Ketoamide compounds, methods for preparing them, pharmaceutical compositions, and their uses.

Abstract

The present invention relates to a ketoamide compound, a method for preparing the same, a pharmaceutical composition, and uses thereof. Specifically, the ketoamide compound is represented by Formula A, its racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically active metabolite, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. The ketoamide compound effectively inhibits coronavirus or Ebola virus, thereby preventing or treating coronavirus-related or Ebola virus-related diseases. Formula A: [Formula 1]

Description

[Technical Field]

[0001] This invention relates to the fields of medicinal chemistry and pharmacotherapy, and more specifically to ketoamide compounds as inhibitors of coronavirus or Ebola virus, methods for preparing the same, pharmaceutical compositions containing such compounds, and their uses. [Background technology]

[0002] Coronaviruses belong to the genus Coronavirus in the family Coronaviridae. Mature coronaviruses have a diameter of approximately 60 nM to 220 nM and are called coronaviruses because they are corona-type or crown-type when viewed under an electron microscope. They are important pathogens of many vertebrates, including those that cause human diseases.

[0003] Coronavirus is a single-stranded positive-sense RNA virus with a genome size of 27-32kb, making it the RNA virus with the largest genome known to date. It contains 6-12 open reading frames similar to the mRNA of eukaryotic cells. Coronavirus replication occurs in the cytoplasm, and after infecting a cell, the virus sheds its outer shell in the cytoplasm, and the positive-sense genomic RNA is activated, performing its role as mRNA. Coronavirus infections are distributed in many regions around the world, and the virus has already been discovered in countries such as China, the UK, the US, Germany, Japan, Russia, Finland, and India. Infections caused by this virus mainly occur in winter and early spring. Household testing in Michigan, USA, proved that coronavirus can infect all age groups, with 0-4 year olds accounting for 29.2% and those 40 years and older accounting for 22%, and the incidence rate being highest in the 15-19 age group. This differs from the epidemic situation of other upper respiratory tract viruses, such as respiratory syncytial virus, in that the incidence rate mainly decreases with age.

[0004] Coronaviruses can be classified into four genera—α, β, γ, and δ—based on their serological characteristics. Among these, the new type of β-genus coronavirus, MERS-CoV (Middle East Respiratory Syndrome-coronavirus), is having a significant impact on global public health. MERS-CoV was first discovered in Saudi Arabia in 2012 and renamed Middle East Respiratory Syndrome in 2013. According to data released by the World Health Organization (WHO), as of March 19, 2018, a total of 2,143 patients had been diagnosed with MERS-CoV in 27 countries worldwide, resulting in 750 deaths and a fatality rate of nearly 35%. This virus has already spread to China.

[0005] Clinical manifestations after MERS-CoV infection in humans include fever, cough, and shortness of breath. Most patients also experience symptoms such as high fever, chills / shivering, cough, shortness of breath, and muscle pain. The majority of MERS-CoV patients are people with chronic illnesses, and all of the most susceptible individuals are children under 15 years of age, the elderly over 65 years of age, pregnant women, patients with chronic conditions such as cardiac tubes or pneumonia, and those with weakened immune systems.

[0006] MERS-CoV is highly pathogenic, not only infecting other species but also spreading from person to person. The mortality rate for MERS-CoV exceeds 30%, and the main modes of transmission are droplet infection and contact infection. SARS-CoV and MERS-CoV belong to the same genus, Coronavirus β. They caused severe acute respiratory syndrome in Shunde, Guangdong, China in 2002, spread to Southeast Asia, and eventually to the rest of the world. The epidemic was gradually brought under control by mid-2003. The SARS virus is expelled from the body through respiratory secretions, transmitted through oral fluids, sneezing, and contact, and infected through airborne droplets. The peak period for infection is autumn, winter, and early spring.

[0007] In summary, there is an urgent need to develop inhibitors against MERS-CoV and SARS-CoV in this field, which is not only a hotspot for international antiviral research but also a crucial task in the prevention and treatment of infectious diseases in China. [Overview of the project] [Problems that the invention aims to solve]

[0008] The object of the present invention is to provide a ketoamide compound represented by formula A having an inhibitory effect against coronavirus or Ebola virus, its racemic mixture, enantiomer, diastereomer or mixture thereof, its pharmaceutically active metabolite, or its pharmaceutically acceptable salt, solvate or prodrug, as well as methods for preparing the same, pharmaceutical compositions and uses. [Means for solving the problem]

[0009] A first aspect of the present invention provides a ketoamide compound represented by formula A, its racemic mixture, enantiomer, diastereomer or mixture thereof, or a pharmaceutically active metabolite thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof. Formula A: [ka]

[0010] Here, R 1 and R 2These are, independently of each other, hydrogen, deuterium, tritium, amino group, hydroxyl group, substituted or unsubstituted C1-C10 alkyl group, substituted or unsubstituted C3-C10 cycloalkyl group, substituted or unsubstituted C3-C10 cycloalkyl group, C1-C10 alkylene group, substituted or unsubstituted C3-C10 heterocycloalkyl group, substituted or unsubstituted C3-C10 heterocycloalkyl group, substituted or unsubstituted C6-C20 aryl group, and substituted or unsubstituted C3-C20 heteroaryl group. Selected from the group consisting of substituted or unsubstituted C6-C20 aryl groups and C1-C10 alkylene groups, substituted or unsubstituted C3-C20 heteroaryl groups and C1-C10 alkylene groups, substituted or unsubstituted C6-C20 aryl groups and C2-C10 alkenylene groups (alkenylene group), substituted or unsubstituted C3-C20 heteroaryl groups and C2-C10 alkenylene groups, acyl groups (acyl group), and sulfonyl groups (sulfonyl group),

[0011] R 3This includes substituted or unsubstituted C1-C10 alkyl groups, substituted or unsubstituted C2-C10 alkenyl groups, substituted or unsubstituted C2-C10 alkynyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups, C1-C10 alkylene groups, substituted or unsubstituted C3-C8 heterocycloalkyl groups, substituted or unsubstituted C3-C8 heterocycloalkyl groups, C1-C10 alkylene groups, substituted or unsubstituted C6-C20 aryl groups, substituted or unsubstituted C3-C20 heteroaryl groups, substituted or unsubstituted C6-C20 aryl groups, C1-C10 alkylene groups, substituted or unsubstituted C6-C20 aryl groups, and C2-C6 alkenylene groups. Selected from the group consisting of substituted or unsubstituted C3-C20 heteroaryl groups C2-C6 alkenylene groups, substituted or unsubstituted C6-C20 aryl groups C2-C6 alkynylene groups (alkynylene group), and substituted or unsubstituted C3-C20 heteroaryl groups C2-C6 alkynylene groups,

[0012] R 4 This includes substituted or unsubstituted C1-C10 alkyl groups, substituted or unsubstituted C2-C10 alkenyl groups, substituted or unsubstituted C2-C10 alkynyl groups, substituted or unsubstituted C3-C10 cycloalkyl groups, substituted or unsubstituted C3-C10 heterocycloalkyl groups, substituted or unsubstituted C6-C20 aryl groups, substituted or unsubstituted C3-C20 heteroaryl groups, and substituted or unsubstituted C6-C20 aryl groups. Selected from the group consisting of a lukylene group, a substituted or unsubstituted C6-C20 aryl group, a C2-C6 alkenylene group, a substituted or unsubstituted C6-C20 aryl group, a C2-C6 alkynylene group, a substituted or unsubstituted C3-C20 heteroaryl group, a C1-C9 alkylene group, a substituted or unsubstituted C3-C20 heteroaryl group, a C2-C9 alkenylene group, and a substituted or unsubstituted C3-C20 heteroaryl group.

[0013] -NHR 5 When -NHR forms a ring with the adjacent -(C=O)-CH2-, R 5 is -(CH2) n -, n is 2 or 3, and

[0014] -NHR 5 When -NHR does not form a ring with the adjacent -(C=O)-CH2-, R 5 is selected from the group consisting of hydrogen, deuterium, tritium, amino group, hydroxyl group, substituted or unsubstituted C1-C10 alkyl group, substituted or unsubstituted C3-C10 cycloalkyl group, substituted or unsubstituted C3-C10 heterocycloalkyl group, substituted or unsubstituted C6-C20 aryl group, substituted or unsubstituted C3-C20 heteroaryl group, substituted or unsubstituted C6-C20 aryl group C1-C6 alkylene group, substituted or unsubstituted C6-C20 aryl group C2-C6 alkenylene group, substituted or unsubstituted C3-C20 heteroaryl group C1-C9 alkylene group, substituted or unsubstituted C3-C20 heteroaryl group C2-C9 alkenylene group, acyl group, sulfonyl group,

[0015] where R 1 , R 2 , R 3 , R 4 and R 5In this context, the substitution refers to each being independently substituted by one, two, three, or four substituents selected from the group consisting of halogen, hydroxyl group, sulfhydryl group, nitro group, cyano group, amine group, imino group, tertiary amine group, azido group, C1-C8 alkyl group, halogenated C1-C8 alkyl group, C1-C8 alkoxy group, halogenated C1-C8 alkoxy group, C1-C6 alkylcarbonyl group, C1-C6 alkylthio group, C1-C8 alkoxycarbonyl group, and trifluoromethyl group, wherein the heterocycloalkyl group and the heteroaryl group each independently contain one, two, three, or four heteroatoms selected from N, O, and S.

[0016] In another preferred example, R 1 and R 2 Each of these is independently selected from the group consisting of hydrogen, deuterium, tritium, amino group, hydroxyl group, substituted or unsubstituted C1-C6 alkyl group, substituted or unsubstituted C3-C8 cycloalkyl group, substituted or unsubstituted C3-C8 cycloalkyl group, C1-C5 alkylene group, substituted or unsubstituted C3-C10 heterocycloalkyl group, substituted or unsubstituted C3-C10 heterocycloalkyl group, C1-C5 alkylene group, substituted or unsubstituted C6-C14 aryl group, substituted or unsubstituted C3-C10 heteroaryl group, substituted or unsubstituted C6-C14 aryl group, C1-C5 alkylene group, substituted or unsubstituted C3-C10 heteroaryl group, C1-C5 alkylene group, substituted or unsubstituted C6-C10 aryl group, C2-C5 alkenylene group, substituted or unsubstituted C3-C10 heteroaryl group, C2-C5 alkenylene group, acyl group, and sulfonyl group.

[0017] R 3 This includes substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C2-C6 alkenyl groups, substituted or unsubstituted C2-C6 alkynyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups, C1-C5 alkylene groups, substituted or unsubstituted C3-C8 heterocycloalkyl groups, substituted or unsubstituted C3-C8 heterocycloalkyl groups, C1-C5 alkylene groups, substituted or unsubstituted C6-C10 aryl groups, and substituted or unsubstituted C3-C10 heterocycloalkyl groups. Selected from the group consisting of a loaryl group, a substituted or unsubstituted C6-C10 aryl group, a C1-C5 alkylene group, a substituted or unsubstituted C3-C10 heteroaryl group, a C1-C5 alkylene group, a substituted or unsubstituted C6-C10 aryl group, a C2-C4 alkenylene group, a substituted or unsubstituted C3-C10 heteroaryl group, a C2-C4 alkenylene group, a substituted or unsubstituted C6-C10 aryl group, a C2-C4 alkylylene group, and a substituted or unsubstituted C3-C10 heteroaryl group.

[0018] Here, R 1 , R 2 and R 3 In this context, the substitution means that each substitution is independently substituted by one, two, or three substituents selected from the group consisting of halogens, hydroxyl groups, C1-C6 alkyl groups, halogenated C1-C6 alkyl groups, C1-C6 alkoxy groups, halogenated C1-C6 alkoxy groups, C1-C4 alkylcarbonyl groups, C1-C4 alkylthio groups, C1-C6 alkoxycarbonyl groups, and trifluoromethyl groups, wherein the heterocycloalkyl group and the heteroaryl group each independently contain one or two heteroatoms selected from N, O, and S.

[0019] In another preferred example, the compound is a compound represented by formula AA, Formula AA: [ka]

[0020] Here, R 1 , R 2 , R 3 , R 4 , R 5 And n are as defined above, * indicates that the stereochemical heterogeneity of each carbon atom can be either R or S independently. In another preferred example, R 4 The group is selected from the group consisting of a 9-10 membered heteroaromatic ring containing 1, 2, or 3 heteroatoms selected from N, O, and S, and a 5-6 membered heteroaromatic ring containing 1, 2, or 3 heteroatoms selected from N, O, and S, wherein the group is substituted or unsubstituted, where substitution means that the hydrogen atoms on the group are substituted by 1, 2, 3, or 4 substituents selected from the group consisting of halogens, hydroxyl groups, C1-C6 alkyl groups, halogenated C1-C6 alkyl groups, C3-C6 cycloalkyl groups, halogenated C3-C6 cycloalkyl groups, C1-C6 alkoxy groups, halogenated C1-C6 alkoxy groups, C1-C6 alkylthio groups, and halogenated C1-C6 alkylthio groups.

[0021] In another preferred example, the heteroaryl group is a 5, 6, 7, 8, 9, or 10-membered saturated or partially saturated heteroaromatic ring. In another preferred example, the heterocycloalkyl group is a 5, 6, 7, 8, 9, or 10-membered unsaturated heterocycle.

[0022] In another preferred example, R 4 teeth, Substituted or unsubstituted quinoxalinyl group, substituted or unsubstituted quinazolinyl group, substituted or unsubstituted cinnolinyl group, Substituted or unsubstituted indolyl group, substituted or unsubstituted isoindolyl group,

[0023] Substituted or unsubstituted 1,3-benzodioxole cyclopentadienyl group, Substituted or unsubstituted benzimidazolyl group, substituted or unsubstituted indazolyl group,

[0024] Substituted or unsubstituted imidazole[1,2-A]pyridyl group, substituted or unsubstituted imidazole[1,5-A]pyridyl group, Substituted or unsubstituted pyrazolyl group, substituted or unsubstituted imidazolyl group, substituted or unsubstituted thiazolyl group, substituted or unsubstituted oxazolyl group, substituted or unsubstituted isoxazolyl group, substituted or unsubstituted 1,2,3-triazolyl group, substituted or unsubstituted 1,2-thiadiazolyl group, substituted or unsubstituted 1,2,4-triazinyl group,

[0025] Substituted or unsubstituted pyridyl group, substituted or unsubstituted pyrrolyl group, substituted or unsubstituted pyrazinyl group, substituted or unsubstituted pyrimidinyl group, Substituted or unsubstituted 3,8a dihydro-2H-benzopyranyl group, substituted or unsubstituted benzopyranyl group,

[0026] Substituted or unsubstituted quinolinyl group, substituted or unsubstituted isoquinolinyl group, Substituted or unsubstituted benzoxazolyl group, substituted or unsubstituted benzothiazolyl group,

[0027] Substituted or unsubstituted benzothienyl group, Selected from the group consisting of substituted or unsubstituted benzofuranyl groups,

[0028] Here, the substitution refers to the substitution of a hydrogen atom on the group with one, two, or three substituents selected from the group consisting of F, Cl, Br, I, a hydroxyl group, a C1-C6 alkyl group, a halogenated C1-C6 alkyl group, a C3-C6 cycloalkyl group, a halogenated C3-C6 cycloalkyl group, a C1-C6 alkoxy group, a halogenated C1-C6 alkoxy group, a C1-C6 alkylthio group, or a halogenated C1-C6 alkylthio group. In this specification, R 4 This is imidazole[1,2-A]pyridine, which corresponds to the compounds numbered A156 to A161 of the present invention.

[0029] In this specification, "imidazole[1,2-A]pyridine", "imidazole[1,2-A]pyridine", "imidazo[1,2-A]pyridine", and "imidazo[1,2-a]pyridine" are interchangeable. In this specification, "imidazole[1,5-A]pyridine", "imidazole[1,5-a]pyridine", "imidazo[1,5-A]pyridine", and "imidazo[1,5-a]pyridine" are interchangeable.

[0030] In this specification, R 4This is 3,8a-dihydro-2H-benzopyran, which corresponds to the compounds numbered A132 to A137 of the present invention. In another preferred example, -NHR 5 When R forms a ring with an adjacent -(C=O)-CH2-, 5 is, -(CH2) n - and n is 3,

[0031] -NHR 5 If R does not form a ring with adjacent -(C=O)-CH2-, 5 This is selected from the group consisting of hydrogen, deuterium, tritium, hydroxyl group, substituted or unsubstituted C1-C6 alkyl group, substituted or unsubstituted C3-C8 cycloalkyl group, substituted or unsubstituted C3-C8 heterocycloalkyl group, substituted or unsubstituted C6-C10 aryl group, substituted or unsubstituted C3-C10 heteroaryl group, substituted or unsubstituted C6-C10 aryl group, C1-C4 alkylene group, substituted or unsubstituted C6-C10 aryl group, C2-C4 alkenylene group, substituted or unsubstituted C3-C10 heteroaryl group, C1-C4 alkylene group, substituted or unsubstituted C3-C10 heteroaryl group, and C2-C4 alkenylene group. Here, the substitution refers to each substitution being independently substituted by one, two, or three substituents selected from the group consisting of F, Cl, Br, I, a hydroxyl group, a C1-C6 alkyl group, a C1-C6 alkoxy group, or a C1-C6 alkylthio group, and each of the heterocycloalkyl group and the heteroaryl group independently contains one, two, or three heteroatoms selected from N, O, and S.

[0032] In another preferred example, the compound is selected from the compounds listed in Table 1. A second aspect of the present invention provides a method for preparing the ketoamide compound, its racemic mixture, enantiomer, diastereomer or mixture thereof, or a pharmaceutically active metabolite thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, comprising the following steps: [ka]

[0033] Step (6): Compound VII is oxidized with an oxidizing agent in an inert solvent to obtain compound VIII. In each of the above equations, R 1 , R 2 , R 3 , R 4 , R 5 And n are as defined in the first aspect of the present invention.

[0034] In another preferred example, the following steps are further included before step (6): [ka] Step (5): Compound VI is reacted with a basic substance in the presence of an organic solvent to obtain compound VII. In another preferred example, the organic solvent is an alcohol solvent, preferably selected from the group consisting of methanol, ethanol, propanol, isopropanol, butanol, ethylene glycol, and aromatic alcohol.

[0035] In another preferred example, the basic substance is selected from the group consisting of LiOH, NaOH, KOH, lithium carbonate, sodium carbonate, potassium carbonate, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, potassium tert-butoxide, sodium tert-butoxide, lithium tert-butoxide, and 1,8-diazabicycloundec-7-ene.

[0036] In another preferred example, the inert solvent is selected from the group consisting of dichloromethane, tetrahydrofuran, N,N-dimethylformamide, dioxane, and chloroform. In another preferred example, the oxidizing agent is selected from the group consisting of Dess-Martin oxidizing agents, dimethyl sulfoxide, oxalyl chloride, PCC oxidizing agents, and PDC oxidizing agents.

[0037] In another preferred example, the following steps are further included before step (5): [ka] Step (4): Compound V is reacted with an isocyanide compound in an inert solvent in the presence of acetic acid to obtain compound VI.

[0038] In another preferred example, the isocyanide compound is selected from the group consisting of benzyl isocyanide, cyclohexyl isocyanide, methyl isocyanoacetate, tert-butyl isocyanide, and tert-butyl 2-isocyanopropionate.

[0039] In another preferred example, the following steps are further included before step (4): [ka] Step (3): Compound IV is oxidized with an oxidizing agent in an inert solvent to obtain compound V. In another preferred example, the following steps are further included before step (3): [ka]

[0040] Step (2): Compound III is reduced with a reducing agent in an inert solvent to obtain compound IV. In another preferred example, the reducing agent is borohydride, preferably selected from the group consisting of sodium borohydride, lithium borohydride, and sodium cyanoborohydride.

[0041] In another preferred example, the following steps are further included before step (2): [ka] Step (1): Compound II is reacted with compound Ic in an inert solvent in the presence of a condensing agent to obtain compound III.

[0042] In another preferred example, the coupling agent is preferably EDCI (1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride) and / or HATU (2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluorophosphate).

[0043] A third aspect of the present invention provides a pharmaceutical composition, the pharmaceutical composition is i) A therapeutically effective amount of one or more ketoamide compounds according to the first aspect of the present invention, racemates, enantiomers, diastereomers or mixtures thereof, or metabolites of their pharmaceutically active properties, or pharmaceutically acceptable salts, solvates or prodrugs thereof, and ii) Containing pharmaceutically acceptable carriers or excipients.

[0044] A fourth aspect of the present invention provides a ketoamide inhibitor, the inhibitor comprising one or more ketoamide compounds described in the first aspect of the present invention, a racemic mixture thereof, an enantiomer, a diastereomer thereof, or a mixture thereof, or a metabolite of its pharmaceutically active properties, or a pharmaceutically acceptable salt thereof, solvate, or prodrug thereof.

[0045] A fifth aspect of the present invention provides uses for the ketoamide compounds described in the first aspect of the present invention, their racemates, enantiomers, diastereomers or mixtures thereof, or metabolites of their pharmaceutically active properties, or pharmaceutically acceptable salts, solvates or prodrugs thereof, which are used to prepare pharmaceutical compositions or formulations, said pharmaceutical compositions or formulations used to treat or prevent diseases associated with coronavirus or diseases associated with Ebola virus.

[0046] In another preferred example, the coronavirus is selected from the group consisting of SARS virus and MERS virus. In another preferred example, the coronavirus-related illness is selected from the group consisting of the common cold, upper respiratory tract infections, severe acute respiratory syndrome, multiple sclerosis, otitis media, and gastrointestinal disorders.

[0047] In another preferred example, the Ebola virus-related illness is selected from the group consisting of hemorrhagic fever, acute onset fever, myalgia, and hemorrhagic rash. In another preferred example, a ketoamide compound described in the first aspect of the present invention, its racemic mixture, enantiomer, diastereomer or mixture thereof, or a metabolite of its pharmaceutically active properties, or a pharmaceutically acceptable salt, solvate or prodrug thereof, is used in combination with other antiviral agents.

[0048] A sixth aspect of the present invention provides a method for non-therapeutic in vitro inhibition of coronavirus or Ebola virus by contacting the coronavirus or Ebola virus with a ketoamide compound described in the first aspect of the present invention, its racemic mixture, enantiomer, diastereomer or mixture thereof, a metabolite of its pharmaceutically active properties, or a pharmaceutically acceptable salt, solvate or prodrug thereof.

[0049] A seventh aspect of the present invention provides a method for preventing or treating a coronavirus-related disease or an Ebola virus-related disease, comprising the step of administering a therapeutically effective amount of one or more ketoamide compounds described in the first aspect of the present invention, a racemic mixture thereof, an enantiomer, a diastereomer thereof, or a mixture thereof, or a metabolite of its pharmaceutically active substance, or a pharmaceutically acceptable salt, solvate, or prodrug thereof to a patient in need. [Effects of the Invention]

[0050] It should be understood that, within the scope of the present invention, new or preferred technical solutions can be constructed by combining the above-described technical features of the present invention with the technical features specifically described below (e.g., in the examples). Due to space limitations, this will not be repeated here. [Brief explanation of the drawing]

[0051] [Figure 1A] While HCoV-OC43 can induce cytopathic phenomena (CPE), such as vacuole formation, after infecting target cells HCT-8, A13 (1 μM) effectively inhibits HCoV-OC43 infection. All figures were measured at the same magnification. [Figure 1B] The inhibitory effect of A13 at various concentrations on CPE in target cells is shown, where "-" means no CPE, "+ / -" means <10% CPE, "+" means 30% CPE, "++" means 60% CPE, and "+++" means 90% CPE. [Figure 1C] This figure evaluates the inhibitory activity of various concentrations of A13 against HCoV-OC43 infection based on the CCK8 method. [Figure 2] This shows the inhibitory activity of compound A13 against MERS-CoV, SARS-CoV, HCoV-229E, and VSV-G pseudovirus (A), and the cytotoxicity of compound A13 against target cells (Huh-7) (B). [Figure 3A-3D] This figure compares the antiviral activity (D) of serum after intraperitoneal administration of compound A13 (100 mg / kg) or DMSO (100 μL) to Balb / c mice (n=4), blood samples were collected 2 hours (A), 12 hours (B), and 24 hours (C) post-administration, serum was separated, and anti-MERS-CoV pseudoviral activity detection was performed. (EC50: Half-effect concentration, measured in serum dilution factors). [Figure 4] This figure shows the changes in body weight of Balb / c mice (n=4) after intraperitoneal administration of compound A13 (100 mg / kg) or DMSO (100 μL) for 7 consecutive days (once daily). [Modes for carrying out the invention]

[0052] Through extensive and detailed research, the inventors synthesized a compound of formula A capable of inhibiting coronavirus and / or Ebola virus. Compared to existing coronavirus inhibitors, the compound exhibits higher inhibitory activity. Based on this, the inventors completed the present invention.

[0053] term In this invention, unless otherwise specified, terms used have the general meanings known to those skilled in the art. In this invention, the term "halogen" refers to F, Cl, Br, and I.

[0054] In the present invention, the term "C1-C10 alkyl group" refers to a linear or branched alkyl group having 1 to 10 carbon atoms, preferably a C1-C6 alkyl group, more preferably a C1-C4 alkyl group, but is not limited to these, and includes methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, and hexyl group, etc.

[0055] In the present invention, the term "C3-C10 cycloalkyl group" refers to a cyclic alkyl group having 3 to 10 carbon atoms in the ring, and is not limited to these, but includes cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, cyclooctyl group, and cyclodecyl group, etc. Preferably, it is a C3-C8 cycloalkyl group, a C3-C7 cycloalkyl group, or a C3-C6 cycloalkyl group.

[0056] In the present invention, the terms "aromatic ring" and "aryl group" have the same meaning, and preferably refer to a "C6-C20 aryl group," more preferably a "C6-C14 aryl group," and more preferably a "C6-C10 aryl group." The term "C6-C10 aryl group" refers to an aromatic ring group having 6 to 10 carbon atoms without heteroatoms on the ring, such as phenyl and naphthyl.

[0057] In this invention, the terms "aromatic heterocycle" and "heteroaryl group" have the same meaning and refer to a heteroaromatic group containing one or more heteroatoms. For example, a "C3-C20 heteroaryl group" refers to an aromatic heterocycle containing 1 to 4 heteroatoms selected from oxygen, sulfur, and nitrogen, and 3 to 20 carbon atoms. Non-limiting examples include furyl group, thienyl group, pyridyl group, pyrazolyl group, pyrrolyl group, N-alkylpyrrolyl group, pyrimidinyl group, pyrazinyl group, imidazolyl group, tetrazolyl group, etc. The heteroaryl ring can be fused to an aryl, heterocyclic, or cycloalkyl ring, where the ring connected to the parent structure is a heteroaryl ring. The heteroaryl group can be either substituted or unsubstituted.

[0058] In this invention, the term "halogenation" refers to substitution with a halogen. In the present invention, the term "C2-C10 alkenyl group" refers to, but is not limited to, a linear or branched alkenyl group having 2 to 10 carbon atoms containing one double bond, and includes vinyl group, propenyl group, butenyl group, isobutenyl group, pentenyl group, and hexenyl group. Preferably, it is a C2-C6 alkenyl group.

[0059] In the present invention, the term "C2-C10 alkynyl group" refers to, but is not limited to, a linear or branched alkynyl group having 2 to 10 carbon atoms containing one triple bond, and includes, however, ethynyl group, propynyl group, butynyl group, isobutynyl group, pentynyl group, and hexynyl group. Preferably, it is a C2-C6 alkynyl group.

[0060] In the present invention, the term "C1-C8 alkoxy group" refers to, but is not limited to, a linear or branched alkoxy group having 1 to 8 carbon atoms, and includes methoxy groups, ethoxy groups, propoxy groups, isopropoxy groups, and butoxy groups. Preferably, it is a C1-C4 alkoxy group.

[0061] In the present invention, the term "acyl group" refers to, but is not limited to, a linear or branched acyl group having 1 to 8 carbon atoms, including, but also including, a formyl group, an acetyl group, and a propionyl group. Preferably, it is a C1-C4 alkanoyl group.

[0062] In the present invention, the term "sulfonyl group" refers to, but is not limited to, a linear or branched sulfonyl group having 1 to 8 carbon atoms, and includes methylsulfonyl group, ethylsulfonyl group, and propylsulfonyl group, etc. Preferably, it is a C1-C4 alkylsulfonyl group.

[0063] In the present invention, the term “substitution” refers to the substitution of one or more hydrogen atoms on a particular group with a particular substituent. The particular substituent is the corresponding substituent described above, or the substituent that appears in each example. Unless otherwise specified, a substituted group may have substituents selected from the particular groups at any of its substituted positions, and the substituents may be the same or different at each position. Those skilled in the art should understand that the substituent combinations expected by the present invention are stable or chemically achievable combinations. The substituents are, for example (but not limited to), halogens, hydroxyl groups, carboxy(-COOH), C1-C8 alkyl groups, C2-C8 alkenyl groups, C3-C8 cycloalkyl groups, 3- to 12-membered heterocyclic groups, aryl groups, heteroaryl groups, C1-C8 aldehyde groups, C2-C10 acyl groups, C2-C10 ester groups, amino groups, C1-C8 alkoxy groups, and C1-C10 sulfonyl groups.

[0064] compound The present invention provides ketoamide compounds represented by formula A, their racemates, enantiomers, diastereomers or mixtures thereof, or pharmaceutically active metabolites thereof, or pharmaceutically acceptable salts, solvates or prodrugs thereof. Formula A: [ka] Here, R 1 , R 2 , R 3 , R 4 , R 5 And n are as defined above. In another preferred example, in the compound, R 1 , R 2 , R 3 , R 4 , R 5 Either and n are groups corresponding to specific compounds listed in Table 1.

[0065] In another preferred example, the compound is preferably the compound prepared in the example. In another preferred example, compounds A1-A236 are compounds prepared in Examples 1-236, respectively. In another preferred example, the compound is selected from the compounds listed in Table 1.

[0066] [Table 1-1]

[0067] [Table 1-2]

[0068] [Table 1-3]

[0069] [Table 1-4]

[0070] Table 1-5

[0071] Table 1-6

[0072] Table 1-7

[0073] Table 1-8

[0074] Table 1-9

[0075] Table 1-10

[0076] Table 1-11

[0077] Table 1-12

[0078] Table 1-13

[0079] Table 1-14

[0080] Table 1-15

[0081] Table 1-16

[0082] Table 1-17

[0083] Table 1-18

[0084] Table 1-19

[0085] Table 1-20

[0086] Table 1-21

[0087] Table 1-22

[0088] Table 1-23

[0089] Table 1-24

[0090] [Table 1-25]

[0091] [Table 1-26]

[0092] [Table 1-27]

[0093] [Table 1-28]

[0094] [Table 1-29]

[0095] [Table 1-30]

[0096] [Table 1-31]

[0097] [Table 1-32]

[0098] [Table 1-33]

[0099] The compounds of the present invention can be used to inhibit enteroviruses and coronaviruses, and in particular, the MERS virus. The compounds of the present invention may further have an asymmetric center, and therein they may exist in the form of a racemate, an R-heterogeneous compound, or an S-heterogeneous compound, or a mixture thereof. Those skilled in the art can obtain the R-heterogeneous compound and / or the S-heterogeneous compound by decomposing the racemate using conventional methods.

[0100] salt As used herein, the term “pharmaceutically acceptable salt” refers to a salt formed by the compound of the present invention with an acid or a base that is suitable for use as a pharmaceutical. pharmaceutically acceptable salts include inorganic salts and organic salts. Preferred salts are those formed by the compound of the present invention with an acid. Acids suitable for salt formation include inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, aminosulfonic acid, and phosphoric acid, as well as citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, naphthalenesulfonic acid, ethanesulfonic acid, naphthalenedisulfonic acid, maleic acid, malic acid, malonic acid, and fumaric maleic acid. (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-aminobenzenesulfonic acidThis includes, but is not limited to, organic acids such as 2-acetoxybenzoic acid and isethionic acid, and amino acids such as proline, phenylalanine, aspartic acid and glutamic acid.

[0101] Other preferred salts are salts formed by the compound of the present invention with a base, such as a base metal salt (e.g., sodium or potassium salt), a basic earth metal salt (e.g., magnesium or calcium salt), an aluminum salt, and amine salts such as methylamine salt, ethylamine salt, ethanolamine salt, propylamine salt, dimethylamine salt, trimethylamine salt, diethylamine salt, triethylamine salt, tert-butylamine salt, ethylenediamine salt, hydroxyethylamine salt, dihydroxyethylamine salt, trihydroxyethylamine salt, and amine salts formed by morpholine, piperazine, and lysine, respectively. These are ammonium salts (e.g., lower base ammonium salts and other pharmaceutically acceptable amine salts) such as salts.

[0102] The term "solvate" refers to a complex in which the compound of the present invention coordinates with a solvent molecule to form a specific ratio. The term "prodrug" includes any substance that may be biologically active or inactive and, when administered in an appropriate manner, undergoes metabolism or / or chemical reactions in the human body to produce a compound of formula A, or a salt or solution composed of a compound of formula A. The prodrug includes, but is not limited to, forms of the compound such as carboxylate, carbonate, phosphate, nitrate, sulfate, sulfone ester, sulfoxide ester, amino compound, carbamate, azo compound, phosphoramide, glucoside, ether, and acetal.

[0103] Preparation method The following describes in more detail the methods for preparing the compound of formula A of the present invention, but these specific methods do not constitute any limitation on the present invention. The compound of the present invention can be conveniently prepared by combining various synthesis methods described herein or known in the art, and such combinations can be readily carried out by those skilled in the art to which the present invention belongs.

[0104] Typically, the process for preparing the compounds of the present invention is as follows, and the raw materials and reagents used can be purchased through commercial channels unless otherwise specified. [ka]

[0105] Step (1): Compound II is reacted with compound Ic in an inert solvent in the presence of a condensing agent to obtain compound III, where the condensing agent is preferably EDCI (1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride). [Chemistry]

[0106] Step (2): In an inert solvent, under specific conditions, Compound III undergoes a reduction reaction to obtain Compound IV. Here, the reducing agent is preferably borohydride. [Chemistry]

[0107] Step (3): In an inert solvent, under specific conditions, Compound IV undergoes an oxidation reaction to obtain Compound V. Here, the oxidizing agent is preferably Dess-Martin oxidant or dimethyl sulfoxide and oxalyl chloride as the oxidizing agent. [Chemistry]

[0108] Step (4): In an inert solvent, in the presence of acetic acid, Compound V is reacted with an isocyanide compound to obtain Compound VI. [Chemistry]

[0109] Step (5): Under the condition of using methanol as the solvent, Compound VI is reacted with a base to obtain Compound VII. Here, the base is preferably LiOH and potassium carbonate. [Chemistry]

[0110] Step (6): In an inert solvent, under specific conditions, Compound VII is oxidized to obtain Compound VIII. Here, the oxidizing agent is preferably Dess-Martin oxidant or dimethyl sulfoxide and oxalyl chloride as the oxidizing agent. In the above formulas, the definitions of each group are as described above.

[0111] Specifically, the present invention further provides a method for synthesizing the compound of formula A, which is prepared by the process shown below, [ka]

[0112] Step a: The amino acids C1 and C2 protected with Boc are dissolved in a solvent, and a condensation reaction is carried out under auxiliary conditions of a coupling agent to obtain compound C3, the solvent being dichloromethane or DMF. Step b: Dissolve C3 in a solvent, stir until the reaction is complete, and spin-dry the reaction solvent to obtain compound C4, the solvent being a mixed solvent of dichloromethane and trifluoroacetic acid. Step c: Substituted carboxylic acids C5 and C4 are dissolved in a solvent, and a condensation reaction is carried out under auxiliary conditions of a condensing agent to obtain compound C6, the solvent being dichloromethane or DMF.

[0113] Step d: Compound C6 is dissolved in a solvent, sodium borohydride is added and stirred to obtain compound C7. The solvents are methanol, tetrahydrofuran, and ethanol. Step e: Compound C7 is dissolved in a solvent, an oxidizing agent is added, a base is added, and the mixture is stirred to obtain compound C8, wherein the solvent is dichloromethane or tetrahydrofuran, the oxidizing agent is Dess-Martin oxidizing agent or dimethyl sulfoxide and oxalyl chloride, and the base is sodium bicarbonate or triethylamine. Step f: Compound C8 is dissolved in a solvent, and acetic acid and an isocyanide compound are added and reacted to obtain compound C9, the solvent being dichloromethane.

[0114] Step g: Compound C9 is dissolved in a solvent, a base is added and stirred to obtain compound C10, where the base is preferably LiOH and potassium carbonate. Step h: Compound C10 is dissolved in a solvent, an oxidizing agent is added, a base is added, and the mixture is stirred to obtain compound C11. The solvent is dichloromethane or tetrahydrofuran, the oxidizing agent is Dess-Martin oxidizing agent or dimethyl sulfoxide and oxalyl chloride, and the base is sodium bicarbonate or triethylamine. R 1 , R 2 , R 3 , R 4 , R 5 And n are as defined above.

[0115] Pharmaceutical composition The present invention further relates to a pharmaceutical composition comprising a therapeutically effective amount of a ketoamide compound represented by formula A, a pharmaceutically acceptable salt thereof, a prodrug thereof, and one or more hydrates and solvates thereof, and optionally a pharmaceutically acceptable carrier, which can be used to treat diseases associated with coronavirus or Ebola virus infection. The pharmaceutical composition can be prepared in various forms according to different routes of administration.

[0116] The pharmaceutical composition of the present invention comprises the compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient or carrier in a safe and effective amount. Here, “safe and effective amount” means that the amount of the compound is sufficient to clearly improve the condition without causing serious side effects. Generally, the pharmaceutical composition contains 1 to 2000 mg of the compound / agent of the present invention, more preferably 10 to 1000 mg of the compound / agent of the present invention. Preferably, the “single dose” is one capsule or tablet.

[0117] "Pharmaceutically acceptable carrier" refers to one or more compatible solid or liquid fillers or gluing substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatible" means that each component of the composition can blend with the compounds of the present invention without significantly reducing the efficacy of the compounds. Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid and magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, and olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, and sorbitol, etc.), emulsifiers (such as TweenR, etc.), wetting agents (such as sodium lauryl sulfate), coloring agents, fragrances, stabilizers, antioxidants, preservatives, and pyrogen-free water, etc.

[0118] One or more ketoamide compounds represented by formula A described in the present invention, their pharmaceutically acceptable salts, their prodrugs, and their hydrates and solvates, or one or more pharmaceutical compositions of the above-mentioned therapeutically effective amount of ketoamide compounds represented by formula A, their pharmaceutically acceptable salts, their prodrugs, and their hydrates and solvates can be used as MERS inhibitors and are used for the treatment of diseases related to coronavirus infection or Ebola virus infection.

[0119] The pharmaceutical compositions provided by the present invention preferably contain an active ingredient in a weight ratio of 1 to 99%, preferably such that the compound represented by formula A accounts for 65 wt% to 99 wt% of the total weight as the active ingredient, and the remainder is a pharmaceutically acceptable carrier, diluent, or solution or salt solution. The compounds and pharmaceutical compositions provided by the present invention may be in various forms, such as tablets, capsules, powders, syrups, solutions, suspensions, and aerosols, and may be present in suitable solid or liquid carriers or diluents, as well as in suitable disinfection devices for injection or dropping.

[0120] Various dosage forms of the pharmaceutical composition of the present invention can be prepared according to conventional preparation methods in the pharmaceutical field. The unit measurement of the formulation contains 1 mg to 700 mg of the compound shown in formula A, preferably 25 mg to 300 mg of the compound in formula A.

[0121] The preparation of pharmaceutically acceptable salts of the compounds of the present invention can be carried out by directly forming a salt reaction between the free base of the compound and an inorganic or organic acid. The inorganic or organic acid can be selected from hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, hydrofluoric acid, hydrobromic acid, formic acid, acetic acid, picric acid, citric acid, maleic acid, methanesulfonic acid, trifluoromethanesulfonic acid, ethanesulfonic acid, and p-toluenesulfonic acid, etc.

[0122] The compounds of the present invention have excellent inhibitory activity against the replication of Ebola and coronaviruses. Therefore, the compounds of the present invention and their various crystalline forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and pharmaceutical compositions having the compounds of the present invention as the main active ingredient can treat, prevent, and alleviate diseases associated with the Ebola virus and coronaviruses.

[0123] The method of administration of the compound or pharmaceutical composition of the present invention is not particularly limited, and typical methods of administration include, but are not limited to, oral, intratumoral, rectal, parenteral (intravenous, intramuscular, or subcutaneous) and topical administration. Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inactive excipient (or carrier), for example, sodium citrate or dicalcium phosphate, (a) fillers or compatibilizers such as starch, lactose, sucrose, glucose, mannitol and silicic acid, (b) binders such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic, (c) humectants such as glycerin, (d) agar, calcium carbonate, potato starch or tapioca starch, alginic acid (a) a disintegrant such as a specific complex silicate and sodium carbonate, (e) a sedative solvent such as paraffin, (f) an absorption enhancer such as quaternary amine compounds, (g) a wetting agent such as cetyl alcohol and glyceryl monostearate, (h) an adsorbent such as kaolin, and (i) a lubricant, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or a mixture thereof, which are mixed with the ingredients, and in the case of capsules, tablets and pills, the dosage form may also include a buffering material.

[0124] Solid dosage forms such as tablets, sugar pills, capsules, pills, and granules can be prepared using coating and shell materials such as enteric coatings and other materials known in the art. They may contain turbidants, and furthermore, the release of the active compound or compound in such compositions can be delayed in a specific portion of the digestive tubule. Examples of usable embedding components are polymers and waxes. If necessary, the active compound can be formed in microcapsule form with one or more of the above excipients.

[0125] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active compound, the liquid dosage form may contain water or other solvents, solubilizers and emulsifiers, and other inert diluents conventionally used in the art, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, sesame oil, and sesame oil, or mixtures thereof. In addition to these inert diluents, the composition may also contain auxiliary agents such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, and fragrances.

[0126] In addition to the active compound, the suspension may include suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan ester, microcrystalline cellulose, aluminum methoxide and agar, or mixtures thereof. Compositions for parenteral injection may include physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous solutions may include carriers, diluents, solvents or excipients, including water, ethanol, polyols, and suitable mixtures thereof. Dosage forms of the compounds of the present invention for topical administration include ointments, powders, patches, sprays, and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants as needed.

[0127] The compounds of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds (e.g., other antiviral agents). The therapeutic method of the present invention can be administered alone or in combination with other therapeutic means or therapeutic drugs.

[0128] The compounds according to the present invention described above can be used clinically in feeding organisms including humans and animals, and can be administered via routes such as oral, nasal, cutaneous, pulmonary, or gastrointestinal tubes, preferably orally. The daily dose is preferably 0.01 to 200 mg / kg body weight taken at once, or 0.01 to 100 mg / kg body weight in divided doses. Regardless of the method of administration, the optimal dose for the individual must be determined based on the specific treatment. Usually, a small dose is started and gradually increased until the optimal dose is found. Of course, the specific dose must also take into account factors such as the route of administration and the patient's health condition, all of which are within the scope of a skilled physician's expertise.

[0129] The main advantages of this invention are as follows: Compared to existing coronavirus inhibitors, the compound exhibits higher inhibitory activity and lower toxicity.

[0130] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are used solely to illustrate the present invention and do not limit its scope. In the following examples, experimental methods that do not specify conditions generally follow the conditions described in Sambrook et al., *Molecular Cloning Laboratory Manual* (New York: Cold Spring Harbor Laboratory Press, 1989) or the conditions proposed by the manufacturer. Unless otherwise specified, percentages and quantities are calculated by weight.

[0131] Unless otherwise defined, all technical and scientific terms used in this specification have the same meaning as those well known to those skilled in the art. Furthermore, any methods and materials similar or equivalent to those described may be applied to the methods of the present invention. The preferred methods and materials described in this specification are for demonstration purposes only. Sample analysis data is measured using the following instruments: NMR is measured using GEMINI-300, Bruker AMX-400, and INVOA-600; TMS (tetramethylsilane) is an internal standard, chemical shift is measured in ppm, and coupling constant is measured in Hz; and mass spectra are measured using Finnigan MAT-711, MAT-95, and LCQ-DECA mass spectrometers and IonSpec 4.7 Tesla mass spectrometer.

[0132] Column chromatography was performed using 200-300 mesh silica gel (manufactured by Qingdao Marine Chemical Co., Ltd.), and the TLC silica gel plates were HSGF-254 thin-layer chromatography prefabricated plates manufactured by Yantai Chemical Co., Ltd. The boiling point range of petroleum ether was 60-90°C. A UV lamp was used, and an iodine cylinder was used to indicate color. Unless otherwise specified, conventional reagents and pharmaceuticals used in the following examples were purchased from SinoPharmGroup. The reagents and solvents used in the experiments were handled according to the specific conditions of the reaction.

[0133] Example 1: Compound A1 [ka]

[0134] Synthesis of Compounds 1-2: Under the protection of argon, dissolve N-tert-butoxycarbonyl-L-glutamic acid dimethyl ester (1-1) (6g, 21.8 mmol) in 60 mL of anhydrous tetrahydrofuran. Slowly add LiHMDS (1M in THF) dropwise to the tetrahydrofuran solution (47 mL, 47 mmol) under -78°C conditions, maintaining the temperature at -78°C for approximately 1 hour during the addition process. After the addition is complete, stir for 1 hour under -78°C conditions. Dissolve bromoacetonitrile (2.79 g, 23.3 mmol) in 20 mL of tetrahydrofuran, then slowly add this solution dropwise to the reaction system, continuing the addition process for 1-2 hours. Maintain the temperature at -78°C and continue the reaction for 3 hours. After the reaction is complete, TLC monitoring (basic potassium manganate color development) is performed. After adding NH4Cl solution to the reaction solution and quenching, the mixture is stirred for 10 minutes and then warmed to room temperature. The mixture is then poured into 40 mL of saturated sodium chloride solution and stirred thoroughly, allowing the reaction system to separate. The organic layer is separated, the aqueous phase is extracted with ethyl acetate (EA), the organic layers are combined, dried over anhydrous sodium sulfate, concentrated, and obtained by column chromatography (Flash, PE:EA = 1:5) to obtain 3.9 g of pale yellow oily substance 1-2, with a yield of 58%.

[0135] Synthesis of compounds 1-3: Dissolve 1-2 (1g, 3.15 mmol) in 25 mL of anhydrous methanol and stir in an ice bath until it reaches 0°C. Then add cobalt dichloride hexahydrate (450 mg, 1.89 mmol). After 10 minutes, gradually add sodium borohydride (715 mg, 18.9 mmol), and continue reacting the solution in an ice bath for 1 hour, then return to room temperature. After 15 hours, quench with 5 mL of saturated NH4Cl solution and continue stirring for 10 minutes. Filter the solid, evaporate the filtrate to dryness, extract with 20 mL of water and 30 × 3 mL of ethyl acetate, combine the organic phases, dry over anhydrous Na2SO4 for 1 hour, concentrate under reduced pressure, and separate by column chromatography [PE:EA=1:2] to obtain 460 mg of a white powder solid. The yield is 51%.

[0136] Synthesis of compounds 1-4: Compound 1-3 (2.6g) was dissolved in a 1 / 1, v / v solution of trifluoroacetic acid in dichloromethane, stirred at room temperature for 1 hour, concentrated, and then 100 mL of dichloromethane was added. The mixture was washed with saturated sodium carbonate solution, the organic layer was dried over anhydrous sodium sulfate, and concentrated to obtain oily substance 1-4 (2.7g) in 99% yield.

[0137] Synthesis of compounds 1-5: Boc-cyclohexylalanine (1.26 g, 5 mmol), EDCI (1.36 g, 6 mmol), and HOBt (0.822 g, 6 mmol) were added to 80 mL of dichloromethane solution and stirred at room temperature for 30 minutes. Subsequently, compound 1-4 (0.896 g, 5 mmol) was added, and 1.2 equivalents of triethylamine were added dropwise, and the mixture was stirred at room temperature. After the TLC monitoring (UV) reaction was complete, the mixture was extracted with dichloromethane, washed with dilute hydrochloric acid, saturated sodium bicarbonate solution, and saturated sodium chloride, and the organic layers were dried together over anhydrous sodium sulfate. After concentration, 1.2 g of a white, viscous solid was obtained, with a yield of 60%.

[0138] Synthesis of compounds 1-6: Compound 1-5 (2.5 g) was dissolved in a 1 / 1, v / v solution of trifluoroacetic acid in dichloromethane, stirred at room temperature for 1 hour, concentrated, and then 100 mL of dichloromethane was added. The mixture was washed with saturated sodium carbonate solution, the organic layer was dried over anhydrous sodium sulfate, and concentrated to obtain oily substance 1-6 (2.61 g), with a yield of 99%.

[0139] Synthesis of compounds 1-7: Indole 2-carboxylic acid (0.795 g, 5 mmol), EDCI (1.36 g, 6 mmol), and HOBt (0.822 g, 6 mmol) were dissolved in 80 mL of dichloromethane solution and stirred at room temperature for 30 minutes. Subsequently, compound 1-6 (2.2 g, 5 mmol) was added, and 1.2 equivalents of triethylamine were added dropwise, and the mixture was stirred at room temperature. After the TLC monitoring (UV) reaction was complete, the mixture was extracted with dichloromethane, washed with dilute hydrochloric acid, saturated sodium bicarbonate solution, and saturated sodium chloride, and the organic layers were dried together over anhydrous sodium sulfate. After concentration, 1.3 g of a white, viscous solid was obtained, with a yield of 60%.

[0140] Synthesis of compounds 1-8: Dissolve 1-7 (243 mg, 0.51 mmol) in 20 mL of methanol, and slowly add sodium borohydride (107 mg, 2.9 mmol) in several portions, stirring at room temperature for about 2 hours to complete the reaction. After the reaction is complete, add about 20 mL of saturated brine to quench, concentrate the reaction system with methanol, and then add dichloromethane to extract. Wash the organic phase with saturated brine, dry it over anhydrous sodium sulfate, and concentrate it to obtain a white solid substance 1-8, which can be used directly in the next reaction.

[0141] Synthesis of compounds 1-9: Intermediate 1-8 (129 mg, 0.29 mmol) was dissolved in 20 mL of dichloromethane solution, and Dess-Martin oxidizing agent (147 mg, 0.35 mmol) and sodium bicarbonate solid (29 mg, 0.35 mmol) were added and the mixture was stirred at room temperature. After the TLC monitoring (UV) reaction was complete, the reaction system was extracted and filtered, and the resulting filtrate was extracted with saturated sodium bicarbonate solution. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated. Separation and purification by flash column chromatography (CH2Cl2:MeOH = 20:1) yielded a total of 77 mg of white solid powder compounds 1-9 in a yield of 60%.

[0142] Synthesis of compounds 1-10: Compounds 1-9 (129 mg, 0.29 mmol) were dissolved in dichloromethane solvent, and acetic acid (19.2 mg, 0.32 mmol) and benzyl isocyanide (37.6 mg, 0.32 mmol) were added and reacted to obtain compounds 1-10. These compounds were separated and purified by flash column chromatography (CH2Cl2:MeOH = 20:1) to obtain a total of 126 mg of white solid powder of compounds 1-10, with a yield of 70%.

[0143] Synthesis of compounds 1-11: Compound 1-10 (187 mg, 0.3 mmol) was dissolved in methanol solvent, and LiOH (0.6 mmol) was added and stirred to obtain compound 1-11. This compound was then separated and purified by flash column chromatography (CH2Cl2:MeOH = 20:1) to obtain a total of 148 mg of compound 1-11 as a white solid powder, with a yield of 85%.

[0144] Synthesis of compounds 1-12: Compound 1-11 (174 mg, 0.3 mmol) was dissolved in dichloromethane solvent, Dess-Martin oxidizing agent (152 mg, 0.36 mmol) was added, and sodium bicarbonate (30 mg, 0.36 mmol) was added. The mixture was stirred to obtain a total of 140 mg of compound 1-12 as a white solid powder, with a yield of 80%.

[0145] 1H NMR(500MHz,Chloroform)δ 9.76(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),4.3 2(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),2.1 2-2.03(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).

[0146] Example 2. N-((S)-1-(((S)-4-(tert-butylamino)-3,4-dione-1-((S)-2-oxopyrrolidine-3-yl)buto-2-yl)amino)-3-cyclohexyl-1-oxoprop-2-yl)-1H-indole-2-carboxamide (A2) 1 H NMR(500MHz,Chloroform)δ 8.38(s,1H),7.51(d,J=18.0Hz,2H),7.38(s,1H),7.12(s,1H),7.06(s,1H),6.2 6(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,3 H),1.73-1.52(m,5H),1.40-1.36(m,2H),1.35-1.29(m,10H),1.20-1.09(m,3H).

[0147] Example 3. N-((S)-3-cyclohexyl-1-(((S)-4-(cyclohexylamino)-3,4-dione-1-((S)-2-oxopyrrolidine-3-yl)buto-2-yl)amino)-3-cyclohexyl-1-oxoprop-2-yl)-1H-indole-2-carboxamide (A3)

[0148] 1 H NMR(500MHz,Chloroform)δ 8.28(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).

[0149] Example 4. N-((S)-3-cyclohexyl-1-(((S)-4-(neopentylamino)-3,4-dione-1-((S)-2-oxopyrrolidine-3-yl)buto-2-yl)amino)-3-cyclohexyl-1-oxoprop-2-yl)-1H-indole-2-carboxamide (A4)

[0150] 1H NMR(500MHz,Chloroform)δ 8.46(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).

[0151] Example 5. N-((S)-1-(((S)-4-(benzylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-3-cyclohexyl-1-oxoprop-2-yl)-1H-indole-2-carboxamide (A5)

[0152] 1 H NMR(500MHz,Chloroform)δ 8.22(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).

[0153] Example 6. N-((S)-1-(((S)-4-(tert-butylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-3-cyclohexyl-1-oxoprop-2-yl)-1H-indole-2-carboxamide (A6)

[0154] 1 H NMR(500MHz,Chloroform)δ 8.30(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).

[0155] Example 7. N-((S)-3-cyclohexyl-1-(((S)-4-(cyclohexylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-3-cyclohexyl-1-oxoprop-2-yl)-1H-indole-2-carboxamide (A7)

[0156] 1H NMR(500MHz,Chloroform)δ 9.29(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),1.5 5-1.50(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).

[0157] Example 8. N-((S)-3-cyclohexyl-1-(((S)-4-(neopentylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-3-cyclohexyl-1-oxoprop-2-yl)-1H-indole-2-carboxamide (A8)

[0158] 1 H NMR(500MHz,Chloroform)δ 8.45(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),6.0 1(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),3.1 3(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).

[0159] Example 9. N-((S)-1-(((S)-4-(benzylamino)-3,4-dione-1-((S)-2-oxopyrrolidine-3-yl)buto-2-yl)amino)-3-cyclohexyl-1-oxoprop-2-yl)-benzofuran-2-carboxamide (A9)

[0160] 1 H NMR(500MHz,Chloroform)δ 7.66(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).

[0161] Example 10. N-((S)-1-(((S)-4-(tert-butylamino)-3,4-dione-1-((S)-2-oxopyrrolidine-3-yl)buto-2-yl)amino)-3-cyclohexyl-1-oxoprop-2-yl)-benzofuran-2-carboxamide (A10)

[0162] 1H NMR(500MHz,Chloroform)δ 9.59(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).

[0163] Example 11. N-((S)-3-cyclohexyl-1-(((S)-4-(cyclohexylamino)-3,4-dione-1-((S)-2-oxopyrrolidine-3-yl)buto-2-yl)amino)-3-cyclohexyl-1-oxoprop-2-yl)-benzofuran-2-carboxamide (A11)

[0164] 1 H NMR(500MHz,Chloroform)δ 7.63(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,3 H),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).

[0165] Example 12. N-((S)-3-cyclohexyl-1-(((S)-4-(neopentylamino)-3,4-dione-1-((S)-2-oxopyrrolidine-3-yl)buto-2-yl)amino)-3-cyclohexyl-1-oxoprop-2-yl)-benzofuran-2-carboxamide (A12)

[0166] 1 H NMR(500MHz,Chloroform)δ 8.31(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),5.4 6(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,4 H),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).

[0167] Example 13. N-((S)-1-(((S)-4-(benzylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-3-cyclohexyl-1-oxoprop-2-yl)-benzofuran-2-carboxamide (A13) 1H NMR(500MHz,Chloroform)δ 7.59(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,4 H),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).

[0168] Example 14. N-((S)-1-(((S)-4-(tert-butylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-3-cyclohexyl-1-oxoprop-2-yl)-benzofuran-2-carboxamide (A14)

[0169] 1 1H NMR (500MHz, Chloroform) δ 7.63(s,1H),7.50(s,1H),7.37(s,1H),7.22(s,1H),7.16(s,1H),6.25(s,1 H),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).

[0170] Example 15. N-((S)-3-cyclohexyl-1-(((S)-4-(cyclohexylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-3-cyclohexyl-1-oxoprop-2-yl)-benzofuran-2-carboxamide (A15)

[0171] 1 H NMR(500MHz,Chloroform)δ 9.45(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).

[0172] Example 16. N-((S)-3-cyclohexyl-1-(((S)-4-(neopentylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-3-cyclohexyl-1-oxoprop-2-yl)-benzofuran-2-carboxamide (A16)

[0173] 1H NMR(500MHz,Chloroform)δ 7.60(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).

[0174] Example 17. N-((S)-1-(((S)-4-(benzylamino)-3,4-dione-1-((S)-2-oxopyrrolidine-3-yl)buto-2-yl)amino)-3-cyclohexyl-1-oxoprop-2-yl)-benzothiophene-2-carboxamide (A17)

[0175] 1 H NMR(500MHz,Chloroform)δ 8.13(s,5H),7.89(s,5H),7.65(s,5H),7.28(dd,J=7.5,4.2Hz,20H),7.21(dd,J=4.2,2.6H z,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),4.2 4(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,1 0H),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).

[0176] Example 18. N-((S)-1-(((S)-4-(tert-butylamino)-3,4-dione-1-((S)-2-oxopyrrolidine-3-yl)buto-2-yl)amino)-3-cyclohexyl-1-oxoprop-2-yl)-benzothiophene-2-carboxamide (A18)

[0177] 1 1H NMR (500MHz, Chloroform) δ 8.37(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).

[0178] Example 19. N-((S)-3-cyclohexyl-1-(((S)-4-(cyclohexylamino)-3,4-dione-1-((S)-2-oxopyrrolidine-3-yl)buto-2-yl)amino)-3-cyclohexyl-1-oxoprop-2-yl)-benzothiophene-2-carboxamide (A19)

[0179] 1H NMR(500MHz,Chloroform)δ 8.95(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=2.0 Hz,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,1 H),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,2 H),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).

[0180] Example 20. N-((S)-3-cyclohexyl-1-(((S)-4-(neopentylamino)-3,4-dione-1-((S)-2-oxopyrrolidine-3-yl)buto-2-yl)amino)-3-cyclohexyl-1-oxoprop-2-yl)-benzothiophene-2-carboxamide (A20)

[0181] 1 H NMR(500MHz,Chloroform)δ 8.36(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).

[0182] Example 21. N-((S)-1-(((S)-4-(benzylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-3-cyclohexyl-1-oxoprop-2-yl)-benzothiophene-2-carboxamide (A21)

[0183] 1 H NMR(500MHz,Chloroform)δ 8.31(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=17.6 Hz,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).

[0184] Example 22. N-((S)-1-(((S)-4-(tert-butylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-3-cyclohexyl-1-oxoprop-2-yl)-benzothiophene-2-carboxamide (A22)

[0185] 11H NMR (500MHz, Chloroform) δ 8.34(s,1H),8.22(s,1H),7.88(s,1H),7.72(s,1H),7.30(d,J=1.5Hz,2H),6.1 5(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),1.73-1.6 8(m,4H),1.66-1.59(m,5H),1.55-1.49(m,2H),1.35(s,1H),1.32-1.28(m,9H).

[0186] Example 23. N-((S)-3-cyclohexyl-1-(((S)-4-(cyclohexylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-3-cyclohexyl-1-oxoprop-2-yl)-benzothiophene-2-carboxamide (A23)

[0187] 1 H NMR(500MHz,Chloroform)δ 8.93(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),5.8 3(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),1.66-1.5 2(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).

[0188] Example 24. N-((S)-1-(((S)-4-(benzylamino)-3,4-dione-1-((S)-2-oxopyrrolidine-3-yl)buto-2-yl)amino)-3-cyclohexyl-1-oxoprop-2-yl)-1-methyl-1H-indole-2-carboxamide (A24)

[0189] 1 H NMR(500MHz,Chloroform)δ 7.61(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).

[0190] Example 25. N-((S)-1-(((S)-4-(tert-butylamino)-3,4-dione-1-((S)-2-oxopyrrolidine-3-yl)buto-2-yl)amino)-3-cyclohexyl-1-oxoprop-2-yl)-1-methyl-1H-indole-2-carboxamide (A25)

[0191] 1H NMR(500MHz,Chloroform)δ 7.40(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,3 H),1.73-1.52(m,5H),1.41-1.37(m,2H),1.35-1.29(m,10H),1.19-1.09(m,3H).

[0192] Example 26. N-((S)-3-cyclohexyl-1-(((S)-4-(cyclohexylamino)-3,4-dione-1-((S)-2-oxopyrrolidine-3-yl)buto-2-yl)amino)-3-cyclohexyl-1-oxoprop-2-yl)-1-methyl-1H-indole-2-carboxamide (A26)

[0193] 1 H NMR(500MHz,Chloroform)δ 7.24(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).

[0194] Example 27. N-((S)-1-(((S)-4-(benzylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-3-cyclohexyl-1-oxoprop-2-yl)-1-methyl-1H-indole-2-carboxamide (A27)

[0195] 1 H NMR(500MHz,Chloroform)δ 7.43(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).

[0196] Example 28. N-((S)-1-(((S)-4-(tert-butylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-3-cyclohexyl-1-oxoprop-2-yl)-1-methyl-1H-indole-2-carboxamide (A28)

[0197] 1H NMR(500MHz,Chloroform)δ 7.46(s,47H),7.26(d,J=19.3Hz,98H),7.17(d,J=7.3Hz,95H),6.39(s,47H),5.92(d,J=11.5H z,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).

[0198] Example 29. N-((S)-3-cyclohexyl-1-(((S)-4-(cyclohexylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-3-cyclohexyl-1-oxoprop-2-yl)-1-methyl-1H-indole-2-carboxamide (A29)

[0199] 1 H NMR(500MHz,Chloroform)δ 7.41(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,7 H),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).

[0200] Example 30. N-((S)-3-cyclohexyl-1-(((S)-4-(cyclohexylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-3-cyclohexyl-1-oxoprop-2-yl)-1-methyl-1H-indole-2-carboxamide (A30)

[0201] 1 H NMR(500MHz,Chloroform)δ 7.87(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).

[0202] Example 31. N-((S)-1-(((S)-4-(benzylamino)-3,4-dione-1-((S)-2-oxopyrrolidine-3-yl)buto-2-yl)amino)-3-cyclohexyl-1-oxoprop-2-yl)-4,6-dichloro-1H-indole-2-carboxamide (A31)

[0203] 11H NMR (500MHz, Chloroform) δ 9.04(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=18.2,9.1 Hz,5H),1.41-1.37(m,2H),1.35-1.27(m,11H),1.24(s,1H),1.05-1.01(m,2H).

[0204] Example 32. N-((S)-1-(((S)-4-(tert-butylamino)-3,4-dione-1-((S)-2-oxopyrrolidine-3-yl)buto-2-yl)amino)-3-cyclohexyl-1-oxoprop-2-yl)-4,6-dichloro-1H-indole-2-carboxamide (A32)

[0205] 1 H NMR(500MHz,Chloroform)δ 8.86(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).

[0206] Example 33. N-((S)-3-cyclohexyl-1-(((S)-4-(cyclohexylamino)-3,4-dione-1-((S)-2-oxopyrrolidine-3-yl)buto-2-yl)amino)-3-cyclohexyl-1-oxoprop-2-yl)-4,6-dichloro-1H-indole-2-carboxamide (A33)

[0207] 1 H NMR(500MHz,Chloroform)δ 8.68(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).

[0208] Example 34. N-((S)-1-(((S)-4-(benzylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-3-cyclohexyl-1-oxoprop-2-yl)-4,6-dichloro-1H-indole-2-carboxamide (A34)

[0209] 11H NMR (500MHz, Chloroform) δ 8.35(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).

[0210] Example 35. N-((S)-1-(((S)-4-(tert-butylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-3-cyclohexyl-1-oxoprop-2-yl)-4,6-dichloro-1H-indole-2-carboxamide (A35)

[0211] 1 H NMR(500MHz,Chloroform)δ 8.51(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=15.4H z,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).

[0212] Example 36. N-((S)-3-Cyclohexyl-1-(((S)-4-(cyclohexylamino)-3,4-dioxo-1-((S)-2-oxopiperidin-3-yl)but-2-yl)amino)-3-cyclohexyl-1-oxoprop-2-yl)-4,6-dichloro-1H-indole-2-carboxamide (A36)

[0213] 1 H NMR (500 MHz, Chloroform) δ 8.98 (s, 1H), 8.03 (d, J = 1.1 Hz, 2H), 7.63 (d, J = 5.1 Hz, 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 = 5.7 Hz, 2H), 1.58 - 1.49 (m, 6H), 1.31 (s, 1H).

[0214] Example 37. N-((S)-1-(((S)-4-(benzylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)but-2-yl)amino)-3-cyclohexyl-1-oxoprop-2-yl)-quinoxaline-2-carboxamide (A37)

[0215] 11H NMR (500MHz, Chloroform) δ 9.39(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).

[0216] Example 38. N-((S)-1-(((S)-4-(tert-butylamino)-3,4-dione-1-((S)-2-oxopyrrolidine-3-yl)buto-2-yl)amino)-3-cyclohexyl-1-oxoprop-2-yl)-quinoxaline-2-carboxamide (A38)

[0217] 1 1H NMR (500MHz, Chloroform) δ 9.09(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).

[0218] Example 39. N-((S)-3-cyclohexyl-1-(((S)-4-(cyclohexylamino)-3,4-dione-1-((S)-2-oxopyrrolidine-3-yl)buto-2-yl)amino)-3-cyclohexyl-1-oxoprop-2-yl)-quinoxaline-2-carboxamide (A39)

[0219] 1 H NMR(500MHz,Chloroform)δ 9.55(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,1 H),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).

[0220] Example 40. N-((S)-1-(((S)-4-(benzylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-3-cyclohexyl-1-oxoprop-2-yl)-quinoxaline-2-carboxamide (A40)

[0221] 1 1H NMR (500MHz, Chloroform) δ 9.29(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).

[0222] Example 41. N-((S)-1-(((S)-4-(tert-butylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-3-cyclohexyl-1-oxoprop-2-yl)-quinoxaline-2-carboxamide (A41)

[0223] 1 H NMR(500MHz,Chloroform)δ 9.64(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).

[0224] Example 42. N-((S)-1-(((S)-4-(benzylamino)-3,4-dione-1-((S)-2-oxopyrrolidine-3-yl)buto-2-yl)amino)-3-cyclohexyl-1-oxoprop-2-yl)-quinoline-2-carboxamide (A42)

[0225] 11H NMR (500 MHz, Chloroform) δ 8.56 (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=2.7 Hz, 2H), 4.43 (s, 1H), 4.33 (s, 1H), 4.11 (s, 1H), 3.83 (d, J=3.7 Hz, 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).

[0226] Example 43. N-((S)-1-(((S)-4-(tert-Butylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)but-2-yl)amino)-3-cyclohexyl-1-oxoprop-2-yl)-quinoline-2-carboxamide (A43)

[0227] 1 1H NMR (500 MHz, Chloroform) δ 9.34 (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).

[0228] Example 44. N-((S)-3-cyclohexyl-1-(((S)-4-(cyclohexylamino)-3,4-dione-1-((S)-2-oxopyrrolidine-3-yl)buto-2-yl)amino)-3-cyclohexyl-1-oxoprop-2-yl)-quinoline-2-carboxamide (A44)

[0229] 1 H NMR(500MHz,Chloroform)δ 8.47(s,1H),8.24(s,1H),8.06(s,1H),7.73(s,1H),7.65(s,1H),7.43(d,J=13.7 Hz,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),2.0 9-2.05(m,2H),1.92(s,1H),1.77-1.56(m,15H),1.55-1.46(m,6H),1.30(s,1H).

[0230] Example 45. N-((S)-1-(((S)-4-(benzylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-3-cyclohexyl-1-oxoprop-2-yl)-quinoline-2-carboxamide (A45)

[0231] 1H NMR(500MHz,Chloroform)δ 8.42(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).

[0232] Example 46. N-((S)-1-(((S)-4-(tert-butylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-3-cyclohexyl-1-oxoprop-2-yl)-quinoline-2-carboxamide (A46)

[0233] 1 H NMR(500MHz,Chloroform)δ 8.46(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).

[0234] Example 47. N-((S)-3-cyclohexyl-1-(((S)-4-(cyclohexylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-3-cyclohexyl-1-oxoprop-2-yl)-quinoline-2-carboxamide (A47)

[0235] 1 H NMR(500MHz,Chloroform)δ 9.06(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),7.3 8(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,24 H),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).

[0236] Example 48. N-((S)-1-(((S)-4-(benzylamino)-3,4-dione-1-((S)-2-oxopyrrolidine-3-yl)buto-2-yl)amino)-1-oxo-3-phenylprop-2-yl)-1H-indole-2-carboxamide (A48)

[0237] 11H NMR (500MHz, Chloroform) δ 8.36(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).

[0238] Example 49. N-((S)-1-(((S)-4-(tert-butylamino)-3,4-dione-1-((S)-2-oxopyrrolidine-3-yl)buto-2-yl)amino)-1-oxo-3-phenylprop-2-yl)-1H-indole-2-carboxamide (A49)

[0239] 1 1H NMR (500MHz, Chloroform) δ 8.26(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).

[0240] Example 50. N-((S)-3-cyclohexyl-1-(((S)-4-(cyclohexylamino)-3,4-dione-1-((S)-2-oxopyrrolidine-3-yl)buto-2-yl)amino)-1-oxo-3-phenylprop-2-yl)-1H-indole-2-carboxamide (A50)

[0241] 1 H NMR(500MHz,Chloroform)δ 8.35(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).

[0242] Example 51. N-((S)-1-(((S)-4-(benzylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-1-oxo-3-phenylprop-2-yl)-1H-indole-2-carboxamide (A51)

[0243] 1 H NMR(500MHz,Chloroform)δ 8.70(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),4.7 0(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).

[0244] Example 52. N-((S)-1-(((S)-4-(tert-butylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-1-oxo-3-phenylprop-2-yl)-1H-indole-2-carboxamide (A52)

[0245] 1 H NMR(500MHz,Chloroform)δ 8.64(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).

[0246] Example 53. N-((S)-3-cyclohexyl-1-(((S)-4-(cyclohexylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-1-oxo-3-phenylprop-2-yl)-1H-indole-2-carboxamide (A53)

[0247] 1H NMR(500MHz,Chloroform)δ 8.76(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).

[0248] Example 54. N-((S)-1-(((S)-4-(benzylamino)-3,4-dione-1-((S)-2-oxopyrrolidine-3-yl)buto-2-yl)amino)-1-oxo-3-phenylprop-2-yl)-benzofuran-2-carboxamide (A54)

[0249] 1 H NMR(500MHz,Chloroform)δ 7.51(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).

[0250] Example 55. N-((S)-1-(((S)-4-(tert-butylamino)-3,4-dione-1-((S)-2-oxopyrrolidine-3-yl)buto-2-yl)amino)-1-oxo-3-phenylprop-2-yl)-benzofuran-2-carboxamide (A55)

[0251] 1 H NMR(500MHz,Chloroform)δ 7.54(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),2.6 1(s,1H),2.18(s,1H),2.09-2.05(m,2H),1.93(s,1H),1.34-1.30(m,9H).

[0252] Example 56. N-((S)-3-cyclohexyl-1-(((S)-4-(cyclohexylamino)-3,4-dione-1-((S)-2-oxopyrrolidine-3-yl)buto-2-yl)amino)-1-oxo-3-phenylprop-2-yl)-benzofuran-2-carboxamide (A56)

[0253] 1H NMR(500MHz,Chloroform)δ 8.77(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),2.1 9(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).

[0254] Example 57. N-((S)-1-(((S)-4-(benzylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-1-oxo-3-phenylprop-2-yl)-benzofuran-2-carboxamide (A57)

[0255] 1 H NMR(500MHz,Chloroform)δ 7.48(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),4.6 3(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).

[0256] Example 58. N-((S)-1-(((S)-4-(tert-butylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-1-oxo-3-phenylprop-2-yl)-benzofuran-2-carboxamide (A58)

[0257] 1 H NMR(500MHz,Chloroform)δ 9.35(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).

[0258] Example 59. N-((S)-1-(((S)-4-(tert-butylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-1-oxo-3-phenylprop-2-yl)-benzofuran-2-carboxamide (A59)

[0259] 1 H NMR(500MHz,Chloroform)δ 9.35(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).

[0260] Example 60. N-((S)-1-(((S)-4-(benzylamino)-3,4-dione-1-((S)-2-oxopyrrolidine-3-yl)buto-2-yl)amino)-1-oxo-3-phenylprop-2-yl)-benzothiophene-2-carboxamide (A60)

[0261] 1 H NMR(500MHz,Chloroform)δ 8.40(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),5.0 3(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).

[0262] Example 61. N-((S)-1-(((S)-4-(tert-butylamino)-3,4-dione-1-((S)-2-oxopyrrolidine-3-yl)buto-2-yl)amino)-1-oxo-3-phenylprop-2-yl)-benzothiophene-2-carboxamide (A61)

[0263] 1 H NMR(500MHz,Chloroform)δ 8.93(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,1 H),3.99(s,1H),3.55(s,1H),3.45(s,1H),3.35(s,1H),3.15(s,1H),2.9 5(s,1H),2.17(s,1H),2.13-2.02(m,2H),1.89(s,1H),1.21-1.17(m,9H).

[0264] Example 62. N-((S)-3-cyclohexyl-1-(((S)-4-(cyclohexylamino)-3,4-dione-1-((S)-2-oxopyrrolidine-3-yl)buto-2-yl)amino)-1-oxo-3-phenylprop-2-yl)-benzothiophene-2-carboxamide (A62)

[0265] 1 H NMR(500MHz,Chloroform)δ 8.73(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).

[0266] Example 63. N-((S)-1-(((S)-4-(benzylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-1-oxo-3-phenylprop-2-yl)-benzothiophene-2-carboxamide (A63)

[0267] 11H NMR (500MHz, Chloroform) δ 8.49(s,1H),8.30(s,1H),8.00(s,1H),7.63(s,1H),7.29(dd,J=19.0,2.9Hz,4 H),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).

[0268] Example 64. N-((S)-1-(((S)-4-(tert-butylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-1-oxo-3-phenylprop-2-yl)-benzothiophen-2-carboxamide (A64)

[0269] 1 1H NMR (500MHz, Chloroform) δ 8.38(s,1H),7.90(s,1H),7.75(s,1H),7.30(dd,J=17.5,1.0Hz,4H),7.26-7.1 9(m,2H),7.17(s,1H),7.02(s,1H),6.45(s,1H),6.10(s,1H),5.93(s,1H),4.9 3(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).

[0270] Example 65. N-((S)-3-cyclohexyl-1-(((S)-4-(cyclohexylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-1-oxo-3-phenylprop-2-yl)-benzothiophene-2-carboxamide (A65)

[0271] 1 H NMR(500MHz,Chloroform)δ 8.28(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).

[0272] Example 66. N-((S)-1-(((S)-4-(benzylamino)-3,4-dione-1-((S)-2-oxopyrrolidine-3-yl)buto-2-yl)amino)-1-oxo-3-phenylprop-2-yl)-1-methyl-1H-indole-2-carboxamide (A66)

[0273] 1 H NMR(500MHz,Chloroform)δ 8.78(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).

[0274] Example 67. N-((S)-1-(((S)-4-(tert-butylamino)-3,4-dione-1-((S)-2-oxopyrrolidine-3-yl)buto-2-yl)amino)-1-oxo-3-phenylprop-2-yl)-1-methyl-1H-indole-2-carboxamide (A67)

[0275] 1 H NMR(500MHz,Chloroform)δ 7.38(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).

[0276] Example 68. N-((S)-3-cyclohexyl-1-(((S)-4-(cyclohexylamino)-3,4-dione-1-((S)-2-oxopyrrolidine-3-yl)buto-2-yl)amino)-1-oxo-3-phenylprop-2-yl)-1-methyl-1H-indole-2-carboxamide (A68)

[0277] 1 1H NMR (500MHz, Chloroform) δ 7.49(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).

[0278] Example 69. N-((S)-1-(((S)-4-(benzylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-1-oxo-3-phenylprop-2-yl)-1-methyl-1H-indole-2-carboxamide (A69)

[0279] 1 1H NMR (500MHz, Chloroform) δ 7.35-7.29(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).

[0280] Example 70. N-((S)-1-(((S)-4-(tert-butylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-1-oxo-3-phenylprop-2-yl)-1-methyl-1H-indole-2-carboxamide (A70)

[0281] 1 H NMR(500MHz,Chloroform)δ 7.51(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,2 H),1.92(s,1H),1.82(s,1H),1.75(s,1H),1.54(s,1H),1.32-1.28(m,9H).

[0282] Example 71. N-((S)-3-cyclohexyl-1-(((S)-4-(cyclohexylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-1-oxo-3-phenylprop-2-yl)-1-methyl-1H-indole-2-carboxamide (A71)

[0283] 1 1H NMR (500MHz, Chloroform) δ 8.25(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).

[0284] Example 72. N-((S)-1-(((S)-4-(benzylamino)-3,4-dione-1-((S)-2-oxopyrrolidine-3-yl)buto-2-yl)amino)-1-oxo-3-phenylprop-2-yl)-4,6-dichloro-1H-indole-2-carboxamide (A72)

[0285] 1H NMR(500MHz,Chloroform)δ 8.55(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),4.7 7(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).

[0286] Example 73. N-((S)-1-(((S)-4-(tert-butylamino)-3,4-dione-1-((S)-2-oxopyrrolidine-3-yl)buto-2-yl)amino)-1-oxo-3-phenylprop-2-yl)-4,6-dichloro-1H-indole-2-carboxamide (A73)

[0287] 1 H NMR(500MHz,Chloroform)δ 8.55(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).

[0288] Example 74. N-((S)-3-cyclohexyl-1-(((S)-4-(cyclohexylamino)-3,4-dione-1-((S)-2-oxopyrrolidine-3-yl)buto-2-yl)amino)-1-oxo-3-phenylprop-2-yl)-4,6-dichloro-1H-indole-2-carboxamide (A74)

[0289] 1 H NMR(500MHz,Chloroform)δ 8.85(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).

[0290] Example 75. N-((S)-1-(((S)-4-(benzylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-1-oxo-3-phenylprop-2-yl)-4,6-dichloro-1H-indole-2-carboxamide (A75)

[0291] 1 H NMR(500MHz,Chloroform)δ 8.67(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,14 H),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).

[0292] Example 76. N-((S)-1-(((S)-4-(tert-butylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-1-oxo-3-phenylprop-2-yl)-4,6-dichloro-1H-indole-2-carboxamide (A76)

[0293] 1 H NMR(500MHz,Chloroform)δ 8.53(s,8H),7.62(s,8H),7.43(s,8H),7.38(s,8H),7.26-7.21(m,16H),7.21-7.1 4(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),2.08-2.0 4(m,16H),1.86(s,6H),1.80(s,7H),1.73(s,6H),1.48(s,6H),1.34-1.30(m,72H).

[0294] Example 77. N-((S)-3-cyclohexyl-1-(((S)-4-(cyclohexylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-1-oxo-3-phenylprop-2-yl)-4,6-dichloro-1H-indole-2-carboxamide (A77)

[0295] 1H NMR(500MHz,Chloroform)δ 9.14(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),3.3 5(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).

[0296] Example 78. N-((S)-1-(((S)-4-(benzylamino)-3,4-dione-1-((S)-2-oxopyrrolidine-3-yl)buto-2-yl)amino)-1-oxo-3-phenylprop-2-yl)quinoxaline-2-carboxamide (A78)

[0297] 1 H NMR(500MHz,Chloroform)δ 9.21(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).

[0298] Example 79. N-((S)-1-(((S)-4-(tert-butylamino)-3,4-dione-1-((S)-2-oxopyrrolidine-3-yl)buto-2-yl)amino)-1-oxo-3-phenylprop-2-yl)-quinoxaline-2-carboxamide (A79)

[0299] 1 H NMR(500MHz,Chloroform)δ 9.43(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).

[0300] Example 80. N-((S)-3-cyclohexyl-1-(((S)-4-(cyclohexylamino)-3,4-dione-1-((S)-2-oxopyrrolidine-3-yl)buto-2-yl)amino)-1-oxo-3-phenylprop-2-yl)-quinoxaline-2-carboxamide (A80)

[0301] 1 H NMR(500MHz,Chloroform)δ 9.46(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).

[0302] Example 81. N-((S)-1-(((S)-4-(benzylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-1-oxo-3-phenylprop-2-yl)-quinoxaline-2-carboxamide (A81)

[0303] 1 H NMR(500MHz,Chloroform)δ 9.04(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).

[0304] Example 82. N-((S)-1-(((S)-4-(tert-butylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-1-oxo-3-phenylprop-2-yl)-quinoxaline-2-carboxamide (A82)

[0305] 1H NMR(500MHz,Chloroform)δ 9.37(s,1H),8.11(d,J=1.9Hz,2H),7.64(d,J=1.0Hz,2H),7.32-7.26(m,2H),7.2 6-7.13(m,3H),6.08(s,1H),5.93(d,J=13.8Hz,2H),5.60(s,1H),4.97(s,1H),4.8 3(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).

[0306] Example 83. N-((S)-3-cyclohexyl-1-(((S)-4-(cyclohexylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-1-oxo-3-phenylprop-2-yl)-quinoxaline-2-carboxamide (A83)

[0307] 1 H NMR(500MHz,Chloroform)δ 9.67(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),2.8 3(s,6H),2.11-2.01(m,13H),2.01-1.94(m,18H),1.75(s,4H),1.71-1.55(m,59H).

[0308] Example 84. N-((S)-1-(((S)-4-(benzylamino)-3,4-dione-1-((S)-2-oxopyrrolidine-3-yl)buto-2-yl)amino)-1-oxo-3-phenylprop-2-yl)-quinoline-2-carboxamide (A84)

[0309] 1 H NMR(500MHz,Chloroform)δ 8.46(s,1H),8.12(s,1H),7.78(s,1H),7.65(s,1H),7.54(s,1H),7.44(s,1H),7.3 1-7.24(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).

[0310] Example 85. N-((S)-1-(((S)-4-(tert-butylamino)-3,4-dione-1-((S)-2-oxopyrrolidine-3-yl)buto-2-yl)amino)-1-oxo-3-phenylprop-2-yl)-quinoline-2-carboxamide (A85)

[0311] 1H NMR(500MHz,Chloroform)δ 8.40(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),3.0 2(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).

[0312] Example 86. N-((S)-3-cyclohexyl-1-(((S)-4-(cyclohexylamino)-3,4-dione-1-((S)-2-oxopyrrolidine-3-yl)buto-2-yl)amino)-1-oxo-3-phenylprop-2-yl)quinoline-2-carboxamide (A86)

[0313] 1 H NMR(500MHz,Chloroform)δ 8.46(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).

[0314] Example 87. N-((S)-1-(((S)-4-(benzylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-1-oxo-3-phenylprop-2-yl)-quinoline-2-carboxamide (A87)

[0315] 1 H NMR(500MHz,Chloroform)δ 8.46(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).

[0316] Example 88. N-((S)-1-(((S)-4-(tert-butylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-1-oxo-3-phenylprop-2-yl)-quinoline-2-carboxamide (A88)

[0317] 1H NMR(500MHz,Chloroform)δ 8.50(d,J=13.8Hz,2H),8.17(s,1H),7.81(s,1H),7.69(s,1H),7.65(s,1H),7.48(s,1 H),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).

[0318] Example 89. N-((S)-3-cyclohexyl-1-(((S)-4-(cyclohexylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-1-oxo-3-phenylprop-2-yl)-quinoline-2-carboxamide (A89)

[0319] 1 H NMR(500MHz,Chloroform)δ 9.70(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=4.0H z,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),2.11-2.0 4(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).

[0320] Example 90. N-((S)-1-(((S)-4-(benzylamino)-3,4-dione-1-((S)-2-oxopyrrolidine-3-yl)buto-2-yl)amino)-4-methyl-1-oxopento-2-yl)-1H-indole-2-carboxamide (A90)

[0321] 1 H NMR(500MHz,Chloroform)δ 8.36(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).

[0322] Example 91. N-((S)-1-(((S)-4-(tert-butylamino)-3,4-dione-1-((S)-2-oxopyrrolidine-3-yl)buto-2-yl)amino)-3-cyclohexyl-1-oxopento-2-yl)-1H-indole-2-carboxamide (A91)

[0323] 11H NMR (500MHz, Chloroform) δ 9.33(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,1 H),1.70(d,J=19.2Hz,2H),1.44(s,1H),1.36-1.32(m,9H),0.99-0.85(m,6H).

[0324] Example 92. N-((S)-3-cyclohexyl-1-(((S)-4-(cyclohexylamino)-3,4-dione-1-((S)-2-oxopyrrolidine-3-yl)buto-2-yl)amino)-3-cyclohexyl-1-oxopento-2-yl)-1H-indole-2-carboxamide (A92)

[0325] 1 H NMR(500MHz,Chloroform)δ 8.38(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).

[0326] Example 93. N-((S)-1-(((S)-4-(benzylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-4-methyl-1-oxopento-2-yl)-1H-indole-2-carboxamide (A93)

[0327] 1 H NMR(500MHz,Chloroform)δ 8.63(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),4.3 7(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).

[0328] Example 94. N-((S)-1-(((S)-4-(tert-butylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-3-cyclohexyl-1-oxopento-2-yl)-1H-indole-2-carboxamide (A94)

[0329] 1H NMR(500MHz,Chloroform)δ 8.38(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).

[0330] Example 95. N-((S)-3-cyclohexyl-1-(((S)-4-(cyclohexylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-3-cyclohexyl-1-oxopento-2-yl)-1H-indole-2-carboxamide (A95)

[0331] 1 H NMR(500MHz,Chloroform)δ 9.04(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).

[0332] Example 96. N-((S)-1-(((S)-4-(benzylamino)-3,4-dione-1-((S)-2-oxopyrrolidine-3-yl)buto-2-yl)amino)-4-methyl-1-oxopento-2-yl)-benzofuran-2-carboxamide (A96)

[0333] 1 H NMR(500MHz,Chloroform)δ 7.74(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).

[0334] Example 97. N-((S)-1-(((S)-4-(tert-butylamino)-3,4-dione-1-((S)-2-oxopyrrolidine-3-yl)buto-2-yl)amino)-3-cyclohexyl-1-oxopento-2-yl)-benzofuran-2-carboxamide (A97)

[0335] 1 H NMR(500MHz,Chloroform)δ 8.17(s,1H),7.45(d,J=28.3Hz,2H),7.22(s,1H),7.15(s,1H),6.41(s,1 H),6.00(s,1H),5.96(s,1H),4.94(s,1H),4.55(s,1H),3.45(s,1H),3.3 5(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).

[0336] Example 98. N-((S)-3-cyclohexyl-1-(((S)-4-(cyclohexylamino)-3,4-dione-1-((S)-2-oxopyrrolidine-3-yl)buto-2-yl)amino)-3-cyclohexyl-1-oxopento-2-yl)-benzofuran-2-carboxamide (A98)

[0337] 1 H NMR(500MHz,Chloroform)δ 7.59(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).

[0338] Example 99. N-((S)-1-(((S)-4-(benzylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-4-methyl-1-oxopento-2-yl)-benzofuran-2-carboxamide (A99)

[0339] 1H NMR(500MHz,Chloroform)δ 7.58(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),1.8 2(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).

[0340] Example 100. N-((S)-1-(((S)-4-(benzylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-4-methyl-1-oxopento-2-yl)-benzofuran-2-carboxamide (A100)

[0341] 1 H NMR(500MHz,Chloroform)δ 7.58(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),1.8 2(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).

[0342] Example 101. N-((S)-3-cyclohexyl-1-(((S)-4-(cyclohexylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-3-cyclohexyl-1-oxopento-2-yl)-benzofuran-2-carboxamide (A101)

[0343] 1 H NMR(500MHz,Chloroform)δ 7.59(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,1 H),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).

[0344] Example 102. N-((S)-1-(((S)-4-(benzylamino)-3,4-dione-1-((S)-2-oxopyrrolidine-3-yl)buto-2-yl)amino)-4-methyl-1-oxopento-2-yl)-benzothiophene-2-carboxamide (A102)

[0345] 1H NMR(500MHz,Chloroform)δ 8.47(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),4.3 6(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).

[0346] Example 103. N-((S)-1-(((S)-4-(tert-butylamino)-3,4-dione-1-((S)-2-oxopyrrolidine-3-yl)buto-2-yl)amino)-3-cyclohexyl-1-oxopento-2-yl)-benzothiophene-2-carboxamide (A103)

[0347] 1 H NMR(500MHz,Chloroform)δ 8.37(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).

[0348] Example 104. N-((S)-3-cyclohexyl-1-(((S)-4-(cyclohexylamino)-3,4-dione-1-((S)-2-oxopyrrolidine-3-yl)buto-2-yl)amino)-3-cyclohexyl-1-oxopento-2-yl)-benzothiophene-2-carboxamide (A104)

[0349] 1 H NMR(500MHz,Chloroform)δ 8.63(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,1 H),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).

[0350] Example 105. N-((S)-1-(((S)-4-(benzylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-4-methyl-1-oxopento-2-yl)-benzothiophene-2-carboxamide (A105)

[0351] 1H NMR(500MHz,Chloroform)δ 8.43(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,1 H),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),1.8 0(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).

[0352] Example 106. N-((S)-1-(((S)-4-(tert-butylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-3-cyclohexyl-1-oxopento-2-yl)-benzothiophene-2-carboxamide (A106)

[0353] 1 1H NMR (500MHz, Chloroform) δ 8.39(s,1H),7.91(s,1H),7.71(s,1H),7.31(d,J=2.6Hz,2H),6.50(s,1H),5.8 7(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).

[0354] Example 107. N-((S)-3-cyclohexyl-1-(((S)-4-(cyclohexylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-3-cyclohexyl-1-oxopento-2-yl)-benzothiophene-2-carboxamide (A107)

[0355] 1 H NMR(500MHz,Chloroform)δ 8.30(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),1.8 6(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).

[0356] Example 108. N-((S)-1-(((S)-4-(benzylamino)-3,4-dione-1-((S)-2-oxopyrrolidine-3-yl)buto-2-yl)amino)-4-methyl-1-oxopento-2-yl)-1-methyl-1H-indole-2-carboxamide (A108)

[0357] 1H NMR(500MHz,Chloroform)δ 7.39(d,J=5.1Hz,10H),7.31-7.22(m,12H),7.22-7.06(m,35H),5.99(s,5H),5.2 9(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).

[0358] Example 109. N-((S)-1-(((S)-4-(tert-butylamino)-3,4-dione-1-((S)-2-oxopyrrolidine-3-yl)buto-2-yl)amino)-3-cyclohexyl-1-oxopento-2-yl)-1-methyl-1H-indole-2-carboxamide (A109)

[0359] 1 1H NMR (500MHz, Chloroform) δ 8.20(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).

[0360] Example 110. N-((S)-3-cyclohexyl-1-(((S)-4-(cyclohexylamino)-3,4-dione-1-((S)-2-oxopyrrolidine-3-yl)buto-2-yl)amino)-3-cyclohexyl-1-oxopento-2-yl)-1-methyl-1H-indole-2-carboxamide (A110)

[0361] 1 H NMR(500MHz,Chloroform)δ 7.37(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,1 1H),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).

[0362] Example 111. N-((S)-1-(((S)-4-(benzylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-4-methyl-1-oxopento-2-yl)-1-methyl-1H-indole-2-carboxamide (A111)

[0363] 1H NMR(500MHz,Chloroform)δ 7.62(s,1H),7.34(s,1H),7.30-7.17(m,8H),6.58(s,1H),6.10(s,1H),5.61(s,1 H),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).

[0364] Example 112. N-((S)-1-(((S)-4-(tert-butylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-3-cyclohexyl-1-oxopento-2-yl)-1-methyl-1H-indole-2-carboxamide (A112)

[0365] 1 H NMR(500MHz,Chloroform)δ 7.57(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).

[0366] Example 113. N-((S)-1-(((S)-4-(tert-butylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-3-cyclohexyl-1-oxopento-2-yl)-1-methyl-1H-indole-2-carboxamide (A113)

[0367] 1 H NMR(500MHz,Chloroform)δ 7.57(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).

[0368] Example 114. N-((S)-1-(((S)-4-(benzylamino)-3,4-dione-1-((S)-2-oxopyrrolidine-3-yl)buto-2-yl)amino)-4-methyl-1-oxopento-2-yl)-4,6-dichloro-1H-indole-2-carboxamide (A114)

[0369] 1H NMR(500MHz,Chloroform)δ 9.48(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).

[0370] Example 115. N-((S)-1-(((S)-4-(tert-butylamino)-3,4-dione-1-((S)-2-oxopyrrolidine-3-yl)buto-2-yl)amino)-3-cyclohexyl-1-oxopento-2-yl)-4,6-dichloro-1H-indole-2-carboxamide (A115)

[0371] 1 H NMR(500MHz,Chloroform)δ 8.36(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).

[0372] Example 116. N-((S)-3-cyclohexyl-1-(((S)-4-(cyclohexylamino)-3,4-dione-1-((S)-2-oxopyrrolidine-3-yl)buto-2-yl)amino)-3-cyclohexyl-1-oxopento-2-yl)-4,6-dichloro-1H-indole-2-carboxamide (A116)

[0373] 1 1H NMR (500MHz, Chloroform) δ 9.33(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,1 H),3.35(s,1H),2.73(s,1H),2.19(s,1H),2.09-2.05(m,2H),2.05-1.90(m,3 H),1.72(s,1H),1.70-1.44(m,9H),1.44(d,J=5.3Hz,1H),0.98-0.85(m,6H).

[0374] Example 117. N-((S)-1-(((S)-4-(benzylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-4-methyl-1-oxopento-2-yl)-4,6-dichloro-1H-indole-2-carboxamide (A117)

[0375] 1H NMR(500MHz,Chloroform)δ 8.38(s,1H),7.67(s,1H),7.42(s,1H),7.29-7.22(m,4H),7.19(s,1H),7.10(d,J=11.4 Hz,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).

[0376] Example 118. N-((S)-1-(((S)-4-(tert-butylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-3-cyclohexyl-1-oxopento-2-yl)-4,6-dichloro-1H-indole-2-carboxamide (A118)

[0377] 1 H NMR(500MHz,Chloroform)δ 8.59(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).

[0378] Example 119. N-((S)-3-cyclohexyl-1-(((S)-4-(cyclohexylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-3-cyclohexyl-1-oxopento-2-yl)-4,6-dichloro-1H-indole-2-carboxamide (A119)

[0379] 1 H NMR(500MHz,Chloroform)δ 8.63(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=17.9H z,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).

[0380] Example 120. N-((S)-1-(((S)-4-(benzylamino)-3,4-dione-1-((S)-2-oxopyrrolidine-3-yl)buto-2-yl)amino)-4-methyl-1-oxopento-2-yl)quinoxaline-2-carboxamide (A120)

[0381] 1H NMR(500MHz,Chloroform)δ 8.79(s,1H),8.05(s,1H),8.01(s,1H),7.64(d,J=1.5Hz,2H),7.36-7.25(m,4H),7.2 0(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,1 H),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,2 H),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).

[0382] Example 121. N-((S)-1-(((S)-4-(tert-butylamino)-3,4-dione-1-((S)-2-oxopyrrolidine-3-yl)buto-2-yl)amino)-3-cyclohexyl-1-oxopento-2-yl)-quinoxaline-2-carboxamide (A121)

[0383] 1 H NMR(500MHz,Chloroform)δ 9.24(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).

[0384] Example 122. N-((S)-3-cyclohexyl-1-(((S)-4-(cyclohexylamino)-3,4-dione-1-((S)-2-oxopyrrolidine-3-yl)buto-2-yl)amino)-3-cyclohexyl-1-oxopento-2-yl)-quinoxaline-2-carboxamide (A122)

[0385] 1 H NMR(500MHz,Chloroform)δ 9.29(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).

[0386] Example 123. N-((S)-1-(((S)-4-(benzylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-4-methyl-1-oxopento-2-yl)quinoxaline-2-carboxamide (A123)

[0387] 1H NMR(500MHz,Chloroform)δ 9.35(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).

[0388] Example 124. N-((S)-1-(((S)-4-(tert-butylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-3-cyclohexyl-1-oxopento-2-yl)-quinoxaline-2-carboxamide (A124)

[0389] 1 H NMR(500MHz,Chloroform)δ 9.23(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),1.76-1.6 9(m,3H),1.51(s,1H),1.40(s,1H),1.33-1.29(m,9H),1.12-0.99(m,6H).

[0390] Example 125. N-((S)-3-cyclohexyl-1-(((S)-4-(cyclohexylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-3-cyclohexyl-1-oxopento-2-yl)-quinoxaline-2-carboxamide (A125)

[0391] 1 H NMR(500MHz,Chloroform)δ 9.32(s,1H),8.97(s,1H),8.11(d,J=3.7Hz,2H),7.65(d,J=2.2Hz,2H),5.73(s,1 H),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).

[0392] Example 126. N-((S)-1-(((S)-4-(benzylamino)-3,4-dione-1-((S)-2-oxopyrrolidine-3-yl)buto-2-yl)amino)-4-methyl-1-oxopento-2-yl)-quinoline-2-carboxamide (A126)

[0393] 1H NMR(500MHz,Chloroform)δ 8.47(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).

[0394] Example 127. N-((S)-1-(((S)-4-(tert-butylamino)-3,4-dione-1-((S)-2-oxopyrrolidine-3-yl)buto-2-yl)amino)-3-cyclohexyl-1-oxopento-2-yl)-quinoline-2-carboxamide (A127)

[0395] 1 1H NMR (500MHz, Chloroform) δ 8.36(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).

[0396] Example 128. N-((S)-3-cyclohexyl-1-(((S)-4-(cyclohexylamino)-3,4-dione-1-((S)-2-oxopyrrolidine-3-yl)buto-2-yl)amino)-3-cyclohexyl-1-oxopento-2-yl)-quinoline-2-carboxamide (A128)

[0397] 1 H NMR(500MHz,Chloroform)δ 9.46(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).

[0398] Example 129. N-((S)-1-(((S)-4-(benzylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-4-methyl-1-oxopento-2-yl)-quinoline-2-carboxamide (A129)

[0399] 1H NMR(500MHz,Chloroform)δ 8.45(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).

[0400] Example 130. N-((S)-1-(((S)-4-(tert-butylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-3-cyclohexyl-1-oxopento-2-yl)-quinoline-2-carboxamide (A130)

[0401] 1 H NMR(500MHz,Chloroform)δ 8.45(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).

[0402] Example 131. N-((S)-3-cyclohexyl-1-(((S)-4-(cyclohexylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-3-cyclohexyl-1-oxopento-2-yl)-quinoline-2-carboxamide (A131)

[0403] 1 H NMR(500MHz,Chloroform)δ 8.45(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,3 H),1.75-1.68(m,5H),1.55-1.44(m,5H),1.44-1.39(m,2H),1.09-0.96(m,6H).

[0404] Example 132. N-((S)-1-(((S)-4-(benzylamino)-3,4-dione-1-((S)-2-oxopyrrolidine-3-yl)buto-2-yl)amino)-1-oxo-3-phenylprop-2-yl)-6-chloro-3,8a-dihydro-2H-benzopyran-3-carboxamide (A132)

[0405] 1H NMR(500MHz,Chloroform)δ 7.39-7.29(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,2 H),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,3 H),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).

[0406] Example 133. N-((S)-1-(((S)-4-(tert-butylamino)-3,4-dione-1-((S)-2-oxopyrrolidine-3-yl)buto-2-yl)amino)-1-oxo-3-phenylprop-2-yl)-6-chloro-3,8a-dihydro-2H-benzopyran-3-carboxamide (A133)

[0407] 1 H NMR(500MHz,Chloroform)δ 7.27-7.21(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).

[0408] Example 134. N-((S)-1-(((S)-4-(cyclohexylamino)-3,4-dione-1-((S)-2-oxopyrrolidine-3-yl)buto-2-yl)amino)-1-oxo-3-phenylprop-2-yl)-6-chloro-3,8a-dihydro-2H-benzopyran-3-carboxamide (A134)

[0409] 1 H NMR(500MHz,Chloroform)δ 8.76(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),3.48-3.4 6(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),2.0 9-2.05(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).

[0410] Example 135. N-((S)-1-(((S)-4-(benzylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-1-oxo-3-phenylprop-2-yl)-6-chloro-3,8a-dihydro-2H-benzopyran-3-carboxamide (A135)

[0411] 1H NMR(500MHz,Chloroform)δ 7.82(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).

[0412] Example 136. N-((S)-1-(((S)-4-(tert-butylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-1-oxo-3-phenylprop-2-yl)-6-chloro-3,8a-dihydro-2H-benzopyran-3-carboxamide (A136)

[0413] 1 H NMR(500MHz,Chloroform)δ 7.32-7.26(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),2.5 3(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).

[0414] Example 137. N-((S)-1-(((S)-4-(cyclohexylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-1-oxo-3-phenylprop-2-yl)-6-chloro-3,8a-dihydro-2H-benzopyran-3-carboxamide (A137)

[0415] 1 H NMR(500MHz,Chloroform)δ 7.30-7.26(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).

[0416] Example 138. N-((S)-1-(((S)-4-(benzylamino)-3,4-dione-1-((S)-2-oxopyrrolidine-3-yl)buto-2-yl)amino)-1-oxo-3-phenylprop-2-yl)benzene[d][1,3]dioxol-5-carboxamide (A138)

[0417] 1H NMR(500MHz,Chloroform)δ 7.52(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).

[0418] Example 139. N-((S)-1-(((S)-4-(tert-butylamino)-3,4-dione-1-((S)-2-oxopyrrolidine-3-yl)buto-2-yl)amino)-1-oxo-3-phenylprop-2-yl)benzene[d][1,3]dioxol-5-carboxamide (A139)

[0419] 1 H NMR(500MHz,Chloroform)δ 7.48(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),4.7 1(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).

[0420] Example 140. N-((S)-1-(((S)-4-(cyclohexylamino)-3,4-dione-1-((S)-2-oxopyrrolidine-3-yl)buto-2-yl)amino)-1-oxo-3-phenylprop-2-yl)benzene[d][1,3]dioxol-5-carboxamide (A140)

[0421] 1H NMR(500MHz,Chloroform)δ 7.30(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).

[0422] Example 141. N-((S)-1-(((S)-4-(benzylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-1-oxo-3-phenylprop-2-yl)benzene[d][1,3]dioxol-5-carboxamide (A141)

[0423] 1 H NMR(500MHz,Chloroform)δ 7.41(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,1 H),2.09-2.03(m,2H),1.79(d,J=5.2Hz,2H),1.73(s,1H),1.57(s,1H).

[0424] Example 142. N-((S)-1-(((S)-4-(tert-butylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-1-oxo-3-phenylprop-2-yl)benzene[d][1,3]dioxol-5-carboxamide (A142)

[0425] 1 H NMR(500MHz,Chloroform)δ 8.38(s,28H),7.44(s,29H),7.30-7.23(m,86H),7.23-7.15(m,82H),7.15(d,J=1.8 Hz,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).

[0426] Example 143. N-((S)-1-(((S)-4-(cyclohexylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-1-oxo-3-phenylprop-2-yl)benzene[d][1,3]dioxol-5-carboxamide (A143)

[0427] 1H NMR(500MHz,Chloroform)δ 8.29(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).

[0428] Example 144. N-((S)-1-(((S)-4-(cyclohexylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-1-oxo-3-phenylprop-2-yl)benzene[d][1,3]dioxol-5-carboxamide (A144)

[0429] 1 H NMR(500MHz,Chloroform)δ 8.29(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).

[0430] Example 145. N-((S)-1-(((S)-4-(tert-butylamino)-3,4-dione-1-((S)-2-oxopyrrolidine-3-yl)buto-2-yl)amino)-1-oxo-3-phenylprop-2-yl)-5-fluoronicotinamide (A145)

[0431] 1 H NMR(500MHz,Chloroform)δ 8.60(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).

[0432] Example 146. N-((S)-1-(((S)-4-(cyclohexylamino)-3,4-dione-1-((S)-2-oxopyrrolidine-3-yl)buto-2-yl)amino)-1-oxo-3-phenylprop-2-yl)-5-fluoronicotinamide (A146)

[0433] 1 H NMR(500MHz,Chloroform)δ 8.82(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,2 H),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).

[0434] Example 147. N-((S)-1-(((S)-4-(benzylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-1-oxo-3-phenylprop-2-yl)-5-fluoronicotinamide (A147)

[0435] 1 H NMR(500MHz,Chloroform)δ 8.80(s,1H),8.58(s,1H),7.99(s,1H),7.41-7.32(m,2H),7.32-7.18(m,6H),7.1 6(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).

[0436] Example 148. N-((S)-1-(((S)-4-(tert-butylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-1-oxo-3-phenylprop-2-yl)-5-fluoronicotinamide (A148)

[0437] 1 H NMR(500MHz,Chloroform)δ 8.82(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),3.3 6(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).

[0438] Example 149. N-((S)-1-(((S)-4-(cyclohexylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-1-oxo-3-phenylprop-2-yl)-5-fluoronicotinamide (A149)

[0439] 1 H NMR(500MHz,Chloroform)δ 8.86(s,7H),8.52(s,7H),7.93(s,7H),7.42(s,7H),7.24-7.19(m,14H),7.14(s,7H),7.1 2-7.04(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).

[0440] Example 150. N-((S)-1-(((S)-4-(benzylamino)-3,4-dione-1-((S)-2-oxopyrrolidine-3-yl)buto-2-yl)amino)-1-oxo-3-phenylprop-2-yl)-1-methyl-1H-pyrazole-4-carboxamide (A150)

[0441] 1H NMR(500MHz,Chloroform)δ 7.52(s,5H),7.32-7.14(m,55H),7.13(t,J=1.5Hz,1H),7.07(s,5H),6.0 9(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).

[0442] Example 151. N-((S)-1-(((S)-4-(tert-butylamino)-3,4-dione-1-((S)-2-oxopyrrolidine-3-yl)buto-2-yl)amino)-1-oxo-3-phenylprop-2-yl)-1-methyl-1H-pyrazole-4-carboxamide (A151)

[0443] 1 H NMR(500MHz,Chloroform)δ 7.86(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=18.2H z,2H),2.17(s,1H),2.13-2.02(m,2H),1.92(s,1H),1.34-1.30(m,9H).

[0444] Example 152. N-((S)-1-(((S)-4-(cyclohexylamino)-3,4-dione-1-((S)-2-oxopyrrolidine-3-yl)buto-2-yl)amino)-1-oxo-3-phenylprop-2-yl)-1-methyl-1H-pyrazole-4-carboxamide (A152)

[0445] 1 1H NMR (500MHz, Chloroform) δ 7.28-7.17(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,1 H),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).

[0446] Example 153. N-((S)-1-(((S)-4-(benzylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-1-oxo-3-phenylprop-2-yl)-1-methyl-1H-pyrazole-4-carboxamide (A153)

[0447] 1 H NMR(500MHz,Chloroform)δ 8.58(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).

[0448] Example 154. N-((S)-1-(((S)-4-(tert-butylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-1-oxo-3-phenylprop-2-yl)-1-methyl-1H-pyrazole-4-carboxamide (A154)

[0449] 1 H NMR(500MHz,Chloroform)δ 9.02(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),3.90-3.8 6(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).

[0450] Example 155. N-((S)-1-(((S)-4-(cyclohexylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-1-oxo-3-phenylprop-2-yl)-1-methyl-1H-pyrazole-4-carboxamide (A155)

[0451] 1H NMR(500MHz,Chloroform)δ 8.38(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).

[0452] Example 156. N-((S)-1-(((S)-4-(benzylamino)-3,4-dione-1-((S)-2-oxopyrrolidine-3-yl)buto-2-yl)amino)-1-oxo-3-phenylprop-2-yl)-6-bromoimidazo[1,2-a]pyridine-2-carboxamide (A156)

[0453] 1 H NMR(500MHz,Chloroform)δ 8.45(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),4.7 7(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).

[0454] Example 157. N-((S)-1-(((S)-4-(tert-butylamino)-3,4-dione-1-((S)-2-oxopyrrolidine-3-yl)buto-2-yl)amino)-1-oxo-3-phenylprop-2-yl)-6-bromoimidazo[1,2-a]pyridine-2-carboxamide (A157)

[0455] 1 H NMR(500MHz,Chloroform)δ 8.80(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).

[0456] Example 158. N-((S)-1-(((S)-4-(benzylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-1-oxo-3-phenylprop-2-yl)-6-bromoimidazo[1,2-a]pyridine-2-carboxamide (A158)

[0457] 1 1H NMR (500MHz, Chloroform) δ 8.39(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).

[0458] Example 159. N-((S)-1-(((S)-4-(tert-butylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-1-oxo-3-phenylprop-2-yl)-6-bromoimidazo[1,2-a]pyridine-2-carboxamide (A159)

[0459] 1 H NMR(500MHz,Chloroform)δ 8.41(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).

[0460] Example 160. N-((S)-1-(((S)-4-(cyclohexylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-1-oxo-3-phenylprop-2-yl)-6-bromoimidazo[1,2-a]pyridine-2-carboxamide (A160)

[0461] 1H NMR(500MHz,Chloroform)δ 9.87(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).

[0462] Example 161. N-((S)-1-(((S)-4-(phenylamino)-3,4-dione-1-((S)-2-oxopyrrolidine-3-yl)buto-2-yl)amino)-1-oxo-3-phenylprop-2-yl)-1H-benzo[d]imidazole-2-carboxamide (A161)

[0463] 1 H NMR(500MHz,Chloroform)δ 7.62(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).

[0464] Example 162. N-((S)-1-(((S)-4-(tert-butylamino)-3,4-dione-1-((S)-2-oxopyrrolidine-3-yl)buto-2-yl)amino)-1-oxo-3-phenylprop-2-yl)-1H-benzo[d]imidazole-2-carboxamide (A162)

[0465] 1 H NMR(500MHz,Chloroform)δ 7.68(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),4.9 8(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).

[0466] Example 163. N-((S)-1-(((S)-4-(cyclohexylamino)-3,4-dione-1-((S)-2-oxopyrrolidine-3-yl)buto-2-yl)amino)-1-oxo-3-phenylprop-2-yl)-1H-benzo[d]imidazole-2-carboxamide (A163)

[0467] 1H NMR(500MHz,Chloroform)δ 7.70(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).

[0468] Example 164. N-((S)-1-(((S)-4-(phenylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-1-oxo-3-phenylprop-2-yl)-1H-benzo[d]imidazole-2-carboxamide (A164)

[0469] 1 1H NMR (500MHz, Chloroform) δ 7.73(s,1H),7.67(s,1H),7.38(t,J=17.9Hz,3H),7.27-7.13(m,9H),7.11(s,1 H),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).

[0470] Example 165. N-((S)-1-(((S)-4-(tert-butylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-1-oxo-3-phenylprop-2-yl)-1H-benzo[d]imidazole-2-carboxamide (A165)

[0471] 1 1H NMR (500MHz, Chloroform) δ 9.34(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,4 H),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).

[0472] Example 166. N-((S)-1-(((S)-4-(cyclohexylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-1-oxo-3-phenylprop-2-yl)-1H-benzo[d]imidazole-2-carboxamide (A166)

[0473] 1H NMR(500MHz,Chloroform)δ 8.45(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).

[0474] Example 167. N-((S)-1-(((S)-4-(benzylamino)-3,4-dione-1-((S)-2-oxopyrrolidine-3-yl)buto-2-yl)amino)-1-oxo-3-phenylprop-2-yl)-1H-indole-5-carboxamide (A167)

[0475] 1 H NMR(500MHz,Chloroform)δ 9.78(s,1H),8.99(s,1H),8.23(s,1H),7.81(s,1H),7.49(d,J=90.0Hz,2H),7.40-7.3 8(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).

[0476] Example 168. N-((S)-1-(((S)-4-(tert-butylamino)-3,4-dione-1-((S)-2-oxopyrrolidine-3-yl)buto-2-yl)amino)-1-oxo-3-phenylprop-2-yl)-1H-indole-5-carboxamide (A168)

[0477] 1 H NMR(500MHz,Chloroform)δ 8.95(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,1 H),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).

[0478] Example 169. N-((S)-1-(((S)-4-(cyclohexylamino)-3,4-dione-1-((S)-2-oxopyrrolidine-3-yl)buto-2-yl)amino)-1-oxo-3-phenylprop-2-yl)-1H-indole-5-carboxamide (A169)

[0479] 1H NMR(500MHz,Chloroform)δ 8.98(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,14 H),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,7 H),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).

[0480] Example 170. N-((S)-1-(((S)-4-(benzylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-1-oxo-3-phenylprop-2-yl)-1H-indole-5-carboxamide (A170)

[0481] 1 H NMR(500MHz,Chloroform)δ 8.99(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),2.8 7-2.77(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).

[0482] Example 171. N-((S)-1-(((S)-4-(tert-butylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-1-oxo-3-phenylprop-2-yl)-1H-indole-5-carboxamide (A171)

[0483] 1 H NMR(500MHz,Chloroform)δ 8.99(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).

[0484] Example 172. N-((S)-1-(((S)-4-(cyclohexylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-1-oxo-3-phenylprop-2-yl)-1H-indole-5-carboxamide (A172)

[0485] 1H NMR(500MHz,Chloroform)δ 8.99(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).

[0486] Example 173. N-((S)-1-(((S)-4-(benzylamino)-3,4-dione-1-((S)-2-oxopyrrolidine-3-yl)buto-2-yl)amino)-1-oxo-3-phenylprop-2-yl)-5-fluoro-1H-indole-2-carboxamide (A173)

[0487] 1 H NMR(500MHz,Chloroform)δ 8.75(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).

[0488] Example 174. N-((S)-1-(((S)-4-(tert-butylamino)-3,4-dione-1-((S)-2-oxopyrrolidine-3-yl)buto-2-yl)amino)-1-oxo-3-phenylprop-2-yl)-5-fluoro-1H-indole-2-carboxamide (A174)

[0489] 1 H NMR(500MHz,Chloroform)δ 8.73(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).

[0490] Example 175. N-((S)-1-(((S)-4-(cyclohexylamino)-3,4-dione-1-((S)-2-oxopyrrolidine-3-yl)buto-2-yl)amino)-1-oxo-3-phenylprop-2-yl)-5-fluoro-1H-indole-2-carboxamide (A175)

[0491] 1 H NMR(500MHz,Chloroform)δ 8.74(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),2.0 2(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).

[0492] Example 176. N-((S)-1-(((S)-4-(benzylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-1-oxo-3-phenylprop-2-yl)-5-fluoro-1H-indole-2-carboxamide (A176)

[0493] 1 1H NMR (500MHz, Chloroform) δ 8.71(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,1 H),2.41(s,1H),2.28(s,1H),2.01(s,1H),1.91(d,J=4.5Hz,2H),1.53(s,1H).

[0494] Example 177. N-((S)-1-(((S)-4-(tert-butylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-1-oxo-3-phenylprop-2-yl)-5-fluoro-1H-indole-2-carboxamide (A177)

[0495] 11H NMR (500MHz, Chloroform) δ 8.68(s,1H),8.29(s,1H),7.54(d,J=25.0Hz,2H),7.49(s,3H),7.24(s,1H),7.1 7(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).

[0496] Example 178. N-((S)-1-(((S)-4-(cyclohexylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-1-oxo-3-phenylprop-2-yl)-5-fluoro-1H-indole-2-carboxamide (A178)

[0497] 1 H NMR(500MHz,Chloroform)δ 8.69(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=1 0.0Hz,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).

[0498] Example 179. N-((S)-1-(((S)-4-(benzylamino)-3,4-dione-1-((S)-2-oxopyrrolidine-3-yl)buto-2-yl)amino)-1-oxo-3-phenylprop-2-yl)-6-fluoro-1H-indole-2-carboxamide (A179)

[0499] 1 H NMR(500MHz,Chloroform)δ 8.73(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),4.3 3(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).

[0500] Example 180. N-((S)-1-(((S)-4-(tert-butylamino)-3,4-dione-1-((S)-2-oxopyrrolidine-3-yl)buto-2-yl)amino)-1-oxo-3-phenylprop-2-yl)-6-fluoro-1H-indole-2-carboxamide (A180)

[0501] 1 H NMR(500MHz,Chloroform)δ 8.71(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),4.8 3(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).

[0502] Example 181. N-((S)-1-(((S)-4-(cyclohexylamino)-3,4-dione-1-((S)-2-oxopyrrolidine-3-yl)buto-2-yl)amino)-1-oxo-3-phenylprop-2-yl)-6-fluoro-1H-indole-2-carboxamide (A181)

[0503] 1 1H NMR (500MHz, Chloroform) δ 8.71(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,3 H),3.54(s,1H),3.29(s,3H),3.04(s,1H),2.58(s,1H),2.22(s,1H),2.02(s,2 H),1.93(s,1H),1.74(s,2H),1.46(t,J=12.5Hz,6H),1.21(s,3H),1.11(s,2H).

[0504] Example 182. N-((S)-1-(((S)-4-(cyclohexylamino)-3,4-dione-1-((S)-2-oxopyrrolidine-3-yl)buto-2-yl)amino)-1-oxo-3-phenylprop-2-yl)-6-fluoro-1H-indole-2-carboxamide (A182)

[0505] 1H NMR(500MHz,Chloroform)δ 8.68(s,2H),8.30(s,2H),7.96(s,2H),7.40(s,2H),7.28(t,J=11.5Hz,12H),7.1 5(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).

[0506] Example 183. N-((S)-1-(((S)-4-(tert-butylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-1-oxo-3-phenylprop-2-yl)-6-fluoro-1H-indole-2-carboxamide (A183)

[0507] 1 H NMR(500MHz,Chloroform)δ 8.68(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),2.1 3(s,1H),2.01(s,1H),1.90(d,J=13.5Hz,1H),1.53(s,1H),1.27(s,9H).

[0508] Example 184. N-((S)-1-(((S)-4-(cyclohexylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-1-oxo-3-phenylprop-2-yl)-6-fluoro-1H-indole-2-carboxamide (A184)

[0509] 1 H NMR(500MHz,Chloroform)δ 8.67(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).

[0510] Example 185. N-((S)-1-(((S)-4-(benzylamino)-3,4-dione-1-((S)-2-oxopyrrolidine-3-yl)buto-2-yl)amino)-3-(3-fluorophenyl)-1-oxoprop-2-yl)-4,6-dichloro-1H-indole-2-carboxamide (A185)

[0511] 1 1H NMR (500MHz, Chloroform) δ 8.92(s,2H),8.83(s,2H),7.84(s,2H),7.49(s,2H),7.33-7.26(m,11H),7.2 2(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).

[0512] Example 186. N-((S)-1-(((S)-4-(tert-butylamino)-3,4-dione-1-((S)-2-oxopyrrolidine-3-yl)buto-2-yl)amino)-3-(3-fluorophenyl)-1-oxoprop-2-yl)-4,6-dichloro-1H-indole-2-carboxamide (A186)

[0513] 1 H NMR(500MHz,Chloroform)δ 8.75(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).

[0514] Example 187. N-((S)-1-(((S)-4-(cyclohexylamino)-3,4-dione-1-((S)-2-oxopyrrolidine-3-yl)buto-2-yl)amino)-3-(3-fluorophenyl)-1-oxoprop-2-yl)-4,6-dichloro-1H-indole-2-carboxamide (A187)

[0515] 1 H NMR(500MHz,Chloroform)δ 8.79(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).

[0516] Example 188. N-((S)-1-(((S)-4-(cyclohexylamino)-3,4-dione-1-((S)-2-oxopyrrolidine-3-yl)buto-2-yl)amino)-3-(3-fluorophenyl)-1-oxoprop-2-yl)-4,6-dichloro-1H-indole-2-carboxamide (A188)

[0517] 1 H NMR(500MHz,Chloroform)δ 9.00(s,4H),8.91(s,4H),7.70(s,4H),7.49(d,J=3.7Hz,8H),7.29(dd,J=9.6,5.4H z,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).

[0518] Example 189. N-((S)-1-(((S)-4-(tert-butylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-3-(3-fluorophenyl)-1-oxoprop-2-yl)-4,6-dichloro-1H-indole-2-carboxamide (A189)

[0519] 11H NMR (500MHz, Chloroform) δ 8.57(s,1H),7.45(s,1H),7.32(d,J=18.3Hz,2H),7.20(d,J=6.7Hz,2H),7.0 4(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).

[0520] Example 190. N-((S)-1-(((S)-4-(cyclohexylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-3-(3-fluorophenyl)-1-oxoprop-2-yl)-4,6-dichloro-1H-indole-2-carboxamide (A190)

[0521] 1 H NMR(500MHz,Chloroform)δ 8.77(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),2.03-1.8 6(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).

[0522] Example 191. N-((S)-1-(((S)-4-(benzylamino)-3,4-dione-1-((S)-2-oxopyrrolidine-3-yl)buto-2-yl)amino)-1-oxo-3-phenylprop-2-yl)-5-methoxy-1H-indole-2-carboxamide (A191)

[0523] 1 H NMR(500MHz,Chloroform)δ 8.78(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).

[0524] Example 192. N-((S)-1-(((S)-4-(tert-butylamino)-3,4-dione-1-((S)-2-oxopyrrolidine-3-yl)buto-2-yl)amino)-1-oxo-3-phenylprop-2-yl)-5-methoxy-1H-indole-2-carboxamide (A192)

[0525] 1H NMR(500MHz,Chloroform)δ 8.78(s,1H),8.27(s,1H),7.75-7.37(m,3H),7.38(s,1H),7.38(s,1H),7.28(d,J=1 5.0Hz,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).

[0526] Example 193. N-((S)-1-(((S)-4-(cyclohexylamino)-3,4-dione-1-((S)-2-oxopyrrolidine-3-yl)buto-2-yl)amino)-1-oxo-3-phenylprop-2-yl)-5-methoxy-1H-indole-2-carboxamide (A193)

[0527] 1 H NMR(500MHz,Chloroform)δ 8.68(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).

[0528] Example 194. N-((S)-1-(((S)-4-(benzylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-1-oxo-3-phenylprop-2-yl)-5-methoxy-1H-indole-2-carboxamide (A194)

[0529] 1 1H NMR (500MHz, Chloroform) δ 8.66(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,2) H),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).

[0530] Example 195. N-((S)-1-(((S)-4-(tert-butylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-1-oxo-3-phenylprop-2-yl)-5-methoxy-1H-indole-2-carboxamide (A195)

[0531] 1H NMR(500MHz,Chloroform)δ 8.46(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).

[0532] Example 196. N-((S)-1-(((S)-4-(cyclohexylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-1-oxo-3-phenylprop-2-yl)-5-methoxy-1H-indole-2-carboxamide (A196)

[0533] 1 H NMR(500MHz,Chloroform)δ 8.61(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),3.2 1(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).

[0534] Example 197. N-((S)-1-(((S)-4-(benzylamino)-3,4-dione-1-((S)-2-oxopyrrolidine-3-yl)buto-2-yl)amino)-3-cyclopropyl-1-oxoprop-2-yl)-1H-indole-2-carboxamide (A197)

[0535] 1 1H NMR (500MHz, Chloroform) δ 8.60(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).

[0536] Example 198. N-((S)-1-(((S)-4-(tert-butylamino)-3,4-dione-1-((S)-2-oxopyrrolidine-3-yl)buto-2-yl)amino)-3-cyclopropyl-1-oxoprop-2-yl)-1H-indole-2-carboxamide (A198)

[0537] 1 H NMR(500MHz,Chloroform)δ 8.59(s,1H),7.98(s,1H),7.61(d,J=10.9Hz,2H),7.12(d,J=16.2Hz,2 H),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).

[0538] Example 199. N-((S)-1-(((S)-4-(cyclohexylamino)-3,4-dione-1-((S)-2-oxopyrrolidine-3-yl)buto-2-yl)amino)-3-cyclopropyl-1-oxoprop-2-yl)-1H-indole-2-carboxamide (A199)

[0539] 1 H NMR(500MHz,Chloroform)δ 8.65(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,2 H),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,3 H),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).

[0540] Example 200. N-((S)-1-(((S)-4-(benzylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-3-cyclopropyl-1-oxoprop-2-yl)-1H-indole-2-carboxamide (A200)

[0541] 1H NMR(500MHz,Chloroform)δ 8.62(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,3 H),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).

[0542] Example 201. N-((S)-1-(((S)-4-(benzylamino)-3,4-dione-1-((S)-2-oxopyrrolidine-3-yl)buto-2-yl)amino)-3-cyclobutyl-1-oxoprop-2-yl)-1H-indole-2-carboxamide (A201)

[0543] 1 H NMR(500MHz,Chloroform)δ 7.98(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),

[0544] Example 202. N-((S)-1-(((S)-4-(tert-butylamino)-3,4-dione-1-((S)-2-oxopyrrolidine-3-yl)buto-2-yl)amino)-3-cyclobutyl-1-oxoprop-2-yl)-1H-indole-2-carboxamide (A202)

[0545] 1 H NMR(500MHz,Chloroform)δ 7.98(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)

[0546] Example 203. N-((S)-1-(((S)-4-(cyclohexylamino)-3,4-dione-1-((S)-2-oxopyrrolidine-3-yl)buto-2-yl)amino)-3-cyclobutyl-1-oxoprop-2-yl)-1H-indole-2-carboxamide (A203)

[0547] 1 H NMR(500MHz,Chloroform)δ 7.98(s,1H),7.60(s,1H),7.10(s,1H),6.98(s,1H),4.95(s,1H),2.7 4(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)

[0548] Example 204. N-((S)-1-(((S)-4-(benzylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-3-cyclobutyl-1-oxoprop-2-yl)-1H-indole-2-carboxamide (A204)

[0549] 1H NMR(500MHz,Chloroform)δ 7.98(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=15.0 Hz,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).

[0550] Example 205. N-((S)-1-(((S)-4-(tert-butylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-3-cyclobutyl-1-oxoprop-2-yl)-1H-indole-2-carboxamide (A205)

[0551] 1 H NMR(500MHz,Chloroform)δ 8.62(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).

[0552] Example 206. N-((S)-1-(((S)-4-(cyclohexylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-3-cyclobutyl-1-oxoprop-2-yl)-1H-indole-2-carboxamide (A206)

[0553] 1 H NMR(500MHz,Chloroform)δ 8.62(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,3 H),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).

[0554] Example 207. N-((S)-1-(((S)-4-(benzylamino)-3,4-dione-1-((S)-2-oxopyrrolidine-3-yl)buto-2-yl)amino)-3-cyclopentyl-1-oxoprop-2-yl)-1H-indole-2-carboxamide (A207)

[0555] 1 1H NMR (500MHz, Chloroform) δ 8.57(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).

[0556] Example 208. N-((S)-1-(((S)-4-(tert-butylamino)-3,4-dione-1-((S)-2-oxopyrrolidine-3-yl)buto-2-yl)amino)-3-cyclopentyl-1-oxoprop-2-yl)-1H-indole-2-carboxamide (A208)

[0557] 1 H NMR(500MHz,Chloroform)δ 8.60(s,1H),7.98(s,1H),7.77(s,1H),7.60(s,1H),7.11(d,J=5.1Hz,82 H),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).

[0558] Example 209. N-((S)-1-(((S)-4-(cyclohexylamino)-3,4-dione-1-((S)-2-oxopyrrolidine-3-yl)buto-2-yl)amino)-3-cyclopentyl-1-oxoprop-2-yl)-1H-indole-2-carboxamide (A209)

[0559] 1H NMR(500MHz,Chloroform)δ 8.54(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).

[0560] Example 210. N-((S)-1-(((S)-4-(benzylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-3-cyclopentyl-1-oxoprop-2-yl)-1H-indole-2-carboxamide (A210)

[0561] 1 H NMR(500MHz,Chloroform)δ 8.51(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).

[0562] Example 211. N-((S)-1-(((S)-4-(tert-butylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-3-cyclopentyl-1-oxoprop-2-yl)-1H-indole-2-carboxamide (A211)

[0563] 1 H NMR(500MHz,Chloroform)δ 8.45(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).

[0564] Example 212. N-((S)-1-(((S)-4-(cyclohexylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-3-cyclopentyl-1-oxoprop-2-yl)-1H-indole-2-carboxamide (A212)

[0565] 1H NMR(500MHz,Chloroform)δ 8.45(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),6.4 4(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,1 H),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,3 H),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).

[0566] Example 213. N-((S)-1-(((S)-4-(benzylamino)-3,4-dione-1-((S)-2-oxopyrrolidine-3-yl)buto-2-yl)amino)-3-cyclohexyl-1-oxoprop-2-yl)-2,2-difluorobenzo[d][1,3]dioxol-5-carboxamide (A213)

[0567] 1 H NMR(500MHz,Chloroform)δ 7.97(s,1H),7.61(s,1H),7.49(s,1H),7.55-7.23(m,6H),7.55-6.98(m,8 H),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).

[0568] Example 214. N-((S)-1-(((S)-4-(tert-butylamino)-3,4-dione-1-((S)-2-oxopyrrolidine-3-yl)buto-2-yl)amino)-3-cyclohexyl-1-oxoprop-2-yl)-2,2-difluorobenzo[d][1,3]dioxol-5-carboxamide (A214)

[0569] 1 H NMR(500MHz,Chloroform)δ 7.73(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).

[0570] Example 215. N-((S)-1-(((S)-4-(cyclohexylamino)-3,4-dione-1-((S)-2-oxopyrrolidine-3-yl)buto-2-yl)amino)-3-cyclohexyl-1-oxoprop-2-yl)-2,2-difluorobenzo[d][1,3]dioxol-5-carboxamide (A215)

[0571] 1H NMR(500MHz,Chloroform)δ 7.55(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,2 H),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).

[0572] Example 216. N-((S)-1-(((S)-4-(benzylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-3-cyclohexyl-1-oxoprop-2-yl)-2,2-difluorobenzo[d][1,3]dioxol-5-carboxamide (A216)

[0573] 1 1H NMR (500MHz, Chloroform) δ 7.55(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),1.7 2(s,1H),1.58(s,1H),1.52(d,J=15.0Hz,2H),1.48-1.41(m,4H),1.34(s,1H).

[0574] Example 217. N-((S)-1-(((S)-4-(tert-butylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-3-cyclohexyl-1-oxoprop-2-yl)-2,2-difluorobenzo[d][1,3]dioxol-5-carboxamide (A217)

[0575] 1 1H NMR (500MHz, Chloroform) δ 7.61(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).

[0576] Example 218. N-((S)-1-(((S)-4-(cyclohexylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-3-cyclohexyl-1-oxoprop-2-yl)-2,2-difluorobenzo[d][1,3]dioxol-5-carboxamide (A218)

[0577] 1H NMR(500MHz,Chloroform)δ 7.58(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,3 H),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).

[0578] Example 219. N-((S)-1-(((S)-4-(cyclohexylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-3-cyclohexyl-1-oxoprop-2-yl)-2,2-difluorobenzo[d][1,3]dioxol-5-carboxamide (A219)

[0579] 1 H NMR(500MHz,Chloroform)δ 7.58(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,3 H),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).

[0580] Example 220. N-((S)-1-(((S)-4-(benzylamino)-3,4-dione-1-((S)-2-oxopyrrolidine-3-yl)buto-2-yl)amino)-1-oxo-3-phenylprop-2-yl)-4,6-dimethoxy-1H-indole-2-carboxamide (A220)

[0581] 1 H NMR(500MHz,Chloroform)δ 9.90(s,1H),8.66(s,1H),8.26(s,1H),7.77(s,1H),7.30(d,J=15.0Hz,5 H),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).

[0582] Example 221. N-((S)-1-(((S)-4-(tert-butylamino)-3,4-dione-1-((S)-2-oxopyrrolidine-3-yl)buto-2-yl)amino)-1-oxo-3-phenylprop-2-yl)-4,6-dimethoxy-1H-indole-2-carboxamide (A221)

[0583] 1 H NMR(500MHz,Chloroform)δ 8.60(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).

[0584] Example 222. N-((S)-1-(((S)-4-(cyclohexylamino)-3,4-dione-1-((S)-2-oxopyrrolidine-3-yl)buto-2-yl)amino)-1-oxo-3-phenylprop-2-yl)-4,6-dimethoxy-1H-indole-2-carboxamide (A222)

[0585] 1 H NMR(500MHz,Chloroform)δ 8.59(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).

[0586] Example 223. N-((S)-1-(((S)-4-(benzylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-1-oxo-3-phenylprop-2-yl)-4,6-dimethoxy-1H-indole-2-carboxamide (A223)

[0587] 1H NMR(500MHz,Chloroform)δ 8.65(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).

[0588] Example 224. N-((S)-1-(((S)-4-(tert-butylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-1-oxo-3-phenylprop-2-yl)-4,6-dimethoxy-1H-indole-2-carboxamide (A224)

[0589] 1 H NMR(500MHz,Chloroform)δ 8.80(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),3.2 9(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).

[0590] Example 225. N-((S)-1-(((S)-4-(cyclohexylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-1-oxo-3-phenylprop-2-yl)-4,6-dimethoxy-1H-indole-2-carboxamide (A225)

[0591] 1 H NMR(500MHz,Chloroform)δ 8.67(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).

[0592] Example 226. N-((S)-1-(((S)-4-(benzylamino)-3,4-dione-1-((S)-2-oxopyrrolidine-3-yl)buto-2-yl)amino)-3-(3,4-difluorophenyl)-1-oxoprop-2-yl)-1H-indole-2-carboxamide (A226)

[0593] 11H NMR (500MHz, Chloroform) δ 8.76(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).

[0594] Example 227. N-((S)-1-(((S)-4-(tert-butylamino)-3,4-dione-1-((S)-2-oxopyrrolidine-3-yl)buto-2-yl)amino)-3-(3,4-difluorophenyl)-1-oxoprop-2-yl)-1H-indole-2-carboxamide (A227)

[0595] 1 H NMR(500MHz,Chloroform)δ 8.72(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,1 H),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).

[0596] Example 228. N-((S)-1-(((S)-4-(cyclohexylamino)-3,4-dione-1-((S)-2-oxopyrrolidine-3-yl)buto-2-yl)amino)-3-(3,4-difluorophenyl)-1-oxoprop-2-yl)-1H-indole-2-carboxamide (A228)

[0597] 1 H NMR(500MHz,Chloroform)δ 8.69(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).

[0598] Example 229. N-((S)-1-(((S)-4-(benzylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-3-(3,4-difluorophenyl)-1-oxoprop-2-yl)-1H-indole-2-carboxamide (A229)

[0599] 1 H NMR(500MHz,Chloroform)δ 8.69(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).

[0600] Example 230. N-((S)-1-(((S)-4-(tert-butylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-3-(3,4-difluorophenyl)-1-oxoprop-2-yl)-1H-indole-2-carboxamide (A230)

[0601] 1 1H NMR (500MHz, Chloroform) δ 8.74(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).

[0602] Example 231. N-((S)-1-(((S)-4-(cyclohexylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-3-(3,4-difluorophenyl)-1-oxoprop-2-yl)-1H-indole-2-carboxamide (A231)

[0603] 1H NMR(500MHz,Chloroform)δ 8.72(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),3.2 1(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).

[0604] Example 232. N-((S)-1-(((S)-4-(benzyl)-3,4-dione-1-(isopropylamino)-2-yl)amino)-3-(cyclohexyl)-1-oxoprop-2-yl)-1H-indole-2-carboxamide (A232)

[0605] 1 H NMR(500MHz,Chloroform)δ 8.57(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).

[0606] Example 233. N-((S)-1-(((S)-4-(benzyl)-3,4-dione-1-(isopropylamino)-2-yl)amino)-3-(phenyl)-1-oxoprop-2-yl)-1H-indole-2-carboxamide (A233)

[0607] 1 H NMR(500MHz,Chloroform)δ 8.85(s,1H),8.41(s,1H),7.98(s,1H),7.60(s,1H),7.29(d,J=15.0Hz,5 H),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).

[0608] Example 234. N-((S)-1-(((S)-4-(cyclohexyl)-3,4-dione-1-(isopropylamino)-2-yl)amino)-3-(phenyl)-1-oxoprop-2-yl)-1H-indole-2-carboxamide (A234)

[0609] 1 H NMR(500MHz,Chloroform)δ 8.73(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=20.0H z,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,1 H),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).

[0610] Example 235. N-((S)-1-(((S)-4-(cyclohexyl)-3,4-dione-1-(cyclohexylamino)-2-yl)amino)-3-(phenyl)-1-oxoprop-2-yl)-1H-indole-2-carboxamide (A235)

[0611] 1 H NMR(500MHz,Chloroform)δ 8.73(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,5 H),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=1 0.0Hz,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).

[0612] Example 236. N-((S)-1-(((S)-4-(benzyl)-3,4-dione-1-(isopropylamino)-2-yl)amino)-3-(cyclohexyl)-1-oxoprop-2-yl)-quinoxaline-2-carboxamide (A236)

[0613] 1H NMR(500MHz,Chloroform)δ 9.45(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).

[0614] Example 237. N-((S)-1-(((S)-4-(cyclohexyl)-3,4-dione-1-(isopropylamino)-2-yl)amino)-3-(cyclohexyl)-1-oxoprop-2-yl)-quinoxaline-2-carboxamide (A237)

[0615] 1 H NMR(500MHz,Chloroform)δ 9.32(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).

[0616] Example 238. N-((S)-1-(((S)-4-(benzyl)-3,4-dione-1-(isopropylamino)-2-yl)amino)-3-(phenyl)-1-oxoprop-2-yl)-quinoxaline-2-carboxamide (A238)

[0617] 1 1H NMR (500MHz, Chloroform) δ 9.34(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).

[0618] Example 239. N-((S)-1-(((S)-4-(benzyl)-3,4-dione-1-(cyclohexylamino)-2-yl)amino)-3-(phenyl)-1-oxoprop-2-yl)-quinoxaline-2-carboxamide (A239)

[0619] 1 H NMR(500MHz,Chloroform)δ 9.31(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),4.3 6(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).

[0620] Example 240. N-((S)-1-(((S)-4-(benzylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-3-cyclohexyl-1-oxoprop-2-yl)-1H-indole-6-fluoro-2-carboxamide (A240)

[0621] 1 H NMR(500MHz,Chloroform)δ 8.12(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).

[0622] Example 241. N-((S)-1-(((S)-4-(benzylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-3-cyclohexyl-1-oxoprop-2-yl)-5-methyloxazole-2-carboxamide (A241)

[0623] 1H NMR(500MHz,Chloroform)δ 7.33-7.27(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),1.8 5(s,1H),1.79(s,1H),1.74-1.55(m,11H),1.48(s,1H),1.46-1.23(m,3H).

[0624] Example 242. N-((S)-1-(((S)-4-(benzylamino)-3,4-dione-1-((S)-2-oxopyrrolidine-3-yl)buto-2-yl)amino)-3-cyclohexyl-1-oxoprop-2-yl)-5-methyloxazole-2-carboxamide (A242)

[0625] 1 H NMR(500MHz,Chloroform)δ 7.33-7.30(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,3 H),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).

[0626] Example 243. N-((S)-1-(((S)-4-(benzylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-3-cyclohexyl-1-oxoprop-2-yl)-benzo[d]1,3-dioxol-5-carboxamide (A243)

[0627] 1 H NMR(500MHz,Chloroform)δ 7.54(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).

[0628] Example 244. N-((S)-1-(((S)-4-(benzylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-3-cyclohexyl-1-oxoprop-2-yl)-1H-benzo[d]imidazole-2-carboxamide (A244)

[0629] 1H NMR(500MHz,Chloroform)δ 7.84(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).

[0630] Example 245. N-((S)-1-(((S)-4-(benzylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-3-cyclohexyl-1-oxoprop-2-yl)-7-methoxy-benzofuran-2-carboxamide (A245)

[0631] 1 H NMR(500MHz,Chloroform)δ 7.60(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).

[0632] Example 246. N-((S)-1-(((S)-4-(benzylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-3-cyclohexyl-1-oxoprop-2-yl)-3-methyl-benzofuran-2-carboxamide (A246)

[0633] 1 H NMR(500MHz,Chloroform)δ 7.60-7.40(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),1.7 3-1.59(m,5H),1.55(s,1H),1.40-1.36(m,2H),1.32(s,1H),1.14-1.05(m,3H).

[0634] Example 247. N-((S)-1-(((S)-4-(benzylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-3-cyclohexyl-1-oxoprop-2-yl)-3,5-dimethyl-benzofuran-2-carboxamide (A247)

[0635] 1H NMR(500MHz,Chloroform)δ 7.50-7.34(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),2.7 3(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).

[0636] Example 248. N-((S)-1-(((S)-4-(benzylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-3-cyclohexyl-1-oxoprop-2-yl)-4,7-dimethoxy-benzofuran-2-carboxamide (A248)

[0637] 1 H NMR(500MHz,Chloroform)δ 7.59(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).

[0638] Example 249. N-((S)-1-(((S)-4-(benzylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-3-cyclohexyl-1-oxoprop-2-yl)-benzofuran-3-carboxamide (A249)

[0639] 1 H NMR(500MHz,Chloroform)δ 8.07(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).

[0640] Example 250. N-((S)-1-(((S)-4-(benzylamino)-3,4-dione-1-((S)-2-oxopiperidine-3-yl)buto-2-yl)amino)-3-cyclohexyl-1-oxoprop-2-yl)-6-chloro-2H-chromen-3-carboxamide (A250)

[0641] 1H NMR(500MHz,Chloroform)δ 8.16(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).

[0642] Example 251. N-((S)-1-(((S)-4-(cyclohexylamino)-3,4-dione-1-((S)-2-oxopyrrolidine-3-yl)buto-2-yl)amino)-3-cyclohexyl-1-oxoprop-2-yl)-6-chloro2,3-dihydrobenzo[b]1,4-dioxin-6-carboxamide (A251)

[0643] 1 H NMR(500MHz,Chloroform)δ 8.51(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).

[0644] Example 252. N-((S)-1-(((S)-4-(cyclohexylamino)-3,4-dione-1-((S)-2-oxopyrrolidine-3-yl)buto-2-yl)amino)-3-phenyl-1-oxoprop-2-yl)-6-chloro2,3-dihydrobenzo[b]1,4-dioxin-6-carboxamide (A252)

[0645] 1 H NMR(500MHz,Chloroform)δ 9.01(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),6.9 2(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).

[0646] Example 253. N-((S)-1-(((S)-4-(cyclohexylamino)-3,4-dione-1-((S)-2-oxopyrrolidine-3-yl)buto-2-yl)amino)-3-cyclohexyl-1-oxoprop-2-yl)-5-methoxyindole-6-carboxamide (A253)

[0647] 1H NMR(500MHz,Chloroform)δ 8.73(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).

[0648] Pharmacological activity testing 1.1. Packaging of fake viruses The packaging method for the MERS-CoV pseudovirus is as follows: a) 24 hours before transfection, digest the 293T cells and place them in a 10 cm tissue culture dish (2 × 10⁶). 6 Plate it on a dish. b) Two hours before transfection, replace the cells with fresh preheated DMEM medium (containing 10% FBS), c) During transfection, use two 1.5 mL EP tubes. Add 500 μL of 0.9% NaCl solution to EP tube 1, which contains 20 μg of pcDNA3.1-S-IRES-GFP plasmid (or VSV-G expression plasmid) and 20 μg of pNL4-3.luc.RE plasmid. Add 500 μL of 0.9% NaCl solution to EP tube 2, then add 10 μL of vigofect transfection reagent, and let each stand for 5 minutes.

[0649] d) Add 500 μL of the solution in EP tube 2 to EP tube 1, one drop at a time, mixing with a pipette as you add, and let it stand at room temperature for 15 minutes. e) Add the above 1 mL of the mixture drop by drop to the plated 293T cell culture dish, ensuring even distribution. f) 8-10 hours after transfection, replace with 10 mL of fresh DMEM culture medium containing 10% FBS. g) After 48 hours, collect the supernatant containing the pseudovirus. h) Centrifuge at 4000 rpm for 4 minutes to remove cell debris, filter through a 0.45 μm sterile filter, package each separately for later use, and store at -80°C.

[0650] 1.2. Detection of false viral titers a) In pseudovirus infection experiments with MERS-CoV, HCoV-229E, and VSV-G, Huh-7 was used as the target cell. Twelve hours before the infection experiment, the target cells were digested to adjust the cell concentration and plated in a 96-well cell plate (10,000 cells per well). As a precaution, the cells were cultured at 37°C in 5% CO2 for 12 hours. b) Dilute the pseudovirus with a 5-fold gradient in a round-bottom 96-well plate (the system volume is 100 μL);

[0651] c) After discarding the culture supernatant of the target cells in the 96-well plate, add the virus diluent (100 μL). d) After 12 hours of incubation, replace with 100 μL of fresh DMEM medium (containing 10% FBS). e) After 48 hours of culture, discard the supernatant and wash the cells twice with PBS, gently moving them to avoid cell detachment, to remove as much PBS as possible.

[0652] f) Add 50 μL of pre-diluted lysate (dilute 5× cell lysate to 1× concentration using ddH2O). Then, place in a vortex mixer and shake to mix until the cells are completely lysated (1-2 hours is sufficient). g) Transfer 30 μL of lysate to a 96-well opaque white microplate, taking care when changing pipettes. h) After adding 50 μL of firefly enzyme detection reagent to each well, quickly use a functional microplate reader to detect the fluorescence value. Typical values ​​are 1000-fold virus dilution of the blank control selected for the pseudovirus inhibition experiment.

[0653] 1.3. Inhibition experiments of pseudoviruses a) Dilute the compound (50 μL system) 2-fold in a 96-well plate using DMEM, taking care to avoid compound precipitation. b) Add 50 μL of pseudovirus at a constant dilution to each well, add DMEM (50 μL) to the blank control well, mix the virus and compound, and incubate at 37°C for 30 minutes. c) Remove the supernatant from the target cells and add the compound / virus mixture (100 μL) to the corresponding target cells. The liquid is replaced after 12 hours, and the fluorescence value is detected after another 48 hours. The experimental results are shown in Table 2.

[0654] [Table 2]

[0655] 2.1 Inhibitory effect of HCoV live virus infection in vitro Currently, we possess live HCoV-OC43 (ATCC-VR1558) virus and constructed an in vitro infection system according to the virus culture conditions provided by ATCC. In this system, we detected the inhibitory effect of compound A13 on HCoV-OC43 live virus infection. In HCT-8 cells infected with HCoV-OC43, numerous vacuoles and other cytopathic phenomena (CPE) occur. However, in the presence of compound A13 (1 μm), viral infection and the resulting CPE (as shown in Figure 1A) can be effectively blocked, and its protective effect on target cells is clearly dose-dependent (as shown in Figure 1B). Using the CCK8 method, we detected the inhibitory effect of compound A13 on HCoV-OC43 live virus infection, and as a result, as shown in Figure 1C, its inhibitory activity was at the low nanomolar level (IC). 50 = 86nM)

[0656] Specifically, Figure 1A shows that compound A13 has an excellent inhibitory effect against HCoV-OC43 infection under low concentration (1 μm) conditions, Figure 1B shows that the antiviral activity of compound A13 is clearly dose-dependent, and Figure 1C shows the specific antiviral activity of compound A13, specifically its semiinhibitory activity (IC). 50 ) is at a low nanomolar level (IC 50 = 86nM)

[0657] 2.2. Broad-spectrum evaluation of the antiviral properties of compound A13 HCoV-229E was selected as the surface of α-type human coronavirus, and MERS-CoV and SARS-CoV were selected as the surface of β-type human coronavirus. In pseudoviruses of these three types of HCoVs, A13 showed effective antiviral activity in all of them, achieving nearly 90% viral inhibition at a concentration of 100 nM. However, in a pseudovirus infection system mediated by the control VSV-G, compound A13 did not show effective inhibitory activity (as shown in Figure 2A). Furthermore, in a system targeting Huh-7 cells, compound A13 exhibited poor cellular properties and its CC50 The particle size exceeds 100 μm (which is more than 1000 times the detection dose, as shown in Figure 2B).

[0658] 2.3. Initial evaluation of the protective activity of compound A13 in vivo To initially evaluate the stability and antiviral activity of compound A13 in vivo, Balb / c mouse models were intraperitoneally administered either the compound or 100 μL of DMSO (100 mg / kg). Blood samples were then collected at 2, 12, and 24 hours after administration, and serum was isolated to detect anti-MERS-CoV pseudoviral activity. The results showed that serum at 2 and 12 hours after administration exhibited high viral inhibitory activity, 24-fold and 15-fold, respectively, compared to DMSO-background serum, while the inhibitory activity of serum at 24 hours after administration was similar to that of DMSO-background serum. These results, as shown in Figure 3, indicate that compound A13 has superior stability and antiviral activity in vivo, and that the compound has a superior half-life in vivo.

[0659] Specifically, Figure 3D shows that in the Balb / c mouse model, compound A13 (100 mg / kg) was administered intraperitoneally, resulting in superior stability and antiviral activity in vivo. The median effect concentration (EC2) of isolated serum was measured at 2 and 12 hours after administration. 50 These correspond to serum dilutions of 3181 and 1133, respectively, and the corresponding EC levels in the DMSO control group. 50 It was much higher.

[0660] 2.4. Initial Safety Assessment of Compound A13 in Vivo Next, the safety of compound A13 in vivo in mice was further evaluated. Mice in the drug group (100 mg / kg) and the DMSO control group were administered via the intraperitoneal route once daily for 7 consecutive days, and the growth status and weight changes of the mice in each group were observed. As shown in Figure 4, there was no difference in weight changes between the drug group mice and the PBS group mice during the administration period, indicating that compound A13 has superior safety in vivo.

[0661] 3.1. Pharmacokinetic studies of a series of compounds in rats Administration scheme Nine CD-1 mice weighing 18-22g were randomly divided into three groups, with three mice in each group. The test compound was administered via gastric tube, intravenous, and intraperitoneal administration, respectively, according to the following scheme. Before the test, the subjects fasted for 12 hours and were allowed to drink water freely. Two hours after administration, they were all given a meal together. Experimental grouping, blood collection timing, and sample processing. Three animals were selected at each point in time, and the grouping and blood sampling times are shown in Table 3 below.

[0662] [Table 3]

[0663] The solution for nasogastric tube administration was prescribed as DMSO / 0.5% HPMC (5 / 95, v / v) up to the final concentration. For intravenous and intraperitoneal administration, it was prescribed as DMSO / PEG300 / EtOH / NaCl (5 / 40 / 5 / 50, v / v / v). Samples of the administration solution were tested (50 μL of the drug solution mixed with 50 μL of DMSO before and after administration). The above dosage was administered, the administration time was recorded, and 20 μL of blood was collected from the femoral plexus of the mouse at the above-specified time and placed in a heparinized test tube. It was immediately centrifuged at 11000 rpm for 5 minutes. Immediately, 10 μL of plasma was accurately aspirated into a pre-filled centrifuge tube containing 100 μL of PK-IS solution (prepared with methanol:acetonitrile (1:1, v / v)), mixed, and frozen at -20°C for testing.

[0664] Pharmacokinetic studies were conducted on compounds A9, A13, A42, A241, and A242. The oral exposure for compound A9 was 584 h*ng / mL, and the intraperitoneal exposure was 8191 h*ng / mL (as shown in Table 4). For compound A13, the oral exposure was 463 h*ng / mL with a bioavailability of 7.99%, and the intraperitoneal exposure was 7298 h*ng / mL with a bioavailability of 126% (as shown in Table 5). For A42, the oral exposure was 742 h*ng / mL, and the intraperitoneal exposure was 5491 h*ng / mL (as shown in Table 6). The gastric tube exposure to compound A241 was 663 h*ng / mL, and the exposure via intraperitoneal injection was 4163 h*ng / mL (as shown in Table 7). The oral exposure to compound A242 was 488 h*ng / mL, and the exposure via intraperitoneal injection was 6890 h*ng / mL (as shown in Table 8).

[0665] [Table 4]

[0666] [Table 5]

[0667] [Table 6]

[0668] [Table 7]

[0669] [Table 8]

[0670] All documents referenced in this invention are cited as references in this application, as if each document were cited individually. Furthermore, after reading the above teachings of this invention, those skilled in the art should understand that various changes or modifications can be made to the invention, and that these equivalent forms are also covered by the patents appended to this application.

Claims

1. A ketoamide compound represented by formula A, or a racemic mixture thereof, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, Formula A: 【Chemistry 1】 The compound of formula A is the compound shown in formula AA, Formula AA: 【Chemistry 2】 Here, * indicates that the stereochemical heterogeneity of each carbon atom can be either R or S independently. R １ This is selected from the group consisting of hydrogen, deuterium, and tritium; R ２ This is selected from the group consisting of unsubstituted C1-C4 alkyl groups, unsubstituted C3-C6 cycloalkyl groups, and unsubstituted C6 aryl-C1 alkylene groups; R ３ This is selected from the group consisting of unsubstituted C3-C6 cycloalkyl-C1 alkylene groups and unsubstituted C6 aryl-C1 alkylene groups; R ４ is a 9-10 membered heteroaromatic ring containing one, two, or three heteroatoms selected from N, O, and S; where the 9-10 membered heteroaromatic ring containing one, two, or three heteroatoms selected from N, O, and S is substituted or unsubstituted; -NHR ５ is adjacent to -(C=O)-CH ２ - to form a ring, R ５ is -(CH ２ ) ｎ - and n is 2 or 3; - NHR ５ Adjacent to -(C=O)-CH ２ - If a ring is not formed, R ５ This is selected from the group consisting of hydrogen, deuterium, tritium, substituted or unsubstituted C1-C6 alkyl groups, and substituted or unsubstituted C3-C8 cycloalkyl groups; Here R ４ and R ５ In this, the substitution is characterized by being independently substituted by one, two, three, or four substituents selected from the group consisting of halogens, hydroxyl groups, sulfhydryl groups, nitro groups, cyano groups, amine groups, imino groups, tertiary amine groups, azide groups, C1-C8 alkyl groups, halogenated C1-C8 alkyl groups, C1-C8 alkoxy groups, halogenated C1-C8 alkoxy groups, C1-C6 alkylcarbonyl groups, C1-C6 alkylthio groups, C1-C8 alkoxycarbonyl groups, and trifluoromethyl groups. The ketoamide compound, or a racemic mixture thereof, an enantiomer, a diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt or solvate thereof.

2. R ４ is a 9-10 membered heteroaromatic ring containing one, two, or three heteroatoms selected from N, O, and S; the 9-10 membered heteroaromatic ring containing one, two, or three heteroatoms selected from N, O, and S is substituted or unsubstituted; wherein substitution means that the hydrogen atoms on the group are substituted by one, two, three, or four substituents selected from the group consisting of halogens, hydroxyl groups, C1-C6 alkyl groups, halogenated C1-C6 alkyl groups, C1-C6 alkoxy groups, halogenated C1-C6 alkoxy groups, and C1-C6 alkylthio groups. A ketoamide compound as described in claim 1, or a racemic mixture thereof, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt or solvate thereof.

3. R ４ teeth, Substituted or unsubstituted quinoxalinyl group, substituted or unsubstituted quinazolinyl group, substituted or unsubstituted synnorinyl group, Substituted or unsubstituted indolyl groups, substituted or unsubstituted isoindyl groups, Substituted or unsubstituted 1,3-benzodioxolecyclopentadienyl group, Substituted or unsubstituted benzimidazolyl group, substituted or unsubstituted indazolyl group, Substituted or unsubstituted imidazole [1,2-A]pyridyl group, substituted or unsubstituted imidazole [1,5-A]pyridyl group, Substituted or unsubstituted 3,8a-dihydro-2H-benzopyranyl group, substituted or unsubstituted benzopyranyl group, Substituted or unsubstituted quinolinyl groups, substituted or unsubstituted isoquinolinyl groups, Substituted or unsubstituted benzoxazolyl group, substituted or unsubstituted benzothiazolyl group, Substituted or unsubstituted benzothienyl groups, and Selected from the group consisting of substituted or unsubstituted benzofuran groups; Here, the substitution refers to the substitution of a hydrogen atom on the group with one, two, or three substituents selected from the group consisting of F, Cl, Br, I, a hydroxyl group, a C1-C6 alkyl group, a halogenated C1-C6 alkyl group, a C1-C6 alkoxy group, a halogenated C1-C6 alkoxy group, and a C1-C6 alkylthio group. A ketoamide compound as described in claim 1, or a racemic mixture thereof, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt or solvate thereof.

4. - NHR ５ Adjacent to -(C=O)-CH ２ -When forming a ring, R ５ is, -(CH ２ ) ｎ - and n is 3; - NHR ５ Adjacent to -(C=O)-CH ２ - If a ring is not formed, R ５ This is selected from the group consisting of hydrogen, deuterium, tritium, substituted or unsubstituted C1-C6 alkyl groups, and substituted or unsubstituted C3-C6 cycloalkyl groups; Here, the substitution is characterized by being independently substituted by one, two, or three substituents selected from the group consisting of F, Cl, Br, I, a hydroxyl group, a C1-C6 alkyl group, a C1-C6 alkoxy group, and a C1-C6 alkylthio group. A ketoamide compound according to any one of claims 1 to 3, or a racemic mixture thereof, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt or solvate thereof.

5. The aforementioned compound, Table 1-1 Table 1-2 Table 1-3 Table 1-4 Table 1-5 Table 1-6 Table 1-7 Table 1-8 Table 1-9 Table 1-10 Table 1-11 Table 1-12 Table 1-13 Table 1-14 Table 1-15 Table 1-16 Table 1-17 Table 1-18 Table 1-19 Table 1-20 Table 1-21 Table 1-22 Table 1-23 Table 1-24 Table 1-25 Table 1-26 Characterized by being selected from the group consisting of, A ketoamide compound according to any one of claims 1 to 4, or a racemic mixture thereof, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt or solvate thereof.

6. A method for preparing a ketoamide compound according to any one of claims 1 to 5, or a racemic mixture thereof, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, 【Transformation 3】 Step (6): The process involves oxidizing compound VII with an oxidizing agent in an inert solvent to obtain compound VIII. In each of the above formulas, R １ , R ２ , R ３ , R ４ , R ５ , and n are as defined in claim 1, A method for preparing a ketoamide compound according to any one of claims 1 to 5, or a racemic mixture thereof, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt or solvate thereof.

7. A pharmaceutical composition, wherein the pharmaceutical composition is i) a therapeutically effective amount of one or more ketoamide compounds according to any one of claims 1 to 5, or a racemic mixture thereof, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt or solvate thereof; and ii) pharmaceutically acceptable carriers or excipients The pharmaceutical composition characterized by containing the following:

8. Ketoamide inhibitors, The ketoamide inhibitor is characterized by comprising one or more ketoamide compounds according to any one of claims 1 to 5, or a racemic mixture thereof, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

9. The use of a ketoamide compound according to any one of claims 1 to 5, or a racemic mixture thereof, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, The use is characterized by being used to prepare a pharmaceutical composition or formulation, wherein the pharmaceutical composition or formulation is used to treat or prevent a disease related to coronavirus.

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