Novel lufamycin analogs having activity against mycobacterium tuberculosis as CLPC1 protease modulators

Abstract

The present invention relates to novel rufamycin analogs that target the ClpC1 protease. The compounds of the present invention have antibacterial activity, e.g., with anti-tuberculosis properties, and are useful in the treatment of e.g. Tuberculosis.

Description

Technical Field

[0001] This invention generally relates to novel rufomycin analogues with antibacterial activity, such as those targeting the ClpC1 protease and possessing anti-tuberculosis properties. The compounds of this invention can be used to treat, for example, Mycobacterium tuberculosis.

[0002] All publications, patents, patent applications, and other references cited in this application are incorporated herein by reference in their entirety for all purposes, and to the same extent that each individual publication, patent, patent application, or other reference is specifically and individually indicated as incorporated herein by reference in its entirety for all purposes. References cited herein should not be construed as an admission that the cited references are prior art to this invention.

[0003] Cross-reference to related applications This application claims priority to U.S. Provisional Patent Application No. 63 / 527,925, filed July 20, 2023, the contents of which are hereby expressly incorporated herein by reference. Background Technology

[0004] Regulation of protein synthesis through transcriptional inhibition by the RNA polymerase (RNAP) inhibitor rifampicin or translational inhibition by the oxazolidinone ribosome inhibitor linezolid has been clinically validated to accelerate the killing of Mycobacterium tuberculosis (M. tb) and promote tissue sterilization (Lee et al., 2012; Steingart et al., 2011). Unfortunately, the efficacy of rifampicin (RIF) is limited by the emergence of RIF resistance, and prolonged use of linezolid is limited by adverse side effects. In recent years, the mycobacterial casein hydrolysate (ClpP) complex has been proposed as an exciting novel drug target because it plays a crucial role in bacterial viability and virulence both in vitro and in vivo (Bosch et al., 2021; Raju et al., 2014; Raju et al., 2012). Proteolysis is essential for the removal of dysfunctional or misfolded proteins and for maintaining protein homeostasis in bacteria. The ClpP proteolytic mechanism is highly conserved and consists of a barrel-shaped protease core and an AAA+ (an ATPase associated with various cellular activities) chaperone ring complex. ClpP proteolysis requires activation of the ATPase subunit ClpC1, which binds to the protein substrate, unfolds the substrate, and transports it to the proteolytic compartment of the ClpP1P2 subunit. The necessity of the Clp protease and ClpC1 chaperone for virulence and cell viability in Mycobacterium tuberculosis has been established (Carroll et al., 2011; Ollinger et al., 2012; Raju et al., 2012; Sassetti et al., 2003), and the identification of natural cyclic peptide ClpC1 inhibitors (Choules et al., 2019; Gao et al., 2015; Gavrish et al., 2014; Schmitt et al., 2011) classifies ClpC1 as a very promising drug target. Targeting protein homeostasis by interfering with the ClpC1 component of the ClpP protease may have multifactorial effects on bacterial viability during infection. First, ClpC1 inhibition may lead to direct toxicity due to the accumulation of cellular proteins and / or ATP uncoupling and ATP depletion. Additionally, inhibitors of Mycobacterium tuberculosis protein homeostasis may impair the bacteria's ability to respond to host-induced stress and enhance the efficacy of other antibiotics.

[0005] Cyclomarin A, a natural ClpC1 inhibitor, is a cyclic nonribosomal peptide produced by *Streptomyces* species that exhibits potent anti-tuberculosis activity in vitro (Schmitt et al., 2011). Ecumicin and lassomycin, natural products derived from soil bacteria and actinomycete extracts, respectively, bind to the N-terminal domain of ClpC1 and also exhibit potent antibacterial activity (Gao et al., 2015; Gavrish et al., 2014). Another peptide, rufumycin, has been identified as having bactericidal activity against *Mycobacterium tuberculosis* through inhibition of ClpC1 and regulation of intracellular protein degradation (Choules et al., 2019). The antibacterial activity of natural ClpC1 inhibitors has been demonstrated using multidrug-resistant *Mycobacterium tuberculosis* strains (Choules et al., 2019; Gao et al., 2015). Mutants resistant to CymA, eculicin, and rufumycin possess mutations in the N-terminal domain of ClpC1 (Choules et al., 2019; Gao et al., 2015; Vasudevan et al., 2013), and in vivo target validation with eculicin has been achieved in a mouse model of Mycobacterium tuberculosis infection (Gao et al., 2015). Despite their high potency, these natural products suffer from metabolic instability and limited oral bioavailability, limiting their use as oral therapeutics and necessitating drug discovery efforts to identify novel ClpC1 inhibitors with improved DMPK properties. Summary of the Invention

[0006] This invention relates to compounds of formula I and formula III. The present invention also relates to pharmaceutical compositions containing the above compounds and methods for treating microbial infections such as tuberculosis. Detailed Implementation

[0007] This patent application covers novel synthetic analogues of rufumycin: Amino acids 2, 4 and / or 6 are independently replaced by other amino acids (the other amino acids are naturally occurring or synthetic amino acids).

[0008] Figure 1. Structure of ilamycins (also known as ilamycin E1 and ilamycin E2) (Rufomycins or ilamycins: Naming Clarifications and Definitive Structural Assignments). Zhou B, Achanta PS, Shetye G, Chen SN, Lee H, Jin YY, Cheng J, Lee MJ, Suh JW, Cho S, Franzblau SG, Pauli GF, McAlpine JB. Journal of Natural Products (J Nat Prod.) 2021; 84(10):2644-2663. Biosynthesis of ilamycins featuring unusual building blocks and engineered production of enhanced anti-tuberculosis agents. Ma J, Huang H, Xie Y, Liu Z, Zhao J, Zhang C, Jia Y, Zhang Y, Zhang H, Zhang T, Ju J., Nature Communications (Nat. Commun.) 2017; 8(1):391.

[0009] In some embodiments, compounds of formula I and formula III are provided: in: R2 is a C1-C5 alkyl group optionally substituted with F or CF3. n = 1-4, wherein the cycloalkyl group is optionally substituted with F. R4 can be H, halogen, lower alkyl (C1-C4), CH2F, CHF2, CF3, OH, or lower alkoxy (mono- or di-). R3 is -CH2-phenyl or CH2-monocyclic heteroaryl or CH2-fused bicyclic heteroaryl, wherein the phenyl or the heteroaryl is optionally substituted.

[0010] R3 instances include: R5 is H, OH, CF3, lower alkyl (C1-C4), lower alkoxy (C1-C4), 4-6 membered cycloalkyl, 4-6 membered saturated heterocycle, lower alkyl-4 to 6 membered saturated heterocycle, lower alkoxy-4 to 6 membered saturated heterocycle, wherein the alkyl, alkoxy, cycloalkyl or heterocycle is optionally substituted with OH, F, lower alkyl, lower alkoxy, NH2, NH-lower alkyl, or N (lower alkyl)2. R6 can be H, F, OH, lower alkyl, lower alkoxy, or CF3.

[0011] It should be understood that the description of the invention has been simplified to illustrate and clearly understand the elements relevant to the invention, while many other elements found in typical pharmaceutical compositions have been omitted for simplification. Those skilled in the art will recognize that other elements and / or steps are desirable and / or required for carrying out the invention. However, because such elements and steps are well known in the art and because they are not conducive to a better understanding of the invention, a discussion of such elements and steps is not provided herein. The disclosure herein relates to all such changes and modifications to such elements and methods known to those skilled in the art. Furthermore, the embodiments identified and shown herein are for illustrative purposes only and are not intended to be exclusive or limiting in their description of the invention.

[0012] The technical and scientific terms used herein have the meanings commonly understood by those skilled in the art as per the terminology involved in this invention, unless otherwise defined. This document references various methods and materials known to those skilled in the art. Standard reference books elucidating the general principles of pharmacology include *Goodman and Gilman's Therapeutic Pharmacology*. The Pharmacological Basis of Therapeutics(10th edition, McGraw Hill Companies Inc., New York, 2001). This invention may be practiced using any suitable materials and / or methods known to those skilled in the art. However, preferred materials and methods are described. Unless otherwise stated, the materials, reagents, etc., referred to in the following description and examples are commercially available.

[0013] The compounds according to the invention are inherently intended to encompass all their stereochemical isomers. The term "stereochemical isomer" as defined above or below refers to all possible stereoisomers that compounds of Formula I and Formula III, as well as their N-oxides, pharmaceutically acceptable salts, or physiologically functional derivatives, may possess. Unless otherwise mentioned or specified, the chemical name of a compound represents a mixture of all possible stereochemical isomer forms. Specifically, the stereoisomeric source center may have an R configuration or an S configuration; substituents on a divalent cyclic (partially) saturated group may have a cis configuration or a trans configuration. Compounds encompassing a double bond may have an E (opposite-side) or Z (same-side) stereochemistry at said double bond. The terms cis, trans, R, S, E, and Z are well known to those skilled in the art.

[0014] The stereochemical isomers of Formula I and Formula III are obviously intended to be included within the scope of this invention. Particular interest is focused on stereochemically pure Formula I and Formula III compounds.

[0015] According to CAS nomenclature conventions, when a stereoisomeric source center with a known absolute configuration exists in a molecule, the lowest-numbered chiral center (i.e., the reference center) is assigned an R descriptor or an S descriptor (based on the Cahn-Ingold-Prelog sequence rule). The configuration of the second stereoisomeric source center is represented using relative descriptors [R*,R*] or [R*,S*], where R* is always designated as the reference center, and [R*,R*] indicates centers with the same chirality, and [R*,S*] indicates centers with different chirality. For example, if the lowest-numbered chiral center in the molecule has an S configuration and the second center is R, the stereodescriptor would be S--[R*,S*]. When using "α" and "β": the position of the highest-priority substituent on the asymmetric carbon atom in the ring system with the lowest ring number is always arbitrarily located in the "α" position of the mean plane determined by the ring system. The position of the highest priority substituent on another asymmetric carbon atom in the ring system relative to the position of the highest priority substituent on the reference atom is named "α" (in the case that it is on the same side of the mean plane determined by the ring system) or "β" (in the case that it is on the other side of the mean plane determined by the ring system).

[0016] When a specific stereoisomer is specified, it means that the form is substantially free of other isomers, i.e., associated with less than 50%, preferably less than 20%, more preferably less than 10%, even more preferably less than 5%, further preferably less than 2%, and most preferably less than 1%. Therefore, when a compound of Formula I or Formula III is specified, for example, as (S,S), it means that the compound is substantially free of the (S,S) isomer.

[0017] Compounds of Formula I and Formula III, as well as some intermediate compounds, consistently have at least one stereoisomer source center in their structure, which may produce at least two stereochemically different structures.

[0018] Compounds of Formula I and Formula III can be synthesized as mixtures of enantiomers, particularly racemic mixtures of enantiomers, which can be separated by another resolution procedure known in the art. A racemic compound of Formula I or Formula III can be converted to its corresponding diastereomeric salt form by reaction with a suitable chiral acid. The diastereomeric salt form is then separated, for example, by selective crystallization or fractional crystallization, and the enantiomer is released therefrom by a base. An alternative method for separating the enantiomeric forms of compounds of Formula I or Formula III involves liquid chromatography using a chiral stationary phase. The pure stereochemical isomer can also be derived from the corresponding pure stereochemical isomer of a suitable starting material, provided that the reaction occurs stereospecifically. Preferably, if a specific stereoisomer is desired, the compound is synthesized by a stereospecific preparation method. These methods will advantageously employ enantiomerically pure starting materials.

[0019] The tautomer forms of Formula I or Formula III compounds are intended to include those Formula I or Formula III compounds in which, for example, an enol group is converted to a ketone group (ketone-enol tautomerism). The tautomer forms of Formula I and Formula III compounds or intermediates thereof of the present invention are intended to be included within the scope of the present invention.

[0020] As used herein, the term "alkyl" refers to a non-branched or branched saturated monovalent hydrocarbon residue containing 1 to 10 carbon atoms. The term "lower alkyl" refers to a straight-chain or branched hydrocarbon residue containing 1 to 6 carbon atoms. As used herein, "C1- 10 "Alkyl" refers to an alkyl group consisting of 1 to 10 carbon atoms. Examples of alkyl groups include, but are not limited to, lower alkyl groups, including methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl or pentyl, isopentyl, neopentyl, hexyl, heptyl and octyl.

[0021] As used in this article, the term "halogen" refers to F, Cl, Br, or I.

[0022] When the term "alkyl" is used as a suffix following another term (such as "phenylalkyl" or "hydroxyalkyl"), it is intended to refer to an alkyl group substituted with one or two substituents selected from other designated names, as defined above. Thus, for example, "phenylalkyl" signifies the group R'R''-, where R' is phenyl and R'' is an alkylene group as defined herein, provided that the connection point of the phenylalkyl moiety is understood to be located on the alkylene group. Examples of arylalkyl groups include, but are not limited to, benzyl, phenethyl, and 3-phenylpropyl. The terms "arylalkyl" or "aralkyl" are similarly interpreted except that R' is aryl. The terms "(hetero)arylalkyl" or "(hetero)arylalkyl" are similarly interpreted except that R' is optionally aryl or heteroaryl.

[0023] The term “haloalkyl” or “lower haloalkyl” or “lower haloalkyl” refers to a straight-chain or branched hydrocarbon residue containing one to six carbon atoms, wherein one or more carbon atoms are replaced by one or more halogen atoms.

[0024] As used herein, the term "alkoxy" means -O-alkyl, wherein the alkyl group is as defined above, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentoxy, hexoxy, including its isomers. As used herein, "lower alkoxy" refers to an alkoxy group having a "lower alkyl group" as previously defined. As used herein, "C1- 10 "Alkoxy" refers to -O-alkyl, where the alkyl group is C. 1-10 .

[0025] The term “haloalkoxy” or “halolower alkoxy” or “lower haloalkoxy” refers to a lower alkoxy group in which one or more carbon atoms are replaced by one or more halogen atoms.

[0026] As used herein, the term "hydroxyalkyl" means an alkyl group in which one to three hydrogen atoms on different carbon atoms are replaced by hydroxyl groups, as defined herein.

[0027] As used herein, the term "carboxyl" refers to a group of the formula -C(=O)R2, wherein each R is independently hydrogen or C. 1-3 Alkyl groups, and lower alkyl groups as defined herein.

[0028] The term "cycloalkyl" refers to a monovalent saturated monocyclic or bicyclic hydrocarbon group having 3 to 10 ring carbon atoms. In a particular embodiment, cycloalkyl refers to a monovalent saturated monocyclic hydrocarbon group having 3 to 8 ring carbon atoms. Bicyclic means consisting of two saturated carbon rings having one or more common carbon atoms. A particular cycloalkyl group is monocyclic. Examples of monocyclic cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. Examples of bicyclic cycloalkyl groups are bicyclic [2.2.1]heptyl or bicyclic [2.2.2]octyl.

[0029] As used herein, the term "amino" denotes a group of the formula -NR'R'', wherein R' and R'' are independently hydrogen, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. Alternatively, R' and R'' together with the nitrogen to which they are attached may form a heterocycloalkyl group. The term "primary amino" indicates a group in which both R' and R'' are hydrogen. The term "secondary amino" indicates a group in which R' is hydrogen and R'' is not hydrogen. The term "tertiary amino" indicates a group in which neither R' nor R'' is hydrogen. Specific secondary and tertiary amines are methylamine, ethylamine, propylamine, isopropylamine, aniline, benzylamine, dimethylamine, diethylamine, dipropylamine, and diisopropylamine.

[0030] The term "heteroaryl" refers to a monovalent aromatic heterocyclic monocyclic or bicyclic system having 5 to 12 ring atoms, including 1, 2, 3 or 4 heteroatoms selected from N, O and S, with the remaining ring atoms being carbon. Examples of heteroaryl moieties include pyrrole, furanyl, thiophene, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrazolyl, pyridinyl, triazinyl, aziridine, diazacycloheptatrienyl, isoxazolyl, benzofuranyl, isothiazolyl, benzothiophene, indolyl, isindolyl, isobenzofuranyl, benzimidazolyl, benzooxazolyl, benzoisooxazolyl, benzothiazolyl, benzooxadiazolyl, benzothiadiazolyl, benzotriazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, or quinoxolinyl.

[0031] The term "heterocyclic alkyl" refers to a monocyclic or bicyclic ring system having 3 to 9 ring atoms, comprising 1, 2, or 3 ring heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon, and is monovalently or partially saturated. In a particular embodiment, a heterocyclic alkyl is a monocyclic ring system having 4 to 7 ring atoms, comprising 1, 2, or 3 ring heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon, and is monovalently saturated. Examples of monocyclic saturated heterocyclic alkyl groups are aziridine propane, ethylene oxide, aziridine butane, oxacyclobutane, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolyl, imidazoyl, oxazolyl, isoxazolyl, thiazoyl, piperidinyl, tetrahydropyranyl, tetrahydrothiaranyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholin-4-yl, aziridine heptane, diaziridine heptane, homopiperazinyl, or oxazaziridine heptane. Examples of bicyclic saturated heterocyclic alkyl groups are 8-aza-bicyclo[3.2.1]octyl, quininecycloyl, 8-oxa-3-aza-bicyclo[3.2.1]octyl, 9-aza-bicyclo[3.3.1]nonyl, 3-oxa-9-aza-bicyclo[3.3.1]nonyl, or 3-thia-9-aza-bicyclo[3.3.1]nonyl. Examples of partially unsaturated heterocyclic alkyl groups are dihydrofuranyl, imidazolinyl, dihydrooxazolyl, tetrahydropyridyl, or dihydropyranyl.

[0032] "Patient" or "subject" refers to a mammal, such as a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or a non-human primate, such as a monkey, chimpanzee, baboon, or rhesus monkey, and the terms "patient" and "subject" are used interchangeably in this document.

[0033] As used in this disclosure, the term "carrier" encompasses carriers, excipients, and diluents, and refers to materials, compositions, or mediators involved in carrying or transporting a pharmaceutical agent from one organ or part of the body to another organ or part of the body, such as liquid or solid fillers, diluents, excipients, solvents, or encapsulating materials.

[0034] The term "treatment" in relation to a subject refers to the improvement of at least one symptom of the subject's condition. Treatment can be curative, improvement, or at least partial relief of the condition.

[0035] Unless otherwise stated, the term “symptom” is used in this disclosure to mean the term disease, symptom or illness, and may be used interchangeably with the term disease, symptom or illness.

[0036] As used in this disclosure, the terms “administer,” “administering,” or “administration” mean the direct administration of a compound or a pharmaceutically acceptable salt or composition thereof to a subject, or the administration of a prodrug derivative or analog of the compound or a pharmaceutically acceptable salt or composition thereof to a subject, which may form an adequate amount of the active compound in the subject’s body.

[0037] As used in this disclosure, the term "optionally substituted" means that a suitable substituent can replace hydrogen bound to carbon. Those skilled in the art will understand that, with respect to any group containing one or more substituents, such a group is not intended to introduce any spatially impractical, synthetically infeasible, and / or inherently unstable substitution or substitution pattern. Furthermore, such combinations are permitted only if the combination of substituents and / or variables within any formula presented herein yields a stable compound or a useful synthetic intermediate, where stability means a reasonably pharmacologically relevant half-life under physiological conditions.

[0038] Dosage and administration: The compounds of the present invention can be formulated in a wide variety of oral dosage forms and carriers. Oral administration can be in the form of tablets, coated tablets, sugar-coated tablets, hard gelatin capsules and soft gelatin capsules, solutions, emulsions, syrups, or suspensions. The compounds of the present invention are effective when administered via other routes of administration, including continuous (intravenous infusion), local parenteral, intramuscular, intravenous, subcutaneous, transdermal (possibly including penetration enhancers), buccal, nasal, inhalation, and suppository administration. A preferred method of administration is generally oral administration using a convenient daily dosage regimen that can be adjusted according to the degree of discomfort and the patient's response to the active ingredient.

[0039] One or more compounds of the present invention, along with their pharmaceutically available salts, together with one or more conventional excipients, carriers, or diluents, can be presented as pharmaceutical compositions and unit dosage forms. The pharmaceutical compositions and unit dosage forms may contain conventional components in conventional proportions, with or without additional active compounds or components, and the unit dosage forms may contain any suitable effective amount of active ingredient commensurate with the intended daily dose range to be used. The pharmaceutical compositions may be in solid form, such as tablets or filled capsules, semi-solids, powders, sustained-release formulations; or in liquid form, such as solutions, suspensions, emulsions, elixirs, or filled capsules for oral administration; or in suppositories for rectal or vaginal administration; or in the form of sterile injectable solutions for parenteral use. Typical formulations will contain one or more active compounds, from about 5% to about 95% (w / w). The terms “formulation” or “dosage form” are intended to include both solid and liquid formulations of the active compound, and those skilled in the art will understand that the active ingredient may be present in different formulations depending on the target organ or tissue and the desired dose and pharmacokinetic parameters.

[0040] As used herein, the term "excipient" refers to a compound that can be used to prepare a pharmaceutical composition, is generally safe and non-toxic, and is neither biologically undesirable nor otherwise undesirable, and includes excipients acceptable for both veterinary and human pharmaceutical use. The compounds of the present invention may be administered alone, but will generally be administered in mixture with one or more suitable pharmaceutical excipients, diluents, or carriers, the selection of which should be based on the intended route of administration and standard pharmaceutical practice.

[0041] "Pharmaceutical acceptable" means that the substances that can be used to prepare pharmaceutical compositions are generally safe, non-toxic, and neither biologically nor otherwise undesirable, and include substances acceptable for veterinary and human pharmaceutical use.

[0042] The “pharmaceutically acceptable salt” form of an active ingredient may initially endow it with desirable pharmacokinetic properties not present in the non-salt form, and may even positively influence the pharmacodynamics of the active ingredient in vivo in terms of its therapeutic activity. The phrase “pharmaceutically acceptable salt” for a compound means a salt that is pharmaceutically acceptable and has the desired pharmacological activity of the parent compound. Such salts include: (1) acid addition salts formed from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or from organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid. Acids, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-en-1-carboxylic acid, glucoheponic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, dodecyl sulfate, gluconic acid, glutamic acid, hydroxynaphthenic acid, salicylic acid, stearic acid, mucoconic acid, etc.; or (2) salts formed when the acidic protons present in the parent compound are replaced by metal ions (e.g., alkali metal ions, alkaline earth ions or aluminum ions) or coordinated with organic bases such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucosamine, etc.

[0043] Solid dosage forms include powders, tablets, pills, capsules, sachets, suppositories, and dispersible granules. Solid carriers can be one or more substances that also function as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrants, or encapsulating materials. In powders, the carrier is typically a finely ground solid, which is a mixture with the finely ground active ingredient. In tablets, the active ingredient is typically mixed with a carrier having the desired binding capacity in a suitable proportion and compacted into the desired shape and size. Suitable carriers include, but are not limited to, magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, astragalus gum, methylcellulose, sodium carboxymethyl cellulose, low-melting-point waxes, cocoa butter, etc. In addition to the active ingredient, solid dosage forms may also contain colorants, flavoring agents, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizers, etc.

[0044] Liquid formulations are also suitable for oral administration, including those comprising emulsions, syrups, elixirs, aqueous solutions, and aqueous suspensions. These liquid formulations include solid formulations intended to be converted into a liquid form shortly before use. Emulsions can be prepared in solution, such as in an aqueous solution of propylene glycol, or may contain emulsifiers such as lecithin, sorbitan monooleate, or gum arabic. Aqueous solutions can be prepared by dissolving the active ingredient in water and adding suitable colorants, flavorings, stabilizers, and thickeners. Aqueous suspensions can be prepared by dispersing finely fragmented active ingredients in water containing viscous materials such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethyl cellulose, and other well-known suspending agents.

[0045] The compounds of the present invention can be formulated for parenteral administration (e.g., by injection, such as bolus injection or continuous infusion) and can be present in unit dosage forms in ampoules, in pre-filled syringes, in small-volume infusion solutions, or in multi-dose containers with added preservatives. The compositions can take the form of suspensions, solutions, or emulsions in oily or aqueous media, such as solutions in aqueous polyethylene glycol solutions. Examples of oily or non-aqueous carriers, diluents, solvents, or mediators include propylene glycol, polyethylene glycol, vegetable oils (e.g., olive oil), and injectable organic esters (e.g., ethyl oleate), and may contain formulation agents such as preservatives, wetting agents, emulsifiers or suspending agents, stabilizers, and / or dispersants. Alternatively, the active ingredient can be in powder form obtained by aseptic separation of a sterile solid or by lyophilization of a solution for reconstitution with a suitable mediator (e.g., sterile pyrogen-free water) prior to use.

[0046] The compounds of the present invention can be formulated for topical application to the epidermis in the form of ointments, creams, or lotions, or as transdermal patches. Ointments and creams can be formulated, for example, with an aqueous or oil-based base by adding suitable thickeners and / or gelling agents. Lotions can be formulated with an aqueous or oil-based base and will generally also contain one or more emulsifiers, stabilizers, dispersants, suspending agents, thickeners, or colorants. Formulations suitable for topical application in the mouth include lozenges containing the active ingredient in a flavoring base (typically sucrose and arabinose or tragacanth gum); soft lozenges containing the active ingredient in an inert base (such as gelatin and glycerin or sucrose and arabinose); and mouthwashes containing the active ingredient in a suitable liquid carrier.

[0047] The compounds of the present invention can be formulated for application in suppository form. First, a mixture of low-melting-point waxes, such as fatty acid glycerides or cocoa butter, is melted, and the active ingredients are homogeneously dispersed, for example, by stirring. The molten homogeneous mixture is then poured into a mold of a convenient size, allowing cooling and solidification.

[0048] The compounds of the present invention can be formulated for vaginal application. In addition to the active ingredient, vaginal suppositories, tampons, creams, gels, pastes, foams, or sprays may contain a suitable carrier such as those known in the art.

[0049] The compounds of the present invention can be formulated for nasal administration. The solution or suspension is applied directly to the nasal cavity by conventional means, such as using a dropper, pipette, or nebulizer. The formulation can be provided in single-dose or multi-dose form. In the latter case, using a dropper or pipette, this is achieved by the patient administering an appropriate, predetermined volume of the solution or suspension. In the case of a nebulizer, this can be achieved, for example, by means of a metering nebulizer pump.

[0050] The compounds of the present invention can be formulated for aerosol administration, particularly for use in the respiratory tract, and include intranasal administration. The compounds will typically have a small particle size, for example, about five (5) micrometers or less. This particle size can be obtained by means known in the art, such as by micronization. The active ingredient is provided in a pressurized package with a suitable propellant, such as chlorofluorocarbons (CFCs), such as dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, or carbon dioxide or other suitable gases. The aerosol may conveniently also contain surfactants, such as lecithin. The dosage of the drug can be controlled by providing a metering valve. Alternatively, the active ingredient can be provided as a dry powder (e.g., a powder mixture of the compound in a suitable powder base, such as lactose, starch, starch derivatives such as hydroxypropyl methylcellulose and polyvinylpyrrolidone (PVP)). The powder carrier will form a gel in the nasal cavity. The powder composition can be presented in unit dosage forms, such as capsules, boxes, or blister packs containing, for example, gelatin, from which the powder can be administered via an inhaler.

[0051] When needed, enteric coatings can be used to prepare formulations suitable for sustained or controlled release of the active ingredient. For example, the compounds of the present invention can be formulated into percutaneous or subcutaneous drug delivery devices. These delivery systems are advantageous when sustained release of the compound is required and patient adherence to treatment regimens is critical. In percutaneous delivery systems, the compounds are typically attached to a skin-adhesive solid carrier. The compounds of interest can also be used in combination with penetration enhancers, such as azone (1-dodecylazacyclohepta-2-one). Sustained-release delivery systems are subcutaneously inserted into the subcutaneous layer via surgical procedure or injection. Subcutaneous implants encapsulate the compounds in a lipid-soluble membrane (e.g., silicone rubber) or a biodegradable polymer (e.g., polylactic acid).

[0052] Suitable formulations, along with drug carriers, diluents, and excipients, are described in Remington: Pharmaceutical Science and Practice (… Remington: The Science and Practice of Pharmacy(1995, edited by EW Martin, Mack Publishing Company, 19th edition, Easton, Pennsylvania). Skilled formulation scientists can modify formulations within the teachings of the specification to provide multiple formulations for specific routes of administration without destabilizing the compositions of the invention or impairing their therapeutic activity.

[0053] Modifications to the compounds of the present invention to make them more soluble in, for example, water or other media can be readily achieved through minor alterations (salt formulation, esterification, etc.) well known to those skilled in the art. It is also well known to those skilled in the art that, in order to achieve maximum beneficial effects in patients, modifications can be made to the route of administration and dosage regimen of a particular compound to manage the pharmacokinetics of the compounds of the present invention.

[0054] As used herein, the term "therapeutic effective dose" refers to the amount required to reduce the symptoms of a disease in an individual. The dose will be adjusted to meet the individual requirements of each specific case. The dose may vary within a wide range of factors including: the severity of the disease to be treated, the patient's age and general health, other medications used to treat the patient, the route and form of administration, and the preferences and experience of the healthcare practitioners involved. For oral administration, a daily dose between about 0.01 mg / kg body weight / day and about 1000 mg / kg body weight / day is appropriate in monotherapy and / or combination therapy. A preferred daily dose is between about 0.1 mg / kg body weight / day and about 500 mg / kg body weight / day, more preferably between 0.1 mg / kg body weight / day and about 100 mg / kg body weight / day, and most preferably between 1.0 mg / kg body weight / day and about 15 mg / kg body weight / day. Therefore, for a person weighing 70 kg, the dose range in one embodiment would be from about 70 mg / day to 0.7 g / day. Daily dosage can be administered as a single dose or in divided doses, typically from 1 dose / day to 5 doses / day. Treatment is usually initiated with a smaller dose than the optimal dose of the compound. Thereafter, the dose is increased in small increments until optimal efficacy is achieved in the individual patient. Those skilled in the art to treat the diseases described herein will be able to determine the therapeutically effective amount of the compounds of the invention for a given disease and patient without excessive experimentation and relying on personal knowledge, experience, and the disclosure of this application.

[0055] These pharmaceutical formulations are preferably in unit dosage form. In this form, the formulation is subdivided into unit doses containing appropriate amounts of the active ingredient. The unit dosage form can be a packaged formulation containing discrete amounts of the formulation, such as packaged tablets, capsules, or powder in vials or ampoules. Similarly, the unit dosage form can be the capsule, tablet, sachets, or lozenges themselves, or any appropriate number of these packaging forms.

[0056] Example The following examples further describe and illustrate specific embodiments within the scope of the invention. Techniques and formulations are typically described in Remington Pharmaceutical Sciences (…). Remington's Pharmaceutical Sciences The information can be found in (McPublishers, Easton, Pennsylvania). This disclosure is further illustrated by the following examples, which should not be construed as limiting the scope or spirit of this disclosure to the specific procedures described herein. It should be understood that the examples are provided to illustrate certain implementations and are not intended to limit the scope of this disclosure thereto. It should be further understood that various other implementations, modifications, and equivalents thereof may be realized by those skilled in the art without departing from the spirit of this disclosure and / or the scope of the appended claims.

[0057] General information for compound synthesis and characterization: The starting materials, reagents, and solvents were all purchased from commercial sources and could be used without further purification.

[0058] Concentration under reduced pressure or reduced pressure means that a rotary evaporator is used.

[0059] Silica gel chromatography was performed using a pre-packed column from Agela on an ISCO Biotage system.

[0060] Proton nuclear magnetic resonance (¹H NMR) spectra were recorded using a Bruker 400 MHz NMR spectrometer. Chemical shifts are expressed as parts per million at low field relative to solvent resonances used as internal standards (e.g., CDCl₃ at 7.26 ppm for ¹H). Peak shapes are represented as follows: s, singlet; d, doublet; t, triplet; q, quartet; p, quintet; m, multiplet; br s, broad singlet; dd, double doublet; dt, double triplet; dq, double quartet.

[0061] Liquid chromatography-mass spectrometry (LCMS) was performed on an Agilent 1260 / G6125B or a Shimadzu LC20-MS2020.

[0062] Mass spectrometry (MS) was performed using an electrospray ionization (ESI) source.

[0063] Typical LCMS conditions: Instrument: Shimadzu LC20-MS2020. Column: Kinetex C18 LC 4.6 × 50 mm, 5 μm, temperature 50℃. Mobile phase A: ACN containing 0.018% TFA; B: water containing 0.037% TFA. Gradient: 0-60% A / B over 5 minutes, maintained at 1.5 mL / min for 0.7 minutes, and then returned to 0% A / B, maintained at 2.0 mL / min for 0.29 minutes.

[0064] Instrument: Agilent 1260 / G6125B. Column: Poroshell 120 EC C18 3.0 × 30 mm, 2.7 μm, temperature 50 °C. Mobile phase A: ACN containing 0.018% TFA; B: water containing 0.037%. Gradient: 5-95% A / B over 3 minutes, then maintained at 1.0 mL / min for 0.6 minutes, and then returned to 5% A / B and maintained at 1.5 mL / min for 0.4 minutes.

[0065] Typical HPLC purity testing conditions: Instrument: Agilent 1290. Column: Kinetex EVO C18 100 A LC column, 150 x 2.1 mm, 1.7 μm, temperature 50 °C. Mobile phase A: H₂O containing 0.1% TFA; B: ACN containing 0.075% TFA. Flow rate: 0.4 mL / min. Detector: PDA, 220 nm and 254 nm.

[0066] abbreviation: Synthesis of key intermediates Intermediate 1 Preparation of compound 2 NaBH3CN (493.4 g, 7.85 mol, 5.00 equivalent) was added fractionally to a solution of compound 1 (500 g, 1.57 mol, 1 equivalent) in HOAc (2500 mL) at 0 °C. The resulting mixture was stirred at 25 °C for 2 h. TLC (EtOAc:PE = 1:5) showed that the starting material was consumed and new spots were formed. The mixture was diluted with ice water (10 L), alkalized to pH = 10 with 30% ammonia solution, and extracted with EtOAc (6 L x 3). The organic layer was concentrated under vacuum. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 6:1 to 1:1) to give compound 2 (315 g, 31.3% yield) as a pale yellow solid.

[0067] Preparation of compound 4 A mixture of compound 2 (315 g, 983.2 mmol, 1.00 equivalent), compound 3 (124.03 g, 983.20 mmol, 1 equivalent), CuCl (19.5 g, 196.6 mmol, 4.70 mL, 0.2 equivalent), and DIPEA (139.78 g, 1.08 mol, 188.38 mL, 1.1 equivalent) in THF (1500 mL) was stirred at 70 °C for 5 hours. TLC (EtOAc:PE = 1:3) showed that the starting material was consumed and new spots were formed. The mixture was diluted with EtOAc (1000 mL), washed with 1 N HCl (1000 mL x 2) and saturated NaHCO3 aqueous solution (1000 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under vacuum. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 10:1 to 5:1) to give compound 4 as a yellow oil (205 g, 53.9% yield).

[0068] Preparation of compound 5 DDQ (120.4 g, 530.4 mmol, 1.00 equivalent) was added partially to a solution of compound 4 (205 g, 530.4 mmol, 1.00 equivalent) in DCM (2000 mL) at 0 °C. The resulting mixture was stirred at 0 °C for 1 hour. TLC (solvent, EtOAc:PE = 1:3) showed that the starting material was consumed and new spots were formed. The mixture was diluted with DCM (600 mL) and washed with saturated aqueous NaHCO3 solution (800 mL x 2) and brine (800 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum to give compound 5 (200 g, crude) as a yellow oil.

[0069] Preparation of compound 6 Lindlar catalyst (47.2 g, 228.9 mmol, 47.2 mL, 0.44 equivalents) was added to a solution of compound 5 (200 g, 520.2 mmol, 1.00 equivalents) and quinoline (113.5 g, 879.1 mmol, 104.17 mL, 1.69 equivalents) in toluene (1000 mL) under N2. The suspension was degassed under vacuum and purged several times with H2. The resulting mixture was stirred at 25 °C for 5 h under H2 15 PSI. TLC (EtOAc:PE = 1:3) showed that the material was consumed and new spots were observed. The mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by column chromatography (SiO2, PE:EtOAc = 50:1 to 10:1) to give compound 6 as a colorless oil (150 g, 388.1 mmol, 74.6% yield).

[0070] Preparation of compound 7 SOCl2 (58.93 g, 495.3 mmol, 35.9 mL, 1.5 equivalent) was added dropwise to a solution of compound 6 (130 g, 330.2 mmol, 1.00 equivalent) in MeOH (1300 mL) at 0 °C. The reaction mixture was stirred at 25 °C for 2 h. TLC (solvent, EtOAc:PE = 1:5) showed that the starting material was consumed and new spots were formed. 2 N NaOH solution was added dropwise to adjust the pH to 8. The reaction mixture was extracted with DCM (500 mL x 2). The organic layer was dried over Na2SO4 and concentrated to dryness under vacuum to give compound 7 (94.5 g, crude) as a yellow oil.

[0071] Preparation of Intermediate 1 LiOH·H2O (41.57 g, 989.99 mmol, 3.00 equivalent) was added to a solution of compound 7 (94.5 g, 330.0 mmol, 1.00 equivalent) in THF (500 mL) / H2O (500 mL). The reaction mixture was stirred at 10 °C for 2 h. After the material was consumed, the pH was adjusted to 8, and Fmoc-OSu (111.4 g, 330.0 mmol, 1.00 equivalent) was added. The reaction mixture was stirred at 25 °C for another 2 h. LCMS (EW16333-36-P1A) showed a peak with the desired MS (Rt = 0.949 min). HPLC (EW16333-36-P1A) showed a peak (Rt = 2.154 min). The reaction mixture was adjusted to pH 4-5 with 1 N HCl solution and extracted with EtOAc (500 mL x 2). The organic layer was dried over Na₂SO₄ and concentrated to dryness under vacuum. The residue was purified by preparative HPLC (TFA conditions) to give intermediate 1 as a white solid (10⁵ g, 210.8 mmol, 63.9% yield, 99.3% purity). LCMS (ESI): m / z 495.1 [M+H] + 1 HNMR (CDCl3, 400 MHz): δ: 9.24 (brs, 1H), 7.80-7.78 (m, 2H), 7.75-7.54 (m, 4H), 7.45-7.36 (m, 2H), 7.36-7.32 (m, 2H), 7.20-7.13 (m, 3H), 6.17-6.13 (m, 1H), 6.12-6.10 (m, 0.16H), 5.38 (d, J = 8.0 Hz, 0.75H), 5.23-5.13(m, 2H), 4.83 (m, 0.77H), 4.56-4.55 (m, 0.185 H), 4.41-4.39 (m, 2H), 4.24-4.22 (m, 0.8H), 4.19-4.14 (m, 0.189H), 3.42-3.30 (m, 1.75H), 3.32-3.12 (m, 0.142H), 1.58 (s, 6H).

[0072] Preparation of compound 3 Ac₂O (160.2 g, 1.57 mol, 146.9 mL, 1.1 equivalent) was added dropwise to a solution of compound 3_1 (120 g, 1.43 mol, 139.3 mL, 1.00 equivalent), DIPEA (368.7 g, 2.85 mol, 496.9 mL, 2.00 equivalent), and DMAP (17.4 g, 142.7 mmol, 0.1 equivalent) in DCM (600 mL). The resulting mixture was heated to 25 °C and stirred for 2 hours. TLC (solvent, PE:EtOAc = 5:1) showed that 3_1 was consumed and new spots formed. The mixture was diluted with DCM (1.5 L), washed with 1 N HCl (1 L x 3) and brine (1 L), dried over anhydrous Na₂SO₄, and filtered. The filtrate was concentrated under vacuum (water bath: < 40°C) to give compound 3 (150 g, crude product) as a colorless oil.

[0073] Intermediate 2 Preparation of compound 2 Paraformaldehyde (101 g, 3.38 mol, 93.0 mL, 6.33 equivalents) was added to a solution of compound 1 (150 g, 533 mmol, 1.00 equivalents) in toluene (1.50 L).p -TsOH (10.7 g, 62.1 mmol). The mixture was heated to 110 °C and stirred at 110 °C for 2 h using a Dean-Stark apparatus to remove water via azeotropic extraction. TLC (solvent, DCM:MeOH = 10:1) showed that the starting material was consumed and large new spots formed. The two batches were combined. The mixture was filtered and the filtrate was concentrated to give compound 2 (322 g, crude product) as a pale yellow oil.

[0074] 1 HNMR (CDCl3, 400 MHz): δ : 10.72 (s, 1H), 7.41 - 7.19 (m, 5H), 5.54 (s, 1H), 5.24 - 5.16 (m, 3H), 4.42 - 4.39 (t, J = 5.6 Hz, 1H), 2.52 - 2.46 (m, 2H), 2.40 - 2.30 (m, 1H), 2.22 - 2.06 (m, 1H).

[0075] Preparation of compound 3 1) Oxaloyl chloride (208 g, 1.64 mol, 143 mL, 1.50 equivalent) and DMF (159.51 mg, 2.18 mmol, 167.91 µL, 0.002 equivalent) were added to a solution of compound 2 (320 g, 1.09 mol, 1.00 equivalent) in DCM (1.6 L), and the mixture was stirred at 10 °C for 3 h. TLC (solvent, PE:EtOAc = 1:1) showed that reactant 2 was consumed and new spots were formed. The two batches were combined. The mixture was concentrated, and the residue was diluted with toluene (500 mL) and then concentrated three times to produce acyl chloride (680 g, crude) as a dark brown solid.

[0076] 2) A solution of lithium tri-tert-butoxy-aluminum hydride (124 g, 491 mmol, 6.06 mL, 0.900 equivalent) in THF (1.00 L) was added to a solution of acyl chloride (170 g, 545 mmol, 1.00 equivalent) in THF (1.00 L) at -70 °C under N2. The mixture was stirred at -70 °C for 2 hours. TLC (solvent, DCM:MeOH = 10:1) showed that reactant 2 was consumed and large new spots formed. The reaction mixture was quenched with H2O (400 mL) and the organic layer was dried over anhydrous Na2SO4 (500 g) at 0 °C. Four batches were combined and the mixture was then filtered, and the filter cake was washed with EtOAc (600 mL x 2), and the filtrate was concentrated to give compound 3 (520 g, crude) as a dark brown oil.

[0077] 1 HNMR (CDCl3, 400 MHz) δ : 9.71 (s, 1H), 7.43 - 7.36 (m, 5H), 5.54 (s,1H), 5.22 - 5.16 (m, 3H), 4.41 - 4.36 (m, 1H), 2.61 - 2.50 (m, 2H), 2.34 -2.20 (m, 2H).

[0078] Preparation of compound 4 NaOAc (53.6 g, 656 mmol, 1.00 equivalent) was added to a solution of compound 3 (260 g, 656 mmol, 1.00 equivalent, HCl salt) in MeOH (1.8 L). The mixture was stirred at 10 °C for 10 min, and NaBH3CN (82.5 g, 1.31 mol, 2.00 equivalent) was slowly added. The mixture was then stirred at 10 °C for 2 h. LCMS showed that reactant 3 was consumed and the expected MW was detected. The two batches were combined. The mixture was concentrated, and the residue was dissolved in H2O (3 L) and EtOAc (2 L). The organic layer was dried over Na2SO4 and concentrated. The residue was purified by column chromatography (SiO2, PE:EtOAc = 1:1) to give compound 4 (220 g, crude) as a yellow oil.

[0079] LCMS: m / z 465.1 (M-17) 1HNMR (CDCl3, 400 MHz): δ : 7.40 - 7.31 (m, 10H), 5.31 - 5.26 (m, 1H), 5.22 - 5.08 (m, 4H), 4.74 (s, 1H), 4.68 - 4.62 (m, 1H), 4.44 (s, 1H), 3.30 -3.21 (m, 2H), 2.07 - 2.05 (m, 1H), 1.98 - 1.95 (m, 2H), 1.78 - 1.72 (m, 3H), 1.29 - 1.25 (m, 1H), 0.96 - 0.91 (m, 6H).

[0080] Preparation of compound 5 TMSCl (49.5 g, 456 mmol, 57.9 mL, 2.00 equivalent) was added to a solution of compound 4 (110 g, 228 mmol, 1.00 equivalent) and NaBH3CN (28.7 g, 456 mmol, 2.00 equivalent) in ACN (550 mL) at 10 °C under N2. The mixture was stirred at 30 °C for 16 h. TLC (PE:EtOAc = 1:1) showed that reactant 4 was consumed and large new spots formed. The two batches were combined. The reaction mixture was poured into water (1.50 L) and the resulting mixture was then extracted with EtOAC (1.5 L x 2). The organic layer was washed with brine (2 L) and dried over Na2SO4. The filtrate was concentrated. The resulting residue was purified by column chromatography (SiO2, PE:EtOAc = 2:1) to give compound 5 as a colorless oil (120 g, 54.7% yield, 97% purity).

[0081] 1 HNMR (CDCl3, 400 MHz) δ : 7.39 - 7.31 (m, 10H), 5.43 - 5.39 (m, 1H), 5.18 - 5.09 (m, 4H), 4.84 - 4.60 (m, 1H), 3.21 - 3.19 (m, 2H), 2.74 - 2.72(m, 3H), 2.09 - 1.97 (m, 2H), 1.85 - 1.74 (m, 4H), 1.60 (m, 1H), 0.96 - 0.91 (m, 6H).

[0082] Preparation of compound 6 Pd / C (42.0 g, 10% purity) was added to a solution of compound 5 (136 g, 282 mmol, 1.00 equivalent) in EtOH (400 mL) under N2. The mixture was degassed and purged three times with H2, and stirred at 30 °C for 12 h under H2 atmosphere (15 psi). LCMS showed that reactant 1 was not consumed, and the mixture was stirred at 30 °C for 36 h under H2 (15 psi). LCMS showed that reactant 5 was consumed, and the expected MS (R) was detected. t = 0.271 minutes). The mixture was filtered and concentrated to give compound 6 as a white solid (70.0 g, crude).

[0083] LCMS: m / z 243.2 (MS (M-17) 1 HNMR (CDCl3, 400 MHz) δ : 7.59 - 7.53 (s, 2H), 5.10 - 5.06 (m, 1H), 3.51 - 3.49 (m, 1H), 3.29 - 3.19 (m, 2H), 2.65 (s, 3H), 2.25 - 2.22 (m, 1H), 2.06 - 2.01 (m, 2H), 1.80 - 1.64 (m, 3H), 1.50 (m, 1H), 0.93 - 0.87 (m, 6H).

[0084] Preparation of intermediate 2 FMOC-OSU (97.5 g, 289 mmol, 1.00 equivalent) was added to a solution of compound 6 (70.0 g, 289 mmol, 1.00 equivalent) in NaHCO3 (648 g, 7.71 mol, 300 mL, 26.7 equivalent) and dioxane (300 mL) at 0 °C, and the mixture was stirred at 10 °C for 2 h. LC-MS showed that reactant 1 was consumed and the desired MS was detected. The reaction mixture was diluted with water (300 mL) and EtOAc was extracted (300 mL x 2), and the organic phase was washed with water (300 mL). The organic layer was dried over Na2SO4 and concentrated to give the crude product. The combined aqueous phases were adjusted to pH 3.0 to 5.0 with aqueous HCl solution (1.0 N) and extracted with EtOAc (500 mL x 3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, DCM:PE = 10:1). The two batches were combined. Intermediate 2 (125 g, 258 mmol, 89.4% yield, 96% purity) was obtained as a white solid.

[0085] LCMS: m / z 465.2 [M+H] + 1 HNMR (CDCl3, 400 MHz) δ : 7.78 - 7.76 (m, 2H), 7.63 - 7.61 (m, 2H), 7.42 - 7.40 (m, 2H), 7.39 - 7.30 (m, 2H), 5.30 - 5.20 (m, 1H), 4.42 - 4.27 (m, 4H), 3.29 - 3.19 (m, 2H), 2.98 - 2.81 (m, 3H), 2.05 - 2.01 (m, 1H), 1.82 -1.80 (m, 5H), 1.50 (m, 1H), 0.98 - 0.93 (m, 6H).

[0086] Intermediate 4 Preparation of compound 2 LiOH•H₂O (56.2 g, 1.34 mol, 3.00 equivalent) and 4-bromobut-1-ene (200 g, 1.48 mol, 150 mL, 3.31 equivalent) were added to a solution of compound 1 (100 g, 446 mmol, 1.00 equivalent, HCl salt) in DMF (1.0 L) at 25 °C. The reaction mixture was stirred at 25 °C for 16 h. TLC (PE:EtOAc = 10:1) showed the formation of a large spot. The reaction mixture was poured into H₂O (1.5 L) and extracted with EtOAc (700 mL x 2). The combined organic layers were washed with brine (500 mL x 2), dried over Na₂SO₄, and concentrated. The residue was purified by column chromatography (ISCO®; 130 g SepaFlash® silica gel rapid column, 250 mL / min, 0% to 20% EtOAc-PE gradient eluent) to give compound 2 as a yellow oil (55.0 g, 227 mmol, 50.9% yield).

[0087] 1 HNMR (CDCl3, 400 MHz) δ 5.84 - 5.74 (m, 1H), 5.14 - 5.00 (m, 2H), 3.14 (t, J = 7.2 Hz, 1H), 2.70 - 2.62 (m, 1H), 2.57 - 2.51 (m, 1H), 2.31 -2.17 (m, 2H), 1.72 - 1.66 (m, 2H), 1.48 (s, 9H), 1.45 - 1.39 (m, 2H), 0.92(dd, J = 6.4 Hz, 12.4 Hz, 7H).

[0088] Compound 2B Preparation A solution of compound 2A (25.0 g, 217 mmol, 1.00 equivalent) in THF (250 mL) and H₂O (250 mL) was added to NaHCO₃ (36.4 g, 434 mmol, 16.8 mL, 2 equivalent) and Fmoc-Osu (69.5 g, 206 mmol, 0.95 equivalent) at 25 °C. The reaction mixture was stirred at 25 °C for 1 h. LCMS showed that compound 2A was consumed and the desired MW was detected. The reaction mixture was extracted with PE (100 mL x 3). The pH of the aqueous layer was adjusted to 2–3 with 1 N HCl and then extracted with EtOAc (500 mL x 3). The combined organic layers were washed with brine (500 mL x 2), dried over Na₂SO₄, and concentrated to give crude compound 2B (65.0 g, 192 mmol, 88.7% yield) as a white solid. The crude product is used in the next step without further purification.

[0089] LCMS: m / z 338.0 [M+H] + Preparation of compound 3 HATU (118 g, 310 mmol, 1.50 equivalence), DIEA (53.5 g, 414 mmol, 72.1 mL, 2.00 equivalence), and compound 2 (55.0 g, 227 mmol, 1.10 equivalence) were added to a solution of compound 2B (69.8 g, 207 mmol, 1.00 equivalence) in DMF (600 mL) at 25 °C. The reaction mixture was stirred at 25 °C for 1 h. LCMS showed that compound 2B was consumed and the desired MW was detected. The reaction mixture was poured into H2O (2 L) and extracted with EtOAC (800 mL x 3). The combined organic layers were washed with H2O (500 mL x 3) and brine (500 mL x 2), dried over Na2SO4, and concentrated. The residue was purified by column chromatography (SiO2, PE:EtOAc = 100:1 to 10:1) to give compound 3 as a pale yellow oil (79.0 g, 136 mmol, 66.0% yield, 97.1% purity).

[0090] LCMS: m / z 583.3 [M+Na] + 1 HNMR (CDCl3, 400 MHz) δ 7.77 (d, J = 7.6 Hz, 2H), 7.60 (d,J = 7.6Hz, 2H), 7.40 (t, J = 7.2 Hz, 2H), 7.31 (t, J = 7.6 Hz, 2H), 5.88 - 5.69 (m,2H), 5.59 (br d, J = 9.2 Hz, 1H), 5.23 - 5.00 (m, 4H), 4.75 - 4.66 (m, 1H), 4.51 - 4.18 (m, 4H), 3.55 - 3.47 (m, 1H), 3.25 - 3.12 (m, 1H), 2.62 - 2.30(m, 4H), 1.92 - 1.81 (m, 1H), 1.74 - 1.63 (m, 1H), 1.58 (s, 3H), 1.45 - 1.38(m, 9H), 1.06 - 0.88 (m, 7H).

[0091] Preparation of compound 4 [1,3-bis(2,4,6-trimethylphenyl)imidazolidine-2-ylidene]-dichloro-[(2-isopropoxyphenyl)methylene]ruthenium (135 mg, 216 μmol, 0.05 equivalent) was added to a solution of compound 3 (2.50 g, 4.33 mmol, 97.1% purity, 1.00 equivalent) in DCE (250 mL) at 25 °C. The reaction mixture was stirred at 85 °C for 16 h. TLC (PE:EtOAc = 3:1) showed the formation of a large spot, but some of compound 3 was retained. LCMS showed the expected MW. The reaction mixture was concentrated. The residue was purified by column chromatography (SiO2, PE:EtOAC = 50:1 to 3:1) to give compound 4 (1.26 g, 2.29 mmol, 52.7% yield, 96.6% purity) as a white solid.

[0092] LCMS m / z 533.3 [M+H] + Preparation of intermediate 4 A solution of compound 4 (10.0 g, 18.2 mmol, 1.0 equivalent) in DCM (100 mL) and TFA (30 mL) was stirred at 25 °C for 1 h. LCMS showed that compound 4 was consumed and the desired MW was detected. The reaction mixture was concentrated to give crude intermediate 4 (17.0 g, 35.6 mmol, 97.5% yield) as a brown solid. The crude product was used in the next step without further purification.

[0093] LCMS: m / z 477.1 [M+H] + Example TBA-315 Peptide synthesis: Peptides were synthesized using standard Fmoc chemical synthesis.

[0094] 1. Resin Preparation: A suspension of 2-CTC resin (6.00 mmol, 1.00 equivalent, Sub 1.07 mmol / g), (S)-2-((S,Z)-3-((((9H-fluorene-9-yl)methoxy)carbonyl)(methyl)amino)-2-oxo-3,4,7,8-tetrahydroazaoct-1(2H)-yl)-4-methylpentanoic acid (intermediate 4, 2.94 g, 6.00 mmol, 1.00 equivalent), and DIEA (24.0 mmol, 4.50 mL, 4.00 equivalent) in DCM (200 mL) was stirred at 20°C under N2 for 2 hours. Then, MeOH (6 mL) was added, and stirring continued under N2 for another 30 minutes. The resin was washed with DMF (300 mL x 5) and filtered to separate the resin.

[0095] 2. Add 200 mL of DMF containing 20% ​​piperidine solution to the above resin, and stir the resulting suspension under N2 for another 30 minutes. Wash the resin with DMF (300 mL x 5) and separate by filtration.

[0096] 3. Coupling: A solution of Fmoc-Ala-OH (2.80 g, 9.00 mmol, 1.50 equivalent), a solution of HOAT (1.16 g, 8.64 mmol, 1.43 equivalent) in DMF (200 mL), and DIC (1.14 g, 9.00 mmol, 1.44 mL, 1.50 equivalent) were added to the above resin. The resulting suspension was stirred at 20 °C under N2 for 1 hour. The resin was then washed with DMF (300 mL x 5) and separated by filtration.

[0097] 4. Repeat steps 2 to 3 above to achieve the coupling of the following amino acids: (steps 3-6 in the table) Fmoc deprotection was performed using DMF containing 20% ​​piperidine for 30 minutes. The coupling reaction was monitored by ninhydrin testing. Resin 1 was washed 5 times with DMF.

[0098] Peptide cleavage, cyclization, and purification: Cleavage buffer (DCM containing 1% TFA) was added to a flask containing the side-chain protected peptide 1 at room temperature, and the mixture was stirred for 30 minutes. The mixture was concentrated under vacuum to obtain crude peptide 2. The peptide was dissolved in DCM (1.00 mmol / L), and the pH of the solution was adjusted to 7–8 with DIEA. TBTU (2.00 equivalence) and HOBT (2.00 equivalence) were added for cyclization. LCMS after 30 minutes of stirring showed a major peak with the desired MW. The solvent was evaporated under vacuum. The residue was purified by preparative HPLC (conditions see table below) to give the final product TBA-315 (1.67 g, 1.32 mmol, 17.3% yield, 96.1% purity) as a yellow solid. Prepare the following analogues in Table I in a manner similar to TBA-315.

[0099] Table I Biological data The MABA MIC value was determined according to the published method (Microplate Alamar Blue Assay (MABA) and Low Oxygen Recovery Assay (LORA) for Mycobacterium tuberculosis). Cho S, Lee HS, Franzblau S. Methods in Molecular Biology 2015;1285:281-92.

[0100] Table 2 Synthesis of intermediates Intermediate 1 Preparation of 1-c: A mixture of 1-a (100 g, 227 mmol), 1-b (159 g, 2.27 mol, 240 mL), CF3COOAg (100 g, 454 mmol), and Cu(OAc)2 (82.5 g, 454 mmol) in MeCN (1.50 L) was added to Pd(OAc)2 (20.4 g, 90.8 mmol). The mixture was stirred at 35 °C for 8 hours. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 10:1 to 3:1) to give 1-c (28.8 g, 56.7 mmol, 25.5% yield) as a yellow oil. LCMS (ESI): m / z 509.2 [M+H] + . 1 H NMR (CDCl3, 400 MHz) δ: 7.77 (d, J = 7.6 Hz, 2H), 7.60 - 7.52 (m, 4H), 7.50 - 7.40 (m, 2H), 7.30 - 7.27 (m, 2H), 7.12 - 7.10 (m, 3H), 6.17 - 6.10(m, 1H), 5.40 (d, J = 8.4 Hz, 1H), 5.23 - 5.12 (m, 2H), 4.77 - 4.75 (m, 1H), 4.39 - 4.37 (m, 2H), 4.25 - 4.24 (m, 1H), 3.71 (s, 3H), 3.32 (d, J = 5.6 Hz, 2H), 1.73 (s, 6H).

[0101] Preparation of Intermediate 1: Under a N2 atmosphere, LiI (185 g, 1.39 mol) was added to a solution of 1-c (92.0 g, 173 mmol) in ethyl acetate (956 mL). The reaction mixture was stirred at 80 °C for 10 h. The pH of the mixture was adjusted to 5 with 1 NHCl aqueous solution and extracted with ethyl acetate (600 mL x 3). The combined organic layers were washed with brine (500 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by reversed-phase silica flash chromatography (column: C18 spherical 20-35 μm, 100 A; mobile phase A: H₂O containing 0.1% HCl, B: ACN; gradient: 15-95% B / A over 90 min; flow rate: 100 mL / min; detector PDA: 220 nm and 254 nm) to give intermediate 1 as a yellow solid (54.0 g, 10⁵ mmol, 61% yield). LCMS (ESI): m / z 495.2 [M+H] + . 1 H NMR (CDCl3, 400 MHz)δ: 7.60 -7.53 (m, 3H), 7.50 - 7.40 (m, 1H), 7.26 - 7.07 (m, 5H), 6.98 - 6.92(m, 4H), 6.09 - 5.84 (m, 1H), 5.83 - 5.68 (m, 1H), 5.00 - 5.94 (m, 2H), 4.57(m, 1H), 4.00 - 3.85 (m, 3H), 3.50 - 3.45 (m, 1H), 3.42 - 3.14 (m, 1H), 1.45(s, 6H).

[0102] Intermediate 2 Preparation of 2-b: Paraformaldehyde (101 g, 3.38 mol, 93.0 mL) and p-TsOH (10.7 g, 62.1 mmol) were added to a solution of 2-a (150 g, 533 mmol) in toluene (1.50 L). The mixture was heated to 110 °C for 2 hours, and water was removed through a Dean-Stark trap. The mixture was filtered, and the filtrate was concentrated to give compound 2-b (161 g, crude) as a pale yellow oil. 1 H NMR (CDCl3, 400 MHz) δ: 10.72 (s, 1H), 7.41 -7.19 (m, 5H), 5.54 (s, 1H), 5.24 - 5.16 (m, 3H), 4.42 - 4.39 (t, J = 5.6 Hz,1H), 2.52 - 2.46 (m, 2H), 2.40 - 2.30 (m, 1H), 2.22 - 2.06 (m, 1H).

[0103] Preparation of 2-c: Oxaloyl chloride (208 g, 1.64 mol, 143 mL) and DMF (2.2 mmol, 168 μL) were added to a solution of 2-b (320 g, 1.09 mol) in DCM (1.6 L). The reaction mixture was stirred at 10 °C for 3 hours under N2 atmosphere. The mixture was concentrated to dryness, and the residue was azeotropically treated three times with toluene (500 mL) to produce acyl chloride (340 g, crude). LiAl(OtBu)3H (124 g, 491 mmol, 6.1 mL) in THF (1.0 L) was added to a solution of acyl chloride (170 g, 545 mmol) in THF (1.0 L) at -70 °C under N2 atmosphere. The mixture was stirred at -70 °C for 2 hours. The reaction mixture was quenched at 0 °C with water (400 mL) and anhydrous sodium sulfate (500 g). The mixture was filtered, and the filter cake was washed with ethyl acetate (600 mL x 2). The filtrate was concentrated under reduced pressure to give 2-c (130 g), which is a dark brown oil. 1 H NMR (CDCl3, 400 MHz) δ : 9.71 (s, 1H), 7.43 - 7.36 (m, 5H), 5.54 (s, 1H), 5.22 - 5.16 (m, 3H), 4.41 - 4.36 (m, 1H), 2.61 - 2.50 (m, 2H), 2.34 - 2.20(m, 2H).

[0104] Preparation of 2-e: NaOAc (53.6 g, 656 mmol) was added to a solution of 2-c (260 g, 656 mmol) and 2-d (169 g, 656 mmol) in MeOH (1.80 L). The mixture was stirred at 10 °C for 10 min, and NaBH3CN (82.5 g, 1.31 mol) was added in portions. The mixture was then stirred at 10 °C for 2 h. The two batches were combined. The mixture was concentrated. The resulting residue was dissolved in H2O (3.0 L) and ethyl acetate (2.0 L). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 1:1) to give 2-e (110 g, crude) as a yellow oil. LCMS (ESI): m / z 465.1 [M-H2O+H] + . 1 H NMR (CDCl3, 400MHz) δ : 7.40 - 7.31 (m, 10H), 5.31 - 5.26 (m, 1H), 5.22 - 5.08 (m, 4H), 4.74(s, 1H), 4.68 - 4.62 (m, 1H), 4.44 (s, 1H), 3.30 - 3.21 (m, 2H), 2.07 - 2.05 (m, 1H), 1.98 - 1.95 (m, 2H), 1.78 - 1.72 (m, 3H), 1.29 - 1.25 (m, 1H), 0.96 - 0.91 (m, 6H).

[0105] Preparation of 2-f: TMSCl (49.5 g, 456 mmol, 57.9 mL) was added dropwise to a solution of 2-e (110 g, 228 mmol) and NaBH3CN (28.7 g, 456 mmol) in MeCN (550 mL) at 10 °C under a N2 atmosphere. The mixture was stirred at 30 °C for 16 h. The two batches were combined. The reaction mixture was poured into ice water (1.5 L) and extracted with ethyl acetate (1.5 L x 2). The combined organic layers were washed with brine (2.0 L) and dried over anhydrous sodium sulfate. The filtrate was concentrated to dryness. The crude product was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 2:1) to give 2-f as a colorless oil (120 g, 249 mmol, 54.7% yield). 1 H NMR (CDCl3, 400 MHz) δ: 7.39 - 7.31 (m, 10H), 5.43 - 5.39 (m, 1H), 5.18 - 5.09 (m, 4H), 4.84 - 4.60 (m, 1H), 3.21 - 3.19(m, 2H), 2.74 - 2.72 (m, 3H), 2.09 - 1.97 (m, 2H), 1.85 - 1.74 (m, 4H), 1.60 (m, 1H), 0.96 - 0.91 (m, 6H).

[0106] Preparation of 2-g: Pd / C (42.0 g, 10% purity) was added to a solution of 2-f (136 g, 282 mmol) in EtOH (400 mL) under a N2 atmosphere. The mixture was degassed, purged three times with H2, and stirred at 30 °C for 48 hours under a H2 atmosphere (15 Psi). The mixture was filtered and concentrated to give 2-g (70.0 g, crude product) as a white solid. LCMS (ESI): m / z 243.2 [M+H] + . 1 H NMR (CDCl3, 400 MHz) δ : 7.59 - 7.53 (s, 2H), 5.10 - 5.06(m, 1H), 3.51 - 3.49 (m, 1H), 3.29 - 3.19 (m, 2H), 2.65 (s, 3H), 2.25 - 2.22(m, 1H), 2.06 - 2.01 (m, 2H), 1.80 - 1.64 (m, 3H), 1.50 (m, 1H), 0.93 - 0.87 (m, 6H).

[0107] Preparation of Intermediate 2: 2 g (70.0 g, 289 mmol, 1.0 equivalent) of NaHCO3 (648 g, 7.71 mol, 300 mL, 26.7 equivalent) and FmocOSu (97.5 g, 289 mmol, 1.00 equivalent) were added to a solution of 1,4-dioxane (300 mL) and H2O (300 mL) at 0 °C. The resulting solution was stirred at 10 °C for 2 hours, diluted with ice water (300 mL), and extracted with ethyl acetate (300 mL x 2). The combined organic layers were washed with water (300 mL), dried over anhydrous sodium sulfate, and concentrated to dryness. The crude product was purified by column chromatography (SiO2, dichloromethane / methanol = 10:1) to give Intermediate 2 (30 g). Simultaneously, the combined aqueous phases were adjusted to pH 3.0–5.0 with 1 N HCl aqueous solution and then extracted with ethyl acetate (500 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give intermediate 2 (95.0 g). The two batches were combined to give intermediate 2 as a white solid (125 g, 258 mmol, 89.4% yield). LCMS (ESI): m / z 465.2 [M+H] + . 1 H NMR (CDCl3, 400 MHz) δ : 7.78 - 7.76(m, 2H), 7.63 - 7.61 (m, 2H), 7.42 - 7.40 (m, 2H), 7.39 - 7.30 (m, 2H),5.30 -5.20 (m, 1H), 4.42 - 4.27 (m, 4H), 3.29 - 3.19 (m, 2H), 2.98 - 2.81 (m, 3H), 2.05 - 2.01 (m, 1H), 1.82 - 1.80 (m, 5H), 1.50 (m, 1H), 0.98 - 0.93 (m, 6H).

[0108] Intermediate 4 Preparation of 4-b: NaHCO3 (36.4 g, 434 mmol) and FmocOSu (69.5 g, 206 mmol) were added to a solution of 4-a (25.0 g, 217 mmol) in THF (250 mL) and H2O (250 mL) at 25 °C. After stirring at 25 °C for 1 hour, the reaction mixture was extracted with petroleum ether (100 mL x 3). The aqueous layer was adjusted to pH 2–3 with 1 N HCl aqueous solution and extracted with ethyl acetate (500 mL x 3). The combined organic layers were washed with brine (500 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to give 4-b as a white solid (65.0 g, 192 mmol, 88.7% yield). LCMS (ESI): m / z 338.0 [M+H] + .

[0109] Preparation of 4-e: LiOH•H2O (56.2 g, 1.34 mol) and 4-d (150 mL, 1.48 mol) were added to a solution of 4-c (100 g, 446 mmol, HCl salt) in DMF (1.0 L) at 25 °C. The reaction mixture was stirred at 25 °C for 16 h and then poured into water (1.50 L) and extracted with ethyl acetate (700 mL x 2). The combined organic layers were washed with brine (500 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 5:1) to give 4-e as a yellow oil (55.0 g, 227 mmol, 50.9% yield). 1 H NMR (CDCl3, 400 MHz) δ: 5.84 - 5.74 (m, 1H), 5.14 - 5.00 (m, 2H), 3.14 (t, J = 7.2 Hz, 1H), 2.70 - 2.62 (m, 1H), 2.57 - 2.51 (m, 1H), 2.31 -2.17 (m, 2H), 1.72 - 1.66 (m, 2H), 1.48 (s, 9H), 1.45 - 1.39 (m, 2H), 0.92(dd, J = 6.4 Hz, 12.4 Hz, 6H).

[0110] Preparation of 4-g: HATU (118 g, 310 mmol), DIEA (53.5 g, 414 mmol, 72.1 mL), and 4-e (55.0 g, 227 mmol) were added to a solution of 4-f (69.8 g, 207 mmol) in DMF (600 mL) at 25 °C. The reaction mixture was stirred at 25 °C for 1 hour and then poured into water (2 L), and extracted with ethyl acetate (800 mL x 3). The combined organic layers were washed with water (500 mL x 3) and brine (500 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 100:1 to 10:1) to give 4-g (79.0 g, 136 mmol, 66.0% yield) as a pale yellow oil. LCMS (ESI): m / z 583.2 [M+Na] + . 1 H NMR (CDCl3, 400 MHz) δ 7.77 (d, J = 7.6 Hz, 2H), 7.60 (d, J = 7.6 Hz, 2H), 7.40 (t, J = 7.2 Hz, 2H), 7.31 (t, J = 7.6 Hz, 2H), 5.88 - 5.69 (m, 2H), 5.59 (br d, J = 9.2 Hz, 1H), 5.23 - 5.00 (m, 4H), 4.75 - 4.66 (m, 1H), 4.51 -4.18 (m, 4H), 3.55 - 3.47 (m, 1H), 3.25 - 3.12 (m, 1H), 2.62 - 2.30 (m, 4H), 1.92 - 1.81 (m, 1H), 1.74 - 1.63 (m, 1H), 1.58 (m, 1H), 1.45 - 1.38 (m, 9H), 1.06 - 0.88 (m, 6H).

[0111] Preparation of 4-h: Hoveyda-Grubbs 2 (135 mg, 216 µmol) was added to a solution of 4-g (2.50 g, 4.33 mmol) in DCE (250 mL) at 25 °C. The reaction mixture was stirred at 85 °C for 16 h and then concentrated. The resulting residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 50:1 to 3:1) to give 4-h as a white solid (1.26 g, 2.29 mmol, 52.7% yield, 96.6% purity). LCMS (ESI): m / z 533.3 [M+H] + . 1 H NMR (CDCl3, 400 MHz) δ 7.80 - 7.78 (d, J = 8.0 Hz, 2H), 7.64 - 7.62 (d, J = 8.0 Hz, 2H), 7.44 - 7.41 (t, J = 8.0 Hz, 2H), 7.36 - 7.32 (t, J = 8.0Hz, 2H), 6.04 - 6.02 (d, J = 8.0 Hz, 1H), 5.75 - 5.71 (m, 1H), 5.62 - 5.60(m, 1H), 5.04 - 5.01 (m, 1H), 4.97 - 4.93 (m, 1H), 4.39 - 4.37 (d, J = 8.0Hz, 2H), 4.27 - 4.23 (t, J = 8.0 Hz, 1H), 3.73 - 3.69 (m, 1H), 3.55 - 3.51(m, 1H), 2.85 - 2.83 (m, 1H), 2.60 - 2.55 (m, 1H), 2.51 - 2.45 (m, 1H), 2.35- 2.30 (m, 1H), 1.75 - 1.72 (m, 1H), 1.59 - 1.51 (m, 2H), 1.47 (s, 9H), 0.97- 0.92 (m, 6H).

[0112] Preparation of intermediate 4: A solution of 4-h (10.0 g, 18.2 mmol) in DCM (100 mL) and TFA (30 mL, 403 mmol) was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give intermediate 4 as a brown solid (17.0 g, 35.6 mmol, 97.5% yield). LCMS (ESI): m / z 477.1 [M+H] + δ: 7.79 - 7.77 (d, J = 8.0 Hz, 2H), 7.62 - 7.60 (d, J = 8.0 Hz, 2H), 7.43 - 7.40 (t, J = 8.0Hz, 2H), 7.35 - 7.33 (t, J = 8.0 Hz, 2H), 6.22 - 6.20 (d, J = 8.0 Hz, 1H),5.74 - 5.68 (m, 1H), 5.60 - 5.57 (m, 1H), 5.04 - 5.01 (m, 2H), 4.38 - 4.36(d, J = 8.0 Hz, 2H), 4.25 - 4.21 (t, J = 8.0 Hz, 1H), 3.86 - 3.82 (m, 1H), 3.46 - 3.42 (m, 1H), 2.88 - 2.86 (m, 1H), 2.63 - 2.60 (m, 1H), 2.48 - 2.40(m, 1H), 2.33 - 2.29 (m, 1H), 1.86 - 1.83 (m, 1H), 1.68 - 1.56 (m, 2H), 0.96 - 0.90 (m, 6H).

[0113] Intermediate 15 Preparation of 15-c: Cs₂CO₃ (43.4 g, 133 mmol) and 15-b (13.6 g, 66.6 mmol) were added to a solution of 15-a (15.0 g, 66.6 mmol) in DMF (500 mL). The mixture was stirred at 100 °C for 12 hours under a N₂ atmosphere. After cooling to room temperature, the reaction mixture was diluted with water (1500 mL) and extracted with ethyl acetate (1000 mL x 3). The combined organic layers were washed with brine (1000 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO₂, petroleum ether:ethyl acetate = 30:1 to 1:1) to give 15-c (6.70 g, 25.6 mmol, 38.5% yield) as a yellow solid. LCMS (ESI): m / z 257.0 / 259.0 [M+H] + . 1 H NMR (DMSO- d 6 , 400 MHz) δ : 9.56 (s, 1H), 8.46 (d, J = 2.4 Hz, 1H), 8.11(dd, J = 2.4, 9.2 Hz, 1H), 7.83 (d, J = 9.2 Hz, 1H), 6.29 (s, 1H), 6.16 (s, 1H).

[0114] Preparation of 15-e: Under a N2 atmosphere, a suspension of Zn (32.5 g, 498 mmol) in DMF (50 mL) was slowly added to a solution of 15-d (25.1 g, 55.6 mmol) in DMF (150 mL). The mixture was stirred at 25 °C for 1.5 h. The supernatant was then pumped to a solution of 15-c (13.0 g, 50.5 mmol) in DMF (50 mL), degassed, and purged three times with N2. PdCl2 (448 mg, 2.53 mmol) was added, followed by Xphos (2.41 g, 5.06 mmol). The resulting mixture was degassed again, purged three times with N2, and then stirred at 25 °C for 12 h under a N2 atmosphere. The reaction mixture was filtered. The filtrate was diluted with water (600 mL) and extracted with ethyl acetate (600 mL x 3). The combined organic layers were washed with water (600 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 100:0 to 2:1) to give 15-e as a yellow solid (20.0 g, 38.5 mmol, 76.2% yield). LCMS (ESI): m / z 502.3 [M+H] + .

[0115] Preparation of intermediate 15: CaCl2 (68.4 g, 617 mmol) was added to a solution of 15-e (20.0 g, 38.5 mmol) in i-PrOH (90 mL) and THF (180 mL) at 0 °C, followed by the addition of LiOH·H2O (7.28 g, 173 mmol) in H2O (90 mL). The resulting mixture was stirred at 25 °C for 12 h, adjusted to pH 5-6 with 1 M HCl aqueous solution, and extracted with ethyl acetate (500 mL x 3). The combined organic layers were washed with water (500 mL) and brine (500 mL * 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by reversed-phase silica flash chromatography (column: C18 spherical 20-35 μm, 100 A; mobile phase A: H₂O containing 0.1% HCl, B: ACN; gradient: 10-95% B over 68 min; flow rate: 100 mL / min; detector PDA: 220 nm and 254 nm) to give intermediate 15 as a white solid (10.0 g, 20.3 mmol, 52.8% yield). LCMS (ESI): m / z 488.2 [M+H] + . 1H NMR (DMSO- d 6 , 400 MHz) δ : 13.04 - 12.63 (m, 1H), 9.48 (s, 1H), 8.07- 7.90 (m, 2H), 7.90 - 7.77 (m, 4H), 7.46 - 7.46 (m, 2H), 7.57-7.37 (m, 2H),7.29 - 7.13 (m, 2H), 6.28 (s, 1H), 6.15 (s, 1H), 4.40 - 4.27 (m, 1H), 4.22 -4.07 (m, 3H), 3.34 - 3.27 (m, 1H), 3.08 (m, 1H).

[0116] The intermediates in Table 3 were prepared in a manner similar to that used in the synthesis of intermediate 15.

[0117] Table 3: Intermediates prepared in a manner similar to that used in the synthesis of intermediate 15 Intermediate 8 Preparation of intermediate 8: BBr3 (1 M in DCM, 6.00 mL) was added to a solution of intermediate 9 (1.00 g, 2.13 mmol) in DCM (5 mL) at -78 °C. The mixture was stirred at 25 °C for 16 h. The mixture was quenched at -78 °C with a pre-mixed solution of MeOH (10 mL) and TEA (0.80 mL), filtered, and concentrated under reduced pressure. The crude product was purified by reversed-phase silica gel chromatography (column: C18 spherical 20-35 μm, 100 A; mobile phase A: H2O containing 0.1% TFA, B: ACN; gradient: 5-75% B over 28 min; flow rate: 100 mL / min; detector PDA: 220 nm and 254 nm) to give intermediate 8 (411 mg, 839 μmol, 39.4% yield) as a yellow solid. LCMS (ESI): m / z 456.1 [M+H] + . 1 H NMR (DMSO- d 6 , 400 MHz) δ : 13.29 - 12.43 (m, 1H), 12.18 - 11.55 (m,1H), 9.34 - 9.03 (m, 1H), 7.87 (br d, J = 7.6 Hz, 2H), 7.81 - 7.70 (m, 2H), 7.69 - 7.48 (m, 3H), 7.39 (br t, J = 7.6 Hz, 2H), 7.32 - 7.05 (m, 3H), 4.32 -4.03 (m, 4H), 3.20 - 3.10 (m, 1H), 2.99 - 2.84 (m, 1H).

[0118] Intermediate 17 Preparation of 17-b: NMM (9.31 mL, 84.6 mmol) and IBCF (12.1 mL, 93.1 mmol) were added to a solution of 17-a (10.0 g, 84.6 mmol) in THF (120 mL) at 0 °C. The mixture was stirred at 25 °C for 0.5 h, then filtered, and added to a solution of NaBH4 (7.05 g, 186 mmol) in H2O (80 mL) at 0 °C. The mixture was stirred at 25 °C for 2 h, then quenched with 1 M HCl solution (100 mL) at 0 °C and extracted with ethyl acetate 300 mL (100 mL x 3). The combined organic layers were washed with brine (300 mL), dried over sodium sulfate, filtered, and concentrated. The resulting residue was purified by column chromatography (SiO2, petroleum ether: ethyl acetate = 100:1 to 1:1) to obtain 17-b as a yellow oil (5.64 g, 54.1 mmol, 63.9% yield). 1 H NMR (DMSO- d 6 , 400 MHz) δ: 5.24 -4.75 (m, 1H), 4.59 (td, J = 5.6 Hz, 18.8 Hz, 1H), 3.37 (t, J = 5.2 Hz, 2H), 2.41 - 2.06 (m, 4H), 1.94 - 1.75 (m, 1H).

[0119] Preparation of 17-c: PCC (17.7 g, 41.9 mmol) was added to a solution of 17-b (3.64 g, 34.9 mmol) in DCM (70 mL) at 0 °C under a N2 atmosphere. The mixture was stirred at 25 °C for 2 hours, then filtered and concentrated under reduced pressure to give 17-c (3.57 g, crude product) as a colorless oil.

[0120] Preparation of 17-e: DBU (15.8 mL, 104 mmol) and 17-d (10.4 g, 31.4 mmol) were added to a solution of 17-c (3.57 g, 34.9 mmol) in DCM (120 mL) at 0 °C. The mixture was stirred at 25 °C for 12 h and then concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 50:1 to 1:1) to obtain 17-e (3.24 g, 8.87 mmol, 25.3% yield) as a yellow oil. LCMS (ESI): m / z 330.0 [M+Na] +. 1 H NMR (DMSO- d 6 , 400 MHz) δ: 9.17 - 8.51 (m, 1H), 7.62 - 7.28 (m, 5H), 6.76 - 6.22 (m, 1H), 5.39 - 4.81 (m, 3H), 3.76 - 3.58 (m, 3H), 3.32 - 3.06(m, 1H), 2.75 - 2.57 (m, 1H), 2.48 - 2.32 (m, 1H), 2.31 - 2.17 (m, 1H), 2.12- 1.95 (m, 1H).

[0121] Preparation of 17-f: 1,2-bis[(2S,5S)-2,5-diethylphosphonyl]benzene(1,5-cyclooctadiene)rhodium trifluoromethanesulfonate (I) (1.03 g, 1.43 mmol) was added to a solution of 26-e (4.40 g, 14.3 mmol) in MeOH (80.0 mL) under a N2 atmosphere. The mixture was stirred at 40 °C for 12 hours under H2 (50 psi). The mixture was filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (instrument: Agilent 1260; column: Gemini C18 110 A 150 * 4.6 mm, 5 μm, 50 °C; mobile phase A: H₂O containing 0.1% FA; B: ACN containing 0.075% FA; flow rate: 0.4 mL / min; detector PDA: 220 nm and 254 nm) to give 17-f as a yellow oil (3.0 g, 9.7 mmol, 67.7% yield).

[0122] Preparation of 17-g: H2O (4 mL) containing LiOH•H2O (325 mg, 7.76 mmol) was added to a solution of 17-f (1.60 g, 5.17 mmol) in THF (16.0 mL). The mixture was stirred at 25 °C for 2 hours, adjusted to pH 4-5 with 1 N HCl aqueous solution, and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain 17-g (1.50 g, crude product) as a yellow oil.

[0123] Preparation of 17-h: Wet Pd / C (700 mg) was added to a solution of 17-g (1.50 g, 5.08 mmol) in THF (15.0 mL) under N2 atmosphere. The mixture was stirred at 20 °C for 2 hours under H2 (15 Psi). The mixture was filtered and concentrated under reduced pressure to give 17-h (800 mg, crude product) as a colorless oil.

[0124] Preparation of intermediate 17: 6 mL of H₂O containing NaHCO₃ (1.25 g, 14.8 mmol) was added to a solution of 17-h (800 mg, 4.96 mmol) in THF (24 mL), followed by the addition of FmocOSu (1.67 g, 4.96 mmol). The mixture was stirred at 20 °C for 12 h, diluted with H₂O (10 mL), adjusted to pH 4-5 with 1 M HCl (aqueous solution), and extracted with 30 mL (10 mL x 3) of ethyl acetate. The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was wet-milled at 25 °C with petroleum ether:methyl tert-butyl ether = 10:1 (40 mL) for 60 min, and then filtered. The filter cake was washed with petroleum ether (200 mL) and dried under reduced pressure to give intermediate 17 as a white solid (1.78 g, 4.44 mmol, 89.4% yield). LCMS (ESI): m / z 406.4 [M+Na] + . 1 H NMR (DMSO- d 6 , 400 MHz) δ : 12.61 (br s, 1H), 7.89 (d, J = 7.6 Hz, 2H), 7.72 (dd, J = 2.0, 7.2 Hz, 2H), 7.62 (br t, J = 8.0 Hz, 1H), 7.47 - 7.37 (m,2H), 7.36 - 7.25 (m, 2H), 5.49 - 4.63 (m, 1H), 4.48 - 4.08 (m, 3H), 4.01 -3.72 (m, 1H), 2.47 - 2.27 (m, 2H), 2.26 - 1.95 (m, 2H), 1.86 - 1.64 (m, 3H).

[0125] Intermediate 46 Preparation of 46-c: 46-b (11.8 g, 161 mmol) was added to a solution of 46-a (10.0 g, 53.7 mmol) in H2O (100 mL). The mixture was stirred at 25 °C for 12 hours and then concentrated under reduced pressure. The residue was diluted with water (20 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain 46-c (12.0 g, crude) as a colorless oil.

[0126] 1 H NMR (CDCl3, 400 MHz) δ: 8.52 (s, 1H), 8.39 (m, 1H), 8.30 (dd, J =1.6, 7.6 Hz, 1H), 7.31 (dd, J = 4.8, 7.6 Hz, 1H), 1.32 (s, 9H).

[0127] Preparation of 46-e: PdCl2(PPh3)2 (291 mg, 414 μmol) and CuI (39.4 mg, 207 μmol) were added to a solution of 46-c (5.00 g, 20.7 mmol) and 46-d (5.65 g, 24.8 mmol) in TEA (100 mL). The mixture was stirred at 55 °C for 2 hours under N2 atmosphere, then filtered and concentrated under reduced pressure to give 46-e (8.00 g, crude product) as a red oil.

[0128] Preparation of 46-f: CuI (393 mg, 2.06 mmol) was added to a solution of 46-e (8.0 g, 20.6 mmol) in DMF (80 mL). The mixture was stirred at 100 °C for 12 h under N2 atmosphere. The mixture was diluted with ethyl acetate (20 mL) and washed with saturated NH4Cl aqueous solution (30 mL x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by reversed-phase silica gel chromatography (column: C18 spherical 20-35 μm, 100 A; mobile phase A: H2O; B: ACN; gradient: 10-85% B over 36 min; flow rate: 100 mL / min; detector PDA: 220 nm and 254 nm) to give 46-f (4.00 g, 11.9 mmol, 57.9% yield) as a brown solid. LCMS (ESI): m / z 332.1 [M+H] + . 1H NMR (CDCl3, 400 MHz) δ : 9.22 (s, 1H), 9.08 (br s, 1H), 8.28 (d, J =8.0 Hz, 1H), 7.76 (s, 1H), 7.52 (dd, J = 4.0, 8.0 Hz, 1H), 5.83 (br d, J =7.6 Hz, 1H), 4.92 - 4.72 (m, 1H), 3.72 (s, 3H), 3.49 (br d, J = 4.8 Hz, 2H), 1.41 (s, 9H).

[0129] Preparation of 46-g: A solution of 46-f (4.20 g, 12.6 mmol) in THF (40.0 mL) was added to H2O (10.0 mL) containing LiOH•H2O (797 mg, 19.0 mmol). The mixture was stirred at 25 °C for 2 hours, then diluted with water (50 mL) and extracted with MTBE (30 mL x 2). The aqueous layer was adjusted to pH 4 with 1 M HCl and extracted with ethyl acetate (15 mL x 5). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain 46-g (3.50 g, 11.0 mmol, 87.02% yield) as a brown solid. LCMS (ESI): m / z 318.2 [M+H] + .

[0130] Preparation of 46-h: HCl / dioxane (4 M, 15 mL) was added to a solution of 46-g (2.0 g, 6.3 mmol) in DCM (15.0 mL). The mixture was stirred at 25 °C for 2 hours and then concentrated under reduced pressure to obtain 46-h (1.37 g, crude product) as a brown solid.

[0131] Preparation of intermediate 46: A solution of 46-h (1.37 g, 6.31 mmol) in 1,4-dioxane (30.0 mL) was supplemented with 10 mL of H₂O containing 1.59 g, 18.9 mmol of NaHCO₃ and 2.13 g, 6.31 mmol of FmocOSu. The mixture was stirred at 25 °C for 3 hours, then diluted with water (30 mL) and extracted with MTBE (30 mL x 2). The aqueous layer was adjusted to pH 3 with 1 M HCl aqueous solution and extracted with ethyl acetate (20 mL x 3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase silica flash chromatography (column: C18 spherical 20-35 μm, 100 A; mobile phase A: H₂O containing 0.1% FA; B: ACN; gradient: 10-90% B over 50 min; flow rate: 100 mL / min; detector PDA: 220 nm and 254 nm) to obtain intermediate 46 (1.5 g, 3.36 mmol, 53.2% yield) as a yellow solid. LCMS (ESI): m / z 440.2 [M+H] + . 1 H NMR (CDCl3, 400 MHz) δ: 9.30 (s,1H), 9.16 (dd, J = 1.6, 4.4 Hz, 1H), 8.37 (br d, J = 8.0 Hz, 1H), 8.04 (s,1H), 7.79 (br d, J = 7.2 Hz, 2H), 7.71 - 7.55 (m, 3H), 7.48 - 7.39 (m, 2H),7.34 (q, J = 6.4 Hz, 2H), 6.29 (br d, J = 6.4 Hz, 1H), 4.87 - 4.73 (m, 1H), 4.55 - 4.37 (m, 2H), 4.34 - 4.22 (m, 1H), 3.78 - 3.57 (m, 2H).

[0132] Intermediate 20, as shown in Table 4, was prepared in a manner similar to that used in the synthesis of intermediate 46.

[0133] Table 4: Intermediate 20 Intermediate 54 Preparation of 54-b: Imidazole (13.1 g, 192 mmol) and TBDPS-Cl (31.6 g, 115 mmol, 29.5 mL) were added to a solution of 54-a (10.0 g, 96.1 mmol) in DCM (200 mL) at 0 °C. The reaction mixture was stirred at 25 °C for 12 h, then filtered, diluted with ice water (800 mL), and extracted with DCM (200 mL x 2). The combined organic layers were washed with brine (200 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude product was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 60:1 to 10:1) to give 54-b (32.2 g, 94.0 mmol, 97.8% yield) as a colorless oil. 1 H NMR (CDCl3, 400 MHz) δ: 7.73 - 7.62 (m, 4H), 7.51 -7.33 (m, 6H), 3.96 (t, J = 6.4 Hz, 2H), 3.70 (s, 3H), 2.59 (t, J = 6.4 Hz, 2H), 1.05 (s, 9H).

[0134] Preparation of 54-c: A 1 M NaOH aqueous solution (66.6 mL) was added to a solution of 54-b (22.2 g, 64.8 mmol) in EtOH (80.0 mL). The reaction mixture was stirred at 25 °C for 12 h, and then concentrated under reduced pressure to remove EtOH. The residue was treated with aqueous HCl (0.5 M) to adjust the pH to 5–6, and extracted with ethyl acetate (100 mL x 2). The combined organic layers were washed with brine (200 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 54-c (18.7 g, 56.9 mmol, 87.8% yield) as a white solid. 1 H NMR (CDCl3, 400 MHz) δ: 7.76 -7.65 (m, 4H), 7.46 - 7.34 (m, 6H), 3.97 (t, J = 6.4 Hz, 2H), 2.63 (t, J = 6.4Hz, 2H), 1.06 (s, 9H).

[0135] Preparation of 54-d: Oxaloyl dichloride (6.93 mL, 79.1 mmol) was added to a solution of 54-c (13.0 g, 39.5 mmol) in DCM (130 mL) at 0 °C. The reaction mixture was stirred at 25 °C for 12 hours under N2 atmosphere and then concentrated under reduced pressure to give 54-d (13.2 g, crude product) as a brown oil.

[0136] Preparation of 54-f: TEA (6.96 mL, 49.9 mmol) was added dropwise to a solution of 54-e (5.0 g, 25.0 mmol) in DCM (50 mL) at 0 °C, followed by the addition of a solution of 54-d (13.0 g, 37.4 mmol) in DCM (50.0 mL). The reaction mixture was stirred at 25 °C for 12 hours and then diluted with ice water (100 mL). The organic phase was washed with water (100 mL x 2) containing 0.5 MHCl, saturated NaHCO3 (100 mL x 2), and brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude product was purified by reversed-phase HPLC (column: C18 spherical 20-35 μm, 100A; mobile phase A: H2O containing 0.1% FA; B: ACN; gradient: 10-85% B over 36 min; flow rate: 100 mL / min; detector PDA: 220 nm and 254 nm) to obtain 54-f as a brown solid. 1 H NMR (DMSO- d 6 , 400 MHz) δ:10.83 (s, 1H), 9.93 (s, 1H), 8.08 (d, J = 8.8 Hz, 1H), 8.03 (d, J = 2.4 Hz, 1H), 7.88 (dd, J = 2.4, 8.8 Hz, 1H), 7.65 - 7.57 (m, 4H), 7.50 - 7.36 (m,6H), 3.97 (t, J = 6.0 Hz, 2H), 2.67 (t, J = 6.0 Hz, 2H), 0.93 (s, 9H).

[0137] Preparation of 54-g: NH3•H2O (34.6 mL, 225 mmol, 25%) was added to a solution of 54-f (4.30 g, 8.42 mmol) in i-PrOH (40.0 mL). The reaction mixture was stirred at 90 °C for 12 h, then cooled to room temperature, diluted with water (120 mL), and extracted with ethyl acetate (100 mL x 2). The combined organic phases were washed with water containing 1 M HCl (200 mL x 2), water containing saturated NaHCO3 (200 mL x 2), and brine (200 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 54-g (4.10 g, 8.34 mmol, 99% yield) as a brown solid. 1 H NMR (DMSO- d 6 , 400 MHz) δ: 9.51 (s, 1H), 8.42 (d, J = 2.0 Hz, 1H), 8.10 (dd, J =2.4, 8.8 Hz, 1H), 7.89 (d, J = 8.8 Hz, 1H), 7.54 - 7.47 (m, 4H), 7.45 - 7.39(m, 2H), 7.37 - 7.32 (m, 4H), 4.24 (t, J = 6.4 Hz, 2H), 3.32 - 3.28 (m, 2H), 0.85 (s, 9H).

[0138] Preparation of 54-i: Xphos (397 mg, 834 μmol), PdCl2 (73.9 mg, 417 μmol), and 54-h (4.31 g, 8.34 mmol) were added to a solution of 54-g (4.10 g, 8.34 mmol) in DMF (40.0 mL). The mixture was degassed, purged three times with N2, and stirred at 25 °C for 12 h under N2 atmosphere. The reaction mixture was filtered. The filtrate was diluted with water (200 mL) and extracted with ethyl acetate (200 mL x 2). The combined organic layers were washed with water (200 mL x 3) and brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 30:0 to 1:1) to give 54-i as a grayish-white solid (5.30 g, 6.68 mmol, 80.1% yield). LCMS (ESI): m / z 736.3. [M+H] +.

[0139] Preparation of 54-j: A solution of 54-i (4.10 g, 5.17 mmol) in HCl / MeOH (2 M, 40 mL) was stirred at 60 °C for 3 h. The reaction mixture was concentrated to dryness under vacuum. The crude product was wet-milled with DCM (50.0 mL) at 25 °C for 1 h, and then filtered. The filter cake was dried under vacuum to give 54-j (2.30 g, 4.58 mmol, 88.6% yield) as a white solid. LCMS (ESI): m / z 498.1 [M+H] + .

[0140] Preparation of intermediate 54: CaCl2 (8.13 g, 73.3 mmol) was added to a solution of 54-j (2.30 g, 4.58 mmol) in THF (24 mL) and i-PrOH (8 mL) at 0 °C, followed by the addition of LiOH·H2O (961 mg, 22.9 mmol) in H2O (8 mL). The mixture was stirred at 25 °C for 12 hours, then adjusted to pH 3-4 with water containing 1 M HCl, and extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with water (100 mL x 2) and brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by reversed-phase HPLC (column: C18 spherical 20-35 μm, 100 A; mobile phase A: H₂O containing 0.1% HCl, B: ACN; gradient: 10-95% B over 68 min; flow rate: 100 mL / min; detector PDA: 220 nm and 254 nm) to give intermediate 54 as a yellow solid (1.03 g, 2.02 mmol, 44.1% yield, 95.0% purity). LCMS (ESI): m / z 484.1 [M+H] + . 1 H NMR (DMSO- d 6 , 400 MHz) δ: 7.79- - 7.77 (m, 2H), 7.63 - 7.47 (m, 3H), 7.47 - 7.36(m, 4H), 7.32 - 7.25 (m, 2H), 7.19 (d, J = 8.4 Hz, 1H), 6.11 - 6.02 (m, 1H), 4.50 (dd, J= 4.4, 10.0 Hz, 1H), 4.33 - 4.26 (m, 1H), 4.26 - 4.11 (m, 2H), 4.10 - 3.94 (m, 2H), 3.53 - 3.32 (m, 2H), 3.10-2.95 (m, 1H), 2.91 - 2.82 (m,2H).

[0141] Intermediate 55 Preparation of intermediate 55: BBr3 (2 M in DCM, 1.26 mL) was added to a solution of 55-a (1.20 g, 1.94 mmol) in DCM (12.0 mL) at 0 °C under N2 atmosphere. The mixture was stirred at 25 °C for 3 h. The reaction mixture was quenched with MeOH (30 mL) at 0 °C and then concentrated to dryness under reduced pressure. The crude product was purified by preparative HPLC (column: Phenomenex Luna C18, 250 x 70 mm, 10 μm; mobile phase A: water containing 0.1% NH4HCO3; B: acetonitrile; gradient: 15% - 45% B over 22 min) to give intermediate 55 as a white solid (203 mg, 374 μmol, 19.2% yield). LCMS (ESI): m / z 528.2 [M+H]+. 1H NMR (DMSO- d 6 , 400 MHz) δ: 9.27(s, 1H), 7.93 - 7.72 (m, 4H), 7.65 - 7.53 (m, 3H), 7.38 (t, J = 6.8 Hz, 2H),7.24-7.23 (m, 2H), 7.04 - 6.92 (m, 1H), 4.70 (br s, 1H), 4.28 - 4.00 (m, 6H),3.24 - 3.14 (m, 1H), 3.12 - 3.03 (m, 1H), 1.23 (s, 6H).

[0142] Intermediate 60: Preparation of 60-c: NMM (19.5 mmol, 2.15 mL) and IBCF (21.5 mmol, 2.82 mL) were added to a solution of 60-a (2.00 g, 19.5 mmol) in THF (20.0 mL) at 0 °C. The mixture was stirred at 0 °C for 0.5 h. Then 60-b (3.92 g, 19.5 mmol) was added. The mixture was stirred at 25 °C for 12 h, diluted with 100 mL of water, and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 20:1 to 2:1) to give 60-c (1.10 g, 14.8% yield, 75% purity) as a red solid. LCMS (ESI): m / z 283.9 [M+H] + .

[0143] Preparation of 60-d: A solution of 60-c (1.10 g, 2.91 mmol) in NH3 gas and MeOH (7 M, 20 mL) was stirred at 25 °C for 7 hours. The mixture was concentrated under vacuum. The resulting residue was purified by column chromatography (SiO2, petroleum ether: ethyl acetate = 20:1 to 2:1) to give 60-d as a yellow solid (590 mg, 76.4% yield). 1 H NMR (CDCl3, 400 MHz) δ: 9.38 (s, 1H), 8.11 (d, J = 2.0 Hz, 1H), 8.05 - 7.96 (m,1H), 7.95 - 7.84 (m, 1H), 5.16 (d, J = 7.6 Hz, 4H), 4.73 - 4.60 (m, 1H).

[0144] Preparation of 60-f: Under a N2 atmosphere, a solution of 60-e (1.55 g, 3.43 mmol) in DMF (5.0 mL) was slowly added to a suspension of Zn (1.29 g, 19.7 mmol) in DMF (5.0 mL). The mixture was stirred at 25 °C for 1.5 h. The supernatant was then pumped to a solution of 60-d (700 mg, 2.64 mmol) in DMF (15.0 mL), degassed, and purged three times with N2. PdCl2 (46.8 mg, 264 μmol) was added, followed by Xphos (125 mg, 264 μmol). The resulting mixture was degassed again, purged three times with N2, and then stirred at 25 °C for 12 h under a N2 atmosphere. The reaction mixture was filtered. The filtrate was diluted with water (30 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with water (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 10:0 to 0:1) to give 60-f (877 mg, 65.1% yield) as a brown solid. LCMS (ESI): m / z 510.3 [M+H] + .

[0145] Preparation of intermediate 60: At 0 °C, a solution of 60-f (770 mg, 1.51 mmol) in THF (4.0 mL) and i-PrOH (2.0 mL) was added to H2O (2.0 mL) containing CaCl2 (2.68 g, 24.1 mmol, 16.0 equivalent) and LiOH·H2O (253 mg, 6.04 mmol). The mixture was stirred at 25 °C for 12 hours. The reaction mixture was diluted with DMF (20 mL) and H2O (20 mL), the pH was adjusted to 5 with an aqueous solution of 1 M HCl, and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with H2O (30 mL x 5) and brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was wet-milled with DCM (20 mL) at 25 °C to obtain intermediate 60 (388 mg, 51% yield, 98.5% purity) as a white solid. LCMS (ESI): m / z 496.3 [M+H] + . 1 H NMR (DMSO- d 6 , 400 MHz) δ: 9.50 (s, 1H), 7.98 - 7.83 (m, 6H), 7.54 - 7.53 (m, 2H), 7.37 (t, J = 7.2Hz, 2H), 7.34 - 7.16 (m, 2H), 4.98 - 4.90 (m, 4H), 4.60 - 4.57 (m, 1H), 4.34- 4.33 (m, 1H), 4.14 - 4.12 (m, 2H), 4.09 - 4.07 (m, 1H), 3.16 - 3.08 (m, 2H).

[0146] Intermediate 61: Preparation of 61-b: 61-b (23 g, 62.4 mmol, 81% yield) was prepared from commercially available 61-a (10 g, 76.8 mmol) using the same procedure described in the synthesis of intermediate 54-b, as a colorless oil. LCMS (ESI): m / z 369.0 [M+H] + .

[0147] Preparation of 61-c: 61-c (28.1 g, 79.2 mmol, 91.2% yield) was prepared from 61-b (32.0 g, 86.8 mmol) using the same procedure described in the synthesis of intermediate 54-c. LCMS (ESI): m / z 377.0 [M+Na] + .

[0148] Preparation of 61-d: 61-d (28 g crude) was prepared from 61-c (28.1 g, 79.2 mmol) as a yellow oil by the same procedure described in the synthesis of intermediate 54-d.

[0149] Preparation of 61-f: 61-f (20 g, 37.2 mmol, 64.5% yield) was prepared from 61-e (11.5 g, 57.7 mmol) using the same procedure described in the synthesis of intermediate 54-f. LCMS (ESI): m / z 538.1 [M+H] + .

[0150] Preparation of 61-g: 61-g (18 g, 34.7 mmol, 93.3% yield) was prepared from 61-f (10.0 g, 18.6 mmol) using the same procedure described in the synthesis of intermediate 54-g. LCMS (ESI): m / z 535.3 [M+H2O] + .

[0151] Preparation of 61-i: 61-i (9.0 g, 11.8 mmol, 61% yield) was prepared from 61-g (10.0 g, 19.3 mmol) in a yellow oil using the same procedure described in the synthesis of intermediate 54-i. LCMS (ESI): m / z 762.4 [M+H] + .

[0152] Preparation of 61-j: 61-j (4.0 g, 7.64 mmol, 72.7% yield) was prepared from 61-i (8.0 g, 10.5 mmol) by the same procedure described in the synthesis of intermediate 54-j. LCMS (ESI): m / z 542.3 [M+H2O] + .

[0153] Preparation of intermediate 61: Intermediate 61 (1.80 g, 3.51 mmol, 45.9% yield, 99.4% purity) was prepared from 61-j (4.00 g, 7.64 mmol) using the same procedure described in the synthesis of intermediate 54. LCMS (ESI): m / z 510.1 [M+H] + . 1 H NMR (DMSO- d 6 , 400 MHz) δ: 12.7 - 13.0 (m, 1H), 9.44 (s, 1H), 7.90 - 7.93 (m, 2H), 7.80 - 7.85 (m, 4H), 7.53 (t, 2H, J = 7.2Hz), 7.36 (t, 2H, J = 7.6 Hz), 7.20 (t, 1H, J = 7.6 Hz), 7.14 (t, 1H, J = 7.6Hz), 5.17 (d, 1H, J = 6.8 Hz), 4.30 - 4.36 (m, 1H), 4.08 - 4.19 (m, 4H), 3.36- 3.40 (m, 1H), 3.22 - 3.27 (m, 1H), 3.09 (dd, 1H, J =10.8, 13.6 Hz), 2.58 -2.62 (m, 2H), 2.24 - 2.32 (m, 2H).

[0154] Intermediate 62: Preparation of 62-c: 62-c (4.2 g, 14.8 mmol, 36.1% yield) was prepared as a white solid from commercially available 62-a (10.0 g, 41.0 mmol) using the same procedure described in the synthesis of intermediate 63-c. LCMS (ESI): m / z 283.0 [M+H] + .

[0155] Preparation of 62-e: 62-e (3.0 g, 5.68 mmol, 53.6% yield) was prepared from 62-c (3.0 g, 10.5 mmol) by the same procedure described in the synthesis of intermediate 63-e. LCMS (ESI): m / z 528.3 [M+H] + .

[0156] Preparation of intermediate 62: Intermediate 62 (1.56 g, 3.0 mmol, 52.8% yield, 99% purity) was prepared from 62-e (3.00 g, 5.68 mmol) using the same procedure described in the synthesis of intermediate 63. LCMS (ESI): m / z 514.2 [M+H] + . 1 H NMR (DMSO- d 6 , 400 MHz) δ: 13.25 - 12.45 (m, 1H), 9.41 -9.27 (m, 1H), 7.91 (s, 1H), 7.88 - 7.79 (m, 4H), 7.73 - 7.64 (m, 1H), 7.60 -7.46 (m, 2H), 7.38 (t, J = 7.2 Hz, 2H), 7.28 - 7.16 (m, 2H), 5.03 - 4.85 (m,1H), 4.29 - 4.25 (m, 2H), 4.24 - 4.09 (m, 4H), 4.09 - 3.95 (m, 1H), 3.67 -3.51 (m, 1H), 3.10 - 3.00 (m, 1H), 1.32 - 1.16 (m, 3H).

[0157] Intermediate 63 Preparation of 63-c: Cs₂CO₃ (20.0 g, 61.6 mmol) and 63-b (8.26 mL, 53.3 mmol) were added to a solution of 63-a (10.0 g, 41.0 mmol) in DMF (200 mL). The reaction mixture was stirred at 60 °C for 12 h, diluted with water (600 mL), and extracted with ethyl acetate (200 mL x 3). The combined organic layers were washed with water (600 mL x 2) and brine (400 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO₂, petroleum ether:ethyl acetate = 40:0 to 0:1) to give 63-c (4.7 g, 12.6 mmol, 31% yield) as a yellow solid. LCMS (ESI): m / z 392.1 [M+Na] + .

[0158] Preparation of 63-e: PdCl2 (134 mg, 760 μmol), Xphos (724 mg, 1.52 mmol), and 63-d (11.0 g, 21.2 mmol) were added to a solution of 63-c (5.6 g, 15.2 mmol) in DMF (60 mL). The mixture was degassed, purged three times with N2, and stirred at 25 °C for 12 h under N2 atmosphere. The reaction mixture was filtered. The filtrate was diluted with water (200 mL) and extracted with ethyl acetate (200 mL x 2). The combined organic layers were washed with water (200 mL x 3) and brine (200 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 30:0 to 1:1) to give 63-e as a white solid (6.80 g, 11.1 mmol, 72.9% yield). LCMS (ESI): m / z 613.3 [M+H] + .

[0159] Preparation of intermediate 63: At 0 °C, a solution of 63-e (6.80 g, 11.1 mmol) in i-PrOH (35 mL) and THF (70 mL) was added to H2O (35 mL) containing CaCl2 (19.7 g, 177 mmol) and LiOH•H2O (1.86 g, 44.4 mmol). The mixture was stirred at 25 °C for 12 hours. The reaction mixture was adjusted to pH 5-6 with 1 M HCl aqueous solution and extracted with ethyl acetate (300 mL x 2). The combined organic layers were washed with brine (300 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by reversed-phase HPLC (column: C18 spherical 20-35 μm, 100 A; mobile phase A: H₂O, B: ACN; gradient: 10-75% B over 58 min; flow rate: 100 mL / min; detector PDA: 220 nm and 254 nm) to give intermediate 63 as a white solid (3.80 g, 6.35 mmol, 57.1% yield). LCMS (ESI): m / z 599.3 [M+H] + . 1 H NMR (DMSO-d 6 , 400 MHz) δ: 13.36 - 12.53(m, 1H), 9.34 (s, 1H), 7.91 (s, 1H), 7.86 (d, J = 7.6 Hz, 3H), 7.79 (d, J =8.4 Hz, 1H), 7.69 (d, J = 8.8 Hz, 1H), 7.58 (dd, J = 4.0, 7.2 Hz, 2H), 7.38( t, J = 7.6 Hz, 2H), 7.29 - 7.16 (m, 2H), 7.05 (s, 1H), 4.38 (t, J = 5.2 Hz,2H), 4.33 - 4.24 (m, 1H), 4.22 - 4.07 (m, 3H), 3.37 (d, J = 5.6 Hz, 2H), 3.29- 3.22 (m, 1H), 3.12 - 2.99 (m, 1H), 1.37 (s, 9H).

[0160] Some intermediates: Intermediate 59 can be prepared in a manner similar to the synthesis of intermediate 54 according to the following scheme: Synthesis scheme of intermediate 64: 64-c can be prepared from commercially available 64-a and 64-b in a manner similar to the synthesis of intermediate 62-c.

[0161] 64-e can be prepared from 64-c and 64-d in a manner similar to the synthesis of intermediate 62-e.

[0162] 64-f can be prepared by hydrolyzing 64-e under alkaline conditions, such as THF / H2O containing 2-4 equivalents of LiOH, at room temperature for several hours.

[0163] 64-g can be prepared from 64-f by removing the Boc group at room temperature for several hours under acidic conditions, such as DCM containing 2 M HCl / dioxane.

[0164] Intermediate 64 can be prepared by protecting 64-g with Fmoc at room temperature for several hours under reaction conditions, such as THF / H2O containing 1.1 equivalents of FmocOSu and 2-3 equivalents of NaHCO3.

[0165] Intermediate 65 can be prepared in a manner similar to the synthesis of intermediate 60, according to the following scheme: Intermediate 66 can be prepared in a manner similar to the synthesis of intermediate 61 according to the following scheme: Synthesis scheme of intermediate 67: 67-c can be prepared from commercially available 67-a and 67-b using the same procedure described in the synthesis of intermediate 63-c.

[0166] 67-e can be prepared from 67-c and 67-d using the same procedure described in the synthesis of intermediate 63-e.

[0167] 67-f can be prepared from 67-e using the same procedure described in the synthesis of intermediate 63.

[0168] The formulation of intermediate 67 can be prepared from 67-f using the same procedure described in the synthesis of intermediate 55.

[0169] Intermediate 68 can be prepared in a manner similar to the synthesis of intermediate 62 according to the following scheme: Intermediate 69 can be prepared in a manner similar to the synthesis of intermediate 63 according to the following scheme: Intermediate 70 can be prepared in a manner similar to the synthesis of intermediate 67 according to the following scheme: Synthesis of compound I: Example TBA-302: (2S,5S,8S,11S,14S,17S,20S)-5-benzyl-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-14-[(6-quinoxalinyl)methyl]-1,4,7,10,13,16,19-heptaazabicyclo[18.3.1]teicosane-3,6,9,12,15,18,24-heptaone Synthesis of TBA-302-Intermediate A: Peptides were synthesized using standard Fmoc chemical synthesis.

[0170] 1) Resin Preparation: A mixture of 2-CTC resin (0.25 mmol, substituted 1.00 mmol / g), (S)-2-((S)-3((((9H-fluorene-9-yl)methoxy)carbonyl)(methyl)amino)-2-oxoazacyclooctane-1-yl)-4-methylpentanoic acid (intermediate 2, 0.12 g, 0.25 mmol), and DIEA (0.13 g, 1.00 mmol, 0.17 mL) in DCM (20.0 mL) was stirred with N2 for 2.00 h at 20 °C. Then, MeOH (0.25 mL) was added. The mixture was stirred with N2 for 30 min and filtered. The resin was washed with DMF (30.0 mL x 5).

[0171] 2) Deprotection: Add 20.0 mL of DMF containing 20% ​​piperidine to the above resin in the flask. Stir the mixture with N2 for 30 minutes and filter. Wash the resin with DMF (30 mL x 5).

[0172] 3) Coupling: Add DIC (47.3 mg, 0.38 mmol, 0.06 mL) to a solution of Fmoc-Ala-OH (116 mg, 0.38 mmol) and HOAT (48.5 mg, 0.36 mmol) in DMF (20 mL). Add the resulting solution to the resin obtained from step 2. Stir the mixture with N2 at 20 °C for 1 hour and filter. Wash with DMF (30 mL x 5).

[0173] 4) Repeat steps 2) to 3) above to couple with the amino acid in steps 3-6 according to the table below to obtain TBA-302-intermediate A. Synthesis of TBA-302-Intermediate B: Add cleavage buffer (1% TFA / 99% DCM) to a flask containing TBA-302-intermediate A at room temperature. Stir the mixture for 30 minutes and filter to collect the filtrate. Treat the filter cake with cleavage buffer for 30 minutes and filter again. Concentrate the combined filtrates under reduced pressure to obtain the crude peptide TBA-302-intermediate B, which was confirmed by LCMS. (ESI) m / z 1023.7 [M+H] + .

[0174] Synthesis of TBA-302: Crude TBA-302 intermediate B was dissolved in DCM (1.0 mmol / L). The pH of the solution was adjusted to 7–8 using DIEA. TBTU (2.00 equivalents) and HOBT (2.00 equivalents) were added for cyclization. LCMS after 30 minutes of stirring showed a major peak with the desired MW. The solvent was evaporated under reduced pressure. The resulting residue was purified by preparative HPLC (conditions shown in the table below) to give the final product TBA-302 (87.8 mg, 85.8 µmol, 34.4% yield, 96.4% purity) as a grayish-white solid. LCMS (ESI): m / z 1023.6 [M+H] + The examples listed in Table 3 were prepared in a manner similar to the synthesis of example TBA-302, using commercially available reagents and intermediates described in this application.

[0175] Table 6: Examples of preparations made in a manner similar to the synthesis of TBA-302 Synthesis of Compounds of Formula III Example TBA-306: (2S,5S,8S,11S,14S,17S,20S,Z)-5-benzyl-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-14-[(6-quinoxalinyl)methyl]-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexadec-22-ene-3,6,9,12,15,18,26-heptaone Synthesis of TBA-306 Intermediate A and TBA-306 Intermediate B: Based on the procedure described in the synthesis of TBA-302-intermediate A and TBA-302-intermediate B, TBA-306-intermediate A was prepared from 2-CTC resin (0.25 mmol, substituted 1.0 mmol / g) and (S)-2-((S,Z)-3-((((9H-fluorene-9-yl)methoxy)carbonyl)(methyl)amino)-2-oxo-3,4,7,8-tetrahydroazaoct-1(2H)-yl)-4-methylpentanoic acid (intermediate 4, 0.12 g, 0.25 mmol), and said TBA-306-intermediate A was converted into TBA-306-intermediate B (LCMS(ESI) m / z 1049.8 [M+H]+).

[0176] Synthesis of TBA-306 The crude intermediate TBA-306-intermediate B was dissolved in DCM (1.0 mmol / L). The pH of the solution was adjusted to 7-8 using DIEA. TBTU (2.0 equivalent) and HOBT (2.0 equivalent) were added for cyclization. LCMS after 30 min stirring showed a major peak with the desired MW. The solvent was evaporated under reduced pressure. The crude product was purified by preparative HPLC using the conditions described in the purification of TBA-302, but with the dissolving solvent changed to water containing 60% ACN and the gradient changed to 18%-82% A / B over 24 min. TBA-306 was obtained as a grayish-white solid (28.4 mg, 27.1 µmol, 10.8% yield, 95.3% purity). LCMS (ESI): m / z 1049.6 [M+H] + .

[0177] The examples listed in Table 7 were prepared in a manner similar to that used in the synthesis of TBA-306, using commercially available reagents and intermediates described in this application.

[0178] Table 7: Examples of preparations made in a manner similar to the synthesis of TBA-306. TBA-386_P1 and TBA-386_P2 were separated by preparative HPLC (instrument: Gilson GX-281; ​​column: Gemini C18 110 A 150 x 4.6 mm, 10 μm, 50 °C; mobile phase A: H2O containing 0.1% TFA; B: ACN; gradient: 16-84% B over 50 min; flow rate: 10 mL / min; detector PDA: 220 nm and 254 nm).

[0179] TBA-387_P1 and TBA-387_P2 were separated by preparative HPLC (instrument: Agilent 1260; column: Fenoxetine Luna C18 110 A 250 x 70 mm, 10 μm, 50 °C; mobile phase A: H2O containing 0.1% NH4HCO3; B: ACN; gradient: 15%–84% B over 45 min; flow rate: 10 mL / min; detector PDA: 220 nm and 254 nm).

[0180] Synthesis of another implementation method: The following examples in Table 8 can be prepared using commercially available reagents and intermediates described in this application, employing the synthetic regimens of Example TBA-302 or Example TBA-306.

[0181] Table 8: Other Implementation Methods Biological data 1. Mtb H37Rv MABA determination All experiments on Mycobacterium tuberculosis (Mtb) were performed in a Biosafety Level 3 (BSL3) laboratory using the previously described Microplate Almar Blue Assay (MABA) (Cho, S. et al., 2015). Briefly, stock solutions of the compounds were prepared in dimethyl sulfoxide (DMSO) at the highest desired final concentration of 100×. The compounds were transferred to assay plates containing Middlebrook 7H12 medium (for 1 L of medium, 4.7 g 7H9 broth, 1 g casein (Bacto), 5 g bovine serum albumin (BSA), 4 mg catalase, and 5.6 mg palmitic acid). Nine 2-fold serial dilutions of the compounds were performed on the assay plates. The plates were inoculated with Mycobacterium tuberculosis strain H37Rv (ATCC 27294) to achieve a final density of approximately 1 × 10⁵ CFU / mL and incubated at 37°C for 7 days. At the end of day 7, a rezinox dye / tween 80 mixture (0.6 mM rezinox dye and 12 μL 20% Tween 80) was added to each well, and the plate was incubated at 37°C for an additional 18 to 24 hours. Fluorescence was measured on day 8 using a CLARIOstar plate reader (BMG LABTECH, Ortenberg, Germany). MIC is an extrapolated value and is defined as the lowest concentration at which a 90% reduction in fluorescence is achieved relative to the DMSO-treated control. MABA MIC values ​​are listed in Table 9.

[0182] 2. Vero cytotoxicity Cytotoxicity was evaluated using green monkey kidney cells (Vero cells ATCC-CCL-81, American Type Culture Collection, Manassas, VA) in the BSL2 laboratory. Stock solutions of the compounds were prepared in dimethyl sulfoxide at the highest desired final concentration of 100×. The compounds were transferred to assay plates containing Eagle's minimum essential medium, 10% fetal bovine serum supplemented with penicillin and streptomycin. Five 2-fold serial dilutions of the compounds were performed in the assay plates. Vero cells were added to achieve a final density of 1 × 10⁵ cells / mL, and the plates were incubated at 37°C and 5% CO₂ for 3 days. Twenty μL of 0.6 mM resazurite was added to each well, and fluorescence was measured at 530 / 590 nm excitation / emission wavelengths using a CLARIOstar (BMG LABTECH, Oltenberg, Germany) after 4 hours. 50 The concentration defined as achieving a 50% reduction in fluorescence relative to untreated cells. Rifampin, bedaquiline, tamoxifen, carbonyl cyanide-3-chlorophenylhydrazone, tacrine, and moxifloxacin were included as positive controls. IC50 50 The values ​​are listed in Table 9.

[0183] 3. Direct binding analysis via surface plasmon resonance (SPR) Direct binding assays were performed by SPR using a Biacore T200 or Biacore 8K (Cytiva LifeSciences) as previously reported (Wolf et al., 2019). Recombinant ClpC1 protein was purified as previously described (Gao et al., 2015). The ClpC1 enzyme was immobilized on a CM5 sensor chip using standard amine coupling with running buffer PBS-P (20 mM phosphate (pH 7.4), 137 mM NaCl, 27 mM KCl, 0.05% surfactant P-20) at 25°C. An unmodified blank surface was used as a control in channel 1. ClpC1 enzyme was diluted to 50 µg / ml with 10 mM sodium acetate (pH 4.0) and immobilized on channels 2, 3, and 4 after sensor surface activation with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) / N-hydroxysuccinimide (NHS), followed by ethanolamine blocking on unoccupied surface areas. All tested compound solutions were initially prepared as 10 mM stock solutions in 100% DMSO and diluted in 100% DMSO to a series of increasing concentrations (50X final concentration) to maintain a final DMSO concentration of 2%. Then, a compound solution was prepared in an SPR binding buffer consisting of 10 mM Na₂HPO₄ (pH 7.4), 1.8 mM KH₂PO₄, 137 mM NaCl, 2.7 mM KCl, 0.5 mM TCEP, and 2% DMSO. This compound solution was injected at 25 °C onto both a blank surface and a ClpC1 protein-immobilized surface at a flow rate of 30 μL / min. All sensor plots were dual-referenced with the blank channel and the concentration of 2% DMSO, and solvent correction cycles were run before and after the compound run. The kinetic association rate (ka) and dissociation rate (kd) constants were determined by globally fitting to a 1:1 Langmuir kinetic model and a multi-site kinetic model using Biacore Insight evaluation software v3.0.12. K was calculated from the determined rate constants. D (Equilibrium dissociation constant) value (K) D = kd / ka). The data is listed in Table 9.

[0184] Table 9: In vitro activity and Vero cytotoxicity References: Bosch, B., DeJesus, MA, Poulton, NC, Zhang, W., Engelhart, CA, Zaveri, A., Lavalette, S., Ruecker, N., Trujillo, C., Wallach, JB, Li, S., Ehrt, S., Chait, BT, Schnappinger, D., and Rock, JM (2021). Genome-wide gene expression tuning reveals diverse vulnerabilities of M. tuberculosis. *Cell* (…). Cell )》, 184 (17), 4579-4592 e4524. https: / / doi.org / 10.1016 / j.cell.2021.06.033 Carroll, P., Faray-Kele, MC, and Parish, T. (2011). Identifying vulnerable pathways in Mycobacterium tuberculosis by using a knockdown approach. *Applied and Environmental Microbiology* Appl Environ Microbiol )》, 77 (14), 5040-5043. https: / / doi.org / 10.1128 / AEM.02880-10 Cho, S., Lee, HS, Franzblau, S. (2015). Microplate Almar Blue Assay (MABA) and Low Oxygen Recovery Assay (LORA) for Mycobacterium tuberculosis. Parish, T., Roberts, D. (eds.) *Mycobacterial Laboratory Protocols: A Methodology of Molecular Biology*, Vol. 1285. Humana Publishing, New York, NY. https: / / doi.org / 10.1007 / 978-1-4939-2450-9_17 Choules, MP, Wolf, NM, Lee, H., Anderson, JR, Grzelak, EM, Wang, Y., Ma, R., Gao, W., McAlpine, JB, Jin, YY, Cheng, J., Lee, H., Suh, JW, Duc, NM, Paik, S., Choe, JH, Jo, EK, Chang, CL, Lee, JS, Cho, S. (2019). Rufomycin Targets ClpC1 Proteolysis in Mycobacterium tuberculosis and M. abscessus. Antimicrob Agents Chemother, 63(3). https: / / doi.org / 10.1128 / AAC.02204-18 Gao, W., Kim, JY, Anderson, JR, Akopian, T., Hong, S., Jin, YY, Kandror, O., Kim, JW, Lee, IA, Lee, SY, McAlpine, JB, Mulugeta, S., Sunoqrot, S., Wang, Y., Yang, SH, Yoon, TM, Goldberg, AL, Pauli, GF, Suh, JW, Cho, S. (2015). The cyclic peptide ecumicin targeting ClpC1 is active against Mycobacterium tuberculosis in vivo. *Antibacterial Drugs and Chemotherapy*, 59 (2), 880-889. https: / / doi.org / 10.1128 / AAC.04054-14 Gavrish, E., Sit, CS, Cao, S., Kandror, O., Spoering, A., Peoples, A., Ling, L., Fetterman, A., Hughes, D., Bissell, A., Torrey, H., Akopian, T., Mueller, A., Epstein, S., Goldberg, A., Clardy, J., and Lewis, K. (2014). Lassomycin, a ribosomally synthesized cyclic peptide, kills mycobacterium tuberculosis by targeting the ATP-dependent protease ClpC1P1P2. (Biochemistry) Chem Biol )》, 21 (4), 509-518. https: / / doi.org / 10.1016 / j.chembiol.2014.01.014 Lee, M., Lee, J., Carroll, MW, Choi, H., Min, S., Song, T., Via, LE, Goldfeder, LC, Kang, E., Jin, B., Park, H., Kwak, H., Kim, H., Jeon, HS, Jeong, I., Joh, JS, Chen, RY, Olivier, KN, Shaw, PA, ... . .Barry, CE 3 (2012). Linezolid for treatment of chronic extensively drug-resistant tuberculosis. The New England Journal of Medicine (... N Engl J Med )》, 367 (16), 1508-1518. https: / / doi.org / 10.1056 / NEJMoa1201964 Ollinger, J., O'Malley, T., Kesicki, EA, Odingo, J., and Parish, T. (2012). Validation of the essential ClpP protease in Mycobacterium tuberculosis as a novel drug target. Journal of Bacteriology (2012). J Bacteriol )》, 194 (3), 663-668. https: / / doi.org / 10.1128 / JB.06142-11 Raju, RM, Jedrychowski, MP, Wei, JR, Pinkham, JT, Park, AS, O'Brien, K., Rehren, G., Schnappinger, D., Gygi, SP, and Rubin, EJ (2014). Post-translational regulation via Clp protease is critical for survival of Mycobacterium tuberculosis. (PLOS Pathogens) PLoS Pathog )》, 10 (3),e1003994. https: / / doi.org / 10.1371 / journal.ppat.1003994 Raju, RM, Unnikrishnan, M., Rubin, DH, Krishnamoorthy, V., Kandror, O., Akopian, TN, Goldberg, AL, and Rubin, EJ (2012). Mycobacterium tuberculosis ClpP1 and ClpP2 function together in protein degradation and are required for viability in vitro and during infection. PLOS Pathogens, 8(2), e1002511. https: / / doi.org / 10.1371 / journal.ppat.1002511 Sassetti, CM, Boyd, DH, and Rubin, EJ (2003). Genes required for mycobacterial growth defined by high-density mutagenesis. *Molecular Microbiology* Mol Microbiol )》, 48 (1), 77-84. https: / / doi.org / 10.1046 / j.1365-2958.2003.03425.x Schmitt, EK, Riwanto, M., Sambandamurthy, V., Roggo, S., Miault, C., Zwingelstein, C., Krastel, P., Noble, C., Beer, D., Rao, SP, Au, M., Niyomrattanakit, P., Lim, V., Zheng, J., Jeffery, D., Pethe, K. and Camacho, LR (2011). The natural product cyclomarin kills Mycobacterium tuberculosis by targeting the ClpC1 subunit of the caseinolytic protease. (Angewandte Chemie International Edition, English version) Angew Chem Int Ed Engl )》, 50 (26), 5889-5891. https: / / doi.org / 10.1002 / anie.201101740 Steingart, KR, Jotblad, S., Robsky, K., Deck, D., Hopewell, PC, Huang, D., and Nahid, P. (2011). Higher-doserifampin for the treatment of pulmonary tuberculosis: a systematic review. *International Journal of Tuberculosis and Lung Disease* (2011). Int J Tuberc Lung Dis )》,15 (3), 305-316. https: / / www.ncbi.nlm.nih.gov / pubmed / 21333096 Vasudevan, D., Rao, SP and Noble, CG (2013). Structural basis of mycobacterial inhibition by cyclomarin A. Journal of Biochemistry ( J Biol Chem )》, 288 (43), 30883-30891. https: / / doi.org / 10.1074 / jbc.M113.493767 Wolf, NM, Lee, H., Choules, MP, Pauli, GF, Phansalkar, R., Anderson, JR, Gao, W., Ren, J., Santarsiero, BD, Lee, H., Cheng, J., Jin, YY, Ho, NA, Duc, NM, Suh, JW, Abad-Zapatero, C., and Cho, S. (2019). High-resolution structure of ClpC1-Rufomycin and Ligand Binding Studies Provide a Framework to Design and Optimize Anti-Tuberculosis Leads. ACS Infectious Diseases, 5(6), 829-840. https: / / doi.org / 10.1021 / acsinfecdis.8b00276 *** Although the present application has been described with reference to embodiments, it should be understood that the scope of the claims should not be limited to the implementation methods set forth in the embodiments, but should be given the broadest interpretation consistent with the entire specification.

Claims

1. A compound of formula I or formula III: in: R2 is: -C1-C5 alkyl groups, optionally substituted with F or CF3, - n = 1-4, wherein the cycloalkyl group is optionally substituted with F, or - ， R4 is H, halogen, (C1-C4) lower alkyl group, CH2F, CHF2, CF3, OH, or lower alkoxy group (mono- or di-); and R3 is a -CH2-phenyl, CH2-monocyclic heteroaryl, or CH2-fused bicyclic heteroaryl, wherein the phenyl or the heteroaryl group is optionally substituted. Or its pharmaceutically acceptable salt.

2. The compound according to claim 1, wherein... R2 is: C1-C5 alkyl groups, optionally substituted with F or CF3, n = 1-4, wherein the cycloalkyl group is optionally substituted with F, or 。 3. The compound according to claim 1, wherein R3 is: R5 can be H, Me, OMe, OCH2F, -CH2CH2-OH, or -O(CH2)2OH. ,and R6 is H, F, lower alkyl, lower alkoxy, or CF3.

4. A compound selected from the group consisting of: (2S,5S,8S,11S,14S,17S,20S)-5-(cyclobutylmethyl)-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-14-[(2-methyl-6-quinazolinyl)methyl]-1,4,7,10,13,16,19-heptaazabicyclo[18.3.1]teicosane-3,6,9,12,15,18,24-heptaone; (2S,5S,8S,11S,14S,17S,20S,Z)-5-(cyclobutylmethyl)-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-14-[(2-methyl-6-quinazolinyl)methyl]-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexadec-22-ene-3,6,9,12,15,18,26-heptaone; (2S,5S,8S,11S,14S,17S,20S)-5-benzyl-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-14-[(6-quinazolinyl)methyl]-1,4,7,10,13,16,19-heptaazabicyclo[18.3.1]teicosane-3,6,9,12,15,18,24-heptaone; (2S,5S,8S,11S,14S,17S,20S)-5-butyl-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-14-[(6-quinazolinyl)methyl]-1,4,7,10,13,16,19-heptaazabicyclo[18.3.1]teicosane-3,6,9,12,15,18,24-heptaone; (2S,5S,8S,11S,14S,17S,20S,Z)-5-(cyclobutylmethyl)-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-14-[(6-quinazolinyl)methyl]-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexadec-22-ene-3,6,9,12,15,18,26-heptaone; (2S,5S,8S,11S,14S,17S,20S)-5-(cyclobutylmethyl)-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-14-[(2-fluoromethoxy-6-quinazolinyl)methyl]-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.3.1]teicosane-3,6,9,12,15,18,24-heptaone; (2S,5S,8S,11S,14S,17S,20S,Z)-5-(cyclobutylmethyl)-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-2,11-bis(isobutyl)-14-[(2-methoxy-7-quinazolinyl)methyl]-10,19-dimethyl-17-methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexadec-22-ene-3,6,9,12,15,18,26-heptaone; (2S,5S,8S,11S,14S,17S,20S,Z)-5-(cyclobutylmethyl)-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-14-[(2-fluoromethoxy-6-quinazolinyl)methyl]-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexadec-22-ene-3,6,9,12,15,18,26-heptaone; (2S,5S,8S,11S,14S,17S,20S,Z)-5-butyl-14-[(1H-1,7-diazaindene-5-yl)methyl]-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexadec-22-ene-3,6,9,12,15,18,26-heptaone; (2S,5S,8S,11S,14S,17S,20S)-5-(cyclobutylmethyl)-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-14-{[2-(2-hydroxyethyl)-6-quinazolinyl]methyl}-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.3.1]teicosane-3,6,9,12,15,18,24-heptaone; (2S,5S,8S,11S,14S,17S,20S,Z)-5-benzyl-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-14-[(6-quinazolinyl)methyl]-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexadec-22-ene-3,6,9,12,15,18,26-heptaone; (2S,5S,8S,11S,14S,17S,20S,Z)-5-benzyl-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-14-[(6-phthalazinyl)methyl]-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexadec-22-ene-3,6,9,12,15,18,26-heptaone; (2S,5S,8S,11S,14S,17S,20S,Z)-5-(cyclobutylmethyl)-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-2,11-bis(isobutyl)-14-[(2-methoxy-6-quinazolinyl)methyl]-10,19-dimethyl-17-methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexadec-22-ene-3,6,9,12,15,18,26-heptaone; (2S,5S,8S,11S,14S,17S,20S,Z)-5-(cyclobutylmethyl)-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-14-[(6-methyl-3-pyridyl)methyl]-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexadec-22-ene-3,6,9,12,15,18,26-heptaone; (2S,5S,8S,11S,14S,17S,20S,Z)-5-(cyclobutylmethyl)-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-14-{[2-(2-hydroxyethyl)-6-quinazolinyl]methyl}-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexadec-22-ene-3,6,9,12,15,18,26-heptaone; (2S,5S,8S,11S,14S,17S,20S,Z)-14-[(1,3-benzothiazo-6-yl)methyl]-5-butyl-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexadec-22-ene-3,6,9,12,15,18,26-heptaone; (2S,5S,8S,11S,14S,17S,20S,Z)-5-(cyclobutylmethyl)-14-[(1,6-diaza-7-naphthyl)methyl]-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexadec-22-ene-3,6,9,12,15,18,26-heptaone; (2S,5S,8S,11S,14S,17S,20S,Z)-5-(cyclobutylmethyl)-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-2,11-bis(isobutyl)-14-[(2-methoxy-8-quinazolinyl)methyl]-10,19-dimethyl-17-methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexadec-22-ene-3,6,9,12,15,18,26-heptaone; (2S,8S,11S,14S,17S,20S)-5-(cyclobutylmethyl)-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-2,11-bis(isobutyl)-14-[(2-methoxy-7-quinazolinyl)methyl]-10,19-dimethyl-17-methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.3.1]teicosane-3,6,9,12,15,18,24-heptaone; (2S,5S,8S,11S,14S,17S,20S,Z)-5-(cyclobutylmethyl)-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-14-[(2-methyl-7-quinazolinyl)methyl]-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexadec-22-ene-3,6,9,12,15,18,26-heptaone; (2S,5S,8S,11S,14S,17S,20S)-5-(cyclopentylmethyl)-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-2,11-bis(isobutyl)-14-[(6-isoquinolinyl)methyl]-10,19-dimethyl-17-methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.3.1]teicosane-3,6,9,12,15,18,24-heptaone; (2S,5S,8S,11S,14S,17S,20S,Z)-5-(cyclopropylmethyl)-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-14-[(6-quinazolinyl)methyl]-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexadec-22-ene-3,6,9,12,15,18,26-heptaone; (2S,5S,8S,11S,14S,17S,20S,Z)-5-(cyclopentylmethyl)-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-2,11-bis(isobutyl)-14-[(6-isoquinolinyl)methyl]-10,19-dimethyl-17-methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexadec-22-ene-3,6,9,12,15,18,26-heptaone; (2S,5S,8S,11S,14S,17S,20S,Z)-5-(cyclobutylmethyl)-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-14-{[2-(2-hydroxyethoxy)-6-quinazolinyl]methyl}-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexadec-22-ene-3,6,9,12,15,18,26-heptaone; (2S,5S,8S,11S,14S,17S,20S)-5-butyl-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-14-[(2-fluoromethoxy-6-quinazolinyl)methyl]-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.3.1]teicosane-3,6,9,12,15,18,24-heptaone; (2S,5S,8S,11S,14S,17S,20S)-5-(cyclobutylmethyl)-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-2,11-bis(isobutyl)-14-[(3-isoquinolinyl)methyl]-10,19-dimethyl-17-methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.3.1]teicosane-3,6,9,12,15,18,24-heptaone; (2S,5S,8S,11S,14S,17S,20S,Z)-5-butyl-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-2,11-bis(isobutyl)-14-[(6-isoquinolinyl)methyl]-10,19-dimethyl-17-methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexadec-22-ene-3,6,9,12,15,18,26-heptaone; (2S,5S,8S,11S,14S,17S,20S)-5-butyl-14-[(1H-1,7-diazaindene-5-yl)methyl]-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.3.1]teicosane-3,6,9,12,15,18,24-heptaone; (2S,5S,8S,11S,14S,17S,20S,Z)-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-5-[(p-fluorophenyl)methyl]-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-14-[(6-quinazolinyl)methyl]-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexadec-22-ene-3,6,9,12,15,18,26-heptaone; (2S,5S,8S,11S,14S,17S,20S)-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-14-[(2-fluoromethoxy-6-quinazolinyl)methyl]-2,11-bis(isobutyl)-5-isopentyl-10,19-dimethyl-17-methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.3.1]teicosane-3,6,9,12,15,18,24-heptaone; (2S,5S,8S,11S,14S,17S,20S)-5-(cyclopentylmethyl)-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-14-[(2-fluoromethoxy-6-quinazolinyl)methyl]-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.3.1]teicosane-3,6,9,12,15,18,24-heptaone; (2S,5S,8S,11S,14S,17S,20S)-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-5-[(2-pyridyl)methyl]-14-[(6-quinazolinyl)methyl]-1,4,7,10,13,16,19-heptaazabicyclo[18.3.1]teicosane-3,6,9,12,15,18,24-heptaone; (2S,5S,8S,11S,14S,17S,20S)-5-(cyclobutylmethyl)-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-2,11-bis(isobutyl)-14-[(2-methoxy-6-quinazolinyl)methyl]-10,19-dimethyl-17-methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.3.1]teicosane-3,6,9,12,15,18,24-heptaone; (2S,5S,8S,11S,14S,17S,20S,Z)-5-butyl-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-14-[(2-fluoromethoxy-6-quinazolinyl)methyl]-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexadec-22-ene-3,6,9,12,15,18,26-heptaone; (2S,5S,8S,11S,14S,17S,20S,Z)-14-[(1,3-benzothiazo-6-yl)methyl]-5-benzyl-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexadec-22-ene-3,6,9,12,15,18,26-heptaone; (2S,5S,8S,11S,14S,17S,20S)-5-(cyclopentylmethyl)-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-14-[(6-phthalazinyl)methyl]-1,4,7,10,13,16,19-heptaazabicyclo[18.3.1]teicosane-3,6,9,12,15,18,24-heptaone; (2S,8S,11S,14S,17S,20S)-5-(cyclobutylmethyl)-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-2,11-bis(isobutyl)-14-[(2-methoxy-8-quinazolinyl)methyl]-10,19-dimethyl-17-methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.3.1]teicosane-3,6,9,12,15,18,24-heptaone; (2S,5S,8S,11S,14S,17S,20S)-5-(cyclopentylmethyl)-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-2,11-bis(isobutyl)-14-[(2-methoxy-6-quinazolinyl)methyl]-10,19-dimethyl-17-methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.3.1]teicosane-3,6,9,12,15,18,24-heptaone; (2S,5S,8S,11S,14S,17S,20S)-5-benzyl-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-14-[(2-methyl-7-quinazolinyl)methyl]-1,4,7,10,13,16,19-heptaazabicyclo[18.3.1]teicosane-3,6,9,12,15,18,24-heptaone; (2S,5S,8S,11S,14S,17S,20S)-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-5-[(3-fluorocyclobutyl)methyl]-14-[(2-fluoromethoxy-6-quinazolinyl)methyl]-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.3.1]teicosane-3,6,9,12,15,18,24-heptaone; (2S,5S,8S,11S,14S,17S,20S)-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-5-[(p-fluorophenyl)methyl]-2,11-bis(isobutyl)-14-[(6-isoquinolinyl)methyl]-10,19-dimethyl-17-methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.3.1]teicosane-3,6,9,12,15,18,24-heptaone; (2S,5S,8S,11S,14S,17S,20S)-5-(cyclobutylmethyl)-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-14-[(2-methyl-7-quinazolinyl)methyl]-1,4,7,10,13,16,19-heptaazabicyclo[18.3.1]teicosane-3,6,9,12,15,18,24-heptaone; (2S,5S,8S,11S,14S,17S,20S)-5-butyl-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-14-[(2-methyl-7-quinazolinyl)methyl]-1,4,7,10,13,16,19-heptaazabicyclo[18.3.1]teicosane-3,6,9,12,15,18,24-heptaone; (2S,5S,8S,11S,14S,17S,20S,Z)-14-[(1,3-benzothiazo-6-yl)methyl]-5-(cyclopentylmethyl)-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexadec-22-ene-3,6,9,12,15,18,26-heptaone; (2S,5S,8S,11S,14S,17S,20S,Z)-5-benzyl-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-2,11-bis(isobutyl)-14-[(6-isoquinolinyl)methyl]-10,19-dimethyl-17-methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexadec-22-ene-3,6,9,12,15,18,26-heptaone; (2S,5S,8S,11S,14S,17S,20S,Z)-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-5-[(p-fluorophenyl)methyl]-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-14-[(6-phthalazinyl)methyl]-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexadec-22-ene-3,6,9,12,15,18,26-heptadecone; (2S,5S,8S,11S,14S,17S,20S,Z)-5-(cyclobutylmethyl)-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-14-[(2-methyl-4-pyridyl)methyl]-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexadec-22-ene-3,6,9,12,15,18,26-heptaone; (2S,5S,8S,11S,14S,17S,20S)-14-[(1,3-benzothiazo-6-yl)methyl]-5-(cyclopentylmethyl)-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.3.1]teicosane-3,6,9,12,15,18,24-heptaone; (2S,5S,8S,11S,14S,17S,20S,Z)-5-(cyclopentylmethyl)-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-2,11-bis(isobutyl)-14-[(2-methoxy-6-quinazolinyl)methyl]-10,19-dimethyl-17-methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexadec-22-ene-3,6,9,12,15,18,26-heptaone; (2S,5S,8S,11S,14S,17S,20S,Z)-5-benzyl-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-14-[(3-quinolinyl)methyl]-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexadec-22-ene-3,6,9,12,15,18,26-heptaone; (2S,5S,8S,11S,14S,17S,20S,Z)-5-benzyl-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-2,11-bis(isobutyl)-14-[(3-isoquinolinyl)methyl]-10,19-dimethyl-17-methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexadec-22-ene-3,6,9,12,15,18,26-heptaone; (2S,5S,8S,11S,14S,17S,20S,Z)-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-5-[(p-fluorophenyl)methyl]-2,11-bis(isobutyl)-14-[(6-isoquinolinyl)methyl]-10,19-dimethyl-17-methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexadec-22-ene-3,6,9,12,15,18,26-heptaone; (2S,5S,8S,11S,14S,17S,20S)-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-5-[(p-fluorophenyl)methyl]-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-14-[(6-quinolinyl)methyl]-1,4,7,10,13,16,19-heptaazabicyclo[18.3.1]teicosane-3,6,9,12,15,18,24-heptaone; (2S,5S,8S,11S,14R,17S,20S,Z)-14-[(1,3-benzothiazo-6-yl)methyl]-5-butyl-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexadec-22-ene-3,6,9,12,15,18,26-heptaone; (2S,5S,8S,11S,14S,17S,20S,Z)-5-(cyclobutylmethyl)-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-14-[(2-fluoromethoxy-7-quinazolinyl)methyl]-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexadec-22-ene-3,6,9,12,15,18,26-heptaone; (2S,5S,8S,11S,14S,17S,20S)-5-(cyclohexylmethyl)-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-14-[(6-phthalazinyl)methyl]-1,4,7,10,13,16,19-heptaazabicyclo[18.3.1]teicosane-3,6,9,12,15,18,24-heptaone; (2S,5S,8S,11S,14S,17S,20S)-5-(cyclobutylmethyl)-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-14-{[2-(2-hydroxyethoxy)-6-quinazolinyl]methyl}-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.3.1]teicosane-3,6,9,12,15,18,24-heptaone; (2S,5S,8S,11S,14S,17S,20S,Z)-5-benzyl-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-14-[(2-fluoromethoxy-6-quinazolinyl)methyl]-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexadec-22-ene-3,6,9,12,15,18,26-heptaone; (2S,5S,8S,11S,14S,17S,20S)-5-(cyclohexylmethyl)-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-14-[(8-fluoro-6-isoquinolinyl)methyl]-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.3.1]teicosane-3,6,9,12,15,18,24-heptaone; (2S,5S,8S,11S,14S,17S,20S,Z)-5-(cyclobutylmethyl)-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-14-[(1,3-thiazolyl-5-yl)methyl]-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexadec-22-ene-3,6,9,12,15,18,26-heptaone; (2S,5S,8S,11S,14S,17S,20S,Z)-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-14-[(2-fluoromethoxy-6-quinazolinyl)methyl]-2,11-bis(isobutyl)-5-isopentyl-10,19-dimethyl-17-methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexadec-22-ene-3,6,9,12,15,18,26-heptaone; (2S,5S,8S,11S,14S,17S,20S,Z)-5-(cyclohexylmethyl)-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-2,11-bis(isobutyl)-14-[(6-isoquinolinyl)methyl]-10,19-dimethyl-17-methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexadec-22-ene-3,6,9,12,15,18,26-heptaone; (2S,5S,8S,11S,14S,17S,20S,Z)-5-benzyl-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-14-[(6-quinolinyl)methyl]-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexadec-22-ene-3,6,9,12,15,18,26-heptaone; (2S,5S,8S,11S,14S,17S,20S)-5-(cyclobutylmethyl)-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-14-[(6-quinazolinyl)methyl]-1,4,7,10,13,16,19-heptaazabicyclo[18.3.1]teicosane-3,6,9,12,15,18,24-heptaone; (2S,5S,8S,11S,14S,17S,20S)-5-(cyclopentylmethyl)-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-14-[(2-methyl-7-quinazolinyl)methyl]-1,4,7,10,13,16,19-heptaazabicyclo[18.3.1]teicosane-3,6,9,12,15,18,24-heptaone; (2S,5S,8S,11S,14S,17S,20S)-5-(cyclobutylmethyl)-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-14-[(2-fluoromethoxy-7-quinazolinyl)methyl]-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.3.1]teicosane-3,6,9,12,15,18,24-heptaone; (2S,5S,8S,11S,14S,17S,20S,Z)-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-5-[(3-fluorocyclobutyl)methyl]-14-[(2-fluoromethoxy-6-quinazolinyl)methyl]-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexadec-22-ene-3,6,9,12,15,18,26-heptaone; (2S,5S,8S,11S,14S,17S,20S)-5-benzyl-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-14-[(6-quinoxalinyl)methyl]-1,4,7,10,13,16,19-heptaazabicyclo[18.3.1]teicosane-3,6,9,12,15,18,24-heptaone; (2S,5S,8S,11S,14S,17S,Z)-5-benzyl-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-14-[(3-methyl-6-isoquinolinyl)methyl]-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexadec-22-ene-3,6,9,12,15,18,26-heptaone; (2S,5S,8S,11S,14S,17S,20S)-5-butyl-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-2,11-bis(isobutyl)-14-[(7-isoquinolinyl)methyl]-10,19-dimethyl-17-methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.3.1]teicosane-3,6,9,12,15,18,24-heptaone; (2S,5S,8S,11S,14S,17S,20S)-5-benzyl-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-2,11-bis(isobutyl)-14-[(7-isoquinolinyl)methyl]-10,19-dimethyl-17-methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.3.1]teicosane-3,6,9,12,15,18,24-heptaone; (2S,5S,8S,11S,14S,17S,20S)-5-benzyl-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-14-[(2-fluoromethoxy-6-quinazolinyl)methyl]-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.3.1]teicosane-3,6,9,12,15,18,24-heptaone; (2S,5S,8S,11S,14S,17S,20S)-5-butyl-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-14-[(6-quinolinyl)methyl]-1,4,7,10,13,16,19-heptaazabicyclo[18.3.1]teicosane-3,6,9,12,15,18,24-heptaone; (2S,5S,8S,11S,14S,17S,20S,Z)-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-5-[(2-pyridyl)methyl]-14-[(6-quinazolinyl)methyl]-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexadec-22-ene-3,6,9,12,15,18,26-heptaone; (2S,5S,8S,11S,14S,17S,20S)-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-14-[(6-quinazolinyl)methyl]-5-[(p-tolyl)methyl]-1,4,7,10,13,16,19-heptaazabicyclo[18.3.1]teicosane-3,6,9,12,15,18,24-heptaone; (2S,5S,8S,11S,14S,17S,20S,Z)-5-(cyclopropylmethyl)-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-14-[(2-fluoromethoxy-6-quinazolinyl)methyl]-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexadec-22-ene-3,6,9,12,15,18,26-heptaone; (2S,5S,8S,11S,14S,17S,20S)-5-butyl-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-14-[(p-hydroxyphenyl)methyl]-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.3.1]teicosane-3,6,9,12,15,18,24-heptaone; (2S,5S,8S,11S,14S,17S,20S,Z)-5-butyl-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-14-[(6-quinolinyl)methyl]-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexadec-22-ene-3,6,9,12,15,18,26-heptaone; (2S,5S,8S,11S,14S,17S,20S,Z)-5-benzyl-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-2,11-bis(isobutyl)-14-[(2-methoxy-6-quinazolinyl)methyl]-10,19-dimethyl-17-methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexadec-22-ene-3,6,9,12,15,18,26-heptaone; (2S,5S,8S,11S,14S,17S,20S,Z)-5-benzyl-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-14-[(6-quinoxalinyl)methyl]-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexadec-22-ene-3,6,9,12,15,18,26-heptaone; (2S,5S,8S,11S,14S,17S,20S)-5-benzyl-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-14-[(2-hydroxy-6-quinazolinyl)methyl]-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.3.1]teicosane-3,6,9,12,15,18,24-heptaone; (2S,5S,8S,11S,14S,17S,20S,Z)-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-14-[(2-fluoromethoxy-6-quinazolinyl)methyl]-5-[(p-fluorophenyl)methyl]-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexadec-22-ene-3,6,9,12,15,18,26-heptaone; (2S,5S,8S,11S,14S,17S,20S)-5-benzyl-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-2,11-bis(isobutyl)-14-[(6-isoquinolinyl)methyl]-10,19-dimethyl-17-methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.3.1]teicosane-3,6,9,12,15,18,24-heptaone; (2S,5S,8S,11S,14S,17S,20S)-5-butyl-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-2,11-bis(isobutyl)-14-[(6-isoquinolinyl)methyl]-10,19-dimethyl-17-methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.3.1]teicosethane-3,6,9,12,15,18,24-heptaone; (2S,5S,8S,11S,14S,17S,20S,Z)-14-[(1,3-benzothiazolyl-6-yl)methyl]-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-5-[(p-fluorophenyl)methyl]-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexadec-22-ene-3,6,9,12,15,18,26-heptaone; (2S,5S,8S,11S,14S,17S,20S,Z)-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-5-[(p-fluorophenyl)methyl]-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-14-[(6-quinolinyl)methyl]-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexadec-22-ene-3,6,9,12,15,18,26-heptaone; (2S,5S,8S,11S,14S,17S,20S,Z)-5-(cyclobutylmethyl)-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-14-[(2-fluoro-4-pyridyl)methyl]-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexadec-22-ene-3,6,9,12,15,18,26-heptaone; (2S,5S,8S,11S,14S,17S,20S,Z)-5-(cyclopentylmethyl)-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-14-[(6-quinolinyl)methyl]-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexadec-22-ene-3,6,9,12,15,18,26-heptaone; (2S,5S,8S,11S,14S,17S,20S,Z)-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-5-[(p-fluorophenyl)methyl]-2,11-bis(isobutyl)-14-[(2-methoxy-6-quinazolinyl)methyl]-10,19-dimethyl-17-methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexadec-22-ene-3,6,9,12,15,18,26-heptaone; (2S,5S,8S,11S,14S,17S,20S,Z)-5-(cyclobutylmethyl)-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-14-[(6-fluoro-3-pyridyl)methyl]-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexadec-22-ene-3,6,9,12,15,18,26-heptaone; (2S,5S,8S,11S,14S,17S,20S,Z)-5-(cyclobutylmethyl)-14-[(1,7-diaza-6-naphthyl)methyl]-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexadec-22-ene-3,6,9,12,15,18,26-heptaone; (2S,5S,8S,11S,14S,17S,20S)-5,14-bis(benzyl)-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.3.1]teicosethane-3,6,9,12,15,18,24-heptaone; (2S,5S,8S,11S,14S,17S,20S,Z)-5-(cyclopentylmethyl)-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-2,11-bis(isobutyl)-14-[(2-methoxy-7-quinazolinyl)methyl]-10,19-dimethyl-17-methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexadec-22-ene-3,6,9,12,15,18,26-heptaone; (2S,5S,8S,11S,14S,17S,20S)-5-[(p-chlorophenyl)methyl]-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-14-[(1-methyl-6-isoquinolinyl)methyl]-1,4,7,10,13,16,19-heptaazabicyclo[18.3.1]teicosane-3,6,9,12,15,18,24-heptaone; (2S,5S,8S,11S,14S,17S,20S)-5-(cyclobutylmethyl)-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-14-[(2-quinazolinyl)methyl]-1,4,7,10,13,16,19-heptaazabicyclo[18.3.1]teicosane-3,6,9,12,15,18,24-heptaone; (2S,5S,8S,11S,14S,17S,20S)-14-[(1,3-benzothiazo-6-yl)methyl]-5-butyl-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.3.1]teicosane-3,6,9,12,15,18,24-heptaone; (2S,5S,8S,11S,14S,17S,20S)-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-5-[(p-fluorophenyl)methyl]-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-14-[(6-quinazolinyl)methyl]-1,4,7,10,13,16,19-heptaazabicyclo[18.3.1]teicosane-3,6,9,12,15,18,24-heptaone; (2S,5S,8S,11S,14S,17S,20S,Z)-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-5-[(3-fluorocyclobutyl)methyl]-2,11-bis(isobutyl)-14-[(2-methoxy-6-quinazolinyl)methyl]-10,19-dimethyl-17-methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexadec-22-ene-3,6,9,12,15,18,26-heptaone; (2S,5S,8S,11S,14S,17S,20S,Z)-5-benzyl-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-14-[(1-thia-3,4-diaza-6-indole)methyl]-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexacarbon-22-ene-3,6,9,12,15,18,26-heptaone; (2S,5S,8S,11S,14S,17S,20S)-14-[(1,3-benzothiazo-6-yl)methyl]-5-benzyl-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.3.1]teicosane-3,6,9,12,15,18,24-heptaone; (2S,5S,8S,11S,14S,17S,20S)-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-2,11-bis(isobutyl)-5-isopentyl-10,19-dimethyl-17-methyl-14-[(2-methyl-7-quinazolinyl)methyl]-1,4,7,10,13,16,19-heptaazabicyclo[18.3.1]teicosane-3,6,9,12,15,18,24-heptaone; (2S,5S,8S,11S,14S,17S,20S)-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-5-[(p-fluorophenyl)methyl]-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-14-[(6-quinoxalinyl)methyl]-1,4,7,10,13,16,19-heptaazabicyclo[18.3.1]teicosane-3,6,9,12,15,18,24-heptaone; (2S,5S,8S,11S,14S,17S,20S,Z)-5-benzyl-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-2,11-bis(isobutyl)-14-[(7-isoquinolinyl)methyl]-10,19-dimethyl-17-methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexadec-22-ene-3,6,9,12,15,18,26-heptaone; (2S,5S,8S,11S,14S,17S,20S)-14-[(1,3-benzothiazolyl-6-yl)methyl]-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-5-[(p-fluorophenyl)methyl]-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.3.1]teicosane-3,6,9,12,15,18,24-heptaone; (2S,5S,8S,11S,14S,17S,20S)-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-5-[(4-pyridyl)methyl]-14-[(6-quinazolinyl)methyl]-1,4,7,10,13,16,19-heptaazabicyclo[18.3.1]teicosane-3,6,9,12,15,18,24-heptaone; (2S,5S,8S,11S,14S,17S,20S)-5-(cyclohexylmethyl)-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-14-[(2-fluoromethoxy-6-quinazolinyl)methyl]-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.3.1]teicosane-3,6,9,12,15,18,24-heptaone; (2S,5S,8S,11S,14S,17S,20S,Z)-5-benzyl-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-14-[(1-oxa-7-aza-5-indole)methyl]-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexadec-22-ene-3,6,9,12,15,18,26-heptaone; (2S,5S,8S,11S,14S,17S,20S,Z)-5-(cyclopentylmethyl)-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-14-[(2-methyl-7-quinazolinyl)methyl]-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexadec-22-ene-3,6,9,12,15,18,26-heptaone; (2S,5S,8S,11S,14S,17S,20S,Z)-5-butyl-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-14-[(1-thia-3,4-diaza-6-indole)methyl]-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexadec-22-ene-3,6,9,12,15,18,26-heptaone; (2S,5S,8S,11S,14S,17S,20S)-5-(cyclopropylmethyl)-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-14-[(2-fluoromethoxy-6-quinazolinyl)methyl]-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.3.1]teicosane-3,6,9,12,15,18,24-heptaone; (2S,5S,8S,11S,14S,17S,20S,Z)-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-2,11-bis(isobutyl)-5-isopentyl-14-[(2-methoxy-6-quinazolinyl)methyl]-10,19-dimethyl-17-methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexadec-22-ene-3,6,9,12,15,18,26-heptaone; (2S,5S,8S,11S,14S,17S,20S)-5-benzyl-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-2,11-bis(isobutyl)-14-[(2-methoxy-6-quinazolinyl)methyl]-10,19-dimethyl-17-methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.3.1]teicosane-3,6,9,12,15,18,24-heptaone; (2S,5S,8S,11S,14R,17S,20S)-5-benzyl-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-2,11-bis(isobutyl)-14-[(3-isoquinolinyl)methyl]-10,19-dimethyl-17-methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.3.1]teicosane-3,6,9,12,15,18,24-heptaone; (2S,5S,8S,11S,14S,17S,20S)-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-5-[(p-fluorophenyl)methyl]-2,11-bis(isobutyl)-14-[(2-methoxy-6-quinazolinyl)methyl]-10,19-dimethyl-17-methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.3.1]teicosane-3,6,9,12,15,18,24-heptaone; (2S,5S,8S,11S,14S,17S,20S,Z)-5-(cyclobutylmethyl)-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-14-[(2-fluoromethoxy-5-quinazolinyl)methyl]-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexadec-22-ene-3,6,9,12,15,18,26-heptaone; (2S,5S,8S,11S,14S,17S,20S,Z)-5-[(3,5-difluorophenyl)methyl]-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-14-[(6-quinolinyl)methyl]-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexadec-22-ene-3,6,9,12,15,18,26-heptaone; (2S,5S,8S,11S,14S,17S,20S)-5-butyl-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-2,11-bis(isobutyl)-14-[(2-methoxy-6-quinazolinyl)methyl]-10,19-dimethyl-17-methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.3.1]teicosane-3,6,9,12,15,18,24-heptaone; (2S,5S,8S,11S,14S,17S,20S)-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-14-[(2-fluoromethoxy-6-quinazolinyl)methyl]-5-[(p-fluorophenyl)methyl]-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.3.1]teicosane-3,6,9,12,15,18,24-heptaone; (2S,5S,8S,11S,14S,17S,20S,Z)-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-14-[(8-fluoro-6-isoquinolinyl)methyl]-5-[(p-fluorophenyl)methyl]-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexadec-22-ene-3,6,9,12,15,18,26-heptaone; (2S,5S,8S,11S,14S,17S,20S,Z)-5-(cyclopropylmethyl)-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-14-[(6-phthalazinyl)methyl]-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexadec-22-ene-3,6,9,12,15,18,26-heptaone; (2S,5S,8S,11S,14S,17S,20S,Z)-5-(cyclobutylmethyl)-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-2,11-bis(isobutyl)-14-[(3-isothiazolyl)methyl]-10,19-dimethyl-17-methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexadec-22-ene-3,6,9,12,15,18,26-heptaone; (2S,5S,8S,11S,17S,20S,Z)-14-[(2,1-benzisothiazol-6-yl)methyl]-5-benzyl-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexadec-22-ene-3,6,9,12,15,18,26-heptaone; (2S,5S,8S,11S,14S,17S,20S,Z)-5-(cyclohexylmethyl)-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-14-[(2-fluoromethoxy-6-quinazolinyl)methyl]-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexadec-22-ene-3,6,9,12,15,18,26-heptaone; (2S,5S,8S,11S,17S,20S,Z)-14-[(1-benzofuran-5-yl)methyl]-5-butyl-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexadec-22-ene-3,6,9,12,15,18,26-heptaone; (2S,5S,8S,11S,17S,20S,Z)-5-butyl-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-14-[(1-oxa-7-aza-5-indole)methyl]-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexadec-22-ene-3,6,9,12,15,18,26-heptaone; (2S,5S,8S,11S,17S,20S,Z)-14-[(1-benzothiophene-5-yl)methyl]-5-benzyl-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexadec-22-ene-3,6,9,12,15,18,26-heptaone; (2S,5S,8S,11S,14S,17S,20S,Z)-5-butyl-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-2,11-bis(isobutyl)-14-[(2-methoxy-6-quinazolinyl)methyl]-10,19-dimethyl-17-methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexadec-22-ene-3,6,9,12,15,18,26-heptaone; (2S,5S,8S,11S,14S,17S,20S,Z)-14-[(1,3-benzoxazol-2-yl)methyl]-5-butyl-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexadec-22-ene-3,6,9,12,15,18,26-heptaone; (2S,5S,8S,11S,14S,17S,20S,Z)-5-benzyl-14-[(7-pyrinyl)methyl]-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexadec-22-ene-3,6,9,12,15,18,26-heptaone; (2S,5S,8S,11S,17S,20S,Z)-5-butyl-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-14-[(1-thia-7-aza-5-indole)methyl]-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexadec-22-ene-3,6,9,12,15,18,26-heptaone; (2S,5S,8S,11S,14S,17S,20S,Z)-5-(cyclopentylmethyl)-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-14-[(2-fluoromethoxy-7-quinazolinyl)methyl]-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexadec-22-ene-3,6,9,12,15,18,26-heptaone; (2S,5S,8S,11S,17S,20S,Z)-5-benzyl-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-14-[(1-thia-7-aza-5-indole)methyl]-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexadec-22-ene-3,6,9,12,15,18,26-heptaone; (2S,5S,8S,11S,14S,17S,20S,Z)-5-benzyl-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-14-[(1-thia-7-aza-2-indole)methyl]-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexadec-22-ene-3,6,9,12,15,18,26-heptaone; (2S,5S,8S,11S,14S,17S,20S,Z)-5-(cyclobutylmethyl)-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-14-[(2-quinazolinyl)methyl]-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexadec-22-ene-3,6,9,12,15,18,26-heptaone; (2S,5S,8S,11S,14S,17S,20S)-5-butyl-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-14-[(6-quinoxalinyl)methyl]-1,4,7,10,13,16,19-heptaazabicyclo[18.3.1]teicosane-3,6,9,12,15,18,24-heptaone; (2S,5S,8S,11S,14S,17S,20S,Z)-5-butyl-14-[(7-pyrinyl)methyl]-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexadec-22-ene-3,6,9,12,15,18,26-heptaone; (2S,5S,8S,11S,14S,17S,20S,Z)-5-(cyclobutylmethyl)-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-2,11-bis(isobutyl)-14-[(3-isoquinolinyl)methyl]-10,19-dimethyl-17-methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexadec-22-ene-3,6,9,12,15,18,26-heptaone; (2S,5S,8S,11S,14S,17S,20S,Z)-5-benzyl-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-14-[(7-quinolinyl)methyl]-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexadec-22-ene-3,6,9,12,15,18,26-heptaone; (2S,5S,8S,11S,14S,17S,20S)-5-butyl-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-14-[(5-indolyl)methyl]-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.3.1]teicosane-3,6,9,12,15,18,24-heptaone; (2S,5S,8S,11S,14S,17S,20S,Z)-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-2,11-bis(isobutyl)-5-isopentyl-10,19-dimethyl-17-methyl-14-[(2-methyl-7-quinazolinyl)methyl]-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexadec-22-ene-3,6,9,12,15,18,26-heptaone; (2S,5S,8S,11S,14S,17S,20S)-5-butyl-14-[(1H-1,7-diazaindene-3-yl)methyl]-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.3.1]teicosethane-3,6,9,12,15,18,24-heptaone; (2S,5S,8S,11S,14S,17S,20S)-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-2,11-bis(isobutyl)-5-[(p-methoxyphenyl)methyl]-10,19-dimethyl-17-methyl-14-[(1-methyl-6-isoquinolinyl)methyl]-1,4,7,10,13,16,19-heptaazabicyclo[18.3.1]teicosane-3,6,9,12,15,18,24-heptaone; (2S,5S,8S,11S,14S,17S,20S,Z)-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-14-[(6-quinazolinyl)methyl]-5-[(p-tolyl)methyl]-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexadec-22-ene-3,6,9,12,15,18,26-heptaone; (2S,5S,8S,11S,14R,17S,20S)-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-5-[(p-fluorophenyl)methyl]-2,11-bis(isobutyl)-14-[(3-isoquinolinyl)methyl]-10,19-dimethyl-17-methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.3.1]teicosane-3,6,9,12,15,18,24-heptaone; (2S,5S,8S,11S,14S,17S,20S,Z)-5-[(3,5-difluorophenyl)methyl]-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-2,11-bis(isobutyl)-14-[(6-isoquinolinyl)methyl]-10,19-dimethyl-17-methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexadec-22-ene-3,6,9,12,15,18,26-heptaone; (2S,5S,8S,11S,14S,17S,20S,Z)-5-(cyclobutylmethyl)-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-14-[(2-fluoromethoxy-4-methyl-6-quinazolinyl)methyl]-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexadec-22-ene-3,6,9,12,15,18,26-heptaone; (2S,5S,8S,11S,14S,17S,20S,Z)-14-[(1-benzofuran-5-yl)methyl]-5-benzyl-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexadec-22-ene-3,6,9,12,15,18,26-heptaone; (2S,5S,8S,11S,14S,17S,20S)-5-(cyclohexylmethyl)-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-2,11-bis(isobutyl)-14-[(6-isoquinolinyl)methyl]-10,19-dimethyl-17-methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.3.1]teicosane-3,6,9,12,15,18,24-heptaone; (2S,5S,8S,11S,14S,17S,20S)-14-benzyl-5-butyl-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.3.1]teicosethane-3,6,9,12,15,18,24-heptaone; (2S,5S,8S,11S,14S,17S,20S,Z)-5-butyl-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-2,11-bis(isobutyl)-14-[(3-methoxy-7-isoquinolinyl)methyl]-10,19-dimethyl-17-methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexadec-22-ene-3,6,9,12,15,18,26-heptaone; (2S,5S,8S,11S,14S,17S,20S,Z)-5-butyl-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-14-[(3-methyl-7-isoquinolinyl)methyl]-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexadec-22-ene-3,6,9,12,15,18,26-heptaone; (2S,5S,8S,11S,14S,17S,20S)-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-14-[(1-methyl-6-isoquinolinyl)methyl]-5-{[p-(trifluoromethyl)phenyl]methyl}-1,4,7,10,13,16,19-heptaazabicyclo[18.3.1]teicosane-3,6,9,12,15,18,24-heptaone; (2S,5S,8S,11S,14S,17S,20S)-5-(cyclopentylmethyl)-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-14-[(2-hydroxy-6-quinazolinyl)methyl]-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.3.1]teicosane-3,6,9,12,15,18,24-heptaone; (2S,5S,8S,11S,14S,17S)-5-butyl-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-14-[(3-methyl-6-isoquinolinyl)methyl]-1,4,7,10,13,16,19-heptaazabicyclo[18.3.1]teicosane-3,6,9,12,15,18,24-heptaone; (2S,5S,8S,11S,14S,17S,20S,Z)-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-5-[(p-fluorophenyl)methyl]-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-14-[(6-quinoxalinyl)methyl]-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexadec-22-ene-3,6,9,12,15,18,26-heptaone; (2S,5S,8S,11S,14S,17S,20S,Z)-5-butyl-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-14-[(1-thia-7-aza-2-indole)methyl]-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexadec-22-ene-3,6,9,12,15,18,26-heptaone; (2S,5S,8S,11S,14S,17S,20S,Z)-5-butyl-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-14-[(3-fluoromethoxy-7-isoquinolinyl)methyl]-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexadec-22-ene-3,6,9,12,15,18,26-heptaone; (2S,8S,11S,14S,17S,20S)-5-(cyclobutylmethyl)-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-14-{[2-(2-hydroxy-2-methylpropoxy)-6-quinazolinyl]methyl}-2,11-diisobutyl-10,19-dimethyl-17-methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.3.1]teicosane-3,6,9,12,15,18,24-heptaone; (2S,5S,8S,11S,14S,17S,20S,22Z)-5-(cyclobutylmethyl)-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-14-{[2-(2-hydroxy-2-methylpropoxy)-6-quinazolinyl]methyl}-2,11-diisobutyl-10,19-dimethyl-17-methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexadec-22-ene-3,6,9,12,15,18,26-heptaone; (2S,8S,11S,14S,17S,20S)-5-(cyclobutylmethyl)-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-14-{[2-(2-hydroxyethoxy)-7-quinazolinyl]methyl}-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.3.1]teicosane-3,6,9,12,15,18,24-heptaone; and (2S,5S,8S,11S,14S,17S,20S,Z)-5-(cyclobutylmethyl)-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-14-{[2-(2-hydroxyethoxy)-7-quinazolinyl]methyl}-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexadec-22-ene-3,6,9,12,15,18,26-heptaone, Or its pharmaceutically acceptable salt.

5. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

6. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 4 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

7. A method for treating tuberculosis, the method comprising administering to a patient in need a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

8. A method for treating tuberculosis, the method comprising administering to a patient in need a therapeutically effective amount of the compound of claim 4 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

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