Novel rufomycin analogs as clpc1 protease modulators having activity against mycobacterium tuberculosis

Abstract

The invention relates to novel rufomycin analogs targeting C1pC1 protease. The compounds of the invention have antibacterial activity, for example, with anti-tuberculosis properties, and are useful for the treatment of, for example, tuberculosis.

Description

[0001]PCT APPLICATION 113645-108076 NOVEL RUFOMYCIN ANALOGS AS CLPC1 PROTEASE MODULATORS HAVING ACTIVITY AGAINST MYCOBACTERIUM TUBERCULOSIS Field of the Invention The invention relates generally to novel rufomycin analogs targeting ClpC1 protease with antibacterial activity, for example, with anti-tuberculosis properties. The compounds of the invention are useful for the treatment of, for example, mycobacterium tuberculosis. 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 as if each individual publication, patent, patent application or other reference was specifically and individually indicated to be incorporated by reference in its entirety for all purposes. Citation of a reference herein shall not be construed as an admission that such is prior art to the present invention. Cross-Reference to Related Applications This application claims priority from U.S. Provisional Patent Application No. 63 / 527,925 filed on July 20, 2023, the contents of which are hereby expressly incorporated by reference herein. Background of the Invention The modulation of protein synthesis via inhibition of transcription by the RNA Polymerase (RNAP) inhibitor rifampicin, or translation by the oxazolidinone ribosome inhibitor, linezolid, has been well validated clinically to accelerate mycobacterium tuberculosis (M. tb) killing and promote tissue sterilization (Lee et al., 2012; Steingart et al., 2011). Unfortunately, the utility of rifampicin (RIF) is limited by the emergence of RIF resistance and extended linezolid use is limited by adverse side effects. In recent years, mycobacterial Caseinolytic Protease (ClpP) complex has been proposed as an 1 3152965.1 PCT APPLICATION 113645-108076 exciting novel drug target because of its essential role in bacterial viability and virulence in vitro and in vivo (Bosch et al., 2021; Raju et al., 2014; Raju et al., 2012). Proteolysis is required for removal of dysfunctional or misfolded proteins and for maintenance of protein homeostasis in bacteria. ClpP proteolytic machinery is highly conserved and consists of a barrel-like protease core and an AAA+ (ATPase Associated with various cellular Activities) chaperone ring complex. Proteolysis by ClpP requires activation of ATPase subunit ClpC1 that binds protein substrates, unfolds, and translocates them into the proteolytic compartment of ClpP1P2 subunit. Essentiality of Clp protease and ClpC1 chaperone in M. tb for virulence and cell viability has been established (Carroll et al., 2011; Ollinger et al., 2012; Raju et al., 2012; Sassetti et al., 2003) and identification of natural cyclic peptide ClpC1 inhibitors (Choules et al., 2019; Gao et al., 2015; Gavrish et al., 2014; Schmitt et al., 2011) rank ClpC1 as a very promising drug target. Targeting protein homeostasis through interference with ClpC1 component of ClpP protease can have multifactorial impact on bacterial viability during course of infection. First, ClpC1 inhibition can lead to direct toxicity through accumulation of cellular proteins and / or ATPase uncoupling and ATP depletion. In addition, M. tuberculosis proteostasis inhibitors may impair the ability of bacteria to respond to host induced stress and enhance efficacy of other antibiotics. Natural product ClpC1 inhibitor cyclomarin A is a cyclic nonribosomal peptide that is produced by streptomyces species with potent antitubercular activity in vitro (Schmitt et al., 2011). Ecumicin and lassomycin are natural products derived from soil bacteria and actinomycetes extracts, respectively, that bind to the N-terminal domain of ClpC1 and likewise exhibit potent antibacterial activity (Gao et al., 2015; Gavrish et al., 2014). Another group of peptides, the rufomycins were identified as bactericidal to M. tuberculosis through the inhibition of ClpC1 and modulation of protein degradation of intracellular proteins (Choules et al., 2019). Antimicrobial activity of natural product inhibitors of ClpC1 was demonstrated with multidrug resistant M. tb strains (Choules 2 3152965.1 PCT APPLICATION 113645-108076 et al., 2019; Gao et al., 2015). Mutants resistant to CymA, ecumicn, and rufomycin have mutations in N-terminal domain of ClpC1 (Choules et al., 2019; Gao et al., 2015; Vasudevan et al., 2013) and in vivo target validation has been achieved with ecumicin in the murine model of M. tuberculosis infection (Gao et al., 2015). While very potent, these natural products suffer from metabolic instability and lack of oral bioavailability limiting their use as oral therapeutics and necessitating drug discovery effort to identify new ClpC1 inhibitors with improved DMPK properties. Summary of the Invention The present invention is directed to compounds of Formulas I and III. The present invention is also directed to pharmaceutical compositions containing the above compounds and to methods of treating microbial infection such as tuberculosis. Detailed Description This patent application covers novel synthetic analogues of rufomycins: 3 3152965.1 PCT APPLICATION 113645-108076 where amino acids 2, 4, and / or 6 are independently replaced by other amino acids (other amino acids being naturally occurring amino acids or synthetic amino acids. Figure 1. Structures of Rufomycins (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. 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., Nat. Commun. 2017; 8(1):391.) In some embodiments, provided are compounds of formula I and III: 4 3152965.1 PCT APPLICATION 113645-108076 wherein: R2 is C1-C5 alkyl optionally substituted with F, CF3, is optionally substituted with F, lower alkyl (C1-C4), CH2F, CHF2, CF3, OH, lower alkoxy, mono or bis, R3 is -CH2-phenyl or CH2-mono heteroaryl or CH2-fused bi-heteroaryl in which the phenyl or heteroaryl is optionally substituted. Examples or R3 include: R6 PCT APPLICATION 113645-108076 cycloalkyl, 4-6 membered saturated heterocycle, lower alkyl-4 to 6 membered saturated heterocycle, lower alkoxy-4 to 6 membered saturated heterocycle, the alkyl, alkoxy, cycloalkyl or heterocycle is optionally substituted with OH, F, lower alkyl, lower alkoxy, NH2, NH-lower alkyl, N(lower alkyl)2, R6 is H, F, OH, lower alkyl, lower alkoxy, CF3. It is to be understood that the descriptions of the present invention have been simplified to illustrate elements that are relevant for a clear understanding of the present invention, while eliminating, for the purpose of clarity, many other elements found in typical pharmaceutical compositions. Those of ordinary skill in the art will recognize that other elements and / or steps are desirable and / or required in implementing the present invention. However, because such elements and steps are well known in the art, and because they do not facilitate a better understanding of the present invention, a 6 3152965.1 PCT APPLICATION 113645-108076 discussion of such elements and steps is not provided herein. The disclosure herein is directed to all such variations and modifications to such elements and methods known to those skilled in the art. Furthermore, the embodiments identified and illustrated herein are for exemplary purposes only and are not meant to be exclusive or limited in their description of the present invention. Technical and scientific terms used herein have the meaning commonly understood by one of skill in the art to which the present invention pertains, unless otherwise defined. Reference is made herein to various methodologies and materials known to those of skill in the art. Standard reference works setting forth the general principles of pharmacology include Goodman and Gilman's The Pharmacological Basis of Therapeutics, 10thEd., McGraw Hill Companies Inc., New York (2001). Any suitable materials and / or methods known to those of skill can be utilized in carrying out the present invention. However, preferred materials and methods are described. Materials, reagents and the like to which reference are made in the following description and examples are obtainable from commercial sources, unless otherwise noted. A compound according to the invention is inherently intended to comprise all stereochemically isomeric forms thereof. The term "stereochemically isomeric forms" as used hereinbefore or hereinafter defines all the possible stereoisomeric forms which the compounds of formula I and III, and their N-oxides, pharmaceutically acceptable salts or physiologically functional derivatives may possess. Unless otherwise mentioned or indicated, the chemical designation of compounds denotes the mixture of all possible stereochemically isomeric forms. In particular, stereogenic centers may have the R- or S-configuration; substituents on bivalent cyclic (partially) saturated radicals may have either the cis- or trans-configuration. Compounds encompassing double bonds can have an E (entgegen) or Z (zusammen)-stereochemistry at said double bond. The terms cis, trans, R, S, E and Z are well known to a person skilled in the art. 7 3152965.1 PCT APPLICATION 113645-108076 Stereochemically isomeric forms of the compounds of formula I and III are obviously intended to be embraced within the scope of this invention. Of special interest are those compounds of formula I and III which are stereochemically pure. Following CAS-nomenclature conventions, when the stereogenic centers of known absolute configuration are present in a molecule, an R or S descriptor is assigned (based on Cahn-Ingold-Prelog sequence rule) to the lowest-numbered chiral center, the reference center. The configuration of the second stereogenic center is indicated using relative descriptors [R*,R*] or [R*,S*], where R* is always specified as the reference center and [R*,R*] indicates centers with the same chirality and [R*,S*] indicates centers of unlike chirality. For example, if the lowest-numbered chiral center in the molecule has an S configuration and the second center is R, the stereo descriptor would be specified as S--[R*,S*]. If "α" and "β" are used: the position of the highest priority substituent on the asymmetric carbon atom in the ring system having the lowest ring number, is arbitrarily always in the "α" position of the mean plane determined by the ring system. The position of the highest priority substituent on the other asymmetric carbon atom in the ring system relative to the position of the highest priority substituent on the reference atom is denominated "α", if it is on the same side of the mean plane determined by the ring system, or "β", if it is on the other side of the mean plane determined by the ring system. When a specific stereoisomeric form is indicated, this means that said form is substantially free, 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% of the other isomer(s). Thus, when a compound of formula I or III is for instance specified as (S,S), this means that the compound is substantially free of the (S,S) isomer. 8 3152965.1 PCT APPLICATION 113645-108076 Compounds of formula I and III and some of the intermediate compounds invariably have at least one stereogenic centers in their structure which may lead to at least 2 stereochemically different structures. The compounds of formula I and III may be synthesized in the form of mixtures, in particular racemic mixtures, of enantiomers which can be separated from one another following art-known resolution procedures. The racemic compounds of formula I or III may be converted into the corresponding diastereomeric salt forms by reaction with a suitable chiral acid. Said diastereomeric salt forms are subsequently separated, for example, by selective or fractional crystallization and the enantiomers are liberated therefrom by alkali. An alternative manner of separating the enantiomeric forms of the compounds of formula I or III involves liquid chromatography using a chiral stationary phase. Said pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically. Preferably if a specific stereoisomer is desired, said compound will be synthesized by stereospecific methods of preparation. These methods will advantageously employ enantiomerically pure starting materials. The tautomeric forms of the compounds of formula I or III are meant to comprise those compounds of formula I or III wherein e.g. an enol group is converted into a keto group (keto-enol tautomerism). Tautomeric forms of the compounds of formula I and III or of intermediates of the present invention are intended to be embraced by the ambit of this invention. The term “alkyl” as used herein denotes an unbranched or branched chain, saturated, monovalent hydrocarbon residue containing 1 to 10 carbon atoms. The term “lower alkyl” denotes a straight or branched chain hydrocarbon residue containing 1 to 6 carbon atoms. "C1-10 alkyl" as used herein refers to an alkyl composed of 1 to 10 carbons. Examples of alkyl groups include, but are not limited to, lower alkyl groups 9 3152965.1 PCT APPLICATION 113645-108076 include methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, t-butyl or pentyl, isopentyl, neopentyl, hexyl, heptyl, and octyl. The term ‘halogen’ as used herein denotes F, Cl, Br or I. When the term “alkyl” is used as a suffix following another term, as in “phenylalkyl,” or “hydroxyalkyl,” this is intended to refer to an alkyl group, as defined above, being substituted with one to two substituents selected from the other specifically-named group. Thus, for example, “phenylalkyl” denotes the radical R'R"-, wherein R' is a phenyl radical, and R" is an alkylene radical as defined herein with the understanding that the attachment point of the phenylalkyl moiety will be on the alkylene radical. Examples of arylalkyl radicals include, but are not limited to, benzyl, phenylethyl, 3- phenylpropyl. The terms “arylalkyl” or "aralkyl" are interpreted similarly except R' is an aryl radical. The terms "(het)arylalkyl" or "(het)aralkyl" are interpreted similarly except R' is optionally an aryl or a heteroaryl radical. The terms “haloalkyl” or “halo lower alkyl” or “lower haloalkyl” refers to a straight or branched chain hydrocarbon residue containing 1 to 6 carbon atoms wherein one or more carbon atoms are substituted with one or more halogen atoms. The term "alkoxy" as used herein means an -O-alkyl group, wherein alkyl is as defined above such as methoxy, ethoxy, n-propyloxy, i-propyloxy, n-butyloxy, i- butyloxy, t-butyloxy, pentyloxy, hexyloxy, including their isomers. "Lower alkoxy" as used herein denotes an alkoxy group with a "lower alkyl" group as previously defined. "C1-10 alkoxy" as used herein refers to an-O-alkyl wherein alkyl is C1-10. The terms “haloalkoxy” or “halo lower alkoxy” or “lower haloalkoxy” refers to a lower alkoxy group, wherein one or more carbon atoms are substituted with one or more halogen atoms. 10 3152965.1 PCT APPLICATION 113645-108076 The term "hydroxyalkyl" as used herein denotes an alkyl radical as herein defined wherein one to three hydrogen atoms on different carbon atoms is / are replaced by hydroxyl groups. The term "carboxyl" as used herein refers to a group of formula -C(=O)R2 wherein each R is independently hydrogen or C1-3 alkyl, and lower alkyl is as defined herein. The term “cycloalkyl” denotes a monovalent saturated monocyclic or bicyclic hydrocarbon group of 3 to 10 ring carbon atoms. In particular embodiments cycloalkyl denotes a monovalent saturated monocyclic hydrocarbon group of 3 to 8 ring carbon atoms. Bicyclic means consisting of two saturated carbocycles having one or more carbon atoms in common. Particular cycloalkyl groups are monocyclic. Examples for monocyclic cycloalkyl are cyclopropyl, cyclobutanyl, cyclopentyl, cyclohexyl or cycloheptyl. Examples for bicyclic cycloalkyl are bicyclo[2.2.1]heptanyl, or bicyclo[2.2.2]octanyl. The term “amino” as used herein 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, can form a heterocycloalkyl. The term “primary amino” denotes a group wherein both R’ and R” are hydrogen. The term “secondary amino” denotes a group wherein R’ is hydrogen and R” is not. The term “tertiary amino” denotes a group wherein both R’ and R” are not hydrogen. Particular secondary and tertiary amines are methylamine, ethylamine, propylamine, isopropylamine, phenylamine, benzylamine dimethylamine, diethylamine, dipropylamine and diisopropylamine. The term “heteroaryl” denotes a monovalent aromatic heterocyclic mono- or bicyclic ring system of 5 to 12 ring atoms, comprising 1, 2, 3 or 4 heteroatoms selected from N, O and S, the remaining ring atoms being carbon. Examples of heteroaryl moieties include pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, 11 3152965.1 PCT APPLICATION 113645-108076 oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, triazinyl, azepinyl, diazepinyl, isoxazolyl, benzofuranyl, isothiazolyl, benzothienyl, indolyl, isoindolyl, isobenzofuranyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzooxadiazolyl, benzothiadiazolyl, benzotriazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, or quinoxalinyl. The term “heterocycloalkyl” denotes a monovalent saturated or partly unsaturated mono- or bicyclic ring system of 3 to 9 ring atoms, comprising 1, 2, or 3 ring heteroatoms selected from N, O and S, the remaining ring atoms being carbon. In particular embodiments, heterocycloalkyl is a monovalent saturated monocyclic ring system of 4 to 7 ring atoms, comprising 1, 2, or 3 ring heteroatoms selected from N, O and S, the remaining ring atoms being carbon. Examples for monocyclic saturated heterocycloalkyl are aziridinyl, oxiranyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydro-thienyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholin-4-yl, azepanyl, diazepanyl, homopiperazinyl, or oxazepanyl. Examples for bicyclic saturated heterocycloalkyl are 8-aza-bicyclo[3.2.1]octyl, quinuclidinyl, 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 for partly unsaturated heterocycloalkyl are dihydrofuryl, imidazolinyl, dihydro-oxazolyl, tetrahydro-pyridinyl, or dihydropyranyl. A “patient” or “subject” is a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey, chimpanzee, baboon or rhesus monkey, and the terms “patient” and “subject” are used interchangeably herein. The term “carrier”, as used in this disclosure, encompasses carriers, excipients, and diluents and means a material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or 12 3152965.1 PCT APPLICATION 113645-108076 transporting a pharmaceutical agent from one organ, or portion of the body, to another organ, or portion of the body. The term “treating”, with regard to a subject, refers to improving at least one symptom of the subject's disorder. Treating can be curing, improving, or at least partially ameliorating the disorder. The term “disorder” is used in this disclosure to mean, and is used interchangeably with, the terms disease, condition, or illness, unless otherwise indicated. The term “administer”, “administering”, or “administration” as used in this disclosure refers to either directly administering a compound or pharmaceutically acceptable salt of the compound or a composition to a subject, or administering a prodrug derivative or analog of the compound or pharmaceutically acceptable salt of the compound or composition to the subject, which can form an equivalent amount of active compound within the subject’s body. The term “optionally substituted,” as used in this disclosure, means a suitable substituent can replace a hydrogen bound to a carbon. It will be understood by those skilled in the art, with respect to any group containing one or more substituents, that such groups are not intended to introduce any substitution or substitution patterns that are sterically impractical, synthetically non-feasible and / or inherently unstable. Furthermore, combinations of substituents and / or variables within any of the Formulae represented herein are permissible only if such combinations result in stable compounds or useful synthetic intermediates wherein stable implies a reasonable pharmologically relevant half-life at physiological conditions. Dosage and Administration: The compounds of the present invention may be formulated in a wide variety of oral administration dosage forms and carriers. Oral administration can be in the form of tablets, coated tablets, dragées, hard and soft gelatin capsules, solutions, emulsions, 13 3152965.1 PCT APPLICATION 113645-108076 syrups, or suspensions. Compounds of the present invention are efficacious when administered by other routes of administration including continuous (intravenous drip) topical parenteral, intramuscular, intravenous, subcutaneous, transdermal (which may include a penetration enhancement agent), buccal, nasal, inhalation and suppository administration, among other routes of administration. The preferred manner of administration is generally oral using a convenient daily dosing regimen which can be adjusted according to the degree of affliction and the patient's response to the active ingredient. A compound or compounds of the present invention, as well as their pharmaceutically useable salts, together with one or more conventional excipients, carriers, or diluents, may be placed into the form of pharmaceutical compositions and unit dosages. The pharmaceutical compositions and unit dosage forms may be comprised of conventional ingredients in conventional proportions, with or without additional active compounds or principles, and the unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed. The pharmaceutical compositions may be employed as solids, such as tablets or filled capsules, semisolids, powders, sustained release formulations, or liquids such as solutions, suspensions, emulsions, elixirs, or filled capsules for oral use; or in the form of suppositories for rectal or vaginal administration; or in the form of sterile injectable solutions for parenteral use. A typical preparation will contain from about 5% to about 95% active compound or compounds (w / w). The term "preparation" or "dosage form" is intended to include both solid and liquid formulations of the active compound and one skilled in the art will appreciate that an active ingredient can exist in different preparations depending on the target organ or tissue and on the desired dose and pharmacokinetic parameters. The term “excipient” as used herein refers to a compound that is useful in preparing a pharmaceutical composition, generally safe, non-toxic and neither biologically nor 14 3152965.1 PCT APPLICATION 113645-108076 otherwise undesirable, and includes excipients that are acceptable for veterinary use as well as human pharmaceutical use. The compounds of this invention can be administered alone but will generally be administered in admixture with one or more suitable pharmaceutical excipients, diluents or carriers selected with regard to the intended route of administration and standard pharmaceutical practice. “Pharmaceutically acceptable” means that which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and neither biologically nor otherwise undesirable and includes that which is acceptable for veterinary as well as human pharmaceutical use. A "pharmaceutically acceptable salt" form of an active ingredient may also initially confer a desirable pharmacokinetic property on the active ingredient which were absent in the non-salt form, and may even positively affect the pharmacodynamics of the active ingredient with respect to its therapeutic activity in the body. The phrase “pharmaceutically acceptable salt” of a compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. Such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with 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, 4-toluenesulfonic acid, camphorsulfonic acid, 4- methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3- phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, 15 3152965.1 PCT APPLICATION 113645-108076 muconic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier may be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material. In powders, the carrier generally is a finely divided solid which is a mixture with the finely divided active component. In tablets, the active component generally is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired. Suitable carriers include but are not limited to magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. Solid form preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like. Liquid formulations also are suitable for oral administration include liquid formulation including emulsions, syrups, elixirs, aqueous solutions, aqueous suspensions. These include solid form preparations which are intended to be converted to liquid form preparations shortly before use. Emulsions may be prepared in solutions, for example, in aqueous propylene glycol solutions or may contain emulsifying agents such as lecithin, sorbitan monooleate, or acacia. Aqueous solutions can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizing, and thickening agents. Aqueous suspensions can be prepared by dispersing the finely divided active component in water with viscous material, such as 16 3152965.1 PCT APPLICATION 113645-108076 natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents. The compounds of the present invention may be formulated for parenteral administration (e.g., by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers with an added preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, for example solutions in aqueous polyethylene glycol. Examples of oily or nonaqueous carriers, diluents, solvents or vehicles include propylene glycol, polyethylene glycol, vegetable oils (e.g., olive oil), and injectable organic esters (e.g., ethyl oleate), and may contain formulatory agents such as preserving, wetting, emulsifying or suspending, stabilizing and / or dispersing agents. Alternatively, the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilisation from solution for constitution before use with a suitable vehicle, e.g., sterile, pyrogen-free water. The compounds of the present invention may be formulated for topical administration to the epidermis as ointments, creams or lotions, or as a transdermal patch. Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and / or gelling agents. Lotions may be formulated with an aqueous or oily base and will in general also containing one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents. Formulations suitable for topical administration in the mouth include lozenges comprising active agents in a flavored base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier. 17 3152965.1 PCT APPLICATION 113645-108076 The compounds of the present invention may be formulated for administration as suppositories. A low melting wax, such as a mixture of fatty acid glycerides or cocoa butter is first melted and the active component is dispersed homogeneously, for example, by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and to solidify. The compounds of the present invention may be formulated for vaginal administration. Pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate. The compounds of the present invention may be formulated for nasal administration. The solutions or suspensions are applied directly to the nasal cavity by conventional means, for example, with a dropper, pipette or spray. The formulations may be provided in a single or multidose form. In the latter case of a dropper or pipette, this may be achieved by the patient administering an appropriate, predetermined volume of the solution or suspension. In the case of a spray, this may be achieved for example by means of a metering atomizing spray pump. The compounds of the present invention may be formulated for aerosol administration, particularly to the respiratory tract and including intranasal administration. The compound will generally have a small particle size for example of the order of five (5) microns or less. Such a particle size may be obtained by means known in the art, for example by micronization. The active ingredient is provided in a pressurized pack with a suitable propellant such as a chlorofluorocarbon (CFC), for example, dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, or carbon dioxide or other suitable gas. The aerosol may conveniently also contain a surfactant such as lecithin. The dose of drug may be controlled by a metered valve. Alternatively the active ingredients may be provided in a form of a dry powder, for example a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and 18 3152965.1 PCT APPLICATION 113645-108076 polyvinylpyrrolidine (PVP). The powder carrier will form a gel in the nasal cavity. The powder composition may be presented in unit dose form for example in capsules or cartridges of e.g., gelatin or blister packs from which the powder may be administered by means of an inhaler. When desired, formulations can be prepared with enteric coatings adapted for sustained or controlled release administration of the active ingredient. For example, the compounds of the present invention can be formulated in transdermal or subcutaneous drug delivery devices. These delivery systems are advantageous when sustained release of the compound is necessary and when patient compliance with a treatment regimen is crucial. Compounds in transdermal delivery systems are frequently attached to a skin-adhesive solid support. The compound of interest can also be combined with a penetration enhancer, e.g., Azone (1-dodecylaza-cycloheptan-2-one). Sustained release delivery systems are inserted subcutaneously into to the subdermal layer by surgery or injection. The subdermal implants encapsulate the compound in a lipid soluble membrane, e.g., silicone rubber, or a biodegradable polymer, e.g., polylactic acid. Suitable formulations along with pharmaceutical carriers, diluents and excipients are described in Remington: The Science and Practice of Pharmacy 1995, edited by E. W. Martin, Mack Publishing Company, 19th edition, Easton, Pennsylvania. A skilled formulation scientist may modify the formulations within the teachings of the specification to provide numerous formulations for a particular route of administration without rendering the compositions of the present invention unstable or compromising their therapeutic activity. The modification of the present compounds to render them more soluble in water or other vehicle, for example, may be easily accomplished by minor modifications (salt formulation, esterification, etc.), which are well within the ordinary skill in the art. It is also well within the ordinary skill of the art to modify the route of administration and 19 3152965.1 PCT APPLICATION 113645-108076 dosage regimen of a particular compound in order to manage the pharmacokinetics of the present compounds for maximum beneficial effect in patients. The term "therapeutically effective amount" as used herein means an amount required to reduce symptoms of the disease in an individual. The dose will be adjusted to the individual requirements in each particular case. That dosage can vary within wide limits depending upon numerous factors such as the severity of the disease to be treated, the age and general health condition of the patient, other medicaments with which the patient is being treated, the route and form of administration and the preferences and experience of the medical practitioner involved. For oral administration, a daily dosage of between about 0.01 and about 1000 mg / kg body weight per day should be appropriate in monotherapy and / or in combination therapy. A preferred daily dosage is between about 0.1 and about 500 mg / kg body weight, more preferred 0.1 and about 100 mg / kg body weight, and most preferred 1.0 and about 15 mg / kg body weight per day. Thus, for administration to a 70 kg person, the dosage range in one embodiment would be about 70 mg to .7 g per day. The daily dosage can be administered as a single dosage or in divided dosages, typically between 1 and 5 dosages per day. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect for the individual patient is reached. One of ordinary skill in treating diseases described herein will be able, without undue experimentation and in reliance on personal knowledge, experience and the disclosures of this application, to ascertain a therapeutically effective amount of the compounds of the present invention for a given disease and patient. The pharmaceutical preparations are preferably in unit dosage forms. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and 20 3152965.1 PCT APPLICATION 113645-108076 powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form. EXAMPLES The following examples further describe and demonstrate particular embodiments within the scope of the present invention. Techniques and formulations generally are found in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, Pa.). The disclosure is further illustrated by the following examples, which are not to be construed as limiting this disclosure in scope or spirit to the specific procedures herein described. It is to be understood that the examples are provided to illustrate certain embodiments and that no limitation to the scope of the disclosure is intended thereby. It is to be further understood that resort may be had to various other embodiments, modifications, and equivalents thereof which may suggest themselves to those skilled in the art without departing from the spirit of the present disclosure and / or scope of the appended claims. General information for compound synthesis and characterization: Starting materials, reagents and solvents were purchased from commercial sources and used without further purification. Concentration under reduced pressure or reduced pressure means that a rotary evaporator was used. Silica gel chromatography was performed using a ISCO Biotage system with pre- packaged columns from Agela. Proton nuclear magnetic resonance spectroscopy (1H NMR) was recorded with Bruker 400 MHz NMR spectrometers. Chemical shifts are expressed in part per million downfield with respect to solvent resonance as the internal standard (for example, 21 3152965.1 PCT APPLICATION 113645-108076 CDCl3 at 7.26 ppm for 1H). The peak shapes are denoted as follows: s, singlet; d, doublet; t, triplet; q, quartet; p, pentet; m, multiplet; br s, broad singlet; dd, doublet of doublets, dt, doublet of triplets; dq, doublet of quartets. Liquid chromatography mass spectrometry (LCMS) was performed on Agilent 1260 / G6125B or Shimadzu LC20-MS2020. Mass spectrometry (MS) was performed via Electrospray Ionization (ESI) ionization sources. Typical LCMS conditions: Instrument: Shimadzu LC20-MS2020. Column: Kinetex C18 LC 4.6×50mm, 5um, temperature 50oC. Mobile phase A: 0.018% TFA in ACN; B: 0.037% TFA in water. Gradient: 0-60% A in B over 5 min, hold for 0.7 min at flow rate of 1.5 mL / min, and then return to 0% A in B, hold for 0.29 min at flow rate of 2.0 mL / min. Instrument: Agilent 1260 / G6125B. Column: Poroshell 120 EC C183.0×30mm, 2.7um, temperature 50oC. Mobile phase A: 0.018% TFA in ACN; B: 0.037% in water. Gradient: 5-95% A in B over 3 min, then hold for 0.6 min at flow rate of 1.0 mL / min, and then return to 5% A in B and hold for 0.4 min at flow rate of 1.5 mL / min. Typical HPLC purity check conditions: Instrument: Agilent1290. Column: Kinetex EVO C18100 A LC Column 150 x 2.1mm, 1.7um, temperature 50oC. Mobile phase A: 0.1%TFA in H2O; B: 0.075%TFA in ACN. Flow rate: 0.4 mL / min. Detector PDA: 220nm & 254nm. Abbreviations: Abbreviations Name 22 3152965.1 PCT APPLICATION 113645-108076 Pre-HPLC Preparative High Performance Liquid Chromatography e 23 3152965.1 PCT APPLICATION 113645-108076 FA Formic acid Synthesis of Key Intermediates Intermediate 1 PCT APPLICATION 113645-108076 To a solution of compound 1 (500 g, 1.57 mol, 1 eq) in HOAc (2500 mL) was added portion- wise NaBH3CN (493.4 g, 7.85 mol, 5.00 eq) at 0°C. The resulting mixture was stirred at 25°C for 2 hrs. TLC (EtOAc: PE = 1: 5) showed the starting material was consumed and a new spot was formed. The mixture was diluted with ice-water (10 L), basified to pH = 10 with 30% aqueous ammonia, extracted with EtOAc (6 L X 3). The organic layer was concentrated under vacuum.. The resulting residue was purified by column chromatography on silica gel ( PE: EtOAc = 6: 1 to 1: 1) to give compound 2 (315 g, 31.3% yield) as a light-yellow solid. Preparation of compound 4 g, , g, mmol, 1 eq), CuCl (19.5 g, 196.6 mmol, 4.70 mL, 0.2 eq) and DIPEA (139.78 g, 1.08 mol, 188.38 mL, 1.1 eq) in THF (1500 mL) was stirred at 70 °C for 5 hr. TLC (EtOAc: PE = 1: 3) showed the starting material was consumed and a new spot was formed. The mixture was diluted with EtOAc (1000 mL), washed with 1N HCl (1000 mL X 2) and sat.aq NaHCO3 (1000 mL), dried over anhydrous Na2SO4 and filtered. The filtrate 25 3152965.1 PCT APPLICATION 113645-108076 was concentrated under vacuum. The resulting residue was purified by column chromatography on silica gel (PE: EtOAc = 10: 1 to 5:1,) to give compound 4 (205 g, 53.9% yield) as a yellow oil. Preparation of compound 5 To a mL) was added DDQ (120.4 g, 530.4 mmol, 1.00 eq) in portions at 0°C. The resulting mixture was stirred at 0°C for 1 hr. TLC (solvent, EtOAc: PE = 1: 3) showed the starting material was consumed and a new spot was formed. The mixture was diluted with DCM (600 mL), washed with sat.aq NaHCO3 (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. Preparation of compound 6 To a solution of compound 5 (200 g, 520.2 mmol, 1.00 eq) and (113.5 g, 879.1 mmol, 104.17 mL, 1.69 eq) in toluene (1000 mL) was added Lindlar Catalyst (47.2 g, 228.9 mmol, 47.2 mL, 0.44 eq) under N2. The suspension was degassed under vacuum and purged with H2 several times. The resulting mixture was stirred at 25 °C 26 3152965.1 PCT APPLICATION 113645-108076 for 5 hrs under H215 PSI. TLC (EtOAc: PE = 1: 3) showed the material was consumed and a new spot was 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 (150 g, 388.1 mmol, 74.6% yield) as colorless oil. Preparation of compound 7 To a mL) was added SOCl2 (58.93 g, 495.3 mmol, 35.9 mL, 1.5 eq) at 0 °C dropwise. The reaction was stirred at 25 °C for 2 hr. TLC (solvent, EtOAc: PE = 1: 5) showed the starting material was consumed and a new spot was formed. 2 N NaOH solution was added dropwise to adjust pH = 8. The reaction mixture was extracted with DCM (500 mL x 2). The organic layer was dried over Na2SO4 and concentrated to dryness in vacuo to give compound 7 (94.5 g, crude) as a yellow oil. Preparation of Intermediate 1 3152965.1 PCT APPLICATION 113645-108076 To a solution of compound 7 (94.5 g, 330.0 mmol, 1.00 eq) in THF (500 mL) / H2O (500 mL) was added LiOH.H2O (41.57 g, 989.99 mmol, 3.00 eq). The reaction was stirred at 10 °C for 2 h. After the material was consumed, the pH was adjusted to 8, then Fmoc-OSu (111.4 g, 330.0 mmol, 1.00 eq) was added into. The reaction was stirred at 25 °C for another 2 h. LCMS (EW16333-36-P1A) showed a peak (Rt = 0.949 min) with desired MS was detected. HPLC (EW16333-36-P1A) showed a peak (Rt = 2.154 min) was detected. The reaction was adjusted to pH = 4-5 with 1 N HCl solution, extracted with EtOAc (500 mL X 2). The organic layer was dried over Na2SO4 and concentrated to dryness in vacuo. The residue was purified by prep-HPLC (TFA condition) to give Intermediate 1 (105 g, 210.8 mmol, 63.9% yield, 99.3% purity) as a white solid. LCMS (ESI): m / z 495.1 [M+H]+1HNMR (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). Preparation of compound 3 To a solution of g, 1.00 eq), DIPEA (368.7 g, 2.85 mol, 496.9 mL, 2.00 eq) and DMAP (17.4 g, 142.7 mmol, 0.1 eq) in DCM (600 mL) was added drop-wise Ac2O (160.2 g, 1.57 mol, 146.9 mL, 1.1 eq) at 0°C. The resulting mixture was warmed to 25°C and stirred for 2 hr. TLC (solvent, PE: EtOAc = 5: 1,) showed 3_1 was consumed, and a new spot formed. The mixture was diluted with DCM (1.5 L), washed with 1N HCl (1 L X 3) and brine (1 L), dried over anhydrous 28 3152965.1 PCT APPLICATION 113645-108076 Na2SO4 and filtered. The filtrate was concentrated under vacuum (water bath: <40°C) to afford Compound 3 (150 g, crude) as a colorless oil. Intermediate 2 Preparation of compound 2 To a solution of compound 1 (150 g, 533 mmol, 1.00 eq) in toluene (1.50 L) was added paraformaldehyde (101 g, 3.38 mol, 93.0 mL, 6.33 eq) and 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 for azeotropic removal of water. TLC (solvent, DCM: MeOH=10: 1) showed that the starting material was consumed, and a major new spot was formed. Two batches 29 3152965.1 PCT APPLICATION 113645-108076 were combined. The mixture was filtered, and filtrate was concentrated to give compound 2 (322 g, crude) as light-yellow oil.1HNMR (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). Preparation of compound 3 1) To a solution of compound 2 (320 g, 1.09 mol, 1.00 eq) in DCM (1.6 L) was added oxalyl chloride (208 g, 1.64 mol, 143 mL, 1.50 eq) and DMF (159.51 mg, 2.18 mmol, 167.91 µL, 0.002 eq) and stirred at 10°C for 3 hrs. TLC (solvent, PE: EtOAc=1: 1) showed that the reactant 2 was consumed and a new spot was formed. Two batches were combined. The mixture was concentrated, and the residue was diluted with toluene (500 mL) and then concentrated three times to give the acyl chloride (680 g, crude) as blackbrown solid. 2) To a solution of acyl chloride (170 g, 545 mmol, 1.00 eq) in THF (1.00 L) was added a solution of lithium tri-tert-butoxyaluminum hydride (124 g, 491 mmol, 6.06 mL, 0.900 eq) in THF (1.00 L) at -70°C under N2. The mixture was stirred at -70°C for 2 h. TLC (solvent, DCM: MeOH=10:1) showed that the reactant 2 was consumed and a major new spot was 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 then the mixture was filtered, and the filter cake was washed by 30 3152965.1 PCT APPLICATION 113645-108076 EtOAc (600 mL X 2) and the filtrate was concentrated to give compound 3 (520 g, crude) as black brown oil.1HNMR (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). Preparation of compound 4 To g, 656 mmol, 1.00 eq, HCl salt) in MeOH (1.8 L) was added NaOAc (53.6 g, 656 mmol, 1.00 eq). The mixture was stirred at 10°C for 10 min and NaBH3CN (82.5 g, 1.31 mol, 2.00 eq) was added slowly. Then the mixture was stirred at 10°C for 2 h. LCMS showed that the reactant 3 was consumed and the desired MW (was detected. Two batches were combined. The mixture was concentrated, and the residue was dissolved with 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 yellow oil. 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). Preparation of compound 5 31 3152965.1 PCT APPLICATION 113645-108076 To a g, 456 mmol, 2.00 eq) in ACN (550 mL) was added TMSCl (49.5 g, 456 mmol, 57.9 mL, 2.00 eq) drop-wise at 10°C under N2. The mixture was stirred at 30°C for 16 h. TLC (PE: EtOAc = 1:1) showed that the reactant 4 was consumed and a major new spot was formed. Two batches were combined. The reaction mixture was poured into water (1.50 L) and then the resulting mixture was extracted with EtOAC (1.5 L X 2). The organic layer was washed with brine (2L), dried over Na2SO4. The filtrate was concentrated. The resulting residue was purified by column (SiO2, PE: EtOAc=2: 1) to give compound 5 (120 g,54.7% yield, 97% purity) as colorless oil.1HNMR (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). Preparation of compound 6 To a solution of compound 5 (136 g, 282 mmol, 1.00 eq) in EtOH (400 mL) was added Pd / C (42.0 g, 10% purity) under N2. The mixture was degassed and purged with H2for 3 times and stirred at 30°C for 12 h under H2 atmosphere (15 Psi). LCMS showed 32 3152965.1 PCT APPLICATION 113645-108076 that the reactant1 was not consumed and the mixture was stirred at 30°C for 36 h under H2 (15 psi). LCMS showed that the reactant 5 was consumed and the desired MS (Rt = 0.271 min) was detected. The mixture was filtered and concentrated to give compound 6 (70.0 g, crude) as white solid. LCMS: m / z 243.2 (MS (M-17)1HNMR (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). Preparation of Intermediate 2 To a solution of compound 6 (70.0 g, 289 mmol, 1.00 eq) in NaHCO3 (648 g, 7.71 mol, 300 mL, 26.7 eq) and dioxane (300 mL) was added FMOC-OSU (97.5 g, 289 mmol, 1.00 eq) at 0 °C and stirred at 10°C for 2 h. LCMS showed that the reactant 1 was consumed and the desired MSwas detected. The reaction mixture was diluted with water (300 mL) and extracted EtOAc (300 mL X 2), and 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 phase was adjusted to pH = 3.0 ~ 5.0 with aq. HCl (1.0 N), and then extracted with EtOAc (500 mL X 3). The combined organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, DCM: PE=10: 1). Two batches were combined. Intermediate 2 (125 g, 258 mmol, 89.4% yield, 96% purity) was obtained as a white solid. 33 3152965.1 PCT APPLICATION 113645-108076 LCMS: m / z 465.2 [M+H]+1HNMR (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). Intermediate 4 PCT APPLICATION 113645-108076 To a solution of compound 1 (100 g, 446 mmol, 1.00 eq, HCl salt) in DMF (1.0 L) was added LiOH•H2O (56.2 g, 1.34 mol, 3.00 eq) and 4-bromobut-1-ene (200 g, 1.48 mol, 150 mL, 3.31 eq) at 25 °C. The reaction mixture was stirred at 25 °C for 16 h. TLC (PE: EtOAc= 10: 1) showed one major spot was formed. The reaction mixture was poured into H2O (1.5 L) and extracted with EtOAc (700 mL X 2). The combined organic layer was washed with brine (500 mL X 2), dried over Na2SO4, and concentrated. The residue was purified by column chromatography (ISCO®; 130 g SepaFlash® Silica Flash Column, Eluent of 0 ~ 20% EtOAc-PE gradient at 250 mL / min) to give compound 2 (55.0 g, 227 mmol, 50.9% yield) as a yellow oil.1HNMR (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). Preparation of compound 2B To a g, mL) and H2O (250 mL) was added NaHCO3 (36.4 g, 434 mmol, 16.8 mL, 2 eq) and Fmoc-Osu (69.5 g, 206 mmol, 0.95 eq) at 25 °C. The reaction mixture was stirred at 25 °C for 1 h. LCMS showed Compound 2A was consumed and desired MW was detected. The reaction mixture was extracted with PE (100 ml X3). The aqueous layer’s pH was adjusted to 2 - 3 with 1 N HCl and then extracted with EtOAc (500 mL X3). The combined organic layer was 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 was used in the next step without further purification. 35 3152965.1 PCT APPLICATION 113645-108076 LCMS: m / z 338.0 [M+H]+Preparation of compound 3 To a solution of Compound 2B (69.8 g, 207 mmol, 1.00 eq) in DMF (600 mL) were added HATU (118 g, 310 mmol, 1.50 eq), DIEA (53.5 g, 414 mmol, 72.1 mL, 2.00 eq), and Compound 2 (55.0 g, 227 mmol, 1.10 eq) at 25 °C. The reaction mixture was stirred at 25 °C for 1 h. LCMS showed Compound 2B was consumed and desired MW was detected. The reaction mixture was poured into H2O (2 L) and extracted with EtOAC (800 mL X 3). The combined organic layer was 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 (79.0 g, 136 mmol, 66.0% yield, 97.1% purity) as a light-yellow oil. LCMS: m / z 583.3 [M+Na]+1HNMR (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 (s, 3H), 1.45 - 1.38 (m, 9H), 1.06 - 0.88 (m, 7H). Preparation of compound 4 36 3152965.1 PCT APPLICATION 113645-108076 (250 mL) was added [1,3-bis(2,4,6-trimethylphenyl)imidazolidin-2-ylidene]-dichloro-[(2- isopropoxyphenyl)methylene]ruthenium (135 mg, 216 µmol, 0.05 eq) at 25 °C. The reaction mixture was stirred at 85 °C for 16 h. TLC (PE: EtOAc = 3: 1) showed one major spot was formed although some Compound 3 remained. LCMS showed desired 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. LCMSm / z 533.3 [M+H]+Preparation of Intermediate 4 A solution of Compound 4 (10.0 g, 18.2 mmol, , 1.0 eq) in DCM (100 mL) and TFA ( 30 mL) was stirred at 25 °C for 1 h. LCMS showed Compound 4 was consumed and 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. LCMS: m / z 477.1 [M+H]+37 3152965.1 PCT APPLICATION 113645-108076 Examples TBA-315 Peptide Synthesis: The peptide was synthesized using standard Fmoc chemistry. 1. Resin preparation: A suspension of 2-CTC resin (6.00 mmol, 1.00 eq, Sub 1.07 mmol / g), (S)-2-((S,Z)-3-((((9H-fluoren-9- yl)methoxy)carbonyl)(methyl)amino)-2-oxo-3,4,7,8-tetrahydroazocin-1(2H)- yl)-4-methylpentanoic acid (Intermediate 4, 2.94 g, 6.00 mmol, 1.00 eq), and DIEA (24.0 mmol, 4.50 mL, 4.00 eq) in DCM (200 mL) was stirred under N2 for 2hrs. at 20°C. MeOH (6 mL) was then added and stirring continued under N2 for another 30 min. The resin was washed with DMF (300 mL X 5) and filtered to isolate the resin. 38 3152965.1 PCT APPLICATION 113645-108076 2. A 20% piperidine solution in DMF (200 mL) was added to the above resin and the resulting suspension was stirred under N2 for another 30 min. The resin was washed with DMF (300 mL X 5) and isolated by filtration. 3. Coupling: A solution of Fmoc-Ala-OH (2.80 g, 9.00 mmol, 1.50 eq), a solution of HOAT (1.16 g, 8.64 mmol, 1.43 eq) in DMF (200 mL), and DIC (1.14 g, 9.00 mmol, 1.44 mL, 1.50 eq) were added to the above resin. The resulting suspension was stirred under N2 for 1 hr at 20°C. The resin was then washed with DMF (300 mL X 5) and isolated by filtration. 4. Steps 2 to 3 above were repeated for the coupling of following amino acids: (steps 3-6 in the table) # Materials Coupling reagents ) ) ) ) ) 20% piperidine in DMF was used for Fmoc deprotection for 30 min. The coupling reaction was monitored by ninhydrin test. The resin 1 was washed with DMF for 5 times. 39 3152965.1 PCT APPLICATION 113645-108076 Peptide Cleavage, Cyclization and Purification: A cleavage buffer (1%TFA in DCM) was added to the flask containing the side chain protected peptide 1 at room temperature and the mixture was stirred for 30 min. The mixture was concentrated under vacuum to give the crude peptide 2.. The peptide was dissolved in DCM (1.00 mmol / L), and the solution pH was adjusted to 7-8 with DIEA. TBTU (2.00 eq) and HOBT (2.00 eq) were added for cyclization. LCMS after 30 min of stirring showed one main peak with the desired MW. The solvents were evaporated under vacuum. The residue was purified by prep-HPLC (see the table below for conditions) to give the final product TBA-315 (1.67 g, 1.32 mmol, 17.3% yield, 96.1% purity) as a yellow solid. Purification condition In a manner similar to TBA-315 the following analogues in table I were prepared. 40 3152965.1 PCT APPLICATION 113645-108076 Table I LC / MS(ESI) Compound ID Structure HPLC Purity 41 3152965.1 PCT APPLICATION 113645-108076 TBA-443 97.4% 1037.5 Biological Data The MABA MIC values were determined according to the methods published (Microplate Alamar Blue Assay (MABA) and Low Oxygen Recovery Assay (LORA) for Mycobacterium tuberculosis. Cho S, Lee HS, Franzblau S. Methods Mol Biol. 2015;1285:281-92). Table 2 CompoundM. TB H37Rv: MIC-VERO Cell: Cytotoxicity- Synthesis of Intermediates 42 3152965.1 PCT APPLICATION 113645-108076 Intermediate 1 HN N N LiI OH , CF3COOAg (100 g, 454 mmol), and Cu(OAc)2 (82.5 g, 454 mmol) in MeCN (1.50 L) was added Pd(OAc)2 (20.4 g, 90.8 mmol) at 35 °C. The mixture was stirred at 35°C for 8 hrs. 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]+.1H 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). Preparation of Intermediate 1: To a solution of 1-c (92.0 g, 173 mmol) in ethyl acetate (956 mL) was added LiI (185 g, 1.39 mol) under N2 atmosphere. The reaction mixture was stirred at 80 °C for 10 hrs. The mixture was adjusted pH to 5 by 1N HCl aqueous solution and extracted with ethyl acetate (600 mL x 3). The combined organic layer was washed with brine (500 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by reversed phase silica gel flash chromatography (Column: C18 spherical 20-35um, 100A. Mobile phase A: 0.1% HCl in H2O; B: ACN. Gradient: 15-95%B in A over 90 min). Flow rate: 100mL / min; Detector PDA: 220nm & 254nm) to give Intermediate 1 (54.0 g, 105 mmol, 61% yield) as a yellow solid. LCMS (ESI): m / z 495.2 [M+H]+.1H 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 43 3152965.1 PCT APPLICATION 113645-108076 (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). Intermediate 2 Preparation of 2-b: To a solution of 2-a (150 g, 533 mmol) in toluene (1.50 L) was added paraformaldehyde (101 g, 3.38 mol, 93.0 mL) and p-TsOH (10.7 g, 62.1 mmol). The mixture was heated to 110 °C for 2 hrs and water was removed by Dean-Stark trap. The mixture was filtered, the filtrate was concentrated to give compound 2-b (161 g, crude) as a light-yellow oil.1H 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). Preparation of 2-c: To a solution of 2-b (320 g, 1.09 mol) in DCM (1.6 L) was added oxalyl chloride (208 g, 1.64 mol, 143 mL) and DMF (2.2 mmol, 168 uL). The reaction was stirred at 10 °C for 3 hrs under N2 atmosphere. The mixture was concentrated to dryness and the residue was treated with toluene (500 mL) azeotropically for three times 44 3152965.1 PCT APPLICATION 113645-108076 to give the acyl chloride (340 g, crude). To a solution of the acyl chloride (170 g, 545 mmol) in THF (1.0 L) was added a solution of LiAl(OtBu)3H (124 g, 491 mmol, 6.1 mL) in THF (1.0 L) at -70 °C under N2. The mixture was stirred at -70 °C for 2 hrs. The reaction mixture was quenched with water (400 mL) and anhydrous sodium sulfate (500 g) at 0 °C. 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) as black brown oil.1H 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). Preparation of 2-e: To a solution of 2-c (260 g, 656 mmol) and 2-d (169 g, 656 mmol) in MeOH (1.80 L) was added NaOAc (53.6 g, 656 mmol). The mixture was stirred at 10 °C for 10 min and NaBH3CN (82.5 g, 1.31 mol) was added in batches. Then the mixture was stirred at 10°C for 2 hrs. 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 yellow oil. LCMS (ESI): m / z 465.1 [M-H2O+H]+.1H NMR (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). Preparation of 2-f: To a solution of 2-e (110 g, 228 mmol) and NaBH3CN (28.7 g, 456 mmol) in MeCN (550 mL) was added TMSCl (49.5 g, 456 mmol, 57.9 mL) dropwise at 10 °C under N2 atmosphere. The mixture was stirred at 30 °C for 16 hrs. 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 layer was washed with brine (2.0 L), dried over anhydrous sodium sulfate. The filtrate was concentrated to dryness. The crude product was purified by column chromatography (SiO2, petroleum ether: ethyl 45 3152965.1 PCT APPLICATION 113645-108076 acetate = 2:1) to give 2-f (120 g, 249 mmol, 54.7% yield) as colorless oil.1H 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). Preparation of 2-g: To a solution of 2-f (136 g, 282 mmol) in EtOH (400 mL) was added Pd / C (42.0 g, 10% purity) under N2 atmosphere. The mixture was degassed and purged with H2 for 3 times and stirred at 30 °C for 48 hrs under H2 atmosphere (15 Psi). The mixture was filtered and concentrated to give 2-g (70.0 g, crude) as a white solid. LCMS (ESI): m / z 243.2 [M+H]+.1H 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). Preparation of Intermediate 2: To a solution of 2-g (70.0 g, 289 mmol, 1.0 eq) in 1,4- dioxane (300 mL) and H2O (300 mL) was added NaHCO3 (648 g, 7.71 mol, 300 mL, 26.7 eq) and FmocOSu (97.5 g, 289 mmol, 1.00 eq) at 0 °C. The resulting solution was stirred at 10 °C for 2 hrs, and then diluted with ice-water (300 mL) and extracted with ethyl acetate (300 mL x 2). The combined organic layer was washed with water (300 mL), dried over anhydrous sodium sulfate and concentrated to dryness. The crude was purified by column chromatography (SiO2, dichloromethane: methanol = 10: 1) to give Intermediate 2 (30 g). Meanwhile, the combined aqueous phase was adjusted pH = 3.0 - 5.0 with aqueous 1N HCl, and then extracted with ethyl acetate (500 mL x 3). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the Intermediate 2 (95.0 g). Two batches were combined to get Intermediate 2 (125 g, 258 mmol, 89.4% yield) as a white solid. LCMS (ESI): m / z 465.2 [M+H]+.1H 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). 46 3152965.1 PCT APPLICATION 113645-108076 Intermediate 4 Fmoc NH NH Fmoc-OSu(S)OH(S) OH 4 (250 mL) was added NaHCO3 (36.4 g, 434 mmol) and FmocOSu (69.5 g, 206 mmol) at 25 °C. After stirring at 25 °C for 1 hr, the reaction mixture was extracted with petroleum ether (100 ml x 3). The aqueous layer was adjusted to pH 2 -3 with aq.1 N HCl and extracted with ethyl acetate (500 mL x 3). The combined organic layer was washed with brine (500 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated to give 4-b (65.0 g, 192 mmol, 88.7% yield) as a white solid. LCMS (ESI): m / z 338.0 [M+H]+. Preparation of 4-e: To a solution of 4-c (100 g, 446 mmol, HCl salt) in DMF (1.0 L) was added LiOH•H2O (56.2 g, 1.34 mol) and 4-d (150 mL, 1.48 mol,) at 25 °C. The reaction mixture was stirred at 25 °C for 16 hrs, and then poured into water (1.50 L) and extracted with ethyl acetate (700 mL x 2). The combined organic layer was 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 (55.0 g, 227 mmol, 50.9% yield) as a yellow oil.1H NMR (CDCl3, 400 MHz) δ: 5.84 - 5.74 (m, 1H), 5.14 - 5.00 (m, 2H), 3.14 (t, J = 7.2 47 3152965.1 PCT APPLICATION 113645-108076 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). Preparation of 4-g: To a solution of 4-f (69.8 g, 207 mmol) in DMF (600 mL) was added HATU (118 g, 310 mmol), DIEA (53.5 g, 414 mmol, 72.1 mL) and 4-e (55.0 g, 227 mmol) at 25 °C. The reaction mixture was stirred at 25 °C for 1 hr, and then poured into water (2 L) and extracted with ethyl acetate (800 mL x 3). The combined organic layer was washed with water (500 mL x 3), 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 light-yellow oil. LCMS (ESI): m / z 583.2 [M+Na]+.1H 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). Preparation of 4-h: To a solution of 4-g (2.50 g, 4.33 mmol) in DCE (250 mL) was added Hoveyda-Grubbs 2nd(135 mg, 216 µmol) at 25 °C. The reaction mixture was stirred at 85 °C for 16 hr 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 (1.26 g, 2.29 mmol, 52.7% yield, 96.6% purity) as a white solid. LCMS (ESI): m / z 533.3 [M+H]+.1H 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 = 8.0 Hz, 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 = 8.0 Hz, 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). 48 3152965.1 PCT APPLICATION 113645-108076 Preparation of Intermediate 4: A solution of 4-h (10.0 g, 18.2 mmol) in DCM (100 mL) and TFA (30mL, 403 mmol) was stirred at 25 °C for 1 hr. The reaction mixture was concentrated under reduced pressure to give Intermediate 4 (17.0 g, 35.6 mmol, 97.5% yield) as a brown solid. 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 = 8.0 Hz, 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). Intermediate 15 Preparation of 15-c: To a solution of 15-a (15.0 g, 66.6 mmol) in DMF (500 mL) was added Cs2CO3 (43.4 g, 133 mmol) and 15-b (13.6 g, 66.6 mmol). The mixture was stirred at 100 °C for 12 hr under 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 layer was washed with brine (1000 mL x 3), 49 3152965.1 PCT APPLICATION 113645-108076 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]+.1H NMR (DMSO-d6, 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). Preparation of 15-e: A solution of 15-d (25.1 g, 55.6 mmol) in DMF (150 mL) was added slowly to a suspension of Zn (32.5 g, 498 mmol) in DMF (50 mL) under N2 atmosphere. The mixture was stirred at 25 °C for 1.5 hrs. Then supernatant was pumped into a solution of 15-c (13.0 g, 50.5 mmol) in DMF (50 mL), degassed and purged with N2 for 3 times, PdCl2 (448 mg, 2.53 mmol) was added, followed by Xphos (2.41 g, 5.06 mmol). The resulting mixture was degassed and purged with N2 for 3 times again, and then stirred at 25 °C for 12 hrs under N2 atmosphere. The reaction mixture was filtered. The filtrate was diluted with water (600 mL), extracted with ethyl acetate (600 mL x 3). The combined organic layer was 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 (20.0 g, 38.5 mmol, 76.2% yield) as a yellow solid. LCMS (ESI): m / z 502.3 [M+H]+. Preparation of Intermediate 15: To a solution of 15-e (20.0 g, 38.5 mmol) in i-PrOH (90 mL) and THF (180 mL) was added CaCl2 (68.4 g, 617 mmol), followed by a solution of LiOH·H2O (7.28 g, 173 mmol) in H2O (90 mL) at 0 °C. The resulting mixture was stirred at 25 °C for 12 hrs, and then adjusted to pH 5-6 with aq. 1M HCl and extracted with ethyl acetate (500 mL x 3). The combined organic layer was 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 gel flash chromatography (Column: C18 spherical 20-35um, 100A. Mobile phase A: 0.1% HCl in H2O, B: ACN. Gradient: 10-95% B over 68 min. Flow 50 3152965.1 PCT APPLICATION 113645-108076 rate: 100mL / min. Detector PDA: 220nm & 254nm) to yield Intermediate 15 (10.0 g, 20.3 mmol, 52.8% yield) as a white solid. LCMS (ESI): m / z 488.2 [M+H]+.1H NMR (DMSO-d6, 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). The Intermediates in Table 3 were prepared in a manner similar to the synthesis of Intermediate 15. Table 3: Intermediates made in a manner similar to the synthesis of Intermediate 15 Compound StructureLCMS (ESI):m / z NMR- - ), , ), 7 51 3152965.1 PCT APPLICATION 113645-108076 1H NMR (DMSO-d6, 400 MHz) δ: 9.50 (s, - 9 6 , , ), 8 5 , ), 6 , , 3 ), , ), , = , ), 2 3152965.1 PCT APPLICATION 113645-108076 1H NMR (DMSO-d6, 400 MHz) δ: 9.72 (d, J = 4 2 , ), 3 5 = , , ), , 2 1 , ) 6 3 3152965.1 PCT APPLICATION 113645-108076 1H NMR (DMSO-d6, 400 MHz) δ: 12.72 (s, - 2 , ), , 2 0 , ), 1 , , , , ), 5 , ) 4 3152965.1 PCT APPLICATION 113645-108076 1H NMR (DMSO-d6, 400 MHz) δ: 12.93 (d, J 6 4 6 , , , ), 1 6 7 J 7 , ), ), = - 3 2 , ), 5 3152965.1 PCT APPLICATION 113645-108076 1H NMR (DMSO-d6, 400 MHz) δ: 12.79 (s, - 5 , ), 2 4, - ), 3 6 - 8 , ), 0 6 3152965.1 PCT APPLICATION 113645-108076 1H NMR (CD3OD, 400 MHz) δ: 8.82 (d, J = 3.2 0 3 8 6 ), 2 , ), 1 0 , ) ), 7 2 , ), 0 9 , ) 7 3152965.1 PCT APPLICATION 113645-108076 1H NMR (DMSO-d6, 400 MHz) δ: 13.42 - ), , , 6 1 7 6 , ), 9 1 , ), J , 0 .2 , , ), 3 8 3152965.1 PCT APPLICATION 113645-108076 1H NMR (DMSO-d6, 400 MHz) δ: 12.75 (s, ), 2 1 ), 4 0 - 6 8 , 6 , , ), 4 4, , 6 9 3152965.1 PCT APPLICATION 113645-108076 1H NMR (DMSO-d6, 400 MHz) δ: 13.06 - J 9 , 8 , ), , 5 , ), , , 3 1 , , ), 3 J , 0 3152965.1 PCT APPLICATION 113645-108076 1H NMR (DMSO-d6, 400 MHz) δ: 7.87 (d, J = , ), 4 , 4, ) = = = 6 0 , , 1 3152965.1 PCT APPLICATION 113645-108076 1H NMR (DMSO-d6, 400 MHz) δ: 8.12 (s, 1 , = = = 0 , - J ), = , ), 2 3152965.1 PCT APPLICATION 113645-108076 1H NMR (DMSO-d6, 400 MHz) δ: 13.01 - 6 4 1 - 8 , = = = - 2 , ) , ), - ), 7 - 3 3152965.1 PCT APPLICATION 113645-108076 1H NMR (DMSO-d6, 400 MHz) δ: 8.29 (d, J = = , 1 J 8 , ), 6 - 3 ), - 4 3152965.1 PCT APPLICATION 113645-108076 1H NMR (DMSO-d6, 400 MHz) δ : 13.33 - 6 4 - , 7 , ), 9 s, 3 , , , ), 4 9 , ), 6 5 3152965.1 PCT APPLICATION 113645-108076 1H NMR (DMSO-d6, 400 MHz) δ: 9.27 (s, ), 8 - 4 , , , , , 6 J J J 9 ), - 9 6 3152965.1 PCT APPLICATION 113645-108076 1H NMR (DMSO-d6, 400 MHz) δ: 12.6 -13.1 ), ), , ), r Intermediate 8 Preparation of Intermediate 8: To a solution of Intermediate 9 (1.00 g, 2.13 mmol) in DCM (5 mL) was added BBr3 (1 M in DCM, 6.00 mL) at -78 °C. The mixture was stirred at 25 °C for 16 hrs. The mixture was quenched with a premixed solution of MeOH (10 mL) and TEA (0.80 mL) at -78 °C, then filtered and concentrated under reduced pressure. The crude product was purified by reversed-phase silica gel chromatography (Column: C18 spherical 20-35um 100A. Mobile phase A: 0.1% TFA in H2O, B: ACN. Gradient: 5-75% B over 28 min. Flow rate: 100mL / min. Detector PDA: 220nm & 254nm) to afford Intermediate 8 (411 mg, 839 μmol, 39.4% yield) as a yellow solid. LCMS (ESI): m / z 456.1 [M+H]+.1H NMR (DMSO-d6, 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 67 3152965.1 PCT APPLICATION 113645-108076 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). Intermediate 17 F 1. IBCF, NMM F PCC F HO O Preparation of 17-b: To a solution of 17-a (10.0 g, 84.6 mmol) in THF (120 mL) was added NMM (9.31 mL, 84.6 mmol,) and IBCF (12.1 mL, 93.1 mmol,) at 0 °C. The mixture was stirred at 25 °C for 0.5 hr, and 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 hr, and then quenched with 1M HCl solution (100 mL) at 0 °C and extracted with ethyl acetate 300 mL (100 mL x 3). The combined organic layer was washed with brine (300 mL), dried over sodium sulfate, filtered, and concentrated. The resulting residue 68 3152965.1 PCT APPLICATION 113645-108076 was purified by column chromatography (SiO2, petroleum ether: ethyl acetate = 100: 1 to 1: 1) to obtain 17-b (5.64 g, 54.1 mmol, 63.9% yield) as a yellow oil.1H NMR (DMSO-d6, 400 MHz) δ: 5.24 - 4.75 (m, 1H), 4.59 (td, J = 5.6 Hz, 18.8 , 3.37 (t, J = 5.2 Hz, 2H), 2.41 - 2.06 (m, 4H), 1.94 - 1.75 (m, 1H). Preparation of 17-c: To a solution of 17-b (3.64 g, 34.9 mmol) in DCM (70 mL) was added PCC (17.7 g, 41.9 mmol) at 0 °C under N2 atmosphere. The mixture was stirred at 25 °C for 2 hr, and then filtered and concentrated under reduced pressure to yield 17- c (3.57 g, crude) as a colorless oil. Preparation of 17-e: To a solution of 17-c (3.57 g, 34.9 mmol) in DCM (120 mL) was added DBU (15.8 mL, 104 mmol) and 17-d (10.4 g, 31.4 mmol) at 0 °C. The mixture was stirred at 25 °C for 12 hr, 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]+.1H NMR (DMSO-d6, 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). Preparation of 17-f: To a solution of 26-e (4.40 g, 14.3 mmol) in MeOH (80.0 mL) was added 1,2-Bis[(2S,5S)-2,5-diethylphospholano]benzene(1,5-cyclooctadiene)rhodium(I) trifluoromethanesulfonate (1.03 g, 1.43 mmol) under N2 atmosphere. The mixture was stirred at 40 °C for 12 hr under H2 (50 psi). The mixture was filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (Instrument: Agilent1260. Column: Gemini C18110A 150*4.6mm, 5um, 50oC. Mobile phase A: 0.1% FA in H2O; B: 0.075% FA in ACN. Flow rate: 0.4mL / min. Detector PDA: 220nm & 254nm) to give 17-f (3.0 g, 9.7 mmol, 67.7% yield) as a yellow oil. 69 3152965.1 PCT APPLICATION 113645-108076 Preparation of 17-g: To a solution of 17-f (1.60 g, 5.17 mmol) in THF (16.0 mL) was added LiOH•H2O (325 mg, 7.76 mmol) in H2O (4 mL). The mixture was stirred at 25 °C for 2 hr, and then adjusted to pH 4 - 5 with 1N HCl aqueous solution and extracted with ethyl acetate (20 mL x 3). The combined organic layer was washed with brine (30 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain 17-g (1.50 g, crude) as a yellow oil. Preparation of 17-h: To a solution of 17-g (1.50 g, 5.08 mmol) in THF (15.0 mL) was added wet Pd / C (700 mg) under N2 atmosphere. The mixture was stirred at 20 °C for 2 hrs under H2 (15 Psi). The mixture was filtered and concentrated under reduced pressure to give 17-h (800 mg, crude) as a colorless oil. Preparation of Intermediate 17: To a solution of 17-h (800 mg, 4.96 mmol) in THF (24 mL) was added NaHCO3 (1.25 g, 14.8 mmol) in H2O (6 mL), followed by FmocOSu (1.67 g, 4.96 mmol). The mixture was stirred at 20 °C for 12 hr, and then diluted with H2O (10 mL), adjusted to pH = 4 - 5 with 1 M HCl (aqueous solution), and extracted with ethyl acetate 30 mL (10 mL x 3). The combined organic layer was washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was triturated with petroleum ether: methyl tert-butyl ether = 10: 1 (40 mL) at 25 °C for 60 min and then filtered. The filter cake was washed with petroleum ether (200 mL) and dried under reduced pressure to afford Intermediate 17 (1.78 g, 4.44 mmol, 89.4% yield) as a white solid. LCMS (ESI): m / z 406.4 [M+Na]+.1H NMR (DMSO-d6, 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). 70 3152965.1 PCT APPLICATION 113645-108076 Intermediate 46 Preparation of 46-c: To a solution of 46-a (10.0 g, 53.7 mmol) in H2O (100 mL) was added 46-b (11.8 g, 161 mmol). The mixture was stirred at 25 °C for 12 hr, 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 layer was 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.1H 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). Preparation of 46-e: 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) was added PdCl2(PPh3)2 (291 mg, 414 μmol) and CuI (39.4 71 3152965.1 PCT APPLICATION 113645-108076 mg, 207 μmol). The mixture was stirred at 55 °C for 2 hr under N2 atmosphere, and then filtered and concentrated under reduced pressure to give 46-e (8.00 g, crude) as a red oil. Preparation of 46-f: To a solution of 46-e (8.0 g, 20.6 mmol) in DMF (80 mL) was added CuI (393 mg, 2.06 mmol). The mixture was stirred at 100 °C for 12 hr under N2 atmosphere. The mixture was diluted with ethyl acetate (20 mL) and washed with saturated aqueous NH4Cl 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 20-35um 100A. Mobile phase A: H2O; B: ACN. Gradient: 10-85% B over 36 min. Flow rate: 100mL / min. Detector PDA: 220nm & 254nm) 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). Preparation of 46-g: To a solution of 46-f (4.20 g, 12.6 mmol) in THF (40.0 mL) was added LiOH•H2O (797 mg, 19.0 mmol) in H2O (10.0 mL). The mixture was stirred at 25 °C for 2 hr, and then diluted with water (50 mL) and extracted with MTBE (30 mL x 2). The aqueous layer was adjusted to pH 4 with 1M HCl and extracted with ethyl acetate (15 mL x 5). The combined organic layer was 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]+. Preparation of 46-h: To a solution of 46-g (2.0 g, 6.3 mmol) in DCM (15.0 mL) was added HCl / dioxane (4 M, 15 mL). The mixture was stirred at 25 °C for 2 hr, and then concentrated under reduced pressure to obtain 46-h (1.37 g, crude) as a brown solid. 72 3152965.1 PCT APPLICATION 113645-108076 Preparation of Intermediate 46: To a solution of 46-h (1.37 g, 6.31 mmol) in 1,4- dioxane (30.0 mL) was added NaHCO3 (1.59 g, 18.9 mmol) in H2O (10 mL) and FmocOSu (2.13 g, 6.31 mmol). The mixture was stirred at 25 °C for 3 hr, and then diluted with water (30 mL) and extracted with MTBE (30 mL x 2). The aqueous layer was adjusted to pH 3 with 1M HCl aqueous solution and extracted with ethyl acetate (20 mL x 3). The combined organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase silica gel flash chromatograph (Column: C18 spherical 20-35um, 100A. Mobile phase A: 0.1% FA in H2O; B: ACN. Gradient: 10-90% B over 50 min. Flow rate: 100mL / min. Detector PDA: 220nm & 254nm) 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]+.1H 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). In a manner similar to the synthesis of Intermediate 46, Intermediate 20 in Table 4 was made. Table 4: Intermediate 20 1H NMR (DMSO-d6, 400 MHz) δ: 12.8 - d, z, 73 37 ), 11 - Intermediate 54 73 3152965.1 PCT APPLICATION 113645-108076 Preparation of 54-b: To a solution of 54-a (10.0 g, 96.1 mmol) in DCM (200 mL) was added imidazole (13.1 g, 192 mmol) and TBDPS-Cl (31.6 g, 115 mmol, 29.5 mL) at 0 °C. The reaction mixture was stirred at 25 °C for 12 hrs, and then filtered and diluted with ice water (800 mL), extracted with DCM (200 mL x 2). The combined organic layer was washed with brine (200 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to dryness. 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 colorless oil.1H 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). 74 3152965.1 PCT APPLICATION 113645-108076 Preparation of 54-c: To a solution of 54-b (22.2 g, 64.8 mmol) in EtOH (80.0 mL) was added 1M NaOH aqueous solution (66.6 mL). The reaction mixture was stirred at 25 °C for 12 hrs, then concentrated under reduced pressure to remove EtOH. The residue was treated with aqueous HCl solution (0.5M) to adjust pH to 5-6 and extracted with ethyl acetate (100 mL x 2). The combined organic layer was 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.1H 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 = 6.4 Hz, 2H), 1.06 (s, 9H). Preparation of 54-d: To a solution of 54-c (13.0 g, 39.5 mmol) in DCM (130 mL) was added oxalyl dichloride (6.93 mL, 79.1 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 12 hrs under N2 atmosphere, and then concentrated under reduced pressure to give 54-d (13.2 g, crude) as brown oil. Preparation of 54-f: To a solution of 54-e (5.0 g, 25.0 mmol) in DCM (50 mL) was added TEA (6.96 mL, 49.9 mmol), followed by a solution of 54-d (13.0 g, 37.4 mmol) in DCM (50.0 mL) dropwise at 0 °C. The reaction mixture was stirred at 25 °C for 12 hrs, and then diluted with ice water (100 mL). The organic phase was washed with 0.5M of HCl in water (100 mL x 2), saturated NaHCO3 (100 mL x 2), brine (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to dryness. The crude product was purified by reversed-phase HPLC (Column: C18 spherical 20-35um 100A. Mobile phase A: 0.1% FA in H2O; B: ACN. Gradient: 10- 85% B over 36 min. Flow rate: 100mL / min. Detector PDA: 220nm & 254nm) to give 54-f as a brown solid.1H NMR (DMSO-d6, 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). 75 3152965.1 PCT APPLICATION 113645-108076 Preparation of 54-g: To a solution of 54-f (4.30 g, 8.42 mmol) in i-PrOH (40.0 mL) was added NH3•H2O (34.6 mL, 225 mmol, 25%). The reaction mixture was stirred at 90 °C for 12 hrs, then cooled to room temperature, diluted with water (120 mL), extracted with ethyl acetate (100 mL x 2). The combined organic phase was washed with 1M HCl in water (200 mL x 2), saturated NaHCO3 in water (200 mL x 2), 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.1H NMR (DMSO-d6, 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). Preparation of 54-i: To a solution of 54-g (4.10 g, 8.34 mmol) in DMF (40.0 mL) was added Xphos (397 mg, 834 μmol), PdCl2 (73.9 mg, 417 μmol) and 54-h (4.31 g, 8.34 mmol). The mixture was degassed and purged with N2 for 3 times and stirred at 25 °C for 12 hrs under N2 atmosphere. The reaction mixture was filtered. The filtrate was diluted with water (200 mL), extracted with ethyl acetate (200 mL x 2). The combined organic layer was 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 (5.30 g, 6.68 mmol, 80.1% yield) as an off-white solid. LCMS (ESI): m / z 736.3. [M+H]+. Preparation of 54-j: A solution of 54-i (4.10 g, 5.17 mmol) in HCl / MeOH (2M, 40 mL) was stirred at 60 °C for 3 hrs. The reaction mixture was concentrated under vacuum to dryness. The crude product was triturated with DCM (50.0 mL) at 25 °C for 1 hr, 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]+. 76 3152965.1 PCT APPLICATION 113645-108076 Preparation of Intermediate 54: To a solution of 54-j (2.30 g, 4.58 mmol) in THF (24 mL) and i-PrOH (8 mL) was added CaCl2 (8.13 g, 73.3 mmol), followed by a solution of LiOH.H2O (961 mg, 22.9 mmol) in H2O (8 mL) at 0°C. The mixture was stirred at 25 °C for 12 hrs, and then adjusted to pH 3-4 with 1M HCl in water and extracted with ethyl acetate (50 mL x 2). The combined organic layer was 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 20-35um, 100A. Mobile phase A: 0.1% HCl in H2O, B: ACN. Gradient: 10-95% B over 68 min. Flow rate: 100mL / min. Detector PDA: 220nm & 254nm) to give Intermediate 54 (1.03 g, 2.02 mmol, 44.1% yield, 95.0% purity) as a yellow solid. LCMS (ESI): m / z 484.1 [M+H]+.1H NMR (DMSO-d6, 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). Intermediate 55 Preparation of Intermediate 55: To a solution of 55-a (1.20 g, 1.94 mmol) in DCM (12.0 mL) was added BBr3 (2M in DCM, 1.26 mL) at 0°C under N2 atmosphere. The mixture was stirred at 25°C for 3 hrs. The reaction mixture was quenched with MeOH (30 mL) at 0°C, then concentrated under reduced pressure to dryness. The crude product was purified by prep-HPLC (column: Phenomenex luna C18, 250 x 70mm, 10 um; mobile phase A: 0.1% NH4HCO3 in water, B: acetonitrile; gradient: 15% - 45% B over 22 min) 77 3152965.1 PCT APPLICATION 113645-108076 to give Intermediate 55 (203 mg, 374 μmol, 19.2% yield) as a white solid. LCMS (ESI): m / z 528.2 [M+H]+. 1H NMR (DMSO-d6, 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). Intermediate 60: Preparation of 60-c: To a solution of 60-a (2.00 g, 19.5 mmol) in THF (20.0 mL) was added NMM (19.5 mmol, 2.15 mL) and IBCF (21.5 mmol, 2.82 mL) at 0 °C. The mixture was stirred at 0 °C for 0.5 hr. Then 60-b (3.92 g, 19.5 mmol) was added. The mixture was stirred at 25 °C for 12 hrs, and then diluted with water 100 mL and extracted with EtOAc (30 mL x 3). The combined organic layer was 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. 78 3152965.1 PCT APPLICATION 113645-108076 LCMS (ESI): m / z 283.9 [M+H]+. 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 hrs. 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 (590 mg, 76.4% yield) as a yellow solid.1H 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). Preparation of 60-f: A solution of 60-e (1.55 g, 3.43 mmol) in DMF (5.0 mL) was added slowly to a suspension of Zn (1.29 g, 19.7 mmol) in DMF (5.0 mL) under N2 atmosphere. The mixture was stirred at 25 °C for 1.5 hrs. Then the supernatant was pumped into a solution of 60-d (700 mg, 2.64 mmol) in DMF (15.0 mL), degassed and purged with N2 for 3 times, PdCl2 (46.8 mg, 264 μmol) was added, followed by Xphos (125 mg, 264 μmol). The resulting mixture was degassed and purged with N2 for 3 times again, and then stirred at 25 °C for 12 hrs under N2 atmosphere. The reaction mixture was filtered. The filtrate was diluted with water (30 mL), extracted with ethyl acetate (20 mL x 3). The combined organic layer was 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]+. Preparation of Intermediate 60: To a solution of 60-f (770 mg, 1.51 mmol) in THF (4.0 mL) and i-PrOH (2.0 mL) was added CaCl2 (2.68 g, 24.1 mmol, 16.0 eq) and LiOH·H2O (253 mg, 6.04 mmol) in H2O (2.0 mL) at 0 °C. The mixture was stirred at 25 °C for 12 hrs. The reaction mixture was diluted with DMF (20 mL) and H2O (20 mL), adjusted pH to 5 with 1M HCl aqueous solution and extracted with EtOAc (10 mL x 3). The combined organic layer was washed with H2O (30 mL x 5) and brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced 79 3152965.1 PCT APPLICATION 113645-108076 pressure. The resulting residue was triturated 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]+.1H NMR (DMSO-d6, 400 MHz) δ: 9.50 (s, 1H), 7.98 - 7.83 (m, 6H), 7.54 - 7.53 (m, 2H), 7.37 (t, J = 7.2 Hz, 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). Intermediate 61:Oimidazole, TBDPSCl O LiOH HO OH OTBD OTBDPS DMF PS THF, H2O OH Preparation of 61-b: 61-b (23 g, 62.4 mmol, 81% yield) was prepared as a colorless oil from commercially available 61-a (10g, 76.8 mmol) via the same procedure described 80 3152965.1 PCT APPLICATION 113645-108076 in the synthesis of Intermediate 54-b. LCMS (ESI): m / z 369.0 [M+H]+. Preparation of 61-c: 61-c (28.1 g, 79.2 mmol, 91.2% yield)) was prepared as a white solid from 61-b (32.0 g, 86.8 mmol) via the same procedure described in the synthesis of Intermediate 54-c. LCMS (ESI): m / z 377.0 [M+Na]+. Preparation of 61-d: 61-d (28 g crude) was prepared as a yellow oil from 61-c (28.1 g, 79.2 mmol) via the same procedure described in the synthesis of Intermediate 54-d. Preparation of 61-f: 61-f (20 g, 37.2 mmol, 64.5% yield) was prepared as a yellow solid from 61-e (11.5 g, 57.7 mmol) via the same procedure described in the synthesis of Intermediate 54-f. LCMS (ESI): m / z 538.1 [M+H]+. Preparation of 61-g: 61-g (18 g, 34.7 mmol, 93.3% yield) was prepared as a yellow solid from 61-f (10.0 g, 18.6 mmol) via the same procedure described in the synthesis of Intermediate 54-g. LCMS (ESI): m / z 535.3 [M+H2O]+. Preparation of 61-i: 61-i (9.0 g, 11.8 mmol, 61% yield) was prepared as a yellow oil from 61-g (10.0 g, 19.3 mmol) via the same procedure described in the synthesis of Intermediate 54-i. LCMS (ESI): m / z 762.4 [M+H]+. Preparation of 61-j: 61-j (4.0 g, 7.64 mmol, 72.7% yield) was prepared as a white solid from 61-i (8.0 g, 10.5 mmol) via the same procedure described in the synthesis of Intermediate 54-j. LCMS (ESI): m / z 542.3 [M+H2O]+. Preparation of Intermediate 61: Intermediate 61 (1.80 g, 3.51 mmol, 45.9% yield, 99.4% purity) was prepared as a white solid from 61-j (4.00 g, 7.64 mmol) via the same procedure described in the synthesis of Intermediate 54. LCMS (ESI): m / z 510.1 [M+H]+.1H NMR (DMSO-d6, 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 = 7.2 Hz), 7.36 (t, 2H, J = 7.6 Hz), 7.20 (t, 1H, J = 7.6 Hz), 7.14 (t, 1H, J = 7.6 Hz), 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). 81 3152965.1 PCT APPLICATION 113645-108076 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) via the same procedure described in the synthesis of Intermediate 63-c. LCMS (ESI): m / z 283.0 [M+H]+. Preparation of 62-e: 62-e (3.0 g, 5.68 mmol, 53.6% yield) was prepared as a yellow solid from 62-c (3.0 g, 10.5 mmol) via the same procedure described in the synthesis of Intermediate 63-e. LCMS (ESI): m / z 528.3 [M+H]+. Preparation of Intermediate 62: Intermediate 62 (1.56 g, 3.0 mmol, 52.8% yield, 99% purity) was prepared as a white solid from 62-e (3.00 g, 5.68 mmol) via the same procedure described in the synthesis of Intermediate 63. LCMS (ESI): m / z 514.2 [M+H]+.1H NMR (DMSO-d6, 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). 82 3152965.1 PCT APPLICATION 113645-108076 Intermediate 63 Preparation of 63-c: To a solution of 63-a (10.0 g, 41.0 mmol) in DMF (200 mL) was added Cs2CO3 (20.0 g, 61.6 mmol) and 63-b (8.26 mL, 53.3 mmol). The reaction mixture was stirred at 60 °C for 12 hrs, and then diluted with water (600 mL) and extracted with ethyl acetate (200 mL x 3). The combined organic layer was washed with water (600 mL x 2), 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]+. Preparation of 63-e: To a solution of 63-c (5.6 g, 15.2 mmol) in DMF (60 mL) was added PdCl2 (134 mg, 760 μmol), Xphos (724 mg, 1.52 mmol) and 63-d (11.0 g, 21.2 mmol). The mixture was degassed and purged with N2 for 3 times and stirred at 25 °C for 12 hrs under N2 atmosphere. The reaction mixture was filtered. The filtrate was 83 3152965.1 PCT APPLICATION 113645-108076 diluted with water (200 mL) and extracted with ethyl acetate (200 mL x 2). The combined organic layer was washed with water (200 mL x 3), 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 (6.80 g, 11.1 mmol, 72.9% yield) as a white solid. LCMS (ESI): m / z 613.3 [M+H]+. Preparation of Intermediate 63: To a solution of 63-e (6.80 g, 11.1 mmol) in i-PrOH (35 mL) and THF (70 mL) was added CaCl2 (19.7 g, 177 mmol) and LiOH•H2O (1.86 g, 44.4 mmol) in H2O (35 mL) at 0 °C. The mixture was stirred at 25 °C for 12 hrs. The reaction mixture was adjusted to pH = 5-6 with 1M HCl aqueous solution and extracted with ethyl acetate (300 mL x 2). The combined organic layer was 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 20-35um, 100A. Mobile phase A: H2O, B: ACN. Gradient: 10- 75% B over 58 min. Flow rate: 100mL / min. Detector PDA: 220nm & 254nm) to give Intermediate 63 (3.80 g, 6.35 mmol, 57.1% yield) as a white solid. LCMS (ESI): m / z 599.3 [M+H]+.1H NMR (DMSO-d6, 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). Certain Intermediates: Intermediates 59 can be made in a similar manner to the synthesis of intermediate 54 according to the following scheme: 84 3152965.1 PCT APPLICATION 113645-108076 O TBDPS-Cl O NaOH O HO O imidazole, DCM TBDPSO O EtOH, H2O TBDPSO OH OH Intermediate 64 synthesis scheme: 3152965.1 PCT APPLICATION 113645-108076 64-c can be made from commercially available 64-a and 64-b in a similar manner to the synthesis of Intermediate 62-c. 64-e can be prepared from 64-c and 64-d in a similar manner to the synthesis of Intermediate 62-e. 64-f can be made by the hydrolysis of 64-e under basic conditions such as 2-4 eq LiOH in THF / H2O at room temperature for several hours. 64-g can be made from 64-f by removal of Boc group under acid conditions, such as 2M HCl / dioxane in DCM at room temperature for several hours. Intermediate 64 can be made by protecting 64-g with Fmoc under reaction conditions such as 1.1 eq FmocOSu and 2-3 eq NaHCO3 in THF / H2O at room temperature for several hours. Intermediate 65 can be made in a similar manner to the synthesis of intermediate 60 according to the following scheme: 86 3152965.1 PCT APPLICATION 113645-108076 Intermediate 66 can be made in a similar manner to the synthesis of Intermediate 61 according to the following scheme: 87 3152965.1 PCT APPLICATION 113645-108076 O imidazole, TBDPSCl O LiOH HO OH OTBDPS DMF OTBDPS THF, H2O O O O Intermediate 67 synthesis scheme: 88 3152965.1 PCT APPLICATION 113645-108076 O 67-b N OMe NI(R)OBn Cl N Br 67-d NHFmoc OH 67-c can be prepared from commercially available 67-a and 67-b via the same procedure described in the synthesis of Intermediate 63-c. 67-e can be prepared from 67-c and 67-d via the same procedure described in the synthesis of Intermediate 63-e. 67-f can be prepared from 67-e via the same procedure described in the synthesis of Intermediate 63. Preparation of Intermediate 67 can be prepared from 67-f via the same procedure described in the synthesis of Intermediate 55. Intermediate 68 can be made in a similar manner to the synthesis of intermediate 62 according to the following scheme: 89 3152965.1 PCT APPLICATION 113645-108076 O Br Fmoc O NH (S) Intermediate 69 can be made in a similar manner to the synthesis of intermediate 63 according to the following scheme: O FmocOBrBrNH(S) PCT APPLICATION 113645-108076 Intermediate 70 can be made in a similar manner to the synthesis of intermediate 67 according to the following scheme: Synthesis of compounds of formula 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]tetracosane- 3,6,9,12,15,18,24-heptone 91 3152965.1 PCT APPLICATION 113645-108076 O OOO Synthesis of TBA-302-Int A: The peptide was synthesized by using standard Fmoc chemistry. 1) Resin preparation: A mixture of 2-CTC resin (0.25 mmol, substitution 1.00 mmol / g), (S)-2-((S)-3((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-2- oxoazocan-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 agitated with N2 for 92 3152965.1 PCT APPLICATION 113645-108076 2.00 h at 20°C. Then MeOH (0.25 mL) was added. The mixture was agitated with N2 for 30 min and filtered. The resin was washed with DMF (30.0 mL x 5). 2) Deprotection: 20% piperidine in DMF (20.0 mL) was added to the above resin in a flask. The mixture was agitated with N2 for 30 min and filtered. The resin was washed with DMF (30 mL x 5). 3) Coupling: To a solution of Fmoc-Ala-OH (116 mg, 0.38 mmol) and HOAT (48.5 mg, 0.36 mmol) in DMF (20 mL) was added DIC (47.3 mg, 0.38 mmol, 0.06 mL). The resulting solution was added to the resin obtained from 2). The mixture was agitated with N2 for 1 hour at 20°C and filtered. The was washed with DMF (30 mL x 5). 4) Repeat above step 2) to step 3) for the coupling with the amino acids in the steps 3- 6 in the following table to obtain TBA-302-Int A. # Materials Coupling reagents ) ) ) ) ) Synthesis of TBA-302-Int B: To a flask containing TBA-302-Int A at room temperature was added cleavage buffer (1%TFA / 99%DCM). The mixture was stirred for 30 min and filtered to collect the filtrate. The filter cake was treated with cleavage buffer for 30 min and filtered. The combined filtrate was concentrated under reduced pressure to give the crude peptide TBA-302-Int B which was confirmed by LCMS. (ESI) m / z 1023.7 [M+H]+. 93 3152965.1 PCT APPLICATION 113645-108076 Synthesis of TBA-302: The crude TBA-302-Int B was dissolved in DCM (1.0 mmol / L). The pH of the solution was adjusted to 7-8 with DIEA. TBTU (2.00 eq) and HOBT (2.00 eq) were added for cyclization. LCMS after 30 min of stirring showed one main peak with the desired MW. The solvents were evaporated under reduced pressure. The resulting residue was purified by prep-HPLC (conditions in the table below) to give the final product TBA- 302 (87.8mg, 85.8 µmol, 34.4% yield, 96.4% purity) as an off white solid. LCMS (ESI): m / z 1023.6 [M+H]+Purification condition In a manner similar to the synthesis of Example TBA-302, the Examples listed in table 3 were prepared from commercially available reagents and the intermediates described in this application. 94 3152965.1 PCT APPLICATION 113645-108076 Table 6: Examples made in a manner similar to the synthesis of TBA-302 Amount LCMS Example IDStructure Chemical Namesobtained m / z ]+66 95 3152965.1 PCT APPLICATION 113645-108076 (2S,5S,8S,11S,14S,17S, 20S)-5-butyl-14-[(p- 96 3152965.1 PCT APPLICATION 113645-108076 (2S,5S,8S,11S,14S,17S, 20S)-14-benzyl-5-butyl- 97 3152965.1 PCT APPLICATION 113645-108076 (2S,5S,8S,11S,14S,17S, 20S)-5-butyl-8-{[1-(1,1- 98 3152965.1 PCT APPLICATION 113645-108076 (2S,5S,8S,11S,14S,17S, 20S)-5-butyl-14-[(1H- 99 3152965.1 PCT APPLICATION 113645-108076 (2S,5S,8S,11S,14S,17S, 20S)-5-[(S)-1- 100 3152965.1 PCT APPLICATION 113645-108076 (2S,5S,8S,11S,14S,17S, 20S)-14-benzyl-8-{[1- 889 101 3152965.1 PCT APPLICATION 113645-108076 (2S,5S,8S,11S,14S,17S, 20S)-5-[(p- 84 102 3152965.1 PCT APPLICATION 113645-108076 3,6,9,12,15,18,24- heptone 99 103 3152965.1 PCT APPLICATION 113645-108076 etracosane- 3,6,9,12,15,18,24- 788 104 3152965.1 PCT APPLICATION 113645-108076 etracosane- 3,6,9,12,15,18,24- 88 105 3152965.1 PCT APPLICATION 113645-108076 3,6,9,12,15,18,24- heptone 877 106 3152965.1 PCT APPLICATION 113645-108076 3,6,9,12,15,18,24- heptone 766 107 3152965.1 PCT APPLICATION 113645-108076 3,6,9,12,15,18,24- heptone 67 108 3152965.1 PCT APPLICATION 113645-108076 3,6,9,12,15,18,24- heptone 87 109 3152965.1 PCT APPLICATION 113645-108076 etracosane- 3,6,9,12,15,18,24- 887 110 3152965.1 PCT APPLICATION 113645-108076 etracosane- 3,6,9,12,15,18,24- 888 111 3152965.1 PCT APPLICATION 113645-108076 heptaazabicyclo[18.3.1]t etracosane- 888 112 3152965.1 PCT APPLICATION 113645-108076 methyl- 1,4,7,10,13,16,19- 88 113 3152965.1 PCT APPLICATION 113645-108076 (2S,5S,8S,11S,14S,17S, 20S)-5- 888 114 3152965.1 PCT APPLICATION 113645-108076 3,6,9,12,15,18,24- heptone 888 115 3152965.1 PCT APPLICATION 113645-108076 3,6,9,12,15,18,24- heptone 888 116 3152965.1 PCT APPLICATION 113645-108076 1,4,7,10,13,16,19- heptaazabicyclo[18.3.1]t 888 117 3152965.1 PCT APPLICATION 113645-108076 quinazolinyl)methyl]- 10,19-dimethyl-17- 7 118 3152965.1 PCT APPLICATION 113645-108076 (2S,5S,8S,11S,14S,17S, 20S)-14-[(1,3- 788 119 3152965.1 PCT APPLICATION 113645-108076 heptaazabicyclo[18.3.1]t etracosane- 66 120 3152965.1 PCT APPLICATION 113645-108076 10,19-dimethyl-17- methyl- 5 6 121 3152965.1 PCT APPLICATION 113645-108076 (2S,5S,8S,11S,14S,17S, 20S)-8-{[1-(1,1- 5 6 122 3152965.1 PCT APPLICATION 113645-108076 3,6,9,12,15,18,24- heptone 6 6 6 123 3152965.1 PCT APPLICATION 113645-108076 heptaazabicyclo[18.3.1]t etracosane- 66 124 3152965.1 PCT APPLICATION 113645-108076 (2S,5S,8S,11S,14S,17S, 20S)-5- 6 125 3152965.1 PCT APPLICATION 113645-108076 (2S,5S,8S,11S,14S,17S, 20S)-5-butyl-8-{[1-(1,1- 6 126 3152965.1 PCT APPLICATION 113645-108076 (2S,5S,8S,11S,14S,17S, 20S)-5-butyl-8-{[1-(1,1- 666 127 3152965.1 PCT APPLICATION 113645-108076 3,6,9,12,15,18,24- heptone 666 128 3152965.1 PCT APPLICATION 113645-108076 heptaazabicyclo[18.3.1]t etracosane- 666 129 3152965.1 PCT APPLICATION 113645-108076 1,4,7,10,13,16,19- heptaazabicyclo[18.3.1]t 666 130 3152965.1 PCT APPLICATION 113645-108076 dimethyl-17-methyl-14- [(2-methyl-7- 66 131 3152965.1 PCT APPLICATION 113645-108076 (2S,8S,11S,14S,17S,20S )-5-(cyclobutylmethyl)- 666 132 3152965.1 PCT APPLICATION 113645-108076 etracosane- 3,6,9,12,15,18,24- 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]hexacos-22-ene- 3,6,9,12,15,18,26-heptone Synthesis of TBA-306-Int A and TBA-306-Int B: From 2-CTC resin (0.25 mmol, substitution 1.0 mmol / g) and (S)-2-((S,Z)-3-((((9H- fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-2-oxo-3,4,7,8-tetrahydroazocin- 1(2H)-yl)-4-methylpentanoic acid (Intermediate 4, 0.12 g, 0.25 mmol), TBA-306-Int A was made and then converted to TBA-306-Int B (LCMS (ESI) m / z 1049.8 [M+H]+), based on the procedures described in the synthesis of TBA-302-Int A and TBA-302-Int B. 133 3152965.1 PCT APPLICATION 113645-108076 Synthesis of TBA-306 The crude intermediate TBA-306-Int B was dissolved in DCM (1.0 mmol / L). The pH of the solution was adjusted to 7-8 with DIEA. TBTU (2.0 eq), and HOBT (2.0 eq) were added for cyclization. LCMS after 30 min of stirring showed one main peak with the desired MW. The solvents were evaporated under reduced pressure. The crude product was purified by prep-HPLC using the conditions described in the purification of TBA-302 but changing dissolution solvent to 60% ACN in water and gradient to 18% - 82% A in B over 24 min. TBA-306 (28.4mg, 27.1 µmol, 10.8% yield, 95.3% purity) was obtained as an off white solid. LCMS (ESI): m / z 1049.6 [M+H]+. In a manner similar to the synthesis of TBA-306, the Examples in Table 7 were prepared using commercially available reagents and the intermediates described in this application. Table 7: Examples made in a manner similar to the synthesis of TBA-306. Amount Example LCMS bt i d+6 134 3152965.1 PCT APPLICATION 113645-108076 (2S,5S,8S,11S,14S,17S, 20S,Z)-5-[(3,5- 688 135 3152965.1 PCT APPLICATION 113645-108076 heptone (2S,5S,8S,11S,14S,17S, 888 136 3152965.1 PCT APPLICATION 113645-108076 (2S,5S,8S,11S,14S,17S, 20S,Z)-5-butyl-14-[(1H- 888 137 3152965.1 PCT APPLICATION 113645-108076 (2S,5S,8S,11S,14S,17S, Z)-5-benzyl-8-{[1-(1,1- 888 138 3152965.1 PCT APPLICATION 113645-108076 (2S,5S,8S,11S,14S,17S, 20S,Z)-8-{[1-(1,1- 878 139 3152965.1 PCT APPLICATION 113645-108076 (2S,5S,8S,11S,14S,17S, 20S,Z)-5-butyl-8-{[1- 888 140 3152965.1 PCT APPLICATION 113645-108076 (2S,5S,8S,11S,14S,17S, 20S,Z)-5-benzyl-8-{[1- 888 141 3152965.1 PCT APPLICATION 113645-108076 (2S,5S,8S,11S,14S,17S, 20S,Z)-5- 888 142 3152965.1 PCT APPLICATION 113645-108076 3,6,9,12,15,18,26- heptone 888 143 3152965.1 PCT APPLICATION 113645-108076 heptaazabicyclo[18.5.1] hexacos-22-ene- 888 144 3152965.1 PCT APPLICATION 113645-108076 heptaazabicyclo[18.5.1] hexacos-22-ene- 888 145 3152965.1 PCT APPLICATION 113645-108076 1,4,7,10,13,16,19- heptaazabicyclo[18.5.1] 888 146 3152965.1 PCT APPLICATION 113645-108076 dimethyl-17-methyl- 1,4,7,10,13,16,19- 88 147 3152965.1 PCT APPLICATION 113645-108076 (2S,5S,8S,11S,14S,17S, 20S,Z)-8-{[1-(1,1- 888 148 3152965.1 PCT APPLICATION 113645-108076 (2S,5S,8S,11S,14S,17S, 20S,Z)-5-butyl-8-{[1- 888 149 3152965.1 PCT APPLICATION 113645-108076 (2S,5S,8S,11S,14S,17S, 20S,Z)-14-[(1,3- 878 150 3152965.1 PCT APPLICATION 113645-108076 (2S,5S,8S,11S,14S,17S, 20S,Z)-14-[(1,3- 888 151 3152965.1 PCT APPLICATION 113645-108076 (2S,5S,8S,11S,17S,20S, Z)-14-[(1-benzofuran-5- 888 152 3152965.1 PCT APPLICATION 113645-108076 (2S,5S,8S,11S,17S,20S, Z)-5-butyl-8-{[1-(1,1- 888 153 3152965.1 PCT APPLICATION 113645-108076 (2S,5S,8S,11S,14S,17S, 20S,Z)-14-[(1- 888 154 3152965.1 PCT APPLICATION 113645-108076 (2S,5S,8S,11S,14S,17S, 20S,Z)-5-benzyl-8-{[1- 888 155 3152965.1 PCT APPLICATION 113645-108076 (2S,5S,8S,11S,14S,17S, 20S,Z)-14-[(1,3- 778 156 3152965.1 PCT APPLICATION 113645-108076 (2S,5S,8S,11S,14S,17S, 20S,Z)-5-benzyl-8-{[1- 878 157 3152965.1 PCT APPLICATION 113645-108076 (2S,5S,8S,11S,14S,17S, 20S,Z)-14-[(1- 888 158 3152965.1 PCT APPLICATION 113645-108076 (2S,5S,8S,11S,14S,17S, 20S,Z)-14-[(1- 878 159 3152965.1 PCT APPLICATION 113645-108076 (2S,5S,8S,11S,14S,17S, 20S,Z)-5- 888 160 3152965.1 PCT APPLICATION 113645-108076 heptone (2S,5S,8S,11S,14S,17S, 888 161 3152965.1 PCT APPLICATION 113645-108076 heptaazabicyclo[18.5.1] hexacos-22-ene- 888 162 3152965.1 PCT APPLICATION 113645-108076 indolyl]methyl}-2,11- bis(isobutyl)-10,19- 163 3152965.1 PCT APPLICATION 113645-108076 (2S,5S,8S,11S,14S,17S, 20S,Z)-5- 164 3152965.1 PCT APPLICATION 113645-108076 hexacos-22-ene- 3,6,9,12,15,18,26- 7 165 3152965.1 PCT APPLICATION 113645-108076 1,4,7,10,13,16,19- heptaazabicyclo[18.5.1] 888 166 3152965.1 PCT APPLICATION 113645-108076 1,4,7,10,13,16,19- heptaazabicyclo[18.5.1] 676 167 3152965.1 PCT APPLICATION 113645-108076 methyl- 1,4,7,10,13,16,19- 688 168 3152965.1 PCT APPLICATION 113645-108076 indolyl]methyl}-2,11- bis(isobutyl)-10,19- 87 169 3152965.1 PCT APPLICATION 113645-108076 (2S,5S,8S,11S,14S,17S, 20S,Z)-5-butyl-8-{[1- 866 170 3152965.1 PCT APPLICATION 113645-108076 1,4,7,10,13,16,19- heptaazabicyclo[18.5.1] 66 171 3152965.1 PCT APPLICATION 113645-108076 (2S,5S,8S,11S,14S,17S, 20S,Z)-8-{[1-(1,1- 666 172 3152965.1 PCT APPLICATION 113645-108076 hexacos-22-ene- 3,6,9,12,15,18,26- 666 173 3152965.1 PCT APPLICATION 113645-108076 10,19-dimethyl-17- methyl- 66 174 3152965.1 PCT APPLICATION 113645-108076 (2S,5S,8S,11S,14S,17S, 20S,Z)-8-{[1-(1,1- 666 175 3152965.1 PCT APPLICATION 113645-108076 heptone (2S,5S,8S,11S,14S,17S, 666 176 3152965.1 PCT APPLICATION 113645-108076 hexacos-22-ene- 3,6,9,12,15,18,26- 66 177 3152965.1 PCT APPLICATION 113645-108076 (2S,5S,8S,11S,14S,17S, 20S,Z)-5- 66 178 3152965.1 PCT APPLICATION 113645-108076 (2S,5S,8S,11S,14S,17S, 20S,Z)-5- 66 179 3152965.1 PCT APPLICATION 113645-108076 (2S,5S,8S,11S,14S,17S, 20S,Z)-5- 6 6 180 3152965.1 PCT APPLICATION 113645-108076 (2S,5S,8S,11S,14S,17S, 20S,Z)-2,11-diisobutyl- 66 181 3152965.1 PCT APPLICATION 113645-108076 (2S,5S,8S,11S,14S,17S, 20S,Z)-5- 66 182 3152965.1 PCT APPLICATION 113645-108076 (2S,5S,8S,11S,14S,17S, 20S,Z)-5- 66 183 3152965.1 PCT APPLICATION 113645-108076 (2S,5S,8S,11S,14S,17S, 20S,Z)-5- 66 184 3152965.1 PCT APPLICATION 113645-108076 (2S,5S,8S,11S,14S,17S, 20S,Z)-5- 6 _ _ p y p p GX-281. Column: Gemini C18110A 150x4.6mm, 10um, 50oC. Mobile phase A: 0.1% TFA in H2O; B: ACN. Gradient: 16-84% B over 50 min. Flow rate: 10 mL / min. Detector PDA: 220nm & 254nm). TBA-387_P1 and TBA-387_P2 were separated by prep-HPLC (Instrument: Agilent1260. Column: Phenomenex luna C18110A 250x70mm, 10 um, 50oC). Mobile phase A: 0.1% NH4HCO3 in H2O; B: ACN. Gradient: 15% - 84% B over 45 min. Flow rate: 10 mL / min. Detector PDA: 220nm & 254nm). Synthesis of Additional Embodiments: The following examples in Table 8 can be made from commercially available reagents and the intermediates described in this application using the synthesis protocols of Example TBA-302 or Example TBA-306. Table 8: Additional Embodiments Example 185 3152965.1 PCT APPLICATION 113645-108076 n- n- - 2- n- 6 3152965.1 PCT APPLICATION 113645-108076 (2S,8S,11S,14S,17S,20S)-5- 1- )- 2- n- n- 2- 7 3152965.1 PCT APPLICATION 113645-108076 N NH (2S,5S,8S,11S,14S,17S,20S)-5- - 2- n- )- 2- 188 3152965.1 PCT APPLICATION 113645-108076 (2S,5S,8S,11S,14S,17S,20S,Z)-5- n- n- - 2- - n- 9 3152965.1 PCT APPLICATION 113645-108076 N (2S5S8S11S14S17S20SZ)-14-((2-(2- 1- )- 2- n- n- 190 3152965.1 PCT APPLICATION 113645-108076 (2S,5S,8S,11S,14S,17S,20S,Z)-5- (cyclobutylmethyl)-14-((2-(2-hydroxy-2- 2- - 2- n- Biological Data 1. Mtb H37Rv MABA assay 191 3152965.1 PCT APPLICATION 113645-108076 All experiments with M. tuberculosis (Mtb) were conducted within a biosafety level 3 (BSL3) laboratory using a previously described Microplate Alamar Blue Assay (MABA) (Cho, S. et al., 2015). Briefly, compound stocks were prepared in dimethyl sulfoxide (DMSO) at 100× of the highest desired final concentration. Compounds were transferred to the assay plate containing Middlebrook 7H12 medium (4.7 g 7H9 broth, 1 g casitone (Bacto), 5 g bovine serum albumin (BSA), 4 mg catalase and 5.6 mg palmitic acid for 1 L media). Two-fold serial dilution of the compounds was performed nine times in the assay plate. Plates were inoculated with M. tuberculosis strain H37Rv (ATCC 27294) to achieve final density of ~ 1 × 105 CFU / mL and incubated for 7 days at 37°C. At the end of 7 days, resazurin dye / tween 80 mixture (0.6 mM resazurin dye and 12 μL of 20% Tween 80) was added to each well, and the plates were incubated for an additional 18 to 24 h at 37°C. Fluorescence was measured using a CLARIOstar (BMG LABTECH, Ortenberg, Germany) plate reader on day 8. The MIC was an interpolated value and defined as the lowest concentration effecting a reduction in fluorescence of 90% relative to that of DMSO-treated controls. The MABA MIC values are listed in Table 9. Vero cytotoxicity Cytotoxicity evaluation was conducted in a BSL2 laboratory using green monkey kidney cells (Vero cell ATCC-CCL-81, American Type Culture Collection, Manassas, VA). Compound stocks were prepared in dimethyl sulfoxide at 100× of the highest desired final concentration. Compounds were transferred to the assay plate containing Eagle’s minimum essential medium 10% fetal bovine serum and supplemented with penicillin and streptomycin. Two-fold serial dilution of the compounds was carried out 5 times in the assay plate. Vero cells were added to achieve a final density of 1 × 105 cells / mL and plates incubated for 3 days at 37°C and 5% CO2. Twenty microliters of 0.6 mM resazurin was added to each well and, 192 3152965.1 PCT APPLICATION 113645-108076 after 4 hours, fluorescence was measured at excitation / emission wavelengths of 530 / 590 nm using a CLARIOstar (BMG LABTECH, Ortenberg, Germany). The IC50 was defined as the concentration effecting a 50% reduction in fluorescence relative to untreated cells. Rifampin, bedaquiline, tamoxifen, carbonyl cyanide-3- chlorophenylhydrazone, tacrine, and moxifloxacin were included as positive controls. The IC50 values are listed in Table 9. Direct binding analysis by Surface Plasmon Resonance (SPR) Direct binding analyses were performed by SPR using either a Biacore T200 or Biacore 8K (Cytiva Life Sciences) as previously reported (Wolf et al., 2019). The recombinant ClpC1 protein was purified as previously described (Gao et al., 2015). ClpC1 enzyme was immobilized on a CM5 sensor chip using standard amine coupling at 25°C with running buffer PBS-P (20 mM phosphate (pH 7.4), 137 mM NaCl, 27 mM KCl, 0.05% surfactant P-20). Unmodified blank surface was used on flow channel 1 as a control. ClpC1 enzyme was diluted with 10 mM sodium acetate (pH 4.0) to 50 µg / ml and immobilized to flow channels 2, 3, and 4 after sensor surface activation with 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) / N-hydroxy succinimide (NHS) followed by ethanolamine blocking on unoccupied surface area. All tested compound solutions were initially prepared as 10 mM stocks in 100% DMSO and diluted to a series of increasing concentrations (50X of final concentrations) in 100% DMSO in order to keep final DMSO concentration at 2%. Compound solutions were then prepared in 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 and injected into both blank surfaces and ClpC1 protein immobilized surfaces at a 30 μL / min of flow rate at 25 °C. All sensorgrams were double referenced with blank channel and 2% DMSO concentration, and solvent correction cycles were run before and after compound runs. Kinetic association rate (ka) and dissociation rate (kd) constants were determined by fitting globally to a 1:1 Langmuir kinetic model and multi-site 193 3152965.1 PCT APPLICATION 113645-108076 kinetic model using Biacore Insight evaluation software v 3.0.12. The KD (equilibrium dissociation constant) values were calculated from the determined rate constants (KD = kd / ka). The data are listed in Table 9. Table 9: In vitro activity and Vero cytotoxicity Example ID Average Average VERO IC50 SPR KD MABA MIC (ug / mL) 194 3152965.1 PCT APPLICATION 113645-108076 TBA-211 0.08 0.08 > 20 TBA-212 0.06 0.99 > 20 195 3152965.1 PCT APPLICATION 113645-108076 TBA-325 0.20 0.06 > 20 TBA-326 0.09 0.43 > 20 196 3152965.1 PCT APPLICATION 113645-108076 TBA-386_P1* 0.37 0.06 TBA-386_P2* 0.05 0.03 197 3152965.1 PCT APPLICATION 113645-108076 TBA-445 0.16 0.06 TBA-446 0.21 0.12 198 3152965.1 PCT APPLICATION 113645-108076 TBA-516 0.11 0.12 TBA-517 0.06 0.07 199 3152965.1 PCT APPLICATION 113645-108076 TBA-602 0.02 TBA-606 0.11 References: Bosch, B., DeJesus, M. A., Poulton, N. C., Zhang, W., Engelhart, C. A., Zaveri, A., Lavalette, S., Ruecker, N., Trujillo, C., Wallach, J. B., Li, S., Ehrt, S., Chait, B. T., Schnappinger, D., & Rock, J. M. (2021). Genome-wide gene expression tuning reveals diverse vulnerabilities of M. tuberculosis. Cell, 184(17), 4579- 4592 e4524. https: / / doi.org / 10.1016 / j.cell.2021.06.033 Carroll, P., Faray-Kele, M. C., & Parish, T. (2011). Identifying vulnerable pathways in Mycobacterium tuberculosis by using a knockdown approach. Appl Environ Microbiol, 77(14), 5040-5043. https: / / doi.org / 10.1128 / AEM.02880-10 Cho, S., Lee, H.S., Franzblau, S. (2015). Microplate Alamar Blue Assay (MABA) and Low Oxygen Recovery Assay (LORA) for Mycobacterium tuberculosis. In: Parish, T., Roberts, D. (eds) Mycobacteria Protocols. Methods in Molecular Biology, vol 1285. Humana Press, New York, NY. https: / / doi.org / 10.1007 / 978-1-4939-2450-9_17 Choules, M. P., Wolf, N. M., Lee, H., Anderson, J. R., Grzelak, E. M., Wang, Y., Ma, R., Gao, W., McAlpine, J. B., Jin, Y. Y., Cheng, J., Lee, H., Suh, J. W., Duc, 200 3152965.1 PCT APPLICATION 113645-108076 N. M., Paik, S., Choe, J. H., Jo, E. K., Chang, C. L., Lee, J. S., 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, J. Y., Anderson, J. R., Akopian, T., Hong, S., Jin, Y. Y., Kandror, O., Kim, J. W., Lee, I. A., Lee, S. Y., McAlpine, J. B., Mulugeta, S., Sunoqrot, S., Wang, Y., Yang, S. H., Yoon, T. M., Goldberg, A. L., Pauli, G. F., Suh, J. W., Cho, S. (2015). The cyclic peptide ecumicin targeting ClpC1 is active against Mycobacterium tuberculosis in vivo. Antimicrob Agents Chemother, 59(2), 880-889. https: / / doi.org / 10.1128 / AAC.04054-14 Gavrish, E., Sit, C. S., Cao, S., Kandror, O., Spoering, A., Peoples, A., Ling, L., H., Akopian, T., Mueller, A., Epstein, S., Goldberg, A., Clardy, J., & Lewis, K. (2014). Lassomycin, a ribosomally synthesized cyclic peptide, kills mycobacterium tuberculosis by targeting the ATP-dependent protease ClpC1P1P2. Chem Biol, 21(4), 509- 518. https: / / doi.org / 10.1016 / j.chembiol.2014.01.014 Lee, M., Lee, J., Carroll, M. W., Choi, H., Min, S., Song, T., Via, L. E., Goldfeder, L. C., Kang, E., Jin, B., Park, H., Kwak, H., Kim, H., Jeon, H. S., Jeong, I., Joh, J. S., Chen, R. Y., Olivier, K. N., Shaw, P. A., ... Barry, C. E., 3rd. (2012). Linezolid for treatment of chronic extensively drug-resistant tuberculosis. N Engl J Med, 367(16), 1508-1518. https: / / doi.org / 10.1056 / NEJMoa1201964 Ollinger, J., O'Malley, T., Kesicki, E. A., Odingo, J., & Parish, T. (2012). Validation of the essential ClpP protease in Mycobacterium tuberculosis as a novel drug target. J Bacteriol, 194(3), 663-668. https: / / doi.org / 10.1128 / JB.06142-11 Raju, R. M., Jedrychowski, M. P., Wei, J. R., Pinkham, J. T., Park, A. S., O'Brien, K., Rehren, G., Schnappinger, D., Gygi, S. P., & Rubin, E. J. (2014). Post- translational regulation via Clp protease is critical for survival of Mycobacterium tuberculosis. PLoS Pathog, 10(3), e1003994. https: / / doi.org / 10.1371 / journal.ppat.1003994 Raju, V., Kandror, O., E. J. (2012). Mycobacterium tuberculosis ClpP1 and ClpP2 function together in protein degradation and are required for viability in vitro and during infection. PLoS Pathog, 8(2), e1002511. https: / / doi.org / 10.1371 / journal.ppat.1002511 Sassetti, C. M., Boyd, D. H., & Rubin, E. J. (2003). Genes required for mycobacterial growth defined by high density mutagenesis. Mol Microbiol, 48(1), 77-84. https: / / doi.org / 10.1046 / j.1365-2958.2003.03425.x Schmitt, E. K., Riwanto, M., Sambandamurthy, V., Roggo, S., Miault, C., Zwingelstein, C., Krastel, P., Noble, C., Beer, D., Rao, S. P., Au, M., Niyomrattanakit, P., Lim, V., Zheng, J., Jeffery, D., Pethe, K., & Camacho, L. R. (2011). The natural product cyclomarin kills Mycobacterium tuberculosis by targeting the ClpC1 subunit of the caseinolytic protease. Angew Chem Int Ed Engl, 50(26), 5889-5891. https: / / doi.org / 10.1002 / anie.201101740 201 3152965.1 PCT APPLICATION 113645-108076 Steingart, K. R., Jotblad, S., Robsky, K., Deck, D., Hopewell, P. C., Huang, D., & Nahid, P. (2011). Higher-dose rifampin for the treatment of pulmonary tuberculosis: a systematic review. Int J Tuberc Lung Dis, 15(3), 305-316. https: / / www.ncbi.nlm.nih.gov / pubmed / 21333096 Vasudevan, D., Rao, S. P., & Noble, C. G. (2013). Structural basis of mycobacterial , 30883-30891. https: / / doi.org / 10.1074 / jbc.M113.493767 Wolf, N. M., Lee, H., Choules, M. P., Pauli, G. F., Phansalkar, R., Anderson, J. R., H., Cheng, J., Jin, Y. Y., Ho, N. A., Duc, N. M., Suh, J. W., Abad-Zapatero, C., & Cho, S. (2019). High- Resolution Structure of ClpC1-Rufomycin and Ligand Binding Studies Provide a Framework to Design and Optimize Anti-Tuberculosis Leads. ACS Infect Dis, 5(6), 829-840. https: / / doi.org / 10.1021 / acsinfecdis.8b00276 * * * While the present application has been described with reference to examples, it is to be understood that the scope of the claims should not be limited by the embodiments set forth in the examples, but should be given the broadest interpretation consistent with the description as a whole. 202 3152965.1

Claims

PCT APPLICATION 113645-108076 WHAT IS CLAIMED IS:

1. A compound of Formula I or Formula III:wherein: R2 is: - C1-C5 alkyl optionally substituted with F, CF3, - n=1-4,optionally substituted with F, or - , R4 islower alkyl, CH2F, CHF2, CF3, OH, lower alkoxy, mono or bis; and R3 is -CH2-phenyl, CH2-mono heteroaryl or CH2-fused bi-heteroaryl in which the phenyl or heteroaryl is optionally substituted, or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, wherein 203 3152965.1PCT APPLICATION 113645-108076 R2 is: C1-C5 alkyl optionally substituted with F, CF3, is optionally substituted with F, or.R3 is: R6PCT APPLICATION 113645-108076R6 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]tetracosane- 3,6,9,12,15,18,24-heptone; (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]hexacos-22- ene-3,6,9,12,15,18,26-heptone; (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]tetracosane- 205 3152965.1PCT APPLICATION 113645-108076 3,6,9,12,15,18,24-heptone; (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]tetracosane- 3,6,9,12,15,18,24-heptone; (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]hexacos-22-ene- 3,6,9,12,15,18,26-heptone; (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]tetracosane- 3,6,9,12,15,18,24-heptone; (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]hexacos-22-ene-3,6,9,12,15,18,26-heptone; (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]hexacos-22-ene-3,6,9,12,15,18,26-heptone; (2S,5S,8S,11S,14S,17S,20S,Z)-5-butyl-14-[(1H-1,7-diazainden-5-yl)methyl]-8-{[1- 206 3152965.1PCT APPLICATION 113645-108076 (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]hexacos-22-ene-3,6,9,12,15,18,26- heptone; (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]tetracosane-3,6,9,12,15,18,24-heptone; (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]hexacos-22-ene- 3,6,9,12,15,18,26-heptone; (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]hexacos-22-ene- 3,6,9,12,15,18,26-heptone; (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]hexacos-22-ene-3,6,9,12,15,18,26-heptone; (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]hexacos-22-ene- 3,6,9,12,15,18,26-heptone; 207 3152965.1PCT APPLICATION 113645-108076 (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]hexacos-22-ene-3,6,9,12,15,18,26-heptone; (2S,5S,8S,11S,14S,17S,20S,Z)-14-[(1,3-benzothiazol-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]hexacos-22-ene-3,6,9,12,15,18,26- heptone; (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]hexacos-22-ene-3,6,9,12,15,18,26-heptone; (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]hexacos-22-ene-3,6,9,12,15,18,26-heptone; (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]tetracosane- 3,6,9,12,15,18,24-heptone; (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]hexacos-22- 208 3152965.1PCT APPLICATION 113645-108076 ene-3,6,9,12,15,18,26-heptone; (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-isoquinolyl)methyl]-10,19-dimethyl-17- methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.3.1]tetracosane-3,6,9,12,15,18,24- heptone; (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]hexacos-22-ene- 3,6,9,12,15,18,26-heptone; (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-isoquinolyl)methyl]-10,19- dimethyl-17-methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexacos-22-ene- 3,6,9,12,15,18,26-heptone; (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]hexacos-22-ene-3,6,9,12,15,18,26-heptone; (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]tetracosane- 3,6,9,12,15,18,24-heptone; (2S,5S,8S,11S,14S,17S,20S)-5-(cyclobutylmethyl)-8-{[1-(1,1-dimethyl-2-propenyl)- 209 3152965.1PCT APPLICATION 113645-108076 3-indolyl]methyl}-2,11-bis(isobutyl)-14-[(3-isoquinolyl)methyl]-10,19-dimethyl-17- methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.3.1]tetracosane-3,6,9,12,15,18,24- heptone; (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-isoquinolyl)methyl]-10,19-dimethyl-17- methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexacos-22-ene-3,6,9,12,15,18,26- heptone; (2S,5S,8S,11S,14S,17S,20S)-5-butyl-14-[(1H-1,7-diazainden-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]tetracosane-3,6,9,12,15,18,24- heptone; (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]hexacos-22-ene- 3,6,9,12,15,18,26-heptone; (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]tetracosane- 3,6,9,12,15,18,24-heptone; (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]tetracosane- 3,6,9,12,15,18,24-heptone; 210 3152965.1PCT APPLICATION 113645-108076 (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]tetracosane- 3,6,9,12,15,18,24-heptone; (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]tetracosane- 3,6,9,12,15,18,24-heptone; (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]hexacos-22-ene- 3,6,9,12,15,18,26-heptone; (2S,5S,8S,11S,14S,17S,20S,Z)-14-[(1,3-benzothiazol-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]hexacos-22-ene-3,6,9,12,15,18,26- heptone; (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]tetracosane- 3,6,9,12,15,18,24-heptone; (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- 211 3152965.1PCT APPLICATION 113645-108076 dimethyl-17-methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.3.1]tetracosane- 3,6,9,12,15,18,24-heptone; (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]tetracosane- 3,6,9,12,15,18,24-heptone; (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]tetracosane- 3,6,9,12,15,18,24-heptone; (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]tetracosane-3,6,9,12,15,18,24-heptone; (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-isoquinolyl)methyl]-10,19- dimethyl-17-methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.3.1]tetracosane- 3,6,9,12,15,18,24-heptone; (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]tetracosane- 3,6,9,12,15,18,24-heptone; 212 3152965.1PCT APPLICATION 113645-108076 (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]tetracosane- 3,6,9,12,15,18,24-heptone; (2S,5S,8S,11S,14S,17S,20S,Z)-14-[(1,3-benzothiazol-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]hexacos-22-ene-3,6,9,12,15,18,26-heptone (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-isoquinolyl)methyl]-10,19-dimethyl-17- methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexacos-22-ene-3,6,9,12,15,18,26- heptone; (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]hexacos-22-ene- 3,6,9,12,15,18,26-heptone; (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]hexacos-22-ene- 3,6,9,12,15,18,26-heptone; (2S,5S,8S,11S,14S,17S,20S)-14-[(1,3-benzothiazol-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]tetracosane-3,6,9,12,15,18,24-heptone; 213 3152965.1PCT APPLICATION 113645-108076 (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]hexacos-22-ene-3,6,9,12,15,18,26-heptone; (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- quinolyl)methyl]-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexacos-22-ene- 3,6,9,12,15,18,26-heptone; (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-isoquinolyl)methyl]-10,19-dimethyl-17- methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexacos-22-ene-3,6,9,12,15,18,26- heptone; (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-isoquinolyl)methyl]-10,19- dimethyl-17-methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexacos-22-ene- 3,6,9,12,15,18,26-heptone; (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- quinolyl)methyl]-1,4,7,10,13,16,19-heptaazabicyclo[18.3.1]tetracosane- 3,6,9,12,15,18,24-heptone; (2S,5S,8S,11S,14R,17S,20S,Z)-14-[(1,3-benzothiazol-6-yl)methyl]-5-butyl-8-{[1- (1,1-dimethyl-2-propenyl)-3-indolyl]methyl}-2,11-bis(isobutyl)-10,19-dimethyl-17- 214 3152965.1PCT APPLICATION 113645-108076 methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexacos-22-ene-3,6,9,12,15,18,26- heptone; (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]hexacos-22-ene-3,6,9,12,15,18,26-heptone; (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]tetracosane- 3,6,9,12,15,18,24-heptone; (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]tetracosane-3,6,9,12,15,18,24-heptone; (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]hexacos-22-ene- 3,6,9,12,15,18,26-heptone; (2S,5S,8S,11S,14S,17S,20S)-5-(cyclohexylmethyl)-8-{[1-(1,1-dimethyl-2-propenyl)- 3-indolyl]methyl}-14-[(8-fluoro-6-isoquinolyl)methyl]-2,11-bis(isobutyl)-10,19- dimethyl-17-methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.3.1]tetracosane- 3,6,9,12,15,18,24-heptone; 215 3152965.1PCT APPLICATION 113645-108076 (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- thiazol-5-yl)methyl]-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexacos-22-ene- 3,6,9,12,15,18,26-heptone; (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]hexacos-22-ene- 3,6,9,12,15,18,26-heptone; (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-isoquinolyl)methyl]-10,19- dimethyl-17-methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexacos-22-ene- 3,6,9,12,15,18,26-heptone; (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- quinolyl)methyl]-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexacos-22-ene- 3,6,9,12,15,18,26-heptone; (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]tetracosane- 3,6,9,12,15,18,24-heptone; (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]tetracosane- 216 3152965.1PCT APPLICATION 113645-108076 3,6,9,12,15,18,24-heptone; (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]tetracosane- 3,6,9,12,15,18,24-heptone; (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]hexacos-22-ene-3,6,9,12,15,18,26-heptone; (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]tetracosane- 3,6,9,12,15,18,24-heptone; (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- isoquinolyl)methyl]-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexacos-22-ene- 3,6,9,12,15,18,26-heptone; (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-isoquinolyl)methyl]-10,19-dimethyl-17- methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.3.1]tetracosane-3,6,9,12,15,18,24- heptone; (2S,5S,8S,11S,14S,17S,20S)-5-benzyl-8-{[1-(1,1-dimethyl-2-propenyl)-3- 217 3152965.1PCT APPLICATION 113645-108076 indolyl]methyl}-2,11-bis(isobutyl)-14-[(7-isoquinolyl)methyl]-10,19-dimethyl-17- methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.3.1]tetracosane-3,6,9,12,15,18,24- heptone; (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]tetracosane- 3,6,9,12,15,18,24-heptone; (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- quinolyl)methyl]-1,4,7,10,13,16,19-heptaazabicyclo[18.3.1]tetracosane- 3,6,9,12,15,18,24-heptone; (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]hexacos-22-ene- 3,6,9,12,15,18,26-heptone; (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]tetracosane- 3,6,9,12,15,18,24-heptone; (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]hexacos-22-ene-3,6,9,12,15,18,26-heptone; 218 3152965.1PCT APPLICATION 113645-108076 (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]tetracosane-3,6,9,12,15,18,24- heptone; (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- quinolyl)methyl]-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexacos-22-ene- 3,6,9,12,15,18,26-heptone; (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]hexacos-22-ene- 3,6,9,12,15,18,26-heptone; (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]hexacos-22-ene- 3,6,9,12,15,18,26-heptone; (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]tetracosane- 3,6,9,12,15,18,24-heptone; (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- 219 3152965.1PCT APPLICATION 113645-108076 bis(isobutyl)-10,19-dimethyl-17-methyl-1,4,7,10,13,16,19- heptaazabicyclo[18.5.1]hexacos-22-ene-3,6,9,12,15,18,26-heptone; (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-isoquinolyl)methyl]-10,19-dimethyl-17- methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.3.1]tetracosane-3,6,9,12,15,18,24- heptone; (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-isoquinolyl)methyl]-10,19-dimethyl-17- methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.3.1]tetracosane-3,6,9,12,15,18,24- heptone; (2S,5S,8S,11S,14S,17S,20S,Z)-14-[(1,3-benzothiazol-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]hexacos-22-ene-3,6,9,12,15,18,26-heptone; (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- quinolyl)methyl]-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexacos-22-ene- 3,6,9,12,15,18,26-heptone; (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]hexacos-22-ene- 3,6,9,12,15,18,26-heptone; 220 3152965.1PCT APPLICATION 113645-108076 (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- quinolyl)methyl]-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexacos-22-ene- 3,6,9,12,15,18,26-heptone; (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]hexacos-22-ene- 3,6,9,12,15,18,26-heptone; (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]hexacos-22-ene- 3,6,9,12,15,18,26-heptone; (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]hexacos-22-ene-3,6,9,12,15,18,26-heptone; (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]tetracosane-3,6,9,12,15,18,24-heptone; (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]hexacos-22-ene-3,6,9,12,15,18,26-heptone; 221 3152965.1PCT APPLICATION 113645-108076 (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-isoquinolyl)methyl]-1,4,7,10,13,16,19-heptaazabicyclo[18.3.1]tetracosane- 3,6,9,12,15,18,24-heptone; (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]tetracosane- 3,6,9,12,15,18,24-heptone; (2S,5S,8S,11S,14S,17S,20S)-14-[(1,3-benzothiazol-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]tetracosane-3,6,9,12,15,18,24- heptone; (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]tetracosane- 3,6,9,12,15,18,24-heptone; (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]hexacos-22-ene-3,6,9,12,15,18,26-heptone; (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- 222 3152965.1PCT APPLICATION 113645-108076 6-indenyl)methyl]-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexacos-22-ene- 3,6,9,12,15,18,26-heptone; (2S,5S,8S,11S,14S,17S,20S)-14-[(1,3-benzothiazol-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]tetracosane-3,6,9,12,15,18,24- heptone; (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]tetracosane- 3,6,9,12,15,18,24-heptone; (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]tetracosane- 3,6,9,12,15,18,24-heptone; (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-isoquinolyl)methyl]-10,19-dimethyl-17- methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexacos-22-ene-3,6,9,12,15,18,26- heptone; (2S,5S,8S,11S,14S,17S,20S)-14-[(1,3-benzothiazol-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]tetracosane- 3,6,9,12,15,18,24-heptone; 223 3152965.1PCT APPLICATION 113645-108076 (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]tetracosane- 3,6,9,12,15,18,24-heptone; (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]tetracosane- 3,6,9,12,15,18,24-heptone; (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- indenyl)methyl]-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexacos-22-ene- 3,6,9,12,15,18,26-heptone; (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]hexacos-22- ene-3,6,9,12,15,18,26-heptone; (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-indenyl)methyl]-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexacos-22-ene- 3,6,9,12,15,18,26-heptone; (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]tetracosane- 224 3152965.1PCT APPLICATION 113645-108076 3,6,9,12,15,18,24-heptone; (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]hexacos-22-ene- 3,6,9,12,15,18,26-heptone; (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]tetracosane- 3,6,9,12,15,18,24-heptone; (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-isoquinolyl)methyl]-10,19-dimethyl-17- methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.3.1]tetracosane-3,6,9,12,15,18,24- heptone; (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]tetracosane- 3,6,9,12,15,18,24-heptone; (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]hexacos-22-ene-3,6,9,12,15,18,26-heptone; (2S,5S,8S,11S,14S,17S,20S,Z)-5-[(3,5-difluorophenyl)methyl]-8-{[1-(1,1-dimethyl- 225 3152965.1PCT APPLICATION 113645-108076 2-propenyl)-3-indolyl]methyl}-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-14-[(6- quinolyl)methyl]-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexacos-22-ene- 3,6,9,12,15,18,26-heptone; (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]tetracosane- 3,6,9,12,15,18,24-heptone; (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]tetracosane-3,6,9,12,15,18,24-heptone; (2S,5S,8S,11S,14S,17S,20S,Z)-8-{[1-(1,1-dimethyl-2-propenyl)-3-indolyl]methyl}- 14-[(8-fluoro-6-isoquinolyl)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]hexacos-22-ene- 3,6,9,12,15,18,26-heptone; (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]hexacos-22-ene- 3,6,9,12,15,18,26-heptone; (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]hexacos-22-ene- 3,6,9,12,15,18,26-heptone; 226 3152965.1PCT APPLICATION 113645-108076 (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]hexacos-22-ene-3,6,9,12,15,18,26- heptone; (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]hexacos-22-ene-3,6,9,12,15,18,26-heptone; (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]hexacos-22-ene-3,6,9,12,15,18,26- heptone; (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- indenyl)methyl]-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexacos-22-ene- 3,6,9,12,15,18,26-heptone; (2S,5S,8S,11S,17S,20S,Z)-14-[(1-benzothiophen-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]hexacos-22-ene-3,6,9,12,15,18,26- heptone; (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- 227 3152965.1PCT APPLICATION 113645-108076 dimethyl-17-methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexacos-22-ene- 3,6,9,12,15,18,26-heptone; (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]hexacos-22-ene-3,6,9,12,15,18,26- heptone; (2S,5S,8S,11S,14S,17S,20S,Z)-5-benzyl-14-[(7-cinnolinyl)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]hexacos-22-ene-3,6,9,12,15,18,26- heptone; (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- indenyl)methyl]-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexacos-22-ene- 3,6,9,12,15,18,26-heptone; (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]hexacos-22-ene-3,6,9,12,15,18,26-heptone; (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- indenyl)methyl]-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexacos-22-ene- 3,6,9,12,15,18,26-heptone; 228 3152965.1PCT APPLICATION 113645-108076 (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- indenyl)methyl]-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexacos-22-ene- 3,6,9,12,15,18,26-heptone; (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]hexacos-22-ene- 3,6,9,12,15,18,26-heptone; (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]tetracosane- 3,6,9,12,15,18,24-heptone; (2S,5S,8S,11S,14S,17S,20S,Z)-5-butyl-14-[(7-cinnolinyl)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]hexacos-22-ene-3,6,9,12,15,18,26- heptone; (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-isoquinolyl)methyl]-10,19- dimethyl-17-methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexacos-22-ene- 3,6,9,12,15,18,26-heptone; (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- quinolyl)methyl]-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexacos-22-ene- 229 3152965.1PCT APPLICATION 113645-108076 3,6,9,12,15,18,26-heptone; (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]tetracosane-3,6,9,12,15,18,24-heptone; (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]hexacos-22-ene- 3,6,9,12,15,18,26-heptone; (2S,5S,8S,11S,14S,17S,20S)-5-butyl-14-[(1H-1,7-diazainden-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]tetracosane-3,6,9,12,15,18,24- heptone; (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-isoquinolyl)methyl]-1,4,7,10,13,16,19-heptaazabicyclo[18.3.1]tetracosane- 3,6,9,12,15,18,24-heptone; (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]hexacos-22-ene- 3,6,9,12,15,18,26-heptone; (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-isoquinolyl)methyl]-10,19- 230 3152965.1PCT APPLICATION 113645-108076 dimethyl-17-methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.3.1]tetracosane- 3,6,9,12,15,18,24-heptone; (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-isoquinolyl)methyl]-10,19- dimethyl-17-methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexacos-22-ene- 3,6,9,12,15,18,26-heptone; (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]hexacos-22-ene-3,6,9,12,15,18,26-heptone; (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]hexacos-22-ene-3,6,9,12,15,18,26- heptone; (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-isoquinolyl)methyl]-10,19-dimethyl-17- methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.3.1]tetracosane-3,6,9,12,15,18,24- heptone; (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]tetracosane-3,6,9,12,15,18,24-heptone (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-isoquinolyl)methyl]-10,19- 231 3152965.1PCT APPLICATION 113645-108076 dimethyl-17-methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexacos-22-ene- 3,6,9,12,15,18,26-heptone; (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- isoquinolyl)methyl]-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexacos-22-ene- 3,6,9,12,15,18,26-heptone; (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-isoquinolyl)methyl]-5- {[p-(trifluoromethyl)phenyl]methyl}-1,4,7,10,13,16,19- heptaazabicyclo[18.3.1]tetracosane-3,6,9,12,15,18,24-heptone; (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]tetracosane- 3,6,9,12,15,18,24-heptone; (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-isoquinolyl)methyl]- 1,4,7,10,13,16,19-heptaazabicyclo[18.3.1]tetracosane-3,6,9,12,15,18,24-heptone; (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]hexacos-22-ene- 3,6,9,12,15,18,26-heptone; (2S,5S,8S,11S,14S,17S,20S,Z)-5-butyl-8-{[1-(1,1-dimethyl-2-propenyl)-3- 232 3152965.1PCT APPLICATION 113645-108076 indolyl]methyl}-2,11-bis(isobutyl)-10,19-dimethyl-17-methyl-14-[(1-thia-7-aza-2- indenyl)methyl]-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexacos-22-ene- 3,6,9,12,15,18,26-heptone; (2S,5S,8S,11S,14S,17S,20S,Z)-5-butyl-8-{[1-(1,1-dimethyl-2-propenyl)-3- indolyl]methyl}-14-[(3-fluoromethoxy-7-isoquinolyl)methyl]-2,11-bis(isobutyl)- 10,19-dimethyl-17-methyl-1,4,7,10,13,16,19-heptaazabicyclo[18.5.1]hexacos-22-ene- 3,6,9,12,15,18,26-heptone; (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]tetracosane-3,6,9,12,15,18,24-heptone; (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]hexacos-22-ene-3,6,9,12,15,18,26-heptone; (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]tetracosane-3,6,9,12,15,18,24-heptone; 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]hexacos-22-ene-3,6,9,12,15,18,26-heptone, 233 3152965.1PCT APPLICATION 113645-108076 or a pharmaceutically acceptable salt thereof.

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

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

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

8. A method for the treatment of tuberculosis, comprising the step of administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 4, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 234 3152965.1

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