Proteasome complex inhibitors targeting CLPP1P2 protease

Abstract

The present invention relates to compounds of formula (IA): including any stereochemically isomeric form thereof or a pharmaceutically acceptable salt thereof for use in the treatment of tuberculosis.

Description

Technical Field

[0001] This invention generally relates to proteasome complex inhibitors that target the ClpP1P2 protease and possess antibacterial activity, such as anti-tuberculosis properties. The compounds of this invention can be used to treat, for example, Mycobacterium tuberculosis.

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

[0003] Cross-reference to related applications This application claims priority to U.S. Provisional Patent Application No. 63 / 527,917, filed July 20, 2023, the contents of which are hereby expressly incorporated herein by reference. Background Technology

[0004] Tuberculosis (TB) is a debilitating disease affecting approximately 100 million people worldwide and causing nearly 2 million deaths annually, making it one of the leading causes of death from infectious diseases. It is estimated that one-third of all humanity has been infected with Mycobacterium tuberculosis (Mtb), and many may continue to carry latent infections that can reactivate into active disease. Standard antibiotic regimens for treating drug-sensitive (DS) forms of Mtb were developed over 50 years ago, but these regimens require treatment durations of six months or longer and are poorly tolerated. These factors contribute to poor patient adherence, which may be exacerbating the increasing resistance to available antibiotics. While new regimens for treating drug-resistant (DR) Mtb have recently been approved, resistance is rapidly evolving and has already threatened the potential durability of these new regimens. Therefore, identifying new drug classes, especially those targeting novel targets without pre-existing concerns about cross-resistance, is crucial to ensuring an opportunity to eradicate this devastating disease.

[0005] Regulated intracellular protein degradation is crucial for maintaining cellular homeostasis through protein quality control and regulation of many biological pathways (Inger and Brondsted (2009) Res. Microbiol 160:704-710; Goldberg (2003) Nature 426:895-899). ClpP protein is a highly conserved multimeric serine protease, which was first discovered (Hwang et al. (1987) Proceedings of the National Academy of Sciences (PNAS) 84:5550-5554; Katayama-Fujimura et al. (1987) Journal of Biol. Chem. 262:4477-4485) and characterized in E. coli (Maurizi et al. (1990) Journal of Biol. Chem. 265(21):12536-45; Maurizi et al. (1998) Biochemistry 37(21):7778-86; Maurizi et al. (1994) Methods Enzymology 244:314-31; Yu and Houry (2007) FEBS Letters Lett. 581(19):3749-57. ClpP homologs are found in a wide range of bacteria as well as in eukaryotic organelles such as mitochondria and chloroplasts (Porankiewicz et al. (1999) Molecular Microbiology 32(3):449-58). In E. coli, the ClpP complex alone can rapidly hydrolyze only unfolded oligopeptides, but not large globulins. Degradation of large proteins requires the presence of AAA ATPase complexes, such as ClpA or ClpX in E. coli or ClpC in other species (Kress et al. (2009) Microbiological Research 160(9):618-28). These hexamer structures associate with the two ends of the ClpP complex, thereby forming an active 4-cyclic ATP-dependent protease (Kim et al. (2001 Nature Struct Biology 8(3):230-3); Maurizi (1991) Journal of the Biochemo Societies 19(3):719-23; Maurizi et al. (1998) Biochemistry 37(21):7778-86).These ATPases selectively bind to certain protein substrates, causing the substrates to unfold and translocate linearized polypeptides to the ClpP proteolytic chamber for degradation (Hoskins et al. (1998) Proceedings of the National Academy of Sciences 95(21):12135-40; Ishikawa et al. (2001) Proceedings of the National Academy of Sciences 98(8):4328-33; Ortega et al. (2000) Molecular Cell 6(6):1515-21; Reid et al. (2001) Proceedings of the National Academy of Sciences 98(7):3768-72). In addition to substrate recognition, the mitochondrial ClpX complex also promotes the assembly of the ClpP complex into its reactive form (Kang et al. (2005) Journal of Biochemistry 280(42):35424-32). In *Escherichia coli*, the ClpXP protease complex plays several roles, including regulating DNA damage responses and degrading SsrA-tagged peptides lodged on ribosomes (Farrell et al. (2005) *Molecular Microbiology* 57:1750-1761; Pruteanu and Baker (2009) *Molecular Microbiology* 71:912-924). ClpP also enhances the virulence of several pathogenic organisms, including Listeria monocytogenes, in which case the protease is essential for the production of α-listeriosomalin (Gaillot et al. (2001) *Infect Immun.* 69:4938-4943; Gaillot et al. (2000) *Molecular Microbiology* 35:1286-1294).

[0006] Therefore, inhibitors of the ClpP complex may provide unique and highly effective therapeutic effects against Mtb when used alone or in combination with other antibiotics that cause misfolding or damaged proteins, or in the chronic and latent phases of TB, in which immune-mediated oxidative stress is prevalent. Summary of the Invention

[0007] This invention relates to compounds of formula IA: R2: -CH2CH2CF3, -CH2CH2CH2CF3, -CH2CH2-p-fluorophenyl; R3: Me, -CH2CH2CH(Me)-OH; R4: R is a phenyl group that is optionally mono-, di-, or tri-substituted with halogen, alkyl, CF3, CN, or alkoxy groups.

[0008] The present invention also relates to pharmaceutical compositions containing the above compounds and methods for treating microbial infections such as tuberculosis. Detailed Implementation

[0009] It should be understood that the description of the invention has been simplified to illustrate and clearly understand the elements relevant to the invention, while many other elements found in typical pharmaceutical compositions have been omitted for simplification. Those skilled in the art will recognize that other elements and / or steps are desirable and / or required for carrying out the invention. However, because such elements and steps are well known in the art and because they are not conducive to a better understanding of the invention, a discussion of such elements and steps is not provided herein. The disclosure herein relates to all such changes and modifications to such elements and methods known to those skilled in the art. Furthermore, the embodiments identified and shown herein are for illustrative purposes only and are not intended to be exclusive or limiting in their description of the invention.

[0010] The technical and scientific terms used herein have the meanings commonly understood by those skilled in the art as per the terminology involved in this invention, unless otherwise defined. This document references various methods and materials known to those skilled in the art. Standard reference books elucidating the general principles of pharmacology include *Goodman and Gilman's Therapeutic Pharmacology*. The Pharmacological Basis of Therapeutics (10th edition, McGraw Hill Companies Inc., New York, 2001). This invention may be practiced using any suitable materials and / or methods known to those skilled in the art. However, preferred materials and methods are described. Unless otherwise stated, the materials, reagents, etc., referred to in the following description and examples are commercially available.

[0011] The compounds according to the invention are inherently intended to encompass all their stereochemical isomers. The term "stereochemical isomer" refers to all possible stereoisomers that a compound of definition (A) as used before or after, as well as its N-oxide, pharmaceutically acceptable salt, or physiologically functional derivative, may possess. Unless otherwise mentioned or specified, the chemical name of a compound represents a mixture of all possible stereochemical isomer forms. Specifically, the stereoisomeric source center may have an R configuration or an S configuration; substituents on a divalent cyclic (partially) saturated group may have a cis configuration or a trans configuration. Compounds encompassing a double bond may have an E (opposite-side) or Z (same-side) stereochemistry at said double bond. The terms cis, trans, R, S, E, and Z are well known to those skilled in the art.

[0012] The stereochemical isomers of compounds of formula (A) are obviously intended to be included within the scope of this invention. Of particular interest are those stereochemically pure compounds of formula (A).

[0013] According to CAS nomenclature conventions, when two stereoisomeric source centers with known absolute configurations exist in a molecule, the lowest-numbered chiral center (i.e., the reference center) is assigned an R descriptor or an S descriptor (based on the Cahn-Ingold-Prelog sequence rule). The configuration of the second stereoisomeric source center is represented using relative descriptors [R*,R*] or [R*,S*], where R* is always designated as the reference center, and [R*,R*] indicates centers with the same chirality, and [R*,S*] indicates centers with different chirality. For example, if the lowest-numbered chiral center in the molecule has an S configuration and the second center is R, the stereodescriptor would be S--[R*,S*]. When using "α" and "β": the position of the highest-priority substituent on the asymmetric carbon atom in the ring system with the lowest ring number is always arbitrarily located in the "α" position of the mean plane determined by the ring system. The position of the highest priority substituent on another asymmetric carbon atom in the ring system relative to the position of the highest priority substituent on the reference atom is named "α" (in the case that it is on the same side of the mean plane determined by the ring system) or "β" (in the case that it is on the other side of the mean plane determined by the ring system).

[0014] When a specific stereoisomer is specified, it means that the form is substantially free of other isomers, i.e., associated with less than 50%, preferably less than 20%, more preferably less than 10%, even more preferably less than 5%, further preferably less than 2%, and most preferably less than 1%. Therefore, when a compound of formula (A) is specified, for example, as (R,S), it means that the compound is substantially free of the (S,R) isomer.

[0015] The compound of formula (A) and some intermediate compounds consistently have at least two stereoisomer source centers in their structure, which may produce at least four stereochemically different structures.

[0016] Compounds of formula (A) can be synthesized as mixtures of enantiomers, particularly racemic mixtures of enantiomers, which can be separated by another resolution procedure known in the art. The racemic compound of formula (A) can be converted to its corresponding diastereomeric salt form by reaction with a suitable chiral acid. The diastereomeric salt form is then separated, for example, by selective crystallization or fractional crystallization, and the enantiomer is released therefrom by a base. An alternative method for separating the enantiomeric form of compounds of formula (A) involves liquid chromatography using a chiral stationary phase. The pure stereochemical isomer can also be derived from the corresponding pure stereochemical isomer of a suitable starting material, provided that the reaction occurs stereospecifically. Preferably, if a specific stereoisomer is desired, the compound is synthesized by a stereospecific preparation method. These methods will advantageously employ enantiomerically pure starting materials.

[0017] The tautomer forms of compounds of formula (A) are intended to include those compounds of formula (A) in which, for example, an enol group is converted to a ketone group (keto-enol tautomerism). The tautomer forms of compounds of formula (A) or intermediates thereof of the present invention are intended to be included within the scope of the present invention.

[0018] As used herein, the term "alkyl" refers to a non-branched or branched saturated monovalent hydrocarbon residue containing 1 to 10 carbon atoms. The term "lower alkyl" refers to a straight-chain or branched hydrocarbon residue containing 1 to 6 carbon atoms. As used herein, "C1- 10 "Alkyl" refers to an alkyl group consisting of 1 to 10 carbon atoms. Examples of alkyl groups include, but are not limited to, lower alkyl groups, including methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl or pentyl, isopentyl, neopentyl, hexyl, heptyl and octyl.

[0019] As used in this article, the term "halogen" refers to F, Cl, Br, or I.

[0020] When the term "alkyl" is used as a suffix following another term (such as "phenylalkyl" or "hydroxyalkyl"), it is intended to refer to an alkyl group substituted with one or two substituents selected from other designated names, as defined above. Thus, for example, "phenylalkyl" signifies the group R'R''-, where R' is phenyl and R'' is an alkylene group as defined herein, provided that the connection point of the phenylalkyl moiety is understood to be located on the alkylene group. Examples of arylalkyl groups include, but are not limited to, benzyl, phenethyl, and 3-phenylpropyl. The terms "arylalkyl" or "aralkyl" are similarly interpreted except that R' is aryl. The terms "(hetero)arylalkyl" or "(hetero)arylalkyl" are similarly interpreted except that R' is optionally aryl or heteroaryl.

[0021] The term “haloalkyl” or “lower haloalkyl” or “lower haloalkyl” refers to a straight-chain or branched hydrocarbon residue containing one to six carbon atoms, wherein one or more carbon atoms are replaced by one or more halogen atoms.

[0022] As used herein, the term "alkoxy" means -O-alkyl, wherein the alkyl group is as defined above, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentoxy, hexoxy, including its isomers. As used herein, "lower alkoxy" refers to an alkoxy group having a "lower alkyl group" as previously defined. As used herein, "C1- 10 "Alkoxy" refers to -O-alkyl, where the alkyl group is C. 1-10 .

[0023] The term “haloalkoxy” or “halolower alkoxy” or “lower haloalkoxy” refers to a lower alkoxy group in which one or more carbon atoms are replaced by one or more halogen atoms.

[0024] As used herein, the term "hydroxyalkyl" means an alkyl group in which one to three hydrogen atoms on different carbon atoms are replaced by hydroxyl groups, as defined herein.

[0025] As used herein, the term "carboxyl" refers to a group of the formula -C(=O)R2, wherein each R is independently hydrogen or C. 1-3 Alkyl groups, and lower alkyl groups as defined herein.

[0026] The term "cycloalkyl" refers to a monovalent saturated monocyclic or bicyclic hydrocarbon group having 3 to 10 ring carbon atoms. In a particular embodiment, cycloalkyl refers to a monovalent saturated monocyclic hydrocarbon group having 3 to 8 ring carbon atoms. Bicyclic means consisting of two saturated carbon rings having one or more common carbon atoms. A particular cycloalkyl group is monocyclic. Examples of monocyclic cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. Examples of bicyclic cycloalkyl groups are bicyclic [2.2.1]heptyl or bicyclic [2.2.2]octyl.

[0027] As used herein, the term "amino" denotes a group of the formula -NR'R'', wherein R' and R'' are independently hydrogen, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. Alternatively, R' and R'' together with the nitrogen to which they are attached may form a heterocycloalkyl group. The term "primary amino" indicates a group in which both R' and R'' are hydrogen. The term "secondary amino" indicates a group in which R' is hydrogen and R'' is not hydrogen. The term "tertiary amino" indicates a group in which neither R' nor R'' is hydrogen. Specific secondary and tertiary amines are methylamine, ethylamine, propylamine, isopropylamine, aniline, benzylamine, dimethylamine, diethylamine, dipropylamine, and diisopropylamine.

[0028] The term "heteroaryl" refers to a monovalent aromatic heterocyclic monocyclic or bicyclic system having 5 to 12 ring atoms, including 1, 2, 3 or 4 heteroatoms selected from N, O and S, with the remaining ring atoms being carbon. Examples of heteroaryl moieties include pyrrole, furanyl, thiophene, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrazolyl, pyridinyl, triazinyl, aziridine, diazacycloheptatrienyl, isoxazolyl, benzofuranyl, isothiazolyl, benzothiophene, indolyl, isindolyl, isobenzofuranyl, benzimidazolyl, benzooxazolyl, benzoisooxazolyl, benzothiazolyl, benzooxadiazolyl, benzothiadiazolyl, benzotriazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, or quinoxolinyl.

[0029] The term "heterocyclic alkyl" refers to a monocyclic or bicyclic ring system having 3 to 9 ring atoms, comprising 1, 2, or 3 ring heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon, and is monovalently or partially saturated. In a particular embodiment, a heterocyclic alkyl is a monocyclic ring system having 4 to 7 ring atoms, comprising 1, 2, or 3 ring heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon, and is monovalently saturated. Examples of monocyclic saturated heterocyclic alkyl groups are aziridine propane, ethylene oxide, aziridine butane, oxacyclobutane, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolyl, imidazoyl, oxazolyl, isoxazolyl, thiazoyl, piperidinyl, tetrahydropyranyl, tetrahydrothiaranyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholin-4-yl, aziridine heptane, diaziridine heptane, homopiperazinyl, or oxazaziridine heptane. Examples of bicyclic saturated heterocyclic alkyl groups are 8-aza-bicyclo[3.2.1]octyl, quininecycloyl, 8-oxa-3-aza-bicyclo[3.2.1]octyl, 9-aza-bicyclo[3.3.1]nonyl, 3-oxa-9-aza-bicyclo[3.3.1]nonyl, or 3-thia-9-aza-bicyclo[3.3.1]nonyl. Examples of partially unsaturated heterocyclic alkyl groups are dihydrofuranyl, imidazolinyl, dihydrooxazolyl, tetrahydropyridyl, or dihydropyranyl.

[0030] "Patient" is a mammal, such as a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or a non-human primate, such as a monkey, chimpanzee, baboon, or rhesus monkey, and the terms "patient" and "subject" are used interchangeably in this document.

[0031] As used in this disclosure, the term "carrier" encompasses carriers, excipients, and diluents, and refers to materials, compositions, or mediators involved in carrying or transporting a pharmaceutical agent from one organ or part of the body to another organ or part of the body, such as liquid or solid fillers, diluents, excipients, solvents, or encapsulating materials.

[0032] The term "treatment" in relation to a subject refers to the improvement of at least one symptom of the subject's condition. Treatment can be curative, improvement, or at least partial relief of the condition.

[0033] Unless otherwise stated, the term “symptom” is used in this disclosure to mean the term disease, symptom or illness, and may be used interchangeably with the term disease, symptom or illness.

[0034] As used in this disclosure, the terms “administer,” “administering,” or “administration” mean the direct administration of a compound or a pharmaceutically acceptable salt or composition thereof to a subject, or the administration of a prodrug derivative or analog of the compound or a pharmaceutically acceptable salt or composition thereof to a subject, which may form an adequate amount of the active compound in the subject’s body.

[0035] As used in this disclosure, the term "optionally substituted" means that a suitable substituent can replace hydrogen bound to carbon. Those skilled in the art will understand that, with respect to any group containing one or more substituents, such a group is not intended to introduce any spatially impractical, synthetically infeasible, and / or inherently unstable substitution or substitution pattern. Furthermore, such combinations are permitted only if the combination of substituents and / or variables within any formula presented herein yields a stable compound or a useful synthetic intermediate, where stability means a reasonably pharmacologically relevant half-life under physiological conditions.

[0036] Dosage and administration: The compounds of the present invention can be formulated in a wide variety of oral dosage forms and carriers. Oral administration can be in the form of tablets, coated tablets, sugar-coated tablets, hard gelatin capsules and soft gelatin capsules, solutions, emulsions, syrups, or suspensions. The compounds of the present invention are effective when administered via other routes of administration, including continuous (intravenous infusion), local parenteral, intramuscular, intravenous, subcutaneous, transdermal (possibly including penetration enhancers), buccal, nasal, inhalation, and suppository administration. A preferred method of administration is generally oral administration using a convenient daily dosage regimen that can be adjusted according to the degree of discomfort and the patient's response to the active ingredient.

[0037] One or more compounds of the present invention, along with their pharmaceutically available salts, together with one or more conventional excipients, carriers, or diluents, can be presented as pharmaceutical compositions and unit dosage forms. The pharmaceutical compositions and unit dosage forms may contain conventional components in conventional proportions, with or without additional active compounds or components, and the unit dosage forms may contain any suitable effective amount of active ingredient commensurate with the intended daily dose range to be used. The pharmaceutical compositions may be in solid form, such as tablets or filled capsules, semi-solids, powders, sustained-release formulations; or in liquid form, such as solutions, suspensions, emulsions, elixirs, or filled capsules for oral administration; or in suppositories for rectal or vaginal administration; or in the form of sterile injectable solutions for parenteral use. Typical formulations will contain one or more active compounds, from about 5% to about 95% (w / w). The terms “formulation” or “dosage form” are intended to include both solid and liquid formulations of the active compound, and those skilled in the art will understand that the active ingredient may be present in different formulations depending on the target organ or tissue and the desired dose and pharmacokinetic parameters.

[0038] As used herein, the term "excipient" refers to a compound that can be used to prepare a pharmaceutical composition, is generally safe and non-toxic, and is neither biologically undesirable nor otherwise undesirable, and includes excipients acceptable for both veterinary and human pharmaceutical use. The compounds of the present invention may be administered alone, but will generally be administered in mixture with one or more suitable pharmaceutical excipients, diluents, or carriers, the selection of which should be based on the intended route of administration and standard pharmaceutical practice.

[0039] "Pharmaceutical acceptable" means that the substances that can be used to prepare pharmaceutical compositions are generally safe, non-toxic, and neither biologically nor otherwise undesirable, and include substances acceptable for veterinary and human pharmaceutical use.

[0040] The “pharmaceutically acceptable salt” form of an active ingredient may initially endow it with desirable pharmacokinetic properties not present in the non-salt form, and may even positively influence the pharmacodynamics of the active ingredient in vivo in terms of its therapeutic activity. The phrase “pharmaceutically acceptable salt” for a compound means a salt that is pharmaceutically acceptable and has the desired pharmacological activity of the parent compound. Such salts include: (1) acid addition salts formed from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or from organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid. Acids, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-en-1-carboxylic acid, glucoheponic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, dodecyl sulfate, gluconic acid, glutamic acid, hydroxynaphthenic acid, salicylic acid, stearic acid, mucoconic acid, etc.; or (2) salts formed when the acidic protons present in the parent compound are replaced by metal ions (e.g., alkali metal ions, alkaline earth ions or aluminum ions) or coordinated with organic bases such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucosamine, etc.

[0041] Solid dosage forms include powders, tablets, pills, capsules, sachets, suppositories, and dispersible granules. Solid carriers can be one or more substances that also function as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrants, or encapsulating materials. In powders, the carrier is typically a finely ground solid, which is a mixture with the finely ground active ingredient. In tablets, the active ingredient is typically mixed with a carrier having the desired binding capacity in a suitable proportion and compacted into the desired shape and size. Suitable carriers include, but are not limited to, magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, astragalus gum, methylcellulose, sodium carboxymethyl cellulose, low-melting-point waxes, cocoa butter, etc. In addition to the active ingredient, solid dosage forms may also contain colorants, flavoring agents, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizers, etc.

[0042] Liquid formulations are also suitable for oral administration, including those comprising emulsions, syrups, elixirs, aqueous solutions, and aqueous suspensions. These liquid formulations include solid formulations intended to be converted into a liquid form shortly before use. Emulsions can be prepared in solution, such as in an aqueous solution of propylene glycol, or may contain emulsifiers such as lecithin, sorbitan monooleate, or gum arabic. Aqueous solutions can be prepared by dissolving the active ingredient in water and adding suitable colorants, flavorings, stabilizers, and thickeners. Aqueous suspensions can be prepared by dispersing finely fragmented active ingredients in water containing viscous materials such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethyl cellulose, and other well-known suspending agents.

[0043] The compounds of the present invention can be formulated for parenteral administration (e.g., by injection, such as bolus injection or continuous infusion) and can be present in unit dosage forms in ampoules, in pre-filled syringes, in small-volume infusion solutions, or in multi-dose containers with added preservatives. The compositions can take the form of suspensions, solutions, or emulsions in oily or aqueous media, such as solutions in aqueous polyethylene glycol solutions. Examples of oily or non-aqueous carriers, diluents, solvents, or mediators include propylene glycol, polyethylene glycol, vegetable oils (e.g., olive oil), and injectable organic esters (e.g., ethyl oleate), and may contain formulation agents such as preservatives, wetting agents, emulsifiers or suspending agents, stabilizers, and / or dispersants. Alternatively, the active ingredient can be in powder form obtained by aseptic separation of a sterile solid or by lyophilization of a solution for reconstitution with a suitable mediator (e.g., sterile pyrogen-free water) prior to use.

[0044] The compounds of the present invention can be formulated for topical application to the epidermis in the form of ointments, creams, or lotions, or as transdermal patches. Ointments and creams can be formulated, for example, with an aqueous or oil-based base by adding suitable thickeners and / or gelling agents. Lotions can be formulated with an aqueous or oil-based base and will generally also contain one or more emulsifiers, stabilizers, dispersants, suspending agents, thickeners, or colorants. Formulations suitable for topical application in the mouth include lozenges containing the active ingredient in a flavoring base (typically sucrose and arabinose or tragacanth gum); soft lozenges containing the active ingredient in an inert base (such as gelatin and glycerin or sucrose and arabinose); and mouthwashes containing the active ingredient in a suitable liquid carrier.

[0045] The compounds of the present invention can be formulated for application in suppository form. First, a mixture of low-melting-point waxes, such as fatty acid glycerides or cocoa butter, is melted, and the active ingredients are homogeneously dispersed, for example, by stirring. The molten homogeneous mixture is then poured into a mold of a convenient size, allowing cooling and solidification.

[0046] The compounds of the present invention can be formulated for vaginal application. In addition to the active ingredient, vaginal suppositories, tampons, creams, gels, pastes, foams, or sprays may contain a suitable carrier such as those known in the art.

[0047] The compounds of the present invention can be formulated for nasal administration. The solution or suspension is applied directly to the nasal cavity by conventional means, such as using a dropper, pipette, or nebulizer. The formulation can be provided in single-dose or multi-dose form. In the latter case, using a dropper or pipette, this is achieved by the patient administering an appropriate, predetermined volume of the solution or suspension. In the case of a nebulizer, this can be achieved, for example, by means of a metering nebulizer pump.

[0048] The compounds of the present invention can be formulated for aerosol administration, particularly for use in the respiratory tract, and include intranasal administration. The compounds will typically have a small particle size, for example, about five (5) micrometers or less. This particle size can be obtained by means known in the art, such as by micronization. The active ingredient is provided in a pressurized package with a suitable propellant, such as chlorofluorocarbons (CFCs), such as dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, or carbon dioxide or other suitable gases. The aerosol may conveniently also contain surfactants, such as lecithin. The dosage of the drug can be controlled by providing a metering valve. Alternatively, the active ingredient can be provided as a dry powder (e.g., a powder mixture of the compound in a suitable powder base, such as lactose, starch, starch derivatives such as hydroxypropyl methylcellulose and polyvinylpyrrolidone (PVP)). The powder carrier will form a gel in the nasal cavity. The powder composition can be presented in unit dosage forms, such as capsules, boxes, or blister packs containing, for example, gelatin, from which the powder can be administered via an inhaler.

[0049] When needed, enteric coatings can be used to prepare formulations suitable for sustained or controlled release of the active ingredient. For example, the compounds of the present invention can be formulated into percutaneous or subcutaneous drug delivery devices. These delivery systems are advantageous when sustained release of the compound is required and patient adherence to treatment regimens is critical. In percutaneous delivery systems, the compounds are typically attached to a skin-adhesive solid carrier. The compounds of interest can also be used in combination with penetration enhancers, such as azone (1-dodecylazacyclohepta-2-one). Sustained-release delivery systems are subcutaneously inserted into the subcutaneous layer via surgical procedure or injection. Subcutaneous implants encapsulate the compounds in a lipid-soluble membrane (e.g., silicone rubber) or a biodegradable polymer (e.g., polylactic acid).

[0050] Suitable formulations, along with drug carriers, diluents, and excipients, are described in Remington: Pharmaceutical Science and Practice (… Remington: The Science and Practice of Pharmacy(1995, edited by EW Martin, Mack Publishing Company, 19th edition, Easton, Pennsylvania). Skilled formulation scientists can modify formulations within the teachings of the specification to provide multiple formulations for specific routes of administration without destabilizing the compositions of the invention or impairing their therapeutic activity.

[0051] Modifications to the compounds of the present invention to make them more soluble in, for example, water or other media can be readily achieved through minor alterations (salt formulation, esterification, etc.) well known to those skilled in the art. It is also well known to those skilled in the art that, in order to achieve maximum beneficial effects in patients, modifications can be made to the route of administration and dosage regimen of a particular compound to manage the pharmacokinetics of the compounds of the present invention.

[0052] As used herein, the term "therapeutic effective dose" refers to the amount required to reduce the symptoms of a disease in an individual. The dose will be adjusted to meet the individual requirements of each specific case. The dose may vary within a wide range of factors including: the severity of the disease to be treated, the patient's age and general health, other medications used to treat the patient, the route and form of administration, and the preferences and experience of the healthcare practitioners involved. For oral administration, a daily dose between about 0.01 mg / kg body weight / day and about 1000 mg / kg body weight / day is appropriate in monotherapy and / or combination therapy. A preferred daily dose is between about 0.1 mg / kg body weight / day and about 500 mg / kg body weight / day, more preferably between 0.1 mg / kg body weight / day and about 100 mg / kg body weight / day, and most preferably between 1.0 mg / kg body weight / day and about 15 mg / kg body weight / day. Therefore, for a person weighing 70 kg, the dose range in one embodiment would be from about 70 mg / day to 0.7 g / day. Daily dosage can be administered as a single dose or in divided doses, typically from 1 dose / day to 5 doses / day. Treatment is usually initiated with a smaller dose than the optimal dose of the compound. Thereafter, the dose is increased in small increments until optimal efficacy is achieved in the individual patient. Those skilled in the art to treat the diseases described herein will be able to determine the therapeutically effective amount of the compounds of the invention for a given disease and patient without excessive experimentation and relying on personal knowledge, experience, and the disclosure of this application.

[0053] These pharmaceutical formulations are preferably in unit dosage form. In this form, the formulation is subdivided into unit doses containing appropriate amounts of the active ingredient. The unit dosage form can be a packaged formulation containing discrete amounts of the formulation, such as packaged tablets, capsules, or powder in vials or ampoules. Similarly, the unit dosage form can be the capsule, tablet, sachets, or lozenges themselves, or any appropriate number of these packaging forms.

[0054] Example The following examples further describe and illustrate specific embodiments within the scope of the invention. Techniques and formulations are typically described in Remington Pharmaceutical Sciences (…). Remington's Pharmaceutical Sciences The information can be found in (McPublishers, Easton, Pennsylvania). This disclosure is further illustrated by the following examples, which should not be construed as limiting the scope or spirit of this disclosure to the specific procedures described herein. It should be understood that the examples are provided to illustrate certain implementations and are not intended to limit the scope of this disclosure thereto. It should be further understood that various other implementations, modifications, and equivalents thereof may be realized by those skilled in the art without departing from the spirit of this disclosure and / or the scope of the appended claims.

[0055] General information for compound synthesis and characterization: The starting materials, reagents, and solvents were all purchased from commercial sources and could be used without further purification.

[0056] Concentration under vacuum or reduced pressure means that a rotary evaporator is used.

[0057] Perform silica gel chromatography using pre-packed columns from Agela with an ISCO or Biotage system.

[0058] Proton nuclear magnetic resonance (¹H NMR) spectra were recorded using a Bruker 400 MHz or a Varian 500 MHz NMR spectrometer. Chemical shifts are expressed as parts per million at low field relative to solvent resonances used as internal standards (e.g., CDCl₃ at 7.26 ppm for ¹H). Peak shapes are represented as follows: s, singlet; d, doublet; t, triplet; q, quartet; p, quintet; m, multiplet; br s, broad singlet; dd, doublet; dt, doubletuplet; dq, doubletuplet.

[0059] Liquid chromatography-mass spectrometry (LCMS) was performed on an Agilent LC1200-MS6110 or a Shimadzu LC20-MS2020.

[0060] Mass spectrometry (MS) is performed using atmospheric pressure chemical ionization (APCI), electrospray ionization (ESI), electron impact ionization (EI), or electron scattering (ES) ionization sources.

[0061] Typical conditions for preparative HPLC: column: YMC-Actus Triart C18 150 x 30 mm, 5 μm; Boston Green ODS 150 x 30 mm, 5 μm; Phenomenex Luna C18 150 x 25 mm, 10 μm; Welch Ultimate C18 150 x 25 mm, 5 μm; Waters Xbridge BEH C18 100 x 25 mm, 5 μm; Daisogel Spods RPS 150 x 25 mm, 5 μm Mobile phase: A: Water containing 0.225% FA, B: MeCN; A: Water containing 0.1% TFA, B: MeCN; A: Water containing 0.04% HCl, B: MeCN; A: Water containing 10 mmol NH4HCO3, B: MeCN; A: Water containing 0.05% NH3·H2O and 10 mmol NH4HCO3, B: MeCN.

[0062] Running time: 10-25 min Flow rate: 25-40 mL / min Typical preparative SFC: Column: Daicel Chiralcel OD (250 mm x 30 mm, 10 μm); Mobile phase: CO2; B: EtOH containing 0.1% NH3H2O; isocratic 30% B and 70% A. Flow rate: 140 mL / min.

[0063] Column: Daicel CHIRALPAK IG (250 mm x 30 mm, 10 μm); Mobile phase: CO2; B: i-PrOH containing 0.1% NH3H2O; isocratic 30% B and 70% A; Flow rate: 80 mL / min.

[0064] Column: Daicel CHIRALPAK AS (250 mm x 30 mm, 10 μm); Mobile phase: A: CO2, B: EtOH; isocratic 10% B and 90% A. Flow rate: 150 mL / min Column: Fenomex-cellulose-2 (250 mm x 30 mm, 10 μm); Mobile phase A: heptane; B: EtOH containing 0.1% TFA; isocratic 40% B and 60% A. Flow rate: 150 mL / min abbreviation: ACN or MeCN: Acetonitrile AcOH: Acetic acid aq: aqueous solution Example: Implementation DCM: Dichloromethane DMF: Dimethylformamide EDCI: 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide EtOAc: Ethyl acetate Eq: Equivalent FA: Formic acid HOBt: 1-Hydroxybenzonitrile HPLC: High Performance Liquid Chromatography TIPSCl: Triisopropylchlorosilane IPA: Isopropyl alcohol THF: Tetrahydrofuran LAH: Lithium Aluminum Hydrogen LCMS or LC-MS: Liquid Chromatography-Mass Spectrometry LDA: Lithium diisopropylamino LiHMDS: Lithium bis(trimethylsilyl)amino MeOH: Methanol TBAF: Tetra-n-Butylammonium Fluoride TEA: Triethylamine TLC: Thin-layer chromatography TMEDA: Tetramethylethylenediamine TMG: 1,1,3,3-Tetramethylguanidine δ: Chemical shift in ppm TFA: 2,2,2-trifluoroacetic acid TFAA: 2,2,2-trifluoroacetic anhydride T3P: 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphacyclohexane 2,4,6-trioxide T4P: 2,4,6-Tributyl-1,3,5,2,4,6-trioxatriphosphazenecyclohexane 2,4,6-trioxide Py: Pyridine MnO2: Active manganese oxide (IV) DIBAL-H: Diisobutylaluminum Hydrogenation DMP: Dess-Martin periodinane Min: minutes hr: hours m / z: Mass-to-charge ratio NMR: Nuclear Magnetic Resonance 1 H NMR: Proton NMR Pd(dppf)Cl2:[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloro Pd(dba)2: Bis(dibenzylacetone)palladium Pd(PPh3)4: Tetra(triphenylphosphine)palladium(0) prep-HPLC: Preparative HPLC psi: pounds per square inch sat: saturation SFC: Supercritical Fluid Chromatography synthesis: Compound A can be synthesized using the general synthetic scheme IA. General Synthesis Scheme IA X: Br, I, or OT Acids: TFA, HCl, formic acid R2: -(CH2)2CF3, -(CH2)3CF3, -(CH2)2-4-fluorophenyl R3: Me, - , -(CH2)2CH(OH)CH3 R4: As defined in structure 1A of the genus. [O]: MnO2, DMP Condensing agents: EDCI / HOBt, T3P, T4P Synthesis of intermediates and embodiments: Example 1: 2-(4-fluorophenyl)-N-((2S)-5-hydroxy-1-oxo-1-(((S)-6,6,6-trifluoro-1-oxo-1-(thiazol-2-yl)hexan-2-yl)amino)hexan-2-yl)thiazol-5-carboxamide (ClpP-1628) Step 1. (2R,5S)-2-isopropyl-3,6-dimethoxy-5-(4,4,4-trifluorobutyl)-2,5-dihydropyrazine Synthesis (2R)-2-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine (33.76 g, 183.26 mmol, 32.78 mL, 1 equivalent) was added dropwise to a solution of LDA (2 M in THF, 109.95 mL, 1.2 equivalent) in THF (200 mL) and purged three times with N2 at -78 °C. Then, after 30 minutes, a mixture of 4-bromo-1,1,1-trifluorobutane (35 g, 183.26 mmol, 1 equivalent) in THF (150 mL) was added to the above solution at -78 °C. The mixture was stirred at 25 °C for 12 hours under a N2 atmosphere. LCMS showed that the desired mass was detected. The reaction mixture was quenched by adding saturated NH4Cl (1000 mL) and extracted with EtOAc (300 mL x 3). The combined organic layers were dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO2, 0-10% EtOAc / petroleum ether). A colorless oil, (2R,5S)-2-isopropyl-3,6-dimethoxy-5-(4,4,4-trifluorobutyl)-2,5-dihydropyrazine (46.8 g, 143.11 mmol, 78% yield, 90% purity) was obtained.

[0065] LCMS (ESI) m / z 295.6 [M+H] + ¹H NMR (400MHz, chloroform-d) δ = 4.04 - 3.99 (m, 1H), 3.98 - 3.95 (m, 1H), 3.70 (m, 6H), 2.27 (m, 1H), 2.18 - 2.02 (m, 2H), 1.96 - 1.84 (m, 1H), 1.82 - 1.70 (m, 1H), 1.63 - 1.50 (m, 2H), 1.05 (d, J=6.9 Hz, 3H), 0.70 (d, J=6.8 Hz, 3H) Step 2. Synthesis of (2S)-2-amino-6,6,6-trifluorohexanoate methyl ester (TFA) salt TFA (92.40 g, 810.36 mmol, 60 mL, 4.75 equivalents) was added to a solution of (2R,5S)-2-isopropyl-3,6-dimethoxy-5-(4,4,4-trifluorobutyl)-2,5-dihydropyrazine (50.2 g, 170.57 mmol, 1 equivalent) in MeCN (240 mL), H₂O (150 mL). The mixture was stirred at 50 °C for 12 hours. TLC indicated that the starting material was completely consumed. The reaction mixture was concentrated to dryness under reduced pressure. Methyl (2S)-2-amino-6,6,6-trifluorohexanoate (53 g, crude, TFA salt) was obtained as a yellow oil. The product was used in the next step without further purification.

[0066] Step 3. Synthesis of methyl (2S)-2-(tert-butoxycarbonylamino)-6,6,6-trifluorohexanoate DIEA (103.18 g, 798.31 mmol, 1 equivalent) and Boc₂O (127.77 g, 585.43 mmol, 134.49 mL, 2.2 equivalents) were added to a solution of (2S)-2-amino-6,6,6-trifluoro-hexanoate (53 g, 266.10 mmol, 1 equivalent) in THF (530 mL). The mixture was stirred at 25 °C for 12 h. TLC indicated two large new spots. The reaction mixture was diluted with H₂O (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were dried over Na₂SO₄ and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO2, 0-10% EtOAc / petroleum ether) to obtain methyl (2S)-2-(tert-butoxycarbonylamino)-6,6,6-trifluorohexanoate (36 g, 117.88 mmol, 44.3% yield, 98% purity) as a colorless oil.

[0067] 1 H NMR (400MHz, DMSO- d 6) δ = 7.31 (br d, J = 8.0 Hz, 1 H), 4.05 - 3.92(m, 1 H), 3.62 (s, 3 H), 2.34 - 2.09 (m, 2 H), 1.79 - 1.59 (m, 2 H), 1.56 -1.47 (m, 2 H), 1.38 (s, 9 H).

[0068] Step 4. Synthesis of N-[(1S)-5,5,5-trifluoro-1-(hydroxymethyl)pentyl]carbamate tert-butyl ester LAH (2.23 g, 58.81 mmol, 1.1 equivalent) was added partially to a solution of methyl (2S)-2-(tert-butoxycarbonylamino)-6,6,6-trifluorohexanoate (16 g, 53.46 mmol, 1 equivalent) in THF (160 mL) at 0 °C under N2. The mixture was stirred at 25 °C for 1 hour. TLC indicated that the starting material was completely consumed. The reaction solution was quenched by slowly adding H2O (2.23 mL), 15% NaOH (2.23 mL), and H2O (6.69 mL) at 0 °C, and then filtered. The filter cake was washed with 200 mL of CH2Cl2. The combined filtrates were dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO2, 0-50% EtoAc / petroleum ether) to give N-[(1S)-5,5,5-trifluoro-1-(hydroxymethyl)pentyl]carbamate tert-butyl ester (11.5 g, 40.27 mmol, 75.3% yield, 95% purity) as a white solid.

[0069] 1 H NMR (400MHz, DMSO- d 6) δ = 6.52 (br d, J = 8.4 Hz, 1 H), 4.60 (t, J = 5.6 Hz, 1 H), 3.43 - 3.35 (m, 1 H), 3.32 - 3.27 (m, 1 H), 3.24 - 3.17 (m, 1H), 2.34 - 2.14(m, 2 H), 1.55 - 1.33 (m, 13 H).

[0070] Step 5. Synthesis of N-[(1S)-5,5,5-trifluoro-1-formyl-pentyl]carbamate tert-butyl ester DMP (19.78 g, 46.63 mmol, 14.44 mL, 1.1 equivalent) was added to a solution of N-[(1S)-5,5,5-trifluoro-1-(hydroxymethyl)pentyl]carbamate tert-butyl ester (11.5 g, 42.39 mmol, 1 equivalent) in DCM (120 mL). The mixture was stirred at 25 °C for 1 h. TLC showed that the starting material was completely consumed. The reaction mixture was diluted with DCM (50 mL) and quenched with saturated NaHCO3 (100 mL). The resulting mixture was filtered. The filtrate was extracted with DCM (50 mL x 2). The combined organic layers were dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO2, 0-30% EtoAc / petroleum ether). The compound N-[(1S)-5,5,5-trifluoro-1-formyl-pentyl]carbamate tert-butyl ester (8.87 g, 31.30 mmol, 73.8% yield, 95% purity) was obtained as a white solid.

[0071] 1 H NMR (400MHz, DMSO- d 6) δ = 9.44 (s, 1 H), 7.37 (br d, J = 7.6 Hz, 1H), 3.93 - 3.77 (m, 1 H), 2.30 - 2.19 (m, 2 H), 1.85 - 1.74 (m, 1 H), 1.53 -1.38 (m, 10 H).

[0072] Step 6. N-[(1S)-5,5,5-trifluoro-1-[hydroxy(thiazolyl-2-yl)methyl]pentyl]carbamate tert-butyl ester Synthesis n-BuLi (2.5 M in n-hexane, 32.94 mL, 2.5 equivalents) and thiazole (6.17 g, 72.47 mmol, 5.14 mL, 2.2 equivalents) were added dropwise to a solution of TMEDA (8.80 g, 75.77 mmol, 11.43 mL, 2.3 equivalents) in THF (90 mL) at -78 °C. The mixture was stirred at -78 °C for 0.5 h under N2. Then, 20 mL of THF containing N-[(1S)-5,5,5-trifluoro-1-formyl-pentyl]carbamate (8.87 g, 32.94 mmol, 1 equivalent) was added dropwise at -78 °C, and the mixture was stirred at -78 °C for 0.5 h. TLC showed that the starting material was completely consumed. The reaction mixture was poured into a saturated aqueous solution of NH4Cl (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO2, 0-40% EtoAc / petroleum ether) to give N-[(1S)-5,5,5-trifluoro-1-[hydroxy(thiazolyl-2-yl)methyl]pentyl]carbamate tert-butyl ester (6.3 g, 16.89 mmol, 51.3% yield, 95% purity) as a yellow oil.

[0073] 1 H NMR (400MHz, DMSO-d6) δ = 7.82 - 7.47 (m, 2 H), 6.36 - 6.29 (m, 1H), 4.88 - 4.72 (m, 1 H), 3.92 - 3.68 (m, 1 H), 2.38 - 2.02 (m, 2 H), 1.61 -1.17 (m,12H).

[0074] Step 7. Synthesis of (2S)-2-(tert-butoxycarbonylamino)-5-oxo-hexanoic acid benzyl ester MeLi (1.6 M in diethyl ether, 234.9 mL, 1.2 equivalent) was added dropwise to a solution of (S)-5-oxopyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-(tert-butyl) ester (100 g, 313.13 mmol, 1 equivalent) in THF (1000 mL) at -60 °C under N2. The mixture was stirred at 25 °C for 1 h under N2. TLC indicated that the starting material was completely consumed. The reaction mixture was poured into 0.25 M HCl aqueous solution (1500 mL) at 0 °C and extracted with EtOAc (500 mL x 3). The combined organic layers were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO2, 0-30% EtOAc / petroleum ether) to obtain (2S)-2-(tert-butoxycarbonylamino)-5-oxo-hexanoate benzyl ester (74.6 g, 211.30 mmol, 67.5% yield, 95% purity) as a colorless oil.

[0075] 1 H NMR (400 MHz, chloroform-d) δ = 7.34 - 7.19 (m, 5 H), 5.23 - 5.00 (m, 3H), 4.28 - 4.18 (m, 1 H), 2.51 - 2.30 (m, 2 H), 2.10 - 1.98 (m, 4 H), 1.87 -1.78 (m, 1 H), 1.38 - 1.30 (m, 9 H).

[0076] Step 8. Synthesis of (2S)-2-(tert-butoxycarbonylamino)-5-hydroxy-hexanoic acid benzyl ester NaBH4 (5.13 g, 135.66 mmol, 1.3 equivalent) was added to a solution of (2S)-2-(tert-butoxycarbonylamino)-5-oxo-hexanoate benzyl ester (35 g, 104.35 mmol, 1 equivalent) in THF (350 mL) and H2O (70 mL) at 0 °C. The mixture was stirred at 0 °C for 0.5 h. TLC indicated that the starting material was consumed. The reaction mixture was diluted with 0.5 M HCl aqueous solution (350 mL) and extracted with EtOAc (400 mL x 2). The combined organic layers were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography (SiO2, 0-30% EtOAc / petroleum ether). The compound (2S)-2-(tert-butoxycarbonylamino)-5-hydroxy-hexanoic acid benzyl ester (41 g, 115.44 mmol, 55.3% yield, 95% purity) was obtained as a yellow oil.

[0077] 1 H NMR (400 MHz, DMSO-d6) δ = 7.45 - 7.20 (m, 6 H), 5.24 - 5.01 (m, 2H), 4.50 - 4.34 (m, 1 H), 4.10 - 3.88 (m, 1 H), 3.63 - 3.49 (m, 1 H), 1.85 -1.57 (m,2H), 1.45 - 1.26 (m, 11H), 1.08 - 0.96 (m, 3H).

[0078] Step 9. Synthesis of (2S)-2-(tert-butoxycarbonylamino)-5-triisopropylsilyloxy-hexanoate benzyl ester become Imidazole (33.09 g, 486.06 mmol, 4 equivalents) and TIPSCl (23.43 g, 121.51 mmol, 1 equivalent) were added to a solution of (2S)-2-(tert-butoxycarbonylamino)-5-hydroxy-hexanoate benzyl ester (41 g, 121.51 mmol, 26.00 mL, 1 equivalent) in DMF (400 mL). The mixture was stirred at 50 °C for 12 h. LCMS showed the desired quality. The reaction mixture was diluted with 100 mL of H2O and extracted with EtOAc (100 mL x 2). The combined organic layers were dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO2, 0-10% EtOAc / petroleum ether). The compound (2S)-2-(tert-butoxycarbonylamino)-5-triisopropylsilyloxy-hexanoate benzyl ester, which was obtained as a colorless oil (39.75 g, 78.90 mmol, 64.9% yield, 98% purity).

[0079] LCMS (ESI) m / z 494.2 [M+H] + 1 H NMR (400 MHz, DMSO- d 6) δ = 7.31 - 7.14 (m, 5 H), 5.12 - 4.93 (m, 2H), 4.00 - 3.72 (m, 2 H), 1.76 - 1.48 (m, 2 H), 1.40 - 1.18 (m, 10 H), 1.00(dd, J = 3.6, 6.0 Hz, 3 H), 0.95 - 0.88 (m, 21 H).

[0080] Step 10. Synthesis of (2S)-2-(tert-butoxycarbonylamino)-5-triisopropylsilyloxyhexanoic acid Pd / C (6 g, 10.13 mmol, 10% purity) was added to a solution of (2S)-2-(tert-butoxycarbonylamino)-5-triisopropylsilyloxy-hexanoate benzyl ester (19.75 g, 40.00 mmol, 1 equivalent) in THF (200 mL) under N2 atmosphere. The suspension was degassed and purged three times with H2. The mixture was stirred at 20 °C for 1 h under H2 (15 psi). LCMS showed that the starting material was completely consumed. The reaction mixture was filtered. The filter cake was washed with MeOH (500 mL). The filtrate was concentrated under reduced pressure. The resulting crude product was purified by reversed-phase HPLC (column: Agela, C18, 20–45 μm, 330 g, 100 A. Mobile phase: A: water; B: ACN. Gradient: 5%–100% B / A over 60 min. Flow rate: 25 mL / min). The compound (2S)-2-(tert-butoxycarbonylamino)-5-triisopropylsilyloxyhexanoic acid (13.93 g, 32.79 mmol, 82% yield, 95% purity) was obtained as a yellow oil.

[0081] LCMS (ESI) m / z 426.2 [M+Na] + 1 H NMR (400 MHz, DMSO-d6) δ = 12.68 - 12.07 (m, 1 H), 7.11 - 6.93 (m,1 H), 4.02 - 3.77 (m, 2 H), 1.81 - 1.67 (m, 1 H), 1.66 - 1.43 (m, 3 H), 1.38 (s, 9 H), 1.13 - 1.09 (m, 3 H), 1.03 (s, 21 H).

[0082] Step 11. Synthesis of (2S)-2-amino-6,6,6-trifluoro-1-thiazolyl-2-ylhexane-1-ol HCl salt To a solution of N-[(1S)-5,5,5-trifluoro-1-[hydroxy(thiazol-2-yl)methyl]pentyl]carbamate tert-butyl ester (6.25 g, 17.64 mmol, 1 equivalent) in EtOAc (31 mL), HCl / EtOAc (4 M, 31 mL, 7.03 equivalents) was added. The mixture was stirred at 25 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to give (2S)-2-amino-6,6,6-trifluoro-1-thiazol-2-yl-hexane-1-ol (5.13 g, crude, HCl salt) as a yellow solid. The product was used in the next step without further purification.

[0083] Step 12. N-[(1S)-1-[[(1S)-5,5,5-trifluoro-1-[hydroxy(thiazolyl-2-yl)methyl]pentyl]amino] Synthesis of tert-butyl carbamate [formyl]-4-triisopropylsilyloxy-pentyl]carbamate A solution of (2S)-2-amino-6,6,6-trifluoro-1-thiazolyl-2-ylhexane-1-ol (5.13 g, 17.65 mmol, 1 equivalent, HCl), (2S)-2-(tert-butoxycarbonylamino)-5-triisopropylsilyloxyhexanoic acid (7.12 g, 17.65 mmol, 1 equivalent) in DMF (60 mL) and a solution of HOBt (4.77 g, 35.29 mmol, 2 equivalent), EDCI (6.77 g, 35.29 mmol, 2 equivalent) in DMF (30 mL) and TEA (7.14 g, 70.58 mmol, 9.82 mL, 4 equivalent) was added to a solution of (2S)-2-amino-6,6,6-trifluoro-1-thiazolyl-2-ylhexane-1-ol (5.13 g, 17.65 mmol, 1 equivalent) in DMF (60 mL) and TEA (7.14 g, 70.58 mmol, 9.82 mL, 4 equivalent) at 0 °C. The mixture was stirred at 25 °C for 12 h. LCMS showed that the target product was detected. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with LiCl (100 mL) (5 wt% in water), dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO2, 0-40% EtoAc / petroleum ether) to give N-[(1S)-1-[[(1S)-5,5,5-trifluoro-1-[hydroxy(thiazolyl-2-yl)methyl]pentyl]carbamoyl]-4-triisopropylsilyloxy-pentyl]carbamate tert-butyl carbamate (7 g, 10.39 mmol, 58.9% yield, 95% purity) as a white solid.

[0084] LCMS (ESI) m / z 640.7 [M+H] + 1H NMR (400MHz, DMSO-d6) δ = 7.77 - 7.45 (m, 3 H), 6.98 - 6.73 (m, 1H), 6.59 - 6.38 (m, 1 H), 4.91 - 4.69 (m, 1 H), 4.30 - 4.08 (m, 1 H), 3.91 -3.76 (m, 2 H), 2.37 - 2.08 (m, 2 H), 1.55 - 1.27 (m, 15 H), 1.07 - 1.00 (m, 24 H).

[0085] Step 13. (2S)-2-amino-5-hydroxy-N-[(1S)-5,5,5-trifluoro-1-[hydroxy(thiazol-2-yl)methyl] Synthesis of pentylhexylamide HCl salt HCl / EtOAc (4 M, 30 mL, 12.80 equivalents) was added to a solution of N-[(1S)-1-[[(1S)-5,5,5-trifluoro-1-[hydroxy(thiazol-2-yl)methyl]pentyl]carbamoyl]-4-triisopropylsilyloxy-pentyl]carbamate tert-butyl ester (6 g, 9.38 mmol, 1 equivalent) in EtOAc (30 mL). The mixture was stirred at 25 °C for 2 h. The target product was detected by LCMS. The mixture was concentrated under reduced pressure to give (2S)-2-amino-5-hydroxy-N-[(1S)-5,5,5-trifluoro-1-[hydroxy(thiazol-2-yl)methyl]pentyl]hexamamide (3.94 g, crude, HCl) as a white solid. The product was used in the next step without further purification.

[0086] LCMS (ESI) m / z 384.1 [M+H] + Step 14. Synthesis of methyl 2-(4-fluorophenyl)thiazole-5-carboxylate (4-fluorophenyl)boronic acid (7.56 g, 54.04 mmol, 1 equivalent) and Na₂CO₃ (14.32 g, 135.10 mmol, 3 equivalent) were added to a solution of methyl 2-bromothiazol-5-carboxylate (10 g, 45.03 mmol, 1 equivalent) in dioxane (100 mL) and H₂O (10 mL). The reaction mixture was degassed and purged three times with N₂, and then Pd(dppf)Cl₂ (1.65 g, 2.25 mmol, 0.05 equivalent) was added. The reaction mixture was stirred at 80 °C for 12 h under N₂ atmosphere. The target product was indicated by LCMS. The reaction mixture was diluted with H₂O (150 mL) and extracted with EtoAc (150 mL x 3). The combined organic layers were dried over Na₂SO₄ and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO2, 0-30% EtOAc / petroleum ether) to give methyl 2-(4-fluorophenyl)thiazolium-5-carboxylate as a white solid (3.60 g, 15.02 mmol, 32.7% yield, 99% purity).

[0087] LCMS (ESI) m / z 237.9 [M+H] + 1H NMR (400MHz, DMSO-d6) δ = 8.50 (s, 1 H), 8.13 - 8.05 (m, 2 H), 7.43 - 7.34 (m, 2 H), 3.90 - 3.85 (m, 3 H).

[0088] Step 15. Synthesis of 2-(4-fluorophenyl)thiazol-5-carboxylic acid A solution of methyl 2-(4-fluorophenyl)thiazol-5-carboxylate (3.58 g, 15.09 mmol, 1 equivalent) in THF (36 mL) was added with H₂O (36 mL) and LiOH·H₂O (6.04 g, 144.00 mmol, 9.54 equivalents). The reaction mixture was stirred at 25 °C for 1 h under a nitrogen atmosphere. LC-MS showed the desired mass. 6 M HCl was added to the reaction mixture until pH = 5, and then the mixture was extracted with EtoAc (20 mL x 3). The combined organic layers were dried over Na₂SO₄ and filtered. The filtrate was concentrated under reduced pressure to give 2-(4-fluorophenyl)thiazol-5-carboxylic acid (3.34 g, 13.77 mmol, 91.2% yield, 92% purity) as a white solid. The product was used in the next step without further purification.

[0089] LCMS (ESI) m / z 223.9 [M+H] + 1H NMR (400MHz, DMSO-d6) δ = 14.09 - 13.16 (m, 1 H), 8.42 (s, 1 H), 8.13 - 8.03 (m, 2 H), 7.43 - 7.35 (m, 2H).

[0090] Step 16. 2-(4-fluorophenyl)-N-[(1S)-4-hydroxy-1-[[(1S)-5,5,5-trifluoro-1-[hydroxy(thiazole- Synthesis of 2-yl)methyl]pentyl]carbamoyl]pentyl]thiazole-5-carboxamide A solution of (2S)-2-amino-5-hydroxy-N-[(1S)-5,5,5-trifluoro-1-[hydroxy(thiazol-2-yl)methyl]pentyl]hexamethyleneamide (3.94 g, 9.38 mmol, 1 equivalent, HCl), 2-(4-fluorophenyl)thiazol-5-carboxylic acid (2.09 g, 9.38 mmol, 1 equivalent) in DMF (40 mL) was added to a solution of HOBt (2.54 g, 18.77 mmol, 2 equivalent), EDCI (3.60 g, 18.77 mmol, 2 equivalent) in DMF (10 mL), and TEA (7.60 g, 75.07 mmol, 10.45 mL, 8 equivalent). The mixture was stirred at 25 °C for 2 h. LC-MS showed the desired quality. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with LiCl (100 mL) (5 wt% in water), dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO2, 0-10% MeOH / DCM). The compound 2-(4-fluorophenyl)-N-[(1S)-4-hydroxy-1-[[(1S)-5,5,5-trifluoro-1-[hydroxy(thiazol-2-yl)methyl]pentyl]carbamoyl]pentyl]thiazol-5-carboxamide (3.41 g, 5.50 mmol, 58.7% yield, 95% purity) was obtained as a yellow solid.

[0091] LCMS (ESI) m / z 589.3 [M+H] + 1 H NMR (400MHz, DMSO- d 6) δ = 8.73 (dd, J = 4.4, 8.0 Hz, 1 H), 8.55 (d, J= 2.8 Hz, 1 H), 8.07 - 7.92 (m, 2 H), 7.72 - 7.55 (m, 2 H), 7.46 - 7.26 (m,2 H), 6.57 -6.35 (m, 1 H), 4.93 - 4.71 (m, 1 H), 4.51 - 4.05 (m, 3 H), 3.55(td, J = 4.8, 10.0 Hz, 1 H), 2.34 - 2.05 (m, 2 H), 1.84 - 1.17 (m, 8 H), 1.10 - 0.91 (m, 3 H).

[0092] Step 17. 2-(4-fluorophenyl)-N-[(1S)-4-hydroxy-1-[[(1S)-5,5,5-trifluoro-1-(thiazole-2-carbonyl)] Synthesis of [5-carbamoyl]pentyl]thiazole-5-carboxamide MnO2 (17.58 g, 202.16 mmol, 35 equivalents) was added to a solution of 2-(4-fluorophenyl)-N-[(1S)-4-hydroxy-1-[[(1S)-5,5,5-trifluoro-1-[hydroxy(thiazol-2-yl)methyl]pentyl]carbamoyl]pentyl]thiazol-5-carboxamide (3.4 g, 5.78 mmol, 1 equivalent) in DCM (100 mL). The mixture was stirred at 25 °C for 2 h. The target product was detected by LCMS. The reaction mixture was filtered and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (column: Ager C18, 20–45 μm, 120 g, 100 A. Mobile phase: A: water; B: MeCN. Gradient: 5%–55% B / A over 60 min. Flow rate: 25 mL / min) to give the title compound 2-(4-fluorophenyl)-N-[(1S)-4-hydroxy-1-[[(1S)-5,5,5-trifluoro-1-(thiazol-2-carbonyl)pentyl]carbamoyl]pentyl]thiazol-5-carboxamide (2.24 g, 3.81 mmol, 66% yield, 99% purity) as a white solid.

[0093] LCMS (ESI) m / z 587.1 [M+H] + 1H NMR (400MHz, DMSO-d6) δ = 8.80 - 8.72 (m, 1 H), 8.68 - 8.52 (m, 2H), 8.26 (d, J = 3.2 Hz, 1 H), 8.19 (d, J = 3.2 Hz, 1 H), 8.09 - 7.99 (m, 2H), 7.36 (t, J = 8.8 Hz, 2 H), 5.40 (m, 1 H), 4.56 - 4.45 (m, 2 H), 3.60 (td,J = 5.6, 11.6 Hz, 1 H), 2.39 - 2.23 (m, 2 H), 2.01 - 1.60 (m, 6 H), 1.49 -1.34 (m, 2 H), 1.05 (dd, J = 2.0, 6.0 Hz, 3 H).

[0094] Example 2: 2-(4-fluorophenyl)-N-((2S)-1-(((S)-4-(4-fluorophenyl)-1-oxo-1-(thiazol-2-yl)butan-2-yl)amino)-5-hydroxy-1-oxohexane-2-yl)thiazol-5-carboxamide (ClpP-1629) Step 1. (2S,5R)-2-[2-(4-fluorophenyl)ethyl]-5-isopropyl-3,6-dimethoxy-2,5-dihydropyridine Synthesis of azines (2R)-2-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine (20.41 g, 110.81 mmol, 19.82 mL, 0.9 equivalent) was added dropwise to a solution of LDA (2 M in THF, 73.87 mL, 1.2 equivalent) in THF (100 mL), and the mixture was purged three times with N2 at -78 °C. After 30 minutes, a solution of 1-(2-bromoethyl)-4-fluorobenzene (25 g, 123.12 mmol, 17.24 mL, 1 equivalent) in THF (150 mL) was added to the above solution at -78 °C. The mixture was stirred at 20 °C for 12 hours under a N2 atmosphere. TLC indicated a large new spot. The reaction mixture was quenched by adding saturated NH4Cl aqueous solution (50 mL), diluted with water (100 mL), and extracted with EtOAc (200 mL x 3). The combined organic layers were dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO2, 0-10% EtoAc / petroleum ether). The compound (2S,5R)-2-[2-(4-fluorophenyl)ethyl]-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine (38 g, 117.83 mmol, 47.9% yield, 95% purity) was obtained as a white solid.

[0095] 1 H NMR (400MHz, chloroform-) d ) δ = 7.15 (dd, J = 5.6, 8.4 Hz, 2 H), 7.00 -6.91 (m, 2 H), 4.07 - 4.01 (m, 1 H), 3.97 (t, J = 3.2 Hz, 1 H), 3.71 (d, J =3.2 Hz, 6 H), 2.70 - 2.51 (m, 2 H), 2.34 - 2.21 (m, 1 H), 2.20 - 2.09 (m, 1H), 2.03 - 1.91 (m, 1 H), 1.06 (d, J = 6.8 Hz, 3 H), 0.71 (d, J = 6.8 Hz, 3H).

[0096] Step 2. Synthesis of (2S)-2-amino-4-(4-fluorophenyl)butyrate methyl ester TFA salt TFA (52.83 g, 463.35 mmol, 34.31 mL, 5.26 equivalents) was added to a solution of (2S,5R)-2-[2-(4-fluorophenyl)ethyl]-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine (27 g, 88.13 mmol, 1 equivalent) in MeCN (150 mL) and H2O (75 mL). The mixture was stirred at 50 °C for 12 h. LC-MS showed the mass. The reaction mixture was concentrated to dryness under reduced pressure. Methyl (2S)-2-amino-4-(4-fluorophenyl)butyrate (28 g, crude, TFA salt) was obtained as a yellow oil. The product was used in the next step without further purification.

[0097] LCMS (ESI) m / z 212.2 [M+H] + Step 3. Synthesis of methyl (2S)-2-(tert-butoxycarbonylamino)-4-(4-fluorophenyl)butanoate DIEA (46.49 g, 359.72 mmol, 62.66 mL, 3 equivalents) and Boc₂O (52.34 g, 239.81 mmol, 55.09 mL, 2 equivalents) were added to a solution of (2S)-2-amino-4-(4-fluorophenyl)butyrate (39 g, 119.91 mmol, 1 equivalent, TFA salt) in THF (400 mL). The mixture was stirred at 20 °C for 12 h. LC-MS showed the desired quality. The reaction mixture was diluted with water (500 mL) and extracted with EtOAc (500 mL × 2). The combined organic layers were dried over Na₂SO₄ and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO₂, 0-30% ethyl acetate / petroleum ether). The compound (2S)-2-(tert-butoxycarbonylamino)-4-(4-fluorophenyl)butyrate methyl ester (38 g, 109.85 mmol, 91.6% yield, 90% purity) was obtained as a colorless oil.

[0098] LCMS (ESI) m / z 212.2 [M-Boc] + 1 H NMR (400MHz, chloroform-) d ) δ = 7.13 (dd, J = 5.6, 8.4 Hz, 2 H), 6.97 (t, J = 8.8 Hz, 2 H), 5.07 (br d, J= 6.8 Hz, 1 H), 4.34 (br d, J = 5.0 Hz, 1 H), 3.74 -3.68 (m, 3 H), 2.72 - 2.57 (m, 2 H), 2.18 - 2.07 (m, 1 H), 1.98 - 1.84 (m, 1 H), 1.46 (s, 9 H).

[0099] Step 4. Synthesis of N-[(1S)-3-(4-fluorophenyl)-1-(hydroxymethyl)propyl] tert-butyl carbamate LAH (2.63 g, 69.38 mmol, 1.2 equivalents) was added to a solution of methyl (2S)-2-(tert-butoxycarbonylamino)-4-(4-fluorophenyl)butyrate (18 g, 57.81 mmol, 1 equivalent) in THF (200 mL) at 0 °C. The mixture was stirred at 20 °C for 1 hour. TLC indicated a large new spot with high polarity. The reaction solution was quenched at 0 °C with 2.9 mL of water and 2.9 mL of 15% NaOH aqueous solution, followed by the addition of 9 mL of water. The precipitate was filtered through a Celite filter. The filter cake was washed with DCM (3 x 200 mL). The combined filtrates were dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give N-[(1S)-3-(4-fluorophenyl)-1-(hydroxymethyl)propyl] tert-butyl carbamate (13 g, 43.59 mmol, 75.4% yield, 95% purity) as a white solid. The product was used in the next step without further purification.

[0100] 1 H NMR (400MHz, DMSO- d 6) δ = 7.21 (dd, J = 5.6, 8.4 Hz, 2 H), 7.13 -7.03 (m, 2 H), 6.58 (br d, J = 8.0 Hz, 1 H), 4.72 - 4.44 (m, 1 H), 3.32 -3.29 (m, 1 H), 3.27- 3.15 (m, 2 H), 2.67 - 2.54 (m, 1 H), 2.45 (br s, 1 H),1.86 - 1.64 (m, 1 H), 1.58 - 1.47 (m, 1 H), 1.41 - 1.36 (m, 9 H).

[0101] Step 5. Synthesis of N-[(1S)-3-(4-fluorophenyl)-1-formylpropyl]carbamate tert-butyl ester DMP (21.41 g, 50.47 mmol, 15.63 mL, 1.1 equivalent) was added to a solution of N-[(1S)-3-(4-fluorophenyl)-1-(hydroxymethyl)propyl]carbamate tert-butyl ester (13 g, 45.88 mmol, 1 equivalent) in DCM (200 mL) at 0 °C. The mixture was stirred at 20 °C for 1 h. TLC indicated a large new spot with low polarity. The reaction mixture was diluted with 300 mL of DCM and washed with saturated NaHCO3 (500 mL x 3). The organic layer was dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO2, 0-30% EtoAc / petroleum ether). The compound N-[(1S)-3-(4-fluorophenyl)-1-formylpropyl]carbamate tert-butyl ester (6.8 g, 21.75 mmol, 47.4% yield, 90% purity) was obtained as a colorless oil.

[0102] 1 H NMR (400MHz, DMSO- d 6) δ = 9.44 (s, 1 H), 7.42 (br d, J = 7.2 Hz, 1H), 7.28 - 7.19 (m, 2 H), 7.10 (br t, J = 8.8 Hz, 2 H), 3.86 - 3.68 (m, 1 H), 2.68 - 2.55 (m, 2 H), 1.99 - 1.92 (m, 1 H), 1.76 - 1.64 (m, 1 H), 1.44 - 1.37 (m, 9 H).

[0103] Step 6. N-[(1S)-3-(4-fluorophenyl)-1-[hydroxy(thiazolyl-2-yl)methyl]propyl]tert-butyl carbamate Ester Synthesis n-BuLi (2.5 M in n-hexane, 22.39 mL, 2.5 equivalents) and thiazole (4.19 g, 49.27 mmol, 3.50 mL, 2.2 equivalents) were added dropwise to a solution of TMEDA (5.99 g, 51.51 mmol, 7.77 mL, 2.3 equivalents) in THF (50 mL) at -78 °C. The mixture was stirred at -78 °C for 0.5 h under N2 atmosphere. Then, a solution of N-[(1S)-3-(4-fluorophenyl)-1-formylpropyl]carbamate tert-butyl ester (6.3 g, 22.39 mmol, 1 equivalent) in THF (50 mL) was added dropwise to the solution and stirred at -78 °C for 0.5 h under N2 atmosphere. TLC indicated a large new spot. The reaction mixture was poured into a saturated aqueous solution of NH4Cl (20 mL) and extracted with EtOAc (100 mL x 2). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO2, 0-30% ethyl acetate / petroleum ether). The compound N-[(1S)-3-(4-fluorophenyl)-1-[hydroxy(thiazolyl-2-yl)methyl]propyl]carbamate tert-butyl ester (5.3 g, 13.74 mmol, 61.3% yield, 95% purity) was obtained as a yellow oil.

[0104] LCMS (ESI) m / z 367.1 [M+H] + 1 H NMR (400MHz, DMSO- d 6) δ = 7.75 - 7.67 (m, 1 H), 7.63 - 7.51 (m, 1H), 7.22 - 7.02 (m, 4 H), 6.28 (dd, J = 2.0, 5.2 Hz, 1 H), 4.94 - 4.74 (m, 1H), 3.88 - 3.67(m, 1 H), 3.38 (br s, 1 H), 2.70 - 2.56 (m, 1 H), 2.48 - 2.29(m, 1 H), 1.79 - 1.49 (m, 2 H), 1.42 - 1.27 (m, 9 H).

[0105] Step 7. Synthesis of (2S)-2-amino-4-(4-fluorophenyl)-1-thiazolyl-2-yl-butane-1-ol HCl salt To a solution of N-[(1S)-3-(4-fluorophenyl)-1-[hydroxy(thiazol-2-yl)methyl]propyl]carbamate tert-butyl ester (5.25 g, 14.33 mmol, 1 equivalent) in EtOAc (25 mL), HCl / EtOAc (4 M in EtOAc, 25 mL, 6.98 equivalents) was added. The mixture was stirred at 25 °C for 1 hour. LC-MS showed the desired mass. The reaction mixture was concentrated under reduced pressure to give (2S)-2-amino-4-(4-fluorophenyl)-1-thiazol-2-yl-butane-1-ol (4.3 g, crude, HCl salt) as a white solid. The product was used in the next step without further purification.

[0106] LCMS (ESI) m / z 267.0 [M+H] + Step 8. N-[(1S)-1-[[(1S)-3-(4-fluorophenyl)-1-[hydroxy(thiazolyl-2-yl)methyl]propyl]amino Synthesis of tert-butyl carbamate [formyl]-4-triisopropylsilyloxy-pentyl]carbamate Add EDCI (8.17 g, 42.60 mmol, 3 equivalents) and HOBt (5.76 g, 42.60 mmol, 3 equivalents) and TEA (8.62 g, 85.21 mmol, 11.86 mL, 6 equivalents) to a solution of (2S)-2-amino-4-(4-fluorophenyl)-1-thiazolyl-2-yl-butane-1-ol (4.3 g, 14.20 mmol, 1 equivalent) in DMF (100 mL). Stir the mixture at 25 °C for 12 h. LC-MS showed the desired quality. Dilute the reaction mixture with 100 mL of water and extract with EtOAc (150 mL x 3). The combined organic layers were washed with LiCl (5 wt% in water, 150 mL x 2). The organic layers were dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO2, 0-30% ethyl acetate / petroleum ether). The compound N-[(1S)-1-[[(1S)-3-(4-fluorophenyl)-1-[hydroxy(thiazolyl-2-yl)methyl]propyl]carbamoyl]-4-triisopropylsilyloxy-pentyl]carbamate tert-butyl ester (6.2 g, 9.32 mmol, 65.6% yield, 98% purity) was obtained as a yellow oil.

[0107] LCMS (ESI) m / z 652.8 [M+H] + 1H NMR (400MHz, DMSO- d 6) δ = 7.73 - 7.66 (m, 1 H), 7.60 - 7.53 (m, 1H), 7.24 - 6.81 (m, 5 H), 6.60 - 6.28 (m, 1 H), 4.97 - 4.72 (m, 1 H), 4.12(br s, 1 H),3.85 (br dd, J = 5.6, 11.6 Hz, 2 H), 3.42 - 3.34 (m, 1 H), 2.58(br d, J = 9.6 Hz, 2 H), 1.91 - 1.42 (m, 6 H), 1.37 (br s, 9 H), 1.10 - 1.05(m, 3 H), 1.01 (d, J = 5.2 Hz, 21 H).

[0108] Step 9. (2S)-2-amino-N-((2S)-4-(4-fluorophenyl)-1-hydroxy-1-(thiazolyl-2-yl)butane-2- Synthesis of 5-hydroxyhexamethylene amide HCl salt To a solution of N-[(1S)-1-[[(1S)-3-(4-fluorophenyl)-1-[hydroxy(thiazol-2-yl)methyl]propyl]carbamoyl]-4-triisopropylsilyloxy-pentyl]carbamate tert-butyl (4.6 g, 7.06 mmol, 1 equivalent) in EtOAc (100 mL), HCl / EtOAc (4 M, 46.00 mL, 26.08 equivalent) was added. The mixture was stirred at 20 °C for 1 hour. LC-MS showed the desired mass. The reaction mixture was concentrated under reduced pressure to give (2S)-2-amino-N-((2S)-4-(4-fluorophenyl)-1-hydroxy-1-(thiazol-2-yl)butan-2-yl)-5-hydroxyhexamamide (3 g, crude, HCl salt) as a white solid. The product was used in the next step without further purification.

[0109] LCMS (ESI) m / z 396.3 [M+H] + Step 10. 2-(4-fluorophenyl)-N-[(1S)-1-[[(1S)-3-(4-fluorophenyl)-1-[hydroxy(thiazol-2-yl)] Synthesis of [methyl]propyl]carbamoyl]-4-hydroxy-pentyl]thiazole-5-carboxamide Add EDCI (3.99 g, 20.84 mmol, 3 equivalents) and HOBt (2.82 g, 20.84 mmol, 3 equivalents) and TEA (4.22 g, 41.67 mmol, 5.80 mL, 6 equivalents) to a solution of (2S)-2-amino-N-((2S)-4-(4-fluorophenyl)-1-hydroxy-1-(thiazol-2-yl)butan-2-yl)-5-hydroxyhexamethylenetetramine (3 g, 6.95 mmol, 1 equivalent) in DMF (50 mL) to a solution of (2S)-2-amino-N-((2S)-4-(4-fluorophenyl)-1-hydroxy-1-(thiazol-2-yl)butan-2-yl)-5-hydroxyhexamethylenetetramine (1.55 g, 6.95 mmol, 1 equivalent) in DMF (50 mL). Stir the mixture at 25 °C for 12 h. LC-MS showed the desired quality. Dilute the reaction mixture with water (50 mL) and extract with EtOAc (100 mL × 3). The combined organic layers were washed with LiCl (5 wt% in water, 50 mL x 2). The organic layers were dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO2, 0-10% MeOH / DCM). The compound 2-(4-fluorophenyl)-N-[(1S)-1-[[(1S)-3-(4-fluorophenyl)-1-[hydroxy(thiazol-2-yl)methyl]propyl]carbamoyl]-4-hydroxy-pentyl]thiazol-5-carboxamide (2.5 g, 4.04 mmol, 58.1% yield, 97% purity) was obtained as a white solid.

[0110] LCMS (ESI) m / z 601.5 [M+H] + 1 H NMR (400MHz, DMSO- d6) δ = 8.83 - 8.71 (m, 1 H), 8.62 - 8.54 (m, 1H), 8.13 - 7.97 (m, 2 H), 7.82 - 7.68 (m, 1 H), 7.64 - 7.57 (m, 1 H), 7.42 -7.33 (m, 2 H),7.25 - 6.99 (m, 4 H), 6.62 - 6.28 (m, 1 H), 4.97 - 4.78 (m, 1H), 4.51 - 4.31 (m, 2 H), 4.28 - 4.10 (m, 1 H), 3.59 (m, 1 H), 3.35 (br s, 1H),2.65 - 2.52 (m, 2H), 1.91 - 1.51 (m, 4 H), 1.45 - 1.23 (m, 2 H), 1.10 -1.00 (m, 3 H).

[0111] Step 11. 2-(4-fluorophenyl)-N-[(1S)-1-[[(1S)-3-(4-fluorophenyl)-1-(thiazol-2-carbonyl)propane] Synthesis of [carbamoyl]-4-hydroxy-pentyl]thiazole-5-carboxamide MnO2 (16.93 g, 194.77 mmol, 30 equivalents) was added to a solution of 2-(4-fluorophenyl)-N-[(1S)-1-[[(1S)-3-(4-fluorophenyl)-1-[hydroxy(thiazol-2-yl)methyl]propyl]carbamoyl]-4-hydroxy-pentyl]thiazol-5-carboxamide (3.9 g, 6.49 mmol, 1 equivalent) in DCM (50 mL). The mixture was stirred at 20 °C for 1 h. LC-MS showed the desired mass. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by SFC (column: Daicel CHIRALPAK AS 250 mm * 50 mm, 10 μm. Mobile phase: A: CO2, B: IPA. Gradient: isocratic 50% B / A, duration 30 min. Flow rate: 140 mL / min). The title compound 2-(4-fluorophenyl)-N-[(1S)-1-[[(1S)-3-(4-fluorophenyl)-1-(thiazol-2-carbonyl)propyl]carbamoyl]-4-hydroxy-pentyl]thiazol-5-carboxamide (1.5 g, 2.51 mmol, 38.6% yield, 100% purity) was obtained as a white solid.

[0112] LCMS (ESI) m / z 599.1 [M+H] + 1 H NMR (400MHz, DMSO- d6) δ = 8.80 (t, J = 6.8 Hz, 1H), 8.68 (dd, J =7.2, 9.6 Hz, 1 H), 8.60 (d, J = 1.2 Hz, 1 H), 8.24 (d, J = 3.2 Hz, 1 H), 8.16(d, J = 3.2 Hz, 1 H), 8.11 - 8.00 (m, 2 H), 7.43 - 7.32 (m, 2 H), 7.24 (dd, J = 5.6, 8.4 Hz, 2 H), 7.04 (t, J = 8.8 Hz, 2 H), 5.40 - 5.29 (m, 1 H), 4.59 -4.46 (m, 2 H), 3.64 (m, 1 H), 2.88 - 2.61 (m, 2 H), 2.26 - 2.14 (m, 1 H),2.02 - 1.62 (m, 3 H), 1.55 - 1.34 (m, 2 H), 1.08 (dd, J = 2.0, 6.1 Hz, 3 H).

[0113] Example 3: 2-(3-chloro-5-fluorophenyl)-N-((2S)-5-hydroxy-1-oxo-1-(((S)-5,5,5-trifluoro-1-oxo-1-(thiazol-2-yl)pentan-2-yl)amino)hexan-2-yl)oxazol-5-carboxamide (ClpP-1767) Step 1. (2R,5S)-2-isopropyl-3,6-dimethoxy-5-(3,3,3-trifluoropropyl)-2,5-dihydropyrazine Synthesis LDA (2 M in THF, 56.26 mL, 1.2 equivalents) was added to a solution of (2R)-2-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine (15.55 g, 84.39 mmol, 15.12 mL, 0.9 equivalents) in THF (150 mL) at -78 °C. The mixture was stirred at -78 °C for 30 min. THF (50 mL) containing 1,1,1-trifluoro-3-iodopropane (21 g, 93.77 mmol, 10.99 mL, 1 equivalent) was added to the above solution. The reaction mixture was stirred and heated to 10 °C for 11.5 h under a N2 atmosphere. LC-MS showed the desired quality. The reaction mixture was diluted with saturated NH4Cl aqueous solution (500 mL) and extracted with EtOAc (300 mL x 3). The combined organic layers were dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography (SiO2, 0-10% ethyl acetate / petroleum ether) to give the compound (2R,5S)-2-isopropyl-3,6-dimethoxy-5-(3,3,3-trifluoropropyl)-2,5-dihydropyrazine (33.2 g, 106.6 mmol, 56.8% yield, 90% purity) as a yellow oil.

[0114] LCMS (ESI) m / z 281.2 [M+H] + 1H NMR (400MHz, DMSO-d6) δ = 4.15 - 4.06 (m, 1 H), 4.00 - 3.91 (m, 1H), 3.69 - 3.58 (m, 6 H), 2.44 - 2.13 (m, 3 H), 2.07 - 1.96 (m, 1 H), 1.82 -1.66 (m, 1 H), 0.99 (d, J = 6.8 Hz, 3 H), 0.67 - 0.60 (m, 3 H).

[0115] Step 2. Synthesis of (2S)-2-amino-5,5,5-trifluoro-valerate methyl ester (TFA) salt TFA (76.75 g, 673.11 mmol, 50 mL, 5.68 equivalents) was added to a solution of (2R,5S)-2-isopropyl-3,6-dimethoxy-5-(3,3,3-trifluoropropyl)-2,5-dihydropyrazine (33.2 g, 118.45 mmol, 1 equivalent) in ACN (200 mL), H₂O (100 mL). The mixture was stirred at 50 °C for 12 hours. The resulting reaction mixture was concentrated under reduced pressure to give methyl (2S)-2-amino-5,5,5-trifluorovalerate (35.4 g, crude, TFA) as a yellow oil. The product was used in the next step without further purification.

[0116] Step 3. Synthesis of methyl (2S)-2-(tert-butoxycarbonylamino)-5,5,5-trifluorovalerate DIEA (45.88 g, 354.99 mmol, 61.83 mL, 3 equivalents) and Boc₂O (56.81 g, 260.32 mmol, 59.80 mL, 2.2 equivalents) were added to a solution of (2S)-2-amino-5,5,5-trifluorovalerate (35.4 g, 118.33 mmol, 1 equivalent) in THF (400 mL). The reaction mixture was stirred at 25 °C for 12 h, diluted with water (100 mL), and extracted with EtOAc (100 mL x 3). The combined organic layers were dried over Na₂SO₄ and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography (SiO2, 0-10% ethyl acetate / petroleum ether) to give the colorless oily compound (2S)-2-(tert-butoxycarbonylamino)-5,5,5-trifluorovalerate methyl ester (35.8 g, 112.9 mmol, 95.4% yield, 90% purity).

[0117] 1H NMR (400MHz, DMSO-d6) δ = 7.52 - 7.17 (m, 1 H), 4.14 - 4.03 (m, 1H), 3.70 - 3.60 (m, 3 H), 2.46 - 2.18 (m, 2 H), 1.95 - 1.73 (m, 2 H), 1.38(s,9H).

[0118] Step 4. Synthesis of N-[(1S)-4,4,4-trifluoro-1-(hydroxymethyl)butyl]carbamate tert-butyl ester LAH (2.5 M in THF, 49.70 mL, 1.1 equivalent) was added to a solution of (2S)-2-(tert-butoxycarbonylamino)-5,5,5-trifluorovalerate (35.8 g, 112.95 mmol, 1 equivalent) in THF (360 mL) at 0 °C. The resulting mixture was stirred at 15 °C for 1 h. TLC indicated a new spot. The reaction solution was quenched by adding water (4.72 mL), 15% NaOH aqueous solution (4.72 mL in water), and water (14.16 mL) at 0 °C, and then filtered. The filter cake was further washed with DCM (300 mL x 3). The combined filtrates were dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography (SiO2, 0-10% ethyl acetate / petroleum ether) to give N-[(1S)-4,4,4-trifluoro-1-(hydroxymethyl)butyl]carbamate tert-butyl ester (22.3 g, 65.0 mmol, 57.5% yield, 75% purity) as a white solid.

[0119] 1H NMR (400MHz, DMSO-d6) δ = 6.66 (d, J = 8.4 Hz, 1 H), 4.72 (t, J =5.6 Hz, 1 H), 3.41 (m, 1 H), 3.38 - 3.34 (m, 1 H), 3.28 - 3.17 (m, 1 H), 2.28-2.12 (m, 2 H), 1.81-1.70 (m, 1 H), 1.57-1.42 (m, 1 H), 1.38 (s, 9 H).

[0120] Step 5. Synthesis of N-[(1S)-4,4,4-trifluoro-1-formyl-butyl]carbamate tert-butyl ester DMP (40.44 g, 95.35 mmol, 29.54 mL, 1.1 equivalent) was added to a solution of N-[(1S)-4,4,4-trifluoro-1-(hydroxymethyl)butyl]carbamate (22.3 g, 86.69 mmol, 1 equivalent) in DCM (400 mL) at 0 °C. The mixture was stirred at 15 °C for 1 hour. TLC indicated a large new spot. The reaction mixture was added to saturated NaHCO3 (400 mL) at 0 °C and quenched with DCM (300 mL x 3). The combined organic layers were dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give N-[(1S)-4,4,4-trifluoro-1-formyl-butyl]carbamate (22 g, crude) as a colorless oil. The product was used in the next step without further purification.

[0121] Step 6. N-[(1S)-4,4,4-trifluoro-1-[hydroxy(thiazolyl-2-yl)methyl]butyl]carbamate tert-butyl Synthesis n-BuLi (2.5 M in n-hexane, 34.48 mL, 2.5 equivalents) and thiazole (6.46 g, 75.85 mmol, 5.39 mL, 2.2 equivalents) were added dropwise to a solution of TMEDA (9.22 g, 79.30 mmol, 11.97 mL, 2.3 equivalents) in THF (60 mL). The mixture was stirred at -78 °C under N2 for 0.5 h. Then, THF (50 mL) containing N-[(1S)-4,4,4-trifluoro-1-formyl-butyl]carbamate (11 g, 34.48 mmol, 1 equivalent) was added dropwise at -78 °C. The product was then stirred at -78 °C for 0.5 h. LC-MS showed the desired quality. The reaction mixture was poured into saturated NH4Cl (100 mL in water) at 0 °C and extracted with EtOAc (150 mL x 2). The combined organic layers were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO2, 0-50% EtOAc / petroleum ether) to give N-[(1S)-4,4,4-trifluoro-1-[hydroxy(thiazolyl-2-yl)methyl]butyl]carbamate tert-butyl ester (12 g, 31.7 mmol, 46.0% yield, 90% purity) as a yellow oil.

[0122] LCMS (ESI) m / z 341.2 [M+H] + 1H NMR (400MHz, DMSO-d6) δ = 7.74 (s, 1 H), 7.62 (s, 1 H), 6.56 -6.46 (m, 1 H), 6.45 - 6.37 (m, 1 H), 4.94 - 4.77 (m, 1 H), 3.95 - 3.76 (m, 1H), 2.28 - 2.10 (m, 2 H), 1.83 - 1.61 (m, 1 H), 1.59 - 1.46 (m, 1 H), 1.33 (br d, J = 10.4 Hz, 9 H).

[0123] Step 7. Synthesis of (2S)-2-amino-5,5,5-trifluoro-1-thiazolyl-2-ylpentane-1-ol HCl salt Add HCl-containing EtOAc (4 M, 50 mL, 7.24 equivalents) to a solution of N-[(1S)-4,4,4-trifluoro-1-[hydroxy(thiazol-2-yl)methyl]butyl]carbamate (9.4 g, 27.62 mmol, 1 equivalent) in EtOAc (50 mL). Stir the mixture at 25 °C for 1 hour. Concentrate the reaction mixture under reduced pressure to give (2S)-2-amino-5,5,5-trifluoro-1-thiazol-2-yl-pentan-1-ol (7.64 g, crude, HCl) as a white solid. The product was used in the next step without further purification.

[0124] LCMS (ESI) m / z 241.2.1 [M+H] + Step 8. N-[(1S)-1-[[(1S)-4,4,4-trifluoro-1-[hydroxy(thiazolyl-2-yl)methyl]butyl]aminomethyl Synthesis of tert-butyl [acyl]-4-triisopropylsilyloxy-pentyl]carbamate Add EDCI (10.97 g, 57.23 mmol, 2.1 equivalents), HOBt (7.73 g, 57.23 mmol, 2.1 equivalents), and TEA (8.27 g, 81.76 mmol, 11.38 mL, 3 equivalents) to a solution of (2S)-2-amino-5,5,5-trifluoro-1-thiazo-2-yl-pentane-1-ol (7.54 g, 27.25 mmol, 1 equivalent) in DMF (70 mL). The resulting mixture was stirred at 25 °C for 12 h. LCMS showed the desired mass. The reaction solution was diluted with EtOAc (150 mL) and washed with H2O (50 mL). The organic layer was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO2, 0-30% ethyl acetate / petroleum ether) to give N-[(1S)-1-[[(1S)-4,4,4-trifluoro-1-[hydroxy(thiazolyl-2-yl)methyl]butyl]carbamoyl]-4-triisopropylsilyloxy-pentyl]carbamate tert-butyl ester (13.6 g, 21.3 mmol, 78.1% yield, 98% purity) as a yellow solid.

[0125] LCMS (ESI) m / z 626.5 [M+H] + 1H NMR (400 MHz, DMSO-d6) δ = 7.65 (m, 2 H), 6.94 (m, 1 H), 6.57 (m,1 H), 4.87 (m, 1 H), 4.24 (m, 1 H), 3.82 (m, 2 H), 2.21 (m, 2 H), 1.87 (m, 1H), 1.60 (m, 3H), 1.35 (m, 10H), 1.22 (m, 2H), 1.02 (m, 23H).

[0126] Step 9. (2S)-2-amino-5-hydroxy-N-[(1S)-4,4,4-trifluoro-1-[hydroxy(thiazol-2-yl)methyl] Synthesis of butylhexylamide HCl salt To a solution of N-[(1S)-1-[[(1S)-4,4,4-trifluoro-1-[hydroxy(thiazol-2-yl)methyl]butyl]carbamoyl]-4-triisopropylsilyloxy-pentyl]carbamate tert-butyl (11.2 g, 17.90 mmol, 1 equivalent) in EtOAc (55 mL), HCl / EtOAc (4 M, 55 mL, 12.29 equivalents) was added. The mixture was stirred at 25 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to give (2S)-2-amino-5-hydroxy-N-[(1S)-4,4,4-trifluoro-1-[hydroxy(thiazol-2-yl)methyl]butyl]hexanoamide (7.26 g, crude, HCl) as a white solid. The product was used in the next step without further purification.

[0127] Step 10. Synthesis of ethyl 2-(3-chloro-5-fluoro-phenyl)oxazol-5-carboxylate To a solution of ethyl 2-bromooxazol-5-carboxylate (500 mg, 2.27 mmol, 1 equivalent) and (3-chloro-5-fluorophenyl)boronic acid (594.37 mg, 3.41 mmol, 1.5 equivalent) in dioxane (12.5 mL) and H₂O (1.25 mL), Na₂CO₃ (481.73 mg, 4.55 mmol, 2 equivalent) was added, followed by purging with N₂ three times. Then, Pd(dppf)Cl₂ (166.28 mg, 227.25 μmol, 0.1 equivalent) was added. The reaction mixture was stirred at 80 °C for 12 h under N₂ atmosphere. LC-MS showed the desired quality. The reaction mixture was diluted with water (40 mL) and extracted with EtOAc (40 mL × 3). The combined organic layers were dried over Na₂SO₄ and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO2, 0-5% ethyl acetate / petroleum ether) to give ethyl 2-(3-chloro-5-fluoro-phenyl)oxazol-5-carboxylate as a white solid (4.94 g, 13.3 mmol, 58.8% yield, 73% purity).

[0128] LCMS (ESI) m / z 270.2 [M+H] + Step 11. Synthesis of 2-(3-chloro-5-fluoro-phenyl)oxazol-5-carboxylic acid LiOH·H2O (1.15 g, 27.48 mmol, 1.5 equivalent) was added to a solution of ethyl 2-(3-chloro-5-fluoro-phenyl)oxazol-5-carboxylic acid (4.94 g, 18.32 mmol, 1 equivalent) in THF (50 mL) and H2O (50 mL). The resulting mixture was stirred at 25 °C for 1 h. LCMS showed the desired mass. The reaction mixture was diluted with water (40 mL) and then acidified to pH = 4 with 1 M HCl. The mixture was extracted with EtOAc (50 mL x 2). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give 2-(3-chloro-5-fluoro-phenyl)oxazol-5-carboxylic acid (3.7 g, 15.1 mmol, 82.7% yield, 99% purity) as a white solid. The product was used in the next step without further purification.

[0129] LCMS (ESI) m / z 242.2 [M+H] + 1H NMR (400 MHz, DMSO-d6) δ = 13.92 (br, s, 1 H), 8.12 (s, 1 H), 7.91 (s, 1 H), 7.80 (m, 2 H).

[0130] Step 12. 2-(3-chloro-5-fluoro-phenyl)-N-[(1S)-4-hydroxy-1-[[(1S)-4,4,4-trifluoro-1-[hydroxy Synthesis of (thiazol-2-yl)methyl]butyl]carbamoyl]pentyl]oxazol-5-carboxamide HOBt (5.04 g, 37.29 mmol, 2.1 equivalents), EDCI (7.15 g, 37.29 mmol, 2.1 equivalents), and TEA (5.39 g, 53.27 mmol, 7.41 mL, 3 equivalents) were added to a solution of (2S)-2-amino-5-hydroxy-N-[(1S)-4,4,4-trifluoro-1-[hydroxy(thiazol-2-yl)methyl]butyl]hexamethylenetetramine (7.21 g, 17.76 mmol, 1 equivalent) in DMF (75 mL). The mixture was stirred at 25 °C for 12 h. LC-MS showed the desired mass. The reaction mixture was diluted with EtOAc (150 mL) and washed with H2O (50 mL). The organic layer was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO2, 0-10% MeOH / DCM) to give 2-(3-chloro-5-fluoro-phenyl)-N-[(1S)-4-hydroxy-1-[[(1S)-4,4,4-trifluoro-1-[hydroxy(thiazol-2-yl)methyl]butyl]carbamoyl]pentyl]oxazol-5-carboxamide (5.9 g, 9.5 mmol, 52.3% yield, 96% purity) as a yellow solid.

[0131] LCMS (ESI) m / z 593.3 [M+H] + Step 13. 2-(3-chloro-5-fluoro-phenyl)-N-[(1S)-4-hydroxy-1-[[(1S)-4,4,4-trifluoro-1-(thiazolinone)] Synthesis of oxazol-5-carboxamide: [(2-carbonyl)butyl]carbamoyl]pentyl]oxazol-5-carboxamide This compound was prepared according to the procedure described in the final step of the synthesis in Example 1. 2.27 g of 2-(3-chloro-5-fluoro-phenyl)-N-[(1S)-4-hydroxy-1-[[(1S)-4,4,4-trifluoro-1-[hydroxy(thiazol-2-yl)methyl]butyl]carbamoyl]pentyl]oxazol-5-carboxamide as a white solid was obtained from 5.3 g of 2-(3-chloro-5-fluoro-phenyl)-N-[(1S)-4-hydroxy-1-[[(1S)-4,4,4-trifluoro-1-(thiazol-2-carbonyl)butyl]carbamoyl]pentyl]oxazol-5-carboxamide (42.15% yield, 98% purity).

[0132] LCMS (ESI) m / z 591.2 [M+H] + 1H NMR (400 MHz, DMSO-d6) δ = 8.83 (m, 1 H), 8.74 (m, 1 H), 8.28 (m, 1 H), 8.20 (m, 1 H), 8.04 (m, 1 H), 7.97 (m, 2 H), 7.72 (m, 1 H), 5.36 (m, 1H), 4.45 (m, 2 H), 3.58 (m, 1 H), 2.41 (m, 2 H), 2.18 (m, 1 H), 1.78 (m, 3 H), 1.40 (m, 2 H), 1.04 (dd, J = 6.0, 3.6 Hz, 3 H).

[0133] Example 4: 2-(3-chloro-5-fluoro-phenyl)-N-[(1S)-1-methyl-2-oxo-2-[[(1S)-4,4,4-trifluoro-1-(thiazol-2-carbonyl)butyl]amino]ethyl]oxazol-5-carboxamide (ClpP-1848) Step 1. ((2S)-1-oxo-1-(((2S)-5,5,5-trifluoro-1-hydroxy-1-(thiazolyl-2-yl)pentane-2- Synthesis of tert-butyl propane-2-yl)carbamate EDCI (6.87 g, 35.82 mmol, 2.1 equivalents), HOBt (4.84 g, 35.82 mmol, 2.1 equivalents), and TEA (5.18 g, 51.17 mmol, 7.12 mL, 3 equivalents) were added sequentially to a solution of (2S)-2-amino-5,5,5-trifluoro-1-thiazo-2-yl-pentane-1-ol (4.72 g, 17.06 mmol, 1 equivalent) in DMF (50 mL). The mixture was stirred at 25 °C for 12 h. LC-MS showed the desired mass. The reaction mixture was diluted with EtOAc (100 mL) and washed with H2O (50 mL x 3). The organic layer was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO2, 0-10% MeOH / DCM) to give N-[(1S)-1-methyl-2-oxo-2-[[(1S)-4,4,4-trifluoro-1-[hydroxy(thiazol-2-yl)methyl]butyl]amino]ethyl]carbamate tert-butyl ester (5.1 g, 11.9 mmol, 69.7% yield, 96% purity) as a yellow solid.

[0134] LCMS (ESI) m / z 412.1 [M+H] + Step 2. (2S)-2-amino-N-((2S)-5,5,5-trifluoro-1-hydroxy-1-(thiazolyl-2-yl)pentan-2-yl) Synthesis of Acrylamide HCl Salt To a solution of N-[(1S)-1-methyl-2-oxo-2-[[(1S)-4,4,4-trifluoro-1-[hydroxy(thiazol-2-yl)methyl]butyl]amino]ethyl]carbamate tert-butyl ester (200 mg, 486.10 μmol, 1 equivalent) in EtOAc (1 mL), EtOAc containing HCl was added (4 M, 1 mL, 8.23 ​​equivalents). The resulting mixture was stirred at 25 °C for 1 hour. LCMS showed the desired mass. The mixture was concentrated under reduced pressure to give (2S)-2-amino-N-[(1S)-4,4,4-trifluoro-1-[hydroxy(thiazol-2-yl)methyl]butyl]propionamide (160 mg, crude, HCl) as a white solid. The product was used in the next step without further purification.

[0135] LCMS (ESI) m / z 312.1 [M+H] + Step 3. 2-(3-chloro-5-fluoro-phenyl)-N-[(1S)-1-methyl-2-oxo-2-[[(1S)-4,4,4-trifluoro- Synthesis of 1-[hydroxy(thiazol-2-yl)methyl]butyl]amino]ethyl]oxazol-5-carboxamide HOBt (186.5 mg, 1.38 mmol, 3 equivalents), EDCI (264.6 mg, 1.38 mmol, 3 equivalents), and TEA (186.2 mg, 1.84 mmol, 256.14 μL, 4 equivalents) were added sequentially to a solution of (2S)-2-amino-N-[(1S)-4,4,4-trifluoro-1-[hydroxy(thiazol-2-yl)methyl]butyl]propionamide (160 mg, 460.06 μmol, 1 equivalent) in DMF (2 mL). The mixture was stirred at 25 °C for 12 h. LCMS showed the desired quality. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with LiCl (10 mL) (5 wt% in water). The organic layers were dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography (SiO2, 0-10% MeOH / DCM) to give 2-(3-chloro-5-fluoro-phenyl)-N-[(1S)-1-methyl-2-oxo-2-[[(1S)-4,4,4-trifluoro-1-[hydroxy(thiazol-2-yl)methyl]butyl]amino]ethyl]oxazol-5-carboxamide (160 mg, 284.16 μmol, 61.8% yield, 95% purity) as a yellow oil.

[0136] LCMS (ESI) m / z 535.0 [M+H] + Step 4. 2-(3-chloro-5-fluoro-phenyl)-N-[(1S)-1-methyl-2-oxo-2-[[(1S)-4,4,4-trifluoro- Synthesis of 1-(thiazol-2-carbonyl)butyl]amino]ethyl]oxazol-5-carboxamide DMP (190.30 mg, 448.67 μmol, 139.01 μL, 1.5 equivalents) was added to a solution of 2-(3-chloro-5-fluoro-phenyl)-N-[(1S)-1-methyl-2-oxo-2-[[(1S)-4,4,4-trifluoro-1-[hydroxy(thiazol-2-yl)methyl]butyl]amino]ethyl]oxazol-5-carboxamide (160 mg, 299.12 μmol, 1 equivalent) in DCM (4 mL). The mixture was stirred at 25 °C for 1 h. LCMS showed the desired mass. The reaction mixture was diluted with DCM (20 mL) and washed with saturated NaHCO3 aqueous solution (20 mL x 3). The organic layer was dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (column: Welch Ultimate C18 150 * 25 mm * 5 μm. Mobile phase: A: water containing 0.5% FA, B: MeCN. Gradient: 48%–78% B over 10 min. Flow rate: 25 mL / min) to obtain the title compound 2-(3-chloro-5-fluoro-phenyl)-N-[(1S)-1-methyl-2-oxo-2-[[(1S)-4,4,4-trifluoro-1-(thiazol-2-carbonyl)butyl]amino]ethyl]oxazol-5-carboxamide (81.6 mg, 148.27 μmol, 49.6% yield, 96.8% purity).

[0137] LCMS (ESI) m / z 533.1 [M+H] + 1H NMR (400MHz, DMSO-d6) δ = 8.94 - 8.82 (m, 1H), 8.76 - 8.66 (m,1H), 8.30 - 8.24 (m, 1H), 8.22 - 8.15 (m, 1H), 8.04 (s, 1H), 7.99 - 7.91 (m,2H), 7.72 (td, J=2.1, 8.7 Hz, 1H), 5.50 - 5.32 (m, 1H), 4.62 - 4.50 (m, 1H), 2.48 - 2.32 (m, 2H), 2.25 - 2.13 (m, 1H), 1.96 - 1.80 (m, 1H), 1.36 (d, J=7.3Hz, 3H) in vitro Measurement and Results 1. ClpP1P2 peptidase inhibition assay The peptidase activity of ClpP1P2 was continuously measured using Ac-PKM-amc as a substrate as described below: “Cleavage Specificity of Mycobacterium tuberculosis ClpP1P2 Protease and Identification of Novel Peptide Substrates and Boronate Inhibitors with Anti-bacterial Activity” (Akopian, T. et al., J. Biol. Chem., April 24, 2015; 290(17):11008-20. doi: 10.1074 / jbc.M114.625640). Ki was calculated as follows: “Inhibition constant (Ki) of the enzyme reaction versus inhibitor concentration (IC50)”. 50 The relationship between the inhibition constant (Ki) and the concentration of inhibitor (IC). 50 (Cheng Y. and Prusoff W., Biochemical Pharmacology, Vol. 22, pp. 3099-3108). The Ki values ​​for Examples 1-5 are listed in Table 1.

[0138] 2. Mtb H37Rv MABA determination. All experiments on Mycobacterium tuberculosis (Mtb) were performed in a Biosafety Level 3 (BSL3) laboratory using the previously described Microplate Alamar Blue Assay (MABA) (Cho, S. et al., 2015. Microplate Alamar Blue Assay (MABA) and Low Oxygen Recovery Assay (LORA) for Mycobacterium tuberculosis. 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) In short, the compound stock solution was prepared in dimethyl sulfoxide (DMSO) at the highest desired final concentration of 100×. The compound was transferred to an assay plate containing Middlebrook 7H12 medium (for 1 L of medium, 4.7 g 7H9 broth, 1 g casein (Bacto), 5 g bovine serum albumin (BSA), 4 mg catalase, and 5.6 mg palmitic acid). Nine 2-fold serial dilutions of the compound were performed in the assay plate. The plate was inoculated with Mycobacterium tuberculosis strain H37Rv (ATCC 27294) to achieve a final density of approximately 1 × 10⁵ CFU / mL and incubated at 37°C for 7 days. At the end of 7 days, a rezuril dye / tween 80 mixture (0.6 mM rezuril dye and 12 μL 20% Tween 80) was added to each well, and the plate was incubated at 37°C for an additional 18 to 24 hours. Fluorescence was measured on day 8 using a CLARIOstar plate reader (BMG LABTECH, Ortenberg, Germany). MIC is an extrapolated value and is defined as the lowest concentration at which a 90% reduction in fluorescence is achieved relative to the DMSO-treated control. The MABA MIC values ​​for Examples 1-5 are summarized in Table 1.

[0139] Table 1: ClpP1P2 Ki and Mtb H37Rv MABA MIC Examples 6A and 6B: N-[(1S,4R)-1-{N-(S)-4,4,4-trifluoro-1-[(1,3-thiazol-2-yl)carbonyl]butylcarbamoyl}-4-hydroxypentyl]-2-(3-chloro-5-fluorophenyl)-1,3-oxazol-5-carboxamide (ClpP-1767A) and N-[(1S,4S)-1-{N-(S)-4,4,4-trifluoro-1-[(1,3-thiazol-2-yl)carbonyl]butylcarbamoyl}-4-hydroxypentyl]-2-(3-chloro-5-fluorophenyl)-1,3-oxazol-5-carboxamide (ClpP-1767B) 2-(3-chloro-5-fluoro-phenyl)-N-[(1S)-4-hydroxy-1-[[(1S)-4,4,4-trifluoro-1-(thiazolyl-2-carbonyl)butyl]carbamoyl]pentyl]oxazol-5-carboxamide (Example 3, 700 mg) was separated by SFC (column: Daicel CHIRALPAK IC (250 mm x 30 mm, 10 μm); mobile phase A: CO2; B: EtOH; isocratic 40% B and 60% A. Flow rate: 150 mL / min).

[0140] Peak 1 was randomly assigned to 6A, i.e., N-[(1S,4R)-1-{N-(S)-4,4,4-trifluoro-1-[(1,3-thiazolyl-2-yl)carbonyl]butylcarbamoyl}-4-hydroxypentyl]-2-(3-chloro-5-fluorophenyl)-1,3-oxazol-5-carboxamide (212 mg, 29% yield, 97% purity, white solid). LCMS (ESI) m / z 591.1 [M+H] + 1H NMR (400MHz, DMSO-d6) δ = 8.89 - 8.80 (m, 1H), 8.74 (d, J = 7.2Hz, 1H), 8.28 (d, J = 3.2 Hz, 1H), 8.19 (d, J = 3.2 Hz, 1H), 8.06 - 8.02 (m,1H), 7.99 - 7.93 (m, 2H), 7.72 (td, J = 2.4, 8.4 Hz, 1H), 5.50 - 5.35 (m,1H), 4.57 - 4.41 (m, 2H), 3.67 - 3.52 (m, 1H), 2.47 - 2.35 (m, 2H), 2.27 -2.12 (m, 1H), 1.98 - 1.69 (m, 3H), 1.51 - 1.28 (m, 2H), 1.03 (d, J = 6.0 Hz,3H) Peak 2 was randomly assigned to 6B, i.e., N-[(1S,4S)-1-{N-(S)-4,4,4-trifluoro-1-[(1,3-thiazolyl-2-yl)carbonyl]butylcarbamoyl}-4-hydroxypentyl]-2-(3-chloro-5-fluorophenyl)-1,3-oxazol-5-carboxamide (214 mg, 31% yield, 100% purity, white solid). LCMS (ESI) m / z 591.2 [M+H] + 1H NMR (400MHz, DMSO-d6) δ = 8.86 - 8.80 (m, 1H), 8.79 - 8.74 (m,1H), 8.28 (d, J = 3.2 Hz, 1H), 8.19 (d, J = 3.2 Hz, 1H), 8.03 (d, J = 1.6 Hz,1H), 7.99 - 7.93 (m, 2H), 7.72 (td, J = 2.0, 8.8 Hz, 1H), 5.50 - 5.36 (m,1H), 4.54 - 4.42 (m, 2H), 3.67 - 3.52 (m, 1H), 2.48 - 2.35 (m, 2H), 2.26 -2.11 (m, 1H), 2.00 - 1.83 (m, 2H), 1.75 - 1.58 (m, 1H), 1.49 - 1.29 (m, 2H), 1.04 (d, J = 6.0 Hz, 3H) Synthesis of carboxylic acids: Synthesis of 2-(3,5-difluorophenyl)oxazol-5-carboxylic acid Cs₂CO₃ (296 mg, 909.0 μmol, 2 equivalents) was added to a solution of ethyl 2-bromooxazol-5-carboxylate (100 mg, 454.5 μmol, 1 equivalent), (3,5-difluorophenyl)boronic acid (79 mg, 500.0 μmol, 1.1 equivalents) in dioxane (2 mL) and H₂O (0.2 mL). Pd(dppf)Cl₂ (33 mg, 45.5 μmol, 0.1 equivalents) was then added, and the resulting mixture was stirred at 120 °C under N₂ for 12 hours. The reaction mixture was diluted with 20 mL of water and extracted with EtOAc (30 mL). The aqueous layer was acidified to pH 4 with 1 N HCl and extracted with EtOAc (20 mL x 2). The organic layer was dried over Na₂SO₄ and concentrated under reduced pressure to give 2-(3,5-difluorophenyl)oxazol-5-carboxylic acid (60 mg, 28% yield, 95% purity) as a yellow solid. LCMS (ESI) m / z 225.9 [M+H] + The following carboxylic acids were synthesized using a similar procedure: A yellow solid was obtained 2-(4-Fluorophenyl)oxazol-5-carboxylic acid (Crude product, 95 mg, 25% yield, 75% purity). LCMS (ESI) m / z 208.1 [M+H] + A white solid was obtained 2-(2,4-Difluorophenyl)oxazol-5-carboxylic acid (63 mg, 29% yield, 95% purity). LCMS (ESI) m / z 226.2 [M+H] + A yellow solid was obtained 2-[3-fluoro-5-(trifluoromethyl)phenyl]oxazol-5-carboxylic acid (390 mg, 84% yield, 95% purity). LCMS (ESI) m / z 276.1 [M+H] + Synthesis of 2-(2,5-difluorophenyl)oxazol-5-carboxylic acid Step 1: Cs₂CO₃ (592 mg, 1.8 mmol, 2 equivalents) was added to a solution of ethyl 2-bromooxazol-5-carboxylate (200 mg, 909.0 μmol, 1 equivalent) and (2,5-difluorophenyl)boronic acid (172 mg, 1.1 mmol, 1.2 equivalents) in dioxane (5 mL) and H₂O (0.5 mL). Then Pd(dppf)Cl₂ (67 mg, 90.9 μmol, 0.1 equivalents) was added. The resulting mixture was stirred at 120 °C under N₂ for 12 hours. The reaction mixture was diluted with 20 mL of water and extracted with EtOAc (30 mL x 3). The combined organic layers were dried over Na₂SO₄ and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography (SiO2, 0-20% ethyl acetate / petroleum ether) to give ethyl 2-(2,5-difluorophenyl)oxazol-5-carboxylate (50 mg, 22% yield, 99% purity) as a white solid. LCMS (ESI) m / z 254.1 [M+H] + Step 2: LiOH·H₂O (5 M, 4 mL) was added to a solution of ethyl 2-(2,5-difluorophenyl)oxazol-5-carboxylate (50 mg, 197.5 μmol, 1 equivalent) in THF (2 mL) and H₂O (2 mL). The mixture was stirred at 25 °C for 12 hours. Next, most of the solvent was removed under reduced pressure. The residue was diluted with water (10 mL), acidified to pH 4 with 1 N HCl aqueous solution, and extracted with EtOAc (20 mL x 2). The organic layer was dried over Na₂SO₄ and concentrated under reduced pressure to give 2-(2,5-difluorophenyl)oxazol-5-carboxylic acid (44 mg, 98% yield, 99% purity) as a white solid. LCMS (ESI) m / z 226.2 [M+H] + Synthesis of 2-(o-tolyl)thiazolyl-4-carboxylic acid Step 1: A mixture of ethyl 2-bromothiazol-4-carboxylate (1.04 g, 4.4 mmol, 1 equivalent), K₂CO₃ (2 M in water, 4 mL), and o-tolylboronic acid (599 mg, 4.4 mmol, 1 equivalent) in toluene (10 mL) was degassed and purged with N₂. Pd(PPh₃)₄ (255 mg, 220.3 μmol, 0.05 equivalent) was added, and the mixture was stirred at 90 °C under N₂ for 12 hours. The reaction mixture was diluted with 10 mL of EtOAc and washed with 1 M NaOH aqueous solution (10 mL). The aqueous layer was extracted with EtOAc (2 x 20 mL). The combined organic layers were dried over Na₂SO₄ and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography (SiO2, 0-10% ethyl acetate / petroleum ether) to give ethyl 2-(o-tolyl)thiazolium-4-carboxylate as a yellow oil (660 mg, 58% yield, 95% purity). LCMS (ESI) m / z 248.1 [M+H] + Step 2: LiOH·H₂O (4 M in water, 3 mL) was added to a solution of ethyl 2-(o-tolyl)thiazolyl-5-carboxylic acid (200 mg, 808.7 μmol, 1 equivalent) in THF (3 mL). The reaction mixture was stirred at 30 °C for 12 h. The resulting mixture was adjusted to pH 4–5 with 1 M HCl aqueous solution and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na₂SO₄ and filtered. The filtrate was concentrated under reduced pressure to give 2-(o-tolyl)thiazolyl-5-carboxylic acid (170 mg, 93% yield, 97% purity) as a colorless oil. LCMS (ESI) m / z 220.0 [M+H] + Synthesis of 2-(2-cyanophenyl)thiazol-5-carboxylic acid Step 1: A solution of 2-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)benzonitrile (1.94 g, 8.5 mmol, 2 equivalents) in dioxane (10 mL) and H₂O (1 mL) was reacted with Na₂CO₃ (898 mg, 8.5 mmol, 2 equivalents) and ethyl 2-bromothiazolyl-5-carboxylate (1 g, 4.2 mmol, 1 equivalent), followed by the addition of Pd(PPh₃)₄ (489 mg, 423.6 μmol, 0.1 equivalents). The reaction mixture was stirred at 100 °C under N₂ for 12 hours. The reaction mixture was diluted with H₂O (40 mL) and filtered. The filtrate was extracted with EtOAc (20 mL x 3). The combined organic layers were dried over Na₂SO₄ and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography (SiO2, 0-30% ethyl acetate / petroleum ether) to give ethyl 2-(2-cyanophenyl)thiazolium-5-carboxylate as a yellow solid (278 mg, 20% yield, 79% purity). LCMS (ESI) m / z 259.2 [M+H] + Step 2: To a solution of ethyl 2-(2-cyanophenyl)thiazol-5-carboxylate (278 mg, 1.1 mmol, 1 equivalent) in MeOH (15 mL), NaOH (5 M in water, 5 mL) was added. After stirring at 25 °C for 2 hours, the mixture was adjusted to pH 4–5 with 1 M HCl aqueous solution and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na₂SO₄ and filtered. The filtrate was concentrated under reduced pressure to give 2-(2-cyanophenyl)thiazol-5-carboxylic acid (215 mg, crude) as a yellow solid. LCMS (ESI) m / z 231.0 [M+H] + Synthesis of 2-(2,5-dichlorophenyl)oxazol-5-carboxylic acid Step 1: To a solution of ethyl 2-bromooxazol-5-carboxylate (200 mg, 909 μmol, 1 equivalent), (2,5-dichlorophenyl)boronic acid (260 mg, 1.4 mmol, 1.5 equivalent) in dioxane (5 mL) and H₂O (0.5 mL), Na₂CO₃ (193 mg, 1.8 mmol, 2 equivalent) and Pd(dppf)Cl₂ (67 mg, 90.9 μmol, 0.1 equivalent) were added. The mixture was stirred at 80 °C under N₂ for 12 hours. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (30 mL). The organic layer was dried over Na₂SO₄ and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography (SiO2, 0-10% ethyl acetate / petroleum ether) to give ethyl 2-(2,5-dichlorophenyl)oxazolium-5-carboxylate as a white solid (300 mg, 996.1 μmol, 73% yield, 95% purity). LCMS (ESI) m / z 286.0 [M+H] + Step 2: LiOH·H₂O (88 mg, 2.1 mmol, 2 equivalents) was added to a solution of ethyl 2-(2,5-dichlorophenyl)oxazol-5-carboxylate (300 mg, 1.1 mmol, 1 equivalent) in THF (3 mL) and H₂O (3 mL). The mixture was stirred at 25 °C for 2 hours. Next, most of the solvent was removed under reduced pressure. The residue was diluted with water (10 mL), acidified to pH = 4 with 1 M HCl aqueous solution, and extracted with EtOAc (20 mL x 2). The organic layer was dried over Na₂SO₄ and filtered. The filtrate was concentrated under reduced pressure to give 2-(2,5-dichlorophenyl)oxazol-5-carboxylic acid (260 mg, 91% yield, 95% purity) as a white solid. LCMS (ESI) m / z 258.0 [M+H] + The following carboxylic acids were synthesized using a similar procedure: A white solid was obtained 2-(2,5-Dichlorophenyl)oxazol-5-carboxylic acid (260 mg, 91% yield, 95% purity). LCMS (ESI) m / z 258.0 [M+H] + A white solid was obtained 2-(2-chloro-4-fluoro-phenyl)oxazol-5-carboxylic acid (270 mg, 92% yield, 95% purity). LCMS (ESI) m / z 242.2 [M+H] + A yellow solid was obtained 2-(4-chloro-2-fluoro-phenyl)oxazol-5-carboxylic acid(290 mg, 78% yield, 97% purity). LCMS (ESI) m / z 242.1 [M+H] + A white solid was obtained 2-(2,4-Dichlorophenyl)oxazol-5-carboxylic acid (100 mg, 100% yield, 90% purity). LCMS (ESI) m / z 257.9 [M+H] + A yellow solid was obtained 2-(3-Fluorophenyl)oxazol-5-carboxylic acid (120 mg, 83% yield, 97% purity). LCMS (ESI) m / z 207.8 [M+H] + A yellow solid was obtained 2-(3-Chlorophenyl)oxazol-5-carboxylic acid (165 mg, 93% yield, 93% purity). LCMS (ESI) m / z 223.8 [M+H] + A white solid was obtained 2-(4-Chlorophenyl)oxazol-5-carboxylic acid (45 mg, 97% yield, 96% purity). LCMS (ESI) m / z 224.0 [M+H] + A white solid was obtained 2-(3,5-Dichlorophenyl)thiazol-5-carboxylic acid (120 mg, 84% yield, 95% purity). LCMS (ESI) m / z 273.9 [M+H] + A white solid was obtained 2-(2-chloro-5-fluoro-phenyl)thiazol-5-carboxylic acid (140 mg, 98% yield, 95% purity). LCMS (ESI) m / z 257.9 [M+H] + Synthesis of 2-(4-cyanophenyl)thiazol-5-carboxylic acid Step 1: Ethyl 2-bromothiazol-5-carboxylate (1 g, 4.2 mmol, 1 equivalent), (4-cyanophenyl)boronic acid (685 mg, 4.7 mmol, 1.1 equivalent), Pd(dppf)Cl2 (310 mg, 423.6 μmol, 0.1 equivalent), and Na2CO3 (1.35 g, 12.7 mmol, 3 equivalent) were degassed in a mixture of DME (10 mL) and H2O (1 mL) and stirred at 80 °C for 12 hours under N2. The reaction mixture was quenched with 10 mL of water and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography (SiO2, 0-30% ethyl acetate / petroleum ether). Ethyl 2-(4-cyanophenyl)thiazole-5-carboxylate was obtained as a white solid (180 mg, 15% yield, 94% purity). LCMS (ESI) m / z 259.1 [M+H] + Step 2: LiOH·H₂O (1 M in water, 1.5 mL, 2 equivalents) was added to a solution of ethyl 2-(4-cyanophenyl)thiazol-5-carboxylate (180 mg, 696.9 μmol, 1 equivalent) in THF (3 mL). The mixture was stirred at 20 °C for 1 hour. The reaction mixture was quenched with 1 M HCl (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na₂SO₄, and filtered. The filtrate was concentrated under reduced pressure to give 2-(4-cyanophenyl)thiazol-5-carboxylic acid (130 mg, 75% yield, 92% purity) as a white solid. LCMS (ESI) m / z 231.1 [M+H] + The following carboxylic acids were synthesized using a similar procedure: A white solid was obtained 2-(3-cyanophenyl)thiazolyl-4-carboxylic acid (Crude product, 210 mg, 40% yield, 85% purity). LCMS (ESI) m / z 231.1 [M+H] + A white solid was obtained 2-(2,5-Difluorophenyl)thiazol-5-carboxylic acid (307 mg, 51% yield, 91% purity). LCMS (ESI) m / z 241.9 [M+H] + A white solid was obtained 2-(2,6-Difluorophenyl)thiazol-5-carboxylic acid (Crude product, 200 mg, 45% yield, 80% purity). LCMS (ESI) m / z 242.0 [M+H] + A white solid was obtained 2-(3,5-Difluorophenyl)thiazol-4-carboxylic acid (Crude product, 293 mg, 30% yield, 75% purity). LCMS (ESI) m / z 242.0 [M+H] + A white solid was obtained 2-(2,4-Difluorophenyl)thiazol-5-carboxylic acid (350 mg, 85% yield, 98% purity). LCMS (ESI), m / z: 242.0 [M+1] + A white solid was obtained 2-(5-chloro-2-fluoro-phenyl)oxazol-5-carboxylic acid (180 mg, 90% yield, 99% purity). LCMS (ESI) m / z 242.0 [M+H] + A white solid was obtained 2-(2-chloro-5-fluoro-phenyl)oxazol-5-carboxylic acid (100 mg, 82% yield, 95% purity). LCMS (ESI) m / z 242.0 [M+H] + A white solid was obtained 2-(2,5-Difluorophenyl)oxazol-5-carboxylic acid (210 mg, 99% yield, 99% purity). LCMS (ESI) m / z 226.1 [M+H] + A white solid was obtained 2-(2-Fluorophenyl)oxazol-5-carboxylic acid (120 mg, 92% yield, 95% purity). LCMS (ESI) m / z 208.1 [M+H] + A white solid was obtained 2-(5-chloro-2-fluoro-phenyl)thiazol-5-carboxylic acid (180 mg, 90% yield, 95% purity). LCMS (ESI) m / z 258.0 [M+H] + A yellow solid was obtained 2-(2,5-Dichlorophenyl)thiazol-5-carboxylic acid (Crude product, 350 mg, 62% yield, 80% purity). LCMS (ESI) m / z 274.0 [M+H] + A yellow oil was obtained 2-[2-(trifluoromethyl)phenyl]thiazol-5-carboxylic acid (220 mg, 83% yield, 90% purity). LCMS (ESI) m / z 273.9 [M+H] + A white solid was obtained 2-[3-(trifluoromethyl)phenyl]thiazol-5-carboxylic acid (Crude product, 180 mg). LCMS (ESI) m / z 274.0 [M+H] + A white solid was obtained 2-[4-(trifluoromethyl)phenyl]thiazol-5-carboxylic acid(513 mg, 46% yield, 92% purity). LCMS (ESI) m / z 273.9 [M+H] + A yellow solid was obtained 2-(3-cyano-5-fluoro-phenyl)thiazolyl-5-carboxylic acid (360 mg, 61% yield, 95% purity). LCMS (ESI) m / z 248.8 [M+H] + A yellow solid was obtained 2-(3-chloro-5-cyano-phenyl)thiazolyl-5-carboxylic acid (320 mg, 47% yield, 90% purity). LCMS (ESI) m / z 264.7 [M+H] + Synthesis of 2-(3-cyano-5-fluoro-phenyl)oxazol-5-carboxylic acid Step 1: A mixture of 3-bromo-5-fluorobenzonitrile (2 g, 10.0 mmol, 2 equivalents), ethyl oxazolium-5-carboxylate (706 mg, 5.0 mmol, 1 equivalent), Cs₂CO₃ (3.26 g, 10.0 mmol, 2 equivalents), and Pd(PPh₃)₄ (578 mg, 500 μmol, 0.1 equivalents) in dioxane (20 mL) was degassed and purged three times with N₂. The mixture was stirred at 100 °C for 12 h under N₂. The reaction mixture was quenched with water (10 mL) at 20 °C. The resulting mixture was extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na₂SO₄, and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography (SiO₂, 0-15% ethyl acetate / petroleum ether). Ethyl 2-(3-cyano-5-fluoro-phenyl)oxazol-5-carboxylate was obtained as a yellow solid (360 mg, 19% yield, 67% purity). LCMS (ESI) m / z 260.9 [M+H] + Step 2: LiOH·H₂O (4 M in water, 2 mL) was added to a solution of ethyl 2-(3-cyano-5-fluoro-phenyl)oxazol-5-carboxylic acid (260 mg, 999.2 μmol, 1 equivalent) in THF (2 mL). The mixture was stirred at 20 °C for 1 hour. The reaction mixture was quenched by adding 1 M HCl aqueous solution to pH = 4 and then extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na₂SO₄, and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography (SiO₂, 0–7% (methanol + 0.5% formic acid) / DCM). 2-(3-cyano-5-fluoro-phenyl)oxazol-5-carboxylic acid (130 mg, 37% yield, 90% purity) was obtained as a white solid. 1 H NMR (400 MHz, DMSO- d 6) δ ppm 8.08 -8.19 (m, 3 H) 8.29 (t, J =1.37 Hz, 1 H).

[0141] The following carboxylic acids were synthesized using a similar procedure: A white solid was obtained 2-(2,6-difluorophenyl)oxazol-5-carboxylic acid (323 mg, 86% yield, 100% purity). LCMS (ESI) m / z 226.0 [M+H] + 2-(2-chloro-6-fluoro-phenyl)oxazol-5-carboxylic acid (White solid, crude product, 150 mg).

[0142] A white solid was obtained 2-(4-chloro-3-fluoro-phenyl)oxazol-5-carboxylic acid (256 mg, 93% yield, 98% purity). LCMS (ESI) m / z 242.0 [M+H] + A white solid was obtained 2-(2-cyano-4-fluoro-phenyl)oxazol-5-carboxylic acid (500 mg, 72% yield, 90% purity). LCMS (ESI) m / z 233.0 [M+H] + A white solid was obtained 2-(3-chloro-5-cyano-phenyl)oxazol-5-carboxylic acid (240 mg, 51% yield, 95% purity). LCMS (ESI) m / z 248.9 [M+H] + A white solid was obtained 2-(3-Fluoro-5-methoxy-phenyl)oxazol-5-carboxylic acid (1.35 g, 91% yield, 100% purity). LCMS (ESI) m / z 237.8 [M+H] + Synthesis of 2-[5-fluoro-2-(fluoromethyl)phenyl]thiazol-5-carboxylic acid Step 1: A solution of (5-fluoro-2-formyl-phenyl)boronic acid (1 g, 6.0 mmol, 1 equivalent), ethyl 2-bromothiazol-5-carboxylate (1.41 g, 6.0 mmol, 1 equivalent) in dioxane (20 mL) and H₂O (4 mL) was reacted with K₂CO₃ (2.06 g, 14.9 mmol, 2.5 equivalent), followed by the addition of Pd(PPh₃)₄ (413 mg, 357.3 μmol, 0.06 equivalent). The mixture was stirred at 80 °C for 12 hours under N₂. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography (SiO₂, 0% to 10% ethyl acetate / petroleum ether). Ethyl 2-(5-fluoro-2-formyl-phenyl)thiazol-5-carboxylate (crude, 500 mg) was obtained as a white solid. LCMS (ESI) m / z 280.1 [M+H] + Step 2: NaBH4 (41 mg, 1.1 mmol, 0.6 equivalent) was added to a solution of ethyl 2-(5-fluoro-2-formyl-phenyl)thiazole-5-carboxylate (500 mg, 1.8 mmol, 1 equivalent) in THF (10 mL) at 0 °C. The mixture was stirred at 0 °C for 1 hour. The reaction mixture was acidified with 1 M HCl aqueous solution (4 mL) and then extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography (SiO2, 0% to 30% ethyl acetate / petroleum ether). Ethyl 2-[5-fluoro-2-(hydroxymethyl)phenyl]thiazole-5-carboxylate (340 mg, 65% yield, 96% purity) was given as a white solid. LCMS (ESI) m / z 282.2 [M+H] + Step 3: DAST (292 mg, 1.8 mmol, 1.5 equivalents) was added to a solution of ethyl 2-[5-fluoro-2-(fluoromethyl)phenyl]thiazole-5-carboxylate (340 mg, 1.2 mmol, 1 equivalent) in DCM (20 mL) at 0 °C. The mixture was stirred at 25 °C for 0.5 h. NH4Cl aqueous solution (20 mL) was added, and the mixture was then extracted with DCM (30 mL). The organic layer was dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography (SiO2, 0% to 50% ethyl acetate / petroleum ether). Ethyl 2-[5-fluoro-2-(fluoromethyl)phenyl]thiazole-5-carboxylate (280 mg, 82% yield, 100% purity) was given as a white solid. LCMS (ESI) m / z 284.1 [M+H] + Step 4: To a solution of ethyl 2-[5-fluoro-2-(fluoromethyl)phenyl]thiazol-5-carboxylate (280 mg, 988.4 μmol, 1 equivalent) in EtOH (10 mL), NaOH (1 M in water, 7 mL) was added. The mixture was stirred at 20 °C for 12 hours. The reaction mixture was diluted with 5 mL of water, adjusted to pH = 4 with 1 M HCl aqueous solution, and extracted with EtOAc (30 mL x 3). The combined organic layers were dried over Na₂SO₄ and filtered. The filtrate was concentrated under reduced pressure to give 2-[5-fluoro-2-(fluoromethyl)phenyl]thiazol-5-carboxylic acid (230 mg, 91% yield, 100% purity) as a white solid. LCMS (ESI) m / z 256.1 [M+H] + Precursor synthesis: Example 7 - Precursor: 2-(3-fluoro-5-methoxyphenyl)-N-((2S)-5-hydroxy-1-oxo-1-(((2S)-5,5,5-trifluoro-1-hydroxy-1-(thiazol-2-yl)pentan-2-yl)amino)hexan-2-yl)oxazol-5-carboxamide This compound was prepared according to the procedure described in step 16 of the synthesis in Example 1. 105 mg of the 7-precursor (36% yield, 97% purity) was obtained as a yellow oil from 114 mg of acid and 195 mg of 3-K. LCMS (ESI) m / z 589.0 [M+H] + Example 8 - Precursor: 2-(3,5-difluorophenyl)-N-((2S)-5-hydroxy-1-oxo-1-(((2S)-6,6,6-trifluoro-1-hydroxy-1-(thiazolyl)hexane-2-yl)amino)hexane-2-yl)oxazol-5-carboxamide This compound was prepared according to the procedure described in step 16 of the synthesis in Example 1. 51 mg of the 8-precursor (51% yield, 91% purity) was obtained as a yellow oil from 65 mg of 1-Q and 36 mg of acid. LCMS (ESI) m / z 591.7 [M+H] + Example 9 - Precursor: 2-(2,5-difluorophenyl)-N-((2S)-5-hydroxy-1-oxo-1-(((2S)-6,6,6-trifluoro-1-hydroxy-1-(thiazolyl)hexane-2-yl)amino)hexane-2-yl)oxazol-5-carboxamide This compound was prepared according to the procedure described in step 16 of the synthesis in Example 1. 50 mg of the 9-precursor (42% yield, 98% purity) as a white solid was obtained from 44 mg of acid and 90 mg of 1-Q. LCMS (ESI) m / z 591.5 [M+H] + Example 10 - Precursor: 2-(4-fluorophenyl)-N-((2S)-5-hydroxy-1-oxo-1-(((2S)-6,6,6-trifluoro-1-hydroxy-1-(thiazolyl)hexane-2-yl)amino)hexane-2-yl)oxazol-5-carboxamide This compound was prepared according to the procedure described in step 16 of the synthesis in Example 1. 70 mg of the 10- precursor (37% yield, 95% purity) as a yellow oil was obtained from 131 mg of 1-Q and 65 mg of acid. LCMS (ESI) m / z 573.1 [M+H] + Example 11 - Precursor: 2-(2,4-difluorophenyl)-N-((2S)-5-hydroxy-1-oxo-1-(((2S)-6,6,6-trifluoro-1-hydroxy-1-(thiazolyl)hexane-2-yl)amino)hexane-2-yl)oxazol-5-carboxamide This compound was prepared according to the procedure described in step 16 of the synthesis in Example 1. 52 mg of the 11- precursor (34% yield, 99% purity) was obtained as a white solid from 72 mg of 1-Q and 40 mg of acid. LCMS (ESI) m / z 591.4 [M+H] + Example 12 - Precursor: 2-(3-chloro-5-fluorophenyl)-N-((2S)-5-hydroxy-1-oxo-1-(((2S)-6,6,6-trifluoro-1-hydroxy-1-(thiazolyl)hexane-2-yl)amino)hexane-2-yl)oxazol-5-carboxamide This compound was prepared according to the procedure described in step 16 of the synthesis in Example 1. 100 mg of the 12- precursor (43% yield, 98% purity) was obtained as a white solid from 131 mg of 1-Q and 75 mg of acid. LCMS (ESI) m / z 607.2 [M+H] + Example 13 - Precursor: N-((2S)-1-(((2S)-4-(4-fluorophenyl)-1-hydroxy-1-(thiazol-2-yl)butan-2-yl)amino)-5-hydroxy-1-oxohexane-2-yl)-2-phenylthiazol-5-carboxamide This compound was prepared according to the procedure described in step 16 of the synthesis in Example 1. 126 mg of the 13- precursor, present as a brown oil, was obtained from 132 mg of 2-K and 63 mg of acid (55% yield, 78% purity). LCMS (ESI) m / z 583.2 [M+H] + Example 14 - Precursor: 2-(4-chlorophenyl)-N-((2S)-1-(((2S)-4-(4-fluorophenyl)-1-hydroxy-1-(thiazol-2-yl)butan-2-yl)amino)-5-hydroxy-1-oxohexane-2-yl)thiazol-5-carboxamide This compound was prepared according to the procedure described in step 16 of the synthesis in Example 1. 80 mg of the 14-precursor (crude product) as a white solid was obtained from 66 mg of 2-K and 37 mg of acid. LCMS (ESI) m / z 617.1 [M+H] + Example 15 - Precursor: 2-(3-fluorophenyl)-N-((2S)-1-(((2S)-4-(4-fluorophenyl)-1-hydroxy-1-(thiazol-2-yl)butan-2-yl)amino)-5-hydroxy-1-oxohexane-2-yl)thiazol-5-carboxamide This compound was prepared according to the procedure described in step 16 of the synthesis in Example 1. 200 mg of the 15- precursor (crude product) was obtained as a white solid from 132 mg of 2-K and 72 mg of acid. LCMS (ESI) m / z 601.3 [M+H] + Example 16 - Precursor: 2-(2-fluorophenyl)-N-((2S)-1-(((2S)-4-(4-fluorophenyl)-1-hydroxy-1-(thiazol-2-yl)butan-2-yl)amino)-5-hydroxy-1-oxohexane-2-yl)thiazol-5-carboxamide This compound was prepared according to the procedure described in step 16 of the synthesis in Example 1. 38 mg of the 16-precursor (26% yield, 93% purity) was obtained as a colorless oil from 99 mg of 2-K and 51 mg of acid. LCMS (ESI) m / z 601.2 [M+H] + Example 17 - Precursor: 2-(3-chlorophenyl)-N-((2S)-1-(((2S)-4-(4-fluorophenyl)-1-hydroxy-1-(thiazol-2-yl)butan-2-yl)amino)-5-hydroxy-1-oxohexane-2-yl)thiazol-5-carboxamide This compound was prepared according to the procedure described in step 16 of the synthesis in Example 1. 92 mg of the 17- precursor, present as a yellow oil, was obtained from 73 mg of acid and 132 mg of 2-K (45% yield, 93% purity). LCMS (ESI) m / z 617.1 [M+H] + Example 18 - Precursor: 2-(2-chlorophenyl)-N-((2S)-1-(((2S)-4-(4-fluorophenyl)-1-hydroxy-1-(thiazol-2-yl)butan-2-yl)amino)-5-hydroxy-1-oxohexane-2-yl)thiazol-5-carboxamide This compound was prepared according to the procedure described in step 16 of the synthesis in Example 1. 46 mg of the 18-precursor (30% yield, 91% purity) was obtained as a yellow solid from 96 mg of 2-K and 53 mg of acid. LCMS (ESI) m / z 617.3 [M+H] + Example 19 - Precursor: N-((2S)-1-(((2S)-4-(4-fluorophenyl)-1-hydroxy-1-(thiazol-2-yl)butan-2-yl)amino)-5-hydroxy-1-oxohexane-2-yl)-2-(p-tolyl)thiazol-5-carboxamide This compound was prepared according to the procedure described in step 16 of the synthesis in Example 1. 43 mg of the 19- precursor (44% yield, 92% purity) was obtained as a colorless oil from 66 mg of 2-K and 37 mg of acid. LCMS (ESI) m / z 597.2 [M+H] + Example 20 - Precursor: N-((2S)-1-(((2S)-4-(4-fluorophenyl)-1-hydroxy-1-(thiazolyl-2-yl)butan-2-yl)amino)-5-hydroxy-1-oxohexane-2-yl)-2-(m-tolyl)thiazolylcarboxamide This compound was prepared according to the procedure described in step 16 of the synthesis in Example 1. 80 mg of the 20- precursor (48% yield, 98% purity) as a white solid was obtained from 119 mg of 2-K and 61 mg of acid. LCMS (ESI) m / z 597.1 [M+H] + Example 21 - Precursor: N-((2S)-1-(((2S)-4-(4-fluorophenyl)-1-hydroxy-1-(thiazol-2-yl)butan-2-yl)amino)-5-hydroxy-1-oxohexane-2-yl)-2-(o-tolyl)thiazol-5-carboxamide This compound was prepared according to the procedure described in step 16 of the synthesis in Example 1. 80 mg of the 21-precursor (crude product) as a yellow solid was obtained from 66 mg of 2-K and 37 mg of acid. The product was used in the next step without further purification. LCMS (ESI) m / z 597.3 [M+H] Example 22 - Precursor: 2-(4-cyanophenyl)-N-((2S)-1-(((2S)-4-(4-fluorophenyl)-1-hydroxy-1-(thiazol-2-yl)butan-2-yl)amino)-5-hydroxy-1-oxohexane-2-yl)thiazol-5-carboxamide This compound was prepared according to the procedure described in step 16 of the synthesis in Example 1. 76 mg of the 22- precursor (41% yield, 75% purity) as a yellow oil was obtained from 52 mg of acid and 99 mg of 2-K. LCMS (ESI) m / z 608.2 [M+H] + Example 23 - Precursor: 2-(3-cyanophenyl)-N-((2S)-1-(((2S)-4-(4-fluorophenyl)-1-hydroxy-1-(thiazol-2-yl)butan-2-yl)amino)-5-hydroxy-1-oxohexane-2-yl)thiazol-5-carboxamide This compound was prepared according to the procedure described in step 16 of the synthesis in Example 1. 50 mg of the 23- precursor (49% yield, 90% purity) as a white solid was obtained from 66 mg of 2-K and 42 mg of acid. LCMS (ESI) m / z 608.2 [M+H] + Example 24 - Precursor: 2-(2-cyanophenyl)-N-((2S)-1-(((2S)-4-(4-fluorophenyl)-1-hydroxy-1-(thiazol-2-yl)butan-2-yl)amino)-5-hydroxy-1-oxohexane-2-yl)thiazol-5-carboxamide This compound was prepared according to the procedure described in step 16 of the synthesis in Example 1. 34 mg of the 24- precursor (33% yield, 90% purity) was obtained as a white solid from 66 mg of 2-K and 42 mg of acid. LCMS (ESI) m / z 608.2 [M+H] + Example 25 - Precursor: 2-(2,5-difluorophenyl)-N-((2S)-1-(((2S)-4-(4-fluorophenyl)-1-hydroxy-1-(thiazol-2-yl)butan-2-yl)amino)-5-hydroxy-1-oxohexane-2-yl)thiazol-5-carboxamide This compound was prepared according to the procedure described in step 16 of the synthesis in Example 1. 82 mg of the 25- precursor (31% yield, 71% purity) as a yellow oil was obtained from 132 mg of 2-K and 74 mg of acid. LCMS (ESI) m / z 619.1 [M+H] + Example 26 - Precursor: 2-(2,6-difluorophenyl)-N-((2S)-1-(((2S)-4-(4-fluorophenyl)-1-hydroxy-1-(thiazol-2-yl)butan-2-yl)amino)-5-hydroxy-1-oxohexane-2-yl)thiazol-5-carboxamide This compound was prepared according to the procedure described in step 16 of the synthesis in Example 1. 60 mg of the 26- precursor (62% yield, 97% purity) as a white solid was obtained from 66 mg of 2-K and 41 mg of acid. LCMS (ESI) m / z 619.3 [M+H] + Example 27 - Precursor: 2-(3,5-difluorophenyl)-N-((2S)-1-(((2S)-4-(4-fluorophenyl)-1-hydroxy-1-(thiazol-2-yl)butan-2-yl)amino)-5-hydroxy-1-oxohexane-2-yl)thiazol-5-carboxamide This compound was prepared according to the procedure described in step 16 of the synthesis in Example 1. 75 mg of the 27- precursor (57% yield, 72% purity) was obtained as a white solid from 66 mg of 2-K and 39 mg of acid. LCMS (ESI) m / z 619.2 [M+H] + Example 28 - Precursor: 2-(2,4-difluorophenyl)-N-((2S)-1-(((2S)-4-(4-fluorophenyl)-1-hydroxy-1-(thiazol-2-yl)butan-2-yl)amino)-5-hydroxy-1-oxohexane-2-yl)thiazol-5-carboxamide This compound was prepared according to the procedure described in step 16 of the synthesis in Example 1. 85 mg of the 28-precursor (47% yield, 80% purity) was obtained as a colorless oil from 99 mg of 2-K and 55 mg of acid. LCMS (ESI), m / z: 619.1 [M+1] + Example 29 - Precursor: 2-(4-fluorophenyl)-N-((2S)-5-hydroxy-1-oxo-1-(((2S)-5,5,5-trifluoro-1-hydroxy-1-(thiazol-2-yl)pentan-2-yl)amino)hexan-2-yl)thiazol-5-carboxamide This compound was prepared according to the procedure described in step 16 of the synthesis in Example 1. 40 mg of the 29- precursor (39% yield, 90% purity) was obtained as a colorless oil from 64 mg of 3-K and 35 mg of acid. LCMS (ESI) m / z 575.1 [M+H] + Example 30 - Precursor: 2-(3-fluorophenyl)-N-((2S)-5-hydroxy-1-oxo-1-(((2S)-5,5,5-trifluoro-1-hydroxy-1-(thiazol-2-yl)pentan-2-yl)amino)hexan-2-yl)thiazol-5-carboxamide This compound was prepared according to the procedure described in step 16 of the synthesis in Example 1. 129 mg of the 30- precursor (89% yield, 95% purity) was obtained as a white solid from 97 mg of 3-K and 54 mg of acid. LCMS (ESI) m / z 575.2 [M+H] + Example 31 - Precursor: 2-(3-chlorophenyl)-N-((2S)-5-hydroxy-1-oxo-1-(((2S)-5,5,5-trifluoro-1-hydroxy-1-(thiazol-2-yl)pentan-2-yl)amino)hexan-2-yl)thiazol-5-carboxamide This compound was prepared according to the procedure described in step 16 of the synthesis in Example 1. 53 mg of the 31-precursor (43% yield, 93% purity) was obtained as a white solid from 39 mg of acid and 65 mg of 3-K. LCMS (ESI) m / z 591.1 [M+H] + Example 32 - Precursor: 2-(4-cyanophenyl)-N-((2S)-5-hydroxy-1-oxo-1-(((2S)-5,5,5-trifluoro-1-hydroxy-1-(thiazol-2-yl)pentan-2-yl)amino)hexan-2-yl)thiazol-5-carboxamide This compound was prepared according to the procedure described in step 16 of the synthesis in Example 1. 30 mg of the 32- precursor (28% yield, 86% purity) as a white solid was obtained from 38 mg of acid and 64 mg of 3-K. LCMS (ESI) m / z 582.2 [M+H] + Example 33 - Precursor: 2-(3,5-difluorophenyl)-N-((2S)-5-hydroxy-1-oxo-1-(((2S)-5,5,5-trifluoro-1-hydroxy-1-(thiazol-2-yl)pentan-2-yl)amino)hexan-2-yl)oxazol-5-carboxamide This compound was prepared according to the procedure described in step 16 of the synthesis in Example 1. 67 mg of the 33- precursor (62% yield, 85% purity) as a white solid was obtained from 65 mg of 3-K and 36 mg of acid. LCMS (ESI) m / z 577.1 [M+H] + Example 34 - Precursor: 2-(3,5-difluorophenyl)-N-((2S)-5-hydroxy-1-oxo-1-(((2S)-5,5,5-trifluoro-1-hydroxy-1-(thiazol-2-yl)pentan-2-yl)amino)hexan-2-yl)thiazol-5-carboxamide This compound was prepared according to the procedure described in step 16 of the synthesis in Example 1. 43 mg of the 34-precursor (38% yield, 83% purity) was obtained as a white solid from 64 mg of 3-K and 38 mg of acid. LCMS (ESI) m / z 593.1 [M+H] + Example 35 - Precursor: 2-(3-chloro-5-fluorophenyl)-N-((2S)-5-hydroxy-1-oxo-1-(((2S)-5,5,5-trifluoro-1-hydroxy-1-(thiazol-2-yl)pentan-2-yl)amino)hexan-2-yl)thiazol-5-carboxamide This compound was prepared according to the procedure described in step 16 of the synthesis in Example 1. 75 mg of the 35- precursor (75 mg, 65% yield, 83% purity) was obtained as a white solid from 64 mg of 3-K and 45 mg of acid. LCMS (ESI) m / z 609.0 [M+H] + Example 36 - Precursor: 2-(3,5-dichlorophenyl)-N-((2S)-5-hydroxy-1-oxo-1-(((2S)-5,5,5-trifluoro-1-hydroxy-1-(thiazol-2-yl)pentan-2-yl)amino)hexan-2-yl)oxazol-5-carboxamide This compound was prepared according to the procedure described in step 16 of the synthesis in Example 1. 60 mg of the 36-precursor (53% yield, 84% purity) was obtained as a white solid from 75 mg of 3-K and 40 mg of acid. LCMS (ESI) m / z 609.2 [M+H] + Example 37 - Precursor: 2-(3-fluoro-5-(trifluoromethyl)phenyl)-N-((2S)-5-hydroxy-1-oxo-1-(((2S)-5,5,5-trifluoro-1-hydroxy-1-(thiazolyl)pentan-2-yl)amino)hexan-2-yl)oxazol-5-carboxamide DIEA (41 mg, 315.4 μmol, 2 equivalents) and T3P (120 mg, 189.2 μmol, 50% purity, in EtOAc, 1.2 equivalents) were added to a solution of 3-K (64 mg, 157.7 μmol, 1 equivalent, HCl) and 2-[3-fluoro-5-(trifluoromethyl)phenyl]oxazol-5-carboxylic acid (39 mg, 141.9 μmol, 0.9 equivalents) in DCM (1 mL) at 0 °C. The mixture was stirred at 15 °C for 12 h. The reaction mixture was diluted with water (10 mL) and extracted with DCM (10 mL x 3). The combined organic layers were dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography (SiO2, 0-7% methanol / DCM). A colorless oily 37-precursor (20 mg, 31.9 μmol, 20% yield) was obtained. LCMS (ESI) m / z 627.3 [M+H] + Example 38 - Precursor: 2-(5-chloro-2-fluorophenyl)-N-((2S)-5-hydroxy-1-oxo-1-(((2S)-5,5,5-trifluoro-1-hydroxy-1-(thiazol-2-yl)pentan-2-yl)amino)hexan-2-yl)oxazol-5-carboxamide This compound was prepared according to the procedure described in step 16 of the synthesis in Example 1. 67 mg of the 38-precursor (39% yield, 93% purity) was obtained as a white solid from 129 mg of 3-K and 64 mg of acid. LCMS (ESI) m / z 593.3 [M+H] + Example 39 - Precursor: 2-(2-chloro-5-fluorophenyl)-N-((2S)-5-hydroxy-1-oxo-1-(((2S)-5,5,5-trifluoro-1-hydroxy-1-(thiazol-2-yl)pentan-2-yl)amino)hexan-2-yl)oxazol-5-carboxamide This compound was prepared according to the procedure described in step 16 of the synthesis in Example 1. 160 mg of the 39- precursor (55% yield, 95% purity) was obtained as a colorless oil from 190 mg of 3-K and 113 mg of acid. LCMS (ESI) m / z 593.1 [M+H] + Example 40 - Precursor: 2-(2,5-difluorophenyl)-N-((2S)-5-hydroxy-1-oxo-1-(((2S)-5,5,5-trifluoro-1-hydroxy-1-(thiazol-2-yl)pentan-2-yl)amino)hexan-2-yl)oxazol-5-carboxamide This compound was prepared according to the procedure described in step 16 of the synthesis in Example 1. 100 mg of the 40- precursor (41% yield, 93% purity) as a white solid was obtained from 129 mg of 3-K and 60 mg of acid. LCMS (ESI) m / z 577.3 [M+H] + Example 41 - Precursor: 2-(2,5-dichlorophenyl)-N-((2S)-5-hydroxy-1-oxo-1-(((2S)-5,5,5-trifluoro-1-hydroxy-1-(thiazol-2-yl)pentan-2-yl)amino)hexan-2-yl)oxazol-5-carboxamide This compound was prepared according to the procedure described in step 16 of the synthesis in Example 1. 160 mg of the 41-precursor (49% yield, 90% purity) was obtained as a yellow oil from 194 mg of 3-K and 123 mg of acid. LCMS (ESI) m / z 609.1 [M+H] + Example 42 - Precursor: 2-(2-chloro-4-fluorophenyl)-N-((2S)-5-hydroxy-1-oxo-1-(((2S)-5,5,5-trifluoro-1-hydroxy-1-(thiazol-2-yl)pentan-2-yl)amino)hexan-2-yl)oxazol-5-carboxamide This compound was prepared according to the procedure described in step 16 of the synthesis in Example 1. 160 mg of the 42- precursor (51% yield, 90% purity) was obtained as a yellow oil from 194 mg of 3-K and 115 mg of acid. LCMS (ESI) m / z 593.1 [M+H] + Example 43 - Precursor: 2-(4-chloro-2-fluorophenyl)-N-((2S)-5-hydroxy-1-oxo-1-(((2S)-5,5,5-trifluoro-1-hydroxy-1-(thiazol-2-yl)pentan-2-yl)amino)hexan-2-yl)oxazol-5-carboxamide T4P (346 mg, 960.9 μmol, 50% purity, in DMF, 3 equivalents) and DIEA (124 mg, 960.9 μmol, 3 equivalents) were added to a solution of 2-(4-chloro-2-fluoro-phenyl)oxazol-5-carboxylic acid (77 mg, 320.3 μmol, 1 equivalent, HCl) in DMF (4 mL). The mixture was stirred at 25 °C under N2 for 2 h. The mixture was then added to 5% LiCl (20 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography (SiO2, 0-10% methanol / DCM). A yellow solid 43-progenitor (145 mg, 212.7 μmol, 58% yield, 87% purity) was obtained. LCMS (ESI) m / z 593.0 [M+H] + Example 44 - Precursor: 2-(2,4-dichlorophenyl)-N-((2S)-5-hydroxy-1-oxo-1-(((2S)-5,5,5-trifluoro-1-hydroxy-1-(thiazol-2-yl)pentan-2-yl)amino)hexan-2-yl)oxazol-5-carboxamide This compound was prepared according to the procedure described in step 16 of the synthesis in Example 1. 100 mg of the 44-precursor (44% yield, 80% purity) was obtained as a colorless oil from 120 mg of 3-K and 76 mg of acid. LCMS (ESI) m / z 609.0 [M+H] + Example 45 - Precursor: 2-(3-cyano-5-fluorophenyl)-N-((2S)-5-hydroxy-1-oxo-1-(((2S)-5,5,5-trifluoro-1-hydroxy-1-(thiazolyl)pentan-2-yl)amino)hexan-2-yl)oxazol-5-carboxamide This compound was prepared according to the procedure described in step 16 of the synthesis in Example 1. 200 mg of the 45- precursor (68% yield, 96% purity) was obtained as a colorless oil from 112 mg of acid and 259 mg of 3-K. LCMS (ESI) m / z 584.2 [M+H] + Example 46 - Precursor: 2-(3,5-difluorophenyl)-N-((2S)-1-oxo-1-(((2S)-5,5,5-trifluoro-1-hydroxy-1-(thiazol-2-yl)pentan-2-yl)amino)propan-2-yl)oxazol-5-carboxamide This compound was prepared according to the procedure described in step 16 of the synthesis in Example 1. 60 mg of the 46- precursor (40% yield, 90% purity) as a yellow solid was obtained from 92 mg of 4-C and 59 mg of acid. LCMS (ESI) m / z 519.2 [M+H] + Example 47 - Precursor: 2-(2-fluorophenyl)-N-((2S)-1-oxo-1-(((2S)-5,5,5-trifluoro-1-hydroxy-1-(thiazol-2-yl)pentan-2-yl)amino)propan-2-yl)oxazol-5-carboxamide This compound was prepared according to the procedure described in step 16 of the synthesis in Example 1. 170 mg of the 47- precursor (63% yield, 85% purity) was obtained as a yellow oil from 160 mg of 4-C and 95 mg of acid. LCMS (ESI) m / z 501.2 [M+H] + Example 48 - Precursor: 2-(3-fluorophenyl)-N-((2S)-1-oxo-1-(((2S)-5,5,5-trifluoro-1-hydroxy-1-(thiazol-2-yl)pentan-2-yl)amino)propan-2-yl)oxazol-5-carboxamide This compound was prepared according to the procedure described in step 16 of the synthesis in Example 1. 100 mg of the 48- precursor (51% yield, 92% purity) as a yellow solid was obtained from 84 mg of 4-C and 50 mg of acid. LCMS (ESI) m / z 501.2 [M+H] + Example 49 - Precursor: 2-(4-fluorophenyl)-N-((2S)-1-oxo-1-(((2S)-5,5,5-trifluoro-1-hydroxy-1-(thiazol-2-yl)pentan-2-yl)amino)propan-2-yl)oxazol-5-carboxamide This compound was prepared according to the procedure described in step 16 of the synthesis in Example 1. 100 mg of the 49- precursor (52% yield, 90% purity) as a yellow oil was obtained from 120 mg of 4-C and 64 mg of acid. LCMS (ESI) m / z 501.1 [M+H] + Example 50 - Precursor: 2-(2-chlorophenyl)-N-((2S)-1-oxo-1-(((2S)-5,5,5-trifluoro-1-hydroxy-1-(thiazol-2-yl)pentan-2-yl)amino)propan-2-yl)oxazol-5-carboxamide This compound was prepared according to the procedure described in step 16 of the synthesis in Example 1. 200 mg of the 50- precursor (76% yield, 90% purity) as a yellow oil was obtained from 160 mg of 4-C and 100 mg of acid. LCMS (ESI) m / z 517.1 [M+H] + Example 51 - Precursor: 2-(3-chlorophenyl)-N-((2S)-1-oxo-1-(((2S)-5,5,5-trifluoro-1-hydroxy-1-(thiazol-2-yl)pentan-2-yl)amino)propan-2-yl)oxazol-5-carboxamide This compound was prepared according to the procedure described in step 16 of the synthesis in Example 1. 180 mg of the 51- precursor (82% yield, 85% purity) as a yellow oil was obtained from 126 mg of 4-C and 81 mg of acid. LCMS (ESI) m / z 516.9 [M+H] + Example 52 - Precursor: 2-(4-chlorophenyl)-N-((2S)-1-oxo-1-(((2S)-5,5,5-trifluoro-1-hydroxy-1-(thiazol-2-yl)pentan-2-yl)amino)propan-2-yl)oxazol-5-carboxamide This compound was prepared according to the procedure described in step 16 of the synthesis in Example 1. 56 mg of the 52- precursor (51% yield, 95% purity) as a yellow oil was obtained from 70 mg of 4-C and 41 mg of acid. LCMS (ESI) m / z 517.1 [M+H] + Example 53 - Precursor: 2-(3,5-dichlorophenyl)-N-((2S)-1-oxo-1-(((2S)-5,5,5-trifluoro-1-hydroxy-1-(thiazol-2-yl)pentan-2-yl)amino)propan-2-yl)oxazol-5-carboxamide This compound was prepared according to the procedure described in step 16 of the synthesis in Example 1. 160 mg of the 53- precursor (53.1% yield, 88% purity) as a yellow solid was obtained from 155 mg of 4-C and 94 mg of acid. LCMS (ESI) m / z 550.8 [M+H] + Example 54 - Precursor: 2-(2-chloro-5-fluorophenyl)-N-((2S)-1-oxo-1-(((2S)-5,5,5-trifluoro-1-hydroxy-1-(thiazol-2-yl)pentan-2-yl)amino)propan-2-yl)oxazol-5-carboxamide This compound was prepared according to the procedure described in step 16 of the synthesis in Example 1. 80 mg of the colorless oily 54- precursor (57.9% yield, 90% purity) was obtained from 62 mg of acid and 81 mg of 4-C. LCMS (ESI) m / z 535.2 [M+H] + Example 55 - Precursor: 2-(5-chloro-2-fluorophenyl)-N-((2S)-1-oxo-1-(((2S)-5,5,5-trifluoro-1-hydroxy-1-(thiazol-2-yl)pentan-2-yl)amino)propan-2-yl)oxazol-5-carboxamide This compound was prepared according to the procedure described in step 16 of the synthesis in Example 1. 140 mg of the 55- precursor (77% yield, 90% purity) was obtained as a yellow oil from 120 mg of 4-C and 83 mg of acid. LCMS (ESI) m / z 535.0 [M+H] + Example 56 - Precursor: 2-(2-fluorophenyl)-N-((2S)-1-oxo-1-(((2S)-5,5,5-trifluoro-1-hydroxy-1-(thiazol-2-yl)pentan-2-yl)amino)propan-2-yl)thiazol-5-carboxamide This compound was prepared according to the procedure described in step 16 of the synthesis in Example 1. 100 mg of the 56- precursor (47.5% yield, 90% purity) as a white solid was obtained from 85 mg of 4-C and 65 mg of acid. LCMS (ESI) m / z 517.1 [M+H] + Example 57 - Precursor: 2-(3-fluorophenyl)-N-((2S)-1-oxo-1-(((2S)-5,5,5-trifluoro-1-hydroxy-1-(thiazol-2-yl)pentan-2-yl)amino)propan-2-yl)thiazol-5-carboxamide This compound was prepared according to the procedure described in step 16 of the synthesis in Example 1. 95 mg of the 57- precursor (53% yield, 97% purity) as a yellow oil was obtained from 118 mg of 4-C and 83 mg of acid. LCMS (ESI) m / z 516.7 [M+H] + Example 58 - Precursor: 2-(4-fluorophenyl)-N-((2S)-1-oxo-1-(((2S)-5,5,5-trifluoro-1-hydroxy-1-(thiazol-2-yl)pentan-2-yl)amino)propan-2-yl)thiazol-5-carboxamide This compound was prepared according to the procedure described in step 16 of the synthesis in Example 1. 110 mg of the 58- precursor (59% yield, 95% purity) was obtained as a yellow solid from 120 mg of 4-C and 77 mg of acid. LCMS (ESI) m / z 517.1 [M+H] + Example 59 - Precursor: 2-(2-chlorophenyl)-N-((2S)-1-oxo-1-(((2S)-5,5,5-trifluoro-1-hydroxy-1-(thiazol-2-yl)pentan-2-yl)amino)propan-2-yl)thiazol-5-carboxamide This compound was prepared according to the procedure described in step 16 of the synthesis in Example 1. 245 mg of the 59- precursor (70% yield, 95% purity) was obtained as a colorless oil from 169 mg of 4-C and 113 mg of acid. LCMS (ESI) m / z 533.1 [M+H] + Example 60 - Precursor: 2-(3-chlorophenyl)-N-((2S)-1-oxo-1-(((2S)-5,5,5-trifluoro-1-hydroxy-1-(thiazol-2-yl)pentan-2-yl)amino)propan-2-yl)thiazol-5-carboxamide This compound was prepared according to the procedure described in step 16 of the synthesis in Example 1. 180 mg of the 60- precursor, present as a yellow oil, was obtained from 126 mg of 4-C and 87 mg of acid (86.7% yield, 93% purity). LCMS (ESI) m / z 533.0 [M+H] + Example 61 - Precursor: 2-(4-chlorophenyl)-N-((2S)-1-oxo-1-(((2S)-5,5,5-trifluoro-1-hydroxy-1-(thiazol-2-yl)pentan-2-yl)amino)propan-2-yl)thiazol-5-carboxamide This compound was prepared according to the procedure described in step 16 of the synthesis in Example 1. 130 mg of the 61- precursor (67.2% yield, 95% purity) as a yellow oil was obtained from 120 mg of 4-C and 83 mg of acid. LCMS (ESI) m / z 533.1 [M+H] + Example 62 - Precursor: 2-(3-chloro-5-fluorophenyl)-N-((2S)-1-oxo-1-(((2S)-5,5,5-trifluoro-1-hydroxy-1-(thiazol-2-yl)pentan-2-yl)amino)propan-2-yl)thiazol-5-carboxamide This compound was prepared according to the procedure described in step 16 of the synthesis in Example 1. 120 mg of the 62- precursor (60% yield, 95% purity) was obtained as a yellow solid from 120 mg of 4-C and 89 mg of acid. LCMS (ESI) m / z 551.0 [M+H] + Example 63 - Precursor: 2-(3,5-dichlorophenyl)-N-((2S)-1-oxo-1-(((2S)-5,5,5-trifluoro-1-hydroxy-1-(thiazol-2-yl)pentan-2-yl)amino)propan-2-yl)thiazol-5-carboxamide This compound was prepared according to the procedure described in step 16 of the synthesis in Example 1. 140 mg of the 63- precursor (68% yield, 95% purity) was obtained as a yellow solid from 120 mg of 4-C and 95 mg of acid. LCMS (ESI) m / z 567.0 [M+H] + Example 64 - Precursor: 2-(3,5-difluorophenyl)-N-((2S)-1-oxo-1-(((2S)-5,5,5-trifluoro-1-hydroxy-1-(thiazol-2-yl)pentan-2-yl)amino)propan-2-yl)thiazol-5-carboxamide This compound was prepared according to the procedure described in step 16 of the synthesis in Example 1. 49 mg of the colorless oily 64- precursor (38.0% yield) was obtained from 64 mg of acid and 85 mg of 4-C. LCMS (ESI) m / z 535.0 [M+H] + Example 65 - Precursor: 2-(2,5-difluorophenyl)-N-((2S)-1-oxo-1-(((2S)-5,5,5-trifluoro-1-hydroxy-1-(thiazol-2-yl)pentan-2-yl)amino)propan-2-yl)thiazol-5-carboxamide This compound was prepared according to the procedure described in step 16 of the synthesis in Example 1. 100 mg of the 65- precursor (71% yield, 98% purity) as a white solid was obtained from 90 mg of 4-C and 75 mg of acid. LCMS (ESI) m / z 535.2 [M+H] + Example 66 - Precursor: 2-(2-chloro-5-fluorophenyl)-N-((2S)-1-oxo-1-(((2S)-5,5,5-trifluoro-1-hydroxy-1-(thiazol-2-yl)pentan-2-yl)amino)propan-2-yl)thiazol-5-carboxamide This compound was prepared according to the procedure described in step 16 of the synthesis in Example 1. 140 mg of the 66-precursor (91.2% yield, 98% purity) was obtained as a white solid from 95 mg of 4-C and 84 mg of 287-B. LCMS (ESI) m / z 551.0 [M+H] + Example 67 - Precursor: 2-(5-chloro-2-fluorophenyl)-N-((2S)-1-oxo-1-(((2S)-5,5,5-trifluoro-1-hydroxy-1-(thiazol-2-yl)pentan-2-yl)amino)propan-2-yl)thiazol-5-carboxamide This compound was prepared according to the procedure described in step 16 of the synthesis in Example 1. 200 mg of the 67- precursor (71.0% yield, 90% purity) as a yellow oil was obtained from 160 mg of 4-C and 119 mg of acid. LCMS (ESI) m / z 551.1 [M+H] + Example 68 - Precursor: 2-(2,5-dichlorophenyl)-N-((2S)-1-oxo-1-(((2S)-5,5,5-trifluoro-1-hydroxy-1-(thiazol-2-yl)pentan-2-yl)amino)propan-2-yl)thiazol-5-carboxamide This compound was prepared according to the procedure described in step 16 of the synthesis in Example 1. 100 mg of the 68- precursor (30.7% yield, 75% purity) as a yellow oil was obtained from 150 mg of 4-C and 118 mg of acid. LCMS (ESI) m / z 567.0 [M+H] + Example 69 - Precursor: 2-(4-chlorophenyl)-N-((2S)-5-hydroxy-1-oxo-1-(((2S)-6,6,6-trifluoro-1-hydroxy-1-(thiazol-2-yl)hexane-2-yl)amino)hexane-2-yl)thiazol-5-carboxamide This compound was prepared according to the procedure described in step 16 of the synthesis in Example 1. 53 mg of the 69- precursor (50.8% yield, 90% purity) as a colorless oil was obtained from 66 mg of 1-Q and 37 mg of acid. LCMS (ESI) m / z 605.1 [M+H] + Example 70 - Precursor: 2-(2-fluorophenyl)-N-((2S)-5-hydroxy-1-oxo-1-(((2S)-6,6,6-trifluoro-1-hydroxy-1-(thiazol-2-yl)hexane-2-yl)amino)hexane-2-yl)thiazol-5-carboxamide This compound was prepared according to the procedure described in step 16 of the synthesis in Example 1. 80 mg of the 70- precursor (71% yield, 98% purity) as a white solid was obtained from 78 mg of 1-Q and 42 mg of acid. LCMS (ESI) m / z 589.2 [M+H] + Example 71 - Precursor: 2-(3-chlorophenyl)-N-((2S)-5-hydroxy-1-oxo-1-(((2S)-6,6,6-trifluoro-1-hydroxy-1-(thiazol-2-yl)hexane-2-yl)amino)hexane-2-yl)thiazol-5-carboxamide This compound was prepared according to the procedure described in step 16 of the synthesis in Example 1. 96 mg of the 71- precursor, present as a yellow oil, was obtained from 55 mg of acid and 98 mg of 1-Q (63% yield, 94% purity). LCMS (ESI) m / z 605.1 [M+H] + Example 72 - Precursor: 2-(2-chlorophenyl)-N-((2S)-5-hydroxy-1-oxo-1-(((2S)-6,6,6-trifluoro-1-hydroxy-1-(thiazol-2-yl)hexane-2-yl)amino)hexane-2-yl)thiazol-5-carboxamide This compound was prepared according to the procedure described in step 16 of the synthesis in Example 1. 71 mg of the 72- precursor (72% yield, 94% purity) was obtained as a yellow solid from 65 mg of 1-Q and 33 mg of acid. LCMS (ESI) m / z 605.2 [M+H] + Example 73 - Precursor: N-((2S)-5-hydroxy-1-oxo-1-(((2S)-6,6,6-trifluoro-1-hydroxy-1-(thiazolyl)hexane-2-yl)amino)hexane-2-yl)-2-(p-tolyl)thiazolyl-5-carboxamide This compound was prepared according to the procedure described in step 16 of the synthesis in Example 1. 75 mg of the 73- precursor (53% yield, 97% purity) was obtained as a colorless oil from 65 mg of 1-Q and 34 mg of acid. LCMS (ESI) m / z 585.2 [M+H] + Example 74 - Precursor: N-((2S)-5-hydroxy-1-oxo-1-(((2S)-6,6,6-trifluoro-1-hydroxy-1-(thiazolyl)hexane-2-yl)amino)hexane-2-yl)-2-(m-tolyl)thiazolyl-5-carboxamide This compound was prepared according to the procedure described in step 16 of the synthesis in Example 1. 75 mg of the 74- precursor (67% yield, 98% purity) was obtained as a white solid from 78 mg of 1-Q and 41 mg of acid. LCMS (ESI) m / z 585.3 [M+H] + Example 75 - Precursor: N-((2S)-5-hydroxy-1-oxo-1-(((2S)-6,6,6-trifluoro-1-hydroxy-1-(thiazolyl-2-yl)hexan-2-yl)amino)hexan-2-yl)-2-(o-tolyl)thiazolyl-5-carboxamide This compound was prepared according to the procedure described in step 16 of the synthesis in Example 1. 85 mg of the 75- precursor (59% yield, 95% purity) as a white solid was obtained from 98 mg of 1-Q and 56 mg of acid. LCMS (ESI) m / z 585.1 [M+H] + Example 76 - Precursor: 2-(4-cyanophenyl)-N-((2S)-5-hydroxy-1-oxo-1-(((2S)-6,6,6-trifluoro-1-hydroxy-1-(thiazol-2-yl)hexane-2-yl)amino)hexane-2-yl)thiazol-5-carboxamide This compound was prepared according to the procedure described in step 16 of the synthesis in Example 1. 79 mg of the 76-precursor, present as a yellow oil, was obtained from 53 mg of acid and 98 mg of 1-Q (44% yield, 78% purity). LCMS (ESI) m / z 596.1 [M+H] + Example 77 - Precursor: 2-(3-cyanophenyl)-N-((2S)-5-hydroxy-1-oxo-1-(((2S)-6,6,6-trifluoro-1-hydroxy-1-(thiazol-2-yl)hexane-2-yl)amino)hexane-2-yl)thiazol-5-carboxamide This compound was prepared according to the procedure described in step 16 of the synthesis in Example 1. 80 mg of the 77- precursor (52% yield, 90% purity) as a white solid was obtained from 66 mg of 1-Q and 43 mg of acid. LCMS (ESI) m / z 596.2 [M+H] + Example 78 - Precursor: 2-(2-cyanophenyl)-N-((2S)-5-hydroxy-1-oxo-1-(((2S)-6,6,6-trifluoro-1-hydroxy-1-(thiazol-2-yl)hexane-2-yl)amino)hexane-2-yl)thiazol-5-carboxamide This compound was prepared according to the procedure described in step 16 of the synthesis in Example 1. 55 mg of the 78- precursor (35% yield, 90% purity) as a white solid was obtained from 98 mg of 1-Q and 64 mg of acid. LCMS (ESI) m / z 596.1 [M+H] + Example 79 - Precursor: 2-(2,6-difluorophenyl)-N-((2S)-5-hydroxy-1-oxo-1-(((2S)-6,6,6-trifluoro-1-hydroxy-1-(thiazol-2-yl)hexane-2-yl)amino)hexane-2-yl)thiazol-5-carboxamide This compound was prepared according to the procedure described in step 16 of the synthesis in Example 1. 85 mg of the 79- precursor (87% yield, 96% purity) as a white solid was obtained from 65 mg of 1-Q and 37 mg of acid. LCMS (ESI) m / z 607.2 [M+H] + Example 80 - Precursor: 2-(3,5-difluorophenyl)-N-((2S)-5-hydroxy-1-oxo-1-(((2S)-6,6,6-trifluoro-1-hydroxy-1-(thiazol-2-yl)hexane-2-yl)amino)hexane-2-yl)thiazol-5-carboxamide This compound was prepared according to the procedure described in step 16 of the synthesis in Example 1. 53 mg of the 80- precursor (39% yield, 70% purity) as a white solid was obtained from 66 mg of 1-Q and 39 mg of acid. LCMS (ESI) m / z 607.2 [M+H] + Example 81 - Precursor: 2-(2,4-difluorophenyl)-N-((2S)-5-hydroxy-1-oxo-1-(((2S)-6,6,6-trifluoro-1-hydroxy-1-(thiazol-2-yl)hexane-2-yl)amino)hexane-2-yl)thiazol-5-carboxamide This compound was prepared according to the procedure described in step 16 of the synthesis in Example 1. 80 mg of the 81- precursor (53% yield, 84% purity) as a colorless oil was obtained from 87 mg of 1-Q and 50 mg of acid. LCMS (ESI) m / z: 607.1 [M+H] + Example 82 - Precursor: N-((2S)-5-hydroxy-1-oxo-1-(((2S)-6,6,6-trifluoro-1-hydroxy-1-(thiazol-2-yl)hexane-2-yl)amino)hexane-2-yl)-2-phenylthiazol-5-carboxamide This compound was prepared according to the procedure described in step 16 of the synthesis in Example 1. 3.3 g of the 82- precursor (5.6 mmol, 67% yield, 95% purity) as a white solid was obtained from 3.5 g of 1-Q and 1.7 g of acid. LCMS (ESI) m / z 571.3 [M+H] + Example 83 - Precursor: 2-(3-fluorophenyl)-N-((2S)-5-hydroxy-1-oxo-1-(((2S)-6,6,6-trifluoro-1-hydroxy-1-(thiazol-2-yl)hexane-2-yl)amino)hexane-2-yl)oxazol-5-carboxamide This compound was prepared according to the procedure described in step 16 of the synthesis in Example 1. 60 mg of the colorless oily 83- precursor (34% yield, 94% purity) was obtained from 40 mg of acid and 64 mg of 1-Q. LCMS (ESI) m / z 573.2 [M+H] + Example 84 - Precursor: 2-(5-fluoro-2-methylphenyl)-N-((2S)-5-hydroxy-1-oxo-1-(((2S)-6,6,6-trifluoro-1-hydroxy-1-(thiazol-2-yl)hexane-2-yl)amino)hexane-2-yl)thiazol-5-carboxamide This compound was prepared according to the procedure described in step 16 of the synthesis in Example 1. 81 mg of the 84- precursor, present as a yellow oil, was obtained from 55 mg of acid and 98 mg of 1-Q (52% yield, 91% purity). LCMS (ESI) m / z 603.1 [M+H] + Example 85 - Precursor: 2-(5-fluoro-2-(fluoromethyl)phenyl)-N-((2S)-5-hydroxy-1-oxo-1-(((2S)-6,6,6-trifluoro-1-hydroxy-1-(thiazol-2-yl)hexane-2-yl)amino)hexane-2-yl)thiazol-5-carboxamide This compound was prepared according to the procedure described in step 16 of the synthesis in Example 1. 57 mg of the 85- precursor (59% yield, 100% purity) as a yellow solid was obtained from 65 mg of 1-Q and 39 mg of acid. LCMS (ESI) m / z 621.1 [M+H] + Example 86 - Precursor: N-((2S)-5-hydroxy-1-oxo-1-(((2S)-6,6,6-trifluoro-1-hydroxy-1-(thiazolyl-2-yl)hexan-2-yl)amino)hexan-2-yl)-2-(2-(trifluoromethyl)phenyl)thiazolyl-5-carboxamide This compound was prepared according to the procedure described in step 16 of the synthesis in Example 1. 75 mg of the 86- precursor (63% yield, 99% purity) as a white solid was obtained from 50 mg of acid and 64 mg of 1-Q. LCMS (ESI) m / z 639.0 [M+H] + Example 87 - Precursor: N-((2S)-5-hydroxy-1-oxo-1-(((2S)-6,6,6-trifluoro-1-hydroxy-1-(thiazol-2-yl)hexan-2-yl)amino)hexan-2-yl)-2-(3-(trifluoromethyl)phenyl)thiazol-5-carboxamide This compound was prepared according to the procedure described in step 16 of the synthesis in Example 1. 73 mg of the 87- precursor (73% yield, 98% purity) as a yellow oil was obtained from 65 mg of 1-Q and 42 mg of acid. LCMS (ESI) m / z 639.4 [M+H] + Example 88 - Precursor: N-((2S)-5-hydroxy-1-oxo-1-(((2S)-6,6,6-trifluoro-1-hydroxy-1-(thiazolyl)hexane-2-yl)amino)hexane-2-yl)-2-(4-(trifluoromethyl)phenyl)thiazolyl-5-carboxamide This compound was prepared according to the procedure described in step 16 of the synthesis in Example 1. 53 mg of the 88- precursor (48% yield, 91% purity) as a white solid was obtained from 65 mg of 1-Q and 44 mg of acid. LCMS (ESI) m / z 639.2 [M+H] + Example 89 - Precursor: 2-(3-fluorophenyl)-N-((2S)-5-hydroxy-1-oxo-1-(((2S)-6,6,6-trifluoro-1-hydroxy-1-(thiazol-2-yl)hexane-2-yl)amino)hexane-2-yl)thiazol-5-carboxamide This compound was prepared according to the procedure described in step 16 of the synthesis in Example 1. 180 mg of the 89- precursor (50% yield, 56% purity) as a white solid was obtained from 111 mg of 1-Q and 62 mg of acid. LCMS (ESI) m / z 589.3 [M+H] + Example 90 - Precursor: 2-(2,5-difluorophenyl)-N-((2S)-5-hydroxy-1-oxo-1-(((2S)-6,6,6-trifluoro-1-hydroxy-1-(thiazol-2-yl)hexane-2-yl)amino)hexane-2-yl)thiazol-5-carboxamide This compound was prepared according to the procedure described in step 16 of the synthesis in Example 1. 76 mg of the 90- precursor (35% yield, 88% purity) was obtained as a yellow oil from 131 mg of 1-Q and 75 mg of acid. LCMS (ESI) m / z 607.1 [M+H] + Example 91 - Precursor: 2-(2,3-difluorophenyl)-N-((2S)-1-oxo-1-(((2S)-5,5,5-trifluoro-1-hydroxy-1-(thiazol-2-yl)pentan-2-yl)amino)propan-2-yl)oxazol-5-carboxamide This compound was prepared according to the procedure described in step 16 of the synthesis in Example 1. 101 mg of the 91- precursor (53% yield, 99% purity) was obtained as a white solid from 85 mg of 4-C and 55 mg of acid. LCMS (ESI) m / z 519.0 [M+H] + Example 92 - Precursor: 2-(2,3-dichlorophenyl)-N-((2S)-1-oxo-1-(((2S)-5,5,5-trifluoro-1-hydroxy-1-(thiazol-2-yl)pentan-2-yl)amino)propan-2-yl)oxazol-5-carboxamide This compound was prepared according to the procedure described in step 16 of the synthesis in Example 1. 125 mg of the 92- precursor (63% yield, 100% purity) was obtained as a white solid from 126 mg of 4-C and 93 mg of acid. LCMS (ESI) m / z 551.0 [M+H] + Example 93 - Precursor: 2-(2-chloro-3-fluorophenyl)-N-((2S)-1-oxo-1-(((2S)-5,5,5-trifluoro-1-hydroxy-1-(thiazol-2-yl)pentan-2-yl)amino)propan-2-yl)oxazol-5-carboxamide This compound was prepared according to the procedure described in step 16 of the synthesis in Example 1. 130 mg of the 93- precursor (70% yield, 99% purity) was obtained as a white solid from 120 mg of 4-C and 92 mg of acid. LCMS (ESI) m / z 534.9 [M+H] + Example 94 - Precursor: 2-(3-chloro-2-fluorophenyl)-N-((2S)-1-oxo-1-(((2S)-5,5,5-trifluoro-1-hydroxy-1-(thiazol-2-yl)pentan-2-yl)amino)propan-2-yl)oxazol-5-carboxamide This compound was prepared according to the procedure described in step 16 of the synthesis in Example 1. 122 mg of the 94- precursor (62% yield, 99% purity) was obtained as a white solid from 126 mg of 4-C and 88 mg of acid. LCMS (ESI) m / z 535.0 [M+H] + Example 95 - Precursor: 2-(2,3-difluorophenyl)-N-((2S)-5-hydroxy-1-oxo-1-(((2S)-5,5,5-trifluoro-1-hydroxy-1-(thiazol-2-yl)pentan-2-yl)amino)hexan-2-yl)oxazol-5-carboxamide This compound was prepared according to the procedure described in step 16 of the synthesis in Example 1. 58 mg of the 95- precursor (39% yield, 93% purity) as a white solid was obtained from 36 mg of acid and 65 mg of 3-K. LCMS (ESI) m / z 576.9 [M+H] + Example 96 - Precursor: 2-(2-chloro-3-fluorophenyl)-N-((2S)-5-hydroxy-1-oxo-1-(((2S)-5,5,5-trifluoro-1-hydroxy-1-(thiazol-2-yl)pentan-2-yl)amino)hexan-2-yl)oxazol-5-carboxamide This compound was prepared according to the procedure described in step 16 of the synthesis in Example 1. 70 mg of the 96- precursor (44% yield, 90% purity) as a white solid was obtained from 69 mg of acid and 97 mg of 3-K. LCMS (ESI) m / z 593.1 [M+H] + Example 97 - Precursor: 2-(2,4-difluorophenyl)-N-((2S)-5-hydroxy-1-oxo-1-(((2S)-5,5,5-trifluoro-1-hydroxy-1-(thiazol-2-yl)pentan-2-yl)amino)hexan-2-yl)oxazol-5-carboxamide This compound was prepared according to the procedure described in step 16 of the synthesis in Example 1. 130 mg of the 97- precursor (66% yield, 93% purity) as a white solid was obtained from 86 mg of acid and 129 mg of 3-K. LCMS (ESI) m / z 577.2 [M+H] + Example 98 - Precursor: 2-(2,6-difluorophenyl)-N-((2S)-5-hydroxy-1-oxo-1-(((2S)-5,5,5-trifluoro-1-hydroxy-1-(thiazol-2-yl)pentan-2-yl)amino)hexan-2-yl)oxazol-5-carboxamide This compound was prepared according to the procedure described in step 16 of the synthesis in Example 1. 201 mg of the 98- precursor (45% yield, 83% purity) was obtained as a yellow oil from 158 mg of acid and 259 mg of 3-K. LCMS (ESI) m / z 577.2 [M+H] + Example 99 - Precursor: 2-(2-chloro-6-fluorophenyl)-N-((2S)-5-hydroxy-1-oxo-1-(((2S)-5,5,5-trifluoro-1-hydroxy-1-(thiazol-2-yl)pentan-2-yl)amino)hexan-2-yl)oxazol-5-carboxamide This compound was prepared according to the procedure described in step 16 of the synthesis in Example 1. 100 mg of the 99- precursor (37% yield, 100% purity) was obtained as a colorless oil from 110 mg of acid and 168 mg of 3-K. LCMS (ESI) m / z 593.0 [M+H] + Example 100 - Precursor: 2-(4-chloro-3-fluorophenyl)-N-((2S)-5-hydroxy-1-oxo-1-(((2S)-5,5,5-trifluoro-1-hydroxy-1-(thiazol-2-yl)pentan-2-yl)amino)hexan-2-yl)oxazol-5-carboxamide This compound was prepared according to the procedure described in step 16 of the synthesis in Example 1. 133 mg of the 100- precursor (55% yield, 98% purity) was obtained as a colorless oil from 96 mg of acid and 162 mg of 3-K. LCMS (ESI) m / z 593.1 [M+H] + Example 101 - Precursor: 2-(2-cyano-4-fluorophenyl)-N-((2S)-5-hydroxy-1-oxo-1-(((2S)-5,5,5-trifluoro-1-hydroxy-1-(thiazolyl)pentan-2-yl)amino)hexan-2-yl)oxazol-5-carboxamide This compound was prepared according to the procedure described in step 16 of the synthesis in Example 1. 90 mg of the 101- precursor (43% yield, 90% purity) as a white solid was obtained from 74 mg of acid and 130 mg of 3-K. LCMS (ESI) m / z 584.0 [M+H] + Example 102 - Precursor: 2-(3-chloro-5-cyanophenyl)-N-((2S)-5-hydroxy-1-oxo-1-(((2S)-5,5,5-trifluoro-1-hydroxy-1-(thiazolyl)pentan-2-yl)amino)hexan-2-yl)oxazol-5-carboxamide This compound was prepared according to the procedure described in step 16 of the synthesis in Example 1. 70 mg of the 10²⁻ precursor (47% yield, 96% purity) was obtained as a colorless oil from 39 mg of acid and 64 mg of 3-K. LCMS (ESI) m / z 600.2 [M+H] + Example 103 - Precursor: 2-(3-cyano-5-fluorophenyl)-N-((2S)-5-hydroxy-1-oxo-1-(((2S)-5,5,5-trifluoro-1-hydroxy-1-(thiazol-2-yl)pentan-2-yl)amino)hexan-2-yl)thiazol-5-carboxamide This compound was prepared according to the procedure described in step 16 of the synthesis in Example 1. 160 mg of the 10³- precursor (53% yield, 95% purity) was obtained as a yellow solid from 80 mg of acid and 130 mg of 3-K. LCMS (ESI) m / z 600.2 [M+H] + Example 104 - Precursor: 2-(3-chloro-5-cyanophenyl)-N-((2S)-5-hydroxy-1-oxo-1-(((2S)-5,5,5-trifluoro-1-hydroxy-1-(thiazol-2-yl)pentan-2-yl)amino)hexan-2-yl)thiazol-5-carboxamide This compound was prepared according to the procedure described in step 16 of the synthesis in Example 1. 230 mg of the 10⁴- precursor (49% yield, 95% purity) was obtained as a yellow solid from 85 mg of acid and 130 mg of 3-K. LCMS (ESI) m / z 616.1 [M+H] + Synthesis of Examples 7-104: Examples 7-46, 69-90, and 95-104 were prepared from the corresponding precursors according to the procedure described in the final step of the synthesis in Example 1. Examples 47-68 and 91-94 were prepared from the corresponding precursors according to the procedure described in the final step of the synthesis in Example 4. The chemical structures, names, LC / MS analyses, amounts prepared, and purities are summarized in Table 2.

[0143] Table 2: Examples 7-104 Biochemical assay: 1. Protein expression Mycobacterium tuberculosis (Mtb) ClpP1P2: Escherichia coli Bl21 carrying plasmids encoding ClpP1 and ClpP2 (Compton CL, Schmitz KR, Sauer RT, Sello JK. Antibacterial activity of and resistance to small molecule inhibitors of the ClpP peptidase. ACS Chem Biol. 20 December 2013;8(12):2669-77. doi: 10.1021 / cb400577b. Electronic version 4 October 2013. PMID:24047344;PMCID: PMC4287380). The strain was grown and protein expression was induced using an auto-induction medium at 30°C (Fraga H, Rodriguez B, Bardera A, Cid C, Akopian T, Kandror O, Park A, Colmenarejo G, Lelievre J, Goldberg A. Development of high throughput screening methods for inhibitors of ClpC1P1P2 from Mycobacteria tuberculosis. *AnalBiochem.* 2019 Feb 15;567:30-37. doi: 10.1016 / j.ab.2018.12.004. Electronic version 2018 Dec 10. PMID: 30543804; PMCID: PMC6484444).

[0144] 2. Protein purification As previously described, the protein was purified (Mtb ClpP1, ClpP2) (Akopian T, Kandror O, Raju RM, Unnikrishnan M, Rubin EJ, Goldberg AL. The active ClpP protease from M. tuberculosis is a complex composed of a heptameric ClpP1 and a ClpP2 ring. EMBO J. March 21, 2012;31(6):1529-41. doi: 10.1038 / emboj.2012.5. e.g. January 27, 2012. PMID: 22286948; PMCID: PMC3321190). Enzyme purification was performed at 4°C using the following buffers: Buffer A: 50 mM potassium phosphate, 100 mM KCl, 5 mM MgCl2, β-mercaptoethanol, and 10% glycerol at pH 7.6; Buffer B: 50 mM potassium phosphate, 100 mM KCl, 5 mM MgCl2, and 5% glycerol at pH 7.6. In typical purification, frozen cells (5–10 g) expressing ClpP1 or ClpP2 were resuspended in two volumes of Buffer A and ruptured using a French press at 1500 psi. The extract was centrifuged at 100,000 g and mixed with 5 ml of Ni-NTA agarose previously equilibrated in Buffer A. After incubation at 4°C for 4 hours, Ni-NTA agarose resin was transferred to an empty column, and proteins were eluted using a step gradient (0 mM, 25 mM, 50 mM, 100 mM, and 200 mM imidazole / buffer B). Fractions containing near-homogeneous ClpP1 or ClpP2 proteins were combined, concentrated on a Millipore MWCO 10,000 cutoff filter, and further purified by gel filtration on a Sephacryl S-300 column (1.5 × 12 cm) equilibrated with buffer B. The specific activity of the purified enzyme was in the range of 4–5 μmole / mg / min. High molecular weight protein peaks were combined, concentrated to approximately 2–5 mg / ml, and maintained at -80°C.

[0145] 3. Measurement of peptidase activity Acetyl-PKM-7-amino-4-methylcoumarin (Ac-PKM-amc) was used as a substrate to continuously measure the peptidase activity of ClpP1P2 as described below (Akopian T, Kandror O, Tsu C, Lai JH, Wu W, Liu Y, Zhao P, Park A, Wolf L, Dick LR, Rubin EJ, Bachovchin W, Goldberg AL. Cleavage specificity of Mycobacterium tuberculosis ClpP1P2 protease and identification of novel peptide substrates and antimicrobial borate inhibitors. Journal of Biochemistry, April 24, 2015; 290(17):11008-20. doi: 10.1074 / jbc.M114.625640. Electronic version March 10, 2015. PMID: 25759383; PMCID: PMC4409261). All peptidase activities were measured in black 96-well plates at 37°C. Each well contained 60 μL of 25 mM phosphate-buffered saline with 100 mM KCl, 5% glycerol, 0.5 mM activator 5132, and 10 μM of the fluorescent peptide substrate Ac-PKM-amc. The reaction was initiated by adding 15–20 nM of MtbClpP1P2. After shaking for 30 seconds, peptidase activity was measured at 37°C by continuously monitoring the rate of fluorescence 7-amino-4-methylcoumarin (AMC) generated from the fluorescent peptide substrate at 460 nm (excited at 380 nm) using a SpectraMax M5 plate reader (Molecular Devices, USA). Ki values ​​were calculated based on four-parameter logistic regression (Cheng Y, Prusoff WH. “Relationship between the inhibition constant (Ki) and the concentration of inhibitor which causes 50% inhibition (IC50) of an enzymatic reaction” Biochemical Pharmacology, December 1, 1973; 22(23):3099-108. doi: 10.1016 / 0006-2952(73)90196-2. PMID: 4202581).

[0146] The Ki values ​​for the inhibition of Mtb ClpP1P2 are listed in Table 3.

[0147] Cell-based assays 1. Mtb H37Rv MABA determination All experiments on Mycobacterium tuberculosis (Mtb) were performed in a Biosafety Level 3 (BSL3) laboratory using the previously described Microplate Almarin Blue Assay (MABA) (Cho, S. et al., 2015. Microplate Almarin Blue Assay (MABA) and Hypoxia Recovery Assay (LORA) for Mycobacterium tuberculosis. Parish, T., Roberts, D. (eds.) Mycobacterial Laboratory Protocols: Methods in Molecular Biology, Vol. 1285. Humana Publishers, New York, NY https: / / doi.org / 10.1007 / 978-1-4939-2450-9_17). Briefly, stock solutions of the compounds were prepared in dimethyl sulfoxide (DMSO) at the highest desired final concentration of 100×. The compound was transferred to an assay plate containing Middlebrook 7H12 medium (for 1 L of medium, 4.7 g 7H9 broth, 1 g casein (Bacto), 5 g bovine serum albumin (BSA), 4 mg catalase, and 5.6 mg palmitic acid). Nine 2-fold serial dilutions of the compound were performed in the assay plate. The plate was inoculated with Mycobacterium tuberculosis strain H37Rv (ATCC 27294) to achieve a final density of approximately 1 × 10⁵ CFU / mL and incubated at 37°C for 7 days. At the end of 7 days, a rezuril dye / tween 80 mixture (0.6 mM rezuril dye and 12 μL 20% Tween 80) was added to each well, and the plate was incubated at 37°C for an additional 18 to 24 hours. Fluorescence was measured on day 8 using a CLARIOstar plate reader (BMG LABTECH, Ortenberg, Germany). MIC is an extrapolated value and is defined as the lowest concentration at which a 90% reduction in fluorescence is achieved relative to the DMSO-treated control. MABA MIC values ​​are listed in Table 3.

[0148] 2. Vero cytotoxicity Cytotoxicity was evaluated using green monkey kidney cells (Vero cells ATCC-CCL-81, American Type Culture Collection, Manassas, VA) in the BSL2 laboratory. Stock solutions of the compounds were prepared in dimethyl sulfoxide at the highest desired final concentration of 100×. The compounds were transferred to assay plates containing Eagle's minimum essential medium, 10% fetal bovine serum supplemented with penicillin and streptomycin. Five 2-fold serial dilutions of the compounds were performed in the assay plates. Vero cells were added to achieve a final density of 1 × 10⁵ cells / mL, and the plates were incubated at 37°C and 5% CO₂ for 3 days. Twenty μL of 0.6 mM resazurite was added to each well, and fluorescence was measured at 530 / 590 nm excitation / emission wavelengths using a CLARIOstar (BMG LABTECH, Oltenberg, Germany) after 4 hours. 50 The concentration defined as achieving a 50% reduction in fluorescence relative to untreated cells. Rifampin, bedaquiline, tamoxifen, carbonyl cyanide-3-chlorophenylhydrazone, tacrine, and moxifloxacin were included as positive controls. IC50 50 The values ​​are listed in Table 3.

[0149] Table 3. ClpP1P2 Ki, Mtb H37Rv MABA MIC and Vero IC 50 *** Although the present application has been described with reference to embodiments, it should be understood that the scope of the claims should not be limited to the implementation methods set forth in the embodiments, but should be given the broadest interpretation consistent with the entire specification.

Claims

1. A compound of formula 1A: in: R2 is -CH2CH2CF3, -CH2CH2CH2CF3 or -CH2CH2-p-fluorophenyl; R3 is a lower alkyl group or -CH2CH2CH(Me)-OH; R4 is ; R is a phenyl group that is optionally and independently mono-, di-, or tri-substituted with a halogen, alkyl, CF3, CN, or alkoxy group, and X is O or S. Or its pharmaceutically acceptable salt.

2. The compound according to claim 1, wherein R2 is -CH2CH2CF3 or CH2CH2CH2CF3.

3. The compound according to claim 1, wherein R3 is a lower alkyl group.

4. The compound according to claim 1, wherein R is an unsubstituted phenyl group.

5. The compound according to claim 1, wherein R is a phenyl group that is independently mono- or di-substituted by F, Cl, CH3, CF3, CN or -OCH3.

6. The compound according to claim 1, wherein X is O.

7. The compound according to claim 1, wherein X is S.

8. A compound selected from the group consisting of: N-[(1S)-1-{N-(S)-5,5,5-trifluoro-1-[(1,3-thiazolyl-2-yl)carbonyl]pentylcarbamoyl}-4-hydroxypentyl]-2-phenyl-1,3-thiazolyl-5-carboxamide; N-[(1S)-1-{N-(S)-3-(p-fluorophenyl)-1-[(1,3-thiazolyl-2-yl)carbonyl]propylcarbamoyl}-4-hydroxypentyl]-2-phenyl-1,3-thiazolyl-5-carboxamide; N-[(1S)-1-{N-(S)-5,5,5-trifluoro-1-[(1,3-thiazolyl-2-yl)carbonyl]pentylcarbamoyl}-4-hydroxypentyl]-2-(p-chlorophenyl)-1,3-thiazolyl-5-carboxamide; N-[(1S)-1-{N-(S)-3-(p-fluorophenyl)-1-[(1,3-thiazolyl-2-yl)carbonyl]propylcarbamoyl}-4-hydroxypentyl]-2-(p-chlorophenyl)-1,3-thiazolyl-5-carboxamide; N-[(1S)-1-{N-(S)-5,5,5-trifluoro-1-[(1,3-thiazolyl-2-yl)carbonyl]pentylcarbamoyl}-4-hydroxypentyl]-2-(p-fluorophenyl)-1,3-thiazolyl-5-carboxamide; N-[(1S)-1-{N-(S)-3-(p-fluorophenyl)-1-[(1,3-thiazolyl-2-yl)carbonyl]propylcarbamoyl}-4-hydroxypentyl]-2-(p-fluorophenyl)-1,3-thiazolyl-5-carboxamide; N-[(1S)-1-{N-(S)-5,5,5-trifluoro-1-[(1,3-thiazolyl-2-yl)carbonyl]pentylcarbamoyl}-4-hydroxypentyl]-2-(m-fluorophenyl)-1,3-thiazolyl-5-carboxamide; N-[(1S)-1-{N-(S)-3-(p-fluorophenyl)-1-[(1,3-thiazolyl-2-yl)carbonyl]propylcarbamoyl}-4-hydroxypentyl]-2-(m-fluorophenyl)-1,3-thiazolyl-5-carboxamide; N-[(1S)-1-{N-(S)-5,5,5-trifluoro-1-[(1,3-thiazolyl-2-yl)carbonyl]pentylcarbamoyl}-4-hydroxypentyl]-2-(o-fluorophenyl)-1,3-thiazolyl-5-carboxamide; N-[(1S)-1-{N-(S)-3-(p-fluorophenyl)-1-[(1,3-thiazolyl-2-yl)carbonyl]propylcarbamoyl}-4-hydroxypentyl]-2-(o-fluorophenyl)-1,3-thiazolyl-5-carboxamide; N-[(1S)-1-{N-(S)-5,5,5-trifluoro-1-[(1,3-thiazolyl-2-yl)carbonyl]pentylcarbamoyl}-4-hydroxypentyl]-2-(m-chlorophenyl)-1,3-thiazolyl-5-carboxamide; N-[(1S)-1-{N-(S)-3-(p-fluorophenyl)-1-[(1,3-thiazolyl-2-yl)carbonyl]propylcarbamoyl}-4-hydroxypentyl]-2-(m-chlorophenyl)-1,3-thiazolyl-5-carboxamide; N-[(1S)-1-{N-(S)-5,5,5-trifluoro-1-[(1,3-thiazolyl-2-yl)carbonyl]pentylcarbamoyl}-4-hydroxypentyl]-2-(o-chlorophenyl)-1,3-thiazolyl-5-carboxamide; N-[(1S)-1-{N-(S)-3-(p-fluorophenyl)-1-[(1,3-thiazolyl-2-yl)carbonyl]propylcarbamoyl}-4-hydroxypentyl]-2-(o-chlorophenyl)-1,3-thiazolyl-5-carboxamide; N-[(1S)-1-{N-(S)-5,5,5-trifluoro-1-[(1,3-thiazolyl-2-yl)carbonyl]pentylcarbamoyl}-4-hydroxypentyl]-2-(p-tolyl)-1,3-thiazolyl-5-carboxamide; N-[(1S)-1-{N-(S)-3-(p-fluorophenyl)-1-[(1,3-thiazolyl-2-yl)carbonyl]propylcarbamoyl}-4-hydroxypentyl]-2-(p-tolyl)-1,3-thiazolyl-5-carboxamide; N-[(1S)-1-{N-(S)-5,5,5-trifluoro-1-[(1,3-thiazolyl-2-yl)carbonyl]pentylcarbamoyl}-4-hydroxypentyl]-2-(m-tolyl)-1,3-thiazolyl-5-carboxamide; N-[(1S)-1-{N-(S)-3-(p-fluorophenyl)-1-[(1,3-thiazolyl-2-yl)carbonyl]propylcarbamoyl}-4-hydroxypentyl]-2-(m-tolyl)-1,3-thiazolyl-5-carboxamide; N-[(1S)-1-{N-(S)-5,5,5-trifluoro-1-[(1,3-thiazolyl-2-yl)carbonyl]pentylcarbamoyl}-4-hydroxypentyl]-2-(o-tolyl)-1,3-thiazolyl-5-carboxamide; N-[(1S)-1-{N-(S)-3-(p-fluorophenyl)-1-[(1,3-thiazolyl-2-yl)carbonyl]propylcarbamoyl}-4-hydroxypentyl]-2-(o-tolyl)-1,3-thiazolyl-5-carboxamide; N-[(1S)-1-{N-(S)-5,5,5-trifluoro-1-[(1,3-thiazolyl-2-yl)carbonyl]pentylcarbamoyl}-4-hydroxypentyl]-2-(p-cyanophenyl)-1,3-thiazolyl-5-carboxamide; N-[(1S)-1-{N-(S)-3-(p-fluorophenyl)-1-[(1,3-thiazolyl-2-yl)carbonyl]propylcarbamoyl}-4-hydroxypentyl]-2-(p-cyanophenyl)-1,3-thiazolyl-5-carboxamide; N-[(1S)-1-{N-(S)-5,5,5-trifluoro-1-[(1,3-thiazolyl-2-yl)carbonyl]pentylcarbamoyl}-4-hydroxypentyl]-2-(m-cyanophenyl)-1,3-thiazolyl-5-carboxamide; N-[(1S)-1-{N-(S)-3-(p-fluorophenyl)-1-[(1,3-thiazolyl-2-yl)carbonyl]propylcarbamoyl}-4-hydroxypentyl]-2-(m-cyanophenyl)-1,3-thiazolyl-5-carboxamide; N-[(1S)-1-{N-(S)-5,5,5-trifluoro-1-[(1,3-thiazolyl-2-yl)carbonyl]pentylcarbamoyl}-4-hydroxypentyl]-2-(o-cyanophenyl)-1,3-thiazolyl-5-carboxamide; N-[(1S)-1-{N-(S)-3-(p-fluorophenyl)-1-[(1,3-thiazolyl-2-yl)carbonyl]propylcarbamoyl}-4-hydroxypentyl]-2-(o-cyanophenyl)-1,3-thiazolyl-5-carboxamide; N-[(1S)-1-{N-(S)-5,5,5-trifluoro-1-[(1,3-thiazolyl-2-yl)carbonyl]pentylcarbamoyl}-4-hydroxypentyl]-2-(2,5-difluorophenyl)-1,3-thiazolyl-5-carboxamide; N-[(1S)-1-{N-(S)-3-(p-fluorophenyl)-1-[(1,3-thiazolyl-2-yl)carbonyl]propylcarbamoyl}-4-hydroxypentyl]-2-(2,5-difluorophenyl)-1,3-thiazolyl-5-carboxamide; N-[(1S)-1-{N-(S)-5,5,5-trifluoro-1-[(1,3-thiazolyl-2-yl)carbonyl]pentylcarbamoyl}-4-hydroxypentyl]-2-(2,6-difluorophenyl)-1,3-thiazolyl-5-carboxamide; N-[(1S)-1-{N-(S)-3-(p-fluorophenyl)-1-[(1,3-thiazolyl-2-yl)carbonyl]propylcarbamoyl}-4-hydroxypentyl]-2-(2,6-difluorophenyl)-1,3-thiazolyl-5-carboxamide; N-[(1S)-1-{N-(S)-5,5,5-trifluoro-1-[(1,3-thiazolyl-2-yl)carbonyl]pentylcarbamoyl}-4-hydroxypentyl]-2-(3,5-difluorophenyl)-1,3-thiazolyl-5-carboxamide; N-[(1S)-1-{N-(S)-3-(p-fluorophenyl)-1-[(1,3-thiazolyl-2-yl)carbonyl]propylcarbamoyl}-4-hydroxypentyl]-2-(3,5-difluorophenyl)-1,3-thiazolyl-5-carboxamide; N-[(1S)-1-{N-(S)-5,5,5-trifluoro-1-[(1,3-thiazolyl-2-yl)carbonyl]pentylcarbamoyl}-4-hydroxypentyl]-2-(2,4-difluorophenyl)-1,3-thiazolyl-5-carboxamide; N-[(1S)-1-{N-(S)-3-(p-fluorophenyl)-1-[(1,3-thiazolyl-2-yl)carbonyl]propylcarbamoyl}-4-hydroxypentyl]-2-(2,4-difluorophenyl)-1,3-thiazolyl-5-carboxamide; N-[(1S)-1-{N-(S)-5,5,5-trifluoro-1-[(1,3-thiazolyl-2-yl)carbonyl]pentylcarbamoyl}-4-hydroxypentyl]-2-(m-fluorophenyl)-1,3-oxazol-5-carboxamide; N-[(1S)-1-{N-(S)-5,5,5-trifluoro-1-[(1,3-thiazolyl-2-yl)carbonyl]pentylcarbamoyl}-4-hydroxypentyl]-2-(5-fluoro-2-tolyl)-1,3-thiazolyl-5-carboxamide; N-[(1S)-1-{N-(S)-5,5,5-trifluoro-1-[(1,3-thiazolyl-2-yl)carbonyl]pentylcarbamoyl}-4-hydroxypentyl]-2-[5-fluoro-2-(fluoromethyl)phenyl]-1,3-thiazolyl-5-carboxamide; N-[(1S)-1-{N-(S)-5,5,5-trifluoro-1-[(1,3-thiazolyl-2-yl)carbonyl]pentylcarbamoyl}-4-hydroxypentyl]-2-[o-(trifluoromethyl)phenyl]-1,3-thiazolyl-5-carboxamide; N-[(1S)-1-{N-(S)-5,5,5-trifluoro-1-[(1,3-thiazolyl-2-yl)carbonyl]pentylcarbamoyl}-4-hydroxypentyl]-2-[m-(trifluoromethyl)phenyl]-1,3-thiazolyl-5-carboxamide; N-[(1S)-1-{N-(S)-5,5,5-trifluoro-1-[(1,3-thiazolyl-2-yl)carbonyl]pentylcarbamoyl}-4-hydroxypentyl]-2-[p-(trifluoromethyl)phenyl]-1,3-thiazolyl-5-carboxamide; N-[(1S)-1-{N-(S)-4,4,4-trifluoro-1-[(1,3-thiazolyl-2-yl)carbonyl]butylcarbamoyl}-4-hydroxypentyl]-2-(p-fluorophenyl)-1,3-thiazolyl-5-carboxamide; N-[(1S)-1-{N-(S)-4,4,4-trifluoro-1-[(1,3-thiazolyl-2-yl)carbonyl]butylcarbamoyl}-4-hydroxypentyl]-2-(m-fluorophenyl)-1,3-thiazolyl-5-carboxamide; N-[(1S)-1-{N-(S)-4,4,4-trifluoro-1-[(1,3-thiazolyl-2-yl)carbonyl]butylcarbamoyl}-4-hydroxypentyl]-2-(m-chlorophenyl)-1,3-thiazolyl-5-carboxamide; N-[(1S)-1-{N-(S)-4,4,4-trifluoro-1-[(1,3-thiazolyl-2-yl)carbonyl]butylcarbamoyl}-4-hydroxypentyl]-2-(p-cyanophenyl)-1,3-thiazolyl-5-carboxamide; N-[(1S)-1-{N-(S)-5,5,5-trifluoro-1-[(1,3-thiazolyl-2-yl)carbonyl]pentylcarbamoyl}-4-hydroxypentyl]-2-(3,5-difluorophenyl)-1,3-oxazol-5-carboxamide; N-[(1S)-1-{N-(S)-5,5,5-trifluoro-1-[(1,3-thiazolyl-2-yl)carbonyl]pentylcarbamoyl}-4-hydroxypentyl]-2-(2,5-difluorophenyl)-1,3-oxazol-5-carboxamide; N-[(1S)-1-{N-(S)-5,5,5-trifluoro-1-[(1,3-thiazolyl-2-yl)carbonyl]pentylcarbamoyl}-4-hydroxypentyl]-2-(p-fluorophenyl)-1,3-oxazol-5-carboxamide; N-[(1S)-1-{N-(S)-5,5,5-trifluoro-1-[(1,3-thiazolyl-2-yl)carbonyl]pentylcarbamoyl}-4-hydroxypentyl]-2-(2,4-difluorophenyl)-1,3-oxazol-5-carboxamide; N-[(1S)-1-{N-(S)-4,4,4-trifluoro-1-[(1,3-thiazolyl-2-yl)carbonyl]butylcarbamoyl}-4-hydroxypentyl]-2-(3,5-difluorophenyl)-1,3-oxazol-5-carboxamide; N-[(1S)-1-{N-(S)-4,4,4-trifluoro-1-[(1,3-thiazolyl-2-yl)carbonyl]butylcarbamoyl}-4-hydroxypentyl]-2-(3,5-difluorophenyl)-1,3-thiazolyl-5-carboxamide; N-[(1S)-1-{N-(S)-4,4,4-trifluoro-1-[(1,3-thiazo-2-yl)carbonyl]butylcarbamoyl}-4-hydroxypentyl]-2-(3-chloro-5-fluorophenyl)-1,3-oxazol-5-carboxamide; N-[(1S,4R)-1-{N-(S)-4,4,4-trifluoro-1-[(1,3-thiazolyl-2-yl)carbonyl]butylcarbamoyl}-4-hydroxypentyl]-2-(3-chloro-5-fluorophenyl)-1,3-oxazol-5-carboxamide; N-[(1S,4S)-1-{N-(S)-4,4,4-trifluoro-1-[(1,3-thiazo-2-yl)carbonyl]butylcarbamoyl}-4-hydroxypentyl]-2-(3-chloro-5-fluorophenyl)-1,3-oxazol-5-carboxamide; N-[(1S)-1-{N-(S)-4,4,4-trifluoro-1-[(1,3-thiazolyl-2-yl)carbonyl]butylcarbamoyl}-4-hydroxypentyl]-2-(3-chloro-5-fluorophenyl)-1,3-thiazolyl-5-carboxamide; N-[(1S)-1-{N-(S)-5,5,5-trifluoro-1-[(1,3-thiazo-2-yl)carbonyl]pentylcarbamoyl}-4-hydroxypentyl]-2-(3-chloro-5-fluorophenyl)-1,3-oxazol-5-carboxamide; N-[(1S)-1-{N-(S)-4,4,4-trifluoro-1-[(1,3-thiazolyl-2-yl)carbonyl]butylcarbamoyl}-4-hydroxypentyl]-2-(3,5-dichlorophenyl)-1,3-oxazol-5-carboxamide; N-[(1S)-1-{N-(S)-4,4,4-trifluoro-1-[(1,3-thiazo-2-yl)carbonyl]butylcarbamoyl}-4-hydroxypentyl]-2-[3-fluoro-5-(trifluoromethyl)phenyl]-1,3-oxazol-5-carboxamide; N-[(S)-1-{N-(S)-4,4,4-trifluoro-1-[(1,3-thiazolyl-2-yl)carbonyl]butylcarbamoyl}ethyl]-2-(3,5-difluorophenyl)-1,3-oxazol-5-carboxamide; N-[(1S)-1-{N-(S)-4,4,4-trifluoro-1-[(1,3-thiazolyl-2-yl)carbonyl]butylcarbamoyl}-4-hydroxypentyl]-2-(5-chloro-2-fluorophenyl)-1,3-oxazol-5-carboxamide; N-[(1S)-1-{N-(S)-4,4,4-trifluoro-1-[(1,3-thiazo-2-yl)carbonyl]butylcarbamoyl}-4-hydroxypentyl]-2-(2-chloro-5-fluorophenyl)-1,3-oxazol-5-carboxamide; N-[(1S)-1-{N-(S)-4,4,4-trifluoro-1-[(1,3-thiazolyl-2-yl)carbonyl]butylcarbamoyl}-4-hydroxypentyl]-2-(2,5-difluorophenyl)-1,3-oxazol-5-carboxamide; N-[(1S)-1-{N-(S)-4,4,4-trifluoro-1-[(1,3-thiazolyl-2-yl)carbonyl]butylcarbamoyl}-4-hydroxypentyl]-2-(2,5-dichlorophenyl)-1,3-oxazol-5-carboxamide; N-[(1S)-1-{N-(S)-4,4,4-trifluoro-1-[(1,3-thiazo-2-yl)carbonyl]butylcarbamoyl}-4-hydroxypentyl]-2-(2-chloro-4-fluorophenyl)-1,3-oxazol-5-carboxamide; N-[(1S)-1-{N-(S)-4,4,4-trifluoro-1-[(1,3-thiazo-2-yl)carbonyl]butylcarbamoyl}-4-hydroxypentyl]-2-(4-chloro-2-fluorophenyl)-1,3-oxazol-5-carboxamide; N-[(1S)-1-{N-(S)-4,4,4-trifluoro-1-[(1,3-thiazo-2-yl)carbonyl]butylcarbamoyl}-4-hydroxypentyl]-2-(2,4-dichlorophenyl)-1,3-oxazol-5-carboxamide; N-[(S)-1-{N-(S)-4,4,4-trifluoro-1-[(1,3-thiazolyl-2-yl)carbonyl]butylcarbamoyl}ethyl]-2-(o-fluorophenyl)-1,3-oxazol-5-carboxamide; N-[(S)-1-{N-(S)-4,4,4-trifluoro-1-[(1,3-thiazolyl-2-yl)carbonyl]butylcarbamoyl}ethyl]-2-(m-fluorophenyl)-1,3-oxazol-5-carboxamide; N-[(S)-1-{N-(S)-4,4,4-trifluoro-1-[(1,3-thiazolyl-2-yl)carbonyl]butylcarbamoyl}ethyl]-2-(p-fluorophenyl)-1,3-oxazol-5-carboxamide; N-[(S)-1-{N-(S)-4,4,4-trifluoro-1-[(1,3-thiazolyl-2-yl)carbonyl]butylcarbamoyl}ethyl]-2-(o-chlorophenyl)-1,3-oxazol-5-carboxamide; N-[(S)-1-{N-(S)-4,4,4-trifluoro-1-[(1,3-thiazolyl-2-yl)carbonyl]butylcarbamoyl}ethyl]-2-(m-chlorophenyl)-1,3-oxazol-5-carboxamide; N-[(S)-1-{N-(S)-4,4,4-trifluoro-1-[(1,3-thiazolyl-2-yl)carbonyl]butylcarbamoyl}ethyl]-2-(p-chlorophenyl)-1,3-oxazol-5-carboxamide; N-[(S)-1-{N-(S)-4,4,4-trifluoro-1-[(1,3-thiazo-2-yl)carbonyl]butylcarbamoyl}ethyl]-2-(3-chloro-5-fluorophenyl)-1,3-oxazol-5-carboxamide; N-[(S)-1-{N-(S)-4,4,4-trifluoro-1-[(1,3-thiazo-2-yl)carbonyl]butylcarbamoyl}ethyl]-2-(3,5-dichlorophenyl)-1,3-oxazol-5-carboxamide; N-[(S)-1-{N-(S)-4,4,4-trifluoro-1-[(1,3-thiazo-2-yl)carbonyl]butylcarbamoyl}ethyl]-2-(2-chloro-5-fluorophenyl)-1,3-oxazol-5-carboxamide; N-[(S)-1-{N-(S)-4,4,4-trifluoro-1-[(1,3-thiazo-2-yl)carbonyl]butylcarbamoyl}ethyl]-2-(5-chloro-2-fluorophenyl)-1,3-oxazol-5-carboxamide; N-[(S)-1-{N-(S)-4,4,4-trifluoro-1-[(1,3-thiazolyl-2-yl)carbonyl]butylcarbamoyl}ethyl]-2-(o-fluorophenyl)-1,3-thiazolyl-5-carboxamide; N-[(S)-1-{N-(S)-4,4,4-trifluoro-1-[(1,3-thiazolyl-2-yl)carbonyl]butylcarbamoyl}ethyl]-2-(m-fluorophenyl)-1,3-thiazolyl-5-carboxamide; N-[(S)-1-{N-(S)-4,4,4-trifluoro-1-[(1,3-thiazolyl-2-yl)carbonyl]butylcarbamoyl}ethyl]-2-(p-fluorophenyl)-1,3-thiazolyl-5-carboxamide; N-[(S)-1-{N-(S)-4,4,4-trifluoro-1-[(1,3-thiazolyl-2-yl)carbonyl]butylcarbamoyl}ethyl]-2-(o-chlorophenyl)-1,3-thiazolyl-5-carboxamide; N-[(S)-1-{N-(S)-4,4,4-trifluoro-1-[(1,3-thiazolyl-2-yl)carbonyl]butylcarbamoyl}ethyl]-2-(m-chlorophenyl)-1,3-thiazolyl-5-carboxamide; N-[(S)-1-{N-(S)-4,4,4-trifluoro-1-[(1,3-thiazolyl-2-yl)carbonyl]butylcarbamoyl}ethyl]-2-(p-chlorophenyl)-1,3-thiazolyl-5-carboxamide; N-[(S)-1-{N-(S)-4,4,4-trifluoro-1-[(1,3-thiazo-2-yl)carbonyl]butylcarbamoyl}ethyl]-2-(3-chloro-5-fluorophenyl)-1,3-thiazo-5-carboxamide; N-[(S)-1-{N-(S)-4,4,4-trifluoro-1-[(1,3-thiazolyl-2-yl)carbonyl]butylcarbamoyl}ethyl]-2-(3,5-dichlorophenyl)-1,3-thiazolyl-5-carboxamide; N-[(S)-1-{N-(S)-4,4,4-trifluoro-1-[(1,3-thiazolyl-2-yl)carbonyl]butylcarbamoyl}ethyl]-2-(3,5-difluorophenyl)-1,3-thiazolyl-5-carboxamide; N-[(S)-1-{N-(S)-4,4,4-trifluoro-1-[(1,3-thiazolyl-2-yl)carbonyl]butylcarbamoyl}ethyl]-2-(2,5-difluorophenyl)-1,3-thiazolyl-5-carboxamide; N-[(S)-1-{N-(S)-4,4,4-trifluoro-1-[(1,3-thiazo-2-yl)carbonyl]butylcarbamoyl}ethyl]-2-(2-chloro-5-fluorophenyl)-1,3-thiazo-5-carboxamide; N-[(S)-1-{N-(S)-4,4,4-trifluoro-1-[(1,3-thiazo-2-yl)carbonyl]butylcarbamoyl}ethyl]-2-(5-chloro-2-fluorophenyl)-1,3-thiazo-5-carboxamide; N-[(S)-1-{N-(S)-4,4,4-trifluoro-1-[(1,3-thiazolyl-2-yl)carbonyl]butylcarbamoyl}ethyl]-2-(2,5-dichlorophenyl)-1,3-thiazolyl-5-carboxamide; N-[(S)-1-{N-(S)-4,4,4-trifluoro-1-[(1,3-thiazolyl-2-yl)carbonyl]butylcarbamoyl}ethyl]-2-(2,3-difluorophenyl)-1,3-oxazol-5-carboxamide; N-[(S)-1-{N-(S)-4,4,4-trifluoro-1-[(1,3-thiazo-2-yl)carbonyl]butylcarbamoyl}ethyl]-2-(2,3-dichlorophenyl)-1,3-oxazol-5-carboxamide; N-[(S)-1-{N-(S)-4,4,4-trifluoro-1-[(1,3-thiazo-2-yl)carbonyl]butylcarbamoyl}ethyl]-2-(2-chloro-3-fluorophenyl)-1,3-oxazol-5-carboxamide; N-[(S)-1-{N-(S)-4,4,4-trifluoro-1-[(1,3-thiazo-2-yl)carbonyl]butylcarbamoyl}ethyl]-2-(3-chloro-2-fluorophenyl)-1,3-oxazol-5-carboxamide; N-[(1S)-1-{N-(S)-4,4,4-trifluoro-1-[(1,3-thiazolyl-2-yl)carbonyl]butylcarbamoyl}-4-hydroxypentyl]-2-(2,3-difluorophenyl)-1,3-oxazol-5-carboxamide; N-[(1S)-1-{N-(S)-4,4,4-trifluoro-1-[(1,3-thiazo-2-yl)carbonyl]butylcarbamoyl}-4-hydroxypentyl]-2-(2-chloro-3-fluorophenyl)-1,3-oxazol-5-carboxamide; N-[(1S)-1-{N-(S)-4,4,4-trifluoro-1-[(1,3-thiazolyl-2-yl)carbonyl]butylcarbamoyl}-4-hydroxypentyl]-2-(3-cyano-5-fluorophenyl)-1,3-oxazol-5-carboxamide; N-[(1S)-1-{N-(S)-4,4,4-trifluoro-1-[(1,3-thiazolyl-2-yl)carbonyl]butylcarbamoyl}-4-hydroxypentyl]-2-(2,4-difluorophenyl)-1,3-oxazol-5-carboxamide; N-[(1S)-1-{N-(S)-4,4,4-trifluoro-1-[(1,3-thiazolyl-2-yl)carbonyl]butylcarbamoyl}-4-hydroxypentyl]-2-(2,6-difluorophenyl)-1,3-oxazol-5-carboxamide; N-[(1S)-1-{N-(S)-4,4,4-trifluoro-1-[(1,3-thiazolyl-2-yl)carbonyl]butylcarbamoyl}-4-hydroxypentyl]-2-(2-chloro-6-fluorophenyl)-1,3-oxazol-5-carboxamide; N-[(1S)-1-{N-(S)-4,4,4-trifluoro-1-[(1,3-thiazo-2-yl)carbonyl]butylcarbamoyl}-4-hydroxypentyl]-2-(4-chloro-3-fluorophenyl)-1,3-oxazol-5-carboxamide; N-[(1S)-1-{N-(S)-4,4,4-trifluoro-1-[(1,3-thiazolyl-2-yl)carbonyl]butylcarbamoyl}-4-hydroxypentyl]-2-(2-cyano-4-fluorophenyl)-1,3-oxazol-5-carboxamide; N-[(1S)-1-{N-(S)-4,4,4-trifluoro-1-[(1,3-thiazo-2-yl)carbonyl]butylcarbamoyl}-4-hydroxypentyl]-2-(3-chloro-5-cyanophenyl)-1,3-oxazol-5-carboxamide; N-[(1S)-1-{N-(S)-4,4,4-trifluoro-1-[(1,3-thiazolyl-2-yl)carbonyl]butylcarbamoyl}-4-hydroxypentyl]-2-(3-cyano-5-fluorophenyl)-1,3-thiazolyl-5-carboxamide; N-[(1S)-1-{N-(S)-4,4,4-trifluoro-1-[(1,3-thiazo-2-yl)carbonyl]butylcarbamoyl}-4-hydroxypentyl]-2-(3-chloro-5-cyanophenyl)-1,3-thiazo-5-carboxamide; and N-[(1S)-1-{N-(S)-4,4,4-trifluoro-1-[(1,3-thiazolyl-2-yl)carbonyl]butylcarbamoyl}-4-hydroxypentyl]-2-(3-fluoro-5-methoxyphenyl)-1,3-oxazol-5-carboxamide, Or its pharmaceutically acceptable salt.

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

10. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 8 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

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

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

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