CN107108467A - 细胞坏死抑制剂 - Google Patents
细胞坏死抑制剂 Download PDFInfo
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- CN107108467A CN107108467A CN201580071413.1A CN201580071413A CN107108467A CN 107108467 A CN107108467 A CN 107108467A CN 201580071413 A CN201580071413 A CN 201580071413A CN 107108467 A CN107108467 A CN 107108467A
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- compound
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- heteroatom
- methyl
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- 230000017074 necrotic cell death Effects 0.000 title claims description 25
- 239000003112 inhibitor Substances 0.000 title claims description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 276
- 239000000203 mixture Substances 0.000 claims abstract description 73
- 150000003839 salts Chemical class 0.000 claims abstract description 44
- 150000004678 hydrides Chemical class 0.000 claims abstract description 30
- 229940124530 sulfonamide Drugs 0.000 claims abstract description 29
- 150000003456 sulfonamides Chemical class 0.000 claims abstract description 29
- 101001109145 Homo sapiens Receptor-interacting serine/threonine-protein kinase 1 Proteins 0.000 claims abstract description 9
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 9
- 238000000034 method Methods 0.000 claims description 131
- -1 amide compound Chemical class 0.000 claims description 105
- 125000005842 heteroatom Chemical group 0.000 claims description 67
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 54
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 46
- 125000000217 alkyl group Chemical group 0.000 claims description 41
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 38
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 37
- 125000003118 aryl group Chemical group 0.000 claims description 31
- 229910052757 nitrogen Inorganic materials 0.000 claims description 29
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 28
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 23
- 201000010099 disease Diseases 0.000 claims description 19
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 19
- 229910052717 sulfur Inorganic materials 0.000 claims description 18
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 17
- 239000011593 sulfur Substances 0.000 claims description 17
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 16
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 16
- 229910052760 oxygen Inorganic materials 0.000 claims description 16
- 239000001301 oxygen Substances 0.000 claims description 16
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims description 14
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 14
- 229910052698 phosphorus Inorganic materials 0.000 claims description 14
- 239000011574 phosphorus Substances 0.000 claims description 14
- 229910052739 hydrogen Inorganic materials 0.000 claims description 12
- 239000001257 hydrogen Substances 0.000 claims description 12
- 102100022501 Receptor-interacting serine/threonine-protein kinase 1 Human genes 0.000 claims description 11
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 10
- 125000003342 alkenyl group Chemical group 0.000 claims description 9
- 125000000304 alkynyl group Chemical group 0.000 claims description 9
- 208000035475 disorder Diseases 0.000 claims description 9
- 239000003814 drug Substances 0.000 claims description 9
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 8
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 claims description 8
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 8
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 8
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 8
- ZSWFCLXCOIISFI-UHFFFAOYSA-N cyclopentadiene Chemical compound C1C=CC=C1 ZSWFCLXCOIISFI-UHFFFAOYSA-N 0.000 claims description 8
- LPIQUOYDBNQMRZ-UHFFFAOYSA-N cyclopentene Chemical compound C1CC=CC1 LPIQUOYDBNQMRZ-UHFFFAOYSA-N 0.000 claims description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 8
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical class C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- 125000001624 naphthyl group Chemical group 0.000 claims description 6
- WUHLVXDDBHWHLQ-UHFFFAOYSA-N pentazole Chemical compound N=1N=NNN=1 WUHLVXDDBHWHLQ-UHFFFAOYSA-N 0.000 claims description 6
- 150000003536 tetrazoles Chemical class 0.000 claims description 6
- 229940124597 therapeutic agent Drugs 0.000 claims description 6
- 150000003852 triazoles Chemical class 0.000 claims description 6
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 5
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 5
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 5
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 5
- XKTYXVDYIKIYJP-UHFFFAOYSA-N 3h-dioxole Chemical compound C1OOC=C1 XKTYXVDYIKIYJP-UHFFFAOYSA-N 0.000 claims description 4
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims description 4
- XPKYHSSPBGYNND-UHFFFAOYSA-N S1C=CC=C1.O1COC=C1 Chemical compound S1C=CC=C1.O1COC=C1 XPKYHSSPBGYNND-UHFFFAOYSA-N 0.000 claims description 4
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 4
- 125000004122 cyclic group Chemical group 0.000 claims description 4
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 4
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 4
- 125000000623 heterocyclic group Chemical group 0.000 claims description 4
- ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical compound C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 claims description 4
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 claims description 4
- RGSFGYAAUTVSQA-UHFFFAOYSA-N pentamethylene Natural products C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 claims description 4
- 102000057669 human RIPK1 Human genes 0.000 claims description 3
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 2
- SFLGIMGLWCVAHP-UHFFFAOYSA-N 5h-oxathiole Chemical compound C1OSC=C1 SFLGIMGLWCVAHP-UHFFFAOYSA-N 0.000 claims description 2
- OOFGXDQWDNJDIS-UHFFFAOYSA-N oxathiolane Chemical compound C1COSC1 OOFGXDQWDNJDIS-UHFFFAOYSA-N 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 abstract description 139
- 238000011282 treatment Methods 0.000 abstract description 6
- 150000001408 amides Chemical class 0.000 abstract description 5
- 108091000080 Phosphotransferase Proteins 0.000 abstract description 2
- 230000036541 health Effects 0.000 abstract description 2
- 102000020233 phosphotransferase Human genes 0.000 abstract description 2
- 102000004169 proteins and genes Human genes 0.000 abstract description 2
- 108090000623 proteins and genes Proteins 0.000 abstract description 2
- 102100021009 Cytochrome b-c1 complex subunit Rieske, mitochondrial Human genes 0.000 abstract 1
- 101000643956 Homo sapiens Cytochrome b-c1 complex subunit Rieske, mitochondrial Proteins 0.000 abstract 1
- 101001099199 Homo sapiens RalA-binding protein 1 Proteins 0.000 abstract 1
- 230000003993 interaction Effects 0.000 abstract 1
- 239000000825 pharmaceutical preparation Substances 0.000 abstract 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 142
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 118
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 62
- 229910001868 water Inorganic materials 0.000 description 54
- NQMRYBIKMRVZLB-UHFFFAOYSA-N methylamine hydrochloride Chemical compound [Cl-].[NH3+]C NQMRYBIKMRVZLB-UHFFFAOYSA-N 0.000 description 53
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 52
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 43
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 35
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 34
- 125000001424 substituent group Chemical group 0.000 description 29
- VVCMGAUPZIKYTH-VGHSCWAPSA-N 2-acetyloxybenzoic acid;[(2s,3r)-4-(dimethylamino)-3-methyl-1,2-diphenylbutan-2-yl] propanoate;1,3,7-trimethylpurine-2,6-dione Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O.CN1C(=O)N(C)C(=O)C2=C1N=CN2C.C([C@](OC(=O)CC)([C@H](C)CN(C)C)C=1C=CC=CC=1)C1=CC=CC=C1 VVCMGAUPZIKYTH-VGHSCWAPSA-N 0.000 description 24
- 239000007832 Na2SO4 Substances 0.000 description 22
- 229910052938 sodium sulfate Inorganic materials 0.000 description 22
- 239000000243 solution Substances 0.000 description 22
- 239000012044 organic layer Substances 0.000 description 21
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 21
- 239000012267 brine Substances 0.000 description 19
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- UFPLYFAJLZOKEO-UHFFFAOYSA-N n-methyl-1-(2,3,5-trifluorophenyl)methanamine Chemical compound CNCC1=CC(F)=CC(F)=C1F UFPLYFAJLZOKEO-UHFFFAOYSA-N 0.000 description 18
- 235000019439 ethyl acetate Nutrition 0.000 description 17
- 206010028851 Necrosis Diseases 0.000 description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Substances OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 16
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 125000001072 heteroaryl group Chemical group 0.000 description 14
- 125000004432 carbon atom Chemical group C* 0.000 description 13
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- 229910052736 halogen Inorganic materials 0.000 description 12
- 150000002367 halogens Chemical class 0.000 description 12
- 210000004027 cell Anatomy 0.000 description 11
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- 125000004404 heteroalkyl group Chemical group 0.000 description 11
- 238000010898 silica gel chromatography Methods 0.000 description 11
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 11
- LDJUYMIFFNTKOI-UHFFFAOYSA-N 2,2-dimethylbutanoyl chloride Chemical compound CCC(C)(C)C(Cl)=O LDJUYMIFFNTKOI-UHFFFAOYSA-N 0.000 description 10
- NUJZRPMPPRZBQO-LBPRGKRZSA-N CC(C(=O)N[C@@H](CC(=O)O)C1=CC=CC=C1)(CC)C Chemical compound CC(C(=O)N[C@@H](CC(=O)O)C1=CC=CC=C1)(CC)C NUJZRPMPPRZBQO-LBPRGKRZSA-N 0.000 description 10
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- FTKFLJLKMQIDRI-UHFFFAOYSA-N n-methyl-1-(3,4,5-trifluorophenyl)methanamine Chemical compound CNCC1=CC(F)=C(F)C(F)=C1 FTKFLJLKMQIDRI-UHFFFAOYSA-N 0.000 description 9
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- WFOVEDJTASPCIR-UHFFFAOYSA-N 3-[(4-methyl-5-pyridin-4-yl-1,2,4-triazol-3-yl)methylamino]-n-[[2-(trifluoromethyl)phenyl]methyl]benzamide Chemical compound N=1N=C(C=2C=CN=CC=2)N(C)C=1CNC(C=1)=CC=CC=1C(=O)NCC1=CC=CC=C1C(F)(F)F WFOVEDJTASPCIR-UHFFFAOYSA-N 0.000 description 7
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- 229910000104 sodium hydride Inorganic materials 0.000 description 6
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- 150000001412 amines Chemical class 0.000 description 5
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- 125000000592 heterocycloalkyl group Chemical group 0.000 description 5
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 5
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- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
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- UDQTXCHQKHIQMH-KYGLGHNPSA-N (3ar,5s,6s,7r,7ar)-5-(difluoromethyl)-2-(ethylamino)-5,6,7,7a-tetrahydro-3ah-pyrano[3,2-d][1,3]thiazole-6,7-diol Chemical compound S1C(NCC)=N[C@H]2[C@@H]1O[C@H](C(F)F)[C@@H](O)[C@@H]2O UDQTXCHQKHIQMH-KYGLGHNPSA-N 0.000 description 3
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- XFJBGINZIMNZBW-CRAIPNDOSA-N 5-chloro-2-[4-[(1r,2s)-2-[2-(5-methylsulfonylpyridin-2-yl)oxyethyl]cyclopropyl]piperidin-1-yl]pyrimidine Chemical compound N1=CC(S(=O)(=O)C)=CC=C1OCC[C@H]1[C@@H](C2CCN(CC2)C=2N=CC(Cl)=CN=2)C1 XFJBGINZIMNZBW-CRAIPNDOSA-N 0.000 description 3
- HCCNBKFJYUWLEX-UHFFFAOYSA-N 7-(6-methoxypyridin-3-yl)-1-(2-propoxyethyl)-3-(pyrazin-2-ylmethylamino)pyrido[3,4-b]pyrazin-2-one Chemical compound O=C1N(CCOCCC)C2=CC(C=3C=NC(OC)=CC=3)=NC=C2N=C1NCC1=CN=CC=N1 HCCNBKFJYUWLEX-UHFFFAOYSA-N 0.000 description 3
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Abstract
本发明提供了抑制细胞坏死和/或人受体相互作用蛋白1激酶(RIP1)的酰胺,包括其相应的磺酰胺,及其药学上可接受的盐,氢化物和立体异构体。这些化合物用于药物组合物,以及制备和使用方法,包括用有效量的所述化合物或组合物治疗有需要的人,并检测人的健康或状况的改善结果。
Description
技术领域
肿瘤坏死因子α(TNF-α)诱导的NF-κB活化在免疫系统和炎性反应中起核心作用。受体相互作用蛋白1(RIP1)是涉及介导核因子κB(NF-κB)活化、细胞凋亡和程序性坏死的多功能信号转导子。RIP1的激酶活性关键地参与介导细胞程序性坏死,一种不依赖于半胱天冬酶的坏死性细胞死亡通路。Holler et al.Nat Immunol 2000;1:489–495;Degterev etal.Nat Chem Biol 2008;4:313–321.
细胞程序性坏死在细胞死亡的多种病理形式中起作用,包括缺血性脑损伤、神经变性疾病和病毒感染。Dunai,et al.,Dec 2011,Pathol.Oncol.Res.:POR 17(4):791–800.坏死性凋亡抑制剂-1(Nec-1),RIP1激酶活性的小分子抑制剂,可以阻断细胞程序性坏死。Degterev et al.Nat Chem Biol 2005;1:112–119.
相关专利出版物包括:US6756394,US8278344,US2012122889,US2009099242,US2010317701,US2011144169,US20030083386,US20120309795,WO2009023272,WO2010075290,WO2010075561,WO2012125544。
发明内容
本发明提供细胞坏死和/或人受体相互作用蛋白1激酶(RIP1)的抑制剂,即如式的酰胺化合物:
其中:
R1是C3-C14环或杂环部分,特别是取代或未取代的,0-3个杂原子C3-C9环烷基,环烯基,环炔基;或取代或未取代的,0-3个杂原子C5-C14芳基;
R2-R4独立地是:氢原子,取代或未取代的杂原子,取代或未取代的,0-3个杂原子C1-C9烷基,取代或未取代的,0-3个杂原子C2-C9烯基,取代或未取代的,0-3个杂原子C2-C9炔基,和取代或未取代的,0-3个杂原子C5-C14芳基,其中每个杂原子独立地是氧,磷,硫或氮;或
该酰胺化合物的相应磺酰胺,或
该化合物药学上可接受的盐,氢化物或立体异构体;
前提是如果R1是苯基,R3是氢原子,且R4是1,1-二甲基丙基,则R2不是氢原子,优选取代或未取代的杂原子,取代或未取代的,0-3个杂原子C1-C9烷基,取代或未取代的,0-3个杂原子C2-C9烯基,取代或未取代的,0-3个杂原子C2-C9炔基,和取代或未取代的,0-3个杂原子C5-C14芳基,其中每个杂原子独立地是氧,磷,硫或氮。
本发明还提供了所有一般和特别公开的酰胺的相应磺酰胺,如:
其中S可以是双键链接一个或两个氧原子,或其药学上可接受的盐,氢化物或立体异构体,其中R部分如本文所述,或其药学上可接受的盐,氢化物或立体异构体。
本发明提供了包含主题化合物的药物组合物,以及制备和使用主题化合物的方法,包括抑制细胞坏死和/或者人RIP1的方法。组合物可以包含药学上可接受的赋形剂,以有效的单位剂型,和/或包含另一种不同的用于靶向疾病或病症的治疗剂。在实施方案中,本发明提供了用有效量的主题化合物或药物组合物治疗对其有需要的人的方法,并且任选地检测该人的健康或状况的改善结果。该方法还可任选地包括确定该人,特别是诊断和适用的疾病或病症(本文)的前提步骤。
本发明包括本文所述的特定实施方案的所有组合。
本发明的具体实施方案的描述
具体实施方案和实施例的以下描述是通过说明而非限制的方式提供的。本领域技术人员将容易地认识到可以改变或修改各种非关键参数以产生基本相似的结果。本发明提供了极多的实施方案。
1.本发明提供了细胞坏死和/或人受体相互作用蛋白1激酶(RIP1)的酰胺抑制剂。
2.在具体实施方案中,主题化合物具有下式:
其中:
R1是C3-C14环状或杂环状部分,优选取代或未取代的,0-3个杂原子C3-C9环烷基,环烯基,环炔基;或取代或未取代的,0-3个杂原子C5-C14芳基;
R2-R4独立地为:氢原子,取代或未取代的杂原子,取代或未取代的,0-3个杂原子C1-C9烷基,取代或未取代的,0-3个杂原子C2-C9烯基,取代或未取代的,0-3个杂原子C2-C9炔基,和取代或未取代的,0-3个杂原子C5-C14芳基,其中每个杂原子独立地是氧,磷,硫或氮;或
该酰胺化合物的相应磺酰胺,或
该化合物药学上可接受的盐,氢化物或立体异构体。
从本发明的范围排除的是初始化合物文库筛选选中的结构式:
例如,式I的化合物包括前提是,如果R1是苯基,R3是H,且R4是1,1-二甲基丙基,那么R2不是H,即取代或未取代的杂原子,取代或未取代的0-3个杂原子C1-C9烷基,取代或未取代的0-3个杂原子C2-C9烯基,取代或未取代的0-3个杂原子C2-C9炔基,和取代或未取代的0-3个杂原子C5-C14芳基,其中每个杂原子独立地是氧,磷,硫或氮。
2.在特定方面:
R1是(a)取代或未取代的苯基;
(b)取代或未取代的2-,3-或4-吡啶;
(c)取代或未取代的萘基或3-氮杂萘基;
(d)0-3个杂原子环己基,环戊基,如四氢呋喃;或
(e)0-3个杂原子环戊烯或环戊二烯,如吡咯,唑(例如吡唑,咪唑,三唑,四唑,戊唑,恶唑,异恶唑,噻唑或异噻唑),呋喃,间二氧杂环戊烯噻吩,二硫杂环戊烯或氧硫杂环戊烯,优选2-部分,如2-唑,2-吡咯,2-唑(例如2-吡唑,2-咪唑,2-恶唑,2-异恶唑,2-噻唑或2-异噻唑),2-呋喃,2-噻吩,2-氧杂环戊二烯,间二氧杂环戊烯或2-硫杂环戊二烯;和/或
R2是氢原子,羟基,C1-C4烷基(例如甲基,乙基,丙基)或C1-C4烷氧基(例如甲氧基);和/或
R3是氢原子或甲基,和/或
R4是1-二甲基丙基。
所有可能的组合都包括在内,仿如每个都被明确地列举;因此,方面和实施方案包括,例如,其中R1是取代或未取代的苯基的组合;R2是氢原子,羟基,C1-C4烷基或C1-C4烷氧基,R3是氢原子或甲基,且R4是1-二甲基丙基。
3.作为这种组合的另一个实例,在一个方面,该化合物具有式:
其中:
R1是(a)取代或未取代的苯基,
(b)取代或未取代的2-,3-或4-吡啶,或
(c)取代或未取代的萘基或3-氮杂萘基;
(d)0-3个杂原子环己基,环戊基,如四氢呋喃基;
(e)0-3杂原子环戊烯或环戊二烯,如吡咯,唑(特别是吡唑,咪唑,三唑,四唑,戊唑,恶唑,异恶唑,噻唑或异噻唑),呋喃,间二氧杂环戊烯噻吩,二硫杂环戊烯或氧硫杂环戊烯;
R2是氢原子,羟基,C1-C4烷基(例如甲基,乙基,丙基)或C1-C4烷氧基(例如甲氧基);且
R3是氢原子或甲基;或
该酰胺化合物的相应磺酰胺,或
该化合物药学上可接受的盐,氢化物或立体异构体。
4.另一方面,该化合物具有式:
其中:
R1是取代或未取代的苯基;且
R2是氢原子,羟基或取代或未取代的C1-C9烷基;
该酰胺化合物的相应磺酰胺,或
该化合物药学上可接受的盐,氢化物或立体异构体。
5.在实施方案中,R1和R2如下:
6.另一方面,该化合物具有式:
其中,
R1是取代或未取代的2-,3-或4-吡啶,且
R2是氢原子,甲基;或
该酰胺化合物的相应磺酰胺,或
该化合物药学上可接受的盐,氢化物或立体异构体。
7.在实施方案中,R1如下:
。
8.另一方面,该化合物具有式:
其中,
R1是取代或未取代的环己基;或
该酰胺化合物的相应磺酰胺,或
该化合物药学上可接受的盐,氢化物或立体异构体。
9.在实施方案中R1如下:
。
10.另一方面,该化合物具有式:
其中,
R1是取代或未取代的2-唑,2-吡咯,2-呋喃,2-噻吩,2-氧杂环戊二烯,间二氧杂环戊烯或2-硫杂环戊二烯,优选其中2-唑是:2-吡唑,2-咪唑,三唑,四唑,戊唑,2-恶唑,2-异恶唑,2-噻唑或2-异噻唑;
R2是甲基,羟基或甲氧基;且
R3是氢原子或甲基,或者
该酰胺化合物的的相应磺酰胺,或
该化合物药学上可接受的盐,氢化物或立体异构体。
11.在实施方案中R1,R2和单键或双键如下:
。
12.另一方面,该化合物具有式:
其中,
R1是取代或未取代的萘基或3-氮杂萘基,或
该酰胺化合物的相应磺酰胺,或
该化合物药学上可接受的盐,氢化物或立体异构体。
13.在实施方案中R1如下:
。
14.另一方面,该化合物具有式:
其中,
R1是取代或未取代的苯基;优选未取代的苯基,
R2是氢原子,甲基,羟基,羟甲基或甲氧基;且
R3是氢原子,甲基,羟基,羟甲基,甲氧基或取代或未取代的C1-C6烷基,优选未取代的,或
该酰胺化合物的相应磺酰胺,或
该化合物药学上可接受的盐,氢化物或立体异构体。
15.在实施方案中,R1,R2和R3如下:
。
16.另一方面,该化合物具有式:
其中,
R2是氢原子,羟基或取代或未取代的C1-C6烷基,且
R4是取代或未取代的,0-3个杂原子C1-C6烷基,取代或未取代的,0-3个杂原子C2-C6烯基,取代或未取代的,0-3个杂原子C2-C6炔基,以及取代或未取代的,0-3个杂原子C6-C14芳基,其中每个杂原子独立地是氧,磷,硫或氮,
n为0,1,2,3,4或5,或
该酰胺化合物的相应磺酰胺,或
该化合物药学上可接受的盐,氢化物或立体异构体。
在实施方案中,R4是1-二甲基丙基,或氟化形式,例如1-二甲基-2-二氟丙基。
17.在实施方案中(F)n,R2和R4如下:
。
18.另一方面,该化合物具有式:
其中,
R1是取代或未取代的苯基;且
R3是取代或未取代的杂原子和取代或未取代的0-3个杂原子C1-C6烷基,其中每个杂原子独立地是氧,磷,硫或氮;或
该酰胺化合物的相应磺酰胺,或
该化合物药学上可接受的盐,氢化物或立体异构体。
19.在实施方案中R1和R3如下:
。
20.另一方面,该化合物具有式:
其中,
R1是取代或未取代的苯基;
R2是氢原子或甲基;且
R3是氢原子或甲基;或
该酰胺化合物的相应磺酰胺,或
该化合物药学上可接受的盐,氢化物或立体异构体。
21.在实施方案中R1,R2和R3如下:
。
22.另一方面,化合物具有式:
其中,
R1是取代或未取代的苯基;
R3是H或甲基;且
R4是取代或未取代的C1-C6烷基,或
该酰胺化合物的相应磺酰胺,或
该化合物药学上可接受的盐,氢化物或立体异构体。
23.在实施方案中,R1,R2和R3如下:
。
24.另一方面,化合物具有式:
其中,
R1是取代或未取代的苯基;
R2是氢原子,甲基或乙基;且
R3和R4独立地是氢原子,低级烷基,并且可以连接形成取代或未取代的C3-C8环烷基,或
该酰胺化合物的相应磺酰胺,或
该化合物药学上可接受的盐,氢化物或立体异构体。
25.在实施方案中R1,R2,R3和R4如下:
。
26.在实施方案中,主题化合物具有表1的式。
27.在实施方案中,本发明提供了包含单位剂量的主题化合物以及药学上可接受的赋形剂的药物组合物。
28.在实施方案中,本发明提供了包含单位剂量的主题化合物和药学上可接受的赋形剂,以及一种不同的用于细胞坏死相关疾病或病症的治疗剂的药物组合物。
29.在实施方案中,本发明提供了治疗细胞坏死相关疾病或病症的方法,包含向有需要的患者施用有效量的主题化合物或组合物。
30.在实施方案中,本发明提供了治疗方法,其包含诊断细胞坏死相关疾病或病症的前期步骤,或检测细胞坏死相关疾病或病症的改善结果的后续步骤。
适用的疾病或病症为细胞坏死(包括细胞程序性坏死)相关的,以及包括中枢或周围神经系统的神经变性疾病,内毒素/败血性休克,末端回肠炎,心肌炎,关节炎,动脉粥样硬化,急性肠炎,缺血性坏死,由肾衰竭或细胞死亡引起的病理,包括视网膜神经元、心肌或免疫细胞死亡,比如化学或放射性诱导的坏死;肝脏疾病,包括药物诱发的肝损伤或毒性、急性肝炎等,胰腺疾病,包括坏死性胰腺炎,心脏、肠系膜、视网膜,肝或脑/大脑缺血性损伤,肾炎,再灌注或器官储存期间的缺血性损伤,头部创伤,包括创伤性脑损伤,中风,败血性休克,冠心病,心肌症,心肌梗塞,股无血管性坏死,镰状细胞病,肌肉消瘦,胃肠疾病,结核病,糖尿病,血管病理改变,肌营养不良症,移植物抗宿主疾病,病毒、细菌和真菌感染,克罗恩氏病,溃疡性结肠炎,哮喘等。
示例性适用的病毒为人免疫缺陷病毒(HIV),爱泼斯坦-巴尔病毒(EBV),巨细胞病毒(CMV)5,人疱疹病毒(HHV),单纯性疱疹病毒(HSV),人T细胞白血病病毒(HTLV)5,水痘-带状疱疹病毒(VZV),麻疹病毒,乳头多瘤空泡病毒(JC和BK),肝炎病毒,腺病毒,细小病毒,以及人乳头状瘤病毒。由病毒感染引起的示例性疾病包括但不限于水痘,巨细胞病毒感染,生殖器疱疹,乙型和丙型肝炎,流行性感冒,以及带状疱疹。
示例性适用的细菌包括但不仅限于空肠弯曲杆菌,肠杆菌属,屎肠球菌,粪肠球菌,大肠杆菌(如,大肠杆菌O157:H7),A组链球菌,流感嗜血杆菌,幽门螺杆菌,李斯特菌属,结核分支杆菌,绿脓假单胞菌,肺炎链球菌,沙门氏菌,志贺氏菌,金黄色葡萄球菌,以及表皮葡萄球菌。由细菌感染引起的示例性疾病包括但不限于炭疽,霍乱,白喉,食源性疾病,麻风病,脑膜炎,消化性溃疡病,肺炎,败血症,破伤风,结核病,伤寒以及尿路感染。
示例性适用的神经变性疾病是阿尔兹海默症,亨廷顿病,帕金森氏病,肌萎缩性脊髓侧索硬化症,HIV相关性痴呆,脑缺血,多发性硬化症,路易体病,Menke氏病,,威尔逊氏病,克雅氏病以及Fahr疾病。
示例性适用的肌营养不良症或相关疾病是贝克氏肌营养不良症,杜氏肌营养不良症,肌强直性营养不良症,肢带型肌营养不良症,兰迪二式肌营养不良,面肩胛肱型肌营养不良(Steinert氏病),先天性肌强直症,汤姆森氏病和庞贝氏症。肌肉消瘦可能与癌症,艾滋病,充血性心力衰竭和慢性阻塞性肺疾病有关,还包括重症监护病人的坏死性肌病。
除非有相反的提示或另有说明,在这些描述和整个说明书中,术语“一个”是指一个或多个,术语“或”指和/或,并且多核苷酸序列应被理解为包括相反链以及本文所述的可选择骨架。此外,属类为该属类所有成员的叙述的简称;例如,(C1-C3)烷基的叙述是所有C1-C3烷基叙述的简写:甲基,乙基和丙基,包括其异构体。
本文所述术语“杂原子”通常是指碳或氢之外的任何原子。优选的杂原子包括氧(O)、磷(P)、硫(S)、氮(N)和卤素,且优选的杂原子官能团为卤代甲酰基、羟基、醛、胺、偶氮、羧基、氰基、硫氰酸盐、羰基、卤素、过氧羟基、亚胺、醛亚胺、异氰化物、异氰酸酯、硝酸盐、腈、亚硝酸盐、硝基、亚硝基、磷酸盐、膦酰基、硫化物、磺酰基、磺基和巯基。
除非另外说明,术语“烷基”本身或作为另一取代基的一部分,是指直链或支链或者环状烃基,或其组合,其为完全饱和的具有指定碳原子数(即C1-C8指1至8个碳)。烷基的实例包括甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、仲丁基、环己基、(环己基)甲基、环丙基甲基,以及如正戊基、正己基、正庚基、正辛基等同系物和异构体。
术语“烯基”本身或作为另一取代基的一部分,是指直链或支链或环状烃基或其组合,其可以是单不饱和或多不饱和的,具有指定的碳原子数(即C2-C8指2至8个碳)和一个或多个双键。烯基的实例包括乙烯基、2-丙烯基、巴豆基、2-异戊烯基、2-(丁二烯基)、2,4-戊二烯基、3-(1,4-戊二烯基)及其高级同系物和异构体。
术语“炔基”本身或作为另一取代基的一部分,是指直链或支链烃基或其组合,其可以是单不饱和或多不饱和的,具有指定的碳原子数(即C2-C8指2至8个碳)和一个或多个三键。炔基的实例包括乙炔基、1-和3-丙炔基、3-丁炔基及其高级同系物和异构体。
术语“亚烷基”本身或作为另一取代基的一部分是指衍生自烷基的二价基团,例如以-CH2-CH2-CH2-CH2-实例。通常,烷基(或亚烷基)基团将具有1至24个碳原子,在本发明中优选具有10个或更少碳原子的那些基团。“低级烷基”或“低级亚烷基”为较短链的烷基或亚烷基,通常具有8个或更少的碳原子。
术语“烷氧基”,“烷基氨基”和“烷硫基”(或硫代烷氧基)以其常规含义使用,并且分别指的是通过氧原子、氨基或硫原子与分子剩余部分连接的那些烷基。
除非另外说明,术语“杂烷基”本身或与另一术语组合是指稳定的直链或支链或环状烃基或其组合,由确定数目的碳原子和一至三个选自氧、氮、磷、硅和硫的杂原子组成,其中氮、硫和磷原子可任选地被氧化,且氮杂原子可任选地被季铵化。杂原子氧、氮、磷和硫可置于杂烷基的任何内部位置。杂原子硅可置于杂烷基的任何位置,包括烷基与分子剩余部分连接的位置。实例包括-CH2-CH2-O-CH3,-CH2-CH2-NH-CH3,,-CH2-CH2-N(CH3)-CH3,-CH2-S-CH2-CH3,-CH2-CH2,-S(O)-CH3,-CH2-CH2-S(O)2-CH3,-CH=CH-O-CH3,-Si(CH3)3,-CH2-CH=N-OCH3,和-CH=CH-N(CH3)-CH3。最多两个杂原子可以是连续的,例如-CH2-NH-OCH3和-CH2-O-Si(CH3)3。
类似地,术语“杂亚烷基”本身或作为另一取代基的一部分是指衍生自杂烷基的二价基团,例如以-CH2-CH2-S-CH2-CH2-和-CH2-S-CH2-CH2-NH-CH2-为实例。对于杂亚烷基,杂原子也可以占据链末端的任一个或两个(例如亚烷基氧基、亚烷基二氧基、亚烷基氨基、亚烷基二氨基等)。此外,对于亚烷基和杂亚烷基连接基团,没有暗示连接基团的取向。
除非另外说明,术语“环烷基”和“杂环烷基”自身或与其它术语组合,分别表示“烷基”和“杂烷基”的环状形式。相应地,环烷基具有指定的碳原子数(即C3-C8表示3至8个碳),并且还可以具有一个或两个双键。杂环烷基由指定的碳原子数和选自氧,氮,硅和硫的一至三个杂原子组成,并且其中氮和硫原子可任选地被氧化,且氮杂原子可任选地被季铵化。另外,对于杂环烷基,杂原子可以占据杂环与分子的剩余部分连接的位置。环烷基的实例包括环戊基、环己基、1-环己烯基、3-环己烯基、环庚基等。杂环烷基的实例包括1-(1,2,5,6-四氢吡啶基)、1-哌啶基、2-哌啶基、3-哌啶基、4-吗啉基、3-吗啉基、四氢呋喃-2-基、四氢呋喃-3-基、四氢噻吩-2-基、四氢噻吩-3-基、1-哌嗪基、2-哌嗪基等。
除非另有说明,术语“卤代”和“卤素”本身或作为另一取代基的一部分,是指氟,氯,溴或碘原子。另外,术语例如“卤代烷基”是指包括被一个到(2m'+1)的数目范围内的相同或不同的卤素原子取代的烷基,其中m'是烷基中碳原子的总数。例如,术语“卤代(C1-C4)烷基”是指包括三氟甲基、2,2,2-三氟乙基、4-氯丁基、3-溴丙基等。因此,术语“卤代烷基”包括单卤代烷基(被一个卤素原子取代的烷基)和多卤代烷基(被2至(2m'+1)个卤素原子取代的烷基,其中m'为烷基中碳原子的总数)。除非另外说明,术语“全卤代烷基”是指被(2m'+1)个卤素原子取代的烷基,其中m'是烷基中的碳原子的总数。例如术语“全卤代(C1-C4)烷基”是指包括三氟甲基、五氯乙基、1,1,1-三氟-2-溴-2-氯乙基等。
术语“酰基”是指通过除去酸的羟基部分衍生自有机酸的那些基团。相应地,酰基是指包括如乙酰基、丙酰基、丁酰基、癸酰基、新戊酰基、苯甲酰基等。
除非另外说明,术语“芳基”是指多不饱和的,通常为芳香族的烃取代基,其可以是稠合在一起或共价连接的单环或多环(至多三个环)。芳基的非限制性实例包括苯基、1-萘基、2-萘基、4-联苯基和1,2,3,4-四氢萘。
术语“杂芳基”是指含有0至4个选自氮,氧和硫的杂原子的芳基(或环),其中氮和硫原子任选地被氧化,且氮杂原子任选地被季铵化。杂芳基可以通过杂原子连接到分子的剩余部分。杂芳基的非限制性实例包括1-吡咯基、2-吡咯基、3-吡咯基、3-吡唑基、2-咪唑基、4-咪唑基、吡嗪基、2-恶唑基、4-恶唑基、2-苯基-4-恶唑基、5-恶唑基、3-异恶唑基、4-异恶唑基、5-异恶唑基、2-噻唑基、4-噻唑基、5-噻唑基、2-呋喃基、3-呋喃基、2-噻吩基、3-噻吩基、2-吡啶基、3-吡啶基、4-吡啶基、2-嘧啶基、4-嘧啶基、5-苯并噻唑基、嘌呤基、2-苯并咪唑基、5-吲哚基、1-异喹啉基、5-异喹啉基、2-喹喔啉基、5-喹喔啉基、3-喹啉基和6-喹啉基。
为简便起见,当与其它术语(例如芳氧基芳基硫氧基芳基烷基)组合使用时,术语“芳基”包括如上定义的芳环和杂芳基环。因此,术语“芳基烷基”是指包括其中芳基连接至烷基的那些基团(例如苄基、苯乙基、吡啶基甲基等),所述烷基包括其碳原子(例如亚甲基基团)被例如氧原子替代的烷基基团(如苯氧基甲基、2-吡啶基氧基甲基、3-(1-萘氧基)丙基等)。
上述术语(如“烷基”、“杂烷基”、“芳基”和“杂芳基”)中的每一个是指包含所示基团的取代和未取代两种形式。每种类型的基团的优选取代基提供如下。
烷基和杂烷基(以及被称为亚烷基、烯基、杂亚烷基、杂烯基、炔基、环烷基、杂环烷基、环烯基和杂环烯基的那些基团)的取代基可以是选自以下的各种基团:-OR'、=O、=NR'、=N-OR'、-NR'R"、-SR'、卤素、-SiR'R"R″′、-OC(O)R'、-C(O)R'、-CO2R'、-CONR'R"、-OC(O)NR'R"、-NR"C(O)R'、-NR'-C(O)NR"R″′、-NR'-SO2NR″′、-NR"CO2R'、-NH-C(NH2)=NH、-NR'C(NH2)=NH、-NH-C(NH2)=NR'、-S(O)R'、-SO2R'、-SO2NR'R"、-NR"SO2R,-CN和-NO2,数量范围从0至3,那些具有0、1或2个取代基的基团是特别优选的。R'、R"和R″′每个独立地指氢、未取代的(C1-C8)烷基和杂烷基、未取代的芳基、被一至三个卤素取代的芳基、未取代的烷基、烷氧基或硫代烷氧基,或芳基-(C1-C4)烷基基团。当R'和R"连接到相同的氮原子时,它们可以与氮原子组合形成5-,6-或7-元环。例如,-NR'R"是指包括1-吡咯烷基和4-吗啉基。通常,烷基或杂烷基具有0至3个取代基,在本发明中优选具有两个或更少取代基的那些基团。更优选地,烷基或杂烷基将是未取代的或单取代的。最优选地,烷基或杂烷基是未取代的。从上述取代基的讨论中,本领域技术人员将理解术语“烷基”意指包括例如三卤代烷基(例如,-CF3和-CH2CF3)的基团。
烷基和杂烷基的优选取代基选自:-OR'、=O、-NR'R"、-SR'、卤素、-SiR'R"R″′、-OC(O)R'、-C(O)R'、-CO2R'、-CONR'R"、OC(O)NR'R"、-NR"C(O)R'、-NR"CO2R'、-NR'-SO2NR"R″′、-S(O)R'、-SO2R'、-SO2NR'R"、-NR"SO2R、-CN和-NO2,其中R'和R"如上面所定义的。进一步优选的取代基选自:-OR'、=O、-NR'R"、卤素、-OC(O)R'、-CO2R'、-CONR'R"、-OC(O)NR'R"、-NR"C(O)R'、-NR"CO2R'、-NR'-SO2NR"R″′、-SO2R'、-SO2NR'R"、-NR"SO2R,-CN和-NO2。
类似地,芳基和杂芳基的取代基是不同的,并且选自:卤素、-OR'、-OC(O)R'、-NR'R"、-SR'、-R'、-CN、-NO2、-CO2R'、-CONR'R"、-C(O)R'、-OC(O)NR'R"、-NR"C(O)R'、-NR"CO2R'、-NR'-C(O)NR"R″′、-NR'-SO2NR"R″′、-NH-C(NH2)=NH、-NR'C(NH2)=NH、-NH-C(NH2)=NR'、-S(O)R'、-SO2R'、-SO2NR'R"、-NR"SO2R、-N3、-CH(Ph)2,全氟(C1-C4)烷氧基和全氟(C1-C4)烷基,数量范围为0至芳族环系统上的开放化合价的总数;并且其中R',R"和R″′独立地选自氢、(C1-C8)烷基和杂烷基、未取代的芳基和杂芳基、(未取代的芳基)-(C1-C4)烷基和(未取代的芳基)氧基-(C1-C4)烷基。当芳基是1,2,3,4-四氢萘时,它可以被取代或未取代的(C3-C7)螺环烷基取代。(C3-C7)螺环烷基可以以本文对“环烷基”所定义的相同方式取代。通常,芳基或杂芳基具有0至3个取代基,在本发明中优选具有两个或更少取代基的那些基团。在本发明的一个实施方案中,芳基或杂芳基是未取代的或单取代的。在另一个实施方案中,芳基或杂芳基将是未取代的。
芳基和杂芳基的优选取代基选自:卤素、-OR'、-OC(O)R'、-NR'R"、-SR'、-R'、-CN、-NO2、-CO2R'、-CONR'R"、-C(O)R'、-OC(O)NR'R"、-NR"C(O)R'、-S(O)R'、-SO2R'、-SO2NR'R"、-NR"SO2R、-N3、-CH(Ph)2、全氟(C1-C4)烷氧基和全氟(C1-C4)烷基,其中R'和R"如上所定义。进一步优选的取代基选自:卤素、-OR'、-OC(O)R'、-NR'R"、-R'、-CN、-NO2、-CO2R'、-CONR'R"、-NR"C(O)R'、-SO2R'、-SO2NR'R"、-NR"SO2R,全氟(C1-C4)烷氧基和全氟(C1-C4)烷基。
本文所用的取代基-CO2H包括其生物电子等排置换;参见例如The Practice ofMedicinal Chemistry;Wermuth,C.G.,Ed.;Academic Press:New York,1996;p.203。
芳环或杂芳基环的相邻原子上的两个取代基可任选地被式-T-C(O)-(CH2)q-U-的取代基替代,其中T和U独立地为-NH-、-O-,-CH2-或单键,且q为0-2的整数。或者,芳环或杂芳基环的相邻原子上的两个取代基可任选地被式-A-(CH2)r-B-的取代基替代,其中A和B独立地为-CH2-、-O-、-NH-、-S-、-S(O)-、-S(O)2-,-S(O)2NR'-或单键,且r为1-3的整数。如此形成的新环的单键之一可任选地被双键代替。或者,芳环或杂芳基环的相邻原子上的两个取代基可任选地被式-(CH2)s-X-(CH2)t-的取代基替代,其中s和t独立地为0至3的整数,并且X为-O-、-NR'-、-S-、-S(O)-,-S(O)2-或-S(O)2NR'-。-NR'-和-S(O)2NR'-中的取代基R'选自氢或未取代的(C1-C6)烷基。
本文公开了优选的取代基并在表格、结构,实施例和权利要求中举例说明,并且取代基可以应用于本发明的不同化合物,即任何给定化合物的取代基可以与其它化合物组合使用。
在具体的实施方案中,适用的取代基独立地为取代或未取代的杂原子,取代或未取代的、0-3个杂原子C1-C6烷基,取代或未取代的、0-3个杂原子C2-C6烯基,取代或未取代的、0-3个杂原子C2-C6炔基,或取代或未取代的、0-3个杂原子C6-C14芳基,其中每个杂原子独立地为氧、磷,硫或氮。
在更具体的实施方案中,适用的取代基独立地为醛、醛亚胺、烷酰氧基、烷氧基、烷氧基羰基、烷氧基、烷基、胺、偶氮、卤素、氨基甲酰基、羰基、甲酰氨基、羧基、氰基、酯、卤代、卤代甲酰基、过氧烃基、羟基、亚胺、异氰化物、异氰酸酯、N-叔丁氧羰基、硝酸盐、腈、亚硝酸盐、硝基、亚硝基、磷酸酯、膦酰基、硫化物、磺酰基、磺基、巯基、硫醇、硫氰基,三氟甲基或三氟甲基醚(OCF3)。
术语“药学上可接受的盐”意指包括用相对无毒的酸或碱制备的活性化合物的盐,这取决于在本文所述化合物上发现的具体取代基。当本发明的化合物含有相对酸性的官能团时,碱加成盐可以通过使这种化合物的中性形式与足量的所需碱(要么是纯的要么在合适的惰性溶剂中)接触来获得。药学上可接受的碱加成盐的实例包括钠、钾、钙、铵,有机胺或镁盐,或类似的盐。当本发明的化合物含有相对碱性的官能团时,酸加成盐可以通过将这种化合物的中性形式与足量的所需酸(要么是在纯的要么在合适的惰性溶剂中)接触来获得。药学上可接受的酸加成盐的实例包括那些衍生自无机酸的如盐酸、氢溴酸、硝酸、碳酸、一氢碳酸、磷酸、一氢磷酸、二氢磷酸、硫酸、一氢硫酸,氢碘酸或亚磷酸等,和衍生自相对无毒的有机酸如乙酸、丙酸、异丁酸、草酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、富马酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸,甲磺酸等的盐。还包括氨基酸,例如精氨酸等的盐,以及有机酸,如葡糖醛酸或半乳糖醛酸等的盐。本发明的某些特定化合物同时含有碱性和酸性官能团,其允许化合物转化为碱或酸加成盐。
化合物的中性形式可以通过使盐与碱或酸接触并以常规方式分离母体化合物来再生成。化合物的母体形式在某些物理特性,例如在极性溶剂中的溶解度方面,不同于各种盐的形式,但是对于本发明的目的而言,这些盐等同于化合物的母体形式。
除了盐形式之外,本发明提供了前药形式的化合物。本文所述的化合物的前药是指在生理条件下经过化学变化以提供本发明化合物的那些化合物。另外,前药可以在体外环境中通过化学或生物化学方法转化为本发明的化合物。例如,当与合适的酶或化学试剂共同置于透皮贴剂储库中时,前药可被缓慢转化为本发明的化合物。前药通常是有用的,因为在一些情况下,它们可能比母体药物更容易施用。例如,它们可能比母体药物更具口服生物利用度。前药在药物组合物中也可能有比母体药物改善的溶解性。本领域已知各种各样的前药衍生物,例如依赖于水解裂解或氧化活化的那些前药。前药的一个非限制性实例是本发明中的一个化合物作为酯(“前药”)给药,但随后代谢水解成羧酸,即活性形式。另外的实例包括本发明化合物的肽基衍生物。
本发明的某些化合物可以非溶剂化形式以及溶剂化形式存在,包括水合物形式。通常,溶剂化形式等同于非溶剂化形式,并且包括在本发明的范围内。本发明的某些化合物可以以多种结晶或无定形形式存在。通常,所有物理形式对于本发明考虑的用途是等效的,并且包含在本发明的范围内。
本发明某些化合物具有不对称碳原子(光学中心)或双键;外消旋体、非对映异构体,几何异构体和单个异构体都旨在包括在本发明的范围内。
本发明的化合物还可以在构成这种化合物的一个或多个原子处含有非天然比例的原子同位素。例如,化合物可以用放射性同位素放射性标记,例如氚(3H),碘-125(125I)或碳-14(14C)。本发明化合物的所有同位素变体,无论是否是放射性的,都旨在包括在本发明的范围内。
术语“治疗有效量”是指将在一定程度上引起组织、系统、动物或人的生物或医学反应的题述化合物的量,这正是研究者、兽医、医生或其他临床医生所寻求的,例如当施用时,足以预防所治疗的病症或障碍的一种或多种症状的发展或在一定程度上减轻所治疗的病症或障碍的一种或多种症状。治疗有效量会根据化合物、疾病及其严重程度,以及待治疗的哺乳动物的年龄、体重等的不同而变化。
本发明还提供了包含题述化合物和药学上可接受的赋形剂的药物组合物,特别是包含单位剂量的题述化合物的组合物,尤其是该组合物与描述组合物用于治疗适用疾病或病症(本文中)的说明书共包装。
施用的组合物可以是散装液体溶液或悬浮液或散装粉末的形式。然而,更普遍地,组合物以单位剂型呈现以促进精确给药。术语“单位剂型”是指适合作为人类受试者和其它哺乳动物的单位剂量的物理上不连续的单位,每个单位含有计算产生所需治疗效果的预定量的活性物质,并与合适的药物辅料结合。典型的单位剂型包括液体组合物的预先填充的、预先测量的安瓿或注射器,或在固体组合物的情况下的丸剂、片剂、胶囊、锭剂等。在这样的组合物中,化合物通常是次要组分(约从0.1%至50%重量,或优选地约为从1%至40%重量),其余是各种载体和加工助剂,有助于形成所需剂量。
合适的赋形剂或载体和用于制备可施用组合物的方法是本领域技术人员已知或显而易见的,并且在诸如Remington's Pharmaceutical Science,Mack Publishing Co,NJ(1991)的出版物中有更详细地描述。此外,该化合物与本文所述的或本领域已知的其它治疗剂、特别是其它抗坏死剂,联合用药时可有利地使用。因此,组合物可以单独、联合或组合施用于单一剂量单位。
施用量取决于化合物剂型,施用途径等,并且通常在常规试验中凭经验确定,并且根据靶标、宿主和施用途径等将必然发生变化。通常,根据具体应用,单位剂量制剂中活性化合物的量可以从约1,3,10或30到约30,100,300或1000mg变化或调节。在一个具体实施方案中,单位剂型包装在适于顺序使用的多包装中,例如泡罩包装,包括至少6,9或12个单位剂型的片材。所用的实际剂量可以根据患者的需要和所治疗的病症的严重程度而变化。对于特定情况的适当剂量的确定在本领域的技术范围内。通常,用小于化合物最佳剂量的较小剂量开始治疗。此后,剂量增加少量,直到达到在这种情况下的最佳效果。为了方便起见,如果需要,总日剂量可以分开并在当天内分批给药。
化合物可以通过多种方法施用,包括但不限于胃肠外、体表、口服或局部施用,例如通过气雾剂或经皮,用于预防和/或治疗性处理。此外,根据熟练临床医生的知识,治疗方案(例如,给药的剂量和次数)可以视所观察到的给予的治疗剂对患者的作用及所观察到的疾病与所施用的治疗剂的反应而变化。
在用于治疗患者的治疗有效方案的过程中,可以以治疗有效剂量和总量施用本发明的治疗剂。对于更有效的化合物,每千克患者的微克(μg)量可能是足够的,例如在约1,10或100ug/kg至约0.01,0.1,1,10或100mg/kg的患者体重范围内,尽管最佳剂量是化合物特定的,并且通常每种化合物是根据经验确定的。
一般来说,临床试验中的常规实验将确定最佳治疗效果的具体范围,对于每种治疗剂,每种给药方案,并且对特定患者的给药也将根据患者状况和对初始剂量的反应被调整到有效和安全的范围内。然而,最终给药方案将根据主治临床医生的判断,考虑诸如年龄、病人的状况和大小以及化合物效力、所治疗疾病的严重性等因素来调整。例如,化合物的剂量方案可以是以两至四个(优选两个)分开的剂量口服给药,从10毫克至2000毫克/天,优选的是10至1000毫克/天,更优选的是50至600毫克/天。还可以使用间歇治疗(例如,三周内一周或四周内三周)。
应理解,本文所述的实施例和实施方案仅用于说明目的,并且鉴于本领域技术人员会联想到其各种修改或变化,且包括在本申请的精神和范围以及所附权利要求的范围内。本文引用的所有出版物、专利和专利申请(包括其中的引用)在此以其全文并入作为参考用于所有目的。
实施例
1.表1.化合物列表
2.化合物的制备
化合物1:N-(2-氟苄基)-2,2-二甲基丁酰胺的制备
在搅拌下,将SOCl2(30mL)加入到甲苯中的2,2-二甲基丁酸(5.22g)中。然后将反应混合物加热至80℃保持5小时。除去溶剂后,得到4.268g 2,2-二甲基丁酰氯,将其溶解在DCM中,并在0℃滴加到溶于含有TEA(4.8g)和溶于DCM中的(2-氟苯基)甲胺(1.698g)中。在室温下继续搅拌10小时。在通过TLC判定所有胺消耗后,用冰水猝灭混合物。用DCM萃取,用Na2SO4干燥,浓缩并通过硅胶柱色谱纯化,得到所需产物(2.57g,72.6%)。1H NMR(CDCl3):δ7.30-7.34(m,1H),7.23-7.25(m,1H),7.00-7.11(m,2H),6.06(br,1H),4.48(d,2H,J=6.0Hz),1.55(q,2H,J=7.6Hz),1.16(s,6H),0.81(t,3H,J=7.6Hz).
化合物2:N-苄基三甲基乙酰胺的制备
苯基甲胺(80.3mg)和三乙胺(0.625mL)溶解在DCM(2mL)中,在0℃下加入新戊酰氯(120mg),室温下搅拌3小时。混合物用冰水淬灭。用DCM萃取,用Na2SO4干燥,浓缩并通过硅胶柱色谱纯化,得到所需产物(58.6mg,40.9%)。1H NMR(CDCl3):δ7.25-7.37(m,5H),5.89(br,1H),4.45(d,2H,J=5.6Hz),1.23(s,9H).
化合物3:N-(2-溴苄基)-2,2-二甲基丁酰胺的制备
根据化合物1概述的步骤,由(2-溴苯基)甲胺(93mg)和2,2-二甲基丁酰氯(80.76mg)制备标题化合物3,产率为58.3%。1H NMR(CDCl3):δ7.55(d,1H,J=8.0Hz),7.37-7.40(m,1H),7.26-7.30(m,1H),7.12-7.17(m,1H)6.14(br,1H),4.50(d,2H,J=6.0Hz),1.55(q,2H,J=7.6Hz),1.16(s,6H),0.80(t,3H,J=7.6Hz).
化合物4:2,2-二甲基-N-(2-(三氟甲基)苄基)丁酰胺的制备
根据化合物1概述的步骤,由2-(三氟甲基)苯基)-甲胺(87.6mg)和2,2-二甲基丁酰氯(105mg)制备标题化合物4,产率为71%。1H NMR(CDCl3):δ7.64-7.66(d,1H,J=8.0Hz),7.50-7.56(m,2H),7.36-7.40(m,1H),5.97(br,1H),4.62(d,2H,J=4.8Hz),1.55(q,2H,J=7.6Hz),1.15(s,6H),0.80(t,3H,J=7.6Hz).
化合物5:N-(3-氟苄基)-2,2-二甲基丁酰胺的制备
根据化合物1概述的步骤,从(3-氟苯基)甲胺(93mg)和2,2-二甲基丁酰氯(80.74mg)制备标题化合物5,产率为70%。1H NMR(400MHz,CDCl3)δ:7.33–7.27(m,1H),7.04(d,J=8.0Hz,1H),6.93-6.98(m,2H),4.45(d,J=5.8Hz,2H),1.58(q,J=7.5Hz,3H),1.19(s,6H),0.86(t,J=7.5Hz,3H)。
化合物6:N-(3-溴苄基)-2,2-二甲基丁酰胺的制备
根据化合物1概述的步骤,由(3-溴苯基)甲胺(93mg)和2,2-二甲基丁酰氯(105mg)制备标题化合物6,产率为87%。1H NMR(CDCl3):δ7.38-7.41(m,2H),7.17-7.21(m,2H),5.96(br,1H),4.42(d,2H,J=6.0Hz),1.55(q,2H,J=7.6Hz),1.15(s,6H),0.80(t,3H,J=7.6Hz).
化合物7:N-(2,4-二氟苄基)-2,2-二甲基丁酰胺的制备
根据化合物1概述的步骤,由(2,4-二氟苄基)-甲胺(228.8mg)和2,2-二甲基丁酰氯(430.3mg)制备标题化合物7,收率:40.9%。1H NMR(CDCl3):δ7.30-7.36(m,1H),6.77-6.86(m,2H),5.97(br,1H),4.44(d,2H,J=6.0Hz),1.55(q,2H,J=7.6Hz),1.17(s,6H),0.80(t,3H,J=7.6Hz).
化合物8:N-(3,4-二氟苄基)-2,2-二甲基丁酰胺的制备
根据化合物1概述的步骤,由(3,4-二氟苄基)-甲胺(114.4mg)和2,2-二甲基丁酰氯(215mg)制备标题化合物8,收率:71.3%。1H NMR(CDCl3):δ7.06-7.14(m,2H),6.97-7.00(m,1H),5.95(br,1H),4.40(d,2H,J=6.0Hz),1.56(q,2H,J=7.6Hz),1.17(s,6H),0.84(t,3H,J=7.6Hz).
化合物9:2,2-二甲基-N-(吡啶-3-基甲基)丁酰胺的制备
根据化合物1概述的步骤,由吡啶-3-基甲胺(54.07mg)和2,2-二甲基丁酰氯(134.6mg)制备化合物9,收率,51.2%。1H NMR(CDCl3):δ8.52(s,2H)7.61-7.64(m,1H),7.25-7.28(m,1H),6.05(br,1H),4.47(d,2H,J=6.0Hz),1.58(q,2H,J=7.6Hz),1.18(s,6H),0.84(t,3H,J=7.6Hz).
化合物10:N-乙基-N-(2-氟苄基)-2,2-二甲基丁酰胺的制备
将N-(2-氟苄基)-2,2-二甲基丁酰胺(40mg)溶于4mL无水DMF中,在0℃和N 2下加入8.61mg NaH,并搅拌2小时。加入碘乙烷(56.2mg),使混合物温热至室温并搅拌11小时。将混合物用冷水淬灭并用DCM萃取,合并的有机层用水,盐水洗涤,用Na2SO4干燥,浓缩,残余物通过硅胶柱色谱纯化,得到产物(9.3mg,20.6%)。1H NMR(CDCl3):δ7.22-7.26(m,2H),7.03-7.12(m,2H),4.69(s,2H),3.43(d,2H,J=5.2Hz),1.67(q,2H,J=7.6Hz),1.26(s,6H),1.17(t,3H,J=6.8Hz),0.89(t,3H,J=7.6Hz).
化合物11:N-(2-氟苄基)-2,2-二甲基-N-(丙-2-炔-1-基)丁酰胺的制备
按照化合物10概述的步骤,以42%的收率制备N-(2-氟苄基)丙-2-炔-1-胺,使用68.2mg的酰胺作为起始原料,并与2,2-二甲基丁酰氯(170mg)反应,所需化合物11以30%的收率制备。1H NMR(CDCl3):δ7.23-7.26(m,2H),7.03-7.13(m,2H),4.83(s,2H),4.15(d,2H,J=2.4Hz),2.23(t,1H,J=2.4Hz),1.70(q,2H,J=7.6Hz),1.29(s,6H),0.89(t,3H,J=7.6Hz)。
化合物12:N-(2-氟苄基)-2,2-二甲基-N-(3-氧代丁基)丁酰胺的制备
将(2-氟苯基)甲胺(125mg),多聚甲醛(36mg),丙酮(116mg)和浓盐酸(0.1mL)在EtOH(1ml)中的混合物在密封的烧瓶中在110℃下加热16小时。混合物冷却至室温,除去溶剂并加入EtOAc,所得悬浮液剧烈搅拌1小时,然后过滤并用EtAc洗涤,得到200mg4-((2-氟苄基)氨基)丁-2-酮,其不经进一步纯化直接用于下一步骤。
将所得酰胺(200mg)溶于无水THF(10mL)中,加入TEA(0.3mL)。将混合物冷却至0℃,加入2,2-二甲基丁酰氯(274mg),并在室温下搅拌4小时。混合物用水淬灭并用EtOAc萃取。合并的有机层用盐水洗涤,用Na2SO4干燥。除去溶剂后,残余物通过硅胶柱色谱纯化,得到化合物12(180mg,60%)。1H NMR(CDCl3):δ7.23-7.28(m,1H),7.10-7.19(m,2H),7.02-7.07(m,1H),4.75(s,2H),3.54(br,2H),2.77(t,2H,J=7.2Hz),2.13(s,3H),1.66(q,2H,J=7.6Hz),1.23(s,6H),0.89(t,3H,J=7.6Hz).
化合物13:N-(2-氟苄基)-N,2,2-三甲基丁酰胺的制备
试剂和条件:(a):(1)CH3NH2.HCl,K2CO3,MeOH,室温,1.5h;(b):NaBH4(c)2,2-二甲基丁酰氯,DIEA,THF,室温,2小时。
将K2CO3(207mg,1.5mmol)和甲胺盐酸盐(202mg,3.0mmol)在5mL MeOH中的混合物在室温下搅拌30分钟。然后向混合物中加入2-氟苯甲醛(248mg,2.0mmol),并在室温下搅拌1小时。将混合物冷却至0℃,分批加入NaBH4(113.5mg,3.0mmol)。将混合物在0℃下搅拌1小时。将固体过滤并用EtOAc洗涤。将滤液蒸发至干,将残余物溶于EtOAc中,用水,盐水洗涤,用Na2SO4干燥。将残余物溶于10mL无水THF中。加入DIEA(264mg,2.05mmol),在0℃,氮气下将2,2-二甲基丁酰氯(275mg,2.05mmol)缓慢加入到溶液中,然后在室温下搅拌2小时。向溶液中加入15mL水,用EtOAc(10mL×3)萃取。将合并的有机物用1M HCl,盐水洗涤,用Na2SO4干燥并真空浓缩。残余物通过硅胶柱色谱法(PE/EA=1/2)纯化,得到230mg褐色固体的1(总产率:45.1%)。1H NMR(CDCl3,400MHz):δ(ppm)7.22-7.28(m,2H),7.01-7.12(m,2H),4.68(s,2H),3.05(s,3H),1.65(q,2H,J=7.6Hz),1.27(s,6H),0.89(t,3H,J=7.6Hz)LC-MS(ESI)[M+H]+C14H20FNO计算值,238.2;测得值,238.4。
化合物14:N-(2-氯苄基)-N,2,2-三甲基丁酰胺的制备
根据化合物13概述的步骤,由2-氯苯甲醛(281mg),甲胺盐酸盐(202mg)和2,2-二甲基丁酰氯(275mg)制备标题化合物14,产率48%。1H NMR(CDCl3,400M Hz):δ7.35-7.37(m,1H),7.16-7.25(m,3H),4.74(s,2H),3.05(s,3H),1.70(q,2H,J=7.6Hz),1.28(s,6H),0.91(t,3H,J=7.6Hz).LC-MS(ESI)[M+H]+计算值C14H20ClNO,254.2;测得值,254.4。
化合物15:N-(2-甲氧基苄基)-N,2,2-三甲基丁酰胺的制备
根据化合物13概述的步骤,由2-甲氧基苯甲醛(136mg),甲胺盐酸盐(101mg)和2,2-二甲基丁酰氯(140mg)制备标题化合物15,产率65%。1H NMR(CDCl3,400M Hz):δ7.21-7.26(m,1H),7.09-7.13(m,1H),6.86-6.95(m,2H),4.66(s,2H),3.83(s,3H),2.99(s,3H),1.68(q,2H,J=7.6Hz),1.26(s,6H),0.90(t,3H,J=7.6Hz)LC-MS(ESI)[M+H]+计算值C15H23NO2,250.1;测得值250.3。
化合物16:N-(3-氟苄基)-N,2,2-三甲基丁酰胺的制备
根据化合物13概述的步骤,由3-氟苯甲醛(124mg),甲胺盐酸盐(101mg)和2,2-二甲基丁酰氯(140mg)制备标题化合物16,产率65%。1H NMR(CDCl3,400M Hz):δ7.25-7.31(m,1H),6.91-7.01(m,3H),4.61(s,2H),3.01(s,3H),1.69(q,2H,J=7.6Hz),1.29(s,6H),0.90(t,3H,J=7.6Hz).LC-MS(ESI)[M+H]+计算值C14H20FNO,238.1;测得值,238.4。
化合物17:N-(3-氰基苄基)-N,2,2-三甲基丁酰胺的制备
根据化合物13概述的步骤,由3-甲酰基苄腈(131mg),甲胺盐酸盐(101mg)和2,2-二甲基丁酰氯(140mg),制备标题化合物17,产率62%。1H NMR(CDCl3,400M Hz):δ7.41-7.56(m,4H),4.61(s,2H),3.05(s,3H),1.68(q,2H,J=7.6Hz),1.28(s,6H),0.88(t,3H,J=7.6Hz).LC-MS(ESI)[M+H]+计算值C15H20N2O,245.1;测得值,245.3。
化合物18:N-(3-氯苄基)-N,2,2-三甲基丁酰胺的制备
根据化合物13概述的步骤,由3-氯苯甲醛(140mg),甲胺盐酸盐(101mg)和2,2-二甲基丁酰氯(140mg),制备标题化合物18,产率48%。1H NMR(CDCl3,400M Hz):δ7.20-7.26(m,3H),7.10-7.12(m,1H),4.59(s,2H),3.01(s,3H),1.68(q,2H,J=7.6Hz),1.28(s,6H),0.90(t,3H,J=7.6Hz).LC-MS(ESI)[M+H]+计算值C14H20ClNO,254.1;测得值254.3。
化合物19:N-(3-溴苄基)-N,2,2-三甲基丁酰胺的制备
根据化合物13概述的步骤,由3-溴苯甲醛(185mg),甲胺盐酸盐(101mg)和2,2-二甲基丁酰氯(140mg),制备标题化合物19,产率48%。1H NMR(CDCl3,400M Hz):δ77.36-7.40(m,2H),7.16-7.22(m,2H),4.59(s,2H),3.01(s,3H),1.69(q,2H,J=7.6Hz),1.29(s,6H),0.90(t,3H,J=7.6Hz).LC-MS(ESI)[M+H]+计算值C14H20BrNO,298.1;测得值298.3,300.4。
化合物20:N-(3-甲氧基苄基)-N,2,2-三甲基丁酰胺的制备
根据化合物13概述的步骤,由3-甲氧基苯甲醛(136mg),甲胺盐酸盐(101mg)和2,2-二甲基丁酰氯(140mg)制备标题化合物20,产率57%。1H NMR(CDCl3,400M Hz):δ7.22-7.25(m,1H),6.76-6.81(m,3H),4.61(s,2H),3.78(s,3H),2.98(s,3H),1.69(q,2H,J=7.6Hz),1.29(s,6H),0.91(t,3H,J=7.6Hz).LC-MS(ESI)[M+H]+计算值C15H23NO2,250.2;测得值250.4。
化合物21:N-(3-羟基苄基)-N,2,2-三甲基丁酰胺的制备
根据化合物1概述的步骤,由3-羟基苯甲醛(122mg),甲胺盐酸盐(101mg)和2,2-二甲基丁酰氯(140mg)制备标题化合物21,产率33%。1H NMR(CDCl3,400M Hz):δ7.17(t,1H,J=7.6Hz),6.71-6.79(m,3H),4.58(s,2H),2.98(s,3H),1.68(q,2H,J=7.6Hz),1.29(s,6H),0.90(t,3H,J=7.6Hz).LC-MS(ESI)[M+H]+calad forC14H21NO2,236.2;found,236.4.
化合物22:N-(3-(2-羟基乙氧基)苄基)-N,2,2-三甲基丁酰胺的制备
根据化合物13概述的步骤,由4-(2-羟基乙氧基)苯甲醛(166mg),甲胺盐酸盐(101mg)和2,2-二甲基丁酰氯(140mg)制备标题化合物22,产率48%。1HNMR(CDCl3,400MHz):δ7.14-7.17(m,2H),6.85-6.89(m,2H),4.56(s,2H),4.06-4.08(m,2H),3.94-3.96(m,2H),2.96(s,3H),1.67(q,2H,J=7.6Hz),1.27(s,6H),0.88(t,3H,J=7.6Hz).LC-MS(ESI)[M+H]+计算值C16H25NO3,280.2;测得值,280.4。
化合物23:3-((N,2,2-三甲基丁酰氨基)甲基)苯甲酸甲酯的制备
根据化合物13概述的步骤,由3-甲酰基苯甲酸甲酯(164mg),甲胺盐酸盐(101mg)和2,2-二甲基丁酰氯(140mg),制备标题化合物23,产率46%。1H NMR(CDCl3,400M Hz):δ7.87-7.94(m,2H),7.38-7.45(m,2H),4.66(s,2H),3.90(s,3H),3.01(s,3H),1.69(q,2H,J=7.6Hz),1.29(s,6H),0.90(t,3H,J=7.6Hz).LC-MS(ESI)[M+H]+计算值C16H23NO3,278.2;测得值,278.4。
化合物24:N-(2,4-二氟苄基)-N,2,2-三甲基丁酰胺的制备
根据化合物13概述的步骤,由2,4-二氟苯甲醛(284mg),甲胺盐酸盐(202mg)和2,2-二甲基丁酰氯(275mg)制备标题化合物24,产率56%。1H NMR(CDCl3,400M Hz):δ7.25-7.31(m,1H),6.76-6.86(m,2H),4.60(s,2H),3.06(s,3H),1.65(q,2H,J=7.6Hz),1.26(s,6H),0.85(t,3H,J=7.6Hz).LC-MS(ESI)[M+H]+计算值C14H19F2NO,256.1;测得值,256.3。
化合物25:N-(2,5-二氟苄基)-N,2,2-三甲基丁酰胺的制备
根据化合物13概述的步骤,由2,5二氟苯甲醛(284mg),甲胺盐酸盐(202mg)和2,2-二甲基丁酰氯(275mg)制备标题化合物25,产率59%。1H NMR(CDCl3,400M Hz):δ6.89-7.02(m,3H),4.63(s,2H),3.08(s,3H),1.68(q,2H,J=7.6Hz),1.28(s,6H),0.88(t,3H,J=7.6Hz).LC-MS(ESI)[M+H]+计算值:C14H19F2NO,256.1;测得值,256.4。
化合物26:N-(3,4-二氟苄基)-N,2,2-三甲基丁酰胺的制备
根据化合物1概述的步骤,由3,5-二氟苯甲醛(284mg),甲胺盐酸盐(202mg)和2,2-二甲基丁酰氯(275mg)制备标题化合物14,产率59%。1H NMR(CDCl3,400M Hz):δ6.89-6.75(m,3H),4.57(s,2H),3.04(s,3H),1.69(q,2H,J=7.6Hz),1.29(s,6H),0.90(t,3H,J=7.6Hz).LC-MS(ESI)[M+H]+计算值:C14H19F2NO,256.1;测得值,256.3。
化合物27:N-(4-氯-2-氟苄基)-N,2,2-三甲基丁酰胺的制备
根据化合物13概述的步骤,由4-氯-2-氟苯甲醛(316mg),甲胺盐酸盐(202mg)和2,2-二甲基丁酰氯(275mg)制备标题化合物27,产率59%。1H NMR(CDCl3,400M Hz):δ7.21-7.26(m,1H),7.05-7.11(m,2H),4.60(s,2H),3.06(s,3H),1.65(q,2H,J=7.6Hz),1.26(s,6H),0.85(t,3H,J=7.6Hz).LC-MS(ESI)[M+H]+计算值C14H19ClFNO,272.1;测得值,272.4。
化合物28:N-(2-氟-4-甲氧基苄基)-N,2,2-三甲基丁酰胺的制备
根据化合物13概述的步骤,由2-氟-4-甲氧基苯甲醛(208mg),甲胺盐酸盐(202mg)和2,2-二甲基丁酰氯(275mg)制备标题化合物28,产率57%。1H NMR(CDCl3,400M Hz):δ7.20(t,1H,J=8.8Hz),6.57-6.67(m,2H),4.59(s,2H),3.78(s,3H),3.01(s,3H),1.65(q,2H,J=7.6Hz),1.26(s,6H),0.86(t,3H,J=7.6Hz).LC-MS(ESI)[M+H]+计算值:C15H22FNO2,268.2;测得值,268.4。
化合物29:N-(2,4-二氟苄基)-N-乙基-2,2-二甲基丁酰胺的制备
根据化合物13概述的步骤,由2,4-二氟苯甲醛(284mg),乙胺盐酸盐(248mg)and2,2-二甲基丁酰氯(275mg)制备标题化合物29,产率57%。1H NMR(CDCl3,400M Hz):δ7.22-7.26(m,1H),6.74-6.83(m,2H),4.59(s,2H),3.41-3.42(m,2H),1.63(q,2H,J=7.6Hz),1.23(s,6H),1.15(t,3H,J=7.6Hz),0.85(t,3H,J=7.6Hz).LC-MS(ESI)[M+H]+计算值:C15H21F2NO,270.2;测得值,270.4。
化合物30:N,2,2-三甲基-N-(3-硝基-4-(哌啶-1-基)苄基)丁酰胺的制备
根据化合物13概述的步骤,由3-硝基-4-(哌啶-1-基)苯甲醛(234mg),甲胺盐酸盐(101mg)和2,2-二甲基丁酰氯(193mg)制备标题化合物30,产率66%。1H NMR(CDCl3,400MHz):δ7.61(d,1H,J=2.4Hz),7.35(dd,1H,J=8.4,2.4Hz),7.16(d,1H,J=8.4Hz),4.54(s,2H),3.03-3.06(m,7H),1.73-1.77(m,4H),1.68(q,2H,J=7.6Hz),1.57-1.62(m,2H),1.28(s,6H),0.89(t,3H,J=7.6Hz).LC-MS(ESI)[M+H]+计算值:C19H29N3O3,348.2;测得值,348.4。
化合物31:N-(2,3-二甲基苄基)-N,2,2-三甲基丁酰胺(31)的制备
根据化合物13概述的步骤,由2,3-二甲基苯甲醛(134mg),甲胺盐酸盐(101mg)和2,2-二甲基丁酰氯(134mg)制备标题化合物31,产率76%。1H NMR(CDCl3,400M Hz):δ7.05-7.09(m,2H),6.93-6.95(m,1H),4.65(s,2H),2.97(s,3H),2.29(s,3H),2.16(s,3H),1.69(q,2H,J=7.6Hz),1.28(s,6H),0.92(t,3H,J=7.6Hz).LC-MS(ESI)[M+H]+计算值:C16H25NO,248.2;测得值,248.4。
化合物32:N-(3,5-二甲基苄基)-N,2,2-三甲基丁酰胺的制备
根据化合物13概述的步骤,由3,5-二甲基苯甲醛(134mg),甲胺盐酸盐(101mg)和2,2-二甲基丁酰氯(134mg)制备标题化合物32,产率76%。1H NMR(CDCl3,400M Hz):δ6.89(s,1H),6.82(s,2H),4.57(s,2H),2.96(s,3H),2.29(s,6H),1.69(q,2H,J=7.6Hz),1.29(s,6H),0.91(t,3H,J=7.6Hz).LC-MS(ESI)[M+H]+计算值:C16H25NO,248.2;测得值248.4。
化合物33:N-(2-氟-3-(三氟甲氧基)苄基)-N,2,2-三甲基丁酰胺的制备
根据化合物13概述的步骤,从2-氟-3-(三氟甲氧基)苯甲醛(192mg),甲胺盐酸盐(101mg)和2,2-二甲基丁酰氯(134mg)制备标题化合物33,收率76%。1HNMR(CDCl3,400MHz):δ7.51(t,2H,J=7.2Hz),7.20(t,1H,J=7.6Hz),4.68(s,2H),3.11(s,3H),1.68(q,2H,J=7.6Hz),1.27(s,6H),0.86(t,3H,J=7.6Hz).LC-MS(ESI)[M+H]+计算值C15H19F4NO2,322.1;测得值,322.3。
化合物34:N,2,2-三甲基-N-(吡啶-4-基甲基)丁酰胺的制备
根据化合物13概述的步骤,由异烟醛(214mg),甲胺盐酸盐(202mg)和2,2-二甲基丁酰氯(289mg)制备标题化合物34,产率86%。1HNMR(CDCl3,400M Hz):δ8.55(brs,2H),7.13(d,2H,J=5.6Hz),4.59(s,2H),3.05(s,3H),1.69(q,2H,J=7.6Hz),1.28(s,6H),0.89(t,3H,J=7.6Hz).LC-MS(ESI)[M+H]+计算值C13H20N2O,221.2;测得值,221.4.
化合物35:N,2,2-三甲基-N-(吡啶-3-基甲基)丁酰胺的制备
根据化合物概述的步骤13,由烟碱醛(214mg),甲胺盐酸盐(202mg)和2,2-二甲基丁酰氯(289mg)制备标题化合物35,产率86%。1HNMR(CDCl3,400M Hz):δ8.48-8.51(m,2H),7.58-7.61(m,1H),7.24-7.27(m,1H),4.59(s,2H),3.03(s,3H),1.66(q,2H,J=7.6Hz),1.27(s,6H),0.86(t,3H,J=7.6Hz).LC-MS(ESI)[M+H]+计算值C13H20N2O,221.2;测得值,221.4。
化合物36:N-((3-氟吡啶-4-基)甲基)-N,2,2-三甲基丁酰胺的制备
根据化合物13概述的步骤,由3-氟异烟醛(125mg),甲胺盐酸盐(101mg)和2,2-二甲基丁酰氯(134mg)制备标题化合物36,产率78%。1HNMR(CDCl3,400M Hz):δ8.41(d,1H,J=1.6Hz),8.35(d,1H,J=4.8Hz),7.18(dd,1H,J=6.0,5.2Hz),4.65(s,2H),3.12(s,3H),1.68(q,2H,J=7.6Hz),1.27(s,6H),0.87(t,3H,J=7.6Hz).LC-MS(ESI)[M+H]+计算值C13H19FN2O,239.1;测得值,239.3。
化合物37:N-((2-甲氧基吡啶-3-基)甲基)-N,2,2-三甲基丁酰胺的制备
根据化合物13概述的步骤,由2-甲氧基吡啶甲醛(137mg),甲胺盐酸盐(101mg)和2,2-二甲基丁酰氯(160mg)制备标题化合物37,产率72%。1HNMR(CDCl3,400M Hz):δ8.06(dd,1H,J=5.2,2.0Hz),7.40(d,1H,J=7.2Hz),6.86(dd,1H,J=7.2,5.2Hz),4.56(s,2H),3.97(S,3H),3.05(s,3H),1.67(q,2H,J=7.6Hz),1.25(s,6H),0.87(t,3H,J=7.6Hz).LC-MS(ESI)[M+H]+计算值C14H22N2O2,251.2;测得值,251.4。
化合物38:N-((6-甲氧基吡啶-3-基)甲基)-N,2,2-三甲基丁酰胺的制备
根据化合物13概述的步骤,由6-甲氧基吡啶甲醛(137mg),甲胺盐酸盐(101mg)和2,2-二甲基丁酰氯(160mg)制备标题化合物38,收率72%。1HNMR(CDCl3,400M Hz):δ8.01-8.02(m,1H),7.53(d,1H,J=8.4),6.71(d,1H,J=8.4),4.51(s,2H),3.92(s,3H),3.00(s,3H),1.66(q,2H,J=7.6Hz),1.26(s,6H),0.85(t,3H,J=7.6Hz).LC-MS(ESI)[M+H]+计算值C14H22N2O2,251.2;测得值251.4.
化合物39:N-(环己基甲基)-N,2,2-三甲基丁酰胺的制备
根据化合物13概述的步骤,由环己基甲醛(112mg),甲胺盐酸盐(101mg)和2,2-二甲基丁酰氯(160mg)制备标题化合物39,收率62%。1HNMR(CDCl3,400MHz):δδ3.16(d,2H,J=6.8Hz),3.07(s,3H),1.92(m,1H),1.63-1.73(m,8H),1.24(s,6H),1.08-1.19(m,4H),0.87(t,3H,J=7.6Hz).LC-MS(ESI)[M+H]+计算值C14H27NO,226.2;测得值,226.4。
化合物40:N,2,2-三甲基-N-(噻吩-2-基甲基)丁酰胺的制备
根据化合物13概述的步骤,由噻吩-2-甲醛(224mg),甲胺盐酸盐(101mg)和2,2-二甲基丁酰氯(119mg)制备标题化合物40,产率62%。1HNMR(CDCl3,400MHz):δ7.21(dd,1H,J=4.8,1.6Hz),6.92-6.95(m,2H),4.71(s,2H),3.05(s,3H),1.66(q,2H,J=7.6Hz),1.27(s,6H),0.86(t,3H,J=7.6Hz).LC-MS(ESI)[M+H]+计算值C12H19NOS,226.1;测得值,226.4。
化合物41:N,2,2-三甲基-N-((3-甲基噻吩-2-基)甲基)丁酰胺的制备
根据化合物13概述的方法,由3-甲基噻吩-2-甲醛(200mg),甲胺盐酸盐(161mg)和2,2-二甲基丁酰氯(218mg)制备标题化合物41,产率42%。1HNMR(CDCl3,400MHz):δ7.11(d,1H,J=5.2Hz),6.78(d,1H,J=5.2Hz),4.68(s,2H),3.03(s,3H),2.23(s,3H),1.67(q,2H,J=7.6Hz),1.27(s,6H),0.89(t,3H,J=7.6Hz).LC-MS(ESI)[M+H]+计算值C13H21NOS,234.1;测得值,234.4。
化合物42:N,2,2-三甲基-N-((5-甲基噻吩-2-基)甲基)丁酰胺的制备
根据化合物13概述的步骤,由5-甲噻吩-2-甲醛(200mg),甲胺盐酸盐(161mg)和2,2-二甲基丁酰氯(218mg)制备标题化合物42,产率42%。1HNMR(CDCl3,400MHz):δ6.72(d,1H,J=3.2Hz),6.56-6.57(m,1H),4.62(s,2H),3.03(s,3H),2.43(d,3H,J=1.2Hz),1.661(q,2H,J=7.6Hz),1.269(s,6H),0.877(t,3H,J=7.6Hz).LC-MS(ESI)[M+H]+计算值C13H21NOS,234.1;测得值,234.4。
化合物43:N-(呋喃-2-基甲基)-N,2,2-三甲基丁酰胺的制备
根据化合物13概述的步骤,由呋喃-2-甲醛(500mg),甲胺盐酸盐(527mg)和2,2-二甲基丁酰氯(714mg)制备标题化合物43,产率22%。1HNMR(CDCl3,400MHz):7.34-7.35(m,1H),6.31-6.33(m,1H),6.21-6.22(m,1H),4.57(s,2H),3.06(s,3H),1.63(q,2H,J=7.6Hz),1.27(s,6H),0.85(t,3H,J=7.6Hz)LC-MS(ESI)[M+H]+计算值C12H19NO2,210.1;测得值210.3。
化合物44:N,2,2-三甲基-N-((2-甲基噻唑-5-基)甲基)丁酰胺的制备
根据化合物13概述的步骤,由2-甲基噻唑-5-甲醛(60mg),甲胺盐酸盐(48mg)和2,2-二甲基丁酰氯(74mg)制备标题化合物44,产率23%。1HNMR(CDCl3,400MHz):δ7.50(s,1H),4.59(s,2H),3.07(s,3H),2.67(s,3H),1.64(q,2H,J=7.6Hz),1.25(s,6H),0.84(t,3H,J=7.6Hz).LC-MS(ESI)[M+H]+计算值C12H20N2OS,241.1;测得值241.4。
化合物45:N,2,2-三甲基-N-((1-甲基-1H-吡唑-3-基)甲基)丁酰胺的制备
根据化合物13概述的步骤,由N,1-二甲基-1H-吡唑-3-胺(30mg)和2,2-二甲基丁酰氯(48mg)制备标题化合物45,产率23%。1HNMR(CDCl3,400MHz):δ7.26(d,1H,J=4.0Hz),6.12(d,1H,J=4.0Hz),4.57(s,2H),3.85(s,3H),3.01(s,3H),1.65(q,2H,J=7.6Hz),1.26(s,6H),0.85(t,3H,J=7.6Hz).LC-MS(ESI)[M+H]+计算值C12H21N3O,224.2;测得值,224.4。
化合物46:N,2,2-三甲基-N-(萘-2-基甲基)丁酰胺的制备
根据化合物13概述的步骤,由2-萘甲醛(312mg),甲胺盐酸盐(202mg)和2,2-二甲基丁酰氯(275mg)制备标题化合物46,收率74%。1HNMR(CDCl3,400MHz):δ7.80(m,3H),7.63(m,1H),7.46(m,3H),4.78(s,2H),3.00(s,3H),1.70(q,2H,J=7.6Hz)),1.30(s,6H),0.93(t,3H,J=7.6Hz).LC-MS(ESI)[M+H]+计算值C18H23NO,270.2;测得值,270.4。
化合物47:N,2,2-三甲基-N-(喹啉-3-基甲基)丁酰胺的制备
根据化合物13概述的步骤,由喹啉-3-甲醛(157mg),甲胺盐酸盐(101mg)2,2-二甲基丁酰氯(175mg),参照化合物13的合成方法合成,收率60%。1HNMR(CDCl3,400MHz):δ8.85(d,1H,J=4.4Hz),8.13(d,1H,J=8.4Hz),7.97(d,1H,J=8.4Hz),7.68-7.73(m,1H),7.53-7.57(m,1H),7.155(d,1H,J=4.4Hz),5.10(s,2H),3.07(s,3H),1.70(q,2H,J=7.6Hz),1.29(s,6H),0.91(t,3H,J=7.6Hz).LC-MS(ESI)[M+H]+计算值C17H22N2O,271.2;测得值271.4.
化合物48:N,2,2-三甲基-N-(2,4,6-三氟苄基)丁酰胺的制备
根据化合物13概述的步骤,2,4,6-三氟苯甲醛(320mg),甲胺盐酸盐(202mg)和2,2-二甲基丁酰氯(275mg)制备标题化合物48,产率63%。1HNMR(CDCl3,400MHz):δ6.61-6.69(m,2H),4.64(s,2H),3.06(s,3H),1.64(q,2H,J=7.6Hz),1.24(s,6H),0.82(t,3H,J=7.6Hz).LC-MS(ESI)[M+H]+计算值C14H18F3NO,274.1;测得值,274.3。
化合物49:N,2,2-三甲基-N-(2,3,4-三氟苄基)丁酰胺的制备
根据化合物13概述的步骤,由2,3,4-三氟苯甲醛(160mg),甲胺盐酸盐(101mg)和2,2-二甲基丁酰氯(175mg)制备标题化合物49,产率66%。1HNMR(CDCl3,400MHz):δ7.03-7.05(m,1H),6.88-6.95(m,1H),4.61(s,2H),3.09(s,3H),1.66(q,2H,J=7.6Hz),1.26(s,6H),0.84(t,3H,J=7.6Hz).LC-MS(ESI)[M+H]+计算值C14H18F3NO,274.1;测得值274.3。
化合物50:N-(2,6-二氟-3-甲基苄基)-N,2,2-三甲基丁酰胺的制备
根据化合物13概述的步骤,由2,6-二氟-3-甲基苯甲醛(156mg),甲胺盐酸盐(101mg)和2,2-二甲基丁酰氯(140mg)制备标题化合物50,产率66%。1HNMR(CDCl3,400MHz):δ7.06(q,1H,J=8.4Hz),6.77(t,1H,J=8.8Hz),4.71(s,2H),3.02(s,3H),2.22(s,3H),1.66(q,2H,J=7.6Hz),1.26(s,6H),0.85(t,3H,J=7.6Hz).LC-MS(ESI)[M+H]计算值C15H21F2NO,270.2;测得值,270.4。
化合物51:N,2,2-三甲基-N-(2,3,5,6-四氟苄基)丁酰胺的制备
根据化合物13概述的步骤,由2,3,5,6-四氟苯甲醛(178mg),甲胺盐酸盐(101mg)2,2-二甲基丁酰氯(140mg)制备标题化合物51,产率66%。1HNMR(CDCl3,400MHz):δ6.95-7.03(m,1H)4.70(s,2H),3.16(s,3H),1.65(q,2H,J=7.6Hz),1.24(s,6H),0.83(t,3H,J=7.6Hz).LC-MS(ESI)[M+H]+计算值C14H17F4NO,292.1;测得值,292.4。
化合物52:2,2-二甲基-N-(1-苯乙基)丁酰胺的制备
将1-苯基乙胺(1g,8.26mmol)和三乙胺(0.918g,9.09mmol)溶解在20mL无水CH2Cl2中。在0℃和氮气下,将2,2-二甲基丁酰氯(1.223g,9.09mmol)在2mL CH2Cl2中缓慢加入到该溶液中。将混合物在室温下搅拌2小时,用CH2Cl2和水稀释。有机层用饱和NaHCO3和盐水洗涤,用Na2SO4干燥并浓缩。残余物通过色谱法纯化,得到化合物52(1.35g,74.6%),为白色固体。1HNMR(CDCl3,400MHz):δ7.26-7.34(m,5H),5.77(brs,1H),5.10-5.17(m,1H),1.545(q,2H,J=8Hz),1.485(d,3H,J=4Hz),1.15(s,6H),0.82(t,3H,J=8Hz).LC-MS(ESI)[M+H]+计算值C14H21NO,220.2;测得值,220.4.
化合物53:N,2,2-三甲基-N-(1-苯乙基)丁酰胺的制备
在0℃和氮气下向化合物52(50mg)的无水THF(1ml)溶液中加入氢化钠(13.7mg)。将混合物在0℃下搅拌30分钟,然后加入碘甲烷(38.9mg)。该混合物在室温下搅拌2小时,用冷水淬灭并用CH2Cl2萃取。合并的有机层用水洗涤,用Na2SO4干燥并浓缩。残余物通过色谱法纯化,得到化合物53(8mg,15%),为无色油状物。1HNMR(CDCl3,400MHz):δ7.32-7.35(m,2H),7.22-7.27(m,3H),5.62-6.30(m,1H),2.70(s,3H),1.68(q,2H,J=7.6Hz),1.51(d,3H,J=6.0Hz),1.30(s,3H),1.29(s,3H),0.91(t,3H,J=7.6Hz).LC-MS(ESI)[M+H]+计算值C15H23NO,234.2;测得值,234.4。
化合物54:2,2-二甲基-N-(1-苯基环丙基)丁酰胺的制备
根据化合物52概述的步骤,由1-苯基环丙胺(106mg)和2,2-二甲基丁酰氯(160mg)制备标题化合物54,产率96%。1HNMR(CDCl3,400MHz):δ7.22-7.29(m,4H),7.15-7.19(m,1H),6.25(brs,1H),1.54(q,2H,J=7.6Hz),1.24-1.29(m,2H),1.18-1.22(m,2H),1.16(s,6H),0.81(t,3H,J=7.6Hz).LC-MS(ESI)[M+H]+计算值C15H21NO,232.1;测量值,232.4。
化合物55:N,2,2-三甲基-N-(1-苯基环丙基)丁酰胺的制备
根据化合物53概述的步骤,由化合物42(90mg),氢化钠(32mg)和碘甲烷(85.2mg)制备标题化合物55,收率30%。1HNMR(CDCl3,400MHz):7.28-7.30(m,2H),7.15-7.19(m,3H),3.12(s,3H),1.67(q,2H,J=7.6Hz),1.30-1.32(m,2H),1.26(s,6H),1.24-1.25(m,1H),0.81(t,3H,J=7.6Hz)。LC-MS(ESI)[M+H]+计算值C16H23NO,246.1;测得值,246.4。
化合物56:N-(2-溴-5-氟苄基)-N,2,2-三甲基丁酰胺的制备
根据化合物13概述的步骤,由2-溴-5-氟苯甲醛(500mg),甲胺盐酸盐(249mg)和2,2-二甲基丁酰氯(317mg)制备标题化合物56,产率56%。1HNMR(CDCl3,400MHz):7.48-7.52(m,1H),7.04-7.10(m,2H),4.80(s,2H),3.15(s,3H),1.71(q,2H,J=7.6Hz),1.30(s,6H),0.91(t,3H,J=7.6Hz)。LC-MS(ESI)[M+H]+计算值C14H19BrFNO,316.1;测得值,316.1,318.2。
化合物57:N-(2-氰基-5-氟苄基)-N,2,2-三甲基丁酰胺的制备
将化合物56(30mg),碘化钠(1.4mg)和氰化铜(I)(22mg)的无水DMF(1mL)混合物在180℃下搅拌6小时。将混合物用饱和NaHCO3水溶液(2ml)稀释,水层用二氯甲烷(5mL×3)萃取。将合并的有机层用盐水洗涤,用Na2SO4干燥,过滤并浓缩。残余物通过预TLC纯化,得到化合物57(18mg,72%)。1H-NMR(CDCl3,400MHz):δ7.64-7.67(m,1H),6.83-6.88(m,2H),4.65(s,2H),3.09(s,3H),1.71(q,2H,J=7.6Hz),1.29(s,6H),0.93(t,3H,J=7.6Hz)MS(ES)[M+H]+计算值C15H19FN2O,263.1;测得值,263.3。
化合物58:N-苄基-2,2-二甲基丁酰胺的制备
根据化合物52概述的步骤,由苯甲胺(107mg)和3,3-二甲基丁酰氯(140mg)制备标题化合物58,产率84%。1H NMR(CDCl3):δ7.25-7.36(m,5H),5.88(br,1H),4.45(d,2H,J=8.0Hz),1.58(q,2H,J=5.6Hz),1.19(s,6H),0.81(t,3H,J=5.6Hz)。
化合物59:N-(2-氟苄基)-N,3,3-三甲基丁酰胺的制备
根据化合物13概述的步骤,由2-氟苯甲醛(124mg),甲胺盐酸盐(101mg)和3,3-二甲基丁酰氯(140mg)制备标题化合物59,产率34%。1HNMR(CDCl3,400MHz):δ7.22-7.36(m,2H),7.01-7.15(m,2H),4.65(s,2H),2.97(s,3H),2.31(s,2H),1.07(s,9H).LC-MS(ESI)[M+H]+计算值C14H20FNO,238.2;测得值,238.4。
化合物60:N-(2-氟苄基)-N-甲基环己烷甲酰胺的制备
根据化合物13概述的步骤,由2-氟苯甲醛(124mg),甲胺盐酸盐(101mg)和环己烷碳酰氯(153mg)制备标题化合物60,产率66%。1HNMR(CDCl3,400MHz):7.23-7.28(m,2H),7.01-7.11(m,2H),4.63(s,2H),2.97(s,3H),2.51-2.56(m,1H),1.52-1.79(m,7H),1.24-1.31(m,3H).LC-MS(ESI)[M+H]+计算值C15H20FNO,250.2;测得值,250.4。
化合物61:N-(2-氟苄基)-N-甲基苯酰胺的制备
根据化合物1概述的步骤,由2-氟苯甲醛(124mg),甲胺盐酸盐(101mg)和苯甲酰氯(147mg)制备标题化合物61,产率56%。1HNMR(DMSO,400MHz):δ7.20-7.42(m,9H),4.70(s,1H),4.50(s,1H),2.84(s,3H).LC-MS(ESI)[M+H]+计算值C15H14FNO,244.1;测得值,244.3。
化合物62:N-(2-氟苄基)-N-甲基环丙烷甲酰胺的制备
根据化合物13概述的步骤,由2-氟苯甲醛(124mg),甲胺盐酸盐(101mg)和环丙烷甲酰氯(147mg)制备标题化合物62,产率54%。1HNMR(CDCl3,400MHz):δ7.25-7.27(m,2H),7.03-7.14(m,2H),4.76(s,2H),3.11(s,3H),1.69-1.83(m,1H),1.01-1.05(m,2H),0.69-0.86(m,2H).LC-MS(ESI)[M+H]+计算值C12H14FNO,208.1;测得值,208.3。
化合物63:N-(3-氟苄基)-N-(3-甲氧基丙基)-2,2-二甲基丁酰胺的制备
在DMF(5ml)中的(2-氟苯基)甲胺(125mg),碳酸钾(414mg)和1-氯-3-甲氧基丙烷(108mg)的混合物在100℃下搅拌16小时。将混合物用CH2Cl2稀释,用H2O洗涤,用Na2SO4干燥。除去溶剂后,得到粗的N-(3-氟苄基)-3-甲氧基丙-1-胺(200mg)。将所得化合物溶于无水THF(10ml)中,加入DIPEA(193mg)。将混合物冷却至0℃,加入2,2-二甲基丁酰氯(201mg),并在室温下搅拌4小时。将混合物用水淬灭并用EtOAc萃取。将合并的有机层用盐水洗涤并用Na2SO4干燥。除去溶剂后,残余物通过硅胶色谱纯化,得到化合物63(177mg,60%)。1HNMR(CDCl3,400MHz):δ7.27-7.31(m,1H),6.88-6.98(m,3H),4.66(s,2H),3.41(m,2H),3.36(t,2H,J=6.0Hz),3.29(s,3H),1.84-1.86(m,2H),1.67(q,2H,J=7.6Hz),1.28(s,6H),0.90(t,3H,J=7.6Hz).LC-MS(ESI)[M+H]+计算值C17H26FNO2,296.2;测得值,296.4。
化合物64:N-(环丙基甲基)-N-(3-氟苄基)-2,2-二甲基丁酰胺的制备
根据化合物63概述的步骤,由(2-氟苯基)甲胺(125mg),(溴甲基)环丙烷(135mg)和2,2-二甲基丁酰氯(201mg)制备标题化合物64,产率54%。1HNMR(CDCl3,400MHz):δ7.24-7.30(m,1H),6.88-6.98(m,3H),4.81(s,2H),3.24(d,2H,J=6.4Hz),1.70(q,2H,J=7.6Hz),1.29(s,6H),0.94(t,3H,J=7.6Hz),0.87-0.90(m,1H),0.51(m,2H),0.13(m,2H).LC-MS(ESI)[M+H]+calad forC17H24FNO,278.2;found 278.3.
化合物65:N,1-二甲基-N-(2,3,5-三氟苄基)环己烷甲酰胺的制备
N-甲基-1-(2,3,5-三氟苯基)甲胺(37mg,0.211mmol),其根据化合物13概述的步骤,由2,3,5-三氟苯甲醛和甲胺盐酸盐制备得到,且1-甲基环己烷羧酸(30mg,0.211mmoL)溶于无水DMF(1mL)中,2-(7-氮杂-1H-苯并三唑-1-基)-1,1,3,3-四甲基脲六氟磷酸盐(119.7mg,0.315mmol)和N,N-二异丙基乙胺(54.2mg,0.42mmol)加入到该溶液中。将混合物在室温下搅拌16小时。在减压下除去溶剂,残余物通过柱色谱法纯化,得到12mg无色油状的期望化合物65(产率为19.5%)。1H NMR:(CDCl3,400M Hz)δ(ppm)6.80-6.82(m,1H),6.72-6.76(m,1H),4.65(s,2H),3.10(s,3H),2.06-2.11(m,2H),1.36-1.54(m,8H),1.27(s,3H).LC-MS(ESI)[M+H]+计算值C16H20F3NO,300.1;测得值,300.3。
化合物66:3-羟基-N,2,2-三甲基-N-(3,4,5-三氟苄基)丙酰胺的制备
根据化合物65概述的步骤,标题化合物66由N-甲基-1-(3,4,5-三氟苯基)甲胺(447mg),其为由3,4,5-三氟苯甲醛和甲胺盐酸盐根据化合物13概述的步骤制得,和3-羟基-2,2-二甲基丙酸(300mg)制得,产率34%。1H NMR:(CDCl3,400M Hz):δ6.82(m,2H),4.52(s,2H),3.57(s,2H),3.06(s,3H),1.32(s,6H).LC-MS(ESI)[M+H]+计算值C13H16F3NO2,276.1;测得值,276.3。
化合物67:2-甲氧基-N,2-二甲基-N-(2,3,5-三氟苄基)丙酰胺的制备
根据化合物65概述的步骤,由2-甲氧基-2-甲基丙酸(300mg)和N-甲基-1-(2,3,5-三氟苯基)甲胺(447mg)制备标题化合物67,产率14%。1H NMR:(CDCl3,400M Hz):δ7.01-7.04(m,2H),4.64(s,2H),3.42(s,3H),3.37(s,3H),1.62(s,6H).LC-MS(ESI)[M+H]+计算值C13H16F3NO2,276.1;测得值,276.3。
化合物68:N,2,2-三甲基-3-(甲基氨基)-N-(3,4,5-三氟苄基)丙酰胺的制备
将3-氯-N,2,2-三甲基-N-(3,4,5-三氟苄基)丙酰胺(60mg),甲胺盐酸盐(27mg),碳酸钾(138mg)和碘化钾(33.2mg)在甲基腈(5mL)的混合物回流过夜。混合物用水(2mL)稀释,水层用二氯甲烷(5mL×3)萃取。合并有机层并浓缩。残余物通过Pre-HPLC纯化,得到2mg化合物68,为TFA盐。1H NMR:(CDCl3,400M Hz)δ6.80-6.88(m,2H),4.51(s,2H),4.22(brs,1H),3.00-3.16(m,5H),2.82(s,3H),1.51(s,6H).LC-MS(ESI)[M+H]+计算值C14H19F3N2O,289.2;测得值,289.4。
化合物69:N-甲基-N-(3,4,5-三氟苄基)三甲基乙酰胺的制备
根据化合物65概述的步骤,由新戊酸(14.6mg)和N-甲基-1-(3,4,5-三氟苯基)甲胺(25mg)制备标题化合物69,产率27%。1H NMR:(CDCl3,400M Hz):δ6.79-6.86(m,2H),4.52(s,2H),3.05(s,3H),1.33(s,9H).LC-MS(ESI)[M+H]+计算值C13H16F3NO,260.1;测得值,260.3。
化合物70:2,2-二甲基-N-(2,3,5-三氟苄基)丁酰胺的制备
根据化合物52概述的步骤,从(2,3,5-三氟苯基)甲胺(30mg)和2,2-二甲基丁酰氯(27.6mg)制备标题化合物58,产率41.5%。1H NMR:(CDCl3,400M Hz):δ6.81-6.87(m,2H),6.02(brs,1H),4.50(d,1H,J=1.2Hz),4.48(d,1H,J=1.2Hz),1.56(q,2H,J=7.6Hz),1.18(s,6H),0.82(t,3H,J=7.6Hz).LC-MS(ESI)[M+H]+计算值C13H16F3NO,260.1;测得值,260.3。
化合物71:3-甲氧基-N,2,2-三甲基-N-(3,4,5-三氟苄基)丙酰胺的制备
根据化合物65概述的步骤,由3-甲氧基-2,2-二甲基-丙酸(14mg)和N-甲基-1-(3,4,5-三氟苯基)甲胺(447mg)制备标题化合物71,产率13%。1H NMR:(CDCl3,400M Hz):δ6.84-6.88(m,2H),4.54(s,2H),3.48(s,2H),3.36(s,3H),3.04(s,3H),1.33(s,6H).LC-MS(ESI)[M+H]+计算值C14H18F3NO2,290.1;测得值,290.4。
化合物72:2-乙基-N,2-二甲基-N-(3,4,5-三氟苄基)丁酰胺的制备
根据化合物65概述的步骤,由N-甲基-1-(3,4,5-三氟苯基)甲胺(20mg)和2-乙基-2-甲基丁酸(15mg)制备标题化合物72,收率18%。1H NMR:(CDCl3,400M Hz):δ6.87-6.91(m,2H),4.50(s,2H),3.05(s,3H),1.77-1.84(m,2H),1.47-1.56(m,2H),1.23(s,3H),0.87(t,6H,J=7.6Hz).LC-MS(ESI)[M+H]+calad forC15H20F3NO,288.1;found 288.3.
化合物73:2-乙基-2-甲基-N-(2,3,5-三氟苄基)丁酰胺的制备
根据化合物65概述的步骤,从(2,3,5-三氟苯基)甲胺(30mg)和2-乙基-2-甲基丁酸(24.4mg)制备标题化合物73,产率12%。1H NMR:(CDCl3,400M Hz):δ6.82-6.88(m,2H),6.03(brs,1H),4.49(d,2H,J=6.0Hz),1.61-1.69(m,2H),1.39-1.48(m,2H),1.12(s,3H),0.80(t,6H,J=7.6Hz).LC-MS(ESI)[M+H]+计算值C14H18F3NO,274.1;测得值,274.3。
化合物74:N-乙基-N-(2,3,5-三氟苄基)环己烷甲酰胺的制备
根据化合物13概述的步骤,由2,3,5-三氟苯甲醛(320mg),乙胺盐酸盐(244mg)和2,2-二甲基丁酰氯(275mg)制备标题化合物74,产率53%。1HNMR(CDCl3,400MHz):δ6.77-683(m,1H),6.59-6.75(m,1H),4.61(s,2H),3.35(q,2H,J=7.2Hz),2.47-2.54(m,1H),1.41-1.95(m,10H),1.20(t,3H,J=7.2Hz).LC-MS(ESI)[M+H]+计算值C16H20F3NO,300.1;测得值,300.3。
化合物75:N,2,2-三甲基-N-(2,3,5-三氟苄基)丁酰胺的合成的制备
根据化合物13概述的步骤,由2,3,5-三氟苯甲醛(320mg),甲胺盐酸盐(202mg)和2,2-二甲基丁酰氯(275mg)制备标题化合物75,产率50%。1HNMR(CDCl3,400MHz):δ6.75-6.85(m,2H),4.64(s,2H),3.11(s,3H),1.68(q,2H,J=7.6Hz),1.28(s,6H),0.88(t,3H,J=7.6Hz).LC-MS(ESI)[M+H]+计算值C14H18F3NO,274.1;测得值,274.3。
化合物76:N-甲基-N-(2,3,5-三氟苄基)金刚烷-1-甲酰胺的制备
根据化合物13概述的步骤,由2,3,5-三氟苯甲醛(50mg),甲胺盐酸盐(29mg)和金刚烷-1-碳酰氯(40mg)制备标题化合物76,产率16%。1HNMR(CDCl3,400MHz):δ7.30-7.51(m,1H),6.66-6.70(m,1H),4.58(s,2H),3.10(s,3H),1.93-1.96(m,10H),1.64-1.67(m,4H).LC-MS(ESI)[M+H]+计算值C19H22F3NO,338.2;测得值,338.4。
化合物77:N-(2-羟乙基)-2,2-二甲基-N-(2,3,5-三氟苄基)丁酰胺的制备
根据化合物52概述的步骤,从2-((2,3,5-三氟苄基)氨基)乙醇(50mg)和2,2-二甲基丁酰氯(33mg)制备标题化合物77,产率30%。1HNMR(CDCl3,400MHz):δ6.92-6.97(m,1H),6.80-6.87(m,1H),4.21(t,2H,J=5.2Hz),3.92(s,2H),2.89(t,2H,J=5.2Hz),1.57(q,2H,J=7.2Hz),1.16(s,6H),0.83(t,3H,J=7.2Hz).LC-MS(ESI)[M+H]+计算值C15H20F3NO2,304.1;测得值,304.3。
化合物78:N,2-二甲基-N-(2,3,5-三氟苄基)丙烷-2-亚磺酰胺的制备
根据化合物52概述的步骤,由N-甲基-1-(2,3,5-三氟苯基)甲胺(50mg)和2,2-二甲基丁酰氯(57mg)制备标题化合物78,收率30%。1HNMR(CDCl3,400MHz):δ6.83-6.94(m,2H),4.23-4.32(m,2H),2.64(s,3H),1.21(s,9H).LC-MS(ESI)[M+H]+计算值C12H16F3NOS,280.1;测得值,280.2。
化合物79:N-甲基-N-(2,3,5-三氟苄基)环己烷磺酰胺的制备
根据化合物52概述的步骤,由N-甲基-1-(2,3,5-三氟苯基)甲胺(20mg)和环己烷磺酰氯(30mg)制备标题化合物79,产率11%。1HNMR(CDCl3,400MHz):δ7.02-7.07(m,1H),6.84-6.91(m,1H),4.46(s,2H),2.99-3.05(m,1H),2.86(s,3H),1.95-2.15(m,2H),1.91-1.94(m,2H),1.57-1.74(m,5H),1.21-1.28(m,1H).LC-MS(ESI)[M+H]+计算值C14H18F3NO2S,322.1;测得值,322.3.
化合物80:N,1-二甲基-N-(2,3,5-三氟苄基)环丙烷甲酰胺的制备
根据化合物65概述的步骤,从1-甲基环丙烷羧酸(20mg)和N-甲基-1-(2,3,5-三氟苯基)甲胺(35mg)制备标题化合物80,产率35%。1H NMR:(CDCl3,400M Hz):δ6.80-6.83(m,2H),4.52(s,2H),3.05(s,3H),1.34(s,3H),0.98(t,2H,J=4.8Hz),0.63(t,2H,J=4.8Hz).LC-MS(ESI)[M+H]+计算值C13H14F3NO,258.1;测得值,258.3。
化合物81:N,2,2,3,3-五甲基-N-(3,4,5-三氟苄基)-环丙烷甲酰胺的制备
根据化合物65概述的步骤,由2,2,3,3-四甲基环丙烷甲酸(30mg)和N-甲基-1-(3,4,5-三氟苯基)甲胺(37mg)制备标题化合物81,产率28.5%。1H NMR:(CDCl3,400M Hz):δ6.83-6.87(m,2H),4.50(s,2H),2.96(s,3H),1.21(s,6H),1.18(s,6H).LC-MS(ESI)[M+H]+计算值C16H20F3NO,300.1;测得值,300.3。
化合物82:N-甲基-1-苯基-N-(2,3,5-三氟苄基)环丙烷甲酰胺的制备
根据化合物65概述的步骤,由苯基环丙烷甲酸(50mg)和N-甲基-1-(2,3,5-三氟苯基)甲胺(55mg)制备标题化合物82,产率30%。1H NMR:(CDCl3,400M Hz):δ7.26-7.30(m,1H),7.16-7.26(m,3H),6.74-6.94(m,3H),4.65(s,2H),2.85(s,3H),1.43-1.46(m,2H),1.23(m,2H).LC-MS(ESI)[M+H]+测得值C18H16F3NO,320.1;测得值,320.3。
化合物83:N-甲基-N-(2,3,5-三氟苄基)环丁烷甲酰胺的制备
根据化合物65概述的步骤,由环丁烷羧酸(20mg)和N-甲基-1-(2,3,5-三氟苯基)甲胺(35mg)制备标题化合物83,产率29.2%。1H NMR:(CDCl3,400M Hz):δ6.76-6.86(m,2H),4.61(s,2H),3.29-3.33(m,1H),2.89(s,3H),2.32-2.41(m,2H),2.17-2.22(m,2H),1.86-1.99(m,2H).LC-MS(ESI)[M+H]+计算值C13H14F3NO,258.2;测得值,258.4。
化合物84:N-甲基-N-(2,3,5-三氟苄基)-1-(三氟甲基)环丁烷甲酰胺的制备
根据化合物65概述的步骤,由1-(三氟甲基)环丁烷甲酸(30mg)和N-甲基-1-(2,3,5-三氟苯基)甲胺(31mg)制备标题化合物84,产率25.9%。1H NMR:(CDCl3,400M Hz):δ6.80-6.89(m,1H),6.74-6.77(m,1H),4.66(s,2H),2.92(s,3H),2.68-2.77(m,2H),2.52-2.58(m,2H),2.08-2.16(m,1H),1.83-1.87(m,1H).LC-MS(ESI)[M+H]+计算值C14H13F6NO,326.1;测得值,326.4。
化合物85:N-甲基-N-(3,4,5-三氟苄基)环戊烷甲酰胺的制备
根据化合物65概述的步骤,从环戊烷甲酸(30mg)和N-甲基-1-(3,4,5-三氟苯基)甲胺(46mg)制备标题化合物85,产率25.2%。1H NMR:(CDCl3,400M Hz):δ6.28-6.86(m,2H),4.50(s,2H),2.99(s,3H),2.93-2.97(m,1H),1.73-1.89(m,6H),1.57-1.62(m,2H).LC-MS(ESI)[M+H]+计算值C14H16F3NO,272.1;测得值,272.3。
化合物86:N-甲基-N-(2,3,5-三氟苄基)-1-(三氟甲基)环戊烷甲酰胺的制备
根据化合物65概述的步骤,由1-(三氟甲基)环戊烷甲酸(30mg)和N-甲基-1-(2,3,5-三氟苯基)甲胺(29mg)制备标题化合物86,产率26.9%。1H NMR:(CDCl3,400M Hz):δ6.79-6.85(m,1H),6.65-6.69(m,1H),4.65(s,2H),3.07(s,3H),2.38-2.44(m,2H),2.15-2.21(m,2H),1.59-1.74(m,4H).LC-MS(ESI)[M+H]+计算值C15H15F6NO,340.1;测得值,340.3。
化合物87:N-甲基-1-苯基-N-(2,3,5-三氟苄基)环戊烷甲酰胺的制备
根据化合物65概述的步骤,由1-苯基环戊烷甲酸(50mg)和N-甲基-1-(2,3,5-三氟苯基)甲胺(47mg)制备标题化合物87,产率29.5%。1H NMR:(CDCl3,400M Hz):δ7.19-7.31(m,5H),6.74-6.77(m,2H),4.60(s,2H),2.54(s,3H),2.37-2.43(m,2H),2.02-2.05(m,2H),1.66-1.77(m,4H).LC-MS(ESI)[M+H]+计算值C20H20F3NO,348.1;测得值,348.3。
化合物88:1-N-乙基-N-甲基-N-(3,4,5-三氟苄基)环丁烷甲酰胺的制备
根据化合物65概述的步骤,从1-乙基环丁烷羧酸(18mg)和N-甲基-1-(3,4,5-三氟苯基)甲胺(25mg)制备标题化合物88,产率19.7%。1H NMR:(CDCl3,400M Hz):δ6.74-6.94(m,2H),4.46(s,2H),2.82(s,3H),2.46-2.55(m,2H),1.74-1.98(m,6H),0.88(t,3H,J=7.6Hz).LC-MS(ESI)[M+H]+计算值C15H18F3NO,286.1;测得值,286.4。
化合物89:1-N-乙基-N-甲基-N-(3,4,5-三氟苄基)环戊烷甲酰胺的制备
根据化合物65概述的步骤,由1-乙基环戊烷羧酸(20mg)和N-甲基-1-(3,4,5-三氟苯基)甲胺(25mg)制备标题化合物89,产率18.7%。1H NMR:(CDCl3,400M Hz):δ6.82-6.90(m,2H),4.50(s,2H),2.99(s,3H),2.18-2.27(m,2H),1.66(q,2H,J=7.6Hz),1.57-1.62(m,6H),0.84(t,3H,J=7.6Hz).LC-MS(ESI)[M+H]+计算值C16H20F3NO,300.2;测得值,300.4。
化合物90:N-苄基-N,2,2-三甲基丁酰胺的制备
根据化合物10概述的步骤,由N-(2-氟苄基)-2,2-二甲基丁酰胺(1.312g)和碘甲烷(1g)制备标题化合物90,收率72%。1H NMR(CDCl3):δ7.21-7.33(m,5H),4.64(s,2H),2.99(s,3H),1.68(q,2H,J=7.6Hz),1.29(s,6H),0.90(t,3H,J=7.6Hz).
化合物91:N-(3,4-二氟苄基)-N,2,2-三甲基丁酰胺的制备
根据化合物10概述的步骤,由化合物8(71.7mg)和碘甲烷(84.5mg)制备标题化合物91,收率45%。1H NMR(CDCl3):δ7.03-7.14(m,2H),6.94-6.98(m,1H),4.55(s,2H),3.02(s,3H),1.69(q,2H,J=7.6Hz),1.29(s,6H),0.89(t,3H,J=7.6Hz)。
化合物92:N-苄基-N-羟基-2,2-二甲基丁酰胺的制备
将正苄基羟胺盐酸盐(100mg)溶于2ml THF/H2O(1/1)和0.45ml饱和NaHCO3水溶液中。将溶液冷却至0℃,加入2,2-二甲基丁酰氯(81mg),将混合物在室温下搅拌16小时。混合物用EtOAc萃取,合并的有机层用盐水洗涤,干燥(Na2SO4)并真空浓缩。通过硅胶色谱纯化,得到化合物80(60mg,43.3%),为白色固体。1H NMR(CDCl3,400MHz):δ7.34-37(m,2H),7.31-7.33(m,3H),4.89(s,2H),1.69(q,2H,J=7.6Hz),1.26(s,6H),0.86(t,6H,J=7.6Hz).LC-MS(ESI)[M+H]+计算值C13H19NO2,222.1;测得值,222.4。
化合物93:N-羟基-2,2-二甲基-N-(2,3,5-三氟苄基)丁酰胺的制备
试剂与条件;(a)(叔丁氧基羰基)氧基氨基甲酸叔丁酯,1N NaOH,TBAB,DCM;(b)TFA,DCM;(c)2,2-二甲基丁酰氯,NaHCO3水溶液,THF,水。
将叔丁基(叔丁氧基羰基)氧基氨基甲酸酯(104mg)和1-(溴甲基)-2,3,5-三氟苯(100mg)溶解在CH2Cl2(10ml)中。加入1M NaOH(4.5ml)和四丁基溴化铵(7mg),并在室温下搅拌过夜。将所得混合物用水洗涤并用Na2SO4干燥,真空浓缩,通过硅胶色谱纯化,得到(叔丁氧基羰基)氧基(2,3,5-三氟苄基)-氨基甲酸酯(150mg,89%)。1HNMR(CDCl3,400MHz):δ6.95-6.98(m,1H),6.81-6.89(m,1H),4.82(s,2H),1.50(s,9H),1.49(s,9H).
将上述中间体溶于二氯甲烷(2.5ml)中,在0℃下加入TFA(0.8mL)。将混合物在室温下搅拌4小时并浓缩,得到作为TFA盐的N-(2,3,5-三氟苄基)羟胺(100mg),其不经进一步纯化而使用。
将上述中间体溶于THF(3ml)中,加入水(3ml),加入1ml饱和NaHCO3水溶液。将混合物在室温下搅拌30分钟,然后冷却至0℃,加入2,2-二甲基丁酰氯(54mg)并搅拌过夜。混合物用EtOAc萃取,用盐水洗涤,干燥(Na 2SO4),真空浓缩,通过硅胶色谱纯化,得到化合物93(80mg,总产率65%)。1HNMR(CDCl3,400MHz):δ9.80(s,1H),7.41-7.48(m,1H),6.91-6.96(m,1H),4.74(s,2H),1.64(q,2H,J=7.6Hz),1.13(s,6H),0.72(t,3H,J=7.6Hz).LC-MS(ESI)[M+H]+计算值C13H16F3NO2,276.1;测得值,276.2.
化合物94:N-(4-氟苄基)-N-羟基-2,2-二甲基丁酰胺的制备
根据化合物93概述的步骤,由叔丁基(叔丁氧基羰基)氧基氨基甲酸叔丁酯(247mg),1-(溴甲基)-4-氟苯(200mg)和2,2-二甲基丁酰氯(135mg)制备标题化合物94,产率71%。1HNMR(CDCl3,400MHz):δ7.27-7.31(m,2H),7.02-7.06(m,2H),4.85(s,2H),1.68(q,2H,J=7.6Hz),1.26(s,6H),0.84(t,3H,J=7.6Hz).LC-MS(ESI)[M+H]+计算值,C13H18FNO2,240.1;测得值,240.2。
化合物95:N-(3,4-二氟苄基)-N-羟基-2,2-二甲基丁酰胺的制备
根据化合物93概述的步骤,由叔丁基(叔丁氧基羰基)氧基氨基甲酸酯(225mg),4-(溴甲基)-1,2-二氟苯(200mg)和2,2-二甲基丁酰氯(135mg)制备标题化合物95,产率71%。1HNMR(CDCl3,400MHz):δ7.10-7.17(m,2H),7.02-7.06(m,1H),4.81(s,2H),1.68(q,2H,J=7.6Hz),1.25(s,6H),0.84(t,3H,J=7.6Hz).LC-MS(ESI)[M+H]+计算值C13H17F2NO2,258.1;测得值,258.2。
化合物96:N-(2,4-二氟苄基)-N-羟基-2,2-二甲基丁酰胺的制备
根据化合物93概述的步骤,由(叔丁氧基羰基)氧基氨基甲酸叔丁酯(225mg),1-(溴甲基)-2,4-二氟苯(200mg)和2,2-二甲基丁酰氯(135mg)制备标题化合物96,产率65%。1HNMR(CDCl3,400MHz):δ77.32-7.38(m,1H),6.80-6.90(m,2H),4.90(s,2H),1.68(q,2H,J=7.6Hz),1.25(s,6H),0.84(t,3H,J=7.6Hz).LC-MS(ESI)[M+H]+计算值C13H17F2NO2,258.1;测得值,258.2。
化合物97:N-羟基-2,2-二甲基-N-(2,3,4-三氟苄基)丁酰胺的合成的制备
根据化合物93概述的步骤,由叔丁基(叔丁氧基羰基)氧基氨基甲酸叔丁酯(104mg),1-(溴甲基)-2,3,4-三氟苯(100mg)和2,2-二甲基丁酰氯(54mg)制备标题化合物97,收率65%。1HNMR(CDCl3,400MHz):δ7.08-7.14(m,1H),6.93-7.00(m,1H),4.92(s,2H),1.68(q,2H,J=7.6Hz),1.25(s,6H),0.84(t,3H,J=7.6Hz).LC-MS(ESI)[M+H]+计算值,C13H16F3NO2,276.1;测得值,276.2。
化合物98:N-羟基-2,2-二甲基-N-(2,4,5-三氟苄基)丁酰胺的合成的制备
根据化合物93概述的步骤,由叔丁基(叔丁氧基羰基)氧基氨基甲酸叔丁酯(104mg),1-(溴甲基)-2,4,5-三氟苯(100mg)和2,2-二甲基丁酰氯(54mg)制得标题化合物98,产率65%。1HNMR(CDCl3,400MHz):δ7.19-7.24(m,1H),6.91-6.98(m,1H),4.88(s,2H),1.68(q,2H,J=7.6Hz),1.25(s,6H),0.84(t,3H,J=7.6Hz).LC-MS(ESI)[M+H]+计算值C13H16F3NO2,276.1;测得值,276.2。
化合物99:N-羟基-2,2-二甲基-N-(3,4,5-三氟苄基)丁酰胺的合成的制备
根据化合物93概述的步骤,由叔丁基(叔丁氧基羰基)氧基氨基甲酸叔丁酯(104mg),5-(溴甲基)-1,2,3-三氟苯(100mg)和2,2-二甲基丁酰氯(54mg)制得标题化合物99,产率65%。1HNMR(CDCl3,400MHz):δ6.92-7.00(m,2H),4.79(s,2H),1.68(q,2H,J=7.6Hz),1.26(s,6H),0.85(t,3H,J=7.6Hz).LC-MS(ESI)[M+H]+calad forC13H16F3NO2,276.1;found,276.2.
化合物100:(S)-3-(2,2-二甲基丁酰氨基)-3-苯基丙酸甲酯的制备
(S)-3-氨基-3-苯基丙酸(1g)溶于甲醇(10ml)中,在0℃下加入1ml亚硫酰氯。将混合物回流4小时。将溶剂蒸发至干,所得固体用石油醚洗涤。将粗产物和三乙胺(0.7ml)溶于15ml CH2Cl2中,在0℃,氮气下缓慢加入2,2-二甲基丁酰氯(1g)。将混合物在室温下搅拌4小时。除去溶剂后,通过硅胶柱色谱纯化,得到化合物100(110mg,32%)。1HNMR(CDCl3,400MHz):δ7.31-7.35(m,2H),7.23-7.28(m,3H),5.40-5.45(m,1H),3.62(s,3H),2.87(m,2H),1.57(q,2H,J=7.6Hz),1.19(s,3H),1.18(s,3H),0.83(t,3H,J=7.6Hz).LC-MS(ESI)[M+H]+计算值C16H23NO3,278.2;测得值,278.4。
化合物101:(S)-2,2-二甲基-N-(3-(二甲基氨基)-3-氧代-1-苯基丙基)丁酰胺的制备
将化合物100(840mg)溶于30mL甲醇中,加入1M NaOH(40mL)。将混合物在室温下搅拌5小时。除去溶剂并用1N HCl酸化。水相用二氯甲烷萃取。合并的有机层用水洗涤,用Na2SO4干燥。过滤并蒸发至干,得到褐色油状的(S)-3-(2,2-二甲基丁酰氨基)-3-苯基丙酸(780mg,98%)。1HNMR(CDCl3,400MHz):δ7.31-7.34(m,2H),7.24-7.28(m,3H),6.75(d,1H,J=8.4Hz),5.40-5.45(m,1H),2.83-2.93(m,2H),1.55(q,2H,J=7.6Hz),1.16(s,1H),1.15(s,1H),0.81(t,3H,J=7.6Hz).
根据化合物65概述的步骤,由(S)-3-(2,2-二甲基丁酰胺基)-3-苯基丙酸(30mg)和盐酸甲胺(9.2mg)制备标题化合物101,收率55%。1HNMR(CDCl3,400MHz):δ7.83(brs,1H),7.26-7.33(m,3H),7.21-7.25(m,2H),5.92(brs,1H),5.26-5.31(m,1H),3.67-3.72(m,1H),3.12-3.19(m,1H),2.71(d,3H,J=4.8Hz),1.58(m,2H),1.20(s,3H),1.19(s,3H),0.82(t,3H,J=7.6Hz).LC-MS(ESI)[M+H]+计算值C15H21NO3,277.2;测得值277.4.
化合物102:(S)-N-(3–((2-(2-甲氧基乙氧基)乙基)氨基)-3-氧代-1-苯基丙基)-2,2-二甲基丁酰胺的制备
根据化合物101概述的步骤,由(S)-3-(2,2-二甲基丁酰胺基)-3-苯基丙酸(30mg)和2-(2-甲氧基乙氧基)乙胺(16.3mg)制备标题化合物102,产率51%。1HNMR(CDCl3,400MHz):δ7.98-8.01(brs,1H),7.27-7.33(m,4H),7.21-7.25(m,1H),6.41-6.45(brs,1H),5.27-5.32(m,1H),3.67-3.74(m,1H),3.40-3.56(m,5H),3.36(s,3H),3.13-3.19(m,2H),2.78-2.83(m,1H),2.68-2.73(m,1H),1.54-1.62(m,2H),1.22(s,3H),1.21(s,3H),0.83(t,3H,J=7.2Hz).LC-MS(ESI)[M+H]+计算值C20H32N2O4,365.2;测得值,365.4.。
化合物103:(S)-N-(3-(乙基氨基)-3-氧代-1-苯基丙基)-2,2-二甲基丁酰胺的制备
根据化合物101概述的步骤,从(S)-3-(2,2-二甲基丁酰胺基)-3-苯基丙酸(30mg)和盐酸乙胺(11mg)制备标题化合物103,产率39%。1HNMR(CDCl3,400MHz):δ1H-NMR(CDCl3)δ7.87-7.89(brs,1H),7.27-7.32(m,4H),7.23-7.25(m,1H),5.74(brs,1H),5.28-5.32(m,1H),3.12-3.24(m,2H),2.757(dd,1H,J=4.8,14.4Hz),2.582(dd,1H,J=5.6,14.4Hz),1.56-1.62(qd,2H,J=7.2,1.6Hz),1.21(s,3H),1.21(s,3H),1.006(t,3H,J=7.2Hz),0.823(t,3H,J=7.2Hz)LC-MS(ESI)[M+H]+计算值C17H26N2O2,291;测得值,291.2。
化合物104:(S)-N-(3-(环己基氨基)-3-氧代-1-苯基丙基)-2,2-二甲基丁酰胺的制备
根据化合物101概述的步骤,由(S)-3-(2,2-二甲基丁酰氨基)-3-苯基丙酸(30mg)和环己胺(14mg)制备标题化合物104,产率21%。1HNMR(CDCl3,400MHz):δ7.95(brs,1H),7.27-7.31(m,3H),7.20-7.24(m,2H),5.41(brs,1H),5.28-5.32(m,1H),3.62-3.71(m,1H),2.73(dd,1H,J=4.8,14.4Hz),2.50(dd,1H,J=4.8,14.4Hz),1.79-1.82(m,2H),1.56-1.67(m,6H),1.26-1.36(m,2H),1.21(s,3H),1.20(s,3H),1.01-1.13(m,2H),0.82(t,3H,J=7.6Hz).LC-MS(ESI)[M+H]+计算值C21H32N2O2,345.2;测得值,345.4。
化合物105:(S)-2,2-二甲基-N-(3-氧代-1-苯基-3-(哌啶-1-基)丙基)丁酰胺的制备
根据化合物101概述的步骤,从(S)-3-(2,2-二甲基丁酰胺基)-3-苯基丙酸(30mg)和哌啶(14mg)制备标题化合物105,产率29%。1HNMR(CDCl3,400MHz):δ7.99(brs,1H),7.27-7.32(m,4H),7.19-7.23(m,1H),5.32(m,1H),3.56-3.60(m,1H),3.32-3.39(m,1H),3.17-3.24(m,2H),3.033(dd,1H,J=5.6,14.4Hz),2.679(dd,1H,J=4.8,14.4Hz),1.55-1.61(m,2H),1.50-1.54(m,2H),1.36-1.48(m,3H),1.20(s,3H),1.19(s,3H),1.04-1.10(m,1H),0.83(t,3H,J=7.6Hz).LC-MS(ESI)[M+H]+计算值C20H30N2O2,331.2,测得值331.4.
化合物106:(S)-2,2-二甲基-N-(3-氧代-1-苯基-3-(苯基氨基)丙基)丁酰胺的制备
根据化合物101概述的步骤,从(S)-3-(2,2-二甲基丁酰胺基)-3-苯基丙酸(30mg)和苯胺(13mg)制备标题化合物106,产率28%。1HNMR(CDCl3,400MHz):δ7.65(brs,1H),7.27-7.40(m,9H),7.106(t,1H,J=7.2Hz),5.41-5.45(m,1H),2.83-2.99(m,2H),1.578(q,2H,J=7.6Hz),1.19(s,6H),0.81(t,3H,J=7.6Hz).LC-MS(ESI)[M+H]+计算值C21H26N2O2,339.2;测得值,339.4。
化合物107:(S)-N-(3-(苄基氨基)-3-氧代-1-苯基丙基)-2,2-二甲基丁酰胺的制备
根据化合物101概述的步骤,从(S)-3-(2,2-二甲基丁酰胺基)-3-苯基丙酸(30mg)和苯基甲胺(15mg)制备标题化合物107,产率28%。1HNMR(CDCl3,400MHz):δ7.91(brs,1H),7.28-7.39(m,8H),7.02-7.04(m,2H),6.29(brs,1H),5.33-5.36(m,1H),4.39(d,2H,J=5.2Hz),2.84-2.91(m,1H),2.71-2.76(m,1H),1.59(qd,2H,J=1.2,7.6Hz),1.21(s,3H),1.20(s,3H),0.83(t,3H,J=7.6Hz).LC-MS(ESI)[M+H]+计算值C22H28N2O2,353.2;测得值,353.4.
化合物108:(S)-2,2-二甲基-N-(3-氧代-3-(苯乙基氨基)-1-苯基丙基)丁酰胺的制备
根据化合物101概述的步骤,从(S)-3-(2,2-二甲基丁酰胺基)-3-苯基丙酸(30mg)和苯基甲胺(16mg)制备标题化合物108,产率31%。1HNMR(CDCl3,400MHz):δ7.96-7.98(brs,1H),7.27-7.34(m,4H),7.17-7.25(m,4H),6.94-6.97(m,2H),5.59(brs,1H),5.28-5.32(m,1H),3.46-3.55(m,1H),3.25-3.33(m,1H),2.67-2.75(m,2H),2.49-2.61(m,2H),1.58(qd,2H,J=2.0,7.6Hz),1.22(s,3H),1.21(s,3H),0.84(t,3H,J=7.6Hz).LC-MS(ESI)[M+H]+计算值C23H30N2O2,367.2;测得值,367.4。
化合物109:(R)-N-(2-羟基-1-苯基乙基)-2,2-二甲基丁酰胺的制备
将(R)-2-氨基-2-苯基乙醇(50mg,0.365mmol)和NaHCO3(91.9mg,1.0945mmol)溶于2mL THF/H2O(v/v=1/1)。在0℃,氮气下将2,2-二甲基丁酰氯(43mg,0.398mmol)缓慢加入到溶液中。将混合物在室温下搅拌16小时,并用EtOAc(15mL×3)萃取。合并的有机层用盐水洗涤,用Na2SO4干燥。过滤并蒸发至干。残余物通过柱色谱纯化,得到合物109,为白色固体(45mg,59.2%)。1H NMR:(CDCl3,400M Hz):δ(ppm)7.35-7.39(m,2H),7.28-7.32(m,3H),6.26(brs,1H),5.05-5.09(m,1H),3.87-3.94(m,2H),2.70(brs,1H),1.59(q,2H,J=7.6Hz),1.20(s,3H),1.19(s,3H),0.87(t,3H,J=7.6Hz).LC-MS(ESI)[M+H]+计算值C14H21NO2,236.2;测得值,236.3。
化合物110:N-(2-羟基-1-苯基乙基)-2,2-二甲基丁酰胺的制备
根据化合物109概述的步骤,由2-氨基-2-苯基乙醇(50mg)和2,2-二甲基丁酰氯(54mg)制备标题化合物110,产率78.3%。1H NMR:(CDCl3,400M Hz)δ7.36-7.40(m,2H),7.28-7.33(m,3H),6.27(brs,1H),5.07(dd,1H,J=5.6,10.8Hz),3.88-3.92(m,2H),2.72(brs,1H),1.58(q,2H,J=7.6Hz),1.20(s,3H),1.19(s,3H),0.87(t,3H,J=7.6Hz).LC-MS(ESI)[M+H]+计算值C15H23NO2,236.2;测得值,236.3。
化合物111:N-(2-羟基-1-苯基乙基)-N,2,2-三甲基丁酰胺的制备
根据化合物109概述的步骤,从2-(甲基氨基)-2-苯基乙醇(50mg)和2,2-二甲基丁酰氯(48mg)制备标题化合物111,产率9.8%。1H NMR:(MeOD,400M Hz)δ7.43-7.44(m,3H),7.28-7.38(m,2H),4.29-4.38(m,2H),5.88(m,1H),2.43(s,3H),1.528(q,2H,J=7.6Hz),1.11(s,6H),0.75(t,3H,J=7.6Hz).LC-MS(ESI)[M+H]+计算值C15H23NO2,250.2;测得值,250.3。
化合物112:N-(2-甲氧基-1-苯基乙基)-N,2,2-三甲基丁酰胺的制备
将N-(2-羟基-1-苯基乙基)-2,2-二甲基丁酰胺(40mg,0.17mmol)溶于2mL无水THF中。在0℃,氮气下,将NaH(20.4mg,0.51mmol,60%,在原料油中)分批加入到该溶液中。在0℃下搅拌0.5小时后,加入碘甲烷(72.5mg,0.51mmol)。将混合物在室温下搅拌16小时,用水(1mL)淬灭并用EtOAc萃取。将合并的有机层蒸发至干,残余物通过柱色谱纯化,得到化合物112(20mg,44.7%)。1H NMR:(CDCl3,400M Hz)δ7.31-7.35(m,2H),7.22-7.28(m,3H),5.70-6.20(m,1H),3.81-3.90(m,2H),3.41(s,3H),2.84(s,3H),1.63-1.73(m,2H),1.29(s,3H),1.28(s,3H),0.91(t,3H,J=7.6Hz).LC-MS(ESI)[M+H]+计算值C16H25NO2,264.2;测得值,264.4。
化合物113:3-环己基-1-(2-氟苄基)-1-甲基脲的制备
向1-(2-氟苯基)-N-甲基甲胺(97mg)的THF(10ml)溶液中加入N,N-二异丙基乙胺(135mg),然后加入在THF(1ml)中的异氰酸根合环己烷(131mg)。将混合物搅拌过夜并用水稀释。水层用CH2Cl2萃取,合并的有机层用水和盐水洗涤,干燥(Na2SO4)并真空浓缩。残余物通过柱色谱纯化,得到化合物113(65mg,35%)。1HNMR:(CDCl3,400M Hz):δ7.22-7.34(m,2H),7.02-7.14(m,2H),4.53(s,2H),3.59-3.71(m,1H),2.90(s,3H),1.91-1.97(m,2H),1.57-1.71(m,3H),1.31-1.42(m,2H),1.03-1.18(m,3H).LC-MS(ESI)[M+H]+计算值C15H21FN2O,265.2;测得值,265.4。
化合物114:1-(2-氟苄基)-3-异丙基-1-甲基脲的制备
根据化合物113概述的步骤,从2-异丙基异氰酸酯(92mg)和1-(2-氟苯基)-N-甲基甲胺(97mg)制备标题化合物117,产率30%。1H NMR:(CDCl3,400M Hz):δ7.22-7.32(m,2H),7.02-7.14(m,2H),4.53(s,2H),3.96-4.03(m,1H),2.89(s,3H),1.15(d,6H,J=6.4Hz),LC-MS(ESI)[M+H]+计算值C12H17FN2O,225.1;测得值,225.2。
化合物115:1-乙基-3-异丙基-3-甲基-1-(2,3,5-三氟苄基)脲的制备
在0℃,氮气下,向有三光气(154mg)的二氯甲烷(4mL)溶液中加入N-甲基丙-2-胺(40mg)。将混合物在0℃下搅拌4小时。然后除去溶剂,加入N-(2,3,5-三氟苄基)-乙胺(60mg)的二氯甲烷(2mL)溶液。将混合物在35℃下搅拌过夜,用水稀释。水层用EtOAc(5mL×3)萃取。将合并的有机层用饱和NaHCO 3和盐水洗涤,用Na2SO4干燥,过滤并蒸发至干。残余物通过柱色谱纯化,得到化合物115(4mg,2.5%),为黄色油状物。1H NMR:(CDCl3,400M Hz):δ6.86-6.89(m,1H),6.76-6.81(m,1H),4.38(s,2H),4.07(m,1H),3.09-3.14(q,2H,J=7.2Hz),2.70(s,3H),1.13-1.17(m,9H).LC-MS(ESI)[M+H]+计算值C14H19F3N2O,289.1;测得值,289.2。
化合物116:2-乙基-N-甲基-N-(2,3,5-三氟苄基)哌啶-1-甲酰胺的制备
根据化合物115概述的步骤,由三光气(77.1mg),2-乙基哌啶(29.4mg)和N-甲基-1-(2,3,5-三氟苯基)甲胺(30mg)制备标题化合物116,产率14.9%。1H NMR:(CDCl3,400MHz):δ6.79-6.88(m,2H),4.45(d,1H,J=15.6Hz),4.29(d,1H,J=15.6Hz),3.72-3.74(m,1H),3.43-3.48(m,1H),2.94-3.01(m,1H),2.77(s,3H),1.57-1.70(m,8H),0.98(t,3H,J=7.6Hz).LC-MS(ESI)[M+H]+计算值C16H21F3N2O,315.2;测得值,315.3。
化合物117:N,2-二甲基-N-(2,3,5-三氟苄基)哌啶-1-甲酰胺的制备
根据化合物115概述的步骤,由三光气(77.1mg),2-甲基哌啶(25.71mg)和N-甲基-1-(2,3,5-三氟苯基)甲胺(30mg)制备标题化合物117,产率15.6%。1H NMR:(CDCl3,400MHz):δ6.78-6.84(m,2H),4.43(d,1H,J=16Hz),4.34(d,1H,J=16Hz),3.90-3.93(m,1H),3.32-3.36(m,1H),2.95-3.02(m,1H),2.76(s,3H),1.44-1.68(m,6H),1.18(d,3H,J=4Hz).LC-MS(ESI)[M+H]+计算值C15H19F3N2O,301.1;测得值,301.3。
化合物118:N,3-二甲基-N-(2,3,5-三氟苄基)哌啶-1-甲酰胺的制备
根据化合物115概述的步骤,从三光气(84.8mg),2-甲基哌啶(28.3mg)和N-甲基-1-(2,3,5-三氟苯基)甲胺(30mg)制备标题化合物118,产率9.7%。1H NMR:(CDCl3,400MHz):δ7.05-7.07(m,1H),6.89-6.91(m,1H),4.42-4.84(m,2H),2.80(s,3H),3.49-3.53(m,2H),2.75-2.77(m,2H),1.77-1.79(m,1H),1.57-1.67(m,4H),0.98(d,3H,J=6.4Hz).LC-MS(ESI)[M+H]+计算值C15H19F3N2O,301.1;测得值,301.3。
化合物119:1,1-二异丙基-3-甲基-3-(2,3,5-三氟苄基)脲的制备
根据化合物115概述的步骤,由三光气(84.8mg),二异丙基胺(26.86mg)和N-甲基-1-(2,3,5-三氟苯基)甲胺(30mg)制备标题化合物119,产率19.3%。1H NMR:(CDCl3,400MHz):δ6.79-6.82(m,2H),4.30(s,2H),3.58-3.62(m,2H),2.68(s,3H),1.26(d,12H,J=6.4Hz).LC-MS(ESI)[M+H]+计算值C15H21F3N2O,303.2;测得值,303.4。
化合物120:异丙基-1,3-二甲基-3-(2,3,5-三氟苄基)脲的制备
根据化合物115概述的步骤,由三光气(84.8mg),N-甲基丙-2-胺(20.86mg)和N-甲基-1-(2,3,5-三氟苯基)甲胺(30mg)制备标题化合物120,产率20.8%。1H NMR:(CDCl3,400MHz):δ6.80-6.87(m,2H),4.38(s,2H),4.00-4.11(m,1H),2.75(s,3H),2.67(s,3H),1.10(d,6H,J=6.4Hz).LC-MS(ESI)[M+H]+计算值C13H17F3N2O,275.1;测得值,275.2。
化合物121:N,2,6-三甲基-N-(2,3,5-三氟苄基)哌啶-1-甲酰胺的制备
根据化合物115概述的步骤,由三光气(84.8mg),2,6-二甲基哌啶(32.28mg)和N-甲基-1-(2,3,5-三氟苯基)甲胺(30mg)制备标题化合物121,收率14.5%。1H NMR:(CDCl3,400M Hz):δ6.80-6.90(m,2H),4.61(s,2H,),3.18-3.23(m,2H),2.97(s,3H),1.70-1.75(m,1H),1.59-1.65(m,2H),1.32-1.45(m,1H),1.22-1.39(m,2H),1.12(d,6H,J=6.4Hz).LC-MS(ESI)[M+H]+计算值C16H21F3N2O,315.2;测得值,315.4。
化合物122:(R)-2,2-二甲基-N-(2-(甲基氨基)-2-氧代-1-苯乙基)丁酰胺的制备
根据化合物65概述的步骤,由(R)-2-(2,2-二甲基丁酰胺基)-2-苯基乙酸(30mg),其为根据化合物101概述的步骤由(R)-2-氨基-2-苯基乙酸制备得到,和盐酸甲胺盐酸盐(10mg)制备标题化合物122,收率35%。1HNMR(CDCl3,400MHz):δ7.28-7.38(m,5H),7.14(brs,1H),6.38(brs,1H),5.52(d,J=6.8Hz,1H),2.77(d,J=4.8Hz,3H),1.51-1.60(m,2H),1.18(s,3H),1.17(s,3H),0.78(t,3H,J=7.6Hz).LC-MS(ESI)[M+H]+计算值C15H22N2O2,263.2;测得值,263.3。
化合物123:(R)-N-(2-(二甲基氨基)-2-氧代-1-苯基乙基)-2,2-二甲基丁酰胺的制备
根据化合物65概述的步骤,由(R)-2-(2,2-二甲基丁酰胺基)-2-苯基乙酸(30mg)和二甲胺(6.48mg)制备标题化合物123,产率35%。1HNMR(CDCl3,400MHz):δ7.28-7.41(m,5H),5.80(d,1H,J=6.8Hz),2.99(s,3H),2.89(s,3H),1.45-1.55(m,2H),1.13(s,3H),1.12(s,3H),0.70(t,3H,J=7.6Hz).LC-MS(ESI)[M+H]+计算值C16H24N2O2,277.2;测得值,277.4。
化合物124:(R)-N-(2-(苄基氨基)-2-氧代-1-苯乙基)-2,2-二甲基丁酰胺的制备
根据化合物65概述的步骤,由(R)-2-(2,2-二甲基丁酰胺基)-2-苯基乙酸(30mg)和苯基甲胺(15.4mg)制备标题化合物124,产率37%。1HNMR(CDCl3,400MHz):δ7.28-7.38(m,5H),7.23-7.26(m,2H),7.07-7.12(m,3H),6.14(brs,1H),5.49(d,1H,J=6.4Hz),4.42(d,2H,J=5.2Hz),1.49-1.55(m,2H),1.16(s,3H),1.15(s,3H),0.76(t,3H,J=7.6Hz).LC-MS(ESI)[M+H]+计算值C21H26N2O2,339.2;测得值,339.4。
化合物125:(R)-2,2-二甲基-N-(2-氧代-2-(苯乙基氨基)-1-苯基乙基)丁酰胺的制备
根据化合物65概述的步骤,从(R)-2-(2,2-二甲基丁酰胺基)-2-苯基乙酸(30mg)和2-苯基乙胺(17.4mg)制备标题化合物125,收率38%。1HNMR(CDCl3,400MHz):δ7.28-7.35(m,5H),7.17-7.23(m,3H),7.11-7.12(brs,1H),6.92-6.94(m,2H),5.57(brs,1H),5.25-5.27(d,1H,J=6.0Hz),3.57-3.65(m,1H),3.32-3.40(m,1H),2.63-2.77(m,2H),1.50-1.56(qd,2H,J=7.6,2.0Hz),1.16(s,3H),1.15(s,3H),0.76(t,3H,J=7.6Hz).LC-MS(ESI)[M+H]+计算值C22H28N2O2,353.2;测得值,353.4。
化合物126:(S)-2,2-二甲基-N-(3-氧代-3-((2-苯氧基乙基)氨基)-1-苯基丙基)丁酰胺的制备
根据化合物65概述的步骤,从(S)-3-(2,2-二甲基丁酰氨基)-3-苯基丙酸(30mg)和2-苯氧基乙胺(19mg)制备标题化合物126,产率42%。1HNMR(CDCl3,400MHz):δ7.79-7.81(brs,1H),7.27-7.31(m,2H),7.19-7.26(m,4H),7.09-7.13(m,1H),6.95-7.00(m,1H),6.78-6.81(m,2H),5.94(brs,1H),5.31-5.35(m,1H),3.90-3.94(m,1H),3.79-3.84(m,1H),3.50-3.61(m,2H),2.77(dd,1H,J=4.8,14.4Hz),2.62(dd,1H,J=4.8,14.4Hz),1.56-1.63(m,2H),1.21(s,3H),1.20(s,3H),0.83(t,3H,J=7.6Hz).LC-MS(ESI)[M+H]+计算值C23H30N2O3,383.2,测得值,383.4。
化合物127:(R)-2,2-二甲基-N-(2-氧代-2-((2-苯氧基乙基)氨基)-1-苯乙基)丁酰胺的制备
根据化合物65概述的步骤,从(R)-2-(2,2-二甲基丁酰胺基)-2-苯基乙酸(30mg)和2-苯氧基乙胺(20mg)制备标题化合物127,产率40%。1HNMR(CDCl3,400MHz):δ7.27-7.36(m,5H),7.23-7.25(m,1H),6.92-7.00(m,2H),6.77-6.80(m,2H),6.10(brs,1H),5.41(d,1H,J=6.4Hz),3.94-4.03(m,2H),3.57-3.71(m,2H),1.51-1.57(m,2H),1.17(s,3H),1.16(s,3H),0.77(t,3H,J=7.6Hz).LC-MS(ESI)[M+H]+计算值C22H28N2O3,369.2;测得值,369.4。
化合物128:N-((4,5-二甲基噻唑-2-基)甲基)-N,2,2-三甲基丁酰胺的制备
根据化合物52概述的步骤,由1-(4,5-二甲基噻吩-2-基)-N-甲基甲胺(60mg),其为根据化合物13概述的步骤由4,5-二甲基噻吩-2-甲醛和甲胺制备得到,和2,2-二甲基丁酰氯(57mg)制备标题化合物128,产率36%。1H NMR:(CDCl3,400M Hz):δ6.61(s,1H),4.58(s,2H),3.03(s,3H),2.28(s,3H),2.07(s,3H),1.66(q,2H,J=7.6Hz),1.27(s,6H),0.88(t,3H,J=7.6Hz).LC-MS(ESI)[M+H]+计算值C14H23NOS254.2;测得值,254.3。
化合物129:2,6-二氯-N-甲基-N-(3,4,5-三氟苄基)苯甲酰胺的制备
按照化合物52概述的步骤,由N-甲基-1-(3,4,5-三氟苯基)甲胺(30mg)和2,6-二氯苯甲酰氯(39.5mg)制备标题化合物129,产率77%。1H NMR:(CDCl3,400M Hz):δ7.33-7.36(m,2H),7.26-7.29(m,1H),7.04-7.07(m,2H),4.72(s,2H),2.77(s,3H).LC-MS(ESI)[M+H]+计算值C15H10Cl2F3NO,348.0;测得值,348.2。
化合物130-135和151:
化合物130-135根据方案1的方法制备:
方案1:试剂和条件:(a):NaOH,二甲基硫酸盐,DCM/水
化合物136-147:
化合物136-147根据方案2的方法制备:
方案2:试剂和条件:(a):NH2OH*HCl;Na2CO3;(b):Na(CN)BH3;(c)2,2-二甲基丁酰氯或2,2-二甲基丁-3-烯酰氯,NaHCO3,THF/水,0℃30分钟,室温,16小时。
化合物148和149:
化合物148和149根据方案3的方法制备:
方案3:试剂和条件:(a):NaHCO3,碳酸氯乙酯,THF/DCM(b)LiAlH4,THF,室温,16小时(c):2,2-二甲基丁酰氯NaHCO3,THF/水,0℃30分钟,室温,16小时。
化合物150:
化合物150根据方案3的方法制备:
方案4:条件和试剂:(a):NaHCO3,碳酸氯乙酯,THF/DCM,0℃30分钟,室温,16小时。
化合物S1:N-(2,3,5-三氟苄基)三甲基乙酰胺的制备
(2,3,5-三氟苯基)甲胺(42mg,0.263mmol)和三乙胺(53.2mg,0.526mmol)溶于2mL无水CH2Cl2中。在氮气,0℃下,将新戊酰氯(38mg,0.316mmol)缓慢加入溶液中。将混合物在室温下搅拌2小时,用CH2Cl2和水稀释。有机层用饱和NaHCO3溶液,盐水洗涤,用Na2SO4干燥并浓缩。物残余通过色谱法纯化,得到化合物S1(49mg,74%),为淡黄色油状物。1H NMR(400MHz,CDCl3)δ6.86–6.77(m,2H),4.47(d,J=4.9Hz,2H),1.21(s,9H).LC-MS(ESI)[M+H]+计算值C12H15F3NO,246.11;测得值,246.17。
化合物S2:N-甲基-N-(2,3,5-三氟苄基)三甲基乙酰胺的制备
将化合物S1(70mg)溶于2mL无水THF中,在0℃和N2下加入17mg NaH(60%),并搅拌2小时。加入碘甲烷(0.026mL),使混合物温热至室温并搅拌12小时。混合物用冷水淬灭并用DCM萃取,合并的有机层用水,盐水洗涤,用Na2SO4干燥,浓缩,残余物通过制TLC纯化,得到产物S2(35mg,47%).1H NMR(400MHz,CDCl3)δ6.82-6.71(m,2H),4.65(s,2H),3.11(s,3H),1.33(s,9H).LC-MS(ESI)[M+H]+计算值C13H17F3NO,260.13;测得值,260.19。
化合物S3:N-乙酰氧基-N-苄基-2,2-二甲基丁酰胺的制备
将正苄基羟胺盐酸盐(100mg)溶于2mL THF/H2O(1:1)和0.45mL饱和NaHCO3水溶液中。将溶液冷却至0℃,加入2,2-二甲基丁酰氯(81mg),将混合物在室温下搅拌16小时。混合物用EtOAc萃取,合并的有机层用盐水洗涤,干燥(Na2SO4)并真空浓缩。通过硅胶色谱纯化,得到为白色固体的N-苄基-N-羟基-2,2-二甲基丁酰胺(60mg,43.3%)。1H NMR(400MHz,CDCl3)δ7.37-7.34(m,2H),7.33-7.31(m,3H),4.89(s,2H),1.69(q,J=7.6Hz,2H),1.26(s,6H),0.86(t,J=7.6Hz,6H).
将N-苄基-N-羟基-2,2-二甲基丁酰胺(800mg)和TEA(2.5mL)溶解在20mL DCM中。在0℃下将乙酰氯(0.283mL)缓慢加入到混合物中,将混合物在室温下搅拌16小时,浓缩,残余物通过色谱法纯化,得到产物S3(260mg,27.3%).1H NMR(400MHz,CDCl3)δ7.33–7.23(m,5H),4.89(s,2H),2.09(s,3H),1.53(q,J=7.5Hz,2H),1.16(s,6H),0.80(t,J=7.5Hz,3H).
化合物S4:N-苄基-N-甲氧基-2,2-二甲基丁酰胺的制备
将N-苄基-N-羟基-2,2-二甲基丁酰胺(800mg),碘甲烷(565.2mg)和KOH(179.4mg)加入到30mL乙醇中。将混合物在50℃下搅拌5小时并蒸发至干。残余物用CH2Cl2和水稀释。有机层用盐水洗涤,用Na2SO4干燥并浓缩。残余物通过色谱法纯化,得到化合物S4(210mg,28.2%).1H NMR(400MHz,CDCl3)δ7.34–7.22(m,5H),4.79(s,2H),3.64(s,3H),1.63(q,J=7.5Hz,2H),1.20(s,6H),0.79(t,J=7.5Hz,3H).
化合物S5:3,3-二氟-N,2,2-三甲基-N-(2,3,5-三氟苄基)丁酰胺的制备
将K2CO3(324mg,2.35mmol)和甲胺盐酸盐(316mg,4.69mmol)在10mL MeOH中的混合物在室温下搅拌30分钟。然后向混合物中加入2,3,5-三氟苯甲醛(500mg,3.125mmol),在室温下搅拌2小时。将混合物冷却至0℃,分批加入NaBH4(178.2mg,4.69mmol)。将混合物在0℃下搅拌1小时,升温至室温并搅拌12小时。将固体过滤并用EtOAc洗涤。将滤液蒸发至干,将残余物溶于EtOAc中,有机层用水,盐水洗涤,用Na2SO4干燥,浓缩,得到N-甲基-1-(2,3,5-三氟苯基)甲胺(260mg),其不经进一步纯化用于下一步骤。1H NMR(400MHz,CDCl3)δ6.94–6.87(m,1H),6.86–6.76(m,1H),3.81(d,J=1.4Hz,2H),2.44(s,3H).
向N-甲基-1-(2,3,5-三氟苯基)甲胺(44mg)和3,3-二氟-2,2-二甲基丁酸(38mg)的无水DMF(1mL)溶液,加入2-(7-氮杂-1H-苯并三唑-1-基)-1,1,3,3-四甲基脲六氟磷酸盐(142mg)和DIEA(0.08mL)。将混合物在室温下搅拌12小时并真空浓缩,残余物用CH2Cl2和水稀释。水层用CH2Cl2萃取。合并的有机层用饱和食盐水洗涤,用Na2SO4干燥并浓缩,残余物通过预TLC纯化,得到化合物S5(36mg,46%)。1H NMR(400MHz,CDCl3)δ6.88–6.78(m,1H),6.71(m,1H),4.67(s,2H),3.15(s,3H),1.66(t,J=19.4Hz,3H),1.46(s,6H).LC-MS(ESI)[M+H]+计算值C14H17F5NO,310.12;测得值,310.21.
化合物S6:N-苄基-3,3-二氟-N-羟基-2,2-二甲基丁酰胺的制备
向正苄基羟胺盐酸盐(36.8mg)和3,3-二氟-2,2-二甲基丁酸(35mg)的无水DMF(1mL)溶液中加入1-乙基-3-(3-二甲基氨基丙基)碳二亚胺盐酸盐(66mg)和DIEA(0.16mL)。将混合物在室温下搅拌12小时并真空浓缩。残余物用二氯甲烷和水稀释。水层用二氯甲烷萃取。有机层用饱和食盐水洗涤,用Na2SO4干燥并浓缩,残余物通过预TLC纯化,得到化合物S6(10mg,17%)。1H NMR(400MHz,CDCl3)δ7.34–7.25(m,5H),4.64(s,2H),1.73(t,J=19.8Hz,3H),1.38(s,6H).
化合物S7:N-(4-氟苄基)-N,2,2-三甲基丁酰胺的制备
将K2CO3(207mg,1.5mmol)和甲胺盐酸盐(202mg,3.0mmol)在5mL MeOH中的混合物在室温下搅拌30分钟,然后向混合物中加入4-氟苯甲醛(248mg,2.0mmol),并在室温下搅拌1小时。将混合物冷却至0℃,分批加入NaBH4(113.5mg,3.0mmol)。将混合物在0℃下搅拌1小时,升温至室温并搅拌2小时。将固体过滤并用EtOAc洗涤。将滤液蒸发至干,将残余物溶于EtOAc中,有机层用水,盐水洗涤,用Na2SO 4干燥。将残余物溶于10mL无水THF中。加入DIEA(264mg,2.05mmol),在0℃,氮气下,将2,2-二甲基丁酰氯(275mg,2.05mmol)缓慢加入到溶液中,然后在室温下搅拌2小时。向溶液中加入15mL水,用EtOAc(10mL×3)萃取。将合并的有机物用1M HCl,盐水洗涤,用Na 2SO4干燥并真空浓缩。残余物通过硅胶柱色谱法(PE/EA=1/2)纯化,得到189mg作为棕色固体的S7(总产率=40%)。1H NMR(400M Hz,CDCl3)δ7.21–7.12(m,2H),6.98-6.93(m,2H),4.54(s,2H),2.95(s,3H),1.64(q,J=7.5Hz,2H),1.24(s,6H),0.84(t,J=7.5Hz,3H).LC-MS(ESI)[M+H]+计算值:C14H21F2NO,256.16;测得值,256.18.
化合物S8:N-(2,3-二氟苄基)-N,2,2-三甲基丁酰胺的制备
根据化合物S7概述的步骤,由2,3-二氟苯甲醛(284mg),甲胺盐酸盐(202mg)和2,2-二甲基丁酰氯(275mg)制备化合物S8,产率56%。1H NMR(400M Hz,CDCl3)δ7.11–6.94(m,3H),4.66(s,2H),3.06(s,3H),1.66(q,J=7.5Hz,2H),1.25(s,6H),0.85(t,J=7.5Hz,3H).LC-MS(ESI)[M+H]+计算值C14H20F2NO,256.15;测得值,256.18。
化合物S9-S20:
化合物S9-S20根据方案1中概述的步骤制备:
方案5:试剂和条件;(a)叔丁基(叔丁氧基羰基)氧基氨基甲酸叔丁酯,1N NaOH,TBAB,DCM;(b)TFA,DCM;(c)3,3-二氟-2,2-二甲基丁酸,EDCI,DIEA,DMF,室温,12小时(d)NaH,MeI,THF.
3.RIPK1的激酶测定
材料:具有N端GST-标签(目录编号#R07-34G)的重组全长RIPK1蛋白购自SignalChem。ADP-GloTM激酶测定试剂盒(目录编号#V9102)来自Promega。MBP蛋白(目录编号#M2295)和其它所有化学试剂来自Sigma。384孔测试板(目录编号#3674,白板,不透明)购自Corning。
激酶活性测定和数据分析:RIPK1激酶测定在白色384孔板中进行。测试缓冲液含有25mM HEPES(pH7.2),20mM氯化镁,12.5mM氯化锰,5mM EGTA,2mM EDTA,12.5mMβ-甘油磷酸和2mM DTT。首先将RIPK1与化合物或DMSO对照孵育15分钟,之后加入ATP/MBP的底物混合物以引发反应。RIPK1的终浓度为161nM,ATP终浓度为50μM,MBP为20μM。室温下反应90分钟后,按ADP-GloTM激酶测定试剂盒(Promega)的技术手册添加ADP-Glo试剂和检测溶液,在PerkinElmer Enspire上测量发光。数据使用Graphpad Prim(GraphPad软件:www.graphpad.com)进行分析。使用具有S型剂量反应的非线性回归模型拟合曲线。
结果:hRIP1激酶测定的pIC50与我们的细胞坏死测定的pEC50相关。示例性数据如下所示:
4.4.细胞坏死测定
方法:
在McCoy’s 5A培养基(Invitrogen)中培养HT-29细胞。第一天,HT-29细胞以每孔2500-3500个细胞的密度覆盖在96孔分析板中。第二天,通过加入20ng/ml TNF-α(T),100nMSmac模拟物(S),和20mM z-VAD(Z)诱导细胞坏死。同时,将来自约20万个化合物的化学文库的10mM化合物输送到每孔中。处理24小时后,通过使用CellTiter-Glo发光细胞活力测定试剂盒测量ATP水平来测定细胞活性。根据制造商的说明进行CellTiter-Glo测定(Promega),化学发光使用PerkinElmer Enspire多模式读数器记录。将存活的细胞归一化为用DMSO处理的那些细胞。Nec-1作为筛选坏死抑制剂的阳性对照。数据表示为重复的平均值±标准偏差。
通过如上所述测量ATP水平来测定HT-29细胞中化合物对坏死的剂量依赖型抑制。
化合物坏死的活性数据如下:
Claims (30)
1.一种酰胺化合物,其为细胞坏死和/或人受体相互作用蛋白1激酶(RIP1)抑制剂,其式:
其中:
R1是C3-C14环状或杂环状部分,特别是取代或未取代的,0-3个杂原子C3-C9环烷基,环烯基或环炔基;或取代或未取代的,0-3个杂原子的C5-C14芳基;
R2-R4独立地是:氢原子,取代或未取代的杂原子,取代或未取代的,0-3个杂原子C1-C9烷基,取代或未取代的,0-3个杂原子C2-C9烯基,取代或未取代的,0-3个杂原子C2-C9炔基,和取代或未取代的,0-3个杂原子C5-C14芳基,其中每个杂原子独立地是氧,磷,硫或氮;或
该酰胺化合物的相应磺酰胺,或
该化合物药学上可接受的盐,氢化物或立体异构体;
前提是如果R1是苯基,R3是氢原子,且R4是1,1-二甲基丙基,则R2不是氢原子,优选取代或未取代的杂原子,取代或未取代的,0-3个杂原子C1-C9烷基,取代或未取代的,0-3个杂原子C2-C9烯基,取代或未取代的,0-3个杂原子C2-C9炔基,以及取代或未取代的,0-3个杂原子C5-C14芳基,其中每个杂原子独立地是氧,磷,硫或氮。
2.权利要求1的化合物,其中:
R1是:(a)取代或未取代的苯基;
(b)取代或未取代的2-,3-或4-吡啶;
(c)取代或未取代的萘基或3-氮杂萘基;
(d)0-3个杂原子环己基,环戊基,如四氢呋喃;或,
(e)0-3个杂原子环戊烯或环戊二烯,如吡咯,唑(例如吡唑,咪唑,三唑,四唑,戊唑,恶唑,异恶唑,噻唑或异噻唑),呋喃,间二氧杂环戊烯噻吩,二硫杂环戊烯或氧硫杂环戊烯,优选2-部分,例如2-唑,2-吡唑,2-唑(例如2-吡唑,2-咪唑,2-恶唑,2-异恶唑,2-噻唑或2-异噻唑),2-呋喃,2-噻吩,2-氧杂环戊二烯,间二氧杂环戊烯或2-硫杂环戊二烯;
R2是氢原子,羟基,C1-C4烷基(例如甲基,乙基,丙基)或C1-C4烷氧基(例如甲氧基);
R3是氢原子或甲基;和/或
R4是1-二甲基丙基。
3.权利要求1的化合物,其式:
其中:
R1是:(a)取代或未取代的苯基,
(b)取代或未取代的2-,3-或4-吡啶,或
(c)取代或未取代的萘基或3-氮杂萘基;
(d)0-3个杂原子环己基,环戊基,如四氢呋喃;
(e)0-3杂原子环戊烯或环戊二烯,如吡咯,唑(特别是吡唑,咪唑,三唑,四唑,戊唑,恶唑,异恶唑,噻唑或异噻唑),呋喃,间二氧杂环戊烯噻吩,二硫杂环戊烯或氧硫杂环戊烯;
R2是氢原子,羟基,C1-C4烷基(例如甲基,乙基,丙基),或C1-C4烷氧基(例如甲氧基);
R3是氢原子或甲基;或
该酰胺化合物的相应磺酰胺,或
该化合物药学上可接受的盐,氢化物或立体异构体。
4.权利要求1的化合物,其式:
其中:
R1是取代或未取代的苯基;且
R2是氢原子,羟基或取代或未取代的C1-C9烷基;或
该酰胺化合物的相应磺酰胺,或
该化合物药学上可接受的盐,氢化物或立体异构体。
5.权利要求4的化合物,其中R1和R2如下:
6.权利要求1的化合物,其式:
其中,
R1是取代或未取代的2-,3-或4-吡啶;且
R2是氢原子,甲基;或
该酰胺化合物的相应磺酰胺,或
该化合物药学上可接受的盐,氢化物或立体异构体。
7.权利要求6的化合物,其中R1如下:
。
8.权利要求1的化合物,其式:
其中,
R1是取代或未取代的环己基;或
该酰胺化合物的相应磺酰胺,或
该化合物药学上可接受的盐,氢化物或立体异构体。
9.权利要求8的化合物,其中R1如下:
。
10.权利要求1的化合物,其式:
其中,
R1是取代或未取代的2-唑,2-吡咯,2-呋喃,2-噻吩,2-氧杂环戊二烯,间二氧杂环戊烯或2-硫杂环戊二烯,优选其2-唑是:2-吡唑,2-咪唑,三唑,四唑,戊唑,2-恶唑,2-异恶唑,2-噻唑或2-异噻唑;R2是甲基,羟基或甲氧基;且R3是氢原子或甲基;或
该酰胺化合物的相应磺酰胺,或
该化合物药学上可接受的盐,氢化物或立体异构体。
11.权利要求10的化合物,其中R1,R2和单/双键如下:
。
12.权利要求1的化合物,其式:
其中,
R1是取代或未取代的萘基或3-氮杂萘基;或
该酰胺化合物的相应磺酰胺,或
该化合物药学上可接受的盐,氢化物或立体异构体。
13.权利要求12的化合物,其中R1如下:
。
14.权利要求1的化合物,其式:
其中,
R1是取代或未取代的苯基;优选未取代的苯基,
R2是氢原子,甲基,羟基,羟甲基,或甲氧基;且
R3是氢原子,甲基,羟基,羟甲基,甲氧基,或取代或未取代的C1-C6烷基,优选未取代的,或
该酰胺化合物的相应磺酰胺,或
该化合物药学上可接受的盐,氢化物或立体异构体。
15.权利要求10的化合物,其中R1,R2和R3如下:
。
16.权利要求1的化合物,其式:
其中,
R2是氢原子,羟基或取代或未取代的C1-C6烷基;且R4是取代或未取代的,0-3个杂原子C1-C6烷基,取代或未取代的,0-3个杂原子C2-C6烯基,取代或未取代的,0-3个杂原子C2-C6炔基,以及取代或未取代的,0-3个杂原子C6-C14芳基,其中每个杂原子独立地是氧,磷,硫或氮;n为0,1,2,3,4或5;或
该酰胺化合物的相应磺酰胺,或
该化合物药学上可接受的盐,氢化物或立体异构体。
17.权利要求16的化合物,其中(F)n,R2和R4如下:
。
18.权利要求1的化合物,其式:
其中,
R1是取代或未取代的苯基;且
R3是取代或未取代的杂原子和取代或未取代的,0-3个杂原子C1-C6烷基,其中每个杂原子独立地是氧,磷,硫或氮;或
该酰胺化合物的相应磺酰胺,或
该化合物药学上可接受的盐,氢化物或立体异构体。
19.权利要求18的化合物,其中R1和R3如下:
。
20.权利要求1的化合物式,其式:
其中,
R1是取代或未取代的苯基;
R2是氢原子或甲基;且
R3是氢原子或甲基;或
该酰胺化合物的相应磺酰胺,或
该化合物药学上可接受的盐,氢化物或立体异构体。
21.权利要求20的化合物,其中R1,R2和R3如下:
。
22.权利要求1的化合物,其式:
其中,
R1是取代或未取代的苯基;
R3是H或甲基;且
R4是取代或未取代的C1-C6烷基;或
该酰胺化合物的相应磺酰胺,或
该化合物药学上可接受的盐,氢化物或立体异构体。
23.权利要求22的的化合物,其中R1,R2和R3如下:
。
24.一种化合物,其式:
其中,
R1是取代或未取代的苯基;
R2是氢原子,甲基或乙基;且
R3和R4独立地是氢原子,低级烷基,并且可以连接形成取代或未取代的C3-C8环烷基;或
该酰胺化合物的相应磺酰胺,或
该化合物药学上可接受的盐,氢化物或立体异构体。
25.权利要求24的化合物,其中R1,R2,R3和R4如下:
。
26.权利要求1的化合物,其具有表1的式。
27.一种药物组合物,其包含单位剂量的权利要求1的化合物以及药学上可接受的赋形剂。
28.一种药物组合物,其包含单位剂量的权利要求1的化合物和药学上可接受的赋形剂,以及一种不同的用于细胞坏死相关疾病或病症的治疗剂。
29.一种治疗坏死相关疾病或病症的方法,包括向有需要的患者施用有效剂量的权利要求1的化合物或权利要求27或28的组合物。
30.权利要求29所述的方法,其进一步包含诊断细胞坏死相关疾病或病症的前期步骤,或检测细胞坏死相关疾病或病症的改善结果的后续步骤。
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