WO2021151387A1 - 一种酮酰胺类化合物的药物用途 - Google Patents
一种酮酰胺类化合物的药物用途 Download PDFInfo
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- WO2021151387A1 WO2021151387A1 PCT/CN2021/074228 CN2021074228W WO2021151387A1 WO 2021151387 A1 WO2021151387 A1 WO 2021151387A1 CN 2021074228 W CN2021074228 W CN 2021074228W WO 2021151387 A1 WO2021151387 A1 WO 2021151387A1
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Definitions
- the present invention relates to the field of medicine, in particular to the medical use of a ketoamide compound.
- 2019-nCoV 2019-nCoV or SARS-CoV-2
- 2019-nCoV virus can be transmitted through droplets and contact, and there is human-to-human transmission, medical staff infection, a certain risk of community transmission, and the virus may mutate.
- the 2019-nCoV coronavirus belongs to the genus Coronavirus of the Coronavirus family, and is a single-stranded positive-sense RNA virus with an envelope. Similar to other known coronaviruses, the 2019-nCoV coronavirus also completes the proliferation of progeny viruses through several processes such as adsorption, penetration, uncoating, biosynthesis, and assembly and release of progeny viruses.
- the infection of host cells by the 2019-nCoV coronavirus starts when the spike glycoprotein on the surface of the virus envelope binds to the receptor on the surface of the host cell, and then membrane fusion occurs. The virus enters the host cell and is released under the action of cell lysosomes and other organelles.
- the single-stranded sense RNA of the virus’s genetic material is translated to produce polyproteins under the action of the host cell’s mitochondria, ribosomes and other protein synthesis elements and necessary raw materials.
- the two essential cysteamines of the 2019-nCoV coronavirus Acid protease Papain-like protease (PL pro ) and 3C-like protease (3C-like protease, 3CL pro ) cleave and process polyprotein precursors at specific sites, producing multiple important factors for the virus life cycle Non-structural protein.
- the viral RNA replicates the nucleic acid material of the progeny virus, and a large number of required structural proteins are translated to complete the assembly and release of the progeny virus.
- Any link or key enzyme in the life cycle of cells infected by the 2019-nCoV coronavirus can be used as research targets for antiviral drugs, such as the cysteine proteases PL pro and 3CL pro that hydrolyze and cleave polyprotein precursors, which are responsible for the completion of the product.
- 3CL protease (3 chymotrypsin-like protease, 3CL pro ), also known as the main protease (M pro ), is the key protease in the process of producing multiple non-structural proteins after the coronavirus RNA is translated into polyproteins pp1a and pp1ab. Inhibition of the catalytic function of 3CL protease can effectively inhibit the cleavage of viral polyprotein precursors, block viral replication and inhibit the generation of progeny viruses.
- 3CL pro is a cysteine protease, which is a key protease that catalyzes the proteolysis of single positive-strand RNA virus precursors, and plays an important role in the replication activity of coronaviruses such as 2019-nCoV. Therefore, 3CL pro is currently recognized as an ideal target for the development of anti-coronavirus drugs.
- Human cathepsin L belongs to the cysteine protease of the lysosomal papain-like protease family. It has a variety of biological functions. As a target, it has been widely used in the research and development of antiparasitic drugs, such as Chagas disease caused by trypanosomal infection. . Cathepsin L first exists as an inactive zymogen in the cell and needs to be cleaved in the acidic environment of endosomes or lysosomes, or activated by other proteases to form a mature enzyme with catalytic activity. A large number of studies have reported that human cathepsin L is closely related to the occurrence of a variety of tumors and also plays an important role in heart disease.
- S protein spike protein of SARS-CoV-2 needs to be hydrolyzed and activated by the host protease before it can mediate the membrane fusion between the virus and the host cell and promote the virus's invasion of the host cell.
- the virus invasion pathway can be divided into Type II transmembrane serine protease (TMPRSSII) mediated surface membrane fusion pathway, human cathepsin L (cathepsin L) mediated endocytic membrane fusion pathway, so these host proteases can be used as entry inhibitors for coronavirus to invade host cells .
- TMPRSSII Type II transmembrane serine protease
- human cathepsin L cathepsin L
- human cathepsin L inhibitors are ideal targets for the development of anti-SARS-CoV-2, and are expected to solve the potential risks and problems of mutation resistance of virus-targeted antiviral drugs. .
- 2019-nCoV coronavirus 3CL pro and/or human cathepsin L an antiviral drug with novel structure, low toxicity and high efficiency and independent intellectual property rights has been developed to meet the clinical needs of patients with 2019-nCoV coronavirus infection at home and abroad. Social significance.
- the purpose of the present invention is to provide a new use of ketoamide compounds.
- the present invention provides the ketoamide compound represented by general formula A as a 2019 novel coronavirus (2019-nCov) 3CL protease inhibitor and/or human cathepsin L inhibitor in the preparation of treatment and/or prevention and alleviation Use in medicines for respiratory infections, pneumonia and other related diseases caused by 2019 new coronavirus infection.
- 2019-nCov 2019 novel coronavirus
- human cathepsin L inhibitor in the preparation of treatment and/or prevention and alleviation Use in medicines for respiratory infections, pneumonia and other related diseases caused by 2019 new coronavirus infection.
- a ketoamide compound represented by the general formula (A), or a pharmaceutically acceptable salt, enantiomer, diastereomer or racemate thereof The use of, for the preparation of (a) 2019 new coronavirus (2019-nCov) 3CL protease inhibitor and/or human cathepsin L inhibitor; and (b) treatment and/or prevention and alleviation of the 2019 new coronavirus (2019-nCov) 3CL protease inhibitor and/or human cathepsin L inhibitor; -nCov) Drugs for related diseases caused by infection:
- R 1 and R 2 are each independently selected from the following group: hydrogen, deuterium, tritium, amino, hydroxyl, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 cycloalkyl C1-C10 alkylene, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl C1-C10 alkylene, substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted C3-C20 heteroaryl, substituted or unsubstituted C6-C20 aryl C1-C10 alkylene, substituted or unsubstituted C3-C20 heteroaryl C1-C10 Alkylene, substituted or unsubstituted C6-C20 aryl C
- R 3 is selected from the following group: substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted C2-C10 alkynyl, substituted or unsubstituted C3-C8 cycloalkane Group, substituted or unsubstituted C3-C8 cycloalkyl, C1-C10 alkylene, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, C1-C10 alkylene Group, substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted C3-C20 heteroaryl, substituted or unsubstituted C6-C20 aryl, C1-C10 alkylene, substituted or unsubstituted C3-C20 Heteroaryl C1-C
- R 4 is selected from the following group: substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted C2-C10 alkynyl, substituted or unsubstituted C3-C10 cycloalkane Group, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted C3-C20 heteroaryl, substituted or unsubstituted C6-C20 aryl C1- C6 alkylene, substituted or unsubstituted C6-C20 aryl, C2-C6 alkenylene, substituted or unsubstituted C6-C20 aryl, C2-C6 alkynylene, substituted or unsubstituted C3-C20 heteroaryl C1-C9 alkylene, substituted or un
- R 6 is selected from the following group: hydrogen, deuterium, tritium, amino, hydroxyl, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycle Alkyl, substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted C3-C20 heteroaryl, substituted or unsubstituted C6-C20 aryl, C1-C6 alkylene, substituted or unsubstituted C6- C20 aryl C2-C6 alkenylene, substituted or unsubstituted C3-C20 heteroaryl, C1-C9 alkylene, substituted or unsubstituted C3-C20 heteroaryl, C2-C9 alkenylene, acyl, sulfonyl ;
- R 5 is selected from the following group: hydrogen, deuterium, tritium, amino, hydroxyl, substituted or unsubstituted C1-C10 alkyl , Substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted C3-C20 heteroaryl, substituted Or unsubstituted C6-C20 aryl C1-C6 alkylene, substituted or unsubstituted C6-C20 aryl C2-C6 alkenylene, substituted or unsubstituted C3-C20 heteroaryl C1-C9 alkylene , Substituted or unsubstituted C3-C20 heteroaryl C2-C
- substitutions each independently refer to substitution by 1, 2, 3 or 4 substituents selected from the following group: halogen, hydroxyl , Mercapto, nitro, cyano, amine, imino, tertiary amino, azide, C1-C8 alkyl, halogenated C1-C8 alkyl, C1-C8 alkoxy, halogenated C1-C8 Alkoxy, C1-C6 alkylcarbonyl, C1-C6 alkylthio, C1-C8 alkoxycarbonyl, trifluoromethyl; the heterocycloalkyl group and the heteroaryl group each independently comprise 1, 2 , 3 or 4 heteroatoms selected from N, O, S.
- the 5-6 membered heterocyclic ring contains 1 N heteroatom, and the remaining ring atoms are C.
- substitutions are each independently substituted by 1, 2, 3 or 4 substituents selected from the group consisting of halogen, hydroxy, C1-C8 alkyl, C3-C8 cycloalkyl, halogenated C1-C8 Alkyl, C1-C8 alkoxy, halogenated C1-C8 alkoxy, trifluoromethyl.
- Part of it is a substituted or unsubstituted 5-6 membered heterocyclic group, wherein each of the substitutions independently refers to substitution by 1, 2, 3 or 4 substituents selected from the group consisting of halogen, hydroxyl, mercapto, nitro , Cyano, oxo, amino, imino, tertiary amino, azido, C1-C8 alkyl, C3-C8 cycloalkyl, halogenated C1-C8 alkyl, C1-C8 alkoxy , Halogenated C1-C8 alkoxy, C1-C6 alkylcarbonyl, C1-C6 alkylthio, C1-C8 alkoxycarbonyl, trifluoromethyl; preferably Partly Wherein, n1 is 1 or 2.
- the related disease caused by the 2019 novel coronavirus infection is selected from the following group: respiratory tract infection, pneumonia and its complications, or a combination thereof.
- R 1 and R 2 are each independently selected from the following group: hydrogen, deuterium, tritium, amino, hydroxyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 ring Alkyl, substituted or unsubstituted C3-C8 cycloalkyl C1-C5 alkylene, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl C1-C5 alkylene Alkyl, substituted or unsubstituted C6-C14 aryl, substituted or unsubstituted C3-C10 heteroaryl, substituted or unsubstituted C6-C14 aryl, C1-C5 alkylene, substituted or unsubstituted C3- C10 heteroaryl, C1-C5 alkylene, substituted or unsubstituted C1-C6
- R 3 is selected from the following group: substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C3-C8 cycloalkane Group, substituted or unsubstituted C3-C8 cycloalkyl C1-C5 alkylene, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl C1-C5 alkylene Group, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted C3-C10 heteroaryl, substituted or unsubstituted C6-C10 aryl, C1-C5 alkylene, substituted or unsubstituted C3-C10 Heteroaryl C1-C5 al
- substitutions each independently refer to substitution by 1, 2 or 3 substituents selected from the group consisting of halogen, hydroxyl, C1-C6 alkyl, halogenated C1- C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C1-C4 alkylcarbonyl, C1-C4 alkylthio, C1-C6 alkoxycarbonyl, trifluoromethyl; the hetero
- the cycloalkyl group and the heteroaryl group each independently contain 1 or 2 heteroatoms selected from N, O, and S.
- the compound is a compound represented by formula AA,
- R 1 , R 2 , R 3 , R 4 , R 5 and n are as defined above;
- R 4 is selected from the following group: 9-10 membered heteroaromatic ring containing 1, 2 or 3 heteroatoms selected from N, O, S, and containing 1, 2 or 3 selected from N 5-6 membered heteroaromatic ring with heteroatoms of, O, and S; the above-mentioned groups are substituted or unsubstituted; wherein, the substitution means that the hydrogen atoms on the group are 1, 2, 3, or 4 selected from the following Substituent group substitution: halogen, hydroxy, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl, halogenated C3-C6 cycloalkyl, C1-C6 alkoxy, halogenated C1 -C6 alkoxy, C1-C6 alkylthio, halogenated C1-C6 alkylthio.
- R 6 is selected from the following group: hydrogen, deuterium, tritium, amino, hydroxyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted Substituted C3-C10 heterocycloalkyl.
- the heteroaryl group is a 5-, 6, 7, 8, 9- or 10-membered saturated or partially saturated heteroaromatic ring.
- the heterocycloalkyl group is a 5-, 6, 7, 8, 9- or 10-membered unsaturated heterocyclic ring.
- R 4 is selected from the following group:
- substitution means that the hydrogen atom on the group is substituted by 1, 2 or 3 substituents selected from the following group: F, Cl, Br, I, hydroxyl, C1-C6 alkyl, halogenated C1-C6 alkane Group, C3-C6 cycloalkyl, halogenated C3-C6 cycloalkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C1-C6 alkylthio, halogenated C1-C6 alkylthio.
- R 4 is imidazole [1,2-A]pyridine, which corresponds to the compounds numbered A156 to A161 of the present invention.
- imidazole[1,2-A]pyridine "imidazole[1,2-a]pyridine”, “imidazo[1,2-A]pyridine” and “imidazo[1,2-a] ]Pyridine” can be used interchangeably.
- imidazole[1,5-A]pyridine "imidazole[1,5-a]pyridine”, “imidazo[1,5-A]pyridine” and “imidazo[1,5-a ]Pyridine” can be used interchangeably.
- R 4 is 3,8a dihydro-2H-benzopyran, which corresponds to the compounds numbered A132 to A137 of the present invention.
- R 5 is -(CH 2 ) n -, and n is 3;
- R 5 is selected from the following group: hydrogen, deuterium, tritium, hydroxyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted C3- C10 heteroaryl, substituted or unsubstituted C6-C10 aryl, C1-C4 alkylene, substituted or unsubstituted C6-C10 aryl, C2-C4 alkenylene, substituted or unsubstituted C3-C10 heteroaryl C1-C4 alkylene, substituted or unsubstituted C3-C10 heteroaryl C
- substitutions each independently refer to substitution by 1, 2, or 3 substituents selected from the following group: F, Cl, Br, I, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C1- C6 alkylthio; the heterocycloalkyl group and the heteroaryl group each independently contain 1, 2 or 3 heteroatoms selected from N, O, and S.
- the R1, R2, R3, R4, R5, and R6 are each independently a corresponding group in the specific compound (A1-A310) in the embodiment.
- the compound of general formula (A) is selected from the following group:
- a pharmaceutical composition which comprises (a) a therapeutically effective amount of a ketoamide compound represented by general formula (A), or a pharmaceutically acceptable salt or enantiomer thereof Isomers, diastereomers or racemates or prodrugs, and (b) a pharmaceutically acceptable carrier, wherein the ketoamide compound represented by the general formula (A) is as described in the first aspect of the present invention Narrated.
- the use of the pharmaceutical composition according to the second aspect of the present invention is provided, which is used for preparing treatment and/or prevention and alleviation of related diseases caused by 2019 novel coronavirus (2019-nCov) infection. drug.
- the related disease caused by the 2019 novel coronavirus infection is selected from the following group: respiratory tract infection, pneumonia and its complications, or a combination thereof.
- a method for treating, preventing, and/or alleviating related diseases caused by 2019 novel coronavirus (2019-nCov) infection including the steps of: administering to a subject in need a safe and effective amount of The ketoamide compound represented by the general formula (A), or a pharmaceutically acceptable salt, enantiomer, diastereomer, or racemate thereof, wherein the general formula (A) is
- the ketoamide compounds shown are as described above.
- the subject is a primate mammal, such as a human.
- a method for inhibiting the activity of the 3CL protease of the 2019 novel coronavirus (2019-nCov) comprises the steps of: combining the ketoamide compound represented by the general formula (A), or the pharmacological agent thereof The above-acceptable salt, enantiomer, diastereomer or racemate is contacted with the 3CL protease of 2019-nCov and/or human cathepsin L, thereby inhibiting the 3CL protease and/or of 2019-nCov Activity of human cathepsin L.
- the method is non-therapeutic and non-diagnostic.
- the method is in vitro.
- the 3CL protease of 2019-nCov is a recombinant or expressed 3CL protease of 2019-nCov.
- the sixth aspect of the present invention provides a compound of formula (A) described in the first aspect, or a pharmaceutically acceptable salt, enantiomer, diastereomer or racemate thereof,
- R 1 and R 2 are each independently selected from the following group: hydrogen, deuterium, tritium, amino, hydroxyl, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 cycloalkyl C1-C10 alkylene, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl C1-C10 alkylene, substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted C3-C20 heteroaryl, substituted or unsubstituted C6-C20 aryl C1-C10 alkylene, substituted or unsubstituted C3-C20 heteroaryl C1-C10 Alkylene, substituted or unsubstituted C6-C20 aryl C
- R 3 is selected from the following group: substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted C2-C10 alkynyl, substituted or unsubstituted C3-C8 cycloalkane Group, substituted or unsubstituted C3-C8 cycloalkyl, C1-C10 alkylene, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, C1-C10 alkylene Group, substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted C3-C20 heteroaryl, substituted or unsubstituted C6-C20 aryl, C1-C10 alkylene, substituted or unsubstituted C3-C20 Heteroaryl C1-C
- R 4 is selected from the following group: substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted C2-C10 alkynyl, substituted or unsubstituted C3-C10 cycloalkane Group, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted C3-C20 heteroaryl, substituted or unsubstituted C6-C20 aryl C1- C6 alkylene, substituted or unsubstituted C6-C20 aryl, C2-C6 alkenylene, substituted or unsubstituted C6-C20 aryl, C2-C6 alkynylene, substituted or unsubstituted C3-C20 heteroaryl C1-C9 alkylene, substituted or un
- R 6 is selected from the following group: hydrogen, deuterium, tritium, amino, hydroxyl, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycle Alkyl, substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted C3-C20 heteroaryl, substituted or unsubstituted C6-C20 aryl, C1-C6 alkylene, substituted or unsubstituted C6- C20 aryl C2-C6 alkenylene, substituted or unsubstituted C3-C20 heteroaryl, C1-C9 alkylene, substituted or unsubstituted C3-C20 heteroaryl, C2-C9 alkenylene, acyl, sulfonyl ;
- R 5 is selected from the following group: hydrogen, deuterium, tritium, amino, hydroxyl, substituted or unsubstituted C1-C10 alkyl , Substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted C3-C20 heteroaryl, substituted Or unsubstituted C6-C20 aryl C1-C6 alkylene, substituted or unsubstituted C6-C20 aryl C2-C6 alkenylene, substituted or unsubstituted C3-C20 heteroaryl C1-C9 alkylene , Substituted or unsubstituted C3-C20 heteroaryl C2-C
- substitutions each independently refer to substitution by 1, 2, 3 or 4 substituents selected from the following group: halogen, hydroxyl , Mercapto, nitro, cyano, amine, imino, tertiary amino, azide, C1-C8 alkyl, halogenated C1-C8 alkyl, C1-C8 alkoxy, halogenated C1-C8 Alkoxy, C1-C6 alkylcarbonyl, C1-C6 alkylthio, C1-C8 alkoxycarbonyl, trifluoromethyl; the heterocycloalkyl group and the heteroaryl group each independently comprise 1, 2 , 3 or 4 heteroatoms selected from N, O, S.
- the compound is a compound represented by formula AA,
- R 1 , R 2 , R 3 , R 4 , R 5 and n are as defined above;
- the compound is compound A254-A310 (ie, embodiments 254-310). It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described in the following (such as the embodiments) can be combined with each other to form a new or preferred technical solution. Due to space limitations, I will not repeat them one by one here.
- Figure 1 shows that the compounds of the present invention can inhibit the replication of 2019nCoV virus.
- Figure 2 shows the inhibition curve and EC50 value of some compounds of the present invention in inhibiting the 2019 novel coronavirus (2019-nCov).
- the inventors unexpectedly developed a class of active ingredients that can effectively inhibit the 2019 novel coronavirus (2019-nCov), that is, the compound represented by general formula A or its pharmacologically Accepted salts, enantiomers, diastereomers or racemates.
- 2019-nCov the compound represented by general formula A or its pharmacologically Accepted salts, enantiomers, diastereomers or racemates.
- Tests have shown that the active ingredients of the present invention can effectively inhibit the activity of the 3CL protease and/or human cathepsin L of the 2019 novel coronavirus (2019-nCov), thereby inhibiting the replication and viability of 2019-nCov.
- the present invention has been completed on this basis.
- new coronavirus As used herein, the terms “new coronavirus”, “2019-nCov” or “SARS-CoV-2” are used interchangeably.
- This new coronavirus is the seventh coronavirus known to infect humans and causes new coronary pneumonia ( COVID-19) is one of the serious infectious diseases that threaten human health around the world.
- COVID-19 new coronary pneumonia
- the term also includes wild-type and mutant virus strains.
- substituted refers to the substitution of one or more hydrogen atoms on the group with a substituent selected from the following group: C 1 ⁇ C 10 alkyl, C 3 ⁇ C 10 cycloalkane Group, C 1 ⁇ C 10 alkoxy, halogen, hydroxyl, carboxyl (-COOH), C 1 ⁇ C 10 aldehyde group, C 2 ⁇ C 10 acyl group, C 2 ⁇ C 10 ester group, amino, phenyl;
- the phenyl group includes an unsubstituted phenyl group or a substituted phenyl group having 1 to 3 substituents, and the substituents are selected from the group consisting of halogen, C 1 -C 10 alkyl, cyano, OH, nitro, C 3 -C 10 cycloalkyl, C 1 -C 10 alkoxy, amino.
- each chiral carbon atom may optionally be in the R configuration or the S configuration, or a mixture of the R configuration and the S configuration.
- C1-C6 alkyl group refers to a straight or branched chain alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, Tert-butyl, or similar group.
- 3-8 membered heterocyclic group refers to a group formed by losing one hydrogen atom of a 3-8 membered saturated ring with 1-3 heteroatoms selected from the group: N, S, O; for example, pyrrolidinyl, Piperidinyl, piperazinyl, morpholinyl, or similar groups.
- 6-10 membered aryl group refers to a group formed by losing one hydrogen atom of a 6-10 membered aryl group; for example, a phenyl group, a naphthyl group, or the like.
- 5- to 10-membered heteroaryl refers to a 5- to 8-membered aryl group with 1-3 heteroatoms selected from the group consisting of N, S, O, each of which is formed by losing one hydrogen atom.
- the ring system of the group can be monocyclic or polycyclic; for example, pyrrolyl, pyridyl, thienyl, furyl, imidazolyl, pyrimidinyl, benzothienyl, indolyl, imidazopyridyl, quinolinyl Or similar groups.
- C1 ⁇ C6 alkoxy refers to a straight or branched alkoxy group having 1-6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, iso Butoxy, sec-butoxy, tert-butoxy, or similar groups.
- C2-C6 alkenyl refers to a group formed by the loss of one or two hydrogen atoms of an olefin with 2-6 carbon atoms.
- halogen refers to F, Cl, Br, and I.
- the structural formula described in the present invention is intended to include all isomeric forms (such as enantiomers, diastereomers and geometric isomers (or conformational isomers): for example, containing asymmetric centers
- the R and S configurations, the (Z), (E) isomers and the (Z), (E) conformational isomers of the double bond Therefore, the single stereochemical isomers of the compounds of the present invention or their enantiomers Mixtures of isomers, diastereomers or geometric isomers (or conformational isomers) all fall within the scope of the present invention.
- tautomers means that structural isomers with different energies can exceed the low energy barrier and thus convert into each other.
- proton tautomers ie, proton transfer
- interconversion through proton transfer such as 1H-indazole and 2H-indazole, 1H-benzo[d]imidazole and 3H-benzo[d]imidazole
- Valence tautomers include interconversion through some bond-forming electron recombination.
- C1 ⁇ C6 means that the group can have 1 to 6 carbon atoms, for example, 1, 2, 3, 4, or 5.
- an active ingredient that can effectively inhibit the replication of the 2019 novel coronavirus (2019-nCov) is provided.
- the active ingredient is a compound represented by general formula A, and the active ingredient can effectively prevent, treat and/or alleviate 2019-nCov related diseases.
- the active ingredient of the present invention includes the ketoamide compound represented by the general formula (A), or a pharmaceutically acceptable salt, enantiomer, diastereomer or racemate, or Its prodrug. It should be understood that the active ingredients of the present invention also include crystalline forms, amorphous compounds, and deuterated compounds of the compound of general formula (A).
- the "pharmaceutically acceptable salt” refers to the reaction of a compound of general formula (A) with an inorganic acid or an organic acid to form a conventional non-toxic salt.
- a conventional non-toxic salt can be prepared by reacting a compound of the general formula (A) with an inorganic acid or organic acid.
- the inorganic acid includes hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, aminosulfonic acid and phosphoric acid, etc.
- Organic acids include citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, naphthalenesulfonic acid, ethanesulfonic acid, naphthalene disulfonic acid, maleic acid, malic acid, malonic acid Acid, fumaric acid, succinic acid, propionic acid, oxalic acid, trifluoroacetic acid, stearic acid, pamoic acid, hydroxymaleic acid, phenylacetic acid, benzoic acid, salicylic acid, glutamic acid, ascorbic acid, p-aminobenzene Sulfonic acid, 2-acetoxy benzoic acid and isethionic acid, etc.; or compounds of general formula (A) and propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid,
- One or more mixtures are the use of active ingredients in the preparation of medicines for the treatment and/or prevention and alleviation of respiratory tract infections, pneumonia and other related diseases caused by 2019 novel coronavirus infection.
- the pharmaceutical composition provided by the present invention preferably contains the active ingredient in a weight ratio of 0.001-99wt%, and the preferred ratio is that the compound of general formula A as the active ingredient accounts for 0.1wt% to 90wt% of the total weight, and the rest is pharmaceutically acceptable.
- the carrier includes conventional diluents, excipients, fillers, binders, wetting agents, disintegrants, absorption promoters, surfactants, adsorption carriers, lubricants and the like in the pharmaceutical field.
- the compounds and pharmaceutical compositions provided by the present invention can be in various forms, such as tablets, capsules, powders, syrups, solutions, suspensions and aerosols, etc., and can be present in suitable solid or liquid carriers or diluents. Neutralization is suitable for sterilization equipment for injection or drip infusion.
- the unit measurement of the formulation formulation usually contains 0.05-400 mg of the compound of the general formula A, preferably, the unit measurement of the formulation formulation contains 1 mg-500 mg of the compound of the general formula A.
- the compounds and pharmaceutical compositions of the present invention can be used clinically on mammals, including humans and animals, and can be administered via oral, nose, skin, lung, or gastrointestinal tract. Most preferred is oral administration.
- the most preferred daily dose is 0.01-400 mg/kg body weight, taken in one time, or 0.01-200 mg/kg body weight in divided doses. Regardless of the method of administration, the individual's optimal dosage should be determined based on the specific treatment. Usually, start with a small dose and gradually increase the dose until the most suitable dose is found.
- the drugs or inhibitors of the present invention can be administered in various ways, for example, can be introduced into the body by injection, spraying, nose drops, eye drops, penetration, absorption, physical or chemically mediated methods such as muscle, intradermal, subcutaneous, and intravenous methods. , Mucosal tissue; or mixed or wrapped by other substances into the body.
- the compound of the present invention can effectively inhibit 2019-nCoV 3CL protease, and the IC 50 value of some compounds reaches about 2.4 ⁇ M.
- the compounds of the present invention can inhibit human cathepsin L efficiently, and the IC 50 value of some compounds reaches about 0.45 nM.
- the compound of the present invention has low toxic and side effects and good drug-making properties.
- the analytical data of the samples were measured by the following instruments: NMR was measured by GEMINI-300, Bruker AMX-400 and INVOA-600 nuclear magnetic resonance instruments, TMS (tetramethylsilane) was internal standard, chemical shift unit was ppm, coupling The constant unit is Hz; the mass spectrum is measured by Finnigan MAT-711, MAT-95 and LCQ-DECA mass spectrometers and IonSpec 4.7 Tesla mass spectrometers.
- N-tert-butoxycarbonyl-L-glutamic acid dimethyl ester (1-1) (6g, 21.8mmol) in 60mL anhydrous tetrahydrofuran, and slowly drop LiHMDS( 1M in THF) tetrahydrofuran solution (47mL, 47mmol), the dripping process keeps the temperature stable at -78°C for about 1 hour. After dripping, it was stirred at -78°C for 1 hour. Bromoacetonitrile (2.79 g, 23.3 mmol) was dissolved in 20 ml of tetrahydrofuran, and then the solution was slowly dropped into the reaction system, and the dropping process lasted 1 to 2 hours.
- Dissolve compound 1-3 (2.6g) in a dichloromethane solution (1/1, v/v) of trifluoroacetic acid, stir at room temperature for 1 hour, add 100ml of dichloromethane after concentration, and wash with saturated sodium carbonate solution. The layer was dried with anhydrous sodium sulfate and concentrated to obtain an oily substance 1-4 (2.7g) with a yield of 99%.
- Boc-cyclohexylalanine (1.26g, 5mmol), EDCI (1.36g, 6mmol) and HOBt (0.822g, 6mmol) were added to 80ml of dichloromethane solution and stirred at room temperature for 30min. Subsequently, compound 1-4 (0.896 g, 5 mmol) was added, 1.2 equivalent of triethylamine was added dropwise, and the mixture was stirred at room temperature. TLC monitoring (UV) After the reaction is complete, the reaction is extracted with dichloromethane, washed with dilute hydrochloric acid, saturated sodium bicarbonate solution and saturated sodium chloride, and the organic layers are combined and dried over anhydrous sodium sulfate. After concentration, 1.2 g of a white viscous solid is obtained , The yield is 60%.
- Dissolve compound 1-5 (2.5g) in a dichloromethane solution (1/1, v/v) of trifluoroacetic acid, stir at room temperature for 1 hour, add 100ml of dichloromethane after concentration, and wash with saturated sodium carbonate solution. The layer was dried with anhydrous sodium sulfate and concentrated to obtain an oily substance 1-6 (2.61 g) with a yield of 99%.
- Indole 2-carboxylic acid (0.795g, 5mmol), EDCI (1.36g, 6mmol), HOBt (0.822g, 6mmol) were added to 80ml of dichloromethane solution and stirred at room temperature for 30min. Subsequently, compound 1-6 (2.2 g, 5 mmol) was added, 1.2 equivalent of triethylamine was added dropwise, and the mixture was stirred at room temperature.
- Dissolve 1-7 (243 mg, 0.51 mmol) in 20 ml of methanol, slowly add sodium borohydride (107 mg, 2.9 mmol) in batches, and stir at room temperature for about 2 hours to complete the reaction. After the reaction was completed, about 20 ml of saturated brine was added to quench the reaction, the reaction system was concentrated with methanol, and dichloromethane was added for extraction. The organic phase is washed with saturated brine, dried with anhydrous sodium sulfate, and concentrated to obtain a white solid substance 1-8, which can be directly used in the next step of the reaction.
- Example 2-310 was synthesized using a method similar to that of Example 1.
- Example 104 N-((S)-3-cyclohexyl-1-(((S)-4-(cyclohexylamino)-3,4-dione-1-((S)-2-oxopyrrole)) (Alk-3-yl)but-2-yl)amino)-3-cyclohexyl-1-oxopent-2-yl)-benzothiophene-2-carboxamide (A104)
- Example 217 N-((S)-1-(((S)-4-(tert-butylamino)-3,4-dione-1-((S)-2-oxopiperidine-3- (Yl)but-2-yl)amino)-3-cyclohexyl-1-oxopropan-2-yl)-2,2-difluorobenzo[d][1,3]dioxole -5-Carboxamide (A217)
- Fluorescence resonance energy transfer (FRET) technology was used to determine the enzyme level inhibitory activity of the 3C protease inhibitor.
- FRET Fluorescence resonance energy transfer
- FRET Fluorescence resonance energy transfer
- the fluorescence parameters were measured with a Tecan Infinite 200pro fluorometer, the excitation wavelength and emission wavelength were 360nm and 465nm, respectively, kept at 25°C, and read the data after 30min. A negative control was used, where no compound was added to the control, and the rest were the same. The obtained data was processed by the software GraphPad Prism 8.0, and the experimental results are shown in Table 2.
- Compound number IC 50 (nM) Compound number IC 50 (nM) A5(DC406104) 0.45 ⁇ 0.02 A13(DC403113) 1.36 ⁇ 0.04 A284(DC406016) 0.45 ⁇ 0.01 A289(DC406009) 0.66 ⁇ 0.008 A290(DC406020) 0.47 ⁇ 0.06 A309(DC406068) 0.63 ⁇ 0.08 A310(DC406067) 0.57 ⁇ 0.01 To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To
- test compound has excellent inhibitory activity against human cathepsin L, with IC 50 reaching nanomolar level, even less than 1 nM (such as compound A5, A284, A289, A290, A309, A310).
- ketoamide compounds of the present invention can effectively inhibit the replication of the 2019 novel coronavirus (Figure 1), and have certain inhibition on different isolated virus strains.
- CQ was used as a positive control, and the compounds in the patent were tested under different concentration gradients.
- Compounds A13 (3113, DC403113), A42 (4001, DC404001), A289 (6009, DC406009) all have excellent virus inhibition active.
- CQ exhibit excellent resistance to 2019-nCoV Potential ( Figure 2).
- the purpose of this test is to observe the potential toxicity to the body of SD rats after intravenous injection of DC406009 for 7 consecutive days, and to determine the possible target organs of toxicity. Provide non-toxic reaction dose and/or toxic reaction dose to provide reference for subsequent toxicity test design and clinical trial design. In order to evaluate the exposure level of the drug in the body, a toxicokinetic evaluation was carried out.
- 36 SD rats were divided into 8 groups (3 in the toxicity test group/sex/group, 5 groups in total; 1 in the toxic satellite group/sex/group, 3 groups), and the vehicle was given intravenously (5% DMSO/5 %EtOH/40%PEG300/50%NaCl), 0.9% sodium chloride injection and DC406009 (5, 15, 30mg/kg/day), once a day for 7 consecutive days, all animals were euthanized on Day 8 Anatomy.
- the following indicators were evaluated: toxicology (only samples collected), clinical observation, body weight, food consumption, clinical pathology (hematology, blood coagulation, plasma biochemistry), and anatomical naked eye morphology observation and examination.
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Abstract
一类酮酰胺类化合物的用途，具体而言，如通式A所示的酮酰胺类化合物作为2019新型冠状病毒(2019-nCov)3CL蛋白酶抑制剂和/或人组织蛋白酶L抑制剂在制备治疗和/或预防、缓解由2019新型冠状病毒感染引起的呼吸道感染、肺炎等相关疾病的药物中的用途。还涉及该类化合物的药用组合物、它们的药用盐、对映体形式、非对映异构体及外消旋化合物在制备治疗和/或预防、缓解由2019新型冠状病毒感染引起的呼吸道感染、肺炎等相关疾病的药物中的用途。
Description
本发明涉及医药领域，具体地涉及一种酮酰胺类化合物的医药用途。
在急性传染病中，绝大部分都是病毒性传染病，病毒性传染病的发病率高，死亡率也很高。由于检测和诊断手段有限，导致新病毒引发的新疫情爆发往往具有突发性、随机性和不可预测性等特点，一旦爆发，如无有效的防治手段，极易造成大规模流行，严重威胁人民健康生命安全。新型冠状病毒(2019-nCoV或SARS-CoV-2)感染，引起严重肺炎。2019-nCoV病毒能通过飞沫和接触传播，且存在人传人、医务人员感染，一定社区传播风险，且病毒存在变异的可能。目前对于新型冠状病毒所致疾病没有特异的预防和治疗方法。
2019-nCoV冠状病毒属于冠状病毒科冠状病毒属，为具有包膜的单链正义RNA病毒。和其他已知冠状病毒类似，2019-nCoV冠状病毒也经过吸附、穿入、脱壳、生物合成、子代病毒的组装与释放等几个过程完成子代病毒的增殖。2019-nCoV冠状病毒感染宿主细胞起始于病毒包膜表面的刺突糖蛋白与宿主细胞表面的受体结合，随后发生膜融合，病毒进入宿主细胞，在细胞溶酶体等细胞器作用下，释放出病毒的遗传物质单链正义RNA，在宿主细胞的线粒体、核糖体等蛋白质合成元件以及必须的原料等作用下，翻译产生多聚蛋白，之后，2019-nCoV冠状病毒的两大必需半胱氨酸蛋白酶：木瓜样蛋白酶(papain-like protease,PL
pro)和3C样蛋白酶(3C-like protease,3CL
pro)在特定位点切割加工多聚蛋白前体，产生多个对病毒生命周期非常重要的非结构蛋白。在这些非结够蛋白的作用下，病毒RNA复制出子代病毒核酸物质，并大量翻译出所需的结构蛋白，完成子代病毒的组装和释放。2019-nCoV冠状病毒感染细胞的生命周期的任何环节或关键酶均可以作为抗病毒药物的研究靶点，如水解切割多聚蛋白前体的半胱氨酸蛋白酶PL
pro和3CL
pro，负责完成子代病毒遗传物质复制的RNA聚合酶等。
3CL蛋白酶(3 chymotrypsin-like protease,3CL
pro)，又称主蛋白酶(M
pro)，是冠状病毒RNA翻译出多聚蛋白pp1a和pp1ab后水解产生多个非结构蛋白过程中的关键蛋白酶，对病毒的复制和感染至关重要，抑制3CL蛋白酶的催化功能可有效抑制病毒多聚蛋白前体的切割，阻断病毒复制，抑制子代病毒生成。3CL
pro属于半胱氨酸蛋白酶，是催化单正链RNA病毒前体蛋白水解的关键蛋白酶，对2019-nCoV等冠状病毒的复制活性具有重要的作用。因此，3CL
pro是目前公认的研发抗冠状病毒药物的理想靶点。
人组织蛋白酶L属于溶酶体木瓜样蛋白酶家族半胱氨酸蛋白酶，其具有多种生物学功能，其作为靶标已被广泛应用于抗寄生虫感染药物研发领域，如锥虫感染导致的Chagas病。组织蛋白酶L在胞内首先以无活性的酶原形式存在，需要在胞内体或者溶酶体的酸性环境下自行剪切，或者通过其他蛋白酶活化才能形成具有催化活性的成熟酶。大量研究报道，人组织蛋白酶L与多种肿瘤的发生有着密切关系，且在心脏疾病中也发挥重要作用，此外，研究还发现人组织蛋白酶还参与病原微生物侵染宿主细胞。 越来越多证据表明人组织蛋白酶L可以作为药物靶标，用于抗肿瘤、心脏疾病以及抗感染类药物的研发。SARS-CoV-2的刺突蛋白(S蛋白)需要经宿主蛋白酶水解活化后才能介导病毒与宿主细胞发生膜融合进而促进病毒侵入宿主细胞，根据宿主蛋白酶作用阶段差异，病毒侵入途径可分为II型跨膜丝氨酸蛋白酶(TMPRSSII)介导的表面膜融合途径，人组织蛋白酶L(cathepsin L)介导的内吞膜融合途径，因此这些宿主蛋白酶均可作为冠状病毒侵入宿主细胞的进入抑制剂。抑制人组织蛋白酶L可以有效阻止病毒侵入宿主细胞，因此人组织蛋白酶L抑制剂是抗SARS-CoV-2研发的理想靶标，有望解决靶向病毒的抗病毒药物出现突变耐药的潜在风险和问题。
目前，针对2019-nCoV冠状病毒导致的严重肺炎疾病尚无特效的疫苗和抗病毒药物。这些感染性疾病严重影响了人们的生命健康，研发效果好的小分子抗病毒药物迫在眉睫。针对2019-nCoV冠状病毒3CL
pro和/或人组织蛋白酶L开发出结构新颖、低毒高效且具有自主知识产权的抗病毒药物，以满足国内外2019-nCoV冠状病毒感染患者的临床需求，具有重大的社会意义。
综上所述，本领域迫切需要开发针对2019-nCoV冠状病毒3CL蛋白酶的抑制剂和/或人组织蛋白酶L用于治疗新型冠状病毒感染引起的肺炎。
发明内容
本发明的目的是提供一种酮酰胺类化合物的新用途。
具体地，本发明提供了通式A所示的酮酰胺类化合物作为2019新型冠状病毒(2019-nCov)3CL蛋白酶抑制剂和/或人组织蛋白酶L抑制剂在制备治疗和/或预防、缓解由2019新型冠状病毒感染引起的呼吸道感染、肺炎等相关疾病的药物中的用途。
在本发明第一方面，提供了一种通式(A)所示的酮酰胺类化合物、或其药学上可接受的盐、对映异构体、非对映异构体或外消旋体的用途，用于制备(a)2019新型冠状病毒(2019-nCov)3CL蛋白酶抑制剂和/或人组织蛋白酶L抑制剂；和(b)治疗和/或预防、缓解由2019新型冠状病毒(2019-nCov)感染引起的相关疾病的药物：
其中，
*表示碳原子的立体化学异构分别独立地为R和/或S；
R
1和R
2各自独立地选自下组：氢、氘、氚、氨基、羟基、取代或未取代的C1-C10烷基、取代或未取代的C3-C10环烷基、取代或未取代的C3-C10环烷基C1-C10亚烷基、取代或未取代的C3-C10杂环烷基、取代或未取代的C3-C10杂环烷基C1-C10亚烷基、取代或未取代的C6-C20芳基、取代或未取代的C3-C20杂芳基、取代或未取代的C6-C20芳基C1-C10亚烷基、取代或未取代的C3-C20杂芳基C1-C10亚烷基、取代或未取代的C6-C20芳基C2-C10亚烯基、 取代或未取代的C3-C20杂芳基C2-C10亚烯基、酰基、磺酰基；
R
3选自下组：取代或未取代的C1-C10烷基、取代或未取代的C2-C10烯基、取代或未取代的C2-C10炔基、取代或未取代的C3-C8环烷基、取代或未取代的C3-C8环烷基C1-C10亚烷基、取代或未取代的C3-C8杂环烷基、取代或未取代的C3-C8杂环烷基C1-C10亚烷基、取代或未取代的C6-C20芳基、取代或未取代的C3-C20杂芳基、取代或未取代的C6-C20芳基C1-C10亚烷基、取代或未取代的C3-C20杂芳基C1-C10亚烷基、取代或未取代的C6-C20芳基C2-C6亚烯基、取代或未取代的C3-C20杂芳基C2-C6亚烯基、取代或未取代的C6-C20芳基C2-C6亚炔基、取代或未取代的C3-C20杂芳基C2-C6亚炔基；
R
4选自下组：取代或未取代的C1-C10烷基、取代或未取代的C2-C10烯基、取代或未取代的C2-C10炔基、取代或未取代的C3-C10环烷基、取代或未取代的C3-C10杂环烷基、取代或未取代的C6-C20芳基、取代或未取代的C3-C20杂芳基、取代或未取代的C6-C20芳基C1-C6亚烷基、取代或未取代的C6-C20芳基C2-C6亚烯基、取代或未取代的C6-C20芳基C2-C6亚炔基、取代或未取代的C3-C20杂芳基C1-C9亚烷基、取代或未取代的C3-C20杂芳基C2-C9亚烯基、取代或未取代的C3-C20杂芳基C2-C9亚炔基；
R
6选自下组：氢、氘、氚、氨基、羟基、取代或未取代的C1-C10烷基、取代或未取代的C3-C10环烷基、取代或未取代的C3-C10杂环烷基、取代或未取代的C6-C20芳基、取代或未取代的C3-C20杂芳基、取代或未取代的C6-C20芳基C1-C6亚烷基、取代或未取代的C6-C20芳基C2-C6亚烯基、取代或未取代的C3-C20杂芳基C1-C9亚烷基、取代或未取代的C3-C20杂芳基C2-C9亚烯基、酰基、磺酰基；
当-NR
5与其相邻的-(C＝O)-CH
2-成环时，R
5为-(CH
2)
n-，n为2或3；
当-NR
5不与其相邻的-(C＝O)-CH
2-成环时，R
5选自下组：氢、氘、氚、氨基、羟基、取代或未取代的C1-C10烷基、取代或未取代的C3-C10环烷基、取代或未取代的C3-C10杂环烷基、取代或未取代的C6-C20芳基、取代或未取代的C3-C20杂芳基、取代或未取代的C6-C20芳基C1-C6亚烷基、取代或未取代的C6-C20芳基C2-C6亚烯基、取代或未取代的C3-C20杂芳基C1-C9亚烷基、取代或未取代的C3-C20杂芳基C2-C9亚烯基、酰基、磺酰基；
其中，在R
1、R
2、R
3、R
4、R
5和R
6中，所述取代各自独立地指被选自下组的1、2、3或4个取代基取代：卤素、羟基、巯基、硝基、氰基、胺基、亚胺基、叔胺基、叠氮基、C1-C8烷基、卤代C1-C8烷基、C1-C8烷氧基、卤代C1-C8烷氧基、C1-C6烷基羰基、C1-C6烷硫基、C1-C8烷氧基羰基、三氟甲基；所述杂环烷基和所述杂芳基各自独立地包含1、2、3或4个选自N、O、S的杂原子。
在另一优选例中，当R
6为H时，-NR
5(或-NR
5R
6)可与其相邻的-(C＝O)-CH
2-成环(如5-6元杂环)或不成环。所述的5-6元杂环在环上含有1个N杂原子，其余的环原子为C。在另一优选例中，当-NR
5与其相邻的-(C＝O)-CH
2-成环时，R
5为取代或未取代的-(CH
2)
n-，n为2或3，其中，所述取代各自独立地指被选自下组的1、2、3或4个取代基取代：卤素、羟基、C1-C8烷基、C3-C8环烷基、卤代C1-C8烷基、C1-C8烷氧基、卤代C1-C8烷氧基、三氟甲基。
在另一优选例中，
部分为取代或未取代的5-6元杂环基，其中，所述取代各 自独立地指被选自下组的1、2、3或4个取代基取代：卤素、羟基、巯基、硝基、氰基、氧代基、胺基、亚胺基、叔胺基、叠氮基、C1-C8烷基、C3-C8环烷基、卤代C1-C8烷基、C1-C8烷氧基、卤代C1-C8烷氧基、C1-C6烷基羰基、C1-C6烷硫基、C1-C8烷氧基羰基、三氟甲基；优选地
部分为
其中，n1为1或2。
在另一优选例中，所述由2019新型冠状病毒感染引起的相关疾病选自下组：呼吸道感染、肺炎及其并发症、或其组合。
在另一优选例中，R
1和R
2各自独立地选自下组：氢、氘、氚、氨基、羟基、取代或未取代的C1-C6烷基、取代或未取代的C3-C8环烷基、取代或未取代的C3-C8环烷基C1-C5亚烷基、取代或未取代的C3-C10杂环烷基、取代或未取代的C3-C10杂环烷基C1-C5亚烷基、取代或未取代的C6-C14芳基、取代或未取代的C3-C10杂芳基、取代或未取代的C6-C14芳基C1-C5亚烷基、取代或未取代的C3-C10杂芳基C1-C5亚烷基、取代或未取代的C6-C10芳基C2-C5亚烯基、取代或未取代的C3-C10杂芳基C2-C5亚烯基、酰基、磺酰基；
R
3选自下组：取代或未取代的C1-C6烷基、取代或未取代的C2-C6烯基、取代或未取代的C2-C6炔基、取代或未取代的C3-C8环烷基、取代或未取代的C3-C8环烷基C1-C5亚烷基、取代或未取代的C3-C8杂环烷基、取代或未取代的C3-C8杂环烷基C1-C5亚烷基、取代或未取代的C6-C10芳基、取代或未取代的C3-C10杂芳基、取代或未取代的C6-C10芳基C1-C5亚烷基、取代或未取代的C3-C10杂芳基C1-C5亚烷基、取代或未取代的C6-C10芳基C2-C4亚烯基、取代或未取代的C3-C10杂芳基C2-C4亚烯基、取代或未取代的C6-C10芳基C2-C4亚炔基、取代或未取代的C3-C10杂芳基C2-C4亚炔基；
其中，在R
1、R
2和R
3中，所述取代各自独立地指被选自下组的1、2或3个取代基取代：卤素、羟基、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、C1-C4烷基羰基、C1-C4烷硫基、C1-C6烷氧基羰基、三氟甲基；所述杂环烷基和所述杂芳基各自独立地包含1或2个选自N、O、S的杂原子。
在另一优选例中，所述化合物为式AA所示的化合物，
其中，R
1、R
2、R
3、R
4、R
5和n如上文中所限定；
*表示碳原子的立体化学异构分别独立地为R和/或S。
在另一优选例中，R
4选自下组：含1、2或3个选自N、O、S的杂原子的9-10元杂芳环、含1、2或3个选自N、O、S的杂原子的5-6元杂芳环；上述基团为取代或未取代的；其中，所述取代指基团上的氢原子被1、2、3或4个选自下组的取代基取代：卤素、羟基、C1-C6烷基、卤代C1-C6烷基、C3-C6环烷基、卤代C3-C6环烷基、C1-C6烷氧基、卤代C1-C6烷氧 基、C1-C6烷硫基、卤代C1-C6烷硫基。
在另一优选例中，R
6选自下组：氢、氘、氚、氨基、羟基、取代或未取代的C1-C6烷基、取代或未取代的C3-C8环烷基、取代或未取代的C3-C10杂环烷基。
在另一优选例中，所述杂芳基是5、6、7、8、9或10元的饱和或部分饱和的杂芳环。
在另一优选例中，所述杂环烷基是5、6、7、8、9或10元的不饱和杂环。
在另一优选例中，R
4选自下组：
取代或未取代的喹喔啉基、取代或未取代的喹唑啉基、取代或未取代的噌啉基、
取代或未取代的吲哚基、取代或未取代的异吲哚基、
取代或未取代的1,3-苯并二噁茂基、
取代或未取代的苯并咪唑基、取代或未取代的吲唑基、
取代或未取代的咪唑[1,2-A]吡啶基、取代或未取代的咪唑[1,5-A]吡啶基、
取代或未取代的吡唑基、取代或未取代的咪唑基、取代或未取代的噻唑基、取代或未取代的噁唑基、取代或未取代的异噁唑基、取代或未取代的1，2，3-三唑基、取代或未取代的1，2-噻二唑基、取代或未取代的1，2，4-三嗪基、
取代或未取代的吡啶基、取代或未取代的吡咯基、取代或未取代的吡嗪基、取代或未取代的嘧啶基、
取代或未取代的3,8a二氢-2H-苯并吡喃基、取代或未取代的苯并吡喃基、
取代或未取代的喹啉基、取代或未取代的异喹啉基、
取代或未取代的苯并噁唑基、取代或未取代的苯并噻唑基、
取代或未取代的苯并噻吩基、
取代或未取代的苯并呋喃基；
其中，所述取代指基团上的氢原子被1、2或3个选自下组的取代基取代：F、Cl、Br、I、羟基、C1-C6烷基、卤代C1-C6烷基、C3-C6环烷基、卤代C3-C6环烷基、C1-C6烷氧基、卤代C1-C6烷氧基、C1-C6烷硫基、卤代C1-C6烷硫基。
在本文中，R
4为咪唑[1,2-A]吡啶对应本发明编号为A156至A161的化合物。
在本文中，“咪唑[1,2-A]吡啶”、“咪唑[1,2-a]吡啶”、“咪唑并[1,2-A]吡啶”和“咪唑并[1,2-a]吡啶”可互换使用。
在本文中，“咪唑[1,5-A]吡啶”、“咪唑[1,5-a]吡啶”、“咪唑并[1,5-A]吡啶”和“咪唑并[1,5-a]吡啶”可互换使用。
在本文中，R
4为3,8a二氢-2H-苯并吡喃对应本发明编号为A132至A137的化合物。
在另一优选例中，当R
6为H时，-NR
5可与其相邻的-(C＝O)-CH
2-成环(如5-6元杂环)或不成环。
在另一优选例中，当-NR
5(或-NR
5R
6)与其相邻的-(C＝O)-CH
2-成环时，R
5为-(CH
2)
n-，n为3；
当-NR
5(或-NR
5R
6)不与其相邻的-(C＝O)-CH
2-成环时，R
5选自下组：氢、氘、氚、羟基、取代或未取代的C1-C6烷基、取代或未取代的C3-C8环烷基、取代或未取代的C3-C8杂环烷基、取代或未取代的C6-C10芳基、取代或未取代的C3-C10杂芳基、取代或未取代的C6-C10 芳基C1-C4亚烷基、取代或未取代的C6-C10芳基C2-C4亚烯基、取代或未取代的C3-C10杂芳基C1-C4亚烷基、取代或未取代的C3-C10杂芳基C2-C4亚烯基；
其中，所述取代各自独立地指被选自下组的1、2或3个取代基取代：F、Cl、Br、I、羟基、C1-C6烷基、C1-C6烷氧基、C1-C6烷硫基；所述杂环烷基和所述杂芳基各自独立地包含1、2或3个选自N、O、S的杂原子。
在另一优选例中，所述R1、R2、R3、R4、R5和R6各自独立地为实施例中具体化合物(A1-A310)中对应的基团。
在另一优选例中，所述通式(A)化合物选自下组：
在本发明第二方面，提供了一种药物组合物，其包括(a)治疗有效量的通式(A)所示的酮酰胺类化合物、或其药学上可接受的盐、对映异构体、非对映异构体或外消旋体或前 药，和(b)药学上可接受的载体，其中，通式(A)所示的酮酰胺类化合物如本发明第一方面中所述。
在本发明第三方面，提供了本发明第二方面所述的药物组合物的用途，它用于制备治疗和/或预防、缓解由2019新型冠状病毒(2019-nCov)感染引起的相关疾病的药物。
在另一优选例中，所述由2019新型冠状病毒感染引起的相关疾病选自下组：呼吸道感染、肺炎及其并发症、或其组合。
在本发明的第四方面，提供了一种治疗、预防、和/或缓解由2019新型冠状病毒(2019-nCov)感染引起的相关疾病的方法，包括步骤：给需要的对象施用安全有效量的通式(A)所示的酮酰胺类化合物、或其药学上可接受的盐、对映异构体、非对映异构体或外消旋体，其中所述的通式(A)所示的酮酰胺类化合物如上所述。
在另一优选例中，所述的对象为灵长目哺乳动物，如人。
在本发明的第五方面，提供了一种抑制2019新型冠状病毒(2019-nCov)的3CL蛋白酶的活性的方法，包括步骤：将通式(A)所示的酮酰胺类化合物、或其药学上可接受的盐、对映异构体、非对映异构体或外消旋体与2019-nCov的3CL蛋白酶和/或人组织蛋白酶L接触，从而抑制2019-nCov的3CL蛋白酶和/或人组织蛋白酶L的活性。
在另一优选例中，所述的方法是非治疗性和非诊断性的。
在另一优选例中，所述的方法是体外的。
在另一优选例中，所述的2019-nCov的3CL蛋白酶是重组的或2019-nCov表达的3CL蛋白酶。
本发明第六方面，提供了一种第一方面所述的式(A)化合物、或其药学上可接受的盐、对映异构体、非对映异构体或外消旋体，
其中，
*表示碳原子的立体化学异构分别独立地为R和/或S；
R
1和R
2各自独立地选自下组：氢、氘、氚、氨基、羟基、取代或未取代的C1-C10烷基、取代或未取代的C3-C10环烷基、取代或未取代的C3-C10环烷基C1-C10亚烷基、取代或未取代的C3-C10杂环烷基、取代或未取代的C3-C10杂环烷基C1-C10亚烷基、取代或未取代的C6-C20芳基、取代或未取代的C3-C20杂芳基、取代或未取代的C6-C20芳基C1-C10亚烷基、取代或未取代的C3-C20杂芳基C1-C10亚烷基、取代或未取代的C6-C20芳基C2-C10亚烯基、取代或未取代的C3-C20杂芳基C2-C10亚烯基、酰基、磺酰基；
R
3选自下组：取代或未取代的C1-C10烷基、取代或未取代的C2-C10烯基、取代或未取代的C2-C10炔基、取代或未取代的C3-C8环烷基、取代或未取代的C3-C8环烷基C1-C10亚烷基、取代或未取代的C3-C8杂环烷基、取代或未取代的C3-C8杂环烷基C1-C10亚烷基、取代 或未取代的C6-C20芳基、取代或未取代的C3-C20杂芳基、取代或未取代的C6-C20芳基C1-C10亚烷基、取代或未取代的C3-C20杂芳基C1-C10亚烷基、取代或未取代的C6-C20芳基C2-C6亚烯基、取代或未取代的C3-C20杂芳基C2-C6亚烯基、取代或未取代的C6-C20芳基C2-C6亚炔基、取代或未取代的C3-C20杂芳基C2-C6亚炔基；
R
4选自下组：取代或未取代的C1-C10烷基、取代或未取代的C2-C10烯基、取代或未取代的C2-C10炔基、取代或未取代的C3-C10环烷基、取代或未取代的C3-C10杂环烷基、取代或未取代的C6-C20芳基、取代或未取代的C3-C20杂芳基、取代或未取代的C6-C20芳基C1-C6亚烷基、取代或未取代的C6-C20芳基C2-C6亚烯基、取代或未取代的C6-C20芳基C2-C6亚炔基、取代或未取代的C3-C20杂芳基C1-C9亚烷基、取代或未取代的C3-C20杂芳基C2-C9亚烯基、取代或未取代的C3-C20杂芳基C2-C9亚炔基；
R
6选自下组：氢、氘、氚、氨基、羟基、取代或未取代的C1-C10烷基、取代或未取代的C3-C10环烷基、取代或未取代的C3-C10杂环烷基、取代或未取代的C6-C20芳基、取代或未取代的C3-C20杂芳基、取代或未取代的C6-C20芳基C1-C6亚烷基、取代或未取代的C6-C20芳基C2-C6亚烯基、取代或未取代的C3-C20杂芳基C1-C9亚烷基、取代或未取代的C3-C20杂芳基C2-C9亚烯基、酰基、磺酰基；
当-NR
5与其相邻的-(C＝O)-CH
2-成环时，R
5为-(CH
2)
n-，n为2或3；
当-NR
5不与其相邻的-(C＝O)-CH
2-成环时，R
5选自下组：氢、氘、氚、氨基、羟基、取代或未取代的C1-C10烷基、取代或未取代的C3-C10环烷基、取代或未取代的C3-C10杂环烷基、取代或未取代的C6-C20芳基、取代或未取代的C3-C20杂芳基、取代或未取代的C6-C20芳基C1-C6亚烷基、取代或未取代的C6-C20芳基C2-C6亚烯基、取代或未取代的C3-C20杂芳基C1-C9亚烷基、取代或未取代的C3-C20杂芳基C2-C9亚烯基、酰基、磺酰基；
其中，在R
1、R
2、R
3、R
4、R
5和R
6中，所述取代各自独立地指被选自下组的1、2、3或4个取代基取代：卤素、羟基、巯基、硝基、氰基、胺基、亚胺基、叔胺基、叠氮基、C1-C8烷基、卤代C1-C8烷基、C1-C8烷氧基、卤代C1-C8烷氧基、C1-C6烷基羰基、C1-C6烷硫基、C1-C8烷氧基羰基、三氟甲基；所述杂环烷基和所述杂芳基各自独立地包含1、2、3或4个选自N、O、S的杂原子。
在另一优选例中，所述化合物为式AA所示的化合物，
其中，R
1、R
2、R
3、R
4、R
5和n如上文中所限定；
*表示碳原子的立体化学异构分别独立地为R和/或S。
在另一优选例中，所述化合物为化合物A254-A310(即实施例254-310)。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。
图1显示了本发明化合物可抑制2019nCoV病毒的复制。
图2显示了本发明部分化合物抑制2019新型冠状病毒(2019-nCov)的抑制曲线和EC50值。
本发明人经过广泛而深入的研究，通过大量筛选，首次意外地开发了一类可有效抑制2019新型冠状病毒(2019-nCov)的活性成分，即通式A所示的化合物或其药学上可接受的盐、对映异构体、非对映异构体或外消旋体。试验表明，本发明的活性成分可高效地抑制2019新型冠状病毒(2019-nCov)的3CL蛋白酶和/或人组织蛋白酶L的活性，从而抑制2019-nCov的复制和活力。在此基础上完成了本发明。
术语
如本文所用，术语“新型冠状病毒”、“2019-nCov”或“SARS-CoV-2”可互换使用，该新型冠状病毒是已知感染人的第7种冠状病毒，并且造成新冠肺炎(COVID-19)，是威胁全球人类健康的严重传染性疾病之一。此外，该术语还包括野生型和突变型病毒株。
在本文中，除特别说明之处，术语“取代”指基团上的一个或多个氢原子被选自下组的取代基取代：C
1～C
10烷基、C
3～C
10环烷基、C
1～C
10烷氧基、卤素、羟基、羧基(-COOH)、C
1～C
10醛基、C
2～C
10酰基、C
2～C
10酯基、氨基、苯基；所述的苯基包括未取代的苯基或具有1-3个取代基的取代苯基，所述取代基选自：卤素、C
1-C
10烷基、氰基、OH、硝基、C
3～C
10环烷基、C
1～C
10烷氧基、氨基。
除特别说明之处，本发明的所有化合物之中，各手性碳原子可以任选地为R构型或S构型，或R构型和S构型的混合物。
术语“C1～C6烷基”指具有1～6个碳原子的直链或支链烷基，例如甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、或类似基团。
术语“3-8元杂环基”指具有选自下组的1-3个杂原子的3～8元饱和环失去一个氢原子形成的基团：N、S、O；例如吡咯烷基、哌啶基、哌嗪基、吗啉基、或类似基团。
术语“6-10元芳基”指6～10元芳基失去一个氢原子形成的基团；例如苯基、萘基，或类似基团。
术语“5-10元杂芳基”指具有选自下组的1-3个杂原子的5～8元芳基失去一个氢原子形成的基团：N、S、O，其中每个杂芳基的环状体系可以是单环或多环的；例如吡咯基、吡啶基、噻吩基、呋喃基、咪唑基、嘧啶基、苯并噻吩基、吲哚基、咪唑并吡啶基、喹啉基或类似基团。
术语“C1～C6烷氧基”指具有1-6个碳原子的直链或支链烷氧基，例如甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、仲丁氧基、叔丁氧基、或类似基团。
术语“C2-C6酯基”指具有2-6个碳原子的R-O-C(＝O)-基团，如-COOCH
3、-COOC
2H
5、 -COOC
3H
7、-COOC
4H
9，或类似基团。
术语“C2-C6烯基”指具有2-6个碳原子的烯烃失去一个或两个氢原子所形成的基团，所述的烯烃可以是单烯烃、二烯烃或三烯烃，例如-CH＝CH
2、-C
2H
4＝CH
2、-CH＝C
2H
4，或类似基团。
术语“卤素”指F、Cl、Br和I。
除非特别说明，本发明所描述的结构式意在包括所有的同分异构形式(如对映异构，非对映异构和几何异构体(或构象异构体)：例如含有不对称中心的R、S构型，双键的(Z)、(E)异构体和(Z)、(E)的构象异构体。因此本发明的化合物的单个立体化学异构体或其对映异构体、非对映异构体或几何异构体(或构象异构体)的混合物都属于本发明的范围。
术语“互变异构体”表示具有不同能量的结构同分异构体可以超过低能垒，从而互相转化。比如，质子互变异构体(即质子移变)包括通过质子迁移进行互变，如1H-吲唑与2H-吲唑、1H-苯并[d]咪唑与3H-苯并[d]咪唑，化合价互变异构体包括通过一些成键电子重组而进行互变。
在本文中，形如“C1～C6”，表示该基团可以具有1个至6个碳原子，例如1个、2个、3个、4个或5个。
活性成分
在本发明中，提供了一种可有效抑制2019新型冠状病毒(2019-nCov)复制的活性成分。该活性成分为通式A所示的化合物，该活性成分可有效预防、治疗和/或缓解2019-nCov相关疾病。
试验表明，本发明的活性成分可有效地抑制2019新型冠状病毒(2019-nCov)的3CL蛋白酶和/或人组织蛋白酶L，从而抑制2019新型冠状病毒(2019-nCov)的复制，进而预防、治疗和/或缓解2019-nCov相关疾病。
应理解，本发明的活性成分包括通式(A)所示的酮酰胺类化合物、或其药学上可接受的盐、对映异构体、非对映异构体或外消旋体、或其前药。应理解，本发明的活性成分还包括通式(A)化合物的晶型、无定形化合物、以及氘代化合物等形式。
所述“药学上可接受的盐”为通式(A)化合物与无机酸或有机酸反应形成常规的无毒盐。例如，常规的无毒盐可通过通式(A)化合物与无机酸或有机酸反应制得，所述无机酸包括盐酸、氢溴酸、硫酸、硝酸、胺基磺酸和磷酸等，所述有机酸包括柠檬酸、酒石酸、乳酸、丙酮酸、乙酸、苯磺酸、对甲苯磺酸、甲磺酸、萘磺酸、乙磺酸、萘二磺酸、马来酸、苹果酸、丙二酸、富马酸、琥珀酸、丙酸、草酸、三氟乙酸、硬酯酸、扑酸、羟基马来酸、苯乙酸、苯甲酸、水杨酸、谷氨酸、抗坏血酸、对胺基苯磺酸、2-乙酰氧基苯甲酸和羟乙磺酸等；或者通式(A)化合物与丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、天冬氨酸或谷氨酸形成酯后再与无机碱形成的钠盐、钾盐、钙盐、铝盐或铵盐；或者通式(A)化合物与有机碱形成的甲胺盐、乙胺盐或乙醇胺盐；或者通式(A)化合物与赖氨酸、精氨酸、鸟氨酸形成酯后再与盐酸、氢溴酸、氢氟酸、硫酸、硝酸或磷酸形成的对应的无机酸盐或与甲酸、乙酸、苦味酸、甲磺酸或乙磺酸形成的 对应的有机酸盐。
药物组合物和应用
本发明还提供了以通式(A)所示的酮酰胺类化合物、或其药学上可接受的盐、对映异构体、非对映异构体或外消旋体及前药中的一种或多种的混合物为有效成分在制备治疗和/或预防、缓解由2019新型冠状病毒感染引起的呼吸道感染、肺炎等相关疾病的药物中的用途。
本发明所提供的药物组合物优选含有重量比为0.001-99wt％的活性成份，优选的比例是通式A化合物作为活性成分占总重量的0.1wt％～90wt％，其余部分为药学可接受的载体、稀释液或溶液或盐溶液。
需要的时候，在本发明药物中还可以加入一种或多种药学上可接受的载体。所述载体包括药学领域常规的稀释剂、赋形剂、填充剂、粘合剂、润湿剂、崩解剂、吸收促进剂、表面活性剂、吸附载体、润滑剂等。
本发明所提供的化合物和药物组合物可以是多种形式，如片剂、胶囊、粉剂、糖浆、溶液状、悬浮液和气雾剂等，并可以存在于适宜的固体或液体的载体或稀释液中和适宜的用于注射或滴注的消毒器具中。
本发明的药物组合物的各种剂型可按照药学领域的常规制备方法制备。其制剂配方的单位计量中通常包含0.05-400mg通式A化合物，优选地，制剂配方的单位计量中包含1mg-500mg通式A化合物。
本发明的化合物和药物组合物可对哺乳动物临床使用，包括人和动物，可以通过口、鼻、皮肤、肺或者胃肠道等的给药途径。最优选为口服。最优选日剂量为0.01-400mg/kg体重，一次性服用，或0.01-200mg/kg体重分次服用。不管用何种服用方法，个人的最佳剂量应依据具体的治疗而定。通常情况下是从小剂量开始，逐渐增加剂量一直到找到最适合的剂量。
本发明的药物或抑制剂可通过各种不同方式施用，例如可通过注射、喷射、滴鼻、滴眼、渗透、吸收、物理或化学介导的方法导入机体如肌肉、皮内、皮下、静脉、粘膜组织；或是被其他物质混合或包裹导入机体。
本发明的主要优点包括：
(a)本发明化合物可高效地抑制2019-nCoV 3CL蛋白酶，部分化合物的IC
50值达到约2.4μM。
(b)本发明化合物可高效地抑制人组织蛋白酶L，部分化合物的IC
50值达到约0.45nM。
(c)本发明化合物在病毒水平上对2019-nCoV的抑制率优于阳性对照CQ，展现出较好的抗2019-nCoV潜力，部分化合物的EC
50值达到约0.3μM。
(d)本发明化合物的毒副作用低，成药性好。
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。
样品的分析数据由以下仪器测定：核磁共振由GEMINI-300型、Bruker AMX-400型和INVOA-600型核磁共振仪测定，TMS(四甲基硅烷)为内标，化学位移单位为ppm，耦合常数单位为Hz；质谱由Finnigan MAT-711型，MAT-95和LCQ-DECA型质谱仪以及IonSpec 4.7Tesla质谱仪测定。
柱层析用硅胶200-300目(青岛海洋化工厂生产)；TLC硅胶板为烟台化工厂生产的HSGF-254型薄层层析预制板；石油醚沸程为60-90℃；采用紫外灯，碘缸显色。除另有说明外，以下实施例中所用常规试剂、药品均购自国药集团。实验中所用试剂及溶剂均按反应具体情况处理。
实施例1化合物A1
化合物1-2的合成：
氩气保护下，将N-叔丁氧羰基-L-谷氨酸二甲酯(1-1)(6g，21.8mmol)溶于60mL无水四氢呋喃中，于-78℃条件下缓慢滴LiHMDS(1M in THF)的四氢呋喃溶液(47mL,47mmol)，滴加过程保持温度稳定在-78℃，约持续1小时。滴毕后在-78℃条件搅拌1小时。将溴乙腈(2.79g，23.3mmol)溶于20ml四氢呋喃中，随后将该溶液缓慢滴入到反应体系中，滴加过程持续1～2小时。控温-78℃，继续反应3小时。TLC监测(碱性高锰酸钾显色)反应完毕后，向反应液中加入NH4Cl溶液淬灭反应，搅拌10min后升至室温。倾 入40mL饱和氯化钠溶液充分搅拌，可见反应体系分层。分离有机层，并用乙酸乙酯(EA)萃取水相，合并有机层后用无水硫酸钠干燥，浓缩，柱层析(Flash,PE:EA＝1:5)得到淡黄色油状物1-2 3.9g，收率为58％。
化合物1-3的合成：
将1-2(1g，3.15mmol)溶于无水甲醇25mL，冰浴下搅拌至0℃后加入六水合二氯化钴(450mg，1.89mmol)。10min后分次少量加入硼氢化钠(715mg，18.9mmol)，反应液继续在冰浴下反应1h后转为室温反应。15h后用饱和NH4Cl溶液5mL淬灭后继续搅拌10min，利用滤除固体后将滤液蒸干，用水20mL和乙酸乙酯30×3mL萃取，合并有机相，以无水Na
2SO
4干燥1h后减压浓缩，柱层析分离[PE:EA＝1:2]得到白色粉末状固体460mg，产率51％。
化合物1-4的合成：
将化合物1-3(2.6g)溶于三氟乙酸的二氯甲烷溶液(1/1,v/v)中，室温搅拌1小时，浓缩后加入二氯甲烷100ml，饱和碳酸钠溶液洗，有机层用无水硫酸钠干燥，浓缩得油状物1-4(2.7g)，收率99％。
化合物1-5的合成：
将Boc-环己基丙氨酸(1.26g,5mmol)和EDCI(1.36g,6mmol)、HOBt(0.822g,6mmol)加入到80ml二氯甲烷溶液中，室温搅拌30min。随后加入化合物1-4(0.896g,5mmol)，滴入1.2当量的三乙胺，室温下搅拌。TLC监测(紫外)反应完全后采用二氯甲烷萃取，经稀盐酸、饱和碳酸氢钠溶液和饱和氯化钠洗涤后，合并有机层无水硫酸钠干燥，浓缩后得白色粘稠状固体1.2g，产率60％。
化合物1-6的合成：
将化合物1-5(2.5g)溶于三氟乙酸的二氯甲烷溶液(1/1,v/v)中，室温搅拌1小时，浓缩后加入二氯甲烷100ml，饱和碳酸钠溶液洗，有机层用无水硫酸钠干燥，浓缩得油状物1-6(2.61g)，收率99％。
化合物1-7的合成：
将吲哚2-甲酸(0.795g,5mmol)和EDCI(1.36g,6mmol)、HOBt(0.822g,6mmol)加入到80ml二氯甲烷溶液中，室温搅拌30min。随后加入化合物1-6(2.2g,5mmol)，滴入1.2当量的三乙胺，室温下搅拌。TLC监测(紫外)反应完全后采用二氯甲烷萃取，经稀盐酸、饱和碳酸氢钠溶液和饱和氯化钠洗涤后，合并有机层无水硫酸钠干燥，浓缩后得白色粘稠状固体1.3g，产率60％。
化合物1-8的合成：
将1-7(243mg,0.51mmol)溶于20ml甲醇中，分批缓慢加入硼氢化钠(107mg,2.9mmol)，室温下搅拌约2小时反应完全。待反应完毕后，加入约20ml饱和食盐水淬灭反应，浓缩反应体系甲醇后，加入二氯甲烷萃取。有机相经饱和食盐水洗涤、无水硫酸钠干燥后，浓缩得到白色固体物质1-8，可直接用于下步反应。
化合物1-9的合成：
将中间体1-8(129mg,0.29mmol)溶于20ml二氯甲烷溶于中，加入戴斯-马汀氧化 剂(147mg,0.35mmol)和碳酸氢钠固体(29mg,0.35mmol)，在室温下搅拌。TLC监测(紫外)反应完全后，抽滤反应体系，所得滤液用饱和碳酸氢钠溶于萃取，有机层经饱和食盐
水洗涤，无水硫酸钠干燥后浓缩。经快速柱色谱(CH2Cl2:MeOH＝20:1)分离纯化，得到白色固体粉末化合物1共77mg，产率60％。
化合物1-10的合成：
将化合物1-9(129mg,0.29mmol)溶解在二氯甲烷溶剂中，加入醋酸(19.2mg，0.32mmol)和苄基异氰(37.6mg，0.32mmol)反应，得到化合物1-10，经快速柱色谱(CH
2Cl
2:MeOH＝20:1)分离纯化，得到白色固体粉末化合物1-10共126mg，产率70％。
化合物1-11的合成：
将化合物1-10(187mg,0.3mmol)溶解在甲醇溶剂中，加入LiOH(0.6mmol)搅拌，得到化合物1-11，经快速柱色谱(CH
2Cl
2:MeOH＝20:1)分离纯化，得到白色固体粉末化合物1-11共148mg，产率85％。
化合物1-12的合成：
将化合物1-11(174mg,0.3mmol)溶解在二氯甲烷溶剂中，加入Dess-Martin氧化剂(152mg,0.36mmol)，加入碳酸氢钠(30mg,0.36mmol)，搅拌，得化合物白色固体粉末化合物1-12共140mg，产率80％.
1H NMR(500MHz,Chloroform)δ9.76(s,1H),7.73(s,1H),7.39(s,1H),7.32–7.26(m,2H),7.22(s,1H),7.20–7.10(m,3H),7.01(s,1H),6.82(s,1H),6.68(s,1H),6.14(s,1H),5.57(s,1H),5.43(s,1H),4.38(s,1H),4.32(d,J＝19.2Hz,2H),3.45(s,1H),3.35(s,1H),3.06(s,1H),2.20(dd,J＝15.4,2.3Hz,4H),2.12–2.03(m,2H),1.92(s,1H),1.77(s,1H),1.73–1.67(m,3H),1.66–1.53(m,6H),1.37(s,1H).；
使用与实施例1相似的方法合成实施例2-310。
实施例2 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-1H-吲哚-2-羧酰胺(A2)
1H NMR(500MHz,Chloroform)δ8.38(s,1H),7.51(d,J＝18.0Hz,2H),7.38(s,1H),7.12(s,1H),7.06(s,1H),6.26(s,1H),6.04(s,1H),5.80(s,1H),5.25(s,1H),4.81(s,1H),4.67(s,1H),3.45(s,1H),3.35(s,1H),2.55(s,1H),2.18(s,1H),2.09–2.05(m,2H),1.96–1.91(m,3H),1.73–1.52(m,5H),1.40–1.36(m,2H),1.35–1.29(m,10H),1.20–1.09(m,3H).
实施例3 N-((S)-3-环己基-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-1H-吲哚-2-羧酰胺(A3)
1H NMR(500MHz,Chloroform)δ8.28(s,1H),7.48(d,J＝1.2Hz,2H),7.34(s,1H),7.10(d,J＝1.0Hz,2H),7.03(s,1H),6.05(s,1H),5.59(s,1H),5.30(s,1H),4.63(s,1H),4.45(s,1H),3.58(s,1H),3.45(s,1H),3.35(s,1H),2.95(s,1H),2.18(s,1H),2.09–2.05(m,2H),1.98–1.90(m,3H),1.73–1.67 (m,3H),1.65–1.61(m,2H),1.51(dtd,J＝12.9,8.9,1.3Hz,13H),1.45–1.39(m,3H),1.38–1.34(m,2H).
实施例4 N-((S)-3-环己基-1-(((S)-4-(新戊基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-1H-吲哚-2-羧酰胺(A4)
1H NMR(500MHz,Chloroform)δ8.46(s,1H),7.53(d,J＝3.4Hz,2H),7.40(d,J＝17.1Hz,2H),7.12(s,1H),7.06(s,1H),6.16(d,J＝14.3Hz,2H),5.65(s,1H),5.23(s,1H),4.44(s,1H),3.44(d,J＝11.4Hz,2H),3.35(s,1H),3.09(s,1H),2.97(s,1H),2.19(s,1H),2.09–2.05(m,2H),1.92(s,1H),1.75–1.68(m,4H),1.62(s,1H),1.48(dt,J＝16.0,8.0Hz,5H),1.37–1.31(m,2H),1.28(s,1H),1.09–1.05(m,9H).
实施例5 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-1H-吲哚-2-羧酰胺(A5)
1H NMR(500MHz,Chloroform)δ8.22(s,1H),7.96(s,1H),7.53(s,1H),7.42(s,1H),7.38(s,1H),7.29–7.24(m,4H),7.17(d,J＝29.6Hz,2H),7.07(s,1H),6.54(s,1H),5.74(s,1H),5.27(s,1H),5.06(s,1H),4.49(s,1H),4.41(s,1H),4.31(s,1H),3.24(d,J＝17.4Hz,2H),2.56(s,1H),2.08–2.04(m,2H),1.95–1.88(m,2H),1.78(d,J＝6.9Hz,2H),1.69(dt,J＝6.3,3.5Hz,7H),1.51(s,1H),1.40–1.36(m,2H),1.32(s,1H),1.15–1.11(m,2H),1.08(s,1H).
实施例6 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-1H-吲哚-2-羧酰胺(A6)
1H NMR(500MHz,Chloroform)δ8.30(s,2H),7.48(s,2H),7.43(s,2H),7.35(s,2H),7.10(s,2H),7.03(s,2H),6.45(s,2H),5.99(s,2H),5.76(s,2H),5.25(s,2H),4.81(s,2H),4.29(s,2H),3.24(d,J＝17.1Hz,4H),2.75(s,2H),2.05(t,J＝8.9Hz,6H),1.79(s,2H),1.71(t,J＝2.5Hz,7H),1.58–1.54(m,3H),1.51–1.33(m,10H),1.33–1.29(m,20H),1.23(s,2H),1.15–1.11(m,3H),0.94–0.90(m,3H
)..
实施例7 N-((S)-3-环己基-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-1H-吲哚-2-羧酰胺(A7)
1H NMR(500MHz,Chloroform)δ9.29(s,1H),8.69(s,1H),7.52(s,1H),7.43(d,J＝15.1Hz,2H),7.13(s,1H),7.06(s,1H),5.93(s,1H),5.59(d,J＝3.5Hz,2H),5.11(s,1H),4.51(s,1H),3.41(s,1H),3.24(d,J＝16.6Hz,2H),2.66(s,1H),2.54(s,1H),2.08–2.04(m,2H),2.01–1.89(m,2H),1.89–1.77(m,4H),1.73–1.61(m,7H),1.55–1.50(m,3H),1.48(s,1H),1.44–1.39(m,2H),1.39–1.35(m,2H),1.31(s,1H),1.09–0.99(m,3H).
实施例8 N-((S)-3-环己基-1-(((S)-4-(新戊基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-1H-吲哚-2-羧酰胺(A8)
1H NMR(500MHz,Chloroform)δ8.45(s,4H),7.50(d,J＝31.7Hz,8H), 7.46–7.46(m,1H),7.39(s,5H),7.13(s,4H),7.06(s,4H),6.01(s,4H),5.44(s,4H),5.40(s,4H),5.23(s,4H),4.89(s,4H),4.47(s,4H),3.30–3.20(m,12H),3.13(s,4H),2.30(s,4H),2.10–2.02(m,8H),1.97(s,3H),1.81–1.76(m,11H),1.71(t,J＝1.6Hz,11H),1.69–1.63(m,13H),1.50(s,3H),1.39–1.35(m,7H),1.31(s,4H),1.14–1.05(m,44H),1.02(s,3H).
实施例9 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-苯并呋喃-2-羧酰胺(A9)
1H NMR(500MHz,Chloroform)δ7.66(s,1H),7.34–7.28(m,5H),7.22(d,J＝7.1Hz,2H),7.10(s,1H),6.72(s,1H),6.17(s,1H),5.97(s,1H),5.84(s,1H),5.47(s,1H),4.42(s,1H),4.34(d,J＝9.3Hz,2H),3.45(s,1H),3.35(s,1H),3.22(s,1H),2.64(s,1H),2.18(s,1H),2.09–2.05(m,2H),2.05–1.98(m,2H),1.92(s,1H),1.75–1.66(m,4H),1.66–1.55(m,6H),1.36(s,1H).
实施例10 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-苯并呋喃-2-羧酰胺(A10)
1H NMR(500MHz,Chloroform)δ9.59(s,1H),8.31(s,1H),7.63(s,1H),7.50(s,1H),7.41(s,1H),7.22(s,1H),7.16(s,1H),6.40(s,1H),5.82(s,1H),4.81(s,1H),4.64(s,1H),3.97(s,1H),3.35(s,1H),2.69(s,1H),2.19(s,1H),2.09–2.05(m,2H),1.94–1.88(m,3H),1.76–1.66(m,2H),1.66–1.48(m,3H),1.36–1.32(m,11H),1.28(s,1H),1.20(s,1H),0.99–0.95(m,2H).
实施例11 N-((S)-3-环己基-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-苯并呋喃-2-羧酰胺(A11)
1H NMR(500MHz,Chloroform)δ7.63(s,4H),7.47(s,4H),7.36(s,4H),7.26(s,4H),7.21(s,4H),7.14(s,4H),5.98(s,4H),5.77(s,4H),5.16(s,4H),4.60(s,4H),4.32(s,4H),3.53(s,3H),3.45(s,4H),3.35(s,3H),2.58(s,3H),2.19(s,3H),2.09–2.05(m,8H),1.95–1.88(m,11H),1.74–1.68(m,27H),1.65–1.61(m,6H),1.61–1.47(m,31H),1.44–1.39(m,8H),1.35–1.31(m,6H),1.24(s,3H).
实施例12 N-((S)-3-环己基-1-(((S)-4-(新戊基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-苯并呋喃-2-羧酰胺(A12)
1H NMR(500MHz,Chloroform)δ8.31(s,4H),7.60(s,4H),7.49(s,4H),7.40(s,4H),7.21(s,4H),7.15(s,4H),6.18(s,4H),5.46(s,4H),5.25(s,4H),5.12(s,4H),4.63(s,4H),3.43(d,J＝18.9Hz,8H),3.35(s,3H),3.11(s,4H),2.76(s,4H),2.17(s,3H),2.13–2.01(m,8H),1.93(s,4H),1.85–1.81(m,6H),1.73–1.69(m,7H),1.69–1.62(m,7H),1.61–1.42(m,16H),1.33–1.29(m,6H),1.26(s,3H),1.14–1.10(m,3H).
实施例13 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-苯并呋喃-2-羧酰胺(A13)
1H NMR(500MHz,Chloroform)δ7.59(s,4H),7.51(d,J＝1.4Hz,1H),7.46(d,J＝36.6Hz,7H),7.32–7.14(m,29H),6.56(s,4H),5.75(s,4H),5.66(s,4H),5.09(s,4H),4.56(s,4H),4.41(s,4H),4.32(s,4H),3.24(d,J＝17.0Hz,8H),2.32(s,4H),2.10–2.02(m,9H),1.99(s,4H),1.97–1.89(m,8H),1.79(s,4H),1.75–1.52(m,28H),1.40–1.36(m,7H),1.32(s,4H),1.23–1.19(m,8H),1.16(s,3H).
实施例14 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-苯并呋喃-2-羧酰胺(A14)
1H NMR(500MHz,Chloroform)δ7.63(s,1H),7.50(s,1H),7.37(s,1H),7.22(s,1H),7.16(s,1H),6.25(s,1H),6.08(s,1H),5.76(s,1H),4.70(d,J＝19.7Hz,2H),3.24(d,J＝14.7Hz,2H),2.83(s,1H),2.08–2.04(m,2H),2.01(s,1H),1.90(s,1H),1.85–1.78(m,3H),1.75–1.64(m,5H),1.56–1.41(m,6H),1.32(s,1H),1.25–1.21(m,9H).
实施例15 N-((S)-3-环己基-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-苯并呋喃-2-羧酰胺(A15)
1H NMR(500MHz,Chloroform)δ9.45(s,1H),8.16(s,1H),7.51(s,1H),7.42(s,1H),7.22(s,1H),7.16(s,1H),6.16(s,1H),6.07(s,1H),5.85(s,1H),5.08(s,1H),4.48(s,1H),3.32(s,1H),3.24(d,J＝16.1Hz,2H),2.92(s,1H),2.16–2.08(m,2H),2.08–2.04(m,2H),2.02(s,1H),1.80(s,1H),1.76–1.66(m,8H),1.65(s,1H),1.57(s,1H),1.55–1.40(m,8H),1.40–1.37(m,1H),1.31(s,1H),1.12(s,1H),0.90–0.82(m,2H).
实施例16 N-((S)-3-环己基-1-(((S)-4-(新戊基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-苯并呋喃-2-羧酰胺(A16)
1 1H NMR(500MHz,Chloroform)δ7.60(s,1H),7.49(s,1H),7.40(s,1H),7.21(s,1H),7.15(s,1H),6.20(s,1H),5.99(s,1H),5.91(s,1H),5.65(s,1H),4.86(s,1H),4.76(s,1H),3.30(s,1H),3.24(d,J＝17.4Hz,2H),2.92(s,1H),2.65(s,1H),2.08–2.04(m,2H),2.01(s,1H),1.90–1.84(m,2H),1.82(s,1H),1.77–1.65(m,5H),1.60–1.53(m,4H),1.52–1.48(m,2H),1.40(s,1H),1.34(s,1H),1.07–1.03(m,9H).
实施例17 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-苯并噻吩-2-羧酰胺(A17)
1H NMR(500MHz,Chloroform)δ8.13(s,5H),7.89(s,5H),7.65(s,5H),7.28(dd,J＝7.5,4.2Hz,20H),7.21(dd,J＝4.2,2.6Hz,2H),7.20–7.08(m,13H),6.14(s,5H),5.53(s,5H),5.37(s,5H),4.39–4.32(m,15H),4.24(s,5H),3.45(s,5H),3.35(s,4H),3.24(s,5H),2.94(s,4H),2.19(s,4H),2.09–2.05(m,10H),1.92(s,4H),1.80–1.67(m,25H),1.59–1.49(m,15H),1.46–1.38(m,19H),1.23(s,5H).
实施例18 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-苯并噻吩-2-羧酰胺(A18)
1H NMR(500MHz,Chloroform)δ8.37(s,1H),7.89(s,1H),7.73(s,1H),7.31(d,J＝1.5Hz,2H),6.28(s,1H),6.05(s,1H),5.80(s,1H),5.25(s,1H),4.82(s,1H),4.68(s,1H),3.45(s,1H),3.35(s,1H),2.56(s,1H),2.18(s,1H),2.09–2.05(m,2H),1.95–1.88(m,3H),1.73–1.52(m,5H),1.41–1.37(m,2H),1.35–1.29(m,10H),1.18–1.09(m,3H).
实施例19 N-((S)-3-环己基-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-苯并噻吩-2-羧酰胺(A19)
1H NMR(500MHz,Chloroform)δ8.95(s,1H),8.43(s,1H),8.26(s,1H),7.90(s,1H),7.74(s,1H),7.61(s,1H),7.31(d,J＝2.0Hz,2H),5.94(s,1H),4.69(s,1H),4.53(s,1H),3.44(d,J＝9.6Hz,2H),3.35(s,1H),2.95(s,1H),2.19(s,1H),2.09–2.05(m,2H),1.91(t,J＝7.7Hz,3H),1.75–1.68(m,5H),1.68–1.63(m,2H),1.62–1.58(m,2H),1.58–1.46(m,8H),1.45–1.40(m,2H),1.22–1.14(m,2H),1.07(s,1H).
实施例20 N-((S)-3-环己基-1-(((S)-4-(新戊基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-苯并噻吩-2-羧酰胺(A20)
1H NMR(500MHz,Chloroform)δ8.36(s,1H),7.88(s,1H),7.73(s,1H),7.30(d,J＝2.5Hz,2H),6.53(s,1H),6.04(s,1H),5.82(s,1H),5.52(s,1H),4.68(d,J＝6.4Hz,2H),3.45(s,1H),3.35(d,J＝3.1Hz,2H),2.90(s,1H),2.43(s,1H),2.19(s,1H),2.09–2.05(m,2H),1.91(t,J＝5.9Hz,3H),1.74–1.65(m,4H),1.60–1.51(m,6H),1.34(s,1H),1.08–1.04(m,9H).
实施例21 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-苯并噻吩-2-羧酰胺(A21)
1H NMR(500MHz,Chloroform)δ8.31(s,1H),7.92(s,1H),7.74(s,1H),7.34–7.23(m,6H),7.20(s,1H),6.76(s,1H),5.59(s,1H),5.49(s,1H),5.08(s,1H),4.52(s,1H),4.42(s,1H),4.34(s,1H),3.24(d,J＝17.6Hz,2H),2.68(s,1H),2.08–2.04(m,2H),1.74–1.67(m,5H),1.64(dd,J＝2.9,1.7Hz,4H),1.36–1.32(m,2H),1.30(s,1H),1.26(s,1H),1.17(s,1H),1.13–1.05(m,2H),0.98(s,1H).
实施例22 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-苯并噻吩-2-羧酰胺(A22)
1H NMR(500MHz,Chloroform)δ8.34(s,1H),8.22(s,1H),7.88(s,1H),7.72(s,1H),7.30(d,J＝1.5Hz,2H),6.15(s,1H),6.10(s,1H),5.41(s,1H),4.64(d,J＝11.7Hz,2H),3.24(d,J＝14.8Hz,2H),2.90(s,1H),2.11–2.01(m,2H),1.89–1.81(m,4H),1.77(s,1H),1.73–1.68(m,4H),1.66–1.59(m,5H),1.55–1.49(m,2H),1.35(s,1H),1.32–1.28(m,9H).
实施例23 N-((S)-3-环己基-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-苯并噻吩-2-羧酰胺(A23)
1H NMR(500MHz,Chloroform)δ8.93(s,1H),8.55(s,1H),7.91(s,1H),7.72(s,1H),7.30(d,J＝2.6Hz,2H),6.05(s,1H),5.83(s,1H),5.68(s,1H),5.13(s,1H),4.34(s,1H),3.33(s,1H),3.24(d,J＝15.0Hz,2H),2.73(s,1H),2.43(s,1H),2.08–2.04(m,5H),1.85(s,1H),1.78(s,1H),1.73–1.67(m,5H),1.66–1.52(m,7H),1.51(s,2H),1.44–1.39(m,3H),1.34–1.30(m,2H),1.27(s,1H),0.83–0.72(m,2H).
实施例24 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-1-甲基-1H-吲哚-2-羧酰胺(A24)
1H NMR(500MHz,Chloroform)δ7.61(s,2H),7.40–7.26(m,10H),7.18(dd,J＝24.7,8.9Hz,9H),6.51(s,2H),6.14(s,2H),5.17(s,2H),4.61(s,2H),4.40(s,2H),4.27(s,2H),4.19(s,2H),3.60–3.56(m,6H),3.52(s,2H),3.45(s,2H),3.35(s,2H),2.87(s,2H),2.18(s,2H),2.09–2.05(m,4H),1.92(s,2H),1.73–1.69(m,4H),1.60–1.50(m,11H),1.36–1.32(m,3H),1.18(s,2H),1.07–1.03(m,3H).
实施例25 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-1-甲基-1H-吲哚-2-羧酰胺(A25)
1H NMR(500MHz,Chloroform)δ7.40(s,1H),7.27(d,J＝5.4Hz,2H),7.18(d,J＝11.2Hz,2H),6.05(d,J＝0.5Hz,2H),5.79(s,1H),5.25(s,1H),4.80(s,1H),4.65(s,1H),3.88–3.84(m,3H),3.45(s,1H),3.35(s,1H),2.58(s,1H),2.18(s,1H),2.09–2.05(m,2H),1.95–1.91(m,3H),1.73–1.52(m,5H),1.41–1.37(m,2H),1.35–1.29(m,10H),1.19–1.09(m,3H).
实施例26 N-((S)-3-环己基-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-1-甲基-1H-吲哚-2-羧酰胺(A26)
1H NMR(500MHz,Chloroform)δ7.24(s,1H),7.17(s,1H),7.12(d,J＝0.8Hz,2H),7.05(s,1H),6.01(s,1H),5.68(d,J＝17.0Hz,2H),4.92(s,1H),4.81(s,1H),3.98(s,1H),3.81(s,1H),3.74–3.70(m,3H),3.35(s,1H),2.62(s,1H),2.19(s,1H),2.09–2.05(m,2H),1.95–1.91(m,3H),1.90–1.77(m,4H),1.73–1.69(m,2H),1.66–1.54(m,13H),1.39–1.35(m,2H),1.33(s,1H).
实施例27 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-1-甲基-1H-吲哚-2-羧酰胺(A27)
1H NMR(500MHz,Chloroform)δ7.43(s,1H),7.38–7.24(m,7H),7.20(d,J＝8.0Hz,2H),5.93(s,1H),5.87(s,1H),5.57(s,1H),5.47(s,1H),4.73(s,1H),4.55(s,1H),4.39(d,J＝18.9Hz,2H),3.61–3.57(m,3H),3.23(d,J＝15.5Hz,2H),2.08–2.04(m,2H),1.96–1.92(m,3H),1.85(s,1H),1.73–1.64(m,6H),1.61(s,1H),1.41(t,J＝7.7Hz,3H),1.32(s,1H),1.24(s,1H),1.14–1.07(m, 2H).
实施例28 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-1-甲基-1H-吲哚-2-羧酰胺(A28)
1H NMR(500MHz,Chloroform)δ7.46(s,47H),7.26(d,J＝19.3Hz,98H),7.17(d,J＝7.3Hz,95H),6.39(s,47H),5.92(d,J＝11.5Hz,95H),5.44(s,47H),4.71(s,46H),4.53(s,46H),3.74–3.70(m,141H),3.24(d,J＝18.1Hz,90H),2.77(s,44H),2.11–2.01(m,97H),1.91(s,34H),1.81(s,43H),1.77–1.69(m,222H),1.66–1.62(m,70H),1.61–1.42(m,241H),1.49–1.42(m,10H),1.40–1.36(m,70H),1.32–1.22(m,478H).
实施例29 N-((S)-3-环己基-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-1-甲基-1H-吲哚-2-羧酰胺(A29)
1H NMR(500MHz,Chloroform)δ7.41(s,1H),7.35–7.22(m,2H),7.19(d,J＝7.5Hz,2H),5.92(s,1H),5.54(s,1H),5.38(s,1H),5.23(s,1H),5.04(s,1H),4.34(s,1H),3.99–3.95(m,3H),3.86(s,1H),3.24(d,J＝15.7Hz,2H),2.86(s,1H),2.08–2.02(m,4H),1.99(s,1H),1.81(s,1H),1.78–1.67(m,7H),1.66–1.51(m,10H),1.43(s,1H),1.41–1.37(m,2H),1.30(s,1H),0.77–0.70(m,2H).
实施例30 N-((S)-3-环己基-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-1-甲基-1H-吲哚-2-羧酰胺(A30)
1H NMR(500MHz,Chloroform)δ7.87(s,1H),7.29(t,J＝9.9Hz,3H),7.22–7.11(m,2H),6.98(s,1H),6.61(s,1H),6.43(s,1H),6.20(s,1H),5.62(s,1H),4.55(s,1H),4.43(d,J＝15.9Hz,2H),4.32(s,1H),3.45(s,1H),3.35(s,1H),3.12(s,1H),2.33(s,1H),2.18(s,1H),2.09–2.05(m,2H),1.94–1.88(m,3H),1.74–1.66(m,4H),1.63–1.55(m,6H),1.35(s,1H).
实施例31 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-4,6-二氯-1H-吲哚-2-羧酰胺(A31)
1H NMR(500MHz,Chloroform)δ9.04(s,1H),8.68(s,1H),8.53(s,1H),7.42(s,1H),7.38(s,1H),7.06(s,1H),6.78(s,1H),5.77(s,1H),4.93(s,1H),4.55(s,1H),3.99(s,1H),3.35(s,1H),2.63(s,1H),2.19(s,1H),2.10–2.04(m,4H),1.93(s,1H),1.69(dt,J＝18.2,9.1Hz,5H),1.41–1.37(m,2H),1.35–1.27(m,11H),1.24(s,1H),1.05–1.01(m,2H).
实施例32 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-4,6-二氯-1H-吲哚-2-羧酰胺(A32)
1H NMR(500MHz,Chloroform)δ8.86(s,1H),8.48(s,1H),7.54(s,1H),7.41(s,1H),7.06(s,1H),6.01(s,1H),5.47(s,1H),5.20(s,1H),5.05(s,1H),4.55(s,1H),4.00(s,1H),3.58(s,1H),3.51(s,1H),3.35(s,1H),2.19(s,1H),2.12–2.02(m,2H),2.00–1.96(m,2H),1.94–1.87(m,3H),1.73–1.46(m, 14H),1.40–1.36(m,2H),1.32(s,1H),1.12–1.06(m,3H).
实施例33 N-((S)-3-环己基-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-4,6-二氯-1H-吲哚-2-羧酰胺(A33)
1H NMR(500MHz,Chloroform)δ8.68(s,11H),7.45(s,11H),7.38(s,11H),7.31–7.23(m,34H),7.23–7.17(m,26H),7.16(s,8H),7.11(s,11H),5.89(s,11H),5.79(s,11H),4.76(s,11H),4.51(s,11H),4.35(s,11H),4.29(s,11H),3.24(d,J＝17.5Hz,21H),2.73(s,11H),2.10–2.04(m,23H),2.02(s,9H),1.83(s,10H),1.81–1.74(m,33H),1.73–1.65(m,23H),1.65–1.50(m,45H),1.52(d,J＝5.6Hz,2H),1.34–1.30(m,19H),1.28(s,11H),0.99–0.93(m,32H).
实施例34 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-4,6-二氯-1H-吲哚-2-羧酰胺(A34)
1H NMR(500MHz,Chloroform)δ8.35(s,1H),7.62(s,1H),7.39(s,1H),7.05(s,1H),6.43(s,1H),5.97(s,1H),5.59(s,1H),5.50(d,J＝15.7Hz,2H),4.67(s,1H),3.24(d,J＝17.3Hz,2H),2.48(s,1H),2.08–2.04(m,2H),1.87(t,J＝9.6Hz,3H),1.78(s,1H),1.72(dd,J＝8.3,4.2Hz,4H),1.67(s,1H),1.65–1.50(m,6H),1.45(s,1H),1.36–1.28(m,10H).
实施例35 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-4,6-二氯-1H-吲哚-2-羧酰胺(A35)
1H NMR(500MHz,Chloroform)δ8.51(s,1H),8.33(s,1H),8.28(s,1H),7.42(s,1H),7.07(s,1H),6.66(s,1H),6.41(s,1H),5.86(s,1H),5.04(s,1H),4.52(s,1H),3.32(s,1H),3.24(d,J＝16.6Hz,2H),2.97(s,1H),2.16–2.01(m,5H),2.01–1.92(m,2H),1.82(s,1H),1.78–1.69(m,8H),1.65(d,J＝15.4Hz,2H),1.56–1.46(m,3H),1.44–1.40(m,4H),1.32(s,1H),1.17(s,1H),1.07–1.00(m,2H).
实施例36 N-((S)-3-环己基-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-4,6-二氯-1H-吲哚-2-羧酰胺(A36)
1H NMR(500MHz,Chloroform)δ8.98(s,1H),8.03(d,J＝1.1Hz,2H),7.63(d,J＝5.1Hz,2H),7.37–7.27(m,4H),7.21(s,1H),6.95(s,1H),6.43(s,1H),6.01(s,1H),4.94(s,1H),4.85(s,1H),4.67(s,1H),4.41(s,1H),4.32(s,1H),3.45(s,1H),3.35(s,1H),2.77(s,1H),2.19(s,1H),2.13–2.01(m,2H),1.89(s,1H),1.83–1.74(m,2H),1.74–1.69(m,2H),1.66(d,J＝5.7Hz,2H),1.58–1.49(m,6H),1.31(s,1H).
实施例37 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-喹喔啉-2-羧酰胺(A37)
1H NMR(500MHz,Chloroform)δ9.39(s,1H),8.47(s,1H),8.11(s,1H),7.62(d,J＝3.2Hz,2H),6.17(d,J＝6.0Hz,2H),5.59(s,1H),5.27(s,1H),4.98(s, 1H),4.91(s,1H),3.45(s,1H),3.35(s,1H),2.51(s,1H),2.19(s,1H),2.09–2.05(m,2H),1.98–1.95(m,2H),1.92(s,1H),1.73–1.61(m,5H),1.41–1.37(m,2H),1.34–1.28(m,10H),1.21–1.11(m,3H).
实施例38 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-喹喔啉-2-羧酰胺(A38)
1H NMR(500MHz,Chloroform)δ9.09(s,1H),8.31(s,1H),8.03(d,J＝4.8Hz,2H),7.61(d,J＝2.2Hz,2H),6.41(s,1H),6.06(s,1H),5.27(s,1H),5.20(s,1H),4.45(s,1H),3.72(s,1H),3.45(s,1H),3.35(s,1H),2.73(s,1H),2.39–2.31(m,2H),2.19(s,1H),2.09–2.05(m,2H),1.92(s,1H),1.76–1.56(m,15H),1.55–1.45(m,6H),1.30(s,1H).
实施例39 N-((S)-3-环己基-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-喹喔啉-2-羧酰胺(A39)
1H NMR(500MHz,Chloroform)δ9.55(s,1H),9.32(s,1H),8.12(s,1H),7.96(s,1H),7.64(d,J＝11.6Hz,2H),7.29–7.22(m,4H),7.19(s,1H),6.56(s,1H),6.06(s,1H),5.63(s,1H),5.02(s,1H),4.71(s,1H),4.41(s,1H),4.31(s,1H),3.24(d,J＝17.3Hz,2H),2.37(s,1H),2.10–2.02(m,2H),2.02–1.96(m,3H),1.82(s,1H),1.72(t,J＝9.8Hz,3H),1.69–1.57(m,3H),1.53(s,1H),1.38–1.34(m,2H),1.31(s,1H),1.13–1.04(m,3H).
实施例40 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-喹喔啉-2-羧酰胺(A40)
1H NMR(500MHz,Chloroform)δ9.29(s,1H),8.16(s,1H),8.11(s,1H),7.65(d,J＝4.6Hz,2H),7.22(s,1H),5.87(d,J＝8.3Hz,2H),5.65(s,1H),4.94(s,1H),4.46(s,1H),3.24(d,J＝14.8Hz,2H),2.72(s,1H),2.11–2.01(m,2H),1.79(d,J＝1.0Hz,2H),1.76–1.62(m,5H),1.59(s,1H),1.49–1.42(m,4H),1.35–1.28(m,11H),1.25(s,1H),1.21–1.15(m,2H).
实施例41 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-喹喔啉-2-羧酰胺(A41)
1H NMR(500MHz,Chloroform)δ9.64(s,4H),8.11(d,J＝10.4Hz,8H),7.65(d,J＝1.9Hz,8H),6.00(s,4H),5.76(s,4H),5.70(s,4H),5.64(s,4H),5.04(s,4H),4.45(s,4H),3.86(s,4H),3.24(d,J＝17.3Hz,8H),2.85(s,4H),2.11–2.01(m,9H),1.99–1.91(m,12H),1.91–1.80(m,9H),1.75(s,2H),1.75–1.53(m,62H),1.55–1.53(m,1H),1.51(s,3H),1.38–1.34(m,7H),1.30(s,4H),1.06(s,3H),1.03–0.99(m,8H).
实施例42 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-喹啉-2-羧酰胺(A42)
1H NMR(500MHz,Chloroform)δ8.56(s,1H),8.19(s,1H),7.82(s,1H),7.58(s,1H),7.42(s,1H),7.42–7.28(m,5H),7.21(s,1H),6.00(d,J＝2.7Hz,2H), 4.43(s,1H),4.33(s,1H),4.11(s,1H),3.83(d,J＝3.7Hz,2H),3.45(s,1H),3.35(s,1H),3.25(s,1H),2.15(s,1H),2.09–2.05(m,2H),1.91(s,1H),1.73–1.69(m,2H),1.62–1.55(m,3H),1.36–1.27(m,6H),1.23(s,1H),1.20–1.14(m,2H).
实施例43 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-喹啉-2-羧酰胺(A43)
1H NMR(500MHz,Chloroform)δ9.34(s,1H),8.46(s,1H),8.17(s,1H),7.82(s,1H),7.72(s,1H),7.55(s,1H),7.50(s,1H),5.96(s,1H),5.84(s,1H),5.40(s,1H),5.22(s,1H),4.77(s,1H),3.45(s,1H),3.35(s,1H),2.83(s,1H),2.18(s,1H),2.09–2.05(m,2H),1.94–1.81(m,3H),1.73–1.63(m,5H),1.40–1.36(m,2H),1.36–1.27(m,10H),1.18(s,1H),1.14–1.10(m,2H).
实施例44 N-((S)-3-环己基-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-喹啉-2-羧酰胺(A44)
1H NMR(500MHz,Chloroform)δ8.47(s,1H),8.24(s,1H),8.06(s,1H),7.73(s,1H),7.65(s,1H),7.43(d,J＝13.7Hz,2H),6.58(s,1H),6.06(s,1H),5.40(s,1H),5.20(s,1H),4.45(s,1H),3.73(s,1H),3.45(s,1H),3.35(s,1H),2.72(s,1H),2.34–2.30(m,2H),2.19(s,1H),2.09–2.05(m,2H),1.92(s,1H),1.77–1.56(m,15H),1.55–1.46(m,6H),1.30(s,1H).
实施例45 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-喹啉-2-羧酰胺(A45)
1H NMR(500MHz,Chloroform)δ8.42(s,1H),8.15(s,1H),7.79(s,1H),7.69(s,1H),7.47(s,1H),7.42(s,1H),7.34–7.25(m,4H),7.20(s,1H),6.77(s,1H),5.89(s,1H),5.82(s,1H),5.57(d,J＝7.5Hz,2H),4.42(d,J＝5.7Hz,2H),4.34(s,1H),3.24(d,J＝19.0Hz,2H),2.81(s,1H),2.43(s,1H),2.11–2.01(m,2H),1.95(s,1H),1.86(s,1H),1.81–1.74(m,3H),1.69(dt,J＝17.1,8.6Hz,5H),1.47(s,1H),1.41–1.37(m,2H),1.31(s,1H),0.84–0.77(m,2H).
实施例46 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-喹啉-2-羧酰胺(A46)
1H NMR(500MHz,Chloroform)δ8.46(s,3H),8.13(s,3H),7.79(s,3H),7.69(d,J＝0.8Hz,6H),7.44(d,J＝32.8Hz,6H),6.55(s,3H),6.05(s,3H),5.75(s,3H),4.77(d,J＝2.1Hz,6H),3.25(s,3H),3.21(s,3H),2.70(s,3H),2.11–2.01(m,6H),1.96–1.87(m,6H),1.79(d,J＝13.1Hz,5H),1.70(dt,J＝19.3,3.5Hz,19H),1.60–1.51(m,18H),1.35–1.30(m,30H).
实施例47 N-((S)-3-环己基-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-喹啉-2-羧酰胺(A47)
1H NMR(500MHz,Chloroform)δ9.06(s,3H),8.44(s,3H),8.15(s,3H),7.79(s,3H),7.75(s,3H),7.70(s,3H),7.48(d,J＝8.2Hz,6H),7.38(s,3H),5.73 (s,3H),4.96(s,3H),4.57(s,3H),3.90(s,3H),3.24(d,J＝14.7Hz,6H),2.92(s,3H),2.15–2.11(m,5H),2.11–2.01(m,9H),1.99(t,J＝7.9Hz,7H),1.80(s,2H),1.76–1.65(m,18H),1.65–1.58(m,24H),1.45(t,J＝13.5Hz,10H),1.36(dd,J＝21.5,15.7Hz,2H),1.33(s,3H),1.20(s,2H),1.11–1.04(m,6H).
实施例48 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-1H-吲哚-2-羧酰胺(A48)
1H NMR(500MHz,Chloroform)δ8.36(s,1H),7.55(d,J＝12.3Hz,2H),7.34(t,J＝21.8Hz,3H),7.30–7.17(m,9H),7.15(d,J＝2.2Hz,2H),7.09(s,1H),6.35(s,1H),6.01(s,1H),5.67(s,1H),5.03(s,1H),4.88(s,1H),4.37(s,1H),4.30(s,1H),3.45(s,1H),3.35(s,1H),3.15(d,J＝18.6Hz,2H),2.94(s,1H),2.19(s,1H),2.10–2.04(m,2H),1.92(s,1H).
实施例49 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-1H-吲哚-2-羧酰胺(A49)
1H NMR(500MHz,Chloroform)δ8.26(s,1H),7.46(s,1H),7.32(t,J＝17.0Hz,3H),7.20(dd,J＝7.8,5.2Hz,4H),7.12(s,1H),7.06(s,1H),6.01(s,1H),5.57(s,1H),4.84(s,1H),4.69(s,1H),4.53(s,1H),3.45(s,1H),3.41(s,1H),3.35(s,1H),3.30(s,1H),3.19(s,1H),2.96(s,1H),2.16(s,1H),2.13–2.01(m,2H),1.89(s,1H),1.30–1.26(m,9H).
实施例50 N-((S)-3-环己基-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-1H-吲哚-2-羧酰胺(A50)
1H NMR(500MHz,Chloroform)δ8.35(s,1H),7.90(s,1H),7.52(d,J＝25.5Hz,2H),7.39(s,1H),7.29–7.21(m,4H),7.14(d,J＝3.6Hz,2H),7.08(s,1H),6.52(s,1H),6.16(s,1H),5.70(s,1H),4.92(s,1H),4.78(s,1H),3.46(d,J＝5.2Hz,2H),3.35(s,1H),3.21(s,1H),2.85(d,J＝4.0Hz,2H),2.17(s,1H),2.13–2.02(m,2H),2.00–1.90(m,3H),1.68(s,1H),1.56–1.50(m,2H),1.49–1.45(m,3H),1.44–1.40(m,2H).
实施例51 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-1H-吲哚-2-羧酰胺(A51)
1H NMR(500MHz,Chloroform)δ8.70(s,1H),7.50(s,1H),7.39–7.20(m,5H),7.20–7.11(m,4H),7.09(d,J＝4.4Hz,2H),7.06–6.94(m,2H),6.90(s,1H),6.19(s,1H),5.93(s,1H),5.51(s,1H),4.70(s,1H),4.25(d,J＝17.1Hz,2H),3.79(d,J＝9.5Hz,2H),3.24(t,J＝8.3Hz,3H),3.04(s,1H),2.16(s,1H),2.12–2.04(m,3H),1.78(s,1H),1.72(s,1H),1.62(s,1H).
实施例52 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-1H-吲哚-2-羧酰胺(A52)
1H NMR(500MHz,Chloroform)δ8.64(d,J＝17.0Hz,2H),8.19(s,1H),7.56(s,1H),7.43(s,1H),7.36–7.27(m,2H),7.27–7.22(m,2H),7.14(d,J＝12.9Hz, 2H),7.08(s,1H),5.63(s,1H),5.01(d,J＝14.2Hz,2H),4.78(d,J＝1.3Hz,2H),3.24(d,J＝18.2Hz,2H),3.18(s,1H),3.03(s,1H),2.97(s,1H),2.06(t,J＝3.5Hz,3H),1.94(s,1H),1.88(s,1H),1.81(s,1H),1.21–1.17(m,9H).
实施例53 N-((S)-3-环己基-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-1H-吲哚-2-羧酰胺(A53)
1H NMR(500MHz,Chloroform)δ8.76(s,1H),7.53(s,1H),7.41(d,J＝25.5Hz,2H),7.27–7.21(m,2H),7.21–7.18(m,2H),7.15(d,J＝7.6Hz,2H),7.08(s,1H),5.95(s,1H),5.61(s,1H),5.25(s,1H),5.14(s,1H),4.78(s,1H),3.42(s,1H),3.25(t,J＝12.6Hz,3H),2.87(s,1H),2.70(s,1H),2.56(s,1H),2.08–2.04(m,2H),2.02–1.90(m,2H),1.87(s,1H),1.80(s,1H),1.68(d,J＝3.3Hz,2H),1.55–1.51(m,4H),1.48(s,1H),1.45–1.39(m,2H).
实施例54 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-苯并呋喃-2-羧酰胺(A54)
1H NMR(500MHz,Chloroform)δ7.51(d,J＝8.2Hz,2H),7.41(s,1H),7.30–7.12(m,12H),6.67(s,1H),5.69–5.61(m,3H),5.09(s,1H),4.88(s,1H),4.41(s,1H),4.33(s,1H),3.45(s,1H),3.35(s,1H),3.26(s,1H),3.16(s,1H),3.07(s,1H),2.19(s,1H),2.09–2.05(m,2H),1.92(s,1H).
实施例55 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-苯并呋喃-2-羧酰胺(A55)
1H NMR(500MHz,Chloroform)δ7.54(s,1H),7.47(d,J＝17.7Hz,2H),7.28–7.22(m,3H),7.18(dd,J＝20.8,5.2Hz,4H),6.42(s,1H),6.05(s,1H),5.83(s,1H),5.27(s,1H),4.98(s,1H),4.85(s,1H),3.45(s,1H),3.35(s,1H),3.19(s,1H),2.96(s,1H),2.61(s,1H),2.18(s,1H),2.09–2.05(m,2H),1.93(s,1H),1.34–1.30(m,9H).
实施例56 N-((S)-3-环己基-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-苯并呋喃-2-羧酰胺(A56)
1H NMR(500MHz,Chloroform)δ8.77(s,2H),8.67(s,2H),7.56(s,1H),7.50(s,3H),7.41(s,2H),7.28–7.19(m,6H),7.16(d,J＝4.9Hz,4H),7.13–7.04(m,4H),6.04(s,2H),5.93(s,2H),5.05(s,2H),4.66(s,2H),3.70(s,2H),3.45(s,2H),3.35(s,1H),3.25(s,2H),3.05(s,2H),2.88(s,2H),2.19(s,2H),2.09–2.05(m,4H),1.97–1.91(m,5H),1.68–1.64(m,3H),1.64–1.43(m,13H).
实施例57 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-苯并呋喃-2-羧酰胺(A57)
1H NMR(500MHz,Chloroform)δ7.48(s,1H),7.29(d,J＝38.0Hz,2H),7.25(s,1H),7.27–7.19(m,3H),7.19–7.05(m,10H),6.97(s,1H),6.43(s,1H),6.07(s,1H),5.18(d,J＝3.4Hz,2H),4.73(s,1H),4.63(s,1H),4.36(s,1H),4.29(s,1H),3.24(d,J＝16.8Hz,2H),3.10(s,1H),2.86(d,J＝21.8Hz,2H),2.43(s, 1H),2.08–2.04(m,2H),1.85(s,1H),1.79(s,1H),1.64(s,1H).
实施例58 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-苯并呋喃-2-羧酰胺(A58)
1H NMR(500MHz,Chloroform)δ9.35(s,5H),7.60(s,5H),7.48(d,J＝29.1Hz,10H),7.28–7.18(m,27H),7.16(d,J＝17.5Hz,8H),5.86(s,5H),5.55(s,5H),4.94(s,5H),4.69(s,5H),3.24(t,J＝10.0Hz,14H),2.90(s,5H),2.66(s,5H),2.09–2.02(m,10H),1.92(s,4H),1.84–1.80(m,8H),1.76(s,4H),1.30–1.26(m,44H).
实施例59 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-苯并呋喃-2-羧酰胺(A59)
1H NMR(500MHz,Chloroform)δ9.35(s,5H),7.60(s,5H),7.48(d,J＝29.1Hz,10H),7.28–7.18(m,27H),7.16(d,J＝17.5Hz,8H),5.86(s,5H),5.55(s,5H),4.94(s,5H),4.69(s,5H),3.24(t,J＝10.0Hz,14H),2.90(s,5H),2.66(s,5H),2.09–2.02(m,10H),1.92(s,4H),1.84–1.80(m,8H),1.76(s,4H),1.30–1.26(m,44H).
实施例60 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-苯并噻吩-2-羧酰胺(A60)
1H NMR(500MHz,Chloroform)δ8.40(s,1H),7.91(s,1H),7.76(s,1H),7.33(d,J＝3.7Hz,2H),7.32–7.16(m,10H),7.13(d,J＝16.7Hz,2H),6.27(s,1H),5.97(s,1H),5.64(s,1H),5.03(s,1H),4.89(s,1H),4.34(d,J＝4.2Hz,2H),3.45(s,1H),3.35(s,1H),3.15–3.11(m,2H),2.94(s,1H),2.19(s,1H),2.09–2.05(m,2H),1.92(s,1H).
实施例61 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-苯并噻吩-2-羧酰胺(A61)
1H NMR(500MHz,Chloroform)δ8.93(s,1H),7.82(d,J＝4.4Hz,2H),7.28(dd,J＝20.7,7.2Hz,4H),7.22–7.11(m,3H),6.05(s,1H),4.70(s,1H),4.64(s,1H),4.59(s,1H),4.39(s,1H),3.99(s,1H),3.55(s,1H),3.45(s,1H),3.35(s,1H),3.15(s,1H),2.95(s,1H),2.17(s,1H),2.13–2.02(m,2H),1.89(s,1H),1.21–1.17(m,9H).
实施例62 N-((S)-3-环己基-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-苯并噻吩-2-羧酰胺(A62)
1H NMR(500MHz,Chloroform)δ8.73(s,1H),8.54(s,1H),8.35(s,1H),7.91(s,1H),7.74(s,1H),7.32(d,J＝1.5Hz,2H),7.28–7.23(m,2H),7.15(s,1H),7.12–7.05(m,2H),6.14(s,1H),5.94(s,1H),5.04(s,1H),4.66(s,1H),3.45(d,J＝3.2Hz,2H),3.35(s,1H),3.26(s,1H),3.05(s,1H),2.89(s,1H),2.19(s,1H),2.09–2.05(m,2H),1.95–1.91(m,3H),1.73–1.64(m,3H),1.56–1.52(m,2H),1.50(s,1H),1.46–1.40(m,2H).
实施例63 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-苯并噻吩-2-羧酰胺(A63)
1H NMR(500MHz,Chloroform)δ8.49(s,1H),8.30(s,1H),8.00(s,1H),7.63(s,1H),7.29(dd,J＝19.0,2.9Hz,4H),7.18–7.07(m,5H),7.07–6.97(m,3H),6.33(s,1H),6.11(s,1H),4.93–4.89(m,2H),4.36(d,J＝9.1Hz,2H),4.29(s,1H),3.28–3.20(m,3H),2.92(s,1H),2.58(s,1H),2.16(s,1H),2.08–2.04(m,2H),1.83(s,1H),1.77(s,1H),1.73(s,1H).
实施例64 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-苯并噻吩-2-羧酰胺(A64)
1H NMR(500MHz,Chloroform)δ8.38(s,1H),7.90(s,1H),7.75(s,1H),7.30(dd,J＝17.5,1.0Hz,4H),7.26–7.19(m,2H),7.17(s,1H),7.02(s,1H),6.45(s,1H),6.10(s,1H),5.93(s,1H),4.93(s,1H),4.86(s,1H),3.27–3.11(m,3H),2.95(s,1H),2.83(s,1H),2.11–2.01(m,2H),1.95(s,1H),1.83(s,1H),1.76(s,1H),1.56(s,1H),1.35–1.31(m,9H).
实施例65 N-((S)-3-环己基-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-苯并噻吩-2-羧酰胺(A65)
1H NMR(500MHz,Chloroform)δ8.28(s,6H),7.86(s,6H),7.60(s,6H),7.27(dd,J＝17.2,1.6Hz,20H),7.24–7.12(m,22H),5.78(s,6H),5.41(s,6H),5.09(s,6H),4.97(s,6H),4.85(s,6H),3.31–3.10(m,30H),2.97(s,6H),2.60(s,4H),2.51(s,5H),2.12–2.00(m,12H),1.97–1.86(m,12H),1.71(t,J＝16.5Hz,17H),1.58–1.45(m,30H),1.45–1.36(m,12H),1.12(s,4H).
实施例66 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-1-甲基-1H-吲哚-2-羧酰胺(A66)
1H NMR(500MHz,Chloroform)δ8.78(s,1H),7.69(s,1H),7.49(s,1H),7.34–7.13(m,12H),7.13–7.05(m,2H),6.10(s,1H),5.99(s,1H),5.07(s,1H),4.69(s,1H),4.36(d,J＝3.5Hz,2H),3.78–3.74(m,3H),3.45(s,1H),3.35(s,1H),3.24(s,1H),3.06(s,1H),2.88(s,1H),2.19(s,1H),2.09–2.05(m,2H),1.93(s,1H).
实施例67 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-1-甲基-1H-吲哚-2-羧酰胺(A67)
1H NMR(500MHz,Chloroform)δ7.38(s,1H),7.29–7.13(m,9H),6.07(s,1H),5.82(d,J＝4.8Hz,2H),5.28(s,1H),4.94(s,1H),4.87(s,1H),3.67–3.63(m,3H),3.45(s,1H),3.35(s,1H),3.19(s,1H),2.93(s,1H),2.68(s,1H),2.18(s,1H),2.09–2.05(m,2H),1.94(s,1H),1.34–1.30(m,9H).
实施例68 N-((S)-3-环己基-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-1-甲基-1H-吲哚-2-羧酰胺(A68)
1H NMR(500MHz,Chloroform)δ7.49(s,3H),7.34–7.20(m,23H),7.20(s, 3H),7.15(s,2H),6.73(s,3H),6.27(s,3H),5.73(s,3H),5.11(s,3H),4.83(s,3H),3.98(s,2H),3.76(s,3H),3.58–3.54(m,9H),3.35(s,2H),3.22(s,3H),2.88(s,3H),2.63(s,3H),2.19(s,2H),2.09–2.05(m,6H),1.95–1.91(m,7H),1.76–1.66(m,7H),1.66–1.55(m,20H).
实施例69 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-1-甲基-1H-吲哚-2-羧酰胺(A69)
1H NMR(500MHz,Chloroform)δ7.35–7.29(m,2H),7.29–7.26(m,1H),7.26–7.06(m,11H),6.67(s,1H),6.05(d,J＝11.7Hz,2H),5.74(s,1H),4.95(s,1H),4.77(s,1H),4.39(s,1H),4.34(s,1H),3.86–3.82(m,3H),3.29–3.17(m,3H),2.95(s,1H),2.56(s,1H),2.44(s,1H),2.12–2.00(m,2H),1.85(s,1H),1.78(s,1H),1.41(s,1H),1.15(s,1H).
实施例70 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-1-甲基-1H-吲哚-2-羧酰胺(A70)
1H NMR(500MHz,Chloroform)δ7.51(s,1H),7.31(s,1H),7.22(ddd,J＝42.8,13.4,8.7Hz,8H),6.91(s,1H),6.06(s,1H),5.93(s,1H),5.54(s,1H),4.80(s,1H),4.71(s,1H),3.73–3.69(m,3H),3.26(t,J＝14.0Hz,3H),2.82(d,J＝27.3Hz,2H),2.11–2.01(m,2H),1.92(s,1H),1.82(s,1H),1.75(s,1H),1.54(s,1H),1.32–1.28(m,9H).
实施例71 N-((S)-3-环己基-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-1-甲基-1H-吲哚-2-羧酰胺(A71)
1H NMR(500MHz,Chloroform)δ8.25(s,1H),7.38(s,1H),7.28(dd,J＝15.9,3.4Hz,4H),7.24–7.12(m,5H),5.93(s,1H),5.32(s,1H),5.07(s,1H),4.75(s,1H),4.41(s,1H),3.85–3.77(m,4H),3.27–3.20(m,3H),3.04(s,1H),2.84(s,1H),2.49(s,1H),2.17–2.10(m,2H),2.10–2.02(m,2H),1.86–1.75(m,6H),1.65(s,1H),1.58–1.52(m,4H).
实施例72 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-4,6-二氯-1H-吲哚-2-羧酰胺(A72)
1H NMR(500MHz,Chloroform)δ8.55(s,1H),7.52(s,1H),7.44(s,1H),7.38(s,1H),7.32–7.27(m,4H),7.27–7.12(m,8H),7.10(s,1H),6.00(s,1H),5.04(s,1H),4.92(s,1H),4.77(s,1H),4.38(s,1H),4.30(s,1H),3.45(s,1H),3.35(s,1H),3.27(s,1H),3.12(s,1H),2.87(s,1H),2.19(s,1H),2.09–2.05(m,2H),1.92(s,1H).
实施例73 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-4,6-二氯-1H-吲哚-2-羧酰胺(A73)
1H NMR(500MHz,Chloroform)δ8.55(s,1H),8.14(s,1H),7.52(s,1H),7.44(s,1H),7.28–7.22(m,2H),7.22–7.11(m,3H),7.09(s,1H),6.01(s,1H),5.55(s,1H),5.12(s,1H),4.74(s,1H),4.31(s,1H),3.45(s,1H),3.35(s,1H), 3.30(s,1H),3.08(s,1H),2.92(s,1H),2.18(s,1H),2.09–2.05(m,2H),1.92(s,1H),1.39–1.35(m,9H).
实施例74 N-((S)-3-环己基-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-4,6-二氯-1H-吲哚-2-羧酰胺(A74)
1H NMR(500MHz,Chloroform)δ8.85(s,1H),8.44(s,1H),8.39(s,1H),7.58(s,1H),7.42(s,1H),7.28–7.23(m,2H),7.15(s,1H),7.12–7.06(m,3H),6.10(s,1H),5.94(s,1H),5.03(s,1H),4.66(s,1H),3.45(d,J＝5.0Hz,2H),3.35(s,1H),3.27(s,1H),3.06(s,1H),2.90(s,1H),2.19(s,1H),2.09–2.05(m,2H),1.95–1.91(m,3H),1.72–1.68(m,3H),1.56–1.52(m,2H),1.50(s,1H),1.46–1.41(m,2H).
实施例75 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-4,6-二氯-1H-吲哚-2-羧酰胺(A75)
1H NMR(500MHz,Chloroform)δ8.67(s,13H),7.46(s,13H),7.30–7.24(m,28H),7.24–7.14(m,80H),7.12–7.00(m,30H),7.00(s,11H),6.93(d,J＝12.0Hz,26H),6.07(s,13H),4.91(s,13H),4.80(s,13H),4.36(s,13H),4.31(s,13H),4.27(s,13H),4.04(s,13H),3.31(d,J＝52.2Hz,35H),3.22(s,5H),3.01(s,14H),2.86(s,11H),2.31(s,9H),2.08–2.04(m,25H),1.83(s,12H),1.77(s,10H),1.54(s,9H).
实施例76 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-4,6-二氯-1H-吲哚-2-羧酰胺(A76)
1H NMR(500MHz,Chloroform)δ8.53(s,8H),7.62(s,8H),7.43(s,8H),7.38(s,8H),7.26–7.21(m,16H),7.21–7.14(m,21H),7.14–7.11(m,4H),7.09(s,8H),5.81(s,8H),5.66(s,8H),5.34(s,8H),4.92(s,8H),4.75(s,8H),3.33–3.20(m,24H),2.87(s,7H),2.59(s,7H),2.08–2.04(m,16H),1.86(s,6H),1.80(s,7H),1.73(s,6H),1.48(s,6H),1.34–1.30(m,72H).
实施例77 N-((S)-3-环己基-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-4,6-二氯-1H-吲哚-2-羧酰胺(A77)
1H NMR(500MHz,Chloroform)δ9.14(s,1H),9.09(s,1H),7.58(s,1H),7.47(s,1H),7.33–7.27(m,2H),7.27–7.14(m,3H),7.10(s,1H),6.82(s,1H),5.96(s,1H),5.80(s,1H),4.98(s,1H),4.82(s,1H),3.35(s,1H),3.24(d,J＝14.7Hz,2H),3.16(s,1H),2.96(s,1H),2.83(s,1H),2.16–2.04(m,5H),1.82(s,1H),1.75(dd,J＝19.9,8.6Hz,4H),1.59–1.49(m,4H),1.44–1.40(m,2H).
实施例78 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-喹喔啉-2-羧酰胺(A78)
1H NMR(500MHz,Chloroform)δ9.21(s,1H),8.80(s,1H),8.10(d,J＝21.9Hz,2H),7.71(s,1H),7.63(d,J＝6.0Hz,2H),7.30–7.11(m,10H),6.38(s,1H),5.97(s,1H),4.90(s,1H),4.69(s,1H),4.36(d,J＝4.9Hz,2H),3.45(s,1H),3.35 (s,1H),3.16(s,1H),2.95(s,1H),2.86(s,1H),2.19(s,1H),2.09–2.05(m,2H),1.93(s,1H).
实施例79 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-喹喔啉-2-羧酰胺(A79)
1H NMR(500MHz,Chloroform)δ9.43(s,1H),9.01(s,1H),8.10(d,J＝11.8Hz,2H),7.68–7.64(m,2H),7.25–7.19(m,1H),7.19–7.09(m,4H),6.12(s,1H),6.04(s,1H),5.51(s,1H),5.09(s,1H),4.74(s,1H),3.45(s,1H),3.35(d,J＝2.3Hz,2H),3.11(s,1H),2.89(s,1H),2.19(s,1H),2.09–2.05(m,2H),1.92(s,1H),1.39–1.35(m,9H).
实施例80 N-((S)-3-环己基-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-喹喔啉-2-羧酰胺(A80)
1H NMR(500MHz,Chloroform)δ9.46(s,1H),8.10(d,J＝1.3Hz,2H),7.64(d,J＝1.4Hz,2H),7.29–7.21(m,4H),7.15(s,1H),6.17(s,1H),5.60(s,1H),5.41(s,1H),5.16(s,1H),4.42(s,1H),3.77(s,1H),3.45(s,1H),3.35(d,J＝2.0Hz,2H),2.94(s,1H),2.49(s,1H),2.19(s,1H),2.09–2.05(m,2H),1.93(s,1H),1.81–1.74(m,6H),1.74–1.70(m,2H),1.57–1.51(m,2H).
实施例81 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-喹喔啉-2-羧酰胺(A81)
1H NMR(500MHz,Chloroform)δ9.04(s,1H),8.07(d,J＝5.3Hz,2H),7.62(d,J＝0.9Hz,2H),7.30–7.20(m,5H),7.20–7.12(m,5H),7.10(s,1H),6.69(s,1H),5.68(d,J＝19.5Hz,2H),5.14(s,1H),5.08(s,1H),4.42(s,1H),4.34(s,1H),3.37(s,1H),3.24(d,J＝17.2Hz,2H),2.95(s,1H),2.15(s,1H),2.09–2.03(m,2H),1.76(s,1H),1.70(s,1H),1.63(s,1H),1.43(s,1H).
实施例82 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-喹喔啉-2-羧酰胺(A82)
1H NMR(500MHz,Chloroform)δ9.37(s,1H),8.11(d,J＝1.9Hz,2H),7.64(d,J＝1.0Hz,2H),7.32–7.26(m,2H),7.26–7.13(m,3H),6.08(s,1H),5.93(d,J＝13.8Hz,2H),5.60(s,1H),4.97(s,1H),4.83(s,1H),3.24(d,J＝16.7Hz,2H),3.18(s,1H),2.93(s,1H),2.70(s,1H),2.11–2.01(m,2H),1.98(s,1H),1.78(s,1H),1.71(s,1H),1.42(s,1H),1.35–1.31(m,9H).
实施例83 N-((S)-3-环己基-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-喹喔啉-2-羧酰胺(A83)
1H NMR(500MHz,Chloroform)δ9.67(s,6H),8.12(d,J＝8.3Hz,12H),7.66(d,J＝1.4Hz,12H),7.26–7.16(m,25H),7.14(s,6H),6.12(s,6H),5.79(s,6H),5.56(s,6H),5.33(s,6H),5.10(s,6H),4.95(s,6H),3.84(s,6H),3.27(t,J＝34.6Hz,16H),3.21(d,J＝6.1Hz,2H),3.02(s,6H),2.83(s,6H),2.11–2.01(m,13H),2.01–1.94(m,18H),1.75(s,4H),1.71–1.55(m,59H).
实施例84 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-喹啉-2-羧酰胺(A84)
1H NMR(500MHz,Chloroform)δ8.46(s,1H),8.12(s,1H),7.78(s,1H),7.65(s,1H),7.54(s,1H),7.44(s,1H),7.31–7.24(m,4H),7.24–7.14(m,4H),7.12(s,2H),5.72(s,1H),5.54(s,1H),5.14(s,1H),4.70(s,1H),4.59(s,1H),4.29(d,J＝9.5Hz,2H),3.74(s,1H),3.35(s,1H),3.31(s,1H),3.08(s,1H),2.72(s,1H),2.17(s,1H),2.10–2.05(m,2H),1.89(s,1H).
实施例85 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-喹啉-2-羧酰胺(A85)
1H NMR(500MHz,Chloroform)δ8.40(d,J＝39.3Hz,11H),8.36–8.34(m,1H),8.19(s,6H),7.80(s,6H),7.71(s,6H),7.49(d,J＝5.7Hz,12H),7.30–7.25(m,12H),7.25–7.15(m,14H),7.14(s,4H),6.20(s,6H),5.92(s,6H),5.07(s,6H),4.75(s,6H),3.45(s,6H),3.38(d,J＝25.1Hz,12H),3.32(s,1H),3.02(s,6H),2.35(s,5H),2.19(s,4H),2.09–2.05(m,12H),1.92(s,5H),1.36–1.32(m,53H).
实施例86 N-((S)-3-环己基-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-喹啉-2-羧酰胺(A86)
1H NMR(500MHz,Chloroform)δ8.46(s,1H),8.12(s,1H),7.81(s,1H),7.69(s,1H),7.49(d,J＝7.1Hz,2H),7.26–7.20(m,2H),7.20–7.09(m,3H),5.94(d,J＝1.5Hz,2H),5.63(s,1H),5.44(s,1H),4.91(s,1H),4.76(s,1H),3.89(s,1H),3.45(s,1H),3.34(d,J＝11.1Hz,2H),3.01(s,1H),2.19(d,J＝10.9Hz,2H),2.14–2.04(m,4H),1.92(s,1H),1.65–1.49(m,8H).
实施例87 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-喹啉-2-羧酰胺(A87)
1H NMR(500MHz,Chloroform)δ8.46(s,1H),8.10(s,1H),7.78(s,1H),7.66(s,1H),7.55(s,1H),7.45(s,1H),7.26–7.11(m,10H),6.86(s,1H),5.98(s,1H),5.89(s,1H),5.56(d,J＝16.8Hz,2H),4.75(s,1H),4.44(s,1H),4.32(s,1H),3.44(s,1H),3.23(d,J＝18.1Hz,2H),2.84(s,1H),2.72(s,1H),2.11–2.01(m,2H),1.98(s,1H),1.63(s,1H),1.56(s,1H),1.25(s,1H).
实施例88 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-喹啉-2-羧酰胺(A88)
1H NMR(500MHz,Chloroform)δ8.50(d,J＝13.8Hz,2H),8.17(s,1H),7.81(s,1H),7.69(s,1H),7.65(s,1H),7.48(s,1H),7.28–7.24(m,1H),7.24–7.11(m,4H),6.95(s,1H),6.17(s,1H),5.50(s,1H),5.00(s,1H),4.79(s,1H),3.24(d,J＝15.4Hz,2H),3.08(s,1H),2.90(s,1H),2.69(s,1H),2.11–2.01(m,2H),1.90(s,1H),1.84(d,J＝3.8Hz,2H),1.78(s,1H),1.29–1.25(m,9H).
实施例89 N-((S)-3-环己基-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-喹啉-2-羧酰胺(A89)
1H NMR(500MHz,Chloroform)δ9.70(s,4H),8.44(s,4H),8.18(s,4H),7.80(s,4H),7.69(d,J＝18.4Hz,8H),7.48(d,J＝4.0Hz,8H),7.32–7.26(m,8H),7.23–7.13(m,12H),6.67(s,4H),5.84(s,4H),4.95(s,4H),4.88(s,4H),3.90(s,4H),3.31(d,J＝56.1Hz,10H),3.22(s,2H),2.99(s,4H),2.86(s,4H),2.11–2.04(m,8H),2.01(t,J＝7.0Hz,12H),1.81(s,3H),1.74(s,3H),1.67–1.60(m,35H),1.45(s,3H).
实施例90 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-4-甲基-1-氧代戊-2-基)-1H-吲哚-2-羧酰胺(A90)
1H NMR(500MHz,Chloroform)δ8.36(s,1H),7.52(d,J＝19.2Hz,2H),7.39(s,1H),7.26–7.19(m,4H),7.18(s,1H),7.13(s,1H),7.07(s,1H),6.32(s,1H),6.24(s,1H),6.05(s,1H),5.47(s,1H),5.27(s,1H),4.61(s,1H),4.41(s,1H),4.32(s,1H),3.59(s,1H),3.45(s,1H),2.17(s,1H),2.09–2.05(m,2H),1.92(s,1H),1.73(d,J＝11.4Hz,2H),1.63(s,1H),1.55(s,1H),1.12–0.99(m,6H).
实施例91 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-环己基-1-氧代戊-2-基)-1H-吲哚-2-羧酰胺(A91)
1H NMR(500MHz,Chloroform)δ9.33(s,1H),8.28(s,1H),7.46(d,J＝15.1Hz,2H),7.35(s,1H),7.10(s,1H),7.03(s,1H),6.79(s,1H),6.12(s,1H),5.28(s,1H),4.95(s,1H),4.31(s,1H),3.45(s,1H),3.35(s,1H),2.75(s,1H),2.19(s,1H),2.09–2.05(m,2H),1.92(s,1H),1.70(d,J＝19.2Hz,2H),1.44(s,1H),1.36–1.32(m,9H),0.99–0.85(m,6H).
实施例92 N-((S)-3-环己基-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-环己基-1-氧代戊-2-基)-1H-吲哚-2-羧酰胺(A92)
1H NMR(500MHz,Chloroform)δ8.38(s,1H),7.51(d,J＝17.6Hz,2H),7.37(s,1H),7.12(s,1H),7.06(s,1H),6.50(s,1H),6.00(s,1H),5.60(s,1H),5.50(s,1H),5.00(s,1H),4.68(s,1H),3.45(s,1H),3.35(s,1H),3.29(s,1H),2.71(s,1H),2.19(s,1H),2.09–2.05(m,2H),1.97–1.91(m,3H),1.70(t,J＝9.1Hz,3H),1.59–1.55(m,2H),1.50(dd,J＝10.4,1.1Hz,4H),1.43–1.38(m,2H),1.13–1.00(m,6H).
实施例93 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-4-甲基-1-氧代戊-2-基)-1H-吲哚-2-羧酰胺(A93)
1H NMR(500MHz,Chloroform)δ8.63(s,1H),7.56(s,1H),7.46(d,J＝25.5Hz,2H),7.29–7.24(m,2H),7.24–7.17(m,3H),7.17–7.06(m,3H),6.14(s,1H),5.63(s,1H),5.02(d,J＝15.0Hz,2H),4.43(s,1H),4.37(s,1H),4.30(s,1H),3.24(d,J＝17.4Hz,2H),2.81(s,1H),2.21(s,1H),2.08–2.04(m,2H),1.85(s,1H),1.77(t,J＝13.2Hz,3H),1.51(s,1H),1.41(s,1H),1.04–0.90(m,6H).
实施例94 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基) 丁-2-基)氨基)-3-环己基-1-氧代戊-2-基)-1H-吲哚-2-羧酰胺(A94)
1H NMR(500MHz,Chloroform)δ8.38(s,1H),8.13(s,1H),7.49(s,1H),7.41(s,1H),7.37(s,1H),7.12(s,1H),7.04(s,1H),5.95(s,1H),5.30(d,J＝18.0Hz,2H),4.86(s,1H),4.51(s,1H),3.23(d,J＝15.7Hz,2H),2.45(s,1H),2.19(s,1H),2.08–2.04(m,2H),1.96(s,1H),1.75(s,1H),1.69(d,J＝8.0Hz,2H),1.51(s,1H),1.36–1.27(m,10H),1.12–0.99(m,6H).
实施例95 N-((S)-3-环己基-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代戊-2-基)-1H-吲哚-2-羧酰胺(A95)
1H NMR(500MHz,Chloroform)δ9.04(s,1H),8.28(s,1H),7.50(d,J＝31.2Hz,2H),7.38(s,1H),7.13(s,1H),7.06(s,1H),6.19(s,1H),5.81(s,1H),5.63(s,1H),4.78(s,1H),4.59(s,1H),3.94(s,1H),3.24(d,J＝18.2Hz,2H),2.35(s,1H),2.13–2.04(m,4H),2.00(s,1H),1.83–1.60(m,8H),1.57(s,1H),1.52–1.46(m,2H),1.45–1.41(m,2H),1.33(s,1H),1.13–1.01(m,6H).
实施例96 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-4-甲基-1-氧代戊-2-基)-苯并呋喃-2-羧酰胺(A96)
1H NMR(500MHz,Chloroform)δ7.74(s,1H),7.42(s,1H),7.36–7.26(m,4H),7.23(s,1H),7.17(s,1H),7.07(s,1H),6.96(s,1H),6.46(s,1H),6.22(s,1H),5.75(s,1H),5.06(s,1H),4.63(s,1H),4.46(d,J＝17.5Hz,2H),4.34(s,1H),3.45(s,1H),3.35(s,1H),3.28(s,1H),2.19(s,1H),2.09–2.05(m,2H),1.93(s,1H),1.67(s,1H),1.55(s,1H),1.19(s,1H),1.07–0.94(m,6H).
实施例97 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-环己基-1-氧代戊-2-基)-苯并呋喃-2-羧酰胺(A97)
1H NMR(500MHz,Chloroform)δ8.17(s,1H),7.45(d,J＝28.3Hz,2H),7.22(s,1H),7.15(s,1H),6.41(s,1H),6.00(s,1H),5.96(s,1H),4.94(s,1H),4.55(s,1H),3.45(s,1H),3.35(s,1H),2.53(s,1H),2.18(s,1H),2.13–2.02(m,2H),1.93(s,1H),1.76(s,1H),1.65(s,1H),1.35–1.31(m,9H),1.25(s,1H),1.07–0.94(m,6H).
实施例98 N-((S)-3-环己基-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-环己基-1-氧代戊-2-基)-苯并呋喃-2-羧酰胺(A98)
1H NMR(500MHz,Chloroform)δ7.59(s,4H),7.55–7.39(m,12H),7.22(s,4H),7.15(s,4H),6.04(s,4H),5.94(s,4H),5.89(s,4H),4.87(s,4H),4.48(s,4H),3.80(s,4H),3.45(s,4H),3.35(s,3H),2.58(s,4H),2.18(s,4H),2.11–2.04(m,8H),1.95–1.88(m,19H),1.87(t,J＝3.1Hz,4H),1.75(d,J＝29.9Hz,6H),1.71(d,J＝3.3Hz,2H),1.69–1.64(m,8H),1.62(s,3H),1.59–1.51(m,8H),1.06–0.93(m,24H).
实施例99 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-4-甲基-1-氧代戊-2-基)-苯并呋喃-2-羧酰胺(A99)
1H NMR(500MHz,Chloroform)δ7.58(s,1H),7.52(d,J＝13.8Hz,2H),7.38–7.32(m,2H),7.30(s,1H),7.26(s,1H),7.23–7.16(m,3H),6.21(s,1H),5.77(s,1H),5.68(s,1H),4.86(s,1H),4.82(s,1H),4.56(s,1H),4.37(s,1H),4.33(s,1H),3.24(d,J＝17.0Hz,2H),2.63(s,1H),2.05(t,J＝5.4Hz,3H),1.82(s,1H),1.75(s,1H),1.60(d,J＝3.4Hz,2H),1.48(s,1H),1.39(s,1H),1.09–1.00(m,6H).
实施例100 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-4-甲基-1-氧代戊-2-基)-苯并呋喃-2-羧酰胺(A100)
1H NMR(500MHz,Chloroform)δ7.58(s,1H),7.52(d,J＝13.8Hz,2H),7.38–7.32(m,2H),7.30(s,1H),7.26(s,1H),7.23–7.16(m,3H),6.21(s,1H),5.77(s,1H),5.68(s,1H),4.86(s,1H),4.82(s,1H),4.56(s,1H),4.37(s,1H),4.33(s,1H),3.24(d,J＝17.0Hz,2H),2.63(s,1H),2.05(t,J＝5.4Hz,3H),1.82(s,1H),1.75(s,1H),1.60(d,J＝3.4Hz,2H),1.48(s,1H),1.39(s,1H),1.09–1.00(m,6H).
实施例101 N-((S)-3-环己基-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代戊-2-基)-苯并呋喃-2-羧酰胺(A101)
1H NMR(500MHz,Chloroform)δ7.59(s,1H),7.48(d,J＝9.6Hz,2H),7.20(s,1H),7.14(s,1H),5.80(s,1H),5.26(s,1H),5.11(d,J＝5.2Hz,2H),4.91(s,1H),3.81(s,1H),3.24(d,J＝17.3Hz,2H),2.61(s,1H),2.09–2.02(m,4H),1.95–1.87(m,2H),1.84(s,1H),1.77(s,1H),1.69(s,1H),1.58(d,J＝5.5Hz,2H),1.51–1.44(m,4H),1.26–1.22(m,4H),1.08–0.95(m,6H).
实施例102 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-4-甲基-1-氧代戊-2-基)-苯并噻吩-2-羧酰胺(A102)
1H NMR(500MHz,Chloroform)δ8.47(s,1H),7.91(s,1H),7.78(s,1H),7.33(d,J＝6.1Hz,2H),7.28–7.17(m,5H),6.42(s,1H),6.05(s,1H),5.73(s,1H),5.38(s,1H),5.27(s,1H),4.46(s,1H),4.36(d,J＝16.9Hz,2H),3.45(s,1H),3.35(s,1H),2.67(s,1H),2.18(s,1H),2.09–2.05(m,2H),1.92(s,1H),1.82(s,1H),1.70(s,1H),1.52(s,1H),1.10–0.96(m,6H).
实施例103 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-环己基-1-氧代戊-2-基)-苯并噻吩-2-羧酰胺(A103)
1H NMR(500MHz,Chloroform)δ8.37(s,1H),7.89(s,1H),7.73(s,1H),7.30(d,J＝2.2Hz,2H),6.58(s,1H),6.03(s,1H),5.61(s,1H),5.53(s,1H),5.02(s,1H),4.70(s,1H),3.45(s,1H),3.35(s,1H),2.69(s,1H),2.19(s,1H),2.09–2.05(m,2H),1.93(s,1H),1.69(d,J＝8.4Hz,2H),1.49(s,1H),1.32–1.28(m,9H),1.10–1.02(m,6H).
实施例104 N-((S)-3-环己基-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-环己基-1-氧代戊-2-基)-苯并噻吩-2-羧酰胺(A104)
1H NMR(500MHz,Chloroform)δ8.63(s,1H),7.91(s,1H),7.74(s,1H),7.34–7.30(m,2H),6.18(d,J＝11.5Hz,2H),6.02(s,1H),4.62(s,1H),4.48(s,1H),3.45(s,1H),3.35(s,1H),3.27(s,1H),2.56(s,1H),2.19(s,1H),2.11–2.05(m,3H),1.92(s,1H),1.83–1.70(m,3H),1.69(s,1H),1.59–1.54(m,3H),1.50(t,J＝6.7Hz,3H),1.42–1.37(m,2H),1.12–0.98(m,6H).
实施例105 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-4-甲基-1-氧代戊-2-基)-苯并噻吩-2-羧酰胺(A105)
1H NMR(500MHz,Chloroform)δ8.43(s,1H),7.93(d,J＝0.7Hz,2H),7.74(s,1H),7.33(d,J＝2.2Hz,2H),7.30–7.25(m,4H),7.20(s,1H),6.65(s,1H),6.05(s,1H),5.58(s,1H),4.71(s,1H),4.52(s,1H),4.40(s,1H),4.30(s,1H),3.23(d,J＝15.8Hz,2H),2.73(s,1H),2.16(s,1H),2.08–2.04(m,2H),1.80(s,1H),1.69(d,J＝6.6Hz,2H),1.63(s,1H),1.44(s,1H),1.35(s,1H),1.12–0.99(m,6H).
实施例106 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代戊-2-基)-苯并噻吩-2-羧酰胺(A106)
1H NMR(500MHz,Chloroform)δ8.39(s,1H),7.91(s,1H),7.71(s,1H),7.31(d,J＝2.6Hz,2H),6.50(s,1H),5.87(s,1H),5.71(s,1H),5.57(s,1H),4.80(s,1H),4.75(s,1H),3.23(d,J＝15.7Hz,2H),2.64(s,1H),2.08–2.04(m,2H),1.87(d,J＝17.5Hz,2H),1.68(d,J＝6.0Hz,2H),1.61(d,J＝2.0Hz,2H),1.37(s,1H),1.32–1.28(m,9H),1.10–0.97(m,6H).
实施例107 N-((S)-3-环己基-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代戊-2-基)-苯并噻吩-2-羧酰胺(A107)
H NMR(500MHz,Chloroform)δ8.30(s,15H),8.25(s,15H),7.87(s,15H),7.71(s,15H),7.30(d,J＝1.3Hz,30H),6.03(s,15H),5.58(s,15H),5.39(s,15H),5.03(s,15H),4.37(s,15H),3.85(s,15H),3.24(d,J＝16.7Hz,29H),2.67(s,11H),2.57(s,13H),2.08–2.04(m,30H),1.96–1.90(m,46H),1.86(s,15H),1.79(s,12H),1.76–1.53(m,169H),1.58(d,J＝5.6Hz,3H),1.05–0.92(m,93H).
实施例108 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-4-甲基-1-氧代戊-2-基)-1-甲基-1H-吲哚-2-羧酰胺(A108)
1H NMR(500MHz,Chloroform)δ7.39(d,J＝5.1Hz,10H),7.31–7.22(m,12H),7.22–7.06(m,35H),5.99(s,5H),5.29(s,5H),4.40(d,J＝4.6Hz,10H),4.30(d,J＝5.3Hz,1H),4.24(d,J＝52.5Hz,9H),3.68–3.64(m,15H),3.58(s,5H),3.45(s,5H),2.78(s,5H),2.17(s,3H),2.15–1.95(m,17H),1.89(s,4H),1.81(s,5H),1.62(s,5H),1.48(s,4H),1.07–0.94(m,31H).
实施例109 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-环己基-1-氧代戊-2-基)-1-甲基-1H-吲哚-2-羧酰胺(A109)
1H NMR(500MHz,Chloroform)δ8.20(s,1H),7.48(s,1H),7.27(d,J＝17.1Hz, 2H),7.18(d,J＝7.0Hz,2H),6.13(s,1H),5.90(s,1H),5.38(s,1H),5.08(s,1H),4.65(s,1H),3.79–3.75(m,3H),3.45(s,1H),3.35(s,1H),2.81(s,1H),2.17(s,1H),2.13–2.02(m,2H),1.93(s,1H),1.67(s,1H),1.60(s,1H),1.55(s,1H),1.34–1.30(m,9H),1.13–1.00(m,6H).
实施例110 N-((S)-3-环己基-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-环己基-1-氧代戊-2-基)-1-甲基-1H-吲哚-2-羧酰胺(A110)
1H NMR(500MHz,Chloroform)δ7.37(s,3H),7.28(d,J＝4.7Hz,6H),7.19(d,J＝11.4Hz,6H),6.24(s,3H),5.90(s,3H),5.81(s,3H),5.30(s,3H),4.90(s,3H),4.68(s,3H),3.90–3.86(m,9H),3.45(s,3H),3.37–3.33(m,5H),2.70(s,3H),2.19(s,3H),2.12–2.04(m,6H),1.93(s,3H),1.86–1.76(m,9H),1.71–1.60(m,11H),1.60–1.54(m,1H),1.51(dd,J＝18.4,1.5Hz,11H),1.44–1.38(m,6H),1.08–0.95(m,18H).
实施例111 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-4-甲基-1-氧代戊-2-基)-1-甲基-1H-吲哚-2-羧酰胺(A111)
1H NMR(500MHz,Chloroform)δ7.62(s,1H),7.34(s,1H),7.30–7.17(m,8H),6.58(s,1H),6.10(s,1H),5.61(s,1H),5.41(s,1H),4.83(s,1H),4.48(s,1H),4.37(s,1H),4.32(s,1H),3.76–3.72(m,3H),3.24(d,J＝17.6Hz,2H),2.57(s,1H),2.08–2.04(m,2H),1.80(s,1H),1.76(s,1H),1.71–1.65(m,2H),1.56(d,J＝15.2Hz,2H),1.21(s,1H),1.10–0.97(m,6H).
实施例112 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代戊-2-基)-1-甲基-1H-吲哚-2-羧酰胺(A112)
1H NMR(500MHz,Chloroform)δ7.57(s,1H),7.51(s,1H),7.31(s,1H),7.25(s,1H),7.18(d,J＝5.1Hz,2H),5.92(s,1H),5.59(s,1H),5.43(s,1H),4.99(s,1H),4.47(s,1H),3.74–3.70(m,3H),3.24(d,J＝16.8Hz,2H),2.71(s,1H),2.41(s,1H),2.08–2.04(m,2H),1.76(dd,J＝34.2,16.8Hz,4H),1.55(s,1H),1.45(s,1H),1.30–1.26(m,9H),1.09–0.96(m,6H).
实施例113 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代戊-2-基)-1-甲基-1H-吲哚-2-羧酰胺(A113)
1H NMR(500MHz,Chloroform)δ7.57(s,1H),7.51(s,1H),7.31(s,1H),7.25(s,1H),7.18(d,J＝5.1Hz,2H),5.92(s,1H),5.59(s,1H),5.43(s,1H),4.99(s,1H),4.47(s,1H),3.74–3.70(m,3H),3.24(d,J＝16.8Hz,2H),2.71(s,1H),2.41(s,1H),2.08–2.04(m,2H),1.76(dd,J＝34.2,16.8Hz,4H),1.55(s,1H),1.45(s,1H),1.30–1.26(m,9H),1.09–0.96(m,6H).
实施例114 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-4-甲基-1-氧代戊-2-基)-4,6-二氯-1H-吲哚-2-羧酰胺(A114)
1H NMR(500MHz,Chloroform)δ9.48(s,5H),7.69(s,5H),7.37(s,5H),7.29 (d,J＝6.5Hz,3H),7.28–7.15(m,23H),7.06(s,5H),6.19(s,5H),5.64(s,5H),5.49(s,5H),5.18(s,5H),4.42(s,5H),4.35(d,J＝14.2Hz,10H),3.45(s,5H),3.35(d,J＝1.5Hz,9H),3.05(s,5H),2.19(s,4H),2.09–2.05(m,10H),1.92(s,4H),1.68(s,5H),1.58(s,5H),1.52(s,5H),1.02–0.89(m,31H).
实施例115 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-环己基-1-氧代戊-2-基)-4,6-二氯-1H-吲哚-2-羧酰胺(A115)
1H NMR(500MHz,Chloroform)δ8.36(s,1H),7.60(s,1H),7.40(s,1H),7.06(s,1H),6.45(s,1H),6.04(s,1H),5.52(d,J＝2.2Hz,2H),4.99(s,1H),4.68(s,1H),3.45(s,1H),3.35(s,1H),2.72(s,1H),2.19(s,1H),2.09–2.05(m,2H),1.93(s,1H),1.70(d,J＝9.3Hz,2H),1.49(s,1H),1.32–1.28(m,9H),1.11–1.02(m,6H).
实施例116 N-((S)-3-环己基-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-环己基-1-氧代戊-2-基)-4,6-二氯-1H-吲哚-2-羧酰胺(A116)
1H NMR(500MHz,Chloroform)δ9.33(s,1H),8.27(s,1H),7.54(s,1H),7.37(s,1H),7.03(s,1H),6.84(s,1H),6.14(s,1H),5.29(s,1H),4.95(s,1H),4.31(s,1H),3.83(s,1H),3.45(s,1H),3.35(s,1H),2.73(s,1H),2.19(s,1H),2.09–2.05(m,2H),2.05–1.90(m,3H),1.72(s,1H),1.70–1.44(m,9H),1.44(d,J＝5.3Hz,1H),0.98–0.85(m,6H).
实施例117 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-4-甲基-1-氧代戊-2-基)-4,6-二氯-1H-吲哚-2-羧酰胺(A117)
1H NMR(500MHz,Chloroform)δ8.38(s,1H),7.67(s,1H),7.42(s,1H),7.29–7.22(m,4H),7.19(s,1H),7.10(d,J＝11.4Hz,2H),6.65(s,1H),5.62(s,1H),5.55(s,1H),4.99(s,1H),4.48(s,1H),4.37(s,1H),4.33(s,1H),3.24(d,J＝16.8Hz,2H),2.56(s,1H),2.45(s,1H),2.08–2.04(m,2H),1.80(d,J＝3.6Hz,2H),1.72(d,J＝14.6Hz,2H),1.55(s,1H),1.46(s,1H),1.10–0.97(m,6H).
实施例118 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代戊-2-基)-4,6-二氯-1H-吲哚-2-羧酰胺(A118)
1H NMR(500MHz,Chloroform)δ8.59(s,1H),7.55(s,1H),7.41(s,1H),7.05(s,1H),6.20(s,1H),5.74(s,1H),5.41(s,1H),4.71(s,1H),4.48(s,1H),3.24(d,J＝17.3Hz,2H),2.48(s,1H),2.06(t,J＝2.1Hz,3H),1.86–1.74(m,3H),1.68(s,1H),1.58(s,1H),1.53(s,1H),1.32–1.28(m,9H),1.15–1.01(m,6H).
实施例119 N-((S)-3-环己基-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代戊-2-基)-4,6-二氯-1H-吲哚-2-羧酰胺(A119)
1H NMR(500MHz,Chloroform)δ8.63(s,1H),8.33(s,1H),7.58(s,1H),7.40 (s,1H),7.07(s,1H),6.32(s,1H),5.80(s,1H),5.52(s,1H),4.79(s,1H),4.59(s,1H),3.96(s,1H),3.24(d,J＝17.9Hz,2H),2.36(s,1H),2.15–2.08(m,2H),2.08–2.04(m,2H),2.00(s,1H),1.74–1.68(m,5H),1.68–1.60(m,3H),1.60–1.50(m,5H),1.33(s,1H),1.13–1.01(m,6H).
实施例120 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-4-甲基-1-氧代戊-2-基)-喹喔啉-2-羧酰胺(A120)
1H NMR(500MHz,Chloroform)δ8.79(s,1H),8.05(s,1H),8.01(s,1H),7.64(d,J＝1.5Hz,2H),7.36–7.25(m,4H),7.20(s,1H),5.82(s,1H),5.78(s,1H),5.24(s,1H),4.97(s,1H),4.68(s,1H),4.36(s,1H),4.23(s,1H),3.68(s,1H),3.45(s,1H),3.35(s,1H),2.21(s,1H),2.09–2.05(m,2H),1.90(d,J＝15.7Hz,2H),1.76(s,1H),1.65(s,1H),1.45(s,1H),1.10–0.97(m,6H).
实施例121 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-环己基-1-氧代戊-2-基)-喹喔啉-2-羧酰胺(A121)
1H NMR(500MHz,Chloroform)δ9.24(s,1H),8.11(d,J＝7.7Hz,2H),7.85(s,1H),7.65(d,J＝1.9Hz,2H),6.22(s,1H),6.11(s,1H),5.66(s,1H),4.77(s,1H),4.62(s,1H),3.45(s,1H),3.35(s,1H),2.79(s,1H),2.17(s,1H),2.13–2.02(m,2H),1.92(s,1H),1.67(d,J＝2.5Hz,2H),1.51(s,1H),1.34–1.30(m,9H),1.11–1.02(m,6H).
实施例122 N-((S)-3-环己基-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-环己基-1-氧代戊-2-基)-喹喔啉-2-羧酰胺(A122)
1H NMR(500MHz,Chloroform)δ9.29(s,1H),8.09(d,J＝18.4Hz,2H),7.60(d,J＝2.0Hz,2H),6.27(s,1H),6.23(s,1H),5.90(s,1H),5.24(s,1H),4.80(s,1H),4.70(s,1H),3.45(s,1H),3.35(d,J＝1.2Hz,2H),2.58(s,1H),2.18(s,1H),2.11–2.03(m,2H),1.93(s,1H),1.86–1.71(m,3H),1.71–1.60(m,4H),1.55–1.46(m,4H),1.44–1.39(m,2H),1.09–0.96(m,6H).
实施例123 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-4-甲基-1-氧代戊-2-基)-喹喔啉-2-羧酰胺(A123)
1H NMR(500MHz,Chloroform)δ9.35(s,1H),8.12(s,1H),7.95(s,1H),7.64(d,J＝15.8Hz,2H),7.33–7.26(m,3H),7.26–7.21(m,2H),6.55(s,1H),6.29(s,1H),5.62(d,J＝10.0Hz,2H),4.84(s,1H),4.54(s,1H),4.16(d,J＝16.2Hz,2H),3.24(d,J＝17.4Hz,2H),2.98(s,1H),2.32(s,1H),2.10–2.04(m,3H),1.85(s,1H),1.78(s,1H),1.71(s,1H),1.59(s,1H),1.45(s,1H),1.13–1.00(m,6H).
实施例124 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代戊-2-基)-喹喔啉-2-羧酰胺(A124)
1H NMR(500MHz,Chloroform)δ9.23(s,1H),8.12(d,J＝11.8Hz,2H),7.65(d,J＝2.9Hz,2H),6.31(s,1H),6.08(s,1H),5.70(s,1H),5.63(s,1H),4.89 (s,1H),4.62(s,1H),3.24(d,J＝17.3Hz,2H),2.62(s,1H),2.04(t,J＝12.6Hz,3H),1.80(s,1H),1.76–1.69(m,3H),1.51(s,1H),1.40(s,1H),1.33–1.29(m,9H),1.12–0.99(m,6H).
实施例125 N-((S)-3-环己基-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代戊-2-基)-喹喔啉-2-羧酰胺(A125)
1H NMR(500MHz,Chloroform)δ9.32(s,1H),8.97(s,1H),8.11(d,J＝3.7Hz,2H),7.65(d,J＝2.2Hz,2H),5.73(s,1H),5.60(s,1H),5.56(s,1H),4.72(s,1H),4.51(s,1H),3.31–3.20(m,3H),2.59(s,1H),2.08–2.00(m,5H),1.81(s,1H),1.69(d,J＝9.0Hz,2H),1.62(s,1H),1.60–1.54(m,3H),1.53–1.42(m,3H),1.39(dd,J＝11.3,3.2Hz,4H),1.09–0.96(m,6H).
实施例126 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-4-甲基-1-氧代戊-2-基)-喹啉-2-羧酰胺(A126)
1H NMR(500MHz,Chloroform)δ8.47(s,1H),8.14(s,1H),7.80(s,1H),7.68(s,1H),7.52(s,1H),7.47(s,1H),7.30–7.26(m,1H),7.26–7.17(m,5H),6.50(s,1H),6.42(s,1H),6.10(s,1H),5.27(s,1H),4.65(d,J＝5.3Hz,2H),4.40(s,1H),4.32(s,1H),3.45(s,1H),3.35(s,1H),2.65(s,1H),2.19(s,1H),2.09–2.05(m,2H),1.93(s,1H),1.69(s,1H),1.59(d,J＝10.7Hz,2H),1.13–1.00(m,7H).
实施例127 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-环己基-1-氧代戊-2-基)-喹啉-2-羧酰胺(A127)
1H NMR(500MHz,Chloroform)δ8.36(s,1H),8.14(s,1H),7.77(s,1H),7.69(s,1H),7.46(s,1H),7.40(s,1H),6.36(s,1H),6.13(s,1H),6.02(s,1H),5.67(s,1H),4.93(s,1H),4.61(s,1H),3.45(s,1H),3.35(s,1H),2.63(s,1H),2.18(s,1H),2.09–2.05(m,2H),1.92(s,1H),1.73(d,J＝1.3Hz,2H),1.52(s,1H),1.33–1.29(m,9H),1.09–1.03(m,6H).
实施例128 N-((S)-3-环己基-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-环己基-1-氧代戊-2-基)-喹啉-2-羧酰胺(A128)
1H NMR(500MHz,Chloroform)δ9.46(s,1H),8.44(s,1H),8.17(s,1H),7.80(s,1H),7.71(s,1H),7.47(d,J＝10.8Hz,2H),5.88(s,1H),5.82(s,1H),5.18(s,1H),4.96(s,1H),4.52(s,1H),3.74(s,1H),3.45(s,1H),3.35(s,1H),2.64(s,1H),2.19(s,1H),2.09–2.05(m,2H),1.95(t,J＝7.9Hz,3H),1.71(s,1H),1.57(tt,J＝16.6,2.2Hz,9H),1.44(s,1H),1.11–0.98(m,6H).
实施例129 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-4-甲基-1-氧代戊-2-基)-喹啉-2-羧酰胺(A129)
1H NMR(500MHz,Chloroform)δ8.45(s,1H),8.18(s,1H),7.81(s,1H),7.72(s,1H),7.47(d,J＝14.9Hz,2H),7.29–7.21(m,4H),7.19(s,1H),6.66(s,1H),6.36(s,1H),5.90(s,1H),5.60(s,1H),5.00(s,1H),4.50(s,1H),4.34(d, J＝14.6Hz,2H),3.24(d,J＝16.9Hz,2H),2.47(d,J＝1.9Hz,2H),2.08–2.04(m,2H),1.80(s,1H),1.77–1.69(m,3H),1.55(s,1H),1.46(s,1H),1.09–0.96(m,6H).
实施例130 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代戊-2-基)-喹啉-2-羧酰胺(A130)
1H NMR(500MHz,Chloroform)δ8.45(s,1H),8.17(s,1H),7.81(s,1H),7.71(s,1H),7.48(d,J＝2.3Hz,2H),5.90(s,1H),5.74(s,1H),5.54(s,1H),5.27(s,1H),5.13(s,1H),4.51(s,1H),3.24(d,J＝17.6Hz,2H),2.61(s,1H),2.08–2.04(m,2H),1.89–1.64(m,5H),1.48(d,J＝18.1Hz,2H),1.33–1.29(m,9H),1.09–0.96(m,6H).
实施例131 N-((S)-3-环己基-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代戊-2-基)-喹啉-2-羧酰胺(A131)
1H NMR(500MHz,Chloroform)δ8.45(s,1H),8.17(s,1H),7.81(s,1H),7.71(s,1H),7.49(d,J＝4.2Hz,2H),6.05(s,1H),5.83(s,1H),5.54(s,1H),5.39(s,1H),5.11(s,1H),4.52(s,1H),3.30–3.20(m,3H),2.61(s,1H),2.08–2.04(m,2H),2.02–1.90(m,2H),1.87–1.77(m,3H),1.75–1.68(m,5H),1.55–1.44(m,5H),1.44–1.39(m,2H),1.09–0.96(m,6H).
实施例132 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-6-氯-3,8a-二氢-2H-苯并吡喃-3-羧酰胺(A132)
1H NMR(500MHz,Chloroform)δ7.39–7.29(m,2H),7.29–7.20(m,7H),7.18(s,1H),6.65(s,1H),6.45(d,J＝4.2Hz,2H),6.24(s,1H),6.13(d,J＝3.8Hz,2H),6.03(s,1H),5.47(s,1H),4.93(d,J＝16.9Hz,2H),4.66(s,1H),4.42(s,1H),4.33(s,1H),3.66(s,1H),3.45(s,1H),3.40–3.30(m,3H),3.18(s,1H),2.96(d,J＝11.1Hz,2H),2.18(s,1H),2.12–2.02(m,2H),1.93(s,1H).
实施例133 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-6-氯-3,8a-二氢-2H-苯并吡喃-3-羧酰胺(A133)
1H NMR(500MHz,Chloroform)δ7.27–7.21(m,2H),7.21–7.11(m,3H),7.10(s,1H),6.49(s,1H),6.31(s,1H),6.20(s,1H),6.13(s,1H),5.96(d,J＝15.6Hz,2H),5.67(s,1H),4.90(s,1H),4.85(s,1H),4.66(s,1H),4.14(s,1H),3.69(s,1H),3.42(d,J＝26.2Hz,2H),3.33(d,J＝15.0Hz,2H),3.23(s,1H),2.83(s,1H),2.68(s,1H),2.17(s,1H),2.09–2.05(m,2H),1.91(s,1H),1.36–1.32(m,10H).
实施例134 N-((S)-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-6-氯-3,8a-二氢-2H-苯并吡喃-3-羧酰胺(A134)
1H NMR(500MHz,Chloroform)δ8.76(s,5H),8.45(s,5H),7.29–7.23(m,10H),7.16(s,5H),7.14–7.05(m,10H),6.44(s,5H),6.29(s,5H),6.03(s,5H),5.93(d,J＝10.5Hz,10H),5.21(s,5H),5.05(s,5H),4.64(d,J＝18.2Hz,10H), 3.67(s,4H),3.48–3.46(m,2H),3.43(t,J＝11.4Hz,14H),3.37(dt,J＝43.5,18.6Hz,29H),3.05(s,5H),2.86(s,5H),2.19(s,5H),2.09–2.05(m,10H),1.95–1.86(m,15H),1.72–1.64(m,15H),1.56–1.52(m,9H),1.50(s,6H),1.45–1.40(m,10H).
实施例135 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-6-氯-3,8a-二氢-2H-苯并吡喃-3-羧酰胺(A135)
1H NMR(500MHz,Chloroform)δ7.82(s,1H),7.30–7.22(m,4H),7.21–7.07(m,6H),6.48(s,1H),6.29(s,1H),6.16(s,1H),6.09(s,1H),5.96(d,J＝19.6Hz,2H),5.31(s,1H),4.94(s,1H),4.66(s,1H),4.61(s,1H),4.41(s,1H),4.33(s,1H),3.72(s,1H),3.51–3.12(m,5H),3.24(d,J＝16.9Hz,2H),3.24(d,J＝16.9Hz,2H),2.96(s,1H),2.43(s,1H),2.19(s,1H),2.08–2.03(m,2H),1.80(s,1H),1.73(s,1H),1.55(s,1H).
实施例136 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-6-氯-3,8a-二氢-2H-苯并吡喃-3-羧酰胺(A136)
1H NMR(500MHz,Chloroform)δ7.32–7.26(m,2H),7.18(s,1H),7.15–7.08(m,2H),6.45(s,1H),6.28(s,1H),6.02(s,1H),5.94(d,J＝3.0Hz,2H),5.80(s,1H),5.63(s,1H),5.14(s,1H),4.66(s,1H),4.55(s,1H),3.91(s,1H),3.65(s,1H),3.49–3.10(m,5H),3.25(t,J＝14.8Hz,3H),3.25(t,J＝14.8Hz,3H),3.01(s,1H),2.53(s,1H),2.08–2.04(m,2H),1.94(s,1H),1.80(d,J＝1.0Hz,2H),1.73(s,1H),1.34–1.30(m,9H).
实施例137 N-((S)-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-6-氯-3,8a-二氢-2H-苯并吡喃-3-羧酰胺(A137)
1H NMR(500MHz,Chloroform)δ7.30–7.26(m,1H),7.26–7.14(m,4H),6.52(s,1H),6.47(s,1H),6.14(s,1H),6.04(s,1H),5.96(s,1H),5.87(d,J＝16.5Hz,2H),5.02(d,J＝1.5Hz,2H),4.66(s,1H),4.48(s,1H),3.68(s,1H),3.51(s,1H),3.40(s,1H),3.31(d,J＝10.7Hz,2H),3.24(d,J＝17.3Hz,2H),3.01(d,J＝17.6Hz,2H),2.12–2.04(m,5H),1.96(s,1H),1.82(s,1H),1.75(s,1H),1.71–1.64(m,3H),1.56–1.52(m,2H),1.48(s,1H),1.45–1.40(m,2H).
实施例138 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)苯[d][1,3]间二氧杂环戊烯-5-羧酰胺(A138)
1H NMR(500MHz,Chloroform)δ7.52(s,1H),7.43–7.23(m,8H),7.23–7.19(m,3H),7.16(s,1H),6.92(s,1H),6.04(s,1H),5.92–5.88(m,2H),5.21(s,1H),4.83(s,1H),4.75(s,1H),4.44(s,1H),4.38(s,1H),3.45(s,1H),3.36(d,J＝13.2Hz,2H),2.95(s,1H),2.80(s,1H),2.18(s,1H),2.09–2.05(m,2H),1.92(s,1H).
实施例139 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)苯[d][1,3]间二氧杂环戊烯-5-羧酰胺(A139)
1H NMR(500MHz,Chloroform)δ7.48(s,1H),7.32(s,1H),7.29–7.23(m,2H),7.23–7.14(m,3H),6.91(s,1H),5.95(s,1H),5.92–5.88(m,2H),4.76(d,J＝1.1Hz,2H),4.71(s,1H),3.46(d,J＝12.3Hz,2H),3.35(s,1H),3.08(s,1H),2.99(s,1H),2.19(s,1H),2.09–2.05(m,2H),1.93(s,1H),1.40–1.36(m,9H).
实施例140 N-((S)-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)苯[d][1,3]间二氧杂环戊烯-5-羧酰胺(A140)
1H NMR(500MHz,Chloroform)δ7.30(dd,J＝21.6,15.7Hz,4H),7.28–7.23(m,1H),7.28–7.14(m,4H),6.89(s,1H),6.05(s,1H),5.92–5.88(m,2H),5.08(s,1H),4.75(d,J＝16.1Hz,2H),3.59(s,1H),3.45(d,J＝2.5Hz,2H),3.35(s,1H),3.12(s,1H),2.99(s,1H),2.19(s,1H),2.10–2.04(m,4H),1.93(s,1H),1.81–1.70(m,3H),1.58–1.54(m,2H),1.51(s,1H),1.47–1.42(m,2H).
实施例141 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)苯[d][1,3]间二氧杂环戊烯-5-羧酰胺(A141)
1H NMR(500MHz,Chloroform)δ7.41(s,1H),7.36(s,1H),10.00–7.08(m,14H),6.54(s,1H),6.07(s,1H),5.92–5.88(m,2H),5.10(s,1H),4.42(s,1H),4.37(d,J＝6.5Hz,2H),4.30(s,1H),3.60(s,1H),3.25(t,J＝13.9Hz,3H),3.03(s,1H),2.73(s,1H),2.09–2.03(m,2H),1.79(d,J＝5.2Hz,2H),1.73(s,1H),1.57(s,1H).
实施例142 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)苯[d][1,3]间二氧杂环戊烯-5-羧酰胺(A142)
1H NMR(500MHz,Chloroform)δ8.38(s,28H),7.44(s,29H),7.30–7.23(m,86H),7.23–7.15(m,82H),7.15(d,J＝1.8Hz,4H),6.98(s,29H),5.92–5.85(m,85H),5.21(s,28H),5.00(s,27H),4.81(s,28H),4.66(s,28H),3.26(t,J＝21.5Hz,87H),2.91(s,30H),2.78(s,26H),2.21(s,20H),2.11–2.02(m,61H),2.00(s,21H),1.83(s,25H),1.77(s,21H),1.32–1.28(m,251H).
实施例143 N-((S)-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)苯[d][1,3]间二氧杂环戊烯-5-羧酰胺(A143)
1H NMR(500MHz,Chloroform)δ8.29(s,1H),7.48(s,1H),7.38(s,1H),7.28–7.23(m,2H),7.23–7.11(m,3H),6.94(s,1H),6.09(s,1H),5.92–5.88(m,2H),5.06(s,1H),4.91(s,1H),4.73(s,1H),4.38(s,1H),3.36(s,1H),3.31–3.20(m,3H),3.07(s,1H),2.85(s,1H),2.08–2.03(m,4H),1.88(s,1H),1.81(s,1H),1.78–1.69(m,3H),1.67(s,1H),1.58(s,1H),1.51(t,J＝7.6Hz,3H),1.43–1.39(m,2H).
实施例144 N-((S)-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)苯[d][1,3]间二氧杂环戊烯-5-羧酰胺(A144)
1H NMR(500MHz,Chloroform)δ8.29(s,1H),7.48(s,1H),7.38(s,1H),7.28–7.23(m,2H),7.23–7.11(m,3H),6.94(s,1H),6.09(s,1H),5.92–5.88 (m,2H),5.06(s,1H),4.91(s,1H),4.73(s,1H),4.38(s,1H),3.36(s,1H),3.31–3.20(m,3H),3.07(s,1H),2.85(s,1H),2.08–2.03(m,4H),1.88(s,1H),1.81(s,1H),1.78–1.69(m,3H),1.67(s,1H),1.58(s,1H),1.51(t,J＝7.6Hz,3H),1.43–1.39(m,2H).
实施例145 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-5-氟烟酰胺(A145)
1H NMR(500MHz,Chloroform)δ8.60(d,J＝2.3Hz,2H),7.83(s,1H),7.23(d,J＝6.4Hz,1H),7.22–7.08(m,5H),5.97(s,1H),5.48(s,1H),4.88(s,1H),4.38(s,1H),4.01(s,1H),3.45(s,1H),3.35(s,1H),3.26(s,1H),2.96(s,1H),2.69(s,1H),2.40(s,1H),2.16(s,1H),2.09–2.05(m,2H),1.92(s,1H),1.32–1.28(m,10H).
实施例146 N-((S)-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-5-氟烟酰胺(A146)
1H NMR(500MHz,Chloroform)δ8.82(s,1H),8.50(s,1H),7.89(s,1H),7.31–7.24(m,4H),7.17(s,1H),6.22(s,1H),5.95(s,1H),5.47(s,1H),5.14(s,1H),4.38(s,1H),3.45(s,1H),3.37(d,J＝16.6Hz,2H),3.29(s,1H),2.86(s,1H),2.47(s,1H),2.19(s,1H),2.09–2.05(m,2H),1.93(s,1H),1.91–1.79(m,2H),1.70(s,1H),1.58–1.51(m,4H),1.50(s,1H),1.45–1.40(m,2H).
实施例147 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-5-氟烟酰胺(A147)
1H NMR(500MHz,Chloroform)δ8.80(s,1H),8.58(s,1H),7.99(s,1H),7.41–7.32(m,2H),7.32–7.18(m,6H),7.16(s,1H),7.09(s,1H),6.51(s,1H),6.23(s,1H),5.85(s,1H),4.87(s,1H),4.36(s,1H),4.30(d,J＝5.9Hz,2H),3.24(d,J＝15.2Hz,2H),3.09(s,1H),2.82(s,1H),2.57(s,1H),2.08–2.04(m,2H),1.98(s,1H),1.82(s,1H),1.76(s,1H),1.65(s,1H).
实施例148 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-5-氟烟酰胺(A148)
1H NMR(500MHz,Chloroform)δ8.82(s,1H),8.52(s,1H),8.05(s,1H),7.30–7.22(m,4H),7.15(s,1H),6.03(s,1H),5.79(s,1H),5.01(s,1H),4.84(s,1H),4.27(s,1H),3.36(s,1H),3.24(d,J＝14.9Hz,2H),2.95(s,1H),2.72(s,1H),2.07(t,J＝5.5Hz,3H),1.85(s,1H),1.78(s,1H),1.70(s,1H),1.32–1.28(m,9H).
实施例149 N-((S)-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-5-氟烟酰胺(A149)
1H NMR(500MHz,Chloroform)δ8.86(s,7H),8.52(s,7H),7.93(s,7H),7.42(s,7H),7.24–7.19(m,14H),7.14(s,7H),7.12–7.04(m,14H),6.15(d,J＝16.5Hz,14H),5.79(s,7H),4.89(s,7H),4.62(s,7H),3.87(s,7H),3.27(t,J＝22.0Hz, 22H),3.17(t,J＝12.5Hz,1H),3.11(d,J＝17.0Hz,14H),2.12(s,5H),2.10–2.01(m,16H),2.01–1.94(m,14H),1.87(s,5H),1.80(s,5H),1.67–1.58(m,67H).
实施例150 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-1-甲基-1H-吡唑-4-羧酰胺(A150)
1H NMR(500MHz,Chloroform)δ7.52(s,5H),7.32–7.14(m,55H),7.13(t,J＝1.5Hz,1H),7.07(s,5H),6.09(s,5H),6.01(s,5H),5.64(s,5H),5.02(s,5H),4.84(s,5H),4.36(s,5H),4.29(s,5H),3.89–3.85(m,15H),3.45(s,5H),3.35(s,4H),3.17(s,4H),3.11(s,5H),2.93(s,5H),2.19(s,4H),2.10–2.04(m,10H),1.92(s,4H).
实施例151 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-1-甲基-1H-吡唑-4-羧酰胺(A151)
1H NMR(500MHz,Chloroform)δ7.86(s,1H),7.42(s,1H),10.00–7.19(m,6H),7.17(s,1H),7.05(s,1H),5.92(d,J＝15.2Hz,2H),5.77(s,1H),5.06(s,1H),4.87(s,1H),3.89–3.85(m,3H),3.45(s,1H),3.35(s,1H),3.18(s,1H),2.88(d,J＝18.2Hz,2H),2.17(s,1H),2.13–2.02(m,2H),1.92(s,1H),1.34–1.30(m,9H).
实施例152 N-((S)-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-1-甲基-1H-吡唑-4-羧酰胺(A152)
1H NMR(500MHz,Chloroform)δ7.28–7.17(m,5H),7.15(s,1H),7.08(s,1H),6.04(s,1H),5.89(s,1H),4.77(s,1H),4.30(s,1H),4.02–3.98(m,3H),3.83(s,1H),3.71(s,1H),3.45(s,1H),3.35(s,1H),3.30(s,1H),3.05(s,1H),2.97(s,1H),2.65(s,1H),2.20(s,1H),2.09–2.05(m,2H),2.04–2.00(m,1H),1.91(s,1H),1.67–1.55(m,7H).
实施例153 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-1-甲基-1H-吡唑-4-羧酰胺(A153)
1H NMR(500MHz,Chloroform)δ8.58(s,7H),8.29(s,7H),7.42(s,7H),7.32–7.24(m,28H),7.18(dt,J＝57.0,25.2Hz,40H),7.08–7.07(m,2H),6.51(s,7H),6.01(s,7H),5.10(s,7H),4.81(s,7H),4.38(s,7H),4.32(s,7H),3.93–3.89(m,21H),3.30(d,J＝53.3Hz,17H),3.21(s,3H),3.21(s,6H),2.99(s,7H),2.17(s,6H),2.11–2.01(m,14H),1.76(d,J＝12.9Hz,12H),1.68(s,5H),1.42(s,6H).
实施例154 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-1-甲基-1H-吡唑-4-羧酰胺(A154)
1H NMR(500MHz,Chloroform)δ9.02(s,1H),7.53(s,1H),7.31–7.25(m,2H),7.17(dd,J＝16.8,9.4Hz,4H),6.20(s,1H),6.11(s,1H),5.60(s,1H),5.16(s,1H),4.76(s,1H),3.90–3.86(m,3H),3.24(d,J＝15.4Hz,2H),3.12(s,1H),2.92(d,J＝17.7Hz,2H),2.05(t,J＝4.4Hz,3H),1.82(s,1H),1.76(s,1H),1.56 (s,1H),1.31–1.27(m,9H).
实施例155 N-((S)-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-1-甲基-1H-吡唑-4-羧酰胺(A155)
1H NMR(500MHz,Chloroform)δ8.38(s,1H),7.28–7.22(m,2H),7.22–7.11(m,3H),7.04(s,1H),6.62(s,1H),5.99(s,1H),4.76(s,1H),4.62(s,1H),4.30(s,1H),3.83–3.79(m,3H),3.26(dd,J＝17.5,12.1Hz,4H),3.05(s,1H),3.01(s,1H),2.72(s,1H),2.20–2.13(m,3H),2.09–2.03(m,2H),1.86(s,1H),1.80(s,1H),1.72–1.66(m,3H),1.56(t,J＝5.2Hz,3H),1.49(s,1H),1.46–1.41(m,2H).
实施例156 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-6-溴咪唑并[1,2-a]吡啶-2-羧酰胺(A156)
1H NMR(500MHz,Chloroform)δ8.45(s,1H),7.77(s,1H),7.68(s,1H),7.58(s,1H),7.40(s,1H),7.32–7.26(m,4H),7.26–7.11(m,7H),6.00(s,1H),5.04(s,1H),4.92(s,1H),4.77(s,1H),4.38(s,1H),4.30(s,1H),3.45(s,1H),3.35(s,1H),3.27(s,1H),3.11(s,1H),2.85(s,1H),2.19(s,1H),2.09–2.05(m,2H),1.92(s,1H).
实施例157 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-6-溴咪唑并[1,2-a]吡啶-2-羧酰胺(A157)
1H NMR(500MHz,Chloroform)δ8.80(s,1H),8.37(s,1H),7.69(d,J＝2.2Hz,2H),7.59(s,1H),7.28–7.21(m,2H),7.21–7.11(m,3H),6.78(s,1H),5.98(s,1H),5.45(s,1H),4.93(s,1H),4.66(s,1H),3.45(s,1H),3.35(s,1H),3.22(s,1H),2.96(d,J＝29.5Hz,2H),2.19(s,1H),2.09–2.05(m,2H),1.92(s,1H),1.34–1.30(m,9H).
实施例158 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-6-溴咪唑并[1,2-a]吡啶-2-羧酰胺(A158)
1H NMR(500MHz,Chloroform)δ8.39(s,1H),7.69(d,J＝16.1Hz,2H),7.60(s,1H),7.36–7.20(m,9H),7.19(d,J＝13.6Hz,2H),6.50(s,1H),6.28(s,1H),6.16(s,1H),6.10(s,1H),4.75(d,J＝4.7Hz,2H),4.39(s,1H),4.30(s,1H),3.24(t,J＝8.9Hz,3H),3.01(s,1H),2.72(s,1H),2.11–2.01(m,2H),1.84(s,1H),1.80(s,1H),1.73(s,1H),1.36(s,1H).
实施例159 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-6-溴咪唑并[1,2-a]吡啶-2-羧酰胺(A159)
1H NMR(500MHz,Chloroform)δ8.41(s,1H),8.18(s,1H),7.79–7.57(m,3H),7.27–7.21(m,2H),7.21–7.10(m,3H),6.09(s,1H),5.52(s,1H),5.08(s,1H),4.74(s,1H),4.45(s,1H),3.25(t,J＝9.9Hz,3H),3.01(s,1H),2.85(s,1H),2.10–2.02(m,2H),1.88(s,1H),1.81(s,1H),1.68(s,1H),1.60(s,1H),1.35–1.31(m,9H).
实施例160 N-((S)-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-6-溴咪唑并[1,2-a]吡啶-2-羧酰胺(A160)
1H NMR(500MHz,Chloroform)δ9.87(s,1H),8.26(s,1H),7.68(s,1H),7.57(d,J＝11.2Hz,2H),7.27–7.21(m,2H),7.21–7.10(m,3H),6.07(s,1H),4.94(s,1H),4.78(s,1H),4.51(s,1H),3.54(s,1H),3.45(s,1H),3.24(d,J＝16.2Hz,2H),3.17(s,1H),2.97(s,1H),2.92(s,1H),2.28(s,1H),2.09–2.04(m,4H),1.81(s,1H),1.74(s,1H),1.70(s,1H),1.59–1.52(m,4H),1.49(d,J＝1.6Hz,2H),1.47–1.41(m,2H).
实施例161 N-((S)-1-(((S)-4-(苯基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-1H-苯并[d]咪唑-2-羧酰胺(A161)
1H NMR(500MHz,Chloroform)δ7.62(d,J＝18.9Hz,2H),7.34–7.23(m,9H),7.23–7.12(m,3H),6.92(s,1H),6.17(s,1H),5.35(s,1H),5.03(s,1H),4.70(d,J＝4.7Hz,2H),4.38(s,1H),4.33(s,1H),4.03(s,1H),3.35(s,1H),3.27(s,1H),3.04(s,1H),2.82(s,1H),2.17(s,1H),2.12–2.03(m,2H),1.93(s,1H).
实施例162 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-1H-苯并[d]咪唑-2-羧酰胺(A162)
1H NMR(500MHz,Chloroform)δ7.68(s,1H),7.59(s,1H),7.30–7.25(m,2H),7.22–7.16(m,2H),7.16–7.06(m,3H),6.17(s,1H),5.89(s,1H),5.84(s,1H),5.11(s,1H),4.98(s,1H),3.45(s,1H),3.35(s,1H),3.25(s,1H),3.04(s,1H),2.28(s,1H),2.19(s,1H),2.11–2.03(m,2H),1.92(s,1H),1.35–1.31(m,9H).
实施例163 N-((S)-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-1H-苯并[d]咪唑-2-羧酰胺(A163)
1H NMR(500MHz,Chloroform)δ7.70(s,1H),7.57(d,J＝4.5Hz,2H),7.22(dd,J＝17.6,7.1Hz,4H),7.18–7.07(m,3H),5.97(s,1H),5.74(s,1H),5.03(s,1H),4.50(d,J＝11.0Hz,2H),4.41(s,1H),3.61(s,1H),3.45(s,1H),3.35(s,1H),3.21(s,1H),3.03(s,1H),2.80(s,1H),2.17(s,1H),2.09–2.05(m,2H),1.93–1.78(m,3H),1.71(s,1H),1.64–1.60(m,2H),1.58–1.54(m,2H),1.50(s,1H),1.48–1.42(m,2H).
实施例164 N-((S)-1-(((S)-4-(苯基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-1H-苯并[d]咪唑-2-羧酰胺(A164)
1H NMR(500MHz,Chloroform)δ7.73(s,1H),7.67(s,1H),7.38(t,J＝17.9Hz,3H),7.27–7.13(m,9H),7.11(s,1H),6.99(s,1H),6.45(s,1H),5.48(s,1H),4.94(d,J＝7.2Hz,2H),4.89(s,1H),4.32(s,1H),4.26(s,1H),3.42(s,1H),3.24(d,J＝18.2Hz,2H),3.06(s,1H),2.92(s,1H),2.13(s,1H),2.11–2.00(m,2H),1.92(s,1H),1.86(s,1H),1.79(s,1H).
实施例165 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-1H-苯并[d]咪唑-2-羧酰胺(A165)
1H NMR(500MHz,Chloroform)δ9.34(s,4H),7.98(s,4H),7.79(s,4H),7.62(s,4H),7.54(s,4H),7.42–7.28(m,23H),7.28–7.26(m,2H),7.16(s,4H),5.87(s,4H),5.43(s,4H),5.16(s,4H),4.27(s,4H),3.33–3.20(m,12H),2.94(s,4H),2.82(s,4H),2.08–2.04(m,8H),1.96(s,3H),1.82(s,3H),1.76(s,3H),1.63(s,3H),1.33–1.29(m,36H).
实施例166 N-((S)-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-1H-苯并[d]咪唑-2-羧酰胺(A166)
1H NMR(500MHz,Chloroform)δ8.45(s,1H),8.24(s,1H),7.65(s,1H),7.60(s,1H),7.53(s,1H),7.24(dd,J＝20.9,2.1Hz,4H),7.16–7.04(m,3H),5.61(s,1H),5.36(s,1H),5.09(s,1H),4.63(s,1H),3.50(s,1H),3.41(s,1H),3.24(d,J＝15.7Hz,2H),2.98(s,1H),2.66(s,1H),2.57(s,1H),2.27–2.16(m,2H),2.08–2.04(m,2H),1.98(s,1H),1.85(s,1H),1.78(s,1H),1.72(s,1H),1.63–1.55(m,4H),1.55–1.44(m,3H).
实施例167 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-1H-吲哚-5-羧酰胺(A167)
1H NMR(500MHz,Chloroform)δ9.78(s,1H),8.99(s,1H),8.23(s,1H),7.81(s,1H),7.49(d,J＝90.0Hz,2H),7.40–7.38(m,4H),7.30(d,J＝15.0Hz,5H),7.19(s,34H),7.14(s,4H),7.07(s,1H),6.56(s,1H),6.10(s,1H),5.29(s,1H),5.09(s,1H),4.85(s,1H),4.34(s,2H),3.63(s,21H),3.51(s,1H),3.33(s,1H),3.08(s,1H),2.65(s,1H),2.20(s,1H),2.02(s,1H),1.90(s,1H).
实施例168 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-1H-吲哚-5-羧酰胺(A168)
1H NMR(500MHz,Chloroform)δ8.95(s,1H),8.26(d,J＝60.3Hz,2H),7.78(s,1H),7.55(s,1H),7.31–7.18(m,4H),7.16(s,1H),7.31–6.84(m,7H),6.55(d,J＝16.4Hz,2H),5.97(s,1H),5.15(s,1H),4.79(s,1H),3.63(s,1H),3.51(s,1H),3.32(s,1H),3.07(s,1H),2.54(s,1H),2.21(s,1H),2.02(s,1H),1.91(s,1H),1.26(s,9H).
实施例169 N-((S)-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-1H-吲哚-5-羧酰胺(A169)
1H NMR(500MHz,Chloroform)δ8.98(s,13H),8.34(s,13H),8.22(s,14H),7.80(s,13H),7.57(s,14H),7.37–7.20(m,2H),7.18(s,14H),7.37–6.87(m,82H),6.56(s,13H),6.49(s,13H),5.99(s,13H),5.17(s,7H),4.95(s,5H),4.79(s,7H),3.64(s,6H),3.52(s,6H),3.33(s,15H),3.08(s,14H),2.55(s,5H),2.20(d,J＝14.4Hz,31H),2.02(s,14H),1.88(d,J＝38.0Hz,37H),1.80(s, 5H),1.62(s,9H),1.37(s,27H),1.31(s,11H),1.20(s,23H).
实施例170 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-1H-吲哚-5-羧酰胺(A170)
1H NMR(500MHz,Chloroform)δ8.99(s,2H),8.23(s,2H),8.06(s,2H),7.81(s,2H),7.58(s,2H),7.29(d,J＝15.0Hz,9H),7.19(s,1H),7.14(s,9H),7.05(d,J＝24.0Hz,3H),6.56(s,2H),6.06(s,2H),5.05(s,2H),4.76(s,1H),4.34(s,4H),3.55–2.80(m,10H),3.48–2.77(m,10H),3.28–2.80(m,8H),2.87–2.77(m,1H),2.70(s,1H),2.34(s,1H),2.01(s,1H),1.91(d,J＝2.6Hz,2H),1.60(s,1H).
实施例171 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-1H-吲哚-5-羧酰胺(A171)
1H NMR(500MHz,Chloroform)δ8.99(s,1H),8.23(s,1H),7.91(s,1H),7.81(s,1H),7.58(s,1H),7.26–7.21(m,4H),7.19(s,1H),7.26–6.88(m,6H),6.57(d,J＝15.1Hz,2H),6.06(s,1H),5.06(s,1H),4.71(s,1H),3.33(s,1H),3.21(d,J＝15.0Hz,2H),3.08(s,1H),2.93(s,1H),2.43(s,1H),2.39(s,1H),2.01(s,1H),1.91(d,J＝1.1Hz,1H),1.58(s,13H),1.27(s,9H).
实施例172 N-((S)-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-1H-吲哚-5-羧酰胺(A172)
1H NMR(500MHz,Chloroform)δ8.99(s,1H),8.23(s,1H),7.81(s,1H),7.68(s,1H),7.58(s,1H),7.26–7.21(m,7H),7.19(s,1H),7.26–6.88(m,6H),6.53(d,J＝28.7Hz,2H),6.50–6.48(m,5H),6.08(s,1H),5.06(s,1H),4.95(s,1H),4.70(s,1H),3.33(s,1H),3.21(d,J＝15.0Hz,2H),3.08(s,1H),2.94(s,1H),2.44(d,J＝13.0Hz,2H),2.19(s,2H),2.03–1.73(m,5H),1.84(s,3H),1.84(s,2H),1.60(d,J＝15.4Hz,2H),1.37(s,2H),1.31(s,1H),1.20(s,2H).
实施例173 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-5-氟-1H-吲哚-2-羧酰胺(A173)
1H NMR(500MHz,Chloroform)δ8.75(s,2H),8.14(s,2H),7.54(d,J＝24.9Hz,4H),7.37–7.24(m,13H),7.17(s,1H),7.11(d,J＝10.0Hz,11H),6.85(s,2H),6.14(s,2H),5.18(s,2H),4.86(s,1H),4.33(s,4H),3.65(s,1H),3.53(s,1H),3.28(s,4H),3.03(s,1H),2.54(s,2H),2.22(s,2H),2.02(s,2H),1.93(s,1H).
实施例174 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-5-氟-1H-吲哚-2-羧酰胺(A174)
1H NMR(500MHz,Chloroform)δ8.73(s,1H),8.12(s,1H),7.55(d,J＝25.0Hz,2H),7.51(s,3H),7.16(dd,J＝31.6,6.6Hz,7H),6.56(s,1H),6.10(s,1H),5.19(s,1H),4.83(s,1H),3.65(s,1H),3.54(s,1H),3.29(s,1H),3.04(s,1H),2.58(s,1H),2.22(s,1H),2.02(s,1H),1.92(s,5H),1.27(s,9H).
实施例175 N-((S)-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-5-氟-1H-吲哚-2-羧酰胺(A175)
1H NMR(500MHz,Chloroform)δ8.74(s,1H),8.08(s,1H),7.55(d,J＝25.0Hz,2H),7.51(s,3H),7.19(d,J＝2.2Hz,2H),7.13(d,J＝10.0Hz,5H),6.44(s,1H),6.11(s,1H),5.19(s,1H),4.83(s,1H),3.67(d,J＝15.7Hz,1H),3.54(s,1H),3.29(s,1H),3.04(s,1H),2.58(s,1H),2.22(s,1H),2.02(s,1H),1.92(s,1H),1.74(s,1H),1.46(t,J＝12.5Hz,3H),1.21(s,1H),1.11(s,1H).
实施例176 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-5-氟-1H-吲哚-2-羧酰胺(A176)
1H NMR(500MHz,Chloroform)δ8.71(s,2H),8.61(s,2H),7.69(s,2H),7.58(s,2H),7.53(s,1H),7.33–7.20(m,12H),7.19(s,1H),7.13(d,J＝10.0Hz,10H),5.84(s,2H),5.09(s,1H),4.57(s,1H),4.34(s,4H),3.29(s,1H),3.21(d,J＝15.0Hz,4H),3.04(s,2H),2.73(s,1H),2.41(s,1H),2.28(s,1H),2.01(s,1H),1.91(d,J＝4.5Hz,2H),1.53(s,1H).
实施例177 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-5-氟-1H-吲哚-2-羧酰胺(A177)
1H NMR(500MHz,Chloroform)δ8.68(s,1H),8.29(s,1H),7.54(d,J＝25.0Hz,2H),7.49(s,3H),7.24(s,1H),7.17(s,1H),7.11(d,J＝10.0Hz,5H),6.61(s,1H),5.90(s,1H),5.05(s,1H),4.68(s,1H),3.28(s,1H),3.22(s,1H),3.11(d,J＝77.9Hz,2H),2.85(s,1H),2.33(s,1H),2.13(s,1H),2.01(s,1H),1.89(d,J＝13.2Hz,11H),1.53(s,5H),1.27(s,9H).
实施例178 N-((S)-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-5-氟-1H-吲哚-2-羧酰胺(A178)
1H NMR(500MHz,Chloroform)δ8.69(s,1H),8.21(s,1H),7.58(s,1H),7.53(s,1H),7.23(s,1H),7.19(s,1H),7.13(d,J＝10.0Hz,5H),6.53(s,1H),5.93(s,1H),5.07(s,1H),4.95(s,1H),4.67(s,1H),3.29(s,1H),3.25–2.88(m,3H),2.85(s,1H),2.36(s,1H),2.17(d,J＝18.2Hz,3H),2.01(s,1H),1.90(d,J＝11.3Hz,1H),1.84(s,2H),1.62(s,1H),1.53(s,1H),1.37(s,2H),1.31(s,1H),1.20(s,2H).
实施例179 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-6-氟-1H-吲哚-2-羧酰胺(A179)
1H NMR(500MHz,Chloroform)δ8.73(s,1H),8.13(s,1H),7.95(s,1H),7.32–7.18(m,7H),7.08(d,J＝49.9Hz,6H),7.03(s,1H),7.03(s,1H),6.74(s,1H),6.16(s,1H),5.20(s,1H),4.86(s,1H),4.33(s,2H),3.66(s,1H),3.54(s,1H),3.16(d,J＝124.8Hz,2H),3.01(d,J＝6.4Hz,1H),2.57(s,1H),2.22(s,1H),2.02(s,1H),1.93(s,1H).
实施例180 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基) 丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-6-氟-1H-吲哚-2-羧酰胺(A180)
1H NMR(500MHz,Chloroform)δ8.71(s,1H),8.11(s,1H),7.96(s,1H),7.46–6.88(m,8H),7.04(s,1H),7.04(s,1H),6.57(s,1H),6.10(s,1H),5.19(s,1H),4.83(s,1H),3.65(s,1H),3.54(s,1H),3.29(s,1H),3.04(s,1H),2.58(s,1H),2.22(s,1H),2.02(s,1H),1.92(s,1H),1.27(s,9H).
实施例181 N-((S)-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-6-氟-1H-吲哚-2-羧酰胺(A181)
1H NMR(500MHz,Chloroform)δ8.71(s,2H),8.04(s,2H),7.96(s,2H),7.46–6.88(m,16H),7.04(s,2H),7.04(s,2H),6.46(s,2H),6.12(s,2H),5.20(s,2H),4.83(s,1H),3.67(d,J＝17.5Hz,3H),3.54(s,1H),3.29(s,3H),3.04(s,1H),2.58(s,1H),2.22(s,1H),2.02(s,2H),1.93(s,1H),1.74(s,2H),1.46(t,J＝12.5Hz,6H),1.21(s,3H),1.11(s,2H).
实施例182 N-((S)-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-6-氟-1H-吲哚-2-羧酰胺(A182)
1H NMR(500MHz,Chloroform)δ8.68(s,2H),8.30(s,2H),7.96(s,2H),7.40(s,2H),7.28(t,J＝11.5Hz,12H),7.15(dd,J＝57.0,32.0Hz,15H),7.04(s,2H),7.04(s,2H),5.92(s,2H),5.05(s,1H),4.71(s,1H),4.34(s,4H),3.29(s,1H),3.21(d,J＝15.0Hz,4H),3.04(s,2H),2.86(s,1H),2.39(s,1H),2.18(s,1H),2.01(s,1H),1.90(d,J＝6.3Hz,4H),1.54(s,1H).
实施例183 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-6-氟-1H-吲哚-2-羧酰胺(A183)
1H NMR(500MHz,Chloroform)δ8.68(s,1H),8.30(s,11H),7.96(s,1H),7.45–6.97(m,8H),7.04(s,1H),7.04(s,1H),6.62(s,1H),5.92(s,1H),5.06(s,1H),4.69(s,1H),3.29(s,1H),3.21(d,J＝15.0Hz,2H),3.04(s,1H),2.85(s,1H),2.33(s,1H),2.13(s,1H),2.01(s,1H),1.90(d,J＝13.5Hz,1H),1.53(s,1H),1.27(s,9H).
实施例184 N-((S)-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-6-氟-1H-吲哚-2-羧酰胺(A184)
1H NMR(500MHz,Chloroform)δ8.67(s,1H),8.20(s,1H),7.96(s,1H),7.45–6.89(m,8H),7.14(s,4H),7.09(d,J＝50.0Hz,5H),7.04(s,1H),6.53(s,1H),5.93(s,1H),5.07(s,1H),4.95(s,1H),4.67(s,1H),3.29(s,1H),3.25–2.88(m,3H),2.85(s,1H),2.35(s,1H),2.17(d,J＝17.6Hz,3H),2.01(s,1H),1.90(d,J＝11.7Hz,1H),1.84(s,1H),1.62(s,1H),1.53(s,1H),1.37(s,2H),1.31(s,1H),1.20(s,2H).
实施例185 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-(3-氟苯基)-1-氧代丙-2-基)-4,6-二氯-1H-吲哚-2-羧酰胺(A185)
1H NMR(500MHz,Chloroform)δ8.92(s,2H),8.83(s,2H),7.84(s,2H), 7.49(s,2H),7.33–7.26(m,11H),7.22(s,2H),7.02(d,J＝21.6Hz,6H),6.97(dd,J＝5.6,2.6Hz,1H),6.77(s,2H),6.28(s,2H),5.16(s,2H),4.91(s,1H),4.34(s,4H),3.67(s,1H),3.55(s,1H),3.29(s,3H),3.04(s,1H),2.61(s,1H),2.23(s,2H),2.02(s,2H),1.93(s,1H).
实施例186 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-(3-氟苯基)-1-氧代丙-2-基)-4,6-二氯-1H-吲哚-2-羧酰胺(A186)
1H NMR(500MHz,Chloroform)δ8.75(s,1H),7.97(s,1H),7.45(s,1H),7.31–7.15(m,3H),6.97(d,J＝7.1Hz,5H),6.50(s,1H),6.15(s,1H),5.18(s,1H),4.82(s,1H),3.65(s,1H),3.53(s,1H),3.27(s,1H),3.03(s,3H),2.60(s,1H),2.22(s,1H),2.01(s,1H),1.92(s,1H),1.26(s,9H).
实施例187 N-((S)-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-(3-氟苯基)-1-氧代丙-2-基)-4,6-二氯-1H-吲哚-2-羧酰胺(A187)
1H NMR(500MHz,Chloroform)δ8.79(s,2H),8.00(s,2H),7.48(s,2H),7.31(d,J＝14.5Hz,4H),7.19(s,2H),7.01(d,J＝5.2Hz,5H),6.40(s,2H),6.18(s,2H),5.20(s,2H),4.85(s,1H),3.68(d,J＝15.6Hz,3H),3.55(s,1H),3.29(s,1H),3.04(s,3H),2.61(s,2H),2.23(s,1H),2.02(s,2H),1.93(s,1H),1.74(s,2H),1.46(t,J＝12.5Hz,6H),1.21(s,3H),1.11(s,2H).
实施例188 N-((S)-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-(3-氟苯基)-1-氧代丙-2-基)-4,6-二氯-1H-吲哚-2-羧酰胺(A188)
1H NMR(500MHz,Chloroform)δ9.00(s,4H),8.91(s,4H),7.70(s,4H),7.49(d,J＝3.7Hz,8H),7.29(dd,J＝9.6,5.4Hz,26H),7.21(s,5H),7.00(d,J＝5.1Hz,11H),6.69(s,4H),4.96(d,J＝17.8Hz,6H),4.33(s,8H),3.29(s,3H),3.21(d,J＝15.0Hz,8H),2.96(d,J＝80.6Hz,8H),2.85–2.81(m,1H),2.48(s,4H),2.27(s,4H),2.00(d,J＝2.8Hz,4H),1.91(s,6H),1.53(s,2H).
实施例189 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-(3-氟苯基)-1-氧代丙-2-基)-4,6-二氯-1H-吲哚-2-羧酰胺(A189)
1H NMR(500MHz,Chloroform)δ8.57(s,1H),7.45(s,1H),7.32(d,J＝18.3Hz,2H),7.20(d,J＝6.7Hz,2H),7.04(s,1H),7.00(s,1H),6.57(s,1H),5.75(s,1H),5.11(s,1H),4.79(s,1H),3.29(s,1H),3.21(d,J＝15.0Hz,2H),3.04(s,1H),2.75(s,1H),2.47(s,1H),2.36(s,1H),2.01(s,1H),1.95(s,1H),1.91(s,1H),1.51(s,1H),1.27(s,9H).
实施例190 N-((S)-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-(3-氟苯基)-1-氧代丙-2-基)-4,6-二氯-1H-吲哚-2-羧酰胺(A190)
1H NMR(500MHz,Chloroform)δ8.77(s,1H),7.93(s,1H),7.48(s,41H),7.34–7.15(m,3H),7.00(s,1H),6.83(s,2H),6.56(s,1H),6.15(s,1H),5.71(s,1H),5.05(s,2H),4.95(s,2H),4.90(s,1H),3.36–3.12(m,4H),3.20(s,1H),3.12(d,J＝78.0Hz,2H),2.32(s,2H),2.31–2.17(m,3H),2.03–1.86(m, 3H),1.84(s,2H),1.62(s,1H),1.49(s,2H),1.37(s,2H),1.31(s,1H),1.20(s,2H).
实施例191 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-5-甲氧基-1H-吲哚-2-羧酰胺(A191)
1H NMR(500MHz,Chloroform)δ8.78(s,1H),8.27(s,1H),7.75–7.37(m,3H),7.38(s,1H),7.38(s,1H),7.28(d,J＝15.0Hz,5H),7.20–6.87(m,6H),6.90(s,1H),6.90(s,1H),6.78(s,1H),5.71(s,1H),5.15(s,1H),5.06(s,1H),4.33(s,2H),3.80(s,3H),3.63(s,1H),3.50(s,1H),3.29(s,2H),3.04(s,1H),2.54(s,1H),2.22(s,1H),2.02(s,2H),1.91(s,1H).
实施例192 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-5-甲氧基-1H-吲哚-2-羧酰胺(A192)
1H NMR(500MHz,Chloroform)δ8.78(s,1H),8.27(s,1H),7.75–7.37(m,3H),7.38(s,1H),7.38(s,1H),7.28(d,J＝15.0Hz,5H),7.20–6.87(m,6H),6.90(s,1H),6.90(s,1H),6.78(s,1H),5.71(s,1H),5.15(s,1H),5.06(s,1H),4.33(s,2H),3.80(s,3H),3.63(s,1H),3.50(s,1H),3.29(s,2H),3.04(s,1H),2.54(s,1H),2.22(s,1H),2.02(s,2H),1.91(s,1H)，1.27(s,9H).
实施例193 N-((S)-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-5-甲氧基-1H-吲哚-2-羧酰胺(A193)
1H NMR(500MHz,Chloroform)δ8.68(s,1H),8.12(s,1H),7.59(s,1H),7.45(s,1H),7.16(t,J＝12.5Hz,6H),6.79(s,1H),6.44(s,1H),6.10(s,1H),5.19(s,1H),4.95(s,1H),4.82(s,2H),3.81(s,3H),3.65(s,1H),3.54(s,1H),3.29(s,1H),3.04(s,1H),2.58(s,2H),2.21(d,J＝16.4Hz,2H),2.02(s,1H),1.88(d,J＝41.9Hz,3H),1.80(s,1H),1.62(s,2H),1.37(s,2H),1.31(s,1H),1.20(s,2H).
实施例194 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-5-甲氧基-1H-吲哚-2-羧酰胺(A194)
1H NMR(500MHz,Chloroform)δ8.66(s,1H),8.34(s,1H),7.59(s,1H),7.45(s,1H),7.29(d,J＝15.0Hz,5H),7.24–6.99(m,7H),6.79(s,1H),5.90(s,1H),5.04(s,1H),4.72(s,1H),4.34(s,2H),3.81(s,3H),3.29(s,1H),3.21(d,J＝15.0Hz,2H),3.04(s,1H),2.86(s,1H),2.29(s,1H),2.11(s,1H),2.01(s,21H),1.90(d,J＝11.7Hz,1H),1.52(s,1H).
实施例195 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-5-甲氧基-1H-吲哚-2-羧酰胺(A195)
1H NMR(500MHz,Chloroform)δ8.46(s,1H),7.57(s,1H),7.43(s,1H),7.17(s,1H),7.12(s,4H),7.00(s,1H),6.92(s,1H),6.77(s,1H),6.49(s,1H),5.75(s,1H),5.20(s,1H),4.67(s,1H),3.80(s,3H),3.28(s,1H),3.20(d,J＝15.0Hz,2H),3.03(s,1H),2.77(s,1H),2.40(s,1H),2.30(s,1H),2.00 (s,1H),1.94(s,41H),1.90(s,1H),1.51(s,1H),1.27(s,9H).
实施例196 N-((S)-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-5-甲氧基-1H-吲哚-2-羧酰胺(A196)
1H NMR(500MHz,Chloroform)δ8.61(s,1H),8.10(s,1H),7.59(s,1H),7.45(s,1H),7.19(d,J＝2.6Hz,2H),7.14(s,4H),6.72(d,J＝66.4Hz,2H),5.95(s,1H),5.05(s,1H),4.95(s,1H),4.71(s,1H),3.81(s,3H),3.29(s,1H),3.21(d,J＝15.0Hz,2H),3.04(s,1H),2.86(s,1H),2.37(s,61H),2.21–2.17(m,2H),2.01(s,1H),1.90(d,J＝11.5Hz,1H),1.84(s,2H),1.62(s,1H),1.54(s,1H),1.37(s,2H),1.31(s,1H),1.20(s,2H).
实施例197 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-环丙基-1-氧代丙-2-基)-1H-吲哚-2-羧酰胺(A197)
1H NMR(500MHz,Chloroform)δ8.60(s,1H),7.97(s,1H),7.59(s,1H),7.38(s,1H),7.29(d,J＝15.0Hz,5H),7.16(s,1H),7.10(d,J＝9.2Hz,2H),6.97(s,1H),6.16(s,1H),4.87(s,1H),4.67(s,1H),4.34(s,2H),3.65(s,1H),3.54(s,1H),2.61(s,1H),2.22(s,1H),2.02(s,1H),1.92(s,1H),1.76(s,1H),1.11(s,1H),0.60(s,1H),0.35(s,1H).
实施例198 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-环丙基-1-氧代丙-2-基)-1H-吲哚-2-羧酰胺(A198)
1H NMR(500MHz,Chloroform)δ8.59(s,1H),7.98(s,1H),7.61(d,J＝10.9Hz,2H),7.12(d,J＝16.2Hz,2H),6.98(s,1H),6.56(s,1H),6.12(s,1H),4.81(s,1H),4.67(s,1H),3.65(s,1H),3.54(s,1H),2.59(s,1H),2.22(s,1H),2.02(s,1H),1.92(s,1H),1.76(s,1H),1.27(s,9H),1.11(s,1H),0.58(s,1H),0.33(s,1H).
实施例199 N-((S)-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-环丙基-1-氧代丙-2-基)-1H-吲哚-2-羧酰胺(A199)
1H NMR(500MHz,Chloroform)δ8.65(s,1H),8.25(s,1H),7.98(s,1H),7.60(s,1H),7.12(d,J＝24.7Hz,2H),7.10–7.07(m,1H),6.98(s,1H),6.41(s,1H),6.15(s,1H),4.82(s,1H),4.58(s,1H),3.66(d,J＝5.6Hz,2H),3.54(s,1H),2.59(s,1H),2.23(s,1H),2.02(s,1H),1.93(s,1H),1.75(d,J＝10.0Hz,3H),1.46(t,J＝12.5Hz,3H),1.21(s,2H),1.11(d,J＝0.5Hz,2H),0.57(s,21H),0.28(s,1H).
实施例200 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环丙基-1-氧代丙-2-基)-1H-吲哚-2-羧酰胺(A200)
1H NMR(500MHz,Chloroform)δ8.62(s,1H),8.00(d,J＝20.6Hz,2H),7.60(s,1H),7.30(d,J＝15.0Hz,5H),7.18(d,J＝6.9Hz,2H),7.10(s,1H),6.98(s,1H),6.09(s,1H),4.85(s,1H),4.33(d,J＝13.7Hz,3H),3.21(d,J＝15.0Hz,2H),2.91(s,1H),2.62(s,1H),2.54(s,1H),2.01(s,1H),1.92(d,J＝12.0Hz,1H), 1.76(s,2H),1.59(s,1H),1.11(s,1H),0.45(s,1H),0.13(s,1H).
实施例201 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-环丁基-1-氧代丙-2-基)-1H-吲哚-2-羧酰胺(A201)
1H NMR(500MHz,Chloroform)δ7.98(s,1H),7.60(s,1H),7.29(d,J＝15.0Hz,5H),7.10(s,1H),6.98(s,1H),4.34(s,2H),2.75(s,1H),2.67(s,1H),2.09(s,1H),2.03(d,J＝6.8Hz,4H),1.94(s,1H),1.92–1.82(m,3H),1.76(s,1H),1.66(d,J＝10.0Hz,2H),1.61(s,1H),0.45(s,1H),
实施例202 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-环丁基-1-氧代丙-2-基)-1H-吲哚-2-羧酰胺(A202)
1H NMR(500MHz,Chloroform)δ7.98(s,1H),7.60(s,1H),7.29(m,3H),7.10(s,1H),6.98(s,1H),6.29(m,3H),2.75(s,1H),2.67(s,1H),2.09(s,2H),2.03(d,J＝6.8Hz,3H),1.94(s,1H),1.92–1.82(m,3H),1.76(s,1H),1.66(d,J＝10.0Hz,2H),1.61(s,1H),1.27(s,9H),0.45(s,1H)
实施例203 N-((S)-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-环丁基-1-氧代丙-2-基)-1H-吲哚-2-羧酰胺(A203)
1H NMR(500MHz,Chloroform)δ7.98(s,1H),7.60(s,1H),7.10(s,1H),6.98(s,1H),4.95(s,1H),2.74(s,1H),2.66(s,1H),2.19(s,2H),2.09(s,1H),2.03(d,J＝6.9Hz,2H),1.94(s,1H),1.86(dd,J＝18.2,10.2Hz,5H),1.76(s,2H),1.64(dd,J＝22.9,7.1Hz,3H),1.37(s,1H),1.31(s,2H),1.20(s,2H),0.45(s,1H)
实施例204 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环丁基-1-氧代丙-2-基)-1H-吲哚-2-羧酰胺(A204)
1H NMR(500MHz,Chloroform)δ7.98(s,1H),7.60(s,1H),7.29(d,J＝15.0Hz,4H),7.10(s,1H),6.98(s,1H),6.05(m,2H),4.34(s,2H),3.21(d,J＝15.0Hz,2H),2.09(s,1H),2.06–1.69(m,9H),1.76(s,2H),1.76(s,2H),1.65(s,1H),1.61(s,1H),0.53(s,1H),0.39(s,1H).
实施例205 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环丁基-1-氧代丙-2-基)-1H-吲哚-2-羧酰胺(A205)
1H NMR(500MHz,Chloroform)δ8.62(s,1H),8.00(d,J＝20.6Hz,2H),7.60(s,1H),7.30(d,J＝15.0Hz,5H),7.18(d,J＝6.9Hz,2H),7.10(s,1H),6.98(s,1H),6.09(s,1H),4.85(s,1H),4.33(d,J＝13.7Hz,3H),3.21(d,J＝15.0Hz,2H),2.91(s,1H),2.62(s,1H),2.54(s,1H),2.01(s,1H),1.92(d,J＝12.0Hz,1H),1.76(s,2H),1.59(s,1H),1.27(s,9H),1.11(s,3H),0.45(s,1H),0.13(s,1H).
实施例206 N-((S)-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环丁基-1-氧代丙-2-基)-1H-吲哚-2-羧酰胺(A206)
1H NMR(500MHz,Chloroform)δ8.62(s,1H),8.00(d,J＝20.6Hz,2H),7.60(s,1H),7.30(d,J＝15.0Hz,5H),7.18(d,J＝6.9Hz,2H),7.10(s,1H),6.98(s, 1H),6.09(s,1H),4.85(s,1H),4.33(d,J＝13.7Hz,3H),3.21(d,J＝15.0Hz,2H),2.91(s,1H),2.62(s,1H),2.54(s,1H),2.01(s,1H),1.92(d,J＝12.0Hz,1H),1.76(s,2H),1.59(s,1H),1.11(s,1H),0.45(s,21H),0.13(s,1H).
实施例207 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-环戊基-1-氧代丙-2-基)-1H-吲哚-2-羧酰胺(A207)
1H NMR(500MHz,Chloroform)δ8.57(s,1H),7.98(s,1H),7.60(s,1H),7.38(s,1H),7.30(d,J＝15.0Hz,5H),7.13–7.07(m,2H),6.98(d,J＝4.1Hz,2H),6.13(s,1H),4.81(d,J＝3.3Hz,1H),4.34(s,2H),3.65(s,1H),3.55(s,1H),2.60(s,1H),2.22(s,1H),2.02(s,1H),1.92(s,3H),1.76(s,3H),1.66(d,J＝4.7Hz,3H),1.36(s,1H),1.23(s,1H).
实施例208 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-环戊基-1-氧代丙-2-基)-1H-吲哚-2-羧酰胺(A208)
1H NMR(500MHz,Chloroform)δ8.60(s,1H),7.98(s,1H),7.77(s,1H),7.60(s,1H),7.11(d,J＝5.1Hz,82H),6.98(s,1H),6.57(s,1H),6.14(s,1H),4.83(s,1H),4.61(s,1H),3.66(s,1H),3.54(s,1H),2.59(s,1H),2.22(s,1H),2.02(s,1H),1.93(s,1H),1.76(s,3H),1.65(d,J＝11.9Hz,5H),1.34(s,4H),1.26(d,J＝8.6Hz,9H).
实施例209 N-((S)-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-环戊基-1-氧代丙-2-基)-1H-吲哚-2-羧酰胺(A209)
1H NMR(500MHz,Chloroform)δ8.54(s,1H),7.98(s,1H),7.60(s,1H),7.28(s,1H),7.08(d,J＝16.5Hz,2H),6.98(s,1H),6.46(s,1H),6.14(s,1H),4.80(s,1H),4.75(s,1H),3.64(d,J＝19.8Hz,2H),3.54(s,1H),2.59(s,1H),2.22(s,1H),2.02(s,1H),1.93(s,1H),1.75(d,J＝10.0Hz,6H),1.65(d,J＝6.5Hz,63H),1.46(t,J＝12.5Hz,4H),1.35(s,3H),1.27(s,1H),1.21(s,2H),1.11(s,1H).
实施例210 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环戊基-1-氧代丙-2-基)-1H-吲哚-2-羧酰胺(A210)
1H NMR(500MHz,Chloroform)δ8.51(s,1H),7.98(s,1H),7.60(s,1H),7.30(d,J＝15.0Hz,5H),7.24(s,1H),7.09(d,J＝13.7Hz,2H),6.98(s,1H),6.89(s,1H),6.11(s,1H),4.79(s,1H),4.65(s,11H),4.34(s,2H),3.21(d,J＝15.0Hz,2H),2.91(s,1H),2.50(d,J＝13.8Hz,2H),2.01(s,1H),1.92(d,J＝5.3Hz,1H),1.76(s,3H),1.65(d,J＝5.8Hz,3H),1.58(s,1H),1.36(s,1H),1.23(s,1H).
实施例211 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环戊基-1-氧代丙-2-基)-1H-吲哚-2-羧酰胺(A211)
1H NMR(500MHz,Chloroform)δ8.45(s,1H),7.98(s,1H),7.60(s,1H),7.10(s,1H),7.00(d,J＝18.5Hz,2H),6.89(s,1H),6.53(s,1H),6.10(s,1H),4.78(s,1H),4.65(s,1H),3.21(d,J＝15.0Hz,2H),2.90(s,1H),2.49(d,J＝13.5Hz, 2H),2.01(s,1H),1.91(d,J＝1.6Hz,1H),1.76(s,3H),1.63(t,J＝21.9Hz,4H),1.55–1.52(m,1H),1.37(s,1H),1.27(s,9H),1.22(s,1H).
实施例212 N-((S)-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环戊基-1-氧代丙-2-基)-1H-吲哚-2-羧酰胺(A212)
1H NMR(500MHz,Chloroform)δ8.45(s,1H),7.98(s,1H),7.60(s,1H),7.10(s,1H),7.00(d,J＝19.1Hz,42H),6.88(s,1H),6.44(s,1H),6.10(s,1H),4.95(s,1H),4.77(s,1H),4.64(s,1H),3.21(d,J＝15.0Hz,2H),2.90(s,1H),2.49(d,J＝19.3Hz,2H),2.19(s,2H),2.01(s,1H),1.93–1.89(m,1H),1.84(s,2H),1.76(s,3H),1.73–1.60(m,6H),1.57(s,1H),1.37(d,J＝2.4Hz,3H),1.31(s,1H),1.21(d,J＝13.0Hz,2H).
实施例213 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-2,2-二氟苯并[d][1,3]间二氧杂环戊烯-5-羧酰胺(A213)
1H NMR(500MHz,Chloroform)δ7.97(s,1H),7.61(s,1H),7.49(s,1H),7.55–7.23(m,6H),7.55–6.98(m,8H),6.13(s,1H),4.86(s,1H),4.49(s,1H),4.34(s,2H),3.66(s,1H),3.54(s,1H),2.59(s,1H),2.23(s,1H),2.02(s,1H),1.93(s,1H),1.80(s,3H),1.69(d,J＝10.0Hz,3H),1.31(s,1H),1.26(s,1H),1.11(s,1H),1.03(s,1H).
实施例214 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-2,2-二氟苯并[d][1,3]间二氧杂环戊烯-5-羧酰胺(A214)
1H NMR(500MHz,Chloroform)δ7.73(s,1H),7.61(s,1H),7.49(s,1H),7.16(s,1H),6.52(s,1H),6.13(s,1H),4.83(s,1H),4.55(s,1H),3.66(s,1H),3.54(s,1H),2.58(s,1H),2.22(s,1H),2.02(s,1H),1.93(s,1H),1.80(s,2H),1.58(s,1H),1.51(d,J＝15.0Hz,3H),1.48–1.41(m,4H),1.28(d,J＝5.4Hz,9H).
实施例215 N-((S)-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-2,2-二氟苯并[d][1,3]间二氧杂环戊烯-5-羧酰胺(A215)
1H NMR(500MHz,Chloroform)δ7.55(d,J＝60.0Hz,2H),7.16(d,J＝2.8Hz,2H),6.45(s,1H),6.14(s,1H),4.95(s,1H),4.77(s,1H),4.66(s,1H),3.66(s,1H),3.54(s,1H),2.58(s,1H),2.21(d,J＝17.0Hz,2H),2.02(s,1H),1.92(s,1H),1.84(s,2H),1.80(s,1H),1.64(d,J＝16.1Hz,3H),1.51(d,J＝15.0Hz,2H),1.44(dd,J＝12.8,7.8Hz,6H),1.37(s,3H),1.31(s,1H),1.20(s,2H).
实施例216 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-2,2-二氟苯并[d][1,3]间二氧杂环戊烯-5-羧酰胺(A216)
1H NMR(500MHz,Chloroform)δ7.55(d,J＝60.0Hz,2H),7.46–7.26(m,6H),7.16(s,1H),7.09(s,1H),6.08(s,1H),4.79(s,1H),4.41(s,1H),4.34(s,2H),3.21(d,J＝15.0Hz,2H),2.85(s,1H),2.53(d,J＝12.1Hz,2H),2.01(s,1H),1.91(d,J＝3.6Hz,1H),1.80(s,1H),1.72(s,1H),1.58(s,1H),1.52(d,J＝15.0Hz,2H),1.48–1.41(m,4H),1.34(s,1H).
实施例217 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-2,2-二氟苯并[d][1,3]间二氧杂环戊烯-5-羧酰胺(A217)
1H NMR(500MHz,Chloroform)δ7.61(s,2H),7.49(s,2H),7.16(s,2H),6.89(s,2H),6.53(s,2H),6.09(s,2H),4.76(s,1H),4.44(s,1H),3.21(d,J＝15.0Hz,4H),2.88(s,2H),2.49(d,J＝3.0Hz,4H),2.01(s,1H),1.93–1.89(m,2H),1.80(s,3H),1.69(d,J＝10.0Hz,2H),1.57(s,1H),1.31(d,J＝4.8Hz,2H),1.27(s,9H),1.11(s,1H),1.03(s,3H).
实施例218 N-((S)-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-2,2-二氟苯并[d][1,3]间二氧杂环戊烯-5-羧酰胺(A218)
1H NMR(500MHz,Chloroform)δ7.58(s,1H),7.46(s,1H),7.13(s,1H),6.47(d,J＝5.5Hz,2H),5.81(s,1H),4.93(d,J＝6.0Hz,2H),4.37(s,1H),3.34(s,1H),3.20(d,J＝15.0Hz,2H),2.37(d,J＝18.2Hz,2H),2.18(s,2H),2.00(s,1H),1.90(d,J＝0.5Hz,1H),1.81(d,J＝19.9Hz,6H),1.69(s,2H),1.64(d,J＝29.9Hz,3H),1.51(s,1H),1.37(s,3H),1.31(s,2H),1.18(d,J＝16.6Hz,3H),1.11(s,1H),1.03(s,2H).
实施例219 N-((S)-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-2,2-二氟苯并[d][1,3]间二氧杂环戊烯-5-羧酰胺(A219)
1H NMR(500MHz,Chloroform)δ7.58(s,1H),7.46(s,1H),7.13(s,1H),6.47(d,J＝5.5Hz,2H),5.81(s,1H),4.93(d,J＝6.0Hz,2H),4.37(s,1H),3.34(s,1H),3.20(d,J＝15.0Hz,2H),2.37(d,J＝18.2Hz,2H),2.18(s,2H),2.00(s,1H),1.90(d,J＝0.5Hz,1H),1.81(d,J＝19.9Hz,6H),1.69(s,2H),1.64(d,J＝29.9Hz,3H),1.51(s,1H),1.37(s,3H),1.31(s,2H),1.18(d,J＝16.6Hz,3H),1.11(s,1H),1.03(s,2H).
实施例220 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-4,6-二甲氧基-1H-吲哚-2-羧酰胺(A220)
1H NMR(500MHz,Chloroform)δ9.90(s,1H),8.66(s,1H),8.26(s,1H),7.77(s,1H),7.30(d,J＝15.0Hz,5H),7.23–7.03(m,6H),6.71(s,1H),6.26(s,1H),5.98(s,1H),5.15(s,1H),4.87(s,1H),4.34(s,2H),3.79(s,6H),3.64(s,1H),3.52(s,1H),3.29(s,1H),3.04(s,1H),2.52(s,1H),2.22(s,1H), 2.02(s,1H),1.92(s,2H).
实施例221 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-4,6-二甲氧基-1H-吲哚-2-羧酰胺(A221)
1H NMR(500MHz,Chloroform)δ8.60(s,1H),8.35(s,1H),7.76(s,1H),7.17(d,J＝25.0Hz,5H),6.69(s,1H),6.58(s,1H),6.23(s,1H),6.00(s,1H),5.18(s,1H),4.81(s,1H),3.79(s,6H),3.64(s,1H),3.53(s,1H),3.29(s,1H),3.04(s,1H),2.55(s,1H),2.22(s,1H),2.02(s,1H),1.92(s,1H),1.27(s,9H).
实施例222 N-((S)-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-4,6-二甲氧基-1H-吲哚-2-羧酰胺(A222)
1H NMR(500MHz,Chloroform)δ8.59(s,1H),8.10(s,1H),7.68(s,1H),7.15(d,J＝25.0Hz,5H),6.67(s,1H),6.45(s,1H),6.21(s,1H),6.07(s,1H),5.18(s,1H),4.94(s,1H),4.80(s,1H),3.78(s,6H),3.64(s,1H),3.53(s,1H),3.28(s,1H),3.03(s,1H),2.56(s,1H),2.20(d,J＝16.3Hz,3H),2.02(s,1H),1.88(d,J＝41.4Hz,3H),1.80(s,1H),1.62(s,1H),1.37(s,2H),1.31(s,1H),1.20(s,2H).
实施例223 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-4,6-二甲氧基-1H-吲哚-2-羧酰胺(A223)
1H NMR(500MHz,Chloroform)δ8.65(s,1H),8.29(s,1H),8.02(s,1H),7.27(d,J＝15.0Hz,5H),7.14(d,J＝24.9Hz,5H),6.92(s,1H),6.59(s,1H),6.20(s,1H),6.08(s,1H),5.01(s,1H),4.76(s,1H),4.33(s,2H),3.78(s,6H),3.28(s,1H),3.20(d,J＝15.0Hz,2H),3.03(s,1H),2.85(d,J＝1.0Hz,2H),2.32(s,1H),2.00(s,1H),1.90(d,J＝1.3Hz,1H),1.61(s,1H).
实施例224 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-4,6-二甲氧基-1H-吲哚-2-羧酰胺(A224)
1H NMR(500MHz,Chloroform)δ8.80(d,J＝11.2Hz,2H),7.09(t,J＝61.7Hz,6H),6.94(s,1H),6.94(s,1H),6.77(s,1H),6.63(s,1H),6.56(s,1H),5.04(d,J＝1.0Hz,2H),4.99(s,1H),3.79(s,6H),3.29(s,1H),3.21(d,J＝15.0Hz,3H),2.93(d,J＝106.3Hz,2H),2.79–2.70(m,1H),2.40(s,1H),2.27(s,1H),2.01(s,1H),1.92(d,J＝8.4Hz,1H),1.46(s,1H),1.27(s,9H).
实施例225 N-((S)-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-4,6-二甲氧基-1H-吲哚-2-羧酰胺(A225)
1H NMR(500MHz,Chloroform)δ8.67(s,1H),7.80(s,1H),7.65(s,1H),7.08(t,J＝67.3Hz,6H),6.91(s,1H),6.91(s,1H),6.55(s,1H),6.49(s,1H),6.07(s,1H),5.09(s,1H),4.95(s,1H),4.69(s,1H),3.79(s,6H),3.29(s,1H),3.21(d,J＝15.0Hz,2H),3.04(s,1H),2.93(s,1H),2.42(d,J＝15.8Hz,2H),2.19(s,2H),2.03–1.73(m,5H),1.84(s,3H),1.84(s,2H),1.60(d,J＝16.9Hz, 2H),1.37(s,2H),1.31(s,1H),1.20(s,2H).
实施例226 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-(3,4-二氟苯基)-1-氧代丙-2-基)-1H-吲哚-2-羧酰胺(A226)
1H NMR(500MHz,Chloroform)δ8.76(s,1H),8.12(s,1H),7.98(s,1H),7.89(s,1H),7.60(s,1H),7.29(d,J＝15.0Hz,5H),7.19(d,J＝17.1Hz,2H),7.10(d,J＝2.2Hz,2H),6.99(d,J＝15.0Hz,2H),6.31(s,1H),5.05(s,1H),4.91(s,1H),4.34(s,2H),3.67(s,1H),3.56(s,1H),3.29(s,1H),3.04(s,1H),2.70(s,1H),2.23(s,1H),2.02(s,2H),1.93(s,1H).
实施例227 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-(3,4-二氟苯基)-1-氧代丙-2-基)-1H-吲哚-2-羧酰胺(A227)
1H NMR(500MHz,Chloroform)δ8.72(s,1H),8.44(s,1H),7.96(s,1H),7.59(s,1H),7.25(s,1H),7.16(s,1H),7.09(d,J＝2.1Hz,2H),6.98(d,J＝15.0Hz,2H),6.60(s,1H),5.97(s,1H),5.12(s,1H),4.82(s,1H),3.64(s,1H),3.52(s,1H),3.28(s,1H),3.03(s,1H),2.54(s,1H),2.22(s,1H),2.02(s,1H),1.92(s,1H),1.27(s,9H).
实施例228 N-((S)-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-(3,4-二氟苯基)-1-氧代丙-2-基)-1H-吲哚-2-羧酰胺(A228)
1H NMR(500MHz,Chloroform)δ8.69(s,1H),8.41(s,1H),7.94(s,1H),7.56(s,1H),7.23(s,1H),7.13(s,1H),7.06(d,J＝0.9Hz,2H),6.96(d,J＝14.9Hz,2H),6.65(s,1H),5.95(s,1H),5.11(s,1H),4.92(s,1H),4.81(s,1H),3.63(s,1H),3.51(s,1H),3.27(s,1H),3.02(s,1H),2.53(s,1H),2.19(d,J＝14.6Hz,2H),2.01(s,1H),1.87(d,J＝40.1Hz,3H),1.79(s,1H),1.61(s,1H),1.36(s,2H),1.30(s,1H),1.19(s,2H).
实施例229 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-(3,4-二氟苯基)-1-氧代丙-2-基)-1H-吲哚-2-羧酰胺(A229)
1H NMR(500MHz,Chloroform)δ8.69(s,1H),8.11(s,1H),7.95(s,1H),7.57(s,1H),7.43(s,1H),7.27(d,J＝15.0Hz,5H),7.14(s,1H),7.07(s,1H),6.97(d,J＝15.0Hz,2H),6.82(s,1H),6.58(s,1H),6.04(s,1H),5.01(s,21H),4.83(s,1H),4.32(s,2H),3.28(s,1H),3.20(d,J＝15.0Hz,2H),3.03(s,1H),2.89(s,1H),2.70(s,1H),2.25(s,1H),2.00(s,1H),1.90(d,J＝2.9Hz,1H),1.60(s,1H).
实施例230 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-(3,4-二氟苯基)-1-氧代丙-2-基)-1H-吲哚-2-羧酰胺(A230)
1H NMR(500MHz,Chloroform)δ8.74(s,1H),8.06(s,1H),7.98(s,1H),7.60(s,1H),7.17(s,1H),7.11(d,J＝8.4Hz,2H),7.03–6.90(m,3H),6.53(s,1H),5.75(s,1H),5.12(s,1H),4.72(s,1H),3.29(s,1H),3.21(d,J＝15.0Hz,2H),3.04(s,1H),2.75(s,1H),2.43(s,1H),2.33(s,1H),2.01(s,1H),1.96 (s,1H),1.91(s,1H),1.52(s,1H),1.27(s,9H).
实施例231 N-((S)-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-(3,4-二氟苯基)-1-氧代丙-2-基)-1H-吲哚-2-羧酰胺(A231)
1H NMR(500MHz,Chloroform)δ8.72(s,1H),7.99(d,J＝25.5Hz,2H),7.59(s,1H),7.16(s,1H),7.09(d,J＝4.0Hz,2H),6.97(t,J＝11.7Hz,3H),6.45(s,1H),6.07(s,1H),5.09(s,1H),4.94(s,1H),4.68(s,1H),3.28(s,1H),3.21(d,J＝15.0Hz,2H),3.03(s,1H),2.95(s,1H),2.44(d,J＝17.0Hz,2H),2.19(s,2H),2.03–1.73(m,5H),1.84(s,2H),1.84(s,2H),1.60(d,J＝13.6Hz,2H),1.37(s,2H),1.31(s,1H),1.20(s,2H).
实施例232 N-((S)-1-(((S)-4-(苄基)-3,4-二酮-1-(异丙基氨基)并-2-基)氨基)-3-(环己基)-1-氧代丙-2-基)-1H-吲哚-2-羧酰胺(A232)
1H NMR(500MHz,Chloroform)δ8.57(s,1H),7.94(s,1H),7.57(s,1H),7.40(s,1H),7.26(d,J＝14.9Hz,4H),7.16–7.03(m,3H),6.95(s,1H),6.45(s,1H),5.67(s,1H),4.95(s,1H),4.48(s,1H),4.32(s,2H),3.79(s,1H),2.20(s,1H),2.15(s,1H),2.04(s,2H),1.77(d,J＝19.9Hz,3H),1.68(d,J＝10.0Hz,4H),1.37(s,1H),1.30(s,1H),1.11(s,1H),1.01(d,J＝14.9Hz,6H).
实施例233 N-((S)-1-(((S)-4-(苄基)-3,4-二酮-1-(异丙基氨基)并-2-基)氨基)-3-(苯基)-1-氧代丙-2-基)-1H-吲哚-2-羧酰胺(A233)
1H NMR(500MHz,Chloroform)δ8.85(s,1H),8.41(s,1H),7.98(s,1H),7.60(s,1H),7.29(d,J＝15.0Hz,5H),7.20(d,J＝16.0Hz,2H),7.12(d,J＝20.0Hz,5H),6.98(s,1H),6.69(s,1H),5.05(s,1H),5.01(s,1H),4.74(s,1H),4.34(s,2H),3.81(s,1H),3.29(s,2H),3.04(s,1H),2.21(d,J＝5.4Hz,2H),2.05(s,2H),1.00(s,6H).
实施例234 N-((S)-1-(((S)-4-(环己基)-3,4-二酮-1-(异丙基氨基)并-2-基)氨基)-3-(苯基)-1-氧代丙-2-基)-1H-吲哚-2-羧酰胺(A234)
1H NMR(500MHz,Chloroform)δ8.73(s,1H),8.16(s,1H),7.98(s,1H),7.60(s,1H),7.27(s,1H),7.19(s,1H),7.12(d,J＝20.0Hz,5H),7.07(s,1H),6.98(s,1H),6.53(s,1H),5.87(s,1H),5.64(s,1H),4.92(s,1H),4.86(s,1H),3.81(s,1H),3.29(s,3H),3.02(d,J＝18.8Hz,3H),2.19(d,J＝11.4Hz,2H),2.05(s,2H),1.80(s,1H),1.69(d,J＝10.0Hz,3H),1.58(s,1H),1.31(s,1H),1.11(s,1H),1.01(d,J＝15.0Hz,8H).
实施例235 N-((S)-1-(((S)-4-(环己基)-3,4-二酮-1-(环己基氨基)并-2-基)氨基)-3-(苯基)-1-氧代丙-2-基)-1H-吲哚-2-羧酰胺(A235)
1H NMR(500MHz,Chloroform)δ8.73(s,1H),8.14(s,1H),7.98(s,1H),7.60(s,1H),7.26(s,1H),7.19(s,1H),7.12(d,J＝20.0Hz,5H),6.98(s,1H),6.56(s,1H),5.90(s,1H),5.63(s,1H),4.93(d,J＝16.9Hz,2H),4.86(s,1H),3.29 (s,1H),3.02(d,J＝18.8Hz,3H),2.23–2.14(m,4H),2.05(s,2H),1.82(d,J＝20.0Hz,4H),1.69(d,J＝10.0Hz,3H),1.62(s,1H),1.37(d,J＝0.9Hz,3H),1.31(s,3H),1.20(s,2H),1.11(s,1H),1.03(s,2H).
实施例236 N-((S)-1-(((S)-4-(苄基)-3,4-二酮-1-(异丙基氨基)并-2-基)氨基)-3-(环己基)-1-氧代丙-2-基)-喹喔啉-2-羧酰胺(A236)
1H NMR(500MHz,Chloroform)δ9.45(s,1H),7.80(s,2H),7.67(s,2H),7.35–7.26(m,6H),7.11(s,1H),6.67(s,1H),5.75(s,1H),5.11(s,1H),4.33(d,J＝6.4Hz,3H),3.81(s,1H),2.16(d,J＝10.5Hz,2H),2.05(s,1H),1.76(s,1H),1.60(s,1H),1.51(d,J＝15.0Hz,2H),1.48–1.41(m,4H),1.32(s,1H),1.00(s,6H).
实施例237 N-((S)-1-(((S)-4-(环己基)-3,4-二酮-1-(异丙基氨基)并-2-基)氨基)-3-(环己基)-1-氧代丙-2-基)-喹喔啉-2-羧酰胺(A237)
1H NMR(500MHz,Chloroform)δ9.32(s,1H),8.17(s,1H),8.12(s,1H),7.76(s,1H),7.66(d,J＝4.6Hz,2H),7.33–7.27(m,4H),7.19(s,1H),5.70(s,1H),4.93(s,1H),4.80(s,1H),4.75(s,1H),4.03(s,1H),3.98(s,1H),3.24(s,1H),3.02–2.98(m,3H),2.30–2.26(m,2H),2.18(s,1H),2.10(s,1H),1.82–1.75(m,2H),1.75–1.71(m,2H),1.67(s,1H),1.45–1.41(m,2H),1.33(s,1H),1.30–1.20(m,6H),1.14–1.07(m,3H).
实施例238 N-((S)-1-(((S)-4-(苄基)-3,4-二酮-1-(异丙基氨基)并-2-基)氨基)-3-(苯基)-1-氧代丙-2-基)-喹喔啉-2-羧酰胺(A238)
1H NMR(500MHz,Chloroform)δ9.34(s,1H),8.08(d,J＝10.7Hz,2H),7.62(d,J＝0.9Hz,2H),7.30–7.21(m,8H),7.19(s,1H),7.14(s,1H),6.23(s,1H),6.03(s,1H),5.22(s,1H),5.08(s,1H),4.95(s,1H),4.88(s,1H),4.33(s,1H),4.28(s,1H),3.96(s,1H),3.22(s,1H),2.99(s,1H),2.38–2.34(m,2H),2.21(s,1H),2.16(s,1H),1.33–1.20(m,6H).
实施例239 N-((S)-1-(((S)-4-(苄基)-3,4-二酮-1-(环己基氨基)并-2-基)氨基)-3-(苯基)-1-氧代丙-2-基)-喹喔啉-2-羧酰胺(A239)
1H NMR(500MHz,Chloroform)δ9.31(s,1H),8.12(d,J＝31.2Hz,2H),7.73(s,1H),7.63(d,J＝6.0Hz,2H),7.36–7.24(m,8H),7.17(d,J＝11.8Hz,2H),6.32(s,1H),5.10(s,1H),4.76(s,1H),4.67(s,1H),4.36(s,1H),4.30(d,J＝18.6Hz,2H),4.12(s,1H),3.24(s,1H),2.97(s,1H),2.31–2.27(m,2H),2.12(d,J＝3.2Hz,2H),1.94–1.87(m,2H),1.73–1.63(m,4H),1.61–1.55(m,4H).
实施例240 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-1H-吲哚-6-氟-2-羧酰胺(A240)
1H NMR(500MHz,Chloroform)δ8.12(s,1H),7.57(s,1H),7.52(s,1H),7.36–7.25(m,4H),7.20(d,J＝7.7Hz,2H),6.84(s,1H),6.18(s,1H),5.49(d,J＝11.0Hz,2H),4.70(s,1H),4.39(d,J＝17.7Hz,2H),4.08(s,1H),3.24(d,J ＝17.5Hz,2H),2.54(s,1H),2.08–2.04(m,2H),1.82(s,1H),1.78–1.67(m,6H),1.66–1.62(m,2H),1.58(dd,J＝9.5,3.3Hz,5H),1.44(s,1H),1.37–1.27(m,3H).
实施例241 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-5-甲基噁唑-2-羧酰胺(A241)
1H NMR(500MHz,Chloroform)δ7.33–7.27(m,4H),7.23(s,1H),6.79(d,J＝13.7Hz,2H),6.29(s,1H),6.09(s,1H),5.05(s,1H),4.99(d,J＝9.8Hz,2H),4.41(s,1H),4.34(s,1H),3.24(d,J＝14.9Hz,2H),2.92(s,1H),2.36–2.32(m,3H),2.08–2.04(m,2H),1.85(s,1H),1.79(s,1H),1.74–1.55(m,11H),1.48(s,1H),1.46–1.23(m,3H).
实施例242 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-5-甲基噁唑-2-羧酰胺(A242)
1H NMR(500MHz,Chloroform)δ7.33–7.30(m,22H),7.28(t,J＝15.0Hz,33H),6.83(s,9H),6.14(s,9H),6.09(s,9H),5.94(s,9H),5.19(s,9H),5.01(s,9H),4.36(d,J＝0.5Hz,18H),3.45(s,9H),3.35(s,7H),2.59(s,9H),2.38–2.34(m,27H),2.18(s,8H),2.09–2.05(m,18H),1.96–1.88(m,24H),1.88(s,3H),1.73–1.60(m,46H),1.40–1.36(m,16H),1.32(s,9H),1.15(s,7H),1.12–1.08(m,17H).
实施例243 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-苯并[d]1,3-二氧杂环戊烯-5-羧酰胺(A243)
1H NMR(500MHz,Chloroform)δ7.54(s,6H),7.45(s,6H),7.29–7.18(m,30H),6.96(s,6H),6.49(s,6H),6.01(s,6H),5.92–5.88(m,12H),5.58(s,6H),5.11(s,6H),4.93(s,6H),4.63(s,6H),4.29(s,6H),4.24(s,6H),3.24(d,J＝17.5Hz,11H),2.86(s,6H),2.05(t,J＝4.2Hz,18H),1.95–1.87(m,12H),1.84(s,6H),1.76(t,J＝4.8Hz,17H),1.63(dd,J＝40.8,34.9Hz,22H),1.51(dd,J＝4.6,1.3Hz,1H),1.40–1.36(m,10H),1.32(s,6H),1.17–1.09(m,17H).
实施例244 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-1H-苯并[d]咪唑-2-羧酰胺(A244)
1H NMR(500MHz,Chloroform)δ7.84(s,1H),7.73(s,1H),7.62(s,1H),7.38(s,1H),7.31–7.23(m,6H),7.16(s,1H),6.17(s,1H),5.59(s,1H),5.10(s,1H),4.75(s,1H),4.53(s,1H),4.36(d,J＝17.3Hz,2H),3.24(d,J＝17.5Hz,2H),2.88(s,1H),2.06(t,J＝2.7Hz,3H),1.96–1.81(m,3H),1.77(s,1H),1.73–1.60(m,5H),1.53(s,1H),1.40–1.36(m,2H),1.32(s,1H),1.22–1.15(m,3H).
实施例245 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-7-甲氧基-苯并呋喃-2-羧酰胺(A245)
1H NMR(500MHz,Chloroform)δ7.60(s,8H),7.34–7.22(m,33H),7.15(d,J＝10.0Hz,16H),7.06(s,8H),6.81(s,8H),6.54(s,8H),6.22(s,8H),5.59(s, 8H),5.08(s,8H),4.92(s,8H),4.63(s,8H),4.32(d,J＝1.1Hz,16H),3.89–3.85(m,24H),3.24(d,J＝17.4Hz,15H),2.94(s,8H),2.07(t,J＝5.1Hz,23H),1.93–1.85(m,18H),1.84(s,6H),1.78(s,6H),1.73–1.51(m,49H),1.51(d,J＝5.5Hz,1H),1.40–1.36(m,14H),1.32(s,8H),1.16–1.07(m,23H).
实施例246 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-3-甲基-苯并呋喃-2-羧酰胺(A246)
1H NMR(500MHz,Chloroform)δ7.60–7.40(m,3H),7.32–7.18(m,7H),6.67(s,1H),5.57(s,1H),5.15(s,1H),4.67(s,1H),4.55(s,1H),4.30(d,J＝14.7Hz,2H),3.24(d,J＝17.3Hz,2H),2.73(s,1H),2.15–2.10(m,4H),2.08–2.04(m,2H),1.88–1.81(m,3H),1.77(s,1H),1.73–1.59(m,5H),1.55(s,1H),1.40–1.36(m,2H),1.32(s,1H),1.14–1.05(m,3H).
实施例247 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-3，5-二甲基-苯并呋喃-2-羧酰胺(A247)
1H NMR(500MHz,Chloroform)δ7.50–7.34(m,3H),7.32–7.26(m,4H),7.23(s,1H),7.11(s,1H),6.68(s,1H),5.57(s,1H),5.15(s,1H),4.69(s,1H),4.55(s,1H),4.30(d,J＝14.8Hz,2H),3.24(d,J＝17.3Hz,2H),2.73(s,1H),2.45–2.41(m,3H),2.15–2.10(m,4H),2.08–2.04(m,2H),1.88–1.81(m,3H),1.77(s,1H),1.73–1.59(m,5H),1.55(s,1H),1.40–1.36(m,2H),1.32(s,1H),1.14–1.05(m,3H).
实施例248 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-4，7-二甲氧基-苯并呋喃-2-羧酰胺(A248)
1H NMR(500MHz,Chloroform)δ7.59(s,1H),7.34–7.27(m,2H),7.27–7.22(m,2H),7.10(s,1H),6.86(s,1H),6.82(s,1H),6.38(s,1H),6.32(s,1H),5.56(s,1H),5.35(s,1H),4.66(d,J＝18.6Hz,2H),4.28(s,1H),4.17(s,1H),3.91–3.87(m,3H),3.85–3.81(m,3H),3.24(d,J＝17.8Hz,2H),3.06(s,1H),2.05(t,J＝6.8Hz,3H),1.96–1.88(m,2H),1.84(s,1H),1.77(s,1H),1.73–1.54(m,5H),1.52(s,1H),1.40–1.36(m,2H),1.32(s,1H),1.17–1.08(m,3H).
实施例249 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-苯并呋喃-3-羧酰胺(A249)
1H NMR(500MHz,Chloroform)δ8.07(s,91H),7.62(s,92H),7.58(s,94H),7.47(s,94H),7.27(dd,J＝9.9,8.1Hz,379H),7.20(t,J＝5.8Hz,274H),6.24(s,91H),5.61(s,91H),5.16(s,90H),4.93(s,91H),4.52(s,89H),4.32(d,J＝0.6Hz,182H),3.24(d,J＝17.5Hz,174H),2.89(s,93H),2.06(t,J＝2.7Hz,257H),1.92–1.80(m,277H),1.81(s,7H),1.77(s,70H),1.73–1.51(m,541H),1.51(d,J＝1.8Hz,6H),1.40–1.36(m,160H),1.32(s,86H),1.22–1.16(m,264H).
实施例250 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-6-氯-2H-色烯-3-羧酰胺(A250)
1H NMR(500MHz,Chloroform)δ8.16(s,1H),7.32(s,1H),7.32–7.24(m,4H),7.23–7.09(m,3H),6.84(s,1H),6.05(s,1H),5.64(s,1H),5.33(s,1H),5.06–5.02(m,2H),4.50(d,J＝9.3Hz,2H),4.39(s,1H),4.32(s,1H),3.24(d,J＝17.4Hz,2H),2.99(s,1H),2.15(s,1H),2.08–2.04(m,2H),1.85(s,1H),1.79(s,1H),1.73–1.69(m,2H),1.69–1.62(m,5H),1.55(s,1H),1.39–1.35(m,2H),1.31(s,1H),1.23–1.19(m,2H),1.17(s,1H).
实施例251 N-((S)-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-6-氯2,3-二氢苯并[b]1,4-二噁英-6-羧酰胺(A251)
1H NMR(500MHz,Chloroform)δ8.51(s,1H),7.66(s,1H),7.55(s,1H),7.11(s,1H),5.40(s,1H),5.16(s,1H),4.65(s,1H),4.52(s,1H),4.38–4.34(m,4H),3.45(s,1H),3.36(d,J＝13.4Hz,2H),2.68(s,1H),2.18(s,1H),2.11–2.02(m,2H),1.99–1.84(m,3H),1.78–1.72(m,2H),1.71–1.62(m,5H),1.58(dd,J＝9.0,3.3Hz,5H),1.55–1.50(m,2H),1.48(s,1H),1.43–1.39(m,4H),1.37–1.29(m,3H).
实施例252 N-((S)-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-苯基-1-氧代丙-2-基)-6-氯2,3-二氢苯并[b]1,4-二噁英-6-羧酰胺(A252)
1H NMR(500MHz,Chloroform)δ9.01(s,1H),7.52(s,1H),7.29–7.23(m,2H),7.23–7.17(m,2H),7.15(s,1H),7.04(s,1H),6.92(s,1H),6.21(s,1H),5.12(s,1H),5.05(s,1H),4.87(s,1H),4.52(s,1H),4.38–4.34(m,4H),3.44(d,J＝12.5Hz,2H),3.37–3.20(m,3H),2.98(s,1H),2.19(s,1H),2.12–2.04(m,2H),1.92(s,1H),1.85–1.78(m,2H),1.66(s,1H),1.56–1.52(m,2H),1.48–1.39(m,3H),1.23–1.11(m,2H).
实施例253 N-((S)-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-5-甲氧基吲哚-6-羧酰胺(A253)
1H NMR(500MHz,Chloroform)δ8.73(s,5H),8.50(s,5H),7.45(s,5H),7.37(s,5H),7.18(s,5H),6.75(s,5H),6.03(s,5H),5.67(s,5H),5.61(s,5H),4.89(s,5H),4.57(s,5H),3.84–3.80(m,15H),3.43(d,J＝16.9Hz,10H),3.35(s,4H),2.70(s,5H),2.19(s,5H),2.09–2.06(m,9H),2.06–2.04(m,1H),2.06–1.91(m,16H),1.73–1.61(m,35H),1.60–1.46(m,47H),1.46–1.39(m,11H),1.35–1.26(m,9H),1.22(s,4H).
实施例254 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-4氟苯基-1-氧代丙-2-基)-5-甲基-苯并呋喃-2-羧酰胺(A254)
1H NMR(500MHz,Chloroform-d)δ8.35(d,J＝9.7Hz,1H),8.11(t,J＝5.8Hz,1H),7.83(d,J＝9.3Hz,1H),7.68(d,J＝2.1Hz,1H),7.60(dd,J＝2.7,1.8Hz,1H),7.41(d,J＝8.2Hz,1H),7.35–7.22(m,7H),7.22–7.17(m,1H),7.07–7.00(m, 2H),6.26(t,J＝4.0Hz,1H),4.75(dt,J＝9.7,6.2Hz,1H),4.54–4.46(m,1H),4.50–4.45(m,1H),4.47(t,J＝0.9Hz,1H),3.27–3.14(m,2H),3.08(ddt,J＝6.2,2.9,1.1Hz,2H),2.61(tdd,J＝8.9,6.9,4.3Hz,1H),2.13(ddd,J＝15.0,8.8,7.3Hz,1H),1.99(ddd,J＝15.2,8.8,7.3Hz,1H),1.81–1.61(m,4H).
实施例255 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-3-氯-苯并呋喃-2-羧酰胺(A255)
1H NMR(500MHz,Chloroform)δ7.75(s,1H),7.58(s,1H),7.49(s,1H),7.29(d,J＝15.0Hz,6H),7.21(s,1H),6.10(s,1H),4.78(s,1H),4.52(s,1H),4.34(s,2H),3.21(d,J＝15.0Hz,2H),2.91(s,1H),2.53(d,J＝13.0Hz,2H),2.01(s,1H),1.91(d,J＝6.4Hz,1H),1.76(s,1H),1.64(s,1H),1.58(s,1H),1.55–1.37(m,9H).
实施例256 N-((S)-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-5-氯-苯并呋喃-2-羧酰胺(A256)
1H NMR(500MHz,Chloroform)δ7.66(s,1H),7.44(s,1H),7.23(s,1H),7.15(s,1H),6.88(s,1H),6.44(s,1H),6.11(s,1H),4.95(s,1H),4.76(s,1H),4.54(s,1H),3.21(d,J＝15.0Hz,2H),2.88(s,1H),2.50(d,J＝13.5Hz,2H),2.19(s,2H),2.01(s,1H),1.91(d,J＝0.5Hz,1H),1.84(s,2H),1.76(s,1H),1.59(dd,J＝42.7,19.7Hz,5H),1.53(s,1H),1.51(d,J＝15.0Hz,3H),1.44(dd,J＝9.2,5.8Hz,5H),1.37(s,3H),1.31(s,1H),1.20(s,2H).
实施例257 N-((S)-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-6-溴-苯并呋喃-2-羧酰胺(A257)
1H NMR(500MHz,Chloroform)δ7.54(t,J＝2.6Hz,1H),7.46(d,J＝71.6Hz,5H),7.18(s,3H),7.11(d,J＝2.3Hz,4H),6.42(s,3H),5.73(s,3H),5.65(s,3H),5.03(s,2H),4.95(s,1H),4.47(s,1H),3.21(d,J＝15.0Hz,6H),2.99(s,2H),2.72(s,3H),2.34(s,2H),2.19(s,5H),2.01(s,1H),1.93(d,J＝16.1Hz,5H),1.89–1.74(m,10H),1.69(d,J＝10.0Hz,8H),1.62(s,2H),1.51(s,1H),1.39(d,J＝6.9Hz,1H),1.38–1.28(m,4H),1.20(s,3H),1.11(s,2H),1.03(s,3H).
实施例258 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-1-氧代-3-环己基丙-2-基)-5-氟烟酰胺(A258)
1H NMR(500MHz,Chloroform)δ8.58(s,1H),8.40(s,1H),7.77(s,1H),7.29(d,J＝15.0Hz,4H),7.22(s,1H),7.05(s,1H),6.30(s,1H),5.77(s,1H),4.90(s,1H),4.45(s,1H),4.34(s,2H),3.21(d,J＝15.0Hz,2H),2.97(s,1H),2.67(s,1H),2.13(s,1H),2.01(s,1H),1.93(d,J＝16.5Hz,2H),1.78(m,2H),1.75(d,J＝7.8Hz,1H),1.57(s,1H),1.46(m,9H).
实施例259 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-5-乙氧基-苯并呋喃-2-羧酰胺(A259)
1H NMR(500MHz,Chloroform)δ7.78–7.52(m,1H),7.29(d,J＝15.0Hz,1H),7.23(d,J＝10.0Hz,1H),7.11(s,1H),6.36(s,1H),5.85(s,1H),4.82(s,1H),4.45(s,1H),4.34(s,1H),4.06(s,1H),3.21(d,J＝15.0Hz,1H),2.82(s,2H),2.45(d,J＝1.0Hz,1H),2.01(s,1H),1.91(s,2H),1.79–1.57(m,2H),1.62–1.57(m,2H),1.55–1.41(m,2H),1.33(d,J＝7.5Hz,1H).
实施例260 N-((S)-1-(((S)-4-(3甲基苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-苯并呋喃-2-羧酰胺(A260)
1H NMR(500MHz,Chloroform)δ7.59(s,1H),7.50(d,J＝5.0Hz,2H),7.28(s,1H),7.21(d,J＝5.0Hz,1H),7.11(d,J＝1.5Hz,2H),7.03(s,1H),6.94(s,1H),6.88(s,1H),5.72(s,1H),4.68(s,1H),4.63(s,1H),4.34(s,2H),3.21(d,J＝15.0Hz,2H),2.78(s,1H),2.38–2.29(m,5H),2.08–2.03(m,1H),2.08–1.89(m,2H),1.76(s,1H),1.67(s,1H),1.55–1.41(m,8H).
实施例261 N-((S)-1-(((S)-4-(4氟苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-苯并呋喃-2-羧酰胺(A261)
1H NMR(500MHz,Chloroform)δ7.59(s,1H),7.50(s,1H),7.38(d,J＝2.0Hz,2H),7.28(s,1H),7.22(s,1H),7.16(s,1H),7.07(s,1H),6.86(s,1H),6.12(s,1H),4.80(s,1H),4.53(s,1H),4.34(s,1H),3.21(d,J＝15.0Hz,2H),2.91(s,1H),2.51(d,J＝9.5Hz,2H),2.01(s,1H),1.91(d,J＝4.1Hz,1H),1.76(s,1H),1.65(s,1H),1.58(s,1H),1.51(d,J＝15.0Hz,2H),1.44(dd,J＝8.0,7.0Hz,6H).
实施例262 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-5-氯-7氮杂吲哚-2-羧酰胺(A262)
1H NMR(500MHz,Chloroform)δ8.71(s,1H),8.52(s,1H),8.09(s,1H),7.29(d,J＝15.0Hz,5H),7.19(s,1H),7.14(s,1H),6.93(s,1H),6.09(s,1H),4.80(s,1H),4.45(s,1H),4.34(s,2H),3.21(d,J＝15.0Hz,2H),2.90(s,1H),2.44(d,J＝5.0Hz,2H),2.01(s,1H),1.91(d,J＝1.4Hz,1H),1.76(s,1H),1.72(s,1H),1.59–1.48(m,3H),1.48–1.41(m,4H),1.36(s,1H).
实施例263 N-((S)-1-(((S)-4-(4氯苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-苯并呋喃-2-羧酰胺(A263)
1H NMR(500MHz,Chloroform)δ7.59(s,1H),7.50(s,1H),7.38(d,J＝9.2Hz,5H),7.28(s,1H),7.22(s,1H),7.16(s,1H),6.86(s,1H),6.12(s,1H),4.80(s,1H),4.53(s,1H),4.34(s,2H),3.21(d,J＝15.0Hz,2H),2.92(s,1H),2.51(d,J＝13.5Hz,2H),2.01(s,1H),1.91(d,J＝3.7Hz,1H),1.76(s,1H),1.65(s,1H),1.58(s,1H),1.51(d,J＝15.0Hz,2H),1.44(dd,J＝8.3,6.7Hz,6H).
实施例264 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-6-溴-苯并呋喃-2-羧酰胺(A264)
1H NMR(500MHz,Chloroform)δ7.50(d,J＝32.8Hz,1H),7.34–7.26(m,3H), 7.18(s,1H),7.11(s,1H),6.87(s,1H),6.12(s,1H),4.78(s,1H),4.54(s,1H),4.34(s,1H),3.21(d,J＝15.0Hz,1H),2.90(s,2H),2.54(d,J＝18.2Hz,1H),2.01(s,1H),1.92(d,J＝6.0Hz,1H),1.76(s,2H),1.65(s,2H),1.58(s,2H),1.51(d,J＝15.0Hz,1H),1.44(dd,J＝8.2,6.8Hz,3H).
实施例265 N-((S)-1-(((S)-4-(3，4-二氟苄基氨基)-3,4-二酮-1-(2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-苯并呋喃-2-羧酰胺(A265)
1H NMR(500MHz,Chloroform)δ7.53(d,J＝44.9Hz,1H),7.34(s,1H),7.28–7.12(m,2H),7.05(s,1H),6.84(s,1H),6.11(s,1H),4.79(s,1H),4.53(s,1H),4.33(s,1H),3.21(d,J＝15.0Hz,1H),2.92(s,1H),2.50(d,J＝17.5Hz,1H),2.01(s,1H),1.91(d,J＝3.9Hz,2H),1.76(s,1H),1.65(s,1H),1.58(s,1H),1.55–1.41(m,4H).
实施例266 N-((S)-1-(((S)-4-(2氯苄基氨基)-3,4-二酮-1-(2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-苯并呋喃-2-羧酰胺(A266)
1H NMR(500MHz,Chloroform)δ7.66(s,1H),7.44(s,1H),7.23(s,1H),7.15(s,1H),6.88(s,1H),6.44(s,1H),6.11(s,1H),4.95(s,1H),4.76(s,1H),4.54(s,1H),3.21(d,J＝15.0Hz,2H),2.88(s,1H),2.50(d,J＝13.5Hz,1H),2.19(s,2H),2.01(s,1H),1.91(d,J＝0.5Hz,1H),1.84(s,1H),1.76(s,1H),1.59(dd,J＝42.7,19.7Hz,5H),1.53(s,1H),1.51(d,J＝15.0Hz,3H),1.44(dd,J＝9.2,5.8Hz,5H),1.37(s,3H),1.31(s,1H),1.20(s,2H).
实施例267 N-((S)-1-(((S)-4-(2甲氧基苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-苯并呋喃-2-羧酰胺(A267)
1H NMR(500MHz,Chloroform)δ7.54(s,1H),7.30–7.20(m,2H),7.15(s,1H),6.95–6.82(m,2H),6.11(s,1H),4.78(s,1H),4.53(s,1H),4.23(s,1H),3.72(s,1H),3.21(d,J＝15.0Hz,1H),2.89(s,1H),2.55(d,J＝18.5Hz,1H),2.01(s,1H),1.91(d,J＝5.9Hz,1H),1.76(s,1H),1.65(s,1H),1.58(s,1H),1.55–1.35(m,4H).
实施例268 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-哒嗪-2-羧酰胺(A268)
1H NMR(500MHz,Chloroform)δ9.81(s,1H),8.52(s,1H),7.99(s,1H),7.33–7.26(m,6H),6.71(s,1H),6.06(s,1H),4.75(s,1H),4.45(s,1H),4.34(s,2H),3.21(d,J＝15.0Hz,2H),2.83(s,1H),2.65(s,1H),2.52(s,1H),2.01(s,1H),1.90(d,J＝8.1Hz,1H),1.76(s,1H),1.65–1.28(m,9H),1.39–1.28(m,1H).
实施例269 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-4,5吲哚-2-羧酰胺(A269)
1H NMR(500MHz,Chloroform)δ8.49(s,1H),7.33–7.26(m,7H),7.20(s,2H),7.10(s,1H),6.87(s,1H),6.11(s,1H),4.78(s,1H),4.52(s,1H),4.34 (s,2H),3.21(d,J＝15.0Hz,2H),2.92(s,1H),2.54(d,J＝17.0Hz,3H),2.01(s,1H),1.92(d,J＝8.4Hz,2H),1.76(s,1H),1.64(s,1H),1.58(s,1H),1.51(d,J＝15.0Hz,4H),1.44(dd,J＝9.9,5.2Hz,6H).
实施例270 N-((S)-1-(((S)-4-(3，5二氟苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-苯并呋喃-2-羧酰胺(A270)
1H NMR(500MHz,Chloroform)δ7.54(d,J＝45.0Hz,1H),7.35(s,1H),7.27(s,1H),7.21(s,1H),7.15(s,2H),6.85(d,J＝1.8Hz,5H),6.79(s,1H),6.11(s,2H),4.79(s,1H),4.53(s,1H),4.33(s,3H),3.21(d,J＝15.0Hz,4H),2.91(s,1H),2.52(s,2H),2.48(s,2H),2.01(s,1H),1.91(d,J＝3.5Hz,2H),1.76(s,2H),1.65(s,2H),1.58(s,2H),1.55–1.41(m,7H).
实施例271 N-((S)-1-(((S)-4-(4甲氧基苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-苯并呋喃-2-羧酰胺(A271)
1H NMR(500MHz,Chloroform-d)δ8.19(d,J＝9.9Hz,1H),8.13(t,J＝5.7Hz,1H),7.89(d,J＝9.3Hz,1H),7.76(d,J＝2.0Hz,1H),7.75–7.68(m,1H),7.60–7.52(m,1H),7.43–7.34(m,2H),7.19(dt,J＝8.4,1.0Hz,2H),6.87–6.82(m,2H),6.26(t,J＝4.0Hz,1H),4.50(ddt,J＝5.8,3.7,1.1Hz,2H),4.44(dt,J＝9.2,7.4Hz,1H),4.26(dt,J＝9.9,6.7Hz,1H),3.78(s,2H),3.27–3.14(m,2H),2.61(tdd,J＝8.9,6.9,4.2Hz,1H),2.13(ddd,J＝15.0,8.8,7.3Hz,1H),1.99(ddd,J＝15.2,8.8,7.3Hz,1H),1.86–1.59(m,7H),1.57–1.34(m,8H),1.31–1.20(m,2H).ESI-MS m/z 631.31[M+H]
+.
实施例272 N-((S)-1-(((S)-4-(4甲基苄基甲氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-苯并呋喃-2-羧酰胺(A272)
1H NMR(500MHz,Chloroform-d)δ8.19(d,J＝9.9Hz,1H),7.85(d,J＝9.7Hz,1H),7.76(d,J＝1.9Hz,1H),7.75–7.68(m,1H),7.60–7.52(m,1H),7.43–7.34(m,2H),7.14(dt,J＝8.0,1.1Hz,2H),7.10(dq,J＝7.3,0.7Hz,2H),6.26(t,J＝4.0Hz,1H),4.55–4.48(m,2H),4.50–4.43(m,1H),4.26(dt,J＝9.9,6.7Hz,1H),3.27–3.14(m,2H),2.99(s,2H),2.61(tdd,J＝8.7,6.8,4.1Hz,1H),2.16(ddd,J＝15.0,8.8,7.6Hz,1H),1.94(ddd,J＝15.0,8.8,7.6Hz,1H),1.86–1.59(m,7H),1.57–1.34(m,8H),1.31–1.20(m,2H).ESI-MS m/z 629.33[M+H]
+.
实施例273 N-((S)-1-(((S)-4-(4硝基苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-苯并呋喃-2-羧酰胺(A273)
1H NMR(500MHz,Chloroform-d)δ8.21–8.13(m,3H),8.10(t,J＝5.8Hz,1H),7.89(d,J＝9.3Hz,1H),7.76(d,J＝1.9Hz,1H),7.75–7.68(m,1H),7.60(q,J＝1.1Hz,1H),7.60–7.52(m,2H),7.43–7.34(m,2H),6.26(t,J＝4.0Hz,1H),4.50(ddt,J＝5.6,4.6,0.9Hz,2H),4.44(dt,J＝9.2,7.4Hz,1H),4.26(dt,J＝9.9,6.7Hz,1H),3.27–3.14(m,2H),2.61(tdd,J＝8.9,6.9,4.2Hz,1H),2.13(ddd,J＝15.0,8.8,7.3Hz,1H),1.99(ddd,J＝15.2,8.8,7.3Hz,1H),1.86–1.71(m,4H), 1.74–1.59(m,3H),1.57–1.34(m,8H),1.31–1.20(m,2H).ESI-MS m/z 646.28[M+H]
+.
实施例274 N-((S)-1-(((S)-4-(2，4，6-三甲基苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-苯并呋喃-2-羧酰胺(A274)
1H NMR(500MHz,Chloroform-d)δ8.19(d,J＝9.9Hz,1H),7.89(d,J＝9.3Hz,1H),7.80–7.75(m,2H),7.75–7.68(m,1H),7.60–7.52(m,1H),7.43–7.34(m,2H),6.78(s,2H),6.26(t,J＝4.0Hz,1H),4.50(dd,J＝6.0,2.9Hz,2H),4.44(dt,J＝9.2,7.4Hz,1H),4.26(dt,J＝9.9,6.7Hz,1H),3.27–3.14(m,2H),2.61(tdd,J＝8.9,6.9,4.2Hz,1H),2.23(s,2H),2.13(ddd,J＝15.0,8.8,7.3Hz,1H),1.99(ddd,J＝15.2,8.8,7.3Hz,1H),1.86–1.59(m,7H),1.57–1.34(m,8H),1.31–1.20(m,2H).ESI-MS m/z 643.34[M+H]
+.
实施例275 N-((S)-1-(((S)-4-(4苯基苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-苯并呋喃-2-羧酰胺(A275)
1H NMR(500MHz,Chloroform-d)δ8.19(d,J＝9.9Hz,1H),8.13(t,J＝5.7Hz,1H),7.89(d,J＝9.3Hz,1H),7.76(d,J＝1.9Hz,1H),7.75–7.68(m,1H),7.62–7.49(m,5H),7.48–7.41(m,2H),7.43–7.34(m,3H),7.30(dt,J＝8.4,1.0Hz,2H),6.26(t,J＝4.0Hz,1H),4.49(ddt,J＝5.7,2.1,1.0Hz,2H),4.44(dt,J＝9.2,7.4Hz,1H),4.26(dt,J＝9.9,6.7Hz,1H),3.27–3.14(m,2H),2.61(tdd,J＝8.9,6.9,4.2Hz,1H),2.13(ddd,J＝15.0,8.8,7.3Hz,1H),1.99(ddd,J＝15.2,8.8,7.3Hz,1H),1.86–1.59(m,7H),1.57–1.34(m,8H),1.31–1.20(m,2H).ESI-MS m/z677.33[M+H]
+.
实施例276 N-((S)-1-(((S)-4-(2，4，6-三甲基苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-苯并呋喃-2-羧酰胺(A276)
1H NMR(500MHz,Chloroform-d)δ8.19(d,J＝9.9Hz,1H),7.89(d,J＝9.3Hz,1H),7.79–7.72(m,2H),7.75–7.68(m,1H),7.60–7.52(m,1H),7.43–7.34(m,2H),7.08(dd,J＝8.1,7.1Hz,1H),7.00–6.95(m,2H),6.26(t,J＝4.0Hz,1H),4.53–4.44(m,2H),4.46–4.39(m,1H),4.26(dt,J＝9.9,6.7Hz,1H),3.27–3.14(m,2H),2.61(tdd,J＝8.9,6.9,4.2Hz,1H),2.13(ddd,J＝15.0,8.8,7.3Hz,1H),1.99(ddd,J＝15.2,8.8,7.3Hz,1H),1.86–1.59(m,7H),1.57–1.34(m,8H),1.31–1.20(m,2H).ESI-MS m/z 629.33[M+H]
+.
实施例277 N-((S)-1-(((S)-4-(4氰基苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-苯并呋喃-2-羧酰胺(A277)
1H NMR(500MHz,Chloroform-d)δ8.19(d,J＝9.9Hz,1H),8.13(t,J＝5.7Hz,1H),7.89(d,J＝9.3Hz,1H),7.76(d,J＝1.9Hz,1H),7.75–7.68(m,1H),7.62–7.56(m,2H),7.59–7.52(m,1H),7.44–7.34(m,4H),6.26(t,J＝4.0Hz,1H),4.49(ddt,J＝5.7,2.1,0.9Hz,2H),4.44(dt,J＝9.2,7.4Hz,1H),4.26(dt,J＝9.9,6.7Hz,1H),3.27–3.14(m,2H),2.61(tdd,J＝8.9,6.9,4.2Hz,1H),2.13(ddd,J＝15.0, 8.8,7.3Hz,1H),1.99(ddd,J＝15.2,8.8,7.3Hz,1H),1.86–1.59(m,7H),1.57–1.34(m,8H),1.31–1.20(m,2H).ESI-MS m/z 626.29[M+H]
+.
实施例278 N-((S)-1-(((S)-4-(4三氟甲氧基苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-苯并呋喃-2-羧酰胺(A278)
1H NMR(500MHz,Chloroform-d)δ8.19(d,J＝9.9Hz,1H),8.13(t,J＝5.7Hz,1H),7.89(d,J＝9.3Hz,1H),7.76(d,J＝1.9Hz,1H),7.75–7.68(m,1H),7.60–7.52(m,1H),7.43–7.34(m,2H),7.23(dt,J＝8.3,1.1Hz,2H),7.17–7.11(m,2H),6.26(t,J＝4.0Hz,1H),4.50(ddt,J＝5.8,3.6,1.0Hz,2H),4.44(dt,J＝9.2,7.4Hz,1H),4.26(dt,J＝9.9,6.7Hz,1H),3.27–3.14(m,2H),2.61(tdd,J＝8.9,6.9,4.2Hz,1H),2.13(ddd,J＝15.0,8.8,7.3Hz,1H),1.99(ddd,J＝15.2,8.8,7.3Hz,1H),1.86–1.59(m,7H),1.57–1.34(m,8H),1.31–1.20(m,2H).ESI-MS m/z685.27[M+H]
+.
实施例279 N-((S)-1-(((S)-4-(2氰基苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-苯并呋喃-2-羧酰胺(A279)
1H NMR(500MHz,Chloroform-d)δ8.23–8.16(m,2H),7.89(d,J＝9.3Hz,1H),7.76(d,J＝1.9Hz,1H),7.75–7.68(m,1H),7.64–7.58(m,1H),7.61–7.52(m,1H),7.43–7.32(m,5H),6.26(t,J＝4.0Hz,1H),4.56(dd,J＝5.7,1.0Hz,2H),4.44(dt,J＝9.2,7.4Hz,1H),4.26(dt,J＝9.9,6.7Hz,1H),3.27–3.14(m,2H),2.61(tdd,J＝8.9,6.9,4.2Hz,1H),2.13(ddd,J＝15.0,8.8,7.3Hz,1H),1.99(ddd,J＝15.2,8.8,7.3Hz,1H),1.86–1.59(m,7H),1.57–1.34(m,8H),1.31–1.20(m,2H).ESI-MS m/z 626.30[M+H]
+.
实施例280 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-7氮杂吲哚-2-羧酰胺(A280)
1H NMR(500MHz,Chloroform-d)δ8.69(dd,J＝3.8,1.8Hz,1H),8.48(d,J＝8.2Hz,1H),8.28(dt,J＝7.3,1.9Hz,1H),8.11(t,J＝5.8Hz,1H),7.89(d,J＝9.3Hz,1H),7.54(d,J＝2.2Hz,1H),7.40–7.32(m,1H),7.34–7.30(m,1H),7.32–7.27(m,2H),7.30–7.22(m,2H),6.26(t,J＝4.0Hz,1H),4.48(t,J＝1.0Hz,1H),4.49–4.39(m,3H),3.27–3.14(m,2H),2.61(tdd,J＝8.9,6.9,4.2Hz,1H),2.13(ddd,J＝15.0,8.8,7.3Hz,1H),1.99(ddd,J＝15.2,8.8,7.3Hz,1H),1.86–1.59(m,7H),1.57–1.34(m,8H),1.31–1.20(m,2H).ESI-MS m/z 601.31[M+H]
+.
实施例281 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-5-氯-苯并呋喃-2-羧酰胺(A281)
1H NMR(500MHz,Chloroform-d)δ8.19–8.08(m,2H),7.89(d,J＝9.3Hz,1H),7.83(t,J＝2.1Hz,1H),7.75(d,J＝2.1Hz,1H),7.69(d,J＝8.4Hz,1H),7.48(dd,J＝8.4,2.0Hz,1H),7.35–7.22(m,5H),6.26(t,J＝4.0Hz,1H),4.50–4.39(m,3H),4.26(dt,J＝9.9,6.7Hz,1H),3.27–3.14(m,2H),2.61(tdd,J＝8.9,6.9,4.2Hz,1H),2.13(ddd,J＝15.0,8.8,7.3Hz,1H),1.99(ddd,J＝15.2,8.8,7.3Hz, 1H),1.86–1.74(m,3H),1.77–1.59(m,4H),1.57–1.34(m,8H),1.31–1.20(m,2H).ESI-MS m/z 635.26[M+H]
+.
实施例282 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-5-甲氧基-苯并呋喃-2-羧酰胺(A282)
1H NMR(500MHz,Chloroform-d)δ8.16(d,J＝9.9Hz,1H),8.11(t,J＝5.8Hz,1H),7.89(d,J＝9.3Hz,1H),7.67(d,J＝2.1Hz,1H),7.51(d,J＝8.4Hz,1H),7.35–7.22(m,5H),7.16(t,J＝2.0Hz,1H),7.08(dd,J＝8.4,1.8Hz,1H),6.26(t,J＝4.0Hz,1H),4.47(dt,J＝5.7,1.0Hz,2H),4.44(dt,J＝9.2,7.4Hz,1H),4.26(dt,J＝9.9,6.7Hz,1H),3.82(s,2H),3.27–3.14(m,2H),2.61(tdd,J＝8.9,6.9,4.2Hz,1H),2.13(ddd,J＝15.0,8.8,7.3Hz,1H),1.99(ddd,J＝15.2,8.8,7.3Hz,1H),1.86–1.71(m,4H),1.75–1.59(m,3H),1.57–1.34(m,8H),1.31–1.20(m,2H).ESI-MS m/z 631.31[M+H]
+.
实施例283 N-((R)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-苯并呋喃-2-羧酰胺(A283)
1H NMR(500MHz,Chloroform-d)δ8.19(d,J＝9.9Hz,1H),8.11(t,J＝5.8Hz,1H),7.89(d,J＝9.3Hz,1H),7.76(d,J＝1.9Hz,1H),7.75–7.68(m,1H),7.60–7.52(m,1H),7.43–7.35(m,2H),7.35–7.22(m,5H),6.26(t,J＝4.0Hz,1H),4.50–4.39(m,3H),4.26(dt,J＝9.9,6.7Hz,1H),3.27–3.14(m,2H),2.61(tdd,J＝8.9,6.9,4.2Hz,1H),2.13(ddd,J＝15.0,8.8,7.3Hz,1H),1.99(ddd,J＝15.2,8.8,7.3Hz,1H),1.86–1.59(m,7H),1.57–1.34(m,8H),1.32–1.20(m,2H).ESI-MS m/z 601.29[M+H]
+.
实施例284 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-(3-氟苯基)-1-氧代丙-2-基)-苯并呋喃-2-羧酰胺(A284)
1H NMR(500MHz,Chloroform-d)δ8.37(d,J＝9.7Hz,1H),8.11(t,J＝5.8Hz,1H),7.83(d,J＝9.3Hz,1H),7.76(d,J＝1.9Hz,1H),7.75–7.68(m,1H),7.60–7.52(m,1H),7.43–7.35(m,2H),7.35–7.22(m,6H),7.01(td,J＝7.8,1.9Hz,2H),6.96(dtt,J＝7.9,1.9,1.0Hz,1H),6.26(t,J＝4.0Hz,1H),4.78(dt,J＝9.7,6.2Hz,1H),4.54–4.46(m,1H),4.48(s,1H),4.47(t,J＝0.9Hz,1H),3.27–3.14(m,2H),3.05–2.93(m,2H),2.61(tdd,J＝8.9,6.9,4.3Hz,1H),2.13(ddd,J＝15.0,8.8,7.3Hz,1H),1.99(ddd,J＝15.2,8.8,7.3Hz,1H),1.81–1.61(m,4H).ESI-MS m/z613.24[M+H]
+.
实施例285 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-苯基-1-氧代丙-2-基)-5-氟-吲哚-2-羧酰胺(A285)
1H NMR(500MHz,Chloroform-d)δ9.91(s,1H),8.35(d,J＝8.1Hz,1H),7.83(d,J＝9.3Hz,1H),7.63(dt,J＝8.0,2.5Hz,1H),7.50(dd,J＝7.2,5.0Hz,1H),7.30–7.14(m,7H),7.08(ddd,J＝8.1,7.1,2.7Hz,1H),6.13(t,J＝3.1Hz,1H),4.78(dt,J＝8.1,6.2Hz,1H),4.44(dt,J＝9.3,7.3Hz,1H),3.33–3.26(m,1H), 3.29–3.22(m,1H),3.08–3.01(m,1H),3.04–2.97(m,1H),2.68(tdd,J＝7.7,5.7,3.9Hz,1H),2.17–2.08(m,1H),2.02(dt,J＝15.0,7.5Hz,1H),1.94–1.86(m,1H),1.82(dtd,J＝12.2,3.7,2.3Hz,1H).ESI-MS m/z 564.25[M+H]
+.
实施例286 N-((S)-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-5-甲氧基-吲哚-2-羧酰胺(A286)
1H NMR(500MHz,Chloroform-d)δ9.91(s,1H),8.32(d,J＝8.2Hz,1H),7.89(d,J＝9.3Hz,1H),7.48(d,J＝8.2Hz,1H),7.37–7.31(m,2H),6.82(dd,J＝7.3,2.4Hz,1H),6.13(t,J＝3.1Hz,1H),4.49–4.36(m,2H),3.83(s,2H),3.67(dp,J＝8.2,4.9Hz,1H),3.33–3.22(m,2H),2.68(tdd,J＝7.7,5.7,3.9Hz,1H),2.13(dt,J＝15.2,7.5Hz,1H),2.02(dt,J＝15.0,7.5Hz,1H),1.94–1.33(m,21H),1.31–1.20(m,2H).ESI-MS m/z 608.34[M+H]
+.
实施例287 N-((S)-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-苯基-1-氧代丙-2-基)-1-甲基-吲哚-2-羧酰胺(A287)
1H NMR(500MHz,Chloroform-d)δ8.18(d,J＝7.7Hz,1H),7.85–7.75(m,2H),7.48(d,J＝8.2Hz,1H),7.43(dd,J＝8.3,1.2Hz,1H),7.31–7.15(m,8H),6.13(t,J＝3.1Hz,1H),4.75(dt,J＝7.5,6.2Hz,1H),4.41(dt,J＝9.2,7.4Hz,1H),3.93(s,2H),3.67(dp,J＝8.2,4.9Hz,1H),3.33–3.26(m,1H),3.29–3.22(m,1H),3.02(ddt,J＝6.2,3.2,1.0Hz,2H),2.67(tdd,J＝7.8,5.7,3.9Hz,1H),2.13(dt,J＝15.3,7.5Hz,1H),2.02(dt,J＝15.0,7.5Hz,1H),1.94–1.86(m,1H),1.82(dtd,J＝12.2,3.7,2.3Hz,1H),1.75–1.40(m,8H),1.43–1.36(m,2H),1.40–1.33(m,1H).ESI-MS m/z 586.29[M+H]
+.
实施例288 N-((S)-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-苯基-1-氧代丙-2-基)-5-氟-吲哚-2-羧酰胺(A288)
1H NMR(500MHz,Chloroform-d)δ9.91(s,1H),8.35(d,J＝8.0Hz,1H),7.83(d,J＝9.3Hz,1H),7.63(dt,J＝7.9,2.5Hz,1H),7.53–7.46(m,2H),7.30–7.14(m,5H),7.08(ddd,J＝8.1,7.1,2.7Hz,1H),6.13(t,J＝3.1Hz,1H),4.78(dt,J＝8.1,6.2Hz,1H),4.41(dt,J＝9.2,7.4Hz,1H),3.67(dp,J＝8.2,4.9Hz,1H),3.33–3.26(m,1H),3.29–3.22(m,1H),3.02(ddt,J＝6.2,3.2,1.0Hz,2H),2.68(tdd,J＝7.7,5.7,3.9Hz,1H),2.13(dt,J＝15.2,7.5Hz,1H),2.02(dt,J＝15.0,7.5Hz,1H),1.94–1.86(m,1H),1.82(dtd,J＝12.2,3.7,2.3Hz,1H),1.75–1.33(m,11H).ESI-MS m/z 590.27[M+H]
+.
实施例289 N-((R)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-(4-氟苯基)-1-氧代丙-2-基)-苯并呋喃-2-羧酰胺(A289)
1H NMR(500MHz,Chloroform-d)δ8.37(d,J＝9.7Hz,1H),8.11(t,J＝5.8Hz,1H),7.83(d,J＝9.3Hz,1H),7.76(d,J＝1.9Hz,1H),7.75–7.68(m,1H),7.60–7.52(m,1H),7.43–7.35(m,2H),7.38–7.22(m,8H),7.07–7.00(m,2H),6.26(t,J＝4.0Hz,1H),4.75(dt,J＝9.7,6.2Hz,1H),4.54–4.46(m,1H),4.50–4.45(m,1H), 4.47(t,J＝0.9Hz,1H),3.27–3.14(m,2H),3.08(ddt,J＝6.2,2.9,1.1Hz,2H),2.61(tdd,J＝8.9,6.9,4.3Hz,1H),2.13(ddd,J＝15.0,8.8,7.3Hz,1H),1.99(ddd,J＝15.2,8.8,7.3Hz,1H),1.81–1.61(m,4H).ESI-MS m/z 613.24[M+H]
+.
实施例290 N-((R)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-(3,4-二氟苯基)-1-氧代丙-2-基)-苯并呋喃-2-羧酰胺(A290)
1H NMR(500MHz,Chloroform-d)δ8.37(d,J＝9.7Hz,1H),8.11(t,J＝5.8Hz,1H),7.83(d,J＝9.3Hz,1H),7.76(d,J＝1.9Hz,1H),7.75–7.68(m,1H),7.60–7.52(m,1H),7.43–7.35(m,2H),7.35–7.22(m,5H),7.10–7.03(m,1H),7.03–6.96(m,2H),6.26(t,J＝4.0Hz,1H),4.78(dt,J＝9.7,6.2Hz,1H),4.54–4.46(m,1H),4.50–4.45(m,1H),4.47(t,J＝0.9Hz,1H),3.27–3.14(m,2H),3.07–2.95(m,2H),2.61(tdd,J＝8.9,6.9,4.3Hz,1H),2.13(ddd,J＝15.0,8.8,7.3Hz,1H),1.99(ddd,J＝15.2,8.8,7.3Hz,1H),1.81–1.61(m,4H).ESI-MS m/z 631.23[M+H]
+.
实施例291 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-苯基-1-氧代丙-2-基)-苯并呋喃-2-羧酰胺(A291)
1H NMR(500MHz,Chloroform-d)δ8.37(d,J＝9.7Hz,1H),7.83(d,J＝9.2Hz,1H),7.76(d,J＝2.2Hz,1H),7.75–7.68(m,1H),7.60–7.52(m,1H),7.43–7.34(m,2H),7.30–7.16(m,6H),6.13(t,J＝3.1Hz,1H),4.70(dt,J＝9.7,6.2Hz,1H),4.44(dt,J＝9.3,7.3Hz,1H),3.33–3.26(m,1H),3.29–3.22(m,1H),3.08–2.97(m,2H),2.68(tdd,J＝7.7,5.7,3.9Hz,1H),2.17–2.08(m,1H),2.02(dt,J＝15.0,7.5Hz,1H),1.94–1.86(m,1H),1.82(dtd,J＝12.2,3.7,2.3Hz,1H).ESI-MS m/z547.25[M+H]
+.
实施例292 N-((S)-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-2,3-二氢苯并[b]1,4-二噁英-6-羧酰胺(A292)
1H NMR(500MHz,Chloroform-d)δ7.95–7.87(m,2H),7.54–7.46(m,2H),7.40(d,J＝2.1Hz,1H),6.89(d,J＝8.5Hz,1H),6.13(t,J＝3.1Hz,1H),4.40(dt,J＝9.3,7.3Hz,1H),4.36–4.29(m,1H),4.29(dd,J＝4.8,2.4Hz,2H),4.27(ddd,J＝4.7,3.0,2.2Hz,2H),3.67(dp,J＝8.2,4.9Hz,1H),3.33–3.26(m,1H),3.29–3.22(m,1H),2.67(tdd,J＝7.8,5.7,3.9Hz,1H),2.13(dt,J＝15.2,7.5Hz,1H),2.02(dt,J＝15.0,7.5Hz,1H),1.94–1.86(m,1H),1.86–1.77(m,2H),1.80–1.66(m,4H),1.68–1.61(m,1H),1.64–1.58(m,1H),1.61–1.49(m,2H),1.53–1.38(m,10H),1.41–1.33(m,2H),1.31–1.20(m,2H).ESI-MS m/z597.33[M+H]
+.
实施例293 N-((S)-1-(((S)-4-((R)-1苯基-乙基)-氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)–喹啉-2-羧酰胺(A293)
1H NMR(500MHz,Chloroform-d)δ8.39–8.32(m,2H),8.20(d,J＝8.3Hz,1H),8.07–8.01(m,1H),7.97–7.91(m,1H),7.89(d,J＝9.3Hz,1H),7.73(td,J＝7.9, 1.1Hz,1H),7.53(td,J＝7.8,1.2Hz,1H),7.36–7.29(m,2H),7.32–7.22(m,4H),6.13(t,J＝3.1Hz,1H),5.01(dtdd,J＝8.4,6.1,5.1,1.1Hz,1H),4.48–4.37(m,2H),3.33–3.26(m,1H),3.29–3.22(m,1H),2.68(tdd,J＝7.7,5.7,3.9Hz,1H),2.17–2.08(m,1H),2.02(dt,J＝15.0,7.5Hz,1H),1.94–1.86(m,1H),1.86–1.68(m,4H),1.57–1.34(m,12H),1.31–1.20(m,2H).ESI-MS m/z 612.31[M+H]
+.
实施例294 N-((S)-1-(((S)-4-吗啉基-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)–喹啉-2-羧酰胺(A294)
1H NMR(500MHz,Chloroform-d)δ8.39–8.32(m,2H),8.20(d,J＝8.3Hz,1H),8.07–8.01(m,1H),7.94(dt,J＝8.0,0.8Hz,1H),7.84(d,J＝9.7Hz,1H),7.73(td,J＝7.9,1.1Hz,1H),7.53(td,J＝7.9,1.2Hz,1H),6.13(t,J＝3.1Hz,1H),4.52(dt,J＝9.7,7.7Hz,1H),4.41(dt,J＝9.3,6.6Hz,1H),3.71(ddd,J＝9.7,6.3,3.6Hz,4H),3.63(dd,J＝6.4,3.6Hz,2H),3.55(dd,J＝6.4,3.6Hz,2H),3.33–3.26(m,1H),3.29–3.22(m,1H),2.64(tdd,J＝7.8,5.7,3.9Hz,1H),2.16(dt,J＝15.3,7.6Hz,1H),2.01(dt,J＝15.1,7.7Hz,1H),1.94–1.86(m,1H),1.86–1.80(m,1H),1.82–1.77(m,1H),1.80–1.75(m,1H),1.77–1.68(m,1H),1.57–1.34(m,8H),1.31–1.20(m,2H).ESI-MS m/z 578.29[M+H]
+.
实施例295 N-((S)-1-(((S)-4-((S)-1苯基-乙基)-氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)–喹啉-2-羧酰胺(A295)
1H NMR(500MHz,Chloroform-d)δ8.39–8.32(m,2H),8.20(d,J＝8.3Hz,1H),8.07–8.01(m,1H),7.97–7.91(m,1H),7.89(d,J＝9.3Hz,1H),7.73(td,J＝7.9,1.1Hz,1H),7.53(td,J＝7.8,1.2Hz,1H),7.36–7.29(m,2H),7.32–7.22(m,4H),6.13(t,J＝3.1Hz,1H),5.03(dqt,J＝8.1,6.1,1.1Hz,1H),4.48–4.37(m,2H),3.33–3.26(m,1H),3.29–3.22(m,1H),2.68(tdd,J＝7.7,5.7,3.9Hz,1H),2.17–2.08(m,1H),2.02(dt,J＝15.0,7.5Hz,1H),1.94–1.86(m,1H),1.86–1.68(m,4H),1.57–1.34(m,12H),1.31–1.20(m,2H).ESI-MS m/z 612.31[M+H]
+.
实施例296 N-((S)-1-(((S)-4-二乙胺基-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)–喹啉-2-羧酰胺(A296)
1H NMR(500MHz,Chloroform-d)δ8.39–8.32(m,2H),8.20(d,J＝8.3Hz,1H),8.07–8.01(m,1H),7.97–7.91(m,1H),7.85(d,J＝9.7Hz,1H),7.73(td,J＝7.9,1.1Hz,1H),7.53(td,J＝7.8,1.2Hz,1H),6.13(t,J＝3.1Hz,1H),4.52(dt,J＝9.7,7.7Hz,1H),4.41(dt,J＝9.3,6.6Hz,1H),3.45(q,J＝7.3Hz,4H),3.33–3.26(m,1H),3.29–3.22(m,1H),2.67(tdd,J＝7.9,5.7,3.9Hz,1H),2.17(dt,J＝15.3,7.7Hz,1H),2.01(dt,J＝15.1,7.6Hz,1H),1.94–1.86(m,1H),1.86–1.70(m,4H),1.57–1.34(m,8H),1.31–1.20(m,2H),1.20(t,J＝7.3Hz,6H).ESI-MS m/z564.31[M+H]
+.
实施例297 N-((S)-1-(((S)-4-(4氟苄基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)–喹啉-2-羧酰胺(A297)
1H NMR(500MHz,Chloroform-d)δ8.39–8.32(m,2H),8.20(d,J＝8.2Hz,1H),8.13(t,J＝5.7Hz,1H),8.07–8.01(m,1H),7.97–7.91(m,1H),7.89(d,J＝9.3Hz,1H),7.73(td,J＝7.9,1.1Hz,1H),7.53(td,J＝7.7,1.1Hz,1H),7.32(ddt,J＝7.5,5.0,1.0Hz,2H),7.11–7.03(m,2H),6.13(t,J＝3.1Hz,1H),4.55–4.45(m,3H),4.41(dt,J＝9.3,6.6Hz,1H),3.33–3.26(m,1H),3.29–3.22(m,1H),2.67(tdd,J＝7.8,5.7,3.9Hz,1H),2.13(dt,J＝15.2,7.5Hz,1H),2.02(dt,J＝15.0,7.5Hz,1H),1.94–1.86(m,1H),1.86–1.77(m,2H),1.80–1.75(m,1H),1.77–1.68(m,1H),1.57–1.34(m,8H),1.31–1.20(m,2H).ESI-MS m/z 616.28[M+H]
+.
实施例298 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-5-溴咪唑并[1,2-a]吡啶-2-羧酰胺(A298)
1H NMR(500MHz,Chloroform-d)δ8.39–8.32(m,2H),8.20(d,J＝8.2Hz,1H),8.13(t,J＝5.7Hz,1H),8.07–8.01(m,1H),7.94(dt,J＝8.0,0.8Hz,1H),7.89(d,J＝9.3Hz,1H),7.73(td,J＝7.9,1.1Hz,1H),7.53(td,J＝7.9,1.2Hz,1H),7.19(dt,J＝8.4,1.0Hz,2H),6.87–6.82(m,2H),6.13(t,J＝3.1Hz,1H),4.55–4.49(m,1H),4.52–4.44(m,2H),4.41(dt,J＝9.3,6.6Hz,1H),3.78(s,2H),3.33–3.26(m,1H),3.29–3.22(m,1H),2.67(tdd,J＝7.8,5.7,3.9Hz,1H),2.13(dt,J＝15.2,7.5Hz,1H),2.07–1.99(m,1H),1.94–1.86(m,1H),1.86–1.68(m,4H),1.57–1.34(m,8H),1.31–1.20(m,2H).ESI-MS m/z 628.31[M+H]
+.
实施例299 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-5-溴咪唑并[1,2-a]吡啶-2-羧酰胺(A299)
1H NMR(500MHz,Chloroform-d)δ9.03(d,J＝6.6Hz,1H),8.11(t,J＝5.8Hz,1H),8.01(t,J＝1.6Hz,1H),7.92(dd,J＝23.3,8.9Hz,2H),7.79(dd,J＝7.4,1.6Hz,1H),7.44(s,0H),7.35–7.17(m,6H),6.69(dd,J＝3.3,2.0Hz,1H),6.13(t,J＝3.1Hz,1H),4.54–4.46(m,1H),4.47(dd,J＝5.8,0.9Hz,2H),4.33(dt,J＝8.4,6.7Hz,1H),3.33–3.26(m,1H),3.29–3.22(m,1H),2.68(tdd,J＝7.7,5.7,3.9Hz,1H),2.17–2.08(m,1H),2.02(dt,J＝15.0,7.5Hz,1H),1.94–1.86(m,1H),1.86–1.69(m,4H),1.57–1.34(m,9H),1.31–1.20(m,2H).ESI-MS m/z586.30[M+H]
+.
实施例300 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-5-溴咪唑并[1,2-a]吡啶-2-羧酰胺(A300)
1H NMR(500MHz,Chloroform-d)δ8.74–8.70(m,1H),8.58(d,J＝9.3Hz,1H),8.47(s,1H),8.11(t,J＝5.8Hz,1H),7.89(d,J＝9.3Hz,1H),7.52(dd,J＝8.8,1.3Hz,1H),7.42(d,J＝8.8Hz,1H),7.35–7.22(m,5H),6.13(t,J＝3.1Hz,1H),4.54–4.46(m,1H),4.48(d,J＝0.9Hz,1H),4.47(t,J＝0.9Hz,1H),4.41(dt,J＝9.3,6.6Hz,1H),3.33–3.26(m,1H),3.29–3.22(m,1H),2.68(tdd,J＝7.7,5.7,3.9Hz,1H),2.17–2.08(m,1H),2.02(dt,J＝15.0,7.5Hz,1H),1.94–1.86(m,1H),1.86–1.68(m,4H),1.57–1.34(m,8H),1.31–1.20(m,2H).ESI-MS m/z 665.20[M+H]
+.
实施例301 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-7-溴-喹啉-2-羧酰胺(A301)
1H NMR(500MHz,Chloroform-d)δ8.36–8.30(m,2H),8.19(d,J＝2.1Hz,1H),8.15(d,J＝8.2Hz,1H),8.11(t,J＝5.8Hz,1H),7.94–7.86(m,2H),7.62(dd,J＝8.5,2.3Hz,1H),7.35–7.22(m,5H),6.13(t,J＝3.1Hz,1H),4.54–4.45(m,3H),4.41(dt,J＝9.3,6.6Hz,1H),3.33–3.26(m,1H),3.29–3.22(m,1H),2.68(tdd,J＝7.7,5.7,3.9Hz,1H),2.17–2.08(m,1H),2.02(dt,J＝15.0,7.5Hz,1H),1.94–1.86(m,1H),1.86–1.80(m,1H),1.82–1.77(m,1H),1.80–1.75(m,1H),1.77–1.68(m,1H),1.57–1.34(m,8H),1.31–1.20(m,2H).ESI-MS m/z676.20[M+H]
+.
实施例302 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-2,3-二氢苯并[b]1,4-二噁英-6-羧酰胺(A302)
1H NMR(500MHz,Chloroform-d)δ8.11(t,J＝5.8Hz,1H),7.95–7.87(m,2H),7.52(dd,J＝8.4,2.2Hz,1H),7.40(d,J＝2.1Hz,1H),7.35–7.22(m,5H),6.89(d,J＝8.5Hz,1H),6.13(t,J＝3.1Hz,1H),4.54–4.46(m,1H),4.48(d,J＝0.9Hz,1H),4.47(t,J＝0.9Hz,1H),4.36–4.29(m,1H),4.29(dd,J＝4.8,2.4Hz,2H),4.27(ddd,J＝4.7,3.0,2.2Hz,2H),3.33–3.26(m,1H),3.29–3.22(m,1H),2.68(tdd,J＝7.7,5.7,3.9Hz,1H),2.17–2.08(m,1H),2.02(dt,J＝15.0,7.5Hz,1H),1.94–1.86(m,1H),1.86–1.69(m,4H),1.57–1.34(m,9H),1.31–1.20(m,2H).ESI-MS m/z 605.29[M+H]
+.
实施例303 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-5-甲基-异噁唑-2-羧酰胺(A303)
1H NMR(500MHz,Chloroform-d)δ8.36(d,J＝9.3Hz,1H),8.11(t,J＝5.8Hz,1H),7.89(d,J＝9.3Hz,1H),7.35–7.22(m,5H),6.50(s,1H),6.13(t,J＝3.1Hz,1H),4.47(dt,J＝5.4,0.9Hz,2H),4.48–4.37(m,2H),3.33–3.26(m,1H),3.29–3.22(m,1H),2.67(tdd,J＝7.8,5.7,3.9Hz,1H),2.52(s,2H),2.13(dt,J＝15.2,7.5Hz,1H),2.02(dt,J＝15.0,7.5Hz,1H),1.94–1.86(m,1H),1.86–1.80(m,1H),1.82–1.77(m,1H),1.80–1.75(m,1H),1.77–1.68(m,1H),1.57–1.34(m,8H),1.31–1.20(m,2H).ESI-MS m/z 552.27[M+H]
+.
实施例304 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-(2氟苯基)-1-氧代丙-2-基)-喹啉-2-羧酰胺(A304)
1H NMR(500MHz,Chloroform-d)δ8.43–8.32(m,2H),8.20(d,J＝8.2Hz,1H),8.11(t,J＝5.8Hz,1H),8.04(dd,J＝8.1,1.2Hz,1H),7.97–7.91(m,1H),7.83(d,J＝9.1Hz,1H),7.73(td,J＝7.9,1.1Hz,1H),7.53(td,J＝7.7,1.2Hz,1H),7.36–7.15(m,7H),7.10(td,J＝7.9,1.2Hz,1H),6.13(t,J＝3.1Hz,1H),4.80 (dt,J＝9.2,7.3Hz,1H),4.54–4.46(m,1H),4.47(dd,J＝5.8,0.9Hz,2H),3.33–3.22(m,2H),3.21(ddd,J＝15.8,7.4,0.9Hz,1H),3.09(ddd,J＝15.9,7.3,0.7Hz,1H),2.68(tdd,J＝7.7,5.7,3.9Hz,1H),2.13(dt,J＝15.2,7.5Hz,1H),2.07–1.99(m,1H),1.90(dddd,J＝12.1,6.1,3.8,2.5Hz,1H),1.82(dtd,J＝12.2,3.7,2.3Hz,1H).ESI-MS m/z 610.24[M+H]
+.
实施例305 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-(3-氟苯基)-1-氧代丙-2-基)-喹啉-2-羧酰胺(A305)
1H NMR(500MHz,Chloroform-d)δ8.43(d,J＝9.1Hz,1H),8.35(d,J＝8.3Hz,1H),8.20(d,J＝8.2Hz,1H),8.11(t,J＝5.8Hz,1H),8.04(dd,J＝8.1,1.2Hz,1H),7.97–7.91(m,1H),7.83(d,J＝9.3Hz,1H),7.73(td,J＝7.9,1.1Hz,1H),7.53(td,J＝7.7,1.2Hz,1H),7.35–7.22(m,6H),7.01(td,J＝7.8,1.9Hz,2H),6.96(dtt,J＝7.9,1.9,1.0Hz,1H),6.13(t,J＝3.1Hz,1H),4.80(dt,J＝9.3,6.3Hz,1H),4.54–4.46(m,1H),4.47(dd,J＝5.8,0.9Hz,2H),3.33–3.22(m,2H),3.05–2.93(m,2H),2.68(tdd,J＝7.7,5.7,3.9Hz,1H),2.13(dt,J＝15.2,7.5Hz,1H),2.07–1.99(m,1H),1.90(dddd,J＝12.1,6.1,3.8,2.4Hz,1H),1.82(dtd,J＝12.3,3.7,2.3Hz,1H).ESI-MS m/z 610.23[M+H]
+.
实施例306 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-(4-氟苯基)-1-氧代丙-2-基)-喹啉-2-羧酰胺(A306)
1H NMR(500MHz,Chloroform-d)δ8.43(d,J＝9.1Hz,1H),8.35(d,J＝8.2Hz,1H),8.20(d,J＝8.3Hz,1H),8.11(t,J＝5.8Hz,1H),8.07–8.01(m,1H),7.97–7.91(m,1H),7.83(d,J＝9.3Hz,1H),7.73(td,J＝7.9,1.1Hz,1H),7.53(td,J＝7.8,1.2Hz,1H),7.35–7.22(m,7H),7.07–7.00(m,2H),6.13(t,J＝3.1Hz,1H),4.77(dt,J＝9.2,6.2Hz,1H),4.54–4.46(m,1H),4.48(d,J＝0.9Hz,1H),4.47(t,J＝0.9Hz,1H),3.33–3.26(m,1H),3.29–3.22(m,1H),3.13–3.01(m,2H),2.67(tdd,J＝7.8,5.7,3.9Hz,1H),2.13(dt,J＝15.2,7.5Hz,1H),2.07–1.99(m,1H),1.94–1.86(m,1H),1.82(dtd,J＝12.2,3.7,2.2Hz,1H).ESI-MS m/z 610.24[M+H]
+.
实施例307 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-(3,4-二氟苯基)-1-氧代丙-2-基)-喹啉-2-羧酰胺(A307)
1H NMR(500MHz,Chloroform-d)δ8.43(d,J＝9.1Hz,1H),8.35(d,J＝8.2Hz,1H),8.20(d,J＝8.3Hz,1H),8.11(t,J＝5.8Hz,1H),8.07–8.01(m,1H),7.97–7.91(m,1H),7.83(d,J＝9.3Hz,1H),7.73(td,J＝7.9,1.1Hz,1H),7.53(td,J＝7.8,1.2Hz,1H),7.35–7.22(m,5H),7.10–7.03(m,1H),7.03–6.96(m,2H),6.13(t,J＝3.1Hz,1H),4.80(dt,J＝9.3,6.3Hz,1H),4.54–4.46(m,1H),4.47(dd,J＝5.7,0.9Hz,2H),3.33–3.26(m,1H),3.29–3.22(m,1H),3.00(ddt,J＝6.2,2.8,1.0Hz,2H),2.68(tdd,J＝7.7,5.7,3.9Hz,1H),2.17–2.08(m,1H),2.07–1.99(m,1H),1.94–1.86(m,1H),1.82(dtd,J＝12.2,3.7,2.2Hz,1H).ESI-MS m/z 628.23[M+H]
+.
实施例308 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁 -2-基)氨基)-3-(2-氟苯基)-1-氧代丙-2-基)–苯并呋喃-2-羧酰胺(A308)
1H NMR(500MHz,Chloroform-d)δ8.33(d,J＝9.7Hz,1H),8.11(t,J＝5.8Hz,1H),7.83(d,J＝9.1Hz,1H),7.76(d,J＝1.9Hz,1H),7.75–7.68(m,1H),7.60–7.52(m,1H),7.43–7.34(m,2H),7.37–7.26(m,5H),7.29–7.23(m,1H),7.26–7.18(m,1H),7.21–7.17(m,1H),7.10(td,J＝7.9,1.2Hz,1H),6.26(t,J＝4.0Hz,1H),4.77(dt,J＝9.7,7.3Hz,1H),4.54–4.46(m,1H),4.48(s,1H),4.47(t,J＝0.9Hz,1H),3.27–3.14(m,3H),3.09(ddd,J＝15.9,7.3,0.8Hz,1H),2.61(tdd,J＝8.9,6.9,4.3Hz,1H),2.13(ddd,J＝15.0,8.8,7.3Hz,1H),1.99(ddd,J＝15.2,8.8,7.3Hz,1H),1.81–1.61(m,4H).ESI-MS m/z 613.23[M+H]
+.
实施例309 N-((S)-1-(((S)-4-(环丙基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-苯并呋喃-2-羧酰胺(A309)
1H NMR(500MHz,DMSO-d6)δ8.71(d,J＝5.1Hz,1H),8.57(t,J＝8.4Hz,2H),7.81–7.75(m,1H),7.68(dd,J＝8.4,1.0Hz,1H),7.63(d,J＝1.0Hz,1H),7.47(m,2H),7.37–7.30(m,1H),5.08(m,1H),4.59(m,1H),3.10(m,2H),2.72(m,1H),2.28(m,1H),2.11(m,1H),1.90(m,1H),1.77–1.49(m,6H),1.45–1.34(m,2H),1.29–1.06(m,3H),0.97–0.87(m,2H),0.74–0.59(m,2H),0.59–0.26(m,2H).ESI-MS m/z 551.27[M+H]
+.
实施例310 N-((S)-1-(((S)-4-(环丙基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-(4-氟苯基)-1-氧代丙-2-基)-苯并呋喃-2-羧酰胺(A310)
1H NMR(500MHz,DMSO-d6)δ8.78–8.63(m,3H),7.76(d,J＝7.8Hz,1H),7.65(d,J＝8.4Hz,1H),7.55(s,1H),7.49–7.43(m,2H),7.41–7.35(m,2H),7.32(t,J＝7.8Hz,1H),7.07(t,J＝8.4Hz,2H),5.13(m,1H),4.78(m,1H),3.16–3.06(m,3H),3.06–2.97(m,1H),2.73(m,1H),2.27(m,1H),2.14(m,1H),2.08–1.89(m,1H),1.73(m,2H),1.56(m,1H),1.42(m,1H),0.71–0.60(m,2H),0.60–0.42(m,2H).ESI-MS m/z 563.22[M+H]
+.
活性测试例1：2019新型冠状病毒3CL蛋白酶抑制活性评价
测定化合物对2019新型冠状病毒3CL蛋白酶(2019-nCoV 3CL
pro)的抑制活性：利用荧光共振能量转移(fluorescence resonance energy transfer FRET)技术测定针对3C蛋白酶的抑制剂的酶水平抑制活性。在96孔板上，每孔中加入27.5μL缓冲液(20mM Tris，100mM NaCl，1mM EDTA，pH 7.4)，同时加入2.5μL化合物(最终浓度分别为2μM、4μM、6μM、8μM、10μM、12μM、14μM、16μM、18μM、20μM)和5μL EV713Cpro(最终浓度3μM)。在37℃下共孵育15min。之后加入15μL缓冲液稀释的荧光底物(最终浓度20μM)。利用Ge n5荧光分度计测定荧光参数，激发波长和发射波长分别为340nm和490nm，保持37℃，10min后读取数据。采用阴性对照，其中对照不加入化合物，其余相同。 所得数据利用软件GraphPad Prism 5处理，实验结果如表1所示。
表1:2019新型冠状病毒3CL蛋白酶抑制活性
注：化合物A42、或DC404001、或4001(省略了“DC40XXXX”中的“DC40”)指同一个化合物；其他化合物依此类推。
实验结果显示：多数化合物对2019-nCoV 3CL蛋白酶具有较好的抑制活性，其中化合物A13(DC403113)和A42(DC404001)对2019-nCoV 3CL蛋白酶的抑制活性IC
50达到2.4μM和3.0μM。
活性测试例2：人组织蛋白酶L抑制活性评价
测定化合物对人组织蛋白酶L(cathepsin L,CatL)的抑制活性：利用荧光共振能量转移(fluorescence resonance energy transfer,FRET)技术测定针对组织蛋白酶L的酶水平抑制活性。在96孔板上，每孔中加入10μL缓冲液(50mM CH
3COONa,pH 5.5,1mM DTT,2mM EDTA)，同时加入0.2μL化合物(最终浓度分别为100nM,10nM,1nM,0.1nM和0.01nM)和10μL组织蛋白酶L。在25℃下共孵育15min。之后加入10μL缓冲液稀释的荧光底物(Z-Phe-Arg-AMC，最终浓度20μM)。利用Tecan Infinite 200pro荧光分度计测定荧光参数，激发波长和发射波长分别为360nm和465nm，保持25℃，30min后读取数据。采用阴性对照，其中对照不加入化合物，其余相同。所得数据利用软件GraphPad Prism 8.0处理，实验结果如表2所示。
表2:人组织蛋白酶L抑制活性
| 化合物编号 | IC 50(nM) | 化合物编号 | IC 50(nM) |
| A5(DC406104) | 0.45±0.02 | A13(DC403113) | 1.36±0.04 |
| A284(DC406016) | 0.45±0.01 | A289(DC406009) | 0.66±0.008 |
| A290(DC406020) | 0.47±0.06 | A309(DC406068) | 0.63±0.08 |
| A310(DC406067) | 0.57±0.01 |
实验结果显示：测试化合物对人组织蛋白酶L具有优异的抑制活性，IC
50均达纳摩尔级，甚至小于1nM(如化合物A5、A284、A289、A290、A309、A310)。
活性测试例3：化合物2019新型冠状病毒复制抑制活性评价
测定化合物对各2019新型冠状病毒(2019-nCov)复制抑制活性：在96孔中加入100μl/孔梯度浓度的化合物，随后加入50μl/孔病毒缓冲液，随后立即加入50μl/孔培养好后的RD细胞(rhabdomyosarcoma cells)，37℃培养3-4天，直到观察到最大细胞病变效果。吸去培养基，加入75μl 5％MTS的酚红培养基，37℃，5％CO
2培养1.5小时，测定各孔在498nM波长的荧光值，画出化合物浓度与细胞反应的曲线图，用在Accelrys公司定制的软件计算化合物抑制病毒的EC
50。
试验结果如图1和2所示。
结果表明，本发明的酮酰胺类化合物可有效地抑制2019新型冠状病毒的复制(图1)，对不同分离的病毒株有一定的抑制。
目前抗2019-nCoV的阳性化合物为CQ，其抑制2019-nCoV病毒复制的抑制率EC
50＝1.13μM。结果显示：以CQ为阳性对照，在不同的浓度梯度下对专利中的化合物进行测试，化合物A13(3113，DC403113)，A42(4001，DC404001)，A289(6009，DC406009)均具有优良的抑制病毒活性。其中3113的EC
50为9237nM，6009和4001的EC
50分别为296.5nM和580.5nM，6009和4001在病毒水平上对2019-nCoV的抑制率优于阳性对照CQ，展现出优异的抗2019-nCoV潜力(图2)。
活性测试例4：DC406009：SD大鼠重复静脉输注给药14天毒性试验
本试验的目的是观察SD大鼠连续7天静脉注射DC406009后对机体潜在的毒性，确定可能的毒性靶器官。提供无毒性反应剂量和/或毒性反应剂量，为后续的毒性试验设计以及临床试验的方案设计提供参考。为了评估药物在体内的暴露水平，伴随进行毒代动力学评价。
SD大鼠36只，分为8组(毒性试验组3只/性别/组，共5组；毒代卫星组1只/性别/组，3组)，静脉注射给予溶媒(5％DMSO/5％EtOH/40％PEG300/50％NaCl)、0.9％氯化钠注射液和DC406009(5、15、30mg/kg/day)，每天1次，连续给药7天，所有动物于Day 8进行安乐死解剖。试验期间，对下列指标进行了评价：毒代(仅采集样品)、临床观察、体重、耗食量、临床病理(血液学、血凝、血浆生化)和解剖肉眼形态学观察检查。
结果显示：在本试验条件下，SD大鼠静脉注射给予DC406009(5、15、30mg/kg/day)，每天1次，连续7天，动物均可耐受，最大耐受剂量(MTD)为大于30mg/kg/day，表明化合物DC406009具有良好的安全性。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，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 (16)
- 一种通式(A)所示的酮酰胺类化合物、或其药学上可接受的盐、对映异构体、非对映异构体或外消旋体的用途，其特征在于，用于制备(a)2019新型冠状病毒(2019-nCov)3CL蛋白酶抑制剂和/或人组织蛋白酶L抑制剂；和(b)治疗和/或预防、缓解由2019新型冠状病毒(2019-nCov)感染引起的相关疾病的药物：
其中，*表示碳原子的立体化学异构分别独立地为R和/或S；R 1和R 2各自独立地选自下组：氢、氘、氚、氨基、羟基、取代或未取代的C1-C10烷基、取代或未取代的C3-C10环烷基、取代或未取代的C3-C10环烷基C1-C10亚烷基、取代或未取代的C3-C10杂环烷基、取代或未取代的C3-C10杂环烷基C1-C10亚烷基、取代或未取代的C6-C20芳基、取代或未取代的C3-C20杂芳基、取代或未取代的C6-C20芳基C1-C10亚烷基、取代或未取代的C3-C20杂芳基C1-C10亚烷基、取代或未取代的C6-C20芳基C2-C10亚烯基、取代或未取代的C3-C20杂芳基C2-C10亚烯基、酰基、磺酰基；R 3选自下组：取代或未取代的C1-C10烷基、取代或未取代的C2-C10烯基、取代或未取代的C2-C10炔基、取代或未取代的C3-C8环烷基、取代或未取代的C3-C8环烷基C1-C10亚烷基、取代或未取代的C3-C8杂环烷基、取代或未取代的C3-C8杂环烷基C1-C10亚烷基、取代或未取代的C6-C20芳基、取代或未取代的C3-C20杂芳基、取代或未取代的C6-C20芳基C1-C10亚烷基、取代或未取代的C3-C20杂芳基C1-C10亚烷基、取代或未取代的C6-C20芳基C2-C6亚烯基、取代或未取代的C3-C20杂芳基C2-C6亚烯基、取代或未取代的C6-C20芳基C2-C6亚炔基、取代或未取代的C3-C20杂芳基C2-C6亚炔基；R 4选自下组：取代或未取代的C1-C10烷基、取代或未取代的C2-C10烯基、取代或未取代的C2-C10炔基、取代或未取代的C3-C10环烷基、取代或未取代的C3-C10杂环烷基、取代或未取代的C6-C20芳基、取代或未取代的C3-C20杂芳基、取代或未取代的C6-C20芳基C1-C6亚烷基、取代或未取代的C6-C20芳基C2-C6亚烯基、取代或未取代的C6-C20芳基C2-C6亚炔基、取代或未取代的C3-C20杂芳基C1-C9亚烷基、取代或未取代的C3-C20杂芳基C2-C9亚烯基、取代或未取代的C3-C20杂芳基C2-C9亚炔基；R 6选自下组：氢、氘、氚、氨基、羟基、取代或未取代的C1-C10烷基、取代或未取代的C3-C10环烷基、取代或未取代的C3-C10杂环烷基、取代或未取代的C6-C20芳基、取代或未取代的C3-C20杂芳基、取代或未取代的C6-C20芳基C1-C6亚烷基、取代或未取代的C6-C20芳基C2-C6亚烯基、取代或未取代的C3-C20杂芳基C1-C9亚烷基、取代或未取代的C3-C20杂芳基C2-C9亚烯基、酰基、磺酰基；当-NR 5与其相邻的-(C＝O)-CH 2-成环时，R 5为-(CH 2) n-，n为2或3；当-NR 5不与其相邻的-(C＝O)-CH 2-成环时，R 5选自下组：氢、氘、氚、氨基、羟基、取代或未取代的C1-C10烷基、取代或未取代的C3-C10环烷基、取代或未取代的C3-C10杂环烷基、取代或未取代的C6-C20芳基、取代或未取代的C3-C20杂芳基、取代或未取代的C6-C20芳基C1-C6亚烷基、取代或未取代的C6-C20芳基C2-C6亚烯基、取代或未取代的C3-C20杂芳基C1-C9亚烷基、取代或未取代的C3-C20杂芳基C2-C9亚烯基、酰基、磺酰基；其中，在R 1、R 2、R 3、R 4、R 5和R 6中，所述取代各自独立地指被选自下组的1、2、3或4个取代基取代：卤素、羟基、巯基、硝基、氰基、胺基、亚胺基、叔胺基、叠氮基、C1-C8烷基、卤代C1-C8烷基、C1-C8烷氧基、卤代C1-C8烷氧基、C1-C6烷基羰基、C1-C6烷硫基、C1-C8烷氧基羰基、三氟甲基；所述杂环烷基和所述杂芳基各自独立地包含1、2、3或4个选自N、O、S的杂原子。 - 如权利要求1所述的用途，其特征在于，所述由2019新型冠状病毒感染引起的相关疾病选自下组：呼吸道感染、肺炎及其并发症、或其组合。
- 如权利要求1或2所述的用途，其特征在于，R 1和R 2各自独立地选自下组：氢、氘、氚、氨基、羟基、取代或未取代的C1-C6烷基、取代或未取代的C3-C8环烷基、取代或未取代的C3-C8环烷基C1-C5亚烷基、取代或未取代的C3-C10杂环烷基、取代或未取代的C3-C10杂环烷基C1-C5亚烷基、取代或未取代的C6-C14芳基、取代或未取代的C3-C10杂芳基、取代或未取代的C6-C14芳基C1-C5亚烷基、取代或未取代的C3-C10杂芳基C1-C5亚烷基、取代或未取代的C6-C10芳基C2-C5亚烯基、取代或未取代的C3-C10杂芳基C2-C5亚烯基、酰基、磺酰基；R 3选自下组：取代或未取代的C1-C6烷基、取代或未取代的C2-C6烯基、取代或未取代的C2-C6炔基、取代或未取代的C3-C8环烷基、取代或未取代的C3-C8环烷基C1-C5亚烷基、取代或未取代的C3-C8杂环烷基、取代或未取代的C3-C8杂环烷基C1-C5亚烷基、取代或未取代的C6-C10芳基、取代或未取代的C3-C10杂芳基、取代或未取代的C6-C10芳基C1-C5亚烷基、取代或未取代的C3-C10杂芳基C1-C5亚烷基、取代或未取代的C6-C10芳基C2-C4亚烯基、取代或未取代的C3-C10杂芳基C2-C4亚烯基、取代或未取代的C6-C10芳基C2-C4亚炔基、取代或未取代的C3-C10杂芳基C2-C4亚炔基；其中，在R 1、R 2和R 3中，所述取代各自独立地指被选自下组的1、2或3个取代基取代：卤素、羟基、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、C1-C4烷基羰基、C1-C4烷硫基、C1-C6烷氧基羰基、三氟甲基；所述杂环烷基和所述杂芳基各自独立地包含1或2个选自N、O、S的杂原子。
- 如权利要求1或2所述的用途，其特征在于，所述化合物为式AA所示的化合物，
其中，R 1、R 2、R 3、R 4、R 5和n如权利要求1中所限定；*表示碳原子的立体化学异构分别独立地为R和/或S。 - 如权利要求1或2所述的用途，其特征在于，R 4选自下组：含1、2或3个选自N、O、S的杂原子的9-10元杂芳环、含1、2或3个选自N、O、S的杂原子的5-6元杂芳环；上述基团为取代或未取代的；其中，所述取代指基团上的氢原子被1、2、3或4个选自下组的取代基取代：卤素、羟基、C1-C6烷基、卤代C1-C6烷基、C3-C6环烷基、卤代C3-C6环烷基、C1-C6烷氧基、卤代C1-C6烷氧基、C1-C6烷硫基、卤代C1-C6烷硫基。
- 如权利要求1或2所述的用途，其特征在于，当-NR 5与其相邻的-(C＝O)-CH 2-成环时，R 5为-(CH 2) n-，n为2或3；当-NR 5不与其相邻的-(C＝O)-CH 2-成环时，R 5选自下组：氢、氘、氚、羟基、取代或未取代的C1-C6烷基、取代或未取代的C3-C8环烷基、取代或未取代的C3-C8杂环烷基、取代或未取代的C6-C10芳基、取代或未取代的C3-C10杂芳基、取代或未取代的C6-C10芳基C1-C4亚烷基、取代或未取代的C6-C10芳基C2-C4亚烯基、取代或未取代的C3-C10杂芳基C1-C4亚烷基、取代或未取代的C3-C10杂芳基C2-C4亚烯基；其中，所述取代各自独立地指被选自下组的1、2或3个取代基取代：F、Cl、Br、I、羟基、C1-C6烷基、C1-C6烷氧基、C1-C6烷硫基；所述杂环烷基和所述杂芳基各自独立地包含1、2或3个选自N、O、S的杂原子。
- 如权利要求1或2所述的用途，其特征在于，R 4选自下组：取代或未取代的喹喔啉基、取代或未取代的喹唑啉基、取代或未取代的噌啉基、取代或未取代的吲哚基、取代或未取代的异吲哚基、取代或未取代的1,3-苯并二噁茂基、取代或未取代的苯并咪唑基、取代或未取代的吲唑基、取代或未取代的咪唑[1,2-A]吡啶基、取代或未取代的咪唑[1,5-A]吡啶基、取代或未取代的吡唑基、取代或未取代的咪唑基、取代或未取代的噻唑基、取代或未取代的噁唑基、取代或未取代的异噁唑基、取代或未取代的1，2，3-三唑基、取代或未取代的1，2-噻二唑基、取代或未取代的1，2，4-三嗪基、取代或未取代的吡啶基、取代或未取代的吡咯基、取代或未取代的吡嗪基、取代或未取代的嘧啶基、取代或未取代的3,8a二氢-2H-苯并吡喃基、取代或未取代的苯并吡喃基、取代或未取代的喹啉基、取代或未取代的异喹啉基、取代或未取代的苯并噁唑基、取代或未取代的苯并噻唑基、取代或未取代的苯并噻吩基、取代或未取代的苯并呋喃基；其中，所述取代指基团上的氢原子被1、2或3个选自下组的取代基取代：F、Cl、Br、I、羟基、C1-C6烷基、卤代C1-C6烷基、C3-C6环烷基、卤代C3-C6环烷基、C1-C6烷氧基、卤代C1-C6烷氧基、C1-C6烷硫基、卤代C1-C6烷硫基。
- 如权利要求1或2所述的用途，其特征在于，所述化合物选自下组：
- 一种药物组合物，其特征在于，所述的药物组合物含有(a)通式(A)所示的酮酰胺类化合物、或其药学上可接受的盐、对映异构体、非对映异构体或外消旋体；以及(b)药学上可接受的载体，
其中，*表示碳原子的立体化学异构分别独立地为R和/或S；R 1和R 2各自独立地选自下组：氢、氘、氚、氨基、羟基、取代或未取代的C1-C10烷基、 取代或未取代的C3-C10环烷基、取代或未取代的C3-C10环烷基C1-C10亚烷基、取代或未取代的C3-C10杂环烷基、取代或未取代的C3-C10杂环烷基C1-C10亚烷基、取代或未取代的C6-C20芳基、取代或未取代的C3-C20杂芳基、取代或未取代的C6-C20芳基C1-C10亚烷基、取代或未取代的C3-C20杂芳基C1-C10亚烷基、取代或未取代的C6-C20芳基C2-C10亚烯基、取代或未取代的C3-C20杂芳基C2-C10亚烯基、酰基、磺酰基；R 3选自下组：取代或未取代的C1-C10烷基、取代或未取代的C2-C10烯基、取代或未取代的C2-C10炔基、取代或未取代的C3-C8环烷基、取代或未取代的C3-C8环烷基C1-C10亚烷基、取代或未取代的C3-C8杂环烷基、取代或未取代的C3-C8杂环烷基C1-C10亚烷基、取代或未取代的C6-C20芳基、取代或未取代的C3-C20杂芳基、取代或未取代的C6-C20芳基C1-C10亚烷基、取代或未取代的C3-C20杂芳基C1-C10亚烷基、取代或未取代的C6-C20芳基C2-C6亚烯基、取代或未取代的C3-C20杂芳基C2-C6亚烯基、取代或未取代的C6-C20芳基C2-C6亚炔基、取代或未取代的C3-C20杂芳基C2-C6亚炔基；R 4选自下组：取代或未取代的C1-C10烷基、取代或未取代的C2-C10烯基、取代或未取代的C2-C10炔基、取代或未取代的C3-C10环烷基、取代或未取代的C3-C10杂环烷基、取代或未取代的C6-C20芳基、取代或未取代的C3-C20杂芳基、取代或未取代的C6-C20芳基C1-C6亚烷基、取代或未取代的C6-C20芳基C2-C6亚烯基、取代或未取代的C6-C20芳基C2-C6亚炔基、取代或未取代的C3-C20杂芳基C1-C9亚烷基、取代或未取代的C3-C20杂芳基C2-C9亚烯基、取代或未取代的C3-C20杂芳基C2-C9亚炔基；R 6选自下组：氢、氘、氚、氨基、羟基、取代或未取代的C1-C10烷基、取代或未取代的C3-C10环烷基、取代或未取代的C3-C10杂环烷基、取代或未取代的C6-C20芳基、取代或未取代的C3-C20杂芳基、取代或未取代的C6-C20芳基C1-C6亚烷基、取代或未取代的C6-C20芳基C2-C6亚烯基、取代或未取代的C3-C20杂芳基C1-C9亚烷基、取代或未取代的C3-C20杂芳基C2-C9亚烯基、酰基、磺酰基；当-NR 5与其相邻的-(C＝O)-CH 2-成环时，R 5为-(CH 2) n-，n为2或3；当-NR 5不与其相邻的-(C＝O)-CH 2-成环时，R 5选自下组：氢、氘、氚、氨基、羟基、取代或未取代的C1-C10烷基、取代或未取代的C3-C10环烷基、取代或未取代的C3-C10杂环烷基、取代或未取代的C6-C20芳基、取代或未取代的C3-C20杂芳基、取代或未取代的C6-C20芳基C1-C6亚烷基、取代或未取代的C6-C20芳基C2-C6亚烯基、取代或未取代的C3-C20杂芳基C1-C9亚烷基、取代或未取代的C3-C20杂芳基C2-C9亚烯基、酰基、磺酰基；其中，在R 1、R 2、R 3、R 4、R 5和R 6中，所述取代各自独立地指被选自下组的1、2、3或4个取代基取代：卤素、羟基、巯基、硝基、氰基、胺基、亚胺基、叔胺基、叠氮基、C1-C8烷基、卤代C1-C8烷基、C1-C8烷氧基、卤代C1-C8烷氧基、C1-C6烷基羰基、C1-C6烷硫基、C1-C8烷氧基羰基、三氟甲基；所述杂环烷基和所述杂芳基各自独立地包含1、2、3或4个选自N、O、S的杂原子。 - 一种如权利要求9所述的药物组合物的用途，其特征在于，用于制备治疗和/或预防、缓解由2019新型冠状病毒(2019-nCov)感染引起的相关疾病的药物。
- 如权利要求10所述的用途，其特征在于，所述由2019新型冠状病毒感染引起的 相关疾病选自下组：呼吸道感染、肺炎及其并发症、或其组合。
- 一种治疗、预防、和/或缓解由2019新型冠状病毒(2019-nCov)感染引起的相关疾病的方法，其特征在于，包括步骤：给需要的对象施用安全有效量的通式(A)所示的酮酰胺类化合物、或其药学上可接受的盐、对映异构体、非对映异构体或外消旋体，其中所述的通式(A)所示的酮酰胺类化合物如权利要求1中所述。
- 一种抑制2019新型冠状病毒(2019-nCov)的3CL蛋白酶的活性的方法，包括步骤：将通式(A)所示的酮酰胺类化合物、或其药学上可接受的盐、对映异构体、非对映异构体或外消旋体与2019-nCov的3CL蛋白酶接触，从而抑制2019-nCov的3CL蛋白酶的活性,其中所述的通式(A)所示的酮酰胺类化合物如权利要求1中所述。
- 一种抑制人组织蛋白酶L的活性的方法，包括步骤：将通式(A)所示的酮酰胺类化合物、或其药学上可接受的盐、对映异构体、非对映异构体或外消旋体与人组织蛋白酶L接触，从而抑制人组织蛋白酶L的活性,其中所述的通式(A)所示的酮酰胺类化合物如权利要求1中所述。
- 一种式(A)化合物、或其药学上可接受的盐、对映异构体、非对映异构体或外消旋体，
其中，*表示碳原子的立体化学异构分别独立地为R和/或S；R 1和R 2各自独立地选自下组：氢、氘、氚、氨基、羟基、取代或未取代的C1-C10烷基、取代或未取代的C3-C10环烷基、取代或未取代的C3-C10环烷基C1-C10亚烷基、取代或未取代的C3-C10杂环烷基、取代或未取代的C3-C10杂环烷基C1-C10亚烷基、取代或未取代的C6-C20芳基、取代或未取代的C3-C20杂芳基、取代或未取代的C6-C20芳基C1-C10亚烷基、取代或未取代的C3-C20杂芳基C1-C10亚烷基、取代或未取代的C6-C20芳基C2-C10亚烯基、取代或未取代的C3-C20杂芳基C2-C10亚烯基、酰基、磺酰基；R 3选自下组：取代或未取代的C1-C10烷基、取代或未取代的C2-C10烯基、取代或未取代的C2-C10炔基、取代或未取代的C3-C8环烷基、取代或未取代的C3-C8环烷基C1-C10亚烷基、取代或未取代的C3-C8杂环烷基、取代或未取代的C3-C8杂环烷基C1-C10亚烷基、取代或未取代的C6-C20芳基、取代或未取代的C3-C20杂芳基、取代或未取代的C6-C20芳基C1-C10亚烷基、取代或未取代的C3-C20杂芳基C1-C10亚烷基、取代或未取代的C6-C20芳基C2-C6亚烯基、取代或未取代的C3-C20杂芳基C2-C6亚烯基、取代或未取代的C6-C20芳基C2-C6亚炔基、取代或未取代的C3-C20杂芳基C2-C6亚炔基；R 4选自下组：取代或未取代的C1-C10烷基、取代或未取代的C2-C10烯基、取代或未取 代的C2-C10炔基、取代或未取代的C3-C10环烷基、取代或未取代的C3-C10杂环烷基、取代或未取代的C6-C20芳基、取代或未取代的C3-C20杂芳基、取代或未取代的C6-C20芳基C1-C6亚烷基、取代或未取代的C6-C20芳基C2-C6亚烯基、取代或未取代的C6-C20芳基C2-C6亚炔基、取代或未取代的C3-C20杂芳基C1-C9亚烷基、取代或未取代的C3-C20杂芳基C2-C9亚烯基、取代或未取代的C3-C20杂芳基C2-C9亚炔基；R 6选自下组：氢、氘、氚、氨基、羟基、取代或未取代的C1-C10烷基、取代或未取代的C3-C10环烷基、取代或未取代的C3-C10杂环烷基、取代或未取代的C6-C20芳基、取代或未取代的C3-C20杂芳基、取代或未取代的C6-C20芳基C1-C6亚烷基、取代或未取代的C6-C20芳基C2-C6亚烯基、取代或未取代的C3-C20杂芳基C1-C9亚烷基、取代或未取代的C3-C20杂芳基C2-C9亚烯基、酰基、磺酰基；当-NR 5与其相邻的-(C＝O)-CH 2-成环时，R 5为-(CH 2) n-，n为2或3；当-NR 5不与其相邻的-(C＝O)-CH 2-成环时，R 5选自下组：氢、氘、氚、氨基、羟基、取代或未取代的C1-C10烷基、取代或未取代的C3-C10环烷基、取代或未取代的C3-C10杂环烷基、取代或未取代的C6-C20芳基、取代或未取代的C3-C20杂芳基、取代或未取代的C6-C20芳基C1-C6亚烷基、取代或未取代的C6-C20芳基C2-C6亚烯基、取代或未取代的C3-C20杂芳基C1-C9亚烷基、取代或未取代的C3-C20杂芳基C2-C9亚烯基、酰基、磺酰基；其中，在R 1、R 2、R 3、R 4、R 5和R 6中，所述取代各自独立地指被选自下组的1、2、3或4个取代基取代：卤素、羟基、巯基、硝基、氰基、胺基、亚胺基、叔胺基、叠氮基、C1-C8烷基、卤代C1-C8烷基、C1-C8烷氧基、卤代C1-C8烷氧基、C1-C6烷基羰基、C1-C6烷硫基、C1-C8烷氧基羰基、三氟甲基；所述杂环烷基和所述杂芳基各自独立地包含1、2、3或4个选自N、O、S的杂原子。 - 如权利要求15所述的化合物、或其药学上可接受的盐、对映异构体、非对映异构体或外消旋体，其特征在于，所述化合物为化合物A254-A310。
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| CN118922415A (zh) * | 2022-04-11 | 2024-11-08 | 上海科技大学 | 一种化合物及其在制备治疗肠道病毒相关疾病的药物中的应用 |
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| US12065428B2 (en) | 2021-09-17 | 2024-08-20 | Aligos Therapeutics, Inc. | Anti-viral compounds |
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| AU2021213137B2 (en) | 2024-10-03 |
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| EP4098258A4 (en) | 2024-02-28 |
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