WO2022033455A1 - 具有egfr抑制活性的三嗪衍生物及其制备方法和应用 - Google Patents
具有egfr抑制活性的三嗪衍生物及其制备方法和应用 Download PDFInfo
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- WO2022033455A1 WO2022033455A1 PCT/CN2021/111694 CN2021111694W WO2022033455A1 WO 2022033455 A1 WO2022033455 A1 WO 2022033455A1 CN 2021111694 W CN2021111694 W CN 2021111694W WO 2022033455 A1 WO2022033455 A1 WO 2022033455A1
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- Prior art keywords
- alkyl
- deuterium
- membered
- substituted
- halogen
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- 238000002360 preparation method Methods 0.000 title claims abstract description 53
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- YOHYSYJDKVYCJI-UHFFFAOYSA-N n-[3-[[6-[3-(trifluoromethyl)anilino]pyrimidin-4-yl]amino]phenyl]cyclopropanecarboxamide Chemical compound FC(F)(F)C1=CC=CC(NC=2N=CN=C(NC=3C=C(NC(=O)C4CC4)C=CC=3)C=2)=C1 YOHYSYJDKVYCJI-UHFFFAOYSA-N 0.000 claims abstract 5
- 125000000217 alkyl group Chemical group 0.000 claims description 350
- 229910052805 deuterium Inorganic materials 0.000 claims description 239
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims description 237
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- 125000000623 heterocyclic group Chemical group 0.000 claims description 173
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- 239000001257 hydrogen Substances 0.000 claims description 104
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- -1 C 6- 10 -aryl Chemical group 0.000 claims description 94
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- 125000001424 substituent group Chemical group 0.000 claims description 66
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- 125000005844 heterocyclyloxy group Chemical group 0.000 claims description 51
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- 125000004432 carbon atom Chemical group C* 0.000 claims description 26
- 229910052799 carbon Inorganic materials 0.000 claims description 24
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 22
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 21
- 239000000460 chlorine Substances 0.000 claims description 18
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 17
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 17
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- 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 16
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- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 12
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- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 11
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- 238000011282 treatment Methods 0.000 claims description 9
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
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- 201000010151 inverted papilloma Diseases 0.000 claims description 7
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 7
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 7
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 6
- 210000000481 breast Anatomy 0.000 claims description 6
- 125000006263 dimethyl aminosulfonyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])S(*)(=O)=O 0.000 claims description 6
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 6
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 6
- 229910052717 sulfur Inorganic materials 0.000 claims description 6
- 208000002699 Digestive System Neoplasms Diseases 0.000 claims description 5
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- 208000009849 Female Genital Neoplasms Diseases 0.000 claims description 5
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- 150000001336 alkenes Chemical class 0.000 claims description 5
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
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- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 4
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- 208000002495 Uterine Neoplasms Diseases 0.000 claims description 4
- 201000011510 cancer Diseases 0.000 claims description 4
- 208000029742 colonic neoplasm Diseases 0.000 claims description 4
- 206010017758 gastric cancer Diseases 0.000 claims description 4
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 4
- 208000025426 neoplasm of thorax Diseases 0.000 claims description 4
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- 206010046766 uterine cancer Diseases 0.000 claims description 4
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims description 3
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims description 3
- 206010041823 squamous cell carcinoma Diseases 0.000 claims description 3
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 3
- 229920002554 vinyl polymer Polymers 0.000 claims description 3
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 2
- 125000002373 5 membered heterocyclic group Chemical group 0.000 claims description 2
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 150000003254 radicals Chemical class 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 3
- 230000000069 prophylactic effect Effects 0.000 claims 2
- 230000001225 therapeutic effect Effects 0.000 claims 2
- 150000001335 aliphatic alkanes Chemical class 0.000 claims 1
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- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 34
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- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- YKIOKAURTKXMSB-UHFFFAOYSA-N adams's catalyst Chemical compound O=[Pt]=O YKIOKAURTKXMSB-UHFFFAOYSA-N 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 229920000180 alkyd Polymers 0.000 description 1
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229940008421 amivantamab Drugs 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000012300 argon atmosphere Substances 0.000 description 1
- HTZCNXWZYVXIMZ-UHFFFAOYSA-M benzyl(triethyl)azanium;chloride Chemical compound [Cl-].CC[N+](CC)(CC)CC1=CC=CC=C1 HTZCNXWZYVXIMZ-UHFFFAOYSA-M 0.000 description 1
- 229910000085 borane Inorganic materials 0.000 description 1
- ICXXXLGATNSZAV-UHFFFAOYSA-N butylazanium;chloride Chemical compound [Cl-].CCCC[NH3+] ICXXXLGATNSZAV-UHFFFAOYSA-N 0.000 description 1
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- 150000001733 carboxylic acid esters Chemical class 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 239000006143 cell culture medium Substances 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 238000012200 cell viability kit Methods 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- IAQRGUVFOMOMEM-ARJAWSKDSA-N cis-but-2-ene Chemical compound C\C=C/C IAQRGUVFOMOMEM-ARJAWSKDSA-N 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- KZZKOVLJUKWSKX-UHFFFAOYSA-N cyclobutanamine Chemical compound NC1CCC1 KZZKOVLJUKWSKX-UHFFFAOYSA-N 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000002188 cycloheptatrienyl group Chemical group C1(=CC=CC=CC1)* 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000003678 cyclohexadienyl group Chemical group C1(=CC=CCC1)* 0.000 description 1
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 description 1
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 1
- WLVKDFJTYKELLQ-UHFFFAOYSA-N cyclopropylboronic acid Chemical compound OB(O)C1CC1 WLVKDFJTYKELLQ-UHFFFAOYSA-N 0.000 description 1
- 230000002380 cytological effect Effects 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- RCJVRSBWZCNNQT-UHFFFAOYSA-N dichloridooxygen Chemical compound ClOCl RCJVRSBWZCNNQT-UHFFFAOYSA-N 0.000 description 1
- 125000003963 dichloro group Chemical group Cl* 0.000 description 1
- 125000004772 dichloromethyl group Chemical group [H]C(Cl)(Cl)* 0.000 description 1
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 231100000371 dose-limiting toxicity Toxicity 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 230000037437 driver mutation Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- PUYJJCLTRCBKFG-UHFFFAOYSA-N ethyl 2-(5-bromo-3-nitropyridin-2-yl)-2-methylpropanoate Chemical compound CCOC(C(C)(C)C(C([N+]([O-])=O)=C1)=NC=C1Br)=O PUYJJCLTRCBKFG-UHFFFAOYSA-N 0.000 description 1
- YEDHWTBDEHRYPG-UHFFFAOYSA-N ethyl 2-methyl-2-(3-nitropyridin-2-yl)propanoate Chemical compound CCOC(=O)C(C)(C)C1=NC=CC=C1[N+]([O-])=O YEDHWTBDEHRYPG-UHFFFAOYSA-N 0.000 description 1
- HZAIHFIZXXSPFA-UHFFFAOYSA-N ethynylcyclopropane Chemical compound [C+]#CC1CC1 HZAIHFIZXXSPFA-UHFFFAOYSA-N 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 108700039708 galantide Proteins 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 238000003306 harvesting Methods 0.000 description 1
- 210000003128 head Anatomy 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 239000013038 irreversible inhibitor Substances 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 150000002641 lithium Chemical class 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 238000003760 magnetic stirring Methods 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- XONPDZSGENTBNJ-UHFFFAOYSA-N molecular hydrogen;sodium Chemical compound [Na].[H][H] XONPDZSGENTBNJ-UHFFFAOYSA-N 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 230000036438 mutation frequency Effects 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
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 210000003739 neck Anatomy 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
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 230000002611 ovarian Effects 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- UXCDUFKZSUBXGM-UHFFFAOYSA-N phosphoric tribromide Chemical compound BrP(Br)(Br)=O UXCDUFKZSUBXGM-UHFFFAOYSA-N 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 229950009876 poziotinib Drugs 0.000 description 1
- 238000004237 preparative chromatography Methods 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- AZSRSNUQCUDCGG-UHFFFAOYSA-N propan-2-yl 2-[4-[2-(dimethylamino)ethyl-methylamino]-2-methoxy-5-(prop-2-enoylamino)anilino]-4-(1-methylindol-3-yl)pyrimidine-5-carboxylate Chemical compound C(C=C)(=O)NC=1C(=CC(=C(C=1)NC1=NC=C(C(=N1)C1=CN(C2=CC=CC=C12)C)C(=O)OC(C)C)OC)N(C)CCN(C)C AZSRSNUQCUDCGG-UHFFFAOYSA-N 0.000 description 1
- 239000001294 propane Substances 0.000 description 1
- RIBFXMJCUYXJDZ-UHFFFAOYSA-N propanoyl bromide Chemical compound CCC(Br)=O RIBFXMJCUYXJDZ-UHFFFAOYSA-N 0.000 description 1
- 229940080818 propionamide Drugs 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl 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
- 230000008707 rearrangement Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 102220014441 rs397517109 Human genes 0.000 description 1
- 102220055958 rs727504263 Human genes 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- MSGMXYUAWZYTFC-UHFFFAOYSA-N sodium;2,2,2-trifluoroethanolate Chemical compound [Na+].[O-]CC(F)(F)F MSGMXYUAWZYTFC-UHFFFAOYSA-N 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 150000003457 sulfones Chemical class 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 238000002626 targeted therapy Methods 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- IAQRGUVFOMOMEM-ONEGZZNKSA-N trans-but-2-ene Chemical compound C\C=C\C IAQRGUVFOMOMEM-ONEGZZNKSA-N 0.000 description 1
- 230000005945 translocation Effects 0.000 description 1
- 125000004784 trichloromethoxy group Chemical group ClC(O*)(Cl)Cl 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- 238000004235 valence bond calculation Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- GTLDTDOJJJZVBW-UHFFFAOYSA-N zinc cyanide Chemical compound [Zn+2].N#[C-].N#[C-] GTLDTDOJJJZVBW-UHFFFAOYSA-N 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
- A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
-
- 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
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/10—Spiro-condensed systems
-
- 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
Definitions
- the invention belongs to the field of drug synthesis, in particular to a triazine derivative with EGFR inhibitory activity and a preparation method and application thereof.
- Lung cancer is the leading cause of cancer death worldwide, with non-small cell lung cancer (NSCLC) accounting for 85%.
- Targets epidermal growth factor receptor (EGFR) mutation, anaplastic lymphoma kinase (ALK) translocation, ROS1 proto-oncogene receptor tyrosine kinase (ROS1) rearrangement and B-raf proto-oncogene, serine/threonine Kinase (BRAF) multi-target therapy has been successfully developed and clinically validated.
- Inhibitors targeting EGFR can significantly improve the progression-free survival of adenocarcinoma in NSCLC, and its acquired resistance mutations can be targeted by third-generation EGFR inhibitors.
- Exon 20 Although classical EGFR activating mutations (exons 19 and 21) and resistance mutations (T790M) can be inhibited by existing drugs, insertional mutations in exon 20 (Exon 20) also lead to structural EGFR signaling activated and were insensitive to existing EGFR inhibitors. Exon 20 mutations are heterogeneous and include insertions or duplications of 1-7 amino acids between amino acids 762-774 of the EGFR protein. In NSCLC, the mutation frequency of EGFR exon 20 accounts for 4-10% of all mutations in EGFR. These mutations were mutually exclusive with other known oncogene driver mutations and were enriched in adenocarcinomas in women, non-smokers, Asian populations, and patients with non-small cell lung cancer.
- EGFR exon 20 insertion mutations are also seen in a rare type of head and neck cancer, nasal squamous cell carcinoma (SNSCC).
- SNSCC nasal squamous cell carcinoma
- a structurally similar exon 20 insertion mutation was also found in HER2, another member of the EGFR family.
- the purpose of the present invention is to provide a triazine derivative with EGFR inhibitory activity, a preparation method and application thereof, the series of compounds of the present invention have a strong inhibitory effect on EGFR exon 20 insertion, deletion or other mutant cytological activity, It has high selectivity for EGFR wild type, and can be widely used in the preparation of drugs for the treatment and/or prevention of cancer, tumor or metastatic disease at least partially related to EGFR exon 20 insertion, deletion or other mutations, especially overtreatment Drugs for proliferative diseases and cell death-inducing disorders are expected to lead to the development of next-generation EGFR inhibitors.
- a first aspect of the present invention provides a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:
- X is CH or N;
- Y is a bond, O or S;
- Z 1 and Z 2 are each independently CR 10 or N;
- R 1 is selected from hydrogen, deuterium, hydroxyl, C 1-6 alkyl, halogen-substituted C 1-6 alkyl, deuterium-substituted C 1-6 alkyl, C 2-4 alkenyl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl;
- R 2 and R 3 are each independently selected from hydrogen, deuterium, hydroxyl, C 1-6 alkyl, C 2-4 alkenyl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl, the above groups independently optionally further substituted with one or more C 1-10 alkyl groups selected from deuterium, halogen, hydroxy, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halogen substituted C 1-10 alkyl, Deuterium-substituted C 1-10 alkyl, C 1-10 alkoxy, C 3-12 cycloalkyl, C 3-12 cycloalkoxy, 3-12-membered heterocyclyl, 3-12-membered heterocyclyloxy , C 6-10 aryl, C 6-10 aryloxy, 5-10-membered heteroaryl, 5-10-membered heteroaryloxy and substituents of -C 0-8 alkyl-NR 14 R 15 ;
- R 2 , R 4 or R 5 and the moiety to which R 1 is directly attached together form a 4-8 membered heterocyclyl
- the other two of R 2 , R 4 or R 5 are as previously defined, or
- R One of 4 or R 5 and R 2 together with the moiety to which R 2 is directly attached form a 4-8 membered heterocyclyl group
- the other of R 4 or R 5 is as defined above
- R 6 is selected from hydrogen, deuterium, C 1-10 alkyl, C 2-10 alkenyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl and 5-10 membered Heteroaryl, the above-mentioned groups are independently optionally further selected from one or more groups selected from deuterium, halogen, hydroxy, oxo, cyano, C 1-10 alkyl, C 1-10 alkoxy, C 3-12 Cycloalkyl, C 3-12 cycloalkoxy, 3-12-membered heterocyclyl, 3-12-membered heterocyclyloxy, C 6-10 aryl, C 6-10 aryloxy, 5-10-membered heterocycle Aryl, 5-10-membered heteroaryloxy and substituents of -NR 14 R 15 ;
- R 7 is selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered Heterocyclyl, -C(O)OR 12 , -C(O)R 13 , -C(O)-NR 14 R 15 and -C 0-4 alkyl-NR 14 R 15 ;
- R 8 and R 9 are each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C6-10 membered aryl and 5-10 membered heteroaryl, alternatively, R8 and R9 together with the carbon atom to which they are directly attached form a C3-6 ring Alkyl or 3-6 membered heterocyclic group, the above-mentioned groups are independently optionally further selected from one or more groups selected from deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2- 10 alkenyl, C 2-10 alkynyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6- 10 -aryl, 5-10-
- Each R 11 is independently selected from hydrogen, deuterium, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 Aryl, 5-10 membered heteroaryl and -NR 14 R 15 , the above-mentioned groups independently optionally further selected by one or more groups selected from deuterium, halogen, hydroxyl, oxo, C 1-10 alkyl, C 1 -10 alkoxy, C 3-12 cycloalkyl, C 3-12 cycloalkoxy, 3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy, C 6-10 aryl, C 6- 10 -aryloxy, 5-10-membered heteroaryl, 5-10-membered heteroaryloxy and substituents of -NR 14 R 15 ;
- Each R 12 is independently selected from hydrogen, deuterium, C 1-10 alkyl, C 2-10 alkenyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl and 5-10-membered heteroaryl groups, the above-mentioned groups are independently optionally further selected from one or more groups selected from deuterium, halogen, hydroxyl, oxo, cyano, C 1-10 alkyl, C 1-10 alkoxy , C 3-12 cycloalkyl, C 3-12 cycloalkoxy, 3-12-membered heterocyclyl, 3-12-membered heterocyclyloxy, C 6-10 aryl, C 6-10 aryloxy, 5-10-membered heteroaryl, 5-10-membered heteroaryloxy and -NR 14 R 15 substituents;
- Each R 13 is independently selected from hydrogen, deuterium, hydroxyl, C 1-10 alkyl, C 1-10 alkoxy, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 Cycloalkyl, C 3-12 cycloalkoxy, 3-12-membered heterocyclyl, 3-12-membered heterocyclyloxy, C 6-10 aryl, C 6-10 aryloxy, 5-10-membered heterocycle Aryl, 5-10-membered heteroaryloxy and -NR 14 R 15 , the above-mentioned groups are independently optionally further selected by one or more groups selected from deuterium, halogen, hydroxyl, cyano, C 1-10 alkyl, C 1-10 alkoxy, C 3-12 cycloalkyl, C 3-12 cycloalkoxy, 3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy, C 6-10 aryl, C 6 -10 -aryloxy, 5-10-membered heteroaryl,
- R 14 and R 15 is independently selected from hydrogen, deuterium, hydroxy, C 1-10 alkoxy, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 -membered cycloalkyl, 3-12-membered heterocyclyl, C 6-10 -membered aryl, 5-10-membered heteroaryl, sulfinyl, sulfonyl, methanesulfonyl, isopropylsulfonyl, cyclopropylsulfonyl Acyl, p-toluenesulfonyl, aminosulfonyl, dimethylaminosulfonyl, amino, mono-C 1-10 alkylamino, di-C 1-10 alkylamino and C 1-10 alkanoyl, the above groups are independently any is further selected by one or more selected from deuterium, halogen, hydroxyl, C 1-10 alkyl, C 2-10
- R 14 and R 15 are taken together with the nitrogen atom to which they are directly attached to form a 4-10 membered heterocyclic group or a 5-10 membered heteroaryl group independently optionally further substituted by one or more selected from the group consisting of deuterium, halogen, Hydroxy, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 1-10 alkoxy , C 3-12 cycloalkyl, C 3-12 cycloalkoxy, 3-12-membered heterocyclyl, 3-12-membered heterocyclyloxy, C 6-10 aryl, C 6-10 aryloxy, Substituted by substituents of 5-10-membered heteroaryl, 5-10-membered heteroaryloxy, amino, mono-C 1-10 alkylamino, di-C 1-10 alkylamino and C 1-10 alkanoyl;
- n 0, 1 or 2;
- n 0, 1, or 2;
- Each r is independently 0, 1, or 2.
- R 6 is selected from hydrogen, deuterium, C 1-4 alkyl, C 2-4 alkenyl , C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-8 membered aryl and 5-8 membered heteroaryl, the above-mentioned groups are independently optionally further selected from one or more groups selected from deuterium, halogen , hydroxyl, oxo, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkoxy, 3-8 membered heterocyclyl, 3 -8-membered heterocyclyloxy, C 6-8 aryl, C 6-8 aryloxy, 5-8-membered heteroaryl, 5-8-membered heteroaryloxy and substituents of -NR 14 R 15 ;
- R 7 is selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 3-8 cycloalkyl, 3-8 membered Heterocyclyl and -C 0-4 alkyl-NR 14 R 15 ;
- R 14 and R 15 are as defined in the compound of formula (I).
- R 8 and R 9 are each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-8 aryl and 5-8 membered heteroaryl, alternatively, R8 and R9 are taken together with the carbon atom to which they are directly attached to form a C3-6 cycloalkyl or 3-6 membered heterocyclyl, independently optionally further substituted by one or Multiple selected from deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogen-substituted C 1-4 alkyl, Deuterium substituted C 1-4 alkyl, C 3-8 cycloalkyl,
- R 11 , R 12 , R 13 , R 14 , R 15 and r are as defined in the compound of formula (I).
- each R 10 is independently selected from hydrogen, deuterium, halogen, cyano, nitro, azide Nitrogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5 -8-membered heteroaryl, -SF 5 , -S(O) r R 11 , -OR 12 , -C(O)OR 12 , -C(O)R 13 , -OC(O)R 13 , -NR 14 R 15 , -C(O)NR 14 R 15 and -N(R 14 )-C(O)R 13 , or, two adjacent R 10s together with their directly connected moieties form C 4-8 cycloalkane group or 4-8 membered heterocyclic group, the above-mentioned groups are independently optional
- R 11 , R 12 , R 13 , R 14 , R 15 and r are as defined in the compound of formula (I).
- R 1 is selected from hydrogen, deuterium, hydroxyl, C 1-4 alkyl, halogen substituted C 1- 4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkenyl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl;
- R 2 and R 3 are each independently selected from hydrogen, deuterium and C 1-4 alkyl, and the above-mentioned groups are independently optionally further selected from one or more of deuterium, halogen, hydroxyl, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 1-4 alkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkoxy, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, C 6-8 aryl, C 6-8 aryloxy, 5-8 membered heteroaryl, 5- 8-membered heteroaryloxy and -C 0-4 alkyl-NR 14 R 15 substituents;
- R 4 and R 5 are each independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkene base, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, -OR 12 , -C(O) OR 12 , -C(O)R 13 , -OC(O)R 13 , -NR 14 R 15 , -C(O)NR 14 R 15 and -N(R 14 )-C(O)R 13 ;
- R 2 , R 4 or R 5 and the moiety to which R 1 is directly attached together form the following structure:
- R 2 , R 4 or R 5 wherein the other two are as previously defined, and R 3 as previously defined;
- R 4 or R 5 is as previously defined, and R 1 or R 3 is as previously defined;
- R 12 , R 13 , R 14 and R 15 are as defined in the compound of formula (I).
- the compound of formula (I) is the following compound of formula (IIa):
- X is CH or N
- Z 2 is CH or N
- R 2 , R 4 or R 5 and the moiety to which R 1 is directly attached together form the following structure:
- Each R 2 and R 3 is independently selected from hydrogen, deuterium and C 1-4 alkyl, independently optionally further selected by one or more groups selected from deuterium, halogen, hydroxyl, C 1-4 alkyl , C 2-4 alkenyl, C 2-4 alkynyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl and -C 0-4 alkyl-NR 14 R 15 substituent replaced;
- Each R 1 is each independently selected from hydrogen, deuterium, C 1-4 alkyl, halo-substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, and C 2-4 alkenyl;
- Each R3 is independently selected from hydrogen, deuterium and C1-4 alkyl, independently optionally further selected by one or more groups selected from deuterium, halogen, hydroxyl, C1-4 alkyl, C2 -4 alkenyl, C 2-4 alkynyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl and -C 0-4 alkyl -NR 14 R 15 substituents;
- R 6 is selected from hydrogen, deuterium, C 1-4 alkyl, halo-substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkenyl, C 3-8 cycloalkyl and 3 -8-membered heterocyclyl;
- R 8 and R 9 are each independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-8 aryl and 5-8 membered heteroaryl, alternatively, R8 and R9 together with the carbon atom to which they are directly attached form C3-6 cycloalkyl or 3-6 membered Heterocyclyl, the above-mentioned groups are independently optionally further selected from one or more groups selected from deuterium, halogen, cyano, hydroxyl, C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkenyl , C 2-4 alkynyl, halogen substituted C 1-4 alkyl, halogen substituted C 1-4 alkoxy, deuterium substituted C 1-4 alkyl, deuterium substituted C 1-4 alkoxy, C 3- Substituted by substituents
- Each R 10 is independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3 -6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, -SF 5 , -S(O) r R 11 , -OR 12 , -C(O ) OR 12 , -C(O)R 13 , -OC(O)R 13 , -NR 14 R 15 , -C(O)NR 14 R 15 and -N(R 14 )-C(O)R 13 ,
- the adjacent two R 10 together with their directly connected moieties form a C 4-6 cycloalkyl or 4-6 membered heterocyclic group, which are independently optionally further selected from one or more groups selected from deuterium, halogen , cyano, nitro, azido, C
- Each R 11 is independently selected from hydrogen, deuterium, hydroxyl, C 1-4 alkyl, C 2-4 alkenyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-8 Aryl, 5-8 membered heteroaryl, and -NR 14 R 15 , the above-mentioned groups independently optionally further selected by one or more groups selected from deuterium, halogen, hydroxy, oxo, C 1-4 alkyl, C 1 -4 alkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkoxy, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, C 6-8 aryl, C 6- 8 -aryloxy, 5-8-membered heteroaryl, 5-8-membered heteroaryloxy and substituents of -NR 14 R 15 ;
- Each R 12 is independently selected from hydrogen, deuterium, C 1-4 alkyl, C 2-4 alkenyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-8 aryl and 5-8 membered heteroaryl groups, the above-mentioned groups are independently optionally further selected from one or more groups selected from deuterium, halogen, hydroxyl, oxo, cyano, C 1-4 alkyl, C 1-4 alkoxy , C 3-8 cycloalkyl, C 3-8 cycloalkoxy, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, C 6-8 aryl, C 6-8 aryloxy, 5-8-membered heteroaryl, 5-8-membered heteroaryloxy and substituents of -NR 14 R 15 ;
- Each R 13 is independently selected from hydrogen, deuterium, hydroxyl, C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 Cycloalkyl, C 3-8 cycloalkoxy, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, C 6-8 aryl, C 6-8 aryloxy, 5-8 membered heterocycle Aryl, 5-8 membered heteroaryloxy and -NR 14 R 15 , the above-mentioned groups are independently optionally further selected from one or more groups selected from deuterium, halogen, hydroxyl, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkoxy, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, C 6-8 aryl, C 6 -8 -aryloxy, 5-8-membered heteroaryl, 5-8-member
- R 14 and R 15 is independently selected from hydrogen, deuterium, hydroxy, C 1-4 alkoxy, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, sulfinyl, sulfonyl, methanesulfonyl, isopropylsulfonyl, cyclopropylsulfonyl Acyl, p-toluenesulfonyl, aminosulfonyl, dimethylaminosulfonyl, amino, mono-C 1-4 alkylamino, di-C 1-4 alkylamino and C 1-4 alkanoyl, the above groups are independently any is further selected from the group consisting of one or more deuterium, halogen, hydroxyl, C 1-4 alkyl, C 2-4 alkenyl, C 2-4
- R 14 and R 15 are taken together with the nitrogen atom to which they are directly attached to form a 4-8 membered heterocyclic group or a 5-8 membered heteroaryl group independently optionally further substituted by one or more selected from the group consisting of deuterium, halogen, Hydroxy, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 1-4 alkoxy , C 3-8 cycloalkyl, C 3-8 cycloalkoxy, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, C 6-8 aryl, C 6-8 aryloxy, Substituted by substituents of 5-8-membered heteroaryl, 5-8-membered heteroaryloxy, amino, mono-C 1-4 alkylamino, di-C 1-4 alkylamino and C 1-4 alkanoyl;
- n 0, 1 or 2;
- n 0, 1, or 2;
- Each r is independently 0, 1, or 2.
- the compound of formula (I) is the compound of the following formula (IIIa):
- X is CH or N
- Z 2 is CH or N
- R 2 , R 4 or R 5 and the moiety to which R 1 is directly attached together form the following structure:
- R and R together with their directly attached moieties form the following structure:
- R 6 is selected from hydrogen, deuterium, C 1-2 alkyl, halogen substituted C 1-2 alkyl and deuterium substituted C 1-2 alkyl;
- R8 and R9 are each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, cyclopropyl, -CHF2, -CF3 , -CHD2 and - CD3 ;
- R 10a and R 10b are each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, cyclopropyl, -CHF2, -CF3 , -CHD 2 , -CD 3 , methoxy, azetidinyl, vinyl, ethynyl and phenyl, alternatively, R 10a and R 10b together with their directly attached moieties form C 4-6 cycloalkyl or 4-6 membered heterocyclic group.
- the compound of formula (I) is the compound of the following formula (IIb):
- X is CH or N;
- Y is a bond, O or S;
- Z 1 is CR 10 or N;
- Z 2 is CH or N;
- R 1 is selected from hydrogen, deuterium, C 1-4 alkyl, halo-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl and C 2-4 alkenyl;
- R 2 and R 3 are each independently selected from hydrogen, deuterium and C 1-4 alkyl, and the above-mentioned groups are independently optionally further selected from one or more of deuterium, halogen, hydroxyl, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl and -C 0-4 alkyl-NR 14 R 15 substituents ;
- R 4 is selected from hydrogen, deuterium, halogen, C 1-4 alkyl, halogen substituted C 1-4 alkyl and deuterium substituted C 1-4 alkyl;
- R 5 is selected from hydrogen, deuterium, halogen, C 1-4 alkyl, halogen substituted C 1-4 alkyl and deuterium substituted C 1-4 alkyl;
- R 6 is selected from hydrogen, deuterium, C 1-4 alkyl, halo-substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkenyl, C 3-8 cycloalkyl and 3 -8-membered heterocyclyl;
- R 8 and R 9 are each independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-8 aryl and 5-8 membered heteroaryl, alternatively, R8 and R9 together with the carbon atom to which they are directly attached form C3-6 cycloalkyl or 3-6 membered Heterocyclyl, the above-mentioned groups are independently optionally further selected from one or more groups selected from deuterium, halogen, cyano, hydroxyl, C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkenyl , C 2-4 alkynyl, halogen substituted C 1-4 alkyl, halogen substituted C 1-4 alkoxy, deuterium substituted C 1-4 alkyl, deuterium substituted C 1-4 alkoxy, C 3- Substituted by substituents
- Each R 10 is independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3 -6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, -SF 5 , -S(O) r R 11 , -OR 12 , -C(O ) OR 12 , -C(O)R 13 , -OC(O)R 13 , -NR 14 R 15 , -C(O)NR 14 R 15 and -N(R 14 )-C(O)R 13 ,
- the adjacent two R 10 together with their directly connected moieties form a C 4-6 cycloalkyl or 4-6 membered heterocyclic group, which are independently optionally further selected from one or more groups selected from deuterium, halogen , cyano, nitro, azido, C
- Each R 11 is independently selected from hydrogen, deuterium, hydroxyl, C 1-4 alkyl, C 2-4 alkenyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-8 Aryl, 5-8 membered heteroaryl, and -NR 14 R 15 , the above-mentioned groups independently optionally further selected by one or more groups selected from deuterium, halogen, hydroxy, oxo, C 1-4 alkyl, C 1 -4 alkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkoxy, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, C 6-8 aryl, C 6- 8 -aryloxy, 5-8-membered heteroaryl, 5-8-membered heteroaryloxy and substituents of -NR 14 R 15 ;
- Each R 12 is independently selected from hydrogen, deuterium, C 1-4 alkyl, C 2-4 alkenyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-8 aryl and 5-8 membered heteroaryl groups, the above-mentioned groups are independently optionally further selected from one or more groups selected from deuterium, halogen, hydroxyl, oxo, cyano, C 1-4 alkyl, C 1-4 alkoxy , C 3-8 cycloalkyl, C 3-8 cycloalkoxy, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, C 6-8 aryl, C 6-8 aryloxy, 5-8-membered heteroaryl, 5-8-membered heteroaryloxy and substituents of -NR 14 R 15 ;
- Each R 13 is independently selected from hydrogen, deuterium, hydroxyl, C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 Cycloalkyl, C 3-8 cycloalkoxy, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, C 6-8 aryl, C 6-8 aryloxy, 5-8 membered heterocycle Aryl, 5-8 membered heteroaryloxy and -NR 14 R 15 , the above-mentioned groups are independently optionally further selected from one or more groups selected from deuterium, halogen, hydroxyl, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkoxy, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, C 6-8 aryl, C 6 -8 -aryloxy, 5-8-membered heteroaryl, 5-8-member
- R 14 and R 15 is independently selected from hydrogen, deuterium, hydroxy, C 1-4 alkoxy, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, sulfinyl, sulfonyl, methanesulfonyl, isopropylsulfonyl, cyclopropylsulfonyl Acyl, p-toluenesulfonyl, aminosulfonyl, dimethylaminosulfonyl, amino, mono-C 1-4 alkylamino, di-C 1-4 alkylamino and C 1-4 alkanoyl, the above groups are independently any is further selected from the group consisting of one or more deuterium, halogen, hydroxyl, C 1-4 alkyl, C 2-4 alkenyl, C 2-4
- R 14 and R 15 are taken together with the nitrogen atom to which they are directly attached to form a 4-8 membered heterocyclic group or a 5-8 membered heteroaryl group independently optionally further substituted by one or more selected from the group consisting of deuterium, halogen, Hydroxy, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 1-4 alkoxy , C 3-8 cycloalkyl, C 3-8 cycloalkoxy, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, C 6-8 aryl, C 6-8 aryloxy, Substituted by substituents of 5-8-membered heteroaryl, 5-8-membered heteroaryloxy, amino, mono-C 1-4 alkylamino, di-C 1-4 alkylamino and C 1-4 alkanoyl;
- n 0, 1 or 2;
- n 0, 1, or 2;
- Each r is independently 0, 1, or 2.
- the compound of formula (I) is the following compound of formula (IIIb):
- X is CH or N;
- Y is a bond, O or S;
- Z 1 is CR 10 or N;
- Z 2 is CH or N;
- R 6 is selected from hydrogen, deuterium, C 1-4 alkyl, halogen substituted C 1-2 alkyl and deuterium substituted C 1-2 alkyl;
- R8 and R9 are each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, cyclopropyl, -CHF2, -CF3 , -CHD2 and - CD3 ;
- R 10 and R 10a are each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethynyl, azacycle Butyl, pyrazole and phenyl, alternatively, R 10 and R 10a together with their directly attached moieties form a cyclopentyl or 5-membered heterocyclic group independently optionally further selected by one or more groups selected from deuterium, substituted by substituents of fluorine, chlorine, bromine, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogen substituted C 1-4 alkyl and cyclopropyl,
- the condition is that when X is CH, Y is a bond, and n is 1, one of R 10 and R 10a is hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl,
- n 0, 1 or 2.
- the compounds of formula (I), their stereoisomers or their pharmaceutically acceptable salts include but are not limited to the following compounds:
- the second aspect of the present invention provides a preparation method of the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt, comprising the following steps:
- R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , X, Y, Z 1 , Z 2 , m and n are as in formula (I) Compounds are defined in.
- a third aspect of the present invention provides a pharmaceutical composition
- a pharmaceutical composition comprising a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
- the present invention also relates to the compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof in the preparation of the treatment and/or prevention of cancers, tumors at least partially associated with EGFR exon 20 insertions, deletions or other mutations or the use of drugs in metastatic disease.
- the present invention also relates to a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the prevention and/or treatment of tumors, cancers and/or metastatic diseases caused by hyperproliferative and cell death-inducing disorders use in.
- the present invention also relates to the aforementioned compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt in the preparation of prevention and/or treatment of lung cancer, colon cancer, pancreatic cancer, head and neck cancer, breast cancer, ovarian cancer, uterine cancer, Gastric cancer, non-small cell lung cancer, leukemia, myelodysplastic syndrome, malignant lymphoma, head and neck tumors, thoracic tumors, gastrointestinal tumors, endocrine tumors, breast and other gynecological tumors, urological tumors, skin tumors, sarcomas, Use in a medicament for inverting papilloma of the sinuses or squamous cell carcinoma of the paranasal sinuses associated with inverting papilloma of the sinuses.
- the present invention also relates to said compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, for use as a medicament.
- the present invention also relates to said compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, for use in the treatment and/or prevention of cancers associated at least in part with EGFR exon 20 insertions, deletions or other mutations , tumor or metastatic disease.
- the present invention also relates to said compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, for use in the prevention and/or treatment of tumors, cancers and/or metastases caused by hyperproliferative and cell death-inducing disorders use of sexually transmitted diseases.
- the present invention also relates to said compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, for use in the treatment and/or prevention of lung cancer at least partially associated with EGFR exon 20 insertion, deletion or other mutation , colon cancer, pancreatic cancer, head and neck cancer, breast cancer, ovarian cancer, uterine cancer, gastric cancer, non-small cell lung cancer, leukemia, myelodysplastic syndrome, malignant lymphoma, head and neck tumors, thoracic tumors, gastrointestinal tumors , endocrine tumors, breast and other gynecological tumors, urological tumors, skin tumors, sarcomas, nasal and sinus inverted papilloma, or nasal and sinus squamous cell carcinoma associated with nasal and sinus inverted papilloma.
- the present invention also relates to a method of treating and/or preventing cancer, tumor or metastatic disease associated at least in part with EGFR exon 20 insertions, deletions or other mutations, comprising administering to a patient in need thereof a therapeutically effective amount of said A compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
- the present invention also relates to a method of preventing and/or treating tumors, cancers and/or metastatic diseases caused by hyperproliferative and induced cell death disorders, comprising administering to a patient in need thereof a therapeutically effective amount of said formula (I) A compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
- the present invention also relates to a method for the treatment and/or prevention of lung, colon, pancreatic, head and neck, breast, ovarian, uterine, gastric, non- Small cell lung cancer, leukemia, myelodysplastic syndrome, malignant lymphoma, head and neck tumors, thoracic tumors, gastrointestinal tumors, endocrine tumors, breast and other gynecological tumors, urological tumors, skin tumors, sarcomas, intranasal and paranasal tumors
- a method for inverted papilloma or naso-inverted papilloma-associated squamous cell carcinoma of the paranasal sinuses comprising administering to a patient in need thereof a therapeutically effective amount of said compound of formula (I), a stereoisomer thereof or Its pharmaceutically acceptable salts.
- an EGFR inhibitor with the structure of the following formula (I). 20 Drugs for cancers, tumors or metastatic diseases associated with insertions, deletions or other mutations, especially for hyperproliferative and cell death-inducing disorders, are expected to be developed into next-generation EGFR inhibitors. On this basis, the present invention has been completed.
- Alkyl refers to a straight-chain or branched-chain saturated aliphatic hydrocarbon group, preferably a straight-chain alkyl group and a branched-chain alkyl group comprising 1 to 10 or 1 to 6 carbon atoms or 1 to 4 carbon atoms, Including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1, 2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methyl propylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3- Dimethylbutyl,
- C 1-10 alkyl refers to straight-chain alkyl groups including 1 to 10 carbon atoms and branched alkyl groups
- C 1-6 alkyl refers to straight-chain alkyl groups including 1 to 6 carbon atoms and A branched-chain alkyl group
- C 1-4 alkyl refers to a straight-chain alkyl group containing 1 to 4 carbon atoms and a branched alkyl group
- C 1-2 alkyl refers to a group containing 1 to 2 carbon atoms
- the straight-chain alkyl group “C 0-8 alkyl” refers to a straight-chain alkyl group including 0 to 8 carbon atoms and a branched alkyl group
- C 0-4 alkyl refers to a group including 0 to 4 carbon atoms
- the straight-chain alkyl group and the branched-chain alkyl group, "C 0-2 alkyl” refers to the straight-chain alkyl group and the branched alky
- Cycloalkyl or “carbocycle” refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, and the partially unsaturated cyclic hydrocarbon means that the cyclic hydrocarbon may contain one or more (preferably 1, 2 or 3) double bonds, but none of the rings has a completely conjugated ⁇ electron system, cycloalkyl is divided into monocyclic cycloalkyl, polycyclic cycloalkyl, preferably including 3 to 12 or 3 to 8 or 3 Cycloalkyl groups of up to 6 carbon atoms, for example, "C 3-12 cycloalkyl” refers to cycloalkyl groups including 3 to 12 carbon atoms, “C 3-8 cycloalkyl” refers to cycloalkyl groups including 3 to 8 carbon atoms atomic cycloalkyl, “C 3-6 cycloalkyl” refers to a cycloalkyl group including 3 to 6 carbon atoms, "C 4-8
- Monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, Cyclooctyl etc.
- Polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups.
- “Spirocycloalkyl” refers to polycyclic groups in which a single carbon atom (called a spiro atom) is shared between the monocyclic rings, these may contain one or more (preferably 1, 2 or 3) double bonds, but none of the rings have Fully conjugated pi electron system. According to the number of spiro atoms shared between the rings, spirocycloalkyl groups are classified into single spirocycloalkyl groups, double spirocycloalkyl groups or polyspirocycloalkyl groups, and spirocycloalkyl groups include but are not limited to:
- fused cycloalkyl refers to an all-carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings may contain one or more (preferably 1, 2 or 3) double bonds, but none of the rings have a fully conjugated pi electron system. According to the number of formed rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl groups, fused cycloalkyl groups include but are not limited to:
- “Bridged cycloalkyl” refers to an all-carbon polycyclic group in which any two rings share two non-directly attached carbon atoms, these may contain one or more (preferably 1, 2 or 3) double bonds, but none The ring has a fully conjugated pi electron system. According to the number of formed rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, including but not limited to:
- the cycloalkyl ring can be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring connected to the parent structure is a cycloalkyl, including but not limited to indanyl, tetrahydronaphthyl , benzocycloheptyl, etc.
- Heterocyclyl or “heterocycle” refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, and the partially unsaturated cyclic hydrocarbon refers to a cyclic hydrocarbon that may contain one or more (preferably 1, 2 or 3) double bonds, but none of the rings have a fully conjugated pi-electron system, heterocyclyl wherein one or more (preferably 1, 2, 3 or 4) ring atoms are selected from nitrogen, oxygen or S(O ) heteroatoms of r (wherein r is an integer of 0, 1, 2), excluding ring moieties of -OO-, -OS- or -SS-, the remaining ring atoms being carbon, preferably including 3 to 12 or 3 to Heterocyclyl groups of 8 or 3 to 6 ring atoms, for example, "3-6 membered heterocyclyl” refers to a ring group containing 3 to 6 ring atoms, and "3-8 membered heterocyclyl” refer
- Monocyclic heterocyclyl groups include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like.
- Polycyclic heterocyclyls include spiro, fused and bridged heterocyclyls.
- “Spiroheterocyclyl” refers to a polycyclic heterocyclic group in which a single atom (called a spiro atom) is shared between the monocyclic rings, wherein one or more (preferably 1, 2, 3 or 4) ring atoms are selected from nitrogen, oxygen or a heteroatom of S(O) r (where r is an integer 0, 1, 2) and the remaining ring atoms are carbon. These may contain one or more double bonds (preferably 1, 2 or 3), but none of the rings have a fully conjugated pi-electron system.
- Spiroheterocyclyls are classified into mono-, bis-, or poly-spiroheterocyclyls according to the number of spiro atoms shared between the rings.
- Spiroheterocyclyl groups include, but are not limited to:
- “Fused heterocyclic group” refers to a polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, one or more (preferably 1, 2, 3 or 4) rings may be contains one or more (preferably 1, 2, or 3) double bonds, but none of the rings has a fully conjugated pi-electron system, wherein one or more (preferably 1, 2, 3 or 4) ring atoms are selected from A heteroatom of nitrogen, oxygen or S(O) r (where r is an integer 0, 1, 2) and the remaining ring atoms are carbon. According to the number of formed rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocycloalkyl groups, fused heterocyclic groups include but are not limited to:
- Bridged heterocyclyl refers to a polycyclic heterocyclic group in which any two rings share two atoms that are not directly connected, these may contain one or more (preferably 1, 2 or 3) double bonds, but none of the rings having a fully conjugated pi-electron system in which one or more (preferably 1, 2, 3 or 4) ring atoms are selected from nitrogen, oxygen or S(O) r (where r is an integer 0, 1, 2) Heteroatoms, the remaining ring atoms are carbon. According to the number of formed rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, bridged heterocyclic groups include but are not limited to:
- the heterocyclyl ring can be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclyl, including but not limited to:
- Aryl or “aromatic ring” refers to an all-carbon monocyclic or fused polycyclic (ie, rings sharing adjacent pairs of carbon atoms) groups, polycyclic rings having a conjugated pi electron system (ie, with adjacent ring) groups for carbon atoms, preferably all-carbon aryl groups containing 6-10 or 6-8 carbons, for example, “C 6-10 aryl” refers to all-carbon aryl groups containing 6-10 carbons, “C 6-8 aryl” refers to a full carbon aryl group containing 6-8 carbons, including but not limited to phenyl and naphthyl.
- the aryl ring can be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, including but not limited to:
- Heteroaryl refers to a heteroaromatic system containing one or more (preferably 1, 2, 3 or 4) heteroatoms including nitrogen, oxygen and S(O)r (where r is the integer 0 , 1, 2) heteroatoms, preferably heteroaromatic systems containing 5-10 or 5-8 or 5-6 ring atoms, for example, "5-8 membered heteroaryl” means containing 5-8 ring atoms Heteroaromatic systems of ring atoms, "5-10 membered heteroaryl” refers to heteroaromatic systems containing 5-10 ring atoms, including but not limited to furyl, thienyl, pyridyl, pyrrolyl, N-alkane pyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl and the like.
- the heteroaryl ring can be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the
- Alkenyl means an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, preferably a straight or branched chain alkenyl group containing 2-10 or 2-4 carbons
- C 2-10 alkenyl refers to a straight-chain or branched alkenyl containing 2-10 carbons
- C 2-4 alkenyl refers to a straight-chain or branched alkenyl containing 2-4 carbons Branched alkenyl.
- Alkynyl means an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, preferably a straight-chain or branched-chain alkynyl group containing 2-10 or 2-4 carbons,
- C 2-10 alkynyl refers to a straight or branched chain alkynyl group containing 2-10 carbons
- C 2-4 alkynyl refers to a straight or branched chain containing 2-4 carbons alkynyl.
- ethynyl 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl, and the like.
- Alkoxy refers to -O-alkyl, where alkyl is as defined above, eg, "C 1-10 alkoxy” refers to an alkyloxy group containing 1-10 carbons, “C 1-4 "Alkoxy” refers to an alkyloxy group containing 1-4 carbons including, but not limited to, methoxy, ethoxy, propoxy, butoxy, and the like.
- Cycloalkoxy refers to -O-cycloalkyl, where cycloalkyl is as defined above, for example, “C 3-12 cycloalkoxy” refers to a cycloalkyloxy group containing 3-12 carbons, “C 3-8 cycloalkoxy” refers to a cycloalkyloxy group containing 3-8 carbons, including but not limited to cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy and the like.
- Heterocyclyloxy refers to -O-heterocyclyl, wherein heterocyclyl is as defined above, and heterocyclyloxy, including but not limited to azetidinyloxy, oxetanyloxy, nitrogen Heterocyclopentyloxy, nitrogen, oxhexyloxy, etc.
- C 1-10 alkanoyl refers to the monovalent atomic group remaining after C 1-10 alkyl acid removes the hydroxyl group, usually also expressed as “C 0-9 alkyl-C(O)-", for example, “C 1 "Alkyl-C(O)-” means acetyl; “ C2alkyl -C(O)-” means propionyl; “ C3alkyl -C(O)-” means butyryl or isobutyl Acyl.
- Halo-substituted C 1-6 alkyl refers to 1-6 carbon alkyl groups in which the hydrogen on the alkyl group is optionally substituted by fluorine, chlorine, bromine, or iodine atoms, including but not limited to difluoromethyl (-CHF 2 ), dichloromethyl (-CHCl 2 ), dibromomethyl (-CHBr 2 ), trifluoromethyl (-CF 3 ), trichloromethyl (-CCl 3 ), tribromomethyl (-CBr 3 ) etc.
- Halo-substituted C 1-10 alkoxy refers to a 1-10 carbon alkoxy group in which the hydrogen on the alkyl group is optionally substituted with fluorine, chlorine, bromine, or iodine atoms. Including but not limited to difluoromethoxy, dichloromethoxy, dibromomethoxy, trifluoromethoxy, trichloromethoxy, tribromomethoxy and the like.
- Deuterium substituted C1-6 alkyl refers to a 1-6 carbon alkyl group in which the hydrogen on the alkyl group is optionally substituted with a deuterium atom. Including, but not limited to, deuteromethyl ( -CH2D ), dideuteromethyl ( -CHD2 ), trideuteromethyl ( -CD3 ), and the like.
- Deuterium substituted C 1-10 alkoxy refers to 1-10 carbon alkyl groups in which the hydrogen on the alkyl group is optionally substituted with a deuterium atom. Including but not limited to mono-deuteromethoxy, di-deuteromethoxy, tri-deuteromethoxy and the like.
- Halogen refers to fluorine, chlorine, bromine or iodine.
- Optional or “optionally” means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs or does not occur, that is, both substituted and unsubstituted .
- a heterocyclic group optionally substituted with an alkyl group means that an alkyl group may, but need not, be present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with an alkyl group .
- Substituted means that one or more "hydrogen atoms" in a group are, independently of one another, substituted with the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, in accordance with valence bond theory in chemistry, and those skilled in the art can determine (either experimentally or theoretically) possible or impossible without undue effort replacement. For example, amino or hydroxyl groups with free hydrogen may be unstable when combined with carbon atoms with unsaturated bonds, such as alkenes.
- Stereoisomer its English name is stereoisomer, refers to the isomers produced by the different arrangements of atoms in the molecule in space. It can be divided into cis-trans isomers and enantiomers. It can also be divided into two categories: enantiomers and diastereomers. Stereoisomers due to rotation of a single bond are called conformational stereo-isomers, and are sometimes called rotamers. Stereoisomers caused by bond length, bond angle, double bond in the molecule, ring, etc. are called configuration stereo-isomers, and configuration isomers are divided into two categories.
- the isomers caused by the double bond or the single bond of the ring carbon atom not being able to rotate freely are called geometric isomers, also known as cis-trans isomers, which are divided into Z, E two configurations.
- geometric isomers also known as cis-trans isomers, which are divided into Z, E two configurations.
- cis-2-butene and trans-2-butene are a pair of geometric isomers, if the compound of the present invention contains a double bond, if not specified, it can be understood as containing E and/or Z form.
- Stereoisomers with different optical properties due to the absence of anti-axial symmetry in the molecule are called optical isomers and are divided into R and S configurations.
- the "stereoisomer" can be understood to include one or more of the above-mentioned enantiomers, configuration isomers and conformation isomers unless otherwise specified, preferably S configuration type.
- “Pharmaceutically acceptable salts” in the present invention refer to pharmaceutically acceptable acid addition salts or base addition salts, including inorganic and organic acid salts, which can be prepared by methods known in the art.
- “Pharmaceutical composition” means a mixture containing one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, with other chemical components, and other components such as a physiological/pharmaceutically acceptable carrier and excipients.
- the purpose of the pharmaceutical composition is to facilitate the administration to the organism, facilitate the absorption of the active ingredient and then exert the biological activity.
- the structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) or/and liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts ([delta]) are given in parts per million (ppm). NMR was measured by Bruker AVANCE-400/500 nuclear magnetic instrument, the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated methanol (CD 3 OD) and deuterated chloroform (CDCl 3 ), internal standard For tetramethylsilane (TMS).
- DMSO-d 6 dimethyl sulfoxide
- CD 3 OD deuterated methanol
- CDCl 3 deuterated chloroform
- TMS internal standard For tetramethylsilane
- the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the specifications used for TLC are 0.15mm ⁇ 0.20mm, and the specifications used for TLC separation and purification products are 0.4mm ⁇ 0.5mm.
- Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.
- the starting materials in the examples of the present invention are known and commercially available, or can be synthesized using or according to methods known in the art.
- the preparation of intermediate A2 can refer to the synthesis method of intermediate A1 by replacing (R)-N,N - dimethylpyrrolidin-3-amine with N1,N1, N2 -trimethylethane- 1 , 2-Diamine was prepared.
- the first step the synthesis of 6-bromo-2-methoxy-3-nitropyridine
- the second step the synthesis of 6-bromo-2-methoxypyridin-3-amine
- the third step the synthesis of N-(6-bromo-2-methoxypyridin-3-yl)acetamide
- the fourth step the synthesis of N-(6-bromo-2-methoxy-5-nitropyridin-3-yl)acetamide
- the fifth step synthesis of (R)-N-(6-(3-(dimethylamino)pyrrolidin-1-yl)-2-methoxy-5-nitropyridin-3-yl)acetamide
- the first step synthesis of N-(6-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitropyridin-3-yl)acetamide
- N-(6-bromo-2-methoxy-5-nitropyridin-3-yl)acetamide 1.0 g, 3.4 mmol, 1 eq.
- acetonitrile 20 mL
- N 1 , N 1 , N 2 -trimethylethane-1,2-diamine 520 mg, 5.1 mmol, 1.5 eq.
- the reaction solution was stirred at 80°C for 1 hour.
- the second step synthesis of N 2 -(2-(dimethylamino)ethyl)-6-methoxy-N 2 -methyl-3-nitropyridine-2,5-diamine
- the first step the synthesis of 6-bromo-3-nitro-2-(2,2,2-trifluoroethoxy)pyridine
- reaction solution was poured into ice water (100 mL), MTBE (methyl tert-butyl ether) (100 mL*3) was added for extraction, the organic phases were combined, saturated brine was added for washing, the organic phase was concentrated, and the crude product was separated to obtain 6-Bromo-3-nitro-2-(2,2,2-trifluoroethoxy)pyridine (3.2 g, yield: 60%).
- MTBE methyl tert-butyl ether
- the third step synthesis of N-(6-bromo-2-(2,2,2-trifluoroethoxy)pyridin-3-yl)acetamide
- the fourth step the synthesis of N-(6-bromo-5-nitro-2-(2,2,2-trifluoroethoxy)pyridin-3-yl)acetamide
- reaction solution was slowly poured into ice water, stirred for 1 hour, a solid was precipitated, filtered with suction, and the filter cake was dried to obtain N-(6-bromo-5-nitro-2-(2,2,2-trifluoroethoxy)pyridine) -3-yl)acetamide (2.14 g, yield: 86%). used directly in the next reaction.
- N-(6-Bromo-5-nitro-2-(2,2,2-trifluoroethoxy)pyridin-3-yl)acetamide (1.0 g, 2.79 mmol) was dissolved in acetonitrile (20 mL) , and (R)-N,N-dimethylpyrrolidin-3-amine (382 mg, 3.35 mmol) was added to the solution at room temperature. The temperature of the reaction solution was raised to 80°C, and the reaction was completed after 1 hour.
- N-(6-Bromo-5-nitro-2-(2,2,2-trifluoroethoxy)pyridin-3-yl)acetamide (1.0 g, 2.79 mmol) was dissolved in acetonitrile (20 mL) , N 1 , N 1 , N 2 -trimethylethane-1,2-diamine (426 mg, 4.17 mmol) was added to the solution at room temperature. The temperature of the reaction solution was raised to 80°C, and the reaction was completed after 1 hour.
- the first step the synthesis of 6-chloro-5-fluoro-3,3-dimethylindoline-2-one
- the second step the synthesis of 6-chloro-5-fluoro-3,3-dimethylindoline
- the first step Synthesis of 5,6-difluoro-3,3-dimethylindoline-2-one
- the first step synthesis of diethyl 2-(3-nitropyridin-2-yl) malonate
- the second step the synthesis of ethyl 2-(3-nitropyridin-2-yl) acetate
- reaction solution was cooled to room temperature, washed with water, extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, distilled under reduced pressure, and the crude product was separated by a flash silica gel column [eluent: ethyl acetate/petroleum ether: 0-50%] to obtain ethyl acetate 2-(3-nitropyridin-2-yl)acetate (3.1 g, yield: 73.8%).
- ESI-MS 211.0[M+1] + .
- the third step the synthesis of ethyl 2-methyl-2-(3-nitropyridin-2-yl) propionate
- the fourth step synthesis of 3,3-dimethyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one
- the first step Synthesis of 2-iodo-N-(2-methallyl)-6-(trifluoromethyl)pyridin-3-amine
- the first step Synthesis of 2-iodo-6-methyl-N-(2-methallyl)pyridin-3-amine
- reaction solution was filtered, the filtrate was washed with water, extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, distilled under reduced pressure, and the crude product was separated by a flash silica gel column [eluent: ethyl acetate/petroleum ether: 0-30%] to obtain 3, 3,5-Trimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine (660 mg, yield: 81%).
- ESI-MS 163.0[M+1] + .
- the first step the synthesis of 6-chloro-2-iodopyridin-3-amine
- the second step the synthesis of 6-chloro-2-iodo-N-(2-methallyl)pyridin-3-amine
- the third step Synthesis of 5-chloro-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine
- 6-chloro-2-iodo-N-(2-methallyl)pyridin-3-amine (15.5g, 50.2mmol), sodium formate (4.2g, 60.3mmol), tetrabutyl chloride Ammonium (16.8 g, 60.3 mmol), triethylamine (15.3 g, 150.7 mmol), palladium acetate (1.69 g, 7.5 mmol), dimethyl sulfoxide (200 mL) and water (6.7 mL).
- the mixture was purged with nitrogen three times and heated to 120°C with stirring for 1 hour under nitrogen protection.
- the fourth step synthesis of tert-butyl 5-chloro-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1-carboxylate
- tert-butyl 5-chloro-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1-carboxylate 706 mg, 2.5 mmol
- cesium carbonate (1.22g, 3.75mmol
- 1,1'-binaphthyl-2,2'-bisdiphenylphosphine 0.3mg, 0.5mmol
- cyclobutylamine (428mg, 7.5mmol
- palladium acetate (112 mg, 0.5 mmol
- 1,4-dioxane 8 mL.
- the mixture was purged with nitrogen three times, sealed and heated to 120°C with stirring for 16 hours.
- the first step Synthesis of 1-tert-butyl 3-ethyl 2-(6-methoxy-3-nitropyridin-2-yl)malonate
- Ethyl tert-butyl malonate (8.4 g, 44.5 mmol) was dissolved in anhydrous tetrahydrofuran (100 mL), sodium hydride (1.8 g, 44.5 mmol) was added in portions, the reaction was stirred at room temperature for 20 minutes, and 2 -Chloro-6-methoxy-3-nitropyridine (7.0 g, 37.1 mmol), the reaction was stirred at 80°C for 2 hours. After the reaction was completed, the reaction solution was separated with ethyl acetate (100 mL) and saturated brine (100 mL), and the organic phase was washed with saturated brine (50 mL).
- the second step the synthesis of ethyl 2-(6-methoxy-3-nitropyridin-2-yl) acetate
- the third step the synthesis of ethyl 2-(6-methoxy-3-nitropyridin-2-yl)-2-methyl propionate
- the fourth step Synthesis of 5-methoxy-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-2-one
- the sixth step Synthesis of 3,3-dimethyl-1H,2H,3H,4H,5H-pyrrolo[3,2-b]pyridin-5-one
- the seventh step Synthesis of 5-bromo-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridine
- the first step Synthesis of 3-nitro-1,5,6,7-tetrahydro-2H-cyclopentadieno[b]pyridin-2-one
- the second step Synthesis of 2-chloro-3-nitro-6,7-dihydro-5H-cyclopentadieno[b]pyridine
- the third step synthesis of diethyl 2-(3-nitro-6,7-dihydro-5H-cyclopentadieno[b]pyridin-2-yl)malonate
- the fourth step the synthesis of ethyl 2-(3-nitro-6,7-dihydro-5H-cyclopentadieno[b]pyridin-2-yl) acetate
- reaction solution was cooled to room temperature, washed with water, extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, distilled under reduced pressure, and the crude product was separated by a flash silica gel column [eluent: ethyl acetate/petroleum ether: 0-50%] to obtain ethyl acetate 2-(3-nitro-6,7-dihydro-5H-cyclopentadieno[b]pyridin-2-yl)acetate (240 mg, yield: 76.0%).
- ESI-MS 251.0[M+1] + .
- the fifth step the synthesis of ethyl 2-methyl-2-(3-nitro-6,7-dihydro-5H-cyclopentadieno[b]pyridin-2-yl)propionate
- the sixth step Synthesis of 3,3-dimethyl-3,5,6,7-tetrahydrocyclopentadieno[b]pyrrolo[2,3-e]pyridin-2(1H)-one
- Step 7 Synthesis of 3,3-dimethyl-1,2,3,5,6,7-hexahydrocyclopentadieno[b]pyrrolo[2,3-e]pyridine
- the first step the synthesis of ethyl 2-(5-bromo-3-nitropyridin-2-yl) acetate
- the second step the synthesis of ethyl 2-(5-bromo-3-nitropyridin-2-yl)-2-methyl propionate
- the third step Synthesis of 6-bromo-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-2-one
- the fourth step Synthesis of 3,3-dimethyl-6-phenyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-2-one
- the first step the synthesis of methyl 5-amino-6-iodopyridine-2-carboxylate
- Methyl 5-aminopyridine-2-carboxylate (10 g, 65.7 mmol) was dissolved in N,N-dimethylformamide (60 mL), iodine (18.35 g, 72.3 mmol) and sodium periodate (33.7 mmol) were added g, 157.7 mmol). The reaction was stirred at 60°C for 6 hours. It was poured into water, extracted three times with ethyl acetate, the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate.
- the second step the synthesis of methyl 6-iodo-5-((2-methallyl)amino)picolinate
- Methyl 5-amino-6-iodopyridine-2-carboxylate (11 g, 39.56 mmol) was dissolved in tetrahydrofuran (150 mL) to a solution of potassium tert-butoxide in tetrahydrofuran (47.5 mL, 47.5 mmol) and 3-bromo-2 - Methylprop-1-ene (4.78 mL, 47.5 mmol). The reaction was stirred at room temperature for 1 hour, then quenched with 10 mL of methanol and stirring continued for 10 minutes.
- the third step synthesis of methyl 3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridine-5-carboxylate
- Methyl 6-iodo-5-((2-methallyl)amino)picolinate (5.0 g, 15.05 mmol) was dissolved in dimethyl sulfoxide (90 mL) and water (36 mL), added Sodium formate (1.23 g, 18.06 mmol), triethylamine (6.3 mL, 45.16 mmol), tetrabutylammonium chloride (1.6 g, 5.7 mmol) and palladium acetate (0.51 g, 2.26 mmol). The reaction was stirred under nitrogen at 120°C for 1 hour. Poured into water and extracted three times with ethyl acetate.
- the fourth step Synthesis of 1-tert-butyl 5-methyl 3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridine-1,5-dicarboxylate
- the fifth step the synthesis of tert-butyl 5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridine-1-carboxylate
- the sixth step synthesis of tert-butyl 5-formyl-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridine-1-carboxylate
- tert-Butyl 5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridine-1-carboxylate (2.2 g, 7.9 mmol) Dissolve in dichloromethane (80 mL) and add manganese dioxide (6.87 g, 79 mmol). The reaction was stirred at room temperature for 2 hours, filtered and concentrated to give tert-butyl 5-formyl-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridine-1-carboxylic acid Ester (1.8 g, yield: 82.4%). ESI-MS: 277.0[M+1] + .
- the seventh step synthesis of tert-butyl 5-ethynyl-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridine-1-carboxylate
- the first step the synthesis of 2-bromo-2-methyl-N-(2-carbonyl-1,2-dihydropyridin-3-yl) propionamide
- the second step Synthesis of 3,3-dimethyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-2-one
- the third step Synthesis of 3,3-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine
- intermediate B17 was prepared according to the method of intermediate B16.
- the first step the synthesis of N-(4-fluorophenyl)-3-methylbut-2-enamide
- the second step the synthesis of 6-fluoro-4,4-dimethyl-3,4-dihydroquinolin-2(1H)-one
- the third step synthesis of 6-fluoro-4,4-dimethyl-1,2,3,4-tetrahydroquinoline
- 6-Fluoro-4,4-dimethyl-3,4-dihydroquinolin-2(1H)-one (7.7 g, 40 mmol) was dissolved in tetrahydrofuran (100 mL), and a 1M solution of borane in tetrahydrofuran (80 mL) was added. , 80 mmol). The reaction solution was heated to 90°C and reacted overnight.
- the first step Synthesis of 4-chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-1,3,5-triazine-2-amine
- Example 1 (R)-N-(5-((4-(3,3-Dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl) Preparation of -1,3,5-triazin-2-yl)amino)-2-(3-(dimethylamino)pyrrolidin-1-yl)-4-methoxyphenyl)acrylamide
- reaction solution was quenched with 0.1 mL of water, and then separated by reverse phase column chromatography [40-50% acetonitrile/water] to obtain (R)-N-(5-((4-(3,3-dimethyl-2, 3-Dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1,3,5-triazin-2-yl)amino)-2-(3-(dimethylamino)pyrrole Alk-1-yl)-4-methoxyphenyl)acrylamide (19.5 mg, yield: 13%).
- ESI-MS 530.2[M+1] + .
- Example 48 N-(5-((4-(5-Cyano-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl)-1 ,3,5-triazin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)prop-2-enamide preparation
- the first step N-(5-((4-(5-bromo-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl)-1, Synthesis of 3,5-triazin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)prop-2-enamide
- N 4 -(4-(5-Bromo-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl)-1,3,5-triazine -2-yl)-N 1 -(2-(dimethylamino)ethyl)-5-methoxy-N 1 -methylbenzene-1,2,4-triamine 120 mg, 0.22 mmol was dissolved in Acetonitrile (10 mL) in water (10 mL). To the solution was added diisopropylethylamine (143 mg, 1.11 mmol). Acryloyl chloride (60 mg, 0.66 mmol) was added to the reaction solution at 0°C and stirred for 30 minutes.
- reaction solution was separated by reverse phase column chromatography (40-50% acetonitrile/water) to obtain N-(5-((4-(5-bromo-3,3-dimethyl-1H,2H,3H-pyrrolo[3] ,2-b]pyridin-1-yl)-1,3,5-triazin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4 -Methoxyphenyl)prop-2-enamide (37.0 mg, yield: 28%).
- ESI-MS 597.1 [M+1] + .
- the second step N-(5-((4-(5-cyano-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl)-1 ,3,5-triazin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)prop-2-enamide synthesis
- the first step N 4 -(4-(3,3-dimethyl-5-(1-methyl-1H-pyrazol-4-yl)-1H,2H,3H-pyrrolo[3,2- b] Pyridin-1-yl)-1,3,5-triazin-2-yl)-N 1 -(2-(dimethylamino)ethyl)-5-methoxy-N 1 -methyl- Synthesis of 2-nitrobenzene-1,4-diamine
- the third step N-(5-((4-(3,3-dimethyl-5-(1-methyl-1H-pyrazol-4-yl)-1H,2H,3H-pyrrolo[3 ,2-b]pyridin-1-yl)-1,3,5-triazin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4 Synthesis of -methoxyphenyl)prop-2-enamide
- Example 51 N-(5-((4-(5-(2-cyclopropylethynyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridine -1-yl)-1,3,5-triazin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl) Preparation of prop-2-enamide
- the first step N 4 -(4-(5-(2-cyclopropylethynyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridine-1- yl)-1,3,5-triazin-2-yl)-N 1 -(2-(dimethylamino)ethyl)-5-methoxy-N 1 -methyl-2-nitrobenzene- Synthesis of 1,4-Diamine
- the second step N 4 -(4-(5-(2-cyclopropylethynyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridine-1- yl)-1,3,5-triazin-2-yl)-N 1 -(2-(dimethylamino)ethyl)-5-methoxy-N 1 -methylbenzene-1,2,4 -Synthesis of triamines
- the third step N-(5-((4-(5-(2-cyclopropylethynyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridine -1-yl)-1,3,5-triazin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl) Synthesis of Prop-2-enamide
- N 4 -(4-(5-Bromo-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl)-1,3,5-triazine -2-yl)-N 1 -(2-(dimethylamino)ethyl)-5-methoxy-N 1 -methylbenzene-1,2,4-triamine 35 mg, 0.066 mmol was dissolved in Acetonitrile (10 mL) in water (10 mL). To the solution was added diisopropylethylamine (86 mg, 0.66 mmol). Acryloyl chloride (18 mg, 0.22 mmol) was added to the reaction solution at 0°C and stirred for 30 minutes.
- reaction solution was separated by reverse phase column chromatography [40-50% acetonitrile/water] to obtain N-(5-((4-(5-bromo-3,3-dimethyl-1H,2H,3H-pyrrolo[3] ,2-b]pyridin-1-yl)-1,3,5-triazin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4 -Methoxyphenyl)prop-2-enamide (3.2 mg, yield: 8%).
- ESI-MS 582.3[M+1] + .
- Example 2 to 47 The preparations of Examples 2 to 47, Example 50, and Examples 52 to 56 were prepared with reference to the synthetic method of Example 1 or Example 49:
- cell line cell culture medium Cell density 1 A431 DMEM+15%FBS 5000 2 Ba/F3 EGFR-WT RPMI1640+10%FBS 3000 3 Ba/F3 EGFR-D770-N771ins_SVD RPMI1640+10%FBS 3000 4 Ba/F3 EGFR-V769_D770insASV RPMI1640+10%FBS 3000
- the cells were placed in a 96-well plate filled with drugs at a temperature of 37°C, 5% CO 2 and 95% humidity, and cultured for 72 hours, followed by CTG analysis.
- Cell survival rate (%) (Lum test drug-Lum culture medium control)/(Lum cell control-Lum culture medium control) ⁇ 100%.
- the series of compounds of the present invention have a strong inhibitory effect on EGFR exon 20 insertion, deletion or other mutations at the cellular level.
- some compounds have high selectivity for EGFR WT.
Abstract
公开了具有EGFR抑制活性的三嗪衍生物及其制备方法和应用。特别地,公开了一种具有式(I)结构的EGFR抑制剂及其制备方法、含有其的药物组合物,以及其制备EGFR抑制剂的用途和其在制备治疗和/或预防至少部分与EGFR外显子20插入、缺失或其他突变相关的癌症、肿瘤或转移性疾病的药物中的用途,特别是在制备治疗和/或预防过度增殖性疾病和诱导细胞死亡障碍疾病的药物中的用途。其中式(I)的各取代基与说明书中的定义相同。
Description
本发明属于药物合成领域,具体涉及具有EGFR抑制活性的三嗪衍生物及其制备方法和应用。
肺癌是全世界癌症死亡的主要原因,其中非小细胞肺癌(NSCLC)占85%。针对表皮生长因子受体(EGFR)突变、间变性淋巴瘤激酶(ALK)易位、ROS1原癌基因受体酪氨酸激酶(ROS1)重排和B-raf原癌基因、丝氨酸/苏氨酸激酶(BRAF)的多靶点治疗已经成功开发并在临床上得到验证。针对EGFR的抑制剂能显著提高NSCLC中腺癌的无进展生存期,而其获得性耐药突变能够被第三代EGFR抑制剂所靶向。
尽管经典的EGFR激活突变(外显子19和21)和耐药突变(T790M)能够被现有的药物所抑制,但外显子20(Exon 20)的插入突变也导致了EGFR信号的结构性激活,并且对现有的EGFR抑制剂都不敏感。外显子20突变是异质性的,包括1-7个氨基酸在EGFR蛋白的762-774位氨基酸之间的插入或重复。在NSCLC中,EGFR外显子20的突变频率占EGFR所有突变的4-10%。这些突变与其他已知的致癌基因驱动突变相互排斥,并且在女性、非吸烟者、亚洲人群和非小细胞肺癌患者的腺癌中富集。除NSCLC外,EGFR外显子20插入突变还见于一种罕见的头颈部癌,即鼻腔鳞状细胞癌(SNSCC)。此外,在EGFR家族的另一成员HER2中也发现了结构类似的外显子20插入突变。
多个回顾性分析研究表明,目前可用的第1代、第2代和第3代EGFR抑制剂对外显子20插入突变的疗效有限,但A763-Y764insFQEA突变除外。不可逆抑制剂波齐替尼(Poziotinib)和EGFR/MET双特异性抗体Amivantamab正在临床试验中。几种小分子抑制剂包括TAK-788和TAS-6417,在EGFR外显子20非小细胞肺癌患者中显示出临床上有意义的功效。但是,由于它们对EGFR野生型的选择性有限,在临床使用中的不良反应是不可避免的,并可能导致剂量限制性毒性。同时,临床上显示现有化合物可能存在暴露量不足的问题。因此,对于这些患者而言,迫切需要针对EGFR外显子20插入突变具有更高暴露量和/或高选择性的小分子抑制剂。
发明内容
本发明的目的在于提供一种具有EGFR抑制活性的三嗪衍生物及其制备方法和应用,本发明系列化合物对EGFR外显子20插入、缺失或其他突变细胞学活性 具有很强的抑制作用,并对EGFR野生型具有高选择性,可广泛应用于制备治疗和/或预防至少部分与EGFR外显子20插入、缺失或其他突变相关的癌症、肿瘤或转移性疾病的药物,特别是治疗过度增殖性疾病和诱导细胞死亡障碍疾病的药物,从而有望开发出新一代EGFR抑制剂。
本发明第一方面提供一种式(I)化合物、其立体异构体或其药学上可接受盐:
其中,X为CH或N;Y为键、O或S;Z
1和Z
2各自独立地为CR
10或N;
R
1选自氢、氘、羟基、C
1-6烷基、卤取代C
1-6烷基、氘取代C
1-6烷基、C
2-4链烯基、C
3-6环烷基和3-6元杂环基;
R
2和R
3各自独立地选自氢、氘、羟基、C
1-6烷基、C
2-4链烯基、C
3-6环烷基和3-6元杂环基,上述基团独立地任选进一步被一个或多个选自氘、卤素、羟基、C
1-10烷基、C
2-10链烯基、C
2-10链炔基、卤取代C
1-10烷基、氘取代C
1-10烷基、C
1-10烷氧基、C
3-12环烷基、C
3-12环烷氧基、3-12元杂环基、3-12元杂环氧基、C
6-10芳基、C
6-10芳氧基、5-10元杂芳基、5-10元杂芳氧基和-C
0-8烷基-NR
14R
15的取代基所取代;
R
4和R
5各自独立地选自氢、氘、卤素、氰基、硝基、叠氮基、C
1-10烷基、卤取代C
1-10烷基、氘取代C
1-10烷基、C
2-10链烯基、C
2-10链炔基、C
3-12环烷基、3-12元杂环基、C
6-10芳基、5-10元杂芳基、-SF
5、-S(O)
rR
11、-OR
12、-C(O)OR
12、-C(O)R
13、-O-C(O)R
13、-NR
14R
15、-C(=NR
14)R
13、-N(R
14)-C(=NR
15)R
13、-C(O)NR
14R
15和-N(R
14)-C(O)R
13;
或者,R
2、R
4或R
5其中一个和R
1与其直接相连的部分一起形成4-8元杂环基,R
2、R
4或R
5其中另两个如前所定义,或者,R
4或R
5其中之一和R
2与其直接相连的部分一起形成4-8元杂环基,R
4或R
5其中另一个如前所定义,所述4-8元杂环基任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C
1-10烷基、卤取代C
1-10烷基、氘取代C
1-10烷基、C
2-10链烯基、C
2-10链炔基、C
3-12环烷基、3-12元杂环基、C
6-10芳基、5-10元杂芳基、=O、-SF
5、-S(O)
rR
11、-OR
12、-C(O)OR
12、-C(O)R
13、-O-C(O)R
13、-NR
14R
15、-C(=NR
14)R
13、-N(R
14)-C(=NR
15)R
13、-C(O)NR
14R
15和-N(R
14)-C(O)R
13的取代基所取代;
R
6选自氢、氘、C
1-10烷基、C
2-10链烯基、C
3-12环烷基、3-12元杂环基、C
6-10芳基和5-10元杂芳基,上述基团独立地任选进一步被一个或多个选自氘、卤素、 羟基、氧代、氰基、C
1-10烷基、C
1-10烷氧基、C
3-12环烷基、C
3-12环烷氧基、3-12元杂环基、3-12元杂环氧基、C
6-10芳基、C
6-10芳氧基、5-10元杂芳基、5-10元杂芳氧基和-NR
14R
15的取代基所取代;
R
7选自氢、氘、卤素、氰基、C
1-4烷基、卤取代C
1-4烷基、氘取代C
1-4烷基、C
3-6环烷基、3-6元杂环基、-C(O)OR
12、-C(O)R
13、-C(O)-NR
14R
15和-C
0-4烷基-NR
14R
15;
R
8和R
9各自独立地选自氢、氘、卤素、氰基、硝基、叠氮基、C
1-10烷基、C
2-10链烯基、C
2-10链炔基、C
3-12环烷基、3-12元杂环基、C
6-10芳基和5-10元杂芳基,或者,R
8和R
9与其直接相连的碳原子一起形成C
3-6环烷基或3-6元杂环基,上述基团独立地任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C
1-10烷基、C
2-10链烯基、C
2-10链炔基、卤取代C
1-10烷基、氘取代C
1-10烷基、C
3-12环烷基、3-12元杂环基、C
6-10芳基、5-10元杂芳基、=O、-SF
5、-S(O)
rR
11、-O-R
12、-C(O)OR
12、-C(O)R
13、-O-C(O)R
13、-NR
14R
15、-C(=NR
14)R
13、-N(R
14)-C(=NR
15)R
13、-C(O)NR
14R
15和-N(R
14)-C(O)R
13的取代基所取代;
每个R
10各自独立地选自氢、氘、卤素、氰基、硝基、叠氮基、C
1-10烷基、C
2-10链烯基、C
2-10链炔基、C
3-12环烷基、3-12元杂环基、C
6-10芳基、5-10元杂芳基、-SF
5、-S(O)
rR
11、-O-R
12、-C(O)OR
12、-C(O)R
13、-O-C(O)R
13、-NR
14R
15、-C(=NR
14)R
13、-N(R
14)-C(=NR
15)R
13、-C(O)NR
14R
15和-N(R
14)-C(O)R
13,或者,相邻的两个R
10与其直接相连的部分一起形成C
4-8环烷基或4-8元杂环基,上述基团独立地任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C
1-10烷基、C
2-10链烯基、C
2-10链炔基、卤取代C
1-10烷基、氘取代C
1-10烷基、C
3-12环烷基、3-12元杂环基、C
6-10芳基、5-10元杂芳基、=O、-SF
5、-S(O)
rR
11、-O-R
12、-C(O)OR
12、-C(O)R
13、-O-C(O)R
13、-NR
14R
15、-C(=NR
14)R
13、-N(R
14)-C(=NR
15)R
13、-C(O)NR
14R
15和-N(R
14)-C(O)R
13的取代基所取代;
每个R
11各自独立地选自氢、氘、羟基、C
1-10烷基、C
2-10链烯基、C
3-12环烷基、3-12元杂环基、C
6-10芳基、5-10元杂芳基和-NR
14R
15,上述基团独立地任选进一步被一个或多个选自氘、卤素、羟基、氧代、C
1-10烷基、C
1-10烷氧基、C
3-12环烷基、C
3-12环烷氧基、3-12元杂环基、3-12元杂环氧基、C
6-10芳基、C
6-10芳氧基、5-10元杂芳基、5-10元杂芳氧基和-NR
14R
15的取代基所取代;
每个R
12各自独立地选自氢、氘、C
1-10烷基、C
2-10链烯基、C
3-12环烷基、3-12元杂环基、C
6-10芳基和5-10元杂芳基,上述基团独立地任选进一步被一个或多个选自氘、卤素、羟基、氧代、氰基、C
1-10烷基、C
1-10烷氧基、C
3-12环烷基、C
3-12环烷氧基、3-12元杂环基、3-12元杂环氧基、C
6-10芳基、C
6-10芳氧基、5-10元杂芳基、5-10元杂芳氧基和-NR
14R
15的取代基所取代;
每个R
13各自独立地选自氢、氘、羟基、C
1-10烷基、C
1-10烷氧基、C
2-10链烯基、C
2-10链炔基、C
3-12环烷基、C
3-12环烷氧基、3-12元杂环基、3-12元杂环氧基、C
6-10 芳基、C
6-10芳氧基、5-10元杂芳基、5-10元杂芳氧基和-NR
14R
15,上述基团独立地任选进一步被一个或多个选自氘、卤素、羟基、氰基、C
1-10烷基、C
1-10烷氧基、C
3-12环烷基、C
3-12环烷氧基、3-12元杂环基、3-12元杂环氧基、C
6-10芳基、C
6-10芳氧基、5-10元杂芳基、5-10元杂芳氧基和-NR
14R
15的取代基所取代;
每个R
14和R
15各自独立地选自氢、氘、羟基、C
1-10烷氧基、C
1-10烷基、C
2-10链烯基、C
2-10链炔基、C
3-12环烷基、3-12元杂环基、C
6-10芳基、5-10元杂芳基、亚磺酰基、磺酰基、甲磺酰基、异丙磺酰基、环丙基磺酰基、对甲苯磺酰基、氨基磺酰基、二甲氨基磺酰基、氨基、单C
1-10烷基氨基、二C
1-10烷基氨基和C
1-10烷酰基,上述基团独立地任选进一步被一个或多个选自氘、卤素、羟基、C
1-10烷基、C
2-10链烯基、C
2-10链炔基、卤取代C
1-10烷基、氘取代C
1-10烷基、C
1-10烷氧基、C
3-12环烷基、C
3-12环烷氧基、3-12元杂环基、3-12元杂环氧基、C
6-10芳基、C
6-10芳氧基、5-10元杂芳基、5-10元杂芳氧基、氨基、单C
1-10烷基氨基、二C
1-10烷基氨基和C
1-10烷酰基的取代基所取代,
或者,R
14和R
15与其直接相连的氮原子一起形成4-10元杂环基或5-10元杂芳基,上述基团独立地任选进一步被一个或多个选自氘、卤素、羟基、C
1-10烷基、C
2-10链烯基、C
2-10链炔基、卤取代C
1-10烷基、氘取代C
1-10烷基、C
1-10烷氧基、C
3-12环烷基、C
3-12环烷氧基、3-12元杂环基、3-12元杂环氧基、C
6-10芳基、C
6-10芳氧基、5-10元杂芳基、5-10元杂芳氧基、氨基、单C
1-10烷基氨基、二C
1-10烷基氨基和C
1-10烷酰基的取代基所取代;
m为0、1或2;
n为0、1或2;且
每个r各自独立地为0、1或2。
作为优选的方案,在所述式(I)化合物、其立体异构体或其药学上可接受盐中,R
6选自氢、氘、C
1-4烷基、C
2-4链烯基、C
3-8环烷基、3-8元杂环基、C
6-8芳基和5-8元杂芳基,上述基团独立地任选进一步被一个或多个选自氘、卤素、羟基、氧代、氰基、C
1-4烷基、C
1-4烷氧基、C
3-8环烷基、C
3-8环烷氧基、3-8元杂环基、3-8元杂环氧基、C
6-8芳基、C
6-8芳氧基、5-8元杂芳基、5-8元杂芳氧基和-NR
14R
15的取代基所取代;
R
7选自氢、氘、卤素、氰基、C
1-4烷基、卤取代C
1-4烷基、氘取代C
1-4烷基、C
3-8环烷基、3-8元杂环基和-C
0-4烷基-NR
14R
15;
其中,R
14和R
15如式(I)化合物中所定义。
作为优选的方案,在所述式(I)化合物、其立体异构体或其药学上可接受盐中,R
8和R
9各自独立地选自氢、氘、卤素、氰基、硝基、叠氮基、C
1-4烷基、C
2-4链烯基、C
2-4链炔基、C
3-8环烷基、3-8元杂环基、C
6-8芳基和5-8元杂芳基,或者,R
8和R
9与其直接相连的碳原子一起形成C
3-6环烷基或3-6元杂环基,上述基团独立地任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C
1-4烷基、C
2-4 链烯基、C
2-4链炔基、卤取代C
1-4烷基、氘取代C
1-4烷基、C
3-8环烷基、3-8元杂环基、C
6-8芳基、5-8元杂芳基、=O、-SF
5、-S(O)
rR
11、-O-R
12、-C(O)OR
12、-C(O)R
13、-O-C(O)R
13、-NR
14R
15、-C(=NR
14)R
13、-N(R
14)-C(=NR
15)R
13、-C(O)NR
14R
15和-N(R
14)-C(O)R
13的取代基所取代;
其中,R
11、R
12、R
13、R
14、R
15和r如式(I)化合物中所定义。
作为优选的方案,在所述式(I)化合物、其立体异构体或其药学上可接受盐中,每个R
10各自独立地选自氢、氘、卤素、氰基、硝基、叠氮基、C
1-4烷基、C
2-4链烯基、C
2-4链炔基、C
3-6环烷基、3-6元杂环基、C
6-8芳基、5-8元杂芳基、-SF
5、-S(O)
rR
11、-O-R
12、-C(O)OR
12、-C(O)R
13、-O-C(O)R
13、-NR
14R
15、-C(O)NR
14R
15和-N(R
14)-C(O)R
13,或者,相邻的两个R
10与其直接相连的部分一起形成C
4-8环烷基或4-8元杂环基,上述基团独立地任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C
1-4烷基、C
2-4链烯基、C
2-4链炔基、卤取代C
1-4烷基、C
3-8环烷基、3-8元杂环基、C
6-8芳基、5-8元杂芳基、=O、-SF
5、-S(O)
rR
11、-O-R
12、-C(O)OR
12、-C(O)R
13、-O-C(O)R
13、-NR
14R
15、-C(=NR
14)R
13、-N(R
14)-C(=NR
15)R
13、-C(O)NR
14R
15和-N(R
14)-C(O)R
13的取代基所取代;
其中,R
11、R
12、R
13、R
14、R
15和r如式(I)化合物中所定义。
作为优选的方案,在所述式(I)化合物、其立体异构体或其药学上可接受盐中,R
1选自氢、氘、羟基、C
1-4烷基、卤取代C
1-4烷基、氘取代C
1-4烷基、C
2-4链烯基、C
3-6环烷基和3-6元杂环基;
R
2和R
3各自独立地选自氢、氘和C
1-4烷基,上述基团独立地任选进一步被一个或多个选自氘、卤素、羟基、C
1-4烷基、C
2-4链烯基、C
2-4链炔基、卤取代C
1-4烷基、氘取代C
1-4烷基、C
1-4烷氧基、C
3-8环烷基、C
3-8环烷氧基、3-8元杂环基、3-8元杂环氧基、C
6-8芳基、C
6-8芳氧基、5-8元杂芳基、5-8元杂芳氧基和-C
0-4烷基-NR
14R
15的取代基所取代;
R
4和R
5各自独立地选自氢、氘、卤素、氰基、C
1-4烷基、卤取代C
1-4烷基、氘取代C
1-4烷基、C
2-4链烯基、C
2-4链炔基、C
3-8环烷基、3-8元杂环基、C
6-8芳基、5-8元杂芳基、-OR
12、-C(O)OR
12、-C(O)R
13、-O-C(O)R
13、-NR
14R
15、-C(O)NR
14R
15和-N(R
14)-C(O)R
13;
或者,R
2、R
4或R
5其中一个和R
1与其直接相连的部分一起形成如下结构:
R
2、R
4或R
5其中另两个如前所定义,R
3如前所定义;
或者,R
4或R
5其中之一和R
2与其直接相连的部分一起形成如下结构:
R
4或R
5其中另一个如前所定义,R
1或R
3如前所定义;
其中,R
12、R
13、R
14和R
15如式(I)化合物中所定义。
作为进一步优选的方案,式(I)化合物为如下式(Ⅱa)化合物:
其中,X为CH或N;Z
2为CH或N;
R
2、R
4或R
5其中一个和R
1与其直接相连的部分一起形成如下结构:
每个R
2和R
3各自独立地选自氢、氘和C
1-4烷基,上述基团独立地任选进一步被一个或多个选自氘、卤素、羟基、C
1-4烷基、C
2-4链烯基、C
2-4链炔基、卤取代C
1-4烷基、氘取代C
1-4烷基和-C
0-4烷基-NR
14R
15的取代基所取代;
或者,R
4或R
5其中之一和R
2与其直接相连的部分一起形成如下结构:
每个R
1各自独立地选自氢、氘、C
1-4烷基、卤取代C
1-4烷基、氘取代C
1-4烷基和C
2-4链烯基;
每个R
3各自独立地选自氢、氘和C
1-4烷基,上述基团独立地任选进一步被一个或多个选自氘、卤素、羟基、C
1-4烷基、C
2-4链烯基、C
2-4链炔基、卤取代C
1-4烷基、氘取代C
1-4烷基和-C
0-4烷基-NR
14R
15的取代基所取代;
R
6选自氢、氘、C
1-4烷基、卤取代C
1-4烷基、氘取代C
1-4烷基、C
2-4链烯基、C
3-8环烷基和3-8元杂环基;
R
8和R
9各自独立地选自氢、氘、卤素、氰基、C
1-4烷基、C
2-4链烯基、C
2-4链炔基、C
3-8环烷基、3-8元杂环基、C
6-8芳基和5-8元杂芳基,或者,R
8和R
9与其直接相连的碳原子一起形成C
3-6环烷基或3-6元杂环基,上述基团独立地任选进 一步被一个或多个选自氘、卤素、氰基、羟基、C
1-4烷基、C
1-4烷氧基、C
2-4链烯基、C
2-4链炔基、卤取代C
1-4烷基、卤取代C
1-4烷氧基、氘取代C
1-4烷基、氘取代C
1-4烷氧基、C
3-8环烷基、C
3-8环烷氧基、3-8元杂环基、3-8元杂环氧基、C
6-8芳基和5-8元杂芳基的取代基所取代;
每个R
10各自独立地选自氢、氘、卤素、氰基、硝基、叠氮基、C
1-4烷基、C
2-4链烯基、C
2-4链炔基、C
3-6环烷基、3-6元杂环基、C
6-8芳基、5-8元杂芳基、-SF
5、-S(O)
rR
11、-O-R
12、-C(O)OR
12、-C(O)R
13、-O-C(O)R
13、-NR
14R
15、-C(O)NR
14R
15和-N(R
14)-C(O)R
13,或者,相邻的两个R
10与其直接相连的部分一起形成C
4-6环烷基或4-6元杂环基,上述基团独立地任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C
1-4烷基、C
2-4链烯基、C
2-4链炔基、卤取代C
1-4烷基、C
3-8环烷基、3-8元杂环基、C
6-8芳基、5-8元杂芳基、=O、-SF
5、-S(O)
rR
11、-O-R
12、-C(O)OR
12、-C(O)R
13、-O-C(O)R
13、-NR
14R
15、-C(=NR
14)R
13、-N(R
14)-C(=NR
15)R
13、-C(O)NR
14R
15和-N(R
14)-C(O)R
13的取代基所取代;
每个R
11各自独立地选自氢、氘、羟基、C
1-4烷基、C
2-4链烯基、C
3-8环烷基、3-8元杂环基、C
6-8芳基、5-8元杂芳基和-NR
14R
15,上述基团独立地任选进一步被一个或多个选自氘、卤素、羟基、氧代、C
1-4烷基、C
1-4烷氧基、C
3-8环烷基、C
3-8环烷氧基、3-8元杂环基、3-8元杂环氧基、C
6-8芳基、C
6-8芳氧基、5-8元杂芳基、5-8元杂芳氧基和-NR
14R
15的取代基所取代;
每个R
12各自独立地选自氢、氘、C
1-4烷基、C
2-4链烯基、C
3-8环烷基、3-8元杂环基、C
6-8芳基和5-8元杂芳基,上述基团独立地任选进一步被一个或多个选自氘、卤素、羟基、氧代、氰基、C
1-4烷基、C
1-4烷氧基、C
3-8环烷基、C
3-8环烷氧基、3-8元杂环基、3-8元杂环氧基、C
6-8芳基、C
6-8芳氧基、5-8元杂芳基、5-8元杂芳氧基和-NR
14R
15的取代基所取代;
每个R
13各自独立地选自氢、氘、羟基、C
1-4烷基、C
1-4烷氧基、C
2-4链烯基、C
2-4链炔基、C
3-8环烷基、C
3-8环烷氧基、3-8元杂环基、3-8元杂环氧基、C
6-8芳基、C
6-8芳氧基、5-8元杂芳基、5-8元杂芳氧基和-NR
14R
15,上述基团独立地任选进一步被一个或多个选自氘、卤素、羟基、氰基、C
1-4烷基、C
1-4烷氧基、C
3-8环烷基、C
3-8环烷氧基、3-8元杂环基、3-8元杂环氧基、C
6-8芳基、C
6-8芳氧基、5-8元杂芳基、5-8元杂芳氧基和-NR
14R
15的取代基所取代;
每个R
14和R
15各自独立地选自氢、氘、羟基、C
1-4烷氧基、C
1-4烷基、C
2-4链烯基、C
2-4链炔基、C
3-8环烷基、3-8元杂环基、C
6-8芳基、5-8元杂芳基、亚磺酰基、磺酰基、甲磺酰基、异丙磺酰基、环丙基磺酰基、对甲苯磺酰基、氨基磺酰基、二甲氨基磺酰基、氨基、单C
1-4烷基氨基、二C
1-4烷基氨基和C
1-4烷酰基,上述基团独立地任选进一步被一个或多个选自氘、卤素、羟基、C
1-4烷基、C
2-4链烯基、C
2-4链炔基、卤取代C
1-4烷基、氘取代C
1-4烷基、C
1-4烷氧基、C
3-8环烷基、C
3-8环烷氧基、3-8元杂环基、3-8元杂环氧基、C
6-8芳基、C
6-8芳氧基、5-8元杂芳 基、5-8元杂芳氧基、氨基、单C
1-4烷基氨基、二C
1-4烷基氨基和C
1-4烷酰基的取代基所取代,
或者,R
14和R
15与其直接相连的氮原子一起形成4-8元杂环基或5-8元杂芳基,上述基团独立地任选进一步被一个或多个选自氘、卤素、羟基、C
1-4烷基、C
2-4链烯基、C
2-4链炔基、卤取代C
1-4烷基、氘取代C
1-4烷基、C
1-4烷氧基、C
3-8环烷基、C
3-8环烷氧基、3-8元杂环基、3-8元杂环氧基、C
6-8芳基、C
6-8芳氧基、5-8元杂芳基、5-8元杂芳氧基、氨基、单C
1-4烷基氨基、二C
1-4烷基氨基和C
1-4烷酰基的取代基所取代;
m为0、1或2;
n为0、1或2;且
每个r各自独立地为0、1或2。
作为更进一步优选的方案,式(I)化合物为如下式(Ⅲa)化合物:
其中,X为CH或N;Z
2为CH或N;
R
2、R
4或R
5其中一个和R
1与其直接相连的部分一起形成如下结构:
R
6选自氢、氘、C
1-2烷基、卤取代C
1-2烷基和氘取代C
1-2烷基;
R
8和R
9各自独立地选自氢、氘、氟、氯、溴、甲基、乙基、丙基、异丙基、环丙基、-CHF
2、-CF
3、-CHD
2和-CD
3;
R
10a和R
10b各自独立地选自氢、氘、氟、氯、溴、氰基、甲基、乙基、丙基、异丙基、环丙基、-CHF
2、-CF
3、-CHD
2、-CD
3、甲氧基、氮杂环丁基、乙烯基、乙炔基和苯基,或者,R
10a和R
10b与其直接相连的部分一起形成C
4-6环烷基或4-6元杂环基。
作为进一步优选的方案,式(I)化合物为如下式(Ⅱb)化合物:
其中,X为CH或N;Y为键、O或S;Z
1为CR
10或N;Z
2为CH或N;
R
1选自氢、氘、C
1-4烷基、卤取代C
1-4烷基、氘取代C
1-4烷基和C
2-4链烯基;
R
2和R
3各自独立地选自氢、氘和C
1-4烷基,上述基团独立地任选进一步被一个或多个选自氘、卤素、羟基、C
1-4烷基、C
2-4链烯基、C
2-4链炔基、卤取代C
1-4烷基、氘取代C
1-4烷基和-C
0-4烷基-NR
14R
15的取代基所取代;
R
4选自氢、氘、卤素、C
1-4烷基、卤取代C
1-4烷基和氘取代C
1-4烷基;
R
5选自氢、氘、卤素、C
1-4烷基、卤取代C
1-4烷基和氘取代C
1-4烷基;
R
6选自氢、氘、C
1-4烷基、卤取代C
1-4烷基、氘取代C
1-4烷基、C
2-4链烯基、C
3-8环烷基和3-8元杂环基;
R
8和R
9各自独立地选自氢、氘、卤素、氰基、C
1-4烷基、C
2-4链烯基、C
2-4链炔基、C
3-8环烷基、3-8元杂环基、C
6-8芳基和5-8元杂芳基,或者,R
8和R
9与其直接相连的碳原子一起形成C
3-6环烷基或3-6元杂环基,上述基团独立地任选进一步被一个或多个选自氘、卤素、氰基、羟基、C
1-4烷基、C
1-4烷氧基、C
2-4链烯基、C
2-4链炔基、卤取代C
1-4烷基、卤取代C
1-4烷氧基、氘取代C
1-4烷基、氘取代C
1-4烷氧基、C
3-8环烷基、C
3-8环烷氧基、3-8元杂环基、3-8元杂环氧基、C
6-8芳基和5-8元杂芳基的取代基所取代;
每个R
10各自独立地选自氢、氘、卤素、氰基、硝基、叠氮基、C
1-4烷基、C
2-4链烯基、C
2-4链炔基、C
3-6环烷基、3-6元杂环基、C
6-8芳基、5-8元杂芳基、-SF
5、-S(O)
rR
11、-O-R
12、-C(O)OR
12、-C(O)R
13、-O-C(O)R
13、-NR
14R
15、-C(O)NR
14R
15和-N(R
14)-C(O)R
13,或者,相邻的两个R
10与其直接相连的部分一起形成C
4-6环烷基或4-6元杂环基,上述基团独立地任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C
1-4烷基、C
2-4链烯基、C
2-4链炔基、卤取代C
1-4烷基、C
3-8环烷基、3-8元杂环基、C
6-8芳基、5-8元杂芳基、=O、-SF
5、-S(O)
rR
11、-O-R
12、-C(O)OR
12、-C(O)R
13、-O-C(O)R
13、-NR
14R
15、-C(=NR
14)R
13、-N(R
14)-C(=NR
15)R
13、-C(O)NR
14R
15和-N(R
14)-C(O)R
13的取代基所取代,条件是,当X为CH,Y为键,n为1时,R
10与R
10a其中之一为氢、卤素或C
1-4烷基时,另一个不为氢、卤素或C
1-4烷基;
每个R
11各自独立地选自氢、氘、羟基、C
1-4烷基、C
2-4链烯基、C
3-8环烷基、3-8元杂环基、C
6-8芳基、5-8元杂芳基和-NR
14R
15,上述基团独立地任选进一步被一个或多个选自氘、卤素、羟基、氧代、C
1-4烷基、C
1-4烷氧基、C
3-8环烷基、C
3-8环烷氧基、3-8元杂环基、3-8元杂环氧基、C
6-8芳基、C
6-8芳氧基、5-8元杂芳基、 5-8元杂芳氧基和-NR
14R
15的取代基所取代;
每个R
12各自独立地选自氢、氘、C
1-4烷基、C
2-4链烯基、C
3-8环烷基、3-8元杂环基、C
6-8芳基和5-8元杂芳基,上述基团独立地任选进一步被一个或多个选自氘、卤素、羟基、氧代、氰基、C
1-4烷基、C
1-4烷氧基、C
3-8环烷基、C
3-8环烷氧基、3-8元杂环基、3-8元杂环氧基、C
6-8芳基、C
6-8芳氧基、5-8元杂芳基、5-8元杂芳氧基和-NR
14R
15的取代基所取代;
每个R
13各自独立地选自氢、氘、羟基、C
1-4烷基、C
1-4烷氧基、C
2-4链烯基、C
2-4链炔基、C
3-8环烷基、C
3-8环烷氧基、3-8元杂环基、3-8元杂环氧基、C
6-8芳基、C
6-8芳氧基、5-8元杂芳基、5-8元杂芳氧基和-NR
14R
15,上述基团独立地任选进一步被一个或多个选自氘、卤素、羟基、氰基、C
1-4烷基、C
1-4烷氧基、C
3-8环烷基、C
3-8环烷氧基、3-8元杂环基、3-8元杂环氧基、C
6-8芳基、C
6-8芳氧基、5-8元杂芳基、5-8元杂芳氧基和-NR
14R
15的取代基所取代;
每个R
14和R
15各自独立地选自氢、氘、羟基、C
1-4烷氧基、C
1-4烷基、C
2-4链烯基、C
2-4链炔基、C
3-8环烷基、3-8元杂环基、C
6-8芳基、5-8元杂芳基、亚磺酰基、磺酰基、甲磺酰基、异丙磺酰基、环丙基磺酰基、对甲苯磺酰基、氨基磺酰基、二甲氨基磺酰基、氨基、单C
1-4烷基氨基、二C
1-4烷基氨基和C
1-4烷酰基,上述基团独立地任选进一步被一个或多个选自氘、卤素、羟基、C
1-4烷基、C
2-4链烯基、C
2-4链炔基、卤取代C
1-4烷基、氘取代C
1-4烷基、C
1-4烷氧基、C
3-8环烷基、C
3-8环烷氧基、3-8元杂环基、3-8元杂环氧基、C
6-8芳基、C
6-8芳氧基、5-8元杂芳基、5-8元杂芳氧基、氨基、单C
1-4烷基氨基、二C
1-4烷基氨基和C
1-4烷酰基的取代基所取代,
或者,R
14和R
15与其直接相连的氮原子一起形成4-8元杂环基或5-8元杂芳基,上述基团独立地任选进一步被一个或多个选自氘、卤素、羟基、C
1-4烷基、C
2-4链烯基、C
2-4链炔基、卤取代C
1-4烷基、氘取代C
1-4烷基、C
1-4烷氧基、C
3-8环烷基、C
3-8环烷氧基、3-8元杂环基、3-8元杂环氧基、C
6-8芳基、C
6-8芳氧基、5-8元杂芳基、5-8元杂芳氧基、氨基、单C
1-4烷基氨基、二C
1-4烷基氨基和C
1-4烷酰基的取代基所取代;
m为0、1或2;
n为0、1或2;且
每个r各自独立地为0、1或2。
作为更进一步优选的方案,式(I)化合物为如下式(Ⅲb)化合物:
其中,X为CH或N;Y为键、O或S;Z
1为CR
10或N;Z
2为CH或N;
R
6选自氢、氘、C
1-4烷基、卤取代C
1-2烷基和氘取代C
1-2烷基;
R
8和R
9各自独立地选自氢、氘、氟、氯、溴、甲基、乙基、丙基、异丙基、环丙基、-CHF
2、-CF
3、-CHD
2和-CD
3;
R
10和R
10a各自独立地选自氢、氘、氟、氯、溴、氰基、甲基、乙基、丙基、异丙基、环丙基、甲氧基、乙炔基、氮杂环丁基、吡唑和苯基,或者,R
10与R
10a其直接相连的部分一起形成环戊基或5元杂环基,上述基团独立地任选进一步被一个或多个选自氘、氟、氯、溴、氰基、C
1-4烷基、C
2-4链烯基、C
2-4链炔基、卤取代C
1-4烷基和环丙基的取代基所取代,条件是,当X为CH,Y为键,n为1时,R
10与R
10a其中之一为氢、氘、氟、氯、溴、氰基、甲基、乙基、丙基或异丙基时,另一个不为氢、氘、氟、氯、溴、氰基、甲基、乙基、丙基或异丙基;
n为0、1或2。
作为最优选的方案,所述式(I)化合物、其立体异构体或其药学上可接受盐包括但不限于如下化合物:
本发明第二方面提供式(I)化合物、其立体异构体或其药学上可接受盐的制备方法,包括如下步骤:
或者,
其中,R
1、R
2、R
3、R
4、R
5、R
6、R
7、R
8、R
9、R
10、X、Y、Z
1、Z
2、m和n如式(I)化合物中所定义。
本发明第三方面提供一种药物组合物,其包括式(I)化合物、其立体异构体或其药学上可接受盐及可药用的载体。
本发明还涉及所述式(I)化合物、其立体异构体或其药学上可接受盐在制备治疗和/或预防至少部分与EGFR外显子20插入、缺失或其他突变相关的癌症、肿瘤或转移性疾病的药物中的用途。
本发明还涉及式(I)化合物、其立体异构体或其药学上可接受盐在制备预防和/或治疗由过度增殖和诱导细胞死亡障碍引起的肿瘤、癌症和/或转移性疾病的药物中的用途。本发明还涉及前述式(I)化合物、其立体异构体或其药学上可接受盐在制备预防和/或治疗肺癌、结肠癌、胰腺癌、头颈癌、乳腺癌、卵巢癌、子宫癌、胃癌、非小细胞肺癌、白血病、骨髓增生异常综合症、恶性淋巴瘤、头颈部肿瘤、胸腔肿瘤、胃肠道肿瘤、内分泌肿瘤、乳腺和其他妇科肿瘤、泌尿科肿瘤、皮肤肿瘤、肉瘤、鼻腔鼻窦内翻性乳头状瘤或鼻腔鼻窦内翻性乳头状瘤相关的鼻腔鼻窦鳞状细胞癌药物中的用途。
本发明还涉及所述式(I)化合物、其立体异构体或其药学上可接受盐,其用作药物。
本发明还涉及所述式(I)化合物、其立体异构体或其药学上可接受盐,其用于治疗和/或预防至少部分与EGFR外显子20插入、缺失或其他突变相关的癌症、肿瘤或转移性疾病的用途。
本发明还涉及所述式(I)化合物、其立体异构体或其药学上可接受盐,其用于预防和/或治疗由过度增殖和诱导细胞死亡障碍引起的肿瘤、癌症和/或转移性疾病的用途。
本发明还涉及所述式(I)化合物、其立体异构体或其药学上可接受盐,其用于治疗和/或预防至少部分与EGFR外显子20插入、缺失或其他突变相关的肺癌、结肠癌、胰腺癌、头颈癌、乳腺癌,卵巢癌,子宫癌、胃癌、非小细胞肺癌、白血病、骨髓增生异常综合症、恶性淋巴瘤、头颈部肿瘤、胸腔肿瘤、胃肠道肿瘤、内分泌肿瘤、乳腺和其他妇科肿瘤、泌尿科肿瘤、皮肤肿瘤、肉瘤、鼻腔鼻窦内翻性乳头状瘤或鼻腔鼻窦内翻性乳头状瘤相关的鼻腔鼻窦鳞状细胞癌的用途。
本发明还涉及一种治疗和/或预防至少部分与EGFR外显子20插入、缺失或其 他突变相关的癌症、肿瘤或转移性疾病的方法,其包括向所需患者施用治疗有效量的所述式(I)化合物、其立体异构体或其药学上可接受盐。
本发明还涉及一种预防和/或治疗由过度增殖和诱导细胞死亡障碍引起的肿瘤、癌症和/或转移性疾病的方法,其包括向所需患者施用治疗有效量的所述式(I)化合物、其立体异构体或其药学上可接受盐。
本发明还涉及一种治疗和/或预防至少部分与EGFR外显子20插入、缺失或其他突变相关的肺癌、结肠癌、胰腺癌、头颈癌、乳腺癌,卵巢癌,子宫癌、胃癌、非小细胞肺癌、白血病、骨髓增生异常综合症、恶性淋巴瘤、头颈部肿瘤、胸腔肿瘤、胃肠道肿瘤、内分泌肿瘤、乳腺和其他妇科肿瘤、泌尿科肿瘤、皮肤肿瘤、肉瘤、鼻腔鼻窦内翻性乳头状瘤或鼻腔鼻窦内翻性乳头状瘤相关的鼻腔鼻窦鳞状细胞癌的方法,其包括向所需患者施用治疗有效量的所述式(I)化合物、其立体异构体或其药学上可接受盐。
本申请的发明人经过广泛而深入地研究,首次研发出一种具有如下式(Ⅰ)结构的EGFR抑制剂,本发明系列化合物可广泛应用于制备治疗和/或预防至少部分与EGFR外显子20插入、缺失或其他突变相关的癌症、肿瘤或转移性疾病的药物,特别是治疗过度增殖性疾病和诱导细胞死亡障碍疾病的药物,有望开发成新一代EGFR抑制剂。在此基础上,完成了本发明。
详细说明:除非有相反陈述或特别说明,下列用在说明书和权利要求书中的术语具有下述含义。
“烷基”指直链或含支链的饱和脂族烃基团,优选包括1至10个或1至6个碳原子或1至4个碳原子的直链烷基和含支链烷基,包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基戊基、2,4-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、2,2-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基或其各种支链异构体等。“C
1-10烷基”指包括1至10个碳原子的直链烷基和含支链烷基,“C
1-6烷基”指包括1至6个碳原子的直链烷基和含支链烷基,“C
1-4烷基”指包括1至4个碳原子的直链烷基和含支链烷基,“C
1-2烷基”指包括1至2个碳原子的直链烷基,“C
0-8烷基”指包括0至8个碳原子的直链烷基和含支链烷基,“C
0-4烷基”指包括0 至4个碳原子的直链烷基和含支链烷基,“C
0-2烷基”指包括0至2个碳原子的直链烷基和含支链烷基。
烷基可以是任选取代的或未取代的,当被取代时,取代基优选为一个或多个(优选1、2、3或4个)以下基团,独立地选自氘、卤素、氰基、硝基、叠氮基、C
1-10烷基、C
2-10链烯基、C
2-10链炔基、卤取代C
1-10烷基、氘取代C
1-10烷基、C
3-12环烷基、3-12元杂环基、C
6-10芳基、5-10元杂芳基、=O、-SF
5、-S(O)
rR
11、-O-R
12、-C(O)OR
12、-C(O)R
13、-O-C(O)R
13、-NR
14R
15、-C(=NR
14)R
13、-N(R
14)-C(=NR
15)R
13、-C(O)NR
14R
15或-N(R
14)-C(O)R
13的取代基所取代。
“环烷基”或“碳环”指饱和或部分不饱和单环或多环环状烃取代基,所述部分不饱和环状烃是指环状烃可以含有一个或多个(优选1、2或3个)双键,但没有一个环具有完全共轭的π电子系统,环烷基分为单环环烷基、多环环烷基,优选包括3至12个或3至8个或3至6个碳原子的环烷基,例如,“C
3-12环烷基”指包括3至12个碳原子的环烷基,“C
3-8环烷基”指包括3至8个碳原子的环烷基,“C
3-6环烷基”指包括3至6个碳原子的环烷基,“C
4-8环烷基”指包括4至8个碳原子的环烷基,“C
4-6环烷基”指包括4至6个碳原子的环烷基,其中:
单环环烷基包括但不限于环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等。
多环环烷基包括螺环、稠环和桥环的环烷基。“螺环烷基”指单环之间共用一个碳原子(称螺原子)的多环基团,这些可以含有一个或多个(优选1、2或3个)双键,但没有一个环具有完全共轭的π电子系统。根据环与环之间共用螺原子的数目将螺环烷基分为单螺环烷基、双螺环烷基或多螺环烷基,螺环烷基包括但不限于:
“稠环烷基”指系统中的每个环与体系中的其他环共享毗邻的一对碳原子的全碳多环基团,其中一个或多个环可以含有一个或多个(优选1、2或3个)双键,但没有一个环具有完全共轭的π电子系统。根据组成环的数目可以分为双环、三环、四环或多环稠环烷基,稠环烷基包括但不限于:
“桥环烷基”指任意两个环共用两个不直接连接的碳原子的全碳多环基团,这些可以含有一个或多个(优选1、2或3个)双键,但没有一个环具有完全共轭的π电子系统。根据组成环的数目可以分为双环、三环、四环或多环桥环烷基,桥环烷基包括但不限于:
所述环烷基环可以稠合于芳基、杂芳基或杂环烷基环上,其中与母体结构连接在一起的环为环烷基,包括但不限于茚满基、四氢萘基、苯并环庚烷基等。
环烷基可以是任选取代的或未取代的,当被取代时,取代基优选为一个或多个(优选1、2、3或4个)以下基团,独立地选自氘、卤素、氰基、硝基、叠氮基、C
1-10烷基、C
2-10链烯基、C
2-10链炔基、卤取代C
1-10烷基、氘取代C
1-10烷基、C
3-12环烷基、3-12元杂环基、C
6-10芳基、5-10元杂芳基、=O、-SF
5、-S(O)
rR
11、-O-R
12、-C(O)OR
12、-C(O)R
13、-O-C(O)R
13、-NR
14R
15、-C(=NR
14)R
13、-N(R
14)-C(=NR
15)R
13、-C(O)NR
14R
15或-N(R
14)-C(O)R
13的取代基所取代。
“杂环基”或“杂环”指饱和或部分不饱和单环或多环环状烃取代基,所述部分不饱和环状烃是指环状烃可以含有一个或多个(优选1、2或3个)双键,但没有一个环具有完全共轭的π电子系统,杂环基其中一个或多个(优选1、2、3或4个)环原子选自氮、氧或S(O)
r(其中r是整数0、1、2)的杂原子,但不包括-O-O-、-O-S-或-S-S-的环部分,其余环原子为碳,优选包括3至12个或3至8个或3至6个环原子的杂环基,例如,“3-6元杂环基”指包含3至6个环原子的环基,“3-8元杂环基”指包含3至8个环原子的环基,“3-12元杂环基”指包含3至12个环原子的环基,“4-6元杂环基”指包含4至6个环原子的环基,“4-8元杂环基”指包含4至8个环原子的环基,“4-10元杂环基”指包含4至10个环原子的环基,“5元杂环基”指包含5个环原子的环基。
单环杂环基包括但不限于吡咯烷基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基等。
多环杂环基包括螺环、稠环和桥环的杂环基。“螺杂环基”指单环之间共用一个原子(称螺原子)的多环杂环基团,其中一个或多个(优选1、2、3或4个)环原子选自氮、氧或S(O)
r(其中r是整数0、1、2)的杂原子,其余环原子为碳。这些可以含有一个或多个双键(优选1、2或3个),但没有一个环具有完全共轭的π电子系统。根据环与环之间共用螺原子的数目将螺杂环基分为单螺杂环基、双螺杂环基或多螺杂环基。螺杂环基包括但不限于:
“稠杂环基”指系统中的每个环与体系中的其他环共享毗邻的一对原子的多环杂环基团,一个或多个(优选1、2、3或4个)环可以含有一个或多个(优选1、2或3个)双键,但没有一个环具有完全共轭的π电子系统,其中一个或多个(优选1、2、3或4个)环原子选自氮、氧或S(O)
r(其中r是整数0、1、2)的杂原子,其余环原子为碳。根据组成环的数目可以分为双环、三环、四环或多环稠杂环烷基,稠杂环基包括但不限于:
“桥杂环基”指任意两个环共用两个不直接连接的原子的多环杂环基团,这些可以含有一个或多个(优选1、2或3个)双键,但没有一个环具有完全共轭的π电子系统,其中一个或多个(优选1、2、3或4个)环原子选自氮、氧或S(O)
r(其中r是整数0、1、2)的杂原子,其余环原子为碳。根据组成环的数目可以分为双环、三环、四环或多环桥杂环基,桥杂环基包括但不限于:
所述杂环基环可以稠合于芳基、杂芳基或环烷基环上,其中与母体结构连接在一起的环为杂环基,包括但不限于:
杂环基可以是任选取代的或未取代的,当被取代时,取代基优选为一个或多个(优选1、2、3或4个)以下基团,独立地选自氘、卤素、氰基、硝基、叠氮基、C
1-10烷基、C
2-10链烯基、C
2-10链炔基、卤取代C
1-10烷基、氘取代C
1-10烷基、C
3-12环烷基、3-12元杂环基、C
6-10芳基、5-10元杂芳基、=O、-SF
5、-S(O)
rR
11、-O-R
12、-C(O)OR
12、-C(O)R
13、-O-C(O)R
13、-NR
14R
15、-C(=NR
14)R
13、-N(R
14)-C(=NR
15)R
13、-C(O)NR
14R
15或-N(R
14)-C(O)R
13的取代基所取代。
“芳基”或“芳环”指全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团,具有共轭的π电子体系的多环(即其带有相邻对碳原子的环)基团,优选含有6-10个或6-8个碳的全碳芳基,例如,“C
6-10芳基”指含有6-10个碳的全碳芳基,“C
6-8芳基”指含有6-8个碳的全碳芳基,包括但不限于苯基和萘基。所述芳基环可以稠合于杂芳基、杂环基或环烷基环上,其中与母体结构连接在一起的环为芳基环,包括但不限于:
“芳基”可以是取代的或未取代的,当被取代时,取代基优选为一个或多个(优选1、2、3或4个)以下基团,独立地选自氘、卤素、氰基、硝基、叠氮基、C
1-10烷基、C
2-10链烯基、C
2-10链炔基、卤取代C
1-10烷基、氘取代C
1-10烷基、C
3-12环烷基、3-12元杂环基、C
6-10芳基、5-10元杂芳基、=O、-SF
5、-S(O)
rR
11、-O-R
12、-C(O)OR
12、-C(O)R
13、-O-C(O)R
13、-NR
14R
15、-C(=NR
14)R
13、-N(R
14)-C(=NR
15)R
13、-C(O)NR
14R
15或-N(R
14)-C(O)R
13的取代基所取代。
“杂芳基”指包含一个或多个(优选1、2、3或4个)杂原子的杂芳族体系,所述杂原子包括氮、氧和S(O)r(其中r是整数0、1、2)的杂原子,优选含有5-10个或5-8个或5-6个环原子的杂芳族体系,例如,“5-8元杂芳基”指含有5-8个环原子的杂芳族体系,“5-10元杂芳基”指含有5-10个环原子的杂芳族体系,包括但不限于呋喃基、噻吩基、吡啶基、吡咯基、N-烷基吡咯基、嘧啶基、吡嗪基、咪唑基、四唑基等。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上,其中与母体结构连接在一起的环为杂芳基环,包括但不限于:
“杂芳基”可以是任选取代的或未取代的,当被取代时,取代基优选为一个或多个(优选1、2、3或4个)以下基团,独立地选自氘、卤素、氰基、硝基、叠氮基、C
1-10烷基、C
2-10链烯基、C
2-10链炔基、卤取代C
1-10烷基、氘取代C
1-10烷基、C
3-12环烷基、3-12元杂环基、C
6-10芳基、5-10元杂芳基、=O、-SF
5、-S(O)
rR
11、-O-R
12、-C(O)OR
12、-C(O)R
13、-O-C(O)R
13、-NR
14R
15、-C(=NR
14)R
13、-N(R
14)-C(=NR
15)R
13、-C(O)NR
14R
15或-N(R
14)-C(O)R
13的取代基所取代。
“链烯基”指由至少两个碳原子和至少一个碳-碳双键组成的如上述定义的烷基,优选含有2-10个或2-4个碳的直链或含支链烯基,例如,“C
2-10链烯基”指含有2-10个碳的直链或含支链烯基,“C
2-4链烯基”指含有2-4个碳的直链或含支链烯基。包括但不限于乙烯基、1-丙烯基、2-丙烯基、1-,2-或3-丁烯基等。
“链烯基”可以是取代的或未取代的,当被取代时,取代基优选为一个或多个(优选1、2、3或4个)以下基团,独立地选自氘、卤素、氰基、硝基、叠氮基、C
1-10烷基、C
2-10链烯基、C
2-10链炔基、卤取代C
1-10烷基、氘取代C
1-10烷基、C
3-12环烷基、3-12元杂环基、C
6-10芳基、5-10元杂芳基、=O、-SF
5、-S(O)
rR
11、-O-R
12、-C(O)OR
12、-C(O)R
13、-O-C(O)R
13、-NR
14R
15、-C(=NR
14)R
13、-N(R
14)-C(=NR
15)R
13、-C(O)NR
14R
15或-N(R
14)-C(O)R
13的取代基所取代。
“链炔基”指至少两个碳原子和至少一个碳-碳三键组成的如上所定义的烷基,优选含有2-10个或2-4个碳的直链或含支链炔基,例如,“C
2-10链炔基”指含有2-10个碳的直链或含支链炔基,“C
2-4链炔基”指含有2-4个碳的直链或含支链炔基。包括但不限于乙炔基、1-丙炔基、2-丙炔基、1-,2-或3-丁炔基等。
“链炔基”可以是取代的或未取代的,当被取代时,取代基优选为一个或多个(优选1、2、3或4个)以下基团,独立地选自氘、卤素、氰基、硝基、叠氮基、C
1-10烷基、C
2-10链烯基、C
2-10链炔基、卤取代C
1-10烷基、氘取代C
1-10烷基、C
3-12环烷基、3-12元杂环基、C
6-10芳基、5-10元杂芳基、=O、-SF
5、-S(O)
rR
11、-O-R
12、-C(O)OR
12、-C(O)R
13、-O-C(O)R
13、-NR
14R
15、-C(=NR
14)R
13、-N(R
14)-C(=NR
15)R
13、-C(O)NR
14R
15或-N(R
14)-C(O)R
13的取代基所取代。
“烷氧基”指-O-烷基,其中烷基的定义如上所述,例如,“C
1-10烷氧基”指含1-10个碳的烷基氧基,“C
1-4烷氧基”指含1-4个碳的烷基氧基包括但不限于甲氧基、乙氧基、丙氧基、丁氧基等。
“烷氧基”可以是任选取代的或未取代的,当被取代时,取代基,优选为一个或 多个(优选1、2、3或4个)以下基团,独立地选自氘、卤素、氰基、硝基、叠氮基、C
1-10烷基、C
2-10链烯基、C
2-10链炔基、卤取代C
1-10烷基、氘取代C
1-10烷基、C
3-12环烷基、3-12元杂环基、C
6-10芳基、5-10元杂芳基、=O、-SF
5、-S(O)
rR
11、-O-R
12、-C(O)OR
12、-C(O)R
13、-O-C(O)R
13、-NR
14R
15、-C(=NR
14)R
13、-N(R
14)-C(=NR
15)R
13、-C(O)NR
14R
15或-N(R
14)-C(O)R
13的取代基所取代。
“环烷氧基”指-O-环烷基,其中环烷基的定义如上所述,例如,“C
3-12环烷氧基”指含3-12个碳的环烷基氧基,“C
3-8环烷氧基”指含3-8个碳的环烷基氧基,包括但不限于环丙氧基、环丁氧基、环戊氧基、环己氧基等。
“环烷氧基”可以是任选取代的或未取代的,当被取代时,取代基优选为一个或多个(优选1、2、3或4个)以下基团,独立地选自氘、卤素、氰基、硝基、叠氮基、C
1-10烷基、C
2-10链烯基、C
2-10链炔基、卤取代C
1-10烷基、氘取代C
1-10烷基、C
3-12环烷基、3-12元杂环基、C
6-10芳基、5-10元杂芳基、=O、-SF
5、-S(O)
rR
11、-O-R
12、-C(O)OR
12、-C(O)R
13、-O-C(O)R
13、-NR
14R
15、-C(=NR
14)R
13、-N(R
14)-C(=NR
15)R
13、-C(O)NR
14R
15或-N(R
14)-C(O)R
13的取代基所取代。
“杂环氧基”指-O-杂环基,其中杂环基的定义如上所述,杂环基氧基,包括但不限于氮杂环丁基氧基、氧杂环丁氧基、氮杂环戊基氧基、氮、氧杂环己基氧基等。
“杂环氧基”可以是任选取代的或未取代的,当被取代时,取代基优选为一个或多个(优选1、2、3或4个)以下基团,独立地选自氘、卤素、氰基、硝基、叠氮基、C
1-10烷基、C
2-10链烯基、C
2-10链炔基、卤取代C
1-10烷基、氘取代C
1-10烷基、C
3-12环烷基、3-12元杂环基、C
6-10芳基、5-10元杂芳基、=O、-SF
5、-S(O)
rR
11、-O-R
12、-C(O)OR
12、-C(O)R
13、-O-C(O)R
13、-NR
14R
15、-C(=NR
14)R
13、-N(R
14)-C(=NR
15)R
13、-C(O)NR
14R
15或-N(R
14)-C(O)R
13的取代基所取代。
“C
1-10烷酰基”指C
1-10烷基酸去掉羟基后剩下的一价原子团,通常也表示为“C
0-9烷基-C(O)-”,例如,“C
1烷基-C(O)-”是指乙酰基;“C
2烷基-C(O)-”是指丙酰基;“C
3烷基-C(O)-”是指丁酰基或异丁酰基。
“-C
0-8-NR
14R
15”指-NR
14R
15中的氮原子连接在C
0-8烷基上,其中C
0-8烷基的定义如上所述。
“卤取代C
1-6烷基”指烷基上的氢任选的被氟、氯、溴、碘原子取代的1-6个碳烷基团,包括但不限于二氟甲基(-CHF
2)、二氯甲基(-CHCl
2)、二溴甲基(-CHBr
2)、三氟甲基(-CF
3)、三氯甲基(-CCl
3)、三溴甲基(-CBr
3)等。
“卤取代C
1-10烷氧基”指烷基上的氢任选的被氟、氯、溴、碘原子取代的1-10个碳烷氧基团。包括但不限于二氟甲氧基、二氯甲氧基、二溴甲氧基、三氟甲氧基、三氯甲氧基、三溴甲氧基等。
“氘取代C
1-6烷基”指烷基上的氢任选的被氘原子取代的1-6个碳烷基团。包括但不限于一氘甲基(-CH
2D)、二氘甲基(-CHD
2)、三氘甲基(-CD
3)等。
“氘取代C
1-10烷氧基”指烷基上的氢任选的被氘原子取代的1-10个碳烷基团。包括但不限于一氘甲氧基、二氘甲氧基、三氘甲氧基等。
“卤素”指氟、氯、溴或碘。
“任选”或“任选地”意味着随后所描述地事件或环境可以但不必发生,该说明包括该事件或环境发生或不发生地场合,也即包括取代的或未取代的两种情形。例如,“任选被烷基取代的杂环基团”意味着烷基可以但不必须存在,该说明包括杂环基团被烷基取代的情形和杂环基团不被烷基取代的情形。
“取代的”指基团中的一个或多个“氢原子”彼此独立地被相应数目的取代基取代。不言而喻,取代基仅处在它们的可能的化学位置,符合化学上的价键理论,本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如,具有游离氢的氨基或羟基与具有不饱和键的碳原子(如烯烃)结合时可能是不稳定的。
“立体异构体”,其英文名称为stereoisomer,是指由分子中原子在空间上排列方式不同所产生的异构体,它可分为顺反异构体、对映异构体两种,也可分为对映异构体和非对映异构体两大类。由于单键的旋转而引起的立体异构体称为构象异构体(conformational stereo-isomer),有时也称为旋转异构体(rotamer)。因键长、键角、分子内有双键、有环等原因引起的立体异构体称为构型异构体(configuration stereo-isomer),构型异构体又分为两类。其中因双键或成环碳原子的单键不能自由旋转而引起的异构体成为几何异构体(geometric isomer),也称为顺反异构体(cis-trans isomer),分为Z、E两种构型。例如:顺-2-丁烯和反-2-丁烯是一对几何异构体,本发明化合物如果包含双键,如未特别指明,可理解为包含E和/或Z型。因分子中没有反轴对称性而引起的具有不同旋光性能的立体异构体称为旋光异构体(optical isomer),分为R、S构型。在本发明中所述“立体异构体”如未特别指明,可理解为包含上述对映异构体、构型异构体和构象异构体中的一种或几种,优选为S构型。
“药学上可接受盐”在本发明中是指药学上可接受的酸加成盐或碱加成盐,包括无机酸盐和有机酸盐,这些盐可通过本专业已知的方法制备。
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上/可药用的盐或前体药物与其他化学组分的混合物,以及其他组分例如生理学/可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药,利于活性成分的吸收进而发挥生物活性。
下面结合实施例对本发明做进一步详细、完整地说明,但绝非限制本发明,本发明也并非仅局限于实施例的内容。
本发明的化合物结构是通过核磁共振(NMR)或/和液质联用色谱(LC-MS)来确定的。NMR化学位移(δ)以百万分之一(ppm)的单位给出。NMR的测定是用Bruker AVANCE-400/500核磁仪,测定溶剂为氘代二甲基亚砜(DMSO-d
6),氘代甲 醇(CD
3OD)和氘代氯仿(CDCl
3),内标为四甲基硅烷(TMS)。
液质联用色谱LC-MS的测定用Agilent 6120质谱仪。HPLC的测定使用安捷伦1200DAD高压液相色谱仪(Sunfire C18 150×4.6mm色谱柱)和Waters 2695-2996高压液相色谱仪(Gimini C18 150×4.6mm色谱柱)。
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板,TLC采用的规格是0.15mm~0.20mm,薄层层析分离纯化产品采用的规格是0.4mm~0.5mm。柱层析一般使用烟台黄海硅胶200~300目硅胶为载体。
本发明实施例中的起始原料是已知的并且可以在市场上买到,或者可以采用或按照本领域已知的方法来合成。
在无特殊说明的情况下,本发明的所有反应均在连续的磁力搅拌下,在干燥氮气或氩气氛下进行,溶剂为干燥溶剂,反应温度单位为摄氏度(℃)。
一、中间体的制备
中间体A1:(R)-1-(4-氨基-5-甲氧基-2-硝基苯基)-N,N-二甲基吡咯烷-3-胺的制备
将4-氟-2-甲氧基-5-硝基苯胺(500mg,2.69mmol)溶于N,N-二甲基甲酰胺(10mL)中。室温下,向溶液中加入(R)-N,N-二甲基吡咯烷-3-胺(367mg,3.22mmol)及碳酸钾(742mg,5.38mmol)。反应在室温下搅拌16小时。向溶液中加入水,用乙酸乙酯萃取三次。合并有机相后,用饱和食盐水洗涤,经无水硫酸钠干燥。除去溶剂后,硅胶柱层析分离[二氯甲烷:甲醇=10:1]得到(R)-1-(4-氨基-5-甲氧基-2-硝基苯基)-N,N-二甲基吡咯烷-3-胺(480mg,收率:60%)。ESI-MS:281.0[M+1]
+。
中间体A2:N
1-(2-(二甲氨基)乙基)-5-甲氧基-N
1-甲基-2-硝基苯-1,4-二胺的制备
中间体A2的制备可参照中间体A1的合成方法将(R)-N,N-二甲基吡咯烷-3-胺换成N
1,N
1,N
2-三甲基乙烷-1,2-二胺制备得到。
中间体A3:(R)-6-(3-(二甲氨基)吡咯烷-1-基)-2-甲氧基-5-硝基吡啶-3-胺的制备
第一步:6-溴-2-甲氧基-3-硝基吡啶的合成
冰浴下,在2,6-二溴-3-硝基吡啶(20g,70.9mmol,1eq.)的四氢呋喃(300mL)溶液中加入甲醇钠(5.3g,78.0mmol,1.1eq.)。反应在室温下搅拌3小时。将反应液倒入冰水中,加入乙酸乙酯萃取。合并有机相,加入饱和食盐水洗涤,有机相浓缩后柱层析分离[石油醚:乙酸乙酯=5:1]得到6-溴-2-甲氧基-3-硝基吡啶(13.9g,收率:85%)。ESI-MS:217.1[M-15]
+。
第二步:6-溴-2-甲氧基吡啶-3-胺的合成
在6-溴-2-甲氧基-3-硝基吡啶(13.9g,60.1mmol,1eq.)的[乙醇/水=2:1]溶液中,加入铁粉(26.9g,480.8mmol,8eq.)及氯化铵(25.9g,480.8mmol,8eq.)。反应在约90℃下搅拌3小时。用二氯甲烷和水分层。有机相浓缩后柱层析分离[石油醚:乙酸乙酯=3:1]得到6-溴-2-甲氧基吡啶-3-胺(9.1g,收率:75%)。ESI-MS:203.1[M+1]
+。
1H NMR(400MHz,DMSO-d
6)δ6.89(d,J=7.9Hz,1H),6.83(d,J=7.9Hz,1H),5.10(s,2H),3.84(s,3H)。
第三步:N-(6-溴-2-甲氧基吡啶-3-基)乙酰胺的合成
冰浴下,在6-溴-2-甲氧基吡啶-3-胺(9.1g,44.8mmol,1eq.)的二氯甲烷(200mL)溶液中,加入三乙胺(6.7g,67.2mmol,1.5eq.)和乙酰氯(3.8g,49.2mmol,1.1eq.)。反应在冰浴下搅拌1小时。用二氯甲烷和水分层,有机相浓缩后柱层析分离[石油醚:乙酸乙酯=5:1]得到N-(6-溴-2-甲氧基吡啶-3-基)乙酰胺(9.5g,收率:86%)。直接用于下一步。
第四步:N-(6-溴-2-甲氧基-5-硝基吡啶-3-基)乙酰胺的合成
冰浴下,在N-(6-溴-2-甲氧基吡啶-3-基)乙酰胺(9.5g,38.9mmol,1eq.)的三氟乙酸酐(80mL)溶液中,加入浓硝酸(65%,46.6mmol,1.2eq.)。反应在冰浴下搅拌1小时。反应液缓慢倒入冰水中,搅拌1小时,析出固体,抽滤,滤饼干燥得到N-(6-溴-2-甲氧基-5-硝基吡啶-3-基)乙酰胺(11.5g,收率:100%)。ESI-MS:290.1[M+1]
+。
1H NMR(400MHz,DMSO-d
6)δ9.90(s,1H),9.12(s,1H),4.06(s,3H),2.16(s,3H)。
第五步:(R)-N-(6-(3-(二甲氨基)吡咯烷-1-基)-2-甲氧基-5-硝基吡啶-3-基)乙酰胺的合成
在N-(6-溴-2-甲氧基-5-硝基吡啶-3-基)乙酰胺(1.0g,3.4mmol,1eq.)的乙腈(20mL)溶液中,加入(R)-N,N-二甲基吡咯烷-3-胺(581mg,5.1mmol,1.5eq.)。反应液在80℃下搅拌1小时。除去溶剂后,硅胶柱层析分离[二氯甲烷:甲醇=10:1]得到(R)-N-(6-(3-(二甲氨基)吡咯烷-1-基)-2-甲氧基-5-硝基吡啶-3-基)乙酰胺(864mg,收率:86%)。ESI-MS:324.3[M+1]
+。
第六步:(R)-6-(3-(二甲氨基)吡咯烷-1-基)-2-甲氧基-5-硝基吡啶-3-胺的合成
在(R)-N-(6-(3-(二甲氨基)吡咯烷-1-基)-2-甲氧基-5-硝基吡啶-3-基)乙酰胺(864mg,2.9mmol,1eq.)的甲醇(10mL)溶液中,加入浓盐酸(37%,1.5mL,18mmol,6.2eq.)。反应在60℃下搅拌5小时。用饱和NaHCO
3溶液和二氯甲烷分层。有机相浓缩后得到(R)-6-(3-(二甲氨基)吡咯烷-1-基)-2-甲氧基-5-硝基吡啶-3-胺(845mg,收率:100%)。ESI-MS:282.3[M+1]
+。
中间体A4:N
2-(2-(二甲氨基)乙基)-6-甲氧基-N
2-甲基-3-硝基吡啶-2,5-二胺的制备
第一步:N-(6-((2-(二甲氨基)乙基)(甲基)氨基)-2-甲氧基-5-硝基吡啶-3-基)乙酰胺的合成
在N-(6-溴-2-甲氧基-5-硝基吡啶-3-基)乙酰胺(1.0g,3.4mmol,1eq.)的乙腈(20mL)溶液中,加入N
1,N
1,N
2-三甲基乙烷-1,2-二胺(520mg,5.1mmol,1.5eq.)。反应液在80℃下搅拌1小时。除去溶剂后,硅胶柱层析分离[二氯甲烷:甲醇=10:1]得到N-(6-((2-(二甲氨基)乙基)(甲基)氨基)-2-甲氧基-5-硝基吡啶-3-基)乙酰胺(756mg,收率:71%)。ESI-MS:312.3[M+1]
+。
第二步:N
2-(2-(二甲氨基)乙基)-6-甲氧基-N
2-甲基-3-硝基吡啶-2,5-二胺的合成
在N-(6-((2-(二甲氨基)乙基)(甲基)氨基)-2-甲氧基-5-硝基吡啶-3-基)乙酰胺(756mg,2.4mmol,1eq.)的甲醇(10mL)溶液中,加入浓盐酸(37%,1.5mL,18mmol,7.5eq.)。反应在60℃下搅拌5小时。用饱和NaHCO
3溶液和二氯甲烷分层。有机相浓缩后得到N
2-(2-(二甲氨基)乙基)-6-甲氧基-N
2-甲基-3-硝基吡啶-2,5-二胺(645mg,收率:100%)。ESI-MS:270.3[M+1]
+。
中间体A5:(R)-6-(3-(二甲氨基)吡咯烷-1-基)-5-硝基-2-(2,2,2-三氟乙氧基)吡啶-3-胺的制备
第一步:6-溴-3-硝基-2-(2,2,2-三氟乙氧基)吡啶的合成
冰浴下,向三氟乙醇(2.0g,0.2mmol)的四氢呋喃(10mL)溶液中慢慢加入钠氢(60%,0.88g,0.22mmol)。冰浴下搅拌1小时。室温下,向三口瓶中依次加入2,6-二溴-3-硝基吡啶(5g,17.7mmol)、THF(150mL),冰浴下加入三氟乙醇钠的四氢呋喃溶液。反应结束后,将反应液倒入冰水(100mL)中,加入MTBE(甲基叔丁基醚)(100mL*3)萃取,合并有机相,加入饱和食盐水洗涤,有机相浓缩,粗品分离得到6-溴-3-硝基-2-(2,2,2-三氟乙氧基)吡啶(3.2g,收率:60%)。
1H NMR(400MHz,CDCl
3)δ8.22(d,J=8.4Hz,1H),7.36(d,J=4.0Hz,1H),4.94-4.87(m,2H)。
第二步:6-溴-2-(2,2,2-三氟乙氧基)吡啶-3-胺的合成
将6-溴-3-硝基-2-(2,2,2-三氟乙氧基)吡啶(3.2g,10.6mmol)溶于90mL的混合溶液中[乙醇/水=2:1]中,室温下往溶液中加入铁粉(2.97g,53mmol)及氯化铵(2.86g,53mmol)。反应液升温至90℃,1小时后反应结束。反应液经硅藻土过滤后浓缩,加水,用乙酸乙酯萃取三次。合并有机相后,用饱和食盐水洗涤,经无水硫酸钠干燥。除去溶剂后,得到6-溴-2-(2,2,2-三氟乙氧基)吡啶-3-胺(2.8g,收率:100%)。ESI-MS:271.1[M+1]
+。
第三步:N-(6-溴-2-(2,2,2-三氟乙氧基)吡啶-3-基)乙酰胺的合成
将6-溴-2-(2,2,2-三氟乙氧基)吡啶-3-胺(2.8g,10.6mmol)溶于醋酐(8.6g,84.8mmol)中,室温下搅拌1小时后,反应结束。反应液加水搅拌1小时,析出固体,抽滤,滤饼干燥得到N-(6-溴-2-(2,2,2-三氟乙氧基)吡啶-3-基)乙酰胺(2.2g,收率:68%)。ESI-MS:312.8.[M+1]
+。
第四步:N-(6-溴-5-硝基-2-(2,2,2-三氟乙氧基)吡啶-3-基)乙酰胺的合成
将N-(6-溴-2-(2,2,2-三氟乙氧基)吡啶-3-基)乙酰胺(2.2g,7.0mmol)溶于三氟乙酸酐(20mL)中,降温至0℃,冰浴下加入浓硝酸(65%,1.13g,10.5mmol)。冰浴下搅拌1小时后,反应结束。反应液缓慢倒入冰水中,搅拌1小时,析出固体,抽滤,滤饼干燥得到N-(6-溴-5-硝基-2-(2,2,2-三氟乙氧基)吡啶-3-基)乙酰胺(2.14g,收率:86%)。直接用于下一步反应。
第五步:(R)-N-(6-(3-(二甲氨基)吡咯烷-1-基)-5-硝基-2-(2,2,2-三氟乙氧基)吡啶-3-基)乙酰胺的合成
将N-(6-溴-5-硝基-2-(2,2,2-三氟乙氧基)吡啶-3-基)乙酰胺(1.0g,2.79mmol)溶于乙腈(20mL)中,室温下往溶液中加入(R)-N,N-二甲基吡咯烷-3-胺(382mg,3.35mmol)。反应液升温至80℃,1小时后反应结束。除去溶剂后,硅胶柱层析分离[二氯甲烷:甲醇=10:1]得到(R)-N-(6-(3-(二甲氨基)吡咯烷-1-基)-5-硝基-2-(2,2,2-三氟乙氧基)吡啶-3-基)乙酰胺(684mg,收率:63%)。ESI-MS:392.0.[M+1]
+。
第六步:(R)-6-(3-(二甲氨基)吡咯烷-1-基)-5-硝基-2-(2,2,2-三氟乙氧基)吡啶-3-胺的合成
将(R)-N-(6-(3-(二甲氨基)吡咯烷-1-基)-5-硝基-2-(2,2,2-三氟乙氧基)吡啶-3-基)乙酰胺(658mg,1.68mmol)溶于甲醇(5mL)中,室温下加入浓盐酸(37%,331mg,3.36mmol)。反应升温至60℃,搅拌10小时后,反应结束。将反应液加饱和NaHCO
3溶液中和至pH=8~9。除去溶剂后,加水,用二氯甲烷萃取。合并有机相后,用饱和食盐水洗涤,经无水硫酸钠干燥。除去溶剂后,硅胶柱层析分离[二氯甲烷:甲醇=10:1]得到(R)-6-(3-(二甲氨基)吡咯烷-1-基)-5-硝基-2-(2,2,2-三氟乙氧基)吡啶-3-胺(530mg,收率:90%)。ESI-MS:350.0[M+1]
+。
中间体A6~A8的制备可参照中间体A1的制备方法制备得到:
中间体A9:N
2-(2-(二甲氨基)乙基)-N
2-甲基-3-硝基-6-(2,2,2-三氟乙氧基)吡啶-2,5-二胺的制备
第一步:N-(6-((2-(二甲氨基)乙基)(甲基)氨基)-5-硝基-2-(2,2,2-三氟乙氧基)吡啶-3-基)乙酰胺的合成
将N-(6-溴-5-硝基-2-(2,2,2-三氟乙氧基)吡啶-3-基)乙酰胺(1.0g,2.79mmol)溶于乙腈(20mL)中,室温下往溶液中加入N
1,N
1,N
2-三甲基乙烷-1,2-二胺(426mg,4.17mmol)。反应液升温至80℃,1小时后反应结束。除去溶剂后,硅胶柱层析分离[二氯甲烷:甲醇=10:1]得到N-(6-((2-(二甲氨基)乙基)(甲基)氨基)-5-硝基-2-(2,2,2-三氟乙氧基)吡啶-3-基)乙酰胺(795mg,收率:75%)。ESI-MS:380.0[M+1]
+。
第二步:N
2-(2-(二甲氨基)乙基)-N
2-甲基-3-硝基-6-(2,2,2-三氟乙氧基)吡啶-2,5-二胺的合成
将N-(6-((2-(二甲氨基)乙基)(甲基)氨基)-5-硝基-2-(2,2,2-三氟乙氧基)吡啶-3-基)乙酰胺(795mg,2.09mmol)溶于甲醇(5mL)中,室温下加入浓盐酸(37%,412mg,4.18mmol)。反应升温至60℃,搅拌10小时后,反应结束。将反应液加饱和NaHCO
3溶液中和至pH=8~9。除去溶剂后,加水,用二氯甲烷萃取。合并有机相后,用饱和食盐水洗涤,经无水硫酸钠干燥。除去溶剂后,硅胶柱层析分离[二氯甲烷:甲醇=10:1]得到N
2-(2-(二甲氨基)乙基)-N
2-甲基-3-硝基-6-(2,2,2-三氟乙氧基)吡啶-2,5-二胺(633mg,收率:90%)。ESI-MS:338.0[M+1]
+。
中间体A10~A11的制备参照中间体A9的制备方法制备得到:
中间体B1:6-氯-5-氟-3,3-二甲基二氢吲哚的制备
第一步:6-氯-5-氟-3,3-二甲基二氢吲哚-2-酮的合成
-78℃下,在6-氯-5-氟二氢吲哚-2-酮(4.0g,21.6mmol,1eq.)和氯化锂(4.5g,108mmol,5eq.)的四氢呋喃(100mL)悬浊液中,慢慢滴入2.5M的正丁基锂溶液(43.2mL,108mmol,5eq.)。反应在-78℃下搅拌30分钟,然后加入碘甲烷(15.3g,108mmol,5eq.)。反应在-78℃下继续搅拌30分钟,然后室温搅拌2小时。用乙酸乙酯和水分层。有机相依次用水和饱和氯化钠洗涤,然后用无水硫酸钠干燥,过滤,浓缩后柱层析分离[石油醚/乙酸乙酯=5:1]得到6-氯-5-氟-3,3-二甲基二氢吲 哚-2-酮(2.8g,收率:60%)。ESI-MS:214.0[M+1]
+。
1H NMR(400MHz,DMSO-d
6)δ10.44(s,1H),7.48(d,J=8.9Hz,1H),6.94(d,J=6.2Hz,1H),1.26(d,J=2.1Hz,6H)。
第二步:6-氯-5-氟-3,3-二甲基二氢吲哚的合成
在6-氯-5-氟-3,3-二甲基二氢吲哚-2-酮(2.2g,10.2mmol,1eq.)的四氢呋喃(80mL)溶液中,加入2.5M的四氢锂铝的四氢呋喃溶液(12.2mL,30.6mmol,3eq.)。在50℃下搅拌3个小时。加入十水合硫酸钠淬灭,过滤。有机相浓缩后柱层析分离[石油醚/乙酸乙酯=3:1]得到6-氯-5-氟-3,3-二甲基二氢吲哚(1.7g,收率:83%)。ESI-MS:200.2[M+1]
+。
中间体B2:5,6-二氟-3,3-二甲基二氢吲哚的制备
第一步:5,6-二氟-3,3-二甲基二氢吲哚-2-酮的合成
-78℃下,在5,6-二氟二氢吲哚-2-酮(5.0g,29.5mmol,1eq.)和氯化锂(6.2g,148mmol,5eq.)的四氢呋喃(100mL)悬浊液中,慢慢滴入2.5M的正丁基锂溶液(59.2mL,148mmol,5eq.)。反应在-78℃下搅拌30分钟,然后加入碘甲烷(21.0g,148mmol,5eq.)。反应在-78℃下继续搅拌30分钟,然后室温搅拌2小时。用乙酸乙酯和水分层。有机相依次用水和饱和氯化钠洗涤,然后用无水硫酸钠干燥,过滤,浓缩后柱层析分离[石油醚/乙酸乙酯=5:1]得到5,6-二氟-3,3-二甲基二氢吲哚-2-酮(3.6g,收率:61%)。ESI-MS:198.0[M+1]
+。
第二步:5,6-二氟-3,3-二甲基二氢吲哚的合成
在5,6-二氟-3,3-二甲基二氢吲哚-2-酮(3.6g,18mmol,1eq.)的四氢呋喃(80mL)溶液中,加入2.5M的四氢锂铝的四氢呋喃溶液(28.8mL,72mmol,4eq.)。在50℃下搅拌3小时。加入十水合硫酸钠淬灭,过滤。有机相浓缩后柱层析分离[石油醚/乙酸乙酯=3:1]得到5,6-二氟-3,3-二甲基二氢吲哚(1.8g,收率:54%)。ESI-MS:184.0[M+1]
+。
1H NMR(400MHz,DMSO-d
6)δ7.03(dd,J=10.4,8.3Hz,1H),6.40(dd,J=11.8,6.7Hz,1H),5.58(s,1H),3.19(s,2H),1.20(s,6H)。
中间体B3:3,3-二甲基-2,3-二氢-1H-吡咯并[3,2-b]吡啶的制备
第一步:二乙基2-(3-硝基吡啶-2-基)丙二酸酯的合成
在0℃将丙二酸二乙酯(21.1mL,139.3mmol)缓慢滴入氢化钠(3.33g,139.3mmol)的二甲基亚砜(140mL)的悬浮溶液中。混合物在室温下搅拌0.5小时,再将2-氯-3-硝基吡啶(9.58g,60.6mmol)加入到混合物中。反应液在100℃搅拌1.5小时,反应完毕,冷却至0℃,缓慢加入饱和碳酸氢钠将反应淬灭。混合物水洗,乙酸乙酯萃取,无水硫酸钠干燥有机层,减压蒸馏,粗品通过快速硅胶柱分离[洗脱剂:乙酸乙酯/石油醚:0-50%]得到二乙基2-(3-硝基吡啶-2-基)丙二酸酯(15.2g,收率:88.9%)。ESI-MS:283.0[M+1]
+。
第二步:乙基2-(3-硝基吡啶-2-基)乙酸酯的合成
向二乙基2-(3-硝基吡啶-2-基)丙二酸酯(5.6g,20mmol)的二甲基亚砜(65mL)的溶液中加入水(0.37ml,20mmol),氯化锂(2.1g,50mmol)。混合物在100℃搅拌4天。反应液冷却至室温,水洗,乙酸乙酯萃取,无水硫酸钠干燥有机层,减压蒸馏,粗品通过快速硅胶柱分离[洗脱剂:乙酸乙酯/石油醚:0-50%]得到乙基2-(3-硝基吡啶-2-基)乙酸酯(3.1g,收率:73.8%)。ESI-MS:211.0[M+1]
+。
第三步:乙基2-甲基-2-(3-硝基吡啶-2-基)丙酸酯的合成
在0℃向乙基2-(3-硝基吡啶-2-基)乙酸酯(3.1g,14.7mmol)的N,N二甲基甲酰胺(30mL)溶液中加入碘甲烷(6.25g,44mmol),18-冠醚-6(0.39g,1.47mmol),再将氢化钠(1.2g,29.4mmol)缓慢加入,混合物在0℃搅拌1小时,反应完毕,冰水淬灭反应,水洗,乙酸乙酯萃取,无水硫酸钠干燥有机层,减压蒸馏,粗品通过快速硅胶柱分离[洗脱剂:乙酸乙酯/石油醚:0-25%]得到乙基2-甲基-2-(3-硝基吡啶-2-基)丙酸酯(3.2g,收率:91%)。ESI-MS:239.0[M+1]+。
第四步:3,3-二甲基-1,3-二氢-2H-吡咯并[3,2-b]吡啶-2-酮的合成
向2-甲基-2-(3-硝基吡啶-2-基)丙酸酯(3.2g,13.4mmol)的乙醇(20mL)的溶液中加入甲酸铵(3.4g,53.7mmol),10%钯碳(300mg),混合物在90℃搅拌反应2小时。反应完毕,过滤反应液,滤液浓缩,剩余物用水洗,乙酸乙酯萃取,无水硫酸钠干燥有机层,减压蒸馏,得到粗品3,3-二甲基-1,3-二氢-2H-吡咯并[3,2-b]吡啶-2-酮(1.72g,收率:79%),直接用于下一步反应。ESI-MS:163.0[M+1]
+。
第五步:3,3-二甲基-2,3-二氢-1H-吡咯并[3,2-b]吡啶的合成
将3,3-二甲基-1,3-二氢-2H-吡咯并[3,2-b]吡啶-2-酮(1.22g,7.53mmol)溶于四氢呋喃(20mL),冷却至0℃,向溶液中滴加四氢铝锂的四氢呋喃溶液(4mL,2.5M)。混合物在50℃搅拌3小时。反应完毕,反应液用十水硫酸钠淬灭至无气泡产生。混合物过滤,滤液减压蒸馏得到3,3-二甲基-2,3-二氢-1H-吡咯并[3,2-b]吡啶(1.2g,收率:100%)。ESI-MS:149.0[M+1]
+。
中间体B4:3,3-二甲基-5-(三氟甲基)-2,3-二氢-1H-吡咯并[3,2-b]吡啶的制备
第一步:2-碘-N-(2-甲代烯丙基)-6-(三氟甲基)吡啶-3-胺的合成
在室温下向2-碘-6-(三氟甲基)吡啶-3-胺(2g,6.94mmol)的四氢呋喃(30mL)溶液中加入叔丁醇钾(933mg,8.33mmol)。混合物室温下搅拌15分钟。再将3-溴-2-甲基丙-1-烯(1.17g,8.33mmol)缓慢滴加至混合物中。反应液在室温下搅拌2小时,反应完毕,减压浓缩除去溶剂,剩余物通过快速硅胶柱分离[洗脱剂:乙酸乙酯/石油醚:0-20%]得到2-碘-N-(2-甲代烯丙基)-6-(三氟甲基)吡啶-3-胺(888mg,收率:37%)。ESI-MS:342.9[M+1]
+。
第二步:3,3-二甲基-5-(三氟甲基)-2,3-二氢-1H-吡咯并[3,2-b]吡啶的合成
向反应瓶中加入2-碘-N-(2-甲代烯丙基)-6-(三氟甲基)吡啶-3-胺(888mg,2.6mmol),甲酸钠(212mg,3.1mmol),四丁基氯化铵(862mg,3.1mmol),三乙胺(788mg,7.8mmol),醋酸钯(116mg,0.52mmol),二甲基亚砜(10mL)和水(1mL)。混合物氮气置换三次,在氮气保护下,加热到100℃搅拌1小时。反应液过滤,滤液水洗,乙酸乙酯萃取,无水硫酸钠干燥有机层,减压蒸馏,粗品通过快速硅胶柱分离[洗脱剂:乙酸乙酯/石油醚:0-30%]得到3,3-二甲基-5-(三氟甲基)-2,3-二氢-1H-吡咯并[3,2-b]吡啶(430mg,收率:76%)。ESI-MS:217.0[M+1]
+。
中间体B5:3,3,5-三甲基-2,3-二氢-1H-吡咯并[3,2-b]吡啶的制备
第一步:2-碘-6-甲基-N-(2-甲代烯丙基)吡啶-3-胺的合成
在室温下向2-碘-6-甲基吡啶-3-胺(2g,8.5mmol)的四氢呋喃(40mL)溶液中加入叔丁醇钾(1.14g,10.2mmol)。混合物室温下搅拌15分钟。再将3-溴-2-甲基丙-1-烯(1.27g,9.4mmol)缓慢滴加至混合物中。反应液在室温下搅拌2小时,反应完毕,减压浓缩除去溶剂,剩余物通过快速硅胶柱分离[洗脱剂:乙酸乙酯/石油醚:0-20%]得到2-碘-6-甲基-N-(2-甲代烯丙基)吡啶-3-胺(1.46g,收率:59%)。ESI-MS:288.9[M+1]
+。
第二步:3,3,5-三甲基-2,3-二氢-1H-吡咯并[3,2-b]吡啶的合成
向反应瓶中加入2-碘-6-甲基-N-(2-甲代烯丙基)吡啶-3-胺(1.46g,5mmol),甲酸钠(413mg,6mmol),四丁基氯化铵(1.67g,6mmol),三乙胺(1.5g,15mmol),醋酸钯(224mg,1mmol),二甲基亚砜(40mL)和水(1.5mL)。混合物氮气置换三次,在氮气保护下,加热到120℃搅拌1小时。反应液过滤,滤液水洗,乙酸乙酯萃取,无水硫酸钠干燥有机层,减压蒸馏,粗品通过快速硅胶柱分离[洗脱剂:乙酸乙酯/石油醚:0-30%]得到3,3,5-三甲基-2,3-二氢-1H-吡咯并[3,2-b]吡啶(660mg,收率:81%)。ESI-MS:163.0[M+1]
+。
中间体B6:5-(吖丁啶-1-基)-3,3-二甲基-2,3-二氢-1H-吡咯并[3,2-b]吡啶的制备
第一步:6-氯-2-碘吡啶-3-胺的合成
在室温下向6-氯吡啶-3-胺(10g,77.8mmol)的N,N-二甲基甲酰胺(150mL)溶液中加入N-碘代丁二酰亚胺(19.3g,85.6mmol)。混合物室温下搅拌过夜。反应完毕,反应液水洗,乙酸乙酯萃取,无水硫酸钠干燥有机层,减压浓缩除去溶剂,剩余物通过快速硅胶柱分离[洗脱剂:乙酸乙酯/石油醚:0-20%]得到6-氯-2-碘吡啶-3-胺(15.5g,收率:78.3%)。ESI-MS:254.8[M+1]
+。
第二步:6-氯-2-碘-N-(2-甲代烯丙基)吡啶-3-胺的合成
在室温下向6-氯-2-碘吡啶-3-胺(15.5,60.9mmol)的四氢呋喃(200mL)溶液中加入叔丁醇钾(8.2g,73.1mmol)。混合物室温下搅拌15分钟。再将3-溴-2-甲基丙-1-烯(9.9g,73.1mmol)缓慢滴加至混合物中。反应液在室温下搅拌2小时,反应完毕,减压浓缩除去溶剂,剩余物通过快速硅胶柱分离[洗脱剂:乙酸乙酯/石油醚:0-20%]得到6-氯-2-碘-N-(2-甲代烯丙基)吡啶-3-胺(15.5g,收率:82.5%)。ESI-MS:308.8[M+1]
+。
第三步:5-氯-3,3-二甲基-2,3-二氢-1H-吡咯并[3,2-b]吡啶的合成
向反应瓶中加入6-氯-2-碘-N-(2-甲代烯丙基)吡啶-3-胺(15.5g,50.2mmol),甲酸钠(4.2g,60.3mmol),四丁基氯化铵(16.8g,60.3mmol),三乙胺(15.3g,150.7mmol),醋酸钯(1.69g,7.5mmol),二甲基亚砜(200mL)和水(6.7mL)。混合物氮气置换三次,在氮气保护下,加热到120℃搅拌1小时。反应液过滤,滤液水洗,乙酸乙酯萃取,无水硫酸钠干燥有机层,减压蒸馏,粗品通过快速硅胶柱分离[洗脱剂:乙酸乙酯/石油醚:0-30%]得到5-氯-3,3-二甲基-2,3-二氢-1H-吡咯并[3,2-b]吡啶(6.6g,收率:70.8%)。ESI-MS:183.1[M+1]
+。
第四步:叔-丁基5-氯-3,3-二甲基-2,3-二氢-1H-吡咯并[3,2-b]吡啶-1-羧酸酯的合成
在室温下向5-氯-3,3-二甲基-2,3-二氢-1H-吡咯并[3,2-b]吡啶(1g,5.5mmol)的1,4-二氧六环(15mL)溶液中加入二碳酸二叔丁酯(5mL)和三乙胺(1mL)。混合物120℃搅拌过夜。反应完毕,反应液水洗,乙酸乙酯萃取,无水硫酸钠干燥有机层,减压浓缩除去溶剂,剩余物通过快速硅胶柱分离[洗脱剂:乙酸乙酯/石油醚:0-20%]得到叔-丁基5-氯-3,3-二甲基-2,3-二氢-1H-吡咯并[3,2-b]吡啶-1-羧酸酯(1.32g,收率:84.6%)。ESI-MS:283.1[M+1]
+。
第五步:叔-丁基5-(吖丁啶-1-基)-3,3-二甲基-2,3-二氢-1H-吡咯并[3,2-b]吡啶-1-羧酸酯的合成
向封管中加入叔-丁基5-氯-3,3-二甲基-2,3-二氢-1H-吡咯并[3,2-b]吡啶-1-羧酸酯(706mg,2.5mmol),碳酸铯(1.22g,3.75mmol),1,1'-联萘-2,2'-双二苯膦(0.3mg,0.5mmol),环丁胺(428mg,7.5mmol),醋酸钯(112mg,0.5mmol),1,4-二氧六环(8mL)。混合物氮气置换三次,封管,加热到120℃搅拌16小时。反应液过滤,滤液水洗,乙酸乙酯萃取,无水硫酸钠干燥有机层,减压蒸馏,粗品通过快速硅胶柱分离[洗脱剂:乙酸乙酯/石油醚:0-30%]得到叔-丁基5-(吖丁啶-1-基)-3,3-二甲基-2,3-二氢-1H-吡咯并[3,2-b]吡啶-1-羧酸酯(534mg,收率:70.8%)。ESI-MS:304.1[M+1]
+。
第六步:5-(吖丁啶-1-基)-3,3-二甲基-2,3-二氢-1H-吡咯并[3,2-b]吡啶的合成
向叔-丁基5-(吖丁啶-1-基)-3,3-二甲基-2,3-二氢-1H-吡咯并[3,2-b]吡啶-1-羧酸酯(534mg,1.8mmol)的二氯甲烷(6mL)溶液中加入三氟乙酸(2mL)。反应液室温下搅拌2小时,反应完毕,加入饱和碳酸氢钠水溶液,二氯甲烷萃取,无水硫酸钠干燥有机层,减压浓缩除去溶剂得到5-(吖丁啶-1-基)-3,3-二甲基-2,3-二氢-1H-吡咯并[3,2-b]吡啶(350mg,收率:98.9%)。ESI-MS:204.1[M+1]
+。
中间体B7:5-环丙基-3,3-二甲基-2,3-二氢-1H-吡咯并[3,2-b]吡啶的制备
向反应瓶中加入5-氯-3,3-二甲基-2,3-二氢-1H-吡咯并[3,2-b]吡啶(450mg,2.5mmol),环丙基硼酸(1.1g,12.4mmol),磷酸钾(1.94g,9.1mmol),三环己基膦(138mg,0.5mmol),醋酸钯(55mg,0.3mmol),甲苯(30mL)。混合物氮气置换三次,在氮气保护下,加热到110℃搅拌6小时。反应液过滤,滤液水洗,乙酸乙酯萃取,无水硫酸钠干燥有机层,减压蒸馏,粗品通过快速硅胶柱分离[洗脱剂:乙酸乙酯/石油醚:0-30%]得到5-环丙基-3,3-二甲基-2,3-二氢-1H-吡咯并[3,2-b]吡啶(152mg,收率:33.0%)。ESI-MS:189.0[M+1]
+。
中间体B8:5-甲氧基-3,3-二甲基-1H,2H,3H-吡咯并[3,2-b]吡啶的制备
将5-氯-3,3-二甲基-1H,2H,3H-吡咯并[3,2-b]吡啶(210mg,1.15mmol)溶于N,N-二甲基甲酰胺(20mL)中,加入甲醇钠的甲醇溶液(2.1mL)和碘化亚铜(110mg,0.575mmol)。反应液升温至140℃,2小时后反应结束。加水,用二氯甲烷萃取三次。合并有机相后,用饱和食盐水洗涤,经无水硫酸钠干燥。除去溶剂后,硅胶柱层析分离[石油醚:乙酸乙酯=1:1]得到5-甲氧基-3,3-二甲基-1H,2H,3H-吡咯并[3,2-b]吡啶(110mg,收率:54%)。ESI-MS:179.0[M+1]
+。
中间体B9:5-溴-3,3-二甲基-1H,2H,3H-吡咯并[3,2-b]吡啶的制备
第一步:1-叔-丁基3-乙基2-(6-甲氧基-3-硝基吡啶-2-基)丙二酸酯的合成
将丙二酸乙酯叔丁酯(8.4g,44.5mmol)溶于无水四氢呋喃(100mL)中,分批加入氢化钠(1.8g,44.5mmol),反应在室温下搅拌20分钟后,加入2-氯-6-甲氧基-3-硝基吡啶(7.0g,37.1mmol),反应在80℃下搅拌2小时。反应结束,反应液用乙酸乙酯(100mL)和饱和食盐水(100mL)分层,有机相用饱和食盐水(50mL)洗。所得有机相浓缩得到1-叔-丁基3-乙基2-(6-甲氧基-3-硝基吡啶-2-基)丙二酸酯(10.2g,收率:80%)。ESI-MS:225.0[M-56]
+。
第二步:乙基2-(6-甲氧基-3-硝基吡啶-2-基)乙酸酯的合成
将1-叔-丁基3-乙基2-(6-甲氧基-3-硝基吡啶-2-基)丙二酸酯(10.2g,30mmol)溶于二氯甲烷(30mL),加入三氟乙酸(25mL),反应液加热回流2小时,反应结束,反应液浓缩,剩余物用乙酸乙酯(100mL)和饱和食盐水(100mL)分层,有机相用饱和食盐水(50mL)洗。所得有机相浓缩得到乙基2-(6-甲氧基-3-硝基吡啶-2-基)乙酸酯(6.9g,收率:95%)。ESI-MS:241.0[M+1]
+。
第三步:乙基2-(6-甲氧基-3-硝基吡啶-2-基)-2-甲基丙酸酯的合成
将乙基2-(6-甲氧基-3-硝基吡啶-2-基)乙酸酯(4.0g,16.6mmol)溶于四氢呋喃(100mL),反应液加入碘甲烷(2.6mL,41.6mmol)和氢化钠(2.0g,50.0mmol)。反应液在氮气保护0℃下搅拌3小时,LCMS显示反应结束,反应液用乙酸乙酯(100mL)和饱和食盐水(100mL)分层,有机相用饱和食盐水(50mL)洗。所得有机相浓缩,剩余物通过快速硅胶柱分离[石油醚/乙酸乙酯=3/1]得到乙基2-(6-甲氧基-3-硝基吡啶-2-基)-2-甲基丙酸酯(4.2g,收率:94%)。ESI-MS:269.0[M+1]
+。
第四步:5-甲氧基-3,3-二甲基-1H,2H,3H-吡咯并[3,2-b]吡啶-2-酮的合成
将乙基2-(6-甲氧基-3-硝基吡啶-2-基)-2-甲基丙酸酯(4.2g,15.7mmol),钯碳(200mg,10%)溶于甲醇(50mL)。反应在室温氢气下搅拌2小时。反应液通过硅藻土过滤,滤液在90℃下继续搅拌16小时,反应结束,反应液浓缩。所得剩余物用乙酸乙酯(100mL)和饱和食盐水(100mL)分层。有机相浓缩,剩余物通过快速硅胶柱分离[石油醚/乙酸乙酯=2/1]得到5-甲氧基-3,3-二甲基-1H,2H,3H-吡咯并[3,2-b]吡啶-2-酮(2.3g,收率:66%)。ESI-MS:193.0[M+1]
+。
第五步:5-甲氧基-3,3-二甲基-1H,2H,3H-吡咯并[3,2-b]吡啶的合成
将5-甲氧基-3,3-二甲基-1H,2H,3H-吡咯并[3,2-b]吡啶-2-酮(2.3g,12.0mmol)溶于四氢呋喃(50mL),反应液加入硼烷四氢呋喃溶液(36mL,36.0mmol),反应液 在氮气保护下室温搅拌16小时,反应结束。反应液用乙酸乙酯(50mL)和饱和食盐水(50mL)分层,有机相用饱和食盐水(50mL)洗。所得有机相浓缩,剩余物通过快速硅胶柱分离[石油醚/乙酸乙酯=2/1]得到5-甲氧基-3,3-二甲基-1H,2H,3H-吡咯并[3,2-b]吡啶(1.98g,收率:93%)。ESI-MS:179.1[M+1]
+。
第六步:3,3-二甲基-1H,2H,3H,4H,5H-吡咯并[3,2-b]吡啶-5-酮的合成
将5-甲氧基-3,3-二甲基-1H,2H,3H-吡咯并[3,2-b]吡啶(1.98g,11.1mmol)溶于溴化氢溶液(20ml,40%),反应液在90℃下搅拌3小时,反应结束,反应液直接浓缩至干,得到粗品3,3-二甲基-1H,2H,3H,4H,5H-吡咯并[3,2-b]吡啶-5-酮(1.6g,收率:88%)。ESI-MS:165.1[M+1]
+。
第七步:5-溴-3,3-二甲基-1H,2H,3H-吡咯并[3,2-b]吡啶的合成
将3,3-二甲基-1H,2H,3H,4H,5H-吡咯并[3,2-b]吡啶-5-酮(1.6g,9.7mmol)溶于三溴氧磷(10mL,98mmol)中,反应在100℃下搅拌18小时,反应液淬灭至二氯甲烷(200mL)和饱和碳酸钠(200mL)中,有机相用饱和食盐水(50mL)洗。所得有机相浓缩,剩余物通过快速硅胶柱分离[二氯甲烷/甲醇=10/1]得到5-溴-3,3-二甲基-1H,2H,3H-吡咯并[3,2-b]吡啶(280mg,收率:12%)。ESI-MS:226.9,228.9[M+1]
+。
中间体B10:3,3-二甲基-1,2,3,5,6,7-六氢环戊二烯并[b]吡咯并[2,3-e]吡啶的制备
第一步:3-硝基-1,5,6,7-四氢-2H-环戊二烯并[b]吡啶-2-酮的合成
在0℃下,向1,5,6,7-四氢-2H-环戊二烯并[b]吡啶-2-酮(450mg,2.5mmol)的浓硫酸(98%质量分数,30mL)中缓慢滴加硝酸(65%质量分数,5.4g,55.6mmol),混合物在0℃搅拌1小时,缓慢倒入冰水中,搅拌1小时,过滤,干燥滤饼得到3-硝基-1,5,6,7-四氢-2H-环戊二烯并[b]吡啶-2-酮(3.5g,收率:52.5%)。ESI-MS:181.0[M+1]
+。
第二步:2-氯-3-硝基-6,7-二氢-5H-环戊二烯并[b]吡啶的合成
向3-硝基-1,5,6,7-四氢-2H-环戊二烯并[b]吡啶-2-酮(2.5g,13.9mmol)的乙腈(50mL)溶液中加入三氯氧磷(6.4g,41.6mmol),三乙基苄基氯化铵(1.9g,7.0mmol),混合物在80℃搅拌1小时,减压浓缩除去溶剂,剩余物缓慢倒入冰水中,搅拌30分钟。用二氯甲烷萃取,无水硫酸钠干燥有机层,减压蒸馏,粗品通过快速硅胶柱分离[洗脱剂:乙酸乙酯/石油醚:0-50%]得到2-氯-3-硝基-6,7-二氢-5H-环戊二烯并[b]吡啶(985mg,收率:36.0%)。ESI-MS:198.9[M+1]
+。
第三步:二乙基2-(3-硝基-6,7-二氢-5H-环戊二烯并[b]吡啶-2-基)丙二酸酯的合成
在0℃下,向2-氯-3-硝基-6,7-二氢-5H-环戊二烯并[b]吡啶(814mg,5.1mmol)的二甲基亚砜(10mL)溶液中加入氢化钠(220mg,5.5mmol),混合物在0℃搅拌0.5小时,将丙二酸二乙酯(840mg,4.2mmol)加入混合物中,反应物在100℃下搅拌1小时,冷却至室温,用饱和氯化铵溶液淬灭反应,水洗反应液,乙酸乙酯萃取,无水硫酸钠干燥有机层,减压蒸馏,粗品通过快速硅胶柱分离[洗脱剂:乙酸乙酯/石油醚:0-30%]得到二乙基2-(3-硝基-6,7-二氢-5H-环戊二烯并[b]吡啶-2-基)丙二酸酯(409mg,收率:30.0%)。ESI-MS:323.0[M+1]
+。
第四步:乙基2-(3-硝基-6,7-二氢-5H-环戊二烯并[b]吡啶-2-基)乙酸酯的合成
向二乙基2-(3-硝基-6,7-二氢-5H-环戊二烯并[b]吡啶-2-基)丙二酸酯(409mg,1.3mmol)的二甲基亚砜(5mL)的溶液中加入水(0.91ml,5.1mmol),氯化锂(267mg,6.4mmol)。混合物在100℃搅拌24小时。反应液冷却至室温,水洗,乙酸乙酯萃取,无水硫酸钠干燥有机层,减压蒸馏,粗品通过快速硅胶柱分离[洗脱剂:乙酸乙酯/石油醚:0-50%]得到乙基2-(3-硝基-6,7-二氢-5H-环戊二烯并[b]吡啶-2-基)乙酸酯(240mg,收率:76.0%)。ESI-MS:251.0[M+1]
+。
第五步:乙基2-甲基-2-(3-硝基-6,7-二氢-5H-环戊二烯并[b]吡啶-2-基)丙酸酯的合成
在0℃向乙基2-(3-硝基-6,7-二氢-5H-环戊二烯并[b]吡啶-2-基)乙酸酯(240mg,0.96mmol)的N,N二甲基甲酰胺(5mL)溶液中加入碘甲烷(300mg,2.1mmol),18-冠醚-6(26mg,0.1mmol),再将氢化钠(88mg,2.2mmol)缓慢加入,混合物在0℃搅拌1小时,反应完毕,冰水淬灭反应,水洗,乙酸乙酯萃取,无水硫酸钠干燥有机层,减压蒸馏,粗品通过快速硅胶柱分离[洗脱剂:乙酸乙酯/石油醚:0-25%]得到乙基2-甲基-2-(3-硝基-6,7-二氢-5H-环戊二烯并[b]吡啶-2-基)丙酸酯(150mg,收率:56.0%)。ESI-MS:279.0[M+1]
+。
第六步:3,3-二甲基-3,5,6,7-四氢环戊二烯并[b]吡咯并[2,3-e]吡啶-2(1H)-酮的合成
向2-甲基-2-(3-硝基-6,7-二氢-5H-环戊二烯并[b]吡啶-2-基)丙酸酯(150mg,0.54mmol)的乙醇(5mL)的溶液中加入甲酸铵(272mg,4.3mmol),10%钯碳(50mg),混合物在90℃搅拌反应16小时。反应完毕,过滤反应液,滤液浓缩,剩余物用水洗,乙酸乙酯萃取,无水硫酸钠干燥有机层,减压蒸馏,得到粗品3,3-二甲基-3,5,6,7-四氢环戊二烯并[b]吡咯并[2,3-e]吡啶-2(1H)-酮,直接用于下一步反应。ESI-MS:203.0[M+1]
+。
第七步:3,3-二甲基-1,2,3,5,6,7-六氢环戊二烯并[b]吡咯并[2,3-e]吡啶的合成
将3,3-二甲基-3,5,6,7-四氢环戊二烯并[b]吡咯并[2,3-e]吡啶-2(1H)-酮粗品溶于四氢呋喃(5mL),冷却至0℃,向溶液中滴加四氢铝锂的四氢呋喃溶液(2mL,2.5M)。混合物在室温搅拌4小时。反应完毕,反应液用十水硫酸钠淬灭至无气泡产生。混合物过滤,滤液减压蒸馏得到3,3-二甲基-1,2,3,5,6,7-六氢环戊二烯并[b]吡咯并[2,3-e]吡啶粗品。ESI-MS:189.0[M+1]
+。
中间体B11:3,3-二甲基-6-苯基-1H,2H,3H-吡咯并[3,2-b]吡啶的制备
第一步:乙基2-(5-溴-3-硝基吡啶-2-基)乙酸酯的合成
将5-溴-2-氯-3-硝基吡啶(2.5g,10.53mmol)溶于乙腈(50mL)。加入3-乙氧基-3-羰基丙酸钾(2.15g,12.64mmol),氯化镁(1.5g,15.79mmol)和三乙胺(2.93mL,21.06mmol)。反应在70℃下搅拌16小时。反应液用1N HCl调节至pH=7,用二氯甲烷(100mL)萃取,有机相用依次用水(50mL),饱和食盐水(50mL)洗。有机相浓缩,剩余物用快速硅胶柱分离[石油醚:乙酸乙酯=3:1]得到乙基2-(5-溴-3-硝基吡啶-2-基)乙酸酯(890mg,29%)。ESI-MS:289.0,290.9[M+1]
+。
第二步:乙基2-(5-溴-3-硝基吡啶-2-基)-2-甲基丙酸酯的合成
将乙基2-(5-溴-3-硝基吡啶-2-基)乙酸酯(710mg,2.46mmol)溶于四氢呋喃(50mL),反应液加入18-冠醚-6(64.9mg,0.25mmol),碘甲烷(0.46mL,7.37mmol)和氢化钠(177mg,7.37mmol)。反应液在氮气保护0℃下搅拌3小时,反应结束,反应液用乙酸乙酯(100mL)饱和食盐水(100mL)分层,有机相用饱和食盐水(50mL)洗。所得有机相浓缩,剩余物通过快速硅胶柱[石油醚/乙酸乙酯=3/1]得到乙基2-(5-溴-3-硝基吡啶-2-基)-2-甲基丙酸酯(532mg,68%)。ESI-MS:317.0,319.0[M+1]
+。
第三步:6-溴-3,3-二甲基-1H,2H,3H-吡咯并[3,2-b]吡啶-2-酮的合成
将乙基2-(5-溴-3-硝基吡啶-2-基)-2-甲基丙酸酯(532mg,1.68mmol),铁粉(940mg,16.77mmol)溶于冰醋酸(10mL)。反应液在80℃下搅拌16小时。反应液通过硅藻土过滤,滤液浓缩。所得剩余物用乙酸乙酯(50mL),饱和食盐水(50mL)分层。有机相浓缩,剩余物通过快速硅胶柱分离[石油醚/乙酸乙酯=2/1]得到6-溴-3,3-二甲基-1H,2H,3H-吡咯并[3,2-b]吡啶-2-酮(270mg,66%)。ESI-MS:241.0,243.0[M+1]
+。
第四步:3,3-二甲基-6-苯基-1H,2H,3H-吡咯并[3,2-b]吡啶-2-酮的合成
将6-溴-3,3-二甲基-1H,2H,3H-吡咯并[3,2-b]吡啶-2-酮(140mg,0.58mmol),苯硼酸(106mg,0.87mmol),[1,1'-双(二苯基膦基)二茂铁]二氯化钯(42mg,0.058mmol)和碳酸钾(161mg,1.16mmol)溶于二甲氧基乙二醇(5mL),反应液在氮气 保护下90℃搅拌1小时,反应结束。反应液用乙酸乙酯(50mL)饱和食盐水(50mL)分层,有机相用饱和食盐水(50mL)洗。所得有机相浓缩,剩余物通过快速硅胶柱分离[石油醚/乙酸乙酯=2/1]得到3,3-二甲基-6-苯基-1H,2H,3H-吡咯并[3,2-b]吡啶-2-酮(110mg,78%)。ESI-MS:239.0[M+1]
+。
第五步:3,3-二甲基-6-苯基-1H,2H,3H-吡咯并[3,2-b]吡啶的合成
将3,3-二甲基-6-苯基-1H,2H,3H-吡咯并[3,2-b]吡啶-2-酮(110mg,0.46mmol)溶于四氢呋喃(20mL),反应液加入硼烷四氢呋喃溶液(1.4mL,1.4mmol),反应液在氮气保护下70℃搅拌16小时,反应结束。反应液用乙酸乙酯(50mL)饱和食盐水(50mL)分层,有机相用饱和食盐水(50mL)洗。所得有机相浓缩,剩余物通过快速硅胶柱分离[石油醚/乙酸乙酯=2/1]得到3,3-二甲基-6-苯基-1H,2H,3H-吡咯并[3,2-b]吡啶(91mg,88%)。ESI-MS:225.0[M+1]
+。
中间体B12~B14制备参照中间体B11的制备方法制备得到:
中间体B15:5-乙炔基-3,3-二甲基-1H,2H,3H-吡咯并[3,2-b]吡啶的制备
第一步:甲基5-氨基-6-碘吡啶-2-羧酸酯的合成
将甲基5-氨基吡啶-2-羧酸酯(10g,65.7mmol)溶于N,N-二甲基甲酰胺(60mL), 加入碘(18.35g,72.3mmol)和高碘酸钠(33.7g,157.7mmol)。反应在60℃搅拌6小时。倒入水中,用乙酸乙酯萃取三次,合并有机相后,用饱和食盐水洗涤,经无水硫酸钠干燥。除去溶剂后,硅胶柱层析分离[石油醚:乙酸乙酯=1:1]得到甲基5-氨基-6-碘吡啶-2-羧酸酯(12g,收率:65.6%)。ESI-MS:278.8[M+1]
+。
第二步:甲基6-碘-5-((2-甲代烯丙基)氨基)甲基吡啶酸酯的合成
将甲基5-氨基-6-碘吡啶-2-羧酸酯(11g,39.56mmol)溶于四氢呋喃(150mL)加入叔丁醇钾的四氢呋喃溶液(47.5mL,47.5mmol)和3-溴-2-甲基丙-1-烯(4.78mL,47.5mmol)。反应在室温下搅拌1小时,然后加10mL甲醇淬灭,继续搅拌10分钟。除去溶剂后,硅胶柱层析分离[石油醚:乙酸乙酯=1:1]得到甲基6-碘-5-((2-甲代烯丙基)氨基)甲基吡啶酸酯(5.2g,收率:39.57%)。ESI-MS:333.1[M+1]
+。
第三步:甲基3,3-二甲基-1H,2H,3H-吡咯并[3,2-b]吡啶-5-羧酸酯的合成
将甲基6-碘-5-((2-甲代烯丙基)氨基)甲基吡啶酸酯(5.0g,15.05mmol)溶于二甲基亚砜(90mL)和水(36mL),加入甲酸钠(1.23g,18.06mmol),三乙胺(6.3mL,45.16mmol),四丁基氯化铵(1.6g,5.7mmol)和醋酸钯(0.51g,2.26mmol)。反应在氮气保护下120℃搅拌1小时。倒入水中,用乙酸乙酯萃取三次。合并有机相,用饱和食盐水洗涤,经无水硫酸钠干燥。除去溶剂后,硅胶柱层析分离[石油醚:乙酸乙酯=1:1]得到甲基3,3-二甲基-1H,2H,3H-吡咯并[3,2-b]吡啶-5-羧酸酯(2.2g,71%)。ESI-MS:207.2[M+1]
+。
第四步:1-叔-丁基5-甲基3,3-二甲基-1H,2H,3H-吡咯并[3,2-b]吡啶-1,5-二羧酸酯的合成
将甲基3,3-二甲基-1H,2H,3H-吡咯并[3,2-b]吡啶-5-羧酸酯(2.2g,10.67mmol)溶于1,4-二氧六环(50mL)中,加入二碳酸二叔丁酯(7.65g,35mmol)。反应在120℃搅拌2小时。浓缩后硅胶柱层析分离[石油醚:乙酸乙酯=1:1]得到1-叔-丁基5-甲基3,3-二甲基-1H,2H,3H-吡咯并[3,2-b]吡啶-1,5-二羧酸酯(3.25g,收率:96.47%)。ESI-MS:307.2[M+1]
+。
第五步:叔-丁基5-(羟甲基)-3,3-二甲基-1H,2H,3H-吡咯并[3,2-b]吡啶-1-羧酸 酯的合成
将1-叔-丁基5-甲基3,3-二甲基-1H,2H,3H-吡咯并[3,2-b]吡啶-1,5-二羧酸酯(3.2g,10.45mmol)溶于四氢呋喃(60mL)中,加入四氢铝锂(2.0g,92mmol)。室温搅拌1小时。加入十水合硫酸钠淬灭,过滤后,用乙酸乙酯和水分层,合并有机相,干燥后浓缩得到叔-丁基5-(羟甲基)-3,3-二甲基-1H,2H,3H-吡咯并[3,2-b]吡啶-1-羧酸酯(2.2g,收率:76%)。ESI-MS:279.3[M+1]
+。
第六步:叔-丁基5-甲酰基-3,3-二甲基-1H,2H,3H-吡咯并[3,2-b]吡啶-1-羧酸酯的合成
将叔-丁基5-(羟甲基)-3,3-二甲基-1H,2H,3H-吡咯并[3,2-b]吡啶-1-羧酸酯(2.2g,7.9mmol)溶于二氯甲烷(80mL)中,加入二氧化锰(6.87g,79mmol)。反应在室温下搅拌2小时,过滤后浓缩得到叔-丁基5-甲酰基-3,3-二甲基-1H,2H,3H-吡咯并[3,2-b]吡啶-1-羧酸酯(1.8g,收率:82.4%)。ESI-MS:277.0[M+1]
+。
第七步:叔-丁基5-乙炔基-3,3-二甲基-1H,2H,3H-吡咯并[3,2-b]吡啶-1-羧酸酯的合成
将叔-丁基5-甲酰基-3,3-二甲基-1H,2H,3H-吡咯并[3,2-b]吡啶-1-羧酸酯(811mg,2.94mmol)溶于甲醇(3.0mL),加入碳酸钾(811mg,5.87mmol),然后滴加(1Z)-1-(重氮基炔-1-正离子-1-基)-1-(二甲氧基磷基)丙-1-烯-2-醇酸(620mg,2.23mmol)的甲醇(3.0mL)溶液。反应在室温搅拌1.5小时,反应液倒入碳酸钠溶液(1mol/L)中,用乙酸乙酯萃取三次。合并有机相后,用饱和食盐水洗涤,经无水硫酸钠干燥。除去溶剂后,硅胶柱层析分离[乙醚=100%]得到叔-丁基5-乙炔基-3,3-二甲基-1H,2H,3H-吡咯并[3,2-b]吡啶-1-羧酸酯(740mg,收率:93%)。ESI-MS:273.3[M+1]
+。
第八步:5-乙炔基-3,3-二甲基-1H,2H,3H-吡咯并[3,2-b]吡啶的合成
将叔-丁基5-乙炔基-3,3-二甲基-1H,2H,3H-吡咯并[3,2-b]吡啶-1-羧酸酯(650mg,2.38mmol)溶于二氯甲烷(4.0mL)中,加入三氟乙酸(2.0mL)。室温下搅拌5小时,浓缩后加入饱和碳酸氢钠溶液,用二氯甲烷萃取三次,合并有机相,浓缩后得到5-乙炔基-3,3-二甲基-1H,2H,3H-吡咯并[3,2-b]吡啶(350mg,收率:96.10%)。ESI-MS:173.3[M+1]
+。
中间体B16:3,3-二甲基-2,3-二氢-1H-吡啶并[2,3-b][1,4]噁嗪的制备
第一步:2-溴-2-甲基-N-(2-羰基-1,2-二氢吡啶-3-基)丙酰胺的合成
在冰浴下向3-氨基吡啶-2(1H)-酮(4.1g,37.2mmol)的四氢呋喃(150mL)溶液中加入三乙胺(7.5g,74.4mmol)和2-溴-2-甲基丙酰溴化(9.4g,40.9mmol)。反应液在冰浴下搅拌1.5小时。反应完毕,用乙酸乙酯和水萃取分层。有机相浓缩后通过快速硅胶柱分离[洗脱剂:乙酸乙酯/石油醚=0-50%]得到2-溴-2-甲基-N-(2-羰基-1,2-二氢吡啶-3-基)丙酰胺(5.7g,收率:59%)。ESI-MS:261.1[M+1]
+。
第二步:3,3-二甲基-1H,2H,3H-吡啶并[2,3-b][1,4]噁嗪-2-酮的合成
在室温下向2-溴-2-甲基-N-(2-羰基-1,2-二氢吡啶-3-基)丙酰胺(5.7g,21.9mmol)的N,N-二甲基甲酰胺(50mL)溶液中加入碳酸钾(7.6g,54.9mmol)。反应液在70℃下搅拌3小时。反应完毕,用乙酸乙酯和水萃取分层。有机相浓缩后通过快速硅胶柱分离[洗脱剂:乙酸乙酯/石油醚=0-50%]得到3,3-二甲基-1H,2H,3H-吡啶并[2,3-b][1,4]噁嗪-2-酮(1.0g,收率:25%)。ESI-MS:179.2[M+1]
+。
第三步:3,3-二甲基-2,3-二氢-1H-吡啶并[2,3-b][1,4]噁嗪的合成
在冰浴下向3,3-二甲基-1H,2H,3H-吡啶并[2,3-b][1,4]噁嗪-2-酮(500mg,2.8mmol)的四氢呋喃(20mL)溶液中加入2.5M的LiAlH
4的四氢呋喃溶液(1.1mL, 2.8mmol)。反应液在室温下搅拌2小时。反应完毕,加入十水合硫酸钠淬灭,浓缩后通过快速硅胶柱分离[洗脱剂:乙酸乙酯/石油醚=0-50%]得到3,3-二甲基-2,3-二氢-1H-吡啶并[2,3-b][1,4]噁嗪(460mg,收率:91%)。ESI-MS:165.3[M+1]
+。
中间体B17:2,2-二甲基-3,4-二氢-2H-苯并[b][1,4]噁嗪的制备
中间体B17的制备参照中间体B16的方法制备得到。ESI-MS:164.2[M+1]
+。
中间体B18:6-氟-4,4-二甲基-1,2,3,4-四氢喹啉的制备
第一步:N-(4-氟苯基)-3-甲基丁-2-烯酰胺的合成
将4-氟苯胺(5.55g,50mmol)溶于二氯甲烷(100mL)中,加入碳酸钾(10.35g,75mmol),再缓慢滴加3-甲基巴豆酰氯(7.1g,60mmol)。反应液在室温下搅拌2小时。反应液倒入水中,用乙酸乙酯萃取三遍,合并有机相,浓缩干燥,得到N-(4-氟苯基)-3-甲基丁-2-烯酰胺(8.69g,收率:90.1%)。ESI-MS:194.1[M+1]
+。
第二步:6-氟-4,4-二甲基-3,4-二氢喹啉-2(1H)-酮的合成
将N-(4-氟苯基)-3-甲基丁-2-烯酰胺(8.69g,45mmol)溶于二氯甲烷(100mL)中,冰浴下加入无水三氯化铝(9g,67.5mmol),反应液在室温搅拌2小时。冰浴下,缓慢滴加1M盐酸淬灭反应,反应液分层,水相二氯甲烷萃取,合并有机相,浓缩后得到粗产物6-氟-4,4-二甲基-3,4-二氢喹啉-2(1H)-酮(7.7g,收率:89.1%),ESI-MS:194.1[M+1]
+。
第三步:6-氟-4,4-二甲基-1,2,3,4-四氢喹啉的合成
将6-氟-4,4-二甲基-3,4-二氢喹啉-2(1H)-酮(7.7g,40mmol)溶于四氢呋喃(100mL)中,加入1M硼烷四氢呋喃溶液(80mL,80mmol)。将反应液升温至90℃,反应过夜。缓慢滴加冰水(50mL)淬灭反应,用乙酸乙酯萃取两遍,合并有机相,浓 缩干燥,硅胶柱层析分离得到6-氟-4,4-二甲基-1,2,3,4-四氢喹啉(5.1g,收率:72%)。ESI-MS:180.3[M+1]
+。
中间体B19~B21的制备参照中间体B18的制备方法制备得到:
中间体C1:(R)-N
1-(4-(3,3-二甲基-2,3-二氢-1H-吡咯并[3,2-b]吡啶-1-基)-1,3,5-三嗪-2-基)-4-(3-(二甲氨基)吡咯烷-1-基)-6-甲氧基苯-1,3-二胺的制备
第一步:1-(4-氯-1,3,5-三嗪-2-基)-3,3-二甲基-2,3-二氢-1H-吡咯并[3,2-b]吡啶的合成
室温下,将2,4-二氯-1,3,5-三嗪(747mg,4.98mmol)溶解在二氯甲烷(20mL)中,依次加入3,3-二甲基-2,3-二氢-1H-吡咯并[3,2-b]吡啶(614mg,4.15mmol)及N,N-二异丙基乙胺(1.2g,9.30mmol)。反应液室温下搅拌1小时。反应结束后,除去溶剂,经硅胶柱层析分离[石油醚:乙酸乙酯=4:1]得到1-(4-氯-1,3,5-三嗪-2-基)-3,3-二甲基-2,3-二氢-1H-吡咯并[3,2-b]吡啶(684mg,收率:63%)。ESI-MS:262.1[M+1]
+。
第二步:(R)-4-(3,3-二甲基-2,3-二氢-1H-吡咯并[3,2-b]吡啶-1-基)-N-(4-(3-(二甲氨基)吡咯烷-1-基)-2-甲氧基-5-硝基苯基)-1,3,5-三嗪-2-胺的合成
将(R)-1-(4-氨基-5-甲氧基-2-硝基苯基)-N,N-二甲基吡咯烷-3-胺(156mg,0.56mmol)溶于5mL正丁醇。向溶液中加入1-(4-氯-1,3,5-三嗪-2-基)-3,3-二甲基-2,3-二氢-1H-吡咯并[3,2-b]吡啶(121mg,0.46mmol)和三氟乙酸(0.5mL)。该反应溶液在50℃下反应16小时。反应结束后,将反应液浓缩,除去溶剂后,硅胶柱层析分离[二氯甲烷:甲醇=5:1]得到(R)-4-(3,3-二甲基-2,3-二氢-1H-吡咯并[3,2-b]吡啶-1-基)-N-(4-(3-(二甲氨基)吡咯烷-1-基)-2-甲氧基-5-硝基苯基)-1,3,5-三嗪-2-胺(242mg,收率:89%)。ESI-MS:506.2[M+1]
+。
第三步:(R)-N
1-(4-(3,3-二甲基-2,3-二氢-1H-吡咯并[3,2-b]吡啶-1-基)-1,3,5-三嗪-2-基)-4-(3-(二甲氨基)吡咯烷-1-基)-6-甲氧基苯-1,3-二胺的合成
将(R)-4-(3,3-二甲基-2,3-二氢-1H-吡咯并[3,2-b]吡啶-1-基)-N-(4-(3-(二甲氨基)吡咯烷-1-基)-2-甲氧基-5-硝基苯基)-1,3,5-三嗪-2-胺(242mg,0.48mmol)溶于20mL甲醇中。往溶液中加入二氧化铂(15mg)。反应液在室温下搅拌16小时。反应结束后,用硅藻土过滤。除去溶剂后用硅胶柱层析分离[洗脱剂:二氯甲烷/甲醇(5:1)]得到(R)-N
1-(4-(3,3-二甲基-2,3-二氢-1H-吡咯并[3,2-b]吡啶-1-基)-1,3,5-三嗪-2-基)-4-(3-(二甲氨基)吡咯烷-1-基)-6-甲氧基苯-1,3-二胺(133mg,收率:58%)。ESI-MS:476.2.[M+1]
+。
中间体C2-1:(R)-4-(6-氯-5-氟-3,3-二甲基二氢吲哚-1-基)-N-(4-(3-(二甲氨基)吡咯烷-1-基)-2-甲氧基-5-硝基苯基)-1,3,5-三嗪-2-胺的制备
第一步:4-氯-N-(4-氟-2-甲氧基-5-硝基苯基)-1,3,5-三嗪-2-胺的合成
室温下,将2,4-二氯-1,3,5-三嗪(9.67g,64.46mmol)溶解在二氯甲烷(150mL)中,依次加入4-氟-2-甲氧基-5-硝基苯胺(10g,53.72mmol)及N,N-二异丙基乙胺(13.86g,107.44mmol)。反应液室温下搅拌1小时。反应结束后,除去溶剂得到粗品,加入二氯甲烷(80mL),搅拌30分钟后过滤。得到的滤饼用二氯甲烷洗涤两次,经干燥后得到4-氯-N-(4-氟-2-甲氧基-5-硝基苯基)-1,3,5-三嗪-2-胺(10.15g,收率:63%)。ESI-MS:300.1[M+1]
+。
第二步:4-(6-氯-5-氟-3,3-二甲基二氢吲哚-1-基)-N-(4-氟-2-甲氧基-5-硝基苯基)-1,3,5-三嗪-2-胺的合成
在6-氯-5-氟-3,3-二甲基二氢吲哚(270mg,1.35mmol,1eq.)的1,4-二氧六环(20mL)溶液中加入4-氯-N-(4-氟-2-甲氧基-5-硝基苯基)-1,3,5-三嗪-2-胺(444mg,1.48mmol,1.1eq.)和一水合对甲苯磺酸(256mg,1.35mmol,1eq.)。反应在100℃下搅拌1小时。用乙酸乙酯和水分层。有机相依次用水和饱和氯化钠洗涤,然后用无水硫酸钠干燥,过滤,浓缩后得到4-(6-氯-5-氟-3,3-二甲基二氢吲哚-1-基)-N-(4-氟-2-甲氧基-5-硝基苯基)-1,3,5-三嗪-2-胺(660mg,收率:100%)。ESI-MS:463.1[M+1]
+。
第三步:(R)-4-(6-氯-5-氟-3,3-二甲基二氢吲哚-1-基)-N-(4-(3-(二甲氨基)吡咯烷-1-基)-2-甲氧基-5-硝基苯基)-1,3,5-三嗪-2-胺的合成
在4-(6-氯-5-氟-3,3-二甲基二氢吲哚-1-基)-N-(4-氟-2-甲氧基-5-硝基苯基)-1,3,5-三嗪-2-胺(660mg,1.42mmol,1eq.)的N,N-二甲基甲酰胺(20mL)溶液中加入(R)-N,N-二甲基吡咯烷-3-胺(161mg,1.42mmol,1eq.)和碳酸钾(587mg,4.26 mmol,3eq.)。反应在90℃下搅拌2小时。用二氯甲烷和水分层。有机相依次用水和饱和氯化钠洗涤,然后用无水硫酸钠干燥,过滤,浓缩后柱层析分离[二氯甲烷:甲醇=10:1]得到(R)-4-(6-氯-5-氟-3,3-二甲基二氢吲哚-1-基)-N-(4-(3-(二甲氨基)吡咯烷-1-基)-2-甲氧基-5-硝基苯基)-1,3,5-三嗪-2-胺(690mg,收率:87%)。ESI-MS:557.3[M+1]
+。
中间体C2:(R)-N
1-(4-(6-氯-5-氟-3,3-二甲基二氢吲哚-1-基)-1,3,5-三嗪-2-基)-4-(3-(二甲氨基)吡咯烷-1-基)-6-甲氧基苯-1,3-二胺的制备
在(R)-4-(6-氯-5-氟-3,3-二甲基二氢吲哚-1-基)-N-(4-(3-(二甲氨基)吡咯烷-1-基)-2-甲氧基-5-硝基苯基)-1,3,5-三嗪-2-胺(690mg,1.23mmol,1eq.)的甲醇/水(200mL/50ml)的悬浊液中加入铁粉(688mg,12.3mmol,10eq.)和氯化铵(664mg,12.3mmol,10eq.)。反应在95℃搅拌2小时。用二氯甲烷和水分层,有机相依次用水和饱和氯化钠洗涤,然后用无水硫酸钠干燥,过滤,浓缩后得到(R)-N
1-(4-(6-氯-5-氟-3,3-二甲基二氢吲哚-1-基)-1,3,5-三嗪-2-基)-4-(3-(二甲氨基)吡咯烷-1-基)-6-甲氧基苯-1,3-二胺(600mg,收率:92%)。ESI-MS:527.3[M+1]
+。
中间体C3~C54的制备参照中间体C1、C2-1或C2的合成方法制备得到:
二、具体实施例的制备
实施例1:(R)-N-(5-((4-(3,3-二甲基-2,3-二氢-1H-吡咯并[3,2-b]吡啶-1-基)-1,3,5-三嗪-2-基)氨基)-2-(3-(二甲氨基)吡咯烷-1-基)-4-甲氧苯基)丙烯酰胺的制备
将(R)-N
1-(4-(3,3-二甲基-2,3-二氢-1H-吡咯并[3,2-b]吡啶-1-基)-1,3,5-三嗪-2-基)-4-(3-(二甲氨基)吡咯烷-1-基)-6-甲氧基苯-1,3-二胺(133mg,0.28mmol)溶于无水DMF(1.5mL)中。向溶液中加入三乙胺(85mg,0.84mmol)。反应液于0℃下加入丙烯酰氯(27mg,0.33mmol)。反应液用0.1mL水淬灭后,反相柱层析分离[40-50%乙腈/水]得到(R)-N-(5-((4-(3,3-二甲基-2,3-二氢-1H-吡咯并[3,2-b]吡啶-1-基)-1,3,5-三嗪-2-基)氨基)-2-(3-(二甲氨基)吡咯烷-1-基)-4-甲氧苯基)丙烯酰胺(19.5mg,收率:13%)。ESI-MS:530.2[M+1]
+。
1H NMR(400MHz,DMSO-d
6)δ9.36(s,1H),8.90-8.67(m,2H)8.34(s,1H),8.09(s,1H),7.36-7.02(m,2H),6.51(s,2H),6.19-6.13(m,1H),5.74–5.62(m,1H),3.95(s,2H),3.79(s,3H),3.39-3.22(m,4H)2.70(d,J=8.0Hz,1H),2.17(s,6H),2.08(s,1H),1.74(t,J=9.8Hz,1H),1.31(s,6H)。
实施例48:N-(5-((4-(5-氰基-3,3-二甲基-1H,2H,3H-吡咯并[3,2-b]吡啶-1-基)-1,3,5-三嗪-2-基)氨基)-2-((2-(二甲氨基)乙基)(甲基)氨基)-4-甲氧苯基)丙-2-烯酰胺的制备
第一步:N-(5-((4-(5-溴-3,3-二甲基-1H,2H,3H-吡咯并[3,2-b]吡啶-1-基)-1,3,5-三嗪-2-基)氨基)-2-((2-(二甲氨基)乙基)(甲基)氨基)-4-甲氧苯基)丙-2-烯酰胺的合成
将N
4-(4-(5-溴-3,3-二甲基-1H,2H,3H-吡咯并[3,2-b]吡啶-1-基)-1,3,5-三嗪-2-基)-N
1-(2-(二甲氨基)乙基)-5-甲氧基-N
1-甲基苯-1,2,4-三胺(120mg,0.22mmol)溶于乙腈(10mL),水(10mL)中。向溶液中加入二异丙基乙胺(143mg,1.11mmol)。反应液于0℃下加入丙烯酰氯(60mg,0.66mmol)搅拌30分钟。反应液反相柱层析分离(40-50%乙腈/水]得到N-(5-((4-(5-溴-3,3-二甲基-1H,2H,3H-吡咯并[3,2-b]吡啶-1-基)-1,3,5-三嗪-2-基)氨基)-2-((2-(二甲氨基)乙基)(甲基)氨基)-4-甲氧苯基)丙-2-烯酰胺(37.0mg,收率:28%)。ESI-MS:597.1[M+1]
+。
1H NMR(400MHz,CDCl
3)δ10.01(s,1H),9.68(s,1H),8.54–8.30(m,2H),7.76(s,1H),7.26(s,1H),6.77(s,1H),6.44(br,2H),5.71(br,1H),,4.38(s,2H),3.88(s,3H),2.92(s,2H),2.72(s,3H),2.33(s,8H),1.47(s,6H)。
第二步:N-(5-((4-(5-氰基-3,3-二甲基-1H,2H,3H-吡咯并[3,2-b]吡啶-1-基)-1,3,5-三嗪-2-基)氨基)-2-((2-(二甲氨基)乙基)(甲基)氨基)-4-甲氧苯基)丙-2-烯酰胺的合成
将N-(5-((4-(5-溴-3,3-二甲基-1H,2H,3H-吡咯并[3,2-b]吡啶-1-基)-1,3,5-三嗪-2-基)氨基)-2-((2-(二甲氨基)乙基)(甲基)氨基)-4-甲氧苯基)丙-2-烯酰胺(15mg,0.025mmol),氰化锌(9mg,0.075mmol),四三苯基磷钯(3mg,0.003mmol)溶于N,N-二甲基甲酰胺(2mL),反应液在氮气保护下80℃搅拌1小时,反应结束。反应液用乙酸乙酯(50mL)饱和食盐水(50mL)分层,有机相用饱和食盐水(50mL)洗。所得有机相浓缩,剩余物通过制备色谱柱分离得到N-(5-((4-(5-氰基-3,3-二甲基-1H,2H,3H-吡咯并[3,2-b]吡啶-1-基)-1,3,5-三嗪-2-基)氨基)-2-((2-(二甲氨基)乙基)(甲基)氨基)-4-甲氧苯基)丙-2-烯酰胺。ESI-MS:543.2[M+1]
+。
1H NMR(400MHz,CDCl
3)δ10.07(s,1H),9.66(s,1H),8.63(d,J=8.4Hz,1H),8.46(s,1H),7.83(s,1H),7.52(s,1H),6.78(s,1H),6.44(br,2H),5.73(br,1H),4.43(s,2H),3.89(s,3H),2.90(s,4H),2.73(s,3H),2.44–2.20(m,6H),1.48(s,6H)。
实施例49:N-(5-((4-(3,3-二甲基-5-(1-甲基-1H-吡唑-4-基)-1H,2H,3H-吡咯并[3,2-b]吡啶-1-基)-1,3,5-三嗪-2-基)氨基)-2-((2-(二甲氨基)乙基)(甲基)氨基)-4-甲氧苯基)丙-2-烯酰胺的制备
第一步:N
4-(4-(3,3-二甲基-5-(1-甲基-1H-吡唑-4-基)-1H,2H,3H-吡咯并[3,2-b]吡啶-1-基)-1,3,5-三嗪-2-基)-N
1-(2-(二甲氨基)乙基)-5-甲氧基-N
1-甲基-2-硝基苯-1,4-二胺的合成
将N
4-(4-(5-溴-3,3-二甲基-1H,2H,3H-吡咯并[3,2-b]吡啶-1-基)-1,3,5-三嗪-2-基)-N
1-(2-(二甲氨基)乙基)-5-甲氧基-N
1-甲基-2-硝基苯-1,4-二胺(参照中间体C2-1合成路线)(50mg,0.087mmol),1-甲基-4-(四甲基-1,3,2-二噁硼戊环-2-基)-1H-吡唑(28mg,0.131mmol),Pd(dppf)Cl
2(7mg,0.009mmol)和碳酸钾(24mg,0.175mmol)溶于二氧六环-水(4:1)(10mL),反应液在氮气保护下90℃搅拌1小时,反应结束。 反应液用乙酸乙酯(50mL)饱和食盐水(50mL)分层,有机相用饱和食盐水(50mL)洗。所得有机相浓缩,剩余物通过快速硅胶柱分离[二氯甲烷:甲醇=10:1]得到N
4-(4-(3,3-二甲基-5-(1-甲基-1H-吡唑-4-基)-1H,2H,3H-吡咯并[3,2-b]吡啶-1-基)-1,3,5-三嗪-2-基)-N
1-(2-(二甲氨基)乙基)-5-甲氧基-N
1-甲基-2-硝基苯-1,4-二胺(40mg,收率:80%)。ESI-MS:574.3[M+1]
+。
第二步:N
4-(4-(3,3-二甲基-5-(1-甲基-1H-吡唑-4-基)-1H,2H,3H-吡咯并[3,2-b]吡啶-1-基-1,3,5-三嗪-2-基)-N
1-(2-(二甲氨基)乙基)-5-甲氧基-N
1-甲基苯-1,2,4-三胺的合成
在N
4-(4-(3,3-二甲基-5-(1-甲基-1H-吡唑-4-基)-1H,2H,3H-吡咯并[3,2-b]吡啶-1-基)-1,3,5-三嗪-2-基)-N
1-(2-(二甲氨基)乙基)-5-甲氧基-N
1-甲基-2-硝基苯-1,4-二胺(40mg,0.070mmol,1eq.)的甲醇/水(20mL/5ml)的悬浊液中加入铁粉(39mg,0.70mmol,10eq.)和氯化铵(37mg,0.70mmol,10eq.)。反应在95℃搅拌2小时。用二氯甲烷和水分层,有机相依次用水和饱和氯化钠洗涤,然后用无水硫酸钠干燥,过滤,浓缩后得到N
4-(4-(3,3-二甲基-5-(1-甲基-1H-吡唑-4-基)-1H,2H,3H-吡咯并[3,2-b]吡啶-1-基)-1,3,5-三嗪-2-基)-N
1-(2-(二甲氨基)乙基)-5-甲氧基-N
1-甲基苯-1,2,4-三胺(35mg,收率:92%)。ESI-MS:544.3[M+1]
+。
第三步:N-(5-((4-(3,3-二甲基-5-(1-甲基-1H-吡唑-4-基)-1H,2H,3H-吡咯并[3,2-b]吡啶-1-基)-1,3,5-三嗪-2-基)氨基)-2-((2-(二甲氨基)乙基)(甲基)氨基)-4-甲氧苯基)丙-2-烯酰胺的合成
将N
4-(4-(3,3-二甲基-5-(1-甲基-1H-吡唑-4-基)-1H,2H,3H-吡咯并[3,2-b]吡啶-1-基)-1,3,5-三嗪-2-基)-N
1-(2-(二甲氨基)乙基)-5-甲氧基-N
1-甲基苯-1,2,4-三胺(35mg,0.064mmol)溶于乙腈(10mL),水(10mL)中。向溶液中加入二异丙基乙胺(83mg, 0.64mmol)。反应液于0℃下加入丙烯酰氯(17mg,0.20mmol)搅拌30分钟。反应液反相柱层析分离[40-50%乙腈/水]得到N-(5-((4-(3,3-二甲基-5-(1-甲基-1H-吡唑-4-基)-1H,2H,3H-吡咯并[3,2-b]吡啶-1-基)-1,3,5-三嗪-2-基)氨基)-2-((2-(二甲氨基)乙基)(甲基)氨基)-4-甲氧苯基)丙-2-烯酰胺(7.9mg,收率:20%)。ESI-MS:598.4[M+1]
+。
1H NMR(400MHz,CDCl
3)δ10.00(s,1H),9.71(s,1H),8.53(d,J=8.5Hz,1H),8.42(s,1H),7.91(d,J=3.4Hz,2H),7.72(s,1H),6.79(s,1H),6.43(br,2H),5.85–5.56(m,1H),4.38(s,2H),3.95(s,3H),3.88(s,3H),2.91(s,2H),2.83–2.61(m,3H),2.31(s,8H),1.49(s,6H)。
实施例51:N-(5-((4-(5-(2-环丙基乙炔基)-3,3-二甲基-1H,2H,3H-吡咯并[3,2-b]吡啶-1-基)-1,3,5-三嗪-2-基)氨基)-2-((2-(二甲氨基)乙基)(甲基)氨基)-4-甲氧苯基)丙-2-烯酰胺的制备
第一步:N
4-(4-(5-(2-环丙基乙炔基)-3,3-二甲基-1H,2H,3H-吡咯并[3,2-b]吡啶-1-基)-1,3,5-三嗪-2-基)-N
1-(2-(二甲氨基)乙基)-5-甲氧基-N
1-甲基-2-硝基苯-1,4-二胺的合成
将N
4-(4-(5-溴-3,3-二甲基-1H,2H,3H-吡咯并[3,2-b]吡啶-1-基)-1,3,5-三嗪-2-基)-N
1-(2-(二甲氨基)乙基)-5-甲氧基-N
1-甲基-2-硝基苯-1,4-二胺(参照中间体C2-1合成路线)(70mg,0.122mmol),乙炔基环丙烷(0.1mL,1.22mmol),双三苯基磷二氯化钯(9mg,0.012mmol)和碘化亚铜(3mg,0.012mmol)溶于四氢呋喃(5mL)和三乙胺(5mL)中,反应液在氮气保护下50℃搅拌16小时,反应结束。反应液用乙酸乙酯(50mL),饱和食盐水(50mL)分层,有机相用饱和食盐水(50mL)洗。所得有机 相浓缩,剩余物通过快速硅胶柱分离[二氯甲烷:甲醇=10:1]得到N
4-(4-(5-(2-环丙基乙炔基)-3,3-二甲基-1H,2H,3H-吡咯并[3,2-b]吡啶-1-基)-1,3,5-三嗪-2-基)-N
1-(2-(二甲氨基)乙基)-5-甲氧基-N
1-甲基-2-硝基苯-1,4-二胺(40mg,收率:58%)。ESI-MS:558.3[M+1]
+。
第二步:N
4-(4-(5-(2-环丙基乙炔基)-3,3-二甲基-1H,2H,3H-吡咯并[3,2-b]吡啶-1-基)-1,3,5-三嗪-2-基)-N
1-(2-(二甲氨基)乙基)-5-甲氧基-N
1-甲基苯-1,2,4-三胺的合成
在N
4-(4-(5-(2-环丙基乙炔基)-3,3-二甲基-1H,2H,3H-吡咯并[3,2-b]吡啶-1-基)-1,3,5-三嗪-2-基)-N
1-(2-(二甲氨基)乙基)-5-甲氧基-N
1-甲基-2-硝基苯-1,4-二胺(40mg,0.072mmol,1eq.)的甲醇/水(20mL/5ml)的悬浊液中加入铁粉(40mg,0.72mmol,10eq.)和氯化铵(40mg,0.72mmol,10eq.)。反应在95℃搅拌2小时。用二氯甲烷和水分层,有机相依次用水和饱和氯化钠洗涤,然后用无水硫酸钠干燥,过滤,浓缩后得到N
4-(4-(5-(2-环丙基乙炔基)-3,3-二甲基-1H,2H,3H-吡咯并[3,2-b]吡啶-1-基)-1,3,5-三嗪-2-基)-N
1-(2-(二甲氨基)乙基)-5-甲氧基-N
1-甲基苯-1,2,4-三胺(35mg,收率:91%)。ESI-MS:529.3[M+1]
+。
第三步:N-(5-((4-(5-(2-环丙基乙炔基)-3,3-二甲基-1H,2H,3H-吡咯并[3,2-b]吡啶-1-基)-1,3,5-三嗪-2-基)氨基)-2-((2-(二甲氨基)乙基)(甲基)氨基)-4-甲氧苯基)丙-2-烯酰胺的合成
将N
4-(4-(5-溴-3,3-二甲基-1H,2H,3H-吡咯并[3,2-b]吡啶-1-基)-1,3,5-三嗪-2-基)-N
1-(2-(二甲氨基)乙基)-5-甲氧基-N
1-甲基苯-1,2,4-三胺(35mg,0.066mmol)溶于乙腈(10mL),水(10mL)中。向溶液中加入二异丙基乙胺(86mg,0.66mmol)。反 应液于0℃下加入丙烯酰氯(18mg,0.22mmol)搅拌30分钟。反应液反相柱层析分离[40-50%乙腈/水]得到N-(5-((4-(5-溴-3,3-二甲基-1H,2H,3H-吡咯并[3,2-b]吡啶-1-基)-1,3,5-三嗪-2-基)氨基)-2-((2-(二甲氨基)乙基)(甲基)氨基)-4-甲氧苯基)丙-2-烯酰胺(3.2mg,收率:8%)。ESI-MS:582.3[M+1]
+。
1H NMR(400MHz,CDCl
3)δ9.95(s,1H),9.68(s,1H),8.55–8.26(m,2H),7.75(s,1H),7.26(s,1H),6.78(s,1H),6.44(br,2H),5.91–5.63(m,1H),4.36(s,2H),3.88(s,3H),2.93(s,2H),2.71(s,3H),2.34(s,6H),1.85(s,2H),1.48(s,6H),1.34–1.14(m,1H),0.87(br,4H)。
实施例2~47,实施例50,实施例52~56的制备参照实施例1或实施例49的合成方法制备得到:
上述实施例制备得到的化合物核磁数据如下:
生物学测试评价
一、细胞增殖实验
(一)试剂和耗材
胎牛血清FBS(GBICO,Cat#10099-141)
(二)仪器
SpectraMax多标记微孔板检测仪MD,2104-0010A;
二氧化碳培养箱,Thermo Scientific 3100系列;
生物安全柜,Thermo Scientific,1300系列A2型;
倒置显微镜,Olympus,CKX41SF;
西门子冰箱KK25E76TI。
(三)细胞系和培养条件
No. | 细胞系 | 细胞培养基 | 细胞密度 |
1 | A431 | DMEM+15%FBS | 5000 |
2 | Ba/F3 EGFR-WT | RPMI1640+10%FBS | 3000 |
3 | Ba/F3 EGFR-D770-N771ins_SVD | RPMI1640+10%FBS | 3000 |
4 | Ba/F3 EGFR-V769_D770insASV | RPMI1640+10%FBS | 3000 |
(四)实验步骤
1、细胞培养和接种:
(1)收获处于对数生长期的细胞,并使用血小板计数器对细胞进行计数。通过台盼蓝排除法检测细胞活力,以确保细胞活力在90%以上。
(2)调整细胞浓度以达到所需的最终密度;将90μL细胞悬液添加到96孔板中。
(3)将细胞在96孔板中于37℃,5%CO
2和95%湿度下孵育过夜。
2、T0基准数据:
(1)在装有细胞的T0平板的每个孔中加入10μL PBS。
(2)解冻CTG试剂,并将细胞板平衡至室温30分钟。
(3)向每个孔中添加等体积的CTG溶液。
(4)在定轨摇床上振动5分钟以裂解细胞。
(5)将细胞板在室温下放置20分钟以稳定发光信号。
(6)读取T0荧光信号值。
3、化合物稀释和添加
(1)根据化合物信息表,将相应体积的DMSO加入相应的化合物粉末中,以制备10mM储备液。
(2)准备1000倍,3.16倍稀释的化合物溶液。
(3)用PBS将1000×稀释的化合物溶液稀释100倍,以制备10倍的化合物溶液,最高浓度为10μM,9种浓度,稀释3.16倍,在接种有96孔板的每个孔中加入10μL药物溶液,接种细胞。每个化合物的浓度设置三个重复孔,DMSO的最终浓度为0.1%。
(4)将细胞置于装有药物的96孔板中,温度为37℃,5%CO
2和95%湿度,继续培养72小时,然后进行CTG分析。
4、荧光信号读取
(1)解冻CTG试剂,并将细胞板平衡至室温30分钟。
(2)向每个孔中添加等体积的CTG溶液。
(3)在定轨摇床上振动5分钟以裂解细胞。
(4)将细胞板在室温放置20分钟以稳定荧光信号。
(5)读取荧光值。
5、数据处理
使用GraphPad Prism 7.0软件分析数据,并使用非线性S曲线回归拟合数据以获得剂量效应曲线,并据此计算IC
50值(单位:nM),具体实验结果见表1:
细胞存活率(%)=(Lum试验药物-Lum培养液对照)/(Lum细胞对照-Lum培养液对照)×100%。
表1:生物学测试结果
从具体实施例化合物生物活性数据来看,本发明系列化合物在细胞水平上对EGFR外显子20插入、缺失或其它突变具有很强的抑制作用。另外,部分化合物对EGFR WT具有很高的选择性。
在本发明提及的所有文献都在本申请中引用作为参考,就如同每一篇文献被单独引用作为参考那样。此外应理解,在阅读了本发明的上述公开内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落于本申请所附权利要求书所限定的范围。
Claims (16)
- 式(I)化合物、其立体异构体或其药学上可接受盐:其中,X为CH或N;Y为键、O或S;Z 1和Z 2各自独立地为CR 10或N;R 1选自氢、氘、羟基、C 1-6烷基、卤取代C 1-6烷基、氘取代C 1-6烷基、C 2-4链烯基、C 3-6环烷基和3-6元杂环基;R 2和R 3各自独立地选自氢、氘、羟基、C 1-6烷基、C 2-4链烯基、C 3-6环烷基和3-6元杂环基,上述基团独立地任选进一步被一个或多个选自氘、卤素、羟基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 1-10烷氧基、C 3-12环烷基、C 3-12环烷氧基、3-12元杂环基、3-12元杂环氧基、C 6-10芳基、C 6-10芳氧基、5-10元杂芳基、5-10元杂芳氧基和-C 0-8烷基-NR 14R 15的取代基所取代;R 4和R 5各自独立地选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-12环烷基、3-12元杂环基、C 6-10芳基、5-10元杂芳基、-SF 5、-S(O) rR 11、-OR 12、-C(O)OR 12、-C(O)R 13、-O-C(O)R 13、-NR 14R 15、-C(=NR 14)R 13、-N(R 14)-C(=NR 15)R 13、-C(O)NR 14R 15和-N(R 14)-C(O)R 13;或者,R 2、R 4或R 5其中一个和R 1与其直接相连的部分一起形成4-8元杂环基,R 2、R 4或R 5其中另两个如前所定义,或者,R 4或R 5其中之一和R 2与其直接相连的部分一起形成4-8元杂环基,R 4或R 5其中另一个如前所定义,所述4-8元杂环基任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-12环烷基、3-12元杂环基、C 6-10芳基、5-10元杂芳基、=O、-SF 5、-S(O) rR 11、-OR 12、-C(O)OR 12、-C(O)R 13、-O-C(O)R 13、-NR 14R 15、-C(=NR 14)R 13、-N(R 14)-C(=NR 15)R 13、-C(O)NR 14R 15和-N(R 14)-C(O)R 13的取代基所取代;R 6选自氢、氘、C 1-10烷基、C 2-10链烯基、C 3-12环烷基、3-12元杂环基、C 6-10 芳基和5-10元杂芳基,上述基团独立地任选进一步被一个或多个选自氘、卤素、羟基、氧代、氰基、C 1-10烷基、C 1-10烷氧基、C 3-12环烷基、C 3-12环烷氧基、3-12元杂环基、3-12元杂环氧基、C 6-10芳基、C 6-10芳氧基、5-10元杂芳基、5-10元杂芳氧基和-NR 14R 15的取代基所取代;R 7选自氢、氘、卤素、氰基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 3-6环烷基、3-6元杂环基、-C(O)OR 12、-C(O)R 13、-C(O)-NR 14R 15和-C 0-4烷基-NR 14R 15;R 8和R 9各自独立地选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-12环烷基、3-12元杂环基、C 6-10芳基和5-10元杂芳基,或者,R 8和R 9与其直接相连的碳原子一起形成C 3-6环烷基或3-6元杂环基,上述基团独立地任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 3-12环烷基、3-12元杂环基、C 6-10芳基、5-10元杂芳基、=O、-SF 5、-S(O) rR 11、-O-R 12、-C(O)OR 12、-C(O)R 13、-O-C(O)R 13、-NR 14R 15、-C(=NR 14)R 13、-N(R 14)-C(=NR 15)R 13、-C(O)NR 14R 15和-N(R 14)-C(O)R 13的取代基所取代;每个R 10各自独立地选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-12环烷基、3-12元杂环基、C 6-10芳基、5-10元杂芳基、-SF 5、-S(O) rR 11、-O-R 12、-C(O)OR 12、-C(O)R 13、-O-C(O)R 13、-NR 14R 15、-C(=NR 14)R 13、-N(R 14)-C(=NR 15)R 13、-C(O)NR 14R 15和-N(R 14)-C(O)R 13,或者,相邻的两个R 10与其直接相连的部分一起形成C 4-8环烷基或4-8元杂环基,上述基团独立地任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 3-12环烷基、3-12元杂环基、C 6-10芳基、5-10元杂芳基、=O、-SF 5、-S(O) rR 11、-O-R 12、-C(O)OR 12、-C(O)R 13、-O-C(O)R 13、-NR 14R 15、-C(=NR 14)R 13、-N(R 14)-C(=NR 15)R 13、-C(O)NR 14R 15和-N(R 14)-C(O)R 13的取代基所取代;每个R 11各自独立地选自氢、氘、羟基、C 1-10烷基、C 2-10链烯基、C 3-12环烷基、3-12元杂环基、C 6-10芳基、5-10元杂芳基和-NR 14R 15,上述基团独立地任选进一步被一个或多个选自氘、卤素、羟基、氧代、C 1-10烷基、C 1-10烷氧基、C 3-12环烷基、C 3-12环烷氧基、3-12元杂环基、3-12元杂环氧基、C 6-10芳基、C 6-10芳氧基、5-10元杂芳基、5-10元杂芳氧基和-NR 14R 15的取代基所取代;每个R 12各自独立地选自氢、氘、C 1-10烷基、C 2-10链烯基、C 3-12环烷基、3-12元杂环基、C 6-10芳基和5-10元杂芳基,上述基团独立地任选进一步被一个或多个选自氘、卤素、羟基、氧代、氰基、C 1-10烷基、C 1-10烷氧基、C 3-12环烷基、C 3-12环烷氧基、3-12元杂环基、3-12元杂环氧基、C 6-10芳基、C 6-10芳氧基、5-10元杂芳基、5-10元杂芳氧基和-NR 14R 15的取代基所取代;每个R 13各自独立地选自氢、氘、羟基、C 1-10烷基、C 1-10烷氧基、C 2-10链烯基、 C 2-10链炔基、C 3-12环烷基、C 3-12环烷氧基、3-12元杂环基、3-12元杂环氧基、C 6-10芳基、C 6-10芳氧基、5-10元杂芳基、5-10元杂芳氧基和-NR 14R 15,上述基团独立地任选进一步被一个或多个选自氘、卤素、羟基、氰基、C 1-10烷基、C 1-10烷氧基、C 3-12环烷基、C 3-12环烷氧基、3-12元杂环基、3-12元杂环氧基、C 6-10芳基、C 6-10芳氧基、5-10元杂芳基、5-10元杂芳氧基和-NR 14R 15的取代基所取代;每个R 14和R 15各自独立地选自氢、氘、羟基、C 1-10烷氧基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-12环烷基、3-12元杂环基、C 6-10芳基、5-10元杂芳基、亚磺酰基、磺酰基、甲磺酰基、异丙磺酰基、环丙基磺酰基、对甲苯磺酰基、氨基磺酰基、二甲氨基磺酰基、氨基、单C 1-10烷基氨基、二C 1-10烷基氨基和C 1-10烷酰基,上述基团独立地任选进一步被一个或多个选自氘、卤素、羟基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 1-10烷氧基、C 3-12环烷基、C 3-12环烷氧基、3-12元杂环基、3-12元杂环氧基、C 6-10芳基、C 6-10芳氧基、5-10元杂芳基、5-10元杂芳氧基、氨基、单C 1-10烷基氨基、二C 1-10烷基氨基和C 1-10烷酰基的取代基所取代,或者,R 14和R 15与其直接相连的氮原子一起形成4-10元杂环基或5-10元杂芳基,上述基团独立地任选进一步被一个或多个选自氘、卤素、羟基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 1-10烷氧基、C 3-12环烷基、C 3-12环烷氧基、3-12元杂环基、3-12元杂环氧基、C 6-10芳基、C 6-10芳氧基、5-10元杂芳基、5-10元杂芳氧基、氨基、单C 1-10烷基氨基、二C 1-10烷基氨基和C 1-10烷酰基的取代基所取代;m为0、1或2;n为0、1或2;且每个r各自独立地为0、1或2。
- 根据权利要求1所述的式(I)化合物、其立体异构体或其药学上可接受盐,其特征在于,R 6选自氢、氘、C 1-4烷基、C 2-4链烯基、C 3-8环烷基、3-8元杂环基、C 6-8芳基和5-8元杂芳基,上述基团独立地任选进一步被一个或多个选自氘、卤素、羟基、氧代、氰基、C 1-4烷基、C 1-4烷氧基、C 3-8环烷基、C 3-8环烷氧基、3-8元杂环基、3-8元杂环氧基、C 6-8芳基、C 6-8芳氧基、5-8元杂芳基、5-8元杂芳氧基和-NR 14R 15的取代基所取代;R 7选自氢、氘、卤素、氰基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 3-8环烷基、3-8元杂环基和-C 0-4烷基-NR 14R 15;其中,R 14和R 15如权利要求1中所定义。
- 根据权利要求1所述的式(I)化合物、其立体异构体或其药学上可接受盐,其特征在于,R 8和R 9各自独立地选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-4 烷基、C 2-4链烯基、C 2-4链炔基、C 3-8环烷基、3-8元杂环基、C 6-8芳基和5-8元杂芳基,或者,R 8和R 9与其直接相连的碳原子一起形成C 3-6环烷基或3-6元杂环基,上述基团独立地任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 3-8环烷基、3-8元杂环基、C 6-8芳基、5-8元杂芳基、=O、-SF 5、-S(O) rR 11、-O-R 12、-C(O)OR 12、-C(O)R 13、-O-C(O)R 13、-NR 14R 15、-C(=NR 14)R 13、-N(R 14)-C(=NR 15)R 13、-C(O)NR 14R 15和-N(R 14)-C(O)R 13的取代基所取代;其中,R 11、R 12、R 13、R 14、R 15和r如权利要求1中所定义。
- 根据权利要求1所述的式(I)化合物、其立体异构体或其药学上可接受盐,其特征在于,每个R 10各自独立地选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、-SF 5、-S(O) rR 11、-O-R 12、-C(O)OR 12、-C(O)R 13、-O-C(O)R 13、-NR 14R 15、-C(O)NR 14R 15和-N(R 14)-C(O)R 13,或者,相邻的两个R 10与其直接相连的部分一起形成C 4-8环烷基或4-8元杂环基,上述基团独立地任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、卤取代C 1-4烷基、C 3-8环烷基、3-8元杂环基、C 6-8芳基、5-8元杂芳基、=O、-SF 5、-S(O) rR 11、-O-R 12、-C(O)OR 12、-C(O)R 13、-O-C(O)R 13、-NR 14R 15、-C(=NR 14)R 13、-N(R 14)-C(=NR 15)R 13、-C(O)NR 14R 15和-N(R 14)-C(O)R 13的取代基所取代;其中,R 11、R 12、R 13、R 14、R 15和r如权利要求1中所定义。
- 根据权利要求1所述的式(I)化合物、其立体异构体或其药学上可接受盐,其特征在于,R 1选自氢、氘、羟基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 3-6环烷基和3-6元杂环基;R 2和R 3各自独立地选自氢、氘和C 1-4烷基,上述基团独立地任选进一步被一个或多个选自氘、卤素、羟基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 1-4烷氧基、C 3-8环烷基、C 3-8环烷氧基、3-8元杂环基、3-8元杂环氧基、C 6-8芳基、C 6-8芳氧基、5-8元杂芳基、5-8元杂芳氧基和-C 0-4烷基-NR 14R 15的取代基所取代;R 4和R 5各自独立地选自氢、氘、卤素、氰基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-8环烷基、3-8元杂环基、C 6-8芳基、5-8元杂芳基、-OR 12、-C(O)OR 12、-C(O)R 13、-O-C(O)R 13、-NR 14R 15、-C(O)NR 14R 15和-N(R 14)-C(O)R 13;或者,R 2、R 4或R 5其中一个和R 1与其直接相连的部分一起形成如下结构:R 2、R 4或R 5其中另两个如前所定义,R 3如前所定义;或者,R 4或R 5其中之一和R 2与其直接相连的部分一起形成如下结构:R 4或R 5其中另一个如前所定义,R 1或R 3如前所定义;其中,R 12、R 13、R 14和R 15如权利要求1中所定义。
- 根据权利要求1所述的式(I)化合物、其立体异构体或其药学上可接受盐,其特征在于,式(I)化合物为如下式(Ⅱa)化合物:其中,X为CH或N;Z 2为CH或N;R 2、R 4或R 5其中一个和R 1与其直接相连的部分一起形成如下结构:每个R 2和R 3各自独立地选自氢、氘和C 1-4烷基,上述基团独立地任选进一步被一个或多个选自氘、卤素、羟基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、卤取代C 1-4烷基、氘取代C 1-4烷基和-C 0-4烷基-NR 14R 15的取代基所取代;或者,R 4或R 5其中之一和R 2与其直接相连的部分一起形成如下结构:每个R 1各自独立地选自氢、氘、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基和C 2-4链烯基;每个R 3各自独立地选自氢、氘和C 1-4烷基,上述基团独立地任选进一步被一个或多个选自氘、卤素、羟基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、卤取代C 1-4烷基、氘取代C 1-4烷基和-C 0-4烷基-NR 14R 15的取代基所取代;R 6选自氢、氘、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 3-8环烷基和3-8元杂环基;R 8和R 9各自独立地选自氢、氘、卤素、氰基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-8环烷基、3-8元杂环基、C 6-8芳基和5-8元杂芳基,或者,R 8和R 9与其直接相连的碳原子一起形成C 3-6环烷基或3-6元杂环基,上述基团独立地任选进一步被一个或多个选自氘、卤素、氰基、羟基、C 1-4烷基、C 1-4烷氧基、C 2-4链烯基、C 2-4链炔基、卤取代C 1-4烷基、卤取代C 1-4烷氧基、氘取代C 1-4烷基、氘取代C 1-4烷氧基、C 3-8环烷基、C 3-8环烷氧基、3-8元杂环基、3-8元杂环氧基、C 6-8芳基和5-8元杂芳基的取代基所取代;每个R 10各自独立地选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、-SF 5、-S(O) rR 11、-O-R 12、-C(O)OR 12、-C(O)R 13、-O-C(O)R 13、-NR 14R 15、-C(O)NR 14R 15和-N(R 14)-C(O)R 13,或者,相邻的两个R 10与其直接相连的部分一起形成C 4-6环烷基或4-6元杂环基,上述基团独立地任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、卤取代C 1-4烷基、C 3-8环烷基、3-8元杂环基、C 6-8芳基、5-8元杂芳基、=O、-SF 5、-S(O) rR 11、-O-R 12、-C(O)OR 12、-C(O)R 13、-O-C(O)R 13、-NR 14R 15、-C(=NR 14)R 13、-N(R 14)-C(=NR 15)R 13、-C(O)NR 14R 15和-N(R 14)-C(O)R 13的取代基所取代;每个R 11各自独立地选自氢、氘、羟基、C 1-4烷基、C 2-4链烯基、C 3-8环烷基、3-8元杂环基、C 6-8芳基、5-8元杂芳基和-NR 14R 15,上述基团独立地任选进一步被一个或多个选自氘、卤素、羟基、氧代、C 1-4烷基、C 1-4烷氧基、C 3-8环烷基、C 3-8环烷氧基、3-8元杂环基、3-8元杂环氧基、C 6-8芳基、C 6-8芳氧基、5-8元杂芳基、5-8元杂芳氧基和-NR 14R 15的取代基所取代;每个R 12各自独立地选自氢、氘、C 1-4烷基、C 2-4链烯基、C 3-8环烷基、3-8元杂环基、C 6-8芳基和5-8元杂芳基,上述基团独立地任选进一步被一个或多个选自氘、卤素、羟基、氧代、氰基、C 1-4烷基、C 1-4烷氧基、C 3-8环烷基、C 3-8环烷氧基、3-8元杂环基、3-8元杂环氧基、C 6-8芳基、C 6-8芳氧基、5-8元杂芳基、5-8元杂芳氧基和-NR 14R 15的取代基所取代;每个R 13各自独立地选自氢、氘、羟基、C 1-4烷基、C 1-4烷氧基、C 2-4链烯基、 C 2-4链炔基、C 3-8环烷基、C 3-8环烷氧基、3-8元杂环基、3-8元杂环氧基、C 6-8芳基、C 6-8芳氧基、5-8元杂芳基、5-8元杂芳氧基和-NR 14R 15,上述基团独立地任选进一步被一个或多个选自氘、卤素、羟基、氰基、C 1-4烷基、C 1-4烷氧基、C 3-8环烷基、C 3-8环烷氧基、3-8元杂环基、3-8元杂环氧基、C 6-8芳基、C 6-8芳氧基、5-8元杂芳基、5-8元杂芳氧基和-NR 14R 15的取代基所取代;每个R 14和R 15各自独立地选自氢、氘、羟基、C 1-4烷氧基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-8环烷基、3-8元杂环基、C 6-8芳基、5-8元杂芳基、亚磺酰基、磺酰基、甲磺酰基、异丙磺酰基、环丙基磺酰基、对甲苯磺酰基、氨基磺酰基、二甲氨基磺酰基、氨基、单C 1-4烷基氨基、二C 1-4烷基氨基和C 1-4烷酰基,上述基团独立地任选进一步被一个或多个选自氘、卤素、羟基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 1-4烷氧基、C 3-8环烷基、C 3-8环烷氧基、3-8元杂环基、3-8元杂环氧基、C 6-8芳基、C 6-8芳氧基、5-8元杂芳基、5-8元杂芳氧基、氨基、单C 1-4烷基氨基、二C 1-4烷基氨基和C 1-4烷酰基的取代基所取代,或者,R 14和R 15与其直接相连的氮原子一起形成4-8元杂环基或5-8元杂芳基,上述基团独立地任选进一步被一个或多个选自氘、卤素、羟基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 1-4烷氧基、C 3-8环烷基、C 3-8环烷氧基、3-8元杂环基、3-8元杂环氧基、C 6-8芳基、C 6-8芳氧基、5-8元杂芳基、5-8元杂芳氧基、氨基、单C 1-4烷基氨基、二C 1-4烷基氨基和C 1-4烷酰基的取代基所取代;m为0、1或2;n为0、1或2;且每个r各自独立地为0、1或2。
- 根据权利要求6所述的式(I)化合物、其立体异构体或其药学上可接受盐,其特征在于,式(I)化合物为如下式(Ⅲa)化合物:其中,X为CH或N;Z 2为CH或N;R 2、R 4或R 5其中一个和R 1与其直接相连的部分一起形成如下结构:R 6选自氢、氘、C 1-2烷基、卤取代C 1-2烷基和氘取代C 1-2烷基;R 8和R 9各自独立地选自氢、氘、氟、氯、溴、甲基、乙基、丙基、异丙基、环丙基、-CHF 2、-CF 3、-CHD 2和-CD 3;R 10a和R 10b各自独立地选自氢、氘、氟、氯、溴、氰基、甲基、乙基、丙基、异丙基、环丙基、-CHF 2、-CF 3、-CHD 2、-CD 3、甲氧基、氮杂环丁基、乙烯基、乙炔基和苯基,或者,R 10a和R 10b与其直接相连的部分一起形成C 4-6环烷基或4-6元杂环基。
- 根据权利要求1所述的式(I)化合物、其立体异构体或其药学上可接受盐,其特征在于,式(I)化合物为如下式(Ⅱb)化合物:其中,X为CH或N;Y为键、O或S;Z 1为CR 10或N;Z 2为CH或N;R 1选自氢、氘、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基和C 2-4链烯基;R 2和R 3各自独立地选自氢、氘和C 1-4烷基,上述基团独立地任选进一步被一个或多个选自氘、卤素、羟基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、卤取代C 1-4烷基、氘取代C 1-4烷基和-C 0-4烷基-NR 14R 15的取代基所取代;R 4选自氢、氘、卤素、C 1-4烷基、卤取代C 1-4烷基和氘取代C 1-4烷基;R 5选自氢、氘、卤素、C 1-4烷基、卤取代C 1-4烷基和氘取代C 1-4烷基;R 6选自氢、氘、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 3-8环烷基和3-8元杂环基;R 8和R 9各自独立地选自氢、氘、卤素、氰基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-8环烷基、3-8元杂环基、C 6-8芳基和5-8元杂芳基,或者,R 8和R 9与 其直接相连的碳原子一起形成C 3-6环烷基或3-6元杂环基,上述基团独立地任选进一步被一个或多个选自氘、卤素、氰基、羟基、C 1-4烷基、C 1-4烷氧基、C 2-4链烯基、C 2-4链炔基、卤取代C 1-4烷基、卤取代C 1-4烷氧基、氘取代C 1-4烷基、氘取代C 1-4烷氧基、C 3-8环烷基、C 3-8环烷氧基、3-8元杂环基、3-8元杂环氧基、C 6-8芳基和5-8元杂芳基的取代基所取代;每个R 10和R 10a各自独立地选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、-SF 5、-S(O) rR 11、-O-R 12、-C(O)OR 12、-C(O)R 13、-O-C(O)R 13、-NR 14R 15、-C(O)NR 14R 15和-N(R 14)-C(O)R 13,或者,R 10和R 10a与其直接相连的部分一起形成C 4-6环烷基或4-6元杂环基,上述基团独立地任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、卤取代C 1-4烷基、C 3-8环烷基、3-8元杂环基、C 6-8芳基、5-8元杂芳基、=O、-SF 5、-S(O) rR 11、-O-R 12、-C(O)OR 12、-C(O)R 13、-O-C(O)R 13、-NR 14R 15、-C(=NR 14)R 13、-N(R 14)-C(=NR 15)R 13、-C(O)NR 14R 15和-N(R 14)-C(O)R 13的取代基所取代,条件是,当X为CH,Y为键,n为1时,R 10与R 10a其中之一为氢、卤素或C 1-4烷基时,另一个不为氢、卤素或C 1-4烷基;每个R 11各自独立地选自氢、氘、羟基、C 1-4烷基、C 2-4链烯基、C 3-8环烷基、3-8元杂环基、C 6-8芳基、5-8元杂芳基和-NR 14R 15,上述基团独立地任选进一步被一个或多个选自氘、卤素、羟基、氧代、C 1-4烷基、C 1-4烷氧基、C 3-8环烷基、C 3-8环烷氧基、3-8元杂环基、3-8元杂环氧基、C 6-8芳基、C 6-8芳氧基、5-8元杂芳基、5-8元杂芳氧基和-NR 14R 15的取代基所取代;每个R 12各自独立地选自氢、氘、C 1-4烷基、C 2-4链烯基、C 3-8环烷基、3-8元杂环基、C 6-8芳基和5-8元杂芳基,上述基团独立地任选进一步被一个或多个选自氘、卤素、羟基、氧代、氰基、C 1-4烷基、C 1-4烷氧基、C 3-8环烷基、C 3-8环烷氧基、3-8元杂环基、3-8元杂环氧基、C 6-8芳基、C 6-8芳氧基、5-8元杂芳基、5-8元杂芳氧基和-NR 14R 15的取代基所取代;每个R 13各自独立地选自氢、氘、羟基、C 1-4烷基、C 1-4烷氧基、C 2-4链烯基、C 2-4链炔基、C 3-8环烷基、C 3-8环烷氧基、3-8元杂环基、3-8元杂环氧基、C 6-8芳基、C 6-8芳氧基、5-8元杂芳基、5-8元杂芳氧基和-NR 14R 15,上述基团独立地任选进一步被一个或多个选自氘、卤素、羟基、氰基、C 1-4烷基、C 1-4烷氧基、C 3-8环烷基、C 3-8环烷氧基、3-8元杂环基、3-8元杂环氧基、C 6-8芳基、C 6-8芳氧基、5-8元杂芳基、5-8元杂芳氧基和-NR 14R 15的取代基所取代;每个R 14和R 15各自独立地选自氢、氘、羟基、C 1-4烷氧基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-8环烷基、3-8元杂环基、C 6-8芳基、5-8元杂芳基、亚磺酰基、磺酰基、甲磺酰基、异丙磺酰基、环丙基磺酰基、对甲苯磺酰基、氨基磺酰基、二甲氨基磺酰基、氨基、单C 1-4烷基氨基、二C 1-4烷基氨基和C 1-4烷酰基,上 述基团独立地任选进一步被一个或多个选自氘、卤素、羟基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 1-4烷氧基、C 3-8环烷基、C 3-8环烷氧基、3-8元杂环基、3-8元杂环氧基、C 6-8芳基、C 6-8芳氧基、5-8元杂芳基、5-8元杂芳氧基、氨基、单C 1-4烷基氨基、二C 1-4烷基氨基和C 1-4烷酰基的取代基所取代,或者,R 14和R 15与其直接相连的氮原子一起形成4-8元杂环基或5-8元杂芳基,上述基团独立地任选进一步被一个或多个选自氘、卤素、羟基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 1-4烷氧基、C 3-8环烷基、C 3-8环烷氧基、3-8元杂环基、3-8元杂环氧基、C 6-8芳基、C 6-8芳氧基、5-8元杂芳基、5-8元杂芳氧基、氨基、单C 1-4烷基氨基、二C 1-4烷基氨基和C 1-4烷酰基的取代基所取代;n为0、1或2;且每个r各自独立地为0、1或2。
- 根据权利要求8所述的式(I)化合物、其立体异构体或其药学上可接受盐,其特征在于,式(I)化合物为如下式(Ⅲb)化合物:其中,X为CH或N;Y为键、O或S;Z 1为CR 10或N;Z 2为CH或N;R 6选自氢、氘、C 1-4烷基、卤取代C 1-2烷基和氘取代C 1-2烷基;R 8和R 9各自独立地选自氢、氘、氟、氯、溴、甲基、乙基、丙基、异丙基、环丙基、-CHF 2、-CF 3、-CHD 2和-CD 3;R 10和R 10a各自独立地选自氢、氘、氟、氯、溴、氰基、甲基、乙基、丙基、异丙基、环丙基、甲氧基、乙炔基、氮杂环丁基、吡唑和苯基,或者,R 10和R 10a与其直接相连的部分一起形成环戊基或5元杂环基,上述基团独立地任选进一步被一个或多个选自氘、氟、氯、溴、氰基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、卤取代C 1-4烷基和环丙基的取代基所取代,条件是,当X为CH,Y为键,n为1时,R 10与R 10a其中之一为氢、氘、氟、 氯、溴、氰基、甲基、乙基、丙基或异丙基时,另一个不为氢、氘、氟、氯、溴、氰基、甲基、乙基、丙基或异丙基;n为0、1或2。
- 一种药物组合物,其包含根据权利要求1-10中任一项所述的式(I)化合物、其立体异构体或其药学上可接受盐及可药用的载体。
- 根据权利要求1-10中任一项所述的式(I)化合物、其立体异构体或其药学上可接受盐在制备治疗和/或预防至少部分与EGFR外显子20插入、缺失或其他突变相关的癌症、肿瘤或转移性疾病的药物中的用途。
- 根据权利要求1-10中任一项所述的式(I)化合物、其立体异构体或其药学 上可接受盐在制备预防和/或治疗由过度增殖和诱导细胞死亡障碍引起的肿瘤、癌症和/或转移性疾病的药物中的用途。
- 根据权利要求1-10中任一项所述的式(I)化合物、其立体异构体或其药学上可接受盐在制备预防和/或治疗至少部分与EGFR外显子20插入、缺失或其他突变相关的肺癌、结肠癌、胰腺癌、头颈癌、乳腺癌、卵巢癌、子宫癌、胃癌、非小细胞肺癌、白血病、骨髓增生异常综合症、恶性淋巴瘤、头颈部肿瘤、胸腔肿瘤、胃肠道肿瘤、内分泌肿瘤、乳腺和其他妇科肿瘤、泌尿科肿瘤、皮肤肿瘤、肉瘤、鼻腔鼻窦内翻性乳头状瘤或鼻腔鼻窦内翻性乳头状瘤相关的鼻腔鼻窦鳞状细胞癌的药物中的用途。
- 根据权利要求1-10中任一项所述的式(I)化合物、其立体异构体或其药学上可接受盐,其用于治疗和/或预防至少部分与EGFR外显子20插入、缺失或其他突变相关的肺癌、结肠癌、胰腺癌、头颈癌、乳腺癌、卵巢癌、子宫癌、胃癌、非小细胞肺癌、白血病、骨髓增生异常综合症、恶性淋巴瘤、头颈部肿瘤、胸腔肿瘤、胃肠道肿瘤、内分泌肿瘤、乳腺和其他妇科肿瘤、泌尿科肿瘤、皮肤肿瘤、肉瘤、鼻腔鼻窦内翻性乳头状瘤或鼻腔鼻窦内翻性乳头状瘤相关的鼻腔鼻窦鳞状细胞癌的用途。
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