WO2022247641A1 - Wee1抑制剂及其用途 - Google Patents
Wee1抑制剂及其用途 Download PDFInfo
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- WO2022247641A1 WO2022247641A1 PCT/CN2022/092348 CN2022092348W WO2022247641A1 WO 2022247641 A1 WO2022247641 A1 WO 2022247641A1 CN 2022092348 W CN2022092348 W CN 2022092348W WO 2022247641 A1 WO2022247641 A1 WO 2022247641A1
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- Prior art keywords
- alkyl
- alkylene
- halogen
- substituted
- hydrogen
- Prior art date
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- 239000003112 inhibitor Substances 0.000 title claims description 10
- 101150040313 Wee1 gene Proteins 0.000 title description 14
- 150000001875 compounds Chemical class 0.000 claims abstract description 251
- 239000003814 drug Substances 0.000 claims abstract description 13
- 229940079593 drug Drugs 0.000 claims abstract description 12
- 238000002360 preparation method Methods 0.000 claims abstract description 10
- 125000000217 alkyl group Chemical group 0.000 claims description 317
- 229910052736 halogen Inorganic materials 0.000 claims description 179
- -1 halogen substituted Chemical class 0.000 claims description 99
- 229910052739 hydrogen Inorganic materials 0.000 claims description 97
- 239000001257 hydrogen Substances 0.000 claims description 97
- 150000002367 halogens Chemical class 0.000 claims description 92
- 125000003342 alkenyl group Chemical group 0.000 claims description 64
- 125000004452 carbocyclyl group Chemical group 0.000 claims description 64
- 125000000304 alkynyl group Chemical group 0.000 claims description 62
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 57
- 150000002431 hydrogen Chemical class 0.000 claims description 46
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 45
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 44
- 125000004429 atom Chemical group 0.000 claims description 25
- 229910052757 nitrogen Inorganic materials 0.000 claims description 25
- 229910052717 sulfur Inorganic materials 0.000 claims description 21
- 125000002947 alkylene group Chemical group 0.000 claims description 19
- 150000003839 salts Chemical class 0.000 claims description 17
- 229910052760 oxygen Inorganic materials 0.000 claims description 15
- 125000005842 heteroatom Chemical group 0.000 claims description 12
- 239000000126 substance Substances 0.000 claims description 12
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 10
- 238000006467 substitution reaction Methods 0.000 claims description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 5
- 206010028980 Neoplasm Diseases 0.000 claims description 3
- 239000002671 adjuvant Substances 0.000 claims description 2
- 201000011510 cancer Diseases 0.000 claims description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 2
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 230000002265 prevention Effects 0.000 claims description 2
- 239000003981 vehicle Substances 0.000 claims description 2
- 230000002401 inhibitory effect Effects 0.000 abstract description 9
- 101000621390 Homo sapiens Wee1-like protein kinase Proteins 0.000 abstract description 2
- 102100023037 Wee1-like protein kinase Human genes 0.000 abstract description 2
- 230000015572 biosynthetic process Effects 0.000 description 214
- 238000003786 synthesis reaction Methods 0.000 description 213
- 238000001308 synthesis method Methods 0.000 description 174
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 159
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 132
- 238000006243 chemical reaction Methods 0.000 description 121
- 238000000034 method Methods 0.000 description 82
- 239000000047 product Substances 0.000 description 75
- 239000000758 substrate Substances 0.000 description 73
- 238000005481 NMR spectroscopy Methods 0.000 description 72
- 230000002829 reductive effect Effects 0.000 description 71
- 238000004128 high performance liquid chromatography Methods 0.000 description 65
- 239000012074 organic phase Substances 0.000 description 54
- 239000000243 solution Substances 0.000 description 51
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 49
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 47
- 238000004440 column chromatography Methods 0.000 description 43
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 42
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 33
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 32
- 238000012360 testing method Methods 0.000 description 32
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 31
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 30
- 238000003756 stirring Methods 0.000 description 27
- 210000004027 cell Anatomy 0.000 description 22
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical group [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 19
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 13
- 238000002474 experimental method Methods 0.000 description 13
- 238000012544 monitoring process Methods 0.000 description 13
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 13
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 12
- 239000012043 crude product Substances 0.000 description 12
- BKWJAKQVGHWELA-UHFFFAOYSA-N 1-[6-(2-hydroxypropan-2-yl)-2-pyridinyl]-6-[4-(4-methyl-1-piperazinyl)anilino]-2-prop-2-enyl-3-pyrazolo[3,4-d]pyrimidinone Chemical compound C1CN(C)CCN1C(C=C1)=CC=C1NC1=NC=C2C(=O)N(CC=C)N(C=3N=C(C=CC=3)C(C)(C)O)C2=N1 BKWJAKQVGHWELA-UHFFFAOYSA-N 0.000 description 11
- 125000003118 aryl group Chemical group 0.000 description 11
- 239000012071 phase Substances 0.000 description 11
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 10
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 10
- 229950009557 adavosertib Drugs 0.000 description 10
- 238000004809 thin layer chromatography Methods 0.000 description 10
- 239000000706 filtrate Substances 0.000 description 9
- 230000005764 inhibitory process Effects 0.000 description 9
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- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical class [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- 125000004434 sulfur atom Chemical group 0.000 description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 7
- 229910052799 carbon Inorganic materials 0.000 description 7
- 238000011534 incubation Methods 0.000 description 7
- 238000004949 mass spectrometry Methods 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- 125000004430 oxygen atom Chemical group O* 0.000 description 7
- 239000000741 silica gel Substances 0.000 description 7
- 229910002027 silica gel Inorganic materials 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 125000004432 carbon atom Chemical group C* 0.000 description 6
- 238000011156 evaluation Methods 0.000 description 6
- 239000002609 medium Substances 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 239000011550 stock solution Substances 0.000 description 6
- 239000012224 working solution Substances 0.000 description 6
- CXNIUSPIQKWYAI-UHFFFAOYSA-N xantphos Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 description 6
- HUWSZNZAROKDRZ-RRLWZMAJSA-N (3r,4r)-3-azaniumyl-5-[[(2s,3r)-1-[(2s)-2,3-dicarboxypyrrolidin-1-yl]-3-methyl-1-oxopentan-2-yl]amino]-5-oxo-4-sulfanylpentane-1-sulfonate Chemical compound OS(=O)(=O)CC[C@@H](N)[C@@H](S)C(=O)N[C@@H]([C@H](C)CC)C(=O)N1CCC(C(O)=O)[C@H]1C(O)=O HUWSZNZAROKDRZ-RRLWZMAJSA-N 0.000 description 5
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 5
- 102000004190 Enzymes Human genes 0.000 description 5
- 108090000790 Enzymes Proteins 0.000 description 5
- 239000005909 Kieselgur Substances 0.000 description 5
- 239000000872 buffer Substances 0.000 description 5
- 229940125904 compound 1 Drugs 0.000 description 5
- 238000000502 dialysis Methods 0.000 description 5
- BRZYSWJRSDMWLG-CAXSIQPQSA-N geneticin Chemical compound O1C[C@@](O)(C)[C@H](NC)[C@@H](O)[C@H]1O[C@@H]1[C@@H](O)[C@H](O[C@@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](C(C)O)O2)N)[C@@H](N)C[C@H]1N BRZYSWJRSDMWLG-CAXSIQPQSA-N 0.000 description 5
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- 238000001556 precipitation Methods 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 5
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 4
- SGTNSNPWRIOYBX-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-{[2-(3,4-dimethoxyphenyl)ethyl](methyl)amino}-2-(propan-2-yl)pentanenitrile Chemical group C1=C(OC)C(OC)=CC=C1CCN(C)CCCC(C#N)(C(C)C)C1=CC=C(OC)C(OC)=C1 SGTNSNPWRIOYBX-UHFFFAOYSA-N 0.000 description 4
- 108010017384 Blood Proteins Proteins 0.000 description 4
- 102000004506 Blood Proteins Human genes 0.000 description 4
- 241000699670 Mus sp. Species 0.000 description 4
- FFDGPVCHZBVARC-UHFFFAOYSA-N N,N-dimethylglycine Chemical compound CN(C)CC(O)=O FFDGPVCHZBVARC-UHFFFAOYSA-N 0.000 description 4
- 210000004978 chinese hamster ovary cell Anatomy 0.000 description 4
- 229940126142 compound 16 Drugs 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- SHFJWMWCIHQNCP-UHFFFAOYSA-M hydron;tetrabutylazanium;sulfate Chemical compound OS([O-])(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC SHFJWMWCIHQNCP-UHFFFAOYSA-M 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 description 4
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- 239000012452 mother liquor Substances 0.000 description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 description 4
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- 125000006413 ring segment Chemical group 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 4
- 229960001722 verapamil Drugs 0.000 description 4
- ASGMFNBUXDJWJJ-JLCFBVMHSA-N (1R,3R)-3-[[3-bromo-1-[4-(5-methyl-1,3,4-thiadiazol-2-yl)phenyl]pyrazolo[3,4-d]pyrimidin-6-yl]amino]-N,1-dimethylcyclopentane-1-carboxamide Chemical compound BrC1=NN(C2=NC(=NC=C21)N[C@H]1C[C@@](CC1)(C(=O)NC)C)C1=CC=C(C=C1)C=1SC(=NN=1)C ASGMFNBUXDJWJJ-JLCFBVMHSA-N 0.000 description 3
- UAOUIVVJBYDFKD-XKCDOFEDSA-N (1R,9R,10S,11R,12R,15S,18S,21R)-10,11,21-trihydroxy-8,8-dimethyl-14-methylidene-4-(prop-2-enylamino)-20-oxa-5-thia-3-azahexacyclo[9.7.2.112,15.01,9.02,6.012,18]henicosa-2(6),3-dien-13-one Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12C(N=C(NCC=C)S4)=C4CC(C)(C)[C@H]1[C@H](O)[C@]3(O)OC2 UAOUIVVJBYDFKD-XKCDOFEDSA-N 0.000 description 3
- 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
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- 208000029824 high grade glioma Diseases 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- GRRNUXAQVGOGFE-NZSRVPFOSA-N hygromycin B Chemical compound O[C@@H]1[C@@H](NC)C[C@@H](N)[C@H](O)[C@H]1O[C@H]1[C@H]2O[C@@]3([C@@H]([C@@H](O)[C@@H](O)[C@@H](C(N)CO)O3)O)O[C@H]2[C@@H](O)[C@@H](CO)O1 GRRNUXAQVGOGFE-NZSRVPFOSA-N 0.000 description 1
- 229940097277 hygromycin b Drugs 0.000 description 1
- 125000002632 imidazolidinyl group Chemical group 0.000 description 1
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- 238000002955 isolation Methods 0.000 description 1
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- 230000000670 limiting effect Effects 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- DLBFLQKQABVKGT-UHFFFAOYSA-L lucifer yellow dye Chemical compound [Li+].[Li+].[O-]S(=O)(=O)C1=CC(C(N(C(=O)NN)C2=O)=O)=C3C2=CC(S([O-])(=O)=O)=CC3=C1N DLBFLQKQABVKGT-UHFFFAOYSA-L 0.000 description 1
- 238000004020 luminiscence type Methods 0.000 description 1
- VXWPONVCMVLXBW-UHFFFAOYSA-M magnesium;carbanide;iodide Chemical compound [CH3-].[Mg+2].[I-] VXWPONVCMVLXBW-UHFFFAOYSA-M 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 201000011614 malignant glioma Diseases 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
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- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 210000005012 myelin Anatomy 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 238000003305 oral gavage Methods 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 125000005961 oxazepanyl group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 125000003566 oxetanyl group Chemical group 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 230000010412 perfusion Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 238000009521 phase II clinical trial Methods 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 230000000865 phosphorylative effect Effects 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 229920000515 polycarbonate Polymers 0.000 description 1
- 239000004417 polycarbonate Substances 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- 238000002953 preparative HPLC Methods 0.000 description 1
- 238000004237 preparative chromatography Methods 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 239000012460 protein solution Substances 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 125000004621 quinuclidinyl group Chemical group N12C(CC(CC1)CC2)* 0.000 description 1
- 239000011535 reaction buffer Substances 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
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- 238000004007 reversed phase HPLC Methods 0.000 description 1
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- 238000007789 sealing Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 1
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical class [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 1
- NPCBDQZLUSJKOW-UHFFFAOYSA-M sodium;4-[5-(4-chlorophenyl)-3,4-dihydropyrazol-2-yl]benzenesulfonate Chemical compound [Na+].C1=CC(S(=O)(=O)[O-])=CC=C1N1N=C(C=2C=CC(Cl)=CC=2)CC1 NPCBDQZLUSJKOW-UHFFFAOYSA-M 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 238000003153 stable transfection Methods 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
- ZXUCBXRTRRIBSO-UHFFFAOYSA-L tetrabutylazanium;sulfate Chemical compound [O-]S([O-])(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC.CCCC[N+](CCCC)(CCCC)CCCC ZXUCBXRTRRIBSO-UHFFFAOYSA-L 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000005942 tetrahydropyridyl group Chemical group 0.000 description 1
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- 125000004632 tetrahydrothiopyranyl group Chemical group S1C(CCCC1)* 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical group C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 230000016596 traversing start control point of mitotic cell cycle Effects 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- NHDIQVFFNDKAQU-UHFFFAOYSA-N tripropan-2-yl borate Chemical compound CC(C)OB(OC(C)C)OC(C)C NHDIQVFFNDKAQU-UHFFFAOYSA-N 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/538—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with carbocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- 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
Definitions
- the present invention relates to a class of novel compound with Weel inhibitory effect and its application in preparing medicine.
- the cell cycle is a highly regulated and controlled process designed to allow cells to proliferate only in response to specific stimuli and appropriate conditions.
- the normal cell cycle will go through G1 phase, S phase (DNA synthesis phase), G2 phase and M phase (cell division phase) in sequence.
- G1 phase S phase
- G2 phase DNA synthesis phase
- M phase cell division phase
- the Wee1 protein is a tyrosine kinase that is a key component of the G2-M cell cycle checkpoint that prevents cells from DNA damage from entering mitosis.
- CDK1 Cyclin-dependent kinase 1
- MYT1 myelin transcription factor
- Wee1 is therefore a negative regulator of mitosis entry during the G2-M transition and plays an important monitoring role.
- Wee1 is overexpressed in many malignancies, such as liver cancer, breast cancer, malignant glioma, melanoma, adult and childhood brain tumors.
- Wee1 inhibitors play a key role in anticancer therapy and have become a hot spot in the research and development of anticancer drugs.
- Wee1 inhibitors have been reported (WO2007126128, WO2004007499, etc.), but no Wee1 inhibitor has been marketed yet.
- the compound with the fastest development progress is AZD-1775, which has entered phase II clinical trials, but the incidence of adverse reactions in clinical trials is high, and new Wee1 inhibitor drugs with better activity and higher safety need to be developed.
- the present invention provides a compound represented by formula I, or its deuterated compound, or its stereoisomer, or its pharmaceutically acceptable salt:
- R 1 is selected from hydrogen, halogen, cyano, -C 1 ⁇ 6 alkyl, -C 2 ⁇ 6 alkenyl, -C 2 ⁇ 6 alkynyl, halogen substituted -C 1 ⁇ 6 alkyl, halogen substituted - C 2 ⁇ 6 alkenyl, halogen-substituted -C 2 ⁇ 6 alkynyl, -C 0 ⁇ 4 alkylene-OR 11 , -C 0 ⁇ 4 alkylene-NR 12 R 12 ;
- R 11 is selected from -C 1 ⁇ 6 alkyl, -C 2 ⁇ 6 alkenyl, -C 2 ⁇ 6 alkynyl, halogen substituted -C 1 ⁇ 6 alkyl, halogen substituted -C 2 ⁇ 6 alkenyl, -C 2 ⁇ 6 alkynyl substituted by halogen;
- Each R 12 is independently selected from hydrogen, -C 1 ⁇ 6 alkyl, -C 2 ⁇ 6 alkenyl, -C 2 ⁇ 6 alkynyl, halogen substituted -C 1 ⁇ 6 alkyl, halogen substituted -C 2 ⁇ 6 alkenyl, -C 2 ⁇ 6 alkynyl substituted by halogen;
- X 1 , X 2 , and X 4 are independently selected from N or CR 4 ;
- X 3 is selected from N or CR 3 ;
- X 5 is selected from O, S or NR 4 ;
- X 6 is selected from CR 4 or N;
- X 8 is selected from CR 4 R 4 , O;
- X 7 is selected from S, NR 4 ; R 2 is selected from
- R 21 and R 22 are independently selected from hydrogen, halogen, cyano, -C 1 ⁇ 6 alkyl, -C 2 ⁇ 6 alkenyl, -C 2 ⁇ 6 alkynyl, halogen substituted -C 1 ⁇ 6 alkyl , Halogen substituted -C 2 ⁇ 6 alkenyl, Halogen substituted -C 2 ⁇ 6 alkynyl, -C 0 ⁇ 4 alkylene -OR 24 , -C 0 ⁇ 4 alkylene -NR 24 R 24 ;
- Each R 24 is independently selected from hydrogen, -C 1 ⁇ 6 alkyl, -C 2 ⁇ 6 alkenyl, -C 2 ⁇ 6 alkynyl, halogen substituted -C 1 ⁇ 6 alkyl, halogen substituted -C 2 ⁇ 6 alkenyl, -C 2 ⁇ 6 alkynyl substituted by halogen;
- R 21 and R 22 together with the connected atoms form a 3-8 membered carbocyclic group, a 4-8 membered heterocycloalkyl group,
- R 23 is selected from hydrogen, halogen, cyano, -C 1 ⁇ 6 alkyl, -C 2 ⁇ 6 alkenyl, -C 2 ⁇ 6 alkynyl, halogen substituted -C 1 ⁇ 6 alkyl, halogen substituted - C 2 ⁇ 6 alkenyl, halogen-substituted -C 2 ⁇ 6 alkynyl, -C 0 ⁇ 4 alkylene-C(O)R 25 , -C 0 ⁇ 4 alkylene-C(O)NR 25 R 25 , -C 0 ⁇ 4 alkylene-C(O)OR 25 , -C 0 ⁇ 4 alkylene-S(O) 2 R 25 , -C 0 ⁇ 4 alkylene-S(O)R 25 , -C 0 ⁇ 4 alkylene-S(O)(NH)R 25 , -C 0 ⁇ 4 alkylene-S(NH) 2 R 25 , -C 0 ⁇ 4 alkylene-S(O
- Each R 25 is independently selected from hydrogen, -C 1 ⁇ 6 alkyl, -C 2 ⁇ 6 alkenyl, -C 2 ⁇ 6 alkynyl, halogen substituted -C 1 ⁇ 6 alkyl, halogen substituted -C 2 ⁇ 6 alkenyl, -C 2 ⁇ 6 alkynyl substituted by halogen;
- R 23 , R 3 together with the connected atoms form a 4-8 membered carbocyclyl, 4-8 membered heterocycloalkyl;
- R 3 is selected from hydrogen, halogen, cyano, -C 1 ⁇ 6 alkyl, -C 2 ⁇ 6 alkenyl, -C 2 ⁇ 6 alkynyl, hydroxyl substituted -C 1 ⁇ 6 alkyl, halogen substituted- C 1 ⁇ 6 alkyl, halogen substituted -C 2 ⁇ 6 alkenyl, halogen substituted -C 2 ⁇ 6 alkynyl, -C 0 ⁇ 4 alkylene-OH, -C 0 ⁇ 4 alkylene-O (C 1 ⁇ 6 alkyl), -C 0 ⁇ 4 alkylene-NH 2 , -C 0 ⁇ 4 alkylene-NH(C 1 ⁇ 6 alkyl), -C 0 ⁇ 4 alkylene-N (C 1 ⁇ 6 alkyl)(C 1 ⁇ 6 alkyl);
- Each R4 is independently selected from hydrogen, halogen, cyano, -C 1 ⁇ 6 alkyl, -C 2 ⁇ 6 alkenyl, -C 2 ⁇ 6 alkynyl, halogen substituted -C 1 ⁇ 6 alkyl, Halogen substituted -C 2 ⁇ 6 alkenyl, halogen substituted -C 2 ⁇ 6 alkynyl, -C 0 ⁇ 4 alkylene-OH, -C 0 ⁇ 4 alkylene-O(C 1 ⁇ 6 alkyl ), -C 0 ⁇ 4 alkylene-NH 2 , -C 0 ⁇ 4 alkylene-NH(C 1 ⁇ 6 alkyl), -C 0 ⁇ 4 alkylene-N(C 1 ⁇ 6 alkyl )(C 1 ⁇ 6 alkyl);
- R 5 is selected from hydrogen, -C 1 ⁇ 6 alkyl
- Y 1 , Y 2 , Y 3 , Y 4 are independently selected from N or CRY ;
- Each R Y is independently selected from hydrogen, halogen, cyano, -C 1 ⁇ 6 alkyl, -C 2 ⁇ 6 alkenyl, -C 2 ⁇ 6 alkynyl, halogen substituted -C 1 ⁇ 6 alkyl, Halogen substituted -C 2 ⁇ 6 alkenyl, halogen substituted -C 2 ⁇ 6 alkynyl, -C 0 ⁇ 4 alkylene-OH, -C 0 ⁇ 4 alkylene-O(C 1 ⁇ 6 alkyl ), -C 0 ⁇ 4 alkylene-NH 2 , -C 0 ⁇ 4 alkylene-NH(C 1 ⁇ 6 alkyl), -C 0 ⁇ 4 alkylene-N(C 1 ⁇ 6 alkyl )(C 1 ⁇ 6 alkyl);
- Ring B is selected from 3-12 membered carbocyclyl, 4-12 membered heterocycloalkyl; said carbocyclyl and heterocycloalkyl can be further substituted by one, two, three, four or five R B ;
- Each R B is independently selected from hydrogen, halogen, cyano, -C 1 ⁇ 6 alkyl, -C 2 ⁇ 6 alkenyl, -C 2 ⁇ 6 alkynyl, halogen substituted -C 1 ⁇ 6 alkyl, Halogen-substituted -C 2-6 alkenyl, halogen-substituted-C 2-6 alkynyl, -C 0-4 alkylene-OR B1 , -C 0-4 alkylene-OC(O)R B1 , -C 0 ⁇ 4 alkylene-SR B1 , -C 0 ⁇ 4 alkylene-S(O) 2 R B1 , -C 0 ⁇ 4 alkylene-S(O)R B1 , -C 0 ⁇ 4 Alkylene-S(O) 2 NR B1 R B1 , -C 0 ⁇ 4 Alkylene-S(O)NR B1 R B1 , -C 0 ⁇ 4 Alkylene-S(
- Each R B1 is independently selected from hydrogen, -C 1 ⁇ 6 alkyl, -C 2 ⁇ 6 alkenyl, -C 2 ⁇ 6 alkynyl, halogen substituted -C 1 ⁇ 6 alkyl, halogen substituted -C 2 ⁇ 6 alkenyl, -C 2 ⁇ 6 alkynyl substituted by halogen;
- R 6 , R 7 , R 8 , and R 9 are independently selected from hydrogen, halogen, cyano, -C 1 ⁇ 6 alkyl, -C 2 ⁇ 6 alkenyl, -C 2 ⁇ 6 alkynyl, halogen substituted- C 1 ⁇ 6 alkyl, halogen substituted -C 2 ⁇ 6 alkenyl, halogen substituted -C 2 ⁇ 6 alkynyl, -C 0 ⁇ 4 alkylene-OH, -C 0 ⁇ 4 alkylene-O (C 1 ⁇ 6 alkyl), -C 0 ⁇ 4 alkylene-NH 2 , -C 0 ⁇ 4 alkylene-NH(C 1 ⁇ 6 alkyl), -C 0 ⁇ 4 alkylene-N (C 1 ⁇ 6 alkyl)(C 1 ⁇ 6 alkyl);
- R 6 , R 7 together with the connected atoms form a 3-8 membered carbocyclyl, 4-8 membered heterocycloalkyl; or, R 8 , R 9 together with the connected atoms form a 3-8 membered carbocyclyl, 4 ⁇ 8 membered heterocycloalkyl;
- Y 5 and Y 6 are independently selected from chemical bonds, -C 0 ⁇ 4 alkylene-O-, -C 0 ⁇ 4 alkylene-S-, -C 0 ⁇ 4 alkylene-NR Y51 -, CRY51 R Y51 ;
- Each R Y51 is independently selected from hydrogen, -C 1 ⁇ 6 alkyl, -C 2 ⁇ 6 alkenyl, -C 2 ⁇ 6 alkynyl, halogen substituted -C 1 ⁇ 6 alkyl, halogen substituted -C 2-6 alkenyl, -C 2-6 alkynyl substituted by halogen, -C 0-4 alkylene-OH, -C 0-4 alkylene-O(C 1-6 alkyl), -C 0 ⁇ 4 alkylene-NH 2 , -C 0 ⁇ 4 alkylene-NH(C 1 ⁇ 6 alkyl), -C 0 ⁇ 4 alkylene-N(C 1 ⁇ 6 alkyl)(C 1 ⁇ 6 alkyl) 6 alkyl);
- Y7 is selected from O, S or NR Y71 ;
- R Y71 is selected from hydrogen, -C 1 ⁇ 6 alkyl, -C 2 ⁇ 6 alkenyl, -C 2 ⁇ 6 alkynyl, halogen substituted -C 1 ⁇ 6 alkyl, halogen substituted -C 2 ⁇ 6 alkenyl Group, halogen substituted -C 2 ⁇ 6 alkynyl, -C 0 ⁇ 4 alkylene-OH, -C 0 ⁇ 4 alkylene-O(C 1 ⁇ 6 alkyl), -C 0 ⁇ 4 alkylene -NH 2 , -C 0 ⁇ 4 alkylene-NH(C 1 ⁇ 6 alkyl), -C 0 ⁇ 4 alkylene-N(C 1 ⁇ 6 alkyl)(C 1 ⁇ 6 alkyl) ;
- R 10 is selected from hydrogen, halogen, cyano, -C 1 ⁇ 6 alkyl, -C 2 ⁇ 6 alkenyl, -C 2 ⁇ 6 alkynyl, halogen substituted -C 1 ⁇ 6 alkyl, halogen substituted - C 2 ⁇ 6 alkenyl, halogen-substituted -C 2 ⁇ 6 alkynyl, -C 0 ⁇ 4 alkylene-OH, -C 0 ⁇ 4 alkylene-O(C 1 ⁇ 6 alkyl), -C 0 ⁇ 4 alkylene-NH 2 , -C 0 ⁇ 4 alkylene-NH(C 1 ⁇ 6 alkyl), -C 0 ⁇ 4 alkylene-N(C 1 ⁇ 6 alkyl)(C 1 ⁇ 6 alkyl groups).
- R 1 is selected from hydrogen, halogen, cyano, -C 1 ⁇ 6 alkyl, -C 1 ⁇ 6 alkyl substituted by halogen, -OR 11 , -NR 12 R 12 ;
- R 11 is selected from -C 1 ⁇ 6 alkyl, -C 2 ⁇ 6 alkenyl, -C 2 ⁇ 6 alkynyl, halogen substituted -C 1 ⁇ 6 alkyl;
- Each R 12 is independently selected from hydrogen, -C 1 ⁇ 6 alkyl, halogen substituted -C 1 ⁇ 6 alkyl;
- R 10 is selected from hydrogen, halogen, cyano, -C 1 ⁇ 6 alkyl, -C 1 ⁇ 6 alkyl substituted by halogen, -OH, -O(C 1 ⁇ 6 alkyl), -NH 2 , -NH (C 1-6 alkyl), -N(C 1-6 alkyl)(C 1-6 alkyl).
- R 1 is selected from hydrogen, halogen, cyano, -C 1 ⁇ 6 alkyl, trifluoromethyl, -O(C 1 ⁇ 6 alkyl), -O(C 2 ⁇ 6 alkenyl), -O(tri Fluoromethyl), -NH 2 , -NH(C 1 ⁇ 6 alkyl), -N(C 1 ⁇ 6 alkyl)(C 1 ⁇ 6 alkyl);
- R 10 is selected from hydrogen, halogen, -C 1-6 alkyl, -O(C 1-6 alkyl).
- R2 is selected from
- R 21 and R 22 are independently selected from hydrogen, halogen, cyano, -C 1 ⁇ 6 alkyl, halogen substituted -C 1 ⁇ 6 alkyl, -OR 24 ;
- Each R 24 is independently selected from hydrogen, -C 1 ⁇ 6 alkyl
- R 21 , R 22 together with the connected atoms form carbonyl, 3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl, 6-membered carbocyclyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkane Base, 6-membered heterocycloalkyl; the heteroatom in the heterocycloalkyl is selected from N, O, S;
- R 23 is selected from hydrogen, halogen, cyano, -C 1 ⁇ 6 alkyl, -C 1 ⁇ 6 alkyl substituted by halogen, -S(O) 2 R 25 , -S(O)R 25 , -S( O)(NH)R 25 , -S(NH) 2 R 25 ;
- Each R 25 is independently selected from hydrogen, -C 1-6 alkyl.
- R2 is selected from
- C ring selected from R2 is selected from
- R 21 and R 22 are independently selected from hydrogen, halogen, cyano, -C 1 ⁇ 6 alkyl, halogen substituted -C 1 ⁇ 6 alkyl, -OR 24 ;
- Each R 24 is independently selected from hydrogen, -C 1 ⁇ 6 alkyl
- R 23 and R 3 together with the connected atoms form a 4-membered carbocyclyl, 5-membered carbocyclyl, 6-membered carbocyclyl, 7-membered carbocyclyl, 5-membered heterocycloalkyl, or 6-membered heterocycloalkyl.
- R2 is selected from
- R 21 and R 22 are independently selected from hydrogen and -C 1-6 alkyl.
- Y 1 , Y 2 , Y 3 , Y 4 are independently selected from N or CRY ;
- Each R Y is independently selected from hydrogen, halogen, cyano, -C 1 ⁇ 6 alkyl, -C 1 ⁇ 6 alkyl substituted by halogen, -C 0 ⁇ 4 alkylene-OH, -C 0 ⁇ 4 Alkylene-O(C 1 ⁇ 6 alkyl), -C 0 ⁇ 4 alkylene-NH 2 , -C 0 ⁇ 4 alkylene-NH(C 1 ⁇ 6 alkyl), -C 0 ⁇ 4 Alkylene-N(C 1 ⁇ 6 alkyl)(C 1 ⁇ 6 alkyl);
- Ring B is selected from 3-8 membered monocarbocyclyl, 4-8 membered monoheterocycloalkyl, 5-10 membered bridged carbocyclyl, 5-10 membered bridged heterocycloalkyl, 5-10 membered spirocarbocyclyl , 5-10 membered spiroheterocycloalkyl, 8-12 membered condensed carbocyclyl, 8-12 membered condensed heterocycloalkyl; Cycloalkyl, spirocarbocyclyl, spiroheterocycloalkyl, fused carbocyclyl, fused heterocycloalkyl can be further substituted by one, two, three, four or five RB ;
- Each R B is independently selected from hydrogen, halogen, cyano, -C 1 ⁇ 6 alkyl, -C 1 ⁇ 6 alkyl substituted by halogen, -OR B1 , -SR B1 , -S(O) 2 R B1 , -S(O)R B1 , -C(O)R B1 , -C(O)OR B1 , -NR B1 R B1 , 3-12 membered carbocyclyl, 4-12 membered heterocycloalkyl; Carbocyclyl, heterocycloalkyl can be further substituted by one, two, three, four or five R B1 ; alternatively, two independent R B together with connected atoms form
- Each R B1 is independently selected from hydrogen, -C 1 ⁇ 6 alkyl, halogen substituted -C 1 ⁇ 6 alkyl;
- Y 5 is selected from O, S, NR Y51 , CR Y51 RY51 ;
- Each R Y51 is independently selected from hydrogen, -C 1-6 alkyl.
- Y 1 , Y 2 , Y 3 , Y 4 are independently selected from N or CRY ;
- Each R Y is independently selected from hydrogen, halogen, cyano, -C 1 ⁇ 6 alkyl, -C 1 ⁇ 6 alkyl substituted by halogen, -C 0 ⁇ 4 alkylene-OH, -C 0 ⁇ 4 Alkylene-O(C 1 ⁇ 6 alkyl), -C 0 ⁇ 4 alkylene-NH 2 , -C 0 ⁇ 4 alkylene-NH(C 1 ⁇ 6 alkyl), -C 0 ⁇ 4 Alkylene-N(C 1 ⁇ 6 alkyl)(C 1 ⁇ 6 alkyl);
- R 6 , R 7 , R 8 , and R 9 are each independently selected from hydrogen, -C 1-6 alkyl;
- R 6 and R 7 form 3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl, 6-membered carbocyclyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl, 6-membered heterocycloalkyl; or, R 8 , R 9 together with the connected atoms form 3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl, 6-membered carbocyclyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl, 6-membered heterocycloalkyl;
- R B is selected from hydrogen, -C 1 ⁇ 6 alkyl, -C 1 ⁇ 6 alkyl substituted by halogen, -S(O) 2 R B1 , -S(O)R B1 , -C(O)R B1 , -C(O)OR B1 ;
- Each R B1 is independently selected from hydrogen, -C 1-6 alkyl, halogen-substituted -C 1-6 alkyl.
- Y 1 , Y 2 , and Y 4 are independently selected from N or CRY ;
- Each R Y is independently selected from hydrogen, halogen, cyano, -C 1 ⁇ 6 alkyl, -C 1 ⁇ 6 alkyl substituted by halogen, -C 0 ⁇ 4 alkylene-OH, -C 0 ⁇ 4 Alkylene-O(C 1 ⁇ 6 alkyl), -C 0 ⁇ 4 alkylene-NH 2 , -C 0 ⁇ 4 alkylene-NH(C 1 ⁇ 6 alkyl), -C 0 ⁇ 4 Alkylene-N(C 1 ⁇ 6 alkyl)(C 1 ⁇ 6 alkyl);
- R B is selected from hydrogen, -C 1 ⁇ 6 alkyl, -C 1 ⁇ 6 alkyl substituted by halogen, -S(O) 2 R B1 , -S(O)R B1 , -C(O)R B1 , -C(O)OR B1 ;
- Each R B1 is independently selected from hydrogen, -C 1 ⁇ 6 alkyl, halogen substituted -C 1 ⁇ 6 alkyl;
- Y 5 is selected from chemical bond, O, S, NR Y51 , CR Y51 RY51 ;
- Each R Y51 is independently selected from hydrogen, -C 1-6 alkyl.
- a ring is selected from,
- Y 1 , Y 2 , and Y 4 are independently selected from N or CRY ;
- Each R Y is independently selected from hydrogen, halogen, cyano, -C 1 ⁇ 6 alkyl, -C 1 ⁇ 6 alkyl substituted by halogen, -C 0 ⁇ 4 alkylene-OH, -C 0 ⁇ 4 Alkylene-O(C 1 ⁇ 6 alkyl), -C 0 ⁇ 4 alkylene-NH 2 , -C 0 ⁇ 4 alkylene-NH(C 1 ⁇ 6 alkyl), -C 0 ⁇ 4 Alkylene-N(C 1 ⁇ 6 alkyl)(C 1 ⁇ 6 alkyl);
- R B is selected from hydrogen, -C 1 ⁇ 6 alkyl, -C 1 ⁇ 6 alkyl substituted by halogen, -S(O) 2 R B1 , -S(O)R B1 , -C(O)R B1 , -C(O)OR B1 ;
- Each R B1 is independently selected from hydrogen, -C 1 ⁇ 6 alkyl, halogen substituted -C 1 ⁇ 6 alkyl;
- Y 5 and Y 6 are independently selected from chemical bonds, -C 0 ⁇ 1 alkylene-O-, -C 0 ⁇ 1 alkylene-S-, -C 0 ⁇ 1 alkylene-NR Y51 -, CRY51 R Y51 ;
- Each R Y51 is independently selected from hydrogen, -C 1-6 alkyl.
- Y 1 is selected from N or CRY ;
- R Y is selected from hydrogen, halogen, cyano, -C 1 ⁇ 6 alkyl, -C 1 ⁇ 6 alkyl substituted by halogen, -C 0 ⁇ 4 alkylene-OH, -C 0 ⁇ 4 alkylene- O(C 1 ⁇ 6 alkyl), -C 0 ⁇ 4 alkylene-NH 2 , -C 0 ⁇ 4 alkylene-NH(C 1 ⁇ 6 alkyl), -C 0 ⁇ 4 alkylene- N(C 1 ⁇ 6 alkyl)(C 1 ⁇ 6 alkyl);
- Ring B is selected from 3 to 8 membered monocarbocyclic groups and 4 to 8 membered monoheterocycloalkyl groups; R B replaced;
- Each R B is independently selected from hydrogen, halogen, cyano, -C 1 ⁇ 6 alkyl, -C 1 ⁇ 6 alkyl substituted by halogen, -OR B1 , -SR B1 , -S(O) 2 R B1 , -S(O)R B1 , -C(O)R B1 , -C(O)OR B1 , -NR B1 R B1 ; or, two independent R B1 together with connected atoms form
- Each R B1 is independently selected from hydrogen, -C 1 ⁇ 6 alkyl, halogen substituted -C 1 ⁇ 6 alkyl;
- Y7 is selected from O, S or NR Y71 ;
- R Y71 is selected from hydrogen, -C 1 ⁇ 6 alkyl, -C 1 ⁇ 6 alkyl substituted by halogen, -C 1 ⁇ 4 alkylene-OH, -C 1 ⁇ 4 alkylene-O(C 1 ⁇ 4 6 alkyl), -C 1 ⁇ 4 alkylene-NH 2 , -C 1 ⁇ 4 alkylene-NH(C 1 ⁇ 6 alkyl), -C 1 ⁇ 4 alkylene-N(C 1 ⁇ 4 6 alkyl) (C 1 ⁇ 6 alkyl).
- the compound shown in formula I is specifically:
- the present invention also provides the use of any one of the compounds described above, or its deuterated compound, or its stereoisomer, or a pharmaceutically acceptable salt thereof in the preparation of a Weel inhibitor drug.
- the present invention also provides the use of any one of the above-mentioned compounds, or their deuterated compounds, or their stereoisomers, or their pharmaceutically acceptable salts in the prevention and/or treatment of cancer.
- the present invention also provides a pharmaceutical composition, which comprises any one of the above-mentioned compounds, or deuterated compounds thereof, or stereoisomers thereof, or pharmaceutically acceptable salts thereof.
- the above-mentioned pharmaceutical composition further includes a pharmaceutically acceptable carrier, adjuvant, and vehicle.
- the compounds and derivatives provided in the present invention may be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) nomenclature system.
- substitution means that the hydrogen atom in the molecule is replaced by other different atoms or groups; or the lone pair of electrons of atoms in the molecule is replaced by other atoms or groups, for example, the lone pair of electrons on the S atom can be replaced by O atomic substitution formation
- C a-b alkyl indicates any alkyl group containing "a" to "b" carbon atoms.
- C 1-6 alkyl refers to an alkyl group containing 1-6 carbon atoms.
- Alkyl means a saturated hydrocarbon chain having the indicated number of member atoms. Alkyl groups can be straight or branched. Representative branched alkyl groups have one, two or three branches. Alkyl groups may be optionally substituted with one or more substituents as defined herein. Alkyl groups include methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl and tert-butyl), pentyl (n-pentyl, isopentyl and neopentyl base) and hexyl. Alkyl groups may also be part of other groups such as -O(C 1-6 alkyl).
- Alkylene means a divalent saturated aliphatic hydrocarbon group having the indicated number of member atoms.
- C a ⁇ b alkylene refers to an alkylene group having a to b carbon atoms.
- Alkylene groups include branched and straight chain hydrocarbyl groups.
- the term "propylene” can be exemplified by the following structures:
- the term "dimethylbutylene” can be exemplified, for example, by any of the following structures:
- the -C 0-4 alkylene in the present invention can be C 0 alkylene, C 1 alkylene (such as -CH 2 -), C 2 alkylene (such as -CH 2 CH 2 -, etc.), C 3 Alkylene or C 4 alkylene;
- C 0 alkylene means that the groups here are connected in the form of chemical bonds, such as AC 0 alkylene-B means AB, that is, A group and B group connected directly by chemical bonds.
- the "carbocyclyl” mentioned in the present invention refers to a saturated or non-aromatic partially saturated group with a single ring or multiple rings (fused, bridged, spiro) having multiple carbon atoms and no ring heteroatoms. cyclic group.
- the term "carbocyclyl” includes cycloalkenyl groups such as cyclohexenyl. Examples of monocarbocyclyl groups include, for example, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclooctyl, cyclopentenyl and cyclohexenyl.
- Examples of carbocyclyl groups of condensed carbocyclyl systems include bicyclohexyl, bicyclopentyl, bicyclooctyl, etc., and two such bicycloalkyl polycyclic structures are exemplified and named below: Bicyclohexyl and Bicyclohexyl.
- Examples of carbocyclyl groups of bridged carbocyclyl systems include Adamantyl, etc.
- Examples of carbocyclyl groups for spirocarbocyclyl systems include Wait.
- Carbocyclyl also includes the case of a partially saturated cyclic group formed by the fusion of an aromatic ring and a non-aromatic ring, and the point of attachment may be at a non-aromatic carbon atom or an aromatic carbon atom, examples include 1,2, 3,4-tetrahydronaphthalen-5-yl, 5,6,7,8-tetrahydronaphthalen-5-yl.
- saturated in the present invention means that the groups or molecules contain carbon-carbon double bonds, carbon-carbon triple bonds, carbon-oxygen double bonds, carbon-sulfur double bonds, carbon-nitrogen triple bonds, and the like.
- heterocycloalkyl refers to a saturated ring or a non-aromatic partially saturated ring with a single ring or multiple rings (fused, bridged, spiro) containing at least one heteroatom ;
- heteroatom refers to nitrogen atom, oxygen atom, sulfur atom, etc.
- heterocycloalkyl groups for monoheterocycloalkyl systems are oxetanyl, azetidinyl, pyrrolidinyl, 2-oxo-pyrrolidin-3-yl, tetrahydrofuranyl, tetrahydro- Thienyl, pyrazolidinyl, imidazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1- Dioxo-thiomorpholin-4-yl, azepanyl, diazepanyl, homopiperazinyl or oxazepanyl, etc.
- heterocycloalkyl groups for fused heterocycloalkyl systems include 8-aza-bicyclo[3.2.1]octyl, quinuclidinyl, 8-oxa-3-aza-bicyclo[3.2 .1] Octyl, 9-aza-bicyclo[3.3.1]nonyl, etc.
- heterocycloalkyl groups for bridged heterocycloalkyl systems include Wait.
- heterocycloalkyl groups for spiroheterocycloalkyl systems include Wait.
- partially saturated heterocycloalkyl are dihydrofuranyl, imidazolinyl, tetrahydro-pyridyl or dihydropyranyl and the like.
- heterocycloalkyl also includes the case where an aromatic ring containing at least one heteroatom is fused with a non-aromatic ring to form a partially saturated cyclic group, and the point of attachment may be at a non-aromatic carbon atom, an aromatic carbon atom or heteroatoms, examples include
- aromatic ring group refers to an aromatic hydrocarbon group having multiple carbon atoms.
- Aryl groups are typically monocyclic, bicyclic or tricyclic aryl groups having multiple carbon atoms.
- aryl refers to an aromatic substituent which may be a single aromatic ring or a plurality of aromatic rings fused together. Non-limiting examples include phenyl, naphthyl or tetrahydronaphthyl.
- aromatic heterocyclic group refers to an aromatic unsaturated ring containing at least one heteroatom; wherein the heteroatom refers to nitrogen atom, oxygen atom, sulfur atom and the like.
- Aromatic monocyclic or bicyclic hydrocarbons usually containing multiple ring atoms, wherein one or more ring atoms are selected from O, N, S heteroatoms. There are preferably one to three heteroatoms.
- Heterocyclic aryl represents for example: pyridyl, indolyl, quinoxalinyl, quinolinyl, isoquinolyl, benzothienyl, benzofuryl, benzothienyl, benzopyranyl, benzene Thiopyranyl, furyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, imidazolyl, thienyl, oxadiazolyl, benzimidazole benzothiazolyl, benzoxazolyl.
- halogen refers to fluorine, chlorine, bromine or iodine.
- halogen substituted alkyl in the present invention means that one or more hydrogen atoms in the alkyl are replaced by halogen; for example, monofluoromethyl, difluoromethyl, trifluoromethyl.
- deuterium-substituted alkyl group means that one or more hydrogen atoms in the alkyl group are replaced by deuterium atoms; for example, trideuteromethyl group.
- the oxygen atom in "-C(O)R", “-S(O) 2 R” and the like described in the present invention is connected with a carbon atom or a sulfur atom with a double bond, and the R group is connected with an oxygen atom or a sulfur atom Connected by a single bond;
- another example "-S(O)(NH)R” means that the oxygen atom and nitrogen atom are connected to the sulfur atom by a double bond, and the R group is connected to the sulfur atom by a single bond.
- the "deuterated compound” of the present invention means that one or more hydrogen atoms in a molecule or group are replaced by deuterium atoms, wherein the proportion of deuterium atoms is greater than the abundance of deuterium in nature.
- pharmaceutically acceptable means that a certain carrier, carrier, diluent, excipient, and/or formed salt are generally chemically or physically compatible with other ingredients that constitute a pharmaceutical dosage form, and are physiologically compatible Compatible with receptors.
- salts and “pharmaceutically acceptable salt” refer to the above-mentioned compounds or their stereoisomers, acidic and/or basic salts formed with inorganic and/or organic acids and bases, and also include zwitterionic salts (internal salts), also include quaternary ammonium salts, such as alkyl ammonium salts. These salts may be obtained directly in the final isolation and purification of the compounds. It can also be obtained by mixing the above-mentioned compound, or its stereoisomer, with a certain amount of acid or base as appropriate (for example, equivalent).
- salts may form precipitates in solution and be collected by filtration, or may be recovered after evaporation of the solvent, or may be obtained by freeze-drying after reaction in an aqueous medium.
- Said salt in the present invention can be hydrochloride, sulfate, citrate, benzene sulfonate, hydrobromide, hydrofluoride, phosphate, acetate, propionate, dibutyl salt, oxalate, malate, succinate, fumarate, maleate, tartrate, or trifluoroacetate.
- one or more compounds of the invention may be used in combination with each other.
- the compound of the present invention may be used in combination with any other active agents for the preparation of drugs or pharmaceutical compositions for regulating cell functions or treating diseases. If a group of compounds is used, the compounds may be administered to the subject simultaneously, separately or sequentially.
- NMR nuclear magnetic resonance
- MS mass spectroscopy
- LC-MS Shimadzu LC-MS 2020 (ESI)).
- HPLC measurement used a Shimadzu high pressure liquid chromatograph (Shimadzu LC-20A).
- MPLC Medium Pressure Preparative Chromatography
- Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates are used for thin-layer chromatography silica gel plates, and the specifications of thin-layer chromatography separation and purification products are 0.4mm to 0.5mm.
- Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.
- the known starting materials of the present invention can be adopted or synthesized according to methods known in the art, or can be purchased from companies such as Anaiji Chemical, Chengdu Kelong Chemical, Shaoyuan Chemical Technology, and Bailingwei Technology.
- the reaction is carried out under a nitrogen atmosphere.
- the solution refers to an aqueous solution.
- the temperature of the reaction is room temperature.
- M is moles per liter.
- HPLC test conditions are as follows:
- Embodiment 1 the synthesis of compound 1
- Substrate 1-1 (247.51mg, 1.29mmol), 1-2 (200mg, 1.29mmol) was added to a dry single-necked flask, dissolved in acetic acid (2mL) and 1,4-dioxane (2mL), heated to Stir overnight at 110°C, monitored by LC-MS. After the reaction was completed, it was extracted three times with water and ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to obtain product 1-3 (400 mg, 1.29 mmol).
- Substrate 1-4 (2 g, 8.44 mmol), dimethylsulfinimide (786.42 mg, 8.44 mmol), Pd(dba) 2 (48.55 mg, 84.43 ⁇ mol), BINAP ( 52.57mg, 84.43 ⁇ mol), potassium tert-butoxide (1.89g, 16.89mmol), add toluene (10mL) to dissolve, microwave reaction at 120°C for 30min under the protection of nitrogen, and monitor by LC-MS. After the reaction was completed, it was extracted three times with water and ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to obtain product 1-5 (800 mg, 3.21 mmol).
- Embodiment 2 the synthesis of compound 2
- Substrate 2-1 (15g, 69.43mmol) was added to a dry single-necked flask, dissolved in THF (50mL) and methylmagnesium bromide (20.70g, 173.59mmol) was added under ice-cooling, reacted overnight at room temperature, LC - MS monitoring. After the reaction was completed, it was extracted three times with water and ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to obtain product 2-2 (15 g, 69.42 mmol).
- step 3 in Example 1 According to the synthesis method of step 3 in Example 1, 1-5 (109.92 mg, 441.22 umol) in step 3 was replaced by 2-1 (45.40 mg, 210.11 umol), and the synthesis method was the same to obtain compound 2 (10.2 mg, 22.95 ⁇ mol).
- Embodiment 3 the synthesis of compound 3
- Substrate 3-3 (3 g, 10.10 mmol) was added to a dry one-necked flask, hydrochloric acid (368.11 mg, 10.10 mmol) was added, dissolved in methanol (10 mL), reacted at room temperature overnight, and monitored by LC-MS. After the reaction was completed, it was extracted three times with water and ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to obtain product 3-4 (2.4 g, 9.96 mmol).
- Substrate 3-4 400mg, 2.03mmol
- p-toluenesulfonic acid 171.46mg, 995.68 ⁇ mol
- toluene 10mL
- the temperature was raised to 115°C to react overnight, monitored by LC-MS.
- the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to obtain product 3-5 (400 mg, 2.03 mmol).
- step 3 in Example 1 According to the synthesis method of step 3 in Example 1, 1-5 (109.92 mg, 441.22 ⁇ mol) in step 3 was replaced by 3-6 (89.05 mg, 399.20 ⁇ mol), and the synthesis method was the same to obtain compound 3 (30 mg, 66.44 ⁇ mol).
- Embodiment 4 the synthesis of compound 4
- Substrate 4-3 (10 g, 49.99 mmol) and potassium carbonate (13.71 g, 99.35 mmol) were dissolved in methanol (50 mL) into a dry one-necked flask, stirred overnight at room temperature, and monitored by LC-MS. After the reaction was completed, it was extracted three times with water and ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to obtain product 4-4 (13 g, 48.14 mmol).
- step 3 in Example 1 According to the synthesis method of step 3 in Example 1, 1-5 (109.92 mg, 441.22 ⁇ mol) in step 3 was replaced by 4-4 (113.48 mg, 420.21 ⁇ mol), and the synthesis method was the same to obtain compound 4 (60 mg, 120.36 ⁇ mol).
- Embodiment 5 the synthesis of compound 5
- step 3 in Example 1 According to the synthesis method of step 3 in Example 1, 1-5 (109.92 mg, 441.22 ⁇ mol) in step 3 was replaced by 5-4 (116.04 mg, 420.21 ⁇ mol), and the synthesis method was the same to obtain compound 5 (20 mg, 39.63 ⁇ mol).
- Embodiment 6 the synthesis of compound 6
- Step 1 in Example 1 According to the synthesis method of Step 1 in Example 1, 1-1 (247.51 mg, 1.29 mmol) in Step 1 was replaced by 6-1 (115.32 mg, 647.01 ⁇ mol), and the synthesis method was the same to obtain compound 6-2 (122 mg ,262.62 ⁇ mol).
- step 3 in Example 1 According to the synthesis method of step 3 in Example 1, 1-3 (105 mg, 339.40 ⁇ mol) in step 3 was replaced by 6-2 (100 mg, 337.47 ⁇ mol), and the synthesis method was the same to obtain compound 6 (122 mg, 262.62 ⁇ mol) .
- Embodiment 7 the synthesis of compound 7
- Step 1 in Example 1 According to the synthesis method of Step 1 in Example 1, 1-1 (247.51 mg, 1.29 mmol) in Step 1 was replaced with 7-1 (224.93 mg, 905.81 ⁇ mol), and the synthesis method was the same to obtain compound 7-2 (331 mg ,0.90mmol).
- step 3 in Example 1 According to the synthesis method of step 3 in Example 1, 1-3 (105 mg, 339.40 ⁇ mol) in step 3 was replaced with 7-2 (224.93 mg, 905.81 ⁇ mol), and the synthesis method was the same to obtain compound 7-3 (100 mg, 187.04 ⁇ mol).
- Substrate 7-3 (350 mg, 93.52 ⁇ mol) was dissolved in 4M HCl/EA (10 mL) in a dry one-necked flask, stirred at room temperature for 2 hours, and monitored by LC-MS. After the reaction was completed, it was extracted three times with water and ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to obtain product 7 (32 mg, 73.65 ⁇ mol).
- Embodiment 8 the synthesis of compound 8
- Substrate 8-1 (200 mg, 805.41 ⁇ mol) was dissolved in dry THF (10 mL) in a dry single-necked flask, and lithium aluminum hydride (152.84 mg, 4.03 mmol) was added in an ice bath and stirred at room temperature for 30 min, LC- MS monitoring. After the reaction was completed, it was extracted three times with water and ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to obtain product 8-2 (130 mg, 801.33 ⁇ mol).
- Step 1-1 (247.51 mg, 1.29 mmol) in Step 1 was replaced by 8-2 (130 mg, 801.33 ⁇ mol), and the synthesis method was the same to obtain compound 8-3 (224 mg, 799.07 ⁇ mol).
- step 3 in Example 1 According to the synthesis method of step 3 in Example 1, 1-3 (105 mg, 339.4 ⁇ mol) in step 3 was replaced with 8-3 (100 mg, 356.73 ⁇ mol), and the synthesis method was the same to obtain compound 8 (16 mg, 35.67 ⁇ mol) .
- Embodiment 9 the synthesis of compound 9
- Substrate 9-3 (3.52g, 14.12mmol) was added to a dry single-necked flask, methanol (10mL) was added and stirred to dissolve, then Pd/C (170.51mg, 1.40mmol) was added, and H 2 was replaced 3 times, at room temperature The reaction was carried out for 3 hours and monitored by LC-MS. After the reaction was completed, Pd/C was removed by filtration with celite, the organic phase was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain product 9-4 (2.1 g, 9.57 mmol).
- Step 1-1 (247.51 mg, 1.29 mmol) in Step 1 was replaced with 9-4 (123 mg, 560.81 ⁇ mol), and the synthesis method was the same to obtain compound 9-6 (189 mg, 560.13 ⁇ mol).
- step 3 in Example 1 According to the synthesis method of step 3 in Example 1, 1-3 (105 mg, 339.40 ⁇ mol) in step 3 was replaced by 9-6 (189 mg, 560.13 ⁇ mol), and the synthesis method was the same to obtain compound 9 (20 mg, 39.55 ⁇ mol) .
- Embodiment 10 the synthesis of compound 10
- Substrate 10-1 (3g, 18.62mmol) and iodomethane (8.7g, 61.43mmol) were dissolved in DMF (20mL) into a dry one-necked flask, heated to 70°C, stirred for 15 hours, and monitored by LC-MS. After the reaction was completed, it was quenched with water, extracted 3 times by adding ethyl acetate, the organic phases were combined, washed with saturated brine, the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by column chromatography to obtain the product 10-2( 3.4 g, 16.73 mmol).
- Substrate 10-2 (3.3g, 16.24mmol) was added in a dry single-necked flask and dissolved in H 2 SO 4 (10mL), and HNO 3 (1.02g, 16.24mmol) was slowly added dropwise under ice-cooling, and stirred at 0°C for 6 hours, TLC monitoring. After the reaction was completed, it was quenched with water, extracted three times with ethyl acetate, the organic phases were combined, washed with saturated brine, the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by column chromatography to obtain the product 10-3( 3.9 g, 15.71 mmol).
- Substrate 10-3 (270mg, 1.09mmol) was dissolved in THF (10mL) in a dry single-necked flask, and BMS (334.82mg, 4.35mmol) was slowly added dropwise under ice-cooling, heated to 70°C and stirred for 24 hours, LC - MS monitoring. After the reaction was completed, it was quenched with saturated sodium sulfite, extracted three times with ethyl acetate, the organic phases were combined, washed with saturated brine, the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by column chromatography to obtain the product 10 -4 (200 mg, 907.99 ⁇ mol).
- Substrate 10-4 (200mg, 907.99 ⁇ mol) was added to a dry single-necked flask, dissolved in ethanol (10mL), and Pd/C (110.28mg, 907.99 ⁇ mol) was added to replace H 2 for 3 times, then stirred under hydrogen for 3 hours, and LC - MS monitoring. After the reaction was completed, it was filtered with diatomaceous earth, the organic phase was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain product 10-5 (170 mg, 893.40 ⁇ mol).
- Step 1-1 (247.51 mg, 1.29 mmol) in Step 1 was replaced with 10-5 (132 mg, 693.70 ⁇ mol), and the synthesis method was the same to obtain compound 10-6 (213 mg, 690.71 ⁇ mol).
- step 3 in Example 1 According to the synthesis method of step 3 in Example 1, 1-3 (105 mg, 339.40 ⁇ mol) in step 3 was replaced with 10-6 (100 mg, 324.28 ⁇ mol), and the synthesis method was the same to obtain compound 10 (27 mg, 54.95 ⁇ mol) .
- Embodiment 11 the synthesis of compound 11
- Embodiment 12 the synthesis of compound 12
- Embodiment 13 the synthesis of compound 13
- step 3 in the synthesis of Example 1 1-5 (109.92 mg, 441.22 ⁇ mol) in step 3 was replaced with 13-2 (80 mg, 250.0 ⁇ mol), and the synthesis method was the same to obtain compound 13 (25 mg, 39.91 ⁇ mol), prepared by acid method, the product is trifluoroacetate.
- Embodiment 14 the synthesis of compound 14
- Substrate 14-1 (182mg, 1.42mmol), 14-2 (200mg, 1.29mmol) and K 2 CO 3 (534mg, 3.87mmol) were added to a dry three-necked flask, dissolved in DMF (10mL), and Under the protection of 2 , the temperature was raised to 90° C. for 3 h, monitored by LC-MS. After the reaction was completed, it was extracted three times with water and ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure without purification. The crude product was directly used in the next reaction to obtain 14-3 (100 mg, crude). LCMS (ESI + ) m/z: 264.3 [M+H] + .
- Substrate 14-3 (100 mg, 43.0 ⁇ mol) was dissolved in MeOH (5 mL) in a dry one-necked flask, and Pd/C (30 mg) was added, replaced with H 2 three times, stirred at room temperature for 30 min, and monitored by LC-MS. After the reaction was completed, it was filtered with celite, and the filtrate was concentrated under reduced pressure to obtain the crude product 14-4 (109 mg, crude), LCMS (ESI + ) m/z: 234.2[M+H] + .
- step 3 in Example 1 According to the synthesis method of step 3 in Example 1, 1-3 (105 mg, 339.40 ⁇ mol) in step 3 was replaced by 14-4 (53 mg, 151.0 ⁇ mol), and the synthesis method was the same to obtain compound 14 (11.9 mg, 22.93 ⁇ mol) ).
- Embodiment 15 the synthesis of compound 15
- step 3 in Example 1 According to the synthesis method of step 3 in Example 1, 1-3 (105 mg, 339.40 ⁇ mol) in step 3 was replaced by 15-2 (35 mg, 101.0 ⁇ mol), and the synthesis method was the same to obtain compound 15 (11.9 mg, 22.93 ⁇ mol ).
- Embodiment 16 the synthesis of compound 16
- step 3 in Example 1 According to the synthesis method of step 3 in Example 1, 1-3 (105 mg, 339.40 ⁇ mol) in step 3 was replaced by 16-2 (98 mg, 303.0 ⁇ mol), and the synthesis method was the same to obtain compound 16 (22.4 mg, 45.53 ⁇ mol) ).
- Embodiment 17 the synthesis of compound 17
- step 1 in Example 14 According to the synthesis method of step 1 in Example 14, 14-1 (182 mg, 1.42 mmol) in step 1 was replaced by 17-1 (200 mg, 0.952 mmol), and 14-2 (200 mg, 1.29 mmol) was replaced by 17- 2 (105mg, 1.05mmol) was synthesized by the same method to obtain the product 17-3 (400mg, crude).
- Substrate 17-3 (100mg, 0.346mmol) was dissolved in EtOH (5mL) in a dry one-necked flask, Fe powder (97mg, 1.73mmol) and AcOH (0.1mL) were added, heated to 80°C and stirred for 1h, LC- MS monitoring. After the reaction was completed, it was filtered with celite, and the filtrate was concentrated under reduced pressure to obtain the product 17-4 (66 mg, crude), LCMS (ESI + ) m/z: 260.1[M+H] + .
- Embodiment 18 the synthesis of compound 18
- step 3 in Example 1 According to the synthesis method of step 3 in Example 1, 1-3 (105 mg, 339.40 ⁇ mol) in step 3 was replaced with HGC041-02 (60 mg, 194.57 ⁇ mol), and the synthesis method was the same to obtain compound 18 (23 mg, 47.78 ⁇ mol) .
- Embodiment 19 the synthesis of compound 19
- step 3 in Example 1 According to the synthesis method of step 3 in Example 1, 1-3 (105 mg, 339.40 ⁇ mol) in step 3 was replaced with 19-2 (80 mg, 245.0 ⁇ mol), and the synthesis method was the same to obtain compound 19 (14 mg, 28.27 ⁇ mol) .
- Embodiment 20 the synthesis of compound 20
- step 3 in Example 1 According to the synthesis method of step 3 in Example 1, 1-3 (105 mg, 339.40 ⁇ mol) in step 3 was replaced by 20-2 (80 mg, 204.0 ⁇ mol), and the synthesis method was the same to obtain compound 20 (20.6 mg, 36.79 ⁇ mol ).
- Embodiment 21 the synthesis of compound 21
- step 3 in Example 1 According to the synthesis method of step 3 in Example 1, 1-3 (105 mg, 339.40 ⁇ mol) in step 3 was replaced by 16-2 (74 mg, 229.0 ⁇ mol), and 1-5 (109.92 mg, 441.22 ⁇ mol) was replaced by 2 -1 (41 mg, 191.0 ⁇ mol) was synthesized in the same way to obtain compound 21 (20.6 mg, 15.72 ⁇ mol).
- Embodiment 22 the synthesis of compound 22
- step 3 in Example 1 According to the synthesis method of step 3 in Example 1, 1-3 (105 mg, 339.40 ⁇ mol) in step 3 was replaced with 22-2 (50 mg, 147.32 ⁇ mol), and the synthesis method was the same to obtain compound 22 (40 mg, 78.8 ⁇ mol) .
- Embodiment 23 the synthesis of compound 23
- step 3 in Example 1 According to the synthesis method of step 3 in Example 1, 1-3 (105 mg, 339.40 ⁇ mol) in step 3 was replaced with 23-2 (100 mg, 294.64 ⁇ mol), and the synthesis method was the same to obtain compound 23 (70 mg, 137.9 ⁇ mol) .
- Embodiment 24 the synthesis of compound 24
- step 3 in Example 1 According to the synthesis method of step 3 in Example 1, 1-3 (105 mg, 339.40 ⁇ mol) in step 3 was replaced by 24-2 (65 mg, 0.172 mmol), and the synthesis method was the same to obtain compound 24 (31.8 mg, 58.35 ⁇ mol) ).
- Embodiment 25 the synthesis of compound 25
- step 3 in Example 1 According to the synthesis method of step 3 in Example 1, 1-3 (105 mg, 339.40 ⁇ mol) in step 3 was replaced with 25-4 (60 mg, 158.95 ⁇ mol), and the synthesis method was the same to obtain compound 25 (35 mg, 51.31 ⁇ mol) .
- Embodiment 26 the synthesis of compound 26
- step 3 in Example 1 According to the synthesis method of step 3 in Example 1, 1-3 (105 mg, 339.40 ⁇ mol) in step 3 was replaced with 26-2 (60 mg, 176.79 ⁇ mol), and the synthesis method was the same to obtain compound 26 (31 mg, 59.85 ⁇ mol) .
- Embodiment 27 the synthesis of compound 27
- Substrate 27-A1 (18 mg, 49.39 ⁇ mol) and tetrahydrofuran (2 mL) were added to a dry single-necked flask, stirred and dissolved, then m-CPBA (10.23 mg, 59.27 ⁇ mol) was added, reacted at room temperature for 1 h, and monitored by LC-MS. After the reaction, DIPEA (33.39 mg, 258.36 ⁇ mol) was added, and after stirring for 10 min, 1-1 (20.11 mg, 105.14 ⁇ mol) was added and reacted at room temperature, monitored by LC-MS.
- Substrate 27-B1 (26 mg, 71.34 ⁇ mol) and tetrahydrofuran (2 mL) were added to a dry single-necked flask, stirred and dissolved, then m-CPBA (14.77 mg, 85.61 ⁇ mol) was added, reacted at room temperature for 1 h, and monitored by LC-MS. After the reaction, DIPEA (40.81 mg, 315.77 ⁇ mol) was added, and after stirring for 10 min, 1-1 (30.17 mg, 157.71 ⁇ mol) was added and reacted at room temperature, monitored by LC-MS.
- Embodiment 28 the synthesis of compound 28
- Substrate 28-1 (500mg, 2.60mmol), dimethylsulfinimide (169.41mg, 1.82mmol), Xantphos (75.17mg, 129.91 ⁇ mol), Pd2(dba)3( 47.58mg, 51.96 ⁇ mol) and Cs 2 CO 3 (880.41mg, 2.70mmol), add 1,4-dioxane (30mL) to dissolve, stir in microwave at 110°C for 12 hours under the protection of nitrogen, monitor by LC-MS. After the reaction was completed, it was extracted three times with water and ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to obtain product 28-2 (113.4 mg, 217.97 ⁇ mol). LCMS (ESI + ) m/z: 205.1 [M+H] + .
- Embodiment 29 Synthesis of compound 29
- Substrate 29-1 (500mg, 2.91mmol) was added into a dry three-necked flask and dissolved in THF (10ml) for N2 replacement three times, and methylmagnesium bromide (764mg, 6.41mmol) was added dropwise at 0°C, and stirred at room temperature 1h, LC-MS monitoring. After the reaction was completed, it was quenched with saturated ammonium chloride solution, extracted three times with water and ethyl acetate, the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by column chromatography to obtain product 29-2 (165mg, 0.965 mmol). LCMS (ESI + ) m/z: 172.2 [M+H] + .
- step 2 in Example 28 According to the synthesis method of step 2 in Example 28, 28-2 (55.13 mg, 269.37 ⁇ mol) in step 2 was replaced with 29-2 (38 mg, 0.22 mmol), and the synthesis method was the same to obtain compound 29 (18 mg, 4.054 ⁇ mol) ).
- Embodiment 30 the synthesis of compound 30
- step 1 in Example 28 According to the synthesis method of step 1 in Example 28, 28-1 (500 mg, 2.60 mmol) in step 1 was replaced with 30-1 (500 mg, 2.12 mmol), and the synthesis method was the same to obtain the product 30-2 (340 mg, 1.37 mmol).
- step 3 in Example 1 According to the synthesis method of step 3 in Example 1, 1-5 (109.92 mg, 441.22 ⁇ mol) in step 3 was replaced by 30-2 (67 mg, 0.27 mmol), and the synthesis method was the same to obtain compound 30 (22.8 mg, 44.17 ⁇ mol).
- Embodiment 31 the synthesis of compound 31
- step 1 in Example 28 According to the synthesis method of step 1 in Example 28, 28-1 (500 mg, 2.60 mmol) in step 1 was replaced with 31-1 (300 mg, 1.27 mmol), and the synthesis method was the same to obtain the product 31-2 (310 mg, 1.24 mmol).
- step 3 in Example 1 According to the synthesis method of step 3 in Example 1, 1-5 (109.92 mg, 441.22 ⁇ mol) in step 3 was replaced by 31-2 (40 mg, 0.16 mmol), and the synthesis method was the same to obtain compound 31 (25.3 mg, 52.50 ⁇ mol).
- Embodiment 32 the synthesis of compound 32
- step 1 in Example 29-1 500 mg, 2.91 mmol
- step 1 32-1 (300 mg, 1.39 mmol)
- the synthesis method was the same to obtain the product 32-2 (374 mg, crude ).
- step 3 in Example 1-5 (109.92 mg, 441.22 ⁇ mol) in step 3 was replaced with 32-2 (52 mg, 0.24 mmol), and the synthesis method was the same to obtain compound 32 (9.8 mg, 21.65 ⁇ mol).
- Embodiment 33 the synthesis of compound 33
- step 1 in Example 28 According to the synthesis method of step 1 in Example 28, 28-1 (500mg, 2.60mmol) in step 1 was replaced by 33-1 (300mg, 1.18mmol), and the synthesis method was the same to obtain the product 33-2 (230mg, 0.864 mmol).
- step 3 in Example 1-5 (109.92 mg, 441.22 ⁇ mol) in step 3 was replaced with 33-2 (60 mg, 0.23 mmol), and the synthesis method was the same to obtain compound 33 (5.4 mg, 10.59 ⁇ mol).
- Embodiment 34 the synthesis of compound 34
- step 3 in Example 1 According to the synthesis method of step 3 in Example 1, 1-5 (109.92 mg, 441.22 ⁇ mol) in step 3 was replaced with 34-2 (59 mg, 0.272 mmol), and the synthesis method was the same to obtain compound 34 (30.7 mg, 66.91 ⁇ mol).
- Embodiment 35 the synthesis of compound 35
- step 1 in Example 29-1 500 mg, 2.91 mmol
- step 1 35-1 (400 mg, 1.86 mmol)
- the synthesis method was the same to obtain the product 35-2 (360 mg, crude ).
- step 3 in Example 1 According to the synthesis method of step 3 in Example 1, 1-5 (109.92 mg, 441.22 ⁇ mol) in step 3 was replaced by 35-2 (52 mg, 0.242 mmol), and 1-3 (105 mg, 339.40 ⁇ mol) was replaced by 24 -2 (97mg, 0.259mmol) was synthesized in the same way to obtain compound 35 (4.6mg, 7.81 ⁇ mol).
- Embodiment 36 the synthesis of compound 36
- step 3 in Example 1 According to the synthesis method of step 3 in Example 1, 1-5 (109.92 mg, 441.22 ⁇ mol) in step 3 was replaced with 36-1 (37 mg, 0.162 mmol), and the synthesis method was the same to obtain compound 36 (32.5 mg, 64.85 ⁇ mol).
- Embodiment 37 the synthesis of compound 37
- step 3 in Example 1 According to the synthesis method of step 3 in Example 1, 1-5 (109.92 mg, 441.22 ⁇ mol) in step 3 was replaced with 37-1 (55 mg, 0.259 mmol), and the synthesis method was the same to obtain compound 37 (5.9 mg, 13.11 ⁇ mol).
- Embodiment 38 the synthesis of compound 38
- step 3 in Example 1 According to the synthesis method of step 3 in Example 1, 1-5 (109.92 mg, 441.22 ⁇ mol) in step 3 was replaced by 38-1 (37 mg, 0.162 mmol), and the synthesis method was the same to obtain compound 38 (28.7 mg, 53.80 ⁇ mol).
- Embodiment 39 the synthesis of compound 39
- Substrate 39-2 (7.00g, 23.90mmol), K 2 CO 3 (3.96g, 28.68mmol), dissolved in ACN (50ml) was added to a dry one-necked flask, stirred at room temperature for 1h, monitored by LC-MS. After the reaction was completed, it was extracted with water and ethyl acetate three times, the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by column chromatography to obtain product 39-3 (1.41g, 6.59mmol), LCMS (ESI + ) m/z: 215.1[M+H]+.
- Substrate 39-3 (427.9mg, 2.00mmol) was added to a dry single-necked flask, dissolved in ACN (4ml), and NaBH 4 (151.8mg, 4.00mmol) was added slowly under ice bath, reacted in ice-water bath for 1h, TLC monitor. After the reaction was completed, it was extracted three times with water and ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain product 39-4 (210.00 mg, 0.98 mmol).
- step 3 in Example 1 According to the synthesis method of step 3 in Example 1, 1-5 (109.92 mg, 441.22 ⁇ mol) in step 3 was replaced with 39-4 (42.79 mg, 0.20 mmol), and the synthesis method was the same to obtain compound 39 (10.0 mg, 22.56 ⁇ mol).
- Embodiment 40 the synthesis of compound 40
- step 1 in Example 29-1 500 mg, 2.91 mmol
- step 1 in step 1 was replaced with 40-1 (423.90 mg, 2.00 mmol), and the synthesis method was the same to obtain compound 40-2 (210.00 mg , 0.98 mmol), LCMS (ESI + ) m/z: 211.2 [M+HH 2 O] + .
- step 3 in Example 1 According to the synthesis method of step 3 in Example 1, 1-5 (109.92 mg, 441.22 ⁇ mol) in step 3 was replaced by 40-2 (45.59 mg, 0.20 mmol), and the synthesis method was the same to obtain compound 40 (20.00 mg, 43.74 ⁇ mol).
- Embodiment 41 the synthesis of compound 41:
- step 3 in Example 1 According to the synthesis method of step 3 in Example 1, 1-5 (109.92 mg, 441.22 ⁇ mol) in step 3 was replaced with 41-1 (38 mg, 0.194 mmol), and the synthesis method was the same to obtain compound 41 (2.0 mg, 4.50 ⁇ mol).
- Embodiment 42 the synthesis of compound 42:
- step 1 in Example 29-1 500 mg, 2.91 mmol
- step 1 in step 1 was replaced with 42-1 (1 g, 4.29 mmol), and the synthesis method was the same to obtain compound 42-2 (850 mg, crude ).
- step 3 in Example 1-5 (109.92 mg, 441.22 ⁇ mol) in step 3 was replaced by 42-2 (63 mg, 0.269 mmol), and the synthesis method was the same to obtain compound 42 (12 mg, 23.56 ⁇ mol) ).
- Embodiment 43 the synthesis of compound 43
- step 1 in Example 29-1 500 mg, 2.91 mmol
- step 1 in step 1 was replaced with 43-1 (452.00 mg, 2.00 mmol), and the synthesis method was the same to obtain compound 43-2 (200 mg, 0.88 mmol), LCMS (ESI + ) m/z: 209.2 [M+HH 2 O] + .
- step 3 in Example 1 According to the synthesis method of step 3 in Example 1, 1-5 (109.92 mg, 441.22 ⁇ mol) in step 3 was replaced with 43-2 (45.20 mg, 0.20 mmol), and the synthesis method was the same to obtain compound 43 (10.00 mg, 21.96 ⁇ mol).
- Embodiment 44 the synthesis of compound 44
- step 1 in Example 29-1 (500mg, 2.91mmol) in step 1 was replaced by 44-1 (452.00mg, 2.00mmol) and the synthesis method was the same to obtain compound 44-2 (200.00mg , 0.88 mmol), LCMS (ESI + ) m/z: 209.2 [M+HH 2 O] + .
- step 3 in Example 1 According to the synthesis method of step 3 in Example 1, 1-5 (109.92 mg, 441.22 ⁇ mol) in step 3 was replaced by 44-2 (45.20 mg, 0.20 mmol), and the synthesis method was the same to obtain compound 44 (10.0 mg, 21.96 ⁇ mol).
- Embodiment 45 the synthesis of compound 45
- Substrate 45-2 (214.0 mg, 1.0 mmol) and CH(OMe) 3 (3 mL) were added into a dry one-necked flask, stirred at room temperature for 1 h, and monitored by LC-MS. After the reaction, it was concentrated under reduced pressure to obtain the product 45-3 (210.00 mg, 0.95 mmol), LCMS (ESI + ) m/z: 225.2[M+H] + .
- step 3 in Example 1 According to the synthesis method of step 3 in Example 1, 1-5 (109.92 mg, 441.22 ⁇ mol) in step 3 was replaced with 45-3 (44.79 mg, 0.20 mmol), and the synthesis method was the same to obtain compound 45 (10.00 mg, 22.06 ⁇ mol).
- Embodiment 46 the synthesis of compound 46
- step 3 in Example 1 According to the synthesis method of step 3 in Example 1, 1-5 (109.92 mg, 441.22 ⁇ mol) in step 3 was replaced with 46-1 (57 mg, 0.269 mmol), and the synthesis method was the same to obtain compound 46 (8.8 mg, 19.26 ⁇ mol).
- Embodiment 47 the synthesis of compound 47
- Embodiment 48 the synthesis of compound 48
- reaction solution was filtered with diatomaceous earth, the mother liquor was extracted with water and ethyl acetate three times, the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by column chromatography to obtain the product 48-3 (250.00mg , 1.03 mmol), LCMS (ESI + ) m/z: 250.1 [M+H] + .
- step 3 in Example 1 According to the synthesis method of step 3 in Example 1, 1-5 (109.92 mg, 441.22 ⁇ mol) in step 3 was replaced with 48-3 (49.79 mg, 0.20 mmol), and the synthesis method was the same to obtain compound 48 (12.00 mg, 25.09 ⁇ mol).
- Embodiment 49 the synthesis of compound 49
- step 3 in Example 1 According to the synthesis method of step 3 in Example 1, 1-5 (109.92 mg, 441.22 ⁇ mol) in step 3 was replaced with 49-3 (40.69 mg, 0.18 mmol), and the synthesis method was the same to obtain compound 49 (1.50 mg, 2.84 ⁇ mol).
- Embodiment 50 the synthesis of compound 50
- step 1 in Example 29-1 500 mg, 2.91 mmol
- step 1 50-1 (434.04 mg, 2 mmol)
- the synthesis method was the same to obtain compound 50-2 (200 mg, 878.09 ⁇ mol) as a white solid.
- step 3 in Example 1 According to the synthesis method of step 3 in Example 1, 1-5 (109.92 mg, 441.22 ⁇ mol) in step 3 was replaced by 50-2 (37.89 mg, 174.55 ⁇ mol), and the synthesis method was the same to obtain compound 50 (17 mg, 38.16 ⁇ mol).
- Embodiment 51 the synthesis of compound 51
- Substrate 51-1 600 mg, 3.19 mmol
- triethyl orthoacetate 1.5 mL
- the reaction was monitored by LC-MS. After the reaction was completed, it was concentrated under reduced pressure, extracted three times with water and ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain the crude product 51-2 (650 mg, crude), which was directly used in the next reaction.
- step 3 in Example 1 According to the synthesis method of step 3 in Example 1, 1-5 (109.92 mg, 441.22 ⁇ mol) in step 3 was replaced with 51-2 (65.80 mg, 310.31 ⁇ mol), and 1,4-dioxane (3 mL ) was replaced by DMF (2 mL), and the synthesis method was the same to obtain compound 51 (18.1 mg, 36.78 ⁇ mol).
- Embodiment 52 the synthesis of compound 52
- step 1 in Example 29-1 500 mg, 2.91 mmol
- step 1 52-1 (500.00 mg, 2.15 mmol)
- the synthesis method was the same to obtain compound 52-2 (300 mg, 1.29 mmol).
- step 3 in Example 1 According to the synthesis method of step 3 in Example 1, 1-5 (109.92 mg, 441.22 ⁇ mol) in step 3 was replaced by 52-2 (67.81 mg, 290.92 ⁇ mol), and the synthesis method was the same to obtain compound 52 (4.5 mg, 9.23 ⁇ mol).
- Embodiment 53 the synthesis of compound 53
- step 1 in Example 29-1 500 mg, 2.91 mmol
- step 1 was replaced with 53-1 (1.11 g, 5 mmol), and the synthesis method was the same to obtain compound 53-2 (1.0 g, 4.49 mmol).
- step 3 in Example 1 According to the synthesis method of step 3 in Example 1, 1-5 (109.92 mg, 441.22 ⁇ mol) in step 3 was replaced with 53-2 (39.80 mg, 180.00 ⁇ mol), and the synthesis method was the same to obtain compound 53 (7.1 mg, 12.10 ⁇ mol).
- Embodiment 54 the synthesis of compound 54
- reaction solution was filtered with diatomaceous earth, the mother liquor was extracted with water and ethyl acetate three times, the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by column chromatography to obtain the product 54-2 (100 mg, 398.28 ⁇ mol).
- step 3 in Example 1 According to the synthesis method of step 3 in Example 1, 1-5 (109.92 mg, 441.22 ⁇ mol) in step 3 was replaced with 54-2 (49.51 mg, 197.18 ⁇ mol), and the synthesis method was the same to obtain compound 54 (20 mg, 38.12 ⁇ mol).
- Embodiment 55 the synthesis of compound 55
- step 1 in Example 29-1 500 mg, 2.91 mmol
- step 1 was replaced with 55-1, and the synthesis method was the same to obtain compound 55-2.
- step 3 in Example 1 According to the synthesis method of step 3 in Example 1, 1-5 (109.92 mg, 441.22 ⁇ mol) in step 3 was replaced by 55-2 (50 mg, 195.99 ⁇ mol), and the synthesis method was the same to obtain compound 55 (17 mg, 35.16 ⁇ mol ).
- Embodiment 56 the synthesis of compound 56
- step 3 in Example 1 According to the synthesis method of step 3 in Example 1, 1-5 (109.92 mg, 441.22 ⁇ mol) in step 3 was replaced by 30-2 (332.41 mg, 2 mmol), and 1-3 (105 mg, 339.40 ⁇ mol) was replaced by 56 -2 (330.85mg, 1.33mmol) was synthesized in the same way to obtain compound 56-3 (252mg, 755.78 ⁇ mol).
- Substrate 56-3 (66.69mg, 0.2mmol), m-CPBA (26.45mg, 300.00 ⁇ mol) and THF (0.8mL) were added to a dry single-necked flask, and after stirring at room temperature for 10min, DIPEA (129.24mg, 1.00mmol ), after stirring at room temperature for 5 min, the substrate 56-4 (57.68 mg, 300.00 ⁇ mol) was added, reacted at 100° C. for 6 h, and monitored by LCMS.
- DIPEA 129.24mg, 1.00mmol
- Embodiment 57 the synthesis of compound 57
- Step 1 Synthesis of Compound 57-3:
- Substrate 57-4 (22.3g, 103.58mmol) was added in a dry three-necked flask dissolved in DMF (75.46mL), POCl 3 (39.71g, 258.95mmol) and MgSO 4 were added dropwise at -10°C under nitrogen protection (22.40g, 186.08mmol), after stirring at room temperature for 1h, the temperature was raised to 105°C for 16h, monitored by LC-MS. After the reaction was completed, it was quenched with ice water, and the pH was adjusted to 9-10 with 30% aqueous sodium hydroxide solution.
- Substrate 57-7 (3.74g, 17.67mmol), K 2 CO 3 (7.32g, 53.01mmol) and MeOH solution (40mL) were added to a dry one-necked flask, stirred at 15°C for 2h, monitored by LCMS. After the reaction was completed, it was filtered and concentrated under reduced pressure. The residue was purified by column chromatography to obtain the product 57-8 (1.94 g, 11.44 mmol) as a bright yellow oil, LCMS (ESI + ) m/z: 170.1 [M+H] + .
- Substrate 57-8 (3.74g, 17.67mmol) was added to a dry one-necked flask, dissolved in DCM (40mL), added Dess-martin Periodinane (7.36g, 17.36mmol), stirred at 15°C for 2h, monitored by LCMS. After the reaction, the pH was adjusted to 8-9 with saturated sodium bicarbonate solution, extracted three times with DCM, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the product 57-9 (2 g, crude) as a white solid, LCMS (ESI+ ) m/z: 168.0[M+H]+.
- Embodiment 58 the synthesis of compound 58
- Step 1 Synthesis of Compound 58-2:
- Substrate 58-1 (87mg, 395.46 ⁇ mol) and methylamine (120.00mg, 3.86mmol, 1M tetrahydrofuran solution) were added to a dry one-necked flask, reacted at room temperature for 2h, and monitored by LC-MS. After the reaction, the reaction solution was concentrated under reduced pressure to obtain the crude product 58-2, which was directly used in the next reaction.
- Substrate 58-3 (25 mg, crude) and triethyl orthoacetate (1 mL) were added into a dry one-necked bottle, reacted at room temperature for 2 h, and monitored by LC-MS. After the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain product 58-4 (7 mg, 31.10 ⁇ mol).
- step 3 in Example 1 According to the synthesis method of step 3 in Example 1, 1-5 (109.92 mg, 441.22 ⁇ mol) in step 3 was replaced by 58-4 (34.7 mg, 154.16 ⁇ mol), and the synthesis method was the same to obtain compound 58 (2.0 mg, 4.41 ⁇ mol).
- Embodiment 59 the synthesis of compound 59
- Step 1 Synthesis of Compound 59-2:
- step 3 in Example 1 According to the synthesis method of step 3 in Example 1, 1-5 (109.92 mg, 441.22 ⁇ mol) in step 3 was replaced by 59-3 (34.60 mg, 135.11 ⁇ mol), and the synthesis method was the same to obtain compound 59 (3.49 mg, 7.07 ⁇ mol).
- Embodiment 60 the synthesis of compound 60
- step 2 in Example 28 According to the synthesis method of step 2 in Example 28, 28-2 (55.13 mg, 269.37 ⁇ mol) in step 2 was replaced with 60-2 (35.22 mg, 193.94 ⁇ mol), and the synthesis method was the same to obtain compound 60 (4.13 mg, 8.20 ⁇ mol).
- Embodiment 61 the synthesis of compound 61
- Substrate 61-2 (700mg, 2.94mmol), ethyl iodide (458.57mg, 2.94mmol), Cs 2 CO 3 (1.05g, 3.23mmol) were added to a single-necked flask, DMF (3mL) was added and stirred to dissolve. The reaction was carried out at °C for 8h, monitored by LCMS.
- step 3 in Example 1 According to the synthesis method of step 3 in Example 1, 1-5 (109.92 mg, 441.22 ⁇ mol) in step 3 was replaced with 61-3 (30 mg, 112.73 ⁇ mol), and the synthesis method was the same to obtain compound 61 (8.85 mg, 17.89 ⁇ mol).
- Embodiment 62 the synthesis of compound 62
- Substrates 62-2 (142 mg, 755.2 ⁇ mol), 62-3 (77.1 mg, 755.2 ⁇ mol) and methanol (2 mL) were added into a dry microwave tube, and reacted in an oil bath at 60°C under nitrogen protection for 1 h. After the reaction was complete, the reaction solution was concentrated under reduced pressure, then 1,4-dioxane (2 mL) and iodobenzene acetate (267.2 mg, 830.7 ⁇ mol) were added, and reacted overnight under nitrogen protection at room temperature, monitored by LC-MS.
- reaction solution was concentrated under reduced pressure, extracted three times with ethyl acetate and water, the organic phase was washed three times with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product 62-4 (116 mg, 429.5 ⁇ mol) as an orange solid.
- step 3 in Example 1 replace 1-5 (109.92 mg, 441.22 ⁇ mol) in step 3 with 62-4 (134 mg, 496.14 ⁇ mol), the synthesis method is the same, and during the reaction, a decarboxylation reaction occurs , thus obtaining compound 62 (10 mg, 19.06 ⁇ mol).
- AZD-1775 used in some biological evaluation experiments in this part of the examples is used as a control, and the structural information of AZD-1775 (CAS number: 955365-80-7) is as follows:
- Test Example 1 Evaluation of compound binding to Tracer 178 on Wee1 protein by TR-FRET method.
- Tracer 178 and MAb Anti-GST-Eu crypate are configured in buffer (50mM HEPES pH 7.5, 10mM MgCl2, 1mM EGTA, 0.01% Brij-35), and the final reaction concentration of Tracer178 is 50 nM, MAb Anti-GST-Eu crypate The final concentration was 2nM, and the negative control (minimum signal control) used an equal amount of buffer instead of protein solution.
- Compound number IC50 measured value Compound number IC50 measured value Compound number IC50 measured value Compound number IC50 measured value 1 ++++ twenty three ++++ 43B +++ 2 +++ twenty four +++ 44 ++ 3 +++ 25 ++++ 45 +++ 4 +++ 26 ++++ 46 +++ 5 +++ 27A ++++ 47 ++ 6 +++ 27B +++ 48 +++ 7 ++++ 28 ++ 49 ++ 8 ++++ 29 ++ 50 ++ 9 ++++ 30 +++ 51 +++ 10 ++++ 31 +++ 52 ++ 11 +++ 32 ++ 53 +++
- Test Example 2 The anti-proliferation effect of the compound on H1299 and MIA Paca-2 cells was evaluated by the Cell Titer-Glo method.
- DMSO was dissolved to a concentration of 10 mM test compound and 10 mM reference compound AZD1775, and the compounds were serially diluted in the medium, with a total of 9 dose points, and 2 parallel replicates were set for each concentration.
- the cell growth group without compound was used as a positive control (maximum signal control), and the culture medium was used as a negative control (minimum signal control), while ensuring that the final DMSO content in each reaction well was 0.2%.
- IC50 of the compound on cell activity inhibition was calculated by GraphPad Prism 6 with log(inhibitor)vs.response–Variable slope model fitting.
- the compound of the present invention has strong cell proliferation inhibitory activity on H1299 and MIA Paca-2
- Test Example 3 Evaluation of metabolic stability of liver microsomes (mouse and human) in vitro
- the microsomes were taken out from the -80°C refrigerator, quickly thawed in a 37°C water bath, and placed on ice for use.
- the test article was diluted with DMSO to make a 10 mM stock solution, and then diluted with acetonitrile to make a 0.5 mM secondary stock solution.
- Use Buffer C to dilute NADPH to 6mM working solution, which is the starting solution.
- the internal standard is Verapamil-HCl with a concentration of 4 ng/ml.
- the reaction was carried out on an incubator and shaking device, and 15 ⁇ L/sample of the starting solution was sucked up with a discharge gun, and added to the reaction plate. Shake slightly to start the reaction, use a timer to accurately time and record;
- the compounds of the present invention have good metabolic stability in liver microsomes (mouse and human) in vitro.
- Sample preparation Dissolve the compound in DMSO into a 10mM stock solution, then dilute the compound into a 0.02mM secondary stock solution with PBS, and then use blank plasma to dilute the above 0.02mM to 1 ⁇ M, which is the sample to be incubated.
- Dialysis device preparation first add 400 ⁇ L of blank PBS to the white well of the equilibrium dialysis plate, add 200 ⁇ L of the prepared plasma sample to the red well, and seal the dialysis plate with a sealing film.
- acetonitrile Verapamil-HCl, 4 ng/mL
- the dialysis device and the T5 plate were placed in a microplate constant temperature shaker and incubated together for 5 hours (37° C., using 300 rpm or the minimum rotation speed). After incubation, 300 ⁇ L of acetonitrile (Verapamil-HCl, 4 ng/mL) was added, followed by 50 ⁇ L of PBS solution. After the dialysis incubation, take a new 96-well deep-well plate.
- ⁇ Plasma protein binding rate [(Rpe-Rb)/Rpe] ⁇ 100%
- R pe ratio of the peak area of the test product on the plasma side to the internal standard
- R b ratio of the peak area of the test product on the buffer side to the internal standard
- ⁇ R 5 Incubator stability sample peak area to internal standard ratio
- ⁇ R 0 The ratio of the peak area of the refrigerator stability sample to the internal standard
- the compound of the present invention has a good ratio of plasma protein binding to free drug. Compared with AZD-1775, the plasma protein binding of the compound of the present invention is similar, and the fluctuation difference among species is smaller.
- Caco-2 cells were purchased from the American Type Tissue Cell Collection (Rockville, MD).
- the cell culture medium is modified Eagle's medium (MEM) containing 10% inactivated fetal bovine serum and 1% non-essential amino acids.
- MEM modified Eagle's medium
- Cells were inoculated on polycarbonate filter membrane (product number: 3396) and cultured in a 37°C, 5% CO 2 incubator.
- Cells cultured for 21-28 days after inoculation can be used for transport experiments, and the compactness of the cell monolayer can be characterized and verified by the apparent permeability coefficient (P app ) of Lucifer yellow.
- P app apparent permeability coefficient
- the compound was dissolved in DMSO to prepare a 10 mM stock solution, and was diluted with Hanks' balanced salt solution (HBSS, Invitrogen, Cat#14025-092) containing 25 mM HEPES (pH 7.4) to obtain a working solution. Add 10 ⁇ M working solution of the compound to be tested to the apical side and basolateral side of Caco-2 and incubate at 37°C for 90 minutes.
- HBSS Hanks' balanced salt solution
- HEPES pH 7.4
- the compounds of the present invention have good membrane-permeability properties.
- the compound was given to 6 male ICR mice at corresponding doses by oral gavage (10 mg/kg).
- Anticoagulant whole blood was collected at 5min, 30min, 2h, and 8h after the administration of the mice in group B, and the anticoagulant whole blood was collected at 15min, 1h, 4h, and 24h after the administration of the mice in group B, and the plasma was separated;
- Plasma concentrations of compounds were determined by standard curve calibration using LC-MS. The plasma concentration-time data were fitted to pharmacokinetic parameters using Winnolin 5.2 software.
- PK parameters AZD-1775 Compound 1 Compound 28 Compound 40 T1/2, hr 0.77 1.71 1.78 0.70 C max (ng/mL) 445 169 337 377 AUC inf_Pred (hr*ng/mL) 500 260 743 493 Cl_pred (L/hr/kg) 20.8 39.5 13.8 24.3
- the compound of the present invention has good in vivo pharmacokinetic properties, can significantly increase the half-life of the compound and reduce the clearance rate.
- Test Example 8 Evaluation of compound's inhibition of cytochrome P450
- Enzyme experiments use the fluorescence generated by the oxidation of substrates by cytochrome P450 to quantitatively detect the inhibition of small molecule inhibitors on the enzymatic activity of each subtype of CYP450.
- the experiment was carried out in a 384-well plate (Corning, Cat#3575), and the reaction buffer used was: 142.86mM Potassium Phosphate, pH 7.4.
- the components of Solution A used in the experiment are: 26.13mM NADP+ (Sigma-aldrich, Cat#N0505), 65.77mM G6P (J&K, Cat#968161) and 65.42mM MgCl2 (Sigma-aldrich, Cat#M2670).
- the composition of Solution B used in the experiment is: 40U/mL G6PDH (Sigma-aldrich, Cat#G6378).
- the composition of the substrate mixed solution is: 0.05X Solution A, 0.01X Solution B, 50mM Potassium Phosphate, 0.01mM BOMCC/0.01mM EOMCC/0.001mM DBOMF.
- the reaction system is 50 ⁇ L or 20 ⁇ L, respectively, including 3 nM CYP3A4 or 120 nM CYP2C9, BOMCC substrate mixed solution and different concentrations of test compounds.
- the reaction system is 20 ⁇ L, including 12.5nM CYP2C19, 80nM CYP2D6 or 1nM CYP1A2, EOMCC substrate mixed solution and different concentrations of test compounds.
- the reaction system is 50 ⁇ L, including 1.5 nM CYP2C8, DBOMF substrate mixed solution and different concentrations of the test compound.
- the cell line used in the patch clamp experiment was the 10th passage CHO cells overexpressing the hERG potassium ion channel cDNA.
- CHO hERG cells were cultured in culture dishes or flasks in a 37°C, 5% CO2 incubator. 24-48 hours before the electrophysiological experiment, the cells were dropped on a circular glass slide and cultured in the cell culture medium, and used for the experiment after the cells adhered to the wall.
- the final concentration of the compound used for electrophysiological detection was 5, 20 ⁇ M, and the final concentration of DMSO was 0.1%.
- Cisapride (C4740-10 mg, Sigma) was used as a positive control in the experiment to ensure that the cells used had a normal response.
- test data in the report needs to meet the following criteria:
- the hERG inhibitory activity of the compound of the present invention is significantly lower than that of AZD-1775.
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Abstract
Description
化合物编号 | IC 50测定值 | 化合物编号 | IC 50测定值 | 化合物编号 | IC 50测定值 |
1 | ++++ | 23 | ++++ | 43B | +++ |
2 | +++ | 24 | +++ | 44 | ++ |
3 | +++ | 25 | ++++ | 45 | +++ |
4 | +++ | 26 | ++++ | 46 | +++ |
5 | +++ | 27A | ++++ | 47 | ++ |
6 | +++ | 27B | +++ | 48 | +++ |
7 | ++++ | 28 | ++ | 49 | ++ |
8 | ++++ | 29 | ++ | 50 | ++ |
9 | ++++ | 30 | +++ | 51 | +++ |
10 | ++++ | 31 | +++ | 52 | ++ |
11 | +++ | 32 | ++ | 53 | +++ |
12 | +++ | 33 | ++ | 54 | +++ |
13 | ++++ | 34 | ++ | 55 | +++ |
14 | ++++ | 35 | ++ | 56 | ++ |
15 | +++ | 36 | +++ | 57 | ++ |
16 | ++++ | 37 | +++ | 58 | +++ |
17 | +++ | 38 | +++ | 59 | +++ |
18 | ++++ | 39 | +++ | 60 | +++ |
19 | +++ | 40 | +++ | 61 | ++ |
20 | ++++ | 41 | +++ | 62 | ++ |
21 | +++ | 42 | +++ | AZD-1775 | ++++ |
22 | ++ | 43A | +++ |
PK参数 | AZD-1775 | 化合物1 | 化合物28 | 化合物40 |
T1/2,hr | 0.77 | 1.71 | 1.78 | 0.70 |
C max(ng/mL) | 445 | 169 | 337 | 377 |
AUC inf_Pred(hr*ng/mL) | 500 | 260 | 743 | 493 |
Cl_pred(L/hr/kg) | 20.8 | 39.5 | 13.8 | 24.3 |
化合物编号 | 溶解度(mg/mL) |
AZD-1775 | 0.03 |
化合物1 | 0.12 |
化合物3 | 0.06 |
化合物16 | 0.35 |
Claims (27)
- 式I所示的化合物、或其氘代化合物、或其立体异构体、或其药学上可接受的盐:其中,R 1选自氢、卤素、氰基、-C 1~6烷基、-C 2~6烯基、-C 2~6炔基、卤素取代的-C 1~6烷基、卤素取代的-C 2~6烯基、卤素取代的-C 2~6炔基、-C 0~4亚烷基-OR 11、-C 0~4亚烷基-NR 12R 12;R 11选自-C 1~6烷基、-C 2~6烯基、-C 2~6炔基、卤素取代的-C 1~6烷基、卤素取代的-C 2~6烯基、卤素取代的-C 2~6炔基;每个R 12分别独立选自氢、-C 1~6烷基、-C 2~6烯基、-C 2~6炔基、卤素取代的-C 1~6烷基、卤素取代的-C 2~6烯基、卤素取代的-C 2~6炔基;X 1、X 2、X 4分别独立选自N或CR 4;X 3选自N或CR 3;X 5选自O、S或NR 4;X 6选自CR 4或N;X 8选自CR 4R 4、O;X 7选自S、NR 4;X 9选自CR 4R 4;R 21、R 22分别独立选自氢、卤素、氰基、-C 1~6烷基、-C 2~6烯基、-C 2~6炔基、卤素取代的-C 1~6烷基、卤素取代的-C 2~6烯基、卤素取代的-C 2~6炔基、-C 0~4亚烷基-OR 24、-C 0~4亚烷基-NR 24R 24;每个R 24分别独立选自氢、-C 1~6烷基、-C 2~6烯基、-C 2~6炔基、卤素取代的-C 1~6烷基、卤素取代的-C 2~6烯基、卤素取代的-C 2~6炔基;R 23选自氢、卤素、氰基、-C 1~6烷基、-C 2~6烯基、-C 2~6炔基、卤素取代的-C 1~6烷基、卤素取代的-C 2~6烯基、卤素取代的-C 2~6炔基、-C 0~4亚烷基-C(O)R 25、-C 0~4亚烷基-C(O)NR 25R 25、-C 0~4亚烷基-C(O)OR 25、-C 0~4亚烷基-S(O) 2R 25、-C 0~4亚烷基-S(O)R 25、-C 0~4亚烷基-S(O)(NH)R 25、-C 0~4亚烷基-S(NH) 2R 25、-C 0~4亚烷基-S(O) 2NR 25R 25、-C 0~4亚烷基-S(O)NR 25R 25、-C 0~4亚烷基-S(O)(NH)NR 25R 25、-C 0~4亚烷基-S(NH) 2NR 25R 25、-C 0~4亚烷基-OR 25、-C 0~4亚烷基-OC(O)R 25、-C 0~4亚烷基-OS(O) 2R 25、-C 0~4亚烷基-OS(O)R 25、-C 0~4亚烷基-NR 25R 25、-C 0~4亚烷基-NR 25C(O)R 25、-C 0~4亚烷基-NR 25S(O) 2R 25、-C 0~4亚烷基-NR 25S(O)R 25、-C 0~4亚烷基-NR 25S(O)(NH)R 25、-C 0~4亚烷基-NR 25S(NH) 2R 25;每个R 25分别独立选自氢、-C 1~6烷基、-C 2~6烯基、-C 2~6炔基、卤素取代的-C 1~6烷基、卤素取代的-C 2~6烯基、卤素取代的-C 2~6炔基;或者,R 23、R 3与相连原子一起形成4~8元碳环基、4~8元杂环烷基;R 3选自氢、卤素、氰基、-C 1~6烷基、-C 2~6烯基、-C 2~6炔基、羟基取代的-C 1~6烷基、卤素取代的-C 1~6烷基、卤素取代的-C 2~6烯基、卤素取代的-C 2~6炔基、-C 0~4亚烷基-OH、-C 0~4亚烷基-O(C 1~6烷基)、-C 0~4亚烷基-NH 2、-C 0~4亚烷基-NH(C 1~6烷基)、-C 0~4亚烷基-N(C 1~6烷基)(C 1~6烷基);每个R 4分别独立选自氢、卤素、氰基、-C 1~6烷基、-C 2~6烯基、-C 2~6炔基、卤素取代的-C 1~6烷基、卤素取代的-C 2~6烯基、卤素取代的-C 2~6炔基、-C 0~4亚烷基-OH、-C 0~4亚烷基-O(C 1~6烷基)、-C 0~4亚烷基-NH 2、-C 0~4亚烷基-NH(C 1~6烷基)、-C 0~4亚烷基-N(C 1~6烷基)(C 1~6烷基);R 5选自氢、-C 1~6烷基;Y 1、Y 2、Y 3、Y 4分别独立选自N或CR Y;每个R Y分别独立选自氢、卤素、氰基、-C 1~6烷基、-C 2~6烯基、-C 2~6炔基、卤素取代的-C 1~6烷基、卤素取代的-C 2~6烯基、卤素取代的-C 2~6炔基、-C 0~4亚烷基-OH、-C 0~4亚烷基-O(C 1~6烷基)、-C 0~4亚烷基-NH 2、-C 0~4亚烷基-NH(C 1~6烷基)、-C 0~4亚烷基-N(C 1~6烷基)(C 1~6烷基);B环选自3~12元碳环基、4~12元杂环烷基;所述碳环基、杂环烷基可进一步被一个、两个、三个、四个或五个R B取代;每个R B分别独立选自氢、卤素、氰基、-C 1~6烷基、-C 2~6烯基、-C 2~6炔基、卤素取代的-C 1~6烷基、卤素取代的-C 2~6烯基、卤素取代的-C 2~6炔基、-C 0~4亚烷基-OR B1、-C 0~4亚烷基-OC(O)R B1、-C 0~4亚烷基-SR B1、-C 0~4亚烷基-S(O) 2R B1、-C 0~4亚烷基-S(O)R B1、-C 0~4亚烷基-S(O) 2NR B1R B1、-C 0~4亚烷基-S(O)NR B1R B1、-C 0~4亚烷基-C(O)R B1、-C 0~4亚烷基-C(O)OR B1、-C 0~4亚烷基-C(O)NR B1R B1、-C 0~4亚烷基-NR B1R B1、-C 0~4亚烷基-NR B1C(O)R B1、3~12元碳环基、4~12元杂环烷基;所述碳环基、杂环烷基可进一步被一个、两个、三个、四个或五个R B1取代;或者,两个独立的R B与相连原子一起形成每个R B1分别独立选自氢、-C 1~6烷基、-C 2~6烯基、-C 2~6炔基、卤素取代的-C 1~6烷基、卤素取代的-C 2~6烯基、卤素取代的-C 2~6炔基;R 6、R 7、R 8、R 9分别独立选自氢、卤素、氰基、-C 1~6烷基、-C 2~6烯基、-C 2~6炔基、卤素取代的-C 1~6烷基、卤素取代的-C 2~6烯基、卤素取代的-C 2~6炔基、-C 0~4亚烷基-OH、-C 0~4亚烷基-O(C 1~6烷基)、-C 0~4亚烷基-NH 2、-C 0~4亚烷基-NH(C 1~6烷基)、-C 0~4亚烷基-N(C 1~6烷基)(C 1~6 烷基);或者,R 6、R 7与相连原子一起形成3~8元碳环基、4~8元杂环烷基;或者,R 8、R 9与相连原子一起形成3~8元碳环基、4~8元杂环烷基;Y 5、Y 6分别独立选自化学键、-C 0~4亚烷基-O-、-C 0~4亚烷基-S-、-C 0~4亚烷基-NR Y51-、CR Y51R Y51;每个R Y51分别独立选自氢、-C 1~6烷基、-C 2~6烯基、-C 2~6炔基、卤素取代的-C 1~6烷基、卤素取代的-C 2~6烯基、卤素取代的-C 2~6炔基、-C 0~4亚烷基-OH、-C 0~4亚烷基-O(C 1~6烷基)、-C 0~4亚烷基-NH 2、-C 0~4亚烷基-NH(C 1~6烷基)、-C 0~4亚烷基-N(C 1~6烷基)(C 1~6烷基);Y 7选自O、S或NR Y71;R Y71选自氢、-C 1~6烷基、-C 2~6烯基、-C 2~6炔基、卤素取代的-C 1~6烷基、卤素取代的-C 2~6烯基、卤素取代的-C 2~6炔基、-C 0~4亚烷基-OH、-C 0~4亚烷基-O(C 1~6烷基)、-C 0~4亚烷基-NH 2、-C 0~4亚烷基-NH(C 1~6烷基)、-C 0~4亚烷基-N(C 1~6烷基)(C 1~6烷基);R 10选自氢、卤素、氰基、-C 1~6烷基、-C 2~6烯基、-C 2~6炔基、卤素取代的-C 1~6烷基、卤素取代的-C 2~6烯基、卤素取代的-C 2~6炔基、-C 0~4亚烷基-OH、-C 0~4亚烷基-O(C 1~6烷基)、-C 0~4亚烷基-NH 2、-C 0~4亚烷基-NH(C 1~6烷基)、-C 0~4亚烷基-N(C 1~6烷基)(C 1~6烷基)。
- 根据权利要求1所述的化合物,其特征在于:R 1选自氢、卤素、氰基、-C 1~6烷基、卤素取代的-C 1~6烷基、-OR 11、-NR 12R 12;R 11选自-C 1~6烷基、-C 2~6烯基、-C 2~6炔基、卤素取代的-C 1~6烷基;每个R 12分别独立选自氢、-C 1~6烷基、卤素取代的-C 1~6烷基;R 10选自氢、卤素、氰基、-C 1~6烷基、卤素取代的-C 1~6烷基、-OH、-O(C 1~6烷基)、-NH 2、-NH(C 1~6烷基)、-N(C 1~6烷基)(C 1~6烷基)。
- 根据权利要求2所述的化合物,其特征在于:R 1选自氢、卤素、氰基、-C 1~6烷基、三氟甲基、-O(C 1~6烷基)、-O(C 2~6烯基)、-O(三氟甲基)、-NH 2、-NH(C 1~6烷基)、-N(C 1~6烷基)(C 1~6烷基);R 10选自氢、卤素、-C 1~6烷基、-O(C 1~6烷基)。
- 根据权利要求4所述的化合物,其特征在于:R 21、R 22分别独立选自氢、卤素、氰基、-C 1~6烷基、卤素取代的-C 1~6烷基、-OR 24;每个R 24分别独立选自氢、-C 1~6烷基;或者,R 21、R 22与相连原子一起形成羰基、3元碳环基、4元碳环基、5元碳环基、6元碳环基、4元杂环烷基、5元杂环烷基、6元杂环烷基;所述杂环烷基中的杂原子选自N、O、S;R 23选自氢、卤素、氰基、-C 1~6烷基、卤素取代的-C 1~6烷基、-S(O) 2R 25、-S(O)R 25、-S(O)(NH)R 25、-S(NH) 2R 25;每个R 25分别独立选自氢、-C 1~6烷基。
- 根据权利要求1所述的化合物,其特征在于:Y 1、Y 2、Y 3、Y 4分别独立选自N或CR Y;每个R Y分别独立选自氢、卤素、氰基、-C 1~6烷基、卤素取代的-C 1~6烷基、-C 0~4亚烷基-OH、-C 0~4亚烷基-O(C 1~6烷基)、-C 0~4亚烷基-NH 2、-C 0~4亚烷基-NH(C 1~6烷基)、-C 0~4亚烷基-N(C 1~6烷基)(C 1~6烷基);B环选自3~8元单碳环基、4~8元单杂环烷基、5~10元桥碳环基、5~10元桥杂环烷基、5~10元螺碳环基、5~10元螺杂环烷基、8~12元稠碳环基、8~12元稠杂环烷基;所述单碳环基、单杂环烷基、桥碳环基、桥杂环烷基、螺碳环基、螺杂环烷基、稠碳环基、稠杂环烷基可进一步被一个、两个、三个、四个或五个R B取代;每个R B分别独立选自氢、卤素、氰基、-C 1~6烷基、卤素取代的-C 1~6烷基、-OR B1、-SR B1、-S(O) 2R B1、-S(O)R B1、-C(O)R B1、-C(O)OR B1、-NR B1R B1、3~12元碳环基、4~12元杂环烷基; 所述碳环基、杂环烷基可进一步被一个、两个、三个、四个或五个R B1取代;或者,两个独立的R B与相连原子一起形成每个R B1分别独立选自氢、-C 1~6烷基、卤素取代的-C 1~6烷基;Y 5选自O、S、NR Y51、CR Y51R Y51;每个R Y51分别独立选自氢、-C 1~6烷基。
- 根据权利要求1所述的化合物,其特征在于:Y 1、Y 2、Y 3、Y 4分别独立选自N或CR Y;每个R Y分别独立选自氢、卤素、氰基、-C 1~6烷基、卤素取代的-C 1~6烷基、-C 0~4亚烷基-OH、-C 0~4亚烷基-O(C 1~6烷基)、-C 0~4亚烷基-NH 2、-C 0~4亚烷基-NH(C 1~6烷基)、-C 0~4亚烷基-N(C 1~6烷基)(C 1~6烷基);R 6、R 7、R 8、R 9分别独立选自氢、-C 1~6烷基;或者,R 6、R 7与相连原子一起形成3元碳环基、4元碳环基、5元碳环基、6元碳环基、4元杂环烷基、5元杂环烷基、6元杂环烷基;或者,R 8、R 9与相连原子一起形成3元碳环基、4元碳环基、5元碳环基、6元碳环基、4元杂环烷基、5元杂环烷基、6元杂环烷基;R B选自氢、-C 1~6烷基、卤素取代的-C 1~6烷基、-S(O) 2R B1、-S(O)R B1、-C(O)R B1、-C(O)OR B1;每个R B1分别独立选自氢、-C 1~6烷基、卤素取代的-C 1~6烷基。
- 根据权利要求1所述的化合物,其特征在于:Y 1、Y 2、Y 4分别独立选自N或CR Y;每个R Y分别独立选自氢、卤素、氰基、-C 1~6烷基、卤素取代的-C 1~6烷基、-C 0~4亚烷基-OH、-C 0~4亚烷基-O(C 1~6烷基)、-C 0~4亚烷基-NH 2、-C 0~4亚烷基-NH(C 1~6烷基)、-C 0~4亚烷基-N(C 1~6烷基)(C 1~6烷基);R B选自氢、-C 1~6烷基、卤素取代的-C 1~6烷基、-S(O) 2R B1、-S(O)R B1、-C(O)R B1、-C(O)OR B1;每个R B1分别独立选自氢、-C 1~6烷基、卤素取代的-C 1~6烷基;Y 5选自化学键、O、S、NR Y51、CR Y51R Y51;每个R Y51分别独立选自氢、-C 1~6烷基。
- 根据权利要求1所述的化合物,其特征在于:Y 1、Y 2、Y 4分别独立选自N或CR Y;每个R Y分别独立选自氢、卤素、氰基、-C 1~6烷基、卤素取代的-C 1~6烷基、-C 0~4亚烷基-OH、-C 0~4亚烷基-O(C 1~6烷基)、-C 0~4亚烷基-NH 2、-C 0~4亚烷基-NH(C 1~6烷基)、-C 0~4亚烷基-N(C 1~6烷基)(C 1~6烷基);R B选自氢、-C 1~6烷基、卤素取代的-C 1~6烷基、-S(O) 2R B1、-S(O)R B1、-C(O)R B1、-C(O)OR B1;每个R B1分别独立选自氢、-C 1~6烷基、卤素取代的-C 1~6烷基;Y 5、Y 6分别独立选自化学键、-C 0~1亚烷基-O-、-C 0~1亚烷基-S-、-C 0~1亚烷基-NR Y51-、CR Y51R Y51;每个R Y51分别独立选自氢、-C 1~6烷基。
- 根据权利要求1所述的化合物,其特征在于:Y 1选自N或CR Y;R Y选自氢、卤素、氰基、-C 1~6烷基、卤素取代的-C 1~6烷基、-C 0~4亚烷基-OH、-C 0~4亚烷基-O(C 1~6烷基)、-C 0~4亚烷基-NH 2、-C 0~4亚烷基-NH(C 1~6烷基)、-C 0~4亚烷基-N(C 1~6烷基)(C 1~6烷基);B环选自3~8元单碳环基、4~8元单杂环烷基;所述单碳环基、单杂环烷基可进一步被一个、两个、三个、四个或五个R B取代;每个R B分别独立选自氢、卤素、氰基、-C 1~6烷基、卤素取代的-C 1~6烷基、-OR B1、-SR B1、-S(O) 2R B1、-S(O)R B1、-C(O)R B1、-C(O)OR B1、-NR B1R B1;或者,两个独立的R B与相连原子一起形成每个R B1分别独立选自氢、-C 1~6烷基、卤素取代的-C 1~6烷基;Y 7选自O、S或NR Y71;R Y71选自氢、-C 1~6烷基、卤素取代的-C 1~6烷基、-C 1~4亚烷基-OH、-C 1~4亚烷基-O(C 1~6烷基)、-C 1~4亚烷基-NH 2、-C 1~4亚烷基-NH(C 1~6烷基)、-C 1~4亚烷基-N(C 1~6烷基)(C 1~6烷基)。
- 权利要求1~23任一所述的化合物、或其氘代化合物、或其立体异构体、或其药学上可接受的盐在制备Wee1抑制剂药物中的用途。
- 权利要求1~23任一所述的化合物、或其氘代化合物、或其立体异构体、或其药学上可接受的盐在制备预防和/或治疗癌症中的用途。
- 一种药物组合物,包括权利要求1~23任一所述的化合物、或其氘代化合物、或其立体异构体、或其药学上可接受的盐制备而成的制剂。
- 根据权利要求26所述的药物组合物,其进一步包括药学上可接受的载体、辅料、媒介物。
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