粗品利用过柱纯化(石油醚:乙酸乙酯＝3：1)，再进行制备HPLC(色谱柱:Phenomenex Luna C18250*50mm*10μm；流动相:[水(0.05％盐酸)-乙腈]；(乙腈)％:65％-95％,10min)进行分离，得到化合物21-9的盐酸盐。MS m/z＝776.3[M+H]
+。
步骤9：中间体21-10的合成
将化合物21-9的盐酸盐(1.2g)溶于N,N-二甲基甲酰胺(5mL)，降温至0℃，然后加入N-溴代丁二酰亚胺(330.13mg,1.85mmoL,1.2eq)，20℃搅拌1hr。向反应液中加入30mL水，乙酸乙酯萃取(30mL*2)，合并有机相，饱和食盐水洗(20mL*2)，无水硫酸钠干燥过滤浓缩。过柱纯化(石油醚：乙酸乙酯＝3:1-1:1)得化合物21-10。MS m/z＝856.1[M+H]
+。
步骤10：中间体21-11的合成
将二氯甲烷(10mL)加入到一个干燥的反应瓶中，再加入化合物21-10(0.3g,350.8μmoL,1eq)开始搅拌，然后加入间氯过氧苯甲酸((213.6mg,1052.3μmoL,85％含量,3eq)，反应体系在25℃的条件下搅拌1小时。反应液用10mL二氯甲烷稀释，利用5mL 5％硫代硫酸钠溶液和10mL饱和食盐水洗涤两次，用无水硫酸钠干燥过滤，滤液减压浓缩得到粗品，进行制备HPLC(色谱柱:Phenomenex Luna 80*30mm*3μm；流动相:[水(0.05％盐酸)-乙腈]；(乙腈)％:50％-80％,8min)分离，得到化合物21-11。MS m/z＝872.1[M+H]
+。
步骤11：中间体21-12的盐酸盐合成
将化合物1-2A(274.09mg,1.72mmoL,5eq)加入无水四氢呋喃(10mL)中，加入叔丁醇钠(148.91mg,1.55mmoL,4.5eq)，-15℃反应30min，加入化合物21-11(0.3g,344.33μmoL,1eq)，于-15℃反应1hr。向反应液加入5mL饱和氯化铵溶液，加入乙酸乙酯(5mL*2)萃取，合并有机相，用饱和食盐水(5mL*2)洗涤，无水硫酸钠干燥后浓缩，进行制备HPLC分离(色谱柱:Phenomenex Luna C18 80*40mm*3μm；流动相:[水(0.05％盐酸)-乙腈]；(乙腈)％:46％-66％,7min)，得到化合物21-12的盐酸盐。MS m/z＝967.3[M+H]
+。
步骤12：化合物21的盐酸盐合成
将化合物21-12的盐酸盐(90.00mg)加入三氟乙酸(2.12g,18.63mmoL,1.38mL,200eq)的无水二氯(7mL)中，于-10-0℃反应1hr。将产物倒入10mL水中，用乙酸乙酯(5mL*2)萃取，合并有机相，再用饱和食盐水(5mL*2)洗涤，无水硫酸钠干燥后浓缩。进行制备HPLC分离(色谱柱:Phenomenex Luna 80*30mm*3μm；流动相:[水(0.05％盐酸)-乙腈]；(乙腈)％:15％-35％,8min)，得到化合物21的盐酸盐。MS m/z＝627.1[M+H]
+。
实施例22
步骤1：中间体22-2的合成
将化合物22-1(50g,387.28mmol,1eq)、碘化钾(64.29g,387.28mmol,1eq)和无水碳酸钾(133.81g,968.19mmol,2.5eq)加入到N,N-二甲基甲酰胺(500mL)中，在搅拌下滴加对甲氧基氯苄(121.30g,774.55mmol,105.48mL,2eq)，60℃反应5hr。将反应液加入300mL水中，加入乙酸乙酯(200mL*2)进行萃取，合并有机相，用100mL饱和食盐水洗涤，再利用无水硫酸钠干燥后过滤浓缩，粗品过柱纯化(石油醚：乙酸乙酯＝1：0-0：1)，得到化合物22-2。MS m/z＝370.0[M+H]
+.
步骤2：中间体22-3的合成
将2,2,6,6-四甲基哌啶(81.22g,574.98mmol,97.62mL,4eq)加入到无水四氢呋喃(500mL)中，降温至-5℃，滴加正丁基锂(2.5M,229.99mL,4eq)，于-5-0℃反应15分钟，降温至-60℃，加入化合物22-2(59g,143.75mmol,1eq)的四氢呋喃(50mL)溶液，-60℃反应0.5小时，快速加入N,N-二甲基甲酰胺(210.13g,2.87mol,221.19mL,20eq)，于-60℃反应10min，反应液倒入300mL饱和氯化铵中，用甲基叔丁醚(100mL*2)萃取，合并有机相，再用100mL饱和食盐水洗涤，无水硫酸钠干燥过滤后浓缩，粗品过柱纯化(石油醚：乙酸乙酯＝10：1)得到化合物22-3。MS m/z＝398.1[M+H]
+。
步骤3：中间体22-4的合成
将NaH(5.31g,132.86mmol,60％含量,2.2eq)和无水四氢呋喃(150mL)在氮气保护下0℃反应0.5hr，滴加乙酰乙酸甲酯(15.43g,132.86mmol,14.28mL,2.2eq)，于0℃反应0.5hr，滴加n-BuLi(2.5M,53.14mL,2.2eq)，于0℃反应0.5hr，降温至-50℃，滴加化合物22-3(24g,60.39mmol,1eq)的无水四氢呋喃溶液(50mL)，于-50℃反应0.5hr。向反应液中加入80mL的饱和氯化铵溶液，用乙酸乙酯(50mL*2)萃取，合并有机相后再用100mL饱和食盐水洗涤，无水硫酸钠进行干燥后浓缩，粗品过柱纯化(石油醚：乙酸乙酯＝1：0-3：1)得到化合物22-4。
1H NMR(400MHz,CDCl
3)δ＝7.18–7.16(m,4H),6.84-6.82(m,4H),6.76(m,1H),6.48(m 1H),5.52-5.44(m,1H),4.21(s,4H),3.88-3.67(m,9H),3.53(s,2H),3.30(d,J＝4Hz,1H),3.01-2.88(m,2H)。MS m/z＝514.2[M+H]
+。
步骤4：中间体22-5的合成
将化合物22-4(12g,23.37mmol,1eq)溶于无水二氯(50mL)中，氮气保护下加入N,N-二甲基甲酰胺二甲基缩醛(4.18g,35.05mmol,4.66mL,1.5eq)，25℃反应16hr，加入三氟化硼***(6.63g,46.74mmol,5.77mL,2eq)，20℃反应1hr，将反应液加入到20mL饱和碳酸氢钠溶液中，分液，水相继续用20mL二氯甲烷萃取，合并有机相，用20mL饱和食盐水洗涤后，无水硫酸钠干燥过滤后浓缩。粗品过柱纯化(石油醚：乙酸乙酯＝1:0-3:1)得到化合物22-5。MS m/z＝524.2[M+H]
+。
步骤5：中间体22-6的合成
将化合物22-5(10.5g,20.06mmol,1eq)加入无水四氢呋喃(30mL)中，在氮气保护下加入三仲丁基硼氢化锂(1M,22.06mL,1.1eq)，于-60℃反应1hr。将反应物加入30mL稀盐酸中，用乙酸乙酯(10mL*2)分液萃取，合并有机相，用20mL饱和食盐水洗涤后用无水硫酸钠干燥后浓缩，粗品过柱纯化(石油醚：乙酸乙酯＝1：0-3：1)得到化合物22-6。MS m/z＝526.2[M+H]
+。
步骤6：中间体22-7的合成
将化合物22-6(4g,7.61mmol,1eq)加入到乙醇(16mL)和水(4mL)中，加入碳酸氢钠(1.61g,15.22mmol,2eq)和甲基异硫脲硫酸盐(2.06g,22.83mmol,3eq)，于45-50℃反应16hr，将反应物加入到10mL水中，用乙酸乙酯(10mL*2)萃取，合并有机相，再用饱和食盐水(10mL*2)洗涤，无水硫酸钠干燥后浓缩，粗品直接投下一步，得到化合物22-7。MS m/z＝566.2[M+H]
+。
步骤7：中间体22-8的合成
将化合物22-7(4.8g,4.67mmol,1eq)加入到无水二氯甲烷(20mL)中，加入三氟甲磺酸酐(1.98g,7.00mmol,1.16mL,1.5eq)，降温到0-10℃，将N,N-二异丙基乙胺(1.81g,14.00mmol,2.44mL,3eq)缓慢滴加，0℃反应0.5hr。加入到20mL饱和氯化铵中，分液，有机相用饱和食盐水(5mL*2)洗涤，无水硫酸钠干燥过滤后浓缩，粗品过柱纯化(石油醚：乙酸乙酯＝1:0-5：1)得到化合物22-8。
1H NMR(400MHz,CDCl
3)δ＝7.17-7.15(m,4H),6.86-6.83(m,4H),6.75-6.72(m,1H),6.54-6.50(m,1H),5.09–5.00(m,2H),4.83-4.79(m,1H),4.23-4.20(m,5H),3.82-3.80(m,7H),2.56(s,3H)。MS m/z＝698.1[M+H]
+。
步骤8：中间体22-9的合成
将化合物22-8(3.7g,5.30mmol,1eq)，化合物1-1A(2.25g,10.61mmol,2eq)，N,N-二异丙基乙胺(2.06g,15.91mmol,2.77mL,3eq)加入到N,N-二甲基甲酰胺(20mL)中，50℃反应1hr。将反应液加入20mL饱和氯化铵中，用乙酸乙酯(20mL*2)萃取，合并有机相，利用20mL饱和食盐水洗涤，无水硫酸钠干燥后浓缩，粗品利用过柱纯化(石油醚:乙酸乙酯＝3：1)，得到化合物22-9。
1H NMR(400MHz,CDCl
3)δ＝7.17- 7.15(m,4H),6.85-6.83(m,4H),6.72-6.70(m,1H),6.50-6.46(m,1H),5.11-5.07(m,1H),4.83-4.71(m,2H),4.32-4.23(m,6H),3.80(s,6H),3.43-2.84(m,5H),2.51(s,3H),2.01-1.93(m,3H),1.69-1.66(m,2H),1.50(s,9H)。MS m/z＝760.3[M+H]
+。
步骤9：中间体22-10的合成
将化合物22-9(0.6g,789.58μmol,1eq)溶于N,N-二甲基甲酰胺(10mL)，加入N-溴代丁二酰亚胺(98.37mg,552.70μmol,0.7eq)，0-10℃反应1hr，与将反应液中加入20mL水，用乙酸乙酯(10mL*2)萃取，合并有机相，再用饱和食盐水(10mL*2)洗涤，无水硫酸钠干燥浓缩。用制备板石油醚：乙酸乙酯＝1：1)分离得到产物化合物22-10。MS m/z＝838.2[M+H]
+。
步骤10：中间体22-11的合成
将化合物22-10(0.3g,357.65μmol,1eq)、氟磺酰基二氟乙酸甲酯(343.55mg,1.79mmol,227.52μL,5eq)、碘化亚铜(136.23mg,715.31μmol,2eq)溶于N,N-二甲基甲酰胺(10mL)，氮气置换三次，氮气保护下100℃反应2hr。反应液倒入10mL水中，用甲基叔丁醚(10mL*2)萃取，合并有机相，再用10mL饱和食盐水洗涤，无水硫酸钠干燥后浓缩。进行制备HPLC(色谱柱:Phenomenex luna C18(250*70mm,15μm)；流动相:[水(0.05％盐酸)-乙腈]；(乙腈)％:50％-98％,20min)分离，分离后溶液用饱和碳酸氢钠溶液调pH＝7-8，再用乙酸乙酯萃取，饱和食盐水洗涤，无水硫酸钠干燥，过滤浓缩，得到化合物22-11。MS m/z＝828.3[M+H]
+。
步骤11：中间体22-12的合成
将二氯甲烷(10mL)加入到一个干燥的反应瓶中，再加入化合物22-11(130mg,157.02μmol,1eq)，开始搅拌，然后加入间氯过氧苯甲酸(22.32mg,109.92μmol,85％含量,0.7eq)，反应体系在25℃的条件下搅拌1小时。反应液用10mL二氯甲烷稀释，利用5mL 5％硫代硫酸钠溶液和10mL饱和食盐水洗涤两次，用无水硫酸钠干燥，过滤，滤液减压浓缩得到粗品，用制备板(二氯甲烷：甲醇＝10：1)分离得到化合物22-12。
1H NMR(400MHz,CDCl
3)δ＝7.17-7.10(m,4H),6.87-6.83(m,4H),6.58-6.53(m,1H),5.21-5.10(m,1H),4.87-4.75(m,2H),4.44-4.22(m,6H),3.80(s,6H),3.58-3.44(m,3H),3.20-3.14(m,2H),2.97(m,4H),2.05-1.92(m,4H),1.49(s,9H)，MS m/z＝844.3[M+H]
+。
步骤12：中间体22-13的合成
将化合物1-2A(226.38mg,1.42mmol,20eq)加入无水四氢呋喃(10mL)中，加入叔丁醇钠(109.32mg,1.14mmol,16eq)，-15℃反应15min，加入化合物22-12(60mg,71.10μmol,1eq)，-15℃反应1hr。反应液加入5mL饱和氯化铵，合并反应液后，用乙酸乙酯(10mL*3)萃取，合并有机相，再用饱和食盐水(20mL*2)洗涤后，用无水硫酸钠干燥，过滤浓缩，经过制备板(二氯甲烷：甲醇＝10：1)分离得到化合物22-13。MS m/z＝939.5[M+H]
+。
步骤13：化合物22的盐酸盐合成
将化合物22-13(60.00mg,63.90μmol,1eq)加入三氟乙酸(1.46g,12.78mmol,946.19μL,200eq)无水二氯(5mL)中，-10-0℃反应1hr。将产物倒入10mL水中，水相用乙酸乙酯(5mL*2)萃取，合并有机相，再用饱和食盐水(5mL*2)洗涤，无水硫酸钠干燥后浓缩。制备HPLC分离(色谱柱:Phenomenex luna C18 80*40mm*3μm；流动相:[水(0.05％盐酸)-乙腈]；(乙腈)％:1％-30％,7min)，得到化合物22的盐酸盐。
1H NMR(400MHz,CD
3OD)δ＝6.65-6.60(m,1H),6.74-6.53(m,1H),5.66-5.53(m,1H),5.22-5.19(m,1H), 4.99-4.96(m,3H),4.25-4.18(m,2H),4.04–3.87(m,5H),3.55–3.38(m,3H),3.08–2.73(m,1H),2.67-1.87(m,11H)。MS m/z＝599.2[M+H]
+。
实施例23
步骤1：中间体23-2的合成
将化合物23-1(1.2g,4.78mmol,1eq)和双-(4-甲氧基苄基)-胺(2.46g,9.56mmol,2eq)加入到N-甲基吡咯烷酮(30mL)中，微波200℃反应1小时。将反应液用250mL乙酸乙酯稀释，然后用水(20mL×3)和饱和食盐水20mL洗涤，有机相干燥，过滤除去干燥剂，滤液减压除去溶剂得到粗品。粗品过柱纯化(乙酸乙酯/石油醚＝0～35％)得到化合物23-2。MS m/z＝428.6[M+H]
+。
步骤2：中间体23-3的合成
将化合物23-2(4g,9.36mmol,1eq)溶解于无水四氢呋喃(20mL)中，氮气保护下冷却到-78℃，然后向其中滴加正丁基锂(2.5M,6.74mL,1.1eq)，滴毕，搅拌反应1小时，然后向其中滴加N,N-二甲基甲酰胺(2.05g,28.08mmol,3eq)，滴毕搅拌反应0.5小时.向其中加入10mL饱和氯化铵和20mL水淬灭反应，然后用乙酸乙酯(50mL×2)萃取，合并有机相，旋干得到粗品。粗品过柱纯化(乙酸乙酯/石油醚＝0～15％)得到化合物23-3。
1H-NMR(400MHz,CDCl
3)δ：9.93(s,1H),7.23(s,1H),7.15(d,J＝8.8Hz,4H),6.86(d,J＝ 8.8Hz,4H),6.49(s,1H),4.77(s,4H),3.81(s,6H),2.26(s,3H)。
步骤3：中间体23-4的合成
将化合物23-3(2.09g,2.66mmol,1eq)溶解于DMF(20mL)中，然后加入NBS(988.15mg,5.55mmol,1eq)，所得反应液氮气保护下，室温20℃搅拌反应2小时。将反应液用60mL乙酸乙酯稀释，然后用水(20mL×3)和饱和食盐水20mL洗涤，有机相旋干得到粗品，粗品过柱纯化(乙酸乙酯/石油醚＝0～25％)得到化合物23-4。
步骤4：中间体23-5的合成
将化合物23-4(1.98g,4.34mmol,1eq)和氟磺酰基二氟乙酸甲酯(4.17g,2.17mmol,5eq)加入到DMF(20mL)中，然后加入CuI(205mg,1.08mol,1eq)，所得反应液氮气置换后置于100℃油浴中搅拌反应8小时。反应液旋干得到粗品。粗品过柱纯化(乙酸乙酯/石油醚＝0～25％)得到化合物23-5。MS m/z＝445.1[M+H]
+。
步骤5：中间体23-6的合成
将钠氢(899.91mg,22.50mmol,60％含量,2eq)悬浮于无水四氢呋喃(50mL)中，氮气保护下冷却到0℃，然后缓慢向其中滴加乙酰乙酸甲酯(2.61g,22.50mmol,2.42mL,2.0eq)，滴毕搅拌30分钟，然后向其中滴加正丁基锂(2.5M,9.0mL,2eq)，滴毕搅拌30分钟。撤去冰浴，冷却到-78℃，最后向其中滴加化合物23-5(5g,11.25mmol,1eq)的无水四氢呋喃(10mL)溶液，滴毕，搅拌反应1小时。向反应液中加入20mL水淬灭反应，然后用乙酸乙酯(50mL×3)萃取，合并有机相，旋干得到粗品。粗品过柱纯化(乙酸乙酯/石油醚＝0～45％)得到化合物23-6。MS m/z＝561.2[M+H]
+。
步骤6：中间体23-7的合成
将化合物23-6(2.9g,5.17mmol,1eq)和N,N-二甲基甲酰胺缩二甲醇(1.85g,15.52mmol,2.06mL,3eq)加入到无水二氯甲烷(20mL)中，室温20℃搅拌反应24小时，然后冷却到0℃，最后向其中加入三氟化硼***(734.25mg,5.17mmol,636.26μL,1eq)，加毕，20℃搅拌反应1小时。将反应液旋干得到粗品。粗品过柱纯化(乙酸乙酯/石油醚＝0～40％)得到化合物23-7。MS m/z＝593.1[M+Na]
+。
步骤7：中间体23-8的合成
将化合物23-7(635mg,1.11mmol,1eq)溶解于无水四氢呋喃(5mL)中，氮气保护下冷却到-78℃，然后向其中滴加三仲丁基硼氢化锂(1M,1.11mL,1eq)，滴比搅拌反应1小时，用1M盐酸1mL淬灭反应，然后加入20mL饱和食盐水和50mL乙酸乙酯搅拌5分钟，分出有机相，旋干得到粗品，粗品过柱纯化(乙酸乙酯/石油醚＝0～25％)得到化合物23-8。MS m/z＝573.2[M+H]
+。
步骤8：中间体23-9的合成
将化合物23-8(630mg,1.1mmol,1eq)和2-甲基硫脲单硫酸盐(621.31mg,3.30mmol,3eq)加入到无水乙醇(10mL)中，然后加入碳酸钠(233.24mg,2.2mmol,2eq)，所得反应液置于60℃油浴中搅拌反应18小时。将反应液旋干，残留物中加入水5mL和乙酸乙酯50mL，并用2M盐酸调节pH～6-7，分出有机相，水相用30mL乙酸乙酯萃取，合并有机相，用无水硫酸钠干燥，过滤除去干燥剂，滤液减压除去溶剂得到化合物23-9。MS m/z＝613.2[M+H]
+。
步骤9：中间体23-10的合成
将化合物23-9(541mg,883.63mmol,1eq)溶解于N,N-二甲基甲酰胺(4mL)中，然后加入PhNTf
2(473.19mg,1.32mmol,1.5eq)和N,N-二异丙基乙基胺(342.38mg,2.65mmol,461.43μL,3eq)。所得反应液在室温20℃下搅拌反应1.5小时。将反应液用100mL乙酸乙酯稀释，然后用水(10mL×3)和饱和食盐水10mL洗涤，有机相旋干得到粗品，粗品过柱纯化(乙酸乙酯/石油醚＝0～10％)得到化合物23-10。MS m/z＝745.3[M+H]
+。
步骤10：中间体23-11的合成
将化合物23-10(240mg,322.27μmol,1eq)和化合物1-1A(82.1mg,386.72μmol,1.3eq)加入到N,N-二甲基甲酰胺(3mL)中，然后加入N,N-二异丙基乙基胺(124.95mg,966.80μmol,168.40μL,3eq)，所得反应液置于100℃油浴中搅拌反应1小时。将反应液旋干得到粗品，粗品过柱纯化(乙酸乙酯/石油醚＝0～35％)得到化合物23-11。MS m/z＝807.4[M+H]
+。
步骤11：中间体23-12的合成
将化合物23-11(210mg,260.27μmol,1eq)溶解于无水二氯甲烷(2mL)中，然后加入间氯过氧苯甲酸(105.67mg,520.49μmol,85％含量,2eq)，所得反应液20℃搅拌反应2小时。将反应液旋干得到粗品，粗品过柱纯化(乙酸乙酯/石油醚＝0～45％)得到化合物23-12。MS m/z＝839.3[M+H]
+。
步骤12：中间体23-13的合成
将化合物1-2A(121.83mg,765.26μmol,3eq)和叔丁醇钠(49.03mg,510.17μmol,2eq)加入到四氢呋喃(2mL)中搅拌反应1小时，然后加入化合物23-12(214mg,255.09μmol,1eq)的四氢呋喃(1mL)溶液，反应液在20℃下搅拌反应1小时。将反应液旋干，残留物中加入30mL乙酸乙酯和5mL饱和食盐水搅拌至澄清，分出有机相，旋干得到粗品，粗品过柱纯化(甲醇/二氯甲烷＝0～10％)得到化合物23-13。MS m/z＝918.2[M+H]
+。
步骤13：化合物23的甲酸盐合成
将化合物23-13(194mg,221.32μmol,1eq)加入到三氟乙酸(2mL)中，55℃搅拌反应15小时。将反应液旋干，残留物中加入碳酸钠300mg和乙酸乙酯5mL搅拌20分钟，过滤，滤液减压除去溶剂得到粗品.粗品高效液相色谱制备分离：(分离条件：色谱柱:Phenomenex C18 150*40mm*5μm；mobile流动相:[水(0.025％甲酸)-乙腈]；(乙腈)％:1％-30％,10min)，得到化合物23的甲酸盐。MS m/z＝578.4[M+H]
+。
实施例24
步骤1：中间体24-1的合成
将钠氢(866.75mg,21.67mmol,60％含量,2eq)悬浮于无水四氢呋喃(50mL)中，氮气保护下冷却到0℃，然后缓慢向其中滴加化合物24-1A(3.38g,21.67mmol,2eq)，滴毕搅拌30分钟，然后向其中滴加正丁基锂(2.5M,8.67mL,2eq)，滴毕搅拌30分钟。撤去冰浴，冷却到-78℃，最后向其中滴加化合物A1-5(5g,10.84mmol,1eq)的无水四氢呋喃(10mL)溶液，滴毕，搅拌反应1小时。向反应液中加入30mL水淬灭反应，然后用乙酸乙酯(50mL×3)萃取，合并有机相，旋干得到粗品。粗品过柱纯化(乙酸乙酯/石油醚＝0～45％)得到化合物24-1。MS m/z＝640.1[M+Na]
+。
步骤2：中间体24-2的合成
将化合物24-1(6.50g,10.52mmol,1eq)和N,N-二甲基甲酰胺缩二甲醇(3.76g,31.57mmol,4.19mL,3eq)加入到无水二氯甲烷(20mL)中，室温20℃搅拌反应24小时，然后冷却到0℃，最后向其中加入三氟化硼***(1.49g,10.52mmol,1.30mL,1eq)，加毕，20℃搅拌反应4小时。向反应液中加入20mL 饱和碳酸氢钠溶液淬灭反应，然后用乙酸乙酯(50mL×3)萃取，合并有机相，用无水硫酸干燥，过滤，滤液减压浓缩得到粗品。粗品过柱纯化(乙酸乙酯/石油醚＝0～45％)得到化合物24-2。MS m/z＝628.2[M+H]
+。
步骤3：中间体24-3的合成
将化合物24-2(5.0g,7.97mmol,1eq)溶解于无水四氢呋喃(30mL)中，氮气保护下冷却到-78℃，然后向其中滴加三仲丁基硼氢化锂(1M,7.97mL,1eq)，滴毕，搅拌反应1小时，用1M盐酸10mL淬灭反应，然后用乙酸乙酯(3×50mL)萃取，合并有机相，浓缩得到粗品，粗品过柱纯化(乙酸乙酯/石油醚＝0～25％)得到化合物24-3。MS m/z＝630.2[M+H]
+。
步骤4：中间体24-4的合成
将化合物24-3(2.93g,4.65mmol,1eq)和2-甲基硫脲单硫酸盐(2.63g,13.96mmol,3eq)加入到无水乙醇(10mL)中，然后加入碳酸钠(986.43mg,9.31mmol,2eq)，所得反应液置于60℃油浴中搅拌反应18小时。将反应液旋干，残留物中加入水15mL和乙酸乙酯80mL，并用2M盐酸调节pH～6-7，分出有机相，水相用乙酸乙酯(50mL×3)萃取，合并有机相，用无水硫酸钠干燥，过滤除去干燥剂，滤液浓缩得到化合物24-4粗品。MS m/z＝670.2[M+H]
+。
步骤5：中间体24-5的合成
将化合物24-4(3.15g,4.70mmol,1eq)溶解于N,N-二甲基甲酰胺(30mL)中，然后加入化合物PhNTf
2(2.52g,7.06mmol,1.5eq)和N,N-二异丙基乙基胺(1.82g,14.11mmol,2.46mL,3eq)。所得最终反应液室温20℃搅拌反应2小时。将反应液旋干得到粗品，粗品过柱纯化(乙酸乙酯/石油醚＝0～15％)得到化合物24-5。MS m/z＝802.2[M+H]
+。
步骤6：中间体24-6的合成
将化合物24-5(3.15g,4.70mmol,1eq)溶解于N,N-二甲基甲酰胺(30mL)中，然后加入化合物1-1A(2.52g,7.06mmol,1.5eq)和N,N-二异丙基乙基胺(1.82g,14.11mmol,2.46mL,3eq)。所得最终反应液室温20℃搅拌反应2小时。将反应液旋干得到粗品，粗品过柱纯化(乙酸乙酯/石油醚＝0～15％)得到化合物24-6。MS m/z＝864.3[M+H]
+。
步骤7：中间体24-7的合成
将化合物24-6(160mg,185.19μmol,1eq)溶解于无水二氯甲烷(2mL)中，然后加入间氯过氧苯甲酸(75.19mg,370.37μmol,85％含量,2eq)，所得反应液20℃搅拌反应15小时。将反应液旋干得到粗品，粗品过柱纯化(乙酸乙酯/石油醚＝0～25％)得到化合物24-7。MS m/z＝896.3[M+H]
+。
步骤8：中间体24-8的合成
将化合物1-2A(35.89mg,225.45μmol,2eq)和叔丁醇钠(21.67mg,225.45μmol,2eq)加入到四氢呋喃(1mL)中搅拌反应1小时，然后加入化合物24-7(101mg,112.72μmol,1eq)的四氢呋喃(1mL)溶液，最终反应液在25℃下搅拌反应1小时。将反应液浓缩得到粗品，粗品过柱纯化(乙酸乙酯/石油醚＝0～65％)得到化合物24-8。MS m/z＝975.4[M+H]
+。
步骤9：化合物24A的盐酸盐和化合物24B的合成
将化合物24-8(94mg,96.40μmol,1eq)加入到三氟乙酸(2mL)中，25℃搅拌反应1小时。浓缩得到粗品，粗品高效液相色谱制备分离：(分离条件：Phenomenex C18 150*40mm*5μm；流动相[水(0.025％甲酸)- 乙腈]；(乙腈)％:5％-35％,10min)，再进行手性分离，分离条件(色谱柱:DAICEL CHIRALPAK IG(250mm*30mm,10μm)；流动相:[0.1％氨水乙醇]；(乙醇)％:45％-45％)保留时间Rt＝2.034min，得到化合物24B。MS m/z＝635.9[M+H]
+。另外异构体(保留时间Rt＝2.469min)继续用高效液相色谱制备分离，分离条件(色谱柱:Welch Xtimate C18 100*40mm*3μm；流动相:[水(0.025％甲酸)-乙腈]；(乙腈)％:10％-40％,8min)，加0.5mL HCl/1,4-二氧六环，得到化合物24A的盐酸盐。MS m/z＝635.8[M+H]
+。
实施例25
步骤1：中间体25-1的合成
将化合物16-1(00mg,113.40μmol,1eq)，化合物25-1A(42.71mg,170.10μmol,47.56μL,50％THF溶液,1.5eq)和碳酸钾(31.35mg,226.80μmol,2eq)加入到混合溶剂二氧六环(2mL)/水(0.4mL)中，然后加入Pd(dppf)Cl
2(16.60mg,22.68μmol,0.2eq)，所得反应液氮气置换后，加热到95℃搅拌反应15小时。将反应液浓缩得到粗品，粗品过柱纯化(乙酸乙酯/石油醚＝0～30％)得到化合物25-1。
步骤2：中间体25-2的合成
将化合物25-1(72mg,93.51μmol,1eq)溶解于无水二氯甲烷(1mL)中，然后加入间氯过氧苯甲酸(18.98mg,93.51μmol,85％含量,1eq)，所得反应液15℃搅拌反应1小时。将反应液浓缩得到化合物25-2。MS m/z＝786.3[M+H]
+。
步骤3：中间体25-3的合成
将化合物1-2A(45.57mg,286.27μmol,3eq)，叔丁醇钠(18.34mg,190.85μmol,2eq)和化合物25-2(75mg,95.42μmol,1eq)加入到甲苯(2mL)中在15℃下搅拌反应2小时，将反应液用30mL乙酸乙酯 稀释，然后用水5mL和饱和食盐水5mL洗涤，有机相浓缩得到粗品，粗品过柱纯化(甲醇/二氯甲烷＝0～5％)
得到化合物25-3。MS m/z＝881.9[M+H]
+。
步骤4：中间体25的盐酸盐合成
将化合物25-3(71mg,80.58μmol,1eq)加入到三氟乙酸(2mL)中，50℃搅拌反应5小时。将反应液浓缩得到粗品，粗品高效液相色谱制备分离(分离条件：色谱柱:Xtimate C18 150*40mm*5μm；流动相:[水(0.05％盐酸)-乙腈]；(乙腈)％:1％-30％,10min)，得到化合物25的盐酸盐，MS m/z＝541.3[M+H]
+。
实施例26
步骤1:中间体26-1的制备
向17-3(420mg，0.40mmol)的四氢呋喃溶液(10mL)中加入四甲基氟化铵(150mg,1.61mmol)体系在60℃下加热16小时，然后用50mL乙酸乙酯稀释，再用30mL饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液浓缩得到26-1。MS m/z:891.6[M+1]
+。
步骤2:中间体26-2的制备
向26-1(250mg,280.57μmol,1eq)的甲醇(10mL)溶液中加入钯/碳(20mg,10％含量)，体系在20℃下，氢气压力为15psi下搅拌1小时。过滤，将滤液浓缩得到26-2。MS m/z:895.6[M+1]
+。
步骤3:化合物26的盐酸盐制备
向26-2(220mg,245.79μmol,1eq)的二氯甲烷(3mL)溶液中加入三氟乙酸(3mL)，体系在45℃下搅拌20小时。将反应液旋干。通过制备HPLC(色谱柱:Phenomenex C18 150*40mm*5μm；流动相:[水(0.05％盐酸)-乙腈]；(乙腈)％:1％-30％,10min)分离得到化合物26的盐酸盐。
1H NMR(400MHz,CD
3OD)δ＝6.71(d,J＝9.0Hz,1H),5.48-5.19(m,2H),4.74-4.59(m,3H),4.31-4.14(m,3H),3.97-3.52(m,4H),3.48-3.37(m,2H),3.30-3.06(m,3H),2.92-2.63(m,3H),2.45-2.27(m,2H),2.24(s,3H),2.22-1.84(m,8H),1.12(t,J＝7.4Hz,3H)。MS m/z:555.2[M+1]
+。
实施例27
步骤1:中间体27-1的制备
将15-3(200mg,0.212mmol)和环丙基硼酸(92mg,1.059mmol)加入1,4-二氧六环(10mL)和水(1mL)的混合溶液，再加入二苯基磷二茂铁二氯化钯(20mg)和碳酸钠(45mg,0.425mmol)，用氮气置换三次，体系在90℃下反应15小时，过滤，将滤液旋干，通过制备薄层色谱(展开剂：二氯甲烷/甲醇＝10:1)分离得到27-1。MS m/z:907.6[M+H]
+。
步骤2:化合物27的盐酸盐制备
向27-1(60mg,0.066mmol)的二氯甲烷(2mL)溶液中加入三氟乙酸(2mL)，体系在20℃下搅拌1小时，浓缩，通过制备HPLC(色谱柱:Phenomenex C18 150*40mm*5μm；流动相:[水(0.05％盐酸)-乙腈]；(乙腈)％:1％-30％,10min)分离得到化合物27的盐酸盐。MS m/z:565.5[M+H]
+。
实施例28
步骤1:化合物28的三氟乙酸盐制备
向26-1(50mg,56.11μmol)的二氯甲烷(0.5mL)溶液中加入三氟乙酸(0.5mL)，体系在20℃下搅拌2小时，将反应液浓缩，通过制备HPLC(色谱柱:Welch Xtimate C18 100*40mm*3μm；流动相:[水(0.025％三氟乙酸)-乙腈]；(乙腈)％:0％-30％,8min)分离得到化合物28的三氟乙酸盐。
1H NMR(400MHz,CD
3OD)δ＝6.69(d,J＝8.4Hz,1H),5.69-5.15(m,2H),4.75-4.71(m,2H),4.60-4.36(m,4H),4.22-3.96(m,3H),3.95-3.65(m,5H),3.53-3.42(m,1H),3.21-3.11(m,1H),3.07-2.97(m,1H),2.75-2.55(m,2H),2.45(s,3H),2.43-2.25(m,4H),2.20-1.96(m,7H)。
实施例29
步骤1：中间体29-2的合成
将化合物29-1(50g,139.46mmol,1eq)加入到无水二氯甲烷(500mL)中，加入N,N-二异丙基乙二胺(54.07g,418.39mmol,72.87mL,3eq)，降温至0℃，缓慢滴加入氯甲基甲醚(15.59g,193.64mmol,14.71mL,1.39eq)，缓慢升温至18℃反应1小时。将反应液加入到500mL的冰水中，用DCM(100mL*2)萃取，合并有机相，再用500mL的饱和碳酸钠，500mL的饱和氯化铵和500mL的半饱和食盐水分别洗涤洗涤，无水硫酸钠干燥过滤后浓缩，粗品经柱层析(乙酸乙酯/石油醚＝0～50％)纯化得到化合物29-2。MS m/z＝403.2[M+H]
+。
步骤2：中间体29-3的合成
将化合物29-2(36g,89.42mmol,1eq)和N,N-二异丙基乙二胺(34.67g,268.27mmol,46.73mL,3eq)加入到无水二氯甲烷(360mL)中，降温至-40℃，滴加入三氟甲磺酸酐(37.85g,134.14mmol,22.13mL,1.5eq)，反应1小时。将反应液加入到300mL的冰水中，分液萃取，有机相用200mL的饱和碳酸氢钠溶液洗涤，再用200mL的饱和氯化铵洗涤，200mL的食盐水洗涤，无水硫酸钠干燥过滤后浓缩。粗品用柱层析(乙酸乙酯/石油醚＝0～30％)纯化得到化合物29-3。
1H NMR(400MHz,CDCl
3)δ＝7.71(dd,J＝5.2,9.2Hz,1H),7.43 (d,J＝2.4Hz,1H),7.36(d,J＝2.0Hz,1H),7.33(t,J＝8.8Hz,1H),5.28(s,2H),3.53(s,3H),1.28-1.18(m,21H)。
步骤3：中间体29-4的合成
将化合物29-3(34g,63.59mmol,1eq)加入到N,N-二甲基甲酰胺(340mL)中，加入乙烯基三丁基锡(42.03g,132.55mmol,38.56mL,2.08eq)和氯化锂(10.78g,254.38mmol,5.21mL,4eq)，氮气置换三次，氮气保护下加入三苯基膦二氯化钯(4.46g,6.36mmol,0.1eq)，30℃反应20小时。向反应液中加入300mL的20％的KF水溶液和300mL甲基叔丁基醚搅拌20分钟，垫硅藻土过滤，滤饼用甲基叔丁基醚(50mL*4)淋洗，除去水相，有机相用500mL的饱和食盐水洗涤，无水硫酸钠干燥过滤后减压浓缩。粗品经过柱
(乙酸乙酯/石油醚＝20％)纯化得到化合物29-4。MS m/z＝413.3[M+H]
+。
步骤4：中间体29-5的合成
将化合物29-4(20g,48.47mmol,1eq)加入到无水四氢呋喃(200mL)和水(50mL)中，降温至0℃，加入高碘酸钠(31.10g,145.42mmol,8.06mL,3eq)和四氧化锇(1.5g,5.90mmol,306.12μL,1.22e-1eq)，缓慢升温至18℃，反应1小时。将反应液加入到300mL10％硫代硫酸钠溶液中，用乙酸乙酯(100mL*2)萃取，500mL的饱和食盐水洗涤，无水硫酸钠干燥过滤后浓缩。粗品经过柱(乙酸乙酯/石油醚＝20％)纯化得到化合物29-5。MS m/z＝415.3[M+H]
+。
步骤5：中间体29-7的合成
向化合物29-6(1g,4.05mmol)和1-1A(1.03g,4.86mmol)的二氯甲烷溶液中加入N,N-二异丙基乙胺(1.05g,8.11mmol)，得到的混合物室温25℃搅拌小时。向反应液中加入水(20mL)和二氯甲烷(50mL)，搅拌5分钟，除去水相，有机相减压浓缩，残余物经过过柱机纯化(乙酸乙酯/石油醚＝20％)得到的化合物29-7。MS m/z＝423.1[M+H]
+。
步骤6：中间体29-8的合成
冰水浴0℃氮气保护下，向化合物29-7(0.6g,1.42mmol)的四氢呋喃(5mL)溶液中分批加入四氢铝锂(0.1g,2.84mmol)，得到的混合物自然升至25℃搅拌2小时，向反应液中依次滴加水(0.1g)、15％氢氧化钠水溶液(0.1g)和水(0.3g)搅拌30分钟，过滤，四氢呋喃(10mL)，滤液减压浓缩，得到化合物29-8。MS m/z＝381.1[M+H]
+。
步骤7：中间体29-9的合成
干冰-乙酸乙酯浴-65℃氮气保护下，向化合物29-8(0.5g,1.33mmol)的四氢呋喃(10mL)溶液中滴加二异丙基氨基锂(1.51mL,3.02mmol,2M)，搅拌30分钟后滴加化合物29-5(0.5g,1.51mmol)的四氢呋喃(5mL)溶液，得到的混合物自然升至25℃，向反应液中加入0.1M稀盐酸水溶液(15mL)和乙酸乙酯(20mL)，搅拌10分钟，除去水相，有机相减压浓缩，残余物经过过柱机纯化(乙酸乙酯/石油醚＝20％)，得到化合物29-9。MS m/z＝795.4[M+H]
+。
步骤8：中间体29-10的合成
干冰-乙酸乙酯浴-65℃氮气保护下，向化合物29-9(0.51g,641.44μmol)的四氢呋喃(10mL)溶液中滴加正丁基锂(2.5M,564.47μL)，搅拌30分钟后，滴加对甲苯磺酰氯(183.43mg,962.16μmol)的四氢呋喃(3mL)，得到的混合物自然升至25℃搅拌2小时，向反应液中加入50毫升饱和氯化铵水溶液淬灭反应，再加入50毫升乙酸乙酯萃取，除去水相，有机相减压浓缩。残余物经过过柱机纯化(乙酸乙酯/石油醚＝30％)，得到化 合物29-10。MS m/z＝777.4[M+H]
+。
步骤9：中间体29-11的合成
向化合物29-10(45mg,57.91μmol)的二氯甲烷(2mL)溶液中加入间氯过氧苯甲酸(14.11mg,69.49μmol,85％含量)，得到的混合物室温25℃搅拌2小时。向反应液中加入2毫升饱和碳酸氢钠水溶液和2毫升饱和亚硫酸钠水溶液和5毫升二氯甲烷搅拌5分钟，除去水相，有机相减压浓缩。残余物经过制备TLC纯化(石油醚/乙酸乙酯＝20％)，得化合物29-11。MS m/z＝793.4[M+H]
+。
步骤10：中间体29-12的合成
冰水浴0℃氮气保护下，向化合物1-2A(32.12mg,201.76μmol)的四氢呋喃(2mL)溶液中加入叔丁醇钠(19.39mg,201.76μmol)，搅拌30分钟后加入化合物29-11(40mg,50.44μmol)，得到的混合物自然升至25℃搅拌2小时。向反应液中加入0.5M稀盐酸调节pH值约为6，加入5毫升乙酸乙酯和2毫升饱和食盐水搅拌5分钟，除去水相，有机相减压浓缩，得到化合物29-12。MS m/z＝888.5[M+H]
+。
步骤11：中间体29-13的合成
向化合物29-12(45mg,50.67μmol)的二氯甲烷(1mL)溶液中加入盐酸-乙酸乙酯(4M,126.67μL)，得到的混合物室温25℃搅拌2小时，反应液直接减压浓缩得化合物29-13的三氟乙酸盐。MS m/z＝744.4[M+H]
+。
步骤12：化合物29A和化合物29B的合成
向化合物29-13(40mg,三氟乙酸盐)的DMF(1mL)溶液中加入氟化铯(40.83mg,268.82μmol)和碳酸钾(22.29mg,161.29μmol)，得到的混合物室温25℃搅拌2小时，反应液过滤，加入5毫升甲醇洗涤，滤液减压浓缩，残余物经过制备HPLC纯化(色谱柱:Phenomenex Luna C18 75*30mm*3μm；流动相:[水(0.025％甲酸)-乙腈]；乙腈％:10％-40％,8min)，再进行手性分离(色谱柱:DAICEL CHIRALCEL OD(250mm*30mm,10μm)；流动相:[0.1％氨水甲醇]；甲醇％:40％-40％,12min)，得化合物29A(Rt＝1.386min)和化合物29B(Rt＝2.079min)。MS m/z＝588.3[M+H]
+。
生物测试数据：
实验例1.KRAS
G12D抑制活性测试
1.目的
通过TR-FRET的方法，筛选出能有效抑制KRAS与GTP结合的化合物。
2.耗材和仪器
表1.耗材和仪器
| 名称 | 供应商 | 货号 |
| HEPES(4-(2-羟乙基)-1-哌嗪乙磺酸)pH 7.3 | 赛默飞 | BP299-500 |
| 氯化钠 | 普洛麦格 | V4221 |
| EDTA(乙二胺四乙酸) | EMD Millipore | 324506 |
| 吐温20 | 伯乐 | 1706531 |
| 氯化镁 | MP生物医学 | 191421 |
| Bodipy GDP(鸟苷5'-二磷酸，BODIPY TM FL 2'-(或-3')- | 英杰 | G22360 |
| O-(N-(2-氨基乙基)尿烷)，二(三乙基铵)盐) | ||
| GTP(鸟嘌呤-5'-三磷酸) | 西格玛 | G8877 |
| Tb-SA(铽标记链霉亲和素) | 英杰 | PV3576 |
| SOS(son of sevenless)蛋白 | ||
| KRAS G12D(Kirsten rat sarcoma viral oncogene)蛋白 | ||
| 化合物板 | Labcyte | LP-0200 |
| 实验板 | 柏金埃尔默 | 6008269 |
| 15毫升离心管 | 康宁 | 430791 |
| 1.5毫升离心管 | 爱思进 | MCT-150-C |
| Dragonfly自动加样仪 | TTP | |
| Bravo | 安捷伦 | |
| Echo 550 | Labcyte | |
| Envision | 柏金埃尔默 |
3.试剂准备
a.储存试剂：
1)KRAS核苷酸交换缓冲液
取20mL 1000mM HEPES，20mL 500mM EDTA，10mL 5M氯化钠，100％0.1mL吐温20，949.9mL水，配制成1L溶液，用过滤法消毒，4℃条件下储存。
2)KRAS实验缓冲液
取20mL 1000mM HEPES，10mL 1000mM氯化镁，30mL 5M氯化钠，100％0.05mL吐温20，939.95mL水，配制成1L溶液，用过滤法消毒，4℃条件下储存。
3)KRAS/Bodipy GDP/Tb-SA混合液
取9.5μL 95μM KRAS
G12D蛋白，440.5μL KRAS核苷酸交换缓冲液混合，室温下孵育1小时后，与8.4μL17.9μM Tb-SA，1.8μL 5mM Bodipy GDP，9539.8μL KRAS实验缓冲液，配制成1L溶液，混合后室温下静置6小时，储存至-80℃条件下。
b.实验试剂：
1)KRAS酶溶液
取73.3μL KRAS/Bodipy GDP/Tb-SA混合液，2126.7μL KRAS实验缓冲液，配制成2200μL溶液。
2)SOS/GTP混合液
取1.59μL 166μM SOS蛋白，198μL 100mM GTP，2000.41μL KRAS实验缓冲液，配制成2200μL溶液。
4.实验流程
1)对照化合物母液浓度为1mM，待测化合物母液浓度为10mM。转移9μL对照化合物和待测化合物至384-LDV板内；
2)使用Bravo将LDV板上的化合物进行10点3倍稀释；
3)使用ECHO将LDV板上的化合物转移9nL至实验板；
4)使用Dragonfly自动加样仪依次向实验板每孔中加入3μL 3nM Kras/0.5nM TB-SA/30nM BodipyGDP混合液和3μL Ras buffer，以1000rpm/min，将实验板离心1分钟；
5)实验板在室温中孵育1小时；
6)使用Dragonfly自动加样仪在实验板每孔加入3μL 120nM SOS/9mM GTP混合液，以1000rpm/min，将实验板离心1分钟；
7)实验板在室温中孵育1小时；
8)使用Envision读板并记录数据；
9)使用Excel和Xlfit进行数据分析，计算待测化合物IC
50。
5实验结果
结果见表2。
表2化合物对KRAS
G12D酶抑制的IC
50值
| 化合物编号 | KRAS G12D IC 50(nM) |
| 化合物1的盐酸盐 | 2.5 |
| 化合物2的盐酸盐 | 23 |
| 化合物3的盐酸盐 | 425 |
| 化合物5的盐酸盐 | 12.7 |
| 化合物6的盐酸盐 | 30 |
| 化合物7的盐酸盐 | 0.1 |
| 化合物8的盐酸盐 | 78.3 |
| 化合物9 | 1.1 |
| 化合物10的甲酸盐 | 3.3 |
实验结论：本发明化合物具有显著的KRAS
G12D酶抑制作用。
实验例2.AGS细胞p-ERK抑制测试
1.目的
通过HTRF的方法，筛选出能有效抑制AGS细胞p-ERK的化合物。
2.实验流程
1).AGS细胞种于透明96孔细胞培养板中，80μL细胞悬液每孔，每孔包含10000个细胞，细胞板放入二氧化碳培养箱，37度过夜孵育；
2).结束孵育后，弃掉细胞上清，加入80μL每孔的培养基，培养基含0.02％血清，细胞板放入二氧化碳培养箱，37度过夜孵育；
3).取2μL化合物加入78μL细胞培养基，混匀后，取20μL化合物溶液加入到对应细胞板孔中，细胞板放回二氧化碳培养箱继续孵育3小时；
4).结束孵育后，弃掉细胞上清加入50μL 1X细胞裂解液每孔，室温摇晃孵育30分钟；
5).使用detection buffer将Phospho-ERK1/2 Eu Cryptate antibody和Phospho-ERK1/2 d2 antibody稀释20倍；
6).取16μL细胞裂解物上清每孔到新的384白色微孔板中，再加入2μL Phospho-ERK1/2 Eu Cryptate antibody稀释液和2μL Phospho-ERK1/2 d2 antibody稀释液，常温孵育至少4小时；
7).孵育结束后使用多标记分析仪读取HTRF excitation:320nm,emission:615nm，665nm；
8).计算待测化合物IC
50。
3实验结果
结果见表3。
表3化合物对AGS细胞p-ERK抑制的IC
50值
| 化合物编号 | AGS p-ERK IC 50(nM) |
| 化合物1的盐酸盐 | 45 |
实验结论：本发明化合物具有显著的AGS细胞p-ERK抑制作用。
实验例3.GP2D细胞p-ERK抑制测试
1.目的
通过HTRF的方法，筛选出能有效抑制GP2D细胞p-ERK的化合物。
2.实验流程
1).GP2D细胞种于透明96孔细胞培养板中，80μL细胞悬液每孔，每孔包含8000个细胞，细胞板放入二氧化碳培养箱，37度过夜孵育；
2).取2μL化合物加入78μL细胞培养基，混匀后，取20μL化合物溶液加入到对应细胞板孔中，细胞板放回二氧化碳培养箱继续孵育1小时；
3).结束孵育后，弃掉细胞上清加入50μL 1X细胞裂解液每孔，室温摇晃孵育30分钟；
4).使用detection buffer将Phospho-ERK1/2 Eu Cryptate antibody和Phospho-ERK1/2 d2 antibody稀释20倍；
5).取16μL细胞裂解物上清每孔到新的384白色微孔板中，再加入2μL Phospho-ERK1/2 Eu Cryptate antibody稀释液和2μL Phospho-ERK1/2 d2 antibody稀释液，常温孵育至少4小时；
6).孵育结束后使用多标记分析仪读取HTRF excitation:320nm,emission:615nm，665nm；
7).计算待测化合物IC
50。
3实验结果
结果见表4。
表4化合物对GP2D细胞p-ERK抑制的IC
50值
| 化合物编号 | GP2D p-ERK IC 50(nM) |
| 化合物1的盐酸盐 | 0.8 |
| 化合物7的盐酸盐 | 1.1 |
| 化合物8的盐酸盐 | 78 |
| 化合物11A的盐酸盐 | 3.4 |
| 化合物11B的盐酸盐 | 75.9 |
| 化合物12的甲酸盐 | 20.9 |
| 化合物14的盐酸盐 | 5.2 |
| 化合物15的盐酸盐 | 8.4 |
| 化合物16的盐酸盐 | 2.9 |
| 化合物17 | 27.1 |
| 化合物18 | 66.4 |
| 化合物19的盐酸盐 | 17.5 |
| 化合物20B | 1.3 |
| 化合物21的盐酸盐 | 2.6 |
| 化合物22的盐酸盐 | 2.7 |
| 化合物23的甲酸盐 | 23.4 |
| 化合物25的盐酸盐 | 96.4 |
| 化合物26的盐酸盐 | 18.8 |
| 化合物27的盐酸盐 | 118.3 |
实验结论：本发明化合物具有显著的GP2D细胞p-ERK抑制作用。
实验例4.PANC0403细胞p-ERK抑制测试
1.实验材料：
PANC0403细胞购自南京科佰；RPMI-1640培养基购自Biological Industries；胎牛血清购自Biosera；Advanced Phospho-ERK1/2(THR202/TYR204)KIT购自Cisbio。
Advanced Phospho-ERK1/2(THR202/TYR204)KIT成分见表5。
表5
| 成分名称 | 储存温度 |
| Advanced PhosphoERK1/2 Eu Cryptate antibody | ≤-16℃ |
| Advanced PhosphoERK1/2 d2 antibody | ≤-16℃ |
| Blocking reagent(stock solution 100X) | ≤-16℃ |
| Lysis buffer#1(stock solution 4X) | ≤-16℃ |
| Detection buffer(ready-to-use) | ≤-16℃ |
2.实验方法：
1)PANC0403细胞种于透明96孔细胞培养板中，80μL细胞悬液每孔，每孔包含10000个PANC0403细胞，细胞板放入二氧化碳培养箱，37度过夜孵育；
2)将待测化合物用100％DMSO稀释到2mM作为第一个浓度，然后再用移液器进行5倍稀释至第8个 浓度，即从2mM稀释至25.6nM。取2μL化合物加入78μL细胞饥饿培养基，混匀后，取20μL化合物溶液加入到对应细胞板孔中，细胞板放回二氧化碳培养箱继续孵育3小时，此时化合物浓度为10μM至0.128nM，DMSO浓度为0.5％；
3)结束孵育后，弃掉细胞上清加入50μL细胞裂解液每孔，室温摇晃孵育30分钟；
4)使用Detection buffer将Phospho-ERK1/2 Eu Cryptate antibody和Phospho-ERK1/2 d2 antibody稀释20倍；
5)取16μL细胞裂解物上清每孔到新的384白色微孔板中，再加入2μL Phospho-ERK1/2 Eu Cryptate antibody稀释液和2μL Phospho-ERK1/2 d2 antibody稀释液，常温孵育过夜；
6)孵育结束后使用多标记分析仪读取HTRF excitation:320nm,emission:615nm，665nm。
3.数据分析：
利用方程式(Sample-Min)/(Max-Min)*100％将原始数据换算成抑制率，IC50的值即可通过四参数进行曲线拟合得出(GraphPad Prism中log(inhibitor)vs.response--Variable slope模式得出)。
Max孔:阳性对照孔读值为1X裂解液
Min孔：阴性对照孔读值为0.5％DMSO细胞孔细胞裂解液
4.实验结果
结果见表6。
表6化合物对PANC0403细胞p-ERK抑制的IC
50值
| 化合物编号 | PANC0403 p-ERK IC 50(nM) |
| 化合物29B | 574.2 |
实验结论：本发明化合物具有显著的PANC0403细胞p-ERK抑制作用。
实验例5.化合物在肿瘤细胞系AsPC-1和GP2D中的抗细胞增殖作用
研究目的
本实验通过检测化合物在肿瘤细胞系AsPC-1和GP2D中对体外细胞活性的影响而研究化合物抑制细胞增殖的作用。
实验材料
表7.实验材料
| 细胞系 | 肿瘤类型 | 生长特点 | 培养方法 |
| AsPC-1 | 胰腺癌 | 贴壁生长 | RPMI 1640+10％FBS |
| GP2D | 结肠癌 | 贴壁生长 | DMEM+10％FBS+2mM L-glutamine |
Ultra Low Cluster-96孔板(Corning-7007)
Greiner CELLSTAR 96-孔板(#655090)
Promega CellTiter-Glo 3D发光法细胞活性检测试剂盒(Promega-G9683)
2104-10 EnVision读板器，PerkinElmer
RPMI 1640，DMEM，PBS(磷酸盐缓冲溶液)，FBS(胎牛血清)，Antibiotic-antimycotic(抗生素- 抗真菌药)，L-glutamine(L-谷氨酰胺)，DMSO(二甲基亚砜)
实验方法及步骤
细胞培养
将肿瘤细胞系按培养方法所示的培养条件在37℃，5％CO
2的培养箱中进行培养。定期传代，取处于对数生长期的细胞用于铺板。
细胞铺板
用台盼兰进行细胞染色并计数活细胞。
将细胞浓度调整至合适浓度。
表8.细胞密度
| 细胞系 | 密度(每孔) |
| AsPC-1 | 7000个细胞 |
| GP2D | 8000个细胞 |
在ULA培养板中每孔加入135μL细胞悬液，在空白对照空中加入同样体积且不含细胞的培养液。
铺板后，立刻在室温条件下将ULA培养板离心10分钟，离心条件1000rpm。注意：在离心后，务必小心处理后续操作，不要造成不必要的震荡。
将培养板在37℃,5％CO
2,及100％相对湿度的培养箱中培养过夜。
10X化合物工作液的配制及化合物处理细胞(第一天)
配制好10X化合物工作液(DMSO 10X工作液)后，分别向ULA培养板内加入15μL的10X化合物工作液，在溶媒对照和空白对照中加入15μL DMSO-细胞培养液混合液。
将96孔细胞板放回培养箱中培养120小时。
每天观察细胞成球情况直至实验终点。
CellTiter-Glo发光法细胞活性检测(第五天)
以下步骤按照Promega CellTiter-Glo 3D发光法细胞活性检测试剂盒(Promega#G9683)的说明书来进行。
在每孔中加入150μL(等于每孔中细胞培养液体积)的CellTiter-Glo 3D试剂。用铝箔纸包裹细胞板以避光。
将培养板在轨道摇床上振摇5分钟。
小心的用移液管上下吹打10次，混匀空内混合物。在继续下一步之前需确保细胞球体充分被分离。
然后将ULA培养板内的溶液转移至黑底培养板(#655090)中，在室温放置25分钟以稳定发光信号。
在2104 EnVision读板器上检测发光信号。
数据分析
用下列公式来计算检测化合物的抑制率(Inhibition rate，IR)：IR(％)＝(1–(RLU化合物–RLU空白对照)/(RLU溶媒对照–RLU空白对照))*100％。在Excel中计算不同浓度化合物的抑制率，然后用GraphPad Prism软件作抑制曲线和计算相关参数，包括最小抑制率，最大抑制率及IC
50。
实验结果
结果见表9。
表9化合物对KRAS
G12D细胞抑制的IC
50值
| 化合物编号 | KRAS G12D AsPC-1IC 50(nM) | KRAS G12D GP2D IC 50(nM) |
| 化合物1的盐酸盐 | 315 | 37 |
| 化合物2的盐酸盐 | 1865 | 332 |
实验结论：本发明化合物具有KRAS
G12D细胞突变抑制作用。
实验例6.血浆蛋白结合实验(PPB)实验
实验目的
采用平衡透析法测定化合物在CD-1小鼠、Sprague-Dawley大鼠、比格犬、食蟹猴和人血浆中的蛋白结合率。
实验方法
采用上述五个物种的血浆分别配制化合物浓度为2μM的血浆样品，置于96孔快速平衡透析装置中，在37±1℃下用磷酸盐缓冲溶液透析4h。本实验采用华法林作为对照化合物。血浆和透析缓冲液中待测物的浓度用LC-MS/MS法进行测定。
实验结果
在2μM测试浓度下，化合物1的盐酸盐的未结合率(％)如下表10所示。
表10 PPB测试结果
| 化合物编号 | Unbound PPB H/C/D/R/M |
| 化合物1的盐酸盐 | 7.0/6.3/5.2/3.0/2.7 |
化合物1在透析装置中的回收率(％)为82.4～109.5，满足本实验对回收率和稳定性的要求。
实验结论
在2μM的测试浓度下，本发明化合物在上述五个物种的血浆中表现出较好的游离态浓度。
实验例7.CD-1小鼠口服及静脉注射受试化合物的药代动力学研究
实验目的
测试CD-1小鼠口服及静脉注射化合物的体内药代动力学。
实验步骤
受试化合物与5％DMSO+95％(10％HP-β-CD)水溶液混合，涡旋并超声，制备得到0.5mg/mL澄清溶液(静脉)或3mg/mL澄清溶液(口服)，微孔滤膜过滤后备用。选取7至10周龄的雄性SD小鼠，静脉注射给予候选化合物溶液，剂量约为2mg/kg。口服给予候选化合物溶液，剂量约为30mg/kg。收集一定时间的全血，制备得到血浆，以LC-MS/MS方法分析药物浓度，并用Phoenix WinNonlin软件(美国Pharsight公司)计算药代参数。
实验结果
结果见表11和12。
表11静脉(IV)PK数据
| 供试品 | 化合物1的盐酸盐 | 化合物11A的盐酸盐 | 化合物20B |
| 给药剂量(mg/kg) | 1.82 | 2.14 | 2.04 |
| C 0(nM) | 1400 | 1593 | 449 |
| T 1/2(h) | 23.1 | 15.6 | 11.2 |
| V d(L/kg) | 148 | 56.2 | 97.2 |
| Cl(mL/Kg/min) | 106 | 62.8 | 138 |
| AUC 0-last(nM.h) | 353 | 690 | 371 |
表12口服(PO)PK数据
| 供试品 | 化合物1的盐酸盐 | 化合物11A的盐酸盐 | 化合物20B |
| 给药剂量(mg/kg) | 29.3 | 30.3 | 30.3 |
| C max(nM) | 228 | 617 | 2095 |
| T max | 4.5 | 2 | 1.5 |
| T 1/2(h) | ND | 8 | 14.4 |
| AUC 0-inf(nM.h) | 1350 | 2403 | 4710 |
| F | 25.5％ | 23.2％ | 85％ |
实验结论
本发明化合物具有良好的口服生物利用度。
实验例8.体内药效学研究
实验方法：
建立人结肠癌GP2D细胞皮下异种移植肿瘤Balb/c nude小鼠模型，将0.2mL(2×10
6个)GP2D细胞(加基质胶，体积比为1:1)皮下接种于每只小鼠的右后背，当肿瘤平均体积达到149mm
3时开始分组给药，每组6只。实验当天动物按组别给予相对应的药物。第一组G1设阴性对照组，单独灌胃给予5％DMSO+95％(10％HP-β-CD)，第二组G2-第四组G4给予给化合物1的盐酸盐，给药剂量和方案如表13所示。
表13受试物对人弥漫大B淋巴瘤TMD8小鼠移植瘤的药效研究
注：PO表示口服，QD表示每日一次，BID表示每日一次。
实验期间每周测定2次动物的体重和肿瘤的大小，同时每天观察并记录动物的临床症状，每次给药均参考最近一次称量的动物体重。
肿瘤的测量用数显游标卡尺来测定长(a)和宽(b)，肿瘤体积(Tumor volume，TV)的计算公式为：TV＝a×b
2/2。
实验结果：
化合物1的盐酸盐对人结肠癌GP2D小鼠异种移植瘤有显著的抑制作用，给药20天后，第二组G2(3mg/kg,PO,BID)在第20天时，肿瘤体积抑制率TGI(％)为19.4％；第三组G3(10mg/kg,PO,BID)和第四组G4(30mg/kg,PO,BID)在第20天时，肿瘤体积抑制率TGI(％)分别为53.9％和83.7％；详细结果如表14所示。
表14受试物在人结肠癌GP2D小鼠异种移植瘤模型中对动物肿瘤大小的影响
注：N/A表示未检测。
实验结论：在体内药效方面，本发明化合物在GP2D细胞系中表现出良好的抑制肿瘤作用，存在明显的剂量相关性。
Claims (15)
- 式(III)所示化合物或其药学上可接受的盐，
结构单元选自
选自单键或双键；
T 1选自CR 7R 8、NR 9和O；T 2选自CH和N；L 1选自-CH 2-和键；R 1、R 2、R 3、R 4和R 5分别独立地选自H和C 1-3烷基，所述C 1-3烷基任选被1、2或3个R a取代；R 6选自C 6-10芳基和5-10元杂芳基，所述C 6-10芳基和5-10元杂芳基任选被1、2、3、4或5个R b取代；R 7和R 8分别独立地选自H、CH 3和NH 2；R 9选自H和CH 3；R 10选自4-8元杂环烷基和所述4-8元杂环烷基和
任选被1、2或3个R c取代；
R 11和R 12分别独立地选自H、C 1-3烷基和C 3-5环烷基，所述C 1-3烷基和C 3-5环烷基任选被1、2或3个卤素取代；结构单元选自5-6元杂环烯基；
结构单元选自C 3-5环烷基；
结构单元选自4-5元杂环烷基；
m选自0、1或2；n选自0、1或2；p选自0、1或2；q选自1、2或3；r选自1或2；s选自1、2或3；各R a分别独立地选自F、Cl、Br和I；各R b分别独立地选自F、Cl、Br、I、OH、NH 2、CN、C 1-3烷基、C 1-3烷氧基、C 2-3炔基、C 2-3烯基、-C(＝O)C 1- 3烷基和C 3-5环烷基，所述C 1-3烷基、C 1-3烷氧基、C 2-3炔基、C 2-3烯基、-C(＝O)C 1-3烷基和C 3-5环烷基任选被1、2、3、4或5个R取代；各R c分别独立地选自H、F、Cl、Br、I、OH、CN、C 1-3烷基、C 1-3烷氧基和-C 1-3烷基-O-C(＝O)-C 1-3烷氨基；各R分别独立地选自F、Cl、Br和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 1、R 2、R 3、R 4和R 5分别独立地选自H、CH 3、CH 2CH 3和CH(CH 3) 2，所述CH 3、CH 2CH 3和CH(CH 3) 2任选被1、2或3个R a取代。
- 根据权利要求1或2所述化合物或其药学上可接受的盐，其中，R 1、R 2、R 3、R 4和R 5分别独立地选自H和CH 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，结构单元选自
- 根据权利要求1所述化合物或其药学上可接受的盐，其中，各R b分别独立地选自F、Cl、Br、I、OH、NH 2、CN、CH 3、CH 2CH 3、OCH 3、OCH 2CH 3、-CH＝CH 2、-CH 2-CH＝CH 2、-C≡CH、-C(＝O)CH 3和环丙基，所述CH 3、CH 2CH 3、OCH 3、OCH 2CH 3、-CH＝CH 2、-CH 2-CH＝CH 2、-C≡CH、-C(＝O)CH 3和环丙基任选被1、2、3、4或5个R取代。
- 根据权利要求5所述化合物或其药学上可接受的盐，其中，各R b分别独立地选自F、Cl、Br、I、OH、NH 2、CN、CH 3、CF 3、CH 2CH 3、CF 2CF 3、-CH＝CH 2、-C≡CH、-C(＝O)CH 3和环丙基。
- 根据权利要求1、5或6任意一项所述化合物或其药学上可接受的盐，其中，R 6选自苯基、吡啶基、萘基、吲哚基和吲唑基，所述苯基、吡啶基、萘基、吲哚基和吲唑基任选被1、2、3、4或5个R b取代。
- 根据权利要求7所述化合物或其药学上可接受的盐，其中，R 6选自
- 根据权利要求1所述化合物或其药学上可接受的盐，其中，各R c分别独立地选自H、F、Cl、Br、OH、CN、CH 3、CH 2CH 3、CH 2CF 3、OCH 3、OCF 3和
- 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 10选自四氢吡咯基、六氢-1H-吡咯里嗪基和1,2,3,4-四氢异喹啉基，所述四氢吡咯基、六氢-1H-吡咯里嗪基和1,2,3,4-四氢异喹啉基任选被1、2或3个R c取代。
- 根据权利要求1、9或10任意一项所述化合物或其药学上可接受的盐，其中，R 10选自
- 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 11和R 12分别独立地选自H和CH 3。
- 下式所示化合物或其药学上可接受的盐，
- 根据权利要求13所述的化合物或其药学上可接受的盐，其选自，
- 根据权利要求1～14任意一项所述的化合物或其药学上可接受的盐在制备治疗与KRAS G12D突变相关疾病的药物中的应用。
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| WO2023284881A1 (en) * | 2021-07-16 | 2023-01-19 | Silexon Ai Technology Co., Ltd. | Heterocyclic compounds useful as kras g12d inhibitors |
| WO2023138601A1 (zh) * | 2022-01-21 | 2023-07-27 | 南京明德新药研发有限公司 | 桥环取代的杂芳基并吡喃类衍生物及其应用 |
| WO2023198078A1 (zh) * | 2022-04-11 | 2023-10-19 | 杭州英创医药科技有限公司 | 作为kras g12d抑制剂的多环化合物 |
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| WO2024064335A1 (en) * | 2022-09-23 | 2024-03-28 | Ikena Oncology, Inc. | Naphthyl-substituted pyranopyrimidinones and related compounds and their use in treating medical conditions |
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