WO2022222966A1 - 一种选择性parp1抑制剂及其应用 - Google Patents
一种选择性parp1抑制剂及其应用 Download PDFInfo
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- WO2022222966A1 WO2022222966A1 PCT/CN2022/087969 CN2022087969W WO2022222966A1 WO 2022222966 A1 WO2022222966 A1 WO 2022222966A1 CN 2022087969 W CN2022087969 W CN 2022087969W WO 2022222966 A1 WO2022222966 A1 WO 2022222966A1
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- Prior art keywords
- alkyl
- compound
- optionally further
- halogen
- further substituted
- Prior art date
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- 239000003112 inhibitor Substances 0.000 title abstract description 9
- 101150063226 parp-1 gene Proteins 0.000 title 1
- 125000000217 alkyl group Chemical group 0.000 claims description 139
- 150000001875 compounds Chemical class 0.000 claims description 117
- 229910052736 halogen Inorganic materials 0.000 claims description 72
- 150000002367 halogens Chemical class 0.000 claims description 72
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 56
- 229910052799 carbon Inorganic materials 0.000 claims description 46
- 238000002360 preparation method Methods 0.000 claims description 46
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 44
- 125000001424 substituent group Chemical group 0.000 claims description 44
- 229910052739 hydrogen Inorganic materials 0.000 claims description 41
- 125000000623 heterocyclic group Chemical group 0.000 claims description 39
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 38
- 125000003545 alkoxy group Chemical group 0.000 claims description 36
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 31
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 19
- 229910052757 nitrogen Inorganic materials 0.000 claims description 17
- 229910052717 sulfur Inorganic materials 0.000 claims description 16
- 229910052760 oxygen Inorganic materials 0.000 claims description 15
- 125000004431 deuterium atom Chemical group 0.000 claims description 14
- 125000005842 heteroatom Chemical group 0.000 claims description 13
- 125000002950 monocyclic group Chemical group 0.000 claims description 11
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 10
- 125000003367 polycyclic group Chemical group 0.000 claims description 8
- 238000006467 substitution reaction Methods 0.000 claims description 8
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims description 7
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- 239000004480 active ingredient Substances 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 239000002246 antineoplastic agent Substances 0.000 claims 1
- 229940041181 antineoplastic drug Drugs 0.000 claims 1
- 108010064218 Poly (ADP-Ribose) Polymerase-1 Proteins 0.000 abstract description 14
- 102000015087 Poly (ADP-Ribose) Polymerase-1 Human genes 0.000 abstract 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 149
- 239000007787 solid Substances 0.000 description 136
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 135
- 238000005481 NMR spectroscopy Methods 0.000 description 105
- 229940125904 compound 1 Drugs 0.000 description 57
- 238000000034 method Methods 0.000 description 55
- -1 neobutyl Chemical group 0.000 description 49
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- 238000006243 chemical reaction Methods 0.000 description 32
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 29
- 230000002829 reductive effect Effects 0.000 description 28
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- 210000004027 cell Anatomy 0.000 description 13
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- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 8
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
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- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- 229910052794 bromium Inorganic materials 0.000 description 6
- 229910052801 chlorine Inorganic materials 0.000 description 6
- 229910052731 fluorine Inorganic materials 0.000 description 6
- 239000005457 ice water Substances 0.000 description 6
- 239000002609 medium Substances 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 229920006395 saturated elastomer Polymers 0.000 description 6
- HJUGFYREWKUQJT-UHFFFAOYSA-N tetrabromomethane Chemical compound BrC(Br)(Br)Br HJUGFYREWKUQJT-UHFFFAOYSA-N 0.000 description 6
- 238000004809 thin layer chromatography Methods 0.000 description 6
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 6
- IMGPUNJHYPPTNC-UHFFFAOYSA-N O=C1NC2=CC(CBr)=CN=C2C=C1C1CC1 Chemical compound O=C1NC2=CC(CBr)=CN=C2C=C1C1CC1 IMGPUNJHYPPTNC-UHFFFAOYSA-N 0.000 description 5
- 229920000776 Poly(Adenosine diphosphate-ribose) polymerase Polymers 0.000 description 5
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- 125000000753 cycloalkyl group Chemical group 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
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- 230000002401 inhibitory effect Effects 0.000 description 5
- 230000005764 inhibitory process Effects 0.000 description 5
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- HUWSZNZAROKDRZ-RRLWZMAJSA-N (3r,4r)-3-azaniumyl-5-[[(2s,3r)-1-[(2s)-2,3-dicarboxypyrrolidin-1-yl]-3-methyl-1-oxopentan-2-yl]amino]-5-oxo-4-sulfanylpentane-1-sulfonate Chemical compound OS(=O)(=O)CC[C@@H](N)[C@@H](S)C(=O)N[C@@H]([C@H](C)CC)C(=O)N1CCC(C(O)=O)[C@H]1C(O)=O HUWSZNZAROKDRZ-RRLWZMAJSA-N 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- YSUIQYOGTINQIN-UZFYAQMZSA-N 2-amino-9-[(1S,6R,8R,9S,10R,15R,17R,18R)-8-(6-aminopurin-9-yl)-9,18-difluoro-3,12-dihydroxy-3,12-bis(sulfanylidene)-2,4,7,11,13,16-hexaoxa-3lambda5,12lambda5-diphosphatricyclo[13.2.1.06,10]octadecan-17-yl]-1H-purin-6-one Chemical compound NC1=NC2=C(N=CN2[C@@H]2O[C@@H]3COP(S)(=O)O[C@@H]4[C@@H](COP(S)(=O)O[C@@H]2[C@@H]3F)O[C@H]([C@H]4F)N2C=NC3=C2N=CN=C3N)C(=O)N1 YSUIQYOGTINQIN-UZFYAQMZSA-N 0.000 description 4
- IASUFRKFRACNAN-UHFFFAOYSA-N 2-fluoro-N-methyl-4-piperazin-1-ylbenzamide Chemical compound CNC(=O)c1ccc(cc1F)N1CCNCC1 IASUFRKFRACNAN-UHFFFAOYSA-N 0.000 description 4
- QBWKPGNFQQJGFY-QLFBSQMISA-N 3-[(1r)-1-[(2r,6s)-2,6-dimethylmorpholin-4-yl]ethyl]-n-[6-methyl-3-(1h-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]-1,2-thiazol-5-amine Chemical compound N1([C@H](C)C2=NSC(NC=3C4=NC=C(N4C=C(C)N=3)C3=CNN=C3)=C2)C[C@H](C)O[C@H](C)C1 QBWKPGNFQQJGFY-QLFBSQMISA-N 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
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- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000298 cyclopropenyl group Chemical group [H]C1=C([H])C1([H])* 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 229910052805 deuterium Inorganic materials 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 101150042537 dld1 gene Proteins 0.000 description 1
- 125000003438 dodecyl 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])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000012154 double-distilled water Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000003979 granulating agent Substances 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
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000000155 isotopic effect Effects 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 125000002757 morpholinyl group Chemical group 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
- 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
- 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
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 125000006574 non-aromatic ring group Chemical group 0.000 description 1
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 125000003566 oxetanyl group Chemical group 0.000 description 1
- 125000000466 oxiranyl group Chemical group 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
- 125000002262 penten-4-yl group Chemical group C=CCC(C)* 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- 230000005731 poly ADP ribosylation Effects 0.000 description 1
- 229920001223 polyethylene glycol Polymers 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
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000022532 regulation of transcription, DNA-dependent Effects 0.000 description 1
- 238000007634 remodeling Methods 0.000 description 1
- 230000008521 reorganization Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 150000003839 salts Chemical class 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
- 238000000926 separation method Methods 0.000 description 1
- 125000003003 spiro group Chemical group 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000003554 tetrahydropyrrolyl group Chemical group 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical group C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical class [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
-
- 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
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
- C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic 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
Abstract
一种选择性PARP1抑制剂及其应用 (I)
Description
本发明涉及一种选择性PARP1抑制剂或者其立体异构体及其在医药上的应用。
PARPs(ploy(ADP-ribose)polymerases)是一类聚ADP-核糖聚合酶,催化多种蛋白聚二磷酸腺苷核糖基化(Poly-ADP-ribosylation),该过程在DNA损伤修复、转录调控、染色质重组和重塑等许多细胞过程中发挥重要作用。目前,虽然有多个PARP1/2抑制剂成功上市,但在临床上无论单独用药还是联用用药,仍然普遍存在血液、胃肠道等副作用,导致临床应用受到限制。因此,开发更安全有效的PARP抑制剂依然是临床亟需解决的问题。一系列研究表明,与PARP1/2抑制剂相比,高选择性PARP1抑制剂具有更好的疗效和更低的毒性,有望减少目前临床上PARP类药物的潜在风险,拓宽临床应用范围,提高患者的生活质量。
发明内容
本发明的目的是提供一种选择性PARP1抑制剂或者其立体异构体、其药物组合物,以及其在医药上的应用。
本发明提供一种通式(I)所示的化合物或者其立体异构体:
其中:
R
a0选自卤素、C
1-6烷基、C
3-8环烷基、C
3-8杂环烷基、C
2-6烯基或者C
2-6炔基,所述的C
1-6烷基、C
3-8环烷基、C
3-8杂环烷基、C
2-6烯基或者C
2-6炔基任选地进一步被1个或者多个选自卤素或者C
1-6烷基的取代基取代;
R
a1选自H、卤素或者C
1-6烷基,所述的C
1-6烷基任选地进一步被1个或者多个选自卤素或者C
1-6烷基的取代基取代;
L
a1、L
a2、L
a3各自独立地为N或者CR
L;
R
L选自H、卤素、羟基、氰基、C
1-6烷基、C
1-6烷氧基或者C
3-8环烷基;
L选自-NH-、-CO-或者-(CR
1R
2)
n-;
R
1、R
2各自独立地选自H或C
1-6烷基,所述的C
1-6烷基任选地进一步被1个或者多个选自卤素、羟基或者氰基的取代基取代;
B为4至12元杂环,所述的4至12元杂环选自4至12元单环、5至12元螺环、4至12元并环或者4至12元桥环,所述的4至12元杂环可以包含1至4个选自N、O或S的杂原子,且可以任选地进一步被1个或者多个R
b取代;
R
b选自H、羟基、氰基或C
1-6烷基,所述C
1-6烷基任选地进一步被1个或者多个选自羟基、卤素或者氰基的取代基取代;
或者,任意两个R
b可以形成3至8元环;
X
1、X
2、X
3各自独立地选自CH或者N,所述的X
1或者X
2为CH时,可以任选地进一步被卤素取代,且当X
3选自N时,X
1和X
2不能同时为CH;
R
3、R
4各自独立地选自H、卤素、氰基或者C
1-6烷基;
R
c选自H、C
1-6烷基、C
1-6烷氧基、C
3-8环烷基或者C
3-8杂环烷基,所述C
1-6烷基、C
1-6烷氧基、C
3-8环烷基或者C
3-8杂环烷基任选地进一步被1个或者多个选自D、卤素、羟基、氰基、NR
c1R
c2、C
1-6烷基、C
1-6烷氧基、C
3-8环烷基或者C
3-8杂环烷基的取代基取代;
R
c1、R
c2各自独立地选自H或者C
1-6烷基;
n为1或者2;
条件是:
所述的通式(I)化合物任选进一步被1个或者多个氘取代。
本发明提供一种化合物或者其立体异构体,所述的化合物选自通式(II)所示的化合物或者其立体异构体:
其中:
R
a0选自卤素、C
1-6烷基、C
3-8环烷基、C
3-8杂环烷基、C
2-6烯基或者C
2-6炔基,所述的C
1-6烷基、C
3-8环烷基、C
3-8杂环烷基、C
2-6烯基或者C
2-6炔基任选地进一步被1个或者多个选自卤素或者C
1-6烷基的取代基取代;
R
a1选自H、卤素或者C
1-6烷基,所述的C
1-6烷基任选地进一步被1个或者多个选自卤素或者C
1-6烷基的取代基取代;
Z
1、Z
2各自独立地为N或者CR
L;
R
L选自H、卤素、羟基、氰基、C
1-6烷基、C
1-6烷氧基或者C
3-8环烷基;
L选自-NH-、-CO-或者-(CR
1R
2)
n-;
R
1、R
2各自独立地选自H或C
1-6烷基,所述的C
1-6烷基任选地进一步被1个或者多个选自卤素、羟基或者氰基的取代基取代;
B为4至12元杂环,所述的4至12元杂环选自4至12元单环、5至12元螺环、4至12元并环或者4至12元桥环,所述的4至12元杂环可以包含1至4个选自N、O或S的杂原子,且可以任选地进一步被1个或者多个R
b取代;
R
b选自H、羟基、氰基或C
1-6烷基,所述C
1-6烷基任选地进一步被1个或者多个选自羟基、卤素或者氰基的取代基取代;
或者,任意两个R
b可以形成3至8元环;
X
1、X
2、X
3各自独立地选自CH或者N,所述的X
1或者X
2为CH时,可以任选地进一步被卤素取代,且当X
3选自N时,X
1和X
2不能同时为CH;
R
3、R
4各自独立地选自H、卤素、氰基或者C
1-6烷基;
R
c选自H、C
1-6烷基、C
1-6烷氧基、C
3-8环烷基或者C
3-8杂环烷基,所述C
1-6烷基、C
1-6烷氧基、C
3-8环烷基或者C
3-8杂环烷基任选地进一步被1个或者多个选自D、卤素、羟基、氰基、NR
c1R
c2、C
1-6烷基、C
1-6烷氧基、C
3-8环烷基或者C
3-8杂环烷基的取代基取代;
R
c1、R
c2各自独立地选自H或者C
1-6烷基;
n为1或者2;
所述的通式(II)化合物任选进一步被1个或者多个氘原子取代。
本发明提供的化合物或者其立体异构体:
其中:
R
a0选自C
1-6烷基、C
3-8环烷基或者C
2-6烯基,所述的C
1-6烷基、C
3-8环烷基或者C
2-
6烯基任选地进一步被1个或者多个选自卤素或者C
1-6烷基的取代基取代;
L
a1、L
a2、L
a3各自独立地为N或者CR
L;
R
L选自H、卤素、羟基、氰基、C
1-6烷基、C
1-6烷氧基或者C
3-8环烷基;
L为-(CR
1R
2)
n-;
R
1、R
2各自独立地选自H或C
1-6烷基,所述的C
1-6烷基任选地进一步被1个或者多个选自卤素、羟基或者氰基的取代基取代;
B为4至12元杂环,所述的4至12元杂环选自4至12元单环、5至12元螺环、4至12元并环或者4至12元桥环,所述的4至12元杂环可以包含1至4个选自N、O或S的杂原子,且可以任选地进一步被1个或者多个R
b取代;
R
b为H或C
1-6烷基,所述C
1-6烷基任选地进一步被1个或者多个选自卤素或者氰基的取代基取代;
或者,任意两个R
b可以形成3至8元环;
X
1、X
2、X
3各自独立地选自CH或者N,所述的X
1或者X
2为CH时,可以任选地进一步被卤素取代,且当X
3选自N时,X
1和X
2不能同时为CH;
R
3、R
4各自独立地选自H、卤素、氰基或者C
1-6烷基;
R
c选自H、C
1-6烷基、C
1-6烷氧基、C
3-8环烷基或者C
3-8杂环烷基,所述C
1-6烷基、C
1-6烷氧基、C
3-8环烷基或者C
3-8杂环烷基任选地进一步被1个或者多个选自D、卤素、羟基、NR
c1R
c2、C
1-6烷基或者C
3-8杂环烷基的取代基取代;
R
c1、R
c2各自独立地选自H或者C
1-6烷基;
n为1或者2;
条件是:
所述的化合物任选进一步被1个或者多个氘原子取代。
本发明提供的所述的化合物或者其立体异构体:
其中:
R
a0选自C
1-6烷基、C
3-8环烷基或者C
2-6烯基,所述的C
1-6烷基、C
3-8环烷基或者C
2-
6烯基任选地进一步被1个或者多个选自卤素或者C
1-6烷基的取代基取代;
L
a1、L
a2、L
a3各自独立地为CH或者N;
L为-(CR
1R
2)
n-;
R
1、R
2各自独立地为H或C
1-6烷基;
B为4至12元杂环,所述的4至12元杂环选自4至12元单环、5至12元螺环、4至12元并环或者4至12元桥环,所述的4至12元杂环可以包含1至4个选自N、O或S的杂原子,且可以任选地进一步被1个或者多个R
b取代;
R
b为H或C
1-6烷基,所述C
1-6烷基任选地进一步被1个或者多个选自卤素或者氰基的取代基取代;
或者,任意两个R
b可以形成3至8元环;
X
1、X
2、X
3各自独立地选自CH或者N,所述的X
1或者X
2为CH时,可以任选地进一步被卤素取代,且当X
3选自N时,X
1和X
2不能同时为CH;
R
3、R
4各自独立地选自H、卤素、氰基或者C
1-6烷基;
R
c选自H、C
1-6烷基或者C
3-8环烷基,所述C
1-6烷基或者C
3-8环烷基任选地进一步被1个或者多个选自D、卤素或者C
1-6烷基的取代基取代;
n为1或者2;
条件是:
所述的化合物任选进一步被1个或者多个氘原子取代。
本发明提供的所述的化合物或者其立体异构体,所述的化合物选自通式(III)所示的化合物或者其立体异构体:
Ra
2为C
1-6烷基或者C
3-8环烷基,所述C
1-6烷基任选地进一步被1个或者多个选自卤素的取代基取代;
R
d选自H、C
1-6烷基、C
1-6烷氧基、C
3-8环烷基或者C
3-8杂环烷基,所述C
1-6烷基、C
1-6烷氧基、C
3-8环烷基或者C
3-8杂环烷基任选地进一步被1个或者多个选自D、卤素、羟基或者C
1-6烷基的取代基取代;
所述的通式(III)所示的化合物任选进一步被1个或者多个氘原子取代。
本发明所述的化合物或者其立体异构体,所述的化合物选自通式(IV)所示的化合物或者其立体异构体:
Ra
3为C
1-6烷基或者C
3-8环烷基;
R
e选自H、C
1-6烷基、C
1-6烷氧基或者C
3-8杂环烷基任选地进一步被1个或者多个选自羟基的取代基取代;
所述的通式(IV)所示的化合物任选进一步被1个或者多个氘原子取代。
本发明提供的所述的化合物或者其立体异构体:
其中:
R
a0为C
1-6烷基,所述C
1-6烷基任选地进一步被1个或者多个选自卤素的取代基取代;
L
a1、L
a2、L
a3各自独立地为CH或者N;
L为-(CR
1R
2)
n-;
R
1、R
2各自独立地为H或C
1-3烷基;
R
b为H或C
1-6烷基,所述C
1-6烷基任选地进一步被1个或者多个选自卤素或者氰基的取代基取代;
或者,任意两个R
b可以形成3至8元环;
R
c为H或C
1-6烷基;
n为1或者2;
m为0、1或者2;
所述的化合物任选进一步被1个或者多个氘原子取代。
本发明提供的化合物或者其立体异构体,所述的化合物选自:
所述的化合物任选进一步被1个或者多个氘原子取代。
本发明的一个或多个实施方式提供药物组合物,所述药物组合物包含:
(1)本发明的化合物或其立体异构体;
(2)任选的一种或者多种其他活性成分;以及
(3)药学上可接受的载体和/或赋形剂。
本发明的一个或多个实施方式提供本发明的化合物或其立体异构体或者本发明的药物组合物在制备用于治疗癌症的药物中的用途。
除非有相反的陈述,在说明书和权利要求书中使用的术语具有下述含义。
本发明所述基团和化合物中所涉及的碳、氢、氧、硫、氮或F、Cl、Br、I均包括它们的同位素情况,及本发明所述基团和化合物中所涉及的碳、氢、氧、硫或氮任选进一步被一个或多个它们对应的同位素所替代,其中碳的同位素包括
12C、
13C和
14C,氢的同位素包括氕(H)、氘(D,又叫重氢)、氚(T,又叫超重氢),氧的同位素包括
16O、
17O和
18O,硫的同位素包括
32S、
33S、
34S和
36S,氮的同位素包括
14N和
15N,氟的同位素包括
17F和
19F,氯的同位素包括
35Cl和
37Cl,溴的同位素包括
79Br和
81Br。
“烷基”是指1至20个碳原子的直链或支链饱和脂肪族烃基,优选为1至8个碳原子的烷基,更优选为1至6个碳原子的烷基,进一步优选为1至4个碳原子的烷基。非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、仲丁基、新丁基、叔丁基、正戊基、异戊基、新戊基、正己基及其各种支链异构体;当烷基被取代基时,可以任选进一步被1个或者多个取代基所取代。
“烷氧基”是指烷基中至少1个碳原子被氧原子取代所形成的基团。非限制性实施例包括甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、叔丁氧基、正戊氧基、正己氧基、环丙氧基和环丁氧基。所述的烷基定义与上文所述的“烷基”定义相同。
“环烷基”是指饱和的环烃基,其环可以为3至10元的单环、4至12元双环或者10至20元多环体系,环碳原子优选3至10个碳原子,进一步优选3至8个碳原子。“环烷基”非限制性实施例包括环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环丙烯基、环丁烯基、环戊烯基、环己烯基、环庚烯基、1,5-环辛二烯基、1,4-环己二烯基和环庚三烯基等。当被取代时,可以任选进一步被0个或者多个取代基所取代。
“杂环烷基”是指取代的或未取代的饱和非芳香环基,其可以是3至8元的单环、4至12元双环或者10至15元三环体系,且包含1至3个选自N、O或S的杂原子,优选3至8元杂环基。“杂环烷基”的环中选择性取代的N、S可被氧化成各种氧化态;“杂环烷基”可以连接在杂原子或者碳原子上;“杂环烷基”可以为桥环或者螺环。“杂环烷基”非限制性实施例包括环氧乙基、氮杂环丙基、氧杂环丁基、氮杂环丁基、1,3-二氧戊环基、1,4-二氧戊环基、1,3-二氧六环基、氮杂环庚基、哌啶基、哌叮基、吗啉基、硫代吗啉基、1,3-二噻烷基、四氢呋喃基、四氢吡咯基、四氢咪唑基、四氢噻唑基、四氢吡喃基、氮杂二环[3.2.1]辛烷基、氮杂二环[5.2.0]壬烷基、氧杂三环[5.3.1.1]十二烷基、氮杂金刚烷基和氧杂螺[3.3]庚烷基。
“烯基”是指含有1至10个(例如1、2、3、4、5、6、7、8、9、10个)碳-碳双键,由2至20个碳原子组成的直链或者支链不饱和脂肪族烃基,优选2至12个(例如2、3、4、5、6、7、8、9、10、11、12个)碳原子的烯基,更优选2至8个碳原子的烯基,进一步优选2至6个碳原子的烯基。非限制性实施例包括乙烯基、丙烯-2-基、丁烯-2-基、丁烯-2-基、戊烯-2-基、戊烯-4-基、己烯-2-基、己烯-3基、庚烯-2-基、庚烯-3-基、庚烯-4-基、辛烯-3-基、壬烯-3-基、癸烯-4-基和十一烯-3-基。所述的烯基可以任选进一步被1个或者多个取代基所取代。
“炔基”是指含有1至3个碳-碳叁键,由2至20个碳原子组成的直链或者支链不饱和脂肪族烃基,优选2至12个碳原子的炔基,更优选2至8个碳原子的炔基,进一步优选2至6个碳原子的炔基。非限制性实施例包括乙炔基、丙炔-1-基、丙炔-2-基、丁炔-1-基、丁炔-2-基、丁炔-3-基、3,3-二甲基丁炔-2-基、戊炔-1-基、戊炔-2-基、己炔-1-基、1-庚炔-1-基、庚炔-3-基、庚炔-4-基、辛炔-3-基、壬炔-3-基、癸炔-4-基、十一炔-3-基、十二炔-4-基。所述的炔基可以任选进一步被0至4个选自F、Cl、Br、I、烷基、烷氧基、直链烯基、直链炔基、氨基、硝基、氰基、巯基、酰胺基、碳环基或者杂环基的取代基所取代。
“杂环”或“杂环基”是指饱和或不饱和的芳香性杂环或者非芳香性杂环,当为芳香性杂环时,其定义与上文“杂芳基”定义相同;当为非芳香性杂环时,其可以是3至10元(例如3、4、5、6、7、8、9、10元)的单环、4至12元(例如4、5、6、7、8、9、10、11、12元)双环或者10至15元(例如10、11、12、13、14、15元)三环体系,且包含1至4个(例如1、2、3、4个)选自N、O或S的杂原子,优选3至8元杂环基。“杂环基”或“杂环”的环中选择性取代的1至4个(例如1、2、3、4个)N、S可被氧化成各种氧化态;“杂环基”或“杂环”可以连接在杂原子或者碳原子上;“杂环基”或“杂环”可以为并环、桥环或者螺环。所述的“杂环基”或“杂环”可以任选进一步被1个或者多个取代基所取代。
当上文所述的“烷基”、“烷氧基”、“烯基”、“炔基”、“杂环基”、“杂环”、“环烷基”或者“杂环烷基”被取代时,可以任选进一步被0、1、2、3、4、5、6、7、8、9或者10个选自F、Cl、Br、I、羟基、巯基、硝基、氰基、氨基、C
1-6烷基氨基、=O、C
1-6烷基、C
1-6烷氧基、C
2-6烯基、C
2-6炔基、-NR
q4R
q5、=NR
q6、-C(=O)OC
1-6烷基、-OC(=O)C
1-6烷基、-C(=O)NR
q4R
q5、C
3-8环烷基、C
3-8杂环烷基、C
6-10芳基、C
5-10杂芳基、-C(=O)OC
6-10芳基、-OC(=O)C
6-10芳基、-OC(=O)C
5-10杂芳基、-C(=O)OC
5-10杂芳基、-OC(=O)C
3-8杂环烷基、-C(=O)OC
3-8杂环烷基、-OC(=O)C
3-8环烷基、-C(=O)OC
3-8环烷基、-NHC(=O)C
3-8杂环烷基、-NHC(=O)C
6-10芳基、-NHC(=O)C
5-10杂芳基、-NHC(=O)C
3-8环烷基、-NHC(=O)C
3-8杂环烷基、-NHC(=O)C
2-6烯基或者-NHC(=O)C
2-6炔基的取代基所取代,且其中所述的取代基C
1-6烷基、C
1-6烷氧基、C
2-6烯基、C
2-6炔基、C
3-8环烷基、C
3-8杂环烷基、C
6-10芳基、C
5-10杂芳基、-NHC(=O)C
6-10芳基、-NHC(=O)C
5-10杂芳基、-NHC(=O)C
3-8杂环烷基或者-NHC(=O)C
3-8环烷基任选进一步被1至3个选自OH、F、Cl、Br、I、C
1-6烷基、C
1-6烷氧基、-NR
q4R
q5或者=O的取代基所取代;R
q1选自C
1-6烷基、C
1-6烷氧基或者C
6-10芳基;R
q2、R
q3选自H或者C
1-6烷基;R
q4、R
q5选自H、C
1-6烷基、-NH(C=NR
q1)NR
q2R
q3、-S(=O)
2NR
q2R
q3、-C(=O)R
q1或者-C(=O)NR
q2R
q3,其中所述的C
1-6烷基任选进一步被1个或者多个选自OH、F、Cl、Br、I、C
1-6烷基、C
1-6烷氧基、C
6-10芳基、C
5-10杂芳基、C
3-8环烷基或者C
3-8杂环烷基的取代基所取代;或者R
q4与R
q5及N原子形成一个3至8元杂环,所述的环可以含有1个或者多个选自N、O或者S的杂原子。
“药物组合物”是指一种或多种本发明所述化合物、其药学上可接受的盐或前药和其它化学组分形成的混合物,其中,“其它化学组分”是指药学上可接受的载体、赋形剂和/或一种或多种其它治疗剂。
“载体”是指不会对生物体产生明显刺激且不会消除所给予化合物的生物活性和特性的材料。
“赋形剂”是指加入到药物组合物中以促进化合物给药的惰性物质。非限制性实施例包括碳酸钙、磷酸钙、糖、淀粉、纤维素衍生物(包括微晶纤维素)、明胶、植物油、聚乙二醇类、稀释剂、成粒剂、润滑剂、粘合剂和崩解剂。
“立体异构体”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,包括顺反异构体、对映异构体和构象异构体。
“任选”或“任选地”或“选择性的”或“选择性地”是指随后所述的事件或状况可以但未必发生,该描述包括其中发生该事件或状况的情况及其中未发生的情况。例如,“选择性地被烷基取代的杂环基”是指该烷基可以但未必存在,该描述包括其中杂环基被烷基取代的情况,及其中杂环基未被烷基取代的情况。
以下实施例详细说明本发明的技术方案,但本发明的保护范围包括但是不限于此。
化合物的结构是通过核磁共振(NMR)或(和)质谱(MS)来确定的。NMR位移(δ)以10
-
6(ppm)的单位给出。NMR的测定是用Bruker Avance III 400和Bruker Avance 300核磁仪,测定溶剂为氘代二甲基亚砜(DMSO-d
6),氘代氯仿(CDCl
3),氘代甲醇(CD
3OD),内标为四甲基硅烷(TMS);
MS的测定用Agilent 6120B(ESI)和Agilent 6120B(APCI);
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板,薄层色谱法(TLC)使用的硅胶板采用的规格是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。
中间体1
2-氟-N-甲基-4-(哌嗪-1-基)苯甲酰胺中间体1
2-fluoro-N-methyl-4-(piperazin-1-yl)benzamide
第一步:
4-(3-氟-4-(甲基氨基甲酰基)苯基)哌嗪-1-羧酸叔丁酯1c
tert-butyl 4-(3-fluoro-4-(methylcarbamoyl)phenyl)piperazine-1-carboxylate
将1a(2g,8.62mmol)、1b(1.77g,9.48mmol)溶解于15mL甲苯中,再加入醋酸钯(194mg,0.86mmol)、1,1'-联萘-2,2'-双二苯膦(537mg,0.86mmol),加入完毕后氮气保护,将反应体系置于120℃下反应,16h后反应完毕,加入20mL水和乙酸乙酯(3×30mL)萃取三次,收集有机相,减压浓缩,再柱层析纯化(PE:EA=2:1-1:2),得到1c粗品。
第二步:
2-氟-N-甲基-4-(哌嗪-1-基)苯甲酰胺中间体1
2-fluoro-N-methyl-4-(piperazin-1-yl)benzamide
将1c加入到15mL盐酸的1,4-二氧六环溶液(4M)中,在室温下搅拌反应16h,反应完后将反应体系过滤,收集滤饼,即得到中间体1(白色固体,1.4g,产率69%)。
1H NMR(400MHz,DMSO-d6)δ9.67(dr s,1H),8.58(dr s,1H),7.81(t,J=8.6Hz,1H),7.12-6.93(m,2H),3.60-3.56(m,4H),2.97(d,J=2.6Hz,3H),3.12-3.09(m,4H).
LCMS m/s=238.30[M+1].
中间体2
7-(溴甲基)-3-乙基-1,5-萘啶-2(1H)-酮中间体2
7-(bromomethyl)-3-ethyl-1,5-naphthyridin-2(1H)-one
中间体2根据专利WO2021013735的中间体14的合成方法制备得到,m/z(ES
+)[M]
+=267。
中间体3
2-氟-N-(甲基-d3)-4-(哌嗪-1-基)苯甲酰胺中间体3
2-fluoro-N-(methyl-d3)-4-(piperazin-1-yl)benzamide
按照中间体1的制备方法,得到中间体3(白色固体,1.5g,产率75%)。
1H NMR(400MHz,DMSO-d6)δ9.54(dr s,1H),7.83(d,J=4.8Hz,1H),7.59(t,J=8.8Hz,1H),6.87–6.85(m,1H),6.83(s,1H),3.60–3.45(m,4H),3.18–3.13(m,4H).
LCMS m/s=241.20[M+1].
中间体4
2-氟-4-(哌嗪-1-基)苯甲酰胺中间体4
2-fluoro-4-(piperazin-1-yl)benzamide
按照中间体1的制备方法,得到中间体4(白色固体,1.4g,产率70%)。
1H NMR(400MHz,DMSO-d6)δ9.85(dr s,2H),7.90(t,J=8.9Hz,1H),7.33-7.03(m,2H),6.85(s,1H),3.84-3.68(m,4H),3.28-3.19(m,4H).
LCMS m/s=224.10[M+1].
中间体5
2-氯-N-甲基-4-(哌嗪-1-基)苯甲酰胺中间体5
2-chloro-N-methyl-4-(piperazin-1-yl)benzamide
按照中间体1的制备方法,得到中间体5(白色固体,1.5g,产率73%)。
LCMS m/s=254.10[M+1].
中间体6
4-(3,6-二氮杂双环[3.1.1]庚烷-3-基)-2-氟-N-甲基苯甲酰胺中间体6
4-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-2-fluoro-N-methylbenzamide
按照中间体1的制备方法,得到中间体6(白色固体,1.4g,产率86%)。
1H NMR(400MHz,DMSO-d6)δ9.45(dr s,1H),8.33(dr s,1H),7.62(t,J=9.0Hz,1H),6.62-6.59(m,1H),6.58–6.51(m,1H),3.65-3.62(m,2H),3.45-3.39(m,2H),3.31-3.28(m,2H),2.75(d,J=4.5Hz,3H),2.58–2.52(m,1H),1.47-1.44(m,1H).
LCMS m/s=250.1[M+1].
中间体7
N-环丙基-2-氟-4-(哌嗪-1-基)苯甲酰胺中间体7
N-cyclopropyl-2-fluoro-4-(piperazin-1-yl)benzamide
按照中间体1的制备方法,得到中间体7(棕色固体,1.4g,产率81%)。
1H NMR(400MHz,DMSO-d6)δ9.73(dr s,1H),8.69(dr s,1H),7.95(t,J=8.4Hz,1H),7.64-7.28(m,2H),3.56-3.50(m,4H),2.81-2.77(m,1H),3.18-3.15(m,4H),0.68-0.64(m,2H),0.56-0.51(m,2H).
LCMS m/s=264.1[M+1].
中间体8
3-氟-N-甲基-4-(哌嗪-1-基)苯甲酰胺中间体8
3-fluoro-N-methyl-4-(piperazin-1-yl)benzamide
按照中间体1的制备方法,得到中间体8(白色固体,1.2g,产率85%)。
1H NMR(400MHz,DMSO-d6)δ9.56(s,1H),8.50(d,J=3.1Hz,1H),7.67(s,1H),7.63(s,1H),7.13(t,J=8.7Hz,1H),4.42-4.36(m,4H),3.23-3.18(m,4H),2.75(d,J=3.1Hz,3H).
LCMS m/s=238.1[M+1].
中间体9
(R)-2-氟-4-(哌嗪-1-基)-N-(四氢呋喃-3-基)苯甲酰胺中间体9
(R)-2-fluoro-4-(piperazin-1-yl)-N-(tetrahydrofuran-3-yl)benzamide
按照中间体1的制备方法,得到中间体9(白色固体,2.1g,产率87%)。
1H NMR(400MHz,DMSO-d6)δ9.56(s,1H),8.07(dd,J=7.0,2.9Hz,1H),7.90(dd,J=8.0,4.6Hz,1H),7.55(dt,J=21.6,9.0Hz,2H),4.25(t,J=6.7Hz,1H),3.84-3.77(m,2H),3.76-3.64(m,4H),3.52(d,J=4.5Hz,4H),3.48(t,J=6.3Hz,2H),2.12(dq,J=12.8,7.7Hz,1H),1.93-1.81(m,1H).
LCMS m/s=294.3[M+1].
中间体10
(S)-2-氟-4-(哌嗪-1-基)-N-(四氢呋喃-3-基)苯甲酰胺中间体10
(S)-2-fluoro-4-(piperazin-1-yl)-N-(tetrahydrofuran-3-yl)benzamide
按照中间体1的制备方法,得到中间体10(白色固体,1.7g,产率89%)。
1H NMR(400MHz,DMSO-d6)δ9.54(s,1H),8.06(dd,J=7.0,2.9Hz,1H),7.90(dd,J=8.0,4.6Hz,1H),7.54(dt,J=21.6,9.0Hz,2H),4.24(t,J=6.7Hz,1H),3.82-3.74(m,2H),3.77-3.66(m,4H),3.52(d,J=4.5Hz,4H),3.48(t,J=6.3Hz,2H),2.11(dq,J=12.8,7.7Hz,1H),1.92-1.80(m,1H).
LCMS m/s=294.3[M+1].
中间体11
4-(3,6-二氮杂双环[3.1.1]庚烷-6-基)-2-氟-N-甲基苯甲酰胺中间体11
4-(3,6-diazabicyclo[3.1.1]heptan-6-yl)-2-fluoro-N-methylbenzamide
按照中间体1的制备方法,得到中间体11(白色固体,1.2g,产率70%)。
1H NMR(400MHz,DMSO-d6)δ9.46(dr,1H),8.35(dr,1H),7.65(m,1H),6.62-6.58(m,1H),6.43–6.40(m,1H),4.38-4.33(m,2H),3.81–3.64(m,2H),3.31-3.21(M,2H),2.73(d,3H),2.67–2.59(m,1H),1.55(d,J=8.7Hz,1H).
LCMS m/s=250.10[M+1].
中间体12
2-氯-6-氟-N-甲基-4-(哌嗪-1-基)苯甲酰胺中间体12
3-2-chloro-6-fluoro-N-methyl-4-(piperazin-1-yl)benzamide
按照中间体1的制备方法,得到中间体12(黄色固体,630mg,产率83%)。
1H NMR(400MHz,DMSO-d6)δ9.57(s,1H),8.42(q,J=4.6Hz,1H),6.91-6.86(m,2H),3.57–3.48(m,4H),3.18-3.05(m,4H),2.72(d,J=4.6Hz,3H).
LCMS m/s=272.1[M+1]
中间体13
2,3,5,6-四氟-N-甲基-4-(哌嗪-1-基)苯甲酰胺中间体13
2,3,5,6-tetrafluoro-N-methyl-4-(piperazin-1-yl)benzamide
按照中间体1的制备方法,得到中间体13(黄色固体,91mg,产率31%)。
1H NMR(400MHz,DMSO-d6)δ9.57(s,1H),8.69(q,J=4.8Hz,1H),3.45-3.43(m,2H),3.20-3.17(m,2H),2.96-2.94(m,4H),1.43(d,J=4.8Hz,3H).
LCMS m/s=292.1[M+1].
中间体14
3-溴-2,5,6-三氟-N-甲基-4-(哌嗪-1-基)苯甲酰胺中间体14
3-bromo-2,5,6-trifluoro-N-methyl-4-(piperazin-1-yl)benzamide
按照中间体1的制备方法,得到中间体14(黄色固体,187mg,产率63%)。
1H NMR(400MHz,DMSO-d6)δ9.57(s,1H),8.51(q,J=4.8Hz,1H),2.96-2.94(m,4H),2.79-2.76(m,4H),1.43(d,J=4.8Hz,3H).
LCMS m/s=352.0[M+1].
中间体15
(S)-2-氟-N-甲基-4-(3-甲基哌嗪-1-基)苯甲酰胺中间体15
(S)-2-fluoro-N-methyl-4-(3-methylpiperazin-1-yl)benzamide
按照中间体1的制备方法,得到中间体15(黄色固体,480mg,产率85%)。
1H NMR(400MHz,DMSO-d6)δ9.60(s,1H),7.85(q,J=4.8Hz,1H),7.59(t,J=8.8Hz,1H),6.90–6.81(m,2H),3.97–3.86(m,2H),3.36–3.23(m,2H),3.13–2.87(m,3H),2.74(d,J=4.8Hz,3H),1.30(d,J=6.5Hz,3H).
LCMS m/s=252.2[M+1].
中间体16
(R)-2-氟-N-甲基-4-(3-甲基哌嗪-1-基)苯甲酰胺中间体16
(R)-2-fluoro-N-methyl-4-(3-methylpiperazin-1-yl)benzamide
按照中间体1的制备方法,得到中间体16(黄色固体,460mg,产率81%)。
1H NMR(400MHz,DMSO-d6)δ9.75(S,2H),7.87(q,J=4.7Hz,1H),7.58(t,J=8.8 Hz,1H),6.90–6.78(m,2H),4.76(d,J=4.7Hz,3H),3.96-3.87(m,2H),3.33–3.13(m,3H),3.02-2.92(m,2H),1.31(d,J=6.4Hz,3H).
LCMS m/s=252.2[M+1].
中间体17
(S)-4-(3-(氰甲基)哌嗪-1-基)-2-氟-N-甲基苯甲酰胺中间体17
(S)-4-(3-(cyanomethyl)piperazin-1-yl)-2-fluoro-N-methylbenzamide
按照中间体1的制备方法,得到中间体17(黄色固体,1.1g,产率85%)。
1H NMR(400MHz,DMSO-d6)δ9.81(s,1H),7.88q,J=4.5Hz,1H),7.64-7.59(m,1H),6.93–6.80(m,2H),4.00–3.85(m,2H),3.73-3.69(m,2H),3.39-3.35(m,1H),3.25–3.15(m,2H),3.13(d,J=6.3Hz,2H),2.75(d,J=4.5Hz,3H).
LCMS m/s=277.1[M+1].
中间体18
(R)-2-氟-4-(3-(羟甲基)哌嗪-1-基)-N-甲基苯甲酰胺中间体18
(R)-2-fluoro-4-(3-(hydroxymethyl)piperazin-1-yl)-N-methylbenzamide
按照中间体1的制备方法,得到中间体18(黄色固体,210mg,产率61%)。
LCMS m/s=268.1[M+1].
中间体19
(S)-2-氟-4-(3-(羟甲基)哌嗪-1-基)-N-甲基苯甲酰胺中间体19
(S)-2-fluoro-4-(3-(hydroxymethyl)piperazin-1-yl)-N-methylbenzamide
按照中间体1的制备方法,得到中间体19(黄色固体,240mg,产率67%)。
LCMS m/s=268.1[M+1].
中间体20
2-氰基-N-甲基-4-(哌嗪-1-基)苯甲酰胺中间体20
2-cyano-N-methyl-4-(piperazin-1-yl)benzamide
按照中间体1的制备方法,得到中间体20(黄色固体,920mg,产率87%)。
LCMS m/s=245.1[M+1].
中间体21
3-氟-N-甲基-4-(1,2,3,6-四氢吡啶-4-基)苯甲酰胺中间体21
3-fluoro-N-methyl-4-(1,2,3,6-tetrahydropyridin-4-yl)benzamide
第一步:
4-(2-氟-4-(甲基氨基甲酰基)苯基)-3,6-二氢吡啶-1(2H)-羧酸叔丁酯21b
tert-butyl 4-(2-fluoro-4-(methylcarbamoyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate
将8a(500mg,2.17mmol)、21a(610mg,1.98mmol)溶解于15mL1,4-二氧六环中,再加入四(三苯基膦)钯(231mg,0.20mmol)、碳酸铯(968mg,2.97mmol),加入完毕后氮气保护,将反应体系置于120℃下反应,16h后反应完毕,加入20mL水和乙酸乙酯(3×30mL)萃取三次,收集有机相,减压浓缩,再柱层析纯化(PE:EA=2:1-1:2),得到21b粗品。
第二步:
3-氟-N-甲基-4-(1,2,3,6-四氢吡啶-4-基)苯甲酰胺中间体21
3-fluoro-N-methyl-4-(1,2,3,6-tetrahydropyridin-4-yl)benzamide
将21b加入到15mL盐酸的1,4-二氧六环溶液(4M)中,在室温下搅拌反应16h,反应完后过滤,收集滤饼,即得到中间体21(白色固体,465mg,产率84%)。
LCMS m/s=235.1[M+1].
中间体22
N-甲基-4-(哌嗪-1-基)苯甲酰胺中间体22
N-methyl-4-(piperazin-1-yl)benzamide
按照中间体1的制备方法,得到中间体22(黄色固体,1g,产率69%)。
1H NMR(400MHz,DMSO-d6)δ9.68(dr,1H),8.46(d,1H),7.78(d,2H),7.00(d,2H),3.51–3.38(m,4H),3.23–3.20(m,4H),2.74(d,3H).
LCMS m/s=220.10[M+1].
中间体23
2,5-二氟-氮-甲基-4-(哌嗪-1-基)苯甲酰胺中间体23
2,5-difluoro-N-methyl-4-(piperazin-1-yl)benzamide
按照中间体1的制备方法,得到中间体23(白色固体,1.8g,产率84%)。
1H NMR(400MHz,DMSO-d6)δ9.36(s,1H),8.14-8.04(m,1H),7.44(dd,J=13.3,6.7Hz,1H),7.04(dd,J=12.5,7.1Hz,1H),3.57-3.43(m,4H),3.36(dd,J=6.6,3.7Hz,4H),2.76(d,J=4.5Hz,3H).
LCMS m/s=256.27[M+1].
中间体24
2,5-二氟-氮-甲基-4-(哌嗪-1-基)苯甲酰胺中间体24
2,5-difluoro-N-methyl-4-(piperazin-1-yl)benzamide
按照中间体1的制备方法,得到中间体24(白色固体,1.1g,产率86%)。
1H NMR(400MHz,DMSO-d6)δ9.39(s,1H),8.19(dq,J=6.2,3.9Hz,1H),7.39(td,J=8.3,7.8,2.0Hz,1H),6.97(td,J=8.5,8.0,1.8Hz,1H),3.58(d,J=11.6Hz,2H),3.37(d,J=4.6Hz,2H),3.23(q,J=4.7Hz,4H),2.76(d,J=4.6Hz,3H).
LCMS m/s=256.27[M+1].
中间体25
氮-(2-(二甲氨基)乙基)-2-氟-4-(哌嗪-1-基)苯甲酰胺中间体25
N-(2-(dimethylamino)ethyl)-2-fluoro-4-(piperazin-1-yl)benzamide
按照中间体1的制备方法,得到中间体25(白色固体,1.4g,产率89%)。
LCMS m/s=295.37[M+1].
中间体26
2-氟-氮-(氧杂环丁烷-3-基)-4-(哌嗪-1-基)苯甲酰胺中间体26
2-fluoro-N-(oxetan-3-yl)-4-(piperazin-1-yl)benzamide
按照中间体1的制备方法,得到中间体26(白色固体,1.1g,产率84%)。
1H NMR(400MHz,DMSO-d6)δ9.43(s,1H),7.76–7.69(m,1H),7.63(t,J=8.8Hz,1H),7.06(dd,J=23.5,12.7Hz,1H),6.89(d,J=2.5Hz,1H),4.52(d,J=33.3Hz,8H),4.16(q,J=6.4Hz,1H),3.79–3.74(m,2H),3.48(dd,J=11.0,6.5Hz,2H).
LCMS m/s=280.32[M+1].
中间体27
2-氟-氮-(1-甲基氮杂环丁烷-3-基)-4-(哌嗪-1-基)苯甲酰胺中间体27
2-fluoro-N-(1-methylazetidin-3-yl)-4-(piperazin-1-yl)benzamide
按照中间体1的制备方法,得到中间体27(白色固体,1.2g,产率87%)。
LCMS m/s=293.36[M+1].
中间体28
2-氟-氮-(2-甲氧基乙基)-4-(哌嗪-1-基)苯甲酰胺中间体28
2-fluoro-N-(2-methoxyethyl)-4-(piperazin-1-yl)benzamide
按照中间体1的制备方法,得到中间体28(白色固体,1.7g,产率83%)。
1H NMR(400MHz,DMSO-d6)δ9.48(s,1H),7.89–7.80(m,1H),7.60(t,J=8.8Hz,1H),6.86(d,J=2.5Hz,1H),6.83(q,J=2.2Hz,1H),3.54(t,J=5.3Hz,4H),3.41(qd,J=8.3,3.0Hz,4H),3.26(s,3H),3.16(t,J=5.1Hz,4H).
LCMS m/s=282.33[M+1].
中间体29
2-氟-氮-(2-羟乙基)-4-(哌嗪-1-基)苯甲酰胺中间体29
2-fluoro-N-(2-hydroxyethyl)-4-(piperazin-1-yl)benzamide
按照中间体1的制备方法,得到中间体29(白色固体,1.4g,产率81%)。
1H NMR(400MHz,DMSO-d6)δ9.48(s,1H),7.89–7.80(m,1H),7.60(t,J=8.8Hz,1H),6.86(d,J=2.5Hz,1H),6.83(q,J=2.2Hz,1H),5.14(s,1H),3.54(t,J=5.3Hz,4H),3.41(qd,J=8.3,3.0Hz,4H),3.16(t,J=5.1Hz,4H).
LCMS m/s=268.30[M+1].
中间体30
3-氟-氮-(2-甲氧基乙基)-4-(哌嗪-1-基)苯甲酰胺中间体30
3-fluoro-N-(2-methoxyethyl)-4-(piperazin-1-yl)benzamide
按照中间体1的制备方法,得到中间体30(白色固体,1.5g,产率81%)。
LCMS m/s=282.15[M+1].
中间体31
3-氟-N-((1s,3s)-3-羟基环丁基)-4-(哌嗪-1-基)苯甲酰胺中间体31
3-fluoro-N-((1s,3s)-3-hydroxycyclobutyl)-4-(piperazin-1-yl)benzamide
按照中间体1的制备方法,得到中间体31(白色固体,430mg,产率83%)。
LCMS m/s=294.15[M+1].
中间体32
3-氟-N-((1r,3r)-3-羟基环丁基)-4-(哌嗪-1-基)苯甲酰胺中间体32
3-fluoro-N-((1r,3r)-3-hydroxycyclobutyl)-4-(piperazin-1-yl)benzamide
按照中间体1的制备方法,得到中间体32(白色固体,370mg,产率86%)。
LCMS m/s=294.15[M+1].
中间体33
3-氟-N-(2-羟基-2-甲基丙基)-4-(哌嗪-1-基)苯甲酰胺中间体33
3-fluoro-N-(2-hydroxy-2-methylpropyl)-4-(piperazin-1-yl)benzamide
按照中间体1的制备方法,得到中间体33(白色固体,1.1g,产率91%)。
1H NMR(400MHz,DMSO-d6)δ9.32(s,1H),8.30(t,1H),7.73(q,1H),7.70(d,1H),7.15(t,1H),5.09(s,1H),3.36–3.30(m,4H),3.27(s,2H),3.23(d,4H),1.08(s,6H).
LCMS m/s=296.36[M+1].
中间体34
3-氟-N-甲基-4-(哌啶-4-基)苯甲酰胺中间体34
3-fluoro-N-methyl-4-(piperidin-4-yl)benzamide
第一步:
3-氟-N-甲基-4-(哌啶-4-基)苯甲酰胺中间体34
3-fluoro-N-methyl-4-(piperidin-4-yl)benzamide
将中间体21(150mg,2.17mmol)、甲酸铵(120mg,1.98mmol)、10%Pd/C(150mg)溶解于3mL无水甲醇中,反应体系置于80℃下反应5小时,过滤,收集滤液,减压浓缩,得到中间体34(白色固体,170mg,产率82%)。
LCMS m/s=237.13[M+1].
中间体35
(S)-3-氟-N-(2-羟丙基)-4-(哌嗪-1-基)苯甲酰胺中间体35
(S)-3-fluoro-N-(2-hydroxypropyl)-4-(piperazin-1-yl)benzamide
按照中间体1的制备方法,得到中间体35(白色固体,1.3g,产率94%)。
LCMS m/s=282.15[M+1].
中间体36
(R)-3-氟-N-(2-羟丙基)-4-(哌嗪-1-基)苯甲酰胺中间体36
(R)-3-fluoro-N-(2-hydroxypropyl)-4-(piperazin-1-yl)benzamide
按照中间体1的制备方法,得到中间体36(白色固体,0.9g,产率85%)。
LCMS m/s=282.15[M+1].
中间体37
N-(2-羟乙基)-6-(哌嗪-1-基)烟酰胺中间体37
N-(2-hydroxyethyl)-6-(piperazin-1-yl)nicotinamide
按照中间体1的制备方法,得到中间体37(白色固体,0.8g,产率82%)。
LCMS m/s=251.14[M+1].
中间体38
3-氯-N-甲基-4-(哌嗪-1-基)苯甲酰胺中间体38
3-chloro-N-methyl-4-(piperazin-1-yl)benzamide
按照中间体1的制备方法,得到中间体38(白色固体,1.2g,产率77%)。
LCMS m/s=254.10[M+1].
中间体39
4-氟-N-((1-羟基环丙基)甲基)-4-(哌嗪-1-基)苯甲酰胺中间体39
4-fluoro-N-((1-hydroxycyclopropyl)methyl)-4-(piperazin-1-yl)benzamide
按照中间体1的制备方法,得到中间体39(白色固体,0.9g,产率85%)。
LCMS m/s=294.15[M+1].
中间体40
7-(溴甲基)-3-环丙基-1,5-萘啶-2(1H)-酮中间体40
7-(bromomethyl)-3-cyclopropyl-1,5-naphthyridin-2(1H)-one
第一步
6-甲酰基-5-硝基烟酸乙酯40b
ethyl 6-formyl-5-nitronicotinate
将6-甲基-5-硝基烟酸乙酯40a(购自江苏艾康生物医药研发有限公司,10g,45.6mmol),二氧化硒(7.6g,68.4mmol)溶于二氧六环(100mL),在110℃下回流4h,反应完后热过滤,将滤液减压浓缩,柱层析得到化合物40b(黄色固体,9.7g,产率90%)。
LC-MS m/z(ESI)=225.10[M+1].
第二步
6-(2-溴-3-乙氧基-3-氧丙烷-1-烯-1-基)-5-硝基烟酸乙酯40c
ethyl 6-(2-bromo-3-ethoxy-3-oxoprop-1-en-1-yl)-5-nitronicotinate
将2-溴-2-(二乙氧基磷酰)乙酸乙酯(购自上海迈瑞尔化学技术有限公司,20g,66.6mmol)溶于四氢呋喃(100mL),-78℃下缓慢加入钠氢(1.6g,66.6mmol),缓慢升温至40℃反应10min,再降温到-78℃下缓慢滴加40b(9.7g,44.4mmol)的四氢呋喃溶液,反应15min后加入饱和氯化铵水溶液(100mL)淬灭,乙酸乙酯(100mL×3)萃取,合并有机相减压浓缩,柱层析得到40c(黄色固体,13g,产率81%,E/Z=10:3)。
1H NMR(400MHz,DMSO-d6)δ9.42(d,1H),9.23(d,0.3H),8.86(d,1H),8.80(d,0.3H),8.61(s,1H),7.89(s,0.3H),4.46-4.38(m,2.6H),4.34(q,2H),4.16(q,0.6H),1.39-1.34(m,3.9H),1.32(t,3H),1.08(t,0.9H).
LC-MS m/z(ESI)=373.00[M+1].
第三步
5-氨基-6-(2-溴-3-乙氧基-3-氧代丙-1-烯-1-基)烟酸乙酯40d
ethyl 5-amino-6-(2-bromo-3-ethoxy-3-oxoprop-1-en-1-yl)nicotinate
化合物40c(13g,34.8mmol)溶于醋酸(130mL)中,加入铁粉(5.8g,104.5mmol),室温反应2h后加入蒸馏水(100mL)淬灭反应,乙酸乙酯(100mL×3)萃取,合并有机相减压浓缩,得到化合物40d(黄色固体,10g,产率83%)。
LC-MS m/z(ESI)=343.00[M+1].
第四步
7-溴-6-氧-5,6-二氢-1,5-萘啶-3-羧酸乙酯40e
ethyl 7-bromo-6-oxo-5,6-dihydro-1,5-naphthyridine-3-carboxylate
将化合物40d(10g,29.1mmol)置于反应瓶中,氮气保护下加入溴化氢的醋酸溶液(100mL),50℃下反应4h后减压浓缩,饱和碳酸氢钠水溶液(100mL)淬灭反应,乙酸乙酯(50mL×3)萃取,减压浓缩,柱层析得到化合物40e(黄色固体,2g,产率23%)。
1H NMR(400MHz,DMSO-d
6)δ12.54(s,1H),8.88(d,1H),8.51(s,1H),8.14(d,1H),4.37(q,2H),1.35(t,3H).
LC-MS m/z(ESI)=297.00[M+1].
第五步
7-环丙基-6-氧代-5,6-二氢-1,5-萘啶-3-羧酸乙酯40f
ethyl 7-cyclopropyl-6-oxo-5,6-dihydro-1,5-naphthyridine-3-carboxylate
将化合物40e(400mg,1.3mmol),[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(购自成都叮当时代医药科技有限公司,328mg,0.40mmol),碳酸钾(745mg,5.4mmol),环丙基硼酸(杭州艾康生物技术有限公司,231mg,2.7mmol)溶于二氧六环(4mL),110℃下回流8h后加水(5mL)淬灭,乙酸乙酯(5mL×3)萃取,减压浓缩柱层析纯化,得到化合物40f(黄色固体,270mg,产率77%)。
1H NMR(400MHz,DMSO-d6)δ12.07(s,1H),8.85(d,1H),8.12(d,1H),7.46(s,1H),4.36(q,2H),2.25-2.12(m,1H),1.34(t,3H),1.02(dt,2H),0.90(dt,2H).
LC-MS m/z(ESI)=259.10[M+1].
第六步
3-环丙基-7-(羟甲基)-1,5-萘啶-2(1H)-酮40g
3-cyclopropyl-7-(hydroxymethyl)-1,5-naphthyridin-2(1H)-one
将化合物40f(270mg,1mmol)溶于四氢呋喃(2mL),在冰水浴下缓慢滴加四氢铝锂的四氢呋喃溶液(购自安耐吉化学,2mL,2mmol),滴加完搅拌10min,加入乙酸乙酯(1mL),减压浓缩柱层析得到化合物40g(黄色固体,100mg,产率44%)。
1H NMR(400MHz,DMSO-d6)δ11.92(s,1H),8.35(d,1H),7.59(d,1H),7.41(s,1H),5.45(t,1H),4.60(d,2H),2.16-2.09(m,1H),0.96(dt,2H),0.82(dt,2H).
LC-MS m/z(ESI)=217.10[M+1].
第七步
7-(溴甲基)-3-环丙基-1,5-萘啶-2(1H)-酮中间体40
7-(bromomethyl)-3-cyclopropyl-1,5-naphthyridin-2(1H)-one
将化合物40g(100mg,0.46mmol)和三苯基膦(购自上海阿达玛斯试剂有限公司,242mg,0.92mmol)溶于二氯甲烷(1mL),在冰水浴下加入四溴化碳(购自安耐吉化学,306mg,0.92mmol)的二氯甲烷(0.5mL)溶液,反应0.5h,反应液减压浓缩后经柱层析得到化合物中间体40(黄色固体,100mg,产率78%)。
LC-MS m/z(ESI)=279.00[M+1].
中间体41
(R)-6-(哌嗪-1-基)-N-(四氢呋喃-3-基)烟酰胺中间体41
(R)-6-(piperazin-1-yl)-N-(tetrahydrofuran-3-yl)nicotinamide
按照中间体1的制备方法,得到中间体35(白色固体,0.4g,产率87%)。
LCMS m/s=277.16[M+1].
中间体42
N-甲基-4-(哌嗪-1-基)吡啶酰胺中间体42
N-methyl-4-(piperazin-1-yl)picolinamide
按照中间体1的制备方法,得到中间体42(黄色固体,500mg,产率74%)。
LCMS m/s=221.28[M+1].
中间体43
N-甲基-5-(哌嗪-1-基)吡嗪-2-甲酰胺中间体43
N-methyl-5-(piperazin-1-yl)pyrazine-2-carboxamide
按照中间体1的制备方法,得到中间体43(黄色固体,1.1g,产率72%)。
LCMS m/s=222.26[M+1].
中间体44
5-氟-N-甲基-6-(哌嗪-1-基)烟酰胺中间体44
5-fluoro-N-methyl-6-(piperazin-1-yl)nicotinamide
按照中间体1的制备方法,得到中间体44(黄色固体,530mg,产率78%)。
LCMS m/s=239.12[M+1].
中间体45
3,5-二氟-N-甲基-4-(哌嗪-1-基)苯甲酰胺中间体45
3,5-difluoro-N-methyl-4-(piperazin-1-yl)benzamide
按照中间体1的制备方法,得到中间体45(白色固体,1.4g,产率69%)。
1H NMR(400MHz,DMSO-d6)δ9.40(s,1H),8.60(q,1H),7.58(s,1H),7.55(s,1H),3.46–3.36(m,4H),3.20–3.11(m,4H),2.76(d,3H).
LCMS m/s=256.10[M+1].
中间体46
2-氯-5-氟-N-甲基-4-(哌嗪-1-基)苯甲酰胺中间体46
2-chloro-5-fluoro-N-methyl-4-(piperazin-1-yl)benzamide
按照上述同样的方法,同理得到中间体46(白色固体,1.5g,产率75%)。
1H NMR(400MHz,DMSO-d6)δ9.49(s,1H),8.32(q,1H),7.32(d,1H),7.15(d,1H),3.39–3.26(m,4H),3.24–3.16(m,4H),2.72(d,3H).
LCMS m/s=272.10[M+1].
中间体47
2,6-二氯-N-甲基-4-(哌嗪-1-基)苯甲酰胺中间体47
2,6-dichloro-N-methyl-4-(piperazin-1-yl)benzamide
按照上述同样的方法,同理得到中间体47(白色固体,1.4g,产率70%)。
1H NMR(400MHz,DMSO-d6)δ9.47(s,1H),8.39(q,1H),7.06(s,2H),3.55–3.45(m, 4H),3.18–3.09(m,4H),2.72(d,3H).
LCMS m/s=288.10[M+1].
中间体48
7-(溴甲基)-3-甲基-1,5-萘啶-2(1H)-酮中间体48
7-(bromomethyl)-3-methyl-1,5-naphthyridin-2(1H)-one
中间体48根据专利WO2021013735的中间体14的合成方法,使用三乙基2-膦酰基丙酯替代三乙基2-丁基丙烯酯制备得到,LCMS m/s=253.10[M+1]。
中间体49
(R)-3-氯-4-(哌嗪-1-基)-N-(四氢呋喃-3-基)苯甲酰胺中间体49
(R)-3-chloro-4-(piperazin-1-yl)-N-(tetrahydrofuran-3-yl)benzamide
按照中间体1的制备方法,得到中间体49(白色固体,1.3g,产率94%)。
LCMS m/s=310.7[M+1].
中间体50
3-氯-N-((3S,4R)-4-羟基四氢呋喃-3-基)-4-(哌嗪-1-基)苯甲酰胺中间体50
3-chloro-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-4-(piperazin-1-yl)benzamide
按照中间体1的制备方法,得到中间体50(白色固体,1.6g,产率94%)。
LCMS m/s=326.1[M+1].
中间体51
3-氯-N-(3-甲基四氢呋喃-3-基)-4-(哌嗪-1-基)苯甲酰胺中间体51
3-chloro-N-(3-methyltetrahydrofuran-3-yl)-4-(piperazin-1-yl)benzamide
按照中间体1的制备方法,得到中间体51(白色固体,1.1g,产率92%)。
LCMS m/s=324.1[M+1].
中间体52
N-(3-恶唑环[3.1.0]己烷-6-基)-3-氯-4-(哌嗪-1-基)苯甲酰胺中间体52
N-(3-oxabicyclo[3.1.0]hexan-6-yl)-3-chloro-4-(piperazin-1-yl)benzamide
按照中间体1的制备方法,得到中间体52(白色固体,1.3g,产率91%)。
LCMS m/s=322.1[M+1].
实施列1
4-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-2-氟-N-甲基苯甲酰胺化合物1
4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-2-fluoro-N-methylbenzamide
将中间体2(100mg,0.37mmol)和中间体1(98mg,0.41mmol)溶解于5mL乙腈中,再加入N,N-二异丙基乙胺(241.5mg,1.9mmol),在70℃氮气保护下反应,3 h后反应完毕,减压浓缩得到粗品,再柱层析纯化(MeOH:DCM=1:60到1:15),得到化合物1(白色固体,50mg,产率:32%)。
1H NMR(400MHz,DMSO-d6)δ11.85(s,1H),8.40(d,J=2.0Hz,1H),8.22(dr s,1H),7.75(s,1H),7.62(s,1H),7.56(t,J=9.0Hz,1H),6.82-6.72(m,2H),3.64(s,2H),3.29-3.26(m,4H),2.74(d,J=4.5Hz,3H),2.54-2.51(m,6H),1.18(t,J=7.4Hz,3H).
LCMS m/s=424.50[M+1].
实施列2
4-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-2-氟-N-(甲基-D3)苯甲酰胺化合物2
4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-2-fluoro-N-(methyl-d3)benzamide
按照化合物1的方法,制备得到化合物2(白色固体,100mg,产率:62%)。
1H NMR(400MHz,DMSO-d6)δ11.85(s,1H),8.40(d,J=1.9Hz,1H),7.75(dr s,1H),7.73(d,J=5.6Hz,1H),7.62(d,J=1.9Hz,1H),7.56(t,J=9.0Hz,1H),6.81–6.70(m,2H),3.63(s,2H),3.29–3.26(m,4H),2.59–2.51(m,6H),1.18(t,J=7.4Hz,3H).
LCMS m/s=427.20[M+1].
实施列3
4-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-2-氟苯甲酰胺化合物3
4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-2-fluorobenzamide
按照化合物1的方法,制备得到化合物3(白色固体,5mg,产率:7%)。
1H NMR(400MHz,DMSO-d6)δ11.85(s,1H),8.40(d,J=1.9Hz,1H),7.75(s,1H),7.62(d,J=1.6Hz,1H),7.59(d,J=9.0Hz,1H),7.32(dr s,1H),7.20(dr s,1H),6.83–6.67(m,2H),3.64(s,2H),3.32-3.27(m,4H),2.54-2.50(m,6H),1.18(t,J=7.4Hz,3H).
LCMS m/s=410.20[M+1].
实施列4
2-氯-4-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N-甲基苯甲酰胺化合物4
2-chloro-4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-methylbenzamide
按照化合物1的方法,制备得到化合物4(白色固体,50mg,产率:30%)。
LCMS m/s=440.20[M+1].
实施列5
4-(6-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)-2-氟-N-甲基苯甲酰胺化合物5
4-(6-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)-2-fluoro-N-methylbenzamide
按照化合物1的方法,制备得到化合物5(白色固体,18mg,产率:23%)。
1H NMR(400MHz,DMSO-d6)δ12.01(s,1H),8.53(s,1H),7.90–7.53(m,4H),6.76–6.47(m,2H),3.88-3.61(m,4H),3.21-3.12(m,4H)2.77(s,3H),2.62–2.51(m,3H),1.29-1.25(m,1H),1.15(s,3H).
LCMS m/s=436.20[M+1].
实施例6
N-环丙基-4-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-2-氟苯甲酰胺化合物6
N-cyclopropyl-4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin -1-yl)-2-fluorobenzamide
按照化合物1的方法,制备得到化合物6(白色固体,18mg,产率:6%)。
1H NMR(400MHz,DMSO-d6)δ11.72(s,1H),8.39(d,J=1.8Hz,1H),7.85(s,1H),
7.75(d,J=5.4Hz,1H),7.68(d,J=1.8Hz,1H),7.47(t,J=8.9Hz,1H),6.81-6.70(m,2H),3.63(s,2H),3.27-3.24(m,4H),2.80-2.77(m,1H),2.56-2.55(m,6H),1.17(t,J=7.5Hz,3H).0.68-0.65(m,2H),0.53-0.50(m,2H).
LCMS m/s=450.2[M+1].
实施例7
4-(4-((7-乙基-6-羰基-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-3-氟-N-甲基苯甲酰胺化合物7
4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-3-fluoro-N-methylbenzamide
按照化合物1的方法,制备得到化合物7(白色固体,50mg,产率:78%)。
1H NMR(400MHz,DMSO-d
6)δ11.86(s,1H),8.40(s,1H),8.33(q,J=4.1Hz,1H),7.75(s,1H),7.68–7.52(m,3H),7.05(t,J=8.6Hz,1H),3.65(s,2H),3.14-3.08(m,4H),2.75(d,J=4.1Hz,3H),2.59–2.55(m,4H),2.54-2.51(m,2H),1.18(t,J=7.4Hz,3H).
LCMS m/s=424.2[M+1]
实施例8
(R)-4-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-2-氟-N-(四氢呋喃-3-基)苯甲酰胺化合物8
(R)-4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-2-fluoro-N-(tetrahydrofuran-3-yl)benzamide
按照化合物1的方法,制备得到化合物8(白色固体,40mg,产率:82%)。
1H NMR(400MHz,DMSO-d6)δ11.82(s,1H),8.40(d,J=1.8Hz,1H),7.96(dd,J=6.7,3.6Hz,1H),7.75(s,1H),7.62(s,1H),7.49(t,J=8.8Hz,1H),6.82-6.69(m,2H),4.40(d,J=5.6Hz,1H),3.81(td,J=9.5,6.8Hz,2H),3.73-3.66(m,1H),3.64(s,2H),3.53(dd,J=8.8,4.4Hz,1H),3.28(s,4H),2.54(d,J=8.3Hz,6H),2.17-2.06(m,1H),1.87(dd,J=12.2,5.8Hz,1H),1.18(t,J=7.4Hz,3H).
LCMS m/s=480.5[M+1].
实施例9
(S)-4-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-2-氟-N-(四氢呋喃-3-基)苯甲酰胺化合物9
(S)-4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-2-fluoro-N-(tetrahydrofuran-3-yl)benzamide
按照化合物1的方法,制备得到化合物9(白色固体,46mg,产率:84%)。
1H NMR(400MHz,DMSO-d
6)δ11.85(s,1H),8.40(d,J=1.9Hz,1H),7.96(dd,J=6.6,3.5Hz,1H),7.75(s,1H),7.62(d,J=1.8Hz,1H),7.49(t,J=8.8Hz,1H),6.80-6.70(m,2H),4.39(d,J=6.1Hz,1H),3.85-3.77(m,2H),3.73-3.67(m,1H),3.63(s,2H),3.53(dd,J=8.8,4.4Hz,1H),3.27(d,J=5.4Hz,4H),2.59-2.51(m,6H),2.18-2.06(m,1H),1.85(dq,J=12.5,6.2Hz,1H),1.18(t,J=7.4Hz,3H).
LCMS m/s=480.5[M+1].
实施例10
4-(4-((7-环丙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-3-氟-氮-甲基苯甲酰胺化合物10
4-(4-((7-cyclopropyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-3-fluoro-N-methylbenzamide
第一步
6-甲酰基-5-硝基硝基乙酯10B
ethyl 6-formyl-5-nitronicotinat
将6-甲基-5-硝基烟酸乙酯化合物10A(购自江苏艾康生物医药研发有限公司,10g,45.6mmol),二氧化硒(7.6g,68.4mmol)溶于二氧六环(100mL),在110℃下回流4h,反应完后热过滤,将滤液减压浓缩,柱层析得到化合物10B(黄色固体,9.7g,产率90%)。
LC-MS m/z(ESI)=225.10[M+1].
第二步
6-(2-溴-3-乙氧基-3-丙氧酸-1-烯-1-基)-5-硝基烟酸乙酯10C
ethyl 6-(2-bromo-3-ethoxy-3-oxoprop-1-en-1-yl)-5-nitronicotinate
将2-溴-2-(二乙氧基磷酰)乙酸乙酯(购自上海迈瑞尔化学技术有限公司,20g,66.6mmol)溶于四氢呋喃(100mL),-78℃下缓慢加入钠氢(1.6g,66.6mmol),缓慢升温至40℃反应10min,再降温到-78℃下缓慢滴加10B(9.7g,44.4mmol)的四氢呋喃溶液,反应15min后加入饱和氯化铵水溶液(100mL)淬灭,乙酸乙酯(100mL×3)萃取,合并有机相减压浓缩,柱层析得到10C(黄色固体,13g,产率81%,E/Z=10:3)。
1H NMR(400MHz,DMSO-d
6)δ9.42(d,1H),9.23(d,0.3H),8.86(d,1H),8.80(d,0.3H),8.61(s,1H),7.89(s,0.3H),4.46–4.38(m,2.6H),4.34(q,2H),4.16(q,0.6H),1.39–1.34(m,3.9H),1.32(t,3H),1.08(t,0.9H).
LC-MS m/z(ESI)=373.00[M+1].
第三步
5-氨基-6-(2-溴-3-乙氧基-3-氧代丙-1-烯-1-基)烟酸乙酯10D
ethyl 5-amino-6-(2-bromo-3-ethoxy-3-oxoprop-1-en-1-yl)nicotinate
化合物10C(13g,34.8mmol)溶于醋酸(130mL)中,加入铁粉(5.8g,104.5mmol),室温反应2h后加入蒸馏水(100mL)淬灭反应,乙酸乙酯(100mL×3)萃取,合并有机相减压浓缩,得到化合物10D(黄色固体,10g,产率83%)。
LC-MS m/z(ESI)=343.00[M+1].
第四步
7-溴-6-氧代-5,6-二氢-1,5-萘啶-3-羧酸乙酯10E
ethyl 7-bromo-6-oxo-5,6-dihydro-1,5-naphthyridine-3-carboxylate
将化合物10D(10g,29.1mmol)置于反应瓶中,氮气保护下加入溴化氢的醋酸溶液(100mL),50℃下反应4h后减压浓缩,饱和碳酸氢钠水溶液(100mL)淬灭反应,乙酸乙酯(50mL×3)萃取,减压浓缩,柱层析得到化合物10E(黄色固体,2g,产率23%)。
1H NMR(400MHz,DMSO-d
6)δ12.54(s,1H),8.88(d,1H),8.51(s,1H),8.14(d,1H),4.37(q,2H),1.35(t,3H).
LC-MS m/z(ESI)=297.00[M+1].
第五步
7-环丙基-6-氧代-5,6-二氢-1,5-萘啶-3-羧酸乙酯10F
ethyl 7-cyclopropyl-6-oxo-5,6-dihydro-1,5-naphthyridine-3-carboxylate
将化合物10E(400mg,1.3mmol),[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(购自成都叮当时代医药科技有限公司,328mg,0.40mmol),碳酸钾(745mg,5.4mmol),环丙基硼酸(杭州艾康生物技术有限公司,231mg,2.7mmol)溶于二氧六环(4mL),110℃下回流8h后加水(5mL)淬灭,乙酸乙酯(5mL×3)萃取,减压浓缩柱层析纯化,得到化合物10F(黄色固体,270mg,产率77%)。
1H NMR(400MHz,DMSO-d
6)δ12.07(s,1H),8.85(d,1H),8.12(d,1H),7.46(s,1H),4.36(q,2H),2.25–2.12(m,1H),1.34(t,3H),1.02(dt,2H),0.90(dt,2H).
LC-MS m/z(ESI)=259.10[M+1].
第六步
3-环丙基-7-(羟甲基)-1,5-萘啶-2(1氢)-酮10G
3-cyclopropyl-7-(hydroxymethyl)-1,5-naphthyridin-2(1H)-one
将化合物10F(270mg,1mmol)溶于四氢呋喃(2mL),在冰水浴下缓慢滴加四氢铝锂的四氢呋喃溶液(购自安耐吉化学,2mL,2mmol),滴加完搅拌10min,加入乙酸乙酯(1mL),减压浓缩柱层析得到化合物10G(黄色固体,100mg,产率44%)。
1H NMR(400MHz,DMSO-d
6)δ11.92(s,1H),8.35(d,1H),7.59(d,1H),7.41(s,1H),5.45(t,1H),4.60(d,2H),2.16–2.09(m,1H),0.96(dt,2H),0.82(dt,2H).
LC-MS m/z(ESI)=217.10[M+1].
第七步
7-(溴甲基)-3-环丙基-1,5-萘啶-2(1氢)-酮10H
7-(bromomethyl)-3-cyclopropyl-1,5-naphthyridin-2(1H)-one
将化合物10G(100mg,0.46mmol)和三苯基膦(购自上海阿达玛斯试剂有限公司,242mg,0.92mmol)溶于二氯甲烷(1mL),在冰水浴下加入四溴化碳(购自安耐吉化学,306 mg,0.92mmol)的二氯甲烷(0.5mL)溶液,反应0.5h,反应液减压浓缩后经柱层析得到化合物10H(黄色固体,100mg,产率78%)。
LC-MS m/z(ESI)=279.00[M+1].
第八步
4-(4-((7-环丙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-3-氟-氮-甲基苯甲酰胺化合物10
4-(4-((7-cyclopropyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-3-fluoro-N-methylbenzamide
将化合物10H(100mg,0.36mmol),3-氟-N-甲基-4-(哌嗪-1-基)苯甲酰胺(93mg,0.39mmol)中间体8,N,N-二异丙基乙胺(230mg,1.8mmol)溶解在乙腈(4mL)中,80℃下反应4h,反应液减压浓缩经制备色谱得到化合物10(白色固体,40mg,产率27%)。
1H NMR(400MHz,DMSO-d
6)δ11.88(s,1H),8.37(d,1H),8.35–8.31(m,1H),7.64–7.53(m,3H),7.41(s,1H),7.05(t,1H),3.63(d,2H),3.12–3.09(m,4H),2.75(d,3H),2.57–2.54(m,4H),2.19–2.11(m,1H),1.02–0.92(m,2H),0.87–0.74(m,2H).
LC-MS m/z(ESI)=436.20[M+1]。
实施例11
4-(4-((7-乙基-2,6-二氧基-1,2,5,6-四氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-3-氟-N-甲基苯甲酰胺化合物11
4-(4-((7-ethyl-2,6-dioxo-1,2,5,6-tetrahydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-3-fluoro-N-methylbenzamide
第一步
(5-乙酰基-7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)乙酸甲酯11B
(5-acetyl-7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl acetate
化合物11A(1.02g,5mmol;根据专利WO2021013735的中间体13的合成方法制备得到,LC-MS m/s=205.1[M+1])和乙酸酐(10.2g,100mmol)加入100mL反应瓶,在氮气氛围下至于100℃油浴锅中搅拌反应8h,TLC监控反应完全,减压浓缩除去溶剂,柱层析分离(PE:EA=5:1),得到化合11B(淡黄色固体,1.15g,产率80%)。
LC-MS m/s=289.1[M+1].
第二步
3-乙基-7-(羟甲基)-1,5-二氢-1,5-萘啶-2,6-二酮11C
3-ethyl-7-(hydroxymethyl)-1,5-dihydro-1,5-naphthyridine-2,6-dione
取50mL反应瓶,干燥,加入化合物11B(1.15g,4mmol)和10mL二氯甲烷,置换氮气,冰水浴条件下分批加入间氯过氧苯甲酸(756mg,4.4mmol),自然恢复至室温搅拌反应5h,TLC监控反应完全,加入饱和碳酸氢钠水溶液(20mL),二氯甲烷(3×20mL)萃取,合并有机相,无水硫酸钠干燥,减压浓缩除去有机溶剂。加入醋酸酐(10mL),回流搅拌反应2h后加入蒸馏水(8mL),继续回流搅拌反应2h,减压浓缩除去有机溶剂,加入甲醇(20mL)和碳酸钾(2.76g,20mmol),室温搅拌反应1h,过滤,滤饼用甲醇洗涤,收集滤液,减压浓缩除去有机溶剂,粗产物经反相柱分离得到化合11C(棕色固体,310mg,产率35%)。
1H NMR(400MHz,DMSO-d
6)δ10.50(s,2H),6.94(d,1H),6.73(s,1H),5.37(t,1H),4.20(dd,2H),2.35(qd,2H),1.08(t,3H).
LC-MS m/s=221.1[M+1].
第三步
3-(溴甲基)-7-乙基-1,5-二氢-1,5-萘啶-2,6-二酮11D
3-(bromomethyl)-7-ethyl-1,5-dihydro-1,5-naphthyridine-2,6-dione
将化合物11C(310mg,1.41mmol)和三苯基膦(购自上海阿达玛斯试剂有限公司,739mg,2.82mmol)溶于二氯甲烷(5mL),在冰水浴条件下加入四溴化碳(购自安耐吉化学,933mg,2.82mmol)的二氯甲烷(2mL)溶液,反应0.5h,反应液减压浓缩后经柱层析得到化合物11D(黄色固体,160mg,产率40%)。
1H NMR(400MHz,DMSO-d6)δ10.22(s,2H),6.99(s,1H),6.73(s,1H),3.97(d,2H),2.33(qd,2H),1.08(t,3H).
LC-MS m/s=283.0[M+1].
第四步
4-(4-((7-乙基-2,6-二氧基-1,2,5,6-四氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-3-氟-N-甲基苯甲酰胺化合物11
4-(4-((7-ethyl-2,6-dioxo-1,2,5,6-tetrahydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-3-fluoro-N-methylbenzamide
将化合物11D(100mg,0.35mmol),中间体8(93mg,0.39mmol),N,N-二异丙基乙胺(230mg,1.8mmol)溶解在乙腈(4mL)中,80℃下反应4h,反应液减压浓缩经制备色谱得到化合物11(白色固体,31mg,产率27%)。
1H NMR(400MHz,DMSO-d6)δ10.55(s,1H),10.52(s,1H),8.28(s,1H),7.63(dd,1H),7.31(dd,1H),6.96–6.60(m,3H),4.13(d,2H),3.08(t,4H),2.81(s,3H),2.56(d,3H),2.49–2.22(m,2H),1.15(t,3H).
LC-MS m/s=440.2[M+1].
实施例12
4-(3-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)-2-氟-氮-甲基苯甲酰胺化合物12
4-(3-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl)-2-fluoro-N-methylbenzamide
按照化合物1的方法,制备得到化合物12(白色固体,50mg,产率:47%)。
1H NMR(400MHz,DMSO-d6)δ11.77(s,1H),8.14(s,1H),7.75-7.72(m,1H),7.70(s,1H),7.54(t,1H),7.46(s,1H),6.36(s,1H),6.34(s,1H),4.33-4.32(m,2H),3.59(s,2H),3.04-3.01(m,2H),2.82–2.69(m,5H),2.55-2.52(m,2H),1.99-1.97(m,1H),1.23-1.21(m,1H),1.17(t,3H).
LCMS m/s=436.20[M+1].
实施例13
2-氯-4-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-6-氟-氮-甲基苯甲酰胺化合物13
2-chloro-4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylbenzamide
按照化合物1的方法,得到化合物13(白色固体,17.7mg,产率:42%)。
1H NMR(400MHz,DMSO-d6)δ11.86(s,1H),8.40(s,1H),8.36(q,J=4.6Hz,1H),7.75(s,1H),7.62(s,1H),6.82(s,1H),6.78-6.76(m,1H),3.62(s,2H),3.28-3.22(m,4H),3.16-3.12(m,2H),2.71(d,J=4.6Hz,3H),2.57–2.51(m,4H),1.18(t,J=7.4Hz,3H).
19F NMR(377MHz,DMSO-d6)δ-113.43(s).
LCMS m/s=458.2[M+1].
实施例14
4-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-2,3,5,6-四氟-氮-甲基苯甲酰胺化合物14
4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-2,3,5,6-tetrafluoro-N-methylbenzamide
按照化合物1的方法,得到化合物14(白色固体,6.5mg,产率:41%)。
1H NMR(400MHz,DMSO-d6)δ11.85(s,1H),8.68(d,J=4.6Hz,1H),8.39(s,1H),7.75(s,1H),7.62(s,1H),3.65(s,2H),3.27-3.22(s,4H),2.76(d,J=4.6Hz,3H),2.57-2.54(m,4H),2.54(d,J=7.4Hz,2H),1.18(t,J=7.4Hz,3H).
19F NMR(377MHz,DMSO-d6)δ-144.07(dd,J=22.8,8.3Hz),-150.60(dd,J=22.8,8.3Hz).
LCMS m/s=478.2[M+1].
实施例15
4-溴-4-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-2,5,6-三氟-N-甲基苯甲酰胺化合物15
3-bromo-4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-2,5,6-trifluoro-N-methylbenzamide
按照化合物1的方法,得到化合物15(白色固体,15.3mg,产率:44%)。
1H NMR(400MHz,DMSO-d6)δ11.85(s,1H),8.53(q,J=4.6Hz,1H),8.38(s,1H),7.74(s,1H),7.63(s,1H),3.60(s,2H),3.15-3.10(m,4H),3.05-2.99(m,4H),2.77(d,J=4.6Hz,3H),2.57–2.52(m,2H),1.18(d,J=7.4Hz,3H).
19F NMR(377MHz,DMSO-d6)δ-117.65(d,J=11.5Hz),-133.54(d,J=25.6Hz),-143.13(dd,J=25.6,11.5Hz).
LCMS m/s=538.1[M+1].
实施例16
(S)-4-(4-((7-乙基-6-羰基5,6-二氢-1,5-萘啶-3-基)甲基)-3-甲基哌嗪-1-基)-2-氟-氮-甲基苯甲酰胺化合物16
(S)-4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-3-methylpiperazin- 1-yl)-2-fluoro-N-methylbenzamide
按照化合物1的方法,得到化合物16(白色固体,43mg,产率:46%)。
1H NMR(400MHz,DMSO-d6)δ12.16(s,1H),8.54(q,J=4.4Hz,1H),7.95-7.59(m,5H),6.84(s,1H),3.64-3.60(m,4H),3.18–3.12(m,4H),2.95-2.87(m,1H),2.74(d,J=4.4Hz,3H),2.59–2.53(m,2H),1.46(d,J=6.5Hz,3H),1.18(t,J=8.0Hz,3H).
19F NMR(377MHz,DMSO-d6)δ-111.44.
LCMS m/s=438.2[M+1].
实施例17
(R)-4-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)-3-甲基哌嗪-1-基)-2-氟-氮-甲基苯甲酰胺化合物17
(R)-4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-3-methylpiperazin-1-yl)-2-fluoro-N-methylbenzamide
按照化合物1的方法,得到化合物17(白色固体,41mg,产率:43%)。
1H NMR(400MHz,DMSO-d6)δ11.82(s,1H),8.40(d,J=4.7Hz,1H),7.75(s,2H),7.62(s,1H),7.55(t,J=8.9Hz,1H),6.82–6.68(m,2H),3.64-3.58(m,4H),3.15–3.11(m,4H),2.93-2.84(m,1H),2.74(d,J=4.7Hz,3H),2.58–2.51(m,2H),1.17(m,6H).
19F NMR(377MHz,DMSO-d6)δ-111.57.
LCMS m/s=438.2[M+1]
实施例18
(S)-4-(3-(氰甲基)-4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-2-氟-氮-甲基苯甲酰胺化合物18
(S)-4-(3-(cyanomethyl)-4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-2-fluoro-N-methylbenzamide
按照化合物1的方法,得到化合物18(白色固体,39mg,产率:45%)。
1H NMR(400MHz,DMSO-d6)δ11.81(s,1H),8.47(q,J=4.4Hz,1H),8.27(s,1H),7.91-7.63(m,3H),6.91-6.83(m,2H),3.65(s,2H),3.33–3.27(m,4H),3.13-3.09(m,4H),2.91-2.86(m,1H),2.73(d,J=4.4Hz,3H),2.59–2.53(m,2H),1.17(t,J=7.8Hz,3H).
19F NMR(377MHz,DMSO-d6)δ-111.53.
LCMS m/s=463.2[M+1].
实施例19
(R)-4-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)-3-(羟甲基)哌嗪-1-基)-2-氟-氮-甲基苯甲酰胺化合物19
(R)-4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-3-(hydroxymethyl)piperazin-1-yl)-2-fluoro-N-methylbenzamide
按照化合物1的方法,得到化合物19(白色固体,42mg,产率:43%)。
1H NMR(400MHz,DMSO-d6)δ11.81(s,1H),8.42(q,J=4.6Hz,1H),7.76(s,2H),7.65(s,1H),7.57(t,J=9.0Hz,1H),6.80–6.67(m,2H),4.77(t,J=5.2Hz,1H),3.78–3.43(m,6H),3.05–2.94(m,4H),2.75(d,J=4.6Hz,3H),2.70-2.68(m,1H),2.56-2.53(m,2H),1.18(t,J=7.4Hz,3H).
19F NMR(377MHz,DMSO-d6)δ-111.56.
LCMS m/s=454.2[M+1].
实施例20
(S)-4-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)-3-(羟甲基)哌嗪-1-基)-2-氟-氮 -甲基苯甲酰胺化合物20
(S)-4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-3-(hydroxymethyl)piperazin-1-yl)-2-fluoro-N-methylbenzamide
按照化合物1的方法,得到化合物20(白色固体,46mg,产率:45%)。
1H NMR(400MHz,DMSO-d6)δ11.83(s,1H),8.41(q,J=4.7Hz,1H),7.75(s,2H),7.64(s,1H),7.57(t,J=8.9Hz,1H),6.79–6.67(m,2H),4.79(t,J=5.2Hz,1H),3.83–3.40(m,6H),3.07-2.99(m,4H),2.74(d,J=4.7Hz,3H),2.71-2.67(m,1H),2.57–2.52(m,2H),1.17(t,J=7.4Hz,3H).
LCMS m/s=454.2[M+1].
实施例21
2-氰基-4-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N-甲基苯甲酰胺化合物21
2-cyano-4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-methylbenzamide
按照化合物1的方法,得到化合物21(白色固体,43mg,产率:44%)。
1H NMR(400MHz,DMSO-d6)δ11.85(s,1H),9.62(s,1H),8.40(q,J=4.7Hz,1H),7.91(d,J=8.5Hz,1H),7.75(s,2H),7.27–7.18(m,2H),3.64(s,2H),3.09-3.87(m,4H),2.75(d,J=4.7Hz,3H),2.54-2.51(m,6H),1.18(t,J=7.4Hz,.3H).
LCMS m/s=431.2[M+1].
实施例22
4-(1-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)-1,2,3,6-四氢吡啶-4-基)-3-氟-N-甲基苯甲酰胺化合物22
4-(1-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)-3-fluoro-N-methylbenzamide
按照化合物1的方法,得到化合物22(白色固体,39mg,产率:46%)。
1H NMR(400MHz,DMSO-d6)δ11.85(s,1H),8.51(q,J=4.5Hz,1H),8.41(s,1H),7.75(s,1H),7.70–7.57(m,3H),7.49–7.41(m,1H),6.08(s,1H),3.71(s,2H),3.14-3.12(m,2H),2.77(d,J=4.5,3H),2.69-2.64(m,2H),2.58–2.51(m,4H),1.18(d,J=7.5,3H).
19F NMR(377MHz,DMSO-d6)δ-114.94.
LCMS m/s=421.2[M+1].
实施例23
4-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N-甲基苯甲酰胺化合物23
4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-methylbenzamide
按照化合物1的方法,得到化合物23(白色固体,100mg,产率:70%)。
1H NMR(400MHz,DMSO-d6)δ11.85(s,1H),8.40(d,1H),8.13(q,1H),7.75(d,1H),7.72–7.67(m,2H),7.62(d,1H),6.97–6.90(m,2H),3.64(s,2H),3.27–3.24(m,4H),2.73(d,3H),2.57–2.52(m,6H),1.18(t,3H).
LCMS m/s=406.20[M+1].
实施例24
(R)-4-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-3-氟-氮-(四氢呋喃-3-基)苯甲酰胺化合物24
(R)-4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-3-fluoro-N-(tetrahydrofuran-3-yl)benzamide
第一步
(R)-4-溴-3-氟-N-(四氢呋喃-3-基)苯甲酰胺24B
(R)-4-bromo-3-fluoro-N-(tetrahydrofuran-3-yl)benzamide
将化合物24A(2g,9.9mmol)溶解在二氯甲烷(20mL)中,在冰水浴下,滴加入(R)-四氢呋喃-3-胺(1.73g,19.8mmol)、HATU(3.5g,14.8mmol)、三乙胺(2ml),室温下反应90min,反应完减压浓缩过柱纯化得到24B(黄色固体,2.1g,产率78%)。
LC-MS m/z(ESI)=287.10[M+1].
第二步
(R)-4-(2-氟-4-((四氢呋喃-3-基)氨甲酰)苯基)哌嗪-1-羧酸叔丁酯24C
tert-butyl(R)-4-(2-fluoro-4-((tetrahydrofuran-3-yl)carbamoyl)phenyl)piperazine-1-carboxylate
参考化合物1c的合成方法,合成分离得到化合物24C(白色固体,1.8g,产率88%)。
1H NMR(400MHz,DMSO-d6)δ8.36(dd,1H),7.80(d,1H),7.74(d,1H),7.62(d,1H),3.23–3.03(m,4H),2.86-2.71(m,3H),2.67–2.42(m,4H),2.49–2.29(m,2H),2.23(dt,1H),1.95–1.83(m,1H),1.50(s,9H).
LC-MS m/z(ESI)=394.12[M+1].
第三步
(R)-3-氟-4-(哌嗪-1-基)-氮-(四氢呋喃-3-基)苯甲酰胺24D
(R)-3-fluoro-4-(piperazin-1-yl)-N-(tetrahydrofuran-3-yl)benzamide
参考中间体1的合成方法,合成分离得到化合物24D(白色固体,1.0g,产率81%)
LC-MS m/z(ESI)=294.15[M+1].
第四步
(R)-4-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-3-氟-氮-(四氢呋喃-3-基)苯甲酰胺化合物24
(R)-4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-3-fluoro-N-(tetrahydrofuran-3-yl)benzamide
参考化合物1的合成方法,合成分离得到化合物24(白色固体,26mg,产率54%)。
1H NMR(400MHz,DMSO-d6)δ11.87(s,1H),8.40(dd,1H),8.00–7.48(m,5H),7.05(t,1H),4.41(dtt,1H),3.96–3.48(m,6H),3.23–3.00(m,4H),2.64–2.39(m,4H),2.13(dtd,1H),1.96–1.81(m,1H),1.37–1.21(m,2H),1.18(t,3H).
实施例25
(S)-4-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-3-氟-氮-(四氢呋喃-3-基)苯甲酰胺化合物25
(S)-4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-3-fluoro-N-(tetrahydrofuran-3-yl)benzamide
第一步
(S)-4-溴-3-氟-氮-(四氢呋喃-3-基)苯甲酰胺25A
(S)-4-bromo-3-fluoro-N-(tetrahydrofuran-3-yl)benzamide
参考化合物24B的合成方法,合成分离得到化合物25A(黄色固体,2.3g,产率82%)。
LC-MS m/z(ESI)=287.10[M+1].
第二步
(S)-4-(2-氟-4-((四氢呋喃-3-基)氨甲酰)苯基)哌嗪-1-羧酸叔丁酯25B
tert-butyl(S)-4-(2-fluoro-4-((tetrahydrofuran-3-yl)carbamoyl)phenyl)piperazine-1-carboxylate
参考化合物1c的合成方法,合成分离得到化合物25B(白色固体,2.5g,产率89%)。
1H NMR(400MHz,DMSO-d6)δ8.36(dd,1H),7.80(d,1H),7.74(d,1H),7.62(d,1H),3.23–3.03(m,4H),2.86-2.71(m,3H),2.67–2.42(m,4H),2.49–2.29(m,2H),2.23(dt,1H),1.95–1.83(m,1H),1.50(s,9H).
LC-MS m/z(ESI)=394.12[M+1].
第三步
(S)-3-氟-4-(哌嗪-1-基)-N-(四氢呋喃-3-基)苯甲酰胺25C
(S)-3-fluoro-4-(piperazin-1-yl)-N-(tetrahydrofuran-3-yl)benzamide
参考中间体1的合成方法,合成分离得到化合物25C(白色固体,1.6g,产率83%)
LC-MS m/z(ESI)=294.15[M+1].
第四步
(S)-4-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-3-氟-氮-(四氢呋喃-3-基)苯甲酰胺化合物25
(S)-4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-3-fluoro-N-(tetrahydrofuran-3-yl)benzamide
参考化合物1的合成方法,合成分离得到化合物25(白色固体,19mg,产率42%)。
1H NMR(400MHz,DMSO-d6)δ11.87(s,1H),8.40(dd,1H),8.00–7.48(m,5H),7.05(t,1H),4.41(dtt,1H),3.96–3.48(m,6H),3.23–3.00(m,4H),2.64–2.39(m,4H),2.13(dtd,1H),1.96–1.81(m,1H),1.37–1.21(m,2H),1.18(t,3H)
实施例26
4-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-3-氟-N-(2-羟乙基)苯甲酰胺化合物26
4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-3-fluoro-N-(2-hydroxyethyl)benzamide
第一步
4-溴-3-氟-N-(2-羟乙基)苯甲酰胺26A
4-bromo-3-fluoro-N-(2-hydroxyethyl)benzamide
参考化合物24B的合成方法,合成分离得到化合物26A(黄色固体,2.5g,产率82%)。
LC-MS m/z(ESI)=261.98[M+1].
第二步
4-(2-氟-4-((2-羟乙基)氨基甲酰基)苯基)哌嗪-1-羧酸叔丁酯26B
tert-butyl 4-(2-fluoro-4-((2-hydroxyethyl)carbamoyl)phenyl)piperazine-1-carboxylate
参考化合物1c的合成方法,合成分离得到化合物26B(白色固体,2.2g,产率83%)。
1H NMR(400MHz,DMSO-d6)δ8.35(d,1H),7.78(d,1H),7.42–7.12(m,2H),5.41(s,1H),3.15(s,6H),2.65–2.42(m,6H),1.51(s,9H).
LC-MS m/z(ESI)=394.12[M+1].
第三步
3-氟-4-(哌嗪-1-基)-氮-(四氢呋喃-3-基)苯甲酰胺26C
3-fluoro-4-(piperazin-1-yl)-N-(tetrahydrofuran-3-yl)benzamide
参考中间体1的合成方法,合成分离得到化合物26C(白色固体,1.6g,产率83%)
LC-MS m/z(ESI)=254.12[M+1].
第四步
4-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-3-氟-N-(2-羟乙基)苯甲酰胺化合物26
4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-3-fluoro-N-(2-hydroxyethyl)benzamide
参考化合物1的合成方法,合成分离得到化合物26(白色固体,19mg,产率42%)。
1H NMR(400MHz,DMSO-d6)δ8.41(d,1H),8.17(d,1H),7.75(d,1H),7.64(d,1H),7.42–7.14(m,2H),5.25(s,1H),4.44(d,2H),3.69(s,3H),3.19(s,6H),2.69–2.51(m,7H),1.17(t,3H).
实施例27
4-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-2-氟-氮-(2-羟乙基)苯甲酰胺化合物27
4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-2-fluoro-N-(2-hydroxyethyl)benzamide
按照化合物1的方法,制备得到化合物27(白色固体,42mg,产率:74%)。
1H NMR(400MHz,DMSO-d6)δ11.87(s,1H),8.40(s,1H),7.75(s,1H),7.69(s,1H),7.62(s,1H),7.58(d,J=9.0Hz,1H),6.79(d,J=9.4Hz,1H),6.74(d,J=15.3Hz,1H),4.74(t,J=5.4Hz,1H),3.63(d,J=4.6Hz,2H),3.47(t,J=5.6Hz,2H),3.29(d,J=4.8Hz,8H),2.54(d,J=8.1Hz,4H),1.18(t,J=7.4Hz,3H).
LCMS m/s=454.52[M+1].
实施例28
4-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-2-氟-N-(2-甲氧基乙基)苯甲酰胺化合物28
4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-2-fluoro-N-(2-methoxyethyl)benzamide
按照化合物1的方法,制备得到化合物28(白色固体,42mg,产率:74%)。
1H NMR(400MHz,DMSO-d6)δ11.85(s,1H),8.40(d,J=1.8Hz,1H),7.75(s,1H),7.73(s,1H),7.62(d,J=1.8Hz,1H),7.57(t,J=9.0Hz,1H),6.79(dd,J=8.8,2.4Hz,1H),6.77–6.71(m,1H),3.64(s,2H),3.46–3.34(m,6H),3.28(d,J=5.4Hz,4H),3.26(s,3H),2.57–2.52(m,4H),1.18(t,J=7.4Hz,3H).
LCMS m/s=468.55[M+1].
实施例29
4-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-2-氟-氮-(1-甲基氮杂环丁烷-3-基)苯甲酰胺化合物29
4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-2-fluoro-N-(1-methylazetidin-3-yl)benzamide
按照化合物1的方法,制备得到化合物29(白色固体,11mg,产率:63%)。
1H NMR(400MHz,DMSO-d6)δ11.87(s,1H),8.59–8.50(m,2H),7.80(s,1H),7.76(s,1H),7.64(td,J=8.9,2.8Hz,1H),6.95–6.84(m,2H),4.85–4.71(m,1H),4.53–4.29(m,4H),4.09(d,J=40.8Hz,4H),3.22(s,4H),2.88(dd,J=7.4,4.7Hz,3H),2.60(s,4H),1.19(t,J=7.4Hz,3H).
LCMS m/s=479.57[M+1].
实施例30
4-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-2-氟-氮-(氧代烷-3-基)苯甲酰胺化合物30
4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-2-fluoro-N-(oxetan-3-yl)benzamide
按照化合物1的方法,制备得到化合物30(白色固体,17mg,产率:64%)。
1H NMR(400MHz,DMSO-d6)δ11.93(s,1H),9.37(s,1H),8.43(s,1H),7.75(s,1H),7.66(d,J=8.0Hz,2H),6.84–6.73(m,2H),4.85(t,J=5.6Hz,1H),4.42–4.21(m,2H),4.18(q,J=7.1,6.3Hz,2H),3.59(ddt,J=10.0,7.4,3.3Hz,4H),3.45(d,J=15.0Hz,2H),3.11(qd,J=7.4,4.1Hz,2H),2.56(s,4H),1.17(t,J=7.4Hz,3H).
LCMS m/s=466.53[M+1].
实施例31
N-(2-(二甲氨基)乙基)-4-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-2-氟苯甲酰胺化合物31
N-(2-(dimethylamino)ethyl)-4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-2-fluorobenzamide
按照化合物1的方法,制备得到化合物31(白色固体,16mg,产率:57%)。
1H NMR(400MHz,DMSO-d6)δ11.87(s,1H),8.59(d,J=1.8Hz,1H),8.24(d,J=5.8Hz,1H),7.82(d,J=5.2Hz,2H),7.66(t,J=8.8Hz,1H),6.93–6.85(m,2H),4.76(s,2H),3.78(d,J=6.4Hz,2H),3.52(d,J=5.7Hz,6H),3.22(d,J=5.4Hz,4H),3.08(s,6H),2.59(t,J=7.4Hz,2H),1.18(d,J=7.3Hz,3H).
LCMS m/s=481.59[M+1].
实施例32
4-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-2-氟-氮-(氧代烷-3-基)苯甲酰胺化合物32
4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-2-fluoro-N-(oxetan-3-yl)benzamide
按照化合物1的方法,制备得到化合物32(白色固体,68mg,产率:72%)。
1H NMR(400MHz,DMSO-d6)δ11.07(s,1H),8.40(d,J=1.9Hz,1H),8.06–7.99(m,1H),7.75(s,1H),7.61(d,J=1.8Hz,1H),7.39(dd,J=13.5,6.8Hz,1H),6.89(dd,J=12.7,7.1Hz,1H),3.64(s,2H),3.13(t,J=4.8Hz,4H),2.75(d,J=4.5Hz,3H),2.54(d,J=8.5Hz,6H),1.18(t,J=7.4Hz,3H).
LCMS m/s=442.48[M+1].
实施例33
4-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-2,5-二氟-氮-甲基苯甲酰胺化合物33
4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-2,5-difluoro-N-methylbenzamide
按照化合物1的方法,制备得到化合物33(白色固体,57mg,产率:64%)。
1H NMR(400MHz,DMSO-d6)δ11.07(s,1H),8.37(d,J=1.9Hz,1H),8.06–7.99(m,1H),7.75(s,1H),7.61(d,J=1.8Hz,1H),7.29(dd,J=13.5,6.8Hz,1H),6.89(dd,J=12.7,7.1Hz,1H),3.64(s,2H),3.13(t,J=4.8Hz,4H),2.75(d,J=4.5Hz,3H),2.54(d,J=8.5Hz,6H),1.18(t,J=7.4Hz,3H).
LCMS m/s=442.48[M+1].
实施例34
4-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-3-氟-N-(2-甲氧基乙基)苯甲酰胺化合物34
4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-3-fluoro- N-(2-methoxyethyl)benzamide
按照化合物1的方法,制备得到化合物34(白色固体,36mg,产率:68%)。
1H NMR(400MHz,DMSO-d6)δ11.87(s,1H),8.43(t,J=5.3Hz,1H),8.40(d,J=1.8Hz,1H),7.75(s,1H),7.66–7.58(m,3H),7.05(t,J=8.7Hz,1H),3.64(s,2H),3.44-3.38(m,4H),3.25(s,3H),3.16–3.08(m,4H),2.60–2.52(m,6H),1.18(t,J=7.4Hz,3H).
LCMS m/s=468.23[M+1].
实施例35
4-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-3-氟-N-((1s,3s)-3-羟基环丁基)苯甲酰胺化合物35
4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-3-fluoro-N-((1s,3s)-3-hydroxycyclobutyl)benzamide
按照化合物1的方法,制备得到化合物35(白色固体,41mg,产率:65%)。
1H NMR(400MHz,DMSO-d6)δ11.87(s,1H),8.44(s,1H),8.40(d,J=1.8Hz,1H),7.75(s,1H),7.67–7.60(m,3H),7.04(t,J=8.8Hz,1H),5.10(d,J=5.5Hz,1H),3.90–3.80(m,2H),3.65(s,2H),3.17-3.11(m,4H),2.59–2.52(m,6H),1.92-1.85(m,2H),1.28–1.23(m,2H),1.18(t,J=7.4Hz,3H).
19F NMR(377MHz,DMSO-d6)δ-122.18.
LCMS m/s=480.23[M+1].
实施例36
4-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-3-氟-N-((1r,3r)-3-羟基环丁基)苯甲酰胺化合物36
4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-3-fluoro-N-((1r,3r)-3-hydroxycyclobutyl)benzamide
按照化合物1的方法,制备得到化合物36(白色固体,44mg,产率:68%)。
1H NMR(400MHz,DMSO-d6)δ11.87(s,1H),8.45(d,J=6.8Hz,1H),8.40(d,J=1.8Hz,1H),7.75(s,1H),7.64-7.60(m,3H),7.05(t,J=8.7Hz,1H),5.02(d,J=5.3Hz,1H),4.45–4.26(m,2H),3.65(s,2H),3.19–3.08(m,4H),2.58-2.53(m,6H),2.27-2.21(m,2H),2.16-2.09m,2H),1.18(t,J=7.4Hz,3H).
LCMS m/s=480.23[M+1].
实施例37
4-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-3-氟-N-(2-甲氧基乙基)苯甲酰胺化合物37
4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-3-fluoro-N-(2-methoxyethyl)benzamide
按照化合物1的方法,制备得到化合物37(白色固体,32mg,产率:84%)。
1H NMR(400MHz,DMSO-d
6)δ11.87(s,1H),8.40(d,1H),8.19(t,1H),7.75(d,1H),7.66(d,1H),7.65–7.60(m,2H),7.06(t,1H),4.56(s,1H),3.65(s,2H),3.22(d,2H),3.11(d,4H),2.61–2.51(m,6H),1.18(t,3H),1.07(s,6H).
LCMS m/s=482.57[M+1].
实施例38
(S)-4-(4-((7-氯-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-3-氟-N-(四氢呋喃-3-基)苯甲酰胺化合物38
(S)-4-(4-((7-chloro-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-3-fluoro-N-(tetrahydrofuran-3-yl)benzamide
第一步
7-氯-6-氧代-5,6-二氢-1,5-萘啶-3-羧酸乙酯38A
ethyl 7-chloro-6-oxo-5,6-dihydro-1,5-naphthyridine-3-carboxylate
将中间体10D(1g,2.9mmol)在室温下加入到盐酸-1,4-二氧六环溶液(10mL,4mol/L)中,在80℃下反应16小时,反应完成后过滤得到38A(黄色固体,700mg,产率95%)。
LC-MS m/z(ESI)=253.00[M+1].
第二步
3-氯-7-(羟甲基)-1,5-萘啶-2(1H)-酮38B
3-chloro-7-(hydroxymethyl)-1,5-naphthyridin-2(1H)-one
参考化合物10G的合成方法,得到中间体38B(黄色固体,500mg,产率85%)。
1H NMR(400MHz,DMSO-d
6)δ12.50(dr,1H),8.45(d,1H),8.27(d,1H),7.68(d,1H),5.53(dr,1H),4.64(d,2H).
LC-MS m/z(ESI)=211.00[M+1].
第三步
7-(溴甲基)-3-氯-1,5-萘啶-2(1H)-酮38C
7-(bromomethyl)-3-chloro-1,5-naphthyridin-2(1H)-one
参考化合物10H的合成方法,得到中间体38C(黄色固体,400mg,产率62%)。
LC-MS m/z(ESI)=273.00[M+1].
第四步
(S)-4-(4-((7-氯-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-3-氟-N-(四氢呋喃-3-基)苯甲酰胺化合物38
(S)-4-(4-((7-chloro-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-3-fluoro-N-(tetrahydrofuran-3-yl)benzamide
按照化合物1的方法,制备得到化合物38(白色固体,20mg,产率:20%)。
1H NMR(400MHz,DMSO-d
6)δ11.89(dr,1H),8.46(d,1H),8.41(d,1H),7.80–7.48(m,3H),7.44(s,1H),6.79(d,1H),4.42(dtt,1H),3.96–3.50(m,6H),3.25–3.01(m,4H), 2.64–2.39(m,2H),2.12(dtd,1H),1.94–1.81(m,1H),1.38–1.22(m,2H).
LCMS m/s=486.20[M+1].
实施例39
4-(4-((7-氯-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)3-氟-N-(2-羟乙基)苯甲酰胺化合物39
4-(4-((7-chloro-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-3-fluoro-N-(2-hydroxyethyl)benzamide
按照化合物1的方法,制备得到化合物39(白色固体,25mg,产率:28%)。
1H NMR(400MHz,DMSO-d
6)δ11.87(s,1H),8.47(d,1H),8.40(d,1H),7.79(d,1H),7.70(d,1H),7.60(t,1H),7.58(d,1H),6.75(d,1H),4.74(t,1H),3.63(d,2H),3.47(t,2H),3.29–3.18(m,6H),2.54–2.48(m,4H).
LCMS m/s=460.20[M+1].
实施例40
4-(1-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌啶-4-基)-3-氟-N-甲基苯甲酰胺化合物40
4-(1-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperidin-4-yl)-3-fluoro-N-methylbenzamide
按照化合物1的方法,制备得到化合物40(白色固体,28mg,产率:81%)。
1H NMR(400MHz,DMSO-d
6)δ11.85(s,1H),8.46(d,1H),8.39(s,1H),7.75(s,1H),7.68–7.51(m,3H),7.44(t,1H),3.61(s,2H),2.93-2.82(m,3H),2.77(d,3H),2.56-2.52(m,2H),2.14-2.10(m,2H),1.75-1.72(m,4H),1.18(t,3H).
LCMS m/s=423.21[M+1].
实施例41
(S)-4-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-3-氟-N-(2-羟丙基)苯甲酰胺化合物41
(S)-4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-3-fluoro-N-(2-hydroxypropyl)benzamide
按照化合物1的方法,制备得到化合物41(白色固体,42mg,产率:77%)。
1H NMR(400MHz,DMSO-d
6)δ11.86(s,1H),8.40(d,1H),8.32(t,1H),7.75(d,1H),7.65-7.60(m,3H),7.05(t,1H),4.73(d,1H),3.80–3.72(m,1H),3.65(s,2H),3.18-3.14(m,2H),3.12-3.10(m,4H),2.60–2.52(m,6H),1.18(t,3H),1.04(d,3H).
LCMS m/s=468.23[M+1].
实施例42
(R)-4-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-3-氟-N-(2-羟丙基)苯甲酰胺化合物42
(R)-4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-3-fluoro-N-(2-hydroxypropyl)benzamide
按照化合物1的方法,制备得到化合物42(白色固体,54mg,产率:82%)。
1H NMR(400MHz,DMSO-d
6)δ11.86(s,1H),8.40(d,1H),8.31(t,1H),7.75(d,1H),7.64-7.60(m,3H),7.05(t,1H),4.73(d,1H),3.80–3.71(m,1H),3.65(s,2H),3.18-3.14(m,2H),3.12-3.10(m,4H),2.60–2.52(m,6H),1.18(t,3H),1.04(d,3H).
LCMS m/s=468.23[M+1].
实施例43
6-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N-(2-羟乙基)烟酰胺化合物43
6-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(2-hydroxyethyl)nicotinamide
按照化合物1的方法,制备得到化合物43(白色固体,44mg,产率:73%)。
1H NMR(400MHz,DMSO-d
6)δ11.86(s,1H),8.40(d,1H),8.31(t,1H),7.75(d,1H),7.64-7.60(m,3H),7.05(t,1H),4.73(d,1H),3.80–3.71(m,1H),3.65(s,2H),3.18-3.14(m,2H),3.12-3.10(m,4H),2.60–2.52(m,6H),1.18(t,3H),1.04(d,J=6.2Hz,3H).
LCMS m/s=437.22[M+1].
实施例44
4-氯-4-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N-甲基苯甲酰胺化合物44
4-chloro-4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-methylbenzamide
按照化合物1的方法,制备得到化合物44(白色固体,49mg,产率:88%)。
1H NMR(400MHz,DMSO-d
6)δ11.88(s,1H),8.59–8.25(m,2H),7.86(d,1H),7.76(d,2H),7.66–7.57(m,1H),7.18(d,1H),3.66(s,2H),3.05(s,4H),2.75(d,3H),2.64–2.51(m,6H),1.19(q,3H).
LCMS m/s=440.18[M+1].
实施例45
4-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-3-氟-N-((1-羟基环丙基)甲基)苯甲酰胺化合物45
4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-3-fluoro-N-((1-hydroxycyclopropyl)methyl)benzamide
按照化合物1的方法,制备得到化合物45(白色固体,37mg,产率:71%)。
1H NMR(400MHz,DMSO-d
6)δ11.87(s,1H),8.70(t,1H),8.40(d,1H),7.75(s,1H),7.71–7.56(m,3H),7.08(t,1H),4.37–3.98(m,5H),3.65(s,2H),3.23–3.05(m,4H),2.62–2.51(m,4H),2.46(t,2H),1.42(s,2H),0.94(t,3H).
LCMS m/s=480.56[M+1].
实施例46
4-(4-((7-环丙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-3-氟-N-(2-甲氧基乙基)苯甲酰胺化合物46
4-(4-((7-cyclopropyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-3-fluoro-N-(2-methoxyethyl)benzamide
按照化合物1的方法,制备得到化合物46(白色固体,34mg,产率:65%)。
1H NMR(400MHz,DMSO-d
6)δ11.90(s,1H),8.43(t,1H),8.37(d,1H),7.69–7.53(m,3H),7.41(s,1H),7.04(t,1H),3.62(s,2H),3.41(dd,4H),3.25(s,3H),3.10(t,4H),2.55(t,4H),2.13(tt,1H),0.96(dt,2H),0.86–0.72(m,2H).
LCMS m/s=480.23[M+1].
实施例47
(R)-4-(4-((7-环丙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-3-氟-N-(四氢呋喃-3-基)苯甲酰胺化合物47
(R)-4-(4-((7-cyclopropyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-3-fluoro-N-(tetrahydrofuran-3-yl)benzamide
按照化合物1的方法,制备得到化合物47(白色固体,33mg,产率:64%)。
1H NMR(400MHz,DMSO-d
6)δ11.88(s,1H),8.41(t,1H),8.37(dd,1H),7.65–7.51(m,3H),7.41(s,1H),7.04(t,1H),4.43(dtt,1H),3.92–3.44(m,3H),3.21–3.00(m,4H),2.64–2.39(m,3H),2.13(dtd,1H),1.96–1.81(m,1H),1.33–1.20(m,2H),1.15(t,3H).0.95(dt,2H),0.85–0.70(m,2H).
LCMS m/s=492.23[M+1].
实施例48
4-(4-((7-环丙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-3-氟-N-(2-羟乙基)苯甲酰胺化合物48
4-(4-((7-cyclopropyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-3-fluoro-N-(2-hydroxyethyl)benzamide
按照化合物1的方法,制备得到化合物48(白色固体,31mg,产率:62%)。
1H NMR(400MHz,DMSO-d
6)δ11.89(s,1H),8.46–8.27(m,2H),7.68–7.56(m,3H),7.42(s,1H),7.05(t,1H),4.74(t,1H),3.63(s,2H),3.48(dd,2H),3.29(d,2H),2.56(t,4H),2.20–2.07(m,2H),1.23(s,3H),1.02–0.90(m,2H),0.87–0.74(m,2H).
LCMS m/s=466.22[M+1].
实施例49
(R)-6-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N-(四氢呋喃-3-基)烟酰胺化合物49
(R)-6-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(tetrahydrofuran-3-yl)nicotinamide
按照化合物1的方法,制备得到化合物49(白色固体,41mg,产率:65%)。
1H NMR(400MHz,DMSO-d
6)δ11.87(s,1H),8.60(d,1H),8.40(d,1H),8.28(d,1H),7.97(dd,1H),7.75(s,1H),7.62(d,1H),6.84(d,1H),4.47–4.38(m,1H),3.86-3.81(m,2H),3.72-3.66(m,1H),3.63(s,2H),3.61-3.59(m,4H),3.56-3.52(m,1H),2.59–2.52(m,2H),2.49-2.47(m,4H),2.19–2.07(m,1H),1.94–1.83(m,1H),1.18(t,3H).
LCMS m/s=463.24[M+1].
实施例50
5-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N-甲基吡嗪-2-甲酰胺化合物50
5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-methylpyrazine-2-carboxamide
按照化合物1的方法,得到化合物50(白色固体,37mg,产率:76%)。
1H NMR(400MHz,DMSO-d
6)δ11.86(s,1H),8.59(d,1H),8.40(d,1H),8.34(d,1H),8.26(d,1H),7.75(s,1H),7.62(d,1H),3.70(t,4H),3.65(s,2H),2.77(d,3H),2.58–2.51(m,6H),1.18(t,3H).
LCMS m/s=408.48[M+1].
实施例51
6-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-5-氟-N-甲基烟酰胺化合物51
6-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-5-fluoro-N-methylnicotinamide
按照化合物1的方法,得到化合物51(白色固体,31mg,产率:67%)。
1H NMR(400MHz,DMSO-d
6)δ8.52–8.32(m,3H),7.92–7.52(m,4H),3.59(d,6H),3.17(d,2H),2.76(d,3H),2.52(s,4H),1.18(t,3H).
LCMS m/s=404.49[M+1].
实施例52
4-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-3,5-二氟-N-甲基苯甲酰胺化合物52
4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-3,5-difluoro-N-methylbenzamide
按照化合物1的方法,得到化合物52(白色固体,50mg,产率:32%)。
1H NMR(400MHz,DMSO-d
6)δ11.84(s,1H),8.45(q,1H),8.39(d,H),7.74(d,1H),7.63(d,1H),7.50(s,1H),7.47(s,1H),3.64(s,2H),3.23-3.17(m,4H),2.75(d,3H),2.57-2.51(m,6H),1.18(t,3H).
LCMS m/s=442.20[M+1].
实施例53
2-氯-4-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-5-氟-N-甲基苯甲酰胺化合物53
2-chloro-4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-5-fluoro-N-methylbenzamide
按照化合物1的方法,得到化合物53(白色固体,40mg,产率:45%)。
1H NMR(400MHz,DMSO-d
6)δ11.86(s,1H),8.40(s,1H),8.27–8.22(m,1H),7.75(s,1H),7.61(s,1H),7.26(d,1H),7.03(d,1H),3.65(s,2H),3.11–3.05(m,4H),2.72(d,3H),2.63–2.52(m,6H),1.18(t,3H).
LCMS m/s=458.20[M+1].
实施例54
2,6-二氯-4-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N-甲基苯甲酰胺化合物54
2,6-dichloro-4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-methylbenzamide
按照化合物1的方法,得到化合物54(白色固体,15mg,产率:14%)。
1H NMR(400MHz,DMSO-d
6)δ11.86(s,1H),8.39(d,1H),8.37–8.31(m,1H),7.75(s,1H),7.61(d,1H),6.96(s,2H),3.63(s,2H),3.27–3.21(m,4H),2.71(d,3H),2.58–2.51(m,6H),1.18(t,3H).
LCMS m/s=474.10[M+1].
实施例55
(R)-3-氯-4-(4-((7-甲基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N-(四氢呋喃-3-基)苯甲酰胺化合物55
(R)-3-chloro-4-(4-((7-methyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(tetrahydrofuran-3-yl)benzamide
按照化合物1的方法,制备得到化合物55(白色固体,36mg,产率:67%)。
1H NMR(400MHz,DMSO-d6)δ11.87(s,1H),8.50(d,1H),8.40(d,1H),7.93(d,1H),7.85–7.76(m,2H),7.62(d,1H),7.18(d,1H),4.48–4.36(m,1H),3.87–3.79(m,2H),3.75–3.63(m,3H),3.56(dd,1H),3.06(s,4H),2.58(s,4H),2.13(d,3H),2.09(d,1H),1.94–1.85(m,1H).
LCMS m/s=482.98[M+1].
实施例56
3-氯-4-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N-((3S,4R)-4-羟基四氢呋喃-3-基)苯甲酰胺化合物56
3-chloro-4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)benzamide
按照化合物1的方法,制备得到化合物56(白色固体,30mg,产率:62%)。
1H NMR(400MHz,DMSO-d
6)δ11.86(s,1H),8.55–8.30(m,2H),7.93(d,1H),7.80(dd,1H),7.75(s,1H),7.62(s,1H),7.19(d,1H),5.27(d,1H),4.18(d,2H),3.98(dd,1H),3.89(dd,1H),3.66(s,2H),3.61(dd,1H),3.52(dd,1H),3.06(s,4H),2.58-2.50(m,6H),1.18(t,3H).
LCMS m/s=512.21[M+1].
实施例57
3-氯-4-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N-((3S,4R)-4-羟基四氢呋喃-3-基)苯甲酰胺化合物57
3-chloro-4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)benzamide
按照化合物1的方法,制备得到化合物57(白色固体,34mg,产率:71%)。
1H NMR(400MHz,DMSO-d
6)δ11.86(s,1H),8.56–8.31(m,2H),7.91(d,1H),7.80(dd,1H),7.76(s,1H),7.61(s,1H),7.15(d,1H),4.18(d,2H),3.98(dd,1H),3.89(dd,1H),3.66(s,2H),3.61(dd,1H),3.52(dd,1H),3.06(s,4H),2.58-2.50(m,6H),1.39(s,3H)1.18(t,3H).
LCMS m/s=510.22[M+1].
实施例58
N-(3-恶唑环[3.1.0]己烷-6-基)-3-氯-4-(4-((7-乙基-6-氧-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)苯甲酰胺化合物58
N-(3-oxabicyclo[3.1.0]hexan-6-yl)-3-chloro-4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)benzamide
按照化合物1的方法,制备得到化合物58(白色固体,30mg,产率:58%)。
1H NMR(400MHz,DMSO-d
6)δ11.87(s,1H),8.50–8.37(m,2H),7.86(d,1H),7.81–7.70(m,2H),7.62(s,1H),7.19(d,1H),3.85(d,2H),3.72–3.52(m,4H),3.06(s,4H),2.69–2.53(m,7H),1.90–1.83(m,2H),1.18(t,3H).
LCMS m/s=508.20[M+1].
生物学试验
1.PARP1/PARP2 trapping实验操作:
1.1 PARP1 trapping实验:
(1)用缓冲液制备4×PARP1(购买自BPS Bioscience公司,货号:80501)和Mab anti GST-Tb(购买自cisbio公司,货号:61GSTTLA)混合液,向384孔板(购买自Greiner公司,货号:784075)中加入该混合液4μL/孔;
(2)用缓冲液制备4×DSB DNA probe-1(购买自Generay),向384孔板中加入4μL/孔;
(3)向384孔板中加入4μL/孔抑制(初始浓度为10μM,按1:5倍比稀释10个浓度),室温孵育1h;
(4)用缓冲液制备4×NAD(购买自Sigma公司,货号:10127965001),向384孔板中加入4μL/孔,室温孵育10min;
(5)结果采用TR-FRET检测,利用GraphPad 5.0拟合曲线,并进行IC
50的计算。
1.2 PARP2 trapping实验:
(1)用缓冲液制备4×PARP2(购买自BPS Bioscience公司,货号:80502)和Mab anti GST-Tb(购买自cisbio公司,货号:61GSTTLA)混合液,向384孔板(购买自Greiner公司,货号:784075)中加入该混合液4μL;
(2)用缓冲液制备4×PARP2 probe2(购买自Generay公司),向384孔板中加入4μL/孔;
(3)向384孔板中加入4μL/孔抑制(初始浓度为10μM,按1:5倍比稀释10个浓度),室温孵育45min;
(4)用缓冲液制备4×NAD(购买自Sigma公司,货号:10127965001),向384孔板中加入4μL/孔,室温孵育10min;
(5)结果采用TR-FRET检测,利用GraphPad 5.0拟合曲线,并进行IC
50的计算。
注:对照例1为J.Med.Chem(2021),64(19)14498–14512的化合物25,对照例按照其制备方法制备得到。
结论:本发明化合物对PARP1 trapping具有显著抑制活性,且相对于PARP2 trapping具有良好的选择性。
2.PARP1、PARP2活性抑制试验
通过PARP1 Chemiluminescent assay(购买自BPS Bioscience公司,货号:80551)、PARP2 Chemiluminescent assay(购买自BPS Bioscience公司,货号:80552)分别检测化合物对PARP1、PARP2的抑制活性。利用化学发光对结果进行定量,具体实验方案如下:
(1)使用1×histone mixture(50μL/孔)对96孔板进行过夜包被;
(2)弃包被液;每孔加入Blocking buffer 3(200μL),室温孵育90min;
(3)弃封闭液,PBST洗2遍;加25μL主混合物(含2.5μL 10×PARP buffer、2.5μL 10×PARP Assay mixture、5μL活化DNA、15μL ddH2O)、5μL抑制剂(抑制剂初始浓度为10μM,按1:5倍比稀释8个浓度)、20μL酶(2ng/μL);室温孵育1h;
(4)弃液体,PBST洗2遍;加入Streptavidin-HRP(Blocking buffer 3稀释50倍)50μL;室温孵育30min;
(5)弃液体,PBST洗3遍;加入100μL ELISA ECL Substrate A/B mix(各50μL);
(6)酶标仪检测结果,利用GraphPad Prism 8进行IC
50的计算。
结果表明,本发明化合物对PARP1具有显著的抑制活性,且相对于PARP2具备良好的选择性。
3.DLD1 BRCA2-/-细胞增殖抑制实验
1640(10%FBS,1%PS)培养基培养DLD-1BRCA2-/-细胞(购买自Horizon Discovery Ltd.公司),培养条件为37℃,5%CO
2。当细胞生长至对数生长期时,重悬细胞,并用1640培养基稀释至15000个/mL。使用Echo移液器向384孔白板(PerkinElmer)中每孔加入40nL待测化合物(终浓度分别为10μM、2μM、400nM、80nM、16nM、3.2nM、0.64nM、0.128nM、0.0256nM、0.00512nM);每个浓度梯度做2个重复,设置对照组1(加入0.1%DMSO)和对照组2(空白培养基)。随后384孔白板(PerkinElmer)每孔加入40μL(600个)细胞悬液(对照组2不加细胞)。
将上述384孔板置于CO
2培养箱(37℃,5%CO
2)中继续培养7天,取出384孔板,室温放置30min。每孔加入20μL Celltiter Glo检测液,震板机震荡2min,室温放置30min。酶标仪(PerkinElmer;EnVision)测定化学发光值。
GraphPad Prism 8.0进行曲线拟合和IC
50计算。酶标仪检测结果,利用GraphPad Prism 8进行IC
50的计算。
结果表明,本发明化合物对DLD1BRCA2-/-细胞增殖具有明显抑制作用。
4.MDA-MB-436细胞增殖抑制实验
DMEM培养基(10%FBS,1%PS)培养MDA-MB-436细胞(供应商ATCC),培养条件为37℃,5%CO
2。当细胞生长至对数生长期时,用DMEM培养基重悬并稀释细胞至1500个/ml。384孔板中以每孔40μL加入待测化合物(终浓度分别为10000nM、2000nM、400nM、80nM、16nM、3.2nM、0.64nM、0.128nM、0.0256nM、0.00512nM);每个浓度梯度做2个重复,设置对照组1(加入0.1%DMSO)和对照组2(空白培养基)。随后向384孔板中加入40μL细胞悬液(对照组2不加细胞)。
将上述384孔板置于培养箱(37℃,5%CO
2)中连续培养7天,然后取出384孔板,室温放置30min。每孔加入30μL Celltiter Glo assay kit检测液,震板机震荡3min,室温放置30min。酶标仪(PerkinElmer;EnVision)测定化学发光值。
检测结果用GraphPad Prism 8进行曲线拟合和IC
50的计算。
对照例2根据专利WO200905337的化合物62的合成方法制备得到。
结果表明,本发明化合物对MDA-MB-436细胞增殖具有明显抑制作用。
本发明说明书对具体实施方案进行了详细描述,本领域技术人员应认识到,上述实施方案是示例性的,不能理解为对本发明的限制,对于本领域技术人员来说,在不脱离本发明原理的前提下,通过对本发明进行若干改进和修饰,这些改进和修饰获得技术方案也落在本发明的权利要求书的保护范围内。
Claims (10)
- 一种通式(I)所示的化合物或者其立体异构体:其中:R a0选自卤素、C 1-6烷基、C 3-8环烷基、C 3-8杂环烷基、C 2-6烯基或者C 2-6炔基,所述的C 1-6烷基、C 3-8环烷基、C 3-8杂环烷基、C 2-6烯基或者C 2-6炔基任选地进一步被1个或者多个选自卤素或者C 1-6烷基的取代基取代;R a1选自H、卤素或者C 1-6烷基,所述的C 1-6烷基任选地进一步被1个或者多个选自卤素或者C 1-6烷基的取代基取代;L a1、L a2、L a3各自独立地为N或者CR L;R L选自H、卤素、羟基、氰基、C 1-6烷基、C 1-6烷氧基或者C 3-8环烷基;L选自-NH-、-CO-或者-(CR 1R 2) n-;R 1、R 2各自独立地选自H或C 1-6烷基,所述的C 1-6烷基任选地进一步被1个或者多个选自卤素、羟基或者氰基的取代基取代;B为4至12元杂环,所述的4至12元杂环选自4至12元单环、5至12元螺环、4至12元并环或者4至12元桥环,所述的4至12元杂环可以包含1至4个选自N、O或S的杂原子,且可以任选地进一步被1个或者多个R b取代;R b选自H、羟基、氰基或C 1-6烷基,所述C 1-6烷基任选地进一步被1个或者多个选自羟基、卤素或者氰基的取代基取代;或者,任意两个R b可以形成3至8元环;X 1、X 2、X 3各自独立地选自CH或者N,所述的X 1或者X 2为CH时,可以任选地进一步被卤素取代,且当X 3选自N时,X 1和X 2不能同时为CH;R 3、R 4各自独立地选自H、卤素、氰基或者C 1-6烷基;R c选自H、C 1-6烷基、C 1-6烷氧基、C 3-8环烷基或者C 3-8杂环烷基,所述C 1-6烷基、C 1-6烷氧基、C 3-8环烷基或者C 3-8杂环烷基任选地进一步被1个或者多个选自D、卤素、羟基、氰基、NR c1R c2、C 1-6烷基、C 1-6烷氧基、C 3-8环烷基或者C 3-8杂环烷基的取代基取代;R c1、R c2各自独立地选自H或者C 1-6烷基;n为1或者2;条件是:所述的通式(I)化合物任选进一步被1个或者多个氘取代。
- 根据权利要求1所述的化合物或者其立体异构体,所述的化合物选自通式(II)所示的化合物或者其立体异构体:其中:R a0选自卤素、C 1-6烷基、C 3-8环烷基、C 3-8杂环烷基、C 2-6烯基或者C 2-6炔基,所述的C 1-6烷基、C 3-8环烷基、C 3-8杂环烷基、C 2-6烯基或者C 2-6炔基任选地进一步被1个或者多个选自卤素或者C 1-6烷基的取代基取代;R a1选自H、卤素或者C 1-6烷基,所述的C 1-6烷基任选地进一步被1个或者多个选自卤素或者C 1-6烷基的取代基取代;Z 1、Z 2各自独立地为N或者CR L;R L选自H、卤素、羟基、氰基、C 1-6烷基、C 1-6烷氧基或者C 3-8环烷基;L选自-NH-、-CO-或者-(CR 1R 2) n-;R 1、R 2各自独立地选自H或C 1-6烷基,所述的C 1-6烷基任选地进一步被1个或者多个选自卤素、羟基或者氰基的取代基取代;B为4至12元杂环,所述的4至12元杂环选自4至12元单环、5至12元螺环、4至12元并环或者4至12元桥环,所述的4至12元杂环可以包含1至4个选自N、O或S的杂原子,且可以任选地进一步被1个或者多个R b取代;R b选自H、羟基、氰基或C 1-6烷基,所述C 1-6烷基任选地进一步被1个或者多个选自羟基、卤素或者氰基的取代基取代;或者,任意两个R b可以形成3至8元环;X 1、X 2、X 3各自独立地选自CH或者N,所述的X 1或者X 2为CH时,可以任选地进一步被卤素取代,且当X 3选自N时,X 1和X 2不能同时为CH;R 3、R 4各自独立地选自H、卤素、氰基或者C 1-6烷基;R c选自H、C 1-6烷基、C 1-6烷氧基、C 3-8环烷基或者C 3-8杂环烷基,所述C 1-6烷基、C 1-6烷氧基、C 3-8环烷基或者C 3-8杂环烷基任选地进一步被1个或者多个选自D、卤素、羟基、氰基、NR c1R c2、C 1-6烷基、C 1-6烷氧基、C 3-8环烷基或者C 3-8杂环烷基的取代基取代;R c1、R c2各自独立地选自H或者C 1-6烷基;n为1或者2;所述的通式(II)化合物任选进一步被1个或者多个氘原子取代。
- 根据权利要求1所述的化合物或者其立体异构体:其中:R a0选自C 1-6烷基、C 3-8环烷基或者C 2-6烯基,所述的C 1-6烷基、C 3-8环烷基或者C 2- 6烯基任选地进一步被1个或者多个选自卤素或者C 1-6烷基的取代基取代;L a1、L a2、L a3各自独立地为N或者CR L;R L选自H、卤素、羟基、氰基、C 1-6烷基、C 1-6烷氧基或者C 3-8环烷基;L为-(CR 1R 2) n-;R 1、R 2各自独立地选自H或C 1-6烷基,所述的C 1-6烷基任选地进一步被1个或者多个选自卤素、羟基或者氰基的取代基取代;B为4至12元杂环,所述的4至12元杂环选自4至12元单环、5至12元螺环、4至12元并环或者4至12元桥环,所述的4至12元杂环可以包含1至4个选自N、O或S的杂原子,且可以任选地进一步被1个或者多个R b取代;R b为H或C 1-6烷基,所述C 1-6烷基任选地进一步被1个或者多个选自卤素或者氰基的取代基取代;或者,任意两个R b可以形成3至8元环;X 1、X 2、X 3各自独立地选自CH或者N,所述的X 1或者X 2为CH时,可以任选地进一步被卤素取代,且当X 3选自N时,X 1和X 2不能同时为CH;R 3、R 4各自独立地选自H、卤素、氰基或者C 1-6烷基;R c选自H、C 1-6烷基、C 1-6烷氧基、C 3-8环烷基或者C 3-8杂环烷基,所述C 1-6烷基、C 1-6烷氧基、C 3-8环烷基或者C 3-8杂环烷基任选地进一步被1个或者多个选自D、卤素、羟基、NR c1R c2、C 1-6烷基或者C 3-8杂环烷基的取代基取代;R c1、R c2各自独立地选自H或者C 1-6烷基;n为1或者2;条件是:所述的化合物任选进一步被1个或者多个氘原子取代。
- 根据权利要求1、3任一项所述的化合物或者其立体异构体:其中:R a0选自C 1-6烷基、C 3-8环烷基或者C 2-6烯基,所述的C 1-6烷基、C 3-8环烷基或者C 2- 6烯基任选地进一步被1个或者多个选自卤素或者C 1-6烷基的取代基取代;L a1、L a2、L a3各自独立地为CH或者N;L为-(CR 1R 2) n-;R 1、R 2各自独立地为H或C 1-6烷基;B为4至12元杂环,所述的4至12元杂环选自4至12元单环、5至12元螺环、4至12元并环或者4至12元桥环,所述的4至12元杂环可以包含1至4个选自N、O或S的杂原子,且可以任选地进一步被1个或者多个R b取代;R b为H或C 1-6烷基,所述C 1-6烷基任选地进一步被1个或者多个选自卤素或者氰基的取代基取代;或者,任意两个R b可以形成3至8元环;X 1、X 2、X 3各自独立地选自CH或者N,所述的X 1或者X 2为CH时,可以任选地进一步被卤素取代,且当X 3选自N时,X 1和X 2不能同时为CH;R 3、R 4各自独立地选自H、卤素、氰基或者C 1-6烷基;R c选自H、C 1-6烷基或者C 3-8环烷基,所述C 1-6烷基或者C 3-8环烷基任选地进一步被1个或者多个选自D、卤素或者C 1-6烷基的取代基取代;n为1或者2;条件是:所述的化合物任选进一步被1个或者多个氘原子取代。
- 药物组合物,所述药物组合物包括:(1)权利要求1至6所述的化合物或其立体异构体;(2)任选的一种或者多种其他活性成分;以及(3)药学上可接受的载体和/或赋形剂。
- 权利要求7所述的药物组合物或者权利要求1至6任一项所述的化合物或其立体异构体在制备抗肿瘤药物中的用途。
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WO2023138541A1 (zh) * | 2022-01-20 | 2023-07-27 | 微境生物医药科技(上海)有限公司 | 吡啶酰胺类parp抑制剂、及其制备方法和医药用途 |
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- 2022-04-20 WO PCT/CN2022/087969 patent/WO2022222966A1/zh active Application Filing
- 2022-04-20 CN CN202280010392.2A patent/CN116710433A/zh active Pending
- 2022-04-22 TW TW111115533A patent/TWI812183B/zh active
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Cited By (9)
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US11591331B2 (en) | 2021-04-19 | 2023-02-28 | Xinthera, Inc. | PARP1 inhibitors and uses thereof |
US11802128B2 (en) | 2021-10-01 | 2023-10-31 | Xinthera, Inc. | Azetidine and pyrrolidine PARP1 inhibitors and uses thereof |
WO2023109521A1 (zh) * | 2021-12-17 | 2023-06-22 | 凯复(苏州)生物医药有限公司 | Parp抑制剂、包含其的药物组合物及其用途 |
WO2023138541A1 (zh) * | 2022-01-20 | 2023-07-27 | 微境生物医药科技(上海)有限公司 | 吡啶酰胺类parp抑制剂、及其制备方法和医药用途 |
US11939329B2 (en) | 2022-01-21 | 2024-03-26 | Xinthera, Inc. | PARP1 inhibitors and uses thereof |
WO2023146960A1 (en) * | 2022-01-28 | 2023-08-03 | Xinthera, Inc. | Parp1 inhibitors and uses thereof |
US11795173B1 (en) | 2022-04-28 | 2023-10-24 | Xinthera, Inc. | Substituted pyridines as PARP1 inhibitors |
WO2024046366A1 (zh) * | 2022-09-01 | 2024-03-07 | 浙江文达医药科技有限公司 | 选择性parp1抑制剂 |
WO2024083218A1 (zh) * | 2022-10-20 | 2024-04-25 | 成都赜灵生物医药科技有限公司 | 取代四氢吡啶类化合物及其用途 |
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CN116710433A (zh) | 2023-09-05 |
TW202246265A (zh) | 2022-12-01 |
TWI812183B (zh) | 2023-08-11 |
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