Proteosome complex inhibitors targeting clpp1p2 protease

Abstract

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

Description

[0001] PROTEOSOME COMPLEX INHIBITORS TARGETING CLPP1P2 PROTEASE

[0002] Field of the Invention

[0003] The invention relates generally to proteosome complex inhibitors targeting ClpPlP2 protease with antibacterial activity, for example, with anti -tuberculosis properties. The compounds of the invention are useful for the treatment of. for example, mycobacterium tuberculosis.

[0004] All publications, patents, patent applications, and other references cited in this application are incorporated herein by reference in their entirety for all purposes and to the same extent as if each individual publication, patent, patent application or other reference was specifically and individually indicated to be incorporated by reference in its entirety for all purposes. Citation of a reference herein shall not be construed as an admission that such is prior art to the present invention.

[0005] Cross-Reference to Related Applications

[0006] This application claims priority from U.S. Provisional Patent Application No. 63 / 527,917 filed on July 20, 2023, the contents of which are hereby expressly incorporated by reference herein.

[0007] Background of the Invention

[0008] Tuberculosis is a debilitating disease that affects about 100 million people worldwide and causes nearly 2 million deaths annually, making it one of leading causes of infectious disease mortality. It has been estimated that a third of all humans have been infected with Mycobacterium tuberculosis (Mtb) and many may continue to harbor latent infections that can reactivate to active disease. The standard antibiotic regimen to treat drug-sensitive (DS) forms of Mtb were developed over 50 years ago, require treatment durations of six months or longer, and are poorly tolerated. These factors result in poor compliance by patients which may be exacerbating the increasing resistance to available antibiotics. While new regimens have been recently approved for treatment of drug-resistant (DR) Mtb, resistance is developing rapidly and already threatening the potential durability of these new regimens. Therefore, identifying new drug classes, especially for novel targets without pre-existing cross-resistance concerns, is critical to ensure opportunity to eradicate this devastating disease.

[0009] Regulated intracellular protein degradation is critical for maintaining cellular homeostasis through protein quality' control and regulation of numerous biological pathways (Inger and Brondsted (2009) Res. Microbiol 160:704-710; Goldberg (2003) Nature 426:895-899). The ClpP proteins are highly conserved, multimeric serine proteases originally discovered (Hwang et al. (1987) PNAS 84:5550-5554; Katayama- Fujimura et al. (1987) J. Biol. Chem. 262:4477-4485) and characterized in E. coli (Maurizi et al. (1990) J Biol Chem. 265(21): 12536-45; Maurizi et al. (1998) Biochemistry 37(21):7778-86.; Maurizi et al., (1994) Methods Enzymol. 244:314-31; Yu and Homy (2007) FEBS Eett. 581(19):3749-57). ClpP homologs exist in a wide range of bacteria, as well as in the eukaryotic organelles, mitochondria and chloroplasts (Porankiewicz et al. (1999) Mol Microbiol 32(3):449-58). In E. coli, the ClpP complex, alone, is able to rapidly hydrolyze only unfolded oligopeptides, but not large globular proteins. The degradation of large proteins requires the presence of an AAA ATPase complex, such as ClpA or ClpX in E. coli or ClpC in other species (Kress et al. (2009) Res Microbiol 160(9): 618-28). These hexameric structures associate with both ends of the ClpP complex to form the active 4-ring ATP- dependent protease (Kim et al. (2001 Nat Struct Biol 8(3):230-3); Maurizi (1991) Biochem Soc Trans 19(3):719-23; Maurizi et al. (1998) Biochemistry 37(21):7778-86). These ATPases bind selectively to certain protein substrates, unfold them, and translocate the linearized polypeptides into the ClpP proteolytic chamber for degradation (Hoskins et al. (1998) PNAS 95(21): 12135- 40; Ishikawa et al. (2001) PNAS 98(8):4328-33; Ortega et al. (2000) Mol Cell. 6(6): 1515-21; Reid et al. (2001) PNAS 98(7):3768-72). In addition to substrate recognition, the mitochondrial ClpX complex promotes the assembly of the ClpP complex into an active form (Kang et al. (2005) J Biol Chem 280(42): 35424-32). In E. coli, the ClpXP protease complex has several roles, including regulation of the DNA damage response and degradation of SsrA-tagged peptides stalled on the ribosome (Farrell et al. (2005) Mol. Microbiol. 57: 1750-1761; Pruteanu and Baker (2009) Mol. Microbiol. 71 :912-924). ClpP also increases the virulence of several pathogenic organisms, including Listeria monocytogenes, where the protease is required for the production of a-listeriolysin (Gaillot et al. (2001) Infect Immun. 69:4938-4943; Gaillot et al. (2000) Mol. Microbiol. 35:1286-1294).

[0010] Therefore, inhibitors of the ClpP complex may provide a unique and highly effective therapeutic effect against Mtb when used alone or in combination with other antibiotics that induce misfolded or damaged proteins, or in chronic and latent stages of TB disease where immune-mediated oxidative stress is prevalent.

[0011] Summary of the Invention

[0012] The present invention is directed to compounds of Formula IA: alkoxy.

[0013] The present invention is also directed to pharmaceutical compositions containing the above compounds and to methods of treating microbial infection such as tuberculosis.

[0014] Detailed Description

[0015] It is to be understood that the descriptions of the present invention have been simplified to illustrate elements that are relevant for a clear understanding of the present invention, while eliminating, for the purpose of clarity, many other elements found in typical pharmaceutical compositions. Those of ordinary skill in the art will recognize that other elements and / or steps are desirable and / or required in implementing the present invention. However, because such elements and steps are well known in the art, and because they do not facilitate a better understanding of the present invention, a discussion of such elements and steps is not provided herein. The disclosure herein is directed to all such variations and modifications to such elements and methods known to those skilled in the art. Furthermore, the embodiments identified and illustrated herein are for exemplary purposes only, and are not meant to be exclusive or limited in their description of the present invention.

[0016] Technical and scientific terms used herein have the meaning commonly understood by one of skill in the art to which the present invention pertains, unless otherwise defined. Reference is made herein to various methodologies and materials known to those of skill in the art. Standard reference works setting forth the general principles of pharmacology include Goodman and Gilman's The Pharmacological Basis of Therapeutics, 10thEd., McGraw Hill Companies Inc., New York (2001). Any suitable materials and / or methods known to those of skill can be utilized in canydng out the present invention. However, preferred materials and methods are described. Materials, reagents and the like to which reference are made in the following description and examples are obtainable from commercial sources, unless otherwise noted. A compound according to the invention is inherently intended to comprise all stereochemically isomeric forms thereof. The term "stereochemically isomeric forms" as used hereinbefore or hereinafter defines all the possible stereoisomeric forms which the compounds of formula (A), and their N-oxides. pharmaceutically acceptable salts or physiologically functional derivatives may possess. Unless otherwise mentioned or indicated, the chemical designation of compounds denotes the mixture of all possible stereochemically isomeric forms. In particular, stereogenic centers may have the R- or S-configuration; substituents on bivalent cyclic (partially) saturated radicals may have either the cis- or trans-configuration. Compounds encompassing double bonds can have an E (entgegen) or Z (zusammen)-stereochemistry at said double bond. The terms cis, trans, R, S, E and Z are well known to a person skilled in the art.

[0017] Stereochemically isomeric forms of the compounds of formula (A) are obviously intended to be embraced within the scope of this invention. Of special interest are those compounds of formula (A) which are stereochemically pure.

[0018] Following CAS-nomenclature conventions, when two stereogenic centers of known absolute configuration are present in a molecule, an R or S descriptor is assigned (based on Cahn-Ingold-Prelog sequence rule) to the lowest-numbered chiral center, the reference center. The configuration of the second stereogenic center is indicated using relative descriptors [R*,R*] or [R*,S*], where R* is always specified as the reference center and [R*,R*] indicates centers with the same chirality and [R*,S*] indicates centers of unlike chirality. For example, if the low est-numbered chiral center in the molecule has an S configuration and the second center is R, the stereo descriptor would be specified as S— [R*,S*]. If "a" and "0" are used: the position of the highest priority substituent on the asymmetric carbon atom in the ring system having the lowest ring number, is arbitrarily alw ays in the "a" position of the mean plane determined by the ring system. The position of the highest priority substituent on the other asymmetric carbon atom in the ring system relative to the position of the highest priority substituent on the reference atom is denominated "a", if it is on the same side of the mean plane determined by the ring system, or "0", if it is on the other side of the mean plane determined by the ring system.

[0019] When a specific stereoisomeric form is indicated, this means that said form is substantially free, i.e. associated with less than 50%, preferably less than 20%, more preferably less than 10%, even more preferably less than 5%, further preferably less than 2% and most preferably less than 1% of the other isomer(s). Thus, when a compound of formula (A) is for instance specified as (R,S), this means that the compound is substantially free of the (S,R) isomer.

[0020] Compounds of formula (A) and some of the intermediate compounds invariably have at least two stereogenic centers in their structure which may lead to at least 4 stereochemically different structures.

[0021] The compounds of formula (A) may be synthesized in the form of mixtures, in particular racemic mixtures, of enantiomers which can be separated from one another following art-known resolution procedures. The racemic compounds of formula (A) may be converted into the corresponding diastereomeric salt forms by reaction with a suitable chiral acid. Said diastereomeric salt forms are subsequently separated, for example, by selective or fractional crystallization and the enantiomers are liberated therefrom by alkali. An alternative manner of separating the enantiomeric forms of the compounds of formula (A) involves liquid chromatography using a chiral stationary phase. Said pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically. Preferably if a specific stereoisomer is desired, said compound will be synthesized by stereospecific methods of preparation. These methods will advantageously employ enantiomerically pure starting materials.

[0022] The tautomeric forms of the compounds of formula (A) are meant to comprise those compounds of formula (A) wherein e.g. an enol group is converted into a keto group (keto-enol tautomerism). Tautomeric forms of the compounds of formula (A) or of intermediates of the present invention are intended to be embraced by the ambit of this invention.

[0023] The term “alkyl” as used herein denotes an unbranched or branched chain, saturated, monovalent hydrocarbon residue containing 1 to 10 carbon atoms. The term “lower alkyl” denotes a straight or branched chain hydrocarbon residue containing 1 to 6 carbon atoms. "Ci-io alkyl" as used herein refers to an alkyl composed of 1 to 10 carbons. Examples of alkyl groups include, but are not limited to, lower alkyl groups include methyl, ethyl, propyl, z-propyl. w-butyl, z-butyl, / -butyl or pentyl, isopentyl, neopentyl, hexyl, heptyl, and octyl.

[0024] The term ‘halogen’ as used herein denotes F, Cl, Br or I.

[0025] When the term “alkyl” is used as a suffix following another term, as in “phenylalkyl.” or "hydroxyalkyl." this is intended to refer to an alkyd group, as defined above, being substituted with one to two substituents selected from the other specifically-named group. Thus, for example, “phenylalky l” denotes the radical R'R"-, wherein R' is a phenyl radical, and R" is an alkylene radical as defined herein with the understanding that the attachment point of the phenylalkyl moiety7will be on the alkylene radical. Examples of arylalkyl radicals include, but are not limited to, benzyl, phenylethyl, 3- phenylpropyl. The terms “arylalkyl” or "aralkyl" are interpreted similarly except R' is an aryl radical. The terms "(het)arylalkyl" or "(het)aralkyl" are interpreted similarly except R' is optionally an aryl or a heteroaryl radical.

[0026] The terms “haloalkyl” or “halo lower alky l” or “lower haloalkyl” refers to a straight or branched chain hydrocarbon residue containing 1 to 6 carbon atoms wherein one or more carbon atoms are substituted with one or more halogen atoms.

[0027] The term "alkoxy" as used herein means an -O-alkyl group, wherein alkyl is as defined above such as methoxy, ethoxy, w-propyloxy. z-propyloxy, n-bulyloxy. i- butyloxy. / -butyloxy, pentyloxy. hexyloxy, including their isomers. "Lower alkoxy as used herein denotes an alkoxy group with a "lower alkyl" group as previously defined. "Ci-io alkoxy" as used herein refers to an-O-alkyl wherein alkyd is Ci-io.

[0028] The terms ‘'haloalkoxy” or “halo lower alkoxy” or “lower haloalkoxy” refers to a lower alkoxy group, wherein one or more carbon atoms are substituted with one or more halogen atoms.

[0029] The term "hydroxyalky 1" as used herein denotes an alkyd radical as herein defined wherein one to three hydrogen atoms on different carbon atoms is / are replaced by hydroxyl groups.

[0030] The term "carboxyl" as used herein refers to a group of formula -C(=O)R.2 wherein each R is independently hydrogen or C1-3 alkyd, and lower alkyl is as defined herein.

[0031] The term “cycloalkyl” denotes a monovalent saturated monocyclic or bicyclic hydrocarbon group of 3 to 10 ring carbon atoms. In particular embodiments cycloalkyd denotes a monovalent saturated monocyclic hydrocarbon group of 3 to 8 ring carbon atoms. Bicyclic means consisting of two saturated carbocycles having one or more carbon atoms in common. Particular cycloalkyl groups are monocyclic. Examples for monocyclic cycloalkyl are cyclopropyl, cyclobutanyl, cyclopentyl, cyclohexyl or cycloheptyd. Examples for bicyclic cycloalkyl are bicyclo[2.2.1]heptanyl, or bicyclo[2.2.2]octanyl.

[0032] The term “amino” as used herein denotes a group of the formula -NR’R” wherein R‘ and R” are independently hydrogen, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl. Alternatively, R' and R”, together with the nitrogen to which they are attached, can form a heterocycloalkyl. The term “primary amino” denotes a group wherein both R’ and R” are hydrogen. The term “secondary amino” denotes a group wherein R’ is hydrogen and R” is not. The term “tertiary amino” denotes a group wherein both R’ and R” are not hydrogen. Particular secondary and tertiary amines are methylamine, ethylamine, propylamine, isopropylamine, phenylamine, benzylamine dimethylamine, diethylamine, dipropylamine and diisopropylamine.

[0033] The term “heteroaryl” denotes a monovalent aromatic heterocyclic mono- or bicyclic ring system of 5 to 12 ring atoms, comprising 1, 2, 3 or 4 heteroatoms selected from N, O and S, the remaining ring atoms being carbon. Examples of heteroaryl moieties include pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, triazinyl, azepinyl, diazepinyl, isoxazolyl, benzofuranyl, isothiazolyl, benzothienyl, indolyl, isoindolyl, isobenzofuranyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzooxadiazolyl, benzothiadiazolyl, benzotriazolyl, purinyl. quinolinyl, isoquinolinyl, quinazolinyl, or quinoxalinyl.

[0034] The term “heterocycloalkyl” denotes a monovalent saturated or partly unsaturated mono- or bicyclic ring system of 3 to 9 ring atoms, comprising 1, 2, or 3 ring heteroatoms selected from N, O and S, the remaining ring atoms being carbon. In particular embodiments, heterocycloalkyl is a monovalent saturated monocyclic ring system of 4 to 7 ring atoms, comprising 1, 2, or 3 ring heteroatoms selected from N, O and S, the remaining ring atoms being carbon. Examples for monocyclic saturated heterocycloalkyl are aziridinyl, oxiranyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydro-thienyl, pyrazolidinyl. imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl, l,l-dioxo-thiomorpholin-4-yl, azepanyl, diazepanyl, homopiperazinyl, or oxazepanyl. Examples for bicyclic saturated heterocycloalkyl are 8-aza-bicyclo[3.2. l]octyl, quinuclidinyl. 8-oxa-3-aza- bicyclo[3.2.1]octyl, 9-aza-bicyclo[3.3.1]nonyl, 3-oxa-9-aza-bicyclo[3.3.1]nonyl, or 3- thia-9-aza-bicyclo[3.3.1]nonyl. Examples for partly unsaturated heterocycloalkyl are dihydrofuryl, imidazolinyl, dihydro-oxazolyl, tetrahydro-pyridinyl, or dihydropyranyl. A “patient” is a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey, chimpanzee, baboon or rhesus monkey, and the terms “patient” and “subj ect” are used interchangeably herein.

[0035] The term “carrier”, as used in this disclosure, encompasses carriers, excipients, and diluents and means a material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting a pharmaceutical agent from one organ, or portion of the body, to another organ, or portion of the body.

[0036] The term “treating”, with regard to a subject, refers to improving at least one symptom of the subject's disorder. Treating can be curing, improving, or at least partially ameliorating the disorder.

[0037] The term "disorder” is used in this disclosure to mean, and is used interchangeably with, the terms disease, condition, or illness, unless otherwise indicated.

[0038] The term “administer”, “administering”, or “administration” as used in this disclosure refers to either directly administering a compound or pharmaceutically acceptable salt of the compound or a composition to a subject, or administering a prodrug derivative or analog of the compound or pharmaceutically acceptable salt of the compound or composition to the subject, which can form an equivalent amount of active compound within the subject’s body.

[0039] The term “optionally substituted,” as used in this disclosure, means a suitable substituent can replace a hydrogen bound to a carbon. It will be understood by those skilled in the art. with respect to any group containing one or more substituents, that such groups are not intended to introduce any substitution or substitution patterns that are sterically impractical, synthetically non-feasible and / or inherently unstable. Furthermore, combinations of substituents and / or variables within any of the Formulae represented herein are permissible only if such combinations result in stable compounds or useful synthetic intermediates wherein stable implies a reasonable pharmologically relevant half-life at physiological conditions.

[0040] Dosage and Administration:

[0041] The compounds of the present invention may be formulated in a wide variety of oral administration dosage forms and carriers. Oral administration can be in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions, syrups, or suspensions. Compounds of the present invention are efficacious when administered by other routes of administration including continuous (intravenous drip) topical parenteral, intramuscular, intravenous, subcutaneous, transdermal (which may include a penetration enhancement agent), buccal, nasal, inhalation and suppository administration, among other routes of administration. The preferred manner of administration is generally oral using a convenient daily dosing regimen which can be adjusted according to the degree of affliction and the patient's response to the active ingredient.

[0042] A compound or compounds of the present invention, as well as their pharmaceutically useable salts, together with one or more conventional excipients, carriers, or diluents, may be placed into the form of pharmaceutical compositions and unit dosages. The pharmaceutical compositions and unit dosage forms may be comprised of conventional ingredients in conventional proportions, with or without additional active compounds or principles, and the unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed. The pharmaceutical compositions may be employed as solids, such as tablets or filled capsules, semisolids, powders, sustained release formulations, or liquids such as solutions, suspensions, emulsions, elixirs, or filled capsules for oral use; or in the form of suppositories for rectal or vaginal administration; or in the form of sterile injectable solutions for parenteral use. A typical preparation will contain from about 5% to about 95% active compound or compounds (w / w). The term "preparation" or "dosage form" is intended to include both solid and liquid formulations of the active compound and one skilled in the art will appreciate that an active ingredient can exist in different preparations depending on the target organ or tissue and on the desired dose and pharmacokinetic parameters.

[0043] The term "excipient" as used herein refers to a compound that is useful in preparing a pharmaceutical composition, generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes excipients that are acceptable for veterinary use as well as human pharmaceutical use. The compounds of this invention can be administered alone but will generally be administered in admixture with one or more suitable pharmaceutical excipients, diluents or carriers selected with regard to the intended route of administration and standard pharmaceutical practice.

[0044] “Pharmaceutically acceptable” means that which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic. and neither biologically nor otherwise undesirable and includes that which is acceptable for veterinary as well as human pharmaceutical use.

[0045] A "pharmaceutically acceptable salt" form of an active ingredient may also initially confer a desirable pharmacokinetic property on the active ingredient which were absent in the non-salt form, and may even positively affect the pharmacodynamics of the active ingredient with respect to its therapeutic activity in the body. The phrase “pharmaceutically acceptable salt” of a compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. Such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2- hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2- naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4- methylbicyclo[2.2.2]-oct-2-ene-l-carboxylic acid, glucoheptonic acid, 3- phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like.

[0046] Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier may be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material. In powders, the carrier generally is a finely divided solid which is a mixture with the finely divided active component. In tablets, the active component generally is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired. Suitable carriers include but are not limited to magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. Solid form preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.

[0047] Liquid formulations also are suitable for oral administration include liquid formulation including emulsions, syrups, elixirs, aqueous solutions, aqueous suspensions. These include solid form preparations which are intended to be converted to liquid form preparations shortly before use. Emulsions may be prepared in solutions, for example, in aqueous propylene glycol solutions or may contain emulsifying agents such as lecithin, sorbitan monooleate, or acacia. Aqueous solutions can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizing, and thickening agents. Aqueous suspensions can be prepared by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents.

[0048] The compounds of the present invention may be formulated for parenteral administration (e.g., by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers with an added preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, for example solutions in aqueous polyethylene glycol. Examples of oily or nonaqueous carriers, diluents, solvents or vehicles include propylene glycol, polyethylene glycol, vegetable oils (e.g, olive oil), and injectable organic esters (e.g, ethyl oleate), and may contain formulatory agents such as preserving, wetting, emulsifying or suspending, stabilizing and / or dispersing agents. Alternatively, the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilisation from solution for constitution before use with a suitable vehicle, e.g., sterile, pyrogen-free water.

[0049] The compounds of the present invention may be formulated for topical administration to the epidermis as ointments, creams or lotions, or as a transdermal patch. Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and / or gelling agents. Lotions may be formulated with an aqueous or oily base and will in general also containing one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents. Formulations suitable for topical administration in the mouth include lozenges comprising active agents in a flavored base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.

[0050] The compounds of the present invention may be formulated for administration as suppositories. A low melting wax, such as a mixture of fatty acid glycerides or cocoa butter is first melted and the active component is dispersed homogeneously, for example, by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and to solidify.

[0051] The compounds of the present invention may be formulated for vaginal administration. Pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate.

[0052] The compounds of the present invention may be formulated for nasal administration. The solutions or suspensions are applied directly to the nasal cavity by conventional means, for example, with a dropper, pipette or spray. The formulations may be provided in a single or multidose form. In the latter case of a dropper or pipette, this may be achieved by the patient administering an appropriate, predetermined volume of the solution or suspension. In the case of a spray, this may be achieved for example by means of a metering atomizing spray pump.

[0053] The compounds of the present invention may be formulated for aerosol administration, particularly to the respiratory tract and including intranasal administration. The compound will generally have a small particle size for example of the order of five (5) microns or less. Such a particle size may be obtained by means known in the art. for example by micronization. The active ingredient is provided in a pressurized pack with a suitable propellant such as a chlorofluorocarbon (CFC). for example, dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, or carbon dioxide or other suitable gas. The aerosol may conveniently also contain a surfactant such as lecithin. The dose of drug may be controlled by a metered valve. Alternatively the active ingredients may be provided in a form of a dry powder, for example a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidine (PVP). The powder carrier will form a gel in the nasal cavity. The powder composition may be presented in unit dose form for example in capsules or cartridges of e.g., gelatin or blister packs from which the powder may be administered by means of an inhaler.

[0054] When desired, formulations can be prepared with enteric coatings adapted for sustained or controlled release administration of the active ingredient. For example, the compounds of the present invention can be formulated in transdermal or subcutaneous drug delivery devices. These delivery systems are advantageous when sustained release of the compound is necessary and when patient compliance with a treatment regimen is crucial. Compounds in transdermal delivery systems are frequently attached to a skin-adhesive solid support. The compound of interest can also be combined with a penetration enhancer, e.g., Azone (l-dodecylaza-cycloheptan-2-one). Sustained release delivery systems are inserted subcutaneously into to the subdermal layer by surgery or injection. The subdermal implants encapsulate the compound in a lipid soluble membrane, e.g., silicone rubber, or a biodegradable polymer, e.g.. polylactic acid.

[0055] Suitable formulations along with pharmaceutical carriers, diluents and excipients are described in Remington: The Science and Practice of Pharmacy 1995, edited by E. W. Martin, Mack Publishing Company, 19th edition, Easton, Pennsylvania. A skilled formulation scientist may modify the formulations within the teachings of the specification to provide numerous formulations for a particular route of administration without rendering the compositions of the present invention unstable or compromising their therapeutic activity.

[0056] The modification of the present compounds to render them more soluble in water or other vehicle, for example, may be easily accomplished by minor modifications (salt formulation, esterification, etc.), which are well within the ordinary skill in the art. It is also well within the ordinary skill of the art to modify the route of administration and dosage regimen of a particular compound in order to manage the pharmacokinetics of the present compounds for maximum beneficial effect in patients.

[0057] The term "therapeutically effective amount" as used herein means an amount required to reduce symptoms of the disease in an individual. The dose will be adjusted to the individual requirements in each particular case. That dosage can vary within wide limits depending upon numerous factors such as the severity of the disease to be treated, the age and general health condition of the patient, other medicaments with which the patient is being treated, the route and form of administration and the preferences and experience of the medical practitioner involved. For oral administration, a daily dosage of between about 0.01 and about 1000 mg / kg body weight per day should be appropriate in monotherapy and / or in combination therapy. A preferred daily dosage is between about 0. 1 and about 500 mg / kg body weight, more preferred 0.1 and about 100 mg / kg body weight, and most preferred 1.0 and about 15 mg / kg body weight per day. Thus, for administration to a 70 kg person, the dosage range in one embodiment would be about 70 mg to .7 g per day. The daily dosage can be administered as a single dosage or in divided dosages, typically between 1 and 5 dosages per day. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect for the individual patient is reached. One of ordinary skill in treating diseases described herein will be able, without undue experimentation and in reliance on personal knowledge, experience and the disclosures of this application, to ascertain a therapeutically effective amount of the compounds of the present invention for a given disease and patient.

[0058] The pharmaceutical preparations are preferably in unit dosage forms. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.

[0059] EXAMPLES

[0060] The following examples further describe and demonstrate particular embodiments within the scope of the present invention. Techniques and formulations generally are found in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, Pa.). The disclosure is further illustrated by the following examples, which are not to be construed as limiting this disclosure in scope or spirit to the specific procedures herein described. It is to be understood that the examples are provided to illustrate certain embodiments and that no limitation to the scope of the disclosure is intended thereby. It is to be further understood that resort may be had to various other embodiments, modifications, and equivalents thereof which may suggest themselves to those skilled in the art without departing from the spirit of the present disclosure and / or scope of the appended claims.

[0061] General information for compound synthesis and characterization:

[0062] Starting materials, reagents and solvents were purchased from commercial sources and used without further purification.

[0063] Concentration under vacuum or reduced pressure means that a rotary evaporator was used.

[0064] Silica gel chromatography was performed using a ISCO or Biotage system with prepackaged columns from Agela.

[0065] Proton nuclear magnetic resonance spectroscopy (1H NMR) was recorded with Bruker 400 MHz or Varian 500 MHz NMR spectrometers. Chemical shifts are expressed in part per million downfield with respect to solvent resonance as the internal standard (for example, CDCls at 7.26 ppm for 1H). The peak shapes are denoted as follows: s, singlet; d, doublet; t. triplet; q. quartet; p, pentet; m, multiplet; br s, broad singlet; dd. doublet of doublets, dt, doublet of triplets; dq, doublet of quartets.

[0066] Liquid chromatography mass spectrometry (LCMS) was performed on Agilent LC1200-MS6110 or Shimadzu LC20-MS2020.

[0067] Mass spectrometry (MS) was performed via atmospheric pressure chemical ionization (APCI), electrospray Ionization (ESI), electron impact ionization (El) or electron scatter (ES) ionization sources.

[0068] Typical conditions for Prep-HPLC:

[0069] Column:

[0070] YMC-Actus Triart C18 150 x 30mm, 5um; Boston Green ODS 150 x 30mm, 5um;

[0071] Phenomenex luna C18 150 x 25mm, lOum; Welch Xtimate C18 150 x 25mm, 5um; Waters Xbridge BEH C18 100 x 25mm, 5um; Daisogel SP ODS RPS 150 x 25mm, 5um

[0072] Mobile phase:

[0073] A: 0.225% FA in water, B: MeCN; A: 0.1% TFA in water, B: MeCN; A: 0.04% HC1 in water, B: MeCN; A: 10 mmol NH4HCO3 in water, B: MeCN; A: 0.05% NH3.H2O and 10 mmol NH4HCO3 in water, B: MeCN.

[0074] Run time: 10-25 min

[0075] Flow rate: 25-40 mL / min

[0076] Typical Prep-SFC:

[0077] Column: DAICEL CHIRALCEL OD (250mm x 30mm, lOum); mobile phase A: CO2; B: 0.1%NH3H2O in EtOH; isocratic 30%B and 70%A. Flow rate: 140 mL / min.

[0078] Column: DAICEL CHIRALPAK IG (250mm x 30mm, lOum); mobile phase A: CO2; B: 0.1%NH3H2O in i-PrOH; isocratic 30%B and 70%A; Flow rate: 80 mL / min.

[0079] Column: DAICEL CHIRALPAK AS (250mm x 30mm, lOum; mobile phase: A: CO2, B: EtOH; isocratic 10% B and 90% A. Flow rate: 150 mL / min Column: Phenomenex-Cellulose-2 (250mm x 30mm, lOum); mobile phase A: heptane;

[0080] B: 0.1% TFAin EtOH: isocratic 40%B and 60%A. Flow rate: 150 mL / min

[0081] Abbreviations:

[0082] ACN or MeCN: acetonitrile

[0083] AcOH: acetic acid aq.: aqueous

[0084] Ex.: example

[0085] DCM: dichloromethane

[0086] DMF: dimethylformamide

[0087] EDCI: l-ethyl-3-(3-dimethylaminopropyl)carbodiimide

[0088] EtOAc: ethyl acetate

[0089] Eq: equivalent

[0090] FA: formic acid

[0091] HOBt: 1 -hydroxybenzonitrile

[0092] HPLC: high performance liquid chromatography

[0093] TIPSC1: chlorotriisopropylsilane

[0094] IPA: isopropyl alcohol

[0095] THF. tetrahydrofuran

[0096] LAH: lithium aluminium hydride

[0097] LCMS or LC-MS: liquid chromatography mass spectrometry

[0098] LDA: lithium diisopropylamide

[0099] LiHMDS: lithium bis(trimethylsilyl)amide

[0100] MeOH: methanol

[0101] TBAF: tetra-n-butylammonium fluoride

[0102] TEA: triethylamine

[0103] TLC: thin-layer chromatography

[0104] TMEDA: tetramethylethylenediamine

[0105] TMG: 1 , 1 ,3,3-tetramethylguanidine 5: chemical shift in ppm

[0106] TFA: 2,2,2-trifluoroacetic acid

[0107] TFAA: 2,2,2-trifluoroacetic anhydride

[0108] T3P: 2.4.6-tripropyl-1.3.5.2.4.6-trioxatriphosphinane 2.4.6-trioxide

[0109] T4P: 2,4,6-tributyd-l,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide

[0110] Py: pyridine

[0111] MnCh: Manganese(IV) oxide, activated

[0112] DIBAL-H: diisobutylaluminum hydride

[0113] DMP: Dess-Martin periodinane

[0114] Min: minute hr: hour m / z: mass-to-charge ratio

[0115] NMR: nuclear magnetic resonance

[0116] 'H NMR: proton NMR

[0117] Pd(dppf)Ch: [l,r-Bis(diphenylphosphino)ferrocene]dichloro palladium (II)

[0118] Pd(dba)2: Bis(dibenzylideneacetone)palladium

[0119] Pd(PPh3)4: Tetrakis(triphenylphosphine)palladium(0) prep-HPLC: preparative HPLC psi: pound per square inch sat.: saturated

[0120] SFC: supercritical fluid chromatography

[0121] Synthesis:

[0122] The compounds of Formula A can be synthesized according to the general synthesis schemes IA

[0123] General Synthesis Scheme IA

[0124]

[0125] X: Br, I or OTs

[0126] Acid: TFA. HC1, formic acid

[0127] R2: -(CH2)2CF3, -(CH2)3CF3, -(CH2)2-4-fluorophenyl

[0128] Rs: Me, - -(CH2)2CH(OH)CH3,

[0129] R as defined in the genus structure 1A

[0130] [O]: MnO2. DMP

[0131] Condensation agent: EDCI / HOBt, T3P, T4P

[0132] Synthesis of intermediates and examples:

[0133] Example 1: 2-(4-fluorophenyl)-N-((2S)-5-hydroxy-l-oxo-l-(((S)-6,6,6-trifluoro-l- oxo-l-(thiazol-2-yl)hexan-2-yl)amino)hexan-2-yl)thiazole-5-carboxamide (ClpP- 1628) Step 1. Synthesis of (2R>5S)-2-isopropyl-3,6-dimethoxy-5-(4,4>4-trifluorobutyl)-2,5- dihydro pyrazine

[0134] To a solution of LDA (2 M in THF, 109.95 mL, 1.2 eq) in THF (200 mL) was added dropwise (2R)-2-isopro pyl-3,6-dimethoxy-2,5-dihydropyrazine (33.76 g, 183.26 mmol, 32.78 mL. 1 eq) and purged withN2 for 3 times at -78 °C. Then 30 minutes later, a mixture of 4-bromo- 1 , 1, 1 -trifluoro-butane (35 g, 183.26 mmol, 1 eq) in THF (150 mL) was added to the above solution at -78 °C. The mixture was stirred at 25 °C for 12 hr under N2 atmosphere. LCMS showed desired mass was detected. The reaction mixture was quenched by addition of sat. NH4Q (1000 mL) and extracted with EtOAc (300 mL x 3). The combined organic layer was dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiCh, 0-10% EtOAc in petroleum ether). (2R,5S)-2- isopropyl-3,6-dimethoxy-5-(4,4,4-trifluorobutyl)-2,5-dihydro pyrazine (46.8 g. 143.11 mmol, 78% yield, 90% purity) was obtained as colorless oil.

[0135] LCMS (ESI) m / z 295.6 [M+H]+

[0136] 1H NMR (400MHz, CHLOROFORM-d) 8 = 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)

[0137] Step 2. Synthesis of methyl (2S)-2-amino-6,6,6-trifluoro-hexanoate TFA salt

[0138] 1-B 1-C

[0139] 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 eq) in MeCN (240 mL), H2O (150 rnL) was added TFA (92.40 g, 810.36 mmol, 60 mL, 4.75 eq). The mixture was stirred at 50 °C for 12 hr. TLC indicated the starting material was consumed completely. The reaction mixture was concentrated under reduced pressure to dryness. Methyl (2S)-2-amino- 6,6.6-trifluoro-hexanoate (53 g, crude, TFA salt) was obtained as yellow oil. It was used in the next step without further purification.

[0140] Step 3. Synthesis of methyl (2S)-2-(tert-butoxycarbonylamino)-6,6,6-trifluoro- hexanoate

[0141] 1-C 1-D

[0142] To a solution of methyl (2S)-2-amino-6,6,6-trifluoro-hexanoate (53 g, 266.10 mmol, 1 eq) in THF (530 mL) was added DIEA (103.18 g, 798.31 mmol, 139.05 mL, 3 eq) and BOC2O (127.77 g, 585.43 mmol, 134.49 mL, 2.2 eq). The mixture was stirred at 25 °C for 12 hr. TLC indicated two major new spots. The reaction mixture was diluted with H2O (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layer was dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiCh. 0-10% EtOAc in petroleum ether) to afford methyl (2S)-2-(tert-butoxycarbonylamino)-6,6,6- trifluoro-hexanoate (36 g, 117.88 mmol. 44.3% yield, 98% purity) as a colorless oil. 'H NMR (400MHz, DMSO-6) 5 = 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).

[0143] Step 4. Synthesis of tert-butyl N-[(lS)-5,5,5-trifluoro-l-(hydroxymethyl)pentyl] carbamate

[0144] 1-D 1-E

[0145] To a solution of methyl (2S)-2-(tert-butoxycarbonylamino)-6,6,6-trifluoro-hexanoate (16 g, 53.46 mmol, 1 eq) in THF (160 mL) was added LAH (2.23 g, 58.81 mmol, 1.1 eq in portions under N2 at 0 °C. The mixture was stirred at 25 °C for 1 hr. TLC indicated the starting material was consumed completely. The reaction was quenched by addition of H2O (2.23 mL), 15% NaOH (2.23 mL) and H2O (6.69 mL) slowly at 0 °C, and then filtered. The filter cake was washed with 200 mL of CH2CI2. The combined filtrate was dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (S1O2. 0-50% EtoAc in petroleum ether) to afford compound tert-butyl N-[(l S)-5,5,5-trifluoro-l -(hydroxylmethyl)pentyl] carbamate (11.5 g, 40.27 mmol, 75.3% yield, 95% purity) as a white solid.

[0146] 'H NMR (400MHz, DMSO-dfe) 5 = 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, 1 H), 2.34 - 2.14(m, 2 H), 1.55 - 1.33 (m, 13 H).

[0147] Step 5. Synthesis of tert-butyl N-[(lS)-5, 5, 5-trifluoro-l-formyl-pentylJcarbamate

[0148] To a solution of tert-butyl N-[(lS)-5,5,5-trifluoro-l-(hydroxymethyl)pentyl]carbamate (11.5 g, 42.39 mmol, 1 eq) in DCM (120 mL) was added DMP (19.78 g, 46.63 mmol, 14.44 mL, 1.1 eq). The mixture was stirred at 25 °C for 1 hr. TLC showed the starting material was consumed completely. The reaction mixture was diluted with DCM (50 mL) and quenched by Sat. NaHCCh (100 mL). The resulting mixture was filtered. The filtrate was extracted with DCM (50 mL x 2). The combined organic layer was dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiCh, 0-30% EtoAc in petroleum ether). Compound tert-butyl N-[(lS)-5,5,5-trifluoro-l-formyl- pentyl] carbamate (8.87 g, 31.30 mmol, 73.8% yield. 95% purity ) was obtained as a white solid.

[0149] 'H NMR (400MHz, DMSO-A) 8 = 9.44 (s, 1 H), 7.37 (br d, J= 7.6 Hz, 1 H), 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).

[0150] Step 6. Synthesis of tert-butyl N-[(lS)-5, 5, 5-trifluoro-l-[hydroxy(thiazol-2-yl)methyl] pentyljcarbamate

[0151] To a solution of TMEDA (8.80 g, 75.77 mmol, 11.43 mL, 2.3 eq) in THF (90 mL) was added n-BuLi (2.5 M in n-hexane, 32.94 mL, 2.5 eq) and thiazole (6.17 g. 72.47 mmol. 5.14 mL, 2.2 eq) dropwisely at -78 °C. The mixture was stirred at -78 °C for 0.5 h under N2. Then tert-butyl N-[(lS)-5,5,5-trifluoro-l-formyl-pentyl]carbamate (8.87 g, 32.94 mmol, 1 eq) in THF (20 mL) was added dropwisely at -78 °C and stirred at -78 °C for 0.5 hr. TLC showed the starting material was consumed completely. The reaction mixture was poured into sat. aq. NH4CI (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layer was dried over anhydrous Na2SO4, filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO2, 0-40% EtoAc in petroleum ether) to afford tert-butyl N-[(lS)-5,5,5-trifluoro-l-[hydroxy(thiazol-2-yl)methyl]pentyl]carbamate (6.3 g, 16.89 mmol, 51.3% yield, 95% purity) as ayellow oil.

[0152] 'H NMR (400MHz, DMSO-de) 5 = 7.82 - 7.47 (m, 2 H), 6.36 - 6.29 (m, 1 H), 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, 12 H).

[0153] Step 7. Synthesis of benzyl (2S)-2-(tert-butoxycarbonylamino)-5-oxo-hexanoate

[0154] 1-H 1-j

[0155] To a solution of 2-benzyl 1 -(tert-butyl) (S)-5-oxopyrrolidine-l,2-dicarboxylate (100 g, 313.13 mmol, 1 eq) in THF (1000 mL) was added MeLi (1.6 M in ethyl ether, 234.9 mL, 1.2 eq) dropwisely at -60 °C under N2. The mixture was stirred at 25 °C for 1 hr under N2. TLC indicated the starting material was consumed completely. The reaction mixture was poured into aq. 0.25 M HC1 (1500 mL) at 0 °C and extracted with EtOAc (500 mL x 3). The combined organic layer was dried over anhydrous Na2SO4, filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiCh, 0-30% EtOAc in Petroleum ether) to afford benzyl (2S)-2-(tert-butoxycarbonylamino)-5-oxo-hexanoate (74.6 g, 211.30 mmol, 67.5% yield, 95% purity) was obtained as a colorless oil. 'H NMR (400 MHz, CHLOROFORM-d) 5 = 7.34 - 7.19 (m, 5 H), 5.23 - 5.00 (m, 3 H). 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).

[0156] Step 8. Synthesis of benzyl (2S)-2-(tert-butoxycarbonylamino)-5-hydroxy-hexanoate

[0157] 1-J 1-K

[0158] To a solution of benzyl (2S)-2-(tert-butoxycarbonylamino)-5-oxo-hexanoate (35 g, 104.35 mmol, 1 eq) in THF (350 mL) and H2O (70 mL) was added NaBH4 (5.13 g, 135.66 mmol, 1.3 eq) at 0 °C. The mixture was stirred at 0 °C for 0.5 hr. TLC indicated the starting material was consumed. The reaction mixture was diluted with aq. 0.5 M HC1 (350 mL) and extracted with EtOAc (400 mL x 2). The combined organic layer was dried over anhydrous Na2SO4, filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography (SiCh, 0-30% EtOAc in Petroleum ether). Compound benzyd (2S)-2-(tert-butoxycarbonylamino)-5-hydroxy-hexanoate (41 g, 115.44 mmol, 55.3% yield, 95% purity) was obtained as yellow oil.

[0159] 'H NMR (400 MHz, DMSO-de) 5 = 7.45 - 7.20 (m, 6 H), 5.24 - 5.01 (m, 2 H), 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,2 H), 1.45 - 1.26 (m, 11 H). 1.08 - 0.96 (m. 3 H).

[0160] Step 9. Synthesis of benzyl (2S)-2-(tert-butoxycarbonylamino)-5-triisopropylsilyloxy- hexanoate To a solution of benzyl (2S)-2-(tert-butoxycarbonylamino)-5-hydroxy -hexanoate (41 g. 121.51 mmol, 1 eq) in DMF (400 mL) was added imidazole (33.09 g, 486.06 mmol, 4 eq) and TIPSC1 (23.43 g, 121.51 mmol. 26.00 mL, 1 eq). The mixture was stirred at 50 °C for 12 hr. LCMS showed desired mass. The reaction mixture was diluted with 100 mL of H2O and extracted with EtOAc (100 mL x 2). The combined organic layer was dried over Na2SC>4, filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography (S1O2. 0-10% EtOAc in Petroleum ether). Compound benzyl (2S)-2-(tert-butoxycarbonylamino)-5- triisopropylsilyloxy-hexanoate (39.75 g, 78.90 mmol, 64.9% yield, 98% purity) was obtained as a colorless oil.

[0161] LCMS (ESI) m / z 494.2 [M+H]+

[0162] 'H NMR (400 MHz, DMSO-cL) 5 = 7.31 - 7. 14 (m, 5 H), 5.12 - 4.93 (m, 2 H), 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).

[0163] Step 10. Synthesis of (2S)-2-(tert-butoxycarbonylatnino)-5-triisopropylsilyloxy- hexanoic acid

[0164] 1-L 1-M

[0165] To a solution of benzyl (2S)-2-(tert-butoxycarbonylamino)-5-triisopropylsilyloxy- hexanoate (19.75 g, 40.00 mmol, 1 eq) in THF (200 mL) was added Pd / C (6 g, 10.13 mmol, 10% purity) under N2 atmosphere. The suspension was degassed and purged with H2 for 3 times. The mixture was stirred under H2 (15 Psi) at 20 °C for 1 hr. LCMS showed starting material was consumed completely. 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. Cl 8. 20-45 pm. 330 g. 100 A. Mobile phase: A: water; B: ACN. Gradient: 5%-100% B in A over 60min. Flow rate: 25 mL / min). Compound (2S)-2- (tert-butoxycarbonylamino)-5-triisopropylsilyloxy-hexanoic acid (13.93 g. 32.79 mmol, 82% yield, 95% purity) was obtained as a yellow oil.

[0166] LCMS (ESI) m / z 426.2 | M+Na|+iH NMR (400 MHz, DMSO-ds) 5 = 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).

[0167] Step 11. Synthesis of (2S)-2-amino-6,6,6-trifluoro-l-thiazol-2-yl-hexan-l-ol HCl salt

[0168] 1-G 1-N

[0169] To a solution of tert-butyl N-[(lS)-5,5,5-trifluoro-l-[hydroxy(thiazol-2- yl)methyl]pentyl] carbamate (6.25 g, 17.64 mmol, 1 eq) in EtOAc (31 mL) was added HCl / EtOAc (4 M, 31 mL. 7.03 eq). The mixture was stirred at 25 °C for 1 hr. The reaction mixture was concentrated under reduced pressure to afford (2S)-2-amino- 6,6.6-trifluoro-l-thiazol-2-yl-hexan-l-ol (5.13 g, crude. HCl salt) as a yellow solid. It was used in the next step without further purification.

[0170] Step 12. Synthesis of tert-butyl N-[(lS)-l-[[(lS)-5,5,5-trifluoro-l-[hydroxy(thiazol-2- yl)methyl] pentyl]carbamoyl]-4-triisopropylsilyloxy-pentyl]carbamate

[0171] To a solution of (2S)-2-amino-6,6,6-trifluoro-l-thiazol-2-yl-hexan-l-ol (5.13 g, 17.65 mmol, 1 eq, HCl), (2S)-2-(tert-butoxycarbonylamino)-5-triisopropylsilyloxy-hexanoic acid (7.12 g, 17.65 mmol, 1 eq) in DMF (60 mL) was added a solution of HOBt (4.77 g, 35.29 mmol, 2 eq), EDCI (6.77 g, 35.29 mmol, 2 eq) in DMF (30 mL) and TEA (7. 14 g, 70.58 mmol, 9.82 mL, 4 eq) at 0 °C. The mixture was stirred at 25 °C for 12 hr. LCMS showed the desired product was detected. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layer was washed with LiCl (100 mL) (5 wt% in water), dried over Na2SO4, filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO2, 0-40% EtoAc in petroleum ether) to afford tert-butyl N-[(lS)-l-[[(lS)-5,5,5-trifluoro-l-[hydroxy(thiazol-2-yl)methyl]pentyl]carbamoyl]-4- triisopropylsilyloxy-pentyl] carbamate (7g, 10.39 mmol, 58.9% yield, 95% purity) was obtained as a white solid.

[0172] LCMS (ESI) m / z 640.7 [M+H]+

[0173] 'H NMR (400MHz, DMSO-de) 6 = 7.77 - 7.45 (m, 3 H), 6.98 - 6.73 (m, 1 H), 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).

[0174] Step 13. Synthesis of (2S)-2-amino-5-hydroxy-N-[(lS)-5,5,5-trifluoro-l-

[0175] [hydroxy(thiazol-2-yl)me thyl]pentyl]hexanamide HCl salt

[0176] To a solution of tert-butyl N-[(lS)-l-[[(lS)-5,5,5-trifluoro-l-[hydroxy(thiazol-2- yl)methyl]pentyl]ca rbamoyl]-4-triisopropylsilyloxy-pentyl]carbamate (6 g, 9.38 mmol, 1 eq) in EtOAc (30 mL) was added HCl / EtOAc (4 M, 30 mL, 12.80 eq). The mixture was stirred at 25 °C for 2 hr. LCMS showed the desired product was detected. The mixture was concentrated under reduced pressure to give (2S)-2-amino-5-hydroxy-N- [(lS)-5,5,5-trifluoro-l-[hydroxy(thiazol-2- yl)methyl]pentyl]hexanamide (3.94 g, crude, HC1) as a white solid. It w as used in the next step without further purification. LCMS (ESI) m / z 384.1 [M+H]+

[0177] Step 14. Synthesis of methyl 2-(4-fluorophenyl)thiazole-5-carboxylate

[0178] To a solution of methyl 2-bromothiazole-5-carboxylate (10 g, 45.03 mmol. 1 eq) in dioxane (100 mL) and H2O (10 mL) was added (4-fluorophenyl) boronic acid (7.56 g, 54.04 mmol, 1.2 eq) and Na2COs (14.32 g, 135.10 mmol, 3 eq). The reaction mixture w as degassed and purged with N2 for three times, then Pd(dppf)Ch (1.65 g, 2.25 mmol, 0.05 eq) was added. The reaction mixture was stirred at 80 °C for 12 hr under N2 atmosphere. LCMS indicated desired product. The reaction mixture was diluted with H2O (150 mL) and extracted with EtoAc (150 mL x 3). The combined organic layer was dried over Na2SC>4, filtered. The filtrate w as concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiCh. 0-30% EtOAc in petroleum ether) to afford methyl 2-(4-fluorophenyl)thiazole-5-carboxylate (3.60 g, 15.02 mmol, 32.7% yield, 99% purity) as a white solid.

[0179] LCMS (ESI) m / z 237.9 [M+H]+

[0180] 1H NMR (400MHz, DMSO-d6) 5 = 8.50 (s. 1 H). 8. 13 - 8.05 (m. 2 H). 7.43 - 7.34 (m.

[0181] 2 H), 3.90 - 3.85 (m, 3 H).

[0182] Step 15. Synthesis of 2-(4-fluorophenyl)thiazole-5-carboxylic acid

[0183] To a solution of methyl 2-(4-fluorophenyl)thiazole-5-carboxylate (3.58 g, 15.09 mmol, 1 eq) in THF (36 mL) was added H2O (36 mL) and LiOH.H2O (6.04 g, 144.00 mmol, 9.54 eq). The reaction mixture was stirred at 25 °C for 1 hr under N2 atmosphere. LC- MS showed the desired mass. To the reaction mixture was added 6 M HC1 until pH = 5, then extracted with EtoAc (20 mL x 3). The combined organic layer was dried over Na2SO4, filtered. The filtrate was concentrated under reduced pressure to afford compound 2-(4-fluorophenyl)thiazole-5-carboxylic acid (3.34 g, 13.77 mmol, 91.2% yield. 92% purity) as a white solid. It was used in the next step without further purification.

[0184] LCMS (ESI) m / z 223.9 [M+H]+

[0185] 1H NMR (400MHz, DMSO-d6) 5 = 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).

[0186] Step 16. Synthesis of 2-(4-fluorophenyl)-N-[(lS)-4-hydroxy-l-[[(lS)-5,5,5-trifluoro- l-[hydroxy (thiazol-2-yl)methyl]pentyl]carbamoyl]pentyl]thiazole-5-carboxamide

[0187] 1-U

[0188] To a solution of (2S)-2-arrrino-5-hydroxy-N-[(lS)-5.5.5-trifluoro-l-|hydroxy(thiazol- 2-yl)methyl]pentyl]hexanamide (3.94 g, 9.38 mmol, 1 eq, HC1), 2-(4- fluorophenyl)thiazole-5-carboxylic acid (2.09 g, 9.38 mmol, 1 eq) in DMF (40 mL) was added a solution of HOBt (2.54 g, 18.77 mmol, 2 eq), EDCI (3.60 g. 18.77 mmol, 2 eq) in DMF (10 mL) and TEA (7.60 g, 75.07 mml, 10.45 mL, 8 eq). The mixture was stirred at 25 °C for 2 hr. LC-MS showed the desired mass. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (50 mL x 3). The combined organic layer was washed with LiCl (100 mL) (5 wt% in water), dried over Na2SC>4, filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiCh, 0-10% MeOH in DCM). Compound 2-(4- fluorophenyl)-N- [(lS)-4-hydroxy-l-[[(lS)-5,5,5-trifluoro-l-[hydroxy(thiazol-2- yl)methyl]pentyl]carbamoyl]pentyl] thiazole-5 -carboxamide (3.41 g, 5.50 mmol, 58.7% yield, 95% purity) was obtained as a yellow solid.

[0189] LCMS (ESI) m / z 589.3 [M+H]+

[0190] 'H NMR (400MHz, DMSO-A) 5 = 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).

[0191] Step 17. Synthesis of 2f4fluorophenyl)-N-[(lS)-4-hydroxy-l-[[(lS)-5,5,5-trifluoro- l-(thiazole- 2-carbonyl)pentyl]carbamoyl]pentyl]thiazole-5-carboxamide

[0192]

[0193] To a solution of 2-(4-fluorophenyl)-N-[(lS)-4-hydroxy-l-[[(lS)-5,5,5-trifluoro-l- [hydroxy(thiazol-2-yl)methyl]pentyl]carbamoyl]pentyl]thiazole-5-carboxamide (3.4 g, 5.78 mmol. 1 eq) in DCM (100 mL) was added MnCh (17.58 g, 202.16 mmol, 35 eq). The mixture was stirred at 25 °C for 2 hr. LCMS showed the desired product was detected. The reaction mixture was filtered and concentrated under reduced pressure. The resulting residue was purified by prep-HPLC (Column: Agela Cl 8, 20-45 pm, 120 g, 100 A. Mobile phase: A: water; B: MeCN. Gradient: 5%-55% B in A over 60 min. Flow rate: 25 mL / min) to afford the title compound 2-(4-fluorophenyl)-N-[(lS)-4- hydroxy-l-[[(lS)-5,5,5-trifhroro-l-(thiazole-2- arbonyl)pentyl]carbamoyl]pentyl]thiazole-5-carboxamide (2.24 g, 3.81 mmol, 66% yield. 99% purity) as a white solid.

[0194] LCMS (ESI) m / z 587.1 [M+H]+

[0195] 1H NMR (400MHz, DMSO-d6) 5 = 8.80 - 8.72 (m, 1 H), 8.68 - 8.52 (m, 2 H), 8.26 (d, J = 3.2 Hz, 1 H), 8.19 (d, J = 3.2 Hz, 1 H), 8.09 - 7.99 (m, 2 H), 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).

[0196] Example 2: 2-(4-fluorophenyl)-N-((2S)-l-(((S)-4-(4-fluorophenyl)-l-oxo-l-

[0197] (thiazol-2-yl)butan-2-yl)amino)-5-hydroxy-l-oxohexan-2-yl)thiazole-5- carboxamide (ClpP-1629)

[0198] Step 1. Synthesis of (2S,5R)-2-[2-(4-fluorophenyl)ethyl]-5-isopropyl-3,6-dimethoxy-

[0199] 2,5-dihydro pyrazine

[0200] To a solution of LDA (2 M in THE 73.87 mL, 1.2 eq) in THF (100 mL) was added dropwisely (2R)-2-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine (20.41 g, 110.81 mmol, 19.82 mL, 0.9 eq) and purged with N2 for 3 times at -78 °C. 30 minutes later, a solution of 1 -(2-bromoethyl)-4-fluoro-benzene (25 g, 123.12 mmol, 17.24 mL, 1 eq) in THF (150 mL) was added to the above solution at -78 °C. The mixture was stirred at 20 °C for 12 hr under N2 atmosphere. TLC indicated one major new spot. The reaction mixture was quenched by addition of sat. aq. NH4CI (50 mL), diluted with water (100 mL) and then extracted with EtOAc (200 mL x 3). The combined organic layer was dried over Na2SO4, filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiCh, 0-10% EtoAc in petroleum ether). Compound (2S,5R)-2-[2-(4-fluorophenyl)ethyl]-5-isopropyl-3,6- dimethoxy-2.5 -dihydro pyrazine (38 g, 117.83 mmol, 47.9% yield, 95% purity) was obtained as a white solid.

[0201] 1H NMR (400MHz, CHLOROFORM-d) S = 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, 1 H), 2.03 - 1.91 (m, 1 H), 1.06 (d, J= 6.8 Hz, 3 H), 0.71 (d, J= 6.8 Hz, 3 H).

[0202] To a solution of (2S,5R)-2-[2-(4-fluorophenyl)ethyl]-5-isopropyl-3,6-dimethoxy-2,5- dihy dropyrazine (27 g, 88.13 mmol, 1 eq) in MeCN (150 mL) and H2O (75 mL) was added TFA (52.83 g, 463.35 mmol, 34.31 mL, 5.26 eq). The mixture was stirred at 50 °C for 12 hr. LC-MS showed the mass. The reaction mixture was concentrated under reduced pressure to dryness. Compound methyl (2S)-2-amino-4-(4- fluorophenyl)butanoate (28 g, crude, TFA salt) was obtained as yellow oil. It was used in the next step without further purification.

[0203] LCMS (ESI) m / z 212.2 [M+H]+

[0204] Step 3. Synthesis of methyl (2S)-2-(tert-butoxycarbonylamino)-4-(4- fluorophenyl)butanoate

[0205] To a solution of methyl (2S)-2-amino-4-(4-fluorophenyl)butanoate (39 g, 119.91 mmol, 1 eq, TFA salt) in THF (400 mL) was added DIEA (46.49 g, 359.72 mmol. 62.66 mL, 3 eq) and BOC2O (52.34 g, 239.81 mmol, 55.09 mL, 2 eq). The mixture was stirred at 20 °C for 12 hr. LC-MS showed the desired mass. The reaction mixture was diluted with water (500 mL) and extracted with EtOAc (500 mL x 2). The combined organic layer was dried over Na2SO4, filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiCh. 0-30% ethyl acetate in petroleum ether). Compound methyl (2S)-2-(tert- butoxycarbonylamino)-4-(4-fluorophenyl)butanoate (38 g, 109.85 mmol, 91.6% yield, 90% purity) was obtained as a colorless oil.

[0206] LCMS (ESI) m / z 212.2 [M-Boc]+

[0207] 'H NMR (400MHz, CHLOROFORM-rf) 5 = 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).

[0208] Step 4. Synthesis of tert-butyl N-[( 1 S)-3-(4-fluorophenyl)-l -

[0209] To a solution of methyl (2S)-2-(tert-butoxycarbonylamino)-4-(4- fluorophenyl)butanoate (18 g, 57.81 mmol. 1 eq) in THF (200 mL) was added LAH (2.63 g, 69.38 mmol, 1.2 eq) at 0 °C. The mixture was stirred at 20 °C for 1 hr. TLC indicated one major new spot with larger polarity. The reaction was quenched with 2.9 ml of water and 2.9 ml of 15% aqueous NaOH at 0 °C. And followed by addition of 9 mL of water. The precipitates were filtered through Celite. The filter cake was washed with DCM (3 x 200 mL). The combined filtrate was dried over Na2SO4, filtered. The filtrate was concentrated under reduced pressure to afford tert-butyl N-[( 1 S)-3-(4- fluorophenyl)-l -(hydroxymethyl) propyl] carbamate (13 g, 43.59 mmol, 75.4% yield, 95% purity) as a white solid. It was used in the next step without further purification.

[0210] 1H NMR (400MHz, DMSO-tfc) 8 = 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).

[0211] Step 5. Synthesis of tert-butyl N-[(lS)-3-(4-fluorophenyl)-l-formyl-propyl]carbaniate

[0212] 2-E 2-F

[0213] To a solution of tert-butyl N-[(lS)-3-(4-fluorophenyl)-l- (hydroxymethyl)propyl] carbamate (13 g, 45.88 mmol, 1 eq) in DCM (200 mL) was added DMP (21.41 g, 50.47 mmol, 15.63 mL, 1.1 eq) at 0 °C. The mixture was stirred at 20 °C for 1 hr. TLC indicated one major new spot with lower polarity. The reaction mixture was diluted with 300 mL of DCM and washed with sat. NaHCCh (500 mL x 3). The organic layer was dried over Na2SO4, filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiCh, 0-30% EtoAc in petroleum ether). Compound tert-butyl N-[(lS)-3-(4-fluorophenyl)-l- formyl-propyl] carbamate (6.8 g, 21.75 mmol, 47.4% yield, 90% purity) was obtained as colorless oil.

[0214] 'H NMR (400MHz, DMSO-A) 5 = 9.44 (s, 1 H), 7.42 (br d, J = 7.2 Hz, 1 H), 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).

[0215] Step 6. Synthesis of tert-butyl N-[(lS)-3-(4-fluorophenyl)-l-[hydroxy(thiazol-2- yl)methyl] propyljcarbamate

[0216]

[0217] To a solution of TMEDA (5.99 g, 51.51 mmol, 7.77 mL, 2.3 eq) in THF (50 mL) was added n-BuLi (2.5 M in n-hexane, 22.39 mL, 2.5 eq) and thiazole (4.19 g, 49.27 mmol, 3.50 mL, 2.2 eq) dropwise at -78 °C. The mixture was stirred at -78 °C for 0.5 hr under N2. Then a solution of tert-butyl N-[(lS)-3-(4-fluorophenyl)-l-formyl- propyl] carbamate (6.3 g. 22.39 mmol, 1 eq) in THF (50 mL) was added dropwise at - 78 °C and stirred at -78 °C for 0.5 hr under N2 atmosphere. TLC indicated one major new spot. The reaction mixture was poured into sat. aq. NH4CI (20 mL) and extracted with EtOAc (100 mL x 2). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiCh, 0-30% ethyl acetate in petroleum ether). Compound tert-butyl N-[(lS)-3-(4-fluorophenyl)-l-[hydroxy(thiazol-2- yl)methyl]propyl] carbamate (5.3 g, 13.74 mmol, 61.3% yield, 95% purity) was obtained as a yellow oil.

[0218] LCMS (ESI) m / z 367.1 [M+H]+

[0219] 'H NMR (400MHz, DMSO- d ) 5 = 7.75 - 7.67 (m, 1 H), 7.63 - 7.51 (m, 1 H), 7.22 - 7.02 (m, 4 H), 6.28 (dd, J= 2.0, 5.2 Hz, 1 H), 4.94 - 4.74 (m, 1 H), 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).

[0220] Step 7. Synthesis of (2S)-2-amino-4-(4-fluorophenyl)-l-thiazol-2-yl-butan-l-ol HCl salt

[0221]

[0222] To a solution of tert-butyl N-[(lS)-3-(4-fluorophenyl)-l-[hydroxy(thiazol-2- yl)methyl]propyl] carbamate (5.25 g, 14.33 mmol, 1 eq) in EtOAc (25 mL) was added HCl / EtOAc (4 M in EtOAc, 25 mL, 6.98 eq). The mixture was stirred at 25 °C for 1 hr. LC-MS showed desired mass. The reaction mixture was concentrated under reduced pressure to afford (2S)-2-amino-4-(4-fluorophenyl)-l-thiazol-2-yl-butan-l-ol (4.3 g, crude, HC1 salt) was obtained as a white solid. It was used in the next step without further purification.

[0223] LCMS (ESI) m / z 267.0 [M+H]+

[0224] Step 8. Synthesis of tert-butyl N-[(lS)-l-[[(lS)-3-(4-fluorophenyl)-l-

[0225] [hydroxy(thiazol-2-yl)methyl]propyl]carbamoyl]-4-triisopropylsilyloxy-

[0226] To a solution of (2S)-2-amino-4-(4-fluorophenyl)-l-thiazol-2-yl-butan-l-ol (4.3 g, 14.20 mmol, 1 eq, HC1), (2S)-2-(tert-butoxycarbonylamino)-5-triisopropylsilyloxy- hexanoic acid (5.73 g, 14.20 mmol, 1 eq) in DMF (100 mL) was added EDCI (8.17 g, 42.60 mmol, 3 eq) and HOBt (5.76 g, 42.60 mmol, 3 eq), TEA (8.62 g, 85.21 mmol, 11.86 mL, 6 eq). The mixture was stirred at 25 °C for 12 hr. LC-MS showed desired mass. The reaction mixture was diluted with 100 mL of water and extracted with EtOAc (150 mL x 3). The combined organic layer was washed with LiCl (5 wt% in water, 150 mL x 2). The organic layer was dried over Na2SO4, filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography (S1O2. 0-30% ethyl acetate in petroleum ether). Compound tert-butyl N-[(lS)-l-[[(lS)-3-(4-fluorophenyl)-l-[hydroxy(thiazol-2-yl)methyl]propyl] carbamoyl]-4-triisopropylsilyloxy-pentyl] carbamate (6.2 g, 9.32 mmol, 65.6% yield, 98% purity) was obtained as a yellow oil.

[0227] LCMS (ESI) m / z 652.8 [M+H]+

[0228] ’H NMR (400MHz, DMSO-6) 5 = 7.73 - 7.66 (m, 1 H), 7.60 - 7.53 (m, 1 H), 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).

[0229] Step 9. Synthesis of (2S)-2-amino-N-((2S)-4-(4-fluorophenyl)-l-hydroxy-l-(thiazol-

[0230] To a solution of tert-butyl N-[(l S)-l-[[(l S)-3-(4-fluorophenyl)-l -[hydroxy(thiazol-2- yl)methyl] propyl] carbamoyl]-4-triisopropylsilyloxy-pentyl] carbamate (4.6 g, 7.06 mmol, 1 eq) in EtOAc (100 mL) was added HCl / EtOAc (4 M, 46.00 mL, 26.08 eq). The mixture was stirred at 20 °C for 1 hr. LC-MS showed desired mass. The reaction mixture was concentrated under reduced pressure to afford (2S)-2-amino-N-((2S)-4-(4- fluorophenyl)-l-hydroxy-l-(thiazol-2-yl)butan-2-yl)-5-hydroxy hexanamide (3 g, crude, HC1 salt) as a white solid. It was used in the next step without further purification.

[0231] LCMS (ESI) m / z 396.3 [M+H]+

[0232] Step 10. Synthesis of 2-(4-fluorophenyl)-N-[(lS)-l-[[(lS)-3-(4-fluorophenyl)-l-

[0233] [hydroxy(thiazol-2-yl)methyl]propyl]carbamoyl]-4-hydroxy-pentyl]thiazole-

[0234] 5-carboxamide

[0235] To a solution of (2S)-2-amino-N-((2S)-4-(4-fluorophenyl)-l-hydroxy-l-(thiazol-2- yl)butan-2-yl)-5-hydroxyhexanamide (3 g, 6.95 mmol. 1 eq. HC1 salt), 2-(4- fluorophenyl)thiazole-5-carboxylic acid (1.55 g, 6.95 mmol, 1 eq) in DMF (50 mL) was added EDCI (3.99 g. 20.84 mmol, 3 eq) and HOBt (2.82 g, 20.84 mmol, 3 eq). TEA (4.22 g, 41.67 mmol, 5.80 mL, 6 eq). The mixture was stirred at 25 °C for 12 hr. LCMS showed desired mass. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (100 mL x 3). The combined organic layer was washed with LiCl (5wt% in water, 50 mL x 2). The organic layer was dried over NaeSCh and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiCh, 0-10% MeOH in DCM). Compound 2-(4- fluorophenyl)-N-[(lS)-l-[[(lS)-3-(4-fluorophenyl)-l-[hydroxy(thiazol-2-yl)methyl] propyl]carbamoyl]-4-hydroxy-pentyl]thiazole-5-carboxamide (2.5 g, 4.04 mmol, 58.1 % yield. 97% purity) was obtained as a white solid.

[0236] LCMS (ESI) m / z 601.5 [M+H]+

[0237] 'H NMR (400MHz, DMSO- de 5 = 8.83 - 8.71 (m, 1 H), 8.62 - 8.54 (m, 1 H), 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. 1 H), 4.51 - 4.31 (m, 2 H), 4.28 - 4.10 (m, 1 H), 3.59 (m, 1 H), 3.35 (br s, 1 H),2.65 - 2.52 (m, 2 H), 1.91 - 1.51 (m, 4 H),

[0238] 1.45 - 1.23 (m. 2 H), 1.10 - 1.00 (m, 3 H).

[0239] Step 11. Synthesis of 2-(4-fluorophenyl)-N-[(lS)-l-[[(lS)-3-(4-fluorophenyl)-l-

[0240] (thiazole-2-carbonyl)propyl]carbamoyl]-4-hydroxy-pentyl]thiazole-5- carboxamide

[0241] 2-L

[0242] To a solution of 2-(4-fluorophenyl)-N-[(lS)-l-[[(lS)-3-(4-fluorophenyl)-l- [hydroxy(thiazol-2-yl)methyl]propyl]carbamoyl]-4-hydroxy-pentyl]thiazole-5- carboxamide (3.9 g, 6.49 mmol, 1 eq) in DCM (50 mL) was added MnCh (16.93 g, 194.77 mmol, 30 eq). The mixture was stirred at 20 °C for 1 hr. LC-MS showed 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 250mm*50mm, lOum. Mobile phase: A: CO2, B: IPA. Gradient: isocratic 50% B in Afor 30 min. Flow rate: 140 mL / min). The title compound 2-(4-fluorophenyl)-N-[(lS)- l-[[(lS)-3-(4-fluorophenyl)-l-(thiazole-2-carbonyl)propyl] carbamoyl] -4-hydroxy- pentyl]thiazole-5-carboxamide (1.5 g, 2.51 mmol. 38.6% yield, 100% purity) was obtained as a white solid.

[0243] LCMS (ESI) m / z 599. 1 [M+H]+

[0244] 'H NMR (400MHz, DMSO- e) 5 = 8.80 (t, J= 6.8 Hz, 1H), 8.68 (dd, J = 7.2, 9.6 Hz,

[0245] 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,

[0246] 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

[0247] Hz. 3 H).

[0248] Example 3: 2-(3-chloro-5-fluorophenyl)-N-((2S)-5-hydroxy-l-oxo-l-(((S)-5,5,5- trifluoro-l-oxo-l-(thiazol-2-yl)pentan-2-yl)amino)hexan-2-yl)oxazole-5- carboxamide (ClpP-1767)

[0249] Step 1. Synthesis of (2R,5S)-2-isopropyl-3,6-dimethoxy-5-(3,3,3-trifluoropropyl)-

[0250] 2,5- dihydropyrazine

[0251] To a solution of (2R)-2-isopropyl-3.6-dimethoxy-2.5-dihydropyrazine (15.55 g, 84.39 mmol, 15.12 mL, 0.9 eq) in THF (150 mL) was added LDA (2 M in THF, 56.26 mL, 1.2 eq) at -78 °C. The mixture was stirred at -78 °C for 30 min. l,l,l-trifluoro-3-iodo- propane (21 g, 93.77 mmol, 10.99 mL, 1 eq) in THF (50 mL) was then added to the above solution. The reaction mixture was stirred and warmed to 10 °C for 11.5 hr under N2 atmosphere. LC-MS showed desired mass. The reaction mixture was diluted with sat. aq. NHrCl (500 mL) and extracted with EtOAc (300mLx 3). The combined organic layer was dried over Na2SO4, fdtered. The fdtrate was concentrated under reduced pressure and purified by column chromatography (S1O2, 0-10% ethyl acetate in petroleum ether) to afford 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.

[0252] LCMS (ESI) m / z 281.2[M+H]+

[0253] 1H NMR (400MHz, DMSO-d6) 5 = 4.15 - 4.06 (m, 1 H), 4.00 - 3.91 (m, 1 H), 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).

[0254] To a solution of (2R,5S)-2-isopropyl-3,6-dimethoxy-5-(3,3,3-trifluoropropyl)-2,5- dihydropyrazine (33.2 g, 11 .45 mmol, 1 eq) in ACN (200 mL), H2O (100 mL) was added TFA (76.75 g, 673.11 mmol, 50 mL, 5.68 eq). The mixture was stirred at 50 °C for 12 hr. The resulting reaction mixture was concentrated under reduced pressure to afford methyl (2S)-2-amino-5,5,5-trifluoro-pentanoate (35.4 g, crude, TFA) as a yellow oil. It was used in the next step without further purification.

[0255] Step 3. Synthesis of methyl (2S)-2-(tert-butoxycarbonylamino)-5,5,5-trifluoro- pentanoate To a solution of methyl (2S)-2-amino-5,5,5-trifluoro-pentanoate (35.4 g, 118.33 mmol, 1 eq, TFA) in THF (400 mL) was added DIEA (45.88 g. 354.99 mmol, 61.83 mL. 3 eq) and BOC2O (56.81 g, 260.32 mmol, 59.80 mL, 2.2 eq). The reaction mixture was stirred at 25 °C for 12 hr, and then diluted with water ( 100 mL) and extracted with EtOAc ( 100 mL x 3). The combined organic layer was dried over Na2SC>4, and fdtered. The filtrate was concentrated under reduced pressure and purified by column chromatography (SiCh, 0-10% ethyl acetate in petroleum ether) to afford compound methyl (2S)-2-(tert- butoxycarbonylamino)-5,5,5-trifluoro-pentanoate (35.8 g, 112.9 mmol, 95.4%yield, 90% purity) as a colorless oil.

[0256] 1H NMR (400MHz, DMSO-d6) 5 = 7.52 - 7.17 (m, 1 H), 4.14 - 4.03 (m, 1 H), 3.70 - 3.60 (m, 3 H), 2.46 - 2.18 (m, 2 H), 1.95 - 1.73 (m, 2 H), 1.38 (s, 9 H).

[0257] Step 4. Synthesis of tert-butyl N-[(lS)-4, 4, 4-trifluoro-l-

[0258] (hydroxymethyl)butyl]carbanuite

[0259] To a solution of methyl (2S)-2-(tert-butoxycarbonylamino)-5,5,5-trifluoro-pentanoate (35.8 g, 112.95 mmol, 1 eq) in THF (360 mL) was added LAH (2.5 M in THF, 49.70 mL, 1.1 eq) at 0 °C. The resulting mixture was stirred at 15 °C for 1 hr. TLC indicated one new spot. The reaction was quenched by addition of water (4.72 mL), 15% aqueous NaOH (4.72 mL in water), and water (14.16 mL) at 0° C, and then fdtered. The fdter cake was further w ashed with DCM (300 mL x 3). The combined fdtrate was dried over Na2SO4, and fdtered. The fdtrate was concentrated under reduced pressure and purified by column chromatography (SiCh, 0-10% ethyl acetate in petroleum ether) to afford tert-butyl N-[(lS)-4,4,4-trifluoro - I -(hydroxymethyl (butyl | carbamate (22.3 g, 65.0 mmol, 57.5% yield, 75% purity) as a white solid.

[0260] 1H NMR (400MHz, DMSO-d6) 5 = 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).

[0261] Step 5. Synthesis of tert-butyl N-[(lS)-4, 4, 4-trifluoro-l-formyl-butyl]carbamate

[0262] To a solution of tert-butyl N-[(lS)-4,4,4-trifluoro-l-(hydroxymethyl)butyl]carbamate (22.3 g, 86.69 mmol. 1 eq) in DCM (400 mL) was added DMP (40.44 g. 95.35 mmol, 29.54 mL, 1.1 eq) at 0 °C. The mixture was stirred at 15 °C for 1 hr. TLC indicated one major new spot. The reaction mixture was added into sat. NaHCO? (400 mL) at 0 °C. and then extracted with DCM (300 mL x 3). The combined organic layer was dried over NazSCL, and filtered. The filtrate was concentrated under reduced pressure to afford tert-buty l N-[(lS)-4,4,4-trifluoro-l-formyl-butyl]carbamate (22 g, crude) as a colorless oil. It was used in the next step without further purification.

[0263] Step 6. Synthesis of tert-butyl N-[(lS)-4, 4, 4-trifluoro-l-[hydroxy(thiazol-2- yl)methyl]butyl] carbamate

[0264] To a solution of TMEDA (9.22 g, 79.30 mmol, 11.97 mL. 2.3 eq) in THF (60 mL) was added n-BuLi (2.5 M in n-hexane, 34.48 mL, 2.5 eq) and thiazole (6.46 g, 75.85 mmol, 5.39 mL, 2.2 eq) at -78 °C. The mixture was stirred at -78 °C for 0.5 hr under N2. Then tert-butyl N-[(lS)-4,4,4-trifluoro -l-formyl-butyl]carbamate (11 g, 34.48 mmol, 1 eq) in THF (50 mL) was added dropwise at -78 °C. Then it was stirred at -78 °C for 0.5 hr. LC-MS showed desired mass. The reaction mixture was poured into sat. NH4Q (100 mL in water) at 0 °C and extracted with EtOAc (150 mL x 2). The combined organic layer was dried over anhydrous Na2SO4. and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiC>2, 0-50% EtOAc in petroleum ether) to afford tert-butyl N-[(lS)-4,4,4-trifluoro-l- [hydroxy(thiazol-2-yl)methyl]butyl]carbamate (12 g, 31.7 mmol, 46.0% yield, 90% purity) as a yellow oil.

[0265] LCMS (ESI) m / z 341.2 [M+H]+

[0266] 1H NMR (400MHz, DMSO-d6) 5 = 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, 1 H), 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).

[0267] Step 7. Synthesis of (2S)-2-amino-5,5,5-trifluoro-l-thiazol-2-yl-pentan-l-ol HCl salt

[0268] 3-G 3-H

[0269] To a solution of tert-butyl N-[(lS)-4.4,4-trifluoro-l-[hydroxy(thiazol-2- yl)methyl]butyl] carbamate (9.4 g, 27.62 mmol, 1 eq) in EtOAc (50 mL) was added HCl in EtOAc (4 M. 50 mL. 7.24 eq). The mixture was stirred at 25 °C for 1 hr. The reaction mixture was concentrated under reduced pressure to afford (2S)-2-amino-5,5,5- trifluoro-l-thiazol-2-yl-pentan-l-ol (7.64 g, crude, HCl) as a white solid. It was used in the next step without further purification.

[0270] LCMS (ESI) m / z 241.2. 1 [M+H]+ Step 8. Synthesis of tert-butyl N-[(lS)-l-[[(lS)-4,4,4-trifluoro-l-[hydroxy(thiazol-2-

[0271] To a solution of (2S)-2-amino-5,5,5-trifluoro-l-thiazol-2-yl-pentan-l-ol (7.54 g, 27.25 mmol, 1 eq, HCl), (2S)-2-(tert-butoxycarbonylamino)-5-triisopropylsilyloxy-hexanoic acid (11 g, 27.25 mmol, 1 eq) in DMF (70 mL) was added EDCI (10.97 g. 57.23 mmol, 2.1 eq), HOBt (7.73 g, 57.23 mmol, 2.1 eq) and TEA (8.27 g, 81.76 mmol, 11.38 mL, 3 eq). The resulting mixture was stirred at 25 °C for 12 hr. 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 (S1O2. 0-30% ethyl acetate in petroleum ether) to afford tert-butyl N- [(lS)-l-[[(lS)-4,4,4-trifluoro-l-[hydroxy(thiazol-2-yl)methyl]butyl]carbamoyl]-4- triisopropylsilyloxy-pentyllcarbamate (13.6 g. 21.3 mmol, 78. 1% yields 98% purity) as a yellow solid.

[0272] LCMS (ESI) m / z 626.5 [M+H]+

[0273] 1H NMR (400 MHz. DMSO-d6) 6 = 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, 1 H), 1.60 (m, 3 H), 1.35 (m. 10 H), 1.22 (m, 2 H), 1.02 (m. 23 H).

[0274] Step 9. Synthesis of (2S)-2-amino-5-hydroxy-N-[(lS)-4,4,4-trifluoro-l-

[0275] [hydroxyl(thiazol-2-yl) niethyljbutyljhexananiide HCl salt

[0276] To a solution of tert-butyl N-[(lS)-l-[[(lS)-4,4,4-trifluoro-l-[hydroxy(thiazol-2- yl)methyl]butyl] carbamoyl]-4-triisopropylsilyloxy-pentyl]carbamate (11.2 g, 17.90 mmol, 1 eq) in EtOAc (55 mL) was added HCl / EtOAc (4 M, 55 mL, 12.29 eq). The mixture was stirred at 25 °C for 1 hr. The reaction mixture was concentrated under reduced pressure to afford (2S)-2-amino-5-hydroxy-N-[(lS)-4.4,4-trifluoro-l- [hydroxy(thiazol-2-yl) methyl]butyl]hexanamide (7.26 g, crude, HC1) as a white solid. It w as used in the next step without further purification.

[0277] 3-M 3-N

[0278] To a solution of ethyl 2-bromooxazole-5-carboxylate (500 mg. 2.27 mmol, 1 eq) and (3-chloro-5-fluoro- phenyl)boronic acid (594.37 mg, 3.41 mmol, 1.5 eq) in dioxane (12.5 mL) and H2O (1.25 mL) was added NaiCCL (481.73 mg, 4.55 mmol, 2 eq) and purged with N2 for 3 times. Then Pd(dppf)Ch (166.28 mg, 227.25 pmol, 0.1 eq) was added. The reaction mixture w as stirred at 80 °C for 12 hr under N2 atmosphere. LC- MS showed desired mass. The reaction mixture was diluted with water (40 mL) and extracted with EtOAc (40 mL x 3). The combined organic layer was dried overNa2SO4, and filtered. The filtrate w as concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO2, 0-5% ethyl acetate in petroleum ether) to afford ethyl 2-(3-chloro-5-fluoro-phenyl)oxazole-5-carboxylate (4.94 g, 13.3 mmol, 58.8% yield, 73% purity) as a white solid.

[0279] LCMS (ESI) m / z 270.2 [M+H]+

[0280] Step 11. Synthesis of 2-(3-chloro-5-fluoro-phenyl)oxazole-5-carboxylic acid

[0281] To a solution of ethyl 2-(3-chloro-5-fluoro-phenyl)oxazole-5-carboxylate (4.94 g, 18.32 mmol, 1 eq) in THF (50 rnL) and H2O (50 mL) was added LiOH.H2O (1.15 g, 27.48 mmol, 1.5 eq). The resulting mixture was stirred at 25 °C for 1 hr. LCMS showed desired mass. The reaction mixture was diluted with water (40 rnL), and then acidified to pH=4 with 1 M HC1. The mixture was extracted by EtOAc (50 mL x 2). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to afford 2-(3- chloro-5-fluoro-phenyl)oxazole-5-carboxylic acid (3.7 g, 15.1 mmol, 82.7% yield, 99% purity) as a white solid. It was used in the next step without further purification.

[0282] LCMS (ESI) m / z 242.2 [M+H]+

[0283] 1H NMR (4OO MHz, DMSO-d6) 5 = 13.92 (br, s, 1 H), 8.12 (s, 1 H), 7.91 (s, 1 H), 7.80 (m, 2 H).

[0284] Step 12. Synthesis of 2-(3-chloro-5-fluoro-phenyl)-N-[(lS)-4-hydroxy-l-[[(lS)- 4,4,4-trifluoro-l- [hydroxy(thiazol-2-yl)methyl]butyl]carbamoyl]pentyl]oxazole-5- carboxamide To a solution of (2S)-2-amino-5-hydroxy-N-[(lS)-4.4.4-trifluoro-l-[hydroxy(thiazol- 2-yl) methyl]butyl]hexanamide (7.21 g, 17.76 mmol, 1 eq, HC1), 2-(3-chloro-5-fluoro- phenyl)oxazole-5- carboxylic acid (4.29 g, 17.76 mmol, 1 eq) in DMF (75 mL) was added HOBt (5.04 g, 37.29 mmol, 2.1 eq), EDCI (7.15 g, 37.29 mmol, 2.1 eq) and TEA (5.39 g, 53.27 mmol, 7.41 mL, 3 eq). The mixture was stirred at 25 °C for 12 hr. LC- MS showed the desired mass. The reaction mixture was diluted with EtOAc (150mL) 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 (SiCh, 0-10% MeOH in DCM) to afford 2-(3- chloro-5-fluoro-phenyl)-N-[(lS)-4-hydroxy-l-[[(lS)-4,4,4-trifluoro-l- [hydroxy(thiazol-2-yl)methyl]butyl] carbamoyl] pentyl ]oxazole-5-carboxamide (5.9 g, 9.5 mmol, 52.3% yield, 96% purity) as a yellow solid.

[0285] LCMS (ESI) m / z 593.3 [M+H]

[0286] Step 13. Synthesis of 2-(3-chloro-5-fluoro-phenyl)-N-[(lS)-4-hydroxy-l-[[(lS)-

[0287] 4,4,4-trifluoro-l- (thiazole-2-carbonyl)butyl]carbamoyl]pentyl]oxazole-5- carboxamide

[0288] 3-L

[0289] This compound was prepared according to the procedure described in the final step of the synthesis of Example 1. From 5.3 g of 2-(3-chloro-5-fluoro-phenyl)-N-[(lS)-4- hydroxy-l-[[(lS)-4,4,4-trifluoro-l- [hydroxy(thiazol-2- yl)methyl]butyl]carbamoyl]pentyl]oxazole-5-carboxamide, 2.27 g of 2-(3-chloro-5- fluoro-phenyl)-N-t(lS)-4-hydroxy-l-t[(lS)-4.4.4-trifluoro-l-(thiazole-2- carbonyl)butyl] carbamoyl]pentyl]oxazole-5-carboxamide (42.15% yield, 98% purity) was obtained as a white solid.

[0290] LCMS (ESI) m / z 591.2 [M+H]+

[0291] 1H NMR (400 MHz, DMSO-d6) 5 = 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. 1 H).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).

[0292] Example 4: 2-(3-chloro-5-fluoro-phenyl)-N- [( IS)- l-methyl-2-oxo-2- [ [(lS)-4,4,4- trifluor o- l-(thiazole-2-carbonyl)butyl] amino] ethyl] oxazole-5-carboxamide (ClpP-1848)

[0293] Step 1. Synthesis of tert-butyl ((2S)-l-oxo-l-(((2S)-5,5,5-trifluoro-l-hydroxy-l-

[0294] (thiazol-2-yl)pentan-2-yl)amino)propan-2-yl)carbamate

[0295] To a solution of (2S)-2-amino-5,5,5-trifluoro-l-thiazol-2-yl-pentan-l -ol (4.72 g, 17.06 mmol, 1 eq, HC1 salt), (2S)-2-(tert-butoxycarbonylamino)propanoic acid (3.23 g, 17.06 mmol, 1 eq) in DMF (50 mL), EDCI (6.87 g, 35.82 mmol, 2.1 eq), HOBt (4.84 g, 35.82 mmol, 2.1 eq) and TEA (5.18 g, 51.17 mmol, 7.12 mL, 3 eq) was added successively. The mixture was stirred at 25 °C for 12 hr. LC-MS showed 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 (SiCh, 0-10% MeOH in DCM) to afford compound tert-butyl N-[(1S)- l-methyl-2-oxo-2-[[(lS)-4,4,4-trifluoro-l-[hydroxyl(thiazol-2-yl)methyl]butyl]amino] ethyl] carbamate (5.1 g, 11.9 mmol, 69.7% yield, 96% purity) as a yellow solid.

[0296] LCMS (ESI) m / z 412.1 [M+H]+

[0297] Step 2. Synthesis of (2S)-2-anuno-N-((2S)-5,5,5-trifluoro-l-hydroxy-l-(thiazol-2- yl)pentan-2-yl)propenamide HCl salt

[0298] To a solution of tert-butyl N-[(lS)-l-methyl-2-oxo-2-[[(lS)-4,4,4-trifluoro-l- [hydroxy(thiazol-2-yl) methyl]butyl]amino]ethyl]carbamate (200 mg, 486.10 pmol, 1 eq) in EtOAc (1 mb) was added HCl in EtOAc (4 M, 1 mL, 8.23 eq). The resulting mixture was stirred at 25 °C for 1 hr. LCMS showed desired mass. The mixture was concentrated under reduced pressure to afford (2S)-2-amino-N-[(lS)-4,4,4-trifluoro-l- [hydroxy(thiazol-2-yl)methyl]butyl]pr opanamide (160 mg, crude, HCl) as a white solid. It was used in the next step without further purification.

[0299] LCMS (ESI) m / z 312.1 [M+H]+

[0300] Step 3. Synthesis of 2-(3-chloro-5-fluoro-phenyl)-N-[(lS)-l-methyl-2-oxo-2-[[(lS)- 4,4,4-trifluor o-l-[hydroxy(thiazol-2-yl)niethyl]butyl]amino]ethyl]oxazole-5- carboxamide

[0301] To a solution of (2S)-2-amino-N-[(lS)-4,4,4-trifluoro-l-[hydroxy(thiazol-2- yl)methyl]butyl]propane mide (160 mg. 460.06 pmol, 1 eq, HCI salt). 2-(3-chloro-5- fluoro-phenyl)oxazole-5 -carboxylic acid (111.2 mg, 460.06 pmol, 1 eq) in DMF (2 mL), was added HOBt (186.5 mg, 1.38 mmol. 3 eq), EDCI (264.6 mg, 1.38 mmol, 3 eq) and TEA (186.2 mg, 1.84 mmol, 256.14 pL, 4 eq) successively. The mixture was stirred at 25 °C for 12 hr. LCMS showed desired mass. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (lOmL x 3). The combined organic layer was washed with LiCl (10 mL) (5wt% in water). The organic layer was dried over Na2SO4 and fdtered. The filtrate was concentrated under reduced pressure and purified by column chromatography (SiO2, 0-10% MeOH in DCM) to afford 2-(3-chloro-5-fluoro- phenyl)-N-[(lS)-l-methyl-2-oxo-2-[[(lS)-4,4,4-trifluoro-l -[hydroxy (thiazol-2- yl)methyl]butyl]amino]ethyl]oxazole-5-carboxamide (160 mg. 284.16 pmol. 61.8% yield, 95% purity) as a yellow oil.

[0302] LCMS (ESI) m / z 535.0 [M+H]+

[0303] Step 4. Synthesis of 2-(3-chloro-5-fluoro-phenyl)-N-[(lS)-l-methyl-2-oxo-2-[[(lS)-

[0304] 4,4,4-trifiuor o-l-(thiazole-2-carbonyl)butyl]amino]ethyl]oxazole-5-carboxamide

[0305] To a solution of 2-(3-chloro-5-fluoro-phenyl)-N-[(lS)-l-methyl-2-oxo-2-[[(lS)-4,4,4- trifluoro-l-[hy droxy(thiazol-2-yl)methyl]butj 1] amino] ethyl] oxazole-5 -carboxamide (160 mg, 299.12 pmol, 1 eq) in DCM (4 mL) was added DMP (190.30 mg. 448.67 pmol, 139.01 pL. 1.5 eq). The mixture was stirred at 25 °C for 1 hr. LCMS showed the desired mass. The reaction mixture was diluted with DCM (20 mL) and washed with sat. aq. NaHCOs(20 mL x 3). The organic layer was dried over Na2SOr and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by prep- HPLC (Column: Welch Xtimate C18 150*25mm*5um. Mobile phase: A: 0.5% FA in water, B: MeCN. Gradient: 48%-78% B over 10 min. Flow rate: 25 mL / min) to afford the title compound 2-(3-chloro-5-fluoro-phenyl)-N- [(lS)-l-methyl-2-oxo-2-[[(lS)- 4,4,4-trifluoro-l-(thiazole-2-carbonyl)butyl]amino]ethyl]oxazole-5-carboxamide (81.6 mg, 148.27 pmol, 49.6% yield, 96.8% purity) was obtained as a colorless oil.

[0306] LCMS (ESI) m / z 533.1 [M+H]+

[0307] 1H NMR (400MHz, DMSO-d6) 6 = 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=7.3 Hz, 3H)

[0308] In Vitro Assays and Results

[0309] 1. ClpPlP2 peptidase enzyme inhibition assay

[0310] Peptidase activity of ClpPlP2 was measured continuously using Ac-PKM-amc as a substrate, as described in “Cleavage Specificity of Mycobacterium tuberculosis ClpPlP2 Protease and Identification of Novel Peptide Substrates and Boronate Inhibitors with Anti-bacterial Activity” (Akopian, T. et al., J. Biol. Chem. 2015 Apr 24;290(l 7): 11008-20. doi: 10. 1074 / jbc.Ml 14.625640). Ki was calculated as described in “Relationship between the inhibition constant (Ki) and the concentration of inhibitor (IC50) of an enzymatic reaction” (Cheng Y. and Prusoff W.. Biochemical Pharmacology, Volume 22, 3099-3108). The Ki values of Examples 1-5 are listed in Table 1.

[0311] 2. Mtb H37Rv MABA assay. All experiments with M. tuberculosis (Mtb) were conducted within a biosafety level 3 (BSL3) laboratory using a previously described Microplate Alamar Blue Assay (MABA) (Cho, S. et al., 2015. Microplate Alamar Blue Assay (MABA) and Low Oxygen Recovery Assay (LORA) for Mycobacterium tuberculosis. In: Parish. T. Roberts, D. (eds) Mycobacteria Protocols. Methods in Molecular Biology; vol 1285. Humana Press, New York. NY. https: / / doi.org / 10.1007 / 978-l-4939-2450-9_17). Briefly, compound stocks were prepared in dimethyl sulfoxide (DMSO) at 100x of the highest desired final concentration. Compounds were transferred to the assay plate containing Middlebrook 7H12 medium (4.7 g 7H9 broth, 1 g casitone (Bacto), 5 g bovine serum albumin (BSA), 4 mg catalase and 5.6 mg palmitic acid for 1 L media). Two-fold serial dilution of the compounds was performed nine times in the assay plate. Plates were inoculated with M. tuberculosis strain H37Rv (ATCC 27294) to achieve final density of ~ 1 x 105 CFU / mL and incubated for 7 days at 37°C. At the end of 7 days, resazurin dye / tween 80 mixture (0.6 mM resazurin dye and 12 pL of 20% Tween 80) was added to each well, and the plates were incubated for an additional 18 to 24 h at 37°C. Fluorescence was measured using a CLARIOstar (BMG LABTECH, Ortenberg, Germany) plate reader on day 8. The MIC was an interpolated value and defined as the lowest concentration effecting a reduction in fluorescence of 90% relative to that of DMSO-treated controls. The MABA MIC values of Examples 1-5 are summarized in Table 1.

[0312] Table 1: ClpPlP2 Ki and Mtb H37Rv MABA MIC

[0313] Examples 6A and 6B: N-[(lS,4R)-l-{N-(S)-4,4,4-trifluoro-l-[(l,3-thiazol-2- yl)carbonyl] butylcarbamoyl}-4-hydroxypentyl]-2-(3-chloro-5-fluorophenyl)-l,3- oxazole-5-carboxamide (ClpP-1767A) and N-[(lS,4S)-l-{N-(S)-4,4,4-trifluoro-l- [(l,3-thiazol-2-yl)carbonyl]butylcarbamoyl}-4-hydroxypentyl]-2-(3-chloro-5- fluorophenyl)-l,3-oxazole-5-carboxamide (ClpP-1767B)

[0314] 6A 6B

[0315] 2-(3-chloro-5-fluoro-phenyl)-N-[(lS)-4-hydroxy-l-[[(lS)-4,4,4-trifluoro-l-(thiazole- 2-carbonyl)butyl]carbamoyl]pentyl]oxazole-5-carboxamide (Example 3. 700 mg) was separated by SFC (column: DAICEL CHIRALPAK IC (250mm x 30mm, lOum); mobile phase A: CO2; B: EtOH; isocratic 40%B and 60%A. Flow rate: 150 mL / min).

[0316] Peakl was arbitrarily assigned as 6A, N-[(lS,4R)-l-{N-(S)-4,4,4-trifluoro-l-[(l,3- thiazol-2-yl)carbonyl]butylcarbamoyl}-4-hydroxypentyl]-2-(3-chloro-5- fluorophenyl)-l,3-oxazole-5-carboxamide (212 mg, 29% yield, 97% purity, white solid). LCMS (ESI) m / z 591.1 [M+H]+

[0317] 1H NMR (400MHz, DMSO-d6) 5 = 8.89 - 8.80 (m, 1H), 8.74 (d, J = 7.2 Hz, 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 arbitrarily assigned as 6B, N-[(lS.4S)-l-{N-(S)-4.4.4-trifluoro-l-[(l,3- thiazol-2-yl)carbonyl]butylcarbamoyl]-4-hydroxypentyl]-2-(3-chloro-5- fluorophenyl)-l,3-oxazole-5-carboxamide (214 mg, 31% yield. 100% purity, white solid). LCMS (ESI) m / z 591.2 [M+H]+

[0318] 1H NMR (400MHz. DMSO-d6) 5 = 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)

[0319] Synthesis of carboxylic acids:

[0320] To a solution of ethyl 2-bromooxazole-5-carboxylate (100 mg, 454.5 umol, 1 eq), (3,5- difluorophenyl)boronic acid (79 mg, 500.0 umol. 1.1 eq) in dioxane (2 mL) and H2O (0.2 mL) was added CS2CO3 (296 mg, 909.0 umol, 2 eq). Then Pd(dppf)Ch (33 mg, 45.5 umol, 0.1 eq) was added and the resulting mixture was stirred at 120 °C for 12 hr under N2. 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 HC1 and extracted with EtOAc (20 mL x 2). The organic layer was dried overNa2SO4, concentrated under reduced pressure to give crude 2-(3,5-difluorophenyl)oxazole-5-carboxylic acid (60 mg, 28% yield, 95% purity) as a yellow solid. LCMS (ESI) m / z 225.9 [M+H]+

[0321] The following carboxylic acids were synthesized via similar procedure :

[0322] 2-(4-fluorophenyl)oxazole-5-carboxylic acid (crude, 95 mg, 25% yield, 75% purity) was obtained as a yellow solid. LCMS (ESI) m / z 208.1 [M+H]+2-(2,4-difluorophenyl)oxazole-5-carboxylic acid (63 mg. 29% yield. 95% purity) was obtained as a white solid. LCMS (ESI) m / z 226.2 [M+H]+

[0323] 2-[3-fluoro-5-(trifluoromethyl)phenyl]oxazole-5-carboxylic acid (390 mg. 84% yield, 95% purity) was obtained as a yellow7solid. LCMS (ESI) m / z 276.1 [M+H]+

[0324] Synthesis of 2-(2, 5-difluorophenyl) oxazole-5-carboxylic acid2-(2, 5-

[0325] Step 1:

[0326] To a solution of ethyl 2-bromooxazole-5 -carboxylate (200 mg, 909.0 umol, 1 eq), (2, 5-difluorophenyl) boronic acid (172 mg. 1.1 mmol, 1.2 eq) in dioxane (5 mL) and H2O (0.5 mL) was added CS2CO3 (592 mg, 1.8 mmol, 2 eq). Then Pd(dppf)Ch (67 mg, 90.9 umol, 0.1 eq) was added. The resulting mixture was stirred at 120 °C for 12 hr under N2. The reaction mixture was diluted with 20 mL of water and extracted with EtOAc (30 mL x 3). The combined organic layer was dried over Na2SC>4 and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography (SiCh, 0-20% ethyl acetate in petroleum ether) to afford ethyl 2-(2,5- difluorophenyl)oxazole-5-carboxylate (50 mg, 22% yield, 99% purity ) as a white solid. LCMS (ESI) m / z 254.1 [M+H]+

[0327] Step 2:

[0328] To a solution of ethyl 2-(2, 5-difluorophenyl)oxazole-5-carboxylate (50 mg, 197.5 umol, 1 eq) in THF (2 mL) and H2O (2 mL) was added LiOH.H2O (5 M, 4 mL). The mixture was stirred at 25 °C for 12 hr. Most of the solvent was removed under reduced pressure. The residue was diluted with water (10 mL), acidified to pH 4 with aq. IN HC1 and extracted with EtOAc (20 mL x 2). The organic layer was dried over Na2SC>4 and concentrated under reduced pressure to give 2-(2,5-difluorophenyl)oxazole-5- carboxylic acid (44 mg, 98% yield, 99% purity) as a white solid. LCMS (ESI) m / z 226.2 [M+H]+

[0329] Synthesis of 2-(o-tolyl)thiazole-4-carboxylic acid

[0330] Step 1:

[0331] A mixture of ethyl 2-bromothiazole-4-carboxylate (1.04 g, 4.4 mmol, 1 eq), K2CO3 (2 M in water, 4 mL), o-tolylboronic acid (599 mg, 4.4 mmol, 1 eq) in toluene (10 mL) was degassed and purged with N2. Pd(PPty)4 (255 mg, 220.3 umol, 0.05 eq) was added and stirred at 90 °C for 12 hr under N2. The reaction mixture was then diluted with 10 mL of EtOAc and washed with IM aq. NaOH (10 mL). The aqueous layer was extracted with EtOAc (2 x 20 mL). The combined 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 in petroleum ether) to afford ethyl 2-(o- tolyl)thiazole-4-carboxylate (660 mg, 58% yield, 95% purity) as a yellow oil. LCMS (ESI) m / z 248. 1 [M+H]+

[0332] Step 2:

[0333] To a solution of ethyl 2-(o-tolyl)thiazole-5-carboxylate (200 mg, 808.7 umol, 1 eq) in THF (3 mL) was added LiOH.H2O (4 M in water, 3 mL). The reaction was stirred at 30 °C for 12 hr. The resulting mixture was adjusted to pH 4-5 with aq. IM HC1 and extracted with EtOAc (10 mL x 3). The combined organic layer was dned overNa2SO4 and filtered. The filtrate was concentrated under reduced pressure to give 2-(o- tolyl)thiazole-5-carboxylic acid (170 mg, 93 % yield, 97% purity) as a colorless oil. LCMS (ESI) m / z 220.0 [M+H]

[0334] Synthesis of 2-(2-cyanophenyl) thiazole- 5-carboxylic acid

[0335] Step 1:

[0336] To a solution of 2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzonitrile (1.94 g, 8.5 mmol, 2 eq) in dioxane (10 mL) and H2O (1 mL) was added Na^COs (898 mg, 8.5 mmol, 2 eq) and ethyl 2-bromothiazole-5 -carboxylate (1 g, 4.2 mmol, 1 eq), followed by Pd(PPhs)4 (489 mg, 423.6 umol, 0.1 eq). The reaction was stirred at 100 °C for 12 hr under N2. The reaction mixture was diluted with H2O (40 mL) and filtrated. The filtrate was extracted with EtOAc (20 mL x 3). The combined organic layer was dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography (SiO2, 0 - 30% ethyl acetate in petroleum ether) to afford ethyl 2-(2-cyanophenyl) thiazole-5- carboxylate (278 mg, 20% yield. 79% purity) as a yellow solid. LCMS (ESI) m / z 259.2 [M+H]+

[0337] Step 2:

[0338] To a solution of ethyl 2-(2-cyanophenyl)thiazole-5-carboxylate (278 mg. 1.1 mmol, 1 eq) in MeOH (15 mL) was added NaOH (5 M in water, 5 mL). After stirring at 25 °C for 2 hr, the mixture was adjusted to pH 4-5 with aq. IM HC1 and extracted with EtOAc (10 mL x 3). The combined organic layer was dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to afford 2-(2-cyanophenyl)thiazole- 5-carboxylic acid (215 mg, crude) as a yellow solid. LCMS (ESI) m / z 231.0 [M+H]+

[0339] Synthesis of 2-(2,5-dichlorophenyl)oxazole- 5-carboxylic acid

[0340] Step 1

[0341] To a solution of ethyl 2-bromooxazole-5-carboxylate (200 mg, 909 pmol, 1 eq), (2,5- dichlorophenyl)boronic acid (260 mg, 1.4 mmol, 1.5 eq) in dioxane (5 mL) and H2O (0.5 mL) was added NazCOs (193 mg, 1.8 mmol, 2 eq) and Pd(dppf)C12 (67 mg, 90.9 pmol, 0. 1 eq). The mixture was stirred at 80 °C for 12 hr under N2. 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 (SiOz, 0-10% ethyl acetate in petroleum ether) to afford ethyl 2-(2,5-dichloro phenyl)oxazole-5-carboxylate (300 mg, 996.1 pmol, 73% yield, 95% purity) as a white solid. LCMS (ESI) m / z 286.0 [M+H]+

[0342] Step 2

[0343] To a solution of ethyl 2-(2,5-dichlorophenyl)oxazole-5-carboxylate (300 mg, 1. 1 mmol, 1 eq) in THF (3 mL) and H2O (3 mL) was added LiOH.LLO (88 mg, 2.1 mmol, 2 eq). The mixture was stirred at 25 °C for 2 hr. Most of the solvent was removed under reduced pressure. The residue was diluted with water (10 mL), acidified to pH = 4 with aq. IM HC1, and then 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)oxazole-5-carboxylic acid (260 mg, 91% yield. 95% purity) as a white solid. LCMS (ESI) m / z 258.0 [M+H]+

[0344] The following carboxylic acids were synthesized via similar procedure :

[0345] 2-(2,5-dichlorophenyl)oxazole-5-carboxylic acid (260 mg, 91% yield. 95% purity) was obtained as a white solid. LCMS (ESI) m / z 258.0 [M+H]+

[0346] 2-(2-chloro-4-fluoro-phenyl)oxazole-5-carboxylic acid (270 mg. 92% yield, 95% purity) was obtained as a white solid. LCMS (ESI) m / z 242.2 [M+H]+ 2-(4-chloro-2-fluoro-phenyl)oxazole-5-carboxylic acid (290 mg, 78% yield, 97% purity) was obtained as a yellow solid. LCMS (ESI) m / z 242. 1 [M+H]+

[0347] 2-(2, 4-dichlorophenyl) oxazole- 5-carboxylic acid (100 mg, 100% yield, 90% urity) was obtained as a white solid. LCMS (ESI) m / z 257.9 [M+H]+

[0348] 2-(3-fluorophenyl)oxazole-5-carboxylic acid (120 mg, 83% yield, 97% purity ) was obtained as a yellow solid. LCMS (ESI) m / z 207.8 [M+H]+

[0349] 2-(3-chlorophenyl)oxazole-5-carboxylic acid (165 mg, 93% yield, 93% purity) was obtained as a yellow solid. LCMS (ESI) m / z 223.8 [M+H]+

[0350] 2-(4-chlorophenyl)oxazole-5-carboxylic acid (45 mg, 97% yield, 96% purity) was obtained as a white solid. LCMS (ESI) m / z 224.0 [M+H]+

[0351] 2-(3,5-dichlorophenyl)thiazole-5-carboxylic acid (120 mg, 84% yield, 95% purity) was obtained as a white solid. LCMS (ESI) m / z 273.9 [M+H]+

[0352] 2-(2-chloro-5-fluoro-phenyl) thiazole- 5-carboxylic acid (140 mg, 98% yield, 95% purity') was obtained as a white solid. LCMS (ESI) m / z 257.9 [M+H]+

[0353] Step 1:

[0354] A mixture of ethyl 2-bromothiazole-5 -carboxylate (1 g, 4.2 mmol, 1 eq), (4- cyanophenyl)boronic acid (685 mg, 4.7 mmol, 1.1 eq), Pd(dppf)Ch (310 mg, 423.6 umol, 0. 1 eq), Na2COs (1.35 g, 12.7 mmol. 3 eq) in DME (10 mL) and H2O (1 rnL) was degassed and stirred at 80 °C for 12 hr under N2. The reaction mixture was quenched by 10 mL of water and then extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SC>4 and fdtered. The fdtrate was concentrated under reduced pressure and purified by column chromatography (SiO2, 0-30% ethyl acetate in petroleum ether). Ethyl 2-(4-cyanophenyl)thiazole-5- carboxylate (180 mg, 15% yield, 94% purity) was obtained as a white solid. LCMS (ESI) m / z 259.1 [M+H]+

[0355] Step 2:

[0356] To a solution of ethyl 2-(4-cyanophenyl)thiazole-5-carboxylate (180 mg, 696.9 umoL 1 eq) in THF (3 mL) was added L1OH H2O (1 M in water, 1.5 mL, 2 eq). The mixture was stirred at 20 °C for 1 hr. The reaction mixture was quenched with 1 M HC1 (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layer was washed with brine (30 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give 2-(4-cyanophenyl)thiazole-5-carboxylic acid (130 mg, 75% yield, 92% purity) as a white solid. LCMS (ESI) m / z 231.1 [M+H]+

[0357] The following carboxylic acids were synthesized via similar procedure :

[0358] 2-(3-cyanophenyl)thiazole-4-carboxylic acid (crude, 210 mg, 40% yield, 85% purity ) was obtained as a white solid. LCMS (ESI) m / z 231.1 [M+H]+

[0359] 2-(2,5-difluorophenyl)thiazole-5-carboxylic acid (307 mg, 51% yield, 91% purity) was obtained as a white solid. LCMS (ESI) m / z 241.9 [M+HJ+

[0360] 2-(2,6-difluorophenyl)thiazole-5-carboxylic acid (crude, 200 mg, 45% yield, 80% purity) was obtained as a white solid. LCMS (ESI) m / z 242.0 [M+H]+

[0361] 2-(3,5-difluorophenyl)thiazole-4-carboxylic acid (crude, 293 mg, 30 % yield, 75% purity) was obtained as a white solid. LCMS (ESI) m / z 242.0 [M+H]+

[0362] 2-(2,4-difluorophenyl)thiazole-5-carboxylic acid (350 mg, 85% yield, 98% purity) was obtained as a white solid. LCMS (ESI), m / z: 242.0 [M+l]+

[0363] 2-(5-chloro-2-fluoro-phenyl)oxazole-5-carboxylic acid (180 mg. 90% yield, 99% purity) was obtained as a white solid. LCMS (ESI) m / z 242.0 [M+H]+

[0364] 2-(2-chloro-5-fluoro-phenyl)oxazole-5-carboxylic acid (100 mg, 82% yield, 95% purity) was obtained as a white solid. LCMS (ESI) m / z 242.0 [M+H]+ 2-(2,5-difluorophenyl)oxazole-5-carboxylic acid (210 mg, 99% yield, 99% purity) was obtained as a white solid. LCMS (ESI) m / z 226.1 [M+H]+

[0365] 2-(2-fluorophenyl)oxazole-5-carboxylic acid (120 mg, 92% yield, 95% purity) was obtained as a white solid. LCMS (ESI) m / z 208.1 [M+H]+

[0366] 2-(5-chloro-2-fluoro-phenyl)thiazole-5-carboxylic acid (180 mg, 90% yield, 95% purity) was obtained as a white solid. LCMS (ESI) m / z 258.0 [M+H]+

[0367] 2-(2,5-dichlorophenyl)thiazole-5-carboxylic acid (crude, 350 mg, 62% yield, 80% purity) was obtained as a yellow solid. LCMS (ESI) m / z 274.0 [M+H]+

[0368] 2-[2-(trifluoromethyl)phenyl]thiazole-5-carboxylic acid (220 mg. 83 % yield, 90% purity) was obtained as yellow oil. LCMS (ESI) m / z 273.9 [M+H]+

[0369] 2-[3-(trifluoromethyl)phenyl]thiazole-5-carboxylic acid (crude, 180 mg) was obtained as a white solid. LCMS (ESI) m / z 274.0 [M+H]+

[0370] 2-[4-(trifluoromethyl)phenyl]thiazole-5-carboxylic acid (513 mg, 46% yield. 92% purity) was obtained as a white solid. LCMS (ESI) m / z 273.9 [M+H]+

[0371] 2-(3-cyano-5-fluoro-phenyl)thiazole-5-carboxylic acid (360 mg, 61% yield, 95% purity) was obtained as a yellow solid. LCMS (ESI) m / z 248.8 [M+H]+

[0372] 2-(3-chloro-5-cyano-phenyl)thiazole-5-carboxylic acid (320 mg. 47% yield, 90% purity) was obtained as a yellow solid. LCMS (ESI) m / z 264.7 [M+H]+

[0373] Synthesis of 2-(3-cyano-5-fluoro-phenyl)oxazole-5-carboxyHc acid

[0374] Step 1:

[0375] A mixture of 3-bromo-5-fluoro-benzonitrile (2 g, 10.0 mmol, 2 eq), ethyl oxazole-5- carboxylate (706 mg. 5.0 mmol, 1 eq), CS2CO3 (3.26 g. 10.0 mmol, 2 eq), and Pd(PPh?)4 (578 mg, 500 pmol, 0. 1 eq) in dioxane (20 rnL) was degassed and purged with N2 for 3 times. The mixture was stirred at 100 °C for 12 hr 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 layer was washed with brine (30 mL), dried over NazSCL and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography (SiCh, 0-15% ethyl acetate in petroleum ether). Ethyl 2-(3- cyano-5-fluoro-phenyl)oxazole-5 -carboxylate (360 mg, 19% yield, 67% purity) was obtained as a yellow solid. LCMS (ESI) m / z 260.9 [M+H]+

[0376] Step 2:

[0377] To a solution of ethyl 2-(3-cyano-5-fluoro-phenyl)oxazole-5-carboxylate (260 mg, 999.2 pmol, 1 eq) in THF (2 mL) was added LiOH.LhO (4 M in water, 2 mL). The mixture was stirred at 20 °C for 1 hr. The reaction mixture was quenched by addition of aq. IM HC1 to pH=4. and then extracted with EtOAc (10 mL x 3). The combined organic layer was 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) in DCM). 2-(3-cyano-5- fluoro-phenyl)oxazole-5-carboxylic acid (130 mg, 37% yield, 90% purity) was obtained as a white solid. 'H NMR (400 MHz, DMSO-t / e) 5 ppm 8.08 - 8.19 (m, 3 H) 8.29 (t. .7=1.37 Hz. 1 H).

[0378] The following carboxylic acids were synthesized via similar procedure :

[0379] 2- (2,6-difluorophenyl) oxazole- 5-carboxylic acid (323 mg, 86% yield, 100% purity ) was obtained as a white solid. LCMS (ESI) m / z 226.0 [M+H]+2-(2-chloro-6-fluoro-phenyl)oxazole-5-carboxylic acid (yvhite solid, crude, 150 mg). 2-(4-chloro-3-fluoro-phenyl)oxazole-5-carboxylic acid (256 mg, 93% yield, 98% purity) was obtained as a white solid. LCMS (ESI) m / z 242.0 [M+H]+2-(2-cyano-4-fluoro-phenyl)oxazole-5-carboxylic acid (500 mg, 72% yield, 90% purity) was obtained as a white solid. LCMS (ESI) m / z 233.0 [M+H]+2-(3-chloro-5-cyano-phenyl)oxazole-5-carboxylic acid (240 mg, 51% yield, 95% purity) was obtained as a white solid. LCMS (ESI) m / z 248.9 [M+H]+ 2- (3-fluoro-5-methoxy-phenyl) oxazole-5-carboxylic acid (1.35g, 91% yield, 100% purity) was obtained as a white solid. LCMS (ESI) m / z 237.8 [M+H]+

[0380] Synthesis of 2-[5-fluoro-2-(fluoromethyl)phenyl]thiazole-5-carboxylic acid

[0381] Step 1:

[0382] To a solution of (5-fluoro-2-formyl-phenyl)boronic acid (1 g, 6.0 mmol, 1 eq), ethyl 2- bromothiazole-5 -carboxylate (1.41 g, 6.0 mmol, 1 eq) in dioxane (20 mL) and H2O (4 mL) was added K2CO3 (2.06 g, 14.9 mmol, 2.5 eq), followed by Pd(PPhs)4 (413 mg, 357.3 umol, 0.06 eq). The mixture was stirred at 80 °C under N2 for 12 h. The reaction mixture w as filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography (SiCh, 0-10% ethyl acetate in petroleum ether). Ethyl 2- (5-fluoro-2-formyl-phenyl)thiazole-5-carboxylate (crude 500 mg) was obtained as a white solid. LCMS (ESI) m / z 280.1 )M+H]+

[0383] Step 2:

[0384] To a solution of ethyl 2-(5-fluoro-2-formyl-phenyl)thiazole-5-carboxylate (500 mg, 1.8 mmol, 1 eq) in THF (10 mL) was added NaBH4 (41 mg, 1.1 mmol, 0.6 eq) at 0 °C. The mixture was stirred at 0 °C for 1 hr. The reaction mixture was acidified by aq. IM HC1 (4 mL), and then extracted with ethyl acetate (30 mL x 3). The combined organic layer was washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure purified by column chromatography (SiCh, 0~30 % ethyl acetate in petroleum ether). Ethyl 2-[5-fluoro-2-(hydroxymethyl)phenyl] thiazole- 5-carboxylate (340 mg, 65% yield, 96% purity) was obtained as a white solid. LCMS

[0385] (ESI) m / z 282.2 [M+H]+

[0386] Step 3:

[0387] To a solution of ethyl 2-[5-fluoro-2-(hydroxymethyl)phenyl]thiazole-5-carboxylate (340 mg. 1.2 mmol, 1 eq) in DCM (20 mL) was added DAST (292 mg, 1.8 mmol. 1.5 eq) at 0 °C. The mixture was stirred at 25 °C for 0.5 hr. Aq. NHrCl (20 mL) was added and then extracted by DCM (30 mL). The organic layer was dried with Na2SO4 and filtrated. The filtrate was concentrated under reduced pressure and purified by column chromatography (SiCh, 0~50 % ethyl acetate in petroleum ether). Ethyl 2-[5-fluoro-2- (fluoromethyl)phenyl]thiazole-5-carboxylate (280 mg, 82% yield, 100% purity) was obtained as a white solid. LCMS (ESI) m / z 284.1 [M+H]+

[0388] Step 4:

[0389] To a solution of ethyl 2-[5-fluoro-2-(fluoromethyl)phenyl]thiazole-5-carboxylate (280 mg, 988.4 umol, 1 eq) in EtOH (10 mL) was added NaOH (1 M in water, 7 mL). The mixture was stirred at 20 °C for 12 hr. The reaction mixture was diluted with 5 mL of water, adjusted to pH =4 with aq. IM HC1, and then extracted with EtOAc (30 mL x 3). The combined organic layer was dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to afford 2-[5-fluoro-2-(fluoromethyl) phenyl]thiazole-5-carboxylic acid (230 mg, 91% yield, 100% purity) as a white solid. LCMS (ESI) m / z 256.1 [M+H]+

[0390] Synthesis of precursors:

[0391] Example 7-Precursor: 2-(3-fluoro-5-methoxyphenyl)-N-((2S)-5-hydroxy-l-oxo-l-

[0392] (((2S)-5,5,5-trifluoro-l-hydroxy-l-(thiazol-2-yl)pentan-2-yl)amino)hexan-2- yl)oxazole-5-carboxamide

[0393] 3-K 7-Precursor

[0394] This compound was prepared according to the procedure described in the step 16 of the synthesis of example 1. From 114 mg of the acid and 195 mg of 3-K, 105 mg of 7- Precursor (36% yield, 97% purity) was obtained as ayellow oil. LCMS (ESI) m / z 589.0 [M+H]+

[0395] Example 8-Precursor: 2-(3,5-difluorophenyl)-N-((2S)-5-hyd roxy- 1-oxo- 1-(((2S)-

[0396] 6,6,6-trifluoro-l-hydroxy-l-(thiazol-2-yl)hexan-2-yl)amino)hexan-2-yl)oxazole-5- carboxamide

[0397] This compound was prepared according to the procedure described in the step 16 of the synthesis of example 1. From 65 mg of 1 -Q and 36 mg of the acid, 51 mg of 8-Precursor (51% yield, 91% purity) was obtained as a yellow oil. LCMS (ESI) m / z 591.7 [M+H]+

[0398] Example 9-Precursor: 2-(2,5-difluorophenyl)-N-((2S)-5-hydroxy-l-oxo-l-(((2S)- 6,6,6-trifluoro-l-hydroxy-l-(thiazol-2-yl)hexan-2-yl)amino)hexan-2-yl)oxazole-5- carboxamide

[0399] This compound was prepared according to the procedure described in the step 16 of the synthesis of example 1. From 44 mg of the acid and 90 mg of 1-Q. 50 mg of 9-Precursor (42% yield, 98% purity) was obtained as a white solid. LCMS (ESI) m / z 591.5 [M+H]+

[0400] Example 10-Precursor: 2-(4-fluorophenyl)-N-((2S)-5-hydroxy-l-oxo-l-(((2S)-

[0401] 6,6,6-trifluoro-l-hydroxy-l-(thiazol-2-yl)hexan-2-yl)amino)hexan-2-yl)oxazole-5- carboxamide

[0402] This compound was prepared according to the procedure described in the step 16 of the synthesis of example 1. From 131 mg of 1-Q and 65 mg of the acid, 70 mg of 10- Precursor (37% yield, 95% purity) was obtained as ayellow oil. LCMS (ESI) m / z 573. 1 [M+H]+

[0403] Example 11-Precursor: 2-(2,4-difluorophenyl)-N-((2S)-5-hydroxy-l-oxo-l-(((2S)-

[0404] 6,6,6-trifluoro-l-hydroxy-l-(thiazol-2-yl)hexan-2-yl)amino)hexan-2-yl)oxazole-5- carboxamide

[0405] This compound was prepared according to the procedure described in the step 16 of the synthesis of example 1. From 72 mg of 1-Q and 40 mg of the acid, 52 mg of 11- Precursor (34% yield, 99% purity) was obtained as a white solid. LCMS (ESI) m / z

[0406] 591.4 [M+H]+

[0407] Example 12-Precursor: 2-(3-chloro-5-fluorophenyl)-N-((2S)-5-hydroxy-l-oxo-l-

[0408] (((2S)-6,6,6-trifluoro-l-hydroxy-l-(thiazol-2-yl)hexan-2-yl)amino)hexan-2- yl)oxazole-5-carboxamide

[0409] This compound was prepared according to the procedure described in the step 16 of the synthesis of example 1. From 131 mg of 1-Q and 75 mg of the acid, 100 mg of 12- Precursor (43% yield, 98% purity) was obtained as a white solid. LCMS (ESI) m / z 607.2 [M+H]+

[0410] Example 13-Precursor: N-((2S)-l-(((2S)-4-(4-fluorophenyl)-l-hydroxy-l-(thiazol-

[0411] 2-yl)butan-2-yl)amino)-5-hydroxy-l-oxohexan-2-yl)-2-phenylthiazole-5- carboxamide

[0412] This compound was prepared according to the procedure described in the step 16 of the synthesis of example 1. From 132 mg of 2-K and 63 mg of the acid, 126 mg of 13- Precursor (55% yield, 78% purity’) was obtained as a brown oil. LCMS (ESI) m / z 583.2 [M+H]+ Example 14-Precursor: 2-(4-chlorophenyl)-N-((2S)-l-(((2S)-4-(4-fluorophenyl)-l- hydroxy-l-(thiazol-2-yl)butan-2-yl)amino)-5-hydroxy-l-oxohexan-2-yl)thiazole-

[0413] 5-carboxamide

[0414] This compound was prepared according to the procedure described in the step 16 of the synthesis of example 1. From 66 mg of 2-K and 37 mg of the acid. 80 mg of 14- Precursor (crude) was obtained as a white solid. LCMS (ESI) m / z 617.1 [M+H]+

[0415] Example 15-Precursor: 2-(3-fhiorophenyl)-N-((2S)- l-(((2S)-4-(4-fluorophenyl)- 1- hydroxy-l-(thiazol-2-yl)butan-2-yl)amino)-5-hydroxy-l-oxohexan-2-yl)thiazole- 5-carboxamide

[0416] This compound w as prepared according to the procedure described in the step 16 of the synthesis of example 1. From 132 mg of 2-K and 72 mg of the acid, 200 mg of 15- Precursor (crude) w as obtained as a white solid. LCMS (ESI) m / z 601.3 [M+H]+

[0417] Example 16-Precursor : 2-(2-fluorophenyl)-N-((2S)- l-(((2S)-4-(4-fluorophenyl)- 1- hydroxy-l-(thiazol-2-yl)butan-2-yl)amino)-5-hydroxy-l-oxohexan-2-yl)thiazole- 5-carboxamide

[0418]

[0419] 2-K 16-Precursor

[0420] This compound was prepared according to the procedure described in the step 16 of the synthesis of example 1. From 99 mg of 2-K and 51 mg of the acid, 38 mg of 16- Precursor (26% yield, 93% purity) was obtained as a colorless oil. LCMS (ESI) m / z 601.2 [M+H]+

[0421] Example 17-Precursor: 2-(3-chlorophenyl)-N-((2S)-l-(((2S)-4-(4-fluorophenyl)-l- hydroxy-l-(thiazol-2-yl)butan-2-yl)amino)-5-hydroxy-l-oxohexan-2-yl)thiazole-

[0422] 5-carboxamide

[0423] This compound was prepared according to the procedure described in the step 16 of the synthesis of example 1. From 73 mg of the acid and 132 mg of 2-K, 92 mg of 17- Precursor (45% yield, 93% purity) was obtained as a yellow oil. LCMS (ESI) m / z 617.1 [M+H]+

[0424] Example 18-Precursor: 2-(2-chlorophenyl)-N-((2S)-l-(((2S)-4-(4-fluorophenyl)-l- hydroxy-l-(thiazol-2-yl)butan-2-yl)amino)-5-hydroxy-l-oxohexan-2-yl)thiazole-

[0425] 5-carboxamide

[0426] This compound was prepared according to the procedure described in the step 16 of the synthesis of example 1. From 96 mg of 2-K and 53 mg of the acid. 46 mg of 18- Precursor (30 % yield, 91% purity) was obtained as a yellow solid. LCMS (ESI) m / z 617.3 [M+H]+

[0427] Example 19-Precursor: N-((2S)-l-(((2S)-4-(4-fluorophenyl)-l-hydroxy-l-(thiazol-

[0428] 2-yl)butan-2-yl)amino)-5-hydroxy-l-oxohexan-2-yl)-2-(p-tolyl)thiazole-5- carboxamide

[0429] This compound was prepared according to the procedure described in the step 16 of the synthesis of example 1. From 66 mg of 2-K and 37 mg of the acid, 43 mg of 19- Precursor (44% yield, 92% purity) was obtained as a colorless oil. LCMS (ESI) m / z 597.2 [M+H]+

[0430] Example 20-Precursor: N-((2S)-l-(((2S)-4-(4-fluorophenyl)-l-hydroxy-l-(thiazol-

[0431] 2-yl)butan-2-yl)amino)-5-hydroxy-l-oxohexan-2-yl)-2-(m-tolyl)thiazol carboxamide

[0432]

[0433] This compound was prepared according to the procedure described in the step 16 of the synthesis of example 1. From 119 mg of 2-K and 61 mg of the acid, 80 mg of 20- Precursor (48% yield, 98% purity) was obtained as a white solid. LCMS (ESI) m / z 597.1 [M+H]+

[0434] Example 21-Precursor: N-((2S)-l-(((2S)-4-(4-fluorophenyl)-l-hydroxy-l-(thiazol-

[0435] 2-yl)butan-2-yl)amino)-5-hydroxy-l-oxohexan-2-yl)-2-(o-tolyl)thiazole-5- carboxamide

[0436] This compound was prepared according to the procedure described in the step 16 of the synthesis of example 1. From 66 mg of 2-K and 37 mg of the acid, 80 mg of 21- Precursor (crude) was obtained as a yellow solid. It was used in the next step without further purification. LCMS (ESI) m / z 597.3 [M+H]

[0437] Example 22-Precursor : 2-(4-cyanophenyl)-N-((2S)- l-(((2S)-4-(4-fluorophenyl)- 1- hydroxy-l-(thiazol-2-yl)butan-2-yl)amino)-5-hydroxy-l-oxohexan-2-yl)thiazole-

[0438] 5-carboxamide

[0439] This compound was prepared according to the procedure described in the step 16 of the synthesis of example 1. From 52 mg of the acid and 99 mg of 2-K. 76 mg of 22- Precursor (41 % yield, 75% purity) was obtained as a yellow oil. LCMS (ESI) m / z

[0440] 608.2 [M+H]+

[0441] Example 23-Precursor : 2-(3-cyanophenyl)-N-((2S)- l-(((2S)-4-(4-fluorophenyl)- 1- hydroxy-l-(thiazol-2-yl)butan-2-yl)amino)-5-hydroxy-l-oxohexan-2-yl)thiazole- 5-carboxamide

[0442] This compound was prepared according to the procedure described in the step 16 of the synthesis of example 1. From 66 mg of 2-K and 42 mg of the acid. 50 mg of 23- Precursor (49% yield, 90% purity ) was obtained as a white solid. LCMS (ESI) m / z 608.2 [M+H]+

[0443] Example 24-Precursor : 2-(2-cyanophenyl)-N-((2S)- l-(((2S)-4-(4-fluorophenyl)- 1- hydroxy-l-(thiazol-2-yl)butan-2-yl)amino)-5-hydroxy-l-oxohexan-2-yl)thiazole-

[0444] 5-carboxamide

[0445]

[0446] This compound was prepared according to the procedure described in the step 16 of the synthesis of example 1. From 66 mg of 2-K and 42 mg of the acid. 34 mg of 24- Precursor (33% yield, 90% purity) was obtained as a white solid. LCMS (ESI) m / z 608.2 [M+H]+

[0447] Example 25-Precursor: 2-(2,5-difluorophenyl)-N-((2S)-l-(((2S)-4-(4-fluoro phenyl)-l-hydroxy-l-(thiazol-2-yl)butan-2-yl)amino)-5-hydroxy-l-oxohexan-2- yl)thiazole-5-carboxamide

[0448] This compound was prepared according to the procedure described in the step 16 of the synthesis of example 1. From 132 mg of 2-K and 74 mg of the acid, 82 mg of 25- Precursor (31% yield, 71 % purity) was obtained as a yellow oil. LCMS (ESI) m / z 619.1 [M+H]+

[0449] Example 26-Precursor : 2-(2,6-difluorophenyl)-N-((2S)- l-(((2S)-4-(4-fluoro phenyl)-l-hydroxy-l-(thiazol-2-yl)butan-2-yl)amino)-5-hydroxy-l-oxohexan-2- yl)thiazole-5-carboxamide

[0450]

[0451] This compound was prepared according to the procedure described in the step 16 of the synthesis of example 1. From 66 mg of 2-K and 41 mg of the acid. 60 mg of 26- Precursor (62% yield, 97% purity) was obtained as a white solid. LCMS (ESI) m / z 619.3 [M+H]+

[0452] Example 27-Precursor: 2-(3,5-difhiorophenyl)-N-((2S)-l-(((2S)-4-(4-fluoro phenyl)-l-hydroxy-l-(thiazol-2-yl)butan-2-yl)amino)-5-hydroxy-l-oxohexan-2- yl)thiazole-5-carboxamide

[0453] This compound was prepared according to the procedure described in the step 16 of the synthesis of example 1. From 66 mg of 2-K and 39 mg of the acid. 75 mg of 27-

[0454] Precursor (57% yield, 72% purity ) was obtained as a white solid. LCMS (ESI) m / z

[0455] 619.2 [M+H]+

[0456] Example 28-Precursor: 2-(2,4-difhiorophenyl)-N-((2S)-l-(((2S)-4-(4-fluoro phenyl)-l-hydroxy-l-(thiazol-2-yl)butan-2-yl)amino)-5-hydroxy-l-oxohexan-2- yl)thiazole-5-carboxamide

[0457] This compound was prepared according to the procedure described in the step 16 of the synthesis of example 1. From 99 mg of 2-K and 55 mg of the acid. 85 mg of 28- Precursor (47% yield, 80% purity) was obtained as a colorless oil. LCMS (ESI), m / z: 619.1 [M+l]+

[0458] Example 29-Precursor: 2-(4-fluorophenyl)-N-((2S)-5-hydroxy-l-oxo-l-(((2S)- 5,5,5-trifluoro-l-hydroxy-l-(thiazol-2-yl)pentan-2-yl)amino)hexan-2-yl)thiazole- 5-carboxamide

[0459] This compound was prepared according to the procedure described in the step 16 of the synthesis of example 1. From 64 mg of 3-K and 35 mg of the acid. 40 mg of 29- Precursor (39% yield, 90% purity) was obtained as a colorless oil. LCMS (ESI) m / z 575.1 [M+H]+

[0460] Example 30-Precursor: 2-(3-fluorophenyl)-N-((2S)-5-hydroxy-l-oxo-l-(((2S)-

[0461] 5,5,5-trifluoro-l-hydroxy-l-(thiazol-2-yl)pentan-2-yl)amino)hexan-2-yl)thiazole-

[0462] 5-carboxamide This compound was prepared according to the procedure described in the step 16 of the synthesis of example 1. From 97 mg of 3-K and 54 mg of the acid, 129 mg of 30- Precursor (89% yield, 95% urity) was obtained as white solid. LCMS (ESI) m / z 575.2 [M+H]+

[0463] Example 31-Precursor: 2-(3-chlorophenyl)-N-((2S)-5-hydroxy-l-oxo-l-(((2S)- 5,5,5-trifluoro-l-hydroxy-l-(thiazol-2-yl)pentan-2-yl)amino)hexan-2-yl)thiazole- 5-carb oxamide

[0464] This compound was prepared according to the procedure described in the step 16 of the synthesis of example 1. From 39 mg of the acid and 65 mg of 3-K, 53 mg of 31- Precursor (43% yield, 93% purity) was obtained as a white solid. LCMS (ESI) m / z 591.1 [M+H]+

[0465] Example 32-Precursor: 2-(4-cyanophenyl)-N-((2S)-5-hydroxy- l-oxo-l-(((2S)-

[0466] 5,5,5-trifluoro-l-hydroxy-l-(thiazol-2-yl)pentan-2-yl)amino)hexan-2-yl)thiazole- 5-carboxamide

[0467] This compound was prepared according to the procedure described in the step 16 of the synthesis of example 1. From 38 mg of the acid and 64 mg of 3-K, 30 mg of 32- Precursor (28% yield, 86% purity) was obtained as a white solid. LCMS (ESI) m / z 582.2 [M+H]+ Example 33-Precursor: 2-(3,5-difluorophenyl)-N-((2S)-5-hydroxy-l-oxo-l-(((2S)-

[0468] 5,5,5-trifluoro-l-hydroxy-l-(thiazol-2-yl)pentan-2-yl)amino)hexan-2-yl)oxazole-

[0469] 5-carboxamide

[0470] This compound was prepared according to the procedure described in the step 16 of the synthesis of example 1. From 65 mg of 3-K and 36 mg of the acid. 67 mg of 33- Precursor (62% yield, 85% purity) was obtained as a white solid. LCMS (ESI) m / z

[0471] 577.1 [M+H]+

[0472] Example 34-Precursor: 2-(3,5-difluorophenyl)-N-((2S)-5-hydroxy-l-oxo-l-(((2S)-

[0473] 5,5,5-trifluoro-l-hydroxy-l-(thiazol-2-yl)pentan-2-yl)amino)hexan-2-yl)thiazole-

[0474] 5-carboxamide

[0475] This compound was prepared according to the procedure described in the step 16 of the synthesis of example 1. From 64 mg of 3-K and 38 mg of the acid, 43 mg of 34- Precursor (38% yield, 83% purity) was obtained as a white solid. LCMS (ESI) m / z 593.1 [M+H]+

[0476] Example 35-Precursor: 2-(3-chloro-5-fluorophenyl)-N-((2S)-5-hydroxy-l-oxo-l-

[0477] (((2S)-5,5,5-trifluoro-l-hydroxy-l-(thiazol-2-yl)pentan-2-yl)amino)hexan-2- yl)thiazole-5-carboxamide

[0478] 35-Precursor

[0479] This compound was prepared according to the procedure described in the step 16 of the synthesis of example 1. From 64 mg of 3-K and 45 mg of the acid. 75 mg of 35- Precursor (75 mg, 65% yield, 83% purity) was obtained as a white solid. LCMS (ESI) m / z 609.0 [M+H]+

[0480] Example 36-Precursor: 2-(3,5-dichlorophenyl)-N-((2S)-5-hydroxy-l-oxo-l-(((2S)-

[0481] 5,5,5-trifluoro-l-hydroxy-l-(thiazol-2-yl)pentan-2-yl)amino)hexan-2-yl)oxazole-

[0482] 5-carboxamide

[0483] This compound was prepared according to the procedure described in the step 16 of the synthesis of example 1. From 75 mg of 3-K and 40 mg of the acid, 60 mg of 36-

[0484] Precursor (53% yield, 84% purity) was obtained as a white solid. LCMS (ESI) m / z

[0485] 609.2 [M+H]+

[0486] Example 37-Precursor: 2-(3-fhioro-5-(trifluoromethyl)phenyl)-N-((2S)-5- hydroxy-l-oxo-l-(((2S)-5,5,5-trifluoro-l-hydroxy-l-(thiazol-2-yl)pentan-2- yl)amino)hexan-2-yl)oxazole-5-carboxamide

[0487] To a solution of 3-K (64 mg, 157.7 pmol, 1 eq, HC1) and 2-[3-fluoro-5- (trifluoromethyl)phenyl]oxazole-5 -carboxylic acid (39 mg, 141.9 pmol, 0.9 eq) in DCM (1 mL) was added DIEA (41 mg. 315.4 pmol, 2 eq) and TsP (120 mg, 189.2 pmol. 50% purity in EtOAc, 1.2 eq) at 0 °C. The mixture was stirred at 15 °C for 12 hr. The reaction mixture was diluted with water (10 mL) and extracted with DCM (10 mL x 3). The combined organic layers were dried over Na2SC>4 and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography (S1O2, 0- 7% methanol in DCM). 37-Precursor (20 mg, 31.9 pmol, 20% yield) was obtained as a colorless oil. LCMS (ESI) m / z 627.3 [M+H]+

[0488] Example 38-Precursor: 2-(5-chloro-2-fluorophenyl)-N-((2S)-5-hydroxy-l-oxo-l-

[0489] (((2S)-5,5,5-trifluoro-l-hydroxy-l-(thiazol-2-yl)pentan-2-yl)amino)hexan-2- yl)oxazole-5-carboxamide

[0490] This compound was prepared according to the procedure described in the step 16 of the synthesis of example 1. From 129 mg of 3-K and 64 mg of the acid, 67 mg of 38- Precursor (39% yield, 93% purity) was obtained as a white solid. LCMS (ESI) m / z 593.3 [M+H]+

[0491] Example 39-Precursor: 2-(2-chloro-5-fluorophenyl)-N-((2S)-5-hydroxy-l-oxo-l-

[0492] (((2S)-5,5,5-trifluoro-l-hydroxy-l-(thiazol-2-yl)pentan-2-yl)amino)hexan-2- yl)oxazole-5-carboxamide This compound was prepared according to the procedure described in the step 16 of the synthesis of example 1. From 190 mg of 3-K and 113 mg of the acid. 160 mg of 39- Precursor (55% yield, 95% purity) was obtained as a colorless oil. LCMS (ESI) m / z 593.1 [M+H]+

[0493] Example 40-Precursor: 2-(2,5-difhiorophenyl)-N-((2S)-5-hydroxy-l-oxo-l-(((2S)-

[0494] 5,5,5-trifluoro-l-hydroxy-l-(thiazol-2-yl)pentan-2-yl)amino)hexan-2-yl)oxazole-

[0495] 5-carboxamide

[0496] This compound was prepared according to the procedure described in the step 16 of the synthesis of example 1. From 129 mg of 3-K and 60 mg of the acid, 100 mg of 40- Precursor (41% yield, 93% purity) was obtained as a white solid. LCMS (ESI) m / z 577.3 [M+H]+

[0497] Example 41-Precursor: 2-(2,5-dichlorophenyl)-N-((2S)-5-hydroxy-l-oxo-l-(((2S)-

[0498] 5,5,5-trifluoro-l-hydroxy-l-(thiazol-2-yl)pentan-2-yl)amino)hexan-2-yl)oxazole-

[0499] 5-carboxamide

[0500] This compound was prepared according to the procedure described in the step 16 of the synthesis of example 1. From 194 mg of 3-K and 123 mg of the acid, 160 mg of 41- Precursor (49% yield, 90% purity) was obtained as a yellow oil. LCMS (ESI) m / z 609. 1 [M+H]+ Example 42-Precursor: 2-(2-chloro-4-fluorophenyl)-N-((2S)-5-hydroxy-l-oxo-l-

[0501] (((2S)-5,5,5-trifluoro-l-hydroxy-l-(thiazol-2-yl)pentan-2-yl)amino)hexan-2- yl)oxazole-5-carboxamide

[0502] This compound was prepared according to the procedure described in the step 16 of the synthesis of example 1. From 194 mg of 3-K and 115 mg of the acid, 160 mg of 42- Precursor (51% yield, 90% purity) was obtained as a yellow oil. LCMS (ESI) m / z 593.1 [M+H]+

[0503] Example 43-Precursor: 2-(4-chloro-2-fluorophenyl)-N-((2S)-5-hydroxy-l-oxo-l- (((2S)-5,5,5-trifluoro-l-hydroxy-l-(thiazol-2-yl)pentan-2-yl)amino)hexan-2- yl)oxazole-5-carboxamide

[0504] To a solution of 2-(4-chloro-2-fluoro-phenyl)oxazole-5-carboxylic acid (77 mg, 320.3 pmol, 1 eq) and (2S)-2-amino-5-hydroxy-N-[(lS)-4,4,4-trifluoro-l-[hydroxy(thiazol- 2-yl)methyl]butyl]hexanamide (130 mg, 320.3 pmol, 1 eq, HCI) in DMF (4 mL) was added T4P (346 mg, 960.9 pmol. 50% purity in DMF. 3 eq) and DIEA (124 mg, 960.9 pmol, 3 eq). The mixture was stirred at 25 °C for 2 hr under N2. The mixture was added 5% LiCl (20 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over NazSCL and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography (SiCh, 0-10% methanol in DCM). 43-Precursor (145 mg, 212.7 pmol, 58% yield, 87% purity ) was obtained as a yellow solid. LCMS (ESI) m / z 593.0 [M+H]

[0505] Example 44-Precursor: 2-(2,4-dichlorophenyl)-N-((2S)-5-hydroxy-l-oxo-l-(((2S)-

[0506] 5,5,5-trifluoro-l-hydroxy-l-(thiazol-2-yl)pentan-2-yl)amino)hexan-2-yl)oxazole-

[0507] 5-carboxamide

[0508] This compound was prepared according to the procedure described in the step 16 of the synthesis of example 1. From 120 mg of 3-K and 76 mg of the acid, 100 mg of 44- Precursor (44% yield, 80% purity) was obtained as colorless oil. LCMS (ESI) m / z 609.0 [M+H]+

[0509] Example 45-Precursor : 2-(3-cyano-5-fluorophenyl)-N-((2S )-5-hydroxy- 1-oxo- 1-

[0510] (((2S)-5,5,5-trifluoro-l-hydroxy-l-(thiazol-2-yl)pentan-2-yl)amino)hexan-2- yl)oxazole-5-carboxamide

[0511] This compound was prepared according to the procedure described in the step 16 of the synthesis of example 1. From 112 mg of the acid and 259 mg of 3-K, 200 mg of 45- Precursor (68% yield, 96% purity) was obtained as a colorless oil. LCMS (ESI) m / z 584.2 [M+H]+

[0512] Example 46-Precursor: 2-(3,5-difluorophenyl)-N-((2S)-l-oxo-l-(((2S)-5,5,5- trifluoro-l-hydroxy-l-(thiazol-2-yl)pentan-2-yl)amino)propan-2-yl)oxazole-5- carboxamide

[0513] 46-Precursor

[0514] This compound was prepared according to the procedure described in the step 16 of the synthesis of example 1. From 92 mg of 4-C and 59 mg of the acid, 60 mg of 46- Precursor (40% yield, 90% purity) was obtained as a yellow solid. LCMS (ESI) m / z 519.2 [M+H]+

[0515] Example 47-Precursor: 2-(2-fhiorophenyl)-N-((2S)-l-oxo-l-(((2S)-5,5,5-trifluoro- l-hydroxy-l-(thiazol-2-yl)pentan-2-yl)amino)propan-2-yl)oxazole-5-carboxamide

[0516] 4-C 47-Precursor

[0517] This compound was prepared according to the procedure described in the step 16 of the synthesis of example 1. From 160 mg of 4-C and 95 mg of the acid, 170 mg of 47- Precursor (63% yield, 85% purity) was obtained as a yellow oil. LCMS (ESI) m / z 501.2 [M+H]+

[0518] Example 48-Precursor: 2-(3-fhiorophenyl)-N-((2S)-l-oxo-l-(((2S)-5,5,5-trifluoro- l-hydroxy-l-(thiazol-2-yl)pentan-2-yl)amino)propan-2-yl)oxazole-5-carboxamide

[0519] This compound was prepared according to the procedure described in the step 16 of the synthesis of example 1. From 84 mg of 4-C and 50 mg of the acid, 100 mg of 48- Precursor (51% yield, 92% purity) was obtained as a yellow solid. LCMS (ESI) m / z 501.2 [M+H]+ Example 49-Precursor: 2-(4-fluorophenyl)-N-((2S)-l-oxo-l-(((2S)-5,5,5-trifluoro- l-hydroxy-l-(thiazol-2-yl)pentan-2-yl)amino)propan-2-yl)oxazole-5-carboxamide

[0520] This compound was prepared according to the procedure described in the step 16 of the synthesis of example 1. From 120 mg of 4-C and 64 mg of the acid, 100 mg of 49- Precursor (52% yield, 90% purity) was obtained as a yellow oil. LCMS (ESI) m / z 501. 1 [M+H]+

[0521] Example 50-Precursor: 2-(2-chlorophenyl)-N-((2S)-l-oxo-l-(((2S)-5,5,5-trifluoro- l-hydroxy-l-(thiazol-2-yl)pentan-2-yl)amino)propan-2-yl)oxazole-5-carboxamide

[0522] 50-Precursor

[0523] This compound was prepared according to the procedure described in the step 16 of the synthesis of example 1. From 160 mg of 4-C and 100 mg of the acid. 200 mg of 50- Precursor (76% yield, 90% purity) was obtained as a yellow oil. LCMS (ESI) m / z 517.1 [M+H]+

[0524] Example 51-Precursor: 2-(3-chlorophenyl)-N-((2S)-l-oxo-l-(((2S)-5,5,5-trifluoro- l-hydroxy-l-(thiazol-2-yl)pentan-2-yl)amino)propan-2-yl)oxazole-5-carboxamide

[0525] 4-C 51-Precursor

[0526] This compound was prepared according to the procedure described in the step 16 of the synthesis of example 1. From 126 mg of 4-C and 81 mg of the acid, 180 mg of 51- Precursor (82%yield, 85% purity) was obtained as ayellow oil. LCMS (ESI) m / z 516.9 [M+H]+

[0527] Example 52-Precursor: 2-(4-chlorophenyl)-N-((2S)-l-oxo-l-(((2S)-5,5,5-trifluoro- l-hydroxy-l-(thiazol-2-yl)pentan-2-yl)amino)propan-2-yl)oxazole-5-carboxamide

[0528] This compound was prepared according to the procedure described in the step 16 of the synthesis of example 1. From 70 mg of 4-C and 41 mg of the acid. 56 mg of 52- Precursor (51 % yield, 95% purity) was obtained as a yellow oil. LCMS (ESI) m / z 517.1 [M+H]+

[0529] Example 53-Precursor : 2-(3,5-dichlorophenyl)-N-((2S)- 1-oxo- l-(((2S)-5,5,5- trifluoro-l-hydroxy-l-(thiazol-2-yl)pentan-2-yl)amino)propan-2-yl)oxazole-5- carboxamide

[0530] This compound was prepared according to the procedure described in the step 16 of the synthesis of example 1. From 155 mg of 4-C and 94 mg of the acid, 160 mg of 53- Precursor (53.1% yield, 88% purity) was obtained as a yellow solid. LCMS (ESI) m / z 550.8 [M+H]+

[0531] Example 54-Precursor: 2-(2-chloro-5-fluorophenyl)-N-((2S)-l-oxo-l-(((2S)-5,5,5- trifluoro-l-hydroxy-l-(thiazol-2-yl)pentan-2-yl)amino)propan-2-yl)oxazole-5- carboxamide

[0532] This compound was prepared according to the procedure described in the step 16 of the synthesis of example 1. From 62 mg of the acid and 81 mg of 4-C, 80 mg of 54- Precursor (57.9% yield, 90% purity) was obtained as a colorless oil. LCMS (ESI) m / z

[0533] 535.2 [M+H]+

[0534] Example 55-Precursor: 2-(5-chloro-2-fluorophenyl)-N-((2S)-l-oxo-l-(((2S)-5,5,5- trifluoro-l-hydroxy-l-(thiazol-2-yl)pentan-2-yl)amino)propan-2-yl)oxazole-5- carboxamide

[0535] 4-C 55-Precursor

[0536] This compound was prepared according to the procedure described in the step 16 of the synthesis of example 1. From 120 mg of 4-C and 83 mg of the acid, 140 mg of 55- Precursor (77% yield, 90% purity) was obtained as ayellow oil. LCMS (ESI) m / z 535.0 [M+H]+

[0537] Example 56-Precursor: 2-(2-fluorophenyl)-N-((2S)-l-oxo-l-(((2S)-5,5,5-trifluoro- l-hydroxy-l-(thiazol-2-yl)pentan-2-yl)ainino)propan-2-yl)thiazole-5- carboxamide

[0538] 4-C 56-Precursor

[0539] This compound was prepared according to the procedure described in the step 16 of the synthesis of example 1. From 85 mg of 4-C and 65 mg of the acid, 100 mg of 56- Precursor (47.5% yield, 90% purity) was obtained as a white solid. LCMS (ESI) m / z 517.1 [M+H]

[0540] Example 57-Precursor: 2-(3-fluorophenyl)-N-((2S)-l-oxo-l-(((2S)-5,5,5-trifhioro- l-hydroxy-l-(thiazol-2-yl)pentan-2-yl)amino)propan-2-yl)thiazole-5- carboxamide

[0541] 4-C 57-Precursor

[0542] This compound was prepared according to the procedure described in the step 16 of the synthesis of example 1. From 118 mg of 4-C and 83 mg of the acid, 95 mg of 57- Precursor (53% yield, 97% purity) was obtained as a yellow oil. LCMS (ESI) m / z 516.7 [M+H]+

[0543] Example 58-Precursor: 2-(4-fluorophenyl)-N-((2S)-l-oxo-l-(((2S)-5,5,5-trifluoro- l-hydroxy-l-(thiazol-2-yl)pentan-2-yl)amino)propan-2-yl)thiazole-5- carboxamide

[0544] 4-C 58-Precursor

[0545] This compound was prepared according to the procedure described in the step 16 of the synthesis of example 1. From 120 mg of 4-C and 77 mg of the acid, 110 mg of 58- Precursor (59% yield, 95% purity) was obtained as a yellow solid. LCMS (ESI) m / z 517.1 [M+H]+

[0546] Example 59-Precursor: 2-(2-chlorophenyl)-N-((2S)-l-oxo-l-(((2S)-5,5,5-trifluoro-

[0547] 1 -hydroxy-1 -(thiazol-2-yl)pentan-2-yI)amino)propan-2-yl)thiazoIe-5- carboxamide

[0548] This compound was prepared according to the procedure described in the step 16 of the synthesis of example 1. From 169 mg of 4-C and 113 mg of the acid, 245 mg of 59- Precursor (70% yield, 95% purity) was obtained as a colorless oil. LCMS (ESI) m / z 533.1 [M+H]+

[0549] Example 60-Precursor: 2-(3-chlorophenyl)-N-((2S)-l-oxo-l-(((2S)-5,5,5-trifluoro- l-hydroxy-l-(thiazol-2-yl)pentan-2-yl)amino)propan-2-yl)thiazole-5- carboxamide

[0550] This compound was prepared according to the procedure described in the step 16 of the synthesis of example 1. From 126 mg of 4-C and 87 mg of the acid, 180 mg of 60- Precursor (86.7% yield, 93% purity) was obtained as a yellow oil. LCMS (ESI) m / z 533.0 [M+H]+

[0551] Example 61-Precursor: 2-(4-chlorophenyl)-N-((2S)-l-oxo-l-(((2S)-5,5,5-trifluoro- l-hydroxy-l-(thiazol-2-yl)pentan-2-yl)amino)propan-2-yl)thiazole-5- carboxamide

[0552] This compound was prepared according to the procedure described in the step 16 of the synthesis of example 1. From 120 mg of 4-C and 83 mg of the acid, 130 mg of 61- Precursor (67.2% yield, 95% purity) was obtained as a yellow oil. LCMS (ESI) m / z 533.1 [M+H]

[0553] Example 62-Precursor: 2-(3-chloro-5-fluorophenyl)-N-((2S)-l-oxo-l-(((2S)-5,5,5- trifluoro-l-hydroxy-l-(thiazol-2-yl)pentan-2-yl)amino)propan-2-yl)thiazole-5- carboxamide

[0554] This compound was prepared according to the procedure described in the step 16 of the synthesis of example 1. From 120 mg of 4-C and 89 mg of the acid, 120 mg of 62- Precursor (60% yield, 95% purity) was obtained as a yellow solid. LCMS (ESI) m / z 551.0 [M+H]+

[0555] Example 63-Precursor: 2-(3,5-dichlorophenyl)-N-((2S)- 1-oxo- l-(((2S)-5,5,5- trilluoro-l-hydroxy-l-(thiazol-2-yl)pentan-2-yl)amino)propan-2-yl)thiazole-5- carboxamide

[0556] 4-C 63-Precursor

[0557] This compound was prepared according to the procedure described in the step 16 of the synthesis of example 1. From 120 mg of 4-C and 95 mg of the acid, 140 mg of 63- Precursor (68% yield, 95% purity) was obtained as a yellow solid. LCMS (ESI) m / z 567.0 [M+H]+

[0558] Example 64-Precursor: 2-(3,5-difluorophenyl)-N-((2S)-l-oxo-l-(((2S)-5,5,5- trifluoro-l-hydroxy-l-(thiazol-2-yl)pentan-2-yl)amino)propan-2-yI)thiazole-5- carboxamide

[0559] This compound was prepared according to the procedure described in the step 16 of the synthesis of example 1. From 64 mg of the acid and 85 mg of 4-C, 49 mg of 64- Precursor (38.0% yield) was obtained as a colorless oil. LCMS (ESI) m / z 535.0 [M+H]+

[0560] Example 65-Precursor: 2-(2,5-difhiorophenyl)-N-((2S)-l-oxo-l-(((2S)-5,5,5- trifluoro-l-hydroxy-l-(thiazol-2-yl)pentan-2-yl)amino)propan-2-yl)thiazole-5- carboxamide

[0561] 4-C 65-Precursor

[0562] This compound was prepared according to the procedure described in the step 16 of the synthesis of example 1. From 90 mg of 4-C and 75 mg of the acid, 100 mg of 65- Precursor (71% yield, 98% purity) was obtained as a white solid. LCMS (ESI) m / z 535.2 [M+H]+

[0563] Example 66-Precursor: 2-(2-chloro-5-fluorophenyl)-N-((2S)-l-oxo-l-(((2S)-5,5,5- trifluoro-l-hydroxy-l-(thiazol-2-yl)pentan-2-yl)amino)propan-2-yl)thiazole-5- carboxamide

[0564] 4-C 66-Precursor

[0565] This compound was prepared according to the procedure described in the step 16 of the synthesis of example 1. From 95 mg of 4-C and 84 mg of 287-B, 140 mg of 66- Precursor (91.2% yield, 98% purity ) was obtained as a white solid. LCMS (ESI) m / z 551.0 [M+H]

[0566] Example 67-Precursor: 2-(5-chloro-2-fluorophenyl)-N-((2S)-l-oxo-l-(((2S)-5,5,5- trifluoro-l-hydroxy-l-(thiazol-2-yl)pentan-2-yl)amino)propan-2-yl)thiazole-5- carboxamide

[0567] 4-C 67-Precursor

[0568] This compound was prepared according to the procedure described in the step 16 of the synthesis of example 1. From 160 mg of 4-C and 119 mg of the acid. 200 mg of 67- Precursor (71.0% yield, 90% purity) was obtained as a yellow oil. LCMS (ESI) m / z 551.1 [M+H]+

[0569] Example 68-Precursor : 2-(2,5-dichlorophenyl)-N-((2S)- 1-oxo- l-(((2S)-5,5,5- trifluoro-l-hydroxy-l-(thiazol-2-yl)pentan-2-yl)amino)propan-2-yl)thiazole-5- carboxamide

[0570] 4-C 68-Precursor

[0571] This compound was prepared according to the procedure described in the step 16 of the synthesis of example 1. From 150 mg of 4-C and 118 mg of the acid. 100 mg of 68- Precursor (30.7% yield, 75% purity) was obtained as a yellow oil. LCMS (ESI) m / z 567.0 [M+H]+

[0572] Example 69-Precursor: 2-(4-chlorophenyl)-N-((2S)-5-hydroxy-l-oxo-l-(((2S)- 6,6,6-trifluoro-l-hydroxy-l-(thiazol-2-yl)hexan-2-yl)amino)hexan-2-yl)thiazole-5- carboxamide

[0573] This compound was prepared according to the procedure described in the step 16 of the synthesis of example 1. From 66 mg of 1-Q and 37 mg of the acid. 53 mg of 69- Precursor (50.8% yield, 90% purity ) was obtained as a colorless oil. LCMS (ESI) m / z 605.1 [M+H]+

[0574] Example 70-Precursor: 2-(2-fluorophenyl)-N-((2S)-5-hydroxy-l-oxo-l-(((2S)- 6,6,6-trifluoro-l-hydroxy-l-(thiazol-2-yl)hexan-2-yl)amino)hexan-2-yl)thiazole-5- carboxamide

[0575] This compound was prepared according to the procedure described in the step 16 of the synthesis of example 1. From 78 mg of 1-Q and 42 mg of the acid. 80 mg of 70- Precursor (71% yield, 98% purity) was obtained as a white solid. LCMS (ESI) m / z 589.2 [M+H]+

[0576] Example 71-Precursor: 2-(3-chlorophenyl)-N-((2S)-5-hydroxy-l-oxo-l-(((2S)-

[0577] 6,6,6-trifluoro-l-hydroxy-l-(thiazol-2-yl)hexan-2-yl)amino)hexan-2-yl)thiazole-5- carboxamide This compound was prepared according to the procedure described in the step 16 of the synthesis of example 1. From 55 mg of the acid and 98 mg of 1-Q. 96 mg of 71- Precursor (63% yield, 94% purity) was obtained as a yellow oil. LCMS (ESI) m / z 605. 1 [M+H]+

[0578] Example 72-Precursor: 2-(2-chlorophenyl)-N-((2S)-5-hydroxy-l-oxo-l-(((2S)-

[0579] 6,6,6-trifluoro-l-hydroxy-l-(thiazol-2-yl)hexan-2-yl)amino)hexan-2-yl)thiazole-5- carboxamide

[0580] This compound was prepared according to the procedure described in the step 16 of the synthesis of example 1. From 65 mg of 1-Q and 33 mg of the acid, 71 mg of 72- Precursor (72% yield, 94% purity) was obtained as a yellow solid. LCMS (ESI) m / z 605.2 [M+H]+

[0581] Example 73-Precursor: N-((2S)-5-hydroxy-l-oxo-l-(((2S)-6,6,6-trifluoro-l- hydroxy-l-(thiazol-2-yl)hexan-2-yl)amino)hexan-2-yl)-2-(p-tolyl)thiazole-5- carboxamide

[0582] This compound was prepared according to the procedure described in the step 16 of the synthesis of example 1. From 65 mg of 1-Q and 34 mg of the acid, 75 mg of 73- Precursor (53% yield, 97% purity) was obtained as a colorless oil. LCMS (ESI) m / z 585.2 [M+H]+ Example 74-Precursor: N-((2S)-5-hy droxy- l-oxo-l-(((2S)-6,6,6-trifluoro- 1- hydroxy-l-(thiazol-2-yl)hexan-2-yl)amino)hexan-2-yl)-2-(m-tolyl)thiazole-5- carboxamide

[0583] This compound was prepared according to the procedure described in the step 16 of the synthesis of example 1. From 78 mg of 1-Q and 41 mg of the acid, 75 mg of 74- Precursor (67% yield, 98% purity) was obtained as a white solid. LCMS (ESI) m / z 585.3 [M+H]+

[0584] Example 75 -Precursor: N-((2S)-5-hydroxy- l-oxo-l-(((2S)-6, 6, 6- trifluoro- 1- hydroxy-l-(thiazol-2-yl)hexan-2-yl)amino)hexan-2-yl)-2-(o-tolyl)thiazole-5- carboxamide

[0585] This compound was prepared according to the procedure described in the step 16 of the synthesis of example 1. From 98 mg of 1-Q and 56 mg of the acid. 85 mg of 75- Precursor (59 % yield, 95% purity ) was obtained as a withe solid. LCMS (ESI) m / z

[0586] 585.1 [M+H]+

[0587] Example 76-Precursor: 2-(4-cyanophenyl)-N-((2S)-5-hydroxy-l-oxo-l-(((2S)- 6,6,6-trifluoro-l-hydroxy-l-(thiazol-2-yl)hexan-2-yl)amino)hexan-2-yl)thiazole-5- carboxamide

[0588] This compound was prepared according to the procedure described in the step 16 of the synthesis of example 1. From 53 mg of the acid and 98 mg of 1-Q. 79 mg of 76- Precursor (44% yield, 78% purity) was obtained as a yellow oil. LCMS (ESI) m / z 596. 1 [M+H]+

[0589] Example 77-Precursor: 2-(3-cyanophenyl)-N-((2S)-5-hydroxy-l-oxo-l-(((2S)-

[0590] 6,6,6-trifluoro-l-hydroxy-l-(thiazol-2-yl)hexan-2-yl)amino)hexan-2-yl)thiazole-5- carboxamide

[0591] This compound was prepared according to the procedure described in the step 16 of the synthesis of example 1. From 66 mg of 1-Q and 43 mg of the acid, 80 mg of 77- Precursor (52% yield, 90% purity) was obtained as a white solid. LCMS (ESI) m / z 596.2 [M+H]+

[0592] Example 78-Precursor : 2-(2-cyanophenyl)-N-((2S)-5-hydroxy- 1-oxo- 1-(((2S)-

[0593] 6,6,6-trifluoro-l-hydroxy-l-(thiazol-2-yl)hexan-2-yl)amino)hexan-2-yl)thiazole-5- carboxamide

[0594] This compound was prepared according to the procedure described in the step 16 of the synthesis of example 1. From 98 mg of 1-Q and 64 mg of the acid, 55 mg of 78- Precursor (35% yield, 90% purity) was obtained as a white solid. LCMS (ESI) m / z

[0595] 596.1 [M+H]+

[0596] Example 79-Precursor: 2-(2,6-difluorophenyl)-N-((2S)-5-hydroxy-l-oxo-l-(((2S)-

[0597] 6,6,6-trifluoro-l-hydroxy-l-(thiazol-2-yl)hexan-2-yl)amino)hexan-2-yl)thiazole-5- carboxamide

[0598] This compound was prepared according to the procedure described in the step 16 of the synthesis of example 1. From 65 mg of 1-Q and 37 mg of the acid. 85 mg of 79- Precursor (87% yield, 96% purity) was obtained as a white solid. LCMS (ESI) m / z 607.2 [M+H]+

[0599] Example 80-Precursor: 2-(3,5-difluorophenyl)-N-((2S)-5-hydroxy-l-oxo-l-(((2S)-

[0600] 6,6,6-trifluoro-l-hydroxy-l-(thiazol-2-yl)hexan-2-yl)amino)hexan-2-yl)thiazole-5- carboxamide

[0601] This compound was prepared according to the procedure described in the step 16 of the synthesis of example 1. From 66 mg of 1-Q and 39 mg of the acid, 53 mg of 80- Precursor (39% yield, 70% purity) was obtained as a white solid. LCMS (ESI) m / z 607.2 [M+H]+ Example 81-Precursor: 2-(2,4-difluorophenyl)-N-((2S)-5-hydroxy-l-oxo-l-(((2S)-

[0602] 6,6,6-trifluoro-l-hydroxy-l-(thiazol-2-yl)hexan-2-yl)amino)hexan-2-yl)thiazole-5- carboxamide

[0603] This compound was prepared according to the procedure described in the step 16 of the synthesis of example 1. From 87 mg of 1-Q and 50 mg of the acid, 80 mg of 81- Precursor (53% yield, 84% purity) was obtained as a colorless oil. LCMS (ESI) m / z: 607.1 [M+H]+

[0604] Example 82-Precursor: N-((2S)-5-hydroxy-l-oxo-l-(((2S)-6,6,6-trifluoro-l- hydroxy-l-(thiazol-2-yl)hexan-2-yl)amino)hexan-2-yl)-2-phenylthiazoIe-5- carboxamide

[0605] This compound was prepared according to the procedure described in the step 16 of the synthesis of example 1. From 3.5 g of 1-Q and 1.7 g of the acid, 3.3 g of 82-Precursor (5.6 mmol, 67% yield, 95% purity) was obtained as a white solid. LCMS (ESI) m / z 571.3 [M+H]+

[0606] Example 83-Precursor: 2-(3-lluorophenyl)-N-((2S)-5-hydroxy-l-oxo-l-(((2S)- 6,6,6-trifluoro-l-hydroxy-l-(thiazol-2-yl)hexan-2-yl)amino)hexan-2-yl)oxazole-5- carboxamide

[0607] This compound was prepared according to the procedure described in the step 16 of the synthesis of example 1. From 40 mg of the acid and 64 mg of 1-Q. 60 mg of 83- Precursor (34% yield, 94% purity ) was obtained as colorless oil. LCMS (ESI) m / z 573.2 [M+H]+

[0608] Example 84-Precursor: 2-(5-fluoro-2-methylphenyl)-N-((2S)-5-hydroxy-l-oxo-l-

[0609] (((2S)-6,6,6-trifluoro-l-hydroxy-l-(thiazol-2-yl)hexan-2-yl)amino)hexan-2- yl)thiazole-5-carboxamide

[0610] This compound was prepared according to the procedure described in the step 16 of the synthesis of example 1. From 55 mg of the acid and 98 mg of 1-Q, 81 mg of 84- Precursor (52% yield, 91% purity’) was obtained as a yellow oil. LCMS (ESI) m / z 603. 1 [M+H]+

[0611] Example 85-Precursor: 2-(5-fluoro-2-(fluoromethyl)phenyl)-N-((2S)-5-hydroxy-l- oxo-l-(((2S)-6,6,6-trifluoro-l-hydroxy-l-(thiazol-2-yl)hexan-2-yl)amino)hexan-2- yl)thiazole-5-carboxamide

[0612] This compound was prepared according to the procedure described in the step 16 of the synthesis of example 1. From 65 mg of 1-Q and 39 mg of the acid, 57 mg of 85- Precursor (59% yield, 100% purity) was obtained as a yellow solid. LCMS (ESI) m / z

[0613] 621.1 [M+H]+

[0614] Example 86-Precursor: N-((2S)-5-hydroxy-l-oxo-l-(((2S)-6,6,6-trifluoro-l- hydroxy-l-(thiazol-2-yl)hexan-2-yl)amino)hexan-2-yl)-2-(2-

[0615] (trifluoromethyl)phenyl)thiazole-5-carboxamide

[0616] This compound was prepared according to the procedure described in the step 16 of the synthesis of example 1. From 50 mg of the acid and 64 mg of 1-Q. 75 mg of 86- Precursor (63% yield, 99% purity) was obtained as a white solid. LCMS (ESI) m / z 639.0 [M+H]+

[0617] Example 87-Precursor: N-((2S)-5-hydroxy-l-oxo-l-(((2S)-6,6,6-trifluoro-l- hydroxy-l-(thiazol-2-yl)hexan-2-yl)amino)hexan-2-yl)-2-(3- (trifluoromethyl)phenyl)thiazole-5-carboxamide

[0618] 87-Precursor

[0619] This compound was prepared according to the procedure described in the step 16 of the synthesis of example 1. From 65 mg of 1-Q and 42 mg of the acid. 73 mg of 87- Precursor (73% yield, 98% purity) was obtained as a yellow oil. LCMS (ESI) m / z 639.4 [M+H]1

[0620] Example 88-Precursor: N-((2S)-5-hydroxy-l-oxo-l-(((2S)-6,6,6-trifluoro-l- hydroxy-l-(thiazol-2-yl)hexan-2-yl)amino)hexan-2-yl)-2-(4-

[0621] (trifluoromethyl)phenyl)thiazole-5-carboxamide

[0622] This compound was prepared according to the procedure described in the step 16 of the synthesis of example 1. From 65 mg of 1-Q and 44 mg of the acid, 53 mg of 88- Precursor (48% yield, 91% purity) was obtained as a white solid. LCMS (ESI) m / z 639.2 [M+H]+

[0623] Example 89-Precursor: 2-(3-fluorophenyl)-N-((2S)-5-hydroxy-l-oxo-l-(((2S)-

[0624] 6,6,6-trifluoro-l-hydroxy-l-(thiazol-2-yl)hexan-2-yl)amino)hexan-2-yl)thiazole-5- carboxamide

[0625] This compound was prepared according to the procedure described in the step 16 of the synthesis of example 1. From 111 mg of 1-Q and 62 mg of the acid, 180 mg of 89- Precursor (50% yield, 56% purity) was obtained as a white solid. LCMS (ESI) m / z 589.3 [M+H]+

[0626] Example 90-Precursor: 2-(2,5-difluorophenyl)-N-((2S)-5-hydroxy-l-oxo-l-(((2S)-

[0627] 6,6,6-trifluoro-l-hydroxy-l-(thiazol-2-yl)hexan-2-yl)amino)hexan-2-yl)thiazole-5- carboxamide

[0628] This compound was prepared according to the procedure described in the step 16 of the synthesis of example 1. From 131 mg of 1-Q and 75 mg of the acid, 76 mg of 90- Precursor (35% yield, 88% purity) was obtained as a yellow oil. LCMS (ESI) m / z 607. 1 [M+H]+

[0629] Example 91-Precursor: 2-(2,3-difhiorophenyl)-N-((2S)-l-oxo-l-(((2S)-5,5,5- trifluoro-l-hydroxy-l-(thiazol-2-yl)pentan-2-yl)amino)propan-2-yl)oxazole-5- carboxamide

[0630] This compound was prepared according to the procedure described in the step 16 of the synthesis of example 1. From 85 mg of 4-C and 55 mg of the acid, 101 mg of 91- Precursor (53% yield, 99% purity) was obtained as a white solid. LCMS (ESI) m / z 519.0 [M+H]+

[0631] Example 92-Precursor: 2-(2,3-dichlorophenyl)-N-((2S)- 1-oxo- l-(((2S)-5,5,5- trifluoro-l-hydroxy-l-(thiazol-2-yl)pentan-2-yl)amino)propan-2-yI)oxazole-5- carboxamide

[0632] This compound was prepared according to the procedure described in the step 16 of the synthesis of example 1. From 126 mg of 4-C and 93 mg of the acid, 125 mg of 92- Precursor (63% yield, 100% purity) was obtained as a white solid. LCMS (ESI) m / z

[0633] 551.0 [M+H]+

[0634] Example 93-Precursor: 2-(2-chloro-3-fluorophenyl)-N-((2S)-l-oxo-l-(((2S)-5,5,5- trifluoro-l-hydroxy-l-(thiazol-2-yl)pentan-2-yl)amino)propan-2-yl)oxazole-5- carboxamide

[0635] This compound was prepared according to the procedure described in the step 16 of the synthesis of example 1. From 120 mg of 4-C and 92 mg of the acid, 130 mg of 93- Precursor (70% yield, 99% purity) was obtained as a white solid. LCMS (ESI) m / z 534.9 [M+H]+

[0636] Example 94-Precursor: 2-(3-chloro-2-fluorophenyl)-N-((2S)-l-oxo-l-(((2S)-5,5,5- trifluoro-l-hydroxy-l-(thiazol-2-yl)pentan-2-yl)amino)propan-2-yl)oxazole-5- carboxamide

[0637] This compound was prepared according to the procedure described in the step 16 of the synthesis of example 1. From 126 mg of 4-C and 88 mg of the acid, 122 mg of 94- Precursor (62% yield, 99% purity) was obtained as a white solid. LCMS (ESI) m / z 535.0 [M+HJ+

[0638] Example 95-Precursor: 2-(2,3-difluorophenyl)-N-((2S)-5-hydroxy-l-oxo-l-(((2S)-

[0639] 5,5,5-trifluoro-l-hydroxy-l-(thiazol-2-yl)pentan-2-yl)amino)hexan-2-yl)oxazole-

[0640] 5-carboxamide

[0641] 3-K 95-Precursor

[0642] This compound was prepared according to the procedure described in the step 16 of the synthesis of example 1. From 36 mg of the acid and 65 mg of 3-K. 58 mg of 95- Precursor (39% yield, 93% purity) was obtained as a white solid. LCMS (ESI) m / z 576.9 [M+H]+

[0643] Example 96-Precursor: 2-(2-chloro-3-fluorophenyl)-N-((2S)-5-hydroxy-l-oxo-l-

[0644] (((2S)-5,5,5-trifluoro-l-hydroxy-l-(thiazol-2-yl)pentan-2-yl)amino)hexan-2- yl)oxazole-5-carboxamide

[0645] 3-K 96-Precursor

[0646] This compound was prepared according to the procedure described in the step 16 of the synthesis of example 1. From 69 mg of the acid and 97 mg of 3-K, 70 mg of 96- Precursor (44% yield, 90% purity) was obtained as a white solid. LCMS (ESI) m / z 593.1 [M+H]+

[0647] Example 97-Precursor: 2-(2,4-difluorophenyl)-N-((2S)-5-hydroxy-l-oxo-l-(((2S)-

[0648] 5,5,5-trifluoro-l -hydroxy- l-(thiazol-2-yl)pentan-2-yI)amino)hexaii-2-yl)oxazole- 5-carboxamide

[0649] 3-K 97-Precursor

[0650] This compound was prepared according to the procedure described in the step 16 of the synthesis of example 1. From 86 mg of the acid and 129 mg of 3-K, 130 mg of 97- Precursor (66% yield, 93% purity) was obtained as a white solid. LCMS (ESI) m / z 577.2 [M+H]+

[0651] Example 98-Precursor: 2-(2,6-difluorophenyl)-N-((2S)-5-hydroxy-l-oxo-l-(((2S)-

[0652] 5,5,5-trifluoro-l-hydroxy-l-(thiazol-2-yl)pentan-2-yl)amino)hexan-2-yl)oxazole-

[0653] 5-carboxamide

[0654] 3-K 98-Precursor

[0655] This compound was prepared according to the procedure described in the step 16 of the synthesis of example 1. From 158 mg of the acid and 259 mg of 3-K, 201 mg of 98- Precursor (45% yield, 83% purity) was obtained as as a yellow oil. LCMS (ESI) m / z 577.2 [M+H]+

[0656] Example 99-Precursor: 2-(2-chloro-6-fluorophenyl)-N-((2S)-5-hydroxy-l-oxo-l-

[0657] (((2S)-5,5,5-trifluoro-l-hydroxy-l-(thiazol-2-yI)pentan-2-yl)amino)hexan-2- yl)oxazole-5-carboxamide no

[0658] This compound was prepared according to the procedure described in the step 16 of the synthesis of example 1. From 110 mg of the acid and 168 mg of 3-K, 100 mg of 99- Precursor (37% yield, 100% purity) was obtained as a colorless oil. LCMS (ESI) m / z 593.0 [M+H]+

[0659] Example 100-Precursor: 2-(4-chloro-3-fluorophenyl)-N-((2S)-5-hydroxy-l-oxo-l-

[0660] (((2S)-5,5,5-trifluoro-l-hydroxy-l-(thiazol-2-yl)pentan-2-yl)amino)hexan-2- yl)oxazole-5-carboxamide

[0661] This compound was prepared according to the procedure described in the step 16 of the synthesis of example 1. From 96 mg of the acid and 162 mg of 3-K, 133 mg of 100- Precursor (55% yield, 98% purity) was obtained as a colorless oil. LCMS (ESI) m / z 593.1 [M+H]+

[0662] Example 101-Precursor: 2-(2-cyano-4-fluorophenyl)-N-((2S)-5-hydroxy-l-oxo-l-

[0663] (((2S)-5,5,5-trifluoro-l-hydroxy-l-(thiazol-2-yI)pentan-2-yl)amino)hexan-2- yl)oxazole-5-carboxamide

[0664] 3-K 101-Precursor

[0665] This compound was prepared according to the procedure described in the step 16 of the synthesis of example 1. From 74 mg of the acid and 130 mg of 3-K, 90 mg of 101- Precursor (43% yield, 90% purity) was obtained as a white solid. LCMS (ESI) m / z 584.0 [M+H]+

[0666] Example 102-Precursor: 2-(3-chloro-5-cyanophenyl)-N-((2S)-5-hydroxy-l-oxo-l-

[0667] (((2S)-5,5,5-trifluoro-l-hydroxy-l-(thiazol-2-yl)pentan-2-yl)amino)hexan-2- yl)oxazole-5-carboxamide

[0668] 102-Precursor

[0669] This compound was prepared according to the procedure described in the step 16 of the synthesis of example 1. From 39 mg of the acid and 64 mg of 3-K, 70 mg of 102- Precursor (47% yield, 96% purity) was obtained as a colorless oil. LCMS (ESI) m / z 600.2 [M+H]+

[0670] Example 103-Precursor: 2-(3-cyano-5-fluorophenyl)-N-((2S)-5-hydroxy-l-oxo-l-

[0671] (((2S)-5,5,5-trifluoro-l-hydroxy-l-(thiazol-2-yI)pentan-2-yl)amino)hexan-2- yl)thiazole-5-carboxamide

[0672] 3-K 103-Precursor

[0673] This compound was prepared according to the procedure described in the step 16 of the synthesis of example 1. From 80 mg of the acid and 130 mg of 3-K, 160 mg of 103- Precursor (53% yield, 95% purity) was obtained as a yellow solid. LCMS (ESI) m / z 600.2 [M+H]+

[0674] Example 104-Precursor: 2-(3-chloro-5-cyanophenyl)-N-((2S)-5-hydroxy-l-oxo-l-

[0675] (((2S)-5,5,5-trifluoro-l-hydroxy-l-(thiazol-2-yl)pentan-2-yl)amino)hexan-2- yl)thiazole-5-carboxamide

[0676] 104-Precursor

[0677] This compound was prepared according to the procedure described in the step 16 of the synthesis of example 1. From 85 mg of the acid and 130 mg of 3-K, 230 mg of 104- Precursor (49% yield, 95% purity) was obtained as a yellow solid. LCMS (ESI) m / z 616.1 [M+H]+

[0678] Synthesis of Examples 7-104:

[0679] Examples 7-46, 69-90, and 95-104 were made from the corresponding precursors according to the procedures described in the last step of the synthesis of Example 1. Examples 47-68 and 91-94 were made from the corresponding precursors according to the procedures described in the last step of the synthesis of Example 4. The chemical structures, names, LC / MS analysis, amount made and purity were summarized in Table 2. Table 2: Examples 7-104

[0680]

[0681]

[0682]

[0683]

[0684]

[0685]

[0686] Biochemical assays:

[0687] 1. Protein expression

[0688] Mycobacterium tuberculosis (Mtb) ClpPlP2: E. coli B121 carrying plasmids encoding ClpPl 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. 2013 Dec 20;8(12):2669-77. doi: 10.1021 / cb400577b. Epub 2013 Oct 4. PMID: 24047344; PMCID: PMC4287380.) were used. Strains were grown and protein expression was induced using autoinduction media 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 ClpClPlP2 from Mycobacteria tuberculosis. Anal Biochem. 2019 Feb 15;567:30-37. doi: 10.1016 / j.ab.2018.12.004. Epub 2018 Dec 10. PMID: 30543804; PMCID: PMC6484444).

[0689] 2. Protein purification

[0690] Proteins (Mtb ClpPl, ClpP2) were purified as described previously (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 ClpPl and a ClpP2 ring. EMBO J. 2012 Mar 21;31(6):1529-41. doi: 10. 1038 / emboj.2012.5. Epub 2012 Jan 27. PMID: 22286948; PMCID: PMC3321190.). Enzyme purification was carried out at 4°C using the following buffers: Buffer A: 50 mM potassium phosphate pH 7.6 100 mM KC1, 5 mM MgC12, P-mercaptoethanol, and 10% glycerol; buffer B: 50 mM potassium phosphate pH 7.6 100 mM KC1. 5 mM MgC12. and 5% glycerol. In a typical purification, frozen cells (5-10 g) expressing ClpPl or ClpP2 were suspended in two volumes of buffer A and broken by French press at 1500 p.s.i. The extract was centrifuged at 100 000 g and mixed with 5 ml Ni-NTA agarose previously equilibrated in buffer A. After incubating at 4°C for 4 h. Ni-NTA agarose resin was transferred to empty column and proteins were eluted using step gradient (0, 25, 50, 100, and 200 mM of imidazole in buffer B). The fractions containing near homogeneous ClpPl or ClpP2 proteins were combined, concentrated on Millipore MWCO 10,000 cut filter and purified further by gel filtration on Sephacryl S-300 column (1.5 x 12 cm) equilibrated with buffer B. The specific activity of the purified enzyme was in the range 4-5 pmole / mg / min High molecular weight protein peaks were combined, concentrated to ~2-5 mg / ml, and kept at -80°C. Measurements of Peptidase Activities

[0691] Peptidase activity of ClpPl P2 was measured continuously using acetyl-PKM- 7-amido-4-methylcoumarin (Ac-PKM-amc) as a substrate, as described in (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 ClpPlP2 Protease and Identification of Novel Peptide Substrates and Boronate Inhibitors with Anti-bacterial Activity. J Biol Chem. 2015 Apr 24;290(17): 11008-20. doi: 10. 1074 / jbc.Ml 14.625640. Epub 2015 Mar 10. PMID: 25759383; PMCID: PMC440926L). All assays of peptidase activities were performed at 37°C in black 96- well plates. Each well contained 60 pL of 25 mM phosphate buffer with 100 mM KC1, 5% glycerol, 0.5mM activator 5132 and 10 pM of fluorescent peptide substrate Ac-PKM- amc. The reaction was initiated by the addition of Mtb ClpPl P2 at 15-20 nM. After shaking for 30 seconds, peptidase activities were assayed at 37°C by continuously monitoring the rate of production of fluorescent 7-amino-4- methylcoumarin (AMC) from fluorogenic peptide substrates at 460 nm (Ex at 380 nm) using Plate Reader SpectraMax M5 (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. Biochem Pharmacol. 1973 Dec l;22(23):3099-108. doi: 10.1016 / 0006-2952(73)90196-2. PMID: 4202581.)

[0692] The inhibition Ki values against Mtb ClpPlP2 are listed in Table 3.

[0693] Cell-based assays

[0694] 1. Mtb H37Rv MABA assay

[0695] All experiments with M. tuberculosis (Mtb) were conducted within a biosafety level 3 (BSL3) laboratory using a previously described Microplate Alamar Blue Assay (MABA) (Cho, S. et al., 2015. Microplate Alamar Blue Assay (MABA) and Low Oxygen Recovery Assay (LORA) for Mycobacterium tuberculosis. In: Parish, T., Roberts, D. (eds) Mycobacteria Protocols. Methods in Molecular Biology , vol 1285. Humana Press, New York, NY. https: / / doi.org / 10.1007 / 978- l-4939-2450-9_17). Briefly, compound stocks were prepared in dimethyl sulfoxide (DMSO) at 100* of the highest desired final concentration. Compounds were transferred to the assay plate containing Middlebrook 7H12 medium (4.7 g 7H9 broth, 1 g casitone (Bacto). 5 g bovine serum albumin (BSA), 4 mg catalase and 5.6 mg palmitic acid for 1 L media). Two-fold serial dilution of the compounds was performed nine times in the assay plate. Plates were inoculated with M. tuberculosis strain H37Rv (ATCC 27294) to achieve final density of- 1 x 105 CFU / mL and incubated for 7 days at 37°C. At the end of 7 days, resazurin dye / tween 80 mixture (0.6 mM resazurin dye and 12 pL of 20% Tween 80) was added to each well, and the plates were incubated for an additional 18 to 24 h at 37°C. Fluorescence was measured using a CLARIOstar (BMG LABTECH. Ortenberg. Germany) plate reader on day 8. The MIC was an interpolated value and defined as the lowest concentration effecting a reduction in fluorescence of 90% relative to that of DMSO-treated controls. The

[0696] MABA MIC values are listed in Table 3. Vero cytotoxicity

[0697] Cytotoxicity evaluation was conducted in a BSL2 laboratory using green monkey kidney cells (Vero cell ATCC-CCL-81, American Type Culture Collection. Manassas, VA). Compound stocks were prepared in dimethyl sulfoxide at 100x of the highest desired final concentration. Compounds were transferred to the assay plate containing Eagle’s minimum essential medium 10% fetal bovine serum and supplemented with penicillin and streptomycin. Twofold serial dilution of the compounds was carried out 5 times in the assay plate. Vero cells were added to achieve a final density of 1 x 105 cells / mL and plates incubated for 3 days at 37°C and 5% CO2. Twenty microliters of 0.6 mM resazurin was added to each well and, after 4 hours, fluorescence was measured at excitation / emission wavelengths of 530 / 590 nm using a CLARIOstar (BMG LABTECH, Ortenberg, Germany). The IC50 was defined as the concentration effecting a 50% reduction in fluorescence relative to untreated cells. Rifampin, bedaquiline, tamoxifen, carbonyl cyanide-3-chlorophenylhydrazone, tacrine, and moxifloxacin were included as positive controls. The IC50 values are listed in Table 3.

[0698] Table 3. CIpPlP2 Ki, Mtb H37Rv MABA MIC and Vero IC50

[0699]

[0700] *Average values for the compounds tested more than one time.

[0701] ** Assay media without catalase.

[0702] * * *

[0703] While the present application has been described with reference to examples, it is to be understood that the scope of the claims should not be limited by the embodiments set forth in the examples, but should be given the broadest interpretation consistent with the description as a whole.

Claims

WHAT IS CLAIMED IS:

1. A compound of Formula 1 A:R is phenyl, optionally mono-, bi- or tri-substituted independently with halogen, alkyl,CF3, CN or alkoxy, andX is O or S, or a pharmaceutically acceptable salt thereof.

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

3. The compound according to claim 1, wherein R3 is lower alkyd.

4. The compound according to claim 1, wherein R is unsubstituted pheny l.

5. The compound according to claim 1, wherein R is phenyl mono- or bi-substituted independently with 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-[(lS)-l-{N-(S)-5,5,5-trifhroro-l-[(l,3-thiazol-2-yl)carbonyl]pentylcarbamoyl}-4- hydroxypentyl]-2-phenyl-l,3-thiazole-5-carboxamide;N-[(lS)-l-{N-(S)-3-(p-fhiorophenyl)-l-[(l,3-thiazol-2- yl)carbonyl]propylcarbamoyl}-4-hydroxypentyl]-2-phenyl-l,3-thiazole-5- carboxamide;N-[(lS)-l-{N-(S)-5,5,5-trifluoro-l-[(l,3-thiazol-2-yl)carbonyl]pentylcarbamoyl}-4- hydroxypentyl]-2-(p-chlorophenyl)-l,3-thiazole-5-carboxamide;N-[(lS)-l-{N-(S)-3-(p-fluorophenyl)-l-[(l,3-thiazol-2- yl)carbonyl]propylcarbamoyl}-4-hydroxypentyl]-2-(p-chlorophenyl)-l,3-thiazole-5- carboxamide;N-[(lS)-l-{N-(S)-5,5,5-trifhioro-l-[(l,3-thiazol-2-yl)carbonyl]pentylcarbamoyl}-4- hydroxypentyl]-2-(p-fluorophenyl)-l,3-thiazole-5-carboxamide;N-[(lS)-l-{N-(S)-3-(p-fhrorophenyl)-l-[(l,3-thiazol-2- yl)carbonyl]propylcarbamoyl}-4-hydroxypentyl]-2-(p-fluorophenyl)-1.3-thiazole-5- carboxamide;N-[(lS)-l-{N-(S)-5,5,5-trifhioro-l-[(l,3-thiazol-2-yl)carbonyl]pentylcarbamoyl}-4- hydroxypentyl]-2-(m-fluorophenyl)-l,3-thiazole-5-carboxamide;N-[( 1 S)- 1 - {N-(S)-3-(p-fluorophenyl)- 1 -[( 1 ,3-thiazol-2- yl)carbonyl]propylcarbamoyl}-4-hydroxypentyl]-2-(m-fluorophenyl)-l,3-thiazole-5- carboxamide;N-[(lS)-l-{N-(S)-5,5,5-trifhroro-l-[(l,3-thiazol-2-yl)carbonyl]pentylcarbamoyl}-4- hydroxypentyl]-2-(o-fluorophenyl)-l,3-thiazole-5-carboxamide;N-[(lS)-l-{N-(S)-3-(p-fhrorophenyl)-l-[(l,3-thiazol-2- yl)carbonyl]propylcarbamoyl}-4-hydroxypentyl]-2-(o-fluorophenyl)-l,3-thiazole-5-carboxamide;N-[(lS)-l-{N-(S)-5,5,5-trifluoro-l-[(l,3-thiazol-2-yl)carbonyl]pentylcarbamoyl}-4- hydroxypentylJ-2-(m-chlorophenyl)- 1 ,3-thiazole-5-carboxamide;N-[(lS)-l-{N-(S)-3-(p-fluorophenyl)-l-[(l,3-thiazol-2- yl)carbonyl]propylcarbamoyl}-4-hydroxypentyl]-2-(m-chlorophenyl)-l,3-thiazole-5- carboxamide;N-[(!S)-l-{N-(S)-5,5,5-trifluoro-l-[(l,3-thiazol-2-yl)carbonyl]pentylcarbamoyl}-4- hydroxypentyl]-2-(o-chlorophenyl)-l,3-thiazole-5-carboxamide;N-[(!S)-l-{N-(S)-3-(p-fluorophenyl)-l-[(l,3-thiazol-2- yl)carbonyl]propylcarbamoyl}-4-hydroxypentyl]-2-(o-chlorophenyl)-1.3-thiazole-5- carboxamide;N-[(lS)-l-{N-(S)-5,5,5-trifluoro-l-[(l,3-thiazol-2-yl)carbonyl]pentylcarbamoyl}-4- hydroxypentyl]-2-(p-tolyl)-l,3-thiazole-5-carboxamide;N-[( 1 S)- 1 - {N-(S)-3-(p-fluorophenyl)- 1 -[( 1 ,3-thiazol-2- yl)carbonyl]propylcarbamoyl}-4-hydroxypentyl]-2-(p-tolyl)-l,3-thiazole-5- carboxamide;N-[(lS)-l-{N-(S)-5,5,5-trifluoro-l-[(l,3-thiazol-2-yl)carbonyl]pentylcarbamoyl}-4- hydroxypentyl]-2-(m-tolyl)-l,3-thiazole-5-carboxamide;N-[(1S)-1- {N-(S)-3-(p-fluorophenyl)- !-[(!, 3-thiazol-2- yl)carbonyl]propylcarbamoyl}-4-hydroxypentyl]-2-(m-tolyl)-l,3-thiazole-5- carboxamide;N-[(lS)-l-{N-(S)-5,5,5-trifluoro-l-[(l,3-thiazol-2-yl)carbonyl]pentylcarbamoyl}-4- hydroxypenty!J-2-(o-tolyl)-l,3-thiazole-5-carboxamide;N-[(lS)-l-{N-(S)-3-(p-fluorophenyl)-l-[(l,3-thiazol-2- yl)carbonyl]propylcarbamoyl}-4-hydroxypentyl]-2-(o-tolyl)-l,3-thiazole-5- carboxamide;N-[(lS)-l-{N-(S)-5,5,5-trifluoro-l-[(l,3-thiazol-2-yl)carbonyl]pentylcarbamoyl}-4- hy droxy pentyl] -2-(p-cy anophenyl)-!, 3-thiazole-5-carboxamide;N-[(lS)-l-{N-(S)-3-(p-fluorophenyl)-l-[(l,3-thiazol-2- yl)carbonyl]propylcarbamoyl}-4-hy droxypentyl]-2-(p-cy anophenyl)-!, 3-thiazole-5- carboxamide;N-[(!S)-l-{N-(S)-5,5,5-trifluoro-l-[(l,3-thiazol-2-yl)carbonyl]pentylcarbamoyl}-4- hy droxy pentyl] -2-(m-cy anophenyl)-!, 3-thiazole-5-carboxamide;N-[(lS)-l-{N-(S)-3-(p-fluorophenyl)-l-[(l,3-thiazol-2- yl)carbonyl]propylcarbamoyl] -4-hydroxy pentyl |-2-('m-cy anophenyl)-!, 3-thiazole-5- carboxamide;N-[(lS)-l-{N-(S)-5,5,5-trifluoro-l-[(l,3-thiazol-2-yl)carbonyl]pentylcarbamoyl}-4- hy droxy pentyl] -2-(o-cy anophenyl)-!, 3-thiazole-5-carboxamide;N- [( 1 S)- 1 - {N-(S)-3 -(p-fluorophenyl)- 1 - [( 1 ,3 -thiazol-2- yl)carbonyl]propylcarbamoyl}-4-hy droxy pentyl]-2-(o-cy anophenyl)- l,3-thiazole-5- carboxamide;N-[(lS)-l-{N-(S)-5,5,5-trifluoro-l-[(l,3-thiazol-2-yl)carbonyl]pentylcarbamoyl}-4- hydroxypentyl]-2-(2.5-difluorophenyl)-l,3-thiazole-5-carboxamide;N-[(lS)-l-{N-(S)-3-(p-fluorophenyl)-!-[(!,3-thiazol-2- yl)carbonyl]propylcarbamoyl}-4-hydroxypentyl]-2-(2,5-difluorophenyl)-1.3-thiazole- 5 -carboxamide;N-[(lS)-l-{N-(S)-5,5,5-trifluoro-l-[(l,3-thiazol-2-yl)carbonyl]pentylcarbamoyl}-4- hydroxypentyl]-2-(2,6-difluorophenyl)-l,3-thiazole-5-carboxamide;N-[(lS)-l-{N-(S)-3-(p-fluorophenyl)-l-[(l,3-thiazol-2- yl)carbonyl]propylcarbamoyl}-4-hydroxypentyl]-2-(2,6-difluorophenyl)-l,3-thi azole- 5 -carboxamide;N-[(lS)-l-{N-(S)-5,5,5-trifluoro-l-[(l,3-thiazol-2-yl)carbonyl]pentylcarbamoyl}-4- hydroxypentyl]-2-(3,5-difluorophenyl)-!,3-thiazole-5-carboxamide;N-[(!S)-l-{N-(S)-3-(p-fluorophenyl)-l-[(l,3-thiazol-2- yl)carbonyl]propylcarbamoyl}-4-hydroxypentyl]-2-(3,5-difluorophenyl)-l,3-thiazole- 5 -carboxamide;N-[(lS)-l-{N-(S)-5,5,5-trifluoro-l-[(l,3-thiazol-2-yl)carbonyl]pentylcarbamoyl}-4- hydroxypentyl]-2-(2,4-difluorophenyl)-l,3-thiazole-5-carboxamide;N-[(!S)-l-{N-(S)-3-(p-fluorophenyl)-l-[(l,3-thiazol-2- yl)carbonyl]propylcarbamoyl}-4-hydroxypentyl]-2-(2,4-difluorophenyl)-l,3-thiazole- 5 -carboxamide;N-[(lS)-l-{N-(S)-5,5,5-trifluoro-l-[(l,3-thiazol-2-yl)carbonyl]pentylcarbamoyl}-4- hydroxypentyl]-2-(m-fluorophenyl)-l,3-oxazole-5-carboxamide;N-}(lS)-l-{N-(S)-5,5,5-trifluoro-l-}(l,3-thiazol-2-yl)carbonylJpentylcarbamoyl}-4- hydro.\ypentyl|-2-(5-fluoro-2-tolyl)-l .3-thiazole-5-carboxamide;N-[(lS)-l-{N-(S)-5,5,5-trifluoro-l-[(l,3-thiazol-2-yl)carbonyl]pentylcarbamoyl}-4- hydroxypentyl]-2-[5-fluoro-2-(fluoromethyl)phenyl]-l,3-thiazole-5-carboxamide;N-[(lS)-l-{N-(S)-5,5,5-trifluoro-l-[(l,3-thiazol-2-yl)carbonyl]pentylcarbamoyl}-4- hydroxypentyl]-2-[o-(trifluoromethyl)phenyl]-l,3-thiazole-5-carboxamide;N-[(lS)-l-{N-(S)-5,5,5-trifluoro-l-[(l,3-thiazol-2-yl)carbonyl]pentylcarbamoyl}-4- hydroxypentyl]-2-[m-(trifluoromethyl)phenyl]-l,3-thiazole-5-carboxamide;N-[(lS)-l-{N-(S)-5,5,5-trifluoro-l-[(l,3-thiazol-2-yl)carbonyl]pentylcarbamoyl}-4- hydroxypentyl]-2-[p-(trifluoromethyl)phenyl]-l,3-thiazole-5-carboxamide;N-[(lS)-l-{N-(S)-4,4,4-trifluoro-l-[(l,3-thiazol-2-yl)carbonyl]butjdcarbamoyl}-4- hydroxypentyl]-2-(p-fluorophenyl)-l,3-thiazole-5-carboxamide;N-[(lS)-l-{N-(S)-4,4,4-trifluoro-l-[(l,3-thiazol-2-yl)carbonyl]butj 1 carbamoyl} -4- hydroxypentyl]-2-(m-fluorophenyl)-1.3-thiazole-5-carboxamide;N-[(lS)-l-{N-(S)-4,4,4-trifluoro-l-[(l,3-thiazol-2-yl)carbonyl]butj 1 carbamoyl} -4- hydroxypentyl]-2-(m-chlorophenyl)- 1 ,3-thiazole-5-carboxamide;N-[(lS)-l-{N-(S)-4,4,4-trifluoro-l-[(l,3-thiazol-2-yl)carbonyl]butylcarbamoyl}-4- hy droxy pentyl] -2-(p-cy anophenyl)-!, 3-thiazole-5-carboxarmde;N-[(lS)-l-{N-(S)-5,5,5-trifluoro-l-[(l,3-thiazol-2-yl)carbonyl]pentylcarbamoyl}-4- hydroxypentylJ-2-(3,5-difluorophenyl)-l,3-oxazole-5-carboxamide;N-[(lS)-l-{N-(S)-5,5,5-trifluoro-l-[(l,3-thiazol-2-yl)carbonyl]pentylcarbamoyl}-4- hydroxypentyl]-2-(2,5-difluorophenyl)-l,3-oxazole-5-carboxamide;N-[(lS)-l-{N-(S)-5,5,5-trifluoro-l-[(l,3-thiazol-2-yl)carbonyl]pentylcarbamoyl}-4- hydroxypentyl]-2-(p-fluorophenyl)-l,3-oxazole-5-carboxamide;N-[(lS)-l-{N-(S)-5,5,5-trifluoro-l-[(l,3-thiazol-2-yl)carbonyl]pentylcarbamoyl}-4- hydroxypentyl]-2-(2,4-difluorophenyl)-l,3-oxazole-5-carboxamide;N-[(lS)-l-{N-(S)-4,4,4-trifluoro-l-[(l,3-thiazol-2-yl)carbonyl]butylcarbamoyl}-4-hydroxypentyl]-2-(3.5-difluorophenyl)-l,3-oxazole-5-carboxamide;N-[(lS)-l-{N-(S)-4,4,4-trifluoro-l-[(l,3-thiazol-2-yl)carbonyl]butylcarbamoyl}-4- hydroxypentylJ-2-(3,5-difluorophenyl)-l,3-thiazole-5-carboxarmde;N-[(lS)-l-{N-(S)-4,4,4-trifluoro-l-[(l,3-thiazol-2-yl)carbonyl]butylcarbarnoyl}-4- hydroxypentyl]-2-(3-chloro-5-fluorophenyl)-l,3-oxazole-5-carboxamide;N-[(lS,4R)-l-{N-(S)-4,4,4-trifluoro-l-[(L3-thiazol-2-yl)carbonyl]butylcarbamoyl}- 4-hydroxypentyl]-2-(3-chloro-5-fluorophenyl)-l,3-oxazole-5-carboxamide;N-[(lS,4S)-l-{N-(S)-4,4,4-trifluoro-l-[(l,3-thiazol-2-yl)carbonyl]butylcarbamoyl}-4- hydroxypentyl]-2-(3-chloro-5-fluorophenyl)-l,3-oxazole-5-carboxamide;N-[(lS)-l-{N-(S)-4,4,4-trifluoro-l-[(l,3-thiazol-2-yl)carbonyl]butylcarbamoyl}-4- hydroxypentyl]-2-(3-chloro-5-fluorophenyl)-l,3-thiazole-5-carboxamide;N-[(lS)-l-{N-(S)-5,5,5-trifluoro-l-[(l,3-thiazol-2-yl)carbonyl]pentylcarbamoyl}-4- hydroxypentyl]-2-(3-chloro-5-fluorophenyl)-l,3-oxazole-5-carboxamide;N-[(lS)-l-{N-(S)-4,4,4-trifluoro-l-[(l,3-thiazol-2-yl)carbonyl]butylcarbamoyl}-4- hydroxypentyl]-2-(3,5-dichlorophenyl)-l,3-oxazole-5-carboxamide;N-[(lS)-l-{N-(S)-4,4,4-trifluoro-l-[(l,3-thiazol-2-yl)carbonyl]butylcarbamoyl}-4- hydroxypentyl]-2-[3-fluoro-5-(trifluoromethyl)phenyl]-l,3-oxazole-5-carboxamide;N-[(S)-1 - {N-(S)-4,4,4-trifluoro- 1-[(1 ,3-thiazol-2-yl)carbonyl]butylcarbamoyl} ethyl]- 2-(3,5-difluorophenyl)-l,3-oxazole-5-carboxamide;N-[(lS)-l-{N-(S)-4,4,4-trifluoro-l-[(l,3-thiazol-2-yl)carbonyl]butylcarbamoyl}-4- hydroxypentyl]-2-(5-chloro-2-fluorophenyl)-l,3-oxazole-5-carboxamide;N-[(lS)-l-{N-(S)-4,4,4-trifluoro-l-[(l,3-lhiazol-2-yl)carbonyl]butylcarbamoyl}-4- hydroxy pentyl ]-2-(2-chloro-5 -fluorophenyl)- 1 ,3-oxazole-5-carboxamide;N-[(lS)-l-{N-(S)-4,4,4-trifluoro-l-[(l,3-thiazol-2-yl)carbonyl]butylcarbamoyl}-4- hydroxypentyl]-2-(2,5-difluorophenyl)-l,3-oxazole-5-carboxamide;N-[(lS)-l-{N-(S)-4,4,4-trifluoro-l-[(l,3-thiazol-2-yl)carbonyl]butylcarbamoyl}-4- hydroxypentyl]-2-(2,5-dichlorophenyl)-l,3-oxazole-5-carboxamide;N-[(lS)-l-{N-(S)-4,4,4-trifluoro-l-[(l,3-thiazol-2-yl)carbonyl]butylcarbamoyl}-4- hydroxypentyl]-2-(2-chloro-4-fluorophenyl)-l,3-oxazole-5-carboxamide;N-[(1S)-1- {N-(S)-4, 4, 4-trifluoro-l-[(l, 3-thi azol-2 -yl)carbonyl] butylcarbamoyl} -4- hydroxypentyl]-2-(4-chloro-2-fluorophenyl)-l,3-oxazole-5-carboxamide;N-[(lS)-l-{N-(S)-4,4,4-trifluoro-l-[(l,3-thiazol-2-yl)carbonyl]butylcarbamoyl}-4- hydroxypentyl]-2-(2,4-dichlorophenyl)-l,3-oxazole-5-carboxamide;N-[(S)-l-{N-(S)-4,4,4-trifluoro-l-[(l, 3-thi azol-2 -yl)carbonyl]butylcarbamoyl}ethyl]- 2-(o-fluorophenyl)-l,3-oxazole-5-carboxamide;N-[(S)-l-{N-(S)-4.4,4-trifluoro-l-[(l, 3-thi azol-2 -yl)carbonyl]butylcarbamoyl}ethyl]-2-(m-fluorophenyl)-l,3-oxazole-5-carboxamide;N-[(S)-l-{N-(S)-4.4.4-trifluoro-l-[(l, 3-thi azol-2 -yl)carbonyl]butylcarbamoyl}ethyl]-2-(p-fluorophenyl)-l,3-oxazole-5-carboxamide;N-[(S)-l-{N-(S)-4.4.4-trifluoro-l-[(l, 3-thi azol-2 -yl)carbonyl]butylcarbamoyl}ethyl]-2-(o-chlorophenyl)-l,3-oxazole-5-carboxamide;N-[(S)-l-{N-(S)-4.4.4-trifluoro-l-[(l, 3-thi azol-2 -yl)carbonyl]butylcarbamoyl}ethyl]-2-(m-chlorophenyl)-l,3-oxazole-5-carboxamide;N-[(S)-l-{N-(S)-4.4.4-trifluoro-l-f(l,3-thiazol-2-yl)carbonyl]butylcarbamoyl}ethyl]-2-(p-chlorophenyl)-l,3-oxazole-5-carboxamide;N-[(S)-1 -{N-(S)-4.4.4-tri fluoro- 1-[( 1 ,3-thi azol-2 -yl)carbonyl] butylcarbamoyl} ethyl]- 2-(3-chloro-5-fluorophenyl)-l,3-oxazole-5-carboxamide;N-[(S)-1 -{N-(S)-4.4.4-trifluoro-l-[(l.3-thi azol-2 -yl)carbonyl] butylcarbamoyl} ethyl]-2-(3,5-dichlorophenyl)-l,3-oxazole-5-carboxamide;N-t(S)-l-{N-(S)-4A4-trifluoro-l-[(l,3-thiazol-2-yl)carbonylJbutylcarbamoyl}ethylJ- 2-(2-chloro-5-fluorophenyl)-1.3-oxazole-5-carboxamide;N-[(S)-l-{N-(S)-4,4,4-trifluoro-l-[(l,3-thiazol-2-yl)carbonyl]butylcarbamoyl}ethyl]- 2-(5-chloro-2-fluorophenyl)-1.3-oxazole-5-carboxamide;N-[(S)-l-{N-(S)-4,4,4-trifluoro-l-[(l,3-thiazol-2-yl)carbonyl]butylcarbamoyl}ethyl]-2-(o-fluorophenyl)-l, 3-thi azole-5-carboxamide;N-[(S)-l-{N-(S)-4,4,4-trifluoro-l-[(l,3-thiazol-2-yl)carbonyl]butylcarbamoyl}ethyl]-2-(m-fluorophenyl)-l, 3-thi azole-5 -carboxamide;N-[(S)-l-{N-(S)-4.4.4-trifluoro-l-[(1.3-thiazol-2-yl)carbonyl]butylcarbamoyl}ethyl]- 2-(p-fluorophenyl)-l,3-thiazole-5-carboxamide;N-t(S)-l-{N-(S)-4,4,4-trifluoro-l-[(l,3-thiazol-2-yl)carbonylJbutylcarbamoyl}ethylJ- 2-(o-chlorophenyl)-l,3-thiazole-5-carboxamide;N-[(S)-l-{N-(S)-4,4,4-trifluoro-l-[(l,3-thiazol-2-yl)carbonyl]butylcarbamoyl}ethyl]- 2-(m-chlorophenyl)-l,3-thiazole-5-carboxamide;N-[(S)-l-{N-(S)-4,4,4-trifluoro-l-[(l,3-thiazol-2-yl)carbonyl]butylcarbamoyl}ethyl]- 2-(p-chlorophenyl)-l,3-thiazole-5-carboxamide;N-[(S)-l-{N-(S)-4,4,4-trifluoro-l-[(l,3-thiazol-2-yl)carbonyl]butylcarbamoyl}ethyl]- 2-(3-chloro-5-fluorophenyl)-1.3-thiazole-5-carboxamide;N-[(S)-l-{N-(S)-4,4,4-trifluoro-l-[(l,3-thiazol-2-yl)carbonyl]butylcarbamoyl}ethyl]- 2-(3,5-dichlorophenyl)-l,3-thiazole-5-carboxamide;N-[(S)-l-{N-(S)-4,4,4-trifluoro-l-[(l,3-thiazol-2-yl)carbonyl]butylcarbamoyl}ethyl]- 2-(3,5-difluorophenyl)-l,3-thiazole-5-carboxamide;N-[(S)-l-{N-(S)-4,4,4-trifluoro-l-[(l,3-thiazol-2-yl)carbonyl]butylcarbamoyl}ethyl]- 2-(2,5-difluorophenyl)-l,3-thiazole-5-carboxamide;N-[(S)-l-{N-(S)-4,4,4-trifluoro-l-[(l,3-thiazol-2-yl)carbonyl]butylcarbamoyl}ethyl]- 2-(2-chloro-5-fluorophenyl)-1.3-thiazole-5-carboxamide;N-[(S)-l-{N-(S)-4,4,4-trifluoro-l-[(l,3-thiazol-2-yl)carbonyl]butylcarbamoyl}ethyl]- 2-(5-chloro-2-fluorophenyl)-1.3-thiazole-5-carboxamide;N-[(S)-l-{N-(S)-4,4,4-trifluoro-l-[(l,3-thiazol-2-yl)carbonyl]butylcarbamoyl}ethyl]- 2-(2,5-dichlorophenyl)-l,3-thiazole-5-carboxamide;N-[(S)-l-{N-(S)-4,4,4-trifluoro-l-[(l,3-thiazol-2-yl)carbonyl]butylcarbamoyl}ethyl]- 2-(2,3-difluorophenyl)-l,3-oxazole-5-carboxamide;N-[(S)-l-{N-(S)-4,4,4-trifluoro-l-[(l,3-thiazol-2-yl)carbonyl]butylcarbamoyl}ethyl]- 2-(2,3-dichlorophenyl)-l,3-oxazole-5-carboxamide;N-[(S)-l-{N-(S)-4,4,4-trifluoro-l-[(l,3-thiazol-2-yl)carbonyl]butylcarbamoyl}ethyl]- 2-(2-chloro-3-fluorophenyl)-l,3-oxazole-5-carboxamide;N-[(S)-l-{N-(S)-4,4,4-trifluoro-l-[(l,3-thiazol-2-yl)carbonyl]butylcarbamoyl}ethyl]-2-(3-chloro-2-fluorophenyl)-1.3-oxazole-5-carboxamide;N-[(lS)-l-{N-(S)-4,4,4-trifluoro-l-[(l,3-thiazol-2-yl)carbonyl]butylcarbamoyl}-4- hydroxypentylJ-2-(2,3-difluorophenyl)-l,3-oxazole-5-carboxamide;N-[(lS)-l-{N-(S)-4,4,4-trifluoro-l-[(l,3-thiazol-2-yl)carbonyl]butylcarbamoyl}-4- hydroxypentyl]-2-(2-chloro-3-fluorophenyl)-l,3-oxazole-5-carboxamide;N-[(lS)-l-{N-(S)-4,4,4-trifluoro-l-[(l,3-thiazol-2-yl)carbonyl]butylcarbamoyl}-4- hydroxypentyl]-2-(3-cyano-5-fluorophenyl)-l,3-oxazole-5-carboxamide;N-[(lS)-l-{N-(S)-4,4,4-trifluoro-l-[(l,3-thiazol-2-yl)carbonyl]butylcarbamoyl}-4- hydroxypentyl]-2-(2,4-difluorophenyl)-l,3-oxazole-5-carboxamide;N-[(lS)-l-{N-(S)-4,4,4-trifluoro-l-[(l,3-thiazol-2-yl)carbonyl]butjdcarbamoyl}-4- hydroxypentyl]-2-(2.6-difluorophenyl)-l,3-oxazole-5-carboxamide;N-[(lS)-l-{N-(S)-4,4,4-trifluoro-l-[(l,3-thiazol-2-yl)carbonyl]butjdcarbamoyl}-4- hydroxypentyl]-2-(2-chloro-6-fluorophenyl)-l,3-oxazole-5-carboxamide;N-[(lS)-l-{N-(S)-4,4,4-trifluoro-l-[(l,3-thiazol-2-yl)carbonyl]butylcarbarnoyl}-4- hydroxypentyl]-2-(4-chloro-3-fluorophenyl)-l,3-oxazole-5-carboxamide;N-[(lS)-l-{N-(S)-4,4,4-trifluoro-l-[(l,3-thiazol-2-yl)carbonyl]butylcarbarnoyl}-4- hydroxypentyl]-2-(2-cyano-4-fluorophenyl)-l,3-oxazole-5-carboxamide;N-[(lS)-l-{N-(S)-4,4,4-trifluoro-l-[(l,3-thiazol-2-yl)carbonyl]butylcarbamoyl}-4- hydroxypentyl]-2-(3-chloro-5-cy anophenyl)-!, 3-oxazole-5-carboxamide;N-[(lS)-l-{N-(S)-4,4,4-trifluoro-l-[(l,3-thiazol-2-yl)carbonyl]butylcarbamoyl}-4- hydroxypenty!J-2-(3-cyano-5-fluorophenyl)-l,3-thiazole-5-carboxamide;N-[(lS)-l-{N-(S)-4,4,4-trifluoro-l-[(l,3-thiazol-2-yl)carbonyl]butylcarbamoyl}-4- hydroxypentyl]-2-(3-chloro-5-cyanophenyl)-l,3-thiazole-5-carboxamide; andN-[(lS)-l-{N-(S)-4,4,4-trifluoro-l-[(l,3-thiazol-2-yl)carbonyl]butylcarbamoyl}-4- hydroxypentyl]-2-(3-fluoro-5-methoxyphenyl)-l,3-oxazole-5-carboxamide, or a pharmaceutically acceptable salt thereof.

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

10. A pharmaceutical composition, comprising a therapeutically effective amount of a compound according to claim 8, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.1 1. A method for the treatment of tuberculosis, comprising the step of administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

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

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