WO2020244518A1 - 一种具有苄氧基芳环结构的化合物，其制备方法和用途 - Google Patents

一种具有苄氧基芳环结构的化合物，其制备方法和用途 Download PDF

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WO2020244518A1
WO2020244518A1 PCT/CN2020/094013 CN2020094013W WO2020244518A1 WO 2020244518 A1 WO2020244518 A1 WO 2020244518A1 CN 2020094013 W CN2020094013 W CN 2020094013W WO 2020244518 A1 WO2020244518 A1 WO 2020244518A1
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alkyl
compound
hydrogen atom
oxy
group
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French (fr)
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赵玉军
朱棣
周飞龙
严子琴
刘成龙
张希晨
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中国科学院上海药物研究所
复旦大学
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Definitions

  • the present invention belongs to the field of pharmaceutical synthesis, and specifically relates to a class of compounds with a benzyloxy aromatic ring structure, its stereoisomers, enantiomers or pharmaceutically acceptable salts thereof, preparation methods and uses thereof.
  • the use of antibody drugs to bind to the PD-1 receptor or to the PD-L1 protein can block the interaction between PD-1/PD-L1 and achieve good anti-tumor effects in the human body ( Nature Review Cancer,2012,12,252).
  • the PD-1 monoclonal antibody Pembrolizumab (Merck), Nivolumab (BMS) can selectively bind to the PD-1 receptor of T cells
  • the PD-L1 monoclonal antibody Atezolizumab (Genentech/Roche), Durvalumab (Medimmune/AstraZeneca)
  • Avelumab (Merck KGaA and Pfize) can selectively bind to PD-1 receptors.
  • These antibodies can block the interaction between PD-1/PD-L1.
  • tumors including non- Small cell lung cancer, small cell lung cancer, melanoma, head and neck cancer, kidney cancer, bladder cancer, locally advanced or metastatic urothelial cancer, breast cancer, cervical cancer, metastatic Merkel cell carcinoma, prostate cancer, liver cancer, bowel Cancer, gastric cancer, multiple myeloma, mantle cell lymphoma, diffuse large B-cell lymphoma, liver cancer, Hodgkin’s lymphoma, chronic lymphocytic leukemia, squamous cell carcinoma and other cancers (J. Gong, A.
  • small molecule compounds and polypeptide compounds can also selectively bind to PD-1 or PD-L1. These compounds have the potential to block the interaction between PD-1/PD-L1, activate T cell functions, and specifically kill tumor cells (the Journal of Medicinal Chemistry, 2019, 62, 1715-1530). Small molecule compounds CA-170, BMS-986189, CA-327, AUNP-12 and MAX-10129 can all act on the PD-1/PD-L1 signaling pathway and have certain anti-tumor effects in animals.
  • small molecule compounds can block the interaction between PD-1/PD-L1
  • such compounds may block the binding between tumor cell PD-L1 protein and immune cell PD-1. It is possible to exhibit anti-cancer effects in animals and humans, and have potential drug uses for treating malignant tumors in humans.
  • PD-1/PD-L1 blockers can be used in the clinical treatment of a variety of tumors.
  • antibody drugs have their own characteristics, such as high production cost, poor stability, need to be administered by injection, and easy to produce immunogenicity.
  • Small molecule drugs have the advantages of good tissue permeability, convenient storage and transportation, low production cost, no immunogenicity, and usually oral administration. Therefore, the research and development of small molecule inhibitors of PD-1/PD-L1 has significant advantages Application value and social value.
  • the purpose of the present invention is to provide a small molecule inhibitor for inhibiting the interaction of PD1-PD-L1.
  • the first aspect of the present invention provides a compound represented by the general formula (I), its stereoisomer, enantiomer, or a pharmaceutically acceptable salt thereof:
  • X is N or CH
  • Y is a hydrogen atom or a C1-C4 alkyl group
  • R 1 is selected from the following group:
  • R 2 is selected from the following group of substituted or unsubstituted groups: hydrogen atom, C1-C6 alkyl, C3-C6 cycloalkyl, 5-10 membered heterocyclic group, Ar 1 -(CH 2 ) m -, C6- C10 aromatic ring or 5-12 membered heteroaromatic ring; Ar 1 is 5-10 membered heterocyclic group, substituted or unsubstituted C6-C10 aromatic ring or 5-12 membered heteroaromatic ring; wherein, the substitution means Substituted by one or more (such as 2, 3, 4 or 5) groups selected from the group: hydroxyl, halogen, carboxyl, cyano, C1-C6 alkyl, -NRaRb, 5-6 membered heteroaryl , C3-C6 cycloalkyl, 5-10 membered heterocyclic group;
  • R 3 is selected from the following group of substituted or unsubstituted groups: hydrogen atom, C1-C6 alkyl, C3-C6 cycloalkyl, Ar-CH 2 -, or 5-12 membered heterocyclic group; wherein, Ar is Substituted or unsubstituted C6-C10 aromatic ring or 5-12 membered heteroaromatic ring,
  • the said substitution means that one or more (such as 2, 3, 4 or 5) hydrogen atoms on the group are substituted by a substituent selected from the following group: halogen, C1-C4 alkyl, (C1- C4) Alkoxy, hydroxyl, amino, cyano, trifluoromethyl, difluoromethyl, (C1-C4)alkylsulfonyl, (C1-C4)alkylsulfinyl, (C1-C4)alkane Sulfonylamino, aminosulfonyl, (C1-C5) acylamino, halo(C1-C4)alkylsulfonyl, halo(C1-C4)alkylsulfinyl, halo(C1-C4)alkane Sulfonylamino;
  • R 4 is selected from: hydrogen atom, halogen, C1-C4 alkyl, C1-C4 alkoxy, or halogenated (C1-C4) alkyl;
  • R 5 is selected from: hydrogen atom, halogen, C1-C4 alkyl, C1-C4 alkoxy, cyano, or halo (C1-C4) alkyl;
  • R 6 is selected from: substituted or unsubstituted benzene ring, wherein said substitution means that one or more (such as 2, 3, 4, or 5) hydrogen atoms on the group are replaced by a substituent selected from the following group Substitution: p-methoxybenzyloxy, benzyloxy, (C1-C5)alkoxy, hydroxyl, halogen;
  • R 6 is selected from:
  • Z is a hydrogen atom or a C1-C4 alkyl group
  • R 1a is selected from:
  • R 2a is selected from the following group of substituted or unsubstituted groups: hydrogen atom, C1-C6 alkyl, C3-C6 cycloalkyl, 5-10 membered heterocyclic group, Ar 1 -(CH 2 ) m -, C6- C10 aromatic ring or 5-12 membered heteroaromatic ring; Ar 1 is a substituted or unsubstituted 5-10 membered heterocyclic group, C6-C10 aromatic ring or 5-12 membered heteroaromatic ring; wherein, the substitution means Substituted by one or more (such as 2, 3, 4 or 5) groups selected from the group: hydroxyl, halogen, carboxyl, cyano, C1-C6 alkyl, -NRaRb, 5-6 membered heteroaryl , C3-C6 cycloalkyl, 5-10 membered heterocyclic group;
  • R 3a is selected from: hydrogen atom, C1-C6 alkyl, C3-C6 cycloalkyl, Ar-CH 2 -, or C3-C6 heterocyclic group,
  • R 4a is selected from: hydrogen atom, halogen, C1-C4 alkyl, (C1-C4) alkoxy, halogenated (C1-C4) alkyl;
  • R 5a is selected from: hydrogen atom, halogen, C1-C4 alkyl, (C1-C4) alkoxy, cyano, halogenated (C1-C4) alkyl;
  • Rg is selected from: -NRdRe
  • Ra, Rb, and Rc are each independently selected from: hydrogen atom, C1-C5 alkyl, -O-CH 2 -O-CO-(C1-C5 alkyl), -CH 2 -O-CO-(C1-C5 alkyl);
  • Rd and Re are each independently selected from: hydrogen atom, C1-C5 alkyl, -CO-Rf, wherein Rf is independently selected from: hydrogen atom, trifluoromethyl, C1-C5 alkyl, 5-6 membered hetero Aryl, C3-C6 cycloalkyl, 5-10 membered heterocyclic group;
  • Rx is selected from: hydrogen atom, C1-C6 alkyl, C3-C6 cycloalkyl, 5-10 membered heterocyclic group;
  • R 11 , R 12 , R 13 , R 14 , R 15 , and R 16 are each independently selected from: hydrogen, hydroxyl, -O-CHO, (C1-C4 alkyl)carbonyl-O-, HO 2 C- ;
  • n 2, 3, or 4
  • m 1, 2, or 3.
  • R 2 is selected from the following group: hydrogen atom, C1-C6 alkyl, C1-C6 alkyl substituted with hydroxy, C1-C6 alkyl substituted with carboxyl, (C1-C4 alkyl) 2 N -Group substituted C1-C6 alkyl, 5-6 membered heteroaryl substituted C1-C6 alkyl, 5-10 membered heterocyclyl substituted C1-C6 alkyl, C3-C6 cycloalkyl, (C1- C4) 2 N-group substituted C3-C6 cycloalkyl, 5-10 membered heterocyclic group, 1-3 halogen atoms substituted (C1-C4) alkyl, Ar 1 -(CH 2 ) m -, phenyl Or a five-membered heteroaryl group, wherein Ar 1 is a substituted or unsubstituted 5-6 membered heterocyclic group, a phenyl group or a 5
  • X is N or CH
  • Y is a hydrogen atom or a C1-C4 alkyl group
  • R 1 is selected from the following group:
  • R 2 is selected from the following group: hydrogen atom, C1-C6 alkyl, C3-C6 cycloalkyl, 5-10 membered heterocyclic group, or halogenated (C1-C4) alkyl;
  • R 3 is selected from the following group: hydrogen atom, C1-C6 alkyl, C3-C6 cycloalkyl, Ar-CH 2 -, or 5-12 membered heterocyclic group;
  • Ar is a substituted or unsubstituted C6-C10 aromatic ring, or a 5-12 membered heteroaromatic ring, wherein the substitution refers to one or more (such as 2, 3, 4 or 5) on the group
  • the hydrogen atom is replaced by a substituent selected from the group consisting of halogen, C1-C4 alkyl, (C1-C4) alkoxy, hydroxyl, amino, cyano, trifluoromethyl, difluoromethyl, (C1- C4) alkylsulfonyl, (C1-C4)alkylsulfinyl, (C1-C4)alkylsulfonylamino, aminosulfonyl, (C1-C5)acylamino;
  • R 4 is selected from: hydrogen atom, halogen, C1-C4 alkyl, C1-C4 alkoxy, or halogenated (C1-C4) alkyl;
  • R 5 is selected from: hydrogen atom, halogen, C1-C4 alkyl, C1-C4 alkoxy, cyano, or halo (C1-C4) alkyl;
  • R 6 is selected from: substituted or unsubstituted benzene ring, wherein said substitution means that one or more (such as 2, 3, 4, or 5) hydrogen atoms on the group are replaced by a substituent selected from the following group Substitution: p-methoxybenzyloxy, benzyloxy, (C1-C5)alkoxy, hydroxyl, halogen;
  • R 6 is selected from:
  • Z is a hydrogen atom or a C1-C4 alkyl group
  • R 1a is selected from:
  • R 2a is selected from: hydrogen atom, C1-C6 alkyl, C3-C6 cycloalkyl, 5-10 membered heterocyclic group, or halogenated (C1-C4) alkyl;
  • R 3a is selected from: hydrogen atom, C1-C6 alkyl, C3-C6 cycloalkyl, Ar-CH 2 -, or C3-C6 heterocyclic group,
  • R 4a is selected from: hydrogen atom, halogen, C1-C4 alkyl, (C1-C4) alkoxy, halogenated (C1-C4) alkyl;
  • R 5a is selected from: hydrogen atom, halogen, C1-C4 alkyl, (C1-C4) alkoxy, cyano, halogenated (C1-C4) alkyl;
  • Ra, Rb, and Rc are each independently selected from: hydrogen atom, C1-C5 alkyl, -O-CH 2 -O-CO-(C1-C5 alkyl), -CH 2 -O-CO-(C1-C5 alkyl);
  • Rx is selected from: hydrogen atom, C1-C6 alkyl, C3-C6 cycloalkyl, 5-10 membered heterocyclic group;
  • R 11 , R 12 , R 13 , R 14 , R 15 , and R 16 are each independently selected from: hydrogen, hydroxyl, -O-CHO, (C1-C4 alkyl)carbonyl-O-, HO 2 C-;
  • n 2, 3, or 4.
  • the compound of general formula (I), its stereoisomer, enantiomer, or pharmaceutically acceptable salt thereof in another preferred embodiment, the compound of general formula (I), its stereoisomer, enantiomer, or pharmaceutically acceptable salt thereof,
  • R 2 is selected from: hydrogen atom, C1-C6 alkyl, C3-C6 cycloalkyl, trifluoromethyl, or difluoromethyl;
  • R 3 is selected from: hydrogen atom, C1-C6 alkyl, C3-C6 cycloalkyl, Ar-CH 2 -, wherein Ar is a substituted or unsubstituted benzene ring or a nitrogen-containing six-membered heteroaromatic ring, wherein the The substitution means that one or more (such as 2, 3, 4, or 5) hydrogen atoms on the group are replaced by a substituent selected from the following group: halogen, C1-C4 alkyl, (C1-C4) alkoxy Group, hydroxyl, amino, cyano, trifluoromethyl, difluoromethyl, (C1-C4)alkylsulfonyl, (C1-C4)alkylsulfinyl, (C1-C4)alkylsulfonylamino , Aminosulfonyl, (C1-C5) acylamino;
  • R 4 is selected from: hydrogen atom, halogen, C1-C4 alkyl, (C1-C4)alkoxy, trifluoromethyl, difluoromethyl;
  • R 5 is selected from: hydrogen atom, halogen, C1-C4 alkyl, (C1-C4)alkoxy, cyano, trifluoromethyl, difluoromethyl;
  • R 2a is selected from: hydrogen atom, C1-C6 alkyl, C3-C6 cycloalkyl, trifluoromethyl, or difluoromethyl;
  • R 3a is selected from: hydrogen atom, C1-C6 alkyl, C3-C6 cycloalkyl, or Ar-CH 2 -, wherein substituted or unsubstituted Ar represents a benzene ring or a nitrogen-containing six-membered heteroaromatic ring, and the substituents are selected From: halogen, (C1-C4) alkyl, (C1-C4) alkoxy, hydroxyl, amino, cyano, trifluoromethyl, difluoromethyl, (C1-C4) alkylsulfonyl, (C1 -C4)alkylsulfinyl, (C1-C4)alkylsulfonylamino, aminosulfonyl, (C1-C5)acylamino;
  • R 4a is selected from: hydrogen atom, halogen, C1-C4 alkyl, C1-C4 alkoxy, trifluoromethyl, difluoromethyl;
  • R 5a is selected from: hydrogen atom, halogen, C1-C4 alkyl, C1-C4 alkoxy, cyano, trifluoromethyl, difluoromethyl;
  • Ra, Rb, and Rc are each independently selected from: hydrogen atom, C1-C5 alkyl group, -O-CH 2 -O-CO-(C1-C5 alkyl group);
  • Rx is selected from: hydrogen atom, C1-C6 alkyl, C3-C6 cycloalkyl;
  • n 2, 3, or 4.
  • said R 1 is selected from: Among them, Ra, Rb, Rc, R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , and R g are defined as described above.
  • n 2, 3, or 4
  • Ra, R 2 -R 6 , X, and Y have the above-mentioned definitions.
  • Ra is H.
  • the compound of general formula (I) has a structure represented by formula (I-2):
  • n 2, 3, or 4
  • Rb, Rc, R 2 -R 6 , X, and Y have the above-mentioned definitions.
  • Rb and Rc are each independently H or C1-C5 alkyl.
  • the compound of general formula (I) has the structure shown in formula (I-3) and (I-4):
  • n 2, 3, or 4
  • R 2 -R 6 , X, and Y have the above-mentioned definitions.
  • the compound of general formula (I) has a structure represented by formula (I-5), (I-6) or (I-7):
  • R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 2 -R 6 , X, and Y have the above-mentioned definitions.
  • the compound of general formula (I) has a structure represented by formula (I-8):
  • R 1 -R 5 , R 1a , R 2a , R 3a , R 4a , R 5a , X, Y, and Z have the above-mentioned definitions.
  • the compound of general formula (I) has a structure represented by formula (I-9), (I-10) or (I-11):
  • n 2, 3, or 4
  • R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 2 -R 6 , X and Y have the above-mentioned definitions.
  • the compound of general formula (I) has a structure represented by formula (I-14):
  • n 2, 3, or 4
  • R 2 , R 3 , R 4 , R 5 , R 6 , R g , and Y have the above-mentioned definitions.
  • R 3 is Ar-CH 2 -; wherein, Ar is a substituted or unsubstituted C6-C10 aromatic ring, or a 5-12 membered heteroaromatic ring, wherein the The substitution means that one or more (such as 2, 3, 4 or 5) hydrogen atoms on the group are replaced by a substituent selected from the following group: C1-C4 alkyl, (C1-C4) alkoxy, Hydroxy, amino, cyano, trifluoromethyl, difluoromethyl, (C1-C4)alkylsulfonyl, (C1-C4)alkylsulfinyl, (C1-C4)alkylsulfonylamino, amino Sulfonyl, (C1-C5) acylamino, halo(C1-C4)alkylsulfonyl, halo(C1-C4)alkylsulfinyl, halo(C1-C4)alkylsulfiny
  • R 3 is Ar-CH 2 -, where Ar is a substituted or unsubstituted benzene ring or a nitrogen-containing six-membered heteroaromatic ring, wherein the substituent refers to One or more (such as 2, 3, 4 or 5) hydrogen atoms on the group is replaced by a substituent selected from the following group: cyano, (C1-C4)alkylsulfonyl, (C1-C4)alkane Group sulfinyl, (C1-C4) alkylsulfonylamino, aminosulfonyl, (C1-C5) acylamino, halogenated (C1-C4) alkylsulfonyl, halogenated (C1-C4) alkylene Sulfonyl, halo(C1-C4)alkylsulfonylamino.
  • R 3 is Ar-CH 2 -, wherein Ar is a substituted or unsubstituted benzene ring or pyridyl group, wherein the substitution refers to one or more of the group One (such as 2, 3, 4 or 5) hydrogen atoms are replaced by a substituent selected from the group consisting of cyano, (C1-C4)alkylsulfonyl, (C1-C4)alkylsulfinyl, ( C1-C4)alkylsulfonylamino, aminosulfonyl, (C1-C5)acylamino, halo(C1-C4)alkylsulfonyl, halo(C1-C4)alkylsulfinyl, halo( C1-C4) alkylsulfonylamino.
  • the compound of general formula (I) has a structure represented by formula (I-12):
  • R m is selected from:
  • R 7 is C1-C4 alkyl or C1-C4 alkyl substituted with 1-3 F atoms;
  • n 2, 3, or 4 and R 2 , R 4 , R 5 , R 6 , Ra, and Y are as defined above.
  • the compound of general formula (I) has a structure represented by formula (I-13):
  • n, Ra, Rb, R m , n, R 2 , R 4 , R 5 , R 6 , and Y are as defined above.
  • the compound of general formula (I) has a structure represented by formula (I-15):
  • n, Rg, R m, n , R 2, R 4, R 5, R Y is as described above.
  • R g is selected from: -NH 2 , -NHCHO, -NHCO-(C1-C4 alkyl), -NH-(C1-C4 alkyl), -NHCOPh.
  • R 6 is selected from: Preferably, R 6 is
  • the compound of general formula (I) has one or more of the following characteristics:
  • R 1 is selected from:
  • R 2 is selected from the following group: hydrogen atom, C1-C6 alkyl, C1-C6 alkyl substituted with hydroxy, C1-C6 alkyl substituted with carboxyl, (C1-C4 alkyl) 2 C1-C6 substituted with N-group Alkyl, 5-6 membered heteroaryl substituted C1-C6 alkyl, 5-10 membered heterocyclic substituted C1-C6 alkyl, C3-C6 cycloalkyl, (C1-C4) 2 N-group substituted C3-C6 cycloalkyl, 5-10 membered heterocyclic group, 1-3 halogen atom substituted (C1-C4) alkyl, Ar 1 -(CH 2 ) m -, phenyl or five-membered heteroaryl, Wherein, Ar 1 is a substituted or unsubstituted 5-6 membered heterocyclic group, a phenyl group or a 5-6 membered heteroaromatic
  • R 4 is selected from: hydrogen atom, halogen, C1-C4 alkyl, C1-C4 alkoxy, or halogenated (C1-C4) alkyl; preferably halogen, C1-C4 alkyl;
  • R 5 is selected from: hydrogen atom, halogen, C1-C4 alkyl, C1-C4 alkoxy, cyano, or halo (C1-C4) alkyl; preferably H;
  • R 6 is selected from: Preferably, R 6 is
  • Z, X, R 1a , R 2a , R 3a , R 4a , and R 5a are as defined above.
  • R 1a is selected from:
  • R 2a is selected from: hydrogen atom, C1-C6 alkyl, C3-C6 cycloalkyl, 5-10 membered heterocyclic group, or halogenated (C1-C4) alkyl;
  • R 3a is selected from: hydrogen atom, C1-C6 alkyl, C3-C6 cycloalkyl, Ar-CH 2 -, or C3-C6 heterocyclic group,
  • R 4a is selected from: hydrogen atom, halogen, C1-C4 alkyl, (C1-C4) alkoxy, halogenated (C1-C4) alkyl;
  • R 5a is selected from: hydrogen atom, halogen, C1-C4 alkyl, (C1-C4) alkoxy, cyano, halogenated (C1-C4) alkyl;
  • Ra, Rb, and Rc are each independently selected from: hydrogen atom, C1-C5 alkyl, -O-CH 2 -O-CO-(C1-C5 alkyl), -CH 2 -O-CO-(C1-C5 alkyl);
  • Rg is selected from: -NRdRe
  • Rd and Re are each independently selected from: hydrogen atom, C1-C5 alkyl, -CO-Rf, wherein Rf is independently selected from: hydrogen atom, trifluoromethyl, C1-C5 alkyl, 5-6 membered hetero Aryl, C3-C6 cycloalkyl, 5-10 membered heterocyclic group;
  • Rx is selected from: hydrogen atom, C1-C6 alkyl, C3-C6 cycloalkyl, 5-10 membered heterocyclic group;
  • R 11 , R 12 , R 13 , R 14 , R 15 , and R 16 are each independently selected from: hydrogen, hydroxyl, -O-CHO, (C1-C4 alkyl)carbonyl-O-, HO 2 C- ;
  • n 2, 3, or 4
  • m 1, 2, or 3.
  • R 1 -R 6 ie R 1 , R 2 , R 3 , R 4 , R 5 , R 6 ), X, Y are embodiments 1-21, 23-33, 35-131 The specific group corresponding to each specific compound in.
  • the compound, its stereoisomer or pharmaceutically acceptable salt thereof is selected from the following group:
  • the compound of formula (I) is a compound other than compound 34 in Table 2.
  • the second aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising an effective amount of the compound described in the first aspect, its stereoisomers, enantiomers or pharmaceutically acceptable salts thereof, and any Selected pharmaceutically acceptable excipients or carriers.
  • the second cancer therapeutic agent includes radioactive agents, cytotoxic agents, kinase inhibitors, immunotargeting inhibitors and angiogenesis inhibitors.
  • the second cancer therapeutic agent is one or more selected from the following group:
  • PD-1 inhibitors such as nivolumab, pembrolizumab, JS-001, SHR-120, BGB-A317, IBI-308, GLS-010, GB-226, STW204, HX008, HLX10, BAT1306, AK105 , LZM 009 or biosimilars of the above drugs, etc.
  • PD-L1 inhibitors such as devaluzumab, atezolizumab, CS1001, KN035, HLX20, SHR-1316, BGB-A333, JS003, CS1003, KL-A167, F520, GR1405, MSB2311 or biological analogues of the above drugs, etc.
  • CD20 antibodies such as rituximab, obin utuzumab, ofatumumab, tositumomab, Titumomab, etc.
  • CD47 antibodies such as Hu5F9-G4, CC-90002, TTI-621,
  • the third aspect of the present invention provides the compound of the first aspect, its stereoisomer, enantiomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition of the second aspect for preparing PD1- Use in PDL1 interaction inhibitor.
  • the compound, its stereoisomers or pharmaceutically acceptable salts thereof are used in combination medication regimens, such as combined tumor chemotherapy regimens, other tumor immunotherapeutics (small molecule compounds and antibodies, etc.) , Radiotherapy regimens, tumor-targeted drugs, tumor vaccines, etc., such as human papilloma virus (HPV), hepatitis virus (HBV and HCV) and Kaposi herpes sarcoma virus (KHSV); it can be before, after or at the same time as the agent Administration, or can be co-administered with other known therapies.
  • combination medication regimens such as combined tumor chemotherapy regimens, other tumor immunotherapeutics (small molecule compounds and antibodies, etc.) , Radiotherapy regimens, tumor-targeted drugs, tumor vaccines, etc., such as human papilloma virus (HPV), hepatitis virus (HBV and HCV) and Kaposi herpes sarcoma virus (KHSV); it can be before, after or at the same time as the agent
  • the compound, its stereoisomer or its pharmaceutically acceptable salt is used alone or in combination for the treatment of patients exposed to a specific toxin or pathogen; including but not limited to various Treatment of viruses, pathogenic bacteria, pathogenic fungi, pathogenic parasites, etc.; such as HIV, hepatitis virus (A, B, C), influenza virus, herpes virus, Giardia, malaria, Leishmania, Staphylococcus aureus, An established infection with pathogens such as Pseudomonas aeruginosa.
  • viruses pathogenic bacteria, pathogenic fungi, pathogenic parasites, etc.
  • pathogens such as HIV, hepatitis virus (A, B, C), influenza virus, herpes virus, Giardia, malaria, Leishmania, Staphylococcus aureus, An established infection with pathogens such as Pseudomonas aeruginosa.
  • the compound, its stereoisomer or its pharmaceutically acceptable salt is used to induce a therapeutic autoimmune response to treat patients with inappropriate accumulation of other autoantigens, such as amyloid Protein deposits, including A ⁇ in Alzheimer's disease, cytokines such as TNFa and IgE.
  • autoantigens such as amyloid Protein deposits, including A ⁇ in Alzheimer's disease, cytokines such as TNFa and IgE.
  • the PD1-PDL1 interaction inhibitor is used to prevent and/or treat cancer.
  • the cancer is selected from: non-small cell lung cancer, melanoma, head and neck cancer, kidney cancer, bladder epithelial cancer, locally advanced or metastatic urothelial cancer, metastatic Merkel cell carcinoma, Prostate cancer, liver cancer, bowel cancer, multiple myeloma, mantle cell lymphoma, diffuse large B-cell lymphoma, liver cancer, Hodgkin's lymphoma, chronic lymphocytic leukemia, etc.
  • Figure 1 shows the co-culture test of tumor cells and T cells.
  • Figure 2 is a test of the compound of the present invention for promoting T cells to kill cancer cells. Effector cells (T cells) and target cells (tumor cells) are co-cultured in two ratios, and different concentrations of compounds promote the killing of tumor cells.
  • Figure 3 shows the anti-tumor efficacy of the compound of the present invention in suppressing tumors in B16 mice, wherein Figure 3A shows the anti-tumor efficacy of compound 120 (ZD41) in B16F10 mouse xenografts; Figure 3B shows the compound Anti-tumor efficacy of 89 (ZE132) in transplanted tumors of B16F10 mice.
  • Figure 3A shows the anti-tumor efficacy of compound 120 (ZD41) in B16F10 mouse xenografts
  • Figure 3B shows the compound Anti-tumor efficacy of 89 (ZE132) in transplanted tumors of B16F10 mice.
  • the inventor found a class of compounds that have a better ability to inhibit the interaction of PD1/PD-L1.
  • the compound of the present invention has a better effect of promoting T cells to kill cancer cells, better pharmacodynamic performance and lower toxicity. On this basis, the present invention has been completed.
  • the term “about” means that the value can vary from the recited value by no more than 1%.
  • the expression “about 100” includes all values between 99 and 101 (eg, 99.1, 99.2, 99.3, 99.4, etc.).
  • the manufacturer's instructions on the use of the kit can be used, or the reaction and purification can be performed in a manner known in the art or the instructions of the present invention.
  • the above-mentioned techniques and methods can be implemented according to the descriptions in a number of summary and more specific documents cited and discussed in this specification according to conventional methods well known in the art.
  • groups and their substituents can be selected by those skilled in the art to provide stable structural parts and compounds.
  • substituent When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes chemically equivalent substituents obtained when the structural formula is written from right to left. For example, -CH 2 O- is equivalent to -OCH 2 -.
  • C1-C6 alkyl refers to an alkyl group as defined below having a total of 1 to 6 carbon atoms.
  • the total number of carbon atoms in the simplified notation does not include carbons that may be present in the substituents of the group.
  • halogen means fluorine, chlorine, bromine or iodine.
  • Hydroalkyl refers to an alkyl group as defined below that is substituted with a hydroxyl group (-OH).
  • Niro refers to -NO 2 .
  • Cyano refers to -CN.
  • Amino refers to -NH 2 .
  • Substituted amino refers to an amino group substituted with one or two alkyl, alkylcarbonyl, aralkyl, heteroaralkyl groups as defined below, for example, monoalkylamino, dialkylamino, alkyl Amido, aralkylamino, heteroaralkylamino.
  • Carboxy refers to -COOH.
  • (C1-C4) alkylsulfonyl means (C1-C4) alkyl -SO 2 -, wherein the alkyl group defined as described below.
  • (C1-C4)alkylsulfinyl refers to (C1-C4)alkyl-SO-, wherein the alkyl group is defined as described below.
  • (C1-C4) alkylsulfonylamino means: (C1-C4) alkyl -SO 2 -NH-, wherein said alkyl is defined as described below.
  • Aminosulfonyl means: -SO 2 -NH 2 .
  • alkyl refers to a fully saturated linear or branched hydrocarbon chain group, It consists only of carbon atoms and hydrogen atoms, has, for example, 1 to 6 (preferably 1 to 4) carbon atoms, and is connected to the rest of the molecule through a single bond, such as but not limited to methyl, ethyl, n-propyl Base, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, etc.
  • the alkyl group (as a group or part of another group) also intends to include substituted alkyl groups, for example, the substitution is selected from halogen, hydroxyl, cyano, nitro, amino, carboxy, Sulfonyl etc.
  • cycloalkyl refers to a fully saturated cyclic alkane consisting only of carbon atoms and hydrogen atoms, having, for example, 3 to 6 carbon atoms (ie C3-C6 cycloalkyl), and having a single bond with the rest of the molecule Partial connections include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, for example.
  • the cycloalkyl group (as a group or part of another group) also intends to include a substituted cycloalkyl group, for example, the substitution is selected from halogen, hydroxyl, cyano, nitro, amino, Carboxy, sulfonyl, etc.
  • Halo(C1-C4)alkyl refers to a C1-C4 alkyl substituted with 1 or 2 or 3 halogen atoms, such as trifluoromethyl and difluoromethyl.
  • heterocyclic group means a group consisting of 2 to 14 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, phosphorus, oxygen and sulfur
  • the heterocyclic group may be a monocyclic, bicyclic, tricyclic or more ring system, which may include a fused ring system, a bridged ring system or a spiro ring system; in the heterocyclic group
  • the nitrogen, carbon, or sulfur atoms of may be optionally oxidized; the nitrogen atom may be optionally quaternized; and the heterocyclic group may be partially or fully saturated.
  • the heterocyclic group can be connected to the rest of the molecule via a carbon atom or a heteroatom and through a single bond.
  • heterocyclic groups containing fused rings one or more rings may be aryl or heteroaryl as defined below, provided that the point of attachment to the rest of the molecule is a non-aromatic ring atom.
  • the heterocyclic group is preferably a stable 4- to 11-membered non-aromatic monocyclic, bicyclic, bridged ring or spirocyclic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur
  • the group is more preferably a stable 4- to 8-membered non-aromatic monocyclic, bicyclic, bridged ring or spirocyclic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur.
  • heterocyclic groups include, but are not limited to: pyrrolidinyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, thiomorpholinyl, 2,7-diaza-spiro[3.5]non Alkyl-7-yl, 2-oxa-6-aza-spiro[3.3]heptane-6-yl, 2,5-diaza-bicyclo[2.2.1]heptan-2-yl, aza Cyclobutanyl, pyranyl, tetrahydropyranyl, thiopyranyl, tetrahydrofuranyl, oxazinyl, dioxopentyl, tetrahydroisoquinolinyl, decahydroisoquinolinyl, imidazolinyl, Imidazolidinyl, quinazinyl, thiazolidinyl, isothiazolidinyl, isoxazolidinyl, in
  • the heterocyclic group (as a group or part of another group) is also intended to include a substituted heterocyclic group, for example, the substitution is selected from halogen, hydroxyl, cyano, nitro, amino, Carboxy, sulfonyl, etc.
  • aryl or aromatic ring means having 6 to 18 carbon atoms (preferably having 6 to 10 carbon atoms, ie C6-C10)
  • the conjugated hydrocarbon ring system group can be a monocyclic, bicyclic, tricyclic or more cyclic ring system, and can also be fused with a cycloalkyl or heterocyclic group as defined above, provided that the aryl group passes through The atoms on the aromatic ring are connected to the rest of the molecule through a single bond.
  • aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthryl, fluorenyl, 2,3-dihydro-1H-isoindolyl, 2-benzoxazolinone, 2H-1, 4-benzoxazine-3(4H)-one-7-yl and the like.
  • the aryl group (or aromatic ring) (as a group or a part of another group) is also intended to include a substituted aryl group (or aromatic ring), for example, the substitution is selected from: halogen, hydroxyl, Cyano, nitro, amino, carboxy, sulfonyl, etc.
  • heteroaryl or heteroaromatic ring means having 1 to 15 carbon atoms (preferably having 1 to 10 carbon atoms) and 1 A 5- to 16-membered conjugated ring system group of up to 6 heteroatoms selected from nitrogen, oxygen and sulfur.
  • heteroaryl groups can be monocyclic, bicyclic, tricyclic or more cyclic ring systems, and can also be fused with cycloalkyl or heterocyclic groups as defined above, provided that the hetero The aryl group is connected to the rest of the molecule via a single bond through an atom on the aromatic ring.
  • the nitrogen, carbon or sulfur atoms in the heteroaryl group can be optionally oxidized; the nitrogen atom can be optionally quaternized.
  • the heteroaryl group is preferably a stable 5- to 12-membered aromatic group containing 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur, and more preferably contains 1 to 4 selected heteroatoms.
  • heteroaryl groups include, but are not limited to, thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, Benzimidazolyl, benzopyrazolyl, indolyl, furyl, pyrrolyl, triazolyl, tetrazolyl, triazinyl, indazinyl, isoindolyl, indazolyl, isoindazolyl , Purinyl, Quinolinyl, Isoquinolinyl, Diazonaphthyl, Naphthyridinyl, Quinoxolinyl, Pteridinyl, Carbazolyl, Carboline, Phenanthridinyl, Phenanthrolinyl, Acridine Group, phen
  • heteroaryl group (or heteroaromatic ring) (as a group or part of another group) is also intended to include substituted heteroaryl groups (or heteroaromatic rings), for example, the substitution is selected from: Halogen, hydroxyl, cyano, nitro, amino, carboxy, sulfonyl, etc.
  • multiple refers to 2, 3, 4, or 5.
  • the terms "compounds of the present invention” or “active ingredients of the present invention” are used interchangeably and refer to formula I and its stereoisomers, enantiomers, or pharmaceutically acceptable salts thereof.
  • the term also includes racemates, optical isomers, isotopic compounds (such as deuterated compounds) or prodrugs.
  • the compound of formula (I) has the following structure:
  • R 1 -R 6 ie, R 1 , R 2 , R 3 , R 4 , R 5 , R 6
  • X and Y are defined as described above.
  • the compound of formula (I) has a structure represented by formula (I-1):
  • n 2, 3, or 4
  • Ra, R 2 -R 6 ie, R 2 , R 3 , R 4 , R 5 , R 6
  • X, Y are defined as described above.
  • the compound of formula (I) has the structure shown in formula (I-2)-(I-11):
  • R 1a , R 2a , R 3a , R 4a , and R 5a are as described above.
  • the compound of formula (I) has a structure represented by formula (I-14):
  • n, R 2 , R 3 , R 4 , R 5 , R 6 , and R g are as defined above.
  • the compound of general formula (I) has a structure represented by formula (I-12):
  • n, Ra, R m , n, R 2 , R 4 , R 5 , R 6 , and Y are as defined above.
  • the compound of general formula (I) has the structure shown in formula (I-15):
  • n, R g , R m , n, R 2 , R 4 , R 5 , R 6 , and Y are as defined above.
  • R 6 is selected from:
  • R 6 is Among them, Z, X, R 1a , R 2a , R 3a , R 4a , and R 5a are as defined above.
  • R 2 is selected from the following group: hydrogen atom, C1-C6 alkyl, C1-C6 alkyl substituted with hydroxy, C1-C6 alkyl substituted with carboxyl, (C1-C4 alkyl) 2 N-group substituted C1-C6 alkyl, 5-6 membered heteroaryl substituted C1-C6 alkyl, 5-10 membered heterocyclic substituted C1-C6 alkyl, C3-C6 cycloalkyl, (C1 -C4) 2 N-group substituted C3-C6 cycloalkyl, 5-10 membered heterocyclic group, 1-3 halogen atom substituted (C1-C4) alkyl, Ar 1 -(CH 2 ) m -, benzene Group or five-membered heteroaryl group, more preferably, R 2 is selected from hydrogen atom, C1-C6 alkyl, C3-C6 cycloalkyl, 5
  • R 3 is Ar-CH 2 -; wherein, Ar is a substituted or unsubstituted C6-C10 aromatic ring (such as phenyl), or a 5-12 membered heteroaromatic ring (such as pyridyl) ), wherein the said substitution means that one or more hydrogen atoms on the group are substituted by a substituent selected from the following group: C1-C4 alkyl, (C1-C4) alkoxy, hydroxyl, amino, cyanide Group, trifluoromethyl, difluoromethyl, (C1-C4)alkylsulfonyl, (C1-C4)alkylsulfinyl, (C1-C4)alkylsulfonylamino, aminosulfonyl, (C1 -C5) acylamino, halo(C1-C4)alkylsulfonyl, halo(C1-C4)alkylsulfulfonyl, hal
  • R 4 is selected from: hydrogen atom, halogen, C1-C4 alkyl, C1-C4 alkoxy, or halogenated (C1-C4) alkyl; preferably halogen, C1-C4 alkyl.
  • R 5 is selected from: hydrogen atom, halogen, C1-C4 alkyl, C1-C4 alkoxy, cyano, or halo (C1-C4) alkyl; preferably H.
  • Steps refer to compounds that consist of the same atoms and are bonded by the same bonds, but have different three-dimensional structures.
  • the present invention will cover various stereoisomers and mixtures thereof.
  • Tautomer refers to an isomer formed by transferring a proton from one atom of a molecule to another atom of the same molecule. All tautomeric forms of the compounds of the present invention will also be included in the scope of the present invention.
  • the compound of the present invention or a pharmaceutically acceptable salt thereof may contain one or more chiral carbon atoms, and therefore may produce enantiomers, diastereomers and other stereoisomeric forms.
  • Each chiral carbon atom can be defined as (R)- or (S)- based on stereochemistry.
  • the present invention is intended to include all possible isomers, as well as their racemates and optically pure forms.
  • racemates, diastereomers or enantiomers can be selected as raw materials or intermediates.
  • Optically active isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as crystallization and chiral chromatography.
  • the present invention also includes isotopically labeled compounds, which are equivalent to the original compounds disclosed herein. However, in fact, it usually occurs when one or more atoms are replaced by atoms whose atomic weight or mass number is different.
  • isotopes that can be classified as compounds of the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine isotopes, such as 2 H, 3 H, 13 C, 11 C, 14 C, 15 N, and 18 O, respectively. , 17 O, 31 P, 32 P, 35 S, 18 F and 36 Cl.
  • the compounds of the present invention or enantiomers, diastereomers, isomers, or pharmaceutically acceptable salts or solvates, which contain isotopes or other isotopic atoms of the above compounds are all within the scope of the present invention.
  • Certain isotope-labeled compounds in the present invention such as radioisotopes of 3 H and 14 C, are also among them, which are useful in tissue distribution experiments of drugs and substrates.
  • Isotopically-labeled compounds can be prepared by general methods by replacing readily available isotope-labeled reagents with non-isotopic reagents, using the protocol disclosed in the examples.
  • pharmaceutically acceptable salt includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
  • “Pharmaceutically acceptable acid addition salt” refers to a salt formed with an inorganic acid or an organic acid that can retain the biological effectiveness of the free base without other side effects.
  • Inorganic acid salts include, but are not limited to, hydrochloride, hydrobromide, sulfate, nitrate, phosphate, etc.
  • organic acid salts include, but are not limited to, formate, acetate, and 2,2-dichloroacetate , Trifluoroacetate, propionate, caproate, caprylate, caprate, undecylenate, glycolate, gluconate, lactate, sebacate, hexanoate Acid salt, glutarate, malonate, oxalate, maleate, succinate, fumarate, tartrate, citrate, palmitate, stearate, oleate , Cinnamate, laurate, malate, glutamate, pyroglutamate, aspartate, benzoate, methanesulfonate,
  • “Pharmaceutically acceptable base addition salt” refers to a salt formed with an inorganic base or an organic base that can maintain the biological effectiveness of the free acid without other side effects.
  • Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like.
  • Preferred inorganic salts are ammonium, sodium, potassium, calcium and magnesium salts.
  • Salts derived from organic bases include but are not limited to the following salts: primary amines, secondary amines and tertiary amines, substituted amines, including natural substituted amines, cyclic amines and basic ion exchange resins , Such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, bicyclic Hexylamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperazine Pyridine, N-ethylpiperidine, polyamine resin, etc.
  • Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine
  • a specific enantiomer of the compound of the present invention can be prepared by asymmetric synthesis, or derivatized with a chiral adjuvant, separating the resulting diastereomeric mixture, and then removing the chiral adjuvant.
  • the pure enantiomer if the molecule contains a basic functional group, such as an amino acid, or an acidic functional group, such as a carboxyl group, a suitable optically active acid or base can be used to form a diastereomeric salt with it, and then through separation crystallization or chromatography, etc. After separation by conventional means, the pure enantiomers are obtained.
  • the compounds of the present invention can be combined with any number of substituents or functional groups to expand their coverage.
  • the general formula including substituents in the formula of the present invention refers to the replacement of hydrogen radicals with designated structural substituents.
  • each position of the substituents may be the same or different.
  • substitution as used herein includes all permissible substitution of organic compounds. Broadly speaking, the permissible substituents include acyclic, cyclic, branched unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic organic compounds.
  • the heteroatom nitrogen may have a hydrogen substituent or any permitted organic compound as described above to supplement its valence.
  • the present invention is not intended to limit the permitted substitution of organic compounds in any way.
  • the present invention believes that the combination of substituents and variable groups is excellent in the treatment of diseases in the form of stable compounds.
  • stable refers to a compound that is stable and can be tested for a long enough time to maintain the structural integrity of the compound, preferably for a long enough time to be effective, and is used herein for the above purpose.
  • the pharmaceutical composition of the present invention is used to prevent and/or treat cancer, immune diseases, metabolic diseases and the like.
  • pharmaceutical composition refers to a preparation of a compound of the present invention and a medium generally accepted in the art for delivering a biologically active compound to a mammal (such as a human).
  • the medium includes a pharmaceutically acceptable carrier.
  • the purpose of the pharmaceutical composition is to promote the administration of the organism, which is conducive to the absorption of the active ingredient and thus the biological activity.
  • pharmaceutically acceptable refers to a substance (such as a carrier or diluent) that does not affect the biological activity or properties of the compound of the present invention, and is relatively non-toxic, that is, the substance can be administered to an individual without causing undesirable biological activity. Reacts or interacts in an undesirable manner with any components included in the composition.
  • pharmaceutically acceptable excipients include, but are not limited to, any adjuvants, carriers, excipients, glidants, enhancers that are approved by the relevant government administration as acceptable for human or livestock use.
  • the “cancer” or “tumor” in the present invention includes, but is not limited to, non-small cell lung cancer, melanoma, head and neck cancer, kidney cancer, bladder epithelial cancer, locally advanced or metastatic urothelial cancer, and metastatic Merkel cell carcinoma , Prostate cancer, liver cancer, bowel cancer, multiple myeloma, mantle cell lymphoma, diffuse large B-cell lymphoma, liver cancer, Hodgkin’s lymphoma, chronic lymphocytic leukemia, etc.
  • prevention includes reducing the likelihood of the occurrence or exacerbation of a disease or condition in a patient.
  • an effective amount refers to at least one agent or compound that is sufficient to relieve one or more symptoms of the disease or condition being treated after administration The amount.
  • the result can be a reduction and/or alleviation of signs, symptoms or causes, or any other desired changes in the biological system.
  • the "effective amount” for treatment is the amount of the composition containing the compound disclosed herein that is required to provide significant disease relief clinically. Techniques such as dose escalation tests can be used to determine the effective amount suitable for any individual case.
  • administration refers to methods capable of delivering a compound or composition to a desired site for biological action. These methods include, but are not limited to, oral routes, transduodenal routes, parenteral injections (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical administration, and rectal administration.
  • parenteral injections including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion
  • topical administration and rectal administration.
  • Those skilled in the art are familiar with the application techniques that can be used for the compounds and methods described herein, for example in Goodman and Gilman, The Pharmaceutical Basis of Therapeutics, current ed.; Pergamon; and Remington's, Pharmaceutical (current edition), Mack Publishing Co., Those discussed in Easton, Pa.
  • the compounds and compositions discussed herein are administered orally.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or mixed with the following ingredients: (a) fillers or compatibilizers, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) humectant, For example, glycerin; (d) disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) Absorption accelerators, such as quaternary amine compounds; (g) wetting agents, such as cetyl alcohol and gly
  • Solid dosage forms such as tablets, sugar pills, capsules, pills and granules can be prepared with coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifying agents, and the active compound or the release of the compound in such a composition may be released in a certain part of the digestive tract in a delayed manner. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the active compound can also be formed into microcapsules with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
  • the liquid dosage form may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-Butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.
  • composition may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.
  • the suspension may contain suspending agents, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
  • suspending agents for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
  • composition for parenteral injection may contain physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
  • non-fixed combination refers to the simultaneous administration, combination or sequential administration of at least one compound described herein and at least one synergistic agent to a patient in the form of separate entities. These also apply to cocktail therapy, such as the administration of three or more active ingredients.
  • the drugs or active ingredients that can be used in combination with the compound of formula (I) include but are not limited to: PD-1 inhibitors (such as nivolumab, pembrolizumab, JS-001, SHR-120, BGB-A317, IBI-308, GLS-010, GB-226, STW204, HX008, HLX10, BAT1306, AK105, LZM 009 or biological analogues of the above drugs, etc.), PD-L1 inhibitors (such as devaluzumab) , Atezolizumab, CS1001, KN035, HLX20, SHR-1316, BGB-A333, JS003, CS1003, KL-A167, F520, GR1405, MSB2311 or biological analogues of the above drugs, etc.), CD20 antibodies (such as Li Tuximab, obin utuzumab, ofatumumab, tositumomab, ibritumo
  • Pabocinib, Rebosine, Abemaciclib, Lerociclib, etc. MEK inhibitors (e.g. Simetinib (AZD6244), Trametinib (GSK1120212), PD0325901, U0126, AS-703026, PD184352 ( CI-1040), etc.), Akt inhibitors (such as MK-2206, Ipatasertib, Capivasertib, Afuresertib, Uprosertib, etc.), mTOR inhibitors (such as Vistusertib, etc.), SHP2 inhibitors (such as RMC-4630, JAB-3068, TNO155, etc.) ), IGF-1R inhibitors (such as Ceritinib, okatinib, linsitinib, BMS-754807, GSK1838705A, etc.) or a combination thereof.
  • MEK inhibitors e.g. Simetinib (AZD6244), Tra
  • a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage is the pharmaceutically effective dosage considered to be administered.
  • the daily administration dose is usually 1 to 2000 mg, preferably 50 to 1000 mg.
  • the specific dosage should also consider factors such as the route of administration, the patient's health status, etc., which are within the skill range of a skilled physician.
  • the present invention also provides a method for preparing a pharmaceutical composition, which includes the steps of: combining a pharmaceutically acceptable carrier with the compound of general formula (I) or its crystal form, pharmaceutically acceptable salt, hydrate or The solvates are mixed to form a pharmaceutical composition.
  • the present invention also provides a treatment method, which comprises the steps of: administering the compound of general formula (I), its stereoisomer, enantiomer or its pharmaceutically acceptable Salt, or administration of the pharmaceutical composition of the present invention, is used to inhibit PD1-PDL1 interaction.
  • each reaction is usually carried out in an inert solvent at room temperature to reflux temperature (such as 0°C to 150°C, preferably 10°C to 100°C).
  • the reaction time is usually 0.1 hour to 60 hours, preferably 0.5 to 48 hours.
  • the preparation method of the compound represented by general formula (I) is as follows:
  • compound I-1a is under the action of acid or base to obtain compound I-1b.
  • the base in step 2) is selected from potassium carbonate, sodium carbonate, triethylamine or diisopropylethylamine.
  • the acid in step 4) is hydrochloric acid and sulfuric acid.
  • the alkali in step 4) is NaOH and KOH.
  • I-2a is under the action of acid or base to obtain compound I-2b;
  • the base in step 2) is selected from potassium carbonate, sodium carbonate, triethylamine or diisopropylethylamine.
  • the acid in step 4') is hydrochloric acid or sulfuric acid.
  • the alkali in step 4') is NaOH or KOH.
  • compound S3 and compound S4 can generate compound S5 under the action of a base;
  • the base in step 2) is selected from potassium carbonate, sodium carbonate, triethylamine or diisopropylethylamine.
  • the condensing agent in step 4) is selected from: EDC-HCl/HOBt, HBTU, HATU or DCC.
  • the base in step 2) is selected from potassium carbonate, sodium carbonate, triethylamine or diisopropylethylamine.
  • the condensing agent in step 4) is selected from: EDC-HCl/HOBt, HBTU, HATU or DCC.
  • the base in step 2) is selected from potassium carbonate, sodium carbonate, triethylamine or diisopropylethylamine.
  • compound S5 undergoes reductive amination reaction with compound S15 to obtain compound I-6a;
  • the base in step 2) is selected from potassium carbonate, sodium carbonate, triethylamine or diisopropylethylamine.
  • the base in step 2) is selected from potassium carbonate, sodium carbonate, triethylamine or diisopropylethylamine.
  • the base in step 2) is selected from potassium carbonate, sodium carbonate, triethylamine or diisopropylethylamine.
  • the palladium catalyst in step 1) is Pd(OAc) 2 .
  • the phosphorus-containing ligand in step 1) is tBuXphos.
  • R 2 , R 3 , R 4 , R 5 , R 6 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , X, and Y groups have the above definitions.
  • R 2 , R 3 , R 4 , R 5 , R 6 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , X and Y in all the above synthetic methods are as follows:
  • X is N or CH
  • Y is a hydrogen atom or a C1-C4 alkyl group
  • R 1 is selected from the following group:
  • R 2 is selected from the following group of substituted or unsubstituted groups: hydrogen atom, C1-C6 alkyl, C3-C6 cycloalkyl, 5-10 membered heterocyclic group, Ar 1 -(CH 2 ) m -, C6- C10 aromatic ring or 5-12 membered heteroaromatic ring; Ar 1 is a substituted or unsubstituted 5-10 membered heterocyclic group, C6-C10 aromatic ring or 5-12 membered heteroaromatic ring; wherein, the substitution means Substituted by one or more groups selected from the following group: hydroxy, halogen, carboxy, cyano, C1-C6 alkyl, -NRaRb, 5-6 membered heteroaryl, C3-C6 cycloalkyl, 5-10 Membered heterocyclic group;
  • Ar is a substituted or unsubstituted C6-C10 aromatic ring, or a 5-12 membered heteroaromatic ring,
  • R 4 is selected from: hydrogen atom, halogen, C1-C4 alkyl, C1-C4 alkoxy, or halogenated (C1-C4) alkyl;
  • R 5 is selected from: hydrogen atom, halogen, C1-C4 alkyl, C1-C4 alkoxy, cyano, or halo (C1-C4) alkyl;
  • R 6 is selected from: a substituted or unsubstituted benzene ring, wherein the said substitution refers to one or more hydrogen atoms on the group being substituted by a substituent selected from the following group: p-methoxybenzyloxy, Benzyloxy, (C1-C5)alkoxy, hydroxyl, halogen;
  • R 6 is selected from:
  • Z is a hydrogen atom or a C1-C4 alkyl group
  • R 1a is selected from:
  • R 2a is selected from the following group of substituted or unsubstituted groups: hydrogen atom, C1-C6 alkyl, C3-C6 cycloalkyl, 5-10 membered heterocyclic group, Ar 1 -(CH 2 ) m -, C6- C10 aromatic ring or 5-12 membered heteroaromatic ring; Ar 1 is a substituted or unsubstituted 5-10 membered heterocyclic group, C6-C10 aromatic ring or 5-12 membered heteroaromatic ring; wherein, the substitution means Substituted by one or more groups selected from the following group: hydroxy, halogen, carboxy, cyano, C1-C6 alkyl, -NRaRb, 5-6 membered heteroaryl, C3-C6 cycloalkyl, 5-10 Membered heterocyclic group;
  • R 4a is selected from: hydrogen atom, halogen, C1-C4 alkyl, (C1-C4) alkoxy, halogenated (C1-C4) alkyl;
  • R 5a is selected from: hydrogen atom, halogen, C1-C4 alkyl, (C1-C4) alkoxy, cyano, halogenated (C1-C4) alkyl;
  • Ra, Rb, and Rc are each independently selected from: hydrogen atom, C1-C5 alkyl, -O-CH 2 -O-CO-(C1-C5 alkyl), -CH 2 -O-CO-(C1-C5 alkyl);
  • Rg is selected from: -NRdRe
  • Rx is selected from: hydrogen atom, C1-C6 alkyl, C3-C6 cycloalkyl, 5-10 membered heterocyclic group;
  • R 11 , R 12 , R 13 , R 14 , R 15 , and R 16 are each independently selected from: hydrogen, hydroxyl, -O-CHO, (C1-C4 alkyl)carbonyl-O-, HO 2 C-;
  • the functional group of the intermediate compound may need to be protected by an appropriate protecting group.
  • Such functional groups include hydroxyl, amino, mercapto and carboxylic acid.
  • Suitable hydroxy protecting groups include trialkylsilyl or diarylalkylsilyl (e.g. tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl) , Tetrahydropyranyl, benzyl, etc.
  • Suitable protecting groups for amino, amidino and guanidino include tert-butoxycarbonyl, benzyloxycarbonyl and the like.
  • Suitable protecting groups for mercapto include -C(O)-R" (wherein R" is an alkyl, aryl or aralkyl), p-methoxybenzyl, trityl and the like.
  • Suitable carboxyl protecting groups include alkyl, aryl or aralkyl esters.
  • Protecting groups can be introduced and removed according to standard techniques known to those skilled in the art and as described herein. The use of protective groups is detailed in Greene, T.W. and P.G.M. Wuts, Protective Groups in Organi Synthesis, (1999), 4th Ed., Wiley.
  • the protecting group can also be a polymer resin.
  • the reagents or materials used in the present invention can be obtained commercially or in the manner given in literature reports.
  • the compound of the present invention has a better ability to inhibit the interaction of PD1/PD-L1, which is 20 times or even higher than the BMS-1266 reported in the prior art;
  • the compound of the present invention has a better effect of promoting T cells to kill cancer cells;
  • the compound of the present invention has better pharmacodynamic properties.
  • Step 1 Synthesis of 5-chloro-4-((3-(2,3-dihydrobenzo[b][1,4]dioxen-6-yl)-2-methylbenzyl) (Oxy)-2-hydroxybenzaldehyde (ZA52)
  • ZA03 (728mg, 2.84mmol) and 5-chloro-2,4-dihydroxybenzaldehyde (SM1,488mg, 2.84mmol) were added to the reaction flask, then PPh 3 (820mg, 3.13mmol) was added and dissolved in THF, After cooling down in an ice-water bath, DIAD (574 mg, 2.84 mmol) was added dropwise, and then slowly raised to room temperature, and stirred overnight. After the reaction is over, it is quenched by adding saturated sodium bicarbonate solution and extracted with ethyl acetate.
  • DIAD 574 mg, 2.84 mmol
  • Step 2 Synthesis of 5-((4-chloro-5-((3-(2,3-dihydrobenzo[b][1,4]dioxe-6-yl)-2-methyl (Benzyl)oxy)-2-formylphenoxy)methyl)nicotinonitrile (ZD07)
  • ZA52 (609 mg, 1.56 mmol) and 5-(chloromethyl) nicotinonitrile (285 mg, 1.875 mmol) were dissolved in DMF, and then Cs 2 CO 3 was added to react at room temperature overnight. After the reaction is completed, it is quenched with water, extracted with dichloromethane three times, the organic phase is washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, the solvent is spin-dried, and separated and purified by a chromatography column to obtain 546 mg of the target compound.
  • Step 2 Synthesis of (3-(2,3-dihydrobenzo[b][1,4]dioxen-6-yl)-2-methylphenyl)methanol (ZA03)
  • Step three 4-((3-(2,3-dihydrobenzo[b][1,4]dioxen-6-yl)-2-methylbenzyl)oxy)-2 -Hydroxy-5-methylbenzaldehyde (ZA88)
  • ZA03 (637mg, 2.5mmol) was added to the reaction flask, and then 2,4-dihydroxy-5-methylbenzaldehyde (377 mg, 2.5mmol), PPh 3 (717.1mg, 2.74mmol), and THF ( 15ml) was dissolved, DIAD (diisopropyl azodicarboxylate) (503mg, 2.5mmol) was added dropwise after cooling in an ice-water bath, and then slowly raised to room temperature and stirred overnight. After the completion of the reaction, it was quenched by adding saturated sodium bicarbonate solution and extracted with ethyl acetate.
  • DIAD diisopropyl azodicarboxylate
  • Step 4 Synthesis of 3-((5-((3-(2,3-dihydrobenzo[b][1,4]dioxen-6-yl)-2-methylbenzyl) (Oxy)-2-formyl-4-methylphenoxy)methyl)benzonitrile (ZA80)
  • Step 5 Synthesis of 3-((2-(((3-aminopropyl)(methyl)amino)methyl)-5-((3-(2,3-dihydrobenzo[b][1, 4) Dioxan-6-yl)-2-methylbenzyl)oxy)-4-methylphenoxy)methyl)benzonitrile (ZA91)
  • ZA80 (520mg, 1.0mmol), (3-(methylamino)propyl) tert-butyl carbamate (564mg, 3.0mmol) were dissolved in dry THF, then AcOH (0.2ml) was added, and NaBH( OAc) 3 (1.10g, 5.0eq), react at room temperature overnight. After the reaction, saturated sodium bicarbonate solution was added, then extracted with dichloromethane, the organic phase was dried with anhydrous sodium sulfate and spin-dried, and finally separated and purified by a chromatography column to obtain 301 mg of intermediate, yield: 43%.
  • Step 6 Synthesis of N-(3-((2-((3-cyanobenzyl)oxy)-4-((3-(2,3-dihydrobenzo[b][1,4] (Oxacyclohexen-6-yl)-2-methylbenzyl)oxy)-5-methylbenzyl)(methyl)amino)propyl)but-2-ynamide (ZA89)
  • Step 1 Synthesis of 2–((2–((3-cyanobenzyl)oxy)-4–((3-(2,3-dihydrobenzo[b][1,4]dioxin- 6-yl)-2-methylbenzyl)oxy)-5-methylbenzyl)(methyl)amino)ethane-1-isopropyl sulfonate (ED09)
  • Step 2 Synthesis of 2-((2-((3-cyanobenzyl)oxy)-4-((3-(2,3-dihydrobenzo[b][1,4] dioxane (Hexen-6-yl)-2-methylbenzyl)oxy)-5-methylbenzyl)(methyl)amino)ethane-1-sulfonic acid (ED11)
  • step 2 Dissolve all the crude ED09 obtained in step 1 in 10 mL of methanol, add 1 mL of concentrated hydrochloric acid, and stir overnight at room temperature. The reaction solution was concentrated to obtain the crude product, and the crude product was purified by reverse phase liquid phase purification to obtain 30 mg of the target compound.
  • Step 1 Synthesis of 2–((2–((3-cyanobenzyl)oxy)-4–((3-(2,3-dihydrobenzo[b][1,4]dioxin- 6-yl)-2-methylbenzyl)oxy)-5-methylbenzyl)(methyl)amino)diethyl ethane-1-phosphonate (ED18)
  • ZA80 (0.1mmol, 50mg), diethyl (2-aminoethyl) phosphonate (1.0mmol, 181mg) were dissolved in THF (4mL) and methanol (2mL), stirred at room temperature for 1 hour, and NaBH 4 ( 160mg, 4.2mmol), stirred overnight.
  • the reaction was diluted with water, the aqueous phase was extracted with CH 2 Cl 2 , dried and concentrated to obtain 125 mg of the crude product of the target compound, which was directly used in the next reaction without further purification.
  • Step 2 Synthesis of 2–((2–((3-cyanobenzyl)oxy)-4–((3-(2,3-dihydrobenzo[b][1,4]dioxin- 6-yl)-2-methylbenzyl)oxy)-5-methylbenzyl)(methyl)amino)ethane-1-phosphonic acid monoethyl ester (ED19-2)
  • Example 6/7 Synthesis of (2–((2–((3-cyanobenzyl)oxy)-4–((3-(2,3-dihydrobenzo[b][1,4] Dioxin-6-yl)-2-methylbenzyl)oxy)-5-methylbenzyl)(methyl)amino)ethyl)phosphonic acid (ED55-1) and (2-((2 –((3-cyanobenzyl)oxy)-4–((3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methyl (Benzyl)oxy)-5-methylbenzyl)amino)ethyl)phosphonic acid (ED55-2)
  • Step 1 Synthesis of (((2-((2-((3-cyanobenzyl)oxy)-4-((3-(2,3-dihydrobenzo[b][1,4] two (Oxin-6-yl)-2-methylbenzyl)oxy)-5-methylbenzyl)(methyl)amino)ethyl)phosphoryl)bis(oxy))bis(methylene)bis( 2,2-Dimethylpropionate) (ED52-1) and (((2-((2-((3-cyanobenzyl)oxy)-4-((3-(2,3- Dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylbenzyl)oxy)-5-methylbenzyl)amino)ethyl)phosphoryl)bis(oxy) )Bis(methylene)bis(2,2-dimethylpropionate) (ED52-2)
  • Step 2 Synthesis of (2–((2–((3-cyanobenzyl)oxy)-4–((3-(2,3-dihydrobenzo[b][1,4]dioxin -6-yl)-2-methylbenzyl)oxy)-5-methylbenzyl)(methyl)amino)ethyl)phosphonic acid (ED55-1) and (2--((2--(( 3-cyanobenzyl)oxy)-4--((3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylbenzyl) (Oxy)-5-methylbenzyl)amino)ethyl)phosphonic acid (ED55-2)
  • Example 8 Synthesis of (3-((2-((3-cyanobenzyl)oxy)-4-((3-(2,3-dihydrobenzo[b][1,4]diox Heterohexene-6-yl)-2-methylbenzyl)oxy)-5-methylbenzyl)(methyl)amino)propyl)phosphonic acid (ED57)
  • Step 1 Synthesis of 3-((5-((3-(2,3-dihydrobenzo[b][1,4]dioxen-6-yl)-2-methylbenzyl) Oxy)-4-methyl-2-((methylamino)methyl)phenoxy)methyl)benzonitrile (ED54)
  • Step 2 (3-((2-((3-cyanobenzyl)oxy)-4-((3-(2,3-dihydrobenzo[b][1,4]dioxe (Hexen-6-yl)-2-methylbenzyl)oxy)-5-methylbenzyl)(methyl)amino)propyl)phosphonic acid (ED57)
  • Example 12 Synthesis of N-(3-((2-((3-cyanobenzyl)oxy)-4-((3-(2,3-dihydrobenzo[b][1,4] Dioxol-6-yl)-2-methylbenzyl)oxy)-5-methylbenzyl)(methyl)amino)propyl)oxirane-2-carboxamide (ZB101 )
  • Step 1 Synthesis of 3-((2-(((2-aminoethyl)(methyl)amino)methyl)-5-((3-(2,3-dihydrobenzo[b][1, 4) Dioxan-6-yl)-2-methylbenzyl)oxy)-4-methylphenoxy)methyl)benzonitrile (EC106)
  • Step 2 Synthesis of N-(2-((2-((3-cyanobenzyl)oxy)-4-((3-(2,3-dihydrobenzo[b][1,4] (Oxacyclohexen-6-yl)-2-methylbenzyl)oxy)-5-methylbenzyl)(methyl)amino)ethyl)oxirane-2-carboxamide (ZB44)
  • Example 16 Synthesis of 3-((5-((3-(2,3-dihydrobenzo[b][1,4]dioxen-6-yl)-2-methylbenzyl )Oxy)-4-methyl-2-((methyl(2-(((3S,4R)-3,4,5-trihydroxypentyl)amino)ethyl)amino)methyl)phenoxy (Yl)methyl)benzonitrile (ZB83)
  • Step 1 Synthesis of 2-((2,4-difluorobenzyl)oxy)-4-((3-(2,3-dihydrobenzo[b][1,4]dioxene -6-yl)-2-methylbenzyl)oxy)-5-methylbenzaldehyde (ZA59)
  • Step 2 Synthesis of (2R,3R,4R,5S)-6-((2-((2,4-difluorobenzyl)oxy)-4-((3-(2,3-dihydrobenzo [b][1,4]Dioxin-6-yl)-2-methylbenzyl)oxy)-5-methylbenzyl)amino)hexane-1,2,3,4,5- Penta alcohol (ZC124)
  • Step 1 Synthesis of 4-(3-(2,3-dihydrobenzo[b][1,4]dioxen-6-yl)-2-methylbenzyl)oxy)-5 -Methyl-2-(pyrazin-2-ylmethoxy)benzaldehyde (ZA65)
  • ZA88 (156 mg, 0.4 mmol) and 2-(chloromethyl)pyrazine (285 mg, 1.875 mmol) were dissolved in DMF, and then Cs 2 CO 3 (195.5 mg, 0.6 mmol) was added to react at room temperature overnight. After the reaction is over, it is quenched by adding water, extracted with dichloromethane three times, the organic phase is washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, the solvent is spin-dried, and separated and purified by a chromatography column to obtain 131 mg of the target compound.
  • Step 2 Synthesis of (2R,3R,4R,5S)-6-((4-((3-(2,3-dihydrobenzo[b][1,4]dioxe-6- (Yl)-2-methylbenzyl)oxy)-5-methyl-2-(pyrazin-2-ylmethoxy)benzyl)amino)hexane-1,2,3,4,5- Penta alcohol (ZC125)
  • Step 1 2-((3-chloro-4-fluorobenzyl)oxy)-4-((3-(2,3-dihydrobenzo[b][1,4]dioxene -6-yl)-2-methylbenzyl)oxy)-5-methylbenzaldehyde (ZA42)
  • Step 2 Synthesis of (2R,3R,4R,5S)-6-((2-((3-chloro-4-fluorobenzyl)oxy)-4-((3-(2,3-dihydrobenzene And [b][1,4]dioxen-6-yl)-2-methylbenzyl)oxy)-5-methylbenzyl)amino)hexane-1,2,3, 4,5-Pentanol (ZC127)
  • ZA42 40mg, 0.058mmol
  • D-glucosamine 60mg, 0.348mmol
  • NaBH 4 70mg, 1.16mmol
  • Step 1 4-((3-(2,3-Dihydrobenzo[b][1,4]dioxe-6-yl)-2-methylbenzyl)oxy)-5 -Methyl-2-(pyridin-3-ylmethoxy)benzaldehyde (ZA84)
  • Step 2 Synthesis of ((2R,3R,4R,5S)-6-((4-((3-(2,3-dihydrobenzo[b][1,4]dioxene-6 -Yl)-2-methylbenzyl)oxy)-5-methyl-2-(pyridin-3-ylmethoxy)benzyl)amino)hexane-1,2,3,4,5- Pentaol (ZC133)
  • ZA84 (30mg, 0.058mmol) and D-glucosamine (60mg, 0.348mmol) were dissolved in a mixed solvent of THF:MeOH (1:1) to react overnight at room temperature, and then NaBH 4 (70mg, 1.84mmol) was added at room temperature The reaction is about 5h. After the reaction, the solvent was spin-dried and purified by HPLC to obtain 8.3 mg of the target compound.
  • Step 1 Synthesis of isopropyl 2-((2-((2,4-difluorobenzyl)oxy)-4-((3-(2,3-dihydrobenzo[b][1,4 ]Dioxin-6-yl)-2-methylbenzyl)oxy)-5-methylbenzyl)(methyl)amino)ethane-1-sulfonate (ZD02)
  • Step 2 Synthesis of 2-((2-((2,4-difluorobenzyl)oxy)-4-((3-(2,3-dihydrobenzo[b][1,4]diox Heterocyclohexen-6-yl)-2-methylbenzyl)oxy)-5-methylbenzyl)(methyl)amino)ethane-1-sulfonic acid (ZD02-N)
  • step 1 The crude ZD02 obtained in step 1 was dissolved in MeOH, then 0.1ml of concentrated hydrochloric acid was added, and the reaction was heated at 60°C for 2h. After the reaction, the solvent was spin-dried and purified by HPLC to obtain 9 mg of the target compound.
  • ZA88 (609 mg, 1.56 mmol) and 5-(chloromethyl) nicotinonitrile (285 mg, 1.875 mmol) were dissolved in DMF, and then Cs 2 CO 3 (826 mg, 2.34 mmol) was added to react at room temperature overnight. After the reaction is over, it is quenched by adding water, extracted with dichloromethane three times, the organic phase is washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, the solvent is spin-dried, and separated and purified by a chromatography column to obtain 602 mg of the target compound.
  • Step 1 5-Chloro-4-((3-(2,3-dihydrobenzo[b][1,4]dioxen-6-yl)-2-methylbenzyl)oxy Yl)-2-(pyrazin-2-ylmethoxy)benzaldehyde (ZA72)
  • ZA52 250 mg, 0.61 mmol
  • 2-(chloromethyl)pyrazine 134 mg, 1.22 mmol
  • Cs 2 CO 3 was added to react at room temperature overnight.
  • the reaction is quenched with water, extracted with dichloromethane three times, the organic phase is washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, the solvent is spin-dried, and separated and purified by a chromatography column to obtain 290 mg of the target compound.
  • Step 2 Synthesis of (2R,3R,4R,5S)-6-((5-chloro-4-((3-(2,3-dihydrobenzo[b][1,4]dioxane (En-6-yl)-2-methylbenzyl)oxy)-2-(pyrazin-2-ylmethoxy)benzyl)amino)hexane-1,2,3,4,5- Penta alcohol (ZC132)
  • ZA72 (30mg, 0.058mmol) and D-glucosamine (65mg, 0.348mmol) were dissolved in a mixed solvent of THF:MeOH (1:1) to react overnight at room temperature, and then NaBH 4 (70mg, 1.16mmol) was added at room temperature The reaction is about 5h. After the reaction, the solvent was spin-dried and purified by HPLC to obtain 11.3 mg of the target compound.
  • Step 1 Synthesis of 5-chloro-4-((3-(2,3-dihydrobenzo[b][1,4]dioxen-6-yl)-2-methylbenzyl) Oxy)-2-(pyridin-3-ylmethoxy)benzaldehyde (ZA85)
  • ZA52 (205 mg, 0.5 mmol) and 3-(chloromethyl)pyridine (109 mg, 1.0 mmol) were dissolved in DMF, and then Cs 2 CO 3 (244 mg, 0.75 mmol) was added to react at room temperature overnight. After the reaction is completed, it is quenched by adding water, extracted with dichloromethane three times, the organic phase is washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, the solvent is spin-dried, and separated and purified by a chromatography column to obtain 180 mg of the target compound.
  • Step 2 Synthesis of (2R,3R,4R,5S)-6-((5-chloro-4-((3-(2,3-dihydrobenzo[b][1,4]dioxane (En-6-yl)-2-methylbenzyl)oxy)-2-(pyridin-3-ylmethoxy)benzyl)amino)hexane-1,2,3,4,5-penta Alcohol (ZC134)
  • Step one Synthesis of 3-((4-chloro-5-((3-(2,3-dihydrobenzo[b][1,4]dioxen-6-yl)-2-methyl (Benzyl)oxy)-2-formylphenoxy)methyl)benzonitrile (ZA50)
  • Step 2 Synthesis of 3-((4-chloro-5-((3-(2,3-dihydrobenzo[b][1,4]dioxe-6-yl)-2-methyl Benzyl)oxy)-2-((((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)amino)methyl)phenoxy)methyl)benzene
  • ZD05
  • ZA50 35mg, 0.067mmol
  • D-glucosamine 36.2mg, 0.200mmol
  • a mixed solvent of THF: MeOH 3ml: 3ml
  • NaBH 4 50.6mg, 1.33mmol
  • the solvent was spin-dried and purified by HPLC to obtain 22 mg of the target product.
  • Example 28 Synthesis of 3-((5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((3-(2,3-dihydrobenzo[b] [1,4]Dioxol-6-yl)-2-methylbenzyl)oxy)benzyl)(methyl)amino)propane-1-sulfonic acid (ZD39)
  • Step one Synthesis of 5-((4-chloro-5-((3-(2,3-dihydrobenzo[b][1,4]dioxe-6-yl)-2-methyl (Benzyl)oxy)-2-((methylamino)methyl)phenoxy)methyl)nicotinonitrile (ZD36)
  • Step 2 3-((5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((3-(2,3-dihydrobenzo[b][1 ,4)Dioxol-6-yl)-2-methylbenzyl)oxy)benzyl)(methyl)amino)propane-1-sulfonic acid (ZD39)
  • Step 1 Synthesis of (4'-((4-methoxybenzyl)oxy)-2-methyl-[1,1'-biphenyl]-3-yl)methanol (ZA140)
  • Step 2 Synthesis of 5-chloro-2-hydroxy-4-((4'-((4-methoxybenzyl)oxy)-2-methyl-[1,1'-biphenyl]-3- (Yl)methoxy)benzaldehyde (ZA142)
  • ZA140 400mg, 1.2mmol
  • 5-chloro-2,4-dihydroxybenzaldehyde (SM1,206mg, 1.2mmol) were added to the reaction flask, then PPh 3 (345mg, 1.32mmol) was added and dissolved in THF, After cooling in an ice-water bath, DIAD (242 mg, 1.2 mmol) was added dropwise, and then slowly raised to room temperature, and stirred overnight. After the completion of the reaction, it was quenched by adding saturated sodium bicarbonate solution, and extracted with ethyl acetate.
  • Step 3 Synthesis of 3-((4-chloro-2-formyl-5-((4'-((4-methoxybenzyl)oxy)-2-methyl-[1,1'- Benzene)-3-yl)methoxy)phenoxy)methyl)benzonitrile (ZA144)
  • ZA142 (118.4 mg, 0.24 mmol) and 3-(bromomethyl)benzonitrile (57 mg, 0.29 mmol) were dissolved in DMF, then Cs 2 CO 3 (118.4 mg, 0.36 mmol) was added, and the reaction was carried out at room temperature overnight. After the reaction is completed, it is quenched by adding water, extracted with dichloromethane three times, the organic phase is washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, the solvent is spin-dried, and separated and purified by a chromatography column to obtain 205.3 mg of the target compound.
  • Step 4 Synthesis of (2S, 3R, 4R, 5R)-6-((5-chloro-4-((3-(2,3-dihydrobenzo[b][1,4]dioxane (En-6-yl)-2-methylbenzyl)oxy)-2-(pyridin-3-ylmethoxy)benzyl)amino)hexane-1,2,3,4,5-penta Alcohol (ZC126)
  • Step 5 Synthesis of 3-((4-chloro-5-((4'-hydroxy-2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2-((( (2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)amino)methyl)phenoxy)methyl)benzonitrile (ZC136)
  • ZC126 (20mg) was dissolved in a mixed solvent of DCM:TFA (3ml:1ml) and reacted at room temperature for 1h. After the reaction, the solvent was spin-dried, and then purified by HPLC to obtain 12 mg of the target compound.
  • Step 1 Synthesis of (3'-((4-methoxybenzyl)oxy)-2-methyl-[1,1'-biphenyl]-3-yl)methanol (ZA141)
  • Step 2 Synthesis of 5-chloro-2-hydroxy-4-((3'-((4-methoxybenzyl)oxy)-2-methyl-[1,1'-biphenyl]-3- (Yl)methoxy)benzaldehyde (ZA143-2)
  • ZA141 334.4mg, 1.0mmol
  • 5-chloro-2,4-dihydroxybenzaldehyde (SM1, 172mg, 1.0mmol) were added to the reaction flask, then PPh 3 (288mg, 1.1mmol) was added and dissolved in THF
  • DIAD (202 mg, 1.0 mmol) was added dropwise, and then slowly raised to room temperature, and stirred overnight. After the reaction is over, it is quenched by adding saturated sodium bicarbonate solution and extracted with ethyl acetate.
  • Step 3 Synthesis of 3-(4-chloro-2-formyl-5-((3'-((4-methoxybenzyl)oxy)-2-methyl-[1,1'-biphenyl )-3-yl)methoxy)phenoxy)methyl)benzonitrile (ZA145)
  • Step 4 3-((4-Chloro-5-((3'-((4-methoxybenzyl)oxy)-2-methyl-[1,1'-biphenyl]-3-yl )Methoxy)-2-((((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)amino)methyl)phenoxy)methyl)benzonitrile (ZC131)
  • Step 5 Synthesis of 3-((4-chloro-5-((3'-hydroxy-2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2-((( (2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)amino)methyl)phenoxy)methyl)benzonitrile (ZD24)
  • ZC131 (21.6mg) was dissolved in a mixed solvent of DCM:TFA (3ml:1ml) and reacted at room temperature for 1h. After the reaction, the solvent was spin-dried, and then purified by HPLC to obtain 8.2 mg of the target compound.
  • Step 1 Synthesis of 2-methoxy-6–((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)3-pyridinecarbaldehyde (ED22)
  • Step 2 Synthesis of (2R, 3R, 4R, 5S)-6-(((2-methoxy-6-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy (Yl)pyridin-3-yl)methyl)amino)hexane-1,2,3,4,5-pentaol (ED58)
  • Step 1 Synthesis of (2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl) dimethanol (ZC92)
  • Step 2 Synthesis of 4,4'-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy )) Bis(5-chloro-2-hydroxybenzaldehyde)(ZC93)
  • Step 3 Synthesis of 5,5'-((((((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene)) two (Oxy))bis(4-chloro6-formyl-3,1-phenylene))bis(oxy))bis(methylene))dicotinonitrile (ZC153-3)
  • Step 4 5,5'-(((((((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(methylene))bis( Oxy)) bis(4-chloro 6-((((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)amino)methyl)-3,1-phenylene (Base)) bis (oxy)) bis (methylene)) dinicotinonitrile (ZD04)
  • Example 33 Synthesis of (R)-2-((5-chloro-4-((3'-((2-chloro-5-((5-cyanopyridin-3-yl)methoxy)-4 -(((2,3-Dihydroxypropyl)amino)methyl)phenoxy)methyl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl) Methoxy)-2-((5-cyanopyridin-3-yl)methoxy)benzyl)(methyl)amino)ethane-1-sulfonic acid (ZD19)
  • Step 2 Synthesis of (R)-2-((5-chloro-4-((3'-((2-chloro-5-((5-cyanopyridin-3-yl)methoxy)-4- (((2,3-Dihydroxypropyl)amino)methyl)phenoxy)methyl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methyl Oxy)-2-((5-cyanopyridin-3-yl)methoxy)benzyl)(methyl)amino)ethane-1-sulfonic acid (ZD19)
  • ZA91 (40 mg, 0.07 mmol) was dissolved in dry CH 2 Cl 2 , then triethylamine (21 mg, 0.21 mmol) was added, and finally acryloyl chloride (6.3 mg, 0.07 mmol) was added dropwise, and reacted at room temperature for 1 h. After the reaction, the solvent was spin-dried and purified by HPLC to obtain 12.5 mg of the target compound.
  • Example 35 See Example 4 Synthesis of 2-((2-((3-cyanobenzyl)oxy)-4-((3-(2,3-dihydrobenzo[b][1,4 ]Dioxin-6-yl)-2-methylbenzyl)oxy)-5-methylbenzyl)(methyl)amino)ethane-1-isopropyl sulfonate (ED09).
  • Example 36 See Example 5 for the synthesis of 2-((2-((3-cyanobenzyl)oxy)-4-((3-(2,3-dihydrobenzo[b][1,4 ]Dioxin-6-yl)-2-methylbenzyl)oxy)-5-methylbenzyl)(methyl)amino)ethane-1-phosphonic acid diethyl ester (ED18).
  • Example 37/38 See Example 6/7 Synthesis (((2-((2-((3-cyanobenzyl)oxy)-4-((3-(2,3-dihydrobenzo [b][1,4]Dioxin-6-yl)-2-methylbenzyl)oxy)-5-methylbenzyl)(methyl)amino)ethyl)phosphoryl)bis(oxy) ) Bis(methylene)bis(2,2-dimethylpropionate) (ED52-1) and (((2-((2-((3-cyanobenzyl)oxy)-4- ((3-(2,3-Dihydrobenzo(b)(1,4)dioxin-6-yl)-2-methylbenzyl)oxy)-5-methylbenzyl)amino)ethyl Yl)phosphoryl)bis(oxy))bis(methylene)bis(2,2-dimethylpropionate).
  • Step 1 Synthesis of 5-chloro-4–((3-(2,3-dihydrobenzo[b][1,4]dioxe-6-yl)-2-methylbenzyl) Oxy)-2-((3-methoxybenzyl)oxy)benzaldehyde (ZD47)
  • Step 2 Synthesis of (2R,3R,4R,5S)-6-((5-chloro-4-((3-(2,3-dihydrobenzo[b][1,4]dioxane En-6-yl)-2-methylbenzyl)oxy)-2-((3-methoxybenzyl)oxy)benzyl)amino)hexane-1,2,3,4,5 -Pentanol (ZD53)
  • Example 40 Synthesis of 4-((4-chloro-5-((3-(2,3-dihydrobenzo[b][1,4]dioxen-6-yl)-2- Methylbenzyl)oxy)-2-((((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)amino)methyl)phenoxy)methyl) Benzoonitrile (ZD56)
  • Step 1 Synthesis of 4–((4-chloro-5-((3-(2,3-dihydrobenzo[b][1,4]dioxe-6-yl)-2-methyl (Benzyl)oxy)-2-formylphenoxy)methyl)benzonitrile (ZD50)
  • Step 2 Synthesis of 4-((4-chloro-5-((3-(2,3-dihydrobenzo[b][1,4]dioxe-6-yl)-2-methyl Benzyl) oxy)-2-((((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)amino)methyl)phenoxy)methyl)benzene
  • Step 2 Synthesis of 4-((4-chloro-5-((3-(2,3-dihydrobenzo[b][1,4]dioxe-6-yl)-2-methyl Benzyl) oxy)-2-((((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)amino)methyl)phenoxy)methyl)benzene
  • ZD56
  • Step one Synthesis of 2-((4-chloro-5-((3-(2,3-dihydrobenzo[b][1,4]dioxe-6-yl)-2-methyl (Benzyl)oxy)-2-formylphenoxy)methyl)benzonitrile (ZD51)
  • Step two Synthesis of 2-((4-chloro-5-((3-(2,3-dihydrobenzo[b][1,4]dioxe-6-yl)-2-methyl Benzyl)oxy)-2-((((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)amino)methyl)phenoxy)methyl)benzene
  • Step two Synthesis of 2-((4-chloro-5-((3-(2,3-dihydrobenzo[b][1,4]dioxe-6-yl)-2-methyl Benzyl)oxy)-2-((((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)amino)methyl)phenoxy)methyl)benzene
  • ZD57
  • Example 42 Synthesis of 6-((4-chloro-5-((3-(2,3-dihydrobenzo[b][1,4]dioxe-6-yl)-2- Methylbenzyl)oxy)-2-((((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)amino)methyl)phenoxy)methyl) -2-Cyanopyridine (ZD58)
  • Step one Synthesis of 6-((4-chloro-5-((3-(2,3-dihydrobenzo[b][1,4]dioxen-6-yl)-2-methyl (Benzyl)oxy)-2-formylphenoxy)methyl)-2-cyanopyridine (ZD52)
  • Step two Synthesis of 6-((4-chloro-5-((3-(2,3-dihydrobenzo[b][1,4]dioxen-6-yl)-2-methyl Benzyl)oxy)-2-(((((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)amino)methyl)phenoxy)methyl)- 2-cyanopyridine (ZD58)
  • Step 1 5-Chloro-2-((3-chlorobenzyl)oxy)-4-((3-(2,3-dihydrobenzo[b][1,4]dioxene -6-yl)-2-methylbenzyl)oxy)benzaldehyde (ZD59)
  • Step 2 Synthesis of (2R, 3R, 4R, 5S)-6-((5-chloro-2-((3-chlorobenzyl)oxy)-4-((3-(2,3-dihydrobenzene And [b][1,4]dioxan-6-yl)-2-methylbenzyl)oxy)benzyl)amino)hexane-1,2,3,4,5-pentaol (ZD62)
  • Step 1 5-Chloro-4-((3-(2,3-dihydrobenzo[b][1,4]dioxe-6-yl)-2-methylbenzyl)oxy Yl)-2-((3-fluorobenzyl)oxy)benzaldehyde (ZD60)
  • Step 2 Synthesis of ((2R,3R,4R,5S)-6-((5-chloro-4-((3-(2,3-dihydrobenzo[b][1,4] dioxane (Hexen-6-yl)-2-methylbenzyl)oxy)-2-((3-fluorobenzyl)oxy)benzyl)amino)hexane-1,2,3,4,5- Penta alcohol (ZD65)
  • Step 1 Synthesis of 5-chloro-4-((3-(2,3-dihydrobenzo[b][1,4]dioxen-6-yl)-2-methylbenzyl) Oxy)-2-(pyridin-2-ylmethoxy)benzaldehyde (ZD72)
  • Step 2 Synthesis of (2R,3R,4R,5S)-6-((5-chloro-4-((3-(2,3-dihydrobenzo[b][1,4]dioxane (En-6-yl)-2-methylbenzyl)oxy)-2-(pyridin-2-ylmethoxy)benzyl)amino)hexane-1,2,3,4,5-penta Alcohol (ZD75)
  • Step 1 5-chloro-2-((3-chloro-4-fluorobenzyl)oxy)-4-((3-(2,3-dihydrobenzo[b][1,4]diox Heterohexen-6-yl)-2-methylbenzyl)oxy)benzaldehyde (ZD76)
  • Step 2 Synthesis of (2R,3R,4R,5S)-6-((5-chloro-2-((3-chloro-4-fluorobenzyl)oxy)-4-((3-(2,3 -Dihydrobenzo[b][1,4]dioxen-6-yl)-2-methylbenzyl)oxy)benzyl)amino)hexane-1,2,3,4 ,5-Pentanol (ZD77)
  • Step 1 Synthesis of 5-chloro-4-((3-(2,3-dihydrobenzo[b][1,4]dioxen-6-yl)-2-methylbenzyl) Oxy)-2-(pyridin-4-ylmethoxy)benzaldehyde (ZD74)
  • Step 2 Synthesis of (2R,3R,4R,5S)-6–((5-chloro-4–((3-(2,3-dihydrobenzo[b][1,4]dioxane (En-6-yl)-2-methylbenzyl)oxy)-2-(pyridin-4-ylmethoxy)benzyl)amino)hexane-1,2,3,4,5-penta Alcohol (ZD78)
  • Step 1 5-Chloro-2-((2,4-difluorobenzyl)oxy)-4-((3-(2,3-dihydrobenzo[b][1,4]dioxa Cyclohexen-6-yl)-2-methylbenzyl)oxy)benzaldehyde (ZD80)
  • Step 2 Synthesis of (2R,3R,4R,5S)-6-((5-chloro-2-((2,4-difluorobenzyl)oxy)-4-((3-(2,3- Dihydrobenzo[b][1,4]dioxen-6-yl)-2-methylbenzyl)oxy)benzyl)amino)hexane-1,2,3,4, 5-Pentanol (ZD81)
  • Step 1 Synthesis of 2-(benzyloxy)-5-chloro-4-((3-(2,3-dihydrobenzo[b][1,4]dioxe-6-yl) -2-Methylbenzyl)oxy)benzaldehyde (ZD79)
  • Step 2 Synthesis of (2R,3R,4R,5S)-6-((2-(benzyloxy)-5-chloro-4-((3-(2,3-dihydrobenzo[b][1 ,4)Dioxol-6-yl)-2-methylbenzyl)oxy)benzyl)amino)hexane-1,2,3,4,5-pentaol (ZD82)
  • Step 1 Synthesis of 5-chloro-4-((3-(2,3-dihydrobenzo[b][1,4]dioxen-6-yl)-2-methylbenzyl) Oxy)-2-((3-methoxybenzyl)oxy)benzaldehyde (ZD47)
  • Step 2 Synthesis of (2R,3R,4R,5S)-6-((5-chloro-4-((3-(2,3-dihydrobenzo[b][1,4]dioxane En-6-yl)-2-methylbenzyl)oxy)-2-((3-methoxybenzyl)oxy)benzyl)amino)hexane-1,2,3,4,5 -Pentanol (ZD53)
  • Step 1 Synthesis of 4-((4-chloro-5-((3-(2,3-dihydrobenzo[b][1,4]dioxe-6-yl)-2-methyl (Benzyl)oxy)-2-formylphenoxy)methyl)benzonitrile (ZD50)
  • Step 2 Synthesis of 4-((4-chloro-5-((3-(2,3-dihydrobenzo[b][1,4]dioxe-6-yl)-2-methyl Benzyl)oxy)-2-(((((2R,3R,4R,5S)-2,3,4,5,6-pentahydroxyhexyl)amino)methyl)phenoxy)methyl)benzene
  • Step 2 Synthesis of 4-((4-chloro-5-((3-(2,3-dihydrobenzo[b][1,4]dioxe-6-yl)-2-methyl Benzyl)oxy)-2-((((2R,3R,4R,5S)-2,3,4,5,6-pentahydroxyhexyl)amino)methyl)phenoxy)methyl)benzene
  • ZD56
  • Step one Synthesis of 2-((4-chloro-5-((3-(2,3-dihydrobenzo[b][1,4]dioxe-6-yl)-2-methyl (Benzyl)oxy)-2-formylphenoxy)methyl)benzonitrile (ZD51)
  • Step two Synthesis of 2-((4-chloro-5-((3-(2,3-dihydrobenzo[b][1,4]dioxe-6-yl)-2-methyl Benzyl)oxy)-2-(((((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)amino)methyl)phenoxy)methyl)benzene
  • Step two Synthesis of 2-((4-chloro-5-((3-(2,3-dihydrobenzo[b][1,4]dioxe-6-yl)-2-methyl Benzyl)oxy)-2-((((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)amino)methyl)phenoxy)methyl)benzene
  • ZD57
  • Example 54 Synthesis of 6-((4-chloro-5-((3-(2,3-dihydrobenzo[b][1,4]dioxe-6-yl)-2- (Methylbenzyl)oxy)-2-((((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)amino)methyl)phenoxy)methyl) -2-Cyanopyridine (ZD58)
  • Step one Synthesis of 6-((4-chloro-5-((3-(2,3-dihydrobenzo[b][1,4]dioxen-6-yl)-2-methyl (Benzyl)oxy)-2-formylphenoxy)methyl)-2-cyanopyridine (ZD52)
  • Step two Synthesis of 6-((4-chloro-5-((3-(2,3-dihydrobenzo[b][1,4]dioxen-6-yl)-2-methyl Benzyl)oxy)-2-((((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)amino)methyl)phenoxy)methyl)- 2-cyanopyridine (ZD58)
  • Step 1 5-Chloro-2-((3-chlorobenzyl)oxy)-4-((3-(2,3-dihydrobenzo[b][1,4]dioxene -6-yl)-2-methylbenzyl)oxy)benzaldehyde (ZD59)
  • Step 2 Synthesis of (2R, 3R, 4R, 5S)-6-((5-chloro-2-((3-chlorobenzyl)oxy)-4-((3-(2,3-dihydrobenzene And [b][1,4]dioxan-6-yl)-2-methylbenzyl)oxy)benzyl)amino)hexane-1,2,3,4,5-pentaol (ZD62)
  • Step 1 5-Chloro-4-((3-(2,3-dihydrobenzo[b][1,4]dioxe-6-yl)-2-methylbenzyl)oxy Yl)-2-((3-fluorobenzyl)oxy)benzaldehyde (ZD60)
  • Step 2 Synthesis of ((2R,3R,4R,5S)-6-((5-chloro-4-((3-(2,3-dihydrobenzo[b][1,4] dioxane (Hexen-6-yl)-2-methylbenzyl)oxy)-2-((3-fluorobenzyl)oxy)benzyl)amino)hexane-1,2,3,4,5- Penta alcohol (ZD65)
  • Step 1 Synthesis of 5-chloro-4-((3-(2,3-dihydrobenzo[b][1,4]dioxen-6-yl)-2-methylbenzyl) Oxy)-2-(pyridin-2-ylmethoxy)benzaldehyde (ZD72)
  • Step 1 Synthesis of 5-chloro-2-((3-chloro-4-fluorobenzyl)oxy)-4-((3-(2,3-dihydrobenzo[b][1,4] (Oxacyclohexen-6-yl)-2-methylbenzyl)oxy)benzaldehyde (ZD76)
  • Step 2 Synthesis of (2R,3R,4R,5S)-6-((5-chloro-2-((3-chloro-4-fluorobenzyl)oxy)-4-((3-(2,3 -Dihydrobenzo[b][1,4]dioxen-6-yl)-2-methylbenzyl)oxy)benzyl)amino)hexane-1,2,3,4 ,5-Pentanol (ZD77)
  • Step 1 Synthesis of 5-chloro-4-((3-(2,3-dihydrobenzo[b][1,4]dioxen-6-yl)-2-methylbenzyl) Oxy)-2-(pyridin-4-ylmethoxy)benzaldehyde (ZD74)
  • Step 2 Synthesis of (2R,3R,4R,5S)-6-((5-chloro-4-((3-(2,3-dihydrobenzo[b][1,4]dioxane (En-6-yl)-2-methylbenzyl)oxy)-2-(pyridin-4-ylmethoxy)benzyl)amino)hexane-1,2,3,4,5-penta Alcohol (ZD78)
  • Step 1 Synthesis of 5-chloro-2-((2,4-difluorobenzyl)oxy)-4-((3-(2,3-dihydrobenzo[b][1,4]diox Heterohexen-6-yl)-2-methylbenzyl)oxy)benzaldehyde (ZD80)
  • Step 2 Synthesis of (2R,3R,4R,5S)-6-((5-chloro-2-((2,4-difluorobenzyl)oxy)-4-((3-(2,3- Dihydrobenzo[b][1,4]dioxen-6-yl)-2-methylbenzyl)oxy)benzyl)amino)hexane-1,2,3,4, 5-Pentanol (ZD81)
  • Example 62 Synthesis of N-(5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((3-(2,3-dihydrobenzo[b][ 1,4]Dioxol-6-yl)-2-methylbenzyl)oxy)benzyl)-N-methyloxirane-2-carboxamide (ZD83)
  • Step 1 Synthesis of 5-((4-chloro-5-((3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylbenzyl )Oxy)-2-((methylamino)methyl)phenoxy)methylnicotinonitrile (ZD110)
  • Step 2 Synthesis of N-(5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((3-(2,3-dihydrobenzo[b][1 ,4)Dioxol-6-yl)-2-methylbenzyl)oxy)benzyl)-N-methyloxirane-2-carboxamide (ZD83)
  • Example 63 Synthesis of N-(3-((5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((3-(2,3-dihydrobenzo [b][1,4]Dioxin-6-yl)-2-methylbenzyl)oxy)benzyl)(methyl(amino)propyl)oxirane-2-carboxamide (ZD85 )
  • Step 1 Synthesis of tert-butyl (3-((5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((3-(2,3-dihydrobenzo [b][1,4]Dioxin-6-yl)-2-methylbenzyl)oxy)benzyl)(methyl)amino)propyl)carbamate (ZD70)
  • Step 2 Synthesis of 5-((2-(((((3-aminopropyl)(methyl)amino)methyl)-4-chloro-5-((3-(2,3-dihydrobenzo[ b][1,4]Dioxin-6-yl)-2-methylbenzyl)oxy)phenoxy)methyl)nicotinonitrile (ZD85-1)
  • Step 3 Synthesis of N-(3-((5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((3-(2,3-dihydrobenzo[ b][1,4]Dioxin-6-yl)-2-methylbenzyl)oxy)benzyl)(methyl(amino)propyl)oxirane-2-carboxamide (ZD85)
  • Step 1 5-Chloro-4-((3-(2,3-dihydrobenzo[b][1,4]dioxen-6-yl)-2-methylbenzyl)oxy Yl)-2-((3-nitrobenzyl)oxy)benzaldehyde (ZD113)
  • Step 2 Synthesis of (2R,3R,4R,5S)-6-((5-chloro-4-((3-(2,3-dihydrobenzo[b][1,4]dioxane En-6-yl)-2-methylbenzyl)oxy)-2-((3-nitrobenzyl)oxy)benzyl)amino)hexane-1,2,3,4,5- Pentaol (ZD114)
  • Step 1 Synthesis of 5-chloro-2-((2-chloropyridin-4-yl)methoxy)-4-((3-(2,3-dihydrobenzo[b][1,4] (Oxan-6-yl)-2-methylbenzyl)oxy)benzaldehyde (ZD112)
  • Step 2 Synthesis of (2R,3R,4R,5S)-6-((5-chloro-2-((2-chloropyridin-4-yl)methoxy)-4-((3-(2,3 -Dihydrobenzo[b][1,4]dioxen-6-yl)-2-methylbenzyl)oxy)benzyl)amino)hexane-1,2,3,4 ,5-Pentanol (ZD115)
  • Step 1 5-Chloro-4-((3-(2,3-dihydrobenzo[b][1,4]dioxen-6-yl)-2-methylbenzyl)oxy Yl)-2-((3-methylbenzyl)oxy)benzaldehyde (ZD111)
  • Step 2 Synthesis of (2R,3R,4R,5S)-6-((5-chloro-4-((3-(2,3-dihydrobenzo[b][1,4]dioxane En-6-yl)-2-methylbenzyl)oxy)-2-((3-methylbenzyl)oxy)benzyl)amino)hexane-1,2,3,4,5- Penta alcohol (ZD116)
  • ZD111 (30mg, 0.058mmol) and D-glucosamine (31.7mg, 0.175mmol) were dissolved in a mixed solvent of THF (3ml) and MeOH (3ml) to react overnight at room temperature, and then NaBH 4 (44.3mg, 1.17mmol) ), react at room temperature for about 5 hours. After the reaction, the solvent was spin-dried and purified by HPLC. 7.7 mg of the target compound was obtained.
  • Example 68 Synthesis of 5-((4-chloro-5-((3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylbenzyl Yl)oxy)-2-((methyl((2R,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)amino)methyl)phenoxy)methyl)nitrogen Nitrile (ZD121)
  • Step 1 5-Chloro-4-((3-(2,3-dihydrobenzo[b][1,4]dioxen-6-yl)-2-methylbenzyl)oxy Yl)-2-((3-(trifluoromethyl)benzyl)oxy)benzaldehyde (ZD118)
  • Step 2 Synthesis of (2R,3R,4R,5S)-6-((5-chloro-4-((3-(2,3-dihydrobenzo[b][1,4]dioxane En-6-yl)-2-methylbenzyl)oxy)-2-((3-methylbenzyl)oxy)benzyl)amino)hexane-1,2,3,4,5- Penta Alcohol (ZD122)
  • Example 70 Synthesis of (2R, 3R, 4R, 5S)-6-((5-chloro-2-((6-chloropyridin-2-yl)methoxy)-4-((3-(2, 3-Dihydrobenzo[b][1,4]dioxen-6-yl)-2-methylbenzyl)oxy)benzyl)amino)hexane-1,2,3, 4,5-Pentanol (ZD123)
  • Step one 5-chloro-2-((6-chloropyridin-2-yl)methoxy)-4-((3-(2,3-dihydrobenzo[b][1,4]diox Heterohexen-6-yl)-2-methylbenzyl)oxy)benzaldehyde (ZD117)
  • Step 2 Synthesis of (2R,3R,4R,5S)-6-((5-chloro-2-((6-chloropyridin-2-yl)methoxy)-4-((3-(2,3 -Dihydrobenzo[b][1,4]dioxen-6-yl)-2-methylbenzyl)oxy)benzyl)amino)hexane-1,2,3,4 ,5-Pentanol (ZD123)
  • Example 71 Synthesis of 5-((4-chloro-5-((3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylbenzyl Yl)oxy)-2-((methyl((2R,3R,4S,5R)-2,3,4,5,6-pentahydroxyhexyl)amino)methyl)phenoxy)methyl)nitrogen Nitrile (ZD127)
  • Step 2 Synthesis of 5-chloro-4-((3-(2,3-dihydrobenzo[b][1,4]dioxen-6-yl)-2-methylbenzyl) Oxy)-2-((3-(methylsulfonyl)benzyl)oxy)benzaldehyde (ZD128)
  • Step 3 Synthesis of (2R,3R,4R,5S)-6-((5-chloro-4-((3-(2,3-dihydrobenzene[b][1,4]dioxin-6- (Yl)-2-methylbenzyl)oxy)-2-((3-(methylsulfonyl)benzyl)oxy)benzyl)amino)hexene-1,2,3,4,5-pentanol (ZD132)
  • Example 73 Synthesis of 4-((4-chloro-5-((3-(2,3-dihydrobenzo[b][1,4]dioxen-6-yl)-2- (Methylbenzyl)oxy)-2-((((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)amino)methyl)phenoxy)methyl) -2-Cyanopyridine (ZD133)
  • Step 2 Synthesis of 4-((4-chloro-5-((3-(2,3-dihydrobenzo[b][1,4]dioxe-6-yl)-2-methyl (Benzyl)oxy)-2-formylphenoxy)methyl)-2-cyanopyridine (ZD131)
  • ZA52 120 mg, 0.308 mmol
  • ZD129 60.78 mg, 0.40 mmol
  • Cs 2 CO 3 271.3 mg, 0.769 mmol
  • Step 2 4-((4-chloro-5-((3-(2,3-dihydrobenzo[b][1,4]dioxen-6-yl)-2-methyl Benzyl)oxy)-2-((((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)amino)methyl)phenoxy)methyl)-2 -Cyanopyridine (ZD133)
  • Example 74 Synthesis of 5-((4-chloro-5-((3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylbenzyl Yl)oxy)-2-((methyl((2S,3R,4R)-2,3,4,5-tetrahydroxypentyl)amino)methyl)phenoxy)methyl)nicotinonitrile (ZD135 )
  • Example 75 Synthesis of 5-((4-chloro-5-((3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylbenzyl Yl)oxy)-2-((methyl((2S,3S,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)amino)methyl)phenoxy)methyl)nicotine Nitrile (ZD136)
  • Example 76 Synthesis of 5-((4-chloro-5-((3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylbenzyl Yl)oxy)-2-((methyl((2S,3R,4S)-2,3,4,5-tetrahydroxypentyl)amino)methyl)phenoxy)methyl)nicotinonitrile (ZD137 )
  • Step 1 5-Chloro-4-((3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylbenzyl)oxy)- 2-((4-Fluorobenzyloxy)benzaldehyde (ZD141)
  • Step 2 Synthesis of (2R, 3R, 4R, 5S)-6-((5-chloro-4-((3-(2,3-dihydrobenzo[b][1,4]dioxin-6 -Yl)-2-methylbenzyl)oxy)-2-(((4-fluorobenzyl)oxy)benzyl)amino)hexane-1,2,3,4,5-pentanol ( ZD146)
  • Step 1 Synthesis of 5-chloro-4-((3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylbenzyl)oxy) -2-((4-methoxybenzyl)oxy)benzaldehyde (ZD144)
  • ZA52 120mg, 0.308mmol
  • 1-(chloromethyl)-4-methoxybenzene 57.6mg, 0.369mmol
  • Cs 2 CO 3 168.2mg, 0.461 mmol
  • the reaction is quenched by adding water, extracted with dichloromethane three times, the organic phase is washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, the solvent is spin-dried, and separated and purified by a chromatography column to obtain 118 mg of the target compound.
  • Step 2 Synthesis of (2R,3R,4R,5S)-6-((5-chloro-4-((3-(2,3-dihydrobenzo[b][1,4]dioxin-6 -Yl)-2-methylbenzyl)oxy)-2-(((4-methoxybenzyl)oxy)benzyl)amino)hexane-1,2,3,4,5-pentyl Alcohol (ZD148)
  • Step 1 5-Chloro-4-((3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylbenzyl)oxy)- 2-((2-Methoxybenzyl)oxy)benzaldehyde (ZD145)
  • ZA52 120mg, 0.308mmol
  • 1-(chloromethyl)-2-methoxybenzene 57.6mg, 0.369mmol
  • Cs 2 CO 3 162.8mg, 0.461mmol
  • Step 2 (2R,3R,4R,5S)-6-((5-chloro-4-((3-(2,3-dihydrobenzo[b][1,4]dioxene -6-yl)-2-methylbenzyl)oxy)-2-((3-methylbenzyl)oxy)benzyl)amino)hexane-1,2,3,4,5-penta Alcohol (ZD149)
  • Example 80 Synthesis of 5-((4-chloro-5-((3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylbenzyl Yl)oxy)-2-((methyl((3S,4R)-3,4,5-trihydroxypentyl)amino)methyl)phenoxy)methyl)nicotinonitrile (ZE01)
  • Example 81 Synthesis of 5-((4-chloro-5-((3-(2,3-dihydrobenzo[b][1,4]dioxen-6-yl)-2- (Methylbenzyl)oxy)-2-((((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)amino)methyl)phenoxy)methyl) -2-cyanopyridine (ZE10)
  • Methyl 6-cyanonicotinate (620mg, 3.8mmol) was dissolved in methanol (3ml), then LiCl (462mg, 7.7mmol) was added, and finally NaBH 4 (290mg, 7.7mmol) was added to react at room temperature for 2 hours and then spin under reduced pressure. Dry the solvent, then add saturated ammonium chloride solution into the reaction flask and extract with ethyl acetate. The organic phase is dried over anhydrous sodium sulfate and spin-dried, and separated and purified by a chromatography column to obtain 78 mg of the target compound.
  • Step 3 Synthesis of 5-chloro-4-((3-(2,3-dihydrobenzo[b][1,4]dioxen-6-yl)-2-methylbenzyl) (Oxy)-2-hydroxybenzaldehyde (ZE07)
  • ZA52 120mg, 0.308mmol
  • ZE05 ZE05
  • Cs 2 CO 3 230mg, 0.84mmol
  • the organic phase is washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and the solvent is spin-dried, and separated and purified by a chromatography column to obtain 52 mg of the target compound.
  • Step 4 Synthesis of 5-((4-chloro-5-((3-(2,3-dihydrobenzo[b][1,4]dioxen-6-yl)-2-methyl Benzyl)oxy)-2-((((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)amino)methyl)phenoxy)methyl)- 2-cyanopyridine (ZE10)
  • ZE07 (26mg, 0.049mmol) and D-glucosamine (25mg, 0.146mmol) were dissolved in a mixed solvent of THF (3ml) and MeOH (3ml) to react overnight at room temperature, and then NaBH 4 (46mg, 1.21mmol) was added. Continue to react for about 5h. After the reaction, the solvent was spin-dried and purified by HPLC. 10.2 mg of the target compound was obtained.
  • Example 82 Synthesis of 3-((4-chloro-5-((3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylbenzyl Yl)oxy)-2-(((((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)amino)methyl)phenoxy)methyl)-2- Cyanopyridine (ZE12)
  • Step 2 Synthesis of 3-((4-chloro-5-((3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylbenzyl )Oxy)-2-formylphenoxy)methyl)-2-cyanopyridine (ZE08)
  • ZA52 120mg, 0.308mmol
  • ZD151 56.12mg, 0.369mmol
  • K 2 CO 3 63.8mg, 0.461mmol
  • the reaction is quenched with water, extracted three times with ethyl acetate, the organic phase is washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and the solvent is spin-dried, and separated and purified by a chromatography column to obtain 106 mg of the target compound.
  • Step 3 Synthesis of 3-((4-chloro-5-((3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylbenzyl )Oxy)-2-(((((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)amino)methyl)phenoxy)methyl)-2-cyano Pyridine (ZE12)
  • ZE08 25mg, 0.049mmol
  • D-glucosamine (26.4mg, 0.146mmol) were dissolved in a mixed solvent of THF (3ml) and MeOH (3ml) to react overnight at room temperature, then NaBH 4 (37mg, 0.974mmol) was added , Continue to react for about 5h. After the reaction, the solvent was spin-dried and purified by HPLC. 11.3 mg of the target compound was obtained.
  • ZD114 (20mg, 0.028mmol) was dissolved in methanol (15ml), Pd/C (5mg, 0.047mmol) was added after deoxygenation, again deoxygenated and filled with hydrogen, and reacted at room temperature overnight. After the reaction, the Pd/C was removed by filtration, the solvent was spin-dried and purified by HPLC to obtain 9.1 mg of the target compound.
  • Example 84 Synthesis of (2R,3R,4R,5S)-6-((5-chloro-2-((4-chlorobenzyl)oxy)-4-((3-(2,3-dihydro Benzo[b][1,4]dioxin-6-yl)-2-methylbenzyl)oxy)benzyl)amino)hexane-1,2,3,4,5-pentanol ( ZE31)
  • Step 1 Synthesis of 5-chloro-2-((4-chlorobenzyl)oxy)-4-((3-(2,3-dihydrobenzo[b][1,4]dioxin-6 -Yl)-2-methylbenzyl)oxy)benzaldehyde (ZE29)
  • Step 2 Synthesis of (2R,3R,4R,5S)-6-((5-chloro-2-((4-chlorobenzyl)oxy)-4-((3-(2,3-dihydrobenzene And [b][1,4]dioxin-6-yl)-2-methylbenzyl)oxy)benzyl)amino)hexane-1,2,3,4,5-pentanol (ZE31 )
  • ZE29 (26mg, 0.049mmol) and D-glucosamine (26.4mg, 0.146mmol) were dissolved in a mixed solvent of THF (3ml) and MeOH (3ml) to react overnight at room temperature, and then NaBH 4 (37mg, 0.974mmol) was added , Continue to react for about 5h. After the reaction, the solvent was spin-dried and purified by HPLC. 16.2 mg of the target compound was obtained.
  • Step 2 Synthesis of (2R,3R,4R,5S)-6-((5-chloro-4-((3-(2,3-dihydrobenzo[b][1,4]dioxin-6 -Yl)-2-methylbenzyl)oxy)-2-(((4-(trifluoromethyl)benzyl)oxy)benzyl)amino)hexane-1,2,3,4, 5-pentanol (ZE32)
  • ZE30 (30mg, 0.053mmol) and D-glucosamine (28.7mg, 0.158mmol) were dissolved in a mixed solvent of THF (3ml) and MeOH (3ml) to react overnight at room temperature, and then NaBH 4 (40.1mg, 1.056mmol) ), react at room temperature for about 5 hours. After the reaction, the solvent was spin-dried and purified by HPLC. 18.3 mg of the target compound was obtained.
  • Example 86 Synthesis of 6-((4-chloro-5-((3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylbenzyl Yl)oxy)-2-(((((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)amino)methyl)phenoxy)methyl)nicotinonitrile ( ZE35)
  • Step 1 6-((4-chloro-5-((3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylbenzyl) (Oxy)-2-formylphenoxy)methyl)nicotinonitrile (ZE34)
  • ZA52 120 mg, 0.308 mmol
  • 6-(chloromethyl) nicotinonitrile 56.1 mg, 0.369 mmol
  • Cs 2 CO 3 162.8 mg, 0.461 mmol
  • the reaction is quenched by adding water, extracted with dichloromethane three times, the organic phase is washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, the solvent is spin-dried, and separated and purified by a chromatography column to obtain 77.3 mg of the target compound.
  • Step 2 Synthesis of 6-((4-chloro-5-((3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylbenzyl )Oxy)-2-((((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)amino)methyl)phenoxy)methyl)nicotinonitrile (ZE35 )
  • ZE34 (26mg, 0.045mmol) and D-glucosamine (24.1mg, 0.133mmol) were dissolved in a mixed solvent of THF (3ml) and MeOH (3ml) to react overnight at room temperature, and then NaBH 4 (33.7mg, 0.887mmol) ), react at room temperature for about 5 hours. After the reaction, the solvent was spin-dried and purified by HPLC. 6.2 mg of the target compound was obtained.
  • Step 1 Synthesis of 5-chloro-4-((3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylbenzyl)oxy) -2-((4-nitrobenzyl)oxy)benzaldehyde (ZE33)
  • Step 2 Synthesis of (2R,3R,4R,5S)-6-((5-chloro-4-((3-(2,3-dihydrobenzo[b][1,4]dioxin-6 -Yl)-2-methylbenzyl)oxy)-2-((4-nitrobenzyloxy)benzyl)amino)hexane-1,2,3,4,5-pentanol (ZE36)
  • ZE33 25mg, 0.046mmol
  • D-glucosamine 25mg, 0.138mmol
  • NaBH 4 35mg, 0.92mmol
  • Example 88 Synthesis of 2-(5-chloro-2-(5-cyanopyridin-3-yl)methoxy)-4-(3-(2,3-dihydrobenzyl[b][1,4 ]Dioxin-6-yl)-2-methylbenzyl)oxy)benzyl)(3-hydroxypropyl)amino)ethane-1-sulfonic acid (ZE131)
  • Step 1 Synthesis of 5-((4-chloro-5-((3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylbenzyl )Oxy)-2-((((3-hydroxypropyl)amino)methyl)phenoxy)methyl)nicotinonitrile (ZE127)
  • Step 2 Synthesis of 2-(5-chloro-2-(5-cyanopyridin-3-yl)methoxy)-4-(3-(2,3-dihydrobenzyl[b][1,4] Dioxin-6-yl)-2-methylbenzyl)oxy)benzyl)(3-hydroxypropyl)amino)ethane-1-sulfonic acid (ZE131)
  • Example 89 Synthesis of 2-((5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((3-(2,3-dihydrobenzo[b] [1,4]Dioxin-6-yl)-2-methylbenzyl)oxy)benzyl)(3-(dimethylamino)propyl)amino)ethane-1-sulfonic acid (ZE132 )

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Abstract

本发明提供了一种通式(I)所示的苄氧基芳环结构的化合物，其立体异构体、对映体或其药学上可接受的盐，其制备方法，包含其的药物组合物及其用途。所述通式(I)所示的化合物可用于制备PD1/PD-L1相互作用的小分子抑制剂，其可用于预防和/或治疗与PD1/PD-L1相互作用相关的疾病，尤其是癌症，例如，尤其是非小细胞肺癌、小细胞肺癌、黑色素瘤、头颈癌、肾癌、膀胱癌、局部晚期或转移性尿路上皮癌、乳腺癌、宫颈癌、转移性默克尔细胞癌、前列腺癌、肝癌、肠癌、胃癌、多发性骨髓瘤、套细胞淋巴癌、弥漫性大B细胞淋巴瘤肝癌、霍奇金淋巴瘤、慢性淋巴细胞白血病、鳞状细胞癌等癌症。

Description

一种具有苄氧基芳环结构的化合物，其制备方法和用途 技术领域
本发明属于药物合成领域，具体涉及一类具有苄氧基芳环结构的化合物，其立体异构体、对映体或其药学上可接受的盐，其制备方法和用途。
背景技术
在正常情况下，人体内的免疫细胞,例如CD4/CD8+T细胞具有对于癌症细胞的杀伤作用，使免疫功能正常人能够免于癌症。然而，T细胞膜表面的PD-1(Programmed death 1)受体被肿瘤细胞表达的PD-L1(Programmed death-ligand 1)蛋白结合之后，T细胞的免疫功能被严重抑制，无法正常发挥免疫功能，其抑制癌细胞增殖的能力严重削弱(the New England Journal of Medicine,2012,366,2517)。利用肿瘤细胞的PD-L1蛋白免疫T细胞的PD-1受体的结合，肿瘤细胞实现免疫逃逸，得以存活生长。生物学和医学研究表明，利用抗体药物结合PD-1受体或者结合PD-L1蛋白，能够阻断PD-1/PD-L1之间的相互作用，在人体内可以实现良好的抗肿瘤效果(Nature Review Cancer,2012,12,252)。例如，PD-1单抗Pembrolizumab(Merck公司),Nivolumab(BMS公司)可以选择性结合T细胞的PD-1受体，PD-L1单抗Atezolizumab(Genentech/Roche公司),Durvalumab(Medimmune/AstraZeneca公司),Avelumab(Merck KGaA and Pfize公司)可以选择性结合PD-1受体，这些抗体都能够阻断PD-1/PD-L1之间的相互作用，目前已经在临床治疗多种肿瘤，包括非小细胞肺癌、小细胞肺癌、黑色素瘤、头颈癌、肾癌、膀胱癌、局部晚期或转移性尿路上皮癌、乳腺癌、宫颈癌、转移性默克尔细胞癌、前列腺癌、肝癌、肠癌、胃癌、多发性骨髓瘤、套细胞淋巴癌、弥漫性大B细胞淋巴瘤肝癌、霍奇金淋巴瘤、慢性淋巴细胞白血病、鳞状细胞癌等癌症(J.Gong,A.Chehrazi-Raffle,S.Reddi,R.Salgia,2018,Journal for ImmunoTherapy of Cancer,6:8)。阻断PD-1/PD-L1之间的相互作用,能够治疗病人体内的恶性肿瘤,这一药物研究的理念已经得到临床实践的科学验证。
另外一方面，小分子化合物和多肽化合物也可以选择性与PD-1或PD-L1结合。这些化合物具有阻断PD-1/PD-L1之间的相互作用的潜力，具有激活T细胞功能，特异性杀死肿瘤细胞的活性(the Journal of Medicinal Chemistry，2019,62,1715-1730)。小分子化合物CA-170、BMS-986189、CA-327、AUNP-12和MAX-10129都可以作用于PD-1/PD-L1信号通路，在动物体内具有一定的抗肿瘤效果。
综上所述，小分子化合物如果能够阻断PD-1/PD-L1之间的相互作用，那么这样的化合物就可能阻断肿瘤细胞PD-L1蛋白和免疫细胞PD-1之间的结合，就有可能在动物体内、人体内表现出抗癌效果，具有治疗人体内恶性肿瘤的潜在药物用途。
目前多个已上市的靶向PD-1或者PD-L1的单克隆抗体药物证实PD-1/PD-L1的阻断 剂可用于多种肿瘤的临床治疗。然而抗体药物有其自身的特点，如生产成本高，稳定性较差，需经注射给药及易产生免疫原性等。而小分子药物具有组织渗透性好，储存运输方便，生产成本较低，无免疫原性及通常可口服给药等优势，因此研究开发PD-1/PD-L1的小分子抑制剂具有显著的应用价值和社会价值。
发明内容
本发明目的是提供一种用于抑制PD1-PD-L1相互作用的小分子抑制剂。
本发明第一方面，提供一种通式(I)所示的化合物，其立体异构体、对映异构体，或其药学上可接受的盐：
Figure PCTCN2020094013-appb-000001
其中：
X为N或者CH；
Y为氢原子或者C1-C4烷基；
R 1选自下组：
Figure PCTCN2020094013-appb-000002
Figure PCTCN2020094013-appb-000003
R 2选自取代或未取代的下组基团：氢原子、C1-C6烷基、C3-C6环烷基、5-10元杂环基、Ar 1-(CH 2) m-、C6-C10芳环或者5-12元的杂芳环；Ar 1为5-10元杂环基、取代或者未取代的C6-C10芳环或者5-12元杂芳环；其中，所述取代是指被选自下组的一个或多个(如2、3、4或5个)基团取代：羟基、卤素、羧基、氰基、C1-C6烷基、-NRaRb、5-6元杂芳基、C3-C6环烷基、5-10元杂环基；
R 3选自取代或未取代的下组基团：氢原子、C1-C6烷基、C3-C6环烷基、Ar-CH 2-、或5-12元的杂环基；其中，Ar为取代或者未取代的C6-C10芳环或者5-12元杂芳环，
其中，所述的取代指基团上的一个或多个(如2、3、4或5个)氢原子被选自下组的取代基所取代：卤素、C1-C4烷基、(C1-C4)烷氧基、羟基、氨基、氰基、三氟甲基、二氟甲基、(C1-C4)烷基磺酰基、(C1-C4)烷基亚磺酰基、(C1-C4)烷基磺酰基氨基、氨基磺酰基、(C1-C5)酰基氨基、卤代(C1-C4)烷基磺酰基、卤代(C1-C4)烷基亚磺酰基、卤代(C1-C4)烷基磺酰基氨基；
R 4选自：氢原子、卤素、C1-C4烷基、C1-C4烷氧基、或卤代(C1-C4)烷基；
R 5选自：氢原子、卤素、C1-C4烷基、C1-C4烷氧基、氰基、或卤代(C1-C4)烷基；
R 6选自：取代或未取代的苯环，其中，所述的取代指基团上的一个或多个(如2、3、4或5个)氢原子被选自下组的取代基所取代：对甲氧基苄基氧基、苄氧基、(C1-C5)烷氧基、羟基、卤素；
或者R 6选自：
Figure PCTCN2020094013-appb-000004
其中，Z为氢原子或者C1-C4烷基；
R 1a选自：
Figure PCTCN2020094013-appb-000005
Figure PCTCN2020094013-appb-000006
R 2a选自取代或未取代的下组基团：氢原子、C1-C6烷基、C3-C6环烷基、5-10元杂环基、Ar 1-(CH 2) m-、C6-C10芳环或者5-12元的杂芳环；Ar 1为取代或者未取代的5-10元杂环基、C6-C10芳环或者5-12元杂芳环；其中，所述取代是指被选自下组的一个或多个(如2、3、4或5个)基团取代：羟基、卤素、羧基、氰基、C1-C6烷基、-NRaRb、5-6元杂芳基、C3-C6环烷基、5-10元杂环基；
R 3a选自：氢原子、C1-C6烷基、C3-C6环烷基、Ar-CH 2-、或C3-C6杂环基，
R 4a选自：氢原子、卤素、C1-C4烷基、(C1-C4)烷氧基、卤代(C1-C4)烷基；
R 5a选自：氢原子、卤素、C1-C4烷基、(C1-C4)烷氧基、氰基、卤代(C1-C4)烷基；
Rg选自：-NRdRe；
Ra、Rb、Rc各自独立地选自：氢原子、C1-C5烷基、-O-CH 2-O-CO-(C1-C5烷基)、-CH 2-O-CO-(C1-C5烷基)；
Rd、Re各自独立地选自：氢原子、C1-C5烷基、-CO-Rf，其中，Rf独立地选自：氢原子、三氟甲基、C1-C5烷基、5-6元杂芳基、C3-C6环烷基、5-10元杂环基；
Rx选自：氢原子、C1-C6烷基、C3-C6环烷基、5-10元杂环基；
其中，R 11、R 12、R 13、R 14、R 15、R 16各自独立地选自：氢、羟基、-O-CHO、(C1-C4烷基)羰基-O-、HO 2C-；
其中，n表示2、3、或者4，m为1、2、或3。
在另一优选例中，R 2选自下组：氢原子、C1-C6烷基、羟基取代的C1-C6烷基、羧基取代的C1-C6烷基、(C1-C4烷基) 2N-基取代的C1-C6烷基、5-6元杂芳基取代的C1-C6烷基、5-10元杂环基取代的C1-C6烷基、C3-C6环烷基、(C1-C4) 2N-基取代的C3-C6环烷基、5-10元杂环基、1-3个卤素原子代(C1-C4)烷基、Ar 1-(CH 2) m-、苯基或五元杂芳基，其中，Ar 1为取代或者未取代的5-6元杂环基、苯基或者5-6元杂芳环，其中，m为1、2、或3，所述取代是指被选自下组的一个或多个(如2、3、4或5个)基团取代：羟基、卤素、羧基、氰基、C1-C6烷基、-NRaRb、5-6元杂芳基、C3-C6环烷基、5-10元杂环基；Ra、Rb各自独立地选自：氢原子、C1-C5烷基、-O-CH 2-O-CO-(C1-C5烷基)、-CH 2-O-CO-(C1-C5烷基)。
在另一优选例中，所述的通式(I)化合物，其立体异构体、对映异构体，或其药学上可接受的盐：
Figure PCTCN2020094013-appb-000007
其中：
X为N或者CH；
Y为氢原子或者C1-C4烷基；
R 1选自下组：
Figure PCTCN2020094013-appb-000008
Figure PCTCN2020094013-appb-000009
R 2选自下组：氢原子、C1-C6烷基、C3-C6环烷基、5-10元杂环基、或卤代(C1-C4)烷基；
R 3选自下组：氢原子、C1-C6烷基、C3-C6环烷基、Ar-CH 2-、或5-12元的杂环基；
其中Ar为取代或者未取代的C6-C10芳环，或者5-12元的杂芳环，其中，所述的取代指基团上的一个或多个(如2、3、4或5个)氢原子被选自下组的取代基所取代：卤素、C1-C4烷基、(C1-C4)烷氧基、羟基、氨基、氰基、三氟甲基、二氟甲基、(C1-C4)烷基磺酰基、(C1-C4)烷基亚磺酰基、(C1-C4)烷基磺酰基氨基、氨基磺酰基、(C1-C5)酰基氨基；
R 4选自：氢原子、卤素、C1-C4烷基、C1-C4烷氧基、或卤代(C1-C4)烷基；
R 5选自：氢原子、卤素、C1-C4烷基、C1-C4烷氧基、氰基、或卤代(C1-C4)烷基；
R 6选自：取代或未取代的苯环，其中，所述的取代指基团上的一个或多个(如2、3、4或5个)氢原子被选自下组的取代基所取代：对甲氧基苄基氧基、苄氧基、(C1-C5)烷氧基、羟基、卤素；
或者R 6选自：
Figure PCTCN2020094013-appb-000010
其中，Z为氢原子或者C1-C4烷基；
R 1a选自：
Figure PCTCN2020094013-appb-000011
Figure PCTCN2020094013-appb-000012
R 2a选自：氢原子、C1-C6烷基、C3-C6环烷基、5-10元杂环基、或卤代(C1-C4)烷基；
R 3a选自：氢原子、C1-C6烷基、C3-C6环烷基、Ar-CH 2-、或C3-C6杂环基，
R 4a选自：氢原子、卤素、C1-C4烷基、(C1-C4)烷氧基、卤代(C1-C4)烷基；
R 5a选自：氢原子、卤素、C1-C4烷基、(C1-C4)烷氧基、氰基、卤代(C1-C4)烷基；
Ra、Rb、Rc各自独立地选自：氢原子、C1-C5烷基、-O-CH 2-O-CO-(C1-C5烷基)、-CH 2-O-CO-(C1-C5烷基)；
Rx选自：氢原子、C1-C6烷基、C3-C6环烷基、5-10元杂环基；
其中R 11、R 12、R 13、R 14、R 15、R 16分别独立的选自：氢、羟基、-O-CHO、(C1-C4烷基)羰基-O-、HO 2C-；
其中，n表示2、3、或者4。
在另一优选例中，所述的通式(I)化合物，其立体异构体、对映异构体，或其药学上可接受的盐，
R 2选自：氢原子、C1-C6烷基、C3-C6环烷基、三氟甲基、或二氟甲基；
R 3选自：氢原子、C1-C6烷基、C3-C6环烷基、Ar-CH 2-，其中Ar为取代或者未取代的苯环或者含氮六元杂芳环，其中，所述的取代指基团上的一个或多个(如2、3、4或5个)氢原子被选自下组的取代基所取代：卤素、C1-C4烷基、(C1-C4)烷氧基、羟基、氨基、氰基、三氟甲基、二氟甲基、(C1-C4)烷基磺酰基、(C1-C4)烷基亚磺酰基、(C1-C4)烷基磺酰基氨基、氨基磺酰基、(C1-C5)酰基氨基；
R 4选自：氢原子、卤素、C1-C4烷基、(C1-C4)烷氧基、三氟甲基、二氟甲基；
R 5选自：氢原子、卤素、C1-C4烷基、(C1-C4)烷氧基、氰基、三氟甲基、二氟甲基；
R 2a选自：氢原子、C1-C6烷基、C3-C6环烷基、三氟甲基、或二氟甲基；
R 3a选自：氢原子、C1-C6烷基、C3-C6环烷基、或Ar-CH 2-，其中取代或者未取代Ar表示苯环或者含氮六元杂芳环，其取代基选自：卤素、(C1-C4)烷基、(C1-C4)烷氧基、羟基、氨基、氰基、三氟甲基、二氟甲基、(C1-C4)烷基磺酰基、(C1-C4)烷基亚磺酰基、(C1-C4)烷基磺酰基氨基、氨基磺酰基、(C1-C5)酰基氨基；
R 4a选自：氢原子、卤素、C1-C4烷基、C1-C4烷氧基、三氟甲基、二氟甲基；
R 5a选自：氢原子、卤素、C1-C4烷基、C1-C4烷氧基、氰基、三氟甲基、二氟甲基；
Ra、Rb、Rc各自独立地选自：氢原子、C1-C5烷基、-O-CH 2-O-CO-(C1-C5烷基)；
Rx选自：氢原子、C1-C6烷基、C3-C6环烷基；
其中n表示2、3、或者4。
在另一优选例中，所述的R 1选自：
Figure PCTCN2020094013-appb-000013
Figure PCTCN2020094013-appb-000014
Figure PCTCN2020094013-appb-000015
其中，Ra、Rb、Rc、R 11、R 12、R 13、R 14、R 15、R 16、R g的定义如上所述。
在另一优选例中，所述的化合物，其立体异构体或其药学上可接受的盐，所述通式(I)化合物具有式(I-1)所示的结构：
Figure PCTCN2020094013-appb-000016
其中，n为2、3、或者4，Ra、R 2-R 6、X、Y具有如上所述的定义。
在另一优选例中，式(I-1)中，Ra为H。
在另一优选例中，所述通式(I)化合物具有式(I-2)所示的结构：
Figure PCTCN2020094013-appb-000017
其中，n为2、3、或者4，Rb、Rc、R 2-R 6、X、Y具有如上所述的定义。
在另一优选例中，式(I-2)中，Rb和Rc各自独立地为H或C1-C5烷基。
在另一优选例中，所述通式(I)化合物具有式(I-3)和(I-4)所示的结构：
Figure PCTCN2020094013-appb-000018
其中，n为2、3、或者4，R 2-R 6、X、Y具有如上所述的定义。
在另一优选例中，所述通式(I)化合物具有式(I-5)、(I-6)或(I-7)所示的结构：
Figure PCTCN2020094013-appb-000019
其中，R 11、R 12、R 13、R 14、R 15、R 16、R 2-R 6、X、Y具有如上所述的定义。
在另一优选例中，所述通式(I)化合物具有式(I-8)所示的结构：
Figure PCTCN2020094013-appb-000020
其中，R 1-R 5、R 1a、R 2a、R 3a、R 4a、R 5a、X、Y、Z具有如上所述的定义。
在另一优选例中，所述通式(I)化合物具有式(I-9)、(I-10)或(I-11)所示的结构：
Figure PCTCN2020094013-appb-000021
其中，n为2、3、或者4，R 11、R 12、R 13、R 14、R 15、R 16、R 2-R 6、X、Y具有如上所述的定义。
在另一优选例中，所述通式(I)化合物具有式(I-14)所示的结构：
Figure PCTCN2020094013-appb-000022
其中，
n为2、3、或者4，R 2、R 3、R 4、R 5、R 6、R g、Y具有如上所述的定义。
在另一优选例中，上述各式中，R 3为Ar-CH 2-；其中，Ar为取代或者未取代的C6-C10芳环，或者5-12元的杂芳环，其中，所述的取代指基团上的一个或多个(如2、3、4或5个)氢原子被选自下组的取代基所取代：C1-C4烷基、(C1-C4)烷氧基、羟基、氨基、氰基、三氟甲基、二氟甲基、(C1-C4)烷基磺酰基、(C1-C4)烷基亚磺酰基、(C1-C4)烷基磺酰基氨基、氨基磺酰基、(C1-C5)酰基氨基、卤代(C1-C4)烷基磺酰基、卤代(C1-C4)烷基亚磺酰基、卤代(C1-C4)烷基磺酰基氨基。
在另一优选例中，上述各通式中，R 3为Ar-CH 2-，其中，Ar为取代或者未取代的苯环 或者含氮六元杂芳环，其中，所述的取代指基团上的一个或多个(如2、3、4或5个)氢原子被选自下组的取代基所取代：氰基、(C1-C4)烷基磺酰基、(C1-C4)烷基亚磺酰基、(C1-C4)烷基磺酰基氨基、氨基磺酰基、(C1-C5)酰基氨基、卤代(C1-C4)烷基磺酰基、卤代(C1-C4)烷基亚磺酰基、卤代(C1-C4)烷基磺酰基氨基。
在另一优选例中，上述各式中，R 3为Ar-CH 2-，其中，Ar为取代或者未取代的苯环或者吡啶基，其中，所述的取代指基团上的一个或多个(如2、3、4或5个)氢原子被选自下组的取代基所取代：氰基、(C1-C4)烷基磺酰基、(C1-C4)烷基亚磺酰基、(C1-C4)烷基磺酰基氨基、氨基磺酰基、(C1-C5)酰基氨基、卤代(C1-C4)烷基磺酰基、卤代(C1-C4)烷基亚磺酰基、卤代(C1-C4)烷基磺酰基氨基。
在另一优选例中，所述通式(I)化合物具有式(I-12)所示的结构：
Figure PCTCN2020094013-appb-000023
其中，R m选自：
Figure PCTCN2020094013-appb-000024
R 7为C1-C4烷基或1-3个F原子取代的C1-C4烷基；
n为2、3、或者4，R 2、R 4、R 5、R 6、Ra、Y的定义如上所述。
在另一优选例中，所述通式(I)化合物具有式(I-13)所示的结构：
Figure PCTCN2020094013-appb-000025
其中，n、Ra、Rb、R m、n、R 2、R 4、R 5、R 6、Y的定义如上所述。
在另一优选例中，所述通式(I)化合物具有式(I-15)所示的结构：
Figure PCTCN2020094013-appb-000026
其中，n、Rg、R m、n、R 2、R 4、R 5、R 6、Y的定义如上所述。
在另一优选例中，R g选自：-NH 2、-NHCHO、-NHCO-(C1-C4烷基)、-NH-(C1-C4烷基)、-NHCOPh。
在另一优选例中，上述各式中，R 6选自：
Figure PCTCN2020094013-appb-000027
Figure PCTCN2020094013-appb-000028
优选地，R 6为
Figure PCTCN2020094013-appb-000029
其中，Z、X、R 1a、R 2a、R 3a、R 4a、R 5a的定义如上所述。
在另一优选例中，所述通式(I)化合物具有如下一个或多个特征：
R 1选自：
Figure PCTCN2020094013-appb-000030
Figure PCTCN2020094013-appb-000031
R 2选自下组：氢原子、C1-C6烷基、羟基取代的C1-C6烷基、羧基取代的C1-C6烷基、(C1-C4烷基) 2N-基取代的C1-C6烷基、5-6元杂芳基取代的C1-C6烷基、5-10元杂环基取代的C1-C6烷基、C3-C6环烷基、(C1-C4) 2N-基取代的C3-C6环烷基、5-10元杂环基、1-3个卤素原子代(C1-C4)烷基、Ar 1-(CH 2) m-、苯基或五元杂芳基，其中，Ar 1为取代或者未取代的5-6元杂环基、苯基或者5-6元杂芳环，其中，m为1、2、或3，所述取代是指被选自下组的一个或多个(如2、3、4或5个)基团取代：羟基、卤素、羧基、氰基、C1-C6烷基、-NRaRb、5-6元杂芳基、C3-C6环烷基、5-10元杂环基；
R 3为Ar-CH 2-；其中，Ar为取代或者未取代的C6-C10芳环，或者5-12元的杂芳环，其中，所述的取代指基团上的一个或多个(如2、3、4或5个)氢原子被选自下组的取代基所取代：C1-C4烷基、(C1-C4)烷氧基、羟基、氨基、氰基、三氟甲基、二氟甲基、(C1-C4)烷基磺酰基、(C1-C4)烷基亚磺酰基、(C1-C4)烷基磺酰基氨基、氨基磺酰基、(C1-C5)酰基氨基、卤代(C1-C4)烷基磺酰基、卤代(C1-C4)烷基亚磺酰基、卤代(C1-C4)烷基磺酰基氨基；
R 4选自：氢原子、卤素、C1-C4烷基、C1-C4烷氧基、或卤代(C1-C4)烷基；优选地为卤素、C1-C4烷基；
R 5选自：氢原子、卤素、C1-C4烷基、C1-C4烷氧基、氰基、或卤代(C1-C4)烷基；优选地为H；
R 6选自：
Figure PCTCN2020094013-appb-000032
优选地，R 6为
Figure PCTCN2020094013-appb-000033
其中，Z、X、R 1a、R 2a、R 3a、R 4a、R 5a的定义如上所述。
R 1a选自：
Figure PCTCN2020094013-appb-000034
Figure PCTCN2020094013-appb-000035
R 2a选自：氢原子、C1-C6烷基、C3-C6环烷基、5-10元杂环基、或卤代(C1-C4)烷基；
R 3a选自：氢原子、C1-C6烷基、C3-C6环烷基、Ar-CH 2-、或C3-C6杂环基，
R 4a选自：氢原子、卤素、C1-C4烷基、(C1-C4)烷氧基、卤代(C1-C4)烷基；
R 5a选自：氢原子、卤素、C1-C4烷基、(C1-C4)烷氧基、氰基、卤代(C1-C4)烷基；
Ra、Rb、Rc各自独立地选自：氢原子、C1-C5烷基、-O-CH 2-O-CO-(C1-C5烷基)、-CH 2-O-CO-(C1-C5烷基)；
Rg选自：-NRdRe；
Rd、Re各自独立地选自：氢原子、C1-C5烷基、-CO-Rf，其中，Rf独立地选自：氢原子、三氟甲基、C1-C5烷基、5-6元杂芳基、C3-C6环烷基、5-10元杂环基；
Rx选自：氢原子、C1-C6烷基、C3-C6环烷基、5-10元杂环基；
其中，R 11、R 12、R 13、R 14、R 15、R 16各自独立地选自：氢、羟基、-O-CHO、(C1-C4烷基)羰基-O-、HO 2C-；
其中，n表示2、3、或者4，m表示1、2、或者3。。
在另一优选例中，R 1-R 6(即R 1、R 2、R 3、R 4、R 5、R 6)、X、Y为实施例1-21、23-33、35-131中各具体化合物相对应的具体基团。
在另一优选例中，所述的化合物，其立体异构体或其药学上可接受的盐，选自下组：
Figure PCTCN2020094013-appb-000036
Figure PCTCN2020094013-appb-000037
Figure PCTCN2020094013-appb-000038
Figure PCTCN2020094013-appb-000039
Figure PCTCN2020094013-appb-000040
Figure PCTCN2020094013-appb-000041
在另一优选例中，所述式(I)化合物为表2中除化合物34之外的化合物。
本发明的第二方面，提供了一种药物组合物，其包含有效量的第一方面所述的化合物，其立体异构体、对映异构体或其药学上可接受的盐，和任选的药学上可接受的赋形剂或载体。
在另一优选例中，所述药物组合物还包括第二癌症治疗剂。
在另一优选例中，所述的第二癌症治疗剂包括放射剂、细胞毒试剂、激酶抑制剂、免疫靶向抑制剂和血管生成抑制剂。
在另一优选例中，所述第二癌症治疗剂是选自下组的一种或多种：
PD-1抑制剂(如纳武单抗、派姆单抗、JS-001、SHR-120、BGB-A317、IBI-308、GLS-010、GB-226、STW204、HX008、HLX10、BAT1306、AK105、LZM 009或上述药物的生物类似药等)、PD-L1抑制剂(如德瓦鲁单抗、阿特珠单抗、CS1001、KN035、HLX20、SHR-1316、BGB-A333、JS003、CS1003、KL-A167、F 520、GR1405、MSB2311或上述药物的生物类似药等)、CD20抗体(如利妥昔单抗、奥滨尤妥珠单抗、奥法木单抗、托西莫单抗、替伊莫单抗等)、CD47抗体(如Hu5F9-G4、CC-90002、TTI-621、TTI-622、OSE-172、SRF-231、ALX-148、NI-1701、SHR-1603、IBI188、IMM01)、ALK抑制剂(如色瑞替尼、艾乐替尼、布加替尼、劳拉替尼、奥卡替尼)、PI3K抑制剂(如艾代拉里斯、Dactolisib、Taselisib、Buparlisib等)、BTK抑制剂(如依鲁替尼、Tirabrutinib、Acalabrutinib等)、EGFR抑制剂(如阿法替尼、吉非替尼、厄洛替尼、拉帕替尼、达克替尼、埃克替尼、卡奈替尼等)、VEGFR抑制剂(如索拉非尼、帕唑帕尼、瑞伐替尼、卡博替尼、舒尼替尼、多纳非尼等)、HDAC抑制剂(如Givinostat、Droxinostat、恩替诺特、达西司特、泰克地那林等)、CDK抑制剂(如帕博西尼、瑞博西尼、Abemaciclib、Lerociclib等)、MEK抑制剂(如司美替尼(AZD6244)、曲美替尼(GSK1120212)、PD0325901、U0126、AS-703026、PD184352(CI-1040)等)、Akt抑制剂(如MK-2206、Ipatasertib、Capivasertib、Afuresertib、Uprosertib等)、mTOR抑制剂(如Vistusertib等)、SHP2抑制剂(如RMC-4630、JAB-3068、TNO155等)、IGF-1R抑制剂(如Ceritinib、奥卡替尼、linsitinib、BMS-754807、GSK1838705A等)或其组合。
本发明第三方面，提供了第一方面所述的化合物，其立体异构体、对映异构体或其药学上可接受的盐，或第二方面所述的药物组合物在制备PD1-PDL1相互作用抑制剂中的用途。
在另一优选例中，所述的化合物，其立体异构体或其药学上可接受的盐用于联合用药方案，例如联合肿瘤化疗方案，其他肿瘤免疫治疗剂(小分子化合物及抗体等)，放疗方案，肿瘤靶向药，肿瘤疫苗等，如人类乳头瘤病毒(HPV)、肝炎病毒(HBV和HCV)和卡波西疱疹肉瘤病毒(KHSV)；可以在所述药剂之前、之后或同时施用，或者可以与其它已知疗法共施用。
在另一优选例中，所述的化合物，其立体异构体或其药学上可接受的盐单独或联合使用用于治疗暴露于特定毒素或病原体的患者的治疗；其中包括但不限于各种病毒，病原体细菌，病原体真菌，病原体寄生虫等的治疗；如HIV、肝炎病毒(甲、乙、丙)、流感病毒、疱疹病毒、贾第虫、疟疾、利什曼原虫、金黄色葡萄球菌、绿脓杆菌等病原体已建立的感染。
在另一优选例中，所述的化合物，其立体异构体或其药学上可接受的盐用于诱导治疗性自身免疫应答，以治疗具有不恰当的其他自身抗原积累的患者，如淀粉状蛋白沉积物，包括阿尔茨海默病中的Αβ、细胞因子如TNFa和IgE。
在另一优选例中，所述PD1-PDL1相互作用抑制剂用于预防和/或治疗癌症。
在另一优选例中，所述的癌症选自：非小细胞肺癌、黑色素瘤、头颈癌、肾癌、膀胱上皮癌、局部晚期或转移性尿路上皮癌、转移性默克尔细胞癌、前列腺癌、肝癌、肠癌、多发性骨髓瘤、套细胞淋巴癌、弥漫性大B细胞淋巴瘤肝癌、霍奇金淋巴瘤、慢性淋巴细胞白血病等。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
附图说明
图1为肿瘤细胞和T细胞共培养测试。
图2为本发明化合物对促进T细胞杀伤癌细胞测试，效应细胞(T细胞)和靶细胞(肿瘤细胞)按照两个比例共培养，不同浓度化合物对肿瘤细胞杀伤的促进作用。
图3为本发明化合物在B16小鼠抑制瘤中的抗肿瘤药效，其中，图3A示出了化合物120(ZD41)在B16F10小鼠移植瘤中的抗肿瘤药效；图3B示出了化合物89(ZE132)在B16F10小鼠移植瘤中的抗肿瘤药效。
具体实施方式
本发明人经过广泛而深入的研究，发现了一类具有较好的抑制PD1/PD-L1相互作用能力的化合物。此外，本发明化合物具有较好的促进T细胞杀伤癌细胞的作用，较好的药效学性能以及更低的毒性。在此基础上，完成了本发明。
术语说明
除非另外定义，否则本文中所用的全部技术与科学术语均具有如本发明所属领域的普通技术人员通常理解的相同含义。
如本文所用，在提到具体列举的数值中使用时，术语“约”意指该值可以从列举的值变动不多于1％。例如，如本文所用，表述“约100”包括99和101和之间的全部值(例如，99.1、99.2、99.3、99.4等)。
如本文所用，术语“含有”或“包括(包含)”可以是开放式、半封闭式和封闭式的。
基团定义
可在参考文献(包括Carey and Sundberg"ADVANCED ORGANIC CHEMISTRY 4TH ED."Vols.A(2000)and B(2001),Plenum Press,New York)中找到对标准化学术语的定义。除非另有说明，否则采用本领域技术范围内的常规方法，如质谱、NMR、IR和UV/VIS光谱法和药理学方法。除非提出具体定义，否则本文在分析化学、有机合成化学以及药物和药物化学的有关描述中采用的术语是本领域已知的。可在化学合成、化学分析、药物制备、制剂和递送，以及对患者的治疗中使用标准技术。例如，可利用 厂商对试剂盒的使用说明，或者按照本领域公知的方式或本发明的说明来实施反应和进行纯化。通常可根据本说明书中引用和讨论的多个概要性和较具体的文献中的描述，按照本领域熟知的常规方法实施上述技术和方法。在本说明书中，可由本领域技术人员选择基团及其取代基以提供稳定的结构部分和化合物。
当通过从左向右书写的常规化学式描述取代基时，该取代基也同样包括从右向左书写结构式时所得到的在化学上等同的取代基。举例而言，-CH 2O-等同于-OCH 2-。
本文所用的章节标题仅用于组织文章的目的，而不应被解释为对所述主题的限制。本申请中引用的所有文献或文献部分包括但不限于专利、专利申请、文章、书籍、操作手册和论文，均通过引用方式整体并入本文。
在本文中定义的某些化学基团前面通过简化符号来表示该基团中存在的碳原子总数。例如，C1-C6烷基是指具有总共1至6个碳原子的如下文所定义的烷基。简化符号中的碳原子总数不包括可能存在于所述基团的取代基中的碳。
除前述以外，当用于本申请的说明书及权利要求书中时，除非另外特别指明，否则以下术语具有如下所示的含义。
在本申请中，术语“卤素”是指氟、氯、溴或碘。
“羟基”是指-OH基团。
“羟基烷基”是指被羟基(-OH)取代的如下文所定义的烷基。
“羰基”是指-C(＝O)-基团。
“硝基”是指-NO 2。
“氰基”是指-CN。
“氨基”是指-NH 2。
“取代的氨基”是指被一个或两个如下文所定义的烷基、烷基羰基、芳烷基、杂芳烷基取代的氨基，例如，单烷基氨基、二烷基氨基、烷基酰氨基、芳烷基氨基、杂芳烷基氨基。
“羧基”是指-COOH。
“(C1-C4)烷基磺酰基”是指(C1-C4)烷基-SO 2-，其中，所述烷基定义如下文所述。
“(C1-C4)烷基亚磺酰基”是指(C1-C4)烷基-SO-，其中，所述烷基定义如下文所述。
“(C1-C4)烷基磺酰基氨基”是指：(C1-C4)烷基-SO 2-NH-，其中，所述烷基定义如下文所述。
“氨基磺酰基”是指：-SO 2-NH 2。
“(C1-C5)酰基氨基”是指(C1-C5烷基)(C＝O)NH-，其中，所述烷基定义如下文所述。
在本申请中，作为基团或是其它基团的一部分(例如用在卤素取代的烷基等基团中)，术语“烷基”是指完全饱和的直链或支链的烃链基，仅由碳原子和氢原子组成、具 有例如1至6个(优选为1至4个)碳原子，且通过单键与分子的其余部分连接，例如包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、2-甲基丁基、2,2-二甲基丙基、正己基等。本申请中，所述烷基(作为基团或是其它基团的一部分)还意在包含取代的烷基，例如所述取代选自：卤素、羟基、氰基、硝基、氨基、羧基、磺酰基等。
术语“环烷基”是指完全饱和的环状烷烃，仅由碳原子和氢原子组成、具有例如3至6个碳原子(即C3-C6环烷基)，且通过单键与分子的其余部分连接，例如包括但不限于环丙基、环丁基、环戊基、环己基。本申请中，所述环烷基(作为基团或是其它基团的一部分)还意在包含取代的环烷基，例如所述取代选自：卤素、羟基、氰基、硝基、氨基、羧基、磺酰基等。“卤代(C1-C4)烷基”是指有1或2或3个卤素原子取代的C1-C4烷基，如：三氟甲基、二氟甲基。
在本申请中，作为基团或是其它基团的一部分，术语“杂环基”意指由2至14个碳原子以及1至6个选自氮、磷、氧和硫的杂原子组成的稳定的3元至20元(即3-20元)非芳香族环状基团，优选4-11元杂环基，更优选5-10元杂环基。除非本说明书中另外特别指明，否则杂环基可以为单环、双环、三环或更多环的环体系，其可包括稠合环体系、桥环体系或螺环体系；其杂环基中的氮、碳或硫原子可任选地被氧化；氮原子可任选地被季铵化；且杂环基可为部分或完全饱和。杂环基可以经由碳原子或者杂原子并通过单键与分子其余部分连接。在包含稠环的杂环基中，一个或多个环可以是下文所定义的芳基或杂芳基，条件是与分子其余部分的连接点为非芳香族环原子。就本发明的目的而言，杂环基优选为包含1至3个选自氮、氧和硫的杂原子的稳定的4元至11元非芳香性单环、双环、桥环或螺环基团，更优选为包含1至3个选自氮、氧和硫的杂原子的稳定的4元至8元非芳香性单环、双环、桥环或螺环基团。杂环基的实例包括但不限于：吡咯烷基、吗啉基、哌嗪基、高哌嗪基、哌啶基、硫代吗啉基、2,7-二氮杂-螺[3.5]壬烷-7-基、2-氧杂-6-氮杂-螺[3.3]庚烷-6-基、2,5-二氮杂-双环[2.2.1]庚烷-2-基、氮杂环丁烷基、吡喃基、四氢吡喃基、噻喃基、四氢呋喃基、噁嗪基、二氧环戊基、四氢异喹啉基、十氢异喹啉基、咪唑啉基、咪唑烷基、喹嗪基、噻唑烷基、异噻唑烷基、异噁唑烷基、二氢吲哚基、八氢吲哚基、八氢异吲哚基、吡咯烷基、吡唑烷基、邻苯二甲酰亚氨基等。本申请中，所述杂环基(作为基团或是其它基团的一部分)还意在包含取代的杂环基，例如所述取代选自：卤素、羟基、氰基、硝基、氨基、羧基、磺酰基等。
在本申请中，作为基团或是其它基团的一部分，术语“芳基(或芳环)”意指具有6至18个碳原子(优选具有6至10个碳原子，即C6-C10)的共轭烃环体系基团。就本发明的目的而言，芳基可以为单环、双环、三环或更多环的环体系，还可以与上文所定义的环烷基或杂环基稠合，条件是芳基经由芳香环上的原子通过单键与分子的其余部分连接。芳基的实例包括但不限于苯基、萘基、蒽基、菲基、芴基、2,3-二氢-1H-异吲哚 基、2-苯并噁唑啉酮、2H-1,4-苯并噁嗪-3(4H)-酮-7-基等。本申请中，所述芳基(或芳环)(作为基团或是其它基团的一部分)还意在包含取代的芳基(或芳环)，例如所述取代选自：卤素、羟基、氰基、硝基、氨基、羧基、磺酰基等。
在本申请中，作为基团或是其它基团的一部分，术语“杂芳基(或杂芳环)”意指环内具有1至15个碳原子(优选具有1至10个碳原子)和1至6个选自氮、氧和硫的杂原子的5元至16元共轭环系基团。除非本说明书中另外特别指明，否则杂芳基可为单环、双环、三环或更多环的环体系，还可以与上文所定义的环烷基或杂环基稠合，条件是杂芳基经由芳香环上的原子通过单键与分子的其余部分连接。杂芳基中的氮、碳或硫原子可任选地被氧化；氮原子可任选地被季铵化。就本发明的目的而言，杂芳基优选为包含1至5个选自氮、氧和硫的杂原子的稳定的5元至12元芳香性基团，更优选为包含1至4个选自氮、氧和硫的杂原子的稳定的5元至10元芳香性基团或者包含1至3个选自氮、氧和硫的杂原子的5元至6元芳香性基团。杂芳基的实例包括但不限于噻吩基、咪唑基、吡唑基、噻唑基、噁唑基、噁二唑基、异噁唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、苯并咪唑基、苯并吡唑基、吲哚基、呋喃基、吡咯基、三唑基、四唑基、三嗪基、吲嗪基、异吲哚基、吲唑基、异吲唑基、嘌呤基、喹啉基、异喹啉基、二氮萘基、萘啶基、喹噁啉基、蝶啶基、咔唑基、咔啉基、菲啶基、菲咯啉基、吖啶基、吩嗪基、异噻唑基、苯并噻唑基、苯并噻吩基、噁三唑基、噌啉基、喹唑啉基、苯硫基、中氮茚基、邻二氮杂菲基、异噁唑基、吩噁嗪基、吩噻嗪基、4,5,6,7-四氢苯并[b]噻吩基、萘并吡啶基、[1,2,4]三唑并[4,3-b]哒嗪、[1,2,4]三唑并[4,3-a]吡嗪、[1,2,4]三唑并[4,3-c]嘧啶、[1,2,4]三唑并[4,3-a]吡啶、咪唑并[1,2-a]吡啶、咪唑并[1,2-b]哒嗪、咪唑并[1,2-a]吡嗪等。本申请中，所述杂芳基(或杂芳环)(作为基团或是其它基团的一部分)还意在包含取代的杂芳基(或杂芳环)，例如所述取代选自：卤素、羟基、氰基、硝基、氨基、羧基、磺酰基等。
本发明中，多个是指2、3、4或5个。
活性成分
如本文所用，术语“本发明的化合物”或“本发明的活性成分”可互换使用，指式I其立体异构体、对映异构体，或其药学上可接受的盐。该术语还包括外消旋体、光学异构体、同位素化合物(如氘代化合物)或前药。
所述式(I)化合物具有如下结构：
Figure PCTCN2020094013-appb-000042
其中，R 1-R 6(即R 1、R 2、R 3、R 4、R 5、R 6)、X、Y的定义如上所述。
优选地，所述式(I)化合物具有式(I-1)所示的结构：
Figure PCTCN2020094013-appb-000043
其中，n为2、3、或者4，Ra、R 2-R 6(即R 2、R 3、R 4、R 5、R 6)、X、Y的定义如上所述。
优选地，所述式(I)化合物具有式(I-2)-(I-11)所示的结构：
Figure PCTCN2020094013-appb-000044
其中，n、R 1、R 2、R 3、R 4、R 5、R 6、R 11、R 12、R 13、R 14、R 15、R 16、X、Y、Z、Rb、Rc、R 1a、R 2a、R 3a、R 4a、R 5a的定义如上所述。
优选地，所述式(I)化合物具有式(I-14)所示的结构：
Figure PCTCN2020094013-appb-000045
其中，n、R 2、R 3、R 4、R 5、R 6、R g的定义如上所述。
优选地，所述通式(I)化合物具有式(I-12)所示的结构：
Figure PCTCN2020094013-appb-000046
其中，n、Ra、R m、n、R 2、R 4、R 5、R 6、Y的定义如上所述。
所述通式(I)化合物具有式(I-15)所示的结构：
Figure PCTCN2020094013-appb-000047
其中，n、R g、R m、n、R 2、R 4、R 5、R 6、Y的定义如上所述。
优选地，上述各式中，R 6选自：
Figure PCTCN2020094013-appb-000048
优选地，R 6为
Figure PCTCN2020094013-appb-000049
其中，Z、X、R 1a、R 2a、R 3a、R 4a、R 5a的定义如上所述。
优选地，上述各式中，R 2选自下组：氢原子、C1-C6烷基、羟基取代的C1-C6烷基、羧基取代的C1-C6烷基、(C1-C4烷基) 2N-基取代的C1-C6烷基、5-6元杂芳基取代的C1-C6烷基、5-10元杂环基取代的C1-C6烷基、C3-C6环烷基、(C1-C4) 2N-基取代的C3-C6环烷基、5-10元杂环基、1-3个卤素原子代(C1-C4)烷基、Ar 1-(CH 2) m-、苯基或五元杂芳基，更优选地，R 2选自氢原子、C1-C6烷基、C3-C6环烷基、5-10元杂环基、或卤代(C1-C4)烷基；其中，Ar 1为取代或者未取代的5-6元杂环基、苯基或者5-6元杂芳环，其中，m表示1、2、或者3，所述取代是指被选自下组的一个或多个基团取代：羟基、卤素、羧基、氰基、C1-C6烷基、-NRaRb、5-6元杂芳基、C3-C6环烷基、5-10元杂环基；Ra、Rb各自独立地选自：氢原子、C1-C5烷基、 -O-CH 2-O-CO-(C1-C5烷基)、-CH 2-O-CO-(C1-C5烷基)。
优选地，上述各式中，R 3为Ar-CH 2-；其中，Ar为取代或者未取代的C6-C10芳环(如苯基)，或者5-12元的杂芳环(如吡啶基)，其中，所述的取代指基团上的一个或多个氢原子被选自下组的取代基所取代：C1-C4烷基、(C1-C4)烷氧基、羟基、氨基、氰基、三氟甲基、二氟甲基、(C1-C4)烷基磺酰基、(C1-C4)烷基亚磺酰基、(C1-C4)烷基磺酰基氨基、氨基磺酰基、(C1-C5)酰基氨基、卤代(C1-C4)烷基磺酰基、卤代(C1-C4)烷基亚磺酰基、卤代(C1-C4)烷基磺酰基氨基。
优选地，上述各式中，R 4选自：氢原子、卤素、C1-C4烷基、C1-C4烷氧基、或卤代(C1-C4)烷基；优选地为卤素、C1-C4烷基。
优选地，上述各式中，R 5选自：氢原子、卤素、C1-C4烷基、C1-C4烷氧基、氰基、或卤代(C1-C4)烷基；优选地为H。
“立体异构体”是指由相同原子组成，通过相同的键键合，但具有不同三维结构的化合物。本发明将涵盖各种立体异构体及其混合物。
当本发明的化合物中含有烯双键时，除非另有说明，否则本发明的化合物旨在包含E-和Z-几何异构体。
“互变异构体”是指质子从分子的一个原子转移至相同分子的另一个原子而形成的异构体。本发明的化合物的所有互变异构形式也将包含在本发明的范围内。
本发明的化合物或其药学上可接受的盐可能含有一个或多个手性碳原子，且因此可产生对映异构体、非对映异构体及其它立体异构形式。每个手性碳原子可以基于立体化学而被定义为(R)-或(S)-。本发明旨在包括所有可能的异构体，以及其外消旋体和光学纯形式。本发明的化合物的制备可以选择外消旋体、非对映异构体或对映异构体作为原料或中间体。光学活性的异构体可以使用手性合成子或手性试剂来制备，或者使用常规技术进行拆分，例如采用结晶以及手性色谱等方法。
制备/分离个别异构体的常规技术包括由合适的光学纯前体的手性合成，或者使用例如手性高效液相色谱法拆分外消旋体(或盐或衍生物的外消旋体)，例如可参见Gerald Gübitz and Martin G.Schmid(Eds.),Chiral Separations,Methods and Protocols,Methods in Molecular Biology,Vol.243,2004；A.M.Stalcup,Chiral Separations,Annu.Rev.Anal.Chem.3:341-63,2010；Fumiss et al.(eds.),VOGEL’S ENCYCLOPEDIA OF PRACTICAL ORGANIC CHEMISTRY 5.sup.TH ED.,Longman Scientific and Technical Ltd.,Essex,1991,809-816；Heller,Acc.Chem.Res.1990,23,128。
本发明还包括同位素标记的化合物，等同于原始化合物在此公开。不过实际上对一个或更多的原子被与其原子量或质量序数不同的原子取代通常会出现。可以列为本发明的化合物同位素的例子包括氢、碳、氮、氧、磷、硫、氟和氯同位素，分别如 2H、 3H、 13C、 11C、 14C、 15N、 18O、 17O、 31P、 32P、 35S、 18F和 36Cl。本发明中的化合物，或对映体，非对映体，异构体，或药学上可接受的盐或溶剂化物，其中含有上述 化合物的同位素或其他同位素原子都在本发明的范围之内。本发明中某些同位素标记化合物，例如 3H和 14C的放射性同位素也在其中，在药物和底物的组织分布实验中是有用的。氚，即 3H和碳-14，即 14C，它们的制备和检测比较容易。是同位素中的首选。此外，较重同位素取代如氘，即 2H，由于其很好的代谢稳定性在某些疗法中有优势，例如在体内增加半衰期或减少用量，因此，在某些情况下可以优先考虑。同位素标记的化合物可以用一般的方法，通过用易得的同位素标记试剂替换为非同位素的试剂，用披露在示例中的方案可以制备。在本申请中，术语“药学上可接受的盐”包括药学上可接受的酸加成盐和药学上可接受的碱加成盐。
“药学上可接受的酸加成盐”是指能够保留游离碱的生物有效性而无其它副作用的，与无机酸或有机酸所形成的盐。无机酸盐包括但不限于盐酸盐、氢溴酸盐、硫酸盐、硝酸盐、磷酸盐等；有机酸盐包括但不限于甲酸盐、乙酸盐、2,2-二氯乙酸盐、三氟乙酸盐、丙酸盐、己酸盐、辛酸盐、癸酸盐、十一碳烯酸盐、乙醇酸盐、葡糖酸盐、乳酸盐、癸二酸盐、己二酸盐、戊二酸盐、丙二酸盐、草酸盐、马来酸盐、琥珀酸盐、富马酸盐、酒石酸盐、柠檬酸盐、棕榈酸盐、硬脂酸盐、油酸盐、肉桂酸盐、月桂酸盐、苹果酸盐、谷氨酸盐、焦谷氨酸盐、天冬氨酸盐、苯甲酸盐、甲磺酸盐、苯磺酸盐、对甲苯磺酸盐、海藻酸盐、抗坏血酸盐、水杨酸盐、4-氨基水杨酸盐、萘二磺酸盐等。这些盐可通过本专业已知的方法制备。
“药学上可接受的碱加成盐”是指能够保持游离酸的生物有效性而无其它副作用的、与无机碱或有机碱所形成的盐。衍生自无机碱的盐包括但不限于钠盐、钾盐、锂盐、铵盐、钙盐、镁盐、铁盐、锌盐、铜盐、锰盐、铝盐等。优选的无机盐为铵盐、钠盐、钾盐、钙盐及镁盐。衍生自有机碱的盐包括但不限于以下的盐：伯胺类、仲胺类及叔胺类，被取代的胺类，包括天然的被取代胺类、环状胺类及碱性离子交换树脂，例如氨、异丙胺、三甲胺、二乙胺、三乙胺、三丙胺、乙醇胺、二乙醇胺、三乙醇胺、二甲基乙醇胺、2-二甲氨基乙醇、2-二乙氨基乙醇、二环己胺、赖氨酸、精氨酸、组氨酸、咖啡因、普鲁卡因、胆碱、甜菜碱、乙二胺、葡萄糖胺、甲基葡萄糖胺、可可碱、嘌呤、哌嗪、哌啶、N-乙基哌啶、聚胺树脂等。优选的有机碱包括异丙胺、二乙胺、乙醇胺、三甲胺、二环己基胺、胆碱及咖啡因。这些盐可通过本专业已知的方法制备。
如果要设计一个本发明的化合物特定的对映体的合成，它可以不对称合成制备，或用手性辅剂衍生化，将所产生的非对映混合物分离，再除去手性辅剂而得到纯的对映体。另外，如果分子中含有一个碱性官能团，如氨基酸，或酸性官能团，如羧基，可以用合适的光学活性的酸或碱的与之形成非对映异构体盐，再通过分离结晶或色谱等常规手段分离，然后就得到了纯的对映体。
如本文所述，本发明中的化合物可与任何数量取代基或官能团取而扩大其包涵范围。通常，术语“取代”不论在术语“可选”前面或后面出现，在本发明配方中包括取代基 的通式，是指用指定结构取代基，代替氢自由基。当特定结构中的多个在位置被多个特定的取代基取代时，取代基每一个位置可以是相同或不同。本文中所使用的术语“取代”包括所有允许有机化合物取代。从广义上讲，允许的取代基包括非环状的、环状的、支链的非支链的、碳环的和杂环的，芳环的和非芳环的有机化合物。在本发明中，如杂原子氮可以有氢取代基或任何允许的上文所述的有机化合物来补充其价态。此外，本发明是无意以任何方式限制允许取代有机化合物。本发明认为取代基和可变基团的组合在以稳定化合物形式在疾病的治疗上是很好的。此处术语“稳定”是指具有稳定的化合物，在足够长的时间内检测足以维持化合物结构的完整性，最好是在足够长的时间内都在效，本文在此用于上述目的。
本申请所涉及的化合物及其药学可接受的盐的代谢产物，以及可以在体内转变为本申请所涉及的化合物及其药学可接受的盐的结构的前药，也包含在本申请的权利要求中。
药物组合物和施用方法
本发明所述的药物组合物用于预防和/或治疗癌症、免疫性疾病、代谢性疾病等。在本申请中，“药物组合物”是指本发明化合物与本领域通常接受的用于将生物活性化合物输送至哺乳动物(例如人)的介质的制剂。该介质包括药学上可接受的载体。药物组合物的目的是促进生物体的给药，利于活性成分的吸收进而发挥生物活性。本文所用术语“药学上可接受的”是指不影响本发明化合物的生物活性或性质的物质(如载体或稀释剂)，并且相对无毒，即该物质可施用于个体而不造成不良的生物反应或以不良方式与组合物中包含的任意组分相互作用。
在本申请中，“药学上可接受的赋形剂”包括但不限于任何被相关的政府管理部门许可为可接受供人类或家畜使用的佐剂、载体、赋形剂、助流剂、增甜剂、稀释剂、防腐剂、染料/着色剂、矫味剂、表面活性剂、润湿剂、分散剂、助悬剂、稳定剂、等渗剂、溶剂或乳化剂。
本发明所述“癌症”或“肿瘤”包括但不限于非小细胞肺癌、黑色素瘤、头颈癌、肾癌、膀胱上皮癌、局部晚期或转移性尿路上皮癌、转移性默克尔细胞癌、前列腺癌、肝癌、肠癌、多发性骨髓瘤、套细胞淋巴癌、弥漫性大B细胞淋巴瘤肝癌、霍奇金淋巴瘤、慢性淋巴细胞白血病等。
本文所用术语“预防”包括使病患减少疾病或病症的发生或恶化的可能性。
本文所用的术语“治疗”和其它类似的同义词包括以下含义：
(i)预防疾病或病症在哺乳动物中出现，特别是当这类哺乳动物易患有该疾病或病症，但尚未被诊断为已患有该疾病或病症时；
(ii)抑制疾病或病症，即遏制其发展；
(iii)缓解疾病或病症，即，使该疾病或病症的状态消退；或者
(iv)减轻该疾病或病症所造成的症状。
本文所使用术语“有效量”、“治疗有效量”或“药学有效量”是指服用后足以在某种程度上缓解所治疗的疾病或病症的一个或多个症状的至少一种药剂或化合物的量。其结果可以为迹象、症状或病因的消减和/或缓解，或生物系统的任何其它所需变化。例如，用于治疗的“有效量”是在临床上提供显著的病症缓解效果所需的包含本文公开化合物的组合物的量。可使用诸如剂量递增试验的技术测定适合于任意个体病例中的有效量。
本文所用术语“服用”、“施用”、“给药”等是指能够将化合物或组合物递送到进行生物作用的所需位点的方法。这些方法包括但不限于口服途径、经十二指肠途径、胃肠外注射(包括静脉内、皮下、腹膜内、肌内、动脉内注射或输注)、局部给药和经直肠给药。本领域技术人员熟知可用于本文所述化合物和方法的施用技术，例如在Goodman and Gilman,The Pharmacological Basis of Therapeutics,current ed.；Pergamon；and Remington’s,Pharmaceutical Sciences(current edition),Mack Publishing Co.,Easton,Pa中讨论的那些。在优选的实施方案中，本文讨论的化合物和组合物通过口服施用。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性化合物与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂，或必要时可能需要的推进剂一起混合。本文所使用术语“药物组合”、“药物联用”、“联合用药”、“施用其它治疗”、“施用其它治疗剂”等是指通过混合或组合不止一种活性成分而获得的药物治疗，其包括活性成分的固定和不固定组合。术语“固定组合”是指以单个实体或单个剂型的形式向患者同时施用至少一种本文所述的化合物和至少一种协同药剂。术语“不固定组合”是指以单独实体的形式向患者同时施用、合用或以可变的间隔时间顺次施用至少一种本文所述的化合物和至少一种协同制剂。这些也应用到鸡尾酒疗法中，例如施用三种或更多种活性成分。
可以与通式(I)所述化合物进行药物联用的药物或活性成分包括但不局限为：PD-1抑制剂(如纳武单抗、派姆单抗、JS-001、SHR-120、BGB-A317、IBI-308、GLS-010、GB-226、STW204、HX008、HLX10、BAT1306、AK105、LZM 009或上述药物的生物类似药等)、PD-L1抑制剂(如德瓦鲁单抗、阿特珠单抗、CS1001、KN035、HLX20、SHR-1316、BGB-A333、JS003、CS1003、KL-A167、F 520、GR1405、MSB2311或上述药物的生物类似药等)、CD20抗体(如利妥昔单抗、奥滨尤妥珠单抗、奥法木单抗、托西莫单抗、替伊莫单抗等)、CD47抗体(如Hu5F9-G4、CC-90002、TTI-621、TTI-622、OSE-172、SRF-231、ALX-148、NI-1701、SHR-1603、IBI188、IMM01)、ALK抑制剂(如色瑞替尼、艾乐替尼、布加替尼、劳拉替尼、奥卡替尼)、PI3K抑制剂(如艾代拉里斯、Dactolisib、Taselisib、Buparlisib等)、BTK抑制剂(如依鲁替尼、Tirabrutinib、Acalabrutinib等)、EGFR抑制剂(如阿法替尼、吉非替尼、厄洛替尼、拉帕替尼、达克替尼、埃克替尼、卡奈替尼等)、VEGFR抑制剂(如索拉非尼、帕唑帕尼、瑞伐替尼、卡博替尼、舒尼替尼、多纳非尼等)、HDAC抑制剂(如Givinostat、Droxinostat、恩替诺特、达西司特、泰克地那林等)、CDK抑制剂(如帕博西尼、瑞博西尼、Abemaciclib、Lerociclib等)、MEK抑制剂(如司美替尼(AZD6244)、曲美替尼(GSK1120212)、PD0325901、U0126、AS-703026、PD184352(CI-1040)等)、Akt抑制剂(如MK-2206、Ipatasertib、Capivasertib、Afuresertib、Uprosertib等)、mTOR抑制剂(如Vistusertib等)、SHP2抑制剂(如RMC-4630、JAB-3068、TNO155等)、IGF-1R抑制剂(如Ceritinib、奥卡替尼、linsitinib、BMS-754807、GSK1838705A等)或其组合。
使用药物组合物时，是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人)，其中施用时剂量为药学上认为的有效给药剂量，对于60kg体重的人而言，日给 药剂量通常为1～2000mg，优选50～1000mg。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。
本发明还提供了一种药物组合物的制备方法，包括步骤：将药学上可接受的载体与本发明所述通式(I)化合物或其晶型、药学上可接受的盐、水合物或溶剂合物进行混合，从而形成药物组合物。
本发明还提供了一种治疗方法，它包括步骤：给需要治疗的对象施用本发明中所述通式(I)化合物，其立体异构体、对映异构体或其药学上可接受的盐，或施用本发明所述的药物组合物，用于抑制PD1-PDL1相互作用。
式I化合物的制备
以下方案和实例中描述了制备式I的化合物的方法。原料和中间体从商业来源购买，由已知步骤制备，或以其他方式说明。在某些情况下，可以改变执行反应方案的步骤的顺序，以促进反应或避免不需要的副反应产物。
通常，在制备流程中，各反应通常在惰性溶剂中，在室温至回流温度(如0℃～150℃，优选10℃～100℃)下进行。反应时间通常为0.1小时-60小时，较佳地为0.5-48小时。
优选地，通式(I)所示的化合物制备方法如下：
方法一：
Figure PCTCN2020094013-appb-000050
1)在适当的溶剂(如THF)中，以芳基醛S1和苯甲醇S2为原料，利用Mitsunobu反应，得到化合物S3；
2)在适当的溶剂(如DMF)中，化合物S3与化合物S4在碱的作用下，生成化合物S5；
3)在适当的溶剂(如THF)中，化合物S5与化合物S8发生还原氨化反应，得到化合物I-1a；
4)在适当的溶剂(如甲醇)中，化合物I-1a在酸或碱的作用下，得到化合物I-1b。
在另一优选例中，所述步骤2)中的碱选自：碳酸钾、碳酸钠、三乙基胺或二异丙基乙基胺。
在另一优选例中，所述步骤4)中的酸为盐酸、硫酸。
在另一优选例中，所述步骤4)中的碱为NaOH、KOH。
方法二：
Figure PCTCN2020094013-appb-000051
1)在适当的溶剂(如THF)中，以芳基醛S1和苯甲醇S2为原料，利用Mitsunobu反应，得到化合物S3；
2)在适当的溶剂(如DMF)中，化合物S3与化合物S4在碱的作用下，生成化合物S5；
3)在适当的溶剂(如THF)中，化合物S5与化合物S6发生还原氨化，得到化合物S7；
3’)在适当的溶剂(如THF)中，化合物S5与S9发生还原氨化反应，得到化合物I-2a；
4’)在适当的溶剂(如甲醇)中，I-2a在酸或碱的作用下，得到化合物I-2b；
4”)在适当的溶剂(如THF)中，化合物S7与S10发生反应，得到化合物I-2c。
在另一优选例中，所述步骤2)中的碱选自：碳酸钾、碳酸钠、三乙基胺或二异丙基乙基胺。
在另一优选例中，所述步骤4’)中的酸为盐酸、硫酸。
在另一优选例中，所述步骤4’)中的碱为NaOH、KOH。
方法三：
Figure PCTCN2020094013-appb-000052
1)在适当的溶剂(如THF)中，以芳基醛S1和苯甲醇S2为原料，利用Mitsunobu反应，得到化合物S3；
2)在适当的溶剂(如DMF)中，化合物S3与化合物S4在碱的作用下，生成化合物S5；
3)在适当的溶剂(如THF)中，化合物S5与化合物S6发生还原氨化，得到化合物S7；
4)在适当的溶剂(如二氯甲烷)中，化合物S7与S11，在缩合剂作用下，得到化合物I-3a；
在另一优选例中，所述步骤2)中的碱选自：碳酸钾、碳酸钠、三乙基胺或二异丙基乙基胺。
在另一优选例中，所述步骤4)中的缩合剂选自：EDC-HCl/HOBt、HBTU、HATU或DCC。
方法四：
Figure PCTCN2020094013-appb-000053
1)在适当的溶剂(如THF)中，以芳基醛S1和苯甲醇S2为原料，利用Mitsunobu反应，得到化合物S3；
2)在适当的溶剂(如DMF)中，化合物S3与化合物S4在碱的作用下，生成化合物S5；
3)在适当的溶剂(如THF)中，化合物S5与化合物二胺S12发生还原氨化反应，得到化合物I-4a；
4)在适当的溶剂(如二氯甲烷)中，化合物I-4a与化合物S11，在缩合剂作用下，得到化合物I-4b；
在另一优选例中，所述步骤2)中的碱选自：碳酸钾、碳酸钠、三乙基胺或二异丙基乙基胺。
在另一优选例中，所述步骤4)中的缩合剂选自：EDC-HCl/HOBt、HBTU、HATU或DCC。
方法五：
Figure PCTCN2020094013-appb-000054
1)在适当的溶剂(如THF)中，以芳基醛S1和苯甲醇S2为原料，利用Mitsunobu反应，得到化合物S3；
2)在适当的溶剂(如DMF)中，化合物S3与化合物S4在碱的作用下，生成化合物S5；
3)在适当的溶剂(如THF)中，化合物S5与化合物S6发生还原氨化，得到化合物S7；
3’)在适当的溶剂(如THF)中，化合物S5与化合物S13发生还原氨化反应，得到化合物I-5a；或
4)在适当的溶剂(如THF)中，化合物S7与化合物S14发生还原氨化反应，得到化合物I-5a；
在另一优选例中，所述步骤2)中的碱选自：碳酸钾、碳酸钠、三乙基胺或二异丙基乙基胺。
方法六：
Figure PCTCN2020094013-appb-000055
1)在适当的溶剂(如THF)中，以芳基醛S1和苯甲醇S2为原料，利用Mitsunobu反应，得到化合物S3；
2)在适当的溶剂(如DMF)中，化合物S3与化合物S4在碱的作用下，生成化合物S5；
3)在适当的溶剂(如THF)中，化合物S5与化合物S6发生还原氨化，得到化合物S7；
3’)在适当的溶剂(如THF)中，化合物S5与化合物S15发生还原氨化反应，得到化合物I-6a；或
4)在适当的溶剂(如THF)中，化合物S7与S16发生还原氨化反应，得到化合物I-6a；
在另一优选例中，所述步骤2)中的碱选自：碳酸钾、碳酸钠、三乙基胺或二异丙基乙基胺。
方法七：
Figure PCTCN2020094013-appb-000056
1)在适当的溶剂(如THF)中，以芳基醛S1和苯甲醇S2为原料，利用Mitsunobu反应，得到化合物S3；
2)在适当的溶剂(如DMF)中，化合物S3与化合物S4在碱的作用下，生成化合物S5；
3)在适当的溶剂(如THF)中，化合物S5与化合物S6发生还原氨化，得到化合物S7；
3’)在适当的溶剂(如THF)中，化合物S5与化合物S17发生还原氨化反应，得到化合物I-7a；或
4)在适当的溶剂(如THF)中，化合物S7与化合物S18发生还原氨化反应，得到化合物I-7a；
在另一优选例中，所述步骤2)中的碱选自：碳酸钾、碳酸钠、三乙基胺或二异丙基乙基胺。
方法八：
Figure PCTCN2020094013-appb-000057
LVG＝halide,OMs,OTs
1)在适当的溶剂(如DME)中，碱(如Na 2CO 3)和催化剂(如Pd(dppf)Cl 2)存在下，化合物S19与化合物S20发生Suzuki偶联，得到化合物S21；
2)在适当的溶剂(如THF)中，化合物S21与化合物S1发生Mitsunobu反应，得到化合物S22；
3)在适当的溶剂(如DMF)中，在碱的作用下，化合物S22与化合物S4反应得到化合物S23；
4)在适当的溶剂(如THF)中，化合物S23与化合物S24发生还原氨化反应，得到化合物I-8a；
5)在适当的溶剂(如THF)中，I-8a与S25发生还原氨化反应得到化合物I-8b；
在另一优选例中，所述步骤2)中的碱选自：碳酸钾、碳酸钠、三乙基胺或二异丙基乙基胺。
方法九：
Figure PCTCN2020094013-appb-000058
1)在适当的溶剂(如THF)中，碱(如Cs 2CO 3)存在下，化合物S2与化合物S26在钯催化剂和含磷配体作用下，发生C-O偶联反应，得到化合物S27；
2)在适当的溶剂(如THF)中，化合物S27与化合物S13发生还原氨化反应，得到化合物I-5b；
在另一优选例中，所述步骤1)中的钯催化剂为Pd(OAc) 2。
在另一优选例中，所述步骤1)中的含磷配体为tBuXphos。
方法十：
Figure PCTCN2020094013-appb-000059
1)在适当的溶剂(如THF)中，以芳基醛S1和苯甲醇S2为原料，利用Mitsunobu反应，得到化合物S3；
2)在适当的溶剂(如DMF)中，化合物S3与化合物S4在碱的作用下，生成化合物S5；
3)在适当的溶剂(如THF)中，化合物S5与化合物二胺S12发生还原氨化反应，得到化合物I-4a；
4)在适当的溶剂(如THF)中，化合物I-4a与化合物S14发生还原氨化反应，得到化合物I-9；
4’)在适当的溶剂(如THF)中，化合物I-4a与化合物S16发生还原氨化反应，得到化合物I-10；
4”)在适当的溶剂(如THF)中，化合物I-4a与化合物S18发生还原氨化反应，得到化合物I-11；
方法十：
Figure PCTCN2020094013-appb-000060
1)在适当的溶剂(如乙腈)中，适当的碱条件下(如K 2CO 3)，以中间体S7和取代磺酰氯S30(或者S31)为原料，发生取代反应得到化合物S32；
2)在适当的溶剂(如乙腈)中，化合物S32与NaN 3反应，生成化合物S33；
3)在适当的溶剂(如丙酮)中，适当的碱条件下(如三乙胺)，中间体S33和乙酰丙酮发生反应，可以得到化合物I-14(Rg＝NH 2)；
4)在适当的溶剂(如DMF)中，适当的碱条件下(如2,6-二甲基吡啶)，中间体S33和硫代羧酸S34发生反应，得到化合物I-14。
在另一优选例中，所述步骤2)中的碱选自：碳酸钾、碳酸钠、三乙基胺或二异丙基乙基胺。
上述所有合成方法中R 2、R 3、R 4、R 5、R 6、R 11、R 12、R 13、R 14、R 15、R 16、X、Y基团具有如上所述的定义。
上述所有合成方法中R 2、R 3、R 4、R 5、R 6、R 11、R 12、R 13、R 14、R 15、R 16、X、Y基团的定义如下：
X为N或者CH；
Y为氢原子或者C1-C4烷基；
R 1选自下组：
Figure PCTCN2020094013-appb-000061
Figure PCTCN2020094013-appb-000062
R 2选自取代或未取代的下组基团：氢原子、C1-C6烷基、C3-C6环烷基、5-10元杂环 基、Ar 1-(CH 2) m-、C6-C10芳环或者5-12元的杂芳环；Ar 1为取代或者未取代的5-10元杂环基、C6-C10芳环或者5-12元杂芳环；其中，所述取代是指被选自下组的一个或多个基团取代：羟基、卤素、羧基、氰基、C1-C6烷基、-NRaRb、5-6元杂芳基、C3-C6环烷基、5-10元杂环基；
R 3选自取代或未取代的下组：氢原子、C1-C6烷基、C3-C6环烷基、Ar-CH 2-、或5-12元的杂环基；
其中，Ar为取代或者未取代的C6-C10芳环，或者5-12元的杂芳环，
其中，所述的取代指基团上的一个或多个氢原子被选自下组的取代基所取代：卤素、C1-C4烷基、(C1-C4)烷氧基、羟基、氨基、氰基、三氟甲基、二氟甲基、(C1-C4)烷基磺酰基、(C1-C4)烷基亚磺酰基、(C1-C4)烷基磺酰基氨基、氨基磺酰基、(C1-C5)酰基氨基、卤代(C1-C4)烷基磺酰基、卤代(C1-C4)烷基亚磺酰基、卤代(C1-C4)烷基磺酰基氨基；
R 4选自：氢原子、卤素、C1-C4烷基、C1-C4烷氧基、或卤代(C1-C4)烷基；
R 5选自：氢原子、卤素、C1-C4烷基、C1-C4烷氧基、氰基、或卤代(C1-C4)烷基；
R 6选自：取代或未取代的苯环，其中，所述的取代指基团上的一个或多个氢原子被选自下组的取代基所取代：对甲氧基苄基氧基、苄氧基、(C1-C5)烷氧基、羟基、卤素；
或者R 6选自：
Figure PCTCN2020094013-appb-000063
Figure PCTCN2020094013-appb-000064
其中，Z为氢原子或者C1-C4烷基；
R 1a选自：
Figure PCTCN2020094013-appb-000065
Figure PCTCN2020094013-appb-000066
Figure PCTCN2020094013-appb-000067
R 2a选自取代或未取代的下组基团：氢原子、C1-C6烷基、C3-C6环烷基、5-10元杂环基、Ar 1-(CH 2) m-、C6-C10芳环或者5-12元的杂芳环；Ar 1为取代或者未取代的5-10元杂环基、C6-C10芳环或者5-12元杂芳环；其中，所述取代是指被选自下组的一个或多个基团取代：羟基、卤素、羧基、氰基、C1-C6烷基、-NRaRb、5-6元杂芳基、C3-C6环烷基、5-10元杂环基；
R 3a选自：氢原子、C1-C6烷基、C3-C6环烷基、Ar-CH 2-、或C3-C6杂环基，
R 4a选自：氢原子、卤素、C1-C4烷基、(C1-C4)烷氧基、卤代(C1-C4)烷基；
R 5a选自：氢原子、卤素、C1-C4烷基、(C1-C4)烷氧基、氰基、卤代(C1-C4)烷基；
Ra、Rb、Rc各自独立地选自：氢原子、C1-C5烷基、-O-CH 2-O-CO-(C1-C5烷基)、-CH 2-O-CO-(C1-C5烷基)；
Rg选自：-NRdRe；
Rd、Re各自独立地选自：氢原子、C1-C5烷基、-CO-Rf，其中，Rf独立地选自：氢原子、三氟甲基、C1-C5烷基、5-6元杂芳基、C3-C6环烷基、5-10元杂环基；
Rx选自：氢原子、C1-C6烷基、C3-C6环烷基、5-10元杂环基；
其中R 11、R 12、R 13、R 14、R 15、R 16分别独立的选自：氢、羟基、-O-CHO、(C1-C4烷基)羰基-O-、HO 2C-；
其中，n表示2、3、或者4；m表示1、2、或者3。
本领域技术人员还应当理解，在本文所述的方法中，中间体化合物官能团可能需要由适当的保护基保护。这样的官能团包括羟基、氨基、巯基及羧酸。合适的羟基保护基包括三烷基甲硅烷基或二芳基烷基甲硅烷基(例如叔丁基二甲基甲硅烷基、叔丁基二苯基甲硅烷基或三甲基甲硅烷基)、四氢吡喃基、苄基等。合适的氨基、脒基及胍基的保护基包括叔丁氧羰基、苄氧羰基等。合适的巯基保护基包括-C(O)-R”(其中R”为烷基、芳基或芳烷基)、对甲氧基苄基、三苯甲基等。合适的羧基保护基包括烷基、芳基或芳烷基酯类。
保护基可根据本领域技术人员已知的和如本文所述的标准技术来引入和除去。保护基的使用详述于Greene,T.W.与P.G.M.Wuts,Protective Groups in Organi Synthesis,(1999),4th Ed.,Wiley中。保护基还可为聚合物树脂。
本发明所用试剂或材料均可市售或者文献报道中给出的方式获得。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计 算。部分化合物用反相液相纯化。纯化时，样品制备需要用三氟醋酸将样品酸化，纯化分离时的流动相(水、乙腈或甲醇)含三氟醋酸(0.1％)，故目标化合物浓缩冻干后为三氟醋酸盐形式存在。
本发明主要优点：
1、本发明化合具有较好的抑制PD1/PD-L1相互作用的能力，相较于现有技术报道的BMS-1266具有20倍甚至更高的提升；
2、相较于PDL1抗体，本发明化合物具有更好的促进T细胞杀伤癌细胞的作用；
3、相较于PD1抗体/PDL1抗体，本发明化合物具有更好的药效学性能。
实施例
合成中间体：5–((4-氯-5-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)-2-甲酰基苯氧基)甲基)烟腈(ZD07)
Figure PCTCN2020094013-appb-000068
步骤一：合成5-氯-4-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)-2-羟基苯甲醛(ZA52)
将ZA03(728mg，2.84mmol)和5-氯-2，4-二羟基苯甲醛(SM1,488mg,2.84mmol)加入到反应瓶中，后加入PPh 3(820mg，3.13mmol)、并用THF溶解，冰水浴降温后，滴加DIAD(574mg，2.84mmol)，然后缓慢升至室温，搅拌过夜。待反应结束后，加入饱和碳酸氢钠溶液淬灭，并用乙酸乙酯萃取，有机相用饱和食盐水洗，无水硫酸钠干燥后旋干，最后用层析柱分离后得到目标化合物703mg。ZA52: 1H NMR(400MHz,Chloroform-d)δ11.46(s,1H),9.72(dd,J＝0.6,3.2Hz,1H),7.57(s,1H),7.47(dd,J＝2.8,6.3Hz,1H),7.27(s,1H),6.94(d,J＝8.2Hz,1H),6.86(d,J＝2.0Hz,1H),6.80(dd,J＝2.1,8.2Hz,1H),6.65(s,1H),5.22(s,2H),4.33(s,4H),2.29(s,3H)。
步骤二：合成5–((4-氯-5-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)-2-甲酰基苯氧基)甲基)烟腈(ZD07)
将ZA52(609mg，1.56mmol)、5-(氯甲基)烟腈(285mg，1.875mmol)溶于DMF中，后加入Cs 2CO 3室温反应过夜。待反应结束后，加水淬灭，用二氯甲烷萃取三次，有机相用饱和氯化钠溶液洗，无水硫酸钠干燥后，旋干溶剂，并用层析柱分离纯化，得到目标化 合物546mg。 1H NMR(400MHz,Chloroform-d)δ10.30(s,1H),8.98–8.87(m,2H),8.11(t,J＝2.1Hz,1H),7.94(s,1H),7.42(dd,J＝3.7,5.3Hz,1H),7.29(s,1H),7.28(s,1H),6.94(d,J＝8.2Hz,1H),6.84(d,J＝2.1Hz,1H),6.80(dd,J＝2.1,8.2Hz,1H),6.66(s,1H),5.26(s,2H),5.24(s,2H),4.34(s,4H),2.32(s,3H).
实施例1：合成N-(3-((2-((3-氰基苄基)氧基)-4-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)-5-甲基苄基)(甲基)氨基)丙基)丁-2-炔酰胺(ZA89)
Figure PCTCN2020094013-appb-000069
步骤一：合成(3-溴-2-甲基苯基)甲醇(ZA01)
将3-溴-2-甲基苯甲酸(5.0g,23.4mmol)溶于干燥的THF(四氢呋喃)(100ml)中，冰水浴降温，后加入LiAlH 4(1.06g,27.9mmol)，室温反应过夜。反应结束后，将反应液倒入饱和NaHCO 3中淬灭，过滤，加二氯甲烷(DCM)淋洗，有机相用无水硫酸钠干燥后旋干，得到目标产物(2.0g)。 1H NMR(400MHz,Chloroform-d)δ7.53(dd,J＝1.2,8.0Hz,1H),7.36–7.29(m,1H),7.07(t,J＝7.8Hz,1H),4.72(s,2H),2.43(s,3H)。
步骤二：合成(3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苯基)甲醇(ZA03)
将ZA01(198mg,1.0mmol)和(2,3-二氢苯并[b][1,4]二恶英-6-基)硼酸(450mg,2.5mmol)溶于DME(乙二醇二甲醚)(8ml)和2M的Na 2CO 3(4ml)溶液中，除氧气，充氮气后加入Pd(dppf)Cl 2-CH 2Cl 2(81.6mg)后再次除氧气充氮气，后95℃加热反应过夜。反应结束后加水淬灭，然后用乙酸乙酯萃取，有机相用饱和食盐水洗，无水硫酸钠干燥后旋干，最后用层析柱分离后得到目标化合物ZA03(210mg): 1H NMR(400MHz,Chloroform-d)δ7.39(dd,J＝1.6,7.4Hz,1H),7.24(d,J＝7.5Hz,1H),7.20(dd,J＝1.6,7.7Hz,1H),6.92(d,J＝8.2Hz,1H),6.84(d,J＝2.1Hz,1H),6.78(dd,J＝2.1,8.2Hz,1H),4.79(d,J＝5.7Hz,2H),4.33(s,4H),2.28(s,3H)。
步骤三：4-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)-2-羟基-5-甲基苯甲醛(ZA88)
将ZA03(637mg,2.5mmol)加入到反应瓶中，然后加入2,4-二羟基-5-甲基苯甲醛(377 mg,2.5mmol)、PPh 3(717.1mg，2.74mmol)、并用THF(15ml)溶解，冰水浴降温后滴加DIAD(偶氮二甲酸二异丙酯)(503mg，2.5mmol)，后缓慢升至室温，搅拌过夜。待反应结束后加入饱和碳酸氢钠溶液淬灭，并用乙酸乙酯萃取，有机相用饱和食盐水洗，无水硫酸钠干燥后旋干，最后用层析柱分离后得到目标化合物888.1mg，Yield：91.5％。 1H NMR(400MHz,Chloroform-d)δ11.48(s,1H),9.72(s,1H),7.43(dd,J＝2.7,6.3Hz,1H),7.32–7.30(m,1H),7.27(d,J＝2.6Hz,1H),6.94(d,J＝8.2Hz,1H),6.86(d,J＝2.1Hz,1H),6.81(dd,J＝2.1,8.2Hz,1H),6.56(s,1H),5.15(s,2H),4.34(s,4H),2.28(s,3H),2.24(d,J＝0.8Hz,3H),1.59(s,1H)。
步骤四：合成3-((5-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)-2-甲酰基-4-甲基苯氧基)甲基)苯甲腈(ZA80)
将ZA88(562.6mg,1.44mmol)，3-(溴甲基)苄腈(338.9mg，1.72mmol)溶于干燥的DMF溶液中，然后加入Cs 2CO 3(704mg,2.16mmol)，室温反应过夜。待反应结束后加水淬灭，后用乙酸乙酯萃取，有机相用饱和氯化钠洗、无水硫酸钠干燥，然后旋干溶剂并用色谱柱纯化，得到目标产物700mg，收率：96％。 1H NMR(400MHz,Chloroform-d)δ10.41–10.34(m,1H),7.83–7.63(m,5H),7.57(s,2H),7.39(s,1H),6.95(dd,J＝3.6,8.3Hz,1H),6.85(d,J＝3.6Hz,1H),6.83–6.76(m,1H),6.54(d,J＝3.4Hz,1H),5.21(dd,J＝3.4,9.5Hz,2H),5.15(d,J＝4.1Hz,2H),4.34(d,J＝3.6Hz,4H),2.07(d,J＝3.6Hz,1H),1.59(s,3H),1.58(s,3H)。
步骤五：合成3-((2-(((3-氨基丙基)(甲基)氨基)甲基)-5-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)-4-甲基苯氧基)甲基)苯甲腈(ZA91)
将ZA80(520mg,1.0mmol)、(3-(甲基氨基)丙基)氨基甲酸叔丁酯(564mg，3.0mmol)溶于干燥的THF中，后加入AcOH(0.2ml)，最后加入NaBH(OAc) 3(1.10g,5.0eq),室温反应过夜。反应结束后，加入饱和碳酸氢钠溶液，然后用二氯甲烷萃取，有机相用无水硫酸钠干燥后旋干，最后用层析柱分离纯化，得到中间体301mg，收率：43％。将得到的中间体溶于二氯甲烷和三氟乙酸(4:1)的混合溶液中，室温搅拌2h。反应结束后，旋干溶剂，HPLC纯化，得到目标化合物。 1H NMR(400MHz,Methanol-d 4)δ7.89(s,1H),7.80(d,J＝7.8Hz,1H),7.77–7.72(m,1H),7.61(t,J＝7.8Hz,1H),7.35(dd,J＝1.9,7.1Hz,1H),7.29–7.14(m,3H),6.95–6.84(m,2H),6.80–6.69(m,2H),5.32(s,2H),5.19(s,2H),4.45(s,1H),4.30(s,4H),4.23(s,1H),3.37(s,1H),3.19(d,J＝29.4Hz,1H),3.02(t,J＝7.7Hz,2H),2.82(s,3H),2.26(s,3H),2.21(s,3H),2.15(p,J＝7.9Hz,2H)。
步骤六：合成N-(3-((2-((3-氰基苄基)氧基)-4-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)-5-甲基苄基)(甲基)氨基)丙基)丁-2-炔酰胺(ZA89)
将ZA91(40mg，0.07mmol)、2-丁炔酸(12mg，0.14mmol)溶于DMF中，然后加入二异丙基乙胺(0.2ml)，最后加入PyBop，室温反应过夜。待反应结束后，向反应体系中加入甲醇，然后旋干，再加入适量的水后，用HPLC纯化，得到目标产物18mg。 1H NMR(400 MHz,Methanol-d 4)δ7.90(s,1H),7.82(d,J＝7.8Hz,1H),7.78–7.73(m,1H),7.62(t,J＝7.8Hz,1H),7.41–7.36(m,1H),7.26–7.22(m,2H),7.22–7.16(m,1H),6.93–6.87(m,2H),6.78–6.72(m,2H),5.29(s,2H),5.21(s,2H),4.50(d,J＝13.0Hz,1H),4.30(s,4H),4.07(d,J＝13.0Hz,1H),3.27–3.02(m,3H),2.75(s,3H),2.27(s,3H),2.22(s,3H),1.99(s,3H),1.97–1.79(m,2H)。ESI-MS理论计算值C 40H 41N 3O 5[M+H] +＝644.30，实验测得：644.78。
实施例2：合成3-((5-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)-4-甲基-2-((((2S，3R，4R，5R)-2,3,4,5,6-五羟基己基)氨基)甲基)苯氧基)甲基)苯甲腈(ED01)
Figure PCTCN2020094013-appb-000070
ZA80(0.08mmol,40mg),D-萄糖胺(0.33mmol,60mg)溶解于THF(4mL)和甲醇(4mL)中，室温搅拌1小时，加入NaBH 4(80mg,2.1mmol)，搅拌过夜。反应结束后，用稀盐酸淬灭，浓缩得到粗品，反向液相纯化粗品，得到目标化合物的三氟醋酸盐(3.1mg)。 1H NMR(400M,MeOD-d4):7.90(s,1H),7.82(d,J＝7.98Hz,1H),7.71(d,J＝7.84Hz,1H),7.59(t,J＝7.70Hz,1H),7.34(dd,J＝7.07,1.64Hz,1H),7.24-7.14(m,3H),6.88(d,J＝8.03Hz,1H),6.80(s,1H),6.76-6.71(m,2H),5.30(s,3H),5.15(s,3H),4.28(s,4H),4.21(q,J＝12.34Hz,2H),4.11-4.05(m,1H),3.85(dd,J＝4.44,1.36Hz,1H),3.77(dd,J＝10.60,3.99Hz,1H),3.74-3.61(m,3H),3.25-3.14(m,2H),2.24(s,3H),2.19(s,3H)。ESI-MS理论值C 38H 43N 2O 9[M+H] +＝671.3,测得:671.5。
实施例3：合成(2R，3R，4S，5R)-2-((2-((3-氰基苄基)氧基)-4-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基))-2-甲基苄基)氧基)-5-甲基苄基)氨基)-3,4,5,6-四羟基己酸(ED04)
Figure PCTCN2020094013-appb-000071
ZA80(0.08mmol,40mg),D-氨基葡萄糖酸(0.3mmol,60mg)溶解于THF(4mL)和甲醇(4mL)中，室温搅拌1小时，加入NaBH(OAc) 3(110mg,0.52mmol)，搅拌过夜。反应液浓缩得到粗品，反向液相纯化粗品，得到目标化合物(1.5mg)。 1H NMR(400M,MeOD-d4):7.92(s,1H),7.82(d,J＝7.98Hz,1H),7.71(d,J＝7.84Hz,1H),7.59(t,J＝7.70Hz,1H),7.34(dd,J＝ 7.07,1.64Hz,1H),7.24-7.14(m,3H),6.90(d,J＝7.82Hz,1H),6.81(s,1H),6.76-6.71(m,2H),5.31(s,3H),5.15(s,3H),4.38-4.19(m,3H),4.30(s,4H),3.80-3.53(5H),2.24(s,3H),2.18(s,3H)。ESI-MS理论值C 38H 41N 2O 10[M+H] +＝685.3,测得:685.2。
实施例4：合成2-((2-((3-氰基苄基)氧基)-4-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)-5-甲基苄基)(甲基)氨基)乙烷-1-磺酸(ED11)
Figure PCTCN2020094013-appb-000072
步骤1：合成2–((2–((3-氰基苄基)氧基)-4–((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧)-5-甲基苄基)(甲基)氨基)乙烷-1-磺酸异丙酯(ED09)
ZA80(0.1mmol,50mg),2-(甲基氨基)乙烷-1-磺酸异丙酯(0.88mmol,160mg)溶解于THF(6mL)中，加入AcOH(0.05mL)和NaBH(OAc) 3(100mg,0.47mmol)，搅拌过夜。反应液浓缩得到粗品，反向液相纯化得到粗品ED09。
步骤2：合成2-((2-((3-氰基苄基)氧基)-4-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)-5-甲基苄基)(甲基)氨基)乙烷-1-磺酸(ED11)
将步骤1中获得的全部ED09粗品溶解于10mL甲醇中，加入1mL浓盐酸，室温搅拌过夜。反应液浓缩得到粗品，反向液相纯化粗品得到目标化合物30mg。 1H NMR(400M,DMSO-d6):9.11(s,1H),8.03(s,1H),7.92(d,J＝8.22Hz,1H),7.82(d,J＝8.22Hz,1H),7.62(t,J＝7.79Hz,1H),7.42(d,J＝7.35Hz,1H),7.28-7.21(m,2H),7.20-7.15(m,1H),6.98(s,1H),6.93(d,J＝8.38Hz,1H),6.83-6.72(m,2H),5.33(s,2H),5.17(s,2H),4.35(dd,J＝12.89,4.16Hz,1H),4.29(s,4H),4.22(dd,J＝12.89,5.61Hz,1H),3.67-3.35(m,2H),3.30(septet,J＝6.44Hz,1H),3.04-2.85(m,2H),2.73(d,J＝4.55Hz,3H),2.23(s,3H),2.12(s,3H)。ESI-MS理论值C 35H 37N 2O 7S[M+H] +＝629.2,测得:629.2。
实施例5：合成2–((2–((3-氰基苄基)氧基)-4–((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧)-5-甲基苄基)(甲基)氨基)乙烷-1-膦酸单乙基酯(ED19-2)
Figure PCTCN2020094013-appb-000073
步骤1：合成2–((2–((3-氰基苄基)氧基)-4–((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧)-5-甲基苄基)(甲基)氨基)乙烷-1-膦酸二乙酯(ED18)
将ZA80(0.1mmol,50mg),二乙基(2-氨基乙基)膦酸酯(1.0mmol,181mg)溶解于THF(4mL)和甲醇(2mL)中，室温搅拌1小时，加入NaBH 4(160mg,4.2mmol)，搅拌过夜。加水稀释反应，用CH 2Cl 2萃取水相，干燥浓缩，得到目标化合物的粗品125mg，未进一步纯化直接用于下一步反应。
步骤2：合成2–((2–((3-氰基苄基)氧基)-4–((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧)-5-甲基苄基)(甲基)氨基)乙烷-1-膦酸单乙酯(ED19-2)
将步骤1中的ED18(125mg)溶解于10mL THF，加入10％NaOH水溶液(5mL),回流6小时。浓缩反应溶液，用盐酸酸化反应，再浓缩并用反向液相纯化粗品，得到目标化合物1.2mg。 1H NMR(400M,MeOD-d4):7.89(s,1H),7.83(d,J＝8.06Hz,1H),7.72(d,J＝7.21Hz,1H),7.60(t,J＝7.63Hz,1H),7.33(dd,J＝6.82,1.83Hz,1H),7.24-7.15(m,3H),6.90(d,J＝8.08Hz,1H),6.80(s,1H),6.77-6.71(m,2H),5.32(s,2H),5.16(s,2H),4.29(s,4H),4.20(s,2H),3.98-3.88(m,2H),3.27-3.17(m,2H),2.24(s,3H),2.20(s,3H),2.01-1.90(m,2H),1.24(t,J＝7.02Hz,3H)。ESI-MS理论值C 36H 40N 2O 7P[M+H] +＝643.3,测得:643.3。
实施例6/7：合成(2–((2–((3-氰基苄基)氧基)-4–((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)-5-甲基苄基)(甲基)氨基)乙基)膦酸(ED55-1)和(2–((2–((3-氰基苄基)氧基)-4–((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)-5-甲基苄基)氨基)乙基)膦酸(ED55-2)
Figure PCTCN2020094013-appb-000074
步骤1：合成(((2-((2-((3-氰基苄基)氧基)-4-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧)-5-甲基苄基)(甲基)氨基)乙基)磷酰基)双(氧))双(亚甲基)双(2,2-二甲基丙酸酯)(ED52-1)和(((2-((2-((3-氰基苄基)氧基)-4-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧)-5-甲基苄基)氨基)乙基)磷酰基)双(氧))双(亚甲基)双(2,2-二甲基丙酸酯)(ED52-2)
将ZA80(0.1mmol,48mg),(((2-氨基乙基)磷酰基)双(氧))双(亚甲基)双(2,2-二甲基丙酸酯)(1.0mmol,353mg,参照PCT2010019208方法合成，含新戊酸碘甲酯杂质)溶解于THF(5mL)和甲醇(5mL)，室温搅拌12小时，加入NaBH 4(80mg,2.1mmol)，搅拌过夜。浓缩反应溶液，得到含有ED52-1和ED52-2粗品。
步骤2：合成(2–((2–((3-氰基苄基)氧基)-4–((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)-5-甲基苄基)(甲基)氨基)乙基)膦酸(ED55-1)和(2–((2–((3-氰基苄基)氧基)-4–((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)-5-甲基苄基)氨基)乙基)膦酸(ED55-2)
将上述ED52-1和ED52-2的粗品，溶解于THF(5mL)中，加入3N HCl(6mL),室温搅拌过夜。浓缩反应溶液，并溶解于MeCN(8mL)/水(8mL)，过滤得母液，再浓缩，得到粗品。粗品溶解于THF(5mL)/3N HCl(10mL)中，60℃加热3小时。浓缩反应溶液，并用反向液相纯化粗品得到目标化合物的混合物(比例＝60:40)。ED52-1(60％)： 1H NMR(400M,MeOD-d4):7.88(s,1H),7.85-7.80(m,1H),7.76-7.70(m,1H),7.63-7.57(m,1H),7.37-7.31(m,1H),7.25-7.15(m,1H),6.89(s,1H),6.85(s,1H),6.78-6.71(m,2H),5.31(s,2H),5.19(s,2H),4.29(s,4H),4.42(s,2H),3.31-3.21(m,2H),2.83(s,3H),2.25(s,3H),2.21(s,3H),2.18-2.01(m,2H)。ESI-MS理论值C 35H 38N 2O 7P[M+H] +＝629.2,测得:629.6。
ED52-2(40％)： 1H NMR(400M,MeOD-d4):7.88(s,1H),7.85-7.80(m,1H),7.76-7.70(m,1H),7.63-7.57(m,1H),7.37-7.31(m,1H),7.25-7.15(m,1H),6.90(s,1H),6.81(s,1H),6.78-6.71(m,2H),5.31(s,2H),5.17(s,2H),4.52-4.37(br,1H),4.29(s,4H),3.31-3.21(m,2H),2.24(s,3H),2.20(s,3H),2.18-2.01(m,2H)。ESI-MS理论值C 34H 35N 2NaO 7P[M+Na] +＝637.2,测得:637.8。
实施例8：合成(3-((2-((3-氰基苄基)氧基)-4-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6- 基)-2-甲基苄基)氧基)-5-甲基苄基)(甲基)氨基)丙基)膦酸(ED57)
Figure PCTCN2020094013-appb-000075
步骤1：合成3–((5-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)-4-甲基-2-((甲基氨基)甲基)苯氧基)甲基)苯甲腈(ED54)
将ZA80(50mg,0.1mmol)溶解于THF(10mL)中，加入甲胺溶液(27％,0.2mL)，再加入醋酸0.05mL,最后加入NaBH(OAc) 3(212mg,1mmol)，室温搅拌6小时，浓缩反应溶液，用HPLC纯化的到目标产物的三氟醋酸盐50mg。 1H NMR(400M,MeOD-d4):7.81(s,1H),7.75-7.71(m,1H),7.71-7.66(m,1H),7.68(s,1H),7.57(t,J＝7.64Hz,1H),7.35-7.30(m,1H),7.23-7.17(m,2H),7.15(s,1H),6.88(d,J＝8.27Hz,1H),6.78-6.71(m,2H),6.68(s,1H),5.25(s,2H),5.10(s,2H),4.30(s,4H),4.12(s,2H),2.65(s,3H),2.23(s,3H),2.20(s,3H)。ESI-MS理论值C 33H 33N 2O 4[M+H] +＝521.24，测得:521.01。
步骤2：(3-((2-((3-氰基苄基)氧基)-4-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)-5-甲基苄基)(甲基)氨基)丙基)膦酸(ED57)
将称量ED54(0.1mmol,50mg)和3-溴丙基膦酸(0.2mmol,40mg),加入二异丙基乙基胺(1mL)和无水DMF(10mL)，反应液在80℃加热，过夜之后，再120℃加热6小时。浓缩除去溶剂和二异丙基乙基胺，所得粗品用反向液相纯化粗品，得到目标化合物(3mg)。 1H NMR(400M,MeOD-d4):7.89(s,1H),7.82(d,J＝7.90Hz,1H),7.74(d,J＝8.32Hz,1H),7.62(t,J＝7.81Hz,1H),7.36(dd,J＝6.89,1.68Hz,1H),7.26-7.16(m,3H),6.87(d,J＝8.02Hz,1H),6.86(s,1H),6.77-6.72(m,2H),5.32(s,3H),5.19(s,3H),4.49-4.41(m,1H),4.30(s,4H),4.20-4.09(m,1H),3.52-3.41(m,1H),3.25-3.10(m,1H),2.79(s,3H),2.26(s,3H),2.21(s,3H),2.17-1.96(m,2H),1.84-1.68(m,2H)。ESI-MS理论值C 36H 40N 2O 7P[M+H] +＝643.3,测得:643.1。
实施例9：合成3-((5-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)-4-甲基-2-((甲基(3-(((2S，3R，4R，5R)-2,3,4,5,6-五羟基己基)氨基)丙基)氨基)甲基)苯氧基)甲基)苯甲腈(ZB29)
Figure PCTCN2020094013-appb-000076
将ZA91(26mg，0.045mmol)、D-(+)-葡萄糖(3mg，0.015mmol)溶于THF：MeOH(1:1)的混合溶剂中，后加入AcOH(0.05ml)，室温搅拌20min，最后加入NaBH(OAc) 3(16mg,0.075mmol)，室温反应过夜。反应结束后，旋干溶剂，HPLC纯化，得到目标化合物6.8mg。 1H NMR(400MHz,Methanol-d 4)δ7.88(s,1H),7.80(d,J＝7.9Hz,1H),7.74(d,J＝7.6Hz,1H),7.61(t,J＝7.7Hz,1H),7.34(dd,J＝2.0,7.1Hz,1H),7.26–7.15(m,3H),6.90(d,J＝8.0Hz,1H),6.82(s,1H),6.78–6.70(m,2H),5.31(s,2H),5.17(s,2H),4.30(s,4H),4.23(s,2H),4.02(d,J＝12.5Hz,1H),3.94–3.87(m,1H),3.85–3.75(m,1H),3.75–3.62(m,2H),3.37(s,4H),3.24(d,J＝4.0Hz,2H),3.14(q,J＝7.3,7.8Hz,4H),2.25(s,3H),2.20(s,3H),2.14(d,J＝15.8Hz,2H)。ESI-MS理论值C 42H 51N 3O 9[M+H] +＝742.36，测得：742.65。
实施例10：合成3–((5–((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)-4-甲基-2–((甲基(3-(((3S，4R)-3,4,5-三羟基戊基)氨基)丙基)氨基)甲基)苯氧基)甲基)苯甲腈(ZB94)
Figure PCTCN2020094013-appb-000077
将ZA91(20mg，0.035mmol)、2-脱氧-D-核糖(14.2mg，0.106mmol)溶于THF：MeOH(1:1)的混合溶剂中，后加入AcOH(0.05ml)，室温搅拌20min，最后加入NaBH(OAc) 3(36.7mg，0.17mmol)，室温反应过夜。反应结束后，旋干溶剂，HPLC纯化，得到目标化合物9.6mg。 1H NMR(400MHz,Methanol-d 4)δ7.89(s,1H),7.80(d,J＝7.8Hz,1H),7.75(dt,J＝1.4,7.7Hz,1H),7.62(t,J＝7.8Hz,1H),7.36(dd,J＝1.9,7.1Hz,1H),7.27–7.16(m,3H),6.93–6.83(m,2H),6.79–6.69(m,2H),5.32(s,2H),5.19(s,2H),4.46(d,J＝13.3Hz,1H),4.30(s,4H),4.24(s,1H),3.79–3.66(m,2H),3.62(dd,J＝5.8,11.2Hz,1H),3.54(td,J＝4.4,6.0Hz,1H),3.21(hept,J＝6.0,6.8Hz,2H),3.08(d,J＝9.0Hz,2H),2.82(s,3H),2.26(s,3H),2.21(s,3H),2.18(d,J＝8.2Hz,2H),2.06(dtd,J＝3.1,6.9,7.5,13.9Hz,1H),1.89(dt,J＝7.6,14.6Hz,1H)。ESI-MS理论值C 41H 49N 3O 7[M+H] +＝696.36，测得：696.24。
实施例11：合成3-((5-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)-4-甲基-2-((甲基(3-(((2S，3S，4R)-2,3,4,5-四羟基)氨基)丙基)氨基)甲基)苯氧基)甲基)苯甲腈(ZB95)
Figure PCTCN2020094013-appb-000078
将ZA91(20mg，0.035mmol)、D-核糖(15.6mg，0.106mmol)溶于THF：MeOH(1:1)的混合溶剂中，后加入AcOH(0.05ml)，室温搅拌20min，最后加入NaBH(OAc) 3(36.7mg，0.17mmol)，室温反应过夜，反应结束后，旋干溶剂，HPLC纯化，得到目标化合物13.2mg。 1H NMR(400MHz,Methanol-d 4)δ7.88(t,J＝1.6Hz,1H),7.80(dt,J＝1.4,7.9Hz,1H),7.74(dt,J＝1.4,7.7Hz,1H),7.61(t,J＝7.8Hz,1H),7.35(dd,J＝1.9,7.1Hz,1H),7.26(s,1H),7.24–7.16(m,2H),6.90(d,J＝8.0Hz,1H),6.85(s,1H),6.79–6.69(m,2H),5.32(s,2H),5.18(s,2H),4.44(s,1H),4.38–4.31(m,1H),4.29(s,4H),4.25(dt,J＝2.4,4.8Hz,1H),4.20(d,J＝4.6Hz,1H),4.11(dd,J＝3.7,9.9Hz,2H),4.03(dd,J＝4.6,9.7Hz,1H),3.94–3.88(m,2H),3.85(dd,J＝2.1,9.9Hz,1H),3.27(dd,J＝7.4,12.7Hz,2H),3.21–3.06(m,3H),2.82(d,J＝1.5Hz,3H),2.25(s,3H),2.21(s,3H)。ESI-MS理论值C 41H 49N 3O 8[M+H] +＝712.35，测得：712.23。
实施例12：合成N-(3-((2-((3-氰基苄基)氧基)-4-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)-5-甲基苄基)(甲基)氨基)丙基)环氧乙烷-2-甲酰胺(ZB101)
Figure PCTCN2020094013-appb-000079
将环氧乙烷-2-羧酸(3.14mg，0.035mmol)溶于干燥的二氯甲烷溶液中，冰水浴降温后依次加入N-甲基吗啉(3.58mg，0.035mmol)、氯甲酸异丁酯(5mg，0.032mmol)，冰水浴反应1h后，加入ZA91(20.2mg，0.035mmol)室温反应。反应结束后，旋干溶剂，HPLC纯化，得到目标化合物11.2mg。 1H NMR(400MHz,Methanol-d 4)δ7.94(d,J＝9.3Hz,1H),7.82(d,J＝7.9Hz,1H),7.76(d,J＝7.8Hz,1H),7.61(td,J＝2.8,7.7Hz,1H),7.37(d,J＝7.3Hz,1H),7.28–7.15(m,3H),6.94–6.83(m,2H),6.75(d,J＝8.4Hz,2H),5.31(d,J＝3.4Hz,2H),5.20(d,J＝2.7Hz,2H),4.65–4.43(m,1H),4.30(s,4H),4.11(d,J＝3.7Hz,1H),3.85–3.71(m,2H),3.26–3.01(m,3H),2.76(s,1H),2.72(d,J＝3.7Hz,1H),2.68(d,J＝9.3Hz,1H),2.27(s,3H),2.22(s,3H),2.06(s,01H),1.96(d,J＝6.6Hz,1H),1.86(s,1H)。ESI-MS理论计算值C 39H 41N 3O 6[M+H] +＝648.30，实验测得：648.47。
实施例13：合成N-(2-((2-((3-氰基苄基)氧基)-4-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)-5-甲基苄基)(甲基)氨基)乙基)环氧乙烷-2-甲酰胺(ZB44)
Figure PCTCN2020094013-appb-000080
步骤一：合成3-((2-(((2-氨基乙基)(甲基)氨基)甲基)-5-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)-4-甲基苯氧基)甲基)苯甲腈(EC106)
将ZA80(520mg,1.0mmol)、N-Boc,N’-甲基乙二胺(510mg,3mmol)溶解于THF(20mL)中，加入醋酸0.2mL,再加入NaBH(OAc)3(1.1g,5mmol)，室温搅拌过夜。加入NaHCO 3中和，CH 2Cl 2萃取，有机相合并转干得粗产品800mg。粗品溶解于CH 2Cl 2(8mL),加入三氟醋酸(4mL)，室温搅拌1小时，旋干溶剂，HPLC纯化，得到目标化合物的三氟醋酸盐207mg。 1H NMR(400MHz,Methanol-d 4)：7.87(s,1H),7.81(d,J＝7.84Hz,1H),7.73(d,J＝7.61Hz,1H),7.60(t,J＝7.61Hz,1H),7.35(dd,J＝6.95,1.77Hz,1H),7.28(s,1H),7.24-7.15(m,2H),6.89(d,J＝8.01Hz,1H),6.85(s,1H),6.78-6.71(m,2H),5.31(s,2H),5.18(s,2H),4.40(s,2H),4.29(s,4H),3.55-3.44(m,2H),3.44-3.37(m,2H),2.89(s,3H),2.25(s,3H),2.20(s,3H)。ESI-MS理论值C 35H 38N 3O 4[M+H] +＝564.3，测得：564.8。
步骤二：合成N-(2-((2-((3-氰基苄基)氧基)-4-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)-5-甲基苄基)(甲基)氨基)乙基)环氧乙烷-2-甲酰胺(ZB44)
将环氧乙烷-2-羧酸溶于干燥的二氯甲烷溶液中，冰水浴降温后，依次加入N-甲基吗啉(3.58mg，0.035mmol)、氯甲酸异丁酯(5mg，0.032mmol)，冰水浴反应1h后，加入EC106(20mg，0.035mmol)并补加N-甲基吗啉(3.58mg，0.035mmol)。反应结束后，旋干溶剂，HPLC纯化，得到目标化合物8.3mg。 1H NMR(400MHz,Methanol-d 4)δ7.92(d,J＝2.0Hz,1H),7.86–7.80(m,1H),7.74(dq,J＝1.5,7.7Hz,1H),7.61(td,J＝1.6,7.8Hz,1H),7.37(dd,J＝1.9,7.4Hz,1H),7.28–7.15(m,3H),6.93–6.83(m,2H),6.78–6.71(m,2H),5.31(d,J＝4.9Hz,2H),5.19(d,J＝5.5Hz,2H),4.45(t,J＝14.2Hz,1H),4.29(s,4H),4.24(d,J＝13.0Hz,1H),3.81–3.69(m,1H),3.68–3.45(m,2H),3.37(s,2H),3.30–3.16(m,1H),2.96(d,J＝5.4Hz,1H),2.91–2.82(m,3H),2.81–2.66(m,1H),2.26(d,J＝2.1Hz,3H),2.21(s,3H)。ESI-MS理论值C 39H 41N 3O 6[M+H] +＝634.28，测得：634.76。
实施例14：合成3-((5-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)-4-甲基-2-((甲基(2-(((2S，3R，4R，5R)-2,3,4,5,6-五羟基己基)氨基)乙基)氨基)甲基)苯氧基) 甲基)苯甲腈(ZB66)
Figure PCTCN2020094013-appb-000081
将EC106(20mg，0.035mmol)、D-(+)-葡萄糖(19mg，0.106mmol)溶于THF：MeOH(1:1)的混合溶剂中，后加入AcOH(0.05ml)，室温搅拌20min，最后加入NaBH(OAc) 3(37.5mg，0.177mmol)，室温反应过夜。反应结束后，旋干溶剂，HPLC纯化，得到目标化合物9.3mg。 1H NMR(400MHz,Methanol-d 4)δ7.89(s,1H),7.82(d,J＝7.7Hz,1H),7.75(d,J＝7.6Hz,1H),7.62(t,J＝7.7Hz,1H),7.36(dd,J＝1.9,7.2Hz,1H),7.27(s,1H),7.25–7.15(m,2H),6.94–6.84(m,2H),6.79–6.70(m,2H),5.32(s,2H),5.19(s,2H),4.39(s,2H),4.30(s,4H),4.06–3.94(m,1H),3.90(d,J＝3.2Hz,1H),3.81(dd,J＝3.2,9.5Hz,1H),3.76–3.61(m,2H),3.54(s,3H),3.31–3.09(m,2H),2.89(s,3H),2.25(s,3H),2.21(s,3H).ESI-MS理论值C 41H 49N 3O 9[M+H] +＝728.35，测得：727.86。
实施例15：合成3-((5-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)-4-甲基-2-((甲基(2-(((2S，3S，4R)-2,3,4,5-四羟基)氨基)乙基)氨基)甲基)苯氧基)甲基)苯甲腈(ZB82)
Figure PCTCN2020094013-appb-000082
将EC106(20mg，0.035mmol)、D-核糖(16mg，0.106mmol)溶于THF：MeOH(1:1)的混合溶剂中，后加入AcOH(0.05ml)，室温搅拌20min，最后加入NaBH(OAc) 3(37.5mg，0.177mmol)，室温反应过夜。反应结束后，旋干溶剂，HPLC纯化，得到目标化合物9.6mg, 1H NMR(400MHz,Methanol-d 4)δ7.89(s,1H),7.81(d,J＝7.8Hz,1H),7.76(d,J＝7.8Hz,1H),7.62(t,J＝7.8Hz,1H),7.36(d,J＝7.4Hz,1H),7.25(s,1H),7.23–7.17(m,2H),6.90(d,J＝8.0Hz,1H),6.86(s,1H),6.78–6.71(m,2H),5.30(s,2H),5.19(s,2H),4.30(s,4H),4.26–4.05(m,3H),3.79–3.66(m,2H),3.66–3.48(m,2H),3.24–3.08(m,2H),2.77(s,3H),2.26(s,3H),2.21(s,3H),2.12–1.94(m,1H),1.86(dd,J＝7.6,14.9Hz,1H),1.32(d,J＝8.4Hz,3H).ESI-MS理论值C40H47N3O8[M+H] +＝698.34，测得：698.59。
实施例16：合成3-((5-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)-4-甲基-2-((甲基(2-(((3S，4R)-3,4,5-三羟基戊基)氨基)乙基)氨基)甲基)苯氧基)甲基)苯甲腈(ZB83)
Figure PCTCN2020094013-appb-000083
将EC106(20mg，0.035mmol)、2-脱氧-D-核糖(14.2mg，0.106mmol)溶于THF：MeOH(1:1)的混合溶剂中，后加入AcOH(0.05ml)，室温搅拌20min，最后加入NaBH(OAc) 3(37.5mg，0.177mmol)，室温反应过夜。反应结束后，旋干溶剂，HPLC纯化，得到目标化合物7.3mg。 1H NMR(400MHz,Methanol-d 4)δ7.89(s,1H),7.81(d,J＝7.8Hz,1H),7.76(d,J＝7.8Hz,1H),7.62(t,J＝7.8Hz,1H),7.36(d,J＝7.4Hz,1H),7.25(s,1H),7.23–7.17(m,2H),6.90(d,J＝8.0Hz,1H),6.86(s,1H),6.78–6.71(m,2H),5.30(s,2H),5.19(s,2H),4.30(s,4H),4.26–4.05(m,3H),3.79–3.66(m,2H),3.66–3.48(m,2H),3.24–3.08(m,2H),2.77(s,3H),2.26(s,3H),2.21(s,3H),2.12–1.94(m,1H),1.86(dd,J＝7.6,14.9Hz,1H),1.63(s,1H),1.32(d,J＝8.4Hz,3H)。ESI-MS理论值C 40H 47N 3O 7[M+H] +＝682.34，测得：682.48。
实施例17：合成(2R,3R,4R,5S)-6-((2-((2,4-二氟苄基)氧基)-4-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)-5-甲基苄基)氨基)己烷-1,2,3,4,5-五醇(ZC124)
Figure PCTCN2020094013-appb-000084
步骤一:合成2-((2,4-二氟苄基)氧基)-4-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)-5-甲基苯甲醛(ZA59)
将ZA88(150mg，0.385mmol)、1-(氯甲基)-2,4-二氟苯(75mg，0.463mmol)溶于DMF中，后加入Cs 2CO 3(203mg，0.578mmol)，室温反应过夜。待反应结束后，加水淬灭，用二氯甲烷萃取三次，有机相用饱和氯化钠溶液洗，无水硫酸钠干燥后旋干溶剂，并用层析柱分离纯化，得到目标化合物113.6mg。 1H NMR(400MHz,Chloroform-d)δ10.34(s,1H),7.69(d,J＝1.0Hz,1H),7.53–7.45(m,1H),7.40(q,J＝4.1Hz,1H),7.27(d,J＝4.5Hz,2H),6.99–6.91(m,1H),6.89–6.84(m,2H),6.81(dd,J＝2.1,8.2Hz,1H),6.62(s,1H),5.22(s,2H),5.17(s,2H),4.34(s,4H),2.29(s,3H),2.22(d,J＝0.9Hz,3H)。
步骤二：合成(2R,3R,4R,5S)-6-((2-((2,4-二氟苄基)氧基)-4-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)-5-甲基苄基)氨基)己烷-1,2,3,4,5-五醇(ZC124)
将ZA59(30mg，0.058mmol)、D-萄糖胺(60mg，0.348mmol)溶于THF：MeOH(1:1) 的混合溶剂中，室温反应过夜，后加入NaBH 4(70mg，1.84mmol)，室温反应约5h。反应结束后，旋干溶剂，HPLC纯化，得到目标化合物18.6mg。 1H NMR(400MHz,Methanol-d 4)δ7.61(td,J＝6.3,8.7Hz,1H),7.38(dd,J＝1.8,7.1Hz,1H),7.27–7.14(m,3H),7.08–6.95(m,2H),6.92–6.84(m,2H),6.79–6.69(m,2H),5.27(s,2H),5.21(s,2H),4.30(s,4H),4.23–4.10(m,2H),4.05(dt,J＝4.9,6.8Hz,1H),3.83(dd,J＝1.8,4.5Hz,1H),3.77(dd,J＝3.2,10.8Hz,1H),3.73–3.60(m,3H),3.21–3.13(m,2H),2.27(s,3H),2.20(s,3H)。ESI-MS理论值:C 37H 41F 2NO 9[M+H] +＝682.27，测得：683.07。
实施例18：合成(2R,3R,4R,5S)-6-((4-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)-5-甲基-2-(吡嗪-2-基甲氧基)苄基)氨基)己烷-1,2,3,4,5-五醇(ZC125)
Figure PCTCN2020094013-appb-000085
步骤一:合成4-(3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)-5-甲基-2-(吡嗪-2-基甲氧基)苯甲醛(ZA65)
将ZA88(156mg，0.4mmol)、2-(氯甲基)吡嗪(285mg，1.875mmol)溶于DMF中，后加入Cs 2CO 3(195.5mg，0.6mmol)室温反应过夜。待反应结束后，加水淬灭，用二氯甲烷萃取三次，有机相用饱和氯化钠溶液洗，无水硫酸钠干燥后旋干溶剂，并用层析柱分离纯化，得到目标化合物131mg。 1H NMR(400MHz,Chloroform-d)δ9.78(s,1H),7.74–7.70(m,2H),7.66(d,J＝1.0Hz,1H),7.42–7.38(m,1H),7.35(d,J＝8.1Hz,2H),7.28(s,1H),6.95(d,J＝8.2Hz,1H),6.88–6.84(m,2H),6.81(dd,J＝2.1,8.2Hz,1H),5.09(s,2H),4.34(s,4H),2.28(s,3H),2.27(d,J＝0.8Hz,3H),1.59(s,2H)。
步骤二：合成(2R,3R,4R,5S)-6-((4-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)-5-甲基-2-(吡嗪-2-基甲氧基)苄基)氨基)己烷-1,2,3,4,5-五醇(ZC125)
将ZA65(30mg，0.058mmol)、D-萄糖胺(60mg，0.348mmol)溶于THF：MeOH(1:1)的混合溶剂中，室温反应过夜，后加入NaBH 4(70mg，1.16mmol)，室温反应约5h。反应结束后，旋干溶剂，HPLC纯化，得到目标化合物20.7mg。 1H NMR(400MHz,Methanol-d 4)δ7.82–7.75(m,2H),7.49(d,J＝8.0Hz,2H),7.37(s,1H),7.29(dd,J＝1.8,7.4Hz,1H),7.26–7.16(m,2H),6.90(d,J＝8.1Hz,1H),6.76(q,J＝2.0Hz,2H),6.52(s,1H),4.30(s,4H),4.14(s,2H),4.10(dt,J＝4.8,7.1Hz,1H),3.86(dd,J＝1.5,4.6Hz,1H),3.79(dd,J＝3.1,10.3Hz,1H),3.73–3.64(m,3H),3.24–3.18(m,2H),2.46(s,3H),2.25(s,3H),2.20(s,3H)。ESI-MS理论值:C35H41N3O9[M+H] +＝648.28，测得：647.99。
实施例19：合成(2R,3R,4R,5S)-6-((2-((3-氯-4-氟苄基)氧基)-4-((3-(2,3-二氢苯并[b][1,4]二氧杂环己-6-基)-2-甲基苄基)氧基)-5-甲基苄基)氨基)己烷-1,2,3,4,5-五醇(ZC127)
Figure PCTCN2020094013-appb-000086
步骤一:2-((3-氯-4-氟苄基)氧基)-4-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)-5-甲基苯甲醛(ZA42)
将ZA88(100mg，0.26mmol)、2-氯-4-(氯甲基)-1-氟苯(55.1mg，0.31mmol)溶于DMF中，后加入Cs 2CO 3(135.6mg，0.38mmol)室温反应过夜。待反应结束后，加水淬灭，用二氯甲烷萃取三次，有机相用饱和氯化钠溶液洗，无水硫酸钠干燥后旋干溶剂，并用层析柱分离纯化，得到目标化合物86mg。 1H NMR(400MHz,Chloroform-d)δ10.34(s,1H),7.68(d,J＝0.9Hz,1H),7.50(dd,J＝2.2,6.9Hz,1H),7.37(t,J＝4.5Hz,1H),7.33–7.29(m,1H),7.25(d,J＝4.5Hz,2H),7.17(t,J＝8.6Hz,1H),6.92(d,J＝8.2Hz,1H),6.83(d,J＝2.0Hz,1H),6.78(dd,J＝2.1,8.2Hz,1H),6.53(s,1H),5.12(d,J＝2.5Hz,4H),4.32(s,4H),2.26(s,3H),2.21(d,J＝0.8Hz,3H)。
步骤二：合成(2R,3R,4R,5S)-6-((2-((3-氯-4-氟苄基)氧基)-4-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)-5-甲基苄基)氨基)己烷-1,2,3,4,5-五醇(ZC127)
将ZA42(40mg，0.058mmol)、D-萄糖胺(60mg，0.348mmol)溶于THF：MeOH(1:1)的混合溶剂中室温反应过夜，后加入NaBH 4(70mg，1.16mmol)，室温反应约5h。反应结束后，旋干溶剂，HPLC纯化，得到目标化合物26mg。 1H NMR(400MHz,Methanol-d 4)δ7.67(dd,J＝2.2,7.1Hz,1H),7.47(ddd,J＝2.2,4.6,8.5Hz,1H),7.34(dd,J＝2.0,7.1Hz,1H),7.28(t,J＝8.8Hz,1H),7.24–7.15(m,3H),6.90(d,J＝8.1Hz,1H),6.82(s,1H),6.78–6.71(m,2H),5.22(s,2H),5.17(s,2H),4.30(s,4H),4.19(q,J＝13.1Hz,2H),4.07(q,J＝5.5Hz,1H),3.85(dd,J＝1.7,4.5Hz,1H),3.77(dd,J＝3.2,10.4Hz,1H),3.73–3.61(m,3H),3.18(d,J＝5.9Hz,2H),2.26(s,3H),2.20(s,3H)。ESI-MS理论值Chemical Formula:C 37H 41ClFNO 9[M+H] +＝698.25，测得：698.70。
实施例20：合成((2R,3R,4R,5S)-6-((4-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)-5-甲基-2-(吡啶-3-基甲氧基)苄基)氨基)己烷-1,2,3,4,5-五醇(ZC133)
Figure PCTCN2020094013-appb-000087
步骤一:4-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)-5-甲基-2-(吡啶-3-基甲氧基)苯甲醛(ZA84)
将ZA88(312mg，0.8mmol)、3-(氯甲基)吡啶(182mg，1.6mmol)溶于DMF中，后加入Cs 2CO 3(391mg，1.2mmol)室温反应过夜。待反应结束后，加水淬灭，用二氯甲烷萃取三次，有机相用饱和氯化钠溶液洗，无水硫酸钠干燥后，旋干溶剂，并用层析柱分离纯化，得到目标化合物213mg。 1H NMR(400MHz,Chloroform-d)δ9.78(s,1H),7.79–7.74(m,1H),7.73(s,1H),7.71(d,J＝1.8Hz,1H),7.69–7.65(m,1H),7.42–7.37(m,2H),7.35(d,J＝8.1Hz,2H),6.95(d,J＝8.2Hz,1H),6.88–6.83(m,2H),6.81(dd,J＝2.1,8.2Hz,1H),5.09(s,2H),4.34(s,4H),2.50(d,J＝4.3Hz,2H),2.28(s,3H),2.27(d,J＝0.9Hz,3H)。
步骤二：合成((2R,3R,4R,5S)-6-((4-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)-5-甲基-2-(吡啶-3-基甲氧基)苄基)氨基)己烷-1,2,3,4,5-五醇(ZC133)
将ZA84(30mg，0.058mmol)、D-萄糖胺(60mg，0.348mmol)溶于THF：MeOH(1:1)的混合溶剂中室温反应过夜，后加入NaBH 4(70mg，1.84mmol)，室温反应约5h。反应结束后，旋干溶剂，HPLC纯化，得到目标化合物8.3mg。 1H NMR(400MHz,Methanol-d 4)δ7.82–7.74(m,2H),7.49(d,J＝8.1Hz,2H),7.37(s,1H),7.29(dd,J＝1.8,7.4Hz,1H),7.23(t,J＝7.5Hz,1H),7.19(dd,J＝1.8,7.5Hz,1H),6.90(d,J＝8.1Hz,1H),6.78–6.72(m,2H),6.52(d,J＝2.8Hz,1H),4.14(d,J＝4.1Hz,2H),4.11–4.05(m,1H),4.00(s,2H),3.90–3.83(m,1H),3.82–3.76(m,1H),3.75–3.62(m,3H),3.22(q,J＝3.0,3.7Hz,2H),2.46(s,3H),2.25(s,3H),2.19(s,3H)。Chemical Formula:C 36H 42N 2O 9ESI-MS理论值[M+H] +＝647.29，测得：648.09。
实施例21：合成2-((2-((2,4-二氟苄基)氧基)-4-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)-5-甲基苄基)(甲基)氨基)乙烷-1-磺酸(ZD02-N)
Figure PCTCN2020094013-appb-000088
步骤一：合成异丙基2-((2-((2,4-二氟苄基)氧基)-4-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧)-5-甲基苄基)(甲基)氨基)乙烷-1-磺酸盐(ZD02)
将ZA59(40mg)、2-(甲基氨基)乙烷-1-磺酸异丙酯(110mg)溶于THF中，先向反 应体系中加入AcOH(0.05ml)，然后加入NaBH(OAc) 3(70mg，0.3mmol)室温反应过夜。反应结束后旋干溶剂，直接用于下一步。
步骤二：合成2-((2-((2,4-二氟苄基)氧基)-4-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)-5-甲基苄基)(甲基)氨基)乙烷-1-磺酸(ZD02-N)
将步骤一中得到的ZD02粗品溶于MeOH中，然后加入0.1ml浓盐酸，60℃加热反应2h。反应结束后，旋干溶剂，HPLC纯化，得到目标化合物9mg。 1H NMR(400MHz,Methanol-d 4)δ7.65(q,J＝7.9Hz,1H),7.39(dd,J＝7.3,12.7Hz,2H),7.22(d,J＝2.3Hz,1H),7.21–7.18(m,1H),7.01(t,J＝8.8Hz,2H),6.90(t,J＝4.0Hz,2H),6.80–6.73(m,2H),5.30(s,2H),5.21(s,2H),4.67(s,1H),4.40(d,J＝12.9Hz,1H),4.30(s,4H),4.22(d,J＝13.0Hz,1H),3.65(dt,J＝7.1,13.8Hz,1H),3.43(dt,J＝6.0,13.0Hz,1H),3.24(dt,J＝7.1,14.2Hz,1H),3.19–3.09(m,1H),2.83(s,3H),2.27(s,3H),2.20(s,3H)。Chemical Formula:C 34H 35F 2NO 7S ESI-MS理论值[M+H] +＝640.21，测得：640.65。
实施例22：合成5-((5-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)-2-甲酰基-4-甲基苯氧基)甲基)烟腈(ZD08)
Figure PCTCN2020094013-appb-000089
将ZA88(609mg，1.56mmol)、5-(氯甲基)烟腈(285mg，1.875mmol)溶于DMF中，后加入Cs 2CO 3(826mg,2.34mmol)室温反应过夜。待反应结束后，加水淬灭，用二氯甲烷萃取三次，有机相用饱和氯化钠溶液洗、无水硫酸钠干燥后旋干溶剂，并用层析柱分离纯化，得到目标化合物602mg。 1H NMR(400MHz,Chloroform-d)δ10.33(s,1H),8.92(dd,J＝2.1,6.2Hz,2H),8.12(t,J＝2.1Hz,1H),7.71(d,J＝0.9Hz,1H),7.39(d,J＝4.5Hz,1H),7.27(s,1H),6.94(d,J＝8.2Hz,1H),6.85(d,J＝2.1Hz,1H),6.81(s,0H),6.56(s,1H),5.25(s,2H),5.18(s,2H),4.33(s,4H),2.29(s,3H),2.24(d,J＝0.8Hz,3H)。
实施例23：合成5-((5-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)-4-甲基-2-((((2S，3R，4R，5R)-2,3,4,5,6-五羟基己基)氨基)甲基)苯氧基)甲基)烟腈(ZD13)
Figure PCTCN2020094013-appb-000090
将ZD08(25mg，0.05mmol)、D-萄糖胺(27mg，0.15mmol)溶于THF：MeOH(4ml：4ml)的混合溶剂中，先向反应体系中加入AcOH(0.05ml)后，加入NaBH(OAc) 3(52.3mg，0.25mmol)，室温反应过夜。反应结束后，旋干溶剂，HPLC纯化，得到目标化合物:7.6mg。 1H NMR(400MHz,Methanol-d 4)δ8.97(d,J＝2.1Hz,1H),8.92(d,J＝2.0Hz,1H),8.39(t,J＝ 2.1Hz,1H),7.41–7.34(m,1H),7.25–7.15(m,3H),6.93–6.86(m,2H),6.79–6.71(m,2H),5.36(s,2H),5.22(s,2H),4.30(s,4H),4.28–4.14(m,2H),4.06(q,J＝5.4Hz,1H),3.85(dd,J＝1.5,4.6Hz,1H),3.76(dd,J＝3.1,10.3Hz,1H),3.70–3.60(m,3H),3.23–3.16(m,2H),2.27(s,3H),2.21(s,3H)。Chemical Formula:C 37H 41N 3O 9ESI-MS理论值:[M+H] +＝671.28，测得：671.62。
实施例24：合成(2R,3R,4R,5S)-6-((5-氯-4-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基基)-2-(吡嗪-2-基甲氧基)苄基)氨基)己烷-1,2,3,4,5-五醇(ZC132)
Figure PCTCN2020094013-appb-000091
步骤一:5-氯-4-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)-2-(吡嗪-2-基甲氧基)苯甲醛(ZA72)
将ZA52(250mg，0.61mmol)、2-(氯甲基)吡嗪(134mg，1.22mmol)溶于DMF中，然后加入Cs 2CO 3室温反应过夜。待反应结束后，加水淬灭，用二氯甲烷萃取三次，有机相用饱和氯化钠溶液洗，无水硫酸钠干燥后，旋干溶剂，并用层析柱分离纯化，得到目标化合物290mg。 1H NMR(400MHz,Chloroform-d)δ9.74(s,1H),7.88(s,1H),7.82–7.74(m,1H),7.72–7.67(m,2H),7.46–7.38(m,2H),7.39–7.33(m,3H),7.30(d,J＝2.0Hz,1H),6.99(s,1H),6.94(d,J＝8.2Hz,1H),6.86(d,J＝2.1Hz,1H),6.81(dd,J＝2.1,8.2Hz,1H),5.19(s,2H),4.34(s,4H),2.50(d,J＝3.9Hz,2H),2.47(s,3H),2.30(s,3H)。
步骤二：合成(2R,3R,4R,5S)-6-((5-氯-4-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基基)-2-(吡嗪-2-基甲氧基)苄基)氨基)己烷-1,2,3,4,5-五醇(ZC132)
将ZA72(30mg，0.058mmol)、D-萄糖胺(65mg，0.348mmol)溶于THF：MeOH(1:1)的混合溶剂中室温反应过夜，后加入NaBH 4(70mg，1.16mmol)，室温反应约5h。反应结束后，旋干溶剂，HPLC纯化，得到目标化合物11.3mg。 1H NMR(400MHz,Methanol-d 4)δ7.79(d,J＝8.3Hz,2H),7.68(s,1H),7.50(d,J＝8.1Hz,2H),7.33(dd,J＝1.7,7.3Hz,1H),7.28–7.17(m,2H),6.90(d,J＝8.1Hz,1H),6.80–6.69(m,3H),5.03(s,2H),4.30(s,4H),4.20–4.05(m,3H),3.86(dd,J＝1.6,4.6Hz,1H),3.79(dd,J＝3.0,10.3Hz,1H),3.76–3.62(m,3H),3.28–3.17(m,2H),2.47(s,3H),2.22(s,3H)。ESI-MS理论值:C 34H 38ClN 3O 9[M+H] +＝668.23，测得：668.51。
实施例25：合成(2R,3R,4R,5S)-6-((5-氯-4-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基基)-2-(吡啶-3-基甲氧基)苄基)氨基)己烷-1,2,3,4,5-五醇(ZC134)
Figure PCTCN2020094013-appb-000092
步骤一:合成5-氯-4-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)-2-(吡啶-3-基甲氧基)苯甲醛(ZA85)
将ZA52(205mg,0.5mmol)、3-(氯甲基)吡啶(109mg，1.0mmol)溶于DMF中，后加入Cs 2CO 3(244mg,0.75mmol)室温反应过夜。待反应结束后，加水淬灭，用二氯甲烷萃取三次，有机相用饱和氯化钠溶液洗，无水硫酸钠干燥后，旋干溶剂，并用层析柱分离纯化，得到目标化合物180mg。 1H NMR(400MHz,Chloroform-d)：δ9.74(s,1H),7.88(s,1H),7.72–7.67(m,2H),7.46–7.41(m,1H),7.35(d,J＝8.1Hz,2H),7.30(d,J＝2.0Hz,1H),7.00(s,1H),6.94(d,J＝8.2Hz,1H),6.86(d,J＝2.1Hz,1H),6.81(dd,J＝2.1,8.3Hz,1H),5.19(s,2H),4.34(s,4H),3.53(s,2H),2.47(s,3H),2.30(s,3H)。
步骤二：合成(2R,3R,4R,5S)-6-((5-氯-4-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基基)-2-(吡啶-3-基甲氧基)苄基)氨基)己烷-1,2,3,4,5-五醇(ZC134)
将ZA85(30mg，0.058mmol)、D-萄糖胺(60mg，0.348mmol)溶于THF：MeOH(1:1)的混合溶剂中，室温反应过夜，后加入NaBH 4(70mg，1.16mmol)，室温反应约5h。反应结束后，旋干溶剂，HPLC纯化，得到目标化合物7.9mg。 1H NMR(400MHz,Methanol-d 4)δ7.82–7.76(m,2H),7.68(s,1H),7.50(d,J＝8.1Hz,2H),7.33(dd,J＝1.8,7.3Hz,1H),7.29–7.18(m,2H),6.90(d,J＝8.1Hz,1H),6.80–6.70(m,3H),5.02(s,2H),4.29(s,5H),4.18–4.04(m,3H),3.86(dd,J＝1.5,4.6Hz,1H),3.80(dd,J＝3.0,10.4Hz,1H),3.74–3.58(m,3H),3.29–3.16(m,2H),2.47(s,3H),2.22(s,3H).ESI-MS理论值:C 35H 39ClN 2O 9[M+H] +＝667.23，测得：667.62。
实施例26：合成5-((4-氯-5-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)-2-((((2S，3R，4R，5R)-2,3,4,5,6-五羟基己基)氨基)甲基)苯氧基)甲基)烟腈(ZD03)
Figure PCTCN2020094013-appb-000093
将ZD07(25mg，0.048mmol)、D-萄糖胺(26mg，0.143mmol)溶于THF：MeOH(1:1) 的混合溶剂中，先向反应体系中加入AcOH(0.05ml)后加入NaBH(OAc) 3(50.5mg，0.24mmol)，室温反应过夜。反应结束后，旋干溶剂，HPLC纯化，得到目标化合物6.5mg。 1H NMR(400MHz,Methanol-d 4)δ8.99(d,J＝2.1Hz,1H),8.94(d,J＝2.0Hz,1H),8.40(t,J＝2.1Hz,1H),7.53(s,1H),7.41(dd,J＝2.1,7.0Hz,1H),7.27–7.17(m,2H),7.05(s,1H),6.90(d,J＝8.0Hz,1H),6.80–6.71(m,2H),5.39(s,2H),5.31(s,2H),4.30(s,4H),4.29–4.18(m,2H),4.09–4.03(m,1H),3.85(dd,J＝1.4,4.6Hz,1H),3.76(dd,J＝3.0,10.3Hz,1H),3.71–3.59(m,3H),3.20(d,J＝5.8Hz,2H),2.29(s,3H).ESI-MS理论值:C 36H 38ClN 3O 9[M+H] +＝692.23，测得：692.75。比旋光
Figure PCTCN2020094013-appb-000094
浓度为1.0，溶剂为CHCl 3。
实施例27：合成3-((4-氯-5-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)-2-((((2S，3R，4R，5R)-2,3,4,5,6-五羟基己基)氨基)甲基)苯氧基)甲基)苯甲腈(ZD05)
Figure PCTCN2020094013-appb-000095
步骤一：合成3-((4-氯-5-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)-2-甲酰基苯氧基)甲基)苯甲腈(ZA50)
将ZA52(85mg，0.21mmol)、3-(氯甲基)苯甲腈(49mg，0.25mmol)溶于DMF中，后加入Cs 2CO 3(109.7mg，0.31mmol)室温反应过夜。待反应结束后，加水淬灭，用二氯甲烷萃取三次，有机相用饱和氯化钠溶液洗，无水硫酸钠干燥后，旋干溶剂，并用层析柱分离纯化，得到目标化合物107.2mg。 1H NMR(400MHz,Chloroform-d)δ10.34(s,1H),7.94(s,1H),7.75(s,1H),7.70(dd,J＝1.6,8.0Hz,3H),7.60–7.51(m,1H),7.40(d,J＝3.9Hz,1H),7.27(d,J＝1.7Hz,1H),6.94(d,J＝8.3Hz,1H),6.84(d,J＝2.1Hz,1H),6.79(dd,J＝2.1,8.2Hz,1H),6.63(s,1H),5.22(s,2H),5.21(s,2H),4.34(s,4H),2.30(s,3H)。
步骤二：合成3-((4-氯-5-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)-2-((((2S，3R，4R，5R)-2,3,4,5,6-五羟基己基)氨基)甲基)苯氧基)甲基)苯甲腈(ZD05)
将ZA50(35mg，0.067mmol)、D-萄糖胺(36.2mg，0.200mmol)溶于THF：MeOH(3ml:3ml)的混合溶剂中，室温反应过夜，然后加入NaBH 4(50.6mg，1.33mmol)室温反应5h。反应结束后，旋干溶剂，HPLC纯化，得到目标产物22mg。 1H NMR(400MHz,Methanol-d 4)δ7.93(d,J＝1.7Hz,1H),7.84(dt,J＝1.5,7.9Hz,1H),7.75(dt,J＝1.4,7.8Hz,1H),7.62(t,J＝7.8Hz,1H),7.50(s,1H),7.38(dd,J＝2.3,6.8Hz,1H),7.25–7.16(m,2H),6.99 (s,1H),6.90(d,J＝8.1Hz,1H),6.78–6.71(m,2H),5.34(s,2H),5.26(s,2H),4.30(s,4H),4.28–4.16(m,2H),4.14–4.03(m,1H),3.86(dd,J＝1.5,4.6Hz,1H),3.77(dd,J＝3.0,10.5Hz,1H),3.73–3.60(m,3H),3.21(d,J＝5.9Hz,2H),2.27(s,3H)。ESI-MS理论值:C 37H 39ClN 2O 9[M+H] +＝691.23，测得：691.52。
实施例28：合成3-((5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)苄基)(甲基)氨基)丙烷-1-磺酸(ZD39)
Figure PCTCN2020094013-appb-000096
步骤一：合成5-((4-氯-5-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)-2-((甲基氨基)甲基)苯氧基)甲基)烟腈(ZD36)
将ZD07(25mg，0.048mmol)溶于MeOH(4ml)：THF(4ml)的混合溶液中，加入甲胺的甲醇溶液(47mg，0.456mmol)，然后加入AcOH(0.05ml)，最后加入NaBH(OAc) 3(161mg，0.76mmol)，室温反应过夜。反应结束后，旋干溶剂，HPLC纯化，得到目标化合物72.8mg。 1H NMR(400MHz,Methanol-d 4)δ8.96(d,J＝2.1Hz,1H),8.92(d,J＝2.0Hz,1H),8.36(t,J＝2.1Hz,1H),7.52(s,1H),7.39(dd,J＝2.1,7.0Hz,1H),7.25–7.12(m,2H),7.03(s,1H),6.88(d,J＝8.1Hz,1H),6.77–6.69(m,2H),5.38(s,2H),5.28(s,2H),4.28(s,4H),4.20(s,2H),2.70(s,3H),2.27(s,3H)。
步骤二：3-((5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)苄基)(甲基)氨基)丙烷-1-磺酸(ZD39)
将ZD36(20mg，0.037mmol)、1,3-丙烷磺内酯(5mg，0.041mmol)溶于干燥的DCM(6ml)中，然后加入Et 3N，室温反应过夜。反应结束后，旋干溶剂，HPLC纯化，得到目标化合物8mg。 1H NMR(400MHz,DMSO-d 6)δ9.74(s,1H),9.05(dd,J＝2.0,4.3Hz,2H),8.54(d,J＝2.2Hz,1H),7.63(s,1H),7.46(d,J＝7.4Hz,1H),7.32–7.16(m,3H),6.94(d,J＝8.1Hz,1H),6.84–6.70(m,2H),5.40(d,J＝2.5Hz,2H),5.31(s,2H),4.33(d,J＝15.9Hz,2H),4.29(s,4H),4.16(dd,J＝6.2,13.1Hz,1H),3.26–3.10(m,1H),2.67(d,J＝4.6Hz,3H),2.65–2.54(m,2H),2.25(s,3H),2.01(d,J＝8.4Hz,2H)。ESI-MS理论值:C 34H 34ClN 3O 7S[M+H] +＝664.18，测得：664.86。
实施例29：合成3-((4-氯-5-((4'-羟基-2-甲基-[1,1'-联苯]-3-基)甲氧基)-2-((((2S，3R，4R，5R)-2,3,4,5,6-五羟基己基)氨基)甲基)苯氧基)甲基)苯甲腈(ZC136)
Figure PCTCN2020094013-appb-000097
步骤一：合成(4'-((4-甲氧基苄基)氧基)-2-甲基-[1,1'-联苯]-3-基)甲醇(ZA140)
将2-(4-((4-甲氧基苄基)氧基)苯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷(760mg，2.23mmol)、(3-溴-2-甲基苯基)甲醇(180mg，0.89mmol)溶于DME和2M的Na 2CO 3溶液中，除氧气，充氮气后，加入Pd(dppf)Cl 2-CH 2Cl 2(37mg)后，再次除氧气充氮气，然后95℃加热，反应过夜。反应结束后，加水淬灭，然后用乙酸乙酯萃取，有机相用饱和食盐水洗，无水硫酸钠干燥后旋干，最后用层析柱分离后，得到目标化合物411.8mg。 1H NMR(400MHz,Chloroform-d)δ7.43(d,J＝2.1Hz,1H),7.42–7.37(m,2H),7.27–7.24(m,2H),7.24–7.19(m,2H),7.05(d,J＝2.2Hz,1H),7.04(d,J＝2.0Hz,1H),6.97(d,J＝2.1Hz,1H),6.96(d,J＝2.1Hz,1H),5.06(s,2H),4.79(s,2H),3.86(s,3H),2.28(s,3H)。
步骤二：合成5-氯-2-羟基-4-((4'-((4-甲氧基苄基)氧基)-2-甲基-[1,1'-联苯]-3-基)甲氧基)苯甲醛(ZA142)
将ZA140(400mg，1.2mmol)、5-氯-2，4-二羟基苯甲醛(SM1,206mg,1.2mmol)加入到反应瓶中，后加入PPh 3(345mg，1.32mmol)，并用THF溶解，冰水浴降温后，滴加DIAD(242mg，1.2mmol)，后缓慢升至室温，搅拌过夜。待反应结束后，加入饱和碳酸氢钠溶液淬灭，并用乙酸乙酯萃取，有机相用饱和食盐水洗，无水硫酸钠干燥后旋干，最后用层析柱分离后得到目标化合物118.4mg。 1H NMR(400MHz,Chloroform-d)δ11.46(s,1H),7.57(s,1H),7.54(s,1H),7.47(dd,J＝2.7,6.3Hz,1H),7.45–7.39(m,2H),7.28–7.24(m,2H),7.09–7.03(m,2H),6.99–6.94(m,2H),6.65(d,J＝8.5Hz,2H),5.23(s,2H),5.06(s,2H),3.86(s,3H),2.29(s,3H).
步骤三:合成3-((4-氯-2-甲酰基-5-((4'-((4-甲氧基苄基)氧基)-2-甲基-[1,1'-联苯]-3-基)甲氧基)苯氧基)甲基)苯甲腈(ZA144)
将ZA142(118.4mg，0.24mmol)、3-(溴甲基)苄腈(57mg，0.29mmol)溶于DMF中，后加入Cs 2CO 3(118.4mg，0.36mmol)，室温反应过夜。待反应结束后，加水淬灭，用 二氯甲烷萃取三次，有机相用饱和氯化钠溶液洗，无水硫酸钠干燥后，旋干溶剂，并用层析柱分离纯化，得到目标化合物205.3mg。 1H NMR(400MHz,Chloroform-d)δ10.35(d,J＝3.9Hz,1H),7.95(d,J＝9.2Hz,1H),7.75(s,1H),7.70(d,J＝9.1Hz,4H),7.62–7.52(m,2H),7.47–7.32(m,3H),7.30(s,1H),7.07–6.87(m,4H),6.64(d,J＝2.5Hz,1H),5.22(d,J＝2.7Hz,4H),5.20(s,1H),5.04(s,1H),3.84(s,3H),2.27(s,3H)。
步骤四：合成(2S，3R，4R，5R)-6-((5-氯-4-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基基)-2-(吡啶-3-基甲氧基)苄基)氨基)己烷-1,2,3,4,5-五醇(ZC126)
将ZA144(40mg，0.058mmol)、D-萄糖胺(60mg，0.348mmol)溶于THF：MeOH(1:1)的混合溶剂中，室温反应过夜，后加入NaBH 4(70mg，1.16mmol)，室温反应约5h。反应结束后，旋干溶剂，HPLC纯化，得到目标化合物20mg。 1H NMR(400MHz,Methanol-d 4)δ7.92(s,1H),7.84(d,J＝7.9Hz,1H),7.74(dt,J＝1.4,7.8Hz,1H),7.61(t,J＝7.8Hz,1H),7.50(d,J＝2.5Hz,1H),7.44–7.31(m,3H),7.28–7.15(m,2H),7.03–6.96(m,2H),6.97–6.91(m,1H),6.90–6.83(m,2H),5.34(s,2H),5.26(s,2H),5.05(s,2H),4.31–4.17(m,2H),4.08(q,J＝5.5Hz,1H),3.86(dd,J＝1.4,4.5Hz,1H),3.80(s,3H),3.79–3.73(m,1H),3.71–3.60(m,3H),2.23(s,3H)。
步骤五：合成3-((4-氯-5-((4'-羟基-2-甲基-[1,1'-联苯]-3-基)甲氧基)-2-((((2S，3R，4R，5R)-2,3,4,5,6-五羟基己基)氨基)甲基)苯氧基)甲基)苯甲腈(ZC136)
将ZC126(20mg)溶于DCM：TFA(3ml：1ml)的混合溶剂中，室温反应1h。反应结束后，旋干溶剂，然后用HPLC纯化，得到目标化合物12mg。 1H NMR(400MHz,Methanol-d 4)δ7.93(d,J＝1.6Hz,1H),7.84(d,J＝7.9Hz,1H),7.75(dt,J＝1.4,7.7Hz,1H),7.62(t,J＝7.8Hz,1H),7.51(s,1H),7.40(dd,J＝2.3,6.8Hz,1H),7.29–7.17(m,3H),7.00(s,1H),6.80(ddd,J＝1.0,2.5,8.1Hz,1H),6.77–6.70(m,2H),5.35(s,2H),5.27(s,2H),4.34–4.14(m,2H),4.08(q,J＝5.5Hz,1H),3.86(dd,J＝1.5,4.5Hz,1H),3.77(dd,J＝2.9,10.5Hz,1H),3.73–3.56(m,3H),3.21(d,J＝5.9Hz,2H),2.27(s,3H)。ESI-MS理论值Chemical Formula:C 35H 37ClN 2O 8[M+H] +＝649.22，测得：648.67。
实施例30：合成3-((4-氯-5-((3'-羟基-2-甲基-[1,1'-联苯]-3-基)甲氧基)-2-((((2S，3R，4R，5R)-2,3,4,5,6-五羟基己基)氨基)甲基)苯氧基)甲基)苯甲腈(ZD24)
Figure PCTCN2020094013-appb-000098
步骤一：合成(3'-((4-甲氧基苄基)氧基)-2-甲基-[1,1'-联苯]-3-基)甲醇(ZA141)
将2-(4-((3-甲氧基苄基)氧基)苯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷(1.7g，5.0mmol)、(3-溴-2-甲基苯基)甲醇(402mg，2.0mmol)溶于DME和2M的Na 2CO 3溶液中，除氧气，充氮气后，加入Pd(dppf)Cl 2-CH 2Cl 2(60mg)后，再次除氧气充氮气，后95℃加热反应过夜。反应结束后，加水淬灭，然后用乙酸乙酯萃取，有机相用饱和食盐水洗，无水硫酸钠干燥后旋干，最后用层析柱分离后，得到目标化合物842.4mg。
步骤二：合成5-氯-2-羟基-4-((3'-((4-甲氧基苄基)氧基)-2-甲基-[1,1'-联苯]-3-基)甲氧基)苯甲醛(ZA143-2)
将ZA141(334.4mg，1.0mmol)、5-氯-2，4-二羟基苯甲醛(SM1,172mg,1.0mmol)加入到反应瓶中，后加入PPh 3(288mg，1.1mmol)，并用THF溶解，冰水浴降温后，滴加DIAD(202mg，1.0mmol)，后缓慢升至室温，搅拌过夜。待反应结束后，加入饱和碳酸氢钠溶液淬灭，并用乙酸乙酯萃取，有机相用饱和食盐水洗，无水硫酸钠干燥后，旋干溶剂，最后用层析柱分离后，得到目标化合物170mg。 1H NMR(400MHz,Chloroform-d)δ11.46(s,1H),7.58(s,1H),7.52–7.47(m,1H),7.42–7.37(m,3H),7.35(d,J＝7.9Hz,1H),7.00(d,J＝10.2Hz,1H),6.97–6.93(m,4H),6.92(s,1H),6.66(s,1H),6.19(s,5H),5.23(s,2H),5.05(s,2H),3.84(s,3H),2.26(s,3H).
步骤三:合成3-(4-氯-2-甲酰基-5-((3'-((4-甲氧基苄基)氧基)-2-甲基-[1,1'-联苯]-3-基)甲氧基)苯氧基)甲基)苯甲腈(ZA145)
将5-氯-2-羟基-4-((3'-((4-甲氧基苄基)氧基)-2-甲基-[1,1'-联苯]-3-基)甲氧基)苯甲醛(170mg，0.35mmol)、3-(溴甲基)苄腈(82mg，0.42mmol)溶于DMF(5ml)中，后加入Cs 2CO 3(170mg，0.52mmol)室温反应过夜。待反应结束后，加水淬灭，用二氯甲烷萃取三次，有机相用饱和氯化钠溶液洗，无水硫酸钠干燥后，旋干溶剂，并用层析柱分离纯化，得到目标化合物173mg。 1H NMR(400MHz,Chloroform-d)δ10.34(s,1H),7.94(s,1H),7.75(s,2H),7.70(d,J＝8.2Hz,3H),7.58(d,J＝7.7Hz,1H),7.42(d,J＝8.1Hz,3H),7.30(s,1H),7.25(d,J＝8.6Hz,2H),7.06(d,J＝8.6Hz,2H),6.97(d,J＝8.6Hz,2H),6.64(s,1H),5.23(s,2H),5.22(s,2H),5.06(s,2H),3.86(s,3H),2.30(s,3H)。
步骤四：3-((4-氯-5-((3'-((4-甲氧基苄基)氧基)-2-甲基-[1,1'-联苯]-3-基)甲氧基)-2-((((2S，3R，4R，5R)-2,3,4,5,6-五羟基己基)氨基)甲基)苯氧基)甲基)苯甲腈(ZC131)
将ZA145(50mg，0.058mmol)、D-萄糖胺(80mg，0.348mmol)溶于THF：MeOH(1:1)的混合溶剂中，室温反应过夜，然后加入NaBH 4(70mg，1.16mmol)，室温反应约5h。反应结束后，旋干溶剂，HPLC纯化，得到目标化合物21.6mg，直接用于下一步。
步骤五：合成3-((4-氯-5-((3'-羟基-2-甲基-[1,1'-联苯]-3-基)甲氧基)-2-((((2S，3R，4R，5R)-2,3,4,5,6-五羟基己基)氨基)甲基)苯氧基)甲基)苯甲腈(ZD24)
将ZC131(21.6mg)溶于DCM：TFA(3ml：1ml)的混合溶剂中，室温反应1h。反应结束后，旋干溶剂，然后用HPLC纯化，得到目标化合物8.2mg。 1H NMR(400MHz,Methanol-d 4)δ7.93(d,J＝1.8Hz,1H),7.84(d,J＝7.8Hz,1H),7.79–7.72(m,1H),7.62(t,J＝7.8Hz,1H),7.50(s,1H),7.36(dd,J＝3.4,5.7Hz,1H),7.23–7.17(m,2H),7.15–7.09(m,2H),6.99(s,1H),6.89–6.83(m,2H),5.34(s,2H),5.26(s,2H),4.31–4.14(m,2H),4.07(q,J＝5.6Hz,1H),3.86(dd,J＝1.4,4.5Hz,1H),3.76(dd,J＝2.9,10.4Hz,1H),3.73–3.60(m,3H),3.21(d,J＝5.9Hz,2H),2.27(s,3H)。ESI-MS理论值:C 35H 37ClN 2O 8[M+H] +＝649.22，测得：649.75。
实施例31：合成(2R，3R，4R，5S)-6-(((2-甲氧基-6-((2-甲基-[1,1'-联苯]-3-基)甲氧基)吡啶-3-基)甲基)氨基)己烷-1,2,3,4,5-五醇(ED58)
Figure PCTCN2020094013-appb-000099
步骤1：合成2-甲氧基-6–((2-甲基-[1,1'-联苯]-3-基)甲氧基)3-吡啶甲醛(ED22)
EC18(2.6mmol,514mg),2-甲氧基-6-氯吡啶-3-甲醛(2.0mmol,344mg),tBuXphos(0.4mmol,170mg),Pd(OAc) 2(0.2mmol,45mg)和Cs 2CO 3(4.0mmol,1.30g)称入瓶中，加入甲苯(35mL)，反应体系除去氧气，充氮气，在80℃加热12小时。冷却直接过柱纯化，得目标化合物EC22(270mg)。 1H NMR(400MHz,CDCl 3):10.24(d,J＝0.65Hz,1H),8.09(d,J＝8.44Hz,1H),7.50-7.23(m,8H),6.48(dd,J＝8.44,0.65Hz,1H),5.54(s,2H),4.11(s,3H),2.30(s,3H).
步骤2：合成(2R，3R，4R，5S)-6-(((2-甲氧基-6-((2-甲基-[1,1'-联苯]-3-基)甲氧基)吡啶-3-基)甲基)氨基)己烷-1,2,3,4,5-五醇(ED58)
EC22(33mg,0.1mmol),D-萄糖胺(36mg,0.2mmol)称入50mL反应瓶中,加入THF/MeOH/CH 2Cl 2(5mL/3mL/4mL),室温搅拌过夜，加入NaBH 4(100mg,2.6mmol)并搅拌过夜，反应液浓缩后，用三氟醋酸酸化并用HPLC纯化得目标化合物36mg。 1H NMR(400MHz,CDCl 3):7.70(d,J＝8.04Hz),7.46-7.39(m,3H),7.38-7.32(m,1H),7.30-7.25(m,2H),7.25-7.20(m,1H),7.18(dd,J＝7.68,1.39Hz),6.48(d,J＝8.04Hz,1H),5.50(s,2H),4.22-4.12(m,2H),4.12-4.07(m,1H),4.06(s,3H),3.90-3.85(m,1H),3.83-3.77(m,1H),3.76-3.64(m,5H),2.26(s,3H),3.26-3.15(m,2H)；ESI-MS理论值C 27H 35N 2O 7[M+H] +＝499.2,测得:499.9。
实施例32：合成5,5'-((((((2,2'-二甲基-[1,1'-联苯]-3,3'-二基)双(亚甲基))二(氧基))双(4-氯6-((((2S，3R，4R，5R)-2,3,4,5,6-五羟基己基)氨基)甲基)-3,1-亚苯基))二(氧基))双(亚甲基))二烟腈(ZD04)
Figure PCTCN2020094013-appb-000100
步骤一：合成(2,2'-二甲基-[1,1'-联苯]-3,3'-二基)二甲醇(ZC92)
将(3-溴-2-甲基苯基)甲醇(602mg，3.01mmol)、(2-甲基-3-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯基)甲醇(1.866g，7.5mmol)溶于DME和2M的Na 2CO 3溶液中，除氧气，充氮气后，加入Pd(dppf)Cl 2-CH 2Cl 2(100mg)后，再次除氧气充氮气后，95℃加热反应过夜。反应结束后，加水淬灭，然后用乙酸乙酯萃取，有机相用饱和食盐水洗，无水硫酸钠干燥后，旋干溶剂，最后用层析柱分离后，得到目标化合物514mg。 1H NMR(400MHz,Chloroform-d)δ7.41(dd,J＝1.4,7.6Hz,2H),7.26(d,J＝7.6Hz,2H),7.09(dd,J＝1.4,7.6Hz,2H),4.79(s,4H),2.06(s,6H)。
步骤二：合成4,4'-(((2,2'-二甲基-[1,1'-联苯]-3,3'-二基)双(亚甲基))二(氧基))双(5-氯-2-羟基苯甲醛)(ZC93)
将ZC92(514.8mg，2.13mmol)、5-氯-2,4-二羟基苯甲醛(732mg，4.25mmol)、PPh 3(613mg，2.34mmol)加入到反应瓶中，用干燥的THF(20ml)溶解后，冰水浴降温，最后加入DIAD(431mg)缓慢升至室温过夜。反应结束后，加入饱和碳酸氢钠溶液淬灭，然 后用乙酸乙酯萃取，有机相用无水硫酸钠干燥后，旋干溶剂，柱层析纯化后，得到目标化合物524mg。
步骤三：合成5,5'-((((((2,2'-二甲基-[1,1'-联苯]-3,3'-二基)双(亚甲基))二(氧基))双(4-氯6-甲酰基-3,1-亚苯基))二(氧基))双(亚甲基))二烟腈(ZC153-3)
将ZC93(524mg，0.95mmol)、5-(氯甲基)烟腈(318mg，2.10mmol)溶于DMF中，后加入Cs 2CO 3(380mg，1.43mmol)室温反应过夜。待反应结束后，加水淬灭，用二氯甲烷萃取三次，有机相用饱和氯化钠溶液洗，无水硫酸钠干燥后，旋干溶剂，并用层析柱分离纯化，得到目标化合物375mg。 1H NMR(400MHz,Chloroform-d)δ10.25(s,2H),8.95–8.85(m,4H),7.87(s,2),7.43(dd,J＝7.6,15.7Hz,4H),7.28–7.23(m,2H),7.11(dd,J＝7.7,32.8Hz,4H),5.25(s,8H),2.07(s,6H)。
步骤四：5,5'-((((((2,2'-二甲基-[1,1'-联苯]-3,3'-二基)双(亚甲基))二(氧基))双(4-氯6-((((2S，3R，4R，5R)-2,3,4,5,6-五羟基己基)氨基)甲基)-3,1-亚苯基))二(氧基))双(亚甲基))二烟腈(ZD04)
将ZC153-3(37mg，0.04mmol)、D-萄糖胺(51mg，0.23mmol)溶于THF：MeOH(1:1)的混合溶剂中，先向反应体系中加入AcOH(0.08ml)后，加入NaBH(OAc) 3(65mg，0.31mmol)，室温反应过夜。反应结束后，旋干溶剂，HPLC纯化，得到目标化合物8.2mg。 1H NMR(400MHz,Methanol-d 4)δ9.00(d,J＝2.1Hz,2H),8.96(d,J＝2.0Hz,2H),8.43(t,J＝2.1Hz,2H),7.52(s,2H),7.49–7.45(m,2H),7.42(d,J＝7.5Hz,2H),7.26(td,J＝4.2,7.6Hz,2H),7.05(d,J＝7.5Hz,2H),5.41(s,4H),5.33(s,4H),4.71(s,4H),4.24(q,J＝13.3Hz,4H),4.06(q,J＝5.4Hz,2H),3.85(dd,J＝1.4,4.6Hz,2H),3.76(dd,J＝3.0,10.3Hz,2H),3.72–3.59(m,2H),3.20(d,J＝5.5Hz,4H),2.10(s,6H)。ESI-MS理论值:C 56H 62Cl 2N 6O 14[M+H] +＝1113.37，测得：1112.92。
实施例33：合成(R)-2-((5-氯-4-((3'-((2-氯-5-((5-氰基吡啶-3-基)甲氧基)-4-(((2,3-二羟基丙基基)氨基)甲基)苯氧基)甲基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-2-((5-氰基吡啶-3-基)甲氧基)苄基)(甲基)氨基)乙烷-1-磺酸(ZD19)
Figure PCTCN2020094013-appb-000101
步骤一：合成(R)-5-((4-氯-5-((3'-((2-氯-5-((5-氰基吡啶-3-基)甲氧基)-4-(((2,3-二羟基丙基基)氨基)甲基)苯氧基)甲基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-2-甲酰基苯氧基)甲基)烟腈(ZD17)
将ZC153-3(50mg，0.064mmol)、(R)-3-氨基丙烷-1,2-二醇(6.41mg，0.070mmol)溶于THF：MeOH(4ml：4ml)的混合溶液中，然后加入AcOH(0.05ml)，最后加入NaBH(OAc) 3(68mg，0.32mmol)室温反应过夜。反应结束后，旋干溶剂，HPLC纯化，得到目标化合物13mg。 1H NMR(400MHz,Methanol-d 4)δ8.99(d,J＝2.1Hz,2H),8.96(d,J＝2.0Hz,2H),8.42(t,J＝2.1Hz,2H),7.53(s,2H),7.51–7.45(m,1H),7.42(d,J＝7.1Hz,1H),7.27(td,J＝5.6,7.5,8.3Hz,3H),7.11(t,J＝3.1Hz,2H),7.07–7.02(m,1H),5.40(d,J＝2.0Hz,4H),5.34(s,3H),4.71(s,2H),4.26(s,3H),3.89(dd,J＝4.5,9.0Hz,2H),3.61(dd,J＝4.3,11.2Hz,2H),3.54(dd,J＝5.5,11.3Hz,2H),3.19(dd,J＝3.3,12.7Hz,2H),3.07–3.02(m,2H),3.02(s,1H),2.88(d,J＝0.7Hz,1H),2.11(s,1H),2.10(s,3H),2.09(s,1H),2.07(s,1H),2.03(s,3H)。
步骤二：合成(R)-2-((5-氯-4-((3'-((2-氯-5-((5-氰基吡啶-3-基)甲氧基)-4-(((2,3-二羟基丙基基)氨基)甲基)苯氧基)甲基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-2-((5-氰基吡啶-3-基)甲氧基)苄基)(甲基)氨基)乙烷-1-磺酸(ZD19)
将ZD17(13mg，0.015mmol)、2-(甲基氨基)乙烷-1-磺酸异丙酯(5.7mg，0.030mmol)溶于THF(5ml)中，先向反应体系中加入AcOH(0.02ml)，然后加入NaBH(OAc) 3(13mg，0.061mmol)，室温反应过夜，反应结束后，旋干溶剂，然后再用甲醇溶解，60℃加热2h，反应结束后，旋干溶剂，并用HPLC纯化，得到目标化合物8.1mg。 1H NMR(400MHz,Methanol-d 4)δ8.99(d,J＝2.1Hz,2H),8.96(d,J＝1.9Hz,2H),8.42(t,J＝2.2Hz,2H),7.53(s,2H),7.50–7.44(m,2H),7.42(dd,J＝1.3,7.5Hz,2H),7.26(td,J＝4.7,7.6Hz,2H),7.05(dd,J＝1.4,7.6Hz,2H),5.40(s,4H),5.33(s,4H),4.71(s,4H),4.26(s,4H),3.90(dq,J＝4.3,8.7Hz,2H),3.61(dd,J＝4.4,11.2Hz,2H),3.54(dd,J＝5.5,11.3Hz,2H),3.24–3.14(m,2H),3.03(dd,J＝8.7,12.7Hz,2H),2.10(d,J＝2.7Hz,3H),2.03(s,3H)。ESI-MS理论值:C 50H 50Cl 2N 6O 9S[M+H] +＝981.27，测得：981.14。
实施例34：合成N-(3-((2-((3-氰基苄基)氧基)-4-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)-5-甲基苄基)(甲基)氨基)丙基)丙烯酰胺(ZA92)
Figure PCTCN2020094013-appb-000102
将ZA91(40mg，0.07mmol)溶于干燥的CH 2Cl 2中，然后加入三乙胺(21mg，0.21mmol)，最后滴加丙烯酰氯(6.3mg，0.07mmol)，室温反应1h。反应结束后，旋干溶剂，HPLC纯化，得到目标化合物12.5mg。 1H NMR(400MHz,Methanol-d 4)δ7.91(s,1H),7.82(d,J＝7.8Hz,1H),7.77–7.71(m,1H),7.60(t,J＝7.8Hz,1H),7.38(d,J＝6.8Hz,1H),7.26–7.15(m,3H),6.90(d,J＝8.4Hz,2H),6.78–6.71(m,2H),6.26–6.20(m,2H),5.72(dd,J＝3.0,9.0Hz,1H),5.30(s,2H),5.21(s,2H),4.53(d,J＝12.9Hz,1H),4.30(s,4H),4.05(d,J＝13.0Hz,1H),3.31–2.98(m,5H),2.74(s,3H),2.27(s,3H),2.21(s,3H),2.07–1.84(m,2H)。ESI-MS理论值 C 39H 41N 3O 5[M+H] +＝632.30，测得：632.76。
实施例35:参见实施例4合成2–((2–((3-氰基苄基)氧基)-4–((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧)-5-甲基苄基)(甲基)氨基)乙烷-1-磺酸异丙酯(ED09)。
Figure PCTCN2020094013-appb-000103
实施例36：参见实施例5合成2–((2–((3-氰基苄基)氧基)-4–((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧)-5-甲基苄基)(甲基)氨基)乙烷-1-膦酸二乙酯(ED18)。
Figure PCTCN2020094013-appb-000104
实施例37/38：参见实施例6/7合成(((2-((2-((3-氰基苄基)氧基)-4-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧)-5-甲基苄基)(甲基)氨基)乙基)磷酰基)双(氧))双(亚甲基)双(2,2-二甲基丙酸酯)(ED52-1)和(((2-((2-((3-氰基苄基)氧基)-4-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧)-5-甲基苄基)氨基)乙基)磷酰基)双(氧))双(亚甲基)双(2,2-二甲基丙酸酯)。
Figure PCTCN2020094013-appb-000105
实施例39：合成(2R,3R,4R,5S)-6-((5-氯-4-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)-2-((3-甲氧基苄基)氧基)苄基)氨基)己烷-1,2,3,4,5-五醇(ZD53)
Figure PCTCN2020094013-appb-000106
步骤一：合成5-氯-4–((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)-2-((3-甲氧基苄基)氧基)苯甲醛(ZD47)
将ZA52(150mg，0.384mmol)与1-(氯甲基)-3-甲氧基苯(72.3mg，0.461mmol)加入到反应瓶中用DMF(4ml)溶解，然后加入Cs 2CO 3(203.5mg，0.577mmol)，室温反应过夜。反应结束后加水淬灭，然后用乙酸乙酯萃取，有机相用无水 硫酸钠干燥后旋干，最后用层析柱分离纯化得到目标产物126mg。 1H NMR(400MHz,Chloroform-d)δ10.38(s,1H),7.91(s,1H),7.39(q,J＝4.0,4.4Hz,1H),7.34(t,J＝7.9Hz,1H),7.27(s,2H),7.26(d,J＝1.1Hz,1H),6.99(d,J＝1.8Hz,2H),6.92(d,J＝8.9Hz,2H),6.85(t,J＝2.0Hz,1H),6.80(dt,J＝2.5,8.2Hz,1H),6.66(s,1H),5.19(s,2H),5.16(s,2H),4.34(s,4H),3.84(s,3H),2.28(s,3H)。
步骤二：合成(2R,3R,4R,5S)-6-((5-氯-4-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)-2-((3-甲氧基苄基)氧基)苄基)氨基)己烷-1,2,3,4,5-五醇(ZD53)
将ZD47(18.1mg，0.034mmol)、D-萄糖胺(18.5mg，0.102mmol)溶于THF(4ml)与MeOH(4ml)的混合溶剂中室温反应过夜，然后加入NaBH 4(26mg，0.683mmol)，室温反应约5h。反应结束后旋干溶剂，HPLC纯化，得到目标化合物7.3mg. 1H NMR(400MHz,Methanol-d 4)δ7.47(s,1H),7.37–7.31(m,2H),7.22–7.16(m,2H),7.09–7.04(m,2H),6.97(s,1H),6.96–6.91(m,1H),6.89(d,J＝8.1Hz,1H),6.78–6.71(m,3H),5.26(s,2H),5.21(s,3H),4.30(s,4H),4.23–4.16(m,2H),4.07(q,J＝5.5Hz,1H),3.85(dd,J＝1.6,4.5Hz,1H),3.82(s,3H),3.77(dd,J＝3.2,10.5Hz,1H),3.71–3.63(m,3H),2.25(s,3H)。ESI-MS理论计算值C 37H 42ClNO 10[M+H] +＝696.25，实验测得：696.90。
实施例40：合成4-((4-氯-5-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)-2-((((2S，3R，4R，5R)-2,3,4,5,6-五羟基己基)氨基)甲基)苯氧基)甲基)苯甲腈(ZD56)
Figure PCTCN2020094013-appb-000107
步骤一：合成4–((4-氯-5-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)-2-甲酰基苯氧基)甲基)苯甲腈(ZD50)
将ZA88(120mg，0.31mmol)与4-(氯甲基)苄腈(56mg，0.37mmol)加入到反应瓶中用DMF(5ml)溶解，然后加入Cs 2CO 3(162.8mg，0.46mmol)，室温反应过夜。反应结束后加水淬灭，然后用乙酸乙酯萃取，有机相用无水硫酸钠干燥后旋干，最后用层析柱分离纯化得到目标产物61.7mg。 1H NMR(400MHz,Chloroform-d)δ10.36(s,1H),7.93(s,1H),7.73(d,J＝8.2Hz,2H),7.56(d,J＝8.2Hz,2H),7.38(d,J＝2.3Hz,1H),7.28(s,2H),6.95(d,J＝8.2Hz,1H),6.84(d,J＝2.1Hz,1H),6.79(dd,J＝2.1,8.3Hz,1H),6.60(s,1H),5.24(s,2H),5.21(s,2H),4.34(s,4H),2.29(s,4H).
步骤二：合成4-((4-氯-5-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基) 氧基)-2-((((2S，3R，4R，5R)-2,3,4,5,6-五羟基己基)氨基)甲基)苯氧基)甲基)苯甲腈(ZD56)
将ZD50(32mg，0.061mmol)、D-萄糖胺(33mg，0.183mmol)溶于THF(4ml)室温反应过夜后，加入NaBH 4(46mg，1.22mmol)，室温反应约5h。反应结束后旋干溶剂，HPLC纯化，得到目标化合物22.3mg。 1H NMR(400MHz,Methanol-d 4)δ7.82–7.73(m,2H),7.73–7.64(m,2H),7.50(s,1H),7.33(dd,J＝3.8,5.3Hz,1H),7.20–7.14(m,2H),6.93(s,1H),6.89(d,J＝8.0Hz,1H),6.77–6.68(m,2H),5.37(s,2H),5.24(s,2H),4.27(s,4H),4.27–4.16(m,2H),4.08(dt,J＝4.8,6.8Hz,1H),3.86(dd,J＝1.5,4.6Hz,1H),3.77(dd,J＝3.0,10.5Hz,1H),3.73–3.59(m,3H),3.22(dd,J＝2.3,6.0Hz,2H),2.25(s,3H)。ESI-MS理论计算值C 37H 39ClN 2O 9[M+H] +＝691.23，实验测得：691.09。
实施例41：合成2-((4-氯-5-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)-2-((((2S，3R，4R，5R)-2,3,4,5,6-五羟基己基)氨基)甲基)苯氧基)甲基)苯甲腈(ZD57)
Figure PCTCN2020094013-appb-000108
步骤一：合成2-((4-氯-5-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)-2-甲酰基苯氧基)甲基)苯甲腈(ZD51)
将ZA52(120mg，0.308mmol)与2-(氯甲基)苄腈(56mg，0.37mmol)加入到反应瓶中用DMF(5ml)溶解，然后加入Cs 2CO 3(162.8mg，0.462mmol)，室温反应过夜。反应结束后加水淬灭，然后用乙酸乙酯萃取，有机相用无水硫酸钠干燥后旋干，最后用层析柱分离纯化得到目标产物48.9mg。 1H NMR(400MHz,Chloroform-d)δ10.36(s,1H),7.93(s,1H),7.75(d,J＝7.7Hz,1H),7.72–7.67(m,2H),7.55–7.48(m,1H),7.44(t,J＝4.5Hz,1H),7.27(s,1H),7.27(s,1H),6.94(d,J＝8.2Hz,1H),6.86(d,J＝2.1Hz,1H),6.81(dd,J＝2.1,8.2Hz,1H),6.75(s,1H),5.42(s,2H),5.27(s,2H),4.34(s,4H),2.32(s,3H)。
步骤二：合成2-((4-氯-5-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)-2-((((2S，3R，4R，5R)-2,3,4,5,6-五羟基己基)氨基)甲基)苯氧基)甲基)苯甲腈(ZD57)
将ZD51(12mg，0.023mmol)、D-萄糖胺(12.4mg，0.069mmol)溶于THF(4ml)与MeOH(4ml)的混合溶剂中室温反应过夜，然后加入NaBH 4(17mg，0.460 mmol)，室温反应约5h。反应结束后旋干溶剂，HPLC纯化，得到目标化合物5.5mg。 1H NMR(400MHz,Methanol-d 4)δ7.84(dd,J＝1.1,7.4Hz,1H),7.79–7.70(m,2H),7.57(ddd,J＝2.3,6.6,7.7Hz,1H),7.51(s,1H),7.40(dd,J＝2.1,6.9Hz,1H),7.25–7.15(m,2H),7.04(s,1H),6.89(d,J＝8.0Hz,1H),6.79–6.70(m,2H),5.47(s,2H),5.29(s,2H),4.29(s,4H),4.28–4.19(m,2H),4.06(dt,J＝4.7,6.9Hz,1H),3.83(dd,J＝1.6,4.5Hz,1H),3.76(dd,J＝3.0,10.8Hz,1H),3.71–3.60(m,3H),3.20(dd,J＝2.8,5.9Hz,2H),2.28(s,3H)。ESI-MS理论计算值C 37H 39ClN 2O 9[M+H] +＝691.23，实验测得：691.45。
实施例42：合成6-((4-氯-5-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)-2-((((2S，3R，4R，5R)-2,3,4,5,6-五羟基己基)氨基)甲基)苯氧基)甲基)-2-氰基吡啶(ZD58)
Figure PCTCN2020094013-appb-000109
步骤一：合成6-((4-氯-5-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)-2-甲酰基苯氧基)甲基)-2-氰基吡啶(ZD52)
将ZA52(130mg，0.333mmol)与6-(氯甲基)-2-氰基吡啶(61mg，0.40mmol)加入到反应瓶中用DMF(4ml)溶解，然后加入Cs 2CO 3(176.3mg，0.50mmol)，室温反应过夜。反应结束后加水淬灭，然后用乙酸乙酯萃取，有机相用无水硫酸钠干燥后旋干，最后用层析柱分离纯化得到目标产物132.8mg。 1H NMR(400MHz,Chloroform-d)δ10.39(s,1H),7.97(t,J＝7.8Hz,1H),7.92(s,1H),7.87(d,J＝8.0Hz,1H),7.73(d,J＝7.6Hz,1H),7.49–7.42(m,1H),7.27(s,1H),7.26(s,1H),6.95(d,J＝8.2Hz,1H),6.85(d,J＝2.1Hz,1H),6.80(dd,J＝2.1,8.2Hz,1H),6.74(s,1H),5.36(s,2H),5.23(s,2H),4.34(s,4H),2.32(s,3H)。
步骤二：合成6-((4-氯-5-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)-2-((((2S，3R，4R，5R)-2,3,4,5,6-五羟基己基)氨基)甲基)苯氧基)甲基)-2-氰基吡啶(ZD58)
将ZD52(27.4mg，0.052mmol)、D-萄糖胺(28.3mg，0.156mmol)溶于THF(4ml)与MeOH(4ml)的混合溶剂中室温反应过夜，然后加入NaBH 4(40mg，1.04mmol)，室温反应约5h。反应结束后旋干溶剂，HPLC纯化，得到目标化合物7.3mg。 1H NMR(400MHz,Methanol-d 4)δ8.07(t,J＝7.8Hz,1H),7.89(dd,J＝7.7,9.0Hz, 2H),7.51(s,1H),7.38(dd,J＝2.5,6.7Hz,1H),7.23–7.15(m,2H),7.02(s,1H),6.90(dt,J＝1.3,7.9Hz,1H),6.79–6.66(m,2H),5.45(s,2H),5.26(s,2H),4.33(s,1H),4.30(s,4H),4.25(d,J＝13.2Hz,1H),4.16–4.08(m,1H),3.87(dd,J＝1.3,4.7Hz,1H),3.79–3.73(m,1H),3.72–3.59(m,4H),3.26(dd,J＝2.7,6.2Hz,2H),2.27(s,3H)。ESI-MS理论计算值C 36H 38ClN 3O 9[M+H] +＝692.23，实验测得：692.28。
实施例43：合成(2R,3R,4R,5S)-6-((5-氯-2-((3-氯苄基)氧基)-4-((3-(2,3-二氢苯并[b][1,4]二氧杂环己-6-基)-2-甲基苄基)氧基)苄基)氨基)己烷-1,2,3,4,5-五醇(ZD62)
Figure PCTCN2020094013-appb-000110
步骤一：5-氯-2-((3-氯苄基)氧基)-4-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)苯甲醛(ZD59)
将ZA52(130mg，0.33mmol)与1-氯-3-(氯甲基)苯(64.4mg，0.40mmol)加入到反应瓶中用DMF(4ml)溶解，然后加入Cs 2CO 3(176.4mg，0.50mmol)，室温反应过夜。反应结束后加水淬灭，然后用乙酸乙酯萃取，有机相用无水硫酸钠干燥后旋干，最后用层析柱分离纯化得到目标产物93.7mg。 1H NMR(400MHz,Chloroform-d)δ10.37(s,1H),7.92(s,1H),7.46–7.43(m,1H),7.43–7.39(m,1H),7.39–7.35(m,2H),7.35–7.29(m,1H),7.28–7.26(m,2H),6.94(d,J＝8.3Hz,1H),6.85(d,J＝2.1Hz,1H),6.80(dd,J＝2.1,8.2Hz,1H),6.62(s,1H),5.19(s,2H),5.17(s,2H),4.34(s,4H),2.29(s,3H)。
步骤二：合成(2R,3R,4R,5S)-6-((5-氯-2-((3-氯苄基)氧基)-4-((3-(2,3-二氢苯并[b][1,4]二氧杂环己-6-基)-2-甲基苄基)氧基)苄基)氨基)己烷-1,2,3,4,5-五醇(ZD62)
将ZD59(17.3mg，0.032mmol)、D-萄糖胺(17.6mg，0.097mmol)溶于THF(3ml)与MeOH(3ml)的混合溶剂中室温反应过夜，然后加入NaBH 4(24.6mg，0.648mmol)，室温反应约5h。反应结束后旋干溶剂，HPLC纯化，得到目标化合物12.1mg。 1H NMR(400MHz,Methanol-d 4)δ7.58(d,J＝1.9Hz,1H),7.49(s,1H),7.46(dt,J＝1.8,7.3Hz,1H),7.43(d,J＝7.7Hz,1H),7.41–7.38(m,1H),7.36(dd,J＝2.2,7.1Hz,1H),7.23–7.16(m,2H),6.97(s,1H),6.90(d,J＝8.1Hz,1H),6.77–6.71(m,2H),5.28(s,2H),5.23(s,2H),4.30(s,4H),4.27–4.16(m,2H),4.08(td,J＝4.5,5.9Hz,1H), 3.86(dd,J＝1.6,4.5Hz,1H),3.78(dd,J＝3.1,10.5Hz,1H),3.73–3.60(m,3H),3.20(d,J＝5.9Hz,2H),2.26(s,3H)。ESI-MS理论计算值C 36H 39Cl 2NO 9[M+H] +＝700.20，实验测得：700.00。
实施例44：合成((2R,3R,4R,5S)-6-((5-氯-4-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)-2-((3-氟苄基)氧基)苄基)氨基)己烷-1,2,3,4,5-五醇(ZD65)
Figure PCTCN2020094013-appb-000111
步骤一：5-氯-4-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)-2-((3-氟苄基)氧基)苯甲醛(ZD60)
将ZA52(150mg，0.384mmol)与1-氟-3-(氯甲基)苯(66.7mg，0.461mmol)加入到反应瓶中用DMF(4ml)溶解，然后加入Cs 2CO 3(203.5mg，0.577mmol)，室温反应过夜。反应结束后加水淬灭，然后用乙酸乙酯萃取，有机相用无水硫酸钠干燥后旋干，最后用层析柱分离纯化得到目标产物75.6mg。 1H NMR(400MHz,Chloroform-d)δ10.37(s,1H),7.92(s,1H),7.44–7.36(m,2H),7.27(s,1H),7.26(d,J＝1.8Hz,1H),7.20(d,J＝7.6Hz,1H),7.15(d,J＝9.4Hz,1H),7.08(t,J＝8.8Hz,1H),6.94(d,J＝8.2Hz,1H),6.85(d,J＝2.0Hz,1H),6.80(dd,J＝2.1,8.2Hz,1H),6.62(s,1H),5.20(s,2H),5.18(s,2H),4.34(s,4H),2.29(s,3H)。
步骤二：合成((2R,3R,4R,5S)-6-((5-氯-4-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)-2-((3-氟苄基)氧基)苄基)氨基)己烷-1,2,3,4,5-五醇(ZD65)
将ZD60(16.7mg，0.032mmol)、D-萄糖胺(17.6mg，0.097mmol)溶于THF(3ml)与MeOH(3ml)的混合溶剂中室温反应过夜，然后加入NaBH 4(24.5mg，0.645mmol)，室温反应约5h。反应结束后旋干溶剂，HPLC纯化，得到目标化合物10mg。 1H NMR(400MHz,Methanol-d 4)δ7.49(s,1H),7.44(td,J＝5.8,8.0Hz,1H),7.38–7.33(m,2H),7.33–7.27(m,2H),7.23–7.15(m,2H),7.14–7.07(m,1H),6.96(s,1H),6.89(d,J＝8.1Hz,1H),6.77–6.71(m,2H),5.30(s,2H),5.25(s,2H),4.29(s,4H),4.28–4.15(m,2H),4.08(dt,J＝5.0,6.6Hz,1H),3.86(dd,J＝1.6,4.5Hz,1H),3.77(dd,J＝3.1,10.5Hz,1H),3.66(ddt,J＝5.1,10.1,15.6Hz,3H),3.25–3.17(m,2H),2.26(s,3H)。ESI-MS理论计算值C 36H 39ClFNO 9[M+H] +＝684.23，实验测得：684.24。
实施例45：合成(2R,3R,4R,5S)-6-((5-氯-4-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基基)-2-(吡啶-2-基甲氧基)苄基)氨基)己烷-1,2,3,4,5-五醇(ZD75)
Figure PCTCN2020094013-appb-000112
步骤一：合成5-氯-4-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)-2-(吡啶-2-基甲氧基)苯甲醛(ZD72)
将ZA52(130mg，0.33mmol)与2-(氯甲基)吡啶(65.6mg，0.40mmol)加入到反应瓶中用DMF(4ml)溶解，然后加入Cs 2CO 3(317.4mg，0.89mmol)，室温反应过夜。反应结束后加水淬灭，然后用乙酸乙酯萃取，有机相用无水硫酸钠干燥后旋干，最后用层析柱分离纯化得到目标产物104.3mg。 1H NMR(400MHz,Chloroform-d)δ10.43(s,1H),8.63(d,J＝5.1Hz,1H),7.91(s,1H),7.78(td,J＝1.8,7.7Hz,1H),7.61–7.51(m,1H),7.43(t,J＝4.5Hz,1H),7.31(d,J＝7.7Hz,1H),7.26(d,J＝4.5Hz,2H),6.94(d,J＝8.2Hz,1H),6.86(d,J＝2.1Hz,1H),6.83–6.72(m,2H),5.36(s,2H),5.16(s,2H),4.34(s,4H),2.29(d,J＝1.8Hz,3H)。
步骤二：合成(2R,3R,4R,5S)-6-((5-氯-4-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基基)-2-(吡啶-2-基甲氧基)苄基)氨基)己烷-1,2,3,4,5-五醇(ZD75)
将ZD72(24.3mg，0.049mmol)、D-萄糖胺(26.4mg，0.15mmol)，溶于THF(3ml)与MeOH(3ml)的混合溶剂中室温反应过夜，然后加入NaBH 4(36.9mg，1.0mmol)，室温反应约5h。反应结束后旋干溶剂，HPLC纯化，得到目标化合物9.2mg。 1H NMR(400MHz,Methanol-d 4)δ8.73–8.65(m,1H),7.99(td,J＝1.7,7.7Hz,1H),7.66(d,J＝7.8Hz,1H),7.53–7.45(m,2H),7.37(dd,J＝2.9,6.4Hz,1H),7.22–7.14(m,2H),7.02(s,1H),6.89(d,J＝8.1Hz,1H),6.79–6.70(m,2H),5.46(s,2H),5.24(s,2H),4.29(s,4H),4.25(d,J＝2.7Hz,2H),4.14(dt,J＝5.0,6.9Hz,1H),3.90(dd,J＝1.4,4.8Hz,1H),3.78(dd,J＝2.5,10.5Hz,1H),3.74–3.61(m,3H),3.29–3.20(m,2H),2.26(s,3H)。ESI-MS理论计算值C 35H 39ClN 2O 9[M+H] +＝667.23，实验测得：667.23。
实施例46：合成(2R,3R,4R,5S)-6-((5-氯-2-((3-氯-4-氟苄基)氧基)-4-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)苄基)氨基)己烷-1,2,3,4,5-五醇(ZD77)
Figure PCTCN2020094013-appb-000113
步骤一：5-氯-2-((3-氯-4-氟苄基)氧基)-4-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)苯甲醛(ZD76)
将ZA88(130mg，0.33mmol)与2-氯-4-(氯甲基)-1-氟苯(71.6mg，0.40mmol)加入到反应瓶中用DMF(4ml)溶解，然后加入Cs 2CO 3(176.4mg，0.50mmol)，室温反应过夜。反应结束后加水淬灭，然后用乙酸乙酯萃取，有机相用无水硫酸钠干燥后旋干，最后用层析柱分离纯化得到目标产物122mg。 1H NMR(400MHz,Chloroform-d)δ10.33(s,1H),7.93(s,1H),7.54–7.46(m,1H),7.46–7.35(m,1H),7.31(d,J＝4.0Hz,1H),7.27(d,J＝1.8Hz,1H),7.20(t,J＝8.6Hz,1H),6.94(d,J＝8.2Hz,1H),6.85(d,J＝2.1Hz,1H),6.81(d,J＝2.1Hz,1H),6.79(d,J＝2.1Hz,1H),6.62(s,1H),5.22(s,2H),5.13(s,2H),4.34(s,4H),2.30(s,3H)。
步骤二：合成(2R,3R,4R,5S)-6-((5-氯-2-((3-氯-4-氟苄基)氧基)-4-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)苄基)氨基)己烷-1,2,3,4,5-五醇(ZD77)
将ZD76(21mg，0.038mmol)、D-萄糖胺(20.7mg，0.069mmol)溶于THF(4ml)与MeOH(4ml)的混合溶剂中室温反应过夜，然后加入NaBH 4(28.9mg，0.76mmol)，室温反应约5h。反应结束后旋干溶剂，HPLC纯化，得到目标化合物12.2mg。 1H NMR(400MHz,Methanol-d 4)δ7.68(dd,J＝2.2,7.1Hz,1H),7.53–7.45(m,2H),7.37(dd,J＝2.4,6.7Hz,1H),7.29(t,J＝8.8Hz,1H),7.24–7.15(m,2H),6.97(s,1H),6.89(d,J＝8.1Hz,1H),6.77–6.71(m,2H),5.25(d,J＝2.4Hz,4H),4.29(s,4H),4.26–4.15(m,2H),4.08(dt,J＝5.0,6.6Hz,1H),3.86(dd,J＝1.6,4.5Hz,1H),3.78(dd,J＝3.1,10.4Hz,1H),3.73–3.61(m,3H),3.26–3.16(m,2H),2.27(s,3H)。ESI-MS理论计算值C 36H 38Cl 2FNO 9[M+H] +＝708.19，实验测得：718.30。
实施例47：合成(2R,3R,4R,5S)-6–((5-氯-4–((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基基)-2-(吡啶-4-基甲氧基)苄基)氨基)己烷-1,2,3,4,5-五醇(ZD78)
Figure PCTCN2020094013-appb-000114
步骤一：合成5-氯-4-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)-2-(吡啶-4-基甲氧基)苯甲醛(ZD74)
将ZA52(130mg，0.33mmol)与4-(氯甲基)吡啶(65.6mg，0.40mmol)加入到反应瓶中用DMF(4ml)溶解，然后加入Cs 2CO 3(317.4mg，0.89mmol)，室温反应过夜。反应结束后加水淬灭，然后用乙酸乙酯萃取，有机相用无水硫酸钠干燥后旋干，最后用层析柱分离纯化得到目标产物131mg。 1H NMR(400MHz,Chloroform-d)δ10.39(s,1H),8.72–8.62(m,2H),7.93(s,1H),7.41–7.32(m,3H),7.27–7.23(m,2H),6.94(d,J＝8.3Hz,1H),6.84(d,J＝2.0Hz,1H),6.79(dd,J＝2.1,8.2Hz,1H),6.58(s,1H),5.21(s,2H),5.19(s,2H),4.33(s,4H),2.28(s,3H)。
步骤二：合成(2R,3R,4R,5S)-6–((5-氯-4–((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基基)-2-(吡啶-4-基甲氧基)苄基)氨基)己烷-1,2,3,4,5-五醇(ZD78)
将ZD74(24.3mg，0.05mmol)、D-萄糖胺(26.4mg，0.15mmol)溶于THF(3ml)与MeOH(3ml)的混合溶剂中室温反应过夜，然后加入NaBH 4(36.9mg，0.96mmol)，室温反应约5h。反应结束后旋干溶剂，HPLC纯化，得到目标化合物9.2mg。 1H NMR(400MHz,Methanol-d 4)δ8.93–8.80(m,2H),8.19(d,J＝6.4Hz,2H),7.57(s,1H),7.37(dd,J＝3.1,5.9Hz,1H),7.25–7.12(m,2H),7.00(s,1H),6.89(d,J＝8.0Hz,1H),6.79–6.68(m,2H),5.63(s,2H),5.28(s,2H),4.42–4.32(m,2H),4.29(s,4H),4.17–4.08(m,1H),3.88(dd,J＝1.2,4.6Hz,1H),3.79–3.70(m,1H),3.71–3.58(m,3H),3.28(t,J＝5.8Hz,2H),2.27(s,3H)。ESI-MS理论计算值C 35H 39ClN 2O 9[M+H] +＝667.23，实验测得：667.45。
实施例48：合成(2R,3R,4R,5S)-6-((5-氯-2-((2,4-二氟苄基)氧基)-4-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)苄基)氨基)己烷-1,2,3,4,5-五醇(ZD81)
Figure PCTCN2020094013-appb-000115
步骤一：5-氯-2-((2,4-二氟苄基)氧基)-4-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)苯甲醛(ZD80)
将ZA52(130mg，0.33mmol)与1-(氯甲基)-2,4-二氟苯(65.0mg，0.40mmol)加入到反应瓶中用DMF(4ml)溶解，然后加入Cs 2CO 3(176.4mg，0.50mmol)，室温反应过夜。反应结束后加水淬灭，然后用乙酸乙酯萃取，有机相用无水硫酸钠干燥后旋干，最后用层析柱分离纯化得到目标产物157.9mg。 1H NMR(400MHz,DMSO-d 6)δ10.13(s,1H),7.78–7.72(m,1H),7.71(s,1H),7.51(dd,J＝1.4,7.5Hz,1H),7.39–7.32(m,2H),7.29(t,J＝7.6Hz,1H),7.22(dd,J＝1.5,7.7Hz,1H),7.16(ddd,J＝2.4,7.9,10.4Hz,1H),6.94(d,J＝8.2Hz,1H),6.80(d,J＝2.1Hz,1H),6.77(dd,J＝2.2,8.2Hz,1H),5.42(d,J＝5.2Hz,4H),4.29(s,4H),2.26(s,3H)。
步骤二：合成(2R,3R,4R,5S)-6-((5-氯-2-((2,4-二氟苄基)氧基)-4-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)苄基)氨基)己烷-1,2,3,4,5-五醇(ZD81)
将ZD80(20mg，0.037mmol)、D-萄糖胺(20.3mg，0.112mmol)溶于THF(4ml)与MeOH(4ml)的混合溶剂中室温反应过夜，然后加入NaBH 4(28.4mg，0.746mmol)，室温反应约5h。反应结束后旋干溶剂，HPLC纯化，得到目标化合物14.3mg。 1H NMR(400MHz,Methanol-d 4)δ7.59(td,J＝6.3,8.3Hz,1H),7.42(dd,J＝1.8,7.3Hz,1H),7.30(s,1H),7.25–7.15(m,2H),7.06–6.98(m,2H),6.93(s,1H),6.89(d,J＝8.1Hz,1H),6.79–6.71(m,2H),5.23(s,2H),5.20(s,2H),4.29(s,4H),3.86(dt,J＝4.6,6.4Hz,1H),3.81–3.73(m,2H),3.73–3.67(m,1H),3.66–3.57(m,2H),2.77–2.63(m,2H),2.28(s,3H)。ESI-MS理论计算值C 36H 38ClF 2NO 9[M+H] +＝702.22，实验测得：702.09。
实施例49：合成(2R,3R,4R,5S)-6-((2-(苄氧基)-5-氯-4-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)苄基)氨基)己烷-1,2,3,4,5-五醇(ZD82)
Figure PCTCN2020094013-appb-000116
步骤一：合成2-(苄氧基)-5-氯-4-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)苯甲醛(ZD79)
将ZA52(130mg，0.33mmol)与(氯甲基)苯(68.4mg，0.40mmol)加入到反应瓶中用DMF(4ml)溶解，然后加入Cs 2CO 3(176.4mg，0.50mmol)，室温反应过夜。反应结束后加水淬灭，然后用乙酸乙酯萃取，有机相用无水硫酸钠干燥后旋干，最后用层析柱分离纯化得到目标产物151.5mg。 1H NMR(400MHz,DMSO-d 6)δ10.21(s,1H),7.70(s,1H),7.59–7.51(m,2H),7.49(d,J＝7.4Hz,1H),7.46–7.40(m,2H),7.40–7.34(m,1H),7.33–7.25(m,2H),7.25–7.16(m,1H),6.94(d,J＝8.2Hz,1H),6.82–6.71(m,2H),5.40(s,4H),4.29(s,4H),2.25(s,3H)。
步骤二：合成(2R,3R,4R,5S)-6-((2-(苄氧基)-5-氯-4-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)苄基)氨基)己烷-1,2,3,4,5-五醇(ZD82)
将ZD79(20mg，0.04mmol)、D-萄糖胺(21.7mg，0.12mmol)溶于THF(4ml)与MeOH(4ml)的混合溶剂中室温反应过夜，然后加入NaBH 4(30.4mg，0.80mmol)，室温反应约5h。反应结束后旋干溶剂，HPLC纯化，得到目标化合物32.1mg。 1H NMR(400MHz,Methanol-d 4)δ7.53–7.49(m,2H),7.47(s,1H),7.45–7.39(m,2H),7.37(ddd,J＝1.9,4.4,8.9Hz,2H),7.23–7.15(m,2H),6.97(s,1H),6.89(d,J＝8.2Hz,1H),6.77–6.70(m,2H),5.28(s,2H),5.20(s,2H),4.29(s,4H),4.27–4.15(m,2H),4.07(dt,J＝4.9,6.7Hz,1H),3.84(dd,J＝1.6,4.5Hz,1H),3.78(dd,J＝3.2,10.7Hz,1H),3.73–3.61(m,3H),3.24–3.13(m,2H),2.25(s,3H)。ESI-MS理论计算值C 36H 40ClNO 9[M+H] +＝666.24，实验测得：666.91。
实施例50：合成5-((4-氯-5-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)-2-((甲基((2S,3S,4R)-2,3,4,5-四羟基)氨基)甲基)苯氧基)甲基)烟腈(ZD21)
Figure PCTCN2020094013-appb-000117
将ZD36(0.037mmol,20mg),D-核糖(混合异构体，0.11mmol,17mg)溶解于THF(4mL)和甲醇(4mL)，先加入AcOH(0.05ml)，最后加入NaBH(OAc) 3(39.2mg,0.18mmol),搅拌过夜。反应结束后旋干溶剂，HPLC纯化，得到目标化合物3mg。ZD21: 1H NMR(400MHz,Methanol-d 4)δ8.99(d,J＝2.2Hz,1H),8.95(d,J＝2.1Hz,1H),8.41(d,J＝6.0Hz,1H),7.58(d,J＝6.1Hz,1H),7.43(d,J＝7.0Hz,1H),7.23(q,J＝7.9Hz,2H),7.09(d,J＝3.8Hz,1H),6.90(d,J＝8.0Hz,1H),6.79–6.73(m,2H),5.40(s,2H),5.33(s,2H),4.30(s,4H),4.26–4.19(m,1H),4.18–4.08(m,1H),3.79–3.69(m,1H),3.61(ddd,J＝ 5.0,9.6,14.3Hz,2H),3.52(d,J＝10.4Hz,1H),3.47–3.38(m,1H),3.31–3.21(m,1H),2.92(s,3H),2.81(s,1H),2.29(s,3H)。
实施例51：合成(2R,3R,4R,5S)-6-((5-氯-4-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)-2-((3-甲氧基苄基)氧基)苄基)氨基)己烷-1,2,3,4,5-五醇(ZD53)
Figure PCTCN2020094013-appb-000118
步骤一：合成5-氯-4-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)-2-((3-甲氧基苄基)氧基)苯甲醛(ZD47)
将ZA52(150mg，0.384mmol)与1-(氯甲基)-3-甲氧基苯(72.3mg，0.461mmol)加入到反应瓶中用DMF(4ml)溶解，然后加入Cs 2CO 3(203.5mg，0.577mmol)，室温反应过夜。反应结束后加水淬灭，然后用乙酸乙酯萃取，有机相用无水硫酸钠干燥后旋干，最后用层析柱分离纯化，得到目标产物126mg。 1H NMR(400MHz,Chloroform-d)δ10.38(s,1H),7.91(s,1H),7.39(q,J＝4.0,4.4Hz,1H),7.34(t,J＝7.9Hz,1H),7.27(s,2H),7.26(d,J＝1.1Hz,1H),6.99(d,J＝1.8Hz,2H),6.92(d,J＝8.9Hz,2H),6.85(t,J＝2.0Hz,1H),6.80(dt,J＝2.5,8.2Hz,1H),6.66(s,1H),5.19(s,2H),5.16(s,2H),4.34(s,4H),3.84(s,3H),2.28(s,3H).
步骤二：合成(2R,3R,4R,5S)-6-((5-氯-4-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)-2-((3-甲氧基苄基)氧基)苄基)氨基)己烷-1,2,3,4,5-五醇(ZD53)
将ZD47(18.1mg，0.034mmol)、D-萄糖胺(18.5mg，0.102mmol)溶于THF(4ml)与MeOH(4ml)的混合溶剂中室温反应过夜，然后加入NaBH 4(26mg，0.683mmol)，继续反应5h。反应结束后旋干溶剂，HPLC纯化。得到目标化合物7.3mg. 1H NMR(400MHz,Methanol-d 4)δ7.47(s,1H),7.37–7.31(m,2H),7.22–7.16(m,2H),7.09–7.04(m,2H),6.97(s,1H),6.96–6.91(m,1H),6.89(d,J＝8.1Hz,1H),6.78–6.71(m,3H),5.26(s,2H),5.21(s,3H),4.30(s,4H),4.23–4.16(m,2H),4.07(q,J＝5.5Hz,1H),3.85(dd,J＝1.6,4.5Hz,1H),3.82(s,3H),3.77(dd,J＝3.2,10.5Hz,1H),3.71–3.63(m,3H),2.25(s,3H).ESI-MS理论计算值C 37H 42ClNO 10[M+H] +＝696.25，实验测得：696.90.
实施例52：合成4-((4-氯-5-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)-2-((((2R,3R,4R,5S)-2,3,4,5,6-五羟基己基)氨基)甲基)苯氧基)甲基)苯甲腈(ZD56)
Figure PCTCN2020094013-appb-000119
步骤一：合成4-((4-氯-5-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)-2-甲酰基苯氧基)甲基)苯甲腈(ZD50)
将ZA52(120mg，0.31mmol)与4-(氯甲基)苄腈(56mg，0.37mmol)加入到反应瓶中用DMF(5ml)溶解，然后加入Cs 2CO 3(162.8mg，0.46mmol)，室温反应过夜。反应结束后加水淬灭，然后用乙酸乙酯萃取，有机相用无水硫酸钠干燥后旋干，最后用层析柱分离纯化得到目标产物61.7mg。 1H NMR(400MHz,Chloroform-d)δ10.36(s,1H),7.93(s,1H),7.73(d,J＝8.2Hz,2H),7.56(d,J＝8.2Hz,2H),7.38(d,J＝2.3Hz,1H),7.28(s,2H),6.95(d,J＝8.2Hz,1H),6.84(d,J＝2.1Hz,1H),6.79(dd,J＝2.1,8.3Hz,1H),6.60(s,1H),5.24(s,2H),5.21(s,2H),4.34(s,4H),2.29(s,4H).
步骤二：合成4-((4-氯-5-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)-2-((((2R,3R,4R,5S)-2,3,4,5,6-五羟基己基)氨基)甲基)苯氧基)甲基)苯甲腈(ZD56)
将ZD50(32mg，0.061mmol)、D-萄糖胺(33mg，0.183mmol)溶于THF(4ml)中，室温反应过夜后加入NaBH 4(46mg，1.22mmol)，继续反应5h后旋干溶剂，HPLC纯化。得到目标化合物22.3mg. 1H NMR(400MHz,Methanol-d 4)δ7.82–7.73(m,2H),7.73–7.64(m,2H),7.50(s,1H),7.33(dd,J＝3.8,5.3Hz,1H),7.20–7.14(m,2H),6.93(s,1H),6.89(d,J＝8.0Hz,1H),6.77–6.68(m,2H),5.37(s,2H),5.24(s,2H),4.27(s,4H),4.27–4.16(m,2H),4.08(dt,J＝4.8,6.8Hz,1H),3.86(dd,J＝1.5,4.6Hz,1H),3.77(dd,J＝3.0,10.5Hz,1H),3.73–3.59(m,3H),3.22(dd,J＝2.3,6.0Hz,2H),2.25(s,3H).ESI-MS理论计算值C 37H 39ClN 2O 9[M+H] +＝691.23，实验测得：691.09.
实施例53：合成2-((4-氯-5-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)-2-((((2S,3R,4R,5R)-2,3,4,5,6-五羟基己基)氨基)甲基)苯氧基)甲基)苯甲腈(ZD57)
Figure PCTCN2020094013-appb-000120
步骤一：合成2-((4-氯-5-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)-2-甲酰基苯氧基)甲基)苯甲腈(ZD51)
将ZA52(120mg，0.308mmol)与2-(氯甲基)苄腈(56mg，0.369mmol)加入到反应瓶中用DMF(5ml)溶解，然后加入Cs 2CO 3(162.8mg，0.462mmol)，室温反应过夜。反应结束后加水淬灭，然后用乙酸乙酯萃取，有机相用无水硫酸钠干燥后旋干，最后用层析柱分离纯化得到目标产物48.9mg。 1H NMR(400MHz,Chloroform-d)δ10.36(s,1H),7.93(s,1H),7.75(d,J＝7.7Hz,1H),7.72–7.67(m,2H),7.55–7.48(m,1H),7.44(t,J＝4.5Hz,1H),7.27(s,1H),7.27(s,1H),6.94(d,J＝8.2Hz,1H),6.86(d,J＝2.1Hz,1H),6.81(dd,J＝2.1,8.2Hz,1H),6.75(s,1H),5.42(s,2H),5.27(s,2H),4.34(s,4H),2.32(s,3H).
步骤二：合成2-((4-氯-5-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)-2-((((2S,3R,4R,5R)-2,3,4,5,6-五羟基己基)氨基)甲基)苯氧基)甲基)苯甲腈(ZD57)
将ZD51(12mg，0.023mmol)、D-萄糖胺(12.4mg，0.069mmol)溶于MeOH(4ml)与THF(4ml)的混合溶剂中室温反应过夜，然后加入NaBH 4(17mg，0.460mmol)，继续反应5h。反应结束后旋干溶剂，HPLC纯化。得到目标化合物5.5mg. 1H NMR(400MHz,Methanol-d 4)δ7.84(dd,J＝1.1,7.4Hz,1H),7.79–7.70(m,2H),7.57(ddd,J＝2.3,6.6,7.7Hz,1H),7.51(s,1H),7.40(dd,J＝2.1,6.9Hz,1H),7.25–7.15(m,2H),7.04(s,1H),6.89(d,J＝8.0Hz,1H),6.79–6.70(m,2H),5.47(s,2H),5.29(s,2H),4.29(s,4H),4.28–4.19(m,2H),4.06(dt,J＝4.7,6.9Hz,1H),3.83(dd,J＝1.6,4.5Hz,1H),3.76(dd,J＝3.0,10.8Hz,1H),3.71–3.60(m,3H),3.20(dd,J＝2.8,5.9Hz,2H),2.28(s,3H).ESI-MS理论计算值C 37H 39ClN 2O 9[M+H] +＝691.23，实验测得：691.45.
实施例54：合成6-((4-氯-5-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)-2-((((2S,3R,4R,5R)-2,3,4,5,6-五羟基己基)氨基)甲基)苯氧基)甲基)-2-氰基吡啶(ZD58)
Figure PCTCN2020094013-appb-000121
步骤一：合成6-((4-氯-5-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)-2-甲酰基苯氧基)甲基)-2-氰基吡啶(ZD52)
将ZA52(130mg，0.333mmol)与6-(氯甲基)-2-氰基吡啶(61mg，0.40mmol)加入到反应瓶中用DMF(4ml)溶解，然后加入Cs 2CO 3(176.3mg，0.50mmol)，室温反应过夜。反应结束后加水淬灭，然后用乙酸乙酯萃取，有机相用无水硫酸钠干燥后旋干，最后用 层析柱分离纯化得到目标产物132.8mg。 1H NMR(400MHz,Chloroform-d)δ10.39(s,1H),7.97(t,J＝7.8Hz,1H),7.92(s,1H),7.87(d,J＝8.0Hz,1H),7.73(d,J＝7.6Hz,1H),7.49–7.42(m,1H),7.27(s,1H),7.26(s,1H),6.95(d,J＝8.2Hz,1H),6.85(d,J＝2.1Hz,1H),6.80(dd,J＝2.1,8.2Hz,1H),6.74(s,1H),5.36(s,2H),5.23(s,2H),4.34(s,4H),2.32(s,3H).
步骤二：合成6-((4-氯-5-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)-2-((((2S,3R,4R,5R)-2,3,4,5,6-五羟基己基)氨基)甲基)苯氧基)甲基)-2-氰基吡啶(ZD58)
将ZD52(27.4mg，0.052mmol)、D-萄糖胺(28.3mg，0.156mmol)溶于THF(4ml)与MeOH(4ml)的混合溶剂中室温反应过夜，然后加入NaBH 4(40mg，1.04mmol)，继续反应5h。反应结束后旋干溶剂，HPLC纯化。得到目标化合物7.3mg. 1H NMR(400MHz,Methanol-d 4)δ8.07(t,J＝7.8Hz,1H),7.89(dd,J＝7.7,9.0Hz,2H),7.51(s,1H),7.38(dd,J＝2.5,6.7Hz,1H),7.23–7.15(m,2H),7.02(s,1H),6.90(dt,J＝1.3,7.9Hz,1H),6.79–6.66(m,2H),5.45(s,2H),5.26(s,2H),4.33(s,1H),4.30(s,4H),4.25(d,J＝13.2Hz,1H),4.16–4.08(m,1H),3.87(dd,J＝1.3,4.7Hz,1H),3.79–3.73(m,1H),3.72–3.59(m,4H),3.26(dd,J＝2.7,6.2Hz,2H),2.27(s,3H).ESI-MS理论计算值C 36H 38ClN 3O 9[M+H] +＝692.23，实验测得：692.28.
实施例55：合成(2R,3R,4R,5S)-6-((5-氯-2-((3-氯苄基)氧基)-4-((3-(2,3-二氢苯并[b][1,4]二氧杂环己-6-基)-2-甲基苄基)氧基)苄基)氨基)己烷-1,2,3,4,5-五醇(ZD62)
Figure PCTCN2020094013-appb-000122
步骤一：5-氯-2-((3-氯苄基)氧基)-4-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)苯甲醛(ZD59)
将ZA52(130mg，0.33mmol)与1-氯-3-(氯甲基)苯(64.4mg，0.40mmol)加入到反应瓶中用DMF(4ml)溶解，然后加入Cs 2CO 3(176.4mg，0.50mmol)，室温反应过夜。反应结束后加水淬灭，然后用乙酸乙酯萃取，有机相用无水硫酸钠干燥后旋干，最后用层析柱分离纯化得到目标产物93.7mg。 1H NMR(400MHz,Chloroform-d)δ10.37(s,1H),7.92(s,1H),7.46–7.43(m,1H),7.43–7.39(m,1H),7.39–7.35(m,2H),7.35–7.29(m,1H),7.28–7.26(m,2H),6.94(d,J＝8.3Hz,1H),6.85(d,J＝2.1Hz,1H),6.80(dd,J＝2.1,8.2Hz,1H),6.62(s,1H),5.19(s,2H),5.17(s,2H),4.34(s,4H),2.29(s,3H).
步骤二：合成(2R,3R,4R,5S)-6-((5-氯-2-((3-氯苄基)氧基)-4-((3-(2,3-二氢苯并[b][1,4]二氧杂环己-6-基)-2-甲基苄基)氧基)苄基)氨基)己烷-1,2,3,4,5-五醇(ZD62)
将ZD59(17.3mg，0.032mmol)、D-萄糖胺(17.6mg，0.097mmol)溶于THF(3ml)与MeOH(3ml)的混合溶剂中室温反应过夜，然后加入NaBH 4(24.6mg，0.648mmol)，继续反应5h。反应结束后旋干溶剂，HPLC纯化。得到目标化合物12.1mg. 1H NMR(400MHz,Methanol-d 4)δ7.58(d,J＝1.9Hz,1H),7.49(s,1H),7.46(dt,J＝1.8,7.3Hz,1H),7.43(d,J＝7.7Hz,1H),7.41–7.38(m,1H),7.36(dd,J＝2.2,7.1Hz,1H),7.23–7.16(m,2H),6.97(s,1H),6.90(d,J＝8.1Hz,1H),6.77–6.71(m,2H),5.28(s,2H),5.23(s,2H),4.30(s,4H),4.27–4.16(m,2H),4.08(td,J＝4.5,5.9Hz,1H),3.86(dd,J＝1.6,4.5Hz,1H),3.78(dd,J＝3.1,10.5Hz,1H),3.73–3.60(m,3H),3.20(d,J＝5.9Hz,2H),2.26(s,3H).ESI-MS理论计算值C 36H 39Cl 2NO 9[M+H] +＝700.20，实验测得：700.21.
实施例56：合成((2R,3R,4R,5S)-6-((5-氯-4-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)-2-((3-氟苄基)氧基)苄基)氨基)己烷-1,2,3,4,5-五醇(ZD65)
Figure PCTCN2020094013-appb-000123
步骤一：5-氯-4-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)-2-((3-氟苄基)氧基)苯甲醛(ZD60)
将ZA52(150mg，0.384mmol)与1-氟-3-(氯甲基)苯(66.7mg，0.461mmol)加入到反应瓶中用DMF(4ml)溶解，然后加入Cs 2CO 3(203.5mg，0.577mmol)，室温反应过夜。反应结束后加水淬灭，然后用乙酸乙酯萃取，有机相用无水硫酸钠干燥后旋干，最后用层析柱分离纯化得到目标产物75.6mg。 1H NMR(400MHz,Chloroform-d)δ10.37(s,1H),7.92(s,1H),7.44–7.36(m,2H),7.27(s,1H),7.26(d,J＝1.8Hz,1H),7.20(d,J＝7.6Hz,1H),7.15(d,J＝9.4Hz,1H),7.08(t,J＝8.8Hz,1H),6.94(d,J＝8.2Hz,1H),6.85(d,J＝2.0Hz,1H),6.80(dd,J＝2.1,8.2Hz,1H),6.62(s,1H),5.20(s,2H),5.18(s,2H),4.34(s,4H),2.29(s,3H).
步骤二：合成((2R,3R,4R,5S)-6-((5-氯-4-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)-2-((3-氟苄基)氧基)苄基)氨基)己烷-1,2,3,4,5-五醇(ZD65)
将ZD60(16.7mg，0.032mmol)、D-萄糖胺(17.6mg，0.097mmol)溶于THF(3ml)与MeOH(3ml)的混合溶剂中室温反应过夜，然后加入NaBH 4(24.5mg，0.645mmol)，继续反应5h。反应结束后旋干溶剂，HPLC纯化。得到目标化合物10mg.1H NMR(400MHz,Methanol-d4)δ7.49(s,1H),7.44(td,J＝5.8,8.0Hz,1H),7.38–7.33(m,2H),7.33–7.27(m,2H),7.23–7.15(m,2H),7.14–7.07(m,1H),6.96(s,1H),6.89(d,J＝8.1Hz,1H),6.77 –6.71(m,2H),5.30(s,2H),5.25(s,2H),4.29(s,4H),4.28–4.15(m,2H),4.08(dt,J＝5.0,6.6Hz,1H),3.86(dd,J＝1.6,4.5Hz,1H),3.77(dd,J＝3.1,10.5Hz,1H),3.66(ddt,J＝5.1,10.1,15.6Hz,3H),3.25–3.17(m,2H),2.26(s,3H).ESI-MS理论计算值C 36H 39ClFNO 9[M+H] +＝684.23，实验测得：684.24.
实施例57：合成(2R,3R,4R,5S)-6-((5-氯-4-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基基)-2-(吡啶-2-基甲氧基)苄基)氨基)己烷-1,2,3,4,5-五醇(ZD75)
Figure PCTCN2020094013-appb-000124
步骤一：合成5-氯-4-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)-2-(吡啶-2-基甲氧基)苯甲醛(ZD72)
将ZA52(130mg，0.33mmol)与2-(氯甲基)吡啶(65.6mg，0.40mmol)加入到反应瓶中用DMF(4ml)溶解，然后加入Cs 2CO 3(317.4mg，0.89mmol)，室温反应过夜。反应结束后加水淬灭，然后用乙酸乙酯萃取，有机相用无水硫酸钠干燥后旋干，最后用层析柱分离纯化得到目标产物104.3mg。 1H NMR(400MHz,Chloroform-d)δ10.43(s,1H),8.63(d,J＝5.1Hz,1H),7.91(s,1H),7.78(td,J＝1.8,7.7Hz,1H),7.61–7.51(m,1H),7.43(t,J＝4.5Hz,1H),7.31(d,J＝7.7Hz,1H),7.26(d,J＝4.5Hz,2H),6.94(d,J＝8.2Hz,1H),6.86(d,J＝2.1Hz,1H),6.83–6.72(m,2H),5.36(s,2H),5.16(s,2H),4.34(s,4H),2.29(d,J＝1.8Hz,3H).
步骤二：合成(2R,3R,4R,5S)-6-((5-氯-4-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基基)-2-(吡啶-2-基甲氧基)苄基)氨基)己烷-1,2,3,4,5-五醇(ZD75)
将ZD72(24.3mg，0.049mmol)、D-萄糖胺(26.4mg，0.15mmol)，溶于THF(3ml)与MeOH(3ml)的混合溶剂中室温反应过夜，然后加入NaBH 4(36.9mg，1.0mmol)，继续反应5h。反应结束后旋干溶剂，HPLC纯化。得到目标化合物9.2mg. 1H NMR(400MHz,Methanol-d 4)δ8.73–8.65(m,1H),7.99(td,J＝1.7,7.7Hz,1H),7.66(d,J＝7.8Hz,1H),7.53–7.45(m,2H),7.37(dd,J＝2.9,6.4Hz,1H),7.22–7.14(m,2H),7.02(s,1H),6.89(d,J＝8.1Hz,1H),6.79–6.70(m,2H),5.46(s,2H),5.24(s,2H),4.29(s,4H),4.25(d,J＝2.7Hz,2H),4.14(dt,J＝5.0,6.9Hz,1H),3.90(dd,J＝1.4,4.8Hz,1H),3.78(dd,J＝2.5,10.5Hz,1H),3.74–3.61(m,3H),3.29–3.20(m,2H),2.26(s,3H).ESI-MS理论计算值C 35H 39ClN 2O 9[M+H] +＝667.23，实验测得：667.23.
实施例58：合成(2R,3R,4R,5S)-6-((5-氯-2-((3-氯-4-氟苄基)氧基)-4-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)苄基)氨基)己烷-1,2,3,4,5-五醇(ZD77)
Figure PCTCN2020094013-appb-000125
步骤一：合成5-氯-2-((3-氯-4-氟苄基)氧基)-4-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)苯甲醛(ZD76)
将ZA52(130mg，0.33mmol)与2-氯-4-(氯甲基)-1-氟苯(71.6mg，0.40mmol)加入到反应瓶中用DMF(4ml)溶解，然后加入Cs 2CO 3(176.4mg，0.50mmol)，室温反应过夜。反应结束后加水淬灭，然后用乙酸乙酯萃取，有机相用无水硫酸钠干燥后旋干，最后用层析柱分离纯化得到目标产物122mg。 1H NMR(400MHz,Chloroform-d)δ10.33(s,1H),7.93(s,1H),7.54–7.46(m,1H),7.46–7.35(m,1H),7.31(d,J＝4.0Hz,1H),7.27(d,J＝1.8Hz,1H),7.20(t,J＝8.6Hz,1H),6.94(d,J＝8.2Hz,1H),6.85(d,J＝2.1Hz,1H),6.81(d,J＝2.1Hz,1H),6.79(d,J＝2.1Hz,1H),6.62(s,1H),5.22(s,2H),5.13(s,2H),4.34(s,4H),2.30(s,3H).
步骤二：合成(2R,3R,4R,5S)-6-((5-氯-2-((3-氯-4-氟苄基)氧基)-4-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)苄基)氨基)己烷-1,2,3,4,5-五醇(ZD77)
将ZD76(21mg，0.038mmol)、D-萄糖胺(20.7mg，0.069mmol)溶于THF(4ml)与MeOH(4ml)的混合溶剂中室温反应过夜，然后加入NaBH 4(28.9mg，0.76mmol)，继续反应5h。反应结束后旋干溶剂，HPLC纯化。得到目标化合物12.2mg. 1H NMR(400MHz,Methanol-d 4)δ7.68(dd,J＝2.2,7.1Hz,1H),7.53–7.45(m,2H),7.37(dd,J＝2.4,6.7Hz,1H),7.29(t,J＝8.8Hz,1H),7.24–7.15(m,2H),6.97(s,1H),6.89(d,J＝8.1Hz,1H),6.77–6.71(m,2H),5.25(d,J＝2.4Hz,4H),4.29(s,4H),4.26–4.15(m,2H),4.08(dt,J＝5.0,6.6Hz,1H),3.86(dd,J＝1.6,4.5Hz,1H),3.78(dd,J＝3.1,10.4Hz,1H),3.73–3.61(m,3H),3.26–3.16(m,2H),2.27(s,3H).ESI-MS理论计算值C 36H 38Cl 2FNO 9[M+H] +＝718.19，实验测得：718.30.
实施例59：合成(2R,3R,4R,5S)-6-((5-氯-4-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基基)-2-(吡啶-4-基甲氧基)苄基)氨基)己烷-1,2,3,4,5-五醇(ZD78)
Figure PCTCN2020094013-appb-000126
步骤一：合成5-氯-4-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)-2-(吡啶-4-基甲氧基)苯甲醛(ZD74)
将ZA52(130mg，0.33mmol)与4-(氯甲基)吡啶(65.6mg，0.40mmol)加入到反应瓶中用DMF(4ml)溶解，然后加入Cs 2CO 3(317.4mg，0.89mmol)，室温反应过夜。反应结束后加水淬灭，然后用乙酸乙酯萃取，有机相用无水硫酸钠干燥后旋干，最后用层析柱分离纯化得到目标产物131mg。 1H NMR(400MHz,Chloroform-d)δ10.39(s,1H),8.72–8.62(m,2H),7.93(s,1H),7.41–7.32(m,3H),7.27–7.23(m,2H),6.94(d,J＝8.3Hz,1H),6.84(d,J＝2.0Hz,1H),6.79(dd,J＝2.1,8.2Hz,1H),6.58(s,1H),5.21(s,2H),5.19(s,2H),4.33(s,4H),2.28(s,3H).
步骤二：合成(2R,3R,4R,5S)-6-((5-氯-4-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基基)-2-(吡啶-4-基甲氧基)苄基)氨基)己烷-1,2,3,4,5-五醇(ZD78)
将ZD74(24.3mg，0.05mmol)、D-萄糖胺(26.4mg，0.15mmol)溶于THF(3ml)与MeOH(3ml)的混合溶剂中室温反应过夜，然后加入NaBH 4(36.9mg，0.96mmol)，继续反应5h。反应结束后旋干溶剂，HPLC纯化。得到目标化合物9.2mg.1H NMR(400MHz,Methanol-d 4)δ8.93–8.80(m,2H),8.19(d,J＝6.4Hz,2H),7.57(s,1H),7.37(dd,J＝3.1,5.9Hz,1H),7.25–7.12(m,2H),7.00(s,1H),6.89(d,J＝8.0Hz,1H),6.79–6.68(m,2H),5.63(s,2H),5.28(s,2H),4.42–4.32(m,2H),4.29(s,4H),4.17–4.08(m,1H),3.88(dd,J＝1.2,4.6Hz,1H),3.79–3.70(m,1H),3.71–3.58(m,3H),3.28(t,J＝5.8Hz,2H),2.27(s,3H).ESI-MS理论计算值C 35H 39ClN 2O 9[M+H] +＝667.23，实验测得：667.45.
实施例60：合成(2R,3R,4R,5S)-6-((5-氯-2-((2,4-二氟苄基)氧基)-4-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)苄基)氨基)己烷-1,2,3,4,5-五醇(ZD81)
Figure PCTCN2020094013-appb-000127
步骤一：合成5-氯-2-((2,4-二氟苄基)氧基)-4-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)苯甲醛(ZD80)
将ZA52(130mg，0.33mmol)与1-(氯甲基)-2,4-二氟苯(65.0mg，0.40mmol)加入到反应瓶中用DMF(4ml)溶解，然后加入Cs 2CO 3(176.4mg，0.50mmol)，室温反应过夜。反应结束后加水淬灭，然后用乙酸乙酯萃取，有机相用无水硫酸钠干燥后旋干，最后用层析柱分离纯化得到目标产物157.9mg。 1H NMR(400MHz,DMSO-d6)δ10.13(s,1H),7.78–7.72(m,1H),7.71(s,1H),7.51(dd,J＝1.4,7.5Hz,1H),7.39–7.32(m,2H),7.29(t,J＝7.6Hz,1H),7.22(dd,J＝1.5,7.7Hz,1H),7.16(ddd,J＝2.4,7.9,10.4Hz,1H),6.94(d,J＝8.2Hz,1H),6.80(d,J＝2.1Hz,1H),6.77(dd,J＝2.2,8.2Hz,1H),5.42(d,J＝5.2Hz,4H),4.29(s,4H),2.26(s,3H).
步骤二：合成(2R,3R,4R,5S)-6-((5-氯-2-((2,4-二氟苄基)氧基)-4-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)苄基)氨基)己烷-1,2,3,4,5-五醇(ZD81)
将ZD80(20mg，0.037mmol)、D-萄糖胺(20.3mg，0.112mmol)溶于THF(4ml)与MeOH(4ml)的混合溶剂中室温反应过夜，然后加入NaBH 4(28.4mg，0.746mmol)，室温反应约5h。反应结束后旋干溶剂，HPLC纯化。得到目标化合物14.3mg. 1H NMR(400MHz,Methanol-d 4)δ7.59(td,J＝6.3,8.3Hz,1H),7.42(dd,J＝1.8,7.3Hz,1H),7.30(s,1H),7.25–7.15(m,2H),7.06–6.98(m,2H),6.93(s,1H),6.89(d,J＝8.1Hz,1H),6.79–6.71(m,2H),5.23(s,2H),5.20(s,2H),4.29(s,4H),3.86(dt,J＝4.6,6.4Hz,1H),3.81–3.73(m,2H),3.73–3.67(m,1H),3.66–3.57(m,2H),2.77–2.63(m,2H),2.28(s,3H).ESI-MS理论计算值C 36H 38ClF 2NO 9[M+H] +＝702.22，实验测得：702.09.
实施例61：合成(2R,3R,4R,5S)-6-((2-(苄氧基)-5-氯-4-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)苄基)氨基)己烷-1,2,3,4,5-戊醇(ZD82)
Figure PCTCN2020094013-appb-000128
将ZD79(20mg，0.04mmol)、D-萄糖胺(21.7mg，0.12mmol)溶于THF(4ml)与MeOH(4ml)的混合溶剂中室温反应过夜，然后加入NaBH 4(30.4mg，0.80mmol)，继续反应5h。反应结束后旋干溶剂，HPLC纯化。得到目标化合物32.1mg. 1H NMR(400MHz,Methanol-d4)δ7.53–7.49(m,2H),7.47(s,1H),7.45–7.39(m,2H),7.37(ddd,J＝1.9,4.4,8.9Hz,2H),7.23–7.15(m,2H),6.97(s,1H),6.89(d,J＝8.2Hz,1H),6.77–6.70(m,2H),5.28(s,2H),5.20(s,2H),4.29(s,4H),4.27–4.15(m,2H),4.07(dt,J＝4.9,6.7Hz,1H),3.84(dd,J＝1.6,4.5Hz,1H),3.78(dd,J＝3.2,10.7Hz,1H),3.73–3.61(m,3H),3.24–3.13(m,2H),2.25(s,3H).ESI-MS理论计算值C 36H 40ClNO 9[M+H] +＝666.24，测得：666.91.
实施例62：合成N-(5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧)苯甲基)-N-甲基环氧乙烷-2-甲酰胺(ZD83)
Figure PCTCN2020094013-appb-000129
步骤一：合成5-((4-氯-5-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)-2-((甲基氨基)甲基)苯氧基)甲基烟腈(ZD110)
将ZD07(356.4mg，0.102mmol)、甲胺(209.4mg，2.032mmol，31％in MeOH)溶于THF(5ml)与MeOH(5ml)的混合溶剂中，室温反应过夜。然后依次加入AcOH(0.1ml)、NaBH(OAc) 3(712.8mg，3.387mmol)室温反应过夜。待反应结束后旋干溶剂并用HPLC纯化。得到目标化合物219.1mg。 1H NMR(400MHz,Methanol-d4)δ8.96(d,J＝2.1Hz,1H),8.93(d,J＝1.9Hz,1H),8.36(t,J＝2.1Hz,1H),7.52(s,1H),7.40(dd,J＝6.9,2.1Hz,1H),7.26–7.15(m,2H),7.04(s,1H),6.89(d,J＝8.1Hz,1H),6.80–6.70(m,2H),5.39(s,2H),5.30(s,2H),4.29(s,4H),4.20(s,2H),2.70(s,3H),2.28(s,3H).
步骤二：合成N-(5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧)苯甲基)-N-甲基环氧乙烷-2-甲酰胺(ZD83)
将环氧乙烷-2-羧酸(3.1mg，0.035mmol)溶于干燥的二氯甲烷中，冰水浴降温，然后加入氮甲基吗啉(3.54mg，0.035mmol)、氯甲酸异丁酯(4.3mg，0.032mmol)，混合液在0℃反应1小时后加入ZD110(18.9mg,0.035mmol)并补加N-甲基吗啉(3.54mg，0.035mmol)，室温反应5h后旋干溶剂并用HPLC纯化。得到目标化合物7.6mg。1H NMR(400MHz,Methanol-d4)δ8.92(d,J＝5.6Hz,2H),8.36–8.27(m,1H),7.42(t,J＝6.2Hz,1H),7.26(d,J＝1.6Hz,1H),7.20(ddd,J＝11.8,7.6,2.1Hz,2H),6.98(d,J＝7.2Hz,1H),6.89(d,J＝8.0Hz,1H),6.80–6.72(m,2H),5.30(d,J＝13.3Hz,2H),5.26(d,J＝3.0Hz,2H),4.72–4.49(m,2H),4.30(s,4H),3.83(dd,J＝4.4,2.5Hz,1H),3.12(s,2H),2.99(dd,J＝6.3,4.4Hz,1H),2.88(s,1H),2.85–2.70(m,1H),2.28(s,3H).ESI-MS理论计算值C 34H 30ClN 3O 6[M+H] +＝612.18，测得612.5.
实施例63：合成N-(3-((5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)苄基)(甲基(氨基)丙基)环氧乙烷-2-甲酰胺(ZD85)
Figure PCTCN2020094013-appb-000130
步骤一：合成叔丁基(3-((5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)苄基)(甲基)氨基)丙基)氨基甲酸酯(ZD70)
将ZD07(35mg，0.060mg)、(3-(甲基氨基)丙基)氨基甲酸叔丁酯(33.8mg，0.180mmol)加入到反应瓶中并用干燥的四氢呋喃(8ml)，DCE(1ml)溶解，然后加入AcOH(0.1ml)，最后加入NaBH(OAc) 3(63.3mg,0.299mmol)，室温反应过夜。待反应结束后旋干溶剂并用层析柱分离纯化，得到目标化合物22mg。 1H NMR(400MHz,Chloroform-d)δ8.91(t,J＝1.8Hz,1H),8.87(d,J＝2.3Hz,1H),8.11(s,1H),7.48–7.35(m,2H),7.30–7.20(m,2H),7.03–6.89(m,1H),6.87–6.75(m,2H),6.70–6.57(m,1H),5.24(d,J＝5.9Hz,2H),5.16(d,J＝4.6Hz,2H),4.67(s,1H),4.32(s,4H),3.14(s,1H),2.97(s,1H),2.89(s,1H),2.62(s,1H),2.05(s,1H),1.91–1.82(m,1H),1.77(s,1H),1.45(s,3H),1.43(s,3H),0.09(s,9H).
步骤二：合成5-((2-((((3-氨基丙基)(甲基)氨基)甲基)-4-氯-5-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)苯氧基)甲基)烟腈(ZD85-1)
将ZD70溶于二氯甲烷(3ml)中然后加入TFA(1ml)，室温搅拌1h后旋干溶剂并用HPLC纯化，得到目标化合物13mg。 1H NMR(400MHz,Methanol-d4)δ8.98(d,J＝2.1Hz,1H),8.95(d,J＝2.0Hz,1H),8.37(t,J＝2.1Hz,1H),7.58(s,1H),7.42(dd,J＝2.1,7.0Hz,1H),7.27–7.18(m,2H),7.08(s,1H),6.90(d,J＝8.1Hz,1H),6.79–6.72(m,2H),5.41(s,2H),5.32(s,2H),4.91(s,1H),4.47(s,1H),4.30(s,4H),4.28(s,1H),3.31(s,1H),3.02(t,J＝7.6Hz,2H),2.82(s,3H),2.29(s,3H),2.14(p,J＝8.0Hz,2H).
步骤三：合成N-(3-((5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)苄基)(甲基(氨基)丙基)环氧乙烷-2-甲酰胺(ZD85)
将环丙烷甲酸(2.0mg，0.022mmol)溶于干燥的二氯甲烷中，然后加入N-甲基吗啉(2.25mg，0.022mmol)、氯甲酸异丁酯(2.7mg，0.02mmol)冰水浴搅拌1h，然后加入(ZD85-1)(13mg，0.022mmol)并补加N-甲基吗啉(2.25mg，0.022mmol)室温反应5h。待反应结束后旋干溶剂，HPLC纯化。得到目标化合物3mg。 1H NMR(400MHz,Methanol-d4)δ8.98(d,J＝2.1Hz,1H),8.95(d,J＝1.9Hz,1H),8.40(t,J＝2.1Hz,1H),7.52(s,1H),7.47–7.40(m,1H),7.27–7.17(m,2H),7.07(s,1H),6.90(d,J＝8.0Hz,1H),6.79–6.73(m,2H),5.37(s,2H),5.32(s,2H),4.30(s,4H),4.29(s,1H),4.13(s,1H),3.36(dd,J＝2.5,4.5Hz,1H),3.24(dd,J＝2.6,4.5Hz,1H),3.17(t,J＝6.5Hz,1H),2.95(dd,J＝4.4,6.0Hz,1H),2.71–2.71(m,2H),2.64(s,3H),2.30(s,3H),1.87(d,J＝8.5Hz,2H).ESI-MS理论计算值C 37H 37ClN 4O 6[M+H] +＝669.24， 测得：669.2.
实施例64：合成(2R,3R,4R,5S)-6-((5-氯-4-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)-2-((3-硝基苄基)氧基)苄基)氨基)己烷-1,2,3,4,5-五醇(ZD114)
Figure PCTCN2020094013-appb-000131
步骤一:5-氯-4-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)-2-((3-硝基苄基)氧基)苯甲醛(ZD113)
将ZA52(100mg，0.256mmol)、1-(氯甲基)-3-硝基苯(52.8mg，0.308mmol)溶于DMF中，后加入Cs 2CO 3(135.6mg，0.384mmol)室温反应过夜。待反应结束后加水淬灭，用二氯甲烷萃取三次，有机相用饱和氯化钠溶液洗、无水硫酸钠干燥后旋干溶剂，并用层析柱分离纯化，得到目标化合物128.2mg。 1H NMR(400MHz,Chloroform-d)δ10.36(s,1H),8.34(s,1H),8.27(d,J＝8.2Hz,1H),7.94(s,1H),7.81(d,J＝7.7Hz,1H),7.64(t,J＝8.0Hz,1H),7.45–7.37(m,1H),7.28–7.26(m,2H),6.94(d,J＝8.2Hz,1H),6.84(d,J＝2.1Hz,1H),6.79(dd,J＝2.1,8.2Hz,1H),6.66(s,1H),5.28(s,2H),5.23(s,2H),4.34(s,4H),2.30(s,3H),1.28(s,2H),0.95–0.81(m,2H).
步骤二：合成(2R,3R,4R,5S)-6-((5-氯-4-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)-2-((3-硝基苄基)氧基)苄基)氨基)己烷-1,2,3,4,5-五醇(ZD114)
将ZD113(42mg，0.077mmol)、D-萄糖胺(41.8mg，0.231mmol)溶于溶于THF(3ml)与MeOH(3ml)的混合溶剂中室温反应过夜，后加入NaBH 4(58.6mg，1.54mmol)，室温反应约5h。反应结束后旋干溶剂，HPLC纯化。得到目标化合物9.9mg。 1H NMR(400MHz,Methanol-d 4)δ7.79(d,J＝8.3Hz,2H),7.68(s,1H),7.50(d,J＝8.1Hz,2H),7.33(dd,J＝1.7,7.3Hz,1H),7.28–7.17(m,2H),6.90(d,J＝8.1Hz,1H),6.80–6.69(m,3H),5.03(s,2H),4.30(s,4H),4.20–4.05(m,3H),3.86(dd,J＝1.6,4.6Hz,1H),3.79(dd,J＝3.0,10.3Hz,1H),3.76–3.62(m,3H),3.28–3.17(m,2H),2.47(s,3H),2.22(s,3H).ESI-MS理论值:C 36H 39ClN 2O 11[M+H] +＝711.22，测得：711.3.
实施例65：合成(2R,3R,4R,5S)-6-((5-氯-2-((2-氯吡啶-4-基)甲氧基)-4-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)苄基)氨基)己烷-1,2,3,4,5-五醇(ZD115)
Figure PCTCN2020094013-appb-000132
步骤一:合成5-氯-2-((2-氯吡啶-4-基)甲氧基)-4-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)苯甲醛(ZD112)
将ZA52(100mg，0.256mmol)、3-(氯甲基)-2-氯吡啶(49.5mg，0.308mmol)溶于DMF中，后加入Cs 2CO 3(135.6mg，0.384mmol)室温反应过夜。待反应结束后加水淬灭，用二氯甲烷萃取三次，有机相用饱和氯化钠溶液洗、无水硫酸钠干燥后旋干溶剂，并用层析柱分离纯化，得到目标化合物62mg。 1H NMR(400MHz,Methanol-d4)δ8.44(t,J＝5.5Hz,2H),8.37(d,J＝5.1Hz,1H),7.40(d,J＝0.7Hz,1H),7.32(s,1H),7.24(d,J＝2.3Hz,2H),6.96(d,J＝4.5Hz,1H),6.85(d,J＝2.1Hz,1H),6.79(ddd,J＝8.3,7.0,2.1Hz,2H),5.15(s,2H),5.11(s,2H),4.34(s,4H),4.24–4.11(m,2H),2.30(s,3H).
步骤二：合成(2R,3R,4R,5S)-6-((5-氯-2-((2-氯吡啶-4-基)甲氧基)-4-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)苄基)氨基)己烷-1,2,3,4,5-五醇(ZD115)
将ZD112(42mg，0.077mmol)、D-萄糖胺(42.6mg，0.235mmol)溶于THF(3ml)与MeOH(3ml)的混合溶剂中室温反应过夜，后加入NaBH 4(60mg，1.57mmol)，室温反应约5h。反应结束后旋干溶剂，HPLC纯化。得到目标化合物8.7mg。 1H NMR(400MHz,Methanol-d 4)δ8.40(d,J＝5.2Hz,1H),7.62(s,1H),7.52(d,J＝8.6Hz,2H),7.36–7.28(m,1H),7.18(d,J＝4.5Hz,2H),6.95–6.87(m,2H),6.78–6.71(m,2H),5.37(s,2H),5.26(s,2H),4.30(s,4H),4.25(d,J＝13.2Hz,2H),4.09(t,J＝5.3Hz,1H),3.87(d,J＝4.5Hz,1H),3.82–3.73(m,1H),3.69(d,J＝4.4Hz,2H),3.67–3.58(m,1H),3.24(d,J＝5.9Hz,2H),2.26(s,3H).ESI-MS理论值:C 35H 38Cl 2N 2O 9[M+H] +＝701.20，测得：701.68。
实施例66：合成(2R,3R,4R,5S)-6-((5-氯-4-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)-2-((3-甲基苄基)氧基)苄基)氨基)己烷-1,2,3,4,5-五醇(ZD116)
Figure PCTCN2020094013-appb-000133
步骤一:5-氯-4-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)-2- ((3-甲基苄基)氧基)苯甲醛(ZD111)
将ZA52(100mg,0.256mmol)、1-(氯甲基)-3-甲基苯(43mg，0.308mmol)溶于DMF中，后加入Cs 2CO 3(135.6mg,0.384mmol)室温反应过夜。待反应结束后加水淬灭，用二氯甲烷萃取三次，有机相用饱和氯化钠溶液洗、无水硫酸钠干燥后旋干溶剂，并用层析柱分离纯化，得到目标化合物105mg。 1H NMR(400MHz,Chloroform-d)δ10.37(s,1H),7.40(q,J＝4.4Hz,1H),7.34–7.29(m,3H),7.28–7.24(m,2H),7.21(t,J＝7.4Hz,2H),6.94(d,J＝8.2Hz,1H),6.85(d,J＝2.1Hz,1H),6.80(dd,J＝8.2,2.1Hz,1H),6.66(d,J＝4.3Hz,1H),5.17(s,4H),4.34(s,4H),2.40(s,3H),2.29(s,3H).
步骤二：合成(2R,3R,4R,5S)-6-((5-氯-4-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)-2-((3-甲基苄基)氧基)苄基)氨基)己烷-1,2,3,4,5-五醇(ZD116)
将ZD111(30mg，0.058mmol)、D-萄糖胺(31.7mg，0.175mmol)溶于THF(3ml)与MeOH(3ml)的混合溶剂中室温反应过夜，后加入NaBH 4(44.3mg，1.17mmol)，室温反应约5h。反应结束后旋干溶剂，HPLC纯化。得到目标化合物7.7mg。 1H NMR(400MHz,Methanol-d 4)δ7.46(s,1H),7.37–7.32(m,2H),7.30(dd,J＝2.2,4.6Hz,2H),7.19(dd,J＝2.0,6.3Hz,3H),6.96(s,1H),6.89(d,J＝8.1Hz,1H),6.77–6.70(m,2H),5.24(s,2H),5.20(s,2H),4.29(s,4H),4.20(d,J＝6.3Hz,2H),4.07(dt,J＝5.0,6.8Hz,1H),3.85(dd,J＝1.6,4.5Hz,1H),3.76(d,J＝3.2Hz,1H),3.73–3.60(m,2H),3.23–3.14(m,2H),2.37(s,3H),2.25(s,3H).ESI-MS理论值:C 37H 42ClNO 9[M+H] +＝680.25，测得：680.5。
实施例67：合成5-((4-氯-5-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)-2-((甲基((2R,3S,4S,5S)-2,3,4,5,6-五羟基己基)氨基)甲基)苯氧基)甲基)烟腈(ZD119)
Figure PCTCN2020094013-appb-000134
将ZD110(33.3mg，0.062mmol)、L-葡萄糖(33.26mg，0.186mmol)溶于THF(5ml)与MeOH(5ml)的混合溶剂中室温反应过夜，然后依次加入AcOH(0.08ml)、NaBH(OAc) 3(65.22mg，0.308mmol)室温反应过夜。反应结束后旋干溶剂，HPLC纯化。得到目标化合物11.8mg。 1H NMR(400MHz,Methanol-d4)δ8.98(s,1H),8.94(d,J＝2.2Hz,1H),8.46–8.36(m,1H),7.63–7.53(m,1H),7.42(dd,J＝7.0,1.8Hz,1H),7.27–7.16(m,2H),7.08(s,1H),6.90(d,J＝8.0Hz,1H),6.81–6.70(m,2H),5.40(d,J＝5.3Hz,2H),5.32(s,2H),4.84–4.51(m,1H),4.30(s,4H),4.25–4.05(m,1H),3.99(d,J＝22.6Hz,1H),3.86(d,J＝15.7Hz,1H),3.83–3.75(m,1H),3.71(d,J＝11.3Hz,1H),3.68–3.60(m,1H),3.60–3.46(m,1H),3.46–3.36(m,1H),3.26(dd,J＝13.5,6.6Hz,1H),3.02–2.81(m,3H),2.29(s,3H).ESI-MS理论值:C 37H 40ClN 3O 9[M+H] +＝706.25，测得：706.16；比旋光
Figure PCTCN2020094013-appb-000135
浓度为1.0，溶剂为CHCl 3。
实施例68：合成5-((4-氯-5-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)-2-((甲基((2R,3R,4R,5R)-2,3,4,5,6-五羟基己基)氨基)甲基)苯氧基)甲基)烟腈(ZD121)
Figure PCTCN2020094013-appb-000136
将ZD110(25mg，0.046mmol)、D-(+)-甘露糖(24.97mg，0.139mmol)溶于THF(5ml)与MeOH(5ml)的混合溶剂中室温搅拌20min，然后依次加入AcOH(0.05ml)、NaBH(OAc) 3(48.97mg，0.231mmol)反应过夜。反应结束后旋干溶剂，HPLC纯化。得到目标化合物7.7mg。 1H NMR(400MHz,Methanol-d4)δ8.98(s,1H),8.94(d,J＝2.2Hz,1H),8.41(d,J＝12.5Hz,1H),7.58(d,J＝6.8Hz,1H),7.46–7.36(m,1H),7.27–7.17(m,3H),7.08(s,1H),6.90(d,J＝8.0Hz,1H),6.79–6.71(m,2H),5.40(d,J＝5.4Hz,2H),5.32(s,2H),4.30(s,5H),4.26–4.14(m,1H),4.08(d,J＝6.0Hz,1H),4.04–3.94(m,1H),3.88(s,1H),3.84–3.75(m,1H),3.75–3.59(m,1H),3.59–3.47(m,1H),3.45–3.36(m,1H),3.27(d,J＝13.4Hz,1H),3.03–2.81(m,3H),2.29(s,3H).ESI-MS理论值:C 37H 40ClN 3O 9[M+H] +＝706.25，测得：706.16。
实施例69：合成(2R,3R,4R,5S)-6-((5-氯-4-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)-2-((3-(三氟甲基)苄基)氧基)苄基)氨基)己烷-1,2,3,4,5-五醇(ZD122)
Figure PCTCN2020094013-appb-000137
步骤一:5-氯-4-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)-2-((3-(三氟甲基)苄基)氧基)苯甲醛(ZD118)
将ZA52(100mg,0.256mmol)、1-(氯甲基)-3-(三氟甲基)苯(59.8mg，0.308mmol)溶于DMF中，后加入Cs 2CO 3(135.6mg,0.384mmol)室温反应过夜。待反应结束后加水淬灭，用二氯甲烷萃取三次，有机相用饱和氯化钠溶液洗、无水硫酸钠干燥后旋干溶剂，并用层析柱分离纯化，得到目标化合物82.8mg。 1H NMR(400MHz,Chloroform-d)δ10.33(s,1H),7.91(s,1H),7.70(s,1H),7.64(t,J＝7.6Hz,2H),7.55(t,J＝7.7Hz,1H),7.42–7.37(m,1H),7.25(s,1H),7.24(d,J＝1.5Hz,1H),6.92(d,J＝8.2Hz,1H),6.82(d,J＝2.1Hz,1H),6.77(dd,J＝2.1,8.2Hz,1H),6.63(s,1H),5.22(s,2H),5.18(s,2H),4.31(s,4H),2.27 (s,3H).
步骤二：合成(2R,3R,4R,5S)-6-((5-氯-4-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)-2-((3-甲基苄基)氧基)苄基)氨基)己烷-1,2,3,4,5-五醇(ZD122)
将ZD118(35.7mg，0.063mmol)、D-萄糖胺(34.1mg，0.189mmol)溶于THF(4ml)与MeOH(4ml)的混合溶剂中室温反应过夜，后加入NaBH 4(47.8mg，1.257mmol)，室温反应约5h。反应结束后旋干溶剂，HPLC纯化。得到目标化合物9.2mg。 1H NMR(400MHz,Methanol-d 4)δ7.86(s,1H),7.82(d,J＝7.7Hz,1H),7.70(d,J＝7.9Hz,1H),7.65(d,J＝7.7Hz,1H),7.50(s,1H),7.37(dd,J＝2.4,6.7Hz,1H),7.24–7.15(m,2H),7.01(s,1H),6.89(d,J＝8.1Hz,1H),6.77–6.70(m,2H),5.37(s,2H),5.23(s,2H),4.29(s,4H),4.28–4.17(m,2H),4.08(q,J＝5.5Hz,1H),3.85(dd,J＝1.6,4.5Hz,1H),3.77(dd,J＝3.1,10.5Hz,1H),3.73–3.60(m,2H),3.20(d,J＝5.8Hz,2H),2.26(s,3H).ESI-MS理论值:C37H39ClF3NO9[M+H] +＝734.23，测得：734.05。
实施例70：合成(2R,3R,4R,5S)-6-((5-氯-2-((6-氯吡啶-2-基)甲氧基)-4-((3-(2,3-二氢苯并[b][1，4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)苄基)氨基)己烷-1,2,3,4,5-五醇(ZD123)
Figure PCTCN2020094013-appb-000138
步骤一:5-氯-2-((6-氯吡啶-2-基)甲氧基)-4-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)苯甲醛(ZD117)
将ZA52(100mg,0.256mmol)、2-氯-6-(氯甲基)吡啶(49.5mg，0.308mmol)溶于DMF中，后加入Cs 2CO 3(135.6mg,0.384mmol)室温反应过夜。待反应结束后加水淬灭，用二氯甲烷萃取三次，有机相用饱和氯化钠溶液洗、无水硫酸钠干燥后旋干溶剂，并用层析柱分离纯化，得到目标化合物96.3mg。 1H NMR(400MHz,Chloroform-d)δ10.28(s,1H),8.48(d,J＝2.4Hz,1H),7.92(s,1H),7.77(dd,J＝8.3,2.5Hz,1H),7.46–7.38(m,2H),7.27(d,J＝2.3Hz,2H),6.94(d,J＝8.2Hz,1H),6.85(d,J＝2.1Hz,1H),6.80(dd,J＝8.2,2.1Hz,1H),6.66(s,1H),5.24(s,2H),5.18(s,2H),4.33(s,5H),4.14(q,J＝7.2Hz,1H),2.31(s,3H).
步骤二：合成(2R,3R,4R,5S)-6-((5-氯-2-((6-氯吡啶-2-基)甲氧基)-4-((3-(2,3-二氢苯并[b][1，4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)苄基)氨基)己烷-1,2,3,4,5-五醇(ZD123)
将ZD117(14mg，0.026mmol)、D-萄糖胺(14.2mg，0.078mmol)溶于THF(4ml) 与MeOH(4ml)的混合溶剂中室温反应过夜，后加入NaBH 4(20mg，0.523mmol)，室温反应约5h。反应结束后旋干溶剂，HPLC纯化。得到目标化合物8.0mg。 1H NMR(400MHz,Methanol-d 4)δ8.55(d,J＝2.4Hz,1H),8.01(dd,J＝2.5,8.3Hz,1H),7.53(dd,J＝0.7,8.2Hz,1H),7.50(s,1H),7.39(dd,J＝2.4,6.7Hz,1H),7.26–7.17(m,2H),7.04(s,1H),6.90(d,J＝8.1Hz,1H),6.79–6.71(m,2H),5.32(s,2H),5.30(s,2H),4.29(s,4H),4.21(d,J＝11.7Hz,2H),4.10–4.03(m,1H),3.85(dd,J＝1.5,4.7Hz,1H),3.77(dd,J＝2.9,10.5Hz,1H),3.72–3.62(m,3H),3.25–3.13(m,2H),2.29(s,3H).ESI-MS理论值:C35H38Cl2N2O9[M+H] +＝701.20，测得：701.55。
实施例71：合成5-((4-氯-5-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)-2-((甲基((2R,3R,4S,5R)-2,3,4,5,6-五羟基己基)氨基)甲基)苯氧基)甲基)烟腈(ZD127)
Figure PCTCN2020094013-appb-000139
将ZD110(33.3mg，0.062mmol)、α-D-(+)-塔罗糖(33.26mg，0.185mmol)溶于THF(4ml)与MeOH(4ml)的混合溶剂中，然后依次加入AcOH(0.08ml)、NaBH(OAc) 3(65.2mg，0.308mmol)室温反应过夜。待反应结束后旋干溶剂并用HPLC纯化。得到目标化合物11.2mg。 1H NMR(400MHz,Methanol-d 4)δ9.02–8.91(m,2H),8.44–8.31(m,1H),7.63–7.50(m,1H),7.41(td,J＝10.2,9.1,4.0Hz,1H),7.28–7.16(m,2H),7.13–7.01(m,1H),6.90(d,J＝8.0Hz,1H),6.81–6.69(m,2H),5.47–5.35(m,2H),5.31(dt,J＝5.6,2.6Hz,2H),4.56(dd,J＝13.2,7.3Hz,1H),4.30(s,4H),4.23(dd,J＝16.6,12.3Hz,1H),4.17–4.02(m,1H),4.03–3.95(m,1H),3.87–3.70(m,2H),3.70–3.63(m,1H),3.63–3.54(m,1H),3.55–3.39(m,1H),3.27–3.09(m,1H),2.99–2.77(m,3H),2.29(q,J＝3.1,2.2Hz,3H).ESI-MS理论值:C 37H 40ClN 3O 9[M+H] +＝706.25，测得：706.00。
实施例72：合成(2R,3R,4R,5S)-6-((5-氯-4-((3-(2,3-二氢苯[b][1,4]二恶英-6-基)-2-甲基苄基)氧)-2-((3-(甲基磺酰基)苄基)氧)苄基)氨基)己烯-1,2,3,4,5-戊醇(ZD132)
Figure PCTCN2020094013-appb-000140
步骤一:合成1-(氯甲基)-3-(甲磺酰基)苯(ZD126)
将(3-(甲基磺酰基)苯基)甲醇(0.88g)溶于二氯亚砜(12.6ml)中，80℃反应3h，反应结束后旋干溶剂，得到目标化合物513mg。 1H NMR(400MHz,Chloroform-d)δ8.62(t,J＝1.9Hz,1H),8.35(dt,J＝7.9,1.4Hz,1H),8.16(ddd,J＝7.8,1.9,1.1Hz,1H),4.45(q,J＝7.1Hz,2H),3.11(s,3H).
步骤二:合成5-氯-4-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)-2-((3-(甲基磺酰基)苄基)氧基)苯甲醛(ZD128)
将ZA52(100mg，0.256mmol)、1-(氯甲基)-3-(甲磺酰基)苯(50.6mg，0.333mmol)溶于DMF(3ml)中，后加入K 2CO 3(70.8mg，0.507mmol)室温反应过夜。待反应结束后加水淬灭，用二氯甲烷萃取三次，有机相用饱和氯化钠溶液洗、无水硫酸钠干燥后旋干溶剂，并用层析柱分离纯化，得到目标化合物76mg。 1H NMR(400MHz,Chloroform-d)δ10.33(s,1H),7.99(d,J＝7.6Hz,1H),7.93(s,1H),7.77(d,J＝7.5Hz,1H),7.72–7.66(m,1H),7.49–7.40(m,1H),7.27(d,J＝2.4Hz,1H),6.95(d,J＝4.1Hz,1H),6.85(dd,J＝4.2,2.1Hz,2H),6.80–6.76(m,1H),6.67(d,J＝12.9Hz,2H),5.26(s,2H),5.24(s,2H),4.33(s,4H),2.31(s,3H),2.29(d,J＝1.6Hz,3H).
步骤三：合成(2R,3R,4R,5S)-6-((5-氯-4-((3-(2,3-二氢苯[b][1,4]二恶英-6-基)-2-甲基苄基)氧)-2-((3-(甲基磺酰基)苄基)氧)苄基)氨基)己烯-1,2,3,4,5-戊醇(ZD132)
将ZD128(17.7mg，0.031mmol)、D-萄糖胺(16.6mg，0.092mmol)溶于THF(3ml)与MeOH(3ml)的混合溶剂中室温反应过夜，然后加入NaBH 4(23.27mg，0.612mmol)，继续反应约5h。反应结束后旋干溶剂，HPLC纯化。得到目标化合物5.6mg。 1H NMR(400MHz,Methanol-d4)δ8.17(d,J＝1.8Hz,1H),7.99(dt,J＝7.8,1.4Hz,1H),7.89(d,J＝7.7Hz,1H),7.72(t,J＝7.8Hz,1H),7.51(s,1H),7.40(dd,J＝7.0,2.0Hz,1H),7.26–7.15(m,2H),7.04(s,1H),6.90(d,J＝8.0Hz,1H),6.79–6.70(m,2H),5.41(s,2H),5.27(s,2H),4.30(s,4H),4.28–4.18(m,2H),4.08(dt,J＝6.8,5.0Hz,1H),3.85(dd,J＝4.5,1.5Hz,1H),3.76(dd,J＝10.5,2.9Hz,1H),3.72–3.57(m,3H),3.27–3.20(m,2H),3.18(s,3H),2.28(s,3H).ESI-MS理论值:C 37H 42ClNO 11S[M+H] +＝744.22，测得：744.30。
实施例73：合成4-((4-氯-5-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)-2-((((2S,3R,4R,5R)-2,3,4,5,6-五羟基己基)氨基)甲基)苯氧基)甲基)-2-氰基吡啶(ZD133)
Figure PCTCN2020094013-appb-000141
步骤一：合成4-(氯甲基)-2-氰基吡啶(ZD129)
将4-羟基甲基-2-氰基吡啶(850mg，6.34mmol)溶于二氯甲烷中(15ml)，然后加入二氯亚砜(5ml)加热回流3h。反应结束后旋干溶剂直接用于下一步。 1H NMR(400MHz,Chloroform-d)δ8.74(d,J＝5.1Hz,1H),7.83–7.73(m,1H),7.57(dd,J＝5.1,1.7Hz,1H),4.62(s,2H).
步骤二：合成4-((4-氯-5-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)-2-甲酰基苯氧基)甲基)-2-氰基吡啶(ZD131)
将ZA52(120mg，0.308mmol)、ZD129(60.78mg，0.40mmol)溶于DMF(2ml)中，后加入Cs 2CO 3(271.3mg，0.769mmol)室温反应过夜。待反应结束后加水淬灭，用二氯甲烷萃取三次，有机相用饱和氯化钠溶液洗、无水硫酸钠干燥后旋干溶剂，并用层析柱分离纯化，得到目标化合物76mg。 1H NMR(400MHz,Chloroform-d)δ10.35(s,1H),8.79(d,J＝5.0Hz,1H),7.95(s,1H),7.79(s,1H),7.71–7.61(m,1H),7.38(dd,J＝6.6,2.5Hz,1H),7.25(d,J＝7.7Hz,2H),6.98–6.91(m,1H),6.83(d,J＝2.1Hz,1H),6.79(dd,J＝8.2,2.1Hz,1H),6.58(s,1H),5.25(s,2H),5.23(s,2H),4.34(s,4H),2.31(s,3H).
步骤二：4-((4-氯-5-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)-2-((((2S,3R,4R,5R)-2,3,4,5,6-五羟基己基)氨基)甲基)苯氧基)甲基)-2-氰基吡啶(ZD133)
将ZD131(36mg，0.049mmol)、D-萄糖胺(16.6mg，0.148mmol)溶于THF(4ml)与MeOH(4ml)的混合溶剂中室温反应过夜，然后加入NaBH 4(37.56mg，0.612mmol)，继续反应约5h。反应结束后旋干溶剂，HPLC纯化。得到目标化合物12.2mg。 1H NMR(400MHz,Methanol-d 4)δ8.73(d,J＝5.1Hz,1H),8.03(s,1H),7.80(d,J＝5.1Hz,1H),7.54(s,1H),7.32(dt,J＝7.6,4.0Hz,1H),7.18(d,J＝4.5Hz,2H),6.94(s,1H),6.90(d,J＝8.0Hz,1H),6.80–6.68(m,2H),5.42(s,2H),5.28(s,2H),4.30(s,5H),4.26(d,J＝13.4Hz,1H),4.09(q,J＝5.4Hz,1H),3.87(d,J＝4.7Hz,1H),3.74(d,J＝10.7Hz,1H),3.67(d,J＝2.4Hz,2H),3.65–3.59(m,1H),3.25(d,J＝5.9Hz,2H),2.27(s,3H).ESI-MS理论值:C 36H 38ClN 3O 9[M+H] +＝692.23，测得：692.1。
实施例74：合成5-((4-氯-5-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)-2-((甲基((2S,3R,4R)-2,3,4,5-四羟基戊基)氨基)甲基)苯氧基)甲基)烟腈(ZD135)
Figure PCTCN2020094013-appb-000142
将ZD110(25mg，0.046mmol)、D-木糖(20.81mg，0.139mmol)溶于THF(4ml)与MeOH(4ml)的混合溶剂中，然后依次加入AcOH(0.05ml)、NaBH(OAc) 3(49.0mg，0.231mmol)室温反应过夜。待反应结束后旋干溶剂并用HPLC纯化。得到目标化合物13mg。 1H NMR(400MHz,Methanol-d4)δ9.03–8.91(m,2H),8.50–8.35(m,1H),7.62–7.54(m, 1H),7.43(d,J＝6.8Hz,1H),7.28–7.15(m,2H),7.10(d,J＝7.8Hz,1H),6.90(d,J＝8.0Hz,1H),6.81–6.71(m,2H),5.45–5.36(m,2H),5.33(d,J＝3.4Hz,2H),4.79–4.57(m,1H),4.30(s,4H),4.24(s,1H),4.22–4.09(m,1H),4.03–3.96(m,1H),3.96–3.89(m,1H),3.70(d,J＝9.4Hz,1H),3.65(dd,J＝5.9,1.7Hz,1H),3.62–3.49(m,1H),3.49–3.36(m,1H),3.00–2.78(m,3H),2.29(s,3H).ESI-MS理论值:C 36H 38ClN 3O 8[M+H] +＝676.23，测得：676.15。
实施例75：合成5-((4-氯-5-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)-2-((甲基((2S,3S,4R,5R)-2,3,4,5,6-五羟基己基)氨基)甲基)苯氧基)甲基)烟腈(ZD136)
Figure PCTCN2020094013-appb-000143
将ZD110(25mg，0.046mmol)、D-阿洛糖(24.97mg，0.139mmol)溶于THF(4ml)与MeOH(4ml)的混合溶剂中，然后依次加入AcOH(0.05ml)、NaBH(OAc) 3(49.0mg，0.231mmol)室温反应过夜。待反应结束后旋干溶剂并用HPLC纯化，得到目标化合物9mg。 1H NMR(400MHz,Methanol-d4)δ9.04–8.90(m,2H),8.40(s,1H),7.62–7.53(m,1H),7.43(s,1H),7.28–7.17(m,2H),7.08(d,J＝11.2Hz,1H),6.90(d,J＝8.0Hz,1H),6.82–6.69(m,2H),5.39(d,J＝8.7Hz,2H),5.32(d,J＝4.6Hz,2H),4.72–4.50(m,1H),4.30(s,4H),4.24(dd,J＝17.5,12.4Hz,1H),4.19–4.03(m,1H),3.99(s,1H),3.94(d,J＝10.4Hz,1H),3.84(s,2H),3.71–3.65(m,1H),3.63(d,J＝3.5Hz,1H),3.60–3.47(m,1H),2.93(d,J＝4.6Hz,3H),2.29(d,J＝2.5Hz,3H).ESI-MS理论值:C 37H 40ClN 3O 9[M+H] +＝706.25，测得：706.35。
实施例76：合成5-((4-氯-5-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)-2-((甲基((2S,3R,4S)-2,3,4,5-四羟基戊基)氨基)甲基)苯氧基)甲基)烟腈(ZD137)
Figure PCTCN2020094013-appb-000144
将ZD110(25mg，0.046mmol)、2-脱氧-D-核糖(20.81mg，0.139mmol)溶于THF(4ml)与MeOH(4ml)的混合溶剂中，然后依次加入AcOH(0.05ml)、NaBH(OAc) 3(49.0mg，0.231mmol)室温反应过夜。待反应结束后旋干溶剂并用HPLC纯化。得到目标化合物10mg。 1H NMR(400MHz,Methanol-d 4)δ9.02–8.90(m,2H),8.41(d,J＝11.3Hz,1H),7.62–7.55(m,1H),7.43(t,J＝7.6Hz,1H),7.28–7.16(m,2H),7.13–7.02(m,1H),6.90(d,J＝8.0Hz,1H),6.80–6.71(m,2H),5.40(d,J＝3.1Hz,2H),5.37–5.28(m,2H),4.67–4.43(m,1H),4.35(d,J＝13.2Hz,1H),4.30(s,5H),4.24–4.12(m,1H),4.12–4.05(m,1H),4.05–3.86(m,1H),3.86–3.63(m,1H),3.61–3.36(m,1H),3.19(dd,J＝13.5,7.4Hz,1H),3.01–2.76(m,3H),2.29(d,J＝3.6Hz, 3H).ESI-MS理论值:C 36H 38ClN 3O 8[M+H] +＝676.23，测得：676.43。
实施例77：合成(2R,3R,4R,5S)-6-((5-氯-4-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基]-2-甲基苄基]氧基)-2-(((4-氟苄基)氧基)苄基)氨基)己烷-1,2,3,4,5-戊醇(ZD146)
Figure PCTCN2020094013-appb-000145
步骤一:5-氯-4-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)-2-((4-氟苄基氧基)苯甲醛(ZD141)
将ZA52(150mg，0.384mmol)、1-(氯甲基)-4-氟苯(66.7mg，0.461mmol)溶于DMF(3ml)中，后加入Cs 2CO 3(203mg,0.567mmol)室温反应过夜。待反应结束后加水淬灭，用二氯甲烷萃取三次，有机相用饱和氯化钠溶液洗、无水硫酸钠干燥后旋干溶剂，并用层析柱分离纯化，得到目标化合物66mg。 1H NMR(400MHz,Chloroform-d)δ10.31(s,1H),7.89(s,1H),7.44–7.37(m,3H),7.30–7.24(m,2H),7.14–7.06(m,2H),6.93(d,J＝8.2Hz,1H),6.84(d,J＝2.1Hz,1H),6.79(dd,J＝8.2,2.1Hz,1H),6.65(s,1H),5.19(s,2H),5.15(s,2H),4.32(s,4H),2.29(s,3H).
步骤二：合成(2R，3R，4R，5S)-6-((5-氯-4-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基]-2-甲基苄基]氧基)-2-(((4-氟苄基)氧基)苄基)氨基)己烷-1,2,3,4,5-戊醇(ZD146)
将ZD141(25mg，0.048mmol)、D-萄糖胺(27mg，0.145mmol)溶于THF(3ml)与MeOH(3ml)的混合溶剂中室温反应过夜，后加入NaBH 4(44.3mg，1.17mmol)，继续反应5h。反应结束后旋干溶剂，HPLC纯化。得到目标化合物16.2mg。 1H NMR(500MHz,Methanol-d 4)δ7.58–7.52(m,2H),7.48(s,1H),7.39(dd,J＝7.0,2.1Hz,1H),7.25–7.20(m,2H),7.17(td,J＝9.2,8.8,7.0Hz,2H),7.00(s,1H),6.91(d,J＝8.1Hz,1H),6.79–6.73(m,2H),5.26(d,J＝1.8Hz,4H),4.31(s,4H),4.20(q,J＝13.2Hz,2H),4.12–4.02(m,1H),3.85(dd,J＝4.5,1.7Hz,1H),3.78(dd,J＝10.9,3.4Hz,1H),3.68(tdd,J＝11.8,8.8,5.2Hz,3H),3.24–3.15(m,2H),2.29(s,3H).ESI-MS理论值:C 36H 39ClFNO 9[M+H] +＝684.23，测得：684.32。
实施例78：合成(2R,3R,4R,5S)-6-((5-氯-4-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)-2-((3-甲基苄基)氧基)苄基)氨基)己烷-1,2,3,4,5-五醇(ZD148)
Figure PCTCN2020094013-appb-000146
步骤一:合成5-氯-4-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)-2-((4-甲氧基苄基)氧基)苯甲醛(ZD144)
将ZA52(120mg，0.308mmol)、1-(氯甲基)-4-甲氧基苯(57.6mg，0.369mmol)溶于DMF(2.5ml)中，后加入Cs 2CO 3(168.2mg，0.461mmol)室温反应过夜。待反应结束后加水淬灭，用二氯甲烷萃取三次，有机相用饱和氯化钠溶液洗、无水硫酸钠干燥后旋干溶剂，并用层析柱分离纯化，得到目标化合物118mg。 1H NMR(400MHz,Chloroform-d)δ10.32(s,1H),7.90(s,1H),7.42(t,J＝4.6Hz,1H),7.38–7.31(m,2H),7.27(d,J＝4.5Hz,2H),6.94(dd,J＝8.4,1.6Hz,3H),6.85(d,J＝2.1Hz,1H),6.82–6.77(m,1H),6.68(s,1H),5.19(s,2H),5.13(s,2H),4.33(s,4H),3.84(s,3H),2.30(s,3H).
步骤二：合成(2R,3R,4R,5S)-6-((5-氯-4-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基]-2-甲基苄基]氧基)-2-(((4-甲氧基苄基)氧基)苄基)氨基)己烷-1,2,3,4,5-戊醇(ZD148)
将ZD144(25mg，0.047mmol)、D-萄糖胺(25.6mg，0.141mmol)溶于THF(3ml)与MeOH(3ml)的混合溶剂中室温反应过夜，后加入NaBH 4(35.8mg，0.943mmol)，继续反应约5h。反应结束后旋干溶剂，HPLC纯化。得到目标化合物20mg。 1H NMR(400MHz,Methanol-d 4)δ7.45(s,1H),7.44(s,0H),7.42(d,J＝2.1Hz,1H),7.38(dd,J＝6.9,2.2Hz,1H),7.24–7.16(m,2H),6.99(s,1H),6.97(d,J＝2.1Hz,1H),6.95(d,J＝2.0Hz,1H),6.89(d,J＝8.1Hz,1H),6.77–6.72(m,2H),5.24(s,2H),5.21(s,2H),4.29(s,4H),4.23–4.11(m,2H),4.06(dt,J＝6.7,4.9Hz,1H),3.84(dd,J＝4.5,1.7Hz,1H),3.81(s,3H),3.77(d,J＝3.2Hz,1H),3.72–3.66(m,2H),3.64(d,J＝5.3Hz,1H),3.25–3.11(m,2H),2.27(s,3H).ESI-MS理论值:C 37H 42ClNO 10[M+H] +＝696.25，测得：696.18。
实施例79：合成(2R,3R,4R,5S)-6-((5-氯-4-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)-2-((3-甲基苄基)氧基)苄基)氨基)己烷-1,2,3,4,5-五醇(ZD149)
Figure PCTCN2020094013-appb-000147
步骤一:5-氯-4-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)-2-((2-甲氧基苄 基)氧基)苯甲醛(ZD145)
将ZA52(120mg，0.308mmol)、1-(氯甲基)-2-甲氧基苯(57.6mg，0.369mmol)溶于DMF中，后加入Cs 2CO 3(162.8mg，0.461mmol)室温反应过夜。待反应结束后加水淬灭，用二氯甲烷萃取三次，有机相用饱和氯化钠溶液洗、无水硫酸钠干燥后旋干溶剂，并用层析柱分离纯化，得到目标化合物72.5mg。 1H NMR(400MHz,Chloroform-d)δ10.36(s,1H),7.88(s,1H),7.45–7.40(m,2H),7.36(td,J＝7.9,1.8Hz,1H),7.27–7.25(m,2H),7.01(td,J＝7.5,1.0Hz,1H),6.95–6.91(m,2H),6.84(d,J＝2.0Hz,1H),6.79(dt,J＝8.2,2.1Hz,1H),6.75(s,1H),5.26(s,2H),5.18(s,2H),4.33(s,4H),3.89(s,3H),2.30(s,3H).
步骤二：(2R,3R,4R,5S)-6-((5-氯-4-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)-2-((3-甲基苄基)氧基)苄基)氨基)己烷-1,2,3,4,5-五醇(ZD149)
将ZD145(25mg，0.047mmol)、D-萄糖胺(25.6mg，0.141mmol)溶于THF(3ml)与MeOH(3ml)的混合溶剂中室温反应过夜，后加入NaBH 4(35.8mg，0.943mmol)，室温反应约5h。反应结束后旋干溶剂，HPLC纯化。得到目标化合物12.3mg。 1H NMR(400MHz,Methanol-d4)δ7.44(d,J＝9.7Hz,2H),7.38(ddd,J＝8.4,5.1,2.5Hz,2H),7.25–7.16(m,2H),7.08(d,J＝8.2Hz,1H),7.03–6.97(m,2H),6.90(d,J＝8.1Hz,1H),6.78–6.71(m,2H),5.30(s,2H),5.23(s,4H),4.30(s,4H),4.27–4.13(m,2H),4.05(q,J＝5.5Hz,1H),3.92(s,3H),3.83(dd,J＝4.5,1.7Hz,1H),3.77(dd,J＝10.9,3.1Hz,1H),3.73–3.60(m,3H),3.18(d,J＝5.9Hz,2H),2.27(s,3H).ESI-MS理论值:C 37H 42ClNO 10[M+H] +＝696.25，测得：696.25。
实施例80：合成5-((4-氯-5-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)-2-((甲基((3S,4R)-3,4,5-三羟基戊基)氨基)甲基)苯氧基)甲基)烟腈(ZE01)
Figure PCTCN2020094013-appb-000148
将ZD110(25mg，0.046mmol)、2-脱氧-D-核糖(18.6mg，0.139mmol)溶于THF(3ml)与MeOH(3ml)的混合溶剂中，然后依次加入AcOH(0.05ml)、NaBH(OAc) 3(50mg，0.231mmol)室温反应过夜。待反应结束后旋干溶剂并用HPLC纯化。得到目标化合物10.9mg。 1H NMR(400MHz,Methanol-d4)δ8.97(d,J＝2.1Hz,1H),8.94(d,J＝2.0Hz,1H),8.38(d,J＝2.5Hz,1H),7.57(s,1H),7.44–7.38(m,1H),7.27–7.16(m,2H),7.07(s,1H),6.90(d,J＝8.0Hz,1H),6.79–6.70(m,2H),5.46–5.36(m,2H),5.31(s,2H),4.45(d,J＝7.3Hz,1H),4.29(s,4H),4.22(dd,J＝13.2,4.1Hz,1H),3.65(ddd,J＝11.2,4.4,2.4Hz,2H),3.57(dt,J＝11.1,5.1Hz,1H),3.53–3.35(m,2H),3.25(ddd,J＝20.2,14.6,7.0Hz,1H),2.82(s,3H),2.29(s,3H),2.15–1.84(m,2H).ESI-MS理论值:C 36H 38ClN 3O 7[M+H] +＝660.24，测得：660.5。
实施例81：合成5-((4-氯-5-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧 基)-2-((((2S,3R,4R,5R)-2,3,4,5,6-五羟基己基)氨基)甲基)苯氧基)甲基)-2-氰基吡啶(ZE10)
Figure PCTCN2020094013-appb-000149
步骤一：合成5-(羟甲基)-2-氰基吡啶(ZD158)
将6-氰基烟酸甲酯(620mg，3.8mmol)溶于甲醇(3ml)中，后加入LiCl(462mg，7.7mmol)，最后加入NaBH 4(290mg，7.7mmol)室温反应2h后减压旋干溶剂，然后向反应瓶内加入饱和氯化铵溶液并用乙酸乙酯萃取，有机相用无水硫酸钠干燥后旋干，并用层析柱分离纯化，得到目标化合物78mg。 1H NMR(400MHz,Chloroform-d)δ8.72(dd,J＝2.0,0.9Hz,1H),8.05–7.88(m,1H),7.73(dd,J＝8.0,0.8Hz,1H),4.87(s,2H).
步骤二：合成5-(氯甲基)-2-氰基吡啶(ZE05)
将ZD158(78mg，0.584mmol)溶于干燥的二氯甲烷(5ml)中，用冰水浴降温后加入SOCl 2(137.9mg，1.169mmol)反应结束后旋干溶剂直接用以下一步。 1H NMR(400MHz,Chloroform-d)δ8.73(d,J＝2.1Hz,1H),7.91(dd,J＝8.1,2.2Hz,1H),7.73(d,J＝8.0Hz,1H),4.65(s,2H).
步骤三：合成5-氯-4-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)-2-羟基苯甲醛(ZE07)
将ZA52(120mg,0.308mmol)、ZE05溶于DMF(2.0ml)中，后加入Cs 2CO 3(230mg,0.84mmol)室温反应过夜。待反应结束后加水淬灭，用乙酸乙酯萃取三次，有机相用饱和氯化钠溶液洗、无水硫酸钠干燥后旋干溶剂，并用层析柱分离纯化，得到目标化合物52mg。 1H NMR(400MHz,Methanol-d4)δ8.60(d,J＝2.4Hz,1H),7.98(dd,J＝8.2,2.4Hz,1H),7.50(d,J＝8.3Hz,1H),7.51(s,1H),7.37(d,J＝6.9Hz,1H),7.16(d,J＝6.7Hz,2H),7.01(s,1H),6.88(d,J＝8.1Hz,1H),6.79–6.62(m,2H),5.43(s,2H),5.31(s,2H),4.30(s,5H),4.21(q,J＝13.2Hz,2H),2.30(s,3H).
步骤四：合成5-((4-氯-5-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)-2-((((2S,3R,4R,5R)-2,3,4,5,6-五羟基己基)氨基)甲基)苯氧基)甲基)-2-氰基吡啶(ZE10)
将ZE07(26mg，0.049mmol)、D-萄糖胺(25mg，0.146mmol)溶于THF(3ml)与MeOH(3ml)的混合溶剂中室温反应过夜，后加入NaBH 4(46mg，1.21mmol)，继续反应约5h。反应结束后旋干溶剂，HPLC纯化。得到目标化合物10.2mg。 1H NMR(400MHz,Methanol-d 4)δ 8.55(d,J＝2.4Hz,1H),8.01(dd,J＝8.2,2.4Hz,1H),7.54(d,J＝8.3Hz,1H),7.51(s,1H),7.40(d,J＝6.9Hz,1H),7.21(d,J＝6.7Hz,2H),7.05(s,1H),6.90(d,J＝8.1Hz,1H),6.80–6.71(m,2H),5.33(s,2H),5.30(s,2H),4.30(s,5H),4.21(q,J＝13.2Hz,2H),4.05(t,J＝5.3Hz,1H),3.85(d,J＝4.4Hz,1H),3.81–3.74(m,1H),3.73–3.61(m,3H),3.19(d,J＝5.9Hz,2H),2.29(s,3H).ESI-MS理论值:C 36H 38ClN 3O 9[M+H] +＝692.23，测得：692.6。
实施例82：合成3-((4-氯-5-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)-2-((((2S,3R,4R,5R)-2,3,4,5,6-五羟基己基)氨基)甲基)苯氧基)甲基)-2-氰基吡啶(ZE12)
Figure PCTCN2020094013-appb-000150
步骤一：合成3-(氯甲基)-2-氰基吡啶(ZD151)
将3-甲基2-氰基吡啶(2.0g，16.93mmol)和二氯亚砜(2.72ml，33.86mmol)溶于四氯化碳(40ml)，然后加入过氧化苯甲酰(0.041g，0.17mmol)80℃加热3h。反应结束后冷却至室温，加入二氯甲烷并用水洗，收集有机相并用层析柱分离纯化，得到目标化合物1.23g。 1H NMR(400MHz,Chloroform-d)δ8.91(s,1H),8.86(d,J＝5.2Hz,1H),7.61(d,J＝5.2Hz,1H),4.75(s,2H).
步骤二：合成3-((4-氯-5-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)-2-甲酰基苯氧基)甲基)-2-氰基吡啶(ZE08)
将ZA52(120mg,0.308mmol)、ZD151(56.12mg，0.369mmol)溶于丙酮(5ml)中，后加入K 2CO 3(63.8mg，0.461mmol)室温反应过夜。待反应结束后加水淬灭，用乙酸乙酯萃取三次，有机相用饱和氯化钠溶液洗、无水硫酸钠干燥后旋干溶剂，并用层析柱分离纯化，得到目标化合物106mg。 1H NMR(400MHz,Chloroform-d)δ10.32(s,1H),8.75(dd,J＝4.8,1.6Hz,1H),8.18–8.06(m,1H),7.92(s,1H),7.64(dd,J＝8.1,4.7Hz,1H),7.45(dt,J＝8.3,4.4Hz,2H),7.27(s,1H),6.94(d,J＝8.2Hz,1H),6.86(d,J＝2.1Hz,1H),6.81(dd,J＝8.2,2.0Hz,1H),6.76(s,1H),5.44(s,2H),5.31(s,2H),4.33(s,4H),2.33(s,3H).
步骤三：合成3-((4-氯-5-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)-2-((((2S,3R,4R,5R)-2,3,4,5,6-五羟基己基)氨基)甲基)苯氧基)甲基)-2-氰基吡啶(ZE12)
将ZE08(25mg，0.049mmol)、D-萄糖胺(26.4mg，0.146mmol)溶于THF(3ml)与MeOH(3ml)的混合溶剂中室温反应过夜，后加入NaBH 4(37mg，0.974mmol)，继续反应约5h。反应结束后旋干溶剂，HPLC纯化。得到目标化合物11.3mg。 1H NMR(400MHz,Methanol-d4)δ8.73(dd,J＝4.8,1.5Hz,1H),8.21(dd,J＝8.1,1.5Hz,1H),7.74(dd,J＝8.0,4.8Hz,1H),7.53 (s,1H),7.42(dd,J＝7.1,1.9Hz,1H),7.26–7.16(m,2H),7.08(s,1H),6.90(d,J＝8.1Hz,1H),6.80–6.69(m,2H),5.51(s,2H),5.33(s,2H),4.30(s,4H),4.28–4.19(m,2H),4.05(dt,J＝6.8,4.8Hz,1H),3.83(dd,J＝4.5,1.4Hz,1H),3.75(dd,J＝10.3,2.5Hz,1H),3.70–3.60(m,3H),3.25–3.13(m,2H),2.29(s,3H).ESI-MS理论值:C 36H 38ClN 3O 9[M+H] +＝692.23，测得：692.2。
实施例83：合成(2R,3R,4R,5S)-6-((2-((3-氨基苄基)氧基)-5-氯-4-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)苄基)氨基)己烷-1,2,3,4,5-戊醇(ZE19)
Figure PCTCN2020094013-appb-000151
将ZD114(20mg，0.028mmol)溶于甲醇(15ml)中，除氧后加入Pd/C(5mg，0.047mmol)，再次除氧后充氢气，室温反应过夜。反应结束后过滤除去Pd/C，旋干溶剂后用HPLC纯化，得到目标化合物9.1mg。 1H NMR(400MHz,Methanol-d 4)δ7.48(s,1H),7.40(q,J＝6.8,5.8Hz,2H),7.32–7.25(m,2H),7.25–7.18(m,2H),7.10(d,J＝8.0Hz,1H),6.99(s,1H),6.90(d,J＝8.1Hz,1H),6.78–6.71(m,2H),5.28(s,2H),5.23(s,2H),4.30(s,4H),4.28–4.15(m,2H),4.11–4.03(m,1H),3.85(d,J＝4.6Hz,1H),3.81–3.74(m,1H),3.72–3.63(m,3H),3.24–3.16(m,2H),2.27(s,3H).ESI-MS理论值:C 36H 41ClN 2O 9[M+H] +＝681.25，测得：681.4。
实施例84：合成(2R,3R,4R,5S)-6-((5-氯-2-((4-氯苄基)氧基)-4-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)苄基)氨基)己烷-1,2,3,4,5-戊醇(ZE31)
Figure PCTCN2020094013-appb-000152
步骤一:合成5-氯-2-((4-氯苄基)氧基)-4-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)苯甲醛(ZE29)
将ZA52(120mg,0.308mmol)、1-(氯甲基)-4-氯苯(59.4mg，0.369mmol)溶于DMF(2.5ml)中，后加入Cs 2CO 3(162.8mg,0.461mmol)室温反应过夜。待反应结束后加水淬灭，用乙酸乙酯萃取三次，有机相用饱和氯化钠溶液洗、无水硫酸钠干燥后旋干溶剂，并用层析柱分离纯化，得到目标化合物198mg。 1H NMR(400MHz,Chloroform-d)δ10.34(s,1H),8.04(s,1H),7.91(s,1H),7.38(q,J＝8.6Hz,4H),7.28(t,2H),6.94(d,J＝8.3Hz,1H),6.85(d,J＝2.1Hz,1H),6.80(dd,J＝8.2,2.1Hz,1H),6.63(s,1H),5.19(s,2H),5.16(s,2H),4.34(s,4H),2.30(s,3H).
步骤二：合成(2R,3R,4R,5S)-6-((5-氯-2-((4-氯苄基)氧基)-4-((3-(2,3-二氢苯并[b][1,4]二恶 英-6-基)-2-甲基苄基)氧基)苄基)氨基)己烷-1,2,3,4,5-戊醇(ZE31)
将ZE29(26mg，0.049mmol)、D-萄糖胺(26.4mg，0.146mmol)溶于THF(3ml)与MeOH(3ml)的混合溶剂中室温反应过夜，后加入NaBH 4(37mg，0.974mmol)，继续反应约5h。反应结束后旋干溶剂，HPLC纯化。得到目标化合物16.2mg。 1H NMR(400MHz,Methanol-d4)δ7.52(d,J＝2.0Hz,1H),7.50(d,J＝2.2Hz,1H),7.48(s,1H),7.46–7.39(m,2H),7.35(dd,J＝6.1,3.0Hz,1H),7.25–7.16(m,2H),6.97(s,1H),6.90(d,J＝8.1Hz,1H),6.81–6.71(m,2H),5.27(s,2H),5.25(s,2H),4.30(s,4H),4.26–4.14(m,2H),4.11–4.02(m,1H),3.85(dd,J＝4.6,1.5Hz,1H),3.78(dd,J＝10.6,3.2Hz,1H),3.74–3.61(m,3H),3.24–3.16(m,2H),2.27(s,3H).ESI-MS理论值:C36H39Cl2NO9[M+H] +＝700.20，测得：700.6。
实施例85：合成(2R,3R,4R,5S)-6-((5-氯-4-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基]-2-甲基苄基]氧基)-2-(((4-(三氟甲基)苄基)氧基)苄基)氨基)己烷-1,2,3,4,5-戊醇(ZE32)
Figure PCTCN2020094013-appb-000153
步骤一：合成5-氯-4-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)-2-((4-(三氟甲基)苄基)氧基苯甲醛(ZE30)
将ZA52(120mg，0.308mmol)、1-(氯甲基)-4-三氟甲基苯(71.8mg，0.369mmol)溶于DMF(3.0ml)中，后加入Cs 2CO 3(162.8mg，0.461mmol)室温反应过夜。待反应结束后加水淬灭，用二氯甲烷萃取三次，有机相用饱和氯化钠溶液洗、无水硫酸钠干燥后旋干溶剂，并用层析柱分离纯化，得到目标化合物162.3mg。 1H NMR(400MHz,Chloroform-d)δ10.36(s,1H),7.92(s,1H),7.69(d,J＝8.1Hz,2H),7.56(d,J＝8.3Hz,2H),7.38(dd,J＝6.3,2.7Hz,1H),7.28–7.24(m,2H),6.93(d,J＝8.2Hz,1H),6.87–6.76(m,2H),6.63(s,1H),5.25(s,2H),5.19(s,2H),4.33(s,4H),2.28(s,3H).
步骤二：合成(2R,3R,4R,5S)-6-((5-氯-4-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基]-2-甲基苄基]氧基)-2-(((4-(三氟甲基)苄基)氧基)苄基)氨基)己烷-1,2,3,4,5-戊醇(ZE32)
将ZE30(30mg，0.053mmol)、D-萄糖胺(28.7mg，0.158mmol)溶于THF(3ml)与MeOH(3ml)的混合溶剂中室温反应过夜，后加入NaBH 4(40.1mg，1.056mmol)，室温反应约5h。反应结束后旋干溶剂，HPLC纯化。得到目标化合物18.3mg。 1H NMR(400MHz,Methanol-d4)δ7.73(d,J＝2.1Hz,4H),7.50(s,1H),7.35(d,J＝5.4Hz,1H),7.23–7.14(m,2H),6.99(s,1H),6.90(d,J＝8.1Hz,1H),6.83–6.67(m,2H),5.38(s,2H),5.25(s,2H),4.30(s,4H),4.28–4.17(m, 2H),4.08(q,J＝5.4Hz,1H),3.86(dd,J＝4.6,1.5Hz,1H),3.77(dd,J＝10.6,3.0Hz,1H),3.72–3.60(m,3H),3.22(d,J＝5.6Hz,2H),2.26(s,3H).ESI-MS理论值:C37H39ClF3NO 9[M+H] +＝734.23，测得：734.0.
实施例86：合成6-((4-氯-5-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)-2-((((2S,3R,4R,5R)-2,3,4,5,6-五羟基己基)氨基)甲基)苯氧基)甲基)烟腈(ZE35)
Figure PCTCN2020094013-appb-000154
步骤一:6-((4-氯-5-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)-2-甲酰基苯氧基)甲基)烟腈(ZE34)
将ZA52(120mg，0.308mmol)、6-(氯甲基)烟腈(56.1mg，0.369mmol)溶于DMF中，后加入Cs 2CO 3(162.8mg，0.461mmol)室温反应过夜。待反应结束后加水淬灭，用二氯甲烷萃取三次，有机相用饱和氯化钠溶液洗、无水硫酸钠干燥后旋干溶剂，并用层析柱分离纯化，得到目标化合物77.3mg。 1H NMR(500MHz,Methanol-d4)δ9.02(d,J＝2.1Hz,1H),8.96(d,J＝2.0Hz,1H),8.46(t,J＝2.1Hz,1H),7.58(s,1H),7.44(dd,J＝7.4,1.8Hz,1H),7.28–7.18(m,2H),7.12(s,1H),6.90(d,J＝8.1Hz,1H),6.80–6.73(m,2H),5.40(s,2H),5.33(s,2H),4.30(s,4H),2.30(s,3H).
步骤二：合成6-((4-氯-5-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)-2-((((2S,3R,4R,5R)-2,3,4,5,6-五羟基己基)氨基)甲基)苯氧基)甲基)烟腈(ZE35)
将ZE34(26mg，0.045mmol)、D-萄糖胺(24.1mg，0.133mmol)溶于THF(3ml)与MeOH(3ml)的混合溶剂中室温反应过夜，后加入NaBH 4(33.7mg，0.887mmol)，室温反应约5h。反应结束后旋干溶剂，HPLC纯化。得到目标化合物6.2mg。 1H NMR(500MHz,Methanol-d4)δ8.97(dd,J＝2.1,0.8Hz,1H),8.24(dd,J＝8.2,2.1Hz,1H),7.75(d,J＝8.2Hz,1H),7.51(s,1H),7.34(dd,J＝5.8,3.3Hz,1H),7.23–7.15(m,2H),6.98(s,1H),6.91(d,J＝8.0Hz,1H),6.79–6.71(m,2H),5.52(s,2H),5.27(s,2H),4.31(s,4H),4.30–4.25(m,2H),4.13(dt,J＝6.7,5.0Hz,1H),3.90(dd,J＝4.8,1.4Hz,1H),3.77(dd,J＝11.0,3.0Hz,1H),3.73–3.67(m,2H),3.65(dd,J＝11.2,4.6Hz,1H),3.31–3.26(m,2H),2.27(s,3H).ESI-MS理论值:C 36H 38ClN 3O 9[M+H] +＝692.23，测得：692.3
实施例87：合成(2R,3R,4R,5S)-6-((5-氯-4-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基]-2-甲基 苄基]氧基)-2-((4-硝基苄氧基)苄基)氨基)己烷-1,2,3,4,5-戊醇(ZE36)
Figure PCTCN2020094013-appb-000155
步骤一:合成5-氯-4-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)-2-((4-硝基苄基)氧基)苯甲醛(ZE33)
将ZA52(120mg，0.308mmol)、1-(氯甲基)-4-硝基苯(63.1mg，0.369mmol)溶于DMF中，后加入Cs 2CO 3(162.8mg，0.461mmol)室温反应过夜。待反应结束后加水淬灭，用二氯甲烷萃取三次，有机相用饱和氯化钠溶液洗、无水硫酸钠干燥后旋干溶剂，并用层析柱分离纯化，得到目标化合物88.2mg。 1H NMR(500MHz,Chloroform-d)δ10.37(s,1H),8.30(d,J＝2.3Hz,1H),8.30–8.28(m,1H),8.13–8.08(m,1H),7.93(s,1H),7.63(d,J＝8.4Hz,2H),7.40(q,J＝2.4Hz,1H),7.27(d,J＝2.5Hz,1H),6.94(dd,J＝8.2,1.6Hz,1H),6.83(dd,J＝4.0,2.0Hz,1H),6.81–6.76(m,2H),6.62(s,1H),5.30(s,2H),5.22(s,2H),4.34(s,7H),2.30(s,3H).
步骤二：合成(2R,3R,4R,5S)-6-((5-氯-4-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基]-2-甲基苄基]氧基)-2-((4-硝基苄氧基)苄基)氨基)己烷-1,2,3,4,5-戊醇(ZE36)
将ZE33(25mg，0.046mmol)、D-萄糖胺(25mg，0.138mmol)溶于THF(3ml)与MeOH(3ml)的混合溶剂中室温反应过夜，后加入NaBH 4(35mg，0.92mmol)，继续反应约5h。反应结束后旋干溶剂，HPLC纯化。得到目标化合物5.6mg。 1H NMR(400MHz,Methanol-d4)δ8.33–8.21(m,2H),7.78–7.73(m,2H),7.51(s,1H),7.32(t,J＝4.5Hz,1H),7.20–7.14(m,2H),6.95(s,1H),6.90(dd,J＝7.8,0.8Hz,1H),6.73(d,J＝7.9Hz,2H),5.42(s,2H),5.26(s,2H),4.30(s,4H),4.28–4.19(m,2H),4.08(dt,J＝6.9,4.9Hz,1H),3.86(dd,J＝4.6,1.4Hz,1H),3.76(dd,J＝10.5,2.9Hz,1H),3.72–3.58(m,3H),3.26–3.19(m,2H),2.26(s,3H).ESI-MS理论值:C 36H 39ClN 2O 11[M+H] +＝711.22，测得：711.38。
实施例88：合成2-(5-氯-2-(5-氰基吡啶-3-基)甲氧基)-4-(3-(2,3-二氢苄[b][1,4]二恶英-6-基)-2-甲基苄基)氧)苄基)(3-羟丙基)氨基)乙烷-1-磺酸(ZE131)
Figure PCTCN2020094013-appb-000156
步骤一：合成5-((4-氯-5-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)-2-((((3-羟丙基)氨基)甲基)苯氧基)甲基)烟腈(ZE127)
将ZD07(100mg，0.19mmol)、3-氨基-1-丙醇(42.8mg，0.57mmol)溶于THF(4ml)与MeOH(4ml)的混合溶剂中,室温搅拌20min后依次加入AcOH(0.15ml)、NaBH(OAc) 3(201.4mg，0.95mmol)室温反应过夜。待反应结束后，旋干溶剂并用HPLC纯化，得到目标化合物52.6mg。 1H NMR(400MHz,Methanol-d4)δ9.01–8.92(m,2H),8.38(t,J＝2.1Hz,1H),7.53(s,1H),7.40(dd,J＝6.9,2.1Hz,1H),7.26–7.16(m,2H),7.05(s,1H),6.90(d,J＝8.0Hz,1H),6.81–6.70(m,2H),5.39(s,2H),5.31(s,2H),4.30(s,4H),4.22(s,2H),3.69(t,J＝5.7Hz,2H),3.18(t,J＝7.0Hz,2H),2.28(s,3H),1.88(p,J＝6.4Hz,2H).
步骤二：合成2-(5-氯-2-(5-氰基吡啶-3-基)甲氧基)-4-(3-(2,3-二氢苄[b][1,4]二恶英-6-基)-2-甲基苄基)氧)苄基)(3-羟丙基)氨基)乙烷-1-磺酸(ZE131)
将ZE127(25mg，0.043mmol)、2-溴乙基磺酸钠(18mg，0.085mmol)溶于DMF(3.0ml)中，然后加入N,N-二异丙基乙胺(DIEA，0.6ml)80℃反应过夜。反应结束后降至室温加水，然后用HPLC纯化。得到目标化合物12.2mg。 1H NMR(400MHz,Methanol-d 4)δ9.00(d,J＝2.2Hz,1H),8.93(d,J＝2.0Hz,1H),8.44(t,J＝2.1Hz,1H),7.55(s,1H),7.42(dd,J＝7.2,1.9Hz,1H),7.27–7.15(m,2H),7.06(s,1H),6.90(d,J＝8.1Hz,1H),6.81–6.71(m,2H),5.39(d,J＝2.0Hz,2H),5.31(s,2H),4.57(d,J＝13.3Hz,1H),4.30(s,4H),4.25(d,J＝13.3Hz,1H),3.63–3.53(m,3H),3.53–3.45(m,1H),3.45–3.36(m,1H),3.31–3.23(m,1H),3.23–3.15(m,1H),3.02(dt,J＝14.7,5.4Hz,1H),2.28(s,3H),1.99–1.68(m,2H).ESI-MS理论值:C 35H 36ClN 3O 8S[M+H] +＝694.19，测得：694.3。
实施例89：合成2-((5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)苄基)(3-(二甲基氨基)丙基)氨基)乙烷-1-磺酸(ZE132)
Figure PCTCN2020094013-appb-000157
步骤一：合成5-((4-氯-5-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)-2-((((二甲基氨基)丙基)氨基)甲基)苯氧基)甲基)烟腈(ZE128)
将ZD07(100mg，0.19mmol)、二甲氨基丙胺(58.24mg，0.57mmol)溶于THF(4ml)与MeOH(4ml)的混合溶剂中,室温搅拌20min后依次加入AcOH(0.15ml)、NaBH(OAc) 3(201.4mg，0.95mmol)室温反应过夜。待反应结束后，旋干溶剂并用HPLC纯化，得到目标化合物46.3mg。 1H NMR(400MHz,Methanol-d4)δ8.97(d,J＝2.1Hz,1H),8.93(d,J＝2.0Hz,1H),8.37(t,J＝2.1Hz,1H),7.55(s,1H),7.40(dd,J＝7.0,2.1Hz,1H),7.27–7.11(m,2H),7.03(s,1H),6.89(d,J＝8.1Hz,1H),6.79–6.65(m,2H),5.38(s,2H),5.29(s,2H),4.29(s,4H),4.26(s,2H),3.37(s,3H),3.26–3.19(m,2H),3.18–3.10(m,2H),2.91(s,6H),2.27(s,3H),2.17(tdd,J＝10.7,8.8,4.9Hz,2H).
步骤二：合成2-((5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)苄基)(3-(二甲基氨基)丙基)氨基)乙烷-1-磺酸(ZE132)
将ZE128(25mg，0.04mmol)、2-溴乙基磺酸钠(17.2mg，0.082mmol)溶于DMF(3.0ml)中，然后加入N,N-二异丙基乙胺(DIEA，0.6ml)80℃反应过夜。反应结束后降至室温加水，然后用HPLC纯化。得到目标化合物10.6mg。 1H NMR(500MHz,Chloroform-d)δ8.89(s,1H),8.82(s,1H),8.31(s,1H),7.52(s,1H),7.44–7.34(m,1H),7.27–7.15(m,2H),6.90(d,J＝8.2Hz,1H),6.80(d,J＝2.0Hz,1H),6.75(dd,J＝8.2,2.1Hz,1H),6.70(s,1H),5.22(s,2H),5.10(s,2H),4.30(s,6H),3.57(s,4H),3.30(s,2H),3.23(s,2H),3.14(s,2H),2.81(s,6H),2.24(s,3H).ESI-MS理论值:C 37H 41ClN 4O 7S[M+H] +＝721.24，测得：721.4。
实施例90：合成2-((5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)苄基)(2-羟乙基)氨基)乙烷-1-磺酸(ZE133)
Figure PCTCN2020094013-appb-000158
步骤一：合成5-((4-氯-5-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)-2-((((2- 羟乙基)氨基)甲基)苯氧基)甲基)烟腈(ZE130)
将ZD07(100mg，0.19mmol)、乙醇胺(34.82mg，0.57mmol)溶于THF(3ml)与MeOH(3ml)的混合溶剂中,室温搅拌20min后依次加入AcOH(0.15ml)、NaBH(OAc) 3(201.4mg，0.95mmol)室温反应过夜。待反应结束后，旋干溶剂并用HPLC纯化，得到目标化合物32.4mg。 1H NMR(400MHz,Methanol-d4)δ8.97(d,J＝2.1Hz,1H),8.95(d,J＝2.0Hz,1H),8.40(t,J＝2.1Hz,1H),7.54(s,1H),7.42(dd,J＝7.0,2.0Hz,1H),7.28–7.16(m,2H),7.07(s,1H),6.90(d,J＝8.1Hz,1H),6.79–6.68(m,2H),5.39(s,2H),5.32(s,2H),4.30(s,4H),4.25(s,2H),3.85–3.73(m,2H),3.18–3.05(m,2H),2.29(s,3H).
步骤二：合成2-((5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)苄基)(2-羟乙基)氨基)乙烷-1-磺酸(ZE133)
将ZE130(162mg，0.04mmol)、2-溴乙基磺酸钠(12.2mg，0.088mmol)溶于DMF(3.0ml)中，然后加入N,N-二异丙基乙胺(DIEA，0.6ml)80℃反应过夜。反应结束后降至室温加水，然后用HPLC纯化。得到目标化合物9.1mg。 1H NMR(400MHz,Methanol-d 4)δ8.98(s,1H),8.90(s,1H),8.47(t,J＝2.1Hz,1H),7.54(s,1H),7.41(dd,J＝7.1,1.9Hz,1H),7.27–7.16(m,2H),7.04(s,1H),6.89(d,J＝8.1Hz,1H),6.80–6.69(m,2H),5.41(s,2H),5.29(d,J＝2.3Hz,2H),4.71(d,J＝13.2Hz,1H),4.33–4.25(m,5H),3.84(t,J＝5.1Hz,2H),3.69–3.52(m,2H),3.44(dd,J＝12.1,6.7Hz,1H),3.31–3.14(m,2H),3.09–2.96(m,1H),2.28(s,3H).ESI-MS理论值:C 34H 34ClN 3O 8S[M+H] +＝680.18，测得：680.3。
实施例91：合成(2R,3R,4R,5S)-6-((5-氯-4-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基]-2-甲基苄基]氧基)-2-(((5-(甲基磺酰基)吡啶基-3-基)甲氧基)苄基)氨基)己烷-1,2,3,4,5-戊醇(ZE155)
Figure PCTCN2020094013-appb-000159
步骤一：合成5-氯-4-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)-2-((5-(甲基磺酰基)吡啶-3-基)甲氧基)苯甲醛(ZE154)
将ZA52(150mg，0.385mmol)、3-(氯甲基)-5-(甲基磺酰基)吡啶(94.6mg，0.462mmol)溶于DMF(2.5ml)中，然后加入K 2CO 3(106.2mg，0.769mmol)，室温反应过夜，反应结束后加水，然后用乙酸乙酯萃取，有机相旋干后用层析柱分离纯化。得到目标化合物170mg。 1H NMR(400MHz,Chloroform-d)δ10.28(s,1H),9.20(d,J＝2.2Hz,1H),9.00(d,J＝2.0Hz, 1H),8.40(t,J＝2.2Hz,1H),7.93(s,1H),7.44(t,J＝4.5Hz,1H),7.29(s,1H),7.28(s,1H),6.94(d,J＝8.2Hz,1H),6.85(d,J＝2.0Hz,1H),6.80(dd,J＝8.2,2.1Hz,1H),6.71(s,1H),5.29(s,2H),5.27(s,2H),4.33(s,4H),3.18(s,3H),2.32(s,3H).
步骤二：合成(2R,3R,4R,5S)-6-((5-氯-4-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基]-2-甲基苄基]氧基)-2-(((5-(甲基磺酰基)吡啶基-3-基)甲氧基)苄基)氨基)己烷-1,2,3,4,5-戊醇(ZE155)
将ZE154(20mg，0.035mmol)、D-萄糖胺(18.75mg，0.104mmol)溶于THF(3ml)与MeOH(3ml)的混合溶剂中室温反应过夜，后加入NaBH 4(26.25mg，0.691mmol)，继续反应约5h。反应结束后旋干溶剂，HPLC纯化。得到目标化合物8.2mg。 1H NMR(400MHz,Methanol-d 4)δ9.14(d,J＝2.2Hz,1H),9.06(d,J＝2.0Hz,1H),8.56(t,J＝2.1Hz,1H),7.53(s,1H),7.43(dd,J＝7.2,1.9Hz,1H),7.28–7.17(m,2H),7.11(s,1H),6.90(d,J＝8.0Hz,1H),6.80–6.70(m,2H),5.46(s,2H),5.32(s,2H),4.30(s,4H),4.24(d,J＝12.3Hz,2H),4.06(d,J＝6.3Hz,1H),3.84(dd,J＝4.5,1.4Hz,1H),3.74(d,J＝3.3Hz,1H),3.70–3.60(m,3H),3.29(s,3H),3.24–3.17(m,2H),2.30(s,3H).ESI-MS理论值:C 36H 41ClN 2O 11S[M+H] +＝745.21，测得：745.5。
实施例92：合成2-((5-氯-4-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)-2-((5-(甲基磺酰基)吡啶-3-基)甲氧基)苄基)(甲基)氨基)乙烷-1-磺酸(ZF25)
Figure PCTCN2020094013-appb-000160
步骤一：合成1-(5-氯-4-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)-2-((5-(甲基磺酰基)吡啶-3-基)甲氧基)苯基)-N-甲基甲胺(ZF19)
将ZE154(45mg，0.078mmol)、甲胺(30％in MeOH，24.14mg，0.233mmol)溶于THF(3ml)与MeOH(3ml)的混合溶剂中,室温搅拌20min后依次加入AcOH(0.08ml)、NaBH(OAc) 3(82.37mg，0.389mmol)室温反应过夜。待反应结束后，旋干溶剂并用HPLC纯化，得到目标化合物31mg。 1H NMR(400MHz,Methanol-d4)δ9.12(d,J＝2.2Hz,1H),9.02(d,J＝2.0Hz,1H),8.55(t,J＝2.1Hz,1H),7.51(s,1H),7.42(dd,J＝7.1,1.9Hz,1H),7.26–7.14(m,2H),7.09(s,1H),6.88(d,J＝8.1Hz,1H),6.79–6.68(m,2H),5.45(s,2H),5.29(s,2H),4.28(s,4H),4.20(s,2H),3.27(s,3H),2.72(s,3H),2.28(s,3H).
步骤二：合成2-((5-氯-4-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)-2-((5-(甲基磺酰基)吡啶-3-基)甲氧基)苄基)(甲基)氨基)乙烷-1-磺酸(ZF25)
将ZF19(16mg，0.027mmol)、2-溴乙基磺酸钠(11.37mg，0.054mmol)溶于DMF(3.0ml) 中，然后加入N,N-二异丙基乙胺(DIEA，0.5ml)80℃反应过夜。反应结束后降至室温加水，然后用HPLC纯化。得到目标化合物4.6mg。 1H NMR(400MHz,Methanol-d 4)δ9.12(d,J＝2.2Hz,1H),9.05(d,J＝2.0Hz,1H),8.63(t,J＝2.1Hz,1H),7.54(s,1H),7.43(d,J＝7.0Hz,1H),7.27–7.16(m,2H),7.12(s,1H),6.90(d,J＝8.1Hz,1H),6.80–6.72(m,2H),5.48(s,2H),5.31(s,2H),4.45(d,J＝13.2Hz,1H),4.35(d,J＝13.1Hz,1H),4.30(s,4H),3.65(ddd,J＝14.0,9.4,5.0Hz,1H),3.44(s,1H),3.30(s,3H),3.29–3.18(m,1H),3.13–3.03(m,1H),2.89(s,3H),2.29(s,3H).ESI-MS理论值:C 33H 35ClN 2O 9S 2[M+H] +＝703.15，测得：703.5。
实施例93：合成2-((5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)苄基)(3-(4-甲基哌嗪-1-基)丙基)氨基)乙烷-1-磺酸(ZF59)
Figure PCTCN2020094013-appb-000161
步骤一：合成5-((4-氯-5-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)-2-((((4-甲基哌嗪-1-基)丙基)氨基)甲基)苯氧基)甲基)烟腈(ZF34)
将ZD07(40mg，0.076mmol)、1-(3-氨基丙基)-4-甲基哌嗪(35.86mg，0.228mmol)溶于THF(3ml)与MeOH(3ml)的混合溶剂中，室温搅拌20min后依次加入AcOH(0.05ml)、NaBH(OAc) 3(80.58mg，0.38mmol)室温反应过夜。待反应结束后，旋干溶剂并用HPLC纯化，得到目标化合物50.6mg。 1H NMR(500MHz,Methanol-d4)δ8.98(d,J＝2.1Hz,1H),8.95(d,J＝2.0Hz,1H),8.38(d,J＝2.1Hz,1H),7.55(s,1H),7.41(dd,J＝7.3,1.8Hz,1H),7.26–7.15(m,2H),7.05(s,1H),6.90(d,J＝8.1Hz,1H),6.79–6.70(m,2H),5.39(s,2H),5.31(s,2H),4.30(s,4H),4.25(s,2H),3.51(s,4H),3.29–3.18(m,4H),3.18–3.08(m,2H),2.97(s,3H),2.93(t,J＝7.2Hz,2H),2.29(s,3H),2.05(ddd,J＝12.7,10.1,5.9Hz,2H).
步骤二：合成2-((5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)苄基)(3-(4-甲基哌嗪-1-基)丙基)氨基)乙烷-1-磺酸(ZF59)
将ZF34(27mg，0.053mmol)、乙烯基磺酸异丙酯(12.2mg，0.081mmol)溶于甲醇溶液中室温反应过夜后用UPLC监测反应，反应结束后旋干溶剂，将得到的化合物用丙酮(20ml)溶解，然后加入碘化钠(12.2mg，0.081mmol)加热回流过夜。反应结束后旋干溶剂并用HPLC纯化，得到目标化合物14.4mg。 1H NMR(500MHz,Methanol-d 4)δ9.03(t,J＝2.0Hz,1H),8.97(t,J＝1.9Hz,1H),8.47(d,J＝2.4Hz,1H),7.58(d,J＝2.1Hz,1H),7.45(d,J＝7.3Hz,1H),7.24(dt,J＝12.9,7.7Hz,2H),7.13(d,J＝2.1Hz,1H),6.96–6.87(m,1H),6.83–6.70(m,2H),5.52(d,J＝1.9Hz,2H),5.40(s,2H),5.34(s,2H),4.87(s,6H),4.31(d,J＝1.9Hz,4H),3.54(s,2H),3.31(s,2H),3.18(d,J＝21.2Hz,2H),2.91(d,J＝2.0Hz,3H),2.46–2.35(m,2H),2.31(d,J＝2.0Hz,3H).ESI-MS理论值:C 40H 46ClN 5O 7S[M+H] +＝776.28，测得：776.5。
实施例94：合成2-((5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)苄基)(2-(二甲基氨基)乙基)氨基)乙烷-1-磺酸(ZF48N)
Figure PCTCN2020094013-appb-000162
步骤一：合成2-((2-(二甲基氨基)乙基)氨基)乙烷-1-磺酸异丙酯(ZF46)
将N,N-二甲基乙二胺(15.1mg，0.171mmol)、乙烯基磺酸异丙酯(25.66mg，0.171mmol)溶于甲醇中，室温反应过夜，反应结束后旋干溶剂直接用于下一步。 1H NMR(400MHz,Methanol-d4)δ4.96(p,J＝6.2Hz,1H),3.45–3.36(m,2H),3.07(t,J＝6.9Hz,2H),2.76(t,J＝6.7Hz,2H),2.57–2.46(m,2H),2.31(s,6H),1.43(s,3H),1.41(s,3H).
步骤二：合成2-((5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)苄基)(2-(二甲基氨基)乙基)氨基)乙烷-1-磺酸(ZF48N)
将ZD07(30mg，0.057mmol)、ZF46溶于四氢呋喃溶液中，室温搅拌过夜后依次加入然后依次加入AcOH(0.1ml)、NaBH(OAc) 3(60.4mg，0.285mmol)室温反应过夜。待反应结束后旋干溶剂，用二氯甲烷、乙酸乙酯各萃取两次，收集有机相用无水硫酸钠干燥后旋干。将得到的化合物溶于甲醇(20ml)中，然后加入0.5ml浓盐酸，60℃加热搅拌1h，然后降至室温旋干溶剂后用HPLC纯化，得到目标化合物8.7mg。 1H NMR(400MHz,Chloroform-d)δ8.97(s,1H),8.88(s,1H),8.38(s,1H),7.51(s,1H),7.45–7.34(m,1H),7.26–7.17(m,2H),6.91(d,J＝8.2Hz,1H),6.80(d,J＝2.0Hz,1H),6.79–6.66(m,2H),5.24(s,2H),5.14(s,2H),4.34(s,2H),4.30(s,4H),3.59(s,6H),3.20(s,2H),2.82(s,6H),2.26(s,3H).ESI-MS理论值:C 36H 39ClN 4O 7S[M+H] +＝707.22，测得：707.4。
实施例95：合成2-((5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)苄基)(3-吗啉代丙基)氨基)乙烷-1-磺酸(ZF49N)
Figure PCTCN2020094013-appb-000163
步骤一：合成5-((4-氯-5-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)-2-((((3- 吗啉基丙基)氨基)甲基)苯氧基)甲基)烟腈(ZF38)
将ZD07(45mg，0.086mmol)、3-(4-吗啉基)-1-丙胺(37.0mg，0.257mmol)溶于四氢呋喃(10ml)溶液中，室温搅拌过夜后依次加入AcOH(0.08ml)、NaBH(OAc) 3(90.65mg，0.428mmol)继续反应5h，反应结束后旋干溶剂，HPLC纯化，得到目标化合物35mg。 1H NMR(400MHz,Methanol-d4)δ8.98(d,J＝2.1Hz,1H),8.95(d,J＝2.0Hz,1H),8.38(t,J＝2.1Hz,1H),7.55(s,1H),7.41(dd,J＝7.0,2.2Hz,1H),7.27–7.15(m,2H),7.05(s,1H),6.90(d,J＝8.0Hz,1H),6.81–6.67(m,2H),5.39(s,2H),5.31(s,2H),4.30(s,4H),4.26(s,2H),3.93(s,4H),3.29–3.20(m,4H),3.20–3.09(m,4H),2.28(s,3H),2.20(qd,J＝10.5,9.3,6.4Hz,2H).
步骤二：合成2-((5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)苄基)(3-吗啉代丙基)氨基)乙烷-1-磺酸(ZF49N)
将ZF38(35mg，0.053mmol)、乙烯基磺酸异丙酯(24mg，0.16mmol)溶于甲醇溶液中室温反应过夜后用UPLC监测反应，反应结束后旋干溶剂，将得到的化合物用丙酮(20ml)溶解，然后加入碘化钠(15mg，0.1mmol)加热回流过夜。反应结束后旋干溶剂，然后用HPLC纯化，得到目标化合物12.3mg。 1H NMR(400MHz,Methanol-d 4)δ9.01(d,J＝2.1Hz,1H),8.94(d,J＝2.0Hz,1H),8.42(t,J＝2.1Hz,1H),7.57(s,1H),7.40(dd,J＝6.8,2.3Hz,1H),7.27–7.15(m,2H),7.07(s,1H),6.89(d,J＝8.1Hz,1H),6.81–6.65(m,2H),5.43(s,2H),5.30(s,2H),4.47(s,2H),4.29(s,4H),4.07(s,2H),3.81(s,2H),3.60(t,J＝6.0Hz,2H),3.49(d,J＝12.6Hz,2H),3.27–3.16(m,4H),3.12(s,4H),2.28(s,3H),2.22(s,2H).ESI-MS理论值:C 39H 43ClN 4O 8S[M+H] +＝763.25，测得：763.3。
实施例96：合成2-((3-(1H-咪唑-1-基)丙基)(5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)苄基)氨基)乙烷-1-磺酸(ZF50N)
Figure PCTCN2020094013-appb-000164
步骤一：合成5-((2-((((3-(1H-咪唑-1-基)丙基)氨基)甲基)-4-氯-5-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)苯氧基)甲基)烟腈(ZF40)
将ZD07(45mg，0.086mmol)、1-(3-氨基丙基)咪唑(32.12mg，0.257mmol)溶于四氢呋喃(12ml)溶液中，室温搅拌过夜后依次加入AcOH(0.08ml)、NaBH(OAc) 3(90.65mg，0.428mmol)继续反应5h，反应结束后旋干溶剂，HPLC纯化，得到化合物用碳酸氢钠溶液洗，最终得到目标化合物38mg。 1H NMR(400MHz,Methanol-d4)δ9.01(d,J＝1.5Hz,1H),8.96(d,J＝2.1Hz,1H),8.93(d,J＝2.0Hz,1H),8.37(t,J＝2.1Hz,1H),7.68(t,J＝1.8Hz,1H),7.65(t,J＝1.7Hz,1H),7.53(s,1H),7.41(dd,J＝6.9,2.1Hz,1H),7.27–7.14(m,2H),7.05(s,1H),6.90(d,J＝8.0Hz,1H),6.81–6.71(m,2H),5.38(s,2H),5.31(s,2H),4.38(t,J＝7.3Hz,2H), 4.30(s,4H),4.25(s,2H),3.37(s,1H),3.19–3.09(m,2H),2.32(dd,J＝7.5,4.2Hz,2H),2.29(s,0H).
步骤二：合成2-((3-(1H-咪唑-1-基)丙基)(5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)苄基)氨基)乙烷-1-磺酸(ZF50N)
将ZF40(38mg，0.06mmol)、乙烯基磺酸异丙酯(26.9mg，0.18mmol)溶于甲醇(20ml)溶液中室温反应过夜后用UPLC监测反应，反应结束后旋干溶剂，将得到的化合物用丙酮(20ml)溶解，然后加入碘化钠(15mg，0.1mmol)加热回流过夜。反应结束后旋干溶剂，然后用HPLC纯化，得到目标化合物15.6mg。 1H NMR(400MHz,Methanol-d 4)δ9.01(d,J＝1.5Hz,1H),8.96(d,J＝2.1Hz,1H),8.93(d,J＝2.0Hz,1H),8.37(t,J＝2.1Hz,1H),7.68(t,J＝1.8Hz,1H),7.65(t,J＝1.7Hz,1H),7.53(s,1H),7.41(dd,J＝6.9,2.1Hz,1H),7.27–7.14(m,2H),7.05(s,1H),6.90(d,J＝8.0Hz,1H),6.81–6.71(m,2H),5.38(s,2H),5.31(s,2H),4.38(t,J＝7.3Hz,2H),4.30(s,4H),4.25(s,2H),3.19–3.09(m,2H),2.32(dd,J＝7.5,4.2Hz,2H),2.29(s,3H).ESI-MS理论值:C 38H 38ClN 5O 7S[M+H] +＝744.22，测得：744.2。
实施例97：合成2-((5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)苄基)(3-(吡咯烷基-1-基)丙基)氨基)乙烷-1-磺酸(ZF64N)
Figure PCTCN2020094013-appb-000165
步骤一：合成5-((4-氯-5-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)-2-((((吡咯烷-1-基)丙基)氨基)甲基)苯氧基)甲基)烟腈(ZF61)
将ZD07(40mg，0.076mmol)、1-(3-氨基丙基)吡咯烷(29.23mg，0.228mmol)溶于四氢呋喃(10ml)溶液中，室温搅拌过夜后依次加入AcOH(0.07ml)、NaBH(OAc) 3(80.58mg，0.380mmol)继续反应5h，反应结束后旋干溶剂，用层析柱分离纯化，得到目标化合物36.2mg。 1H NMR(500MHz,Methanol-d4)δ8.98(d,J＝2.1Hz,1H),8.95(d,J＝2.0Hz,1H),8.38(t,J＝2.1Hz,1H),7.55(s,1H),7.41(dd,J＝7.1,1.9Hz,1H),7.31–7.17(m,2H),7.05(s,1H),6.90(d,J＝8.1Hz,1H),6.80–6.71(m,2H),5.40(s,2H),5.31(s,2H),4.30(s,4H),4.26(s,2H),3.69(s,2H),3.32–3.25(m,2H),3.20–3.13(m,2H),3.10(s,2H),2.29(s,3H),2.24–2.12(m,4H),2.07(s,2H).
步骤二：合成2-((5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)苄基)(3-(吡咯烷基-1-基)丙基)氨基)乙烷-1-磺酸(ZF64N)
将ZF61(28mg，0.044mmol)、乙烯基磺酸异丙酯(19.7mg，0.132mmol)溶于甲醇(20ml)溶液中室温反应过夜后用UPLC监测，反应结束后旋干溶剂，将得到的化合物用丙酮(20ml)溶解，然后加入碘化钠(13.2mg，0.088mmol)加热回流过夜。反应结束后旋干溶剂，然后用 HPLC纯化，得到目标化合物9.3mg。 1H NMR(400MHz,Methanol-d 4)δ9.00(dd,J＝11.2,2.2Hz,1H),8.94(d,J＝2.0Hz,1H),8.41(dt,J＝13.9,2.2Hz,1H),7.57(d,J＝4.9Hz,1H),7.40(dd,J＝6.9,2.2Hz,1H),7.26–7.13(m,2H),7.06(d,J＝10.4Hz,1H),6.89(d,J＝8.1Hz,1H),6.80–6.69(m,2H),5.42(d,J＝9.2Hz,2H),5.30(s,2H),4.47(s,1H),4.29(s,4H),4.27(s,1H),3.76–3.70(m,1H),3.65(s,2H),3.59(t,J＝6.1Hz,2H),3.51–3.40(m,1H),3.22(t,J＝8.0Hz,2H),3.17–3.10(m,2H),3.09(s,2H),2.28(s,3H),2.26–2.21(m,2H),2.18(s,2H),2.04(d,J＝8.8Hz,2H).ESI-MS理论值:C 39H 43ClN 4O 7S[M+H] +＝747.25，测得：747.2。
实施例98：合成2-((5-氯-4-((3-((2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)-2-((5-(甲基磺酰基)吡啶-3-基)甲氧基)苄基)(3-(二甲基氨基)丙基)氨基)乙烷-1-磺酸(ZF74N)
Figure PCTCN2020094013-appb-000166
步骤一：合成N1-(5-氯-4-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)-2-((5-(甲基磺酰基)吡啶-3-基)甲氧基)苄基)-N3,N3-二甲基丙烷-1,3-二胺(ZF73)
将(ZE154)(40mg，0.069mmol)、3-二甲胺基丙二胺(21.2mg，0.207mmol)溶于四氢呋喃中，室温搅拌过夜后加入AcOH(0.06ml)、NaBH(OAc) 3,继续反应5h，反应结束后滤除反应液中的固体、旋干溶剂直接用于下一步。
步骤二：合成异丙基2-((5-氯-4-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)-2-((5-(甲基磺酰基)吡啶-3-基)甲氧基)苄基)(3-(二甲基氨基)丙基)氨基)乙烷-1-磺酸盐(ZF74)
将ZF73粗品溶于甲醇溶液中，然后加入乙烯基磺酸异丙酯(20.7mg，0.138mmol)室温反应过夜，并用UPLC检测反应，反应结束后旋干溶剂，加入丙酮(15ml)溶解，然后加入NaI(10mg，0.067mmol)加热回流过夜。待反应结束后旋干溶剂并用HPLC纯化，得到化合物9.3mg。 1H NMR(500MHz,DMSO-d6)δ9.13(d,J＝2.0Hz,1H),9.11(d,J＝2.2Hz,1H),8.54(dt,J＝11.1,2.2Hz,1H),7.64(s,1H),7.48(d,J＝7.4Hz,1H),7.31–7.25(m,2H),7.22(d,J＝1.5Hz,1H),6.95(d,J＝8.2Hz,1H),6.80(dd,J＝4.8,2.1Hz,1H),6.79–6.74(m,1H),5.50(d,J＝5.4Hz,2H),5.32(d,J＝4.3Hz,2H),4.40(s,2H),4.30(s,4H),4.15(s,1H),3.58(t,J＝8.2Hz,1H),3.40(s,6H),3.16(s,2H),3.05(s,3H),2.99(t,J＝8.2Hz,2H),2.76(s,4H),2.26(s,3H),2.03(s,2H).ESI-MS理论值:C 37H 44ClN 3O 9S 2[M+H] +＝774.22，测得：774.1。
实施例99：合成2-((5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)苄基)(3-(哌啶-1-基)丙基)氨基)乙烷-1-磺酸(ZF98D)
Figure PCTCN2020094013-appb-000167
步骤一：合成5-((4-氯-5-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)-2-((((哌啶-1-基)丙基)氨基)甲基苯氧基)甲基)烟腈(ZF91)
将ZD07(32mg，0.061mmol)、3-(哌啶-1-基)丙-1-胺(26mg，0.182mmol)溶于四氢呋喃溶液中，室温搅拌过夜后加入AcOH(0.05ml)、NaBH(OAc) 3(64.5mg，0.304mmol)继续反应5h，反应结束后旋干溶剂，HPLC纯化，得到目标化合物28.6mg。 1H NMR(500MHz,Methanol-d4)δ8.98(d,J＝2.0Hz,1H),8.95(d,J＝1.9Hz,1H),8.38(d,J＝2.1Hz,1H),7.55(s,1H),7.41(dd,J＝7.0,1.9Hz,1H),7.27–7.16(m,2H),7.05(s,1H),6.90(d,J＝8.0Hz,1H),6.80–6.71(m,2H),5.40(s,2H),5.32(s,2H),4.30(s,4H),4.26(s,2H),3.55(d,J＝12.2Hz,2H),3.25–3.10(m,4H),2.95(s,1H),2.29(s,3H),2.18(ddt,J＝10.7,6.5,3.9Hz,2H),1.98(d,J＝14.7Hz,2H),1.93–1.72(m,3H),1.54(d,J＝12.7Hz,1H).
步骤二:合成异丙基2-((5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基]-2-甲基苄基)氧基)苄基)(3-(哌啶-1-基)丙基)氨基)乙烷-1-磺酸盐(ZF98D)
将ZF91(55mg，0.084mmol)、乙烯基磺酸异丙酯(25.4mg，0.169mmol)溶于甲醇溶液中室温反应过夜，反应结束后旋干溶剂，并将得到化合物溶于丙酮(15ml)中，后加入碘化钠(11.41mg，0.076mmol)加热回流过夜，反应结束后旋干溶剂HPLC纯化，得到目标化合物23.1mg，1H NMR(500MHz,Methanol-d4)δ9.01(d,J＝2.0Hz,1H),8.92(d,J＝1.8Hz,1H),8.42(d,J＝2.0Hz,1H),7.58(s,1H),7.45–7.35(m,1H),7.25–7.15(m,2H),7.05(s,1H),6.88(d,J＝8.1Hz,1H),6.80–6.69(m,2H),5.41(s,2H),5.27(s,2H),4.46(s,2H),4.28(s,4H),3.60(t,J＝6.2Hz,2H),3.50(d,J＝12.2Hz,2H),3.12(t,J＝8.1Hz,5H),2.99–2.82(m,2H),2.26(s,3H),2.21(s,2H),1.96(d,J＝14.7Hz,2H),1.81(dt,J＝28.1,15.1Hz,3H),1.54(t,J＝12.8Hz,1H).ESI-MS理论值:C 40H 45ClN 4O 7S[M+H] +＝761.27，测得：761.3。
实施例100：合成2-((5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)苄基)(2-(吡咯烷基-1-基)乙基)氨基)乙烷-1-磺酸(ZF99D)
Figure PCTCN2020094013-appb-000168
步骤一：合成5-((4-氯-5-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)-2-((((2-吡咯烷基-1-基)乙基)氨基)甲基)苯氧基)甲基)烟腈(ZF96)
将ZD07(45mg，0.085mmol)、2-(吡咯烷-1-基)乙-1-胺(29.3mg，0.257mmol)溶于四氢呋喃溶液中，室温搅拌过夜后加入AcOH(0.06ml)、NaBH(OAc) 3(54.4mg，0.257mmol)继续反应5h，反应结束后旋干溶剂，HPLC纯化，得到目标化合物47.6mg。 1H NMR(500MHz,Methanol-d4)δ8.98(s,1H),8.95(s,1H),8.39(s,1H),7.57(s,1H),7.41(d,J＝7.0Hz,1H),7.22(q,J＝7.9Hz,2H),7.06(s,1H),6.90(d,J＝8.1Hz,1H),6.76(d,J＝12.4Hz,2H),5.40(s,2H),5.32(s,2H),4.32(s,3H),4.30(s,4H),3.64–3.56(m,2H),3.53(dd,J＝8.2,5.8Hz,2H),3.47(s,8H),2.29(s,3H).
步骤二:2-((5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)苄基)(2-(吡咯烷基-1-基)乙基)氨基)乙烷-1-磺酸(ZF99D)
将ZF96(47.6mg，0.076mmol)、乙烯基磺酸异丙酯(22.88mg，0.153mmol)溶于甲醇溶液中室温反应过夜，反应结束后旋干溶剂，加入丙酮(15ml)溶解，后加入碘化钠(10.02mg，0.067mmol)加热回流过夜，反应结束后旋干溶剂HPLC纯化，得到目标化合物23.1mg， 1H NMR(500MHz,Methanol-d4)δ8.98(d,J＝1.9Hz,1H),8.92(d,J＝1.8Hz,1H),8.40(d,J＝2.3Hz,1H),7.59(s,1H),7.43–7.35(m,1H),7.25–7.15(m,2H),7.02(s,1H),6.88(d,J＝8.1Hz,1H),6.81–6.69(m,4H),5.36(s,2H),5.27(s,2H),4.28(s,4H),4.16(s,2H),3.47(t,J＝6.9Hz,2H),3.39–3.34(m,2H),3.27(s,4H),3.08(t,J＝5.7Hz,2H),2.27(s,3H),2.05(d,J＝6.5Hz,6H).ESI-MS理论值:C 38H 41ClN 4O 7S[M+H] +＝733.24，测得：733.2。
实施例101：合成2-((5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)苄基)(2-(哌啶-1-基)乙基)氨基)乙烷-1-磺酸(ZF100D)
Figure PCTCN2020094013-appb-000169
步骤一：合成5-((4-氯-5-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)-2-((((2-哌啶-1-基)乙基)氨基)甲基苯氧基)甲基)烟腈(ZF97)
将ZD07(45mg，0.085mmol)、1-(2-氨乙基)哌啶(32.9mg，0.085mmol)溶于四氢呋喃溶液中，室温搅拌过夜后加入AcOH(0.06ml)、NaBH(OAc) 3(54.4mg，0.257mmol)继续反应5h，反应结束后旋干溶剂，HPLC纯化，得到目标化合物51.3mg。 1H NMR(500MHz,Methanol-d4)δ8.98(d,J＝2.0Hz,1H),8.93(d,J＝1.8Hz,1H),8.39(d,J＝2.0Hz,1H),7.56(s,1H),7.40(dd,J＝7.1,1.8Hz,1H),7.25–7.14(m,2H),7.04(s,1H),6.90(d,J＝8.1Hz,1H),6.79–6.68(m,2H),5.39(s,2H),5.30(s,2H),4.31(s,2H),4.30(s,4H),3.73–3.60(m,2H),3.58(s,2H),3.49(dd,J＝8.1,5.8Hz,2H),3.12(s,2H),2.28(s,3H),1.90(s,4H),1.72(s,2H).
步骤二：合成2-((5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)苄基)(2-(哌啶-1-基)乙基)氨基)乙烷-1-磺酸(ZD100D)
将ZF97(51.3mg，0.068mmol)、乙烯基磺酸异丙酯(20.46mg，0.136mmol)溶于甲醇溶液中室温反应过夜，反应结束后旋干溶剂，加入丙酮(15ml)溶解，后加入碘化钠(20.5mg，0.136mmol)加热回流过夜，反应结束后旋干溶剂HPLC纯化，得到目标化合物19.7mg， 1H NMR(500MHz,Methanol-d4)δ9.00(d,J＝2.0Hz,1H),8.96(d,J＝1.9Hz,1H),8.42(s,1H),7.60(s,1H),7.39(d,J＝6.7Hz,1H),7.26–7.17(m,2H),7.05(s,1H),6.90(d,J＝8.0Hz,1H),6.75(d,J＝10.9Hz,2H),5.40(s,2H),5.32(s,2H),4.30(s,4H),4.18(s,2H),4.01(s,6H),3.06(s,2H),2.98–2.67(m,2H),2.30(s,3H),1.79(s,5H),1.64(s,4H).ESI-MS理论值:C 39H 43ClN 4O 7S[M+H] +＝747.25，测得：747.3。
实施例102：合成3-((5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)苄基)(3-(二甲基氨基)丙基)氨基)丙烷-1-磺酸(ZF102)
Figure PCTCN2020094013-appb-000170
将试剂ZE128(15mg，0.025mmol)、1,2-氧杂硫杂环戊烷2,2-二氧化物(3.3mg，0.027mmol) 溶于干燥的DCM中，然后加入三乙胺(3.7mg，0.037mmol)，室温反应过夜。反应结束后旋干溶剂，HPLC纯化。得到目标化合物2.9mg。 1H NMR(500MHz,Methanol-d4)δ8.99(d,J＝2.1Hz,1H),8.95(d,J＝2.0Hz,1H),8.40(t,J＝2.1Hz,1H),7.57(s,1H),7.40(dd,J＝7.1,2.0Hz,1H),7.26–7.16(m,2H),7.06(s,1H),6.90(d,J＝8.1Hz,1H),6.80–6.71(m,2H),5.43(s,2H),5.32(s,2H),4.30(s,4H),4.29(s,2H),3.67–3.56(m,2H),3.48–3.39(m,2H),3.16(s,2H),3.15(s,6H),3.15–3.12(m,2H),2.94–2.89(m,2H),2.29(s,3H),2.27–2.16(m,2H).ESI-MS理论值:C 38H 43ClN 4O 7S[M+H] +＝736.25，测得：736.2。
实施例103：合成2-((5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)苄基)(4-(二甲基氨基)环己基)氨基)乙烷-1-磺酸(ZF119D)
Figure PCTCN2020094013-appb-000171
步骤一：合成5-((4-氯-5-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)-2-((((4-二甲基氨基)环己基)氨基)苯氧基)甲基)烟腈(ZF117)
将ZD07(45mg，0.086mmol)、N,N-二甲基-1,4-环己烷二胺(36.4mg，0.257mmol)溶于四氢呋喃溶液中，室温搅拌过夜后加入AcOH(0.06ml)、NaBH(OAc) 3(54.4mg，0.257mmol)继续反应5h，反应结束后旋干溶剂，HPLC纯化，得到目标化合物25.8mg。 1H NMR(500MHz,Methanol-d4)δ9.00(d,J＝2.0Hz,1H),8.97(d,J＝1.9Hz,1H),8.42(d,J＝2.1Hz,1H),7.56(s,1H),7.44(d,J＝7.3Hz,1H),7.23(dt,J＝13.7,7.5Hz,2H),7.08(s,1H),6.90(d,J＝8.1Hz,1H),6.81–6.71(m,2H),5.36(s,2H),5.34(s,2H),4.30(s,4H),4.28(s,2H),3.43(s,1H),3.32–3.26(m,1H),2.90(s,6H),2.30(s,3H),2.11(d,J＝12.0Hz,2H),1.95(d,J＝10.3Hz,6H).
步骤二：合成2-((5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)苄基)(4-(二甲基氨基)环己基)氨基)乙烷-1-磺酸(ZF119D)
将ZF117(25.8mg，0.04mmol)溶于二氯甲烷中用饱和NaHCO 3洗涤，后收集有机相干燥后旋干，将得到的化合物溶于甲醇(15ml)溶液中，然后加入乙烯基磺酸异丙酯(11.9mg，0.08mmol)室温反应过夜，反应结束后旋干溶剂，并加入丙酮(20ml)溶解，然后加入NaI(12mg，0.08mmol)加热回流过夜。待反应结束后旋干溶剂，HPLC纯化，得到目标化合物11.1mg。 1H NMR(500MHz,Methanol-d 4)δ9.03(d,J＝2.0Hz,1H),8.96(d,J＝1.8Hz,1H),8.45(d,J＝2.1Hz,1H),7.55(s,1H),7.45(d,J＝7.3Hz,1H),7.27–7.17(m,2H),7.10(s,1H),6.90(d,J＝8.1Hz,1H),6.80–6.73(m,2H),5.38(d,J＝15.1Hz,2H),5.32(d,J＝4.4Hz,2H), 4.77(d,J＝13.1Hz,1H),4.30(s,4H),4.07(d,J＝13.1Hz,1H),3.64(d,J＝11.7Hz,2H),3.53(d,J＝15.1Hz,1H),3.32(d,J＝3.6Hz,1H),3.18(q,J＝12.0,11.6Hz,1H),2.97(s,6H),2.82(s,1H),2.34(d,J＝13.6Hz,1H),2.29(s,3H),2.20(d,J＝14.6Hz,1H),1.99(s,1H),1.86(dt,J＝26.4,12.3Hz,3H),1.54(s,1H).ESI-MS理论值:C 40H 45ClN 4O 7S[M+H] +＝761.27，测得：761.3。
实施例104：合成2-((5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)苄基)((1-甲基-1H-吡唑-4-基)甲基)氨基)乙烷-1-磺酸(ZF127D)
Figure PCTCN2020094013-appb-000172
步骤一：合成5-((4-氯-5-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)-2-(((((甲基-1H-吡唑-4-基)甲基)氨基)甲基)苯氧基)甲基)烟腈(ZF122)
将ZD07(45mg，0.086mmol)、(1-甲基-1H-吡唑-4-基)甲胺(28.5mg，0.257mmol)溶于1,2-二氯乙烷中(15ml)，然后依次加入AcOH(0.06ml)、NaBH(OAc) 3(54.4mg，0.257mmol)室温反应过夜。待反应结束后旋干溶剂，HPLC纯化，得到目标化合物54.4mg。 1H NMR(500MHz,Methanol-d4)δ8.97(d,J＝2.0Hz,1H),8.90(d,J＝2.1Hz,1H),8.30(d,J＝2.1Hz,1H),7.75(s,1H),7.54(s,1H),7.50(s,1H),7.41(dd,J＝7.2,1.9Hz,1H),7.27–7.17(m,2H),7.05(s,1H),6.90(d,J＝8.1Hz,1H),6.81–6.70(m,2H),5.35(s,2H),5.32(s,2H),4.30(s,4H),4.19(s,2H),4.16(s,2H),3.92(s,3H),2.29(s,3H).
步骤二：合成2-((5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)苄基)((1-甲基-1H-吡唑-4-基)甲基)氨基)乙烷-1-磺酸(ZF127D)
将ZF122(54.4mg，0.074mmol)溶于二氯甲烷中用饱和NaHCO 3洗涤，后收集有机相干燥后旋干，将得到的化合物溶于甲醇(20ml)溶液中，然后加入乙烯基磺酸异丙酯(16.65mg，0.111mmol)室温反应过夜，反应结束后旋干溶剂，并加入丙酮(20ml)溶解，然后加入NaI(28mg，0.187mmol)加热回流过夜。待反应结束后旋干溶剂，HPLC纯化，得到目标化合物18.6mg。 1H NMR(500MHz,Methanol-d 4)δ8.90(d,J＝1.9Hz,1H),8.83(d,J＝2.0Hz,1H),8.24(d,J＝2.0Hz,1H),7.74(s,1H),7.48(s,1H),7.44(s,1H),7.39(dd,J＝6.9,2.2Hz,1H),7.20(d,J＝6.8Hz,2H),6.95(s,1H),6.88(d,J＝8.2Hz,1H),6.78–6.69(m,2H),5.29(s,2H),5.24(d,J＝10.0Hz,2H),4.59–4.47(m,2H),4.29(s,4H),4.19(d,J＝13.9Hz,1H),4.01(d,J＝13.3Hz,1H),3.88(s,3H),3.52(d,J＝9.9Hz,1H),3.40(t,J＝4.8Hz,1H),3.37(s,3H),3.35(s,1H),2.98 (s,1H),2.27(s,3H).ESI-MS理论值:C 37H 36ClN 5O 7S[M+H] +＝730.20，测得：730.3。
实施例105：合成2-((5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)苄基)(吡啶-4-基甲基)氨基)乙烷-1-磺酸(ZF128D)
Figure PCTCN2020094013-appb-000173
步骤一：合成5-((4-氯-5-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)-2-((((吡啶基-4-基甲基)氨基)甲基)苯氧基)甲基)烟腈(ZF123)
将ZD07(45mg，0.086mmol)、4-甲氨基吡啶(27.7mg，0.257mmol)溶于1,2-二氯乙烷中(15ml)，然后依次加入AcOH(0.06ml)、NaBH(OAc) 3(54.4mg，0.257mmol)室温反应过夜。待反应结束后旋干溶剂，HPLC纯化，得到目标化合物60mg。 1H NMR(500MHz,Methanol-d4)δ8.96(d,J＝1.9Hz,1H),8.93(d,J＝2.0Hz,1H),8.81–8.77(m,2H),8.33(d,J＝2.1Hz,1H),7.87(d,J＝5.8Hz,2H),7.57(s,1H),7.26–7.17(m,2H),7.06(s,1H),6.90(d,J＝8.0Hz,1H),6.80–6.71(m,2H),5.38(s,2H),5.32(s,2H),4.50(s,2H),4.35(s,2H),4.30(s,4H),2.29(s,3H).
步骤二：合成异丙基2-((5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基]-2-甲基苄基)氧基)苄基)(吡啶-4-基甲基)氨基)乙烷-1-磺酸盐(ZF128C)
将ZF123(50mg，0.068mmol)溶于二氯甲烷中用饱和NaHCO 3洗涤，后收集有机相干燥后旋干，将得到的化合物溶于甲醇(20ml)溶液中，然后加入乙烯基磺酸异丙酯(20.5mg，0.137mmol)室温反应过夜，反应结束后旋干溶剂，纯化后得到目标化合物16.3mg。 1H NMR(500MHz,Methanol-d4)δ8.94(d,J＝1.9Hz,2H),8.68(d,J＝6.2Hz,2H),8.33(d,J＝2.1Hz,1H),8.09(d,J＝6.2Hz,2H),7.45–7.39(m,2H),7.24(d,J＝7.6Hz,1H),6.96–6.88(m,2H),6.80–6.70(m,3H),5.29(s,2H),5.24(s,2H),4.30(s,4H),4.04(s,2H),3.78(s,2H),3.46(t,J＝6.8Hz,2H),3.08(t,J＝6.8Hz,2H),2.29(s,4H),1.34(d,J＝6.2Hz,6H).
步骤三：合成2-((5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)苄基)(吡啶-4-基甲基)氨基)乙烷-1-磺酸(ZF128D)
将ZF128C(16.3mg，0.021mmol)溶于丙酮(20ml)中，然后加入NaI(10mg，0.067mmol)加热回流过夜。待反应结束后旋干溶剂，HPLC纯化，得到目标化合物5.4mg。 1H NMR(500MHz,Methanol-d4)δ8.90(d,J＝1.9Hz,1H),8.83(d,J＝2.0Hz,1H),8.24(d,J＝2.0Hz,1H),7.74(s,1H),7.48(s,1H),7.44(s,1H),7.39(dd,J＝6.9,2.2Hz,1H),7.20(d,J＝6.8Hz,2H),6.95 (s,1H),6.88(d,J＝8.2Hz,1H),6.78–6.69(m,2H),5.29(s,2H),5.24(d,J＝10.0Hz,2H),4.59–4.47(m,2H),4.29(s,4H),4.19(d,J＝13.9Hz,1H),4.01(d,J＝13.3Hz,1H),3.88(s,3H),3.52(d,J＝9.9Hz,1H),3.40(t,J＝4.8Hz,1H),3.37(s,3H),3.35(s,1H),2.98(s,1H),2.27(s,3H).ESI-MS理论值:C 38H 35ClN 4O 7S[M+H] +＝727.19，测得：727.4。
实施例106：合成(R)-2-((5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)苄基)(哌啶-3-基)氨基)乙烷-1-磺酸(ZF140)
Figure PCTCN2020094013-appb-000174
步骤一：合成叔丁基(R)-3-((5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)苄基)氨基)哌啶-1-甲酸(ZF132)
将ZD07(72mg，0.137mmol)、(R)-1-叔丁氧羰基-3-氨基哌啶(82.2mg，0.410mmol)溶于1,2-二氯乙烷中(15ml)，然后依次加入AcOH(0.1ml)、NaBH(OAc) 3(86.92mg，0.410mmol)室温反应过夜。待反应结束后旋干溶剂，HPLC纯化，得到目标化合物47.4mg。 1H NMR(500MHz,Methanol-d4)δ8.87(s,2H),8.14(s,1H),7.49–7.35(m,2H),7.35–7.18(m,4H),6.91(d,J＝8.3Hz,1H),6.88–6.75(m,1H),6.58(s,1H),5.13(d,J＝6.6Hz,4H),4.42(s,2H),4.32(d,J＝4.9Hz,4H),3.86(d,J＝11.2Hz,2H),3.77(d,J＝13.3Hz,1H),2.97–2.85(m,1H),2.78(s,1H),2.66(s,1H),2.28(s,3H),1.96(d,J＝43.8Hz,1H),1.68(s,1H),1.45(d,J＝4.6Hz,9H),1.28(d,J＝19.3Hz,2H).
步骤二：合成(R)-2-((5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)苄基)(哌啶-3-基)氨基)乙烷-1-磺酸(ZF140)
将ZF132(47.4mg，0.067mmol)溶于二氯甲烷中用饱和NaHCO 3洗涤，后收集有机相干燥后旋干，将得到的化合物溶于甲醇(20ml)溶液中，然后加入乙烯基磺酸异丙酯(20.01mg，0.133mmol)室温反应过夜，反应结束后旋干溶剂，然后加入二氯甲烷(4ml)与三氟乙酸(1ml)的混合溶液，室温搅拌1h。待反应结束后旋干溶剂，HPLC纯化，得到目标化合物9.8mg。 1H NMR(500MHz,Methanol-d4)δ9.02(d,J＝2.0Hz,1H),8.94(d,J＝1.8Hz,1H),8.44(d,J＝2.2Hz,1H),7.58(s,1H),7.40(d,J＝7.1Hz,1H),7.27–7.16(m,2H),7.07(s,1H),6.90(d,J＝8.1Hz,1H),6.82–6.71(m,2H),5.42(s,2H),5.30(s,2H),4.47(s,2H),4.30(s,4H),3.80(d,J＝12.1Hz,1H),3.63(d,J＝46.5Hz,3H),3.42(dd,J＝12.0,5.9Hz,2H),3.18–3.03(m,2H),3.03–2.91 (m,1H),2.28(s,3H),2.14–1.90(m,3H),1.79(d,J＝13.8Hz,1H).ESI-MS理论值:C 37H 39ClN 4O 7S[M+H] +＝719.22，测得：719.3。
实施例107：合成2-((5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)苄基)(哌啶-4-基)氨基)乙烷-1-磺酸(ZF151)
Figure PCTCN2020094013-appb-000175
步骤一：合成叔丁基4-((5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((3-(2,3-二氢苯并[b][1,4]二恶英-6-))-2-甲基苄基)氧基)苄基)氨基)哌啶-1-甲酸(ZF143)
将ZD07(60mg，0.114mmol)、1-Boc-4-氨基哌啶(68.5mg，0.342mmol)溶于1,2-二氯乙烷(15ml)中，室温搅拌15min后依次加入AcOH(0.08ml)、NaBH(OAc) 3(72.5mg，0.342mmol)，室温反应过夜。反应结束后旋干溶剂并用硅胶柱分离纯化，得到目标化合物74.9mg。 1H NMR(500MHz,Methanol-d4)δ8.98(d,J＝2.0Hz,1H),8.95(d,J＝1.9Hz,1H),8.39(d,J＝2.1Hz,1H),7.53(s,1H),7.42(dd,J＝7.3,1.6Hz,1H),7.26–7.15(m,2H),7.04(s,1H),6.88(d,J＝8.1Hz,1H),6.79–6.69(m,2H),5.35(s,2H),5.30(s,2H),4.28(s,4H),4.15(s,3H),4.12(s,1H),3.20(tt,J＝11.5,3.9Hz,1H),2.79(s,3H),2.28(s,3H),2.13–2.02(m,2H),1.48(s,10H),1.40(ddd,J＝16.3,11.6,4.4Hz,2H).
步骤二：合成2-((5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)苄基)(哌啶-4-基)氨基)乙烷-1-磺酸(ZF151)
将ZF143(39.4mg，0.055mmol)溶于甲醇(20ml)中，然后加入乙烯基磺酸异丙酯(16.6mg，0.111mmol)室温反应过夜。反应结束后旋干溶剂，然后加入二氯甲烷与三氟乙酸(4:1)的混合溶液，室温搅拌1h后旋干溶剂，HPLC纯化，得到目标化合物7.1mg。 1H NMR(500MHz,Methanol-d 4)δ8.99(d,J＝2.1Hz,1H),8.98(d,J＝2.0Hz,1H),8.39(t,J＝2.1Hz,1H),7.56(s,1H),7.42(dd,J＝7.2,1.9Hz,1H),7.26–7.18(m,2H),7.09(s,1H),6.91(d,J＝8.1Hz,1H),6.79–6.73(m,2H),5.40(s,2H),5.34(s,2H),4.31(s,4H),4.30(s,2H),4.13(q,J＝7.1Hz,1H),3.61–3.50(m,2H),3.16–3.03(m,2H),2.39(d,J＝13.6Hz,2H),2.30(d,J＝3.2Hz,3H),1.94–1.79(m,2H).ESI-MS理论值:C 37H 39ClN 4O 7S[M+H] +＝719.22，测得：719.2。
实施例108：合成2-((3-氨基-2,2-二甲基丙基)(5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)苄基)氨基)乙烷-1-磺酸(ZF152N)
Figure PCTCN2020094013-appb-000176
步骤一：合成叔丁基(3-((5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)苄基)氨基)-2,2-二甲基丙基)氨基甲酸酯(ZF150)
将ZD07(70mg，0.133mmol)、(3-氨基-2,2-二甲基丙基)氨基甲酸叔丁酯(80.7mg，0.399mmol)溶于1,2-二氯乙烷(20ml)中，室温搅拌15min后依次加入AcOH(0.1ml)、NaBH(OAc) 3(84.6mg，0.399mmol)，室温反应过夜。反应结束后旋干溶剂并用硅胶柱分离纯化，得到目标化合物92.1mg。 1H NMR(500MHz,Methanol-d4)δ8.98(d,J＝1.9Hz,1H),8.95(d,J＝1.9Hz,1H),8.39(s,1H),7.58(s,1H),7.42(d,J＝7.2Hz,1H),7.28–7.16(m,2H),7.03(s,1H),6.90(d,J＝8.1Hz,1H),6.81–6.73(m,2H),5.39(s,2H),5.30(s,2H),4.30(s,4H),4.15(s,2H),2.92(s,2H),2.76(s,2H),2.30(s,3H),1.38(s,9H),0.98(s,6H).
步骤二：合成2-((3-氨基-2,2-二甲基丙基)(5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)苄基)氨基)乙烷-1-磺酸(ZF152N)
将ZF150(92.1mg，0.129mmol)溶于甲醇(20ml)中，然后加入乙烯基磺酸异丙酯(38.79mg，0.259mmol)室温反应过夜。反应结束后旋干溶剂，然后加入二氯甲烷与三氟乙酸(4:1)的混合溶液，室温搅拌1h后旋干溶剂，HPLC纯化，得到目标化合物23.1mg。 1H NMR(500MHz,Methanol-d4)δ9.00(d,J＝2.0Hz,1H),8.94(d,J＝1.8Hz,1H),8.43(s,1H),7.60(s,1H),7.39(dd,J＝6.9,2.1Hz,1H),7.27–7.15(m,2H),7.06(s,1H),6.90(d,J＝8.1Hz,1H),6.76(dd,J＝11.2,3.2Hz,2H),5.45(s,2H),5.32(s,2H),4.50(d,J＝38.8Hz,2H),4.30(s,4H),3.70(d,J＝70.7Hz,2H),3.25(d,J＝14.7Hz,2H),3.15(s,2H),3.02(d,J＝32.9Hz,2H),2.28(s,3H),0.99(s,6H).ESI-MS理论值:C 37H 41ClN 4O 7S[M+H] +＝721.24，测得：721.3。
实施例109：合成2-((5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)苄基)((1-甲基-1H-咪唑-2-基)甲基)氨基)乙烷-1-磺酸(ZF145D)
Figure PCTCN2020094013-appb-000177
步骤一：合成5-((4-氯-5-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)-2-(((((甲基-1H-咪唑-2-基)甲基)氨基)甲基)苯氧基)甲基)烟腈(ZF124)
将ZD07(40mg，0.076mmol)、1-甲基-5-氨甲基咪唑(25.3mg，0.228mmol)溶于1,2-二氯乙烷(15ml)中，室温搅拌15min后依次加入AcOH(0.06ml)、NaBH(OAc) 3(48.35mg，0.228mmol)，室温反应过夜。反应结束后旋干溶剂并用硅胶柱分离纯化，得到目标化合物27.8mg。 1H NMR(500MHz,Methanol-d4)δ9.03(s,1H),8.95(d,J＝11.6Hz,2H),8.38(d,J＝1.9Hz,1H),7.78(s,1H),7.58(s,1H),7.40(dd,J＝7.2,1.9Hz,1H),7.26–7.14(m,2H),7.04(s,1H),6.89(d,J＝8.1Hz,1H),6.81–6.71(m,2H),5.39(s,2H),5.30(s,2H),4.54(s,2H),4.39(s,2H),4.29(s,4H),3.95(s,3H),2.28(s,3H).
步骤二：合成2-((5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)苄基)((1-甲基-1H-咪唑-2-基)甲基)氨基)乙烷-1-磺酸(ZF145D)
将ZF124(25.8mg，0.074mmol)溶于二氯甲烷中用饱和NaHCO 3洗涤，后收集有机相干燥后旋干，将得到的化合物溶于甲醇(20ml)溶液中，然后加入乙烯基磺酸异丙酯(12.46mg，0.083mmol)室温反应过夜，反应结束后旋干溶剂，并加入丙酮(20ml)溶解，然后加入NaI(12.5mg，0.083mmol)加热回流过夜。待反应结束后旋干溶剂，HPLC纯化，得到目标化合物10.3mg。 1H NMR(500MHz,Methanol-d 4)δ8.98(s,1H),8.94(d,J＝1.8Hz,1H),8.91(d,J＝2.0Hz,1H),8.36(d,J＝2.1Hz,1H),7.85(s,1H),7.59(s,1H),7.40(d,J＝7.0Hz,1H),7.27–7.16(m,2H),7.07(s,1H),6.90(d,J＝8.1Hz,1H),6.80–6.71(m,2H),5.39(s,2H),5.32(s,2H),4.59(s,2H),4.48(s,2H),4.30(s,4H),3.74(s,3H),3.59(t,J＝6.0Hz,2H),3.04(s,2H),2.29(s,3H).ESI-MS理论值:C 37H 36ClN 5O 7S[M+H] +＝730.20，测得：730.2。
实施例110：合成2-((5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)苄基)(1-甲基-1H-吡唑-3-基)氨基)乙烷-1-磺酸(ZF153)
Figure PCTCN2020094013-appb-000178
步骤一：合成5-((4-氯-5-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)-2-((((1-甲基-1H-吡唑-3-基)氨基)甲基)苯氧基)甲基)烟腈(ZF148)
将ZD07(40mg，0.076mmol)、N-甲基-3-氨基吡唑(22.15mg，0.228mmol)溶于1,2-二氯乙烷(15ml)中，室温搅拌15min后依次加入AcOH(0.06ml)、NaBH(OAc) 3(48.4mg，0.228mmol)，室温反应过夜。反应结束后旋干溶剂并用硅胶柱分离纯化，得到目标化合物18.6mg。 1H NMR(500MHz,Methanol-d 4)δ8.90(t,J＝2.6Hz,2H),8.26(d,J＝2.0Hz,1H),7.68(d,J＝2.4Hz,1H),7.46–7.37(m,2H),7.30–7.11(m,2H),7.00(s,1H),6.89(d,J＝8.0Hz,1H),6.78–6.70(m,2H),5.87(d,J＝2.8Hz,1H),5.32(s,2H),5.27(s,2H),4.41(s,2H),4.29(s,4H),3.83(s,3H),2.28(s,3H).
步骤二：合成2-((5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)苄基)(1-甲基-1H-吡唑-3-基)氨基)乙烷-1-磺酸(ZF153)
将ZF148(18.6mg，0.031mmol)、2-溴乙基磺酸钠(12.9mg，0.061mmol)溶于DMF(2.5ml)中，然后加入N,N-二异丙基乙胺(DIEA，0.5ml)80℃反应过夜。反应结束后降至室温，加水然后用HPLC纯化。得到目标化合物9.2mg。ESI-MS理论值:C 36H 34ClN 5O 7S[M+H] +＝716.19，测得：716.2。
实施例111：合成(R)-2-((5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)苄基)(1-甲基吡咯烷-3-基)氨基)乙烷-1-磺酸(ZF156N)
Figure PCTCN2020094013-appb-000179
步骤一：合成(R)-5-((4-氯-5-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)-2-(((1-甲基吡咯烷-3-基)氨基)甲基)苯氧基)甲基)烟腈(ZF156)
将ZD07(40mg，0.076mmol)、(R)-N-甲基-3-氨基吡咯烷(22.15mg，0.228mmol)溶于1,2- 二氯乙烷(15ml)中，室温搅拌15min后依次加入AcOH(0.06ml)、NaBH(OAc) 3(48.3mg，0.228mmol)，室温反应过夜。反应结束后旋干溶剂并用硅胶柱分离纯化，得到目标化合物48.3mg。 1H NMR(500MHz,Methanol-d 4)δ8.95(d,J＝2.0Hz,1H),8.92(d,J＝1.8Hz,1H),8.35(d,J＝2.0Hz,1H),7.44(s,1H),7.41(dd,J＝7.3,1.6Hz,1H),7.26–7.11(m,2H),6.96(s,1H),6.88(d,J＝8.1Hz,1H),6.78–6.69(m,2H),5.30(s,2H),5.24(s,2H),4.28(s,4H),3.87(d,J＝7.7Hz,2H),3.64(s,1H),3.32–3.17(m,2H),3.15–3.02(m,2H),2.74(s,3H),2.32(dd,J＝14.3,7.4Hz,1H),2.27(s,3H),1.94(s,1H).
步骤二：合成(R)-2-((5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)苄基)(1-甲基吡咯烷-3-基)氨基)乙烷-1-磺酸(ZF156N)
将ZF156(24.3mg，0.04mmol)溶于二氯甲烷中用饱和NaHCO 3洗涤，后收集有机相干燥后旋干，将得到的化合物溶于甲醇(20ml)溶液中，然后加入乙烯基磺酸异丙酯(11.9mg，0.08mmol)室温反应过夜，反应结束后旋干溶剂，并加入丙酮(20ml)溶解，然后加入NaI(11.9mg，0.08mmol)加热回流过夜。待反应结束后旋干溶剂，HPLC纯化，得到目标化合物9.1mg。 1H NMR(500MHz,Methanol-d4)δ9.02(d,J＝2.2Hz,1H),8.95(d,J＝1.8Hz,1H),8.43(d,J＝2.1Hz,1H),7.59(d,J＝7.1Hz,1H),7.40(dd,J＝7.1,2.2Hz,1H),7.27–7.14(m,2H),7.06(d,J＝2.7Hz,1H),6.90(d,J＝8.1Hz,1H),6.80–6.71(m,2H),5.40(d,J＝7.8Hz,2H),5.30(d,J＝3.0Hz,2H),4.46(d,J＝13.2Hz,1H),4.35(d,J＝13.4Hz,1H),4.30(s,4H),4.21(d,J＝13.4Hz,1H),4.08–3.98(m,0H),3.98–3.80(m,0H),3.73(t,J＝7.5Hz,1H),3.55(t,J＝6.4Hz,1H),3.45(t,J＝6.4Hz,1H),3.21(s,1H),3.01(s,3H),2.98–2.91(m,1H),2.88(s,1H),2.68(dt,J＝16.1,8.1Hz,1H),2.51(dt,J＝21.0,7.9Hz,1H),2.45–2.33(m,1H),2.28(s,3H).ESI-MS理论值:C 37H 39ClN 4O7S[M+H] +＝719.22，测得：719.2。
实施例112：合成(R)-2-((5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)苄基)(1-甲基哌啶-3-基)氨基)乙烷-1-磺酸(ZF154N)
Figure PCTCN2020094013-appb-000180
步骤一：合成(R)-5-((4-氯-5-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)-2-(((1-甲基哌啶-3-基)氨基)甲基苯氧基)甲基)烟腈(ZF154)
将ZD07(40mg，0.076mmol)、(R)-N-甲基-3-氨基哌啶(26mg，0.228mmol)溶于1,2-二氯乙烷(15ml)中，室温搅拌15min后依次加入AcOH(0.06ml)、NaBH(OAc) 3(48.3mg， 0.228mmol)，室温反应过夜。反应结束后旋干溶剂并用硅胶柱分离纯化，得到目标化合物44.8mg。
步骤二：合成(R)-2-((5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)苄基)(1-甲基哌啶-3-基)氨基)乙烷-1-磺酸(ZF154N)
将ZF154(24.3mg，0.036mmol)溶于二氯甲烷中用饱和NaHCO 3洗涤，后收集有机相干燥后旋干，将得到的化合物溶于甲醇(20ml)溶液中，然后加入乙烯基磺酸异丙酯(10.76mg，0.072mmol)室温反应过夜，反应结束后旋干溶剂，并加入丙酮(20ml)溶解，然后加入NaI(10.76mg，0.072mmol)加热回流过夜。待反应结束后旋干溶剂，HPLC纯化，得到目标化合物6.2mg。 1H NMR(500MHz,Methanol-d 4)δ9.04(d,J＝2.0Hz,1H),8.96(d,J＝2.0Hz,1H),8.45(d,J＝2.1Hz,1H),7.58(s,1H),7.42(d,J＝7.2Hz,1H),7.26–7.16(m,2H),7.09(d,J＝5.0Hz,1H),6.90(d,J＝8.0Hz,1H),6.80–6.72(m,2H),5.42(s,2H),5.31(s,2H),4.45(s,2H),4.30(s,4H),3.87–3.70(m,1H),3.64(d,J＝6.1Hz,2H),3.54(d,J＝13.2Hz,2H),3.44(t,J＝11.7Hz,1H),3.07(s,2H),2.98(t,J＝12.6Hz,1H),2.90(s,3H),2.29(s,3H),2.15–2.02(m,2H),1.86(dt,J＝27.2,13.0Hz,2H).ESI-MS理论值:C 38H 41ClN 4O 7S[M+H] +＝733.24，测得：733.2。
实施例113：合成2-((5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)苄基)((1-甲基哌啶-4-基)甲基)氨基)乙烷-1-磺酸(ZF118N)
Figure PCTCN2020094013-appb-000181
步骤一：合成5-((4-氯-5-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)-2-(((((甲基哌啶-4-基)甲基)氨基)甲基)苯氧基)甲基)烟腈(ZF118)
将ZD07(45mg，0.086mmol)、4-氨基-1-甲基哌啶(29.3mg，0.256mmol)溶于1，2-二氯乙烷中，然后依次加入AcOH(0.06ml)、NaBH(OAc) 3(54.4mg，0.256mmol)室温反应过夜。待反应结束后旋干溶剂，HPLC纯化，得到目标化合物36.6mg。 1H NMR(500MHz,Methanol-d4)δ8.99(d,J＝2.0Hz,1H),8.96(d,J＝1.8Hz,1H),8.39(s,1H),7.56(s,1H),7.42(d,J＝7.1Hz,1H),7.27–7.17(m,2H),7.07(s,1H),6.91(d,J＝8.1Hz,1H),6.80–6.71(m,2H),5.39(s,2H),5.33(s,2H),4.30(d,J＝3.3Hz,6H),3.66(d,J＝12.6Hz,2H),3.50(d,J＝12.8Hz,1H),3.12(t,J＝13.0Hz,2H),2.92(s,3H),2.42(d,J＝13.5Hz,2H),2.29(s,3H),1.99(d,J＝13.0Hz,3H).
步骤二：合成2-((5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)苄基)((1-甲基哌啶-4-基)甲基)氨基)乙烷-1-磺酸(ZF118N)
将ZF118(18.3mg，0.029mmol)溶于二氯甲烷中用饱和NaHCO 3洗涤，后收集有机相干燥后旋干，将得到的化合物溶于甲醇(20ml)溶液中，然后加入乙烯基磺酸异丙酯(8.8mg，0.058mmol)室温反应过夜，反应结束后旋干溶剂，并加入丙酮(20ml)溶解，然后加入NaI(8.8mg，0.058mmol)加热回流过夜。待反应结束后旋干溶剂，HPLC纯化，得到目标化合物6.2mg。 1H NMR(500MHz,DMSO-d 6)δ9.06(s,2H),8.53(s,1H),7.62(d,J＝19.8Hz,1H),7.45(s,1H),7.23(d,J＝20.2Hz,3H),6.94(dd,J＝8.5,4.3Hz,1H),6.89–6.70(m,2H),5.41(d,J＝13.6Hz,2H),5.31(s,2H),4.37(s,1H),4.29(d,J＝4.4Hz,4H),4.20(s,1H),3.67(d,J＝44.3Hz,2H),3.53(s,3H),3.40(d,J＝25.2Hz,2H),3.00(d,J＝31.3Hz,3H),2.75(s,2H),2.69–2.58(m,2H),2.25(d,J＝4.2Hz,3H),1.93(d,J＝34.4Hz,2H).ESI-MS理论值:C 38H 41ClN 4O 7S[M+H] +＝733.24，测得：733.2。
实施例114：合成2-((5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-甲氧基苄基)(3-(二甲氨基)丙基)氨基)乙烷-1-磺酸(ZG11)
Figure PCTCN2020094013-appb-000182
步骤一：合成5-((4-氯-2-甲酰基-5-甲氧基苯氧基)甲基)烟腈(ZG04)
将5-氯-2-羟基-4-甲氧基苯甲醛(200mg，1.075mmol)、5-(氯甲基)烟腈(196.1mg，1.29mmol)溶于DMF(2ml)中，然后加入Cs 2CO 3(525.5mg，1.613mmol)，室温反应过夜，反应结束后加水，然后用乙酸乙酯萃取，有机相旋干后用层析柱分离纯化。得到目标化合物186mg。 1H NMR(500MHz,Chloroform-d)δ10.31(s,1H),8.96(dd,J＝4.3,2.0Hz,2H),8.15(s,1H),7.93(s,1H),6.58(s,1H),5.29(s,2H),4.03(s,3H),1.59(s,3H).
步骤二：合成5-((4-氯-2-((((3-(二甲基氨基)丙基)氨基)甲基)-5-甲氧基苯氧基)甲基)烟腈(ZG07)
将ZG04(40mg，0.132mmol)、N,N-二甲氨基丙胺(40.6mg，0.397mmol)溶于1,2-二氯乙烷(15ml)中，然后依次加入AcOH(0.08ml)、NaBH(OAc) 3(84.16mg，0.397mmol)室温反应过夜。待反应结束后旋干溶剂并用HPLC纯化。得到目标化合物42.3mg。 1H NMR(500MHz,Methanol-d4)δ9.01(d,J＝2.0Hz,1H),8.96(d,J＝1.9Hz,1H),8.42(d,J＝2.2Hz,1H),7.52(s,1H),6.95(s,1H),5.40(s,2H),4.26(s,2H),3.98(s,3H),3.28–3.19(m,2H),3.19–3.08(m,2H),2.92(s,6H),2.23–2.08(m,2H).
步骤三：合成2-((5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-甲氧基苄基)(3-(二甲氨基)丙基)氨 基)乙烷-1-磺酸(ZG11)
将ZG07(42.3mg，0.109mmol)、2-溴乙基磺酸钠(46.0mg，0.218mmol)溶于DMF(2ml)中，然后加入N,N-二异丙基乙胺(DIEA，0.6ml)，80℃反应过夜。反应结束后降至室温，加水然后用HPLC纯化。得到目标化合物18.6mg。 1H NMR(500MHz,Methanol-d4)δ9.05(d,J＝2.0Hz,1H),8.96(d,J＝1.8Hz,1H),8.46(s,1H),7.54(s,1H),6.97(s,1H),5.43(s,2H),4.47(s,2H),3.99(s,3H),3.59(t,J＝6.1Hz,2H),3.32–3.26(m,2H),3.22–2.98(m,4H),2.91(s,6H),2.18(s,2H).ESI-MS理论值:C 22H 29ClN 4O 5S[M+H] +＝497.15，测得：497.3。
实施例115：合成2-((5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((2-甲基苄基氧基)苄基)(3-(二甲基氨基)丙基)氨基)乙烷-1-磺酸(ZG13N)
Figure PCTCN2020094013-appb-000183
步骤一：合成5-氯-2-羟基-4-((2-甲基苄基)氧基)苯甲醛(ZG01)
将邻甲苯甲醇(0.61g，5.0mmol)、5-氯-2,4-二羟基苯甲醛(0.85g，5.0mmol)、三苯基磷(1.44g，5.5mmol)溶于干燥的四氢呋喃(30ml)中，冰水浴降温后缓慢滴加DIAD(1.01g，5.0mmol)，自然升至室温搅拌过夜。反应结束后加入饱和碳酸氢钠溶液淬灭，然后用乙酸乙酯萃取，旋干溶剂后用硅胶柱分离纯化。得到目标化合物573.2mg。 1H NMR(500MHz,Chloroform-d)δ11.45(s,1H),9.73(s,1H),7.57(s,1H),7.47(d,J＝7.4Hz,1H),7.29(dt,J＝15.5,7.3Hz,4H),6.63(s,1H),5.19(s,2H),2.42(s,3H).
步骤二：合成5-((4-氯-2-甲酰基-5-((2-甲基苄基)氧基)苯氧基)甲基)烟腈(ZG05)
将ZG01(250mg，0.906mmol)、5-(氯甲基)烟腈(165.2mg，1.087mmol)溶于DMF(2ml)中，然后加入Cs 2CO 3(442.6mg，1.358mmol)，室温反应过夜，反应结束后加水，然后用乙酸乙酯萃取，有机相旋干后用层析柱分离纯化。得到目标化合物241mg。 1H NMR(500MHz,Chloroform-d)δ10.30(s,1H),8.92(dd,J＝13.1,2.0Hz,2H),8.07(d,J＝2.1Hz,1H),7.94(s,1H),7.41(d,J＝7.4Hz,1H),7.34(t,J＝7.3Hz,1H),7.28–7.24(m,2H),6.60(s,1H),5.23(s,2H),5.22(s,2H),2.43(s,3H).
步骤三：合成5-((4-氯-2-((((3-(二甲基氨基)丙基)氨基)甲基)-5-((2-甲基苄基氧基)苯氧基)甲基)烟腈(ZG08)
将ZG05(40mg，0.102mmol)、N,N-二甲氨基丙胺(31.27mg，0.306mmol)溶于1,2-二氯乙烷(15ml)中，然后依次加入AcOH(0.08ml)、NaBH(OAc) 3(64.9mg，0.306mmol)室温反 应过夜。待反应结束后旋干溶剂并用HPLC纯化。得到目标化合物47.3mg。 1H NMR(500MHz,Methanol-d 4)δ8.97(d,J＝2.1Hz,1H),8.95(d,J＝1.9Hz,1H),8.35(d,J＝2.2Hz,1H),7.55(s,1H),7.39(d,J＝7.5Hz,1H),7.32–7.23(m,2H),7.20(d,J＝7.2Hz,1H),7.00(s,1H),5.39(s,2H),5.27(s,2H),4.26(s,2H),3.28–3.19(m,2H),3.19–3.10(m,2H),2.93(s,6H),2.42(s,3H),2.24–2.08(m,2H).
步骤四：合成2-((5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((2-甲基苄基氧基)苄基)(3-(二甲基氨基)丙基)氨基)乙烷-1-磺酸(ZG13N)
将ZG08(20mg，0.042mmol)溶于甲醇溶液中，然后加入乙烯基磺酸异丙酯(12.6mg，0.084mmol)室温反应过夜，反应结束后旋干溶剂，并加入丙酮(20ml)溶解，然后加入NaI(12.6mg，0.084mmol)加热回流过夜。待反应结束后旋干溶剂，HPLC纯化，得到目标化合物12.1mg。 1H NMR(500MHz,Methanol-d4)δ9.00(d,J＝2.0Hz,1H),8.93(d,J＝1.8Hz,1H),8.40(d,J＝2.1Hz,1H),7.57(s,1H),7.38(d,J＝7.5Hz,1H),7.31–7.22(m,2H),7.19(t,J＝7.3Hz,1H),7.01(s,1H),5.43(s,2H),5.26(s,2H),4.48(s,2H),3.60(t,J＝6.1Hz,2H),3.33–3.28(m,2H),3.24–3.03(m,4H),2.92(s,6H),2.41(s,3H),2.20(s,2H).ESI-MS理论值:C 29H 35ClN 4O 5S[M+H] +＝587.20，测得：587.2。
实施例116：合成2-((5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)苄基)((5-氰基吡啶-3-基)甲基)氨基)乙烷-1-磺酸(ZG16)
Figure PCTCN2020094013-appb-000184
步骤一：合成5-((4-氯-2-(((((5-氰基吡啶-3-基)甲基)氨基)甲基)-5-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)苯氧基)甲基)烟腈(ZG14)
将ZD07(40mg，0.076mmol)、5-(氨基甲基)烟腈(30.3mg，0.228mmol)溶于1,2-二氯乙烷(15ml)与甲醇(5ml)的混合溶液中，然后依次加入AcOH(0.06ml)、NaBH(OAc) 3(48.3mg，0.228mmol)室温反应过夜。待反应结束后旋干溶剂并用HPLC纯化。得到目标化合物21.2mg。 1H NMR(500MHz,Methanol-d4)δ8.94(dd,J＝6.3,1.8Hz,2H),8.89(d,J＝2.0Hz,1H),8.85(d,J＝2.1Hz,1H),8.29(d,J＝2.0Hz,1H),8.26(d,J＝2.1Hz,1H),7.52(s,1H),7.42–7.34(m,1H),7.24–7.13(m,2H),7.02(s,1H),6.88(d,J＝8.0Hz,1H),6.76–6.69(m,2H),5.34(s,2H),5.29(s,2H),4.38(s,2H),4.29(s,2H),4.28(s,4H),2.26(s,3H).
步骤二：合成2-((5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((3-(2,3-二氢苯并[b][1,4]二恶英-6- 基)-2-甲基苄基)氧基)苄基)((5-氰基吡啶-3-基)甲基)氨基)乙烷-1-磺酸(ZG16)
将ZG14(21.2mg，0.033mmol)、2-溴乙基磺酸钠(13.9mg，0.066mmol)溶于DMF(2.5ml)中，然后加入N,N-二异丙基乙胺(DIEA，0.6ml)，80℃反应过夜。反应结束后降至室温，加水然后用HPLC纯化。得到目标化合物6.8mg。 1H NMR(500MHz,Methanol-d 4)δ8.94(d,J＝2.0Hz,1H),8.86(s,1H),8.82(s,1H),8.79(d,J＝2.2Hz,1H),8.27(s,1H),8.23(s,1H),7.48(s,1H),7.39(d,J＝7.5Hz,1H),7.25–7.17(m,2H),6.90(d,J＝8.7Hz,2H),6.80–6.74(m,2H),5.27(s,4H),4.56–4.43(m,1H),4.30(s,5H),3.78–3.66(m,2H),3.66–3.53(m,2H),3.50–3.40(m,2H),3.22–3.18(m,1H),3.14–3.00(m,2H),2.28(s,3H).ESI-MS理论值:C 39H 34ClN 5O 7S[M+H] +＝752.19，测得：752.6。
实施例117：合成2-((5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)苄基)氨基)乙烷-1-磺酰胺(ZG36)
Figure PCTCN2020094013-appb-000185
将ZD07(45mg，0.085mmol)、2-氨基乙烷-1-磺酰胺(31.8mg，0.256mmol)溶于1,2-二氯乙烷(15ml)中，然后依次加入AcOH(0.06ml)、NaBH(OAc) 3(54.4mg，0.256mmol)室温反应过夜。待反应结束后旋干溶剂并用HPLC纯化。得到目标化合物21mg。 1H NMR(500MHz,Methanol-d 4)δ8.97(d,J＝2.1Hz,1H),8.94(d,J＝2.0Hz,1H),8.38(t,J＝2.1Hz,1H),7.54(s,1H),7.40(dd,J＝6.9,2.1Hz,1H),7.27-7.17(m,2H),7.07(s,1H),6.90(d,J＝8.1Hz,1H),6.82–6.71(m,2H),5.41(s,2H),5.32(s,2H),4.31(s,2H),4.30(s,4H),3.54-3.49(m,2H),3.49-3.44(m,2H),2.29(s,3H).ESI-MS理论值:C 32H 31ClN 4O 6S[M+H] +＝635.17，测得：635.2。
实施例118：合成2-((2-((3-氯-4-氟苄基)氧基)-4-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧)-5-甲基苄基)(甲基)氨基)乙烷-1-磺酸(ZC156)
Figure PCTCN2020094013-appb-000186
步骤一：合成乙烯基磺酸异丙酯(ZC151)
将2-氯乙烷磺酰氯(2.0g，12.27mmol)溶于二氯甲烷(10ml)中，降温至-10℃，然后 加入异丙醇(736mg，12.27mmol)搅拌15min，然后加入吡啶(2.0ml)继续反应2h。反应结束后加入0.3N的HCl调pH<3.5，然后加水，乙酸乙酯萃取，有机相用无水硫酸钠干燥后旋干得到目标化合物1.08g，直接用于下一步。 1H NMR(400MHz,Chloroform-d)δ6.55(ddd,J＝16.7,9.9,1.0Hz,1H),6.38(dd,J＝16.6,1.5Hz,1H),6.08(d,J＝9.9Hz,1H),4.87–4.69(m,1H),1.39(d,J＝1.4Hz,3H),1.38(d,J＝1.3Hz,3H).
步骤二：合成2-(甲基氨基)乙烷-1-磺酸异丙酯(ZC152)
将ZC151(1.084g，7.22mmol)溶于甲醇(15ml)中，然后加入甲胺(1.36g，14.44mmol，30％in MeOH)室温反应过夜。反应结束旋干溶剂得到目标化合物1.02g。 1H NMR(400MHz,Chloroform-d)δ4.98(p,J＝6.2Hz,1H),3.28(t,J＝6.4Hz,2H),3.09(t,J＝6.4Hz,2H),2.47(s,3H),1.44(s,3H),1.43(s,3H).
步骤三：合成2-((2-((3-氯-4-氟苄基)氧基)-4-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧)-5-甲基苄基)(甲基)氨基)乙烷-1-磺酸(ZC156)
将ZA42(30mg，0.056mmol)、ZC152(30.6mg，0.169mmol)溶于四氢呋喃(8ml)中室温搅拌15min后依次加入AcOH(0.05ml)、NaBH(OAc) 3(49.0mg，0.231mmol)室温反应过夜。待反应结束后旋干溶剂并加入甲醇(10ml)溶解，然后向反应液中加入0.5ml浓盐酸，60℃加热2h，反应结束后恢复至室温，旋干溶剂并用HPLC纯化。得到目标化合物9.1mg。 1H NMR(400MHz,Methanol-d 4)δ7.66(dd,J＝7.0,2.1Hz,1H),7.52–7.46(m,1H),7.34(d,J＝7.0Hz,1H),7.26(t,J＝8.9Hz,1H),7.21(s,2H),7.20–7.16(m,1H),6.90(d,J＝8.1Hz,1H),6.82(s,1H),6.79–6.71(m,2H),5.25(s,2H),5.17(s,2H),4.42(d,J＝13.0Hz,1H),4.30(s,4H),4.27(d,J＝13.1Hz,1H),3.76–3.60(m,1H),3.50–3.38(m,1H),3.30–3.20(m,1H),3.20–3.07(m,1H),2.86(s,3H),2.25(s,3H),2.20(s,3H)..ESI-MS理论值:C 34H 35ClFNO 7S[M+H] +＝656.18，测得：656.2。
实施例119：合成2-((5-氯-4-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基]-2-(吡嗪-2-基甲氧基)苄基)(甲基)氨基)乙烷-1-磺酸(ZC157)
Figure PCTCN2020094013-appb-000187
将ZA72(30mg，0.06mmol)、ZC152(34.46mg，0.18mmol)溶于四氢呋喃(8ml)中室温搅拌15min后依次加入AcOH(0.05ml)、NaBH(OAc) 3(38.0mg，0.18mmol)室温反应过夜。待反应结束后旋干溶剂并加入甲醇(10ml)溶解，然后向反应液中加入0.5ml浓盐酸，60℃加热2h，反应结束后恢复至室温，旋干溶剂并用HPLC纯化。得到目标化合物6.3mg。ESI-MS理论值:C 31H 32ClN 3O 7S[M+H] +＝626.16，测得：626.2。
实施例120：合成2-((2-((5-氰基吡啶-3-基)甲氧基)-4-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧)-5-甲基苄基)(甲基)氨基)乙烷-1-磺酸(ZD41)
Figure PCTCN2020094013-appb-000188
将ZD110(38.9mg，0.075mmol)、2-溴乙基磺酸钠(31.4mg，0.149mmol)溶于DMF(3ml)中，然后加入N,N-二异丙基乙胺(DIEA，0.8ml)，80℃反应过夜。反应结束后降至室温，加水然后用HPLC纯化。得到目标化合物21.2mg。 1H NMR(400MHz,DMSO-d 6)δ9.04(d,J＝2.1Hz,1H),9.02(d,J＝2.0Hz,1H),8.97(s,1H),8.52(t,J＝2.1Hz,1H),7.47–7.41(m,1H),7.29–7.22(m,2H),7.18(d,J＝7.5Hz,1H),7.02(s,1H),6.93(d,J＝8.2Hz,1H),6.81(d,J＝2.1Hz,1H),6.77(dd,J＝8.2,2.1Hz,1H),5.37(s,2H),5.20(s,2H),4.35(dd,J＝13.1,4.8Hz,1H),4.29(s,4H),4.24(dd,J＝13.2,5.8Hz,1H),3.27(d,J＝6.8Hz,0H),2.92(ddt,J＝28.3,13.9,7.2Hz,2H),2.72(d,J＝4.8Hz,3H),2.23(s,3H),2.13(s,3H).ESI-MS理论值:C 34H 35N 3O 7S[M+H] +＝630.22，测得：630.75。
实施例121：合成2-((5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)苄基)(甲基)氨基)乙烷-1-磺酸(ZD45)
Figure PCTCN2020094013-appb-000189
将ZD110(30mg，0.109mmol)、2-溴乙基磺酸钠(46.0mg，0.218mmol)溶于DMF(2ml)中，然后加入N,N-二异丙基乙胺(DIEA，0.6ml)，80℃反应过夜。反应结束后降至室温，加水然后用HPLC纯化。得到目标化合物18.6mg。ESI-MS理论值:C 33H 32ClN 3O 7S[M+H] +＝650.16，测得：650.7。
实施例122：合成5-((4-氯-5-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)-2-((甲基((2S,3R,4S,5R)-2,3,4,5,6-五羟基己基)氨基)甲基)苯氧基)甲基)烟腈(ZD120)
Figure PCTCN2020094013-appb-000190
将ZD110(25mg，0.046mmol)、D-吡喃葡萄糖(24.97mg，0.139mmol)溶于THF(5ml)与MeOH(5ml)的混合溶剂中室温搅拌20min，然后依次加入AcOH(0.05ml)、NaBH(OAc) 3(48.97mg，0.231mmol)反应过夜。反应结束后旋干溶剂，HPLC纯化。得到目标化合物10.6mg。ESI-MS理论值:C 37H 40ClN 3O 9[M+H] +＝706.25，测得：706.21。
实施例124：合成(2R,3R,4R,5S)-6-((5-氯-4-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基]-2-甲基苄基]氧基)-2-(((2-氟苄基)氧基)苄基)氨基)己烷-1,2,3,4,5-戊醇(ZD147)
Figure PCTCN2020094013-appb-000191
步骤一:合成5-氯-4-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)-2-((2-氟苄基)氧基)苯甲醛(ZD142)
将ZA52(150mg，0.384mmol)、1-(氯甲基)-2-氟苯(66.7mg，0.461mmol)溶于DMF(3ml)中，后加入Cs 2CO 3(203mg,0.567mmol)室温反应过夜。待反应结束后加水淬灭，用二氯甲烷萃取三次，有机相用饱和氯化钠溶液洗、无水硫酸钠干燥后旋干溶剂，并用层析柱分离纯化，得到目标化合物68.3mg。 1H NMR(400MHz,Chloroform-d)δ10.35(s,1H),7.90(s,1H),7.50(t,J＝7.5Hz,1H),7.44(t,J＝4.5Hz,1H),7.38(d,J＝6.9Hz,1H),7.28–7.27(m,1H),7.27(s,1H),7.24–7.18(m,1H),7.17–7.09(m,1H),6.94(d,J＝8.2Hz,1H),6.86(d,J＝2.1Hz,1H),6.80(dd,J＝8.3,2.1Hz,1H),6.73(s,1H),5.29(s,2H),5.22(s,2H),4.34(s,4H),2.31(s,3H).
步骤二：合成(2R,3R,4R,5S)-6-((5-氯-4-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基]-2-甲基苄基]氧基)-2-(((2-氟苄基)氧基)苄基)氨基)己烷-1,2,3,4,5-戊醇(ZD147)
将ZD142(25mg，0.048mmol)、D-萄糖胺(27mg，0.145mmol)溶于THF(3ml)与MeOH(3ml)的混合溶剂中室温反应过夜，后加入NaBH 4(36.65mg，0.96mmol)，继续反应5h。反应结束后旋干溶剂，HPLC纯化。得到目标化合物22mg。 1H NMR(400MHz,Methanol-d 4)δ7.58(td,J＝7.6,1.8Hz,1H),7.48(s,1H),7.42(ddd,J＝14.8,7.2,1.8Hz,2H),7.28–7.15(m,4H),7.04(s,1H),6.89(d,J＝8.1Hz,1H),6.78–6.71(m,2H),5.35(s,2H),5.26(s,2H),4.29(s,4H),4.26–4.12(m,2H),4.06(dt,J＝6.8,5.0Hz,1H),3.83(dd,J＝4.5,1.7Hz,1H),3.78(dd,J＝10.9,3.1Hz,1H),3.74–3.60(m,3H),3.24–3.14(m,2H),2.27(s,3H).ESI-MS理论值:C 36H 39ClFNO 9[M+H] +＝684.23，测得：684.80。
实施例125：合成(R)-2-((5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)苄基)(吡咯烷基-3-基)氨基)乙烷-1-磺酸(ZF139)
Figure PCTCN2020094013-appb-000192
步骤一：合成叔丁基(R)-3-((5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)苄基)氨基)吡咯烷-1-甲酸(ZF131)
将ZD07(72mg，0.137mmol)、(R)-1-Boc-3-氨基吡咯烷(76.46mg，0.411mmol)溶于1,2-二氯乙烷中(15ml)，然后依次加入AcOH(0.1ml)、NaBH(OAc) 3(87.02mg，0.411mmol)室温反应过夜。待反应结束后旋干溶剂，并用硅胶柱分离纯化，得到目标化合物55.2mg。ESI-MS理论值:C 39H 41ClN 4O 6[M+H] +＝697.27，测得：697.3。
步骤二：合成(R)-2-((5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)苄基)(吡咯烷基-3-基)氨基)乙烷-1-磺酸(ZF139)
将ZF131(55.2mg，0.079mmol)溶于二氯甲烷中用饱和NaHCO 3洗涤，后收集有机相干燥后旋干，将得到的化合物溶于甲醇(15ml)溶液中，然后加入乙烯基磺酸异丙酯(23.85mg，0.159mmol)室温反应过夜，反应结束后旋干溶剂，然后加入二氯甲烷(4ml)与三氟乙酸(1ml)的混合溶液，室温搅拌1h。待反应结束后旋干溶剂，HPLC纯化，得到目标化合物16.3mg。ESI-MS理论值:C 36H 37ClN 4O 7S[M+H] +＝705.21，测得：705.2
实施例126：合成2-((5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)苄基)(吡啶-3-基甲基)氨基)乙烷-1-磺酸(ZXD06)
Figure PCTCN2020094013-appb-000193
步骤一：合成5-(4-氯-5-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)-2-((((吡啶-3-基甲基)氨基)甲基)苯氧基)甲基)烟腈(ZXC149)
将ZD07(42mg,0.08mmol)、吡啶-3-甲基胺(25mg,0.24mmol)溶于THF(6ml)中， 室温搅拌过夜，再依次加入AcOH(0.1ml)、NaBH(OAc) 3(85mg，0.4mmol)室温反应5小时，待反应结束后，旋干溶剂并用HPLC纯化，得到目标化合物35.4mg。 1H NMR(500MHz,Methanol-d4)δ8.93(dd,J＝10.0,1.9Hz,2H),8.86(d,J＝2.1Hz,1H),8.83-8.75(m,1H),8.39(dt,J＝8.2,1.7Hz,1H),8.32(d,J＝2.1Hz,1H),7.85(dd,J＝8.0,5.4Hz,1H),7.56(s,1H),7.40(dd,J＝7.2,1.8Hz,1H),7.27-7.11(m,2H),7.03(s,1H),6.89(d,J＝8.1Hz,1H),6.81–6.69(m,2H),5.36(s,2H),5.30(s,2H),4.47(s,2H),4.34(s,2H),4.29(s,4H),2.28(s,3H).
步骤二：合成2-((5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)苄基)(吡啶-3-基甲基)氨基)乙烷-1-磺酸(ZXD06)
将ZXC149(35.4mg，0.057mmol)、乙烯基磺酸异丙酯(8.7mg，0.057mmol)溶于甲醇溶液中室温反应过夜，反应结束后旋干溶剂，加入丙酮(15ml)溶解，后加入碘化钠(16mg，0.114mmol)加热回流过夜。反应结束后旋干溶剂，然后用HPLC纯化，得到目标化合物6mg。 1H NMR(500MHz,Methanol-d4)δ8.96(s,1H),8.84(s,1H),8.79(s,1H),8.72(s,1H),8.26(d,J＝1.9Hz,1H),8.21(d,J＝8.0Hz,1H),7.71-7.58(m,1H),7.52(s,1H),7.38(dd,J＝7.0,2.0Hz,1H),7.27-7.11(m,2H),6.95(s,1H),6.90(d,J＝8.1Hz,1H),6.82-6.68(m,2H),5.30(s,2H),5.27(s,2H),4.64(s,2H),4.41(s,2H),4.30(s,4H),3.62(m,2H),3.20(m,J＝1.7Hz,2H),2.27(s,3H).ESI-MS理论值:C 38H 35ClN 4O 7S[M+H]+＝727.19，测得：727.7。
实施例127：合成N-((2-((5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)苄基)(甲基)氨基)乙基)磺酰基)乙酰胺(ZG58)
Figure PCTCN2020094013-appb-000194
步骤一：合成2-((5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)苄基)(甲基)氨基)乙烷-1-磺酰基叠氮化物(ZG57)
将2-氯乙烷磺酰氯(30.13mg，0.185mmol)溶于乙腈(10ml)中，然后加入NaN 3的水溶液(13.56mg，0.185mmol，1.0ml水)，室温反应3h后依次加入K 2CO 3(51.14mg，0.38mmol)、KI(0.61mg，0.004mmol)、ZD110(100mg，0.185mmol)继续反应3h。反应结束后加H 2O，并用二氯甲烷萃取，最后用硅胶柱分离纯化得到目标化合物102.6mg。 1H NMR(500MHz,Chloroform-d)δ8.90(t,J＝1.9Hz,2H),8.11(t,J＝2.1Hz,1H),7.44(dd,J＝5.4,3.6Hz,1H), 7.38(s,1H),7.28–7.23(m,2H),6.94(d,J＝8.2Hz,1H),6.85(d,J＝2.1Hz,1H),6.80(dd,J＝8.2,2.1Hz,1H),6.62(s,1H),5.18(s,2H),5.12(s,2H),4.34(s,4H),3.58(s,2H),3.49(t,J＝6.7Hz,2H),3.00(t,J＝6.7Hz,2H),2.34(s,3H),2.32(s,3H).ESI-MS理论值:C 33H 31ClN 6O 6S[M+H] +＝675.17，测得：675.2。
步骤二：合成N-((2-((5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)苄基)(甲基)氨基)乙基)磺酰基)乙酰胺(ZG58)
将ZG57(15mg，0.022mmol)、2,6-二甲基吡啶(4.35mg，0.029mmol)溶于DMF(2ml)中，然后滴加硫代乙酸(3.06mg，0.029mmol)的DMF溶液(0.5ml)室温反应30min后加水淬灭，并用HPLC分离纯化，得到目标化合物5.6mg。 1H NMR(500MHz,Methanol-d 4)δ9.01(d,J＝2.1Hz,1H),8.99(d,J＝2.0Hz,1H),8.44(t,J＝2.1Hz,1H),7.62(s,1H),7.48(dd,J＝7.2,1.9Hz,1H),7.32–7.21(m,2H),7.15(s,1H),6.95(d,J＝8.1Hz,1H),6.84–6.76(m,2H),5.45(s,2H),5.38(s,1H),4.48(s,2H),4.35(s,4H),3.98(t,J＝6.9Hz,2H),3.74(d,J＝8.5Hz,2H),2.93(s,3H),2.34(s,3H),2.15(s,2H).ESI-MS理论值:C 35H 35ClN 4O 7S[M+H] +＝691.19，测得：691.3。
实施例128：合成2-((5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)苄基)(甲基)氨基)乙烷-1-磺酰胺(ZG60)
Figure PCTCN2020094013-appb-000195
将乙酰丙酮(5.0mg，0.048mmol)、三乙胺(5.0mg，0.048)溶于丙酮中，然后加入ZG57(15mg，0.022mmol)室温搅拌过夜，反应结束后旋干溶剂并用HPLC纯化，得到目标化合物6.2mg。ESI-MS理论值:C 33H 33ClN 4O 6S[M+H] +＝649.18，测得：649.2。
实施例129：合成3-((5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基]-2-甲基苄基)氧基)苄基)(2-磺乙基)氨基)丙酸(ZG47)
Figure PCTCN2020094013-appb-000196
步骤一：合成3-((5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基]-2-甲基苄基)氧基)苄基)氨基)丙酸(ZG46)
将ZD07(30mg，0.076mmol)、3-氨基丙酸(20.31mg，0.228mmol)溶于N,N-二甲基甲酰胺中(3ml)，然后加入AcOH(0.1ml)室温反应20min，最后加入NaBH 3CN(87.02mg，0.411mmol)室温反应过夜。待反应结束后旋干溶剂，并用硅胶柱分离纯化，得到目标化合物13mg。 1H NMR(500MHz,Methanol-d 4)δ9.00(d,J＝2.0Hz,1H),8.95(d,J＝1.9Hz,1H),8.42(d,J＝2.1Hz,1H),7.54(s,1H),7.42(dd,J＝7.1,1.8Hz,1H),7.27–7.16(m,2H),7.07(s,1H),6.90(d,J＝8.1Hz,1H),6.80–6.71(m,2H),5.41(s,2H),5.33(s,2H),4.30(s,4H),4.26(s,2H),3.28(t,J＝6.4Hz,2H),2.75(t,J＝6.4Hz,2H),2.29(s,3H).
步骤二：合成3-((5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基]-2-甲基苄基)氧基)苄基)(2-磺乙基)氨基)丙酸(ZG47)
将ZG46(13mg，0.022mmol)、2-溴乙基磺酸钠(46.0mg，0.043mmol)溶于DMF(2ml)中，然后加入N,N-二异丙基乙胺(DIEA，0.5ml)，80℃反应过夜。反应结束后降至室温，加水然后用HPLC纯化。得到目标化合物5.2mg。 1H NMR(500MHz,Methanol-d 4)δ9.00(s,1H),8.92(s,1H),8.44(s,1H),7.56(d,J＝6.9Hz,1H),7.40(d,J＝7.1Hz,1H),7.21(q,J＝8.4,8.0Hz,2H),7.03(d,J＝8.7Hz,1H),6.90(d,J＝8.1Hz,1H),6.80–6.71(m,2H),5.41(s,2H),5.31(d,J＝7.3Hz,2H),4.57–4.46(m,1H),4.37(d,J＝13.1Hz,1H),4.30(s,4H),3.57(s,2H),3.48(t,J＝6.9Hz,2H),3.26–3.11(m,1H),3.04(d,J＝24.4Hz,1H),2.90–2.75(m,1H),2.68(s,1H),2.28(d,J＝4.5Hz,3H).ESI-MS理论值:C 35H 34ClN 3O 9S[M+H] +＝708.17，测得：708.2。
实施例130：2-((5-氯-2-((5-(甲基磺酰基)吡啶-3-基)甲氧基)-4-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)苄基)氨基)乙烷-1-磺酰胺(ZG51)
Figure PCTCN2020094013-appb-000197
将ZE154(22.6mg，0.039mmol)、2-氨基乙基磺酰胺(14.5mg，0.117mmol)溶于N,N-二甲基甲酰胺中(3ml)，然后加入AcOH(0.1ml)室温反应20min，最后加入NaBH 3CN(7.35mg， 0.117mmol)室温反应过夜。待反应结束后旋干溶剂，并用硅胶柱分离纯化，得到目标化合物9.6mg。 1H NMR(500MHz,Methanol-d 4)δ9.13(d,J＝2.2Hz,1H),9.04(d,J＝2.0Hz,1H),8.58–8.51(m,1H),7.54(s,1H),7.43(dd,J＝7.3,1.7Hz,1H),7.26–7.17(m,2H),7.12(s,1H),6.90(d,J＝8.2Hz,1H),6.81–6.70(m,2H),5.46(s,2H),5.32(s,2H),4.31(s,2H),4.30(s,4H),3.51(d,J＝5.7Hz,2H),3.48(d,J＝5.6Hz,2H),3.29(s,3H),2.29(s,3H).ESI-MS理论值:C 32H 34ClN 3O 8S 2[M+H] +＝679.15，测得：679.8。
实施例131：合成5-((4-氯-5-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)氧基)-2-((甲基((2S,3R,4R,5R)-2,3,4,5,6-五羟基己基)氨基)甲基)苯氧基)甲基)烟腈(ZD20)
Figure PCTCN2020094013-appb-000198
将ZD110(20mg，0.037mmol)、D-葡萄糖(20mg，0.111mmol)溶于THF(4ml)与MeOH(4ml)的混合溶剂中室温反应过夜，然后依次加入AcOH(0.05ml)、NaBH(OAc) 3(39.2mg，0.184mmol)室温反应过夜。反应结束后旋干溶剂，HPLC纯化。得到目标化合物8.6mg。 1H NMR(400MHz,Methanol-d 4)δ8.98(s,1H),8.94(s,0H),8.41(t,J＝2.1Hz,1H),7.58(d,J＝4.1Hz,1H),7.42(d,J＝6.7Hz,1H),7.23(d,J＝8.1Hz,2H),7.08(d,J＝5.0Hz,1H),6.90(d,J＝8.0Hz,1H),6.80–6.71(m,2H),5.41(d,J＝2.7Hz,2H),5.32(s,2H),4.57(dd,J＝55.2,13.2Hz,1H),4.30(s,4H),4.17(d,J＝13.3Hz,1H),4.14–3.92(m,1H),3.86–3.73(m,2H),3.72–3.59(m,3H),3.45–3.37(m,1H),3.30–3.17(m,1H),2.86(d,J＝27.1Hz,3H),2.29(s,3H).ESI-MS理论值:C 37H 40ClN 3O 9[M+H] +＝706.25，测得：706.60,比旋光值
Figure PCTCN2020094013-appb-000199
浓度为1.0，溶剂为CHCl 3。
上述实施例汇总如下：
表1
Figure PCTCN2020094013-appb-000200
Figure PCTCN2020094013-appb-000201
Figure PCTCN2020094013-appb-000202
Figure PCTCN2020094013-appb-000203
Figure PCTCN2020094013-appb-000204
Figure PCTCN2020094013-appb-000205
Figure PCTCN2020094013-appb-000206
Figure PCTCN2020094013-appb-000207
Figure PCTCN2020094013-appb-000208
Figure PCTCN2020094013-appb-000209
Figure PCTCN2020094013-appb-000210
Figure PCTCN2020094013-appb-000211
Figure PCTCN2020094013-appb-000212
Figure PCTCN2020094013-appb-000213
Figure PCTCN2020094013-appb-000214
Figure PCTCN2020094013-appb-000215
Figure PCTCN2020094013-appb-000216
Figure PCTCN2020094013-appb-000217
参照上述实施例中的方法，使用市售试剂或者文献中报道合成路线化合物为原料，可以合成如下表2所列化合物：
表2
Figure PCTCN2020094013-appb-000218
Figure PCTCN2020094013-appb-000219
Figure PCTCN2020094013-appb-000220
Figure PCTCN2020094013-appb-000221
Figure PCTCN2020094013-appb-000222
生物测试例1HTRF方法检测化合物抑制PD1/PD-L1蛋白相互作用活性
实验中所用的PD1/PD-L1Binding Assay Kit购自Cisbio(#64ICP01PEG)，96孔板购自Cisbio公司(白色，#66PL96025)。多功能酶标仪为TECAN公司产品，型号：SPARK 10M。具体实验方案如下：
1)待测试化合物用DMSO溶解成10mM的标准母液。随后，在EP管中用试剂盒自带的diluent buffer将测试化合物的标准母液稀释成工作样品溶液，依据实验计划设置12个浓度梯度，相邻为5倍稀释。所制备的工作样品溶液浓度＝测试板上所需样品浓度的10倍(10×测试化合溶液)，备用。
2)将Tag1-PD-L1蛋白和Tag2-PD1蛋白用diluent buffer稀释至工作蛋白溶液浓度，所需的工作蛋白溶液浓度＝测试板上所需样品浓度的5倍(5×测试化合溶液)，备用。
3)将Anti-Tag1-Eu3+用试剂盒自带的detection buffer稀释100倍，Anti-Tag2-XL665用试剂盒自带的detection buffer稀释25倍，备用。
4)分别在A1-A12、B1-B12相应孔中加入2uL已稀释好的待测化合物1，在C1-C12、D1-D12相应孔中加入2uL已稀释好的待测化合物2，在E1-E12、F1-F12相应孔中加入2uL已稀释好的待测化合物3。
5)分别在含待测化合物的各孔中加入4uL的Tag1-PD-L1蛋白。
6)分别在含待测化合物的各孔中加入4uL的Tag2-PD1蛋白，室温孵育15min。
7)将已稀释好的Anti-Tag1-Eu3+和Anti-Tag2-XL665各取400uL，按1:1的比例混合均匀后，取10uL加到含待测化合物的各孔中。
8)本实验设计了4组对照，分别是阳性对照组(2uL diluent buffer+4uL
Tag1-PD-L1+4uL Tag2-PD1+5uL Anti-Tag1-Eu3++5uL Anti-Tag2-XL665)、阴性对照组(6uL diluent buffer+4uL Tag2-PD1+5uL Anti-Tag1-Eu3++5uL Anti-Tag2-XL665)、Anti-Tag1-Eu3+对照组(10uL diluent buffer+5uL Anti-Tag1-Eu3+5uL detection buffer)和缓冲液对照组(10uL diluent buffer+10uL detection buffer)。
9)用封板膜将96孔板封闭后，室温孵育2h。
10)移除封板膜后，用酶标仪分别读取Ex320nm/Em612nm、Ex320nm/Em650nm的信号值。用公式10 4×Signal665nm/Signal612nm来计算每孔中供体和受体发射信号的比值。所计算的比值对化合物浓度梯度做曲线，极大值和极小值的中值对应的样本化合物浓度，即为化合物的IC 50值。
Figure PCTCN2020094013-appb-000223
化合物BMS-1266是BMS公司专利中WO2015160641A2的化合物，可以抑制PD-1/PD-L1蛋白的相互作作用。
化合物的活性测试结果如表3所示：
表3
序号 化合物 HTRF IC 50(nM)
  BMS-1266(EC81) 2.83
2 ED01 2.1
3 ED04 10.5
4 ED11 1.7
7 ED55-2 0.43
8 ED57 3.87
9 ZB29 0.7
10 ZB94 5.88
11 ZB95 5.97
12 ZB101 1.12
13 ZB44 9.5
14 ZB66 7.58
15 ZB82 12.2
16 ZB83 34.02
17 ZC124 476.6
19 ZC127 50.6
21 ZD02-N 722.8
22 ZD13 0.27
25 ZC134 <0.1
26 ZD03 0.37
27 ZD05 0.37
28 ZD39 <0.001
29 ZC136 79.93
32 ZD04 0.76
33 ZD19 2.87
36 ED18 31.4
39 ZD53 99.1
40 ZD56 25.1
41 ZD57 288.5
42 ZD58 26.5
43 ZD62 13.4
44 ZD65 29.42
45 ZD75 235.4
47 ZD78 0.66
48 ZD81 230.3
49 ZD82 97.09
50 ZD21 0.28
51 ZD53 99.1
52 ZD56 25.1
53 ZD57 288.5
54 ZD58 26.5
55 ZD62 13.4
56 ZD65 29.42
57 ZD75 235.4
59 ZD78 0.66
60 ZD81 230.3
61 ZD82 97.09
62 ZD83 33.36
63 ZD85 0.01
64 ZD114 8.9
65 ZD115 2.4
66 ZD116 74
67 ZD119 0.97
68 ZD121 0.001
69 ZD122 10.63
70 ZD123 0.49
71 ZD127 0.05
72 ZD132 0.49
73 ZD133 <0.003
74 ZD135 0.31
75 ZD136 0.47
76 ZD137 <1
77 ZD146 18.2
78 ZD148 82.2
79 ZD149 918.9
80 ZE01 0.008
81 ZE10 0.55
82 ZE12 24.22
83 ZE19 28.8
84 ZE31 157.6
85 ZE32 87.62
87 ZE36 33.42
88 ZE131 5.08
89 ZE132 0.88
90 ZE133 0.82
91 ZE155 <0.08
92 ZF25 <0.08
93 ZF59 <0.01
94 ZF48N 0.1
95 ZF49N 0.32
96 ZF50N 12.38
97 ZF64N 0.76
98 ZF74N 3.82
99 ZF98N 6.64
100 ZF99N <0.5
101 ZF100D 2.85
102 ZF102 0.57
103 ZF119D 3.77
104 ZF127D 1.9
105 ZF128D 71.56
106 ZF140 5.66
107 ZF151 <0.5
108 ZF152N 0.36
109 ZF145D 6.1
110 ZF153 53.22
111 ZF156N 1.52
112 ZF154N 8.3
113 ZF118N 0.08
117 ZG36 <0.01
118 ZC156 81.62
120 ZD41 0.006
121 ZD45 0.076
122 ZD120 3.75
124 ZD147 891.4
125 ZF139 2.1
126 ZXD06 83.98
127 ZG58 <0.01
128 ZG60 0.04
130 ZG51 0.56
实验结果表明:本发明化合物具有较好地抑制PD-1/PD-L1蛋白相互作用的能力。与文献报道化合物BMS-1266相比(HTRF IC 50＝2.83 nM)，本发明部分化合物抑制PD-1/PD-L1蛋白相互作用的能力显著提升(>20倍)，例如，化合物25(ZC134)、28(ZD39)、63(ZD85)、68(ZD121)、71(ZD127)、73(ZD133)、80(ZE01)、91(ZE155)、92(ZF25)、93(ZF59)、94(ZF48N)、113(ZF118N)、120(ZD41)、117(ZG36)、121(ZD45)、127(ZG58)、128(ZG60)等的HTRF IC 50均比BMS-1266有>20倍的提升。
生物测试例2:化合物诱导T细胞IFN-γ表达实验
仪器和试剂如表4和表5所示
表4
仪器名称 生产厂商 仪器型号
酶标仪 PerkinElmer VICTOR Nivo
离心机 Eppendorf 5810R
生物安全柜 Thermo A2 1389
二氧化碳细胞培养箱 Thermo 3111
表5
Figure PCTCN2020094013-appb-000224
Figure PCTCN2020094013-appb-000225
实验方法和步骤：
从健康人捐赠者的血浆中分离外周血单核细胞(PBMC)，从人PBMC中分离CD3 +T细胞。Hep3B-OS8-hPDL1细胞用线霉素C(10μg/mL)处理1.5小时，CD3 +T细胞和预处理的Hep3B-OS8-hPDL1被添加到指示培养皿小孔中，然后加入稀释系列化合物(双孔重复)。2个小孔是培养基，2个小孔是5μg/mL Keytruda作为对照组。经过72小时的孵育，通过ELISA采集了细胞上清剂进行IFN-γ测量。
1)使用密度梯度离心分离出人PBMC细胞，并在EasySep缓冲液中重新悬浮，密度为5x10 7/mL。
2)CD3 +T细胞通过使用EasySep TM human T细胞分离试剂盒从PBMC中富集，并在RPMI 1640培养基中重新悬浮，细胞密度为5x10 5/mL。
3)Hep3B-OS8-hPDL1细胞在37℃下用10μg/mL线粒霉素C收集和处理，1.5小时。
4)Hep3B-OS8-hPDL1细胞使用PBS彻底洗涤四次，并在RPMI 1640培养基中重新悬浮，细胞密度为5x10 5/mL。
5)在96孔板中，添加Hep3B-OS8-hPDL1和T细胞(50μL中的2.5x10 4和5x10 4分别在100μL的完整培养基中)，在50μL完整介质中添加4倍最终浓度的测试物品。使用上市抗体药物帕博利珠单抗(Keytruda,5μg/mL)做为对照。
6)96孔板在37℃孵育，5％CO 2孵化器72小时。
7)利用IFN-γELISA检测试剂盒收集上清(150μL)以测量IFN-γ水平。
测试结果如图1所示。
实验结果表明：与空白对照相比，本发明化合物在低浓度条件下，可显著提高上述 体系中的IFN-γ的水平，例如化合物3(ED04)、4(ED11)、5(ED19-2)和9(ZB29)。其中，化合物3(ED04)、4(ED11)在较低浓度(100nM,1uM或10uM)下，与Keytruda抗体提高人源Hep3B-OS8-hPDL1和人源T细胞共培养系统中IFN-γ产量(表达水平)的能力接近或者相当。
生物测试例3:化合物促进T细胞杀伤癌细胞
步骤一.①取OT-I转基因小鼠脾脏，置于含1640培养基的培养皿中，使用注射器座将脾脏组织研磨粉碎直至无肉眼可见组织。②将组织浑浊液转移至15ml离心管中，转移前用40μm滤网过滤，1200rpm离心5min。③弃上清，加入2ml红细胞裂解液重悬，静置6min后，加入8ml 1640完全培养基充分混匀，1200rpm离心5min。④移除上清液，得到免疫细胞。免疫细胞用1640完全培养基重悬，加入SIINFEKL OVA肽(OVA257-264，上海生工)，终浓度为10～100ug/ml，另加入mIL-2(R&D，402-ML-020)，终浓度为10～100ng/ml。⑤转移免疫细胞至12孔板培养，每孔体系为2ml。体外培养5～7天，中间换液1～2次，在培养过程的最后48h，加入不同药物处理，浓度为1/10μM。培养结束后得到T细胞，用于下一步实验。
步骤二.①取对数期生长状态良好的EL4淋巴癌细胞，加入不同药物处理48h，浓度为1/10μM，并设置溶剂空白对照。②分别收集细胞至1.5ml离心管中，1200rpm离心5min。③弃上清，加入1ml无菌PBS洗涤细胞，1200rpm离心5min，弃上清，重复2次后，加入1ml1640完全培养基重悬。④将每组细胞进行均分，分别加入/不加入OVA肽处理，处理浓度为10～100ug/ml，37℃孵育2h。其中OVA肽处理组最终得到EL4+OVA细胞，用作靶细胞。未处理组的EL4细胞作为非靶细胞对照。⑤1200rpm离心5min，弃上清，加入1ml无菌PBS洗涤细胞，再次离心弃上清，重复2次后，加入1ml无菌PBS重悬。⑥对所得细胞分别使用高/低浓度CFSE(Invitrogen,65-0850)处理，其中用10μM CFSE标记靶细胞组EL4+OVA细胞，1μM CFSE标记非靶细胞对照组EL4细胞。37℃避光孵育10min后，冰浴5min淬灭剩余标记。分别离心后，使用1640完全培养基重悬。
步骤三.将靶细胞和非靶细胞与相同药物处理的T细胞以不同比率共同培养。即效靶比(T细胞:靶细胞)按16:1、2:1的比率分别将T细胞和同一药物处理的靶细胞铺入圆底96孔板中共同培养。培养体系中加入不同药物处理，药物种类与浓度与体系中细胞原处理条件相同。参照上述操作，T细胞和同一药物处理的非靶细胞作为空白对照。37℃孵育24h后通过FACS分析(Beckman，CytoFlex S)，计算特异性杀伤百分数。使用PDL1抗体(Bio X Cell，BE0101)作为阳性对照。
测试结果如图2所示。
实验结果表明：化合物89(ZE132)、98(ZF74N)、102(ZF102)、104(ZF127D)、113(ZF118N)，对靶细胞的杀伤效率与空白对照相比有明显的提升，且存在药物浓度依赖和效靶比例依赖。效靶比为2:1时，化合物组T细胞特异性杀伤效率可达到40％甚至50％，相比于抗体组的30％杀伤效率有着明显的提升，表明此条件下化合物提升T细胞 的特异性杀伤能力要优于PDL1抗体。提高效应细胞(T细胞)的比例，在效靶比为16:1时，可以提高化合物组对靶细胞的杀伤效率，最高可达60％左右。
生物测试例4:化合物在肿瘤抑制瘤模型中的抗肿瘤药效
动物实验操作步骤如下：
1.培养B16F10黑色素瘤细胞，待其达到对数期时，将其消化后800rpm离心5min，PBS重悬，细胞浓度为5×10 6cells/ml，并尽快接种于C57BL/6小鼠右腹股沟皮下，每只小鼠注射100ul体积的细胞悬液。操作期间可将细胞悬液放置冰水浴中。
2.待肿瘤体积生长到50mm 3后，根据肿瘤体积将小鼠随机分组，开始记录肿瘤生长曲线。化合物BMS-1266(EC81)/120(ZD41)给药剂量为40mg/kg，每天给药一次；化合物89(ZE132)给药剂量分为40mg/kg，每天给药一次和20mg/kg，每天给药一次。PD1抗体(BioXcell，BE0146)/PDL1抗体(BioXcell，BE0101)给药剂量为10mg/kg，每3天给药一次。每两到三天，测量肿瘤体积。肿瘤体积公式：V＝L*W*W*1/2。待肿瘤体积达到约2000mm 3后终止实验。
实验结果如图3所示，其中，图3A示出了化合物120(ZD41)化合物、BMS-1266(EC81)和PDL1抗体在B16F10小鼠移植瘤中的抗肿瘤药效；图3B示出了化合物89(ZE132)给药剂量分别为40mg/kg和20mg/kg以及PD1抗体/PDL1抗体给药剂量为10mg/kg在B16F10小鼠移植瘤中的抗肿瘤药效。
实验结果表明：化合物120(ZD41)、89(ZE132)在小鼠抑制瘤模型中具有抗肿瘤药效，其中，化合物89(ZE132)在较低的给药剂量(20mg/kg)下，其抗肿瘤药效与PD1抗体/PDL1抗体相当或者有一定提高，化合物89(ZE132)在给药剂量为40mg/kg情况下，其抗肿瘤药效明显优于PD1抗体/PDL1抗体。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (15)

  1. 一种通式(I)所示的化合物，其立体异构体、对映异构体，或其药学上可接受的盐：
    Figure PCTCN2020094013-appb-100001
    其中：
    X为N或者CH；
    Y为氢原子或者C1-C4烷基；
    R 1选自下组：
    Figure PCTCN2020094013-appb-100002
    Figure PCTCN2020094013-appb-100003
    R 2选自取代或未取代的下组基团：氢原子、C1-C6烷基、C3-C6环烷基、5-10元杂环基、Ar 1-(CH 2) m-、C6-C10芳环或者5-12元的杂芳环；Ar 1为取代或者未取代的5-10元杂环基、C6-C10芳环或者5-12元杂芳环；其中，所述取代是指被选自下组的一个或多个基团取代：羟基、卤素、羧基、氰基、C1-C6烷基、-NRaRb、苯基、5-6元杂芳基、C3-C6环烷基、5-10元杂环基；
    R 3选自取代或未取代的下组基团：氢原子、C1-C6烷基、C3-C6环烷基、Ar-CH 2-、或5-12元的杂环基；其中，Ar为取代或者未取代的C6-C10芳环或者5-12元杂芳环，
    其中，所述的取代指基团上的一个或多个氢原子被选自下组的取代基所取代：卤素、C1-C4烷基、(C1-C4)烷氧基、羟基、氨基、氰基、三氟甲基、二氟甲基、(C1-C4)烷基磺酰基、(C1-C4)烷基亚磺酰基、(C1-C4)烷基磺酰基氨基、氨基磺酰基、(C1-C5)酰基氨基、卤代(C1-C4)烷基磺酰基、卤代(C1-C4)烷基亚磺酰基、卤代(C1-C4)烷基磺酰基氨基；
    R 4选自：氢原子、卤素、C1-C4烷基、C1-C4烷氧基、或卤代(C1-C4)烷基；
    R 5选自：氢原子、卤素、C1-C4烷基、C1-C4烷氧基、氰基、或卤代(C1-C4)烷基；
    R 6选自：取代或未取代的苯环，其中，所述的取代指基团上的一个或多个氢原子被选自下组的取代基所取代：对甲氧基苄基氧基、苄氧基、(C1-C5)烷氧基、羟基、卤素；
    或者R 6选自：
    Figure PCTCN2020094013-appb-100004
    其中，Z为氢原子或者C1-C4烷基；
    R 1a选自：
    Figure PCTCN2020094013-appb-100005
    Figure PCTCN2020094013-appb-100006
    R 2a选自取代或未取代的下组基团：氢原子、C1-C6烷基、C3-C6环烷基、5-10元杂环基、Ar 1-(CH 2) m-、C6-C10芳环或者5-12元的杂芳环；Ar 1为取代或者未取代的5-10元杂环基、C6-C10芳环或者5-12元杂芳环；其中，所述取代是指被选自下组的一个或多个基团取代：羟基、卤素、羧基、氰基、C1-C6烷基、-NRaRb、5-6元杂芳基、C3-C6环烷基、5-10元杂环基；
    R 3a选自：氢原子、C1-C6烷基、C3-C6环烷基、Ar-CH 2-、或C3-C6杂环基，
    R 4a选自：氢原子、卤素、C1-C4烷基、(C1-C4)烷氧基、卤代(C1-C4)烷基；
    R 5a选自：氢原子、卤素、C1-C4烷基、(C1-C4)烷氧基、氰基、卤代(C1-C4)烷基；
    Rg选自：-NRdRe；
    Ra、Rb、Rc各自独立地选自：氢原子、C1-C5烷基、-O-CH 2-O-CO-(C1-C5烷基)、-CH 2-O-CO-(C1-C5烷基)；
    Rd、Re各自独立地选自：氢原子、C1-C5烷基、-CO-Rf，其中，Rf独立地选自：氢原子、三氟甲基、C1-C5烷基、5-6元杂芳基、C3-C6环烷基、5-10元杂环基；
    Rx选自：氢原子、C1-C6烷基、C3-C6环烷基、5-10元杂环基；
    其中，R 11、R 12、R 13、R 14、R 15、R 16各自独立地选自：氢、羟基、-O-CHO、(C1-C4烷基)羰基-O-、HO 2C-；
    其中，n表示2、3、或者4；m表示1、2、或者3。
  2. 如权利要求1所述的通式(I)化合物，其立体异构体、对映异构体，或其药学上可接受的盐：
    Figure PCTCN2020094013-appb-100007
    其中：
    X为N或者CH；
    Y为氢原子或者C1-C4烷基；
    R 1选自下组：
    Figure PCTCN2020094013-appb-100008
    Figure PCTCN2020094013-appb-100009
    2选自下组：氢原子、C1-C6烷基、C3-C6环烷基、5-10元杂环基、或卤代(C1-C4)烷基；
    R 3选自下组：氢原子、C1-C6烷基、C3-C6环烷基、Ar-CH 2-、或5-12元的杂环基；
    其中Ar为取代或者未取代的C6-C10芳环，或者5-12元的杂芳环，其中，所述的取代指基团上的一个或多个氢原子被选自下组的取代基所取代：卤素、C1-C4烷基、(C1-C4)烷氧基、羟基、氨基、氰基、三氟甲基、二氟甲基、(C1-C4)烷基磺酰基、(C1-C4)烷基亚磺酰基、(C1-C4)烷基磺酰基氨基、氨基磺酰基、(C1-C5)酰基氨基；
    R 4选自：氢原子、卤素、C1-C4烷基、C1-C4烷氧基、或卤代(C1-C4)烷基；
    R 5选自：氢原子、卤素、C1-C4烷基、C1-C4烷氧基、氰基、或卤代(C1-C4)烷基；
    R 6选自：取代或未取代的苯环，其中，所述的取代指基团上的一个或多个氢原子被选自下组的取代基所取代：对甲氧基苄基氧基、苄氧基、(C1-C5)烷氧基、羟基、卤素；
    或者R 6选自：
    Figure PCTCN2020094013-appb-100010
    其中，Z为氢原子或者C1-C4烷基；
    R 1a选自：
    Figure PCTCN2020094013-appb-100011
    Figure PCTCN2020094013-appb-100012
    R 2a选自：氢原子、C1-C6烷基、C3-C6环烷基、5-10元杂环基、或卤代(C1-C4)烷基；
    R 3a选自：氢原子、C1-C6烷基、C3-C6环烷基、Ar-CH 2-、或C3-C6杂环基，
    R 4a选自：氢原子、卤素、C1-C4烷基、(C1-C4)烷氧基、卤代(C1-C4)烷基；
    R 5a选自：氢原子、卤素、C1-C4烷基、(C1-C4)烷氧基、氰基、卤代(C1-C4)烷基；
    Ra、Rb、Rc各自独立地选自：氢原子、C1-C5烷基、-O-CH 2-O-CO-(C1-C5烷基)、-CH 2-O-CO-(C1-C5烷基)；
    Rx选自：氢原子、C1-C6烷基、C3-C6环烷基、5-10元杂环基；
    其中R 11、R 12、R 13、R 14、R 15、R 16分别独立的选自：氢、羟基、-O-CHO、(C1-C4烷基)羰基-O-、HO 2C-；
    其中n表示2、3、或者4。
  3. 如权利要求1所述的通式(I)化合物，其立体异构体、对映异构体，或其药学上可接受的盐，其特征在于，
    R 2选自：氢原子、C1-C6烷基、C3-C6环烷基、三氟甲基、或二氟甲基；
    R 3选自：氢原子、C1-C6烷基、C3-C6环烷基、Ar-CH 2-，其中Ar为取代或者未取代的苯环或者含氮六元杂芳环，其中，所述的取代指基团上的一个或多个氢原子被选自下组的取代基所取代：卤素、C1-C4烷基、(C1-C4)烷氧基、羟基、氨基、氰基、三氟甲基、二氟甲基、(C1-C4)烷基磺酰基、(C1-C4)烷基亚磺酰基、(C1-C4)烷基磺酰基氨基、氨基磺酰基、(C1-C5)酰基氨基；
    R 4选自：氢原子、卤素、C1-C4烷基、(C1-C4)烷氧基、三氟甲基、二氟甲基；
    R 5选自：氢原子、卤素、C1-C4烷基、(C1-C4)烷氧基、氰基、三氟甲基、二氟甲基；
    R 2a选自：氢原子、C1-C6烷基、C3-C6环烷基、三氟甲基、或二氟甲基；
    R 3a选自：氢原子、C1-C6烷基、C3-C6环烷基、或Ar-CH 2-，其中取代或者未取代Ar表示苯环或者含氮六元杂芳环，其取代基选自：卤素、(C1-C4)烷基、(C1-C4)烷氧基、羟基、氨基、氰基、三氟甲基、二氟甲基、(C1-C4)烷基磺酰基、(C1-C4)烷基亚磺酰基、(C1-C4)烷基磺酰基氨基、氨基磺酰基、(C1-C5)酰基氨基；
    R 4a选自：氢原子、卤素、C1-C4烷基、C1-C4烷氧基、三氟甲基、二氟甲基；
    R 5a选自：氢原子、卤素、C1-C4烷基、C1-C4烷氧基、氰基、三氟甲基、二氟甲基；
    Ra、Rb、Rc各自独立地选自：氢原子、C1-C5烷基、-O-CH 2-O-CO-(C1-C5烷基)；
    Rx选自：氢原子、C1-C6烷基、C3-C6环烷基；
    其中n表示2、3、或者4。
  4. 如权利要求1所述的通式(I)化合物，其立体异构体、对映异构体，或其药学上可接受的盐，其特征在于，所述通式(I)化合物具有式(I-1)所示的结构：
    Figure PCTCN2020094013-appb-100013
    其中，n为2、3、或者4，Ra、R 2-R 6、X、Y具有如权利要求1所述的定义。
  5. 如权利要求1所述的通式(I)化合物，其立体异构体、对映异构体，或其药学上可接受的盐，其特征在于，所述通式(I)化合物具有式(I-2)所示的结构：
    Figure PCTCN2020094013-appb-100014
    其中，n为2、3、或者4，Rb、Rc、R 2-R 6、X、Y具有如权利要求1所述的定义。
  6. 如权利要求1所述通式(I)的化合物，其立体异构体、对映异构体，或其药学上可接受的盐，其特征在于，所述通式(I)化合物具有式(I-3)或(I-4)所示的结构：
    Figure PCTCN2020094013-appb-100015
    其中，n为2、3、或者4，R 2-R 6、X、Y具有如权利要求1所述的定义。
  7. 如权利要求1所述的通式(I)化合物，其立体异构体、对映异构体，或其药学上可接受的盐，其特征在于，所述通式(I)化合物具有式(I-5)、(I-6)或(I-7)所示的结构：
    Figure PCTCN2020094013-appb-100016
    其中，R 11、R 12、R 13、R 14、R 15、R 16、R 2-R 6、X、Y具有如权利要求1所述的定义。
  8. 如权利要求1所述的通式(I)化合物，其立体异构体、对映异构体，或其药学上可接受的盐，其特征在于，所述通式(I)化合物具有式(I-8)所示的结构:
    Figure PCTCN2020094013-appb-100017
    其中，R 1-R 5、R 1a、R 2a、R 3a、R 4a、R 5a、X、Y、Z具有如权利要求1所述的定义。
  9. 如权利要求1所述的通式(I)化合物，其立体异构体、对映异构体，或其药学上可接受的盐，其特征在于，所述通式(I)化合物具有式(I-9)、(I-10)或(I-11)所示的结构：
    Figure PCTCN2020094013-appb-100018
    其中，n为2、3、或者4，R 11、R 12、R 13、R 14、R 15、R 16、R 2-R 6、X、Y具有如权利要求1所述的定义。
  10. 如权利要求1所述的通式(I)化合物，其立体异构体、对映异构体，或其药学上可接受的盐，其特征在于，所述通式(I)化合物具有式(I-14)所示的结构：
    Figure PCTCN2020094013-appb-100019
    其中，
    n为2、3、或者4，R 2、R 3、R 4、R 5、R 6、R g、Y具有如权利要求1所述的定义。
  11. 如权利要求1-10任一项所述的通式(I)化合物，其立体异构体、对映异构体，或其药学上可接受的盐，其特征在于，R 3为Ar-CH 2-，其中，Ar为取代或者未取代的苯环或者含氮六元杂芳环，其中，所述的取代指基团上的一个或多个氢原子被选自下组的取代基所取代：氰基、(C1-C4)烷基磺酰基、(C1-C4)烷基亚磺酰基、(C1-C4)烷基磺酰基氨基、氨基磺酰基、(C1-C5)酰基氨基、卤代(C1-C4)烷基磺酰基、卤代(C1-C4)烷基亚磺酰基、卤代(C1-C4)烷基磺酰基氨基。
  12. 如权利要求1所述的通式(I)化合物，其立体异构体、对映异构体或其药学上可接受的盐，其特征在于，所述化合物选自下组：
    Figure PCTCN2020094013-appb-100020
    Figure PCTCN2020094013-appb-100021
    Figure PCTCN2020094013-appb-100022
    Figure PCTCN2020094013-appb-100023
    Figure PCTCN2020094013-appb-100024
    Figure PCTCN2020094013-appb-100025
    Figure PCTCN2020094013-appb-100026
  13. 一种药物组合物，其包含有效量的权利要求1至12中任一项所述的化合物，其立体异构体、对映异构体或其药学上可接受的盐，和任选的药学上可接受的赋形剂或载体。
  14. 如权利要求1至12中任一项所述的化合物，其立体异构体、对映异构体或其药学上可接受的盐，或根据权利要求13所述的药物组合物在制备PD1-PDL1相互作用抑制剂中的用途。
  15. 如权利要求14所述的用途，其中，所述PD1-PDL1相互作用抑制剂用于预防和/或治疗癌症。
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