HISTON DEACETYLASE HIBITORS FOR THE TREATMENT OR PREVENTION OF HIV INFECTIONS

Description

FIELD OF THE INVENTION

[0001] The present invention relates to inhibitors of histone deacetylase, compositions comprising at least one inhibitor of histone deacetylase, and methods of using the inhibitors of histone deacetylase for treating or preventing HIV infection in a subject.BACKGROUND OF THE INVENTION

[0002] DNA in the nucleus of the cell exists as a hierarchy of compacted chromatin structures. The basic repeating unit in chromatin is the nucleosome, which consists of a histone octamer of proteins in the nucleus of the cell around which DNA is wrapped twice. The orderly packaging of DNA in the nucleus plays an important role in the functional aspects of gene regulation. Covalent modifications of the histones have a key role in altering chromatin higher order structure and function, and ultimately, gene expression. The covalent modification of histones, such as acetylation, occurs by enzymatically mediated process.

[0003] Regulation of gene expression through the inhibition of the nuclear enzyme histone deacetylase (HDAC) is one of the several possible regulatory mechanisms whereby chromatin actively can be affected. The dynamic homeostasis of the nuclear acetylation of histone can be regulated by the opposing activity of the enzymes histone acetyl transferase (HAT) and histone deacetylase (HDAC). Transcriptionally silent chromatin can be characterized by nucleosomes with low levels of acetylated histones. Acetylation reduces the positive charge of histones, thereby expanding the structure of the nucleosome and facilitating the interaction of transcription factors with the DNA. Removal of the acetyl group restores the positive charge, condensing the structure of the nucleosome. While histone acetylation can activate DNA transcription, enhancing gene expression, histone deacetylase can reverse the process and can serve to repress gene expression. Inhibition of the histone deacetylase (HDAC inhibition) can also increase the activation of DNA transcription. See, for example, Grunstein, Nature, 389, 349-352 (1997); Pazin et al., Cell 89, 325-328 (1997); Wade et al., Trends Biochem Sci. 22, 128-132 (1997); and Wolffe, Science 272, 371-372 (1996).

[0004] With the introduction of combination antiretroviral therapy (ART), HIV became a controllable chronic disease. The combination of ART (cART) targets specific stages of the viral life cycle, and is effective at combatting active viral load down to undetectable levels. However, HIV persists within the body of infected individuals undergoing therapy, and cessation of ART leads to a viral rebound within 3-4 weeks. The HIV can persist in resting memory and naive CD4+ T cells and other long-lived cells, such as infected astrocytes and cells of macrophage lineage. HIV can persist in these resting cells by establishing a latent or "silent" infection. In these cells, virus is integrated into the host genome, but viral production does not occur as a result of inhibition of both viral transcriptions from proteins. However, these latently infected cells still do contain replication competent virus, and once cART is stopped, rebound in plasma HIV RNA is observed in nearly all patients.

[0005] One approach currently being explored to eliminate latently infected CD4+ T cells is to activate viral production from these cells in the presence of cART, when the production of the virus should kill the infected cells. Histone deacetylase inhibitors have shown promise in vitro in activating virus production from latent infected cells, and therefore this class of drugs is being studied as part of a strategy aimed at a cure of HIV.

[0006] Eleven members of the HDAC family has been identified in humans, which share a conserved catalytic domain and are grouped into two classes: class I (1,2,3,8), homologous to yeast Rpd3; and class IIa (4,5,7,9) and IIb (6, 10), homologous to yeast Hdal. HDAC 11 shares homology with both classes, but is at the same time distinct from all the other ten subtypes. The first generation of HDAC inhibitors (HDACi) are promising therapeutic agents against cancer and other diseases, and showed in vitro activation of virus production from latent infected cells. However, due to their poor selectivity, those that entered clinical trials, all show similar adverse effects. The poorly selective HDACi's are not suitable for healthy HIV patents on cART, thus the interest is high for the discovery and development of novel and subtype selective HDAC inhibitors. WO2006 / 061638 discloses other HDAC inhibitors.SUMMARY OF THE INVENTION

[0007] The references to methods of treatment in the subsequent paragraphs of this description are to be interpreted as references to the compounds, pharmaceutical compositions and medicaments of the present invention for use in a method for treatment of the human (or animal) body by therapy (or for diagnosis).

[0008] In one aspect, the present invention provides Compounds of Formula I: or a pharmaceutically acceptable salt thereof as defined in the appended claims.

[0009] The Compounds of Formula I and pharmaceutically acceptable salts thereof may be useful, for example, for activating HIV latency for potential complete cure of HIV infection alone or in combination with cART and / or other HIV treatments.

[0010] Accordingly, the present invention provides methods for treating or preventing HIV infection in a subject, comprising administering to the subject an effective amount of at least one compound of Formula I.

[0011] The details of the invention are set forth in the accompanying detailed description below.

[0012] Although any methods and materials similar to those described herein may be used in the practice or testing of the present invention, illustrative methods and materials are now described. Other embodiments, aspects and features of the present invention are either further described in or will be apparent from the ensuing description, examples and appended claims.DETAILED DESCRIPTION OF THE INVENTION

[0013] The present invention includes to inhibitors of histone deacetylase of Formula I as defined in the appended claims, compositions comprising at least one of the inhibitors of histone deacetylase, and methods of using the inhibitors of histone deacetylase for treating or preventing HIV infection in a subject.Definitions and Abbreviations

[0014] The terms used herein have their ordinary meaning and the meaning of such terms is independent at each occurrence thereof. That notwithstanding and except where stated otherwise, the following definitions apply throughout the specification and claims. Chemical names, common names, and chemical structures may be used interchangeably to describe the same structure. These definitions apply regardless of whether a term is used by itself or in combination with other terms, unless otherwise indicated. Hence, the definition of "alkyl" applies to "alkyl" as well as the "alkyl" portions of "hydroxyalkyl," "haloalkyl," "-O-alkyl," etc.

[0015] As used herein, and throughout this disclosure, the following terms, unless otherwise indicated, shall be understood to have the following meanings: A "subject" is a human or non-human mammal. In one embodiment, a subject is a human. In another embodiment, a subject is a primate. In another embodiment, a subject is a monkey. In another embodiment, a subject is a chimpanzee. In still another embodiment, a subject is a rhesus monkey.

[0016] The term "effective amount" as used herein, refers to an amount of Tricyclic Heterocycle Compound and / or an additional therapeutic agent, or a composition thereof that is effective in inhibiting HIV replication and in producing the desired therapeutic, ameliorative, inhibitory or preventative effect when administered to a subject suffering from HIV infection or AIDS. In the combination therapies of the present invention, an effective amount can refer to each individual agent or to the combination as a whole, wherein the amounts of all agents administered are together effective, but wherein the component agent of the combination may not be present individually in an effective amount.

[0017] The terms "treating" or "treatment" as used herein with respect to an HIV viral infection or AIDS, includes inhibiting the severity of HIV infection or AIDS, i.e., arresting or reducing the development of the HIV infection or AIDS or its clinical symptoms; or relieving the HIV infection or AIDS, i.e., causing regression of the severity of HIV infection or AIDS or its clinical symptoms.

[0018] The terms "preventing," or "prohylaxis," as used herein with respect to an HIV viral infection or AIDS, refers to reducing the likelihood or severity of HIV infection or AIDS.

[0019] The term "alkyl," as used herein, refers to an aliphatic hydrocarbon group having one of its hydrogen atoms replaced with a bond. An alkyl group may be straight or branched and contain from about 1 to about 20 carbon atoms. In one embodiment, an alkyl group contains from about 1 to about 12 carbon atoms. In different embodiments, an alkyl group contains from 1 to 6 carbon atoms (C 1 -C 6 alkyl) or from about 1 to about 4 carbon atoms (C 1 -C 4 alkyl). Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, neopentyl, isopentyl, n-hexyl, isohexyl and neohexyl. In one embodiment, an alkyl group is linear. In another embodiment, an alkyl group is branched. Unless otherwise indicated, an alkyl group is unsubstituted.

[0020] The term "alkenyl, as used herein, refers to an aliphatic hydrocarbon group having at least one carbon to carbon double bond. An alkenyl group may be straight or branched and contain from about 2 to about 10 carbon atoms. In one embodiment, an alenyl group contains from about 2 to about 6 carbon atoms. In different embodiments, an alkenyl group contains from 2 to 3 carbon atoms (C 2 - 3 alkyl). Non-limiting examples of alkenyl groups include ethenyl, propenyl, butenyl, pentenyl and hexenyl. In one embodiment, an alkenyl group is linear. In another embodiment, an alkenyl group is branched. Unless otherwise indicated, an alkenyl group is unsubstituted.

[0021] The term "halo," as used herein, means -F, -Cl, -Br or -I.

[0022] The term "haloalkyl," as used herein, refers to an alkyl group as defined above, wherein one or more of the alkyl group's hydrogen atoms has been replaced with a halogen. In one embodiment, a haloalkyl group has from 1 to 6 carbon atoms. In another embodiment, a haloalkyl group is substituted with from 1 to 3 F atoms. Non-limiting examples of haloalkyl groups include -CH 2 F, -CHF 2 , -CF 3 , -CH 2 Cl and -CCl 3 . The term "C 1 -C 6 haloalkyl" refers to a haloalkyl group having from 1 to 6 carbon atoms.

[0023] The term "cycloalkyl" means a monocyclic or bicyclic saturated aliphatic hydrocarbon group having the specified number of carbon atoms. For example, "cycloalkyl" includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and so on. Bicyclic cycloalkyl ring systems include fused ring systems, where two rings share two atoms, and spiro ring systems, where two rings share one atom.

[0024] The term "heteroaryl", as used herein, represents a stable monocyclic or bicyclic ring system of up to 10 atoms in each ring, wherein at least one ring is aromatic, and at least one ring contains from 1 to 4 heteroatoms selected from the group consisting of O, N and S. Bicyclic heteroaryl ring systems include fused ring systems, where two rings share two atoms, and spiro ring systems, where two rings share one atom. Heteroaryl groups within the scope of this definition include but are not limited to: azaindolyl, benzoimidazolyl, benzisoxazolyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthpyridinyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline, pyranyl, pyrazinyl, pyrazolyl, pyrazolopyrimidinyl, pyridazinyl, pyridopyridinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, tetrazolyl, tetrazolopyridyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, dihydrobenzoimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydroindolyl, dihydroquinolinyl, dihydrobenzodioxinyl, dihydropyrazoloxazinyl, dihydropyrazolyothiazinedioxidyl, methylenedioxybenzene, benzothiazolyl, benzothienyl, quinolinyl, isoquinolinyl, oxazolyl, tetra-hydroquinoline and 3-oxo-3,4dihydro-2N-benzo[b][1,4]thiazine. If the heteroaryl contains nitrogen atoms, it is understood that the corresponding N-oxides thereof are also encompassed by this definition.

[0025] The term "heterocycle" or "heterocyclyl" as used herein is intended to mean a stable nonaromatic monocyclic or bicyclic ring system of up to 10 atoms in each ring, unless otherwise specified, containing from 1 to 4 heteroatoms selected from the group consisting of O, N, S, SO, or SO 2 . Bicyclic heterocyclic ring systems include fused ring systems, where two rings share two atoms, and spiro ring systems, where two rings share one atom. "Heterocyclyl" therefore includes, but is not limited to the following: azaspirononanyl, azaspirooctanyl, azetidinyl, dioxanyl, oxadiazaspirodecenyl, oxaspirooctanyl, oxazolidinonyl, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, tetrahydrofumayl, tetrahydropyranyl, dihydropiperidinyl, tetrahydrothiophenyl and the like. If the heterocycle contains a nitrogen, it is understood that the corresponding N-oxides thereof are also encompassed by this definition.

[0026] "Celite ®< " (Fluka) diatomite is diatomaceous earth, and can be referred to as "celite".

[0027] The term "substituted" means that one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds. By "stable compound' or "stable structure" is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

[0028] The term "in substantially purified form," as used herein, refers to the physical state of a compound after the compound is isolated from a synthetic process (e.g., from a reaction mixture), a natural source, or a combination thereof. The term "in substantially purified form," also refers to the physical state of a compound after the compound is obtained from a purification process or processes described herein or well-known to the skilled artisan (e.g., chromatography, recrystallization and the like), in sufficient purity to be characterizable by standard analytical techniques described herein or well-known to the skilled artisan.

[0029] It should also be noted that any carbon as well as heteroatom with unsatisfied valences in the text, schemes, examples and tables herein is assumed to have the sufficient number of hydrogen atom(s) to satisfy the valences.

[0030] When a functional group in a compound is termed "protected", this means that the group is in modified form to preclude undesired side reactions at the protected site when the compound is subjected to a reaction. Suitable protecting groups will be recognized by those with ordinary skill in the art as well as by reference to standard textbooks such as, for example, T. W. Greene et al, Protective Groups in Organic Synthesis (1991), Wiley, New York.

[0031] When any substituent or variable (e.g., R 4< ) occurs more than one time in any constituent or in Formula I, its definition on each occurrence is independent of its definition at every other occurrence, unless otherwise indicated.

[0032] As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results from combination of the specified ingredients in the specified amounts.

[0033] Prodrugs of the compounds of the invention are disclosed herein but are not according to the claims. A discussion of prodrugs is provided in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems (1987) 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, (1987) Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press. The term "prodrug" means a compound (e.g., a drug precursor) that is transformed in vivo to provide a compound of Formula I or a pharmaceutically acceptable salt of the compound. The transformation may occur by various mechanisms (e.g., by metabolic or chemical processes), such as, for example, through hydrolysis in blood. For example, if a compound of Formula I or a pharmaceutically acceptable salt, hydrate or solvate of the compound contains a carboxylic acid functional group, a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a group such as, for example, (C 1 -C 8 )alkyl, (C 2 -C 12 )alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1-methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, 1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms, 3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl, di-N,N-(C 1 -C 2 )alkylamino(C 2 -C 3 )alkyl (such as β-dimethylaminoethyl), carbamoyl-(C 1 -C 2 )alkyl, N,N-di (C 1 -C 2 )alkylcarbamoyl-(C 1 -C 2 )alkyl and piperidino-, pyrrolidino- or morpholino(C 2 -C 3 )alkyl, and the like.

[0034] Similarly, if a compound of Formula I contains an alcohol functional group, a prodrug can be formed by the replacement of one or more of the hydrogen atoms of the alcohol groups with a group such as, for example, (C 1 -C 6 )alkanoyloxymethyl, 1-((C 1 -C 6 )alkanoyloxy)ethyl, 1-methyl-1-((C 1 -C 6 )alkanoyloxy)ethyl, (C 1 -C 6 )alkoxycarbonyloxymethyl, N-(C 1 -C 6 )alkoxycarbonylaminomethyl, succinoyl, (C 1 -C 6 )alkanoyl, α-amino(C 1 -C 4 )alkyl, α-amino(C 1 -C 4 )alkylene-aryl, arylacyl and α-aminoacyl, or α-aminoacyl-α-aminoacyl, where each α-aminoacyl group is independently selected from the naturally occurring L-amino acids, or glycosyl (the radical resulting from the removal of a hydroxyl group of the hemiacetal form of a carbohydrate).

[0035] If a compound of Formula I incorporates an amine functional group, a prodrug can be formed by the replacement of a hydrogen atom in the amine group with a group such as, for example, R-carbonyl-, RO-carbonyl-, NRR'-carbonyl- wherein R and R' are each independently (C 1 -C 10 )alkyl, (C 3 -C 7 ) cycloalkyl, benzyl, a natural α-aminoacyl, -C(OH)C(O)OY 1< wherein Y 1< is H, (C 1 -C 6 )alkyl or benzyl, -C(OY 2< )Y 3< wherein Y 2< is (C 1 -C 4 ) alkyl and Y 3< is (C 1 -C 6 )alkyl; carboxy (C 1 -C 6 )alkyl; amino(C 1 -C 4 )alkyl or mono-N- or diN,N-(C 1 -C 6 )alkylaminoalkyl; -C(Y 4< )Y 5< wherein Y 4< is H or methyl and Y 5< is mono-N- or di-N,N-(C 1 -C 6 )alkylamino morpholino; piperidin-1-yl or pyrrolidin-1-yl, and the like.

[0036] Pharmaceutically acceptable esters of the present compounds, which are disclosed herein but are not according to the claims, include the following groups: (1) carboxylic acid esters obtained by esterification of the hydroxy group of a hydroxyl compound, in which the non-carbonyl moiety of the carboxylic acid portion of the ester grouping is selected from straight or branched chain alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, t-butyl, sec-butyl or n-butyl), alkoxyalkyl (e.g., methoxymethyl), aralkyl (e.g., benzyl), aryloxyalkyl (for example, phenoxymethyl), aryl (e.g., phenyl optionally substituted with, for example, halogen, C 1-4 alkyl, - O-(C 1-4 alkyl) or amino); (2) sulfonate esters, such as alkyl- or aralkylsulfonyl (for example, methanesulfonyl); (3) amino acid esters, including those corresponding to both natural and non-natural amino acids (e.g., L-valyl or L-isoleucyl); (4) phosphonate esters and (5) mono-, di- or triphosphate esters. The phosphate esters may be further esterified by, for example, a C 1-20 alcohol or reactive derivative thereof, or by a 2,3-di (C 6-24 )acyl glycerol.

[0037] One or more compounds of the invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention embrace both solvated and unsolvated forms. "Solvate" means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. "Solvate" encompasses both solution-phase and isolatable solvates. Non-limiting examples of solvates include ethanolates, methanolates, and the like. A "hydrate" is a solvate wherein the solvent molecule is water.

[0038] One or more compounds of the invention may optionally be converted to a solvate. Preparation of solvates is generally known. Thus, for example, M. Caira et al, J. Pharmaceutical Sci., 93(3), 601-611 (2004) describe the preparation of the solvates of the antifungal fluconazole in ethyl acetate as well as from water. Similar preparations of solvates, hemisolvates, hydrates and the like are described by E. C. van Tonder et al, AAPS PharmSciTech., 5(1), article 12 (2004); and A. L. Bingham et al, Chem. Commun., 603-604 (2001). A typical, non-limiting, process involves dissolving the inventive compound in desired amounts of the desired solvent (organic or water or mixtures thereof) at a higher than room temperature, and cooling the solution at a rate sufficient to form crystals which are then isolated by standard methods. Analytical techniques such as, for example IR spectroscopy, show the presence of the solvent (or water) in the crystals as a solvate (or hydrate).

[0039] The compound of Formula I can form salts which are also within the scope of this invention. Reference to a compound of Formula I herein is understood to include reference to salts thereof, unless otherwise indicated. The term "salt(s)", as employed herein, denotes acidic salts formed with inorganic and / or organic acids, as well as basic salts formed with inorganic and / or organic bases. In addition, when a compound of Formula I contains both a basic moiety, such as, but not limited to a pyridine or imidazole, and an acidic moiety, such as, but not limited to a carboxylic acid, zwitterions ("inner salts") may be formed and are included within the term "salt(s)" as used herein. In one embodiment, the salt is a pharmaceutically acceptable (i.e., nontoxic, physiologically acceptable) salt. In another embodiment, the salt is other than a pharmaceutically acceptable salt. Salts of the Compounds of Formula I may be formed, for example, by reacting a compound of Formula I with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.

[0040] Exemplary acid addition salts include acetates, ascorbates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, fumarates, hydrochlorides, hydrobromides, hydroiodides, lactates, maleates, methanesulfonates, naphthalenesulfonates, nitrates, oxalates, phosphates, propionates, salicylates, succinates, sulfates, tartarates, thiocyanates, toluenesulfonates (also known as tosylates) and the like. Additionally, acids which are generally considered suitable for the formation of pharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example, by P. Stahl et al, Camille G. (eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley-VCH; S. Berge et al, Journal of Pharmaceutical Sciences (1977) 66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33 201-217; Anderson et al, The Practice of Medicinal Chemistry (1996), Academic Press, New York; and in The Orange Book (Food & Drug Administration, Washington, D.C. on their website).

[0041] Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as dicyclohexylamine, t-butyl amine, choline, and salts with amino acids such as arginine, lysine and the like. Basic nitrogen-containing groups may be quartemized with agents such as lower alkyl halides (e.g., methyl, ethyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, and dibutyl sulfates), long chain halides (e.g., decyl, lauryl, and stearyl chlorides, bromides and iodides), arylalkyl halides (e.g., benzyl and phenethyl bromides), and others.

[0042] All such acid salts and base salts are intended to be pharmaceutically acceptable salts within the scope of the invention and all acid and base salts are considered equivalent to the free forms of the corresponding compounds for purposes of the invention.

[0043] Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well-known to those skilled in the art, such as, for example, by chromatography and / or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. Sterochemically pure compounds may also be prepared by using chiral starting materials or by employing salt resolution techniques. Also, some of the compound of Formula I may be atropisomers (e.g., substituted biaryls) and are considered as part of this invention. Enantiomers can also be directly separated using chiral chromatographic techniques.

[0044] It is also possible that the compound of Formula I may exist in different tautomeric forms, and all such forms are embraced within the scope of the invention. For example, all keto-enol and imine-enamine forms of the compounds are included in the invention.

[0045] Unless otherwise indicated, all stereoisomers (for example, geometric isomers, optical isomers and the like) of the present compounds (including those of the salts, solvates, hydrates, esters and prodrugs of the compounds as well as the salts, solvates and esters of the prodrugs), such as those which may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this invention. If a compound of Formula I incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the invention.

[0046] When a subsituent on a chiral carbon atom is depicted without specific stereochemistry (by using a straight line bond to a chiral center), it is to be understood that both the alpha and beta configurations of said subtituent group are to be considered part of the present invention. For example, the compound of the present invention, which is drawn as follows: is understood to encompass both stereoisomers at the indicated chiral center, the structures of which are as follows: and

[0047] In the Examples section below, compounds of the present invention that have been purified as individual stereoisomers are sometimes depicted in non-stereospecific form but identifed using one or more of the terms: "diastereomer 1," "diastereomer 2," "isomer 1," "isomer 2," "enantiomer A" and "enantiomer B." In this instance, the absolute stereochemistry of each isolated diastereomer and enantiomeric center has not been determined and the terms used above are used to represent each individual purified stereochemically pure compound.

[0048] Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers. The chiral centers of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations. The use of the terms "salt" and "solvate", are intended to apply equally to the salt and solvate of enantiomers, stereoisomers, rotamers, tautomers, racemates or prodrugs of the inventive compounds.

[0049] In the Compounds of Formula I, the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. The present invention is meant to include all suitable isotopic variations of the compounds of generic Formula I. For example, different isotopic forms of hydrogen (H) include protium ( 1< H) and deuterium ( 2< H). Protium is the predominant hydrogen isotope found in nature. Enriching for deuterium may provide certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples. Isotopically-enriched Compounds of Formula I can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein using appropriate isotopically-enriched reagents and / or intermediates. In one embodiment, a Compound of Formula I has one or more of its hydrogen atoms replaced with deuterium.

[0050] The compounds of Formula I may be useful in human and veterinary medicine for treating or preventing HIV infection in a subject. In one embodiment, the compounds of Formula I can be inhibitors of HIV viral replication. In a specific embodiment, the compound of Formula I are inhibitors of HIV-1. Accordingly, the compounds of Formula I may be useful for treating HIV infections and AIDS. In accordance with the invention, the compounds of Formula I can be administered to a subject in need of treatment or prevention of HIV infection.

[0051] Accordingly, in one embodiment, the invention provides methods for treating HIV infection in a subject comprising administering to the subject an effective amount of at least one compound of Formula I or a pharmaceutically acceptable salt thereof. In a specific embodiment, the present invention provides methods for treating AIDS in a subject comprising administering to the subject an effective amount of at least one compound of Formula I or a pharmaceutically acceptable salt thereof.The Compounds of Formula I

[0052] The present invention provides Compounds of Formula I: wherein is a five-membered heteroaryl ring which is optionally substituted with halo, cyano or C 1-3 alkyl; is selected from isoxazolyl, oxazolyl or thiazolyl which is optionally substituted with C 1-3 alkyl; R 1< is phenyl or heteroaryl, which may be monocyclic or bicyclic, wherein said phenyl and heteroaryl groups are optionally substituted with one to three groups independently selected from the group consisting of halo, oxo, cyano, R 4< , R 6< , OR 4< , OR 6< and SO 2 R 4< ; R 2< is selected from the group consisting of NH 2 , NHR 4< , NHR 6< , and NHCH 2 R 6< ; R 3< is selected from hydrogen or C 1-6 alkyl; or R 2< and R 3< can be taken together with the atoms to which they are attached to form a 5, 6 or 7 membered heterocyclyl group which is optionally substituted with oxo; each R 4< is independently hydrogen or C 1-6 alkyl, which is optionally substituted with one to three halo; each R 5< is independently hydrogen or C 1-6 alkyl, which is optionally substituted with N(R 4< ) 2 or OR 4< ; R 6< is (a) heterocyclyl, which may be monocyclic or bicyclic, (b) C 3-6 cycloalkyl, (c) phenyl, or (d) heteroaryl, which may be monocyclic or bicyclic, wherein said heterocyclyl, cycloalkyl, phenyl and heteroaryl groups are optionally substituted with one to two groups independently selected from the group of oxo, R 5< , OR 4< and heteroaryl; R a< is hydrogen or halo; R d< is hydrogen or halo; or a pharmaceutically acceptable salt thereof.

[0053] In an embodiment, is selected from imidazolyl. In another embodiment of the invention, is isoxazolyl. In another class of the embodiment, is oxadiazolyl. In another class of the embodiment, is oxazolyl. In another class of the embodiment, is pyrazolyl. In another embodiment of the invention, is triazolyl.

[0054] In an embodiment of the invention, is isoxazolyl, oxazolyl or thiazolyl, wherein said groups are optionally substituted with C 1-3 alkyl. In a class of the embodiment, is isoxazolyl. In another class of the embodiment, is oxazolyl. In another class of the embodiment, is thiazolyl.

[0055] In an embodiment of the invention, R 1< is dishydroisoquinolinyl, imidazolyl, isoquinolinyl, napthyridinyl, phenyl, pyrazinyl, pyridinyl, quinolinyl or quinoxalinyl, wherein said groups are optionally substituted with one to three groups optionally selected from the group consisting of halo, oxo, cyano, R 4< , R 6< , OR 4< , OR 6< and SO 2 R 4< .

[0056] In an embodiment of the invention, R 2< is NH 2 .

[0057] In an embodiment of the invention, R 3< is hydrogen.

[0058] In an embodiment of the invention, R a< is hydrogen.

[0059] In an embodiment of the invention, R d< is hydrogen.

[0060] In another embodiment, the Compounds of Formula I are in substantially purified form.

[0061] It is to be understood that any of the aforementioned embodiments may be combined with one or more separate embodiments.

[0062] Other embodiments of the present invention include the following: (a) A pharmaceutical composition comprising an effective amount of a Compound of Formula I, and a pharmaceutically acceptable carrier. (b) The pharmaceutical composition of (a), further comprising a second therapeutic agent selected from the group consisting of HIV antiviral agents, immunomodulators, anti-infective agents, vaccines, and antibodies. (c) The pharmaceutical composition of (b), wherein the HIV antiviral agent is an antiviral selected from the group consisting of HIV protease inhibitors, HIV integrase inhibitors and HIV NNRTI inhibitors. (d) A pharmaceutical combination that is (i) a Compound of Formula I and (ii) a second therapeutic agent selected from the group consisting of HIV antiviral agents, immunomodulators, and anti-infective agents, vaccines, and antibodies; wherein the Compound of Formula I and the second therapeutic agent are each employed in an amount that renders the combination effective for inhibiting HIV replication, or for treating HIV infection and / or reducing the likelihood or severity of symptoms of HIV infection, and eradicates HIV infection. (e) The combination of (d), wherein the HIV antiviral agent is an antiviral selected from the group consisting of HIV protease inhibitors, HIV integrase inhibitors and HIV NNRTI inhibitors. (f) A method of inhibiting HIV replication in a subject in need thereof which comprises administering to the subject an effective amount of a Compound of Formula I. (g) A method of treating HIV infection and / or reducing the likelihood or severity of symptoms of HIV infection in a subject in need thereof which comprises administering to the subject an effective amount of a Compound of Formula I. (h) The method of (g), wherein the Compound of Formula I is administered in combination with an effective amount of at least one second therapeutic agent selected from the group consisting of HIV antiviral agents, immunomodulators, and anti-infective agents. (i) The method of (h), wherein the HIV antiviral agent is an antiviral selected from the group consisting of HIV protease inhibitors, HIV integrase inhibitors and HIV NNRTI inhibitors. (j) A method of inhibiting HIV replication in a subject in need thereof which comprises administering to the subject the pharmaceutical composition of (a), (b) or (c) or the combination of (d) or (e). (k) A method of treating HIV infection and / or reducing the likelihood or severity of symptoms of HIV infection in a subject in need thereof which comprises administering to the subject the pharmaceutical composition of (a), (b) or (c) or the combination of (d) or (e).

[0063] Additional embodiments of the present invention include the following: (l) A pharmaceutical composition comprising an effective amount of a pharmaceutically acceptable salt of a Compound of Formula I, and a pharmaceutically acceptable carrier. (m) The pharmaceutical composition of (l), further comprising a second therapeutic agent selected from the group consisting of HIV antiviral agents, immunomodulators, anti-infective agents, vaccines and antibodies. (n) The pharmaceutical composition of (m), wherein the HIV antiviral agent is an antiviral selected from the group consisting of HIV protease inhibitors and HIV NNRTI inhibitors. (o) A pharmaceutical combination that is (i) a pharmaceutically acceptable salt of a Compound of Formula I and (ii) a second therapeutic agent selected from the group consisting of HIV antiviral agents, immunomodulators, and anti-infective agents; wherein the pharmaceutically acceptable salt of the Compound of Formula I and the second therapeutic agent are each employed in an amount that renders the combination effective for inhibiting HIV replication, or for treating HIV infection and / or reducing the likelihood or severity of symptoms of HIV infection. (p) The combination of (o), wherein the HIV antiviral agent is an antiviral selected from the group consisting of HIV protease inhibitors and HIV NNRTI inhibitors. (q) A method of inhibiting HIV replication in a subject in need thereof which comprises administering to the subject an effective amount of a pharmaceutically acceptable salt of a Compound of Formula I. (r) A method of treating HIV infection and / or reducing the likelihood or severity of symptoms of HIV infection in a subject in need thereof which comprises administering to the subject an effective amount of a pharmaceutically acceptable salt of a Compound of Formula I. (s) The method of (r), wherein the pharmaceutically acceptable salt of the Compound of Formula I is administered in combination with an effective amount of at least one second therapeutic agent selected from the group consisting of HIV antiviral agents, immunomodulators, and anti-infective agents. (t) The method of (s), wherein the HIV antiviral agent is an antiviral selected from the group consisting of HIV protease inhibitors and HIV NS5B polymerase inhibitors. (u) A method of inhibiting HIV replication in a subject in need thereof which comprises administering to the subject the pharmaceutical composition of (l), (m) or (n) or the combination of (o) or (p). (v) A method of treating HIV infection and / or reducing the likelihood or severity of symptoms of HIV infection in a subject in need thereof which comprises administering to the subject the pharmaceutical composition of (l), (m) or (n) or the combination of (o) or (p).

[0064] Further embodiments of the present invention include the following: (w) A pharmaceutical composition comprising an effective amount of a Compound of Formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. (x) The pharmaceutical composition of (w), further comprising a second therapeutic agent selected from the group consisting of HIV antiviral agents, immunomodulators, and anti-infective agents. (y) The pharmaceutical composition of (x), wherein the HIV antiviral agent is an antiviral selected from the group consisting of HIV protease inhibitors and HIV NNRTI inhibitors. (z) A pharmaceutical combination that is (i) a Compound of Formula I and (ii) or a pharmaceutically acceptable salt thereof, a second therapeutic agent selected from the group consisting of HIV antiviral agents, immunomodulators, and anti-infective agents; wherein the Compound of Formula I and the second therapeutic agent are each employed in an amount that renders the combination effective for inhibiting HIV replication, or for treating HIV infection and / or reducing the likelihood or severity of symptoms of HIV infection. (aa) The combination of (z), wherein the HIV antiviral agent is an antiviral selected from the group consisting of HIV protease inhibitors and HIV NNRTI inhibitors. (bb) A method of inhibiting HIV replication in a subject in need thereof which comprises administering to the subject an effective amount of a Compound of Formula I or a pharmaceutically acceptable salt thereof. (cc) A method of treating HIV infection and / or reducing the likelihood or severity of symptoms of HIV infection in a subject in need thereof which comprises administering to the subject an effective amount of a Compound of Formula I or a pharmaceutically acceptable salt thereof. (dd) The method of (cc), wherein the Compound of Formula I or pharmaceutically acceptable salt thereof, is administered in combination with an effective amount of at least one second therapeutic agent selected from the group consisting of HIV antiviral agents, immunomodulators, and anti-infective agents. (ee) The method of (dd), wherein the HIV antiviral agent is an antiviral selected from the group consisting of HIV protease inhibitors and HIV NNRTI inhibitors. (ff) A method of inhibiting HIV replication in a subject in need thereof which comprises administering to the subject the pharmaceutical composition of (w), (x) or (y) or the combination of (z) or (aa). (gg) A method of treating HIV infection and / or reducing the likelihood or severity of symptoms of HIV infection in a subject in need thereof which comprises administering to the subject the pharmaceutical composition of (w), (x) or (y) or the combination of (z) or (aa).

[0065] The present invention also includes a compound of the present invention for use I in, (ii) as a medicament for, or (iii) in the preparation of a medicament for: (a) medicine; (b) inhibiting HIV replication or (c) treating HIV infection and / or reducing the likelihood or severity of symptoms of HIV infection. In these uses, the compounds of the present invention can optionally be employed in combination with one or more second therapeutic agents selected from HIV antiviral agents, anti-infective agents, and immunomodulators.

[0066] Additional embodiments of the invention include the pharmaceutical compositions, combinations and methods set forth in (a)-(gg) above and the uses set forth in the preceding paragraph, wherein the compound of the present invention employed therein is a compound of one of the embodiments, aspects, classes, sub-classes, or features of the compounds described above. In all of these embodiments, the compound may optionally be used in the form of a pharmaceutically acceptable salt or hydrate as appropriate.

[0067] It is further to be understood that the embodiments of compositions and methods provided as (a) through (gg) above are understood to include all embodiments of the compounds, including such embodiments as result from combinations of embodiments.

[0068] Non-limiting examples of the Compounds of Formula I include compounds 1-196 as set forth in the Examples below, and pharmaceutically acceptable salts thereof, excluding any compounds that are labelled as reference examples.Methods For Making the Compounds of Formula I

[0069] The Compounds of Formula I may be prepared from known or readily prepared starting materials, following methods known to one skilled in the art of organic synthesis. Methods useful for making the Compounds of Formula I are set forth in the Examples below and generalized in the Schemes below. Alternative synthetic pathways and analogous structures will be apparent to those skilled in the art of organic synthesis.General List of Abbreviations

[0070] Abbreviations and acronyms employed herein include the following: AcAcetylAqAqueousACNAcetonitrileAIBNAzobisisobutyronitrileAUCArea under the curveBASTBis(2-methoxyethyl)aminosulfur trifluorideBOCtert-butyloxycarbonylBuButylBzBenzoylCDICarbonyldiimidazoleDBDMH1,3-Dibromo-5,5-dimethylhydantoinDCMDichloromethaneDCE1,2-DichloroethaneDHP3,4-dihydro-2H-pyranDIBAL-HDiisobutylaluminium hydrideDIEA, DIPEA or Hünig's baseN,N-diisopropylethylamineDMAP4-dimethylaminopyridineDMEdimethyoxyethaneDMFdimethylformamideDMPDess-Martin periodinaneDppf1,1'-Bis(diphenylphosphino)ferroceneDMSOdimethyl sulfoxideDTBPF1,1'-bis(di-tert-butylphosphino)ferroceneEAEthyl AcetateEDCIN-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochlorideEtEthylEtOHEthanolEtOAcethyl acetateGGramsGIGastrointenstinalHHourHATU1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphateHIVhuman immunodeficiency virusHOBT, HOBt1-Hydroxybenzotriazole hydrateHPBCDhydroxypropyl β-cyclodextrinHPLChigh-performance liquid chromatographymCPBA, CPBAmeta-ChloroperoxybenzoicHzHertzIPAIsopropanolIVIntravenousiPrIsopropylIr[dF(CF 3 )ppy] 2 (dtbpy)PF 6 [4,4'-Bis(1,1-dimethylethyl)-2,2'-bipyridine-N1,N1']bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-N]phenyl-C]Iridium(III) hexafluorophosphateLLiterLCliquid chromatographyLC / MSliquid chromatography mass spectrometryLEDlight-emitting diodeLiHMDSlithium bis(trimethylsilyl)amideMeMethylMeOHMethanolMgMilligramsMHzMegahertzMinMinuteµLMicrolitersmLMillilitersMmolMillimolesMOM-Clchloromethyl methyl etherMPLCmedium pressure liquid chromatographyMSmass spectrometryNBSN-BromosuccinimideNCSN-ChlorosuccinimideNHSnormal human serumNISN-IodosuccinimideNMO4-methylmorpholine N-oxideNMRnuclear magnetic resonance spectroscopyPBMCperipheral blood mononuclear cellPd 2 (dba) 3 Tris(dibenzylideneacetone)dipalladium(0)PhPhenylP.O.OralPPTSPyridinium p-toluenesulfonatePTSApara-toluenesulfonic acidPrPropylRpmrevolutions per minuteRT or rtroom temperature (ambient, about 25 °C)sat or sat'dSaturatedSEMCl2-Chloromethoxyethyl)trimethylsilaneSFCsupercritical fluid chromatographyT3P, T 3 P1-Propanephosphonic anhydride solutionTBAFTetra-n-butylammonium fluorideTBDPSCltert-ButyldiphenylchlorosilaneTBSCltert-Butyldimethylsilyl chloridetButert-butylTEAtriethylamine (Et 3 N)TEMEDTetramethylethylenediamineTFAtrifluoroacetic acidTFVTenofovirTFV-MPTenofovir monophosphoateTFV-DPTenofovir diphosphateTHFTetrahydrofuranTMSTetramethylsilaneTosMICToluenesulfonylmethyl isocyanideTPAPTetrapropylammonium perruthenateTsTosylUPLCultrahigh pressure liquid chromatographyUVUltravioletUV / VISultraviolet / visibleWWattXPhos2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl General Procedures

[0071] Starting materials and intermediates are purchased or are made using known procedures, or as otherwise illustrated. The general route applied to the synthesis of compounds of Formula I is described in the Schemes that follows. In some cases the order of carrying out the reaction steps in the schemes may be varied to facilitate the reaction or to avoid unwanted reaction products.

[0072] Reactions sensitive to moisture or air were performed under nitrogen or argon using anhydrous solvents and reagents. The progress of reactions was determined by either analytical thin layer chromatography (TLC) usually performed with E. Merck pre-coated TLC plates, silica gel 60F-254, layer thickness 0.25 mm or liquid chromatography-mass spectrometry (LC / MS).

[0073] Typically the analytical LC-MS system used consisted of a Waters ZQ ™< platform with electrospray ionization in positive ion detection mode with an Agilent 1100 series HPLC with autosampler. The column was commonly a Waters Xterra MS C18, 3.0 × 50 mm, 5 µm or a Waters Acquity UPLC ®< BEH C18 1.0 x 50 mm, 1.7 µm. The flow rate was 1 mL / min, and the injection volume was 10 µL. UV detection was in the range 210-400 nm. The mobile phase consisted of solvent A (water plus 0.05% TFA) and solvent B (MeCN plus 0.05% TFA) with a gradient of 100% solvent A for 0.7 min changing to 100% solvent B over 3.75 min, maintained for 1.1 min, then reverting to 100% solvent A over 0.2 min. Altematively, the column was commonly a Waters Acquity UPLC ®< BEH C18 1.0 X 50 mm, 1.7 µm. The flow rate was 0.3 mL / min, and the injection volume was 0.5 µL. UV detection was 215 or 254 nm. Either the mobile phase consisted of solvent A (water plus 0.05% TFA) and solvent B (MeCN plus 0.05% TFA) with a gradient of 90% solvent A changing to 99% solvent B over 1.6 min, maintained for 0.4 min, then reverting to 90% solvent A over 0.1 min or the mobile phase consisted of solvent A (water plus 0.05% TFA) and solvent B (MeCN plus 0.05% TFA) with a gradient of 97% solvent A changing to 4% then 50% solvent B over 0.5 min and 0.9 min, 50%-99% solvent B over 0.2 min, maintained for 0.4 min, then reverting to 90% solvent A over 0.1 min.

[0074] Preparative HPLC purifications were usually performed using either a mass spectrometry directed system or a non-mass guided system. Usually they were performed on a Waters Chromatography Workstation configured with LC-MS System consisting of: Waters ZQ ™< single quad MS system with Electrospray Ionization, Waters 2525 Gradient Pump, Waters 2767 Injecto / Collector, Waters 996 PDA Detector, the MS Conditions of: 150-750 amu, Positive Electrospray, Collection Triggered by MS, and a Waters SUNFIRE ®< C-18 5 micron, 30 mm (id) × 100 mm column. The mobile phases consisted of mixtures of acetonitrile (10-100%) in water containing 0.1% TFA. Flow rates were maintained at 50 mL / min, the injection volume was 1800 µL, and the UV detection range was 210-400 nm. An alternate preparative HPLC system used was a Gilson Workstation consisting of: Gilson GX-281 Injector / Collector, Gilson UV / VIS-155 Detector, Gilson 322, 333, and 334 Pumps, and a Phenomenex Gemini-NX C-18 5 micron, 50 mm (id) × 250 mm column, a Waters XBridge ™< C-18 5 micron OBD ™< , 30 mm (id) × 250 mm column, or a Waters SUNFIRE ™< C-18 OBD ™< 10 micron, 30 mm (id) × 150 mm column. The mobile phases consisted of mixtures of acetonitrile (0-90%) in water containing 0.1% or 0.05% TFA. Flow rates were maintained at 50 mL / min for the Waters Xbridge ™< column, 90 mL / min for the Phenomenex Gemini column, and 30 mL / min for the Waters SUNFIRE ™< column. The injection volume ranged from 1000-8000 µL, and the UV detection range was 210-400 nm. Mobile phase gradients were optimized for the individual compounds. Reactions performed using microwave irradiation were normally carried out using an Emrys Optimizer manufactured by Personal Chemistry, or an Initiator manufactured by Biotage. Reactions performed using photon irradiation were normally carried out using either a second generation Merck photoreactor or a Kessil 34 W blue LED lamp. Concentration of solutions was carried out on a rotary evaporator under reduced pressure. Flash chromatography was usually performed using either a Biotage ®< Flash Chromatography apparatus (Dyax Corp.), an ISCO CombiFlash ®< Rf apparatus, or an ISCO CombiFlash ®< Companion XL on silica gel (32-63 microns, 60 Å pore size) in pre-packed cartridges of the size noted. 1< H NMR spectra were acquired at 500 MHz spectrometers in CDCl 3 solutions unless otherwise noted. Chemical shifts were reported in parts per million (ppm). Tetramethylsilane (TMS) was used as internal reference in CDCl 3 solutions, and residual CH 3 OH peak or TMS was used as internal reference in CD 3 OD solutions. Coupling constants (J) were reported in hertz (Hz). Chiral analytical chromatography was most commonly performed on one of CHIRALPAK ®< AS, CHIRALPAK ®< AD, CHIRALCEL ®< OD, CHIRALCEL ®< IA, or CHIRALCEL ®< OJ columns (250 × 4.6 mm) (Daicel Chemical Industries, Ltd.) with noted percentage of ethanol in hexane (%EtOH / Hex), isopropanol in heptane (%IPA / Hep), ethanol in carbon dioxide (% EtOH / CO 2 ), or isopropanol in carbon dioxide (%IPA / CO 2 ) as isocratic solvent systems. Chiral preparative chromatography was conducted on one of CHIRALPAK AS, of CHIRALPAK AD, CHIRALCEL ®< OD, CHIRALCEL ®< IA, CHIRALCEL ®< OJ columns (20 × 250 mm) (Daicel Chemical Industries, Ltd.) with desired isocratic solvent systems identified on chiral analytical chromatography or by supercritical fluid (SFC) conditions.

[0075] Several catalysts are used in the following procedures. "UMICORE M71 SIPR" is also known as Umicore Hoveyda Grubbs Catalyst M71 SIPr" and [1,3-Bis(2,6-diisopropylphenyl)-2-imidazolidinylidene]dichloro[(2-isopropoxy)(5-trifluoroacetamido)benzylidene]ruthenium(II). It is available from Umicore Precious Metals Chemistry USA, LLC, 1305 Main Parkway Catoosa, OK 74015. "Zhan's catalyst" is available from Sigma Aldrich.

[0076] Several methods for preparing the compounds of this invention are also described in the Examples. Starting materials and intermediates were purchased commercially from common catalog sources or were made using known procedures, or as otherwise illustrated. Step 1: Preparation of N-methoxy-N-methylpent-4-enamide (1_2)

[0077] Oxalyl chloride (5.25 ml, 59.9 mmol) was added to the solution of DMF (0.046 ml, 0.599 mmol) and pent-4-enoic acid (1_1, 3.00 g, 30.0 mmol) in DCM (50 ml), the resultant mixture was stirred at 25°C for 2 h. The reaction mixture was poured to a stirred solution of N,O-dimethylhydroxylamine hydrochloride (9.75 g, 0.10 mol) in water (30 mL) at 0°C, and stirred for 1 h. The reaction mixture was separated and the organic layer was washed with brine (30 mL) and dried. The solvent was removed in vacuo to give N-methoxy-N-methylpent-4-enamide (1_2) which was used to the next step without further purification. 1< H NMR (400 MHz, CDCl 3 ) δ 5.86 (m, 1H), 5.06 (d, J= 19.6 Hz, 1H), 4.98 (d, J= 10.0 Hz, 1H), 3.8 (s, 3H), 3.17 (s, 3H), 2.46-2.60 (m, 2H), 2.35-2.40 (m, 2H).Step 2: Preparation of 1-(oxazol-2-yl)pent-4-en-1-one (1)

[0078] To a solution of oxazole (0.904 g, 13.10 mmol) in THF (15 ml) was added drop wise isopropylmagnesium chloride (6.55 ml, 13.10 mmol) at -15°C. The resultant mixture was stirred at -15°C for 40 min, then a solution of N-methoxy-N-methylpent-4-enamide (1_2, 1.50 g, 10.48 mmol) in THF (5 mL) was added to the reaction mixture, and stirred at room temperature for 16 h. The mixture was quenched with aqueous NH 4 Cl (saturated, 10 mL), and the mixture was extracted with ethyl acetate (15 x 2 mL). The combined organic fractions were washed with brine (saturated, 10 mL), dried (Na 2 SO 4 ), filtered and the solvent was evaporated under reduced pressure. The residue was purified by silica gel flash chromatography (ISCORF75; Sepa flash column), eluting with petroleum ether / EtOAc = 20:1-5:1 to give 1-(oxazol-2-yl)pent-4-en-1-one (1). 1< H NMR (400 MHz, CDCl 3 ) δ 7.76 (s, 1H), 7.27 (s, 1H), 5.81 (m, 1H), 4.90-5.08 (m, 2H), 3.13 (t, J = 7.43 Hz, 3H), 2.45 (q, J = 6.78 Hz, 3H). Step 1: Preparation of N-methoxy-N-methylisoxazole-3-carboxamide (2 2)

[0079] HOBt (4.5 g, 29.4 mmol) and EDCI (5.4 g, 28.2 mmol) were added to solution of isoxazole-3-carboxylic acid (2_1, 3 g, 26.5 mmol) and N,O-dimethylhydroxylamine hydrochloride (2.7 g, 27.7 mmol) in DMF (5 ml) and DCM (7ml). 4-methylmorpholine (3 ml, 27.3 mmol) was added, then the mixture was stirred overnight. It was extracted with ether (300 ml) and brine (100 ml), the organic layer was separated, it was washed with brine, dried over Na 2 SO 4 , then filtered and the solvent was evaporated. The residue was purified by chromatography (Redisep 40 g column) eluting with 1 / 1 EtOAc / Hexanes yielding N-methoxy-N-methylisoxazole-3-carboxamide (2_2). LCMS (ESI) calc'd for C 6 H 8 N 2 O 3 [M+H] +< : 157.1, found: 157.1Step 2: Preparation of 1-(isoxazol-3-yl)pent-4-en-1-one (2)

[0080] But-3-en-1-ylmagnesium bromide (50 ml, 25.00 mmol) was added to solution of N-methoxy-N-methylisoxazole-3-carboxamide (2_2, 3 g, 19.21 mmol) in THF (15 ml) at rt, and it was stirred at 60°C for 3 h. It was cooled to room temperature, sat. NH 4 Cl (2 ml) was added, then it was extracted with EtOAc (250 ml) and water (100 ml). The organic layer was separated, it was washed with brine, dried over Na 2 SO 4 , then filtered and the solvent was evaporated. The residue was purified by chromatography (Redisep 40 g column) eluting with 20% EtOAc-Hexanes yielding 1-(isoxazol-3-yl)pent-4-en-1-one (2). LCMS (ESI) calc'd for C 8 H 9 NO 2 [M+H] +< : 152.1, found: 152.1 Step 1: (S)-2-(2-fluorophenyl)-2-oxoethyl 2-((tert-butoxycarbonyl)amino)pent-4-enoate

[0081] A 250 ml one neck round bottom flask was charged with (S)-2-((tert-butoxycarbonyl)amino)pent-4-enoic acid (1.60 g, 7.43 mmol) along with cesium carbonate (1.695 g, 5.20 mmol) and DMF (15 ml). The mixture was stirred and 2-bromo-1-(2-fluorophenyl)ethanone (1.694 g, 7.81 mmol) was added, and the resulting reaction mixture was stirred at room temperature for 2 hrs. The mixture was diluted with ethyl acetate (40 mL), the solid was filtered and washed with ethyl acetate (3x). The filtrate was then concentrated and the crude was purified by MPLC (40 g solica gel, 0 to 40% ethyl acetate in hexanes, 18 CV) to afford white solid product (S)-2-(2-fluorophenyl)-2-oxoethyl 2-((tert-butoxycarbonyl)amino)pent-4-enoate. LC-MS: [M+H] +< = 352.0.Step 2: (S)-tert-butyl (1-(5-(2-fluorophenyl)-1H-imidazol-2-yl)but-3-en-1-yl)carbamate

[0082] A 100 ml one neck round bottom flask was charged with (S)-2-(2-fluorophenyl)-2-oxoethyl 2-((tert-butoxycarbonyl)amino)pent-4-enoate (2.60 g, 7.40 mmol) along with ammonium acetate (5.70 g, 74.0 mmol) in toluene (20 ml). The mixture was then stirred and heated in an oil bath at 110°C for 3 hrs. After it was cooled to room temperature, the mixture was diluted with ethyl acetate (100 mL), washed with NaHCO 3 (sat, 30 mL), water, dried over MgSO 4 , filtered and concentrated to afford (S)-tert-butyl (1-(5-(2-fluorophenyl)-1H-imidazol-2-yl)but-3-en-1-yl)carbamate which is used directly to next step without further purification. LC-MS: [M+H] +< = 332.0.Step 3: (S)-tert-butyl 2-(1-((tert-butoxycarbonyl)amino)but-3-en-1-yl)-4-(2-fluorophenyl)-1H-imidazole-1-carboxylate

[0083] A round bottom flask was charged with (S)-tert-butyl (1-(5-(2-fluorophenyl)-1H-imidazol-2-yl)but-3-en-1-yl)carbamate (2.452 g, 7.40 mmol) along with DMAP (0.045 g, 0.370 mmol) in CH 2 Cl 2 (20 ml). The mixture was stirred while di-tert-butyl dicarbonate (1.696 g, 7.77 mmol) was added in one portion. The resulting reaction mixture was then stirred at room temperature for 3 hrs. The mixture was then concentrated and the crude was purified by MPLC (80 g silica gel, 0 to 30% ethyl acetate in hexanes, 18 CV) to afford the product (S)-tert-butyl 2-(1-((tert-butoxycarbonyl)amino)but-3-en-1-yl)-4-(2-fluorophenyl)-1H-imidazole-1-carboxylate. LC-MS: [M+H] +< = 432.0.Intermediate 4tert-butyl (S)-2-(1-((tert-butoxycarbonyl)amino)but-3-en-1-yl)-4-(4-fluorophenyl)-1H-imidazole-1-carboxylate

[0084]

[0085] Using similar chemistry as the preparation of intermediate 3, starting with 2-bromo-1-(4-fluorophenyl)ethanone, the intermediate 4 tert-butyl (S)-2-(1-((tert-butoxycarbonyl)amino)but-3-en-1-yl)-4-(4-fluorophenyl)-1H-imidazole-1-carboxylate (4) can be prepared. Step 1: Preparation of 2,4,5-tribromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (5 2)

[0086] A dried 500 mL round bottom flask was charged with 2,4,5-tribromoimidazole (5_1, 20.0 g, 65.6 mmol) and anhydrous DMF (100 mL), and the resulting solution was cooled to 0°C. To this cold solution was added NaH (60% in mineral oil, 2.80 g, 70.0 mmol) portionwise with gas evolution under control and an internal temperature maintained below 10°C. After addition, the cold bath was removed and the resulting mixture was stirred at ambient temperature for 30 minutes. The reaction mixture was cooled back to 0°C, and SEMCl (12.2 mL, 69.5 mmol) was added to the reaction via syringe pump over 30 minutes. The reaction was stirred at 0°C for an additional 30 minutes and at room temperature for another 30 minutes. The mixture was partitioned between EtOAc (150 mL) and water (300 mL), the organic phase was washed with dilute aqueous NaCl (5percent w / w) twice, then brine (100 mL), dried (Na 2 SO 4 ), and concentrated. The crude material was re-crystallized from hot petroleum ether (30 mL) and the solids were harvested from the mother liquor at 0°C. The product was washed with cold petroleum ether (30 mL) and dried under vacuum to afford 2,4,5-tribromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (5_2). 1< H NMR (400 MHz, CDCl 3 ) δ 5.31 (s, 2H), 3.59 (t, J = 7.2 Hz, 2H), 0.92 (t, J = 7.2 Hz, 2H), -0.01 (s, 9H).Step 2: Preparation of 4,5-dibromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-2-carbaldehyde (5 3)

[0087] To a cooled (-78°C) solution of 2,4,5-tribromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (5_2, 16 g, 0.03 mol) in THF (160 mL) was added a solution of n-BuLi (13.5 mL, 3 M in hexane; 0.04 mol) dropwise. After 1 h, DMF (14 mL, 0.2 mol) was added dropwise. After 1 h, the reaction was quenched with saturated ammonium chloride solution and then the reaction was allowed to warm to rt. The reaction was extracted with ethyl acetate (2 x 100 mL). The organic layers were combined and washed with 10 percent sodium bicarbonate solution, water, brine and then concentrated. The residue was purified by flash chromatography (gradient elution pet ether: ethyl acetate) gave 4,5-dibromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-2-carbaldehyde (5_3).Step 3: Preparation of (S,Z)-N-((4,5-dibromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methylene)-2-methylpropane-2-sulfinamide (5_4)

[0088] To a solution of 4,5-dibromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-2-carbaldehyde (5_3, 35 g, 0.09 mol) in DCM (350 mL) was added (S)-2-methylpropane-2-sulfinamide (22 g, 0.18 mole) and anhydrous copper sulfate (72 g, 0.45 mol). The resulting suspension was stirred at rt for 20 h. The reaction was filtered through Celite. The filtrate was concentrated and purification by flash chromatography (gradient elution pet ether / ethyl acetate) gave (S,Z)-N-((4,5-dibromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methylene)-2-methylpropane-2-sulfinamide (5_4).Step 4: Preparation of (S)-N-((S)-1-(4,5-dibromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)but-3-en-1-yl)-2-methylpropane-2-sulfinamide (5_5)

[0089] To a cooled (-78°C) solution of (S,Z)-N-((4,5-dibromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methylene)-2-methylpropane-2-sulfinamide (5_4, 17 g, 0.03 mole) in THF (170 mL) was added allylmagnesium bromide (1 M in diethylether, 52.3 mL, 0.05 mol) dropwise. After 1 h, the reaction was quenched with saturated ammonium chloride solution and then the reaction was allowed to warm to rt. The reaction mixture was extracted with ethyl acetate (2 x 250 mL). The organic layers were combined and washed with sodium bicarbonate solution, brine, water, dried over anhydrous sodium sulfate, filtered and concentrated. Purification by flash phase chromatography gave (S)-N-((S)-1-(4,5-dibromo-1-((2-(trimethylsilyl)ethoxy)methyl)- 1H-imidazol-2-yl)but-3-en-1-yl)-2-methylpropane-2-sulfinamide. 1< H NMR (400 MHz, CDCl 3 ) δ 5.71 (m, 1H), 5.60 (d, J= 11.6 Hz, 1H), 5.28 (m, 1H), 5.06 (m, 2H), 4.57 (q, J = 7.2 Hz 1H), 3.98 (d, J = 8.4Hz, 1H), 3.55 (m, 2H), 2.70 (t, J = 7.2 Hz, 2H), 1.2 (s, 9H), 0.92 (m, 2H), -0.01 (s, 9H).Step 5: Preparation of (S)-N-((S)-1-(4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)- 1H-imidazol-2-yl)but-3-en-1-yl)-2-methylpropane-2-sulfinamide (5 6)

[0090] A solution of (S)-N-((S)-1-(4,5-dibromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)but-3-en-1-yl)-2-methylpropane-2-sulfinamide (5_5, 5.25 g, 9.92 mmol) in THF (33.1 mL) was degassed with argon for 15 min. The solution was cooled to -3°C (ice / brine) and isopropylmagnesium chloride, lithium chloride complex in THF (8.00 mL, 10.4 mmol) was added dropwise over 20 min, keeping the temperature below 0°C during the addition. After 30 min, the second equivalent of isopropylmagnesium chloride, lithium chloride complex in THF (8.00 mL, 10.4 mmol) was added dropwise over 20 min, keeping the temperature below 0°C during the addition. After 30 min, the reaction was quenched with sat. ammonium chloride (30 mL) and the reaction was allowed to warm to rt. The reaction was partitioned between EtOAc and sat. ammonium chloride. The aqueous layer was extracted with EtOAc. The organic layers were combined and washed with sat. NaHCO 3 , brine, dried over sodium sulfate, filtered and concentrated. Purification by flash chromatography gave (S)-N-((S)-1-(4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)but-3-en-1-yl)-2-methylpropane-2-sulfinamide (5_6).Step 6: Preparation of (S)-1-(4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl) -1H-imidazol-2-yl)but-3-en-1-amine (5_7)

[0091] Hydrogen chloride (~4 M in EtOAc, 8 ml, 32.0 mmol) was added to a stirred mixture of (S)-N-((S)-1-(4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)but-3-en-1-yl)-2-methylpropane-2-sulfinamide (5_6, 1.0 g, 2.220 mmol) in DCM (10 ml) at room temperature and the mixture was stirred at room temperature for 1 h. The mixture was concentrated to afford (S)-1-(4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)but-3-en-1-amine (5_7) which was used to the next step without further purification. LCMS (ESI) calc'd for C 13 H 24 BrN 3 OSi [M+H] +< : 346.1, found: 346.1Step 7: Preparation of (S)-tert-butyl (1-(4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)but-3-en-1-yl)carbamate (5)

[0092] Bo15O (0.77 ml, 3.32 mmol) was added to a stirred mixture of DIEA (0.70 ml, 4.01 mmol) and (S)-1-(4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)but -3-en-1-amine (5_7, 0.769 g, 2.220 mmol) in DCM (10 ml) at room temperature and the mixture was stirred at room temperature for 1 h. The mixture was concentrated. The residue was purified by silica gel column flash chromatography, eluting with petroleum ether / EtOAc = 10:1 to give (S)-tert-butyl (1-(4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)but-3-en-1-yl)carbamate (5). LCMS (ESI) calc'd for C 18 H 32 BrN 3 O 3 Si [M+H] +< : 446.1, found: 448.1Preparation of Intermediate 6

[0093] Step 1: Preparation of N-methoxy-N-methyloxazole-4-carboxamide (6_2)

[0094] A mixture of oxazole-4-carbonyl chloride (6_1, 696 mg, 5.3 mmol), N,O-dimethylhydroxylamine hydrochloride(1550 mg, 15.9 mmol) and Na 2 CO 3 in water was stirred at rt for 1 h. The product was extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4 and concentrated in vacuo to afford N-methoxy-N-methyloxazole-4-carboxamide (6_2) which was used to the next step without further purification. LCMS (ESI) calc'd for C 6 H 8 N 2 O 3 [M+H] +< : 157.1, found: 157.0Step 2: Preparation of 1-(oxazol-4-yl)pent-4-en-1-one (6)

[0095] But-3-en-1-ylmagnesium bromide (1.7 g, 10.67 mmol) (THF solution) was added to a stirred mixture of N-methoxy-N-methyloxazole-4-carboxamide (6_2, 450 mg, 2.88 mmol) in THF (10 ml) at rt, then the mixture was stirred at rt for 2 h. The mixture was quenched with aqueous NH 4 Cl (saturated, 20 mL), and extracted with ethyl acetate (3 x 20 mL). The combined organic fractions were washed with brine (saturated, 15 mL), dried (Na 2 SO 4 ), filtered and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column flash chromatography, eluting with petroleum ether / EtOAc = 0~10% to give 1-(oxazol-4-yl)pent-4-en-1-one (6). LCMS (ESI) calc'd for C 8 H 9 NO 2 [M+H] +< : 152.1, found: 151.9.

[0096] Step 1: ethyl (S)-5-oxopyrrolidine-2-carboxylateInto a 5-L 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed N,N-dimethylpyridin-4-amine (21.3 g, 174.35 mmol, 0.11 equiv), N-(N-cyclohexylcarboximidoyl)cyclohexanamine (409 g, 1.98 mol, 1.25 equiv), ethanol (2 L). This was followed by the addition of (2S)-5-oxopyrrolidine-2-carboxylic acid (205 g, 1.59 mol, 1.00 equiv) at -10°C. The resulting solution was stirred overnight at 20°C. The solids were filtered out. The residue was applied onto a silica gel column with ethyl acetate / petroleum ether (1:100-1:5). This resulted in ethyl (2S)-5-oxopyrrolidine-2-carboxylate.Step 2: ethyl 2-allyl-5-oxopyrrolidine-2-carboxylate

[0097] Into a 10-L 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed ethyl (2S)-5-oxopyrrolidine-2-carboxylate (205 g, 1.30 mol, 1.00 equiv), tetrahydrofuran (1.6 L), 3-bromoprop-1-ene (610.6 g, 5.05 mol, 4.00 equiv). This was followed by the addition of LiHMDS (1N in THF) (2.6 L, 2.10 equiv)dropwise with stirring at -40°C in 40 min. The resulting solution was stirred for 2 h at 20°C. The reaction was then quenched by the addition of 3 L of NH 4 Cl. The resulting solution was extracted with 3x5 L of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate and concentrated. The residue was applied onto a silica gel column with ethyl acetate / petroleum ether (1:100-1:5). This resulted in ethyl (2R)-5-oxo-2-(prop-2-en-1-yl)pyrrolidine-2-carboxylate.Step 3: (S)-2-allyl-5-oxopyrrolidine-2-carboxylic acid and (R)-2-allyl-5-oxopyrrolidine-2-carboxylic acid

[0098] Into a 2-L 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed ethyl (2R)-5-oxo-2-(prop-2-en-1-yl)pyrrolidine-2-carboxylate (110 g, 557.72 mmol, 1.00 equiv), methanol (660 mL), water (330 mL). This was followed by the addition of potassium hydroxide (62 g, 2.00 equiv), in portions. The resulting solution was stirred for 2 h at 20°C. The pH value of the solution was adjusted to 2 with hydrogen chloride (1 mol / L). The resulting solution was extracted with 3x3 L of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by Prep-SFC with the following conditions: Column, CHIRALPAK AS-3 4.6*100mm, 3um; mobile phase, methanol (0.1%DEA); Detector, UV 220 nm. This resulted in (2S)-5-oxo-2-(prop-2-en-1-yl)pyrrolidine-2-carboxylic acid and (2R)-5-oxo-2-(prop-2-en-1-yl)pyrrolidine-2-carboxylic acid.

[0099] (S)-2-allyl-5-oxopyrrolidine-2-carboxylic acid : (ES, m / z): 170 [M+H] +< , 1< H-NMR: (400MHz, CD 3 OD, ppm): δ 2.14-2.17(1H, t), 2.3-2.45, (3H,q), 2.45-2.6 (1H, t), 2.6-2.75 (1H, t), 5.15-5.30 (2H, t), 5.7-5.9 (1H, q)

[0100] (R)-2-allyl-5-oxopyrrolidine-2-carboxylic acid: (ES, m / z): 170 [M+H] +< ; 1< H-NMR: (400MHz, CDCl 3 , ppm): δ 2.01-2.10 (1H, q), 2.45-2.53, (4H, t), 2.66-2.71 (1H, d), 5.19-5.22 (2H, d), 5.69-5.79 (1H, t), 7.78 (1H, s), 10.795 (1H, s).Step 4: (S)-5-allyl-5-(5-(4-fluorophenyl)-1H-imidazol-2-yl)pyrrolidin-2-one

[0101] A 250 ml one necked round bottom flask was charged with 2-bromo-4'-fluoroacetylphenone (2.3g, 10.60 mmol) and a solution of (S)-2-allyl-5-oxopyrrolidine-2-carboxylic acid (1.5 g, 8.87 mmol) and N-ethyl-N-isopropylpropan-2-amine (2ml, 11.48 mmol) in DMF (10 ml), then it was stirred overnight. The mixture was diluted with EtOAc (100ml) and H 2 O (40ml), the organic layer was separated, dried (Na 2 SO 4 ), then filtered and the solution was concentrated. The crude was purified by chromatography (Redisep 40g column) eluting with 3% MeOH / MeCl 2 , yielding intermediate 2-(4-fluorophenyl)-2-oxoethyl (S)-2-allyl-5-oxopyrrolidine-2-carboxylate. LCMS: [M+H] +< = 306.1. This intermediate was then dissolved in toluene (20ml), ammonium acetate (2 g, 25.9 mmol) was added, then it was stirred at 90°C overnight. After it was cooled to room temperature, it was diluted with EtOAc (200ml) and washed with satd NaHCO 3 (100ml), then dried (Na 2 SO 4 ), filtered and the solvent was evaporated yielding (S)-5-allyl-5-(5-(4-fluorophenyl)-1H-imidazol-2-yl)pyrrolidin-2-one. LC-MS: [M+H]+ = 286.0.Step 5: (S)-tert-butyl 2-(2-allyl-5-oxopyrrolidin-2-yl)-5-(4-fluorophenyl)-1H-imidazole-1-carboxylate

[0102] To a 250 ml one necked round bottom flask was added di-tert-butyl dicrabonate (1.3 g, 5.96 mmol) in CH 2 Cl 2 (5ml) to a solution of (S)-5-allyl-5-(5-(4-fluorophenyl)-1H-imidazol-2-yl)pyrrolidin-2-one (1.8g, 6.31 mmol) in CH 2 Cl 2 (20 ml). DMAP (0.1 g, 0.819 mmol) was added. The mixture was then stirred at room temperature for 2 hours. The mixture was concentrated to about 5ml, then purified by chromatography on Analogix (40g Redisep column) eluting with 3% MeOH / MeCl 2 yielding (S)-tert-butyl 2-(2-allyl-5-oxopyrrolidin-2-yl)-5-(4-fluorophenyl)-1H-imidazole-1-carboxylate (7). LC-MS: [M+H] +< = 386.0Intermediate 8(R)-2-allyl-6-oxopiperidine-2-carboxylic acid and (S)-2-allyl-6-oxopiperidine-2-carboxylic acid

[0103] Step 1: 6-oxopiperidine-2-carboxylic acid

[0104] Into a 5-L 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 2-aminohexanedioic acid (300 g, 1.86 mol, 1.00 equiv), AcOH (3000 mL). The resulting solution was stirred for 6 h at reflux. The reaction mixture was cooled to room temperature. The resulting mixture was concentrated under vacuum. The residue was dissolved in 2000 / 120 mL of toluene / ether. The resulting mixture was concentrated under vacuum. The residue was dissolved in 2000 mL of ether. The solid was filtrated and washed with ether. This resulted in 6-oxopiperidine-2-carboxylic acid.Step 2: ethyl 6-oxopiperidine-2-carboxylate

[0105] Into a 5-L 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed ethanol (2500 mL). This was followed by the addition of thionyl chloride (229 g, 1.92 mol, 1.10 equiv) dropwise with stirring at -5°C. To this was added 6-oxopiperidine-2-carboxylic acid (250 g, 1.75 mol, 1.00 equiv), in portions at -5°C. The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The residue was dissolved in 2000 / 450 mL of toluene / triethylamine. The solids were filtered out and the filtrate was concentrated under vacuum. The residue was treated with 1500 ml of ether and the solids were filtered out. The filtrate was concentrated under vacuum. This resulted in ethyl 6-oxopiperidine-2-carboxylate.Step 3: ethyl 2-allyl-6-oxopiperidine-2-carboxylate

[0106] Into a 10-L 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed ethyl 6-oxopiperidine-2-carboxylate (270 g, 1.58 mol, 1.00 equiv), tetrahydrofuran (3000 mL). This was followed by the addition of LiHMDS (3300 mL, 2.10 equiv, 1M in tetrahydrofuran) dropwise with stirring at -40°C. The resulting solution was stirred for 10 min at -40°C. To this was added 3-bromoprop-1-ene (765 g, 6.32 mol, 4.00 equiv) dropwise with stirring at -40°C. The resulting solution was stirred for 10 min at -40°C. The resulting solution was allowed to react, with stirring, for an additional 2 h at room temperature. The reaction was then quenched by the addition of 3.5 L of saturated NH 4 Cl. The resulting solution was extracted with 3x5 L of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate / petroleum ether (1:2). This resulted in ethyl 6-oxo-2-(prop-2-en-1-yl)piperidine-2-carboxylate.Step 4: (R)-2-allyl-6-oxopiperidine-2-carboxylic acid and (S)-2-allyl-6-oxopiperidine-2-carboxylic acid

[0107] Into a 5-L 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed ethyl 6-oxo-2-(prop-2-en-1-yl)piperidine-2-carboxylate (230 g, 1.09 mol, 1.00 equiv), ethanol (1600 mL), water (800 mL). This was followed by the addition of sodium hydroxide (86.5 g, 2.16 mol, 2.00 equiv), in portions. The resulting solution was stirred for 2 h at room temperature. The ethanol was concentrated under vacuum. The pH value of the residue was adjusted to 2 with hydrogen chloride (1 mol / L). The resulting solution was extracted with 5x1 L of ethyl acetate and the organic layers combined. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by Prep-SFC with the following conditions: Column, CHIRALPAK AD-H 4.6*100 mm,5um; mobile phase, IPA(0.1% DEA); Detector, UV 220 nm. This resulted in (2R)-6-oxo-2-(prop-2-en-1-yl)piperidine-2-carboxylic acid and (2S)-6-oxo-2-(prop-2-en-1-yl)piperidine-2-carboxylic acid.

[0108] (R)-2-allyl-6-oxopiperidine-2-carboxylic acid: LC-MS: (ES, m / z): 184.2 [M+H] +< ; 1< H-NMR: (400MHz, CDCl 3 , ppm): δ 1.76-1.89 (3H, m), 2.15-2.18, (1H, m), 2.20-2.48 (3H, m), 2.50-2.65 (1H, m), 5.17-5.21 (2H, t), 5.70-5.78 (1H, q), 7.78 (1H, s).

[0109] (S)-2-allyl-6-oxopiperidine-2-carboxylic acid: LC-MS: (ES, m / z): 184.2 [M+H] +< ; 1< H-NMR: (300MHz, CDCl 3 , ppm): δ 1.70-1.90 (3H, m), 2.13-2.19 (1H, m), 2.22-2.50 (3H, m), 2.60-2.67 (1H, m), 5.17-5.22 (2H, t), 5.66-5.80 (1H, q), 7.85 (1H, s), 11.17-11.33 (1H,s). Step 1: Preparation of methyl 4-allyl-2-oxooxazolidine-4-carboxylate (9 2)

[0110] CDI (2445 mg, 15.08 mmol) was added to the solution of methyl 2-amino-2-(hydroxymethyl)pent-4-enoate (9_1, 2000 mg, 12.56 mmol) and DIPEA (3.29 ml, 18.85 mmol) in DCM (2 ml), and the reaction mixture was stirred at 30°C for 2 h. The mixture was concentrated in vacuo and the residue was purified by silica gel flash chromatography (ISCORF75; Sepa flash column), eluting with petroleum ether / EtOAc = 5:1-1:1 to give methyl 4-allyl-2-oxooxazolidine-4-carboxylate (9_2).Step 2: Preparation of 4-allyl-2-oxooxazolidine-4-carboxylic acid (9_3)

[0111] LiOH·H 2 O (0.570 g, 13.58 mmol) was added to the solution of methyl 4-allyl-2-oxooxazolidine-4-carboxylate (9_2, 1.70 g, 9.18 mmol) in THF (15 ml) and water (2.00 ml), and the resultant mixture was stirred at rt for 1.5 h. The mixture was quenched with hydrochloric acid (4 M, 3.3 mL), and the mixture was extracted with ethyl acetate (3 x 30 mL) and dried (Na 2 SO 4 ), filtered and the solvent was evaporated under reduced pressure to give 4-allyl-2-oxooxazolidine-4-carboxylic acid (9_3) which was used to the next step without further purification.Step 3: Preparation of 2-(4-fluorophenyl)-2-oxoethyl 4-allyl-2-oxooxazolidine-4-carboxylate (9_4)

[0112] DIPEA (2.403 ml, 13.76 mmol) was added to the solution of 4-allyl-2-oxo-oxazolidine-4-carboxylic acid (9_3, 1.57 g, 9.17 mmol) and 2-bromo-1-(4-fluorophenyl)ethanone (2.011 g, 9.26 mmol) in DMF (30 ml), the resultant mixture was stirred at rt for 1.5 h. The mixture was quenched with aqueous NH 4 Cl (saturated, 10 mL), and the mixture was extracted with ethyl acetate (3 x 30 mL). The combined organic fractions were washed with brine (saturated, 15 mL), dried (Na 2 SO 4 ), filtered and the solvent was evaporated under reduced pressure to give 2-(4-fluorophenyl)-2-oxoethyl 4-allyl-2-oxooxazolidine-4-carboxylate (9_4) which was used to the next step without further purification. LCMS (ESI) calc'd for C 15 H 14 FNO 5 [M+H] +< : 308.1, found: 308.1. 1< H NMR (400 MHz, CDCl 3 ) δ 7.87 (dd, J = 5.48, 8.61 Hz, 2H), 7.13 (t, J = 8.41 Hz, 2H), 5.68-5.91 (m, 1H), 5.16-5.51 (m, 5H), 4.73 (d, J = 9.00 Hz, 1H), 4.26 (d, J = 9.00 Hz, 1H), 2.80 (dd, J = 6.26, 14.09 Hz, 1H), 2.56 (dd, J = 8.22, 13.69 Hz, 1H).Step 4: Preparation of 4-allyl-4-(4-(4-fluorophenyl)-1H-imidazol-2-yl)oxazolidin-2-one (9 5)

[0113] NH 4 OAc (331 mg, 4.30 mmol) was added to the solution of 2-(4-fluorophenyl)-2-oxoethyl 4-allyl-2-oxooxazolidine-4-carboxylate (9_4, 330 mg, 1.074 mmol) in toluene (5 ml), and the resultant mixture was stirred at 100°C for 2.5 h. The mixture was concentrated in vacuo and the residue was purified by silica gel flash chromatography (ISCORF75; Sepa flash column), eluting with petroleum ether / EtOAc = 10:1-1:2 to give 4-allyl-4-(4-(4-fluorophenyl)-1H-imidazol-2-yl)oxazolidin-2-one (9_5). LCMS (ESI) calc'd for C 15 H 14 FN 3 O 2 [M+H] +< : 288.1, found: 288.1Step 5: Preparation of tert-butyl 2-(4-allyl-2-oxooxazolidin-4-yl)-4-(4-fluorophenyl)-1H-imidazole-1-carboxylate (9)

[0114] DMAP (12 mg, 0.098 mmol) was added to the solution of Boc 2 O (0.412 ml, 1.775 mmol) and 4-allyl-4-(4-(4-fluorophenyl)-1H-imidazol-2-yl)oxazolidin-2-one (9_5, 300 mg, 1.044 mmol) in DCM (10 ml), the resultant mixture was stirred at rt for 6 h. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel flash chromatography (ISCORF75; Sepa flash column), eluting with petroleum ether / EtOAc =10:1-2:1 to give tert-butyl 2-(4-allyl-2-oxooxazolidin-4-yl)-4-(4-fluorophenyl)-1H-imidazole-1-carboxylate (9). LCMS (ESI) calc'd for 15 0 H 22 FN 3 O 4 [M+H] -< : 388.1, found: 388.1. Step 1: ethyl 1-allyl-2-oxocyclohexane-1-carboxylate

[0115] Into a 10000-mL 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of ethyl 2-oxocyclohexane-1-carboxylate (500 g, 2.94 mol, 1.00 equiv) in tetrahydrofuran (6 L). This was followed by the addition of (tert-butoxy)potassium (346 g, 3.08 mol, 1.05 equiv) in several batches. To this was added 3-bromoprop-1-ene (373 g, 3.08 mol, 1.05 equiv). The resulting solution was stirred for 18 h at 65°C. The resulting solution was quenched by the addition of H 2 O, extracted with ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate. The residue was applied onto a silica gel column with petroleum ether (1). This resulted in ethyl 2-oxo-1-(prop-2-en-1-yl)cyclohexane-1-carboxylate.Step 2: ethyl (E)-1-allyl-2-(hydroxvimino)cyclohexane-1-carboxylate

[0116] Into a 10000-mL 4-necked round-bottom flask, was placed ethanol (5100 mL), ethyl 2-oxo-1-(prop-2-en-1-yl)cyclohexane-1-carboxylate (510 g, 2.43 mol, 1.00 equiv), CH 3 COONa (637 g, 7.77 mol, 3.20 equiv), and hydroxylamine hydrochloride (506 g, 7.28 mol, 3.00 equiv). The resulting solution was stirred for 12 h at 25°C. The resulting solution was quenched by the addition of H 2 O, extracted with ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate. The crude product was purified by re-crystallization from PE. This resulted in ethyl (2E)-2-(hydroxyimino)-1-(prop-2-en-1-yl)cyclohexane-1-carboxylate.Step 3: ethyl (E)-1-allyl-2-((tosyloxy)imino)cyclohexane-1-carboxylate

[0117] Into a 10000-mL 4-necked round-bottom flask (1 atm), was placed pyridine (2100 mL), ethyl (2E)-2-(hydroxyimino)-1-(prop-2-en-1-yl)cyclohexane-1-carboxylate (420 g, 1.86 mol, 1.00 equiv), 4-dimethylaminopyridine (1.8 g, 14.73 mmol, 0.01 equiv), 4-methylbenzene-1-sulfonyl chloride (710 g, 3.72 mol, 2.00 equiv). The resulting solution was stirred for 14 h at 25°C. The reaction was then quenched by the addition of water. The resulting solution was extracted with dichloromethane and the organic layers combined. The mixture was washed by sodium bicarbonate solution and dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in ethyl (2E)-2-([[(4-methylbenzene)sulfonyl]oxy]imino)-1-(prop-2-en-1-yl)cyclohexane-1-carboxylate.Step 4: Ethyl (2R)-7-oxo-2-(prop-2-en-1-yl)azepane-2-carboxylate and ethyl (2S)-7-oxo-2-(prop-2-en-1-yl)azepane-2-carboxylate

[0118] Into a 20000-mL 4-necked round-bottom flask, was placed ethyl (2E)-2-([[(4-methylbenzene)sulfonyl]oxy]imino)-1-(prop-2-en-1-yl)cyclohexane-1-carboxylate (250 g, 658.81 mmol, 1.00 equiv), dichloromethane (10500 mL), and Silica gel (5500 g, 1500%wt). The resulting solution was stirred for 14 h at 25°C. The residue was applied onto a silica gel column with ethyl acetate / petroleum ether (100:1). The crude product was purified by re-crystallization from EA. The same process was repeated and the overall mixture was combined to work up. The crude product was purified by Prep-SFC with the following conditions: Column, CHIRALPAK-IC-SFC-025cm*25cm (5 um) Chiral-P(IC)006S90ICOSCY-SL001; mobile phase, Solvent A:Solvent B=CO 2 :(DCM:ACN=1:1)=60:40; Detector, uv. This resulted in ethyl (2R)-7-oxo-2-(prop-2-en-1-yl)azepane-2-carboxylate and ethyl (2S)-7-oxo-2-(prop-2-en-1-yl)azepane-2-carboxylate.Step 5: (R)-2-allyl-7-oxoazepane-2-carboxylic acid

[0119] Into a 3000-mL 4-necked round-bottom flask, was placed ethyl (2R)-7-oxo-2-(prop-2-en-1-yl)azepane-2-carboxylate (83 g, 368.42 mmol, 1.00 equiv), oxolane (830 mL). This was followed by the addition of a solution of LiOH (17.7 g, 739.04 mmol, 2.00 equiv) in water (737 mL). The resulting solution was stirred for 2 h at 25°C. The reaction was then quenched by the addition of 500 mL of H 2 O. The resulting solution was extracted with ethyl acetate and the organic layers combined. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in (2R)-7-oxo-2-(prop-2-en-1-yl)azepane-2-carboxylic acid. LC-MS: (ES, m / z): 198 [M+H] +< ; 239 [M+ACN+H] +< ; 261 [M+2ACN+Na] +< ; 302 [M+ACN+Na] +< ; 395 [2M+H] +< .Step 6: (S)-2-allyl-7-oxoazepane-2-carboxylic acid

[0120] Into a 3000-mL 4-necked round-bottom flask (1 atm), was placed ethyl (2S)-7-oxo-2-(prop-2-en-1-yl)azepane-2-carboxylate (83 g, 368.42 mmol, 1.00 equiv), oxolane (830 mL), and a solution of LiOH (17.7 g, 2.00 equiv) in water(737 mL). The resulting solution was stirred for 2 h at 25°C. The reaction was then quenched by the addition of 500 mL of H 2 O. The resulting solution was extracted with ethyl acetate and the organic layers were combined. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in (2S)-7-oxo-2-(prop-2-en-1-yl)azepane-2-carboxylic acid. LC-MS: (ES, m / z): 198 [M+H] +< ; 220 [M+Na] +< ; 261 [M+2ACN+Na] +< ; 417 [2M+Na] +< . 1< H-NMR: (400MHz, CD 3 OD, ppm): δ 5.76 (dddd, J = 16.7, 10.1, 8.3, 6.4 Hz, 1H), 5.30 - 5.18 (m, 2H), 2.68 - 2.37 (m, 4H), 2.31 - 2.21 (m, 1H), 2.00 - 1.88 (m, 1H), 1.82 - 1.59 (m, 3H), 1.52 (dddd, J = 15.4, 12.9, 6.3, 3.7 Hz, 1H). Step 1: Preparation of 6-(1-ethoxyvinyl)-7-methoxy-2-methylquinoline (11 2)

[0121] Tributyl(1-ethoxyvinyl)stannane (8.5 ml, 25.2 mmol) was added to a stirred mixture of PdCl 2 (PPh 3 ) 2 (0.974 g, 1.388 mmol), and 6-bromo-7-methoxy-2-methylquinoline (11_1, 3.5 g, 13.88 mmol) in DMF (100 ml) at room temperature and the mixture was stirred at 80°C for 16 h under N 2 . The mixture was cooled to room temperature, and KF (saturated, 50 mL) was added and the mixture was extracted with ethyl acetate (3 x 40 mL). The combined organic fractions were washed with brine (saturated, 40 mL), dried (Na 2 SO 4 ), filtered and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column flash chromatography, eluting with petroleum ether / EtOAc = 0-40% to give 6-(1-ethoxyvinyl)-7-methoxy-2-methylquinoline (11_2). LCMS (ESI) calc'd for C 15 H 17 NO 2 [M+H] +< : 244.1, found: 244.1.Step 2: Preparation of 2-chloro-1-(7-methoxv-2-methylquinolin-6-yl)ethanone (11 3)

[0122] NCS (1.767 g, 13.23 mmol) was added to a stirred mixture of 6-(1-ethoxyvinyl)-7-methoxy-2-methylquinoline (11_2, 3.5 g, 14.39 mmol) in MeCN (30 ml) and water (7.5 ml) at room temperature and the mixture was stirred at room temperature for 30 min. The mixture was washed with water (100 mL), diluted with ethyl acetate (2*100 mL), washed with brine (50 mL), dried (Na 2 SO 4 ), filtered and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column flash chromatography, eluting with petroleum ether / EtOAc = 0-40% to give 2-chloro-1-(7-methoxy-2-methylquinolin-6-yl)ethanone (11_3). LCMS (ESI) calc'd for C 13 H 12 ClNO 2 [M+H] +< : 250.1, found: 250.0Step 3: Preparation of 2-azido-1-(7-methoxy-2-methvlquinolin-6-yl)ethanone (11_4)

[0123] NaN 3 (0.69 g, 10.61 mmol) was added to a stirred mixture of 2-chloro-1-(7-methoxy-2-methylquinolin-6-yl)ethanone (11_3, 2.2 g, 8.81 mmol) in DMF (20 ml) and the mixture was stirred at rt for 1.5 h. The mixture was diluted with water (10 mL), extracted with ethyl acetate (3 x 8 mL). The combined organic fractions were washed with water (3 x 6 mL), brine (saturated, 5 mL), dried (Na 2 SO 4 ), and filtered to give 2-azido-1-(7-methoxy-2-methylquinolin-6-yl)ethanone ethyl acetate which was used directly to next step without further purification. LCMS (ESI) calc'd for C 13 H 12 N 4 O 2 [M+H] +< : 257.1, found: 257.1Step 4: Preparation of tert-butyl (2-(7-methoxy-2-methylquinolin-6-yl)-2-oxoethyl)carbamate (11_5)

[0124] 10% Pd-C (0.332 g, 0.312 mmol) was added to a stirred mixture of 2-azido-1-(7-methoxy-2-methylquinolin-6-yl)ethanone (11_4, ethyl acetate solution) and Boc 2 O (3.4 ml, 14.64 mmol) in MeOH (2 ml) at rt and the mixture was degassed and backfilled with H 2 three times and then stirred at rt for 2 h. The mixture was filtered and the filter cake was washed with MeOH (2 mL). The filtrate was concentrated to dryness. The residue was purified by silica gel column flash chromatography, eluting with petroleum ether / EtOAc = 0~45% to give tert-butyl (2-(7-methoxy-2-methylquinolin-6-yl)-2-oxoethyl)carbamate (11_5). LCMS (ESI) calc'd for C 18 H 22 N 2 O 4 [M+H] +< : 331.2, found: 331.1Step 5: Preparation of 2-amino-1-(7-methoxv-2-methylquinolin-6-yl)ethanone (11_6)

[0125] HCl / MeOH (4 M, 3 ml, 12.00 mmol) was added to a stirred mixture of tert-butyl (2-(7-methoxy-2-methylquinolin-6-yl)-2-oxoethyl)carbamate (11_5, 1.3 g, 3.93 mmol) in MeOH (3 ml) at room temperature and the mixture was stirred at room temperature for 21 h. The residue was concentrated to give 2-amino-1-(7-methoxy-2-methylquinolin-6-yl)ethanone hydrochloride (11_6) which was used to the next step without further purification. LCMS (ESI) calc'd for C 13 H 14 N 2 O 2 ·ClH [M+H] +< : 231.1, found: 231.1Step 6: Preparation of (S)-tert-butyl (1-((2-(7-methoxy-2-methylquinolin-6-yl)-2-oxoethyl)amino)-1-oxopent-4-en-2-yl)carbamate (11 7)

[0126] HATU (1.882 g, 4.95 mmol) was added to a stirred mixture of DIPEA (7 ml, 40.1 mmol), and (S)-2-((tert-butoxycarbonyl)amino)pent-4-enoic acid (1.065 g, 4.95 mmol) in DMF (20 ml) at room temperature and the mixture was stirred at room temperature for 15 min. Then 2-amino-1-(7-methoxy-2-methylquinolin-6-yl)ethanone hydrochloride (11_6, 1.1 g, 4.12 mmol) was added, and the mixture was stirred at rt for 2 h. The mixture was diluted with ethyl acetate (10 mL), washed with brine (saturated, 3 x 10 mL), dried (Na 2 SO 4 ), filtered and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column flash chromatography, eluting with EtOAc / petroleum ether = 50-100% to give (S)-tert-butyl (1-((2-(7-methoxy-2-methylquinolin-6-yl)-2-oxoethyl)amino)-1-oxopent-4-en-2-yl)carbamate (11_7). LCMS (ESI) calc'd for 15 3 H 29 N 3 O 5 [M+H] +< : 428.2, found: 428.2Step 7: Preparation of (S)-tert-butyl (1-(5-(7-methoxy-2-methylquinolin-6-yl)oxazol-2-yl)but-3-en-1-yl)carbamate (11)

[0127] Burgess reagent (1.449 g, 6.08 mmol) was added to a stirred mixture of (S)-tert-butyl (1-((2-(7-methoxy-2-methylquinolin-6-yl)-2-oxoethyl)amino)-1-oxopent-4-en-2-yl)carbamate (11_7, 1.3 g, 3.04 mmol) in DCM (8 ml). The mixture was stirred at rt for 16 h. The mixture was diluted with dichloromethane (3 x 15 mL), washed with brine (saturated, 2 x 20 mL), dried (Na 2 SO 4 ), filtered and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column flash chromatography, eluting with EtOAc / petroleum ether = 10-80% to give (S)-tert-butyl (1-(5-(7-methoxy-2-methylquinolin-6-yl)oxazol-2-yl)but-3-en-1-yl)carbamate (11). LCMS (ESI) calc'd for 15 3 H 27 N 3 O 4 [M+H] +< : 410.2, found: 410.2 Step 1: Preparation of oxocan-2-one (12_2)

[0128] 3-chlorobenzoperoxoic acid (41.0 g, 178 mmol) was added to a stirred mixture of cycloheptanone (10 g, 89 mmol) in DCM (200 ml) at 0°C and the mixture was stirred at room temperature for 6 days. The mixture was combined with a same scale reaction, filtered and washed with DCM (50 mL). The resulting filtrate was washed with a sat. solution of Na 2 S 2 O 3 (200 mL) and water (200 mL), and aqueous NaHCO 3 (3*300 mL), dried (Na 2 SO 4 ), filtered and the solvent was evaporated under reduced pressure to get oxocan-2-one (12_2) and used directly without further purification.Step 2: Preparation of 7-hydroxy-N-methoxy-N-methylheptanamide (12 3)

[0129] N,O-dimethylhydroxylamine (9.37 g, 153 mmol) was added to a stirred mixture of oxepan-2-one (12_2, 14 g, 123 mmol) in THF (260 ml) at 0°C. Then isopropylmagnesium chloride (153 ml, 307 mmol) was added dropwise into the mixture (10 min) and stirred at 0°C for 2 h. The mixture was combined with a 10 scale recation, quenched with a sat. solution of NH 4 Cl (600 mL) and water (500 mL). It was extracted with EtOAc (3x 300 mL), dried over Na 2 SO 4 , filtered and concentrated. The residue was purified by silica gel column flash chromatography, eluting with petroleum ether / EtOAc = 0-60% to give 7-hydroxy-N-methoxy-N-methylheptanamide (12_3).Step 3: Preparation of 7-((tert-butyldimethylsilyl)oxy)-N-methoxy-N-methylheptanamide (12 4)

[0130] To a mixture of 7-hydroxy-N-methoxy-N-methylheptanamide (12_3, 10 g, 52.8 mmol) in DCM (100 ml) was added imidazole (3.60 g, 52.8 mmol) and a solution of TBSCl (7.96 g, 52.8 mmol) in DCM (20 mL) at room temperature. The mixture was stirred at 30°C for 2 h. Then the mixture was quenched with a sat. solution of NH 4 Cl (100 mL) and water (100 mL). The mixture was extracted with DCM (3x 200 mL), dried over Na 2 SO 4 , filtered and concentrated to afford 7-((tert-butyldimethylsilyl)oxy)-N-methoxy-N-methylheptanamide (12_4) and used in the next step without further purification.Step 4: Preparation of 7-((tert-butyldimethylsilyl)oxy)-1-(oxazol-2-yl)heptan-1-one (12 5)

[0131] To a mixture of oxazole (4.9 ml, 74.5 mmol) in THF (200 ml) at 0°C was added isopropylmagnesium chloride (24.7 ml, 49.4 mmol) dropwise. The reaction was stirred for 30 minutes before adding 7-((tert-butyldimethylsilyl)oxy)-N-methoxy-N-methylheptanamide (12_4, 15 g, 49.4 mmol) in THF dropwise. The mixture was warmed to 30°C and stirred overnight. The residue was quenched with a sat. solution of NH 4 Cl (300 mL) and water (200 mL). It was extracted with EtOAc (3x 200 mL), dried over Na 2 SO 4 , filtered and concentrated. The residue was purified by silica gel column flash chromatography, eluting with petroleum ether / EtOAc = 0-30% to give 7-((tert-butyldimethylsilyl)oxy)-1-(oxazol-2-yl)heptan-1-one (12_5).Step 5: Preparation of 7-hydroxy-1-foxazol-2-yl)heptan-1-one (12 6)

[0132] To a mixture of 7-((tert-butyldimethylsilyl)oxy)-1-(oxazol-2-yl)heptan-1-one (12_5, 7 g, 22.47 mmol) in THF (100 ml) at room temperature was added TBAF (22.5 ml, 22.50 mmol) in THF. The reaction was stirred for 5 h. The residue was evaporated under pressure to get 7-hydroxy-1-(oxazol-2-yl)heptan-1-one (12_6, 5 g crude) which was used to next step.Step 6: Preparation of 6-(2-(oxazol-2-yl)-1,3-dioxolan-2-yl)hexan-1-ol (12 7)

[0133] To a mixture of 7-hydroxy-1-(oxazol-2-yl)heptan-1-one (12_6, 5 g, 25.4 mmol) in toluene (250 ml) at room temperature was added ethane-1,2-diol (31.5 g, 507 mmol) and PPTS (0.319 g, 1.268 mmol). Then the mixture was heated to 130°C and stirred for 15 h. The mixture was evaporated under reduced pressure. The residue was purified by silica gel column flash chromatography, eluting with petroleum ether / EtOAc = 0-50 % to give 6-(2-(oxazol-2-yl)-1,3-dioxolan-2-yl)hexan-1-ol (12_7).Step 7: Preparation of 6-(2-(oxazol-2:yl)-1,3-dioxolan-2-yl)hexanal (12 8)

[0134] TPAP (0.255 g, 0.725 mmol) was added into a mixture of 6-(2-(oxazol-2-yl)-1,3-dioxolan-2-yl)hexan-1-ol (12_7, 3.5 g, 14.51 mmol), and NMO (2.55 g, 21.76 mmol) in DCM (20 ml) at 0°C, then stirred at room temperature for 3 h. The mixture was washed with water (150 mL), and brine (20 mL), the water layer was extracted with DCM (50 mL *2), the combined organic layer was filtered and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column flash chromatography, eluting with petroleum ether / EtOAc = 0-50 % to give 6-(2-(oxazol-2-yl)-1,3-dioxolan-2-yl)hexanal (12_8). LCMS (ESI) calc'd for C 12 H 17 NO 4 [M+H] +< : 240.1, found: 240.1Step 8: Preparation of (R,E)-2-methyl-N-(6-(2-(oxazol-2-yl)-1,3-dioxolan-2-yl)hexylidene)propane-2-sulfinamide (12)

[0135] To a mixture of 6-(2-(oxazol-2-yl)-1,3-dioxolan-2-yl)hexanal (12_8, 1.2 g, 5.02 mmol) in DCM (10 ml) at room temperature was added copper(II) sulfate (8.00 g, 50.2 mmol) and (R)-2-methylpropane-2-sulfinamide (0.912 g, 7.52 mmol). The mixture was stirred at rt for 16 h, filtered through a pad of Celite. The resulting filtrate was concentrated and purified by silica gel column flash chromatography, eluting with petroleum ether / EtOAc = 0-60% to give (R,E)-2-methyl-N-(6-(2-(oxazol-2-yl)-1,3-dioxolan-2-yl)hexylidene)propane-2-sulfinamide (12). LCMS (ESI) calc'd for C 16 H 26 N 2 O 4 S [M+H] -< : 343.2, found: 343.2. 1< H NMR (400 MHz, CDCl 3 ) δ 8.04 (t, J = 4.63 Hz, 1H), 7.61-7.64 (m, 1H), 7.09 (s, 1H), 4.11 (s, 5H), 2.39-2.53 (m, 2H), 2.08-2.19 (m, 2H), 1.58-1.66 (m, 2H), 1.32-1.47 (m, 5H), 1.26 (t, J = 7.17 Hz, 3H), 1.18 (s, 5H). Step 1: Preparation of 1-(isoxazol-3-yl)hept-6-en-1-one (13_1)

[0136] Magnesium (7.45 g, 307 mmol) was stirred vigorously for 15 minutes under N 2 before adding THF (20 ml) and I 2 (0.039 g, 0.153 mmol), and 6-bromohex-1-ene (25 g, 153 mmol) in THF (210 ml) was added dropwise via an addition funnel over 2 h. The resulting solution was added to a stirred mixture of N-methoxy-N-methylisoxazole-3-carboxamide (A2_2, 13 g, 83 mmol) in THF (150 ml) at 0°C, stirred for 30 min, and the mixture was stirred at rt for 15 h. The mixture was quenched with NH 4 Cl (100 mL), extracted with EtOAc (100 mL*3), and the combined organic layers were washed with brine (100 mL), dried over Na 2 SO 4 , filtered and concentrated. The crude product was purified by flash silica gel chromatography (ISCO ®< ; 120 g SepaFlash ®< Silica Flash Column, Eluent of 0~10% EtOAc / Petroleum ether gradient @ 40 mL / min) to give 1-(isoxazol-3-yl)hept-6-en-1-one (13_1).Step 2: Preparation of 7-hydroxy-1-(isoxazol-3-yl)heptan-1-one (13 2)

[0137] 9-BBN (151 ml, 75 mmol) was added to a stirred mixture of 1-(isoxazol-3-yl)hept-6-en-1-one (13_1, 9 g, 50.2 mmol) in THF (100 ml) at rt, the mixture was stirred for 2 h before cooling to 0°C and adding NaOH (20 ml, 100 mmol) dropwise followed by H 2 O 2 (8.8 ml, 101 mmol)) dropwise. The mixture was warmed to room temperature and stirred for 1 h. The mixture was taken up in H 2 O (50 mL) and EtOAc (50 mL). It was extracted with EtOAc (3x 50 mL), and the combined organic layers were washed with brine (10 mL), dried over Na 2 SO 4 , filtered and concentrated. The crude product was purified by flash silica gel chromatography (ISCO ®< ; 80 g SepaFlash ®< Silica Flash Column, Eluent of 0~10% EtOAc / Petroleum ether gradient @ 40 mL / min) to give 7-hydroxy-1-(isoxazol-3-yl)heptan-1-one (13_2).Step 3: Preparation of 6-(2-(isoxazol-3-yl)-1.3-dioxolan-2-yl)hexan-1-ol (13 3)

[0138] A mixture of 7-hydroxy-1-(isoxazol-3-yl)heptan-1-one (13_2, 5.4 g, 27.4 mmol), ethane-1,2-diol (15.27 ml, 274 mmol) and TsOH (0.260 g, 1.369 mmol) in toluene (200 ml) was stirred at 130°C for 13 h. The mixture was cooled, the solvent was evaporated under reduced pressure. The resulting residue was taken up in EtOAc (100 mL), washed with a sat. solution of NaHCO 3 (100 mL), dried over Na 2 SO 4 , and concentrated to get the crude, the crude was purified by flash silica gel chromatography (ISCO ®< ; 40 g SepaFlash ®< Silica Flash Column, Eluent of 0~10% EtOAc / Petroleum ether gradient @ 40 mL / min) to give 6-(2-(isoxazol-3-yl)-1,3-dioxolan-2-yl)hexan-1-ol (13_3). LCMS (ESI) calc'd for C 12 H 19 NO 4 [M+H] +< : 242.2, found: 242.1Step 4: Preparation of 6-(2-(isoxazol-3-yl)-1.3-dioxolan-2-yl)hexanal (13 4)

[0139] To a mixture of 6-(2-(isoxazol-3-yl)-1,3-dioxolan-2-yl)hexan-1-ol (13_3, 4.7 g, 19.48 mmol) in DCM (35 ml) and DMSO (23 ml) was added DIPEA (10.2 ml, 58.4 mmol) and sulfur trioxide pyridine complex (4.65 g, 29.2 mmol) at 0°C, and the mixture was stirred at rt for 3 h. The reaction was quenched with water (50 mL) and taken up in EtOAc (50 mL). The mixture was washed with H 2 O (100 mL), washed with 1 M HCl (50 mL), and sat. solution of NaHCO 3 (50 mL), dried over Na 2 SO 4 , and concentrated to get the crude product. The crude product was purified by flash silica gel chromatography (ISCO ®< ; 20 g SepaFlash ®< Silica Flash Column, Eluent of 0~10% EtOAc / Petroleum ether gradient @ 40 mL / min) to give 6-(2-(isoxazol-3-yl)-1,3-dioxolan-2-yl)hexanal (13_4).Step 5: Preparation of (R,E)-N-(6-(2-(isoxazol-3-yl)-1,3-dioxolan-2-yl)hexylidene)-2-methylpropane-2-sulfinamide (13)

[0140] Copper(II) sulfate (7.74 g, 48.5 mmol) was added to a stirred mixture of 6-(2-(isoxazol-3-yl)-1,3-dioxolan-2-yl)hexanal (13_4, 2.9 g, 12.12 mmol), (R)-2-methylpropane-2-sulfinamide (2.203 g, 18.18 mmol) in DCM (100 ml) at rt, and the mixture was stirred at rt for 20 h. The mixture was combined with a 0.7 g scale reaction, filtered and the filtrate was concentrated to dryness to get the crude product. The crude product was purified by flash silica gel chromatography (ISCO ®< ; 20 g SepaFlash ®< Silica Flash Column, Eluent of 0~10% EtOAc / Petroleum ether gradient @ 40 mL / min) to give (R,E)-N-(6-(2-(isoxazol-3-yl)-1,3-dioxolan-2-yl)hexylidene)-2-methylpropane-2-sulfinamide (13). 1< H NMR (400 MHz, CDCl 3 ) δ 8.37 (d, J = 1.5 Hz, 1H), 8.04 (s, 1H), 6.32 (d, J = 1.5 Hz, 1H), 4.11-4.06 (m, 2H), 3.99-3.94 (m, 2H), 2.50 (dt, J = 4.9, 7.4 Hz, 2H), 2.04-1.99 (m, 2H), 1.67-1.58 (m, 3H), 1.49-134 (m, 4H), 1.19 (s, 9H). Step 1: Preparation of (R)-N-((S)-I-(4,5-dibromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-6-(2-(oxazol-2-yl)-1,3-dioxolan-2-yl)hexyl)-2-methylpropane-2-sulfinamide (14_1)

[0141] Butyllithium (14 ml, 35.0 mmol) was added to a stirred mixture of 2,4,5-tribromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (15.24 g, 35.0 mmol) in THF (80.0 ml) at - 78°C and the mixture was stirred at -78°C for 30 min. (R,E)-2-methyl-N-(6-(2-(oxazol-2-yl)-1,3-dioxolan-2-yl)hexylidene)propane-2-sulfinamide (12, 8.0 g, 23.36 mmol) in THF (20 mL) was added. The mixture was stirred at -78°C for 2 h. The mixture was quenched with aqueous NH 4 Cl (saturated, 80 mL) and the mixture was extracted with ethyl acetate (3 x 80 mL). The combined organic fractions were washed with brine (saturated, 50 mL), dried (Na 2 SO 4 ), filtered and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column flash chromatography, eluting with petroleum ether / EtOAc = 1:1 - 1:2 to give (R)-N-((S)-1-(4,5-dibromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-6-(2-(oxazol-2-yl)-1,3-dioxolan-2-yl)hexyl)-2-methylpropane-2-sulfinamide (14_1). LCMS (ESI) calc'd for 15 5 H 42 Br 2 N 4 O 5 SSi [M+H] +< : 697.1, found: 697.1.Step 2: Preparation of (R)-N-((S)-1-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-6-(2-(oxazol-2-yl)-1,3-dioxolan-2-yl)hexyl)-2-methylpropane-2-sulfinamide (14)

[0142] BuLi (8.8 ml, 22.00 mmol) was added to a stirred mixture of (R)-N-((S)-1-(4,5-dibromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-6-(2-(oxazol-2-yl)-1,3-dioxolan-2-yl)hexyl)-2-methylpropane-2-sulfinamide (14_1, 9.0 g, 12.88 mmol) in THF (100.0 ml) at -78°C and the mixture was stirred at -78°C for 1 h. Propan-2-ol (3.87 g, 64.4 mmol) was added dropwise. The mixture was stirred at -78°C for 20 min. The mixture was quenched further with aqueous NH 4 Cl (saturated, 80 mL) and the mixture was extracted with ethyl acetate (3 x 80 mL). The combined organic fractions were washed with brine (saturated, 2 x 50 mL), dried (Na 2 SO 4 ), filtered and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column flash chromatography, eluting with petroleum ether / EtOAc = 1:1 - 0:1 to give (R)-N-((S)-1-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-6-(2-(oxazol-2-yl)-1,3-dioxolan-2-yl)hexyl)-2-methylpropane-2-sulfinamide (14). LCMS (ESI) calc'd for 15 5 H 43 BrN 4 O 5 SSi [M+H] +< : 619.2, found: 621.2. 1< H NMR (400 MHz, CDCl 3 ) δ 7.61 (s, 1H), 7.07 (s, 1H), 6.88 (s, 1H), 5.39 (d, J = 11.04 Hz, 1H), 5.13 (d, J = 11.04 Hz, 1H), 4.02-4.15 (m, 5H), 3.72 (d, J = 7.53 Hz, 1H), 3.50 (t, J = 8.28 Hz, 2H), 2.17-2.19 (m, 1H), 2.06-2.19 (m, 2H), 2.02 (d, J = 6.78 Hz, 1H), 1.63-1.73 (m, 1H), 1.26-1.48 (m, 7H), 1.08-1.21 (m, 10H), 0.85-0.96 (m, 2H), 0.01 (s, 9H). Step 1: Preparation of ((R)-N-((S)-1-(4,5-dibromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-6-(2-(isoxazol-3-yl)-1,3-dioxolan-2-yl)hexyl)-2-methylpropane-2-sulfinamide (15_1)

[0143] Butyllithium (6.13 ml, 15.33 mmol) was added to a stirred mixture of 2,4,5-tribromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (6.67 g, 15.33 mmol) in THF (35 ml) at -78°C, and the mixture was stirred at -78°C for 30 min. (R,E)-N-(6-(2-(isoxazol-3-yl)-1,3-dioxolan-2-yl)hexylidene)-2-methylpropane-2-sulfinamide (13, 3.5 g, 10.22 mmol) in THF (5ml) was added, and the mixture was stirred at -78°C for 2 h. The mixture was quenched with NH 4 Cl (100 mL), extracted with EtOAc (100 mL*3), the combined organic layers were washed with brine (100 mL), dried over Na 2 SO 4 , filtered and concentrated. The crude product was purified by flash silica gel chromatography (ISCO ®< ; 20 g SepaFlash ®< Silica Flash Column, Eluent of 0~10% EtOAc / Petroleum ether gradient @ 40 mL / min) to give (R)-N-((S)-1-(4,5-dibromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-6-(2-(isoxazol-3-yl)-1,3-dioxolan-2-yl)hexyl)-2-methylpropane-2-sulfinamide (15_1). LC / MS (ESI) calc'd for C 15 H 42 Br 2 N 4 O 5 SSi [M+H] +< : 699.5, found: 698.9.Step 2: Preparation of (R)-N-((S)-1-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-6-(2-(isoxazol-3-yl)-1,3-dioxolan-2-yl)hexyl)-2-methylpropane-2-sulfinamide (15)

[0144] iPrMgCl·LiCl (6.17 ml, 8.02 mmol) was added to a stirred mixture of (R)-N-((S)-1-(4,5-dibromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-6-(2-(isoxazol-3-yl)-1,3-dioxolan-2-yl)hexyl)-2-methylpropane-2-sulfinamide (15_1, 2.8 g, 4.01 mmol) in THF (30 ml) at 0°C, and the mixture was stirred at rt for 30 min. The mixture was quenched with NH 4 Cl (50 mL), extracted with EtOAc (50 mL*3), the combined organic layers were washed with brine (50 mL), dried over Na 2 SO 4 , filtered and concentrated. The crude product was purified by flash silica gel chromatography (ISCO ®< ; 20 g SepaFlash ®< Silica Flash Column, Eluent of 0~50% EtOAc / Petroleum ether gradient @ 40 mL / min) to give (R)-N-((S)-1-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-6-(2-(isoxazol-3-yl)-1,3-dioxolan-2-yl)hexyl)-2-methylpropane-2-sulfinamide (15). 1< H NMR (400 MHz, CDCl 3 ) δ 8.35 (d, J = 1.6 Hz, 1H), 6.89 (s, 1H), 6.31 (d, J = 1.6 Hz, 1H), 5.43-5.34 (m, 1H), 5.17-5.10 (m, 1H), 4.53-4.44 (m, 1H), 4.10-4.03 (m, 2H), 3.99-3.92 (m, 2H), 3.76-3.69 (m, 1H), 3.54-3.45 (m, 2H), 2.18-2.07 (m, 1H), 2.02-1.93 (m, 3H), 1.44-1.29 (m, 6H), 1.16 (s, 11H), 0.97-0.86 (m, 3H), 0.01 (s, 9H). Step 1: Preparation of (S)-1-(4-bromo-1H-imidazol-2-yl)but-3-en-1-amine (16_1)

[0145] To a solution of (S)-N-((S)-1-(4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)but-3-en-1-yl)-2-methylpropane-2-sulfinamide (5_6, 7.1 g, 15.76 mmol) in ethyl acetate (5 ml) was added HCl / dioxane (2 ml, 8.00 mmol). The mixture was stirred at rt for 2 h. The reaction was concentrated to give (S)-1-(4-bromo-1H-imidazol-2-yl)but-3-en-1-amine (16_1) which was used directly in next step.Step 2: Preparation of (S)-tert-butyl 4-bromo-2-(1-((tert-butoxycarbonyl)amino)but-3-en-1-yl)-1H-imidazole-1-carboxylate (16 2)

[0146] A mixture of DIEA (8 ml, 45.8 mmol), (S)-1-(4-bromo-1H-imidazol-2-yl)but-3-en-1-amine (16_1, 4 g crude, 18.51 mmol), DMAP (0.226 g, 1.851 mmol) and Bo15O (10 ml, 43.1 mmol) in DCM (20 ml) was stirred at rt for 10 h. The mixture was concentrated to dryness and purified by silica gel column flash chromatography, eluting with petroleum ether / EtOAc = 10:1-20:1 to give (S)-tert-butyl 4-bromo-2-(1-((tert-butoxycarbonyl)amino)but-3-en-1-yl)-1H-imidazole-1-carboxylate (16_2). LCMS (ESI) calc'd for C 17 H 26 BrN 3 O 4 [M+H] +< : 416.1, 418.1, found: 416.1, 418.1.Step 3: Preparation of (S,E)-tert-butyl 4-bromo-2-(1-((tert-butoxycarbonyl)amino)-7-(oxazol-2-yl)-7-oxohept-3-en-1-yl)-1H-imidazole-1-carboxylate (16)

[0147] A mixture of 1-(oxazol-2-yl)pent-4-en-1-one (1, 290 mg, 1.922 mmol), (S)-tert-butyl 4-bromo-2-(1-((tert-butoxycarbonyl)amino)but-3-en-1-yl)-1H-imidazole-1-carboxylate (16_2, 500 mg, 1.201 mmol) and Zhan's catalyst (44 mg, 0.060 mmol) in toluene (2 mL) was degassed and backfilled with N 2 three times. The mixture was heated at 140°C for 3 h. The mixture was cooled, diluted with ethyl acetate (20 mL), washed with brine (saturated, 5 mL), dried (Na 2 SO 4 ), filtered and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column flash chromatography, eluting with petroleum ether / EtOAc = 20: 1 - 1: 3 to give (S,E)-tert-butyl 4-bromo-2-(1-((tert-butoxycarbonyl)amino)-7-(oxazol-2-yl)-7-oxohept-3-en-1-yl)-1H-imidazole-1-carboxylate (16). LCMS (ESI) calc'd for C 13 H 31 BrN 4 O 6 [M+H] +< : 539.0, 541.0, found: 539.1, 541.1 Step 1: Preparation of (S)-1-(4-bromo-1-((2-(trimethylsilyl) ethoxy)methyl)-1H-imidazol-2-yl)but-3-en-1-amine (17_1)

[0148] To a solution of (S)-N-((S)-1-(4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)but-3-en-1-yl)-2-methylpropane-2-sulfinamide (5_6, 9 g, 19.98 mmol) in MeOH (60 ml) was added HCl / MeOH (5 ml, 20.00 mmol). The mixture was stirred at rt for 1 h and then concentrated to give (S)-1-(4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl) -1H-imidazol-2-yl) but -3-en-1-amine (17_1) which was used directly in next step. LCMS (ESI) calc'd for C 13 H 24 BrN 3 OSi [M+H] +< : 348.0, found: 348.1Step 2: Preparation of (S)-tert-butyl (1-(4-bromo-1-((2-(trimethylsilyl)ethoxy) methyl)-1H-imidazol-2-yl)but-3-en-1-yl)carbamate (17 2)

[0149] A mixture of (S)-1-(4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)but-3-en-1-amine (17_1, 6900 mg), TEA (4.17 ml, 29.9 mmol) and Bo15O (5.80 ml, 24.90 mmol) in DCM (100 ml) was stirred at rt for 16 h. The mixture was concentrated to dryness and purified by silica gel column flash chromatography, eluting with petroleum ether / EtOAc = 100:1-30:1 to give (S)-tert-butyl (1-(4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)but-3-en-1-yl)carbamate (17_2). LCMS (ESI) calc'd for C 18 H 32 BrN 3 O 3 Si [M+H] +< : 446.1 found: 446.2Step 3: Preparation of (S,E)-tert-butyl(1-(4-bromo-1-((2-(trimethylsilyl)eth oxy)methyl)-1H-imidazol-2-yl)-7-(isoxazol-3-yl)-7-oxohept-3-en-1-yl)carbamate (17)

[0150] Zhan's catalyst (82 mg, 0.112 mmol) was added to a mixture of (S)-tert-butyl (1-(4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)but-3-en-1-yl)carbamate (17_2, 1000 mg, 2.240 mmol) and 1-(isoxazol-3-yl)pent-4-en-1-one (A1, 745 mg, 4.93 mmol) in toluene (8 ml) which was bubbled with N 2 for 20 mins at rt. The mixture was degassed and backfilled with N 2 three times and stirred at 100°C for 16 h. Five parallel reactions were combined and concentrated to dryness, then purified by silica gel chromatography eluted with Petro.Ether: EtOAc = 5:1 to give (S,E)-tert-butyl(1-(4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl) -7-(isoxazol-3-yl)-7-oxohept-3-en-1-yl)carbamate (17). LCMS (ESI) calc'd for C 14 H 37 BrN 4 O 5 Si [M+H] +< : 569.2 , found: 571.0Intermediate 18tert-butyl (S)-(1-(1-(2-methyl-2H-indazol-5-yl)-1H-pyrazol-3-yl)but-3-en-1-yl)carbamate

[0151] Step 1: 1-tosyl-1H-pyrazole-3-carbaldehyde

[0152] To a solution of 1H-pyrazole-3-carbaldehyde (5 g, 52.0 mmol) in THF (80 ml) and DMF (40 ml) at 0°C was added NaH (2.289 g, 57.2 mmol) in three equal portions. The reaction mixture was stirred at 0°C under N 2 . After 20 min of stirring, the reaction mixture was treated with Ts-Cl (10.91 g, 57.2 mmol) in three equal portions. The reaction mixture was stirred under N 2 while allowed to warm to RT slowly. After 2 hr of stirring, the reaction mixture was quenched carefully with sat. NaHCO 3 (aq)(5 mL). The reaction mixture was diluted with H 2 O (200 mL) and extracted with EtOAc (3 x 100 mL). The organic extracts were combined, washed with H 2 O (3 x 100 mL), brine (1 x 50 mL), dried over MgSO 4 , filtered and concentrated. The crude product was purified by normal phase silica gel column chromatography using EtOAc / Hexanes as eluents to yield the title compound.Step 2: (S,E)-2-methyl-N-((1-tosyl-1H-pyrazol-3-yl)methylene)propane-2-sulfinamide

[0153] To a solution of 1-tosyl-1H-pyrazole-3-carbaldehyde (4.56 g, 18.22 mmol) in CH 2 Cl 2 (50 ml) were added (S)-2-methylpropane-2-sulfinamide (3.31 g, 27.3 mmol) and copper(II) sulfate (11.63 g, 72.9 mmol). The reaction mixture was stirred at RT under N 2 . After 3 days of stirring, the reaction mixture was filtered through a pad of Celite with CH 2 Cl 2 and the filtrate was concentrated. The crude product was purified by normal phase silica gel column chromatography using EtOAc / Hexanes as eluents to yield the title compound.Step 3: (S)-2-methyl-N-((S)-1-(1-tosyl-1H-pyrazol-3-yl)but-3-en-1-yl)propane-2-sulfinamide

[0154] To a solution of (S,E)-2-methyl-N-((1-tosyl-1H-pyrazol-3-yl)methylene)propane-2-sulfinamide (5.67 g, 16.04 mmol) in THF (100 ml) at -78°C was added allylmagnesium chloride (10.43 ml, 20.85 mmol) dropwise. The reaction mixture was stirred at -78°C under N 2 . After 1 hr of stirring, the reaction mixture was quenched by addition of sat NH 4 Cl(aq) (1 mL) at -78°C. The reaction mixture was warmed to room temperature. The reaction mixture was diluted with H 2 O (50 mL) and EtOAc (100 mL). The layers were separated and the organic layer was washed with sat. NaHCO 3 (aq) (1 x 50 mL), dried over MgSO 4 , filtered, and concentrated. The crude product was purified by normal phase silica gel column chromatography using EtOAc / Hexanes as eluents to yield the title compound.Step 4: tert-butyl (S)-(1-(1H-pyrazol-3-yl)but-3-en-1-yl)carbamate

[0155] To a solution of (S)-2-methyl-N-((S)-1-(1-tosyl-1H-pyrazol-3-yl)but-3-en-1-yl)propane-2-sulfinamide (1.3 g, 3.29 mmol) in MeOH (30 ml) was added HCl (4.11 ml, 16.43 mmol) (4.0 M in dioxane) at RT. The reaction mixture was stirred at 50°C under N 2 . After 1 day of stirring, the reaction mixture was cooled to RT, concentrated by rotorvap, and dried in vacuo. To a solution of the crude product in THF (20 ml) were added Boc 2 O (0.916 ml, 3.95 mmol) and TEA (2.292 ml, 16.44 mmol). The reaction mixture was stirred at RT under N 2 . After 2 hr of stirring, the reaction mixture was diluted with EtOAc (50 mL) and washed with sat NaHCO 3 (aq) (3 x 50 mL), dried over MgSO 4 , filtered, and concentrated. The crude product was purified by normal phase silica gel column chromatography using EtOAc / CH 2 Cl 2 as eluents to yield the title compound.Step 5: tert-butyl (S)-(1-(1-(2-methyl-2H-indazol-5-yl)-1H-pyrazol

[0156] To a solution of (S)-tert-butyl (1-(1H-pyrazol-3-yl)but-3-en-1-yl)carbamate (250 mg, 1.054 mmol) and 5-iodo-2-methyl-2H-indazole (408 mg, 1.580 mmol) in dioxane (5 mL) were added cuprous iodide (20.06 mg, 0.105 mmol), trans-n,n'-dimethylcyclohexane-1,2-diamine (0.034 mL, 0.211 mmol), and Cs 2 CO 3 (687 mg, 2.107 mmol). The reaction mixture was degassed by being under vacuum breifly and flushed with N 2 three times. Then, the reaction mixture was heated at reflux under N 2 . After 2 days of heating, the reaction mixture was cooled to RT and filtered with the help of EtOAc. Then, the filtrate was diluted with EtOAc (50 mL) and washed with sat. NaHCO 3 (aq) (1 x 50 mL), sat NH 4 Cl (1 x 50 mL), brine (1 x 50 mL), dried over MgSO 4 , filtered, and concentrated. The crude product was purified by normal phase silica gel column chromatography using EtOAc / Hexanes as eluents to yield the title compound.Intermediate 19tert-butyl (S)-(1-(1-(4-fluorophenyl)-1H-pyrazol-3-yl)but-3-en-1-yl)carbamate

[0157]

[0158] The title compound was prepared from the appropriate commercially available starting materials using procedures similar to those for the Intermediate 18 Step E.Intermediate20tert-butyl (1-(5-(4-fluorophenyl)isoxazol-3-yl)but-3-en-1-yl)carbamate

[0159] Step 1: (E)-N-((5-(4-fluorophenyl)isoxazol-3-yl)methylene)-2-methylpropane-2-sulfinamide

[0160] To a solution of 5-(4-fluorophenyl)isoxazole-3-carbaldehyde (0.3 g, 1.569 mmol) in CH 2 Cl 2 (5 ml) were added 2-methylpropane-2-sulfinamide (0.285 g, 2.354 mmol) and copper(II) sulfate (1.002 g, 6.28 mmol). The reaction mixture was stirred at RT under N 2 overnight. The reaction mixture was filtered through a pad of Celite and the filtrate was concentrated. The crude product was purified by normal phase silica gel column chromatography using EtOAc / Hexanes as eluents to yield the title compound.Step 2: N-(1-(5-(4-fluorophenyl)isoxazol-3-yl)but-3-en-1-yl)-2-methylpropane-2-sulfinamide

[0161] To a solution of (E)-N-((5-(4-fluorophenyl)isoxazol-3-yl)methylene)-2-methylpropane-2-sulfinamide (410 mg, 1.393 mmol) in THF (20 ml) at -78°C was added allylmagnesium chloride (0.905 ml, 1.811 mmol) dropwise. The reaction mixture was stirred at - 78°C under N 2 . After 1 hr of stirring, the reaction mixture was quenched by addition of sat NH 4 Cl (aq) (1 mL) at -78°C. The reaction mixture was warmed to RT. The reaction mixture was diluted with H 2 O (50 mL) and EtOAc (100 mL). The layers were separated and the organic layer was washed with sat NaHCO 3 (aq) (1 x 50 mL), dried over MgSO 4 , filtered, concentrated, and dried in vacuo. The title compound was used for the next reaction without further purification.Step 3: tert-butyl (1-(5-(4-fluorophenyl)isoxazol-3-yl)but-3-en-1-yl)carbamate

[0162] To a solution of N-(1-(5-(4-fluorophenyl)isoxazol-3-yl)but-3-en-1-yl)-2-methylpropane-2-sulfinamide (469 mg, 1.394 mmol) in MeOH (5 ml) was added HCl (0.523 ml, 2.091 mmol) (4.0 M in dioxane) at room temperature. The reaction mixture was stirred at RT under N 2 . After 1 hr of stirring, the reaction mixture was concentrated by rotorvap and further dried in vacuo. To a suspension of the crude product in THF (10 ml) were added Boc 2 O (0.421 ml, 1.814 mmol) and TEA (0.973 ml, 6.98 mmol). The reaction mixture was stirred at RT under N 2 overnight. The reaction mixture was diluted with EtOAc (50 mL) and washed with sat NaHCO 3 (aq) (2 x 50 mL), dried over MgSO 4 , filtered, and concentrated. The crude product was purified by normal phase silica gel column chromatography using EtOAc / Hexanes as eluents to yield the title compound.Intermediate 21tert-butyl (1-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)but-3-en-1-yl)carbamate

[0163]

[0164] The title compound was prepared from the appropriate commercially available starting materials using procedures similar to those for Intermediate 20.Intermediate 22tert-butyl (1-(2-(4-fluorophenyl)-2H-1,2,3-triazol-4-yl)but-3-en-1-yl)carbamate

[0165]

[0166] The title compound was prepared from the appropriate commercially available starting materials using procedures similar to those for Intermediate 20.Intermediate 23tert-butyl (S)-(1-(5-(2-fluorophenyl)isoxazol-3-yl)but-3-en-1-yl)carbamate

[0167] Step 1: 5-(2-fluorophenyl)-N-methoxy-N-methylisoxazole-3-carboxamide

[0168] To a solution of n,o-dimethylhydroxylamine hydrochloride (1.85 g, 18.97 mmol) and 5-(2-fluorophenyl)isoxazole-3-carboxylic acid (2.5 g, 11.46 mmol) in DMF (50 ml) were added EDC (2.5 g, 13.04 mmol), HOBt (0.018 g, 0.115 mmol), and TEA (7.99 ml, 57.3 mmol). The reaction mixture was stirred at RT under N 2 overnight. The reaction mixture was diluted with H 2 O (200 mL) and extracted with EtOAc (3 x 50 mL). All the organic extracts were combined and washed with sat NaHCO 3 (aq) (2 x 100 mL), H 2 O (5 x 100 mL), dried over MgSO 4 , filtered, and concentrated. The crude product was purified by normal phase silica gel column chromatography using EtOAc / Hexanes as eluents to yield the title compound.Step 2: 5-(2-fluorophenyl)isoxazole-3-carbaldehyde

[0169] To a solution of 5-(2-fluorophenyl)-N-methoxy-N-methylisoxazole-3-carboxamide (1.48 g, 5.91 mmol) in THF (50 ml) at -78 °C under N 2 was added DIBAL-H (14.79 ml, 14.79 mmol) dropwise. The reaction mixture was stirred at -78°C under N 2 . After 2 hr of stirring, the reaction mixture was quenched by addition of 5 mL sat. Rochell salt(aq) at -78°C. The reaction mixture was warmed to RT and diluted with sat. Rochelle salt(aq)(100 mL) and Et 2 O (50 mL). The crude reaction mixture was stirred vigorously at RT overnight. The layers were separated and the aqueous layer was extracted with EtOAc (1 x 50 mL). All the organic layers were combined, dried over MgSO 4 , filtered, concentrated and dried in vacuo to yield the title compound.Step 3: (S,E)-N-((5-(2-fluorophenyl)isoxazol-3-yl)methylene)-2-methylpropane-2-sulfinamide

[0170] To a solution of 5-(2-fluorophenyl)isoxazole-3-carbaldehyde (1.50 g, 7.85 mmol) in CH 2 Cl 2 (20 ml) were added (S)-2-methylpropane-2-sulfinamide (1.427 g, 11.77 mmol) and copper(II) sulfate (5.01 g, 31.4 mmol). The reaction mixture was stirred at room temperature under N 2 overnight. The reaction mixture was filtered through a pad of Celite and the filtrate was concentrated down. The crude product was purified by normal phase silica gel column chromatography using EtOAc / Hexanes as eluents to yield the title compound.Step 4: (S)-N-((S)-1-(5-(2-fluorophenyl)isoxazol-3-yl)but-3-en-1-yl)-2-methlpropane-2-sulfinamide

[0171] To a solution of (S,E)-N-((5-(2-fluorophenyl)isoxazol-3-yl)methylene)-2-methylpropane-2-sulfinamide (1.08 g, 3.67 mmol) in THF (25 ml) at -78°C was added allylmagnesium chloride (2.385 ml, 4.77 mmol) dropwise. The reaction mixture was stirred at -78°C under N 2 . After 1 hr of stirring, the reaction mixture was quenched by addition of sat NH 4 Cl(aq) (5 mL) at -78°C. The reaction mixture was warmed to RT. The reaction mixture was diluted with H 2 O (50 mL) and EtOAc (100 mL). The layers were separated and the organic layer was washed with sat. NaHCO 3 (aq) (1 x 50 mL), dried over MgSO 4 , filtered, and concentrated. The crude product was purified by normal phase silica gel column chromatography using EtOAc / Hexanes as eluents to yield the title compound.Step 5: tert-butyl (S)-(1-(5-(2-fluorophenyl)isoxazol-3-yl)but-3-en-1-yl)carbamate

[0172] To a solution of (S)-N-((S)-1-(5-(2-fluorophenyl)isoxazol-3-yl)but-3-en-1-yl)-2-methylpropane-2-sulfinamide (1.14 g, 3.39 mmol) in MeOH (20 ml) was added HCl (1.271 ml, 5.08 mmol) (4.0M in dioxane) at RT. The reaction mixture was stirred at RT under N 2 . After 1 hr of stirring, the reaction mixture was concentrated down by rotorvap and further dried in vacuo. To a suspension of the crude product in THF (10 ml) were added Boc 2 O (1.023 ml, 4.41 mmol) and TEA (2.363 ml, 16.95 mmol). The reaction mixture was stirred at RT under N 2 overnight. The reaction mixture was diluted with EtOAc (50 mL) and washed with sat NaHCO 3 (aq) (2 x 50 mL), dried over MgSO 4 , filtered, and concentrated. The crude product was purified by normal phase silica gel column chromatography using EtOAc / Hexanes as eluents to yield the title compound.Intermediate 24tert-butyl (S)-(1-(5-(2-methyl-2H-indazol-5-yl)isoxazol-3-yl)but-3-en-1-yl)carbamate

[0173] Step 1: ethyl 5-(2-methyl-2H-indazol-5-yl)isoxazole-3-carboxylate

[0174] To a suspension of ethyl 5-bromoisoxazole-3-carboxylate (4.8 g, 21.82 mmol) and (2-methyl-2H-indazol-5-yl)boronic acid (4.61 g, 26.2 mmol) in 1,4-Dioxane (100 ml) and Water (20.00 ml) were added 2nd generation xphos precatalyst (0.858 g, 1.091 mmol) and Cs 2 CO 3 (11.6 g, 35.6 mmol). The reaction mixture was degassed by N 2 stream for 20 min. Then the reaction mixture was stirred at 90°C under N 2 overnight. The reaction mixture was cooled to RT. The reaction mixture was filtered thru a pad of Celite to remove most of the insoluble ppts and concentrated by rotorvap to remove most of volatiles. Then, the reaction mixture was diluted with EtOAc (200 mL) and H 2 O (200 mL). The layers were separated and the aqueous layer was extracted with EtOAc (1 x 200 mL). All of the organic layers were combined, washed with H 2 O (1 x 50 mL), sat. NaHCO 3 (aq) (2 x 100 mL), dried over MgSO 4 , filtered and concentrated. The crude reaction mixture was purified by normal phase silica gel column chromatography usinge EtOAc / hexanes as eluents to yield the title compound.Step 2: (5-(2-methyl-2H-indazol-5-yl)isoxazol-3-yl)methanol

[0175] To a solution of ethyl 5-(2-methyl-2H-indazol-5-yl)isoxazole-3-carboxylate (3.55 g, 13.09 mmol) in THF (100 ml) and CH 2 Cl 2 (20 mL) at -78°C under N 2 was added DIBAL-H (31.4 ml, 31.4 mmol) dropwise. The reaction mixture was stirred uner N 2 and allowed to warm slowly up to RT. After 18 hr of stirring, the reaction mixture was cooled to -78°C and quenched by addition of 5 mL sat. Rochelle salt(aq) at -78°C. The reaction mixture was warmed to RT and diluted with sat. Rochelle salt(aq) (200 mL) and Et 2 O (200 mL). The crude reaction mixture was stirred vigorously at RT. The layers were separated and the aqueous layer was extracted with EtOAc (3 x 100 mL). All of the organic layers were combined, dried over MgSO 4 , filtered, and concentrated. The crude product was purified by normal phase silica gel column chromatography using EtOAc / Hexanes as eluents to yield the title compounds.Step 3: 5-(2-methyl-2H-indazol-5-yl)isoxazole-3-carbaldehyde

[0176] To a solution of (5-(2-methyl-2H-indazol-5-yl)isoxazol-3-yl)methanol (1.96 g, 8.55 mmol) in 1,4-dioxane (50 ml) was added manganese dioxide (3.72 g, 42.8 mmol). The suspension was heated at reflux under N 2 overnight. The reaction mixture was cooled to room temperature. The reaction mixture was filtered through a pad of Celite. The filtrate was concentrated and dried in vacuo to yield the title compound.Step 4: (S,E)-2-methyl-N-((5-(2-methyl-2H-indazol-5-yl)isoxazol-3-yl)methylene)propane-2-sulfinamide

[0177] To a solution of 5-(2-methyl-2H-indazol-5-yl)isoxazole-3-carbaldehyde (1.943 g, 8.55 mmol) in CH 2 Cl 2 (40 ml) were added (S)-2-methylpropane-2-sulfinamide (1.555 g, 12.83 mmol) and copper(II) sulfate (5.46 g, 34.2 mmol). The reaction mixture was stirred at room temperature under N 2 overnight. The reaction mixture was filtered through a pad of Celite with CH 2 Cl 2 and the filtrate was concentrated. The crude product was purified by normal phase silica gel column chromatography using EtOAc / CH 2 Cl 2 as eluents to yield the title compound.Step 5: (S)-2-methyl-N-((S)-1-(5-(2-methyl-2H-indazol-5-yl)isoxazol-3-yl)but-3-en-1-yl)propane-2-sulfinamide

[0178] To a solution of (S,E)-2-methyl-N-((5-(2-methyl-2H-indazol-5-yl)isoxazol-3-yl)methylene)propane-2-sulfinamide (550 mg, 1.665 mmol) in THF (20 ml) at -78°C was added allylmagnesium chloride (1.082 ml, 2.164 mmol) dropwise. The reaction mixture was stirred at - 78°C under N 2 . After 1 hr of stirring, the reaction mixture was quenched by addition of sat. NH 4 Cl(aq) (5 mL) at -78°C. The reaction mixture was warmed to RT. The reaction mixture was diluted with H 2 O (50 mL) and EtOAc (100 mL). The layers were separated and the organic layer was washed with sat NaHCO 3 (aq) (1 x 50 mL), dried over MgSO 4 , filtered, and concentrated. The crude product was purified by column chromatography using MeOH / CH 2 Cl 2 as eluents to yield the title compound.Step 6: tert-butyl (S)-(1-(5-(2-methyl-2H-indazol-5-yl)isoxazol-3-yl)but-3-en-1-yl)carbamate

[0179] To a solution of (S)-2-methyl-N-((S)-1-(5-(2-methyl-2H-indazol-5-yl)isoxazol-3-yl)but-3-en-1-yl)propane-2-sulfinamide (536.2 mg, 1.440 mmol) in MeOH (5 ml) was added HCl (0.540 ml, 2.159 mmol) (4.0M in dioxane) at RT. The reaction mixture was stirred at RT under N 2 . After 1 hr of stirring, the reaction mixture was concentrated down by rotorvap and dried in vacuo. To a suspension of crude product in THF (15 ml) were added Boc 2 O (0.502 ml, 2.161 mmol) and TEA (1.004 ml, 7.20 mmol). The reaction mixture was stirred at RT under N 2 overnight. The reaction mixture was diluted with EtOAc (50 mL) and washed with sat NaHCO 3 (aq) (2 x 50 mL), dried over MgSO 4 , filtered, and concentrated. The crude product was purified by normal phase silica gel column chromatography using EtOAc / Hexanes as eluents to yield the title compound.Intermediate 25tert-butyl (S)-(1-(5-(7-methoxy-2-methylquinolin-6-yl)isoxazol-3-yl)but-3-en-1-yl)carbamate

[0180]

[0181] The title compound was prepared from the appropriate commercially available starting materials using procedures similar to those for Intermediate 24.Reference Example 1(S)-N-(1-(4-(4-fluorophenyl)-1H-imidazol-2-yl)-7-(oxazol-2-yl)-7-oxoheptyl)-1-methylazetidine-3-carboxamide

[0182] Step 1: tert-butyl (S,E)-2-(1-((tert-butoxycarbonyl)amino)-7-(oxazol-2-yl)-7-oxohept-3-en-1-yl)-4-(4-fluorophenyl)-1H-imidazole-1-carboxylate

[0183] To a 50 ml one neck round bottom flaks was added toluene (5 ml) to mixture of (S)-tert-butyl 2-(1-((tert-butoxycarbonyl)amino)but-3-en-1-yl)-4-(4-fluorophenyl)-1H-imidazole-1-carboxylate ( Intermediate 4, 1 g, 2.317 mmol); Zhan catalyst-1B (100mg, 0.136 mmol) and 1-(oxazol-2-yl)pent-4-en-1-one (Intermediate 1, 900 mg, 5.95 mmol). The mixture was degassed and refilled with nitrogen and then was stirred at 50°C overnight. The reaction mixture was directly purified by Analogix (Redisep 40g column) eluting with 20% EtOAc-hexanes yielding (S,E)-tert-butyl 2-(1-((tert-butoxycarbonyl)amino)-7-(oxazol-2-yl)-7-oxohept-3-en-1-yl)-4-(4-fluorophenyl)-1H-imidazole-1-carboxylate. LC-MS: C 29 H 35 FN 4 O 6 , Caled [M+H] +< : 555.3, found [M+H] +< : 555.1.Step 2: (S,E)-7-amino-7-(4-(4-fluorophenyl)-1H-imidazol-2-yl)-1-(oxazol-2-yl)hept-4-en-1-one

[0184] To a 50 ml one neck round bottom flask was charged a solution of (S,E)-tert-butyl 2-(1-((tert-butoxycarbonyl)amino)-7-(oxazol-2-yl)-7-oxohept-3-en-1-yl)-4-(4-fluorophenyl)-1H-imidazole-1-carboxylate (500 mg, 0.902 mmol) in DCM (5 ml) / TFA (1 ml) and it was stirred overnight. The solvent was evaporated to provide (S,E)-7-amino-7-(4-(4-fluorophenyl)-1H-imidazol-2-yl)-1-(oxazol-2-yl)hept-4-en-1-one, TFA salt. C 19 H 19 FN 4 O 2 , calced Caled [M+H] +< : 355.2, found [M+H] +< : 355.1.Step 3: (S)-7-amino-7-(4-(4-fluorophenyl)-1H-imidazol-2-yl)-1-(oxazol-2-yl)heptan-1-one

[0185] A 50 ml one neck round bottom flask was charged with (S,E)-7-amino-7-(4-(4-fluorophenyl)-1H-imidazol-2-yl)-1-(oxazol-2-yl)hept-4-en-1-one, TFA (350 mg, 0.747 mmol) and 10% Pd / C (5mg) in methanol (10 ml). The flask was connected to a hydrogen balloon through a three-way joint. The flask was vaccumed and refilled with hydrogen three times. The mixture was stirred under a hydrogen balloon for 2 hours. The mixture was then filtered through a Celite pad, and washed with MeOH (10ml). The filtrate was concentrated and the residue was dissolved in CH 2 Cl 2 (100ml), water was added (30ml) and the solution was basified with conc. NH 4 OH (1ml). The organic layer was separated, dried over Na 2 SO 4 , then filtered and evaporated to afford (S)-7-amino-7-(4-(4-fluorophenyl)-1H-imidazol-2-yl)-1-(oxazol-2-yl)heptan-1-one. LC-MS: C 19 H 23 FN 4 O 2 , Caled [M+H] +< : 357.2, found [M+H] +< : 357.1.Step 4: (S)-N-(1-(4-(4-fluorophenyl)-1H-imidazol-2-yl)-7-(oxazol-2-yl)-7-oxoheptyl)-1-methylazetidine-3-carboxamide

[0186] To a 25 ml one neck round bottom flask was added 1-hydroxybenzotriazole (15 mg, 0.111 mmol) and EDCI (20 mg, 0.104 mmol) to solution of 1-methyl-3-azetidine carboxylic acid (15 mg, 0.130 mmol) and (S)-7-amino-7-(4-(4-fluorophenyl)-1H-imidazol-2-yl)-1-(oxazol-2-yl)heptan-1-one (30 mg, 0.084 mmol) in DMF (1 ml). The mixture was then stirred at room temperature overnight. The mixture was partitioned in EtOAc (50ml) and brine (10 ml). The organic layer was separated and dried over Na 2 SO 4 , then filtered and concentrated. The crude was purified on Analogix (Redisep 24g column) eluting with 7% MeOH / MeCl 2 yielding (S)-N-(1-(4-(4-fluorophenyl)-1H-imidazol-2-yl)-7-(oxazol-2-yl)-7-oxoheptyl)-1-methylazetidine-3-carboxamide. LC-MS: C 24 H 28 FN 5 O 3 , Caled [M+H] +< : 454.2, found [M+H] +< : 454.0. 1HNMR (CD 3 OD, 500 MHz) δ: 8.11 (1, 1H), 7.67 (t, 2H), 7.40 (s, 1H), 7.25 (s,1H), 7.09 (t,2H), 5.05 (t, 1H), 3.52 (m, 2H), 3.32 (s, 3H), 3.05 (m, 1H), 2.02 (m, 1H), 1.88 (m, 1H), 1.72 (m,2H), 1.25-1.45 (m, 4H) ppm.

[0187] Using similar chemistry as described above, the following compounds were prepared by using a different acid in Step 4 to provide the final amide coupling products: Example Structure IUPAC Name Exact Mass [M+H] +< Retention time (min) 2* (S)-N-(1-(4-(4-fluorophenyl)-1H-imidazol-2-yl)-7-(oxazol-2-yl)-7-oxoheptyl)thiazole-5-carboxamide468.12.523* (S)-N-(1-(4-(4-fluorophenyl)-1H-imidazol-2-yl)-7-(oxazol-2-yl)-7-oxoheptyl)-1-methylpiperidine-4-carboxamide482.12.154* (S)-N-((S)-1-(4-(4-fluorophenyl)-1H-imidazol-2-yl)-7-(oxazol-2-yl)-7-oxoheptyl)-6-methyl-6-azaspiro [2.5] octane-1-carboxamide508.12.105* N-((S)-1-(4-(4-fluorophenyl)-1H-imidazol-2-yl)-7-(oxazol-2-yl)-7-oxoheptyl)-6-oxaspiro[2.5]octane-1-carboxamide495.01.456* (S)-N-(1-(4-(4-fluorophenyl)-1H-imidazol-2-yl)-7-oxo-7-(thiazol-2-yl)heptyl)-1-methylpiperidine-4-carboxamide498.22.367* (S)-N-(1-(4-(4-fluorophenyl)-1H-imidazol-2-yl)-7-oxo-7-(thiazol-2-yl)heptyl)thiazole-5-carboxamide483.91.258* (S)-N-(1-(4-(4-fluorophenyl)-1H-imidazol-2-yl)-7-(4-methyloxazol-2-yl)-7-oxoheptvl)-1-methylpiperidine-4-carboxamide496.41.17* = reference example Example 9((S)-7-amino-7-(4-(2-methylquinolin-6-yl)-1H-imidazol-2-yl)-1-(oxazol-2-yl)heptan-1-one

[0188] Step 1: Preparation of 2-bromo-1-(2-methylquinolin-6-yl)ethanone (9B)

[0189] A mixture of 6-bromo-2-methylquinoline (9A, 2 g, 9.01 mmol), tributyl(1-ethoxyvinyl)stannane (5.41 g, 14.98 mmol) and Pd(PPh 3 ) 2 Cl 2 (0.316 g, 0.450 mmol) in toluene (20 mL) was degassed and backfilled with N 2 three times. The mixture was heated at 60°C for 12 h. The mixture was cooled and filtered, and the filter cake was washed with ethyl acetate (50 mL). The filtrate was concentrated to dryness. The crude product was purified by silica gel column flash chromatography (ISCO ®< ; 4 g SepaFlash ®< Silica Flash Column, Eluent of 0~20% EtOAc / Petro.Ether gradient @ 40 mL / min) to give 6-(1-ethoxyvinyl)-2-methylquinoline.

[0190] NBS (701 mg, 3.94 mmol) was added to a stirred solution of 6-(1-ethoxyvinyl)-2-methylquinoline (700 mg, 3.28 mmol) in THF (10 mL) at rt and the mixture was stirred at room temperature for 30 min. To the mixture water (30 mL) was added, and the mixture was extracted with ethyl acetate (2 x 20 mL). The combined organic fractions were washed with brine (saturated, 10 mL), dried (Na 2 SO 4 ), filtered and the solvent was evaporated under reduced pressure to give 2-bromo-1-(2-methylquinolin-6-yl)ethanone (9B) which was used in next step without purification. LCMS (ESI) calc'd for C 12 H 10 BrNO [M+H] +< : 264.0, 266.0, found: 263.9, 265.9.Step 2: Preparation of (S)-2-(2-methylquinolin-6-yl)-2-oxoethyl 2-((tert-butoxycarbonyl)amino)pent-4-enoate (9C)

[0191] DIEA (1 mL, 5.73 mmol) was added to a stirred solution of (S)-2-((tert-butoxycarbonyl)amino)pent-4-enoic acid (570 mg, 2.65 mmol) and 2-bromo-1-(2-methylquinolin-6-yl)ethanone (9B, 700 mg, 2.65 mmol) in DMF (2 mL) at rt and the mixture was stirred at rt for 10 h. Water (20 mL) was added to the reaction and the mixture was extracted with ethyl acetate (10 x 2 mL). The combined organic fractions were washed with brine (saturated, 10 mL), dried (Na 2 SO 4 ), filtered and the solvent was evaporated under reduced pressure. The crude product was purified by silica gel column flash chromatography (ISCO ®< ; 4 g SepaFlash ®< Silica Flash Column, Eluent of 0~70 % EtOAc / Petro.Ether gradient @ 40 mL / min) to give (S)-2-(2-methylquinolin-6-yl)-2-oxoethyl 2-((tert-butoxycarbonyl)amino)pent-4-enoate (9C). LCMS (ESI) calc'd for 15 2 H 26 N 2 O 5 [M+H] +< : 399.2, found: 399.1Step 3: Preparation of (S)-tert-butyl (1-(4-(2-methylquinolin-6-yl)-1H-imidazol-2-yl)but-3-en-1-yl)carbamate (9D)

[0192] NH 4 OAc (1.935 g, 25.10 mmol) was added to a stirred mixture of (S)-2-(2-methylquinolin-6-yl)-2-oxoethyl 2-((tert-butoxycarbonyl)amino)pent-4-enoate (9C, 1 g, 2.510 mmol) in toluene (20 mL) at rt and the mixture was stirred at rt for 12 h. The mixture was washed with water (20 mL) and extracted with EtOAc (20 x 3 mL). The combined organic fractions were washed with brine (saturated, 20 mL), dried (Na 2 SO 4 ), filtered and the solvent was evaporated under reduced pressure. The filtrate was concentrated to dryness. The crude product was purified by silica gel column flash chromatography (ISCO ®< ; 12 g SepaFlash ®< Silica Flash Column, Eluent of 0~70% EtOAc / Petro.Ether gradient @ 40 mL / min) to give (S)-tert-butyl (1-(4-(2-methylquinolin-6-yl)-1H-imidazol-2-yl)but-3-en-1-yl)carbamate (9D). LCMS (ESI) calc'd for 15 2 H 26 N 4 O 2 [M+H] +< : 379.2, found: 379.1Step 4: Preparation of ((S)-tert-butyl 2-(1-((tert-butoxvcarbonyl)amino)but-3-en-1-yl)-4-(2-methylquinolin-6-yl)-1H-imidazole-1-carboxylate (9E)

[0193] DMAP (16 mg, 0.131 mmol) was added to a stirred mixture of Bo150 (0.4 mL, 1.723 mmol) and (S)-tert-butyl (1-(4-(2-methylquinolin-6-yl)-1H-imidazol-2-yl)but-3-en-1-yl)carbamate (9D, 500 mg, 1.321 mmol) in DCM (10 mL) at rt and the mixture was stirred at rt for 2 h. The mixture was concentrated to dryness. The crude product was purified by silica gel column flash chromatography (ISCO ®< ; 12 g SepaFlash ®< Silica Flash Column, Eluent of 0~70% EtOAc / Petro.Ether gradient @ 40 mL / min) to give (S)-tert-butyl 2-(1-((tert-butoxycarbonyl)amino)but-3-en-1-yl)-4-(2-methylquinolin-6-yl)-1H-imidazole-1-carboxylate (9E). LCMS (ESI) calc'd for 15 7 H 34 N 4 O 4 [M+H] +< : 479.3, found: 479.3Step 5: Preparation of (S,E)-tert-butyl (1-(4-(2-methylquinolin-6-yl)-1H-imidazol-2-yl)-7-(oxazol-2-yl)-7-oxohept-3-en-1-yl)carbamate (9F)

[0194] A mixture of 1-(oxazol-2-yl)pent-4-en-1-one (1, 120 mg, 0.794 mmol), (S)-tert-butyl 2-(1-((tert-butoxycarbonyl)amino)but-3-en-1-yl)-4-(2-methylquinolin-6-yl)-1H-imidazole-1-carboxylate (9E, 380 mg, 0.794 mmol) and Zhan's catalyst (14 mg, 0.019 mmol) in toluene (5 mL) was degassed and backfilled with N 2 three times. The mixture was heated at 60°C for 12 h. The mixture was concentrated to dryness. The residue was purified by preparative HPLC (reverse phase C-18 column), eluting with acetonitrile / water + 0.1% TFA, to give (S,E)-tert-butyl (1-(4-(2-methylquinolin-6-yl)-1H-imidazol-2-yl)-7-(oxazol-2-yl)-7-oxohept-3-en-1-yl)carbamate (9F). LCMS (ESI) calc'd for 15 8 H 31 N 5 O 4 [M+H] +< : 502.2, found: 502.0Step 6: Preparation of (S)-tert-butyl (1-(4-(2-methylquinolin-6-yl)-1H-imidazol-2-yl)-7-(oxazol-2-yl)-7-oxoheptyl)carbamate (9G)

[0195] A solution of (S,E)-tert-butyl (1-(4-(2-methylquinolin-6-yl)-1H-imidazol-2-yl)-7-(oxazol-2-yl)-7-oxohept-3-en-1-yl)carbamate (9F, 140 mg, 0.279 mmol) in MeOH (5 mL) was added to a 100 mL flask and then Pd / C (30 mg, 0.028 mmol) (10%, wet) was added under Ar. The suspension was degassed under vacuum and purged with N 2 several times. The mixture was then stirred under H 2 (1 atm) at 20°C for 2 h. The mixture was filtered and the filter cake was washed with MeOH (5 mL x 3). The filtrate was concentrated to give (S)-tert-butyl (1-(4-(2-methylquinolin-6-yl)-1H-imidazol-2-yl)-7-(oxazol-2-yl)-7-oxoheptyl)carbamate (9G) which was used to the next step without further purification. LCMS (ESI) calc'd for 15 8 H 33 N 5 O 4 [M+H] +< : 504.2, found: 504.1Step 7: Preparation of (S)-7-amino-7-(4-(2-methylquinolin-6-yl)-1H-imidazol-2-yl)-1-(oxazol-2-yl)heptan-1-one (9)

[0196] TFA (1 mL, 12.98 mmol) was added to a stirred mixture of (S)-tert-butyl 2-(1-((tert-butoxycarbonyl)amino)-7-(oxazol-2-yl)-7-oxoheptyl)-4-(2-methylquinolin-6-yl)-1H-imidazole-1-carboxylate (9G, 100 mg, 0.166 mmol) in DCM (1 mL) at rt and the mixture was stirred at room temperature for 2 h. The mixture was concentrated and the residue was purified by preparative HPLC (reverse phase C-18 column), eluting with acetonitrile / water + 0.1% TFA, and the solution was concentrated and adjusted to pH = 8 with Na 2 CO 3 (sat.). The solution was extracted with DCM (10 mL x 3) and concentrated to give (S)-7-amino-7-(4-(2-methylquinolin-6-yl)-1H-imidazol-2-yl)-1-(oxazol-2-yl)heptan-1-one (9). The solid was dissolved in water and HCl (0.2 mL, 1 M) was added. The solution was lyophilized to give the HCl salt. LCMS (ESI) calc'd for C 23 H 25 N 5 O 2 [M+H] +< : 404.2, found: 404.2. 1< H NMR (400 MHz, MeOD) δ 9.00-9.08 (m, 1H), 8.69-8.76 (m, 1H), 8.58-8.62 (m, 1H), 8.16-8.28 (m, 1H), 8.05-8.14 (m, 2H), 7.93-8.00 (m, 1H), 7.33-7.41 (m, 1H), 2.96-3.14 (m, 8H), 1.66-1.82 (m, 3H), 1.31-1.57 (m, 5H).Example 10(S)-6-(2-(1-amino-7-(oxazol-2-yl)-7-oxoheptyl)-1H-imidazol-4-yl)-2-ethylisoquinolin-1(2H)-one

[0197] Step 1: Preparation of (S,E)-tert-butyl 2-(1-((tert-butoxycarbonyl)amino)-7- (oxazol-2-yl)-7-oxohept-3-en-1-vl)-4-(2-ethyl-1-oxo-1,2-dihydroisoquinolin-6-yl)-1H-imidazole-1-carboxylate (10A)

[0198] PdCl 2 (DTBPF) (18 mg, 0.028 mmol) was added to a stirred mixture of (S,E)-tert-butyl-4-bromo-2-(1-((tert-butoxycarbonyl)amino)-7-(oxazol-2-yl)-7-oxohept-3-en-1-yl)-1H-imidazole-1-carboxylate (16, 150 mg, 0.278 mmol), 2-ethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1(2H)-one (56 mg, 0.187 mmol) and K 3 PO 4 (177 mg, 0.834 mmol) in THF (2 ml) and water (0.5 ml) at room temperature and the mixture was heated with stirring at 70°C for 16 h. The mixture was cooled to room temperature, water (2 mL) was added and the mixture was extracted with ethyl acetate (3 x 5 mL). The combined organic fractions were washed with brine (saturated, 1 x 5 mL), dried (Na 2 SO 4 ), filtered and the solvent was evaporated under reduced pressure. The residue was purified by silica gel flash chromatography (ISCORF75; Sepa flash column), eluting with petroleum ether / EtOAc = 100 / 0 ~ 1 / 2 to give (S,E)-tert-butyl 2-(1-((tert-butoxycarbonyl)amino)-7 -(oxazol-2-yl)-7-oxohept-3-en-1-yl)-4-(2-ethyl-1-oxo-1,2-dihydroisoquinolin-6-yl)-1H-imidazole-1-carboxylate (10A). LCMS (ESI) calc'd for C 34 H 41 N 5 O 7 [M+H] +< : 632.3, found: 632.4Step 2: Preparation of (S,E)-6-(2-(1-amino-7-(oxazol-2-yl)-7-oxohept-3-en-1-yl)- 1H-imidazol-4-yl)-2-ethylisoquinolin-1(2H)-one (10B)

[0199] TFA (0.6 ml, 0.095 mmol) was added to a stirred mixture of (S,E)-tert-butyl-2-(1-((tert-butoxycarbonyl)amino)-7-(oxazol-2-yl)-7-oxohept-3-en-1-yl)-4-(2-ethyl-1-oxo-1,2-dihydroisoquinolin-6-yl)-1H-imidazole-1-carboxylate (4A, 60 mg, 0.095 mmol) in DCM (6 ml) at rt and the mixture was stirred at room temperature for 2 h. All the volatiles were removed by evaporator to give (S,E)-6-(2-(1-amino-7-(oxazol-2-yl)-7-oxohept-3-en-1-yl)-1H-imidazol-4-yl)-2-ethylisoquinolin-1(2H)-one (4B) which was used directly for hydrogenation. A pure batch was purified by preparative HPLC (reverse phase C-18 column), eluting with acetonitrile / water + 0.1% TFA, to give (S,E)-6-(2-(1-amino-7-(oxazol-2-yl)-7-oxohept-3-en-1-yl)-1H-imidazol-4-yl)-2-ethylisoquinolin-1(2H)-one as a white solid. LCMS (ESI) calc'd for 15 4 H 25 N 5 O 3 [M+H] +< : 432.2, found: 432.2. 1< H NMR (400 MHz, MeOD) δ 8.22-8.33 (m, 1H), 7.85-8.05 (m, 3H), 7.69-7.76 (m, 1H), 7.32-7.44 (m, 2H), 6.66-6.75 (m, 1H), 5.59-5.75 (m, 1H), 5.36-5.52 (m, 1H), 4.47-4.58 (m, 1H), 4.04-4.16 (m, 2H), 2.97-3.13 (m, 2H), 2.72-2.88 (m, 2H), 2.37-2.46 (m, 2H), 1.36 (t, J= 8.0 Hz, 3H).Step 3: Preparation of (S)-6-(2-(1-amino-7-foxazol-2-yl)-7-oxoheptyl)-1H- imidazol-4-yl)-2-ethylisoquinolin-1(2H)-one (Example 10)

[0200] A solution of (S,E)-6-(2-(1-amino-7-(oxazol-2-yl)-7-oxohept-3-en-1-yl)- 1H-imidazol-4-yl)-2-ethylisoquinolin-1(2H)-one (35 mg, 0.081 mmol) in MeOH (2 ml) was added to a flask and then Pd-C (20 mg, 0.019 mmol) (10%, wet) was added under Ar. The suspension was degassed under vacuum and purged with N 2 several times. The mixture was then stirred under H 2 (Pressure: 15 psi) at rt for 4 h. It was filtered on Celite then the filter cake was washed with methanol (3 x 5 mL). The filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (reverse phase C-18 column), eluting with acetonitrile / water + 0.05% NH 3 ·H 2 O, to give (S)-6-(2-(1-amino-7-(oxazol-2-yl)-7-oxoheptyl)-1H-imidazol-4-yl)-2-ethylisoquinolin-1(2H)-one (Example 10). LCMS (ESI) calc'd for C 24 H 27 N 5 O 3 [M+H] +< : 434.2, found: 434.2

[0201] L-(+)-tartaric acid (7 mg, 0.047 mmol) was added to a stirred mixture of (S)-6-(2-(1-amino-7-(oxazol-2-yl)-7-oxoheptyl)-1H-imidazol-4-yl)-2-ethylisoquinolin-1(2H)-one (4, 15 mg, 0.035 mmol) in acetonitrile (1 ml) and water (1 ml) at rt and the mixture was lyophylized to give (S)-6-(2-(1-amino-7-(oxazol-2-yl)-7-oxoheptyl)-1H-imidazol-4-yl)-2-ethylisoquinolin-1(2H)-one (2R,3R)-2,3-dihydroxysuccinate (4). 1< H NMR (400 MHz, MeOD) δ 8.25-8.31 (m, 1H), 8.05-8.09 (m, 1H), 7.98-8.04 (m, 1H), 7.89-7.95 (m, 1H), 7.68-7.73 (m, 1H), 7.35-7.40 (m, 2H), 6.66-6.79 (m, 1H), 4.52 (s, 2H), 4.09 (d, J= 7.3 Hz, 2H), 3.03 (s, 2H), 2.14-2.27 (m, 1H), 2.01-2.13 (m, 1H), 1.64-1.77 (m, 2H), 1.28-1.47 (m, 8H).

[0202] The following compounds were prepared using similar porcedures to those described above via Suzuki coupling from intermediate 16 and commercially available reagents or intermediates: Example # Structure Exact Mass[M+H] +< Observed[M+H] +< 11 Calc'd 384.2,found 384.112 Calc'd 434.2,found434.013 Calc'd 421.2,found 421.114 Calc'd 419.2,found 419.115 Calc'd 420.2,Found 420.1 Example 16(S)-7-amino-1-(oxazol-2-yl)-7-(5-(quinolin-6-yl)-1H-imidazol-2-yl)heptan-1-one

[0203] Step 1: Preparation of (R)-2-methyl-N-((S)-6-(2-(oxazol-2-yl)-1,3-dioxolan-2-yl)-1-(5-(quinolin-6-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)hexyl)propane-2-sulfinamide (16A)

[0204] PdCl 2 (DTBPF) (15 mg, 0.023 mmol) was added to a mixture of (R)-N-((S)-1-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-6-(2-(oxazol-2-yl)-1,3-dioxolan-2-yl)hexyl)-2-methylpropane-2-sulfinamide (14, 132 mg, 0.213 mmol), K 3 PO 4 (142 mg, 0.669 mmol) and 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline (67 mg, 0.263 mmol) in co-solvents of THF (2 ml) and water (0.2 ml) at rt and the mixture was stirred at 80°C for 5 h. The mixture was diluted with water (10 mL), and extracted with ethyl acetate (3 x 10 mL). The combined organic fractions were washed with brine (saturated, 8 mL), dried (Na 2 SO 4 ), filtered and the solvent was evaporated under reduced pressure. The residue was purified by preparative TLC on silica gel, eluting with EtOAc to give (R)-2-methyl-N-((S)-6-(2-(oxazol-2-yl)-1,3-dioxolan-2-yl)-1-(5-(quinolin-6-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)hexyl)propane-2-sulfinamide (16A). LCMS (ESI) calc'd for C 34 H 49 N 5 O 5 SSi [M+H] +< : 668.9, found: 668.5Step 2: Preparation of (S)-7-amino-1-(oxazol-2-yl)-7-(5-(quinolin-6-yl)-1H-imidazol-2-yl)heptan-1-one (Example 16)

[0205] HCl (0.014 ml, 0.172 mmol) was added to a stirred mixture of (R)-2-methyl-N-((S)-6-(2-(oxazol-2-yl)-1,3-dioxolan-2-yl)-1-(5-(quinolin-6-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)hexyl)propane-2-sulfinamide (16A, 115 mg, 0.172 mmol) in co-solvents of MeOH (2 ml) and water (0.2 ml) at 50°C and the mixture was stirred at 50°C for 16 h. The solvent was evaporated under reduced pressure. The residue was purified by preparative HPLC (reverse phase C-18 column), eluting with acetonitrile / water + 0.1% TFA, to give a TFA salt of (S)-7-amino-1-(oxazol-2-yl)-7-(5-(quinolin-6-yl)-1H-imidazol-2-yl)heptan-1-one. The TFA salt was neutralized with aqueous Na 2 CO 3 (saturated, 20 mL), and extracted with DCM (3 x 15 mL). The combined organic fractions were washed with brine (saturated, 10 mL), dried (Na 2 SO 4 ), filtered and the solvent was evaporated under reduced pressure to give (S)-7-amino-1-(oxazol-2-yl)-7-(5-(quinolin-6-yl)-1H-imidazol-2-yl)heptan-1-one (6). LCMS (ESI) calc'd for C 22 H 23 N 5 O 2 [M+H] +< : 390.4, found: 390.2.

[0206] L-tartaric acid (17 mg, 0.113 mmol) was added to (S)-7-amino-1-(oxazol-2-yl)-7-(5-(quinolin-6-yl)-1H-imidazol-2-yl)heptan-1-one (6, 45 mg, 0.116 mmol) in co-solvents of acetonitrile (5 ml) and water (30 ml) at rt and the mixture was stirred at rt for 20 mins. The mixture was lyophilized to give (S)-7-amino-1-(oxazol-2-yl)-7-(5-(quinolin-6-yl)-1H-imidazol-2-yl)heptan-1-one 2,3-dihydroxysuccinate (Example 16). 1< H NMR (400 MHz, D 2 O) δ 8.72 (d, J = 5.07 Hz, 1H), 8.62 (d, J = 8.16 Hz, 1H), 8.01-8.10 (m, 2H), 7.88 (d, J = 8.82 Hz, 1H), 7.66 (dd, J = 8.38, 5.29 Hz, 1H), 7.61 (s, 1H), 7.51 (s, 1H), 6.96 (s, 1H), 4.36-4.45 (m, 1H), 4.23 (s, 2H), 2.60-2.80 (m, 2H), 1.89-2.06 (m, 2H), 1.44 (t, J = 6.84 Hz, 2H), 0.97-1.29 (m, 5H).

[0207] The following compounds were prepared using similar porcedures to those described above via Suzuki coupling from intermediate 16 and commercially available reagents or intermediates: Example # Structure Exact Mass [M+H] +< Observed [M+H] +< 17 Calc'd 448.2, found448.218 Calc'd 433.2, found433.119 Calc'd 459.2, found459.120 Calc'd 417.2, found417.021 Calc'd 450.2, found450.022 Calc'd 438.2, found438.0 Example 23(S)-7-amino-7-(4-(7-methoxyquinolin-6-yl)-1H-imidazol-2-yl)-1-(oxazol-2-yl)heptan-1-one

[0208] Step 1: Preparation of (S)-tert-butyl 2-(1-((tert-butoxycarbonyl)amino)but-3-en-1-yl)-4-(7-methoxyquinolin-6-yl)-1H-imidazole-1-carboxylate (23A)

[0209] PdCl 2 (DTBPF) (100 mg, 0.153 mmol) was added to a mixture of (S)-tert-butyl 4-bromo-2-(1-((tert-butoxycarbonyl)amino)but-3-en-1-yl)-1H-imidazole-1-carboxylate (5, 1 g, 2.402 mmol), 7-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline (1.020 g, 3.58 mmol) and K 3 PO 4 (1.56 g, 7.35 mmol) in co-solvents of THF (20 ml) and water (2 ml) at rt and the mixture was stirred at 80°C for 3.5 h. The mixture was cooled to rt, diluted with water (20 mL), extracted with DCM (3 x 20 mL). The combined organic fractions were washed with brine (15 mL), dried (Na 2 SO 4 ), filtered and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column flash chromatography, eluting with petroleum ether / EtOAc = 0~50% to give (S)-tert-butyl 2-(1-((tert-butoxycarbonyl)amino)but-3-en-1-yl)-4-(7-methoxyquinolin-6-yl)-1H-imidazole-1-carboxylate (23A). LCMS (ESI) calc'd for C 27 H 34 N 4 O 5 [M+Na] +< : 495.3, found: 517.0 (M+Na +< ). 1< H NMR (400 MHz, CDCl 3 ) δ 8.81 (d, J= 3.09 Hz, 1H), 8.60-8.67 (m, 1H), 8.20 (d, J = 7.50 Hz, 1H), 7.98 (s, 1H), 7.50 (s, 1H), 7.30 (dd, J = 7.94, 4.41 Hz, 1H), 5.76-5.87 (m, 2H), 5.61 (d, J = 6.17 Hz, 1H), 5.05-5.13 (m, 2H), 4.08-4.12 (m, 3H), 2.68-2.80 (m, 1H), 2.48-2.59 (m, 1H), 1.68 (s, 8H), 1.43-1.53 (m, 8H).Step 2: Preparation of (S)-tert-butyl 2-(1-((tert-butoxycarbonyl)amino)-7-(oxazol-2-yl)-7-oxohept-3-en-1-yl)-4-(7-methoxyquinolin-6-yl)-1H-imidazole-1-carboxylate (23B) UMICORE

[0210] M71 SIPR (11 mg, 0.013 mmol) was added to a mixture of (S)-tert-butyl 2-(1-((tert-butoxycarbonyl)amino)but-3-en-1-yl)-4-(7-methoxyquinolin-6-yl)-1H-imidazole-1-carboxylate (5A, 97 mg, 0.196 mmol) and 1-(oxazol-2-yl)pent-4-en-1-one (5, 112 mg, 0.741 mmol) in toluene (1 ml) which was bubbled with N 2 for 10 mins at rt. The mixture was degassed and backfilled with N 2 three times and stirred at 100°C for 60 min under microwave. The residue was purified by preparative TLC on silica gel, eluting with DCM / MeOH = 20: 1 to give (S)-tert-butyl 2-(1-((tert-butoxycarbonyl)amino)-7-(oxazol-2-yl)-7-oxohept-3-en-1-yl)-4-(7-methoxyquinolin-6-yl)-1H-imidazole-1-carboxylate (23B). LCMS (ESI) calc'd for C 23 H 39 N 5 O 7 [M+H] +< : 618.3, found: 618.3Step 3: Preparation of (S)-7-amino-7-(4-(7-methoxyquinolin-6-yl)-1H-imidazol-2-yl)-1-(oxazol-2-yl)hept-4-en-1-one (23C)

[0211] TFA (0.5 ml, 6.49 mmol) was added to a stirred mixture of (S)-tert-butyl 2-(1-((tert-butoxycarbonyl)amino)-7-(oxazol-2-yl)-7-oxohept-3-en-1-yl)-4-(7-methoxyquinolin-6-yl)-1H-imidazole-1-carboxylate (23B, 32 mg, 0.052 mmol) in DCM (5 ml) at rt and the mixture was stirred at rt for 2 h. The solvent was evaporated under reduced pressure. Half of the residue was purified by preparative HPLC (reverse phase C-18 column), eluting with acetonitrile / water + 0.1% TFA, to give (S)-7-amino-7-(4-(7-methoxyquinolin-6-yl)-1H-imidazol-2-yl)-1-(oxazol-2-yl)hept-4-en-1-one (23C). LCMS (ESI) calc'd for C 23 H 23 N 5 O 3 [M+H] +< : 418.2, found: 418.2. 1< H NMR (400 MHz, MeOD) δ 8.95-9.06 (m, 1H), 8.95 (s, 1H), 8.87-9.07 (m, 1H), 8.90 (brs, 1H), 8.87-8.88 (m, 1H), 8.68-8.77 (m, 1H), 8.03-8.08 (m, 1H), 8.06 (s, 1H), 7.92-7.96 (m, 1H), 7.91-7.92 (m, 1H), 7.83-7.92 (m, 1H), 7.61-7.66 (m, 1H), 7.60-7.66 (m, 1H), 7.63 (s, 1H), 7.56-7.56 (m, 1H), 7.54 (brs, 1 H), 7.32-7.36 (m, 1H), 7.32-7.37 (m, 1H), 7.32-7.37 (m, 1H), 7.35 (s, 1H), 7.28-7.28 (m, 1H), 7.26 (brs, 1H), 5.70 (d, J = 6.61 Hz, 1H), 5.34-5.53 (m, 1H), 4.84 (brs, 1H), 4.54 (d, J= 6.84 Hz, 1H), 4.17-4.18 (m, 1H), 4.14-4.31 (m, 1H), 3.31 (brs, 7H), 3.09 (t, J = 6.62 Hz, 2H), 2.62-2.88 (m, 2H), 2.28-2.52 (m, 2H).Step 5: Preparation of (S)-7-amino-7-(4-(7-methoxyquinolin-6-yl)-1H-imidazol-2-yl)-1-(oxazol-2-yl)heptan-1-one (23)

[0212] Pd-C (10%, 40 mg, 0.038 mmol) was added to a stirred mixture of (S)-7-amino-7-(4-(7-methoxyquinolin-6-yl)-1H-imidazol-2-yl)-1-(oxazol-2-yl)hept-4-en-1-one (23C, 30 mg, 0.072 mmol) in MeOH (10 ml) at rt and the mixture was stirred at rt for 4 h under a H 2 ballon. The mixture was filtered and the filter cake was washed with MeOH (20 mL). The filtrate was concentrated to dryness. The residue was purified by preparative HPLC (reverse phase C-18 column), eluting with acetonitrile / water + 0.05% NH 3 ·H 2 O, to give (S)-7-amino-7-(4-(7-methoxyquinolin-6-yl)-1H-imidazol-2-yl)-1-(oxazol-2-yl)heptan-1-one (5). LCMS (ESI) calc'd for C 23 H 25 N 5 O 3 [M+H] +< : 420.2, found: 420.0

[0213] L-tartaric acid (6 mg, 0.040 mmol) was added to (S)-7-amino-7-(4-(7-methoxyquinolin-6-yl)-1H-imidazol-2-yl)-1-(oxazol-2-yl)heptan-1-one (23, 15 mg, 0.036 mmol) in co-solvents of acetonitrile (5 ml) and water (30 ml) at rt and the mixture was stirred at rt for 20 mins. The mixture was lyophilized to give (S)-7-amino-7-(4-(7-methoxyquinolin-6-yl)-1H-imidazol-2-yl)-1-(oxazol-2-yl)heptan-1-one 2,3-dihydroxysuccinate (23). 1< H NMR (400 MHz, D 2 O) δ 8.64-8.76 (m, 2H), 8.28 (s, 1H), 7.61-7.68 (m, 3H), 7.28 (s, 1H), 6.99 (s, 1H), 4.43-4.50 (m, 2H), 4.38 (s, 6H), 3.94 (s, 3H), 2.60-2.78 (m, 2H), 1.91-2.08 (m, 2H), 1.44 (brs, 2H), 1.18-1.31 (m, 1H), 1.09 (brs, 3H).Example24(S)-7-amino-7-(4-(6-cyclopropyl-2-methoxypyridin-3-yl)-1H-imidazol-2-yl)-1-(oxazol-2-yl)heptan-1-one

[0214] Step 1: (S)-7-amino-7-(4-bromo-1H-imidazol-2-yl)-1-(oxazol-2-yl)heptan-1-one (24A)

[0215] Conc. HCl (5 ml, 60.9 mmol) was added to a stirred mixture of (R)-N-((S)-1-(4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-6-(2-(oxazol-2-yl)-1,3-dioxolan-2-yl)hexyl)-2-methylpropane-2-sulfinamide (14, 1.365 g, 2.203 mmol) in co-solvents of MeOH (20 ml) and water (2 mL) and the mixture was stirred at 60°C for 6 h. The mixture was diluted with MeOH (50 mL) and concentrated in vacuo to give (S)-7-amino-7-(4-bromo-1H-imidazol-2-yl)-1-(oxazol-2-yl)heptan-1-one (60A) which was used to the next step without purification. LCMS (ESI) calc'd for C 13 H 17 BrN 4 O 2 [M+H] +< : 341.1, found: 343.0Step 2: (S)-tert-butyl 4-bromo-2-(1-((tert-butoxycarbonyl)amino)-7-(oxazol-2-yl)-7-oxoheptyl)-1H-imidazole-1-carboxylate (24B)

[0216] Bo15O (2.128 ml, 9.16 mmol) was added to a stirred mixture of DIPEA (3 ml, 17.18 mmol) and (S)-7-amino-7-(4-bromo-1H-imidazol-2-yl)-1-(oxazol-2-yl)heptan-1-one (24A , 650 mg, 1.905 mmol) in DCM (20 ml) and the mixture was stirred at rt for 16 h. The mixture was diluted with DCM (60 mL), washed with brine (saturated, 3 x 20 mL), dried (Na 2 SO 4 ), filtered and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column flash chromatography, eluting with petroleum ether / EtOAc = 0~40% to give (S)-tert-butyl 4-bromo-2-(1-((tert-butoxycarbonyl)amino)-7-(oxazol-2-yl)-7-oxoheptyl)-1H-imidazole-1-carboxylate (24B).Step 3: (S)-tert-butyl 2-(1-((tert-butoxycarbonyl)amino)-7-(oxazol-2-yl)-7-oxoheptyl)-4-(6-chloro-2-methoxypyridin-3-yl)-1H-imidazole-1-carboxylate (24C)

[0217] PdCl 2 (DTBPF) (45 mg, 0.069 mmol) was added to a stirred mixture of (S)-tert-butyl 4-bromo-2-(1-((tert-butoxycarbonyl)amino)-7-(oxazol-2-yl)-7-oxoheptyl)-1H-imidazole-1-carboxylate (24B, 634 mg, 1.171 mmol), (6-chloro-2-methoxypyridin-3-yl)boronic acid (252 mg, 1.345 mmol) and K 3 PO 4 (810 mg, 3.82 mmol) in co-solvents of THF (7 ml) and water (0.7 ml) at rt and the mixture was stirred at 60°C for 2 h. The mixture was diluted with water (20 mL), extracted with DCM (3 x 15 mL). The combined organic fractions were washed with brine (saturated, 20 mL), dried (Na 2 SO 4 ), filtered and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column flash chromatography, eluting with petroleum ether / EtOAc = 0~20 to give (S)-tert-butyl 2-(1-((tert-butoxycarbonyl)amino)-7-(oxazol-2-yl)-7-oxoheptyl)-4-(6-chloro-2-methoxypyridin-3-yl)-1H-imidazole-1-carboxylate (24C). LCMS (ESI) calc'd for C 29 H 38 ClN 5 O 7 [M+H] +< : 604.2, found: 604.3Step 4: (S)-tert-butyl (1-(4-(6-cyclopropyl-2-methoxypyridin-3-yl)-1H-imidazol-2-yl)-7-(oxazol-2-yl)-7-oxoheptyl)carbamate (24D)

[0218] PdCl 2 (DTBPF) (80 mg, 0.123 mmol) was added to a stirred mixture of cyclopropylboronic acid (543 mg, 6.32 mmol), (S)-tert-butyl 2-(1-((tert-butoxycarbonyl)amino)-7-(oxazol-2-yl)-7-oxoheptyl)-4-(6-chloro-2-methoxypyridin-3-yl)-1H-imidazole-1-carboxylate (60C, 420 mg, 0.695 mmol) and Cs 2 CO 3 (2.43 g, 7.46 mmol) in co-solvents of 1,4-dioxane (6 ml) and water (0.6 ml) at rt and the mixture was stirred at 80°C for 12 h. The mixture was diluted with water (15 mL), extracted with DCM (3 x 15 mL). The combined organic fractions were washed with brine (saturated, 20 mL), dried (Na 2 SO 4 ), filtered and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column flash chromatography, eluting with petroleum ether / EtOAc = 0~40% to give (S)-tert-butyl (1-(4-(6-cyclopropyl-2-methoxypyridin-3-yl)-1H-imidazol-2-yl)-7-(oxazol-2-yl)-7-oxoheptyl)carbamate (24D). LCMS (ESI) calc'd for C 22 H 43 N 5 O 7 [M+H] +< : 610.3, found: 610.3Step 5: (S)-7-amino-7-(4-(6-cyclopropyl-2-methoxypyridin-3-y1)-1H-imidazol-2-yl)-1-(oxazol-2-yl)heptan-1-one (Example 24)

[0219] TFA (2mL, 26.0 mmol) was added to (S)-tert-butyl (1-(4-(6-cyclopropyl-2-methoxypyridin-3-yl)-1H-imidazol-2-yl)-7-(oxazol-2-yl)-7-oxoheptyl)carbamate (24D, 80 mg, 0.157 mmol) in DCM (2 ml) and the mixture was stirred at rt for 1 h. TFA and DCM was removed under N 2 flow. The residue was purified by preparative HPLC (reverse phase C-18 column), eluting with acetonitrile / water + 0.1% TFA, to give (S)-7-amino-7-(4-(6-cyclopropyl-2-methoxypyridin-3-yl)-1H-imidazol-2-yl)-1-(oxazol-2-yl)heptan-1-one (Example 24). LCMS (ESI) calc'd for C 22 H 27 N 5 O 3 [M+H] +< : 410.2, found: 410.2. 1< H NMR (400 MHz, MeOD) δ 8.03-8.11 (m, 2H), 7.66 (s, 1H), 7.38 (s, 1H), 6.93 (d, J = 7.72 Hz, 1H), 4.50-4.60 (m, 1H), 4.56 (dd, J = 6.17, 8.82 Hz, 1H), 3.99 (s, 3H), 3.04 (t, J = 7.28 Hz, 2H), 2.05-2.21 (m, 1H), 2.05-2.22 (m, 1H), 2.05-2.22 (m, 1H), 2.02-2.04 (m, 1H), 1.98-2.02 (m, 1H), 1.72 (m, 2H), 1.23-1.49 (m, 1H), 1.23-1.50 (m, 3H), 0.89-1.07 (m, 4H).Example 25(S)-7-amino-7-(4-chloro-2-(4-fluorophenyl)-lH-imidazol-5-yl)-1-(oxazol-2-yl)heptan-1-one

[0220] Step 1: 4,5-dibromo-2-(4-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (25A)

[0221] To a mixture of 2,4,5-tribromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (5_2) (10.50 g, 24.14 mmol) in Dioxane (97 ml) at ambeint temperature was added (4-fluorophenyl)boronic acid (3.38 g, 24.14 mmol) and K 3 PO 4 (12.81 g, 60.3 mmol) dissolved in Water (24.14 ml). Pd(Ph 3 P) 4 (0.837 g, 0.724 mmol) was added and the mixture was heated to 100°C and stirred for 2 hours. The mixture was cooled and water (100 mL) was added. Extract with EtOAc (3x @ 100 mL), dry over Na 2 SO 4 , and concentrate. The resulting residue was purified using an ISCO (220 g, silica) with a solvent system of 2% to 40% 3:1 EtOAc:EtOH / hexanes to give 4,5-dibromo-2-(4-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (25A).Step 2: Preparation of 4-bromo-5-chloro-2-(4-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (25B)

[0222] nBuLi (1.75 ml, 4.38 mmol) was added to a stirred mixture of 4,5-dibromo-2-(4-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (25A, 2.0 g, 4.44 mmol) in THF (20 ml) at -78°C and the mixture was stirred at -78°C for 30 min. Hexachloroethane (0.65 ml, 5.74 mmol) was added. The mixture was stirred at -78°C for 2 h. The mixture was quenched with aqueous NH 4 Cl (saturated, 30 mL) and the mixture was extracted with ethyl acetate (3 x30 mL). The combined organic fractions were washed with brine (saturated, 2 x 30 mL), dried (Na 2 SO 4 ), filtered and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column flash chromatography, eluting with petroleum ether / EtOAc = 10:1 to give 4-bromo-5-chloro-2-(4-fluorophenyl)-1-((2 - (trimethylsilyl)ethoxy)methyl)-1H-imidazole (25B). LCMS (ESI) calc'd for C 15 H 19 BrClFN 2 OSi [M+H] +< : 405.0, found: 407.1.Step 3: Preparation of (R)-N-((S)-1-(4-chloro-2-(4-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-6-(2-(oxazol-2-yl)-1,3-dioxolan-2-yl)hexyl)-2-methylpropane-2-sulfinamide (25C)

[0223] nBuLi (0.3 ml, 0.750 mmol) was added to a stirred mixture of 4-bromo-5-chloro-2-(4-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (25B, 251 mg, 0.619 mmol) in THF (2.0 ml) at -78°C and the mixture was stirred at -78°C for 10 min. (R,E)-2-methyl-N-(6-(2-(oxazol-2-yl) -1,3-dioxolan-2-yl)hexylidene)propane-2-sulfinamide (12, 200 mg, 0.584 mmol) in THF (0.5 mL) was added. The mixture was stirred at -78°C for 1 h. The mixture was quenched with water (20 mL) and the mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic fractions were washed with brine (saturated, 20 mL), dried (Na 2 SO 4 ), filtered and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column flash chromatography, eluting with DCM / MeOH = 10:1 to give (R)-N-((S)-1-(4-chloro-2-(4-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-6-(2-(oxazol-2-yl)-1,3-dioxolan-2-yl)hexyl)-2-methylpropane-2-sulfinamide (25C). LCMS (ESI) calc'd for C 21 H 46 ClFN 4 O 5 SSi [M+H] +< : 669.3, found: 669.3Step 4: Preparation of (S)-7-amino-7-(4-chloro-2-(4-fluorophenyl)-1H -imidazol-5-yl)-1-(oxazol-2-yl)heptan-1-one (Example 25)

[0224] Hydrogen chloride (0.8 ml, 3.20 mmol) was added to the solution of (R)-N-((S)-1-(4-chloro-2-(4-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-6-(2-(oxazol-2-yl)-1,3-dioxolan-2-yl)hexyl)-2-methylpropane-2-sulfinamide (25C, 360 mg, 0.538 mmol) in MeOH (2.0 ml) and water (0.8 ml), and the resultant mixture was stirred at 50°C for 12 h. The mixture was quenched with aqueous NaHCO 3 (saturated) to pH = 7-8 and the mixture was extracted with DCM (3 x 10 mL). The combined organic fractions were washed with brine (saturated, 20 mL), dried (Na 2 SO 4 ), filtered and the solvent was evaporated under reduced pressure. The residue was purified by preparative HPLC (reverse phase C-18 column), eluting with acetonitrile / water + 0.05% HCl, to give (S)-7-amino-7-(4-chloro-2-(4-fluorophenyl)-1H-imidazol-5-yl)-1-(oxazol-2-yl)heptan-1-one (Example 25). LCMS (ESI) calc'd for C 19 H 20 ClFN 4 O 2 [M+H] +< : 391.1, found: 391.1. 1< H NMR (400 MHz, MeOD) δ 8.10 (s, 1H), 7.92-8.06 (m, 2H), 7.39 (s, 1H), 7.25-7.36 (m, 2H), 4.50 (dd, J = 5.29, 9.92 Hz, 1H), 3.06 (t, J = 7.17 Hz, 2H), 2.25 (d, J = 8.38 Hz, 1H), 2.02-2.14 (m, 1H), 1.69-1.83 (m, 2H), 1.27-1.55 (m, 4H).Example 267-amino-7-(5-(2-methylquinolin-6-yl)oxazol-2-yl)-1-(oxazol-2-yl)heptan-1-one (35, L-006157881-001T) and (37, L-006157885-001C)

[0225] Step 1: Preparation of 5-(2-methylquinolin-6-yl)oxazole (26B)

[0226] To a mixture of 2-methylquinoline-6-carbaldehyde (26A, 0.26 g, 1.52 mmol) and K 2 CO 3 in MeOH (10 mL) was added TosMIC (0.36 g, 1.83 mmol). Then the mixture was stirred at 50°C under N 2 atmosphere for 14 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column flash chromatography, eluting with Petro.ether / EtOAc = 1:1 to give 5-(2-methylquinolin-6-yl)oxazole (26B). LCMS (ESI) calc'd for C 13 H 10 N 2 O [M+H] +< : 211.1, found: 211.0.Step 2: Preparation of (R)-2-methyl-N-((S)-1-(5-(2-methylquinolin-6-yl)oxazol-2-yl)-6- (2-(oxazol-2-yl)-1,3-dioxolan-2-yl)hexyl)propane-2-sulfinamide (26C)

[0227] To a cooled (-15°C) solution of 5-(2-methylquinolin-6-yl)oxazole (26B, 223 mg, 1.06 mmol) in THF (3 mL) was added dropwise a solution of i-PrMgCl·LiCl (0.9 mL, 1.3 M in THF, 1.17 mmol). After stirring at -15°C for 0.5 h, a solution of (R,E)-2-methyl-N-(6-(2-(oxazol- 2-yl)-1,3-dioxolan-2-yl)hexylidene)propane-2-sulfinamide (12, 191 mg, 0.558 mmol) in THF (2 mL) was added dropwise into the above mixture. Then the reaction mixture was warmed to rt and stirred for another 24 h. The reaction mixture was quenched with NH 4 Cl solution (aq. saturated, 50 mL) and extracted with EtOAc (30 x 2 mL). The organic layers were combined, washed with brine (saturated, 40 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated. The residue was purified by prep-HPLC (Column: Phenomenex Synergi C18 150 x 30 mm x 4 µm), eluting with water (0.1 % TFA)-acetonitrile (Gradient: 17% to 47%) to give (R)-2-methyl-N-((S)-1-(5-(2-methylquinolin-6-yl)oxazol-2-yl)-6-(2-(oxazol-2-yl)-1,3-dioxolan-2-yl)hexyl)propane-2-sulfinamide (26C). LCMS (ESI) calc'd for C 19 H 36 N 4 O 5 S [M+Na] +< : 553.2, found: 575.1 (M+Na +< ).Step 3: Preparation of 7-amino-7-(5-(2-methylquinolin-6-yl)oxazol-2-yl)-1-(oxazol-2-yl) heptan-1-one hydrochloride (Example 26)

[0228] To a solution of (R)-2-methyl-N-((S)-1-(5-(2-methylquinolin-6-yl)oxazol-2-yl)-6-(2-(oxazol-2-yl)-1,3-dioxolan-2-yl)hexyl)propane-2-sulfinamide (26C, peak 1, 54 mg, 97.7 µmol) in MeOH (1 mL) was added HCl (0.15 mL, 4.0 M, aq.) and H 2 O (0.08 mL). The reaction mixture was stirred at 50°C for 16 h. Then HCl (0.15 mL, 4.0 M, aq.) and H 2 O (0.08 mL) was added and the mixture was stirred at 50°C for another 13 h. The reaction mixture was evaporated under reduced pressure. The residue was purified by prep-HPLC (Column: Phenomenex Synergi C18 250 x 21.2 mm x 4 µm), eluting with water (0.1 % TFA)-acetonitrile (Gradient: 4% to 24%) to give the product. To this product was added HCl (1.5 mL, 0.1 M, aq.) and the mixture was shaken up for 10 min. The above mixture was lyophilized to give 7-amino-7-(5-(2-methylquinolin-6-yl)oxazol-2-yl)-1- (oxazol-2-yl) heptan-1-one hydrochloride (Example 26E1). LCMS (ESI) calc'd for C 13 H 24 N 4 O 3 [M+H] +< : 405.2, found: 405.1. 1< H NMR (400 MHz, MeOD) δ 9.08 (d, J = 8.6 Hz, 1H), 8.65 (s, 1H), 8.47-8.52 (m, 1H), 8.26 (d, J = 8.8 Hz, 1H), 8.09 (s, 1H), 8.00 (d, J= 8.6 Hz, 1H), 7.92 (s, 1H), 7.38 (d, J = 0.6 Hz, 1H), 4.76 (t, J = 6.8 Hz, 1H), 3.08 (t, J= 7.2 Hz, 2H), 3.03 (s, 3H), 2.08-2.28 (m, 2H), 1.76 (t, J= 7.0 Hz, 2H), 1.51 (brs, 4H).

[0229] Compound Example 26E2 was obtained from peak 2 in step 2 using similar methodology. LCMS (ESI) calc'd for C 13 H 24 N 4 O 3 [M+H] +< : 405.2, found: 405.1. 1< H NMR (400 MHz, MeOD) δ 9.02 (d, J = 8.4 Hz, 1H), 8.60 (d, J = 1.2 Hz, 1H), 8.45 (dd, J = 1.6, 8.8 Hz, 1H), 8.22 (d, J = 8.8 Hz, 1H), 8.07 (s, 1H), 7.95 (d, J = 7.6 Hz, 1H), 7.89 (s, 1H) 7.36 (s, 1H), 4.72-4.76 (m, 1H), 3.06 (t, J = 7.2 Hz, 2H), 3.00 (s, 3H), 2.12-2.19 (m, 2H), 1.73-1.77 (m, 2H), 1.27-1.49 (m, 4H).Example 27(S)-7-amino-7-(5-(7-methoxy-2-methylquinolin-6-yl)oxazol-2-yl)-1-(oxazol-2-yl)heptan-1-one

[0230] Step 1: Preparation of 6-(1-ethoxyvinyl)-7-methoxy-2-methylquinoline (27B)

[0231] Tributyl(1-ethoxyvinyl)stannane (11.53 ml, 34.1 mmol) was added to a stirred mixture of PdCl 2 (PPh 3 ) 2 (1.580 g, 2.251 mmol), and 6-bromo-2-methylquinoline (27A, 5 g, 22.51 mmol) in DMF (50 ml) at room temperature and the mixture was stirred at 80°C for 16 h under N 2 . The mixture was cooled to room temperature, KF (saturated, 50 mL) was added and the mixture was extracted with ethyl acetate (3 x 40 mL). The combined organic fractions were washed with brine (saturated, 1 x 40 mL), dried (Na 2 SO 4 ), filtered and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column flash chromatography, eluting with petroleum ether / EtOAc = 4 / 1 to give 6-(1-ethoxyvinyl)-2-methylquinoline (27B). LCMS (ESI) calc'd for C 14 H 15 NO [M+H] +< : 214.1, found: 214.4Step 2: Preparation of 2-chloro-1-(7-methoxv-2-methylquinolin-6-yl)ethanone (27C)

[0232] NCS (1.537 g, 11.51 mmol) was added to a stirred mixture of 6-(1-ethoxyvinyl)-7-methoxy-2-methylquinoline (27B, 2.80 g, 11.51 mmol) in MeCN (30 ml) and water (15.0 ml) at room temperature and the mixture was stirred at room temperature for 30 min. Water (20 mL) was added and the mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic fractions were washed with brine (saturated, 2 x 15 mL), dried (Na 2 SO 4 ), filtered and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column flash chromatography, eluting with petroleum ether / EtOAc = 3 / 1 to give 2-chloro-1-(7-methoxy-2-methylquinolin-6-yl)ethanone (27C).Step 3: Preparation of N-formyl-N-(2-(7-methoxy-2-methylquinolin-6-yl)-2-oxoethyl)formamide (27D)

[0233] Sodium diformylamide (951 mg, 10.01 mmol) was added to a stirred mixture of 2-chloro-1-(7-methoxy-2-methylquinolin-6-yl)ethanone (27C, 1000 mg, 4.00 mmol) in acetonitrile (15 ml) at room temperature, and the mixture was stirred at 60°C for 24 h. The mixture was quenched with brine (saturated, 20 mL), and the mixture was extracted with ethyl acetate (2 x 30 mL). The combined organic fractions were washed with brine (saturated, 20 mL), dried (Na 2 SO 4 ), filtered and the solvent was evaporated under reduced pressure. The residue was purified by silica gel flash chromatography (ISCORF75; Sepa flash column), eluting with petroleum ether / EtOAc = 5:1-1:1 to give N-formyl-N-(2-(7-methoxy-2-methylquinolin-6-yl)-2-oxoethyl)formamide (27D). LCMS (ESI) calc'd for C 15 H 14 N 2 O 4 [M+H] +< : 287.1, found: 287.0Step 4: Preparation of 2-amino-1-(7-methoxy-2-methylquinolin-6-yl)ethanone hydrochloride (27E)

[0234] HCl (1.2 ml, 14.61 mmol) was added to a stirred mixture of N-formyl-N-(2-(7-methoxy-2-methylquinolin-6-yl)-2-oxoethyl)formamide (27D, 520 mg, 1.816 mmol) in EtOH (10 ml) at room temperature, and the mixture was stirred at 60°C for 2 h. The reaction mixture was concentrated in vacuo to give 2-amino-1-(7-methoxy-2-methylquinolin-6-yl)ethanone hydrochloride (27E) which was used to the next step without further purification. LCMS (ESI) calc'd for C 13 H 14 N 2 O 2 ·ClH [M+H] +< : 231.1, found: 231.1Step 5: Preparation of (S)-tert-butyl (1-((2-(7-methoxy-2-methylquinolin-6-yl)-2-oxoethyl)amino)-8-(oxazol-2-yl)-1,8-dioxooctan-2-yl)carbamate (27F)

[0235] HATU (270 mg, 0.710 mmol) was added to the solution of (S)-2-((tert-butoxycarbonyl)amino)-8-(oxazol-2-yl)-8-oxooctanoic acid (230 mg, 0.676 mmol) in DMF (5 ml), and stirred at 25°C for 10 min, then DIPEA (0.590 ml, 3.38 mmol) and 2-amino-1-(7-methoxy-2-methylquinolin-6-yl)ethanone hydrochloride (27E, 234 mg, 0.878 mmol) was added to the reaction mixture, and it was stirred at 25°C for 2 h. The mixture was quenched with brine (saturated, 10 mL), and the mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic fractions were washed with brine (saturated, 10 mL), dried (Na 2 SO 4 ), filtered and the solvent was evaporated under reduced pressure. The residue was purified by silica gel flash chromatography (ISCORF75; Sepa flash column), eluting with EtOAc / MeOH / NH 3 aq.) =10:1:0.02 to give (S)-tert-butyl (1-((2-(7-methoxy-2-methylquinolin-6-yl)-2-oxoethyl)amino)-8-(oxazol-2-yl)-1,8-dioxooctan-2-yl)carbamate (27F). LCMS (ESI) calc'd for C 19 H 36 N 4 O 7 [M+H] +< : 553.3, found: 553.2Step 6: Preparation of (S)-tert-butyl (1-(5-(7-methoxy-2-methylquinolin-6-yl)oxazol-2-yl)-7-(oxazol-2-yl)-7-oxoheptyl)carbamate (27G)

[0236] TEA (0.651 ml, 4.67 mmol) and perchloroethane (368 mg, 1.556 mmol) and triphenylphosphine (408 mg, 1.556 mmol) were added to a stirred mixture of (S)-tert-butyl (1-((2-(7-methoxy-2-methylquinolin-6-yl)-2-oxoethyl)amino)-8-(oxazol-2-yl)-1,8-dioxooctan-2-yl)carbamate (27F, 430 mg, 0.778 mmol) in DCM (10 ml). The mixture was stirred at rt for 16 h, and another potion of perchloroethane (368 mg, 1.556 mmol) and triphenylphosphine (408 mg, 1.556 mmol) was added. The mixture was stirred for another 2 h. The mixture was quenched with water (10 mL), and the mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic fractions were washed with brine (saturated, 10 mL), dried (Na 2 SO 4 ), filtered and the solvent was evaporated under reduced pressure. The residue was purified by silica gel flash chromatography (ISCORF75; Sepa flash column), eluting with petroleum ether / EtOAc = 3:1-1:1 to give (S)-tert-butyl (1-(5-(7-methoxy-2-methylquinolin-6-yl)oxazol-2-yl)-7-(oxazol-2-yl)-7-oxoheptyl)carbamate (27G). LCMS (ESI) calc'd for C 19 H 34 N 4 O 6 [M+H] +< : 535.2, found: 535.3Step 7: Preparation of (S)-7-amino-7-(5-(7-methoxy-2-methylquinolin-6-yl)oxazol-2-yl)-1-(oxazol-2-yl)heptan-1-one (Example 27)

[0237] TFA (0.5 ml, 6.49 mmol) was added to the solution of (S)-tert-butyl (1-(5-(7-methoxy-2-methylquinolin-6-yl)oxazol-2-yl)-7-(oxazol-2-yl)-7-oxoheptyl)carbamate (27G, 240 mg, 0.449 mmol) in DCM (10 ml), and the resultant mixture was stirred at rt for 5 h. The reaction mixture was concentrated in vacuo to give (S)-7-amino-7-(5-(7-methoxy-2-methylquinolin-6-yl)oxazol-2-yl)-1-(oxazol-2-yl)heptan-1-one 2,2,2-trifluoroacetate (Example 27) which can be used without further purification.

[0238] A pure sample was purified by preparative HPLC (reverse phase C-18 column), eluting with acetonitrile / water + 0.1% TFA, to give the title compound. LCMS (ESI) calc'd for C 14 H 26 N 4 O 4 ·15HF 3 O 2 [M+H] +< : 435.2, found: 435. 1< H NMR (400 MHz, MeOD) δ 8.99 (d, J = 8.61 Hz, 1H), 8.66 (s, 1H), 8.06 (s, 1H), 7.72-7.88 (m, 2H), 7.62 (s, 1H), 7.35 (s, 1H), 4.74 (t, J= 6.85 Hz, 1H), 4.25 (s, 3H), 3.04 (t, J = 7.14 Hz, 2H), 2.96 (s, 3H), 2.05-2.27 (m, 2H), 1.73 (t, J = 7.14 Hz, 2H), 1.48 (d, J = 6.26 Hz, 4H).Example 28(S)-7-amino-7-(5-(2-methoxypyridin-3-yl)oxazol-2-yl)-1-(oxazol-2-yl)heptan-1-one

[0239] Step 1: 2-azido-1-(2-methoxypyridin-3-yl)ethanone (28B)

[0240] NaN 3 (1.13 g, 17.38 mmol) was added to a stirred mixture of 2-chloro-1-(2-methoxypyridin-3-yl)ethanone (28A, 2.17 g, 11.69 mmol) in DMF (10 ml) and the mixture was stirred at rt for 2 h. The mixture was diluted with water (40 mL), and extracted with ethyl acetate (4 x 20 mL). The combined organic fractions were washed with water (3 x 15 mL), brine (saturated, 10 mL), dried (Na 2 SO 4 ), and filtered to give 2-azido-1-(2-methoxypyridin-3-yl)ethanone (28B, ethyl acetate solution) which was used to the step without purification. LCMS (ESI) calc'd for C 8 H 8 N 4 O 2 [M+H] +< : 193.1, found: 193.0Step 2: tert-butyl (2-(2-methoxypyridin-3-yl)-2-oxoethyl)carbamate (28C)

[0241] Pd-C (10%, 436 mg, 0.410 mmol) was added to a stirred mixture of 2-azido-1-(2-methoxypyridin-3-yl)ethanone (28B, ethyl acetate solution) and Bo15O (4.6 ml, 19.81 mmol) in MeOH (60 ml) at 25°C and the mixture was degassed and backfilled with H 2 (three times) and stirred at 25°C for 2 h under H 2 (15 psi). The mixture was filtered and the filter cake was washed with MeOH (20 mL). The filtrate was concentrated to dryness. The residue was purified by silica gel column flash chromatography, eluting with petroleum ether / EtOAc = 0~15% to give tert-butyl (2-(2-methoxypyridin-3-yl)-2-oxoethyl)carbamate (28C). LCMS (ESI) calc'd for C 13 H 18 N 2 O 4 [M+H] +< : 267.1, found: 267.1Step 3: 2-amino-1-(2-methoxypyridin-3-yl)ethanone (28D)

[0242] TFA (4 mL, 51.9 mmol) was added to a stirred mixture of tert-butyl (2-(2-methoxypyridin-3-yl)-2-oxoethyl)carbamate (28C, 1.7g, 6.38 mmol) in DCM (20 ml) and the mixture was stirred at rt for 3 h. The solvent was evaporated under reduced pressure to give 2-amino-1-(2-methoxypyridin-3-yl)ethanone (28D) which was used to the next step without purification.Step 4: (S)-tert-butyl (1-((2-(2-methoxypyridin-3-yl)-2-oxoethyl)amino)-1-oxopent-4-en-2-yl)carbamate (28E)

[0243] A mixture of HATU (2.516 g, 6.62 mmol), (S)-2-((tert-butoxycarbonyl)amino)pent-4-enoic acid (1.452 g, 6.75 mmol) and DIEA (5.1 ml, 29.2 mmol) in DMF (10 ml) was stirred at rt for 1 h, then was added 2-amino-1-(2-methoxypyridin-3-yl)ethanone (28D, 1 g, 6.02 mmol) dissolved in DMF (3 ml) and the mixture was stirred at rt for 2 h. The mixture was diluted with water (50 mL), and extracted with ethyl acetate (3 x 20 mL). The combined organic fractions were washed with water (3 x 10 mL), brine (saturated, 10 mL), dried (Na 2 SO 4 ), filtered and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column flash chromatography, eluting with petroleum ether / EtOAc = 0~15% to give (S)-tert-butyl (1-((2-(2-methoxypyridin-3-yl)-2-oxoethyl)amino)-1-oxopent-4-en-2-yl)carbamate (28E). LCMS (ESI) calc'd for C 18 H 25 N 3 O 5 [M+H] +< : 364.2, found: 364.1Step 5: (S)-tert-butyl (1-(5-(2-methoxypyridin-3-yl)oxazol-2-yl)but-3-en-1-yl)carbamate (28F)

[0244] A mixture of (S)-tert-butyl (1-((2-(2-methoxypyridin-3-yl)-2-oxoethyl)amino)-1-oxopent-4-en-2-yl)carbamate (28E, 1.56 g, 4.29 mmol), triphenylphosphine (1.680 g, 6.41 mmol), hexachloroethane (0.734 ml, 6.48 mmol) and TEA (4 ml, 28.7 mmol) in DCM (16 ml) was degassed and backfilled with N 2 three times and stirred at rt for 3 h. The mixture was quenched with water (50 mL), and extracted with DCM (3 x 30 mL). The combined organic fractions were washed with brine (saturated, 20 mL), dried (Na 2 SO 4 ), filtered and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column flash chromatography, eluting with petroleum ether / EtOAc = 0~15% to give (S)-tert-butyl (1-(5-(2-methoxypyridin-3-yl)oxazol-2-yl)but-3-en-1-yl)carbamate (28F). LCMS (ESI) calc'd for C 18 H 23 N 3 O 4 [M+H] +< : 346.2, found: 346.2.Step 6: (S,E)-tert-butyl (1-(5-(2-methoxypyridin-3-yl)oxazol-2-yl)-7-(oxazol-2-yl)-7-oxohept-3-en-1-yl)carbamate (28G)

[0245] Zhan's catalyst (146 mg, 0.199 mmol) was added to a mixture of (S)-tert-butyl (1-(5-(2-methoxypyridin-3-yl)oxazol-2-yl)but-3-en-1-yl)carbamate (28F, 950 mg, 2.75 mmol) and 1-(oxazol-2-yl)pent-4-en-1-one (1, 1436 mg, 9.50 mmol) in toluene (7 ml) which was bubbled with N 2 for 20 mins at rt. The mixture was degassed and backfilled with N 2 (three times) and stirred at 70°C for 10 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column flash chromatography, eluting with petroleum ether / EtOAc = 0~33% to give (S,E)-tert-butyl (1-(5-(2-methoxypyridin-3-yl)oxazol-2-yl)-7-(oxazol-2-yl)-7-oxohept-3-en-1-yl)carbamate (28G). LCMS (ESI) calc'd for C 14 H 28 N 4 O 6 [M+H] +< : 469.2, found: 469.2Step 7: (S)-tert-butyl (1-(5-(2-methoxypyridin-3-yl)oxazol-2-yl)-7-(oxazol-2-yl)-7-oxoheptyl)carbamate (28H)

[0246] Pd-C (10%, 126 mg, 0.118 mmol) was added to (S,E)-tert-butyl (1-(5-(2-methoxypyridin-3-yl)oxazol-2-yl)-7-(oxazol-2-yl)-7-oxohept-3-en-1-yl)carbamate (28G, 590 mg, 1.259 mmol) in MeOH (10 ml) at 26°C and the mixture was degassed and backfilled with H 2 (three times) and stirred at 26°C for 1 h under H 2 (15 psi). The mixture was filtered and the solvent was evaporated under reduced pressure to give (S)-tert-butyl (1-(5-(2-methoxypyridin-3-yl)oxazol-2-yl)-7-(oxazol-2-yl)-7-oxoheptyl)carbamate (28H) which was used to the next step without further purification. LCMS (ESI) calc'd for C 14 H 30 N 4 O 6 [M+H] +< : 471.2, found: 471.3Step 8: (S)-7-amino-7-(5-(2-methoxypyridin-3-yl)oxazol-2-yl)-1-(oxazol-2-yl)heptan-1-one (Example 28)

[0247] TFA (0.6 mL, 7.79 mmol) was added to (S)-tert-butyl (1-(5-(2-methoxypyridin-3-yl)oxazol-2-yl)-7-(oxazol-2-yl)-7-oxoheptyl)carbamate (28H, 25 mg, 0.053 mmol) in DCM (3 ml) and the mixture was stirred at rt for 1 h. The solvent was evaporated under reduced pressure. The residue was purified by preparative HPLC (reverse phase C-18 column), eluting with acetonitrile / water + 0.1% TFA, to give (S)-7-amino-7-(5-(2-methoxypyridin-3-yl)oxazol-2-yl)-1-(oxazol-2-yl)heptan-1-one (Example 28). LCMS (ESI) calc'd for C 19 H 22 N 4 O 4 [M+H] +< : 371.2, found: 371.2. 1< H NMR (400 MHz, MeOD) δ 8.14-8.18 (m, 1H), 8.10-8.13 (m, 1H), 8.09 (s, 1H), 7.61 (s, 1H), 7.38 (s, 1H), 7.10 (dd, J = 5.09, 7.43 Hz, 1H), 4.66 (t, J = 7.04 Hz, 1H), 4.10 (s, 3H), 3.05 (t, J= 7.24 Hz, 2H), 2.02-2.22 (m, 2H), 1.74 (t, J= 6.85 Hz, 2H), 1.47 (d, J= 2.74 Hz, 4H).Example 29(S)-7-amino-7-(1-methyl-4-(2-methylquinolin-6-yl)-1H-imidazol-2-yl)-1-(oxazol-2-yl)heptan-1-one

[0248] Step 1: Preparation of compound 29A

[0249] To a solution of (S)-tert-butyl 2-(1-((tert-butoxycarbonyl)amino)-7-(oxazol-2-yl)-7-oxoheptyl)-4-(2-methylquinolin-6-yl)-1H-imidazole-1-carboxylate (9G, 80 mg, 0.133 mmol) in DMF (1 ml) was added NaH (6 mg, 0.150 mmol) at 0°C. The mixture was stirred at 0°C for 30 min. Then, iodomethane (18 mg, 0.127 mmol) was added. The mixture was stirred at rt for 2 h. Aqueous NH 4 Cl (saturated, 10 mL) was added and the mixture was extracted with ethyl acetate (5 x 2 mL). The combined organic fractions were washed with brine (saturated, 10 mL), dried (Na 2 SO 4 ), filtered and the solvent was evaporated under reduced pressure. The crude product was used directly in the next step. LCMS (ESI) calc'd for 16 4 H 41 N 5 O 6 [M+H] +< : 618.3, found: 618.4. The structure of compound 29A was not confirmed and derived from de-protection product in next step.Step 2: Preparation of (S)-7-amino-7-(1-methyl-4-(2-methylquinolin-6-yl)-1H-imidazol-2-yl)-1-(oxazol-2-yl)heptan-1-one (Example 29)

[0250] A solution of compound 29A (80 mg crude, 0.130 mmol) in DCM (1 ml) was added to TFA (1 ml, 12.98 mmol). The mixture was then stirred at rt for 2 h. The mixture was concentrated and the residue was purified by preparative HPLC (reverse phase C-18 column), eluting with acetonitrile / water + 0.1% TFA, to give (S)-7-(methylamino)-7-(5-(2-methylquinolin-6-yl)-1H-imidazol-2-yl)-1-(oxazol-2-yl)heptan-1-one (Example 29). LCMS (ESI) calc'd for C 14 H 27 N 5 O 2 [M+H] +< : 418.2, found: 418.3

[0251] HCl (0.1 M, 0.5 ml, 0.050 mmol) was added to a stirred mixture of (S)-7-(methylamino)-7-(5-(2-methylquinolin-6-yl)-1H-imidazol-2-yl)-1-(oxazol-2-yl)heptan-1-one (Example 29, 10 mg, 0.024 mmol) in acetonitrile (2 ml) at room temperature, then it was lyophilized to give (S)-7-(methylamino)-7-(5-(2-methylquinolin-6-yl)-1H-imidazol-2-yl)-1-(oxazol-2-yl)heptan-1-one hydrochloride (Example 29). 1< H NMR (400 MHz, MeOD) δ 8.97 (d, J = 8.61 Hz, 1H), 8.64 (brs, 1H), 8.56 (d, J = 9.00 Hz, 1H), 8.15 (d, J = 8.61 Hz, 1H), 8.06 (s, 1H), 7.87-7.94 (m, 2H), 7.35 (s, 1H), 4.68-4.76 (m, 1H), 3.86 (brs, 3H), 2.96-3.05 (m, 6H), 1.72 (t, J = 7.24 Hz, 2H), 1.35-1.47 (m, 2H), 1.28 (brs, 4H).Example 30(S)-7-amino-7-(1-ethyl-4-(2-methylquinolin-6-yl)-1H-imidazol-2-yl)-1-(oxazol-2-yl)heptan-1-one

[0252]

[0253] (S)-7-amino-7-(1-ethyl-4-(2-methylquinolin-6-yl)-1H-imidazol-2-yl)-1-(oxazol-2-yl)heptan-1-one (Example 30) was obtained from EtI with same method described above. LCMS (ESI) calc'd for C 15 H 30 ClN 5 O 2 [M+H] +< : 432.2, found: 432.0. 1< H NMR (400 MHz, MeOD) δ 8.98 (brs, 1H), 9.00 (brs, 1H), 8.65-8.71 (m, 1H), 8.58 (d, J= 7.83 Hz, 1H), 8.18 (d, J = 8.61 Hz, 1H), 8.03-8.10 (m, 2H), 7.89-7.94 (m, 1H), 7.33-7.37 (m, 1H), 4.79 (brs, 1H), 4.16-4.29 (m, 2H), 3.01-3.03 (m, 2H), 2.98-3.00 (m, 3H), 1.66-1.78 (m, 2H), 1.54 (t, J= 7.04 Hz, 3H), 1.37-1.47 (m, 3H), 1.20-1.33 (m, 3H).Example 31(S)-7-amino-1-(isoxazol-3-yl)-7-(4-(7-methoxy-2-methylquinolin-6-yl)-1H-imidazol-2-yl)heptan-1-one

[0254] Step 1: Preparation of (S,E)-tert-butyl (7-(isoxazol-3-yl)-1-(4-(7-methoxy-2-methylquinolin-6-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-7-oxohept-3-en-1-yl)carbamate (31A)

[0255] A stirred mixture of (S,Z)-tert-butyl (1-(4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-7-(isoxazol-3-yl)-7-oxohept-3-en-1-yl)carbamate (17, 300 mg, 0.527 mmol), 7-methoxy-2-methyl- 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline (236 mg, 0.790 mmol) and K 3 PO 4 (335 mg, 1.580 mmol), XPhos Pd G3 (22 mg, 0.026 mmol) in THF (2 ml) and water (0.05 ml) was sealed in a 10 mL vial and stirred at 70°C for 2 h under N 2 protection. The reaction mixture was concentrated to dryness, and purified by silica gel chromatography eluted with Petro.Ether: EtOAc = 1:2 to give (S,E)-tert-butyl (7-(isoxazol-3-yl)-1-(4-(7-methoxy-2-methylquinolin-6-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-7-oxohept-3-en-1-yl)carbamate (31A). LCMS (ESI) calc'd for C 35 H 47 N 5 O 6 Si [M+H] +< : 662.3, found: 662.4Step 2: Preparation of (S)-tert-butyl (7-(isoxazol-3-yl)-1-(4-(7-methoxy-2-methylquinolin-6-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-7-oxoheptyl)carbamate (31B)

[0256] To a solution of ((S,E)-tert-butyl (7-(isoxazol-3-yl)-1-(4-(7-methoxy-2-methylquinolin-6-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-7-oxohept-3-en-1-yl)carbamate (31A, 100 mg, 0.151 mmol) in MeOH (2 ml) was added Pd / C (16 mg, 0.015 mmol) (10%, wet) under Ar. The suspension was degassed under vacuum and purged with N 2 several times. The mixture was then stirred under H 2 (Pressure: 15 psi) at rt for 2 h. It was filtered on Celite then the filter cake was washed with methanol (3 x 5 mL). The filtrate was concentrated under reduced pressure to give (S)-tert-butyl (7-(isoxazol-3-yl)-1-(4-(7-methoxy-2-methylquinolin-6-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-7-oxoheptyl)carbamate (31B) which was used directly for next step without purification. LCMS (ESI) calc'd for C 35 H 49 N 5 O 6 Si [M+H] +< : 664.3, found: 664.4Step 3: Preparation of (S)-7-amino-1-(isoxazol-3-yl)-7-(4-(7-methoxy-2-methylquinolin-6-y1)-1H-imidazol-2-yl)heptan-1-one (Example 31)

[0257] TFA (3 mL, 38.9 mmol) was added to a stirred mixture of (S)-tert-butyl (7-(isoxazol-3-yl)-1-(4-(7-methoxy-2-methylquinolin-6-yl)-1-((2-(trimethylsilyl)ethoxy )methyl)-1H-imidazol-2-yl)-7-oxoheptyl)carbamate (31B, 65 mg, 0.098 mmol) at room temperature and the mixture was stirred at rt for 2 h. The mixture was concentrated and purified by preparative HPLC (reverse phase C-18 column), eluting with acetonitrile / water + 0.1% TFA, to give (S)-7-amino-1-(isoxazol-3-yl)-7-(4-(7-methoxy-2-methylquinolin-6-yl)-1H-imidazol-2-yl)heptan-1-one (Example 31).

[0258] HCl aq (0.1 M, 3.88 ml, 0.388 mmol) was added to a stirred mixture of (S)-7-amino-1-(isoxazol-3-yl)-7-(4-(7-methoxy-2-methylquinolin-6-yl)-1H-imidazol-2-yl)heptan-1-one (Example 31, 42 mg, 0.097 mmol) in water (2.0 ml) at room temperature and the mixture was lyophilized to give (S)-7-amino-1-(isoxazol-3-yl)-7-(4-(7-methoxy-2-methylquinolin-6-yl)-1H-imidazol-2-yl)heptan-1-one dihydrochloride (Example 31). 1< H NMR (400 MHz, MeOD) δ 9.00 (s, 1H), 8.98 (s, 1H), 8.86 (s, 1H), 8.77 (d, J = 1.56 Hz, 1H), 8.23 (s, 1H), 7.80-7.85 (m, 1H), 7.69 (s, 1H), 6.76 (d, J = 1.76 Hz, 1H), 4.85-4.88 (m, 1H), 4.28 (s, 3H), 3.31 (td, J = 1.64, 3.18 Hz, 5H), 3.06 (s, 1H), 3.04-3.09 (m, 1H), 2.99-3.03 (m, 3H), 2.17-2.47 (m, 2H), 1.69-1.82 (m, 2H), 1.30-1.35 (m, 4H).Example 32(S)-6-(2-(1-amino-7-(isoxazol-3-yl)-7-oxoheptyl)-1H-imidazol-4-yl)-1-methylquinolin-2(1H)-one

[0259]

[0260] (S)-6-(2-(1-amino-7-(isoxazol-3-yl)-7-oxoheptyl)-1H-imidazol-4-yl)-1-methylquinolin-2(1H)-one (Example 31) was obtained from 17 utilizing same method as described above. LCMS (ESI) calc'd for C 13 H 25 N 5 O 3 ·2ClH [M+H] +< : 420.2, found: 420.0. 1< H NMR (400 MHz, MeOD) δ 8.77 (d, J = 1.76 Hz, 1H), 8.17 (s, 1H), 8.09 (dd, J = 1.98, 8.82 Hz, 1H), 7.94-8.05 (m, 2H), 7.75 (s, 1H), 6.76 (dd, J = 3.86, 5.62 Hz, 2H), 4.79 (d, J = 7.28 Hz, 1H), 3.78 (s, 3H), 3.07 (t, J = 7.17 Hz, 2H), 2.15-2.38 (m, 2H), 1.76 (quin, J = 7.28 Hz, 2H), 1.29-1.56 (m, 4H).Example 33(S)-7-amino-1-(isoxazol-3-yl)-7-(4-(2-methoxypyridin-3-yl)-1H-imidazol-2-yl)heptan-1-one

[0261] Step 1: Preparation of (S)-tert-butyl (7-(isoxazol-3-yl)-1-(4-(2-methoxypyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-7-oxohept-3-en-1-yl)carbamate (33A)

[0262] XPhos Pd G3 (10 mg, 0.012 mmol) was added to a mixture of (S)-tert-butyl (1-(4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-7-(isoxazol-3-yl)-7-oxohept-3-en-1-yl)carbamate (17, 106 mg, 0.186 mmol), 2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (110 mg, 0.468 mmol) and K 3 PO 4 (123 mg, 0.579 mmol) in co-solvents of dioxane (1.5 ml) and water (0.15 ml) at rt and the mixture was stirred at 100°C for 2 h under N 2 protection. The mixture was cooled, diluted with water (15 mL), and extracted with ethyl acetate (3 x 8 mL). The combined organic fractions were washed with brine (saturated, 8 mL), dried (Na 2 SO 4 ), filtered and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column flash chromatography, eluting with petroleum ether / EtOAc = 0~50% to give (S)-tert-butyl (7-(isoxazol-3-yl)-1-(4-(2-methoxypyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-7-oxohept-3-en-1-yl)carbamate (33A). LCMS (ESI) calc'd for C 30 H 43 N 5 O 6 Si [M+H] +< : 598.3, found: 598.2Step 2: Preparation of (S)-7-amino-1-(isoxazol-3-yl)-7-(4-(2-methoxypyridin-3-yl)-1H-imidazol-2-yl)hept-4-en-1-one (33B)

[0263] TFA (4 mL, 51.9 mmol) was added to (S)-tert-butyl (7-(isoxazol-3-yl)-1-(4-(2-methoxypyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-7-oxohept-3-en-1-yl)carbamate (18A, 42 mg, 0.070 mmol) and the mixture was stirred at rt for 3.5 h. The solvent was evaporated under reduced pressure to give (S)-7-amino-1-(isoxazol-3-yl)-7-(4-(2-methoxypyridin-3-yl)-1H-imidazol-2-yl)hept-4-en-1-one (33B) which was used to the next step without further purification. LCMS (ESI) calc'd for C 19 H 21 N 5 O 3 [M+H] +< : 368.2, found: 368.2.Step 3: Preparation of (S)-7-amino-1-(isoxazol-3-yl)-7-(4-(2-methoxypyridin-3-yl)-1H-imidazol-2-yl)heptan-1-one (Example 33)

[0264] 10% Pd-C (45 mg, 0.042 mmol) was added to (S)-7-amino-1-(isoxazol-3-yl)-7-(4-(2-methoxypyridin-3-yl)-1H-imidazol-2-yl)hept-4-en-1-one (33B, 25 mg, 0.068 mmol) in MeOH (10 ml). The mixture was degassed and backfilled with H 2 (three times) and then stirred at rt for 6 h under H 2 atmosphere (15 psi). The mixture was filtered and the filter cake was washed with MeOH (30 mL). The filtrate was concentrated to dryness. The residue was purified by preparative HPLC (reverse phase C-18 column), eluting with acetonitrile / water + 0.1% TFA, to give (S)-7-amino-1-(isoxazol-3-yl)-7-(4-(2-methoxypyridin-3-yl)-1H-imidazol-2-yl)heptan-1-one (Example 33). LCMS (ESI) calc'd for C 19 H 23 N 5 O 3 [M+H] +< : 370.2, found: 370.2. 1< H NMR (400 MHz, MeOD) δ 8.76 (d, J = 1.32 Hz, 1H), 8.30-8.37 (m, 1H), 8.03-8.09 (m, 1H), 7.70 (s, 1H), 7.04 (dd, J = 7.28, 5.07 Hz, 1H), 6.75 (d, J = 1.32 Hz, 1H), 4.46-4.55 (m, 1H), 4.07 (s, 3H), 3.04 (t, J = 7.28 Hz, 2H), 1.98-2.20 (m, 2H), 1.68-1.81 (m, 2H), 1.28-1.48 (m, 1H), 1.26-1.50 (m, 4H).Example 34(S)-7-amino-1-(isoxazol-3-yl)-7-(4-(7-methoxyquinolin-6-yl)-1H-imidazol-2-yl)heptan-1-one

[0265] Step 1: Preparation of (R)-N-((S)-6-(2-(isoxazol-3-yl)-1,3-dioxolan-2-yl)-1-(5-(7-methoxyquinolin-6-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)hexyl)-2-methylpropane-2-sulfinamide (34A)

[0266] Pd(DTBPF)Cl 2 (16 mg, 0.025 mmol) was added to a stirred mixture of 7-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline (69 mg, 0.242 mmol), (R)-N-((S)-1-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-6-(2-(isoxazol-3-yl)-1,3-dioxolan-2-yl)hexyl)-2-methylpropane-2-sulfinamide (15, 100 mg, 0.161 mmol) and K 3 PO 4 (86 mg, 0.403 mmol) in THF (3 ml) / water (0.6 ml) at room temperature and the mixture was stirred at 75°C for 3 h. The mixture was cooled to room temperature, filtered, evaporated under reduced pressure to afford (R)-N-((S)-6-(2-(isoxazol-3-yl)-1,3-dioxolan-2-yl)-1-(5-(7-methoxyquinolin-6-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)hexyl)-2-methylpropane-2-sulfinamide (24A) which was used to the next step without further purification. LCMS (ESI) calc'd for C 35 H 51 N 5 O 6 SSi [M+H] +< : 698.3, found: 698.4Step 2: Preparation of (S)-7-amino-1-(isoxazol-3-yl)-7-(4-(7-methoxyquinolin-6-yl)-1H-imidazol-2-yl)heptan-1-one (Example 34)

[0267] Hydrogen chloride (2 ml, 8.00 mmol) was added to a stirred mixture of (R)-N-((S)-6-(2-(isoxazol-3-yl)-1,3-dioxolan-2-yl)-1-(5-(7-methoxyquinolin-6-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)hexyl)-2-methylpropane-2-sulfinamide (34A, 120 mg, 0.172 mmol) in MeOH (2 ml) / water (0.2 ml) at room temperature and the mixture was stirred at 65°C for 18 h. The mixture was cooled to room temperature and the residue was purified by preparative HPLC (reverse phase C-18 column), eluting with acetonitrile / water + 0.1% TFA, then transfered to HCl salt to give (S)-7-amino-1-(isoxazol-3-yl)-7-(5-(7-methoxyquinolin-6-yl)-1H-imidazol-2-yl)heptan-1-one hydrochloride (Example 34). LCMS (ESI) calc'd for C 23 H 25 N 5 O 3 ·ClH [M+H] +< : 420.2, found: 420.2. 1< H NMR (400 MHz, CDCl 3 ) δ 8.89-9.09 (m, 3H), 8.46 (s, 1H), 7.96-8.17 (m, 2H), 7.81 (brs, 1H), 6.69 (s, 1H), 5.28 (s, 1H), 5.19 (brs, 1H), 4.23 (brs, 3H), 3.38 (brs, 1H), 3.01 (d, J= 6.46 Hz, 2H), 2.15 (s, 1H), 1.70 (brs, 2H), 1.44 (brs, 3H), 1.16-1.26 (m, 1H), 1.22 (brs, 2H).Example 35(S)-6-(2-(1-amino-7-(isoxazol-3-yl)-7-oxoheptyl)-1H-imidazol-5-yl)-7-methoxy-1-methylquinolin-2(1H)-one

[0268]

[0269] (S)-6-(2-(1-amino-7-(isoxazol-3-yl)-7-oxoheptyl)-1H-imidazol-5-yl)-7-methoxy-1-methylquinolin-2(1H)-one (Example 35) was obtained from 15 using similar methodology as described above. LCMS (ESI) calc'd for C 24 H 27 N 5 O 4 ·ClH [M+H] +< : 450.2, found: 450.0. 1< H NMR (400 MHz, MeOD) δ 8.75 (d, J = 1.8 Hz, 1H), 8.17 (s, 1H), 8.06 (s, 1H), 7.90 (d, J = 9.4 Hz, 1H), 7.17 (s, 1H), 6.74 (d, J = 1.8 Hz, 1H), 6.60 (d, J = 9.4 Hz, 1H), 4.95-4.93 (m, 1H),4.17 (s, 3H), 3.77 (s, 3H), 3.05 (t, J = 7.1 Hz, 2H), 2.42-2.31 (m, 1H), 2.26-2.24 (m, 1H), 1.76-1.72 (m, 2H), 1.50-1.45 (m, 3H), 1.40-1.21 (m, 1H).Example 36(S)-7-amino-7-(5-(2-fluorophenyl)-1H-imidazol-2-yl)-1-(oxazol-4-yl)heptan-1-one

[0270] Step 1: Preparation of (S)-2-(2-fluorophenyl)-2-oxoethyl 2-((tert-butoxycarbonyl)amino)pent-4-enoate (36B)

[0271] DIPEA (2 ml, 11.45 mmol) was added to a solution of (S)-2-((tert-butoxycarbonyl)amino)pent-4-enoic acid (36A, 1.5 g, 6.97 mmol) and 2-bromo-1-(2-fluorophenyl)ethanone (1.528 g, 7.04 mmol) in DMF (20 ml), the resultant mixture was stirred at rt for 1.5 h. The mixture was combined with a 0.5 g reaction and quenched with aqueous NH 4 Cl (saturated, 10 mL), and extracted with ethyl acetate (3 x 50 mL). The combined organic fractions were washed with brine (saturated, 15 mL), dried (Na 2 SO 4 ), filtered and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column flash chromatography, eluting with petroleum ether / EtOAc = 0-20% to give (S)-2-(2-fluorophenyl)-2-oxoethyl 2-((tert-butoxycarbonyl)amino)pent-4-enoate (36B). LCMS (ESI) calc'd for C 18 H 22 FNO 5 [M+H] +< : 352.1, found: 352.1Step 2: Preparation of (S)-tert-butyl (1-(5-(2-fluorophenyl)-1H-imidazol-2-yl)but-3-en-1-yl)carbamate (36C)

[0272] Ammonium acetate (3.07 g, 39.8 mmol) was added to a stirred mixture of (S)-2-(2-fluorophenyl)-2-oxoethyl 2-((tert-butoxycarbonyl)amino)pent-4-enoate (36B, 3.5 g, 9.96 mmol) in toluene (40 ml) at room temperature and the mixture was stirred at 110°C for 18 h. The mixture was cooled and evaporated under reduced pressure. The residue was combined with a 0.5 g reaction and purified by silica gel column flash chromatography, eluting with petroleum ether / EtOAc = 0-40 % to give (S)-tert-butyl (1-(5-(2-fluorophenyl)-1H-imidazol-2-yl)but-3-en-1-yl)carbamate (36C). LCMS (ESI) calc'd for C 18 H 22 FN 3 O 2 [M+H] +< : 332.2, found: 332.2Step 3: Preparation of (S)-tert-butyl (1-(5-(2-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)but-3-en-1-yl)carbamate (36D)

[0273] DIPEA (5 ml, 28.6 mmol) was added to a stirred mixture of (S)-tert-butyl (1-(5-(2-fluorophenyl)-1H-imidazol-2-yl)but-3-en-1-yl)carbamate (36C, 3.2 g, 9.66 mmol) and (2-(chloromethoxy)ethyl)trimethylsilane (2.6 ml, 14.69 mmol) in DMF (30 ml) at room temperature and the mixture was stirred at room temperature for 2 h. It was combined with a 1.2 g reaction. Water (50 mL) was added and the mixture was extracted with EtOAc (3 x 100 mL). The combined organic fractions were washed with brine (saturated, 1 x 20 mL), dried (Na 2 SO 4 ), filtered and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column flash chromatography, eluting with petroleum ether / EtOAc = 0~30% to give (S)-tert-butyl (1-(5-(2-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)but-3-en-1-yl)carbamate (36D). LCMS (ESI) calc'd for C 24 H 36 FN 3 O 3 Si [M+H] +< : 462.3, found: 462.3Step 4: Preparation of (S,E)-tert-butyl (1-(5-(2-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-7-(oxazol-4-yl)-7-oxohept-3-en-1-yl)carbamate (36E)

[0274] UMICORE M71 SIPR (10 mg, 0.014 mmol) was added to a mixture of (S)-tert-butyl (1-(5-(2-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)but-3-en-1-yl)carbamate (36D, 100 mg, 0.217 mmol) and 1-(oxazol-4-yl)pent-4-en-1-one (6, 66 mg, 0.437 mmol) in toluene (1 ml) which was bubbled with N 2 for 20 mins at rt. The mixture was degassed and backfilled with N 2 three times and stirred at 100°C for 15 h. The reaction mixture was concentrated to dryness, and purified by silica gel chromatography eluted with Petro.Ether: EtOAc = 0-50% to give (S,E)-tert-butyl (1-(5-(2-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-7-(oxazol-4-yl)-7-oxohept-3-en-1-yl)carbamate (36E, E, Z mixture). LCMS (ESI) calc'd for C 30 H 41 FN 4 O 5 Si [M+H] +< : 585.3, found: 585.8Step 5: Preparation of (S)-tert-butyl (1-(5-(2-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-7-(oxazol-4-yl)-7-oxoheptyl)carbamate (36F)

[0275] 10% Pd-C (4 mg, 0.019 mmol) was added to a stirred mixture of (S,E)-tert-butyl (1-(5-(2-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-7-(oxazol-4-yl)-7-oxohept-3-en-1-yl)carbamate (36E, 20 mg, 0.034 mmol) in MeOH (2 ml) at room temperature and the mixture was stirred at room temperature for 2 h. The mixture was filtered and the filtrate was evaporated in vacuo to give (S)-tert-butyl (1-(5-(2-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-7-(oxazol-4-yl)-7-oxoheptyl)carbamate (36F,) which was used to the next step without further purification. LCMS (ESI) calc'd for C 30 H 43 FN 4 O 5 Si [M+H] +< : 587.3, found: 587.4Step 6: Preparation of (S)-7-amino-7-(5-(2-fluorophenyl)-1H-imidazol-2-yl)-1-(oxazol-4-yl)heptan-1-one (Example 36)

[0276] TFA (1 mL, 12.98 mmol) was added to a stirred mixture of (S)-tert-butyl (1-(5-(2-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy )methyl)-1H-imidazol-2-yl)-7-(oxazol-4-yl)-7-oxoheptyl)carbamate (36F, 20 mg, 0.034 mmol) at room temperature and the mixture was stirred at room temperature for 18 h. The mixture was evaporated in vacuo to remove TFA. The residue was purified by preparative HPLC (reverse phase C-18 column), eluting with acetonitrile / water + 0.1% TFA, to give (S)-7-amino-7-(5-(2-fluorophenyl)-1H-imidazol-2-yl)-1-(oxazol-4-yl)heptan-1-one (Example 36). LCMS (ESI) calc'd for C 19 H 21 FN 4 O 2 [M+H] +< : 357.2, found: 357.1. 1< H NMR (400 MHz, MeOD) δ 8.58 (s, 1H), 8.24 (s, 1H), 8.00 (t, J= 6.75 Hz, 1H), 7.50 (d, J = 3.72 Hz, 1H), 7.11-7.28 (m, 3H), 4.41-4.47 (m, 1H), 2.88 (t, J = 7.14 Hz, 2H), 2.07-2.18 (m, 1H), 1.98-2.07 (m, 1H), 1.65-1.74 (m, 2H), 1.31-1.46 (m, 4H), 1.26-1.31 (m, 2H).Example 37(S)-7-amino-7-(5-(2-fluorophenyl)-1H-imidazol-2-yl)-1-(isoxazol-3-yl)heptan-1-one

[0277] Step 1: tert-butyl (S,E)-2-(1-((tert-butoxycarbonyl)amino)-7-(isoxazol-3-yl)-7-oxohept-3-en-1-yl)-5-(2-fluorophenyl)-1H-imidazole-1-carboxylate (37E)

[0278] A100 ml one neck round bottom flask was charged with toluene (8ml) and a mixture of (S)-tert-butyl 2-(1-((tert-butoxycarbonyl)amino)but-3-en-1-yl)-4-(2-fluorophenyl)-1H-imidazole-1-carboxylate (36D, 1.1 g, 2.55 mmol); 1-(isoxazol-3-yl)pent-4-en-1-one (2, 800mg, 5.29 mmol) and UMICOREM71 SIPR (80 mg, 0.097 mmol). The mixture was degassed and refilled with nitrogen, and then stirred at 65°C overnight. After it was cooled to room temperature, the mixture was Purified on Analogix (Redisep 80g column) eluting with 30% EtOAc-Hexanes yielding (S,E)-tert-butyl 2-(1-((tert-butoxycarbonyl)amino)-7-(isoxazol-3-yl)-7-oxohept-3-en-1-yl)-4-(2-fluorophenyl)-1H-imidazole-1-carboxylate (37E). LCMS (ESI) calc'd for C 29 H 35 FN 4 O 6 [M+H] +< : 555.1, found: 555.1.Step 2: (S,E)-7-amino-7-(5-(2-fluorophenyl)-1H-imidazol-2-yl)-1-(isoxazol-3-yl)hept-4-en-1-one (37F)

[0279] A 50 ml one neck round bottom flask was charged with (S,E)-tert-butyl 2-(1-((tert-butoxycarbonyl)amino)-7-(isoxazol-3-yl)-7-oxohept-3-en-1-yl)-4-(2-fluorophenyl)-1H-imidazole-1-carboxylate (37E) (280 mg, 0.865 mmol) in TFA (2 ml) / DCM (10 ml). The mixture was then stirred at room temperature for 1 hour. The reaction mixture was then concentrated, and the residue was dissolved in CH 2 Cl 2 (20ml). The re-evaporation provided (S,E)-7-amino-7-(4-(2-fluorophenyl)-1H-imidazol-2-yl)-1-(isoxazol-3-yl)hept-4-en-1-one (37F), TFA crude which was used directly to next step. LCMS (ESI) calc'd for C 19 H 19 FN 4 O 2 [M+H] +< : 355.1, found: 355.0.Step 3: (S)-7-amino-7-(5-(2-fluorophenyl)-1H-imidazol-2-yl)-1-(isoxazol-3-yl)heptan-1-one (Example 37)

[0280] To a 50 ml one neck round bottom flask was added 10% Pd / C, 50% in H 2 O(10mg) to solution of (S,E)-7-amino-7-(4-(2-fluorophenyl)-1H-imidazol-2-yl)-1-(isoxazol-3-yl)hept-4-en-1-one, TFA (37F) (280 mg, 0.213 mmol) in MeOH (5 ml). The system was connected to a hydrogen balloon through a three way joint. It was vacummed and refilled with hydrogen three times. The mixture was then stirred under hy drogen atomosphere for 3 hours. The mixture was filtered through celite, washed with methanol, and the filtrate was evaporated to provide residue, which was purified by RP-HPLC (TFA_50ml_10_40_8m_V 3 _C1 yielding (S)-7-amino-7-(4-(2-fluorophenyl)-1H-imidazol-2-yl)-1-(isoxazol-3-yl)heptan-1-one (Example 37), TFA. LCMS (ESI) calc'd for C 19 H 21 FN 4 O 2 [M+H] +< : 356.1, found: 357.0.Reference Example 38(S)-N-(1-(5-(2-fluorophenyl)-1H-imidazol-2-yl)-7-(isoxazol-3-yl)-7-oxoheptyl)-1-methylazetidine-3-carboxamide

[0281]

[0282] To a 25 ml one neck round bottom flask was added dissolved (S)-7-amino-7-(4-(2-fluorophenyl)-1H-imidazol-2-yl)-1-(isoxazol-3-yl)heptan-1-one (from Example 37) (20 mg, 0.053 mmol) in methylene chloride (1 mL). Then 1-hydroxybenzotriazole (10 mg, 0.074 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (15 mg, 0.078 mmol) was addded to the solution, followed by 1-methyl-3-azetidinecarboxylic acid (10 mg, 0.087 mmol) in DMF (1 ml). Finally, 4-methylmorpholine (0.05 ml, 0.455 mmol) was added and the resulting reaction mixture was stirred at room temperature overnight. The mixture was purified by RP HPLC yielding the product which was dissolved in acetonitrile / water and freeze dried / lyopholyzed yielding (S)-N-(1-(4-(2-fluorophenyl)-1H-imidazol-2-yl)-7-(isoxazol-3-yl)-7-oxoheptyl)-1-methylazetidine-3-carboxamide (Example 38), TFA. LCMS (ESI) calc'd for C 24 H 28 FN 5 O 3 [M+H] +< : 454.2.1, found: 454.0. 1< H NMR (400 MHz, MeOD) δ 8.77 (1H, s), 7.92 (1H, s), 7.34 (1H, s), 7.29 (2H, m), 7.13 (1H, m), 6.77 (1H, s), 5.04 (1H, t), 3.65 (2H, m), 3.42 (2H, m), 3.31 (3H, s), 3.05 (2H, m), 1.95 (2H, m), 1.79 (2H, m), 1.2-1.5 (8H, m) ppm.

[0283] The following examples were prepared using the same procedure as Example 38, using different acids and amines for coupling. Example # Structure Exact Mass [M+H] +< Observed [M+H] +< 39* Calc'd 508.2508.140* Calc'd 545.2545.341* Calc'd 505.3505.342* Calc'd 531.2530.943* Calc'd 501.3501.144* Calc'd 555.3555.245 Calc'd 371.3371.146* Calc'd 505.3505.347* Calc'd 442.3442.148* Calc'd 456.3456.049* Calc'd 454.3454.250* Calc'd 533.3533.451* Calc'd 517.3517.452* Calc'd 531.3531.453* Calc'd 545.3545.454* Calc'd 547.3547.455* Calc'd 533.3533.556* Calc'd 533.3533.457* Calc'd 545.3545.458* Calc'd 599.3599.559* Calc'd 468.3468.160* Calc'd 454.3454.461* Calc'd 456.3456.562* Calc'd 468.3468.463* Calc'd 482.3482.564* Calc'd 496.3496.5* = reference example Example 65(R)-5-(5-(4-fluorophenyl)-1H-imidazol-2-yl)-5-(6-(oxazol-2-y)-6-oxohexyl)pyrrolidin-2-one

[0284] Step 1: Preparation of (S,E)-tert-butyl 5-(4-fluorophenyl)-2-(2-(6-(oxazol-2-yl)-6-oxohex-2-en-1-yl)-5-oxopyrrolidin-2-yl)-1H-imidazole-1-carboxylate (65B)

[0285] Toluene (1 ml) was added to (S)-tert-butyl 2-(2-allyl-5-oxopyrrolidin-2-yl)-5-(4-fluorophenyl)-1H-imidazole-1-carboxylate (7, 105 mg, 0.272 mmol) and 1-(oxazol-2-yl)pent-4-en-1-one (165 mg, 1.090 mmol) and Zhan catalyst-1B (10 mg, 0.014 mmol), the solvent was degassed, then it was stirred at 60°C for 20 h. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel flash chromatography (ISCORF75; Sepa flash column), eluting with petroleum ether / EtOAc = 10 :1-1:1 to give (S,E)-tert-butyl 5-(4-fluorophenyl)-2-(2-(6-(oxazol-2-yl)-6-oxohex-2-en-1-yl)-5-oxopyrrolidin-2-yl)-1H-imidazole-1-carboxylate (65B). LCMS (ESI) calc'd for C 27 H 29 FN 4 O 5 [M+H] +< : 509.2, found: 509.3.Step 2: Preparation of (R)-tert-butyl 5-(4-fluorophenyl)-2-(2-(6-(oxazol-2-yl)-6-oxohexyl)-5-oxopyrrolidin-2-yl)-1H-imidazole-1-carboxylate (65C)

[0286] A solution of (S,E)-tert-butyl 5-(4-fluorophenyl)-2-(2-(6-(oxazol-2-yl) -6-oxohex-2-en-1-yl)-5-oxopyrrolidin-2-yl)-1H-imidazole-1-carboxylate (65B, 37 mg, 0.073 mmol) in ethanol (5 ml) was added to a 100 mL three-necked bottle and then Pd-C (20 mg, 0.019 mmol) (10%, dry) was added under Ar. The suspension was degassed under vacuum and purged with H 2 several times. The mixture was then stirred under H 2 (15 psi) at 25°C for 1 h. The mixture was filtered and the filter cake was washed with ethanol (5 mL), concentrated to give (R)-tert-butyl 5-(4-fluorophenyl)-2-(2-(6-(oxazol-2-yl)-6-oxohexyl)-5-oxopyrrolidin-2-yl)-1H-imidazole-1-carboxylate (65C) which was used in the next step without purification. LCMS (ESI) calc'd for C 17 H 31 FN 4 O 5 [M+H] +< : 511.2, found: 511.3.Step 5: Preparation of (R)-5-(5-(4-fluorophenyl)-1H-imidazol-2-yl)-5-(6-(oxazol-2-yl)hept-6-en-1-yl)pyrrolidin-2-one (Example 65)

[0287] TFA (200 µl, 2.60 mmol) was added to the solution of (R)-tert-butyl 5-(4-fluorophenyl)-2-(2-(6-(oxazol-2-yl)-6-oxohexyl)-5-oxopyrrolidin-2-yl)-1H-imidazole-1-carboxylate (65C, 150 mg, 0.294 mmol) in DCM (1 ml) at rt and stirred at rt for 2 h. The mixture was concentrated in vacuo and the residue was purified by preparative HPLC (reverse phase C-18 column), eluting with acetonitrile / water + 0.1% TFA, to give (R)-5-(5-(4-fluorophenyl)-1H-imidazol-2-yl)-5-(6-(oxazol-2-yl)-6-oxohexyl)pyrrolidin-2-one (Example 65). LCMS (ESI) calc'd for C 12 H 23 FN 4 O 3 [M+H] -< : 411.2, found: 411.1. 1< H NMR (400 MHz, MeOD) δ 8.09 (s, 1H), 7.73-7.83 (m, 3H), 7.38 (s, 1H), 7.27 (t, J = 8.80 Hz, 2H), 3.06 (t, J = 7.24 Hz, 2H), 2.44-2.54 (m, 5H), 2.06-2.24 (m, 2H), 1.75 (quin, J = 7.24 Hz, 2H), 1.38-1.58 (m, 4H).Example 664-(4-(4-fluorophenyl)-1H-imidazol-2-yl)-4-(6-(oxazol-2-yl)-6-oxohexyl)oxazolidin-2-one

[0288] Step 1: Preparation of 4-allyl-4-(4-(4-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)oxazolidin-2-one (66A)

[0289] SEMCl (2.223 ml, 12.53 mmol) was added to the solution of 4-allyl-4-(4-(4-fluorophenyl)-1H-imidazol-2-yl)oxazolidin-2-one (9, 900 mg, 3.13 mmol), DMAP (10 mg, 0.082 mmol) and DIPEA (2.74 ml, 15.66 mmol) in DMF (15 ml), the resultant mixture was stirred at rt for 16 h. The mixture was quenched with brine (saturated, 10 mL), and the mixture was extracted with ethyl acetate (2 x 15 mL). The combined organic fractions were washed with brine (saturated, 20 mL), dried (Na 2 SO 4 ), filtered and the solvent was evaporated under reduced pressure. The residue was purified by silica gel flash chromatography (ISCORF75; Sepa flash column), eluting with petroleum ether / EtOAc = 10:1-2:1 to give 4-allyl-4-(4-(4-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)oxazolidin-2-one (66A). LCMS (ESI) calc'd for C 21 H 28 FN 3 O 3 Si [M+H] +< : 418.2, found: 418.2Step 2: Preparation of (E)-4-(4-(4-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-4-(6-(oxazol-2-yl)-6-oxohex-2-en-1-yl)oxazolidin-2-one (66B)

[0290] Zhan's catalyst (88 mg, 0.120 mmol) (in three potions by a interval of 3 h) was added to the solution of 1-(oxazol-2-yl)pent-4-en-1-one (1, 1086 mg, 7.18 mmol) in 4 potions with catalyst) and 4-allyl-4-(4-(4-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)oxazolidin-2-one (66A, 500 mg, 1.197 mmol) in degassed toluene (10 ml), the resultant mixture was stirred at 105°C for 16 h under N 2 atmosphere. The mixture was concentrated in vacuo. The residue was purified by silica gel flash chromatography (ISCORF75; Sepa flash column), eluting with petroleum ether / EtOAc = 10:1-1:1 to give (E)-4-(4-(4-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-4-(6-(oxazol-2-yl)-6-oxohex-2-en-1-yl)oxazolidin-2-one (66B). LCMS (ESI) calc'd for C 27 H 33 FN 4 O 5 Si [M+H] +< : 541.2, found: 541.3Step 3: Preparation of 4-(4-(4-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-4-(6-(oxazol-2-yl)-6-oxohexyl)oxazolidin-2-one (66C)

[0291] A solution of (E)-4-(4-(4-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-4-(6-(oxazol-2-yl)-6-oxohex-2-en-1-yl)oxazolidin-2-one (66A, 150 mg, 0.277 mmol) in MeOH (10 ml) was added to a 100 mL bottle and then Pd / C (30 mg, 0.028 mmol) (10%, wet) was added under N 2 . The suspension was degassed under vacuum and purged with H 2 several times. The mixture was then stirred under H 2 (Pressure: 15 psi) at room temperature for 4 h. The mixture was filtered through Celite and the filter cake was washed with MeOH (2 *20 mL). The filtrate was concentrated to dryness and the residue was purified by preparative HPLC (reverse phase C-18 column), eluting with acetonitrile / water + 0.1% TFA, to give 4-(4-(4-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-4-(6-(oxazol-2-yl)-6-oxohexyl)oxazolidin-2-one (66C). LCMS (ESI) calc'd for C 27 H 35 FN 4 O 5 Si [M+H] +< : 543.2, found: 543.3

[0292] The racemate was further separated by chiral SFC using a ChiralPak AD column, to afford two singer isomers.Step 4: Preparation of 4-(4-(4-fluorophenyl)-1H-imidazol-2-yl)-4-(6-(oxazol-2-yl)-6-oxohexyl)oxazolidin-2-one (Example 66E1 and Example 66E2)

[0293] TFA (5 ml, 64.9 mmol) was added to the solution of 4-(4-(4-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-4-(6-(oxazol-2-yl)-6-oxohexyl)oxazolidin-2-one (66CE1, peak 1, 40 mg, 0.074 mmol) in DCM (1 ml), and the resultant mixture was stirred at rt for 16 h. The reaction mixture was concentrated in vacuo and the residue was purified by preparative HPLC (reverse phase C-18 column), eluting with acetonitrile / water + 0.1% TFA, to give 4-(4-(4-fluorophenyl)-1H-imidazol-2-yl)-4-(6-(oxazol-2-yl)-6-oxohexyl)oxazolidin-2-one (Example 66E1). LCMS (ESI) calc'd for C 21 H 21 FN 4 O 4 [M+H] +< : 413.2, found: 413.2. 1< H NMR (400 MHz, MeOD) δ 8.08 (s, 1H), 7.78 (brs, 3H), 7.38 (s, 1H), 7.23 (t, J = 8.41 Hz, 2H), 4.58 (q, J = 9.13 Hz, 2H), 3.06 (t, J = 7.04 Hz, 2H), 2.20 (t, J = 7.73 Hz, 2H), 1.68-1.83 (m, 2H), 1.23-1.63 (m, 4H).

[0294] Compound Example 66E2 was prepared using similar methodology from peak 2, yield 94%, white solid. LCMS (ESI) calc'd for C 21 H 21 FN 4 O 4 [M+H] +< : 413.2, found: 413.2. 1< H NMR (400 MHz, MeOD) δ 8.09 (s, 1H), 7.67-7.82 (m, 3H), 7.38 (s, 1H), 7.23 (t, J = 8.71 Hz, 2H), 4.46-4.65 (m, 2H), 3.07 (t, J = 7.24 Hz, 2H), 2.18 (t, J = 7.92 Hz, 2H), 1.76 (quin, J = 7.19 Hz, 2H), 1.24-1.62 (m, 4H).Example 67(S)-5-(4-(2-fluoro-4-(oxazol-2-yl)phenyl)-1H-imidazol-2-yl)-5-(6-(isoxazol-3-yl)-6-oxohexyl)pyrrolidin-2-one

[0295] Step 1: Preparation of (R)-2-(4-bromo-2-fluorophenyl)-2-oxoethyl 2-allyl-5-oxopyrrolidine-2-carboxylate (67A)

[0296] DIPEA (0.883 ml, 5.05 mmol) was added to the solution of (R)-2-allyl-5-oxopyrrolidine-2-carboxylic acid (7-3, 570 mg, 3.37 mmol) and 2-bromo-1-(4-bromo-2-fluorophenyl)ethanone (1007 mg, 3.40 mmol) in DMF (20 ml), and the resultant mixture was stirred at rt for 1.5 h. The mixture was quenched with aqueous NH 4 Cl (saturated, 10 mL), and the mixture was extracted with ethyl acetate (3 x 30 mL). The combined organic fractions were washed with brine (saturated, 15 mL), dried (Na 2 SO 4 ), filtered and the solvent was evaporated under reduced pressure to give (R)-2-(4-bromo-2-fluorophenyl)-2-oxoethyl-2-allyl-5-oxopyrrolidine -2-carboxylate (67A) which was used to the next step without further purification. LCMS (ESI) calc'd for C 16 H 15 BrFNO 4 [M+H] +< : 384.0, found: 386.1Step 2: Preparation of (R)-5-allyl-5-(5-(4-bromo-2- fluorophenyl)-1H-imidazol-2-yl)pyrrolidin-2-one (67B)

[0297] NH 4 OAc (1023 mg, 13.27 mmol) was added to the solution of (R)-2-(4-bromo-2-fluorophenyl)-2-oxoethyl 2-allyl-5-oxopyrrolidine-2-carboxylate (67A, 5100 mg, 13.27 mmol) in toluene (10 ml), the resultant mixture was stirred at 110°C for 2 h. The mixture was concentrated in vacuo. The residue was purified by silica gel flash chromatography (ISCORF75; Sepa flash column), eluting with petroleum ether / EtOAc = 10:1-1:2 to give (R)-5-allyl-5-(5-(4-bromo-2-fluorophenyl)-1H-imidazol-2-yl)pyrrolidin-2-one (67B). LCMS (ESI) calc'd for C 16 H 15 BrFN 3 O [M+H] +< : 364, found: 363.9Step 3: Preparation of (R)-5-allyl-5-(4-(4-bromo-2-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)pyrrolidin-2-one (67C)

[0298] DIPEA (1.3 ml, 7.14 mmol) was added to the solution of (R)-5-allyl-5-(5-(4-bromo-2-fluorophenyl)-1H-imidazol-2-yl)pyrrolidin-2-one (67B, 1300 mg, 3.57 mmol) in DMF (25 ml) at 0°C, the resultant mixture was stirred at rt for 0.5 h. (2-(chloromethoxy)ethyl)trimethylsilane (1.9 ml, 10.71 mmol) was added to the mixture, and the resultant mixture was stirred at rt for 16 h. The mixture was quenched with aqueous NH 4 Cl (saturated, 25 mL) and the mixture was extracted with ethyl acetate (2 x 10 mL). The combined organic fractions were washed with brine (saturated, 20 mL), dried (Na 2 SO 4 ), filtered and the solvent was evaporated under reduced pressure. The residue was purified by silica gel flash chromatography (ISCORF75; Sepa flash column), eluting with petroleum ether / EtOAc = 10:1 - 2:1 to give (R)-5-allyl-5-(4-(4-bromo-2-fluorophenyl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)pyrrolidin-2-one (67C). LCMS (ESI) calc'd for C 22 H 29 BrFN 3 O 2 Si [M+H] +< : 494.1, found: 496.1Step 4: Preparation of (R,E)-5-(5-(4-bromo-2-fluorophenyl)- 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-5-(5-(2-(isoxazol-3-yl)-1,3-dioxolan-2-yl)pent-2-en-1-yl)pyrrolidin-2-one (67D)

[0299] Zhan's catalyst (54 mg, 0.074 mmol) was added to a mixture of (R)-5-allyl-5-(5-(4-bromo-2-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)pyrrolidin-2-one (67C, 600 mg, 1.213 mmol) and 3-(2-(but-3-en-1-yl)-1,3-dioxolan-2-yl)isoxazole (Prepared from 2, 474 mg, 2.427 mmol) in toluene (5 ml) which was bubbled with N 2 for 20 mins at rt. The mixture was degassed and backfilled with N 2 three times and stirred at 70°C for 16 h. The reaction mixture was concentrated to dryness, and purified by silica gel chromatography eluted with Petro.Ether: EtOAc = 1:1 to give (R,E)-5-(5-(4-bromo-2-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-5-(5-(2-(isoxazol-3-yl)-1,3-dioxolan-2-yl)pent-2-en-1-yl)pyrrolidin-2-one (67D). LCMS (ESI) calc'd for C 30 H 38 BrFN 4 O 5 Si [M+H] +< : 661.2, found: 663.2Step 5: Preparation of (R,E)-5-(5-(2-fluoro-4-(oxazol-2-yl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-5-(5-(2-(isoxazol-3-yl)-1,3-dioxolan-2-yl)pent-2-en-1-yl)pyrrolidin-2-one (67E)

[0300] A mixture of (R,E)-5-(5-(4-bromo-2-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-5-(5-(2-(isoxazol-3-yl)-1,3-dioxolan-2-yl)pent-2-en-1-yl)pyrrolidin-2-one (67D, 45 mg, 0.068 mmol), 2-(tributylstannyl)oxazole (50 mg, 0.140 mmol) XPhos Pd-G2 (10.70 mg, 0.014 mmol) in toluene (4 ml) was degassed and backfilled with N 2 three times. The mixture was heated to 85°C for 18 h, the mixture was filtered and the filter cake was washed with ethyl acetate (20 mL). The filtrate was concentrated to dryness. The residue was purified by silica gel flash chromatography (ISCORF75; Sepa flash column), eluting with Petro.Ether / EtOAc = 1:2 to give (R,E)-5-(5-(2-fluoro-4-(oxazol-2-yl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-5-(5-(2-(isoxazol-3-yl)-1,3-dioxolan-2-yl)pent-2-en-1-yl)pyrrolidin-2-one (67E). LCMS (ESI) calc'd for C 33 H 40 FN 5 O 6 Si [M+H] +< : 650.3, found: 650.3.Step 6: Preparation of (S)-5-(5-(2-fluoro-4-(oxazol-2-yl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-5-(5-(2-(isoxazol-3-yl)-1,3-dioxolan-2-yl)pentyl)pyrrolidin-2-one (67F)

[0301] A solution of (R,E)-5-(5-(2-fluoro-4-(oxazol-2-yl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-5-(5-(2-(isoxazol-3-yl)-1,3-dioxolan-2-yl)pent-2-en-1-yl)pyrrolidin-2-one (67E, 36 mg, 0.055 mmol) in MeOH (5 ml) was added Pd / C (6 mg, 5.64 µmol) (10%, wet) under Ar. The suspension was degassed under vacuum and purged with N 2 several times. The mixture was then stirred under H 2 (Pressure: 15 psi) at 25°C for 2 h. It was filtered on Celite, and the filter cake was washed with methanol (3 x 5 mL). The filtrate was concentrated under reduced pressure to give (S)-5-(5-(2-fluoro-4-(oxazol-2-yl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-5-(5-(2-(isoxazol-3-yl)-1,3-dioxolan-2-yl)pentyl)pyrrolidin-2-one (67F) which was used directly for next step without purification. LCMS (ESI) calc'd for C 33 H 42 FN 5 O 6 Si [M+H] +< : 652.3 , found: 652.3Step 7: Preparation of (S)-5-(5-(2-fluoro-4-(oxazol-2-yl)phenyl)- 1H-imidazol-2-yl)-5-(6-(isoxazol-3-yl)-6-oxohexyl)pyrrolidin-2-one (Example 67)

[0302] HCl (1 ml, 4.00 mmol) was added to the solution of (S)-5-(5-(2-fluoro-4-(oxazol-2-yl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-5-(5-(2-(isoxazol-3-yl)-1,3-dioxolan-2-yl)pentyl)pyrrolidin-2-one (67F, 30 mg, 0.046 mmol) in MeOH (1.0 ml) and Water (1 ml), and the resultant mixture was stirred at 65°C for 12 h. The mixture was quenched with aqueous NaHCO 3 (saturated) to pH = 7-8 and the mixture was extracted with DCM (3 x 3 mL). The combined organic fractions were washed with brine (saturated, 20 mL), dried (Na 2 SO 4 ), filtered and the solvent was evaporated under reduced pressure to afford (S)-5-(5-(2-fluoro-4-(oxazol-2-yl)phenyl)-1H-imidazol-2-yl)-5-(6-(isoxazol-3-yl)-6-oxohexyl)pyrrolidin-2-one (Example 67). LCMS (ESI) calc'd for C 25 H 24 FN 5 O 4 [M+H] +< : 478.2 , found: 478.1.

[0303] (S)-5-(5-(2-fluoro-4-(oxazol-2-yl)phenyl)-1H-imidazol-2-yl)-5-(6-(isoxazol-3-yl)-6-oxohexyl)pyrrolidin-2-one (Example 67, 15 mg, 0.029 mmol) was added to L-(+)-tartaric acid (5 mg, 0.033 mmol) in water (2 ml) at rt and the mixture was stirred at the same temperature for 15 min. The mixture was lyophilized to give (S)-5-(5-(2-fluoro-4-(oxazol-2-yl)phenyl)-1H-imidazol-2-yl)-5-(6-(isoxazol-3-yl)-6-oxohexyl)pyrrolidin-2-one 2,3-dihydroxysuccinate (67). 1< H NMR (400 MHz, MeOD) δ 8.76 (d, J = 1.76 Hz, 1H), 8.14 (t, J = 8.12 Hz, 1H), 8.02 (d, J = 0.78 Hz, 1H), 7.86-7.92 (m, 1H), 7.76-7.82 (m, 1H), 7.53 (d, J = 3.91 Hz, 1H), 7.34 (d, J = 0.78 Hz, 1H), 6.77 (d, J = 1.76 Hz, 1H), 4.54 (s, 5H), 3.32 (td, J = 1.59, 3.28 Hz, 1H), 3.01-3.08 (m, 2H), 2.47 (d, J = 7.04 Hz, 3H), 2.33-2.40 (m, 1H), 2.02-2.20 (m, 2H), 1.70-1.80 (m, 2H), 1.25-1.49 (m, 6H).Example 68(S)-5-(4-(4-cyclopropyl-2-fluorophenyl)-1H-imidazol-2-yl)-5-(6-(isoxazol-3-yl)-6-oxohexyl)pyrrolidin-2-one

[0304] Step 1: Preparation of (R,E)-5-(5-(4-cyclopropyl-2-fluorophenyl) -1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-5-(5-(2-(isoxazol-3-yl)-1,3-dioxolan-2-yl)pent-2-en-1-yl)pyrrolidin-2-one (68A)

[0305] PdCl 2 (DTBPF) (6 mg, 9.21 µmol) was added to a stirred mixture of cyclopropylboronic acid (13 mg, 0.151 mmol), (R,E)-5-(5-(4-bromo-2-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-5-(5-(2-(isoxazol-3-yl)-1,3-dioxolan-2-yl)pent-2-en-1-yl)pyrrolidin-2-one (67D, 50 mg, 0.076 mmol) and Cs 2 CO 3 (74 mg, 0.227 mmol) in co-solvents of toluene (2 ml) and water (0.05 ml) at rt and the mixture was stirred at 100°C for 18 h. The mixture was concentrated in vacuo and the residue was purified by silica gel flash chromatography (ISCORF75; Sepa flash column), eluting with petroleum ether / EtOAc = 10:1-1:2 to give (R,E)-5-(5-(4-cyclopropyl-2-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-5-(5-(2-(isoxazol-3-yl)-1,3-dioxolan-2-yl)pent-2-en-1-yl)pyrrolidin-2-one (68A). LCMS (ESI) calc'd for C 33 H 43 FN 4 O 5 Si [M+H] +< : 623.3, found: 623.3Step 2: Preparation of (S)-5-(5-(4-cyclopropyl-2-fluorophenyl)-1- ((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-5-(5-(2-(isoxazol-3-yl)-1,3-dioxolan-2-yl)pentyl)pyrrolidin-2-one (68B)

[0306] A solution of (R,E)-5-(5-(4-cyclopropyl-2-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-5-(5-(2-(isoxazol-3-yl)-1,3-dioxolan-2-yl)pent-2-en-1-yl)pyrrolidin-2-one (68A, 21 mg, 0.034 mmol)) in MeOH (3 ml) was added Pd / C (35.9 mg, 0.034 mmol) (10%, wet) was added under Ar. The suspension was degassed under vacuum and purged with N 2 several times. The mixture was then stirred under H 2 (Pressure: 15 psi) at rt for 2 h. The mixture was filtered and concentrated to afford the title compound (68B) which was used directly for next step without purification. LCMS (ESI) calc'd for C 33 H 45 FN 4 O 5 Si [M+H] +< : 625.3, found: 625.4.Step 3: Preparation of (S)-5-(4-(4-cyclopropyl-2-fluorophenyl)-1H-imidazol-2-yl)-5-(6-(isoxazol-3-yl)-6-oxohexyl)pyrrolidin-2-one (Example 68)

[0307] HCl (2 µl, 8.00 µmol) was added to the solution of (S)-5-(5-(4-cyclopropyl-2-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-5-(5-(2-(isoxazol-3-yl)-1,3-dioxolan-2-yl)pentyl)pyrrolidin-2-one (68B, 20 mg, 0.032 mmol) in MeOH (2 ml) and water (2 ml) the resultant mixture was stirred at 65°C for 12 h. The mixture was purified by preparative HPLC (reverse phase C-18 column), eluting with acetonitrile / water, to give (S)-5-(5-(4-cyclopropyl-2-fluorophenyl)-1H-imidazol-2-yl)-5-(6-(isoxazol-3-yl)-6-oxohexyl)pyrrolidin-2-one (Example 68). LCMS (ESI) calc'd for C 25 H 27 FN 4 O 3 [M+H] +< : 451.2, found: 451.0. 1< H NMR (400 MHz, MeOD) δ 8.77 (d, J = 1.6 Hz, 1H), 7.61-7.68 (m, 2H), 7.04-7.09 (m, 1H), 6.96-7.03 (m, 1H), 6.75-6.78 (m, 1H), 3.06 (s, 2H), 2.49 (s, 4H), 2.09-2.20 (m, 2H), 1.95-2.04 (m, 1H), 1.71-1.81 (m, 2H), 1.40-1.53 (m, 3H), 1.20-1.31 (m, 1H), 1.08 (dd, J = 2.0, 8.31 Hz, 2H), 0.77 (dd, J = 2.0, 4.70 Hz, 2H).Example 69(S)-5-(4-(2-fluorophenyl)-1H-imidazol-2-yl)-5-(6-(isoxazol-3-yl)-6-oxohexyl)pyrrolidin-2-one

[0308] Step 1: Preparation of (S)-5-(4-(2-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-5-(6-(isoxazol-3-yl)-6-oxohexyl)pyrrolidin-2-one (69A)

[0309] A solution of (R,E)-5-(5-(4-bromo-2-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-5-(5-(2-(isoxazol-3-yl)-1,3-dioxolan-2-yl)pent-2-en-1-yl)pyrrolidin-2-one (67D, 14 mg, 0.021 mmol) in MeOH (1.5 ml) was added Pd / C (4 mg, 3.76 µmol) (10%, wet) was added under Ar. The suspension was degassed under vacuum and purged with N 2 several times. The mixture was then stirred under H 2 (Pressure: 15 psi) at 25°C for 2 h. The mixture was filtered and concentrated to afford (S)-5-(4-(2-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-5-(6-(isoxazol-3-yl)-6-oxohexyl)pyrrolidin-2-one (69A) which was used directly for next step without purification. LCMS (ESI) calc'd for C 30 H 41 FN 4 O 6 Si [M+H] +< : 585.3, found: 585.4Step 3: Preparation of (S)-5-(5-(2-fluorophenyl)-1H-imidazol -2-yl)-5-(6-(isoxazol-3-yl)-6-oxohexyl)pyrrolidin-2-one (Example 69)

[0310] HCl (1 mL, 4.00 mmol) was added to the solution of (S)-5-(5-(2-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-5-(5-(2-(isoxazol-3-yl)-1,3-dioxolan-2-yl)pentyl)pyrrolidin-2-one (69A, 18 mg, 0.031 mmol) in MeOH (1 ml) and water (1 mL), and the resultant mixture was stirred at 65 °C for 12 h. The residue was purified by preparative HPLC (reverse phase C-18 column), eluting with acetonitrile / water, to give (S)-5-(5-(2-fluorophenyl)-1H-imidazol-2-yl)-5-(6-(isoxazol-3-yl)-6-oxohexyl)pyrrolidin-2-one (Example 69). LCMS (ESI) calc'd for C 22 H 23 FN 4 O 3 [M+H] +< : 411.2, found: 411.2. 1< H NMR (400 MHz, MeOD) δ 8.78 (d, J = 1.8 Hz, 1H), 7.78-7.84 (m, 1H), 7.75 (d, J = 2.2 Hz, 1H), 7.48-7.55 (m, 1H), 7.28-7.39 (m, 2H), 6.77 (d, J = 1.6 Hz, 1H), 3.07 (t, J = 7.2 Hz, 2H), 2.50 (s, 4H), 2.11-2.21 (m, 2H), 1.72-1.82 (m, 2H), 1.41-1.58 (m, 3H), 1.21-1.32 (m, 1H).Example 70(R)-5-(6-(isoxazol-3-yl)-6-oxohexyl)-5-(5-(7-methoxy-2-methylquinolin-6-yl)-1H-imidazol-2-yl)pyrrolidin-2-one

[0311] Step 1: Preparation of (S)-2-(7-methoxy-2-methylquinolin-6-yl)-2-oxoethyl-2-allyl-5-oxopyrrolidine- 2-carboxylate (70BA)

[0312] DIPEA (1.38 ml, 7.90 mmol) was added to a stirred mixture of 2-chloro-1-(7-methoxy-2-methylquinolin-6-yl)ethanone (70A, 850 mg, 3.40 mmol) and (S)-2-allyl-5-oxopyrrolidine-2-carboxylic acid (7-3, 634 mg, 3.74 mmol) in DMF (10 ml) at room temperature and the mixture was stirred at room temperature for 24 h. Another acid (100 mg) and DIPEA (0.2 mL) were added then it was continued to be stirred at rt for 20 h. Water (10 mL) was added and the mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic fractions were washed with aqueous NaHCO 3 (saturated, 1 x 10 mL), dried (Na 2 SO 4 ), filtered and the solvent was evaporated under reduced pressure. The residue was purified by silica gel flash chromatography (ISCORF75; Sepa flash column), eluting with petroleum ether / EtOAc = 50% ~ 100% to give (S)-2-(7-methoxy-2-methylquinolin-6-yl)-2-oxoethyl-2-allyl-5-oxopyrrolidine-2-carboxylate (70B). LCMS (ESI) calc'd for C 21 H 22 N 2 O 5 [M+H] +< : 383.2, found: 383.1Step 2: Preparation of (S)-5-allyl-5-(5-(7-methoxy-2-methylquinolin-6-yl)-1H-imidazol-2-yl)pyrrolidin-2-one (70C)

[0313] Ammonium acetate (1.8 g, 23.35 mmol) was added to a stirred mixture of (S)-2-(7-methoxy-2-methylquinolin-6-yl)-2-oxoethyl-2-allyl-5-oxopyrrolidine-2-carboxylate (70B, 900 mg, 2.353 mmol) in toluene (30 ml) at room temperature and the mixture was heated with stirring at 110°C for 18 h. All the volatiles were removed by evaporator. Water (30 mL) was added and the mixture was extracted with DCM (5 x 30 mL). The combined organic fractions were washed with aqueous NaHCO 3 (saturated, 2 x 30 mL), then washed with brine (1 x 30 mL), dried (Na 2 SO 4 ), filtered and the solvent was evaporated under reduced pressure to give (S)-5-allyl-5-(5-(7-methoxy-2-methylquinolin-6-yl)-1H-imidazol-2-yl)pyrrolidin-2-one (70C) which was used directly for next step.Step 3: Preparation of (S)-5-allyl-5-(5-(7-methoxy-2-methylquinolin-6-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)pyrrolidin-2-one (70D)

[0314] DIPEA (1.2 ml, 6.87 mmol) was added to a stirred mixture of (S)-5-allyl-5-(5-(7-methoxy-2-methylquinolin-6-yl)-1H-imidazol-2-yl)pyrrolidin-2-one (70C, 750 mg, 2.069 mmol) and (2-(chloromethoxy)ethyl)trimethylsilane (0.5 ml, 2.83 mmol) in DMF (10 ml) at room temperature and the mixture was stirred at room temperature for 3 h. Water (20 mL) was added and the mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic fractions were washed with brine (saturated, 1 x 20 mL), dried (Na 2 SO 4 ), filtered and the solvent was evaporated under reduced pressure. The residue was purified by silica gel flash chromatography (ISCORF75; Sepa flash column), eluting with petroleum ether / EtOAc = 0 ~ 50% to give (S)-5-allyl-5-(5-(7-methoxy-2-methylquinolin-6-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)pyrrolidin-2-one (70D). LCMS (ESI) calc'd for C 27 H 36 N 4 O 3 Si [M+H] +< : 493.3, found: 493.3.Step 4: Preparation of (S, E)-5-(6-(isoxazol-3-yl)-6-oxohex-2-en-1-yl)-5-(5-(7-methoxy-2-methylquinolin-6-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)pyrrolidin-2-one (70E)

[0315] UMICORE M71 SIPR (50 mg, 0.061 mmol) was added to a stirred mixture of (S)-5-allyl-5-(5-(7-methoxy-2-methylquinolin-6-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)pyrrolidin-2-one (70D, 300 mg, 0.609 mmol) and 1-(isoxazol-3-yl)pent-4-en-1-one (2, 92 mg, 0.609 mmol) in degassed toluene (5 mL) at room temperature and the mixture was heated with stirring at 100°C for 18 h. Then UMICORE M71 SIPR (50 mg, 0.061 mmol) and 1-(isoxazol-3-yl)pent-4-en-1-one (2, 92 mg, 0.609 mmol) were added again twice every 2 hours. Excess toluene was removed by evaporator. The residue was purified by silica gel flash chromatography (ISCORF75; Sepa flash column), eluting with petroleum ether / EtOAc = 50% ~ 100% to give (S, E)-5-(6-(isoxazol-3-yl)-6-oxohex-2-en-1-yl)-5-(5-(7-methoxy-2-methylquinolin-6-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)pyrrolidin-2-one (70E). LCMS (ESI) calc'd for C 33 H 41 N 5 O 5 Si [M+H] +< : 616.3, found: 616.4.Step 5: Preparation of (S, E)-5-(6-(isoxazol-3-yl)-6-oxohex-2-en-1-yl)-5-(5-(7-methoxy-2-methylquinolin-6-yl)-1H-imidazol-2-yl)pyrrolidin-2-one 2,2,2-trifluoroacetate (70F)

[0316] TFA (1.0 mL, 12.98 mmol) was added to (S, E)-5-(6-(isoxazol-3-yl)-6-oxohex-2-en-1-yl)-5-(5-(7-methoxy-2-methylquinolin-6-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)pyrrolidin-2-one (70E, 90 mg, 0.146 mmol) at room temperature and the mixture was stirred at room temperature for 4 h. All the volatiles were removed by evaporator to give (S, E)-5-(6-(isoxazol-3-yl)-6-oxohex-2-en-1-yl)-5-(5-(7-methoxy-2-methylquinolin-6-yl)-1H-imidazol-2-yl)pyrrolidin-2-one 2,2,2-trifluoroacetate (70F) which was used directly for the next step. LCMS (ESI) calc'd for C 27 H 27 N 5 O 4 [M+H] +< : 486.2, found: 486.3.Step 6: Preparation of (R)-5-(6-(isoxazol-3-yl)-6-oxohexyl)-5-(5-(7-methoxy-2-methylquinolin-6-yl)-1H-imidazol-2-yl)pyrrolidin-2-one (Example 70)

[0317] A solution of (S, E)-5-(6-(isoxazol-3-yl)-6-oxohex-2-en-1-yl)-5-(5-(7-methoxy-2-methylquinolin-6-yl)-1H-imidazol-2-yl)pyrrolidin-2-one 2,2,2-trifluoroacetate (70F, 88 mg, 0.147 mmol) in MeOH (2 ml) was added to a 100 mL three-necked bottle and then Pd / C (10 mg, 9.40 µmol) (10%, wet) was added under Ar. The suspension was degassed under vacuum and purged with N 2 several times. The mixture was then stirred under H 2 (Pressure: 15 psi) at 25°C for 10 h. The mixture was filtered and the filter cake was washed with MeOH (3 x 5 mL). The filtrate was concentrated to dryness. The residue was purified by preparative HPLC (reverse phase C-18 column), eluting with acetonitrile / water + 0.1% TFA, to give the TFA salt of the target compound. Then it was made dry by lyophilization and neutralized with Sat. NaHCO 3 (1 mL), extracted with ethyl acetate (3 x 5 mL), dried with anhydrous Na 2 SO 4 , filtered and concentrated to give (R)-5-(6-(isoxazol-3-yl)-6-oxohexyl)-5-(5-(7-methoxy-2-methylquinolin-6-yl)-1H-imidazol-2-yl)pyrrolidin-2-one (Example 70). LCMS (ESI) calc'd for C 17 H 29 N 5 O 4 [M+H] +< : 488.2, found: 488.3

[0318] L-(+)-tartaric acid (6 mg, 0.040 mmol) was added to a stirred mixture of (R)-5-(6-(isoxazol-3-yl)-6-oxohexyl)-5-(5-(7-methoxy-2-methylquinolin-6-yl)-1H-imidazol-2-yl)pyrrolidin-2-one (18 mg, 0.037 mmol) in acetonitrile (2 ml) and water (2 mL) at room temperature. Then it was made dry by lyophilization to give (R)-5-(6-(isoxazol-3-yl)-6-oxohexyl)-5-(5-(7-methoxy-2-methylquinolin-6-yl)-1H-imidazol-2-yl)pyrrolidin-2-one (2R,3R)-2,3-dihydroxysuccinate (Example 70). 1< H NMR (400 MHz, MeOD) δ 8.74 (d, J = 1.6 Hz, 1H), 8.48 (s, 1H), 8.41 (d, J = 8.6 Hz, 1H), 7.67 (s, 1H), 7.48 (s, 1H), 7.42 (d, J = 8.6 Hz, 1H), 6.73 (d, J = 1.6 Hz, 1H), 4.50 (s, 2H), 4.13 (s, 3H), 3.02 (t, J = 7.2 Hz, 2H), 2.78 (s, 3H), 2.51-2.61 (m, 1H), 2.43-2.50 (m, 2H), 2.32-2.42 (m, 1H), 1.99-2.23 (m, 2H), 1.72-1.76 (m, 2H), 1.38-1.45 (m, 2H), 1.25-1.34 (m, 2H).Example 71(S)-6-(6-(isoxazol-3-yl)-6-oxohexyl)-6-(4-(2-methoxypyridin-3-yl)-1H-imidazol-2-yl)piperidin-2-one

[0319] Step 1: Preparation of (S)-2-(2-methoxypyridin-3-yl)-2-oxoethyl 2-allyl-6-oxopiperidine-2-carboxylate (71A)

[0320] 2-chloro-1-(2-methoxypyridin-3-yl)ethanone (760 mg, 3.28 mmol) was added to a stirred mixture of DIPEA (1 ml, 5.73 mmol), and (S)-2-allyl-6-oxopiperidine-2-carboxylic acid (8-S, 600 mg, 3.28 mmol) in DMF (20 ml) at room temperature and the mixture was stirred at room temperature for 30 h. The mixture was diluted with ethyl acetate (15 mL), washed with brine (saturated, 3 x 15 mL), dried (Na 2 SO 4 ), filtered and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column flash chromatography, eluting with EtOAc / petroleum ether = 0 - 30% to give (S)-2-(2-methoxypyridin-3-yl)-2-oxoethyl 2-allyl-6-oxopiperidine-2-carboxylate (71A). LCMS (ESI) calc'd for C 17 H 20 N 2 O 5 [M+H] +< : 333.1, found: 333.1Step 2: Preparation of (S)-6-allyl-6-(4-(2-methoxypyridin-3-yl)-1H-imidazol-2-yl)piperidin-2-one (71B)

[0321] NH 4 OAc (2.0 g, 25.9 mmol) was added to a stirred mixture of (S)-2-(2-methoxypyridin-3-yl)-2-oxoethyl 2-allyl-6-oxopiperidine-2-carboxylate (71A, 0.8 g, 2.407 mmol) in toluene (8 ml) at room temperature and the mixture was stirred at 130°C for 5 h. The mixture was cooled, diluted with ethyl acetate (20 mL), washed with brine (saturated, 3 x 20 mL), dried (Na 2 SO 4 ), filtered and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column flash chromatography, eluting with MeOH / DCM = 0 - 20% to give (S)-6-allyl-6-(4-(2-methoxypyridin-3-yl)-1H-imidazol-2-yl)piperidin-2-one (71B). LCMS (ESI) calc'd for C 17 H 20 N 4 O 2 [M+H] +< : 313.2, found: 313.1Step 3: Preparation of (S)-6-allyl-6-(4-(2-methoxypyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-y])piperidin-2-one (71C)

[0322] SEMCl (0.5 ml, 2.82 mmol) was added to a stirred mixture of DIEA (1.2 ml, 6.87 mmol) and (S)-6-allyl-6-(4-(2-methoxypyridin-3-yl)-1H-imidazol-2-yl)piperidin-2-one (71B, 600 mg, 1.921 mmol) in DMF (3 ml) at 0°C and the mixture was stirred at room temperature for 12 h. The mixture was cooled to 0°C, water (15 mL) was added and the mixture was extracted with DCM (3 x 10 mL). The combined organic fractions were washed with brine (saturated, 2 x 15 mL), dried (Na 2 SO 4 ), filtered and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column flash chromatography, eluting with EtOAc / petroleum ether = 0 - 20% to give (S)-6-allyl-6-(4-(2-methoxypyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)piperidin-2-one (71C). LCMS (ESI) calc'd for C 23 H 34 N 4 O 3 Si [M+H] +< : 443.2, found: 443.2Step 4: Preparation of (S,E)-6-(6-(isoxazol-3-yl)-6-oxohex-2-en-1-yl)-6-(4-(2-methoxypyridin-3-y1)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)piperidin-2-one (71D)

[0323] Zhan's catalyst (30 mg, 0.041 mmol) was added to a stirred mixture of 1-(isoxazol-3-yl)pent-4-en-1-one (2, 205 mg, 1.356 mmol), and (S)-6-allyl-6-(4-(2-methoxypyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)piperidin-2-one (71C, 300 mg, 0.678 mmol) in toluene (3 ml) at room temperature under N 2 atmosphere and the mixture was stirred at 65°C for 12 h under N 2 . The mixture was cooled, diluted with ethyl acetate (10 mL), washed with brine (saturated, 3 x 10 mL), dried (Na 2 SO 4 ), filtered and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column flash chromatography, eluting with EtOAc / petroleum ether = 0 - 50% to give (S,E)-6-(6-(isoxazol-3-yl)-6-oxohex-2-en-1-yl)-6-(4-(2-methoxypyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)piperidin-2-one (71D). LCMS (ESI) calc'd for C 29 H 39 N 5 O 5 Si [M+H] +< : 566.3, found: 566.4Step 5: Preparation of (S,E)-6-(6-(isoxazol-3-yl)-6-oxohex-2-en-1-yl)-6-(4-(2-methoxypyridin-3-yl)-1H-imidazol-2-yl)piperidin-2-one (71E)

[0324] (S,E)-6-(6-(isoxazol-3-yl)-6-oxohex-2-en-1-yl)-6-(4-(2-methoxypyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)piperidin-2-one (71D, 54 mg, 0.095 mmol) was added in TFA (1 ml, 12.98 mmol) at room temperature, the mixture was stirred at room temperature for 2 h and concentrated to afford (S,E)-6-(6-(isoxazol-3-yl)-6-oxohex-2-en-1-yl)-6-(4-(2-methoxypyridin-3-yl)-1H-imidazol-2-yl)piperidin-2-one (71E). LCMS (ESI) calc'd for C 23 H 25 N 5 O 4 [M+H] +< : 436.2, found: 436.2, tR = 0.924 min.Step 6: Preparation of (R)-6-(6-(isoxazol-3-yl)-6-oxohexyl)-6-(4-(2-methoxypyridin-3-yl)-1H-imidazol-2-yl)piperidin-2-one (Example 71)

[0325] 10% Pd-C (10 mg, 9.40 µmol) was added to a stirred mixture of (S,E)-6-(6-(isoxazol-3-yl)-6-oxohex-2-en-1-yl)-6-(4-(2-methoxypyridin-3-yl)-1H-imidazol-2-yl)piperidin-2-one (71E, 40 mg, 0.092 mmol) in MeOH (1 ml) at room temperature and the mixture was stirred at room temperature for 0.5 h under H 2 . The mixture was filtered and concentrated, the residue was purified by preparative HPLC, eluting with acetonitrile / water + 0.05% NH 3 , to give (R)-6-(6-(isoxazol-3-yl)-6-oxohexyl)-6-(4-(2-methoxypyridin-3-yl)-1H-imidazol-2-yl)piperidin-2-one (77). LCMS (ESI) calc'd for C 23 H 27 N 5 O 4 [M+H] +< : 438.2, found: 438.2

[0326] L-(+)-tartaric acid (8 mg, 0.053 mmol) in water (1 ml) was added to a stirred mixture of (R)-6-(6-(isoxazol-3-yl)-6-oxohexyl)-6-(4-(2-methoxypyridin-3-yl)-1H-imidazol-2-yl)piperidin-2-one (Example 71, 25 mg free, 0.057 mmol) in MeCN (1 ml) at room temperature and the mixture was concentrated to give (R)-6-(6-(isoxazol-3-yl)-6-oxohexyl)-6-(4-(2-methoxypyridin-3-yl)-1H-imidazol-2-yl)piperidin-2-one (2R,3R)-2,3-dihydroxysuccinate (Example 71). 1< H NMR (400 MHz, MeOD) δ 8.76 (d, J = 1.5 Hz, 1H), 8.22 (dd, J = 1.8, 7.5 Hz, 1H), 8.05 (dd, J = 1.9, 5.0 Hz, 1H), 7.57 (s, 1H), 7.04 (dd, J = 5.0, 7.6 Hz, 1H), 6.75 (d, J = 1.8 Hz, 1H), 4.53 (s, 3H), 4.05 (s, 3H), 3.03 (t, J = 7.3 Hz, 2H), 2.38 (d, J = 5.1 Hz, 3H), 1.98-2.03 (m, 3H), 1.81-1.87 (m, 1H), 1.69-1.75 (m, 2H), 1.54 (br s, 1H), 1.36-1.43 (m, 2H), 1.22-1.33 (m, 2H), 1.17-1.19 (m, 1H).Example 72(S)-7-(4-(2-fluorophenyl)-1H-imidazol-2-yl)-7-(6-(isoxazol-3-yl)-6-oxohexyl)azepan-2-one

[0327] Step 1: Preparation of (S)-2-(2-fluorophenyl)-2-oxoethyl 2-allyl-7-oxoazepane-2-carboxylate (72A)

[0328] In a 50 mL round bottomed flask was added (S)-2-allyl-7-oxoazepane-2-carboxylic acid (10, 1 g, 5.07 mmol) in THF (10 ml). 2-bromo-1-(2-fluorophenyl)ethanone (1.100 g, 5.07 mmol) and DIEA (1.328 ml, 7.61 mmol) were added. The mixture was stirred at room temperature for 16 h. The mixture was diluted with ethyl acetate (10 mL), washed with brine (saturated, 2 *10 ml), dried (Na 2 SO 4 ), filtered and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column flash chromatography, eluting with petroleum ether / EtOAc = 10:1-1:1 to give (S)-2-(2-fluorophenyl)-2-oxoethyl 2-allyl-7-oxoazepane-2-carboxylate (72A). LCMS (ESI) calc'd for C 18 H 20 FNO 4 [M+H] +< : 334.1. found: 334.5Step 2: Preparation of (R)-7-allyl-7-(4-(2-fluorophenyl)-1H-imidazol-2-yl)azepan-2-one (72B)

[0329] NH 4 OAc (1041 mg, 13.50 mmol) was added to a stirred mixture of (S)-2-(2-fluorophenyl)-2-oxoethyl 2-allyl-7-oxoazepane-2-carboxylate (72A, 900 mg, 2.70 mmol) in toluene at room temperature and the mixture was heated to 120°C and stirred for 18 h. The mixture was diluted with ethyl acetate, washed with water (saturated, 2 x20 mL), dried (Na 2 SO 4 ), filtered and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column flash chromatography, eluting with petroleum ether / EtOAc = 5:1-1:5 to give (R)-7-allyl-7-(4-(2-fluorophenyl)-1H-imidazol-2-yl)azepan-2-one (72B). LCMS (ESI) calc'd for C 18 H 20 FN 3 O [M+H] +< : 314.2, found: 314.1Step 3: Preparation of (R)-tert-butyl 2-(2-allyl-7-oxoazepan-2-yl)-4-(2-fluorophenyl)-1H-imidazole-1-carboxylate (72C)

[0330] Bo15O (0.372 ml, 1.604 mmol) was added to the solution of DMAP (10 mg, 0.082 mmol) and (R)-7-allyl-7-(4-(2-fluorophenyl)-1H-imidazol-2-yl)azepan-2-one (72B, 304 mg, 0.970 mmol) in DCM (10 ml), the resultant mixture was stirred at rt for 16 h. The mixture was quenched with water (10 mL), and the mixture was extracted with DCM (20 mL). The combined organic fractions were washed with water (10 mL) and brine (10 ml), dried (Na 2 SO 4 ), filtered and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column flash chromatography, eluting with petroleum ether / EtOAc = 5:1 to give (R)-tert-butyl 2-(2-allyl-7-oxoazepan-2-yl)-4-(2-fluorophenyl)-1H-imidazole-1-carboxylate (72C, 220 mg, 55% yield) as a colorless gum. LCMS (ESI) calc'd for C 23 H 28 FN 3 O 3 [M+H] +< : 414.2, found: 414.2Step 4: Preparation of (R,E)-tert-butyl 4-(2-fluorophenyl)-2-(2-(6-(isoxazol-3-yl)-6-oxohex-2-en-1-yl)-7-oxoazepan-2-yl)-1H-imidazole-1-carboxylate (72D)

[0331] UMICORE M71 SIPR (80 mg, 0.097 mmol) (in 4 batches with an interval of 4 h) was added to the mixture of 1-(isoxazol-3-yl)pent-4-en-1-one (2, 439 mg, 2.90 mmol) and (R)-tert-butyl 2-(2-allyl-7-oxoazepan-2-yl)-4-(2-fluorophenyl)-1H-imidazole-1-carboxylate (72C, 200 mg, 0.484 mmol) (in 4 batches with catalyst) in degassed toluene (5 ml), the resultant mixture was stirred at 75°C for 20 h. The reaction mixture was concentrated in vacuo. The residue was purified by silica gel flash chromatography (ISCORF75; Sepa flash column), eluting with petroleum ether / EtOAc = 10:1-2:1 to give (R,E)-tert-butyl 4-(2-fluorophenyl)-2-(2-(6-(isoxazol-3-yl)-6-oxohex-2-en-1-yl)-7-oxoazepan-2-yl)-1H-imidazole-1-carboxylate (72D). LCMS (ESI) calc'd for C 29 H 33 FN 4 O 5 [M+H] -< : 537.2, found: 537.3Step 5: Preparation of (R,E)-7-(4-(2-fluorophenyl)-1H-imidazol-2-yl)-7-(6-(isoxazol-3-yl)-6-oxohex-2-en-1-yl)azepan-2-one (72E)

[0332] TFA (50 µl, 0.037 mmol) was added to the solution of (R,E)-tert-butyl 4-(2-fluorophenyl)-2-(2-(6-(isoxazol-3-yl)-6-oxohex-2-en-1-yl)-7-oxoazepan-2-yl)-1H-imidazole-1-carboxylate (72D, 20 mg, 0.037 mmol) in DCM (1 ml), and the resultant mixture was stirred at rt for 2 h. The mixture was concentrated in vacuo to give (R,E)-7-(4-(2-fluorophenyl)-1H-imidazol-2-yl)-7-(6-(isoxazol-3-yl)-6-oxohex-2-en-1-yl)azepan-2-one (72E) which was used in next step without further purification. LCMS (ESI) calc'd for C 24 H 25 FN 4 O 3 [M+H] +< : 437.2, found: 437.2Step 6: Preparation of (S)-7-(4-(2-fluorophenyl)-1H-imidazol-2-yl)-7-(6-(isoxazol-3-yl)-6-oxohexyl)azepan-2-one (Example 72)

[0333] A solution of (R,E)-7-(4-(2-fluorophenyl)-1H-imidazol-2-yl)-7-(6-(isoxazol-3-yl)-6-oxohex-2-en-1-yl)azepan-2-one (72E, 56 mg, 0.128 mmol) in MeOH (5 ml) was added to a 100 mL bottle and then Pd / C (30 mg, 0.014 mmol) (10%, wet) was added under N 2 . The suspension was degassed under vacuum and purged with H 2 several times. The mixture was then stirred under H 2 (15 psi) at rt for 4 h. The reaction mixture was filtered and concentrated in vacuo. The residue was purified by preparative HPLC (reverse phase C-18 column), eluting with acetonitrile / water + 0.1% TFA and lyophilized to give the TFA salt of product. The solid was dissolved in MeOH (1 mL) and aq.NaHCO 3 (3 mL) was added, the aqueous layer was extracted with EtOAc (3 * 5 mL). The combined organic layer was concentrated in vacuo to give (S)-7-(4-(2-fluorophenyl)-1H-imidazol-2-yl)-7-(6-(isoxazol-3-yl)-6-oxohexyl)azepan-2-one (Example 72). LCMS (ESI) calc'd for C 24 H 27 FN 4 O 3 [M+H] +< : 439.2, found: 439.3

[0334] A solution of L-(+)-tartaric acid (6 mg, 0.040 mmol) in water (5.0 ml) was added to the solution of (S)-7-(4-(2-fluorophenyl)-1H-imidazol-2-yl)-7-(6-(isoxazol-3-yl)-6-oxohexyl)azepan-2-one (Example 72, 15 mg, 0.034 mmol) in MeOH (2 ml), MeOH was removed in vacuo, the aqueous residue was lyophilized to give (S)-7-(4-(2-fluorophenyl)-1H-imidazol-2-yl)-7-(6-(isoxazol-3-yl)-6-oxohexyl)azepan-2-one (2R,3R)-2,3-dihydroxysuccinate (92). 1< H NMR (400 MHz, MeOD) δ 8.72 (d, J= 0.78 Hz, 1H), 7.91 (t, J= 7.73 Hz, 1H), 7.41 (d, J= 3.13 Hz, 1H), 7.08-7.30 (m, 3H), 6.71 (d, J= 0.98 Hz, 1H), 4.51 (s, 2H), 2.96 (t, J= 7.14 Hz, 2H), 2.58 (d, J= 10.76 Hz, 1H), 2.36 (dd, J= 7.73, 13.99 Hz, 1H), 2.05-2.17 (m, 1H), 1.78-1.94 (m, 4H), 1.57-1.72 (m, 3H), 1.21-1.29 (m, 6H).Reference Example 737-(5-(2-methoxyquinolin-3-yl)-1H-imidazol-2-yl)-1-(oxazol-2-yl)heptan-1-one

[0335] Step 1: Preparation of 2-(2-methoxyquinolin-3-yl)-2-oxoethyl pent-4-enoate (73B)

[0336] 2-hydroxy-1-(2-methoxyquinolin-3-yl)ethanone (73A, 1 g, 4.60 mmol) and DMAP (0.169 g, 1.381 mmol) were added to a stirred mixture of pent-4-enoic acid (0.922 g, 9.21 mmol), HOBT (0.775 g, 5.06 mmol), EDCI (1.139 g, 6.45 mmol) in DMF (5 ml) at room temperature and the mixture was stirred at rt for 18 h. The mixture was diluted with ethyl acetate (50 mL*2), washed with water (30 mL) and brine (30 mL), dried (Na 2 SO 4 ), filtered and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column flash chromatography, eluting with Petro.Ether / EtOAc = 0-40% to give 2-(2-methoxyquinolin-3-yl)-2-oxoethyl pent-4-enoate (73B). LCMS (ESI) calc'd for C 17 H 17 NO 4 [M+H] +< : 300.1, found: 300.0Step 2: 3-(2-(but-3-en-1-yl)-1H-imidazol-4-yl)-2-methoxyquinoline (73C)

[0337] NH 4 OAc (3.208 g, 41.6 mmol) was added to a stirred mixture of 2-(2-methoxyquinolin-3-yl)-2-oxoethyl pent-4-enoate (73B, 820 mg, 2.74 mmol) in toluene (40 ml) at rt and the mixture was stirred at 120°C for 2.5 h. The mixture was evaporated under reduced pressure. The residue was purified by silica gel column flash chromatography, eluting with DCM / MeOH = 0~7% to give 3-(2-(but-3-en-1-yl)-1H-imidazol-5-yl)-2-methoxyquinoline (73C). LCMS (ESI) calc'd for C 17 H 17 N 3 O [M+H] +< : 280.3, found: 280.4Step 3: 3-(2-(but-3-en-1-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)-2-methoxyquinoline (73D)

[0338] SEM-Cl (0.6 ml, 3.38 mmol) was added to a stirred mixture of 3-(2-(but-3-en-1-yl)-1H-imidazol-5-yl)-2-methoxyquinoline (73C, 440 mg, 1.575 mmol) and DIEA (1.1 ml, 6.30 mmol) in DMF (6 ml) at rt and the mixture was stirred at rt for 2 h. The mixture was diluted with water (30 mL) and extracted with ethyl acetate (3 x 15 mL). The combined organic fractions were washed with water (3 x 10 mL), dried (Na 2 SO 4 ), filtered and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column flash chromatography, eluting with petroleum ether / EtOAc = 0~5% to give 3-(2-(but-3-en-1-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-2-methoxy quinoline (73D). LCMS (ESI) calc'd for C 23 H 31 N 3 O 2 Si [M+H] +< : 410.5, found: 411.0. 1< H NMR (400 MHz, CDCl 3 ) δ 8.81 (brs, 1H), 7.81 (brs, 2H), 7.50-7.64 (m, 3H), 7.36 (brs, 1H), 7.26 (d, J = 3.33 Hz, 1H), 5.28 (d, J = 3.33 Hz, 2H), 5.15 (brs, 1H), 5.11 (brs, 1H), 5.04 (d, J= 10.76 Hz, 1H), 4.21 (d, J= 3.13 Hz, 4H), 3.57 (brs, 2H), 2.91 (brs, 2H), 2.62 (brs, 2H), 0.93 (d, J = 7.43 Hz, 3H), 0.07-0.05 (m, 11H).Step 4: 7-(4-(2-methoxyquinolin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-1-(oxazol-2-yl)hept-4-en-1-one (73E)

[0339] Zhan's catalyst (22 mg, 0.030 mmol) was added to a mixture of 3-(2-(but-3-en-1-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)-2-methoxyquinoline (73D, 130 mg, 0.317 mmol) and 1-(oxazol-2-yl)pent-4-en-1-one (1, 110 mg, 0.728 mmol) in toluene (1.5 ml) which was bubbled with N 2 for 10 mins at rt. The mixture was degassed and backfilled with N 2 three times and stirred at 100°C for 16 h. The mixture was combined with two parallel reactions, concentrated in vacuo. The residue was purified by silica gel column flash chromatography, eluting with DCM / MeOH = 0~3% to give 7-(4-(2-methoxyquinolin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-1-(oxazol-2-yl)hept-4-en-1-one (73E). LCMS (ESI) calc'd for C 29 H 36 N 4 O 4 Si [M+H] +< : 533.7, found: 533.2Step 5: 7-(4-(2-methoxyquinolin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-1-(oxazol-2-yl)heptan-1-one (73F)

[0340] 10% Pd-C (28 mg, 0.263 mmol) was added to a stirred mixture of (E)-7-(4-(2-methoxyquinolin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-1-(oxazol-2-yl)hept-4-en-1-one (33E, 40 mg, 0.075 mmol) in MeOH (10 ml). The mixture was degassed and backfilled with H 2 (three times), then stirred at 18°C for 2.5 h under H 2 atmosphere (15psi). The mixture was filtered and the filter cake was washed with MeOH (30 mL). The filtrate was concentrated to give 7-(4-(2-methoxyquinolin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-1-(oxazol-2-yl)heptan-1-one (73F), which was used to the next step without purification. LCMS (ESI) calc'd for C 29 H 38 N 4 O 4 Si [M+H] +< : 535.7, found: 535.3Step 6: 7-(5-(2-methoxyquinolin-3-yl)-1H-imidazol-2-yl)-1-(oxazol-2-yl)heptan-1-one (Example 73)

[0341] TFA (3 mL, 38.9 mmol) was added to 7-(4-(2-methoxyquinolin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-1-(oxazol-2-yl)heptan-1-one (73F, 38 mg, 0.071 mmol) and the mixture was stirred at rt for 3 h. The solvent was evaporated under reduced pressure. The residue was purified by preparative HPLC (reverse phase C-18 column), eluting with acetonitrile / water + 0.1% TFA, to give 7-(4-(2-methoxyquinolin-3-yl)-1H-imidazol-2-yl)-1-(oxazol-2-yl)heptan-1-one (Example 73). LCMS (ESI) calc'd for C 23 H 24 N 4 O 3 [M+Na] +< : 427.4, found: 427.2, tR = 1.038 min. 1< H NMR (400 MHz, MeOD) δ 8.50-8.52 (m, 1H), 8.51 (s, 1H), 8.09 (s, 1H), 7.83-7.92 (m, 3H), 7.71 (t, J = 7.24 Hz, 1H), 7.48 (t, J = 7.19 Hz, 1H), 7.39 (s, 1H), 4.20 (s, 3H), 3.30 (td, J = 1.57, 3.25 Hz, 4H), 3.07 (dt, J = 2.87, 7.50 Hz, 4H), 1.83-1.95 (m, 2H), 1.75 (t, J = 7.17 Hz, 2H), 1.41-1.54 (m, 4H).Example 74(S)-7-(ethylamino)-7-(5-(2-methylquinolin-6-yl)-1H-imidazol-2-yl)-1-(oxazol-2-yl)heptan-1-one

[0342] Step 1: Preparation of (R)-N-(1-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-6-(2-(oxazol-2-yl)-1,3-dioxolan-2-yl)hexyl)-N-ethyl-2-methylpropane-2-sulfinamide (74A)

[0343] To a solution of (R)-N-(1-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-6-(2-(oxazol-2-yl)-1,3-dioxolan-2-yl)hexyl)-2-methylpropane-2-sulfinamide (14, 100 mg, 0.161 mmol) in DMF (1 mL) was added NaH (60%, 8 mg, 0.2 mmol) at 0°C. The mixture was stirred at 0°C for 30 min. Then iodoethane (25 mg, 0.161 mmol) was added. The mixture was stirred at rt for 2 h. Aqueous NH 4 Cl (saturated, 10 mL) was added and the mixture was extracted with ethyl acetate (5 x 2 mL). The combined organic fractions were washed with brine (saturated, 10 mL), dried (Na 2 SO 4 ), filtered and the solvent was evaporated under reduced pressure. The crude product was purified by preparative TLC on silica gel, eluting with petroleum ether / EtOAc = 1:1 to give (R)-N-(1-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-6-(2-(oxazol-2-yl)-1,3-dioxolan-2-yl)hexyl)-N-ethyl-2-methylpropane-2-sulfinamide (74A). LCMS (ESI) calc'd for C 27 H 47 BrN 4 O 5 SSi [M+H] +< : 647.2, 649.2, found: 647.3, 649.3. 1< H NMR (400 MHz, MeOD) δ 7.96-8.04 (m, 1H), 7.87-7.94 (m, 1H), 7.22-7.31 (m, 1H), 7.09-7.20 (m, 1H), 5.84-6.05 (m, 1H), 5.13-5.23 (m, 1H), 4.60-4.71 (m, 1H), 4.04-4.07 (m, 2H), 4.01-4.04 (m, 2H), 3.38-3.62 (m, 4H), 2.95-3.10 (m, 5H), 2.81-2.93 (m, 4H), 2.00-2.11 (m, 3H), 1.77-1.92 (m, 1H), 1.14-1.42 (m, 16H), 0.91-0.98 (m, 4H), -0.02-0.03 (m, 9H).Step 2: Preparation of (R)-N-ethyl-2-methyl-N-((S)-1-(5-(2-methylquinolin-6-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-6-(2-(oxazol-2-yl)-1,3-dioxolan-2-yl)hexyl)propane-2-sulfinamide (74B)

[0344] A mixture of Pd(DTBPF)Cl 2 (6 mg, 9.21 µmol), 2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline (25 mg, 0.093 mmol), (R)-N-((S)-1-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-6-(2-(oxazol-2-yl)-1,3-dioxolan-2-yl)hexyl)-N-ethyl-2-methylpropane-2-sulfinamide (74A, 60 mg, 0.093 mmol) and K 3 PO 4 (50 mg, 0.236 mmol) in THF (2 mL) and water (0.4 mL) was degassed and backfilled with N 2 three times. The mixture was heated at 85°C for 3 h. The mixture was filtered and the filter cake was washed with ethyl acetate (20 mL). The filtrate was concentrated to dryness. The residue was purified by silica gel flash chromatography (ISCORF75; Sepa flash column), eluting with DCM / MeOH = 100: 1 - 9: 1 to give (R)-N-ethyl-2-methyl-N-((S)-1-(5-(2-methylquinolin-6-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-6-(2-(oxazol-2-yl)-1,3-dioxolan-2-yl)hexyl)propane-2-sulfinamide (74B). LCMS (ESI) calc'd for C 27 H 55 N 5 O 5 SSi [M+H] +< : 710.4, found: 710.4Step 3: Preparation of (S)-7-(ethylamino)-7-(5-(2-methylquinolin-6-yl)-1H-imidazol-2-yl)-1-(oxazol-2-yl)heptan-1-one (Example 74)

[0345] HCl (0.5 mL, 6.09 mmol) was added to a stirred mixture of (R)-N-ethyl-2-methyl-N-((S)-1-(5-(2-methylquinolin-6-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-6-(2-(oxazol-2-yl)-1,3-dioxolan-2-yl)hexyl)propane-2-sulfinamide (74B, 40 mg, 0.056 mmol) in co-solvents of MeOH (2 mL) and water (0.2 mL) at rt and the mixture was stirred at 65°C for 10 h. The solvent was evaporated under reduced pressure. The residue was purified by preparative HPLC (reverse phase C-18 column), eluting with acetonitrile / water + 0.1% TFA, to give (S)-7-(ethylamino)-7-(5-(2-methylquinolin-6-yl)-1H-imidazol-2-yl)-1-(oxazol-2-yl)heptan-1-one (Example 74). LCMS (ESI) calc'd for C 25 H 29 N 5 O 2 [M+H] +< : 432.2, found: 432.3

[0346] Hydrogen chloride (0.1 M, 1 mL, 0.1 mmol) was added to a stirred mixture of (S)-7-(ethylamino)-7-(5-(2-methylquinolin-6-yl)-1H-imidazol-2-yl)-1-(oxazol-2-yl)heptan-1-one (Example 74, 20 mg, 0.046 mmol) in acetonitrile (2 mL) at room temperature, then it was lyophilized to give (S)-7-(ethylamino)-7-(5-(2-methylquinolin-6-yl)-1H-imidazol-2-yl)-1-(oxazol-2-yl)heptan-1-one hydrochloride (41). LCMS (ESI) calc'd for C 25 H 30 ClN 5 O 2 [M+H] +< : 432.2, found: 432.1. 1< H NMR (400 MHz, MeOD) δ 8.95-9.05 (m, 1H), 8.63-8.74 (m, 1H), 8.55-8.62 (m, 1H), 8.15-8.23 (m, 1H), 8.02-8.08 (m, 1H), 7.95-8.01 (m, 1H), 7.89-7.96 (m, 1H), 7.31-7.39 (m, 1H), 4.47-4.58 (m, 1H), 3.06-3.19 (m, 1H), 3.00 (s, 5H), 2.93-3.06 (m, 1H), 2.10-2.35 (m, 2H), 2.10-2.35 (m, 2H), 1.60-1.78 (m, 2H), 1.22-1.46 (m, 7H).Example 75(S)-7-(methylamino)-7-(5-(2-methylquinolin-6-yl)-1H-imidazol-2-yl)-1-(oxazol-2-yl)heptan-1-one

[0347]

[0348] Example 75 was obtained from 14 using a similar method starting with MeI. LCMS (ESI) calc'd for C 24 H 27 N 5 O 2 [M+H] +< : 418.2, found: 418.1. 1< H NMR (400 MHz, MeOD) δ 8.73-8.86 (m, 1H), 8.44-8.60 (m, 2H), 8.00-8.13 (m, 2H), 7.75-7.91 (m, 2H), 7.28-7.38 (m, 1H), 4.32-4.45 (m, 1H), 2.98-3.05 (m, 2H), 2.90-2.95 (m, 3H), 2.90-2.95 (m, 1H), 2.63-2.73 (m, 3H), 2.05-2.31 (m, 2H), 1.63-1.76 (m, 2H), 1.36-1.45 (m, 2H), 1.22-1.33 (m, 3H).Example 76(S)-7-methoxy-1-methyl-6-(2-(1-(methylamino)-7-(oxazol-2-yl)-7-oxoheptyl)-1H-imidazol-5-yl)quinolin-2(1H)-one

[0349] Step 1: Preparation of (S)-N-((S)-1-(5-(7-methoxy-1-methyl-2-oxo-1,2-dihydroquinolin-6-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-6-(2-(oxazol-2-yl)-1,3-dioxolan-2-yl)hexyl)-2-methylpropane-2-sulfinamide (76A)

[0350] PdCl 2 (DTBPF) (45 mg, 0.069 mmol) was added to a mixture of (S)-N-((S)-1-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-6-(2-(oxazol-2-yl)-1,3-dioxolan-2-yl)hexyl)-2-methylpropane-2-sulfinamide (14, 400 mg, 0.645 mmol), 7-methoxy-1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-2(1H)-one (415 mg, 0.658 mmol) and K 3 PO 4 (411 mg, 1.936 mmol) in co-solvents of THF (4 ml) and water (0.4 ml) at room temperature and the mixture was stirred at 70°C for 2.5 h. Water (5 mL) was added, and the mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic fractions were washed with brine (saturated, 10 mL), dried (Na 2 SO 4 ), filtered and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column flash chromatography, eluting with DCM / MeOH = 0~10% to give (S)-N-((S)-1-(5-(7-methoxy-1-methyl-2-oxo-1,2-dihydroquinolin-6-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-6-(2-(oxazol-2-yl)-1,3-dioxolan-2-yl)hexyl)-2-methylpropane-2-sulfinamide (76A). LCMS (ESI) calc'd for C 36 H 53 N 5 O 7 SSi [M+H] +< : 728.3, found: 728.4Step 2: Preparation of (S)-N-((S)-1-(5-(7-methoxy-1-methyl-2-oxo-1,2-dihydroquinolin-6-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-6-(2-(oxazol-2-yl)-1,3-dioxolan-2-yl)hexyl)-N,2-dimethylpropane-2-sulfinamide (76B)

[0351] NaH (60%, 7 mg, 0.175 mmol) was added to a stirred mixture of (S)-N-((5)-1-(5-(7-methoxy-1-methyl-2-oxo-1,2-dihydroquinolin-6-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-6-(2-(oxazol-2-yl)-1,3-dioxolan-2-yl)hexyl)-2-methylpropane-2-sulfinamide (76A, 100 mg, 0.137 mmol) in THF (1 ml) at room temperature then MeI (0.02 ml, 0.320 mmol) was added and the mixture was stirred at room temperature for 2 h. It was done twice in the same way then they were combined together for further operation. Water (5 mL) was added and the mixture was extracted with ethyl acetate (3 x 5 mL). The combined organic fractions were washed with brine (saturated, 1 x 5 mL), dried (Na 2 SO 4 ), filtered and the solvent was evaporated under reduced pressure. The residue was purified by silica gel flash chromatography (ISCORF75; Sepa flash column), eluting with petroleum ether / EtOAc = 0~100% to give (S)-N-((S)-1-(5-(7-methoxy-1-methyl-2-oxo-1,2-dihydroquinolin-6-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-6-(2-(oxazol-2-yl)-1,3-dioxolan-2-yl)hexyl)-N,2-dimethylpropane-2-sulfinamide (76B). LCMS (ESI) calc'd for C 37 H 55 N 5 O 7 SSi [M+H] +< : 742.4, found: 742.4Step 3: Preparation of (S)-7-methoxy-1-methyl-6-(2-(1-(methylamino)-7-(oxazol-2-yl)-7-oxoheptyl)-1H-imidazol-5-yl)quinolin-2(1H)-one (Example 76)

[0352] HCl (0.2 mL, 0.800 mmol) was added to a stirred mixture of (S)-N-((S)-1-(5-(7-methoxy-1-methyl-2-oxo-1,2-dihydroquinolin-6-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-6-(2-(oxazol-2-yl)-1,3-dioxolan-2-yl)hexyl)-N,2-dimethylpropane-2-sulfinamide (76B, 90 mg, 0.121 mmol) in MeOH (1.0 mL) and water (0.2 ml) at room temperature and the mixture was stirred at 50°C for 28 h. It was done twice in the same way and they were combined together for purification. The residue was purified by preparative HPLC (reverse phase C-18 column), eluting with acetonitrile / water + 0.1% TFA, to give its TFA salt of the target compound. It was then dissolved in the mixture of 3 mL water and 1 mL CH 3 CN, neutralized with NaHCO 3 (sat.), extracted with ethyl acetate (3 x 5 mL), dried with anhydrous Na 2 SO 4 , and concentrated under reduced pressure to give (S)-7-methoxy-1-methyl-6-(2-(1-(methylamino)-7-(oxazol-2-yl)-7-oxoheptyl)-1H-imidazol-5-yl)quinolin-2(1H)-one (Example 76). LCMS (ESI) calc'd for C 25 H 29 N 5 O 4 [M+H] +< : 464.2, found: 464.3

[0353] L-(+)-tartaric acid (26 mg, 0.173 mmol) was added to a stirred mixture of (S)-7-methoxy-1-methyl-6-(2-(1-(methylamino)-7-(oxazol-2-yl)-7-oxoheptyl)-1H-imidazol-5-yl)quinolin-2(1H)-one (Example 76, 80 mg, 0.173 mmol) in acetonitrile (2 ml) and water (2 mL) at room temperature. Then, it was lyophilized to give (S)-7-methoxy-1-methyl-6-(2-(1-(methylamino)-7-(oxazol-2-yl)-7-oxoheptyl)-1H-imidazol-5-yl)quinolin-2(1H)-one (2R,3R)-2,3-dihydroxysuccinate (Example 76). 1< H NMR (400 MHz, MeOD) δ 8.23 (s, 1H), 8.05 (s, 1H), 7.86 (d, J= 9.3 Hz, 1H), 7.65 (s, 1H), 7.34 (s, 1H), 7.03 (brs, 1H), 6.54 (d, J = 9.3 Hz, 1H), 4.49 (s, 2H), 4.40 (d, J = 5.95 Hz, 1H), 4.10 (s, 3H), 3.75 (s, 3H), 2.99 (t, J = 7.1 Hz, 2H), 2.63 (s, 3H), 2.06-2.37 (m, 2H), 1.61-1.77 (m, 2H), 1.20-1.50 (m, 4H).Example 77(S)-6-(2-(1-(ethylamino)-7-(oxazol-2-yl)-7-oxoheptyl)-1H-imidazol-5-yl)-7-methoxy-1-methylquinolin-2(1H)-one

[0354]

[0355] Example 77 was obtained from 76B using a similar method starting with EtI. LCMS (ESI) calc'd for C 26 H 31 N 5 O 4 ·17H 6 O 6 [M+H] +< : 478.2, found: 478.3. 1< H NMR (400 MHz, MeOD) δ 8.21 (s, 1H), 8.03 (s, 1H), 7.86 (d, J= 9.00 Hz, 1H), 7.64 (s, 1H), 7.33 (s, 1H), 7.01 (s, 1H), 6.52 (d, J= 9.39 Hz, 1H), 4.45 (s, 2H), 4.39 (brs, 1H), 4.09 (s, 3H), 3.74 (s, 3H), 2.98 (t, J = 7.04 Hz, 1H), 2.82-3.05 (m, 1H), 2.89 (brs, 1H), 2.80-2.93 (m, 1H), 2.28 (brs, 1H), 2.10 (brs, 1H), 1.66 (d, J = 6.65 Hz, 2H), 1.38 (brs, 4H), 1.24-1.32 (m, 3H).Example 78(S)-7-((1-methylpiperidin-4-yl)amino)-7-(5-(2-methylquinolin-6-yl)-1H-imidazol-2-yl)-1-(oxazol-2-yl)heptan-1-one

[0356]

[0357] aBH(OAc) 3 (193 mg, 0.909 mmol) was added to a stirred mixture of (S)-7-amino-7-(4-(2-methylquinolin-6-yl)-1H-imidazol-2-yl)-1-(oxazol-2-yl)heptan-1-one hydrochloride (Example 9, 40 mg, 0.091 mmol) and 1-methylpiperidin-4-one (103 mg, 0.909 mmol) in MeOH (2.0 ml) at room temperature. The mixture was stirred at 40°C for 12 h. The residue was purified by preparative HPLC (reverse phase C-18 column), eluting with acetonitrile / water + 0.1% TFA, to give (S)-7-((1-methylpiperidin-4-yl) amino)-7-(5-(2-methylquinolin-6-yl)-1H-imidazol-2-yl)-1-(oxazol-2-yl)heptan-1-one (Example 78). LCMS (ESI) calc'd for C 29 H 36 N 6 O 2 [M+H] +< : 501.3, found: 501.3. 1< H NMR (400 MHz, MeOD) δ 8.94 (d, J = 8.60 Hz, 1H), 8.63 (s, 1H), 8.56 (d, J = 8.82 Hz, 1H), 8.16 (d, J = 8.82 Hz, 1H), 8.07 (s, 1H), 7.86-7.99 (m, 2H), 7.36 (s, 1H), 4.63 (brs, 1H), 3.54-3.69 (m, 2H), 2.94-3.20 (m, 7H), 2.84 (brs, 3H), 2.53 (d, J = 13.45 Hz, 1H), 1.92-2.33 (m, 6H), 1.62-1.77 (m, 2H), 1.42 (d, J = 6.17 Hz, 3H), 1.28 (d, J = 16.76 Hz, 1H).Example 79(S)-7-(5-(2-methylquinolin-6-yl)-1H-imidazol-2-yl)-1-(oxazol-2-yl)-7-((tetrahydro-2H-pyran-4-yl)amino)heptan-1-one

[0358]

[0359] NaBH(OAc) 3 (193 mg, 0.909 mmol) was added to a stirred mixture of (S)-7-amino-7-(4-(2-methylquinolin-6-yl)-1H-imidazol-2-yl)-1-(oxazol-2-yl)heptan-1-one hydrochloride (Example 9, 40 mg, 0.091 mmol) and dihydro-2H-pyran-4(3H)-one (91 mg, 0.909 mmol) in MeOH (2.0 ml) at room temperature and the mixture was stirred at 40 °C for 12 h. The residue was purified by preparative HPLC (reverse phase C-18 column), eluting with acetonitrile / water + 0.1% TFA, to give (S)-7-(5-(2-methylquinolin-6-yl)-1H-imidazol-2-yl)-1-(oxazol-2-yl)-7-((tetrahydro-2H-pyran-4-yl)amino)heptan-1-one (Example 79). LCMS (ESI) calc'd for C 28 H 33 N 5 O 3 [M+H] +< : 488.3, found: 488.1. 1< H NMR (400 MHz, MeOD) δ 8.95 (d, J = 8.60 Hz, 1H), 8.50-8.67 (m, 2H), 8.15 (d, J = 8.82 Hz, 1H), 8.07 (s, 1H), 7.85-7.95 (m, 2H), 7.36 (s, 1H), 4.56-4.63 (m, 1H), 4.00 (dd, J = 12.24, 18.63 Hz, 2H), 3.34-3.41 (m, 2H), 3.26 (brs, 1H), 2.95-3.06 (m, 4H), 2.25 (brs, 1H), 2.15 (d, J= 12.35 Hz, 2H), 1.92 (d, J= 13.01 Hz, 1H), 1.63-1.79 (m, 4H), 1.14-1.51 (m, 5H).Example 80(S)-7-(5-(7-methoxy-2-methylquinolin-6-yl)-1H-imidazol-2-yl)-1-(oxazol-2-yl)-7-((tetrahydro-2H-pyran-4-yl)amino)heptan-1-one

[0360]

[0361] Example 80 was obtained from compound Example 12 using a similar method. LCMS (ESI) calc'd for C 29 H 35 N 5 O 4 [M+H] +< : 518.3, found: 518.1, tR = 1.908 min. 1< H NMR (400 MHz, MeOD) δ 8.84-8.90 (m, 2H), 8.06 (s, 1H), 7.91 (s, 1H), 7.73 (d, J = 8.38 Hz, 1H), 7.56 (s, 1H), 7.35 (s, 1H), 4.61 (dd, J = 4.08, 10.47 Hz, 1H), 4.24 (s, 3H), 3.91-4.07 (m, 3H), 3.33-3.40 (m, 2H), 3.19-3.26 (m, 1H), 3.00 (t, J = 7.39 Hz, 2H), 2.96 (s, 3H), 2.25 (brs, 1H), 2.15 (d, J = 9.70 Hz, 1H), 1.91 (d, J = 11.03 Hz, 1H), 1.64-1.79 (m, 4H), 1.40 (brs, 3H), 1.22 (brs, 1H).Example 81(S)-7-(benzylamino)-7-(5-(2-methylquinolin-6-yl)-1H-imidazol-2-yl)-1-(oxazol-2-yl)heptan-1-one

[0362]

[0363] Benzaldehyde (50 mg, 0.471 mmol) was added to a stirred mixture of (S)-7-amino-7-(4-(2-methylquinolin-6-yl)-1H-imidazol-2-yl)-1-(oxazol-2-yl)heptan-1-one hydrochloride (Example 9, 30 mg, 0.068 mmol) in MeOH (1.0 ml) at room temperature and the mixture was stirred at room temperature for 2 h. NaBH(OAc) 3 (145 mg, 0.682 mmol) was added. The mixture was stirred at room temperature for 12 h. The residue was purified by preparative HPLC (reverse phase C-18 column), eluting with acetonitrile / water + 0.1% TFA, to give (S)-7-(benzylamino)-7-(5-(2-methylquinolin-6-yl)-1H-imidazol-2-yl)-1-(oxazol-2-yl)heptan-1-one (Example 81). LCMS (ESI) calc'd for C 20 H 31 N 5 O 2 [M+H] +< : 494.3, found: 494.1. 1< H NMR (400 MHz, MeOD) δ 8.96 (d, J = 8.38 Hz, 1H), 8.66 (d, J = 1.54 Hz, 1H), 8.58-8.64 (m, 1H), 8.17 (d, J = 8.82 Hz, 1H), 8.08 (d, J = 0.66 Hz, 1H), 7.89-7.94 (m, 2H), 7.45 (s, 5H), 7.37 (s, 1H), 4.47 (dd, J = 4.19, 10.36 Hz, 1H), 4.28 (d, J = 13.01 Hz, 1H), 4.14 (d, J = 13.01 Hz, 1H), 2.97-3.06 (m, 5H), 2.16-2.27 (m, 2H), 1.64-1.73 (m, 2H), 1.41 (brs, 3H), 1.28 (d, J = 11.91 Hz, 1H).Example 82(S)-7-(benzylamino)-7-(5-(7-methoxy-2-methylquinolin-6-yl)-1H-imidazol-2-yl)-1-(oxazol-2-yl)heptan-1-one

[0364]

[0365] Example 82 was obtained from compound Example 12 using a similar method. LCMS (ESI) calc'd for C 21 H 33 N 5 O 3 [M+H] +< : 524.3, found: 524.1. 1< H NMR (400 MHz, MeOD) δ 8.85-8.93 (m, 2H), 8.06 (s, 1H), 7.92 (s, 1H), 7.74 (d, J = 8.60 Hz, 1H), 7.57 (s, 1H), 7.44 (s, 5H), 7.36 (s, 1H), 4.48 (d, J = 5.51 Hz, 1H), 4.20-4.31 (m, 4H), 4.13 (d, J = 13.23 Hz, 1H), 2.91-3.04 (m, 5H), 2.25 (d, J = 9.92 Hz, 1H), 2.20 (dd, J = 5.18, 10.47 Hz, 1H), 1.65-1.76 (m, 2H), 1.36-1.47 (m, 3H), 1.25 (brs, 1H).Example 83(S)-7-(5-(2-methylquinolin-6-yl)-1H-imidazol-2-yl)-7-morpholino-1-(oxazol-2-yl)heptan-1-one

[0366] Step 1: Preparation of (S)-1-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-6-(2-(oxazol-2-yl)-1,3-dioxolan-2-yl)hexan-1-amine (83A)

[0367] HCl / dioxane (3.75 mL, 15.00 mmol) was added to a stirred mixture of (R)-N-((S)-1-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-6-(2-(oxazol-2-yl)-1,3-dioxolan-2-yl)hexyl)-2-methylpropane-2-sulfinamide (14, 1.5 g, 2.421 mmol) in MeOH (15 ml) and water (7.5 mL) at room temperature and the mixture was stirred at room temperature for 2 h. 2 mL HCl / dioxane was added and the mixture continued to be stirred at room temperature for 2 h. Aqueous NaHCO 3 (saturated, 15 mL) was added to adjust the pH to around 7 and the mixture was extracted with DCM (3 x 15 mL). The combined organic fractions were washed with brine (saturated, 1 x 15 mL), dried (Na 2 SO 4 ), filtered and the solvent was evaporated under reduced pressure to give (S)-1-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-6-(2-(oxazol-2-yl)-1,3-dioxolan-2-yl)hexan-1-amine (49A). LCMS (ESI) calc'd for C 21 H 35 BrN 4 O 4 Si [M+H] +< : 515.2, 517.2, found: 515.1,517.1Step 2: Preparation of (S)-4-(1-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-6-(2-(oxazol-2-yl)-1,3-dioxolan-2-yl)hexyl)morpholine (83B)

[0368] DIPEA (0.08 ml, 0.458 mmol) was added to a stirred mixture of (S)-1-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-6-(2-(oxazol-2-yl)-1,3-dioxolan-2-yl)hexan-1-amine (83A, 130 mg, 0.252 mmol) and 1-bromo-2-(2-bromoethoxy)ethane (60 mg, 0.259 mmol) in acetonitrile (7 ml) at room temperature and the mixture was heated with stirring at 80°C for 42 h. Then NaI (40 mg, 0.267 mmol) and 1-bromo-2-(2-bromoethoxy)ethane (60 mg, 0.259 mmol) was added and it continued to be stirred at 80°C for 24 h. The mixture was cooled to room temperature, the solvent was removed by evaporator, then water (5 mL) was added and the mixture was extracted with DCM (3 x 10 mL). The combined organic fractions were washed with brine (saturated, 1 x 10 mL), dried (Na 2 SO 4 ), filtered and the solvent was evaporated under reduced pressure. The residue was purified by silica gel flash chromatography (ISCORF75; Sepa flash column), eluting with petroleum ether / EtOAc = 0~60% to give (S)-4-(1-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol- 2-yl)-6-(2-(oxazol-2-yl)-1,3-dioxolan-2-yl)hexyl)morpholine (83B). LCMS (ESI) calc'd for C 25 H 41 BrN 4 O 5 Si [M+H] +< : 585.2, 587.2, found: 585.3, 587.3Step 3: Preparation of (S)-4-(1-(5-(2-methylquinolin-6-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-6-(2-(oxazol-2-yl)-1,3-dioxolan-2-yl)hexyl)morpholine (83C)

[0369] Pd(DTBPF)Cl 2 (11 mg, 0.017 mmol) was added to a stirred mixture of 2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline (46 mg, 0.171 mmol), (S)-4-(1-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-6-(2-(oxazol-2-yl)-1,3-dioxolan-2-yl)hexyl)morpholine (83B, 100 mg, 0.171 mmol), K 3 PO 4 (109 mg, 0.512 mmol) in THF (1 ml) / water (0.25 ml) at room temperature and the mixture was stirred at 65°C for 18 h. The mixture was concentrated and the residue was purified by silica gel flash chromatography (ISCORF75; Sepa flash column), eluting with petroleum ether / EtOAc = 0~100% to give (S)-4-(1-(5-(2-methylquinolin-6-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-6-(2-(oxazol-2-yl)-1,3-dioxolan-2-yl)hexyl)morpholine (83C). LCMS (ESI) calc'd for C 25 H 49 N 5 O 5 Si [M+H] +< : 648.4, found: 648.4Step 4: Preparation of (S)-7-(5-(2-methylquinolin-6-yl)-1H-imidazol-2-yl)-7-morpholino-1-(oxazol-2-yl)heptan-1-one (Example 83)

[0370] HCl (0.7 mL, 2.80 mmol) was added to a stirred mixture of (S)-4-(1-(5-(2-methylquinolin-6-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-6-(2-(oxazol-2-yl)-1,3-dioxolan-2-yl)hexyl)morpholine (83C, 65 mg, 0.100 mmol) in MeOH (2.8 ml) and water (0.28 mL) at room temperature and the mixture was stirred at 65°C for 16 h. The mixture was cooled to room temperature, and aqueous NaHCO 3 (saturated, 3 mL) was added to adjust the pH to 7. Most of the solvent was removed by evaporator. The residue was purified by preparative HPLC (reverse phase C-18 column), eluting with acetonitrile / water + 0.05% NH 3 ·H 2 O, to give (S)-7-(5-(2-methylquinolin-6-yl)-1H-imidazol-2-yl)-7-morpholino-1-(oxazol-2-yl)heptan-1-one (Example 83). LCMS (ESI) calc'd for C 27 H 31 N 5 O 3 [M+H] +< : 474.2, found: 474.2.

[0371] L-(+)-Tartaric acid (12 mg, 0.080 mmol) was added to a stirred mixture of (S)-7-(5-(2-methylquinolin-6-yl)-1H-imidazol-2-yl)-7-morpholino-1-(oxazol-2-yl)heptan-1-one (Example 83, 35 mg, 0.074 mmol) in acetonitrile (2 ml) and water (2 ml) at room temperature and the mixture was made dry by lyophilization to give (S)-7-(5-(2-methylquinolin-6-yl)-1H-imidazol-2-yl)-7-morpholino-1-(oxazol-2-yl)heptan-1-one (2R,3R)-2,3-dihydroxysuccinate (Example 83). LCMS (ESI) calc'd for C 27 H 31 N 5 O 3 [M+H] +< : 474.2, found: 474.1. 1< H NMR (400 MHz, MeOD) δ 8.29 (d, J = 8.6 Hz, 1H), 8.25 (d, J= 1.5 Hz, 1H), 8.12 (dd, J = 2.0, 8.8 Hz, 1H), 8.05 (s, 1H), 7.97 (d, J = 8.8 Hz, 1H), 7.68 (s, 1H), 7.47 (d, J = 8.6 Hz, 1H), 7.35 (s, 1H), 4.50 (s, 2H), 3.84-3.91 (m, 1H), 3.68-3.78 (m, 4H), 2.99-3.06 (m, 2H), 2.74 (s, 5H), 2.56-2.67 (m, 2H), 2.07 (d, J= 7.7 Hz, 2H), 1.65-1.75 (m, 2H), 1.15-1.50 (m, 4H).Example 84(S)-7-(5-(7-methoxy-2-methylquinolin-6-yl)-1H-imidazol-2-yl)-7-((3-methoxycyclobutyl)amino)-1-(oxazol-2-yl)heptan-1-one

[0372] Step 1: Preparation of (R)-N-((S)-1-(5-(7-methoxy-2-methylquinolin-6-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-6-(2-(oxazol-2-yl)-1,3-dioxolan-2-yl)hexyl)-2-methylpropane-2-sulfinamide (84A)

[0373] Pd(DTBPF)Cl 2 (0.13 g, 0.199 mmol) was added to a stirred mixture of 7-methoxy-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline (1.01 g, 3.38 mmol), (R)-N-((S)-1-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-6-(2-(oxazol-2-yl)-1,3-dioxolan-2-yl)hexyl)-2-methylpropane-2-sulfinamide (14, 2.0 g, 3.23 mmol) and K 3 PO 4 (2.056 g, 9.69 mmol) in THF (20 ml) and water (1.0 ml) at room temperature and the mixture was stirred at 80°C for 4 h under N 2 . The mixture was concentrated. The residue was purified by silica gel column flash chromatography, eluting with petroleum ether / EtOAc = 1:1 - 0 :1 to give (R)-N-((S)-1-(5-(7-methoxy-2-methylquinolin-6-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-6-(2-(oxazol-2-yl)-1,3-dioxolan-2-yl)hexyl)-2-methylpropane-2-sulfinamide (84A). LCMS (ESI) calc'd for C 26 H 53 N 5 O 6 SSi [M+H] +< : 712.4, found: 712.4Step 2: Preparation of (S)-1-(5-(7-methoxy-2-methylquinolin-6-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-6-(2-(oxazol-2-yl)-1,3-dioxolan-2-yl)hexan-1-amine (84B)

[0374] Hydrogen chloride (3.0 ml, 12.00 mmol) was added to a stirred mixture of (R)-N-((S)-1-(5-(7-methoxy-2-methylquinolin-6-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-6-(2-(oxazol-2-yl)-1,3-dioxolan-2-yl)hexyl)-2-methylpropane-2-sulfinamide (84A, 800 mg, 1.124 mmol) in MeOH (3.0 ml) at room temperature and the mixture was stirred at room temperature for 12 h. The mixture was quenched with aqueous NaHCO 3 (saturated) to pH = 7-9 and the mixture was extracted with DCM (3 x 30 mL). The combined organic fractions were washed with brine (saturated, 30 mL), dried (Na 2 SO 4 ), filtered and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column flash chromatography, eluting with DCM / MeOH = 10 : 1 to give (S)-1-(5-(7-methoxy-2-methylquinolin-6-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-6-(2-(oxazol-2-yl)-1,3-dioxolan-2-yl)hexan-1-amine (84B). LCMS (ESI) calc'd for C 22 H 45 N 5 O 5 Si [M+H] +< : 608.3, found: 608.4Step 3: Preparation of (S)-3-methoxy-N-(1-(5-(7-methoxy-2-methylquinolin-6-yl) -1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-6-(2-(oxazol-2-yl)-1,3-dioxolan-2-yl)hexyl)cyclobutanamine (84C)

[0375] 3-methoxycyclobutanone (40 mg, 0.400 mmol) was added to a stirred mixture of (S)-1-(5-(7-methoxy-2-methylquinolin-6-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-6-(2-(oxazol-2-yl)-1,3-dioxolan-2-yl)hexan-1-amine (84B, 60 mg, 0.099 mmol) in MeOH (1.0 ml) at room temperature and the mixture was stirred at 40°C for 12 h. The residue was purified by silica gel column flash chromatography, eluting with petroleum ether / EtOAc = 1:1 - 0 :1 to give (S)-3-methoxy-N-(1-(5-(7-methoxy-2-methylquinolin-6-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-6-(2-(oxazol-2-yl)-1,3-dioxolan-2-yl)hexyl)cyclobutanamine (84C). LCMS (ESI) calc'd for C 27 H 53 N 5 O 6 Si [M+H] +< : 692.4, found: 692.4Step 4: Preparation of (S)-7-(5-(7-methoxy-2-methylquinolin-6-yl)-1H-imidazol -2-yl)-7-((3-methoxycyclobutyl)amino)-1-(oxazol-2-yl)heptan-1-one (Example 84)

[0376] Hydrogen chloride (1.5 ml, 6.00 mmol) was added to a stirred mixture of (S)-3-methoxy-N-(1-(5-(7-methoxy-2-methylquinolin-6-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-6-(2-(oxazol-2-yl)-1,3-dioxolan-2-yl)hexyl)cyclobutanamine (84C, 40 mg, 0.058 mmol) in MeOH (2.0 ml) at room temperature and the mixture was stirred at 50°C for 6 h. The residue was purified by preparative HPLC (reverse phase C-18 column), eluting with acetonitrile / water + 0.1% TFA, to give (S)-7-(5-(7-methoxy-2-methylquinolin-6-yl)-1H-imidazol-2-yl)-7-((3-methoxycyclobutyl)amino)-1-(oxazol-2-yl)heptan-1-one (Example 84). LCMS (ESI) calc'd for C 29 H 35 N 5 O 4 [M+H] +< : 518.3, found: 518.0. 1< H NMR (400 MHz, MeOD) δ 8.83-8.92 (m, 2H), 8.06 (s, 1H), 7.90 (s, 1H), 7.73 (d, J = 8.60 Hz, 1H), 7.57 (brs, 1H), 7.35 (s, 1H), 4.38 (d, J= 10.80 Hz, 1H), 4.24 (s, 3H), 3.78-4.02 (m, 1H), 3.67 (td, J= 7.06, 13.67 Hz, 1H), 3.33-3.39 (m, 1H), 3.19 (s, 3H), 3.00 (t, J = 7.39 Hz, 2H), 2.96 (s, 3H), 2.74 (dt, J = 6.39, 11.91 Hz, 1H), 2.35-2.51 (m, 1H), 2.22-2.33 (m, 1H), 2.05-2.17 (m, 2H), 1.92 (td, J = 8.30, 11.41 Hz, 1H), 1.64-1.75 (m, 2H), 1.40 (brs, 3H), 1.22 (brs, 1H).Example 85(S)-7-(5-(7-methoxy-2-methylquinolin-6-yl)-1H-imidazol-2-yl)-1-(oxazol-2-yl)-7-(pyrimidin-2-ylamino)heptan-1-one

[0377] Step 1: Preparation of (S)-N-(1-(5-(7-methoxy-2-methylquinolin-6-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-6-(2-(oxazol-2-yl)-1,3-dioxolan-2-yl)hexyl)pyrimidin-2-amine (85A)

[0378] To a solution of (S)-1-(5-(7-methoxy-2-methylquinolin-6-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-6-(2-(oxazol-2-yl)-1,3-dioxolan-2-yl)hexan-1-amine (84B, 100 mg, 0.165 mmol) and TEA (0.1 mL, 0.717 mmol) in ethanol (1 mL) was added 2-chloropyrimidine (19 mg, 0.166 mmol) at rt. The mixture was stirred at 90 °C for 48 h. The mixture was concentrated to dryness and the residue was purified by silica gel flash chromatography (ISCORF75; Sepa flash column), eluting with DCM / MeOH = 100:1 - 9:1 to give (S)-N-(1-(5-(7-methoxy-2-methylquinolin-6-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-6-(2-(oxazol-2-yl)-1,3-dioxolan-2-yl)hexyl)pyrimidin-2-amine (85A). LCMS (ESI) calc'd for C 36 H 47 N 7 O 5 Si [M+H] +< : 686.3, found: 686.3Step 2: Preparation of (S)-7-(5-(7-methoxy-2-methylquinolin-6-yl)-1H-imidazol-2-yl)-1-(oxazol-2-yl)-7-(pyrimidin-2-ylamino)heptan-1-one (Example 85)

[0379] HCl (0.5 mL, 6.09 mmol) was added to a stirred mixture of (S)-N-(1-(5-(7-methoxy-2-methylquinolin-6-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-6-(2-(oxazol-2-yl)-1,3-dioxolan-2-yl)hexyl)pyrimidin-2-amine (85A, 40 mg, 0.058 mmol) in co-solvents of MeOH (2 mL) and water (0.2 mL) at rt and the mixture was stirred at 65°C for 10 h. The residue was purified by preparative HPLC (reverse phase C-18 column), eluting with Acetonitrile / Water + 0.1% TFA, and HCl (0.1 M, 0.6 mL, 0.060 mmol) was added before lyophilization to give (S)-7-(5-(7-methoxy-2-methylquinolin-6-yl)-1H-imidazol-2-yl)-1-(oxazol-2-yl)-7-(pyrimidin-2-ylamino)heptan-1-one hydrochloride (Example 85). LCMS (ESI) calc'd for ClH·C 28 H 29 N 7 O 3 [M+H] +< : 512.2, found: 512.1. 1< H NMR (400 MHz, MeOD) δ 8.81-8.96 (m, 1H), 8.50-8.62 (m, 1H), 8.27-8.39 (m, 2H), 8.04-8.13 (m, 1H), 7.95-8.00 (m, 1H), 7.74-7.83 (m, 1H), 7.59-7.70 (m, 1H), 7.33-7.44 (m, 1H), 6.67-6.78 (m, 1H), 5.25-5.35 (m, 1H), 5.25-5.35 (m, 1H), 4.15-4.25 (m, 3H), 3.01-3.10 (m, 2H), 2.91-3.00 (m, 3H), 2.06-2.23 (m, 2H), 1.68-1.82 (m, 2H), 1.42-1.64 (m, 4H).Reference Example 86(S)-methyl (1-(5-(7-methoxy-2-methylquinolin-6-yl)-1H-imidazol-2-yl)-7-(oxazol-2-yl)-7-oxoheptyl)carbamate

[0380] Step 1: Preparation of (S)-methyl (1-(5-(7-methoxy-2-methylquinolin-6-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-6-(2-(oxazol-2-yl)-1,3-dioxolan-2-yl)hexyl)carbamate (86A)

[0381] To a solution of (S)-1-(5-(7-methoxy-2-methylquinolin-6-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-6-(2-(oxazol-2-yl)-1,3-dioxolan-2-yl)hexan-1-amine (84B, 100 mg, 0.165 mmol) and triethylamine (2 mL, 14.35 mmol) in DCM (2 mL) was added methyl carbonochloridate (600 mg, 6.35 mmol) at 0°C. The mixture was stirred at 0°C for 1 h. The mixture was washed with water (10 mL) and extracted with ethyl acetate (10 x 3 mL), dried (Na 2 SO 4 ), filtered and the solvent was evaporated under reduced pressure to give (S)-methyl (1-(5-(7-methoxy-2-methylquinolin-6-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-6-(2-(oxazol-2-yl)-1,3-dioxolan-2-yl)hexyl)carbamate (84A) which was used directly in next step. LCMS (ESI) calc'd for C 34 H 47 N 5 O 7 Si [M+H] +< : 666.3, found: 666.4Step 2: Preparation of (S)-methyl (1-(5-(7-methoxy-2-methylquinolin-6-yl)-1H-imidazol-2-yl)-7-(oxazol-2-yl)-7-oxoheptyl)carbamate hydrochloride (Example 86)

[0382] HCl (0.5 ml, 6.09 mmol) was added to a stirred mixture of (S)-methyl (1-(5-(7-methoxy-2-methylquinolin-6-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-6-(2-(oxazol-2-yl)-1,3-dioxolan-2-yl)hexyl)carbamate (86A, 100 mg, 0.15 mmol) in co-solvents of MeOH (2 ml) and water (0.2 ml) at rt and the mixture was stirred at 65°C for 10 h. The residue was purified by preparative HPLC (reverse phase C-18 column), eluting with acetonitrile / water + 0.1% TFA, to give (S)-methyl (1-(5-(7-methoxy-2-methylquinolin-6-yl)-1H-imidazol-2-yl)-7-(oxazol-2-yl)-7-oxoheptyl)carbamate (Example 86). HCl (0.1 M, 1.7 mL, 0.170 mmol) was added to a stirred mixture of (S)-methyl (1-(5-(7-methoxy-2-methylquinolin-6-yl)-1H-imidazol-2-yl)-7-(oxazol-2-yl)-7-oxoheptyl)carbamate (Example 86, 40 mg, 0.081 mmol) in acetonitrile (2 ml) at room temperature, then it was lyophilized to give (S)-methyl (1-(5-(7-methoxy-2-methylquinolin-6-yl)-1H-imidazol-2-yl)-7-(oxazol-2-yl)-7-oxoheptyl)carbamate hydrochloride (43). LCMS (ESI) calc'd for C 26 H 29 N 5 O 5 ·ClH [M+H] +< : 492.2, found: 492.1. 1< H NMR (400 MHz, MeOD) δ 8.89-8.98 (m, 1H), 8.53-8.64 (m, 1H), 8.05-8.11 (m, 1H), 7.96-8.04 (m, 1H), 7.76-7.84 (m, 1H), 7.62-7.68 (m, 1H), 7.32-7.41 (m, 1H), 4.93-5.03 (m, 1H), 4.22 (s, 3H), 3.61-3.71 (m, 3H), 3.03-3.10 (m, 2H), 2.93-3.01 (m, 3H), 1.98-2.09 (m, 2H), 1.68-1.80 (m, 2H), 1.36-1.55 (m, 4H).Reference Example 87(S)-N-(1-(5-(2-methylquinolin-6-yl)-1H-imidazol-2-yl)-7-(oxazol-2-yl)-7-oxoheptyl)acetamide

[0383]

[0384] T3P (116 mg, 0.182 mmol) was added to a stirred mixture of (S)-7-amino-7-(4-(2-methylquinolin-6-yl)-1H-imidazol-2-yl)-1-(oxazol-2-yl)heptan-1-one hydrochloride (Example 9, 40 mg, 0.091 mmol), acetic acid (11 mg, 0.183 mmol) and DIPEA (60 mg, 0.46 mmol) in DMF (2.0 ml) at room temperature and the mixture was stirred at room temperature for 12 h. The residue was purified by preparative HPLC (reverse phase C-18 column), eluting with acetonitrile / water + 0.1% TFA, to give (S)-N-(1-(5-(2-methylquinolin-6-yl)-1H-imidazol-2-yl)-7-(oxazol-2-yl)-7-oxoheptyl) acetamide (Example 87). LCMS (ESI) calc'd for C 25 H 27 N 5 O 3 [M+H] +< : 446.2, found: 446.1. 1< H NMR (400 MHz, MeOD) δ 8.85 (d, J = 7.28 Hz, 1H), 8.56 (brs, 1H), 8.37 (brs, 1H), 8.23 (brs, 1H), 8.00-8.12 (m, 2H), 7.89 (d, J = 7.72 Hz, 1H), 7.40 (s, 1H), 5.11 (t, J= 6.95 Hz, 1H), 3.08 (t, J= 7.17 Hz, 2H), 2.97 (s, 3H), 2.06 (s, 4H), 1.74-1.79 (m, 1H), 1.63-1.71 (m, 1H), 1.43-1.58 (m, 3H), 1.37 (dd, J= 3.53, 6.39 Hz, 1H), 0.98-1.06 (m, 1H).Reference Example 88(S)-N-(1-(4-chloro-2-(4-fluorophenyl)-1H-imidazol-5-yl)-7-(oxazol-2-yl)-7-oxoheptyl)thiazole-5-carboxamide

[0385]

[0386] T3P (244 mg, 0.384 mmol) was added to a stirred mixture of thiazole-5-carboxylic acid (34 mg, 0.263 mmol), (S)-7-amino-7-(4-chloro-2-(4-fluorophenyl)-1H-imidazol-5-yl)-1-(oxazol-2-yl)heptan-1-one (88D, 100 mg, 0.256 mmol) and DIEA (0.089 ml, 0.511 mmol) in THF (2.0 ml) at room temperature and the mixture was stirred at room temperature for 12 h. The mixture was concentrated and the residue was purified by preparative HPLC (reverse phase C-18 column), eluting with acetonitrile / water + 0.1% TFA, to give (S)-N-(1-(4-chloro-2-(4-fluorophenyl)-1H-imidazol-5-yl)-7-(oxazol-2-yl)-7 -oxoheptyl)thiazole-5-carboxamide (Example 88). LCMS (ESI) calc'd for C 23 H 21 ClFN 5 O 3 S [M+H] +< : 502.1, found: 501.9. 1< H NMR (400 MHz, MeOD) δ 9.06-9.32 (m, 1H), 8.49 (s, 1H), 8.09 (s, 1H), 7.82-7.96 (m, 2H), 7.39 (s, 1H), 7.26 (t, J = 8.66 Hz, 2H), 5.15 (t, J = 7.78 Hz, 1H), 3.07 (t, J = 7.15 Hz, 2H), 1.99-2.19 (m, 2H), 1.68-1.83 (m, 2H), 1.40-1.56 (m, 3H), 1.40-1.55 (m, 1H).Reference Example 89(S)-2-(dimethylamino)-N-(1-(5-(7-methoxy-2-methylquinolin-6-yl)-1H-imidazol-2-yl)-7-(oxazol-2-yl)-7-oxoheptyl)acetamide

[0387]

[0388] T 3 P (348 mg, 0.547 mmol) was added to a stirred mixture of 2-(dimethylamino)acetic acid (38 mg, 0.369 mmol), (S)-7-amino-7-(5-(7-methoxy-2-methylquinolin-6-yl)-1H-imidazol-2-yl)-1-(oxazol-2-yl)heptan-1-one (Example 82, 158 mg, 0.364 mmol) and DIEA (0.2 mL, 1.145 mmol) in THF (2.0 mL) at room temperature and the mixture was stirred at room temperature for 12 h. The mixture was concentrated and the residue was purified by preparative HPLC (reverse phase C-18 column), eluting with acetonitrile / water + 0.05% NH 3 ·H 2 O, to give (S)-2-(dimethylamino)-N-(1-(5-(7-methoxy-2-methylquinolin-6-yl)-1H-imidazol-2-yl)-7-(oxazol-2-yl)-7-oxoheptyl)acetamide (Example 89). LCMS (ESI) calc'd for C 28 H 34 N 6 O 4 [M+H] +< : 519.2, found: 519.4. 1< H NMR (400 MHz, MeOD) δ 8.73-8.84 (m, 1H), 8.54-8.66 (m, 1H), 8.02-8.12 (m, 1H), 7.84-7.93 (m, 1H), 7.66-7.75 (m, 1H), 7.51-7.61 (m, 1H), 7.31-7.42 (m, 1H), 5.13-5.28 (m, 1H), 4.14-4.26 (m, 3H), 3.96-4.13 (m, 2H), 3.01-3.10 (m, 2H), 2.93 (d, J = 4.89 Hz, 9H), 1.96-2.18 (m, 2H), 1.69-1.81 (m, 2H), 1.59-1.65 (m, 1H), 1.59-1.65 (m, 1H), 1.37-1.52 (m, 4H), 0.97-1.05 (m, 1H).

[0389] The following compounds were prepared using similar procedures to those described above using T3P as coupling reagent: Example #Structure Exact Mass [M+H] +< Observed[M+H] +< 90* Calc'd 476.2, found476.091* Calc'd 519.3, found519.392* Calc'd 535.3, found535.393* Calc'd 535.2, found535.3* = reference example Reference Example 94(S)-2-(dimethylamino)-N-(1-(5-(2-ethyl-7-methoxy-1-oxo-1,2-dihydroisoquinolin-6-yl)-1H-imidazol-2-yl)-7-(isoxazol-3-yl)-7-oxoheptyl)acetamide

[0390] Step 1: Preparation of (R)-N-((S)-1-(5-(2-ethyl-7-methoxy-1-oxo-1,2-dihydroisoquinolin-6-vl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-6-(2-(isoxazol-3-yl)-1,3-dioxolan-2-yl)hexyl)-2-methylpropane-2-sulfinamide (94A)

[0391] Pd(DTBPF)Cl 2 (11 mg, 0.017 mmol) was added to a stirred mixture of 2-ethyl-7-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1(2H)-one (53 mg, 0.161 mmol), (R)-N-((S)-1-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methy1)-1H-imidazol-2-yl)-6-(2-(isoxazol-3-yl)-1,3-dioxolan-2-yl)hexyl)-2-methylpropane-2-sulfinamide ( 15, 100 mg, 0.161 mmol), K 3 PO 4 (103 mg, 0.484 mmol) in THF (1 ml) / water (0.25 ml) at room temperature and the mixture was stirred at 80°C for 2 h. The mixture was cooled to room temperature then evaporated under reduced pressure. The residue was purified by silica gel column flash chromatography, eluting with petroleum ether / EtOAc = 0-100% to give (R)-N-((S)-1-(5-(2-ethyl-7-methoxy-1-oxo-1,2-dihydroisoquinolin-6-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-6-(2-(isoxazol-3-yl)-1,3-dioxolan-2-yl)hexyl)-2-methylpropane-2-sulfinamide (94A). LCMS (ESI) calc'd for C 37 H 55 N 5 O 7 SSi [M+H] +< : 742.4, found: 742.4Step 2: Preparation of (S)-6-(2-(1-amino-7-(isoxazol-3-yl)-7-oxoheptyl)-1H-imidazol-5-yl)-2-ethyl-7-methoxyisoquinolin-1(2H)-one dihydrochloride (94B)

[0392] Hydrogen chloride (4M) (0.6 ml, 2.400 mmol) was added to a stirred mixture of (R)-N-((S)-1-(5-(2-ethyl-7-methoxy-1-oxo-1,2-dihydroisoquinolin-6-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-6-(2-(isoxazol-3-yl)-1,3-dioxolan-2-yl)hexyl)-2-methylpropane-2-sulfinamide (94A, 60 mg, 0.081 mmol) in co-solvents of MeOH (2.4 ml) and water (0.24 ml) at room temperature and the mixture was stirred at 65°C for 20 h. All the volatiles were removed by evaporator to give (S)-6-(2-(1-amino-7-(isoxazol-3-yl)-7-oxoheptyl)-1H-imidazol-5-yl)-2-ethyl-7-methoxyisoquinolin-1(2H)-one dihydrochloride (94B) which was used to the next step without further purification. LCMS (ESI) calc'd for C 25 H 29 N 5 O 4 [M+H] +< : 464.2, found: 464.3Step 3: Preparation of (S)-2-(dimethylamino)-N-(1-(5-(2-ethyl-7-methoxy-1-oxo-1,2-dihydroisoquinolin-6-yl)-1H-imidazol-2-yl)-7-(isoxazol-3-yl)-7-oxoheptyl)acetamide (Example 94)

[0393] DIPEA (0.08 mL, 0.458 mmol) was added to a stirred mixture of 2-(dimethylamino)acetic acid (10 mg, 0.097 mmol) and HATU (37 mg, 0.097 mmol) in DMF (0.5 mL) at room temperature and the mixture was stirred at room temperature for 15 min. Then (S)-6-(2-(1-amino-7-(isoxazol-3-yl)-7-oxoheptyl)-1H-imidazol-5-yl)-2-ethyl-7-methoxyisoquinolin-1(2H)-one dihydrochloride (94B, 50 mg, 0.093 mmol) in DMF (0.5 mL) was added. The mixture was stirred at rt for 1 h. The mixture was purified by preparative HPLC (reverse phase C-18 column), eluting with acetonitrile / water + 0.05% NH 3 ·H 2 O, to give (S)-2-(dimethylamino)-N-(1-(5-(2-ethyl-7-methoxy-1-oxo-1,2-dihydroisoquinolin-6-yl)-1H-imidazol-2-yl)-7-(isoxazol-3-yl)-7-oxoheptyl)acetamide (Example 94).

[0394] L-(+)-tartaric acid (13 mg, 0.087 mmol) was added to a stirred mixture of (S)-2-(dimethylamino)-N-(1-(5-(2-ethyl-7-methoxy-1-oxo-1,2-dihydroisoquinolin-6-yl)-1H-imidazol-2-yl)-7-(isoxazol-3-yl)-7-oxoheptyl)acetamide (Example 94, 45 mg, 0.082 mmol) in acetonitrile (2 ml) and water (2 ml) at room temperature. Then the mixture was made dry by lyophilization to give (S)-2-(dimethylarmino)-N-(1-(5-(2-ethyl-7-methoxy-1-oxo-1,2-dihydroisoquinolin-6-yl)-1H-imidazol-2-yl)-7-(isoxazol-3-yl)-7-oxoheptyl)acetamide (2R,3R)-2,3- dihydroxysuccinate (Example 94). LCMS (ESI) calc'd for C 29 H 36 N 6 O 5 [M+H] +< : 549.3, found: 549.1. 1< H NMR (400 MHz, MeOD) δ 8.75 (d, J = 1.8 Hz, 1H), 8.14 (s, 1H), 7.79 (s, 1H), 7.72 (s, 1H), 7.25 (d, J = 7.3 Hz, 1H), 6.75 (d, J = 1.8 Hz, 1H), 6.70 (d, J = 7.3 Hz, 1H), 5.13-5.23 (m, 1H), 4.49 (s, 2H), 4.04 (s, 7H), 3.03 (t, J = 7.2 Hz, 2H), 2.91 (s, 6H), 2.02 (brs, 2H), 1.72 (t, J = 6.8 Hz, 2H), 1.32-1.52 (m, 7H).Reference Example 95(S)-2-(dimethylamino)-N-(7-(oxazol-2-yl)-7-oxo-1-(5-(quinoxalin-6-yl)-1H-imidazol-2-yl)heptyl)acetamide

[0395] Step 1: Preparation of (S)-7-amino-7-(5-bromo-1H-imidazol-2-yl)-1-(oxazol-2-yl)heptan-1-one (95A)

[0396] HCl (0.242 mL, 0.968 mmol) was added to a stirred mixture of (R)-N-((S)-1-(4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-6-(2-(oxazol-2-yl)-1,3-dioxolan-2-yl)hexyl)-2-methylpropane-2-sulfinamide (14, 100 mg, 0.161 mmol) in MeOH (0.2 mL) and water (0.04 ml) at room temperature and the mixture was stirred at 40°C for 16 h and then at 60°C for 5 h. It was then concentrated to afford (S)-7-amino-7-(4-bromo-1H-imidazol-2-yl)-1-(oxazol-2-yl)heptan-1-one dihydrochloride (95A) which was used to the next step without further purification. LCMS (ESI) calc'd for C 13 H 17 BrN 4 +O 2 ·2HCl [M+H] +< : 341.1, found: 343.0Step 2: Preparation of (S)-N-(1-(5-bromo-1H-imidazol-2-yl)-7-(oxazol-2-yl)-7-oxoheptyl)-2-(dimethylamino)acetamide (95B)

[0397] T 3 P (154 mg, 0.242 mmol) was added to a stirred mixture of (S)-7-amino-7-(4-bromo-1H-imidazol-2-yl)-1-(oxazol-2-yl)heptan-1-one (95A, 55 mg, 0.161 mmol), 2-(dimethylamino)acetic acid (35 mg, 0.339 mmol) and DIEA (0.084 ml, 0.484 mmol) in THF (3.0 mL) at room temperature and the mixture was stirred at rt for 2 h. Another batch of 2-(dimethylamino)acetic acid (35 mg, 0.339 mmol), DIEA (0.084 ml, 0.484 mmol) and T 3 P (154 mg, 0.242 mmol) were added to the mixture and it was stirred at rt for 24 h. The mixture was washed with water (2.0 ml), and extracted with ethyl acetate (10 mL). The combined organic fractions were washed with brine (saturated, 5 mL), dried (Na 2 SO 4 ), filtered and the solvent was evaporated under reduced pressure. The product was purified by preparative HPLC (reverse phase C-18 column), eluting with acetonitrile / water + 0.1% TFA, to give (S)-N-(1-(4-bromo-1H-imidazol-2-yl)-7-(oxazol-2-yl)-7-oxoheptyl)-2-(dimethylamino)acetamide (95B). LCMS (ESI) calc'd for C 17 H 24 BrN 5 O 3 [M+H] +< : 426.1, found: 426.0.Step 3: Preparation of (S)-2-(dimethylamino)-N-(7-(oxazol-2-yl)-7-oxo-1-(5-(quinoxalin-6-yl)-1H-imidazol-2-yl)heptyl)acetamide (Example 95)

[0398] Pd(DTBPF)Cl 2 (10 mg, 0.015 mmol) was added to a stirred mixture of 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoxaline (36 mg, 0.141 mmol), (S)-N-(1-(4-bromo-1H-imidazol-2-yl)-7-(oxazol-2-yl)-7-oxoheptyl)-2-(dimethylamino)acetamide (95B, 40 mg, 0.094 mmol) and K 3 PO 4 (60 mg, 0.283 mmol) in THF (2.0 mL) and water (0.5 mL) at room temperature and the mixture was stirred at 70°C for 2 h. It was then heated to 90°C for 4 h., filtered and the residue was purified by preparative HPLC (reverse phase C-18 column), eluting with acetonitrile / water + 0.1% TFA, to give (S)-2-(dimethylamino)-N-(7-(oxazol-2-yl)-7-oxo-1-(4-(quinoxalin-6-yl)-1H-imidazol-2-yl)heptyl)acetamide (95). LCMS (ESI) calc'd for C 25 H 29 N 7 O 3 [M+H] +< : 476.2, found: 476.3.

[0399] HCl (0.1 M, 0.213 ml, 0.021 mmol) was added to a stirred mixture of (S)-2-(dimethylamino)-N-(7-(oxazol-2-yl)-7-oxo-1-(4-(quinoxalin-6-yl)-1H-imidazol-2-yl)heptyl)acetamide bis(2,2,2-trifluoroacetate) (95, 5 mg, 7.11 µmol) in water (1.0 ml) at room temperature and the mixture was lyophilized to give (S)-2-(dimethylamino)-N-(7-(oxazol-2-yl)-7-oxo-1-(4-(quinoxalin-6-yl)-1H-imidazol-2-yl)heptyl)acetamide dihydrochloride (95). 1< H NMR (400 MHz, MeOD) δ 8.88-9.01 (m, 2H), 8.51 (s, 1H), 8.22 (d, J = 0.98 Hz, 2H), 8.01-8.20 (m, 2H), 7.38 (s, 1H), 5.24 (t, J = 7.24 Hz, 1H), 4.16 (s, 2H), 3.07 (t, J = 7.24 Hz, 2H), 2.95 (d, J = 9.00 Hz, 7H), 2.06-2.24 (m, 2H), 1.67-1.83 (m, 2H), 1.39-1.63 (m, 5H).Reference Example 96(S)-2-(dimethylamino)-N-(1-(5-(2-ethyl-7-methoxy-1-oxo-1,2-dihydroisoquinolin-6-yl)-1H-imidazol-2-yl)-7-(oxazol-2-yl)-7-oxoheptyl)acetamide

[0400]

[0401] Compound 96 was obtained from compound 95B utilizing a similar method. LCMS (ESI) calc'd for C 29 H 36 N 6 O 5 ·2ClH [M+H] +< : 549.3, found: 549.1. 1< H NMR (400 MHz, MeOD) δ 8.10 (s, 2H), 7.89-8.02 (m, 2H), 7.33-7.43 (m, 2H), 6.75 (s, 1H), 5.22-5.31 (m, 1H), 4.88-4.90 (m, 2H), 4.19 (d, J = 3.97 Hz, 2H), 4.07-4.14 (m, 5H), 3.08 (t, J = 7.17 Hz, 2H), 2.97 (d, J = 9.26 Hz, 6H), 2.13 (d, J = 7.50 Hz, 2H), 1.71-1.82 (m, 2H), 1.44-1.58 (m, 4H), 1.37 (t, J = 7.17 Hz, 3H).Reference Example 97(S)-N-((S)-1-(4-chloro-2-(4-fluorophenyl)-1H-imidazol-5-yl)-7-(oxazol-2-yl)-7-oxoheptyl)-6-ethyl-6-azaspiro[2.5]octane-1-carboxamide

[0402]

[0403] (S)-7-amino-7-(4-chloro-2-(4-fluorophenyl)-1H-imidazol-5-yl)-1-(oxazol-2-yl)heptan-1-one (27D, 100 mg, 0.256 mmol) was added to a stirred mixture of (S)-6-ethyl-6-azaspiro[2.5]octane-1-carboxylic acid (70 mg, 0.382 mmol), HATU (145 mg, 0.381 mmol) and DIPEA (0.18 ml, 1.031 mmol) in DMF (1 ml) at room temperature and the mixture was stirred at room temperature for 1 h. Another batch of (S)-6-ethyl-6-azaspiro[2.5]octane-1-carboxylic acid (35 mg, 0.191 mmol), HATU (72 mg, 0.191 mmol) and DIPEA (0.09 mL, 0.515 mmol) were added and it was stirred at rt for 1 h. Water (2 mL) was added and the mixture was extracted with DCM (3 x 5 mL). The combined organic fractions were washed with brine (saturated, 1 x 5 mL), dried (Na 2 SO 4 ), filtered and the solvent was evaporated under reduced pressure. The residue was purified by preparative HPLC (reverse phase C-18 column), eluting with acetonitrile / water + 0.1% TFA, to give (S)-N-((S)-1-(4-chloro-2-(4-fluorophenyl)-1H-imidazol-5-yl)-7-(oxazol-2-yl)-7-oxoheptyl)-6-ethyl-6-azaspiro[2.5]octane-1-carboxamide (Example 97). LCMS (ESI) calc'd for C 29 H 35 ClFN 5 O 3 [M+H] +< : 556.2, found: 556.2

[0404] HCl (2.5 mL, 0.250 mmol) was added to a stirred mixture of (S)-N-((S)-1-(4-chloro-2-(4-fluorophenyl)-1H-imidazol-5-yl)-7-(oxazol-2-yl)-7-oxoheptyl)-6-ethyl-6-azaspiro[2.5]octane-1-carboxamide bis(2,2,2-trifluoroacetate) (97, 60 mg, 0.077 mmol) in acetonitrile (1 ml) at rt and the mixture was made dry by lyophilization to give (S)-N-((S)-1-(4-chloro-2-(4-fluorophenyl)- 1H-imidazol-5-yl)-7-(oxazol-2-yl)-7-oxoheptyl)-6-ethyl-6-azaspiro[2.5]octane-1-carboxamide dihydrochloride (97). 1< H NMR (400 MHz, MeOD) δ 8.14-8.21 (m, 1H), 7.99-8.13 (m, 2H), 7.33-7.46 (m, 3H), 4.78-4.93 (m, 1H), 3.43-3.65 (m, 2H), 2.99-3.27 (m, 4H), 2.22-2.52 (m, 1H), 1.70-2.10 (m, 7H), 1.27-1.56 (m, 7H), 1.19-1.24 (m, 1H), 1.06-1.18 (m, 3H), 0.98-1.06 (m, 1H).Reference Example 98(S)-N-(1-(5-(7-methoxy-2-methylquinolin-6-yl) -1H-imidazol-2-yl)-7-(oxazol-2-yl)-7-oxoheptyl)-1-methylpiperidine-4-carboxamide

[0405]

[0406] (S)-7-amino-7-(5-(7-methoxy-2-methylquinolin-6-yl)-1H-imidazol-2-yl)-1-(oxazol-2-yl)heptan-1-one hydrochloride (Example 12, 40 mg, 0.085 mmol) was added to a stirred mixture of 1-methylpiperidine-4-carboxylic acid (37 mg, 0.258 mmol), DIPEA (110 mg, 0.851 mmol) and T3P (162 mg, 0.255 mmol) in DMF (2.0 ml) at room temperature and the mixture was stirred at room temperature and for 2 h. The residue was purified by preparative HPLC (reverse phase C-18 column), eluting with acetonitrile / water + 0.1% TFA, to give (S)-N-(1-(5-(7-methoxy-2-methylquinolin-6-yl)-1H-imidazol-2-yl)-7-(oxazol-2-yl)-7-oxoheptyl)-1-methylpiperidine-4-carboxamide (Example 98). LCMS (ESI) calc'd for C 31 H 38 N 6 O 4 [M+H] +< : 559.3, found: 559.1. 1< H NMR (400 MHz, MeOD) δ 8.89 (brs, 1H), 8.57-8.70 (m, 1H), 8.11 (s, 1H), 8.00 (brs, 1H), 7.72-7.82 (m, 1H), 7.67 (brs, 1H), 7.40 (s, 1H), 5.19 (brs, 1H), 4.22 (brs, 3H), 3.63-3.75 (m, 1H), 3.57 (brs, 1H), 3.08 (t, J = 7.28 Hz, 2H), 2.93-3.01 (m, 3H), 2.87 (brs, 2H), 2.81-2.90 (m, 1H), 2.69 (brs, 1H), 2.11 (brs, 2H), 1.94 (brs, 1H), 1.73-1.81 (m, 2H), 1.61-1.69 (m, 2H), 1.46 (d, J = 6.84 Hz, 3H), 1.37 (dd, J = 3.53, 6.62 Hz, 1H), 1.02 (q, J = 7.50 Hz, 3H), 0.01-0.01 (m, 1H).Reference Example 99(S)-N-(1-(5-(7-methoxy-2-methylquinolin-6-yl)-1H-imidazol-2-yl)-7-(oxazol-2-yl)-7-oxoheptyl)-1-methylazetidine-3-carboxamide

[0407]

[0408] T3P (162 mg, 0.255 mmol) was added to a stirred mixture of 1-methylazetidine-3-carboxylic acid (30 mg, 0.261 mmol), N-ethyl-N-isopropylpropan-2-amine (55 mg, 0.426 mmol), (S)-7-amino-7-(5-(7-methoxy-2-methylquinolin-6-yl)-1H-imidazol-2-yl)-1-(oxazol-2-yl)heptan-1-one hydrochloride (Example 12, 40 mg, 0.085 mmol) in DMF (2.0 ml) at room temperature and the mixture was stirred at room temperature for 2 h. The residue was purified by preparative HPLC (reverse phase C-18 column), eluting with acetonitrile / water + 0.1% TFA, to give (S)-N-(1-(5-(7-methoxy-2-methylquinolin-6-yl)-1H-imidazol-2-yl)-7-(oxazol-2-yl)-7-oxoheptyl)-1-methylazetidine-3-carboxamide (Example 99). LCMS (ESI) calc'd for C 29 H 34 N 6 O 4 [M+H] +< : 531.3, found: 531.1. 1< H NMR (400 MHz, MeOD) δ 8.86 (d, J = 8.16 Hz, 1H), 8.64 (s, 1H), 8.10 (s, 1H), 7.99 (brs, 1H), 7.77 (d, J = 8.16 Hz, 1H), 7.60-7.70 (m, 1H), 7.39 (s, 1H), 5.22 (brs, 1H), 4.39-4.57 (m, 2H), 4.05-4.24 (m, 4H), 3.73 (brs, 1H), 3.07 ...

Claims

1. A compound of the formula: wherein is a five-membered heteroaryl ring which is optionally substituted with halo, cyano or C1-3 alkyl; is selected from isoxazolyl, oxazolyl or thiazolyl which is optionally substituted with C1-3 alkyl; R1 is phenyl or heteroaryl, wherein said phenyl and heteroaryl groups are optionally substituted with one to three groups independently selected from the group consisting of halo, oxo, cyano, R4, R6, OR4, OR6 and SO2R4; R2 is selected from the group consisting of NH2, NHR4, NHR6, and NHCH2R6; R3 is selected from hydrogen or C1-6 alkyl; or R2 and R3 can be taken together with the atoms to which they are attached to form a 5, 6 or 7 membered heterocyclyl group which is optionally substituted with oxo; each R4 is independently hydrogen or C1-6 alkyl, which is optionally substituted with one to three halo; each R5 is independently hydrogen or C1-6 alkyl, which is optionally substituted with N(R4)2 or OR4; R6 is (a) heterocyclyl, (b) C3-6 cycloalkyl, (c) phenyl, or (d) heteroaryl, which may be monocyclic or bicyclic, wherein said heterocyclyl, cycloalkyl, phenyl and heteroaryl groups are optionally substituted with one to two groups independently selected from the group of oxo, R5, OR4 and heteroaryl; Ra is hydrogen or halo; Rb is hydrogen or halo; or a pharmaceutically acceptable salt thereof; wherein a heteroaryl is a monocyclic or bicyclic ring system of up to 10 atoms in each ring, wherein at least one ring is aromatic, and at least one ring contains from 1 to 4 heteroatoms selected from the group consisting of O, N and S; and wherein a heterocyclyl is a nonaromatic monocyclic or bicyclic ring system of up to 10 atoms in each ring containing from 1 to 4 heteroatoms selected from the group consisting of O, N, S, SO, or SO2.

2. The compound of Claim 1 wherein is selected from imidazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazolyl or triazolyl, wherein said groups are optionally substituted with halo, cyano or C1-3 alkyl; or a pharmaceutically acceptable salt thereof.

3. The compound of any of Claims 1 to 2 wherein R1 is dihydroisoquinolinyl, imidazolyl, isoquinolinyl, napthyridinyl, phenyl, pyrazinyl, pyridinyl, quinolinyl or quinoxalinyl, wherein said groups are optionally substituted with one to three groups optionally selected from the group consisting of halo, oxo, cyano, R4, R6, OR4, OR6 and SO2R4; or a pharmaceutically acceptable salt thereof.

4. The compound of any of Claims 1 to 3 wherein R2 is NH2, or a pharmaceutically acceptable salt thereof.

5. A compound according to claim 1 selected from the group consisting of: ((S)-7-amino-7-(4-(2-methylquinolin-6-yl)-1H-imidazol-2-yl)-1-(oxazol-2-yl)heptan-1-one; (S)-6-(2-(1-amino-7-(oxazol-2-yl)-7-oxoheptyl)-1H-imidazol-4-yl)-2-ethylisoquinolin-1(2H)-one; (S)-7-amino-1-(oxazol-2-yl)-7-(5-(quinolin-6-yl)-1H-imidazol-2-yl)heptan-1-one; (S)-7-amino-7-(4-(7-methoxyquinolin-6-yl)-1H-imidazol-2-yl)-1-(oxazol-2-yl)heptan-1-one; (S)-7-amino-7-(4-(6-cyclopropyl-2-methoxypyridin-3-yl)-1H-imidazol-2-yl)-1-(oxazol-2-yl)heptan-1-one; (S)-7-amino-7-(4-chloro-2-(4-fluorophenyl)-1H-imidazol-5-yl)-1-(oxazol-2-yl)heptan-1-one; 7-amino-7-(5-(2-methylquinolin-6-yl)oxazol-2-yl)-1-(oxazol-2-yl)heptan-1-one (35, L-006157881-001T) and (37, L-006157885-001C); (S)-7-amino-7-(5-(7-methoxy-2-methylquinolin-6-yl)oxazol-2-yl)-1-(oxazol-2-yl)heptan-1-one; (S)-7-amino-7-(5-(2-methoxypyridin-3-yl)oxazol-2-yl)-1-(oxazol-2-yl)heptan-1-one; (S)-7-amino-7-(1-methyl-4-(2-methylquinolin-6-yl)-1H-imidazol-2-yl)-1-(oxazol-2-yl)heptan-1-one; (S)-7-amino-7-(1-ethyl-4-(2-methylquinolin-6-yl)-1H-imidazol-2-yl)-1-(oxazol-2-yl)heptan-1-one; (S)-7-amino-1-(isoxazol-3-yl)-7-(4-(7-methoxy-2-methylquinolin-6-yl)-1H-imidazol-2-yl)heptan-1-one; (S)-6-(2-(1-amino-7-(isoxazol-3-yl)-7-oxoheptyl)-1H-imidazol-4-yl)-1-methylquinolin-2(1H)-one; (S)-7-amino-1-(isoxazol-3-yl)-7-(4-(2-methoxypyridin-3-yl)-1H-imidazol-2-yl)heptan-1-one; (S)-7-amino-1-(isoxazol-3-yl)-7-(4-(7-methoxyquinolin-6-yl)-1H-imidazol-2-yl)heptan-1-one; (S)-6-(2-(1-amino-7-(isoxazol-3-yl)-7-oxoheptyl)-1H-imidazol-5-yl)-7-methoxy-1-methylquinolin-2(1H)-one; (S)-7-amino-7-(5-(2-fluorophenyl)-1H-imidazol-2-yl)-1-(oxazol-4-yl)heptan-1-one; (S)-7-amino-7-(5-(2-fluorophenyl)-1H-imidazol-2-yl)-1-(isoxazol-3-yl)heptan-1-one; (R)-5-(5-(4-fluorophenyl)-1H-imidazol-2-yl)-5-(6-(oxazol-2-yl)-6-oxohexyl)pyrrolidin-2-one; 4-(4-(4-fluorophenyl)-1H-imidazol-2-yl)-4-(6-(oxazol-2-yl)-6-oxohexyl)oxazolidin-2-one; (S)-5-(4-(2-fluoro-4-(oxazol-2-yl)phenyl)-1H-imidazol-2-yl)-5-(6-(isoxazol-3-yl)-6-oxohexyl)pyrrolidin-2-one; (S)-5-(4-(4-cyclopropyl-2-fluorophenyl)-1H-imidazol-2-yl)-5-(6-(isoxazol-3-yl)-6-oxohexyl)pyrrolidin-2-one; (S)-5-(4-(2-fluorophenyl)-1H-imidazol-2-yl)-5-(6-(isoxazol-3-yl)-6-oxohexyl)pyrrolidin-2-one; (R)-5-(6-(isoxazol-3-yl)-6-oxohexyl)-5-(5-(7-methoxy-2-methylquinolin-6-yl)-1H-imidazol-2-yl)pyrrolidin-2-one; (S)-6-(6-(isoxazol-3-yl)-6-oxohexyl)-6-(4-(2-methoxypyridin-3-yl)-1H-imidazol-2-yl)piperidin-2-one; (S)-7-(4-(2-fluorophenyl)-1H-imidazol-2-yl)-7-(6-(isoxazol-3-yl)-6-oxohexyl)azepan-2-one; (S)-7-(ethylamino)-7-(5-(2-methylquinolin-6-yl)-1H-imidazol-2-yl)-1-(oxazol-2-yl)heptan-1-one; (S)-7-(methylamino)-7-(5-(2-methylquinolin-6-yl)-1H-imidazol-2-yl)-1-(oxazol-2-yl)heptan-1-one; (S)-7-methoxy-1-methyl-6-(2-(1-(methylamino)-7-(oxazol-2-yl)-7-oxoheptyl)-1H-imidazol-5-yl)quinolin-2(1H)-one; (S)-6-(2-(1-(ethylamino)-7-(oxazol-2-yl)-7-oxoheptyl)-1H-imidazol-5-yl)-7-methoxy-1-methylquinolin-2(1H)-one; (S)-7-((1-methylpiperidin-4-yl)amino)-7-(5-(2-methylquinolin-6-yl)-1H-imidazol-2-yl)-1-(oxazol-2-yl)heptan-1-one; (S)-7-(5-(2-methylquinolin-6-yl)-1H-imidazol-2-yl)-1-(oxazol-2-yl)-7-((tetrahydro-2H-pyran-4-yl)amino)heptan-1-one; (S)-7-(5-(7-methoxy-2-methylquinolin-6-yl)-1H-imidazol-2-yl)-1-(oxazol-2-yl)-7-((tetrahydro-2H-pyran-4-yl)amino)heptan-1-one; (S)-7-(benzylamino)-7-(5-(2-methylquinolin-6-yl)-1H-imidazol-2-yl)-1-(oxazol-2-yl)heptan-1-one; (S)-7-(benzylamino)-7-(5-(7-methoxy-2-methylquinolin-6-yl)-1H-imidazol-2-yl)-1-(oxazol-2-yl)heptan-1-one; (S)-7-(5-(2-methylquinolin-6-yl)-1H-imidazol-2-yl)-7-morpholino-1-(oxazol-2-yl)heptan-1-one; (S)-7-(5-(7-methoxy-2-methylquinolin-6-yl)-1H-imidazol-2-yl)-7-((3-methoxycyclobutyl)amino)-1-(oxazol-2-yl)heptan-1-one; (S)-7-(5-(7-methoxy-2-methylquinolin-6-yl)-1H-imidazol-2-yl)-1-(oxazol-2-yl)-7-(pyrimidin-2-ylamino)heptan-1-one; (S)-7-amino-7-(5-(4-fluorophenyl)isoxazol-3-yl)-1-(isoxazol-3-yl)heptan-1-one; (R)-7-amino-7-(5-(4-fluorophenyl)isoxazol-3-yl)-1-(isoxazol-3-yl)heptan-1-one; (7S)-7-amino-7-[1-(4-fluorophenyl)-1H-pyrazol-3-yl]-1-isoxazol-3-ylheptan-1-one; 7-amino-7-[1-(4-fluorophenyl)-1H-pyrazol-4-yl]-1-isoxazol-3-ylheptan-1-one; 7-amino-7-[1-(4-fluorophenyl)-1H-pyrazol-4-yl]-1-isoxazol-3-ylheptan-1-one; 7-amino-7-[2-(4-fluorophenyl)-2H-1,2,3-triazol-4-yl]-1-isoxazol-3-ylheptan-1-one; 7-amino-7-[2-(4-fluorophenyl)-2H-1,2,3-triazol-4-yl]-1-isoxazol-3-ylheptan-1-one; (7S)-7-amino-7-[5-(2-fluorophenyl)isoxazol-3-yl]-1-isoxazol-3-ylheptan-1-one; (7S)-7-amino-1-isoxazol-3-yl-7-[5-(2-methyl-2H-indazol-5-yl)isoxazol-3-yl]heptan-1-one; (7R)-7-amino-7-[1-(2-methyl-2H-indazol-5-yl)-1H-pyrazol-3-yl]-1-(1,3-oxazol-2-yl)heptan-1-one; (7S)-7-amino-7-[1-(2-methyl-2H-indazol-5-yl)-1H-pyrazol-3-yl]-1-(1,3-oxazol-2-yl)heptan-1-one; (S)-7-amino-7-(5-(5-fluoro-2-methoxypyridin-4-yl)-1H-imidazol-2-yl)-1-(oxazol-2-yl)heptan-1-one; (7S)-7-amino-7-{5-[5-(cyclobutyloxy)-2-fluorophenyl]-1H-imidazol-2-yl}-1-(1,3-oxazol-2-yl)heptan-1-one; (7S)-7-amino-7-[5-(5-cyclopropylpyrazin-2-yl)-1H-imidazol-2-yl]-1-(1,3-oxazol-2-yl)heptan-1-one; 5-{2-[(1S)-1-amino-7-(1,3-oxazol-2-yl)-7-oxoheptyl]-1H-imidazol-5-yl}pyrazine-2-carbonitrile; 6-{2-[(1S)-1-amino-7-(1,3-oxazol-2-yl)-7-oxoheptyl]-1H-imidazol-5-yl}pyrazine-2-carbonitrile; (7S)-7-amino-7-{5-[2-fluoro-4-(1H-pyrazol-1-yl)phenyl]-1H-imidazol-2-yl}-1-(1,3-oxazol-2-yl)heptan-1-one; (7S)-7-amino-7-[5-(2,5-difluorophenyl)-1H-imidazol-2-yl]-1-(1,3-oxazol-2-yl)heptan-1-one; (7S)-7-amino-7-[5-(2,3-difluorophenyl)-1H-imidazol-2-yl]-1-(1,3-oxazol-2-yl)heptan-1-one; (7S)-7-amino-7-{5-[2-fluoro-5-(trifluoromethyl)phenyl]-1H-imidazol-2-yl}-1-(1,3-oxazol-2-yl)heptan-1-one; (7S)-7-amino-7-{5-[2-fluoro-3-(trifluoromethyl)phenyl]-1H-imidazol-2-yl}-1-(1,3-oxazol-2-yl)heptan-1-one; (7S)-7-amino-7-{5-[2-fluoro-4-(trifluoromethyl)phenyl]-1H-imidazol-2-yl}-1-(1,3-oxazol-2-yl)heptan-1-one; (7S)-7-amino-7-[5-(2-fluoro-4-methoxyphenyl)-1H-imidazol-2-yl]-1-(1,3-oxazol-2-yl)heptan-1-one; (7S)-7-amino-7-{5-[2-fluoro-4-(trifluoromethoxy)phenyl]-1H-imidazol-2-yl}-1-(1,3-oxazol-2-yl)heptan-1-one; (7S)-7-amino-7-{5-[2-fluoro-5-(trifluoromethoxy)phenyl]-1H-imidazol-2-yl}-1-(1,3-oxazol-2-yl)heptan-1-one; (7S)-7-amino-7-{5-[2-fluoro-4-(methylsulfonyl)phenyl]-1H-imidazol-2-yl}-1-(1,3-oxazol-2-yl)heptan-1-one; (7S)-7-amino-7-(5-{2-fluoro-3-methoxy-5-[(trans-3-methoxycyclobutyl)oxy]phenyl}-1H-imidazol-2-yl)-1-(1,3-oxazol-2-yl)heptan-1-one; (S)-5-(1-amino-7-(oxazol-2-yl)-7-oxoheptyl)-2-(4-fluorophenyl)-1H-imidazole-4-carbonitrile; (S)-5-(1-amino-7-(oxazol-2-yl)-7-oxoheptyl)-2-(4-fluorophenyl)oxazole-4-carbonitrile; (S)-7-amino-7-(4-chloro-5-(4-fluorophenyl)-1H-imidazol-2-yl)-1-(isoxazol-3-yl)heptan-1-one; or a pharmaceutically acceptable salt thereof.

6. A pharmaceutical composition comprising a compound of any previous Claim, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

7. A compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, for use in the treatment of infection by HIV or for the treatment, prophylaxis, or delay in the onset or progression of AIDS.

8. The pharmaceutical composition of claim 6, further comprising one or more additional therapeutic agents selected from raltegravir, lamivudine, abacavir, ritonavir, darunavir, atazanavir, emtricitabine, tenofovir, rilpivirine, doravirine, EFdA and lopinavir.

9. A combination comprising a compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents selected from raltegravir, lamivudine, abacavir, ritonavir, darunavir, atazanavir, emtricitabine, tenofovir, rilpivirine, doravirine, EFdA and lopinavir, for use in treating infection by HIV or for treating, preventing or delaying the onset or progression of AIDS.

10. A compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, for use in therapy.