TW202200574A - Bcl-2抑制劑 - Google Patents
Bcl-2抑制劑 Download PDFInfo
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- TW202200574A TW202200574A TW110113455A TW110113455A TW202200574A TW 202200574 A TW202200574 A TW 202200574A TW 110113455 A TW110113455 A TW 110113455A TW 110113455 A TW110113455 A TW 110113455A TW 202200574 A TW202200574 A TW 202200574A
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- TW
- Taiwan
- Prior art keywords
- isopropylphenyl
- azaspiro
- nonane
- mmol
- compound
- Prior art date
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- 229940123711 Bcl2 inhibitor Drugs 0.000 title description 6
- 239000012664 BCL-2-inhibitor Substances 0.000 title description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 126
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 31
- 238000000034 method Methods 0.000 claims abstract description 22
- 201000010099 disease Diseases 0.000 claims abstract description 19
- 230000001640 apoptogenic effect Effects 0.000 claims abstract description 7
- -1 -C 3 - 10 cycloalkyl Chemical group 0.000 claims description 496
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 324
- 125000000623 heterocyclic group Chemical group 0.000 claims description 102
- 125000000217 alkyl group Chemical group 0.000 claims description 93
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 56
- 229910052757 nitrogen Inorganic materials 0.000 claims description 43
- 229910052739 hydrogen Inorganic materials 0.000 claims description 40
- 239000001257 hydrogen Substances 0.000 claims description 40
- 125000005842 heteroatom Chemical group 0.000 claims description 38
- 125000003118 aryl group Chemical group 0.000 claims description 37
- 229910052760 oxygen Inorganic materials 0.000 claims description 35
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 35
- 125000002950 monocyclic group Chemical group 0.000 claims description 34
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 32
- 125000001072 heteroaryl group Chemical group 0.000 claims description 32
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 30
- 239000001301 oxygen Substances 0.000 claims description 28
- 229910052736 halogen Inorganic materials 0.000 claims description 27
- 125000001424 substituent group Chemical group 0.000 claims description 27
- 125000003342 alkenyl group Chemical group 0.000 claims description 24
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 24
- 150000002367 halogens Chemical group 0.000 claims description 24
- 125000000304 alkynyl group Chemical group 0.000 claims description 23
- 150000003839 salts Chemical class 0.000 claims description 23
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 22
- 125000003545 alkoxy group Chemical group 0.000 claims description 21
- 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 21
- 229910052717 sulfur Inorganic materials 0.000 claims description 21
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 20
- 125000002619 bicyclic group Chemical group 0.000 claims description 19
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 18
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 17
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 17
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 15
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 15
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 14
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 14
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 14
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 12
- 239000000460 chlorine Substances 0.000 claims description 11
- 239000008194 pharmaceutical composition Substances 0.000 claims description 11
- 125000004076 pyridyl group Chemical group 0.000 claims description 11
- 239000011593 sulfur Chemical group 0.000 claims description 11
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 10
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 9
- 239000011737 fluorine Substances 0.000 claims description 9
- 229910052731 fluorine Inorganic materials 0.000 claims description 9
- 150000002431 hydrogen Chemical class 0.000 claims description 9
- 125000006299 oxetan-3-yl group Chemical group [H]C1([H])OC([H])([H])C1([H])* 0.000 claims description 8
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 7
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 7
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 7
- 229910052794 bromium Inorganic materials 0.000 claims description 7
- 229910052801 chlorine Inorganic materials 0.000 claims description 7
- 125000003566 oxetanyl group Chemical group 0.000 claims description 7
- 125000001246 bromo group Chemical group Br* 0.000 claims description 6
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 6
- 125000002541 furyl group Chemical group 0.000 claims description 6
- 125000001475 halogen functional group Chemical group 0.000 claims description 6
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 6
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 6
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 5
- 125000005605 benzo group Chemical group 0.000 claims description 5
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 5
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 5
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 4
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 4
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 4
- 125000002618 bicyclic heterocycle group Chemical group 0.000 claims description 4
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
- 230000002062 proliferating effect Effects 0.000 claims description 4
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 3
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 3
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 3
- 125000004575 3-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 3
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 claims description 3
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 3
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 claims description 3
- 125000002911 monocyclic heterocycle group Chemical group 0.000 claims description 3
- 208000015122 neurodegenerative disease Diseases 0.000 claims description 3
- 125000004574 piperidin-2-yl group Chemical group N1C(CCCC1)* 0.000 claims description 3
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 claims description 3
- 125000004215 2,4-difluorophenyl group Chemical group [H]C1=C([H])C(*)=C(F)C([H])=C1F 0.000 claims description 2
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 claims description 2
- 125000005809 3,4,5-trimethoxyphenyl group Chemical group [H]C1=C(OC([H])([H])[H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 claims description 2
- 125000003762 3,4-dimethoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 claims description 2
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 claims description 2
- 125000004801 4-cyanophenyl group Chemical group [H]C1=C([H])C(C#N)=C([H])C([H])=C1* 0.000 claims description 2
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 2
- 125000002393 azetidinyl group Chemical group 0.000 claims description 2
- 125000004533 benzofuran-5-yl group Chemical group O1C=CC2=C1C=CC(=C2)* 0.000 claims description 2
- 125000000000 cycloalkoxy group Chemical group 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 125000004498 isoxazol-4-yl group Chemical group O1N=CC(=C1)* 0.000 claims description 2
- 125000003145 oxazol-4-yl group Chemical group O1C=NC(=C1)* 0.000 claims description 2
- 125000004304 oxazol-5-yl group Chemical group O1C=NC=C1* 0.000 claims description 2
- 125000004274 oxetan-2-yl group Chemical group [H]C1([H])OC([H])(*)C1([H])[H] 0.000 claims description 2
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 2
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 2
- 125000004483 piperidin-3-yl group Chemical group N1CC(CCC1)* 0.000 claims description 2
- 125000003386 piperidinyl group Chemical group 0.000 claims description 2
- 230000003331 prothrombotic effect Effects 0.000 claims description 2
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 2
- 125000004192 tetrahydrofuran-2-yl group Chemical group [H]C1([H])OC([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000001617 2,3-dimethoxy phenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C(OC([H])([H])[H])=C1[H] 0.000 claims 1
- 150000001345 alkine derivatives Chemical class 0.000 claims 1
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 claims 1
- CPPKAGUPTKIMNP-UHFFFAOYSA-N cyanogen fluoride Chemical compound FC#N CPPKAGUPTKIMNP-UHFFFAOYSA-N 0.000 claims 1
- 125000004187 tetrahydropyran-2-yl group Chemical group [H]C1([H])OC([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims 1
- 102100021569 Apoptosis regulator Bcl-2 Human genes 0.000 abstract description 37
- 101000971171 Homo sapiens Apoptosis regulator Bcl-2 Proteins 0.000 abstract description 35
- 102220025226 rs74315455 Human genes 0.000 abstract description 11
- 230000002401 inhibitory effect Effects 0.000 abstract description 4
- 102220346888 c.307G>T Human genes 0.000 abstract description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 516
- 239000000203 mixture Substances 0.000 description 451
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 328
- 239000000243 solution Substances 0.000 description 254
- 230000002829 reductive effect Effects 0.000 description 233
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 194
- 235000019439 ethyl acetate Nutrition 0.000 description 163
- 239000012267 brine Substances 0.000 description 144
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 144
- 238000005481 NMR spectroscopy Methods 0.000 description 138
- 239000003921 oil Substances 0.000 description 132
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 122
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 114
- 239000007787 solid Substances 0.000 description 114
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- 229910052938 sodium sulfate Inorganic materials 0.000 description 113
- 235000011152 sodium sulphate Nutrition 0.000 description 113
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 109
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- 238000006243 chemical reaction Methods 0.000 description 83
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 76
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- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 14
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Abstract
本文揭露了一種用於抑制Bcl-2野生型和突變的Bcl-2兩者,特別是Bcl-2 G101V和D103Y的具有式 (I) 之化合物,和一種使用本文揭露的化合物治療失調凋亡疾病之方法。
Description
本文揭露了一種用於抑制Bcl-2野生型和突變的Bcl-2兩者的具有式 (I) 之化合物,和一種使用本文揭露的化合物治療失調凋亡疾病之方法。
B細胞淋巴瘤2(Bcl-2)基因家族係一組與Bcl-2蛋白同源的蛋白質,編碼調節內在凋亡途徑的超過20種蛋白質。由促凋亡和抗凋亡分子組成的Bcl-2家族蛋白可以根據四個BH結構域(BH1、BH2、BH3和BH4)內的序列同源性分為以下三種亞家族:(1) 一種亞家族在所有四個BH結構域內具有序列同源性,如抗凋亡的Bcl-2、Bcl-xl和Bcl-w;(2) 一種亞家族在BH1、BH2和BH4內具有序列同源性,如促凋亡的Bax和Bak;(3) 一種亞家族僅在BH3內具有序列同源性,如促凋亡的Bik、Bid和HRK。BH1、BH2和BH4結構域係抗凋亡活性所需的。相反,BH3結構域係促凋亡活性所必需的,並且其本身就足以具有促凋亡活性。
類似於癌基因成癮(其中腫瘤細胞依賴單個顯性基因以存活),腫瘤細胞也可以變得依賴Bcl-2以存活。Bcl-2過表現常見於急性骨髓性白血病(AML)、急性淋巴球白血病(ALL)、復發/難治性慢性淋巴細胞白血病(CLL)、濾泡性淋巴瘤(FL)、非何杰金氏淋巴瘤(NHL)和實性瘤,如胰臟癌、前列腺癌、乳癌以及小細胞和非小細胞肺癌(Cancer [癌症] 2001, 92, 1122-1129;Cancer Biol. [癌症生物學] 2003; 13: 115-23;Curr. Cancer Drug Targets [當代癌症藥物靶點] 2008, 8, 207-222;Cancers [癌症] 2011, 3, 1527-1549)。失調凋亡途徑也與其他重要疾病如神經退行性病症(凋亡上調)(例如阿茲海默氏症);和增殖性疾病(凋亡下調)(例如癌症、自體免疫性疾病)以及血栓前病症的病理學有關。已報導了靶向Bcl-2或Bcl-xl的許多小分子BH3模擬物。已在藥物開發的不同階段研究了一些Bcl-2小分子抑制劑:Bcl-2/Bcl-xl抑制劑ABT-263(那維妥拉(navitoclax),WO 2009155386)在淋巴惡性腫瘤(如慢性淋巴細胞白血病)中顯示有前景的臨床活性。然而,其在該等情況下的功效受到血小板死亡和伴隨的血小板減少症(由Bcl-xl抑制引起)的限制(Lancet Oncol. [柳葉刀腫瘤學]2010, 11, 1149;J. Clin. Oncol. [臨床腫瘤學雜誌] 2011, 29, 909;J. Clin. Oncol. [臨床腫瘤學雜誌]2012, 30, 488)。進行的新一代Bcl-2選擇性抑制劑維奈妥拉(venetoclax)(ABT-199/GDC-0199)在該等癌症中表現出強大的活性,且還不傷害血小板(Journal of Hematology & Oncology [血液學與腫瘤學雜誌] 2015, 8, 129;Clinical Advances in Hematology & Oncology [血液學和腫瘤學的臨床進展] 2017, 15, 210)。正在臨床試驗階段研究S55746(也稱為BCL201)、APG-101、APG-1252。目前,維奈妥拉(以前稱為ABT-199)係唯一經FDA批准用於治療具有17p缺失的復發性或難治性慢性淋巴細胞白血病(CLL)患者的Bcl-2選擇性抑制劑。
儘管具有高的臨床活性和良好的安全特徵,但隨著時間的推移,患者在持續治療下仍會對維奈妥拉產生獲得性抗性。最近,在患者用Bcl-2抑制劑維奈妥拉(ABT-199)治療19至42個月後,在Bcl2中識別出一種新穎Gly101Val(G101V)突變(Cancer Discov. [癌症發現]2019, 9, 342-353;Haematologica [血液病學] 104, e434-e437, 2019)。Blombery等人證明了Bcl-2中的Gly101Val突變藉由降低維奈妥拉的結合親和力且不破壞促凋亡蛋白與Bcl-2的結合來賦予獲得性難治性。15名患者中有7名在進展中鑒定出在Bcl-2中的新穎Gly101 Val突變,但未進入研究。還預測在CLL患者中觀察到的Bcl-2 Asp103Tyr(D103Y)突變阻礙Bcl-2與維奈妥拉的結合,導致患者的適合度降低(Haematologica [血液病學] 104, e434-e437, 2019)。用維奈妥拉治療的FL(濾泡性淋巴瘤)患者中的Bcl-2 Phel04lle(F104I)突變也被描述為與維奈妥拉的結合顯著降低有關,並且足以賦予細胞抗性(Br J Haematol [英國血液學雜誌], 186 (6): e188-e191, 2019)。
此外,野生型Bcl-2對嗜中性球前體的存活很重要,因此嗜中性球減少症係Bcl-2抑制劑療法中最常見的不良反應。在用維奈妥拉治療的CLL患者中,通常在劑量增加期間觀察到嗜中性球減少症的發作,儘管其發生率隨著治療時間的延長而降低。(Clin Cancer Res [臨床癌症研究]; 24 (18), 2018)。也就是說,過度抑制野生型Bcl-2蛋白可以出現嗜中性球減少症的中靶毒性和副作用。
WO 2019210828揭露了一類新穎的Bcl-2抑制劑。但仍然強烈需要抑制野生型Bcl-2蛋白和Bcl-2突變(在藉由維奈妥拉長期治療後有進展的患者中發現,如G101V和D103Y突變)兩者的新的小分子。
本揭露之發明人發現本文揭露的化合物對野生型Bcl-2和Bcl-2突變(包括G101V和D103Y)兩者均表現出幾乎相等的抑制活性,表明了沒有抗性問題的新型潛在Bcl-2抑制劑。本揭露還提出了有效和安全劑量的新療法用於用維奈妥拉治療後具有突變的臨床復發患者的潛在可能性。
本文揭露了一種具有式 (I) 之化合物(I),
或其藥學上可接受的鹽、或其立體異構物,
其中
X獨立地選自N或CH;
p係選自1或2的整數;
v係選自1或2的整數;
m係選自1、2或3的整數;
n係選自0、1或2的整數;
t係選自1或2的整數;
環A係、、或,其中**2係指附接至式 (I) 的苯基部分的位置;
環B係芳基或5員或6員雜芳基;
L2
係直接鍵、-(CRa
Rb
)q
-、-O-、-S-、-S(O)-、-SO2
-、-C(O)-、C(O)O-、-OC(O)-、-NRa
-、-C(O)NRa
-、-NRa
C(O)-、-NRa
C(O)O-、-NRa
C(O)NRb
-、-SO2
NRa
-、-NRa
SO2
-、-NRa
S(O)2
NRb
-、-NRa
S(O)NRb
-、-C(O)NRa
SO2
-、-C(O)NRa
SO-、-C(=NRa
)NRb
-、或環烷基,其中q係1至7中的一個數字;
R11
係-C1-3
烷基、-C3
-10
環烷基、芳基、5員或6員單環雜芳基、7員至10員二環雜芳基、3員至6員單環雜環基、7員至14員二環雜環基,其各自獨立地視需要被1、2、3或4個取代基R11X
取代,
R11X
在每次出現時獨立地是鹵素、-C1-8
烷基、鹵代C1-8
烷基、-C2-8
烯基、-C2-8
炔基、-C3-8
環烷基、雜環基、芳基、雜芳基、側氧基、-CN、-NO2
、-OR11a
、-SO2
R11a
、-COR11a
、-CO2
R11a
、-CONR11a
R11b
、-C(=NR11a
)NR11b
R11c
、-NR11a
R11b
、-NR11a
COR11b
、-NR11a
CONR11b
R11c
、-NR11a
CO2
R11b
、-NR1a
SONR11b
R11c
、-NR11a
SO2
NR11b
R11c
、-P(=O)R11a
R11b
、或-NR11a
SO2
R11b
,其中所述C3-8
環烷基、雜環基、芳基、或雜芳基視需要被以下取代:鹵素、-C1-8
烷基、-鹵代C1-8
烷基、-C1-8
烷氧基、或-鹵代C1-8
烷氧基;
R11a
、R11b
、和R11c
各自獨立地是氫、-C1-8
烷基、-鹵代C1-8
烷基、-C2-8
烯基、-C2-8
炔基、-C3-8
環烷基、雜環基、芳基、或雜芳基,其中所述C3-8
環烷基、雜環基、芳基、或雜芳基視需要被以下取代:鹵素、-C1-8
烷基、-鹵代C1-8
烷基、-C1-8
烷氧基、或-鹵代C1-8
烷氧基;
R12
係氫、鹵素、-C1-8
烷基、鹵代C1-8
烷基、-C2-8
烯基、-C2-8
炔基、-C3-8
環烷基、雜環基、芳基、雜芳基、側氧基、-CN、-NO2
、-OR1a
、-SO2
R1a
、-COR1a
、-CO2
R1a
、-CONR1a
R1b
、-C(=NR1a
)NR1b
R1c
、-NR1a
R1b
、-NR1a
COR1b
、-NR1a
CONR1b
R1c
、-NR1a
CO2
R1b
、-NR1a
SONR1b
R1c
、-NR1a
SO2
NR1b
R1c
、或-NR1a
SO2
R1b
;
R1a
和R1b
各自獨立地是氫、-C1-8
烷基、-鹵代C1-8
烷基、-C2-8
烯基、-C2-8
炔基、環烷基、雜環基、芳基、或雜芳基;
R1c
係氫、-C1-8
烷基、-鹵代C1-8
烷基、-C2-8
烯基、-C2-8
炔基、環烷基、雜環基、芳基、或雜芳基;
R2
獨立地選自鹵素、-C1-8
烷基、-C2-8
烯基、-C2-8
炔基或-C3-6
環烷基;其中所述-C1-8
烷基、-C2-8
烯基、-C2-8
炔基或-C3-6
環烷基各自獨立地視需要被以下取代:鹵素、羥基、C1-6
烷氧基、或胺基、-C1-8
烷基、-C2-8
烯基、-C2-8
炔基、C3-6
環烷基或C3-6
雜環基;
R3
係-L1
-CyC,
其中
L1
係直接鍵、-(CRa
Rb
)1-4
-、-O-(CRa
Rb
)0-3
-、-NH-(CRa
Rb
)1-3
、或-NH;
CyC係環烷基或雜環基,其各自視需要被一、二、三或四個取代基R3a
取代;
R3a
獨立地選自氫、鹵素、氰基、側氧基、-OR3b
、-NR3b
R3c
、-COR3b
、-SO2
R3b
、-C1-8
烷基、-C2-8
烯基、-C2-8
炔基、-環烷基、或雜環基,所述-C1-8
烷基和雜環基中的每一個視需要被一個或兩個取代基R3e
取代,該取代基R3e
選自氫、鹵素、氰基、-OR3f
、-C1-8
烷基、-環烷基、或雜環基;
其中R3b
和R3c
各自獨立地是氫、-C1-8
烷基、-環烷基、或雜環基,所述-C1-8
烷基視需要被一個或兩個取代基R5e
取代,該取代基R5e
係氫、-NR3f
R3g
、-環烷基、或雜環基;
R3f
和R3g
各自獨立地是氫或-C1-8
烷基;
或在苯基環上的兩個相鄰R3
與苯基環一起形成苯并環,所述環視需要被雜芳基取代;
Ra
和Rb
獨立地是氫、-C1-8
烷基、-C2-8
烯基、-C2-8
炔基、環烷基、雜環基、芳基、或雜芳基;並且
R4
和R5
各自獨立地是氫、鹵素、氰基、-NO2
、-C1-8
烷基、-C2-8
烯基、或-C2-8
炔基。
在一些實施方式中,X係N。
在一些實施方式中,環B係苯基、呋喃基、異㗁唑基、吡啶基、吡唑基、或嘧啶基。
在一些實施方式中,R2
係鹵代、-C1-6
烷基或-C3-4
環烷基;其中所述-C1-6
烷基和-C3-4
環烷基各自獨立地視需要被以下取代:氫、-C1-3
烷基、C3-6
環烷基或C3-6
雜環基。
在一些實施方式中,R2
係氟、甲基、異丙基、異丁基、環丙基、環丁基或𠰌啉代甲基。
在一些實施方式中,n係0,並且L2
係-(CH2
)q
-或-O-,其中q係1-3中的一個數字,較佳的是1。
在一些實施方式中,R11
係-C3
-10
環烷基、芳基、5員或6員單環雜芳基、7員至10員二環雜芳基、3員至6員單環雜環基、7員至14員二環雜環基,其各自獨立地視需要被1、2、或3個取代基R11X
取代,其中R11X
如式 (I) 所定義的。
在一些實施方式中,R11
係環丙基、環丁基、環戊基、環己基、或3員至6員雜環烷基,其含有選自氧和氮原子的1或2個的雜原子。
在一些實施方式中,R11
選自環己基、二環[1.1.1]戊基、四氫-2H-哌喃-1-基、四氫-2H-哌喃-2-基、四氫-2H-哌喃-3-基、四氫-2H-哌喃-4-基 㗁唑-2-基、㗁唑-4-基甲基或㗁唑-5-基。
在一些實施方式中,R11
選自苯基或8員至10員二環芳基,其視需要被1、2或3個取代基R11X
取代。
在一些實施方式中,R11
選自苯基或8員至10員二環芳基,其視需要被1至2個取代基R11X
取代。
在一些實施方式中,R11
係口克唍基、苯并[b][1,4]戴奧辛基(benzo[b][1,4]dioxinyl)、5,6,7,8-四氫萘基、八氫-5H-2,5-甲醇茚基(較佳的是八氫-5H-2,5-甲醇茚-5-基)、2,3,4,5-四氫苯并[b]㗁呯基(較佳的是2,3,4,5-四氫苯并[b]㗁呯-7-基)、金剛烷基(較佳的是金剛烷-1-基),其各自視需要被1或2個R11X
取代。
在一些實施方式中,R11X
係鹵素、氰基、羥基、-C1-8
烷基、鹵代C1-8
烷基、-C2-8
烯基、-C2-8
炔基、C1-6
烷氧基、鹵代C1-6
烷氧基、C3-6
環烷基、雜環基、C3-6
環烷氧基、-NH2
、-NH(C1-8
烷基)、-N(C1-8
烷基)2
或雜環基-O-。
在一些實施方式中,R11x
係-OR11a
,其中R11a
係-C1-8
烷基,較佳的是甲基(-CH3
)、乙基、丙基、異丙基、丁基、或三級丁基。在一些實施方式中,R11x
係-OR11a
,其中R11a
係視需要富含氘的-C1-8
烷基,例如,-CD3
或-CD2
CD3
。
在一些實施方式中,R11x
係-OR11a
,其中R11a
係C3-6
環烷基,較佳的是環丙基、環丁基、環戊基、或環己基。
在一些實施方式中,R11
係被獨立地選自以下的一個、兩個或三個取代基R11X
取代的苯基:
a)氰基、氟、氯、溴、甲基、乙基、丙基、異丙基、丁基、三級丁基、甲氧基、乙氧基、丙氧基、異丙氧基、丁氧基、三級丁氧基、三氟甲基、三氟甲氧基、環丙基、環丁基、環戊基、環己基、氧雜環丁烷-3-基、-NH2
、或-NH(CH3
);或
b) -OR11a
,其中R11a
係C3-6
環烷基,較佳的是環丙基、環丁基、環戊基、或環己基。
在一些實施方式中,R11
係被以下取代的苯基:氰基、氟、氯、溴、甲基、乙基、丙基、異丙基、丁基、三級丁基、甲氧基、乙氧基、丙氧基、異丙氧基、丁氧基、三級丁氧基、二氟甲基、三氟甲基、或三氟甲氧基。
在一些實施方式中,R11
係被以下取代的苯基:環丙基、環丁基、環戊基、或環己基。
在一些實施方式中,R11
係環己基、4-甲氧基環己基、二環[1.1.1]戊烷-1-基、四氫-2H-哌喃-4-基、㗁唑-4-基、苯基、2-氟苯基、3-氟苯基、4-氟苯基、4-氯苯基、2,4-二氟苯基、3,5-二氟苯基、3,4-二氟苯基、4-氰基苯基、4-甲基苯基、4-(三氟甲基)苯基、2-甲氧基苯基、3-甲氧基苯基、4-甲氧基苯基、4-乙氧基苯基、4-甲氧基苯基、4-(三氟甲氧基)苯基、2,4-二甲氧基苯基、2,3-二甲氧基苯基、3,4-二甲氧基苯基、3,5-二甲氧基苯基、3,4,5-三甲氧基苯基、口克唍-6-基、口克唍-4-基、2,3-二氫苯并[b][1,4]戴奧辛-6-基、2,3-二氫苯并[b][1,4]戴奧辛-5-基、或5,6,7,8-四氫萘-2-基、或5,6,7,8-四氫萘-1-基、二環[4.2.0]八-1(6),2,4-三烯-7-基。
在一些實施方式中,R11
係呋喃基、異㗁唑基、吡啶基、吡唑基、嘧啶基、喹㗁啉基、苯并[b]噻吩基、苯并呋喃基、或2,3-二氫苯并呋喃-5-基。
在一些實施方式中,R11
係呋喃-2-基、異㗁唑-4-基、吡啶-3-基、吡啶-2-基、1H-吡唑-4-基、嘧啶-2-基、苯并[b]噻吩-5-基、苯并[b]噻吩-4-基、苯并呋喃-5-基、苯并呋喃-4-基、2,3-二氫苯并[b][1,4]戴奧辛-5-基、苯并[b][1,4]㗁𠯤-5-基、二氫-[1,4]戴奧辛並[2,3-b]吡啶-8-基、或3,4-二氫-2H-苯并[b][1,4]二㗁呯-7-基。
在一些實施方式中,R11
-L2
-選自呋喃-2-基甲基、異㗁唑-4-基甲基、(吡啶-3-基)甲基、(6-甲氧基吡啶-3-基)甲基、(5-甲氧基吡啶-2-基)甲基、(1-甲基-1H-吡唑-4-基)甲基、(3-甲氧基-1-甲基-1H-吡唑-4-基)甲基、(1-環丙基-1H-吡唑-4-基)甲基、(5-甲氧基嘧啶-2-基)甲基、苯并[b]噻吩-5-基甲基、苯并[b]噻吩-4-基甲基、苯并呋喃-5-基甲基、或苯并呋喃-4-基甲基。
在一些實施方式中,R11
-L2
-係環丙基、環丁基、環戊基、環己基或1,2,3,4-四氫萘-1-基、3-苯基環丁-1-基、3-苯基環戊-1-基、4-苯基環己-1-基或3-(4-甲氧基苯基)環戊-1-基。
在一些實施方式中,R11
-L2
-係選自以下的3員至6員單環雜環基:氧雜環丁烷基、四氫呋喃基、或四氫-2H-哌喃基,較佳的是氧雜環丁烷-3-基、四氫呋喃-3-基、和四氫-2H-哌喃-4-基。
在一些實施方式中,R12
係氫。
在一些實施方式中,L2
係-SO2
-或-CO-,並且R11
係-C1-3
烷基或苯基,其各自視需要被C1-3
烷氧基取代。
在一些實施方式中,Ra
係氫或甲基。
在一些實施方式中,m係1,R3
係-L1
-CyC,並且L1
係直接鍵、-(CH2
)0-2
-、-N(CH2
)0-2
、或-O(CH2
)0-2
。
在一些實施方式中,CyC係環丁基、環戊基或環己基,其各自視需要被一個或兩個取代基R3a
取代。
在一些實施方式中,CyC係:
a)選自以下的雜環基:含有一個氮或氧或硫雜原子作為環成員的單環4員至9員雜環基基團;含有選自氧、硫和氮的兩個雜原子作為環成員的單環4員至9員雜環基基團;
b)5員至10員螺雜環基,其包含選自氮、硫和氧的一個或兩個雜原子作為環成員,或,
c)5員至10員橋接的雜環基,其包含選自氮、硫和氧的一個或兩個雜原子作為環成員;
其各自視需要被一、二、三或四個取代基R3a
取代。
在一些實施方式中,CyC係單環4員至6員雜環基基團,其含有一個氮或氧或硫雜原子作為環成員。
在一些實施方式中,Cyc選自氧雜環丁烷基、四氫呋喃基、四氫哌喃基、氮雜環丁烷基、吡咯啶基和哌啶基。
在一些實施方式中,CyC選自氧雜環丁烷-2-基、氧雜環丁烷-3-基、四氫呋喃-4-基、四氫呋喃-2-基、四氫呋喃-3-基、四氫哌喃-2-基、四氫哌喃-3-基、四氫哌喃-4-基、氮雜環丁烷-3-基、氮雜環丁烷-2-基、吡咯啶-2-基、吡咯啶-3-基、哌啶-4-基、哌啶-2-基、和哌啶-3-基。
在一些實施方式中,CyC係單環6員雜環基基團,其含有選自氧和氮的兩個雜原子作為環成員。
在一些實施方式中,CyC係二㗁𠮿基、𠰌啉代、𠰌啉基、或哌𠯤基。
在一些實施方式中,CyC係1,3-二㗁𠮿-2-基、1,3-二㗁𠮿-4-基、1,4-二㗁𠮿-2-基、𠰌啉-1-基、𠰌啉-2-基、或𠰌啉-3-基。
在一些實施方式中,CyC係包含一個或兩個氮或氧作為環成員的4員/4員、3員/5員、4員/5員、4員/6員、5員/5員、或5員/6員單螺雜環基。
在一些實施方式中,R3a
獨立地選自氫、鹵素、氰基、側氧基、-OR3b
、-NR3b
R3c
、-C(=O)R3b
、-SO2
R3b
、-C1-6
烷基、單環C3-6
環烷基、或單環4員至9員雜環基基團,其含有選自氮或氧或硫雜原子的一個或兩個雜原子作為環成員,所述-C1-6
烷基和單環4員至9員雜環基基團中的每一個視需要被一個或兩個取代基R3e
取代。
在一些實施方式中,作為R3a
的環烷基係C3-6
環烷基;更較佳的是環丙基。
在一些實施方式中,作為R3a
的雜環基係4員至6員雜環基基團,其含有選自氮或氧或硫雜原子的一個或兩個雜原子作為環成員。
在一些實施方式中,作為R3a
的雜環基係氧雜環丁烷基、四氫呋喃基、四氫哌喃基、哌𠯤基、或𠰌啉基。
在一些實施方式中,作為R3a
的雜環基係氧雜環丁烷-3-基、四氫呋喃-3-基、四氫-2H-哌喃-4-基、或嗎啡-4-基。
在一些實施方式中,作為R3e
的雜環基係單環4員至9員雜環基基團,其含有選自氮或氧或硫雜原子的一個或兩個雜原子作為環成員。
在一些實施方式中,作為R3e
的雜環基係四氫-哌喃-4-基。
在一些實施方式中,R3a
係-NR3b
R3c
,其中R3b
係氫並且R3c
係雜環基。
在一些實施方式中,R3a
係-NR3b
R3c
,其中R3b
係氫並且R3c
係四氫-哌喃-4-基。
在一些實施方式中,R3a
係-NR3b
R3c
,其中R3b
和R3c
各自獨立地是氫或被環烷基取代的-C1-6
烷基,較佳的是被單環C3-6
環烷基取代的-C1-6
烷基。
在一些實施方式中,R3a
係-OR3b
或-SO2
R3b
,其中R3b
係氫或C1-8
烷基,較佳的是甲基。
在一些實施方式中,R3a
係-COR3b
,其中R3b
係氫或視需要被-NR3f
R3g
取代的C1-6
烷基,其中R3f
和R3g
各自獨立地是氫或C1-6
烷基,較佳的是甲基。
在一些實施方式中,在苯基環上的兩個相鄰R3
與苯基環一起形成被四氫哌喃基取代的吲唑基。
在一些實施方式中,m係1,並且R3
選自由以下組成之群組:、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、或。
在一些實施方式中,R4
係選自以下的鹵素:氟(-F)、氯(-Cl)或溴(-Br),較佳的是氟(-F)。
在一些實施方式中,R4
在吡咯并[2,3-b]吡啶-5-基環的位置3處。
在一些實施方式中,該化合物選自示例的化合物。
在一些實施方式中,該化合物選自
其中吡咯并[2,3-b]吡啶-5-基環上的吡咯環視需要被選自以下的一個取代基R4
取代:氟(-F)、氯(-Cl)或溴(-Br)。
並且,Ry選自、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、或。
本文揭露的化合物具有藉由連接基-L2
-(尤其係-CH2
-,-O-)與分子中的苯基哌𠯤或苯基哌啶部分附接的額外的芳族或碳環部分。此關鍵結構特徵不僅賦予對Bcl-2野生型蛋白相當或稍好的抑制活性,而且出乎意料地對Bcl2突變體(包括G101V和D103Y)表現出強大的效力。Bcl-2 G101V/Bcl-2 wt的IC50
的比率非常低。該等結果表明,本文揭露的化合物係一種沒有突變(如G101V和D103Y)的抗性問題的新的潛在Bcl-2抑制劑。從嗜中性球減少症不良反應的方面來看,該等化合物展現了有效和安全劑量的新療法用於用維奈妥拉治療後具有突變的臨床復發患者的可能性。
在人和小鼠物種中,本揭露之化合物顯示較長的體外半衰期(T1/2
)和低內在性清除率(CLint
),並且本揭露之化合物在肝微粒體中的代謝穩定性顯著提高。
另外,本揭露之化合物在小鼠中具有顯著良好的PK、AUC和Cmax。並且,本揭露化合物的靜脈內給藥的CL值也更低,這與其體外清除數據一致。
本文揭露了一種藥物組成物,該藥物組成物包含本文揭露的化合物或其藥學上可接受的鹽或其立體異構物,以及至少一種藥學上可接受的賦形劑。
本文揭露了一種治療失調凋亡疾病之方法,該方法包括向有需要的受試者投與治療有效量的本文揭露的化合物或其藥學上可接受的鹽或其立體異構物。在一些實施方式中,該失調凋亡疾病係神經退行性病症、增殖性疾病和血栓前病症。在其他實施方式中,該增殖性疾病係癌症。在一些實施方式中,該失調凋亡疾病與Bcl-2的突變有關。在其他實施方式中,Bcl-2的突變包含Bcl-2 G101V和/或Bcl-2 D103Y。在又另一個實施方式中,Bcl-2的突變係Bcl-2 G101V或Bcl-2 D103Y。
定義
除非在本文件的其他地方具體定義,否則本文使用的所有其他技術和科學術語具有本領域的普通技術者通常理解的含義。
如本文使用的,包括所附請求項,例如「一個」、「一種」和「該」的單數形式包括它們相應的複數指代,除非上下文另外明確說明。
除非上下文另外明確說明,否則術語「或」意指術語「和/或」並且可與術語「和/或」互換使用。
術語「烷基」係指烴基團,其選自包含從1至18(例如從1至12,進一步例如從1至10,更進一步例如從1至8、或從1至6、或從1至4)個碳原子的直鏈和支鏈飽和烴基團。包含從1至6個碳原子的烷基基團(即C1-6
烷基)之實例包括但不限於:甲基、乙基、1-丙基或正丙基(「n-Pr」)、2-丙基或異丙基(「i-Pr」)、1-丁基或正丁基(「n-Bu」)、2-甲基-1-丙基或異丁基(「i-Bu」)、1-甲基丙基或二級丁基(「s-Bu」)、1,1-二甲基乙基或三級丁基(「t-Bu」)、1-戊基、2-戊基、3-戊基、2-甲基-2-丁基、3-甲基-2-丁基、3-甲基-1-丁基、2-甲基-1-丁基、1-己基、2-己基、3-己基、2-甲基-2-戊基、3-甲基-2-戊基、4-甲基-2-戊基、3-甲基-3-戊基、2-甲基-3-戊基、2,3-二甲基-2-丁基和3,3-二甲基-2-丁基基團。烷基基團可以視需要富含氘,例如-CD3
、-CD2
CD3
等。
術語「鹵素」係指氟(F)、氯(Cl)、溴(Br)、和碘(I)。
術語「鹵代烷基」係指其中一或多個氫被一或多個鹵素原子(例如氟、氯、溴和碘)替換的烷基。鹵代烷基之實例包括鹵代C1-8
烷基、鹵代C1-6
烷基或鹵代C1-4
烷基,但不限於-CF3
、-CH2
Cl、-CH2
CF3
、-CCl2
、CF3
等。
術語「烷基氧基」或「烷氧基」係指通過氧原子附接至母體分子部分的如上文所定義的烷基基團。烷基氧基(例如C1-6
烷基氧基或C1-4
烷基氧基)之實例包括但不限於:甲氧基、乙氧基、異丙氧基、丙氧基、正丁氧基、三級丁氧基、戊氧基和己氧基等。
術語「環烷基」係指選自包含單環和多環(例如二環和三環)基團(包括稠合的、橋接的或螺的環烷基)的飽和環烴基團的烴基團。
例如,環烷基基團可以包含從3至12個,例如從3至10個,進一步例如3至8個,進一步例如3至6個、3至5個或3至4個碳原子。甚至進一步例如,環烷基基團可以選自包含從3至12個,例如從3至10個,進一步例如3至8個、3至6個碳原子的單環基團。單環環烷基基團之實例包括環丙基、環丁基、環戊基、1-環戊-1-烯基、環己基、環庚基、環辛基、環壬基、環癸基、環十一烷基和環十二烷基基團。特別地,飽和單環環烷基基團(例如C3-8
環烷基)之實例包括但不限於環丙基、環丁基、環戊基、環己基、環庚基、和環辛基基團。在較佳的實施方式中,環烷基係包含3至6個碳原子的單環(簡寫為C3-6
環烷基),包括但不限於:環丙基、環丁基、環戊基、和環己基。二環環烷基基團之實例包括具有從7至12個環原子、具有稠合二環排列(選自[4,4]、[4,5]、[5,5]、[5,6]和[6,6]環系統)或具有橋接的二環排列(選自二環[2.2.1]庚烷、二環[2.2.2]辛烷、和二環[3.2.2]壬烷)的那些。二環環烷基基團的其他實例包括排列成選自[5,6]和[6,6]環系統的二環的那些,如和,其中波浪線表示連接點。該環可為飽和的或具有至少一個雙鍵(即部分不飽和的),但不完全共軛,且是非芳族的,芳族如本文所定義。
術語「螺環烷基」係指含有碳原子並且由至少兩個環形成的環結構,該至少兩個環共用一個原子。術語「7員至10員螺環烷基」係指含有7至10個碳原子並且由至少兩個環形成的環結構,該至少兩個環共用一個原子。
術語「稠和環烷基」係指含有碳原子並且由共用兩個相鄰原子的兩個或多個環形成的稠和環。術語「4員至10員稠和環烷基」係指含有4至10個環碳原子並且由共用兩個相鄰原子的兩個或多個環形成的稠和環。
實例包括但不限於二環[1.1.0]丁基、二環[2.1.0]戊基、二環[3.1.0]己基、二環[4.1.0]庚基、二環[3.3.0]辛基、二環[4.2.0]辛基、萘烷、以及苯并3員至8員環烷基、苯并C4-6
環烯基、2,3-二氫-1H-茚基、1H-茚基、1,2,3,4-四氫萘基、1,4-二氫萘基等。較佳的實施方式是8員至9員稠合環基,其係指以上實例中含有8至9個環原子的環結構。
術語「橋接的環烷基」係指含有碳原子並且由至少兩個環形成的環結構,該至少兩個環共用兩個彼此不相鄰的原子。術語「7員至10員橋接的環烷基」係指含有7至12個碳原子並且由至少兩個環形成的環結構,該至少兩個環共用兩個彼此不相鄰的原子。實例包括但不限於八氫-5H-2,5-甲醇茚基(較佳的是八氫-5H-2,5-甲醇茚-5-基)、或金剛烷基(較佳的是金剛烷-1-基)。
單獨或與其他術語組合使用的術語「芳基」係指選自以下的基團:
a) 5員和6員碳環芳族環,例如苯基;
b) 二環系統(例如7員至12員二環系統),其中至少一個環係碳環和芳族的,例如萘基和二氫茚基;以及,
c) 三環系統(例如10員至15員三環系統),其中至少一個環係碳環和芳族的,例如茀基。
術語「芳族烴環」和「芳基」在貫穿此文的揭露內容中可互換使用。在一些實施方式中,單環或二環芳族烴環具有5至10個成環碳原子(即C5-10
芳基)。單環或二環芳族烴環之實例包括但不限於苯基、萘-1-基、萘-2-基、蒽基、菲基等。在一些實施方式中,芳族烴環係萘環(萘-1-基或萘-2-基)或苯基環。在一些實施方式中,芳族烴環係苯基環。
術語「雜芳基」係指選自以下的基團:
a) 5員、6員或7員芳族單環,其包含選自氮(N)、硫(S)、和氧(O)的至少一個雜原子(例如從1至4個、或在一些實施方式中從1至3個、在一些實施方式中從1至2個雜原子),其中其餘環原子係碳;
b) 8員至12員二環,其包含至少一個選自N、O和S的雜原子,例如從1至4個,或者在一些實施方式中為從1至3個,或者在其他實施方式中為1個或2個雜原子,剩餘環原子為碳,並且其中至少一個環為芳族的且芳族環中存在至少一個雜原子;以及
c) 11員至14員三環,其包含選自N、O和S的至少一個雜原子(例如從1至4個、或在一些實施方式中從1至3個、或在其他實施方式中1或2個雜原子),其中其餘環原子係碳,並且其中至少一個環係芳族的且至少一個雜原子存在於芳族環中。
當雜芳基基團中的S和O原子的總數超過1時,那些雜原子彼此不相鄰。在一些實施方式中,雜芳基基團中的S和O原子的總數不超過2。在一些實施方式中,芳族雜環中的S和O原子的總數不超過1。當雜芳基基團含有一個以上的雜原子環成員時,該等雜原子可為相同的或不同的。雜芳基基團的一或多個環中的氮原子可被氧化以形成N-氧化物。如本文使用的,術語「C-連接的雜芳基」意指藉由來自雜芳基環的C-原子的鍵連接至核心分子的雜芳基基團。
術語「芳族雜環」和「雜芳基」在本文的整個揭露中可互換使用。在一些實施方式中,單環或二環芳族雜環具有5、6、7、8、9或10個成環成員,其中1、2、3、或4個雜原子環成員獨立地選自氮(N)、硫(S)、和氧(O),並且其餘環成員係碳。在一些實施方式中,單環或二環芳族雜環係包含獨立地選自氮(N)、硫(S)、和氧(O)的1或2個雜原子環成員的單環或二環。在一些實施方式中,單環或二環芳族雜環係5員至6員雜芳基環,其係單環並且具有獨立地選自氮(N)、硫(S)、和氧(O)的1或2個雜原子環成員。在一些實施方式中,單環或二環芳族雜環係8員至10員雜芳基環,其係二環並且具有獨立地選自氮、硫和氧的1或2個雜原子環成員。
雜芳基基團、或單環或雙環芳族雜環之實例包括但不限於:(從指定為優先次序1的連接位置開始編號)吡啶基(如2-吡啶基、3-吡啶基、或4-吡啶基)、㖕啉基、吡𠯤基、2,4-嘧啶基、3,5-嘧啶基、2,4-咪唑基、咪唑并吡啶基、異㗁唑基、㗁唑基、噻唑基、異噻唑基、噻二唑基(如1,2,3-噻二唑基、1,2,4-噻二唑基、或1,3,4-噻二唑基)、四唑基、噻吩基(如噻吩-2-基、噻吩-3-基)、三𠯤基、苯并噻吩基、呋喃基或呋喃基、苯并呋喃基、苯并咪唑基、吲哚基、異吲哚基、二氫吲哚基、㗁二唑基(如1,2,3-㗁二唑基、1,2,4-㗁二唑基、或1,3,4-㗁二唑基)、酞𠯤基、吡𠯤基、嗒𠯤基、吡咯基、三唑基(如1,2,3-三唑基、1,2,4-三唑基、或1,3,4-三唑基)、喹啉基、異喹啉基、吡唑基、吡咯并吡啶基(如1H-吡咯并[2,3-b]吡啶-5-基)、吡唑并吡啶基(如1H-吡唑并[3,4-b]吡啶-5-基)、苯并呋喃基、苯并㗁唑基(如苯并[d]㗁唑-6-基)、蝶啶基、嘌呤基、1-氧雜-2,3-二唑基、1-氧雜-2,4-二唑基、1-氧雜-2,5-二唑基、1-氧雜-3,4-二唑基、1-硫雜-2,3-二唑基、1-硫雜-2,4-二唑基、1-硫雜-2,5-二唑基、1-硫雜-3,4-二唑基、呋咱基(如呋咱-2-基、呋咱-3-基)、苯并呋吖基、苯并硫苯基、苯并噻唑基、苯并氧氮茂基、喹唑啉基、喹㗁啉基、萘啶基、氟吡啶基、苯并噻唑基(如苯并[d]噻唑-6-基)、吲唑基(如1H-吲唑-5-基)和5,6,7,8-四氫異喹啉。
「雜環基」、「雜環」或「雜環的」係可互換的,並且係指非芳族雜環基基團(包含選自由NH、O、S、SO或SO2
雜原子組成之群組的一或多個雜原子作為環成員,其中其餘環成員係碳),包括單環的、稠合的、橋接的、和螺的環,即含有單環雜環基、橋接的雜環基、螺雜環基、和稠合雜環基團。
術語「單環雜環基」係指其中至少一個環成員係選自由NH、O、S、SO或SO2
組成之群組的雜原子的單環基團。雜環可為飽和的或部分飽和的。
示例性單環4員至9員雜環基基團包括但不限於:(從指定為優先次序1的連接位置開始編號)吡咯啶-1-基、吡咯啶-2-基、吡咯啶-3-基、咪唑烷酮-2-基、咪唑烷酮-4-基、吡唑烷-2-基、吡唑烷-3-基、哌啶-1-基、哌啶-2-基、哌啶-3-基、哌啶-4-基、2,5-哌𠯤基、哌喃基、𠰌啉基、𠰌啉代、𠰌啉-2-基、𠰌啉-3-基、環氧乙烷基、氮丙環-1-基、氮丙環-2-基、氮雜環辛-1-基、氮雜環辛-2-基、氮雜環辛-3-基、氮雜環辛-4-基、氮雜環辛-5-基、硫雜環丙烷基(thiiranyl)、氮雜環丁烷-1-基、氮雜環丁烷-2-基、氮雜環丁烷-3-基、氧雜環丁烷基、硫雜環丁烷基、1,2-硫代環丁烷、1,3-硫代環丁烷、二氫吡啶基、四氫吡啶基、硫代𠰌啉基、氧硫雜環己烷基、哌𠯤基、高哌𠯤基、高哌啶基、氮雜環庚烷-1-基、氮雜環庚烷-2-基、氮雜環庚烷-3-基、氮雜環庚烷-4-基、氧雜環庚烷基、硫雜環庚基、1,4-氧硫雜環己烷基、1,4-二氧雜環庚烷基、1,4-氧硫雜環庚烷基、1,4-氧雜氮雜環庚烷基、1,4-二硫雜環庚基、1,4-硫氮雜環庚烷基(thiazepanyl)和1,4-二氮雜環庚烷基、1,4-二噻烷基、1,4-氮雜噻烷基、氧氮呯基、二氮呯基、硫氮呯基、二氫噻吩基、二氫哌喃基、二氫呋喃基、四氫呋喃基、四氫噻吩基、四氫哌喃基、四氫噻喃基、1-吡咯啉基、2-吡咯啉基、3-吡咯啉基、二氫吲哚基、2H-哌喃基、4H-哌喃基、1,4-二㗁𠮿基、1,3-二氧戊環基、吡唑啉基、吡唑烷基、二噻烷基、二硫戊環基、吡唑烷基、咪唑啉基、嘧啶酮基、或1,1-二側氧基-硫代𠰌啉基。
術語「螺雜環基」或「雜螺環基」係指具有通過一個共用的碳原子(稱為螺原子)連接的環的5員至20員多環雜環基,其包含選自由NH、O、S、SO或SO2
雜原子組成之群組的一或多個雜原子作為環成員,並且其餘環成員係碳。螺雜環基基團的一或多個環可以含有一或多個雙鍵,但是沒有一個環具有完全軛合的π電子系統。較佳的是,螺雜環基係6員至14員、並且更較佳的是7員至10員。根據共用的螺原子數目,螺雜環基分為單螺雜環基、二-螺雜環基、或多螺雜環基,並且較佳的是係指單螺雜環基或二-螺雜環基,並且更較佳的是4員/4員、3員/5員、4員/5員、4員/6員、5員/5員、或5員/6員單螺雜環基。螺雜環基的代表性實例包括但不限於以下基團:2,3-二氫螺[茚-1,2'-吡咯啶](例如,2,3-二氫螺[茚-1,2'-吡咯啶]-1'-基)、1,3-二氫螺[茚-2,2'-吡咯啶](例如,1,3-二氫螺[茚-2,2'-吡咯啶]-1'-基)、氮雜螺[2.4]庚烷(例如,5-氮雜螺[2.4]庚烷-5-基)、氮雜螺[3.4]辛烷(例如,6-氮雜螺[3.4]辛烷-6-基)、2-氧雜-6-氮雜螺[3.4]辛烷(例如,2-氧雜-6-氮雜螺[3.4]辛烷-6-基)、氮雜螺[3.4]辛烷(例如,6-氮雜螺[3.4]辛烷-6-基)、氮雜螺[3.4]辛烷(例如,6-氮雜螺[3.4]辛烷-6-基)、7-氮雜螺[3.5]壬烷(例如,7-氮雜螺[3.5]壬烷-7-基)、2-氮雜螺[3.5]壬烷(例如,2-氮雜螺[3.5]壬烷-2-基)、1,7-二氧雜螺[4.5]癸烷、2-氧雜-7-氮雜-螺[4.4]壬烷(例如,2-氧雜-7-氮雜-螺[4.4]壬-7-基)、7-氧雜-螺[3.5]壬基和5-氧雜-螺[2.4]庚基。
術語「稠合雜環基團」係指5員至20員多環雜環基基團(其中系統中的每個環與另一個環共用相鄰的原子對(碳和碳原子、或碳和氮原子)),包含選自由NH、O、S、SO或SO2
組成之群組的雜原子的一或多個雜原子作為環成員,並且剩餘的環成員係碳。稠合雜環基團的一或多個環可以含有一或多個雙鍵,但是沒有一個環具有完全軛合的π電子系統。較佳的是,稠合雜環基係6員至14員、並且更較佳的是7員至10員。根據成員環的數目,稠合雜環基分為二環、三環、四環、或多環稠合雜環基,較佳的是係指二環或三環稠合雜環基,並且更較佳的是5員/5員、或5員/6員二環稠合雜環基。稠合雜環的代表性實例包括但不限於以下基團:八氫環戊[c]吡咯(例如八氫環戊[c]吡咯-2-基)、八氫吡咯并[3,4-c]吡咯基、八氫異吲哚基、異吲哚啉基(例如異吲哚啉-2-基)、八氫-苯并[b][1,4]戴奧辛、二氫苯并呋喃基、苯并[d][1,3]二氧雜環戊烯基或2,3,4,5-四氫苯并[b]㗁呯基(較佳的是2,3,4,5-四氫苯并[b]㗁呯-7-基)。
術語「橋接的雜環基」係指5員至14員多環雜環烷基基團(其中系統中的每兩個環共用兩個不連續的原子),包含選自由NH、O、S、SO或SO2
組成之群組的雜原子的一或多個雜原子作為環成員,其中其餘環成員係碳。橋接的雜環基基團的一或多個環可以含有一或多個雙鍵,但是沒有一個環具有完全軛合的π電子系統。較佳的是,橋接的雜環基係6員至14員、並且更較佳的是7員至10員。根據成員環的數目,橋接的雜環基分為二環、三環、四環或多環橋接的雜環基,並且較佳的是係指二環、三環或四環橋接的雜環基,並且更較佳的是二環或三環橋接的雜環基。橋接的雜環基的代表性實例包括但不限於以下基團:2-氮雜二環[2.2.1]庚基、氮雜二環[3.1.0]己基、2-氮雜二環[2.2.2]辛基和2-氮雜二環[3.3.2]癸基。
雜環基環可以與芳基、雜芳基或環烷基環稠合,其中將環結構一起連接到母體雜環基團。
所用的術語「雜環基-O-」係指通過氧原子附接至母體分子部分的如上所定義的雜環基。
所用的「C-連接的雜環基」係指藉由來自雜環基環的碳原子的直接鍵連接到分子的其他部分的雜環基基團。
所用的「N-連接的雜環基」係指藉由來自雜環基環的氮原子的直接鍵連接到分子的其他部分的雜環基基團。
本文揭露的化合物可以含有不對稱中心,因此可以作為鏡像異構物存在。「鏡像異構物」係指化合物的兩種立體異構物,它們係彼此不可重疊的鏡像。當本文揭露的化合物具有兩個或更多個手性中心時,它們可以另外以非鏡像異構物存在。鏡像異構物和非鏡像異構物屬於更廣泛的立體異構物類別。旨在包括所有可能的立體異構物,例如基本上純的拆分的鏡像異構物、其外消旋混合物以及非鏡像異構物的混合物。旨在包括所有本文揭露的化合物和/或其藥學上可接受的鹽的立體異構物。除非另外具體說明,否則提及一種異構物適用於任何可能的異構物。每當未指定異構物的組成時,均包括所有可能的異構物。
如本文使用的,術語「基本上純的」意指目標立體異構物含有按重量計不超過35%,例如不超過30%、進一步例如不超過25%、甚至進一步例如不超過20%的任何一或多種其他立體異構物。在一些實施方式中,術語「基本上純的」意指目標立體異構物含有按重量計不超過10%、例如不超過5%、例如不超過1%的任何一或多種其他立體異構物。
當本文揭露的化合物含有烯烴雙鍵時,除非另外說明,否則此類雙鍵意在包括E和Z幾何異構物。
當本文揭露的化合物含有二取代的環己基或環丁基基團時,在環己基或環丁基環上發現的取代基可以採用順式和反式形成。順式形成意指兩個取代基均位於碳上2個取代基位置的上側,而反式表示它們位於相對側。
將反應產物彼此和/或與起始材料分離可能是有利的。藉由本領域的普通技術,將每個步驟或一系列步驟的所需產物分離和/或純化(以下稱為分離)至所需均勻度。典型地,此類分離涉及多相萃取、從溶劑或溶劑混合物中結晶、蒸餾、昇華或層析法。層析法可以涉及許多方法,包括例如,逆相和正相:粒徑排阻;離子交換;高、中、低壓液相層析法和裝置;小規模分析;模擬移動床(「SMB」)和製備型薄層或厚層層析法,以及小規模薄層和快速層析法的技術。熟悉該項技術者將應用最有可能實現所需分離的技術。
「非鏡像異構物」係指具有兩個或更多個手性中心但彼此不是鏡像的化合物的立體異構物。可以基於其物理化學差異,藉由熟悉該項技術者熟知的方法(例如藉由層析法和/或分步結晶)將非鏡像異構物混合物分成其單獨的非鏡像異構物。鏡像異構物可以如下分離:藉由與適當的光學活性化合物(例如,手性助劑,如手性醇或莫舍酸氯化物(Mosher’s acid chlorid))反應將鏡像異構物混合物轉化成非鏡像異構物混合物,分離該非鏡像異構物,並將單獨的非鏡像異構物轉化(例如,水解)成對應的純鏡像異構物。還可以使用手性HPLC柱分離鏡像異構物。
單一立體異構物(例如基本上純的鏡像異構物)可以藉由使用如下方法拆分外消旋混合物而獲得:使用光學活性拆分劑形成非鏡像異構物(Eliel, E. 和 Wilen, S. Stereochemistry of Organic Compounds.
[有機化合物的立體化學]New York: John Wiley & Sons, Inc.
[紐約:約翰威利父子出版公司],1994 ; Lochmuller, C.H. 等人
「Chromatographic resolution of enantiomers: Selective review.
[鏡像異構物的層析拆分:選擇性綜述]」J. Chromatogr.
[層析雜誌],113 (3) (1975): 第 283-302 頁
)。本發明之手性化合物的外消旋混合物可以藉由任何合適的方法分離和分開,該方法包括:(1) 與手性化合物形成離子型非鏡像異構物鹽,並藉由分級結晶或其他方法分離;(2) 與手性衍生試劑形成非鏡像異構物化合物,分離該等非鏡像異構物並轉化為純立體異構物;以及 (3) 直接在手性條件下分離基本上純的或富集的立體異構物。參見:Wainer, Irving W. 編輯 Drug Stereochemistry: Analytical Methods and Pharmacology.
[藥物立體化學:分析方法和藥理學]New York: Marcel Dekker, Inc.
[紐約:馬塞爾 德克爾公司],1993
。
術語「藥學上可接受的鹽」係指在合理的醫學判斷之範圍內合適用於與人和低等動物的組織接觸,而沒有不適當的毒性、刺激、過敏反應等,並且與合理的益處/風險比相稱的那些鹽。藥學上可接受的鹽可以在本文揭露的化合物的最終分離和純化期間原位製備,或者藉由使游離鹼基團與合適的有機酸反應而分別製備,或藉由使酸性基團與合適的鹼反應而分別製備。
另外,如果以酸加成鹽獲得本文揭露的化合物,則可以藉由鹼化酸式鹽的溶液來獲得游離鹼。相反,如果產物係游離鹼,則可以按照由鹼化合物製備酸加成鹽的常規程序,藉由將游離鹼溶解在合適的有機溶劑中並用酸處理該溶液,來生產加成鹽(例如藥學上可接受的加成鹽)。熟悉該項技術者將識別可以用於製備無毒的藥學上可接受的加成鹽而無需過度實驗的多種合成方法。
如本文所定義的,「其藥學上可接受的鹽」包括至少一種式 (I) 之化合物的鹽,和式 (I) 之化合物的立體異構物的鹽,例如鏡像異構物的鹽,和/或非鏡像異構物的鹽。
本文中的術語「投與(administration、administering)」和「治療(treating、treatment)」,當應用於動物、人、實驗受試者、細胞、組織、器官或生物流體時,意指外源性藥物的、治療的、診斷的藥劑或組成物與動物、人、受試者、細胞、組織、器官或生物流體接觸。細胞的處理涵蓋試劑與細胞的接觸以及試劑與流體的接觸,其中該流體與細胞接觸。術語「投與」和「治療」還意指例如藉由試劑、診斷劑、結合化合物或另一種細胞進行的細胞的體外和離體處理。本文中的術語「受試者」包括任何生物,較佳的是動物,更較佳的是哺乳動物(例如,大鼠、小鼠、狗、貓、兔),最較佳的是人。
術語「有效量」或「治療有效量」係指當投與於受試者以治療疾病、或疾病或障礙的至少一種臨床症狀時,足以影響這種疾病、障礙或症狀的治療的活性成分(例如化合物)的量。「治療有效量」可以隨化合物,疾病,障礙,和/或疾病或障礙的症狀,疾病、障礙、和/或疾病或障礙的症狀的嚴重程度,待治療的受試者的年齡,和/或待治療的受試者的體重而變化。在任何給定情況下的合適量對於熟悉該項技術者而言係顯而易見的,或者可以藉由常規實驗確定。在一些實施方式中,「治療有效量」係本文揭露的至少一種化合物和/或至少一種其立體異構物、和/或至少一種其藥學上可接受的鹽如上文所定義的有效治療受試者的疾病或障礙的量。在組合療法的情況下,「治療有效量」係指用於有效治療疾病、障礙或病症的組成物件的總量。
包含本文揭露的化合物的藥物組成物可以通過口服、吸入、直腸、腸胃外或局部投與至有需要的受試者。對於口服投與,藥物組成物可為常規固體配製物,例如片劑、粉末、顆粒、膠囊等;液體配製物,例如水或油懸浮液;或其他液體配製物,例如糖漿、溶液、懸浮液等;對於腸胃外投與,藥物組成物可為溶液、水溶液、油懸浮液濃縮物、凍乾粉等。較佳的是,藥物組成物的配製物選自片劑、包衣片劑、膠囊、栓劑、鼻噴霧劑或注射劑,更較佳的是片劑或膠囊。藥物組成物可為具有精確劑量的單一單位投與。另外,藥物組成物可以進一步包含其他活性成分。
本文揭露的藥物組成物的所有配製物可以藉由藥物領域中的常規方法生產。例如,可以將活性成分與一或多種賦形劑混合,然後製成所需配製物。「藥學上可接受的賦形劑」係指適合所需藥物配製物的常規藥物載體,例如:稀釋劑、媒介物(如水、各種有機溶劑等)、填充劑(如澱粉、蔗糖等)、黏合劑(如纖維素衍生物、藻酸鹽、明膠和聚乙烯吡咯啶酮(PVP));潤濕劑,如甘油;崩解劑,如瓊脂、碳酸鈣和碳酸氫鈉;吸收增強劑,如四級銨化合物;界面活性劑,如十六烷醇;吸收載體,如高嶺土和皂土;潤滑劑,如滑石、硬脂酸鈣、硬脂酸鎂、聚乙二醇等。另外,藥物組成物還包含其他藥學上可接受的賦形劑,例如分散劑、穩定劑、增稠劑、複合劑、緩衝劑、滲透促進劑、聚合物、芳族化合物、甜味劑和染料。
術語「疾病」係指任何疾病、不適、病、症狀或適應症,並且可以與術語「障礙」或「病症」互換。
在整個本說明書和隨附申請專利範圍中,除非上下文另外要求,否則術語「包含(comprise)」以及例如「包含(comprises和comprising)」等變體旨在指定其後特徵的存在,但不排除一或多個其他特徵的存在或添加。當在本文中使用時,術語「包含」可以用術語「含有」或「包括」來取代,或者有時用「具有」取代。
在整個本說明書和隨附申請專利範圍中,術語「Cn-m
」指示包括端點的範圍,其中n和m係整數,並且指示碳的數目。實例包括C1-8
、C1-6
等。
除非在本文件的其他地方具體定義,否則本發明中使用的所有其他技術和科學術語具有本發明所屬領域的普通技術者通常理解的含義。實例
藉由說明本發明之以下實例進一步示例說明本發明,但不限於該等實例。
在以下實例中,使用以下縮寫:
AcOH或HOAc | 乙酸 |
aq. | 水性 |
BINAP | (2,2'-雙(二苯基膦基)-1,1'-二萘基) |
BH3 | 硼烷 |
Brine | 飽和氯化鈉水溶液 |
Boc2 O | 二(三級丁基)碳酸酯 |
BSA | 牛血清白蛋白 |
DAST | 二乙基胺基三氟化硫 |
DBN | 1,5-二氮雜二環[4.3.0]壬-5-烯 |
DBU | 1,8-二氮雜二環[5.4.0]十一-7-烯 |
DCE | 1,2-二氯乙烷 |
DCM | 二氯甲烷 |
DMAP | 4-二甲基胺基吡啶 |
CH3 MgBr | 甲基 溴化鎂 |
DIPEA | N,N-二異丙基乙胺 |
DMF | N ,N -二甲基甲醯胺 |
DMAC | 二甲基乙醯胺 |
DMSO | 二甲亞碸 |
EA | 乙酸乙酯 |
EDCI | 1-乙基-3-(3-二甲基胺基丙基)碳二亞胺鹽酸鹽 |
EDTA | 乙二胺四乙酸 |
EtOH | 乙醇 |
h或hr | 小時 |
HATU | 1-[雙(二甲基胺基)亞甲基]-1H-1,2,3-三唑并[4,5-b]吡啶陽離子 3-氧化物六氟磷酸酯 |
Hex | 己烷 |
1 H NMR | 質子核磁共振 |
H2 O2 | 過氧化氫 |
HOBt | 羥基苯并三唑 |
IPA(i-PrOH) | 異丙醇 |
KOAc | 乙酸鉀 |
LAH | 氫化鋁鋰 |
LC-MS | 液相層析質譜法 |
LDA | 二異丙基胺基鋰 |
MeOH | 甲醇 |
MsOH | 甲磺酸 |
Min | 分鐘 |
n-BuLi | 正丁基鋰 |
NaH | 氫化鈉 |
NaBH(OAc)3 | 三乙醯氧基硼氫化鈉 |
NaBH₃CN | 氰基硼氫化鈉 |
NH4 Cl | 氯化銨 |
Pd/C | 鈀碳粉 |
Pd(dppf)Cl2 | [1,1'-雙(二苯基膦基)二茂鐵]二氯化鈀(II) |
Pd(PPh3 )4 | 四(三苯基膦)鈀(0) |
Pd(OAc)2 | 乙酸鈀 |
Pd(OH)2 /C | 氫氧化鈀碳粉 |
PE | 石油醚 |
pH | -lg(氫離子濃度) |
Prep-HPLC | 製備型高壓液相層析法 |
Prep-MPLC | 製備型中壓液相層析法 |
Prep-SFC | 超臨界流體層析法 |
Pre-TLC | 製備型薄層層析法 |
p-TsOH | 對甲苯磺酸 |
r.t.或RT | 室溫 |
sat. | 飽和 |
t -BuOK | 三級丁醇鉀 |
TBS | 三級丁基二甲基矽基 |
THF | 四氫呋喃 |
TEA | 三乙胺 |
TFA | 三氟乙酸 |
TsCl | 4-甲基苯磺醯氯 |
以下實例旨在純示例性的,並且不應當視為以任何方式限制。儘管已經做出努力以確保關於所使用的數位(例如,量、溫度等)的準確性,但是應該考慮一些實驗誤差和偏差。除非另有說明,否則溫度為攝氏度。試劑購自商業供應商,如西格瑪奧德里奇公司(Sigma-Aldrich)、阿法埃莎公司(Alfa Aesar)或TCI公司,並且除非另有說明,否則無需進一步純化即可使用。
除非另有說明,否則下文所述之反應在氮氣或氬氣的正壓力下或在無水溶劑中用乾燥管進行;反應燒瓶配有橡膠隔片,用於通過注射器引入底物和試劑;並將玻璃器皿進行烘箱乾燥和/或加熱乾燥。
在400 MHz操作的Agilent儀器上記錄1
H NMR譜。使用CDCl3
、CD2
Cl2
、CD3
OD、D2
O、d6
-DMSO、d6
-丙酮或(CD3
)2
CO作為溶劑以及四甲基矽烷(0.00 ppm)或殘餘溶劑(CDCl3
:7.25 ppm;CD3
OD:3.31 ppm;D2
O:4.79 ppm;d6
-DMSO:2.50 ppm;d6-丙酮:2.05;(CD3
)2
CO:2.05)作為參考標準獲得1
HNMR光譜。當報告多重峰數時,使用以下縮寫:s(單峰)、d(二重峰)、t(三重峰)、q(四重峰)、qn(五重峰)、sx(六重峰)、m(多重峰)、br(寬峰)、dd(雙二重峰)、dt(雙三重峰)。如果給出耦合常數,則以赫茲(Hz)報告。
LC-MS光譜儀(安捷倫公司(Agilent)1260)檢測器:MWD(190-400 nm),品質檢測器:6120 SQ
流動相:A:含有0.1%甲酸的乙腈,B:含有0.1%甲酸的水
柱:Poroshell 120 EC-C18,4.6 × 50 mm,2.7 µm
梯度法:流速:1.8 mL/min
時間(min) A(%) B(%)
0.00 5 95
1.5 95 5
2.0 95 5
2.1 5 95
3.0 5 95
製備型HPLC在柱(150 × 21.2 mm ID,5 μm,Gemini NX- C18)上以不同流速和注射體積,在室溫下進行並在214 nm和254 nm下UV檢測。中間體的製備:
步驟1:三級丁基 4-乙基-2-(2-異丙基苯基)-3-側氧基哌𠯤-1-甲酸酯。
在0°C下,向三級丁基 2-(2-異丙基苯基)-3-側氧基哌𠯤-1-甲酸酯(2.0 g,6.28 mmol)在THF(20 mL)中之溶液中添加NaH(301.47 mg,7.54 mmol),將混合物在0°C下攪拌10 min,然後在0°C下添加C2
H5
I(1.18 g,7.54 mmol)。將混合物在50°C下攪拌16小時。將反應混合物傾倒入H2
O(20 mL)中,用EtOAc(20 mL × 3)萃取。將合併的有機層用鹽水洗滌,經Na2
SO4
乾燥,過濾並在減壓下濃縮。將殘餘物藉由MPLC純化。獲得呈黃色油狀物的化合物三級丁基 4-乙基-2-(2-異丙基苯基)-3-側氧基哌𠯤-1-甲酸酯(1.7 g,產率:78%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.36 (m, 1H), 7.31-7.28 (m, 1H), 7.15-7.10 (m, 1H), 7.09-7.06 (m, 1H), 5.97 (s, 1H), 3.75-3.64 (m, 1H), 3.62-3.53 (m, 2H), 3.46-3.27 (m, 4H), 1.46 (s, 9H), 1.29 (m, 3H), 1.25-1.23 (m, 3H), 1.18 (m, 3H)。
步驟2:1-乙基-3-(2-異丙基苯基)哌𠯤-2-酮。
將三級丁基 4-乙基-2-(2-異丙基苯基)-3-側氧基哌𠯤-1-甲酸酯(1.7 g,4.91 mmol)在DCM(10 mL)和TFA(10 mL)中之混合物在25°C下攪拌2小時。將反應混合物在減壓下濃縮。將殘餘物用H2
O(10 mL)稀釋並添加Na2
CO3
至pH = 9。將混合物用DCM(10 mL × 3)萃取。將合併的有機層用鹽水洗滌,經Na2
SO4
乾燥,過濾並在減壓下濃縮。獲得呈黃色油狀物的化合物1-乙基-3-(2-異丙基苯基)哌𠯤-2-酮(1.2 g,產率:99%)。MS (ESI, m/e) [M+1]+
247.1。
步驟3:三級丁基 2-(4-乙基-2-(2-異丙基苯基)-3-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
在20°C下,向1-乙基-3-(2-異丙基苯基)哌𠯤-2-酮(1.2 g,4.87 mmol)和三級丁基 2-側氧基-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.4 g,5.85 mmol)在DCE(20 mL)中之溶液中添加AcOH(585 mg,9.74 mmol)和NaBH(OAc)3
(2.06 g,9.74 mmol)。將混合物在50°C下攪拌12小時。將反應混合物傾倒入水性Na2
CO3
(20 mL)中,用DCM(20 mL × 3)萃取。將合併的有機層用鹽水洗滌,經Na2
SO4
乾燥,過濾並在減壓下濃縮。將殘餘物藉由MPLC純化以給出呈黃色油狀物的三級丁基 2-(4-乙基-2-(2-異丙基苯基)-3-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.2 g,產率:52%)。MS (ESI, m/e) [M+1]+
470.3。
步驟4:三級丁基 2-(4-乙基-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
將三級丁基 2-(4-乙基-2-(2-異丙基苯基)-3-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.2 g,2.56 mmol)在BH3
.THF(10 mL)中之混合物在70°C下攪拌12小時。將反應混合物在0°C下藉由MeOH(10 mL)淬滅,並在25°C下攪拌30 min。將混合物在減壓下濃縮以給出,獲得呈無色油狀物的三級丁基 2-(4-乙基-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.1 g,粗製)。MS (ESI, m/e) [M+1]+
456.3。
步驟5:2-(4-乙基-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷。
將三級丁基 2-(4-乙基-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.1 g,2.41 mmol)在DCM(5 mL)和TFA(5 mL)中之混合物在25°C下攪拌1 hr。將反應混合物在減壓下濃縮。將殘餘物藉由製備型HPLC(TFA條件)根據HPLC純化。將殘餘物用H2
O(10 mL)稀釋並添加Na2
CO3
至pH = 9。將混合物用EtOAc(10 mL × 3)萃取。將合併的有機層用鹽水洗滌,經Na2
SO4
乾燥,過濾並在減壓下濃縮。獲得呈黃色油狀物的化合物2-(4-乙基-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷(440 mg,產率:51%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.50 (m, 1H), 7.26-7.20 (m, 2H), 7.16-7.10 (m, 1H), 3.66 (m, 2H), 3.45-3.35 (m, 1H), 3.01 (t, 2H), 2.94-2.88 (m, 1H), 2.75-2.61 (m, 5H), 2.46-2.38 (m, 2H), 2.35-2.21 (m, 2H), 2.11 (t, 1H), 1.79 (m, 1H), 1.74-1.65 (m, 1H), 1.49-1.37 (m, 4H), 1.32 (m, 1H), 1.24 (d,J
= 6.8 Hz, 3H), 1.20 (d,J
= 6.8 Hz, 3H), 1.10-1.05 (m, 3H)。MS (ESI, m/e) [M+1]+
356.2。
步驟1:三級丁基 2-(4-環丙基-2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
向三級丁基 2-(2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.5 g,3.4 mmol)在MeOH(20 mL)中之溶液中添加(1-乙氧基環丙氧基)三甲基矽烷(2.96 g,17 mmol)、HOAc(1.43 g,23.8 mmol)、4A MS(500 mg)和NaBH3
CN(641 mg,10.2 mmol)。將混合物在25°C下攪拌12小時。將混合物傾倒入水性NaHCO3
(20 mL)中,用EtOAc(20 mL × 3)萃取。將合併的有機相用鹽水(20 mL × 2)洗滌,用無水Na2
SO4
乾燥,過濾並真空濃縮。將殘餘物藉由柱層析法(矽膠,洗脫液:PE/EA(v/v)= 20/1至10/1)純化以給出呈黃色油狀物的三級丁基 2-(4-環丙基-2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.1 g,產率:70%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.31-7.28 (m, 1H), 7.26-7.22 (m, 1H), 7.11 (m, 1H), 6.99 (d,J
= 8.0 Hz, 1H), 4.99 (br t, 1H), 4.26-4.14 (m, 1H), 3.49-3.42 (m, 1H), 3.38-3.32 (m, 1H), 3.39-3.31 (m, 1H), 3.30-3.12 (m, 6H), 3.07 (m, 1H), 2.71 (m, 1H), 2.20 (br s, 1H), 1.98 (br t, 1H), 1.84 (br s, 1H), 1.64 (m, 2H), 1.41 (s, 9H), 1.39-1.32 (m, 3H), 1.29 (m, 6H), 0.45-0.39 (m, 1H), 0.34 (m, 2H), -0.01 (br s, 1H)。
步驟2:三級丁基 2-(4-環丙基-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
將三級丁基 2-(4-環丙基-2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.1 g,2.28 mmol)和BH3
.THF(10 mL,10 mmol)的混合物加熱至70°C持續12小時。在冷卻至0°C後,將混合物用MeOH(10 mL)小心地淬滅。將混合物真空濃縮以給出呈黃色油狀物的三級丁基 2-(4-環丙基-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(0.8 g,產率:80%),其無需進一步純化即可用於下一步。MS (ESI, m/e) [M+1]+
468.4。
步驟3:2-(4-環丙基-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷。
向三級丁基 2-(4-環丙基-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(800 mg,1.7 mmol)在DCM(30 mL)中之溶液中添加TFA(10 mL)。將混合物在25°C下攪拌2小時。在減壓下濃縮後,將殘餘物溶解於水(20 mL)中。然後將混合物用EtOAc(20 mL × 3)萃取。將合併的有機相用鹽水(20 mL × 2)洗滌,用無水Na2
SO4
乾燥,過濾並真空濃縮以給出呈黃色固體的2-(4-環丙基-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷(405 mg,產率:64%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.52 (br s, 1H), 7.26-7.19 (m, 2H), 7.16-7.11 (m, 1H), 3.57 (m, 1H), 3.38 (m, 1H), 3.03 (br t, 2H), 2.94-2.87 (m, 1H), 2.81 (m, 1H), 2.67-2.58 (m, 4H), 2.56-2.48 (m, 1H), 2.39 (br t, 1H), 2.22 (br t, 1H), 1.93 (br s, 1H), 1.75 (br s, 1H), 1.68 (m, 1H), 1.64-1.60 (m, 1H), 1.42-1.28 (m, 6H), 1.24 (m, 3H), 1.20 (m, 3H), 0.44 (m, 2H), 0.41 (m, 2H)。MS (ESI, m/e) [M+1]+
368.3
步驟1:三級丁基 2-(4-環丁基-2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
向三級丁基 2-(2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.0 g,2.26 mmol)在DCE(20 mL)中之溶液中添加環丁酮(0.24 g,3.40 mmol)和HOAc(0.27 g,4.52 mmol)。在25°C下攪拌1 hr後,然後添加NaBH(OAc)3
(0.96 g,4.52 mmol)。將混合物在25°C下攪拌12小時。然後將水性NH4
Cl(20 mL)添加至混合物中,並且然後將混合物用DCM(20 mL × 3)萃取。將合併的有機相用鹽水(20 mL × 2)洗滌,用無水Na2
SO4
乾燥,過濾並真空濃縮。將殘餘物用過柱層析法(矽膠,洗脫液:PE/EA(v/v)= 5/1)純化以給出呈黃色固體的三級丁基 2-(4-環丁基-2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(0.85 g,產率:76%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.33-7.27 (m, 2H), 7.19-7.14 (m, 1H), 7.08 (m, 1H), 5.05 (m, 1H), 3.29-3.10 (m, 8H), 2.81-2.72 (m, 2H), 2.35 (m, 1H), 2.25-2.19 (m, 1H), 2.04-1.75 (m, 6H), 1.68-1.52 (m, 5H), 1.41 (s, 9H), 1.38-1.35 (m, 2H), 1.29 (d,J
= 6.8 Hz, 3H), 1.27-1.25 (m, 3H)。
步驟2:三級丁基 2-(4-環丁基-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺 [3.5]壬烷-7-甲酸酯。
將三級丁基 2-(4-環丁基-2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(850 mg,1.71 mmol)和BH3
.THF(20 mL,17.1 mmol)的混合物加熱至70°C持續12小時。然後將MeOH(10 mL)小心地添加至該混合物中,並真空濃縮以給出,獲得呈黃色油狀物的三級丁基 2-(4-環丁基-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(800 mg,產率:97%),其無需進一步純化即可直接使用。MS (ESI, m/e) [M+1]+
482.4。
步驟3:2-(4-環丁基-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷。
向三級丁基 2-(4-環丁基-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(700 mg,1.45 mmol)在MeOH(20 mL)中之溶液中添加HCl/MeOH(10 mL)。將混合物在25°C下攪拌1 hr。將混合物在減壓下真空濃縮以給出呈黃色固體的2-(4-環丁基-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷(400 mg,產率:83%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 8.84 (m, 2H), 8.11 (br s, 1H), 7.45 (m, 2H), 7.31 (m, 1H), 5.32 (br s, 1H), 3.60-3.48 (m, 4H), 3.38 (m, 4H), 2.84-2.75 (m, 4H), 2.44-2.34 (m, 3H), 2.24-2.13 (m, 4H), 1.77-1.60 (m, 5H), 1.52 (br s, 2H), 1.44-1.41 (m, 2H), 1.29 (d,J
= 6.8 Hz, 3H), 1.18 (d,J
= 6.8 Hz, 3H)。MS (ESI, m/e) [M+1]+
382.4。
步驟1:三級丁基 2-(2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
將三級丁基 2-(2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(3.6 g,8.15 mmol)在BH3
.THF(40 mL)中之混合物在70°C下攪拌12小時。將反應混合物在0°C下藉由MeOH(40 mL)淬滅,並在25°C下攪拌30 min。將混合物濃縮以給出呈白色固體的三級丁基 2-(2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(3.6 g,粗製)。MS (ESI, m/e) [M+1]+
428.3。
步驟2:三級丁基 2-(2-(2-異丙基苯基)-4-(氧雜環丁烷-3-基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
向三級丁基 2-(2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.0 g,2.34 mmol)和氧雜環丁烷-3-酮(219.08 mg,3.04 mmol)在MeOH(20 mL)中之溶液中添加NaBH3
CN(191.04 mg,3.04 mmol)。將混合物在45°C下攪拌36小時。將反應混合物用水性Na2
CO3
(40 mL)稀釋並用EtOAc(40 mL × 3)萃取。將合併的有機層經Na2
SO4
乾燥,過濾並在減壓下濃縮。將殘餘物藉由MPLC純化。獲得呈黃色油狀物的化合物三級丁基 2-(2-(2-異丙基苯基)-4-(氧雜環丁烷-3-基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(420 mg,產率:37%)。MS (ESI, m/e) [M+1]+
484.3。
步驟3:2-(2-(2-異丙基苯基)-4-(氧雜環丁烷-3-基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷。
將三級丁基 2-(2-(2-異丙基苯基)-4-(氧雜環丁烷-3-基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(420 mg,868.33 umol)在DCM(3 mL)和TFA(1 mL)中之混合物在25°C下攪拌2小時。將反應混合物在減壓下濃縮。將殘餘物藉由製備型HPLC(TFA條件)根據HPLC純化。將殘餘物用H2
O(5 mL)稀釋並添加Na2
CO3
至pH = 9並用EtOAc(5 mL × 3)萃取。將合併的有機層經Na2
SO4
乾燥,過濾並在減壓下濃縮以給出呈黃色油狀物的2-(2-(2-異丙基苯基)-4-(氧雜環丁烷-3-基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷(203 mg,產率:61%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.52-7.41 (m, 1H), 7.27-7.19 (m, 2H), 7.16-7.11 (m, 1H), 4.71-4.62 (m, 2H), 4.62-4.55 (m, 2H), 3.75-3.63 (m, 1H), 3.53-3.45 (m, 1H), 3.44-3.35 (m, 1H), 3.11-3.02 (m, 1H), 2.98-2.89 (m, 1H), 2.84 (m, 1H), 2.72-2.57 (m, 4H), 2.53 (m, 1H), 2.33 (m, 1H), 2.25-2.16 (m, 1H), 2.10-2.04 (m, 1H), 1.92-1.75 (m, 4H), 1.72-1.63 (m, 1H), 1.44-1.31 (m, 4H), 1.27 (d,J
= 6.8 Hz, 3H), 1.21 (d,J
= 6.8 Hz, 3H)。MS (ESI, m/e) [M+1]+
384.2。
中間體 6-1a :
將2-(2-(2-異丙基苯基)-4-(氧雜環丁烷-3-基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷藉由SFC(儀器:Waters SFC 80製備型SFC;柱:Chiralcel OD,250 × 30 mm i.d. 10 um;流動相:A為CO2
並且B為MeOH(0.1% NH3
.H2
O);梯度:B% = 30%等度模式;流速:60 g/min;波長:220 nm;柱溫:40°C;系統背壓:100巴)純化。
獲得(R或S)-2-(2-(2-異丙基苯基)-4-(氧雜環丁烷-3-基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷(728 mg,滯留時間:1.40 min),產率:32.1%。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.45 (d,J
= 6.0 Hz, 1H), 7.27-7.19 (m, 2H), 7.16-7.08 (m, 1H), 6.45-6.05 (m, 1H), 4.72-4.62 (m, 2H), 4.61-4.52 (m, 2H), 3.68 (d,J
= 9.0 Hz, 1H), 3.48 (m, 1H), 3.37 (s, 1H), 3.01 (d,J
= 11.2 Hz, 1H), 2.97-2.68 (m, 6H), 2.53 (d,J
= 11.2 Hz, 1H), 2.35-2.25 (m, 1H), 2.24-2.13 (m, 1H), 2.05 (t,J
= 10.6 Hz, 1H), 1.82 (d,J
= 3.4 Hz, 1H), 1.76-1.68 (m, 1H), 1.65-1.45 (m, 4H), 1.38-1.29 (m, 1H), 1.25 (d,J
= 6.8 Hz, 3H), 1.20 (d,J
= 6.3 Hz, 3H), 1.15 (d,J
= 5.1 Hz, 1H)。MS (ESI, m/e) [M+1]+
384.2。
中間體 6-1b :
獲得(S或R)-2-(2-(2-異丙基苯基)-4-(氧雜環丁烷-3-基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷(649 mg,滯留時間:1.51 min,產率:28.6%)。MS (ESI, m/e) [M+1]+
384.2。
步驟1:三級丁基 2-(4-環戊基-2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
在25°C下,向三級丁基 2-(2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.0 g,2.26 mmol)在DCE(15 mL)中之溶液中添加環戊酮(285.7 mg,3.40 mmol)和AcOH(272.0 mg,5.57 mmol)持續30 min,然後在25°C下添加NaBH(OAc)3
(1.44 g,6.79 mmol)。將混合物在25°C下攪拌12小時。將反應混合物傾倒入水性NaHCO3
(50 mL)中,用DCM(50 mL × 2)萃取。將合併的有機層用鹽水洗滌,經Na2
SO4
乾燥,過濾並在減壓下濃縮。將殘餘物藉由柱層析法(矽膠,洗脫液:PE/EA(v/v)= 10/1至0/1)純化以給出呈黃色油狀物的三級丁基 2-(4-環戊基-2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.0 g,1.96 mmol,產率:86%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.33-7.28 (m, 1H), 7.25 (br s, 1H), 7.16 (m, 1H), 7.09 (s, 1H), 5.06 (br s, 1H), 3.37-3.08 (m, 7H), 3.00-2.89 (m, 1H), 2.58-2.43 (m, 2H), 2.27-2.18 (m, 1H), 2.04-1.95 (m, 1H), 1.94-1.83 (m, 1H), 1.74 (br s, 2H), 1.67-1.46 (m, 8H), 1.42 (s, 9H), 1.40-1.31 (m, 4H), 1.31-1.26 (m, 7H), 1.25-1.09 (m, 2H)。
步驟2:三級丁基 2-(4-環戊基-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
在25°C下,向三級丁基 2-(4-環戊基-2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.0 g,1.96 mmol)在THF(10 mL)中之混合物中添加BH3
.THF(20 mL,1 M)。將混合物在70°C下攪拌12小時。將反應混合物冷卻至0°C-5°C。然後在5°C下滴加MeOH(10 mL)以淬滅反應。將混合物在減壓下濃縮以給出呈白色固體的三級丁基 2-(4-環戊基-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.0 g,粗製),其無需進一步反應即可直接用於下一步。MS (ESI, m/e) [M+1]+
496.5
步驟3:2-(4-環戊基-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷。
在25°C下,向三級丁基 2-(4-環戊基-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.0 g,2.02 mmol)在MeOH(5 mL)中之溶液中添加HCl/MeOH(10 mL,4 M)。將混合物在25°C下攪拌1 hr。將反應混合物濃縮以除去大部分MeOH。然後添加HCl/H2
O(1M)溶液以調節pH = 2-3,將其用EtOAc(10 mL)萃取。向水相中添加飽和Na2
CO3
至pH = 9-10,將其用EtOAc(20 mL × 3)萃取。將合併的有機層用鹽水洗滌,經Na2
SO4
乾燥,過濾並在減壓下濃縮以給出呈黃色油狀物的2-(4-環戊基-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷(577 mg,1.46 mmol,產率:72%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.52 (br d,J
= 7.2 Hz, 1H), 7.26-7.10 (m, 3H), 3.67 (m, 1H), 348-3.33 (m, 1H), 3.05 (m, 2H), 2.96-2.86 (m, 1H), 2.78 (m, 1H), 2.69-2.57 (m, 4H), 2.48 (m, 1H), 2.36-2.24 (m, 2H), 2.18-2.10 (m, 2H), 1.91-1.85 (m, 1H), 1.77 (m, 2H), 1.72-1.63 (m, 3H), 1.57-1.49 (m, 2H), 1.49-1.29 (m, 8H), 1.25 (d,J
= 6.8 Hz, 3H), 1.20 (d,J
= 6.8 Hz, 3H)。MS (ESI, m/e) [M+1]+
396.4。
步驟1:三級丁基 2-(2-(2-異丙基苯基)-6-側氧基-4- (四氫呋喃-3-基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
向三級丁基 2-(2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.0 g,2.26 mmol)和二氫呋喃-3(2H)-酮(292.4 mg,3.40 mmol)在DCE(10 mL)中之溶液中添加HOAc(271.9 mg,4.53 mmol)。將溶液在25°C下攪拌5 min並添加NaBH(OAc)3
(1.06 g,4.98 mmol)。將溶液在25°C下攪拌12小時。向反應中添加水性NaHCO3
至pH = 7,將其用DCM(10 mL × 3)萃取。將合併的有機層經Na2
SO4
乾燥,過濾並在減壓下蒸發。將殘餘物藉由柱層析法(矽膠,洗脫液:PE/EA(v/v)= 10/1至1/1)純化以給出呈黃色油狀物的三級丁基 2-(2-(2-異丙基苯基)-6-側氧基-4-(四氫呋喃-3-基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.0 g,產率:86.3%)。
步驟2:三級丁基 2-(2-(2-異丙基苯基)-4-(四氫呋喃-3-基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
向三級丁基 2-(2-(2-異丙基苯基)-6-側氧基-4-(四氫呋喃-3-基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.0 g,1.95 mmol)在THF(15 mL)中之溶液中添加BH3
.THF(15 mL)。將溶液在70°C下攪拌12小時。在冷卻至室溫後,添加MeOH(10 mL)以淬滅反應。將反應在減壓下蒸發以給出呈白色固體的三級丁基 2-(2-(2-異丙基苯基)-4-(四氫呋喃-3-基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(700 mg,粗製),其無需進一步純化即可直接使用。MS (ESI, m/e) [M+1]+
498.4。
步驟3:2-(2-(2-異丙基苯基)-4-(四氫呋喃-3-基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷。
向三級丁基 2-(2-(2-異丙基苯基)-4-(四氫呋喃-3-基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(0.7 g,1.41 mmol)在DCM(10 mL)中之溶液中添加TFA(5 mL)。然後將溶液在25°C下攪拌2小時。將混合物傾倒入水性NaHCO3
中以調節pH = 7,用DCM(10 mL × 3)萃取。將合併的有機相經Na2
SO4
乾燥,過濾並在減壓下蒸發以給出呈黃色油狀物的2-(2-(2-異丙基苯基)-4-(四氫呋喃-3-基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷(342 mg)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.50 (s, 1H), 7.28-7.14 (m, 4H), 3.93-3.66 (m, 5H), 3.03-2.64 (m, 4H), 2.64-2.85 (m, 5H), 2.77-2.46 (m, 3H), 2.17-1.66 (m, 7H), 1.45-1.36 (m, 4H), 1.20-1.36 (m, 3H)。MS (ESI, m/e) [M+1]+
398.3。
步驟1:三級丁基 2-(4-環己基-2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
向三級丁基 2-(2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.0 g,2.26 mmol)在DCE(20 mL)中之溶液添加環己酮(0.34 g,3.40 mmol)和HOAc(0.27 g,4.52 mmol)。在25°C下攪拌1 hr後,然後添加NaBH(OAc)3
(0.96 g,4.52 mmol)。將混合物在25°C下攪拌12小時。然後將水性NH4
Cl(20 mL)添加至混合物中,並且然後將混合物用DCM(20 mL × 3)萃取。將合併的有機相用鹽水(20 mL × 2)洗滌,用無水Na2
SO4
乾燥,過濾並真空濃縮。將殘餘物藉由柱層析法(矽膠,洗脫液:PE/EA(v/v)= 5/1)純化以給出,獲得呈黃色固體的三級丁基 2-(4-環己基-2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(750 mg,產率:63%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.32-7.28 (m, 1H), 7.25 (br s, 1H), 7.14 (t, 1H), 7.09-7.06 (m, 1H), 5.01 (br s, 1H), 4.26-4.15 (m, 1H), 3.38 (m, 2H), 3.26-3.13 (m, 6H), 2.95 (m, 1H), 2.62 (m, 1H), 2.20 (br s, 2H), 1.98 (br s, 1H), 1.84 (br s, 1H), 1.68 (br s, 3H), 1.61 (br s, 6H), 1.42 (s, 10H), 1.35 (m, 2H), 1.31-1.28 (m, 6H), 1.12 (br s, 2H)。
步驟2:三級丁基 2-(4-環己基-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
將三級丁基 2-(4-環己基-2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(0.75 g,1.43 mmol)和BH3
.THF(14 mL,14.3 mmol)的混合物加熱至70°C持續12小時。然後將MeOH(10 mL)小心地添加至混合物並真空濃縮以給出呈黃色油狀物的三級丁基 2-(4-環己基-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(0.7 g,產率:96%),其無需進一步純化即可直接使用。MS (ESI, m/e) [M+1]+
510.4。
步驟3:2-(4-環己基-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷。
向三級丁基 2-(4-環己基-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(700 mg,1.37 mmol)在MeOH(20 mL)中之溶液中添加HCl/MeOH溶液(10 mL)。將混合物在25°C下攪拌1 hr。在除去溶劑後,將殘餘物溶解於水(20 mL)中。將混合物使用水性Na2
CO3
調節pH = 9-10。將混合物用EtOAc(20 mL × 3)萃取。將合併的有機相用鹽水(20 mL × 2)洗滌,用無水Na2
SO4
乾燥,過濾並真空濃縮以給出呈黃色固體的2-(4-環己基-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷(380 mg,產率:68%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.50 (m, 1H), 7.26-7.19 (m, 2H), 7.15-7.11 (m, 1H), 3.61 (br d,J
= 8.4 Hz, 1H), 3.40 (br s, 1H), 3.05 (m, 1H), 2.97 (m, 1H), 2.93-2.87 (m, 1H), 2.75-2.56 (m, 6H), 2.50 (m, 1H), 2.36-2.18 (m, 5H), 1.89 (br s, 2H), 1.76 (br s, 3H), 1.69 (m, 1H), 1.60 (m, 1H), 1.39-1.30 (m, 5H), 1.25 (m, 3H), 1.20 (m, 7H)。MS (ESI, m/e) [M+1]+
410.4。
步驟1:三級丁基 2-(2-(2-異丙基苯基)-6-側氧基-4-(四氫-2H-哌喃-4-基) 哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
將三級丁基 2-(2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.0 g,2.26 mmol)、二氫-2H-哌喃-4(3H)-酮(340.06 mg,3.40 mmol)和HOAc(271.97 mg,4.53 mmol)在DCE(20 mL)中之混合物在25°C下攪拌30 min。然後將NaBH(OAc)3
(1.44 g,6.79 mmol)分批添加至混合物中並在25°C下攪拌12小時。將反應混合物傾倒入冰-水(20 mL)中,用NaHCO3
調節pH = 8。將所得混合物用DCM(30 mL × 3)萃取。將合併的有機相用無水Na2
SO4
乾燥,過濾並濃縮。將粗品藉由柱層析法(矽膠,洗脫液:PE/EA(v/v)= 3/1至1/1)純化以給出呈黃色固體的三級丁基2-(2-(2-異丙基苯基)-6-側氧基-4-(四氫-2H-哌喃-4-基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.05 g,產率:88%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.30 (m, 1H), 7.14 (m, 1H), 7.09-7.01 (m, 1H), 5.02 (m, 1H), 4.25 (s, 1H), 3.95-3.81 (m, 2H), 3.54-3.04 (m, 10H), 2.98-2.93 (m, 1H), 2.70-2.65 (m, 1H), 2.45-2.34 (m, 1H), 2.26-2.17 (m, 1H), 1.97 (m, 1H), 1.82 (s, 1H), 1.66-1.59 (m, 2H), 1.57-1.52 (m, 1H), 1.46-1.40 (m, 12H), 1.37-1.33 (m, 2H), 1.32-1.27 (m, 6H)。
步驟2:三級丁基 2-(2-(2-異丙基苯基)-4-(四氫-2H-哌喃-4-基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯
在20°C下,向三級丁基 2-(2-(2-異丙基苯基)-6-側氧基-4-(四氫-2H-哌喃-4-基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(900 mg,1.71 mmol)在THF(15 mL)中之溶液中滴加BH3
.THF(30 mL,30 mmol)。將混合物加熱至70°C持續20小時。將反應藉由乙醇(5 mL)淬滅,真空濃縮以給出呈無色油狀物的三級丁基 2-(2-(2-異丙基苯基)-4-(四氫-2H-哌喃-4-基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(876 mg,粗製),其無需進一步純化即可直接用於下一步。MS (ESI, m/e) [M+1]+
512.4。
步驟3:2-(2-(2-異丙基苯基)-4-(四氫-2H-哌喃-4-基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷。
向三級丁基 2-(2-(2-異丙基苯基)-4-(四氫-2H-哌喃-4-基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(900 mg,1.76 mmol)在MeOH(2 mL)中之溶液添加HCl/MeOH溶液(20 mL,4M)。將溶液在25°C下攪拌4小時。將反應溶液真空濃縮。將粗品藉由製備型HPLC純化並凍乾。殘餘物不含飽和NaHCO3
(20 mL),將其用EtOAc(50 mL × 3)萃取。將合併的有機相用無水Na2
SO4
乾燥,過濾並真空濃縮以給出呈白色膠狀物的2-(2-(2-異丙基苯基)-4-(四氫-2H-哌喃-4-基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷(390 mg,產率:54%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.50 (d,J
= 5.6 Hz, 1H), 7.27-7.20 (m, 2H), 7.17-7.11 (m, 1H), 4.03-4.00 (td, 2H), 3.63 (m, 1H), 3.35-3.25 (m, 3H), 3.13-2.99 (m, 2H), 2.91 (m, 1H), 2.75 (m, 1H), 2.70-2.51 (m, 4H), 2.46-2.33 (m, 2H), 2.33-2.20 (m, 2H), 1.90-1.72 (m, 4H), 1.71-1.63 (m, 1H), 1.65-1.55 (m, 2H), 1.48-1.01 (m, 14H)。MS (ESI, m/e) [M+1]+
412.5。
步驟1:三級丁基 2-(4-異丁基-2-(2-異丙基苯基)-3-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
在0°C下,向三級丁基 2-(2-(2-異丙基苯基)-3-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(2.0 g,4.53 mmol)在THF(20 mL)中之溶液中添加NaH(362.28 mg,9.06 mmol)。將混合物在0°C下攪拌10 min。然後在0°C下添加1-碘-2-甲基丙烷(1.67 g,9.06 mmol)。將混合物在65°C下攪拌48 hr。將反應混合物傾倒入H2
O(20 mL)中,用EtOAc(20 mL × 3)萃取。將合併的有機層用鹽水洗滌,經Na2
SO4
乾燥,過濾並在減壓下濃縮。將殘餘物藉由MPLC純化。獲得呈黃色固體的化合物三級丁基 2-(4-異丁基-2-(2-異丙基苯基)-3-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.1 g,2.21 mmol,產率:48%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.27-7.21 (m, 3H), 7.12-7.06 (m, 1H), 4.81 (m, 1H), 4.09 (s, 1H), 3.52-3.39 (m, 2H), 3.29 (m, 1H), 3.27-3.23 (m, 2H), 3.19-3.15 (m, 2H), 3.13 (m, 1H), 2.97 (m, 1H), 2.38 (m, 1H), 1.96-1.88 (m, 1H), 1.71-1.60 (m, 2H), 1.45 (m, 2H), 1.42 (s, 9H), 1.41-1.37 (m, 2H), 1.32 (s, 1H), 1.30 (d,J
= 6.8 Hz, 3H), 1.18 (d,J
= 6.8 Hz, 3H), 1.14 (m, 6H)。
步驟2:三級丁基 2-(4-異丁基-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
將三級丁基 2-(4-異丁基-2-(2-異丙基苯基)-3-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.1 g,2.21 mmol)在BH3
.THF(10 mL)中之混合物在70°C下攪拌12小時。將反應混合物在0°C下藉由MeOH(5 mL)淬滅,並在25°C下攪拌30 min。然後將混合物在減壓下濃縮以得到呈無色油狀物的三級丁基 2-(4-異丁基-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.05 g,粗製)。MS (ESI, m/e) [M+1]+
484.3。
步驟3:2-(4-異丁基-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷。
將三級丁基 2-(4-異丁基-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.05 g,2.17 mmol)在HCl/EtOAc(10 mL)中之混合物在25°C下攪拌2小時。將反應混合物在減壓下濃縮。將殘餘物藉由製備型HPLC(HCl條件)根據HPLC純化。將殘餘物用H2
O(10 mL)稀釋並添加Na2
CO3
至pH = 9。將混合物用EtOAc(10 mL × 3)萃取。將合併的有機層用鹽水洗滌,經Na2
SO4
乾燥,過濾並在減壓下濃縮。獲得呈黃色油狀物的化合物2-(4-異丁基-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷(461 mg,1.18 mmol,產率:54.26%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.50 (d,J
= 4.5 Hz, 1H), 7.27-7.19 (m, 2H), 7.16-7.10 (m, 1H), 3.62 (m, 1H), 3.41 (m, 1H), 2.99 (m, 1H), 2.95-2.85 (m, 2H), 2.71-2.54 (m, 5H), 2.34-2.19 (m, 2H), 2.14-2.04 (m, 3H), 1.85 (s, 2H), 1.80-1.72 (m, 2H), 1.72-1.64 (m, 1H), 1.43-1.29 (m, 5H), 1.27 (d,J
= 6.8 Hz, 3H), 1.21 (d,J
= 6.8 Hz, 3H), 0.88 (m, 6H)。MS (ESI, m/e) [M+1]+
384.4。
步驟1:2-異丙基苯甲醛。
在-78°C下,向1-溴-2-異丙基苯(20 g,0.1 mol)在THF(200 mL)中之溶液中滴加n-BuLi(44 mL,0.11 mol,2.5 M,在己烷中)。在-78°C下攪拌1 hr後,將DMF(8.0 g,0.11 mol)添加至混合物。將混合物在-60°C下攪拌1 hr。然後將水性NH4
Cl(1M,100 mL)添加至混合物。將混合物用EtOAc(300 mL × 3)萃取。將合併的有機相用鹽水(100 mL × 2)洗滌,用無水Na2
SO4
乾燥,過濾並真空濃縮。將殘餘物藉由柱層析法(矽膠,洗脫液:PE)純化。獲得呈黃色油狀物的化合物2-異丙基苯甲醛(14 g,產率:94%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 10.38 (s, 1H), 7.83 (dd,J
= 8.0 Hz, 1.6 Hz, 1H), 7.60-7.53 (m, 1H), 7.49-7.45 (m, 1H), 7.36 (t, 1H), 3.99 (t, 1H), 1.32 (d,J
= 6.8 Hz, 6H)。
步驟2:(E)-N-(2-異丙基亞苄基)-2-甲基丙烷-2-亞磺醯胺。
向2-異丙基苯甲醛(20 g,0.135 mol)在THF(200 mL)中之溶液中添加2-甲基丙烷-2-亞磺醯胺(18 g,0.148 mmol)。在冷卻至0°C後,添加Ti(OEt)4
(62 g,0.27 mol)。將混合物在25°C下攪拌12小時。將反應混合物藉由水(100 mL)小心地淬滅,並且然後藉由矽藻土墊過濾。將濾液用EtOAc(100 mL × 3)萃取並用鹽水(100 mL)洗滌。將合併的有機層經Na2
SO4
乾燥,過濾並在減壓下濃縮。將殘餘物藉由柱層析法(矽膠,洗脫液:PE/EA(v/v)= 100/1至20/1)純化。獲得呈黃色油狀物的化合物(E)-N-(2-異丙基亞苄基)-2-甲基丙烷-2-亞磺醯胺(32.5 g,產率:96%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 9.00 (s, 1H), 7.96 (dd,J
= 8.0 Hz, 2.0 Hz, 1H), 7.51-7.45 (m, 1H), 7.44-7.40 (m, 1H), 7.32-7.27 (m, 1H), 3.72 (t, 1H), 1.33-1.25 (m, 15H)。
步驟3:N-(1-(2-異丙基苯基)-2-硝基乙基)-2-甲基丙烷-2-亞磺醯胺。
在0°C下,向(E)-N-(2-異丙基亞苄基)-2-甲基丙烷-2-亞磺醯胺(32 g,0.13 mol)在THF(300 mL)中之溶液中分幾批添加t-BuOK(21 g,0.19 mol)。在0°C下攪拌1 hr後,添加硝基甲烷(77 g,1.27 mmol)。將混合物在25°C下攪拌12小時。然後將水(100 mL)添加至混合物,並且然後將混合物用EtOAc(100 mL × 3)萃取。將有機層乾燥,過濾並在減壓下濃縮。將殘餘物藉由柱層析法(矽膠,洗脫液:PE/EA(v/v)= 10/1至2/1)純化以給出呈黃色油狀物的N-(1-(2-異丙基苯基)-2-硝基乙基)-2-甲基丙烷-2-亞磺醯胺(26.5 g,產率:67%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.40-7.34 (m, 2H), 7.34-7.28 (m, 1H), 7.26-7.21 (m, 1H), 5.53-5.44 (m, 1H), 4.88-4.78 (m, 1H), 4.76-4.65 (m, 1H), 4.30-4.20 (m, 1H), 3.35-3.22 (m, 1H), 1.34-1.26 (m, 6H), 1.27-1.20 (m, 9H)
步驟4:N-(2-胺基-1-(2-異丙基苯基)乙基)-2-甲基丙烷-2-亞磺醯胺
向N-(1-(2-異丙基苯基)-2-硝基乙基)-2-甲基丙烷-2-亞磺醯胺(23 g,0.074 mol)在MeOH(200 mL)中之溶液中添加雷氏鎳(5.0 g)。將混合物在25°C下在H2
(15 psi)氣氛下攪拌12小時。在通過矽藻土墊過濾後,將濾液在減壓下濃縮以給出呈棕色固體的N-(2-胺基-1-(2-異丙基苯基)乙基)-2-甲基丙烷-2-亞磺醯胺(17.6 g,產率:84%),其無需進一步純化即可用於下一步。MS (ESI, m/e) [M+1]+
283.1。
步驟5:N-(2-((三級丁基亞磺醯基)胺基)-2-(2-異丙基苯基)乙基)-4-甲基苯磺醯胺。
向N-(2-胺基-1-(2-異丙基苯基)乙基)-2-甲基丙烷-2-亞磺醯胺(23 g,0.081 mol)在DCM(300 mL)中之溶液中添加TEA(24.5 g,0.243 mol)。在冷卻至0°C後,分幾批添加TsCl(17 g,0.09 mol)。將混合物在25°C下攪拌2小時。然後將水性NH4
Cl(1M,100 mL)添加至混合物中,並且然後用DCM(100 mL × 3)萃取混合物。將合併的有機相用鹽水(100 mL × 2)洗滌,用無水Na2
SO4
乾燥,過濾並真空濃縮。將殘餘物藉由柱層析法(矽膠,洗脫液:PE/EA(v/v)= 20/1至5/1)純化以給出,獲得呈黃色固體的N-(2-((三級丁基亞磺醯基)胺基)-2-(2-異丙基苯基)乙基)-4-甲基苯磺醯胺(23 g,產率:65%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.79 (d,J
= 8.4 Hz, 2H), 7.32-7.26 (m, 4H), 7.20-7.12 (m, 1H), 4.82-4.69 (m, 1H), 4.25 (br s, 1H), 3.14 (br d,J
= 7.6 Hz, 4H), 3.07-2.97 (m, 1H), 2.41 (s, 3H), 1.42 (t, 6H), 1.23 (s, 9H)。
步驟6:N-(2-胺基-2-(2-異丙基苯基)乙基)-4-甲基苯磺醯胺。
向N-(2-((三級丁基亞磺醯基)胺基)-2-(2-異丙基苯基)乙基)-4-甲基苯磺醯胺(5.0 g,11 mmol)在MeOH(20 mL)中之溶液中添加在MeOH(10 mL,4M)中的HCl(氣體)。將混合物在25°C下攪拌1 hr。將混合物在減壓下濃縮。將殘餘物溶解於水(50 mL)中,並且然後添加水性Na2
CO3
以調節pH = 9。將混合物用EtOAc(50 mL × 2)萃取。將合併的有機層經Na2
SO4
乾燥,過濾並真空濃縮以給出呈黃色油狀物的N-(2-胺基-2-(2-異丙基苯基)乙基)-4-甲基苯磺醯胺(3.8 g,產率:99%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.74 (d,J
= 8.0 Hz, 2H), 7.32-7.23 (m, 5H), 7.21-7.13 (m, 1H), 4.36 (m, 1H), 3.17-3.03 (m, 2H), 2.93 (dd,J
= 12.8, 8.8 Hz, 1H), 2.43 (s, 3H), 1.21-1.18 (m, 6H)。
步驟7:三級丁基 2-((1-(2-異丙基苯基)-2-(4-甲基苯基)磺醯胺基)乙基)胺基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
向N-(2-胺基-2-(2-異丙基苯基)乙基)-4-甲基苯磺醯胺(4.0 g,0.012 mol)在DCE(50 mL)中之溶液中添加三級丁基2-側氧基-7-氮雜螺[3.5]壬烷-7-甲酸酯(3.2 g,0.013 mol)和HOAc(1.44 g,0.024 mol)。在25°C下攪拌1 hr後,然後添加NaBH(OAc)3
(5.1 g,0.024 mol)。將混合物在25°C下攪拌12小時。然後將水性NH4
Cl(50 mL)添加至混合物中,用DCM(50 mL × 3)萃取。將合併的有機相用鹽水(50 mL × 2)洗滌,用無水Na2
SO4
乾燥,過濾並真空濃縮。將殘餘物藉由柱層析法(矽膠,洗脫液:PE/EA(v/v)= 10/1至5/1)純化以給出呈黃色固體的三級丁基 2-((1-(2-異丙基苯基)-2-(4-甲基苯基)磺醯胺基)乙基)胺基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(4.3 g,產率:64%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.73 (d,J
= 8.0 Hz, 2H), 7.32-7.25 (m, 4H), 7.19-7.13 (m, 2H), 4.02 (m, 1H), 3.30-3.22 (m, 4H), 3.09-2.98 (m, 3H), 2.88 (m, 1H), 2.43 (s, 3H), 2.02-1.88 (m, 2H), 1.75 (br s, 3H), 1.44 (s, 9H), 1.40 (m, 3H), 1.17 (m, 6H)。
步驟8:三級丁基 2-(2-氯-N-(1-(2-異丙基苯基)-2-(4-甲基苯基)磺醯胺基)乙基)乙醯胺基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
向三級丁基 2-((1-(2-異丙基苯基)-2-(4-甲基苯基)磺醯胺基)乙基) 胺基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(4.3 g,7.74 mmol)在THF(50 mL)中之溶液中添加TEA(1.56 g,15.48 mmol)。在冷卻至0°C後,滴加2-氯乙醯氯(0.96 g,8.51 mmol)。將混合物在25°C下攪拌2小時。將混合物傾倒入水性NH4
Cl(1 M,50 mL)中,用EtOAc(50 mL × 3)萃取。將合併的有機相用鹽水(50 mL × 2)洗滌,用無水Na2
SO4
乾燥,過濾並真空濃縮。將殘餘物藉由柱層析法(矽膠,洗脫液:PE/EA(v/v)= 20/1至5/1)純化以給出,獲得呈黃色固體的三級丁基 2-(2-氯-N-(1-(2-異丙基苯基)-2-(4-甲基苯基)磺醯胺基)乙基)乙醯胺基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(4.6 g,產率:94%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.74 (d,J
= 8.0 Hz, 2H), 7.32-7.27 (m, 4H), 7.20 (m, 1H), 7.15-7.10 (m, 1H), 5.31-5.20 (m, 1H), 5.08 (br s, 1H), 4.22 (d,J
= 2.8 Hz, 2H), 4.13 (m, 2H), 3.30 (m, 2H), 3.23 (m, 3H), 2.38 (s, 3H), 2.05 (s, 3H), 1.65 (br s, 3H), 1.48-1.45 (m, 3H), 1.44 (s, 9H), 1.27 (m, 6H)。
步驟9:三級丁基 2-(2-(2-異丙基苯基)-6-側氧基-4-甲苯磺醯基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
向三級丁基 2-(2-氯-N-(1-(2-異丙基苯基)-2-(4- 甲基苯基)磺醯胺基)乙基)乙醯胺基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(4.6 g,7.28 mmol)在DMF(50 mL)中之溶液中添加K2
CO3
(2.0 g,14.55 mmol)。將混合物在60°C下攪拌1 hr。然後將水(50 mL)添加至混合物,並且然後將混合物用EtOAc(50 mL × 3)萃取。將合併的有機相用鹽水(50 mL × 2)洗滌,用無水Na2
SO4
乾燥,過濾並真空濃縮。將殘餘物藉由柱層析法(矽膠,洗脫液:PE/EA(v/v)= 20/1至5/1)純化以給出呈黃色固體的三級丁基 2-(2-(2-異丙基苯基)-6-側氧基-4-甲苯磺醯基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(2.6 g,產率:62%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.47 (d,J
= 8.4 Hz, 2H), 7.36-7.30 (m, 2H), 7.23 (d,J
= 8.4 Hz, 2H), 7.16-7.10 (m, 1H), 6.89 (d,J
= 7.75 Hz, 1H), 5.07 (t, 1H), 4.30 (br s, 1H), 4.16-4.10 (m, 1H), 3.97-3.88 (m, 1H), 3.81-3.70 (m, 1H), 3.39 (m, 2H), 3.27-3.21 (m, 2H), 3.21-3.13 (m, 2H), 3.12-3.06 (m, 1H), 2.99-2.85 (m, 1H), 2.41 (s, 3H), 2.22-2.14 (m, 1H), 1.85 (br t, 1H), 1.73-1.58 (m, 2H), 1.46 (m, 2H), 1.41 (s, 9H), 1.30-1.26 (m, 6H)。
步驟10:三級丁基 2-(2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
向三級丁基 2-(2-(2-異丙基苯基)-6-側氧基-4-甲苯磺醯基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(2.6 g,4.47 mmol)在MeOH(50 mL)中之溶液中添加Mg(1.07 g,44.7 mmol)。將混合物在100°C下攪拌2小時。將混合物用水(50 mL)和EtOAc(50 mL)稀釋,並且然後通過矽藻土墊過濾。將濾液用EtOAc(50 mL × 3)萃取。將合併的有機相用鹽水(50 mL × 2)洗滌,用無水Na2
SO4
乾燥,過濾並在減壓下濃縮以給出呈棕色油狀物的三級丁基 2-(2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.3 g,產率:66%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.40-7.36 (d,J
= 7.2 Hz, 1H), 7.32 (t, 1H), 7.20 (t, 1H), 7.00 (d,J
= 8.0 Hz, 1H), 5.02 (br s, 1H), 4.55 (br s, 1H), 3.60 (m, 2H), 3.49 (s, 1H), 3.33 (m, 1H), 3.29-3.24 (m, 2H), 3.21-3.11 (m, 3H), 2.97-2.91 (m, 1H), 2.27-2.20 (m, 1H), 1.90 (br t, 1H), 1.74-1.64 (m, 5H), 1.47-1.44 (m, 2H), 1.42 (s, 9H), 1.29 (t, 6H)。
步驟11:三級丁基 2-(2-(2-異丙基苯基)-4-新戊基-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
向三級丁基 2-(2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.0 g,2.26 mmol)在DCE(20 mL)中之溶液中添加新戊醛(0.29 g,3.40 mmol)和HOAc(0.27 g,4.52 mmol)。在25°C下攪拌1 hr後,然後添加NaBH(OAc)3
(0.96 g,4.52 mmol)。將混合物在25°C下攪拌12小時。將混合物傾倒入水性NH4
Cl(1M,20 mL),用DCM(20 mL × 3)萃取。將合併的有機相用鹽水(20 mL × 2)洗滌,用無水Na2
SO4
乾燥,過濾並真空濃縮。將殘餘物藉由柱層析法(矽膠,洗脫液:PE/EA(v/v)= 20/1至5/1)純化以給出呈黃色固體的三級丁基 2-(2-(2-異丙基苯基)-4-新戊基-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(0.68 g,產率:59%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.29-7.27 (m, 2H), 7.15-7.10 (m, 2H), 4.93 (br s, 1H), 4.45 (br s, 1H), 3.55 (br d,J
= 16.76 Hz, 1H), 3.50 (s, 1H), 3.31-3.07 (m, 8H), 2.96 (m, 1H), 2.76 (m, 1H), 2.22 (m, 1H), 2.01 (br s, 2H), 1.94 (m, 1H), 1.74 (br s, 2H), 1.49-1.45 (m, 3H), 1.42 (s, 9H), 1.30-1.26 (m, 6H), 0.53 (br s, 9H)。
步驟12:三級丁基 2-(2-(2-異丙基苯基)-4-新戊基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
將三級丁基 2-(2-(2-異丙基苯基)-4-新戊基-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(680 mg,1.33 mmol)和BH3
.THF(13 mL,13.3 mmol)的混合加熱至70°C持續12小時。在冷卻至0°C後,將混合物用MeOH(10 mL)小心地淬滅。將混合物真空濃縮以給出呈黃色油狀物的三級丁基 2-(2-(2-異丙基苯基)-4-新戊基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(0.6 g,產率:91%),其無需進一步純化即可用於下一步。MS (ESI, m/e) [M+1]+
498.4
步驟13:2-(2-(2-異丙基苯基)-4-新戊基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷。
向三級丁基 2-(2-(2-異丙基苯基)-4-新戊基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(600 mg,1.21 mmol)在MeOH(20 mL)中之溶液中添加HCl/MeOH(10 mL,4M)溶液。將混合物在25°C下攪拌1 hr。在減壓下濃縮後,將殘餘物溶解於水(20 mL)中。將混合物用水性Na2
CO3
調節至pH = 9-10。將混合物用EtOAc(20 mL × 3)萃取。將合併的有機相用鹽水(20 mL × 2)洗滌,用無水Na2
SO4
乾燥,過濾並真空濃縮以給出呈黃色固體的2-(2-(2-異丙基苯基)-4-新戊基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷(400 mg,83.5%產率)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.49 (m, 1H), 7.26-7.18 (m, 2H), 7.15-7.10 (m, 1H), 3.61 (m, 1H), 3.41 (br s, 1H), 2.97-2.88 (m, 2H), 2.82 (m, 1H), 2.68-2.52 (m, 6H), 2.39 (br t, 1H), 2.32-2.26 (m, 1H), 2.11-2.01 (m, 3H), 1.78-1.72 (m, 1H), 1.69 (m, 1H), 1.45-1.30 (m, 5H), 1.28 (m, 3H), 1.19 (m, 3H), 0.85 (s, 9H)。MS (ESI, m/e) [M+1]+
398.4。
步驟1:三級丁基 2-(2-異丙基苯基)-4-(2-甲氧基乙基)-3-側氧基哌𠯤-1-甲酸酯。
在20°C下,將三級丁基 2-(2-異丙基苯基)-3-側氧基哌𠯤-1-甲酸酯(1.5 g,4.7 mmol)和1-溴-2-甲氧基乙烷(0.72 g,5.2 mmol)在THF(15 mL)中之混合物中分批添加NaH(136 mg,5.6 mmol)。將混合物在50°C下攪拌24小時。將混合物藉由MeOH(2 mL)淬滅,在減壓下濃縮。將殘餘物傾倒入鹽水(20 mL)中,用EtOAc(20 mL × 3)萃取。將合併的有機層經Na2
SO4
乾燥,過濾並在減壓下濃縮以給出呈黃色油狀物的三級丁基 2-(2-異丙基苯基)-4-(2-甲氧基乙基)-3-側氧基哌𠯤-1-甲酸酯(1.5 g,粗製),其無需進一步純化即可直接用於下一步。
步驟2:3-(2-異丙基苯基)-1-(2-甲氧基乙基)哌𠯤-2-酮。
將三級丁基 2-(2-異丙基苯基)-4-(2-甲氧基乙基)-3-側氧基哌𠯤-1-甲酸酯(1.4 g,3.8 mmol)在TFA(5 mL)和DCM(5 mL)中之溶液在27°C下攪拌2小時。將混合物在減壓下濃縮。將殘餘物傾倒入飽和NaHCO3
(30 mL)中,用EtOAc(30 mL × 3)萃取。將合併的有機層經Na2
SO4
乾燥,過濾並在減壓下濃縮以給出呈黃色油狀物的3-(2-異丙基苯基)-1-(2-甲氧基乙基)哌𠯤-2-酮(1.0 g,粗製),其無需進一步純化即可直接用於下一步。
步驟3:三級丁基 2-(2-(2-異丙基苯基)-4-(2-甲氧基乙基)-3-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
向3-(2-異丙基苯基)-1-(2-甲氧基乙基)哌𠯤-2-酮(1.0 g,3.7 mmol)在DCE(10 mL)中之溶液中添加三級丁基 2-側氧基-7-氮雜螺[3.5]壬烷-7-甲酸酯(874 mg,3.7 mmol)和NaBH(OAc)3
(1.6 g,7.3 mmol)。將混合物在27°C下攪拌10小時。將混合物傾倒入飽和NaHCO3
(50 mL)中,用DCM(20 mL × 3)萃取。將合併的有機層經Na2
SO4
乾燥,過濾並在減壓下濃縮以給出呈黃色油狀物的三級丁基 2-(2-(2-異丙基苯基)-4-(2-甲氧基乙基)-3-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.6 g,粗製),其無需進一步純化即可直接用於下一步。
步驟4:三級丁基 2-(2-(2-異丙基苯基)-4-(2-甲氧基乙基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
將三級丁基 2-(2-(2-異丙基苯基)-4-(2-甲氧基乙基)-3-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.4 g,2.8 mmol)在BH3
-THF(10 mL)中之溶液在70°C下攪拌10小時。將混合物藉由MeOH(10 mL)淬滅並在減壓下濃縮以給出呈黃色油狀物的三級丁基 2-(2-(2-異丙基苯基)-4-(2-甲氧基乙基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(2.4 g,粗製),其無需進一步純化即可直接用於下一步。
步驟5:2-(2-(2-異丙基苯基)-4-(2-甲氧基乙基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷。
將三級丁基 2-(2-(2-異丙基苯基)-4-(2-甲氧基乙基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.3 g,2.7 mmol)在TFA(3 mL)和DCM(6 mL)中之溶液在20°C下攪拌2小時。將混合物在減壓下濃縮。將殘餘物藉由備型HPLC(TFA)純化。獲得呈無色油狀物的化合物 2-(2-(2-異丙基苯基)-4-(2-甲氧基乙基) 哌𠯤-1-基)-7-氮雜螺[3.5]壬烷(791 mg,產率:77%)。1
H NMR (400 MHz, CH3
OH-d 4
) δ ppm: 7.48 (br, 1H), 7.32-7.27 (m, 1H), 7.23 (m, 1H), 7.18-7.09 (m, 1H), 3.74 (m, 1H), 3.55-3.50 (m, 2H), 3.44 (m, 1H), 3.33-3.31 (m, 3H), 3.09-2.99 (m, 2H), 2.93 (m, 1H), 2.76-2.69 (m, 1H), 2.67-2.45 (m, 6H), 2.42 - 2.22 (m, 3 H), 1.88-1.79 (m, 1H), 1.72-1.63 (m, 1H), 1.44-1.25 (m, 8H), 1.20 (d,J
= 6.8 Hz, 3H), 1.15-1.03 (m, 1H)。MS (ESI, m/e) [M+1]+
386.4。
將2-(2-(2-異丙基苯基)-4-(2-甲氧基乙基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷藉由SFC(儀器:Waters SFC80製備型SFC;柱:Phenomenex-Cellulose-2(250 × 30 mm i.d. 10 uM);流動相:A為CO2
並且B為MeOH(0.1% NH3
.H2
O);梯度:B% = 40%;流速:70 g/min;波長:220 nm;柱溫:40°C;系統背壓:100巴)分離。獲得(R或S)-2-(2-(2-異丙基苯基)-4-(2-甲氧基乙基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷(452 mg,滯留時間:1.59 min),產率:30%。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.50 (s, 1H), 7.25-7.20 (m, 2H), 7.13 (m, 1H), 3.73-3.67 (m, 1H), 3.50 (m, 2H), 3.40 (br s, 1H), 3.33 (s, 3H), 3.00 (m, 2H), 2.93-2.87 (m, 1H), 2.74-2.65 (m, 4H), 2.58 (t, 2H), 2.33 (m, 2H), 2.23-2.14 (m, 2H), 1.80-1.75 (m, 2H), 1.44-1.34 (m, 6H), 1.22 (m, 6H)。MS (ESI, m/e) [M+1]+
386.3。
中間體 13-1b :
獲得(S或R)-2-(2-(2-異丙基苯基)-4-(2-甲氧基乙基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷(441 mg,滯留時間:1.78 min,產率:29%)。MS (ESI, m/e) [M+1]+
386.3。
步驟1:三級丁基 2-(4-(環戊基甲基)-2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
在25°C下,向三級丁基 2-(2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.0 g,2.26 mmol)、環戊烷甲醛(333 mg,3.40 mmol)和AcOH(339 mg,5.66 mmol)在DCE(10 mL)中之溶液中添加NaBH(OAc)3
(959 mg,4.53 mmol)。將混合物在25°C下攪拌12小時。將反應混合物藉由飽和Na2
CO3
(10 mL)淬滅,用EtOAc(10 mL × 3)萃取。將合併的有機層用鹽水洗滌,用無水Na2
SO4
乾燥,過濾並在減壓下濃縮。將粗產物藉由柱層析法(矽膠,洗脫液:PE/EA(v/v)= 50/1至0/1)純化以給出呈淺黃色油狀物的三級丁基 2-(4-(環戊基甲基)-2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.0 g,產率:84%)。
步驟2:三級丁基 2-(4-(環戊基甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
在0°C下,向三級丁基 2-(4-(環戊基甲基)-2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.0 g,1.91 mmol)的混合物中添加在THF(20 mL)中的BH3
.THF(57 mL,57.28 mmol)。將混合物在80°C下攪拌12小時。在0°C下,向反應溶液中添加MeOH(20 mL)以淬滅反應並將其在減壓下濃縮以給出呈黃色油狀物的三級丁基 2-(4-(環戊基甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.0 g,粗製),其無需進一步純化即可直接用於下一步。
步驟3:2-(4-(環戊基甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷。
在0°C下,向三級丁基 2-(4-(環戊基甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.0 g,1.96 mmol)的混合物中添加HCl/MeOH(40 mL)持續2小時。將反應混合物傾倒入飽和Na2
CO3
(40 mL)中,用EtOAc(40 mL × 3)萃取。將合併的有機相用鹽水(40 mL × 2)洗滌,用無水Na2
SO4
乾燥,過濾並在減壓下濃縮以給出呈淺粉色油狀物的2-(4-(環戊基甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷(712 mg,產率:88%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.58-7.46 (m, 1H), 7.26-7.19 (m, 2H), 7.17-7.10 (m, 1H), 3.68-3.59 (m, 1H), 3.42 (s, 1H), 3.03-2.88 (m, 3H), 2.73-2.57 (m, 5H), 2.28 (m, 4H), 2.16-2.09 (m, 1H), 1.79-1.64 (m, 9H), 1.61-1.56 (m, 2H), 1.41-1.30 (m, 6H), 1.28-1.25 (d,J
= 6.8 Hz, 3H), 1.20-1.22 (d,J
= 6.8 Hz, 3H), 1.16 (m, 2H)。MS (ESI, m/e) [M+1]+
410.3。
步驟1:三級丁基 2-(4-(環己基甲基)-2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
向三級丁基 2-(2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.0 g,2.26 mmol)在DCE(20 mL)中之溶液中添加環己烷甲醛(0.38 g,3.40 mmol)和HOAc(0.27 g,4.52 mmol)。在25°C下攪拌1 hr後,然後添加NaBH(OAc)3
(0.96 g,4.52 mmol)。將混合物在25°C下攪拌12小時。然後將水性NH4
Cl(20 mL)添加至混合物中,並且然後將混合物用DCM(20 mL × 3)萃取。將合併的有機相用鹽水(20 mL × 2)洗滌,用無水Na2
SO4
乾燥,過濾並真空濃縮。將殘餘物藉由柱層析法(矽膠,洗脫液:PE/EA(v/v)= 5/1)純化以給出,獲得呈黃色固體的三級丁基 2-(4-(環己基甲基)-2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.0 g,產率:83%)。MS (ESI, m/e) [M+1]+
538.4。
步驟2:三級丁基 2-(4-(環己基甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
將三級丁基 2-(4-(環己基甲基)-2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.0 g,1.86 mmol)和BH3
.THF(19 mL,18.6 mmol)的混合物加熱至70°C持續12小時。然後將MeOH(10 mL)小心地添加至混合物。將混合物真空濃縮以給出呈黃色油狀物的三級丁基 2-(4-(環己基甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(0.6 g,產率:65%),其無需進一步純化即可直接用於下一步。MS (ESI, m/e) [M+1]+
524.4
步驟3:2-(4-(環己基甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷。
向三級丁基 2-(4-(環己基甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(600 mg,0.99 mmol)在MeOH(20 mL)中之溶液中添加HCl/MeOH(10 mL,4M)溶液。將混合物在25°C下攪拌1 hr。在除去溶劑後,將殘餘物溶解於水(20 mL)中。將混合物使用水性Na2
CO3
調節pH至9-10。將混合物用EtOAc(20 mL × 3)萃取。將合併的有機相用鹽水(20 mL × 2)洗滌,用無水Na2
SO4
乾燥,過濾並真空濃縮以給出呈黃色固體的2-(4-(環己基甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷(450 mg,產率:83%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.49 (br s, 1H), 7.25-7.19 (m, 2H), 7.15-7.10 (m, 1H), 3.62 (m, 1H), 3.46-3.34 (m, 1H), 3.02 (m, 1H), 3.00 (m, 1H), 2.94-2.86 (m, 2H), 2.66-2.57 (m, 5H), 2.31-2.21 (m, 2H), 2.15-2.09 (m, 2H), 1.81-1.73 (m, 3H), 1.71-1.63 (m, 5H), 1.45 (m, 2H), 1.35-1.29 (m, 5H), 1.28-1.25 (d,J
= 6.8 Hz, 3H), 1.21 (d,J
= 6.8 Hz, 3H), 1.16 (m, 3H), 0.91-0.83 (m, 2H)。MS (ESI, m/e) [M+1]+
424.5。
步驟1:三級丁基 2-(2-(2-異丙基苯基)-6-側氧基-4-((四氫-2H-哌喃-4-基)甲基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
在25°C下,向三級丁基 2-(2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.0 g,2.06 mmol)在DCE(10 mL)中之溶液中添加AcOH(339 mg,5.66 mmol)、四氫-2H-哌喃-4-甲醛(387 mg,3.40 mmol)和NaBH(OAc)3
(959 mg,4.53 mmol)。將混合物在25°C下攪拌12小時。將反應混合物傾倒入飽和Na2
CO3
(10 mL)中,用EtOAc(10 mL × 3)萃取。將合併的有機層用鹽水洗滌,用無水Na2
SO4
乾燥,過濾並在減壓下濃縮。將粗產物藉由柱層析法(矽膠,洗脫液:PE/EA(v/v)= 50/1至0/1)純化以給出呈淺黃色油狀物的三級丁基 2-(2-(2-異丙基苯基)-6-側氧基-4-((四氫-2H-哌喃-4-基)甲基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.0 g,產率:82%)。
步驟2:三級丁基 2-(2-(2-異丙基苯基)-4-((四氫-2H-哌喃-4-基)甲基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
在80°C下,向三級丁基 2-(2-(2-異丙基苯基)-6-側氧基-4-((四氫-2H-哌喃-4-基)甲基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(700 mg,1.30 mmol)的混合物中添加在THF(20 mL)中的BH3
.THF(38 mL,38.91 mmol)持續12小時。將反應藉由MeOH(20 mL)淬滅並在減壓下濃縮以給出呈黃色膠狀物的三級丁基 2-(2-(2-異丙基苯基)-4-((四氫-2H-哌喃-4-基)甲基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(660 mg,粗製),其無需進一步純化即可直接用於下一步。
步驟3:2-(2-(2-異丙基苯基)-4-((四氫-2H-哌喃-4-基)甲基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷。
在0°C下,向三級丁基 2-(2-(2-異丙基苯基)-4-((四氫-2H-哌喃-4-基)甲基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(700 mg,1.30 mmol)的混合物中添加HCl/MeOH(40 mL)溶液持續2小時。將反應混合物傾倒入飽和Na2
CO3
(40 mL)中。將混合物用EtOAc(40 mL × 3)萃取。將合併的有機相用鹽水洗滌,用無水Na2
SO4
乾燥,過濾並在減壓下濃縮以給出呈淺粉色油狀物的2-(2-(2-異丙基苯基)-4-((四氫-2H-哌喃-4-基)甲基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷(541 mg,產率:75%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.59-7.44 (m, 1H), 7.26-7.19 (m, 2H), 7.17-7.10 (m, 1H), 4.04-3.91 (m, 2H), 3.60 (m, 1H), 3.45-3.30 (m, 3H), 3.04-2.97 (m, 1H), 2.96-2.84 (m, 2H), 2.67-2.57 (m, 4H), 2.31-2.24 (m, 2H), 2.23-2.16 (m, 2H), 2.14-2.07 (m, 1H), 1.85-1.67 (m, 5H) 1.41-1.28 (m, 4H), 1.21 (d,J
= 6.8 Hz, 3H)。MS (ESI, m/e) [M+1]+
426.4。
步驟1:三級丁基 2-(2-(2-異丙基苯基)-4-(3-(甲氧基羰基)二環[1.1.1]戊烷-1-羰基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
在0°C下,向三級丁基 2-(2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(2.5 g,5.66 mmol)和3-(甲氧基羰基)二環[1.1.1]戊烷-1-甲酸(1.16 g,6.76 mmol)與HOBt(1.15 g,8.49 mmol)及TEA(1.14 g,11.32 mmol)在THF(30 mL)中之混合物中添加EDCI(1.63 g,8.49 mmol)。將混合物在20°C下攪拌12小時。將混合物用H2
O(20 mL)淬滅,用DCM(100 mL)萃取。將合併的有機層用鹽水(10 mL)洗滌,經無水Na2
SO4
乾燥,過濾並在減壓下濃縮。將粗產物藉由柱層析法(矽膠,洗脫液:PE/EA(v/v)= 1/8)純化以給出呈白色固體的三級丁基 2-(2-(2-異丙基苯基)-4-(3-(甲氧基羰基)二環[1.1.1]戊烷-1-羰基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(2.8 g,產率:85%)。MS (ESI, m/e) [M-55]+
538.3。
步驟2:3-(4-(7-(三級丁氧基羰基)-7-氮雜螺[3.5]壬烷-2-基)-3-(2-異丙基苯基)-5-側氧基哌𠯤-1-羰基)二環[1.1.1]戊烷-1-甲酸。
將三級丁基 2-(2-(2-異丙基苯基)-4-(3-(甲氧基羰基)二環[1.1.1] 戊烷-1-羰基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(2.8 g,4.71 mmol)和LiOH.H2
O(0.79 g,18.86 mmol)在MeOH(50 mL)和H2
O(10 mL)中之混合物在20°C下攪拌5小時。將混合物在減壓下濃縮。將殘餘物用H2
O(30 mL)稀釋,藉由檸檬酸酸化至pH = 4-5並過濾。將濾液用EtOAc(100 mL x 2)萃取。將有機相用鹽水(10 mL)洗滌,經Na2
SO4
乾燥,過濾並在減壓下濃縮以得到呈白色固體的3-(4-(7-(三級丁氧基羰基)-7-氮雜螺[3.5]壬烷-2-基)-3-(2-異丙基苯基)-5-側氧基哌𠯤-1-羰基)二環[1.1.1]戊烷-1-甲酸(0.6 g,粗製)。MS (ESI, m/e) [M+Na]+
602.3。
步驟3:三級丁基 2-(2-(2-異丙基苯基)-6-側氧基-4-(3-(((2-硫代吡啶-1(2H)-基)氧基)羰基)二環[1.1.1]戊烷-1-羰基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯
將3-(4-(7-(三級丁氧基羰基)-7-氮雜螺[3.5]壬烷-2-基)-3-(2-異丙基苯基)-5-側氧基哌𠯤-1-羰基)二環[1.1.1]戊烷-1-甲酸(0.5 g,0.86 mmol)和1-羥基吡啶-2(1H)-硫酮(142 mg,1.12 mmol)、DCC(231 mg,1.12 mmol)在DCM(13 mL)中之混合物在0°C下攪拌2小時。將混合物過濾並在減壓下濃縮以得到呈黃色固體的三級丁基 2-(2-(2-異丙基苯基)-6-側氧基-4-(3-(((2-硫代吡啶-1(2H)-基)氧基)羰基)二環[1.1.1]戊烷-1-羰基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(0.5 g,粗製),其無需進一步純化即可直接使用。MS (ESI, m/e) [M+1]+
689.1。
步驟4:三級丁基 2-(4-(二環[1.1.1]戊烷-1-羰基)-2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
在W燈下(300 W),將三級丁基 2-(2-(2-異丙基苯基)-6-側氧基-4-(3-(((2-硫代吡啶-1(2H)-基)氧基)羰基)二環[1.1.1]戊烷-1-羰基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(2.0 g,2.63 mmol)和Bu3
SnH(2.3 g,7.9 mmol)、AIBN(36 mg,0.22 mmol)在甲苯(35 mL)中之混合物在60°C下攪拌1 hr。將混合物用KF溶液(50 mL)淬滅,用EtOAc(100 mL x 3)萃取。將合併的有機相用鹽水(10 mL)洗滌,經Na2
SO4
乾燥,過濾並在減壓下濃縮。將殘餘物藉由製備型HPLC(0.1% TFA,然後中和)純化以得到呈灰白色固體的三級丁基 2-(4-(二環[1.1.1]戊烷-1-羰基)-2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(0.95 g)。MS (ESI, m/e) [M+Na]+
558.4。
步驟5:三級丁基 2-(4-(二環[1.1.1]戊烷-1-基甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
將三級丁基 2-(4-(二環[1.1.1]戊烷-1-羰基)-2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(0.95 g,1.77 mmol)和BH3
.THF(1M,10 mL)在THF(5 mL)中之混合物在70°C下攪拌12.4小時。將反應混合物冷卻至25°C並用MeOH(20 mL)緩慢淬滅。將混合物在減壓下濃縮以給出呈白色固體的三級丁基 2-(4-(二環[1.1.1]戊烷-1-基甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.0 g,粗製),其無需進一步純化即可直接使用。MS (ESI, m/e) [M+1]+
508.5。
步驟6:2-(4-(二環[1.1.1]戊烷-1-基甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷。
將三級丁基 2-(4-(二環[1.1.1]戊烷-1-基甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.0 g,1.97 mmol)在HCl/MeOH(8 mL,4 M)中之混合物在20°C下攪拌3小時。將混合物在減壓下濃縮並藉由製備型HPLC(0.1% TFA)純化,然後藉由Na2
CO3
溶液調節pH = 9。將溶液用EtOAc(20 mL × 2)萃取。將合併的有機物用鹽水(5 mL)洗滌,經Na2
SO4
乾燥,過濾並在減壓下濃縮以給出呈淡黃色固體的2-(4-(二環[1.1.1]戊烷-1-基甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷(327 mg,產率:40%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.57-7.40 (m, 1H), 7.26-7.19 (m, 2H), 7.16-7.10 (m, 1H), 3.70-3.59 (m, 1H), 3.51-3.31 (m, 1H), 3.03-2.86 (m, 4H), 2.77-2.65 (m, 5H), 2.46-2.43 (m, 1H), 2.40-2.37 (m, 2H), 2.34-2.28 (m, 2H), 2.21-2.05 (m, 2H), 1.75 (m, 8H), 1.48-1.30 (m, 5H), 1.28-1.24 (m, 3H), 1.23-1.20 (m, 3H)。MS (ESI, m/e) [M+1]+
408.4。
步驟1:三級丁基 2-(4-(呋喃-3-基甲基)-2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
將三級丁基 2-(2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5] 壬烷-7-甲酸酯(1.0 g,2.26 mmol)、呋喃-3-甲醛(326.37 mg,3.40 mmol)和HOAc(271.97 mg,4.53 mmol)在DCE(20 mL)中之混合物在25°C下攪拌30 min。然後將NaBH(OAc)3
(1.44 g,6.79 mmol)分批添加至以上混合物中並在25°C下攪拌10小時。將反應混合物傾倒入冰-水(20 mL)中,用NaHCO3
調節pH = 8。將所得混合物用DCM(50 mL × 3)萃取。將合併的有機相用無水Na2
SO4
乾燥,過濾並在減壓下濃縮。將粗品藉由柱層析法(矽膠,洗脫液:PE/EA(v/v)= 2/1至1/1)純化以給出呈淡黃色固體的三級丁基 2-(4-(呋喃-3-基甲基)-2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.05 g,89%產率)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.29 (m, 2H), 7.23-7.14 (m, 2H), 7.12-7.07 (m, 1H), 6.91 (s, 1H), 5.86 (s, 1H), 4.97 (s, 1H), 4.38 (s, 1H), 3.53-3.38 (m, 2H), 3.32-2.98 (m, 7H), 2.75-2.64 (m, 2H), 2.28-2.18 (m, 1H), 1.94 (m, 1H), 1.83-1.74 (m, 1H), 1.72-1.62 (m, 2H), 1.50-1.46 (m, 1H), 1.42 (s, 9H), 1.36-1.30 (m, 2H), 1.25 (d,J
= 6.8 Hz, 3H), 1.10 (d,J
= 6.8 Hz, 3H)。
步驟2:三級丁基 2-(4-(呋喃-3-基甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
在25°C下,向三級丁基 2-(4-(呋喃-3-基甲基)-2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.05 g,2.01 mmol)在THF(15 mL)的溶液中滴加BH3
.THF(30 mL,30 mmol)。將混合物加熱至70°C持續15小時。將反應藉由乙醇(10 mL)淬滅,在減壓下濃縮以給出呈白色固體的三級丁基 2-(4-(呋喃-3-基甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.02 g,粗製)。MS (ESI, m/e) [M+1]+
508.4。
步驟3:2-(4-(呋喃-3-基甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷。
在25°C下,向三級丁基 2-(4-(呋喃-3-基甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(200 mg,393.93 umol)在DCM(3 mL)中之溶液中滴加TFA(3 mL)。將溶液在25°C下攪拌12小時。將反應溶液真空濃縮。將粗品藉由製備型HPLC純化並凍乾。殘餘物不含飽和Na2
CO3
(20 mL),將其用EtOAc(30 mL × 5)萃取。將合併的有機相用無水Na2
SO4
乾燥,過濾並真空濃縮以給出呈白色膠狀物的2-(4-(呋喃-3-基甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷(265 mg,0.52 mmol,產率:27%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.46 (s, 1H), 7.36 (m, 1H), 7.31 (s, 1H), 7.26-7.20 (m, 2H), 7.15-7.09 (m, 1H), 6.38 (m, 1H), 3.64 (m, 1H), 3.40 (s, 3H), 3.03-2.85 (m, 4H), 2.83-2.70 (m, 4H), 2.67 (s, 1H), 2.33-2.24 (m, 2H), 2.15 (m, 1H), 1.83-1.68 (m, 2H), 1.60-1.51 (m, 2H), 1.37-1.31 (m, 1H), 1.30-1.20 (m, 5H), 1.17 (d,J
= 6.8 Hz, 3H)。MS (ESI, m/e) [M+1]+
408.3。
步驟1:三級丁基 2-(2-(2-異丙基苯基)-4-(㗁唑-4-基甲基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
在25°C下,向三級丁基 2-(2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.0 g,2.26 mmol)在DCE(15 mL)中之溶液中添加㗁唑-4-甲醛(329.7 mg,3.40 mmol)和AcOH(272 mg,4.53 mmol)持續30 min。然後在25°C下添加NaBH(OAc)3
(1.2 g,5.66 mmol)。將混合物在25°C下攪拌12小時。將反應混合物傾倒入飽和NH4
Cl(50 mL)中,用DCM(50 mL × 2)萃取。將合併的有機相用鹽水(20 mL × 2)洗滌,用無水Na2
SO4
乾燥,過濾並真空濃縮。將殘餘物藉由柱層析法(矽膠,洗脫液:PE/EA(v/v)= 10/1至EA/MeOH(v/v)= 10/1)純化以給出呈黃色油狀物的三級丁基 2-(2-(2-異丙基苯基)-4-(㗁唑-4-基甲基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(360 mg,707.69 umol,產率:30.26%)。MS (ESI, m/e) [M+1]+
509.3。
步驟2:4-((3-(2-異丙基苯基)-4-(7-氮雜螺[3.5]壬烷-2-基)哌𠯤-1-基)甲基)㗁唑。
在25°C下,向三級丁基 2-(2-(2-異丙基苯基)-4-(㗁唑-4-基甲基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(300 mg,1.32 mmol)在DCM(2 mL)中之溶液中添加TFA(0.5 mL)。將混合物在25°C下攪拌2小時。將反應混合物傾倒入飽和Na2
CO3
(20 mL)中,用EtOAc(50 mL × 3)萃取。將合併的有機相用鹽水(20 mL × 2)洗滌,用無水Na2
SO4
乾燥,過濾並真空濃縮以給出呈黃色油狀物的4-((3-(2-異丙基苯基)-4-(7-氮雜螺[3.5]壬烷-2-基)哌𠯤-1-基)甲基)㗁唑(390 mg,374.47 umol,產率:63%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.83 (s, 1H), 7.55 (s, 1H), 7.53-7.45 (m, 1H), 7.26-7.09 (m, 3H), 3.72-3.64 (m, 1H), 3.59-3.46 (m, 2H), 3.42-3.34 (m, 1H), 3.07-2.95 (m, 2H), 2.95-2.86 (m, 1H), 2.73 (m, 1H), 2.69-2.55 (m, 4H), 2.43-2.29 (m, 2H), 2.25 (m, 1H), 1.71 (m, 4H), 1.37-1.29 (m, 4H), 1.25 (d,J
= 6.8 Hz, 3H), 1.17 (d,J
= 6.8 Hz, 3H)。MS (ESI, m/e) [M+1]+
409.3。
步驟
1:三級丁基 2-(2-(2-異丙基苯基)-4-((1-甲基-1H-吡唑-4-基)甲基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
向三級丁基 2-(2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.2 g,2.72 mmol)在DCE(10 mL)中之溶液中添加AcOH(326.36 mg,5.43 mmol)和1-甲基-1H-吡唑-4-甲醛(329.14 mg,2.99 mmol)。將混合物在25°C下攪拌1 hr。然後添加NaBH(OAc)3
(1.73 g,8.15 mmol)並將其在25°C下再攪拌12小時。將反應混合物傾倒入飽和NaHCO3
(50 mL)中,用EtOAc(100 mL × 2)萃取。將合併的有機層用鹽水洗滌,用無水Na2
SO4
乾燥,過濾並在減壓下濃縮。將粗產物藉由柱層析法(矽膠,洗脫液:PE/EA(v/v)= 5/1至2/1)純化以給出呈黃色油狀物的三級丁基 2-(2-(2-異丙基苯基)-4-((1-甲基-1H-吡唑-4-基)甲基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(0.9 g,產率:62%)。
步驟2:三級丁基 2-(2-(2-異丙基苯基)-4-((1-甲基-1H-吡唑-4-基)甲基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
將2-(2-(2-異丙基苯基)-4-((1-甲基-1H-吡唑-4-基)甲基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(0.9 g,1.68 mmol)和BH3
.THF(16.80 mL,16.8 mmol)在THF(20 mL)中之混合物在70°C下攪拌12小時。將反應溶液藉由MeOH(20 mL)淬滅並在0°C下攪拌1 hr。將混合物在減壓下濃縮以給出呈白色油狀物的三級丁基 2-(2-(2-異丙基苯基)-4-((1-甲基-1H-吡唑-4-基)甲基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯,其無需進一步純化即可直接用於下一步。MS (ESI, m/e) [M+1]+
522.4。
步驟3:2-(2-(2-異丙基苯基)-4-((1-甲基-1H-吡唑-4-基)甲基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷。
將三級丁基 2-(2-(2-異丙基苯基)-4-((1-甲基-1H-吡唑-4-基)甲基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(900 mg,1.73 mmol)和HCl(4.31 mL,17.25 mmol)在MeOH(10 mL)中之混合物在25°C下攪拌2小時。將反應溶液在減壓下濃縮。將反應混合物傾倒入飽和NaHCO3
(10 mL)中,用EtOAc(20 mL × 2)萃取。將合併的有機層用鹽水洗滌,用無水Na2
SO4
乾燥,過濾並在減壓下濃縮以給出呈黃色固體的2-(2-(2-異丙基苯基)-4-((1-甲基-1H-吡唑-4-基)甲基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷(518 mg,產率:71%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.47 (br s, 1H), 7.38 (s, 1H), 7.25-7.19 (m, 2H), 7.13 (t, 1H), 3.85 (s, 4H), 3.65 (m, 1H), 3.49 (s, 2H), 3.44-3.32 (m, 3H), 3.02 (m, 1H), 2.70-2.55 (m, 6H), 2.31-2.05 (m, 4H), 1.71-1.60 (m, 3H), 1.25 (m, 4H), 1.17 (m, 6H)。MS (ESI, m/e) [M+1]+
422.4。
將三級丁基 2-(2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(20 g,45.29 mmol)藉由SFC(儀器:Thar SFC350製備型SFC;柱:REGIS(s,s)WHELK-O1,250 × 50 mm i.d.:10 um;流動相:A為CO2並且B為MeOH(0.1% NH3.H2O);梯度:B% = 45%;流速:200 g/min;波長:220 nm;柱溫:40°C;系統背壓:100巴)分離。獲得(R或S)-三級丁基 2-(2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(滯留時間:2.55 min,8.4 g),產率:43%。獲得(S或R)-三級丁基 2-(2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(滯留時間:2.73 min,8.3 g),產率:42%。
步驟1:三級丁基 (R或S)-2-(2-(2-異丙基苯基)-4-((1-甲基-1H-吡唑-4-基)甲基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
向三級丁基 (R或S)-2-(2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.0 g,2.26 mmol)和1-甲基-1H-吡唑-4-甲醛(274.28 mg,2.49 mmol)在DCE(10 mL)中之溶液中添加AcOH(271.97 mg,4.53 mmol)和NaBH(OAc)3
(1.44 g,6.79 mmol)。將混合物在25°C下攪拌12小時。將反應混合物用水性Na2
CO3
(10 mL)和DCM(10 mL × 3)萃取,經Na2
SO4
乾燥,過濾並在減壓下濃縮。將殘餘物藉由MPLC純化。獲得呈黃色油狀物的化合物三級丁基 (R或S)-2-(2-(2-異丙基苯基)-4-((1-甲基-1H-吡唑-4-基)甲基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(950 mg,1.77 mmol,產率:78%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.35-7.30 (m, 2H), 7.22-7.17 (m, 1H), 7.10 (m, 1H), 7.07 (s, 1H), 6.37 (s, 1H), 4.96 (s, 1H), 4.43 (s, 1H), 3.66 (s, 3H), 3.53-3.45 (m, 2H), 3.29-3.12 (m, 6H), 3.02 (m, 1H), 2.66 (s, 2H), 2.29-2.19 (m, 1H), 1.92 (m, 1H), 1.82-1.67 (m, 2H), 1.53-1.45 (m, 2H), 1.41 (s, 9H), 1.36-1.31 (m, 2H), 1.24 (m, 3H), 1.03 (m, 3H)。
步驟2:三級丁基 (R或S)-2-(2-(2-異丙基苯基)-4-((1-甲基-1H-吡唑-4-基)甲基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
將三級丁基 (R或S)-2-(2-(2-異丙基苯基)-4-((1-甲基-1H-吡唑-4-基)甲基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(950 mg,1.77 mmol)在BH3
.THF(15 mL)中之混合物在70°C下攪拌12小時。將反應混合物在0°C下藉由MeOH(20 mL)淬滅,並在25°C下攪拌30 min。然後將混合物在減壓下濃縮以得到呈白色固體的三級丁基 (R或S)-2-(2-(2-異丙基苯基)-4-((1-甲基-1H-吡唑-4-基)甲基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(900 mg,1.73 mmol,粗製)。MS (ESI, m/e) [M+1]+
522.3。
步驟3:(R或S)-2-(2-(2-異丙基苯基)-4-((1-甲基-1H-吡唑-4-基)甲基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷。
將三級丁基 (R或S)-2-(2-(2-異丙基苯基)-4-((1-甲基-1H-吡唑-4-基)甲基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(900 mg,1.73 mmol)在HCl/MeOH(10 mL)溶液中之混合物在25°C下攪拌2小時。將反應將混合物在減壓下濃縮以除去溶劑。將殘餘物用H2
O(10 mL)稀釋並添加Na2
CO3
至pH = 9,將混合物用EtOAc(10 mL × 3)萃取,經Na2
SO4
乾燥,過濾並在減壓下濃縮以除去溶劑。獲得呈白色固體的化合物(R或S)-2-(2-(2-異丙基苯基)-4-((1-甲基-1H-吡唑-4-基)甲基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷(492 mg,1.07 mmol,產率:62.24%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.47 (m, 1H), 7.38 (s, 1H), 7.27-7.20 (m, 3H), 7.15-7.09 (m, 1H), 3.84 (s, 3H), 3.69-3.60 (m, 1H), 3.48-3.35 (m, 3H), 2.99 (m, 1H), 2.96-2.86 (m, 2H), 2.68 (m, 5H), 2.26 (m, 2H), 2.22-2.06 (m, 2H), 1.83-1.73 (m, 1H), 1.67 (m, 1H), 1.50 - 1.32 (m, 5H), 1.24 (m, 3H), 1.17 (m, 3H)。MS (ESI, m/e) [M+1]+
422.3。
在中間體 22-1a
的類似程序後:用(S或R)-三級丁基 2-(2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯作為起始材料,獲得(S或R)-2-(2-(2-異丙基苯基)-4-((1-甲基-1H-吡唑-4-基)甲基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷(607 mg,中間體22-1b),產率:82%。MS (ESI, m/e) [M+1]+
422.4。
步驟1:三級丁基 2-(4-苄基-2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
將三級丁基 2-(2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.0 g,2.26 mmol)、苯甲醛(360.46 mg,3.40 mmol)和AcOH(271.97 mg,4.53 mmol)在DCE(20 mL)中之混合物在25°C下攪拌30 min。然後將NaBH(OAc)3
(1.44 g,6.79 mmol)分批添加至混合物並在20°C下攪拌3小時。將混合物用飽和NaHCO3
(20 mL × 2)洗滌,用無水Na2
SO4
乾燥,過濾並濃縮。將粗品藉由柱層析法(矽膠,洗脫液:PE/EA(v/v)= 5/1至1/1)純化以給出呈白色固體的三級丁基 2-(4-苄基-2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.0 g,1.88 mmol,產率:83%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.33-7.29 (m, 1H), 7.26-7.17 (m, 2H), 7.16-7.04 (m, 4H), 6.85 (d,J
= 6.8 Hz, 2H), 4.95 (s, 1H), 4.43 (s, 1H), 3.61 (m, 1H), 3.52 (m, 1H), 3.35-3.12 (m, 7H), 2.96 (m, 1H), 2.73-2.56 (m, 2H), 2.23 (m, 1H), 1.94 (m, 1H), 1.67-1.82 (m, 2H), 1.48 (m, 2H), 1.42 (s, 9H), 1.33 (s, 1H), 1.21 (d,J
= 6.8 Hz, 3H), 0.92 (d,J
= 6.8 Hz, 3H)。
步驟2:三級丁基 2-(4-苄基-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
在25°C下,向三級丁基 2-(4-苄基-2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.0 g,1.88 mmol)在THF(10 mL)中之溶液中滴加BH3
.THF(30 mL,30 mmol)。將混合物加熱至75°C持續12小時。將反應藉由乙醇(10 mL)淬滅,在減壓下濃縮以給出呈白色固體的三級丁基 2-(4-苄基-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(970 mg,粗製)。MS (ESI, m/e) [M+1]+
518.5。
步驟3:2-(4-苄基-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷。
在25°C下,向三級丁基 2-(4-苄基-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(970 mg,1.82 mmol)在MeOH(10 mL)中之溶液中滴加HCl/MeOH(10 mL,4M)。將溶液在20°C下攪拌4小時。將反應溶液真空濃縮。將殘餘物用HCl(5 mL,1 M)稀釋,用EtOAc(10 mL × 2)萃取。將水相用NaHCO3
調節pH = 8,用EtOAc(20 mL × 5)萃取。將合併的有機相用無水Na2
SO4
乾燥,過濾並濃縮以給出呈白色固體的2-(4-苄基-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷(529 mg,1.27 mmol,產率:68%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.47 (d,J
= 4.4 Hz, 1H), 7.28 (m, 4H), 7.24-7.15 (m, 3H), 7.14-7.06 (m, 1H), 3.83-3.56 (m, 2H), 3.51 (s, 2H), 3.37 (d,J
= 6.8 Hz, 1H), 3.01-2.86 (m, 3H), 2.80-2.59 (m, 5H), 2.38-2.25 (m, 2H), 2.22-2.13 (m, 1H), 1.84-1.54 (m, 3H), 1.53-1.39 (m, 4H), 1.35-1.28 (m, 1H), 1.25-1.22 (d,J
= 6.8 Hz, 3H), 1.12 (d,J
= 6.8 Hz, 3H)。MS (ESI, m/e) [M+1]+
418.4。
步驟1:三級丁基 2-(2-(2-異丙基苯基)-6-側氧基-4-(1-苯基乙基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
向三級丁基 2-(2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.0 g,2.26 mmol)在DMF(10 mL)中之溶液中添加(1-溴乙基)苯(0.84 g,4.53 mmol)和Cs2
CO3
(2.21 g,6.79 mmol)。將混合物在80°C下攪拌2小時。向混合物中添加飽和NH4
Cl(50 mL),將其用EtOAc(30 mL × 3)萃取。將合併的有機相經無水Na2
SO4
乾燥,過濾並真空濃縮。將殘餘物藉由柱層析法(矽膠,洗脫液:PE/EA(v/v)= 5/1)純化以給出呈無色油狀物的三級丁基 2-(2-(2-異丙基苯基)-6-側氧基-4-(1-苯基乙基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.2 g,產率:73%)。
步驟2:三級丁基 2-(2-(2-異丙基苯基)-4-(1-苯基乙基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
將三級丁基 2-(2-(2-異丙基苯基)-6-側氧基-4-(1-苯基乙基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.1 g,2.02 mmol)和BH3
.THF(10 mL)在THF(10 mL)中之混合物在70°C下攪拌16小時。在冷卻至0°C後,向混合物中滴加MeOH(20 mL)並將其在減壓下濃縮以給出呈無色油狀物的三級丁基 2-(2-(2-異丙基苯基)-4-(1-苯基乙基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.1 g,粗製),其無需純化即可直接用於下一步。MS (ESI, m/e) [M+1]+
532.4。
步驟3:2-(2-(2-異丙基苯基)-4-(1-苯基乙基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷。
將三級丁基 2-(2-(2-異丙基苯基)-4-(1-苯基乙基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.0 g,1.88 mmol)在HCl/EtOAc(10 mL,4 M)中之混合物在20°C下攪拌16小時。在除去溶劑後,將殘餘物藉由製備型HPLC(TFA)純化。將混合物真空濃縮,向其中添加H2
O(50 mL)並將其使用水性NaOH(2 M)調節pH = 11。將混合物用EtOAc(10 mL × 3)萃取。將合併的有機相用無水Na2
SO4
乾燥,過濾並在減壓下濃縮以給出呈白色膠狀物的2-(2-(2-異丙基苯基)-4-(1-苯基乙基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷(537 mg,產率:66%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.57-7.35 (m, 2H), 7.31 (m, 2H), 7.27-7.22 (m, 3H), 7.18-7.05 (m, 2H), 3.69-3.53 (m, 1H), 3.40 - 3.34 (m, 1H), 3.16-3.05 (m, 1H), 3.02-2.82 (m, 3H), 2.75-2.52 (m, 5H), 2.46-2.25 (m, 3H), 2.24-2.09 (m, 2H), 1.71-1.64 (m, 1H), 1.37 (m, 3H), 1.33 (m, 3H), 1.31-1.26 (m, 2H), 1.22 (m, 3H), 1.01 (m, 1H)。MS (ESI, m/e) [M+1]+
432.4。
步驟1:1,2,3,4-四氫萘-1-醇。
在0°C下,向3,4-二氫萘-1(2H)-酮(8.0 g,54.72 mmol)在THF(100 mL)中之溶液中添加NaBH4
(8.24 g,219 mmol)。將混合物在20°C下攪拌4小時。將混合物傾倒入H2
O(80 mL)中,用EtOAc(50 mL × 2)萃取。將合併的有機相經無水Na2
SO4
乾燥,過濾並真空濃縮以給出呈黃色油狀物的1,2,3,4-四氫萘-1-醇(6.0 g,產率:74%),其無需進一步純化即可直接用於下一步。
步驟2:1-溴-1,2,3,4-四氫萘。
將1,2,3,4-四氫萘-1-醇(4.0 g,26.99 mmol)和TMSBr(4.96 g,32.39 mmol)的混合物在20°C下攪拌16小時。將混合物傾倒入H2
O(50 mL)中,用EtOAc(20 mL × 3)萃取。將合併的有機相經無水Na2
SO4
乾燥,過濾並真空濃縮。將殘餘物藉由柱層析法(矽膠,洗脫液:PE/EA(v/v)= 5/1)純化以給出呈黃色油狀物的1-溴-1,2,3,4-四氫萘(5.0 g,產率:87%)。
步驟3:三級丁基 2-(2-(2-異丙基苯基)-6-側氧基-4-(1,2,3,4-四氫萘-1-基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
將三級丁基 2-(2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.0 g,2.26 mmol)、1-溴-1,2,3,4-四氫萘(956 mg,14.53 mmol)和Cs2
CO3
(2.21 g,6.79 mmol)在DMF(10 mL)中之混合物在80°C下攪拌16小時。將混合物傾倒入飽和NH4
Cl(50 mL)中,用EtOAc(30 mL × 2)萃取。將合併的有機相經無水Na2
SO4
乾燥,過濾並真空濃縮。將殘餘物藉由柱層析法(矽膠,洗脫液:PE/EA(v/v)= 6/1)純化以給出呈黃色油狀物的三級丁基 2-(2-(2-異丙基苯基)-6-側氧基-4-(1,2,3,4-四氫萘-1-基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(0.9 g,產率:69%)。MS (ESI, m/e) [M+1]+
572.4。
步驟4:三級丁基 2-(2-(2-異丙基苯基)-4-(1,2,3,4-四氫萘-1-基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
將三級丁基 2-(2-(2-異丙基苯基)-6-側氧基-4-(1,2,3,4-四氫萘-1-基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(0.8 g,1.4 mmol)和BH3
.THF(5 mL,5 mmol)在THF(5 mL)中之混合物在70°C下攪拌16小時。在冷卻至0°C後,向混合物中滴加MeOH(10 mL)並將其在減壓下濃縮以給出呈無色油狀物的三級丁基 2-(2-(2-異丙基苯基)-4-(1,2,3,4-四氫萘-1-基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(0.8 g,粗製),其無需純化即可直接用於下一步。
步驟5:2-(2-(2-異丙基苯基)-4-(1,2,3,4-四氫萘-1-基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷。
將三級丁基 2-(2-(2-異丙基苯基)-4-(1,2,3,4-四氫萘-1-基) 哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(700 mg,1.25 mmol)在HCl/EtOAc(10 mL,4 M)中之混合物在20°C下攪拌3小時。在除去溶劑後,將殘餘物藉由製備型HPLC(TFA)純化。將混合物真空濃縮並使用水性NaOH(1 M)調節pH = 9-10。將混合物用EtOAc(10 mL × 3)萃取。將合併的有機相用無水Na2
SO4
乾燥,過濾並真空濃縮以給出呈白色固體的2-(2-(2-異丙基苯基)-4-(1,2,3,4-四氫萘-1-基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷(365 mg,產率:64%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.76 (m, 1H), 7.57-7.42 (m, 1H), 7.24-7.12 (m, 4H), 7.09-6.98 (m, 2H), 3.89-3.39 (m, 4H), 3.16-2.85 (m, 4H), 2.73-2.60 (m, 6H), 2.55-2.33 (m, 2H), 2.24-2.15 (m, 1H), 1.95 (m, 2H), 1.73-1.62 (m, 4H), 1.37-1.22 (m, 11H), 1.02 (m, 1H)。MS (ESI, m/e) [M+1]+
458.3。
步驟1:三級丁基 2-(2-(2-異丙基苯基)-6-側氧基-4-苯乙基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
向三級丁基 2-(2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(700 mg,1.59 mmol)在DCE(10 mL)中之溶液中添加2-苯基乙醛(285.7 mg,2.38 mmo)、HOAc(190.38 mg,3.17 mmol)和NaBH(OAc)3
(739.1 mg,3.49 mmol)。將溶液在25°C下攪拌12小時。將反應傾倒入飽和NaHCO3
中直到pH = 7,用DCM(10 mL x 3)萃取。將合併的有機層用鹽水洗滌,經Na2
SO4
乾燥,過濾並在減壓下濃縮。將殘餘物藉由柱層析法(矽膠,洗脫液:PE/EA(v/v)= 10/1至2/1)純化以給出呈黃色油狀物的三級丁基 2-(2-(2-異丙基苯基)-6-側氧基-4-苯乙基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(0.5 g,產率:58%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.34-7.28 (m, 2H), 7.25-7.03 (m, 6H), 6.85 (d,J
= 7.2 Hz, 2H), 4.95 (br s, 1H), 4.42 (br s, 1H), 3.68-3.46 (m, 2H), 3.37-3.09 (m, 7H), 2.97 (t, 1H), 2.73-2.56 (m, 2H), 2.32-2.18 (m, 1H), 2.02-1.85 (m, 1H), 1.83-1.67 (m, 2H), 1.42 (s, 9H), 1.22 (d,J
= 6.8 Hz, 3H), 0.93 (d,J
= 6.8 Hz, 3H)。
步驟2:三級丁基 2-(2-(2-異丙基苯基)-4-苯乙基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
將三級丁基 2-(2-(2-異丙基苯基)-6-側氧基-4-苯乙基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(0.6 g,1.1 mmol)在BH3
.THF(10 mL,1 M)中之溶液在70°C下攪拌12小時。將反應在0°C下藉由MeOH(5 mL)淬滅,並在25°C下攪拌30 min。將混合物在減壓下濃縮以給出呈黃色油狀物的三級丁基 2-(2-(2-異丙基苯基)-4-苯乙基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(600 mg,粗製)。MS (ESI, m/e) [M+1]+
532.5。
步驟3:2-(2-(2-異丙基苯基)-4-苯乙基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷。
將三級丁基 2-(2-(2-異丙基苯基)-4-苯乙基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(0.6 g,1.1 mmol)在TFA(1 mL)和DCM(10 mL)中之溶液在20°C下攪拌12小時。將反應混合物傾倒入水性Na2
CO3
(300 mL)中,用DCM(20 mL × 3)萃取。將合併的有機層用鹽水洗滌,經Na2
SO4
乾燥,過濾並在減壓下濃縮。將粗產物藉由製備型HPLC(HCl)純化以給出呈白色固體的2-(2-(2-異丙基苯基)-4-苯乙基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷(130 mg,HCl鹽,產率:27%(經由兩個步驟))。1
H NMR (400 MHz, CH3
OH-d 4
) δ ppm: 7.96 (d,J
= 7.6 Hz, 1H), 7.51-7.49 (m, 2H), 7.36-7.26 (m, 5H), 5.25 (s, 1H), 4.05 (m, 1H), 3.85-3.54 (m, 4H), 3.54-3.31 (m, 4H), 3.20-3.17 (m, 2H), 3.03-2.95 (m, 4H), 2.33 (m, 1H), 1.75-1.71 (m, 3H), 1.64-1.61 (m, 2H), 1.38 (d,J
= 6.8 Hz, 3H), 1.28 (d,J
= 6.8 Hz, 3H)。MS (ESI, m/e) [M+1]+
432.4。
步驟1:三級丁基 2-(4-(4-氟苄基)-2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
向三級丁基 2-(2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(700 mg,1.59 mmol)在DCE(10 mL)中之溶液中添加4-氟苯甲醛(671.9 mg,3.17 mmol)、HOAc(190.38 mg,3.17 mmol)和NaBH(OAc)3
(190.38 mg,3.17 mmol)。將溶液在25°C下攪拌12小時。向反應中添加飽和NaHCO3
直至pH = 7,將其用DCM(10 mL x 3)萃取。將合併的有機層用鹽水洗滌,經Na2
SO4
乾燥,過濾並在減壓下濃縮。將殘餘物藉由柱層析法(矽膠,洗脫液:PE/EA(v/v)= 10/1至2/1)純化以給出呈黃色油狀物的三級丁基 2-(4-(4-氟苄基)-2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(0.5 g,產率:57.3%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.23-7.03 (m, 3H), 6.70-6.67 (m, 4H), 4.85 (s, 3H), 4.37 (s, 1H), 3.51-3.43 (m, 2H), 3.20-3.04 (m, 6H), 2.57-2.54 (m, 1H), 2.20-2.10 (m, 2H), 1.82-1.91 (m, 1H), 1.66-1.58 (m, 2H), 1.45-1.38 (m, 2H), 1.20-1.17 (m, 2H), 1.34 (s, 9H), 1.14 (d,J
= 6.8 Hz, 3H), 0.85 (d,J
= 6.8 Hz, 3H)。
步驟2:三級丁基 2-(4-(4-氟苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
將三級丁基 2-(4-(4-氟苄基)-2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(0.5 g,0.91 mmol)在BH3
.THF(10 mL)中之溶液在60°C下攪拌12小時。將反應混合物在0°C下藉由MeOH(10 mL)淬滅,並在25°C下攪拌30 min。將混合物在減壓下濃縮以給出呈黃色油狀物的三級丁基 2-(4-(4-氟苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(600 mg,粗製),其無需進一步純化即可直接使用。MS (ESI, m/e) [M+1]+
536.4。
步驟3:2-(4-(4-氟苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷。
向三級丁基 2-(4-(4-氟苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(0.6 g,1.12 mmol)在DCM(10 mL)中之溶液中添加TFA(1 mL)。將溶液在25°C下攪拌12小時。將混合物在減壓下濃縮。將殘餘物傾倒入水性Na2
CO3
(30 mL)中,用DCM(20 mL × 3)萃取。將合併的有機層用鹽水洗滌,經Na2
SO4
乾燥,過濾並在減壓下濃縮以給出呈黃色固體的2-(4-(4-氟苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷(300 mg,產率:62%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.47 (s, 1H), 7.25-7.12 (m, 3H), 6.99-6.95 (m, 2H), 3.64-3.63 (m, 1H), 3.48 (s, 1H), 2.98-2.87 (m, 2H), 2.65-2.59 (m, 4H), 2.30-2.29 (m, 3H), 1.92 (m, 4H), 1.75 (m, 1H), 1.65 (t, 1H), 1.35-1.32 (m, 4H), 1.25 (d,J
= 6.8 Hz, 3H), 1.13 (d,J
= 6.8 Hz, 3H)。MS (ESI, m/e) [M+1]+
436.3。
步驟1:三級丁基 (R或S)-2-(4-(4-氟苄基)-2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
向三級丁基 (R或S)-2-(2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.0 g,2.26 mmol)在DCE(10 mL)中之溶液中添加4-氟苯甲醛(353.97 mg,2.49 mmol)、HOAc(271.97 mg,4.53 mmol)和NaBH(OAc)3
(1.44 g,6.79 mmol)。將混合物在25°C下攪拌12小時。向反應中添加飽和NaHCO3
直至pH = 9,將其用DCM(10 mL × 3)萃取。將合併的有機層用鹽水洗滌,經Na2
SO4
乾燥,過濾並在減壓下濃縮。將殘餘物藉由柱層析法(矽膠,洗脫液:PE/EA(v/v)= 10/1至2/1)純化以給出呈黃色油狀物的三級丁基 (R或S)-2-(4-(4-氟苄基)-2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(0.9 g,產率:72%)。
步驟2:三級丁基 (R或S)-2-(4-(4-氟苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
將三級丁基 (R或S)-2-(4-(4-氟苄基)-2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(0.9 g,1.64 mmol)在BH3
.THF(16.5 mL)中之溶液在70°C下攪拌12小時。將反應混合物在0°C下用MeOH(10 mL)淬滅,並在25°C下攪拌30 min。將混合物在減壓下濃縮以給出呈黃色油狀物的三級丁基 (R或S)-2-(4-(4-氟苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.0 g,粗製),其無需進一步純化即可直接使用。MS (ESI, m/e) [M+1]+
536.5。
步驟3:(R或S)-2-(4-(4-氟苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷。
向三級丁基 (R或S)-2-(4-(4-氟苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.0 g,1.87 mmol)在MeOH(10 mL)中之溶液中添加HCl(4.67 mL)。將混合物在25°C下攪拌2小時。將混合物在減壓下濃縮。將殘餘物傾倒入飽和Na2
CO3
(30 mL)中,用DCM(20 mL × 3)萃取。將合併的有機層用鹽水洗滌,經Na2
SO4
乾燥,過濾並在減壓下濃縮以給出呈黃色固體的(R或S)-2-(4-(4-氟苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷(435 mg,產率:58%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.48 (br s, 1H), 7.27-7.18 (m, 2H), 7.16-7.10 (m, 1H), 6.97 (t, 2H), 3.63 (m, 1H), 3.48 (s, 2H), 3.36 (br s, 1H), 3.05-2.97 (m, 1H), 2.94-2.84 (m, 2H), 2.66-2.56 (m, 3H), 2.35-2.25 (m, 2H), 2.20-2.13 (m, 2H), 1.86-1.57 (m, 4H), 1.28-1.47 (m, 5H), 1.24-1.27 (d,J
= 6.8 Hz, 3H), 1.13 (d,J
= 6.8 Hz, 3H)。MS (ESI, m/e) [M+1]+
436.3
步驟1:三級丁基 2-(4-(4-氯苄基)-2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
向三級丁基2-(2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.2 g,2.72 mmol)在DCE(10 mL)中之溶液中添加AcOH(326.36 mg,5.43 mmol)和4-氯苯甲醛(420.71 mg,2.99 mmol)。將混合物在25°C下攪拌1 hr。然後將NaBH(OAc)3
(1.73 g,8.15 mmol)添加至溶液中。將混合物在25°C下再攪拌12小時。將反應混合物傾倒入飽和NaHCO3
(50 mL)中,用EtOAc(100 mL × 2)萃取。將合併的有機層用鹽水洗滌,用無水Na2
SO4
乾燥,過濾並在減壓下濃縮。將粗產物藉由柱層析法(矽膠,洗脫液:PE/EA(v/v)= 5/1至2/1)純化以給出呈黃色油狀物的三級丁基 2-(4-(4-氯苄基)-2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.2 g,2.12 mmol,產率:78%)。
步驟2:三級丁基 2-(4-(4-氯苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
將三級丁基 2-(4-(4-氯苄基)-2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.2 g,2.12 mmol)和BH3
.THF(21.19 mL,21.19 mmol)在THF(10 mL)中之混合物在70°C下攪拌12小時。將反應溶液藉由MeOH(10 mL)淬滅並在減壓下濃縮以給出三級丁基 2-(4-(4-氯苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.2 g,粗製),其無需進一步反應即可直接用於下一步。
步驟3:2-(4-(4-氯苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷。
將三級丁基 2-(4-(4-氯苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.2 g,2.17 mmol)和HCl(5.43 mL,21.73 mmol)在MeOH(30 mL)中之混合物在25°C下攪拌2小時。將反應溶液在減壓下濃縮。將反應混合物傾倒入飽和NaHCO3
(50 mL)中,用EtOAc(100 mL × 2)萃取。將合併的有機層用鹽水洗滌,用無水Na2
SO4
乾燥,過濾並在減壓下濃縮以給出呈灰白色固體的2-(4-(4-氯苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷(445 mg,1.36 mmol,產率:45%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.49 (br s, 1H), 7.36-7.28 (m, 2H), 7.26-7.11 (m, 5H), 3.65 (br d,J
= 8.8 Hz, 1H), 3.50 (s, 3H), 3.05-2.97 (m, 2H), 2.96-2.86 (m, 3H), 2.68-2.58 (m, 7H), 2.36-2.14 (m, 4H), 1.71-1.64 (m, 3H), 1.28 (m, 4H), 1.16 (m, 6H)。MS (ESI, m/e) [M+1]+
452.3。
步驟1:三級丁基 (R或S)-2-(4-(4-氯苄基)-2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
向三級丁基 (R或S)-2-(2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.0 g,2.26 mmol)在DCE(15 mL)中之溶液中添加AcOH(271.97 mg,4.53 mmol)和4-氯苯甲醛(477.46 mg,3.40 mmol)。將混合物在20°C下攪拌30 min,然後添加NaBH(OAc)3
(959.86 mg,4.53 mmol)並將其在20°C下再攪拌12小時。將反應混合物傾倒入飽和NaHCO3
(50 mL)中,用EtOAc(100 mL × 2)萃取。將合併的有機層用鹽水洗滌,用無水Na2
SO4
乾燥,過濾並在減壓下濃縮。將粗產物藉由柱層析法(矽膠,洗脫液:PE/EA(v/v)= 5/1至2/1)純化以給出呈黃色油狀物的三級丁基 (R或S)-2-(4-(4-氯苄基)-2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.0 g,產率:78%)。
步驟2:三級丁基 (R或S)-2-(4-(4-氯苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
將三級丁基 (R或S)-2-(4-(4-氯苄基)-2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.0 g,1.77 mmol)和BH3
.THF(17.66 mL,17.66 mmol)在THF(15 mL)中之混合物在70°C下攪拌12小時。將反應溶液用MeOH(10 mL)淬滅並在減壓下濃縮以給出三級丁基 (R或S)-2-(4-(4-氯苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.0 g,粗製),其無需進一步反應即可直接用於下一步。
步驟3:(R或S)-2-(4-(4-氯苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷。
向三級丁基 (R或S)-2-(4-(4-氯苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.0 g,1.81 mmol)在MeOH(5 mL)中之混合物中添加HCl/MeOH溶液(5 mL,4 M)。將混合物在20°C下攪拌2小時。將反應溶液在減壓下濃縮。將反應混合物傾倒入飽和NaHCO3
(50 mL)中,用EtOAc(100 mL × 2)萃取。將合併的有機層用鹽水洗滌,用無水Na2
SO4
乾燥,過濾並在減壓下濃縮以給出呈黃色固體的(R或S)-2-(4-(4-氯苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷(322 mg,產率:39%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.50 (br s, 1H), 7.27 (s, 4H), 7.25-7.19 (m, 2H), 7.15 (d,J
= 6.8 Hz, 1H), 3.67 (br s, 2H), 3.45-3.29 (m, 1H), 3.04-2.87 (m, 3H), 2.69-2.56 (m, 5H), 2.36-2.27 (m, 2H), 2.24-2.16 (m, 1H), 1.78 (s, 1H), 1.73-1.63 (m, 2H), 1.33 (m, 3H), 1.28 (br d,J
= 6.8 Hz, 4H), 1.16 (br d,J
= 6.4 Hz, 4H)。MS (ESI, m/e) [M+1]+
452.4。
步驟1:三級丁基 2-(2-(2-異丙基苯基)-4-(4-甲基苄基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
向三級丁基2-(2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.2 g,2.72 mmol)在DCE(10 mL)中之溶液中添加AcOH(326.36 mg,5.43 mmol)和4-甲基苯甲醛(359.13 mg,2.72 mmol)。將混合物在25°C下攪拌1 hr。然後將NaBH(OAc)3
(1.73 g,8.15 mmol)添加至溶液中。將混合物在25°C下再攪拌12小時。將反應混合物傾倒入飽和NaHCO3
(50 mL)中,用EtOAc(100 mL × 2)萃取。將合併的有機層用鹽水洗滌,用無水Na2
SO4
乾燥,過濾並在減壓下濃縮。將粗產物藉由柱層析法(矽膠,洗脫液:PE/EA(v/v)= 5/1至2/1)純化以給出呈黃色油狀物的三級丁基 2-(2-(2-異丙基苯基)-4-(4-甲基苄基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.18 g,2.16 mmol,產率:79.6%)。
步驟2:三級丁基 2-(2-(2-異丙基苯基)-4-(4-甲基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
將三級丁基 2-(2-(2-異丙基苯基)-4-(4-甲基苄基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.18 g,2.16 mmol)和BH3
.THF(21.62 mL,21.62 mmol)在THF(10 mL)中之混合物在70°C下攪拌12小時。將反應溶液藉由MeOH(10 mL)淬滅,在減壓下濃縮以給出三級丁基 2-(2-(2-異丙基苯基)-4-(4-甲基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.18 g,粗製),其無需進一步純化即可直接用於下一步。
步驟3:2-(2-(2-異丙基苯基)-4-(4-甲基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷。
將三級丁基 2-(2-(2-異丙基苯基)-4-(4-甲基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.18 g,2.22 mmol)和HCl(5.55 mL,22.19 mmol)在MeOH(30 mL)中之混合物在25°C下攪拌2小時。將反應溶液在減壓下濃縮。將反應混合物傾倒入飽和NaHCO3
(50 mL)中,用EtOAc(100 mL × 2)萃取。將合併的有機層用鹽水洗滌,用無水Na2
SO4
乾燥,過濾並在減壓下濃縮以給出呈灰白色固體的2-(2-(2-異丙基苯基)-4-(4-甲基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷(589 mg,1.36 mmol,產率:61.5%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.48 (br s, 1H), 7.25-7.16 (m, 4H), 7.15-7.07 (m, 3H), 3.65 (m, 1H), 3.54-3.44 (m, 2H), 3.02-2.87 (m, 3H), 2.69-2.57 (m, 5H), 2.36-2.21 (m, 6H), 1.79-1.62 (m, 4H), 1.39-1.21 (m, 9H), 1.15 (m, 4H)。MS (ESI, m/e) [M+1]+
432.3。
步驟1:三級丁基 2-(2-(2-異丙基苯基)-4-(4-甲氧基苯乙基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
向三級丁基 2-(2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.0 g,2.26 mmol)在DCE(20 mL)中之溶液中添加2-(4-甲氧基苯基)乙醛(510 g,3.40 mmol)和HOAc(0.27 g,4.52 mmol)。在25°C下攪拌1 hr後,然後添加NaBH(OAc)3
(0.96 g,4.52 mmol)。將混合物在25°C下攪拌12小時。然後將水性NH4
Cl(20 mL)添加至混合物中,並用DCM(20 mL × 3)萃取。將合併的有機相用鹽水(20 mL × 2)洗滌,用無水Na2
SO4
乾燥,過濾並真空濃縮。將殘餘物藉由柱層析法(矽膠,洗脫液:PE/EA(v/v)= 1/1)純化以給出呈黃色固體的三級丁基 2-(2-(2-異丙基苯基)-4-(4-甲氧基苯乙基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(0.85 g,產率:65%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.36-7.29 (m, 2H), 7.19-7.13 (m, 1H), 7.08-7.05 (m, 1H), 6.90 (br d,J
= 8.4 Hz, 2H), 6.73 (d,J
= 8.4 Hz, 2H), 5.05 (m, 1H), 4.23 (br s, 1H), 3.77 (s, 3H), 3.39 (m, 1H), 3.27-3.15 (m, 6H), 2.88 (m, 1H), 2.67 (m, 1H), 2.61-2.48 (m, 4H), 2.22 (m, 1H), 1.97 (br s, 1H), 1.82 (br s, 1H), 1.61 (br s, 1H), 1.42 (s, 10H), 1.33-1.38 (m, 2H), 1.29 (m, 6H)。
步驟2:三級丁基 2-(2-(2-異丙基苯基)-4-(4-甲氧基苯乙基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
將三級丁基 2-(2-(2-異丙基苯基)-4-(4-甲氧基苯乙基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(0.85 g,1.48 mmol)和BH3
.THF(15 mL,14.8 mmol)的混合物加熱至70°C持續12小時。將MeOH(10 mL)小心地添加至混合物,並真空濃縮以給出呈黃色油狀物的三級丁基 2-(2-(2-異丙基苯基)-4-(4-甲氧基苯乙基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(0.8 g,產率:96%),其無需進一步純化即可用於下一步。MS (ESI, m/e) [M+1]+
562.4。
步驟3:2-(2-(2-異丙基苯基)-4-(4-甲氧基苯乙基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷。
向三級丁基 2-(2-(2-異丙基苯基)-4-(4-甲氧基苯乙基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(800 mg,1.42 mmol)在MeOH(20 mL)中之溶液中添加HCl/MeOH(10 mL)溶液。將混合物在25°C下攪拌1 hr。在除去溶劑後,將殘餘物溶解於水(20 mL)中。將混合物使用水性Na2
CO3
調節pH = 9-10。然後將混合物用EtOAc(20 mL × 3)萃取。將合併的有機相用鹽水(20 mL × 2)洗滌,用無水Na2
SO4
乾燥,過濾並真空濃縮以給出呈黃色固體的2-(2-(2-異丙基苯基)-4-(4-甲氧基苯乙基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷(600 mg,產率:91%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.51 (br s, 1H), 7.27-7.21 (m, 2H), 7.17-7.07 (m, 3H), 6.81 (d,J
= 8.4 Hz, 2H), 4.55-4.28 (m, 1H), 3.78 (s, 3H), 3.67 (m, 1H), 3.41 (br s, 1H), 3.03 (m, 2H), 2.94-2.87 (m, 1H), 2.80-2.68 (m, 6H), 2.60-2.52 (m, 2H), 2.41-2.13 (m, 4H), 1.79 (br s, 1H), 1.70 (m, 1H), 1.51-1.38 (m, 4H), 1.23 (m, 6H), 1.15 (br s, 1H)。MS (ESI, m/e) [M+1]+
462.5。
步驟1:三級丁基 (2-((4-甲氧基苄基) (2-側氧基-2-(鄰甲苯基)乙基)胺基)乙基)胺基甲酸酯。
在-78°C下,向1-溴-2-甲基苯(2.8 g,16.39 mmol)在THF(30 mL)中之溶液中添加n-BuLi(6.37 mL,15.92 mmol,2.5 M),並將混合物在-78°C下攪拌10 min。然後添加在THF(20 mL)中的三級丁基 4-(4-甲氧基苄基)-2-側氧基哌𠯤-1-甲酸酯(5.0 g,15.61 mmol)並將混合物在-78°C下攪拌2小時。將反應混合物用水性NH4
Cl(50 mL)淬滅並用EtOAc(50 mL × 3)萃取,用鹽水洗滌,經Na2
SO4
乾燥,過濾並在減壓下濃縮。將殘餘物藉由MPLC純化。獲得呈黃色油狀物的化合物三級丁基 (2-((4-甲氧基苄基) (2-側氧基-2-(鄰甲苯基)乙基)胺基)乙基)胺基甲酸酯(3.1 g,7.51 mmol,產率:48.15%)。MS (ESI, m/e) [M+1]+
413.3。
步驟2:1-(4-甲氧基苄基)-5-(鄰甲苯基)-1,2,3,6-四氫吡𠯤。
向三級丁基 (2-((4-甲氧基苄基)(2-側氧基-2-(鄰甲苯基)乙基)胺基)乙基)胺基甲酸酯(2.1 g,5.09 mmol)在DCM(20 mL)中之混合物中添加TFA(5.8 g,50.91 mmol)。將混合物在20°C下攪拌12小時。將殘餘物用H2
O(20 mL)稀釋並添加Na2
CO3
至pH = 9,用EtOAc(20 mL × 3)萃取,用鹽水洗滌,經Na2
SO4
乾燥,過濾並在減壓下濃縮以給出呈黃色油狀物的1-(4-甲氧基苄基)-5-(鄰甲苯基)-1,2,3,6-四氫吡𠯤(1.4 g,4.76 mmol,粗製)。MS (ESI, m/e) [M+1]+
295.3。
步驟3:1-(4-甲氧基苄基)-3-(鄰甲苯基)哌𠯤。
向1-(4-甲氧基苄基)-5-(鄰甲苯基)-1,2,3,6-四氫吡𠯤(1.4 g,4.76 mmol)在MeOH(20 mL)中之溶液中添加NaBH4
(719.66 mg,19.02 mmol)。將混合物在25°C下攪拌12小時。將混合物藉由H2
O淬滅並在減壓下濃縮。將殘餘物用H2
O(20 mL)稀釋並用DCM(20 mL × 3)萃取,用鹽水洗滌,經Na2
SO4
乾燥,過濾並在減壓下濃縮。將殘餘物藉由MPLC純化。獲得呈黃色油狀物化合物1-(4-甲氧基苄基)-3-(鄰甲苯基)哌𠯤(550 mg,1.75 mmol,產率:39.02%)。MS (ESI, m/e) [M+1]+
297.3
步驟4:三級丁基 2-(4-(4-甲氧基苄基)-2-(鄰甲苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
向1-(4-甲氧基苄基)-3-(鄰甲苯基)哌𠯤(520 mg,1.75 mmol)和三級丁基 2-側氧基-7-氮雜螺[3.5]壬烷-7-甲酸酯(419.83 mg,1.75 mmol)在DCE(10 mL)中之溶液中添加AcOH(210.7 mg,3.15 mmol)和NaBH(OAc)3
(1.12 g,5.36 mmol)。將混合物在25°C下攪拌12小時。將反應混合物用水性Na2
CO3
(20 mL)和DCM(10 mL × 3)萃取,經Na2
SO4
乾燥,過濾並在減壓下濃縮。將殘餘物藉由MPLC純化。獲得呈黃色油狀物的化合物三級丁基 2-(4-(4-甲氧基苄基)-2-(鄰甲苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(630 mg,1.21 mmol,產率:69.1%)。MS (ESI, m/e) [M+1]+
520.6
步驟5:2-(4-(4-甲氧基苄基)-2-(鄰甲苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷。
將三級丁基 2-(4-(4-甲氧基苄基)-2-(鄰甲苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(630 mg,1.21 mmol)在HCl/MeOH(10 mL)中之混合物在25°C下攪拌2小時。將反應將混合物在減壓下濃縮以除去溶劑。將殘餘物藉由製備型HPLC(TFA條件)根據HPLC純化。將殘餘物用H2
O(10 mL)稀釋並添加Na2
CO3
至pH = 9,將混合物用EtOAc(10 mL × 3)萃取,經Na2
SO4
乾燥,過濾並在減壓下濃縮以除去溶劑。獲得呈黃色油狀物的化合物2-(4-(4-甲氧基苄基)-2-(鄰甲苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷(109 mg,294.83 umol,產率:20.57%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.45 (m, 1H), 7.22 (m, 2H), 7.17-7.06 (m, 2H), 7.11-7.06 (m, 1H), 6.83 (m, 2H), 3.79 (s, 3H), 3.51 (m, 1H), 3.46 (s, 2H), 3.02-2.96 (m, 1H), 2.90 (m, 2H), 2.69-2.62 (m, 3H), 2.61-2.54 (m, 2H), 2.35 (s, 3H), 2.27 (m, 2H), 2.15 (m, 1H), 1.79-1.72 (m, 1H), 1.68-1.62 (m, 1H), 1.37-1.26 (m, 5H), 1.20-1.12 (m, 1H)。MS (ESI, m/e) [M+1]+
420.3。
步驟1:三級丁基 4-(4-甲氧基苄基)-2-(2-(2-甲基丙-1-烯-1-基)苯基)哌𠯤-1-甲酸酯。
在N2
下,向三級丁基 2-(2-溴苯基)-4-(4-甲氧基苄基)哌𠯤-1-甲酸酯(0.8 g,1.73 mmol)和4,4,5,5-四甲基-2-(2-甲基丙-1-烯-1-基)-1,3,2-二氧雜環戊硼烷(208 mg,2.08 mmol)在二㗁𠮿(20 mL)和H2
O(4 mL)中之溶液中添加Cs2
CO3
(1.13 g,3.46 mmol)和Pd(dppl)Cl2
.CH2
Cl2
(143 mg,0.173 mmol)。將混合物在100°C下攪拌3小時。將反應混合物過濾並在減壓下濃縮。將殘餘物藉由MPLC純化。獲得呈棕色油狀物的化合物三級丁基 4-(4-甲氧基苄基)-2-(2-(2-甲基丙-1-烯-1-基)苯基)哌𠯤-1-甲酸酯(0.63 g,產率:83%)。MS (ESI, m/e) [M+1]+
437.3。
步驟2:三級丁基 2-(2-異丁基苯基)-4-(4-甲氧基苄基)哌𠯤-1-甲酸酯。
向三級丁基 4-(4-甲氧基苄基)-2-(2-(2-甲基丙-1-烯-1- 基)苯基)哌𠯤-1-甲酸酯(0.63 g,1.44 mmol)在MeOH(20 mL)中之溶液中添加Pt/C(0.5 g)。在H2
(15 Psi)下,將混合物在25°C下攪拌12小時。將溶液過濾並在減壓下濃縮。獲得呈黃色油狀物的化合物三級丁基 2-(2-異丁基苯基)-4-(4-甲氧基苄基)哌𠯤-1-甲酸酯(0.6 g,產率:95%)。MS (ESI, m/e) [M+1]+
439.3。
步驟3:3-(2-異丁基苯基)-1-(4-甲氧基苄基)哌𠯤。
向三級丁基 2-(2-異丁基苯基)-4-(4-甲氧基苄基)哌𠯤-1-甲酸酯(0.6 g,1.37 mmol)在MeOH(10 mL)中之溶液中添加HCl/MeOH溶液(5 mL,4 M)。將混合物在20°C下攪拌2小時。將溶液在減壓下濃縮。將殘餘物用H2
O(50 mL)稀釋並添加水性Na2
CO3
溶液至pH = 9。將水層用EtOAc(50 mL × 3)萃取。將合併的有機層乾燥並在減壓下濃縮。獲得呈紅色油狀物的化合物3-(2-異丁基苯基)-1-(4-甲氧基苄基)哌𠯤(0.42 g,產率:91%)。MS (ESI, m/e) [M+1]+
339.3。
步驟4:三級丁基 2-(2-(2-異丁基苯基)-4-(4-甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
向3-(2-異丁基苯基)-1-(4-甲氧基苄基)哌𠯤(420 mg,1.24 mmol)在DCE(20 mL)中之溶液中添加三級丁基 2-側氧基-7-氮雜螺[3.5]壬烷-7-甲酸酯(356 mg,1.49 mmol)和HOAc(149 mg,2.48 mmol)。在25°C下攪拌1 hr後,然後添加NaBH(OAc)3
(0.79 g,3.72 mmol)。將混合物在25°C下攪拌12小時。然後將水性NaHCO3
(50 mL)添加至混合物中,並且然後將混合物用DCM(20 mL × 3)萃取。將合併的有機相用鹽水(20 mL × 2)洗滌,用無水Na2
SO4
乾燥,過濾並真空濃縮。將殘餘物藉由柱層析法(矽膠,洗脫液:PE/EA(v/v)= 5/1)純化以給出呈黃色油狀物的三級丁基 2-(2-(2-異丁基苯基)-4-(4-甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(400 mg,產率:58%)。MS (ESI, m/e) [M+1]+
562.5。
步驟5:2-(2-(2-異丁基苯基)-4-(4-甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷。
向三級丁基 2-(2-(2-異丁基苯基)-4-(4-甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(400 mg,0.71 mmol)在MeOH(10 mL)中之溶液中添加HCl/MeOH(5 mL,4 M)。將混合物在20°C下攪拌2小時。將溶液在減壓下濃縮。將殘餘物用H2
O(50 mL)稀釋並添加水性Na2
CO3
溶液至pH = 9。將水層用EtOAc(50 mL × 3)萃取。將合併的有機層用無水Na2
SO4
乾燥,並在減壓下濃縮。獲得呈棕色固體的化合物2-(2-(2-異丁基苯基)-4-(4-甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷(300 mg,產率:91%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.48 (m, 1H), 7.21 (m, 2H), 7.15-7.10 (m, 2H), 7.05-7.00 (m, 1H), 6.82 (m, 2H), 3.78 (s, 3H), 3.48-3.38 (m, 2H), 2.99 (m, 1H), 2.89 (m, 2H), 2.70-2.57 (m, 6H), 2.45-2.38 (m, 1H), 2.36-2.22 (m, 3H), 2.23-2.06 (m, 1H), 1.82-1.60 (m, 4H), 1.44-1.36 (m, 4H), 1.30-1.23 (m, 2H), 0.91 (d,J
= 6.4 Hz, 3H), 0.82 (d,J
= 6.4 Hz, 3H)。MS (ESI, m/e) [M+1]+
462.3
步驟1:三級丁基 (2-((2-(2-溴苯基)-2-側氧基乙基)(4-甲氧基苄基)胺基)乙基) 胺基甲酸酯。
在-70°C下,向1-溴-2-碘苯(10 g,35 mmol)在THF(100 mL)中之溶液中添加i-PrMgCl.LiCl(30 Ml,1 M,在THF中)。在攪拌0.5 hr後,添加三級丁基 4-(4-甲氧基苄基)-2-側氧基哌𠯤-1-甲酸酯(10.5 g,33 mmol)。將混合物在20°C下攪拌3小時。將反應混合物在0°C下藉由添加NH4
Cl(100 mL)淬滅,並用EtOAc(50 mL × 3)萃取。將合併的有機層用鹽水(50 mL × 2)洗滌,經Na2
SO4
乾燥,過濾並在減壓下濃縮。將殘餘物藉由柱層析法(矽膠,洗脫液:PE/EA(v/v)= 10/1)純化以給出呈黃色油狀物的三級丁基 (2-((2-(2-溴苯基)-2-側氧基乙基)(4-甲氧基苄基)胺基)乙基)胺基甲酸酯(14 g,產率:84%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.85 (dd,J
= 1.6, 8.0 Hz, 1H), 7.54 (dd,J
= 1.2, 8.0 Hz, 1H), 7.33-7.28 (m, 1H), 7.22 (m, 2H), 7.10 (m, 1H), 6.88-6.82 (d,J
= 8.4 Hz, 2H), 4.47 (s, 1H), 3.91 (m, 1H), 3.81 (s, 3H), 3.57-3.44 (m, 3H), 2.97-2.88 (m, 2H), 2.64-2.55 (m, 2H), 1.27 (m, 2H), 1.14 (s, 9H)。
步驟2:3-(2-溴苯基)-1-(4-甲氧基苄基)哌𠯤。
向三級丁基 (2-((2-(2-溴苯基)-2-側氧基乙基)(4-甲氧基苄基)胺基)乙基)胺基甲酸酯(5.0 g,10 mmol)在DCM(25 mL)中之溶液中添加TFA(25 mL)。將混合物在20°C下攪拌30 min。在減壓下除去溶劑後,將殘餘物溶解於DCE(50 mL)中。然後添加NaBH(OAc)3
(2.2 g,10 mmol)。將混合物在20°C下攪拌1 hr。將反應混合物在減壓下濃縮以除去溶劑。將反應混合物用DCM(10 mL × 3)萃取,然後用水性NaHCO3
(10 mL × 2)洗滌並經Na2
SO4
乾燥,過濾並濃縮以給出呈棕色油狀物的3-(2-溴苯基)-1-(4-甲氧基苄基)哌𠯤(3.5 g,產率:99%),其無需進一步純化即可用於下一步。MS (ESI, m/e) [M+1]+
361.2, 363.2。
步驟3:三級丁基 2-(2-溴苯基)-4-(4-甲氧基苄基)哌𠯤-1-甲酸酯。
向3-(2-溴苯基)-1-(4-甲氧基苄基)哌𠯤(3.4 g,9.4 mmol)在DCM(50 mL)中之溶液中添加TEA(1.9 g,18.8 mmol)。然後添加Boc2
O(2.5 g,11.29 mmol)。將混合物在20°C下攪拌12小時。將反應混合物在0°C下藉由添加NH4
Cl(50 mL)淬滅,並且然後用EtOAc(20 mL × 3)萃取。將合併的有機層用鹽水(20 mL × 2)洗滌,經Na2
SO4
乾燥,過濾並在減壓下濃縮。將殘餘物藉由柱層析法(矽膠,洗脫液:PE/EA(v/v)= 10/1)純化以給出呈黃色油狀物的三級丁基 2-(2-溴苯基)-4-(4-甲氧基苄基)哌𠯤-1-甲酸酯(2.9 g,產率:68%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.58 (m, 1H), 7.52 (m, 1H), 7.31-7.27 (m, 1H), 7.13-7.09 (m, 1H), 7.06 (d,J
= 8.4 Hz, 2H), 6.79-6.75 (m, 2H), 5.33 (m, 1H), 3.94-3.89 (m, 1H), 3.78 (s, 3H), 3.53-3.46 (m, 1H), 3.43 (m, 2H), 3.00 (m, 1H), 2.84 (m, 1H), 2.52 (m, 1H), 2.22 (m, 1H), 1.31 (s, 9H)。
步驟4:三級丁基 2-(2-(環戊-1-烯-1-基)苯基)-4-(4-甲氧基苄基)哌𠯤-1-甲酸酯。
在N2
下,向三級丁基 2-(2-溴苯基)-4-(4-甲氧基苄基)哌𠯤-1-甲酸酯(1.0 g,2.17 mmol)和2-(環戊-1-烯-1-基)-4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷(0.5 g,2.6 mmol)在二㗁𠮿(20 mL)和H2
O(4 mL)中之溶液中添加Cs2
CO3
(1.4 g,4.34 mmol)和Pd(dppl)Cl2
.CH2
Cl2
(180 mg,0.217 mmol)。將混合物在100°C下攪拌3小時。將反應混合物過濾並在減壓下濃縮以給出殘餘物。將殘餘物藉由MPLC純化。獲得呈白色固體的化合物三級丁基 2-(2-(環戊-1-烯-1-基)苯基)-4-(4-甲氧基苄基)哌𠯤-1-甲酸酯(0.73 g,產率:75%)。MS (ESI, m/e) [M+1]+
449.4。
步驟5:三級丁基 2-(2-環戊基苯基)-4-(4-甲氧基苄基)哌𠯤-1-甲酸酯。
向三級丁基 2-(2-(環戊-1-烯-1-基)苯基)-4-(4-甲氧基苄基)哌𠯤-1-甲酸酯(0.73 g,1.63 mmol)在MeOH(20 mL)中之溶液中添加Pt/C(0.5 g)。將混合物在25°C下在H2
(15 Psi)下攪拌12 hr。將溶液過濾並在減壓下濃縮。獲得呈黃色油狀物的化合物三級丁基 2-(2-環戊基苯基)-4-(4-甲氧基苄基)哌𠯤-1-甲酸酯(0.7 g,產率:96%)。MS (ESI, m/e) [M+1]+
451.3。
步驟6:3-(2-環戊基苯基)-1-(4-甲氧基苄基)哌𠯤。
向三級丁基 2-(2-環戊基苯基)-4-(4-甲氧基苄基)哌𠯤-1- 甲酸酯(0.89 g,1.98 mmol)在MeOH(10 mL)中之溶液中添加HCl/MeOH(5 mL,4 M)。將混合物在20°C下攪拌2小時。將溶液在減壓下濃縮。將殘餘物用H2
O(50 mL)稀釋並添加Na2
CO3
溶液至pH = 9。將水層用EtOAc(50 mL × 3)萃取。將合併的有機層乾燥並在減壓下濃縮。獲得呈紅色油狀物的化合物3-(2-環戊基苯基)-1-(4-甲氧基苄基)哌𠯤(0.6 g,產率:87%)。MS (ESI, m/e) [M+1]+
351.3。
步驟7:三級丁基 2-(2-(2-環戊基苯基)-4-(4-甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5] 壬烷-7-甲酸酯。
向3-(2-環戊基苯基)-1-(4-甲氧基苄基)哌𠯤(600 mg,1.71 mmol)在DCE(20 mL)中之溶液中添加三級丁基 2-側氧基-7-氮雜螺[3.5]壬烷-7-甲酸酯(491 mg,2.05 mmol)和HOAc(205 mg,3.42 mmol)。在25°C下攪拌1 hr後,添加NaBH(OAc)3
(1.09 g,5.13 mmol)。將混合物在25°C下攪拌12小時。然後將水性NaHCO3
(50 mL)添加至混合物中,並且然後將混合物用DCM(20 mL × 3)萃取。將合併的有機相用鹽水(20 mL × 2)洗滌,用無水Na2
SO4
乾燥,過濾並真空濃縮。將殘餘物藉由柱層析法(矽膠,洗脫液:PE/EA(v/v)= 5/1)純化以給出,獲得呈黃色油狀物的三級丁基 2-(2-(2-環戊基苯基)-4-(4-甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5] 壬烷-7-甲酸酯(700 mg,產率:71%)。MS (ESI, m/e) [M+1]+
574.4。
步驟8:2-(2-(2-環戊基苯基)-4-(4-甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷。
向三級丁基 2-(2-(2-環戊基苯基)-4-(4-甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(700 mg,1.22 mmol)在MeOH(10 mL)中之溶液中添加HCl/MeOH(5 mL,4 M)溶液。將混合物在20°C下攪拌2小時。將溶液在減壓下濃縮。將殘餘物用H2
O(50 mL)稀釋並添加Na2
CO3
溶液至pH = 9。將水層用EtOAc(50 mL × 3)萃取。將合併的有機層乾燥並在減壓下濃縮。獲得呈棕色固體的化合物2-(2-(2-環戊基苯基)-4-(4-甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷(500 mg,產率:87%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.48 (s, 1H), 7.25-7.18 (m, 4H), 7.15-7.08 (m, 1H), 6.85-6.81 (m, 2H), 3.79 (s, 3H), 3.71-3.59 (m, 1H), 3.50-3.42 (m, 2H), 3.41-3.26 (m, 1H), 2.99 (m, 1H), 2.94-2.84 (m, 2H), 2.75-2.55 (m, 5H), 2.32-2.23 (m, 2H), 2.16 (m, 1H), 2.04-1.96 (m, 1H), 1.89-1.73 (m, 4H), 1.72-1.56 (m, 4H), 1.55-1.20 (m, 7H), 1.19-1.07 (m, 1H)。MS (ESI, m/e) [M+1]+
474.4。
步驟1:三級丁基 4-(4-甲氧基苄基)-2-(2-乙烯基苯基)哌𠯤-1-甲酸酯。
在N2
下,向三級丁基 2-(2-溴苯基)-4-(4-甲氧基苄基)哌𠯤-1-甲酸酯(1.0 g,2.17 mmol)和乙烯基三氟硼酸鉀(406.44 mg,3.03 mmol)在二㗁𠮿(10 mL)和H2
O(1 mL)中之溶液中添加Cs2
CO3
(1.41 g,4.33 mmol)和Pd(dppf)Cl2
(158.59 mg,216.74 umol)。將混合物在90°C下攪拌12小時。將反應混合物過濾並濃縮。將殘餘物用H2
O(10 mL)和EtOAc(10 mL × 3)萃取,經Na2
SO4
乾燥,過濾並濃縮。將殘餘物藉由MPLC純化。獲得呈黃色油狀物的化合物三級丁基 4-(4-甲氧基苄基)-2-(2-乙烯基苯基)哌𠯤-1-甲酸酯(800 mg,1.96 mmol,產率:90.35%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.84-7.80 (m, 1H), 7.47-7.42 (m, 1H), 7.26-7.22 (m, 2H), 7.16 (m, 2H), 7.08 (m, 1H), 6.82 (d,J
= 8.8 Hz, 2H), 5.51 (m, 1H), 5.37 (m, 1H), 5.21 (m, 1H), 3.87-3.81 (m, 1H), 3.80 (s, 3H), 3.48-3.38 (m, 2H), 3.25-3.15 (m, 1H), 3.07 (m, 1H), 2.79 (m, 1H), 2.45 (m, 1H), 2.17 (m, 1H), 1.41 (s, 9H)。
步驟2:三級丁基 2-(2-甲醯基苯基)-4-(4-甲氧基苄基)哌𠯤-1-甲酸酯。
在5°C下,向三級丁基 4-(4-甲氧基苄基)-2-(2-乙烯基苯基)哌𠯤-1-甲酸酯(800 mg,1.96 mmol)在THF(5 mL)和H2
O(5 mL)中之溶液中添加K2
OsO4
.H2
O(28.86 mg,78.33 umol)和NaIO4
(1.68 g,7.83 mmol)並且將混合物在25°C下攪拌3小時。將反應混合物用H2
O(10 mL)稀釋並用EtOAc(10 mL × 3)萃取,用水性Na2
SO3
(10 mL)洗滌,經Na2
SO4
乾燥,過濾並在減壓下濃縮以得到,獲得呈黃色油狀物的三級丁基 2-(2-甲醯基苯基)-4-(4-甲氧基苄基)哌𠯤-1-甲酸酯(800 mg,1.95 mmol,產率:99.52%)。MS (ESI, m/e) [M+1]+
411.2。
步驟3:三級丁基 4-(4-甲氧基苄基)-2-(2-(𠰌啉代甲基)苯基)哌𠯤-1-甲酸酯。
向三級丁基 2-(2-甲醯基苯基)-4-(4-甲氧基苄基)哌𠯤-1-甲酸酯(800 mg,1.95 mmol)、𠰌啉(203.74 mg,2.34 mmol)AcOH(234.06 mg,3.90 mmol)和NaBH(OAc)3
(1.24 g,5.85 mmol)的溶液中添加DCE(10 mL)。將混合物在25°C下攪拌12小時。將反應混合物傾倒入水性Na2
CO3
(10 mL)中並用DCM(10 mL × 3)萃取,經Na2
SO4
乾燥,過濾並在減壓下濃縮。將殘餘物藉由MPLC純化。獲得呈黃色油狀物係化合物三級丁基 4-(4-甲氧基苄基)-2-(2-(𠰌啉代甲基)苯基)哌𠯤-1-甲酸酯(400 mg,830.52 umol,產率:42.62%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.83 (d,J
= 8.0 Hz, 1H), 7.25 (d,J
= 2.8 Hz, 1H), 7.21-7.15 (m, 2H), 7.10 (d,J
= 8.4 Hz, 2H), 6.73 (d,J
= 8.8 Hz, 2 H), 5.27 (d,J
= 2.4 Hz, 1 H), 3.92 (m, 1 H), 3.89-3.83 (m, 1 H), 3.75 (s, 3H), 3.57-3.47 (m, 4H), 3.45-3.28 (m, 3H), 3.07 (d,J
= 12.8 Hz, 1H), 2.91 (d,J
= 11.2 Hz, 2H), 2.44 (m, 1H), 2.41-2.25 (m, 3H), 2.23-2.16 (m, 2H), 1.30 (s, 9H)。
步驟4:4-(2-(4-(4-甲氧基苄基)哌𠯤-2-基)苄基)𠰌啉。
將三級丁基 4-(4-甲氧基苄基)-2-(2-(𠰌啉代甲基)苯基)哌𠯤-1-甲酸酯(400 mg,830.52 umol)在HCl/EtOAc(5 mL)中之混合物在25°C下攪拌6小時。將反應混合物濃縮以除去溶劑。將殘餘物用H2
O(5 mL)稀釋,並添加Na2
CO3
至pH = 9,將混合物用EtOAc(5 mL × 3)萃取,經Na2
SO4
乾燥,過濾並在減壓下濃縮以除去溶劑。獲得呈黃色油狀物的化合物4-(2-(4-(4-甲氧基苄基)哌𠯤-2-基)苄基)𠰌啉(300 mg,786.35 umol,產率:94.68%)。MS (ESI, m/e) [M+1]+
382.2。
步驟5:三級丁基 2-(4-(4-甲氧基苄基)-2-(2-(𠰌啉代甲基)苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
向4-(2-(4-(4-甲氧基苄基)哌𠯤-2-基)苄基)𠰌啉(300 mg,786.35 umol)、三級丁基 2-側氧基-7-氮雜螺[3.5]壬烷-7-甲酸酯(225.82 mg,943.62 umol)、AcOH(94.44 mg,1.57 mmol)和NaBH(OAc)3
(499.58 mg,2.36 mmol)的溶液中添加DCE(6 mL)。將混合物在25°C下攪拌48小時。將反應混合物用水性Na2
CO3
(10 mL)和DCM(10 mL × 3)萃取,經Na2
SO4
乾燥,過濾並濃縮。將殘餘物藉由備型HPLC(TFA條件)純化。獲得呈白色固體的化合物三級丁基 2-(4-(4-甲氧基苄基)-2-(2-(𠰌啉代甲基)苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(255 mg,421.61 umol,產率:53.62%)。MS (ESI, m/e) [M+1]+
605.4。
步驟6:4-(2-(4-(4-甲氧基苄基)-1-(7-氮雜螺[3.5]壬烷-2-基)哌𠯤-2-基)苄基)𠰌啉。
將三級丁基 2-(4-(4-甲氧基苄基)-2-(2-(𠰌啉代甲基)苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(255 mg,421.61 umol)在DCM(4 mL)和TFA(2 mL)中之混合物在25°C下攪拌1 hr。將反應混合物用H2
O(5 mL)稀釋並添加水性Na2
CO3
至pH = 9。將混合物用DCM(5 mL × 3)萃取,經Na2
SO4
乾燥,過濾並在減壓下濃縮以除去溶劑。獲得呈黃色固體的化合物4-(2-(4-(4-甲氧基苄基)-1-(7-氮雜螺[3.5]壬烷-2-基)哌𠯤-2-基)苄基)𠰌啉(135 mg,267.48 umol,產率:63.44%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.58 (d,J
= 7.6 Hz, 1H), 7.25-7.19 (m, 3H), 7.17-7.09 (m, 2H), 6.83 (d,J
= 8.8 Hz, 2H), 3.78 (s, 3H), 3.66-3.50 (m, 5H), 3.39 (s, 2H), 3.32 (m, 1H), 3.22 (m, 1H), 2.97 (m, 2H), 2.85 (m, 1H), 2.76-2.59 (m, 5H), 2.42-2.22 (m, 6H), 2.01 (m, 1H), 1.84-1.76 (m, 1H), 1.70-1.63 (m, 1H), 1.46-1.32 (m, 4H), 1.29-1.23 (m, 1H), 1.11-1.03 (m, 1H)。MS (ESI, m/e) [M+1]+
505.4。
步驟1:三級丁基 2-(2-(2-異丙基苯基)-6-側氧基-4-(4-(三氟甲氧基)苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
在25°C下,向三級丁基 2-(2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(900 mg,2.04 mmol)在DCE(10 mL)中之溶液中添加AcOH(244.77 mg,4.08 mmol)和4-(三氟甲氧基)苯甲醛(426.21 mg,2.24 mmol)。將混合物在25°C下攪拌1 hr。然後添加NaBH(OAc)3
(1.3 g,6.11 mmol)並將其在25°C下再攪拌12小時。將反應混合物傾倒入飽和NaHCO3
(50 mL)中,用EtOAc(100 mL × 2)萃取。將合併的有機層用鹽水洗滌,用無水Na2
SO4
乾燥,過濾並在減壓下濃縮。將粗產物藉由柱層析法(矽膠,洗脫液:PE/EA(v/v)= 5/1至2/1)純化以給出呈黃色油狀物的三級丁基 2-(2-(2-異丙基苯基)-6-側氧基-4-(4-(三氟甲氧基)苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(820 mg,產率:64%)。
步驟2:三級丁基 2-(2-(2-異丙基苯基)-4-(4-(三氟甲氧基)苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
將三級丁基 2-(2-(2-異丙基苯基)-6-側氧基-4-(4-(三氟甲氧基)苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(800 mg,1.30 mmol)和BH3
.THF(12.99 mL,12.99 mmol)在THF中之混合物在70°C下攪拌12小時。將反應溶液藉由MeOH(10 mL)淬滅,在減壓下濃縮以給出呈黃色油狀物的三級丁基 2-(2-(2-異丙基苯基)-4-(4-(三氟甲氧基)苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(800 mg,粗製),其無需進一步純化即可直接用於下一步。
步驟3:2-(2-(2-異丙基苯基)-4-(4-(三氟甲氧基)苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷。
向三級丁基 2-(2-(2-異丙基苯基)-4-(4-(三氟甲氧基)苄基) 哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(800 mg,1.33 mmol)和HCl/MeOH(15 mL,4M)在MeOH(10 mL)中之混合物在25°C下攪拌2小時。將反應溶液在減壓下濃縮。將殘餘物傾倒入飽和NaHCO3
(10 mL)中,用EtOAc(20 mL × 2)萃取。將合併的有機層用鹽水洗滌,用無水Na2
SO4
乾燥,過濾並在減壓下濃縮以給出呈白色固體的2-(2-(2-異丙基苯基)-4-(4-(三氟甲氧基)苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷(606 mg,產率 90%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.48 (br s, 1H), 7.33 (br s, 2H), 7.23 (br s, 2H), 7.14 (br s, 3H), 3.71-3.27 (m, 4H), 3.07-2.85 (m, 3H), 2.61 (br s, 5H), 2.37-2.11 (m, 2H), 1.91-1.52 (m, 4H), 1.47- 0.82 (m, 12H)。MS (ESI, m/e) [M+1]+
502.4。
步驟1:三級丁基 2-(4-(4-乙氧基苄基)-2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
在25°C下,向三級丁基 2-(2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(900 mg,2.04 mmol)在DCE(10 mL)中之溶液中添加AcOH(244.77 mg,4.08 mmol)和4-乙氧基苯甲醛(333.66 mg,2.24 mmol)。將混合物在25°C下攪拌1 hr。然後添加NaBH(OAc)3
(1.3 g,6.11 mmol)並將其在25°C下再攪拌12小時。將反應混合物傾倒入飽和NaHCO3
(50 mL)中,用EtOAc(100 mL × 2)萃取。將合併的有機層用鹽水洗滌,用無水Na2
SO4
乾燥,過濾並在減壓下濃縮。將粗產物藉由柱層析法(矽膠,洗脫液:PE/EA(v/v)= 5/1至2/1)純化以給出呈黃色油狀物的三級丁基 2-(4-(4-乙氧基苄基)-2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(800 mg,產率:68%)。
步驟2:三級丁基 2-(4-(4-乙氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
將三級丁基 2-(4-(4-乙氧基苄基)-2-(2-異丙基苯基) -6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(800 mg,1.39 mmol)和BH3
.THF(13.89 mL,13.89 mmol)在THF中之混合物在70°C下攪拌12小時。將反應溶液藉由MeOH(10 mL)淬滅,在減壓下濃縮以給出呈黃色油狀物的三級丁基 2-(4-(4-乙氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(800 mg,粗製),其無需進一步純化即可直接用於下一步。
步驟3:2-(4-(4-乙氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷。
向三級丁基 2-(4-(4-乙氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(800 mg,1.42 mmol)和HCl(3.56 mL,14.24 mmol)在MeOH(10 mL)中之混合物在25°C下攪拌2小時。將反應溶液在減壓下濃縮。將殘餘物傾倒入飽和NaHCO3
(10 mL)中,用EtOAc(20 mL × 2)萃取。將合併的有機層用鹽水洗滌,用無水Na2
SO4
乾燥,過濾並在減壓下濃縮以給出呈白色固體的2-(4-(4-乙氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷(562 mg,產率:62%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.48 (br s, 1H), 7.25-7.16 (m, 4H), 7.15-7.07 (m, 1H), 6.81 (d,J
= 8.4 Hz, 2H), 4.01 (q, 2H), 3.64 (m, 1H), 3.50-3.31 (m, 3H), 3.01-2.84 (m, 3H), 2.70-2.52 (m, 5H), 2.33-2.23 (m, 2H), 2.21-2.07 (m, 2H), 1.79-1.61 (m, 2H), 1.43-1.32 (m, 6H), 1.31-1.21 (m, 5H), 1.14 (d,J
= 6.8 Hz, 4H)。MS (ESI, m/e) [M+1]+
462.4。
步驟1:三級丁基 2-(2-(2-異丙基苯基)-6-側氧基-4-(4-(三氟甲基)苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
向三級丁基 2-(2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(800 mg,1.87 mmol)在DCE(10 mL)中之溶液中添加AcOH(337 mg,5.61 mmol)和4-(三氟甲基)苯甲醛(179 mg,2.03 mmol)。將混合物在20°C下攪拌1 hr,然後添加NaBH(OAc)3
(1.19 g,5.61 mmol)。將混合物在20°C下攪拌16小時。然後添加飽和NaHCO3
(10 mL)和EtOAc(10 mL)。將混合物在20°C下攪拌0.2 hr。將有機層分離,經Na2
SO4
乾燥,真空蒸發。將殘餘物藉由柱層析法(矽膠,洗脫液:PE/EA(v/v)= 10/1至1/1)純化以得到呈黃色固體的三級丁基 2-(2-(2-異丙基苯基)-6-側氧基-4-(4-(三氟甲基)苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(500 mg,產率:49%)。MS (ESI, m/e) [M+1]+
600.5
步驟2:三級丁基 2-(2-(2-異丙基苯基)-4-(4-(三氟甲基)苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
將三級丁基 2-(2-(2-異丙基苯基)-6-側氧基-4-(4-(三氟甲基)苄基) 哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(500 mg,0.88 mmol)和BH3
.THF(8.8 mL,8.8 mmol)的混合物加熱至70°C持續12小時。在冷卻至0°C後,將混合物用MeOH(10 mL)淬滅。將混合物真空濃縮以給出呈黃色固體的三級丁基 2-(2-(2-異丙基苯基)-4-(4-(三氟甲基)苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(400 mg,產率:80%),其無需進一步純化即可用於下一步。MS (ESI, m/e) [M+1]+
586.3。
步驟3:2-(2-(2-異丙基苯基)-4-(4-(三氟甲基)苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷。
向三級丁基 2-(2-(2-異丙基苯基)-4-(4-(三氟甲基)苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(400 mg,0.68 mmol)在MeOH(10 mL)中之溶液中添加HCl/MeOH溶液(10 mL)。將混合物在25°C下攪拌2小時。在真空濃縮後,將殘餘物溶解於水(20 mL)中。將混合物使用水性Na2
CO3
調節pH = 9-10。將混合物用EtOAc(20 mL × 3)萃取。將合併的有機相用鹽水(20 mL × 2)洗滌,用無水Na2
SO4
乾燥,過濾並真空濃縮以給出呈棕色固體的2-(2-(2-異丙基苯基)-4-(4-(三氟甲基)苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷(220 mg,產率:66%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.55-7.43 (m, 5H), 7.27-7.21 (m, 2H), 7.14-7.11 (m, 1H), 3.66-3.56 (m, 3H), 3.48-3.25 (m, 1H), 3.22-3.02 (m, 1H), 2.91-2.87 (m, 2H), 2.64-2.61 (m, 5H), 2.45-2.20 (m, 4H), 1.80-1.60 (m, 2H), 1.38-1.12 (m, 13H)。MS (ESI, m/e) [M+1]+
486.3
步驟1:三級丁基2-(2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
將三級丁基 2-(2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.0 g,2.26 mmol)和BH3
.THF(22.64 mL,22.64 mmol)在THF(20 mL)中之混合物在70°C下攪拌12小時。將反應溶液藉由MeOH(20 mL)淬滅並在0°C下攪拌1 hr。將混合物在減壓下濃縮以給出呈白色油狀物的三級丁基2-(2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(900 mg,粗製),其無需進一步純化即可直接用於下一步。MS (ESI, m/e) [M+1]+
428.3。
步驟2:三級丁基 2-(4-(4-氰基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
向三級丁基2-(2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(900 mg,2.10 mmol)在DCE(10 mL)中之溶液中添加AcOH(252.78 mg,4.21 mmol)和4-甲醯基苄腈(303.59 mg,2.32 mmol)。將混合物在25°C下攪拌1 hr,然後添加NaBH(OAc)3
(1.34 g,6.31 mmol)並將其在25°C下再攪拌12小時。將反應混合物傾倒入飽和NaHCO3
(50 mL)中,用EtOAc(100 mL × 2)萃取。將合併的有機層用鹽水洗滌,用無水Na2
SO4
乾燥,過濾並在減壓下濃縮。將粗產物藉由柱層析法(矽膠,洗脫液:PE/EA(v/v)= 5/1至2/1)純化以給出呈黃色油狀物的三級丁基 2-(4-(4-氰基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(270 mg,產率:23%)。
步驟3:4-((3-(2-異丙基苯基)-4-(7-氮雜螺[3.5]壬烷-2-基)哌𠯤-1-基) 甲基)苄腈
將2-(4-(4-氰基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(270 mg,497.46 µmol)和TFA(0.38 mL,4.97 mmol)在DCM(10 mL)中之混合物在25°C下攪拌2小時。將反應溶液在減壓下濃縮。將反應混合物傾倒入飽和NaHCO3
(10 mL)中,用EtOAc(20 mL × 2)萃取。將合併的有機層用鹽水洗滌,用無水Na2
SO4
乾燥,過濾並在減壓下濃縮以給出呈黃色固體的4-((3-(2-異丙基苯基)-4-(7-氮雜螺[3.5]壬烷-2-基)哌𠯤-1-基)甲基)苄腈(102 mg,產率:46.32%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.59 (d,J
= 8.4 Hz, 2H), 7.45 (d,J
= 8.0 Hz, 3H), 7.26-7.19 (m, 3H), 7.15-7.09 (m, 1H), 3.65-3.59 (m, 1H), 3.56 (m, 2H), 3.35 (br s, 3H), 3.02-2.83 (m, 3H), 2.72 (m, 5H), 2.59 (m, 1H), 2.39-2.26 (m, 3H), 2.26-2.15 (m, 2H), 1.96 (s, 2H), 1.46 (m, 3H), 1.30-1.23 (m, 6H), 1.13 (br d,J
= 6.8 Hz, 3H), 0.88 (m, 3H)。MS (ESI, m/e) [M+1]+
443.3。
步驟1:三級丁基 2-(2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7- 甲酸酯。
在0°C下,向三級丁基 2-(2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.0 g,2.26 mol)在THF(20 mL)中之溶液中分批添加LiAlH4
(0.17 g,4.53 mol)。將混合物在20°C下攪拌1 hr。然後將H2
O(10 mL)添加至混合物,用乙酸乙酯(20 mL × 3)萃取。將合併的有機相用鹽水(10 mL × 2)洗滌,用無水Na2
SO4
乾燥,過濾並真空濃縮以給出呈黃色油狀物的三級丁基 2-(2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(0.9 g,產率:94%)。MS (ESI, m/e) [M+1]+
428.4。
步驟2:三級丁基 2-(4-(3-氟苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
向三級丁基 2-(2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(0.9 g,2.1 mmol)在DCE(20 mL)中之溶液中添加3-氟苯甲醛(0.31 g,2.5 mmol)和HOAc(0.25 g,4.2 mmol)。在25°C下攪拌1 hr後,添加NaBH(OAc)3
(0.89 g,4.2 mmol)。將混合物在25°C下攪拌12小時。然後將水性NH4
Cl(20 mL)添加至混合物中,並用DCM(20 mL × 3)萃取。將合併的有機相用鹽水(20 mL × 2)洗滌,用無水Na2
SO4
乾燥,過濾並真空濃縮。將殘餘物藉由柱層析法(矽膠,洗脫液:PE/EA(v/v)= 5/1)純化以給出呈黃色固體的三級丁基 2-(4-(3-氟苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(0.5 g,產率:45%)。MS (ESI, m/e) [M+1]+
536.5。
步驟3:2-(4-(3-氟苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷。
向三級丁基 2-(4-(3-氟苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(500 mg,0.934 mmol)在MeOH(20 mL)中之溶液中添加HCl/MeOH溶液(10 mL)。將混合物在25°C下攪拌1 hr。在除去溶劑後,將殘餘物溶解於水(20 mL)中。將混合物藉由水性Na2
CO3
調節pH = 9-10。將混合物用EtOAc(20 mL × 3)萃取。將合併的有機相用鹽水(20 mL × 2)洗滌,用無水Na2
SO4
乾燥,過濾並真空濃縮以給出呈黃色固體的2-(4-(3-氟苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷(370 mg,產率:91%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.47 (br s, 1H), 7.23-7.19 (m, 3H), 7.14-7.10 (m, 1H), 7.10-7.05 (m, 2H), 6.91 (m, 1H), 3.64 (m, 1H), 3.51 (s, 2H), 3.38 (m, 1H), 3.02-2.96 (m, 1H), 2.95-2.87 (m, 2H), 2.75-2.61 (m, 5H), 2.35-2.27 (m, 2H), 2.18 (m, 1H), 1.81-1.73 (m, 1H), 1.70 (m, 1H), 1.48-1.37 (m, 4H), 1.36-1.32 (m, 2H), 1.25 (m, 3H), 1.15-1.12 (m, 3H)。MS (ESI, m/e) [M+1]+
436.3。
步驟1:三級丁基 2-(2-(2-異丙基苯基)-4-(3-甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
在25°C下,向三級丁基 2-(2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.0 g,2.34 mmol)在DCE(10 mL)中之溶液中添加AcOH(280 mg,4.68 mmol)和3-甲氧基苯甲醛(477 mg,3.51 mmol)。將混合物在25°C下攪拌1 hr,然後添加NaBH(OAc)3
(991 mg,4.68 mmol),並將其在25°C下再攪拌12小時。將反應混合物藉由飽和Na2
CO3
(10 mL)淬滅,用EtOAc(10 mL × 3)萃取。將合併的有機層用鹽水洗滌,用無水Na2
SO4
乾燥,過濾並在減壓下濃縮。將粗產物藉由柱層析法(矽膠,洗脫液:PE/EA(v/v)= 50/1至0/1)純化以給出呈淺黃色油狀物的三級丁基 2-(2-(2-異丙基苯基)-4-(3-甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(0.3 g,0.547 mmol,23%產率)。
步驟2:2-(2-(2-異丙基苯基)-4-(3-甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷。
在0°C下,向三級丁基 2-(2-(2-異丙基苯基)-4-(3-甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(300 mg,0.547 mmol)的混合物中添加HCl/MeOH(10 mL,4 M)溶液持續2小時。將反應混合物傾倒入飽和Na2
CO3
(10 ml)中,用EtOAc(10 mL × 3)萃取。將合併的有機相用鹽水(10 mL × 2)洗滌,用無水Na2
SO4
乾燥,過濾並在減壓下濃縮以給出呈淺粉色油狀物的2-(2-(2-異丙基苯基)-4-(3-甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷(183 mg,產率:75%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.55-7.44 (m, 1H), 7.25-7.19 (m, 3H), 7.15-7.09 (m, 1H), 6.91-6.88 (m, 2H), 6.77 (m, 1H), 3.80 (s, 3H), 3.65 (d,J
= 9.2 Hz, 1H), 3.50 (s, 2H), 3.37 (m, 1H), 3.03-2.89 (m, 3H), 2.69-2.60 (m, 5H), 2.33-2.28 (m, 2H), 2.24-2.11 (m, 3H), 1.76 (m, 1H), 172-1.64 (m, 1H), 1.42-1.31 (m, 4H), 1.27-1.25 (d,J
= 6.8 Hz, 3H), 1.15 (d,J
= 6.8 Hz, 3H)。MS (ESI, m/e) [M+1]+
448.2。
步驟1:三級丁基 2-(4-(2-氟苄基)-2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
向三級丁基2-(2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.0 g,2.26 mmol)在DCE(10 mL)中之溶液中添加AcOH(271.97 mg,4.53 mmol)和2-氟苯甲醛(342.88 mg,2.76 mmol)。將混合物在25°C下攪拌1 hr,然後添加NaBH(OAc)3
(1.44 g,6.79 mmol)並將其在25°C下再攪拌12小時。將反應混合物傾倒入飽和NaHCO3
(50 mL)中,用EtOAc(100 mL × 2)萃取。將合併的有機層用鹽水洗滌,用無水Na2
SO4
乾燥,過濾並在減壓下濃縮。將粗產物藉由柱層析法(矽膠,洗脫液:PE/EA(v/v)= 5/1至2/1)純化以給出呈黃色油狀物的三級丁基 2-(4-(2-氟苄基)-2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.2 g,產率:96%)。
步驟2:三級丁基 2-(4-(2-氟苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
將三級丁基 2-(4-(2-氟苄基)-2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.2 g,2.18 mmol)和BH3
.THF(24.01 mL,24.01 mmol)在THF(20 mL)中之混合物在70°C下攪拌12小時。將反應溶液藉由MeOH(20 mL)淬滅並在0°C下攪拌1 hr。將混合物在減壓下濃縮以給出呈白色油狀物的三級丁基 2-(4-(2-氟苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.07 mg,粗製),其無需進一步純化即可直接用於下一步。MS (ESI, m/e) [M+1]+
536.4。
步驟3:2-(4-(2-氟苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷。
將三級丁基 2-(4-(2-氟苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.07 mg,2 mmol)和HCl(4.99 mL,19.97 mmol)在MeOH(10 mL)中之混合物在25°C下攪拌2小時。將反應溶液在減壓下濃縮。將反應混合物傾倒入飽和NaHCO3
(10 mL)中,用EtOAc(20 mL × 2)萃取。將合併的有機層用鹽水洗滌,用無水Na2
SO4
乾燥,過濾並在減壓下濃縮以給出呈黃色固體的2-(4-(2-氟苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷(481 mg,產率:55.28%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.46 (br s, 1H), 7.37 (t, 1H), 7.26-7.17 (m, 3H), 7.16-6.96 (m, 3H), 3.72-3.54 (m, 3H), 3.39 (br s, 1H), 3.00 (br d,J
= 11.2 Hz, 1H), 2.96-2.85 (m, 2H), 2.73-2.57 (m, 6H), 2.44-2.35 (m, 1H), 2.33-2.21 (m, 2H), 1.80-1.71 (m, 1H), 1.71-1.60 (m, 1H), 1.46-1.30 (m, 4H), 1.29-1.21 (m, 4H), 1.15 (d,J
= 6.8 Hz, 4H)。MS (ESI, m/e) [M+1]+
436.3。
步驟1:三級丁基 2-(2-(2-異丙基苯基)-4-(2-甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
向三級丁基 2-(2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.0 g,2.34 mmol)和2-甲氧基苯甲醛(477.5 mg,3.51 mmol)在DCE(10 mL)中之溶液中添加HOAc(280.6 mg,4.68 mmol)。將溶液在25°C下攪拌30 min。然後將NaBH(OAc)3
(1.09 g,5.14 mmol)添加至以上反應中並在25°C下攪拌12小時。向反應中添加飽和NaHCO3
直到pH = 7,將其用DCM(10 mL x 3)萃取。將合併的有機層用鹽水洗滌,經Na2
SO4
乾燥,過濾並在減壓下濃縮。將殘餘物藉由柱層析法(矽膠,洗脫液:PE/EA(v/v)= 5/1至1/1)純化以給出呈黃色油狀物的三級丁基 2-(2-(2-異丙基苯基)-4-(2-甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(230 mg,產率:18%)。
步驟2:2-(2-(2-異丙基苯基)-4-(2-甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷。
向三級丁基 2-(2-(2-異丙基苯基)-4-(2-甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(230 mg,0.42 mmol)在MeOH(10 mL)中之溶液中添加HCl/MeOH(2 mL)溶液。然後,將溶液在25°C下攪拌12小時。將混合物在減壓下濃縮。將殘餘物傾倒入水性Na2
CO3
(30 mL)中,用DCM(20 mL × 3)萃取。將合併的有機層用鹽水洗滌,經Na2
SO4
乾燥,過濾並在減壓下濃縮以給出呈黃色油狀物的2-(2-(2-異丙基苯基)-4-(2-甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷(146 mg,產率:78%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.47 (s, 1H), 7.34 (s, 1H), 7.27-7.18 (m, 5H), 6.90-6.83 (m, 2H), 3.78 (s, 3H), 3.67-3.58 (m, 4H), 2.99-2.71 (m, 3H), 2.65-2.60 (m, 5H), 2.32-2.25 (m, 3H), 1.69-1.60 (m, 3H), 1.35-1.25 (m, 9H), 1.16 (d,J
= 6.8 Hz, 3H)。MS (ESI, m/e) [M+1]+
448.3。
步驟1:三級丁基 2-(4-(2,4-二甲氧基苄基)-2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
向三級丁基 2-(2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.2 g,2.72 mmol)在DCE(10 mL)中之溶液中添加AcOH(326.36 mg,5.43 mmol)和2,4-二甲氧基苯甲醛(496.71 mg,2.99 mmol),將混合物在25°C下攪拌1 hr。向溶液中添加NaBH(OAc)3
(1.73 mg,8.15 mmol),然後將其在25°C下再攪拌12小時。在PH = 9下,將反應混合物用EtOAc(100 mL × 2)萃取。將合併的有機層用鹽水洗滌,用Na2
SO4
乾燥,過濾並真空濃縮。將粗產物藉由柱層析法(矽膠,洗脫液:PE/EA(v/v)= 5/1至2/1)純化以給出呈白色油狀物的三級丁基 2-(4-(2,4-二甲氧基苄基)-2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.2 g,2.72 mmol,產率:75%)。
步驟2:2-(4-(2,4-二甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
將三級丁基 2-(4-(2,4-二甲氧基苄基)-2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.2 g,2.03 mmol)和BH3
.THF(20.28 mL,20.28 mmol,1 M)在THF(10 mL)中之混合物在70°C下攪拌12小時。將反應溶液藉由MeOH(10 mL)淬滅,在減壓下濃縮以給出呈白色膠狀物的三級丁基 2-(4-(2,4-二甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.2 g,粗製),其無需進一步反應即可直接用於下一步。
步驟3:2-(4-(2,4-二甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷。
將三級丁基 2-(4-(2,4-二甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.2 g,2.08 mmol)和HCl/MeOH(30 mL,4 M)的混合物在25°C下攪拌2小時。將反應溶液在減壓下濃縮。將殘餘物傾倒入水性NaHCO3
中以調節pH = 9,用EtOAc(100 mL × 2)萃取。將合併的有機層用鹽水洗滌,用無水Na2
SO4
乾燥,過濾並在減壓下濃縮以給出呈白色固體的2-(4-(2,4-二甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷(651 mg,1.36 mmol,產率:65.2%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.47 (br s, 1H), 7.26-7.17 (m, 4H), 7.15-7.07 (m, 1H), 6.45-6.39 (m, 2H), 3.78 (m, 6H), 3.72-3.62 (m, 2H), 3.59-3.46 (m, 3H), 3.41 (br s, 1H), 3.07-2.83 (m, 4H), 2.75-2.54 (m, 7H), 2.42-2.16 (m, 4H), 2.00-1.61 (m, 6H), 1.28-1.23 (m, 6H), 1.17 (d,J
= 6.8 Hz, 5H)。MS (ESI, m/e) [M+1]+
478.3。
步驟1:三級丁基 (R或S)-2-(4-(2,4-二甲氧基苄基)-2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
向三級丁基 (R或S)-2-(2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.0 g,2.26 mmol)在DCE(15 mL)中之溶液中添加AcOH(271.97 mg,4.53 mmol)和2,4-二甲氧基苯甲醛(564.44 mg,3.40 mmol),將混合物在20°C下攪拌30 min。向溶液中添加NaBH(OAc)3
(959.86 mg,4.53 mmol),將其在20°C下再攪拌12小時。在pH = 9下,將反應混合物用EtOAc(100 mL × 2)萃取。將合併的有機層用鹽水洗滌,用Na2
SO4
乾燥,過濾並真空濃縮。將粗產物藉由柱層析法(矽膠,洗脫液:PE/EA(v/v)= 5/1至2/1)純化以給出呈白色油狀物的三級丁基 (R或S)-2-(4-(2,4-二甲氧基苄基)-2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.13 g,產率84%)。
步驟2:三級丁基 (R或S)-2-(4-(2,4-二甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
將三級丁基 (R或S)-2-(4-(2,4-二甲氧基苄基)-2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.13 g,1.91 mmol)和BH3
.THF(19.09 mL,19.09 mmol,1 M)在THF(15 mL)中之混合物在70°C下攪拌12小時。將反應溶液用MeOH(10 mL)淬滅,在減壓下濃縮以給出呈白色膠狀物的三級丁基 (R或S)-2-(4-(2,4-二甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.0 g,粗製),其無需進一步反應即可直接用於下一步。
步驟3:(R或S)-2-(4-(2,4-二甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷。
向三級丁基 (R或S)-2-(4-(2,4-二甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.0 g,1.73 mmol)在MeOH(10 mL)中之混合物中添加HCl/MeOH溶液(10 mL,4 M)。將混合物在20°C下攪拌3小時。將反應溶液在減壓下濃縮。將殘餘物傾倒入水性NaHCO3
中以調節pH = 9,用EtOAc(100 mL × 2)萃取。將合併的有機層用鹽水洗滌,用無水Na2
SO4
乾燥,過濾並在減壓下濃縮以給出呈黃色固體的(R或S)-2-(4-(2,4-二甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷(500 mg,產率:60.5%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.47 (br s, 1H), 7.26-7.17 (m, 3H), 7.15-7.06 (m, 1H), 6.51-6.30 (m, 2H), 3.81 (s, 1H), 3.79 (s, 3H), 3.76 (s, 3H), 3.66 (br s, 1H), 3.60-3.46 (m, 2H), 3.40 (br s, 1H), 3.02-2.84 (m, 3H), 2.73-2.55 (m, 4H), 2.39-2.19 (m, 4H), 2.15 (m, 1H), 1.75 (m, 1H), 1.84-1.68 (m, 1H), 1.67-1.65 (m, 1H), 1.69-1.61 (m, 1H), 1.43-1.28 (m, 4H), 1.25 (d,J
= 6.8 Hz, 4H), 1.17 (d,J
= 6.8 Hz, 4H)。MS (ESI, m/e) [M+1]+
478.5。
步驟1:三級丁基 2-(4-(3,5-二甲氧基苄基)-2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
向三級丁基 2-(2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.0 g,2.26 mmol)在DCE(20 mL)中之溶液中添加3,5-二甲氧基苯甲醛(0.56 g,3.40 mmol)和HOAc(0.27 g,4.52 mmol)。在25°C下攪拌1 hr後,然後添加NaBH(OAc)3
(0.96 g,4.52 mmol)。將混合物在25°C下攪拌12小時。然後將水性NH4
Cl(20 mL)添加至混合物中,用DCM(20 mL × 3)萃取。將合併的有機相用鹽水(20 mL × 2)洗滌,用無水Na2
SO4
乾燥,過濾並真空濃縮。將殘餘物藉由柱層析法(矽膠,洗脫液:PE/EA(v/v)= 1/1)純化以給出呈黃色固體的三級丁基 2-(4-(3,5-二甲氧基苄基)-2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.1 g,產率:82%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.27 (s, 2H), 7.18-7.13 (m, 2H), 6.24 (s, 1H), 6.12 (s, 2H), 4.94 (br s, 1H), 4.41 (br s, 1H), 3.63-3.57 (m, 2H), 3.55 (s, 6H), 3.29-3.08 (m, 7H), 3.02-2.94 (m, 1H), 2.75-2.64 (m, 2H), 2.26-2.19 (m, 1H), 1.92 (m, 1H), 1.74-1.63 (m, 3H), 1.49-1.44 (m, 2H), 1.42 (s, 9H), 1.34-1.29 (m, 2H), 1.23 (d,J
= 6.8 Hz, 3H), 0.98 (d,J
= 6.8 Hz, 3H)。
步驟2:三級丁基 2-(4-(3,5-二甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
將三級丁基 2-(4-(3,5-二甲氧基苄基)-2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.1 g,1.86 mmol)和BH3
.THF(18 mL,18.6 mmol)的混合物加熱至70°C持續12小時。將MeOH(10 mL)小心地添加至混合物,並真空濃縮至呈黃色油狀物的三級丁基 2-(4-(3,5-二甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(0.9 g,產率:84%),其無需進一步純化即可用於下一步。MS (ESI, m/e) [M+1]+
578.4。
步驟3:2-(4-(3,5-二甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷
向三級丁基 2-(4-(3,5-二甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(900 mg,1.56 mmol)在MeOH(20 mL)中之溶液中添加 HCl/MeOH(10 mL)。將混合物在25°C下攪拌1 hr。在除去溶劑後,將殘餘物溶解於水(20 mL)中。將混合物使用水性Na2
CO3
調節pH = 9-10。將混合物用EtOAc(20 mL × 3)萃取。將合併的有機相用鹽水(20 mL × 2)洗滌,用無水Na2
SO4
乾燥,過濾並真空濃縮以給出呈黃色固體的2-(4-(3,5-二甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷(550 mg,產率:74%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.48 (br s, 1H), 7.25-7.17 (m, 2H), 7.15-7.09 (m, 1H), 6.50 (m, 2H), 6.33 (s, 1H), 3.77 (s, 6H), 3.65 (m, 1H), 3.46 (s, 2H), 3.41 (m, 1H), 3.00 (m, 1H), 2.96-2.87 (m, 2H), 2.72-2.54 (m, 5H), 2.35-2.26 (m, 2H), 2.20-2.14 (m, 1H), 1.93 (br s, 1H), 1.79-1.72 (m, 1 H), 1.70-1.64 (m, 1H), 1.41-1.29 (m, 5H), 1.26 (br d,J
= 6.8 Hz, 3H), 1.15 (br d,J
= 6.8 Hz, 3H)。MS (ESI, m/e) [M+1]+
478.4。
步驟1:三級丁基 2-(4-(2,4-二氟苄基)-2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
向三級丁基 2-(2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.2 g,2.72 mmol)在DCE(10 mL)中之溶液中添加AcOH(326.36 mg,5.43 mmol)和2,4-二氟苯甲醛(424.76 mg,2.99 mmol)。將混合物在25°C下攪拌1 hr,然後添加NaBH(OAc)3
(1.73 g,8.15 mmol)並將其在25°C下再攪拌12小時。將反應混合物傾倒入飽和NaHCO3
(50 mL)中,用EtOAc(100 mL × 2)萃取。將合併的有機層用鹽水洗滌,用無水Na2
SO4
乾燥,過濾並在減壓下濃縮。將粗產物藉由柱層析法(矽膠,洗脫液:PE/EA(v/v)= 5/1至2/1)純化以給出呈黃色油狀物的三級丁基 2-(4-(2,4-二氟苄基)-2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.0 g,1.76 mmol,產率:64%)。
步驟2:三級丁基 2-(4-(2,4-二氟苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
將三級丁基 2-(4-(2,4-二氟苄基)-2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.0 g,1.76 mmol)和BH3
(19.38 mL,19.38 mmol)在THF(10 mL)中之混合物在70°C下攪拌12小時。將反應溶液藉由MeOH(10 mL)淬滅,在減壓下濃縮以給出三級丁基 2-(4-(2,4-二氟苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.2 g,粗製),其無需進一步反應即可直接用於下一步。
步驟3:2-(4-(2,4-二氟苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷
將三級丁基 2-(4-(2,4-二氟苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.2 g,2.17 mmol)和HCl/MeOH(35 mL,4M)的混合物在25°C下攪拌2小時。將反應溶液在減壓下濃縮。將反應混合物傾倒入飽和NaHCO3
(50 mL)中,用EtOAc(100 mL × 2)萃取。將合併的有機層用鹽水洗滌,用無水Na2
SO4
乾燥,過濾並在減壓下濃縮以給出呈黃色固體的2-(4-(2,4-二氟苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷(515 mg,1.14 mmol,產率:52%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.46 (br s, 1H), 7.38-7.30 (m, 1H), 7.23 (m, 2H), 7.16-7.09 (m, 1H), 6.85-6.72 (m, 2H), 3.65-3.51 (m, 3H), 3.37 (br s, 1H), 3.00 (m, 1H), 2.90 (m, 2H), 2.69-2.56 (m, 5H), 2.42-2.21 (m, 4H), 1.80-1.61 (m, 2H), 1.44-1.28 (m, 5H), 1.25 (br d,J
= 6.8 Hz, 3H), 1.15 (br d,J
= 6.8 Hz, 3H)。MS (ESI, m/e) [M+1]+
454.3。
步驟1:三級丁基 2-(4-(3,5-二氟苄基)-2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
向三級丁基 2-(2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(800 mg,1.87 mmol)在DCE(10 mL)中之溶液中添加AcOH(337 mg,5.61 mmol)和3,5-二氟苯甲醛(292 mg,2.06 mmol)。將混合物在20°C下攪拌1 hr。然後添加NaBH(OAc)3
(1.19 g,5.61 mmol)。將混合物在20°C下攪拌16小時。然後添加飽和NaHCO3
(10 mL)和EtOAc(10 mL)。將混合物在20°C下攪拌0.2 hr。將有機層分離,經Na2
SO4
乾燥,真空蒸發。將殘餘物藉由柱層析法(矽膠,洗脫液:PE/EA(v/v)= 10/1至1/1)純化以得到呈黃色固體的三級丁基 2-(4-(3,5-二氟苄基)-2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(500 mg,產率:50%)。MS (ESI, m/e) [M+1]+
568.5
步驟2:三級丁基 2-(4-(3,5-二氟苄基)-2-(2 -異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
將三級丁基 2-(4-(3,5-二氟苄基)-2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(500 mg,0.88 mmol)和BH3
.THF(8.8 mL,8.8 mmol)的混合物加熱至70°C持續12小時。在冷卻至0°C後,將混合物用MeOH(10 mL)淬滅。將混合物真空濃縮以給出呈黃色固體的三級丁基 2-(4-(3,5-二氟苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(400 mg,產率:80%),其無需進一步純化即可用於下一步。MS (ESI, m/e) [M+1]+
554.2。
步驟3:2-(4-(3,5-二氟苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷。
向三級丁基 2-(4-(3,5-二氟苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(400 mg,0.71 mmol)在MeOH(10 mL)中之溶液中添加HCl/MeOH(10 mL)。將混合物在25°C下攪拌2小時,在真空濃縮後,將殘餘物溶解於水(20 mL)中。將混合物用水性Na2
CO3
調節pH = 9-10。將混合物用EtOAc(20 mL × 3)萃取。將合併的有機相用鹽水(20 mL × 2)洗滌,用無水Na2
SO4
乾燥,過濾並真空濃縮以給出呈棕色固體的2-(4-(3,5-二氟苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷(225 mg,產率:70%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.52-7.47 (s, 1H), 7.27-7.21 (m, 2H), 7.14-7.12 (m, 1H), 6.89-6.87 (m, 2H), 6.68-6.66 (m, 1H), 3.65-3.63 (m, 1H), 3.48-3.47 ( m, 2H), 3.46-3.38 (m, 1H), 3.22-3.02 (m, 1H), 3.02-2.88 (m, 2H), 2.67-2.60 (m, 5H), 2.32-2.22 (m, 2H), 2.22-2.15 (m, 1H), 1.80-1.60 (m, 2H), 1.38-1.14 (m, 13H)。MS (ESI, m/e) [M+1]+
454.3
步驟1:三級丁基 2-(4-(3,4-二氟苄基)-2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
向三級丁基 2-(2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(880 mg,1.99 mmol)在DCE(10 mL)中之溶液中添加AcOH(239.33 mg,3.99 mmol)和3,4-二氟苯甲醛(311.49 mg,2.19 mmol)。將混合物在25°C下攪拌1 hr。然後添加NaBH(OAc)3
(1.27 g,5.98 mmol)並將其在25°C下再攪拌12小時。將反應混合物傾倒入飽和NaHCO3
(50 mL)中,用EtOAc(100 mL × 2)萃取。將合併的有機層用鹽水洗滌,用無水Na2
SO4
乾燥,過濾並在減壓下濃縮。將殘餘物藉由柱層析法(矽膠,洗脫液:PE/EA(v/v)= 5/1至2/1)純化以給出呈黃色油狀物的三級丁基 2-(4-(3,4-二氟苄基)-2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.0 g,產率:85%)。
步驟2:三級丁基 2-(4-(3,4-二氟苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
將三級丁基 2-(4-(3,4-二氟苄基)-2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.0 g,1.76 mmol)和BH3
.THF(17.61 mL,17.61 mmol)在THF(15 mL)中之混合物在70°C下攪拌12小時。將反應溶液藉由MeOH(10 mL)淬滅,在減壓下濃縮以給出呈黃色油狀物的三級丁基 2-(4-(3,4-二氟苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(750 mg,粗製),其無需進一步純化即可直接用於下一步。
步驟3:2-(4-(3,4-二氟苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷。
將三級丁基 2-(4-(3,4-二氟苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(750 mg,1.35 mmol)和HCl(3.39 mL,13.54 mmol)在MeOH(10 mL)中之混合物在25°C下攪拌2小時。將反應溶液在減壓下濃縮。將殘餘物傾倒入飽和NaHCO3
(10 mL)中,用EtOAc(20 mL × 2)萃取。將合併的有機層用無水Na2
SO4
乾燥,過濾並在減壓下濃縮以給出呈白色固體的2-(4-(3,4-二氟苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷(423 mg,產率:68%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.47 (br s, 1H), 7.26-6.96 (m, 6H), 3.63 (m, 1H), 3.51-3.28 (m, 3H), 3.09-2.79 (m, 3H), 2.70-2.53 (m, 5H), 2.36-2.23 (m, 3H), 2.21-1.97 (m, 3H), 1.80-1.63 (m, 2H), 1.46-1.21 (m, 10H), 1.14 (br d,J
= 6.8 Hz, 4H)。MS (ESI, m/e) [M+1]+
454.3。
步驟1:三級丁基 (R或S)-2-(4-(3,4-二氟苄基)-2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
向三級丁基 (R或S)-2-(2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.0 g,2.26 mmol)在DCE(10 mL)中之溶液中添加AcOH(271.97 mg,4.53 mmol)和3,4-二氟苯甲醛(309.15 mg,2.49 mmol)。將混合物在25°C下攪拌1小時,然後添加NaBH(OAc)3
(1.44 g,6.79 mmol),將其在25°C下再攪拌12小時。將反應混合物傾倒入飽和NaHCO3
(50 mL)中,用EtOAc(100 mL × 2)萃取。將合併的有機層用鹽水洗滌,用無水Na2
SO4
乾燥,過濾並在減壓下濃縮。將殘餘物藉由柱層析法(矽膠,洗脫液:PE/EA(v/v)= 5/1至2/1)純化以給出呈黃色油狀物的三級丁基 (R或S)-2-(4-(3,4-二氟苄基)-2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.15 g,產率:88%)。
步驟2:三級丁基 (R或S)-2-(4-(3,4-二氟苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
將三級丁基 (R或S)-2-(4-(3,4-二氟苄基)-2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.15 g,2.03 mmol)和BH3
.THF(20.26 mL,20.26 mmol)在THF中之混合物在70°C下攪拌12小時。將反應溶液用MeOH(10 mL)淬滅,在減壓下濃縮以給出呈黃色油狀物的t三級丁基 (R或S)-2-(4-(3,4-二氟苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.1 g,粗製),其無需進一步純化即可直接用於下一步。
步驟3:(R或S)-2-(4-(3,4-二氟苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷。
將三級丁基 (R或S)-2-(4-(3,4-二氟苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.1 g,1.99 mmol)和HCl(4.97 mL,19.87 mmol)在MeOH(10 mL)中之混合物在25°C下攪拌2小時。將反應溶液在減壓下濃縮。將殘餘物傾倒入飽和NaHCO3
(10 mL)中,用EtOAc(20 mL × 2)萃取。將合併的有機層用無水Na2
SO4
乾燥,過濾並在減壓下濃縮以給出呈黃色固體的(R或S)-2-(4-(3,4-二氟苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷(420 mg,產率:47%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.48 (br s, 1H), 7.26-7.15 (m, 3H), 7.15-7.04 (m, 2H), 7.01 (m, 1H), 3.63 (m, 1H), 3.45 (s, 2H), 3.39 (m, 1H), 3.01 (m, 1H), 2.95-2.85 (m, 2H), 2.71-2.57 (m, 4H), 2.36-2.24 (m, 3H), 2.23-2.12 (m, 3H), 1.82-1.55 (m, 2H), 1.45-1.30 (m, 5H), 1.26 (d,J
= 6.8 Hz, 3H), 1.14 (d,J
= 6.8 Hz, 3H)。MS (ESI, m/e) [M+1]+
454.3。
步驟1:三級丁基 2-(4-(口克唍-6-基甲基)-2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
將三級丁基 2-(2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.0 g,2.26 mmol)、口克唍-6-甲醛(404 mg,2.49 mmol)和AcOH(271.97 mg,4.53 mmol)在DCE(20 mL)中之混合物在20°C下攪拌30 min。然後將NaBH(OAc)3
(1.44 g,6.79 mmol)分批添加至以上混合物中,在30°C下攪拌2小時。將反應混合物用DCM(30 mL)稀釋,用飽和NaHCO3
(30 mL)洗滌。將有機層用無水Na2
SO4
乾燥,過濾並在減壓下濃縮。將殘餘物藉由柱層析法(矽膠,洗脫液:PE/EA(v/v)= 3/1至1/1)純化以給出呈白色固體的三級丁基 2-(4-(口克唍-6-基甲基)-2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.25 g,產率:94%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.34-7.28 (m, 1H), 7.27 (s, 1H), 7.24-7.16 (m, 1H), 7.15-7.09 (m, 1H), 6.68-6.58 (m, 1H), 6.57-6.50 (m, 1H), 6.40 (s, 1H), 4.93 (s, 1H), 4.44 (s, 1H), 4.15-4.10 (m, 1H), 3.59-3.46 (m, 2H), 3.33-3.06 (m, 6H), 2.97 (t, 1H), 2.63 (s, 2H), 2.56-2.36 (m, 2H), 2.23 (t, 1H), 1.98-1.83 (m, 3H), 1.81-1.57 (m, 3 H), 1.54-1.38 (m, 11H), 1.37-1.29 (m, 2H), 1.25-1.17 (m, 3H), 0.95 (d,J
= 6.8 Hz, 3H)。MS (ESI, m/e) [M+1]+
588.4。
步驟2:三級丁基 2-(4-(口克唍-6-基甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
在20°C下,向三級丁基 2-(4-(口克唍-6-基甲基)-2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.25 g,2.13 mmol)在THF(15 mL)中之溶液中滴加BH3
.THF(30 mL,30 mmol)。將混合物加熱至70°C持續12小時。將反應藉由甲醇(5 mL)淬滅,在減壓下濃縮以給出呈白色固體的三級丁基 2-(4-(口克唍-6-基甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.22 g,粗製)。MS (ESI, m/e) [M+1]+
574.5。
步驟3:2-(4-(口克唍-6-基甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷。
在20°C下,向三級丁基 2-(4-(口克唍-6-基甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.20 g,2.09 mmol)在MeOH(5 mL)中之溶液中滴加HCl/MeOH(20 mL,4 M)。將溶液在20°C下攪拌2小時。將反應溶液真空濃縮。將殘餘物用HCl(10 mL,1 M)稀釋,用EtOAc(20 mL × 2)萃取。將水相用NaHCO3
調節Ph = 8,用EtOAc/MeOH(20/1,40 mL × 5)萃取。將合併的有機相用無水Na2
SO4
乾燥,過濾並在減壓下濃縮以給出呈白色固體的2-(4-(口克唍-6-基甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷(740 mg,產率:75%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.47 (s, 1H), 7.17-7.25 (m, 2H), 7.08-7.15 (m, 1H), 6.92-7.04 (m, 2H), 6.70 (d,J
= 8.19 Hz, 1H), 4.12-4.21 (m, 2H), 3.57-3.80 (m, 3H), 3.41 (s, 3H), 2.83-3.05 (m, 3H), 2.56-2.82 (m, 7H), 2.21-2.33 (m, 2H), 2.08-2.19 (m, 1H), 1.92-2.03 (m, 2H), 1.60-1.80 (m, 2H), 1.35-1.54 (m, 4H), 1.28-1.34 (m, 1H), 1.24 (d,J
= 6.85 Hz, 3H), 1.14 (d,J
= 6.85 Hz, 3H)。MS (ESI, m/e) [M+1]+
474.4。
步驟1:5,6,7,8-四氫萘-2-甲醛和5,6,7,8-四氫萘-1-甲醛。
將1,2,3,4-四氫萘(3.0 g,22.69 mmol)在DCM(50 mL)中之溶液在劇烈攪拌下冷卻至0°C,經由注射器一次性添加所有SnCl4
(10.4 g,39.94 mmol),最後經10 min,逐滴引入二氯(甲氧基)甲烷(2.61 g,22.69 mmol)。在添加後,將反應在0°C下攪拌0.5 hr。混合物的顏色變為深紅色,並且然後變為黃色。藉由冰淬滅反應混合物。將有機相用水(30 mL × 3)洗滌,用無水Na2
SO4
乾燥,過濾並在減壓下濃縮以給出呈深黃色油狀物的5,6,7,8-四氫萘-2-甲醛和5,6,7,8-四氫萘-1-甲醛的混合物(3.3 g,粗製)。1
H NMR (400 MHz, CDCl3
) δ ppm: 10.39-9.83 (m, 1H), 7.67-7.56 (m, 1H), 7.34-7.20 (m, 1H), 7.12-7.04 (m, 1H), 1.69-3.37 (m, 8H)。
步驟2:三級丁基 2-(2-(2-異丙基苯基)-6-側氧基-4-((5,6,7,8-四氫萘-2-基)甲基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯和三級丁基 2-(2-(2-異丙基苯基)-6-側氧基-4-((5,6,7,8-四氫萘-1-基)甲基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
將三級丁基 2-(2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.0 g,2.26 mmol)、AcOH(271.97 mg,4.53 mmol)以及5,6,7,8-四氫萘-2-甲醛和5,6,7,8-四氫萘-1-甲醛的混合物(435.35 mg,2.72 mmol)在DCE(20 mL)中之混合物在20°C下攪拌30 min。將NaBH(OAc)3(1.44 g,6.79 mmol)分批添加至以上混合物中,並且然後在20°C下攪拌3小時。將反應混合物用DCM(30 mL)稀釋,用飽和Na2
CO3
洗滌,用無水Na2
SO4
乾燥,過濾並在減壓下濃縮。將殘餘物藉由備型HPLC純化,用NaHCO3
調節pH = 8,濃縮,用EtOAc(50 mL × 3)萃取。將合併的有機相用無水Na2
SO4
乾燥,過濾並在減壓下濃縮以給出呈淡黃色固體的三級丁基 2-(2-(2-異丙基苯基)-6-側氧基-4-((5,6,7,8-四氫萘-2-基)甲基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(500 mg,0.86 mmol)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.33-7.27 (m, 2H), 7.22-7.17 (m, 1H), 7.15-7.10 (m, 1H), 6.82 (d,J
= 7.6 Hz, 1H), 6.65 (d,J
= 7.6 Hz, 1H), 6.51 (s, 1H), 4.96 (s, 1H), 4.49-4.31 (m, 1H), 3.62-3.48 (m, 2H), 3.28-3.12 (m, 6H), 3.03-2.92 (m, 1H), 2.71-2.61 (m, 4H), 2.55-2.40 (m, 2H), 2.27-2.19 (m, 1H), 1.93 (t, 1H), 1.81-1.68 (m, 6H), 1.56-1.41 (m, 11H), 1.36-1.31 (m, 2H), 1.22 (d,J
= 6.8 Hz, 3H), 0.95 (d,J
= 6.8 Hz, 3H)。
呈白色固體的三級丁基 2-(2-(2-異丙基苯基)-6-側氧基-4-((5,6,7,8-四氫萘-1-基)甲基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(370 mg,0.63 mmol)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.27-7.16 (m, 3H), 7.12 (td, 1H), 7.03 (d,J
= 7.6 Hz, 1H), 6.96-6.81 (m, 2H), 6.72 (m, 1H), 4.92 (s, 1H), 4.48 (s, 1H), 3.57-3.49 (m, 2H), 3.30-3.04 (m, 6H), 2.94 (m, 1H), 2.73-2.57 (m, 4H), 2.36-2.10 (m, 4H), 1.90 (t, 1H), 1.71 (m, 2H), 1.63-1.58 (m, 1H), 1.55-1.41 (m, 13H), 1.36-1.29 (m, 2H), 1.20 (d,J
= 6.8 Hz, 3 H), 0.91 (d,J
= 6.8 Hz, 3H)。
步驟3:三級丁基 2-(2-(2-異丙基苯基)-4-((5,6,7,8-四氫萘-2-基)甲基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
在20°C下,向三級丁基 2-(2-(2-異丙基苯基)-6-側氧基-4-((5,6,7,8-四氫萘-2-基)甲基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(500 mg,0.86 mmol)在THF(8 mL)中之溶液中滴加BH3
.THF(16 mL,16 mmol)。將混合物加熱至70°C持續12小時。將反應藉由甲醇(5 mL)淬滅,在減壓下濃縮以給出呈白色固體的三級丁基 2-(2-(2-異丙基苯基)-4-((5,6,7,8-四氫萘-2-基)甲基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(488 mg,粗製)。MS (ESI, m/e) [M+1]+
572.5。
步驟4:2-(2-(2-異丙基苯基)-4-((5,6,7,8-四氫萘-2-基)甲基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷。
在20°C下,向三級丁基 2-(2-(2-異丙基苯基)-4-((5,6,7,8-四氫萘-2-基)甲基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(488 mg,0.85 mmol)在MeOH(5 mL)中之溶液中滴加HCl/MeOH(15 mL,4 M)。將溶液在20°C下攪拌2小時。將反應溶液在減壓下濃縮。將殘餘物用HCl(10 mL,1 M)稀釋,用EtOAc(10 mL × 2)萃取。將水相用NaHCO3
調節pH = 8,用EtOAc(20 mL × 3)萃取。將合併的有機相用無水Na2
SO4
乾燥,過濾並在減壓下濃縮以給出呈白色固體的2-(2-(2-異丙基苯基)-4-((5,6,7,8-四氫萘-2-基)甲基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷(311 mg,產率:77%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.47 (s, 1H), 7.26-7.15 (m, 2H), 7.11 (t, 1H), 6.99 (m, 3H), 3.66 (m, 1H), 3.48-3.30 (m, 3H), 3.03-2.82 (m, 3H), 2.82-2.39 (m, 10H), 2.37-2.08 (m, 3H), 1.79-1.60 (m, 6H), 1.41-1.11 (m, 12H)。MS (ESI, m/e) [M+1]+
472.4。
步驟1:三級丁基 2-(2-(2-異丙基苯基)-4-((5,6,7,8-四氫萘-1-基)甲基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
在20°C下,向三級丁基 2-(2-(2-異丙基苯基)-6-側氧基-4-((5,6,7,8-四氫萘-1-基)甲基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(370 mg,0.63 mmol)在THF(6 mL)中之溶液中滴加BH3
.THF(12 mL,12 mmol)。將混合物加熱至70°C持續12小時。將反應藉由甲醇(5 mL)淬滅,在減壓下濃縮以給出呈白色固體的三級丁基 2-(2-(2-異丙基苯基)-4-((5,6,7,8-四氫萘-1-基)甲基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(361 mg,粗製),其無需進一步純化即可直接用於下一步。MS (ESI, m/e) [M+1]+
572.5。
步驟2:2-(2-(2-異丙基苯基)-4-((5,6,7,8-四氫萘-2-基)甲基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷
在20°C下,向三級丁基 2-(2-(2-異丙基苯基)-4-((5,6,7,8-四氫萘-1-基)甲基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(361 mg,0.63 mmol)在MeOH(5 mL)中之溶液中滴加HCl/MeOH(10 mL,4 M)。將溶液在20°C下攪拌2小時。將反應溶液在減壓下濃縮。將殘餘物用HCl(10 mL,1 M)稀釋,用EtOAc(10 mL × 2)萃取。將水相用NaHCO3
調節pH = 8,用EtOAc(20 mL × 3)萃取。將合併的有機相經無水Na2SO4乾燥,過濾並真空濃縮以給出呈白色固體的2-(2-(2-異丙基苯基)-4-((5,6,7,8-四氫萘-2-基)甲基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷(245 mg,產率:83%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.51 (s, 1H), 7.21 (m, 2H), 7.16-7.09 (m, 2H), 7.02 (t, 1H), 6.99-6.92 (m, 1H), 3.64 (s, 2H), 3.45-3.36 (m, 2H), 3.08-2.86 (m, 3H), 2.82-2.45 (m, 10H), 2.39-2.14 (m, 3H), 1.83-1.63 (m, 6H), 1.42-1.06 (m, 12H)。MS (ESI, m/e) [M+1]+
472.4。
MS (ESI, m/e) [M+1]+
472.4。
步驟1:口克唍-4-甲腈。
在0°C下,向口克唍-4-酮(2.0 g,13.50 mmol)在DME(20 mL)和t-BuOH(5 mL)中之溶液中添加TosMIC(11.9 g,40.50 mmol)和t-BuOK(4.5 g,40.50 mmol)。將混合物在20°C下攪拌12小時。將反應混合物傾倒入水(20 mL)中,用EtOAc(50 mL × 3)萃取。將合併的有機相用鹽水(20 mL × 2)洗滌,用無水Na2
SO4
乾燥,過濾並真空濃縮。將粗產物藉由柱層析法(矽膠,洗脫液:PE/EA(v/v)= 100/1至1/1)純化以給出呈黃色油狀物的口克唍-4-甲腈(800 mg,5.03 mmol,產率:37%)。MS (ESI, m/e) [M+1]+
160.0。
步驟2:口克唍-4-甲酸。
在20°C下,向口克唍-4-甲腈(1.6 g,10.06 mmol)在MeOH(30 mL)和H2
O(5 mL)中之混合物中添加NaOH(2.0 g,50.26 mmol)。將混合物在100°C下攪拌12小時。向反應溶液中添加HCl(1 M)至pH = 1,將其用EtOAc(50 mL × 3)萃取。將合併的有機相用鹽水(20 mL)洗滌,用無水Na2
SO4
乾燥,過濾並真空濃縮以給出呈黃色油狀物的口克唍-4-甲酸(850 mg,粗製)。1
H NMR (400 MHz, DMSO-d6) δ ppm: 12.77-12.47 (m, 1H), 7.20 (d,J
= 7.6 Hz, 1H), 7.16-7.09 (m, 1H), 6.85 (m, 1H), 6.79-6.74 (m, 1H), 4.20-4.09 (m, 2H), 3.75 (m, 1H), 2.21-2.01 (m, 2H)。
步驟3:三級丁基 2-(4-(口克唍-4-羰基)-2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
向口克唍-4-甲酸(646 mg,3.62 mmol)在DMF(20 mL)中之溶液中添加DIEA(585 mg,4.53 mmol)、HATU(1.03 g,2.72 mmol),並添加三級丁基 2-(2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.0 g,2.26 mmol)持續3小時(在20°C下)。將反應混合物傾倒入水(50 mL),用EtOAc(50 mL × 3)萃取。將合併的有機相用鹽水洗滌,用無水Na2
SO4
乾燥,過濾並真空濃縮。將殘餘物藉由柱層析法(矽膠,洗脫液:PE/EA(v/v)= 100/1至1/1)純化以給出呈白色固體的三級丁基 2-(4-(口克唍-4-羰基)-2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.1 g,1.83 mmol,產率:82%)。1
H NMR (400 MHz, DMSO-d6) δ ppm: 7.50-7.39 (m, 1H), 7.37-7.19 (m, 2H), 7.17 (s, 1H), 7.04-6.90 (m, 1H), 6.89-6.69 (m, 2H), 6.68-6.54 (m, 1H), 5.41-5.27 (m, 1H), 4.82-4.45 (m, 2H), 4.37-4.15 (m, 1H), 4.13-3.94 (m, 2H), 3.92-3.70 (m, 1H), 3.60-3.38 (m, 2H), 3.20 (br s, 2H), 3.09 (br s, 2H), 2.17-1.73 (m, 4H), 1.68-1.52 (m, 2H), 1.49-1.39 (m, 2H), 1.35 (s, 9H), 1.30-1.15 (m, 8H), 0.91-0.56 (m, 1H)。
步驟4:三級丁基 2-(4-(口克唍-4-基甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
將三級丁基 2-(4-(口克唍-4-羰基)-2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.1 g,1.83 mmol)在BH3
.THF(20 mL,1 M,在THF中)中之溶液在20°C下持續12小時。將反應混合物冷卻至0°C。然後在0°C下滴加MeOH(10 mL),並將其真空濃縮以給出呈白色固體的三級丁基 2-(4-(口克唍-4-基甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.05 g,粗製)。MS (ESI, m/e) [M+1]+
574.4。
步驟5:2-(4-(口克唍-4-基甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷。
在20°C下,向三級丁基 2-(4-(口克唍-4-基甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.0 g,1.74 mmol)在MeOH(5 mL)中之溶液中添加HCl/MeOH(20 mL,4 M)。將混合物在20°C下攪拌2小時。將反應混合物真空濃縮,傾倒入H2
O(20 mL)中並用EtOAc(20 mL)萃取。向水相中添加飽和Na2
CO3
至pH = 10,將其用EtOAc(50 mL × 3)萃取。將合併的有機相用鹽水(20 mL × 2)洗滌,用無水Na2
SO4
乾燥,過濾並真空濃縮以給出呈白色固體的2-(4-(口克唍-4-基甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷(615 mg,374.47 umol,產率:74%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.61-7.40 (m, 1H), 7.28-6.98 (m, 5H), 6.92-6.72 (m, 2H), 4.21-4.10 (m, 2H), 3.73-3.59 (m, 1H), 3.49-3.33 (m, 1H), 3.07-2.80 (m, 4H), 2.65-2.44 (m, 6H), 2.37-2.07 (m, 4H), 2.05-1.87 (m, 2H), 1.82-1.64 (m, 2H), 1.39-1.14 (m, 13H)。MS (ESI, m/e) [M+1]+
474.4。
步驟1:苯并[b]噻吩-5-甲醛
在-60°C下,向5-溴苯并[b]噻吩(1.0 g,4.69 mmol)在THF(30 mL)中之溶液中添加i-PrMgCl.LiCl(25 mL,32.50 mmol)。將混合物在25°C下攪拌12小時。然後滴加DMF(5 mL)。將反應混合物藉由水性NH4
Cl(50 mL)淬滅並用EtOAc(100 mL × 2)萃取。將合併的有機層用鹽水洗滌,用無水Na2
SO4
乾燥,過濾並在減壓下濃縮。將粗產物藉由柱層析法(矽膠,洗脫液:PE/EA(v/v)= 20/1至10/1)純化以給出呈黃色油狀物的苯并[b]噻吩-5-甲醛(452 mg,產率:59%)。
步驟2:三級丁基 2-(4-(苯并[b]噻吩-5-基甲基)-2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
向三級丁基 2-(2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.0 g,2.26 mmol)在DCE(10 mL)中之溶液中添加AcOH(271.97 mg,4.53 mmol)和苯并[b]噻吩-5-甲醛(404.05 mg,2.49 mmol),將混合物在25°C下攪拌1 hr,然後添加NaBH(OAc)3
(1.44 g,6.79 mmol)。將混合物在25°C下再攪拌12小時。將反應混合物傾倒入飽和NaHCO3
(50 mL)中,用EtOAc(100 mL × 2)萃取。將合併的有機層用鹽水洗滌,用無水Na2
SO4
乾燥,過濾並在減壓下濃縮。將粗產物藉由柱層析法(矽膠,洗脫液:PE/EA(v/v)= 5/1至2/1)純化以給出呈黃色油狀物的三級丁基 2-(4-(苯并[b]噻吩-5-基甲基)-2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.2 g,2.04 mmol,產率:90%)。
步驟3:三級丁基 2-(4-(苯并[b]噻吩-4-基甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
對三級丁基 2-(4-(苯并[b]噻吩-5-基甲基)-2-(2-異丙基苯基)-6- 側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.2 g,2.04 mmol)和BH3
.THF(20.41 mL,20.41 mmol)在THF中之混合物在70°C下攪拌12小時。將反應溶液藉由MeOH(10 mL)淬滅,在減壓下濃縮以給出呈黃色油狀物的三級丁基 2-(4-(苯并[b]噻吩-5-基甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.26 g,粗製),其無需進一步反應即可直接用於下一步。MS (ESI, m/e) [M+1]+
574.3。
步驟4:2-(4-(苯并[b]噻吩-5-基甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷。
將三級丁基 2-(4-(苯并[b]噻吩-5-基甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.26 g,2.20 mmol)和TFA(5.1 mL,43.92 mmol)的混合物在25°C下攪拌2小時。將反應溶液在減壓下濃縮。將混合物傾倒入飽和NaHCO3
(50 mL)中,用EtOAc(100 mL × 2)萃取。將合併的有機層用鹽水洗滌,用無水Na2
SO4
乾燥,
過濾並在減壓下濃縮。將殘餘物藉由製備型HPLC(TFA條件)根據HPLC純化。將殘餘物用H2
O(20 mL)稀釋,向其中添加Na2
CO3
至pH = 9,將混合物用EtOAc(20 mL × 3)萃取。將合併的有機層用鹽水洗滌,經Na2
SO4
乾燥,過濾並在減壓下濃縮以給出呈黃色固體的2-(4-(苯并[b]噻吩-5-基甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷(132 mg,278.65 µmol,產率:13%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.80 (d,J
= 8.4 Hz, 1H), 7.75 (s, 1H), 7.48 (br s, 1H), 7.42 (d,J
= 5.6 Hz, 1H), 7.33 (m, 2H), 7.18-7.25 (m, 2H), 7.09-7.15 (m, 1H), 3.64 (m, 2H), 3.30-3.48 (m, 1H), 2.86-3.02 (m, 2H), 2.72 (m, 4H), 2.20-2.38 (m, 3H), 1.62-1.83 (m, 3H), 1.42 (br s, 4H), 1.23-1.28 (m, 4H), 1.13 (m, 4H), 0.89 (br s, 2H)。MS (ESI, m/e) [M+1]+
474.3。
步驟1:苯并[b]噻吩-4-基甲醇。
在0°C下,向苯并[b]噻吩-4-甲酸(900 mg,5.05 mmol)在DCM(10 mL)中之溶液中添加LAH(383.36 mg,10.10 mmol)。將混合物在25°C下攪拌1 hr。將反應混合物藉由水性NaOH(0.8 mL,25%)淬滅並用EtOAc(100 mL × 2)萃取。將合併的有機層用鹽水洗滌,用無水Na2
SO4
乾燥,過濾並在減壓下濃縮。將粗產物藉由柱層析法(矽膠,洗脫液:PE/EA(v/v)= 5/1至2/1)純化以給出呈黃色油狀物的苯并[b]噻吩-4-基甲醇(800 mg,4.87 mmol,產率:96%)。
步驟2:苯并[b]噻吩-4-甲醛。
將苯并[b]噻吩-4-基甲醇(800 mg,4.87 mmol)和MnO2
(4.24 g,48.71 mmol)在DCM(10 mL)中之混合物在50°C下攪拌3小時。將反應過濾並用EtOAc(100 mL × 2)萃取。將合併的有機層用鹽水洗滌,用無水Na2
SO4
乾燥,過濾並在減壓下濃縮。將粗產物藉由柱層析法(矽膠,洗脫液:PE/EA(v/v)= 5/1至2/1)純化以給出呈黃色油狀物的苯并[b]噻吩-4-甲醛(625 mg,3.85 mmol,產率:79%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 10.29-10.20 (s, 1H), 8.39 (d,J
= 5.6 Hz, 1H), 8.14 (d,J
= 8.0 Hz, 1H), 7.86 (d,J
= 7.6 Hz, 1H), 7.73 (d,J
= 5.6 Hz, 1H), 7.58-7.46 (m, 1H)。
步驟3:三級丁基 2-(4-(苯并[b]噻吩-4-基甲基)-2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯
向三級丁基 2-(2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.2 g,2.72 mmol)在DCE(10 mL)中之溶液中添加AcOH(326.36 mg,5.43 mmol)和苯并[b]噻吩-4-甲醛(484.86 mg,2.99 mmol)。將混合物在25°C下攪拌1 hr,將NaBH(OAc)3
(1.73 g,8.15 mmol)添加至溶液中。將混合物在25°C下再攪拌12小時。將反應混合物傾倒入飽和NaHCO3
(50 mL)中,用EtOAc(100 mL × 2)萃取。將合併的有機層用鹽水洗滌,用無水Na2
SO4
乾燥,過濾並在減壓下濃縮。將粗產物藉由柱層析法(矽膠,洗脫液 : PE/EA(v/v)= 5/1至2/1)純化以給出呈黃色油狀物的三級丁基 2-(4-(苯并[b]噻吩-4-基甲基)-2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(900 mg,1.53 mmol,產率:56%)。
步驟4:三級丁基 2-(4-(苯并[b]噻吩-4-基甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
將三級丁基 2-(4-(苯并[b]噻吩-4-基甲基)-2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(900 mg,1.53 mmol)和BH3
(15.31 mL,15.31 mmol)在DCM(10 mL)中之混合物在70°C下攪拌12小時。將反應溶液藉由MeOH(10 mL)淬滅,在減壓下濃縮以給出2-(4-(苯并[b]噻吩-4-基甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(850 mg,粗製),其無需進一步純化即可直接用於下一步。
步驟5:2-(4-(苯并[b]噻吩-4-基甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷。
將2-(4-(苯并[b]噻吩-4-基甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(850 mg,1.48 mmol)和HCl(3.70 mL,14.81 mmol)在MeOH(30 mL)中之混合物在25°C下攪拌2小時。將反應溶液在減壓下濃縮。將殘餘物傾倒入飽和NaHCO3
(50 mL)中,用EtOAc(100 mL × 2)萃取。將合併的有機層用鹽水洗滌,用無水Na2
SO4
乾燥,過濾並在減壓下濃縮。將殘餘物藉由製備型HPLC(TFA條件)根據HPLC純化。將殘餘物用H2
O(20 mL)稀釋,向其中添加Na2
CO3
至pH = 9,將混合物用EtOAc(20 mL × 3)萃取。將合併的有機層用鹽水洗滌,經Na2
SO4
乾燥,過濾並在減壓下濃縮以給出呈黃色油狀物的2-(4-(苯并[b]噻吩-4-基甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷(183 mg,386.31 µmol,產率:26%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.78 (d,J
= 7.6 Hz, 1H), 7.71-7.63 (m, 1H), 7.52-7.43 (m, 2H), 7.32-7.29 (m, 1H), 7.23-7.20 (m, 2H), 7.15-7.07 (m, 2H), 3.83 (s, 2H), 3.63 (m, 1H), 3.02-2.87 (m, 4H), 2.71-2.61 (m, 6H), 2.41-2.24 (m, 4H), 1.70-1.62 (m, 2H), 1.35 (m, 4H), 1.25 (br s, 3H), 1.14 (d,J
= 6.8 Hz, 3H), 1.07 (d,J
= 6.8 Hz, 3H)。MS (ESI, m/e) [M+1]+
474.3。
步驟1:三級丁基 2-(4-苯甲醯基-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
在25°C下,向三級丁基 2-(2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.1 g,2.57 mmol)在DCM(10 mL)中之溶液中添加TEA(1.04 g,10.29 mmol)持續30 min。然後在0°C下滴加苯甲醯氯(723.2 mg,5.14 mmol)。將混合物在0°C下攪拌1 hr。將反應混合物傾倒入飽和NH4
Cl(50 mL)中,用DCM(50 mL)萃取並在減壓下濃縮。將粗產物藉由柱層析法(矽膠,洗脫液:PE/EA(v/v)= 100/1至10/1)純化以給出呈黃色油狀物的三級丁基 2-(4-苯甲醯基-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(700 mg,1.32 mmol,產率:51%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.54-7.29 (m, 6H), 7.25-7.02 (m, 3H), 4.81-4.67 (m, 1H), 4.55-4.43 (m, 1H), 3.83 (br d, J=7.2 Hz, 1H), 3.46 (br s, 2H), 3.28-3.07 (m, 7H), 3.03-2.92 (m, 2H), 2.33-2.18 (m, 1H), 1.85-1.52 (m, 4H), 1.41 (s, 9H), 1.36-1.10 (m, 12H), 0.94 (br s, 2H)。
步驟2:(3-(2-異丙基苯基)-4-(7-氮雜螺[3.5]壬烷-2-基)哌𠯤-1-基)(苯基)甲酮
在25°C下,向三級丁基 2-(4-苯甲醯基-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(700 mg,1.32 mmol)在DCM(100 mL)中之混合物中添加TFA(3 mL)。將混合物在25°C下攪拌45 min。向反應溶液中添加水(40 mL),將其用EtOAc(50 mL)萃取。將水相用飽和Na2
CO3
調節pH至9-10。將所得混合物用EtOAc(50 mL × 3)萃取。將合併的有機相用鹽水洗滌,用無水Na2
SO4
乾燥,過濾並在減壓下濃縮以給出呈黃色油狀物的(3-(2-異丙基苯基)-4-(7-氮雜螺[3.5]壬烷-2-基)哌𠯤-1-基)(苯基)甲酮(390 mg,903.59 umol,產率:68%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.83 (d, J = 7.2 Hz, 1H), 7.57-7.30 (m, 7H), 7.22-7.09 (m, 2H), 4.74 (m, 1H), 4.41-4.79 (m, 1H), 3.63-3.39 (m, 2H), 3.21-3.07 (m, 2H), 3.07-2.83 (m, 2H), 2.75-2.49 (m, 4H), 2.31-2.13 (m, 1H), 1.69 (m, 2H), 1.42-1.15 (m, 10H), 1.06-0.81 (m, 1H)。MS (ESI, m/e) [M+1]+
432.3。
步驟1:三級丁基 2-(2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
向三級丁基 2-(2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(2.0 g,4.53 mmol)在THF(20 mL)中之溶液中添加BH3
.THF(30 mL,22.5 mmol)。將混合物加熱至70°C並在70°C下攪拌12小時。在冷卻至0°C後,將混合物用MeOH(10 mL)淬滅。將混合物真空濃縮以給出粗產物,將該粗產物藉由柱層析法純化以得到呈白色固體的三級丁基 2-(2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(0.7 g,產率:50%)。MS (ESI, m/e) [M+1]+
428.5
步驟2:三級丁基 2-(2-(2-異丙基苯基)-4-(4-甲氧基苯甲醯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
向三級丁基 2-(2-(2-異丙基苯基) 哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(700 mg,1.64 mmol)和4-甲氧基苯甲酸(274 mg,1.8 mmol)在DCM(10 mL)中之溶液中添加HATU(685 mg,1.8 mmol)和Et3
N(364 mg,3.6 mmol)。將混合物在25°C下攪拌16小時。將混合物傾倒入H2
O(20 mL)中,用DCM(20 mL)萃取。將合併的有機相用鹽水(20 mL)洗滌,用無水Na2
SO4
乾燥,過濾並真空濃縮。將殘餘物藉由柱層析法(矽膠,洗脫液:PE/EA(v/v)= 20/1至2/1)純化以給出呈黃色油狀物的三級丁基 2-(2-(2-異丙基苯基)-4-(4-甲氧基苯甲醯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(0.4 g,產率:60%)。MS (ESI, m/e) [M+1]+
562.3。
步驟3:(3-(2-異丙基苯基)-4-(7-氮雜螺[3.5]壬烷-2-基)哌𠯤-1-基)(4-甲氧基苯基)甲酮。
向三級丁基 2-(2-(2-異丙基苯基)-4-(4-甲氧基苯甲醯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(400 mg,0.71 mmol)在MeOH(10 mL)中之溶液中添加HCl/MeOH(10 mL)。將混合物在25°C下攪拌2小時。在真空濃縮後,將殘餘物溶解於水(20 mL)中。將混合物用水性Na2
CO3
調節pH = 9-10。將混合物用EtOAc(20 mL × 3)萃取。將合併的有機相用鹽水(20 mL × 2)洗滌,用無水Na2
SO4
乾燥,過濾並真空濃縮以給出呈白色固體的(3-(2-異丙基苯基)-4-(7-氮雜螺[3.5]壬烷-2-基)哌𠯤-1-基)(4-甲氧基苯基)甲酮(305 mg,產率:93%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.45-7.38 (m, 3H), 7.27-7.14 (m, 3H), 7.00-6.87 (m, 2H), 3.80 (s, 3H), 3.52-3.48 (m, 3H), 3.10-2.91 (m, 3H), 2.70-2.55 (m, 4H), 2.25-2.17 (m, 1H), 1.80-1.61 (m, 2H), 1.52-0.89 (m, 14H)。MS (ESI, m/e) [M+1]+
462.3
步驟1:三級丁基 2-(2-(2-異丙基苯基)-6-側氧基-4-(苯基磺醯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
向三級丁基 2-(2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(0.5 g,1.13 mmol)在DCM(6 mL)中之溶液中添加TEA(206 mg,2.04 mmol)。在冷卻至0°C後,添加苯磺醯氯(300 mg,1.7 mmol)。將混合物在25°C下攪拌2小時。將混合物傾倒入水(10 mL)中,用DCM(20 mL × 3)萃取。將合併的有機相真空濃縮。將殘餘物藉由柱層析法(矽膠,洗脫液:PE/EA(v/v)= 20/1至10/1)純化以給出呈黃色油狀物的三級丁基 2-(2-(2-異丙基苯基)-6-側氧基-4-(苯基磺醯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(0.6 g,產率:91%)。MS (ESI, m/e) [M+1]+
582.3
步驟2:三級丁基 2-(2-(2-異丙基苯基)-4-(苯基磺醯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
將三級丁基 2-(2-(2-異丙基苯基)-6-側氧基-4-(苯基磺醯基) 哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(0.6 g,1.03 mmol)和BH3
.THF(5 mL,5 mmol)的混合物加熱至70°C持續12小時。在冷卻至0°C後,將混合物用MeOH(10 mL)淬滅。將混合物真空濃縮以給出呈黃色油狀物的三級丁基 2-(2-(2-異丙基苯基)-4-(苯基磺醯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(0.45 g,產率:65%)。MS (ESI, m/e) [M+1]+
568.2。
步驟3:2-(2-(2-異丙基苯基)-4-(苯基磺醯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷
向三級丁基 2-(2-(2-異丙基苯基)-4-(苯基磺醯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(450 mg,0.79 mmol)在MeOH(10 mL)中之溶液中添加HCl/MeOH(10 mL)。將混合物在25°C下攪拌2小時。在真空濃縮後,將殘餘物溶解於水(20 mL)中。將混合物用水性Na2
CO3
調節pH = 9-10。將混合物用EtOAc(20 mL × 3)萃取。將合併的有機相用鹽水(20 mL × 2)洗滌,用無水Na2
SO4
乾燥,過濾並真空濃縮以給出呈白色固體的2-(2-(2-異丙基苯基)-4-(苯基磺醯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷(310 mg,產率:94%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.74-7.72 (m, 2H), 7.61 (m, 1H), 7.55-7.53 (m, 2H), 7.28-7.25 (m, 3H), 7.09-7.07 (m, 1H), 3.83-3.80 (m, 1H), 3.74-3.71 (m, 1H), 3.52-3.49 (m, 1H), 3.03-3.00 (m, 1H), 2.88-2.85 (m, 1H), 2.62-2.60 (m, 6H), 2.38-2.35 (m, 3H), 1.77-1.74 (m, 1H), 1.59-1.56 (m, 1H), 1.34-1.24 (m, 11H)。MS (ESI, m/e) [M+1]+
468.3
步驟1:1-苯基丁-2-炔-1-醇。
在-70°C下,向苯甲醛(4.0 g,37.69 mmol)在THF(100 mL)中之溶液中滴加在THF(0.5 M)中的丙-1-炔-1-基溴化鎂(90.5 mL,45.23 mmol)。將混合物溫熱至20°C並在20°C下攪拌12小時。在冷卻至0°C後,將混合物用飽和NH4
Cl水性(100 mL)淬滅。將混合物用EtOAc(50 mL × 2)萃取。將有機層經Na2
SO4
乾燥,真空蒸發以給出呈黃色油狀物的1-苯基丁-2-炔-1-醇(5.0 g,產率:90%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.46-7.44 (d,J
= 6.8 Hz, 2H), 7.31-7.24 (m, 3H), 5.34 (s, 1H), 2.17 (s, 1H), 1.83 (s, 3H)。
步驟2:1-苯基丁-2-炔-1-基 甲磺酸酯。
在25°C下,向1-苯基丁-2-炔-1-醇(2.5 g,17 mmol)和Et3
N(5.1 g,51 mmol)在DCM(25 mL)中之溶液中添加MsCl(2.15 g,18.8 mmol)。將混合物在25°C下攪拌1 hr。將混合物傾倒入H2
O(20 mL)中,用DCM(20 mL)萃取。將合併的有機相用鹽水(20 mL)洗滌,用無水Na2
SO4
乾燥,過濾並真空濃縮以給出呈黃色油狀物的殘餘物(2.6 g,產率:95%),其無需進一步純化而直接用於下一步。
步驟3:三級丁基2-(2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
向三級丁基 2-(2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(2.0 g,4.53 mmol)在THF(20 mL)中之溶液中添加BH3
.THF(30 mL,22.5 mmol)。將混合物加熱至70°C並在70°C下攪拌12小時。在冷卻至0°C後,將混合物用MeOH(10 mL)淬滅。將混合物真空濃縮以給出粗產物,將該粗產物藉由柱層析法純化以得到呈白色固體的三級丁基 2-(2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(0.7 g,產率:50%)。
步驟4:三級丁基 2-(2-(2-異丙基苯基)-4-(1-苯基丁-2-炔-1-基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
向三級丁基 2-(2-(2-異丙基苯基) 哌𠯤-1-基)-7-氮雜螺 [3.5] 壬烷-7-甲酸酯(0.7 g,1.64 mmol)在CH3
CN(20 mL)中之溶液中添加K2
CO3
(0.68 g,4.91 mmol)和1-苯基丁-2-炔-1-基甲磺酸酯(0.55 g,2.46 mmol)。將混合物在50°C下攪拌1 hr。在真空濃縮後,將殘餘物溶解於水(20 mL)中。將混合物用EtOAc(10 mL × 3)萃取。將合併的有機相用鹽水(10 mL × 2)洗滌,用無水Na2
SO4
乾燥,過濾並真空濃縮以給出呈黃色油狀物的三級丁基 2-(2-(2-異丙基苯基)-4-(1-苯基丁-2-炔-1-基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(240 mg,產率:27%)。
步驟5:2-(2-(2-異丙基苯基)-4-(1-苯基丁-2-炔-1-基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷。
向三級丁基 2-(2-(2-異丙基苯基)-4-(1-苯基丁-2-炔-1-基) 哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(240 mg,0.43 mmol)在MeOH(10 mL)中之溶液中添加HCl/MeOH(10 mL)。將混合物在25°C下攪拌2小時。在真空濃縮後,將殘餘物溶解於水(10 mL)中。將混合物使用水性Na2
CO3
調節pH = 9-10。將混合物用EtOAc(10 mL × 3)萃取。將合併的有機相用鹽水(10 mL × 2)洗滌,用無水Na2
SO4
乾燥,過濾並真空濃縮以給出呈黃色固體的2-(2-(2-異丙基苯基)-4-(1-苯基丁-2-炔-1-基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷(170 mg,產率:73%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.54-7.28 (m, 5H), 7.25-7.08 (m, 4H), 4.71-4.50 (d, 1H), 3.68-3.51 (m, 1H), 3.49-3.20 (m, 1H), 3.10-2.93 (m, 1H), 2.92-2.89 (m, 2H), 2.71-2.65 (m, 6H), 2.42-2.19 (m, 3H), 1.90 (s, 3H), 1.72-1.66 (m, 2H), 1.50-1.10 (m, 11H), 1.02-0.98 (m, 2H)。MS (ESI, m/e) [M+1]+
456.4。
步驟1:3-苯基環戊烷-1-酮。
向環戊-2-烯-1-酮(3.0 g,36 mmol)在甲苯(80 mL)和CHCl3
(0.4 mL)中之溶液中添加苯基硼酸(5.27 g,43 mmol)、Pd(OAc)2
(0.81 g,3.6 mmol)、PPh3
(1.9 g,7.2 mmol)和Cs2
CO3
(23 g,72 mmol)。將混合物加熱至80°C持續4小時。在冷卻至室溫後,過濾混合物。真空濃縮濾液。將殘餘物藉由柱層析法(矽膠,洗脫液:PE/EA(v/v)= 10/1)純化以給出呈棕色油狀物的3-苯基環戊烷-1-酮(2.8 g,產率:48%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.39-7.34 (m, 2H), 7.28 (m, 3H), 3.52-3.38 (m, 1H), 2.70 (m, 1H), 2.52-2.29 (m, 4H), 2.09-1.95 (m, 1H)。
步驟2:三級丁基 2-(2-(2-異丙基苯基)-6-側氧基-4-(3-苯基環戊基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
向三級丁基 2-(2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.0 g,2.26 mmol)在DCE(20 mL)中之溶液中添加3-苯基環戊烷-1-酮(540 mg,3.40 mmol)和HOAc(0.27 g,4.52 mmol)。在25°C下攪拌1 hr後,添加NaBH(OAc)3
(0.96 g,4.52 mmol)。將混合物在25°C下攪拌12小時。然後將水性NH4
Cl(20 mL)添加至混合物中,用DCM(20 mL × 3)萃取。將合併的有機相用鹽水(20 mL × 2)洗滌,用無水Na2
SO4
乾燥,過濾並真空濃縮。將殘餘物藉由柱層析法(矽膠,洗脫液:PE/EA(v/v)= 1/1)純化以給出呈黃色固體的三級丁基 2-(2-(2-異丙基苯基)-6-側氧基-4-(3-苯基環戊基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(0.66 g,產率:50%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.33-7.27 (m, 3H), 7.26-7.24 (m, 1H), 7.21-7.14 (m, 3H), 7.13-7.07 (m, 2H), 5.09 (br d,J
= 5.25 Hz, 1H), 4.25-4.10 (m, 1H), 3.44-3.10 (m, 8H), 3.09-2.88 (m, 2H), 2.82-2.65 (m, 1H), 2.64-2.47 (m, 1H), 2.32-2.09 (m, 2H), 2.05-1.95 (m, 2H), 1.94-1.78 (m, 2H), 1.76-1.51 (m, 5H), 1.42 (s, 9H), 1.39-1.35 (m, 2H), 1.31-1.25 (m, 6H)。
步驟3:三級丁基 2-(2-(2-異丙基苯基)-4-(3-苯基環戊基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
將三級丁基 2-(2-(2-異丙基苯基)-6-側氧基-4-(3-苯基環戊基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(0.66 g,1.13 mmol)和BH3
.THF(11 mL,11.3 mmol)的混合物加熱至70°C持續12小時。然後逐滴添加MeOH(10 mL)以淬滅反應。將混合物在減壓下濃縮以給出呈黃色油狀物的三級丁基 2-(2-(2-異丙基苯基)-4-(3-苯基環戊基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(0.6 g,產率:93%),其無需進一步純化即可直接使用。MS (ESI, m/e) [M+1]+
572.4。
步驟4:2-(2-(2-異丙基苯基)-4-(3-苯基環戊基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷。
向三級丁基 2-(2-(2-異丙基苯基)-4-(3-苯基環戊基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(600 mg,1.05 mmol)在MeOH(20 mL)中之溶液中添加HCl/MeOH(10 mL)。將混合物在25°C下攪拌1 hr。在除去溶劑後,將殘餘物溶解於水(20 mL)中。將混合物使用Na2
CO3
調節pH = 9-10,然後用EtOAc(20 mL × 3)萃取混合物。將合併的有機相用鹽水(20 mL × 2)洗滌,用無水Na2
SO4
乾燥,過濾並在減壓下濃縮以給出呈黃色固體的2-(2-(2-異丙基苯基)-4-(3-苯基環戊基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷(450 mg,產率:91%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.52 (br s, 1H), 7.32-7.28 (m, 1H), 7.26-7.11 (m, 7H), 3.70 (br s, 1H), 3.40 (br s, 1H), 3.13-3.00 (m, 3H), 2.92 (br s, 1H), 2.80 (m, 1H), 2.72-2.60 (m, 5H), 2.39-2.25 (m, 3H), 2.23-2.03 (m, 4H), 1.98-1.85 (m, 1H), 1.78 (m, 2H), 1.73-1.57 (m, 3H), 1.46-1.32 (m, 5H), 1.26-1.17 (m, 6H)。MS (ESI, m/e) [M+1]+
472.5。
步驟1:三級丁基 2-(2-異丙基苯基)-3-側氧基-4-苯基哌𠯤-1-甲酸酯。
向三級丁基 2-(2-異丙基苯基)-3-側氧基哌𠯤-1-甲酸酯(1.5 g,4.7 mmol)在DCE(150 mL)中之溶液中添加苯基硼酸(2.3 g,18.8 mmol)、Cu(OAc)2
(1.4 g,9.4 mmol)、4A MS(1.5 g)和TEA(9.5 g,94.2 mmol)。在O2
下,將混合物在75°C下攪拌12小時。將混合物過濾並濃縮以得到殘餘物,用1M HCl(50 mL)和EA(20 mL × 3)萃取。將合併的有機層乾燥並濃縮以得到殘餘物,藉由柱層析法(矽膠,洗脫液:PE/EA(v/v)= 20/1)純化。獲得呈棕色油狀物的化合物三級丁基 2-(2-異丙基苯基)-3-側氧基-4-苯基哌𠯤-1-甲酸酯(1.2 g,產率:64%)。
步驟2:3-(2-異丙基苯基)-1-苯基哌𠯤-2-酮。
將三級丁基 2-(2-異丙基苯基)-3-側氧基-4-苯基哌𠯤-1-甲酸酯(1.1 g,2.8 mmol)在TFA(5 mL)和DCM(5 mL)中之溶液在27°C下攪拌2小時。將混合物濃縮以得到殘餘物,用EA(30 mL × 3)和飽和NaHCO3
(30 mL)萃取。將合併的有機層乾燥並濃縮以給出呈棕色油狀物的、直接使用的3-(2-異丙基苯基)-1-苯基哌𠯤-2-酮(0.82 g,粗製)。
步驟3:三級丁基 2-(2-(2-異丙基苯基)-3-側氧基-4-苯基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
向3-(2-異丙基苯基)-1-苯基哌𠯤-2-酮(820 mg,2.8 mmol)在DCE(10 mL)中之溶液中添加三級丁基 2-側氧基-7-氮雜螺[3.5]壬烷-7-甲酸酯(666 mg,2.8 mmol)和NaBH(OAc)3
(1.2 g,5.6 mmol)。將混合物在27°C下攪拌10小時。將混合物用飽和NaHCO3
(50 mL)和DCM(20 mL × 3)萃取以給出呈黃色油狀物的、直接使用的三級丁基 2-(2-(2-異丙基苯基)-3-側氧基-4-苯基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.3 g,粗製)。
步驟4:三級丁基 2-(2-(2-異丙基苯基)-4-苯基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
將三級丁基 2-(2-(2-異丙基苯基)-3-側氧基-4-苯基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.2 g,2.3 mmol)在BH3-THF(10 mL)中之溶液在70°C下攪拌10小時。將混合物藉由MeOH(10 mL)淬滅並濃縮以給出呈黃色油狀物的、直接使用的三級丁基 2-(2-(2-異丙基苯基)-4-苯基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(2.1 g,粗製)。
步驟5:2-(2-(2-異丙基苯基)-4-苯基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷。
將三級丁基 2-(2-(2-異丙基苯基)-4-苯基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.1 g,2.2 mmol)在TFA(3 mL)和DCM(6 mL)中之溶液在20°C下攪拌2小時。將混合物濃縮以得到殘餘物,藉由製備型HPLC(TFA)純化。獲得呈白色固體的化合物 2-(2-(2-異丙基苯基)-4-苯基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷(570 mg,65%產率)。1
H NMR (400 MHz, METHANOL-d4) δ ppm: 7.53 (d,J
= 7.6 Hz, 1H), 7.36-7.31 (m, 1H), 7.29-7.14 (m, 4H), 6.93 (d,J
= 7.9 Hz, 2H), 6.83 (t,J
= 7.3 Hz, 1H), 3.82-3.70 (m, 2H), 3.49 (br d,J
= 6.3 Hz, 1H), 3.35 (td,J
= 2.6 Hz, 12.2 Hz, 1H), 3.17 (td,J
= 2.5 Hz, 11.5 Hz, 1H), 3.03-2.91 (m, 2H), 2.85 (dd,J
= 10.8 Hz, 12.1 Hz, 1H), 2.68-2.48 (m, 4H), 2.39 (dt,J
= 3.0 Hz, 11.8 Hz, 1H), 1.92-1.83 (m, 1H), 1.75-1.68 (m, 1H), 1.46-1.28 (m, 9H), 1.24 (d,J
= 6.9 Hz, 3H), 1.18-1.10 (m, 1H)。MS (ESI, m/e) [M+1]+
404.4。
步驟1:三級丁基 2-(2-(2-異丙基苯基)-4-(甲基磺醯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
向三級丁基 2-(2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.1 g,2.5 mmol)在DCM(20 mL)中之溶液中添加TEA(506 mg,5.0 mmol)。在冷卻至0°C後,添加MsCl(340 mg,3.0 mmol)。將混合物在25°C下攪拌2小時。將混合物傾倒入水性NH4
Cl(1M,20 mL),用DCM(20 mL × 3)萃取。將合併的有機相用鹽水(20 mL × 2)洗滌,用無水Na2
SO4
乾燥,過濾並真空濃縮。將殘餘物藉由柱層析法(矽膠,洗脫液:PE/EA(v/v)= 20/1至10/1)純化以給出呈黃色油狀物的三級丁基 2-(2-(2-異丙基苯基)-4-(甲基磺醯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.07 g,產率:82%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.41-7.37 (m, 1H), 7.36-7.31 (m, 1H), 7.18 (t, 1H), 6.97 (d,J
= 7.6 Hz, 1H), 5.11 (br s, 1H), 4.52 (br s, 1H), 4.18-4.08 (m, 2H), 4.01-3.94 (m, 1H), 3.71-3.54 (m, 2H), 3.30-3.09 (m, 5H), 2.37 (s, 3H), 2.26 (m, 1H), 1.93 (br t, 1H), 1.82-1.70 (m, 2H), 1.59 (m, 1H), 1.53-1.46 (m, 2H), 1.42 (s, 9H), 1.36 (m, 3H), 1.30 (m, 3H)。
步驟2:三級丁基 2-(2-(2-異丙基苯基)-4-(甲基磺醯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
將三級丁基 2-(2-(2-異丙基苯基)-4-(甲基磺醯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.07 g,2.06 mmol)和BH3
.THF(10 mL,10 mmol)的混合物加熱至70°C持續12小時。在冷卻至0°C後,將混合物用MeOH(10 mL)淬滅。將混合物真空濃縮以給出呈黃色油狀物的三級丁基 2-(2-(2-異丙基苯基)-4-(甲基磺醯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(0.8 g,產率:80%),其無需進一步純化即可用於下一步。MS (ESI, m/e) [M+1]+
506.3。
步驟3:2-(2-(2-異丙基苯基)-4-(甲基磺醯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷。
向三級丁基 2-(2-(2-異丙基苯基)-4-(甲基磺醯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(800 mg,1.58 mmol)在MeOH(20 mL)中之溶液中添加HCl/MeOH(10 mL)。將混合物在25°C下攪拌2小時。在真空濃縮後,將殘餘物溶解於水(20 mL)中。將混合物使用水性Na2
CO3
調節pH = 9-10。將混合物用EtOAc(20 mL × 3)萃取。將合併的有機相用鹽水(20 mL × 2)洗滌,用無水Na2
SO4
乾燥,過濾並真空濃縮以給出呈黃色固體的2-(2-(2-異丙基苯基)-4-(甲基磺醯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷(570 mg,產率:89%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.45 (m, 1H), 7.31-7.27 (m, 2H), 7.18-7.13 (m, 1H), 3.80 (m, 1H), 3.67 (m, 1H), 3.50 (m, 1H), 3.35 (br s, 1H), 3.12 (m, 1H), 2.99-2.91 (m, 2H), 2.77 (s, 3H), 2.67-2.57 (m, 4H), 2.33 (m, 1H), 1.91-1.75 (m, 3H), 1.66-1.60 (m, 1H), 1.39-1.29 (m, 5H), 1.25 (m, 3H), 1.20-1.13 (m, 3H), 1.16 (br s, 1H)。MS (ESI, m/e) [M+1]+
406.3。
步驟1:苄基 2-(2-異丙基苯基)-4-側氧基-3,4-二氫吡啶-1(2H)-甲酸酯。
在-20°C下,向4-甲氧基吡啶(1.82 g,17 mmol)在乾燥THF(50 mL)中之溶液中逐滴添加氯甲酸苄酯(3.2 mL,22 mmol)。將混合物在-20°C下攪拌1 hr。在25°C下,在N2
下,向另一個燒瓶中添加在THF(20 mL)中的菱鎂礦(magnesite)(0.9 g,38 mmol)。添加少量的I2
(22 mg,0.17 mmol),然後逐滴添加1-溴-2-異丙基苯(5.0 g,25 mmol)。將混合物加熱至70°C持續1 hr直到棕色完全消失。在-20°C下,將獲得的格林尼亞試劑溶液滴加至以上吡啶陽離子鹽中。將混合物在-20°C下攪拌1 hr。將混合物傾倒入HCl(1 M,50 mL)中,用EtOAc(20 mL × 3)萃取。將合併的有機相用鹽水(20 mL × 2)洗滌,用無水Na2
SO4
乾燥,過濾並真空濃縮。將殘餘物藉由柱層析法(矽膠,洗脫液:PE/EA(v/v)= 10/1)純化以給出呈棕色油狀物的苄基 2-(2-異丙基苯基)-4-側氧基-3,4-二氫吡啶-1(2H)-甲酸酯(5.5 g,產率:92%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 8.23 (d,J
= 8.4 Hz, 1H), 7.36-7.32 (m, 1H), 7.31-7.22 (m, 4H), 7.15-7.06 (m, 2H), 7.05-7.00 (m, 1H), 5.97 (d,J
=8.4 Hz, 1H), 5.37 (d,J
= 8.4 Hz, 1H), 5.22-5.11 (m, 2H), 3.38 (m, 1H), 3.06 (t, 1H), 2.24 (m, 1H), 1.23 (d,J
= 6.8 Hz, 3H), 1.05 (m, 3H)。
步驟2:苄基 2-(2-異丙基苯基)-4-側氧基哌啶-1-甲酸酯。
在25°C下,向苄基 2-(2-異丙基苯基)-4-側氧基-3,4-二氫吡啶-1(2H)-甲酸酯(5.5 g,0.016 mmol)在HOAc(20 mL)中之溶液中添加鋅(10 g,0.16 mmol)。將混合物在25°C下攪拌12小時。在過濾混合物後,將濾液真空濃縮。將殘餘物溶解於EtOAc(50 mL)中並用飽和NaHCO3
(30 mL × 2)、鹽水(30 mL × 2)洗滌。將有機層經無水Na2
SO4
乾燥,過濾並真空濃縮。將殘餘物藉由柱層析法(矽膠,洗脫液:PE/EA(v/v)= 1/1)純化以給出呈棕色油狀物的苄基 2-(2-異丙基苯基)-4-側氧基哌啶-1-甲酸酯(5.4 g,產率:96%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.33-7.28 (m, 5H), 7.23-7.11 (m, 4H), 5.87 (br s, 1H), 5.26-5.20 (m, 1H), 5.19-5.06 (m, 1H), 4.30 (br s, 1H), 3.35-3.11 (m, 2H), 2.87-2.80 (m, 2H), 2.59-2.46 (m, 2H), 1.20 (d,J
= 6.8 Hz, 3H), 1.03 (d,J
= 5.2 Hz, 3H)。
步驟3:苄基 (E)-4-亞苄基-2-(2-異丙基苯基)哌啶-1-甲酸酯
在0°C下,向溴化苄基三苯基磷鎓(4.44 g,10.24 mmol)在THF(40 mL)中之混合物中分幾批添加NaH(0.41 g,10.24 mmol)。在25°C下攪拌1 hr後,添加在THF(10 mL)中的苄基 2-(2-異丙基苯基)-4-側氧基哌啶-1-甲酸酯(3.0 g,8.54 mmol)。將混合物在25°C下攪拌12小時。將混合物小心地傾倒入水性NH4
Cl(10 mL)中,用EtOAc(50 mL × 2)萃取。將有機層經無水Na2
SO4
乾燥,過濾並真空濃縮。將殘餘物藉由柱層析法(矽膠,洗脫液:PE/EA(v/v)= 10/1)純化以給出呈黃色油狀物的苄基 (E)-4-亞苄基-2-(2-異丙基苯基)哌啶-1-甲酸酯(0.8 g,產率:22%)。MS (ESI, m/e) [M+1]+
426.4。
步驟4:4-苄基-2-(2-異丙基苯基)哌啶。
向苄基 (E)-4-亞苄基-2-(2-異丙基苯基)哌啶-1-甲酸酯(800 mg,1.88 mmol)在MeOH(30 mL)中之溶液中添加Pd(OH)2
/C(0.5 g)。將混合物在H2
(15 psi)氣氛下在30°C下攪拌12小時。在過濾後,將濾液真空濃縮以給出呈黃色油狀物的4-苄基-2-(2-異丙基苯基)哌啶(450 mg,產率:82%),其無需進一步純化即可用於下一步。MS (ESI, m/e) [M+1]+
294.4。
步驟5:三級丁基 2-(4-苄基-2-(2-異丙基苯基)哌啶-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
將4-苄基-2-(2-異丙基苯基)哌啶(450 mg,1.54 mmol)、三級丁基 2-側氧基-7-氮雜螺[3.5]壬烷-7-甲酸酯(611 mg,2.3 mmol)和AcOH(185 mg,3.08 mmol)在DCE(20 mL)中之溶液在25°C下攪拌1 hr,然後分批添加NaBH(OAc)3
(954 mg,4.5 mmol)並將其在25°C下攪拌12小時。將混合物傾倒入飽和NaHCO3
(20 mL)中,用DCM(20 mL × 3)萃取。將合併的有機相用鹽水(20 mL × 2)洗滌,用無水Na2
SO4
乾燥,過濾並真空濃縮。將殘餘物藉由柱層析法(矽膠,洗脫液:PE/EA(v/v)= 5/1)純化以給出呈棕色油狀物的三級丁基 2-(4-苄基-2-(2-異丙基苯基)哌啶-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(300 mg,產率:38%)。MS (ESI, m/e) [M+1]+
517.4。
步驟6:2-(4-苄基-2-(2-異丙基苯基)哌啶-1-基)-7-氮雜螺[3.5]壬烷。
向三級丁基 2-(4-苄基-2-(2-異丙基苯基)哌啶-1-基)-7-氮雜螺[3.5] 壬烷-7-甲酸酯(300 mg,0.58 mmol)在MeOH(20 mL)中之溶液中添加HCl/MeOH溶液(10 mL)。將混合物在25°C下攪拌1 hr。在除去溶劑後,將殘餘物傾倒入水(20 mL)中。將混合物使用水性Na2
CO3
調節pH至9-10。將混合物用EtOAc(20 mL × 3)萃取。將合併的有機相用鹽水(20 mL × 2)洗滌,用無水Na2
SO4
乾燥,過濾並真空濃縮。將殘餘物藉由製備型HPLC(TFA)純化以給出呈TFA鹽的2-(4-苄基-2-(2-異丙基苯基)哌啶-1-基)-7-氮雜螺[3.5]壬烷(200 mg,產率:83%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.58 (d,J
= 8.0 Hz, 1H), 7.47-7.38 (m, 2H), 7.33-7.23 (m, 5H), 7.22-7.17 (m, 1H), 4.84 (br s, 1H), 3.82 (m, 1H), 3.58-3.44 (m, 2H), 3.42-3.34 (m, 1 H), 3.07-2.93 (m, 6 H), 2.49-2.31 (m, 3H), 2.27-2.11 (m, 2H), 1.91 (m, 1H), 1.76-1.50 (m, 6H), 1.41 (d,J
= 6.8 Hz, 3H), 1.19 (d,J
= 6.8 Hz, 3H), 0.94-0.87 (m, 1H)。MS (ESI, m/e) [M+1]+
417.4。
步驟1:苄基 4-羥基-2-(2-異丙基苯基)哌啶-1-甲酸酯。
在0°C下,向苄基 2-(2-異丙基苯基)-4-側氧基哌啶-1-甲酸酯(2.6 g,7.4 mmol)在MeOH(20 mL)中之溶液中分幾批添加NaBH4
(0.56 g,14.8 mmol)。將混合物在25°C下攪拌1 hr。將混合物傾倒入H2
O(20 mL)中,用EtOAc(20 mL × 2)萃取。將合併的有機層用無水Na2
SO4
乾燥,過濾並真空濃縮。將殘餘物藉由柱層析法(矽膠,洗脫液:PE/EA(v/v)= 10/1)純化以給出呈棕色油狀物的苄基 4-羥基-2-(2-異丙基苯基)哌啶-1-甲酸酯(2.02 g,產率:78%)。MS (ESI, m/e) [M+1]+
354.4。
步驟2:苄基 2-(2-異丙基苯基)-4-苯氧基哌啶-1-甲酸酯。
向苄基 4-羥基-2-(2-異丙基苯基)哌啶-1-甲酸酯(2.02 g,5.71 mmol)在THF(50 mL)中之溶液中添加苯酚(0.59 g,6.59 mmol)和PPh3
(1.95 g,7.42 mmol)。在冷卻至0°C後,滴加DIAD(1.5 g,7.42 mmol)。將混合物在0°C-25°C下攪拌12小時。通在減壓下濃縮除去溶劑。將殘餘物藉由柱層析法(矽膠,洗脫液:PE/EA(v/v)= 10/1)純化以給出呈棕色油狀物的苄基 2-(2-異丙基苯基)-4-苯氧基哌啶-1-甲酸酯(1.5 g,產率:61%)。MS (ESI, m/e) [M+1]+
430.4。
步驟3:2-(2-異丙基苯基)-4-苯氧基哌啶。
向苄基 2-(2-異丙基苯基)-4-苯氧基哌啶-1-甲酸酯(1.5 g,3.5 mmol)在MeOH(30 mL)中之溶液中添加Pd(OH)2
/C(0.5 g)。在H2
(15 psi)下,將混合物在30°C下攪拌12小時。在過濾混合物後,將濾液真空濃縮以給出呈黃色油狀物的2-(2-異丙基苯基)-4-苯氧基哌啶(1.0 g,產率:99%),其無需進一步純化即可用於下一步。MS (ESI, m/e) [M+1]+
286.4。
步驟4:三級丁基 2-(2-(2-異丙基苯基)-4-苯氧基哌啶-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
向2-(2-異丙基苯基)-4-苯氧基哌啶(1.0 g,3.39 mmol)在DCE(20 mL)中之溶液中添加三級丁基 2-側氧基-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.8 g,6.77 mmol)和AcOH(410 mg,6.77 mmol)。在25°C下攪拌1 hr後,然後分批添加NaBH(OAc)3
(2.15 g,10.17 mmol)。將混合物在25°C下攪拌12小時。將混合物傾倒入飽和NaHCO3
(20 mL)中,用DCM(20 mL × 3)萃取。將合併的有機相用鹽水(20 mL × 2)洗滌,用無水Na2
SO4
乾燥,過濾並真空濃縮。將殘餘物藉由柱層析法(矽膠,洗脫液:PE/EA(v/v)= 5/1)純化以給出呈棕色油狀物的三級丁基 2-(2-(2-異丙基苯基)-4-苯氧基哌啶-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(400 mg,產率:23%)。MS (ESI, m/e) [M+1]+
519.4。
步驟5:2-(2-(2-異丙基苯基)-4-苯氧基哌啶-1-基)-7-氮雜螺[3.5]壬烷。
向三級丁基 2-(2-(2-異丙基苯基)-4-苯氧基哌啶-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(300 mg,0.58 mmol)在MeOH(20 mL)中之溶液中添加HCl/MeOH(10 mL,4 M)溶液。將混合物在25°C下攪拌2小時。在除去溶劑後,將殘餘物溶解於H2
O(20 mL)中。將混合物使用水性Na2
CO3
調節pH = 9-10。將混合物用EtOAc(20 mL × 3)萃取。將合併的有機相用鹽水(20 mL × 2)洗滌,用無水Na2
SO4
乾燥,過濾並真空濃縮以給出呈黃色固體的2-(2-(2-異丙基苯基)-4-苯氧基哌啶-1-基)-7-氮雜螺[3.5]壬烷(160 mg,產率:41%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.58-7.44 (m, 1H), 7.28-7.09 (m, 5H), 7.02-6.84 (m, 3H), 4.67 (br s, 1H), 3.92 (br d,J
= 8.4 Hz, 1H), 3.43-3.26 (m, 1 H), 3.04-2.85 (m, 2 H), 2.71-2.58 (m, 4 H), 2.55-2.47 (m, 1 H), 2.18 - 2.11 (m, 1H), 2.18-2.10 (m, 1H), 2.06-1.89 (m, 3H), 1.84-1.76 (m, 1H), 1.73-1.66 (m, 1H), 1.48-1.30 (m, 5H), 1.26 (d,J
= 6.8 Hz, 3H), 1.09 (m, 1H), 1.06-0.97 (d,J
= 6.8 Hz, 3H)。MS (ESI, m/e) [M+1]+
419.4。
步驟1:乙基 1-環丙基-1H-吡唑-4-甲酸酯。
向乙基 1H-吡唑-4-甲酸酯(5.0 g,35.68 mmol)、環丙基硼酸(5.82 g,67.79 mmol)、聯吡啶(5.57 g,35.68 mmol)、4A MS(1.0 g)和Na2
CO3
(7.18 g,67.79 mmol)在DCE(150 mL)中之混合物中添加Cu(OAc)2
(6.48 g,35.68 mmol)。在O2
(15 psi)下,將混合物在70°C下攪拌16小時。將混合物用EtOAc(300 mL)稀釋,通過矽藻土過濾。將濾液在減壓下濃縮。將粗品藉由柱層析法(矽膠,洗脫液:PE/EA(v/v)= 10/1至2/1)純化以給出呈淺黃色油狀物的乙基 1-環丙基-1H-吡唑-4-甲酸酯(5.95 g,產率:93%)。MS (ESI, m/e) [M+1]+
181.2。
步驟2:(1-環丙基-1H-吡唑-4-基)甲醇。
在0°C下,向乙基 1-環丙基-1H-吡唑-4-甲酸酯(5.9 g,32.74 mmol)在THF(80 mL)中之溶液中分批添加LAH(1.24 g,32.74 mmol)。將混合物在20°C下攪拌2小時。將混合物傾倒入水性NaOH(4 M,50 mL)中,通過矽藻土過濾,用EtOAc(100 mL × 3)萃取。將合併的有機相用鹽水洗滌,用無水Na2
SO4
乾燥,過濾並濃縮以給出呈黃色油狀物的(1-環丙基-1H-吡唑-4-基)甲醇(2.6 g,粗製)。MS (ESI, m/e) [M+1]+
139.2。
步驟3:1-環丙基-1H-吡唑-4-甲醛。
將(1-環丙基-1H-吡唑-4-基) 甲醇(2.6 g,18.82 mmol)和MnO2
(16.36 g,188.18 mmol)在DCM(60 mL)中之混合物在20°C下攪拌20小時。將混合物用DCM(200 mL)稀釋,通過矽藻土過濾。將濾液在減壓下濃縮以給出呈黃色油狀物的1-環丙基-1H-吡唑-4-甲醛(2.4 g,粗製)。
步驟4:三級丁基 2-(4-((1-環丙基-1H-吡唑-4-基)甲基)-2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
將三級丁基 2-(2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.0 g,2.26 mmol)、1-環丙基-1H-吡唑-4-甲醛(462.46 mg,3.40 mmol)和AcOH(271.97 mg,4.53 mmol)在DCE(20 mL)中之混合物在20°C下攪拌0.5 hr,然後將NaBH(OAc)3
(1.44 g,6.79 mmol)分批添加至以上混合物中,並在20°C下攪拌12小時。將混合物傾倒入飽和NaHCO3
(30 mL)中,用DCM(30 mL × 2)萃取。將合併的有機相用Na2
SO4
乾燥,過濾並在減壓下濃縮。將粗品藉由柱層析法(矽膠,洗脫液:EA/MeOH(v/v)= 1/0至100/1)純化以給出呈黃色固體的三級丁基 2-(4-((1-環丙基-1H-吡唑-4-基)甲基)-2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.2 g,產率:94%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.35-7.29 (m, 2H), 7.23-7.17 (m, 1H), 7.11 (d,J
= 8.0 Hz, 1H), 7.06 (s, 1H), 6.59 (s, 1H), 4.96 (s, 1H), 4.41 (s, 1H), 3.53-3.41 (m, 2H), 3.36 (m, 1H), 3.30-3.10 (m, 6H), 3.03 (m, 1H), 2.74-2.58 (m, 2H), 2.28-2.17 (m, 1H), 1.93 (m, 1H), 1.83-1.54 (m, 3 H), 1.52-1.40 (m, 11H), 1.36-1.33 (m, 1H), 1.26-1.22 (m, 3H), 1.12-1.00 (m, 4H), 0.89 (d,J
= 5.6 Hz, 3H)。
步驟5:三級丁基 2-(4-((1-環丙基-1H-吡唑-4-基)甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
在20°C下,向三級丁基 2-(4-((1-環丙基-1H-吡唑-4-基)甲基)-2- (2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.2 g,2.14 mmol)在THF(15 mL)中之溶液中滴加BH3
.THF(30 mL,30 mmol,1 M,在THF中)。將混合物加熱至75°C持續12小時。將反應藉由MeOH(5 mL)淬滅,在減壓下濃縮以給出呈白色固體的三級丁基 2-(4-((1-環丙基-1H-吡唑-4-基)甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.17 g,粗製)。MS (ESI, m/e) [M+1]+
548.5。
步驟6:2-(4-((1-環丙基-1H-吡唑-4-基)甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷。
將三級丁基 2-(4-((1-環丙基-1H-吡唑-4-基)甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.17 g,2.14 mmol)在HCl/EtOAc(20 mL,4 M)中之溶液在20°C下攪拌4小時。將反應溶液真空乾燥。將殘餘物用HCl(1 M,10 mL)稀釋,用EtOAc(10 mL × 2)萃取。將水相用水性Na2
CO3
調節pH = 10,用EtOAc(30 mL × 3)萃取。將合併的有機相用鹽水洗滌,用Na2
SO4
乾燥,過濾並在減壓下濃縮以給出呈黃色固體的2-(4-((1-環丙基-1H-吡唑-4-基)甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷(507 mg,產率:53%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.46 (s, 1H), 7.35 (d,J
= 7.6 Hz, 2H), 7.26-7.19 (m, 2H), 7.15-7.09 (m, 1H), 4.56 (s, 1H), 3.75-3.48 (m, 3H), 3.44-3.29 (m, 3H), 3.04-2.83 (m, 3H), 2.68 (m, 4H), 2.32-2.20 (m, 2H), 2.17-2.08 (m, 1H), 1.81-1.61 (m, 2H), 1.49-1.32 (m, 4H), 1.23 (d,J
= 7.02 Hz, 3H), 1.16 (d,J
= 6.8 Hz, 3H), 1.12-1.04 (m, 3H), 1.04-0.93 (m, 3H)。MS (ESI, m/e) [M+1]+
448.3。
步驟1:甲基 3-羥基-1H-吡唑-4-甲酸酯。
在20°C下,向二甲基 2-(甲氧基亞甲基)丙二酸酯(30 g,172.26 mmol)在MeOH(300 mL)中之溶液中滴加N2
H4
.H2
O(8.62 g,172.26 mmol)。將混合物加熱至70°C持續12小時。將反應混合物過濾,並將固體用石油醚洗滌。將濾餅真空乾燥以給出呈白色固體的甲基 3-羥基-1H-吡唑-4-甲酸酯(23.5 g,粗製)。1
H NMR (400 MHz, DMSO-d 6
) δ ppm: 12.30 (s, 1H), 10.47-9.71 (m, 1H), 7.93 (s, 1H), 3.67 (s, 3H)。
步驟2:甲基 3-甲氧基-1-甲基-1H-吡唑-4-甲酸酯。
在0°C下,在N2
保護下,向甲基 3-羥基-1H-吡唑-4-甲酸酯(10 g,70.37 mmol)和MeI(20.47 g,144.25 mmol)在DMF(200 mL)中之混合物中分批添加NaH(7.04 g,175.92 mmol)。將混合物在20°C下攪拌2小時。將混合物傾倒入飽和NH4
Cl(300 mL)中,用EtOAc(500 mL × 3)萃取。將合併的有機相用鹽水(1 L)洗滌,用無水Na2
SO4
乾燥,過濾並在減壓下濃縮。將粗品用H2
O(50 mL)稀釋,超音波10 min,過濾。將濾餅用石油醚洗滌,真空乾燥以給出呈黃色固體的甲基 3-甲氧基-1-甲基-1H-吡唑-4-甲酸酯(4.8 g,粗製),其無需進一步純化即可直接用於下一步。1
H NMR (400 MHz, DMSO-d 6
) δ ppm: 8.09 (s, 1H), 3.82 (s, 3H), 3.71 (s, 3H), 3.66 (s, 3H)。
步驟3:(3-甲氧基-1-甲基-1H-吡唑-4-基)甲醇。
在0°C下,向甲基 3-甲氧基-1-甲基-1H-吡唑-4-甲酸酯(4.8 g,28.21 mmol)在THF(72 mL)中之溶液中分批添加LiAlH4
(1.07 g,28.21 mmol)。將混合物在20°C下攪拌2小時。將反應混合物傾倒入水性NaOH(4 M,50 mL)中,通過矽藻土過濾,用EtOAc(100 mL × 3)萃取。將合併的有機相用鹽水(50 mL)洗滌,用無水Na2
SO4
乾燥,過濾並在減壓下濃縮以給出呈黃色油狀物的(3-甲氧基-1-甲基-1H-吡唑-4-基)甲醇(2.7 g,粗製),其無需進一步純化即可直接用於下一步。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.16 (s, 1H) 4.47 (s, 2H) 3.92 (s, 3H) 3.72 (s, 3H)
步驟4:3-甲氧基-1-甲基-1H-吡唑-4-甲醛。
將(3-甲氧基-1-甲基-1H-吡唑-4-基)甲醇(2.6 g,18.29 mmol)和MnO2
(15.9 g,182.90 mmol)在DCM(60 mL)中之混合物在20°C下攪拌20小時。將反應混合物用DCM(200 mL)稀釋,通過矽藻土過濾。將濾液在減壓下濃縮以給出呈綠色固體的3-甲氧基-1-甲基-1H-吡唑-4-甲醛(2.4 g,粗製),其無需進一步純化即可直接用於下一步。1
H NMR (400 MHz, CDCl3
) δ ppm: 9.72 (s, 1H), 7.67 (s, 1H), 3.94-4.04 (m, 3H), 3.78 (s, 3H)。
步驟5:三級丁基 2-(2-(2-異丙基苯基)-4-((3-甲氧基-1-甲基-1H-吡唑-4-基)甲基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
將三級丁基 2-(2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.0 g,2.26 mmol)、3-甲氧基-1-甲基-1H-吡唑-4-甲醛(476.01 mg,3.40 mmol)和AcOH(271.97 mg,4.53 mmol)在DCE(20 mL)中之混合物在20°C下攪拌0.5 hr。然後將NaBH(OAc)3
(1.44 g,6.79 mmol)分批添加至以上混合物中並在20°C下攪拌12小時。將混合物傾倒入飽和NaHCO3
(30 mL)中,用DCM(30 mL × 2)萃取。將合併的有機相用無水Na2
SO4
乾燥,過濾並在減壓下濃縮。將粗品藉由柱層析法(矽膠,洗脫液:EA/MeOH(v/v)= 1/0至100/1)純化以給出呈黃色固體的三級丁基 2-(2-(2-異丙基苯基)-4-((3-甲氧基-1-甲基-1H-吡唑-4-基)甲基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.16 g,產率:91%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.31 (d,J
= 3.2 Hz, 2H), 7.27-7.15 (m, 2H), 7.12-7.06 (m, 1H), 6.18 (s, 1H), 4.98 (s, 1H), 4.35 (s, 1H), 3.81 (s, 3H), 3.52 (s, 3H), 3.46-3.03 (m, 10H), 2.76-2.60 (m, 2H), 2.37-2.15 (m, 1H), 1.97-1.91 (m, 1H), 1.78 (s, 1H), 1.66 (m, 1H), 1.51-1.41 (m, 10H), 1.34 (d,J
= 4.88 Hz, 1H), 1.26 (d,J
= 6.8 Hz, 3H), 1.11 (d,J
= 6.8 Hz, 3H)。
步驟6:三級丁基 2-(2-(2-異丙基苯基)-4-((3-甲氧基-1-甲基-1H-吡唑-4-基)甲基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
在20°C下,向三級丁基 2-(2-(2-異丙基苯基)-4-((3-甲氧基-1-甲基-1H-吡唑-4-基)甲基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.16 g,2.05 mmol)在THF(15 mL)中之溶液中滴加BH3
.THF(30 mL,30 mmol,1 M,在THF中)。將混合物加熱至75°C持續12小時。將反應藉由MeOH(5 mL)淬滅,真空濃縮以給出呈白色固體的三級丁基 2-(2-(2-異丙基苯基)-4-((3-甲氧基-1-甲基-1H-吡唑-4-基)甲基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.13 g,粗製)。MS (ESI, m/e) [M+1]+
552.5。
步驟7:2-(2-(2-異丙基苯基)-4-((3-甲氧基-1-甲基-1H-吡唑-4-基)甲基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷。
在20°C下,向三級丁基 2-(2-(2-異丙基苯基)-4-((3-甲氧基-1-甲基-1H-吡唑-4-基)甲基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.13 g,2.05 mmol)在DCM(25 mL)中之溶液中滴加TFA(5 mL)。將混合物在20°C下攪拌12小時。將反應混合物在減壓下濃縮。將粗品藉由製備型HPLC純化,將溶液濃縮,用Na2
CO3
調節pH = 10,用EtOAc(50 mL × 5)萃取。將合併的有機相用無水Na2
SO4
乾燥,過濾並濃縮以給出呈白色固體的2-(2-(2-異丙基苯基)-4-((3-甲氧基-1-甲基-1H-吡唑-4-基)甲基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷(472 mg,產率:51%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.45 (s, 1H), 7.25-7.20 (m, 2H), 7.16-7.08 (m, 1H), 7.06 (s, 1H), 3.86 (s, 3H), 3.69 (s, 4H), 3.37 (m, 3H), 3.00-2.64 (m, 8H), 2.38-2.11 (m, 3H), 1.79 (s, 1H), 1.72-1.64 (m, 1H), 1.60-1.40 (m, 4H), 1.32-1.07 (m, 9H)。MS (ESI, m/e) [M+1]+
452.4。
步驟1:三級丁基 2-(2-(2-異丙基苯基)-4-((6-甲氧基吡啶-3-基)甲基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
將三級丁基 2-(2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.5 g,3.4 mmol)、6-甲氧基菸醛(698.7 mg,5.1 mmol)和AcOH(509.9 mg,8.49 mmol)在DCE(15 mL)中之溶液在25°C下攪拌15 min。然後分批添加NaBH(OAc)3
(1.44 g,6.79 mmol)。將混合物在20°C下攪拌12小時。將混合物傾倒入飽和NaHCO3
中以調節pH = 8,用DCM(50 mL × 3)萃取。將合併的有機相用鹽水(20 mL)洗滌,經Na2
SO4
乾燥並在減壓下濃縮。將殘餘物藉由柱層析法(矽膠,洗脫液:PE/EA(v/v)= 5/1至0/1)純化以給出呈黃色油狀物的三級丁基 2-(2-(2-異丙基苯基)-4-((6-甲氧基吡啶-3-基)甲基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.6 g,產率:83%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.82 (d,J
= 2.0 Hz, 1H), 7.33-7.27 (m, 2H), 7.22-7.16 (m, 1H), 7.12-7.07 (m, 1H), 6.91 (m, 1H), 6.42 (d,J
= 8.4 Hz, 1H), 4.94 (br s, 1H), 4.42 (br s, 1H), 3.87 (s, 3H), 3.54-3.45 (m, 2H), 3.33-3.08 (m, 7H), 2.98 (m, 1H), 2.74-2.66 (m, 1H), 2.62-2.55 (m, 1H), 2.28-2.17 (m, 1H), 1.98-1.88 (m, 1H), 1.81-1.66 (m, 2H), 1.53-1.40 (m, 12H), 1.22 (d,J
= 6.8 Hz, 3H), 0.97 (d,J
= 6.8 Hz, 3H)。
步驟2:三級丁基 2-(2-(2-異丙基苯基)-4-((6-甲氧基吡啶-3-基)甲基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
向三級丁基 2-(2-(2-異丙基苯基)-4-((6-甲氧基吡啶-3-基)甲基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.2 g,2.13 mmol)在THF(10 mL)中之溶液中添加BH3
.THF(10 mL)。將溶液在70°C下攪拌12小時。在冷卻至0°C後,然後在0°C下,滴加MeOH(30 mL)。將混合物在減壓下濃縮以給出呈白色固體的三級丁基 2-(2-(2-異丙基苯基)-4-((6-甲氧基吡啶-3-基)甲基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.6 g,粗製)。MS (ESI, m/e) [M+1]+
549.5。
步驟3:2-(2-(2-異丙基苯基)-4-((6-甲氧基吡啶-3-基)甲基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷。
在25°C下,向三級丁基 2-(2-(2-異丙基苯基)-4-((6-甲氧基吡啶-3-基)甲基) 哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.6 g,2.92 mmol)在DCM(20 mL)中之溶液中添加TFA(5 mL)。將溶液在25°C下攪拌5小時。將反應混合物傾倒入水性Na2
CO3
(20 mL)中,用DCM(50 mL × 3)萃取。將合併的有機層用鹽水洗滌,用無水Na2
SO4
乾燥,過濾並在減壓下濃縮以給出呈白色固體的2-(2-(2-異丙基苯基)-4-((6-甲氧基吡啶-3-基)甲基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷(1.31 g,產率:100%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 8.93 (br.s, 1H), 8.01 (s, 1H), 7.58-7.55 (m, 1H), 7.45 (s, 1H), 7.24-7.11 (m, 3H), 6.76-6.68 (m, 1H), 4.43-4.39 (m, 1H), 3.91 (s, 3H), 3.61-3.44 (m, 4H), 2.95-2.83 (m, 9H), 2.30-2.20 (m, 3H), 1.91-1.57 (m, 8H), 1.27-1.13 (m, 8H)。MS (ESI, m/e) [M+1]+
449.4。
步驟1:1-溴-2-環丙基苯。
在N2
下,將1-溴-2-碘苯(50 g,176.74 mmol)、環丙基硼酸(45.54 g,530.21 mmol)、K2
CO3
(73.28 g,530.21 mmol)和Pd(dppf)Cl2
(6.64 g,8.84 mmol)在二㗁𠮿(500 mL)中之混合物在75°C下攪拌48小時。將混合物用EtOAc(500 mL)稀釋,用矽藻土過濾並將濾液在減壓下濃縮。將殘餘物藉由柱層析法(矽膠,洗脫液 : PE)純化以給出呈淺黃色油狀物的1-溴-2-環丙基苯(28.9 g,產率:83%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.77 (d,J
= 8.4 Hz, 2H), 7.33 (d,J
= 8.0 Hz, 2H), 5.06-4.97 (m, 1H), 3.71 (t,J
= 4.8 Hz, 2H), 3.13-3.06 (m, 2H), 2.44 (s, 3H), 2.03 (s, 1H)。
步驟2:三級丁基 (2-((2-(2-環丙基苯基)-2-側氧基乙基)(4-甲氧基苄基)胺基)乙基)胺基甲酸酯。
在-70°C下,向1-溴-2-環丙基苯(5.07 g,25.75 mmol)在THF(170 mL)中之溶液中滴加n-BuLi(8.92 mL,2.5 M)。將溶液在-70°C下攪拌10 min。在-70°C下,滴加三級丁基 4-(4-甲氧基苄基)-2-側氧基哌𠯤-1-甲酸酯(5.5 g,17.17 mmol)在THF(30 mL)中之溶液。將溶液在-70°C下攪拌4小時。將混合物傾倒入飽和NH4
Cl(100 mL)中,用EtOAc(100 mL × 2)萃取。將合併的有機相經Na2
SO4
乾燥,過濾並在減壓下濃縮。將殘餘物藉由柱層析法(矽膠,洗脫液:PE/EA(v/v)= 25/1至15/1,0.2% DCM)純化以給出呈黃色油狀物的三級丁基 (2-((2-(2-環丙基苯基)-2-側氧基乙基)(4-甲氧基苄基)胺基)乙基)胺基甲酸酯(5.2 g,產率:69%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.37-7.31 (m, 1H), 7.25-7.15 (m, 4H), 7.00 (d,J
= 7.6 Hz, 1H), 6.85 (d,J
= 8.4 Hz, 2H), 5.18 (s, 1H), 3.82-3.72 (m, 7H), 3.23 (d,J
= 5.6 Hz, 2H), 2.79 (t,J
= 5.2 Hz, 2H), 2.34-2.10 (m, 1H), 1.45 (s, 9H), 0.93-0.85 (m, 2H), 0.65-0.59 (m, 2H)。
步驟3:3-(2-環丙基苯基)-1-(4-甲氧基苄基)哌𠯤
將三級丁基 (2-((2-(2-環丙基苯基)-2-側氧基乙基)(4-甲氧基苄基)胺基) 乙基)胺基甲酸酯(5.2 g,11.86 mmol)和TFA(15 mL)在DCM(45 mL)中之溶液在20°C下攪拌12小時。藉由在減壓下蒸發除去溶劑。將殘餘物溶解於DCE(60 mL)中並分批添加NaBH(OAc)3
(6.76 g,31.91 mmol)。將溶液在20°C下攪拌6小時。將混合物傾倒入水性NaHCO3
中以調節pH = 8,用DCM(50 mL × 3)萃取溶液。將合併的有機相用鹽水洗滌,經Na2
SO4
乾燥,過濾並在減壓下濃縮。將殘餘物藉由柱層析法(矽膠,洗脫液:PE/EA(v/v)= 2/1至EA/MeOH(v/v) = 10/1)純化以給出呈黃色油狀物的3-(2-環丙基苯基)-1-(4-甲氧基苄基)哌𠯤(3.8 g,產率:99%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.57-7.49 (m, 1H), 7.27-7.22 (m, 2H), 7.20-7.15 (m, 2H), 7.04-6.98 (m, 1H), 6.86 (d,J
= 8.8 Hz, 2H), 4.67 (d,J
= 9.6 Hz, 1H), 3.80 (s, 3H), 3.72-3.54 (m, 2H), 3.25-2.89 (m, 4H), 2.43 (s, 1H), 2.31-2.18 (m, 1H), 2.00-1.92 (m, 1H), 1.02-0.81 (m, 2H), 0.63-0.73 (m, 1H), 0.42-0.54 (m, 1H)。MS (ESI, m/e) [M+1]+
323.2。
步驟4:三級丁基 2-(2-(2-環丙基苯基)-4-(4-甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
將3-(2-環丙基苯基)-1-(4-甲氧基苄基)哌𠯤(1.5 g,4.65 mmol)、三級丁基 2-側氧基-7-氮雜螺[3.5]壬烷-7-甲酸酯(2.89 g,12.10 mmol)和NaBH3
CN(877.0 mg,13.96 mmol)在MeOH(10 mL)和AcOH(1 mL)中之溶液在65°C下攪拌24小時。將混合物傾倒入水性Na2
CO3
(20 mL)中以調節pH = 10,用EtOAc(30 mL x 2)萃取。將合併的有機相用鹽水洗滌,經Na2
SO4
乾燥,過濾並在減壓下濃縮。將殘餘物藉由柱層析法(矽膠,洗脫液:PE/EA(v/v)= 3/1至0/1)以給出呈黃色油狀物的三級丁基 2-(2-(2-環丙基苯基)-4-(4-甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.3 g,產率:51%)。MS (ESI, m/e) [M+1]+
546.5。
步驟5:2-(2-(2-環丙基苯基)-4-(4-甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷。
向三級丁基 2-(2-(2-環丙基苯基)-4-(4-甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.3 g,2.38 mmol)在DCM(15 mL)中之溶液中添加TFA(5 mL)。將溶液在20°C下攪拌2小時。將混合物在減壓下濃縮。將殘餘物傾倒入水性HCl(10 mL,1 M)中,用EtOAc(10 mL x 2)萃取。丟棄合併的有機相。將水層用Na2
CO3
調節pH = 10,用EtOAc(10 mL × 5)萃取。將合併的有機相用鹽水洗滌,經Na2
SO4
乾燥,過濾並在減壓下濃縮以給出呈黃色膠狀物的2-(2-(2-環丙基苯基)-4-(4-甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷(400 mg,產率:38%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.47 (s, 1H), 7.22 (d,J
= 8.4 Hz, 2H), 7.16-7.10 (m, 2H), 6.98 (s, 1H), 6.83 (d,J
= 8.8 Hz, 2H), 3.94 (s, 1H), 3.79 (s, 3H), 3.54-3.41 (m, 2H), 3.04-2.88 (m, 3H), 2.75-2.60 (m, 5H), 2.30 (s, 3H), 1.84-1.78 (m, 1H), 1.67-1.61 (m, 1H), 1.55 (d,J
= 5.6 Hz, 1H), 1.44-1.31 (m, 5H), 1.14-1.08 (m, 1H), 0.95-0.88 (m, 2H), 0.59 (s, 2H)。MS (ESI, m/e) [M+1]+
446.5。
步驟1:三級丁基 2-(4-(2,3-二甲氧基苄基)-2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
將三級丁基 2-(2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.0 g,2.26 mmol)、2,3-二甲氧基苯甲醛(333 mg,3.40 mmol)和AcOH(339 mg,5.66 mmol)在DCE(20 mL)中之溶液在25°C下攪拌1 hr,然後分批添加NaBH(OAc)3
(959 mg,4.53 mmol)並將其在25°C下攪拌11小時。將反應混合物藉由飽和Na2
CO3
(20 mL)淬滅,用EtOAc(20 mL × 3)萃取。將合併的有機層用鹽水洗滌,用無水Na2
SO4
乾燥,過濾並在減壓下濃縮。將粗產物藉由柱層析法(矽膠,洗脫液:PE/EA(v/v)= 50/1至0/1)純化以給出呈淺黃色油狀物的三級丁基 2-(4-(2,3-二甲氧基苄基)-2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.0 g,產率:74%)。
步驟2:三級丁基 2-(4-(2,3-二甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
將三級丁基 2-(4-(2,3-二甲氧基苄基)-2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.0 g,1.69 mmol)和BH3
.THF(50 mL,50.69 mmol)在THF(20 mL)中之混合物在70°C下攪拌12小時。在冷卻至0°C後,將反應溶液藉由MeOH(20 mL)淬滅並在0°C下攪拌1 hr。將混合物濃縮以給出呈白色固體的三級丁基 2-(4-(2,3-二甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.3 g,粗製),其無需進一步純化即可直接用於下一步。MS (ESI, m/e) [M+1]+
578.5。
步驟3:2-(4-(2,3-二甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷。
將三級丁基 2-(4-(2,3-二甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.3 g,2.25 mmol)在HCl/MeOH溶液(20 mL)中之混合物在20°C下攪拌3小時。將反應混合物傾倒入飽和Na2
CO3
(40 mL)中,用EtOAc(40 mL × 3)萃取。將合併的有機相用鹽水洗滌,用無水Na2
SO4
乾燥,過濾並在減壓下濃縮以給出呈淺粉色油狀物的2-(4-(2,3-二甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷(610 mg,產率:56%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.54-7.44 (m, 1H), 7.25-7.18 (m, 2H), 7.14-7.09 (m, 1H), 7.01-6.96 (m, 2H), 6.84-6.77 (m, 1H), 4.13-4.09 (m, 1H), 3.85 (s, 3H), 3.81 (s, 3H), 3.74-3.64 (m, 1H), 3.62-3.53 (m, 2H), 3.39 (m, 1H), 3.00-2.87 (m, 3 H), 2.75-2.60 (m, 6H), 2.39-2.22 (m, 3H), 1.80-1.62 (m, 3H), 1.44-1.33 (m, 4H), 1.26-1.24 (m, 3H), 1.16 (d,J
= 6.80 Hz, 3H)。MS (ESI, m/e) [M+1]+
478.3。
步驟1:三級丁基 2-(2-(2-異丙基苯基)-6-側氧基-4-(3,4,5-三甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
將三級丁基 2-(2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.0 g,2.26 mmol)、3,4,5-三甲氧基苯甲醛(666 mg,3.40 mmol)和AcOH(339 mg,5.66 mmol)在DCE(20 mL)中之溶液在25°C下攪拌1 hr,然後分批添加NaBH(OAc)3
(959 mg,4.53 mmol)並將其在25°C下攪拌12小時。將反應混合物藉由飽和Na2
CO3
(20 mL)淬滅,用EtOAc(20 mL × 3)萃取。將合併的有機層用鹽水洗滌,用無水Na2
SO4
乾燥,過濾並在減壓下濃縮。將粗產物藉由柱層析法(矽膠,洗脫液:PE/EA(v/v)= 50/1至0/1)純化以給出呈淺黃色油狀物的三級丁基 2-(2-(2-異丙基苯基)-6-側氧基-4-(3,4,5-三甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.0 g,產率:71%)。
步驟2:三級丁基 2-(2-(2-異丙基苯基)-4-(3,4,5-三甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
將三級丁基 2-(2-(2-異丙基苯基)-6-側氧基-4-(3,4,5-三甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.0 g,1.61 mmol)和BH3
.THF(48 mL,48.25 mmol)在THF(15 mL)中之混合物在70°C下攪拌12小時。在冷卻至0°C後,將混合物藉由MeOH(20 mL)淬滅並在0°C下攪拌1 hr。將混合物在減壓下濃縮以給出呈白色固體的三級丁基 2-(2-(2-異丙基苯基)-4-(3,4,5-三甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.3 g,粗製),其無需進一步反應即可直接用於下一步。MS (ESI, m/e) [M+1]+
608.5。
步驟3:2-(2-(2-異丙基苯基)-4-(3,4,5-三甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷。
將三級丁基 2-(4-(2,3-二甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.3 g,2.14 mmol)在HCl/MeOH溶液(20 mL)中之混合物在20°C下攪拌3小時。將反應混合物傾倒入飽和Na2
CO3
(40 mL)中,用EtOAc(40 mL × 3)萃取。將合併的有機相用無水Na2
SO4
乾燥,過濾並在減壓下濃縮以給出呈淺粉色油狀物的2-(2-(2-異丙基苯基)-4-(3,4,5-三甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷(630 mg,產率:56%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.54-7.46 (m, 1H), 7.26-7.18 (m, 2H), 7.15-7.10 (m, 1H), 6.56 (s, 2H), 3.85 (s, 6H), 3.81 (s, 3H), 3.76-3.61 (m, 2H), 3.54-3.32 (m, 3H), 3.08-2.99 (m, 1H), 2.98-2.88 (m, 2H), 2.70-2.50 (m, 5H), 2.38-2.27 (m, 2H), 2.18-2.10 (m, 1H), 1.82-1.73 (m, 1H), 1.72-1.64 (m, 2H), 1.42-1.28 (m, 5H), 1.27 (d,J
= 6.8 Hz, 3H), 1.15 (d,J
= 6.8 Hz, 3H)。MS (ESI, m/e) [M+1]+
508.3。
步驟1:4-(4-甲氧基苄基)哌𠯤-2-酮。
將哌𠯤-2-酮(25.0 g,249.7 mmol)、PMBCHO(37.4 g,274.6 mmol)和HOAc(30.0 g,499.4 mmol)在DCE(250 mL)中之溶液在20°C下攪拌0.5 hr,然後分批添加NaBH(OAc)3
(79.4 g,374.5 mmol)並將其在20°C下攪拌12小時。將混合物傾倒入飽和NaHCO3
中以調節pH = 8,用DCM(100 mL × 3)萃取。將合併的有機相用鹽水洗滌,經Na2
SO4
乾燥,過濾並在減壓下濃縮。將殘餘物藉由柱層析法(矽膠,洗脫液:PE/EA(v/v)= 10/1至0/1)純化以給出呈黃色固體的4-(4-甲氧基苄基)哌𠯤-2-酮(44 g,產率:80%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.22 (d,J
= 8.8 Hz, 2H), 6.87 (d,J
= 8.8 Hz, 2H), 6.37 (brs, 1H), 3.81 (s, 3H), 3.52 (s, 2H), 3.34 (t,J
= 4.0 Hz, 2H), 3.14 (s, 2H), 2.62 (t,J
= 5.6 Hz, 2H)。
步驟2:三級丁基 4-(4-甲氧基苄基)-2-側氧基哌𠯤-1-甲酸酯。
向4-(4-甲氧基苄基)哌𠯤-2-酮(44 g,199.7 mmol)和DMAP(4.88 g,39.9 mmol)在THF(500 mL)中之溶液中添加Boc2
O(87.2 g,399.5 mmol)(分批添加)。將溶液在20°C下攪拌12小時。將混合物傾倒入H2
O(100 mL)中,用EtOAc(100 mL × 3)萃取。將合併的有機相用鹽水洗滌,經Na2
SO4
乾燥,過濾並在減壓下濃縮。將殘餘物藉由柱層析法(矽膠,洗脫液:PE/EA(v/v)= 10/1至1/1)純化以給出呈黃色固體的三級丁基 4-(4-甲氧基苄基)-2-側氧基哌𠯤-1-甲酸酯(44 g,產率:69%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.23-7.20 (m, 2H), 6.88-6.86 (m, 2H), 3.81 (s, 3H), 3.67-3.64 (m, 2H), 3.49 (s, 2H), 3.23 (s, 2H), 2.66 (t,J
= 5.2 Hz, 2H)。
步驟3:三級丁基 (2-((2-(2-乙基苯基)-2-側氧基乙基)(4-甲氧基苄基)胺基)乙基)胺基甲酸酯。
在-70°C下,向1-溴-2-乙基苯(5.2 g,28.09 mmol)在THF(100 mL)中之溶液中滴加n-BuLi(9.7 mL,2.5 M)。將溶液在-70°C下攪拌0.5 hr。在-70°C下,滴加三級丁基 4-(4-甲氧基苄基)-2-側氧基哌𠯤-1-甲酸酯(6.0 g,18.73 mmol)在THF(20 mL)中之溶液。將溶液在-70°C下攪拌2小時。將混合物傾倒入飽和NH4
Cl(50 mL)中,用EtOAc(50 mL × 3)萃取。將合併的有機相用鹽水洗滌,經Na2
SO4
乾燥,過濾並在減壓下濃縮。將殘餘物藉由柱層析法(矽膠,洗脫液:PE/EA(v/v)= 20/1至5/1)純化以給出呈黃色油狀物的三級丁基 (2-((2-(2-乙基苯基)-2-側氧基乙基)(4-甲氧基苄基)胺基)乙基)胺基甲酸酯(6.5 g,產率:81%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.40-7.21 (m, 6H), 6.88-6.85 (m, 2H), 5.19 (s, 1H), 3.82-3.74 (m, 7H), 3.25-3.23 (m, 2H), 2.79-2.73 (m, 3H), 1.47 (s, 9H), 1.29-1.19 (m, 5H)。
步驟4:3-(2-乙基苯基)-1-(4-甲氧基苄基)哌𠯤
將三級丁基 (2-((2-(2-乙基苯基)-2-側氧基乙基)(4-甲氧基苄基)胺基)乙基) 胺基甲酸酯(4.0 g,9.38 mmol)和TFA(10 mL)在DCM(20 mL)中之溶液在20°C下攪拌3小時。藉由在減壓下蒸發除去溶劑。將殘餘物溶解於MeOH(20 mL)中並分批添加NaBH3
CN(2.95 g,46.89 mmol)。將溶液在20°C下攪拌12小時。將混合物傾倒入水性NaHCO3
中以調節pH = 8,用DCM(50 mL x 3)萃取溶液。將合併的有機相用鹽水洗滌,經Na2
SO4
乾燥,過濾並在減壓下濃縮。將殘餘物藉由柱層析法(矽膠,洗脫液:PE/EA(v/v)= 2/1至EA/MeOH(v/v)= 10/1)純化以給出呈黃色油狀物的3-(2-乙基苯基)-1-(4-甲氧基苄基)哌𠯤(2.2 g,產率:75%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.51 (d,J
= 7.2 Hz, 1H), 7.25-7.16 (m, 5H), 6.87 (d,J
= 8.8 Hz, 2H), 4.34 (d,J
= 8.8 Hz, 1H), 3.80 (s, 3H), 3.64 (s, 1H), 3.18-2.96 (m, 4H), 2.70-2.66 (m, 2H), 2.48-2.38 (m, 2H), 1.17-1.13 (m, 3H)。MS (ESI, m/e) [M+1]+
311.3。
步驟5:三級丁基 2-(2-(2-乙基苯基)-4-(4-甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
將3-(2-乙基苯基)-1-(4-甲氧基苄基)哌𠯤(2.2 g,7.09 mmol), 三級丁基 2-側氧基-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.87 g,7.80 mmol)和NaBH3
CN(890.7 mg,14.17 mmol)在MeOH(20 mL)和AcOH(2 mL)中之溶液在65°C下攪拌12小時。將混合物傾倒入水性NaHCO3
(20 mL)中以調節pH = 8,用EtOAc(30 mL × 3)萃取。將合併的有機相用鹽水洗滌,經Na2
SO4
乾燥,過濾並在減壓下濃縮。將殘餘物藉由柱層析法(矽膠,洗脫液:PE/EA(v/v)= 10/1至0/1)純化以給出呈黃色油狀物的三級丁基 2-(2-(2-乙基苯基)-4-(4-甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.2 g,產率:31%)。MS (ESI, m/e) [M+1]+
534.5。
步驟6:2-(2-(2-乙基苯基)-4-(4-甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷。
向三級丁基 2-(2-(2-乙基苯基)-4-(4-甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.2 g,2.25 mmol)在DCM(10 mL)中之溶液中添加TFA(5 mL)。將溶液在20°C下攪拌2小時。將混合物在減壓下濃縮。將殘餘物傾倒入水性HCl(20 mL,1 M)中,用EtOAc(10 mL × 2)萃取。丟棄合併的有機相。將水層用NaHCO3
溶液調節pH = 8,用EtOAc(20 mL × 3)萃取。將合併的有機相用鹽水洗滌,經Na2
SO4
乾燥,過濾並在減壓下濃縮以給出呈黃色固體的2-(2-(2-乙基苯基)-4-(4-甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷(413 mg,產率:43%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.47 (d,J
= 4.0 Hz, 1H), 7.22-7.11 (m, 5H), 6.84-6.80 (m, 2H), 3.78 (s, 3H), 3.52-3.45 (m, 3H), 2.99-2.61 (m, 10H), 2.27-2.10 (m, 3H), 1.75-1.60 (m, 2H), 1.35-1.18 (m, 6H), 1.16-1.10 (m, 4H)。MS (ESI, m/e) [M+1]+
434.4。
步驟1:4-(4-甲氧基苯基)環己烷-1-酮。
向4-(4-羥基苯基)環己烷-1-酮(1.0 g,5.26 mmol)在DMF(10 mL)中之溶液中添加K2
CO3
(2.54 g,18.40 mmol)和碘甲烷(7.64 g,52.57 mmol)。將混合物在80°C下攪拌12小時。將反應混合物傾倒入H2
O(50 mL)中,用EtOAc(100 mL × 2)萃取。將合併的有機層用鹽水洗滌,用無水Na2
SO4
乾燥,過濾並在減壓下濃縮。將粗產物藉由柱層析法(矽膠,洗脫液:PE/EA(v/v)= 5/1至2/1)純化以給出呈白色固體的4-(4-甲氧基苯基)環己烷-1-酮(1.05 g,產率:98%)。
步驟2:三級丁基 2-(2-(2-異丙基苯基)-4-(4-(4-甲氧基苯基)環己基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯
將三級丁基 2-(2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.0 g,2.34 mmol)、4-(4-甲氧基苯基)環己酮(525.44 mg,2.57 mmol)在DCE(10 mL)中之溶液和AcOH(280.86 mg,4.68 mmol)在25°C下攪拌1 hr,然後添加NaBH(OAc)3
(1.49 g,7.02 mmol)並將其在25°C下再攪拌11小時。將混合物傾倒入飽和NaHCO3
(50 mL)中,用EtOAc(100 mL × 2)萃取。將合併的有機層用鹽水洗滌,用無水Na2
SO4
乾燥,過濾並在減壓下濃縮。將殘餘物藉由柱層析法(矽膠,洗脫液:PE/EA(v/v)= 5/1至2/1)純化以給出呈白色固體的三級丁基 2-(2-(2-異丙基苯基)-4-(4-(4-甲氧基苯基)環己基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.24 g,產率:87%)。
步驟3:三級丁基 2-(2-(2-異丙基苯基)-4-(4-(4-甲氧基苯基)環己基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯
將三級丁基 2-(2-(2-異丙基苯基)-4-(4-(4-甲氧基苯基)環己基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.24 g,1.97 mmol)和BH3
.THF(19.69 mL,19.69 mmol)在THF(20 mL)中之混合物在70°C下攪拌12小時。將反應溶液藉由MeOH(20 mL)淬滅並在0°C下攪拌1 hr。將混合物在減壓下濃縮以給出呈白色油狀物的三級丁基 2-(2-(2-異丙基苯基)-4-(4-(4-甲氧基苯基)環己基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.28 g,粗製),其無需進一步純化即可直接用於下一步。
步驟4:2-(2-(2-異丙基苯基)-4-(4-(4-甲氧基苯基)環己基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷。
將三級丁基 2-(2-(2-異丙基苯基)-4-(4-(4-甲氧基苯基)環己基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.28 mg,2.08 mmol)和HCl(5.21 mL,20.78 mmol)在MeOH(10 mL)中之混合物在25°C下攪拌2小時。將反應溶液在減壓下濃縮。將反應混合物傾倒入飽和NaHCO3
(10 mL)中,用EtOAc(20 mL × 2)萃取。將合併的有機層用鹽水洗滌,用無水Na2
SO4
乾燥,過濾並在減壓下濃縮以給出呈白色固體的2-(2-(2-異丙基苯基)-4-(4-(4-甲氧基苯基)環己基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷(885 mg,產率:82%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.51 (br s, 1H), 7.26-7.08 (m, 5H), 6.89-6.80 (m, 2H), 3.83-3.77 (m, 3H), 3.68-3.56 (m, 1H), 3.42 (br s, 1H), 3.13-2.99 (m, 2H), 2.95-2.74 (m, 2H), 2.68-2.57 (m, 4H), 2.31-2.16 (m, 3H), 2.12-1.98 (m, 2H), 1.96-1.88 (m, 2H), 1.86-1.67 (m, 5H), 1.63-1.50 (m, 3H), 1.46-1.32 (m, 5 H), 1.30-1.25 (m, 4H), 1.24-1.14 (m, 4H)。MS (ESI, m/e) [M+1]+
516.3。
步驟1:三級丁基 2-(4-((2,3-二氫苯并[b][1,4]戴奧辛-6-基)甲基)-2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
將三級丁基 2-(2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.0 g,2.26 mmol)、2,3-二氫苯并[b][1,4]戴奧辛-6-甲醛(333 mg,3.40 mmol)和AcOH(339 mg,5.66 mmol)在DCE(20 mL)中之溶液在25°C下攪拌1 hr,然後添加NaBH(OAc)3
(959 mg,4.53 mmol)並將其在25°C下攪拌11小時。將反應混合物藉由飽和Na2
CO3
(20 mL)淬滅,用EtOAc(50 mL × 3)萃取。將合併的有機層用鹽水洗滌,用無水Na2
SO4
乾燥,過濾並在減壓下濃縮。將殘餘物藉由柱層析法(矽膠,洗脫液:PE/EA(v/v)= 50/1至0/1)純化以給出呈黃色油狀物的三級丁基 2-(4-((2,3-二氫苯并[b][1,4]戴奧辛-6-基)甲基)-2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.0 g,產率:74%)。
步驟2:三級丁基 2-(4-((2,3-二氫苯并[b][1,4]戴奧辛-6-基)甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
將三級丁基 2-(4-((2,3-二氫苯并[b][1,4]戴奧辛-6-基)甲基)-2-(2- 異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.0 g,1.70 mmol)和BH3
.THF(50 mL,50.87 mmol)在THF(20 mL)中之混合物在70°C下攪拌12小時。在冷卻至0°C後,將反應溶液用MeOH(20 mL)淬滅並在0°C下攪拌1 hr。將混合物在減壓下濃縮以給出呈白色固體的三級丁基2-(4-((2,3-二氫苯并[b][1,4]戴奧辛-6-基)甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.3 g,粗製),其無需進一步純化即可直接用於下一步。MS (ESI, m/e) [M+1]+
576.5。
步驟3:2-(4-((2,3-二氫苯并[b][1,4]戴奧辛-6-基)甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷。
在20°C下,向三級丁基 2-(4-((2,3-二氫苯并[b][1,4]戴奧辛-6-基)甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.0 g,2.25 mmol)的混合物中添加HCl/MeOH溶液(20 ml)持續3小時。將反應混合物傾倒入飽和Na2
CO3
(40 ml)中。將混合物用EtOAc(40 mL × 3)萃取。將合併的有機相用鹽水(40 mL × 2)洗滌,用無水Na2
SO4
乾燥,過濾並在減壓下濃縮以給出呈淺粉色油狀物的2-(4-((2,3-二氫苯并[b][1,4]戴奧辛-6-基)甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷(430 mg,0.904 mmol,40%產率)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.48 (br s, 1H), 7.25-7.18 (m, 2H), 7.15-7.09 (m, 1H), 6.83 (s, 1H), 6.77 (s, 2H), 4.23 (s, 4H), 3.64 (m, 1H), 3.52-3.33 (m, 2H), 3.03-2.84 (m, 3H), 2.71-2.54 (m, 5H), 2.28 (d,J
= 7.6 Hz, 2H), 2.19-2.13 (m, 1H), 1.78-1.71 (m, 1H), 1.69-1.63 (m, 1H), 1.39-1.23 (m, 8H), 1.15 (d,J
= 6.8 Hz, 4H)。MS (ESI, m/e) [M+1]+
476.4。
步驟1:三級丁基 2-(4-(2,3-二氫苯并[b][1,4]戴奧辛-5-羰基)-2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
在25°C下,向三級丁基 2-(2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.0 g,2.26 mmol)在DMF(10 mL)中之溶液中添加DIEA(386.69 mg,2.49 mmol)和2,3-二氫苯并[b][1,4]戴奧辛-5-甲酸(407.96 mg,2.26 mmol),然後添加HATU(336.58 mg,2.49 mmol),並將其在25°C下再攪拌12小時。將反應混合物傾倒入飽和NaHCO3
(50 mL)中,用EtOAc(100 mL × 2)萃取。將合併的有機層用鹽水洗滌,用無水Na2
SO4
乾燥,過濾並在減壓下濃縮。將殘餘物藉由柱層析法(矽膠,洗脫液:PE/EA(v/v)= 5/1至2/1)純化以給出呈黃色油狀物的三級丁基 2-(4-(2,3-二氫苯并[b][1,4]戴奧辛-5-羰基)-2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.1 g,產率:80%)。
步驟2:三級丁基 2-(4-((2,3-二氫苯并[b][1,4]戴奧辛-5-基)甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
將三級丁基 2-(4-(2,3-二氫苯并[b][1,4]戴奧辛-5-羰基)-2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.1 g,1.82 mmol)和BH3
.THF(18.22 mL,18.22 mmol)在THF(20 mL)中之混合物在70°C下攪拌12小時。將反應溶液用MeOH(20 mL)淬滅並在0°C下攪拌1 hr。將混合物在減壓下濃縮以給出呈黃色油狀物的三級丁基 2-(4-((2,3-二氫苯并[b][1,4]戴奧辛-5-基)甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(800 mg,粗製),其無需進一步純化即可直接用於下一步。MS (ESI, m/e) [M+1]+
576.4。
步驟3:2-(4-((2,3-二氫苯并[b][1,4]戴奧辛-5-基)甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷。
將三級丁基 2-(4-((2,3-二氫苯并[b][1,4]戴奧辛-5-基)甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(800 mg,1.39 mmol)和HCl(3.47 mL,3.47 mmol)在MeOH(10 mL)中之混合物在25°C下攪拌2小時。將反應溶液在減壓下濃縮。將反應混合物傾倒入飽和NaHCO3
(10 mL)中,用EtOAc(20 mL × 2)萃取。將合併的有機層用鹽水洗滌,用無水Na2
SO4
乾燥,過濾並在減壓下濃縮以給出呈黃色固體的2-(4-((2,3-二氫苯并[b][1,4]戴奧辛-5-基)甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷(213 mg,產率:33%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.47 (br s, 1H), 7.25-7.17 (m, 2H), 7.15-7.08 (m, 1H), 6.91 (d,J
= 4.8 Hz, 1H), 6.80-6.72 (m, 2H), 4.23 (s, 4H), 3.67 (br s, 1H), 3.62-3.51 (m, 2H), 3.41 (br s, 1H), 3.03-2.83 (m, 3H), 2.72 (m, 4H), 2.43-2.24 (m, 3H), 1.76 (br s, 1H), 1.72-1.64 (m, 1H), 1.39 (br s, 4H), 1.25 (d,J
= 6.8 Hz, 5H), 1.17 (d,J
= 6.8 Hz, 4H), 0.89 (br s, 1H)。MS (ESI, m/e) [M+1]+
476.5。 中間體 79-1a : (R)-2-(4-((2,3- 二氫苯并 [b][1,4] 戴奧辛 -5- 基 ) 甲基 )-2-(2- 異丙基苯基 ) 哌 𠯤 -1- 基 )-7- 氮雜螺 [3.5] 壬烷;和中間體 79-1b : (S)-2-(4-((2,3- 二氫苯并 [b][1,4] 戴奧辛 -5- 基 ) 甲基 )-2-(2- 異丙基苯基 ) 哌 𠯤 -1- 基 )-7- 氮雜螺 [3.5] 壬烷。
將化合物2-(4-((2,3-二氫苯并[b][1,4]戴奧辛-5-基)甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷(1.3 g,2.73 mmol)藉由SFC(儀器:Thar SFC80製備型SFC;柱:DAICEL Chiralpak IE 250 × 30 mm i.d. 10 u;流動相:A為CO2
並且B為EtOH(0.1%NH3
H2
O);梯度:B% = 54%等度洗脫模式;流速:80 g/min;波長:220 nm;柱溫:40°C;系統背壓:100巴)分離。
中間體 79-1a :
獲得呈黃色固體的化合物(R) -
2-(4-((2,3-二氫苯并[b][1,4]戴奧辛-5-基)甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷(381 mg,800.98 umol,產率:29%,純度:92.6%)(滯留時間:2.31 min)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.54-7.43 (m, 1H), 7.25-7.19 (m, 2H), 7.14-7.09 (m, 1H), 6.92-6.90 (m, 1H), 6.80-6.71 (m, 2H), 4.23 (s, 4H), 3.71-3.64 (m, 1H), 3.63-3.52 (m, 2H), 3.47-3.37 (m, 1H), 3.07-2.81 (m, 4H), 2.71 (br s, 1H), 2.68-2.55 (m, 4H), 2.43-2.22 (m, 3H), 2.22-2.04 (m, 1H), 1.80-1.73 (m, 1H), 1.69-1.63 (m, 1H), 1.43-1.29 (m, 5H), 1.27-1.25 (d,J
= 6.8 Hz, 3H), 1.17 (d,J
= 6.8 Hz, 3H)。MS (ESI, m/e) [M+1]+
476.5。
中間體 79-1b :
獲得呈黃色固體的化合物(S) -
2-(4-((2,3-二氫苯并[b][1,4]戴奧辛-5-基)甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷(272 mg,571.83 umol,產率:21%,純度:96.6%)(滯留時間:3.13 min)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.52-7.42 (m, 1H), 7.26-7.18(m, 2H), 7.15-7.08 (m, 1H), 6.91-6.90 (m, 1H), 6.80-6.72 (m, 2H), 4.23 (s, 4H), 3.71-3.64 (m, 1H), 3.63-3.51 (m, 2H), 3.47-3.35 (m, 1H), 3.06-2.85 (m, 3H), 2.72 (m, 1H), 2.66-2.56 (m, 3H), 2.47-2.19 (m, 3H), 1.89-1.60 (m, 4H), 1.46-1.27 (m, 5H), 1.26 (d,J
= 6.8 Hz, 3H), 1.17 (d,J
= 6.8 Hz, 3H)。MS (ESI, m/e) [M+1]+
476.5。
步驟1:3-(4-甲氧基苯基)環戊烷-1-酮
向環戊-2-烯-1-酮(1.0 g,12.18 mmol)在甲苯(50 mL)和CHCl3
(0.25 ml)中之溶液中添加Cs2
CO3
(7.94 g,24.36 mmol)、(4-甲氧基苯基)硼酸(2.22 g,14.62 mmol)、PPh3
(638.94 mg,2.44 mmol)和Pd(OAc)2
(638.94 mg,2.44 mmol)(在N2
下添加)。將混合物在80°C下攪拌24小時。將反應混合物傾倒入H2
O(50 mL)中,用EtOAc(100 mL × 2)萃取。將合併的有機層用鹽水洗滌,用無水Na2
SO4
乾燥,過濾並在減壓下濃縮。將粗產物藉由柱層析法(矽膠,洗脫液:PE/EA(v/v)= 10/1中5/1)純化以給出呈黃色油狀物的3-(4-甲氧基苯基)環戊烷-1-酮(1.5 g,產率:65%)。
步驟2:三級丁基 2-(2 (R或S)-2-(2-異丙基苯基)-4-(3-(4-甲氧基苯基)環戊基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
向三級丁基 (R或S)-2-(2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.0 g,2.26 mmol)在DCE(10 mL)中之溶液中添加AcOH(271.97 mg,4.68 mmol)和3-(4-甲氧基苯基)環戊酮(473.84 mg,2.49 mmol)。將混合物在25°C下攪拌1 hr,然後添加NaBH(OAc)3
(1.44 g,6.79 mmol)並將其在25°C下再攪拌11小時。將反應混合物傾倒入飽和NaHCO3
(50 mL)中,用EtOAc(100 mL × 2)萃取。將合併的有機層用鹽水洗滌,用無水Na2
SO4
乾燥,過濾並在減壓下濃縮。將粗產物藉由柱層析法(矽膠,洗脫液:PE/EA(v/v)= 5/1至2/1)純化以給出呈黃色固體的三級丁基 2-(2 (R或S)-2-(2-異丙基苯基)-4-(3-(4-甲氧基苯基)環戊基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.2 g,產率:86%)。
步驟3:三級丁基 2-(2(R或S)-2-(2-異丙基苯基)-4-(3-(4-甲氧基苯基)環戊基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
將三級丁基 2-((2R或2S)-2-(2-異丙基苯基)-4-(3-(4-甲氧基苯基)環戊基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.2 g,1.95 mmol)和BH3
.THF(19.49 mL,19.49 mmol)在THF(20 mL)中之混合物在70°C下攪拌12小時。將反應溶液藉由MeOH(20 mL)淬滅並在0°C下攪拌1 hr。將混合物在減壓下濃縮以給出呈白色油狀物的三級丁基 2-(2(R或S)-2-(2-異丙基苯基)-4-(3-(4-甲氧基苯基)環戊基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.2 g,粗製),其無需進一步純化即可直接用於下一步。
步驟4:2-(2 (R或S)-2-(2-異丙基苯基)-4-(3-(4-甲氧基苯基)環戊基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷。
將三級丁基 2-((2R或2S)-2-(2-異丙基苯基)-4-(3-(4-甲氧基苯基)環戊基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.2 g,1.99 mmol)和HCl(4.98 mL,19.94 mmol)在MeOH(10 mL)中之混合物在25°C下攪拌2小時。將反應溶液在減壓下濃縮。將反應混合物傾倒入飽和NaHCO3
(50 mL)中,用EtOAc(50 mL × 2)萃取。將合併的有機層用鹽水洗滌,用無水Na2
SO4
乾燥,過濾並在減壓下濃縮以給出呈黃色固體的2-(2 (R或S)-2-(2-異丙基苯基)-4-(3-(4-甲氧基苯基)環戊基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷(565 mg,產率:56%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.44 (br s, 1H), 7.28-7.22 (m, 1H), 7.21-7.08 (m, 4H), 6.85-6.77 (m, 2 H), 3.74-3.68 (m, 3H), 3.50 (br s, 1H), 3.09-2.69 (m, 5H), 2.68-2.55 (m, 3H), 2.15 (m, 2H), 1.84-2.04 (m, 4H), 1.71-1.34 (m, 6H), 1.30-1.20 (m, 8H), 1.19-1.03 (m, 5H), 0.87-0.81 (m, 2H)。MS (ESI, m/e) [M+1]+
502.5。
合成程序類似於中間體4-1。化合物2-(4-(3,4-二甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷係白色固體。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.49 (m, 1H), 7.21 (m, 2H), 7.15-7.07 (m, 1H), 6.89 (s, 1H), 6.82-6.73 (m, 2H), 3.89-3.87 (m, 3H), 3.85 (s, 3H), 3.68-3.60 (m, 1H), 3.46 (m, 2H), 3.42-3.30 (m, 1H), 3.01 (m, 1H), 2.95-2.86 (m, 2H), 2.70-2.52 (m, 5H), 2.29 (m, 2H), 2.15 (m, 1H), 1.81-1.72 (m, 1H), 1.70-1.63 (m, 1H), 1.38-1.27 (m, 5H), 1.25 (m, 3H), 1.14 (m, 4H)。MS (ESI, m/e) [M+1]+
478.5。
合成程序類似於中間體4-1。化合物2-(2-(2-異丙基苯基)-4-(4-(甲基磺醯基)苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷係黃色固體。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.87 (d,J
= 8.4 Hz, 2H), 7.58-7.45 (m, 3H), 7.25-7.19 (m, 2H), 7.16-7.10 (m, 1H), 3.69-3.55 (m, 3H), 3.37 (br s, 1H), 3.03 (s, 4H), 2.95-2.84 (m, 2H), 2.70-2.54 (m, 5H), 2.41-2.29 (m, 2H), 2.28-2.18 (m, 1H), 1.77 (br s, 1H), 1.71-1.62 (m, 1H), 1.45-1.29 (m, 5H), 1.29-1.24 (m, 4H), 1.13 (d,J
= 6.8 Hz, 4H)。MS (ESI, m/e) [M+1]+
496.3。
合成程序類似於中間體12-1。化合物6-(2-(2-異丙基苯基)-4-(4-甲氧基苄基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷係黃色固體。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.46 (br s, 1H), 7.25-7.18 (m, 4H), 7.14-7.08 (m, 1H), 6.82 (m, 2H), 3.78 (s, 3H), 3.62 (m, 1H), 3.55-3.49 (m, 1H), 3.48-3.30 (m, 5H), 2.90 (m, 2H), 2.70-2.61 (m, 2H), 2.29-2.21 (m, 2H), 2.17-2.06 (m, 2H), 2.02-1.94 (m, 1H), 1.59 (m, 1H), 1.38 (m, 1H), 1.24 (br d,J
= 6.8 Hz, 3H), 1.13 (br d,J
= 6. 8 Hz, 3H), 0.89-0.84 (m, 1H)。MS (ESI, m/e) [M+1]+
420.5。
合成程序類似於中間體4-1。化合物2-(4-(苯并呋喃-5-基甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷係白色固體。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.60 (d,J
= 2.0 Hz, 1H), 7.55-7.46 (m, 2H), 7.42 (d,J
= 8.4 Hz, 1H), 7.26-7.18 (m, 3H), 7.16-7.08 (m, 1H), 6.71 (d,J
= 2.0 Hz, 1H), 4.17-4.07 (m, 1H), 3.75-3.63 (m, 1H), 3.63-3.54 (m, 2H), 3.47-3.31 (m, 1H), 3.04-2.87 (m, 3H), 2.75-2.50 (m, 5H), 2.37-2.11 (m, 4H), 2.05 (s, 2H), 1.79-1.64 (m, 2H), 1.31-1.22 (m, 9H), 1.12 (br d,J
= 6.8 Hz, 3H)。MS (ESI, m/e) [M+1]+
458.5。
合成程序類似於中間體4-1。化合物2-(2-(2-異丙基苯基)-4-(吡啶-3-基甲基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷係黃色固體。1
H NMR (400 MHz, CDCl3
) δ ppm: 8.60-8.45 (m, 2H), 7.69-7.61 (m, 1H), 7.54-7.43 (m, 1H), 7.25-7.19 (m, 3H), 7.15-7.10 (m, 1H), 3.67-3.60 (m, 1H), 3.52 (s, 2H), 3.37 (m, 1H), 3.03-2.98 (m, 1H), 2.93-2.86 (m, 2H), 2.66-2.56 (m, 5H), 2.38-2.17 (m, 4 ), 1.78-1.73 (m, 1H), 1.72-1.60 (m, 2H), 1.37-1.28 (m, 5H), 1.25 (d,J
= 6.8 Hz, 3H), 1.13 (d,J
= 6.8 Hz, 3H)。MS (ESI, m/e) [M+1]+
419.5。
合成程序類似於中間體4-1。化合物6-(2-(2-異丙基苯基)-4-(4-甲氧基苯乙基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷係黃色固體。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.52 (br d,J
= 5.6 Hz, 1H), 7.20-7.27 (m, 2H), 7.12-7.17 (m, 1H), 7.06-7.11 (m, 2H), 6.82 (d,J
= 8.8 Hz, 2H), 3.78 (s, 3H), 3.67 (m, 1H), 3.31-3.54 (m, 4H), 2.95-3.07 (m, 3H), 2.70-2.80 (m, 4H), 2.52-2.61 (m, 2H), 2.31 (m, 2H), 2.14-2.25 (m, 2H), 2.07-2.15 (m, 1H), 2.02 (m, 1H), 1.59-1.73 (m, 1H), 1.34-1.46 (m, 1H), 1.25-1.28 (d,J
= 6.8 Hz, 3H), 1.22 (d,J
= 6.8 Hz, 3H)。MS (ESI, m/e) [M+1]+
434.5。
合成程序類似於中間體12-1。化合物2-(2-(2-異丙基苯基)-4-(4-甲氧基苄基)-5-甲基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷係黃色固體。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.62-7.50 (m, 1H), 7.25-7.17 (m, 3H), 7.15-7.08 (m, 1H), 6.82 (d,J
= 8.4 Hz, 2H), 3.79 (s, 3H), 3.63-3.45 (m, 3H), 3.37 (br s, 1H), 3.12-3.00 (m, 1H), 2.94-2.87 (m, 1H), 2.80 (m, 1H), 2.72-2.59 (m, 4H), 2.57 (m, 1H), 2.42-2.32 (m, 2H), 1.74-1.67 (m, 1H), 1.66-1.59 (m, 1H), 1.39-1.29 (m, 5H), 1.26 (br s, 1H), 1.23 (m, 7H), 1.11 (d,J
= 6.8 Hz, 3H)。MS (ESI, m/e) [M+1]+
462.5。
合成程序類似於中間體4-1。化合物2-(2-(2-異丙基苯基)-4-((4-甲氧基環己基)甲基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷係黃色固體。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.49 (br s, 1H), 7.26-7.19 (m, 2H), 7.15-7.10 (m, 1H), 3.61 (m, 1H), 3.39 (br s, 1H), 3.34 (s, 3H), 3.32-3.26 (m, 1H), 3.11-3.03 (m, 1H), 2.99 (m, 1H), 2.89 (m, 2H), 2.71-2.56 (m, 5H), 2.25 (m, 2H), 2.16-2.04 (m, 5H), 1.88-1.80 (m, 2H), 1.76 (m, 1H), 1.71-1.66 (m, 1H), 1.45-1.33 (m, 6H), 1.26 (m, 4H), 1.20 (d,J
= 6.8 Hz, 3H), 0.96-0.83 (d,J
= 6.8 Hz, 3H)。MS (ESI, m/e) [M+1]+
454.5。
合成程序類似於中間體4-1。化合物6-(2-異丙基苯基)-4-(4-甲氧基苄基)-1-(7-氮雜螺[3.5]壬烷-2-基)哌𠯤-2-酮係白色固體。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.30-7.28 (m, 2H), 7.21-7.17 (m, 1H), 7.12-7.10 (d,J
= 7.6 Hz, 1H), 6.78-6.75 (d,J
= 8.4 Hz, 2H), 6.63-6.61 (d,J
= 8.4 Hz, 2H), 4.96-4.94 (t, 1H), 4.42 (m, 1H), 3.73 (s, 3H), 3.51 (t, 2H), 3.27 (d,J
= 7.6Hz, 1H), 3.27 (d,J
= 16.4 Hz, 1H), 3.12 (d,J
= 16.4 Hz, 1H), 2.97-2.88 (m, 1H), 2.68-2.59 (m, 6H), 2.25 (t, 1H), 1.95-1.80 (t, 1H), 1.70-1.66 (m, 3H), 1.45 (m, 2H), 1.33 (m, 2H), 1.39-1.32 (m, 4H), 1.22 (d,J
= 6.8 Hz, 3H), 0.95 (d,J
= 6.8 Hz, 3H)。MS (ESI, m/e) [M+1]+
462.4。
合成程序類似於中間體4-1。化合物2-(4-(2-氯-4-甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷係黃色固體。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.49 (br s, 1 H), 7.35 (d,J
= 8.4 Hz, 1H), 7.25-7.18 (m, 2H), 7.15-7.09 (m, 1H), 6.88 (d,J
= 2.8 Hz, 1H), 6.78-6.74 (m, 1H), 4.71 (s, 1H), 4.50 (s, 1H), 3.81 (s, 1H), 3.78-3.77 (m, 3H), 3.64 (m, 1H), 3.57 (s, 2H), 3.43-3.34 (m, 1H), 3.02-2.86 (m, 3H), 2.79-2.57 (m, 5H), 2.44-2.36 (m, 1H), 2.31 - 2.23 (m, 2H), 1.81-1.71 (m, 1H), 1.71-1.65 (m, 1H), 1.52-1.29 (m, 5H), 1.25 (d,J
= 6.8 Hz, 3H), 1.15 (d,J
= 6.8 Hz, 3H)。MS (ESI, m/e) [M+1]+
482.5。
合成程序類似於中間體4-1。化合物2-(4-(2-氯苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷係黃色固體。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.51-7.47 (m, 1H), 7.32 (m, 1H), 7.27-7.05 (m, 4H), 3.69 (m, 1H), 3.64 (s, 2H), 3.39 (br s, 1H), 3.05-2.99 (m, 1H), 2.99-2.89 (m, 2H), 2.74-2.53 (m, 5H), 2.50-2.41 (m, 1H), 2.37-2.25 (m, 2H), 1.76 (m, 1H), 1.72-1.64 (m, 2H), 1.44-1.29 (m, 5H), 1.27 (d,J
= 6.8 Hz, 3H), 1.15 (br d,J
= 6.8 Hz, 3H)。MS (ESI, m/e) [M+1]+
452.4。
步驟1:5-溴-3-氟-1H-吡咯并[2,3-b]吡啶之合成
在20°C下,向5-溴-1H-吡咯并[2,3-b]吡啶(15.0 g,76.13 mmol)在MeCN(375 mL)和AcOH(75 mL)中之溶液中添加Selectfluor氟化試劑(40.4 g,114.19 mmol)。將溶液在90°C下攪拌12小時。藉由在真空下蒸發除去溶劑後,將殘餘物傾倒入水性NaHCO3
中。將混合物的pH值調節至8並用EtOAc(200 mL × 3)萃取。將合併的有機層用鹽水洗滌,經無水Na2
SO4
乾燥,過濾並在減壓下濃縮。將粗產物藉由柱層析法(矽膠,洗脫液:PE/EA(v/v)= 10/1至5/1)純化以給出5-溴-3-氟-1H-吡咯并[2,3-b]吡啶(10 g,粗製),將其直接用於下一步。
步驟2:3-氟-5-甲氧基-1H-吡咯并[2,3-b]吡啶之合成
向5-溴-3-氟-1H-吡咯并[2,3-b]吡啶(10 g,46.51 mmol)在DMF(320 mL)中之溶液中添加MeONa(348.8 mL,5.6 M)和CuBr(13.34 g,93.01 mmol)。將混合物在145°C下攪拌2小時。將混合物冷卻至室溫,傾倒入水性NH3
.H2
O(500 mL,17%)中並且然後用EtOAc(200 mL × 3)萃取。將合併的有機層用鹽水洗滌,用無水Na2
SO4
乾燥,過濾並在減壓下濃縮。將粗產物藉由柱層析法(矽膠,洗脫液:PE/EA(v/v)= 50/1至10/1)純化以給出3-氟-5- 甲氧基-1H-吡咯并[2,3-b]吡啶(1.2 g,產率:9%(兩個步驟中))。1
H NMR (400 MHz, CDCl3
) δ ppm: 9.03 (br, 1H), 8.12 (d,J
= 2.4 Hz, 1H), 7.43 (d,J
= 2.4 Hz, 1H), 7.08-7.03 (m, 1H), 3.91 (s, 3H)。
步驟3:3-氟-1H-吡咯并[2,3-b]吡啶-5-醇之合成
在-30°C下,向3-氟-5-甲氧基-1H-吡咯并[2,3-b]吡啶(1.4 g,8.43 mmol)在DCM(20 mL)中之溶液中滴加BBr3
(8.4 g , 33.7 mmol)。將混合物在25°C下攪拌2小時。將混合物傾倒入水性NaHCO3
溶液(50 mL,4 M)中,用DCM(50 mL × 3)萃取。將合併的有機層用鹽水洗滌,用無水Na2
SO4
乾燥,過濾並在減壓下濃縮。將粗產物藉由柱層析法(矽膠,洗脫液:PE/EA(v/v)= 50/1至10/1)純化以給出3-氟-1H-吡咯并[2,3-b]吡啶-5-醇(0.5 g,產率:39%)。
步驟4:甲基 4-氟-2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)苯甲酸酯之合成
向3-氟-1H-吡咯并[2,3-b]吡啶-5-醇(0.5 g,3.29 mmol)在DGDE(5 mL)中之溶液中添加甲基 2,4-二氟苯甲酸酯(1.13 g,6.57 mmol)和K3
PO4
(1.4 g,6.57 mmol)。將混合物在135°C下攪拌3小時。將混合物冷卻至室溫並且然後傾倒入H2
O(20 mL)中,用EtOAc(20 mL × 3)萃取。將合併的有機層用鹽水洗滌,用無水Na2
SO4
乾燥,過濾並在減壓下濃縮。將粗產物藉由柱層析法(矽膠,洗脫液:PE/EA(v/v)= 10/1)純化以給出呈黃色固體的甲基4-氟-2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)苯甲酸酯(0.35 g,產率:35%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 8.59 (br, 1H), 8.22 (d,J
= 2.8 Hz, 1H), 8.01-7.97 (m, 1H), 7.63 (d,J
= 2.8 Hz, 1H), 7.16-7.14 (m, 1H), 6.88-6.84 (m, 1H), 6.56-6.53 (m, 1H), 3.89 (s, 3H)。MS (ESI, m/e) [M+1]+
305.3。
合成程序類似於中間體12-1。化合物2-(2-(2-異丙基苯基)-4-(4-甲氧基苄基)-3-甲基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷。1H NMR (400 MHz, CDCl3
) δ ppm: 7.61-7.59 (m, 1H), 7.30-7.28 (m, 2H), 7.26-7.22 (m, 2H), 7.20-7.15 (m, 1H), 7.11-7.06 (m, 1H), 6.86-6.84 (m, 2H), 3.92-3.91 (m, 1H), 3.80 (s, 3H), 3.69-3.67 (m, 1H), 3.45-3.42 (m, 1H), 3.28-3.18 (m, 2H), 2.98-2.96 (m, 1H), 2.84-2.82 (m, 1H), 2.77-2.75 (m, 1H), 2.65-2.63 (m, 4H), 2.53-2.43 (m, 2H), 1.83-1.81 (m, 1H), 1.67-1.64 (m, 2H), 1.57-1.52 (m, 1H), 1.47-1.45 (m, 1H), 1.38-1.36 (m, 4H), 1.23-1.21 (m, 4H), 1.09 (d,J
= 6.8 Hz, 3H), 0.85 (d,J
= 6.8 Hz, 3H)。MS (ESI, m/e) [M+1]+
462.5。
步驟1:苄基 2-(2-環丙基苯基)-4-側氧基-3,4-二氫吡啶-1(2H)-甲酸酯。
將少量的I2
(10 mg,催化劑)添加至Mg(0.9 g,38 mmol)在THF(20 mL)中之溶液中(在25°C下在N2
下),然後逐滴添加1-溴-2-環丙基苯(5.0 g,25 mmol)。將混合物加熱至70°C持續1 hr直到棕色消失。在-20°C下,將格林尼亞試劑溶液滴加至獲得自在乾燥THF(50 mL)中的4-甲氧基吡啶(1.85 g,0.017 mol)和氯甲酸苄酯(3.2 mL,0.022 mol)的吡啶陽離子鹽中。將混合物在-20°C下攪拌1 hr。將HCl(1 M,50 mL)添加至混合物中,用EtOAc(20 mL × 3)萃取。將合併的有機相用鹽水(20 mL*2)洗滌,用無水Na2
SO4
乾燥,過濾並真空濃縮。將殘餘物藉由柱層析法(矽膠,洗脫液:PE/EA(v/v)= 10/1)純化以給出呈棕色油狀物的苄基 2- (2-環丙基苯基)-4-側氧基-3,4-二氫吡啶-1(2H)-甲酸酯(4.0 g,產率:68%)。1H NMR (400 MHz, CDCl3
) δ ppm: 8.20 (d,J
= 8.4 Hz, 1H), 7.40-7.27 (m, 3H), 7.21-7.08 (m, 5H), 6.26 (br d,J
= 8.8 Hz, 1H), 5.47 (d,J
= 8.4 Hz, 1H), 5.20-5.11 (m, 2H), 3.23-3.17 (m, 1H), 2.72 (d,J
= 16.4 Hz, 1H), 1.80 (br s, 1H), 0.98-0.83 (m, 2H), 0.72-0.49 (m, 2H)。
步驟2:苄基 2-(2-環丙基苯基)-4-側氧基哌啶-1-甲酸酯。
向苄基 2-(2-環丙基苯基)-4-側氧基-3,4-二氫吡啶-1(2H)-甲酸酯(4.0 g,11.51 mmol)在AcOH(40 mL)中之溶液中添加Zn(7.53 g,115.14 mmol)。將混合物在25°C下攪拌12小時。在過濾混合物後,將濾液真空濃縮。將殘餘物溶解於EtOAc(80 mL)中,將有機層用NaHCO3
水性(30 mL × 2)和鹽水(30 mL × 2)洗滌。將有機層乾燥,過濾並真空濃縮。將殘餘物藉由柱層析法(矽膠,洗脫液:PE/EA(v/v)= 1/1)純化以給出呈棕色油狀物的苄基 2-(2-環丙基苯基)-4-側氧基哌啶-1-甲酸酯(3.9 g,產率:96%),其無需進一步純化即可直接用於下一步。
步驟3:苄基 2-(2-環丙基苯基)-4-((4-甲氧基苄基)(甲基)胺基)哌啶-1-甲酸酯
將苄基 2-(2-環丙基苯基)-4-側氧基哌啶-1-甲酸酯(3.88 g,10.88 mmol)、1-(4-甲氧基苯基)-N-甲基甲胺(1.8 g,11.76 mmol)基和AcOH(1.31 g,21.75 mmol)在DCE(20 mL)中之混合物在25°C下攪拌1 hr。然後添加NaBH(OAc)3
(6.91 g,32.63 mmol)並將其在25°C下再攪拌12小時。將反應混合物傾倒入飽和NaHCO3
(50 mL)中,用EtOAc(100 mL × 2)萃取。將合併的有機層用鹽水洗滌,用Na2
SO4
乾燥,過濾並在減壓下濃縮。將粗產物藉由柱層析法(矽膠,洗脫液:PE/EA(v/v)= 5/1至2/1)純化以給出呈黃色油狀物的苄基 2-(2-環丙基苯基)-4-((4-甲氧基苄基)(甲基)胺基)哌啶-1-甲酸酯(3.3 g,產率:79%)。MS (ESI, m/e) [M+1]+
485.3
步驟4:2-(2-環丙基苯基)-N-(4-甲氧基苄基)-N-甲基哌啶-4-胺。
在0°C下,向苄基 2-(2-環丙基苯基)-4-((4-甲氧基苄基)(甲基)胺基) 哌啶-1-甲酸酯(3.3 g,6.81 mmol)在DCM(10 mL)中之溶液中添加TMSI(5.45 g,27.24 mmol)。將混合物在35°C下攪拌2小時。將反應混合物傾倒入水(50 mL)中,用EtOAc(100 mL × 2)萃取。將合併的有機層用鹽水洗滌,用無水Na2
SO4
乾燥,過濾並在減壓下濃縮。將粗產物藉由柱層析法(矽膠,洗脫液:PE/EA(v/v)= 5/1至2/1)純化以給出呈黃色油狀物的2-(2-環丙基苯基)-N-(4-甲氧基苄基)-N-甲基哌啶-4-胺(1.77 g,產率:74%)。MS (ESI, m/e) [M+1]+
351.3。
步驟5:三級丁基 2-(2-(2-環丙基苯基)-4-((4-甲氧基苄基)(甲基)胺基)哌啶-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
向2-(2-環丙基苯基)-N-(4-甲氧基苄基)-N-甲基哌啶-4-胺(1.0 g,2.85 mmol)在DCE(10 mL)中之溶液中添加AcOH(342.67 mg,5.71 mmol)和三級丁基 2-側氧基-7-氮雜螺[3.5]壬烷-7-甲酸酯(750.51 mg,3.14 mmol)。將混合物在25°C下攪拌1 hr。然後添加NaBH(OAc)3
(1.81 g,8.56 mmol)並將其在25°C下再攪拌12小時。將反應混合物傾倒入飽和NaHCO3
(50 mL)中,用EtOAc(100 mL × 2)萃取。將合併的有機層用鹽水洗滌,用無水Na2SO4乾燥,過濾並在減壓下濃縮。將粗產物藉由柱層析法(矽膠,洗脫液:PE/EA(v/v)= 5/1至2/1)純化以給出呈黃色油狀物的三級丁基 2-(2-(2-環丙基苯基)-4-((4-甲氧基苄基)(甲基)胺基)哌啶-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(870 mg,產率:60%)。
步驟6:2-(2-環丙基苯基)-N-(4-甲氧基苄基)-N-甲基-1-(7-氮雜螺[3.5]壬烷-2-基)哌啶-4-胺。
將三級丁基 2-(2-(2-環丙基苯基)-4-((4-甲氧基苄基)(甲基)胺基) 哌啶-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(870 mg,1.52 mmol)和HCl(3.79 mL,15.16 mmol)在MeOH(10 mL)中之混合物在25°C下攪拌2小時。將反應溶液在減壓下濃縮。將反應混合物傾倒入飽和NaHCO3
(50 mL)中,用EtOAc(50 mL × 2)萃取。將合併的有機層用鹽水洗滌,用無水Na2
SO4
乾燥,過濾並在減壓下濃縮以給出呈黃色固體的2-(2-環丙基苯基)-N-(4-甲氧基苄基)-N-甲基-1-(7-氮雜螺[3.5]壬烷-2-基)哌啶-4-胺(482 mg,產率:67%)。1H NMR (400 MHz, CDCl3
) δ ppm: 7.53 (br s, 1H), 7.26-19 (m, 2H), 7.18-7.07 (m, 2H), 7.05-6.91 (m, 1H), 6.89-6.81 (m, 2H), 3.82-3.80 (m, 3H), 3.57-3.44 (m, 2H), 3.21-3.19 (m, 1H), 3.03-2.95 (m, 1H), 2.90-2.84 (m, 1H), 2.74-2.51 (m, 5H), 2.21-2.11 (m, 4H), 2.04-1.62 (m, 7H), 1.55-1.19 (m, 6H), 1.10-1.00 (m, 1H), 0.99-0.85 (m, 2H), 0.72-0.61 (m, 2H)。MS (ESI, m/e) [M+1]+
474.34。
中間體
107-1
:
2-(4-((3,4-
二氫
-2H-
苯并
[b][1,4]
二㗁呯
-6-
基
)
甲基
)-2-(2-
異丙基苯基
)
哌
𠯤
-1-
基
)-7-
氮雜螺
[3.5]
壬烷。
合成程序類似於中間體4-1。化合物2-(4-((3,4-二氫-2H-苯并[b][1,4]二㗁呯-6-基)甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷係黃色固體。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.47 (s, 1H), 7.26-7.18 (m, 2H), 7.15-7.07 (m, 1H), 7.05-6.96 (m, 1H), 6.94-6.78 (m, 2H), 4.17-4.13 (m, 4H), 3.81-3.17 (m, 6H), 3.08-2.85 (m, 3H), 2.75-2.64 (m, 4 H), 2.44-2.10 (m, 5H), 1.83-1.59 (m, 2H), 1.42-1.39 (m, 4H), 1.32-1.22 (m, 5H) ,1.16 (d,J
= 6.8 Hz, 3H)。MS (ESI, m/e) [M+1]+
490.2。
合成程序類似於中間體4-1。化合物4-((3-(2-異丙基苯基)-4-(7-氮雜螺[3.5]壬烷-2-基)哌𠯤-1-基)甲基)-N,N-二甲基苯胺係黃色固體。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.56-7.41 (m, 1H), 7.25-7.19 (m, 2H), 7.18-7.10 (m, 3H), 6.68 (d,J
= 8.8 Hz, 2H), 3.66-3.64 (m, 1H), 3.52-3.35 (m, 3H), 2.99-2.87 (m, 9H), 2.72-2.59 (m, 5H), 2.29-2.24 (m, 2H), 2.21-2.10 (m, 2H), 1.76-1.74 (m, 1H), 1.69-1.63 (m, 1H), 1.36 (m, 5H), 1.25 (d,J
= 6.8 Hz, 3H), 1.16 (br d,J
= 6.8 Hz, 3H)。MS (ESI, m/e) [M+1]+
461.6。
合成程序類似於中間體4-1。化合物2-(4-(苯并[d][1,3]二氧雜環戊烯-4-基甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷係白色固體。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.46 (s, 1H), 7.26-7.18 (m, 2H), 7.15-7.08 (m, 1H), 6.84-6.68 (m, 3H), 5.91 (s, 2H), 3.69-3.63 (m, 1H), 3.56 (s, 2H), 3.39 (s, 1H), 3.12-2.80 (m, 5H), 2.75-2.55 (m, 5H), 2.43-2.18 (m, 3H), 1.81-1.71 (m, 1H), 1.68-1.62 (m, 1H), 1.47-1.32 (m, 4H), 1.24 (d,J
= 6.8 Hz, 3H), 1.16 (d,J
= 6.8 Hz, 4H)。MS (ESI, m/e) [M+1]+
462.5。
合成程序類似於中間體4-1。化合物2-(4-(3-氯-2-甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷係白色固體。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.41 (br s, 1H), 7.23-7.21 (m, 1H), 7.17-7.13 (m, 3H), 7.06-7.04 (m, 1H), 6.93-6.89 (m, 1H), 3.78 (s, 3H), 3.59-3.47 (m, 3H), 3.44 (br. s, 3H), 2.93-2.82 (m, 3H), 2.61-2.53 (m, 5H), 2.53-2.17 (m, 3H), 1.75-1.55 (m, 2H), 1.29-1.06 (m, 12H)。MS (ESI, m/e) [M+1]+
482.5。
合成程序類似於中間體4-1。化合物2-(4-(4-氟-3-甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷係黃色固體。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.61-7.42 (m, 1H), 7.25-7.19 (m, 2H), 7.15-7.10 (m, 1H), 7.00-6.94 (m, 2H), 6.82-6.79 (m, 1H), 3.89 (s, 3H), 3.65-3.63 (m, 1H), 3.48-3.35 (m, 3H), 3.03-2.98 (m, 1H), 2.94-2.87 (m, 2H), 2.74-2.52 (m, 6H), 2.36-2.25 (m, 2H), 2.19-2.13 (m, 1H) 1.77 (br s, 1H), 1.71-1.64 (m, 1H), 1.46-1.29 (m, 6H), 1.26 (d,J
= 6.8 Hz, 3H), 1.14 (d,J
= 6.8 Hz, 3H)。MS (ESI, m/e) [M+1]+
466.5。
合成程序類似於中間體18-1。化合物2-(4-(苯并[d][1,3]二氧雜環戊烯-5-基甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷係黃色固體。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.54-7.40 (m, 1H), 7.25-7.18 (m, 2H), 7.16-7.06 (m, 1H), 6.84 (s, 1H), 6.76-6.67 (m, 2H), 5.91 (s, 2H), 5.87-5.66 (m, 1H), 3.71-3.54 (m, 1H), 3.48-3.29 (m, 3H), 2.97-2.95 (m, 1 H), 2.93-2.83 (m, 2H), 2.78-2.62 (m, 4H), 2.31-2.21 (m, 2H), 2.21-2.11 (m, 1H), 1.83-1.74 (m, 1H), 1.72-1.61 (m, 1H), 1.55-1.36 (m, 4H), 1.31-1.21 (m, 5H), 1.14 (d,J
= 6.8 Hz, 4H)。MS (ESI, m/e) [M+1]+
462.4。
向甲基 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-氟苯甲酸酯(10 g,34.93 mmol)在DMF(100 mL)中之混合物中添加N-氯琥珀醯亞胺(4.88 g,36.68 mmol),並將其在室溫下攪拌16小時。將反應倒入鹽水(500 mL)中,過濾,並用水(200 mL × 3)洗滌,將沈澱固體過濾並真空乾燥以給出粗產物。將殘餘物放入DCM(50 mL)中並攪拌30分鐘。然後過濾並真空乾燥以給出呈灰白色固體的標題產物(9.3 g,產率:83.02%)。1
H NMR (400 MHz, DMSO-d 6
) δ ppm: 12.13 (s, 1H), 8.20-8.15 (m, 1H), 7.98-7.92 (m, 1H), 7.79-7.74 (m, 1H), 7.58 (s, 1H), 7.15-7.07 (m, 1H), 6.86-6.79 (m, 1H), 3.79 (s, 1H)。MS (ESI, m/e) [M+1]+
321.1。
合成程序類似於中間體4-1。化合物2-(2-(2-異丙基苯基)-4-(吡啶-2-基甲基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷係黃色固體。1
H NMR (400 MHz, CDCl3
) δ ppm: 8.56 (d,J
= 4.0 Hz, 1H), 7.64-7.60 (m, 1H), 7.49 (br s, 1H), 7.37 (d,J
= 7.6 Hz, 1H), 7.19-7.25 (m, 2H), 7.16-7.10 (m, 2H), 3.75-3.65 (m, 3H), 3.38 (br s, 1H), 3.00-2.98 (m, 1H), 2.96-2.89 (m, 2H), 2.72-2.64 (m, 3H), 2.64-2.59 (m, 2H), 2.44-2.35 (m, 2H), 2.33-2.22 (m, 2H), 2.15 (br s, 1H), 1.80-1.73 (m, 1H), 1.70-1.64 (m, 1H), 1.37-1.34 (m, 5H), 1.25 (d,J
= 6.8 Hz, 3H), 1.14 (d,J
= 6.8 Hz, 3H)。MS (ESI, m/e) [M+1]+
419.2。
合成程序類似於中間體109-1。化合物5-((3-(2-異丙基苯基)-4-(7-氮雜螺[3.5]壬烷-2-基)哌𠯤-1-基)甲基)-2-甲氧基苄腈係白色固體。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.57 (s, 1H), 7.45-7.43 (m, 2H), 7.25-7.20 (m, 2H), 7.14-7.11 (m, 1H), 6.88 (br d,J
= 8.4 Hz, 1H), 3.91 (s, 3H), 3.81-3.76 (m, 1H), 3.66-3.59 (m, 1H), 3.45 (br s, 1H), 3.35 (br s, 1H), 2.96-2.71 (m, 6H), 2.61 (s, 1H), 2.29-2.27 (m, 2H), 2.17 (br s, 1H), 1.86-1.69 (m, 3H), 1.38-1.29 (m, 4H), 1.27-1.26 (m, 2H), 1.15 (br d,J
= 6.8 Hz, 6H)。MS (ESI, m/e) [M+1]+
473.6。
合成程序類似於中間體4-1。化合物2-(4-(3-氟-4-甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷係黃色固體。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.48 (br s, 1H), 7.26-7.17 (m, 2H), 7.16-7.06 (m, 2H), 6.97 (d,J
= 8.4 Hz, 1H), 6.90-6.82 (m, 1H), 3.91-3.80 (m, 3H), 3.68-3.58 (m, 1H), 3.51-3.26 (m, 3H), 3.05-2.85 (m, 3H), 2.70-2.53 (m, 5H), 2.34-2.25 (m, 2H), 2.18-2.14 (m, 1H), 1.87-1.71 (m, 2H), 1.70-1.64 (m, 1H), 1.38 - 1.28 (m, 5H), 1.26 (d,J
= 6.8 Hz, 3H), 1.15 (d,J
= 6.8 Hz, 3H)。MS (ESI, m/e) [M+1]+
466.3。
合成程序類似於中間體4-1。化合物2-(4-(3-氯-4,5-二甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷係淡黃色固體。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.48-7.46 (m, 1H), 7.23-7.21 (m, 2H), 7.16-7.09 (m, 1H), 6.99-6.94 (m, 1H), 6.80 (s, 1H), 3.88-3.81 (m, 7H), 3.66-3.64 (m, 1H), 3.50-3.36 (m, 3H) 3.09-2.83 (m, 3H), 2.69-2.60 (m, 5H), 2.39-2.27 (m, 2H), 2.16-2.14 (m, 1H), 1.81-1.64 (m, 1H), 1.47-1.33 (m, 4H), 1.29-1.25 (m, 4H), 1.15 (d,J
= 6.8 Hz, 4H)。MS (ESI, m/e) [M+1]+
512.4。
步驟1:1-((2,3-二氫苯并[b][1,4]戴奧辛-5-基)甲基)-3-(2-異丙基苯基)哌𠯤。
將2-(2-異丙基苯基)哌𠯤(2.6 g,12.7 mmol)、2,3-二氫苯并[b][1,4]戴奧辛-5-甲醛(1.9 g,11.6 mmol)和NaBH(OAc)3
(4.9 g,23.2 mmol)在DCM(20 mL)中之混合物在20°C下攪拌12小時。將混合物藉由水性Na2
CO3
調節pH = 7,用DCM(20 mL × 2)萃取。將合併的有機層用鹽水洗滌,經無水Na2
SO4
乾燥,過濾並真空濃縮。將粗產物藉由柱層析法(矽膠,洗脫液:EA)純化以給出呈黃色固體的1-((2,3-二氫苯并[b][1,4]戴奧辛-5-基)甲基)-3-(2-異丙基苯基)哌𠯤(3.2 g,產率:78%)。MS (ESI, m/e) [M+1]+
353.3。
步驟2:三級丁基 6-(4-((2,3-二氫苯并[b][1,4]戴奧辛-5-基)甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-甲酸酯。
將1-((2,3-二氫苯并[b][1,4]戴奧辛-5-基)甲基)-3-(2-異丙基苯基)哌𠯤(3.2 g,8.97 mmol)、三級丁基 6-側氧基-2-氮雜螺[3.3]庚烷-2-甲酸酯(1.9 g,8.97 mmol)、AcOH(1.1 g,17.9 mmol)和NaBH3
CN(1.1 g,17.9 mmol)在MeOH(30 mL)中之混合物在75°C下攪拌12小時。將混合物藉由水性Na2
CO3
調節pH = 7,用DCM(40 mL × 2)萃取。將合併的有機層用鹽水(50 mL)洗滌,經無水Na2
SO4
乾燥,過濾並真空濃縮。將粗產物藉由柱層析法(矽膠,洗脫液:EA)純化以給出呈黃色固體的三級丁基 6-(4-((2,3-二氫苯并[b][1,4]戴奧辛-5-基)甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-甲酸酯(2.0 g,產率:41%)。MS (ESI, m/e) [M+1]+
548.5。
步驟3:6-(4-((2,3-二氫苯并[b][1,4]戴奧辛-5-基)甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷。
將三級丁基 6-(4-((2,3-二氫苯并[b][1,4]戴奧辛-5-基)甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-甲酸酯(2.0 g,3.65 mmol)在HCl/MeOH(40 mL)中之混合物在20°C下攪拌2小時。將反應混合物傾倒入飽和NaHCO3
(50 mL)中,用EtOAc(50 mL × 2)萃取。將合併的有機層用鹽水洗滌,用無水Na2
SO4
乾燥,過濾並在減壓下濃縮。將殘餘物藉由製備型HPLC(儀器:Shimadzu LC-8A製備型HPLC柱:Phenomenex luna C18(250 × 70 mm,15 um),流動相:A為H2
O(0.09% TFA)並且B為CAN,梯度:在20 min內B從15%至45%,流速:130 mL/min,波長:220 & 254 nm)純化以給出呈黃色固體的6-(4-((2,3-二氫苯并[b][1,4]戴奧辛-5-基)甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷(500 mg,產率:31%)。MS (ESI, m/e) [M+1]+
448.6
中間體
149-1a
:
(R)-6-(4-((2,3-
二氫苯并
[b][1,4]
戴奧辛
-5-
基
)
甲基
)-2-(2-
異丙基苯基
)
哌
𠯤
-1-
基
)-2-
氮雜螺
[3.3]
庚烷;和,中間體
149-1b
:
(S)-6-(4-((2,3-
二氫苯并
[b][1,4]
戴奧辛
-5-
基
)
甲基
)-2-(2-
異丙基苯基
)
哌
𠯤
-1-
基
)-2-
氮雜螺
[3.3]
庚烷。
將化合物6-(4-((2,3-二氫苯并[b][1,4]戴奧辛-5-基)甲基)-2-(2-異丙基苯基)哌𠯤-1-基) -2-氮雜螺[3.3]庚烷(500 mg,1.12 mmol)藉由SFC(儀器:Waters SFC 80製備型SFC;柱:Chiralpak IG,250 × 30 mm i.d.10 um;流動相:A為CO2
並且B為EtOH(0.1% NH3
H2
O);梯度:B% = 30%等度模式;流速:60 g/min;波長:220 nm;柱溫:40°C;系統背壓:100巴)分離。
中間體 149-1a :
獲得呈白色固體的化合物(R)-6-(4-((2,3-二氫苯并[b][1,4]戴奧辛-5-基)甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷(205 mg,0.56 mmol,產率:40%,純度:95%)(較快的峰,滯留時間:1.23 min)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.40-7.39 (m, 1H), 7.31-7.27 (m, 2H), 7.17-7.09 (m, 1H), 6.93-6.79 (m, 3H), 4.25 (s, 4H), 4.07-3.93 (m, 2H), 3.92-3.81 (m, 2H), 3.79-3.64 (m, 3H), 3.34-3.22 (m, 2H), 3.15-3.04 (m, 1H), 2.95 (m, 1H), 2.82-2.69 (m, 2H), 2.66-2.52 (m, 2H), 2.29-2.19 (m, 1H), 2.16-2.06 (m, 1H), 1.72-1.61 (m, 1H), 1.46-1.34 (m, 1H), 1.27 (m, 4H), 1.23 (br d,J
= 6.4 Hz, 3H), 1.18 (d,J
= 6.8 Hz, 3H), 0.95-0.79 (m, 1H)。MS (ESI, m/e) [M+1]+
448.5。
中間體 149-1b :
獲得呈白色固體的化合物 (S)-6-(4-((2,3-二氫苯并[b][1,4]戴奧辛-5-基)甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷(155 mg,0.34 mmol,產率:31%,純度:85%)(較慢的峰,滯留時間:1.29 min)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.51-7.40 (m, 1H), 7.25-7.16 (m, 2H), 7.14-7.05 (m, 1H), 6.94-6.86 (m, 1H), 6.80-6.69 (m, 2H), 4.23-4.22 (m, 4H), 3.70-3.62 (m, 1H), 3.60-3.51 (m, 2H), 3.46-3.31 (m, 2H), 3.04-2.83 (m, 4H), 2.75-2.64 (m, 2H), 2.45-2.17 (m, 3H), 2.01-1.82 (m, 4H), 1.64-1.51 (m, 1H), 1.25-1.21 (m, 3H), 1.16 (t,J
= 6.4 Hz, 3H), 0.66 (d,J
= 6.0 Hz, 1H)。MS (ESI, m/e) [M+1]+
448.6。
合成程序類似於中間體105-1。化合物2-(2-異丙基苯基)-N-(4-甲氧基苯基)-N-甲基-1-(7-氮雜螺[3.5]壬烷-2-基)哌啶-4-胺係黃色固體。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.50-7.48 (m, 1H), 7.23-7.15 (m, 2H), 7.14-7.07 (m, 1H), 7.06-7.04 (m, 1H), 6.86-6.77 (m, 3H), 3.97-3.96 (m, 1H), 3.78-3.74 (m, 3H), 3.35-3.27 (m, 1H), 3.26-3.18 (m, 1H), 2.97-2.96 (m, 1H), 2.87-2.80 (m, 1H), 2.74 (s, 1H), 2.68 (s, 3H), 2.65-2.64 (m, 1H), 2.62-2.60 (m, 2H), 2.04-1.97 (m, 1H), 1.93-1.83 (m, 3H), 1.82-1.76 (m, 2H), 1.74-1.63 (m, 2H), 1.40-1.29 (m, 5H), 1.29-1.25 (m, 2H), 1.22 (d,J
= 6.8 Hz, 3H), 1.17 (br s, 1H), 1.01 (d,J
= 6.8 Hz, 2H)。MS (ESI, m/e) [M+1]+
462.6。
合成程序類似於中間體4-1。化合物2-(4-(3-氟-4,5-二甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷係淡黃色固體。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.49-7.47 (m, 1H), 7.26-7.18 (m, 2H), 7.16-7.08 (m, 1H), 6.74-6.66 (m, 2H), 3.88-3.86 (m, 6H), 3.71-3.59 (m, 2H), 3.49-3.35 (m, 3H), 3.05-2.89 (m, 3H) 2.69-2.51 (m, 5H) 2.34-2.27 (m, 2H), 2.18-2.14 (m, 1H), 1.72-1.62 (m, 3H), 1.45-1.32 (m, 4H), 1.15 (d,J
= 6.8 Hz, 4H), 0.96-0.94 (m, 1H)。MS (ESI, m/e) [M+1]+
496.6。
合成程序類似於中間體4-1。化合物2-(2-(2-異丙基苯基)-4-((5-甲氧基吡𠯤-2-基)甲基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷係白色固體。1
H NMR (400 MHz, CDCl3
) δ ppm: 8.20 (d,J
= 1.6 Hz, 1H), 8.14-8.10 (m, 1H), 8.06 (d,J
= 1.2 Hz, 1H), 7.49 (br s, 1H), 7.26-7.19 (m, 2H), 7.15-7.08 (m, 1H), 3.95 (s, 3H), 3.75-3.53 (m, 3H), 3.47-3.26 (m, 1H), 3.04-2.84 (m, 3H), 2.73-2.58 (m, 5H), 2.44-2.25 (m, 3H), 1.81-1.71 (m, 1H), 1.70-1.62 (m, 1H), 1.48-1.32 (m, 4H), 1.29-1.20 (m, 5H), 1.15 (d,J
= 6.8 Hz, 4H)。MS (ESI, m/e) [M+1]+
405.6。
步驟1:3,4-雙(甲氧基-d3
)苯甲醛。
將3,4-二羥基苯甲醛(1.2 g,8.7 mmol)和K2
CO3
(6.0 g,43.4 mmol)及CD3
I(2.72 g,19.11 mmol)在CH3
CN(40 mL)中之混合物在70°C下攪拌2小時。向混合物中添加水(20 mL),將其用乙酸乙酯(20 mL × 2)萃取。將合併的有機層用鹽水(50 mL)洗滌,經無水Na2
SO4
乾燥,過濾並在減壓下濃縮。將粗產物藉由柱層析法(矽膠,洗脫液:PE/EA(v/v)= 5/1)純化以給出呈無色油狀物的3,4-二甲氧基-d3
-苯甲醛(1.0 g,產率:80%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 9.78 (s, 1H), 7.47-7.45 (m, 2H), 7.41 (d,J
= 0.8 Hz, 1H), 6.99-6.97 (d,J
= 8.4 Hz, 2H)。
步驟2:1-(3,4-雙(甲氧基-d3
)苄基)-3-(2-異丙基苯基)哌𠯤。
將2-(2-異丙基苯基)哌𠯤(0.5 g,2.45 mmol)和3,4-二甲氧基-d3
-苯甲醛(0.44 g,2.45 mmol)以及NaBH(OAc)3
(1.04 g,4.5 mmol)在DCM(10 mL)中之混合物在20°C下攪拌2小時。將混合物用K2
CO3
溶液調節pH = 9,用DCM(20 mL × 2)萃取。將合併的有機層用鹽水洗滌,經無水Na2
SO4
乾燥,過濾並在減壓下濃縮。將粗產物藉由柱層析法(矽膠,洗脫液:EA)純化以給出呈黃色油狀物的1-(3,4-二甲氧基-d3
-苄基)-3-(2-異丙基苯基)哌𠯤(0.4 g,產率:40%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.53-7.51 (m, 1H), 7.24-7.12 (m, 3H), 6.90-6.89 (m, 1H), 6.82-6.75 (m, 2H), 4.19-4.17 (m, 1H), 3.54-3.41 (m, 2H), 3.26-3.24 (m, 1H), 3.11-3.09 (m, 2H), 2.85-2.76 (m, 2H), 2.22-2.12 (m, 1H), 1.99-1.94 (m, 2H), 1.24-1.20 (d,J
= 6.8 Hz, 3H), 1.13-1.11 (d,J
= 6.8 Hz, 3H)。MS (ESI, m/e) [M+1]+
361.2。 中間體 178-1 : 2-(4-(3- 環丙氧基苄基 )-2-(2- 異丙基苯基 ) 哌 𠯤 -1- 基 )-7- 氮雜螺 [3.5] 壬烷
合成程序類似於中間體149-1。化合物2-(4-(3-環丙氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷係灰白色固體。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.53-7.41 (m, 1H), 7.26-7.17 (m, 3H), 7.15-7.09 (m, 1H), 7.01-6.99 (m, 1H), 6.95-6.89 (m, 2H), 3.76-3.71 (m, 1H), 3.69-3.62 (m, 1H), 3.54-3.49 (m, 2H), 3.45-3.30 (m, 1H), 3.04-2.87 (m, 3H), 2.72-2.56 (m, 5H), 2.37-2.24 (m, 2H), 2.22-2.15 (m, 1H), 1.75-1.71 (m, 1H), 1.69-1.67 (m, 1H), 1.41-1.29 (m, 5H), 1.28-1.22 (m, 4H), 1.19-1.10 (m, 4H), 0.79-0.72 (m, 4H)。MS (ESI, m/e) [M+1]+
474.3。
步驟1:苯并[d][1,3]二氧雜環戊烯-2,2-d2-5-甲醛
將3,4-二羥基苯甲醛(0.5 g,3.6 mmol)和Cs2
CO3
(5.9 g,18.1 mmol)以及CD2
Cl2
(1.0 g,11 mmol)在DMSO(5 mL)中之混合物在130°C下攪拌2小時。向混合物中添加水(20 mL),將其用乙酸乙酯(20 mL × 2)萃取。將合併的有機層用鹽水(50 mL)洗滌,經無水Na2
SO4
乾燥,過濾並在減壓下濃縮。將粗產物藉由柱層析法(矽膠,洗脫液:PE/EA(v/v)= 5/1)純化以給出呈無色油狀物的苯并[d][1,3]二氧雜環戊烯-d2-5-甲醛(0.5 g,產率:92%)。
步驟2:1-((苯并[d][1,3]二氧雜環戊烯-5-基-2,2-d2)甲基)-3-(2-異丙基苯基)哌𠯤
將2-(2-異丙基苯基)哌𠯤(0.5 g,2.45 mmol)和苯并[d][1,3]二氧雜環戊烯-d2-5-甲醛(0.42 g,2.45 mmol)以及NaBH(OAc)3
(1.04 g,4.5 mmol)在DCM(10 mL)中之混合物在20°C下攪拌2小時。將混合物藉由K2
CO3
溶液調節pH = 9,用DCM(20 mL × 2)萃取。將合併的有機層用鹽水洗滌,經無水Na2
SO4
乾燥,過濾並在減壓下濃縮。將粗產物藉由柱層析法(矽膠,洗脫液:EA)純化以給出呈棕色油狀物的1-((苯并[d][1,3]二氧雜環戊烯-5-基-2,2-d2)甲基)-3-(2-異丙基苯基)哌𠯤(0.47 g,產率:74%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.59-7.57 (m, 1H), 7.29-7.20 (m, 2H), 7.16-7.14 (m, 1H), 6.84 (s, 1H), 6.82-6.75 (m, 2H), 4.33-4.30 (m, 1H), 3.54-3.48 (m, 2H), 3.38-3.34 (m, 1H), 3.15-3.09 (m, 1H), 2.86-2.82 (m, 1H), 2.38-2.36 (m, 1H), 2.25-2.21 (m, 1H), 2.02-2.00 (m, 1H), 1.26-1.23 (d,J
= 6.8 Hz, 3H), 1.13-1.12 (d,J
= 6.8 Hz, 3H)。MS (ESI, m/e) [M+1]+
341.2。
合成程序類似於中間體149-1。化合物2-(4-(3-環丙氧基-4-甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷係黃色油狀物。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.56-7.43 (m, 1H), 7.26-7.18 (m, 3H), 7.15-7.09 (m, 1H), 6.86-6.81 (m, 1H), 6.79-6.75 (m, 1H), 3.86-3.81 (m, 3H), 3.77-7.75 (m, 1H), 3.69-3.60 (m, 1H), 3.49 (s, 2H), 3.39 (s, 1H), 3.05-2.98 (m, 1H), 2.95-2.88 (m, 2H), 2.70-2.54 (m, 5H), 2.36-2.25 (m, 2H), 2.23-2.12 (m, 1H), 1.81-1.72 (m, 1H), 1.70-1.63 (m, 3H), 1.41-1.29 (m, 5H), 1.26 (d,J
= 6.8 Hz, 3H), 1.15 (d,J
= 6.8 Hz, 3H), 0.87-0.81 (m, 2H), 0.81-0.75 (m, 2H)。MS (ESI, m/e) [M+1]+
503.4。
步驟1:甲基 3,4-二甲氧基苯甲酸酯
向3,4-二甲氧基苯甲酸(2.0 g,10.98 mmol)在MeOH(20 mL)中之溶液中添加H2
SO4
(3.23 g,32.94 mmol)。將溶液在80°C下攪拌2小時。將反應在減壓下濃縮。將殘餘物傾倒入飽和NaHCO3
(20 mL)中,用EtOAc(40 mL × 3)萃取。將合併的有機層用鹽水洗滌,經Na2
SO4
乾燥,過濾並在減壓下濃縮。將殘餘物藉由柱層析法(矽膠,洗脫液:PE/EA(v/v)= 5/1至1/1)純化以給出呈黃色固體的3,4-二甲氧基苯甲酸酯(2.0 g,產率:93%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.70-7.68 (m, 1H), 7.55 (d,J
= 2.0 Hz, 1H), 6.91-6.88 (m, 1H), 3.94 (d, 6H), 3.90 (s, 3H)。
步驟2:(3,4-二甲氧基苯基)甲烷-d 2
-醇
在0°C下,向3,4-二甲氧基苯甲酸酯(2.0 g,10.19 mmol)在DCM(10 mL)中之溶液中添加LiAlD4
(513.35 mg,12.23 mmol)。將溶液在20°C下攪拌2小時。將反應藉由飽和NH4
Cl(30 mL)淬滅,用EA(10 mL × 3)萃取。將合併的有機層用鹽水洗滌,經Na2
SO4
乾燥,過濾並在減壓下濃縮。將殘餘物藉由矽膠柱層析法(矽膠,洗脫液:PE/EA(v/v)= 5/1至2/1)純化以給出呈黃色固體的(3,4-二甲氧基苯基)甲烷-d 2
-醇(1.3 g,產率:79%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 6.96-6.83 (m, 3H), 4.64-4.59 (m, 1H), 3.90-3.89 (m, 6H)。
步驟3:(3,4-二甲氧基苯基)甲基-d 2
甲磺酸酯
在0°C下,向(3,4-二甲氧基苯基)甲烷-d 2
-醇(1.3 g,7.64 mmol)在DCM(103 mL)中之溶液中添加TEA(2.32 g,22.91 mmol)和MsCl(1.31 g,11.46 mmol)。將反應傾倒入水性NH4
Cl(30 mL)中,用DCM(30 mL × 3)萃取。將合併的有機層用鹽水洗滌,經Na2
SO4
乾燥,過濾並在減壓下濃縮以給出呈黃色油狀物的(3,4-二甲氧基苯基)甲基-d 2
甲磺酸酯(1.9 g,粗製),其無需進一步純化即可直接用於下一步。
步驟4:三級丁基 2-(4-((3,4-二甲氧基苯基)甲基-d 2
)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯
向三級丁基 2-(2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.0 g,2.26 mmol)在DMA(10 mL)中之溶液中添加K2
CO3
(625.92 mg,4.53 mmol)和(3,4-二甲氧基苯基)甲基-d 2
甲磺酸酯(618.47 mg,2.49 mmol)。將混合物在80°C下攪拌3小時。將反應傾倒入H2
O(50 mL)中,用DCM(30 mL × 3)萃取。將合併的有機層用鹽水洗滌,經Na2
SO4
乾燥,過濾並在減壓下濃縮。將殘餘物藉由矽膠柱層析法(矽膠,洗脫液 : PE/EA(v/v)= 10/1至2/1)純化以給出呈黃色油狀物的三級丁基 2-(4-((3,4-二甲氧基苯基)甲基-d 2
)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(0.835 g,產率:62%)。
步驟5:2-(4-((3,4-二甲氧基苯基)甲基-d 2
)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷
向三級丁基 2-(4-((3,4-二甲氧基苯基)甲基-d 2
)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(0.835 g,1.44 mmol)在MeOH(3.6 mL)中之溶液中添加HCl/MeOH(3.6 mL,4 M)。將溶液在25°C下攪拌2小時。將混合物在減壓下濃縮。將殘餘物傾倒入飽和Na2
CO3
(30 mL)中,用DCM(20 mL × 3)萃取。將合併的有機層用鹽水洗滌,經Na2
SO4
乾燥,過濾並在減壓下濃縮以給出呈黃色固體的2-(4-((3,4-二甲氧基苯基)甲基-d 2
)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷(425 mg,產率:62%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.48 (br s, 1H), 7.24-7.09 (m, 3H), 6.89 (s, 1H), 6.84-6.74 (m, 2H), 3.88-3.85 (m, 6H), 3.65-3.64 (m, 1H), 3.43-3.38 (m, 1H), 3.06-2.97 (m, 1H), 2.91-2.90 (m, 2H), 2.68-2.55 (m, 5H), 2.34-2.24 (m, 2H), 2.18-2.16 (m, 1H), 1.75-1.62 (m, 4H), 1.33-1.30 (m, 5H), 1.27-1.25 (m, 3H), 1.15-1.13 (m, 3H)。MS (ESI, m/e) [M+1]+
480.4。
步驟1:6-碘-2,3-二甲氧基吡啶
在20°C下,向2-溴-6-碘-3-甲氧基吡啶(2.5 g,7.96 mmol)在DMF(20 mL)中之溶液中添加MeONa(602.33 mg,11.15 mmol,5.4 M)。將溶液在100°C下攪拌2小時。向反應中添加H2
O(50 mL),將其用MTBE(50 mL × 3)萃取。將合併的有機層用鹽水洗滌,經Na2
SO4
乾燥,過濾並在減壓下濃縮。將殘餘物藉由矽膠柱層析法(矽膠,洗脫液:PE/EA(v/v)= 50/1至10/1)純化以給出呈白色油狀物的6-碘-2,3-二甲氧基吡啶(2.5 g,產率:85%)。
步驟2:5,6-二甲氧基吡啶甲醛
在-70°C下,向6-碘-2,3-二甲氧基吡啶(2.4 g,9.05 mmol)在THF(20 mL)中之溶液中添加n-BuLi(4.35 mL,10.87 mmol,2.5 M)。將溶液在-70°C下攪拌0.5 hr。在-70°C下,逐滴添加DMF(1.99 g,27.16 mmol)。將溶液在-70°C下攪拌1.5小時。向反應中添加飽和NH4
Cl(20 mL),將其用EtOAc(50 mL × 3)萃取。將合併的有機層用鹽水洗滌,經Na2
SO4
乾燥,過濾並在減壓下濃縮。將殘餘物藉由矽膠柱層析法(矽膠,洗脫液:PE/EA(v/v)= 30/1至5/1)純化以給出呈白色固體的5,6-二甲氧基吡啶甲醛(1.0 g,產率:66%)。
步驟3:三級丁基 2-(4-((5,6-二甲氧基吡啶-2-基)甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯
向三級丁基 2-(2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.0 g,2.34 mmol)和5,6-二甲氧基吡啶甲醛(390.91 mg,2.34 mmol)在DCM(15 mL)中之溶液中添加AcOH(280.86 mg,4.68 mmol)和NaBH(OAc)3
(991.25 mg,4.68 mmol)。將溶液在20°C下攪拌12小時。向反應中添加飽和NaHCO3
直到pH = 7,將其用DCM(10 mL × 3)萃取。將合併的有機層用鹽水洗滌,經Na2
SO4
乾燥,過濾並在減壓下濃縮。將殘餘物藉由矽膠柱層析法(矽膠,洗脫液:PE/EA(v/v)= 20/1至EA)純化以給出呈棕色油狀物的三級丁基 2-(4-((5,6-二甲氧基吡啶-2-基)甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(790 mg,產率:58%)。
步驟4:2-(4-((5,6-二甲氧基吡啶-2-基)甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷
向三級丁基 2-(4-((5,6-二甲氧基吡啶-2-基)甲基)-2-(2-異丙基苯基) 哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(740 mg,1.28 mmol)在DCM(2 mL)中之溶液中添加TFA(10 mL)。將溶液在20°C下攪拌2小時。將混合物在減壓下濃縮。將殘餘物傾倒入水性Na2
CO3
(30 mL)中,用DCM(20 mL × 3)萃取。將合併的有機層用鹽水洗滌,經Na2
SO4
乾燥,過濾並在減壓下濃縮以給出呈白色油狀物的2-(4-((5,6-二甲氧基吡啶-2-基)甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷(510 mg,產率:83%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.54-7.42 (m, 1H), 7.26-7.18 (m, 2H), 7.15-7.09 (m, 1H), 6.98 (d,J
= 8.0 Hz, 1H), 6.88 (d,J
= 8.0 Hz, 1H), 3.99-3.95 (m, 3H), 3.85 (s, 3H), 3.74-3.64 (m, 1H), 3.57 (s, 2H), 3.40 (s, 1H), 3.01 (d,J
= 9.2 Hz, 2H), 2.93-2.89 (m, 1H), 2.74 (d,J
= 11.2 Hz, 1H), 2.71-2.55 (m, 4H), 2.51-2.24 (m, 5H), 1.84-1.72 (m, 1H), 1.71-1.64 (m, 1H), 1.45-1.32 (m, 4H), 1.25 (d,J
= 6.8 Hz, 3H), 1.17 (d,J
= 6.8 Hz, 3H)。MS (ESI, m/e) [M+1]+
479.4。
中間體
200-1
:
5-((3-(2-
異丙基苯基
)-4-(7-
氮雜螺
[3.5]
壬烷
-2-
基
)
哌
𠯤
-1-
基
)
甲基
)-4-
甲基
-3,4-
二氫
-2H-
苯并
[b][1,4]
㗁
𠯤
合成程序類似於中間體18-1。化合物5-((3-(2-異丙基苯基)-4-(7-氮雜螺[3.5]壬烷-2-基)哌𠯤-1-基)甲基)-4-甲基-3,4-二氫-2H-苯并[b][1,4]㗁𠯤係白色固體。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.50 (br s, 1H), 7.24-7.18 (m, 2H), 7.14-7.10 (m, 1H), 7.06 (d,J
= 6.8 Hz, 1H), 6.88 (t,J
= 8.0 Hz, 1H), 6.74 (d,J
= 8.0 Hz, 1H), 4.17-4.15 (m, 2H), 3.62-3.60 (m, 1 H), 3.54 (d,J
= 13.2 Hz, 2H), 3.43-3.32 (m, 1 H), 3.07-3.03 (m, 2H), 3.00-2.98 (m, 2H), 2.94-2.88 (m, 1H), 2.78 (s, 3H), 2.75-2.60 (m, 6H), 2.43-2.33 (m, 2H), 2.31-2.20 (m, 3H), 1.76 (d,J
= 2.4 Hz, 1H), 1.70 (d,J
= 9.2 Hz, 1H), 1.42-1.34 (m, 4 H), 1.27 (d,J
= 6.8 Hz, 3H), 1.15 (d,J
= 6.8 Hz, 3H)。MS (ESI, m/e) [M+1]+
489.4
中間體
201-1
:
2-(4-((2,2-
二甲基苯并
[d][1,3]
二氧雜環戊烯
-4-
基
)
甲基
)-2-(2-
異丙基苯基
)
哌
𠯤
-1-
基
)-7-
氮雜螺
[3.5]
壬烷
合成程序類似於中間體149-1。化合物2-(4-((2,2-二甲基苯并[d][1,3]二氧雜環戊烯-4-基)甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷係白色固體。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.43 (br d,J
= 4.4 Hz, 1H), 7.26-7.18 (m, 2H), 7.12-7.07 (m, 1H), 6.79-6.69 (m, 2H), 6.62 (d,J
= 7.6 Hz, 1H), 4.85-4.42 (m, 2H), 3.65 (br d,J
= 8.4 Hz, 1H), 3.57 (s, 2H), 3.47-3.29 (m, 1H), 3.02-2.85 (m, 3H), 2.83-2.65 (m, 5H), 2.42-2.24 (m, 3H), 1.79 (d,J
= 3.6 Hz, 1H), 1.72-1.66 (m, 1H), 1.60 (s, 6H), 1.52-1.41 (m, 4H), 1.35-1.29 (m, 1H), 1.24 (d,J
= 6.8 Hz, 3H), 1.17 (d,J
= 6.8 Hz, 3H)。MS (ESI, m/e) [M+1]+
490.6。
中間體
203-1
:
2-(2-(2-
異丙基苯基
)-4-((8-
甲氧基
-2,3-
二氫苯并
[b][1,4]
戴奧辛
-5-
基
)
甲基
)
哌
𠯤
-1-
基
)-7-
氮雜螺
[3.5]
壬烷
合成程序類似於中間體149-1。化合物2-(2-(2-異丙基苯基)-4-((8-甲氧基-2,3-二氫苯并[b][1,4]戴奧辛-5-基)甲基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷係黃色固體。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.45 (br s, 1H), 7.27-7.18 (m, 2H), 7.15-7.07 (m, 1H), 6.80 (d,J
= 8.4 Hz, 1H), 6.44 (d,J
= 8.4 Hz, 1H), 4.34-4.27 (m, 2H), 4.26-4.20 (m, 2H), 3.85 (s, 3H), 3.68-3.65 (m, 1H), 3.59-3.47 (m, 2H), 3.37 (br s, 1H), 3.00-2.68 (m, 8H), 2.41-2.19 (m, 3H), 1.80 (br s, 1H), 1.74-1.67 (m, 1H), 1.63-1.45 (m, 4H), 1.36-1.27 (m, 1H), 1.25-1.21 (d,J
= 6.8 Hz, 3H), 1.17 (d,J
= 6.8 Hz, 3H)。MS (ESI, m/e) [M+1]+
506.3。
合成程序類似於中間體149-1。化合物1-(5-((3-(2-異丙基苯基)-4-(7-氮雜螺[3.5]壬烷-2-基)哌𠯤-1-基)甲基)-2-甲氧基苯基)乙烷-1-酮係黃色油狀物。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.66 (s, 1H), 7.50-7.39 (m, 2H), 7.24-7.18 (m, 2H), 7.15-7.07 (m, 1H), 6.89 (d,J
= 8.4 Hz, 1H), 3.89 (s, 3H), 3.64 (d,J
= 10.8 Hz, 1H), 3.47 (s, 2H), 3.38 (s, 1H), 3.04-2.86 (m, 4H), 2.64 (s, 4H), 2.60 (s, 3H), 2.28 (s, 2H), 2.23-2.15 (m, 1H), 1.75-1.62 (m, 4H), 1.38-1.28 (m, 5H), 1.25 (d,J
= 6.8 Hz, 3H), 1.14 (d,J
= 6.8 Hz, 3H)。MS (ESI, m/e) [M+1]+
490.4
合成程序類似於中間體149-1。化合物2-(4-(苯并呋喃-4-基甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷係黃色固體。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.61 (d,J
= 2.4 Hz, 1H), 7.54-7.44 (m, 1 H), 7.39 (d,J
= 8.0 Hz, 1H), 7.25-7.15 (m, 4H), 7.15-7.08 (m, 1H), 7.02 (d,J
= 1.6 Hz, 1H), 3.80-3.72 (m, 2H), 3.65 (br d,J
= 8.8 Hz, 1H), 3.44-3.25 (m, 1H), 3.04-2.85 (m, 3H), 2.77-2.54 (m, 5H), 2.42-2.17 (m, 3H), 1.81-1.62 (m, 2H), 1.44-1.28 (m, 5H), 1.25 (d,J
= 6.8 Hz, 3H), 1.16-1.14 (m, 1H), 1.08 (d,J
= 6.8 Hz, 3H)。MS (ESI, m/e) [M+1]+
458.3。
中間體
216-1
:
5-((3-(2-
異丙基苯基
)-4-(7-
氮雜螺
[3.5]
壬烷
-2-
基
)
哌
𠯤
-1-
基
)
甲基
)-4-
甲基
-2H-
苯并
[b][1,4]
㗁
𠯤
-3(4H)-
酮
合成程序類似於中間體149-1。化合物5-((3-(2-異丙基苯基)-4-(7-氮雜螺[3.5]壬烷-2-基)哌𠯤-1-基)甲基)-4-甲基-2H-苯并[b][1,4]㗁𠯤-3(4H)-酮係白色固體。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.41 (br s, 1 H), 7.23-7.14 (m, 2H), 7.12-7.07 (m, 1H), 7.05-7.03 (m, 1H), 7.00-6.93 (m, 2H), 4.51 (d,J
= 14.4 Hz, 1H), 4.35 (d,J
= 14.4 Hz, 1H), 3.73-3.66 (m, 1H), 3.53 (d,J
= 14.0 Hz, 1H), 3.43 (br s, 1H), 3.39 (s, 3H), 3.35-3.20 (m, 2H), 2.93 (br d,J
= 11.2 Hz, 1H), 2.88-2.79 (m, 2H), 2.46-2.33 (m, 5H), 2.25-2.18 (m, 1H), 2.15-2.08 (m, 1H), 1.99 (s, 1H), 1.79-1.49 (m, 3H), 1.21-1.17 (m, 5H), 1.17-1.11 (m, 3H), 1.03 (d,J
= 6.8 Hz, 3H)。MS (ESI, m/e) [M+1]+
503.4。
中間體
223-1
:
2-((2R)-4-((3,4-
二甲氧基二環
[4.2.0]
八
-1(6),2,4-
三烯
-7-
基
)
甲基
)-2-(2-
異丙基苯基
)
哌
𠯤
-1-
基
)-7-
氮雜螺
[3.5]
壬烷
合成程序類似於中間體149-1。化合物2-((2R)-4-((3,4-二甲氧基二環[4.2.0]八-1(6),2,4-三烯-7-基)甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷係白色固體。1
H NMR (400 MHz, DMSO-d 6
) δ ppm: 7.46-7.44 (m, 1H), 7.27-7.24 (m, 1H), 7.19 (t,J
= 7.2 Hz, 1H), 7.13-7.09 (m, 1H), 6.75-6.70 (m, 2H), 6.67 (s, 1H), 3.69-3.66 (m, 6H), 3.63 (s, 2H), 3.56-3.46 (m, 3H), 3.20-3.09 (m, 2H), 2.95-2.93 (m, 2H), 2.87 (d,J
= 7.6 Hz, 1H), 2.69-2.61 (m, 4H), 2.46-2.38 (m, 5H), 2.22-2.19 (m, 2H), 2.12-2.06 (m, 1H), 1.62 (s, 3H), 1.22 (d,J
= 6.8 Hz, 3H), 1.16 (d,J
= 6.8 Hz, 3H), 1.06 (s, 1H)。MS (ESI, m/e) [M+1]+
504.3。
化合物2-(2-(5-氟-2-異丙基苯基)-4-(4-甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷係黃色固體。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.27-7.17 (m, 4H), 6.89-6.82 (m, 3H), 3.79 (s, 3H), 3.62-3.60 (m, 2H), 3.46-3.45 (m, 2H), 3.35-3.25 (m, 1H), 2.89-2.82 (m, 3H), 2.66-2.59 (m, 5H), 2.27-2.26 (m, 2H), 2.10-2.05 (m, 1H), 1.36-1.31 (m, 5H), 1.23-1.21 (d,J
= 6.8 Hz, 3H), 1.13-1.11 (d,J
= 6.8 Hz, 3H)。MS (ESI, m/e) [M+1]+
466.2。
化合物(R)-2-(2-(2-異丙基苯基)-4-((7-甲氧基-2,3-二氫苯并呋喃-5-基)甲基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷係黃色油狀物。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.56-7.43 (m, 1H), 7.26-7.23 (m, 2H), 7.16-7.09 (m, 1H), 6.74 (d,J
= 14.8 Hz, 2H), 4.60 (t,J
= 8.8 Hz, 2H), 3.86 (s, 3H), 3.70-3.60 (m, 1H), 3.44 (d,J
= 2.8 Hz, 2H), 3.18 (t,J
= 8.8 Hz, 2H), 3.02 (d,J
= 5.6 Hz, 1H), 3.06-2.82 (m, 3H), 2.70-2.56 (m, 5H), 2.34-2.25 (m, 2H), 2.15 (t,J
= 10.0 Hz, 1H), 1.78-1.75 (m, 1H), 1.67 (s, 3H), 1.41-1.29 (m, 5H), 1.26 (d,J
= 6.8 Hz, 3H), 1.15 (d,J
= 6.8 Hz, 3H)。MS (ESI, m/e) [M+1]+
490.3。
合成程序類似於中間體182-1。化合物(R)-3-(2-異丙基苯基)-1-((5-甲氧基吡啶- 2-基)甲基)哌𠯤係黃色油狀物。1
H NMR (400 MHz, CDCl3
) δ ppm: 8.28 (d,J
= 2.8 Hz, 1H), 7.57-7.52 (m, 1H), 7.31 (d,J
= 8.4 Hz, 1H), 7.27-7.20 (m, 2H), 7.19-7.14 (m, 2H), 4.29-4.26 (m, 1H), 3.88-3.82 (m, 3H), 3.67 (d,J
= 2.0 Hz, 2H), 3.30-3.26 (m, 1 H), 3.20-3.09 (m, 2H), 2.94-2.82 (m, 2H), 2.35-2.30 (m, 1H), 2.17-2.12 (m, 1H), 1.23 (d,J
= 6.8 Hz, 3H), 1.16 (d,J
= 6.8 Hz, 3H)。MS (ESI, m/e) [M+1]+
326.1。
化合物2-(2-(5-氯-2-異丙基苯基)-4-(4-甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷係黃色油狀物。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.27 (s, 1H), 7.22-7.20 (m, 2H), 7.16 (m, 2H), 6.84-6.82 (m, 2H), 4.32-4.28 (m, 1H), 3.61 (s, 3H), 3.46-3.45 (m, 2H), 2.89-2.62 (m, 8H), 2.27-2.25 (m, 2H), 1.65-1.63 (m, 4H), 1.55-1.53 (m, 4H), 1.36-1.35 (m, 2H), 1.23-1.21 (d,J
= 6.8 Hz, 3H), 1.12-1.10 (d,J
= 6.8 Hz, 3H)。MS (ESI, m/e) [M+1]+
482.2。
合成程序類似於中間體18-1。化合物2-((2R)-4-(((1R,3S,5R)-金剛烷-2-基)甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷係白色固體。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.41 (br s, 1H), 7.19-7.09 (m, 2H), 7.09-7.00 (m, 1H), 3.56-3.54 (m, 1H), 3.40-3.23 (m, 1H), 3.01 (br s, 3H), 2.93-2.80 (m, 3H), 2.71-2.51 (m, 5H), 2.39-2.33 (m, 1H), 2.29-2.16 (m, 3H), 2.05-1.97 (m, 1H), 1.81-1.60 (m, 14H), 1.50-1.38 (m, 2H), 1.38-1.27 (m, 4H), 1.18 (d,J
= 6.8 Hz, 3H), 1.12 (d,J
= 6.8 Hz, 3H)。MS (ESI, m/e) [M+1]+
476.3。
合成程序類似於中間體149-1。化合物(R)-2-(2-(2-異丙基苯基)-4-(3-甲氧基-4-甲基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷係淡黃色固體。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.49 (d,J
= 4.4 Hz, 1H), 7.22-7.20 (m, 2H), 7.13-7.160 (m, 1H), 7.03 (d,J
= 7.2 Hz, 1H), 6.81-6.77 (m, 2H), 3.83 (s, 3H), 3.66-3.64 (m, 1H), 3.49 (s, 2H), 3.40 (s, 1H), 3.05-2.89 (m, 3H), 2.76-2.59 (m, 4H), 2.30-2.28 (m, 2H), 2.18 (s, 4H), 1.83-1.60 (m, 4H), 1.38-1.26 (m, 8H), 1.16 (d,J
= 6.4 Hz, 3H)。MS (ESI, m/e) [M+1]+
462.3。
合成程序類似於中間體149-1。化合物(R)-2-(4-(4-異丙基-3-甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷係黃色固體。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.49 (s, 1H), 7.22-7.18 (m, 2H), 7.13-7.09 (m, 2H), 6.83-6.82 (m, 2H), 3.84 (s, 3H), 3.62-3.60 (m, 2H), 3.26-3.24 (m, 1H), 2.98-2.85 (m, 3H), 2.64-2.61 (m, 4H), 2.31-2.29 (m, 2H), 2.26-2.05 (m, 4H), 1.75-1.65 (m, 2H), 1.40-1.24 (m, 8H), 1.24-1.12 (m, 10H)。MS (ESI, m/e) [M+1]+
490.3。
合成程序類似於中間體149-1。化合物(R)-2-(4-(4-乙基-3-甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷係白色固體。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.49 (m, 1H), 7.25-7.17 (m, 2H), 7.16-7.08 (m, 1H), 7.05-7.03(m, 1H), 6.85-6.78 (m, 2H), 3.82 (s, 3H), 3.71-3.61 (m, 1H), 3.54-3.46 (m, 2H), 3.45-3.32 (m, 1H), 3.05-2.97 (m, 1H), 2.97-2.87 (m, 2H), 2.72-2.53 (m, 7H), 2.32-2.30 (m, 2H), 2.19-2.15 (m, 1H), 1.74-1.62 (m, 3H), 1.41-1.28 (m, 5H), 1.26 (d,J
= 6.8 Hz, 3H), 1.18-1.13 (m, 6H)。MS (ESI, m/e) [M+1]+
476.2。
合成程序類似於中間體182-1。化合物(R)-1-(4-乙基-3-甲氧基苄基)-3-(2-異丙基苯基)哌𠯤係黃色油狀物。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.54-7.53 (m, 1H), 7.26-7.20 (m, 2H), 7.19-7.14 (m, 1H), 7.07-7.05 (m, 1H), 6.87 (s, 1H), 6.84-6.82 (m, 1H), 4.22 (br d,J
= 9.6 Hz, 1H), 3.84 (s, 3H), 3.61-3.46 (m, 2H), 3.27-3.22 (m, 1H), 3.14-3.12 (m, 2H), 2.96-2.81 (m, 2H), 2.61-2.59 (m, 2H), 2.29-2.20 (m, 1H), 2.07-2.01 (m, 2H), 1.23 (d,J
= 6.8 Hz, 3H), 1.20-1.12 (m, 6H)。MS (ESI, m/e) [M+1]+
353.1。
合成程序類似於中間體182-1。化合物(R)-1-(4-異丙基-3-甲氧基苄基)-3-(2-異丙基苯基)哌𠯤係無色油狀物。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.57 (br d,J
= 7.2 Hz, 1H), 7.27 (s, 4H), 6.91-6.86 (m, 2H), 4.23 (dd,J
= 2.0, 10.0 Hz, 1H), 3.86 (s, 3H), 3.63 (d,J
= 12.8 Hz, 1H), 3.47 (d,J
= 12.8 Hz, 1H), 3.35-3.25 (m, 2H), 3.19-3.13 (m, 2H), 2.95-2.84 (m, 2H), 2.31-2.22 (m, 1H), 2.00 (t,J
= 10.4 Hz, 1H), 1.28-1.20 (m, 9H), 1.14 (d,J
= 6.8 Hz, 3H)。MS (ESI, m/e) [M+1]+
367.1。
合成程序類似於中間體149-1。化合物(R)-2-(4-(4-氯-3-甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷係黃色固體。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.52-7.43 (m, 1H), 7.26-7.18 (m, 3H), 7.16-7.08 (m, 1H), 6.94 (d, 1H), 6.85-6.82 (m, 1H), 3.90 (s, 3H), 3.64 (br d, 1H), 3.48 (s, 2H), 3.43-3.33 (m, 1H), 3.02-2.97 (m, 1H), 2.94-2.87 (m, 1H), 2.80-2.64 (m, 4H), 2.31-2.29 (m, 2H), 2.22-2.15 (m, 1H), 1.82-1.77 (m, 2H), 1.73-1.69 (m, 1H), 1.47-1.45 (m, 4H), 1.33-1.24 (m, 6H), 1.16 (s, 3H)。MS (ESI, m/e) [M+1]+
482.3。
合成程序類似於中間體149-1。化合物(R)-2-(2-(2-異丙基苯基)-4-(3-甲氧基-4-(三氟甲基)苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷係白色油狀物。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.46 (br d,J
= 7.6 Hz, 2H), 7.25-7.19 (m, 2H), 7.15-7.10 (m, 1H), 7.02 (s, 1H), 6.95 (d,J
= 7.6 Hz, 1H), 3.91 (s, 3H), 3.75-3.59 (m, 2H), 3.58-3.50 (m, 2 H), 3.39 (br s, 1H), 3.04-3.00 (m, 1H), 2.96-2.87 (m, 2H), 2.70-2.52 (m, 5H), 2.34-2.30 (m, 2H), 2.23-2.20 (m, 1H), 1.79-1.74 (m, 1H), 1.69-1.63 (m, 2H), 1.39-1.29 (m, 5H), 1.27 (d,J
= 6.8 Hz, 3H), 1.15 (d,J
= 6.8 Hz, 3H)。MS (ESI, m/e) [M+1]+
516.1。
合成程序類似於中間體306-1。化合物(R)-2-(2-(2-異丙基苯基)-4-((7-甲氧基苯并呋喃-5-基)甲基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷係黃色固體。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.59 (s, 1H), 7.53-7.43 (m, 1H), 7.24-7.19 (m, 2H), 7.14-7.09 (m, 2H), 6.83 (s, 1H), 6.69-6.68 (m, 1H), 4.01 (s, 3H), 3.71-3.61 (m, 1H), 3.58 (s, 2H), 3.43-3.28 (m, 1H), 3.01-2.89 (m, 3H), 2.83-2.67 (m, 5H), 2.88-2.64 (m, 1H), 2.30-2.28 (m, 2H), 2.19-2.16 (m, 1H), 1.82-1.69 (m, 2H), 1.57-1.46 (m, 4H), 1.37-1.30 (m, 1H), 1.24 (d,J
= 6.8 Hz, 3H), 1.13 (d,J
= 6.8 Hz, 3H)。MS (ESI, m/e) [M+1]+
488.2。
合成程序類似於中間體149-1。化合物(R)-2-(4-(口克唍-7-基甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷係白色固體。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.55-7.40 (m, 1H), 7.25-7.17 (m, 2H), 7.15-7.08 (m, 1H), 6.95 (d,J
= 7.6 Hz, 1H), 6.81-6.76 (m, 1H), 6.75 (s, 1H), 4.19-4.12 (m, 2H), 3.65 (d,J
= 8.0 Hz, 1H), 3.52-3.33 (m, 3H), 3.00-2.86 (m, 3H), 2.76-2.73 (m, 2H), 2.70-2.54 (m, 5H), 2.32-2.24 (m, 2H), 2.22-2.14 (m, 1H), 2.08-1.89 (m, 3H), 1.72-1.62 (m, 3H), 1.41-1.28 (m, 5H), 1.25 (d,J
= 6.8 Hz, 3H), 1.16 (d,J
= 6.8 Hz, 3H)。MS (ESI, m/e) [M+1]+
474.2
中間體
286-1
:
(R)-2-(2-(2-
異丙基苯基
)-4-((7-
甲氧基
-3,3-
二甲基
-2,3-
二氫苯并呋喃
-5-
基
)
甲基
)
哌
𠯤
-1-
基
)-7-
氮雜螺
[3.5]
壬烷
合成程序類似於中間體295-1。化合物(R)-2-(2-(2-異丙基苯基)-4-((7-甲氧基-3,3-二甲基-2,3-二氫苯并呋喃-5-基)甲基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷係白色固體。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.49 (d,J
= 5.6 Hz, 1H), 7.25-7.18 (m, 2H), 7.15-7.10 (m, 1H), 6.69 (d,J
= 11.6 Hz, 2H), 4.26 (s, 2H), 3.86 (s, 3H), 3.65 (d,J
= 8.0 Hz, 1H), 3.55-3.49 (m, 1H), 3.46-3.32 (m, 2H), 3.07-2.99 (m, 1H), 2.97-2.87 (m, 2H), 2.71-2.56 (m, 5H), 2.36-2.27 (m, 2H), 2.15-2.13 (m, 1H), 1.91 (br s, 3H), 1.81-1.74 (m, 1H), 1.72-1.65 (m, 1H), 1.41-1.34 (m, 3H), 1.31 (d,J
= 4.0 Hz, 6H), 1.26 (d,J
= 6.8 Hz, 3H), 1.14 (d,J
= 6.8 Hz, 3H)。MS (ESI, m/e) [M+1]+
518.3
合成程序類似於中間體149-1。化合物(R)-2-(4-(4-(二氟甲基)-3-甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷係黃色固體。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.50-7.45 (m, 2H), 7.26-7.19 (m, 2H), 7.14-7.12 (m, 1H), 7.05-6.77 (m, 3H), 3.87 (s, 3H), 3.66-3.64 (m, 1H), 3.53-3.52 (m, 2H), 3.38-3.37 (m, 1H), 2.96-2.89 (m, 5H), 2.69-2.64 (m, 5H), 2.31-2.26 (m, 2H), 2.20-2.15 (m, 2H), 1.77-1.74 (m, 1H), 1.70-1.67 (m, 1H), 1.41-1.37 (m, 5H), 1.26 (d,J
= 6.8 Hz, 3H), 1.15 (d,J
= 6.8 Hz, 3H)。MS (ESI, m/e) [M+1]+
498.2。
合成程序類似於中間體182-1。化合物(R)-3-(2-異丙基苯基)-1-(3-甲氧基-4-(三氟甲基)苄基)哌𠯤係黃色油狀物。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.55 (d,J
= 7.6 Hz, 1H), 7.48 (d,J
= 8.0 Hz, 1H), 7.14-7.26 (m, 3H), 7.06 (s, 1H), 6.97 (d,J
= 8.0 Hz, 1H), 4.22 (d,J
= 9.6 Hz, 1H), 3.92 (s, 3H), 3.49-3.66 (m, 2H), 3.20-3.31 (m, 1H), 3.08-3.18 (m, 2H), 2.77-2.90 (m, 2H), 2.29-2.28 (m, 1H), 2.01-2.11 (m, 2H), 1.25 (d,J
= 6.8 Hz, 3H), 1.13 (d,J
= 6.8 Hz, 3H)。MS (ESI, m/e) [M+1]+
363.0
中間體
292-1
:
2-(2-(2-
異丙基苯基
)-4-((4-
甲氧基二環
[4.2.0]
八
-1(6),2,4-
三烯
-7-
基
)
甲基
)
哌
𠯤
-1-
基
)-7-
氮雜螺
[3.5]
壬烷
合成程序類似於中間體149-1。化合物2-(2-(2-異丙基苯基)-4-((4-甲氧基二環[4.2.0]八-1(6),2,4-三烯-7-基)甲基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷係黃色油狀物。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.27-7.52 (m, 1H), 7.23-7.25 (m, 2H), 7.14-7.23 (m, 1H), 6.94-6.96 (m, 1H), 6.64-6.76 (m, 2H), 3.62-3.76 (m, 5H), 2.64-3.26 (m, 8H), 2.29-2.32 (m, 8H), 0.84-1.44 (m, 14H)。MS (ESI, m/e) [M+1]+
474.3。
步驟1:3-碘-5-甲氧基-4-((2-甲基烯丙基)氧基)苯甲醛
向4-羥基-3-碘-5-甲氧基苯甲醛(4.0 g,14.39 mmol)和3-溴-2-甲基丙-1-烯(2.91 g,21.58 mmol)在MeCN(40 mL)中之溶液中添加K2
CO3
(3.98 g,28.77 mmol)。將混合物在80°C下攪拌12小時。將混合物傾倒入H2
O(30 mL)中,用EtOAc 30 mL(10 mL × 3)萃取。將合併的有機層用鹽水洗滌,經Na2
SO4
乾燥,過濾並在減壓下濃縮。將殘餘物藉由柱層析法(矽膠,洗脫液 : PE/EA(v/v)= 100/1至EA)純化以給出呈無色油狀物的3-碘-5-甲氧基-4-((2-甲基烯丙基)氧基)苯甲醛(4.5 g,產率:94%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 9.82 (s, 1H), 7.85 (d,J
= 1.6 Hz, 1H), 7.40 (d,J
= 1.6 Hz, 1H), 5.17 (d,J
= 0.4 Hz, 1H), 5.01 (s, 1H), 4.53 (s, 2H), 3.91 (s, 3H), 1.94 (s, 3H)。
步驟2:7-甲氧基-3,3-二甲基-2,3-二氫苯并呋喃-5-甲醛
在20°C下,向3-碘-5-甲氧基-4-((2-甲基烯丙基)氧基)苯甲醛(5.2 g,15.66 mmol)在DMF(20 mL)中之溶液中添加Pd(OAc)2
(1.46 g,6.52 mmol)、K2
CO3
(2.16 g,15.66 mmol)、HCOONa(1.02 g,15 mmol)和TBAB(4.21 g,13.05 mmol)。將混合物在100°C下攪拌3小時。將混合物傾倒入H2
O(20 mL)中,用EtOAc(15 mL × 3)萃取。將合併的有機層用鹽水洗滌,經Na2
SO4
乾燥,過濾並在減壓下濃縮。將殘餘物藉由柱層析法(矽膠,洗脫液 : PE/EA(v/v)= 100/1至EA)純化以給出呈無色油狀物的7-甲氧基-3,3-二甲基-2,3-二氫苯并呋喃-5-甲醛(770 mg,產率:23%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 9.83 (s, 1H), 7.31 (d,J
= 3.2 Hz, 2H), 4.43 (s, 2H), 3.94 (s, 3H), 1.39 (s, 6H)。
步驟3:(R)-3-(2-異丙基苯基)-1-((7-甲氧基-3,3-二甲基-2,3-二氫苯并呋喃-5-基)甲基)哌𠯤
在0°C下,向7-甲氧基-3,3-二甲基-2,3-二氫苯并呋喃-5-甲醛(470 mg,2.28 mmol)和(R)-2-(2-異丙基苯基)哌𠯤(512.17 mg,2.51 mmol)在DCM(30 mL)中之溶液中添加NaBH(OAc)3
(965.99 mg,4.56 mmol)。將混合物在20°C下攪拌2小時。將反應混合物傾倒入水性Na2
CO3
(20 mL)中,用DCM(20 mL × 3)萃取。將合併的有機層用鹽水洗滌,經Na2SO4乾燥,過濾並在減壓下濃縮。將殘餘物藉由矽膠柱層析法(矽膠,洗脫液:PE/EA(v/v)= 100/1至EA)純化以給出呈無色油狀物的(R)-3-(2-異丙基苯基)-1-((7- 甲氧基-3,3-二甲基-2,3-二氫苯并呋喃-5-基)甲基)哌𠯤(527 mg,產率:58%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.56 (d,J
= 7.6 Hz, 1H), 7.27-7.15 (m, 3H), 6.78-6.66 (m, 2H), 4.28 (s, 2H), 4.22 (d,J
= 8.4 Hz, 1H), 3.88 (s, 3H), 3.58 (d,J
= 12.8 Hz, 1H), 3.42 (d,J
= 13.2 Hz, 1H), 3.27-3.25 (m, 1H), 3.18-3.11 (m, 2H), 2.94-2.83 (m, 2H), 2.64-2.46 (m, 1H), 2.27-2.24 (m, 1H), 2.01 (br s, 1H), 1.32 (d,J
= 2.8 Hz, 6H), 1.24 (d,J
= 6.8 Hz, 3H), 1.13 (d,J
= 6.8 Hz, 3H)。MS (ESI, m/e) [M+1]+
395.2。
合成程序類似於中間體182-1。化合物(R)-1-((2,3-二氫苯并呋喃-6-基)甲基)-3-(2-異丙基苯基)哌𠯤係無色油狀物。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.55 (br d,J
= 7.6 Hz, 1H), 7.30-7.26 (m, 1H), 7.26-7.21 (m, 1H), 7.20-7.14 (m, 1H), 7.12 (d,J
= 7.6 Hz, 1H), 6.88-6.77 (m, 2H), 4.58-4.54 (m, 2H), 4.25-4.18 (m, 1H), 3.56-3.47 (m, 2H), 3.35-3.29 (m, 1H), 3.22-3.08 (m, 4H), 2.87-2.84 (m, 2H), 2.22-2.20 (m, 1H), 2.08-2.03 (m, 1H), 1.82 (s, 1H), 1.25 (d,J
= 6.8 Hz, 3H), 1.19 (d,J
= 6.8 Hz, 3H)。MS (ESI, m/e) [M+1]+
337.1。
合成程序類似於中間體312-1。化合物(R)-2-(2-(2-異丙基苯基)-4-((8-甲氧基口克唍-6-基)甲基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷係黃色固體。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.54-7.44 (m, 1H), 7.25-7.18 (m, 2H), 7.15-7.09 (m, 1H), 6.69 (s, 1H), 6.57 (s, 1H), 4.26-4.22 (m, 2H), 3.85 (s, 3H), 3.69-3.61 (m, 1H), 3.48-3.34 (m, 3H), 3.04-2.98 (m, 1H), 2.95-2.88 (m, 2H), 2.74 (br t,J
= 6.4 Hz, 2H), 2.70-2.61 (m, 4H), 2.34-2.26 (m, 1H), 2.20-2.05 (m, 2H), 2.02-1.93 (m, 6H), 1.80-1.67 (m, 2H), 1.46-1.28 (m, 6H), 1.26 (d,J
= 6.8 Hz, 3H), 1.15 (d,J
= 6.8 Hz, 3H)。MS (ESI, m/e) [M+1]+
504.3。
合成程序類似於中間體149-1。化合物(R)-2-(4-((2,3-二氫苯并呋喃-6-基)甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷係白色固體。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.48 (s, 1H), 7.26-7.17 (m, 2H), 7.15-7.05 (m, 2H), 6.82-6.73 (m, 2H), 4.54 (t,J
= 8.8 Hz, 2H), 3.65 (d,J
= 8.4 Hz, 1H), 3.52-3.32 (m, 3H), 3.17-3.13 (m, 2H), 3.01-2.86 (m, 3H), 2.69-2.52 (m, 5H), 2.32-2.24 (m, 2H), 2.18 (t,J
= 10.4 Hz, 1H), 1.75 (d,J
= 3.2 Hz, 1H), 1.68-1.62 (m, 1H), 1.41-1.27 (m, 5H), 1.25 (d,J
= 6.8 Hz, 3H), 1.15 (br d,J
= 6.8 Hz, 3H)。MS (ESI, m/e) [M+1]+
460.2。
步驟1:4-羥基-3-甲氧基-5-((三甲基矽基)乙炔基)苯甲醛
在25°C下,向4-羥基-3-碘-5-甲氧基苯甲醛(10 g,35.97 mmol)和乙炔基三甲基矽烷(5.65 g,57.54 mmol)在THF(100 mL)和TEA(20 mL)中之溶液中添加Pd(PPh3
)2
Cl2
(1.26 g,1.80 mmol)和CuI(684 mg,3.60 mmol)。將混合物在25°C下攪拌16小時。將反應混合物通過矽藻土墊過濾並用THF(100 mL)洗滌。將濾液在減壓下濃縮。將殘餘物藉由MPLC(矽膠,洗脫液:PE/EA(v/v)= 10/1至2/1)純化以給出呈黃色固體的4-羥基-3-甲氧基-5-((三甲基矽基)乙炔基)苯甲醛(7 g,產率:78%)。1
H NMR (400 MHz, DMSO-d 6
) δ ppm:10.50 (s, 1H), 9.76 (s, 1H), 7.56 (d,J
= 2.0 Hz, 1H), 7.39 (s, 1H), 3.89 (s, 3H), 0.23-0.22 (m, 9H)。
步驟2:7-甲氧基苯并呋喃-5-甲醛
在20°C下,向4-羥基-3-甲氧基-5-((三甲基矽基)乙炔基)苯甲醛(3.0 g,12.08 mmol)在THF(15 mL)中之溶液中添加TBAF(15 mL,15.34 mmol)。將混合物在70°C下攪拌12小時。將反應混合物用H2
O(20 mL)稀釋並用EtOAc(20 mL × 3)萃取。將合併的有機層用鹽水洗滌,經Na2
SO4
乾燥,過濾並在減壓下濃縮。將殘餘物藉由MPLC(矽膠,洗脫液:PE/EA(v/v)= 10/1至2/1)純化以給出呈白色固體的7-甲氧基苯并呋喃-5-甲醛(1.0 g,產率:46%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 9.94 (s, 1H), 7.74-7.63 (m, 2H), 7.31 (s, 1H), 6.83 (d,J
= 2.0 Hz, 1H), 4.00 (s, 3H)。
步驟3:(R)-3-(2-異丙基苯基)-1-((7-甲氧基苯并呋喃-5-基)甲基)哌𠯤
在0°C下,向7-甲氧基苯并呋喃-5-甲醛(700.0 mg,3.97 mmol)和(R)-2-(2-異丙基苯基)哌𠯤(893.0 mg,4.37 mmol)在DCM(10 mL)中之溶液中添加NaBH(OAc)3
(2.1 g,9.93 mmol)。將混合物在25°C下攪拌12小時。將反應混合物用水性NaHCO3
(20 mL)稀釋並用DCM(20 mL × 3)萃取。將合併的有機層用鹽水洗滌,經無水Na2
SO4
乾燥,過濾並在減壓下濃縮。將殘餘物藉由MPLC(矽膠,洗脫液:PE/EA(v/v)= 10/1至2/1至EA/MeOH(v/v)= 5/1)純化以給出呈黃色油狀物的(R)-3-(2-異丙基苯基)-1-((7-甲氧基苯并呋喃-5-基)甲基) 哌𠯤(744 mg,產率:51%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.60 (d,J
= 2.0 Hz, 1H), 7.56 (d,J
= 7.6 Hz, 1H), 7.26-7.20 (m, 2H), 7.19-7.15 (m, 1H), 7.13 (s, 1H), 6.88 (s, 1H), 6.71 (d,J
= 2.0 Hz, 1H), 4.24 (d,J
= 9.2 Hz, 1H), 4.03 (s, 3H), 3.70-3.65 (m, 1H), 3.62-3.56 (m, 1H), 3.32-3.23 (m, 1H), 3.14 (d,J
= 5.2 Hz, 2H), 2.93-2.86 (m, 2H), 2.30-2.27 (m, 1H), 2.12-1.98 (m, 2H), 1.24 (d,J
= 6.8 Hz, 3H), 1.10 (d,J
= 6.8 Hz, 3H)。MS (ESI, m/e) [M+1]+
365.1。
合成程序類似於中間體182-1。化合物(R)-1-((3,3-二甲基-2,3-二氫苯并呋喃-6-基)甲基)-3-(2-異丙基苯基)哌𠯤係黃色油狀物。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.55-7.53 (m, 1H), 7.25-7.22 (m, 2H), 7.19-7.16 (m, 1H), 7.01 (d,J
= 7.2 Hz, 1H), 6.85-6.79 (m, 2H), 4.24-4.20 (m, 3H), 3.60-3.55 (m, 1H), 350-3.44 (m, 1H), 3.30-3.23 (m, 1H), 3.16-3.09 (m, 2H), 2.91 (d,J
= 10.8 Hz, 1H), 2.84 (d,J
= 10.8 Hz, 1H), 2.30-2.24 (m, 1H), 2.05-1.98 (m, 1H), 1.32 (d,J
= 2.0 Hz, 6H), 1.24 (d,J
= 6.8 Hz, 3H), 1.12 (d,J
= 6.8 Hz, 3H)。MS (ESI, m/e) [M+1]+
365.2。
步驟1:3-(4-溴-2-甲氧基苯氧基)丙酸
在20°C下,向4-溴-2-甲氧基苯酚(5.0 g,24.63 mmol)在DMF(50 mL)中之溶液中添加NaH(5.1 g,28.06 mmol,60 wt%)。在25°C下攪拌30 min後,在25°C下滴加在DMF(25 mL)中的3-溴丙酸(9.0 g,59.10 mmol)。將混合物在50°C下攪拌24小時。向混合物中添加水(200 mL)和1 N HCl(100 mL),將其用EtOAc(100 mL × 3)萃取。將合併的有機層用鹽水洗滌,經無水Na2
SO4
乾燥,過濾並在減壓下濃縮。將粗產物藉由柱層析法(矽膠,洗脫液 : PE/EA(v/v)= 100/1至1/1)純化以給出呈白色固體的3-(4-溴-2-甲氧基苯氧基)丙酸(2.2 g,產率:33%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.04-7.01 (m, 1H), 7.01-6.99 (m, 1H), 6.81 (d,J
= 8.4 Hz, 1H), 4.28 (t,J
= 6.4 Hz, 2H), 3.85 (s, 3H), 2.90 (t,J
= 6.4 Hz, 2H)。
步驟2:6-溴-8-甲氧基口克唍-4-酮
在0°C下,向3-(4-溴-2-甲氧基苯氧基)丙酸(3.0 g,10.91 mmol)在DCM(50 mL)中之溶液中添加草醯二氯(2.8 g,21.81 mmol)。在25°C下攪拌30 min後,將混合物真空濃縮。將殘餘物溶解於DCM(50 mL)中,添加AlCl3
(2.9 g,21.81 mmol)(在0°C下)。將混合物在25°C下攪拌1 hr。向混合物中添加水,將其用DCM萃取,將有機層用鹽水洗滌,經無水Na2
SO4
乾燥,過濾並在減壓下濃縮。將粗產物藉由柱層析法(矽膠,洗脫液 : PE/EA(v/v)= 100/1至1/1)純化以給出呈白色固體的6-溴-8-甲氧基口克唍-4-酮(2.6 g,產率:93%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.63 (d,J
= 2.4 Hz, 1H), 7.13 (d,J
= 2.4 Hz, 1H), 4.65-4.60 (m, 2H), 3.91 (s, 3H), 2.86-2.82 (m, 2H)。
步驟3:6-溴-8-甲氧基口克唍
在25°C下,向6-溴-8-甲氧基口克唍-4-酮(2.6 g,10.11 mmol)在AcOH(150 mL)中之溶液中添加鋅粉(16.5 g,252.84 mmol)。將混合物在100°C下攪拌12小時。將混合物在減壓下濃縮。將殘餘物傾倒入H2
O(50 mL)中,用EtOAc(50 mL × 3)萃取。將合併的有機層用水性NaHCO3
洗滌,經無水Na2
SO4
乾燥,過濾並在減壓下濃縮。將粗產物藉由柱層析法(矽膠,洗脫液 : PE/EA(v/v)= 100/1至1/1)純化以給出呈無色油狀物的6-溴-8-甲氧基口克唍(2.2 g,產率:90%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 6.81 (s, 2H), 4.28-4.23 (m, 2H), 3.85 (s, 3H), 2.76 (t,J
= 6.4 Hz, 2H), 2.04-1.97 (m, 2H)。
步驟4:8-甲氧基口克唍-6-甲醛
在-70°C下,向6-溴-8-甲氧基口克唍(1.0 g,4.11 mmol)在THF(15 mL)中之溶液中添加n-BuLi(3.3 mL,8.23 mmol,2.5 N)。在-70°C下攪拌5 min後,在-70°C下滴加DMF(601 mg,8.23 mmol)。將混合物在-70°C下攪拌1 hr。將混合物傾倒入水性NH4
Cl(20 mL)中,用EtOAc(50 mL × 3)萃取。將合併的有機層用鹽水洗滌,經無水Na2
SO4
乾燥,過濾並在減壓下濃縮。將粗產物藉由柱層析法(矽膠,洗脫液:PE/EA(v/v)= 100/1至5/1)純化以給出呈黃色固體的8-甲氧基口克唍-6-甲醛(520 mg,產率:66%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 9.81 (d,J
= 1.4 Hz, 1H), 7.26 (s, 1H), 7.22 (s, 1H), 4.37 (t,J
= 4.8 Hz, 2H), 3.94 (s, 3H), 2.87 (t,J
= 6.4 Hz, 2H), 2.11-2.04 (m, 2H)。
步驟5:(R)-3-(2-異丙基苯基)-1-((8-甲氧基口克唍-6-基)甲基)哌𠯤
在0°C下,向8-甲氧基口克唍-6-甲醛(640 mg,3.33 mmol)在DCM(10 mL)中之溶液中添加(R)-2-(2-異丙基苯基)哌𠯤(700 mg,3.43 mmol)和NaBH(OAc)3(2.1 g,9.99 mmol)。將混合物在0°C下攪拌4小時。向混合物中添加水性Na2
CO3
至pH = 8-9,將其用DCM萃取。將合併的有機層用鹽水洗滌,經無水Na2
SO4
乾燥,過濾並在減壓下濃縮。將殘餘物藉由柱層析法(矽膠,洗脫液:PE/EA(v/v)= 10/1至2/1至EA)純化以給出呈黃色油狀物的(R)-3-(2-異丙基苯基)-1-((8- 甲氧基口克唍-6-基)甲基)哌𠯤(925 mg,產率:73%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.57 (d,J
= 7.6 Hz, 1H), 7.27-7.21 (m, 2H), 7.20-7.15 (m, 1H), 6.76 (s, 1H), 6.60 (s, 1H), 4.30-4.21 (m, 3H), 3.88 (s, 3H), 3.56-3.52 (m, 1H), 3.44-3.40 (m, 1H), 3.27 (m, 1H), 3.19-3.10 (m, 2H), 2.97-2.83 (m, 2H), 2.76-2.73 (m, 2H), 2.30 (s, 1H), 2.08-1.92 (m, 4H), 1.25 (d,J
= 6.8 Hz, 3H), 1.15 (d,J
= 6.8 Hz, 3H)。MS (ESI, m/e) [M+1]+
381.2。
合成程序類似於中間體182-1。化合物(R)-8-((3-(2-異丙基苯基)哌𠯤-1-基)甲基)-2,2-二甲基-2,3-二氫-[1,4]戴奧辛並[2,3-b]吡啶係無色油狀物。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.77 (d,J
= 5.2 Hz, 1H), 7.55 (d,J
= 7.6 Hz, 1H), 7.27 (s, 1H), 7.26-7.21 (m, 1H), 7.19-7.14 (m, 1H), 7.05 (d,J
= 5.2 Hz, 1H), 4.25 (dd,J
= 2.0, 10.0 Hz, 1H), 4.03 (s, 2H), 3.98-3.83 (m, 1H), 3.58 (s, 2H), 3.30 (td,J
= 6.8, 13.6 Hz, 1H), 3.17-3.08 (m, 2H), 2.86 (br t,J
= 10.8 Hz, 2H), 2.37 (dt,J
= 4.4, 10.8 Hz, 1H), 2.17 (t,J
= 10.8 Hz, 1H), 1.32 (d,J
= 5.6 Hz, 6H), 1.26 (d,J
= 6.8 Hz, 3H), 1.19 (d,J
= 6.8 Hz, 3H)。MS (ESI, m/e) [M+1]+
382.1。
合成程序類似於中間體182-1。化合物(R)-1-((2,2-二甲基-2,3-二氫苯并[b][1,4]戴奧辛-5-基)甲基)-3-(2-異丙基苯基)哌𠯤係黃色油狀物。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.53 (d,J
= 7.2 Hz, 1H), 7.29-7.27 (m, 1H), 7.26-7.20 (m, 1H), 7.19-7.13 (m, 1H), 6.93 (d,J
= 7.6 Hz, 1H), 6.83-6.79 (m, 1H), 6.78-6.72 (m, 1H), 4.28 (d,J
= 9.6 Hz, 1H), 3.86 (s, 2H), 3.79-3.61 (m, 2H), 3.33-3.30 (m, 1H), 3.19-3.08 (m, 2H), 2.98-2.87 (m, 2H), 2.41-2.34 (m, 1H), 2.21-2.15 (m, 1H), 1.32 (d,J
= 1.6 Hz, 6H), 1.25 (d,J
= 6.4 Hz, 3H), 1.19 (d,J
= 6.8 Hz, 3H)。MS (ESI, m/e) [M+1]+
381.1。
合成程序類似於中間體182-1。化合物(R)-8-((3-(2-異丙基苯基)哌𠯤-1-基)甲基)-3,3-二甲基-2,3-二氫-[1,4]戴奧辛並[2,3-b]吡啶係黃色固體。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.78-7.77 (m, 1H), 7.53-7.51 (m, 1H), 7.27-7.13 (m, 3H), 7.01-7.00 (m, 1H), 4.25-4.24 (m, 1H), 3.85 (s, 2H), 3.61 (s, 2H), 3.30-3.28 (m, 2H), 3.14-3.11 (m, 2H), 2.89-2.82 (m, 2H), 2.30-2.26 (m, 1H), 2.14-2.11 (m, 1H), 1.37 (s, 6H), 1.25 (d,J
= 6.8 Hz, 3H), 1.17 (d,J
= 6.8 Hz, 3H)。MS (ESI, m/e) [M+1]+
382.2。
合成程序類似於中間體182-1。化合物(R)-1-(4-環丙氧基-3-甲氧基苄基)-3-(2-異丙基苯基)哌𠯤係黃色油狀物。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.56 (d,J
= 7.6 Hz, 1H), 7.27-7.21 (m, 2H), 7.20-7.13 (m, 2H), 6.93 (s, 1H), 6.87-6.78 (m, 1H), 4.22 (s, 1H), 3.88 (s, 3H), 3.74-3.71 (m, 1H), 3.56 (s, 1H), 3.49-3.45 (m, 1H), 3.22-3.27 (m, 1H), 3.14 (s, 1H), 2.87 (s, 1H), 2.26 (s, 1H), 2.05-1.88 (m, 1H), 1.23 (d,J
= 6.8 Hz, 1H), 1.14 (d,J
= 6.8 Hz, 3H), 0.87-0.82 (m, 2H), 0.75-0.80 (m, 2H)。MS (ESI, m/e) [M+1]+
381.1。
步驟1:7-羥基苯并呋喃-5-甲醛
在0°C下,向7-甲氧基苯并呋喃-5-甲醛(2.0 g,11.35 mmol)在DCM(20 mL)中之溶液中添加BBr3
(5.69 g,22.71 mmol),並將其在25°C下攪拌2小時。向混合物中添加水(20 mL),將其用EtOAc(20 mL × 3)萃取,將有機層用鹽水洗滌,經無水Na2
SO4
乾燥,過濾並在減壓下濃縮。將粗產物藉由柱層析法(矽膠,洗脫液:PE/EA(v/v)= 10/1至1/1)純化以給出呈白色固體的6-溴-8-甲氧基口克唍-4-酮(0.34 g,產率:18%)。7-羥基苯并呋喃-5-甲醛。1
H NMR (400 MHz, CDCl3
) δ ppm: 10.01 (s, 1H), 7.80-7.80 (m, 2H), 7.42 (s, 1H), 6.93 (d,J
= 2.0 Hz, 1H), 5.70 (br s, 1H)。
步驟2:7-(甲氧基-d3)苯并呋喃-5-甲醛
在20°C下,向7-羥基苯并呋喃-5-甲醛(0.34 g,2.10 mmol)在DMF(20 mL)中之溶液中添加K2
CO3
(579 mg,4.19 mmol)和CD3
I(1.52 g,10.48 mmol)。將混合物在20°C下攪拌2小時。將混合物傾倒入H2
O(20 mL)中,用EtOAc(20 mL × 3)萃取。將合併的有機層用鹽水洗滌,經無水Na2
SO4
乾燥,過濾並在減壓下濃縮。將粗產物藉由柱層析法(矽膠,洗脫液 : PE/EA(v/v)= 100/1至1/1)純化以給出呈無色油狀物的7-(甲氧基-d3)苯并呋喃-5-甲醛(0.43 g,粗製)。MS (ESI, m/e) [M+1]+
180.2。
步驟3:(R)-3-(2-異丙基苯基)-1-((7-(甲氧基-d3)苯并呋喃-5-基)甲基)哌𠯤
向(R)-2-(2-異丙基苯基)哌𠯤(490 mg,2.40 mmol)在DCM(20 mL)中之溶液中添加7-(甲氧基-d3)苯并呋喃-5-甲醛(430 mg,2.40 mmol),並添加NaBH(OAc)3
(1.27 g,6.00 mmol)(在0°C下)。將混合物在20°C下攪拌4小時。向混合物中添加水性Na2
CO3
(20 mL),將其用EtOAc(20 mL × 3)萃取。將合併的有機層用鹽水洗滌,經無水Na2
SO4
乾燥,過濾並在減壓下濃縮。將殘餘物藉由矽膠柱層析法(矽膠,洗脫液:PE/EA(v/v)= 10/1至EA)純化以給出呈黃色油狀物的(R)-3-(2-異丙基苯基)-1-((7-d3-甲氧基苯并呋喃-5-基)甲基)哌𠯤(300 mg,產率:33%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.61-7.56 (m, 2H), 7.26-7.21 (m, 2H), 7.18-7.12 (m, 1H), 6.91 (s, 1H), 6.71 (d,J
= 2.4 Hz, 1H), 4.36 (d,J
= 9.2 Hz, 1H), 3.70 (m, 3H), 3.27-3.22 (m, 1H), 3.18-3.17 (m, 2H), 3.01-2.91 (m, 2H), 2.45-2.41 (m, 1H), 2.25-2.18 (m, 1H), 1.29-1.20 (m, 2H), 1.26-1.23 (m, 1H), 1.10 (d,J
= 6.8 Hz, 3H)。MS (ESI, m/e) [M+1]+
368.2。
步驟1:7-羥基-3,3-二甲基-2,3-二氫苯并呋喃-5-甲醛
在0°C下,向7-甲氧基-3,3-二甲基-2,3-二氫苯并呋喃-5-甲醛(4.0 g,19.4 mmol)在DCM(40 mL)中之溶液中添加BBr3(14.6 g,58.19 mmol)。將混合物在20°C下攪拌12小時。向混合物中添加水(200 mL)並將其用DCM(30 mL × 3)萃取。將合併的有機層用鹽水洗滌,經無水Na2
SO4
乾燥,過濾並在減壓下濃縮。將粗產物藉由柱層析法(矽膠,洗脫液:PE/EA(v/v)= 100/1至1/1)純化以給出呈無色油狀物的7-羥基-3,3-二甲基-2,3-二氫苯并呋喃-5-甲醛(2.8 g,產率:75%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 9.79 (s, 1H), 7.32 (dd,J
= 1.2, 14.4 Hz, 2H), 5.97-5.85 (m, 1H), 4.41 (s, 2H), 1.38 (s, 6H)。
步驟2:7-(甲氧基-d3)-3,3-二甲基-2,3-二氫苯并呋喃-5-甲醛
在0°C下,向7-羥基-3,3-二甲基-2,3-二氫苯并呋喃-5-甲醛(1.0 g,5.2 mmol)在DMF(20 mL)中之溶液中添加CD3
I(1.5 g,10.41 mmol)和K2
CO3
(2.2 g,15.61 mmol)。將混合物在20°C下攪拌6小時。向混合物中添加水(30 mL)並將其用EtOAc(20 mL × 3)萃取。將合併的有機層用鹽水洗滌,經無水Na2
SO4
乾燥,過濾並在減壓下濃縮。將粗產物藉由柱層析法(矽膠,洗脫液:PE/EA(v/v)= 100/1至1/1)純化以給出呈無色油狀物的7-(甲氧基-d3)-3,3-二甲基-2,3-二氫苯并呋喃-5-甲醛(1.0 g,產率:92%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 9.83 (s, 1H), 7.32-7.30 (m, 2H), 4.43 (s, 2H), 1.39 (s, 6H)
步驟3:(R)-3-(2-異丙基苯基)-1-((7-(甲氧基-d3)-3,3-二甲基-2,3-二氫苯并呋喃-5-基)甲基)哌𠯤
在0°C下,向7-(甲氧基-d3)-3,3-二甲基-2,3-二氫苯并呋喃-5-甲醛(700 mg,3.35 mmol)和(R)-2-(2-異丙基苯基)哌𠯤(683.5 mg,3.35 mmol)在DCM(10 mL)中之溶液中添加NaBH(OAc)3
(1.77 g,8.36 mmol)。將混合物在20°C下攪拌2小時。將反應混合物在20°C下藉由添加水性NaHCO3
(20 mL)淬滅,用DCM(10 mL × 3)萃取。將合併的有機層用鹽水洗滌,經Na2
SO4
乾燥,過濾並在減壓下濃縮。將殘餘物藉由柱層析法(矽膠,洗脫液:PE/EA(v/v)= 100/1至EA)純化以給出呈無色油狀物的(R)-3-(2-異丙基苯基)-1-((7-(甲氧基-d3)-3,3-二甲基-2,3-二氫苯并呋喃-5-基)甲基)哌𠯤(617 mg,產率:46%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.58 (d,J
= 7.6 Hz, 1H), 7.27 (s, 3H), 6.81-6.66 (m, 2H), 4.30 (s, 2H), 4.27-4.21 (m, 1H), 3.60 (d,J
= 12.8 Hz, 1H), 3.44 (d,J
= 12.8 Hz, 1H), 3.27 (td,J
= 6.8, 13.6 Hz, 1H), 3.20-3.12 (m, 2H), 2.97-2.85 (m, 2H), 2.60-2.49 (m, 1H), 2.33 -2.22 (m, 1H), 2.02-1.96 (m, 1H), 1.34 (d,J
= 2.4 Hz, 6H), 1.26 (d,J
= 6.8 Hz, 3H), 1.15 (d,J
= 6.8 Hz, 3H)。MS (ESI, m/e) [M+1]+
398.1。
合成程序類似於中間體182-1。化合物(R)-1-(4-氯-3-甲氧基苄基)-3-(2-異丙基苯基)哌𠯤係黃色油狀物。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.59 (d,J
= 7.6 Hz, 1H), 7.32-7.29 (m, 1H), 7.24-7.22 (m, 1H), 7.23-7.13 (m, 2H), 7.02-7.00 (br d, 1H), 6.86-6.84 (m, 1H), 4.28 (br s, 1H), 3.92 (s, 3H), 3.39-3.73 (m, 3H), 3.20-3.28 (m, 1H), 3.13 (br s, 2H), 2.80-2.94 (m, 2H), 2.36 (br s, 1H), 2.14 (br s, 1H), 1.26 (d,J
= 7.6 Hz, 3H), 1.14 (d,J
= 7.6 Hz, 3H)。MS (ESI, m/e) [M+1]+
359.0。
合成程序類似於中間體182-1。化合物(R)-1-(4-環丙基-3,5-二甲氧基苄基)-3-(2-異丙基苯基)哌𠯤係無色油狀物。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.55 (d,J
= 7.6 Hz, 1H), 7.27-7.14 (m, 3H), 6.53 (s, 2H), 4.21 (d,J
= 10.0 Hz, 1H), 3.81 (s, 6H), 3.61-3.55 (m, 1H), 3.45-3.40 (m, 1H), 3.29-3.26 (m, 1H), 3.14 (d,J
= 6.4 Hz, 2H), 2.93-2.82 (m, 2H), 2.28-2.21 (m, 1H), 2.05-1.93 (m, 2H), 1.85-1.76 (m, 1H), 1.25 (d,J
= 6.8 Hz, 3H), 1.14 (d,J
= 6.8 Hz, 3H), 0.93-0.88 (m, 2H), 0.84-0.79 (m, 2H)。MS (ESI, m/e) [M+1]+
395.2。
合成程序類似於中間體182-1。化合物(R)-3-(2-異丙基苯基)-1-((8-甲氧基-2,2-二甲基-2H-色烯-6-基)甲基)哌𠯤係黃色油狀物。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.56-7.53 (m, 1H), 7.27-7.17 (m, 3H), 6.79 (d,J
= 1.6 Hz, 1H), 6.59 (d,J
= 1.6 Hz, 1H), 6.28 (d,J
= 9.6 Hz, 1H), 5.60 (d,J
= 9.6 Hz, 1H), 4.21-4.18 (m, 1H), 3.87 (s, 3H), 3.54-3.49 (m, 1H), 3.40-3.35 (m, 1H), 3.28-3.23 (m, 1H), 3.17-3.11 (m, 2H), 2.93-2.83 (m, 2H), 2.24-2.18 (m, 1H), 1.98-1.93 (m, 1H), 1.90-1.82 (m, 1H), 1.46 (d,J
= 2.8 Hz, 6H), 1.23 (d,J
= 6.8 Hz, 3H), 1.14 (d,J
= 6.8 Hz, 3H)。MS (ESI, m/e) [M+1]+
407.1。
合成程序類似於中間體182-1。化合物(R)-3-(2-異丙基苯基)-1-((4-甲氧基苯并呋喃-6-基)甲基)哌𠯤係黃色油狀物。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.48-7.41 (m, 2H), 7.18-7.06 (m, 3H), 7.04 (s, 1H), 6.74-6.73 (m, 1H), 6.64 (s, 1H), 4.19-4.16 (m, 1H), 3.87 (s, 3H), 3.65-3.52 (m, 2H), 3.25-3.14 (m, 1H), 3.11-3.04 (m, 2H), 2.89-2.78 (m, 2H), 2.29-2.17 (m, 1H), 2.03-2.00 (d,J
= 10.8 Hz, 1H), 1.16 (d,J
= 6.8 Hz, 3H), 1.03 (d,J
= 6.8 Hz, 3H)。MS (ESI, m/e) [M+1]+
365.1。
步驟1:甲基 3-(4-溴-2-甲氧基苯氧基)丙酸酯
將4-溴-2-甲氧基苯酚(10.0 g,49.25 mmol)在丙烯酸甲酯(100 mL)中之混合物添加至苄基三甲基氫氧化銨(triton B)(1.0 mL)和MeOH(1.0 mL)中。將混合物回流攪拌12小時。將混合物冷卻至室溫並且然後在減壓下濃縮。將殘餘物傾倒入水(100 mL)中,用EtOAc(100 mL × 3)萃取。將合併的有機層用鹽水洗滌,經無水Na2
SO4
乾燥,過濾並在減壓下濃縮。將粗產物藉由相分離純化以給出呈黃色油狀物的甲基 3-(4-溴-2-甲氧基苯氧基)丙酸酯(5.6 g,產率:39%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 6.97-7.05 (m, 2 H), 6.80 (d,J
= 8.8 Hz, 1H), 4.29-4.26 (m, 2H), 3.84 (s, 3H), 3.73 (s, 3H), 2.87-2.83 (m, 2H)。
步驟2:4-(4-溴-2-甲氧基苯氧基)-2-甲基丁-2-醇。
在-70°C下,向甲基 3-(4-溴-2-甲氧基苯氧基)丙酸酯(5.1 g,17.64 mmol)在THF(50 mL)中之混合物中添加MeMgBr(17.64 mL,52.92 mmol,3.0 N)。將混合物在-70°C下攪拌3小時。將殘餘物傾倒入冰水(100 mL)中,用EtOAc(100 mL × 3)萃取。將合併的有機層用鹽水洗滌,經無水Na2
SO4
乾燥,過濾並在減壓下濃縮。將粗產物藉由柱層析法(矽膠,洗脫液 : PE/EA(v/v)= 100/1至1/1)純化以給出呈黃色固體的4-(4-溴-2-甲氧基苯氧基)-2-甲基丁-2-醇(4.5 g,產率:88%)。MS (ESI, m/e) [M+1]+
290.1。
步驟3:6-溴-8-甲氧基-4,4-二甲基口克唍
在0°C下,將4-(4-溴-2-甲氧基苯氧基)-2-甲基丁-2-醇(3.5 g,12.1 mmol)在MeNO2
(30 mL)中之混合物添加至在MeNO2
(250 mL)中的AlCl3
(2.3 g,16.39 mmol)中並且將混合物在25°C下攪拌2小時。將殘餘物傾倒入冰水(100 mL)中,用EtOAc(50 mL × 3)萃取。將合併的有機層用鹽水洗滌,經無水Na2
SO4
乾燥,過濾並在減壓下濃縮。將殘餘物藉由柱層析法(矽膠,洗脫液 : PE/EA(v/v)= 100/1至1/1)純化以給出呈黃色油狀物的6-溴-8-甲氧基-4,4-二甲基口克唍(2.4 g,產率:73%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.00 (d,J
= 2.0 Hz,1H), 6.80 (d,J
= 2.4 Hz, 1H), 4.30-4.24 (m, 2H), 3.85 (s, 3H), 1.87-1.81 (m, 2H), 1.32 (s, 6H)。
步驟4:8-甲氧基-4,4-二甲基口克唍-6-甲醛
在-70°C下,向6-溴-8-甲氧基-4,4-二甲基口克唍(2.4 g,8.9 mmol)在THF(30 mL)中之溶液中添加n-BuLi(8.9 mL,22.1 mmol,2.5 N)。在-70°C下攪拌5 min後,在-70°C下滴加DMF(3.2 g,44.3 mmol)。將混合物在-70°C下攪拌2小時。將混合物傾倒入水性NH4
Cl(50 mL)中,用EtOAc(30 mL × 3)萃取。將合併的有機層用鹽水洗滌,經無水Na2
SO4
乾燥,過濾並在減壓下濃縮。將粗產物藉由柱層析法(矽膠,洗脫液:PE/EA(v/v)= 100/1至5/1)純化以給出呈淡黃色固體的8-甲氧基-4,4-二甲基口克唍-6-甲醛(1.4 g,產率:72%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 9.82 (s, 1 H), 7.44 (d, J = 1.6 Hz, 1 H), 7.23 (d, J = 1.6 Hz, 1 H), 7.26 - 7.20 (m, 1 H), 4.40 - 4.33 (m, 2 H), 3.92 (s, 3 H), 1.92 - 1.86 (m, 2 H), 1.38 (s, 6 H)。
步驟5:(R)-3-(2-異丙基苯基)-1-((8-甲氧基-4,4-二甲基口克唍-6-基)甲基)哌𠯤
在0°C下,向(R)-2-(2-異丙基苯基)哌𠯤(843 mg,4.1 mmol)在DCM(30 mL)中之溶液中添加8-甲氧基-4,4-二甲基口克唍-6-甲醛(1 g,4.5 mmol)和NaBH(OAc)3(2.2 g,10.3 mmol),並且將混合物在25°C下攪拌12小時。向混合物中添加水性NaHCO3
(30 mL),將其用DCM(30 mL × 3)萃取。將合併的有機層用鹽水洗滌,經無水Na2
SO4
乾燥,過濾並在減壓下濃縮。將殘餘物藉由柱層析法(矽膠,洗脫液:PE/EA(v/v)= 100/1至EA)純化以給出呈黃色固體的(R)-3-(2-異丙基苯基)-1-((8-甲氧基-4,4-二甲基口克唍-6-基)甲基)哌𠯤(1149 mg,產率:68%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.56-7.53 (m, 1H), 7.27-7.16 (m, 3H), 6.81 (d,J
= 1.6 Hz, 1H), 6.73 (d,J
= 1.6 Hz, 1H), 4.28-4.24 (m, 2H), 4.23-4.21 (m, 1H), 3.87 (s, 3H), 3.58-3.53 (m, 1H), 3.44-3.38 (m, 1H), 3.30-3.23 (m, 1H), 3.16-3.11 (m, 2H), 2.92-2.81 (m, 2H), 2.24-2.20 (m, 1H), 2.20-1.98 (m, 1H), 1.85-1.82 (m, 2H), 1.32 (d,J
= 5.6 Hz, 6H), 1.24 (d,J
= 6.8 Hz, 3H), 1.14 (d,J
= 6.8 Hz, 3H)。MS (ESI, m/e) [M+1]+
409.1。
合成程序類似於中間體182-1。化合物(R)-3-(2-異丙基苯基)-1-((9-甲氧基-3,4-二氫-2H-苯并[b][1,4]二㗁呯-7-基)甲基)哌𠯤係黃色油狀物。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.47 (d,J
= 7.6 Hz, 1H), 7.19-7.06 (m, 3H), 6.55 (s, 1H), 6.50 (s, 1H), 4.20-4.17 (m, 2H), 4.15-4.12 (m, 3H), 3.79 (s, 3H), 3.47-3.39 (m, 1H), 3.35-3.27 (m, 1H), 3.23-3.16 (m, 1H), 3.06 (d,J
= 6.0 Hz, 2H), 2.86-2.73 (m, 2H), 2.22-2.10 (m, 3H), 1.97-1.89 (m, 1H), 1.16 (d,J
= 6.8 Hz, 3H), 1.08 (d,J
= 6.8 Hz, 3H)。MS (ESI, m/e) [M+1]+
397.2。
步驟1:3-甲氧基-4-(丙-2-炔-1-基氧基)苯甲醛之合成。
在20°C下,向4-羥基-3-甲氧基苯甲醛(50 g,328.63 mmol)在DMF(80 mL)中之溶液中添加3-溴丙-1-炔(78 g,657.26 mmol)、K2
CO3
(90.84 g,657.26 mmol)。將混合物在80°C下攪拌12小時。將混合物冷卻至室溫並用水(80 mL)稀釋並且然後用EtOAc(500 mL × 3)萃取。將合併的有機層用鹽水洗滌,經無水Na2
SO4
乾燥,過濾並在減壓下濃縮。將粗產物藉由柱層析法(矽膠,洗脫液:PE/EA(v/v)= 100/1至1/1)純化以給出呈白色固體的3-甲氧基-4-(丙-2-炔-1-基氧基)苯甲醛(58 g,產率:93%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 9.89 (s, 1H), 7.48-7.44 (m, 2H), 7.16 (d,J
= 8.4 Hz, 1H), 4.87 (d,J
= 2.4 Hz, 2H), 3.95 (s, 3 H), 2.57 (t,J
= 2.4 Hz, 1H)。
步驟2:7-甲氧基-2-甲基苯并呋喃-5-甲醛之合成。
在20°C下,向3-甲氧基-4-(丙-2-炔-1-基氧基)苯甲醛(39 g,31.55 mmol)的溶液中添加PEG-600(200 mL)。將混合物在220°C下攪拌4小時。將混合物冷卻至室溫並用水(200 mL)稀釋且用EtOAc(200 mL × 3)萃取。將合併的有機層用鹽水洗滌,經無水Na2
SO4
乾燥,過濾並在減壓下濃縮。將粗產物藉由柱層析法(矽膠,洗脫液:PE/EA(v/v)= 100/1至1/1)純化以給出呈白色固體的7-甲氧基-2-甲基苯并呋喃-5-甲醛(14 g,產率:35%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 10.00 (s, 1H), 7.64 (s, 1H), 7.34 (s, 1H), 6.51 (s, 1H), 4.07 (s, 3H), 2.54 (s, 3H)。
步驟3:(R)-3-(2-異丙基苯基)-1-((7-甲氧基-2-甲基苯并呋喃-5-基)甲基)哌𠯤之合成。
在0°C下,向(R)-2-(2-異丙基苯基)哌𠯤(10 g,48.94 mmol)在DCM(200 mL)中之溶液中添加7-甲氧基-2-甲基苯并呋喃-5-甲醛(9.31 g,48.94 mmol)和NaBH(OAc)3
(25.93 g,122.38 mmol)。然後將混合物在室溫下攪拌12小時。將混合物用水性Na2
CO3
(6 M, 200 mL)淬滅,用EtOAc(200 mL × 3)萃取。將合併的有機層用鹽水洗滌,經無水Na2
SO4
乾燥,過濾並在減壓下濃縮。將殘餘物藉由柱層析法(矽膠,洗脫液 : PE/EA(v/v)= 100/1至EA)純化以給出(R)-3-(2-異丙基苯基)-1-((7-甲氧基-2-甲基苯并呋喃-5-基)甲基)哌𠯤(12.2 g,產率:64%)。1
H NMR (400 MHz, CDCl3 )
δ ppm: 7.56-7.54 (m, 1H), 7.24-7.21 (m, 3H), 7.01 (s, 1H), 6.79 (s, 1H), 6.30 (d,J
= 1.2 Hz, 1H), 4.23-4.20 (m, 1H), 4.02 (s, 3H), 3.65-3.53 (m, 2H), 3.33-3.23 (m, 1H), 3.15-3.12 (m, 2H), 2.96-2.83 (m, 2H), 2.46 (d,J
= 0.4 Hz, 3H), 2.31-2.20 (m, 1H), 2.04-1.99 (t,J
= 10.6 Hz, 1H), 1.24 (d,J
= 6.8 Hz, 3H), 1.12 (d,J
= 6.8 Hz, 3H)。MS (ESI, m/e) [M+1]+
379.2。
合成程序類似於中間體182-1。化合物(R)-1-(4-環丁基-3-甲氧基苄基)-3-(2-異丙基苯基)哌𠯤係黃色油狀物。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.58 (d,J
= 7.6 Hz, 1H), 7.27-7.21 (m, 2H), 7.18-7.12 (m, 2H), 6.93-6.83 (m, 2H), 4.35-4.33 (m, 1H), 3.82 (s, 3H), 3.74-3.54 (m, 4H), 3.36-3.14 (m, 2H), 2.99-2.88 (m, 2H), 2.35-2.25 (m, 3H), 2.14-2.02 (m, 5H), 1.84-1.78 (m, 1H), 1.27-1.24 (m, 3H), 1.13 (d,J
= 6.8 Hz, 3H)。MS (ESI, m/e) [M+1]+
379.1。
合成程序類似於中間體182-1。化合物(R)-3-(2-異丙基苯基)-1-(3-甲氧基-4-(氧雜環丁烷-3-基)苄基)哌𠯤係黃色油狀物。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.57 (d,J
= 7.6 Hz, 1H), 7.26-7.14 (m, 4H), 6.96-6.84 (m, 2H), 5.01-4.97 (m, 2H), 4.84-4.79 (m, 2H), 4.51-4.49 (m, 1H), 4.26 (s, 1H), 3.81 (s, 3H), 3.68-3.59 (m, 1H), 3.51-3.49 (m, 1H), 3.30-3.21 (m, 1H), 3.14 (d,J
= 5.6 Hz, 2H), 2.95-2.81 (m, 2H), 2.39-2.28 (m, 1H), 2.13-2.06 (m, 1H), 1.25 (d,J
= 6.8 Hz, 3H), 1.13 (d,J
= 6.8 Hz, 3H)。MS (ESI, m/e) [M+1]+
381.2。
合成程序類似於中間體182-1。化合物(R)-3-(2-異丙基苯基)-1-((9-甲氧基-2,3,4,5-四氫苯并[b]㗁呯-7-基)甲基)哌𠯤係黃色固體。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.56-7.54 (m, 1H), 7.29-7.25 (m, 2H), 7.21-7.19 (m, 1H), 6.80 (s, 1H), 6.68 (s, 1H), 4.32-4.30 (m, 1H), 4.01-4.00 (m, 2H), 3.86 (s, 3H), 3.60-3.43 (m, 2H), 3.25-3.20 (m, 3H), 2.80-2.79 (m, 2H), 2.78-2.77 (m, 2H), 2.35-2.31 (m, 1H), 2.09-2.07 (m, 1H), 2.00-1.96 (m, 2H),1.72-1.71 (m, 2H), 1.26 (d,J
= 6.8 Hz, 3H), 1.15 (d,J
= 6.8 Hz, 3H)。MS (ESI, m/e) [M+1]+
395.2。
合成程序類似於中間體182-1。化合物(R)-1-(4-異丙氧基-3-甲氧基苄基)-3-(2-異丙基苯基)哌𠯤係黃色油狀物。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.56 (d,J
= 7.6 Hz, 1H), 7.27-7.19 (m, 3H), 6.94-6.74 (m, 4H), 5.52-5.46 (m, 1H), 4.50-4.47 (m, 2H), 4.34-4.31 (m, 1H), 3.86 (s, 3H), 3.62-3.51 (m, 2H), 3.23-3.16 (m, 2H), 2.95-2.90 (m, 2H), 1.36-1.32 (m, 6H), 1.24 (d,J
= 6.8 Hz, 3H), 1.12 (d,J
= 6.8 Hz, 3H)。MS (ESI, m/e) [M+1]+
383.2。
合成程序類似於中間體182-1。化合物(R)-1-(4-環丁氧基-3-甲氧基苄基)-3-(2-異丙基苯基)哌𠯤係黃色油狀物。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.55-7.53 (m, 1H), 7.25-7.14 (m, 3H), 6.91 (s, 1H), 6.78-6.76 (m, 1H), 6.66-6.64 (m, 1H), 4.66-4.59 (m, 1H), 4.18-4.08 (m, 1H), 3.88 (s, 3H), 3.57-3.53 (m, 2H), 3.45-3.43 (m, 1H), 3.14-3.12 (m, 2H), 2.45-2.44 (m, 2 H), 2.27-2.24 (m, 4H), 2.23 (s, 1H), 2.22-2.05 (m, 1H), 1.83-1.68 (m, 1H), 1.23-1.22 (m, 3H), 1.13-1.12 (m, 3H)。MS (ESI, m/e) [M+1]+
395.2。
合成程序類似於中間體182-1。化合物(R)-3-(2-異丙基苯基)-1-(3-甲氧基-4-(氧雜環丁烷-3-基氧基)苄基)哌𠯤係黃色油狀物。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.56 (d,J
= 7.6 Hz, 1H), 7.27-7.24 (m, 2H), 7.18-7.16 (m, 1H), 6.99 (s, 1H), 6.78-6.76 (m, 1H), 6.40 (d,J
= 8.0 Hz, 1H), 5.20-5.16 (m, 1H), 4.96-4.92 (m, 2H), 4.85-4.82 (m, 2H), 4.31 (d,J
= 7.2 Hz, 1H), 3.90 (s, 3H), 3.63-3.47 (m, 2H), 3.30-3.09 (m, 3H), 2.97-2.83 (m, 2H), 2.43-2.29 (m, 1H), 2.19-2.09 (m, 1H), 1.26-1.23 (m, 3H), 1.12 (d,J
= 7.2 Hz, 3H)。MS (ESI, m/e) [M+1]+
397.2。
步驟1:3-甲氧基-4-𠰌啉代苯甲醛
在100°C下,向4-氟-3-甲氧基苯甲醛(2 g,12.98 mmol)在DMSO(15 mL)中之溶液中添加𠰌啉(1.6 g,12.98 mmol)、K2
CO3
(3.59 g,25.95 mmol)。將混合物在100°C下攪拌12小時。向混合物中添加水(30 mL)並將其用EtOAc(30 mL × 3)萃取。將合併的有機層用鹽水洗滌,經無水Na2
SO4
乾燥,過濾並在減壓下濃縮。將粗產物藉由柱層析法(矽膠,洗脫液 : PE/EA(v/v)= 100/1至1/1)純化至呈白色固體的3-甲氧基-4-𠰌啉代苯甲醛(2.23 g,產率:87%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 9.86 (s, 1H), 7.45 (d,J
= 2.0 Hz, 1H), 7.43 (d,J
= 2.0 Hz, 1H), 6.99-6.97 (m, 1H), 3.93 (s, 3H), 3.90-3.88 (m, 4H), 3.22-3.20 (m, 4H)。
步驟2:(R)-4-(4-((3-(2-異丙基苯基)哌𠯤-1-基)甲基)-2-甲氧基苯基)𠰌啉
向3-甲氧基-4-𠰌啉代苯甲醛(600 mg,2.58 mmol)在DCM(10 mL)中之溶液中添加3-甲氧基-4-(氧雜環丁烷-3-基氧基)苯甲醛(554.06 mg,2.58 mmol),並在0°C下添加NaBH(OAc)3
(1.15 g,5.16 mmol)。將混合物在20°C下攪拌12小時。向混合物中添加水性Na2
CO3
(20 mL),並將其用EtOAc(20 mL × 3)萃取。將合併的有機層用鹽水洗滌,經無水Na2
SO4
乾燥,過濾並在減壓下濃縮。將殘餘物藉由柱層析法(矽膠,洗脫液:PE/EA(v/v)= 100/1至EA)純化以給出呈黃色油狀物的(R)-4-(4-((3-(2-異丙基苯基)哌𠯤-1-基)甲基)-2-甲氧基苯基)𠰌啉(600 mg,產率:66%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.56 (d,J
= 7.6 Hz, 1H), 7.25-7.22 (m, 2H), 7.21-7.15 (m, 1H), 6.93 (s, 1H), 6.85-6.84 (m, 2H), 4.22 (d,J
= 8.0 Hz, 1H), 3.90-3.88 (m, 8H), 3.59-3.56 (m, 1H), 3.47-3.45 (m, 1H), 3.28-3.25 (m, 1H), 3.14-3.12 (m, 2H), 3.05-3.03 (m, 4H), 2.91-2.80 (m, 2H), 2.26-2.21 (m, 1H), 2.03-1.99 (m, 1H), 1.24 (d,J
= 6.8 Hz, 3H), 1.14 (d,J
= 6.8 Hz, 3H)。MS (ESI, m/e) [M+1]+
410.3。
合成程序類似於中間體182-1。呈黃色油狀物的化合物(R)-3-(2-異丙基苯基)-1-(4-(氧雜環丁烷-3-基)苄基)哌𠯤。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.46 (d,J
= 8.0 Hz, 1H), 7.20-7.14 (m, 6H), 7.12-7.09 (m, 1H), 5.01-4.98 (m, 2H), 4.70-4.67 (m, 2H), 4.19-4.09 (m, 2H), 3.57-3.41 (m, 2H), 3.25-3.14 (m, 1H), 3.09-3.01 (m, 2H), 2.85-2.72 (m, 2H), 2.18-2.17 (m, 1H), 1.99-1.94 (m, 1H), 1.16 (d,J
= 6.8 Hz, 3H), 1.06 (d,J
= 6.8 Hz, 3H)。MS (ESI, m/e) [M+1]+
351.2。
合成程序類似於中間體182-1。化合物(R)-1-(3,4-二環丙氧基苄基)-3-(2-異丙基苯基)哌𠯤係黃色油狀物。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.55-7.53 (m, 1H), 7.27-7.13 (m, 5H), 6.88-6.84 (m, 1H), 4.21 (d,J
= 8.8 Hz, 1H), 3.79-3.69 (m, 2H), 3.62-3.55 (m, 1H), 3.50-3.42 (m, 1H), 3.14-3.06 (m, 2H), 2.94-2.81 (m, 2H), 2.29-2.21 (m, 1H), 2.06-2.05 (m, 1H), 1.23 (d,J
= 6.8 Hz, 3H), 1.14 (d,J
= 6.8 Hz, 3H), 0.83-0.74 (m, 8H)。MS (ESI, m/e) [M+1]+
407.3。實例 3
2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-(4-異丙基-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺
步驟1:三級丁基 2-(2-溴苯基)-3-側氧基哌𠯤-1-甲酸酯。
在0°C下,向3-(2-溴苯基)哌𠯤-2-酮(31.2 g,122.3 mmol)在DCM(300 mL)中之溶液中添加TEA(24.75 g,244.6 mmol)和Boc2
O(29.36 g,134.43 mmol)。將混合物在25°C下攪拌5小時。將反應混合物傾倒入H2
O(400 mL)中,用DCM(300 mL × 3)萃取。將合併的有機層用鹽水洗滌,經Na2
SO4
乾燥,過濾並在減壓下濃縮。將殘餘物藉由MPLC純化。獲得呈黃色固體化合物三級丁基 2-(2-溴苯基)-3-側氧基哌𠯤-1-甲酸酯(34.2 g,產率:78%)。MS (ESI, m/e) [M+1]+
355.0。
步驟2:三級丁基 3-側氧基-2-(2-(丙-1-烯-2-基)苯基)哌𠯤-1-甲酸酯。
在N2
下,向三級丁基 2-(2-溴苯基)-3-側氧基哌𠯤-1-甲酸酯(34.2 g,96.28 mmol)和4,4,5,5-四甲基-2-(丙-1-烯-2-基)-1,3,2-二氧雜環戊硼烷(9.41 g,115.53 mmol)在二㗁𠮿(400 mL)和H2
O(40 mL)中之溶液中添加Cs2
CO3
(62.74 g,192.55 mmol)和Pd(dppf)Cl2
.DCM(7.86 g,9.63 mmol)。將混合物在100°C下攪拌12小時。將反應混合物過濾並在減壓下濃縮。將殘餘物傾倒入H2
O(200 mL)中,用EtOAc(200 mL × 3)萃取。將合併的有機層用鹽水洗滌,經Na2
SO4
乾燥,過濾並在減壓下濃縮。將殘餘物藉由MPLC純化。獲得呈黃色固體的化合物三級丁基 3-側氧基-2-(2-(丙-1-烯-2-基)苯基)哌𠯤-1-甲酸酯(28.2 g,產率:92%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.57 (br s, 1H), 7.31-7.14 (m, 4H), 6.05 (s, 1H), 5.22 (s, 1H), 5.01 (s, 1H), 4.02-3.92 (m, 1H), 3.53-3.43 (m, 1H), 3.36-3.24 (m, 2H), 2.08 (s, 3H), 1.39 (s, 9H)。
步驟3:三級丁基 2-(2-異丙基苯基)-3-側氧基哌𠯤-1-甲酸酯。
向三級丁基 3-側氧基-2-(2-(丙-1-烯-2-基)苯基)哌𠯤-1-甲酸酯(28.2 g,89.13 mmol)在MeOH(100 mL)中之溶液中添加Pd/C(3.8 g,3.16 mmol)。將混合物在50°C下在H2
(50 psi)下攪拌12小時。將反應混合物過濾並在減壓下濃縮以給出呈黃色固體的三級丁基 2-(2-異丙基苯基)-3-側氧基哌𠯤-1-甲酸酯(25.2 g,產率:88%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.55-7.40 (m, 1H), 7.40-7.36 (m, 1H), 7.35-7.29 (m, 1H), 7.26-7.21 (m, 1H), 7.20-7.13 (m, 1H), 6.04 (s, 1H), 3.94 (d,J
= 11.6 Hz, 1H), 3.61-3.51 (m, 2H), 3.38-3.21 (m, 2H), 1.48 (s, 9H), 1.30 (d,J
= 6.8 Hz, 3H), 1.18 (d,J
= 6.8 Hz, 3H)。
步驟4:3-(2-異丙基苯基)哌𠯤-2-酮。
將三級丁基 2-(2-異丙基苯基)-3-側氧基哌𠯤-1-甲酸酯(20 g,62.81 mmol)在DCM(100 mL)和TFA(50 mL)中之混合物在25°C下攪拌6小時。將反應混合物在減壓下濃縮。將殘餘物用H2
O(100 mL)稀釋並將混合物用飽和水性Na2
CO3
調節至pH = 9。將混合物用DCM(100 mL × 3)萃取。將合併的有機層用鹽水洗滌,經Na2
SO4
乾燥,過濾並在減壓下濃縮以給出呈黃色固體的3-(2-異丙基苯基)哌𠯤-2-酮(13.7 g,粗製)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.45-7.32 (m, 3H), 7.30 (br, 1H), 7.28-7.22 (m, 1H), 4.88 (s, 1H), 3.63 (m, 1H), 3.49-3.33 (m, 2H), 3.31-3.21 (m, 1H), 3.20-3.10 (m, 1H), 1.89 (s, 1H), 1.39 (d,J
= 6.8 Hz, 3H), 1.35 (d,J
= 6.8 Hz, 3H)。
步驟5:三級丁基 2-(2-(2-異丙基苯基)-3-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
向3-(2-異丙基苯基)哌𠯤-2-酮(13.7 g,62.76 mmol)和三級丁基 2-側氧基-7-氮雜螺[3.5]壬烷-7-甲酸酯(16.52 g,69.04 mmol)在DCE(200 mL)中之溶液中添加AcOH(7.54 g,125.52 mmol)和NaBH(OAc)3
(26.6 g,125.52 mmol)。將混合物在25°C下攪拌12小時。將反應混合物傾倒入水性Na2
CO3
(300 mL)中,用DCM(200 mL × 3)萃取。將合併的有機層用鹽水洗滌,經Na2
SO4
乾燥,過濾並在減壓下濃縮。將殘餘物藉由MPLC純化。獲得呈黃色固體的化合物三級丁基2-(2-(2-異丙基苯基)-3-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(20 g,產率:72%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.31-7.28 (m, 1H), 7.24 (m, 1H), 7.17-7.07 (m, 2H), 4.12-4.05 (m, 1H), 3.60-3.49 (m, 1H), 3.41 (m, 1H), 3.37-3.31 (m, 1H), 3.25 (m, 2H), 3.18 (m, 2H), 3.11-2.98 (m, 2H), 2.51-2.35 (m, 1H), 1.97-1.86 (m, 1H), 1.64 (m, 1H), 1.50-1.44 (m, 2H), 1.42 (s, 9H), 1.41-1.37 (m, 2H), 1.32 (m, 2H), 1.28 (d,J
= 6.8 Hz, 3H), 1.20 (d,J
= 6.8 Hz, 3H)。
步驟6:三級丁基 2-(4-異丙基-2-(2-異丙基苯基)-3-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
在0°C下,向三級丁基2-(2-(2-異丙基苯基)-3-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(4.0 g,9.06 mmol)在THF(40 mL)中之溶液中添加NaH(1.06 g,27.17 mmol)。將混合物在0°C下攪拌10 min,然後在0°C下添加2-碘丙烷(4.62 g,27.17 mmol)。將混合物在65°C下攪拌48小時。將反應混合物傾倒入H2
O(40 mL)中,用EtOAc(40 mL × 3)萃取。將合併的有機層用鹽水洗滌,經Na2
SO4
乾燥,過濾並在減壓下濃縮。將殘餘物藉由MPLC純化。獲得呈黃色固體的化合物三級丁基 2-(4-異丙基-2-(2-異丙基苯基)-3-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.0 g,產率:223%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.29-7.23 (m, 3H), 7.11-7.06 (m, 1H), 4.15 (s, 1H), 3.69 (m, 1H), 3.49-3.36 (m, 2H), 3.29-3.22 (m, 3H), 3.18 (s, 2H), 3.10 (m, 1H), 3.02-2.93 (m, 2H), 2.47 (m, 1H), 2.05-1.99 (m, 1H), 1.94-1.86 (m, 1H), 1.73-1.60 (m, 2H), 1.50-1.43 (m, 2H), 1.42 (s, 9H), 1.41-1.37 (m, 2H), 1.33 (s, 1H), 1.30 (d,J
= 6.8 Hz, 3H), 1.19 (d,J
= 6.8 Hz, 3H), 0.91 (m, 6H)。
步驟7:三級丁基 2-(4-異丙基-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯。
將三級丁基 2-(4-異丙基-2-(2-異丙基苯基)-3-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(1.0 g,2.07 mmol)在BH3
.THF(10 mL)中之混合物在70°C下攪拌12小時。將反應混合物在0°C下藉由MeOH(5 mL)淬滅並在25°C下攪拌30 min。將混合物在減壓下濃縮以得到,獲得呈無色油狀物的三級丁基 2-(4-異丙基-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(970 mg,粗製)。MS (ESI, m/e) [M+1]+
470.3。
步驟8:2-(4-異丙基-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷(中間體 3-1
)。
將三級丁基 2-(4-異丙基-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(970 mg,2.07 mmol)在HCl/EtOAc(10 mL)中之混合物在25°C下攪拌2小時。將反應混合物在減壓下濃縮。將殘餘物藉由製備型HPLC(HCl條件)根據HPLC純化。將殘餘物用H2
O(10 mL)稀釋並添加Na2
CO3
至pH = 9。將混合物用EtOAc(10 mL × 3)萃取。將合併的有機層用鹽水洗滌,經Na2
SO4
乾燥,過濾並在減壓下濃縮以給出呈黃色油狀物的2-(4-異丙基-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷(455 mg,產率:58%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.51 (d,J
= 6.4 Hz, 1H), 7.27-7.20 (m, 2H), 7.17-7.11 (m, 1H), 3.63 (d,J
= 9.2 Hz, 1H), 3.41 (s, 1H), 3.06 (d,J
= 11.2 Hz, 1H), 2.99-2.87 (m, 2H), 2.71-2.55 (m, 6H), 2.44 (m, 1H), 2.28 (m, 2H), 1.94-1.81 (m, 2H), 1.80-1.72 (m, 1H), 1.71-1.64 (m, 1H), 1.41-1.28 (m, 5H), 1.25 (d,J
= 6.8 Hz, 3H), 1.20 (d,J
= 6.8 Hz, 3H), 1.04 (m, 6H)。MS (ESI, m/e) [M+1]+
370.3。
甲基 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(4-異丙基-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲酸酯之合成
向2-(4-異丙基-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷(200 mg,0.541 mmol,中間體 3-1
)在DMSO(10 mL)中之溶液中添加甲基 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-氟苯甲酸酯(154.8 mg,0.541 mmol)和Na2
CO3
(573.5 mg,541 mmol)。將混合物在100°C下攪拌過夜。將混合物冷卻至室溫,在攪拌下用乙酸乙酯(100 mL)和水(100 mL)稀釋。將有機層分離並用鹽水(100 mL)洗滌,經Na2
SO4
乾燥,過濾並真空濃縮。將殘餘物藉由層析柱(矽膠,洗脫液:DCM/MeOH(v/v)= 50/1至20/1)純化以給出標題化合物(120 mg,產率:35%)。MS (ESI, m/e) [M+1]+
636.0。
2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(4-異丙基-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲酸之合成
向甲基 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(4-異丙基-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲酸酯(120 mg,0.189 mmol)在THF(5 mL)和MeOH(5 mL)中之溶液中添加水性NaOH(2 mL,6 N)。將混合物在50°C下攪拌2小時。在將反應溶液冷卻至室溫後,將混合物用DCM(50 mL)稀釋。將混合物攪拌並用HCl酸(10 mL,1 M)調節至pH值4-5。將有機層分離,經Na2
SO4
乾燥,過濾並真空濃縮。將殘餘物藉由矽膠層析柱(洗脫液:DCM/MeOH(v/v)= 10/1)純化。獲得2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(4-異丙基-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲酸(80 mg,產率:68%)。MS (ESI, m/e) [M+1]+
622.0。
2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-(4-異丙基-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺(實例 3
)之合成:
向2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(4-異丙基-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲酸(80 mg,0.129 mmol)在DCM(20 mL)中之溶液中添加4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯磺醯胺(44 mg,0.129 mmol)、EDCI(32 mg,0.168 mmol)、DMAP(31.5 mg,0.258 mmol)和TEA(65 mg,0.645 mmol)。將混合物在室溫下攪拌過夜。然後將反應混合物用乙酸(30 mL,10%)、飽和水性NaHCO3
(30 mL)和鹽水(20 mL)順序洗滌。將有機層分離,經無水NaSO4乾燥並真空濃縮。將殘餘物藉由層析柱(矽膠,洗脫液:DCM/EA(v/v)=1/1,然後DCM/MeOH(v/v)= 20/1)純化以給出粗的固體。將粗品藉由製備型TLC(洗脫液:DCM/MeOH(v/v)= 20/1)進一步純化。獲得化合物2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-(4-異丙基-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺(20 mg,產率:16%)1
H NMR (400 MHz, DMSO-d 6
) δ ppm: 11.60 (s, 1H), 8.60-8.24 (m, 2H), 7.96 (s, 1H), 7.82-6.77 (m, 10H), 6.77-6.50 (m, 1H), 6.33 (s, 1H), 6.17 (s, 1H), 4.24 (s, 1H), 3.29-3.18 (m, 4H), 3.09-2.77 (m, 9H), 2.02-1.95 (m, 1H), 1.80-1.47 (m, 8H), 1.38-1.26 (m, 7H), 1.23-1.12 (m, 9H), 1.12-0.99 (m, 10H)。MS (ESI, m/e) [M+1]+
948.0。
中間體 3-1a :
將2-(4-異丙基-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷藉由SFC(儀器:Waters SFC80製備型SFC;柱:Lux Cellulose-2,250 × 30 mm i.d.10 um;流動相:A為CO2
並且B為MeOH(0.1% NH3.
H2
O);梯度:B% = 50%等度模式;流速:80 g/min;波長:220 nm;柱溫:40°C;系統背壓:150巴)分離。
獲得(R或S)-2-(4-異丙基-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷(300 mg,滯留時間:1.76 min),產率:37.5%。1H NMR (400 MHz, CDCl3
) δ ppm: 7.51 (br, 1H), 7.26-7.21 (m, 2H), 7.14 (t, 1H), 3.63 (m, 1H), 3.41 (br, 1H), 3.06 (m, 1H), 2.96-2.89 (m, 2H), 2.70-2.58 (m, 6H), 2.47-2.41 (m, 1H), 2.31-2.24 (m, 2H), 2.16 (m, 1H), 1.90 (br, 2H), 1.77 (br, 1H), 1.71-1.65 (m, 1H), 1.37-1.29 (m, 5H), 1.25 (d,J
= 6.8 Hz, 3H), 1.20 (br d,J
= 6.8 Hz, 3H), 1.04 (t, 6H)。MS (ESI, m/e) [M+1]+
370.3。
中間體 3-1b :
獲得(S或R)-2-(4-異丙基-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷(330 mg,滯留時間:2.05 min),產率:41%。MS (ESI, m/e) [M+1]+
370.3。
按照與針對實例3所述之基本相同的程序或使用類似之合成方法或策略,製備表1中列出的實例2和實例4-18。
[表 1
]
實例 19a
實例 | 結構 | 化合物名稱 | 數據 | |
2 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(4-乙基-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.61 (s, 1H), 10.45 (br, 1H), 8.49-8.42 (m, 2H), 7.97 (d,J = 2.4 Hz, 1H), 7.69 (d,J = 9.2 Hz, 1H), 7.52 (d,J = 8.8 Hz, 1H), 7.47-7.40 (m, 2H), 7.39-7.35 (m, 1H), 7.30-7.18 (m, 2H), 7.17-7.12 (m, 1H), 6.94 (d,J = 9.2 Hz, 1H), 6.63 (d,J = 8.8 Hz, 1H), 6.34-6.31 (m, 1H), 6.17 (s, 1H), 4.24 (s, 1H), 3.69-3.52 (m, 1H), 3.33-3.17 (m, 4H), 3.14-2.80 (m, 8H), 2.74-2.60 (m, 2H), 2.50-2.40 (m, 1H), 2.27-1.19 (m, 1H), 1.72-1.50 (m, 8H), 1.39-1.12 (m, 18H), 1.08-1.03 (m, 3H)。MS (ESI, m/e) [M+1]+ 934.0。 | ||
3a | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-((S或R)-4-異丙基-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.61 (s, 1H), 10.45 (br, 1H), 8.49-8.42 (m, 2H), 7.97 (d,J = 2.4 Hz, 1H), 7.69 (d,J = 9.2 Hz, 1H), 7.52 (d,J = 8.8Hz, 1H), 7.47-7.40 (m, 2H), 7.39-7.35 (m, 1H), 7.30-7.18 (m, 2H), 7.17-7.12 (m, 1H), 6.94 (d,J = 9.2 Hz, 1H), 6.63 (d,J = 8.8 Hz, 1H), 6.34-6.31 (m, 1H), 6.17 (s, 1H), 4.24 (s, 1H), 3.69-3.52 (m, 1H), 3.33-3.17 (m, 4H), 3.14-2.80 (m, 8H), 2.74-2.60 (m, 2H), 2.50-2.40 (m, 1H), 2.27-2.19 (m, 1H), 1.72-1.50 (m, 8H), 1.39-1.12 (m, 18H), 1.08-1.03 (m, 3H)。MS (ESI, m/e) [M+1]+ 948.2。 | ||
3b | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-((R或S)-4-異丙基-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm:11.67 (s, 1H), 11.43-10.96 (m, 1H), 8.53 (s, 2H), 8.01 (s, 1H), 7.76 (d,J = 8.4 Hz, 1H), 7.48 (d,J = 8.4 Hz, 4H), 7.28-7.27 (m, 2H), 7.17 (s, 1H), 7.05 (s, 1H), 6.64 (d,J = 8.6 Hz, 1H), 6.37 (s, 1H), 6.14 (s, 1H), 4.24 (s, 1H), 4.03 (s, 1H), 3.38 (s, 1H), 3.27 (s, 3H), 2.95-2.93 (m, 10H), 1.75-1.60 (m, 7H), 1.40-1.11 (m, 17H), 1.10 (s, 4H), 1.01 (s, 1H)。MS (ESI, m/e) [M+1]+ 948.2。 | ||
4 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-((R或S)-4-環丙基-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.68 (s, 1H), 11.42 (s, 1H), 10.28-10.10 (m, 1H), 8.55 (s, 2H), 8.02 (s, 1H), 7.77 (s, 1H), 7.72 (s, 1H), 7.50 (s, 2H), 7.47-7.45 (m, 1H), 7.39 (s, 1H), 7.26 (s, 2H), 7.09-7.04 (m, 1H), 6.66 (s, 1H), 6.37 (s, 1H), 6.16 (s, 1H), 4.53 (s, 1H), 4.24 (s, 1H), 3.78-3.68 (m, 1H), 3.40 (s, 1H), 3.28 (s, 2H), 3.13 (s, 1H), 3.02-2.81 (m, 7H), 1.99-1.98 (m, 2H), 1.86 (s, 1H), 1.68-1.65 (m, 6H), 1.37-1.21 (m, 12H), 1.13-1.10 (m, 9H), 0.77-0.68 (m, 1H), 0.38-0.35 (m, 4H)。MS (ESI, m/e) [M+1]+ 946.1。 | ||
5 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(4-環丁基-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.70 (s, 1H), 11.23 (br, 1H), 8.64-8.52 (m, 2H), 8.03 (s, 1H), 7.79 (d,J = 8.8 Hz, 1H), 7.53-7.12 (m, 7H), 6.94 (d,J = 9.2 Hz, 1H), 7.08 (d,J = 8.8 Hz, 1H), 6.66 (d,J = 8.8 Hz, 1H), 6.38 (s, 1H), 6.14 (s, 1H), 4.26 (s, 1H), 3.99-3.62 (m, 1H), 3.59-3.42 (m, 1H), 3.33-3.17 (m, 4H), 3.17-2.60 (m, 9H), 2.50-2.38 (m, 1H), 2.27-1.85 (m, 4H), 1.78-1.50 (m, 9H), 1.39-1.14 (m, 19H)。MS (ESI, m/e) [M+1]+ 960.0。 | ||
6 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-(2-(2-異丙基苯基)-4-(氧雜環丁烷-3-基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.69 (s, 1H), 11.41 (br, 1H), 8.60-8.57 (m, 2H), 8.03 (s, 1H), 7.79 (d,J = 8.8 Hz, 1H), 7.54-7.35 (m, 4H), 7.28-7.03 (m, 3H), 6.66 (d,J = 8.8 Hz, 1H), 6.37 (s, 1H), 6.14 (s, 1H), 4.59-4.33 (m, 4H), 4.25 (s, 1H), 3.60-3.39 (m, 2H), 3.33-3.24 (m, 2H), 3.07-2.82 (m, 6H), 2.80-2.71 (m, 1H), 2.50-2.35 (m, 1H), 2.23-2.19 (m, 3H), 1.74-1.50 (m, 7H), 1.39-1.12 (m, 16H), 1.08-1.03 (m, 4H)。MS (ESI, m/e) [M+1]+ 962.1。 | ||
6a | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-((S或R)-2-(2-異丙基苯基)-4-(氧雜環丁烷-3-基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.69 (s, 1H), 11.40 (s, 1H), 8.54 (s, 2H), 8.02 (s, 1H), 7.77 (d,J = 9.0 Hz, 1H), 7.49-7.46 (m, 4H), 7.14-7.10 (m, 4H), 6.65 (d,J = 9.0 Hz, 1H), 6.37 (s, 1H), 6.15 (s, 1H), 4.57-4.31 (m, 4H), 4.25 (s, 1H), 3.40 (s, 1H), 3.28 (s, 3H), 2.96-2.90 (m, 7H), 2.46-2.35 (m, 1H), 2.01-2.00 (m, 3H), 1.69-1.65 (m, 4H), 1.56-1.53 (m, 2H), 1.39-1.12 (m, 15H), 1.13-1.10 (m, 5H)。MS (ESI, m/e) [M+1]+ 961.6。 | ||
6b | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-((R或S)-2-(2-異丙基苯基)-4-(氧雜環丁烷-3-基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.68 (s, 1H), 11.41 (br, 1H), 8.62-8.50 (m, 2H), 8.02 (s, 1H), 7.79 (d,J = 8.8 Hz, 1H), 7.52-7.35 (m, 4H), 7.28-7.14 (m, 2H), 7.12-7.01 (m, 2H), 6.66 (d,J = 8.8 Hz, 1H), 6.37 (s, 1H), 6.14 (s, 1H), 4.56-4.40 (m, 3H), 4.38-4.34 (m, 1H), 4.25 (s, 1H), 3.57-3.35 (m, 2H), 3.30-3.25 (m, 3H), 3.03-2.70 (m, 8H), 2.46-2.38 (m, 1H), 2.21-1.85 (m, 4H), 1.74-1.50 (m, 8H), 1.39-1.22 (m, 12H), 1.18-1.06 (m, 4H)。MS (ESI, m/e) [M+1]+ 961.6。 | ||
7 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(4-環戊基-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.70 (s, 1H), 11.43 (s, 1H), 9.79 (s, 1H), 8.57-8.55 (m, 2H), 8.02 (s, 1H), 7.78-7.77 (m, 1H), 7.49-7.47 (m, 4H), 7.29-7.28 (m, 2H), 7.17 (s, 1H), 7.08 (s, 1H), 6.65 (d,J = 8.8 Hz, 1H), 6.37 (s, 1H), 6.13 (s, 1H), 4.26 (s, 1H), 3.87 (s, 1H), 3.28 (s, 3H), 3.00-2.92 (m, 10H), 2.01-1.98 (m, 3H), 1.66 (s, 13H), 1.55-1.54 (m, 4H), 1.40-1.15 (m, 17H), 1.13-1.10 (m, 5H)。MS (ESI, m/e) [M+1]+ 974。 | ||
8 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-(2-(2-異丙基苯基)-4-(四氫呋喃-3-基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.69 (s, 1H), 11.44 (br, 1H), 8.63-8.54 (m, 2H), 8.03 (s, 1H), 7.99-7.85 (m, 1H), 7.79 (d,J = 8.4 Hz, 1H), 7.54-7.35 (m, 4H), 7.34-7.13 (m, 2H), 7.09 (d,J = 8.4 Hz, 1H), 6.67 (d,J = 8.4 Hz, 1H), 6.37 (s, 1H), 6.19-6.13 (m, 1H), 4.63-4.56 (m, 1H), 4.24-3.83 (m, 4H), 3.64-3.52 (m, 1H), 3.33-3.24 (m, 2H), 3.19-2.72 (m, 12H), 2.26-1.93 (m, 5H), 1.74-1.60 (m, 4H), 1.57-1.42 (m, 4H), 1.39-1.27 (m, 7H), 1.18-1.03 (m, 9H)。MS (ESI, m/e) [M+1]+ 976.1。 | ||
9 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(4-環己基-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.70 (s, 1H), 11.42 (s, 0.5H), 9.72 (s, 0.5H), 8.65-8.48 (m, 2H), 8.06-7.97(m, 1H), 7.82-7.71 (m, 1H), 7.59-7.43 (m, 4H), 7.40-6.97 (m, 5H), 6.78-6.55 (m, 1H), 6.38 (s, 1H), 6.13 (s, 1H), 4.26 (s, 1H), 4.04-3.92 (m, 1H), 3.60-3.44 (m, 1H), 3.32-3.21 (m, 3H), 3.19-2.81 (m, 11H), 2.13-1.94 (m, 3H), 1.84-1.48 (m, 11H), 1.43-1.28 (m, 6H), 1.22-1.14 (m, 8H), 1.14-0.99(m, 7H)。MS (ESI, m/e) [M+1]+ 988.0 | ||
10 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-(2-(2-異丙基苯基)-4-(四氫-2H-哌喃-4-基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.69 (s, 1H), 8.57-8.55 (m, 2H), 8.03 (s, 1H), 7.77 (d,J = 9.2 Hz, 1H), 7.56-7.42 (m, 4H), 7.28 (s, 2H), 7.16 (s, 1H), 7.07 (d,J = 9.2 Hz, 1H), 6.66-6.64 (m, 1H), 6.37 (s, 1H), 6.14 (s, 1H), 4.26 (s, 1H), 3.90 (s, 3H), 3.27-3.25 (m, 5H), 2.96-2.94 (m, 9H), 1.91 (s, 2H), 1.63-1.59 (m, 9H), 1.38-1.12 (m, 16H), 1.10 (s, 4H)。MS (ESI, m/e) [M+1]+ 990.2。 | ||
11 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-(4-異丁基-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.64 (s, 1H), 10.95 (br, 1H), 8.51-8.45 (m, 2H), 8.00 (d,J = 2.4 Hz, 1H), 7.74 (d,J = 9.2 Hz, 1H), 7.52-7.35 (m, 4H), 7.29-7.09 (m, 3H), 7.05-6.96 (m, 1H), 6.64 (d,J = 8.8 Hz, 1H), 6.35(s, 1H), 6.15 (s, 1H), 4.24 (s, 1H), 3.65-3.50 (m, 1H), 3.33-3.22 (m, 3H), 3.04-2.80 (m, 7H), 2.70-2.60 (m, 1H), 2.24-2.00 (m, 5H), 1.76-1.50 (m, 8H), 1.39-1.12 (m, 15H), 1.08-1.03 (m, 4H), 0.85 (d,J = 6.8 Hz, 6H)。MS (ESI, m/e) [M+1]+ 962.0。 | ||
12 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-(2-(2-異丙基苯基)-4-新戊基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.69 (s, 1H), 11.43 (s, 1H), 10.09 (s, 1H), 8.66-8.40 (m, 2H), 8.03 (s, 1H), 7.88-7.63 (m, 2H), 7.55-7.33 (m, 4H), 7.31-7.05 (m, 3H), 6.75-6.55 (m, 1H), 6.37 (s, 1H), 6.20-6.05 (m, 1H), 4.67-4.54 (m, 1H), 4.25 (s, 1H), 3.92-3.74 (m, 1H), 3.29-3.25 (m, 2H), 3.10-2.78 (m, 8H), 2.22-2.14 (m, 1H), 2.08-1.90 (m, 3H), 1.75-1.43 (m, 6H), 1.38-1.24 (m, 11H), 1.17-1.00 (m, 9H), 0.90-0.70 (s, 9H)。MS (ESI, m/e) [M/2+1]+ 488.8 | ||
13 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-(2-(2-異丙基苯基)-4-(2-甲氧基乙基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.68 (s, 1H), 8.60-8.50 (m, 2H), 8.03-8.02 (m, 1H), 7.80-7.75 (m, 1H), 7.52-7.45 (m, 4H), 7.17-7.11 (m, 2H), 7.10-7.00 (m, 1H), 7.10-7.05 (m, 1H), 6.65-6.60 (m, 1H), 6.38 (s, 1H), 6.15 (s, 1H), 4.30-4.25 (m, 1H), 3.55-3.50 (m, 2H), 3.35-3.25 (m, 6H), 3.10-2.95 (m, 9H), 1.65-1.35 (m, 8H), 1.30-1.10 (m, 23H)。MS (ESI, m/e) [M+1]+ 962.9。 | ||
13a | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-((S或R)-2-(2-異丙基苯基)-4-(2-甲氧基乙基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm:11.68 (s, 1H), 8.53 (s, 2H), 8.02 (s, 1H), 7.75 (s, 1H), 7.49-7.47 (m, 4H), 7.27 (s, 2H), 7.15 (s, 1H), 7.04 (s, 1H), 6.66 (s, 1H), 6.37 (s, 1H), 6.14 (s, 1H), 4.25 (s, 1H), 3.82-3.67 (m, 1H), 3.55 (s, 2H), 3.48-3.40 (m, 1H), 3.28-3.26 (m, 6H), 2.95-2.94 (m, 9H), 1.99 (s, 1H), 1.73-1.50 (m, 7H), 1.26-1.10 (m, 18H), 1.09 (s, 5H)。MS (ESI, m/e) [M+1]+ 964.1。 | ||
13b | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-((R或S)-2-(2-異丙基苯基)-4-(2-甲氧基乙基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.69 (s, 1H), 11.18 (br, 1H), 8.61-8.53 (m, 2H), 8.02 (s, 1H), 7.89-7.75 (m, 1H), 7.53-7.10 (m, 7H), 7.08 (d,J = 8.4 Hz, 1H), 6.66 (d,J = 8.4 Hz, 1H), 6.37 (s, 1H), 6.13 (s, 1H), 4.24 (s, 1H), 3.93-3.54 (m, 2H), 3.47-3.34 (m, 1H), 3.32-2.80 (m, 18H), 2.49-2.36 (m, 1H), 2.19-1.93 (m, 1H), 1.74-1.49(m, 7H), 1.39-1.08 (m, 18H)。MS (ESI, m/e) [M+1]+ 964.2。 | ||
14 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-(((R)-3-(((1r,4R)-4-羥基環己基)甲基)-5-硝基-3,4-二氫-2H-苯并[b][1,4]㗁𠯤-7-基)磺醯基)-4-(2-(2-(2-異丙基苯基)-4-(2-甲氧基乙基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.94 (s, 1H), 8.74 (s, 1H), 8.16 (s, 1H), 8.01 (s, 1H), 7.49-7.35 (m, 4H), 7.33-7.10 (m, 4H), 6.65 (d,J = 8.4 Hz, 1H), 6.36 (s, 1H), 6.13 (s, 1H), 4.48-4.46 (m, 1H), 4.14-4.02 (m, 2H), 3.83-3.74 (m, 2H), 3.57-3.50 (m, 2H), 3.32-3.18 (m, 4H), 3.15-2.80 (m, 12H), 2.04-1.96(m, 1H), 1.87-1.53(m, 7H), 1.49-1.32(m, 5H), 1.22-1.08 (m, 10H), 1.05-0.85 (m, 4H)。MS (ESI, m/e) [M+1]+ 992.0。 | ||
15 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(4-(環戊基甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.68 (s, 1H), 11.16 (br, 1H), 8.62-8.52 (m, 2H), 8.01 (s, 1H), 7.79-7.73 (m, 1H), 7.53-7.40 (m, 4H), 7.33-7.12 (m, 3H), 7.08-7.00 (m, 1H), 6.68-6.64 (m, 1H), 6.36 (s, 1H), 6.15 (s, 1H), 4.26 (s, 1H), 3.78-3.65 (m, 1H), 3.45-3.37 (m, 1H), 3.31-3.26 (m, 3H), 3.19-2.75 (m, 10H), 2.65-2.55 (m, 1H), 2.22-1.95 (m, 2H), 1.79-1.42 (m, 14H), 1.38-1.23 (m, 10H), 1.15-1.08 (m, 10H)。MS (ESI, m/e) [M+1]+ 987.9。 | ||
16 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(4-(環己基甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.67 (s, 1H), 8.51 (s, 2H), 8.00 (s, 1H), 7.73 (s, 1H), 7.49-7.43 (m, 3H), 7.31-7.19 (m, 2H), 7.13 (s, 1H), 7.01 (s, 1H), 6.64 (d,J = 8.2 Hz, 1H), 6.35 (s, 1H), 6.15 (s, 1H), 4.25 (s, 1H), 3.33 (s, 3H), 3.29-3.23 (m, 2H), 3.17 (d,J = 5.2 Hz, 1H), 3.04-2.80 (m, 8H), 2.25-2.15 (m, 1H), 1.77-1.50 (m, 14H), 1.38-1.08 (m, 21H), 0.93-078 (m, 3H)。MS (ESI, m/e) [M+1]+ 1001.6。 | ||
17 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-(2-(2-異丙基苯基)-4-((四氫-2H-哌喃-4-基)甲基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.69 (s, 1H), 11.44 (s, 1H), 8.64-8.47 (m, 2H), 8.02 (s, 1H), 7.84-7.72 (m, 1H), 7.71-7.34 (m, 5H), 7.34-6.98 (m, 4H), 6.72-6.58 (m, 1H), 6.37 (s, 1H), 6.13 (s, 1H), 4.26 (s, 1H), 3.89-3.72 (m, 2H), 3.32-3.20 (m, 5H), 3.15-2.79 (m, 9H), 2.05-1.92 (m, 2H), 1.78-1.50 (m, 8H), 1.38-1.02 (m, 25H)。MS (ESI, m/e) [M+1]+ 1004.0 | ||
18 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(4-(二環[1.1.1]戊烷-1-基甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.68 (s, 1H), 11.24 (br, 1H), 8.55-8.49 (m, 2H), 8.02 (s, 1H), 7.75 (d,J = 8.0 Hz, 1H), 7.53-7.35 (m, 4H), 7.30-7.02 (m, 4H), 6.66 (d,J = 8.0 Hz, 1H), 6.37 (s, 1H), 6.14 (s, 1H), 4.25 (s, 1H), 3.84-3.40 (m, 1H), 3.30-3.05 (m, 4H), 3.02-2.60 (m, 9H), 2.46-2.30 (m, 3H), 2.07-1.87 (m, 1H), 1.81-1.58 (m, 10H), 1.57-1.50 (m, 2H), 1.39-1.18 (m, 13H), 1.16-1.07 (m, 7H)。MS (ESI, m/e) [M+1]+ 985.5。 |
2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-((R 或 S
)-2-(2-異丙基苯基)-4-(4-甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺(本文稱為「由方法 A 中的中間體 19-1a 合成的實例 19a 」
)
將以下步驟1-12和SFC分離描述為用於合成中間體 19-1a 的方法 A
向2-異丙基苯甲醛(20 g,0.135 mol)在THF(200 mL)中之溶液中添加2-甲基丙烷-2-亞磺醯胺(18 g,0.148 mmol)。在冷卻至0°C後,緩慢添加Ti(OEt)4
(62 g,0.27 mol)。將混合物在25°C下攪拌12小時。將反應混合物用水(100 mL)淬滅,並且然後通過矽藻土墊過濾。將濾液用EA(100 mL × 3)萃取並用鹽水(100 mL)洗滌。將合併的有機層經Na2
SO4
乾燥,過濾並真空濃縮。將殘餘物藉由矽膠柱層析法(洗脫液:PE/EA(v/v)= 100/1至20/1)純化以給出(E)-N-(2-異丙基亞苄基)-2-甲基丙烷-2-亞磺醯胺(32.5 g,產率:96%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 9.00 (s, 1H), 7.96 (dd,J
= 8.0, 2.4 Hz, 1H), 7.51-7.45 (m, 1H), 7.44-7.40 (m, 1H), 7.32-7.27 (m, 1H), 3.72 (m, 1H), 1.33-1.25 (m, 15H)。
在0°C下,向(E)-N-(2-異丙基亞苄基)-2-甲基丙烷-2-亞磺醯胺(32 g,0.13 mol)在THF(300 mL)中之溶液中分幾批添加t-BuOK(21 g,0.19 mol)。在0°C下攪拌1 hr後,然後添加硝基甲烷(77 g,1.27 mmol)。將混合物在25°C下進一步攪拌12小時。將水(100 mL)添加至混合物,並且然後用EA(100 mL × 3)萃取。將合併的有機層乾燥,過濾並真空濃縮。將殘餘物藉由矽膠柱層析法(洗脫液:PE/EA(v/v)= 10/1至2/1)純化以給出N-(1-(2-異丙基苯基)-2-硝基乙基)-2-甲基丙烷-2-亞磺醯胺(26.5 g),產率:67%。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.40-7.34 (m, 2H), 7.34-7.28 (m, 1H), 7.26-7.21 (m, 1H), 5.53-5.44 (m, 1H), 4.88-4.78 (m, 1H), 4.76-4.65 (m, 1H), 4.30-4.20 (m, 1H), 3.35-3.22 (m, 1H), 1.34-1.26 (m, 6H), 1.27-1.20 (m, 9H)。
向N-(1-(2-異丙基苯基)-2-硝基乙基)-2-甲基丙烷-2-亞磺醯胺(23 g,0.074 mol)在MeOH(200 mL)中之溶液中添加雷氏鎳(5 g)。將混合物在H2
(15 psi)氣氛下在25°C下攪拌12小時。在通過矽藻土墊過濾後,將濾液在減壓下濃縮以給出N-(2-胺基-1-(2-異丙基苯基)乙基)-2-甲基丙烷-2-亞磺醯胺(17.6 g,粗製),其無需進一步純化即可用於下一步。MS (ESI, m/e) [M+1]+
283.1。
向N-(2-胺基-1-(2-異丙基苯基)乙基)-2-甲基丙烷-2-亞磺醯胺(23 g,0.081 mol)在DCM(300 mL)中之溶液中添加TEA(24.5 g,0.243 mol)。在將混合物冷卻至0°C後,分幾批添加TsCl(17 g,0.09 mol)。添加後,將混合物在25°C下攪拌2小時並且然後用水性NH4
Cl(100 mL,1 M)淬滅。將混合物用DCM(100 mL × 3)萃取。將合併的有機層用鹽水洗滌,經無水Na2
SO4
乾燥,過濾並真空濃縮。將殘餘物藉由矽膠柱層析法(洗脫液:PE/EA(v/v)= 20/1至5/1)純化以給出N-(2-((三級丁基亞磺醯基)胺基)-2-(2-異丙基苯基)乙基)-4-甲基苯磺醯胺(23 g,產率:65%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.79 (d,J
= 8.4 Hz, 2H), 7.32-7.26 (m, 4H), 7.20-7.12 (m, 1H), 4.82-4.69 (m, 1H), 4.25 (br, 1H), 3.14 (br, 4H), 3.07-2.97 (m, 1H), 2.41 (s, 3H), 1.42 (t, 6H), 1.23 (s, 9H)。
向N-(2-((三級丁基亞磺醯基)胺基)-2-(2-異丙基苯基)乙基)-4-甲基苯磺醯胺(5.0 g,11 mmol)在MeOH(20 mL)中之溶液中添加HCl溶液(10 mL,4 M,在MeOH中)。將混合物在25°C下攪拌1 hr並且然後真空濃縮。將殘餘物用水(50 mL)分配。向混合物中添加水性Na2
CO3
以調節pH = 9。將混合物用EA(50 mL × 3)萃取。將合併的有機層經Na2
SO4
乾燥,過濾並真空濃縮以給出N-(2-胺基-2-(2-異丙基苯基)乙基)-4-甲基苯磺醯胺(3.8 g,粗製),其無需進一步純化即可用於下一步。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.74 (d,J
= 8.0 Hz, 2H), 7.32-7.23 (m, 5H), 7.21-7.13 (m, 1H), 4.36 (m, 1H), 3.17-3.03 (m, 2H), 2.93 (m, 1H), 2.43 (s, 3H), 1.21-1.18 (m, 6H)。MS (ESI, m/e) [M+1]+
333.1。
向N-(2-胺基-2-(2-異丙基苯基)乙基)-4-甲基苯磺醯胺(4 g,0.012 mol)在DCE(50 mL)中之溶液中添加三級丁基 2-側氧基-7-氮雜螺[3.5]壬烷-7- 甲酸酯(3.2 g,0.013 mol)和HOAc(1.44 g,0.024 mol)並將混合物在25°C下攪拌1 hr。在添加NaBH(OAc)3
(5.1 g,0.024 mol)後,將混合物在25°C下攪拌12小時。將反應用水性NH4
Cl(50 mL)淬滅並將混合物用DCM(50 mL × 3)萃取。將合併的有機層用鹽水(50 mL × 2)洗滌,經無水Na2
SO4
乾燥,過濾並真空濃縮。將殘餘物藉由矽膠柱層析法(洗脫液:PE/EA(v/v)= 10/1至5/1)純化以給出三級丁基 2-((1-(2-異丙基苯基)-2-(4-甲基苯基磺醯胺基)乙基)胺基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(4.3 g),產率:64%。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.73 (d,J
= 8.0 Hz, 2H), 7.32-7.25 (m, 4H), 7.19-7.13 (m, 2H), 4.02 (m, 1H), 3.30-3.22 (m, 4H), 3.09-2.98 (m, 3H), 2.88 (m, 1H), 2.43 (s, 3H), 2.02-1.88 (m, 2H), 1.75 (br, 3H), 1.44 (s, 9H), 1.40 (m, 3H), 1.17 (m, 6H)。MS (ESI, m/e) [M+1]+
556.4。
向三級丁基 2-((1-(2-異丙基苯基)-2-(4-甲基苯基磺醯胺基)乙基) 胺基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(4.3 g,7.74 mmol)在THF(50 mL)中之溶液中添加TEA(1.56 g,15.48 mmol),然後滴加2-氯乙醯氯(0.96 g,8.51 mmol)(在0°C下)。將混合物在25°C下攪拌2小時。將混合物傾倒入水性NH4
Cl溶液(50 mL,1 M)中,用EA(50 mL × 3)萃取。將合併的有機層用鹽水(50 mL × 2)洗滌,經無水Na2
SO4
乾燥,過濾並真空濃縮。將殘餘物藉由矽膠柱層析法(洗脫液 : PE/EA(v/v)= 20/1至5/1)純化以給出三級丁基 2-(2-氯-N-(1-(2-異丙基苯基)-2-(4-甲基苯基磺醯胺基)乙基)乙醯胺基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(4.6 g,產率:94%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.74 (d,J
= 8.0 Hz, 2H), 7.32-7.27 (m, 4H), 7.20 (m, 1H), 7.15-7.10 (m, 1H), 5.31-5.20 (m, 1H), 5.08 (br, 1 -H), 4.22 (d,J
= 2.8 Hz, 2H), 4.13 (m, 2H), 3.30 (m, 2H), 3.23 (m, 3H), 2.38 (s, 3H), 2.05 (s, 3H), 1.65 (br, 3H), 1.48-1.45 (m, 3H), 1.44 (s, 9H), 1.27 (m, 6H)。MS (ESI, m/e) [M-100]+
532.3。
向三級丁基 2-(2-氯-N-(1-(2-異丙基苯基)-2-(4- 甲基苯基磺醯胺基)乙基)乙醯胺基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(4.6 g,7.28 mmol)在DMF(50 mL)中之溶液中添加K2
CO3
(2.0 g,14.55 mmol)。將混合物在60°C下攪拌1 hr。然後將混合物傾倒入冰/水(50 mL)中並用EA(50 mL × 3)萃取。將合併的有機層用鹽水(50 mL × 2)洗滌,經無水Na2
SO4
乾燥,過濾並真空濃縮。將殘餘物藉由矽膠柱層析法(洗脫液:PE/EA(v/v)= 20/1至5/1)純化以給出三級丁基 2-(2-(2-異丙基苯基)-6-側氧基-4-甲苯磺醯基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(2.6 g),產率:62%。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.47 (d,J
= 8.0 Hz, 2H), 7.36-7.30 (m, 2H), 7.23 (d,J
= 8.0 Hz, 2H), 7.16-7.10 (m, 1 H), 6.89 (d,J
= 8.0 Hz, 1 H), 5.07 (t, 1 H), 4.30 (br, 1 H), 4.16 - 4.10 (m, 1 H), 3.97-3.88 (m, 1H), 3.81-3.70 (m, 1H), 3.39 (m, 2H), 3.27-3.21 (m, 2H), 3.21-3.13 (m, 2H), 3.12-3.06 (m, 1H), 2.99-2.85 (m, 1H), 2.41 (s, 3H), 2.22-2.14 (m, 1H), 1.85 (br, 1H), 1.73-1.58 (m, 2H), 1.46 (m, 2H), 1.41 (s, 9H), 1.30- 1.26 (m, 6H)。MS (ESI, m/e) [M-100]+
496.3。
向三級丁基 2-(2-(2-異丙基苯基)-6-側氧基-4-甲苯磺醯基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(2.6 g,4.47 mmol)在MeOH(50 mL)中之溶液中添加Mg(1.07 g,44.7 mmol)。將混合物在70°C下攪拌2小時。在將混合物冷卻至室溫後,將上層溶液傾析入水(50 mL)和EA(50 mL)中,並且然後通過矽藻土墊過濾。將濾液用EA(50 mL × 3)萃取。將合併的有機層用鹽水(50 mL × 2)洗滌,經無水Na2
SO4
乾燥,過濾並真空濃縮。獲得化合物三級丁基 2-(2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺 [3.5]壬烷-7-甲酸酯(1.3 g,粗製),產率:66%。將此產物無需進一步純化即用於下一步。MS (ESI, m/e) [M+1]+
442.3。
向三級丁基 2-(2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(3.5 g,7.93 mmol)和4-甲氧基苯甲醛(1.29 g,9.51 mmol)在DCE(50 mL)中之溶液中添加AcOH(951.96 mg,15.85 mmol)和NaBH(OAc)3
(3.36 g,15.85 mmol)。將混合物在25°C下攪拌12小時。將反應混合物傾倒入水性Na2
CO3
(50 mL)中,用DCM(50 mL × 3)萃取,經Na2
SO4
乾燥,過濾並真空濃縮。將殘餘物藉由MPLC(洗脫液:PE/EA(v/v)= 10/1至2/1)進一步純化。獲得94%產率的化合物三級丁基 2-(2-(2-異丙基苯基)-4-(4-甲氧基苄基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(4.2 g)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.33-7.26 (m, 2H), 7.22-7.17 (m, 1H), 7.14-7.08 (m, 1H), 6.78 (m, 2H), 6.63 (m, 2H), 4.94 (m, 1H), 3.73 (s, 3H), 3.57-3.44 (m, 2H), 3.33-3.11 (m, 6H), 2.98 (m, 1H), 2.71-2.56 (m, 2H), 2.30-2.17 (m, 1H), 1.93 (m, 1H), 1.81-1.67 (m, 2H), 1.53-1.44 (m, 2H), 1.41 (s, 9H), 1.37-1.29 (m, 2H), 1.22 (m, 3H), 0.95 (m, 3H)。MS (ESI, m/e) [M+1]+
562.2。
將三級丁基 2-(2-(2-異丙基苯基)-4-(4-甲氧基苄基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(4.2 g,7.48 mmol)在BH3
.THF(40 mL)中之混合物在70°C下攪拌12 hr。將反應混合物在0°C下藉由MeOH(50 mL)淬滅,並在25°C下攪拌30 min。在將混合物在減壓下濃縮後,獲得三級丁基 2-(2-(2-異丙基苯基)-4-(4-甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(4.1 g,粗製)。MS (ESI, m/e) [M+1]+
548.3。
將三級丁基 2-(2-(2-異丙基苯基)-4-(4-甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(4.1 g,7.48 mmol)在HCl溶液(50 mL,4 M。在CH3
OH中)中之混合物在25°C下攪拌2小時。將反應混合物在減壓下濃縮。將殘餘物藉由備型HPLC(TFA條件)純化。將殘餘物用H2
O(30 mL)稀釋並藉由水性Na2
CO3
溶液鹼化至pH = 9。將混合物用EA(30 mL × 3)萃取。將合併的有機層經Na2
SO4
乾燥,過濾並在減壓下濃縮以給出2-(2-(2-異丙基苯基)-4-(4-甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷(2.7 g,產率:80%)。MS (ESI, m/e) [M+1]+
448.3。
將2-(2-(2-異丙基苯基)-4-(4-甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷藉由SFC(儀器:Waters SFC80製備型SFC;柱:Chiralpak IG,250 × 30 mm i.d.10 um;流動相:A為CO2
並且B為EtOH(0.1% NH3
.H2
O);梯度:B% = 40%等度模式;流速:65 g/min;波長:220 nm;柱溫:40°C;系統背壓:100巴)分離。
獲得(R或S)-2-(2-(2-異丙基苯基)-4-(4-甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷(較快的峰,滯留時間:1.64 min,853 mg)(有時稱為「方法 A 中的中間體 19-1a
」),產率:31%。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.48 (m, 1H), 7.26-7.18 (m, 4H), 7.15-7.09 (m, 1H), 6.82 (m, 2H), 3.78 (s, 3H), 3.64 (m, 1H), 3.50-3.43 (m, 2H), 3.39 (m, 1H), 3.04-2.96 (m, 1H), 2.95-2.85 (m, 2H), 2.70-2.53 (m, 5H), 2.34-2.24 (m, 2H), 2.16 (m, 1H), 1.79-1.71 (m, 1H), 1.70-1.62 (m, 1H), 1.50 (s, 1H), 1.40-1.28 (m, 5H), 1.25 (m, 3H), 1.14 (m, 3H)。MS (ESI, m/e) [M+1]+
448.3。
獲得其他異構物中間體 19-1b
(S或R)-2-(2-(2-異丙基苯基)-4-(4-甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷(較慢的峰,滯留時間:1.74 min,890 mg)(有時稱為「方法 A 中的中間體 19-1b
」),產率:33%。MS (ESI, m/e) [M+1]+
448.3。
藉由以下手性HPLC方法進一步分析方法 A 中
的以上分離的異構物中間體 19-1a 和中間體 19-1b
。
柱 | Lux® Amylose-1(Phenomenex,00F-4732-E0) |
柱尺寸 | 4.6 × 150 mm,5 um |
流動相 | 己烷 : EtOH(0.1% DEA)= 90 : 10 |
流速 | 0.8 mL/min |
波長 | UV 214 nm |
溫度 | 22°C |
方法 A 中的中間體 19-1a 的 滯留時間: | 3.9 min |
方法 A 中的中間體 19-1b 的 滯留時間: | 4.4 min |
步驟13:甲基 (R或S)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(2-(2-異丙基苯基)-4-(4-甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲酸酯之合成
將甲基 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-氟苯甲酸酯(5.7 g,20.13 mmol)、方法A中的中間體 19-1a
(R或S )-2-(2-(2-異丙基苯基)-4-(4-甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷(7.5 g,16.78 mmol)和Na2
CO3
(17.8 g,167.8 mmol)在DMSO(110 mL)中的混合物在95°C下攪拌16小時。在將反應冷卻至室溫後,將混合物用EA(300 mL)與H2
O(300 mL)分配。將EA層收集並將水層用EA(300 mL)萃取。將合併的有機層用H2
O(200 mL × 4)和鹽水(100 mL)洗滌,經無水Na2
SO4
乾燥,並真空濃縮。將殘餘物藉由矽膠柱層析法(洗脫液:EA/DCM(v/v)= 1/4,然後MeOH/DCM(v/v)= 1/100至1/20)純化以給出(R或S )-甲基 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(2-(2-異丙基苯基)-4-(4-甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲酸酯(9.2 g),產率:76.7%。1
H NMR (400 MHz, DMSO-d 6
) δ ppm: 11.62 (s, 1H), 7.96 (s, 1H), 7.71 (d,J
= 8.4 Hz, 1H), 7.46 (s, 1H), 7.38 (s, 2H), 7.16 (s, 4H), 7.08 (s, 1H), 6.84 (s, 2H), 6.72 (s, 1H), 6.36 (s, 1H), 6.31 (s, 1H), 3.70 (s, 3H), 3.62 (s, 3H), 3.49 (s, 1H), 3.39-3.36 (m, 1H), 3.05-2.99 (m, 4H), 2.90 (s, 1H), 2.81 (s, 1H), 2.54 (s, 2H), 2.14 (s, 2H), 1.99 (s, 2H), 1.64 (s, 2H), 1.29-1.25 (m, 6H), 1.18 (s, 4H), 1.05 (s, 4H)。MS (ESI, m/e) [M+1]+
714.4。
步驟14:(R或S )-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(2-(2-異丙基苯基)-4-(4-甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲酸之合成
向(R或S )-2-(2-(2-異丙基苯基)-4-(4-甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷(9.2 g,12.90 mmol)在CH3
OH(50 mL)和THF(50 mL)中之溶液中添加NaOH溶液(20 mL,6 N,在水中)。將混合物在50°C下攪拌2.5小時。在將反應溶液冷卻至室溫後,將混合物用DCM(100 mL)稀釋。將混合物攪拌並用HCl酸(70 mL,2 M)調節至pH值約5。將有機層分離,經Na2
SO4
乾燥,真空濃縮以得到粉末。將粗產物藉由在EA(100 mL)中的漿液(回流30 min)進一步純化。將固體過濾並真空乾燥(在50°C下)以給出(R或S)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(2-(2-異丙基苯基)-4-(4-甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲酸(8.4 g),產率:93.3%。1
H NMR (400 MHz, DMSO-d 6
) δ ppm: 11.56 (s, 1H), 7.94 (s, 1H), 7.60 (d,J
= 8.0 Hz, 1H), 7.42 (s, 2H), 7.31 (s, 1H), 7.16 (s, 4H), 7.08 (s, 1H), 6.83 (s, 2H), 6.63 (d,J
= 8.0 Hz, 1H), 6.32 (s, 1H), 6.26 (s, 1H), 3.70 (s, 3H), 3.44 (s, 4H), 2.89-2.83 (m, 8H), 2.47 (s, 1H), 2.14 (s, 2H), 1.94 (s, 1H), 1.64 (s, 2H), 1.30 (s, 5H), 1.18 (s, 3H), 1.04 (s, 4H)。MS (ESI, m/e) [M+1]+
700.4。
步驟15:2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-((R 或 S
)-2-(2-異丙基苯基)-4-(4-甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺(有時稱為「由方法 A 中的中間體 19-1a 合成的實例 19a 」
)之合成
向(R或S )-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(2-(2-異丙基苯基)-4-(4-甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲酸(8.4 g,12.02 mmol)、4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯磺醯胺(4.3 g,12.62 mmol)、EDCI(3.0 g,15.62 mmol)和DMAP(4.5 g,36.05 mmol)在DCM中之溶液中添加TEA(6.1 g,60.08 mmol)。將混合物在室溫下攪拌16小時。將反應混合物用10%乙酸(100 mL × 2)、飽和水性NaHCO3
(200 mL)和鹽水(150 mL)洗滌。將有機層分離並經無水Na2
SO4
乾燥,過濾並真空濃縮。將殘餘物藉由矽膠柱層析(洗脫液:EA/DCM(v/v)= 1/1,然後MeOH/EA/DCM(v/v/v)= 1/40/40至1/15/15)純化。獲得65.0%產率的2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-((R 或 S
)-2-(2-異丙基苯基)-4-(4-甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺(8.0 g)。1
H NMR (400 MHz, DMSO-d6
) δ ppm: 11.66 (s, 1H), 11.12 (s, 1H), 8.52 (s, 2H), 8.00 (s, 1H), 7.74 (d,J
= 12.0 Hz, 1H), 7.57-7.31 (m, 4H), 7.27-6.99 (m, 6H), 6.91-6.78 (m, 2H), 6.68-6.56 (m, 1H), 6.35 (s, 1H), 6.15 (s, 1H), 4.25 (s, 1H), 3.71 (s, 3H), 3.64-3.39 (m, 3H), 3.31-3.18 (m, 3H), 3.02-2.78 (m, 7H), 2.66-2.53 (m, 1H), 2.37-1.97 (m, 3H), 1.78-1.50 (m, 7H), 1.38-1.02 (m, 19H)。MS (ESI, m/e) [M+1]+
1025.6。
藉由本領域的常規技術確定由方法 A 中的中間體 19-1a 合成的實例 19a
的絕對構型。將由方法 A 中的中間體 19-1a 合成的實例 19a
指定為在哌𠯤環的手性碳原子上為(R)-構型(基於其與Bcl-2 G101V蛋白的共晶結構)。確定的詳細方法如下所述。
將具有His和SUMO標籤的重組Bcl-2 G101V突變蛋白在大腸桿菌BL21(DE3)中表現,在16°C下用0.3 mM IPTG誘導16 h。將細胞藉由以5,000 g離心15 min來收集,在含有20 mM Tris(pH 8.0)、300 mM NaCl和5 mM咪唑的裂解緩衝液中重懸,並藉由超音波裂解。在以20,000 g離心40 min後,將上清液與His標籤親和樹脂在4°C下孵育30 min。將樹脂用裂解緩衝液沖洗3次,隨後在4°C下用ULP1蛋白酶處理過夜。將流過物濃縮並順序應用至在含有20 mM Tris(pH 8.0)和150 mM NaCl的緩衝液中的粒徑排阻層析柱(Superdex-75,(通用醫療集團(GE Healthcare)))上。將峰收集並濃縮至約10 mg/ml。將蛋白質溶液與由方法 A 中的中間體 19-1a 合成的實例 19a
在4°C下孵育30 min,然後與含有0.1 M MES(pH 6.5)、0.01 M CoCl2
和1.8 M (NH4
)2
SO4
的儲存溶液混合。藉由從在20°C下培養的懸滴蒸汽擴散獲得Bcl-2 G101V突變體與實例 19a
的共晶體。
X
射線數據收集和結構測定
將尼龍環用於收穫共晶體,並且然後將晶體浸入補充有20%甘油的儲存溶液中持續10秒。繞射數據在光束線BL17U1,上海光源(Shanghai Synchrotron Radiation Facility)上收集,並用XDS程序處理。用程序PHASER使用Bcl-2/ABT-199晶體結構(PDB代碼:6O0K)作為分子置換搜索模型解析該相。將Phenix.refine用於進行剛體、TLS、針對X射線數據的限制細化,然後在COOT程序中手動調整,並在Phenix.refine程序中進一步細化。
數據收集和細化統計
括弧中的值係指最高解析度的邊界(shell)。a
Rmerge=,其中係等效物的平均強度。b
Rwork
=,其中Fo和Fc分別是觀察和計算的結構因子幅度。c
Rfree
=,使用測試數據集計算,從觀察到的反射中隨機選擇總數據的5%。
數據收集 | Bcl-2 G101V+ 實例 19a | |
光束線 | BL17U1 | |
空間群 | P 21 21 21 | |
晶胞尺寸(Å) | a = 32.57 b = 49.81 c = 95.35 | |
角度(°) | α = 90.00 β = 90.00 γ = 90.00 | |
解析度(Å) | 34.44-1.45(1.47-1.45) | |
反射的總數 | 352471(13533) | |
獨特反射的數目 | 28364(1393) | |
完整性(%) | 100(100) | |
平均冗餘 | 12.4(9.7) | |
Rmergea | 0.066(0.678) | |
I/σ(sigma)(I) | 24.2(3.7) | |
Wilson B因子(Å) | 12.05 | |
細化 | ||
解析度(Å) | 26.89-1.45 | |
反射的數目 | 28298 | |
rmsd鍵長(Å) | 0.007 | |
rmsd鍵角(°) | 1.132 | |
Rwork b (%) | 15.96 | |
Rfree c (%) | 18.75 | |
蛋白質的平均B因子 | 17.55 | |
拉馬錢德蘭圖(Ramachandran plot)(%) | ||
有利的(Favored) | 100 | |
允許(Allowed) | 0.00 | |
離群值 | 0.00 |
如圖 1 a
所示,將實例 19a
的哌𠯤環的手性碳原子(箭頭碳)的絕對立體化學指定為(R)-構型(基於其與Bcl-2 G101V蛋白的共晶結構)。
因此,步驟15中獲得的由方法 A 中的中間體 19-1a 合成的實例 19a
具有2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-((R
)-2-(2-異丙基苯基)-4-(4-甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺的化學名稱和化學結構。
鑒於將由方法 A 中的中間體 19-1a 合成的實例 19a
的絕對立體化學指定為(R)-構型(由其與Bcl-2 G101V蛋白的共晶結構)。將方法 A 中的 中間體 19-1a
推斷為具有(R)-構型(如有機化學家所熟知的)。 用於合成 中間體 19-1a 的方法 B
還藉由如下所述之替代程序來合成中間體 19-1a
(R)-2-(2-(2-異丙基苯基)-4-(4-甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷。
方法
B
中的中間體
19-1a
:
在-65°C下,向1-溴-2-異丙基苯(200 g,1.00 mol)在THF(2000 mL)中之溶液中滴加n-BuLi(442.0 mL,1.11 mol,2.5 M,在己烷中)。將溶液在-65°C下攪拌1 hr。然後在-65°C下滴加在THF(500 mL)中的三異丙基硼酸酯(453.4 g,2.41 mmol)。將溶液在-65°C下再攪拌1 hr。將混合物溫熱至20°C並再攪拌1 hr。在20°C下在攪拌下滴加水性HCl酸(1.5 L,1.5 mol,1 N)。將混合物在20°C下再攪拌1 hr並且然後用EtOAc(2 L × 3)萃取。將合併的有機層經Na2
SO4
乾燥,過濾並在減壓下濃縮以給出呈黃色油狀物的(2-異丙基苯基)硼酸(165 g,粗製),其無需進一步純化即可直接用於下一步。
向(2-異丙基苯基)硼酸(165 g,1.0 mol)在二㗁𠮿(1500 mL)和H2
O(150 mL)中之溶液中添加2-氯吡𠯤(138.3 g,1.21 mol)和Pd(PPh3
)4
(17.4 g,15.10 mmol)以及Na2
CO3
(213.3 g,2.01 mmol)。將混合物在90°C下攪拌12小時。在冷卻至室溫後,將混合物通過矽藻土墊過濾並用EtOAc(1 L)洗滌。將濾液在減壓下濃縮。將殘餘物藉由矽膠柱層析法(洗脫液 : PE/EA(v/v)= 400/1至1/1)純化以給出呈黃色油狀物的2-(2-異丙基苯基)吡𠯤(130 g,產率:65%)。
向2-(2-異丙基苯基)吡𠯤(102 g,515.5 mmol)在EtOH(1.5 L)和HOAc(100 mL)中之溶液中添加Pd/C(50 g,濕)。在H2
(60 psi)下,將混合物在60°C下攪拌16小時。將混合物通過矽藻土過濾。將濾餅用MeOH(3 L)和H2
O(1 L)洗滌。將濾液在減壓下濃縮以除去大部分MeOH並且然後用EtOAc(1 L)萃取。將水相用10%水性NaOH鹼化至pH = 13-14。將混合物用DCM(1500 mL × 3)萃取。將合併的有機相(DCM溶液)真空濃縮以給出呈產出固體的2-(2-異丙基苯基)哌𠯤(96.6 g,產率:91%)。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.62-7.55 (m, 1H), 7.32-7.15 (m, 3H), 4.09 (dd,J
= 10.0 Hz, 2.4 Hz, 1H), 3.41-3.29 (m, 1H), 3.16-3.13 (m, 1H), 3.07-2.85 (m, 4H), 2.74-2.71 (m, 1H), 1.26 (d,J
= 6.8 Hz, 6H)。MS (ESI, m/e) [M+1]+
205.5。
根據本領域的拆分方法(例如,Bioorganic & Medicinal Chemistry Letters [生物有機化學與醫藥化學通訊] 12 (2002) 3161-3165)拆分步驟3的化合物。在約50°C下,向2-(2-異丙基苯基)哌𠯤(20.0 g,98 mmol)在MeOH/EA(v/v = 1/10,650 mL)中之溶液中添加可商購自畢得醫藥(Bidepharma)的拆分劑Ac-D-Leu-OH(17.0 g)。將混合物加熱以回流。在添加額外的20 mL MeOH後,形成澄清溶液。然後將溶液緩慢冷卻至室溫(觀察到固體沈澱
)並再攪拌16小時。在過濾懸浮液後,將餅用EA(100 mL)洗滌,收集並真空乾燥(在45°C下)(1 hr)以給出約15 g粉末,然後將其在1 N NaOH(100 mL)與DCM(150 mL)之間分配。將有機層分離並收集,並且將水層用DCM(50 mL)萃取。將合併的有機層經Na2
SO4
乾燥,濃縮以給出固體,在空氣中乾燥以給出呈白色粉末的(R)-2-(2-異丙基苯基)哌𠯤(5.3 g,產率:26.5%,> 99%ee
)。MS (ESI, m/e) [M+1]+
205.5。
將(R)-2-(2-異丙基苯基)哌𠯤(1.5 g,7.353 mmol)、4-甲氧基苯甲醛(1.0 g,7.353 mmol)和NaBH(OAc)3
(2.4 g,11.63 mmol)在DCM(30 mL)中之混合物在室溫下攪拌16小時。將反應藉由飽和NaHCO3
(20 mL)淬滅。將有機層經無水Na2
SO4
乾燥,真空濃縮以得到殘餘物並藉由矽膠柱層析(洗脫液:MeOH/DCM(v/v)= 0/20至1/20)純化以給出呈黃色油狀物的產物。(1.5 g,產率:63.0%)。MS (ESI, m/e) [M+1]+
325.2。
將(R)-3-(2-異丙基苯基)-1-(4-甲氧基苄基)哌𠯤(130 mg,0.401 mmol)、三級丁基 2-側氧基-7-氮雜螺[3.5]壬烷-7-甲酸酯(240 mg,1.003 mmol)、HOAc(60 mg,1.003 mmol)和NaBH3
CN(64 mg,1.003 mmol)的混合物在65°C下攪拌20小時。將反應混合物藉由飽和NaHCO3
(20 mL)淬滅。將有機層經無水Na2
SO4
乾燥,真空濃縮以得到殘餘物並且然後藉由製備型TLC(洗脫液:EA/DCM(v/v)= 1/1)純化以給出呈黃色油狀物的產物。(150 mg,產率:68.3%)。MS (ESI, m/e) [M+1]+
548.4。
向三級丁基 (R)-2-(2-(2-異丙基苯基)-4-(4-甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(150 mg,0.274 mmol)在MeOH(10 mL)中之溶液中添加在1,4-二㗁𠮿(3 mL)中的4 M HCl。將溶液在室溫下攪拌2小時。將反應混合物濃縮。將殘餘物在DCM(20 mL)與1 N NaOH(10 mL)之間分配,將有機層分離,經Na2
SO4
乾燥並濃縮以給出(R)-2-(2-(2-異丙基苯基)-4-(4-甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷(100 mg,產率:81.6%)。MS (ESI, m/e) [M+1]+
448.3。
還藉由以下手性HPLC方法分析方法B中的中間體 19-1a
。
柱 | Lux® Amylose-1(Phenomenex,00F-4732-E0) |
柱尺寸 | 4.6 × 150 mm,5 um |
流動相 | 己烷 : EtOH(0.1% DEA)= 90 : 10 |
流速 | 0.8 mL/min |
波長 | UV 214 nm |
溫度 | 22°C |
方法B中的中間體19-1a的滯留時間 | 3.9 min |
發現方法 B 中的中間體 19-1a
具有3.9 min的滯留時間,這與方法 A 中的中間體 19-1a
的滯留時間一致。兩種中間體的滯留時間之間的一致性證實了方法 B 中的中間體 19-1a
的哌𠯤環的手性碳原子上具有(R)-構型。 用於合成 中間體 19-1a 的方法 C
還藉由如下所述之另一種程序來合成中間體 19-1a
(R)-2-(2-(2-異丙基苯基)-4-(4-甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷。
方法C中的中間體 19-1a
:
(R
或
S)-2-(2-(2-
異丙基苯基
)-4-(4-
甲氧基苄基
)
哌
𠯤
-1-
基
)-7-
氮雜螺
[3.5]
壬烷(方法
C
中的中間體
19-1a
)之合成
步驟1:(R或S)-三級丁基 2-(2-(2-異丙基苯基)-4-(4-甲氧基苄基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯之合成
向(R或S)-三級丁基 2-(2-(2-異丙基苯基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(3 g,6.79 mmol)和4-甲氧基苯甲醛(1.11 g,8.15 mmol)在DCE(40 mL)中之溶液中添加AcOH(815.91 mg,13.59 mmol)和NaBH(OAc)3
(4.32 g,20.38 mmol)。將混合物在25°C下攪拌12小時。將反應混合物傾倒入水性Na2
CO3
(50 mL)中並用DCM(50 mL × 3)萃取。將合併的有機層經Na2
SO4
乾燥,過濾並真空濃縮。將殘餘物藉由MPLC(矽膠,洗脫液:PE/EA(v/v)= 10/1至2/1)純化以給出(R或S)-三級丁基 2-(2-(2-異丙基苯基)-4-(4-甲氧基苄基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(3.6 g),產率:94%。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.33-7.26 (m, 2H), 7.22-7.17 (m, 1H), 7.14-7.08 (m, 1H), 6.78 (m, 2H), 6.63 (m, 2H), 4.94 (m, 1H), 3.73 (s, 3H), 3.57-3.44 (m, 2H), 3.33-3.11 (m, 6H), 2.98 (m, 1H), 2.71-2.56 (m, 2H), 2.30-2.17 (m, 1H), 1.93 (m, 1H), 1.81-1.67 (m, 2H), 1.53-1.44 (m, 2H), 1.41 (s, 9H), 1.37-1.29 (m, 2H), 1.22 (m, 3H), 0.95 (m, 3H)。
步驟2:(R或S)-三級丁基 2-(2-(2-異丙基苯基)-4-(4- 甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯之合成
將(R或S)-三級丁基 2-(2-(2-異丙基苯基)-4-(4-甲氧基苄基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(3.6 g,6.41 mmol)在BH3
.THF(40 mL)中之混合物在70°C下攪拌12小時。將反應混合物在0°C下藉由MeOH(50 mL)淬滅並在25°C下攪拌30 min。將混合物在減壓下濃縮以得到呈白色固體的(R或S)-三級丁基 2-(2-(2-異丙基苯基)-4-(4-甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(3.5 g,粗製)。MS (ESI, m/e) [M+1]+
548.3。
步驟3:(R或S)- 2-(2-(2-異丙基苯基)-4-(4-甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷(方法C中的中間體 19-1a
)之合成
將(R或S)-三級丁基 2-(2-(2-異丙基苯基)-4-(4-甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(3.5 g,6.39 mmol)在HCl溶液(40 mL,4 M,在MeOH中)中之混合物在25°C下攪拌2小時。將反應混合物在減壓下濃縮。將殘餘物藉由備型HPLC(TFA條件)純化。將殘餘物用H2
O(30 mL)稀釋並將混合物用飽和水性Na2
CO3
鹼化至pH = 9。將混合物用EtOAc(30 mL × 3)萃取。將合併的有機層經無水Na2
SO4
乾燥,過濾並真空濃縮以給出(R或S)-2-(2-(2-異丙基苯基)-4-(4-甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷(2.21 g),產率:73%。1
H NMR (400 MHz, CDCl3
) δ ppm: 7.46 (m, 1H), 7.25-7.16 (m, 4H), 7.13-7.07 (m, 1H), 6.82 (m, 2H), 3.78 (s, 3 H), 3.68-3.58 (m, 1H), 3.50-3.41 (m, 2H), 3.40-3.27 (m, 1H), 2.94 (m, 1H), 2.92-2.68 (m, 6H), 2.65 (m, 1H), 2.31-2.20 (m, 2H), 2.20-2.10 (m, 1H), 1.81-1.65 (m, 2H), 1.64-1.45 (m, 4H), 1.35-1.27 (m, 1H), 1.22 (m, 3H), 1.13 (m, 3H)。MS (ESI, m/e) [M+1]+
448.3。實例 19b
2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-((S或R)-2-(2-異丙基苯基)-4-(4-甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺
按照實例 19a
的類似程序用(S或R)-2-(2-(2-異丙基苯基)-4-(4-甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷(中間體 19-1b
)作為材料合成化合物實例 19b 。
按照與製備如上所述之中間體 19-1a
的類似的方法製備(S或R)-2-(2-(2-異丙基苯基)-4-(4-甲氧基苄基) 哌𠯤-1-基)-7-氮雜螺[3.5]壬烷(中間體 19-1b
)。MS (ESI, m/e) [M+1]+
1025.6。
鑒於由方法 A 中的中間體 19-1a 合成的實例 19a
以及方法 A 中的 中間體 19-1a
的絕對立體化學具有(R)-構型,在SFC分離中具有較慢峰的其他異構物,即,方法 A 中的 中間體 19-1b
具有(S)-構型。將來自方法 A 中的中間體 19-1b
的化合物實例 19b
推斷為(S)-構型(如有機化學家所熟知的)。其具有2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-((S
)-2-(2-異丙基苯基)-4-(4-甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺的化學名稱和以下化學結構: 實例 32
(R或S)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-(((4-氟四氫-2H-哌喃-4-基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-(2-(2-異丙基苯基)-4-(4-甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺
向(R或S)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(2-(2-異丙基苯基)-4-(4-甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲酸(50 mg,0.07 mmol)、4-(((4-氟四氫-2H-哌喃-4-基)甲基)胺基)-3-硝基苯磺醯胺(22 mg,0.07 mmol)、EDCI(13 mg,0.07 mmol)、DMAP(17 mg,0.14 mmol)在DCM(20 mL)中之溶液中添加TEA(21 mg,0.21 mmol)。將反應在室溫下攪拌18小時。然後將反應混合物用乙酸(30 mL,10%)、飽和水性NaHCO3
(30 mL)和鹽水(20 mL)順序洗滌。將有機層分離,經無水NaSO4乾燥並真空濃縮。將殘餘物藉由製備型TLC(洗脫液 : DCM/MeOH(v/v)= 20/1)純化。獲得19.30%產率的(R或S)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-(((4-氟四氫-2H-哌喃-4-基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-(2-(2-異丙基苯基)-4-(4-甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺(12 mg)。1
H NMR (400 MHz, DMSO-d 6
) δ ppm: 11.68 (s, 1H), 11.37 (br, 1H), 8.63(s, 1H), 8.56 (s, 1H), 8.01 (s, 1H), 7.79 (d,J
= 8.6 Hz, 1H), 7.48-7.46 (m, 3H), 7.19-7.16 (m, 7H), 6.90 (s, 2H), 6.64 (d,J
= 9.4 Hz, 1H), 6.36 (s, 1H), 6.13 (s, 1H), 3.72 (s, 9H), 3.52 (s, 3H), 2.95-2.92 (m, 7H), 2.78-2.69 (m, 1H), 2.30-2.18 (m, 1H), 1.79-1.76 (m, 4H), 1.64 (s, 2H), 1.23-1.20 (m, 11H), 1.07-1.01 (m, 4H)。MS (ESI) m/e [M+1]+
1015.5。實例 33
N-((4-((((S)-1,4-二㗁𠮿-2-基)甲基)胺基)-3-硝基苯基)磺醯基)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-((R或S)-2-(2-異丙基苯基)-4-(4-甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺
向(R或S)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(2-(2-異丙基苯基)-4-(4-甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲酸(50 mg,0.07 mmol)、(S)-4-(((1,4-二㗁𠮿-2-基)甲基)胺基)-3-硝基苯磺醯胺(22 mg,0.07 mmol)、EDCI(13 mg,0.07 mmol)、DMAP(17 mg,0.14 mmol)在DCM(20 mL)中之溶液中添加TEA(21 mg,0.21 mmol)。將反應在室溫下攪拌18小時。然後將反應混合物用乙酸(30 mL,10%)、飽和水性NaHCO3
(30 mL)和鹽水(20 mL)順序洗滌。將有機層分離,經無水NaSO4乾燥並真空濃縮。將殘餘物藉由製備型TLC純化。獲得(R或S)-N-((4-((((S)-1,4-二㗁𠮿-2-基)甲基)胺基)-3-硝基苯基)磺醯基)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(2-(2-異丙基苯基)-4-(4-甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺(14 mg),產率:19.61%。1
H NMR (400 MHz, DMSO-d 6
) δ ppm: 11.64 (s, 1H), 11.22 (s, 1H), 8.51 (s, 2H), 7.99 (s, 1H), 7.75 (d,J
= 8.4 Hz, 1H), 7.46-7.44 (m, 4H), 7.22-7.20 (m, 4H), 7.08-7.03 (m, 2H), 6.86 (d,J
= 7.8 Hz, 2H), 6.63 (d,J
= 8.8 Hz, 1H), 6.35 (s, 1H), 6.15 (s, 1H), 3.79 (d,J
= 8.8 Hz, 3H), 3.71 (s, 3H), 3.68 - 3.43 (m, 7H), 3.36 (s, 1H), 3.29 (s, 1H), 3.26-3.17 (m, 1H), 2.93-2.90 (m, 7H), 2.55 (s, 1H), 2.18 (s, 2H), 1.61 (s, 2H), 1.23-1.18 (m, 10H), 1.09-1.03 (m, 4H)。MS (ESI) m/e [M+1]+
999.5。實例 81a
2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-((R)-4-(3,4-二甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺
將(R)-2-(2-異丙基苯基)哌𠯤(5.2 g,25.49 mmol)、3,4-二甲氧基苯甲醛(4.2 g,25.49 mmol)和NaBH(OAc)3
(10.8 g,50.98 mmol)在DCM(100 mL)中之混合物在室溫下攪拌16小時。將反應藉由飽和NaHCO3
(50 mL)淬滅。將有機層分離,經無水Na2
SO4
乾燥並真空濃縮。將殘餘物藉由矽膠柱層析(洗脫液:MeOH/DCM(v/v)= 0/20至1/20)純化以給出呈黃色油狀物的標題化合物(6.2 g,產率:68.7%)。MS (ESI, m/e) [M+1]+
355.2。
將(R)-1-(3,4-二甲氧基苄基)-3-(2-異丙基苯基)哌𠯤(2.6 g,7.345 mmol)、甲基 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-側氧基-7-氮雜螺[3.5]壬烷-7-基)苯甲酸酯(3.6 g,8.814 mmol)、HOAc(440 mg,7.345 mmol)和NaBH3
CN(925 mg,14.69 mmol)在MeOH(100 mL)中之混合物在60°C下攪拌4小時。在將反應冷卻至室溫後,將混合物真空濃縮。將殘餘物在DCM(100 mL)與鹽水(20 mL)之間分配。將有機層分離,經Na2
SO4
乾燥,真空濃縮。將殘餘物藉由矽膠柱層析(洗脫液 : MeOH/DCM(v/v)= 0/25至1/25)純化以獲得呈白色固體的甲基 (R)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(4-(3,4-二甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲酸酯。(2.5 g,45.8%)。1
H NMR (400 MHz, DMSO-d6
) δ ppm: 11.61 (s, 1H), 8.00-7.93 (m, 1H), 7.71 (d,J
= 9.2 Hz, 1H), 7.51-7.32 (m, 3H), 7.25-7.01 (m, 3H), 6.91-6.64 (m, 4H), 6.36 (s, 1H), 6.31 (s, 1H), 3.75-3.67 (m, 6H), 3.62 (s, 3H), 3.55-3.33 (m, 3H), 3.31-3.20 (m, 1H), 3.09-2.76 (m, 7H), 2.25-2.08 (m, 2H), 1.98-1.87 (m, 1H), 1.72-1.56 (m, 2H), 1.39-1.00 (m, 13H)。MS (ESI, m/e) [M+1]+
744.5。
向甲基 (R)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(4-(3,4-二甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲酸酯(1.5 g,2.019 mmol)在CH3
OH(20 mL)和THF(20 mL)中之溶液中添加水性NaOH溶液(6 N,10 mL)。將反應混合物在55°C下攪拌1 hr。在將反應冷卻至室溫後,添加DCM(50 mL)和HCl酸(6 N,70 mL)並將混合物的PH值調節至約4-5。將有機層分離,經Na2
SO4
乾燥並真空濃縮以獲得呈白色固體的(R)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(4-(3,4-二甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲酸(1.5 g,粗製),其無需進一步純化即可直接用於下一步。1
H NMR (400 MHz, DMSO-d6
) δ ppm: 12.05 (s, 1H), 11.59 (s, 1H), 8.00-7.90 (m, 1H), 7.71 (d,J
= 9.2 Hz, 1H), 7.50-7.30 (m, 3H), 7.25-7.03 (m, 3H), 6.91-6.63 (m, 4H), 6.35 (s, 1H), 6.30 (s, 1H), 3.76-3.65 (m, 6H), 3.58-3.31 (m, 4H), 3.07-2.79 (m, 7H), 2.26-2.09 (m, 2H), 1.99-1.86 (m, 1H), 1.73-1.55 (m, 2H), 1.42-0.95 (m, 13H)。MS (ESI, m/e) [M+1]+
730.5。
2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-((R)-4-(3,4-二甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺(實例 81a
)之合成
將(R)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(4-(3,4-二甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲酸(1.5 g,2.058 mmol)、4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯磺醯胺(865 mg,2.469 mmol)、EDCI(593 mg,3.086 mmol)、DMAP(753 mg,6.173 mmol)和TEA(623 mg,6.173 mmol)在DCM(100 mL)中之溶液在室溫下攪拌16小時。將反應溶液用10% HOAc(50 mL × 2)、飽和水性NaHCO3
(80 mL)洗滌,濃縮並藉由矽膠柱層析(洗脫液:EA/DCM(v/v)= 1/1至MeOH/DCM(v/v)= 1/10)純化以給出粗產物,將該粗產物藉由製備型TLC(洗脫液:DCM/EA/MeOH(v/v/v)= 10/5/1)純化並凍乾。獲得實例81a(750 mg,35.0%)。1
H NMR (400MHz, DMSO-d6
) δ ppm: 11.71 (s, 1H), 11.43 (br, 1H), 8.57 (s, 2H), 8.04 (s, 1H), 7.80 (d,J
= 8.8 Hz, 1H), 7.57-7.45 (m, 3H), 7.34-7.02 (m, 5H), 6.90 (s, 2H), 6.65 (d,J
= 8.4 Hz, 1H), 6.38 (s, 1H), 6.16 (s, 1H), 4.28 (s, 1H), 4.05-3.62 (m, 9H), 3.32-3.23 (m, 3H), 3.19-2.58 (m, 11H), 1.80-1.49 (m, 7H), 1.38-1.01 (m, 19H)。MS (ESI, m/e) [M+1]+
1056.2。實例 127
4-(2-((R)-4-(3,4-二甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺
步驟1:三級丁基 (R)-2-(2-(2-異丙基苯基)-4-(3,4-二甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯之合成
向(R)-1-(3,4-二甲氧基苄基)-3-(2-異丙基苯基)哌𠯤(12.3 g,34.75 mmol)、三級丁基 2-側氧基-7-氮雜螺[3.5]壬烷-7-甲酸酯(16.6 g,69.49 mmol)在MeOH(200 mL)中之溶液中添加HOAc(4.2 g,69.49 mmol)和NaBH3
CN(4.4 g,69.49 mmol)。將混合物在60°C下攪拌16小時。將混合物冷卻至室溫並真空濃縮。將殘餘物用DCM(100 mL)稀釋,用飽和水性NaHCO3
(50 mL)和鹽水(50 mL × 2)洗滌。將有機層分離,經無水Na2
SO4
乾燥並真空濃縮。將殘餘物藉由矽膠柱層析(洗脫液 : EA/PE(v/v)= 0/1至1/1)純化。獲得三級丁基 (R)-2-(2-(2-異丙基苯基)-4-(3,4-二甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(20.7 g)。MS (ESI, m/e) [M+1]+
578.4。
步驟2:(R)-2-(4-(3,4-二甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷
向三級丁基 (R)-2-(4-(3,4-二甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-甲酸酯(20.7 g,35.81 mmol)在MeOH(200 mL)中之溶液中添加在1,4-二㗁𠮿(200 mL)中的4 M HCl。將溶液在室溫下攪拌6小時。在將混合物在減壓下濃縮後,將殘餘物在DCM(300 mL)與H2
O(200 mL)之間分配。將水層分離並用水性NaOH(2 N)調節至PH約14,用DCM(200 mL × 3)萃取。將合併的有機層經Na2
SO4
乾燥並真空濃縮以給出標題產物(11.7 g,產率:68.8%)。MS (ESI, m/e) [M+1]+
478.3。
步驟3:甲基 (R)-4-(2-(4-(3,4-二甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)苯甲酸酯
將(R)-2-(4-(3,4-二甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷(3.9 g,8.176 mmol)、甲基 4-氟-2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)苯甲酸酯(2.5 g,8.176 mmol)和Na2
CO3
(8.7 g,81.76 mmol)在DMSO(100 mL)中之混合物在95°C下攪拌30小時。將混合物冷卻至室溫並傾倒入H2
O(150 mL)中。在用EA(150 mL × 2)萃取後,將合併的有機層用鹽水(50 mL × 2)洗滌,經無水Na2
SO4
乾燥並真空濃縮。將殘餘物藉由矽膠柱層析(洗脫液:MeOH/DCM(v/v)= 0/30至1/30)純化。獲得甲基 (R)-4-(2-(4-(3,4-二甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)苯甲酸酯(4.3 g,產率:69.4%)。1
H NMR (400 MHz, DMSO-d6
) δ ppm: 11.47 (s, 1H), 8.04 (d,J
= 2.4 Hz, 1H), 7.73 (d,J
= 8.8 Hz, 1H), 7.52-7.29 (m, 3H), 7.24-7.04 (m, 3H), 6.91-6.67 (m, 4H), 6.38 (s, 1H), 3.75-3.67 (m, 6H), 3.61 (s, 3H), 3.55-3.34 (m, 3H), 3.32-3.22 (m, 1H), 3.11-2.79 (m, 7H), 2.25-2.09 (m, 2H), 2.03-1.86 (m, 1H), 1.74-1.58 (m, 2H), 1.40-0.99 (m, 13H)。MS (ESI, m/e) [M+1]+
762.5。
然後按照與實例 81a
類似的程序,獲得4-(2-((R)-4-(3,4-二甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺(350 mg,38.1%)。1
H NMR (400 MHz, DMSO-d6
) δ ppm: 11.75-10.80 (m, 2H), 8.52 (s, 2H), 8.06 (s, 1H), 7.76 (s, 1H), 7.54-6.82 (m, 10H), 6.68 (s, 1H), 6.22 (s, 1H), 4.26 (s, 1H), 4.14-3.62 (m, 9H), 3.30-2.58 (m, 14H), 1.85-1.48 (m, 7H), 1.45-1.04 (m, 19H)。MS (ESI, m/e) [M+1]+
1074.2。實例 141a
4-(6-((R)-4-(3,4-二甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)-2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺
將三級丁基 6-側氧基-2-氮雜螺[3.3]庚烷-2-甲酸酯(4.22 g,20 mmol)在HCl溶液(4 M,在CH3
OH中,20 mL)中之混合物在室溫下攪拌4小時。在真空中濃縮後,將MeOH(50 mL)添加至殘餘物中,然後將所得混合物真空濃縮(重複此處理兩次)。將棕色殘餘物懸浮於EA(150 mL)中,並攪拌1小時。將固體沈澱過濾並真空乾燥以得到呈灰白色粉末的標題產物(3.61 g,產率:83.2%)。1
H NMR (400 MHz, DMSO-d 6
) δ ppm: 9.38 (br, 1H), 3.95-2.86 (m, 4H), 3.02 (s, 6H), 2.33-2.29 (m, 4H)。
將6,6-二甲氧基-2-氮雜螺[3.3]庚烷 氯化氫(1.27 g,6.58 mmol)、甲基 4-氟-2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)苯甲酸酯(1.0 g,3.29 mmol)和Na2
CO3
(3.49 g,32.9 mmol)在DMSO(20 mL)中之混合物加熱至80°C並攪拌16小時。將反應冷卻至室溫並且然後用鹽水(200 mL)淬滅。將混合物用DCM(150 mL × 2)萃取,用鹽水(200 mL × 3)洗滌,經無水Na2
SO4
乾燥並真空濃縮。將殘餘物藉由矽膠層析法(洗脫液 : DCM/EA(v/v)= 5/1)純化以給出呈灰白色固體的甲基 4-(6,6-二甲氧基-2-氮雜螺[3.3]庚烷-2-基)-2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)苯甲酸酯(1.1 g,產率:75.6%)。MS (ESI, m/e) [M+1]+
442.2。
將甲基 4-(6,6-二甲氧基-2-氮雜螺[3.3]庚烷-2-基)-2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)苯甲酸酯(1.1 g,2.49 mmol)和HCl酸(1 N,10 mL)在THF(10 mL)中之混合物攪拌4小時。將反應用水性NaOH(6 N)淬滅並調節至pH至8-10。將混合物用DCM(150 mL)萃取,經無水Na2
SO4
乾燥並真空濃縮。將殘餘物藉由矽膠層析法(洗脫液 : DCM/EA(v/v)= 5/1)純化。獲得呈灰白色固體的甲基 2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(6-側氧基-2-氮雜螺[3.3]庚烷-2-基)苯甲酸酯(940 mg,產率:95.5%)。1
H NMR (400 MHz, DMSO-d6
) δ ppm: 11.52 (s, 1H), 8.10-8.05 (m, 1H), 7.79 (d,J
= 8.8 Hz, 1H), 7.53-7.48 (m, 1H), 7.47-7.44 (m, 1H), 6.33-6.25 (m, 1H), 5.85 (s, 1H), 4.04 (s, 4H), 3.65 (s, 3H), 3.31 (s, 4H)。MS (ESI, m/e) [M+1]+
396.1。
步驟4:甲基 (R)-4-(6-(4-(3,4-二甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)-2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)苯甲酸酯之合成
向(R)-1-(3,4-二甲氧基苄基)-3-(2-異丙基苯基)哌𠯤(844 mg,2.38 mmol)和甲基 2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(6-側氧基-2-氮雜螺[3.3]庚烷-2-基)苯甲酸酯(940 mg,2.38 mmol)在CH3
OH(100 mL)中之混合物中添加NaBH3
CN(450 mg,7.14 mmol)和AcOH(286 mg,4.76 mmol)。將混合物加熱至回流並攪拌過夜。將混合物冷卻至室溫並真空濃縮。將殘餘物用DCM(100 mL)稀釋,用鹽水(50 mL × 2)洗滌,經無水Na2
SO4
乾燥並藉由矽膠層析法(洗脫液:DCM/EA(v/v)= 1/1至DCM/MeOH(v/v)= 20/1)純化。獲得呈灰白色固體的甲基 (R)-4-(6-(4-(3,4-二甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)-2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)苯甲酸酯(820 mg,產率:47.1%)。MS (ESI, m/e) [M+1]+
734.4。
步驟5:(R)-4-(6-(4-(3,4-二甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)-2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)苯甲酸之合成
向甲基 (R)-4-(6-(4-(3,4-二甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)-2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)苯甲酸酯(820 mg,1.12 mmol)在THF/MeOH(10 mL/10 mL)中之溶液中添加水性NaOH(10 mL,6 M)。將混合物加熱至50°C並攪拌2小時。將反應用HCl酸(1 N)淬滅並調節pH值至4-6。將混合物用DCM(100 mL)萃取,經無水Na2
SO4
乾燥並真空濃縮。將殘餘物藉由矽膠層析法(洗脫液 : DCM/EA(v/v)= 1/1至DCM/MeOH(v/v)= 20/1)純化。獲得呈灰白色固體的(R)-4-(6-(4-(3,4-二甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)-2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)苯甲酸(330 mg,產率:40.9%)。1
H NMR (400 MHz, DMSO-d6
) δ ppm: 12.00 (br, 1H), 11.48 (s, 1H), 8.06-7.98 (m, 1H), 7.71 (d,J
= 8.8 Hz, 1H), 7.53-7.18(m, 6H), 7.05-6.73 (m, 3H), 6.16-6.10 (m, 1H), 5.74-5.72 (m, 1H), 3.80-3.72 (m, 6H), 3.68-3.36 (m, 3H), 3.10-2.70 (m, 5H), 2.42-1.85 (m, 4H), 1.76-1.61 (m, 1H), 1.20-1.00 (m, 6H)。MS (ESI, m/e) [M+1]+
720.3。
步驟6:實例141a之合成:4-(6-((R)-4-(3,4-二甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)-2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺
向(R)-4-(6-(4-(3,4-二甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)-2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)苯甲酸(540 mg,0.75 mmol)和4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯磺醯胺(386 mg,1.13 mmol)、EDCI(215 mg,1.13 mmol)、DMAP(275 mg,1.13 mmol)在DCM(100 mL)中之混合物中添加TEA(227 mg,2.25 mmol)。將混合物在室溫下攪拌過夜。然後將反應混合物用乙酸(100 mL × 2,10%)、飽和水性NaHCO3
(150 mL)、和鹽水(100 mL)順序洗滌。將有機層分離,經無水NaSO4
乾燥並真空濃縮。將殘餘物藉由矽膠層析法(洗脫液 : DCM/EA(v/v)= 1/1至DCM/MeOH(v/v)= 20/1)純化以給出粗產物。在藉由製備型TLC(洗脫液 : DCM/MeOH(v/v)= 20/1)進一步純化後獲得4-(6-((R)-4-(3,4-二甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)-2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺(330 mg,產率:42.1%)。1
H NMR (400 MHz, DMSO-d6
) δ ppm: 11.55 (s, 1H), 11.19 (br, 1H), 8.60 - 8.52 (m, 2H), 8.08 (s, 1H), 7.85 (d,J
= 8.8 Hz, 1H), 7.58-7.38(m, 4H), 7.29-7.08 (m, 5H), 6.95-6.80 (m, 2H), 6.09-6.04 (m, 1H), 5.54 (s, 1H), 4.25 (s, 1H), 3.98-3.76 (m, 3H), 3.74 (s, 6H), 3.68-3.36 (m, 5H), 3.32-3.10 (m, 3H), 3.05-2.55 (m, 5H), 2.42-2.28 (m, 1H), 2.06-1.93 (m, 2H), 1.75-1.50 (m, 7H), 1.39-1.10 (m, 9H), 1.08-1.00 (m, 4H)。MS (ESI, m/e) [M+1]+
1046.1。實例 145
2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(6-((R)-4-(3,4-二甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺
步驟1:甲基 (R)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(6-(4-(3,4-二甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)苯甲酸酯之合成
向(R)-1-(3,4-二甲氧基苄基)-3-(2-異丙基苯基)哌𠯤(704 mg,1.989 mmol)在MeOH(50 mL)中之溶液中添加甲基 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(6-側氧基-2-氮雜螺[3.3]庚烷-2-基)苯甲酸酯(750 mg,1.989 mmol)、HOAc(239 mg,3.978 mmol)和NaBH3
CN(251 mg,3.978 mmol)。將混合物在60°C下攪拌16小時。將混合物冷卻至室溫並真空濃縮。將殘餘物用DCM(100 mL)稀釋,用水性NaOH(1 N,10 mL)和鹽水(50 mL × 2)洗滌。將有機層分離,經無水Na2
SO4
乾燥並真空濃縮。將殘餘物藉由矽膠柱層析(洗脫液:EA/DCM(v/v)= 1/1然後MeOH/DCM(v/v)= 0/50至1/50)純化。獲得呈白色固體的甲基 (R)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(6-(4-(3,4-二甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)苯甲酸酯(620 mg,產率:43.6%)。MS (ESI, m/e) [M+1]+
716.4。
向甲基 (R)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(6-(4-(3,4-二甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)苯甲酸酯(620 mg,0.867 mmol)在CH3
OH(10 mL)和THF(10 mL)中之溶液中添加水性NaOH(6 N,3 mL)。將混合物在50°C下攪拌3.5小時並且然後冷卻至室溫。在將混合物在減壓下濃縮後,將殘餘物傾倒入DCM(40 mL)和HCl酸(6 N,3.5 mL)中。將混合物用稀HCl酸調節至PH值約4。將有機層分離,經Na2
SO4
乾燥並真空濃縮以給出呈黃色固體的(R)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(6-(4-(3,4-二甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)苯甲酸。(590 mg,粗製)。MS (ESI, m/e) [M+1]+
702.4。
步驟3:實例145:2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(6-((R)-4-(3,4-二甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺之合成
將(R)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(6-(4-(3,4-二甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)苯甲酸(550 mg,0.785 mmol)、4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯磺醯胺(404 mg,1.177 mmol)、EDCI(226 mg,1.177 mmol)、DMAP(383 mg,3.138 mmol)和TEA(317 mg,3.138 mmol)在DCM(20 mL)中之混合物在室溫下攪拌16小時。然後將反應混合物用DCM(100 mL)稀釋並用10% HOAc(20 mL × 2)、飽和水性NaHCO3
(20 mL)洗滌。將有機層分離,無水Na2
SO4
並真空濃縮。將殘餘物藉由矽膠柱層析(洗脫液 : EA/DCM(v/v)= 1/1然後MeOH/DCM(v/v)= 1/10)純化以給出粗產物。在藉由製備型TLC(DCM/ACN/MeOH(v/v)= 20/10/1)進一步純化後,獲得2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(6-((R)-4-(3,4-二甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺(280 mg,產率:34.8%)。1
H NMR (400 MHz, DMSO-d 6
) δ ppm: 11.73 (s, 1H), 11.22 (s, 1H), 8.66-8.48 (m, 2H), 8.07-8.00 (m, 1H), 7.83 (d,J
= 8.8 Hz, 1H), 7.62-7.07 (m, 9H), 6.92 (s, 2H), 6.40 (s, 1H), 6.04 (d,J
= 8.4 Hz, 1H), 5.49 (s, 1H), 4.25 (s, 1H), 4.12-3.83 (m, 2H), 3.74 (d,J
= 7.6 Hz, 6H), 3.64-3.44 (m, 4H), 3.32-3.26 (m, 3H), 3.17-2.66 (m, 6H), 2.15-1.83 (m, 2H), 1.73-1.50 (m, 6H), 1.41-0.96 (m, 16H)。MS (ESI, m/e) [M+1]+
1028.2。實例 155
2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(6-((R)-2-(2-異丙基苯基)-4-(4-甲氧基苄基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)苯甲醯胺
步驟1:甲基 (R)-2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(6-(2-(2-異丙基苯基)-4-(4-甲氧基苄基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)苯甲酸酯之合成
向(R)-3-(2-異丙基苯基)-1-(4-甲氧基苄基)哌𠯤(2.05 g,6.33 mmol)、甲基 2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(6-側氧基-2-氮雜螺[3.3]庚烷-2-基)苯甲酸酯(2.5 g,6.33 mmol)在MeOH(150 mL)中之混合物中添加NaBH3
CN(1.20 g,19 mmol)和AcOH(1.14 g,19 mmol)。將混合物加熱至回流並攪拌過夜。在冷卻至室溫後,將反應混合物真空濃縮並將殘餘物用DCM(100 mL)稀釋。將此混合物用鹽水(50 mL × 2),並且然後用水(50 mL)洗滌。將有機溶液經無水Na2
SO4
乾燥,過濾並真空濃縮。將殘餘物藉由矽膠層析法(洗脫液:DCM/EA(v/v)= 1/1至DCM/MeOH(v/v)= 20/1)純化。獲得71.8%產率的甲基 (R)-2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(6-(2-(2-異丙基苯基)-4-(4-甲氧基苄基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)苯甲酸酯(3.2 g)。[M+1]+
704.4。
步驟2:(R)-2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(6-(2-(2-異丙基苯基)-4-(4-甲氧基苄基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)苯甲酸之合成
向甲基 (R)-2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(6-(2-(2-異丙基苯基)-4-(4-甲氧基苄基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)苯甲酸酯(3.2 g,4.55 mmol)在THF(10 mL)和MeOH(10 mL)中之溶液中添加NaOH(10 mL,6 N)。將混合物在40°C下攪拌4小時。然後將反應混合物用乙酸(100 mL × 2,10%)、飽和水性NaHCO3
(150 mL)和鹽水(100 mL)順序洗滌。將有機層分離,經無水NaSO4
乾燥並真空濃縮。將殘餘物藉由矽膠層析法(洗脫液:DCM/EA(v/v)= 1/1至DCM/MeOH(v/v)= 20/1)純化。獲得70.1%產率的(R)-2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(6-(2-(2-異丙基苯基)-4-(4-甲氧基苄基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)苯甲酸(2.2 g)。1
H NMR (400 MHz, DMSO-d6
) δ ppm: 11.96 (br, 1H), 11.47 (s, 1H), 8.03 - 7.98 (m,1H), 7.71 (d,J
= 8.8Hz, 1H), 7.53 - 7.08 (m,8H), 7.05 - 6.73 (m, 2H), 6.16 - 6.10 (m, 1H), 5.74 - 5.72 (m, 1H), 3.80 - 3.36 (m, 10H), 3.10 - 2.70 (m, 7H), 2.42 - 1.85 (m, 3H), 1.76 - 1.61 (m, 1H), 1.41 - 1.30 (m, 1H), 1.20 - 1.00 (m, 6H)。MS (ESI, m/e) [M+1]+
690.7。
步驟3:2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(6-((R)-2-(2-異丙基苯基)-4-(4-甲氧基苄基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)苯甲醯胺(實例 155
)之合成
向(R)-2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(6-(2-(2-異丙基苯基)-4-(4-甲氧基苄基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)苯甲酸(2.0 g,2.90 mmol)和4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯磺醯胺(1.50 g,4.35 mmol)在DCM(200 mL)中之混合物中添加EDCI(826 mg,4.35 mmol)、DMAP(1.06 g,8.70 mmol)和TEA(879 mg,8.70 mmol)。將混合物在室溫下攪拌過夜。將反應用鹽水(100 mL)淬滅,用AcOH/H2
O(1/10,100 mL × 2)的溶液,隨後用水性NaHCO3
(250 mL)洗滌。將有機層分離,經Na2
SO4
乾燥並真空濃縮。將殘餘物藉由矽膠層析法(洗脫液 : DCM/EA(v/v)= 1/1至DCM/MeOH(v/v)= 20/1)純化以給出粗產物。將粗產物藉由製備型TLC(洗脫液 : DCM/CH3CN/MeOH(v/v/v)= 25/25/2)進一步純化。獲得33.0%產率的2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(6-((R)-2-(2-異丙基苯基)-4-(4-甲氧基苄基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)苯甲醯胺(972 mg)。1
H NMR (400 MHz, DMSO-d6
) δ ppm: 11.55 (s, 1H), 11.23 (br, 1H), 8.63-8.54 (m, 2H), 8.08 (s, 1H), 7.85-7.78(m, 1H), 7.57-7.48(m, 2H), 7.47-7.08 (m, 8H), 6.95-6.84 (m, 2H), 6.09-6.04 (m, 1H), 5.53 (s, 1H), 4.25 (s, 1H), 3.73 (s, 3H), 3.68-3.36 (m, 7H), 3.32-3.10 (m, 3H), 3.05-2.55 (m, 6H), 2.30-1.90 (m, 3H), 1.70-1.42 (m, 7H), 1.38-1.10 (m, 8H), 1.08-1.00 (m, 5H)。MS (ESI, m/e) [M+1]+
1016.1。實例 232
4-(6-((R)-4-(4-環丙基-3-甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)-2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺
向4-溴-3-甲氧基苯甲醛(25.0 g,116.3 mmol)在1,4-二㗁𠮿(500 mL)中之溶液中添加環丙基硼酸(31.0 g,348.8 mmol)、K2
CO3
(16.0 g,116.3 mmol)、H2
O(10 mL)和Pd(dppf)Cl2
(1.7 g,2.33 mmol)。將混合物在80°C下在N2
氣氛下攪拌48小時。將反應混合物冷卻至室溫,並且然後過濾。將所得的餅用EA(200 mL)洗滌。將合併的濾液經無水Na2
SO4
乾燥,過濾並濃縮。將殘餘物藉由柱層析(矽膠,100-200目,洗脫液 : EA/PE(v/v)= 0/10至1/10)純化。獲得95.1%產率的4-環丙基-3-甲氧基苯甲醛(19.5 g)。MS (ESI, m/e) [M+1]+
177.2。
向(R)-2-(2-異丙基苯基)哌𠯤(8.7 g,42.6 mmol)在DCM(200 mL)中之溶液中添加4-環丙基-3-甲氧基苯甲醛(7.5 g,42.6 mmol)和NaBH(OAc)3
(10.8 g,51.2 mmol)。將混合物在室溫下攪拌20小時。將反應溶液用10% HOAc(100 mL × 2)和飽和水性NaHCO3
(200 mL)順序洗滌。將有機層分離,經無水Na2
SO4
乾燥,過濾並濃縮。將所得粗產物藉由柱層析(矽膠,200-300目,洗脫液 : EA/PE(v/v)= 1/5然後MeOH/DCM(v/v)= 0/30至1/30)進一步純化。獲得63.2%產率的(R)-1-(4-環丙基-3-甲氧基苄基)-3-(2-異丙基苯基)哌𠯤(9.8 g)。MS (ESI, m/e) [M+1]+
365.3。
步驟3:甲基 (R)-4-(6-(4-(4-環丙基-3-甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)-2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)苯甲酸酯之合成
向(R)-1-(4-環丙基-3-甲氧基苄基)-3-(2-異丙基苯基)哌𠯤(9.4 g,25.8 mmol)在MeOH(200 mL)中之溶液中添加甲基 2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(6-側氧基-2-氮雜螺[3.3]庚烷-2-基)苯甲酸酯(11.3 g,28.4 mmol)、HOAc(3.1 g,51.6 mmol)和NaBH3
CN(9.7 g,154.9 mmol)。將混合物在回流下攪拌16小時。將反應冷卻至室溫並真空濃縮。將所得殘餘物在DCM(300 mL)與飽和水性NaHCO3
(100 mL)之間分配。將有機層分離,經無水Na2
SO4
乾燥,過濾並濃縮。將粗產物藉由柱層析(矽膠,200-300目,洗脫液 : MeOH/DCM(v/v)= 0/50至1/50)進一步純化。獲得呈白色固體的甲基 (R)-4-(6-(4-(4-環丙基-3-甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)-2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)苯甲酸酯(18.0 g,產率:93.7%)。1
H NMR (400 MHz, DMSO-d6
) δ ppm: 11.50 (s, 1H), 8.03 (d,J
= 2.8 Hz, 1H), 7.70 (d,J
= 8.4 Hz, 1H), 7.52 - 7.30 (m, 3H), 7.25 - 6.99 (m, 3H), 6.84 (s, 1H), 6.75 - 6.67 (m, 2H), 6.13 (dd,J
= 2.0 Hz, 8.8Hz, 1H), 5.74 (d,J
= 2.0 Hz, 1H), 3.77 (s, 3H), 3.70 - 3.58 (m, 6H), 3.56 - 3.41 (m, 3H), 3.40 - 3.13 (m, 3H), 2.92 - 2.67 (m, 3H), 2.24 - 1.86 (m, 6H), 1.76 - 1.61 (m, 1H), 1.44 - 1.31 (m, 1H), 1.24 - 1.13 (m, 3H), 1.09 - 0.98 (m, 3H), 0.88 - 0.78 (m, 2H), 0.58 - 0.49 (m, 2H)。MS (ESI, m/e) [M+1]+
744.7。
步驟4:(R)-4-(6-(4-(4-環丙基-3-甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)-2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)苯甲酸之合成
向甲基 (R)-4-(6-(4-(4-環丙基-3-甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)-2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)苯甲酸酯(18.0 g,24.2 mmol)在THF(100 mL)和MeOH(100 mL)中之溶液中添加水性NaOH溶液(9.7 g,242.3 mmol,在100 mL H2
O中)。將混合物在50°C下攪拌3小時。在將反應混合物冷卻至室溫後,向其中添加DCM(300 mL)。將所得混合物進一步冷卻至約10°C。將混合物的PH值用6 N HCl酸調節至約5。將有機層分離並用飽和水性NaHCO3
(100 mL)洗滌,經無水Na2
SO4
乾燥,過濾並濃縮。將殘餘物藉由柱層析法(矽膠,200-300目,洗脫液 : MeOH/DCM(v/v)= 0/10至1/10)純化。獲得呈白色固體的(R)-4-(6-(4-(4-環丙基-3-甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)-2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)苯甲酸(15.0 g,產率:84.9%)。1
H NMR (400 MHz, DMSO-d 6
) δ ppm: 11.99 (s, 1H), 11.49 (s, 1H), 8.03 (d,J
= 2.4 Hz, 1H), 7.71 (d,J
= 7.6 Hz, 1H), 7.51 - 7.32 (m, 3H), 7.25 - 6.99 (m, 3H), 6.85 (s, 1H), 6.76 - 6.66 (m, 2H), 6.12 (dd,J
= 2.0 Hz, 8.8 Hz, 1H), 5.75 (d,J
= 2.0 Hz, 1H), 3.77 (s, 3H), 3.70 - 3.15 (m, 9H), 2.93 - 2.66 (m, 3H), 2.24 - 1.88 (m, 6H), 1.75 - 1.61 (m, 1H), 1.44 - 1.30 (m, 1H), 1.24 - 1.13 (m, 3H), 1.09 - 0.98 (m, 3H), 0.88 - 0.78 (m, 2H), 0.58 - 0.49 (m, 2H)。MS (ESI, m/e) [M+1]+
730.6。
步驟5:實例232之合成
向(R)-4-(6-(4-(4-環丙基-3-甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)-2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)苯甲酸(15.0 g,20.6 mmol)和4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯磺醯胺(7.1 g,20.58 mmol)在DCM(300 mL)中之混合物中添加EDCI(5.9 g,30.9 mmol)、DMAP(10.0 g,82.30 mmol)和TEA(8.3 g,82.3 mmol)。將混合物在室溫下攪拌16小時。將反應用鹽水(100 mL)淬滅,用10% HOAc(100 mL × 2)的溶液,隨後用飽和水性NaHCO3
(250 mL)洗滌。將有機層分離,經Na2
SO4
乾燥並真空濃縮。將殘餘物藉由矽膠層析法(200-300目,洗脫液 : MeOH/DCM(v/v)= 0/30至1/30)純化。獲得46.1%產率的標題產物4-(6-((R)-4-(4-環丙基-3-甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)-2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺(10.0 g)。1
H NMR (400 MHz, DMSO-d6
) δ ppm: 11.52 (s, 1H), 11.18 (s, 1H), 8.52 (s, 2H), 8.06 (s, 1H), 7.78 (d,J
= 9.2 Hz, 1H), 7.54 - 7.30 (m, 4H), 7.27 - 6.98 (m, 4H), 6.86 (s, 1H), 6.73 (s, 2H), 6.06 (d,J
= 8.4 Hz, 1H), 5.56 (s, 1H), 4.25 (s, 1H), 3.77 (s, 3H), 3.67 - 3.42 (m, 7H), 3.32 - 3.14 (m, 3H), 2.96 - 2.82 (m, 2H), 2.78 - 2.64 (m, 1H), 2.62 - 2.52 (m, 1H), 2.34 - 2.14 (m, 2H), 2.13 - 1.88 (m, 4H), 1.74 - 1.49 (m, 6H), 1.33 (t,J
= 11.6 Hz, 3H), 1.24 - 0.96 (m, 11H), 0.89 - 0.78 (m, 2H), 0.60 - 0.48 (m, 2H)。MS (ESI, m/e) [M+1]+
1055.8。實例 233
2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(6-((R)-4-(4-環丙基-3-甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺
步驟1:甲基 (R)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(6-(4-(4-環丙基-3-甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)苯甲酸酯之合成
向(R)-1-(4-環丙基-3-甲氧基苄基)-3-(2-異丙基苯基)哌𠯤(2.0 g,5.495 mmol)在MeOH(50 mL)中之溶液中添加甲基 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(6-側氧基-2-氮雜螺[3.3]庚烷-2-基)苯甲酸酯(2.3 g,6.044 mmol)、HOAc(0.6 g,10.99 mmol)和NaBH3
CN(2.1 g,32.97 mmol)。將混合物在回流下攪拌5小時。將反應冷卻至室溫並真空濃縮。將所得殘餘物在DCM(100 mL)與飽和水性NaHCO3
(50 mL)之間分配。將有機層分離,經無水Na2
SO4
乾燥,過濾並濃縮。將殘餘物藉由柱層析(矽膠,200-300目,洗脫液:MeOH/DCM(v/v)= 0/50至1/50)進一步純化。獲得甲基 (R)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(6-(4-(4-環丙基-3-甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)苯甲酸酯(3.0 g,產率:75.4%)。MS (ESI, m/e) [M+1]+
726.7。
步驟2:(R)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(6-(4-(4-環丙基-3-甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)苯甲酸之合成
向甲基 (R)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(6-(4-(4-環丙基-3-甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)苯甲酸酯(3.0 g,4.138 mmol)在THF(30 mL)和MeOH(20 mL)中之溶液中添加水性NaOH溶液(1.7 g,41.4 mmol,在20 mL H2
O中)。將混合物在50°C下攪拌3小時。在將反應混合物冷卻至室溫後,向其中添加DCM(100 mL)。將所得混合物進一步冷卻至約10°C。將混合物的PH值用6 N HCl酸調節至約5。將有機層分離,經無水Na2
SO4
乾燥,濃縮,並藉由矽膠柱層析法(矽膠,200-300目,洗脫液:MeOH/DCM(v/v)= 0/10至1/10)純化。獲得呈白色固體的酸產物(2.7 g,產率:91.8%)。MS (ESI, m/e) [M+1]+
712.7。
步驟3:實例233之合成
向(R)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(6-(4-(4-環丙基-3-甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)苯甲酸(2.7 g,3.797 mmol)、4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯磺醯胺(1.3 g,3.797 mmol)在DCM(100 mL)中之混合物中添加EDCI(1.1 g,5.696 mmol)、DMAP(1.8 g,15.19 mmol)和TEA(1.5 g,15.19 mmol)。將混合物在室溫下攪拌16小時。將反應用10% HOAc(50 mL × 2)的溶液、隨後用飽和水性NaHCO3
(50 mL)洗滌。將有機層分離,經Na2
SO4
乾燥並真空濃縮。將殘餘物藉由矽膠層析法(200-300目,洗脫液 : MeOH/DCM(v/v)= 0/30至1/30)純化。獲得2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(6-((R)-4-(4-環丙基-3-甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺(2.5 g,產率:53.6%)。1
H NMR (400 MHz, DMSO-d6
) δ ppm: 11.70 (s, 1H), 11.11 (s, 1H), 8.55 (s, 2H), 8.02 (s, 1H), 7.80 (d,J
= 8.4 Hz, 1H), 7.60 - 7.28 (m, 4H), 7.26 - 7.00 (m, 4H), 6.85 (s, 1H), 6.72 (s, 2H), 6.38 (s, 1H), 6.03 (d,J
= 7.6 Hz, 1H), 5.50 (s, 1H), 4.25 (s, 1H), 3.77 (s, 3H), 3.66 - 3.40 (m, 7H), 3.31 - 3.14 (m, 3H), 2.96 - 2.80 (m, 2H), 2.78 - 2.64 (m, 1H), 2.61 - 2.52 (m, 1H), 2.32 - 2.12 (m, 2H), 2.11 - 1.86 (m, 4H), 1.76 - 1.48 (m, 6H), 1.33 (t,J
= 6.8 Hz, 3H), 1.23 - 0.96 (m, 11H), 0.88 - 0.78 (m, 2H), 0.60 - 0.48 (m, 2H)。MS (ESI, m/e) [M+1]+
1038.2。實例 338
2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(6-((R)-2-(2-異丙基苯基)-4-((7-甲氧基-2-甲基苯并呋喃-5-基)甲基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)苯甲醯胺
步驟1:甲基 (R)-2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(6-(2-(2-異丙基苯基)-4-((7-甲氧基-2-甲基苯并呋喃-5-基)甲基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)苯甲酸酯之合成
向(R)-3-(2-異丙基苯基)-1-((7-甲氧基-2-甲基苯并呋喃-5-基)甲基)哌𠯤(9.0 g,23.81 mmol)在DCE(300 mL)中之溶液中添加甲基 2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(6-側氧基-2-氮雜螺[3.3]庚烷-2-基)苯甲酸酯(12.3 g,30.95 mmol)、HOAc(2.9 g,47.62 mmol)和NaBH(OAc)3
(10.0 g,47.62 mmol)。將混合物在70°C下攪拌4小時。將反應冷卻至室溫並藉由飽和水性NaHCO3
(300 mL)淬滅。然後將有機層分離,經無水Na2
SO4
乾燥,過濾並濃縮。將殘餘物藉由矽膠柱層析(洗脫液 : MeOH/DCM(v/v)= 0/50至1/50)純化。獲得甲基 (R)-2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(6-(2-(2-異丙基苯基)-4-((7-甲氧基-2-甲基苯并呋喃-5-基)甲基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)苯甲酸酯(13.0 g,產率:72.1%)。1
H NMR (DMSO-d6
) δ ppm: 11.51 (d,J
= 2.4 Hz, 1H), 8.04 (d,J
= 2.8 Hz, 1H), 7.70 (d,J
= 8.4 Hz, 1H), 7.50 (t,J
= 2.4Hz, 1H), 7.46-7.33 (m, 2H), 7.24-7.04 (m, 3H), 6.97 (s, 1H), 6.77 (s, 1H), 6.45 (s, 1H), 6.12 (dd,J
= 2.0 Hz, 8.8 Hz, 1H), 5.74 (d,J
= 2.0 Hz, 1H), 3.87 (s, 3H), 3.70-3.40 (m, 10H), 3.33-3.17 (m, 1H), 2.93-2.81 (m, 2H), 2.79-2.65 (m, 1H), 2.58-2.51 (m, 1H), 2.39 (s, 3H), 2.25-1.86 (m, 5H), 1.76-1.60 (m, 1H), 1.44-1.30 (m, 1H), 1.19 (d,J
= 6.8 Hz, 3H), 1.01 (d,J
= 6.0 Hz, 3H)。MS (ESI, m/e) [M+1]+
758.5。
步驟2:(R)-2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(6-(2-(2-異丙基苯基)-4-((7-甲氧基-2-甲基苯并呋喃-5-基)甲基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)苯甲酸之合成
向甲基 (R)-2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(6-(2-(2-異丙基苯基)-4-((7-甲氧基-2-甲基苯并呋喃-5-基)甲基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)苯甲酸酯(13.0 g,17.17 mmol)在THF(65 mL)和MeOH(65 mL)中之溶液中添加水性NaOH溶液(6.9 g,171.7 mmol,在65 mL H2
O中)。將混合物在55°C下攪拌2小時。然後將反應冷卻至35°C並進一步攪拌16小時。在冷卻至約10°C後,將混合物用DCM(200 mL)稀釋並且然後用6 N HCl酸調節至PH約5。將有機層分離,用飽和水性NaHCO3
(100 mL)洗滌,經無水Na2
SO4
乾燥並濃縮。將殘餘物藉由矽膠柱層析法(洗脫液 : MeOH/DCM(v/v)= 0/15至1/15)純化。獲得86.2%產率的(R)-2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(6-(2-(2-異丙基苯基)-4-((7-甲氧基-2-甲基苯并呋喃-5-基)甲基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)苯甲酸(11.0 g)。1
H NMR (DMSO-d6
) δ ppm: 12.07 (s, 1H), 11.52 (s, 1H), 8.03 (d,J
= 2.4 Hz, 1H), 7.72 (d,J
= 8.8 Hz, 1H), 7.53-6.95 (m, 8H), 6.62-6.39 (m, 1H), 6.13 (d,J
= 8.4 Hz, 1H), 5.75 (s, 1H), 4.47-4.15 (m, 1H), 3.93 (s, 3H), 3.79-3.33 (m, 7H), 3.14-2.58 (m, 5H), 2.42 (s, 3H), 2.29-1.83 (m, 3H), 1.77-1.55 (m, 1H), 1.46-0.92 (m, 8H), 1.42-1.27 (m, 3H), 1.24-0.99 (m, 11H)。MS (ESI, m/e) [M+1]+
744.5。
步驟3:實例338之合成
向(R)-2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(6-(2-(2-異丙基苯基)-4-((7-甲氧基-2-甲基苯并呋喃-5-基)甲基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)苯甲酸(11.0 g,14.80 mmol)、4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯磺醯胺(5.6 g,16.29 mmol)在DCM(500 mL)中之溶液中添加EDCI(4.3 g,22.21 mmol)、DMAP(7.3 g,59.22 mmol)和TEA(6.0 g,59.22 mmol)。將混合物在室溫下攪拌16小時。然後將N, N-二甲基乙二胺(10 mL)添加進反應混合物中並將混合物在室溫下進一步攪拌6小時。將混合物用10% HOAc(300 mL × 2)的溶液,隨後用飽和水性NaHCO3
(400 mL)洗滌。將有機層分離,經Na2
SO4
乾燥並真空濃縮。將殘餘物藉由矽膠柱層析法(洗脫液:MeOH/DCM(v/v)= 0/30至1/30)純化。獲得2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(6-((R)-2-(2-異丙基苯基)-4-((7-甲氧基-2-甲基苯并呋喃-5-基)甲基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)苯甲醯胺(實例338,7.5 g,產率:47.3%)。1
H NMR (DMSO-d6
) δ ppm: 11.48 (s, 1H), 8.55 - 8.38 (m, 2H), 8.01 (s, 1H), 7.72 (d,J
= 8.8Hz, 1H), 7.50 - 7.26 (m, 4H), 7.22 - 6.90 (m, 5H), 6.75 (s, 1H), 6.43 (s, 1H), 6.01 (d,J
= 8.8Hz, 1H), 5.51 (s, 1H), 4.21 (s, 1H), 3.83 (s, 3H), 3.65 - 3.39 (m, 7H), 3.26 - 3.12 (m, 3H), 2.94 - 2.78 (m, 2H), 2.74 - 2.50 (m, 2H), 2.34 (s, 3H), 2.30 - 1.83 (m, 5H), 1.68 - 1.44 (m, 6H), 1.36 - 1.22 (m, 3H), 1.18 - 0.92 (m, 11H)。MS (ESI, m/e) [M+1]+
1069.9。
按照與實例19a的那些程序基本相同的程序或使用類似之合成方法或策略,由各自的中間體製備表2中的實例19-31和實例34-371。
[表 2
]
生物學實例: Bcl-2 TR-FRET 測定:
實例 | 結構 | 化合物名稱 | 數據 | |
19 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-(2-(2-異丙基苯基)-4-(4-甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.68 (s, 1H), 11.25 (s, 1H), 8.54 (s, 2H), 8.02 (s, 1H), 7.76 (s, 1H), 7.48-7.46 (m, 3H), 7.24 (s, 5H), 7.13 (s, 1H), 7.07 (s, 1H), 6.90 (s, 2H), 6.64 (d,J = 8.6 Hz, 1H), 6.37 (s, 1H), 6.13 (s, 1H), 4.24 (s, 1H), 3.73 (s, 4H), 3.28 (s, 3H), 2.96-2.93 (m, 7H), 2.27 (s, 1H), 2.01-1.99 (m, 1H), 1.62-1.60 (m, 7H), 1.37-1.03 (m, 21H)。MS (ESI, m/e) [M+1]+ 1027.0。 | ||
20 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(4-(呋喃-3-基甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.74 (s, 1H), 11.32 (s, 1H), 8.68-8.55 (m, 2H), 8.08 (s, 1H), 7.83 (d,J = 9.4 Hz, 1H), 7.75-7.68(m, 2H), 7.59-7.03 (m, 9H), 6.71 (d,J = 8.7 Hz, 1H), 6.62-6.48 (m, 1H), 6.43 (s, 1H), 6.20 (s, 1H), 4.31 (s, 1H), 3.93-3.65(m, 1H), 3.36-3.27 (m, 4H), 3.18-2.76 (m, 9H), 2.39-1.99 (m, 2H), 1.80-1.55 (m, 7H), 1.44-1.26 (m, 10H), 1.21-1.11 (m, 9H)。MS (ESI, m/e) [M+1]+ 986.1 | ||
21 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-(2-(2-異丙基苯基)-4-(㗁唑-4-基甲基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.69 (s, 1H), 11.49-11.13 (m, 1H), 10.99-10.76 (m, 1H), 8.57-8.54 (m, 2H), 8.35 (s, 1H), 8.02 (s, 2H), 7.77 (d,J = 9.0 Hz, 1H), 7.56-7.41 (m, 3H), 7.29 (s, 3H), 7.07-7.05 (m, 1H), 6.65 (d,J = 9.0 Hz, 1H), 6.37 (s, 1H), 6.15 (s, 1H), 4.27 (s, 1H), 3.59 (s, 3H), 3.28 (s, 2H), 2.96-2.94 (m, 8H), 1.99 (s, 1H), 1.62-1.60 (m, 6H), 1.23 (s, 14H), 1.10 (s, 7H)。MS (ESI, m/e) [M+1]+ 990.2。 | ||
22 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-(2-(2-異丙基苯基)-4-((1-甲基-1H-吡唑-4-基)甲基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.66 (s, 1H), 11.26-10.82 (m, 1H), 8.52 (s, 2H), 8.00 (s, 1H), 7.74 (s, 1H), 7.67 (s, 1H), 7.48 (s, 3H), 7.39 (s, 2H), 7.25 (s, 2H), 7.13 (s, 1H), 7.05 (s, 1H), 6.64 (d,J = 9.2 Hz, 1H), 6.36 (s, 1H), 6.14 (s, 1H), 4.24 (s, 1H), 3.79 (s, 5H), 3.28-3.25 (m, 2H), 2.96-2.90 (m, 8H), 2.34-2.30 (m, 1H), 1.99 (s, 1H), 1.68-1.60 (m, 7H), 1.30-1.18 (m, 14H), 1.11-1.08 (m, 7H)。MS (ESI, m/e) [M+1]+ 999.9。 | ||
22a | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-((R或S)-2-(2-異丙基苯基)-4-((1-甲基-1H-吡唑-4-基)甲基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.68 (s, 1H), 11.08 (s, 1H), 8.62-8.45 (m, 2H), 8.01 (s, 1H), 7.89-7.63 (m, 2H), 7.57-6.95 (m, 9H), 6.72-6.56 (m, 1H), 6.36 (s, 1H), 6.14 (s, 1H), 4.25 (s, 1H), 3.95-3.65 (m, 5H), 3.34-3.21 (m, 5H), 3.20-2.79 (m, 8H), 2.72-2.52 (m, 2H), 2.40-2.23 (m, 1H), 1.80-1.49 (m, 7H), 1.40-1.24 (m, 6H), 1.22-1.02 (m, 12H)。MS (ESI, m/e) [M+1]+ 999.6 | ||
22b | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-((S或R)-2-(2-異丙基苯基)-4-((1-甲基-1H-吡唑-4-基)甲基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.64 (s, 1H), 11.05 (br, 1H), 8.55 - 8.45 (m, 2H), 7.98 (s, 1H), 7.70 (d,J = 8.8 Hz, 1H), 7.58 (s, 1H), 7.49-7.36 (m, 4H), 7.30 (s, 1H), 7.26-7.15 (m, 2H), 7.16-7.05 (m, 1H), 6.98 (d,J = 8.8 Hz, 1H), 6.63 (d,J = 8.8 Hz, 1H), 6.34 (s, 1H), 6.15 (s, 1H), 4.25 (s, 1H), 3.76 (s, 3H), 3.62-3.40(m, 3H), 3.32-3.20 (m, 3H), 3.06-2.80 (m, 8H), 2.70-2.61 (m, 1H), 2.35-1.93 (m, 3H), 1.73-1.52 (m, 7H), 1.38-1.20 (m, 10H), 1.15-1.08 (m, 8H)。MS (ESI, m/e) [M+1]+ 999.6。 | ||
23 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(4-苄基-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.66 (s, 1H), 11.30 (br, 1H), 8.49-8.55 (m, 2H), 8.02 (s, 1H), 7.74 (d,J = 8 Hz, 1H), 7.40-7.51 (m, 4H), 7.02-7.28 (m, 10H), 6.63 (d,J = 8 Hz, 1H), 6.35 (s, 1H), 6.14 (s, 1H), 4.25 (s, 1H), 3.49-3.54 (m, 2H), 3.25-3.28 (m, 2H), 2.89-2.95 (m, 7H), 2.54 (s, 1H), 2.21-2.01 (m, 3H), 1.63-1.69 (m, 4H), 1.52-1.55 (m, 2H), 1.02-1.26 (m, 22H)。MS (ESI, m/e) [M+1]+ 995.6 | ||
24a | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-(2-(2-異丙基苯基)-4-(1-苯基乙基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.68 (s, 1H), 11.36 (br, 1H), 8.60-8.52 (m, 2H), 8.01 (s, 1H), 7.80-7.70 (m, 1H), 7.52-7.45 (m, 3H), 7.43-7.01 (m, 10H), 6.68-6.62 (m, 1H), 6.36 (s, 1H), 6.13 (s, 1H), 4.25 (s, 1H), 3.78-3.67 (m, 1H), 3.45-3.37 (m, 1H), 3.31-3.26 (m, 2H), 3.19-2.75 (m, 9H), 2.65-2.55 (m, 1H), 2.25-1.95 (m, 2H), 1.74-1.52 (m, 7H), 1.38-1.23 (m, 14H), 1.15-1.08 (m, 8H)。MS (ESI, m/e) [M+1]+ 1009.9。 | ||
24b | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-(2-(2-異丙基苯基)-4-(1-苯基乙基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.69 (s, 1H), 11.47 (br, 1H), 8.60-8.52 (m, 2H), 8.02 (s, 1H), 7.80-7.75 (m, 1H), 7.54-7.45 (m, 3H), 7.40-7.01 (m, 10H), 6.68-6.63 (m, 1H), 6.37 (s, 1H), 6.13 (s, 1H), 4.25 (s, 1H), 3.78-3.72 (m, 1H), 3.59-3.42 (m, 2H), 3.31-3.26 (m, 2H), 3.23-2.85 (m, 8H), 2.65-2.55 (m, 1H), 2.09-1.95 (m, 2H), 1.74-1.50 (m, 7H), 1.38-1.23 (m, 14H), 1.17-1.08 (m, 8H)。MS (ESI, m/e) [M+1]+ 1009.9。 | ||
25a | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-(2-(2-異丙基苯基)-4-(1,2,3,4-四氫萘-1-基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.69 (s, 1H), 11.44 (s, 1H), 8.54 (s, 2H), 8.02 (s, 1H), 7.76 (s, 1H), 7.62 (s, 1H), 7.48-7.46 (m, 3H), 7.39 (s, 1H), 7.26 (s, 1H), 7.12-7.00 (m, 5H), 6.66-6.64 (m, 1H), 6.37 (s, 1H), 6.15 (s, 1H), 4.27 (s, 1H), 3.88-3.85 (m, 2H), 3.28 (s, 3H), 2.92 (s, 6H), 2.67 (s, 2H), 1.96-1.93 (m, 4H), 1.60-1.56 (m, 9H), 1.25-1.22 (m, 13H), 1.17-1.06 (m, 9H)。MS (ESI, m/e) [M+1]+ 1035.9。 | ||
25b | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-(2-(2-異丙基苯基)-4-(1,2,3,4-四氫萘-1-基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.70 (s, 1H), 11.45 (s, 1H), 11.08 (s, 1H), 8.54 (s, 2H), 8.02 (s, 1H), 7.83-7.81 (m, 2H), 7.65 (s, 1H), 7.49-7.47 (m, 3H), 7.29 (s, 2H), 7.05-7.02 (m, 8 Hz, 7H), 6.66 (d,J = 8.6 Hz, 1H), 6.37 (s, 1H), 6.16 (s, 1H), 4.27 (s, 1H), 4.01 (s, 1H), 3.82 (s, 1H), 3.28 (s, 2H), 2.98-2.96 (m, 3H), 2.62 (s, 1H), 2.15-2.13 (m, 1H), 1.90 (s, 1H), 1.62-1.60 (m, 5H), 1.24 (s, 7H), 1.11 (s, 3H), 0.98-0.95 (m, 2H)。MS (ESI, m/e) [M+1]+ 1035.9。 | ||
26 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-(2-(2-異丙基苯基)-4-苯乙基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.70 (s, 1H), 11.43-10.78 (m, 1H), 8.65-8.47(m, 2H), 8.03 (s, 1H), 7.90-7.70 (m, 1H), 7.58-7.37 (m, 4H), 7.37-7.11 (m, 8H), 7.11-6.96 (m, 1H), 6.69-6.58 (m, 1H), 6.37 (s, 1H), 6.19-6.05 (m, 1H), 4.25 (s, 1H), 3.97-3.67 (m, 1H), 3.60-3.40 (m, 1H), 3.29- 2.55 (m, 17H), 2.08-1.93(m, 1H), 1.82-1.49 (m, 7H), 1.3.8-1.25 (m, 6H), 1.22-1.14(m, 6H), 1.14-1.05 (m, 5H)。MS (ESI, m/e) [M+1]+ 1010.1。 | ||
27 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(4-苄基-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-(((4-氟四氫-2H-哌喃-4-基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.67 (s, 1H), 11.47-11.20 (m, 1H), 8.62 (s, 1H), 8.54 (s, 1H), 8.01 (s, 1H), 7.79 (d,J = 8.8 Hz, 1H), 7.48-7.47 (m, 3H), 7.28-7.27 (m, 10H), 6.64 (d,J = 8.8 Hz, 1H), 6.36 (s, 1H), 6.14 (s, 1H), 3.73-3.70 (m, 5H), 3.66-3.58 (m, 1H), 3.52 (s, 2H), 2.95-2.94 (m, 7H), 2.29-2.16 (m, 1H), 1.99 (s, 1H), 1.78-1.76 (m, 4H), 1.67-1.56 (m, 1H), 1.49-1.41 (m, 1H), 1.24-1.20 (m, 12H), 1.04 (s, 4H)。MS (ESI, m/e) [M+1]+ 986.0。 | ||
28 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(4-(4-氟苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.68 (s, 1H), 11.29 (s, 1H), 8.55 (d,J = 7.8 Hz, 2H), 8.02 (s, 1H), 7.78-7.76 (m, 1H), 7.49-7.46 (m, 3H), 7.36 (s, 3H), 7.26-7.00 (m, 6H), 6.64 (d,J = 8.6 Hz, 1H), 6.37 (s, 1H), 6.14 (s, 1H), 4.25 (s, 1H), 3.62 (s, 2H), 3.28 (s, 3H), 2.96-2.93 (m, 7H), 2.67 (s, 1H), 2.24 (s, 1H), 2.10- 1.93 (m, 1H), 1.65-1.56 (m, 7H), 1.26-1.05 (m, 21H)。MS (ESI, m/e) [M+1]+ 1014.1 | ||
28a | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-((R或S)-4-(4-氟苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.69 (s, 1H), 11.42-11.17 (m, 1H), 8.57-8.54 (m, 2H), 8.02 (s, 1H), 7.76 (s, 1H), 7.50-7.46 (m, 3H), 7.36 (s, 3H), 7.15-7.10 (m, 5H), 6.66 (s, 1H), 6.37 (s, 1H), 6.13 (s, 1H), 4.25 (s, 1H), 3.62 (s, 2H), 3.38 (s, 1H), 3.28 (s, 3H), 2.96-2.90 (m, 7H), 2.67-2.58 (m, 1H), 2.31-2.16 (m, 1H), 2.00 (s, 1H), 1.66 (s, 4H), 1.57-1.52 (m, 2H), 1.30-1.26 (m, 10H), 1.15-1.10 (m, 11H)。MS (ESI, m/e) [M+1]+ 1013.7。 | ||
29 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(4-(4-氯苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.70 (s, 1H), 11.34 (s, 0.7H), 10.78 (s, 0.3H), 8.63-8.48 (m, 2H), 8.02 (s, 1H), 7.91-7.62 (m, 2H), 7.57-7.01 (m, 12H), 6.73-6.54 (m, 1H), 6.37 (s, 1H), 6.14 (s, 1H), 4.72-4.48 (m, 0.5H), 4.26 (s, 1H), 3.89-3.50 (m, 2.5H), 3.45-3.36 (m, 1H), 3.34-3.10 (m, 4H), 3.10-2.82 (m, 6H), 2.82-2.58 (m, 2H), 2.34-2.16 (m, 1H), 2.15-1.91 (m, 1H), 1.75-1.50 (m, 6H), 1.48-1.27 (m, 5H), 1.23-0.95 (m, 13H)。MS (ESI, m/e) [M+1]+ 1030.8。 | ||
29a | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-((R或S)-4-(4-氯苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.69 (s, 1H), 11.33 (s, 1H), 8.63-8.48 (m, 2H), 8.03 (s, 1H), 7.83-7.73 (m, 1H), 7.55-7.44 (m, 3H), 7.44-7.30 (m, 5H), 7.30-7.15 (m, 2H), 7.15-7.01 (m, 2H), 6.72-6.55 (m, 1H), 6.37 (s, 1H), 6.14 (s, 1H), 4.25 (s, 1H), 3.68-3.50 (m, 2H), 3.48-3.36 (m, 1H), 3.32-3.13 (m, 3H), 3.11-2.80 (m, 7H), 2.72-2.52 (m, 2H), 2.30-2.11 (m, 1H), 2.11-1.92(m, 1H), 1.74-1.50 (m, 6H), 1.39-1.23 (m, 8H), 1.23-1.15 (m, 4H), 1.15-1.00 (m, 7H)。MS (ESI, m/e) [M+1]+ 1030.6。 | ||
30 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-(2-(2-異丙基苯基)-4-(4-甲基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.67 (s, 1H), 11.41 (s, 1H), 8.52 (s, 2H), 8.00 (s, 1H), 7.79-7.68 (m, 1H), 7.52-7.46 (m, 3H), 7.44-7.38 (m, 1H), 7.34 (s, 1H), 7.29-7.08 (m, 7H), 7.03 (s, 1H), 6.64 (d,J = 8.2 Hz, 1H), 6.35 (s, 1H), 6.19-6.11 (m, 1H), 4.25 (s, 1H), 3.81-3.66 (m, 1H), 3.29-3.22 (m, 3H),3.05-2.81 (m, 8H), 2.29-2.23 (m, 4H), 1.75-1.58 (m, 5H), 1.54 (d,J = 12.8 Hz, 3H), 1.41-1.20 (m, 10H), 1.19-1.14 (m, 3H), 1.13 (s, 1H), 1.12-0.95 (m, 9H)。MS (ESI, m/e) [M+1]+ 1009.5。 | ||
31 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-(2-(2-異丙基苯基)-4-(4-甲氧基苯乙基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.65 (s, 1H), 11.29 (s, 1H), 8.50 (s, 2H), 7.99 (s, 1H), 7.78-7.65 (m, 1H), 7.57-7.36 (m, 4H), 7.31-7.18 (m, 2H), 7.17-7.06 (m, 3H), 7.03-6.95 (m, 1H), 6.84 (d,J = 8.0 Hz, 2H), 6.64 (d,J = 8.0 Hz, 1H), 6.35 (s, 1H), 6.15 (s, 1H), 4.24 (s, 1H), 3.70 (s, 3H), 3.29-3.21 (m, 3H), 3.16-3.14 (m, 1H), 3.09-2.71 (m, 11H), 2.69-2.61 (m, 1H), 1.75-1.49 (m, 7H), 1.37-1.24 (m, 7H), 1.22-1.12 (m, 7H), 1.10 (s, 6H)。MS (ESI, m/e) [M+1]+ 1039.5。 | ||
34 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-(4-(4-甲氧基苄基)-2-(鄰甲苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.69 (s, 1H), 8.54 (s, 2H), 8.02 (s, 1H), 7.76 (s, 1H), 7.49-7.47 (m, 3H), 7.29 (s, 3H), 7.12-6.98 (m, 3H), 6.91 (s, 2H), 6.65 (d,J = 8.0 Hz, 1H), 6.37 (s, 1H), 6.12 (s, 1H), 4.25 (s, 1H), 3.73 (s, 4H), 3.58 (s, 1H), 3.28 (s, 2H), 2.96-2.93 (m, 8H), 2.27 (s, 5H), 1.99 (s, 1H), 1.72-1.49 (m, 7H), 1.29-1.26 (m, 10H), 1.13-1.10 (m, 6H)。MS (ESI, m/e) [M+1]+ 997.5。 | ||
35 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-(2-(2-異丁基苯基)-4-(4-甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | MS (ESI, m/e) [M+1]+ 1039.6。 | ||
36 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(2-(2-環戊基苯基)-4-(4-甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.68 (s, 1H), 11.24 (br, 1H), 8.60-8.51 (m, 2H), 8.01 (s, 1H), 7.77 (d,J = 8.4 Hz, 1H), 7.53-7.45 (m, 3H), 7.30-7.02 (m, 7H), 6.89 (d,J = 8.4 Hz, 1H), 6.65 (d,J = 8.4 Hz, 1H), 6.36 (s, 1H), 6.13 (s, 1H), 4.25 (s, 1H), 3.72 (s, 3H), 3.61-3.50 (m, 1H), 3.30-3.25 (m, 3H), 3.07-2.83 (m, 9H), 2.30-2.15 (m, 1H), 2.03-1.87 (m, 3H), 1.84-1.72 (m, 8H), 1.57-1.50 (m, 4H), 1.39-1.26 (m, 7H), 1.19-1.07 (m, 6H)。MS (ESI, m/e) [M+1]+ 1052.5。 | ||
37 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-(4-(4-甲氧基苄基)-2-(2-(𠰌啉代甲基)苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.65 (s, 1H), 8.48 (s, 2H), 8.01 (s, 1H), 7.78-7.69 (m, 1H), 7.65-7.55 (s, 2H), 7.54-7.47 (m, 1H), 7.42-7.24 (m, 5H), 7.21-7.14 (m, 2H), 6.96-6.83 (m, 3H), 6.76-6.63 (m, 1H), 6.39 (s, 1H), 6.27 (s, 1H), 4.33 (s, 1H), 3.79 (s, 3H), 3.70-3.51 (m, 3H), 3.35-3.17 (m, 6H), 3.03-2.87 (m, 7H), 2.32 (s, 3H), 2.22 (s, 3H), 1.81-1.72 (m, 3H), 1.71-1.58 (m, 4H), 1.50-1.35 (dm, 6H), 1.32 (s, 2H), 1.25-1.14 (m, 6H), 1.10-1.03 (m, 1H), 0.97-0.88 (m, 1H)。MS (ESI, m/e) [M+1]+ 1082.6。 | ||
38 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(4-(4-甲氧基苄基)-2-(鄰甲苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((3-硝基-4-(((四氫-2H-哌喃-4-基)甲基)胺基)苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm:1 1.68 (s, 1H), 11.29-10.96 (m, 1.0 H), 8.54 (s, 2H), 8.01 (s, 1H), 7.77 (d,J = 9.0 Hz, 1H), 7.49-7.46 (m, 3H), 7.20-7.15 (m, 7H), 6.89 (s, 2H), 6.65 (d,J = 9.0 Hz, 1H), 6.37 (s, 1H), 6.13 (s, 1H), 3.85-3.83 (m, 2H), 3.73 (s, 3H), 3.55 (s, 1H), 3.30-3.20 (m, 4H), 2.94-2.92 (m, 8H), 2.28 (s, 4H), 1.96-1.90 (m, 2H), 1.63-1.60 (m, 4H), 1.28-1.21 (m, 10H), 1.06 (s, 1H), 0.85 (s, 1H)。MS (ESI, m/e) [M+1]+ 969.6。 | ||
39 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-(2-(2-異丙基苯基)-4-(4-(三氟甲氧基)苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.62 (s, 1H), 11.42 (s, 1H), 8.47 (s, 2H), 7.97 (s, 1H), 7.68 (s, 1H), 7.53-7.35 (m, 6H), 7.31-7.25 (m, 2H), 7.24-7.13 (m, 2H), 7.12-7.04 (m, 1H), 6.94 (s, 1H), 6.62 (d,J = 8.0 Hz, 1H), 6.33 (s, 1H), 6.16 (s, 1H), 4.25 (s, 1H), 3.56-3.42 (m, 3H), 3.29-3.19 (m, 3H), 3.01-2.82 (m, 7H), 2.25-2.15 (m, 2H), 2.04 - 1.93 (m, 1H), 1.72-1.58 (m, 5H), 1.57-1.48 (m, 3H), 1.37-1.25 (m, 8H), 1.18-1.07 (m, 9H), 1.04-0.95 (m, 3H)。MS (ESI, m/e) [M+1]+ 1080.5。 | ||
40 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(4-(4-乙氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.69 (s, 1H), 11.17 (br, 1H), 8.54-8.55 (m, 2H), 8.02 (s, 1H), 7.77 (d,J = 8 Hz, 1H), 7.05-7.49 (m, 10H), 6.84-6.92 (m, 2H), 6.64 (d,J = 8 Hz, 1H), 6.37 (s, 1H), 6.14 (s, 1H), 4.26 (s, 1H), 3.96-4.01 (m, 2H), 3.69-3.86 (m, 2H), 3.55 (s, 1H), 3.26-3.29 (m, 2H), 2.91-2.97 (m, 7H), 2.67-2.75 (m, 2H), 2.01-2.33 (m, 2H), 1.52-1.69 (m, 7H), 1.07-1.36 (m, 24H)。MS (ESI, m/e) [M+1]+ 1039.7 | ||
41 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-(2-(2-異丙基苯基)-4-(4-(三氟甲基)苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.67 (s, 1H), 11.39 (br, 1H), 8.51-8.55 (m, 2H), 8.01 (s, 1H), 7.76 (d,J = 8 Hz, 1H), 7.66 (d,J = 4 Hz, 1H), 7.46-7.53 (m, 5H), 7.16-7.19 (m, 2H), 7.05-7.08 (m, 2H), 6.64 (d,J = 8 Hz, 1H), 6.36 (s, 1H), 6.14 (s, 1H), 4.25 (s, 1H), 3.51-3.57 (m, 2H), 3.25-3.28 (m, 2H), 2.90-2.96 (m, 5H), 2.18-2.23 (m, 2H), 1.99-2.00 (m, 1H), 1.52-1.69 (m, 7H), 1.02-1.35 (m, 24H)。MS (ESI, m/e) [M+1]+ 1064.5 | ||
42 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(4-(4-氰基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.64 (s, 1H), 11.46 (s, 1H), 8.55-8.31 m, 2H), 7.97 (s, 1H), 7.77 (d,J = 8.0 Hz, 2H), 7.71-7.61 (m, 1H), 7.58-7.32 (m, 7H), 7.24-7.05 (m, 3H), 6.62 (d,J = 8.0 Hz, 1H), 6.33 (s, 1H), 6.16 (s, 1H), 4.27 (s, 1H), 3.77-3.66 (m, 1H), 3.64-3.50 (m, 3H), 3.28-3.19 (m, 3H), 3.02-2.76 (m, 9H), 2.32-2.10 (m, 2H), 2.08-1.97(m, 1H), 1.74-1.57 (m, 6H), 1.54-1.48 (m, 3H), 1.37-1.25 (m, 8H), 1.23 (s, 3H), 1.21-1.09 (m, 5H), 1.09 (s, 5H), 1.04-0.97 (m, 4H)。MS (ESI, m/e) [M+1]+ 1020.5。 | ||
43 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(4-(3-氟苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.69 (s, 1H), 11.44 (s, 1H), 8.57-8.55 (m, 2H), 8.02 (s, 1H), 7.78 (d,J = 9.2 Hz, 1H), 7.50 (s, 2H), 7.47-7.46 (m, 1H), 7.35 (s, 3H), 7.21-7.18 (m, 3H), 7.07 (d,J = 9.2 Hz, 2H), 6.66 (d,J = 8.8 Hz, 1H), 6.37 (s, 1H), 6.16 (s, 1H), 4.64 (s, 1H), 4.25 (s, 1H), 3.73 (s, 1H), 3.65 (s, 1H), 3.39 (s, 1H), 3.28 (s, 2H), 3.17 (s, 1H), 2.98 (s, 7H), 2.72 (s, 2H), 2.19 (s, 1H), 2.01 (s, 1H), 1.65-1.58 (m, 6H), 1.32-1.30 (m, 10H), 1.13-1.12 (m, 5H), 1.04 (s, 3H)。MS (ESI, m/e) [M+1]+ 1014.1。 | ||
44 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-(2-(2-異丙基苯基)-4-(3-甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.69 (s, 1H), 11.40 (br, 1H), 8.62-8.53 (m, 2H), 8.02 (s, 1H), 7.94-7.75 (m, 2H), 7.54-7.45 (m, 3H), 7.37-7.32 (m, 1H), 7.31-7.20 (m, 4H), 7.08 (d,J = 8.4 Hz, 1H), 6.93-6.78 (m, 2H), 6.68-6.62 (m, 1H), 6.37 (s, 1H), 6.18-6.12 (m, 1H), 4.68-4.59 (m, 1H), 4.24 (s, 1H), 3.79-3.71 (m, 4H), 3.60 (s, 1H), 3.45-3.37 (m, 2H), 3.33-3.14 (m, 3H), 3.08-2.80 (m, 7H), 2.77-2.57 (m, 2H), 2.09-1.95 (m, 2H), 1.74- 1.61 (m, 4H), 1.58-1.50 (m, 2H), 1.48-1.40 (m, 1H), 1.39-1.26 (m, 7H), 1.19-1.02 (m, 10H)。MS (ESI, m/e) [M+1]+ 1026.0。 | ||
45 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-(((R)-3-(((1r,4R)-4-羥基環己基)甲基)-5-硝基-3,4-二氫-2H-苯并[b][1,4]㗁𠯤-7-基)磺醯基)-4-(2-(2-(2-異丙基苯基)-4-(3-甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.68 (s, 1H), 11.41 (br, 1H), 8.81 (s, 1H), 8.18 (s, 1H), 8.02 (s, 1H), 7.59-7.45 (m, 3H), 7.43-7.10 (m, 6H), 7.03-6.80 (m, 3H), 6.67 (d,J = 8.4 Hz, 1H), 6.37 (s, 1H), 6.15(d,J = 10.8 Hz, 1H), 4.70-4.60 (m, 1H), 4.49 (s, 1H), 4.13-4.02 (m, 2H), 3.83-3.70 (m, 5H), 3.63-3.58 (m, 1H), 3.47-3.40 (m, 1H), 3.32-2.80 (m, 8H), 2.79-2.56 (m, 2H), 2.07-1.94 (m, 1H), 1.86-1.50 (m, 5H), 1.49-1.32 (m, 7H), 1.22-1.02 (m, 14H)。MS (ESI, m/e) [M+1]+ 1054.1。 | ||
46 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(4-(2-氟苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.69 (s, 1H), 11.41 (s, 1 H), 8.55 (s, 2 H), 8.02 (s, 1 H), 7.90 (s, 1 H), 7.76 (s, 1 H), 7.49-7.36 (m, 7 H), 7.17-7.07 (m, 6 H), 6.65 (d,J = 8.2 Hz, 1 H), 6.37 (s, 1 H), 6.16-6.13 (m, 1 H), 4.25 (s, 1 H), 3.71-3.65 (m, 3 H), 3.31-3.24 (m, 3 H), 2.94 (m, 8 H), 2.33-2.08 (m, 4 H), 1.75-1.42 (m, 7H), 1.41-1.18 (m, 10H), 1.13-1.07 (m, 10 H)。MS (ESI, m/e) [M+1]+ 1014.0。 | ||
47 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-(2-(2-異丙基苯基)-4-(2-甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.69 (s, 1H), 11.42 (s, 1H), 8.64-8.48(m, 2H), 8.06-7.96 (m, 1H), 7.94-7.64 (m, 1H), 7.59-7.16 (m, 8H), 7.16-6.77(m, 3H), 6.72-6.60 (m, 1H), 6.37 (s, 1H), 6.14 (s, 1H), 4.30 (s, 1H), 3.79 (s, 3H), 3.52-3.38 (m, 6H), 3.32-2.75 (m, 15H), 2.10-1.92 (m, 1H), 1.78-1.50 (m, 5H), 1.46-1.24 (m, 7H), 1.19-1.01 (m, 8H)。MS (ESI, m/e) [M+1]+ 1026.2。 | ||
48 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(4-(2,4-二甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.69 (s, 1H), 11.41 (br, 1H), 8.62-8.53 (m, 2H), 8.02 (s, 1H), 7.78 (d,J = 8.8 Hz, 1H), 7.54-7.45 (m, 3H), 7.37-7.32 (m, 2H), 7.31-7.20 (m, 2H), 7.19-7.15 (m, 1H), 7.08 (d,J = 8.8 Hz, 1H), 6.68-6.44 (m, 3H), 6.37 (s, 1H), 6.13 (s, 1H), 4.26 (s, 1H), 4.19-3.83 (m, 2H), 3.77 (s, 6H), 3.60 - 3.44 (m, 1H), 3.30-3.22 (m, 3H), 3.17-2.80 (m, 8H), 2.77-2.57 (m, 1H), 2.44-2.30 (m, 1H), 2.09-1.95 (m, 1H), 1.74-1.61 (m, 4H), 1.52 (s, 3H), 1.49-1.16 (m, 12H), 1.14-1.00 (m, 7H)。MS (ESI, m/e) [M+1]+ 1055.9。 | ||
48a | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-((R或S)-4-(2,4-二甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.70 (s, 1H), 11.29 (br, 1H), 8.61-8.53 (m, 2H), 8.03 (s, 1H), 7.83-7.74 (m, 1H), 7.54-7.32 (m, 5H), 7.30-7.03 (m, 4H), 6.70-6.44 (m, 3H), 6.37 (s, 1H), 6.13 (s, 1H), 4.25 (s, 1H), 4.20-3.82 (m, 1H), 3.74-3.65 (m, 6H), 3.60-3.37 (m, 1H), 3.30-3.20 (m, 3H), 3.09-2.60 (m, 9H), 2.45-2.25 (m, 1H), 2.09-1.95 (m, 1H), 1.73-1.51 (m, 6H), 1.39-1.15 (m, 12H), 1.14-1.00 (m, 9H)。MS (ESI, m/e) [M+1]+ 1056.2。 | ||
49 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(4-(3,5-二甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR ((400 MHz, DMSO-d 6 ) δ ppm: 11.69 (s, 1H), 11.51-11.23 (m, 1H), 10.62-10.36 (m, 1H), 8.57-8.55 (m, 2H), 8.03 (s, 1H), 7.78 (d,J = 8.8 Hz, 1H), 7.55-7.44 (m, 3H), 7.36 (s, 1H), 7.23 (s, 2H), 7.07 (d,J = 8.8 Hz, 2H), 6.65 (d,J = 8.8 Hz, 1H), 6.49 (s, 2H), 6.37 (s, 2H), 6.14 (s, 1H), 4.25 (s, 1H), 3.71 (s, 7H), 3.57 (s, 1H), 3.42 (s, 1H), 3.28 (s, 3H), 2.97-2.93 (m, 7H), 2.01 (s, 1H), 1.66 (s, 4H), 1.55-1.53 (m, 2H), 1.28-1.25 (m, 13H), 1.13-1.10 (m, 8H)。MS (ESI, m/e) [M+1]+ 905.1。 | ||
50 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(4-(2,4-二氟苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.49 (s, 1H), 8.33 (s, 1H), 8.31-8.24 (m, 1H), 7.87 (s, 1H), 7.54 (t,J = 9.6 Hz, 2H), 7.48-7.35 (m, 3H), 7.26-7.12 (m, 5H), 7.11-7.06 (m, 1H), 7.05-7.00 (m, 1H), 6.72 (d,J = 8.8 Hz, 1H), 6.58 (d,J = 8.8 Hz, 1H), 6.26 (s, 1H), 6.21 (s, 1H), 4.24 (s, 1H), 3.49 (s, 3H), 3.26-3.17 (m, 3H), 2.93-2.80 (m, 7H), 2.23-2.14 (m, 2H), 2.09-1.94 (m, 2H), 1.71-1.59 (m, 5H), 1.57-1.50 (m, 2H), 1.37-1.29 (m, 6H), 1.24 (s, 3H), 1.19-1.15 (m, 3H), 1.12 (s, 1H), 1.09 (s, 3H), 1.07-1.04 (m, 2H)。MS (ESI, m/e) [M+1]+ 1031.1。 | ||
51 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(4-(3,5-二氟苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.67 (s, 1H), 11.41 (s, 1H), 8.64-8.40 (m, 2H), 8.01 (s, 1H), 7.84-7.68 (m, 1H), 7.461-7.34(m, 4H), 7.34-6.90 (m, 8H), 6.70-6.57 (m, 1H), 6.36 (s, 1H), 6.14 (s, 1H), 4.25 (s, 1H), 3.65-3.44 (m, 4H), 3.31-3.20 (m, 4H), 3.10-2.76 (m ,8H), 2.31-2.11 (m, 2H), 2.06-1.92 (m, 1H), 1.76-1.49 (m, 7H), 1.39-1.28 (m, 4H), 1.20-1.02 (m, 12H)。MS (ESI, m/e) [M+1]+ 1031.7 | ||
52 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(4-(3,4-二氟苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.69 (s, 1H), 11.38 (br, 1H), 8.54-8.57 (m, 2H), 8.02 (s, 1H), 7.77 (d,J = 8 Hz, 1H), 7.37-7.50 (m, 5H), 7.06-7.20 (m, 4H), 6.65 (d,J = 8 Hz, 1H), 6.37 (s, 1H), 6.14 (s, 1H), 4.25 (s, 1H), 3.53-3.63 (m, 2H), 3.26-3.33 (m, 2H), 2.91-2.97 (m, 8H), 2.01-2.33 (m, 3H), 1.52-1.69 (m, 7H), 1.04-1.36 (m, 10H)。MS (ESI, m/e) [M+1]+ 1031.6 | ||
52a | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-((R或S)-4-(3,4-二氟苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.75 (s, 1H), 11.45 (s, 1H), 8.68-8.57 (m, 2H), 8.08 (s, 1H), 7.88-7.78 (m, 1H), 7.59-7.50 (m, 3H), 7.49-7.37 (m, 3H), 7.27 (s, 1H), 7.25-7.19 (m, 2H), 7.17-7.08 (m, 2H), 6.74-6.67 (m, 1H), 6.43 (s, 1H), 6.19 (s, 1H), 4.31 (s, 1H), 3.78-3.46 (m, 3H), 3.34 (s, 3H), 3.12-2.88 (m, 7H), 2.32-2.23 (m, 1H), 2.14-2.03 (m, 1H), 1.79-1.69 (m, 4H), 1.65-1.55 (m, 3H), 1.43-1.35 (m, 4H), 1.34-1.27 (m, 5H), 1.25-1.21 (m, 2H), 1.20-1.18 (m, 1H), 1.18-1.14 (m, 4H), 1.13-1.06 (m, 4H)。MS (ESI, m/e) [M+1]+ 1031.9。 | ||
53 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(4-(口克唍-6-基甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.68 (s, 1H), 11.23-10.95 (m, 1H), 10.74-10.62 (m, 0.5H), 8.57-8.54 (m, 2H), 8.02 (s, 1H), 7.77 (d,J = 8.8 Hz, 1H), 7.49-7.46 (m, 3H), 7.42-7.31 (m, 1H), 7.25 (s, 2H), 7.08-7.05 (m, 4H), 6.65-6.63 (m, 2H), 6.37 (s, 1H), 6.14 (s, 1H), 4.24 (s, 1H), 4.10 (s, 2H), 3.75 (s, 2H), 3.50 (s, 1H), 3.28 (s, 3H), 2.96-2.91 (m, 8H), 2.69 (s, 3H), 2.08 (s, 1H), 1.88 (s, 2H), 1.68-1.58 (m, 7H), 1.38-1.15 (m, 11H), 1.12-1.10 (m, 9H)。MS (ESI, m/e) [M+1]+ 1051.7。 | ||
54 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-(2-(2-異丙基苯基)-4-((5,6,7,8-四氫萘-2-基)甲基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.68 (s, 1H), 11.17 (br, 1H), 8.62-8.53 (m, 2H), 8.02 (s, 1H), 7.78 (d,J = 8.4 Hz, 1H), 7.52-7.45 (m, 3H), 7.38-7.10 (m, 4H), 7.09-6.96 (m, 2H), 6.66 (d,J = 8.4 Hz, 1H), 6.37 (s, 1H), 6.14 (s, 1H), 4.25 (s, 1H), 3.84-3.35 (m, 3H), 3.30-3.25 (m, 3H), 3.07-2.72 (m, 8H), 2.69-2.60 (m, 5H), 2.35-1.95 (m, 2H), 1.74-1.51 (m, 10H), 1.39-1.15 (m, 12H), 1.14-1.02 (m, 8H)。MS (ESI, m/e) [M+1]+ 1049.7。 | ||
55 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-(2-(2-異丙基苯基)-4-((5,6,7,8-四氫萘-1-基)甲基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.68 (s, 1H), 11.47-11.33 (m, 1H), 8.54 (s, 2H), 8.01 (s, 1H), 7.76 (s, 1H), 7.49 (s, 3H), 7.15-7.12 (m, 8H), 6.66 (s, 1H), 6.36 (s, 1H), 6.13 (s, 1H), 4.25 (s, 1H), 3.53 (s, 1H), 3.27 (s, 2H), 2.96-2.94 (m, 7H), 2.69 (s, 5H), 1.98 (s, 1H), 1.69-1.63 (m, 6H), 1.56-1.52 (m, 2H), 1.36-1.30 (m, 5H), 1.26-1.20 (m, 12H), 1.19-1.16 (m, 2H), 1.13 (s, 1H), 1.10-1.06 (m, 4H), 1.03 (s, 2H)。MS (ESI, m/e) [M+1]+ 1049.7。 | ||
56 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(2-(2-異丙基苯基)-4-((5,6,7,8-四氫萘-1-基)甲基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((3-硝基-4-(((四氫-2H-哌喃-4-基)甲基)胺基)苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.68 (s, 1H), 11.30 (s, 1H), 8.58-8.56 (m, 2H), 8.02 (d,J = 2.2 Hz, 1H), 7.77 (d,J = 8.8 Hz, 1H), 7.49-7.46 (m, 3H), 7.22 (s, 2H), 7.12-7.02 (m, 2H), 7.02-6.91 (m, 2H), 6.65 (d,J = 8.8 Hz, 1H), 6.37 (s, 1H), 6.14 (s, 1H), 3.84 (d,J = 8.4 Hz, 2H), 3.51 (s, 2H), 3.32-3.22 (m, 5H), 2.98-2.91 (m, 7H), 2.73-2.70 (m, 6H), 2.20 (s, 1H), 2.08 (s, 1H), 2.01 (s, 1H), 1.91-1.90 (m, 1H), 1.79-1.55 (m, 8H), 1.36-1.15 (m, 11H), 1.03 (s, 4H)。MS (ESI, m/e) [M+1]+ 1021.7。 | ||
57 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(4-(口克唍-4-基甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.55 (s, 1H), 8.40 (s, 2H), 7.92 (s, 1H), 7.65-7.55 (m, 1H), 7.54-7.46 (m, 1H), 7.42 (s, 2H), 7.31 (s, 1H), 7.26-7.06 (m, 5H), 7.04-6.97(m, 1H), 6.90-6.74 (m, 2H), 6.68 (d,J = 8.0 Hz, 1H), 6.59 (d,J = 8.0 Hz, 1H), 6.30 (s, 1H), 6.17 (s, 1H), 4.28 (s, 1H), 4.15-3.98 (m, 3H), 3.26-3.18 (m, 2H), 3.03 (brs, 1H), 2.98-2.80 (m, 8H), 2.73-2.64 (m, 1H), 2.31-2.15 (m, 2H), 1.96-1.83 (m, 2H), 1.70-1.58 (m, 5H), 1.52 (d,J = 12.0 Hz, 2H), 1.38-1.24 (m, 7H), 1.26-1.17 (m, 5H), 1.16-1.11 (m, 4H), 1.08 (s, 5H)。MS (ESI, m/e) [M+1]+ 1051.6。 | ||
58 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(4-(苯并[b]噻吩-5-基甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.67 (s, 1H), 11.32 (s, 1H), 8.54 (s, 2H), 8.02 (s, 1H), 7.95 (d,J = 8.4 Hz, 1H), 7.83 (s, 1H), 7.78-7.75 (m, 2H), 7.48-7.46 (m, 3H), 7.43-7.41 (m, 1H), 7.36 (d,J = 7.4 Hz, 1H), 7.22 (s, 3H), 7.06-7.04 (m, 1H), 6.64 (d,J = 9.2 Hz, 1H), 6.37 (s, 1H), 6.14 (s, 1H), 4.24 (s, 1H), 3.78 (s, 3H), 3.29-3.26 (m, 3H), 2.96-2.94 (m, 7H), 2.72 (s, 1H), 2.33 (s, 1H), 1.63-1.60 (m, 7H), 1.29-1.20 (m, 13H), 1.13-1.10 (m, 4H), 1.05-1.02 (m, 3H)。MS (ESI, m/e) [M+1]+ 1051.7。 | ||
59 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(4-(苯并[b]噻吩-4-基甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.68 (s, 1H), 11.35 (s, 1H), 8.60-8.45 (m, 2H), 8.02 (s, 1H), 7.98-7.85 (m, 1H), 7.83-7.60 (m, 3H), 7.57-6.84 (m, 11H), 6.72-6.59 (m, 1H), 6.37 (s, 1H), 6.13 (s, 1H), 4.24 (s, 1H), 4.10-3.90 (m, 1H), 3.88-3.36 (m, 2H), 3.33-3.22 (m, 3H), 3.05-2.75 (m, 7H), 2.75-2.58 (m, 1H), 2.28-1.93 (m, 2H), 1.76-1.49 (m, 6H), 1.39-1.28 (m, 4H), 1.19-1.06 (m, 8H), 1.05-0.90 (m, 4H)。MS (ESI, m/e) [M+1]+ 1051.7 | ||
60 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(4-苯甲醯基-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.69 (s, 1H), 11.40 (br, 1H), 8.54-8.52 (m, 2H), 8.03 (d,J = 2.4 Hz, 1H), 7.79 (d,J = 8.8 Hz, 1H), 7.63-7.32 (m, 9H), 7.30-7.05 (m, 4H), 6.66 (d,J = 8.8 Hz, 1H), 6.38 (s, 1H), 6.13 (s, 1H), 4.53-4.35 (m, 1H), 4.24 (s, 1H), 3.69-3.42 (m, 1H), 3.33-2.80 (m, 12H), 2.27-2.19 (m, 1H), 1.72-1.50 (m, 7H), 1.39-1.12 (m, 11H), 1.08-1.03 (m, 8H)。MS (ESI, m/e) [M+1]+ 1010.0。 | ||
61 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-(2-(2-異丙基苯基)-4-(4-甲氧基苯甲醯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.69 (s, 1H), 11.41 (br, 1H), 8.55-8.57 (m, 2H), 8.03 (s, 1H), 7.78 (d,J = 8 Hz, 1H), 7.37-7.50 (m, 6H), 7.07-7.20 (m, 4H), 6.91-6.99 (m, 2H), 6.65 (d,J = 8 Hz, 1H), 6.38 (s, 1H), 6.13 (s, 1H), 4.25 (s, 1H), 3.75 (s, 3H), 3.43 (s, 1H), 3.27-3.40 (m, 2H), 2.92-2.97 (m, 6H), 1.99-2.09 (m, 2H), 1.52-1.69 (m, 8H), 1.09-1.36 (m, 21H)。MS (ESI, m/e) [M+1]+ 1039.6。 | ||
62 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-(2-(2-異丙基苯基)-4-(苯基磺醯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.69 (s, 1H), 11.41 (s, 1H), 8.50-8.40 (m, 2H), 8.02 (m, 1H), 7.84-7.65 (m, 6H), 7.55-7.40 (m, 3H), 7.35-7.05 (m, 5H), 6.35(m, 1H), 6.13 (s, 1H), 6.01 (s, 1H), 4.25 (s, 1H), 3.71 (m, 1H), 3.52 (m, 1H), 3.26 (s, 3H), 3.20-2.70 (m, 6H), 2.45-2.30 (m, 1H), 2.21 (m, 2H), 1.78-1.50 (m, 8H), 1.40-1.05 (m, 20H)。MS (ESI, m/e) [M+1]+ 1045.5。 | ||
63 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-(2-(2-異丙基苯基)-4-(1-苯基丁-2-炔-1-基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.67 (s, 1H), 11.43 (br, 1H), 8.60-8.45 (m, 2H), 8.01 (s, 1H), 7.80-7.70 (m, 1H), 7.54-7.42 (m, 5H), 7.37-7.01 (m, 8H), 6.68-6.62 (m, 1H), 6.36 (s, 1H), 6.13 (s, 1H), 4.56 (br, 1H), 4.26 (s, 1H), 3.58-3.35 (m, 2H), 3.31-3.22 (m, 3H), 3.04-2.80 (m, 7H), 2.35-2.21 (m, 2H), 2.09-1.95 (m, 2H), 1.91 (s, 3H), 1.73-1.52 (m, 8H), 1.38-1.20 (m, 7H), 1.15-1.08 (m, 10H)。MS (ESI, m/e) [M+1]+ 1033.6。 | ||
64a | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-(2-(2-異丙基苯基)-4-(3-苯基環戊基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.68 (s, 1H), 11.21 (br, 1H), 8.60-8.53 (m, 2H), 8.02 (s, 1H), 7.78 (d,J = 8.8 Hz, 1H), 7.52-7.43 (m, 4H), 7.33-7.13 (m, 8H), 7.07 (d,J = 8.8 Hz, 1H), 6.66 (d,J = 8.8 Hz, 1H), 6.37 (s, 1H), 6.14 (s, 1H), 4.24 (s, 1H), 3.90-3.81 (m, 1H), 3.60-3.41 (m, 2H), 3.30-3.24 (m, 2H), 3.17-2.80 (m, 10H), 2.44-1.37 (m, 2H), 2.20-1.90 (m, 4H), 1.74-1.51 (m, 9H), 1.39-1.26 (m, 15H), 1.24-1.05 (m, 4H)。MS (ESI, m/e) [M+1]+ 1050.8。 | ||
64b | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.68 (s, 1H), 11.21 (br, 1H), 8.62-8.53 (m, 2H), 8.02 (s, 1H), 7.78 (d,J = 8.8 Hz, 1H), 7.53-7.43 (m, 4H), 7.33-7.15 (m, 8H), 7.07 (d,J = 8.8 Hz, 1H), 6.66 (d,J = 8.8 Hz, 1H), 6.37 (s, 1H), 6.14 (s, 1H), 4.24 (s, 1H), 3.90-3.85 (m, 1H), 3.60-3.41 (m, 2H), 3.30-3.24 (m, 2H), 3.14-2.80 (m, 10H), 2.44-1.32 (m, 2H), 2.15-1.90 (m, 4H), 1.74-1.51 (m, 9H), 1.39-1.26 (m, 15H), 1.24-1.05 (m, 4H)。MS (ESI, m/e) [M+1]+ 1050.7。 | |||
65 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-(2-(2-異丙基苯基)-4-苯基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.72 (s, 1H), 8.70-8.53 (m, 2H), 8.03-8.02 (m, 1H), 7.82 (d,J = 9.1 Hz, 1H), 7.52-7.49 (m, 3H), 7.27-7.21 (m, 5H), 7.14-7.05 (m, 3H), 7.10-7.05 (m, 2H), 6.85-6.80 (m, 1H), 6.65-6.60 (m, 1H), 6.37 (s, 1H), 6.13 (s, 1H), 4.75-4.65 (m, 1H), 4.30-4.25 (m, 1H), 3.35-3.30 (m, 6H), 3.10-2.95 (m, 5H), 1.95-1.85 (m, 5H), 1.80-1.50 (m, 3H), 1.45-1.35 (m, 8H), 1.34-1.22 (m, 8H), 1.18-1.10 (m, 4H)。MS (ESI, m/e) [M+1]+ 982.1。 | ||
66 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-(2-(2-異丙基苯基)-4-(甲基磺醯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.69 (s, 1H), 11.41 (br, 1H), 8.63-8.53 (m, 2H), 8.03 (s, 1H), 7.79 (d,J = 8.8 Hz, 1H), 7.52 (d,J = 8.8 Hz, 1H), 7.47-7.40 (m, 3H), 7.33-7.06 (m, 4H), 6.66 (d,J = 8.8 Hz, 1H), 6.38 (s, 1H), 6.13 (s, 1H), 4.25 (s, 1H), 3.56 (d,J = 9.6 Hz, 2H), 3.33-3.24 (m, 3H), 3.23-3.02 (m, 2H), 3.04-2.85(m, 9H), 2.84-2.74 (m, 1H), 2.25-2.15 (m, 1H), 1.74-1.50 (m, 7H), 1.39-1.12 (m, 16H), 1.08-1.03 (m, 3H)。MS (ESI, m/e) [M+1]+ 984.0。 | ||
67 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(4-苄基-2-(2-異丙基苯基)哌啶-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.68 (s, 1H), 11.45 (s, 1H), 8.63-8.40 (m, 2H), 8.02 (s, 1H), 7.85-7.70 (m, 2H), 7.58-7.42 (m, 3H), 7.38-7.15 (m, 8H), 7.12-6.98 (m, 1H), 6.73-6.60 (m, 1H), 6.37 (s, 1H), 6.18 (s, 1H), 4.90-4.70 (m, 1H), 4.25 (s, 1H), 3.84-3.65 (m, 1H), 3.61-3.48 (m, 1H), 3.28 (s, 3H), 3.05-2.80 (m, 6H), 2.35-1.94 (m, 5H), 1.74-1.58 (m, 4H), 1.58-1.49(m, 2H), 1.49-1.23 (m, 12H), 1.17-1.05 (m, 8H)。MS (ESI, m/e) [M+1]+ 994.7 | ||
68 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-(2-(2-異丙基苯基)-4-苯氧基哌啶-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.69 (s, 1H), 11.43 (s, 1H), 8.56-8.54 (m, 2H), 8.02 (s, 2H), 7.77 (d,J = 9.0 Hz, 1H), 7.48-7.46 (m, 3H), 7.29-7.26 (m, 5H), 7.06 (d,J = 8.0 Hz, 3H), 6.96-6.93 (m, 1H), 6.66 (d,J = 9.0 Hz, 1H), 6.37 (s, 1H), 6.18 (s, 1H), 4.85-4.83 (m, 2H), 4.26 (s, 1H), 3.83 (s, 1H), 3.28 (s, 3H), 2.92-2.90 (m, 5H), 2.46-2.36 (m, 1H), 2.05-2.01 (m, 5H), 1.69-1.65 (m, 7H), 1.55-1.53 (m, 3H), 1.33-1.30 (m, 16H), 1.13-1.10 (m, 5H), 0.85-0.83 (m, 4H), 0.58 (s, 1H)。MS (ESI, m/e) [M+1]+ 996.6。 | ||
69 | (R或S)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(2-(2-異丙基苯基)-4-(4-甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((3-硝基-4-(((四氫-2H-哌喃-4-基)甲基)胺基)苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.68 (s, 1H), 11.30 (s, 1H), 8.60 (s, 1H), 8.54 (s, 1H), 8.01 (s, 1H), 7.76 (s, 1H), 7.49 (s, 3H), 7.43-7.32 (m, 1H), 7.24 (s, 4H), 7.09 (s, 2H), 6.90 (s, 2H), 6.64 (d,J = 8.4 Hz, 1H), 6.37 (s, 1H), 6.14 (s, 1H), 3.87-3.83 (m, 2H), 3.72 (s, 4H), 3.63-3.53 (m, 1H), 3.30-3.22 (m, 4H), 2.96-2.90 (m, 8H), 2.28-2.15 (m, 1H), 1.88 (s, 1H), 1.63-1.60 (m, 4H), 1.23-1.10 (m, 13H), 1.06 (s, 4H)。MS (ESI) m/e [M+1]+ 998.0。 | ||
70 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(4-((1-環丙基-1H-吡唑-4-基)甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.73 (s, 1H), 11.12 (s, 1H), 8.58 (s, 2H), 8.06 (s, 1H), 7.87-7.75 (m, 2H), 7.58-7.49 (m, 3H), 7.48-7.40 (m, 2H), 7.35-7.25 (m, 2H), 7.19 (s, 1H), 7.09 (d,J = 8.8 Hz, 1H), 6.69 (d,J = 8.8 Hz, 1H), 6.42 (s, 1H), 6.20 (s, 1H), 4.30 (s, 1H), 3.82-3.63 (m, 3H), 3.56-3.47 (m, 1H), 3.37-3.28 (m, 3H), 3.15-2.79 (m, 9H), 2.37-2.28(m, 1H), 1.80-1.65 (m, 5H), 1.64-1.56 (m, 3H), 1.43-1.35 (m 4H), 1.29 (s, 4H), 1.24 (s, 3H), 1.15 (s, 6H), 1.07-0.93 (m, 6H)。MS (ESI, m/e) [M+1]+ 1025.6。 | ||
71 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-(2-(2-異丙基苯基)-4-((3-甲氧基-1-甲基-1H-吡唑-4-基)甲基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1H NMR (DMSO-d6) δ 11.69 (s, 1H), 8.65-8.51 (m, 2H), 8.02 (s, 1H), 7.77 (d,J = 7.6 Hz, 1H), 7.61 (s, 1H), 7.55-7.45 (m, 3H), 7.42 (s, 1H), 7.34-7.22 (m, 2H), 7.16 (s, 1H), 7.07 (d,J = 8.4 Hz, 1H), 6.66 (d,J = 8.4 Hz, 1H, 1H), 6.37 (s, 1H), 6.13 (s, 1H), 4.25 (s, 1H), 3.81-3.74(m, 4H), 3.71-3.63 (s, 3H), 3.32-3.23 (m, 4H), 3.08 (s, 4H), 2.99-2.79 (m, 7H), 2.36-2.28 (m, 1H), 2.06-1.93 (m, 1H), 1.73-1.62 (m, 4H), 1.58-1.50 (m, 3H), 1.37-1.29 (m, 4H), 1.26-1.22 (m, 4H), 1.21-1.18 (m, 3H), 1.06(s, 6H)。MS (ESI, m/e) [M+1]+ 1029.5。 | ||
72 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-(2-(2-異丙基苯基)-4-((6-甲氧基吡啶-3-基)甲基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.69 (s, 1H), 11.29 (br, 1H), 8.62-8.53 (m, 2H), 8.09-8.01 (m, 2H), 7.81-7.74 (m, 1H), 7.70-7.64 (m, 1H), 7.54-7.44 (m, 3H), 7.43-7.03 (m, 5H), 6.82-6.76 (m, 1H), 6.68-6.62 (m, 1H), 6.37 (s, 1H), 6.14 (s, 1H), 4.25 (s, 1H), 3.81 (s, 3H), 3.64-3.45 (m, 2H), 3.30-3.25 (m, 2H), 3.07-2.72 (m, 7H), 2.69-2.54 (m, 2H), 2.45-1.85 (m, 3H), 1.74-1.51 (m, 7H), 1.39-1.15 (m, 13H), 1.14-1.02 (m, 7H)。MS (ESI, m/e) [M+1]+ 1027.1。 | ||
73 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(2-(2-環丙基苯基)-4-(4-甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ ppm: 11.67 (s, 1H), 11.29-11.06 (m, 1H), 8.53 (s, 2H), 8.01 (s, 1H), 7.77 (s, 1H), 7.48 (s, 4H), 7.25 (s, 3H), 7.11 (s, 3H), 6.89 (s, 3H), 6.65 (s, 1H), 6.36 (s, 1H), 6.14 (s, 1H), 4.25 (s, 1H), 3.72 (s, 4H), 3.62-3.47 (m, 1H), 3.27 (s, 2H), 2.98-2.90 (m, 8H), 1.99 (s, 1H), 1.66 (s, 3H), 1.56-1.50 (m, 3H), 1.30-1.26 (m, 11H), 1.09 (s, 5H), 0.87-0.83 (m, 5H)。MS (ESI) m/e [M+1]+ 1024.1。 | ||
74 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(4-(2,3-二甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.69 (s, 1H), 11.41-11.12 (m, 1H), 8.57-8.54 (m, 2H), 8.02 (s, 1H), 7.77 (d,J = 8.0 Hz, 1H), 7.49-7.43 (m, 4H), 7.28-6.84 (m, 7H), 6.65 (d,J = 8.0 Hz, 1H), 6.37 (s, 1H), 6.14 (s, 1H), 4.25 (s, 1H), 3.79 (s, 3H), 3.63-3.60 (m, 5H), 3.28 (s, 2H), 2.98-2.90 (m, 7H), 2.68 (s, 1H), 2.03 (s, 1H), 1.73-1.49 (m, 7H), 1.37-0.97 (m, 22H)。MS (ESI) m/e [M+1]+ 1056.1。 | ||
75 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-(2-(2-異丙基苯基)-4-(3,4,5-三甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.69 (s, 1H), 11.29 (br, 1H), 8.61-8.53 (m, 2H), 8.02 (s, 1H), 7.81-7.74 (m, 1H), 7.54-7.44 (m, 3H), 7.43-7.03 (m, 5H), 6.74-6.59 (m, 3H), 6.37 (s, 1H), 6.14 (s, 1H), 4.25 (s, 1H), 3.74 (s, 6H), 3.61 (s, 3H), 3.64-3.45 (m, 2H), 3.30-3.20 (m, 3H), 3.09-2.82 (m, 7H), 2.79-2.55 (m, 1H), 2.45-2.25 (m, 1H), 2.09-1.95 (m, 1H), 1.73-1.51 (m, 6H), 1.39-1.15 (m, 12H), 1.14-1.02 (m, 9H)。MS (ESI, m/e) [M+1]+ 1085.5。 | ||
76 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(2-(2-乙基苯基)-4-(4-甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.69 (s, 1H), 11.17 (br, 1H), 8.62-8.53 (m, 2H), 8.02 (s, 1H), 7.82 (d,J = 8.0 Hz, 1H), 7.54-7.44 (m, 3H), 7.43-7.03 (m, 7H), 6.94-6.85 (m, 2H), 6.65 (d,J = 8.0 Hz, 1H), 6.37 (s, 1H), 6.14 (s, 1H), 4.25 (s, 1H), 3.72 (s, 3H), 3.64-3.47 (m, 3H), 3.30-3.24 (m, 2H), 3.15-2.55 (m, 11H), 2.35-1.95 (m, 2H), 1.72-1.51 (m, 6H), 1.39-1.19 (m, 8H), 1.18-1.00 (m, 9H)。MS (ESI, m/e) [M+1]+ 1011.5。 | ||
77 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-(2-(2-異丙基苯基)-4-(4-(4-甲氧基苯基)環己基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.70 (s, 1H), 11.44 (s, 1H), 8.65-8.48 (m, 2H), 8.19-7.87 (m, 2H), 7.85-7.74 (m, 1H), 7.59-7.13 (m, 8H), 7.11-6.98 (m, 1H), 6.94-6.81 (m, 2H), 6.75-6.81 (m, 1H), 6.37 (s, 1H), 6.37 (s, 1H), 6.16 (s, 1H), 5.81-5.39 (m, 1H), 3.89-3.57 (m, 9H), 3.46-3.34 (m, 4H), 3.34-3.22 (m, 3H), 3.09-2.65 (m, 6H), 2.29-1.76 (m, 8H), 1.76-1.47 (m, 9H), 1.41-1.27 (m, 6H), 1.20-1.01 (m, 9H)。MS (ESI, m/e) [M+1]+ 1093.5 | ||
78 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(4-((2,3-二氫苯并[b][1,4]戴奧辛-6-基)甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.69 (s, 1H), 11.18 (s, 1H), 8.64-8.46 (m, 2H), 8.02 (s, 1H), 7.84-7.62 (m, 1H), 7.57-7.36 (m, 4H), 7.35-7.10(m, 3H), 7.10-6.99 (m, 1H), 6.96-6.72 (m, 3H), 6.72-6.58 (m, 1H), 6.37 (s, 1H), 6.14 (s, 1H), 4.26 (s, 1H), 4.24-4.17 (m, 4H), 3.91-3.43 (m, 3H), 3.32-3.17 (m, 5H), 3.10-2.55 (m, 9H), 1.78-1.50 (m, 6H), 1.41-1.24 (m, 6H), 1.22-1.15 (m, 4H), 1.15-0.98 (m, 9H)。MS (ESI, m/e) [M+1]+ 1053.5 | ||
79 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(4-((2,3-二氫苯并[b][1,4]戴奧辛-5-基)甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.70 (s, 1H), 11.44 (br, 1H), 8.61-8.53 (m, 2H), 8.03 (s, 1H), 7.89-7.74 (m, 2H), 7.54-7.42 (m, 3H), 7.40-7.13 (m, 3H), 7.12-6.62 (m, 5H), 6.38 (s, 1H), 6.16 (s, 1H), 4.28-4.17 (m, 5H), 3.78-3.55 (m, 2H), 3.45-3.35 (m, 5H), 3.30-2.63 (m, 10H), 2.09-1.95 (m, 1H), 1.73-1.51 (m, 6H), 1.39-1.15 (m, 11H), 1.14-1.02 (m, 8H)。MS (ESI, m/e) [M+1]+ 1054.1。 | ||
79a | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(R-4-((2,3-二氫苯并[b][1,4]戴奧辛-5-基)甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.70 (s, 1H), 11.15 (br, 1H), 8.61-8.53 (m, 2H), 8.03 (s, 1H), 7.89-7.74 (m, 1H), 7.54-7.13 (m, 6H), 7.12-6.62 (m, 5H), 6.37 (s, 1H), 6.15 (s, 1H), 4.28-4.17 (m, 5H), 3.94-3.55 (m, 2H), 3.45-3.25 (m, 2H), 3.20-2.63 (m, 12H), 2.09-1.93 (m, 1H), 1.73-1.51 (m, 6H), 1.39-1.15 (m, 10H), 1.14-1.02 (m, 9H)。MS (ESI, m/e) [M+1]+ 1053.8。 | ||
79b | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(S-4-((2,3-二氫苯并[b][1,4]戴奧辛-5-基)甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.70 (s, 1H), 11.45-11.00 (m, 1H), 8.63-8.45 (m, 2H), 8.03 (s, 1H), 7.78 (d,J = 9.2 Hz, 1H), 7.55-6.73 (m, 10H), 6.66 (d,J = 8.4 Hz, 1H), 6.38 (s, 1H), 6.15 (s, 1H), 4.36-3.90 (m, 6H), 3.81-3.39 (m, 2H), 3.31-2.61 (m, 12H), 2.46-2.28 (m, 1H), 2.19-1.93 (m, 1H), 1.73-1.46 (m, 6H), 1.40-0.87 (m, 20H)。MS (ESI, m/e) [1/2M+1]+ 527.8 | ||
80a | (R或S)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-(2-(2-異丙基苯基)-4-(3-(順式或反式)-(4-甲氧基苯基)-環戊基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺; | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.69 (s, 1H), 8.64-8.50 (m, 2H), 8.03 (s, 1H), 7.78 (d,J = 8.0Hz, 1H), 7.56-7.42 (m, 4H), 7.36-7.04 (m, 6H), 6.94-6.80 (m, 2H), 6.71-6.60 (m, 1H), 6.38 (s, 1H), 6.14 (s, 1H), 4.25 (s, 1H), 4.02-3.85 (m , 1H), 3.72 (s, 3H), 3.64-3.42 (m, 2H), 3.31-3.25 (m, 2H), 3.18-2.81 (m, 10H), 2.46-2.24 (m, 1H), 2.14-1.82 (m, 4H), 1.73-1.50 (m, 8H), 1.40-0.95 (m, 20H)。MS (ESI, m/e) [M/2+1]+ 540.6。 | ||
80b | (R或S)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-(2-(2-異丙基苯基)-4-(3-(反式或順式)-(4-甲氧基苯基)-環戊基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.69 (s, 1H), 8.66-8.50 (m, 2H), 8.03 (s, 1H), 7.78 (d,J = 8.0Hz, 1H), 7.58-7.42 (m, 4H), 7.34-7.02 (m, 6H), 6.90-6.78 (m, 2H), 6.71-6.61 (m, 1H), 6.38 (s, 1H), 6.14 (s, 1H), 4.25 (s, 1H), 4.01-3.85 (m , 1H), 3.70 (s, 3H), 3.62-3.40 (m, 2H), 3.30-3.25 (m, 2H), 3.16-2.81 (m, 10H), 2.44-2.19 (m, 1H), 2.10-1.49 (m, 12H), 1.44-0.93 (m, 20H)。MS (ESI, m/e) [M/2+1]+ 540.7。 | ||
81 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(4-(3,4-二甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.69 (s, 1H), 8.57-8.55 (m, 2H), 8.02 (s, 1H), 7.77 (s, 1H), 7.49-7.46 (m, 3H), 7.36 (s, 1H), 7.25 (s, 2H), 7.15 (s, 1H), 7.08 (s, 1H), 6.91 (s, 2H), 6.66 (s, 1H), 6.37 (s, 1H), 6.13 (s, 1H), 4.25 (s, 1H), 3.73 (s, 7H), 3.56 (s, 1H), 3.28 (s, 3H), 3.05-2.93 (m, 8H), 2.03 (s, 1H), 1.73-1.50 (m, 7H), 1.39-0.96 (m, 21H)。MS (ESI, m/e) [M+1]+ 1055.7。 | ||
81b | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-((S)-4-(3,4-二甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.69 (s, 1H), 11.25 (br, 1H), 8.62-8.53 (m, 2H), 8.02 (s, 1H), 7.82-7.75 (m, 1H), 7.54-7.04 (m, 8H), 6.96-6.76 (m, 2H), 6.68-6.63 (m, 1H), 6.37 (s, 1H), 6.14 (s, 1H), 4.25 (s, 1H), 3.98-3.80 (m, 2H), 3.73 (s, 6H), 3.62-3.40 (m, 2H), 3.32-3.25 (m, 2H), 3.20-2.75 (m, 10H), 2.10-1.94 (m, 4H), 1.75-1.52 (m, 7H), 1.39-1.15 (m, 13H), 1.14-1.02 (m, 7H)。MS (ESI, m/e) [M+1]+ 1055.8。 | ||
82 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-(2-(2-異丙基苯基)-4-(4-(甲基磺醯基)苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.69 (s, 1H), 11.41 (s, 1H), 10.41 (s, 0H), 8.57-8.55 (m, 2H), 8.03 (s, 1H), 7.88 (s, 2H), 7.77 (s, 1H), 7.59 (s, 2H), 7.50-7.46 (m, 3H), 7.37 (s, 1H), 7.21 (s, 2H), 7.09 (s, 1H), 6.66 (s, 1H), 6.37 (s, 1H), 6.14 (s, 1H), 4.68 (s, 0H), 4.25 (s, 1H), 3.78 (s, 4H), 3.28 (s, 2H), 3.18 (s, 3H), 2.98-2.96 (m, 8H), 2.22 (s, 1H), 2.05-1.93 (m, 1H), 1.74-1.49 (m, 7H), 1.29-1.20 (m, 11H), 1.18-1.14 (m, 3H), 1.10 (s, 4H), 1.06-1.03 (m, 3H)。MS (ESI, m/e) [M+1]+ 1074.3。 | ||
83 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(6-(2-(2-異丙基苯基)-4-(4-甲氧基苄基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.72 (s, 1H), 11.26 (s, 1H), 8.72-8.51 (m, 2H), 8.03 (s, 1H), 7.86-7.77 (m, 1H), 7.71-6.98 (m, 11H), 6.97-6.78 (m, 2H), 6.40 (s, 1H), 6.10-5.95 (m, 1H), 5.48 (s, 1H), 4.24 (s, 1H), 3.72 (s, 3H), 3.68-3.41 (m, 6H), 3.33-3.16 (m, 4H), 3.10-2.82 (m, 3H), 2.77-2.61 (m, 2H), 2.28-2.15 (m, 1H), 2.03-1.90(m, 2H), 1.75-1.47 (m, 6H), 1.40-1.28 (m, 3H), 1.21-1.00 (m, 11H)。MS (ESI, m/e) [M+1]+ 998.0。 | ||
84 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-((R或S)-2-(2-異丙基苯基)-4-(4-甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((3-硝基-4-((((R)-4-(氧雜環丁烷-3-基)𠰌啉-2-基)甲基)胺基)苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.67 (s, 1H), 8.59 (s, 1H), 8.53 (s, 1H), 8.01 (s, 1H), 7.77 (s, 1H), 7.48 (s, 4H), 7.23 (s, 6H), 6.89 (s, 2H), 6.66 (s, 1H), 6.36 (s, 1H), 6.14 (s, 1H), 4.54 (s, 2H), 4.45 (s, 2H), 3.87-3.84 (m, 1H), 3.73-3.70 (m, 5H), 3.56 (s, 3H), 3.43 (s, 2H), 3.24-3.14 (m, 1H), 2.96-2.91 (m, 7H), 2.78-2.76 (m, 1H), 1.99 (s, 2H), 1.80 (s, 1H), 1.68-1.53 (m, 2H), 1.25-1.20 (m, 15H), 1.06 (s, 4H)。MS (ESI, m/e) [M+1]+ 1055.4。 | ||
85 | (R或S)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(2-(2-異丙基苯基)-4-(4-甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-(((1-甲基哌啶-4-基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.65 (s, 1H), 11.51-11.18 (m, 1H), 8.57-8.55 (m, 2H), 7.98 (s, 1H), 7.72 (s, 1H), 7.45-7.43 (m, 5H), 7.22 (s, 4H), 7.11 (s, 2H), 6.87 (s, 2H), 6.64 (s, 1H), 6.35 (s, 1H), 6.15 (s, 1H), 3.72 (s, 4H), 2.94-2.90 (m, 9H), 2.67 (s, 4H), 2.27-2.11 (m, 1H), 1.99 (s, 2H), 1.89-1.86 (m, 3H), 1.64 (s, 2H), 1.47-1.46 (m, 3H), 1.30-1.28 (m, 3H), 1.20-1.17 (s, 4H), 1.06-1.04 (m, 5H), 0.86-0.84 (m, 3H)。MS (ESI, m/e) [M+1]+ 1010.4。 | ||
86 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-((R或S)-2-(2-異丙基苯基)-4-(4-甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((3-硝基-4-((((S)-1-(四氫-2H-哌喃-4-基)吡咯啶-3-基)甲基)胺基)苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.70 (s, 1H), 8.72 (s, 1H), 8.56 (s, 1H), 8.04 (s, 1H), 7.81 (d,J = 9.2 Hz, 1H), 7.59-7.52 (m, 2H), 7.49-7.40 (m, 2H), 7.35-7.21 (m, 4H), 7.19-7.04 (m, 2H), 6.97-6.88 (m, 2H), 6.68 (d,J = 9.2 Hz, 1H), 6.41 (s, 1H), 6.21 (s, 1H), 3.96 (d,J = 12.0 Hz 2H), 3.77 (s, 3H), 3.69-3.58 (m, 2H), 3.55-3.50 (m, 2H), 3.39 (s, 4H), 3.32 (t,J = 12.0 Hz, 3H), 3.05-2.87 (m, 7H), 2.73 (s, 1H), 2.29-2.23 (m, 1H), 2.18-2.11 (m, 1H), 2.01-1.92 (m, 2H), 1.79-1.59 (m, 5H), 1.42-1.29 (m, 8H), 1.27-1.21 (m, 4H), 1.14-1.06 (m, 4H), 0.92-0.88 (m, 1H)。MS (ESI, m/e) [M+1]+ 1066.7。 | ||
87 | (R或S)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(2-(2-異丙基苯基)-4-(4-甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((3-硝基-4-((2-(3-側氧基𠰌啉代)乙基)胺基)苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.68 (s, 1H), 11.29 (br, 1H), 8.61-8.55 (m, 1H), 8.54 (s, 1H), 8.02 (s, 1H), 7.86-7.75 (m, 1H), 7.54-7.44 (m, 3H), 7.43-7.10 (m, 7H), 6.97-6.83 (m, 2H), 6.69-6.63 (m, 1H), 6.37 (s, 1H), 6.13 (s, 1H), 3.99 (s, 2H), 3.81-3.70 (m, 6H), 3.64-3.53 (m, 5H), 3.43-3.37 (m, 2H), 3.34 (s, 3H), 3.07-3.83 (m, 7H), 2.79-2.60 (m, 2H), 2.35-2.25 (m, 1H), 2.09-1.96 (m, 1H), 1.70-1.53 (m, 1H), 1.34-1.13 (m, 8H), 1.12-0.99 (m, 4H)。MS (ESI, m/e) [M+1]+ 1026.4。 | ||
88 | (R或S)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(2-(2-異丙基苯基)-4-(4-甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-(3-甲基-3-((四氫-2H-哌喃-4-基)甲基)脲基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.69 (s, 1H), 11.50 (br, 1H), 9.72 (s, 2H), 8.46 (s, 2H), 8.19-8.00 (m, 3H), 7.59-7.12 (m, 9H), 7.00-6.85 (m, 2H), 6.67-6.62 (m, 1H), 6.38 (s, 1H), 6.11 (s, 1H), 3.89-3.83 (m, 2H), 3.78-3.70 (m, 3H), 3.46-3.37 (m, 1H), 3.32-3.13 (m, 6H), 3.08-2.80 (m, 10H), 2.74-2.54 (m, 1H), 2.35-2.30 (m, 1H), 2.05-1.86 (m, 2H), 1.60-1.52 (m, 3H), 1.42-0.85 (m, 18H)。MS (ESI, m/e) [M+1]+ 1054.5。 | ||
89 | (R或S)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(2-(2-異丙基苯基)-4-(4-甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((3-硝基-4-((2-(四氫-2H-哌喃-4-基)-2-氮雜螺[3.3]庚烷-6-基)胺基)苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.68 (s, 1H), 8.53 (s, 1H), 8.31 (s, 1H), 8.01 (s, 1H), 7.79 (s, 1H), 7.57-7.55 (m, 2H), 7.49-7.36 (m, 2H), 7.31-7.20 (m, 4H), 7.17 (s, 1H), 6.93 (d,J = 7.6 Hz, 2H), 6.87-6.77 (m, 1H), 6.69 (d,J = 7.6 Hz, 1H), 6.39 (s, 1H), 6.23 (s, 1H), 4.22-4.06 (m, 4H), 4.01 (d,J = 12.0 Hz, 3H), 3.77 (s, 3H), 3.29 (t,J = 12.0 Hz, 3H), 3.04-2.89 (m, 7H), 2.39 (s, 2H), 1.86 (d,J = 12..0 Hz, 3H), 1.68 (s, 3H), 1.43-1.38 (m, 3H), 1.37-1.29 (m, 8H), 1.26-1.21 (m, 4H), 1.14-1.09 (m, 4H), 0.94-0.87 (m, 3H)。MS (ESI, m/e) [M+1]+ 1079.0。 | ||
90 | (R或S)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((4-氟-1-(四氫-2H-哌喃-4-基)哌啶-4-基)甲氧基)-3-硝基苯基)磺醯基)-4-(2-(2-(2-異丙基苯基)-4-(4-甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.56 (s, 1H), 8.21 (s, 1H), 7.95-7.79 (m, 2H), 7.2-7.52 (m, 1H), 7.48-7.35 (m, 2H), 7.35-7.00 (m, 8H), 6.95-6.77 (m, 2H), 6.70-6.52 (m, 1H), 6.30 (s, 1H), 6.19 (s, 1H), 4.39-4.20 (m, 2H), 3.99-3.85 (m, 2H), 3.70 (s, 3H), 3.61-3.57 (m, 2H), 3.33-3.21 (m, 4H), 3.16-3.04 (m, 2H), 2.99-2.80 (m, 7H), 2.78-2.59 (m, 3H), 2.43-2.12 (m, 3H), 2.09-1.98 (m, 2H), 1.97-1.75 (m, 4H), 1.70-1.44 (m, 4H), 1.38-1.25 (m, 4H), 1.20-0.95 (m, 8H)。MS (ESI, m/e) [M+1]+ 1099.6。 | ||
91 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-((R或S)-2-(2-異丙基苯基)-4-(4-甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((3-硝基-4-((4-((四氫-2H-哌喃-4-基)胺基)環己基)胺基)苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.52 (s, 1H), 8.65-8.10 (m, 2H), 8.02-7.85 (m, 2H), 7.72-7.55 (m, 2H), 7.50-7.30 (m, 2H), 7.28-7.01 (m, 6H), 6.95-6.75 (m, 3H), 6.64-6.52 (m, 1H), 6.28 (s, 1H), 6.21 (s, 1H), 3.92-3.82 (m, 2H), 3.69 (s, 3H), 3.53-3.37 (m, 6H), 3.32-3.25 (m, 3H), 3.12-3.00 (m, 1H), 2.96-2.76 (m, 7H), 2.20-1.85 (m, 9H), 1.69-1.30 (m, 11H), 1.20-0.99 (m, 8H)。MS (ESI, m/e) [M+1]+ 1081.5。 | ||
92 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-((R或S)-2-(2-異丙基苯基)-4-(4-甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-(((4-(甲基磺醯基)𠰌啉-2-基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.67 (s, 1H), 8.62 (s, 1H), 8.55 (s, 1H), 8.02 (s, 1H), 7.85-7.72 (m, 1H), 7.56-7.03 (m, 10H), 6.99-6.84 (m, 2H), 6.69-6.59 (m, 1H), 6.37 (s, 1H), 6.20-6.07 (m, 1H), 4.01-3.94 (m, 1H), 3.83-3.40 (m, 11H), 3.24-2.59 (m, 16H), 2.35-1.92 (m, 2H), 1.72-1.52 (m, 1H), 1.37-1.00 (m, 13H)。MS (ESI, m/e) [M+1]+ 1076.7。 | ||
93 | (R或S)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-(((1-乙醯基哌啶-4-基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-(2-(2-異丙基苯基)-4-(4-甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.70 (s, 1H), 11.40-10.95 (m, 1H), 8.64 (s, 1H), 8.56 (s, 1H), 8.02 (s, 1H), 7.84-7.72 (m, 1H), 7.58-7.06 (m, 10H), 6.92 (s, 2H), 6.65 (d,J = 8.8 Hz, 1H), 6.37 (s, 1H), 6.14 (s, 1H), 4.37 (d,J = 13.2 Hz, 1H), 4.02-3.69 (m, 6H), 3.34-3.22 (m, 4H), 3.18-2.62 (m, 11H), 2.48-2.32 (m, 1H), 1.98 (s, 3H), 1.92-1.47 (m, 5H), 1.41-0.74 (m, 15H)。MS (ESI, m/e) [M+1]+ 1038.6。 | ||
94 | (R或S)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(2-(2-異丙基苯基)-4-(4-甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((2-𠰌啉代乙基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.70 (s, 1H), 8.80 (s, 1H), 8.55 (s, 1H), 8.01 (s, 1H), 7.80 (d,J = 8.8 Hz, 1H), 7.53-7.13 (m, 9H), 7.06-6.85 (m, 3H), 6.65 (d,J = 8.4 Hz, 1H), 6.37 (s, 1H), 6.14 (s, 1H), 3.73 (s, 3H), 3.66-3.41 (m, 8H), 3.28-2.61 (m , 14H), 2.41-1.93 (m, 4H), 1.68-1.53 (m, 1H), 1.34-0.98 (m, 14H)。MS (ESI, m/e) [M+1]+ 1012.7。 | ||
95 | 2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-((R或S)-2-(2-異丙基苯基)-4-(4-甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.57 (s, 1H), 8.62 (s, 1H), 8.58 (s, 1H), 8.12 (s, 1H), 7.88-7.76 (m, 1H), 7.59-7.21 (m, 8H), 7.16-6.89 (m, 3H), 6.79-6.68 (m, 1H), 6.33-6.22 (m, 1H), 4.31 (s, 1H), 3.87-3.47 (m, 6H), 3.37-3.29 (m, 3H), 3.22-2.66 (m, 10H), 2.45-1.99 (m, 2H), 1.78-1.55 (m, 6H), 1.44-1.05 (m, 19H)。MS (ESI, m/e) [M+1]+ 1044.3。 | ||
96 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(4-(苯并呋喃-5-基甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.70 (s, 1H), 11.28-11.20 (m, 1H), 8.57-8.54 (m, 2H), 8.03 (s, 2H), 7.79-7.72 (m, 2H), 7.59 (s, 1H), 7.50-7.46 (m, 3H), 7.32-7.20 (m, 4H), 7.07 (d,J = 8.0 Hz, 1H), 6.96 (s, 1H), 6.65 (d,J = 8.0 Hz, 1H), 6.37 (s, 1H), 6.14 (s, 1H), 4.26 (s, 1H), 3.86 (s, 1H), 3.72 (s, 1H), 3.28 (s, 2H), 3.12-2.68 (m, 9H), 2.33 (s, 1H), 2.09-2.06 (m, 1H), 1.72-1.42 (m, 6H), 1.38-1.25 (m, 12H), 1.10 (s, 4H), 1.04 (s, 4H)。MS (ESI, m/e) [M+1]+ 1035.7。 | ||
97 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-(2-(2-異丙基苯基)-4-(吡啶-3-基甲基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.69 (s, 1H), 11.37 (s, 1H), 8.65-8.40 (m, 4H), 8.03 (s, 1H), 7.77 (s, 3H), 7.50-7.46 (m, 4H), 7.36 (s, 2H), 7.22 (s, 2H), 7.09-7.06 (m, 2H), 6.65 (d,J = 8.8 Hz, 1H), 6.37 (s, 1H), 6.14 (s, 1H), 4.25 (s, 1H), 3.69-3.65 (m, 3H), 3.28 (s, 3H), 3.02-2.90 (m, 8H), 2.22 (s, 1H), 2.01 (s, 1H), 1.73-1.50 (m, 7H), 1.36-1.23 (m, 14H), 1.20-1.15 (m, 6H), 1.10 (s, 4H), 1.04 (s, 4H)。MS (ESI, m/e) [M+1]+ 996.7。 | ||
98 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(6-(2-(2-異丙基苯基)-4-(4-甲氧基苯乙基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.73 (s, 1H), 10.98 (s, 1H), 8.70-8.45 (m, 2H), 8.03 (s, 1H), 7.87-7.73 (m, 1H), 7.63-7.37 (m, 4H), 7.35-6.97 (m, 7H), 6.91-6.77 (m, 2H), 6.39 (s, 1H), 6.09-5.97 (m, 1H), 5.49 (s, 1H), 4.25 (s, 1H), 3.92-3.75 (m, 1H), 3.70 (s, 3H), 3.65-3.42 (m, 5H), 3.31-3.22 (m, 4H), 3.16-2.59 (m, 9H), 2.46-2.27(m, 1H), 2.08-1.86 (m, 2H), 1.74-1.49 (m, 6H), 1.39-1.26 (m, 3H), 1.20-1.13 (m, 5H), 1.13-1.04 (m, 4H)。MS (ESI, m/e) [M+1]+ 1011.8。 | ||
99 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-(2-(2-異丙基苯基)-4-(4-甲氧基苄基)-5-甲基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.76 (s, 1H), 11.45 (s, 1H), 8.72-8.55 (m, 2H), 8.09 (s, 1H), 7.92-7.77 (m, 1H), 7.69-7.46 (m, 6H), 7.43-7.18 (m, 4H), 7.18-7.10 (m, 1H), 7.10-6.95 (m, 2H), 6.78-6.65 (m, 1H), 6.44 (s, 1H), 6.19 (s, 1H), 4.32 (s, 1H), 4.20-3.95 (m, 1H), 3.79 (s, 3H), 3.38-3.28 (m, 5H), 3.10-2.85 (m, 7H), 2.76-2.63 (m, 1H), 1.81-1.65 (m, 4H), 1.65-1.45(m, 6H), 1.45-1.28 (m, 10H), 1.22-1.06 (m, 10H)。MS (ESI, m/e) [M+1]+ 1040.3。 | ||
100 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-(2-(2-異丙基苯基)-4-((4-甲氧基環己基)甲基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.67 (s, 1H), 11.29 (br, 1H), 8.60-8.52 (m, 2H), 8.01 (s, 1H), 7.79-7.72 (m, 1H), 7.52-7.30 (m, 4H), 7.29-7.00 (m, 4H), 6.68-6.61 (m, 1H), 6.36 (s, 1H), 6.14 (s, 1H), 4.25 (s, 1H), 3.32-3.27 (m, 3H), 3.20 (s, 3H), 3.07-2.83 (m, 11H), 2.30-2.12 (m, 2H), 2.03-1.92 (m, 3H), 1.79-1.58 (m, 7H), 1.52-1.40 (m, 4H), 1.38-1.18 (m, 15H), 1.17-1.12 (m, 4H), 1.07-0.96 (m, 3H)。MS (ESI, m/e) [M+1]+ 1031.9。 | ||
101 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-(2-(2-異丙基苯基)-4-(4-甲氧基苄基)-6-側氧基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.69 (s, 1H), 11.42 (br, 1H), 8.63-8.54 (m, 2H), 8.04 (s, 1H), 7.80 (d,J = 8.8Hz, 1H), 7.55-7.43 (m, 3H), 7.29-7.22 (m, 2H), 7.19-7.16 (m, 1H), 7.10 (d,J = 8.8Hz, 1H), 6.97-6.94 (m, 1H), 6.74-6.57 (m, 5H), 6.38 (s, 1H), 6.16 (s, 1H), 5.03 (s, 1H), 4.45-4.32 (m, 1H), 4.25 (s, 1H), 3.65 (s, 3H), 3.54-3.46 (m, 1H), 3.30-3.16 (m, 4H), 3.10-2.87 (m, 7H), 2.08-1.84 (m, 3H), 1.74-1.58 (m, 5H), 1.57-1.40 (m, 6H), 1.38-1.18 (m, 9H), 0.90-0.78 (m, 4H)。MS (ESI, m/e) [M+1]+ 1039.6 | ||
102 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(4-(2-氯-4-甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.67 (s, 1H), 11.38 (br, 1H), 8.60-8.51 (m, 2H), 8.00 (s, 1H), 7.85-7.73 (m, 1H), 7.55-7.28 (m, 6H), 7.27-6.95 (m, 4H), 6.93-6.85 (m, 1H), 6.68-6.60 (m, 1H), 6.35 (s, 1H), 6.13 (s, 1H), 4.23 (s, 1H), 3.72 (s, 3H), 3.70-3.54 (m, 2H), 3.45-3.34 (m, 1H), 3.30-3.23 (m, 2H), 3.05-2.67 (m, 8H), 2.28-1.90 (m, 2H), 1.70-1.47 (m, 6H), 1.45-1.12 (m, 13H), 1.10-0.99 (m, 8H)。MS (ESI, m/e) [M+1]+ 1060.7。 | ||
103 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(4-(2-氯苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.67 (s, 1H), 11.38 (br, 1H), 8.60-8.51 (m, 2H), 8.00 (s, 1H), 7.85-7.73 (m, 1H), 7.55-7.35 (m, 6H), 7.33-7.15 (m, 5H), 7.10-7.03 (m, 1H), 6.68-6.60 (m, 1H), 6.35 (s, 1H), 6.13 (s, 1H), 4.23 (s, 1H), 3.83-3.37 (m, 5H), 3.30-3.23 (m, 2H), 3.08-2.69 (m, 9H), 2.28-1.90 (m, 3H), 1.70-1.47 (m, 7H), 1.45-1.12 (m, 13H), 1.10-0.99 (m, 4H)。MS (ESI, m/e) [M+1]+ 1030.7。 | ||
104 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-(2-(2-異丙基苯基)-4-(4-甲氧基苄基)-3-甲基哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.75 (s, 1H), 11.48 (s, 1H), 8.67-8.57 (m, 2H), 8.09 (s, 1H), 7.85 (d,J = 12.0 Hz, 1H), 7.67-7.46 (m, 4H), 7.44-7.37 (m, 1H), 7.36-7.23 (m, 3H), 7.19 (s, 1H), 7.14 (d,J = 8.0 Hz, 1H), 7.06-6.98 (m, 1H), 6.94 (d,J = 8.0 Hz, 1H), 6.77-6.67 (m, 1H), 6.43 (s, 1H), 6.26-6.15 (m, 1H), 4.31 (s, 1H), 3.80 (d,J = 8.0 Hz, 3H), 3.34 (s, 3H), 3.25-3.14 (m, 2H), 3.08-2.93 (m, 5H), 2.85-2.70 (m, 1H), 2.26-2.15 (m, 1H), 2.04-1.90 (m, 1H), 1.78-1.64 (m, 4H), 1.62-1.55 (m, 2H), 1.46-1.33 (m, 6H), 1.32-1.24 (m, 4H), 1.22-1.09 (m, 10H), 1.08-1.01 (m, 4H), 0.95- 0.83 (m, 2H)。MS (ESI, m/e) [M+1]+ 1039.8。 | ||
105 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(2-(2-環丙基苯基)-4-((4-甲氧基苄基)(甲基)胺基)哌啶-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.74 (s, 1H), 11.50 (s, 1H), 10.28 (s, 1H), 8.68-8.54 (m, 2H), 8.08 (s, 1H), 7.90-7.76 (m, 2H), 7.62-7.50 (m, 3H), 7.36-7.31 (m, 3H), 7.17-7.06 (m, 2H), 6.94 (d,J = 8.0 Hz, 2H), 6.73 (d,J = 6.8 Hz, 1H), 6.43 (s, 1H), 6.23 (s, 1H), 5.19 (s, 1H), 4.31 (s, 1H), 4.02-3.92 (m, 1H), 3.80 (s, 3H), 3.66-3.48(m, 2H), 3.33 (s, 3H), 3.11-3.06 (m, 1H), 3.04-2.97 (m, 2H), 2.96-2.89 (m, 1H), 2.64 (s, 1H), 2.44-2.37 (m, 1H), 2.32-2.24 (m, 2H), 2.23-2.16 (m, 2H), 2.12 (s, 3H), 2.06-2.00 (m, 1H), 1.78-1.74 (m, 1H), 1.73-1.70 (m, 1H), 1.62-1.57 (m, 2H), 1.48 (s, 1H), 1.43-1.37 (m, 4H), 1.36-1.33 (m, 2H), 1.29 (s, 2H), 1.20-1.18 (m, 1H), 1.15 (s, 3H), 1.05-1.01(m, 1H), 0.94-0.87 (m, 2H), 0.84-0.80 (m, 1H), 0.78-0.70 (m, 2H), 0.65-0.58 (m, 1H)。MS (ESI, m/e) [M+1]+ 1051.7 | ||
106 | 2-(苯并[b]噻吩-5-基氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-(2-(2-異丙基苯基)-4-(4-甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.25 (s, 1H), 8.60-8.40 (m, 2H), 7.97-7.84 (m, 1H), 7.79-7.70 (m, 1H), 7.64-7.54 (m, 1H), 7.54-7.46 (m, 1H), 7.46-7.07 (m, 8H), 7.07-6.83 (m, 4H), 6.85-6.63(m, 1H), 6.35 (s, 1H), 6.35 (s, 1H), 4.26 (s, 1H), 4.18-3.67 (m, 6H), 3.65-3.39 (m, 3H), 3.28-3.14 (m, 3H), 3.14-2.73 (m, 7H), 2.14 (m, 1H), 1.75-1.50 (m, 6H), 1.50-0.96 (m, 19H)。MS (ESI, m/e) [M+1]+ 1042.6 | ||
107 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(4-((3,4-二氫-2H-苯并[b][1,4]二㗁呯-6-基)甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.69 (s, 1H), 11.22 (s, 1H), 8.66-8.46 (m, 2H), 8.03 (s, 1H), 7.97-7.70 (m, 2H), 7.63-6.80 (m, 11H), 6.80-6.55 (m, 1H), 6.37 (s, 1H), 6.14 (s, 1H), 4.25 (s, 1H), 4.15-4.01 (m, 4H), 3.98-3.56 (m, 3H), 3.48-3.40 (m, 1H), 3.33-3.23 (m, 3H), 3.23-3.13 (m, 1H), 3.13-2.83 (m, 6H), 2.81-2.62 (m, 2H), 2.16-1.94 (m, 3H), 1.78-1.50 (m, 6H), 1.48-1.15 (m, 11H), 1.15-0.96 (m, 8H)。MS (ESI, m/e) [M+1]+ 1067.7 | ||
108 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-((R)-2-(2-異丙基苯基)-4-(4-甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((3-硝基-4-((((S)-4-(氧雜環丁烷-3-基)𠰌啉-2-基)甲基)胺基)苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.66 (s, 1H), 8.58 (s, 1H), 8.53 (s, 1H), 8.00 (s, 1H), 7.77 (s, 1H), 7.55-7.35 (m, 4H), 7.24 (s, 4H), 7.10-7.02 (m, 2H), 6.89 (s, 2H), 6.66-6.65 (m, 1H), 6.36 (s, 1H), 6.15 (s, 1H), 4.54 (s, 2H), 4.45 (s, 2H), 3.88-3.85 (m, 1H), 3.72 (s, 5H), 3.58-3.53 (m, 3H), 3.43 (s, 3H), 3.10-2.82 (m, 7H), 2.78-2.72 (m, 1H), 2.60-2.54 (m, 1H), 1.96 (s, 2H), 1.82-1.80 (m, 1H), 1.58 (s, 2H), 1.30-1.21 (m, 9H), 1.18 (s, 3H), 1.06 (s, 3H)。MS (ESI, m/e) [M+1]+ 1054.6。 | ||
109 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-(4-(4-甲氧基苄基)-2-(2-甲氧基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.75 (s, 1H), 11.51-10.95 (m, 1H), 8.68-8.54 (m, 2H), 8.08 (s, 1H), 7.83 (d,J = 8.8 Hz, 1H), 7.59-7.49 (m, 3H), 7.45-7.24 (m, 3H), 7.12 (d,J = 8.8 Hz, 1H), 7.09-6.88 (m, 4H), 6.71 (d,J = 7.6 Hz, 1H), 6.43 (s, 1H), 6.20 (s, 1H), 4.31 (s, 1H), 3.91-3.82 (m, 3H), 3.78 (s, 3H), 3.62-3.52 (m, 1H), 3.33 (s, 2H), 3.18-2.88 (m, 7H), 2.87-2.63 (m, 3H), 2.17-2.00 (m, 1H), 1.79-1.64 (m, 4H), 1.59 (d,J = 11.6 Hz, 3H), 1.48-1.24 (m, 8H), 1.23-1.10 (m, 6H), 1.00-0.86 (m, 1H)。MS (ESI, m/e) [M+1]+ 1014.1 | ||
110 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-(2-(2-異丙基苯基)-4-(3-(4-甲氧基苯基)環己基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.70 (s, 1H), 11.43 (br, 1H), 8.62-8.54 (m, 2H), 8.03 (s, 1H), 7.84-7.75 (m, 1H), 7.54-6.96 (m, 10H), 6.88-6.63 (m, 3H), 6.38 (s, 1H), 6.14 (s, 1H), 4.25 (s, 1H), 3.70 (s, 3H), 3.54-3.41 (m, 1H), 3.20-2.75 (m, 11H), 2.29-1.80 (m, 5H), 1.79-1.41 (m, 12H), 1.39-1.15 (m, 15H), 1.14-1.02 (m, 7H)。MS (ESI, m/e) [M+1]+ 1093.8。 | ||
111 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.70 (s, 1H), 11.43 (br, 1H), 8.62-8.54 (m, 2H), 8.03 (s, 1H), 7.84-7.75 (m, 1H), 7.54-6.96 (m, 10H), 6.88-6.63 (m, 3H), 6.38 (s, 1H), 6.14 (s, 1H), 4.25 (s, 1H), 3.70 (s, 3H), 3.54-3.41 (m, 1H), 3.20-2.75 (m, 11H), 2.29-1.80 (m, 5H), 1.79-1.41 (m, 12H), 1.39-1.15 (m, 15H), 1.14-1.02 (m, 7H)。MS (ESI, m/e) [M+1]+ 1093.8。 | |||
112 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.63 (s, 1H), 8.60-8.48 (m, 2H), 8.03 (s, 1H), 7.84-7.75 (m, 1H), 7.54-6.96 (m, 10H), 6.88-6.62 (m, 3H), 6.39 (s, 1H), 6.16 (s, 1H), 4.25 (s, 1H), 3.70 (s, 3H), 3.54-3.41 (m, 1H), 3.20-2.75 (m, 11H), 2.29-1.80 (m, 5H), 1.79-1.52 (m, 9H), 1.51-1.15 (m, 21H), 1.14-1.02 (m, 4H)。MS (ESI, m/e) [M+1]+ 1093.9 | |||
113 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-((三氟甲基)磺醯基)苯基)磺醯基)-4-(2-((R)-2-(2-異丙基苯基)-4-(4-甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.72 (s, 1H), 8.15 (s, 1H), 8.03 (s, 1H), 7.93-7.79 (m, 1H), 7.55-6.83 (m, 13H), 6.66 (s, 1H), 6.39 (s, 1H), 6.19-6.07 (m, 1H), 4.25 (s, 1H), 4.16-3.86 (m, 1H), 3.81-3.38 (m, 5H), 3.23 (s, 3H), 3.08-2.56 (m, 9H), 2.44-1.96 (m, 2H), 1.72-1.49 (m, 6H), 1.37-0.95 (m, 19H)。MS (ESI, m/e) [M+1]+ 1112.8。 | ||
114 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(4-(4-(二甲基胺基)苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.70 (s, 1H), 11.36 (s, 1H), 8.75-8.46 (m, 2H), 8.03 (s, 1H), 7.87-7.72 (m, 1H), 7.60-7.32 (m, 5H), 7.33-6.99 (m, 6H), 6.78-6.60 (m, 3H), 6.38 (s, 1H), 6.23-6.06 (s, 1H), 4.26 (s, 1H), 4.20-3.65 (m, 3H), 3.55-3.35 (m, 2H), 3.32-3.15 (m, 4H), 3.09-2.79 (m, 14H), 2.42-2.31 (m, 1H), 2.12-1.92 (m, 1H), 1.76-1.60 (m, 4H), 1.60-1.46 (m, 3H), 1.42-1.26 (m, 5H), 1.23-1.15 (m, 3H), 1.15-1.00 (m, 9H)。MS (ESI, m/e) [M+1]+ 1039.3 | ||
115 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(4-(苯并[d][1,3]二氧雜環戊烯-4-基甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.69 (s, 1H), 11.35 (br, 1H), 8.62-8.54 (m, 2H), 8.03 (s, 1H), 7.81-7.75 (m, 1H), 7.54-7.45 (m, 3H), 7.44-7.05 (m, 5H), 6.90-6.77 (m, 3H), 6.68-6.63 (m, 1H), 6.37 (s, 1H), 6.14 (s, 1H), 5.97 (s, 2H), 4.25 (s, 1H), 3.82-3.38 (m, 4H), 3.32-3.25 (m, 2H), 3.20-2.60 (m, 10H), 2.30-1.96 (m, 2H), 1.74-1.50 (m, 6H), 1.39-1.15 (m, 13H), 1.14-1.02 (m, 8H)。MS (ESI, m/e) [M+1]+ 1040.2。 | ||
116 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(4-(3-乙基-4-甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.71 (s, 1H), 11.25 (s, 1H), 8.62-8.51 (m, 2H), 8.03 (s, 1H), 7.79 (d,J = 9.2 Hz, 1H), 7.56-6.81 (m, 11H), 6.65 (d,J = 8.0 Hz, 1H), 6.38 (s, 1H), 6.15 (s, 1H), 4.26 (s, 1H), 4.12-3.49 (m, 6H), 3.32-3.23 (m, 3H), 3.20-2.60 (m, 10H), 2.33-1.87 (m, 1H), 1.79-1.47 (m, 7H), 1.43-0.86 (m, 24H)。MS (ESI, m/e) [M+1]+ 1053.8。 | ||
117 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(4-(3,4-二氯苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.70 (s, 1H), 11.40 (s, 1H), 8.63-8.51 (m, 2H), 8.03 (s, 1H), 7.79 (d,J = 9.2 Hz, 1H), 7.70-6.69 (m, 11H), 6.66 (d,J = 9.2 Hz, 1H), 6.38 (s, 1H), 6.16 (s, 1H), 4.26 (s, 1H), 3.85-3.38 (m, 4H), 3.33-3.11 (m, 4H), 3.05-2.62 (m, 8H), 2.38-1.93 (m, 2H), 1.75-1.49 (m, 6H), 1.39-0.99 (m, 19H)。MS (ESI, m/e) [M+1]+ 1065.5。 | ||
118 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(4-(2-環丙基-3-甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.73 (s, 1H), 11.41 (s, 1H), 8.58 (s, 2H), 8.07 (s, 1H), 7.80 (s, 1H), 7.59-7.39 (m, 4H), 7.33-7.20 (m, 2H), 7.19-7.12 (m, 2H), 7.09 (s, 1H), 7.01 (d,J = 8.0 Hz, 1H), 6.86 (d,J = 8.4 Hz, 1H), 6.70 (d,J = 8.4 Hz, 1H), 6.42 (s, 1H), 6.21 (s, 1H), 4.31 (s, 1H), 3.77 (s, 3H), 3.74-3.67 (m, 1H), 3.36-3.30 (m, 2H), 3.14-2.83 (m, 8H), 2.36-2.19 (m, 2H), 1.80-1.64 (m, 6H), 1.60 (d,J = 12.0 Hz, 2H), 1.45-1.28 (m, 9H), 1.27-1.21 (m, 3H), 1.19 (s, 1H), 1.16 (s, 4H), 1.13-1.07 (m, 3H), 0.96-0.87 (m, 3H), 0.69-0.60 (m, 2H)。MS (ESI, m/e) [M+1]+ 1065.6 | ||
119 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(4-(3-氯-2-甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.69 (s, 1H), 11.44 (s, 1H), 8.55 (s, 2H), 8.04 (s, 1H), 7.77 (s, 1H), 7.57-7.48 (m, 3H), 7.46-7.36 (m, 3H), 7.33-7.20 (m, 2H), 7.19-7.11 (m, 2H), 7.03 (s, 1H), 6.68 (d,J = 8.0 Hz, 1H), 6.40 (s, 1H), 6.21 (s, 1H), 4.30 (s, 1H), 3.82 (s, 3H), 3.60-3.55 (m, 2H), 3.34-3.30 (m, 2H), 3.06-2.86 (m, 8H), 2.34-2.18 (m, 2H), 1.80-1.55 (m, 8H), 1.43-1.28 (m, 9H), 1.23 (d,J = 4.8 Hz, 3H), 1.20-1.18 (m, 1H), 1.15 (s, 4H), 1.13-1.06 (s, 4H)。MS (ESI, m/e) [M+1]+ 1060.6 | ||
120 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(4-(2-氯-3-甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.69 (s, 1H), 11.41 (s, 1H), 8.56-8.55 (m, 2H), 8.03 (s, 1H), 7.77 (s, 1H), 7.50-7.46 (m, 3H), 7.38 (s, 1H), 7.27 (s, 3H), 7.08 (s, 4H), 6.66 (s, 1H), 6.37 (s, 1H), 6.13 (s, 1H), 4.25 (s, 1H), 3.82 (s, 4H), 3.76-3.70 (m, 1H), 3.43 (s, 2H), 3.29-3.25 (m, 2H), 2.93-2.90 (m, 7H), 1.99 (s, 2H), 1.62-1.56 (m, 7H), 1.32-1.28 (m, 12H), 1.15-1.12 (m, 2H), 1.10 (s, 5H), 1.05 (s, 3H)。MS (ESI, m/e) [M+1]+ 1060.6。 | ||
121 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(4-(4-氟-3-甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.69 (s, 1H), 11.32 (s, 1H), 8.55 (s, 2H), 8.03 (s, 1H), 7.78 (d,J = 8.4 Hz, 1H), 7.50-7.46 (m, 3H), 7.36-7.00 (m, 6H), 6.89 (s, 1H), 6.65 (d,J = 8.0 Hz, 1H), 6.37 (s, 1H), 6.14 (s, 1H), 4.25 (s, 1H), 3.81 (s, 3H), 3.63 (s, 2H), 3.28 (s, 3H), 2.98-2.91 (m, 7H), 2.68 (s, 2H), 2.33 (s, 1H), 2.02 (s, 1H), 1.67-1.52 (m, 6H), 1.39-1.20 (m, 11H), 1.20-1.01 (m, 9H)。MS (ESI, m/e) [M+1]+ 1043.9。 | ||
121a | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-((R)-4-(4-氟-3-甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.68 (s, 1H), 11.30 (br, 1H), 8.54 (s, 2H), 8.02 (s, 1H), 7.77 (d,J = 7.8 Hz, 1H), 7.50-7.45 (m, 3H), 7.30-7.05 (m, 7H), 6.87 (s, 1H), 6.64 (d,J = 7.8 Hz, 1H), 6.37 (s, 1H), 6.14 (s, 1H), 4.24 (s, 1H), 3.89-3.80 (m, 4H), 3.60 (s, 2H), 3.28 (s, 2H), 3.05-2.95 (m, 7H), 2.61 (s, 1H), 2.25 (s, 1H), 1.99 (s, 1H), 1.75-1.50 (m, 6H), 1.37-1.17 (m, 12H), 1.14-1.01 (m, 9H)。MS (ESI, m/e) [M+1]+ 1043.9。 | ||
122 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(4-(苯并[d][1,3]二氧雜環戊烯-5-基甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.69 (s, 1H), 11.23 (s, 1H), 8.55 (s, 2H), 8.02 (s, 1H), 7.78 (d,J = 8.4 Hz, 1H), 7.50-7.46 (m, 3H), 7.31-7.10 (m, 3H), 7.06 (d,J = 9.0 Hz, 1H), 6.96 (s, 1H), 6.88-6.83 (m, 2H), 6.65 (d,J = 8.4 Hz, 1H), 6.37 (s, 1H), 6.15 (s, 1H), 5.99 (s, 2H), 4.25 (s, 1H), 3.70 (s, 3H), 3.28 (s, 3H), 2.98-2.90 (m, 7H), 2.73 (s, 1H), 2.33 (s, 1H), 1.72-1.50 (m, 7H), 1.39-0.99 (m, 20H)。MS (ESI, m/e) [M+1]+ 1039.8。 | ||
123 | 2-((3-氯-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-((R)-2-(2-異丙基苯基)-4-(4-甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.69 (s, 1H), 11.36 (br, 1H), 8.63-8.54 (m, 2H), 8.03 (s, 1H), 7.88-7.75 (m, 1H), 7.54-7.44 (m, 3H), 7.43-7.04 (m, 6H), 6.96-6.88 (m, 1H), 6.68-6.63 (m, 1H), 6.37 (s, 1H), 6.15 (s, 1H), 4.25 (s, 1H), 3.84 (s, 3H), 3.82-3.58 (m, 2H), 3.48-3.37 (m, 1H), 3.32-3.15 (m, 3H), 3.12-2.56 (m, 9H), 2.45-2.26 (m, 1H), 2.14-1.94 (m, 1H), 1.73-1.42 (m, 7H), 1.38-1.16 (m, 10H), 1.14-1.00 (m, 8H)。MS (ESI, m/e) [M+1]+ 1060.9。 | ||
124 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(4-(3-乙氧基-4-甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.69 (s, 1H), 11.25 (br, 1H), 8.64-8.53 (m, 2H), 8.02 (s, 1H), 7.82-7.75 (m, 1H), 7.54-7.04 (m, 9H), 6.96-6.76 (m, 2H), 6.68-6.63 (m, 1H), 6.37 (s, 1H), 6.13 (s, 1H), 4.25 (s, 1H), 4.05-3.90 (m, 3H), 3.73 (s, 3H), 3.60-3.40 (m, 2H), 3.32-3.25 (m, 2H), 3.20-2.75 (m, 11H), 2.10-1.94 (m, 1H), 1.75-1.52 (m, 7H), 1.39-1.15 (m, 15H), 1.14-1.02 (m, 8H)。MS (ESI, m/e) [M+1]+ 1070.0。 | ||
125 | 2-((3-氟-6-甲基-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-((R)-2-(2-異丙基苯基)-4-(4-甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.27 (s, 1H), 8.63-8.39 (m, 2H), 7.71 (d,J = 7.6 Hz, 1H), 7.51-6.79 (m, 12H), 6.68 (d,J = 8.0 Hz, 1H), 6.14 (s, 1H), 4.26 (s, 1H), 3.74 (s, 3H), 3.31-3.12 (m, 5H), 3.05-2.58 (m, 9H), 2.46-2.25 (m, 4H), 2.16-1.91 (m, 1H), 1.76-1.45 (m, 7H), 1.40-0.93 (m, 21H)。MS (ESI, m/e) [M+1]+ 1057.9 | ||
126 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(4-(4-氯-3-甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 12.00 (s, 1H), 11.52 (br, 1H), 8.59-8.47 (m, 2H), 8.08 (s, 1H), 7.80-7.74 (m, 1H), 7.68 (s, 1H), 7.50-7.10 (m, 8H), 7.09-6.86 (m, 3H), 6.68-6.64 (m, 1H), 6.23 (s, 1H), 4.24 (s, 1H), 3.98-3.80 (m, 1H), 3.74 (s, 3H), 3.62-3.40 (m, 1H), 3.32-3.25 (m, 2H), 3.20-2.57 (m, 11H), 2.45-2.30 (m, 1H), 2.10-1.94 (m, 1H), 1.75-1.52 (m, 7H), 1.39-1.15 (m, 12H), 1.14-1.02 (m, 7H)。MS (ESI, m/e) [M+1]+ 1060.7。 | ||
128 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(4-(3-氯-4-甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.69 (s, 1H), 11.31 (s, 1H), 8.71-8.50 (m, 2H), 8.02 (s, 1H), 7.82-7.73 (m, 1H), 7.66-7.31 (m, 6H), 7.31-6.98 (m, 6H), 6.70-6.60 (m, 1H), 6.37 (s, 1H), 6.14 (s, 1H), 4.25 (s, 1H), 3.82 (s, 3H), 3.78-3.38 (m, 7H), 3.32-3.24 (m, 2H), 3.10-2.80 (m, 6H), 2.78-2.54 (m, 3H), 2.12-1.93 (m, 1H), 1.75-1.49 (m, 6H), 1.39-1.25 (m, 6H), 1.22-1.00 (m, 11H)。MS (ESI, m/e) [M+1]+ 1060.7 | ||
129 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(4-((2,2-二氟苯并[d][1,3]二氧雜環戊烯-4-基)甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.68 (s, 1H), 11.40 (s, 1H), 8.65-8.50 (m, 2H), 8.02 (s, 1H), 7.85-7.60 (m, 2H), 7.55-7.43 (m, 3H), 7.43-7.00 (m, 8H), 6.70-6.57 (m, 1H), 6.37 (s, 1H), 6.14 (s, 1H), 4.25 (s, 1H), 3.90-3.40 (m, 4H), 3.32-3.16 (m, 4H), 3.12-2.65 (m, 9H), 2.28-1.90 (m, 3H), 1.72-1.51 (m, 6H), 1.42-1.26 (m, 5H), 1.20-1.00 (m, 11H)。MS (ESI, m/e) [M+1]+ 1075.8 | ||
130 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(4-(口克唍-8-基甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.74 (s, 1H), 8.65-8.56 (m, 2H), 8.08(s, 1H), 7.84 (d,J = 8.0 Hz,1H), 7.58-7.39 (m, 4H), 7.36-6.97 (m, 6H), 6.86 (s, 1H), 6.71 (d,J = 8.0 Hz, 1H),, 6.43 (s, 1H), 6.19 (s, 1H), 4.30 (s, 1H), 4.24-4.14 (m, 2H), 3.90-3.75 (m, 1H), 3.69-3.58 (m, 1H), 3.52-3.42 (m, 1H), 3.35-3.32 (m, 2H), 3.08-2.90 (m, 6H), 2.82-2.76 (m, 2H), 2.42-2.29 (m, 1H), 2.15-2.03 (m, 1H), 1.98-1.91 (m, 2H), 1.78-1.67 (m, 4H), 1.64-1.56 (m, 3H), 1.43-1.35 (m, 4H), 1.33-1.28 (m, 5H), 1.26-1.23 (m, 2H), 1.19-1.13 (m, 8H), 0.94-0.86 (m, 4H)。MS (ESI, m/e) [M+1]+ 1051.7 | ||
131 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-(2-(2-異丙基苯基)-4-(吡啶-2-基甲基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.66 (s, 1H), 8.51-8.48 (m, 3H), 7.99 (s, 1H), 7.75 (s, 2H), 7.46-7.44 (m, 4H), 7.30-7.10 (m, 5H), 6.63 (s, 1H), 6.35 (s, 1H), 6.12 (s, 1H), 4.23 (s, 1H), 3.82-3.50 (m, 4H), 3.25 (s, 2H), 2.90-2.80 (m, 7H), 2.27-2.16 (m, 1H), 1.96 (s, 1H), 1.68-1.60 (m, 5H), 1.52-1.50 (m, 2H), 1.35-1.20 (m, 10H), 1.15 (s, 3H), 1.10-1.00 (m, 8H)。MS (ESI, m/e) [M+1]+ 996.7。 | ||
132 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(4-(3-氰基-4-甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.68 (s, 1H), 11.35 (br, 1H), 8.60-8.52 (m, 2H), 8.01 (d,J = 2.4 Hz, 1H), 7.80-7.76 (m, 1H), 7.68-7.52 (m, 2H), 7.52-7.45 (m, 3H), 7.38-7.15 (m, 5H), 6.66-6.60 (m, 1H), 6.36-6.34 (m, 1H), 6.17-6.07 (m, 1H), 4.24 (s, 1H), 3.86 (s, 6H), 3.79-3.40 (m, 4H), 3.32-3.25 (m, 3H), 3.10-2.75 (m, 9H), 2.30-1.94 (m, 3H), 1.70-1.51 (m, 7H), 1.37-1.15 (m, 13H), 1.14-1.02 (m, 4H)。MS (ESI, m/e) [M+1]+ 1051.0。 | ||
133 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(4-(口克唍-5-基甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.68 (s, 1H), 11.40 (br, 1H), 8.60-8.52 (m, 2H), 8.01 (d,J = 2.4 Hz, 1H), 7.80-7.52 (m, 2H), 7.50-7.42 (m, 3H), 7.35-7.15 (m, 3H), 7.07-6.92 (m, 2H), 6.80-6.74 (m, 1H), 6.66-6.57 (m, 2H), 6.36-6.34 (m, 1H), 6.17-6.07 (m, 1H), 4.24 (s, 1H), 4.09-3.97 (m, 2H), 3.79-3.40 (m, 4H), 3.32-3.05 (m, 3H), 3.03-2.80 (m, 7H), 2.79-2.60 (m, 4H), 2.13-1.94 (m, 2H), 1.92-1.84 (m, 2H), 1.70-1.40 (m, 8H), 1.35-1.15 (m, 14H), 1.14-1.02 (m, 3H)。MS (ESI, m/e) [M+1]+ 1052.1。 | ||
134 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(4-(3-氟-4-甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.68 (s, 1H), 11.35 (br, 1H), 8.60-8.52 (m, 2H), 8.01 (d,J = 2.4 Hz, 1H), 7.80-7.76 (m, 1H), 7.52-7.43 (m, 3H), 7.38-7.05 (m, 8H), 6.66-6.60 (m, 1H), 6.36-6.34 (m, 1H), 6.17-6.08 (m, 1H), 4.24 (s, 1H), 3.78 (s, 3H), 3.79-3.40 (m, 3H), 3.32-3.10 (m, 3H), 3.08-2.52 (m, 10H), 2.30-1.94 (m, 3H), 1.70-1.47 (m, 7H), 1.38-1.10 (m, 14H), 1.08-1.00 (m, 3H)。MS (ESI, m/e) [M+1]+ 1044.0。 | ||
135 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-(2-(2-異丙基苯基)-4-(2-(4-甲氧基苯基)環戊基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.67 (s, 1H), 11.43 (s, 1H), 10.64-10.42 (m, 1H), 8.60-8.54 (m, 2H), 7.99 (s, 1H), 7.74 (s, 2H), 7.53-7.37 (m, 3H), 7.30-7.15 (m, 3H), 7.07 (s, 3H), 6.75-6.71 (m, 2H), 6.63 (s, 1H), 6.34 (s, 1H), 6.12 (s, 1H), 4.24 (s, 1H), 4.07 (s, 1H), 3.67 (s, 3H), 3.27-3.23 (m, 2H), 2.98-2.85 (m, 7H), 2.05-1.99 (m, 5H), 1.75-1.45 (m, 11H), 1.35-1.0 (m, 20H), 0.72 (s, 2H)。MS (ESI, m/e) [M+1]+ 1080.8。 | ||
136 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(4-(3-環丙基-4-甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.71 (s, 1H), 11.41 (s, 1H), 8.68-8.46 (m, 2H), 8.02 (s, 1H), 7.82-7.67 (m, 1H), 7.55-6.72 (m, 11H), 6.72-6.58 (m, 1H), 6.36 (s, 1H), 6.20-6.05 (m, 1H), 4.26 (s, 1H), 4.20-3.95 (m, 2H), 3.83-3.66 (m, 3H), 3.58-3.40 (m, 1H), 3.33-3.21 (m, 3H), 3.20-2.72 (m, 9H), 2.69-2.53 (m, 1H), 2.25-1.90 (m, 2H), 1.70-1.48 (m, 6H), 1.37-1.24 (m, 5H), 1.21-0.96 (m, 13H), 0.95-0.75 (m, 3H), 0.72-0.45 (m, 3H)。MS (ESI, m/e) [M+1]+ 1066.7 | ||
137 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(4-(苯并呋喃-7-基甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.70 (s, 1H), 11.43 (s, 1H), 11.08 (s, 1H), 8.65-8.45 (m, 2H), 8.10-7.95 (m, 2H), 7.95-7.83 (m, 1H), 7.83-7.70 (m, 1H), 7.68-6.90 (m, 11H), 6.80-6.57 (m, 1H), 6.37 (s, 1H), 6.22-6.04 (m, 1H), 4.74-4.56 (m, 1H), 4.26 (s, 1H), 3.99-3.67 (m, 2H), 3.46-3.35 (m, 2H), 3.31-2.59 (m, 13H), 2.20-1.92 (m, 2H), 1.78-1.43 (m, 6H), 1.39-1.24 (m, 5H), 1.22-0.94 (m, 11H)。MS (ESI, m/e) [M+1]+ 1036.6 | ||
138 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-(2-(2-異丙基苯基)-4-(4-甲氧基苯氧基)哌啶-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.68 (s, 1H), 11.43 (s, 1H), 8.64-8.40 (m, 2H), 8.10-7.88 (m, 2H), 7.85-7.67 (m, 1H), 7.54-6.96 (m, 8H), 6.96-6.73 (m, 4H), 6.73-6.57 (m, 1H), 6.35 (s, 1H), 6.14 (s, 1H), 4.76-4.55 (m, 1H), 4.24 (s, 1H), 3.72-3.58 (m, 3H), 3.58-3.34 (m, 3H), 3.30-3.21 (m, 2H), 3.21-2.58 (m, 6H), 2.35-1.85 (m, 6H), 1.73-1.43 (m, 6H), 1.3-1.21 (m, 6H), 1.19-0.94 (m, 10H)。MS (ESI, m/e) [M+1]+ 1027.6 | ||
139 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-(2-(2-異丙基苯基)-4-(1-(4-甲氧基苯基)哌啶-3-基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.68 (s, 1H), 11.43 (br, 1H), 8.52-8.56 (m, 2H), 8.00 (s, 1H), 7.75-7.78 (m, 1H), 7.43-7.49 (m, 3H), 7.36 (s, 1H), 7.06-7.24 (m, 4H), 6.74 (s, 2H), 6.64 (s, 1H), 6.51 (s, 1H), 6.35 (s, 1H), 6.12 (d,J = 8.0 Hz, 1H), 4.25-4.23 (m, 1H), 3.60-3.63 (m, 3H), 3.26-3.27 (m, 3H), 2.90-2.97 (m, 7H), 1.64-1.67 (m, 3H), 1.50-1.54 (m, 3H), 1.07-1.30 (m, 25H)。MS (ESI, m/e) [M+1]+ 1095.6 | ||
140 | N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-(2-(2-異丙基苯基)-4-(4-甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-2-((1-甲基-1H-吡咯并[3,2-b]吡啶-6-基)氧基)苯甲醯胺 | 1 H NMR (400 MHz,DMSO-d 6 ) δ ppm: 11.40-10.53 (m, 1H), 8.53 (s, 1H), 8.46 (d,J = 2.4 Hz, 1H), 8.06 (d,J = 2.4 Hz, 1H), 7.72 (d,J = 9.0 Hz, 1H), 7.50 (d,J = 3.4 Hz, 1H), 7.45 (d,J = 9.0 Hz, 1H), 7.40-7.10 (m, 6H), 7.00 (d,J = 9.4 Hz, 1H), 6.89 (s, 2H), 6.65 (d,J = 7.0 Hz, 1H), 6.46 (d,J = 3.4 Hz, 1H), 6.20 (s, 1H), 4.24 (s, 1H), 3.71 (s, 3H), 3.66 (s, 3H), 3.49 (s, 1H), 3.37 (s, 1H), 3.28-3.22 (m, 3H), 2.85-3.00 (m, 7H), 2.31 (s, 1H), 1.99-1.97 (m, 1H), 1.61-1.70 (m, 4H), 1.53-1.50 (m, 2H), 1.36-1.10 (m, 13H), 1.10-1.0 (m, 7H)。MS (ESI, m/e) [M+1]+ 1039.7。 | ||
141b | 4-(6-((S)-4-(3,4-二甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)-2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.52 (s, 1H), 11.30 (br, 1H), 8.53-8.51 (m, 2H), 8.05 (s, 1H), 7.77 (d,J = 8.8 Hz, 1H), 7.50-7.47 (m, 2H), 7.41 (d,J = 8.8 Hz, 2H), 7.20-7.11 (m, 5H), 6.86 (s, 4H), 6.04 (d,J = 9.4 Hz, 1H), 5.30 (s, 1H), 4.24 (s, 1H), 3.75-3.70 (m, 6H), 3.59 (s, 1H), 3.53 (s, 2H), 3.49 (s, 1H), 2.97-2.85 (m, 5H), 2.70 (s, 2H), 2.23-2.16 (m, 2H), 1.99-1.95 (m, 4H), 1.67 - 1.63 (m, 5H), 1.53-1.50 (m, 3H), 1.35-1.25 (m, 4H), 1.22-1.15 (m, 11H), 1.09-1.5 (m, 8H)。MS (ESI, m/e) [M+1]+ 1046.0。 | ||
142 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(4-(4-乙炔基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.68 (s, 1H), 11.33 (br, 1H), 8.60-8.52 (m, 2H), 8.05-7.98 (m, 1H), 7.80-7.74 (m, 1H), 7.53-7.40 (m, 5H), 7.38-7.05 (m, 6H), 6.66-6.60 (m, 1H), 6.36-6.34 (m, 1H), 6.17-6.08 (m, 1H), 4.24 (s, 1H), 4.19-4.13 (m, 1H), 3.79-3.53 (m, 3H), 3.43-3.34 (m, 1H), 3.32-3.10 (m, 3H), 3.05-2.55 (m, 9H), 2.30-1.94 (m, 3H), 1.70-1.42 (m, 7H), 1.38-1.10 (m, 11H), 1.08-1.00 (m, 8H)。MS (ESI, m/e) [M+1]+ 1019.8 | ||
143 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(4-(3-溴-4-甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.68 (s, 1H), 11.31 (s, 1H), 8.69-8.44 (m, 2H), 8.00 (s, 1H), 7.85-7.64 (m, 1H), 7.64-6.95 (m, 11H), 6.70-6.55 (m, 1H), 6.35 (s, 1H), 6.12 (s, 1H), 4.23 (s, 1H), 3.90-3.45 (m, 6H), 3.45-3.34 (m, 1H), 3.32-3.13 (m, 4H), 3.05-2.78 (m, 6H), 2.75-2.54 (m, 2H), 2.32-2.15 (m, 1H), 2.10-1.92 (m, 1H), 1.71-1.44 (m, 6H), 1.37-1.22 (m, 6H), 1.20-0.93 (m, 12H)。MS (ESI, m/e) [M+1]+ 1105.6 | ||
144 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-(2-(2-異丙基苯基)-4-(4-甲氧基-3-甲基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.68 (s, 1H), 10.85 (s, 1H), 8.64-8.43 (m, 2H), 8.05-7.93(m, 1H), 7.86-7.68 (m, 2H), 7.58-6.77 (m, 11H), 6.70-6.55 (m, 1H), 6.42-6.29 (m, 1H), 6.19-6.05 (m, 1H), 4.24 (s, 1H), 4.10-3.65 (m, 5H), 3.57-3.35 (m, 2H), 3.30-3.18 (m, 3H), 3.07-2.55 (m, 9H), 2.43-2.22 (m, 1H), 2.16-1.89 (m, 4H), 1.77-1.38 (m, 7H), 1.38-1.22 (m, 5H), 1.20-0.94 (m, 12H)。MS (ESI, m/e) [M+1]+ 1040.0 | ||
146 | N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-((R)-2-(2-異丙基苯基)-4-(4-甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-2-((3-甲基-1H-吡咯并[2,3-b]吡啶-5-基)氧基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.34 (s, 1H), 8.55-8.58 (m, 2H), 8.00 (s, 1H), 7.82 (d,J = 12.0 Hz, 1H), 7.35-7.51 (m, 5H), 7.17-7.26 (m, 4H), 7.10 (d,J = 8.0 Hz, 1H), 6.68 (d,J = 8.0 Hz, 1H), 6.87 (d,J = 8.0 Hz, 1H), 6.64 (d,J = 8.0 Hz, 1H), 6.09-6.12 (m, 1H), 4.24 (s, 1H), 3.71-3.76 (m, 3H), 3.56 (s, 1H), 3.55 (s, 1H), 3.27-3.29 (m, 2H), 2.91-2.96 (m, 8H), 2.16 (s, 2H), 1.99-2.07 (m, 2H), 1.66-1.69 (m, 3H), 1.52-1.56 (m, 3H), 1.02-1.37 (m, 25H)。MS (ESI, m/e) [M+1]+ 1039.9 | ||
147 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(6-((R)-2-(2-異丙基苯基)-4-(4-甲氧基苄基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.73 (s, 1H), 11.23 (br, 1H), 8.63-8.54 (m, 2H), 8.07-8.02 (m, 1H), 7.62-7.51(m, 2H), 7.47-7.08 (m, 8H), 6.97-6.80 (m, 2H), 6.43-6.37 (m, 1H), 6.06-6.02 (m, 1H), 5.49 (s, 1H), 4.25 (s, 1H), 3.73 (s, 3H), 3.68-3.36 (m, 7H), 3.32-3.10 (m, 3H), 3.05-2.55 (m, 6H), 2.30-1.94 (m, 3H), 1.70-1.42 (m, 7H), 1.38-1.10 (m, 8H), 1.08-1.00 (m, 5H)。MS (ESI, m/e) [M+1]+ 997.9。 | ||
148 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(4-(3-氯-4,5-二甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.69 (s, 1H), 11.45-11.22 (m, 1H), 8.57-8.55 (m, 2H), 8.03 (s, 1H), 7.78 (d,J = 8.2 Hz, 1H), 7.50 (s, 3H), 7.42-7.31 (m, 1H), 7.22 (s, 2H), 7.07 (d,J = 9.2 Hz, 2H), 6.99 (s, 2H), 6.65 (d,J = 8.8 Hz, 1H), 6.37 (s, 1H), 6.14 (s, 1H), 4.25 (s, 1H), 3.80 (s, 4H), 3.70 (s, 3H), 3.59 (s, 3H), 3.28 (s, 2H), 3.08-2.85 (m, 7H), 2.25 (s, 1H), 1.99 (s, 1H), 1.75-1.50 (m, 7H), 1.40-1.19 (m, 12H), 1.10-1.08 (m, 9H)。MS (ESI, m/e) [M+1]+ 1090.9。 | ||
149a | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(6-((R)-4-((2,3-二氫苯并[b][1,4]戴奧辛-5-基)甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.73 (s, 1H), 11.04 (s, 1H), 8.74-8.34 (m, 2H), 8.03 (s, 1H), 7.90-7.74 (m, 1H), 7.67-7.34 (m, 4H), 7.34-7.04 (m, 5H), 7.04-6.87 (m, 1H), 6.87-6.65 (m, 2H), 6.39 (s, 1H), 6.10-5.95 (m, 1H), 5.48 (s, 1H), 4.30-4.15 (m, 5H), 3.87-3.45 (m, 8H), 3.30-3.23(m, 3H), 3.14-2.61 (m, 5H), 2.38-2.18 (m, 1H), 2.10-1.88 (m, 2H), 1.75-1.45 (m, 6H), 1.42-1.27 (m, 3H), 1.20-1.00 (m, 10H)。MS (ESI, m/e) [M+1]+ 1026.6 | ||
149b | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(6-((S)-4-((2,3-二氫苯并[b][1,4]戴奧辛-5-基)甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.73 (s, 1H), 11.17 (br, 1H), 8.58-8.55 (m, 2H), 8.04 (s, 1H), 7.82 (d,J = 9.0 Hz, 1H), 7.58 (s, 1H), 7.52 (s, 1H), 7.44 (d,J = 9.0 Hz, 2H), 7.24 (s, 2H), 7.11 (d,J = 8.0 Hz, 2H), 6.90 (s, 1H), 6.78 (s, 2H), 6.40 (s, 1H), 6.04 (d,J = 8.8 Hz, 1H), 5.48 (s, 1H), 4.28-4.20 (m, 5H), 3.56-3.50 (m, 7H), 3.29 (s, 2H), 2.92-2.87 (m, 3H), 2.71 (s, 2H), 2.25 (s, 1H), 1.97 (s, 2H), 1.73-1.49 (m, 6H), 1.38-1.30 (m, 3H), 1.25-1.02 (m, 12H)。MS (ESI, m/e) [M+1]+ 1025.9。 | ||
150 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-(2-(2-異丙基苯基)-4-((4-甲氧基苯基)(甲基)胺基)哌啶-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.70 (s, 1H), 11.45 (s, 1H), 10.35 (s, 1H), 8.56 (s, 2H), 8.03 (s, 1H), 7.76 (s, 2H), 7.50 (s, 3H), 7.30 - 7.21 (m, 5H), 7.08 (s, 1H), 6.87 (s, 2H), 6.66 (s, 1H), 6.38 (s, 1H), 6.17 (s, 1H), 4.82 (s, 1H), 4.26 (s, 1H), 3.82 (s, 1H), 3.69 (s, 3H), 3.39 (s, 1H), 3.28 (s, 4H), 2.99-2.80 (m, 5H), 2.60 (s, 3H), 2.21-1.95 (m, 5H), 1.70-1.49 (m, 5H), 1.40-1.20 (m, 12H), 1.15-1.10 (m, 4H), 0.89 (s, 3H), 0.60 (s, 1H)。MS (ESI, m/e) [M+1]+ 1039.8。 | ||
151 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(4-(3-乙炔基-4-甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.69 (s, 1H), 11.41 (s, 0.6H), 10.69 (s, 0.4H), 8.64-8.48 (m, 2H), 8.03 (s, 1H), 7.90-7.71 (m, 2H), 7.67-6.95 (m, 11H), 6.74-6.57 (s, 1H), 6.37 (s, 1H), 6.20-6.05 (m, 1H), 4.69-4.52 (s, 0.5H), 4.31-4.18 (m, 1.5H), 3.88-3.70 (m, 4H), 3.63-3.48 (m, 1H), 3.46-3.38 (m, 1H), 3.35-3.16 (m, 5H), 3.16-2.80 (m, 7H), 2.80-2.57 (m, 2H), 2.09-1.97 (m, 1H), 1.76-1.49 (m, 6H), 1.48-1.26 (m, 6H), 1.23-0.94 (m, 12H)。MS (ESI, m/e) [M+1]+ 1050.5 | ||
152 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(4-(3-氟-4,5-二甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.69 (s, 1H), 11.34 (s, 0.6H), 10.59 (s, 0.4H), 8.68-8.45 (m, 1H), 8.02 (s, 1H), 7.90-7.64 (m, 2H), 7.61-7.01 (m, 8H), 6.97-6.75 (m, 2H), 6.75-6.55 (m, 1H), 6.37 (s, 1H), 6.14 (s, 1H), 4.25 (s, 1H), 3.79 (s, 3H), 3.73 (s, 3H), 3.67-3.41 (m, 4H), 3.32-3.24 (m, 3H), 3.08-2.80 (m, 6H), 2.78-2.54 (m, 2H), 2.37-1.94 (m, 2H), 1.73-1.48 (m, 6H), 1.46-1.24 (m, 8H), 1.21-0.95 (m, 11H)。MS (ESI, m/e) [M+1]+ 1074 | ||
153 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(4-(4-乙基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.70 (s, 1H), 11.34 (br, 1H), 8.64-8.53 (m, 2H), 8.03 (s, 1H), 7.82-7.74 (m, 1H), 7.54-7.30 (m, 5H), 7.38-7.05 (m, 6H), 6.68-6.62 (m, 1H), 6.37 (s, 1H), 6.19-6.10 (m, 1H), 4.25 (s, 1H), 4.09-3.54 (m, 1H), 3.65-3.43 (m, 3H), 3.32-3.10 (m, 3H), 3.05-2.85 (m, 7H), 2.75-2.55 (m, 3H), 2.30-1.94 (m, 2H), 1.74-1.50 (m, 7H), 1.38-1.10 (m, 16H), 1.08-1.00 (m, 3H)。MS (ESI, m/e) [M+1]+ 1024.0。 | ||
154 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-(2-(2-異丙基苯基)-4-((5-甲氧基吡𠯤-2-基)甲基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.69 (s, 1H), 11.40 (br, 1H), 8.64-8.54 (m, 2H), 8.31-8.19 (m, 2H), 8.02 (s, 1H), 7.83-7.76 (m, 1H), 7.54-7.43 (m, 3H), 7.40-7.35 (m, 1H), 7.30-7.04 (m, 4H), 6.68-6.62 (m, 1H), 6.39-6.35 (m, 1H), 6.17-6.10 (m, 1H), 4.25 (s, 1H), 3.89 (s, 3H), 3.85-3.65 (m, 3H), 3.45-3.35 (m, 1H), 3.32-3.25 (m, 2H), 3.08-2.52 (m, 10H), 2.30-1.94 (m, 3H), 1.74-1.50 (m, 7H), 1.38-1.10 (m, 14H), 1.08-1.00 (m, 3H)。MS (ESI, m/e) [M+1]+ 1027.8 | ||
156 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(4-(4-環丙基-3-甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.50 (s, 1H), 8.28-8.33 (m, 2H), 7.87 (s, 1H), 7.52-7.57 (m, 2H), 7.38 (s, 1H), 7.10-7.19 (m, 3H), 7.06-7.10 (m, 1H), 6.65 (s, 1H), 6.71-6.73 (m, 3H), 6.58 (d,J = 8.0 Hz, 2H), 4.26 (s, 1H), 3.77 (s, 3H), 3.44-3.51 (m, 3H), 3.20 (s, 2H), 2.84-2.90 (m, 7H), 2.15-2.19 (m, 2H), 1.99-2.03 (m, 2H), 1.61-1.69 (m, 4H), 1.52-1.55 (m, 2H), 1.18-1.33 (m, 16H), 1.05-1.12 (m, 8H)。0.82-0.84 (m, 2H), 0.54 (s, 2H)。MS (ESI, m/e) [M+1]+ 1065.9 | ||
157 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-(2-(4-異丙基吡啶-3-基)-4-(4-甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.67 (s, 1H), 11.34-11.07 (m, 1H), 8.53 (s, 2H), 8.32 (s, 1H), 8.02 (s, 1H), 7.77 (d,J = 8.2 Hz, 1H), 7.50-7.48 (m, 3H), 7.23-7.22 (m, 3H), 7.05 (d,J = 9.4 Hz, 1H), 6.89-6.85 (m, 2H), 6.64 (d,J = 8.6 Hz, 1H), 6.37 (s, 1H), 6.14 (s, 1H), 4.24 (s, 1H), 3.71 (s, 3H), 3.52 (s, 3H), 3.28 (s, 2H), 3.05-2.91 (m, 7H), 2.14 (s, 1H), 1.75-1.51 (m, 7H), 1.35-1.21 (m, 10H), 1.21-1.03 (m, 13H)。MS (ESI, m/e) [M+1]+ 1026.8。 | ||
158 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(4-(3,4-二甲氧基-5-甲基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.68 (s, 1H), 11.24 (s, 1H), 8.55 (s, 2H), 8.02 (s, 1H), 7.78 (d,J = 8.4 Hz, 1H), 7.50-7.46 (m, 4H), 7.40-7.00 (m, 5H), 6.90-6.83 (m, 1H), 6.76-6.57 (m, 2H), 6.37 (s, 1H), 6.14 (s, 1H), 4.24 (s, 1H), 3.80-3.65 (m, 10H), 3.28 (s, 3H), 3.05-2.85 (m, 8H), 2.71 (s, 1H), 2.14 (s, 3H), 1.65-1.55 (m, 8H), 1.37-1.02 (m, 24H)。MS (ESI, m/e) [M+1]+ 1070.1。 | ||
159 | 4-(2-(4-(3-(二氟甲氧基)-4-甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.67-10.87 (m, 2H), 8.67-8.31 (m, 1H), 8.08-7.99 (m, 1H), 7.81-7.70 (m, 1H), 7.53-7.37 (m, 3H), 7.36-6.95 (m, 9H), 6.74-6.60 (m, 1H), 6.21 (s, 1H), 4.24 (s, 1H), 3.93-3.50 (m, 5H), 3.31-3.20 (m, 5H), 3.10-2.88 (m, 7H), 2.78-2.60 (m, 2H), 2.36-2.18 (m, 1H), 2.10-1.92 (m, 1H), 1.75-1.44 (m, 7H), 1.39-1.25 (m, 6H), 1.21-1.15 (m, 3H), 1.15-1.02 (m, 9H)。MS (ESI, m/e) [M+1]+ 1109.8。 | ||
160 | 4-(2-(4-(4-環丙基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, CDCl3 ) δ ppm: 12.98-12.02 (m, 0.5H), 10.43-9.67 (m, 0.5H), 8.90-8.81 (m, 0.5 H), 8.74-8.56 (m, 0.5H), 8.56-8.42 (m, 1H), 8.27-8.05 (m, 2H), 7.98-7.85 (m, 1H), 7.72-7.62 (m, 1H), 7.55-7.30 (m, 1H), 7.23-7.06 (m, 5H), 7.04-6.95 (m, 2H), 6.93-6.83 (m, 1H), 6.57-6.45 (m, 1H), 5.90 (s, 1H), 3.72-3.38 (m, 3H), 3.33-3.10 (m, 4H), 3.05-2.60 (m, 9H), 2.08-1.93 (m, 1H), 1.93-1.81 (m, 3H), 1.81-1.70 (m, 5H), 1.56-1.44 (m, 6H), 1.44-1.30 (m, 7H), 1.17-1.01 (m, 6H), 0.97-0.90 (m, 2H), 0.68-0.60 (m, 2H)。MS (ESI, m/e) [M+1]+ 1053.8。 | ||
161 | 4-(2-(4-(4-環丙基-3-甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, CDCl3 ) δ ppm: 12.69-12.21 (m, 0.2H), 10.06-9.94(m, 0.8H), 8.87-8.80 (m, 0.5H), 8.70-8.57 (m, 0.5H), 8.55-8.45 (m, 1H), 8.27-8.08 (m, 2H), 7.95-7.85 (m, 1H), 7.72-7.61 (m, 1H), 7.48-7.27 (m, 3H), 7.25-7.06 (m, 2H), 6.94-6.85 (m, 1H), 6.83-6.70 (m, 2H), 6.56-6.46 (m, 1H), 5.96-5.81 (m, 1H), 4.02-3.80 (m, 3H), 3.70-3.33 (m, 4H), 3.31-3.12 (m, 4H), 3.10-2.75 (m, 8H), 2.17-1.96 (m, 3H), 1.92-1.70 (m, 7H), 1.52-1.43 (m, 4H), 1.40-1.29(m, 8H), 1.21-1.03 (m, 8H), 0.66-0.53 (m, 2H)。MS (ESI, m/e) [M+1]+ 1083.8。 | ||
162 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(4-(4-乙炔基-3-甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.66 (s, 1H), 11.33 (br, 1H), 8.58-8.52 (m, 2H), 8.01 (s, 1H), 7.77 (d,J = 9.6 Hz, 1H), 7.52-7.00 (m, 8H), 6.98 (s, 1H), 6.87 (d,J =7.6 Hz, 1H), 6.65 (d,J = 9.6 Hz, 1H), 6.36 (s, 1H), 6.14 (s, 1H), 4.24 (s, 1H), 4.16 (s, 1H), 3.78 (s, 3H), 3.60-3.40 (m, 3H), 3.30-3.23 (m, 3H), 3.00-2.80 (m, 7H), 2.27-2.15 (m, 2H), 2.09-1.95 (m, 1H), 1.73-1.51 (m, 7H), 1.39-1.15 (m, 13H), 1.12-1.02 (m, 7H)。MS (ESI, m/e) [M+1]+ 1050.1。 | ||
163 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-(2-(2-異丙基苯基)-4-(4-甲氧基-3-(三氟甲氧基)苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.68 (s, 1H), 11.34 (br, 1H), 8.58-8.52 (m, 2H), 8.03 (s, 1H), 7.77-7.75 (m, 1H), 7.54-7.03 (m, 11H), 6.66 (d,J = 9.6 Hz, 1H), 6.37 (s, 1H), 6.14 (s, 1H), 4.24 (s, 1H), 3.96 (s, 3H), 3.65-3.40 (m, 2H), 3.30-3.23 (m, 3H), 3.09-2.52 (m, 9H), 2.27-2.15 (m, 1H), 2.09-1.95 (m, 2H), 1.73-1.51 (m, 7H), 1.39-1.15 (m, 13H), 1.12-1.02 (m, 7H)。MS (ESI, m/e) [M+1]+ 1109.8。 | ||
164 | 2-((3-氯-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(6-((R)-4-(3,4-二甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 12.04 (s, 1H), 11.45 (br, 1H), 8.60-8.52 (m, 2H), 8.10 (s, 1H), 7.80 (d,J = 9.6 Hz, 1H), 7.73-7.69(m, 1H), 7.47-7.05 (m, 8H), 6.95-6.85 (m, 2H), 6.09-6.04 (m, 1H), 5.54 (s, 1H), 4.24 (s, 1H), 3.79-3.65 (m, 8H), 3.68-3.36 (m, 6H), 3.32-3.10 (m, 3H), 3.05-2.65 (m, 5H), 2.42-2.28 (m, 1H), 2.06-1.93 (m, 2H), 1.77-1.50 (m, 7H), 1.39-1.10 (m, 13H)。MS (ESI, m/e) [M+1]+ 1063.0。 | ||
165 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-((R)-2-(2-異丙基苯基)-4-(4-甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-(3-𠰌啉代吡咯啶-1-基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.72 (s, 1H), 11.47-11.08 (m, 1H), 8.22 (s, 1H), 8.04 (s, 1H), 7.75 (s, 1H), 7.57-7.43 (m, 3H), 7.40-7.15 (m, 5H), 7.05 (d,J = 8.0 Hz, 1H), 6.95-6.90 (m, 2H), 6.64 (d,J = 8.4 Hz, 1H), 6.40 (s, 1H), 6.11 (s, 1H), 3.73 (s, 3H), 3.59 (s, 4H), 3.21 (s, 5H), 3.10-2.85 (m, 9H), 2.40 (s, 3H), 2.17 (s, 1H), 1.99 (s, 1H), 1.79 (s, 1H), 1.65-1.60 (m, 2H), 1.35-1.10 (m, 12H), 1.09-1.00 (m, 4H)。MS (ESI, m/e) [M+1]+ 1038.9。 | ||
166 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-(2-(2-異丙基苯基)-4-(4-(2-甲氧基乙氧基)苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.69 (s, 1H), 11.51-11.10 (m, 1H), 8.55-8.53 (m, 2H), 8.02 (s, 1H), 7.76 (s, 1H), 7.50 (s, 3H), 7.40-7.20 (m, 6H), 7.08 (s, 1H), 6.91 (s, 2H), 6.65 (d,J = 8.4 Hz, 1H), 6.37 (s, 1H), 6.13 (s, 1H), 4.25 (s, 1H), 4.06 (s, 2H), 3.65-3.62 (m, 3H), 3.29 (s, 6H), 3.05-2.85 (m, 8H), 1.99 (s, 1H), 1.72-1.49 (m, 7H), 1.37-1.00 (m, 24H)。MS (ESI, m/e) [M+1]+ 1070.9。 | ||
167 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-(2-(2-異丙基苯基)-4-(4-(氧雜環丁烷-3-基氧基)苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.68 (s, 1H), 8.55-8.53 (m, 2H), 8.02 (s, 1H), 7.76 (s, 1H), 7.49-7.46 (m, 3H), 7.40-7.10 (m, 6H), 6.75 (s, 2H), 6.64 (d,J = 9.2 Hz, 1H), 6.37 (s, 1H), 6.14 (s, 1H), 5.24 (s, 1H), 4.90 (s, 2H), 4.50 (s, 2H), 4.25 (s, 1H), 3.56 (s, 2H), 3.28 (s, 3H), 3.05 -2.85 (m, 7H), 2.67 (s, 1H), 2.29-2.16 (m, 1H), 1.99 (s, 1H), 1.75-1.50 (m, 7H), 1.35-1.0 (m, 22H)。MS (ESI, m/e) [M+1]+ 1067.9。 | ||
168 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(4-((2,2-二氟苯并[d][1,3]二氧雜環戊烯-5-基)甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.68 (s, 1H), 11.35 (s, 1H), 8.54-8.56 (m, 2H), 8.01-8.02 (m, 1H), 7.77 (d,J = 8.0 Hz, 1H), 7.32-7.55 (m, 7H), 7.05-7.19 (m, 4H), 6.65 (d,J = 8.0 Hz, 1H), 6.37 (s, 1H), 6.14 (s, 1H), 4.25 (s, 1H), 3.51-3.71 (m, 3H), 3.28 (s, 2H), 2.91-2.98 (m, 7H), 2.20-2.24 (m, 1H), 1.97-2.03 (m, 1H), 1.63-1.70 (m, 3H), 1.52-1.56 (m, 2H), 1.01-1.36 (m, 24H)。MS (ESI, m/e) [M+1]+ 1076.0 | ||
169 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(4-(3-(二氟甲氧基)-4-甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.67 (s, 1H), 11.28 (s, 1H), 8.63-850 (m, 2H), 8.06-7.97 (m, 1H), 7.81-7.72 (m, 1H), 7.56-7.43 (m, 3H), 7.43-6.97 (m, 9H), 6.76-6.58 (m, 1H), 6.37 (s, 1H), 6.14 (s, 1H), 4.24 (s, 1H), 3.86-3.75 (m, 4H), 3.69-3.48 (m, 5H), 3.30-3.24 (m, 1H), 3.09-2.81 (m, 6H), 2.74-2.54 (m, 2H), 2.30-2.09 (m, 1H), 1.78-1.47 (m, 7H), 1.38-1.25 (m, 7H), 1.23-1.01 (m, 13H)。MS (ESI, m/e) [M+1]+ 1092.0。 | ||
170 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-(2-(2-異丙基苯基)-4-(4-甲氧基苄基)-1,4-二氮雜環庚烷-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.69 (s, 1H), 11.38 (s, 1H), 8.69-8.40 (m, 2H), 8.12-7.93 (m, 1H), 7.84-7.69 (m, 1H), 7.62-7.24 (m, 6H), 7.25-6.99 (m, 5H), 6.96-6.80 (m, 2H), 6.72-6.61 (m, 1H), 6.38 (s, 1H), 6.16 (s, 1H), 4.25 (s, 1H), 3.73 (s, 3H), 3.33-3.10 (m, 11H), 3.07-2.86 (m, 5H), 2.80-2.58 (m, 2H), 2.15-1.80 (m, 2H), 1.76-1.49 (m, 6H), 1.49-1.25 (m, 7H), 1.18-0.98 (m, 8H), 0.77-0.61 (m, 3H)。MS (ESI, m/e) [M+1]+ 1039.8。 | ||
171 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-(2-(3-異丙基吡啶-4-基)-4-(4-甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, CDCl3 ) δ ppm: 10.10 (s, 1H), 8.88 (s, 1H), 8.65-8.27(m, 3H), 8.27-8.00 (m, 2H), 7.96-7.80 (m, 1H), 7.70 (s, 1H), 7.58-7.28 (m, 3H), 6.94-6.70 (m, 3H), 6.63-6.32 (m, 2H), 5.93 (s, 1H), 3.79 (s, 3H), 3.66-3.36 (m, 2H), 3.35-3.18 (m, 3H), 3.06-2.76 (m, 7H), 1.93-1.80 (m, 3H), 1.80-1.60 (m, 11H), 1.57-1.43 (m, 4H), 1.39-1.32 (m, 4H), 1.23-1.15 (m, 9H)。MS (ESI, m/e) [M+1]+ 1026.8。 | ||
172 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(4-(4-環丙氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.68 (s, 1H), 11.21 (s, 1H), 8.62-8.50 (m, 2H), 8.02 (s, 1H), 7.82-7.71 (m, 1H), 7.59-7.39 (m, 4H), 7.38-6.84 (m, 9H), 6.72-6.50 (m, 1H), 6.37 (s, 1H), 6.14 (s, 1H), 4.75-4.31 (m, 1H), 4.25 (s, 1H), 3.99-3.55 (m, 3H), 3.33-3.22 (m, 5H), 3.07-2.85 (m, 6H), 2.80-2.70 (m, 1H), 1.82-1.45 (m, 7H), 1.41-1.16 (m, 11H), 1.14-0.92 (m, 9H), 0.83-0.70 (m, 2H), 0.65-0.52 (m, 2H)。MS (ESI, m/e) [M+1]+ 1051.9。 | ||
173 | (R)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(6-(4-(3,4-二甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)-N-((3-硝基-4-(((四氫-2H-哌喃-4-基)甲基)胺基)苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.72 (s, 1H), 11.08 (s, 1H), 8.68-8.53 (m, 2H), 8.08-8.00 (m, 1H), 7.83 (d,J = 8.8 Hz, 1H), 7.62-7.04 (m, 9H), 6.91 (s, 2H), 6.40 (s, 1H), 6.04 (d,J = 8.4 Hz, 1H), 5.49 (s, 1H), 4.04-3.80 (m, 4H), 3.78-3.69 (m, 6H), 3.66-3.43 (m, 5H), 3.32-3.20 (m, 4H), 3.18-2.64 (m, 6H), 2.46-2.31 (m, 1H), 2.07-1.82 (m, 3H), 1.70-1.55 (m, 3H), 1.36-0.99 (m, 10H)。MS (ESI, m/e) [M+1]+ 1000.1。 | ||
174 | 2-((3-氯-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-((R)-4-(3,4-二甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.93 (s, 1H), 11.45 (br, 1H), 8.53-8.42 (m, 2H), 8.06 (s,1H), 7.74-7.63 (m, 2H), 7.50 (d,J = 8.4 Hz, 1H), 7.46-6.76 (m, 9H), 6.68 (d,J = 8.4 Hz, 1H), 6.24 (s, 1H), 4.23 (s, 1H), 3.72 (s, 3H), 3.70 (s, 3H), 3.64-3.40 (m, 3H), 3.30-3.23 (m, 3H), 3.06-2.60 (m, 10H), 2.27-2.15 (m, 2H), 2.09-1.95 (m, 1H), 1.74-1.50 (m, 7H), 1.39-1.15 (m, 14H), 1.12-1.02 (m, 3H)。MS (ESI, m/e) [M+1]+ 1091.1。 | ||
175 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(4-(3,4-雙(甲氧基-d3 )苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.68 (s, 1H), 11.34 (br, 1H), 8.59-8.54 (m, 2H), 8.02 (s,1H), 7.79 (d,J = 8.8 Hz, 1H), 7.53-7.06 (m, 8H), 6.95-6.75 (m, 2H), 6.66 (d,J = 8.0 Hz, 1H), 6.37 (s, 1H), 6.13 (s, 1H), 4.23 (s, 1H), 3.96-3.40 (m, 4H), 3.30-3.23 (m, 3H), 3.09-2.52 (m, 9H), 2.44-2.30 (m, 1H), 2.09-1.90 (m, 2H), 1.75-1.51 (m, 7H), 1.39-1.15 (m, 14H), 1.12-1.02 (m, 3H)。MS (ESI, m/e) [M+1]+ 1062.3 | ||
176 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(4-((5,6-二甲氧基吡啶-3-基)甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.68 (s, 1H), 11.47 (br, 1H), 8.60-8.52 (m, 2H), 8.03 (s, 1H), 7.79 (d,J = 8.8 Hz, 1H), 7.65-7.05 (m, 10H), 6.68-6.64 (m, 1H), 6.37 (m, 1H), 6.18-6.12 (m, 1H), 4.23 (s, 1H), 3.82 (s, 3H), 3.77 (s, 3H), 3.66-3.40 (m, 4H), 3.30-3.25 (m, 3H), 3.09-2.60 (m, 10H), 2.27-2.15 (m, 1H), 2.09-1.95 (m, 2H), 1.74-1.50 (m, 7H), 1.39-1.15 (m, 14H), 1.12-1.02 (m, 3H)。MS (ESI, m/e) [M+1]+ 1057.3。 | ||
177 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-(2-(2-異丙基苯基)-4-(1-(4-甲氧基苯基)乙基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.68 (s, 1H), 11.38 (s, 1H), 8.57-8.55 (m, 2H), 8.03-8.02 (m, 1H), 7.78 (d,J = 8.0 Hz, 1H), 7.50-7.45 (m, 4H), 7.36-7.16 (m, 5H),7.09-7.07 (m, 1H), 6.99-6.90 (m, 2H), 6.65 (d,J = 8.0 Hz, 1H), 6.37 (s, 1H), 6.13 (s, 1H), 4.25 (s, 1H), 3.77-3.74 (m, 4H), 3.34-3.28 (m, 2H), 2.97-2.91 (m, 7H), 2.04-1.98 (m, 1H), 1.66-1.53 (m, 9H), 1.33-1.10 (m, 25H)。MS (ESI, m/e) [M+1]+ 1040.2。 | ||
178 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(4-(3-環丙氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.68 (s, 1H), 11.29 (s, 1H), 8.55 (s, 2H), 8.02 (s, 1H), 7.78 (d,J = 8.4 Hz, 1H), 7.53-7.43 (m, 3H), 7.41-6.87 (m, 8H), 6.65 (d,J = 8.6 Hz, 1H), 6.37 (s, 1H), 6.14 (s, 1H), 4.23 (s, 1H), 3.75-3.70 (m, 4H), 3.28 (s, 2H), 3.10-2.89 (m, 7H), 2.67 (s, 2H), 2.07 (s, 1H), 1.75-1.50 (m, 7H), 1.40-0.97 (m, 20H), 0.76 (s, 2H), 0.60 (s, 2H)。MS (ESI, m/e) [M+1]+ 1052.1。 | ||
179 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(4-(3,4-二甲氧基-5-(三氟甲基)苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.68 (s, 1H), 11.35 (s, 1H), 8.55 (s, 2H), 8.03 (s, 1H), 7.78 (d,J = 8.8 Hz, 1H), 7.57-7.01 (m, 9H), 6.65 (d,J = 8.4 Hz, 1H), 6.37 (s, 1H), 6.15 (s, 1H), 4.23 (s, 1H), 3.90-3.70 (m, 9H), 3.42 (s, 1H), 3.28 (s, 2H), 3.10-2.85 (m, 7H), 2.70 (s, 2H), 2.05 (s, 1H), 1.75-1.51 (m, 6H), 1.48-0.96 (m, 21H)。MS (ESI, m/e) [M+1]+ 1125.1。 | ||
180 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-(2-(2-異丙基苯基)-4-(4-(甲氧基甲基)苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm:11.68 (s, 1H), 11.38-11.06 (m, 1H), 8.55 (s, 2H), 8.02 (s, 1H), 7.78 (d,J = 9.0 Hz, 1H), 7.50-7.10 (m, 11H), 6.65 (d,J = 8.4 Hz, 1H), 6.37 (s, 1H), 6.14 (s, 1H), 4.37 (s, 2H), 4.23 (s, 1H), 3.80-3.67 (m, 2H), 3.29-3.25 (m, 6H), 3.10-2.85 (m, 7H), 2.71-2.70 (m, 2H), 2.03 (s, 1H), 1.75-1.50 (m, 6H), 1.40-0.97 (m, 22H)。MS (ESI, m/e) [M+1]+ 1040.1。 | ||
181 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-(4-((1-異丙基-3-甲氧基-1H-吡唑-4-基)甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.68 (s, 1H), 11.39 (br, 1H), 8.62-8.54 (m, 2H), 8.02 (s, 1H), 7.80 (d,J = 8.8 Hz, 1H), 7.54-7.15 (m, 8H), 7.09 (d,J = 8.8 Hz, 1H), 6.66 (d,J = 7.6 Hz, 1H), 6.38 (s, 1H), 6.18-6.10 (m, 1H), 4.49-4.35 (m, 1H), 4.24 (s, 1H), 3.98-3.75 (m, 5H), 3.47-3.40 (m, 1H), 3.30-3.23 (m, 3H), 3.06-2.60 (m, 10H), 2.37-2.30 (m, 1H), 2.09-1.95 (m, 2H), 1.74-1.50 (m, 7H), 1.39-1.15 (m, 20H), 1.12-1.02 (m, 3H)。MS (ESI, m/e) [M+1]+ 1058.1。 | ||
182 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(4-((苯并[d][1,3]二氧雜環戊烯-5-基-2,2-d2)甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.68 (s, 1H), 11.39 (br, 1H), 8.63-8.54 (m, 2H), 8.02 (s, 1H), 7.79 (d,J = 8.8 Hz, 1H), 7.54-7.12 (m, 8H), 7.09 (d,J = 8.8 Hz, 1H), 6.97-6.75 (m, 2H), 6.66 (d,J = 8.0 Hz, 1H), 6.37 (s, 1H), 6.18-6.11 (m, 1H), 4.24 (s, 1H), 3.96-3.40 (m, 3H), 3.30-3.23 (m, 3H), 3.09-2.54 (m, 10H), 2.44-2.30 (m, 1H), 2.09-1.94 (m, 2H), 1.75-1.51 (m, 7H), 1.39-1.15 (m, 14H), 1.12-1.02 (m, 3H)。MS (ESI, m/e) [M+1]+ 1042.1。 | ||
183 | (R)-2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(6-(2-(2-異丙基苯基)-4-(4-甲氧基苄基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)-N-((3-硝基-4-(((四氫-2H-哌喃-4-基)甲基)胺基)苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.53 (s, 1H), 10.91 (br, 1H), 8.64-8.52 (m, 2H), 8.07 (s, 1H), 7.83(d,J = 8.0 Hz, 1H), 7.57-7.08 (m, 10H), 6.98-6.80 (m, 2H), 6.10-6.04 (m, 1H), 5.53 (s, 1H), 4.20-3.81 (m, 3H), 3.74 (s, 3H), 3.68-3.39 (m, 5H), 3.32-3.10 (m, 6H), 3.09-2.55 (m, 6H), 2.44-2.30 (m, 1H), 2.24-1.82 (m, 3H), 1.63 (d,J = 11.6 Hz, 2H), 1.35-1.15 (m, 7H), 1.08-1.00 (m, 2H)。MS (ESI, m/e) [M+1]+ 988.0。 | ||
184 | 2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(6-((R)-4-(4-氟-3-甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.54 (s, 1H), 11.45-11.25 (m, 1H), 8.56-8.54 (m, 2H), 8.07 (s, 1H), 7.81 (d,J = 8.2 Hz, 1H), 7.51 (s, 2H), 7.42 (s, 2H), 7.30-7.10 (m, 6H), 6.87 (s, 1H), 6.07 (s, 1H), 5.53 (s, 1H), 4.23 (s, 1H), 3.82 (s, 3H), 3.70-3.45 (m, 5H), 3.29-3.26 (m, 2H), 2.95 (s, 3H), 2.73 (s, 1H), 1.99 (s, 3H), 1.78-1.48 (m, 7H), 1.40-1.15 (m, 12H), 1.14-1.00 (m, 8H)。MS (ESI, m/e) [M+1]+ 1034.1。 | ||
185 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-((R)-2-(2-異丙基苯基)-4-((6-甲氧基吡啶-3-基)甲基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.70 (s, 1H), 11.41 (s, 1H), 8.67-8.45 (m, 2H), 8.19-7.95 (m, 2H), 7.89-7.42 (m, 6H), 7.42-7.00 (m, 5H), 6.87-6.77 (m, 1H), 6.75-6.60 (m, 1H), 6.38 (s, 1H), 6.15 (s, 1H), 4.26 (s, 1H), 3.82 (s, 3H), 3.77-3.54 (m, 2H), 3.35-3.21 (m, 7H), 3.16-2.56 (m, 10H), 1.78-1.49 (m, 6H), 1.43-1.23 (m, 7H), 1.20-0.97 (m, 10H)。MS (ESI, m/e) [M+1]+ 1026.9 | ||
186 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(4-(3-環丙氧基-4-甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.68 (s, 1H), 11.21 (s, 1H), 8.69-8.40 (m, 2H), 8.07-7.98 (m, 1H), 7.85-7.74 (m, 1H), 7.60-7.01 (m, 10H), 7.01-6.77 (m, 2H), 6.75-6.60 (m, 1H), 6.37 (s, 1H), 6.14 (s, 1H), 4.25 (s, 1H), 4.00-3.82 (m, 1H), 3.82-3.49 (m, 6H), 3.31-3.22 (m, 4H), 3.15-2.61 (m, 10H), 1.80-1.48 (m, 7H), 1.42-1.28 (m, 5H), 1.22-1.15 (m, 3H), 1.15-1.00 (m, 10H), 0.79-0.70 (m, 2H), 0.67-0.55 (m, 2H)。MS (ESI, m/e) [M+1]+ 1082.2 | ||
187 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-(2-(2-異丙基苯基)-4-(3-甲氧基-4-(甲基磺醯基)苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.69 (s, 1H), 11.42 (s, 1H), 8.70-8.47 (m, 2H), 8.09-8.00 (m, 1H), 7.98-7.71 (m, 3H), 7.65-7.02 (m, 10H), 6.73-6.60 (m, 1H), 6.43-6.32 (m, 1H), 6.15 (s, 1H), 4.25 (s, 1H), 3.94 (s, 3H), 3.85-3.60 (m, 3H), 3.33-3.24 (m, 4H), 3.24-3.14 (m, 4H), 3.07-2.80 (m, 6H), 2.80-2.60 (m, 2H), 2.18-1.95 (m, 1H), 1.79-1.43 (m, 7H), 1.43-1.24 (m, 7H), 1.22-0.95 (m, 10H)。MS (ESI, m/e) [M+1]+ 1104.4 | ||
188 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(4-(4-乙醯基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.69 (s, 1H), 11.31 (s, 1H), 8.66-8.41 (m, 2H), 8.07-7.98 (m, 1H), 7.97-7.65 (m, 4H), 7.55-7.41 (m, 5H), 7.41-7.00 (m, 5H), 6.75-6.60 (m, 1H), 6.42-6.33 (m, 1H), 6.15 (s, 1H), 4.26 (s, 1H), 3.82-3.65 (m, 2H), 3.35-3.22 (m, 9H), 3.07-2.83 (m, 6H), 2.79-2.61 (m, 2H), 2.55 (s, 3H), 1.76-1.50 (m, 6H), 1.42-1.23 (m, 7H), 1.19-0.97 (m, 10H)。MS (ESI, m/e) [M+1]+ 1038.3 | ||
189 | (R)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(4-(3,4-二甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((3-硝基-4-(((四氫-2H-哌喃-4-基)甲基)胺基)苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.66 (s, 1H), 8.68-8.41 (m, 2H), 8.01 (s, 1H), 7.76 (d,J = 8.4 Hz, 1H), 7.62-6.73 (m, 11H), 6.64 (d,J = 7.6 Hz, 1H), 6.36 (s, 1H), 6.15 (s, 1H), 3.95-3.52 (m, 11H), 3.47-3.11 (m, 7H), 3.08-2.77 (m, 7H), 2.74-2.60 (m, 1H), 2.44-2.14 (m, 2H), 1.97-1.80 (m, 1H), 1.70-1.51 (m, 3H), 1.08-0.94 (m, 14H)。MS (ESI, m/e) [M+1]+ 1028.2 | ||
190 | 2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-((R)-4-(4-氟-3-甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.50 (s, 1H), 8.60-8.45 (m, 2H), 8.06 (s, 1H), 7.80 (d,J = 8.8 Hz, 1H), 7.53-7.01 (m, 10H), 6.89 (s, 1H), 6.67 (d,J = 8.4 Hz, 1H), 6.21 (s, 1H), 4.24 (s, 1H), 3.88-3.34 (m, 7H), 3.30-2.58 (m, 12H), 3.40-2.25 (m, 1H), 2.15-1.96 (m, 1H), 1.73-1.90 (m, 6H), 1.39-1.01 (m, 19H)。MS (ESI, m/e) [M+1]+ 1062.1 | ||
191 | (R)-4-(2-(4-(3,4-二甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((3-硝基-4-(((四氫-2H-哌喃-4-基)甲基)胺基)苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.46 (s, 1H), 8.63-8.40 (m, 2H), 8.04 (s, 1H), 7.73 (d,J = 8.8 Hz, 1H), 7.55-6.75 (m, 11H), 6.66 (d,J = 8.4 Hz, 1H), 6.22 (s, 1H), 3.91-3.80 (m, 2H), 3.77-3.49 (m, 9H), 3.32-3.20 (m, 6H), 3.08-2.82 (m, 7H), 2.72-2.59 (m, 1H), 2.46-2.12 (m, 2H), 1.95-1.82 (m, 1H), 1.78-1.53 (m, 4H), 1.41-0.99 (m, 14H)。MS (ESI, m/e) [M+1]+ 1046.1 | ||
192 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-(2-(2-異丙基苯基)-4-((1-甲基-1H-1,2,4-三唑-3-基)甲基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.68 (s, 1H), 11.40 (s, 1H), 8.57-8.55 (m, 2H), 8.03-8.02 (m, 1H), 7.79-7.77 (m, 2H), 7.50-7.06 (m, 8H), 6.65 (d,J = 8.0 Hz, 1H), 6.37 (s, 1H), 6.14 (s, 1H), 4.25 (s, 1H), 3.85 (s, 3H), 3.76-3.67 (m, 2H), 3.29-3.28 (m, 2H), 2.97-2.91 (m, 6H), 2.18-1.97 (m, 2H), 1.70-1.53 (m, 7H), 1.33-1.05 (m, 24H)。MS (ESI, m/e) [M+1]+ 1001.1 | ||
193 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(4-((3,4-二甲氧基苯基)甲基-d2 )-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.68 (s, 1H), 11.23 (s, 1H), 8.57-8.55 (m, 2H), 8.02 (s, 1H), 7.78 (d,J = 8.4 Hz, 1H), 7.57-7.01 (m, 8H), 6.95-6.93 (m, 2H), 6.65 (d,J = 8.4 Hz, 1H), 6.37 (s, 1H), 6.14 (s, 1H), 4.24 (s, 1H), 3.78-3.74 (m, 6H), 3.28 (s, 2H), 3.19-3.10 (m, 1H), 3.05-2.85 (m, 7H), 2.70 (s, 1H), 1.71-1.45 (m, 7H), 1.40-0.98 (m, 20H)。MS (ESI, m/e) [M+1]+ 1058.1。 | ||
194 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(4-((5,6-二甲氧基吡啶-2-基)甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.69 (s, 1H), 11.45 (br, 1H), 8.63-8.54 (m, 2H), 8.02 (s, 1H), 7.82 (d,J = 9.2 Hz, 1H), 7.57-7.40 (m, 3H), 7.39-6.92 (m, 6H), 6.69-6.64 (m, 1H), 6.37 (s, 1H), 6.18-6.10 (m, 1H), 4.24 (s, 1H), 3.88-3.56 (m, 7H), 3.45-3.36 (m, 1H), 3.32-3.12 (m, 4H), 3.10-2.55 (m, 9H), 2.45-2.30 (m, 1H), 2.09-1.94 (m, 1H), 1.74-1.50 (m, 6H), 1.42-1.15 (m, 13H), 1.14-1.05 (m, 9H)。MS (ESI, m/e) [M+1]+ 1057.1。 | ||
195 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-(2-(2-異丙基苯基)-4-(4-(2,2,2-三氟乙氧基)苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.69 (s, 1H), 11.27 (br, 1H), 8.63-8.54 (m, 2H), 8.03 (s, 1H), 7.79 (d,J = 8.0 Hz, 1H), 7.57-6.96 (m,12H), 6.69-6.62 (m, 1H), 6.37 (s, 1H), 6.18-6.10 (m, 1H), 4.82-4.54 (m, 2H), 4.24 (s, 1H), 3.88-3.46 (m, 3H), 3.32-3.12 (m, 4H), 3.10-2.55 (m, 9H), 2.45-2.30 (m, 1H), 2.09-1.94 (m, 1H), 1.74-1.50 (m, 6H), 1.42-1.15 (m, 14H), 1.14-1.05 (m, 5H)。MS (ESI, m/e) [M+1]+ 1094.1。 | ||
196 | 4-(2-(4-(4-(1H-吡唑-1-基)苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.66 (s, 1H), 11.29 (br, 1H), 8.60-8.52 (m, 1H), 8.49-8.45 (m, 1H), 8.01 (s, 1H), 7.83-7.70 (m, 4H), 7.54-7.35 (m, 6H), 7.25-7.00 (m, 4H), 6.67-6.60 (m, 1H), 6.52 (s, 1H), 6.36 (s, 1H), 6.14 (s, 1H), 4.23 (s, 1H), 3.68-3.40 (m, 4H), 3.32-3.20 (m, 3H), 3.10-2.80 (m, 8H), 2.65-2.55 (m, 1H), 2.30-2.15 (m, 1H), 2.05-1.94 (m, 1H), 1.74-1.50 (m, 7H), 1.39-1.17 (m, 14H), 1.14-1.05 (m, 3H)。MS (ESI, m/e) [M+1]+ 1063.0。 | ||
197 | 4-(6-((R)-4-(3,4-雙(甲氧基-d3)苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)-2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.55 (s, 1H), 11.32 (br, 1H), 8.61-8.52 (m, 2H), 8.08 (s, 1H), 7.82 (d,J = 8.8 Hz, 1H), 7.57-7.08 (m, 8H), 6.98-6.75 (m, 2H), 6.18-6.02 (m, 1H), 5.53 (s, 1H), 4.24 (s, 1H), 4.20-3.36 (m, 7H), 3.32-3.10 (m, 3H), 3.10-2.55 (m, 6H), 2.45-2.30 (m, 1H), 2.05-1.92 (m, 2H), 1.74-1.50 (m, 6H), 1.39-1.15 (m, 10H), 1.14-1.05 (m, 5H)。MS (ESI, m/e) [M+1]+ 1052.3。 | ||
198 | 4-(2-((R)-4-(3,4-雙(甲氧基-d3)苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.48 (s, 1H), 11.42 (br, 1H), 8.59-8.45 (m, 2H), 8.06 (s, 1H), 7.79 (d,J = 8.8 Hz, 1H), 7.50- 7.10 (m, 7H), 7.09-6.64 (m, 4H), 6.26-6.17 (m, 1H), 4.24 (s, 1H), 4.13-3.36 (m, 4H), 3.32-3.12 (m, 3H), 3.10-2.55 (m, 9H), 2.45-2.30 (m, 1H), 2.09-1.94 (m, 1H), 1.74-1.50 (m, 6H), 1.41-1.15 (m, 11H), 1.14-1.00 (m, 8H)。MS (ESI, m/e) [M+1]+ 1080.2。 | ||
199 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(4-(4-胺基甲醯基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.64 (s, 1H), 8.53 (s, 2H), 8.02 (s, 1H), 7.93-7.71 (m, 4H), 7.54-7.00 (m, 11H), 6.64 (d,J = 8.8 Hz, 1H), 6.37 (s, 1H), 6.14 (s, 1H), 4.21 (s, 1H), 3.69-3.46 (m, 3H), 3.30-3.18 (m, 2H), 3.10-2.77 (m, 8H), 2.27-1.99 (m, 2H), 1.76-1.49 (m, 7H), 1.42-0.96 (m, 21H)。MS (ESI, m/e) [M+1]+ 1039.0 | ||
200 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-(2-(2-異丙基苯基)-4-((4-甲基-3,4-二氫-2H-苯并[b][1,4]㗁𠯤-5-基)甲基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.69 (s, 1H), 11.45-10.97 (m, 1H), 8.63-8.52 (m, 2H), 8.05-8.00 (m, 1H), 7.97-7.85 (m, 1H), 7.85-7.72 (m, 1H), 7.57-6.61 (m, 12H), 6.43-6.30 (m, 1H), 6.28-6.05 (m, 1H), 4.70-4.50 (m, 1H), 4.24 (s, 1H), 4.20-4.05 (m, 2H), 3.85-3.70 (m, 1H), 3.70-3.59 (m, 1H), 3.50-3.40 (m, 1H), 3.32-3.24 (m, 5H), 3.24-2.59 (m, 16H), 2.19-2.00 (m, 1H), 1.80-1.61 (m, 7H), 1.61-12.09 (m, 5H), 1.20-0.93 (m, 10H)。MS (ESI, m/e) [M+1]+ 1066.8 | ||
201 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(4-((2,2-二甲基苯并[d][1,3]二氧雜環戊烯-4-基)甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.68 (s, 1H), 11.48-11.24 (m, 1H), 10.49-10.07 (m, 1H), 8.55 (s, 2H), 8.02 (s, 1H), 7.75-7.73 (m, 1H), 7.48-7.42 (m, 4H), 7.20-7.15 (m, 3H), 6.76 (s, 3H), 6.66 (s, 1H), 6.37 (s, 1H), 6.15-6.13 (m, 1H), 4.62 (s, 1H), 4.24 (s, 1H), 3.76 (s, 1H), 3.60 (s, 1H), 3.41 (s, 1H), 3.28 (s, 2H), 3.05-2.85 (m, 8H), 2.67 (s, 1H), 1.99 (s, 2H), 1.70-1.45 (m, 12H), 1.37-1.23 (m, 10H), 1.17 (s, 2H), 1.13-1.10 (m, 8H)。MS (ESI, m/e) [M+1]+ 1068.1。 | ||
202 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-(2-(2-異丙基苯基)-4-(喹㗁啉-5-基甲基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.68 (s, 1H), 11.54-11.27 (m, 1H), 10.53-10.30 (m, 1H), 8.97 (s, 2H), 8.58-8.54 (m, 2H), 8.03 (s, 2H), 7.97-7.71 (m, 3H), 7.53-7.42 (m, 3H), 7.36 (s, 1H), 7.23 (s, 2H), 7.09-7.06 (m, 1H), 6.65 (d,J = 8.8 Hz, 1H), 6.37 (s, 1H), 6.14 (s, 1H), 4.33 (s, 1H), 4.24 (s, 1H), 3.77 (s, 1H), 3.41 (s, 1H), 3.28 (s, 2H), 3.17-3.07 (m, 1H), 3.05-2.85 (m, 8H), 2.01 (s, 1H), 1.72-1.49 (m, 6H), 1.40-1.04 (m, 21H)。MS (ESI, m/e) [M+1]+ 1048.1。 | ||
203 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-(2-(2-異丙基苯基)-4-((8-甲氧基-2,3-二氫苯并[b][1,4]戴奧辛-5-基)甲基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.70 (s, 1H), 11.51-10.89 (m, 1H), 8.62-8.43 (m, 2H), 8.03 (s, 1H), 7.94-7.71 (m, 1H), 7.61-6.92 (m, 9H), 6.81-6.49 (m, 3H), 6.37 (s, 1H), 6.24-6.07 (m, 1H), 4.31-3.88 (m, 7H), 3.82-3.66 (m, 3H), 3.62-3.36 (m, 2H), 3.32-3.22 (m, 3H), 3.20-2.62 (m, 10H), 2.15-1.96 (m, 1H), 1.77-1.42 (m, 7H), 1.40-1.27 (m, 4H), 1.23-0.96 (m, 13H)。MS (ESI, m/e) [M+1]+ 1084.1 | ||
204 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(4-(4-(二甲基磷醯基)苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.62 (s, 1H), 8.55-8.43 (m, 2H), 7.96 (s, 1H), 7.78-7.57 (m, 3H), 7.48-7.29 (m, 6H), 7.23-6.93 (m, 4H), 6.59 (d,J = 8.8 Hz, 1H), 6.32 (s, 1H), 6.09 (s, 1H), 4.19 (s, 1H), 3.60-3.40 (m, 3H), 3.25-2.15 (m, 3H), 2.98-2.72 (m, 7H), 2.24-1.94 (m, 2H), 1.72-1.44 (m, 14H), 1.34-0.91 (m, 20H)。MS (ESI, m/e) [M+1]+ 1073.0 | ||
205 | 4-(6-((R)-4-((5,6-二甲氧基吡啶-3-基)甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)-2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.55 (s, 1H), 11.45 (br, 1H), 8.60-8.54 (m, 2H), 8.08 (s, 1H), 7.82 (d,J = 8.4 Hz, 1H), 7.70-7.08 (m, 13H), 6.09-6.04 (m, 1H), 5.53 (s, 1H), 4.24 (s, 1H), 3.83 (s, 1H), 3.78 (s, 1H), 3.70-3.36 (m, 6H), 3.32-3.10 (m, 3H), 3.10-2.55 (m, 6H), 2.40-2.25 (m, 1H), 2.05-1.92 (m, 2H), 1.74-1.50 (m, 6H), 1.39-1.15 (m, 9H), 1.14-1.05 (m, 5H)。MS (ESI, m/e) [M+1]+ 1047.1。 | ||
206 | (R)-2-((3-氯-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(6-(2-(2-異丙基苯基)-4-(4-甲氧基苄基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)-N-((3-硝基-4-(((四氫-2H-哌喃-4-基)甲基)胺基)苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 12.06 (s, 1H), 11.02 (br, 1H), 8.64-8.52 (m, 2H), 8.01 (s, 1H), 7.81 (d,J = 8.4 Hz, 1H), 7.47-7.08 (m, 9H), 6.95-6.85 (m, 2H), 6.09-6.04 (m, 1H), 5.54 (s, 1H), 4.30-3.82 (m, 3H), 3.75 (s, 3H), 3.66-3.45 (m, 4H), 3.32-3.10 (m, 6H), 3.05-2.62 (m, 5H), 2.48-2.25 (m, 1H), 2.03-1.83 (m, 3H), 1.63 (d,J = 12.4 Hz, 1H), 1.34-1.15 (m, 6H), 1.13-0.95 (m, 4H)。MS (ESI, m/e) [M+1]+ 1003.8。 | ||
207 | 2-((3-氯-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(6-((R)-2-(2-異丙基苯基)-4-(4-甲氧基苄基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 12.06 (s, 1H), 11.38 (br, 1H), 8.59-8.53 (m, 2H), 8.10 (s, 1H), 7.81 (d,J = 8.0 Hz, 1H), 7.72 (s, 1H), 7.47-7.05 (m, 9H), 6.95-6.85 (m, 2H), 6.14-6.04 (m, 1H), 5.54 (s, 1H), 4.25 (s, 1H), 4.18-3.85 (m, 2H), 3.75 (s, 3H), 3.68-3.45 (m, 5H), 3.32-3.10 (m, 3H), 3.05-2.62 (m, 6H), 2.48-2.30 (m, 1H), 2.03-1.93 (m, 2H), 1.74-1.51 (m, 6H), 1.49-1.15 (m, 8H), 1.10-1.00 (m, 4H)。MS (ESI, m/e) [M+1]+ 1032.9。 | ||
208 | 4-(7-(3-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)胺基甲醯基)苯基)-7-氮雜螺[3.5]壬烷-2-基)-3-(2-異丙基苯基)-N-(4-甲氧基苄基)哌𠯤-1-甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.69 (s, 1H), 11.41 (s, 1H), 8.58-8.55 (m, 2H), 8.03 (s, 1H), 7.80-7.78 (m, 1H), 7.52-7.07 (m, 11H), 6.85-6.83 (m, 2H), 6.65 (d,J = 8.0 Hz, 1H), 6.38 (s, 1H), 6.15-6.13 (m, 1H), 4.43 (s, 1H), 4.17-4.15 (m, 2H), 4.01-3.99 (m, 1H), 3.71 (s, 4H), 3.28-3.24 (m, 2H), 2.98-2.87 (m, 6H), 2.01-1.97 (m, 1H), 1.69-1.53 (m, 7H), 1.36-1.10 (m, 23H)。MS (ESI, m/e) [M+1]+ 1069.1。 | ||
209 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-(4-((1-異丙基-1H-吡唑-4-基)甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.61 (s, 1H), 8.47-8.45 (m, 2H), 7.97-7.95 (m, 1H), 7.69 (d,J = 8.0 Hz, 1H), 7.63 (s, 1H), 7.51-7.39 (m, 4H), 7.30 (s, 1H),7.22-7.11 (m, 3H), 6.94 (d,J = 8.0 Hz, 1H), 6.92 (d,J = 8.0 Hz, 1H), 6.33 (s, 1H), 6.16 (s, 1H), 4.45-4.38 (m, 1H), 4.24 (s, 1H), 3.51-3.45 (m, 2H), 3.26-3.24 (m, 2H), 2.94-2.88 (m, 6H), 2.63-2.61 (m, 1H), 2.20-2.18 (m, 1H), 2.01-1.99 (m, 1H), 1.69-1.52 (m, 7H), 1.38-1.05 (m, 29H)。MS (ESI, m/e) [M+1]+ 1028.2 | ||
210 | 4-(2-((R)-4-(3,4-二甲氧基-5-甲基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.50 (s, 1H), 8.60-8.46 (m, 2H), 8.05 (s, 1H), 7.88-7.70 (m, 1H), 7.52-6.60 (m, 11 H), 6.20 (s, 1H), 4.25 (s, 1H), 4.06-3.37 (m, 9H), 3.31-3.23 (m, 3H), 3.12-2.82 (m, 7H), 2.79-2.53 (m, 2H), 2.44-2.26 (m, 1H), 2.19-1.96 (m, 4H), 1.75-1.50 (m, 6H), 1.40-0.96 (m, 20H)。MS (ESI, m/e) [M+1]+ 1089.0 | ||
211 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-(三氟甲基)環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-((R)-2-(2-異丙基苯基)-4-(4-甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.68 (s, 1H), 11.48-11.21 (m, 1H), 8.63 (s, 1H), 8.55 (s, 1H), 8.02 (s, 1H), 7.76 (s, 1H), 7.54-7.44 (m, 3H), 7.36 (s, 2H), 7.23 (s, 2H), 7.09 (s, 2H), 6.93 (s, 2H), 6.65 (s, 1H), 6.37 (s, 1H), 6.13 (s, 1H), 5.66 (s, 1H), 3.74 (s, 4H), 3.56 (s, 1H), 3.39 (s, 1H), 3.29 (s, 1H), 3.05-2.85 (m, 8H), 2.58 (s, 1H), 2.02 (s, 1H), 1.80-1.55 (m, 7H), 1.46 (s, 2H), 1.40-1.15 (m, 11H), 1.09 (s, 4H)。MS (ESI, m/e) [M+1]+ 1080.1。 | ||
212 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(4-(3-乙醯基-4-甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.68 (s, 1H), 11.49-11.22 (m, 1H), 8.55 (s, 2H), 8.02 (s, 1H), 7.78 (d,J = 8.6 Hz, 2H), 7.67-7.31 (m, 6H), 7.25-7.05 (m, 4H), 6.65 (d,J = 9.0 Hz, 1H), 6.37 (s, 1H), 6.13 (s, 1H), 4.24 (s, 1H), 3.87 (s, 3H), 3.82-3.70 (m, 1H), 3.60 (s, 1H), 3.39 (s, 1H), 3.28 (s, 2H), 3.05-2.85 (m, 7H), 2.78-2.70 (m, 1H), 2.68-2.60 (m, 1H), 2.33 (s, 1H), 2.03 (s, 1H), 1.77-1.45 (m, 7H), 1.44-0.94 (m, 20H)。MS (ESI, m/e) [M+1]+ 1068.2。 | ||
213 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(4-(苯并呋喃-4-基甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.68 (s, 1H), 11.39 (s, 1H), 8.55 (s, 2H), 8.02 (s, 2H), 7.77 (s, 2H), 7.47 (d,J = 17.8 Hz, 4H), 7.34 (s, 1H), 7.30-7.15 (m, 5H), 7.09 (s, 1H), 6.66 (s, 1H), 6.37 (s, 1H), 6.13 (s, 1H), 4.24 (s, 1H), 3.90 (s, 1H), 3.83-3.69 (m, 1H), 3.28 (s, 2H), 3.05-2.85 (m, 9H), 2.67 (s, 2H), 2.00 (s, 2H), 1.78-1.50 (m, 7H), 1.40-1.22 (m, 11H), 1.19-1.08 (m, 7H), 0.96 (s, 3H)。MS (ESI, m/e) [M+1]+ 1036.1。 | ||
214 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1s,4s)-4-羥基-4-(三氟甲基)環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-((R)-2-(2-異丙基苯基)-4-(4-甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.68 (s, 1H), 11.39-10.98 (m, 1H), 8.65 (s, 1H), 8.55 (s, 1H), 8.02 (s, 1H), 7.78 (d,J = 8.8 Hz, 1H), 7.50 (s, 3H), 7.24 (s, 5H), 7.05 (d,J = 9.4 Hz, 1H), 6.91 (s, 2H), 6.64 (d,J = 8.8 Hz, 1H), 6.37 (s, 1H), 6.13 (s, 1H), 5.69 (s, 1H), 3.73 (s, 4H), 3.37 (s, 2H), 3.27-3.21 (m, 1H), 3.05-2.85 (m, 8H), 1.96 (s, 2H), 1.85-1.75 (m, 4H), 1.65 (s, 1H), 1.55-1.40 (m, 5H), 1.39-1.15 (m, 10H), 1.07 (s, 4H)。MS (ESI, m/e) [M+1]+ 1080.2。 | ||
215 | 2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(6-((R)-2-(2-異丙基苯基)-4-((6-甲氧基吡啶-3-基)甲基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.55 (s, 1H), 11.26 (s, 1H), 8.70-8.52 (m, 2H), 8.30-7.98 (m, 2H), 7.92-7.58 (m, 3H), 7.59-7.32 (m, 4H), 7.32-7.00 (m, 4H) 6.92-6.70 (m, 1H), 6.20-5.91 (m, 1H), 5.53 (s, 1H), 4.24 (s, 1H), 3.88-3.79 (m, 3H), 3.77-3.39 (m, 7H), 3.32-3.16 (m, 4H), 2.11-2.87 (m, 2H), 2.82-2.60 (m, 2H), 2.37-2.16 (m, 1H), 2.09-1.89 (m, 2H), 1.83-1.47 (m, 6H), 1.39-1.27 (m, 3H), 1.25-0.95 (m, 11H)。MS (ESI, m/e) [M+1]+ 1017.1 | ||
216 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-(2-(2-異丙基苯基)-4-((4-甲基-3-側氧基-3,4-二氫-2H-苯并[b][1,4]㗁𠯤-5-基)甲基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.69 (s, 1H), 11.41 (s, 1H), 8.64-8.50 (m, 1H), 8.07-7.97 (m, 1H), 7.96-7.71 (m, 2H), 7.68-6.81 (m, 11H), 6.75-6.59 (m, 1H), 6.43-6.30 (m, 1H), 6.15 (s, 1H), 4.62-4.47 (m, 1H), 4.47-4.32 (m, 1H), 4.25 (s, 1H), 3.92-3.64 (m, 2H), 3.51-3.35 (m, 5H), 3.33-3.21 (m, 4H), 3.07-2.59 (m, 8H), 2.16-1.90 (m, 2H), 1.76-1.48 (m, 6H), 1.47-1.24 (m, 7H), 1.21-0.90 (m, 11H)。MS (ESI, m/e) [M+1]+ 1081.1 | ||
217 | 2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-((R)-2-(2-異丙基苯基)-4-((6-甲氧基吡啶-3-基)甲基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.55 (s, 1H), 11.44 (s, 1H), 8.66-8.46 (m, 2H), 8.17-8.07 (m, 2H), 7.89-7.61 (m, 3H), 7.57-7.06 (m, 8H), 6.91-6.80 (m, 1H), 6.77-6.68 (m, 1H), 6.26 (s, 1H), 4.30 (s, 1H), 3.87 (s, 3H), 3.66 (s, 3H), 3.38-3.25 (m, 3H), 3.11-2.88 (m, 6H), 2.82-2.60 (m, 2H), 2.36-2.00 (m, 2H), 1.84-1.55 (m, 7H), 1.52-1.23 (m, 11H), 1.20-1.03 (m, 8H)。MS (ESI, m/e) [M+1]+ 1045.1 | ||
218 | 2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(6-((R)-2-(2-異丙基苯基)-4-(4-(甲氧基-d3)苄基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.56 (s, 1H), 11.25 (br, 1H), 8.59-8.52 (m, 2H), 8.08 (s, 1H), 7.82-7.75 (m, 1H), 7.52-7.03 (m, 10H), 6.89-6.85 (m, 2H), 6.09-6.06 (m, 1H), 5.53 (s, 1H), 4.24 (s, 1H), 3.65-3.45 (m, 6H), 3.32-3.15 (m, 3H), 3.05-2.62 (m, 6H), 2.28-2.15 (m, 1H), 2.06-1.90 (m, 2H), 1.74-1.51 (m, 6H), 1.39-1.15 (m, 8H), 1.05-1.00 (m, 6H)。MS (ESI, m/e) [M+1]+ 1019.2。 | ||
219 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-(((4-羥基四氫呋喃-2-基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-((R)-2-(2-異丙基苯基)-4-(4-甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.66 (s, 1H), 11.44-11.05 (m, 1H), 8.69-8.50 (m, 2H), 8.01 (s, 1H), 7.79-7.76 (m, 1H), 7.49-7.46 (m, 3H), 7.29-7.19 (m, 5H), 7.11 (s, 2H), 6.90 (s, 2H), 6.64 (d,J = 9.0 Hz, 1H), 6.36 (s, 1H), 6.14 (s, 1H), 5.05-4.95 (m, 1H), 4.33 (s, 2H), 4.14 (s, 1H), 3.85 (s, 1H), 3.75-3.69 (m, 5H), 3.54 (s, 2H), 3.39 (s, 1H), 3.26-3.15 (m, 1H), 3.05-2.95 (m, 7H), 2.79-2.70 (m, 1H), 2.64-2.55 (m, 1H), 2.22 (s, 2H), 1.89-1.85 (m, 1H), 1.58 (s, 3H), 1.35-1.15 (m, 9H), 1.07 (s, 4H)。MS (ESI, m/e) [M+1]+ 999.9。 | ||
220 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-(((5-(羥基甲基)四氫呋喃-2-基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-((R)-2-(2-異丙基苯基)-4-(4-甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.66 (s, 1H), 11.54-11.14 (m, 1H), 8.56-8.55 (m, 2H), 8.01 (s, 1H), 7.77 (s, 1H), 7.52-7.43 (m, 3H), 7.36 (s, 2H), 7.23 (s, 3H), 7.10 (s, 2H), 6.95-6.89 (m, 2H), 6.66 (s, 1H), 6.36 (s, 1H), 6.14 (s, 1H), 4.66 (s, 1H), 4.15-4.10 (m, 2H), 3.97-3.94 (m, 2H), 3.74 (s, 4H), 3.56 (s, 1H), 3.37 (s, 2H), 3.05-2.85 (m, 9H), 1.98 (d,J = 34.8 Hz, 3H), 1.67 (s, 3H), 1.35-1.15 (m, 10H), 1.10-1.05 (m, 4H)。MS (ESI, m/e) [M+1]+ 1014.1。 | ||
221 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-(((R)-3-(((1r,4R)-4-羥基環己基)甲基)-5-硝基-3,4-二氫-2H-苯并[b][1,4]㗁𠯤-7-基)磺醯基)-4-(2-((R)-2-(2-異丙基苯基)-4-(4-甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.69 (s, 1H), 11.40 (s, 1H), 10.59-10.31 (m, 1H), 8.56-8.55 (m, 2H), 8.03 (s, 1H), 7.78 (d,J = 8.8 Hz, 1H), 7.55-7.02 (m, 11H), 6.65 (d,J = 8.7 Hz, 1H), 6.37 (s, 1H), 6.15 (s, 1H), 4.24 (s, 1H), 3.85-3.80 (m, 5H), 3.42 (s, 1H), 3.10-2.85 (m, 7H), 2.67 (s, 2H), 2.31-2.17 (m, 1H), 2.04 (s, 1H), 1.73-1.49 (m, 6H), 1.41-0.95 (m, 20H)。MS (ESI, m/e) [M+1]+ 1054.8。 | ||
222 | 4-((4-(7-(3-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)胺基甲醯基)苯基)-7-氮雜螺[3.5]壬烷-2-基)-3-(2-異丙基苯基)哌𠯤-1-基)甲基)苯甲酸 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 12.87 (s, 1H), 11.68 (s, 1H), 11.36 (s, 1H), 8.65-8.45 (m, 2H), 8.02 (s, 1H), 7.93-7.83 (m, 2H), 7.82-7.71 (m, 1H), 7.57-7.00 (m, 10H), 6.66 (s, 1H), 6.37 (s, 1H), 6.14 (s, 1H), 4.25 (s, 1H), 3.79-3.50 (m, 4H), 3.30-3.18 (m, 3H), 3.06-2.79(m, 7H), 2.35-2.08 (m, 2H), 1.74-1.48 (m, 7H), 1.40-0.97 (m, 20H)。MS (ESI, m/e) [M+1]+ 1040.1 | ||
223 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-((2R)-4-((3,4-二甲氧基二環[4.2.0]八-1(6),2,4-三烯-7-基)甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.69 (s, 1H), 11.35 (s, 1H), 8.65-8.47 (m, 2H), 8.09-7.95 (m, 1H), 7.88-7.72 (m, 1H), 7.59-7.41 (m, 4H), 7.41-6.98 (m, 5H), 6.86-6.56 (m, 3H), 6.38 (s, 1H), 6.20-6.05 (m, 1H), 4.25 (s, 1H), 3.75-3.58 (m, 7H), 3.56-3.40 (m, 2H), 3.32-3.25 (m, 3H), 3.24-2.65 (m, 12H), 2.11-1.95 (m, 1H), 1.87-1.50 (m, 7H), 1.46-1.22 (m, 9H), 1.21-0.98 (m, 10H)。MS (ESI, m/e) [M+1]+ 1083.0 | ||
224 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(4-(2-環丙氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.64 (s, 1H), 11.31 (s, 1H), 8.52-8.50 (m, 2H), 7.97 (s, 1H), 7.73 (d,J = 8.0 Hz, 1H), 7.49-7.11 (m, 11H), 7.03-6.87 (m, 2H), 6.60 (d,J = 8.0 Hz, 1H), 6.32 (s, 1H), 6.10 (s, 1H), 4.21 (s, 1H), 3.80 (s, 1H), 3.49-3.46 (m, 1H), 3.71 (s, 4H), 3.24-3.23 (m, 3H), 2.91-2.87 (m, 6H), 2.69-2.63 (m, 1H), 1.98-1.92 (m, 1H), 1.64-1.48 (m, 7H), 1.18-1.05 (m, 24H), 0.82-0.79 (m, 1H), 0.69-0.68 (m, 2H), 0.56-0.48 (m, 2H)。MS (ESI, m/e) [M+1]+ 1052.1。 | ||
225 | (R)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-(((1-氟-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-(2-(2-異丙基苯基)-4-(4-甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.69 (s, 1H), 11.40 (s, 1.0H), 8.56-8.55 (m, 2H), 8.03 (s, 1H), 7.79-7.76 (m, 1H), 7.55-7.02 (m, 10H), 6.92-6.90 (m,2H), 6.65 (d,J = 8.8 Hz, 1H), 6.37 (s, 1H), 6.15 (s, 1H), 4.36 (s, 1H), 3.85-3.80 (m, 8H), 3.42 (s, 1H), 3.10-2.85 (m, 8H), 2.69-2.65 (m, 2H), 2.31-2.17 (m, 1H), 2.04 (s, 1H), 1.95-1.90 (m,2H), 1.73-1.49 (m, 6H), 1.41-0.95 (m, 18H)。MS (ESI, m/e) [M+1]+ 1044。 | ||
226 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.69 (s, 1H), 11.40 (s, 1H), 8.56-8.55 (m, 2H), 8.03 (s, 1H), 7.79-7.76 (m, 1H), 7.55-7.02 (m, 10H), 6.92-6.90 (m,2H), 6.65 (d,J = 8.8 Hz, 1H), 6.37 (s, 1H), 6.15 (s, 1H), 4.36 (s, 1H), 3.85-3.80 (m, 8H), 3.42 (s, 1H), 3.10-2.85 (m, 7H), 2.69-2.65 (m, 2H), 2.31-2.17 (m, 1H), 2.04 (s, 1H), 1.95-1.90 (m,3H), 1.73-1.49 (m, 5H), 1.41-0.95 (m, 16H)。MS (ESI, m/e) [M+1]+ 1044。 | |||
227 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-(2-(2-異丙基苯基)-4-(3-甲氧基-5-(三氟甲基)苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.69 (s, 1H), 11.40 (s, 1H), 8.56-8.55 (m, 2H), 8.03 (s, 1H), 7.79-7.76 (m, 1H), 7.55-7.02 (m, 11H), 6.65 (d,J = 8.8 Hz, 1H), 6.37 (s, 1H), 6.15 (s, 1H), 4.24 (s, 1H), 3.85-3.80 (m, 5H), 3.42 (s, 1H), 3.10-2.85 (m, 7H), 2.67 (s, 2H), 2.31-2.17 (m, 1H), 2.04 (s, 1H), 1.73-1.49 (m, 6H), 1.41-0.95 (m, 20H)。MS (ESI, m/e) [M+1]+ 1094.8。 | ||
228 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-(2-(2-異丙基苯基)-4-(4-甲氧基-3-(甲基磺醯基)苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.69 (s, 1H), 11.38 (br, 1H), 8.61-8.54 (m, 2H), 8.02 (s, 1H), 7.90-7.55 (m, 3H), 7.52-7.05 (m, 9H), 6.69-6.63 (m, 1H), 6.37 (s, 1H), 6.18-6.10 (m, 1H), 4.25 (s, 1H), 3.93 (s, 3H), 3.85-3.35 (m, 4H), 3.32-3.10 (m, 6H), 3.10-2.55 (m, 9H), 2.38-1.95 (m, 3H), 1.74-1.41 (m, 7H), 1.39-1.15 (m, 13H), 1.07-1.00 (m, 3H)。MS (ESI, m/e) [M+1]+ 1104.0。 | ||
229 | 4-(6-((R)-4-(3,4-二氟苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)-2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.55 (s, 1H), 11.45 (br, 1H), 8.63-8.53 (m, 2H), 8.08 (s, 1H), 7.88-7.78 (m, 1H), 7.59-7.00 (m, 10H), 6.16-6.04 (m, 1H), 5.53 (s, 1H), 4.24 (s, 1H), 3.79-3.44 (m, 8H), 3.32-3.12 (m, 3H), 3.05-2.62 (m, 5H), 2.38-2.15 (m, 1H), 2.05-1.80 (m, 2H), 1.74-1.50 (m, 6H), 1.39-1.15 (m, 8H), 1.15-1.00 (m, 7H)。MS (ESI, m/e) [M+1]+ 1022.2。 | ||
230 | 2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(6-((R)-4-(3-氟-4,5-二甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.56 (s, 1H), 11.47 (br, 1H), 8.63-8.53 (m, 2H), 8.08 (s, 1H), 7.88-7.78 (m, 1H), 7.59-6.78 (m, 10H), 6.12-6.04 (m, 1H), 5.54 (s, 1H), 4.25 (s, 1H), 3.81 (s, 3H), 3.75 (s, 3H), 3.71-3.49 (m, 7H), 3.32-3.12 (m, 3H), 3.09-2.55 (m, 6H), 2.44-2.25 (m, 1H), 2.05-1.90 (m, 2H), 1.74-1.50 (m, 6H), 1.39-1.15 (m, 8H), 1.15-1.00 (m, 7H)。MS (ESI, m/e) [M+1]+ 1064.1。 | ||
231 | 4-(6-((R)-4-(3,4-二甲氧基-5-甲基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)-2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.52 (s, 1H), 8.60-8.46 (m, 2H), 8.07 (s, 1H), 7.78 (d,J = 8.8 Hz, 1H), 7.56-7.30 (m, 4H), 7.27-7.01 (m, 4H), 6.80 (s, 1H), 6.69 (s, 1H), 6.06 (d,J = 8.4 Hz, 1H), 5.55 (s, 1H), 4.24 (s, 1H), 3.74 (s, 3H), 3.69 - 3.41 (m, 10H), 3.31-3.18 (m, 4H), 3.00-2.83 (m, 2H), 2.78-2.65 (m, 1H), 2.63-2.52 (m, 1H), 2.36-2.16 (m, 2H), 2.13 (s, 3H), 2.09-1.91 (m, 2H), 1.75-1.59 (m, 4H), 1.58-1.49 (m, 2H), 1.42-1.27 (m, 3H), 1.24-0.99 (m, 11H)。MS (ESI, m/e) [M+1]+ 1060.3 | ||
234 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(6-((R)-4-(3,4-二甲氧基-5-甲基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.70 (s, 1H), 11.14 (s, 1H), 8.65-8.45 (m, 2H), 8.07-7.98 (m, 1H), 7.80 (d,J = 7.6 Hz, 1H), 7.59-6.32 (m, 4H), 7.26-7.00 (m, 4H), 6.78 (s, 1H), 6.67 (s, 1H), 6.39 (s, 1H), 6.03 (d,J = 6.8 Hz, 1H), 5.50 (s, 1H), 4.24 (s, 1H), 3.74 (s, 3H), 3.65-3.36 (m, 10H), 3.31-3.16 (m, 3H), 2.96-2.82 (m, 2H), 2.79-2.65 (m, 1H), 2.59-2.52 (m, 1H), 2.30-1.87 (m, 8H), 1.73-1.49 (m, 6H), 1.33 (t,J = 11.6 Hz, 3H), 1.22-0.98 (m, 11H)。MS (ESI, m/e) [M+1]+ 1042.0 | ||
235 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(2-(5-氟-2-異丙基苯基)-4-(4-甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.68 (s, 1H), 11.4-10.85 (m, 1H), 8.67-8.42 (m, 2H), 8.10-7.93 (m, 1H), 7.89-7.72 (m, 1H), 7.55-7.12 (m, 8H), 7.12-6.98 (m, 2H), 6.96-6.84 (m, 2H), 6.75-6.57 (m, 1H), 6.43-6.30 (m, 1H), 6.14 (s, 1H), 4.25 (s, 1H), 3.90-3.66 (m, 5H), 3.27-2.78 (m, 13H), 2.06-1.92 (m, 1H), 1.72-1.50 (m, 7H), 1.41-1.27 (m, 6H), 1.19-1.00 (m, 13H)。MS (ESI, m/e) [M+1]+ 1044.1 | ||
236 | (R)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((4-羥基-4-甲基環己基)甲氧基)-3-硝基苯基)磺醯基)-4-(2-(2-(2-異丙基苯基)-4-(4-甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.68 (s, 1H), 8.34 (s, 1H), 8.01 (s, 2H), 7.55-7.20 (m, 10H), 6.95-6.90 (m, 2H), 6.64 (d,J = 9.0 Hz, 1H), 6.38 (s, 1H), 6.14 (s, 1H), 4.27 (s, 1H), 4.07 (s, 2H), 3.74 (s, 4H), 3.56 (s, 1H), 3.26-3.13 (m, 1H), 3.05-2.85 (m, 8H), 2.01 (s, 1H), 1.75-1.65 (m, 4H), 1.60-1.52 (m, 3H), 1.42-1.14 (m, 15H), 1.15-1.02 (m, 7H)。MS (ESI, m/e) [M+1]+ 1026.9。 | ||
237 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.70 (s, 1H), 11.63-10.90 (m, 1H), 8.38-8.28 (m, 1H), 8.10-7.80(m, 3H), 7.58-7.13 (m, 10H), 7.02-6.80 (m, 2H), 6.70-6.60 (m, 1H), 6.39 (s, 1H), 6.22-6.07 (m, 1H), 4.72-3.83 (m, 5H), 3.83-3.51 (m, 4H), 3.25-2.55 (m, 12H), 2.14-1.90 (m, 1H), 1.75-1.26 (m, 15H), 1.19-0.96 (m, 9H)。MS (ESI, m/e) [M+1]+ 1027.0 | |||
238 | 2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(6-((S)-2-(2-異丙基苯基)-4-(4-甲氧基苄基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.55 (s, 1H), 8.56-8.50 (m, 2H), 8.08 (s, 1H), 7.81 (d,J = 9.0 Hz, 1H), 7.55-7.50 (m, 2H), 7.47-7.07 (m, 8H), 6.97 (s, 2H), 6.07 (s, 1H), 5.52 (s, 1H), 4.24 (s, 1H), 3.75 (s, 4H), 3.65-3.50 (m, 6H), 3.29 (s, 1H), 3.21 (s, 1H), 3.00 (s, 3H), 2.73 (s, 1H), 2.33 (s, 1H), 1.99 (s, 2H), 1.73-1.49 (m, 6H), 1.38-0.97 (m, 18H)。MS (ESI, m/e) [M+1]+ 1015.9。 | ||
239 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-((R)-2-(2-異丙基苯基)-4-((7-甲氧基-2,3-二氫苯并呋喃-5-基)甲基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.68 (s, 1H), 11.42-0.99 (m, 1H), 8.55 (s, 2H), 8.02 (s, 1H), 7.78 (d,J = 8.4 Hz, 1H), 7.49-7.45 (m, 3H), 7.34-7.10 (m, 4H), 6.86 (s, 2H), 6.65 (d,J = 7.6 Hz, 1H), 6.37 (s, 1H), 6.13 (s, 1H), 4.50 (s, 2H), 4.24 (s, 1H), 3.74 (s, 4H), 3.42 (s, 1H), 3.28 (s, 2H), 3.18-2.78 (m, 11H), 2.60 (s, 2H), 2.40-2.29 (m, 1H), 2.07 (s, 1H), 1.78-1.48 (m, 7H), 1.38-0.99 (m, 21H)。MS (ESI, m/e) [M+1]+ 1067.9。 | ||
240 | (R)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-(((3-羥基-3-甲基環丁基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-(2-(2-異丙基苯基)-4-(4-甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.64 (s, 1H), 11.14 (s, 1H), 8.57-8.46 (m, 1H), 8.46-8.38 (m, 1H), 8.03-7.95 (m, 1H), 7.77-6.98 (m, 1H), 7.52-7.33 (m, 4H), 7.30-7.04 (m, 5H), 7.03-6.80 (m, 3H), 6.70-6.57 (m, 1H), 6.40-6.30 (m, 1H), 6.15 (s, 1H), 4.90 (s, 1H), 3.71 (s, 3H), 3.60-3.37 (m, 7H), 3.02-2.80 (m, 6H), 2.63-2.55 (m, 1H), 2.33-1.92 (m, 6H), 1.84-1.72 (m, 2H), 1.72-1.55 (m, 2H), 1.50-1.28 (m, 5H), 1.23-0.97 (m, 11H)。MS (ESI, m/e) [M+1]+ 997.9 | ||
241 | 2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(6-((R)-2-(2-異丙基苯基)-4-((5-甲氧基吡啶-2-基)甲基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.53 (s, 1H), 11.22 (br, 1H), 8.59-8.52 (m, 2H), 8.20 (s, 1H), 8.06 (s, 1H), 7.82-7.76 (m, 1H), 7.55-7.04 (m, 10H), 6.12-6.04 (m, 1H), 5.55 (s, 1H), 4.24 (s, 1H), 3.80 (s, 3H), 3.79-3.40 (m, 7H), 3.32-3.15 (m, 3H), 3.09-2.60 (m, 5H), 2.30-2.15 (m, 1H), 2.05-1.90 (m, 2H), 1.74-1.50 (m, 6H), 1.39-1.15 (m, 8H), 1.15-1.00 (m, 7H)。MS (ESI, m/e) [M+1]+ 1017.1 | ||
242 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(6-((R)-4-((5,6-二甲氧基吡啶-3-基)甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.72 (s, 1H), 11.21 (br, 1H), 8.62-8.55 (m, 2H), 8.04 (s, 1H), 7.85-7.80 (m, 1H), 7.68-7.08 (m, 10H), 6.40 (s, 1H), 6.09-6.02 (m, 1H), 5.48 (s, 1H), 4.24 (s, 1H), 3.82 (s, 3H), 3.77 (s, 3H), 3.70-3.35 (m, 7H), 3.32-3.10 (m, 3H), 3.09-2.62 (m, 5H), 2.38-2.25 (m, 1H), 2.05-1.90 (m, 2H), 1.73-1.50 (m, 6H), 1.36-1.15 (m, 8H), 1.12-1.05 (m, 7H)。MS (ESI, m/e) [M+1]+ 1029.2。 | ||
243 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(6-((R)-4-(3,4-雙(甲氧基-d3)苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.73 (s, 1H), 11.16 (br, 1H), 8.62-8.56 (m, 2H), 8.04 (s, 1H), 7.83 (d,J = 8.8 Hz, 1H), 7.61-7.09 (m, 9H), 6.98-6.84 (m, 2H), 6.40 (s, 1H), 6.09-6.01 (m, 1H), 5.48 (s, 1H), 4.24 (s, 1H), 4.18-3.85 (m, 2H), 3.69-3.40 (m, 5H), 3.32-3.15 (m, 3H), 3.09-2.60 (m, 6H), 2.45-2.30 (m, 1H), 2.05-1.90 (m, 2H), 1.74-1.50 (m, 6H), 1.39-1.15 (m, 8H), 1.15-1.05 (m, 7H)。MS (ESI, m/e) [M+1]+ 1034.0。 | ||
244 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(6-((R)-4-(3,4-二氟苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.72 (s, 1H), 11.27 (br, 1H), 8.62-8.55 (m, 2H), 8.04 (s, 1H), 7.84 (d,J = 9.2 Hz, 1H), 7.75-7.05 (m, 12H), 6.40 (s, 1H), 6.09-6.01 (m, 1H), 5.48 (s, 1H), 4.24 (s, 1H), 3.65-3.40 (m, 7H), 3.32-3.15 (m, 3H), 3.09-2.60 (m, 6H), 2.30-2.05 (m, 1H), 2.05-1.90 (m, 2H), 1.73-1.50 (m, 6H), 1.39 - 1.15 (m, 8H), 1.15-1.00 (m, 7H)。MS (ESI, m/e) [M+1]+ 1004.1。 | ||
245 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(6-((R)-4-(3-氟-4,5-二甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.73 (s, 1H), 11.27 (br, 1H), 8.63-8.58 (m, 2H), 8.05 (s, 1H), 7.84 (d,J = 8.8 Hz, 1H), 7.62-6.75 (m, 10H), 6.40 (s, 1H), 6.09-6.02 (m, 1H), 5.49 (s, 1H), 4.24 (s, 1H), 3.80 (s, 3H), 3.80 (s, 3H), 3.67-3.40 (m, 6H), 3.32-3.15 (m, 3H), 3.09-2.60 (m, 6H), 2.40-2.25 (m, 1H), 2.05-1.90 (m, 2H), 1.74-1.50 (m, 6H), 1.39-1.15 (m, 8H), 1.15-1.00 (m, 7H)。MS (ESI, m/e) [M+1]+ 1046.0。 | ||
246 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(6-((R)-2-(2-異丙基苯基)-4-((5-甲氧基吡啶-2-基)甲基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.70 (s, 1H), 11.27 (br, 1H), 8.60-8.53 (m, 2H), 8.18 (s, 1H), 8.03 (s, 1H), 7.81 (d,J = 8.8 Hz, 1H), 7.58-7.35 (m, 6H), 7.25-7.05 (m, 4H), 6.39 (s, 1H), 6.06-6.03 (m, 1H), 5.49 (s, 1H), 4.24 (s, 1H), 3.80 (s, 3H), 3.70-3.40 (m, 7H), 3.32-3.15 (m, 3H), 3.09-2.60 (m, 6H), 2.25-2.15 (m, 1H), 2.05-1.90 (m, 2H), 1.74-1.50 (m, 6H), 1.39-1.15 (m, 8H), 1.13-1.00 (m, 7H)。MS (ESI, m/e) [M+1]+ 999.1。 | ||
247 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(2-(5-氯-2-異丙基苯基)-4-(4-甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.67 (s, 1H), 8.54 (s, 2H), 8.02 (s, 1H), 7.76 (s, 1H), 7.49 (s, 5H), 7.25 (s, 4H), 7.10-7.01 (m, 1H), 6.88 (s, 2H), 6.66 (s, 1H), 6.37 (s, 1H), 6.14 (s, 1H), 4.23 (s, 1H), 3.72 (s, 4H), 3.05-2.85 (m, 9H), 1.75-1.52 (m, 9H), 1.38-1.22 (m, 13H), 1.20-1.08 (m, 14H)。MS (ESI, m/e) [M+1]+ 1060.2。 | ||
248 | (R)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-(((4-羥基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-(2-(2-異丙基苯基)-4-(4-甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.68 (s, 1H), 11.55-11.23 (m, 1H), 8.55 (s, 2H), 8.02 (s, 1H), 7.77 (s, 1H), 7.54-7.12 (m, 8H), 7.07 (d,J = 8.4 Hz, 1H), 6.95-6.90 (m, 2H), 6.64 (s, 1H), 6.37 (s, 1H), 6.13 (s, 1H), 4.31 (s, 1H), 3.76-3.73 (m, 5H), 3.56 (s, 1H), 3.40 (s, 1H), 3.26 (s, 3H), 3.05-2.85 (m, 8H), 2.79-2.69 (m, 1H), 2.66-2.55 (m, 1H), 2.03 (s, 1H), 1.62 (s, 4H), 1.47-0.96 (m, 20H)。MS (ESI, m/e) [M+1]+ 1012.0。 | ||
249 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-(((3,4-二羥基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-((R)-2-(2-異丙基苯基)-4-(4-甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm:11.68 (s, 1H), 11.28 (s, 1H), 8.55 (s, 2H), 8.02 (s, 1H), 7.77 (d,J = 8.8 Hz, 1H), 7.57-6.80 (m, 12H), 6.65 (d,J = 9.0 Hz, 1H), 6.37 (s, 1H), 6.14 (s, 1H), 4.38-4.36 (m, 1H), 4.23-4.21 (m, 1H), 3.91 (s, 2H), 3.73 (s, 5H), 3.55 (s, 1H), 3.22 (s, 2H), 3.05-2.85 (m, 8H), 1.96 (s, 1H), 1.83-1.45 (m, 6H), 1.42-0.93 (m, 15H)。MS (ESI, m/e) [M+1]+ 1027.8。 | ||
250 | 4-(2-((R)-4-(3,4-雙(甲氧基-d3)苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-2-((3-氯-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 12.01 (s, 1H), 11.42 (br, 1H), 8.60-8.50 (m, 2H), 8.09 (s, 1H), 7.78 (d,J = 8.4 Hz, 1H), 7.69 (s, 1H), 7.48-7.12 (m, 6H), 7.09-6.65 (m, 4H), 6.25-6.20 (m, 1H), 4.24 (s, 1H), 4.23-3.40 (m, 5H), 3.32-3.15 (m, 3H), 3.09-2.60 (m, 9H), 2.20-1.95 (m, 1H), 1.74-1.50 (m, 7H), 1.39-1.15 (m, 11H), 1.13-1.00 (m, 8H)。MS (ESI, m/e) [M+1]+ 1095.9。 | ||
251 | 2-((3-氯-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-((R)-2-(2-異丙基苯基)-4-(4-(甲氧基-d3)苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 12.01 (s, 1H), 11.33 (br, 1H), 8.59-8.49 (m, 2H), 8.08 (s, 1H), 7.77 (d,J = 8.4 Hz, 1H), 7.68 (s, 1H), 7.49-7.10 (m, 8H), 7.09-6.65 (m, 4H), 6.28-6.18 (m, 1H), 4.24 (s, 1H), 4.23-3.40 (m, 4H), 3.32-3.15 (m, 3H), 3.09-2.60 (m, 10H), 2.21-1.96 (m, 1H), 1.74-1.50 (m, 7H), 1.39-1.15 (m, 11H), 1.13-1.00 (m, 8H)。MS (ESI, m/e) [M+1]+ 1062.8。 | ||
252 | 2-((3-氯-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-((R)-4-(4-環丙基-3-甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 12.01 (s, 1H), 11.48 (br, 1H), 8.59-8.50 (m, 2H), 8.09 (s, 1H), 7.75 (d,J = 8.4 Hz, 1H), 7.69 (s, 1H), 7.49-7.10 (m, 6H), 7.09-6.65 (m, 5H), 6.28-6.20 (m, 1H), 4.24 (s, 1H), 4.18-3.90 (m, 1H), 3.85-3.70 (m, 3H), 3.73-3.35 (m, 2H), 3.30-3.25 (m, 3H), 3.09- 2.60 (m, 9H), 2.20-1.96 (m, 2H), 1.74-1.50 (m, 7H), 1.39-1.15 (m, 11H), 1.13-1.00 (m, 9H), 0.95-0.80 (m, 2H), 0.65-0.52 (m, 2H)。MS (ESI, m/e) [M+1]+ 1099.8。 | ||
253 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-((R)-4-(3,4-雙(甲氧基-d3)苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.65 (s, 1H), 8.58-8.44 (m, 2H), 8.01 (d,J = 2.8 Hz, 1H), 7.76 (d,J = 7.2 Hz, 1H), 7.55-7.35 (m, 4H), 7.26-7.06 (m, 3H), 7.00 (d,J = 9.2 Hz, 1H), 6.93-6.75 (m, 3H), 6.63 (d,J = 7.6 Hz, 1H), 6.35 (s, 1H), 6.15 (s, 1H), 4.25 (s, 1H), 3.70-3.46 (m, 4H), 3.30-3.22 (m, 3H), 3.05-2.80 (m, 7H), 2.68-2.56 (m, 1H), 2.41-2.05 (m, 3H), 1.76-1.49 (m, 7H), 1.40-1.22 (m, 6H), 1.20-0.96 (m, 12H)。MS (ESI, m/e) [M+1]+ 1062.1 | ||
254 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(6-((R)-2-(2-異丙基苯基)-4-((6-甲氧基吡啶-3-基)甲基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.72 (s, 1H), 11.20 (br, 1H), 8.62-8.55 (m, 2H), 8.22-8.20 (m, 1H), 8.04 (s, 1H), 7.85-7.08 (m, 9H), 6.88-6.72 (m, 1H), 6.40 (s, 1H), 6.09-6.02 (m, 1H), 5.48 (s, 1H), 4.24 (s, 1H), 3.53 (s, 3H), 3.48-3.35 (m, 7H), 3.32-3.10 (m, 3H), 3.09-2.62 (m, 5H), 2.38-2.25 (m, 1H), 2.05-1.90 (m, 2H), 1.73-1.50 (m, 6H), 1.36-1.15 (m, 8H), 1.12-1.05 (m, 7H)。MS (ESI, m/e) [M+1]+ 998.9。 | ||
255 | 2-((3-氯-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-((R)-4-(4-氟苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 12.00 (s, 1H), 11.44 (s, 1H), 8.58-8.48 (m, 2H), 8.12-8.05 (s, 1H), 7.91-7.61 (m, 3H), 7.58-6.95 (m, 11H), 6.71-6.63 (m, 1H), 6.24 (s, 1H), 4.69-4.55 (m, 1H), 4.25 (s, 1H), 3.87-3.54 (m, 3H), 3.47-3.37 (m, 1H), 3.32-3.15 (m, 4H), 3.10-2.82 (m, 6H), 2.77-2.59 (m, 2H), 2.11-1.97 (m, 1H), 1.76-1.50 (m, 6H), 1.47-1.23 (m, 8H), 1.22-0.96 (m, 11H)。MS (ESI, m/e) [M+1]+ 1047.9 | ||
256 | 2-((3-氯-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-((R)-4-(4-氯苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 12.00 (s, 1H), 11.47 (s, 1H), 8.57-8.47 (m, 2H), 8.13-8.02 (m, 1H), 7.80-7.62 (m, 3H), 7.53-7.08 (m, 10H), 7.08-7.00 (m, 1H), 6.75-6.62 (m, 1H), 6.24 (s, 1H), 4.25 (s, 1H), 3.78-3.50 (m, 3H), 3.46-3.37 (m, 1H), 3.32-3.15 (m, 4H), 3.11-2.81 (m, 7H), 2.75-2.60 (m, 1H), 2.32-2.18 (m, 1H), 1.72-1.50 (m, 5H), 1.45-1.24 (m, 8H), 1.19-0.97 (m, 11H)。MS (ESI, m/e) [M+1]+ 1065.9 | ||
257 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-((R)-4-(4-環丙基-3-甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.65 (s, 1H), 8.61-8.41 (m, 2H), 8.01 (s, 1H), 7.75 (d,J = 8.8 Hz, 1H), 7.55-7.33 (m, 4H), 7.28-6.97 (m, 4H), 6.87 (s, 1H), 6.79-6.69 (m, 2H), 6.63 (d,J = 8.4 Hz, 1H), 6.40-6.31 (m, 1H), 6.15 (s, 1H), 4.25 (s, 1H), 3.77 (s, 3H), 3.63-3.45 (m, 3H), 3.30-2.21 (m, 3H), 3.06-2.78 (m, 7H), 2.65-2.53 (m, 1H), 2.39-2.10 (m, 2H), 2.08-1.98 (m, 1H), 1.78-1.47 (m, 7H), 1.43-0.94 (m, 20H), 0.89-0.78 (m, 2H), 0.61-0.48 (m, 2H)。MS (ESI, m/e) [M+1]+ 1066.1 | ||
258 | 4-(2-((R)-4-(4-環丙基-3-甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.45 (s, 1H), 8.56-8.41 (m, 2H), 8.03 (s, 1H), 7.72 (d,J = 9.2 Hz, 1H), 7.55-7.30 (m, 4H), 7.28-6.94 (m, 4H), 6.87 (s, 1H), 6.80-6.61 (m, 3H), 6.22 (s, 1H), 4.24 (s, 1H), 3.78 (s, 3H), 3.65-3.46 (m, 3H), 3.30-2.20 (m, 3H), 3.09-2.80 (m, 7H), 2.68-2.54 (m, 1H), 2.39-2.12 (m, 2H), 2.09-1.98 (m, 1H), 1.75-1.49 (m, 7H), 1.40-0.97 (m, 20H), 0.89-0.78 (m, 2H), 0.60-0.50 (m, 2H)。MS (ESI, m/e) [M+1]+ 1084.2 | ||
259 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-((2R)-4-(((1R,3S,5R)-金剛烷-2-基)甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.70 (s, 1H), 11.45 (br, 1H), 8.63-8.54 (m, 2H), 8.02 (s, 1H), 7.82 (d,J = 9.2 Hz, 1H), 7.57-7.40 (m, 7H), 6.69-6.64 (m, 1H), 6.38 (s, 1H), 6.18-6.10 (m, 1H), 4.24 (s, 1H), 3.88-3.56 (m, 3H), 3.32-3.12 (m, 3H), 3.10-2.55 (m, 10H), 2.09-1.94 (m, 1H), 1.74-1.50 (m, 21H), 1.42-1.02 (m, 19H)。MS (ESI, m/e) [M+1]+ 1054.1。 | ||
260 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-((R)-2-(2-異丙基苯基)-4-(3-甲氧基-4-甲基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.69 (s, 1H), 11.49-11.28 (m, 1H), 10.53-10.29 (m, 1H), 8.60-8.55 (m, 2H), 8.02 (s, 1H), 7.77 (s, 1H), 7.54-7.39 (m, 3H), 7.36 (s, 1H), 7.30-7.10 (m, 3H), 7.09-7.05 (m, 2H), 6.90-6.75 (m, 1H), 6.65 (d,J = 8.8 Hz, 1H), 6.38 (s, 1H), 6.14 (d,J = 9.0 Hz, 1H), 4.24 (s, 1H), 3.80-3.75 (m, 4H), 3.60 (s, 1H), 3.41 (s, 1H), 3.29-3.25 (m, 3H), 3.05-2.85 (m, 7H), 2.15-1.95 (m, 4H), 1.75-1.50 (m, 6H), 1.40-1.15 (m, 14H), 1.14-1.00 (m, 7H)。MS (ESI, m/e) [M+1]+ 1040.0。 | ||
261 | 2-((3-氯-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-((R)-2-(2-異丙基苯基)-4-(4-(氧雜環丁烷-3-基氧基)苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.99 (s, 1H), 11.59-10.99 (m, 1H), 8.61-8.44 (m, 2H), 8.08 (d,J = 2.4 Hz, 1H), 7.81-7.68 (m, 2H), 7.50-7.10 (m, 8H), 7.04 (s, 1H), 6.84-6.64 (m, 3H), 6.23 (s, 1H), 5.25 (s, 1H), 4.92-4.90 (m, 2H), 4.58-4.44 (m, 2H), 4.24 (s, 1H), 3.77 (s, 2H), 3.29-3.20 (m, 2H), 3.05-2.85 (m, 7H), 2.72 (s, 2H), 2.01-1.98 (m, 1H), 1.75-1.50 (m, 7H), 1.45-0.93 (m, 21H)。MS (ESI, m/e) [M+1]+ 1101.9。 | ||
262 | 2-((3-氯-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-((R)-4-(4-環丙氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 12.00 (s, 1H), 11.65-11.35 (m, 1H), 8.57-8.55 (m, 2H), 8.08 (d,J = 2.4 Hz, 1H), 7.78-7.70 (m, 1H), 7.68 (d,J = 2.6 Hz, 1H), 7.61-7.20 (m, 7H), 7.06 (s, 3H), 6.68 (d,J = 9.0 Hz, 1H), 6.22 (s, 1H), 4.24 (s, 1H), 3.83 (s, 2H), 3.63-3.42 (m, 1H), 3.29-3.13 (m, 4H), 3.05-2.85 (m, 7H), 2.67 (s, 2H), 2.44-2.30 (m, 1H), 2.12-1.93 (m, 1H), 1.75-1.50 (m, 6H), 1.35-1.02 (m, 20H), 0.76 (s, 3H) 0.76 (s, 2H)。MS (ESI, m/e) [M+1]+ 1085.9。 | ||
263 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-((R)-4-(4-異丙基-3-甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.67 (s, 1H), 11.25 (s, 1H), 8.65-8.41 (m, 2H), 8.10-7.95 (m, 1H), 7.82-7.72 (m, 1H), 7.64-7.37 (m, 4H), 7.34-6.78 (m, 8H), 6.70-6.54 (m, 1H), 6.45-6.30 (m, 1H), 6.14 (s, 1H), 4.26 (s, 1H), 3.86-3.60 (m, 5H), 3.30-3.14 (m, 6H), 2.06-2.85 (m, 6H), 2.73-2.63 (m, 1H), 2.43-2.28 (m, 1H), 1.79-1.49 (m, 7H), 1.40-1.25 (m, 6H), 1.22-0.87 (m, 19H)。MS (ESI, m/e) [M+1]+ 1068.1 | ||
264 | 2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-((R)-4-(4-異丙基-3-甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.57-11.03 (m, 2H), 8.57-8.40 (m, 2H), 8.06-7.95 (m, 1H), 7.92-7.63 (m, 2H), 7.60-6.73 (m, 11H), 6.70-6.54 (m, 1H), 6.16 (s, 1H), 4.21 (s, 1H), 4.12-3.37 (m, 13H), 3.15-2.81 (m, 5H), 2.77-2.59 (m, 1H), 2.03-1.90 (m, 1H), 1.75-1.43 (m, 7H), 1.42-1.20 (m, 9H), 1.17-0.93 (m, 16H)。MS (ESI, m/e) [M+1]+ 1086.1 | ||
265 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-((R)-4-(4-乙基-3-甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.68 (s, 1H), 11.27 (s, 1H), 8.68-8.46 (m, 2H), 8.14-7.97 (m, 1H), 7.87-7.68 (m, 1H), 7.64-6.80 (m, 12H), 6.72-6.60 (m, 1H), 6.48-6.30 (m, 1H), 6.15 (s, 1H), 4.25 (s, 1H), 3.90-3.63 (m, 6H), 3.33-3.16 (m, 6H), 2.13-2.81 (m, 7H), 2.79-2.56 (m, 2H), 2.47-2.25 (m, 1H), 1.73-1.50 (m, 6H), 1.40-1.22 (m, 9H), 1.17-0.98 (m, 13H)。MS (ESI, m/e) [M+1]+ 1054.2 | ||
266 | 4-(2-((R)-4-(4-乙基-3-甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.58-11.10 (m, 2H), 8.64-8.47 (m, 2H), 8.15-7.98 (m, 1H), 7.98-7.69 (m, 2H), 7.56-6.77 (m, 11H), 6.73-6.60 (m, 1H), 6.21 (s, 1H), 4.25 (s, 1H), 3.99-3.71 (m, 6H), 3.70-3.47 (m, 5H), 3.30-2.54 (m, 10H), 2.12-1.92 (m, 1H), 1.87-1.45 (m, 8H), 1.40-1.26 (m, 7H), 1.20-1.00 (m, 13H)。MS (ESI, m/e) [M+1]+ 1072.89 | ||
267 | (R)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(2-(2-異丙基苯基)-4-(4-甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-(((4-甲氧基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.69 (s, 1H), 11.44-11.17 (m, 1H), 8.59-8.56 (m, 2H), 8.02 (s, 1H), 7.89-7.73 (m, 1H), 7.53-7.11 (m, 9H), 7.06 (d,J = 9.0 Hz, 1H), 6.99-6.85 (m, 2H), 6.65 (d,J = 9.0 Hz, 1H), 6.37 (s, 1H), 6.13 (s, 1H), 4.06-3.85 (m, 1H), 3.74 (s, 4H), 3.55 (s, 1H), 3.25-3.20 (m, 6H), 3.10-2.79 (m, 9H), 2.02-1.99 (m, 3H), 1.79-1.76 (m, 2H), 1.57 (s, 3H), 1.35-1.00 (m, 18H)。MS (ESI, m/e) [M+1]+ 1025.9。 | ||
268 | 4-(6-((R)-4-(4-乙基-3-甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)-2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.53 (s, 1H), 11.19 (s, 1H), 8.66-8.45 (m, 2H), 8.12-8.03 (m, 1H), 7.89-7.76 (m, 1H), 7.60-7.32 (m, 4H), 7.32-7.02 (m, 5H), 7.02-6.77 (m, 2H), 6.20-5.91 (m, 1H), 5.54 (s, 1H), 4.23 (s, 1H), 3.93-3.45 (m, 10H), 3.42-3.34 (m, 1H), 3.31-3.16 (m, 3H), 3.13-2.58 (m, 4H), 2.56-2.50 (m, 3H), 2.37-2.20 (m, 1H), 2.08-1.90 (m, 2H), 1.82-1.48 (m, 6H), 1.42-1.27 (m, 3H), 1.22-1.00 (m, 13H)。MS (ESI, m/e) [M+1]+ 1044.2 | ||
269 | 2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(6-((R)-4-(4-異丙基-3-甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.55 (s, 1H), 11.22 (br, 1H), 8.60-8.54 (m, 2H), 8.08 (s, 1H), 7.82-7.76 (m, 1H), 7.55-7.03 (m, 8H), 6.95-6.83 (m, 1H), 6.10-6.03 (m, 1H), 5.54 (s, 1H), 4.24 (s, 1H), 3.98-3.80 (m, 2H), 3.78 (s, 3H), 3.68 - 3.40 (m, 5H), 3.32-3.15 (m, 4H), 3.10-2.62 (m, 5H), 2.41-2.28 (m, 1H), 2.07-1.90 (m, 2H), 1.74-1.51 (m, 6H), 1.39-1.15 (m, 8H), 1.05-1.00 (m, 13H)。MS (ESI, m/e) [M+1]+ 1058.3。 | ||
270 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(6-((R)-4-(4-異丙基-3-甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.72 (s, 1H), 11.24 (br, 1H), 8.64-8.57 (m, 2H), 8.04 (s, 1H), 7.85-7.80 (m, 1H), 7.62-7.03 (m, 10H), 6.95-6.83 (m, 1H), 6.43-6.37 (m, 1H), 6.10-6.03 (m, 1H), 5.48 (s, 1H), 4.24 (s, 1H), 4.06-3.83 (m, 2H), 3.79 (s, 3H), 3.66-3.43 (m, 5H), 3.31-3.17 (m, 4H), 3.10-2.62 (m, 5H), 2.44-2.25 (m, 1H), 2.03-1.95 (m, 2H), 1.73-1.50 (m, 6H), 1.39-1.15 (m, 8H), 1.05-1.00 (m, 13H)。MS (ESI, m/e) [M+1]+ 1040.2。 | ||
271 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(6-((R)-4-(4-乙基-3-甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.72 (s, 1H), 11.11 (s, 1H), 8.64-8.48 (m, 2H), 8.10-7.97 (m, 1H), 7.85-7.72 (m, 1H), 7.63-6.72 (m, 12H), 6.44-6.30 (m, 1H), 6.08-5.95 (m, 1H), 5.48 (s, 1H), 4.24 (s, 1H), 3.97-3.70 (m, 4H), 3.68-3.40 (m, 5H), 3.32-3.22 (m, 4H), 3.15-2.87 (m, 3H), 2.82-2.64 (m, 3H), 2.57-2.52 (m, 1H), 2.41-2.28 (m, 1H), 2.06-1.92 (m, 2H), 1.73-1.49 (m, 6H), 1.40-1.27 (m, 3H), 1.20-0.99 (m, 15H)。MS (ESI, m/e) [M+1]+ 1026.0 | ||
272 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-((2R)-2-(2-異丙基苯基)-4-((3-甲氧基二環[4.2.0]八-1(6),2,4-三烯-7-基)甲基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.69 (s, 1H), 11.38-11.19 (m, 1H), 8.56-8.55 (m, 2H), 8.02 (s, 1H), 7.78 (d,J = 8.6 Hz, 1H), 7.55-7.45 (m, 4H), 7.46 (s, 1H), 7.40-7.15 (m, 4H), 7.10-6.95 (m, 2H), 6.73 (s, 2H), 6.69-6.65 (m, 1H), 6.37 (s, 1H), 6.14 (s, 1H), 4.24 (s, 1H), 3.69 (s, 5H), 3.28 (s, 3H), 3.05-2.85 (m, 8H), 2.02-1.99 (m, 1H), 1.75-1.59 (m, 5H), 1.56-1.50 (m, 2H), 1.40-1.05 (m, 27H)。MS (ESI, m/e) [M+1]+ 1052.1。 | ||
273 | 2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-((R)-2-(2-異丙基苯基)-4-(3-甲氧基-4-甲基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.51 (s, 1H), 11.24 (s, 1H), 8.59-8.56 (m, 2H), 8.09-8.0 (m, 1H), 7.78 (d,J = 9.0 Hz, 1H), 7.53-7.40 (m, 3H), 7.40-7.15 (m, 4H), 7.09-7.05 (m, 2H), 6.95-6.80 (m, 1H), 6.68 (d,J = 8.8 Hz, 1H), 6.25-6.20 (m, 1H), 4.25 (s, 1H), 4.10 (s, 1H), 3.85-3.74 (m, 4H), 3.59 (s, 1H), 3.39 (s, 1H), 3.29-3.20 (m, 2H), 3.22-3.13 (m, 1H), 3.05-2.85 (m, 7H), 2.80-2.65 (m, 1H), 2.18-2.02 (m, 4H), 1.72-1.50 (m, 7H), 1.42-0.97 (m, 19H)。MS (ESI, m/e) [M+1]+ 1058.0。 | ||
274 | 2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(6-((R)-2-(2-異丙基苯基)-4-(3-甲氧基-4-甲基苄基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.55 (s, 1H), 11.45-11.04 (m, 1H), 8.55-8.50 (m, 2H), 8.08 (d,J = 2.2 Hz, 1H), 7.81 (d,J = 9.0 Hz, 1H), 7.51 (s, 2H), 7.45-7.40 (m, 2H), 7.25 (s, 2H), 7.18-7.05 (m, 3H), 6.87 (s, 1H), 6.06 (d,J = 8.8 Hz, 1H), 5.52 (s, 1H), 4.24 (s, 1H), 3.78 (s, 3H), 3.65-3.52 (m, 5H), 3.29-3.26 (m, 2H), 2.97 (s, 3H), 2.74 (s, 2H), 2.33 (s, 1H), 2.11 (s, 3H), 1.99 (s, 2H), 1.75-1.50 (m, 6H), 1.39-0.98 (m, 17H)。MS (ESI, m/e) [M+1]+ 1030.1。 | ||
275 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(6-((R)-2-(2-異丙基苯基)-4-(3-甲氧基-4-甲基苄基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.73(s, 1H), 11.29 (s, 1H), 8.59-8.56 (m, 2H), 8.03 (d,J = 4.0 Hz 1H), 7.83-7.81 (m, 1H), 7.59-7.58 (m, 1H), 7.52-7.51 (m, 1H), 7.45-7.40 (m, 2H), 7.25-7.20 (m, 6H), 6.87 (s, 1H), 6.40-6.39 (m, 1H), 6.04 (d,J = 8.0 Hz 1H), 5.49 (s,1H), 4.26 (s, 1H), 3.95 (s, 1H), 3.77 (s, 3H), 3.63-3.46 (m, 5H), 3.30-3.27 (m, 3H), 3.09-2.94 (m, 2H), 2.74-2.72 (m, 2H), 2.51-2.50 (m, 3H), 2.11 (s,1H), 1.98-1.96 (m, 2H), 1.69-1.52 (m, 6H), 1.36-1.08 (m, 16H)。MS (ESI, m/e) [M+1]+ 1012.1。 | ||
276 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-((R)-4-(4-氯-3-甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.69 (s, 1H), 11.40 (br, 1H), 8.62-8.49 (m, 2H), 8.02 (s, 1H), 7.79-7.73 (m, 1H), 7.54-6.89 (m, 11H), 6.68-6.63 (m, 1H), 6.37 (s, 1H), 6.18-6.12 (m, 1H), 4.24 (s, 1H), 3.83 (s, 3H), 3.80-3.60 (m, 2H), 3.47-3.35 (m, 2H), 3.31-3.17 (m, 3H), 3.09-2.65 (m, 10H), 2.12-1.95 (m, 2H), 1.73-1.45 (m, 7H), 1.39-1.25 (m, 5H), 1.20-1.00 (m, 12H)。MS (ESI, m/e) [M+1]+ 1060.1。 | ||
277 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-((R)-2-(2-異丙基苯基)-4-(3-甲氧基-4-(三氟甲基)苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.69 (s, 1H), 11.41 (br, 1H), 8.62-8.47 (m, 2H), 8.02 (s, 1H), 7.79-7.73 (m, 1H), 7.59-7.03 (m, 11H), 6.68-6.63 (m, 1H), 6.37 (s, 1H), 6.17-6.13 (m, 1H), 4.24 (s, 1H), 3.87 (s, 3H), 3.80-3.68 (m, 2H), 3.47-3.38 (m, 2H), 3.31-3.17 (m, 3H), 3.09-2.65 (m, 10H), 2.13-1.96 (m, 2H), 1.73-1.45 (m, 7H), 1.39-1.25 (m, 7H), 1.20-1.00 (m, 10H)。MS (ESI, m/e) [M+1]+ 1094.2。 | ||
278 | 4-(2-((R)-4-(4-氯-3-甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.51 (s, 1H), 11.42 (br, 1H), 8.60-8.51 (m, 2H), 8.05 (s, 1H), 7.79-7.73 (m, 1H), 7.54-6.89 (m, 11H), 6.72-6.64 (m, 1H), 6.25-6.17 (m, 1H), 4.25 (s, 1H), 3.84 (s, 3H), 3.80-3.60 (m, 2H), 3.49-3.35 (m, 2H), 3.31 - 3.25 (m, 3H), 3.20-2.65 (m, 10H), 2.20-1.96 (m, 2H), 1.75-1.45 (m, 7H), 1.39-1.25 (m, 6H), 1.20-1.00 (m, 11H)。MS (ESI, m/e) [M+1]+ 1078.0。 | ||
279 | 2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-((R)-2-(2-異丙基苯基)-4-(3-甲氧基-4-(三氟甲基)苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.51 (s, 1H), 11.49 (br, 1H), 8.59-8.51 (m, 2H), 8.06 (s, 1H), 7.79-7.75 (m, 1H), 7.58-7.04 (m, 11H), 6.69-6.65 (m, 1H), 6.25-6.17 (m, 1H), 4.25 (s, 1H), 3.87 (s, 3H), 3.81-3.68 (m, 2H), 3.47-3.37 (m, 2H), 3.31-3.17 (m, 3H), 3.09-2.65 (m, 10H), 2.19-1.95 (m, 2H), 1.73-1.45 (m, 7H), 1.39-1.25 (m, 6H), 1.20-1.00 (m, 11H)。MS (ESI, m/e) [M+1]+ 1112.1。 | ||
280 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-((R)-2-(2-異丙基苯基)-4-((7-甲氧基苯并呋喃-5-基)甲基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.69 (s, 1H), 8.59-8.48 (m, 2H), 8.03 (d,J = 2.8 Hz, 1H), 7.94 (d,J = 2.0 Hz, 1H), 7.78 (dd,J = 2.0 Hz, 9.2 Hz, 1H), 7.61-7.39 (m, 4H), 7.28-7.09 (m, 4H), 7.06-6.95 (m, 2H), 6.89 (d,J = 2.0 Hz, 1H), 6.64 (d,J = 8.4 Hz, 1H), 6.40-6.33 (m, 1H), 6.16 (s, 1H), 4.29 (s, 1H), 3.92 (s, 3H), 3.81-3.71 (m, 2H), 3.32-3.20 (m, 4H), 3.12-2.81 (m, 7H), 2.77-2.67 (m, 1H), 2.61-2.52 (m, 1H), 2.46-2.31 (m, 1H), 1.85-1.48 (m, 7H), 1.43-0.84 (m, 20H)。MS (ESI, m/e) [M+1]+ 1066.2 | ||
281 | 2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-((R)-2-(2-異丙基苯基)-4-((7-甲氧基苯并呋喃-5-基)甲基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.48 (s, 1H), 8.58-8.44 (m, 2H), 8.04 (d,J = 2.4 Hz, 1H), 7.94 (d,J = 2.0 Hz, 1H), 7.75 (d,J = 13.2 Hz, 1H), 7.51-7.36 (m, 4H), 7.31-7.09 (m, 4H), 7.07-6.86 (m, 3H), 6.67 (d,J = 7.6 Hz, 1H), 6.22 (s, 1H), 4.26 (s, 1H), 3.92 (s, 3H), 3.88-3.67 (m, 2H), 3.31-3.20 (m, 4H), 3.12-2.86 (m, 7H), 2.81-2.61 (m, 2H), 2.47-2.32 (m, 1H), 1.78-1.48 (m, 7H), 1.41-0.96 (m, 20H)。MS (ESI, m/e) [M+1]+ 1084.1 | ||
282 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-((R)-4-(口克唍-7-基甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.69 (s, 1H), 11.52-11.22 (m, 1H), 8.58-8.55 (m, 2H), 8.03 (s, 1H), 7.79 (s, 1H), 7.56-7.33 (m, 4H), 7.30-6.91 (m, 4H), 6.90-6.64 (m, 3H), 6.37 (s, 1H), 6.13 (s, 1H), 4.25 (s, 1H), 4.10 (s, 2H), 3.77 (s, 1H), 3.53 (s, 1H), 3.28 (s, 2H), 3.05-2.85 (m, 7H), 2.70 (s, 3H), 2.04 (s, 1H), 1.88 (s, 2H), 1.77-1.48 (m, 7H), 1.44-1.00 (m, 20H)。MS (ESI, m/e) [M+1]+ 1052.0 | ||
283 | 4-(2-((R)-4-(口克唍-7-基甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.50 (s, 1H), 8.55-8.52 (m, 2H), 8.05 (s, 1H), 7.76 (d,J = 9.0 Hz, 1H), 7.51-7.35 (m, 4H), 7.25 (s, 2H), 7.15-6.95 (m, 2H), 6.75 (s, 2H), 6.67 (d,J = 8.4 Hz, 1H), 6.20 (s, 1H), 4.25 (s, 1H), 4.09 (s, 2H), 3.53 (s, 1H), 3.40 (s, 1H), 3.29-3.21 (m, 2H), 3.05-2.85 (m, 8H), 2.70 (s, 3H), 2.03 (s, 1H), 1.88 (s, 2H), 1.72-1.50 (m, 7H), 1.43-1.00 (m, 22H)。MS (ESI, m/e) [M+1]+ 1069.9。 | ||
284 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-((R)-4-(4-異丁氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.69 (s, 1H), 11.53-11.21 (m, 1H), 8.57-8.54 (m, 2H), 8.02 (s, 1H), 7.78 (d,J = 9.0 Hz, 1H), 7.54-7.44 (m, 3H), 7.45-7.15 (m, 5H), 7.10-6.95 (m, 1H), 6.96-6.84 (m, 2H), 6.68-6.62 (m, 1H), 6.37 (s, 1H), 6.15-6.12 (m, 1H), 4.25 (s, 1H), 3.76-3.70 (m, 2H), 3.55 (s, 1H), 3.39 (s, 1H), 3.29-3.20 (m, 3H), 3.05-2.85 (m, 8H), 1.99 (s, 2H), 1.75-1.50 (m, 7H), 1.38-1.00 (m, 21H), 0.96 (d,J = 6.6 Hz, 6H)。MS (ESI, m/e) [M+1]+ 1068.1。 | ||
285 | 2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-((R)-2-(2-異丙基苯基)-4-((7-甲氧基-3,3-二甲基-2,3-二氫苯并呋喃-5-基)甲基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.51 (s, 1H), 11.26 (s, 1H), 8.62-8.46 (m, 2H), 8.10-7.91 (m, 1H), 7.82-7.70 (m, 1H), 7.52-7.39 (m, 4H), 7.39-6.83 (m, 6H), 6.83-6.57 (m, 2H), 6.29-6.11 (m, 1H), 4.25 (s, 1H), 4.24-4.13 (m, 2H), 4.12-3.85 (m, 1H), 3.81-3.69 (m, 3H), 3.64-3.36 (m, 2H), 3.32-3.13 (m, 5H), 3.13-2.86 (m, 7H), 2.82-2.57 (m, 2H), 2.21-1.97 (m, 1H), 1.78-1.46 (m, 7H), 1.42-1.26 (m, 6H), 1.23-0.95 (m, 17H)。MS (ESI, m/e) [M+1]+ 1114.2 | ||
286 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-((R)-2-(2-異丙基苯基)-4-((7-甲氧基-3,3-二甲基-2,3-二氫苯并呋喃-5-基)甲基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.69 (s, 1H), 11.33 (s, 1H), 8.66-8.42 (m, 2H), 8.12-7.88 (m, 1H), 7.82-7.73 (m, 1H), 7.61-6.82 (m, 11H), 6.79-6.55 (m, 2H), 6.37 (s, 1H), 6.22-6.07 (m, 1H), 4.25 (s, 1H), 4.24-4.15 (m, 2H), 4.07-3.86 (m, 1H), 3.86-3.67 (m, 4H), 3.63-3.38 (m, 2H), 3.31-3.15 (m, 5H), 3.10-2.78 (m, 9H), 2.77-2.55 (m, 2H), 2.07-1.94 (m, 1H), 1.76-1.47 (m, 8H), 1.41-1.27 (m, 6H), 1.17-0.91 (m, 13H)。MS (ESI, m/e) [M+1]+ 1096.1 | ||
287 | 4-(2-((R)-4-(4-(二氟甲基)-3-甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.50 (s, 1H), 11.47 (br, 1H), 8.59-8.51 (m, 2H), 8.06 (s, 1H), 7.79-7.73 (m, 1H), 7.52-7.02 (m, 11H), 6.68-6.65 (m, 1H), 6.23-6.17 (m, 1H), 4.24 (s, 1H), 3.83 (s, 3H), 3.73-3.68 (m, 1H), 3.47-3.35 (m, 1H), 3.31-3.17 (m, 3H), 3.09-2.60 (m, 9H), 2.35-2.20 (m, 1H), 2.12-1.95 (m, 2H), 1.74-1.52 (m, 6H), 1.39-1.22 (m, 11H), 1.20-1.00 (m, 10H)。MS (ESI, m/e) [M+1]+ 1094.2。 | ||
288 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-((R)-4-(4-(二氟甲基)-3-甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.69 (s, 1H), 11.39 (br, 1H), 8.61-8.52 (m, 2H), 8.02 (s, 1H), 7.83-7.75 (m, 1H), 7.55-7.00 (m, 11H), 6.68-6.62 (m, 1H), 6.37 (m, 1H), 6.18-6.10 (m, 1H), 4.25 (s, 1H), 3.83 (s, 3H), 3.73-3.68 (m, 1H), 3.47-3.35 (m, 1H), 3.31-3.17 (m, 3H), 3.09-2.60 (m, 9H), 2.42-2.20 (m, 1H), 2.12-1.95 (m, 2H), 1.74-1.52 (m, 6H), 1.39-1.22 (m, 12H), 1.20-1.00 (m, 9H)。MS (ESI, m/e) [M+1]+ 1076.1。 | ||
289 | 2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(6-((R)-2-(2-異丙基苯基)-4-(3-甲氧基-4-(三氟甲基)苄基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.55 (s, 1H), 11.35 (br, 1H), 8.60-8.54 (m, 2H), 8.08 (s, 1H), 7.84-7.78 (m, 1H), 7.58-7.50 (m, 3H), 7.46-7.03 (m, 8H), 6.13-6.06 (m, 1H), 5.54 (s, 1H), 4.24 (s, 1H), 3.86 (s, 3H), 3.73-3.44 (m, 7H), 3.31-3.19 (m, 3H), 2.87-2.55 (m, 4H), 2.35-2.20 (m, 1H), 2.12-1.95 (m, 2H), 1.74-1.52 (m, 6H), 1.39-1.22 (m, 9H), 1.20-1.00 (m, 7H)。MS (ESI, m/e) [M+1]+ 1084.1。 | ||
290 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(6-((R)-2-(2-異丙基苯基)-4-(3-甲氧基-4-(三氟甲基)苄基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.73 (s, 1H), 11.28 (br, 1H), 8.62-8.58 (m, 2H), 8.04 (s, 1H), 7.86-7.82 (m, 1H), 7.62-7.52 (m, 3H), 7.47-7.03 (m, 8H), 6.44-6.38 (m, 1H), 6.07-6.04 (m, 1H), 5.49 (s, 1H), 4.25 (s, 1H), 3.86 (s, 3H), 3.73-3.44 (m, 7H), 3.31-3.19 (m, 3H), 2.89-2.54 (m, 4H), 2.35-2.20 (m, 1H), 2.09-1.93 (m, 2H), 1.74-1.52 (m, 6H), 1.39-1.22 (m, 9H), 1.20-1.00 (m, 7H)。MS (ESI, m/e) [M+1]+ 1066.2。 | ||
291 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(2-(2-氟-6-異丙基苯基)-4-(4-甲氧基苄基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.69 (s, 1H), 11.51-11.18 (m, 1H), 8.56 (d,J = 7.6 Hz, 2H), 8.02 (s, 1H), 7.79-7.75 (m, 1H), 7.54-7.44 (m, 3H), 7.30-7.20 (m, 3H), 7.16 (s, 1H), 7.08 (d,J = 9.4 Hz, 1H), 6.94 (s, 3H), 6.65 (d,J = 8.2 Hz, 1H), 6.37 (s, 1H), 6.13 (s, 1H), 4.25 (s, 1H), 3.83-3.70 (m, 3H), 3.28-3.25 (m, 2H), 3.05-2.85 (s, 8H), 2.04-1.97 (m, 1H), 1.75-1.50 (m, 7H), 1.39-1.20 (m, 15H), 1.12-1.0 (m, 9H)。MS (ESI, m/e) [M+1]+ 1044.0 | ||
292 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-((2R)-2-(2-異丙基苯基)-4-((4-甲氧基二環[4.2.0]八-1,3,5-三烯-7-基)甲基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.69 (s, 1H), 11.49-11.03 (m, 1H), 8.58-8.56 (m, 2H), 8.02 (s, 1H), 7.78 (d,J = 8.4 Hz, 1H), 7.55-7.42 (m, 3H), 7.35-7.20 (m, 3H), 7.11-6.95 (m, 2H), 6.80-6.60 (m, 3H), 6.38 (s, 1H), 6.14 (s, 1H), 4.25 (s, 1H), 3.69 (s, 5H), 3.43 (s, 1H), 3.30-3.25 (m, 3H), 3.05-2.85 (m, 10H), 2.73 (s, 1H), 2.06 (s, 1H), 1.75-1.50 (m, 7H), 1.30-1.0 (m, 21H)。MS (ESI, m/e) [M+1]+ 1052.1。 | ||
293 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-((R)-4-(4-異丁基-3-甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.69 (s, 1H), 11.51-11.24 (m, 1H), 8.58-8.56 (m, 3H), 8.02 (s, 1H), 7.78 (d,J = 8.4 Hz, 2H), 7.54-7.40 (m, 3H), 7.35 (s, 1H), 7.30-7.15 (m, 2H), 7.08 (d,J = 9.0 Hz, 1H), 6.90-6.80 (m, 3H), 6.65 (d,J = 8.6 Hz, 2H), 6.37 (s, 1H), 6.13 (s, 1H), 4.25 (s, 1H), 3.80-3.75 (m, 3H), 3.62-3.55 (m, 1H), 3.30-3.27 (s, 2H), 3.05-2.85 (m, 7H), 2.67 (s, 1H), 2.39 (s, 2H), 2.08-1.94 (m, 1H), 1.82 (s, 1H), 1.75-1.50 (m, 6H), 1.35-1.0 (m,2 2H), 0.85-0.78 (m, 7H)。MS (ESI, m/e) [M+1]+ 1082.1。 | ||
294 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-((R)-4-(4-環戊基-3-甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.69 (s, 1H), 11.35 (s, 1H), 8.57-8.55 (m, 2H), 8.02 (s, 1H), 7.91-7.73 (m, 1H), 7.50-7.48 (m, 3H), 7.37-7.03 (m, 6H), 6.87-6.84 (m, 2H), 6.65 (d,J = 9.0 Hz, 1H), 6.37 (s, 1H), 6.13 (s, 1H), 4.25 (s, 1H), 3.79-3.75 (m, 4H), 3.59 (s, 1H), 3.39 (s, 1H), 3.28 (s, 4H), 3.05-2.85 (m, 7H), 2.05 (s, 1H), 1.88 (s, 2H), 1.79-1.39 (m, 14H), 1.38-1.01 (m, 20H)。MS (ESI, m/e) [M+1]+ 1094.1。 | ||
295 | 2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(6-((R)-2-(2-異丙基苯基)-4-((7-甲氧基-3,3-二甲基-2,3-二氫苯并呋喃-5-基)甲基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.56 (s, 1H), 11.39 (br, 1H), 8.63-8.54 (m, 2H), 8.08 (s, 1H), 7.85-7.77 (m, 1H), 7.58-6.71 (m, 10H), 6.09-6.03 (m, 1H), 5.52 (s, 1H), 4.27-3.82 (m, 4H), 3.73 (s, 3H), 3.70-3.35 (m, 7H), 3.31-3.17 (m, 3H), 3.09-2.60 (m, 6H), 2.47-2.30 (m, 1H), 2.05-1.95 (m, 2H), 1.74-1.52 (m, 6H), 1.39-1.22 (m, 14H), 1.20-1.00 (m, 6H)。MS (ESI, m/e) [M+1]+ 1086.1。 | ||
296 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(6-((R)-2-(2-異丙基苯基)-4-((7-甲氧基-3,3-二甲基-2,3-二氫苯并呋喃-5-基)甲基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.73 (s, 1H), 11.30 (br, 1H), 8.63-8.57 (m, 2H), 8.04 (s, 1H), 7.85-7.77 (m, 1H), 7.62-6.71 (m, 10H), 6.43-6.38 (m, 1H), 6.06-6.03 (m, 1H), 5.47 (s, 1H), 4.27-3.75 (m, 4H), 3.72 (s, 3H), 3.70-3.35 (m, 7H), 3.31-3.17 (m, 3H), 3.09-2.60 (m, 6H), 2.47-2.31 (m, 1H), 2.05-1.95 (m, 2H), 1.74-1.52 (m, 6H), 1.39-1.22 (m, 14H), 1.20-1.00 (m, 6H)。MS (ESI, m/e) [M+1]+ 1068.1。 | ||
297 | 4-(6-((R)-4-((2,3-二氫苯并呋喃-6-基)甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)-2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.55 (s, 1H), 11.50 (br, 1H), 8.61-8.57 (m, 2H), 8.08 (s, 1H), 7.83-7.79 (m, 1H), 7.58-7.05 (m, 9H), 6.87-6.64 (m, 2H), 6.06-6.03 (m, 1H), 5.52 (s, 1H), 4.52-4.48 (m, 2H), 4.24 (s, 1H), 3.73-3.44 (m, 6H), 3.31-3.19 (m, 3H), 3.17-2.55 (m, 7H), 2.35-2.20 (m, 1H), 2.06-1.95 (m, 2H), 1.74-1.52 (m, 6H), 1.39-1.22 (m, 8H), 1.20-1.00 (m, 8H)。MS (ESI, m/e) [M+1]+ 1027.9。 | ||
298 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(6-((R)-4-((2,3-二氫苯并呋喃-6-基)甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.73 (s, 1H), 11.26 (br, 1H), 8.61-8.56 (m, 2H), 8.04 (s, 1H), 7.85-7.79 (m, 1H), 7.61-7.10 (m, 9H), 6.92-6.70 (m, 2H), 6.45-6.38 (m, 1H), 6.06-6.03 (m, 1H), 5.47 (s, 1H), 4.57-4.46 (m, 2H), 4.25 (s, 1H), 3.70-3.45 (m, 6H), 3.31-3.19 (m, 3H), 3.18-2.55 (m, 7H), 2.35-2.20 (m, 1H), 2.06-1.95 (m, 2H), 1.74-1.52 (m, 6H), 1.39-1.22 (m, 8H), 1.20-1.00 (m, 8H)。MS (ESI, m/e) [M+1]+ 1010.0。 | ||
299 | 2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-((R)-2-(2-異丙基苯基)-4-((8-甲氧基口克唍-6-基)甲基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.50 (s, 1H), 8.59-8.46 (m, 2H), 8.05 (d,J = 2.4 Hz, 1H), 7.76 (d,J = 8.4 Hz, 1H), 7.55-7.39 (m, 4H), 7.27 (s, 3H), 7.05 (d,J = 9.0 Hz, 1H), 6.67 (d,J = 8.4 Hz, 2H), 6.21 (s, 1H), 4.25 (s, 1H), 4.09 (s, 2H), 3.88 (s, 1H), 3.70 (s, 3H), 3.28 (s, 3H), 3.05-2.85 (m, 8H), 2.67 (s, 3H), 2.39 (s, 1H), 1.86 (s, 2H), 1.75-1.50 (m, 7H), 1.38-0.98 (m, 22H)。MS (ESI, m/e) [M+1]+ 1100.0 | ||
300 | 4-(2-((R)-4-((4,4-二甲基口克唍-7-基)甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.51 (s, 1H), 10.93 (s, 0H), 8.57-8.50 (m, 2H), 8.05 (d,J = 2.4 Hz, 1H), 7.77 (d,J = 8.4 Hz, 1H), 7.60-7.20 (m, 8H), 7.06 (d,J = 9.2 Hz, 1H), 6.85-6.75 (m, 1H), 6.67 (d,J = 8.2 Hz, 1H), 6.20 (s, 1H), 4.26 (s, 1H), 4.11 (s, 2H), 3.76 (s, 1H), 3.51 (s, 1H), 3.28 (s, 3H), 3.05-2.85 (m, 7H), 2.73 (s, 2H), 2.13-1.96 (m, 1H), 1.78-1.49 (m, 10H), 1.40-1.05 (m, 28H)。MS (ESI, m/e) [M+1]+ 1097.9。 | ||
301 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-((R)-4-((4,4-二甲基口克唍-7-基)甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.69 (s, 1H), 11.26 (s, 1H), 8.59-8.49 (m, 2H), 8.02 (d,J = 2.4 Hz, 1H), 7.78 (d,J = 7.6 Hz, 1H), 7.51-7.41 (m, 3H), 7.30-7.20 (m, 4H), 7.06 (d,J = 9.4 Hz, 1H), 6.65 (d,J = 8.2 Hz, 3H), 6.37 (s, 1H), 6.14 (s, 1H), 4.26 (s, 1H), 4.10 (s, 2H), 3.76 (s, 1H), 3.30-3.21 (m, 3H), 3.05-2.85 (m, 7H), 2.74-2.65 (m, 2H), 2.08 (s, 1H), 1.80-1.48 (m, 9H), 1.39-0.96 (m, 28H)。MS (ESI, m/e) [M+1]+ 1079.9。 | ||
302 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-((R)-2-(2-異丙基苯基)-4-((8-甲氧基口克唍-6-基)甲基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.68 (s, 1H), 8.56-8.53 (m, 2H), 8.01 (s, 1H), 7.77 (d,J = 9.4 Hz, 1H), 7.49-7.40 (m, 3H), 7.41-7.01 (m, 5H), 6.64 (d,J = 9.4 Hz, 2H), 6.37 (s, 1H), 6.14 (s, 1H), 4.25 (s, 1H), 4.08 (s, 2H), 3.69 (s, 3H), 3.55 (s, 3H), 3.28 (s, 3H), 3.05-2.85 (m, 7H), 2.69-2.60 (m, 3H), 1.86 (s, 2H), 1.71-1.50 (m, 7H), 1.35-1.07 (m, 22H)。MS (ESI, m/e) [M+1]+ 1082.9。 | ||
303 | 2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-((R)-2-(2-異丙基苯基)-4-((7-甲氧基-2,3-二氫苯并呋喃-5-基)甲基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.50 (s, 1H), 8.58-8.44 (m, 2H), 8.05 (d,J = 2.4 Hz, 1H), 7.76 (d,J = 9.2 Hz, 1H), 7.53-7.37 (m, 3H), 7.34-7.10 (m, 3H), 7.04 (d,J = 9.2 Hz, 1H), 6.97-6.77 (m, 2H), 6.67 (d,J = 7.6 Hz, 1H), 6.22 (s, 1H), 4.50 (t,J = 8.8 Hz, 2H), 4.26 (s, 1H), 4.00-3.58 (m, 6H), 3.30-3.22 (m, 3H), 3.18-2.54 (m, 12H), 1.79-1.47 (m, 7H), 1.43-0.92 (m, 20H)。MS (ESI, m/e) [M+1]+ 1086.1 | ||
304 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-((R)-4-((2,3-二氫苯并呋喃-6-基)甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.70 (s, 1H), 11.45-10.80 (m, 1H), 8.66-8.49 (m, 2H), 8.07-7.97 (m, 1H), 7.85-7..71 (m, 1H), 7.67-7.40 (m, 4H), 7.40-6.98 (m, 6H), 6.96-6.71 (m, 2H), 6.70-6.58 (m, 1H), 6.42-6.32 (m, 1H), 6.15 (s, 1H), 4.57-4.42 (m, 2H), 4.28 (s, 1H), 4.10-3.52 (m, 3H), 3.36-3.22 (m, 5H), 3.22-2.54 (m, 13H), 1.76-1.49 (m, 6H), 1.47-1.24 (m, 7H), 1.21-1.01 (m, 10H)。MS (ESI, m/e) [M+1]+ 1037.9 | ||
305 | 4-(2-((R)-4-((2,3-二氫苯并呋喃-6-基)甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.79-11.35 (m, 2H), 8.74-8.55 (m, 2H), 8.22-8.11 (m, 1H), 7.95-7.82 (m, 1H), 7.67-7.12 (m, 9H), 7.12-6.65 (m, 4H), 6.32 (s, 1H), 4.61 (s, 2H), 4.37 (s, 1H), 4.31-3.64 (m, 2H), 3.44-3.32 (m, 4H), 3.31-2.78 (m, 12H), 2.60-2.46 (m, 1H), 2.22-2.02 (m, 1H), 1.86-1.59 (m, 7H), 1.53-1.37 (m, 6H), 1.29-1.10 (m, 10H)。MS (ESI, m/e) [M+1]+ 1055.9 | ||
306 | 2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(6-((R)-2-(2-異丙基苯基)-4-((7-甲氧基苯并呋喃-5-基)甲基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.56 (s, 1H), 11.22 (br, 1H), 8.60-8.53 (m, 2H), 8.08 (s, 1H), 8.00-7.76 (m, 2H), 7.58-6.85 (m, 11H), 6.09-6.03 (m, 1H), 5.32 (s, 1H), 4.25 (s, 1H), 4.19-3.95 (m, 2H), 3.94 (s, 3H), 3.73-3.44 (m, 5H), 3.31-3.19 (m, 3H), 3.17-2.55 (m, 6H), 2.47-2.30 (m, 1H), 2.05-1.93 (m, 2H), 1.74-1.52 (m, 6H), 1.39-1.16 (m, 7H), 1.12-1.00 (m, 7H)。MS (ESI, m/e) [M+1]+ 1056.0。 | ||
307 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(6-((R)-2-(2-異丙基苯基)-4-((7-甲氧基苯并呋喃-5-基)甲基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.73 (s, 1H), 11.26 (br, 1H), 8.63-8.56 (m, 2H), 8.03-7.93 (m, 1H), 7.84-7.80 (m, 1H), 7.60-6.85 (m, 11H), 6.43-6.39 (m, 1H), 6.07-6.02 (m, 1H), 5.47 (s, 1H), 4.24 (s, 1H), 3.94 (s, 3H), 3.92-3.89 (m, 1H), 3.73-3.44 (m, 6H), 3.31-3.19 (m, 3H), 3.17-2.68 (m, 6H), 2.39-2.30 (m, 1H), 2.05-1.93 (m, 2H), 1.73-1.50 (m, 6H), 1.38-1.14 (m, 7H), 1.12-1.00 (m, 7H)。MS (ESI, m/e) [M+1]+ 1038.1。 | ||
308 | 4-(2-((R)-4-((3,3-二甲基-2,3-二氫苯并呋喃-6-基)甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.51 (s, 1H), 11.48 (br, 1H), 8.58-8.52 (m, 2H), 8.06 (s, 1H), 7.79-7.75 (m, 1H), 7.50-6.65 (m, 12H), 6.24-6.17 (m, 1H), 4.25 (s, 1H), 4.22-4.17 (m, 2H), 3.82-3.40 (m, 3H), 3.31-3.17 (m, 3H), 3.09-2.60 (m, 11H), 2.47-2.30 (m, 1H), 2.05-1.95 (m, 2H), 1.74-1.50 (m, 6H), 1.39-1.22 (m, 20H), 1.12-1.00 (m, 3H)。MS (ESI, m/e) [M+1]+ 1084.1。 | ||
309 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-((R)-4-((3,3-二甲基-2,3-二氫苯并呋喃-6-基)甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.69 (s, 1H), 11.51 (br, 1H), 8.62-8.57 (m, 2H), 8.02 (s, 1H), 7.82-7.75 (m, 1H), 7.54-6.62 (m, 12H), 6.39-6.36 (m, 1H), 6.17-6.11 (m, 1H), 4.25 (s, 1H), 4.22-4.17 (m, 2H), 3.82-3.40 (m, 3H), 3.31-3.17 (m, 3H), 3.09-2.60 (m, 11H), 2.47-2.30 (m, 1H), 2.09-1.90 (m, 2H), 1.73-1.50 (m, 6H), 1.39-.22 (m, 20H), 1.12-1.00 (m, 3H)。MS (ESI, m/e) [M+1]+ 1066.0。 | ||
310 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(6-((R)-4-((3,3-二甲基-2,3-二氫苯并呋喃-6-基)甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.73 (s, 1H), 11.30 (s, 1H), 10.45-10.00 (m, 1H), 8.57 (s, 2H), 8.04 (s, 1H), 7.82 (d,J = 8.2 Hz, 1H), 7.58-7.54 (m, 2H), 7.47-7.06 (m, 7H), 7.00-6.74 (m, 2H), 6.40 (s, 1H), 6.05 (s, 1H), 5.49 (s, 1H), 4.30-4.13 (m, 3H), 3.58-3.50 (m, 5H), 3.01 (s, 4H), 2.70 (s, 1H), 1.97 (s, 3H), 1.70-1.42 (m, 7H), 1.40-1.0 (m, 25H)。MS (ESI, m/e) [M+1]+ 1038.3。 | ||
311 | 4-(6-((R)-4-((3,3-二甲基-2,3-二氫苯并呋喃-6-基)甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)-2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.56 (s, 1H), 11.50-11.22 (m, 1H), 8.58-8.54 (m, 2H), 8.08 (s, 1H), 7.81 (d,J = 8.6 Hz, 1H), 7.58-7.04 (m, 8H), 6.90 (s, 2H), 6.07 (s, 1H), 5.53 (s, 1H), 4.25-4.20 (m, 3H), 3.60-3.52 (m, 5H), 3.41 (s, 1H), 3.31-3.18 (m, 3H), 2.97 (s, 3H), 2.73 (s, 2H), 2.33 (s, 1H), 1.98 (s, 2H), 1.72-1.45 (m, 6H), 1.40-1.0 (m, 21H)。MS (ESI, m/e) [M+1]+ 1056.4。 | ||
312 | 2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(6-((R)-2-(2-異丙基苯基)-4-((8-甲氧基口克唍-6-基)甲基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.56 (s, 1H), 11.43 (br, 1H), 8.61-8.53 (m, 2H), 8.08 (s, 1H), 7.84-7.78 (m, 1H), 7.58-6.55 (m, 10H), 6.10-6.03 (m, 1H), 5.52 (s, 1H), 4.25 (s, 1H), 4.17-3.75 (m, 4H), 3.71 (s, 3H), 3.69-3.40 (m, 5H), 3.31-3.20 (m, 3H), 3.17-2.60 (m, 8H), 2.43-2.30 (m, 1H), 2.04-1.93 (m, 2H), 1.92-1.83 (m, 2H), 1.73-1.50 (m, 6H), 1.38-1.14 (m, 7H), 1.12-1.00 (m, 7H)。MS (ESI, m/e) [M+1]+ 1071.9。 | ||
313 | 4-(6-((R)-4-((2,2-二甲基-2,3-二氫-[1,4]戴奧辛並[2,3-b]吡啶-8-基)甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)-2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.56 (s, 1H), 11.37 (br, 1H), 8.62-8.53 (m, 2H), 8.08 (s, 1H), 7.85-7.66 (m, 2H), 7.57-6.96 (m, 9H), 6.14-6.03 (m, 1H), 5.59-5.51 (m, 1H), 4.25 (s, 1H), 4.09-4.03 (m, 2H), 3.74-3.38 (m, 7H), 3.31-3.22 (m, 3H), 3.21-2.58 (m, 5H), 2.47-2.30 (m, 1H), 2.28-2.14 (m, 1H), 2.05-1.91 (m, 2H), 1.74-1.50 (m, 6H), 1.39-1.14 (m, 14H), 1.12-1.00 (m, 6H)。MS (ESI, m/e) [M+1]+ 1072.9。 | ||
314 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(6-((R)-4-((2,2-二甲基-2,3-二氫-[1,4]戴奧辛並[2,3-b]吡啶-8-基)甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.73 (s, 1H), 11.29 (br, 1H), 8.63-8.56 (m, 2H), 8.04 (s, 1H), 7.87-7.66 (m, 2H), 7.61-6.96 (m, 9H), 6.43-6.37 (m, 1H), 6.09-6.00 (m, 1H), 5.53 (s, 1H), 4.25 (s, 1H), 4.09-4.03 (m, 2H), 3.70-3.36 (m, 7H), 3.31-3.20 (m, 3H), 3.17-2.55 (m, 5H), 2.47-2.30 (m, 1H), 2.28-2.14 (m, 1H), 2.07-1.90 (m, 2H), 1.74-1.50 (m, 6H), 1.39-1.14 (m, 14H), 1.12-1.00 (m, 6H)。MS (ESI, m/e) [M+1]+ 1054.9。 | ||
315 | 4-(6-((R)-4-((2,2-二甲基-2,3-二氫苯并[b][1,4]戴奧辛-5-基)甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)-2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.56 (s, 1H), 11.45-11.26 (m, 1H), 8.60-8.55 (m, 2H), 8.08 (s, 1H), 7.80 (s, 1H), 7.57-7.50 (m, 2H), 7.45-7.40 (m, 2H), 7.30-7.28 (m, 2H), 7.12 (s, 2H), 6.85 (s, 3H), 6.07 (s, 1H), 5.52 (s, 1H), 4.25 (s, 1H), 3.93 (s, 2H), 3.75-3.48 (m, 5H), 3.29 (s, 3H), 3.05-2.9 (m, 3H), 2.67 (s, 1H), 1.98 (s, 2H), 1.71-1.48 (m, 6H), 1.39-0.99 (m, 24H)。MS (ESI, m/e) [M+1]+ 1072.8。 | ||
316 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(6-((R)-4-((3,3-二甲基-2,3-二氫-[1,4]戴奧辛並[2,3-b]吡啶-8-基)甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.73 (s, 1H), 11.26 (s, 1H), 8.63-8.52 (m, 2H), 8.04 (s, 1H), 7.85-7.78 (m, 1H), 7.75-7.63 (m, 1H), 7.63-7.49 (m, 2H), 7.48-7.28 (m, 3H), 7.28-7.04 (m, 4H), 6.96 (s, 1H), 6.40 (s, 1H), 6.12-5.98 (m, 1H), 5.49 (s, 1H), 4.25 (s, 1H), 3.92 (s, 2H), 3.75-3.44 (m, 7H), 3.33-3.18 (m, 3H), 3.09-2.52 (m, 5H), 2.39-1.86 (m, 5H), 1.74-1.49 (m, 6H), 1.38-1.26 (m, 7H), 1.22-1.03 (m, 11H)。MS (ESI, m/e) [M+1]+ 1055.0 | ||
317 | 4-(6-((R)-4-((3,3-二甲基-2,3-二氫-[1,4]戴奧辛並[2,3-b]吡啶-8-基)甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)-2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.56 (s, 1H), 11.35 (s, 1H), 8.63-8.45 (m, 2H), 8.08 (s, 1H), 7.87-7.76 (m, 1H), 7.76-7.64 (m, 1H), 7.59-7.47 (m, 2H), 7.47-7.30 (m, 2H), 7.30-7.03 (m, 4H), 6.97 (s, 1H), 6.14-6.00 (m, 1H), 5.54 (s, 1H), 4.25 (s, 1H), 3.93 (s, 2H), 3.77-3.46 (m, 7H), 3.33-3.21 (m, 3H), 3.05-2.56 (m, 4H), 2.34-1.88 (m, 4H), 1.77-1.50 (m, 6H), 1.42-1.25 (m, 8H), 1.23-1.02 (m, 12H)。MS (ESI, m/e) [M+1]+ 1073.0 | ||
318 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(6-((R)-2-(2-異丙基苯基)-4-((8-甲氧基口克唍-6-基)甲基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.73 (s, 1H), 11.08 (br, 1H), 8.63-8.56 (m, 2H), 8.04 (s, 1H), 7.84-7.79 (m, 1H), 7.60-7.08 (m, 8H), 6.94-6.55 (m, 2H), 6.43-6.38 (m, 1H), 6.07-6.02 (m, 1H), 5.48 (s, 1H), 4.25 (s, 1H), 4.13-3.75 (m, 4H), 3.70 (s, 3H), 3.65-3.40 (m, 5H), 3.31-3.20 (m, 3H), 3.17-2.60 (m, 8H), 2.39-2.30 (m, 1H), 2.05-1.93 (m, 2H), 1.92-1.83 (m, 2H), 1.73-1.50 (m, 6H), 1.38-1.14 (m, 7H), 1.12-1.00 (m, 7H)。MS (ESI, m/e) [M+1]+ 1054.0。 | ||
319 | (R)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(6-(4-(4-環丙基-3-甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)-N-((3-硝基-4-(((四氫-2H-哌喃-4-基)甲基)胺基)苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.68 (s, 1H), 8.64-8.44 (m, 2H), 7.98 (s, 1H), 7.82-7.72 (m, 1H), 7.56-7.32 (m, 3H), 7.26-6.86 (m, 5H), 6.81-6.62 (m, 2H), 6.34 (s, 1H), 5.98 (d,J = 8.7 Hz, 1H), 5.44 (s, 1H), 3.86-3.62 (m, 7H), 3.58-3.38 (m, 5H), 3.28-3.12 (m, 7H), 3.02-2.80 (m, 2H), 2.74-2.60 (m, 1H), 2.44-2.20 (m, 2H), 2.08-1.75 (m, 4H), 1.68-1.46 (m, 3H), 1.32-1.08 (m, 6H), 0.99 (s, 3H), 0.86-0.72 (m, 2H), 0.56-0.44 (m, 2H)。MS (ESI, m/e) [M+1]+ 1009.9。 | ||
320 | (R)-4-(6-(4-(4-環丙基-3-甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)-2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((3-硝基-4-(((四氫-2H-哌喃-4-基)甲基)胺基)苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.55 (s, 1H), 8.64-8.44 (m, 2H), 8.07 (s, 1H), 7.86-7.75 (m, 1H), 7.57-7.37 (m, 3H), 7.30-6.92 (m, 5H), 6.86-6.68 (m, 2H), 6.06 (d,J = 8.7 Hz, 1H), 5.55 (s, 1H), 3.91-3.67 (m, 7H), 3.66-3.45 (m, 5H), 3.33-3.18 (m, 7H), 3.08-2.88 (m, 2H), 2.77-2.66 (m, 1H), 2.49-2.22 (m, 2H), 2.12-1.82 (m, 4H), 1.76-1.54 (m, 3H), 1.40-1.14 (m, 6H), 1.06 (s, 3H), 0.92-0.78 (m, 2H), 0.64-0.50 (m, 2H)。MS (ESI, m/e) [M+1]+ 1028.1。 | ||
321 | 4-(6-((R)-4-(4-環丙氧基-3-甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)-2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.57 (s, 1H), 11.41 (br, 1H), 8.62-8.53 (m, 2H), 8.08 (s, 1H), 7.85-7.78 (m, 1H), 7.59-6.80 (m, 11H), 6.10-6.04 (m, 1H), 5.52 (s, 1H), 4.35-4.02 (s, 3H), 3.85-3.38 (m, 10H), 3.31-3.22 (m, 3H), 3.13-2.55 (m, 6H), 2.05-1.91 (m, 2H), 1.74-1.50 (m, 6H), 1.39-1.05 (m, 14H), 0.80-0.57 (m, 4H)。MS (ESI, m/e) [M+1]+ 1072.1。 | ||
322 | 2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(6-((R)-2-(2-異丙基苯基)-4-((7-(甲氧基-d3)苯并呋喃-5-基)甲基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.56 (s, 1H), 11.45 (br, 1H), 8.61-8.53 (m, 2H), 8.08 (s, 1H), 8.04-7.92 (m, 1H), 7.84-7.78 (m, 1H), 7.58-6.85 (m, 11H), 6.12-6.04 (m, 1H), 5.52 (s, 1H), 4.25 (s, 1H), 4.10-3.41 (m, 7H), 3.31-3.20 (m, 3H), 3.17-2.65 (m, 6H), 2.43-2.35 (m, 1H), 2.04-1.93 (m, 2H), 1.73-1.50 (m, 6H), 1.38-1.14 (m, 8H), 1.12-1.00 (m, 6H)。MS (ESI, m/e) [M+1]+ 1059.1。 | ||
323 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(6-((R)-2-(2-異丙基苯基)-4-((7-(甲氧基-d3)苯并呋喃-5-基)甲基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.73 (s, 1H), 11.29 (br, 1H), 8.63-8.55 (m, 2H), 8.04 (s, 1H), 8.02-7.92 (m, 1H), 7.86-7.79 (m, 1H), 7.58-6.85 (m, 11H), 6.43-6.38 (m, 1H), 6.10-6.02 (m, 1H), 5.47 (s, 1H), 4.25 (s, 1H), 4.10-3.41 (m, 7H), 3.31-3.20 (m, 3H), 3.17-2.65 (m, 6H), 2.43-2.35 (m, 1H), 2.04-1.93 (m, 2H), 1.73-1.50 (m, 6H), 1.38-1.14 (m, 8H), 1.12-1.00 (m, 6H)。MS (ESI, m/e) [M+1]+ 1041.0。 | ||
324 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(6-((R)-2-(2-異丙基苯基)-4-((7-(甲氧基-d3)-3,3-二甲基-2,3-二氫苯并呋喃-5-基)甲基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.73 (s, 1H), 11.30 (s, 1H), 8.58 (s, 2H), 8.04 (s, 1H), 7.82 (s, 1H), 7.60-7.50 (m, 2H), 7.48-7.08 (m, 6H), 6.99-6.90 (m, 2H), 6.40 (s, 1H), 6.05 (s, 1H), 5.46 (s, 1H), 4.35-4.10 (m, 2H), 3.53 (s, 3H), 3.65-3.53 (m, 3H), 1.97 (s, 1H), 1.75-1.50 (m, 4H), 1.40-1.0 (m, 14H)。MS (ESI, m/e) [M+1]+ 1070.9。 | ||
325 | 4-(6-((R)-4-(4-氯-3-甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)-2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.56 (s, 1H), 11.47-11.27 (m, 1H), 8.58-8.55 (m, 2H), 8.08 (s, 1H), 7.80 (s, 1H), 7.52 (s, 2H), 7.47-7.33 (m, 4H), 7.25 (s, 2H), 7.15-7.09 (m, 2H), 6.91 (s, 1H), 6.07 (s, 1H), 5.52 (s, 1H), 4.25 (s, 1H), 3.86 (s, 3H), 3.70-3.50 (m, 6H), 3.29 (s, 3H), 2.97 (s, 3H), 2.73 (s, 2H), 2.33 (s, 1H), 1.98 (s, 1H), 1.74-1.48 (m, 6H), 1.39-0.97 (m, 15H)。MS (ESI, m/e) [M+1]+ 1049.9。 | ||
326 | 2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(6-((R)-2-(2-異丙基苯基)-4-((7-(甲氧基-d3)-3,3-二甲基-2,3-二氫苯并呋喃-5-基)甲基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.56 (s, 1H), 11.41 (s, 1H), 8.58-8.56 (m, 2H), 8.08 (s, 1H), 7.81 (s, 1H), 7.60-7.50 (m, 2H), 7.45-7.40 (m,2H), 7.38-7.15 (m, 3H), 7.15-7.05 (m, 2H), 6.94 (s, 1H), 6.09-6.02 (m, 1H), 5.52 (s, 1H), 4.30-4.10 (m, 5H), 3.60-3.53 (m, 5H), 3.29 (s, 3H), 3.06 (s, 5H), 2.73 (s, 2H), 1.99 (s, 2H), 1.70-1.50 (m, 6H), 1.40-1.20 (m, 24H), 1.15-1.05 (m, 4H)。MS (ESI, m/e) [M+1]+ 1089.2 | ||
327 | 4-(6-((R)-4-(4-環丙基-3,5-二甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)-2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.91 (s, 1H), 11.40 (s, 1H), 8.83-8.65 (m, 2H), 8.22 (s, 1H), 8.08-7.95 (m, 1H), 7.84-7.67 (m, 2H), 7.67-7.19 (m, 7H), 7.03-6.67 (m, 2H), 6.58 (s, 1H), 6.29-6.15 (m, 1H), 5.65 (s, 1H), 4.42 (s, 1H), 4.32-4.13 (m, 1H), 4.00-3.58 (m, 13H), 3.48-3.31 (m, 5H), 3.28-3.05 (m, 3H), 3.02-2.78 (m, 2H), 2.21-2.08 (m, 2H), 2.04-1.92 (m, 1H), 1.91-1.65 (m, 7H), 1.57-1.28 (m, 10H), 1.22-1.18 (m, 1H), 1.12-1.00 (m, 2H), 0.93-0.83 (m, 2H)。MS (ESI, m/e) [M+1]+ 1085.9 | ||
328 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(6-((R)-4-(4-環丙基-3,5-二甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.56 (s, 1H), 11.30 (s, 1H), 8.63-8.42 (m, 2H), 8.08 (s, 1H), 7.88-7.74 (m, 1H), 7.61-6.99 (m, 10H), 6.91-6.60 (m, 2H), 6.18-6.00 (m, 1H), 5.52 (s, 1H), 4.25 (s, 1H), 4.16-3.90 (m, 1H), 3.77-3.46 (m, 12H), 3.32-3.16 (m, 7H), 3.12-2.90 (m, 3H), 2.82-2.63 (m, 2H), 1.98 (s, 2H), 1.86-1.42 (m, 8H), 1.40-1.15 (m, 8H), 1.06-0.97 (m, 2H), 0.94-0.86 (m, 2H), 0.75-0.65 (m, 2H)。MS (ESI, m/e) [M+1]+ 1067.9 | ||
329 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(6-((R)-2-(2-異丙基苯基)-4-((8-甲氧基-2,2-二甲基-2H-色烯-6-基)甲基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.68 (s, 1H), 11.25 (s, 1H), 8.52 (s, 2H), 7.99 (s, 1H), 7.78 (d,J = 8.4 Hz, 1H), 7.55-7.10 (m, 9H), 6.72-6.68 (m, 1H), 6.38-6.21 (m, 2H), 5.99 (s, 1H), 5.75-5.70 (m, 1H), 5.45-5.40 (m, 1H), 4.20 (s, 1H), 3.75-3.68 (m, 3H), 3.55-3.48 (m, 5H), 2.96 (s, 4H), 2.68 (s, 1H), 1.92 (s, 2H), 1.70-1.50 (m, 6H), 1.36-0.95 (m, 24H)。MS (ESI, m/e) [M+1]+ 1079.9 | ||
330 | 2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(6-((R)-2-(2-異丙基苯基)-4-((8-甲氧基-2,2-二甲基-2H-色烯-6-基)甲基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.51 (s, 2H), 8.53-8.50 (m, 2H), 8.03 (s, 1H), 7.75 (s, 1H), 7.56-6.92 (m, 9H), 6.68 (s, 1H), 6.32-6.28 (m, 1H), 6.02 (s, 1H), 5.69 (s, 1H), 5.47 (s, 1H), 4.20 (s, 1H), 4.04-3.85 (m, 1H), 3.74-3.41 (m, 9H), 3.19-3.11 (m, 1H), 2.94 (s, 3H), 2.69 (s, 1H), 1.93 (s, 2H), 1.72-1.42 (m, 7H), 1.35-0.97 (m, 22H)。MS (ESI, m/e) [M+1]+ 1097.9 | ||
331 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(6-((R)-2-(2-異丙基苯基)-4-((4-甲氧基苯并呋喃-6-基)甲基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.68 (s, 1H), 11.13 (s, 1H), 8.52 (s, 2H), 7.99 (s, 1H), 7.90-7.71 (m, 2H), 7.55-7.30 (m, 4H), 7.26-6.99 (m, 5H), 6.85 (s, 2H), 6.35 (s, 1H), 6.00 (s, 1H), 5.43 (s, 1H), 4.20 (s, 1H), 3.84 (s, 4H), 3.53-3.45 (m, 6H), 3.24-3.18 (m, 2H), 2.98-2.90 (m, 2H), 2.66 (s, 2H), 1.93 (s, 2H), 1.68-1.44 (m, 6H), 1.35-0.90 (m, 17H)。MS (ESI, m/e) [M+1]+ 1037.9 | ||
332 | 2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(6-((R)-2-(2-異丙基苯基)-4-((4-甲氧基苯并呋喃-6-基)甲基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.51 (s, 2H), 11.30 (s, 1H), 8.53-8.50 (m, 2H), 8.03 (s, 1H), 7.85-7.80 (m, 2H), 7.55-6.90 (m, 12H), 6.02 (s, 1H), 5.48 (s, 1H), 4.20 (s, 1H), 3.85 (s, 4H), 3.60-3.50 (m, 5H), 3.24 (s, 4H), 2.89-2.70 (m, 4H), 1.93 (s, 2H), 1.70-1.43 (m, 7H), 1.34-0.91 (m, 17H)。MS (ESI, m/e) [M+1]+ 1055.9 | ||
333 | 2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(6-((R)-2-(2-異丙基苯基)-4-((8-甲氧基-4,4-二甲基口克唍-6-基)甲基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.57 (s, 1H), 11.28 (s, 1H), 8.57-8.54 (m, 2H), 8.08 (s, 1H), 7.82-7.80 (m, 1H), 7.55-7.51 (m, 2H), 7.44-7.39 (m, 2H), 7.27-7.25 (m, 2H), 7.16-7.10 (m, 3H), 6.98 (s, 1H), 6.06 (d,J = 8.0 Hz, 1H), 5.53 (s,1H), 4.26 (s, 1H), 4.11 (s, 3H), 3.71-3.51 (m, 9H), 3.29-3.28 (m, 3H), 3.02-3.00 (m, 2H), 2.75-2.73 (m, 1H), 1.99-1.98 (m, 2H), 1.74-1.66 (m, 6H), 1.56-1.53 (m, 2H), 1.36-1.10 (m, 24H)。MS (ESI, m/e) [M+1]+ 1100.0。 | ||
334 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(6-((R)-2-(2-異丙基苯基)-4-((8-甲氧基-4,4-二甲基口克唍-6-基)甲基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.73 (s, 1H), 11.30 (s, 1H), 8.59-8.57 (m, 2H), 8.04 (s, 1H), 7.59 (s, 1H), 7.52 (s, 1H), 7.45-7.39 (m, 2H), 7.27-7.24 (m, 2H), 7.16-7.11 (m, 2H), 7.05 (s, 1H), 6.93 (s, 1H), 6.40 (s, 1H), 6.05-6.03 (m, 1H), 5.47 (s,1H), 4.26 (s, 1H), 4.11 (s, 3H), 3.71-3.48 (m, 9H), 3.29-3.28 (m, 3H), 3.02-3.00 (m, 2H), 2.75-2.73 (m, 1H), 1.99-1.98 (m, 2H), 1.74-1.66 (m, 6H), 1.55-1.52 (m, 2H), 1.36-1.09 (m, 24H)。MS (ESI, m/e) [M+1]+ 1081.9。 | ||
335 | 2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(6-((R)-2-(2-異丙基苯基)-4-((9-甲氧基-3,4-二氫-2H-苯并[b][1,4]二㗁呯-7-基)甲基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.53 (s, 1H), 11.29 (s, 1H), 8.55-8.52 (m, 2H), 8.07 (s, 1H), 7.80-7.78 (m, 1H), 7.50-7.39 (m, 4H), 7.21-7.09 (m, 4H), 6.63 (s, 1H), 6.52 (s, 1H), 6.06 (d,J = 8.0 Hz, 1H), 5.54 (s, 1H), 4.24 (s, 1H), 4.05-4.01 (m, 4H), 3.70 (s, 3H), 3.62-3.50 (m, 6H), 3.29-3.28 (m, 2H), 2.91-2.90 (m, 2H), 2.73-2.71 (m, 1H), 2.22-2.20 (m, 1H), 2.04-1.96 (m, 5H), 1.69-1.52 (m, 7H), 1.36-1.30 (m, 3H), 1.23-1.06 (m, 14H)。MS (ESI, m/e) [M+1]+ 1087.9。 | ||
336 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(6-((R)-2-(2-異丙基苯基)-4-((8-甲氧基-2,2-二甲基口克唍-6-基)甲基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.73 (s, 1H), 11.41 (br, 1H), 8.61-8.53 (m, 2H), 8.04 (s, 1H), 7.90-7.79 (m, 1H), 7.62-7.08 (m, 8H), 6.95-6.62 (m, 2H), 6.43-6.38 (m, 1H), 6.07-5.97 (m, 1H), 5.47 (s, 1H), 4.25 (s, 1H), 3.75-3.41 (m, 9H), 3.31-3.20 (m, 3H), 3.10-2.90 (m, 3H), 2.80-2.60 (m, 4H), 2.43-2.35 (m, 1H), 2.04-1.93 (m, 2H), 1.73-1.50 (m, 8H), 1.38-1.14 (m, 16H), 1.12-1.00 (m, 6H)。MS (ESI, m/e) [M+1]+ 1082.0。 | ||
337 | 2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(6-((R)-2-(2-異丙基苯基)-4-((8-甲氧基-2,2-二甲基口克唍-6-基)甲基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.55 (s, 1H), 11.32 (br, 1H), 8.61-8.53 (m, 2H), 8.07 (s, 1H), 7.82-7.76 (m, 1H), 7.58-7.08 (m, 8H), 6.95-6.60 (m, 2H), 6.08-5.99 (m, 1H), 5.53 (s, 1H), 4.25 (s, 1H), 3.90-3.41 (m, 9H), 3.31-3.20 (m, 3H), 3.10-2.90 (m, 3H), 2.80-2.60 (m, 4H), 2.43-2.35 (m, 1H), 2.04-1.92 (m, 2H), 1.75-1.50 (m, 8H), 1.38-1.12 (m, 16H), 1.12-1.00 (m, 6H)。MS (ESI, m/e) [M+1]+ 1099.9。 | ||
339 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(6-((R)-2-(2-異丙基苯基)-4-((7-甲氧基-2-甲基苯并呋喃-5-基)甲基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.68 (s, 1H), 11.06 (br, 1H), 8.59-8.51 (m, 2H), 7.99 (s, 1H), 7.80-7.76 (m, 1H), 7.58-7.00 (m, 10H), 7.21-6.81 (m, 6H), 6.44-6.42 (m, 1H), 6.35(s, 1H), 6.01-5.95 (m, 1H), 5.43 (s, 1H), 4.20 (s, 1H), 3.84 (s, 3H), 3.75-3.34 (m, 7H), 3.31-3.20 (m, 3H), 3.10-2.50 (m, 6H), 2.35 (s, 3H), 2.30-2.25 (m, 1H), 1.98-1.86 (m, 2H), 1.68-1.45 (m, 6H), 1.32-1.06 (m, 14H), 1.02-0.93 (m, 3H)。MS (ESI, m/e) [M+1]+ 1051.9 | ||
340 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(6-(2-(2-異丙基苯基)-4-甲苯磺醯基哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.68 (s, 1H), 11.25 (br, 1H), 8.58-8.52 (m, 2H), 7.99 (s, 1H), 7.82-7.74 (m, 1H), 7.57-7.35 (m, 7H), 7.23-6.97 (m, 5H), 6.34 (s, 1H), 6.01-5.94 (m, 1H), 5.41 (s, 1H), 4.20 (s, 1H), 3.65-3.34 (m, 7H), 3.31-3.20 (m, 3H), 2.93-2.84 (m, 1H), 2.68-2.57 (m, 1H), 2.34 (s, 3H), 2.32-2.25 (m, 1H), 2.17-2.06 (m, 2H), 1.95-1.82 (m, 2H), 1.67-1.45 (m, 6H), 1.33-1.12 (m, 7H), 1.12-1.00 (m, 7H)。MS (ESI, m/e) [M+1]+ 1031.7。 | ||
341 | 4-(6-((R)-4-(4-環丁基-3-甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)-2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.55 (s, 1H), 11.36-11.06 (m, 1H), 8.57-8.53 (m, 2H), 8.07 (s, 1H), 7.80 (d,J = 8.0 Hz, 1H), 7.55-7.35 (m, 4H), 7.30-6.85 (m, 7H), 6.06 (d,J = 8.0 Hz, 1H), 5.53 (s, 1H), 4.24 (s, 1H), 3.80-3.45 (m, 10H), 3.28 (s, 3H), 2.94 (s, 2H), 2.73 (s, 2H), 2.19 (s, 2H), 1.96 (s, 5H), 1.80-1.45 (m, 7H), 1.40-1.0 (m, 15H)。MS (ESI, m/e) [M+1]+ 1069.8。 | ||
342 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(6-((R)-4-(4-環丁基-3-甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.72 (s, 1H), 11.38-10.93 (m, 1H), 8.57 (s, 2H), 8.04 (s, 1H), 7.82 (d,J = 8.8 Hz, 1H), 7.60-7.50 (m, 2H), 7.48-7.40 (m, 2H), 7.30-7.1 (m, 5H), 6.86 (s, 2H), 6.40 (s, 1H), 6.04 (d,J = 8.0 Hz, 1H), 5.49 (s, 1H), 4.25 (s, 1H), 3.80-3.50 (m, 10H), 3.29 (s, 3H), 2.92 (s, 2H), 2.72 (s, 2H), 2.19 (s, 3H), 1.97 (s, 5H), 1.80-1.50 (m, 7H), 1.40-1.0 (m, 15H)。MS (ESI, m/e) [M+1]+ 1051.8 | ||
343 | 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(6-((R)-4-(4-環丙氧基-3-甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.68 (s, 1H), 11.25 (br, 1H), 8.58-8.49 (m,2H), 7.99 (s, 1H), 7.80-7.74 (m, 1H), 7.56-6.72 (m, 11H), 6.35 (s, 1H), 6.02-5.90 (m, 1H), 5.43 (s, 1H), 4.20 (s, 1H), 3.77-3.34 (m, 12H), 3.31-3.20 (m, 3H), 3.10-2.80 (m, 3H), 2.73-2.57 (m, 2H), 2.32-2.20 (m, 1H), 2.10-1.85 (m, 2H), 1.68-1.45 (m, 6H), 1.33-1.12 (m, 10H), 1.05-1.00 (m, 4H), 0.73-0.65 (m, 2H), 0.60-0.53 (m, 2H)。MS (ESI, m/e) [M+1]+ 1053.9 | ||
344 | N-((4-((((1r,3R,5S)-金剛烷-1-基)甲基)胺基)-3-硝基苯基)磺醯基)-2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(6-((R)-2-(2-異丙基苯基)-4-(4-甲氧基苄基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.49 (s, 1H), 8.47 (s, 2H), 8.01 (s, 1H), 7.73-7.71 (m, 1H), 7.48-7.44 (m, 2H), 7.39-7.37 (m, 2H), 7.19-7.07 (m, 7H), 6.85 (s, 2H), 6.01 (d,J = 8.0 Hz, 1H), 5.49 (s,1H), 3.67 (s, 3H), 3.56-3.45 (m, 6H), 3.03 (s, 2H), 2.90-2.88 (m, 2H), 2.65-2.63 (m, 1H), 1.93-1.89 (m, 5H), 1.64-1.50 (m, 16H), 1.18-1.13 (m, 7H), 1.00 (s, 3H)。MS (ESI, m/e) [M+1]+ 1037.9。 | ||
345 | 2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(6-((R)-2-(2-異丙基苯基)-4-(3-甲氧基-4-(氧雜環丁烷-3-基)苄基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.51 (s, 1H), 11.23 (br, 1H), 8.52-8.48 (m, 2H), 8.02 (s, 1H), 7.76-7.74 (m, 1H), 7.48-7.46 (m, 2H), 7.39-7.37 (m, 2H), 7.19-7.04 (m, 6H), 6.90 (s, 1H), 6.01 (d,J = 8.0 Hz, 1H), 5.49 (s,1H), 4.78 (s, 2H), 4.55 (s, 2H), 4.32-4.31 (m, 1H), 4.21 (s, 1H), 3.68 (s, 3H), 3.58-3.45 (m, 6H), 3.23 (s, 3H), 2.97-2.89 (m, 2H), 2.69-2.67 (m, 2H), 2.30-2.26 (m, 1H), 1.94 (s, 2H), 1.64-1.60 (m, 3H), 1.50-1.47 (m, 2H), 1.30-1.00 (m, 18H)。MS (ESI, m/e) [M+1]+ 1071.9 | ||
346 | 2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(6-((2R)-2-(2-異丙基苯基)-4-((八氫-5H-2,5-甲醇茚-5-基)甲基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.61 (s, 1H), 11.47 (s, 1H), 8.62-8.59 (m, 2H), 8.13 (s, 1H), 7.86 (s, 1H), 7.60-7.45 (m, 4H), 7.28-7.16 (m, 4H), 6.13-6.11 (m, 1H), 5.81 (s, 1H), 5.60 (s, 1H), 5.30 (s, 1H), 5.16-5.09 (m, 1H), 4.60-4.44 (m, 1H), 4.31 (s, 1H), 3.15-2.97 (m, 10H), 2.68-1.94 (m, 9H), 1.71-1.60 (m, 11H), 1.49-1.41 (m, 6H), 1.35-1.29 (m, 7H), 1.19-1.15 (m, 5H), 0.91 (s, 2H)。MS (ESI, m/e) [M+1]+ 1043.6。 | ||
347 | 2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(6-((R)-2-(2-異丙基苯基)-4-((9-甲氧基-2,3,4,5-四氫苯并[b]㗁呯-7-基)甲基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.56 (s, 1H), 11.43-11.07 (m, 1H), 8.58-8.55 (m, 2H), 8.08 (s, 1H), 7.80 (s, 1H), 7.52-7.44 (m, 4H), 7.19-7.16 (m, 4H), 6.75-6.65 (m, 2H), 6.07 (s, 1H), 5.55 (s, 1H), 4.27 (s, 1H), 3.88-3.51 (m, 12H), 2.94 (s, 2H), 2.68 (s, 4H), 2.30-2.24 (m, 1H), 1.99 (s, 3H), 1.86 (s, 2H), 1.73-1.50 (m, 9H), 1.40-1.0 (m, 17H)。MS (ESI, m/e) [M+1]+ 1085.7。 | ||
348 | 4-(6-((R)-4-(4-(環己基氧基)-3-甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)-2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.59 (s, 1H), 11.30 (br, 1H), 8.60-8.57 (m, 2H), 8.11 (s, 1H), 7.85-7.83 (m, 1H), 7.55 (s, 2H), 7.49-7.47 (m, 2H), 7.28-7.25 (m, 2H), 7.14-7.12 (m, 3H), 6.95-6.86 (m, 2H), 6.10 (d,J = 8.0 Hz, 1H), 5.58 (s,1H), 4.30 (s, 1H), 4.24 (s, 1H), 3.77 (m, 3H), 3.66-3.55 (m, 5H), 3.33 (s, 3H), 3.09-2.99 (m, 2H), 2.79-2.77 (m, 1H), 2.38-2.36 (m, 1H), 2.04-2.01 (m, 2H), 1.90-1.88 (m, 2H), 1.73-1.71 (m, 6H), 1.59-1.56 (m, 3H), 1.43-1.08 (m, 24H)。MS (ESI, m/e) [M+1]+ 1113.9。 | ||
349 | 2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(6-((R)-4-(4-異丙氧基-3-甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.46 (s, 1H), 8.4-8.45 (m, 2H), 8.00 (s, 1H), 7.73-7.70 (m, 1H), 7.43-7.35 (m, 4H), 7.16-6.99 (m, 4H), 6.85-6.79 (m, 2H), 6.72-6.70 (m, 1H), 6.01-5.99 (m, 1H), 5.50 (s, 1H), 4.41 (s, 1H), 4.20 (s, 1H), 3.65 (s, 3H), 3.56-3.45 (m, 6H), 3.22-3.16 (m, 4H), 2.87 (s, 3H), 2.68 (s, 3H), 2.16 (s, 3H), 1.98-1.91 (m, 3H), 1.64-1.61 (m, 4H), 1.31-1.24 (m, 3H), 1.14-0.96 (m, 12H)。MS (ESI, m/e) [M+1]+ 1074.65。 | ||
350 | 4-(6-((R)-4-(4-環丁氧基-3-甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)-2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.52 (s, 1H), 8.55-8.51 (m, 2H), 8.06 (s, 1H), 7.79-7.76 (m, 1H), 7.49 (s, 1H), 7.44-7.39 (m, 3H), 7.22-7.05 (m, 4H), 6.93 (s, 1 H), 6.75-6.71 (m, 2H), 6.07-6.05 (m, 1H), 5.54 (s, 1H), 4.57 (s, 1H), 4.25 (s, 1H), 3.71 (s, 3H), 3.61-3.49 (m, 6H), 3.27-3.21 (m, 4H), 2.93 (s, 3H), 2.72 (s, 3H), 2.35 (s, 3H), 2.23 (s, 3H), 2.01-1.96 (m, 4H), 1.94-1.51 (m, 9H), 1.35-1.29 (m, 3H), 1.18-1.03 (m, 12H)。MS (ESI, m/e) [M+1]+ 1086.13。 | ||
351 | 2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(6-((R)-2-(2-異丙基苯基)-4-(3-甲氧基-4-(氧雜環丁烷-3-基氧基)苄基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.53 (s, 1H), 8.54-8.51 (m, 2H), 8.06 (s, 1H), 7.79-7.77 (m, 1H), 7.49 (s, 1H), 7.45-7.39 (m,3H), 7.21-7.08 (m, 4H),6.75-6.73 (m, 1H), 6.53-6.51 (m, 1H), 6.07-6.05 (m, 1H), 5.55 (s, 1H), 5.15 (s, 1H), 4.85 (s, 2H), 4.51 (s, 2H), 4.25 (s, 1H), 3.74 (s, 3H), 3.60-3.49 (m, 6H), 3.27-3.24 (m, 4H), 2.90 (s, 2H), 2.71 (s, 1H), 2.57 (s, 1H), 2.20 (s, 2H), 2.01-1.94 (m, 3H), 1.68-1.66 (m, 4H), 1.55-1.51 (m, 2H), 1.35-1.29 (m, 3H), 1.17-1.02 (m, 12H)。MS (ESI, m/e) [M+1]+ 1088.17。 | ||
352 | 2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(6-((2R)-2-(2-異丙基苯基)-4-(((1r,5R,7S)-3-甲氧基金剛烷-1-基)甲基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.58 (s, 1H), 11.42 (br, 1H), 8.59-8.56 (m, 2H), 8.10 (s, 1H), 7.83-7.81 (m, 1H), 7.55-7.53 (m, 2H), 7.47-7.45 (m, 2H), 7.27-7.11 (m, 4H), 6.09 (d,J = 8.0 Hz, 1H), 5.57 (s,1H), 4.28 (s, 1H), 3.65-3.53 (m, 5H), 3.31 (s, 3H), 3.06 (s, 3H), 2.88-2.84 (m, 2H), 2.13-2.00 (m, 5H), 1.72-1.12 (m, 39H), MS (ESI, m/e) [M+1]+ 1074.7。 | ||
353 | 2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(6-((R)-2-(2-異丙基苯基)-4-(4-甲氧基苯甲醯基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.55 (s, 1H), 11.41 (s, 1H), 8.57-8.54 (m, 2H), 8.08 (s, 1H), 7.82-7.80 (m, 2H), 7.55-7.51 (m, 2H), 7.44-7.36 (m, 4H), 7.20-7.10 (m, 4H), 6.93 (s, 1H), 6.07-6.05 (m, 2H), 5.53 (s, 1H), 4.25 (s, 1H), 3.75 (s, 3H), 3.61-3.51 (m, 5H), 3.28 (s, 3H), 2.96 (s, 3H), 2.76 (s, 6H), 2.07-1.95 (m, 3H), 1.69-1.66 (m, 4H), 1.55-1.52 (m, 2H), 1.36-1.29 (m, 3H), 1.16-1.09 (m, 11H), 0.84 (s, 2H)。MS (ESI, m/e) [M+1]+ 1029.9。 | ||
354 | 4-(6-((R)-4-((4,4-二氟-8-甲氧基口克唍-6-基)甲基)-2-(2-異丙基苯基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)-2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.48 (s, 1H), 11.28 (br, 1H), 8.50-8.47 (m, 2H), 8.01 (s, 1H), 7.74-7.73 (m, 1H), 7.45-7.37 (m, 4H), 7.16-6.96 (m, 6H), 6.02-6.00 (m, 1H), 5.50 (s, 1H), 4.21 (s, 3H), 3.69 (s, 3H), 3.57-3.45 (m, 6H), 3.29 (s, 3H), 2.85 (s, 2H), 2.68 (s, 1H), 2.17 (s, 2H), 1.97-1.93 (m, 3H), 1.61-1.47 (m, 7H), 1.30-0.99 (m, 16H), 0.81 (s, 1H)。MS (ESI, m/e) [M+1]+ 1108.1。 | ||
355 | 2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(6-((2R)-2-(2-異丙基苯基)-4-((3-甲氧基八氫-5H-2,5-甲醇茚-5-基)甲基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.53 (s, 1H), 8.54-8.51 (m, 2H), 8.06 (s, 1H), 7.78-7.77 (m, 1H), 7.49-7.39 (m, 4H), 7.22-7.09 (m, 4H), 6.07-6.05 (m, 2H), 5.55 (s, 1H), 4.25 (s, 1H), 3.61-3.50 (m, 5H), 3.28 (s, 3H), 3.19 (s, 4H), 2.79-2.72 (m, 3H), 2.19 (s, 2H), 1.99-1.92 (m, 6H), 1.81 (s, 2H), 1.69-1.52 (m, 13H), 1.39-1.29 (m, 6H), 1.21-1.09 (m, 13H)。MS (ESI, m/e) [M+1]+ 1073.9。 | ||
356 | 2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(6-((R)-2-(2-異丙基苯基)-4-(4-甲氧基苄基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)-N-((4-((((1S,3R,7S)-4-甲氧基金剛烷-1-基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.50 (s, 1H), 8.48-8.45 (m, 2H), 8.02 (s, 1H), 7.74-7.72 (m, 1H), 7.46 (s, 2H), 7.37-7.35 (m, 2H), 7.22-7.08 (m, 6H), 6.87-6.85 (m, 2H), 6.01 (d,J = 8.0 Hz, 1H), 5.49 (s,1H), 3.68 (s, 3H), 3.58-3.43 (m, 5H), 3.20-3.18 (m, 5H), 3.12-3.10 (m, 1H), 3.06-3.05 (m, 1H), 2.91-2.89 (m, 1H), 2.69-2.65 (m, 1H), 2.22-2.19 (m, 1H), 2.03-1.93 (m, 5H), 1.82-1.81 (m, 1H), 1.72-1.46 (m, 9H), 1.29-1.10 (m, 10H), 1.02-1.01 (m, 3H), MS (ESI, m/e) [M+1]+ 1068.0。 | ||
357 | 2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(6-((R)-2-(2-異丙基苯基)-4-(4-甲氧基苄基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)-N-((4-((((1r,5R,7S)-3-甲氧基金剛烷-1-基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.51 (s, 1H), 8.50 (s, 2H), 8.05 (s, 1H), 7.76-7.73 (m, 1H), 7.49-7.39 (m, 4H), 7.21-7.10 (m, 6H), 6.87-6.85 (m, 2H), 6.06-6.04 (m, 1H), 5.55 (s, 1H), 3.71 (s, 3H), 3.62-3.46 (m, 7H), 3.31 (s, 2H), 3.21-3.19 (m, 3H), 3.08 (s, 3H), 2.89-2.87 (m, 2H), 2.71 (s, 1H), 2.17 (s, 4H), 2.01-1.94 (m, 2H), 1.64-1.55 (m, 5H), 1.50-1.41 (m, 8H), 1.34-1.29 (m, 1H), 1.18-1.17 (m, 3H), 1.04-1.03 (m, 3H)。MS (ESI, m/e) [M+1]+ 1068.4。 | ||
358 | 2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(6-((R)-2-(2-異丙基苯基)-4-(3-甲氧基-4-(甲基胺基)苄基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.61 (s, 1H), 8.62-8.59 (m, 2H), 8.14-8.13 (m, 1H), 7.86-7.84 (m, 1H), 7.57 (s, 2H), 7.52-7.47 (m, 2H), 7.33-7.30 (m, 2H), 7.24-7.21 (m, 2H), 7.15-7.13 (m, 1H), 6.97-6.87 (m, 2H), 6.48-6.46 (m, 1H), 6.14-6.11 (m, 1H), 5.61 (s, 1H), 4.32 (s, 1H), 3.85-3.82 (m, 4H), 3.70-3.55 (m, 6H), 3.36-3.33 (m, 2H), 3.06-3.04 (m, 2H), 2.75-2.73 (m, 4H), 2.08-2.04 (m, 2H), 1.76-1.70 (m, 4H), 1.62-1.59 (m, 2H), 1.42-1.16 (m, 21H), MS (ESI, m/e) [M+1]+ 1045.2。 | ||
359 | 2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(6-((R)-2-(2-異丙基苯基)-4-(3-甲氧基-4-(3-甲氧基氮雜環丁烷-1-基)苄基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.51 (s, 1H), 8.50-8.49 (m, 2H), 8.04 (s, 1H), 7.76-7.74 (m, 1H), 7.48-7.39 (m, 4H), 7.21-7.10 (m, 4H), 6.81-6.67 (m, 2H), 6.31-6.29 (m, 1H), 6.05 (d,J = 8.0 Hz, 1H), 5.55 (s,1H), 4.24 (s, 1H), 4.19-4.17 (m, 1H), 4.04-4.01 (m, 2H), 3.68 (s, 3H), 3.62-3.60 (m, 1H), 3.56-3.47 (m, 5H), 3.26-3.25 (m, 2H), 3.19 (s, 1H), 2.89-2.87 (m, 1H), 2.72-2.70 (m, 1H), 2.22-2.20 (m, 1H), 2.02-1.97 (m, 3H), 1.68-1.65 (m, 4H), 1.54-1.51 (m, 2H), 1.34-1.05 (m, 22H), MS (ESI, m/e) [M+1]+ 1101.5。 | ||
360 | 2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(6-((R)-4-(4-(異丙基胺基)-3-甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.60 (s, 1H), 8.62-8.58 (m, 2H), 8.13-8.12 (m, 1H), 7.86-7.83 (m, 1H), 7.56-7.46 (m, 4H), 7.32-7.12 (m, 5H), 7.02-7.00 (m, 1H), 6.87-6.85 (m, 1H), 6.56-6.54 (m, 1H), 6.12 (d,J = 8.0 Hz, 1H), 5.60 (s,1H), 4.56 (br, 1H), 4.32 (s, 1H), 3.96 (br, 1H), 3.85-3.82 (m, 4H), 3.69-3.54 (m, 6H), 3.35-3.32 (m, 3H), 3.05-3.03 (m, 1H), 2.80-2.78 (m, 1H), 2.46-2.44 (m, 1H), 2.04-2.03 (m, 2H), 1.75-1.70 (m, 4H), 1.61-1.58 (m, 2H), 1.41-1.35 (m, 3H), 1.29-1.25 (m, 4H), 1.19-1.15 (m, 16H), MS (ESI, m/e) [M+1]+ 1072.6。 | ||
361 | 2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(6-((R)-2-(2-異丙基苯基)-4-(3-甲氧基-4-𠰌啉代苄基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.52 (s, 1H), 8.53-8.50 (m, 2H), 8.06-8.05 (m, 1H), 7.78-7.76 (m, 1H), 7.49-7.39 (m, 4H), 7.21-7.04 (m, 4H), 6.89 (s, 1H), 6.79 (s, 2H), 6.07-6.04 (m, 1H), 5.55 (s, 1H), 4.25 (s, 1H), 3.75 (s, 3H), 3.69-3.67 (m, 4H), 3.62-3.47 (m, 7H), 3.31 (s, 2H), 3.28-3.25 (m, 2H), 2.91-2.88 (m, 6H), 2.72 (s, 1H), 2.59 (s, 1H), 2.23-2.19 (m, 1H), 2.03-1.95 (m, 2H), 1.69-1.62 (m, 4H), 1.55-1.51 (m, 2H), 1.35-1.29 (m, 3H), 1.23-1.02 (m, 13H)。MS (ESI, m/e) [M+1]+ 1100.8。 | ||
362 | 2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(6-((R)-2-(2-異丙基苯基)-4-(4-(氧雜環丁烷-3-基)苄基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.54 (s, 1H), 8.56-8.52 (m, 2H), 8.07-8.06 (m, 1H), 7.80-7.78 (m, 1H), 7.51-7.50 (m, 2H), 7.44-7.42 (m, 1H), 7.35-7.29 (m, 4H), 7.22-7.15 (m, 2H), 7.09-7.07 (m, 2H), 6.05-6.04 (m, 1H), 5.53 (s, 1H), 4.93-4.89 (m, 2H), 4.58-4.54 (m, 2H), 4.25 (s, 1H), 4.22-4.16 (m, 1H), 3.61-3.47 (m, 7H), 3.29-3.26 (m, 4H), 2.91-2.82 (m, 2H), 2.71 (s, 1H), 2.59 (s, 1H), 2.23-2.18 (m, 2H), 2.01-1.92 (m, 2H), 1.68-1.62 (m, 4H), 1.54-1.51 (m, 2H), 1.35-1.29 (m, 3H), 1.22-1.01 (m, 13H)。MS (ESI, m/e) [M+1]+ 1041.7。 | ||
363 | 4-(6-((R)-4-(3,4-二環丙氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)-2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.52 (s, 1H), 8.61-8.43 (m, 2H), 8.06 (d,J = 2.4 Hz, 1H), 7.77 (d,J = 8.4 Hz, 1H), 7.54-7.33 (m, 4H), 7.27-6.99 (m, 6H), 6.82 (d,J = 8.4 Hz, 1H), 6.06 (d,J = 8.8 Hz, 1H), 5.56 (s, 1H), 4.25 (s, 1H), 3.77-3.69 (m, 2H), 3.66-3.39 (m, 7H), 3.31-3.15 (m, 3H), 2.99-2.83 (m, 2H), 2.77-2.53 (m, 2H), 2.36-1.86 (m, 5H), 1.74-1.49 (m, 6H), 1.40-1.27 (m, 3H), 1.22-1.00 (m, 11H), 0.76-0.56 (m, 8H)。MS (ESI, m/e) [M+1]+ 1096.9。 | ||
364 | 4-(6-((R)-4-(3-環丙氧基-4-甲氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)-2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.56 (s, 1H), 11.12 (s, 1H), 8.59-8.54 (m, 2H), 8.09-8.08 (m, 1H), 7.82-7.80 (m, 1H), 7.53-7.52 (m, 2H), 7.47-7.42 (m, 2H), 7.25-7.22 (m, 3H), 7.14-7.09 (m, 2H), 6.90 (s, 1H), 6.08 (d,J = 8.0 Hz, 1H), 5.56 (s,1H), 4.27 (s, 1H), 3.80-3.50 (m, 12H), 3.24 (s, 1H), 3.32-3.28 (m, 2H), 3.04-2.97 (m, 2H), 2.73-2.69 (m, 1H), 2.30-2.28 (m, 1H), 2.02-2.00 (m, 2H), 1.71-1.65 (m, 4H), 1.57-1.54 (m, 2H), 1.37-1.31 (m, 3H), 1.25-1.08 (m, 14H), 0.76-0.73 (m, 2H), 0.65-0.62 (m, 2H)。MS (ESI, m/e) [M+1]+ 1071.6。 | ||
365 | 4-(6-((R)-4-(4-環丙氧基苄基)-2-(2-異丙基苯基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)-2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.18 (s, 1H), 8.21-8.16 (m, 2H),7.71-7.70 (m, 1H), 7.44-7.42 (m, 1H), 7.16-7.14 (m, 2H), 7.07-7.02 (m, 2H), 6.94-6.84 (m, 4H), 6.76-6.71 (m, 2H), 6.67-6.64 (m, 2H), 5.68 (d,J = 8.0 Hz, 1H), 5.15 (s,1H), 3.88 (s, 1H), 3.43 (s, 1H), 3.25-3.11 (m, 5H), 2.93-2.89 (m, 2H), 2.85-2.83 (m, 1H), 2.60-2.58 (m, 2H), 2.36-2.30 (m, 1H), 1.91-1.89 (m, 1H), 1.63-1.59 (m, 2H), 1.32-1.25 (m, 4H), 1.18-1.15 (m, 2H), 0.98-0.92 (m, 3H), 0.86-0.69 (m, 16H), 0.39-0.38 (m, 2H), 0.25-0.23 (m, 2H)。MS (ESI, m/e) [M+1]+ 1041.6。 | ||
366 | 2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(6-((R)-2-(2-異丙基苯基)-4-(3-甲氧基-4-((1-甲基氮雜環丁烷-3-基)氧基)苄基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.29 (s, 1H), 8.31-8.25 (m, 2H), 8.08-8.07 (m, 1H), 7.90-7.87 (m, 1H), 7.50-7.45 (m, 2H), 7.33-7.32 (m, 2H), 7.15-7.00 (m, 4H), 6.83 (s, 1H), 6.72-6.70 (m, 1H), 6.65-6.64 (m, 1H), 6.55-6.54 (m, 1H), 6.00-5.98 (m, 1H), 5.61-5.58 (m, 1H), 4.67-4.60 (m, 1H), 4.17 (s, 1H), 3.98-3.79 (m, 3H), 3.65 (s, 4H), 3.53-3.40 (m, 6H), 3.16-3.14 (m, 4H), 2.99-2.93 (m, 1H), 2.80-2.77 (m, 3H), 2.66-2.64 (m, 1H), 2.10 (s, 2H), 1.96-1.84 (m, 2H), 1.62-1.54 (m, 4H), 1.48-1.44 (m, 2H), 1.28-1.23 (m, 3H), 1.16-1.02 (m, 10H), 0.96-0.95 (m, 3H)。MS (ESI, m/e) [M+1]+ 1101.01。 | ||
367 | 2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(6-((R)-2-(2-異丙基苯基)-4-(3-甲氧基-4-(四氫-2H-哌喃-4-基)苄基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.52 (s, 1H), 8.54-8.51 (m, 2H), 8.06-8.05 (m, 1H), 7.79-7.76 (m, 1H), 7.49-7.40 (m, 4H), 7.20-7.08 (m, 5H), 6.90 (s, 1H), 6.84-6.82 (m, 1H), 6.07-6.04 (m, 1H), 5.55 (s, 1H), 4.25 (s, 1H), 3.91-3.89 (m, 2H), 3.75 (s, 3H), 3.62-3.47 (m, 7H), 3.43-3.36 (m, 2H), 3.31 (s, 2H), 3.29-3.26 (m, 2H), 3.08-3.01 (m, 1H), 2.91-2.88 (m, 2H), 2.72 (s, 1H), 2.23-2.19 (m, 1H), 2.02-1.96 (m, 2H), 1.68-1.51 (m, 10H), 1.35-1.29 (m, 3H), 1.23-1.09 (m, 10H), 1.02-1.00 (m, 3H)。MS (ESI, m/e) [M+1]+ 1099.4。 | ||
368 | 2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(6-((R)-2-(2-異丙基苯基)-4-(4-𠰌啉代苄基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.51 (s, 1H), 8.57-8.43 (m, 2H), 8.05 (d,J = 2.8 Hz, 1H), 7.76 (d,J = 8.4 Hz, 1H), 7.53-7.30 (m, 4H), 7.27-6.99 (m, 6H), 6.87 (d,J = 8.4 Hz, 2H), 6.05 (dd,J = 1.6 Hz, 8.8 Hz, 1H), 5.56 (s, 1H), 4.25 (s, 1H), 3.76-3.66 (m, 4H), 3.65-3.39 (m, 7H), 3.31-3.14 (m, 3H), 3.11-3.00 (m, 4H), 2.97-2.82 (m, 2H), 2.77-2.55 (m, 2H), 2.42-1.86 (m, 5H), 1.74-1.49 (m, 6H), 1.40-1.27 (m, 3H), 1.22-1.00 (m, 11H), 0.76-0.56 (m, 8H)。MS (ESI, m/e) [M+1]+ 1070.9。 | ||
369 | 2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(6-((R)-2-(2-異丙基苯基)-4-(3-甲氧基-4-(1-甲基氮雜環丁烷-3-基)苄基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.39 (s, 1H), 8.31-8.25 (m, 2H), 8.38 (s, 2H), 7.97 (s, 1H), 7.62-7.59 (m, 1H), 7.52-7.50 (m, 1H), 7.41 (s, 2H), 7.22-7.06 (m, 5H), 6.93 (s, 1H), 6.87-6.85 (m, 2H), 6.07-6.05 (m, 1H), 5.66 (s, 1H), 4.24 (s, 1H), 4.17 (s, 2H), 3.97 (s, 3H), 3.60-3.42 (m, 8H), 3.24-3.22 (m, 3H), 3.87-3.84 (m, 3H), 2.73 (s, 3H), 2.18-2.17 (m, 2H), 2.05-1.90 (m, 3H), 1.68-1.51 (m, 6H), 1.35-1.29 (m, 3H), 1.23-1.03 (m, 13H)。MS (ESI, m/e) [M+1]+ 1084.7。 | ||
370 | 2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(6-((R)-2-(2-異丙基苯基)-4-(4-(四氫-2H-哌喃-4-基)苄基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.53 (s, 1H), 8.54-8.51 (m, 2H), 8.06-8.05 (m, 1H), 7.78-7.76 (m, 1H), 7.49-7.38 (m, 4H), 7.22-7.16 (m, 6H), 7.07-7.04 (m, 2H), 6.06-6.04 (m, 1H), 5.54 (s, 1H), 4.25 (s, 1H), 3.93-3.90 (m, 2H), 3.60-3.47 (m, 6H), 3.43-3.36 (m, 2H), 3.31 (s, 1H), 3.28-3.25 (m, 2H), 2.89-2.86 (m, 2H), 2.72-2.66 (m, 2H), 2.25-2.18 (m, 2H), 2.02-1.95 (m, 3H), 1.69-1.51 (m, 11H), 1.35-1.29 (m, 3H), 1.22-1.09 (m, 10H), 1.01-0.99 (m, 3H)。MS (ESI, m/e) [M+1]+ 1069.8。 | ||
371 | 2-((3-氟-1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(6-((2R)-2-(2-異丙基苯基)-4-(4-(四氫呋喃-3-基)苄基)哌𠯤-1-基)-2-氮雜螺[3.3]庚烷-2-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.60 (s, 1H), 8.62-8.59 (m, 2H), 8.13 (s, 1H), 7.86-7.84 (m, 1H), 7.57-7.49 (m, 4H), 7.28-7.14 (m, 8H), 6.13-6.11 (m, 1H), 5.60 (s, 1H), 4.32 (s, 1H), 4.01-3.94 (m, 1H), 3.86-3.80 (m, 1H), 3.67-3.52 (m, 7H), 3.34-3.33 (m, 2H), 2.95-2.94 (m, 2H), 2.78-2.77 (m, 1H), 2.34-2.25 (m, 3H), 2.07-1.89 (m, 4H), 1.75-1.58 (m, 7H), 1.41-1.36 (m, 3H), 1.29-1.08 (m, 13H)。MS (ESI, m/e) [M+1]+ 1056.2。 |
在基於時間解析螢光共振能量轉移(TR-FRET)方法的測定中測試用配體阻斷Bcl-2蛋白之本文揭露的化合物。將重組人0.05 nM Bcl-2蛋白與本文揭露的化合物的連續稀釋液(最高的最終濃度為1 uM或0.1 uM或0.02 uM或0.01 uM,10點)在室溫下在含有20 mM磷酸鉀緩衝液(pH 7.5)、50 mM NaCl、1 mM EDTA、0.05%吐溫-20、0.01% BSA的測定緩衝液中預孵育0.5小時。然後將FITC標記的Bak肽Ac-GQVGRQLAIIGDK(FITC)INR-醯胺(0.5 nM)和MAb抗6His Tb穴狀化合物Gold添加到板中,並在室溫下再孵育1小時。在BMG PHERAstar FSX儀器上讀取TR-FRET信號(337 nm-520 nm-490 nm)。基於TR-FRET信號計算化合物在濃度漸增的情況下Bcl-2與其配體相互作用的抑制百分比。藉由Graphpad Prism軟體或Dotmatics將數據擬合到四參數邏輯斯諦方程,從而推導出每種化合物的IC50
。數據示於表3中。生物學實例: Bcl-2-G101V TR-FRET 測定
在基於時間解析螢光共振能量轉移方法的測定中測試用配體阻斷Bcl-2-G101V蛋白之本文揭露的化合物。將0.1 nM重組人Bcl-2-G101V蛋白與本文揭露的化合物的連續稀釋液(最高的最終濃度為10 uM或1 uM或0.1 uM,4倍或3倍連續稀釋,10點)在室溫下在含有20 mM磷酸鉀緩衝液(pH 7.5)、50 mM NaCl、1 mM EDTA、0.05%吐溫-20、0.01% BSA的測定緩衝液中預孵育0.5小時。然後將5 nM FITC標記的Bak肽Ac-GQVGRQLAIIGDK(FITC)INR-醯胺和Mab抗-6His Tb穴狀化合物Gold添加到板中,並在室溫下再孵育1小時。在BMG PHERAstar FSX儀器上讀取TR-FRET信號(ex337 nm、em490 nm/520 nm)。基於490 nm處與520 nm處的螢光比率,計算化合物在濃度漸增情況下對Bcl-2-G101V與其配體的相互作用的抑制百分比。藉由Graphpad Prism軟體或Dotmatics將數據擬合到四參數邏輯斯諦方程,從而推導出每種化合物的IC50。數據示於表3中。生物學實例: RS4;11 細胞增殖測定
將BCL-2依賴性急性淋巴球白血病(ALL)細胞系RS4;11用於研究BCL-2抑制劑的細胞效力。將細胞(ATCC,CRL-1873)在補充有10%胎牛血清(FBS)(吉博科公司(Gibco),10099-1441)、100單位/ml青黴素和100 μg/ml鏈黴素(吉博科公司,15140122)的RPMI-1640完全培養基(RPMI-1640培養基,HEPES(吉博科公司,22400-105))中培養並保持在37°C下的含有5% CO2
的加濕室中。連續稀釋每種化合物(以1 µM作為最大濃度)。為了測試化合物的凋亡作用,將細胞以180 μl/孔接種到96孔板中的50,000個孔中,並在37°C下用每種化合物的10點連續稀釋處理48小時。根據製造商的建議,在處理後使用CellTiter-GLO發光測定(普洛麥格公司(Promega))評估細胞活力。簡而言之,將30 μl的CellTiter-GLO試劑添加進200 μl的細胞培養物中。將混合物在定軌振盪器上攪拌5 min以確保細胞裂解,隨後在室溫孵育7 min以使發光信號生成和穩定,該等發光信號對應於ATP的量,從而對應於代謝活性細胞的量。使用PHERAstar FS測讀器(BMG)測量發光信號。用GraphPad Prism軟體確定平均IC50
值。數據示於表3中。生物學實例: Bcl 2-G101V 敲入 RS4;11 細胞增殖測定
(1) RS4;11 H96 Bcl 2-G101V敲入細胞系的產生
簡而言之,使用Crisper/Cas9基因編輯系統產生RS4;11 BCL2-G101V敲入細胞池並且將BCL2-G101V敲入單選殖H96從該敲入細胞池中挑出並且藉由WES(全外顯子組定序)和RNA-seq驗證。
將BCL-2依賴性急性淋巴球白血病(ALL)細胞系,RS4;11(ATCC,CRL-1873)在補充有10%胎牛血清(FBS)(吉博科公司,10099-1441)、100單位/ml青黴素和100 μg/ml鏈黴素(吉博科公司,15140122)的RPMI-1640完全培養基(RPMI-1640培養基,HEPES(吉博科公司,22400-105))中培養並保持在37°C下的含有5% CO2的加濕室中。
為了獲得BCL2-G101V敲入細胞池,將RS4;11與也表現GFP標記的Cas9-gRNA和含有BCL2-G101V突變序列的供體基因共轉染。在電穿孔48小時後,通過FACSAriaIII細胞分選系統收集GFP陽性細胞。回收細胞池3天,並且然後在2 nM ABT-199壓力下培養4週。TA選殖定序結果顯示ABT-199處理後池中的敲入率為9%。然後將細胞以1個細胞/孔鋪板於96孔U型板的10000孔中,以用於單選殖選擇。在生長3-5週後,藉由PCR定序依次篩選選殖。並挑取三個BCL2-G101V敲入選殖:H96、H142和H233。
藉由基因組DNA和cDNA(mRNA)PCR定序,以及使用西方墨點的BCL-2、BCL-xL和MCL-1表現驗證三個選殖。還藉由WES(全外顯子組定序)和RNA-seq驗證H96選殖。
(2) Bcl 2-G101V敲入RS4;11細胞增殖測定
將BCL-2 G101V敲入細胞系H96(源自RS4;11)用於研究BCL-2抑制劑的細胞效力。將細胞在補充有10%胎牛血清(FBS)(吉博科公司,10099-1441)、100單位/ml青黴素和100 μg/ml鏈黴素(吉博科公司,15140122)的RPMI-1640完全培養基(RPMI-1640培養基,HEPES(吉博科公司,22400-105))中培養並保持在37°C下的含有5% CO2
的加濕室中。連續稀釋每種化合物(以1 µM或10 µM作為最大濃度)。為了測試化合物的凋亡作用,將細胞以90 μl/孔接種到96孔板中的50,000個孔中,並在37°C下用每種化合物的10點連續稀釋處理48小時。根據製造商的建議,在處理後使用CellTiter-GLO發光測定(普洛麥格公司(Promega))評估細胞活力。簡而言之,將30 μl的CellTiter-GLO試劑添加進100 μl的細胞培養物中。將混合物在定軌振盪器上攪拌5 min以確保細胞裂解,隨後在室溫孵育7 min以使發光信號生成和穩定,該等發光信號對應於ATP的量,從而對應於代謝活性細胞的量。使用PHERAstar FS測讀器(BMG)測量發光信號。用GraphPad Prism軟體確定平均IC50
值。數據示於表3中。
[表 3
]:
ND:未確定;WT:野生型。生物學實例: Bcl-2-D103Y 生物化學測定
實例 | 生物化學測定( IC50 , nM ) | 細胞增殖測定( IC50 , nM ) | ||||
Bcl-2 WT | Bcl-2 G101V | Bcl-2 G101V/WT | RS4;11 的比率 | RS4;11 Bcl-2 G101V 敲入 | ||
2 | 0.011 | 0.25 | 22.7 | 0.53 | 3.94 | |
3a | 0.034 | 2.2 | 64.7 | 3.67 | 35.07 | |
3b | 0.0083 | 0.14 | 16.9 | |||
4 | 0.045 | 1.6 | 35.6 | 0.87 | 9.56 | |
5 | 0.037 | 0.45 | 12.2 | 0.58 | 5.329 | |
6 | 0.013 | 0.32 | 24.6 | 0.53 | 4.83 | |
8 | 0.02 | 0.32 | 16.0 | ND | ||
9 | 0.034 | 0.52 | 15.3 | 0.51 | 4.37 | |
10 | 0.012 | 0.21 | 17.5 | 0.42 | 3.16 | |
12 | 0.73 | 14 | 19.2 | 3.0 | 40.5 | |
13 | 0.011 | 0.37 | 33.6 | 0.7 | 5.67 | |
13a | 0.038 | 3.6 | 94.7 | 10.5 | 87.41 | |
13b | 0.0068 | 0.15 | 22.1 | 0.32 | 2.81 | |
14 | 0.0065 | 0.093 | 14.3 | 0.45 | 5.16 | |
16 | 0.26 | 1.7 | 6.5 | 0.81 | 8.6 | |
18 | 0.079 | 0.71 | 9.0 | 0.61 | 4.9 | |
19 | 0.086 | 0.66 | 7.7 | 0.33 | 1.9 | |
19a | 0.057 | 0.18 | 3.2 | 0.15 | 0.57 | |
19b | 0.16 | 10 | 62.5 | 6.8 | 44 | |
20 | 0.053 | 0.58 | 10.9 | 0.62 | 5.91 | |
22 | 0.013 | 0.079 | 6.1 | 0.46 | 2.6 | |
22a | 0.0079 | 0.064 | 8.1 | 0.25 | 1.35 | |
22b | 0.038 | 1.9 | 50.0 | 7.6 | 57.3 | |
23 | 0.45 | 2.1 | 4.7 | 0.39 | 2.66 | |
24a | 0.37 | 6.9 | 18.6 | 3.4 | ||
24b | 0.24 | 1.1 | 4.6 | 0.75 | 6.49 | |
26 | 0.11 | 1.4 | 12.7 | 0.85 | 8.48 | |
27 | 0.27 | 2.7 | 10.0 | 1.05 | 7.77 | |
28 | 0.23 | 0.82 | 3.6 | 0.39 | 2.686 | |
28a | 0.098 | 0.33 | 3.3 | 0.21 | 1.23 | |
29 | 0.29 | 1.5 | 5.2 | 0.43 | 2.95 | |
29a | 0.2 | 0.72 | 3.5 | 0.22 | 1.42 | |
30 | 0.27 | 1.1 | 4.1 | 0.53 | 3.48 | |
32 | 0.096 | 0.28 | 2.9 | 0.18 | 0.96 | |
34 | 0.049 | 1.8 | 36.7 | 1.3 | 13.9 | |
35 | 2.2 | 163 | 74.1 | ND | ND | |
36 | 0.58 | 16 | 27.6 | ND | ND | |
37 | 0.42 | 12 | 28.6 | 77.4 | 289 | |
38 | 0.053 | 4.1 | 77.4 | 2.5 | 37.5 | |
39 | 1.1 | 6.7 | 6.1 | ND | ND | |
40 | 0.19 | 1.3 | 6.8 | 0.85 | 8.4 | |
41 | 0.83 | 3.8 | 4.6 | 0.74 | 7.2 | |
42 | 0.41 | 2.5 | 6.1 | 1.8 | 13.5 | |
43 | 0.31 | 1.3 | 4.2 | 0.48 | 3.27 | |
44 | 0.3 | 0.84 | 2.8 | 0.5 | 3.31 | |
45 | 0.24 | 0.95 | 4.0 | 0.41 | 3.289 | |
46 | 0.34 | 2.7 | 7.9 | 0.91 | 10.2 | |
47 | 0.12 | 0.53 | 4.4 | 1.0 | 5.33 | |
48 | 0.072 | 0.33 | 4.6 | 0.43 | 1.9 | |
48a | 0.045 | 0.21 | 4.6 | 0.16 | 0.81 | |
49 | 0.2 | 0.83 | 4.2 | 0.49 | 2.4 | |
50 | 0.18 | 1.2 | 6.7 | 0.8 | 7.9 | |
51 | 0.42 | 1.6 | 3.8 | 0.49 | 4.0 | |
52 | 0.24 | 0.73 | 3.0 | 0.36 | 2.7 | |
52a | 0.16 | 0.68 | 4.2 | 0.25 | 1.67 | |
53 | 0.17 | 0.6 | 3.5 | 0.47 | 3.1 | |
54 | 0.76 | 4.7 | 6.2 | 0.79 | 11.7 | |
55 | 3.8 | 12 | 3.2 | ND | ND | |
56 | 2.7 | 13 | 4.8 | ND | ND | |
57 | 0.44 | 2.2 | 5.0 | 0.8 | 8.9 | |
58 | 0.62 | 2.0 | 3.2 | 0.74 | 7.6 | |
59 | 0.73 | 3.0 | 4.1 | 0.8 | 10.4 | |
60 | 0.057 | 1.6 | 28.1 | 0.35 | 2.52 | |
62 | 0.33 | 13 | 39.4 | 2.4 | 28.4 | |
63 | 1.4 | 20 | 14.3 | ND | ND | |
65 | 0.86 | 54 | 62.8 | 5.9 | ND | |
66 | 0.034 | 1.6 | 47.1 | 0.6 | 6.605 | |
68 | 0.2 | 0.81 | 4 | 0.47 | 4.7 | |
69 | 0.041 | 0.37 | 8.9 | 0.47 | 2 | |
70 | 0.014 | 0.13 | 9 | 0.38 | 1.5 | |
71 | 0.02 | 0.17 | 8.3 | 0.43 | 2.0 | |
72 | 0.05 | 0.2 | 4 | 0.45 | 1.7 | |
73 | 0.06 | 0.47 | 7.9 | 0.37 | 2.4 | |
75 | 0.059 | 0.28 | 4.7 | 0.35 | 1.5 | |
76 | 0.074 | 1.3 | 17 | 0.69 | 6.5 | |
78 | 0.21 | 0.98 | 4.6 | 0.42 | 2.6 | |
79 | 0.16 | 0.51 | 3.2 | 0.35 | 1.0 | |
81 | 0.038 | 0.2 | 5.2 | 0.286 | 0.878 | |
82 | 0.031 | 0.29 | 9.5 | 0.42 | 2.67 | |
83 | 0.079 | 0.25 | 3.1 | 0.27 | 0.73 | |
84 | 0.028 | 0.15 | 5.2 | 0.206 | 0.6 | |
95 | 0.23 | 0.38 | 1.7 | |||
105 | 0.1 | 0.25 | 2.5 | 2.12 | 16.55 | |
79a | 0.11 | 0.25 | 2.4 | 0.104 | 0.48 | |
79b | 0.33 | 19 | 58 | 0.16 | 0.68 | |
107 | 0.11 | 0.56 | 5.1 | 0.33 | 1.77 | |
81a | 0.038 | 0.075 | 2.0 | 0.146 | 0.48 | |
81b | 0.074 | 2 | 27 | 2.85 | 11.6 | |
114 | 0.12 | 0.83 | 6.9 | 0.6 | 3.65 | |
115 | 0.097 | 0.37 | 3.8 | 0.42 | 2.3 | |
116 | 0.42 | 2 | 4.7 | 0.58 | 4.76 | |
117 | 1.6 | 7.1 | 4.4 | |||
119 | 0.37 | 3.1 | 8.5 | 1.44 | 14.4 | |
120 | 0.42 | 3.4 | 8 | 1.25 | 12.7 | |
121 | 0.28 | 1.1 | 3.8 | 0.24 | 1.13 | |
121a | 0.12 | 0.4 | 3.4 | 0.153 | 0.603 | |
122 | 0.19 | 0.92 | 5 | 0.3 | 2.2 | |
123 | 0.54 | 1.8 | 3.3 | 0.25 | 1.1 | |
124 | 0.15 | 0.51 | 3.4 | 0.24 | 1.2 | |
125 | 0.3 | 0.71 | 2.4 | 0.15 | 0.68 | |
126 | 0.42 | 1.9 | 4.5 | 0.18 | 3.6 | |
127 | 0.071 | 0.13 | 1.8 | 0.167 | 0.367 | |
128 | 0.63 | 2.6 | 4 | 0.36 | 3.94 | |
129 | 1.8 | 7.8 | 4.4 | |||
130 | 0.57 | 1.9 | 3.4 | 0.34 | 2.8 | |
131 | 0.05 | 0.51 | 10 | 0.57 | 4.34 | |
132 | 0.26 | 0.92 | 3.5 | 0.31 | 2.05 | |
133 | 0.57 | 1.9 | 3.4 | 0.34 | 2.8 | |
134 | 0.35 | 1.3 | 3.8 | 0.4 | 3.1 | |
136 | 0.75 | 2.9 | 3.8 | 0.51 | 4.6 | |
137 | 0.62 | 3.2 | 5.1 | 0.89 | 9.6 | |
138 | 0.36 | 1.5 | 4.1 | 0.44 | 3 | |
139 | 0.65 | 5.6 | 8.7 | |||
141a | 0.054 | 0.13 | 2.5 | 0.166 | 0.268 | |
141b | 0.059 | 2.3 | 40 | 0.659 | 4.09 | |
142 | 0.56 | 3 | 5.3 | 0.795 | 6.22 | |
143 | 0.48 | 2.6 | 5.5 | 0.674 | 5.15 | |
144 | 0.26 | 1.1 | 4.1 | 0.463 | 2.8 | |
145 | 0.028 | 0.084 | 3 | 0.104 | 0.23 | |
147 | 0.054 | 0.17 | 3.1 | 0.14 | 0.588 | |
148 | 0.56 | 2.0 | 3.6 | 0.46 | 2.81 | |
149a | 0.11 | 0.27 | 2.6 | 0.17 | 0.67 | |
149b | 0.7 | 8.4 | 12 | 5.8 | 20.4 | |
151 | 0.43 | 2.1 | 4.9 | 0.53 | 3.86 | |
152 | 0.25 | 0.89 | 3.5 | 0.35 | 1.31 | |
153 | 0.6 | 2.7 | 4.4 | 0.75 | 6.48 | |
154 | 0.05 | 0.3 | 6 | 0.38 | 2.22 | |
155 | 0.12 | 0.22 | 1.8 | 0.2 | 0.44 | |
156 | 0.73 | 3.6 | 4.9 | 0.375 | 1.42 | |
158 | 0.27 | 0.75 | 2.8 | 0.322 | 1.52 | |
159 | 0.12 | 0.4 | 3.4 | 0.386 | 1.71 | |
160 | 1.2 | 6 | 5 | 0.564 | 2.87 | |
161 | 0.42 | 3.9 | 6.8 | 0.46 | 1.22 | |
162 | 0.38 | 1.5 | 3.8 | 0.373 | 2.04 | |
163 | 1.3 | 5.5 | 4.3 | 1.08 | 9.2 | |
164 | 0.12 | 0.35 | 3 | 0.23 | 0.82 | |
168 | 0.79 | 4.6 | 5.9 | 0.48 | 1.68 | |
169 | 0.62 | 2.4 | 3.9 | 0.49 | 1.5 | |
172 | 0.35 | 1.9 | 5.5 | 0.43 | 1.64 | |
173 | 0.017 | 0.11 | 6.5 | 0.18 | 0.6 | |
174 | 0.096 | 0.59 | 6.1 | 0.18 | 0.49 | |
175 | 0.041 | 0.29 | 7.0 | 0.33 | 1.0 | |
176 | 0.035 | 0.15 | 4.3 | 0.39 | 1.0 | |
178 | 0.52 | 1.5 | 2.9 | 0.64 | 4.87 | |
179 | 1.5 | 6.2 | 4.3 | ND | ND | |
183 | 0.096 | 0.18 | 1.8 | 0.10 | 0.52 | |
184 | 0.19 | 0.53 | 2.9 | 0.16 | 0.44 | |
185 | 0.031 | 0.14 | 4.5 | 0.14 | 0.60 | |
186 | 0.15 | 0.64 | 4.2 | 0.53 | 2.5 | |
190 | 0.23 | 0.62 | 2.7 | 0.13 | 0.37 | |
191 | 0.061 | 0.2 | 3.3 | 0.15 | 0.52 | |
193 | 0.068 | 0.23 | 3.4 | 0.26 | 0.8 | |
194 | 0.051 | 0.16 | 3.1 | 0.3 | 0.82 | |
197 | 0.076 | 0.15 | 1.9 | 0.16 | 0.29 | |
198 | 0.072 | 0.17 | 2.4 | 0.12 | 0.27 | |
200 | 0.24 | 1.02 | 4.2 | 0.27 | 1.6 | |
201 | 0.28 | 1.1 | 3.9 | 0.74 | 6.2 | |
203 | 0.052 | 0.17 | 3.2 | 0.38 | 0.9 | |
205 | 0.034 | 0.07 | 2 | 0.39 | 0.55 | |
210 | 0.33 | 0.66 | 2 | 0.12 | 0.54 | |
212 | 0.13 | 0.54 | 4.2 | 0.3 | 2.15 | |
213 | 0.7 | 2.6 | 3.7 | 0.32 | 5.2 | |
215 | 0.057 | 0.14 | 2.5 | 0.11 | 0.29 | |
216 | 0.19 | 0.81 | 4.2 | 0.33 | 2.76 | |
217 | 0.074 | 0.17 | 2.4 | 0.11 | 0.41 | |
218 | 0.1 | 0.25 | 2.5 | 0.12 | 0.29 | |
221 | 0.08 | 0.27 | 3.4 | 0.16 | 0.92 | |
225 | 0.092 | 0.37 | 4 | 0.13 | 0.65 | |
226 | 0.17 | 0.64 | 3.9 | ND | ND | |
227 | 2.0 | 6.4 | 3.2 | ND | ND | |
229 | 0.38 | 0.96 | 2.5 | 0.12 | 0.53 | |
230 | 0.19 | 0.52 | 2.8 | 0.10 | 0.28 | |
231 | 0.27 | 0.35 | 1.3 | 0.12 | 0.38 | |
232 | 0.7 | 1.3 | 1.8 | 0.13 | 0.19 | |
233 | 0.43 | 0.95 | 2.2 | 0.13 | 0.25 | |
234 | 0.087 | 0.32 | 3.7 | 0.09 | 0.35 | |
235 | 0.28 | 1.1 | 3.8 | 0.27 | 1.21 | |
236 | 0.16 | 0.56 | 3.5 | 0.16 | 0.80 | |
239 | 0.076 | 0.2 | 2.6 | 0.12 | 0.29 | |
241 | 0.035 | 0.096 | 2.7 | 0.15 | 0.32 | |
242 | 0.03 | 0.077 | 2.6 | 0.17 | 0.28 | |
243 | 0.04 | 0.086 | 2.1 | 0.12 | 0.22 | |
244 | 0.25 | 0.83 | 3.3 | 0.20 | 1.36 | |
245 | 0.13 | 0.32 | 2.5 | 0.15 | 0.53 | |
247 | 0.8 | 3.3 | 4.2 | ND | ND | |
250 | 0.09 | 0.52 | 5.7 | 0.16 | 1.06 | |
252 | 1.2 | 3.5 | 2.8 | 0.26 | 2.6 | |
253 | 0.027 | 0.089 | 3.3 | 0.11 | 0.29 | |
254 | 0.017 | 0.067 | 3.9 | 0.09 | 0.25 | |
257 | 0.40 | 0.99 | 2.5 | 0.15 | 0.53 | |
258 | 0.85 | 1.75 | 2.1 | 0.11 | 0.28 | |
259 | 0.91 | 3.4 | 3.8 | 0.55 | 4.2 | |
260 | 0.34 | 0.75 | 2.2 | 0.13 | 0.33 | |
263 | 1.3 | 4.9 | 3.9 | 0.18 | 1.01 | |
264 | 1.9 | 7.3 | 3.8 | 0.26 | 0.78 | |
265 | 0.66 | 1.9 | 3 | 0.15 | 0.65 | |
266 | 1.4 | 4.1 | 3 | 0.22 | 0.66 | |
268 | 0.79 | 1.3 | 1.6 | 0.1 | 0.25 | |
269 | 2.1 | 4.9 | 2.4 | 0.17 | 0.41 | |
270 | 1.1 | 2.9 | 2.6 | 0.16 | 0.64 | |
271 | 0.47 | 1.5 | 3.1 | 0.11 | 0.4 | |
273 | 0.7 | 1.9 | 2.6 | 0.25 | 0.46 | |
274 | 0.55 | 0.85 | 1.5 | 0.15 | 0.29 | |
275 | 0.27 | 0.54 | 2 | 0.14 | 0.38 | |
276 | 0.48 | 1.1 | 2.3 | 0.15 | 0.71 | |
277 | 1.4 | 3.2 | 2.2 | 0.22 | 1.9 | |
278 | 0.6 | 1.6 | 2.7 | 0.15 | 0.46 | |
279 | 2 | 6.3 | 3.2 | ND | ND | |
280 | 0.26 | 0.56 | 2.2 | 0.14 | 0.43 | |
281 | 0.43 | 0.99 | 2.3 | 0.13 | 0.31 | |
282 | 0.25 | 0.97 | 3.9 | 0.36 | 4.2 | |
285 | 0.26 | 0.87 | 3.4 | 0.18 | 0.41 | |
286 | 0.1 | 0.48 | 4.8 | ND | ND | |
287 | 0.87 | 2.3 | 2.6 | 0.16 | 0.55 | |
288 | 0.52 | 1.3 | 2.5 | 0.19 | 0.87 | |
289 | 1.7 | 4.0 | 2.3 | ND | ND | |
290 | 0.9 | 2.2 | 2.5 | 0.2 | 1.5 | |
293 | 3.2 | 11 | 3.4 | ND | ND | |
294 | 3.2 | 10 | 3.2 | ND | ND | |
295 | 0.19 | 0.56 | 3.0 | 0.29 | 0.49 | |
296 | 0.13 | 0.28 | 2.1 | 0.24 | 0.55 | |
297 | 0.13 | 0.4 | 3.0 | 0.25 | 1.16 | |
298 | 0.099 | 0.45 | 4.6 | 0.24 | 1.82 | |
299 | 0.13 | 0.25 | 1.9 | 0.27 | 0.47 | |
302 | 0.071 | 0.20 | 2.8 | 0.31 | 0.79 | |
303 | 0.11 | 0.26 | 2.3 | 0.3 | 0.52 | |
304 | 0.13 | 0.41 | 3.2 | 0.3 | 2.3 | |
305 | 0.19 | 0.60 | 3.2 | 0.32 | 1.3 | |
306 | 0.31 | 0.97 | 3.1 | 0.12 | 0.15 | |
307 | 0.17 | 0.43 | 2.5 | 0.11 | 0.17 | |
308 | 0.67 | 3.11 | 4.6 | 0.58 | 3.95 | |
311 | 0.43 | 1.5 | 3.4 | 0.42 | 2.3 | |
312 | 0.094 | 0.27 | 2.9 | 0.27 | 0.3 | |
313 | 0.048 | 0.19 | 3.9 | 0.18 | 0.4 | |
314 | 0.032 | 0.13 | 4.2 | 0.17 | 0.61 | |
315 | 0.31 | 0.99 | 3.2 | 0.18 | 0.86 | |
316 | 0.022 | 0.1 | 4.5 | 0.16 | 0.53 | |
317 | 0.033 | 0.12 | 3.6 | 0.19 | 0.43 | |
318 | 0.056 | 0.16 | 2.9 | 0.2 | 0.31 | |
319 | 0.25 | 0.85 | 3.3 | 0.24 | 0.84 | |
320 | 0.55 | 1.7 | 3.1 | 0.19 | 0.47 | |
321 | 0.17 | 0.35 | 2 | 0.22 | 0.24 | |
322 | 0.25 | 0.72 | 2.9 | 0.18 | 0.32 | |
323 | 0.22 | 0.45 | 2.1 | 0.21 | 0.42 | |
324 | 0.16 | 0.31 | 1.9 | 0.22 | 0.51 | |
325 | 0.49 | 0.97 | 2 | 0.21 | 0.53 | |
326 | 0.17 | 0.49 | 3 | 0.19 | 0.34 | |
329 | 0.15 | 0.47 | 3.1 | 0.25 | 1.3 | |
330 | 0.26 | 0.62 | 2.4 | 0.18 | 0.79 | |
331 | 0.29 | 0.62 | 2.1 | 0.16 | 0.69 | |
332 | 0.7 | 1.1 | 1.6 | 0.17 | 0.54 | |
333 | 0.11 | 0.37 | 3.2 | 0.13 | 0.26 | |
334 | 0.12 | 0.33 | 2.8 | 0.17 | 0.65 | |
335 | 0.06 | 0.15 | 2.6 | 0.17 | 0.34 | |
336 | 0.09 | 0.38 | 4.2 | 0.2 | 1.1 | |
337 | 0.12 | 0.37 | 3 | 0.18 | 0.63 | |
338 | 0.59 | 1.4 | 2.3 | 0.11 | 0.15 | |
339 | 0.28 | 0.97 | 3.5 | 0.19 | 0.52 | |
341 | 1.6 | 4.5 | 2.8 | 0.12 | 0.68 | |
342 | 0.97 | 3.3 | 2.9 | 0.28 | 2.0 | |
343 | 0.11 | 0.3 | 2.7 | 0.11 | 0.25 | |
345 | 0.16 | 0.38 | 2.4 | 0.14 | 0.24 | |
347 | 0.2 | 0.47 | 2.3 | 0.13 | 0.34 | |
349 | 0.2 | 0.43 | 2.2 | 0.16 | 0.44 | |
350 | 0.48 | 0.99 | 2.2 | 0.23 | 0.79 | |
351 | 0.042 | 0.11 | 2.6 | 0.09 | 0.13 | |
352 | 0.52 | 2.2 | 4.2 | 0.45 | 4.56 | |
353 | 0.077 | 0.25 | 3.3 | 0.2 | 0.64 | |
354 | 0.9 | 1.9 | 2.2 | 0.14 | 3 | |
355 | 0.31 | 1.1 | 3.6 | 0.2 | 2.8 | |
356 | 1.5 | 4.2 | 2.9 | 0.31 | 1.7 | |
357 | 0.57 | 1.4 | 2.5 | 0.19 | 1 | |
358 | 0.1 | 0.24 | 2.4 | ND | ND | |
359 | 0.19 | 0.64 | 3.4 | 0.16 | 0.63 | |
360 | 0.23 | 0.5 | 2.2 | 0.05 | 0.11 | |
361 | 0.051 | 0.16 | 3.1 | 0.09 | 0.13 | |
362 | 0.07 | 0.14 | 2 | 0.08 | 0.17 | |
363 | 0.34 | 0.89 | 2.6 | 0.11 | 0.14 | |
364 | 0.14 | 0.39 | 2.9 | 0.13 | 0.2 | |
365 | 0.46 | 1.3 | 2.9 | 0.12 | 0.26 | |
367 | 0.35 | 0.9 | 2.6 | 0.11 | 0.3 | |
368 | 0.064 | 0.29 | 4.5 | 0.096 | 0.24 | |
370 | 0.18 | 0.67 | 3.7 | |||
371 | 0.12 | 0.32 | 2.7 |
在基於時間解析螢光共振能量轉移方法的測定中測試用配體阻斷Bcl-2D103Y蛋白之本文揭露的選定化合物。將0.05 nM重組人Bcl-2-D103Y蛋白與本文揭露的化合物的連續稀釋液(最高的最終濃度為1 uM,4倍連續稀釋,10點)在室溫下在含有20 mM磷酸鉀緩衝液(pH 7.5)、50 mM NaCl、1 mM EDTA、0.05%吐溫-20、0.01% BSA的測定緩衝液中預孵育0.5小時。然後將2 nM FITC標記的Bak肽Ac-GQVGRQLAIIGDK(FITC)INR-醯胺和Mab抗-6His Tb穴狀化合物Gold添加到板中,並在室溫下再孵育1小時。在BMG PHERAstar FSX儀器上讀取TR-FRET信號(ex337 nm、em490 nm/520 nm)。基於490 nm處與520 nm處的螢光比率,計算化合物在濃度漸增情況下對Bcl-2 D103Y與其配體的相互作用的抑制百分比。藉由Dotmatics將數據擬合到四參數邏輯斯諦方程,從而推導出每種化合物的IC50。
[表 4
]:突變型 Bcl-2 D103Y 的抑制的生物化學數據
WT:野生型;Bcl-2 D103Y:Bcl-2 Asp103Tyr(D103Y)突變
實例 | Bcl-2 D103Y 生物化學測定( IC50 , nM ) | Bcl-2 WT | Bcl-2 D103Y/ Bcl-2 WT 的比率 | |
WO 2019210828中的F91b | 0.17 | 0.014 | 12 | |
3 | 0.11 | 0.019 | 11 | |
5 | 0.32 | 0.037 | 12 | |
6 | 0.18 | 0.013 | 24 | |
6a | 0.11 | 0.0078 | 13 | |
10 | 0.12 | 0.012 | 10 | |
13 | 0.14 | 0.011 | 13 | |
13b | 0.09 | 0.068 | 12 | |
14 | 0.084 | 0.0065 | 13 | |
16 | 0.63 | 0.26 | 2.5 | |
18 | 0.43 | 0.079 | 5.4 | |
19 | 0.2 | 0.086 | 2.3 | |
19a | 0.15 | 0.057 | 2.6 | |
19b | 16 | 0.16 | 100 | |
20 | 0.25 | 0.053 | 4.6 | |
22 | 0.12 | 0.013 | 9.2 | |
22a | 0.041 | 0.0079 | 5.2 | |
23 | 0.26 | 0.13 | 2 | |
24b | 0.56 | 0.24 | 2.3 | |
26 | 0.51 | 0.11 | 4.7 | |
27 | 0.49 | 0.27 | 1.8 | |
28 | 0.34 | 0.23 | 1.5 | |
28a | 0.20 | 0.098 | 2.1 | |
29 | 0.57 | 0.29 | 1.9 | |
29a | 0.38 | 0.2 | 1.9 | |
30 | 0.42 | 0.27 | 1.6 | |
32 | 0.11 | 0.096 | 1.1 | |
33 | 0.094 | 0.038 | 2.5 | |
39 | 3.8 | 1.1 | 3.5 | |
40 | 0.72 | 0.19 | 3.8 | |
41 | 3.1 | 0.83 | 3.7 | |
42 | 1.7 | 0.41 | 4.1 | |
43 | 0.83 | 0.31 | 2.7 | |
45 | 0.54 | 0.24 | 2.3 | |
46 | 1.8 | 0.34 | 5.1 | |
47 | 0.4 | 0.12 | 3.3 | |
48 | 0.2 | 0.072 | 2.8 | |
48a | 0.10 | 0.045 | 2.3 | |
49 | 0.57 | 0.2 | 2.8 | |
50 | 1.2 | 0.18 | 6.6 | |
51 | 1.5 | 0.42 | 3.5 | |
52 | 0.61 | 0.24 | 2.5 | |
52a | 0.37 | 0.16 | 2.4 | |
53 | 0.38 | 0.17 | 2.2 | |
58 | 1.8 | 0.62 | 2.9 | |
59 | 3.2 | 0.73 | 4.4 | |
68 | 0.87 | 0.2 | 4.3 | |
70 | 0.10 | 0.014 | 7.1 | |
71 | 0.15 | 0.02 | 7.6 | |
72 | 0.08 | 0.05 | 1.6 | |
73 | 0.31 | 0.06 | 5.1 | |
75 | 0.22 | 0.059 | 3.6 | |
78 | 0.62 | 0.21 | 2.9 | |
79 | 0.19 | 0.16 | 1.2 | |
81 | 0.084 | 0.038 | 2.2 | |
82 | 0.17 | 0.031 | 5.6 | |
83 | 0.16 | 0.079 | 2 | |
84 | 0.049 | 0.028 | 1.8 | |
96 | 0.23 | 0.041 | 5.6 | |
79a | 0.2 | 0.11 | 1.9 | |
107 | 0.31 | 0.11 | 2.8 | |
81a | 0.54 | 0.025 | 2.2 | |
114 | 0.4 | 0.12 | 3.4 | |
115 | 0.57 | 0.097 | 5.9 | |
121 | 0.42 | 0.28 | 1.5 | |
122 | 0.47 | 0.19 | 2.5 | |
123 | 0.71 | 0.54 | 1.3 | |
124 | 0.21 | 0.15 | 1.4 | |
125 | 0.33 | 0.3 | 1.1 | |
127 | 0.11 | 0.1 | 1 | |
131 | 0.29 | 0.05 | 5.7 | |
132 | 0.47 | 0.26 | 1.3 | |
134 | 0.67 | 0.35 | 1.9 | |
141a | 0.072 | 0.054 | 1.3 | |
144 | 0.47 | 0.26 | 1.8 | |
145 | 0.045 | 0.028 | 1.6 | |
147 | 0.086 | 0.054 | 1.6 | |
150 | 0.53 | 0.13 | 4.1 | |
155 | 0.14 | 0.12 | 1.2 | |
158 | 0.37 | 0.27 | 1.3 | |
162 | 0.61 | 0.38 | 1.6 | |
164 | 0.12 | 0.12 | 1 | |
174 | 0.14 | 0.096 | 1.4 | |
176 | 0.061 | 0.035 | 1.7 | |
184 | 0.19 | 0.19 | 1 | |
185 | 0.05 | 0.031 | 1.6 | |
190 | 0.34 | 0.23 | 1.5 | |
194 | 0.072 | 0.051 | 1.4 | |
197 | 0.089 | 0.076 | 1.2 | |
198 | 0.08 | 0.072 | 1.1 | |
203 | 0.083 | 0.052 | 1.6 | |
205 | 0.047 | 0.034 | 1.4 | |
207 | 0.22 | 0.20 | 1.1 | |
210 | 0.31 | 0.33 | 0.94 | |
215 | 0.062 | 0.057 | 1.1 | |
217 | 0.10 | 0.074 | 1.4 | |
218 | 0.11 | 0.10 | 1.0 | |
220 | 0.077 | 0.044 | 1.8 | |
225 | 0.10 | 0.092 | 1.1 | |
226 | 0.16 | 0.17 | 1 | |
229 | 0.45 | 0.38 | 1.2 | |
231 | 0.45 | 0.27 | 1.7 | |
232 | 0.95 | 0.59 | 1.6 | |
233 | 0.83 | 0.43 | 1.9 | |
236 | 0.22 | 0.16 | 1.3 | |
239 | 0.12 | 0.076 | 1.5 | |
241 | 0.047 | 0.035 | 1.3 | |
242 | 0.033 | 0.03 | 1.1 | |
243 | 0.041 | 0.041 | 1 | |
258 | 1.5 | 0.85 | 1.8 | |
260 | 0.27 | 0.24 | 1.1 | |
268 | 0.88 | 0.79 | 1.1 | |
273 | 0.82 | 0.70 | 1.2 | |
274 | 0.31 | 0.55 | 0.57 | |
275 | 0.21 | 0.27 | 0.76 | |
280 | 0.23 | 0.26 | 0.89 | |
281 | 0.51 | 0.43 | 1.2 | |
282 | 0.47 | 0.25 | 1.9 | |
285 | 0.49 | 0.26 | 1.9 | |
286 | 0.19 | 0.10 | 1.9 | |
288 | 0.43 | 0.52 | 0.84 | |
295 | 0.25 | 0.19 | 1.3 | |
296 | 0.14 | 0.13 | 1.1 | |
299 | 0.13 | 0.13 | 1.0 | |
302 | 0.069 | 0.071 | 1.0 | |
303 | 0.16 | 0.11 | 1.4 | |
304 | 0.22 | 0.13 | 1.8 | |
306 | 0.31 | 0.31 | 1.0 | |
307 | 0.18 | 0.17 | 1.1 | |
312 | 0.081 | 0.080 | 1.0 | |
317 | 0.057 | 0.033 | 1.7 | |
318 | 0.052 | 0.056 | 0.9 | |
319 | 0.42 | 0.25 | 1.7 | |
320 | 0.52 | 0.55 | 0.93 | |
321 | 0.14 | 0.17 | 0.79 | |
322 | 0.36 | 0.25 | 1.4 | |
323 | 0.19 | 0.22 | 0.87 | |
324 | 0.14 | 0.16 | 0.87 | |
326 | 0.25 | 0.17 | 1.5 | |
337 | 0.39 | 0.12 | 3.2 | |
338 | 1.0 | 0.59 | 1.7 | |
339 | 0.71 | 0.28 | 2.5 | |
343 | 0.09 | 0.11 | 0.8 | |
345 | 0.13 | 0.16 | 0.8 | |
347 | 0.28 | 0.2 | 1.4 | |
349 | 0.17 | 0.2 | 0.9 | |
350 | 0.65 | 0.48 | 1.4 | |
351 | 0.07 | 0.04 | 1.7 | |
353 | 0.12 | 0.07 | 1.5 | |
355 | 1.8 | 0.31 | 5.8 | |
357 | 1.0 | 0.57 | 1.8 | |
358 | 0.11 | 0.1 | 1.1 | |
359 | 0.44 | 0.19 | 2.4 | |
360 | 0.31 | 0.23 | 1.4 | |
361 | 0.079 | 0.048 | 1.6 | |
362 | 0.095 | 0.069 | 1.4 | |
363 | 0.36 | 0.40 | 0.9 | |
364 | 0.14 | 0.14 | 1.0 | |
365 | 0.51 | 0.46 | 1.1 | |
367 | 0.40 | 0.35 | 1.2 | |
371 | 0.31 | 0.12 | 2.6 |
本文揭露的化合物具有藉由連接基(-CH2
-、-O-、或碳環)附接至苯基哌𠯤或苯基哌啶部分的額外的芳族或碳環片段。如表3和表4中所示的數據,此關鍵特徵結構對Bcl-2野生型蛋白展現相當或稍好的抑制活性。出乎意料地,它們還顯示出對突變體G101V和D103Y的強大效力。如表3和表4中確定的,Bcl-2 G101V/Bcl-2 wt(如實例16、19、19a、23、24b、28-32、39-59、61、68-73、75-81、83和84、127、141a、145、155、232、233、338)的IC50的比率比WO 2019210828中的實例F132b和ABT-199(維奈妥拉)低的多。表4中Bcl-2 D103Y/Bcl-2 wt的比率也存在此趨勢,如實例16、19a、22a、23、24b、26-30、32-33、39-43、45-49、51-53、58、59、68、72、75、78-81、83和84、127、141a、145、155,其顯著低於WO 2019210828中的F91b。該等結果表明一種沒有突變(如G101V和D103Y)的抗性問題的新的潛在Bcl-2抑制劑。從嗜中性球減少症不良反應的方面來看,該等化合物展現了有效和安全劑量的新療法用於用維奈妥拉治療後具有突變的臨床復發患者的可能性。生物學實例:代謝穩定性研究
藉由使用體外肝微粒體孵育系統來評價一些化合物的代謝穩定性。簡而言之,在37°C下,將1 µM測試化合物與來自不同物種(人、狗、大鼠和小鼠)的0.5 mg/mL肝微粒體以及NADPH再生系統孵育。將樣本在三個時間點(0、30、60 min)用含有內標物的有機溶劑淬滅,並經由LC-MS/MS來分析上清液的母體損失。將咪唑安定(Midazolam)用作陽性對照以驗證孵育系統。
對於每種化合物,將對數剩餘百分比相對於孵育時間作圖,並使用以下列出的等式將此線性回歸的斜率(-k)轉換為體外半衰期T1/2
和內在清除率CLint
。
T1/2
= -0.693/k
CLint
= k/C蛋白質
其中C蛋白質
係孵育系統中微粒體蛋白質之濃度。
確定WO 2019210818中實例F132b和本揭露代表性化合物的CLint
和T1/2
值,並且將結果示於5中。
[表 5
]:
#:此化合物非常穩定,並且數據超出檢測限。
NA:不適用
化合物 | T1/2 ( min ) | CLint ( µL × min-1 × mg-1 ) | |||
人 | 小鼠 | 人 | 小鼠 | ||
WO 2019210828中的實例F132b | 47.5 | 71.3 | 29.2 | 19.4 | |
實例19a | NA# | 346 | < 1.0# | 4.0 | |
實例19 | 1228 | 292 | 1.1 | 4.7 | |
實例28 | 135 | 200 | 10.3 | 6.9 | |
實例29 | 245 | 2358 | 5.6 | 0.6 | |
實例32 | 533 | 202 | 2.6 | 6.8 | |
實例33 | 1821 | 233 | 0.8 | 5.9 | |
實例41 | 997 | 683 | 1.4 | 2.0 | |
實例43 | 108 | 193 | 12.8 | 7.1 | |
實例46 | 153 | 131 | 9.1 | 10.5 | |
實例48 | 256 | 323 | 5.4 | 4.3 | |
實例49 | 93.4 | 205 | 14.8 | 6.7 | |
實例51 | 234 | 306 | 5.9 | 4.5 | |
實例52 | 145 | NA# | 9.5 | < 1.0# | |
實例67 | 309 | 272 | 4.5 | 5.1 | |
實例72 | 491 | 159 | 2.8 | 8.7 | |
實例79a | 253 | 124 | 5.5 | 11.2 | |
實例81a | NA# | 219 | < 1.0# | 6.32 | |
實例127 | NA# | 182 | < 1.0# | 7.63 | |
實例141a | 343 | 18108 | 4.0 | 0.07 | |
實例145 | 970 | 196 | 1.4 | 7.1 | |
實例147 | NA# | 301 | < 1.0# | 4.6 | |
實例155 | 223 | 522 | 6.2 | 2.65 | |
實例198 | 247 | 222 | 5.6 | 6.3 | |
實例230 | 373 | 183 | 3.7 | 7.6 | |
實例232 | 822 | 206 | 1.7 | 6.7 | |
實例233 | 534 | 253 | 2.6 | 5.5 | |
實例257 | 372 | 254 | 3.7 | 5.5 | |
實例274 | 344 | 289 | 4.0 | 4.8 | |
實例281 | 870 | 564 | 1.6 | 2.5 | |
實例285 | 299 | 177 | 4.6 | 7.8 | |
實例312 | 423 | 362 | 3.3 | 3.8 | |
實例321 | 1017 | 628 | 1.4 | 2.2 | |
實例338 | 659 | 538 | 2.1 | 2.6 | |
實例361 | NA# | 273 | < 1.0# | 5.1 | |
實例363 | NA# | NA# | < 1.0# | < 1.0# |
如在人和小鼠兩者物種中所示的數據,與WO 2019210828中的實例F132b相比,本揭露之化合物顯示更長的體外半衰期(T1/2
)和更低的內在清除率(CLint
)。相對於WO 2019210828中的實例F132b,本揭露之化合物在肝微粒體中的代謝穩定性顯著提高。生物學實例:小鼠 PK 研究
經由靜脈內投與(1 mg/kg的劑量)和口服投與(10 mg/kg的劑量)來評估雄性CD-1小鼠中的化合物之藥物動力學。對於靜脈內投與研究,將測試化合物溶解在DMSO/EtOH/Cremophor EL/D5W(2.5/10/20/67.5,體積)中,並經由尾靜脈注射1 mg/kg劑量。對於口服投與研究,將測試化合物溶解在PEG400/Phosal 50 PG/EtOH(30/60/10,體積)中,並藉由管飼以10 mg/kg投與至小鼠。在投與後5(僅靜脈內)、15和30 min以及1、2、4、8和24 h,將血液收集到EDTA-K2抗凝管中。在每個時間點收集約30 µL血液。並且然後在4°C下,使用離心機將血液以3000 g離心5 min以獲得血漿。將血漿樣本轉移到管中並在約-20°C的冰箱中儲存,直到藉由LC-MS/MS確定濃度。藉由使用WinNonlin軟體(8.1版,帕賽特公司(Pharsight Corporation),加利福尼亞州,美國)用非房室方法來估計藥物動力學參數。盡可能地從血漿濃度-時間數據計算以下藥物動力學參數:靜脈內投與的CL、Vd
、T1/2
、AUClast
、AUCinf
和口服投與的Tmax
、Cmax
、AUClast
、AUCinf
、T1/2
。在實驗前自由飼餵所有動物。結果顯示於表6中。出於比較之目的,使用相同的方法獲得先前揭露的某些化合物的PK結果。
[表 6
]:
NA:不適用
化合物 | 靜脈內給藥( 1 mg/kg ) | 口服給藥( 10 mg/kg ) | |||||
CL ( mL/min/kg ) | Vd ( L/kg ) | AUC(0-t)) ( h·ng/mL ) | T1/2 | Cmax ( ng/mL ) | AUC(0-t)) ( h·ng/mL ) | ||
WO 2019210828中的實例F132b | 12.5 | 0.73 | 1339 | 3.1 | 160 | 1062 | |
實例19a | 1.4 | 0.48 | 12259 | NA | 1587 | 20006 | |
實例32 | 1.5 | 0.48 | 10457 | NA | 1437 | 21215 | |
實例52a | 2.6 | 0.62 | 6509 | 2.3 | 2140 | 20721 | |
實例155 | 2.2 | 1.0 | 7534 | NA | 1084 | 15213 | |
實例232 | 1.2 | 1.2 | 14419 | NA | 1088 | 18272 | |
實例233 | 1.0 | 0.8 | 17153 | NA | 1104 | 17390 | |
實例338 | 0.4 | 0.37 | 42870 | NA | 699 | 11604 |
如表6,本揭露之化合物具有比WO 2019210828中的實例F132b顯著更好的PK。表中選定化合物的AUC(20006 h·ng/mL)和Cmax(1587 ng/mL)數據比WO 2019210828中的實例F132b的那些高至少9倍(在小鼠pk實驗中在相同劑量下)。選定化合物的靜脈內給藥中的CL值也遠低於WO 2019210828中的實例F132b的,這與其體外清除率數據一致。
無
圖1.(a) 由方法A中的中間體19-1a合成的實例19a的構象和其電子密度圖。實例19a顯示為棒狀並以黑色著色,而將密度圖顯示為灰色網格。將箭頭碳的絕對立體化學指定為(R)-構型。(b) 具有Bcl-2 G101V突變體的實例19a的共晶結構。
Claims (52)
- 一種具有式 (I) 之化合物:(I), 或其藥學上可接受的鹽、或其立體異構物, 其中 X獨立地選自N或CH; p係選自1或2的整數; v係選自1或2的整數; m係選自1、2或3的整數; n係選自0、1或2的整數; t係選自1或2的整數; 環A係、、或,其中**2係指附接至苯基的位置; 環B係芳基或5員或6員雜芳基; L2 係直接鍵、-(CRa Rb )q -、-O-、-S-、-S(O)-、-SO2 -、-C(O)-、C(O)O-、-OC(O)-、-NRa -、-C(O)NRa -、-NRa C(O)-、-NRa C(O)O-、-NRa C(O)NRb -、-SO2 NRa -、-NRa SO2 -、-NRa S(O)2 NRb -、-NRa S(O)NRb -、-C(O)NRa SO2 -、-C(O)NRa SO-、-C(=NRa )NRb -、或環烷基,其中q係1至7中的一個數字; R11 係-C1-3 烷基、-C3 -10 環烷基、芳基、5員或6員單環雜芳基、7員至10員二環雜芳基、3員至6員單環雜環基、7員至14員二環雜環基,其各自獨立地視需要被1、2、3或4個取代基R11X 取代, R11X 在每次出現時獨立地是鹵素、-C1-8 烷基、鹵代C1-8 烷基、-C2-8 烯基、-C2-8 炔基、-C3-8 環烷基、雜環基、芳基、雜芳基、側氧基、-CN、-NO2 、-OR11a 、-SO2 R11a 、-COR11a 、-CO2 R11a 、-CONR11a R11b 、-C(=NR11a )NR11b R11c 、-NR11a R11b 、-NR11a COR11b 、-NR11a CONR11b R11c 、-NR11a CO2 R11b 、-NR1a SONR11b R11c 、-NR11a SO2 NR11b R11c 、-P(=O)R11a R11b 、或-NR11a SO2 R11b ,其中所述C3-8 環烷基、雜環基、芳基、或雜芳基視需要被以下取代:鹵素、-C1-8 烷基、-鹵代C1-8 烷基、-C1-8 烷氧基、或-鹵代C1-8 烷氧基; R11a 、R11b 、和R11c 各自獨立地是氫、-C1-8 烷基、-鹵代C1-8 烷基、-C2-8 烯基、-C2-8 炔基、-C3-8 環烷基、雜環基、芳基、或雜芳基,其中所述C3-8 環烷基、雜環基、芳基、或雜芳基視需要被以下取代:鹵素、-C1-8 烷基、-鹵代C1-8 烷基、-C1-8 烷氧基、或-鹵代C1-8 烷氧基; R12 係氫、鹵素、-C1-8 烷基、鹵代C1-8 烷基、-C2-8 烯基、-C2-8 炔基、-C3-8 環烷基、雜環基、芳基、雜芳基、-側氧基、-CN、-NO2 、-OR1a 、-SO2 R1a 、-COR1a 、-CO2 R1a 、-CONR1a R1b 、-C(=NR1a )NR1b R1c 、-NR1a R1b 、-NR1a COR1b 、-NR1a CONR1b R1c 、-NR1a CO2 R1b 、-NR1a SONR1b R1c 、-NR1a SO2 NR1b R1c 、或-NR1a SO2 R1b ; R1a 和R1b 各自獨立地是氫、-C1-8 烷基、-鹵代C1-8 烷基、-C2-8 烯基、-C2-8 炔基、環烷基、雜環基、芳基、或雜芳基; R1c 係氫、-C1-8 烷基、-鹵代C1-8 烷基、-C2-8 烯基、-C2-8 炔基、環烷基、雜環基、芳基、或雜芳基; R2 獨立地選自鹵素、-C1-8 烷基、-C2-8 烯基、-C2-8 炔基或-C3-6 環烷基;其中所述-C1-8 烷基、-C2-8 烯基、-C2-8 炔基或-C3-6 環烷基各自獨立地視需要被以下取代:鹵素、羥基、C1-6 烷氧基、或胺基、-C1-8 烷基、-C2-8 烯基、-C2-8 炔基、C3-6 環烷基或C3-6 雜環基; R3 係-L1 -CyC, 其中 L1 係直接鍵、-(CRa Rb )1-4 -、-O-(CRa Rb )0-3 -、-NH-(CRa Rb )1-3 、-NHC(O)NRa -(CRa Rb )1-3 、或-NH-; CyC係環烷基或雜環基,其各自視需要被一、二、三或四個取代基R3a 取代; R3a 獨立地選自氫、鹵素、氰基、側氧基、-OR3b 、-NR3b R3c 、-COR3b 、-SO2 R3b 、-C1-8 烷基、-C2-8 烯基、-C2-8 炔基、-環烷基、或雜環基,所述-C1-8 烷基和雜環基中的每一個視需要被一個或兩個取代基R3e 取代,該取代基R3e 選自氫、鹵素、氰基、-OR3f 、-C1-8 烷基、-環烷基、或雜環基; 其中R3b 和R3c 各自獨立地是氫、-C1-8 烷基、-環烷基、或雜環基,所述-C1-8 烷基視需要被一個或兩個取代基R5e 取代,該取代基R5e 係氫、-NR3f R3g 、-環烷基、或雜環基; R3f 和R3g 各自獨立地是氫或-C1-8 烷基; 或在苯基環上的兩個相鄰R3 與苯基環一起形成苯并環,所述環視需要被雜芳基取代; Ra 和Rb 獨立地是氫、-C1-8 烷基、-C2-8 烯基、-C2-8 炔基、環烷基、雜環基、芳基、或雜芳基;並且, R4 和R5 各自獨立地是氫、鹵素、氰基、-NO2 、-C1-8 烷基、-C2-8 烯基、或-C2-8 炔基。
- 如請求項1所述之化合物,其中X係N。
- 如請求項1所述之化合物,其中環B係苯基、呋喃基、異㗁唑基、吡啶基、吡唑基、或嘧啶基。
- 如請求項1所述之化合物,其中R2 係鹵代、-C1-6 烷基或-C3-4 環烷基;其中所述-C1-6 烷基和-C3-4 環烷基各自獨立地視需要被以下取代:氫、-C1-3 烷基、C3-6 環烷基或C3-6 雜環基。
- 如請求項1所述之化合物,其中R2 係氟、甲基、異丙基、異丁基、環丙基、環丁基或𠰌啉代甲基。
- 如請求項1所述之化合物,其中n係0,並且L2 係-(CH2 )q -或-O-,其中q係1-3中的一個數字,較佳的是1。
- 如請求項1所述之化合物,其中R11 係-C3 -10 環烷基、芳基、5員或6員單環雜芳基、7員至10員二環雜芳基、3員至6員單環雜環基、7員至14員二環雜環基,其各自獨立地視需要被1、2、或3個取代基R11X 取代,其中R11X 如式 (I) 所定義的。
- 如請求項7所述之化合物,其中R11 係環丙基、環丁基、環戊基、環己基、或3員至6員雜環烷基,其含有選自氧和氮原子的1或2個的雜原子。
- 如請求項7所述之化合物,其中R11 選自環己基、二環[1.1.1]戊基、四氫-2H-哌喃-1-基、四氫-2H-哌喃-2-基、四氫-2H-哌喃-3-基、四氫-2H-哌喃-4-基 㗁唑-2-基、㗁唑-4-基甲基或㗁唑-5-基。
- 如請求項7所述之化合物,其中R11 選自苯基或8員至10員二環芳基,其視需要被1至2個取代基R11X 取代。
- 如請求項10所述之化合物,其中R11 係口克唍基、苯并[b][1,4]戴奧辛基、5,6,7,8-四氫萘基、八氫-5H-2,5-甲醇茚基(較佳的是八氫-5H-2,5-甲醇茚-5-基)、2,3,4,5-四氫苯并[b]㗁呯基(較佳的是2,3,4,5-四氫苯并[b]㗁呯-7-基)、金剛烷基(較佳的是金剛烷-1-基),其各自視需要被1或2個R11X 取代。
- 如請求項7-11中任一項所述之化合物,其中R11X 係鹵素、氰基、羥基、-C1-8 烷基、鹵代C1-8 烷基、-C2-8 烯基、-C2-8 炔基、C1-6 烷氧基、鹵代C1-6 烷氧基、C3-6 環烷基、雜環基、C3-6 環烷氧基、-NH2 、-NH(C1-8 烷基)、-N(C1-8 烷基)2 或雜環基-O-。
- 如請求項10所述之化合物,其中R11 係被以下取代的苯基:氰基、氟、氯、溴、甲基、乙基、丙基、異丙基、丁基、三級丁基、甲氧基、乙氧基、丙氧基、異丙氧基、丁氧基、三級丁氧基、二氟甲基、三氟甲基、三氟甲氧基、環丙基、環丁基、環戊基、環己基、氧雜環丁烷-3-基、環丙氧基、環丁氧基、環丙氧基、環己氧基、-NH2 、或-NH(CH3 )。
- 如請求項7所述之化合物,其中R11 係環己基、4-甲氧基環己基、二環[1.1.1]戊烷-1-基、四氫-2H-哌喃-4-基、㗁唑-4-基、苯基、2-氟苯基、3-氟苯基、4-氟苯基、4-氯苯基、2,4-二氟苯基、3,5-二氟苯基、3,4-二氟苯基、4-氰基苯基、4-甲基苯基、4-(三氟甲基)苯基、2-甲氧基苯基、3-甲氧基苯基、4-甲氧基苯基、4-乙氧基苯基、4-甲氧基苯基、4-(三氟甲氧基)苯基、2,4-二甲氧基苯基、2,3-二甲氧基苯基、3,4-二甲氧基苯基、3,5-二甲氧基苯基、3,4,5-三甲氧基苯基、口克唍-6-基、口克唍-4-基、2,3-二氫苯并[b][1,4]戴奧辛-6-基、2,3-二氫苯并[b][1,4]戴奧辛-5-基、或5,6,7,8-四氫萘-2-基、或5,6,7,8-四氫萘-1-基。
- 如請求項7所述之化合物,其中R11 係呋喃基、異㗁唑基、吡啶基、吡唑基、嘧啶基、苯并[b]噻吩基或苯并呋喃基。
- 如請求項15所述之化合物,其中R11 係呋喃-2-基、異㗁唑-4-基、吡啶-3-基、吡啶-2-基、1H-吡唑-4-基、嘧啶-2-基、苯并[b]噻吩-5-基、苯并[b]噻吩-4-基、苯并呋喃-5-基、或苯并呋喃-4-基。
- 如請求項7所述之化合物,其中R11 -L2 -選自呋喃-2-基甲基、異㗁唑-4-基甲基、(吡啶-3-基)甲基、(6-甲氧基吡啶-3-基)甲基、(5-甲氧基吡啶-2-基)甲基、(1-甲基-1H-吡唑-4-基)甲基、(3-甲氧基-1-甲基-1H-吡唑-4-基)甲基、(1-環丙基-1H-吡唑-4-基)甲基、(5-甲氧基嘧啶-2-基)甲基、苯并[b]噻吩-5-基甲基、苯并[b]噻吩-4-基甲基、苯并呋喃-5-基甲基、或苯并呋喃-4-基甲基。
- 如請求項7所述之化合物,其中R11 -L2 -係環丙基、環丁基、環戊基、環己基或1,2,3,4-四氫萘-1-基、3-苯基環丁-1-基、3-苯基環戊-1-基、4-苯基環己-1-基或3-(4-甲氧基苯基)環戊-1-基。
- 如請求項7所述之化合物,其中R11 -L2 -係選自以下的3員至6員單環雜環基:氧雜環丁烷基、四氫呋喃基、或四氫-2H-哌喃基,較佳的是氧雜環丁烷-3-基、四氫呋喃-3-基、和四氫-2H-哌喃-4-基。
- 如請求項1所述之化合物,其中L2 係-SO2 -或-CO-,並且R11 係-C1-3 烷基或苯基,其各自視需要被C1-3 烷氧基取代。
- 如請求項1所述之化合物,其中m係1,R3 係-L1 -CyC,並且L1 係直接鍵、-(CH2 )0-2 -、-N(CH2 )0-2 、或-O(CH2 )0-2 。
- 如請求項22所述之化合物,其中CyC係環丁基、環戊基或環己基,其各自視需要被一個或兩個取代基R3a 取代。
- 如請求項1所述之化合物,其中CyC係: a) 選自以下的雜環基:含有一個氮或氧或硫雜原子作為環成員的單環4員至9員雜環基基團;含有選自氧、硫和氮的兩個雜原子作為環成員的單環4員至9員雜環基基團; b) 5員至10員螺雜環基,其包含選自氮、硫和氧的一個或兩個雜原子作為環成員,或, c) 5員至10員橋接的雜環基,其包含選自氮、硫和氧的一個或兩個雜原子作為環成員; 其各自視需要被一、二、三或四個取代基R3a 取代。
- 如請求項24所述之化合物,其中CyC係單環4員至6員雜環基基團,其含有一個氮或氧或硫雜原子作為環成員。
- 如請求項25所述之化合物,其中Cyc選自氧雜環丁烷基、四氫呋喃基、四氫哌喃基、氮雜環丁烷基、吡咯啶基和哌啶基。
- 如請求項26所述之化合物,其中CyC選自氧雜環丁烷-2-基、氧雜環丁烷-3-基、四氫呋喃-4-基、四氫呋喃-2-基、四氫呋喃-3-基、四氫哌喃-2-基、四氫哌喃-3-基、四氫哌喃-4-基、氮雜環丁烷-3-基、氮雜環丁烷-2-基、吡咯啶-2-基、吡咯啶-3-基、哌啶-4-基、哌啶-2-基、和哌啶-3-基。
- 如請求項1所述之化合物,其中CyC係單環6員雜環基基團,其含有選自氧和氮的兩個雜原子作為環成員。
- 如請求項28所述之化合物,其中CyC係二㗁𠮿基、𠰌啉代、𠰌啉基、或哌𠯤基。
- 如請求項28所述之化合物,其中CyC係1,3-二㗁𠮿-2-基、1,3-二㗁𠮿-4-基、1,4-二㗁𠮿-2-基、𠰌啉-1-基、𠰌啉-2-基、或𠰌啉-3-基。
- 如請求項1所述之化合物,其中CyC係包含一個或兩個氮或氧作為環成員的4員/4員、3員/5員、4員/5員、4員/6員、5員/5員、或5員/6員單螺雜環基。
- 如請求項32所述之化合物,其中R3a 獨立地選自氫、鹵素、氰基、側氧基、-OR3b 、-NR3b R3c 、-C(=O)R3b 、-SO2 R3b 、-C1-6 烷基、單環C3-6 環烷基、或單環4員至9員雜環基基團,其含有選自氮或氧或硫雜原子的一個或兩個雜原子作為環成員,所述-C1-6 烷基和單環4員至9員雜環基基團中的每一個視需要被一個或兩個取代基R3e 取代。
- 如請求項33所述之化合物,其中作為R3a 的環烷基係C3-6 環烷基;更較佳的是環丙基。
- 如請求項33所述之化合物,其中作為R3a 的雜環基係4員至6員雜環基基團,其含有選自氮或氧或硫雜原子的一個或兩個雜原子作為環成員。
- 如請求項33所述之化合物,其中作為R3a 的雜環基係氧雜環丁烷基、四氫呋喃基、四氫哌喃基、哌𠯤基、或𠰌啉基。
- 如請求項33所述之化合物,其中作為R3a 的雜環基係氧雜環丁烷-3-基、四氫呋喃-3-基、四氫-2H-哌喃-4-基、或嗎啡-4-基。
- 如請求項33所述之化合物,其中作為R3e 的雜環基係單環4員至9員雜環基基團,其含有選自氮或氧或硫雜原子的一個或兩個雜原子作為環成員。
- 如請求項33所述之化合物,其中作為R3e 的雜環基係四氫-哌喃-4-基。
- 如請求項33所述之化合物,其中R3a 係-NR3b R3c ,其中R3b 係氫並且R3c 係雜環基。
- 如請求項33所述之化合物,其中R3a 係-NR3b R3c ,其中R3b 係氫並且R3c 係四氫-哌喃-4-基。
- 如請求項33所述之化合物,其中R3a 係-NR3b R3c ,其中R3b 和R3c 各自獨立地是氫或被環烷基取代的-C1-6 烷基,較佳的是被單環C3-6 環烷基取代的-C1-6 烷基。
- 如請求項33所述之化合物,其中R3a 係-OR3b 或-SO2 R3b ,其中R3b 係氫或C1-8 烷基,較佳的是甲基。
- 如請求項33所述之化合物,其中R3a 係-COR3b ,其中R3b 係氫或視需要被-NR3f R3g 取代的C1-6 烷基,其中R3f 和R3g 各自獨立地是氫或C1-6 烷基,較佳的是甲基。
- 如請求項1所述之化合物,其中在苯基環上的兩個相鄰R3 與苯基環一起形成被四氫哌喃基取代的吲唑基。
- 如請求項1所述之化合物,其中R4 係選自以下的鹵素:氟(-F)、氯(-Cl)或溴(-Br),較佳的是氟(-F)。
- 如請求項1所述之化合物,其中R4 在吡咯并[2,3-b]吡啶-5-基環的位置3處。
- 如請求項1所述之化合物,其中該化合物選自示例的化合物。
- 一種藥物組成物,該藥物組成物包含如請求項1-49中任一項所述之化合物或其藥學上可接受的鹽或其立體異構物,以及至少一種藥學上可接受的賦形劑。
- 一種治療失調凋亡疾病之方法,該方法包括向有需要的受試者投與治療有效量的如請求項1-49中任一項所述之化合物或其藥學上可接受的鹽或其立體異構物。
- 如請求項51所述之方法,其中該失調凋亡疾病係神經退行性病症、增殖性疾病和血栓前病症。
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WO2023078398A1 (en) * | 2021-11-05 | 2023-05-11 | Fochon Pharmaceuticals, Ltd. | Compounds as bcl-2 inhibitors |
AU2022394660A1 (en) * | 2021-11-20 | 2024-06-06 | Fochon Biosciences, Ltd. | Compounds as bcl-2 inhibitors |
CA3238433A1 (en) | 2021-12-06 | 2023-06-15 | Xingguo LIU | Anti-apoptotic protein bcl-2 inhibitor, pharmaceutical composition and uses thereof |
WO2023122000A1 (en) * | 2021-12-20 | 2023-06-29 | Newave Pharmaceutical Inc. | Bcl-2 inhibitors |
CN114292192A (zh) * | 2022-01-17 | 2022-04-08 | 山东泓瑞医药科技股份公司 | 一种3,4-二甲氧基苯甲酸甲酯的合成方法 |
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