Heteroatom containing peptidomimetics targeting viral proteases

Abstract

Disclosed herein are methods for preventing or treating a viral infection, e.g., coronavirus, enterovirus, norovirus, picornavirus, rhinovirus, and / or a herpes virus infection. In certain embodiments, this disclosure relates to peptidomimetic heterocyclic compounds and pharmaceutical compositions comprising the same for uses in methods disclosed herein.

Description

[0001] HETEROATOM CONTAINING PEPTIDOMIMETICS TARGETING VIRAL PROTEASES CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No.63 / 547,771 filed November 8, 2023. The entirety of this application is hereby incorporated by reference for all purposes. BACKGROUND Some common colds are due to certain coronavirus (CoV) strains associated with mild symptoms. More dangerous human strains include severe acute respiratory syndrome associated coronavirus (SARS-CoV-1) and SARS-CoV-2 (also referred to as COVID-19). In humans, SARS-CoV-2 can be transferred from individuals who have mild symptoms or are asymptomatic and has caused numerous deaths worldwide. Medications to treat SARS-CoV-2 are typically limited to use in patients within several days after infection. PaxlovidTMis clinically approved to treat SARS-CoV-2, which includes nirmatrelvir, a SARS-CoV-2 protease inhibitor, and ritonavir, an HIV-1 protease inhibitor. Use is limited to the treatment of mild-to-moderate coronavirus disease 2019 (COVID-19) in adults who are at high risk for progression to severe COVID-19, including hospitalization or death. This treatment is not universally affective. Thus, there is a need to find improved therapies for this class of compounds, namely protease inhibitors. SUMMARY Disclosed herein are compounds for uses in methods of preventing or treating viral infections, e.g., coronavirus infections, norovirus infections, enterovirus infections, rhinoviruses infections, picornavirus infections, and / or herpesvirus infections. In certain embodiments, this disclosure reports heterocyclic peptidomimetics with viral protease activity and pharmaceutical compositions containing the same. In certain embodiments, the heterocyclic peptidomimetics are oxopyrrolidine peptidomimetics or indole peptidomimetics and pharmaceutical compositions useful in treating, preventing, or curing coronavirus, norovirus, enterovirus, e.g., enterovirus 71 (EV71), rhinoviruses, picornavirus, and / or herpes virus infections. In one embodiment, the compounds can be used to treat a subject with a severe acute respiratory syndrome virus, such as human coronavirus SARS-CoV-1 (including 229E, NL63, OC43, HKU1) SARS, MERS, and SARS-CoV-2. In certain embodiments, contemplated methods include the treatment of a patient co-infected with two or more of these viruses, or a combination of one or more of these viruses and norovirus. In certain embodiments, this disclosure relates to pharmaceutical formulations including one or more compounds described herein, in combination with a pharmaceutically acceptable carrier or excipient. In certain embodiments, the formulations include at least one compound described herein and at least one further therapeutic agent. DETAILED DESCRIPTION Before the present disclosure is described in greater detail, it is to be understood that this disclosure is not limited to particular embodiments described, and as such may, of course, vary. An “embodiment” of this disclosure refers to an example and is not necessarily limited to the example. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present disclosure will be limited only by the appended claims or as amended during prosecution. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present disclosure, the preferred methods and materials are now described. All publications and patents cited in this specification are herein incorporated by reference as if each individual publication or patent were specifically and individually indicated to be incorporated by reference and are incorporated herein by reference to disclose and describe the methods and / or materials in connection with which the publications are cited. The citation of any publication is for its disclosure prior to the filing date and should not be construed as an admission that the present disclosure is not entitled to antedate such publication by virtue of prior disclosure. Further, the dates of publication provided could be different from the actual publication dates that may need to be independently confirmed. As will be apparent to those of skill in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein has discrete components and features which may be readily separated from or combined with the features of any of the other several embodiments without departing from the scope or spirit of the present disclosure. Any recited method can be carried out in the order of events recited or in any other order that is logically possible. Embodiments of the present disclosure will employ, unless otherwise indicated, techniques of medicine, organic chemistry, biochemistry, molecular biology, pharmacology, and the like, which are within the skill of the art. Such techniques are explained fully in the literature. It must be noted that, as used in the specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. In this specification and in the claims that follow, reference will be made to a number of terms that shall be defined to have the following meanings unless a contrary intention is apparent. The term “independently” is used herein to indicate that the variable, which is independently applied, varies independently from application to application. Thus, in a compound such as “RXYR”, wherein R” is “independently carbon or nitrogen,” both R” can be carbon, both R” can be nitrogen, or one R” can be carbon and the other R” nitrogen. As used herein, the term “enantiomerically pure” refers to a compound composition that comprises at least approximately 95%, and, preferably, approximately 97%, 98%, 99% or 100% of a single enantiomer of that compound. As used herein, the term “substantially free of” or “substantially in the absence of” refers to a compound composition that includes at least 85 to 90% by weight, preferably 95% to 98% by weight, and, even more preferably, 99% to 100% by weight, of the designated enantiomer of that compound. In a preferred embodiment, the compounds described herein are substantially free of enantiomers. Similarly, the term “isolated” refers to a compound composition that includes at least 85 to 90% by weight, preferably 95% to 98% by weight, and, even more preferably, 99% to 100% by weight, of the compound, the remainder comprising other chemical species or enantiomers. The term “alkyl,” as used herein, unless otherwise specified, refers to a saturated straight, branched, primary, secondary, or tertiary hydrocarbons, including both substituted and unsubstituted alkyl groups. The alkyl group can be optionally substituted with any moiety that does not otherwise interfere with the reaction or that provides an improvement in the process, including but not limited to but limited to halo, haloalkyl, hydroxyl, carboxyl, acyl, aryl, acyloxy, amino, amido, carboxyl derivatives, alkylamino, dialkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, thiol, imine, sulfonyl, sulfanyl, sulfinyl, sulfamoyl, ester, carboxylic acid, amide, phosphonyl, phosphinyl, phosphoryl, phosphine, thioester, thioether, acid halide, anhydride, oxime, hydrazine, carbamate, phosphonic acid, phosphonate, either unprotected, or protected as necessary, as known to those skilled in the art, for example, as taught in Greene, et al., Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991, hereby incorporated by reference. Specifically included are CF3and CH2CF3. In the text, whenever the term “C” (alkyl range) is used, the term independently includes each member of that class as if specifically, and separately set out. The term “alkyl” includes C1-22alkyl moieties, and the term “lower alkyl” includes C1-6alkyl moieties. It is understood to those of ordinary skill in the art that the relevant alkyl radical is named by replacing the suffix “-ane” with the suffix “-yl”. The term “alkenyl” refers to an unsaturated, hydrocarbon radical, linear, or branched, in so much as it contains one or more double bonds. The alkenyl group disclosed herein can be optionally substituted with any moiety that does not adversely affect the reaction process, including but not limited to but not limited to those described for substituents on alkyl moieties. Non-limiting examples of alkenyl groups include ethylene, methylethylene, isopropylidene, 1,2-ethane-diyl, 1,1-ethane-diyl, 1,3-propane-diyl, 1,2-propane-diyl, 1,3-butane-diyl, and 1,4- butane-diyl. The term “alkynyl” refers to an unsaturated, acyclic hydrocarbon radical, linear or branched, in so much as it contains one or more triple bonds. The alkynyl group can be optionally substituted with any moiety that does not adversely affect the reaction process, including but not limited to those described above for alkyl moieties. Non-limiting examples of suitable alkynyl groups include ethynyl, propynyl, hydroxypropynyl, butyn-1-yl, butyn-2- yl, pentyn-1-yl, pentyn-2-yl, 4-methoxypentyn-2-yl, 3-methylbutyn-1-yl, hexyn-1-yl, hexyn-2- yl, and hexyn-3-yl, 3,3-dimethylbutyn-1-yl radicals. The term “alkylamino” or “arylamino” refers to an amino group that has one or two alkyl or aryl substituents, respectively, e.g., CH3- NH- and Ph-NH- respectively. The term “protected” as used herein and unless otherwise defined refers to a group that is added to an oxygen, nitrogen, or phosphorus atom to prevent its further reaction or for other purposes. A wide variety of oxygen and nitrogen protecting groups are known to those skilled in the art of organic synthesis, and are described, for example, in Greene et al., Protective Groups in Organic Synthesis, supra. The term “aryl”, alone or in combination, means a carbocyclic aromatic system containing one, two or three rings wherein such rings can be attached together in a pendent manner or can be fused. Aryl includes polycyclic ring systems containing aromatic and non- aromatic rings, as long as one of the rings is aromatic. Non-limiting examples of aryl include phenyl, biphenyl, or naphthyl. The aryl group can be optionally substituted with substituents as described above for alkyl moieties. Additional examples of aryl substituents include heteroarylamino, N-aryl-N-alkylamino, N-heteroarylamino-N-alkylamino, arylamino, arylalkylamino, arylthio, monoarylamidosulfonyl, arylsulfonamido, diarylamidosulfonyl, monoaryl amidosulfonyl, arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, aroyl, heteroaroyl, hydroxyarylalkyl, hydoxyheteroarylalkyl, haloalkoxyalkyl, aryl, arylalkyl, aryloxy, arylalkoxy, aryloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, and heteroarylalkenyl. The term “alkylaryl” refer to an aryl group (radical) with an alkyl substituent. The term “arylalkyl” refer to an alkyl group (radical) with an aryl substituent. The term “halo,” as used herein, includes chloro, bromo, iodo, and fluoro. The term “acyl” refers to an alkylcarbonyl or arylcarbonyl in which the non-carbonyl moiety of the group is selected from the group consisting of straight, branched, or cyclic alkyl or lower alkyl, arylalkyl, benzyl (benzoyl), aryl (aroyl), wherein the acyl group is optionally substituted with halogen (F, Cl, Br, or I), alkyl (including but not limited to C1, C2, C3, and C4) or alkoxy (including but not limited to C1, C2, C3, and C4), such as alkoxyalkyl, methoxymethyl, aryloxy, such as phenoxymethyl, sulfonate esters such as alkyl or arylalkyl sulphonyl including but not limited to methanesulfonyl, mono, di or triphosphate ester, trityl or monomethoxytrityl, benzyl, trialkylsilyl (e.g., dimethyl-t-butylsilyl) or diphenylmethylsilyl. The term “lower acyl” refers to an acyl group in which the non-carbonyl moiety is lower alkyl. The terms “alkoxy” and “alkoxyalkyl” embrace linear or branched oxy-containing radicals having alkyl moieties, such as methoxy radical. The “alkoxy” radicals can be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide “haloalkoxy” radicals. Examples of such radicals include fluoromethoxy, chloromethoxy, trifluoromethoxy, difluoromethoxy, trifluoroethoxy, fluoroethoxy, tetrafluoroethoxy, pentafluoroethoxy, and fluoropropoxy. The term “alkylamino” denotes “monoalkylamino” and “dialkylamino” containing one or two alkyl radicals, respectively, attached to an amino radical. The terms arylamino denotes “monoarylamino” and “diarylamino” containing one or two aryl radicals, respectively, attached to an amino radical. The term “arylalkylamino”, embraces arylalkyl radicals attached to an amino radical. The term arylalkylamino denotes “monoarylalkylamino” and “diarylalkylamino” containing one or two arylalkyl radicals, respectively, attached to an amino radical. The term arylalkylamino further denotes “monoarylalkyl monoalkylamino” containing one arylalkyl radical and one alkyl radical attached to an amino radical. The term “heteroatom,” as used herein, refers to silicon, oxygen, sulfur, nitrogen, and phosphorus. The term “heterocyclic,” and “heterocyclyl,” refer to mono- and polycyclic ring systems having 1 to 4 heteroatoms selected from nitrogen, oxygen, phosphorus, silicon, or sulfur, and containing at least 1 carbon atom. The mono- and polycyclic ring systems may be aromatic, non-aromatic or mixtures of aromatic and non-aromatic rings. Heterocycle includes heterocarbocycles, heteroaryls, and the like. Further, a second ring may share the same carbon or different carbons to form a spiro ring, condensed ring, or bridged ring. Non-aromatic mono or polycyclic alkyls are referred to herein as "carbocycles" or "carbocyclyl" or “cycloalkyl” groups. Representative saturated carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like; while unsaturated carbocycles include cyclopentenyl and cyclohexenyl, and the like. "Heterocarbocycles" or heterocarbocyclyl" groups are carbocycles which contain from 1 to 4 heteroatoms independently selected from nitrogen, oxygen, phosphorus, silicon, and sulfur which may be saturated or unsaturated (but not aromatic), monocyclic or polycyclic, and wherein the nitrogen and sulfur heteroatoms may be optionally oxidized, and the nitrogen heteroatom may be optionally quaternized. Heterocarbocycles include morpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydroprimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like. The terms “heteroaryl” or “heteroaromatic,” as used herein, refer to an aromatic that includes at least one nitrogen, oxygen, phosphorus, silicon, and sulfur in the aromatic ring. It is contemplated that the use of the term "heteroaryl" includes N-alkylated derivatives such as a 1-methylimidazol-5-yl substituent. Nonlimiting examples of heteroaryl and heterocyclic groups include furyl, furanyl, pyridyl, pyrimidyl, thienyl, isothiazolyl, imidazolyl, tetrazolyl, pyrazinyl, benzofuranyl, benzothiophenyl, quinolyl, isoquinolyl, benzothienyl, isobenzofuryl, pyrazolyl, indolyl, isoindolyl, benzimidazolyl, purinyl, carbazolyl, oxazolyl, thiazolyl, isothiazolyl, 1,2,4- thiadiazolyl, isooxazolyl, pyrrolyl, quinazolinyl, cinnolinyl, phthalazinyl, xanthinyl, hypoxanthinyl, thiophene, furan, pyrrole, isopyrrole, pyrazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, oxazole, isoxazole, thiazole, isothiazole, pyrimidine or pyridazine, and pteridinyl, aziridines, thiazole, isothiazole, 1,2,3-oxadiazole, thiazine, pyridine, pyrazine, piperazine, pyrrolidine, oxazirane, phenazine, phenothiazine, morpholinyl, pyrazolyl, pyridazinyl, pyrazinyl, quinoxalinyl, xanthinyl, hypoxanthinyl, pteridinyl, 5-azacytidinyl, 5- azauracilyl, triazolopyridinyl, imidazolopyridinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, adenine, N6-alkylpurines, N6-benzylpurine, N6-halopurine, N6- vinypurine, N6-acetylenic purine, N6-acyl purine, N6-hydroxyalkyl purine, N6-thioalkyl purine, thymine, cytosine, 6- azapyrimidine, 2-mercaptopyrmidine, uracil, N5- alkylpyrimidine, N5-benzylpyrimidine, N5- halopyrimidine, N5-vinylpyrimidine, N5-acetylenic pyrimidine, N5-acyl pyrimidine, N5- hydroxyalkyl purine, and N6-thioalkyl purine, and isoxazolyl. The heteroaromatic group can be optionally substituted as described above for aryl. The heterocyclic or heteroaromatic group can be optionally substituted with one or more substituents selected from the group consisting of halogen, haloalkyl, alkyl, alkoxy, hydroxy, carboxyl derivatives, amido, amino, alkylamino, and dialkylamino. The heteroaromatic can be partially or totally hydrogenated as desired. As a nonlimiting example, dihydropyridine can be used in place of pyridine. Functional oxygen and nitrogen groups on the heterocyclic or heteroaryl group can be protected as necessary or desired. Suitable protecting groups are well known to those skilled in the art, and include trimethylsilyl, dimethylhexylsilyl, t-butyldimethylsilyl, and t-butyldiphenylsilyl, trityl or substituted trityl, alkyl groups, acyl groups such as acetyl and propionyl, methanesulfonyl, and p-toluenelsulfonyl. The heterocyclic or heteroaromatic group can be substituted with any moiety that does not adversely affect the reaction, including but not limited to but not limited to those described above for aryl. The term “host,” as used herein, refers to a unicellular or multicellular organism in which the virus can replicate, including but not limited to cell lines and animals, and, preferably, human patients. Alternatively, the host can be carrying a part of the viral genome, whose replication or function can be altered by the compounds of the present disclosure. The term host specifically refers to infected cells, cells transfected with all or part of the viral genome and animals, in particular, primates (including but not limited to chimpanzees) and humans. In most animal applications of the present disclosure, the host is a human being. Veterinary applications, in certain indications, however, are clearly contemplated by the present disclosure (such as for use in treating chimpanzees). "Subject" refers to any animal, preferably a human patient, livestock, horse, cow, pig, chicken, turkey, mouse, rodent, monkey, dog, cat, or other domestic pet. As used herein, the terms "prevent" and "preventing" include the prevention of the recurrence, spread or onset. It is not intended that the present disclosure be limited to complete prevention. In some embodiments, the onset is delayed, or the severity of the disease is reduced. As used herein, the terms "treat" and "treating" are not limited to the case where the subject (e.g., patient) is cured and the disease is eradicated. Rather, embodiments, of the present disclosure also contemplate treatment that merely reduces symptoms, and / or delays disease progression. The term "effective amount" or "therapeutically effective amount" refers to that amount of a compound or pharmaceutical composition described herein that is sufficient to effect the intended application including, but not limited to, disease treatment, as illustrated below. The therapeutically effective amount can vary depending upon the intended application (in vitro or in vivo), or the subject and disease condition being treated, e.g., the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art. As used herein, the term "combination with" when used to describe administration of an agent with an additional treatment means such that the agent may be administered prior to, together with, or after the additional treatment, or a combination thereof, such that multiple agents are bioavailable at some overlapping time. The term “pharmaceutically acceptable salt or prodrug” is used throughout the specification to describe any pharmaceutically acceptable prodrug form (such as an ester) compound which, upon administration to a patient, provides the compound. The compounds can also be prepared in the form of water-soluble prodrugs. Water- soluble prodrugs are well-known to those of skill in the art, and include, for example, those disclosed in Bundgaard et al., "A novel solution-stable, water-soluble prodrug type for drugs containing a hydroxyl or an NH-acidic group," J. Med. Chem. 32(12):2503-2507, 1989, Matsumoto et al., Bioorganic & Medicinal Chemistry Letters, Vol. 11, Issue 4, 26 February 2001, Pages 605-609, and Stella et al., “Prodrug strategies to overcome poor water solubility,” Advanced Drug Delivery Reviews, Volume 59, Issue 7, 30 July 2007, Pages 677-694. As the name suggests, water-soluble prodrugs are formulated using the aqueous solubility of the drug and for enhancing the oral drug delivery, generally includes the addition of an ionizable prodrug group to the parent compound (such as phosphate, carboxylate, or sulfonate group). Water-soluble ester prodrugs can improve the aqueous solubility of poorly soluble drugs that contain a hydroxyl group. Commonly used esters for forming prodrugs are those containing ionizable groups such as dicarboxylic acid hemiesters. Phosphate esters, such as oxymethylphosphate (OMP) and oxyethylphosphate (OEP) prodrugs, offer one way to increase the oral bioavailability of many sparingly water-soluble drugs. Pegylated prodrugs, either added to directly, or via a spacer, such as an amino acid spacer (Feng et al., Bioorganic & Medicinal Chemistry Letters, Volume 12, Issue 22, 18 November 2002, Pages 3301-3303), can also increase water-solubility. Pharmaceutically acceptable salts include those derived from pharmaceutically acceptable inorganic or organic bases and acids. Suitable salts include those derived from alkali metals such as potassium and sodium, alkaline earth metals such as calcium and magnesium, among numerous other acids well known in the pharmaceutical art. Pharmaceutically acceptable prodrugs refer to a compound that is metabolized, for example hydrolyzed or oxidized, in the host to form the compound of the present disclosure. Typical examples of prodrugs include compounds that have biologically labile protecting groups on functional moieties of the active compound. Prodrugs include compounds that can be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrolyzed, alkylated, dealkylated, acylated, deacylated, phosphorylated, or dephosphorylated to produce the active compound. The prodrug forms of the compounds of this disclosure can possess antiviral activity, can be metabolized to form a compound that exhibits such activity, or both, Stereoisomerism and Polymorphism Compounds described herein can have asymmetric centers and occur as racemates, racemic mixtures, individual diastereomers or enantiomers, with all isomeric forms being included in the present disclosure. Compounds of the present disclosure having a chiral center can exist in and be isolated in optically active and racemic forms. Some compounds can exhibit polymorphism. The present disclosure encompasses racemic, optically active, polymorphic, or stereoisomeric forms, or mixtures thereof, of a compound of the disclosure, which possess the useful properties described herein. The optically active forms can be prepared by, for example, resolution of the racemic form by recrystallization techniques, by synthesis from optically active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase or by enzymatic resolution. One can either purify the respective compound, then derivatize the compound to form the compounds described herein or purify the compound themselves. Optically active forms of the compounds can be prepared using any method known in the art, including but not limited to by resolution of the racemic form by recrystallization techniques, by synthesis from optically active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase. Examples of methods to obtain optically active materials include at least the following. i) physical separation of crystals: a technique whereby macroscopic crystals of the individual enantiomers are manually separated. This technique can be used if crystals of the separate enantiomers exist, i.e., the material is a conglomerate, and the crystals are visually distinct; ii) simultaneous crystallization: a technique whereby the individual enantiomers are separately crystallized from a solution of the racemate, possible only if the latter is a conglomerate in the solid state; iii) enzymatic resolutions: a technique whereby partial or complete separation of a racemate by virtue of differing rates of reaction for the enantiomers with an enzyme; iv) enzymatic asymmetric synthesis: a synthetic technique whereby at least one step of the synthesis uses an enzymatic reaction to obtain an enantiomerically pure or enriched synthetic precursor of the desired enantiomer; v) chemical asymmetric synthesis: a synthetic technique whereby the desired enantiomer is synthesized from an achiral precursor under conditions that produce asymmetry (i.e., chirality) in the product, which can be achieved using chiral catalysts or chiral auxiliaries; vi) diastereomer separations: a technique whereby a racemic compound is reacted with an enantiomerically pure reagent (the chiral auxiliary) that converts the individual enantiomers to diastereomers. The resulting diastereomers are then separated by chromatography or crystallization by virtue of their now more distinct structural differences and the chiral auxiliary later removed to obtain the desired enantiomer; vii) first- and second-order asymmetric transformations: a technique whereby diastereomers from the racemate equilibrate to yield a preponderance in solution of the diastereomer from the desired enantiomer or where preferential crystallization of the diastereomer from the desired enantiomer perturbs the equilibrium such that eventually in principle all the material is converted to the crystalline diastereomer from the desired enantiomer. The desired enantiomer is then released from the diastereomer; viii) kinetic resolutions: this technique refers to the achievement of partial or complete resolution of a racemate (or of a further resolution of a partially resolved compound) by virtue of unequal reaction rates of the enantiomers with a chiral, non- racemic reagent or catalyst under kinetic conditions; ix) enantiospecific synthesis from non-racemic precursors: a synthetic technique whereby the desired enantiomer is obtained from non-chiral starting materials and where the stereochemical integrity is not or is only minimally compromised over the course of the synthesis; x) chiral liquid chromatography: a technique whereby the enantiomers of a racemate are separated in a liquid mobile phase by virtue of their differing interactions with a stationary phase (including but not limited to via chiral HPLC). The stationary phase can be made of chiral material, or the mobile phase can contain an additional chiral material to provoke the differing interactions; xi) chiral gas chromatography: a technique whereby the racemate is volatilized and enantiomers are separated by virtue of their differing interactions in the gaseous mobile phase with a column containing a fixed non-racemic chiral adsorbent phase; xii) extraction with chiral solvents: a technique whereby the enantiomers are separated by virtue of preferential dissolution of one enantiomer into a particular chiral solvent; xiii) transport across chiral membranes: a technique whereby a racemate is placed in contact with a thin membrane barrier. The barrier typically separates two miscible fluids, one containing the racemate, and a driving force such as concentration or pressure differential causes preferential transport across the membrane barrier. Separation occurs as a result of the non-racemic chiral nature of the membrane that allows only one enantiomer of the racemate to pass through. Chiral chromatography, including but not limited to simulated moving bed chromatography, is used in one embodiment. A wide variety of chiral stationary phases are commercially available. Salt or Prodrug Formulations In cases where compounds are sufficiently basic or acidic to form stable nontoxic acid or base salts, administration of the compound as a pharmaceutically acceptable salt may be appropriate. Examples of pharmaceutically acceptable salts are organic acid, which form a physiological acceptable anion, for example, tosylate, methanesulfonate, acetate, citrate, malonate, tartrate, succinate, benzoate, ascorbate, α-ketoglutarate and α-glycerophosphate. Suitable inorganic salts can also be formed, including but not limited to, sulfate, nitrate, bicarbonate and carbonate salts. For certain transdermal applications, it can be preferred to use fatty acid salts of the compounds described herein. The fatty acid salts can help penetrate the stratum corneum. Examples of suitable salts include salts of the compounds with stearic acid, oleic acid, linoleic acid, palmitic acid, caprylic acid, and capric acid. Pharmaceutically acceptable salts can be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound such as an amine with a suitable acid, affording a physiologically acceptable anion. In those cases where a compound includes multiple amine groups, the salts can be formed with any number of the amine groups. Alkali metal (e.g., sodium, potassium, or lithium) or alkaline earth metal (e.g., calcium) salts of carboxylic acids can also be made. A prodrug is a pharmacological substance that is administered in an inactive (or significantly less active) form and subsequently metabolized in vivo to an active metabolite. Getting more drug to the desired target at a lower dose is often the rationale behind the use of a prodrug and is generally attributed to better absorption, distribution, metabolism, and / or excretion (ADME) properties. Prodrugs are usually designed to improve oral bioavailability, with poor absorption from the gastrointestinal tract usually being the limiting factor. Additionally, the use of a prodrug strategy can increase the selectivity of the drug for its intended target thus reducing the potential for off target effects. Isotopes Compounds described herein include isotopically labeled compounds, which are identical to those recited in the various formula and structures presented herein, but for the fact that one or more atoms are enriched with an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that are incorporated into the present compounds including isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, and chlorine, such as, for example,2H,3H,13C,14C,15N,18O,17O,35S,18F,36Cl, respectively. Certain isotopically labeled compounds described herein, for example those into which radioactive isotopes such as2H are incorporated, are useful in drug and / or substrate tissue distribution assays. Further, in some embodiments, substitution with isotopes such as deuterium, i.e.,2H, can affords certain therapeutic advantages resulting from greater metabolic stability, such as, for example, increased in vivo half-life or reduced dosage requirements. Heterocyclic Peptidomimetic Compounds In certain embodiments, heterocyclic peptidomimetic compounds of this disclosure are any of any of the formulas disclosed herein including prodrugs or derivatives thereof. In certain embodiments, the heterocyclic peptidomimetics are oxopyrrolidine peptidomimetics or indole peptidomimetics. In certain embodiments, compounds are of the following formula (I): formula (I) or a pharmaceutically acceptable salt or prodrug thereof, wherein: R4is an optionally substituted bridging C1-6 alkyl, an optionally substituted bridging C2- 6 alkene, an optionally substituted bridging C2-6 alkyne; R5is -CN, -C(O)H, -CH=C(CN)C(O)NH2, -C(O)CF3, -CH(OH)CF3, -C(OH)SO3- (and an associated cation, such as Na+), or an optionally-substituted epoxide ring, or is –(CH2)q-SH, , OH, -C(O)-CH2-O-P(O)(OR8)2, -C(O)-heteroaryl, -C(O)-CH2-O-C(O)-aryl, -C(O)-CH2-O-C(O)- heteroaryl, -C(O)-C(O)-NH2, -C(O)-C(O)-NH-alkylaryl, -C(O)-C(O)-NH-alkylheteroaryl, -C(O)-C(O)-NH-alkyl, -C(O)-C(O)-NH-cycloalkyl, -C(O)-C(O)-NH2, -CH=C-C(O)-R8, -C(O)-CHFCl, -C(O)-CH2-OCF3; R10and R10’ are independently, hydrogen, CF3, C1-6 alkyl, C1-6 haloalkyl, or C2-6 alkenyl; Y is, independently at each occurrence, O or S; m and n and q are, independently at each occurrence, 0, 1, 2, or 3; R6and R6’are, independently, hydrogen, halogen, CF3, hydroxy, N(R’)S(O)2R’, S(O)2R’, S(O)2N(R’)2, C1-6alkoxy, C2-6alkenyl, cyano, C2-6alkynyl, C3-6alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, C1-6alkyl, arylalkoxycarbonyl, carboxy, C1-6haloalkyl, heterocyclylalkyl, or C1-6 hydroxyalkyl; or R6and R6’, together with the carbon to which they are attached, form a carbonyl; R6and R6’can come together to form an optionally substituted double bond or a C3-6ring optionally containing a N, O, or S heteroatom; each R’ is, independently, H, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-6cycloalkyl, aryl, heteroaryl, alkylaryl, or arylalkyl; the R’ groups can optionally be substituted with one or more substituents, wherein substituents are independently at each occurrence, halo, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, hydroxyl, carboxyl, acyl, aryl, acyloxy, amino, amido, alkylamino, dialkylamino, arylamino, alkoxy, alkoxyalkyl, aryloxy, nitro, cyano, sulfonic acid, thiol, sulfonyl, sulfanyl, sulfinyl, sulfamoyl, carboxylic acid, amide, phosphonyl, phosphinyl, phosphoryl, phosphine, or phosphonic acid; or two R’ residing on the same carbon or nitrogen atom can come together to form a C3-6ring optionally containing a N, O, or S heteroatom; R7and R7’are, independently, hydrogen, CF3, N(R’)S(O)2R’, S(O)2R’, S(O)2N(R’)2, C1-6alkoxy, C2-6alkenyl, cyano, C2-6alkynyl, C3-6alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, C1-6 alkyl, arylalkoxycarbonyl, carboxy, C1-6 haloalkyl, heterocyclylalkyl, or C1-6 hydroxyalkyl; or R7and R7’can come together to form an optionally substituted double bond or a C3-6ring optionally containing a N, O, or S heteroatom; R8is independently at each occurrence H or C1-C3 alkyl; R9is H or C1-C3 alkyl; R11, R11’and R11’’are an optionally substituted C1-6 alkyl, an optionally substituted C2-6 alkene, an optionally substituted C2-6alkyne; or R12, R12’and R12’’are independently, hydrogen, halo, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, hydroxyl, carboxyl, acyl, aryl, acyloxy, amino, amido, alkylamino, dialkylamino, arylamino, alkoxy, alkoxyalkyl, aryloxy, nitro, cyano, sulfonic acid, thiol, sulfonyl, sulfanyl, sulfinyl, sulfamoyl, carboxylic acid, amide, phosphonyl, phosphinyl, phosphoryl, phosphine, or phosphonic acid; or two adjacent R12, R12’and R12’’can come together to form a C3-6ring optionally containing a N, O, or S heteroatom; R13is hydrogen, halogen, CF3, C1-6 alkyl, C1-6 haloalkyl, or C2-6 alkenyl; and R14is hydrogen, halogen, CF3, C1-6 alkyl, C1-6 haloalkyl, or C2-6 alkenyl. In certain embodiments, q is 1 or 2. In certain embodiments, a compound of formula (I) is a compound selected from: , 7-chloro-N-((2R)-1-(((1S)-1-cyano-2-(2-oxopyrrolidin-3-yl)ethyl)amino)-1-oxo-3- (trimethylsilyl)propan-2-yl)-1H-indole-2-carboxamide; 7-chloro-N-((2R)-1-oxo-1-(((2S)-1-oxo-3-(2-oxopyrrolidin-3-yl)propan-2-yl)amino)- 3-(trimethylsilyl)propan-2-yl)-1H-indole-2-carboxamide; or a pharmaceutically acceptable salt or prodrugs thereof. In certain embodiments, compounds are of the following formula (II) or formula (V): formula (V) or a pharmaceutically acceptable salt or prodrugs thereof, wherein: R5is -CN, -C(O)H, -CH=C(CN)C(O)NH2, -C(O)CF3, -CH(OH)CF3, -C(OH)SO3- (and an associated cation, such as Na+), or an optionally-substituted epoxide ring, is –(CH2)q-SH, -C(O)-CH2-O-P(O)(OR8)2, -C(O)-heteroaryl, -C(O)-CH2-O-C(O)-aryl, -C(O)-CH2-O-C(O)- heteroaryl, -C(O)-C(O)-NH2, -C(O)-C(O)-NH-alkylaryl, -C(O)-C(O)-NH-alkylheteroaryl, -C(O)-C(O)-NH-alky, -C(O)-C(O)-NH-cycloalkyl, -C(O)-C(O)-NH2, -CH=C-C(O)-R8, -C(O)- CHFCl, -C(O)-CH2-OCF3; R10and R10’are independently, hydrogen, CF3, C1-6alkyl, C1-6haloalkyl, or C2-6alkenyl; Y is, independently at each occurrence, O or S; m and n and q are, independently at each occurrence 0, 1, 2, or 3; t is 1 or 2; R6and R6’are, independently at each occurrence, hydrogen, halogen, CF3, hydroxy, N(R’)S(O)2R’, S(O)2R’, S(O)2N(R’)2, C1-6 alkoxy, C2-6 alkenyl, cyano, C2-6 alkynyl, C3-6 alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, C1-6alkyl, arylalkoxycarbonyl, carboxy, C1-6haloalkyl, heterocyclylalkyl, or C1-6hydroxyalkyl; or R6and R6’, together with the carbon to which they are attached, form a carbonyl; or R6and R6’can come together to form an optionally substituted double bond or a C3-6ring optionally containing a N, O, or S heteroatom; each R’ is, independently at each occurrence, H, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, aryl, heteroaryl, alkylaryl, or arylalkyl; the R’ groups can optionally be substituted with one or more substituents, which substituents are, independently at each occurrence, halo, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, hydroxyl, carboxyl, acyl, aryl, acyloxy, amino, amido, alkylamino, dialkylamino, arylamino, alkoxy, alkoxyalkyl, aryloxy, nitro, cyano, sulfonic acid, thiol, sulfonyl, sulfanyl, sulfinyl, sulfamoyl, carboxylic acid, amide, phosphonyl, phosphinyl, phosphoryl, phosphine, or phosphonic acid; or two R’ residing on the same carbon or nitrogen atom can come together to form a C3-6ring optionally containing a N, O, or S heteroatom; R7and R7’are, independently at each occurrence, hydrogen, CF3, N(R’)S(O)2R’, S(O)2R’, S(O)2N(R’)2, C1-6 alkoxy, C2-6 alkenyl, cyano, C2-6 alkynyl, C3-6 alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, C1-6alkyl, arylalkoxycarbonyl, carboxy, C1-6haloalkyl, heterocyclylalkyl, or C1-6 hydroxyalkyl; or R7and R7’can come together to form an optionally substituted double bond or a C3-6 ring optionally containing a N, O, or S heteroatom; R8is independently at each occurrence H or C1-C3 alkyl; R9is H or C1-C3 alkyl; R12, R12’and R12’’are independently at each occurrence, hydrogen, halo, C1-6 alkyl, C1- 6 haloalkyl, C1-6 hydroxyalkyl, hydroxyl, carboxyl, acyl, aryl, acyloxy, amino, amido, alkylamino, dialkylamino, arylamino, alkoxy, alkoxyalkyl, aryloxy, nitro, cyano, sulfonic acid, thiol, sulfonyl, sulfanyl, sulfinyl, sulfamoyl, carboxylic acid, amide, phosphonyl, phosphinyl, phosphoryl, phosphine, or phosphonic acid; or two adjacent R12, R12’and R12’’can come together to form a C3-6ring optionally containing a N, O, or S heteroatom; R13is hydrogen, halogen, CF3, C1-6 alkyl, C1-6 haloalkyl, or C2-6 alkenyl; and R14is hydrogen, halogen, CF3, C1-6alkyl, C1-6haloalkyl, or C2-6alkenyl. In certain embodiments, q is 1 or 2. In certain embodiments, a compound of formula (II) or (V) is a compound selected from: , (S)-4-(7-chloro-1H-indole-2-carbonyl)-N-((S)-1-cyano-2-((S)-2-oxopyrrolidin-3- yl)ethyl)morpholine-3-carboxamide; (S)-4-(7-chloro-1H-indole-2-carbonyl)-N-((S)-1-oxo-3-((S)-2-oxopyrrolidin-3- yl)propan-2-yl)morpholine-3-carboxamide, 1-(7-chloro-1H-indole-2-carbonyl)-3,3-dimethyl-N-((S)-1-oxo-3-((S)-2-oxopyrrolidin- 3-yl)propan-2-yl)-1,3-azasilolidine-5-carboxamide; and 1-(7-chloro-1H-indole-2-carbonyl)-N-((S)-1-cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)- 3,3-dimethyl-1,3-azasilolidine-5-carboxamide, or a pharmaceutically acceptable salt or prodrugs thereof. In certain embodiments, this disclosure relates to compounds of the following formulas (III) or formula (IV): formula (III)

[0002] formula (IV) or a pharmaceutically acceptable salt or prodrug thereof, wherein: R1is optionally substituted cycloalkylaryl, alkylaryl, cycloalkylheteroaryl, alkylheteroaryl, alkyl, cycloalkyl, aryl, heteroaryl, aryloxy, heteroaryloxy, arylalkoxy, or heteroarylalkoxy; R3is an optionally substituted C1-6 alkyl, C1-6 haloalkyl, C2-8 alkoxyalkyl, arylalkyl, alkylaryl, heteroarylalkyl, or alkylheteroaryl, -CH2-(hydroxy)phenyl, and –CH2-(halo)phenyl; R4is an optionally substituted bridging C1-6alkyl, an optionally substituted bridging C2-6 alkene, an optionally substituted bridging C2-6 alkyne; R5is -CN, -C(O)H, -CH=C(CN)C(O)NH2, -C(O)CF3, -CH(OH)CF3, -C(OH)SO3- (and an associated cation, such as Na+), or an optionally-substituted epoxide ring, is –(CH2)q-SH, -C(O)-CH2-O-P(O)(OR8)2, -C(O)-heteroaryl, -C(O)-CH2-O-C(O)-aryl, -C(O)-CH2-O-C(O)- heteroaryl, -C(O)-C(O)-NH2, -C(O)-C(O)-NH-alkylaryl, -C(O)-C(O)-NH-alkylheteroaryl, -C(O)-C(O)-NH-alky, -C(O)-C(O)-NH-cycloalkyl, -C(O)-C(O)-NH2, -CH=C-C(O)-R8, -C(O)- CHFCl, -C(O)-CH2-OCF3; R2, R2’, R10and R10’ are, independently at each occurrence, hydrogen, CF3, C1-6 alkyl, C1-6 haloalkyl, or C2-6 alkenyl; X is, independently at each occurrence a bond, O or NH; Y is, independently at each occurrence a bond, O or S; m, n, p, and q are, independently at each occurrence 0, 1, 2, or 3; R6and R6’are, independently at each occurrence, hydrogen, halogen, CF3, hydroxy, N(R’)S(O)2R’, S(O)2R’, S(O)2N(R’)2, C1-6alkoxy, C2-6alkenyl, cyano, C2-6alkynyl, C3-6alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, C1-6 alkyl, arylalkoxycarbonyl, carboxy, C1-6haloalkyl, heterocyclylalkyl, or C1-6hydroxyalkyl; or R6and R6’, together with the carbon to which they are attached, form a carbonyl; each R’ is, independently at each occurrence, H, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, aryl, heteroaryl, alkylaryl, or arylalkyl; the R’ groups can optionally be substituted with one or more substituents, which substituents are, independently at each occurrence, halo, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, hydroxyl, carboxyl, acyl, aryl, acyloxy, amino, amido, alkylamino, dialkylamino, arylamino, alkoxy, alkoxyalkyl, aryloxy, nitro, cyano, sulfonic acid, thiol, sulfonyl, sulfanyl, sulfinyl, sulfamoyl, carboxylic acid, amide, phosphonyl, phosphinyl, phosphoryl, phosphine, or phosphonic acid; or two R’ residing on the same carbon or nitrogen atom can come together to form a C3-6ring optionally containing a N, O, or S heteroatom; or R6and R6’can come together to form an optionally substituted double bond or a C3-6 ring optionally containing a N, O, or S heteroatom; R7and R7’are, independently at each occurrence, hydrogen, CF3, N(R’)S(O)2R’, S(O)2R’, S(O)2N(R’)2, C1-6 alkoxy, C2-6 alkenyl, cyano, C2-6 alkynyl, C3-6 alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, C1-6 alkyl, arylalkoxycarbonyl, carboxy, C1-6 haloalkyl, heterocyclylalkyl, or C1-6hydroxyalkyl; or R7and R7’can come together to form an optionally substituted double bond or a C3-6 ring optionally containing a N, O, or S heteroatom; R8is independently at each occurrence H or C1-C3alkyl; R9is H or C1-C3alkyl; or R11, R11’and R11’’are an optionally substituted C1-6 alkyl, an optionally substituted C2-6 alkene, an optionally substituted C2-6 alkyne. In certain embodiments, q is 1 or 2. In certain embodiments, this disclosure relates to compounds of the following formulas (VI), (VII), (VIII), (IX): formula (VIII)

[0003] formula (IX) or a pharmaceutically acceptable salt or prodrug thereof, wherein m, n, p, q, X, Y, R1, R2, R2’, R3, R5, R6, R6’, R7, R7’, R8, R9, R10, R10’are as defined above and r is 0, 1, 2, or 3; t is 1, 2, or 3; s is 0, 1, 2, or 3, and R15is H, halo, fluoro, hydroxy, an optionally substituted C1-6alkyl, an optionally substituted C2-6 alkene, an optionally substituted C2-6 alkyne, an optionally substituted -O-C1-6 alkyl, an optionally substituted -O-C2-6alkene, an optionally substituted -O-C2-6alkyne, cycloalkyl. In certain embodiments, this disclosure relates to compounds of the following formulas formula (X) formula (XI) or a pharmaceutically acceptable salt or prodrug thereof, wherein p, X, Y, R1, R2, R2’, R3, R4, R8, R11, R11’, R11’’are as defined above; and R16is -CN, -C(O)H, -CH=C(CN)C(O)NH2, -C(O)CF3, -CH(OH)CF3, -C(OH)SO3- (and an associated cation, such as Na+), or an optionally-substituted epoxide ring, –(CH2)q-SH, -C(O)-CH2-O-P(O)(OR8)2, -C(O)-heteroaryl, -C(O)-CH2-O-C(O)-aryl, -C(O)-CH2-O-C(O)- heteroaryl, -C(O)-C(O)-NH2, -C(O)-C(O)-NH-alkylaryl, -C(O)-C(O)-NH-alkylheteroaryl, -C(O)-C(O)-NH-alkyl, -C(O)-C(O)-NH-cycloalkyl, -C(O)-C(O)-NH2, -CH=C-C(O)-R8, -C(O)-CHFCl, -C(O)-CH2-OCF3; R17is H, an optionally substituted C1-6alkyl, an optionally substituted C2-6alkene, an optionally substituted C2-6 alkyne, an optionally substituted C3-7 cycloalkyl B is an optionally substituted aryl, an optionally substituted cycloalkyl or an optionally substituted heteroaryl. In certain embodiments, q is 1 or 2. In certain embodiments, this disclosure relates to compounds of the following formulas formula (XIV)

[0004] formula (XV) or a pharmaceutically acceptable salt or prodrug thereof, wherein p, r, s, t, X, Y, Z, R1, R2, R2’, R3, R8, R15are as defined above; and R16is -CN, -C(O)H, -CH=C(CN)C(O)NH2, -C(O)CF3, -CH(OH)CF3, -C(OH)SO3- (and an associated cation, such as Na+), or an optionally-substituted epoxide ring, is –(CH2)q-SH, -C(O)-CH2-O-P(O)(OR8)2, -C(O)-heteroaryl, -C(O)-CH2-O-C(O)-aryl, -C(O)-CH2-O-C(O)- heteroaryl, -C(O)-C(O)-NH2, -C(O)-C(O)-NH-alkylaryl, -C(O)-C(O)-NH-alkylheteroaryl, -C(O)-C(O)-NH-alkyl, -C(O)-C(O)-NH-cycloalkyl, -C(O)-C(O)-NH2, -CH=C-C(O)-R8, -C(O)-CHFCl, -C(O)-CH2-OCF3; R17is H, an optionally substituted C1-6 alkyl, an optionally substituted C2-6 alkene, an optionally substituted C2-6alkyne, an optionally substituted C3-7cycloalkyl; and B is an optionally substituted aryl, an optionally substituted cycloalkyl or an optionally substituted heteroaryl. In certain embodiments, q is 1 or 2. In certain embodiments, this disclosure relates to compounds disclosed herein optionally substituted with one or more substituents. The term "substituted" refers to a molecule wherein at least one hydrogen atom is replaced with a substituent. When substituted, one or more of the groups are "substituents." The molecule may be multiply substituted. In the case of an oxo substituent ("=O"), two hydrogen atoms are replaced. Example substituents within this context may include halogen, hydroxy, alkyl, alkoxy, nitro, cyano, oxo, carbocyclyl, carbocycloalkyl, heterocarbocyclyl, heterocarbocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, -NRaRb, -NRaC(=O)Rb, -NRaC(=O)NRaNRb, -NRaC(=O)ORb, -NRaSO2Rb, -C(=O)Ra, -C(=O)ORa, -C(=O)NRaRb, -OC(=O)NRaRb, -ORa, -SRa, -SORa, - S(=O)2Ra, -OS(=O)2Ra and -S(=O)2ORa. Ra and Rb in this context may be the same or different and independently hydrogen, halogen hydroxyl, alkyl, alkoxy, alkyl, amino, alkylamino, dialkylamino, carbocyclyl, carbocycloalkyl, heterocarbocyclyl, heterocarbocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl. The term "optionally substituted," as used herein, means that substitution is optional and therefore it is possible for the designated atom to be unsubstituted. As one of ordinary skill in the art will recognize, combinations of substituents envisioned by this disclosure are those combinations that result in the formation of stable or chemically feasible compounds. The term "stable", as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and preferably their recovery, purification, and use for one or more of the purposes disclosed herein. In certain embodiments, compounds disclosed herein are isolated, enantiomerically pure, and substantially free of impurities. In certain embodiments, compounds disclosed herein are in a composition wherein a specific isomer is in excess of 60%, 70%, 80%, 90%, 93%, 95%, or 97% enantiomeric excess and / or diastereomeric excess. Methods of treatment Experiments indicate that compounds described herein have inhibitory activity against proteases. Therefore, it is contemplated that compounds can be used to treat or prevent an infection in a host or reduce the biological activity of a virus. The host can be a mammal, and in particular, a human, infected with a viral infection. In certain embodiments, methods involve administering an effective amount of one or more of the compounds to a subject in need thereof. In certain embodiments, this disclosure relates to methods of managing a viral infection using the heterocyclic peptidomimetic compounds disclosed herein. In certain embodiments, this disclosure relates to methos of treating or preventing a viral infection, including coronavirus, norovirus, enterovirus, picornavirus, and / or Herpesviridae virus infections comprising administering an effective amount of a compound disclosed herein to a subject in need thereof. In certain embodiments, methods further comprise administering a compound disclosed herein in combination with another pharmaceutical agent, antiviral agent, or anti- inflammatory agent. In certain embodiments, the pharmaceutical compositions further comprise a second active agent. In certain embodiments, the second active agent is another antiviral agent or an anti-inflammatory agent. In certain embodiments, compounds disclosed herein are administered in combination with another active pharmaceutical agent. In certain embodiments, the active pharmaceutical is a protease inhibitor. In certain embodiments, the protease inhibitor is administered in combination with a protease inhibitor “booster” such as for example ritonavir, e.g., administered initially in combination with the protease inhibitor and / or administered more than one day, week, or two weeks after an initial administration of the same or alternative antiviral agent. In certain embodiments, the active pharmaceutical is a protease inhibitor. In certain embodiments, the protease inhibitor is administered in combination with ritonavir or another protease inhibitor booster. In certain embodiments, this disclosure relates to methods of treating or preventing a viral infection, coronavirus virus, or SARS-CoV-2 infection comprising administering an effective amount of a compound disclosed herein optionally in combination with nirmatrelvir and ritonavir or combination thereof, remdesivir, molnupiravir, abatacept, ensitrelvir / fumaric acid, montelukast, infliximab, anti-SARS-CoV-2 monoclonal neutralizing antibody, risankizumab, danicopan, fluvoxamine, heparin, or combinations thereof. In certain embodiments, this disclosure relates to methods of treating or preventing a norovirus infection comprising administering an effective amount of a compound disclosed herein optionally in combination with another antiviral agent(s) such as nirmatrelvir, ritonavir, remdesivir, molnupiravir, abatacept, ensitrelvir / fumaric acid, montelukast, anti-norovirus monoclonal neutralizing antibody, danicopan, fluvoxamine, heparin, or combinations thereof. In certain embodiments, this disclosure relates to methods of treating or preventing an enterovirus infection comprising administering an effective amount of a compound disclosed herein optionally in combination with another antiviral agent(s) such as rupintrivir, itraconazole, nirmatrelvir, ritonavir, remdesivir, molnupiravir, abatacept, ensitrelvir / fumaric acid, montelukast, anti-enterovirus monoclonal neutralizing antibody, danicopan, fluvoxamine, heparin, or combinations thereof. In certain embodiments, this disclosure relates to methods of treating or preventing a picornavirus infection comprising administering an effective amount of a compound disclosed herein optionally in combination with another antiviral agent(s) such as nirmatrelvir, ritonavir, remdesivir, molnupiravir, abatacept, ensitrelvir / fumaric acid, montelukast, anti-picornavirus monoclonal neutralizing antibody, danicopan, fluvoxamine, heparin, or combinations thereof. In certain embodiments, this disclosure relates to methods of treating or preventing a Herpesviridae virus infection comprising administering an effective amount of a compound disclosed herein optionally in combination with another antiviral agent(s) such as acyclovir, amenamevir, ganciclovir, cidofovir, vidarabine, foscarnet, docosanol, nelfinavir, nirmatrelvir, ritonavir, remdesivir, molnupiravir, abatacept, ensitrelvir / fumaric acid, montelukast, anti- Herpesviridae virus monoclonal neutralizing antibody, danicopan, fluvoxamine, heparin, or combinations thereof. An “antiviral” refers to molecules that are recognized to aid in the treatment of a viruses. Examples include agents such as abacavir, acyclovir, adefovir, amantadine, amenamevir, amprenavir, ampligen, arbidol, atazanavir, atripla, baloxavir, boceprevir, cidofovir, combivir, daclatasvir, darunavir, delavirdine, didanosine, docosanol, dolutegravir, edoxudine, enfuvirtide, edoxudine, efavirenz, emtricitabine, enfuvirtide, entecavir, famciclovir, fomivirsen, fosamprenavir, foscarnet, fosfonet, ganciclovir, ibacitabine, imunovir, idoxuridine, imiquimod, indinavir, inosine, interferon type III, interferon type II, interferon type I, lamivudine, lopinavir, loviride, maraviroc, moroxydine, methisazone, nelfinavir, nevirapine, nexavir, oseltamivir, peginterferon alfa-2a, penciclovir, peramivir, pleconaril, podophyllotoxin, rilpivirine, raltegravir, ribavirin, rimantadine, ritonavir, saquinavir, stavudine, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide fumarate (TAF), tipranavir, trifluridine, trizivir, tromantadine, truvada, valaciclovir, valganciclovir, vicriviroc, vidarabine, viramidine, zalcitabine, zanamivir, zidovudine or combinations thereof. An “anti-inflammatory” refers to molecules that are recognized to aid in the reduction in immune responses. Examples include agents such as aceclofenac, acemetacin, acetyl- salicylic acid, 5-aminoacetyl salicylic acid, alclofenac, amfenac, bendazac, benoxaprofen, bermoprofen, 5-bromo salicylic acid acetate, butibufen, caffeic acid, carprofen, cinmetacin, clidanac, clopirac, sodium diclofenac, diflunisal, 3,4-dihydroxybenzoic acid, etodolac, felbinac, fenbufen, fendosal, fenoprofen, fentiazac, flufenamic acid, flunixin, flunoxaprofen, flurbiprofen, 1-hydroxynaphthoic acid, ibuprofen, indomethacin, indoprofen, isoxepac, ketoprofen, ketorolac, loxoprofen, meclofenamic acid, mefenamic acid, 3,4- methylenedioxycinnamic acid, montelukast, mycophenolic acid, naproxen, niflumic acid, olsalazine, oxaceprol, oxaprozin, pirprofen, pranoprofen, sulindac, suprofen, tiaprofenic acid, tinoridine acid, tolfenamic acid, tolmetin, xenbucin, ximoprofen, zaltoprofen, zomepirac, or combinations thereof. In certain embodiments, contemplated methods include the treatment of a patient co- infected with two or more of these viruses, or a combination of one or more of these viruses and norovirus. Hosts, including but not limited to humans, infected with a coronavirus, picornavirus, including enterovirus, and / or Herpesviridae virus, including hepatitis E virus, and, optionally, co-infected with norovirus, can be treated by administering to the patient an effective amount of the active compound or a pharmaceutically acceptable prodrug or salt thereof in the presence of a pharmaceutically acceptable carrier or diluent. The active materials can be administered by any appropriate route, for example, orally, parenterally, intravenously, intradermally, subcutaneously, topically, or by inhalation or other form of delivery to the pulmonary tract, in liquid or solid form. A preferred dose of the compound for will be in the range of between about 0.01 and about 10 mg / kg, more generally, between about 0.1 and 5 mg / kg, and, preferably, between about 0.5 and about 2 mg / kg of body weight of the recipient per day. The effective dosage range of the pharmaceutically acceptable salts and prodrugs can be calculated based on the weight of the parent compound to be delivered. If the salt or prodrug exhibits activity in itself, the effective dosage can be estimated as above using the weight of the salt or prodrug, or by other means known to those skilled in the art. In certain embodiments, the compound is conveniently administered in unit any suitable dosage form, including but not limited to but not limited to one containing 7 to 600 mg, preferably 70 to 600 mg of active ingredient per unit dosage form. An oral dosage of 1-400 mg is usually convenient. The concentration of active compound in the drug composition will depend on absorption, inactivation, and excretion rates of the drug as well as other factors known to those of skill in the art. It is to be noted that dosage values will also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed composition. The active ingredient can be administered at once or can be divided into a number of smaller doses to be administered at varying intervals of time. Pharmaceutical Compositions In certain embodiments, this disclosure relates to pharmaceutical compositions comprising a compound disclosed herein, e.g., a heterocyclic compound, and a pharmaceutically acceptable carrier or excipient. In certain embodiments, pharmaceutical composition is in the form of a pill, capsule, tablet, particles, powder, lotion, or gel. In certain embodiments, pharmaceutical composition is in the form of a neutral pH buffered solution optionally comprising isotonic saline or a pharmaceutically acceptable mono or polysaccharide. In certain embodiments, pharmaceutical composition is contained in a device in the form of a power, liquid, or gas, e.g., contained in pressurized container. In certain embodiments, the device is configured to dispense an aerosol spray. In certain embodiments, the pharmaceutical composition is a transdermal composition or a nanoparticulate composition. In certain embodiments, the pharmaceutically acceptable excipient is selected from lactose, sucrose, mannitol, triethyl citrate, dextrose, cellulose, methyl cellulose, ethyl cellulose, hydroxyl propyl cellulose, hydroxypropyl methylcellulose, carboxymethylcellulose, croscarmellose sodium, polyvinyl N-pyrrolidone, crospovidone, ethyl cellulose, povidone, methyl and ethyl acrylate copolymer, polyethylene glycol, fatty acid esters of sorbitol, lauryl sulfate, gelatin, glycerin, glyceryl monooleate, silicon dioxide, titanium dioxide, talc, corn starch, carnauba wax, stearic acid, sorbic acid, magnesium stearate, calcium stearate, castor oil, mineral oil, calcium phosphate, starch, carboxymethyl ether of starch, iron oxide, triacetin, acacia gum, esters, or salts thereof. Oral Formulations In certain embodiments, a mode of administration of the active compound is oral, although for certain patients a sterile injectable form can be given subcutaneous injection, intraperitoneal injection, or intravenous injection. Oral compositions will generally include an inert diluent or an edible carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches or capsules. Pharmaceutically compatible binding agents, and / or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, or corn starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring. When the dosage unit form is a capsule, it can contain, in addition to material of the above type, a liquid carrier such as a fatty oil. In addition, unit dosage forms can contain various other materials that modify the physical form of the dosage unit, for example, coatings of sugar, shellac, or other enteric agents. The compound can be administered as a component of an elixir, suspension, syrup, wafer, chewing gum or the like. A syrup can contain, in addition to the active compound(s), sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors. The compound or a pharmaceutically acceptable prodrug or salts thereof can also be mixed with other active materials that do not impair the desired action, or with materials that supplement the desired action, such as antibiotics, antifungals, anti-inflammatory agents or other antiviral compounds. Solutions or suspensions used for parenteral, intradermal, subcutaneous, or topical application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerin, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents, such as ethylenediaminetetraacetic acid; buffers, such as acetates, citrates or phosphates, and agents for the adjustment of tonicity, such as sodium chloride or dextrose. The parental preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. In certain embodiments, if administered intravenously, preferred carriers are physiological saline or phosphate buffered saline (PBS). Transdermal Formulations In some embodiments, the compositions are present in the form of transdermal formulations, such as that used in the FDA-approved agonist rotigotine transdermal (NeuproTMpatch). Another suitable formulation is that described in U.S. Publication No.20080050424, entitled “Transdermal Therapeutic System for Treating Parkinsonism.” This formulation includes a silicone or acrylate-based adhesive and can include an additive having increased solubility for the active substance, in an amount effective to increase dissolving capacity of the matrix for the active substance. The transdermal formulations can be single-phase matrices that include a backing layer, an active substance-containing self-adhesive matrix, and a protective film to be removed prior to use. In certain embodiments, also contemplated are multiple-layer matrices that may also contain non-adhesive layers and control membranes. If a polyacrylate adhesive is used, it can be crosslinked with multivalent metal ions such as zinc, calcium, aluminum, or titanium ions, such as aluminum acetylacetonate and titanium acetylacetonate. When silicone adhesives are used, they are typically polydimethylsiloxanes. However, other organic residues such as, for example, ethyl groups or phenyl groups may in principle be present instead of the methyl groups. Because the active compounds are amines, it may be advantageous to use amine-resistant adhesives. Representative amine-resistant adhesives are described, for example, in EP 0180377. Representative acrylate-based polymer adhesives include acrylic acid, acrylamide, hexylacrylate, 2-ethylhexylacrylate, hydroxyethylacrylate, octylacrylate, butylacrylate, methylacrylate, glycidylacrylate, methacrylic acid, methacrylamide, hexylmethacrylate, 2- ethylhexylmethacrylate, octylmethacrylate, methylmethacrylate, glycidylmethacrylate, vinylacetate, vinylpyrrolidone, and combinations thereof. In certain embodiments, adhesives have a suitable dissolving capacity for an active substance and the active substance moves within a matrix and crosses through a contact surface to skin. In certain embodiments, contemplated is a transdermal formulation with appropriate transdermal transport of the active substance. Certain pharmaceutically acceptable salts tend to be more preferred for use in transdermal formulations because they can help the active substance pass the barrier of the stratum corneum. Examples include fatty acid salts, such as stearic acid and oleic acid salts. Oleate and stearate salts are relatively lipophilic and can act as a permeation enhancer in the skin. In certain embodiments, alternative permeation enhancers can be used. Representative permeation enhancers include fatty alcohols, fatty acids, fatty acid esters, fatty acid amides, glycerol, or its fatty acid esters, N-methylpyrrolidone, terpenes such as limonene, alpha- pinene, alpha- terpineol, carvone, carveol, limonene oxide, pinene oxide, and 1,8-eucalyptol. The patches can generally be prepared by dissolving or suspending the active agent in ethanol or in another suitable organic solvent, then adding the adhesive solution with stirring. Additional auxiliary substances can be added either to the adhesive solution, the active substance solution or to the active substance-containing adhesive solution. The solution can then be coated onto a suitable sheet, the solvents removed, a backing layer laminated onto the matrix layer, and patches punched out of the total laminate. Formulations for Pulmonary Administration In some embodiments, the compounds are administered to the pulmonary tract (i.e., via pulmonary administration). In one specific embodiment, pulmonary administration comprises inhalation of the compounds, typically in the form of particles or droplets, such as by nasal, oral inhalation, or both. The particles or droplets can be administered in two or more separate administrations (doses). In certain embodiments, particles may be formulated as an aerosol (e.g., liquid droplets of a stable dispersion or suspension of particles which include one or more of the compounds described herein in a gaseous medium). Particles delivered by aerosol may be deposited in the airways by gravitational sedimentation, inertial impaction, and / or diffusion. Any suitable device for generating the aerosol may be used, including but not limited to pressured meter inhalers (pMDI), nebulizers, dry powder inhalers (DPI), and soft-mist inhalers. In certain embodiments, contemplated methods include inhalation of particles including one or more of the compounds described herein aerosolized via nebulization. Nebulizers generally use compressed air or ultrasonic power to create inhalable aerosol droplets of the particles or suspensions thereof. In this embodiment, the nebulizing results in pulmonary delivery to the subject of aerosol droplets of the particles or suspension thereof. In another embodiment, the methods comprise inhalation of particles aerosolized via a pMDI, wherein the particles or suspensions thereof are suspended in a suitable propellant system containing at least one liquefied gas, e.g., including hydrofluoroalkanes (HFAs), in a pressurized container sealed with a metering valve. Actuation of the valve results in delivery of a metered dose of an aerosol spray of the particles or suspensions thereof. Biodegradable particles can be used for the controlled-release and delivery of the compounds described herein. Aerosols for the delivery of therapeutic agents to the respiratory tract have been developed. Adjei, A. and Garren, J. Pharm Res.7, 565-569 (1990); and Zanen, P. and Lamm, J.-W. J. Int. J. Pharm.114, 111-115 (1995). The respiratory tract encompasses the upper airways, including the oropharynx and larynx, followed by the lower airways, which include the trachea followed by bifurcations into the bronchi and bronchiole. The upper and lower airways are called the conducting airways. The terminal bronchiole then divide into respiratory bronchiole which then lead to the ultimate respiratory zone, the alveoli, or deep lung. Gonda, I. "Aerosols for delivery of therapeutic and diagnostic agents to the respiratory tract," in Critical Reviews in Therapeutic Drug Carrier Systems 6:273-313, 1990. The deep lung, or alveoli, are the primary target of inhaled therapeutic aerosols for systemic drug delivery. Accordingly, it can be important to deliver antiviral particles to the deep lung (i.e., the alveolar regions of the lung). Relatively large particles tend to get trapped in the oropharyngeal cavity, which can lead to excessive loss of the inhaled drug. Relatively smaller particles can be delivered to the deep lung but can be phagocytosed. One way to deliver relatively large particles (sized to avoid phagocytosis), which are light enough to avoid excessive entrapment in the oropharyngeal cavity, is to use porous particles. In one embodiment, the particles for delivering the compounds described herein to the alveolar regions of the lung are porous, “aerodynamically-light” particles, as described in U.S. Patent No.6,977,087. Aerodynamically light particles can be made of a biodegradable material, and typically have a tap density less than 0.4 g / cm3and a mass mean diameter between 5 μm and 30 μm. The particles may be formed of biodegradable materials such as biodegradable polymers. For example, the particles may be formed of a functionalized polyester graft copolymer consisting of a linear alpha-hydroxy-acid polyester backbone having at least one amino acid group incorporated herein and at least one poly(amino acid) side chain extending from an amino acid group in the polyester backbone. In one embodiment, aerodynamically light particles having a large mean diameter, for example greater than 5 μm, can be used for enhanced delivery of one or more of the compounds described herein to the alveolar region of the lung. Pharmaceutical formulations adapted for administration by inhalation include fine particle dusts or mists, which may be generated by means of various types of metered dose pressurized aerosols, metered dose inhalers, dry powder inhalers, nebulizers, or insufflators. In certain embodiments, the pharmaceutical composition is contained in a container comprising an aerosolizing propellant. In certain embodiments, the aerosolizing propellant is compressed air, ethanol, nitrogen, carbon dioxide, nitrous oxide, or combinations thereof. In certain embodiments, the container is a pressurized or unpressurized container. In certain embodiments, the container is a manual pump spray, inhaler, meter-dosed inhaler, dry powder inhaler, nebulizer, vibrating mesh nebulizer, jet nebulizer, or ultrasonic wave nebulizer. In certain embodiments, the pharmaceutical composition is an aerosol suspension, a dry powder, or a liquid suspension. In certain embodiments, the pharmaceutical composition is an inhalation pharmaceutical formulation prepared for delivery as a nasal spray or an inhaler, such as a metered dose inhaler (MDI). In certain embodiments, the container is a nebulizer comprising compound for use in pulmonary administration into a mist, optionally using an aqueous saline solution, inhaled through a mouthpiece or face mask. Nanoparticulate Compositions In certain embodiments, the compounds described herein can also be administered in the form of nanoparticulate compositions. In certain embodiments, the controlled release nanoparticulate formulations comprise a nanoparticulate active agent to be administered and a rate-controlling polymer which functions to prolong the release of the agent following administration. In certain embodiments, the compositions can release the active agent, following administration, for a time period ranging from about 2 to about 24 hours or up to 30 days or longer. Representative controlled release formulations including a nanoparticulate form of the active agent are described, for example, in U.S. Patent No.8,293,277. In certain embodiments, the nanoparticulate compositions comprise particles of the active agents described herein, having a non-crosslinked surface stabilizer adsorbed onto, or associated with, their surface. In certain embodiments, the average particle size of the nano particulates is typically less than about 800 nm, more typically less than about 600 nm, still more typically less than about 400 nm, less than about 300 nm, less than about 250 nm, less than about 100 nm, or less than about 50 nm. In certain embodiments, at least 50% of the particles of active agent have an average particle size of less than about 800, 600, 400, 300, 250, 100, or 50 nm, respectively, when measured by light scattering techniques. In certain embodiments, the surface stabilizers are used with nanoparticulate compositions to prevent the particles from clumping or aggregating. Representative surface stabilizers are selected from the group consisting of gelatin, lecithin, dextran, gum acacia, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyethylene glycols, polyoxyethylene stearates, colloidal silicon dioxide, phosphates, sodium dodecyl sulfate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropyl methyl- cellulose phthalate, non-crystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol, polyvinylpyrrolidone, tyloxapol, polyoxamers, polyoxamines, dialkylesters of sodium sulfosuccinic acid, sodium lauryl sulfate, an alkyl aryl polyether sulfonate, a mixture of sucrose stearate and sucrose distearate, p-isononylphenoxypoly-(glycidol), C18H37CH2(CON(CH3)-CH2(CHOH)4(CH2OH)2, decanoyl-N-methylglucamide, n-decyl -D- glucopyranoside, n-decyl-D- maltopyranoside, n-dodecyl-D-glucopyranoside, n-dodecyl-D- maltoside, heptanoyl-N-methylglucamide, n-heptyl-D-glucopyranoside, n-heptyl-D- thioglucoside, n-hexyl-D- glucopyranoside, nonanoyl-N-methylglucamide, n-nonyl-D- glucopyranoside, octanoyl-N- methylglucamide, n-octyl-D-glucopyranoside, and octyl-D- thioglucopyranoside. Lysozymes can also be used as surface stabilizers for nanoparticulate compositions. Certain nanoparticles such as poly(lactic-co-glycolic acid) (PLGA)- nanoparticles are known to target the liver when given by intravenous (IV) or subcutaneously (SQ). In one embodiment, the nanoparticles or other drug delivery vehicles are targeted to the liver. One such type of liver-targeted drug delivery vehicle is described in Park, et al., Mol Imaging. Feb 2011; 10(1): 69–77 and uses Glypican-3 (GPC3) as a molecular target. Park taught using this target for hepatocellular carcinoma (HCC), a primary liver cancer frequently caused by chronic persistent hepatitis. In one aspect of this embodiment, this drug delivery vehicle is also used to target therapeutics to the liver to treat viral infections. Further, since the compounds described herein have anti-cancer uses, this type of system can target the compounds to the liver and treat liver cancers. GPC3 is a heparan sulfate proteoglycan that is not expressed in normal adult tissues, but significantly over-expressed in up to 80% of human HCC’s. GPC3 can be targeted, for example, using antibody-mediated targeting and binding (See Hsu, et al., Cancer Res.1997; 57:5179–84). Another type of drug delivery system for targeting the liver is described in U.S. Patent No.7,304,045. The ‘045 patent discloses a dual-particle tumor or cancer targeting system that includes a first ligand-mediated targeting nanoparticle conjugated with galactosamine, with the ligand being on a target cell. The first nanoparticle includes poly(γ-glutamic acid) / poly(lactide) block copolymers and an antiviral compound, which in this case is a compound described herein, and in the ‘045 patent, was gancyclovir. A second nanoparticle includes poly(γ- glutamic acid) / poly(lactide) block copolymers, an endothelial cell-specific promoter, and a (herpes-simplex-virus)-(thymidine kinase) gene constructed plasmid, which provides enhanced permeability and retention-mediated targeting. The first and said second nanoparticles are mixed in a solution configured for delivering to the liver. When the disorder to be treated is a liver tumor or cancer, the delivery can be directly to, or adjacent to, the liver tumor or cancer. Representative rate controlling polymers into which the nanoparticles can be formulated include chitosan, polyethylene oxide (PEO), polyvinyl acetate phthalate, gum arabic, agar, guar gum, cereal gums, dextran, casein, gelatin, pectin, carrageenan, waxes, shellac, hydrogenated vegetable oils, polyvinylpyrrolidone, hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (HEC), hydroxypropyl methylcellulose (HPMC), sodium carboxymethylcellulose (CMC), poly(ethylene) oxide, alkyl cellulose, ethyl cellulose, methyl cellulose, carboxymethyl cellulose, hydrophilic cellulose derivatives, polyethylene glycol, polyvinylpyrrolidone, cellulose acetate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose acetate trimellitate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetal diethylamino acetate, poly(alkyl methacrylate), poly(vinyl acetate), polymers derived from acrylic or methacrylic acid and their respective esters, and copolymers derived from acrylic or methacrylic acid and their respective esters. In certain embodiments, the nanoparticle formulations including the compounds described herein, may be in the form of a prodrug or a salt, can be used to treat or prevent infections by coronaviruses, picornaviruses, norovirus, enterovirus and / or viruses in the Herpesviridae family, which includes the hepatis E virus. Controlled Release Formulations In certain embodiments, the active compounds are prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including but not limited to implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. In certain embodiments, enterically coated compounds can be used to protect cleavage by stomach acid. Methods for preparation of such formulations will be apparent to those skilled in the art. Suitable materials can also be obtained commercially. In certain embodiments, the liposomal suspensions (including but not limited to liposomes targeted to infected cells with monoclonal antibodies to viral antigens) are used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in US Pat. No. 4,522,811 (incorporated by reference). For example, liposome formulations can be prepared by dissolving appropriate lipid(s) (such as stearoyl phosphatidyl ethanolamine, stearoyl phosphatidyl choline, arachidyl phosphatidyl choline, and cholesterol) in an inorganic solvent that is then evaporated, leaving behind a thin film of dried lipid on the surface of the container. An aqueous solution of the active compound is then introduced into the container. The container is then swirled by hand to free lipid material from the sides of the container and to disperse lipid aggregates, thereby forming the liposomal suspension. EXAMPLES The terms used in describing the disclosure are commonly used and known to those skilled in the art. As used herein, the following abbreviations have the indicated meanings: Boc2O Di-tert-butyl dicarbonate CbzCl Benzyl chloroformate CDI N,N'-Carbonyldiimidazole DCE dichloroethane DCM Dichloromethane DIPEA diisopropyl ethyl amine (Hünig’s base) DMSO dimethylsulfoxide EDC 1-ethyl-3-(3-dimethyllaminopropyl)carbodiimide hydrochloride Et3N Triethylamine EtOAc ethyl acetate EtOH ethanol h hour HOBt Hydroxybenzotriazole KOAC Potassium acetate LiHMDS Lithium bis(trimethylsilyl)amide M molar mCPBA meta-Chloroperoxybenzoic acid MeOH Methanol MePPh3Br Methyltriphenylphosphonium bromide MsCl Methanesulfonyl chloride min minute Py.SO3 Sulfur trioxide pyridine complex rt or RT room temperature TFA trifluoroacetic acid THF tetrahydrofuran TLC Thin layer chromatography TMSCF3 trimethyl(trifluoromethyl)silane General Methods for Preparing Active Compounds Scheme 1 - Reagents and conditions: (a) 4M HCl / 1,4-dioxane, CH3OH, 55 °C, overnight, 50%. (b) 7-chloroindole-3-carboxix acid, HATU, N-methyl morpholine, CH2Cl2, rt, overnight, quantitative yield. (c) lithium hydroxide monohydrate, THF / H2O (V / V, 2:1), rt, 1 h, acidified by 1N HCl, 70%. (d) HATU, N-methyl morpholine, CH2Cl2, rt, 76%. (e) LiBH4, THF, 0 °C, 2 hrs, 35%. (f) DMP, CH2Cl2, rt, overnight, 85%. Methyl (S)-morpholine-3-carboxylate hydrochloride salt (2) To a solution of (S)-morpholine-3-carboxylic acid 1 (1 g, 7.62 mmol) in CH3OH (10 mL) was added 4N HCl in 1,4-dioxane (4 mL), The reaction mixture was stirred at 55 °C overnight, evaporated and washed by diethyl ether to afford the hydrochloride salt 2 (0.69 g, 50%) which was directly used in the next step without further purification (0.69 g, 50%). Methyl (S)-4-(7-chloro-1H-indole-2-carbonyl) morpholine-3-carboxylate (3) To a solution of 7-chloroindole-3-carboxilic acid (300 mg, 1.53 mmol) and morpholine methyl ester hydrochloride 2 (417 mg, 2.29 mmol) in CH2Cl2(15 mL) was added N-methyl morpholine (0.45 mL, 4.09 mmol). The reaction was stirred for 30 min before addition of HATU (1.7 g, 4.47 mmol). The reaction was then stirred at rt overnight before being poured into water. The mixture was extracted with ethyl acetate (10 mL x3) and the combined organic layers were dried over sodium sulfate, concentrated in vacuo. The residue was purified by flash chromatography (CH2Cl2 / CH3OH (V / V) of 0-10%) to afford 3 (0.49 g, quantitative yield). 1H NMR (400 MHz, CDCl3): δ 9.50 (s, 1H), 7.53-7.55 (d, J= 8.0 Hz, 1H), 7.26-7.29 (m, 1H), 7.05-7.09 (t, J= 8.0 Hz, 1H), 6.87 (m, 1H), 5.28 (m, 1H), 4.39-4.54 (m, 2H), 3.75-3.98 (m, 6H), 3.55-3.62 (dt, J= 2.8Hz, J= 12 Hz, 1H);13C NMR (400 MHz, CDCl3): δ 169.83, 163.22, 133.31,129.16,128.65, 123.97, 121.48, 120.59, 117.24, 106.40, 67.81, 66.54, 53.10, 52.85, 44.94; MS calcd for C15H16ClN2O4(M+H)+: 323.1; found: 323.9. (S)-4-(7-Chloro-1H-indole-2-carbonyl) morpholine-3-carboxylic acid (4) To a solution of ester 3 (0.6 g, 1.86 mmol) in THF (6 mL) and water (3 mL) was added lithium hydroxide monohydrate (0.23 g, 5.47 mmol) at rt, after 1 hr, the reaction mixture was acidified to pH 2 by addition of 1N HCl dropwise. The reaction mixture was poured into water and extracted with ethyl acetate (5 mL x 3). The combined organic layers were washed with aqueous salt, dried and concentrated under vacuum. The crude compound was used directly in the next step without further purification (0.4 g, 70%). 1H NMR (400 MHz, CD3OD): δ 7.58-7.60 (d, J= 7.60 Hz, 1H), 7.25-7.27 (d, J= 7.60 Hz, 1H), 7.05-7.09 (m, J= 7.60 Hz, 1H), 6.77 (m, 1H), 5.00-5.16 (m, 1H), 4.18-4.52 (m, 2H), 3.89-3.98 (m, 1H), 3.76-3.80 (m, 2H), 3.57-3.64 (m, 1H);13C NMR (400 MHz, CDCl3): δ 171.20, 164.51, 133.64, 130.04, 128.77, 122.98, 120.70, 120.11, 116.79, 104.61, 67.44, 66.22, 53.08, 45.08; MS calcd for C14H15ClN2O4(M+H)+: 309.1; found: 309.0. Methyl (S)-2-((S)-4-(7-chloro-1H-indole-2-carbonyl) morpholine-3-carboxamido)-3-((S)-2- oxopyrrolidin-3-yl) propanoate (5) To a solution of 4 (0.34 g, 1.10 mmol) and amine hydrochloride 5 (prepared according to WO 2021 / 250648) (0.32 g, 1.43 mmol) in CH2Cl2(10 mL) was added N-methyl morpholine (0.3 mL, 2.72 mmol). The reaction was stirred for 30 mins before addition of HATU (1.03 g, 2.72 mmol). The reaction mixture was stirred at rt overnight before being poured into a saturated solution of sodium bicarbonate. The mixture was extracted with ethyl acetate (8 mL x3) and the combined with organic layers washed with water, brine and dried over sodium sulfate. After concentration under reduce vacuum, the residue was purified by flash chromatography (dichloromethane: methanol (0% to 10%) to afford 5 (0.4 g, 76%). 1HNMR (400 MHz, CD3OD): δ 7.56-7.60 (m, 1H), 7.26-7.27 (m, 1H), 6.93-7.09 (m, 2H), 5.04 (m, 1H), 4.59-4.62 (m, 2H), 4.45-4.48 (m, 2H), 3.92-3.93 (m, 1H), 3.59 (m, 2H), 3.33 (s, 3H), 2.93-3.13 (m, 2H), 2.34-2.51 (m, 2H), 2.10-2.19 (m, 1H), 1.82-1.92 (m, 2H).13C NMR (400 MHz, CD3OD): δ 180.33, 172.28, 170.45, 164.71, 133.56, 130.18, 128.81, 123.07, 120.88, 120.26, 116.74, 105.92, 67.24, 66.28, 56.25, 52.37, 51.51, 40.24, 38.57, 32.18, 27.51, 13.16. MS calcd for C22H26ClN4O6(M+H)+: 477.2; found: 477.2. (S)-4-(7-Chloro-1H-indole-2-carbonyl)-N-((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl) propan-2-yl) morpholine-3-carboxamide (7) To a solution of 6 (0.2 g, 0.42 mmol) in THF (6 mL) at 0 °C was added lithium borohydride (1.2 ml, 2.4 mmol). The reaction mixture was stirred at 0 °C for 2 h and then quenched with 1N HCl (30 mL). The mixture was extracted with ethyl acetate (8 mL x3), washed with water, salt, then dried over sodium sulfate. The organic layer was concentrated under vacuum and the residue purified by flash chromatography to give 7 (65 mg, 35%). 1H NMR (400 MHz, CD3OD): δ 7.56-7.58 (m, 1H), 7.26-7.28 (d, J= 7.2 Hz, 1H), 7.05- 7.09 (t, J= 7.6Hz, 1H), 6.93 (m, 1H), 4.99 (m, 1H), 4.42-4.63 (m, 2H), 4.28 (m, 1H), 3.94-4.15 (m, 2H), 3.54-3.82 (m, 5H), 3.25-3.29 (m, 1H), 2.34-2.43 (m, 2H), 1.78-2.03 (m, 2H), 1.53- 1.59 (m, 1H).13C NMR (400 MHz, CD3OD): δ 181.15, 170.31, 165.06, 133.58, 130.23, 128.78,123.02, 120.79, 120.12, 116.76, 105.64, 67.77, 67.63, 66.26, 64.00, 49.86, 46.99, 40.18, 38.38, 32.26, 27.57. MS calcd for C21H26ClN4O5(M+H)+: 449.2; found: 449.3. (S)-4-(7-Chloro-1H-indole-2-carbonyl)-N-((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl) propan-2- yl) morpholine-3-carboxamide (8) To a solution of 7 (20 mg, 0.04 mmol) in CH2Cl2(2 mL) at 0 °C was added DMP (60 mg, 0.14 mmol). The reaction mixture was stirred at rt overnight and then concentrated under vacuum. The residue was purified by flash chromatography (dichloromethane: methanol (V / V) - 0-10%) to afford 8 (17 mg, 85%). 1H NMR (400 MHz, CD3OD): δ 7.55-7.60 (m, 1H), 7.25-7.27 (d, J= 7.6Hz, 1H), 7.05- 7.09 (m, 1H), 6.94-6.96 (m, 1H), 5.00 (m, 1H), 4.55-4.63 (m, 1H), 4.38-4.43 (m, 1H), 4.20-4.34 (m, 1H), 4.03-4.11 (m, 1H), 3.95-3.97 (m, 1H), 3.59-3.80 (m, 3H), 3.30-3.33 (m,2H), 2.32-2.39 (m, 2H), 1.98-2.04 (m, 1H), 1.75-1.84 (m, 1H), 1.58-1.68 (m, 1H).13C NMR (400 MHz, CD3OD): δ 181.18, 170.37, 164.96, 133.61, 130.20, 128.78, 122.95, 120.71, 120.09, 116.78, 105.45, 97.81, 67.61, 66.25, 51.93, 48.45, 40.09, 38.13, 30.14, 29.83, 27.37. HRMS calcd for C21H24ClN4O5(M+H)+: 447.1435; found: 447.1419. Scheme 2 - Reagents and conditions: (a) NH3 / CH3OH, rt, overnight, 62%. (b) Burgess reagent, CH2Cl2, rt, overnight, 88%. (S)-N-((S)-1-Amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl) propan-2-yl)-4-(7-chloro-1H-indole- 2-carbonyl) morpholine-3-carboxamide (9) A solution of 6 (50 mg, 0.104 mmol) in NH3in CH3OH (3 mL) was stirred overnight at rt. After evaporation, the crude amide 9 was used directly in the next step without further purification (31 mg, 62 %). 1H NMR (400 MHz, CD3OD): δ 7.57-7.61 (m, 1H), 7.26-7.28 (d, J= 7.6 Hz, 1H), 7.05- 7.09 (t, J= 8.0Hz, 1H), 6.98 (m, 1H), 5.05 (m, 1H), 4.48-4.63 (m, 3H), 4.26 (s, 1H), 3.92-3.94 (m, 1H), 3.78-3.82 (m,1H), 3.59-3.64 (m, 2H), 3.29 (m, 1H), 2.33-2.50 (m, 2H), 2.11-2.18 (m, 1H), 1.83-1.91 (m, 2H). MS calcd for C21H24ClN5O5Na (M+Na)+: 484.1; found: 484.2. (S)-4-(7-chloro-1H-indole-2-carbonyl)-N-((S)-1-cyano-2-((S)-2-oxopyrrolidin-3-yl) ethyl) morpholine-3-carboxamide (10) To a solution of amide 9 (41 mg, 0.088 mmol) in CH2Cl2(6 mL) was added the Burgess reagent (60 mg, 0.25 mmol). The reaction was stirred at rt overnight before being diluted with ethyl acetate. The mixture was washed with water, a saturated solution of sodium bicarbonate, brine, dried over sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography (CH2Cl2 / CH3OH (0-10%)) to give the title compound 10 (35 mg, 88%). 1H NMR (400 MHz, CD3OD): δ 7.52-7.59 (m, 1H), 7.26-7.28 (d, J= 7.6Hz, 1H), 7.05- 7.09 (t, J= 7.6Hz, 1H), 6.92 (m, 1H), 5.03-5.13 (m, 2H), 4.43-4.46 (m, 1H), 4.28 (m, 1H), 3.93- 3.95 (m, 1H), 3.60-3.83 (m, 3H), 3.26 (m,2H), 2.26-2.53 (m, 3H), 1.82-2.02 (m, 2H).13C NMR (400 MHz, CD3OD): δ 179.53, 169.91, 164.78, 133.62, 130.02, 128.76, 123.02, 120.77, 120.14, 118.28, 116.79, 105.80, 67.40, 67.13, 66.23, 53.82, 48.46, 40.13, 39.06, 37.95, 33.67, 27.30. MS calcd for C21H23ClN5O4 (M+H)+: 444.1; found: 444.2.

[0005] Scheme 3 - Reagents and conditions: (a) NaHMDS, DMF, 0 °C, 1 hr, 45%. (b) 4N HCl in 1,4-dioxane, CH2Cl2, overnight. (c) 7-chloroindole-3-carboxix acid, HATU, N-methyl morpholine, CH2Cl2, rt, overnight, 95%. (d) monohydrate lithium hydroxide, THF / H2O (V / V, 2:1), rt, 1 hr, 98%. (e) HATU, N-methyl morpholine, CH2Cl2, rt, overnight, 78%. (f) LiBH4, THF, 0 °C, 2 hrs, 60%. (g) DMP, CH2Cl2, rt, overnight, 42%. 1-(tert-butyl) 5-methyl 3,3-dimethyl-1,3-azasilolidine-1,5-dicarboxylate (13) To a mixture of N-Boc-Gly-OMe 11 (3.7 mL, 24.8 mmol), dichlorosilane 12 (3.0 mL, 20.6 mmol), and DMF (29 mL) at 0 °C (cooling in ice-water bath) was added 1 M NaHMDS in THF (37 mL, 37 mmol) dropwise over 2 h with good stirring. After the addition was complete, the mixture was stirred at ambient temperature for an additional 1 h. The yellow suspension was cooled in an ice bath and quenched with 1N HCl then extracted with ethyl acetate (10 mL x3). The combined the organic layers were washed with water and brine and then concentrated under vacuum. The residue was purified by flash chromatography to give 13 (2.5 g, 45%). 1H NMR (400 MHz, CDCl3): δ 4.36-4.52 (m, 1H), 3.49 (s, 3H), 2.59-2.68 (m, 1H), 2.49- 2.53 (m, 1H), 1.20-1.22 (m, 9H), 0.99-1.12 (m, 1H), 0.83-0.87 (dd, J= 3.2Hz, J= 15.2 Hz, 1H), 0.00 (s, 6H). MS calcd for C12H24NO4 (M+H)+: 274.1; found: 274.1. Methyl 3,3-dimethyl-1,3-azasilolidine-5-carboxylate (14) To a solution of compound 13 (1 g) in CH2Cl2(4 mL) was added 4N HCl in dioxane (4 mL). The reaction was stirred overnight and then evaporated under vacuum. The residue was washed with diethylether, and the compound was used in the next step without further purification. Methyl 1-(7-chloro-1H-indole-2-carbonyl)-3,3-dimethyl-1,3-azasilolidine-5-carboxylate (15) To a suspension of 7-chloroindole-3-carboxilic acid (205 mg, 1.04 mmol) and methyl ester 14 (329.7 mg, 1.56 mmol) in CH2Cl2(10 mL) was added HATU (0.79 g, 2.08 mmol) and N-methyl morpholine (0.22 mL, 2.04 mmol). The reaction mixture was stirred overnight and then poured into water. The mixture was extracted with ethyl acetate (8 mL x3) and the combined organic layers were washed with a saturated solution of sodium bicarbonate, brine and dried over sodium sulfate. After concentration under vacuum, the residue was purified by flash chromatography (ethyl acetate / hexane - 10% to 20%) to give 15 (350 mg, 95%). 1H NMR (400 MHz, CDCl3): δ 9.50 (s, 1H), 7.55-7.57 (d, J= 8.0Hz, 1H), 7.26-7.28 (d, J= 7.2Hz, 1H), 7.16 (s, 1H), 7.03-7.07 (t, J= 8.0Hz, 1H), 5.18-5.22 (m, 1H), 3.75 (s, 3H), 3.30- 3.41 (m, 2H), 1.18-1.39 (m, 2H), 0.31-0.35 (2s, 6H). MS calcd for C16H20ClN2O3Si (M+H)+: 351.1; found: 351.1. 1-(7-Chloro-1H-indole-2-carbonyl)-3,3-dimethyl-1,3-azasilolidine-5-carboxylic acid (16) To a solution of methyl ester 15 (380 mg, 1.08 mmol) in THF (10 ml) and water (4 ml) at rt was added lithium hydroxide monohydrate (0.4 g, 9.52 mmol). The reaction mixture was stirred for 1.5 h before being acidified with 1N HCl to pH 2. The mixture was extracted with ethyl acetate (8 ml x3) and the combined organic layers were washed with brine and dried over sodium sulfate to give 16 (360 mg, 98%). 1H NMR (400 MHz, CD3OD): δ 7.63-7.68 (m, 1H), 7.07-7.33 (m, 3H), 5.22-5.37 (m, 1H), 2.85-3.07 (m, 1H), 1.25-1.52 (m, 3H), 0.11-0.41 (m, 6H). MS calcd for C15H18ClN2O3Si (M+H)+: 337.1; found: 337.1. Methyl (2S)-2-(1-(7-chloro-1H-indole-2-carbonyl)-3,3-dimethyl-1,3-azasilolidine-5-carbox amido)-3-((S)-2-oxopyrrolidin-3-yl) propanoate (17) To a solution of 16 (0.36 g, 1.06 mmol) and amine hydrochloride 5 (0.45 g, 2.02 mmol) in CH2Cl2 (6 mL) was added N-methyl morpholine (0.44 ml, 4.04 mmol). The reaction mixture was stirred for 30 mins before addition of HATU (1.5 g, 4.04 mmol). The reaction mixture was then stirred overnight and poured into water. The mixture was extracted with ethyl acetate (8 mL x3) and the combined organic layers washed with saturated aqueous sodium bicarbonate, brine, dried over sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography (dichloromethane and ethyl acetate - 0-10%) to obtain 17 (0.42 g, 78%). 1H NMR (400 MHz, CD3OD): δ 7.40-7.42 (d, J= 8.0Hz, 1H), 7.01-7.07 (m, 2H), 6.85- 6.88 (t, J= 7.6Hz, 1H), 4.91-4.95 (m, 2H), 4.27-4.33 (dd, J= 4.0Hz, J= 11.6Hz, 1H), 3.53 (s, 3H), 2.95-3.20 (m, 3H), 2.11-2.26 (m, 2H), 1.91-2.03 (m, 1H), 1.57-1.68 (m, 2H), 1.01-1.26 (m, 2H), 0.19 (s, 3H), 0.09 (s, 3H).13C NMR (400 MHz, CD3OD): δ 180.47, 174.99, 172.19, 164.42, 133.16, 131.66, 129.21, 123.08, 120.44,120.35, 116.61, 106.99, 61.26, 51.43, 50.45, 40.12, 38.18, 37.65, 32.37, 27.24, 15.13, -4.28. MS calcd for C23H30ClN4O5Si (M+H)+: 505.2; found: 505.3. 1-(7-Chloro-1H-indole-2-carbonyl)-N-((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2- yl)-3,3-dimethyl-1,3-azasilolidine-5-carboxamide (18) To a solution of ester 17 (110 mg, 0.21 mmol) in THF (3 ml) at 0 °C was added lithium borohydride (2.0 M, 0.6 mL, 1.2 mmol). The reaction mixture was stirred at 0 °C for 2 h before being diluted with ethyl acetate (8 mL) and quenched with 1N HCl (15 mL). The organic layer was washed with saturated aqueous sodium bicarbonate, brine, dried over sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography (dichloromethane / methanol 0-10%) to afford 18 (60 mg, 60%). 1H NMR (400 MHz, CD3OD): δ 7.61-7.63 (m, 1H), 7.19-7.28 (m, 2H), 7.05-7.09 (m, 1H), 5.04-5.08 (m, 1H), 4.62 (m, 1H), 3.96-4.00 (m, 1H), 3.53-3.65 (m, 2H), 3.28-3.42 (m, 2H), 2.36-2.67 (m, 2H), 1.75-2.00 (m, 2H), 1.30-1.59 (m, 3H), 1.14-1.19 (m, 1H), 0.37 (s, 3H), 0.29 (s, 3H).13C NMR (400 MHz, CDCl3): δ 181.12, 175.14, 164.45, 133.14, 131.66, 129.28, 123.00, 120.58, 120.45, 116.58, 106.91, 64.16, 61.59, 49.18, 40.13, 38.35, 37.83, 32.09, 27.53, 15.58, -4.27. MS calcd for C22H30ClN4O4Si (M+H)+: 477.2; found: 477.3. 1-(7-Chloro-1H-indole-2-carbonyl)-3,3-dimethyl-N-((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl) propan-2-yl)-1,3-azasilolidine-5-carboxamide (19) A suspension of alcohol 18 (56 mg, 0.11 mmol) and DMP (105.8 mg, 0.24 mmol) in CH2Cl2 (6 mL) was stirred at rt overnight. The mixture was concentrated under vacuum and the residue was purified by flash chromatography to give 19 (50 mg, 42%). 1H NMR (400 MHz, CD3OD): δ 7.61-7.63 (d, J= 7.6Hz, 1H), 7.19-7.28 (m, 2H), 7.05- 7.09 (t, J= 8.0Hz, 1H), 5.07-5.12 (m, 1H), 4.49-4.64 (m,2H), 3.95-4.10 (m, 1H), 3.28-3.29 (m, 2H), 2.14-2.36 (m, 2H), 1.78-2.08 (m, 2H), 1.16-1.62 (m, 4H), 0.34 (s, 3H), 0.29 (s, 3H).13C NMR (400 MHz, CD3OD): δ 181.26, 175.03, 164.41, 133.14, 131.65, 129.22, 123.00, 120.45, 116.59, 106.89, 97.86, 61.75, 51.42, 40.11, 39.07, 37.89, 29.53, 27.65, 15.39, -4.26. LCMS calcd for C22H28ClN4O4Si (M+H)+: 475.2; found: 475.2. Scheme 4 - Reagents and conditions: (a) NH3 / CH3OH, rt, overnight, 56%. (b) Burgess reagent, CH2Cl2, rt, overnight, 62%. N-((S)-1-Amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl) propan-2-yl)-1-(7-chloro-1H-indole-2- carbonyl)-3,3-dimethyl-1,3-azasilolidine-5-carboxamide (20) A solution of ester 17 (110 mg, 0.21 mmol) in NH3in CH3OH (4 mL) was stirred at rt overnight. The reaction was concentrated under vacuum and the residue was purified by flash chromatography (dichloromethane / methanol 0-10%) to afford 20 (60 mg, 56%). 1H NMR (400 MHz, CD3OD): δ 7.60-7.62 (m, 1H), 7.22-7.28 (m, 2H), 7.04-7.08 (t, J= 8.0Hz, 1H), 4.94-5.08 (m, 4H), 4.35-4.43 (m, 1H), 3.29-3.33 (m, 1H), 2.47-2.64 (m, 1H), 2.08- 2.34 (m, 2H), 1.79-2.00 (m, 2H), 1.39-1.47 (m, 1H), 1.13-1.29 (m, 1H), 0.27-0.39 (m, 6H). MS calcd for C22H29ClN5O4Si (M+H)+: 490.2; found: 490.2. 1-(7-chloro-1H-indole-2-carbonyl)-N-((S)-1-cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)-3,3- dimethyl-1,3-azasilolidine-5-carboxamide (21) To a solution of amide 20 (20 mg, 0.04 mmol) in CH2Cl2(3 mL) at 0 °C was added Burgess reagent (30 mg, 0.12 mmol). The reaction mixture was stirred overnight and then concentrated under vacuum. The residue was purified by flash chromatography to afford 21 (12 mg, 62%). 1H NMR (400 MHz, CD3OD): δ 7.46-7.48 (d, J= 7.6Hz, 1H), 7.06-7.12 (m, 2H), 6.89- 6.93 (t, J= 8.0Hz, 1H), 4.82-4.94 (m, 2H), 3.09-3.19 (m, 3H), 2.12-2.55 (m, 3H), 1.64-1.83 (m, 2H), 0.97-1.32 (m, 3H). 0.22 (s, 3H), 0.15 (s, 3H).13C NMR (400 MHz, CD3OD): δ 179.58, 174.63, 164.39, 133.18, 131.48, 129.24, 123.13, 120.50, 118.33, 116.61, 107.18, 61.81, 61.31, 40.06, 38.41, 37.66, 33.77, 27.12, 15.21, -4.35. MS calcd for C22H27ClN5O3Si (M+H)+: 472.2; found: 472.2. Scheme 5 - Reagents and conditions: (a) n-Butyl lithium, THF, -78 °C to rt, overnight, 51%. (b) 10% HCl, CH3OH, 0 °C, 2 hrs. (c)7-chloroindole-3-carboxix acid, HATU, N-methyl morpholine, CH2Cl2, rt, overnight, 47%. (d) monohydrate lithium hydroxide, THF / H2O (V / V, 2:1), rt, 1 hr, 99%. (e) HATU, N-methyl morpholine, CH2Cl2, rt, 73%. (f) LiBH4, THF, 0 °C, 2 hrs, 63%. (g) DMP, CH2Cl2, rt, overnight, 83 (2S,5S)-2-Isopropyl-3,6-dimethoxy-5-((trimethylsilyl)methyl)-2,5-dihydropyrazine (24) (2R)-3,6-Dimethoxy-2-(propan-2-yl)-2,5-dihydropyrazine 22 (2.9 mL, 16 mmol) was dissolved in THF (58 mL) and the solution cooled to -78°C. n-Butyl lithium (10 mL, 1.6 M, 16 mmol) was added dropwise with stirring. Stirring was continued for 15 min at -78°C. (Chloromethyl)(trimethyl)silane 23 (5.0 mL, 36 mmol) was added and the resulting mixture was stirred at ambient temperature overnight. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, filtered, and then concentrated. The crude product was purified by chromatography on silica gel (cyclohexane / ethyl acetate 2%) to afford 24 (2.2 g, 51%.) 1HNMR (400 MHz, CDCl3): δ 3.99-4.02 (m, 1H), 3.81-3.89 (m, 1H), 3.63 (s, 3H), 3.61 (s, 3H), 2.10-2.22 (m, 1H), 1.14-1.19 (m, 1H), 0.98-1.00 (d, J= 6.8 Hz, 3H), 0.78-0.84 (m, 1H), 0.63-0.64 (d, J= 6.8Hz, 3H), 0.00 (s, 9H). MS calcd for C13H27N2O2Si (M+H)+: 271.2; found: 271.4. Methyl (R)-2-amino-3-(trimethylsilyl)propanoate hydrochloride (25) To a solution of pyrazine 24 (2.0 g, 11.1 mmol) in methanol (18 mL) HCl (6 mL, 10%) was added at 0°C. The solution was stirred for 2 h and then concentrated under vacuum. The residue was dissolved in CH2Cl2 and washed by saturated aqueous sodium carbonate (10 mL x2), brine, dried over sodium sulfate and concentrated under vacuum. The residue was used in the next reaction without further purification. Methyl (R)-2-(7-chloro-1H-indole-2-carboxamido)-3-(trimethylsilyl)propanoate (26) To a solution of 7-chloroindole-3-carboxylic acid (300 mg, 1.53 mmol) and crude methyl ester hydrochloride 25 (313 mg, rough 1.5 mmol) in CH2Cl2 (15 mL) at rt was added N- methyl morpholine (0.45 mL, 4.09 mmol). The reaction mixture was stirred at rt for 30 min before addition of HATU (1.14 g, 3.0 mmol). The reaction mixture was stirred at rt overnight and diluted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate, brine and then dried over sodium sulfate. After concentration under vacuum, the crude product was purified by flash chromatography (ethyl acetate: hexane - 0-10%) to afford 26 (253 mg, 47%). 1H NMR (400 MHz, CDCl3): δ 9.10 (s, 1H), 7.42-7.44 (d, J= 8.0 Hz, 1H), 7.15-7.17 (d, J= 7.6 Hz, 1H), 6.94-6.98 (t, J= 7.6 Hz, 1H), 6.79-6.83 (m, 2H), 4.75-4.81 (m, 1H), 3.70 (s, 3H), 1.16-1.21 (dd, J= 5.6 Hz, J= 8.8 Hz, 1H), 1.01-1.08 (m, 1H), 0.00 (s, 9H).13C NMR (400 MHz, CDCl3): δ 175.73, 161.64, 134.84,132.00, 129.99, 125.05, 122.60, 122.56, 121.79, 118.42, 104.65, 53.70, 50.72, 22.26, 0.00. MS calcd for C16H22ClN2O3Si (M+H)+: 353.1; found: 353.1. (R)-2-(7-Chloro-1H-indole-2-carboxamido)-3-(trimethylsilyl)propanoic acid (27) To a solution of ester 26 (300 mg, 0.85 mmol) in THF (10 mL) and water (4 mL) was added lithium hydroxide monohydride (200 mg, mmol). The reaction mixture was stirred at rt for 3 h and then acidified to pH 2 by adding 1N HCl. The mixture was extracted with ethyl acetate (10 mL x3). The combined organic layers were washed with brine and then dried over sodium sulfate. After concentration under vacuum, the crude product was purified by flash chromatography (dichloromethane / methanol - 0-10%) to obtain 27 (280 mg, 99%). 1H NMR (400 MHz, CD3OD): δ 7.45-7.47 (d, J= 8.0 Hz, 1H), 7.14-7.16 (m, 2H), 6.92- 6.96 (t, J= 7.6Hz, 1H), 4.61-4.64 (m, 1H), 1.13-1.21 (m, 2H), 0.00 (s, 6H).13C NMR (400 MHz, CD3OD): 175.63, 161.57, 134.16, 131.64, 129.01, 123.30, 120.71, 120.36, 116.86, 105.74, 49.40, 19.48, -2.56. MS calcd for C15H20ClN2O3Si (M+H)+: 339.1; found: 339.2. Methyl (S)-2-((R)-2-(7-chloro-1H-indole-2-carboxamido)-3-(trimethylsilyl)propanamido)-3- ((S)-2-oxopyrrolidin-3-yl) propanoate (28) A solution of acid 27 (200 mg, 0.59 mmol) and amine hydrochloride 5 (0.26 g, 1.18 mmol) in CH2Cl2 (10 mL) at 0 °C was added N-methyl morpholine (0.22 mL, 2.0 mmol). after stirred for 30 mins, the solvent was added HATU (1.1 g, 2.8 mmol), stirred overnight. The resulting mixture was poured into water, extracted with ethyl acetate (10 mL x3), combined and washed with saturated aqueous sodium bicarbonate, brine and then dried over sodium sulfate. After concentration under vacuum, the crude product was purified by flash chromatography (dichloromethane / methanol - 0-10%) to give 28 (220 mg, 73%).1H NMR (400 MHz, CD3OD): δ 7.46-7.49 (m, 1H), 7.12-7.17 (m, 2H), 6.93-6.97 (t, J= 7.6Hz, 1H), 4.85-4.9 (m, 1H), 4.59-4.64 (m, 1H), 4.38-4.51 (m, 1H), 3.59-3.66 (m, 3H), 3.02- 3.15 (m, 1H), 2.01-2.48 (m, 3H), 1.64-1.76 (m, 2H), 1.07-1.18 (m, 2H), -0.01-0.00 (2s, 9H). MS calcd for C23H32ClN4O5Si (M+H)+: 507.2; found: 507.2. 7-Chloro-N-((R)-1-(((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl) propan-2-yl) amino)-1-oxo- 3-(trimethylsilyl) propan-2-yl)-1H-indole-2-carboxamide (29) To a solution of ester 28 (110 mg, 0.21 mmol) in THF (6 mL) was added lithium borohydride (0.6 ml, 1.2 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 2 h and ethyl acetate (15 mL) was added. The reaction was then quenched by addition of 1N HCl (15 mL) at 0 °C. The mixture was extracted with ethyl acetate (8 mL x3) and the combined organic layers washed with water, with saturated aqueous sodium bicarbonate, brine and then dried over sodium sulfate. After concentration under vacuum, the crude product was purified by flash chromatography (dichloromethane / methanol - 0-10%) to afford 29 (65 mg, 63%). 1H NMR (400 MHz, CD3OD): δ 7.46-7.49 (dd, J= 4.0Hz, J= 8.0Hz, 1H), 7.15-7.17 (d, J= 7.6Hz, 1H), 7.12 (d, J= 1.6Hz, 1H), 6.93-6.97 (t, J= 8.0Hz, 1H), 4.52-4.59 (m, 1H), 3.86- 3.91 (m, 1H), 3.39-3.50 (m,2H), 3.10-3.25 (m,2H), 2.16-2.33 (m, 2H), 1.83-1.93 (m,1H), 1.62- 1.70 (m,1H), 1.41-1.48 (m, 1H), 1.12-1.14 (m, 2H), 0.00 (s, 9H).13C NMR (400 MHz, CD3OD): δ 181.18, 174.78, 161.48, 134.17, 131.70, 129.01, 123.33, 120.74, 120.35, 116.87, 105.68, 64.01, 50.81, 49.28, 40.09, 38.20, 32.12, 27.53, 19.78, -2.44. MS calcd for C22H32ClN4O4Si (M+H)+: 479.2; found: 479.3. 7-Chloro-N-((R)-1-oxo-1-(((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl) propan-2-yl) amino)-3- (trimethylsilyl) propan-2-yl)-1H-indole-2-carboxamide (30) A solution of alcohol 29 (30 mg, 0.062 mmol) and DMP (60 mg, 0.14 mmol) in CH2Cl2 (3 mL) was stirred overnight at rt. The reaction mixture was concentrated under vacuum and the crude product was purified by flash chromatography (dichloromethane / methanol - 0-10%) to afford 30 (25 mg, 83%). 1H NMR (400 MHz, CD3OD): δ 7.45-7.48 (m, 1H), 7.13-7.16 (dd, J= 3.2 Hz, J= 6.0 Hz, 1H), 7.11 (s, 1H), 6.93-6.97 (dt, J= 1.6 Hz, J= 8.0 Hz, 1H), 4.40-4.58 (m, 3H), 3.84-3.91 (m, 1H), 3.02-3.10 (m, 1H), 2.15-2.24 (m, 2H), 1.89-1.96 (m, 1H), 1.44-1.68 (m, 2H), 1.10-1.14 (m, 2H), 0.00 (2s, 9H).13C NMR (400 MHz, CD3OD): 181.36, 174.94, 161.43, 134.17, 131.65, 129.00, 123.34, 120.75, 120.35, 116.58,105.63, 98.06, 51.62, 50.80, 40.07, 38.02, 29.36, 27.44, 19.59, -2.42. MS calcd for C22H30ClN4O4Si (M+H)+: 477.2; found: 477.3. Scheme 6 - Reagents and conditions: (a) NH3 / CH3OH, rt, overnight, 61%. (b) Burgess reagent, CH2Cl2, rt, overnight, 41%. N-((R)-1-(((S)-1-Amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-1-oxo-3- (trimethylsilyl)propan-2-yl)-7-chloro-1H-indole-2-carboxamide (31) A solution of ester 28 (150 mg, 0.29 mmol) and NH3in CH3OH (4 mL) was stirred at rt overnight. The reaction mixture was evaporated in vacuo and the crude product was purified by flash chromatography (CH2Cl2 / CH3OH - 0-10%) to give 31 (89 mg, 61%). 1H NMR (400 MHz, CD3OD): δ 7.46-7.49 (m, 1H), 7.14-7.17 (m, 2H), 6.94-6.98 (t, J= 8.0 Hz, 1H), 4.53-4.62 (m, 2H), 4.30-4.40 (m, 1H), 3.08-3.25 (m, 1H), 2.19-2.45 (m, 2H), 2.03- 2.11 (m, 1H), 1.67-1.78 (m, 2H), 1.14-1.16 (m, 2H), 0.00 (s, 9H). LCMS calcd for C22H31ClN54O4Si (M+H)+: 492.2; found: 492.3. 7-Chloro-N-((R)-1-(((S)-1-cyano-2-((S)-2-oxopyrrolidin-3-yl) ethyl) amino)-1-oxo-3- (trimethylsilyl) propan-2-yl)-1H-indole-2-carboxamide (32) To a solution of amide 31 (50 mg, 0.10 mmol) in CH2Cl2(6 mL) at 0 °C was added Burgess reagent (60 mg, 0.25 mmol). The reaction mixture was stirred at rt overnight and evaporation under vacuum, the crude product was purified by flash chromatography to give 32 (20 mg, 41%). 1H NMR (400 MHz, CD3OD): δ 7.44-7.48 (m, 1H), 7.14-7.16 (d, J= 7.6Hz, 1H), 7.12 (s, 1H), 6.92-6.95 (t, J= 7.6Hz, 1H), 4.88-4.96 (m, 1H), 4.50-4.56 (m, 1H), 3.09-3.18 (m, 1H), 2.15-2.51 (m, 3H), 1.65-1.84 (m,2H), 1.10-1.16 (m, 3H), 0.00 (s, 9H).13C NMR (400 MHz, CD3OD): δ 179.51, 174.25, 161.55, 134.18, 131.56, 129.00, 123.36, 120.75, 120.36, 118.35, 116.87, 105.82, 50.52, 40.03, 38.56, 37.71, 33.74, 27.16, 19.40, -2.50. MS calcd for C22H29ClN5O3Si (M+H)+: 474.2; found: 474.2. Scheme 7 Reagents and conditions: (a) TEA, toluene, 80 °C, 12 hrs, 59%. (b) 1- chloroethyl carbonochloridate, 1 ,2-dichloroethane, 90 °C, 1 hr, 60%. (c) methyl iodide, K2CO3, acetonitrile, 70 ˚C, 12 h, 70%. (d) Pd / C, H2, CH3OH, rt, 12 h. (e) 7-chloroindole-3-carboxylic acid, HATU, N-methyl morpholine, CH2Cl2, rt, overnight, 65%. (f) monohydrate lithium hydroxide, THF / H2O (V / V, 2:1), rt, 1 hr. (g) HATU, N-methyl morpholine, CH2Cl2, rt, 81% in two steps. (h) NH3 / CH3OH, rt, overnight, 72%. (i) Burgess reagent, CH2Cl2, rt, overnight. Ethyl 1,4-dibenzylpiperazine-2-carboxylate (35) To a solution of N1, N2-dibenzyl ethane-1,2-diamine 34 (12 g, 50 mmol) in toluene (50 mL) was added TEA (12.1 g, 120 mmol). The mixture was heated to 80°C, and a solution of ethyl 2,3-dibromopropanoate 33 (13.6 g, 53 mmol) in toluene (50 mL) was added dropwise over a period of 0.5 hour at 80°C. Then the mixture was stirred at 80°C for 12 h and cooled to 25°C. The reaction mixture was washed with saturated sodium bicarbonate, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (hexane / EtOAc (V / V) = 5 / 1) to give 35 (10 g, 59%).1H NMR (400 MHz, CDCl3): δ 7.20-7.33 (m, 10H), 4.09-4.20 (m, 2H), 3.89-3.92 (d, J= 13.2Hz, 1H), 3.59 (s, 1H), 3.53-3.56 (d, J= 13.2Hz, 1H), 3.38-3.42 (d, J= 13.2Hz, 1H), 3.29-3.31 (m,1H), 3.07 (m, 1H), 2.72 (m, 1H), 2.59- 2.61 (m,1H), 2.37-2.47 (m, 3H). 1.20-1.23 (t, J= 7.2Hz, 3H).13C NMR (400 MHz, CDCl3): 172.16, 138.32, 138.09, 129.15, 128.97, 128.28, 128.25, 127.14, 127.11, 77.55, 77.24, 76.92, 62.69, 60.38, 59.68, 55.59, 53.19, 48.67, 14.35. MS calcd for C21H27N2O2(M+H)+: 339.2; found: 339.4. Ethyl 1-benzylpiperazine-2-carboxylate (36) To a solution of ethyl ester 35 (13.5 g, 40 mmol) in 1,2-dichloroethane (40 mL) was added 1-chloroethyl carbonochloridate (6.3 g, 44 mmol) dropwise over a period of 30 minutes at 0°C, and the mixture was stirred at that temperature for another 15 minutes. The mixture was then stirred at 90°C for 1 hour before being concentrated in vacuo. The residue was dissolved in methanol (15 mL) and the mixture was stirred at 70°C for 1 hour before being concentrated in vacuo. The residue was diluted with water and washed with DCM. The aqueous layer was adjusted to pH 9 with aqueous sodium bicarbonate and extracted with DCM. The organic layer was dried over sodium sulfate and concentrated in vacuo to give 36 (6.1 g, 60%). 1H NMR (400 MHz, CDCl3): δ 7.24-7.33 (M, 5H), 4.18-4.24 (dq, J= 0.8Hz, J= 7.2Hz, 2H), 3.78-3.81 (d, J= 13.2Hz, 1H), 3.51-3.54 (d, J= 13.2Hz, 1H), 3.18-3.21 (t, J= 4.8Hz, 1H), 3.08-3.09 (d, J= 4.8Hz, 2H), 2.83-2.95 (m, 3H), 2.24-2.29 (m, 1H), 1.28-1.31 (t, J= 7.2Hz, 3H). MS calcd for C14H21N2O2 (M+H)+: 249.2; found: 249.1. Ethyl 1-benzyl-4-methylpiperazine-2-carboxylate (37) A mixture of compound 36 (1 g, 4.02 mmol), iodomethane (0.73 g, 5.23 mmol) and potassium carbonate (1.1 g, 7.93 mmol) in acetonitrile (50 mL), was stirred at 70 ˚C for 12 h. The reaction was cooled to 25 ˚C, filtered and concentrated in vacuo. The residue was purified by column chromatography (Hexanes / EtOAc (V / V) = 3 / 1) to give 37 (0.73 g, 70%). Ethyl 4-methylpiperazine-2-carboxylate (38) A mixture of crude compound 37 (1 g, 3.81 mmol) and Pd / C (10%, 100 mg) in anhydrous methanol (10 mL) was stirred at 25 ˚C for 12 h under H2. The mixture was filtered and concentrated in vacuo to give 38, which was use directly in the next reaction without further purification. Methyl 1-(7-chloro-1H-indole-2-carbonyl)-4-methylpiperazine-2-carboxylate (39) To a solution of 7-chloroindole-3-carboxylic acid (0.155 g, 0.79 mmol) and compound 38 (0.137 g, 0.79 mmol) in CH2Cl2(5 mL) at rt was added N-methyl morpholine (0.15 mL, 1.36 mmol). The reaction mixture was stirred at rt for 30 min before addition of HATU (600 mg, 1.57 mmol). The reaction mixture was stirred at rt overnight before addition of ethyl acetate. The organic layer was washed with saturated sodium bicarbonate, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (ethyl acetate: hexane - 0-10%) to give 39 (0.17 g, 65%). 1H NMR (400 MHz, CD3OD): δ 7.57-7.59 (m, 1H), 7.25-7.26 (d, J= 7.6Hz, 1H), 7.04- 7.08 (t, J= 7.6Hz, 1H), 6.93 (m, 1H), 5.31 (m, 1H), 4.21-4.30 (m, 3H), 3.32-3.67 (m, 3H), 2.29- 2.40 (m, 4H), 2.08-2.14 (m, 1H), 1.28-1.32 (t, J= 7.2Hz, 3H).13C NMR (400 MHz, CD3OD): δ 169.90, 166.06, 133.63, 130.15, 128.77, 123.02, 120.74, 120.17, 116.80, 105.91, 61.56, 55.26, 54.07, 53.12, 44.83, 37.50, 13.07. MS calcd for C17H21ClN3O3(MH+H)+: 351.1; found: 351.0. 1-(7-Chloro-1H-indole-2-carbonyl)-4-methylpiperazine-2-carboxylic acid (40) To a solution of ethyl ester 39 (95 mg, 0.27 mmol) in THF (2 mL) and water (0.5 mL) was added lithium hydroxide monohydride (22 mg, 0.54 mmol). The reaction mixture was stirred at rt for 5 h, acidified to pH 7 by addition of 1N HCl. The mixture was concentrated under vacuum and compound 40 was used directly in the next step without further purification. Methyl (2S)-2-(1-(7-chloro-1H-indole-2-carbonyl)-4-methylpiperazine-2-carboxamido)-3- ((S)-2-oxopyrrolidin-3-yl)propanoate (41) To a solution of acid 40 (0.27 mmol) and amine hydrochloride 5 (0.13 g, 0.56 mmol) in CH2Cl2 (10 mL) was added N-methyl morpholine (0.22 mL, 2.0 mmol) at 0 °C. After 30 min, HATU (0.55 g, 1.4 mmol) was added, and the reaction was stirred for 2 days. The resulting mixture was then poured into water and extracted with ethyl acetate (8 mL x3). The combined organic layers were washed with saturated sodium bicarbonate, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (dichloromethane / methanol - 0-10%) to give 41 (107 mg, 81%). 1H NMR (400 MHz, CD3OD): δ 7.56-7.59 (m, 1H), 7.25-7.27 (d, J= 7.6Hz, 1H), 7.04- 7.08 (t, J= 6.0Hz, 1H), 6.95 (m, 1H), 5.27-5.36 (m, 1H), 4.51-4.60 (m, 2H), 3.85 (s, 1H), 3.73- 3.75 (2s, 3H), 3.54-3.69 (m, 1H), 3.27-3.33 (m, 2H), 3.00-3.20 (m, 2H), 2.32-2.59 (m, 6H), 2.14-2.19 (m, 1H), 1.78-1.92 (m, 2H).13C NMR (400 MHz, CD3OD): 180.50, 172.36, 170.17, 164.34, 133.66, 129.74, 128.79, 123.18, 120.88, 120.32, 116.75, 106.22, 63.97, 54.53, 53.72, 53.44, 51,71, 44.32, 42.84, 40.25,38.52, 32.13, 27.56. MS calcd for C23H30ClN5O5 (MH+H)+: 491.2; found: 491.1. N-((S)-1-Amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-1-(7-chloro-1H-indole-2- carbonyl)-4-methylpiperazine-2-carboxamide (42) A solution of ester 41 (100 mg, 0.204 mmol) and NH3in CH3OH (4 mL) was stirred for 2 days. After evaporation under vacuum, the residue was purified by flash chromatography (CH2Cl2 / CH3OH (V / V) - 0-10%) to afford 11 (69 mg, 72%). 1H NMR (400 MHz, CD3OD): δ 7.58-7.61 (m, 1H), 7.26 (d, J= 7.2Hz, 1H), 7.06-7.09 (t, J= 7.6Hz, 1H), 6.94-6.99 (m, 1H), 5.23 (m, 2H), 4.49-4.57 (m, 2H), 3.50 (m, 2H), 3.26-3.35 (m, 1H), 2.78-2.97 (m, 1H), 2.51-2.59 (m, 1H), 2.31-.244 (m, 5H), 2.10-2.21 (m, 2H), 1.83- 1.93 (m, 2H). MS calcd for C22H29ClN6O4(MH+H)+: 476.2; found: 476.0. 1-(7-Chloro-1H-indole-2-carbonyl)-N-((S)-1-cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)-4- methylpiperazine-2-carboxamide (43) To a solution of amide 42 (50 mg, 0.10 mmol) in CH2Cl2(6 mL) at 0 °C was added Burgess reagent (60 mg, 0.25 mmol). The reaction mixture was stirred at rt overnight and evaporation under vacuum, the crude product was purified by flash chromatography to give 43. 1H NMR (400 MHz, CD3OD): δ 7.57-7.59 (d, J = 7.6Hz, 1H), 7.26-7.28 (d, J = 7.6Hz, 1H), 7.05-7.09 (t, J = 8.0Hz, 1H), 6.91-6.93 (m, 1H), 5.23 (m, 1H), 5.06-5.13 (m, 1H), 4.63 (m, 2H), 4.35 (m, 1H), 3.44-3.77 (m, 2H), 3.15-3.25 (m, 1H), 2.83 (m, 1H), 2.53-2.61 (m, 1H), 2.28-2.40 (m, 5H), 2.11-2.16 (m, 1H), 1.81-2.00 (m, 2H). MS calcd for C22H27ClN6O3(MH+H)+: 458.2; found: 458.1.

[0006] Scheme 8 - Reagents and conditions: (a) 7-fluoroindole-2-carboxylic acid, HATU, N- methyl morpholine, CH2Cl2, rt, overnight, 70%. (b) lithium hydroxide monohydrate, THF / H2O (V / V, 2:1), rt, 5 h, 97%. (c) HATU, N-methyl morpholine, CH2Cl2, rt, 48%. (d) LiBH4, THF, 0 °C, 2 h, 65%. (e) DMP, CH2Cl2, rt, overnight, 70%. Methyl (R)-2-(7-fluoro-1H-indole-2-carboxamido)-3-(trimethylsilyl)propanoate (44) To a solution of 7-fluoro-1H-indole-2-carboxylic acid (500 mg, 2.79 mmol) and amine hydrochloride 25 (0.886 g, 4.18 mmol) in CH2Cl2 (20 mL) at 0 °C was added N-methyl morpholine (0.83 mL, 8.3 mmol). The reaction mixture was stirred at rt for 30 min before addition of HATU (1.1 g, 5.39 mmol). The reaction mixture was stirred at rt overnight, poured into water and extracted with ethyl acetate (10 mL x3). The organic layer was washed with saturated aqueous sodium bicarbonate, brine and then dried over sodium sulfate. After concentration under vacuum, the crude product was purified by flash chromatography (hexane / ethyl acetate - 0-40%) to give 44 (0.656 mg, 70%). 1H NMR (400 MHz, CD3OD): δ 7.34 (d, J = 8.0 Hz, 1H), 7.13 (d, J = 3.2 Hz, 1H), 6.85- 6.96 (m, 2H), 4.61-4.65 (m, 1H), 3.65 (s, 3H), 1.14-1.16 (m, 2H), 0.00 (m, 9H).19F NMR (376 MHz, CD3OD): δ -135.51(m).13C NMR (100 MHz, CD3OD): δ 174.18, 161.72, 148.60, 131.64, 131.17(d, J = 5 Hz), 125.47(d, J = 14Hz), 119.99(d, J= 6Hz), 117.39 (d, J = 4 Hz), 108.00 (d, J = 16 Hz), 104.65(d, J = 3Hz), 51.35, 49.48, 19.24, -2.67. MS calcd for C16H22FN2O3Si (M+H)+: 337.4; found: 337.5. (R)-2-(7-Fluoro-1H-indole-2-carboxamido)-3-(trimethylsilyl)propanoic acid (45) To a solution of ester 44 (100 mg, 0.29 mmol) in THF (3 mL) and water (1 mL) was added lithium hydroxide monohydride (100 mg, 2.38 mmol). The reaction mixture was stirred at rt for 5 h and then acidified to pH 2 by adding 1N HCl. The mixture was extracted with ethyl acetate (5 mL x3). The combined organic layers were washed with brine, dried over sodium sulfate and then concentrated under vacuum to give 45 (92 mg, 97%). 1H NMR (400 MHz, CD3OD): δ 7.32 (d, J = 8.0 Hz, 1H), 7.11 (m, J = 2.8 Hz, 1H), 6.83-6.93 (m, 2H), 4.58-4.62 (m, 1H), 1.14-1.20 (m, 2H), 0.00 (s, 9H).31C NMR (100 MHz, CD3OD): δ 175.60, 161.67, 148.60, 131.79, 131.18(d, J= 5.2Hz), 125.44 (d, J = 13.7 Hz), 119.95 (d, J = 5.9 Hz), 117.37 (d, J = 3.6 Hz), 107.94 (d, J = 16.2Hz), 104.62(d, J =2.0 Hz). 49.33, 19.43, -2.59.19F NMR (376 MHz, CD3OD): δ -135.58 (m). MS calcd for C15H20FN2O3Si (M+H)+: 323.4; found: 323.4. Methyl (S)-2-((R)-2-(7-fluoro-1H-indole-2-carboxamido)-3-(trimethylsilyl)propanamido)-3- ((S)-2-oxopyrrolidin-3-yl) propanoate (46) To a solution of acid 45 (62 mg, 0.19 mmol) and amine hydrochloride 5 (59 mg, 0.29 mmol) in CH2Cl2(3 mL) at 0 °C was added N-methyl morpholine (0.2 mL, 1.8 mmol). The reaction mixture was stirred at rt for 30 min before addition of HATU (300 mg, 0.78 mmol). The reaction mixture was stirred at rt overnight, poured into water and extracted with ethyl acetate (5 mL x3). The organic layer was washed with saturated aqueous sodium bicarbonate, brine and then dried over sodium sulfate. After concentration under vacuum, the crude product was purified by flash chromatography (dichloromethane / methanol: 0-10%) to give 46 (45 mg, 48%). 1H NMR (400 MHz, CD3OD): δ 7.30-7.33 (m, 1H), 7.098-7.091 (d, J = 2.8 Hz, 1H), 6.83-6.94 (m, 2H), 4.57-4.63 (m, 1H), 4.38-4.47 (m, 1H), 3.62 (s,3H), 3.10-3.21 (m, 2H), 2.21- 2.32 (m, 1H), 2.00-2.18 (m, 2H), 1.64-1.75 (m, 2H), 1.07-1.18 (m, 2H), -0.01-0.00 (2s, 9H).19F NMR (376 MHz, CD3OD): -135.54 (m);13C NMR (100 MHz, CD3OD): δ 180.37, 174.82, 172.27, 161.55, 148.59, 131.76, 131.15(d, J = 5Hz), 125.44 (d, J = 13 Hz), 119.99 (d, J= 6Hz), 117.38 (d, J = 4Hz), 107.98 (d, J = 16Hz), 104.69, 51.44, 50.46 (d, J = 9 Hz), 40.02, 38.16, 32.51, 27.26, 19.50, -2.51; MS calcd for C23H32FN4O5Si (M+H)+: 491.6; found: 491.5. 7-Fluoro-N-((R)-1-(((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl) propan-2-yl) amino)-1-oxo- 3-(trimethylsilyl) propan-2-yl)-1H-indole-2-carboxamide (47) To a solution of ester 46 (100 mg, 0.2 mmol) in THF (6 mL) was added lithium borohydride (0.6 ml, 1.2 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 2 h before addition of ethyl acetate (15 mL). The reaction was then quenched by addition of 1N HCl (15 mL) at 0 °C. The mixture was extracted with ethyl acetate (8 mL x3) and the combined organic layers washed with water, saturated aqueous sodium bicarbonate, brine and then dried over sodium sulfate. After concentration under vacuum, the crude product was purified by flash chromatography (dichloromethane / methanol - 0-10%) to afford 47 (61 mg, 65%). 1H NMR (400 MHz, CD3OD): δ 7.31-7.32 (m, 1H), 7.15-7.17 (d, J = 7.6 Hz, 1H), 7.09 (d, J = 3.2Hz, 1H), 6.83-6.92 (m, 2H), 4.53-4.57 (m, 1H), 3.87-3.91 (m, 1H), 3.39-3.49 (m, 2H), 3.05-3.15 (m, 2H), 2.16-2.45 (m, 2H), 1.85-1.92 (m,1H), 1.62-1.70 (m,1H), 1.40-1.47 (m, 1H), 1.11-1.14 (m, 2H), 0.00 (s, 9H).19F NMR (376 MHz, CD3OD): δ -135.48 (m).13C NMR (100 MHz, CD3OD): δ 181.32, 174.81, 161.56, 148.58, 131.78, 131.15 (d, J = 5.0 Hz), 125.45 (d, J = 14 Hz), 120.00 (d, J = 6 Hz), 117.37 (d, J = 3Hz), 107.98 (d, J = 16Hz),104.66, 64.05, 50.76, 49.23, 40.08, 38.19, 32.12, 27.56, 19.76, -2.45. MS calcd for C22H32FN4O4Si (M+H)+: 663.6; found: 463.5. 7-Fluoro-N-((R)-1-oxo-1-(((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl) propan-2-yl) amino)-3- (trimethylsilyl) propan-2-yl)-1H-indole-2-carboxamide (48) A solution of alcohol 47 (30 mg, 0.062 mmol) and DMP (60 mg, 0.14 mmol) in CH2Cl2 (4 mL) was stirred overnight at rt. The reaction mixture was concentrated under vacuum and the crude product was purified directly by flash chromatography (dichloromethane / methanol - 0-10%) to afford 48 (21 mg, 70%). 1H NMR (400 MHz, CD3OD): δ 7.32 (d, J = 8.0 Hz, 1H), 7.08-7.09 (m, 1H), 6.83-6.94 (m, 2H), 4.54-4.59 (m, 1H), 4.38-4.44 (m, 1H), 3.80-4.00 (m, 1H), 3.02-3.15 (m, 2H), 2.15- 2.37 (m, 2H), 1.39-1.52 (m, 2H), 1.08-1.18 (m, 3H), -0.01-0.00 (2s, 9H).19F NMR (376 MHz, CD3OD): δ -135.51 (m);13C NMR (100 MHz, CD3OD): δ 181.37, 174.94 (d, J = 6Hz), 161.62, 148.60, 131.73, 131.16 (d, J = 5Hz), 125.48 (d, J = 14 Hz), 120.01(d, J = 6Hz), 117.38 (d, J = 4Hz), 107.99(d, J = 17Hz), 104.59, 97.99 (d, J = 9Hz), 51.56, 50.84, 40.05, 37.98, 29.58, 27.47, 19.65, -2.47. MS calcd for C22H30FN4O4Si (M+H)+: 461.5; found: 461.5.

[0007] Scheme 9 - Reagents and conditions: (a) NH3 / CH3OH, rt, overnight, quantitative yield. (b) Burgess reagent, CH2Cl2, rt, overnight, 76%. N-((R)-1-(((S)-1-Amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-1-oxo-3- (trimethylsilyl)propan-2-yl)-7-fluoro-1H-indole-2-carboxamide (49) A solution of ester 46 (50 mg, 0.10 mmol) and NH3 in CH3OH (4 mL) was stirred at rt overnight. The reaction mixture was evaporated in vacuo and co-evaporated with methanol to give 49 (48 mg, 100%). 1H NMR (400 MHz, CD3OD): δ 7.32 (d, J = 8 Hz, 1H), 7.11-7.12 (m, 1H), 6.84-6.94 (m, 2H), 4.51-4.59 (m, 1H), 4.29-4.39 (m, 1H), 3.08-3.19 (m, 2H), 2.33-2.41 (m, 1H), 2.01- 2.24 (m, 2H), 1.66-1.77 (m, 2H), 1.13-1.15 (m, 2H), 0.007, 0.00 (2s, 9H).19F NMR (376 MHz, CD3OD): δ -135.36 (m);13C NMR (100 MHz, CD3OD): δ 180.61, 175.07, 174.76, 161.89, 161.62, 148.58, 131.67, 131.15 (d, J = 5.3 Hz), 125.48 (d, J = 13.5Hz), 120.01 (d, J = 5.9 Hz), 117.41 (d, J = 3.4 Hz), 108.03(d, J = 16 Hz), 104.80(d, J = 2 Hz), 51.47, 50.98, 40.09, 38.37, 33.29, 27.43, 19.29, -2.47. LCMS calcd for C22H31FN5O4Si (M+H)+: 476.6; found: 476.5. 7-Fluoro-N-((R)-1-(((S)-1-cyano-2-((S)-2-oxopyrrolidin-3-yl) ethyl) amino)-1-oxo-3- (trimethylsilyl) propan-2-yl)-1H-indole-2-carboxamide (50) To a solution of amide 49 (48 mg, 0.10 mmol) in CH2Cl2 (4 mL) at 0 °C was added Burgess reagent (60 mg, 0.25 mmol). The reaction mixture was stirred at rt overnight and after evaporation under vacuum, the crude product was purified by flash chromatography (dichloromethane / methanol - 0-8%) to give 50 (35 mg, 76%). 1H NMR (400 MHz, CD3OD): δ 7.30-7.32 (m, 1H), 7.095 (d, J = 3.2 Hz, 1H), 6.82-6.92 (m, 2H), 4.88-4.95 (m, 1H), 4.50-4.54 (m, 1H), 3.12-3.18 (m, 2H), 2.21-2.51 (m, 3H), 1.66- 1.83 (m, 2H), 1.10-1.12 (m, 2H), 0.00, -0.01 (2s, 9H).19F NMR (376 MHz, CD3OD): δ -135.54 (m);13C NMR (100 MHz, CD3OD): δ 179.59, 174.28, 161.65, 148.59, 131.67, 131.15 (d, J= 5Hz), 125.46 (d, J = 14 Hz), 120.00 (d, J = 6 Hz), 118.35 (d, J= 4 Hz), 117.39 (d, J = 3 Hz), 108.00 (d, J = 16 Hz), 104.77, 50.46, 40.02, 38.49, 37.69, 33.75, 27.14, 19.36, -2.52. MS calcd for C22H29FN5O3Si (M+H)+: 458.5; found: 458.5. Scheme 10 - Reagents and conditions: (a) 5,7-Difluoroindole-2-carboxylic acid, HATU, N-methyl morpholine, CH2Cl2, rt, overnight, 38%. (b) lithium hydroxide monohydrate, THF / H2O (V / V, 5:1), rt, 4 h, 95%. (c) HATU, N-methyl morpholine, CH2Cl2, rt, 56%. (d) LiBH4, THF, 0 °C, 2 h, 45%. (e) DMP, CH2Cl2, rt, overnight, 62%. Methyl (R)-2-(5,7-difluoro-1H-indole-2-carboxamido)-3-(trimethylsilyl)propanoate (51) To a solution of 5,7-difluoro-1H-indole-2-carboxylic acid (600 mg, 3.04 mmol) and amine hydrochloride 25 (902 mg, 4.26 mmol) in CH2Cl2 (20 mL) at 0 °C was added N-methyl morpholine (0.85 mL, 8.5 mmol). The reaction mixture was stirred at rt for 30 min before addition of HATU (1.7 g, 4.47 mmol). The reaction mixture was stirred at rt overnight, poured into water and extracted with ethyl acetate (8 mL x3). The organic layer was washed with saturated aqueous sodium bicarbonate, brine and then dried over sodium sulfate. After concentration under vacuum, the crude product was purified by flash chromatography (hexane / ethyl acetate - 0-40%) to give 51 (0.388 g, 38%).1H NMR (400 MHz, CD3OD): δ 7.11 (d, J = 3.2 Hz, 1H), 7.08 (dd, J = 9.2 Hz, J = 2.0 Hz, 1H), 6.76-6.82 (m, 1H), 4.61-4.65 (m, 1H), 3.65 (s, 3H), 1.14-1.16 (m, 2H), 0.00 (m, 9H).19F NMR (376 MHz, CD3OD): δ -123.17 (m), -131.33 (m).31C NMR (100 MHz, CD3OD): δ 174.12, 161.35, 155.80, 147.95, 133.21, 129.82 (q, J = 6 Hz), 122.20(d, J = 13 Hz), 104.52 (q, J = 2 Hz), 101.41(dd, J = 4 Hz, J = 23 Hz), 98.51(q, J = 21 Hz), 51.37, 49.50, 19.22, -2.67. MS calcd for C16H21F2N2O3Si (M+H)+: 355.4; found: 355.5. (R)-2-(5,7-Difluoro-1H-indole-2-carboxamido)-3-(trimethylsilyl)propanoic acid (52) To a solution of ester 51 (400 mg, 1.12 mmol) in THF (10 mL) and water (2 mL) was added lithium hydroxide monohydride (400 mg, mmol). The reaction mixture was stirred at rt for 4 h and then acidified to pH 2 by adding 1N HCl. The mixture was extracted with ethyl acetate (8 mL x3). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under vacuum to give 52 (360 mg, 95%). 1H NMR (400 MHz, CD3OD): δ 7.09 (d, J = 3.2 Hz, 1H), 7.04-7.06 (m, 1H), 6.74-6.80 (m, 1H), 4.58-4.62 (m, 1H), 1.14-1.18 (m, 2H), 0.00 (s, 9H).31C NMR (100 MHz, CD3OD): δ 175.53, 161.31, 155.78, 147.94, 133.37, 129.83 (q, J = 6.6 Hz), 122.17 (d, J = 13.5 Hz), 104.48 (q, J = 2.4 Hz), 101.39 (dd, J = 4.4 Hz, J = 23.3 Hz), 98.43(q, J = 20.6 Hz), 49.34, 19.38, -2.60.19F NMR (376 MHz, CD3OD): δ -123.24 (t, J = 9.77 Hz), -131.41 (t, J = 11.2 Hz). MS calcd for C15H18FN2O3Si (M+H)+: 341.4; found: 341.3. Methyl (S)-2-((R)-2-(5,7-fluoro-1H-indole-2-carboxamido)-3-(trimethylsilyl)propanamido)-3- ((S)-2-oxopyrrolidin-3-yl) propanoate (53) To a solution of acid 52 (140 mg, 0.41 mmol) and amine hydrochloride 5 (200 mg, 0.8 mmol) in CH2Cl2 (5 mL) and DMF (0.5 mL) at 0 °C was added N-methyl morpholine (0.2 mL, 2.0 mmol). The reaction mixture was stirred at rt for 30 min before addition of HATU (550 mg, 1.44 mmol). The reaction mixture was stirred at rt overnight, poured into water and extracted with ethyl acetate (8 mL x3). The combined organic layer was washed with saturated aqueous sodium bicarbonate, brine and then dried over sodium sulfate. After concentration under vacuum, the crude product was purified by flash chromatography (dichloromethane / methanol - 0-8%) to give 53 (117 mg, 56%).1H NMR (400 MHz, CD3OD): δ 7.02-7.07 (m, 2H), 6.73-6.80 (m, 1H), 4.59-4.64 (m, 1H), 4.36-4.48 (m, 1H), 3.62 (s, 3H), 3.05-3.19 (m, 2H), 2.01-2.51 (m, 3H), 1.65-1.76 (m, 2H), 1.08-1.15 (m, 2H), -0.01, 0.00 (2s, 9H).19F NMR (376 MHz, CD3OD): δ -123.17 (q, J = 9.4Hz), -131.41 (t, J = 11.2Hz).13C NMR (100 MHz, CD3OD): δ 180.35, 174.81, 172.27, 161.17, 158.03, 150.24, 133.35, 129.84(t, J = 12.0 Hz), 122.13 (t, J = 5.0 Hz), 104.59, 101.52 (d, J = 23.0 Hz), 98.47 (dd, J = 20.0 Hz, J = 31.0 Hz), 51.46, 50.83, 50.45, 40.05, 38.17, 32.54, 27.27, 19.49, -2.48. MS calcd for C23H31F2N4O5Si (M+H)+: 509.6; found: 509.5. 5, 7-Difluoro-N-((R)-1-(((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl) propan-2-yl) amino)-1- oxo-3-(trimethylsilyl) propan-2-yl)-1H-indole-2-carboxamide (54) To a solution of ester 53 (60 mg, 0.11 mmol) in THF (4 mL) was added lithium borohydride (0.4 ml, 0.8 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 2 h and ethyl acetate (8 mL) was added. The reaction was then quenched by addition of 1N HCl at 0 °C. The mixture was extracted with ethyl acetate (5 mL x3) and the combined organic layers washed with water, saturated aqueous sodium bicarbonate, brine and then dried over sodium sulfate. After concentration under vacuum, the crude product was purified by flash chromatography (dichloromethane / methanol - 0-10%) to afford 54 (25 mg, 45%). 1H NMR (400 MHz, CD3OD): δ 7.04-7.07 (m, 2H), 6.74-6.80 (m, 1H), 4.53-4.58 (m, 1H), 3.890-3.895 (brs, 1H), 3.39-3.49 (m,2H), 3.06-3.16 (m, 2H), 2.19-2.42 (m, 2H), 1.82-1.92 (m,1H), 1.63-1.72 (m,1H), 1.41-1.47 (m, 1H), 1.12-1.14 (m, 2H), 0.00 (s, 9H).19F NMR (376 MHz, CD3OD): δ -123.16 (t, J = 9.02 Hz), -131.33 (m).13C NMR (100 MHz, CD3OD): δ 181.33, 174.77 , 161.27 (d, J = 8.8 Hz), 155.80, 150.28, 133.35, 129.87, 122.21 (d, J = 13.1 Hz), 104.59, 101.53 (d, J = 23.4 Hz), 98.49 (dd, J = 20.4 Hz, J = 31.5 Hz), 64.04, 50.94 (d, J = 29.7 Hz), 49.33 (d, J = 17.6 Hz), 40.11, 38.20 , 32.20 (d, J = 12.3 Hz), 27.56, 19.88 (d, J = 28.5 Hz), -2.45. MS calcd for C22H30F2N4O4Si (M+H)+: 481.5; found: 481.5. 5,7-Difluoro-N-((R)-1-oxo-1-(((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl) propan-2-yl) amino)-3- (trimethylsilyl) propan-2-yl)-1H-indole-2-carboxamide (55) A solution of alcohol 54 (30 mg, 0.062 mmol) and DMP (60 mg, 0.14 mmol) in CH2Cl2(3 mL) was stirred overnight at rt. The reaction mixture was concentrated under vacuum and the crude product was purified by flash chromatography (dichloromethane / methanol: 0-10%) to afford 55 (18.5 mg, 62%). 1H NMR (400 MHz, CD3OD): δ 7.04-7.08 (m, 2H), 6.73-6.80 (m, 1H), 4.55-4.59 (m, 1H), 4.39-4.46 (m, 1H), 3.83-4.00 (m, 1H), 3.05-3.19 (m, 2H), 2.05-2.43 (m, 2H), 1.85-1.96 (m, 1H), 1.39-1.69 (m, 2H), 1.09-1.18 (m, 2H), 0.00 (2s, 9H).19F NMR (376 MHz, CD3OD): δ -123.11 (t, J = 9.4 Hz), -131.28 (q, J = 8.6 Hz).13C NMR (100 MHz, CD3OD): 181.40, 174.91, 161.26, 155.82, 150.28, 104.54, 101.54 (d, J = 23 Hz), 98.52 (m), 98.05, 51.59, 50.86, 40.11, 38.08(d, J = 15.0 Hz), 29.59 (m), 27.52 (d, J = 20.0 Hz), 19.58 (m), -2.45. MS calcd for C22H29F2N4O4Si (M+H)+: 479.5; found: 479.6. Scheme 11 - Reagents and conditions: (a) NH3 / CH3OH, rt, 24 h, quantitative yield. (b) Burgess reagent, CH2Cl2, rt, overnight, 65%. N-((R)-1-(((S)-1-Amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-1-oxo-3- (trimethylsilyl)propan-2-yl)-5,7-difluoro-1H-indole-2-carboxamide (56) A solution of ester 53 (100 mg, 0.19 mmol) and NH3in CH3OH (10 mL) was stirred at rt for 24 h. The reaction mixture was evaporated in vacuo and co-evaporated with methanol to give 56 (97 mg, quantitative yield). 1H NMR (400 MHz, CD3OD): δ 7.04-7.10 (m, 2H), 6.75-6.80 (m, 1H), 4.51-4.58 (m, 1H), 4.29-4.40 (m, 1H), 3.10-3.18 (m, 2H), 2.01-2.48 (m, 3H), 1.67-1.79 (m, 2H), 1.14-1.16 (m, 2H), 0.00 (s, 9H).19F NMR (376 MHz, CD3OD): δ -123.10 (q, J = 7.5 Hz), -131.25 (d, J = 11.28 Hz).13C NMR (100 MHz, CD3OD): δ 180.62, 175.06, 174.69, 161.42, 158.04, 150.26, 133.19 (d, J = 7.3 Hz), 129.85 (q, J = 7.4 Hz), 122.21 (d, J = 13.4 Hz), 104.70 (t, J = 2.7 Hz), 101.42 (dd, J = 4.1 Hz, J = 23.3 Hz), 98.53(q, J = 20.4 Hz), 51.47, 50.98, 40.10, 38.37, 33.16, 27.35, 19.29 (d, J = 3.0 Hz), -2.47. LCMS calcd for C22H30F2N5O4Si (M+H)+: 494.5; found: 494.5. 5,7-Difluoro-N-((R)-1-(((S)-1-cyano-2-((S)-2-oxopyrrolidin-3-yl) ethyl) amino)-1-oxo-3- (trimethylsilyl) propan-2-yl)-1H-indole-2-carboxamide (57) To a solution of amide 56 (40 mg, 0.08 mmol) in CH2Cl2 (3 mL) at 0 °C was added Burgess reagent (48 mg, 0.2 mmol). The reaction mixture was stirred at rt overnight before addition of more Burgess reagent (24 mg, 0.1 mmol). After 12h, the reaction mixture was evaporated under vacuum and the crude product purified by flash chromatography, using dichloromethane / methanol (0-8%), to give 57 (25 mg, 65%). 1H NMR (400 MHz, CD3OD): δ 7.03-7.07 (m, 2H), 6.74-6.79 (m, 1H), 4.88-4.95 (m, 1H), 4.50-4.54 (m, 1H), 3.02-3.16 (m, 2H), 2.13-2.28 (m, 3H), 1.68-1.84 (m,2H), 1.10-1.16 (m, 2H), 0.00, -0.01 (2s, 9H).19F NMR (376 MHz, CD3OD): δ -123.20 (q, J = 9.4 Hz), -131.43 (t, J = 2.25 Hz).13C NMR (100 MHz, CD3OD): δ 179.61, 174.24, 161.29, 155.80, 150.27, 133.24, 129.81 (t, J = 6.0 Hz), 122.21 (d, J = 10 Hz), 118.34 (d, J = 4.0 Hz), 104.68, 101.54 (d, J = 23 Hz), 98.51(q, J = 20 Hz), 50.49, 40.04 (d, J = 4 Hz), 38.50, 37.69, 33.74, 27.14, 19.34, -2.53. MS calcd for C22H28F2N5O3Si (M+H)+: 476.5; found: 476.5. Scheme 12 - Reagents and conditions: (a) 4,6,7-Trifluoroindole-2-carboxylic acid, HATU, N-methyl morpholine, CH2Cl2, rt, overnight, 75%. (b) Lithium hydroxide monohydrate, THF / H2O (V / V, 5:1), rt, 5 h, 95%. (c) HATU, N-methyl morpholine, CH2Cl2, rt, 31%. (d) NH3 / CH3OH, rt, overnight, 77%. (e) Burgess reagent, CH2Cl2, rt, overnight, 51%. Methyl (R)-2-(4,6,7-trifluoro-1H-indole-2-carboxamido)-3-(trimethylsilyl)propanoate (58) To a solution of 4,6,7-trifluoro-1H-indole-2-carboxylic acid (1 g, 4.64 mmol) and amine hydrochloride 5 (1.7 g, 8.02 mmol) in CH2Cl2 (40 mL) at 0 °C was added N-methyl morpholine (1.6 mL, 16 mmol). The reaction mixture was stirred at rt for 30 min before addition of HATU (4.2 g, 10.78 mmol). The reaction mixture was stirred at rt overnight, poured into water and extracted with ethyl acetate (10 mL x3). The organic layer was washed with saturated aqueous sodium bicarbonate, brine and then dried over sodium sulfate. After concentration under vacuum, the crude product was purified by flash chromatography (hexane / ethyl acetate - 0- 40%) to give 58 (1.3 g, 75%) which was used as is in the next step. (R)-2-(4,6,7-Trifluoro-1H-indole-2-carboxamido)-3-(trimethylsilyl)propanoic acid (59) To a solution of ester 58 (500 mg, 1.34 mmol) in THF (10 mL) and water (2 mL) was added lithium hydroxide monohydride (500 mg,11.9 mmol). The reaction mixture was stirred at rt for 4 h and then acidified to pH 2 by adding 1N HCl. The mixture was extracted with ethyl acetate (10 mL x3). The combined organic layers were washed with brine and then dried over sodium sulfate. After concentration under vacuum compound 59 (457 mg, 95%) was used in the next step without further purification. Methyl (S)-2-((R)-2-(4,6,7-trifluoro-1H-indole-2-carboxamido)-3- (trimethylsilyl)propanamido)-3-((S)-2-oxopyrrolidin-3-yl) propanoate (60) To a solution of acid 59400 mg, 1.11 mmol) and amine hydrochloride 5 (372 mg, 1.67 mmol) in CH2Cl2(15 mL) and DMF (1.5 mL) at 0 °C was added N-methyl morpholine (0.33 mL, 3.3 mmol). The reaction mixture was stirred at rt for 30 min before addition of HATU (840 mg, 2.2 mmol). The reaction mixture was stirred at rt overnight, poured into water and extracted with ethyl acetate (10 mL x3). The combined organic layer was washed with saturated aqueous sodium bicarbonate, brine and then dried over sodium sulfate. After concentration under vacuum, the crude product was purified by flash chromatography (dichloromethane / methanol: 0-10%) to give 60 (180 mg, 31%). 1H NMR (400 MHz, CD3OD): δ 7.10-7.15 (m, 1H), 6.65-6.73 (m, 2H), 4.56-4.62 (m, 1H), 4.38-4.49 (m, 1H), 3.63 (s, 1H), 3.11-3.17 (m, 1H), 2.47-2.50 (m, 1H), 2.02-2.25 (m, 3H), 1.64-1.77 (m, 2H), 1.11-1.18 (m, 2H), -0.01-0.00 (2s, 9H).19F NMR (376 MHz, CD3OD): δ - 124.98 (m), -145.18 (m), -165.65 (m).13C NMR (100 MHz, CD3OD): δ 180.37, 175.13, 172.32, 160.67, 152.36 (d, J = 10 Hz), 149.90 (d, J = 11 Hz), 147.06 (d, J = 11 Hz), 144.62 (d. J = 11 Hz), 135.45 (d, J = 16 Hz), 132.89 (t, J = 16 Hz), 126.75 (m), 115.33 (d, J = 25 Hz), 100.02, 51.53, 50.46 (d, J = 4 Hz), 40.08, 38.16, 32.62, 27.26, 19.39, -2.43. MS calcd for C23H30F3N4O5Si (M+H)+: 527.5; found: 527.5. N-((R)-1-(((S)-1-Amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-1-oxo-3- (trimethylsilyl)propan-2-yl)-4,6,7-trifluoro-1H-indole-2-carboxamide (61) A solution of ester 60 (60 mg, 0.11 mmol) and NH3in CH3OH (6 mL) was stirred at rt overnight. The reaction mixture was evaporated in vacuo and the crude product was purified by flash chromatography (CH2Cl2 / CH3OH: 0-10%) to give 61 (45 mg, 77%). 1H NMR (400 MHz, CD3OD): δ 7.152-7.156 (m, 1H), 6.67-6.73 (m, 1H), 4.51-4.57 (m, 1H), 4.35-4.39 (m, 1H), 3.01-3.18 (m, 2H), 2.42-2.47 (m, 1H), 2.21-2.26 (m, 1H), 2.02-2.10 (m, 1H), 1.67-1.79 (m, 2H), 1.13-1.17 (m, 2H), 0.00 (s, 9H).19F NMR (376 MHz, CD3OD): δ -125.10 (q, J = 9.0 Hz), -145.22 (q, J = 11.2 Hz), -165.72 (t, J = 15.0 Hz).13C NMR (100 MHz, CD3OD): δ 180.64, 175.05, 174.70, 161.02, 150.11, 144.84, 133.26, 132.80, 126.97 (d, J= 5.1Hz), 115.58 (d, J = 24.3 Hz), 100.23, 95.52 (t, J = 25.4 Hz), 51.48, 50.99, 40.11, 38.38, 33.34, 27.44, 19.22, -2.49. LCMS calcd for C22H29F3N5O4Si (M+H)+: 512.5; found: 512.5. 4,6,7-trifluoro-N-((R)-1-(((S)-1-Cyano-2-((S)-2-oxopyrrolidin-3-yl) ethyl) amino)-1-oxo-3- (trimethylsilyl) propan-2-yl)-1H-indole-2-carboxamide (62) To a solution of amide 61 (30 mg, 0.058 mmol) in CH2Cl2(6 mL) at 0 °C was added Burgess reagent (50 mg, 0.21 mmol). The reaction mixture was stirred at rt overnight before addition of more of Burgess reagent (25 mg, 0.1 mmol). After 12 h, the reaction mixture was evaporated under vacuum and the crude product was purified by flash chromatography (dichloromethane / methanol (0-8%)) to give 62 (15 mg, 51%). 1H NMR (400 MHz, CD3OD): δ 7.10-7.15 (m, 1H), 6.64-6.70 (m, 1H), 4.88-4.97 (m, 1H), 4.49-4.53 (m, 1H), 3.14-3.20 (m, 2H), 2.15-2.54 (m, 3H), 1.68-1.83 (m, 2H), 1.08-1.16 (m, 2H), 0.00, -0.01 (2s, 9H).19F NMR (376 MHz, CD3OD): δ -125.03 (m), -145.21 (m), - 165.77 (m).13C NMR (100 MHz, CD3OD): δ 179.60, 174.32, 160.79, 150.10, 147.11, 135.63, 132.78, 126.96, 118.38, 115.57 (d, J = 24 Hz), 100.18, 95.63 (d, J = 25 Hz), 50.51, 40.04, 38.52, 37.69, 33.78, 27.14, 19.29, -2.52. MS calcd for C22H27F3N5O3Si (M+H)+: 494.5; found: 494.5. Scheme 13 Reagents and conditions: (a) EtOH, 60oC, MTBE, rt.16 h. (b) MTBE, 1N HCl, rt.1 h, 32% over two steps. (c) HATU, DIPEA, DCM, rt.71%. (d) 4N HCl in Dioxane. (e) R1-COOH, HATU, DIPEA, CH2Cl2, rt, overnight, 55-66%. (f) Burgess reagent, CH2Cl2, rt, overnight, 59-81%.

[0008] Scheme 14 Reagents and conditions: (a) R2COCl, Et3N, DCM, rt, 46-62%. (b) Burgess reagent, CH2Cl2, rt, overnight, 59-81%. (1R)-2-hydroxy-1-phenylethanaminium (5R)-1-(tert-butoxycarbonyl)-3,3-dimethyl-1,3- azasilolidine-5-carboxylate. (65) and (1S)-2-hydroxy-1-phenylethanaminium (5S)-1-(tert- butoxycarbonyl)-3,3- dimethyl-1,3-azasilolidine-5-carboxylate. (74) were prepared by following the procedures reported in Chung, J. Y. L.; Shevlin, M.; Klapars, A.; Journet,M. Org. Lett.2016, 18, 1812−1815. tert-Butyl (R)-5-(((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)carbamoyl)- 3,3-dimethyl-1,3-azasilolidine-1-carboxylate (67) To a solution of acid (R)-1-(tert-butoxycarbonyl)-3,3-dimethyl-1,3-azasilolidine-5- carboxylic acid 65 (350 mg, 1.35 mmol) and amine hydrochloride 66 (280 mg, 1.35 mmol) in CH2Cl2 (10 mL) was added DIPEA (0.71 mL, 4.05 mmol). After 20 min, HATU (530 mg, 1.39 mmol) was added. The resulting mixture was stirred at room temperature overnight before being quenched with 1N HCl (5 mL). The suspension was extracted with DCM (10 mL x3). The combined organic layers were washed with saturated sodium bicarbonate, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (DCM / MeOH = 30:1 to 15:1) to give 67 (395 mg, 71%). 1H NMR (400 MHz, Chloroform-d) δ 7.89 – 7.27 (m, 1H), 7.07 (d, J = 77.6 Hz, 2H), 6.33 (d, J = 65.0 Hz, 1H), 4.50 – 4.10 (m, 2H), 3.58 – 3.33 (m, 5H), 3.14 – 2.96 (m, 2H), 2.75 – 2.40 (m, 2H), 2.23 (q, J = 7.8 Hz, 1H), 2.12 (dtd, J = 15.7, 8.4, 7.7, 2.9 Hz, 1H), 1.96 – 1.67 (m, 1H), 1.60 (dq, J = 12.5, 8.7 Hz, 1H), 1.22 (s, 9H), 1.06 (dd, J = 14.9, 9.9 Hz, 1H), 0.97 – 0.75 (m, 1H), 0.01 and 0.03 (2d, 6H).13C NMR (101 MHz, CDCl3) δ 182.99, 177.27, 176.91, 159.58, 82.39, 63.70, 56.78, 55.97, 54.85, 44.96, 43.06, 40.96, 37.40, 35.44, 19.57, 18.54, 14.82, -0.00, -0.23. HRMS m / z calcd for C18H33N4O5Si [(M +H)]+: 413.2220; found 413.2235. (R)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-1-(4,6-difluoro-1H- indole-2-carbonyl)-3,3-dimethyl-1,3-azasilolidine-5-carboxamide (69a) General Procedure A To a solution of compound 67 (570 mg, 1.38 mmol) in 5 mL of DCM was added HCl (4N in dioxane, 2.5 mL, 10 mmol). The reaction mixture was stirred for 2 h at room temperature and then concentrated under vacuum. The crude HCl salt 68 was dried under high vacuum overnight. A solution of the crude HCl salt 68 (35 mg, 0.1 mmol) and 4,6-difluoroindole-2- carboxylic acid (21.6 mg, 0.11 mmol) in DCM (0.8 mL) was treated with HATU (49 mg, 0.1 mmol) and N,N-diisopropylethylamine (39 mg, 0.3 mmol) at 0oC. The ice bath was removed, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was then diluted with DCM (10 mL) and washed with 1N HCl (2 mL), NaHCO3(5% aqueous solution, 3mL) and brine (3 mL). The organic layer was separated and dried over MgSO4. The solvent was evaporated, and the crude mixture was purified by chromatography (DCM / MeOH 30:1 to 10:1) to afford 69a (27 mg, 55%). 1H NMR (400 MHz, Methanol-d4) δ 7.01 (s, 1H), 6.78 (dd, J = 9.5, 2.0 Hz, 1H), 6.42 (td, J = 10.2, 2.1 Hz, 1H), 4.82 (dd, J = 9.6, 5.3 Hz, 1H), 4.41 (s, 1H), 4.23 – 4.13 (m, 1H), 3.16 (s, 2H), 3.08 – 2.96 (m, 3H), 2.41 (d, J = 10.9 Hz, 1H), 2.10 (s, 1H), 1.91 (ddd, J = 14.0, 11.7, 4.8 Hz, 1H), 1.61 (q, J = 11.6, 9.5 Hz, 2H), 1.26 – 1.11 (m, 2H), 0.97 (dd, J = 15.2, 5.3 Hz, 1H), 0.13 (s, 3H), 0.07 (s, 3H). 13C NMR (101 MHz, MeOD) δ 180.85, 175.43, 175.07, 163.91, 161.81, 159.43, 157.83, 155.50, 137.57, 137.45, 137.42, 137.30, 131.35, 131.32, 113.83, 113.61, 102.33, 95.02, 94.79, 94.72, 94.49, 93.76, 93.51, 62.24, 53.43, 51.62, 40.15, 38.45, 37.67, 32.96, 27.47, 15.11, -4.18, -4.25.19F NMR (377 MHz, Methanol-d4) δ -117.24 (d, J = 5.4 Hz), -119.86 (d, J = 5.3 Hz). HRMS m / z calcd for C22H28F2N5O4Si [(M +H)]+: 492.1879 ; found 492.1888. (R)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-1-(7-chloro-1H-indole-2- carbonyl)-3,3-dimethyl-1,3-azasilolidine-5-carboxamide (69b) Compound 69b was synthesized starting from 67 according to the general procedure A (62% yield). 1H NMR (400 MHz, Chloroform-d) δ 9.90 (s, 1H), 8.43 (d, J = 6.0 Hz, 1H), 7.28 (d, J = 8.0 Hz, 1H), 7.10 – 6.86 (m, 3H), 6.77 (t, J = 7.8 Hz, 1H), 6.26 (s, 1H), 5.96 (s, 1H), 4.82 (dd, J = 9.4, 6.0 Hz, 1H), 4.08 (q, J = 7.4 Hz, 1H), 3.12 – 2.91 (m, 3H), 2.33 – 2.16 (m, 1H), 2.07 (d, J = 15.3 Hz, 1H), 1.74 (q, J = 9.9, 7.6 Hz, 2H), 1.58 – 1.43 (m, 1H), 1.11 (dd, J = 12.9, 5.0 Hz, 4H), 1.07 – 0.86 (m, 1H), 0.09 (s, 3H), -0.00 (s, 3H).13C NMR (101 MHz, CDCl3) δ 180.80, 174.74, 173.91, 164.65, 133.17, 131.47, 129.19, 123.72, 121.06, 120.81, 116.97, 107.85, 62.62, 55.00, 53.41, 50.58, 43.04, 40.85, 38.90, 38.09, 32.53, 28.84, 28.39, 15.38, 12.55, -2.73, -2.86. HRMS m / z calcd for C22H29F2N5O4Si [(M +H)]+: 490.1677; found 490.1656. (R)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-1-(7-fluoro-1H-indole-2- carbonyl)-3,3-dimethyl-1,3-azasilolidine-5-carboxamide (69c) Compound 69c was obtained using general procedure A in 59% yield, using 67 as starting material. 1H NMR (400 MHz, Methanol-d4) δ 7.23 (d, J = 7.8 Hz, 1H), 7.02 (s, 1H), 6.82 – 6.68 (m, 2H), 4.89 – 4.81 (m, 1H), 4.24 – 4.11 (m, 1H), 3.15 (d, J = 6.1 Hz, 2H), 3.05 (d, J = 7.7 Hz, 1H), 2.40 (d, J = 10.4 Hz, 1H), 2.10 (s, 1H), 1.98 – 1.86 (m, 1H), 1.66 – 1.54 (m, 2H), 1.22 (d, J = 12.8 Hz, 1H), 1.14 (dd, J = 7.0, 3.5 Hz, 3H), 1.03 – 0.91 (m, 1H), 0.13 (s, 3H), 0.06 (s, 3H).13C NMR (101 MHz, MeOD) δ 180.81, 164.59, 150.87, 148.43, 131.70, 131.39, 124.64, 124.50, 119.90, 117.54, 108.03, 107.87, 107.11, 62.04, 54.44, 51.65, 42.40, 40.15, 38.46, 37.83, 32.98, 27.50, 27.37, 17.31, 15.88, 15.17, 11.79, -4.23, -4.30.19F NMR (377 MHz, MeOD) δ -135.43. HR-MS m / z calcd for C22H29FN5O4Si [(M +H)]+: 474.1973 ; found 474.1948. (R)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-1-(5,7-difluoro-1H- indole-2-carbonyl)-3,3-dimethyl-1,3-azasilolidine-5-carboxamide (69d) Compound 69d was synthesized in 63% yield according to the general procedure A. 1H NMR (400 MHz, Methanol-d4) δ 6.97 (dd, J = 12.0, 6.1 Hz, 2H), 6.64 (ddd, J = 11.4, 9.6, 2.2 Hz, 1H), 4.83 (dd, J = 9.7, 5.5 Hz, 1H), 4.17 (dd, J = 11.8, 4.1 Hz, 1H), 3.22 – 3.09 (m, 3H), 3.08 – 3.02 (m, 1H), 2.40 (d, J = 11.5 Hz, 1H), 2.11 (s, 1H), 1.98 – 1.85 (m, 1H), 1.69 – 1.50 (m, 2H), 1.31 – 1.19 (m, 1H), 1.18 – 1.08 (m, 1H), 0.98 (dd, J = 15.0, 5.6 Hz, 1H), 0.13 (s, 3H), 0.06 (s, 3H).13C NMR (101 MHz, MeOD) δ 180.81, 175.35, 174.98, 164.27, 158.03, 157.94, 155.68, 155.59, 150.25, 150.10, 147.78, 147.64, 133.30, 130.00, 121.40, 121.26, 106.94, 101.69, 101.45, 98.69, 98.39, 98.18, 67.46, 61.97, 54.45, 51.64, 42.40, 40.15, 38.45, 37.80, 33.01, 27.49, 27.36, 25.09, 17.31, 15.87, 15.16, 11.77, -4.27, -4.33.19F NMR (377 MHz, MeOD) δ -123.36, -131.35. HRMS m / z calcd for C22H28F2N5O4Si [(M +H)]+: 492.1879; found 492.1887. (R)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-1-(7-chloro-1H-indole-3- carbonyl)-3,3-dimethyl-1,3-azasilolidine-5-carboxamide (69e) Compound 69e was synthesized in 66% yield according to the general procedure A. 1H NMR (400 MHz, Methanol-d4) δ 7.87 (s, 3H), 7.21 (dd, J = 7.7, 1.0 Hz, 1H), 7.10 (t, J = 7.8 Hz, 1H), 5.05 (dd, J = 9.8, 4.9 Hz, 1H), 3.25 (dt, J = 17.1, 6.3 Hz, 4H), 2.32 (s, 2H), 1.84 (d, J = 42.3 Hz, 2H), 1.42 (dd, J = 14.9, 9.8 Hz, 1H), 1.13 (dd, J = 14.9, 4.9 Hz, 1H), 0.35 (s, 3H), 0.27 (s, 3H).13C NMR (101 MHz, MeOD) δ 179.63, 174.93, 168.80, 132.92, 128.48, 121.59, 121.10, 119.63, 118.52, 116.68, 111.66, 40.03, 38.32, 37.59, 33.84, 27.09, -4.24, -4.38. HRMS m / z calcd for C22H29ClN5O4Si [(M +H)]+: 490.1677 ; found 490.1655. (R)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-1-(1H-indole-3- carbonyl)-3,3-dimethyl-1,3-azasilolidine-5-carboxamide (69f) Compound 69f was synthesized from 67 in 58% yield following the general procedure A. 1H NMR (400 MHz, Methanol-d4) δ 8.51 (s, 1H), 8.01 – 7.78 (m, 2H), 7.43 (d, J = 8.1 Hz, 1H), 7.26 – 7.01 (m, 2H), 5.12 (d, J = 8.1 Hz, 1H), 4.37 (s, 1H), 3.30 – 3.15 (m, 4H), 2.30 (s, 1H), 2.11 (s, 1H), 1.80 (s, 2H), 1.54 – 1.42 (m, 1H), 1.41 – 1.35 (m, 5H), 1.28 – 1.13 (m, 1H), 0.33 (d, J = 2.0 Hz, 3H), 0.26 (d, J = 2.1 Hz, 3H).13C NMR (101 MHz, MeOD) δ 180.71, 175.46, 169.79, 135.89, 122.10, 120.29, 111.25, 110.45, 54.44, 51.62, 42.40, 40.12, 38.41, 33.02, 27.49, 17.33, 15.89, 11.79, -4.25, -4.37. HRMS m / z calcd for C22H30N5O4Si [(M +H)]+: 456.2067; found 456.2090. (R)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-1-(1H- benzo[d]imidazole-2-carbonyl)-3,3-dimethyl-1,3-azasilolidine-5-carboxamide (69g) Compound 69g was obtained from 67 following the general procedure A (61% yield). 1H NMR (400 MHz, Methanol-d4) δ 7.73 (d, J = 8.2 Hz, 2H), 7.58 (d, J = 8.6 Hz, 1H), 7.31 (dd, J = 22.8, 7.3 Hz, 3H), 6.40 (dd, J = 8.5, 3.7 Hz, 1H), 5.11 (dd, J = 10.0, 4.6 Hz, 1H), 4.40 (ddd, J = 34.0, 11.7, 4.0 Hz, 1H), 3.42 – 3.31 (m, 3H), 3.08 (td, J = 9.3, 2.3 Hz, 1H), 2.72 (td, J = 9.4, 7.4 Hz, 1H), 2.42 – 2.24 (m, 1H), 2.22 – 2.07 (m, 1H), 1.90 – 1.76 (m, 2H), 1.75 – 1.58 (m, 2H), 0.31 (d, J = 5.9 Hz, 6H).13C NMR (101 MHz, MeOD) δ 179.69, 179.37, 174.31, 173.96, 161.91, 161.26, 145.93, 142.56, 133.32, 124.52, 122.65, 119.90, 118.47, 111.73, 61.92, 61.31, 40.05, 39.55, 38.34, 37.85, 37.66, 37.51, 37.26, 35.27, 33.92, 33.87, 27.09, 26.38, 17.36, 15.01, -4.22, -4.25, -4.35. HRMS m / z calcd for C21H29N6O4Si [(M +H)]+: 457.2020; found 457.2031. (R)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3,3-dimethyl-1-(3- methylisoxazole-5-carbonyl)-1,3-azasilolidine-5-carboxamide (71a) General Procedure B A solution of the crude HCl salt 68 (35 mg, 0.1 mmol) and 3-methylisoxazole-5- carbonyl chloride (19 mg, 0.13 mmol) in DCM (1.0 mL) was treated with triethylamine (30 mg, 0.3 mmol) at 0oC. The ice bath was removed, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was then diluted with DCM (10 mL) and washed NaHCO3 (5% aqueous solution, 3mL) and brine (3 mL). The organic layer was separated and dried over MgSO4. The solvent was evaporated, and the residue was purified by chromatography (DCM / MeOH 30:1 to 10:1) to afford 71a (23 mg, 55%). 1H NMR (400 MHz, Chloroform-d) δ 8.44 (d, J = 6.5 Hz, 1H), 7.94 (d, J = 6.7 Hz, 1H), 7.28 (d, J = 2.6 Hz, 1H), 6.96 (d, J = 2.5 Hz, 1H), 6.77 (s, 1H), 6.38 (s, 1H), 6.12 (dd, J = 8.0, 1.0 Hz, 2H), 5.87 – 5.76 (m, 1H), 5.67 (d, J = 2.6 Hz, 1H), 4.99 (d, J = 10.0 Hz, 1H), 4.78 (dd, J = 9.7, 4.8 Hz, 1H), 4.22 (dt, J = 9.9, 6.3 Hz, 1H), 4.17 – 4.06 (m, 1H), 3.29 (d, J = 16.0 Hz, 1H), 3.17 (d, J = 14.5 Hz, 1H), 3.12 (s, 2H), 2.96 (d, J = 14.5 Hz, 1H), 2.51 (d, J = 16.1 Hz, 1H), 2.22 (d, J = 5.7 Hz, 8H), 2.14 – 2.04 (m, 1H), 1.88 (dddd, J = 36.9, 14.3, 10.4, 7.5 Hz, 2H), 1.74 (dt, J = 14.4, 5.2 Hz, 2H), 1.58 (dq, J = 12.5, 8.8 Hz, 2H), 1.12 – 0.86 (m, 3H), 0.15 – 0.03 (m, 16H).13C NMR (101 MHz, CDCl3) δ 182.88, 182.76, 176.72, 176.55, 175.26, 174.91, 172.49, 171.90, 165.23, 163.46, 162.03, 161.62, 105.56, 105.20, 65.81, 64.11, 55.84, 54.78, 43.06, 43.02, 40.96, 40.71, 39.89, 36.28, 35.02, 34.88, 30.90, 30.82, 19.64, 17.57, 14.43, -0.00, -0.21, -0.25, -0.51. HRMS m / z calcd for C18H28N5O5Si [(M +H)]+: 422.1860; found 422.1853. (R)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-1-(2-chlorobenzoyl)-3,3- dimethyl-1,3-azasilolidine-5-carboxamide (71b) Compound 71b was obtained using general procedure B (56% yield). 1H NMR (400 MHz, Methanol-d4) δ 7.25 (dd, J = 7.1, 2.6 Hz, 1H), 7.19 (q, J = 3.9, 3.3 Hz, 2H), 4.79 (s, 1H), 4.27 – 4.15 (m, 1H), 3.21 – 3.10 (m, 1H), 2.48 – 2.32 (m, 2H), 2.16 (ddt, J = 10.9, 8.8, 4.5 Hz, 1H), 1.95 (ddd, J = 13.9, 11.6, 4.7 Hz, 1H), 1.70 – 1.51 (m, 2H), 1.20 (td, J = 10.4, 5.3 Hz, 1H), 0.99 (dd, J = 15.1, 4.9 Hz, 1H), 0.16 – 0.03 (m, 4H), -0.00 (s, 2H).13C NMR (101 MHz, MeOD) δ 180.73, 180.16, 175.25, 174.74, 173.81, 170.63, 169.33, 136.98, 136.50, 130.38, 130.21, 129.46, 129.34, 129.31, 127.88, 127.25, 127.02, 62.44, 60.07, 51.45, 51.38, 40.15, 38.38, 33.77, 33.29, 33.18, 27.50, 27.31, 17.74, 15.58, -3.84, -4.21, -4.62. HRMS m / z calcd for C20H28ClN4O4Si [(M +H)]+: 451.1568; found 451.1554. (5R)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-1-(3,3-dimethyl-2- (2,2,2-trifluoroacetamido)butanoyl)-3,3-dimethyl-1,3-azasilolidine-5-carboxamide (71c) Compound 71c was synthesized from 68 following the general procedure B (62% yield). 1H NMR (400 MHz, Chloroform-d) δ 8.67 – 8.46 (m, 1H), 7.59 – 7.47 (m, 1H), 7.12 (d, J = 2.5 Hz, 1H), 6.35 (d, J = 3.4 Hz, 1H), 5.90 (s, 1H), 5.07 (d, J = 9.0 Hz, 1H), 4.94 (dd, J = 10.3, 3.1 Hz, 1H), 4.78 (s, 2H), 4.29 (dt, J = 11.2, 5.8 Hz, 1H), 3.34 (ddd, J = 11.7, 9.2, 6.2 Hz, 2H), 3.20 – 2.99 (m, 2H), 2.47 – 2.26 (m, 6H), 2.01 (dt, J = 14.5, 4.8 Hz, 1H), 1.94 – 1.74 (m, 1H), 1.39 (dd, J = 15.2, 3.1 Hz, 1H), 1.29 – 1.12 (m, 1H), 1.04 (s, 9H), 0.26 (d, J = 8.6 Hz, 6H).13C NMR (101 MHz, CDCl3) δ 180.48, 174.56, 172.58, 172.47, 157.50, 157.13, 117.40, 114.54, 61.66, 57.44, 53.47, 50.67, 40.70, 38.72, 36.60, 36.18, 32.77, 28.76, 26.43, 15.53, -2.56, -2.70.19F NMR (377 MHz, CDCl3) δ -75.54. HRMS m / z calcd for C21H35F3N5O5Si [(M +H)]+: 522.2360; found 522.2378. Benzyl (R)-5-(((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)carbamoyl)-3,3- dimethyl-1,3-azasilolidine-1-carboxylate (71d) Compound 71d was synthesized from 68 following the general procedure B (54% yield). 1H NMR (400 MHz, CDCl3) δ 7.86 (d, J = 6.5 Hz, 1H) and 7.61 (s, 1H), 7.21 – 7.08 (m, 5H), 6.96 and 6.68 (2s, 1H), 6.26 and 6.11 (2s, 1H), 5.44 and 5.32 (2s, 1H), 5.01 – 4.79 (m, 2H), 4.49 and 4.38 (2m, 1H), 4.17 (dt, J = 9.6, 6.4 Hz, 1H), 3.19 – 2.95 (m, 2H), 2.89 – 2.57 (m, 2H), 2.32 – 2.04 (m, 1H), 2.04 – 1.69 (m, 2H), 1.64 – 1.42 (m, 1H), 0.90 (dd, J = 15.0, 4.8 Hz, 1H), 0.70 – 0.57 (m, 1H), 0.03 and 0.0 (2s, 6H).13C NMR (101 MHz, CDCl3) δ 180.58, 174.23, 157.74, 136.79, 128.48, 127.96, 127.62, 67.38, 62.11, 52.82, 40.70, 38.60, 34.83, 32.58, 29.71, 28.89, 16.38, -2.52, -2.71. ESI-MS m / z calcd for C21H31N4O5Si [(M +H)]+: 447.2; found: 447.5. (R)-N-((S)-1-cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)-1-(4,6-difluoro-1H-indole-2-carbonyl)- 3,3-dimethyl-1,3-azasilolidine-5-carboxamide (70a) General Procedure C To a solution of compound 69a (21 mg, 0.043 mmol) in DCM (0.6 mL) was added Burgess reagent (26 mg, 0.11 mmol). The reaction mixture was stirred at rt overnight. The reaction mixture was then diluted with DCM (10 mL) and washed with brine (3 mL x 2). The organic layer was separated and dried over Na2SO4. The solvent was evaporated, and the residue was purified by preparative TLC (DCM / MeOH = 15:1) to afford 70a (14 mg, 73%). 1H NMR (400 MHz, Methanol-d4) δ 6.98 (s, 1H), 6.76 (dd, J = 9.4, 2.1 Hz, 1H), 6.41 (td, J = 10.2, 2.0 Hz, 1H), 4.78 (dd, J = 10.5, 5.3 Hz, 2H), 4.38 (s, 1H), 3.15 (t, J = 12.8 Hz, 2H), 3.05 (d, J = 8.3 Hz, 1H), 2.47 (s, 1H), 2.09 (d, J = 13.5 Hz, 2H), 1.62 (dt, J = 33.3, 13.0 Hz, 2H), 1.17 (dd, J = 14.8, 10.0 Hz, 1H), 0.94 – 0.80 (m, 1H), 0.15 (s, 3H), 0.07 (s, 3H).13C NMR (101 MHz, MeOD) δ 179.75, 174.61, 163.57, 161.81, 161.69, 159.43, 159.31, 157.98, 157.82, 155.48, 137.56, 137.44, 137.41, 137.28, 131.29, 131.25, 118.50, 113.80, 113.58, 102.19, 95.02, 94.79, 94.72, 94.49, 93.75, 93.71, 93.49, 93.44, 61.55, 40.05, 38.37, 37.65, 33.83, 27.08, 15.01, -4.17, -4.26.19F NMR (377 MHz, Methanol-d4) δ -117.33 (d, J = 5.4 Hz), -119.91 (d, J = 5.2 Hz). HRMS m / z calcd for C22H26F2N5O3Si [(M +H)]+: 474.1773; found 474.1796. (R)-1-(7-chloro-1H-indole-2-carbonyl)-N-((S)-1-cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)-3,3- dimethyl-1,3-azasilolidine-5-carboxamide (70b) Compound 70b was synthesized from 69b following the general procedure C (81% yield). 1H NMR (400 MHz, Chloroform-d) δ 9.72 (s, 1H), 8.39 (d, J = 7.0 Hz, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.26 (d, J = 6.5 Hz, 1H), 7.18 – 7.12 (m, 1H), 7.05 (t, J = 7.8 Hz, 1H), 6.47 (s, 1H), 5.29 (dd, J = 10.0, 3.0 Hz, 1H), 4.88 (dt, J = 10.0, 6.4 Hz, 1H), 3.36 (d, J = 13.4 Hz, 1H), 3.31 – 3.16 (m, 3H), 2.68 – 2.46 (m, 1H), 2.42 – 2.21 (m, 3H), 1.94 (dt, J = 13.8, 6.6 Hz, 1H), 1.81 – 1.68 (m, 1H), 1.36 – 1.25 (m, 1H), 1.17 (dd, J = 15.0, 10.0 Hz, 1H), 0.40 (s, 3H), 0.26 (s, 3H).13C NMR (101 MHz, CDCl3) δ 181.81, 175.55, 165.98, 135.45, 133.53, 131.70, 126.33, 123.66, 123.33, 121.10, 119.45, 110.40, 63.72, 43.03, 41.83, 40.29, 40.05, 36.10, 30.61, 16.99, 0.43, -0.00. HRMS m / z calcd for C22H27ClN5O3Si [(M +H)]+: 472.1572; found 472.1565. (R)-N-((S)-1-cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)-1-(7-fluoro-1H-indole-2- carbonyl)-3,3-dimethyl-1,3-azasilolidine-5-carboxamide (70c) Compound 70c was obtained from 69c following the general procedure C (75% yield). 1H NMR (400 MHz, Methanol-d4) δ 7.22 (d, J = 7.9 Hz, 1H), 6.98 (s, 1H), 6.83 – 6.67 (m, 2H), 4.95 – 4.74 (m, 2H), 3.15 (d, J = 13.5 Hz, 1H), 3.04 (s, 2H), 2.46 (s, 1H), 2.19 – 1.96 (m, 2H), 1.75 – 1.50 (m, 2H), 1.26 – 1.11 (m, 2H), 0.90 (dd, J = 15.2, 5.0 Hz, 1H), 0.14 (s, 3H), 0.06 (s, 3H).13C NMR (101 MHz, MeOD) δ 179.71, 174.62, 164.28, 150.87, 148.44, 131.63, 131.35, 124.63, 124.49, 119.89, 118.49, 117.49, 107.99, 107.83, 106.95, 61.33, 40.03, 38.38, 37.65, 33.83, 27.30, 27.09, 15.06, -4.19, -4.23, -4.31.19F NMR (377 MHz, Methanol-d4) δ - 135.54. HRMS m / z calcd for C22H27FN5O3Si [(M +H)]+: 456.1867; found 456.1871. (R)-N-((S)-1-cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)-1-(5,7-difluoro-1H-indole-2-carbonyl)- 3,3-dimethyl-1,3-azasilolidine-5-carboxamide (70d) Compound 70d was synthesized from 69d following the general procedure C (66% yield). 1H NMR (400 MHz, Methanol-d4) δ 6.94 (d, J = 8.2 Hz, 2H), 6.63 (ddd, J = 11.4, 9.6, 2.2 Hz, 1H), 4.88 – 4.75 (m, 2H), 3.13 (d, J = 13.5 Hz, 1H), 3.05 (q, J = 6.8, 5.6 Hz, 3H), 2.46 (s, 1H), 2.08 (d, J = 11.8 Hz, 2H), 1.71 – 1.46 (m, 2H), 1.18 (dt, J = 14.6, 6.1 Hz, 1H), 0.97 – 0.84 (m, 1H), 0.14 (s, 3H), 0.06 (s, 3H).13C NMR (101 MHz, MeOD) δ 179.71, 174.54, 163.94, 158.04, 157.94, 155.69, 155.59, 150.24, 150.10, 147.77, 147.63, 133.21, 129.97, 121.38, 121.25, 118.49, 106.85, 101.69, 101.45, 98.69, 98.48, 98.38, 98.17, 61.33, 40.04, 38.39, 37.66, 33.85, 27.31, 27.10, 15.06, -4.18, -4.24, -4.32.19F NMR (377 MHz, Methanol-d4) δ -123.37, -131.37. HRMS m / z calcd for C22H27FN5O3Si [(M +H)]+: 474.1773; found 474.1781. (R)-1-(7-Chloro-1H-indole-2-carbonyl)-N-((S)-1-cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)- 3,3-dimethyl-1,3-azasilolidine-5-carboxamide (70e) Compound 70e was obtained from 69e following the general procedure C (64% yield). 1H NMR (400 MHz, CDCl3) δ 9.93 (s, 1H), 8.40 (d, J = 6.9 Hz, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.48 (s, 1H), 6.97 (d, J = 7.6 Hz, 1H), 6.88 (t, J = 7.8 Hz, 1H), 6.69 (s, 1H), 5.16 (s, 1H), 4.64 (s, 1H), 2.93 (t, J = 9.4 Hz, 1H), 2.79 (q, J = 10.0 Hz, 2H), 2.19-2.0 (d, J = 13.7 Hz, 4H), 1.95 (s, 1H), 1.66 (dt, J = 13.6, 6.6 Hz, 1H), 1.42 (t, J = 10.7 Hz, 1H), 1.22 – 1.05 (m, 1H), 1.02 – 0.88 (m, 1H), 0.13 (s, 3H), -0.00 (s, 3H).13C NMR (101 MHz, CDCl3) δ 181.48, 175.99, 175.90, 170.41, 135.13, 134.99, 130.51, 130.48, 124.45, 124.05, 122.37, 120.93, 119.20, 119.15, 114.55, 114.50, 42.77, 42.63, 41.71, 41.60, 40.14, 35.93, 30.21, -0.00, -0.32. HR-MS m / z calcd for C22H27ClN5O3Si [(M +H)]+: 472.1572 ; found 472.1584. (R)-N-((S)-1-cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)-1-(1H-indole-3-carbonyl)-3,3- dimethyl-1,3-azasilolidine-5-carboxamide (70f) Compound 70f was obtained from 69f following the general procedure C (69% yield). 1H NMR (400 MHz, Chloroform-d) δ 9.98 (s, 1H), 8.48 – 8.25 (m, 1H), 7.72 (s, 1H), 7.29 (s, 1H), 7.13 – 7.05 (m, 1H), 6.92 (dt, J = 5.8, 3.5 Hz, 2H), 6.52 (s, 1H), 5.14 (s, 1H), 4.59 (s, 1H), 3.13 – 2.93 (m, 0H), 2.86 (t, J = 9.4 Hz, 1H), 2.73 (q, J = 8.0, 6.6 Hz, 2H), 1.98 (d, J = 17.7 Hz, 3H), 1.87 (d, J = 14.7 Hz, 1H), 1.72 – 1.53 (m, 1H), 1.44 – 1.30 (m, 1H), 1.12 (dd, J = 14.7, 3.1 Hz, 1H), 1.04 – 0.91 (m, 1H), 0.12 (s, 3H), -0.00 (s, 3H).13C NMR (101 MHz, CDCl3) δ 181.49, 176.12, 171.13, 137.92, 128.85, 124.97, 123.27, 120.96, 114.14, 113.15, 42.72, 41.69, 40.07, 35.91, 30.23, -0.00, -0.28. HR-MS m / z calcd for C22H28N5O3Si [(M +H)]+: 438.1961; found 438.1966. (R)-1-(1H-benzo[d]imidazole-2-carbonyl)-N-((S)-1-cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)- 3,3-dimethyl-1,3-azasilolidine-5-carboxamide (70g) Compound 70g was obtained from 69g following the general procedure C (71% yield). 1H NMR (400 MHz, Methanol-d4) δ 7.43 (dd, J = 44.6, 8.2 Hz, 3H), 7.20 – 7.03 (m, 3H), 6.33 (dd, J = 10.5, 2.4 Hz, 1H), 4.85 (ddd, J = 10.1, 8.1, 5.0 Hz, 1H), 3.72 (d, J = 14.8 Hz, 1H), 3.14 (p, J = 1.6 Hz, 4H), 2.87 – 2.72 (m, 2H), 2.30 (td, J = 9.4, 7.3 Hz, 1H), 2.23 – 2.02 (m, 3H), 1.60 – 1.45 (m, 2H), 1.41 – 1.23 (m, 2H), 1.19 – 1.08 (m, 1H), 1.04 – 0.95 (m, 1H), 0.21 – 0.10 (m, 9H).13C NMR (101 MHz, MeOD) δ 179.69, 179.37, 174.31, 173.96, 161.91, 161.26, 145.93, 142.56, 133.32, 124.52, 122.65, 119.90, 118.47, 111.73, 61.92, 61.31, 40.05, 39.55, 38.34, 37.85, 37.66, 37.51, 37.26, 35.27, 33.92, 33.87, 27.09, 26.38, 17.36, 15.01, -4.22, -4.25, -4.35. HRMS m / z calcd for C21H27N6O3Si [(M +H)]+: 439.1914; found 439.1922. (R)-N-((S)-1-cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)-3,3-dimethyl-1-(3-methylisoxazole-5- carbonyl)-1,3-azasilolidine-5-carboxamide (72a) Compound 72a was obtained from 71a following general procedure C (59% yield). 1H NMR (400 MHz, Methanol-d4) δ 6.17 and 6.19 (2s, 1H), 5.32 (s, 1H), 5.07 (dd, J = 10.6, 1.9 Hz, 1H), 4.84 (dd, J = 10.5, 5.6 Hz, 1H), 4.79 – 4.72 (m, 1H), 3.18 – 3.13 (m, 3H), 2.98 – 2.66 (m, 1H), 2.55 – 2.36 (m, 1H), 2.30 and 2.28 (2s, 3H), 2.14 (dddd, J = 21.3, 13.7, 10.7, 4.8 Hz, 2H), 1.79 – 1.56 (m, 2H), 1.26 (ddd, J = 19.0, 15.1, 10.4 Hz, 1H), 1.08 – 0.90 (m, 1H), 0.15, 0.13, 0.12, 0.10 (4s, 6H).13C NMR (101 MHz, MeOD) δ 179.64, 179.58, 173.88, 173.83, 170.53, 170.32, 163.22, 162.11, 159.40, 118.45, 118.38, 102.10, 101.68, 62.37, 60.76, 40.05, 38.27, 38.14, 37.62, 37.53, 37.40, 34.72, 33.79, 33.69, 27.10, 27.02, 17.51, 15.14, 10.45, 10.43, -4.07, -4.12, -4.28, -4.41. HRMS m / z calcd for C18H26N5O4Si [(M +H)]+: 404.1754; found 404.1758. (R)-1-(2-chlorobenzoyl)-N-((S)-1-cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)-3,3-dimethyl-1,3- azasilolidine-5-carboxamide (72b) Compound 72b was obtained from 71b following the general procedure C (74% yield). 1H NMR (400 MHz, Methanol-d4) δ 6.18 (dd, J = 6.9, 1.1 Hz, 1H), 5.07 (dd, J = 10.5, 1.9 Hz, 0H), 4.84 (dd, J = 10.5, 5.6 Hz, 1H), 4.79 – 4.72 (m, 1H), 3.19 – 3.11 (m, 4H), 2.98 – 2.68 (m, 1H), 2.56 – 2.34 (m, 1H), 2.30 (d, J = 0.9 Hz, 2H), 2.13 (dddt, J = 18.1, 14.9, 8.6, 3.7 Hz, 2H), 1.80 – 1.54 (m, 2H), 1.26 (ddd, J = 19.0, 15.1, 10.4 Hz, 1H), 1.09 – 0.90 (m, 1H), 0.19 – 0.02 (m, 6H).13C NMR (101 MHz, MeOD) δ 179.64, 179.58, 173.88, 173.83, 170.53, 170.32, 163.22, 162.11, 159.40, 118.45, 118.38, 102.10, 101.68, 62.37, 60.76, 40.05, 38.27, 38.14, 37.62, 37.53, 37.40, 34.72, 33.79, 33.69, 27.10, 27.02, 17.51, 15.14, 10.45, 10.43, -4.07, -4.12, -4.28, -4.41. HRMS m / z calcd for C20H26ClN4O3Si [(M +H)]+: 433.1463; found 433.1469. (R)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-1-((S)-3,3-dimethyl-2- (2,2,2-trifluoroacetamido)butanoyl)-3,3-dimethyl-1,3-azasilolidine-5-carboxamide (72c) Compound 72c was synthesized from 71c following the general procedure C (75% yield). 1H NMR (400 MHz, Chloroform-d) δ 8.29 (d, J = 6.6 Hz, 1H), 7.19 (d, J = 8.9 Hz, 1H), 6.10 (s, 1H), 5.31 (s, 1H), 5.10 (dd, J = 10.1, 1.7 Hz, 1H), 4.97 (d, J = 8.9 Hz, 1H), 4.75 (dt, J = 10.4, 6.1 Hz, 1H), 3.42 (q, J = 7.3 Hz, 1H), 3.34 (dd, J = 9.1, 6.3 Hz, 2H), 3.10 (d, J = 13.7 Hz, 1H), 2.84 (d, J = 13.7 Hz, 1H), 2.40 (dddd, J = 24.0, 12.1, 8.4, 5.7 Hz, 1H), 2.24 (ddd, J = 14.2, 10.4, 7.3 Hz, 1H), 1.96 (dt, J = 14.3, 5.6 Hz, 1H), 1.83 (dq, J = 11.9, 9.2 Hz, 1H), 1.52 – 1.39 (m, 2H), 1.02 (s, 9H), 0.30 (s, 3H), 0.26 (s, 3H).13C NMR (101 MHz, MeOD) δ 179.69, 174.11, 171.70, 118.39, 117.53, 60.46, 57.22, 39.98, 38.19, 37.59, 36.43, 35.40, 34.00, 26.99, 25.39, 15.38, 7.81, -3.95, -4.25.19F NMR (377 MHz, Chloroform-d) δ -75.60. HRMS m / z calcd for C21H33N5F3O4Si [(M +H)]+: 504.2254; found 504.2250. Benzyl (R)-5-(((S)-1-cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)carbamoyl)-3,3-dimethyl-1,3- azasilolidine-1-carboxylate (72d) Compound 72d was synthesized from 71d following the general procedure C in 63% yield. 1H NMR (400 MHz, CDCl3) δ 8.04 (s) and 7.70 (d, J = 7.3 Hz)(1H), 7.13-7.07 (m, 5H), 6.30 and 6.12 (2s, 1H), 4.98 and 4.84 (2d, J = 12.8 Hz, 1H), 4.67 and 4.51 (2d, J = 8.7 Hz, 1H), 3.06 (q, J = 10.4 Hz, 2H), 2.83 and 2.74 (2d, J = 14.7 Hz, 1H), 2.26 and 1.96 (2d, J = 9.2 Hz, 1H), 2.12-2.04 (m, 2H), 1.71-1.55 (m, 2H), 1.17 – 0.96 (m, 2H), 0.90 (t, J = 12.5 Hz, 1H), 0.10 and 0.00 (2s, 6H).13C NMR (101 MHz, CDCl3) δ 181.08, 175.47, 159.48, 138.76, 130.55, 130.00, 129.84, 129.62, 120.59, 69.33, 62.81, 52.85, 42.52, 41.19, 39.74, 36.52, 35.87, 30.20, 17.34, -0.00, -0.50. HR-MS m / z calcd for C21H29N4O4Si [(M +H)]+: 429.1958; found: 429.1963.

[0009] Scheme 15 Reagents and conditions: (a) EtOH, 60oC, MTBE, rt.16 h. (b) MTBE, 1N HCl, rt.1 h, 27% over two steps. (c) HATU, DIPEA, CH2Cl2, rt, overnight, 65%. (d) 4N HCl in dioxane. (e) R1CO2H, HATU, DIPEA, DCM, rt. 55-62%. (f) Burgess reagent, CH2Cl2, rt, overnight, 68-77%.

[0010] Scheme 16 Reagents and conditions: (a) R2COCl, Et3N, DCM, rt, 57-67%. (b) Burgess reagent, CH2Cl2, rt, overnight, 68-77%. tert-Butyl (S)-5-(((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)carbamoyl)-3,3- dimethyl-1,3-azasilolidine-1-carboxylate (75) Compound 75 was synthesized following the procedure described above for compound 67 (62% yield). 1H NMR (400 MHz, CDCl3) δ 7.86 (d, J = 7.7 Hz, 1H), 7.21 (s, 1H), 6.53 (s, 1H), 5.73 (s, 1H), 4.33 (dd, J = 9.7, 3.9 Hz, 1H), 4.17 (q, J = 8.0 Hz, 1H), 3.21 – 3.04 (m, 3H), 2.58 (d, J = 4.8 Hz, 2H), 2.45 (s, 2H), 2.22 (q, J = 7.8 Hz, 1H), 2.12 (d, J = 8.7 Hz, 1H), 1.86 (dt, J = 13.5, 6.6 Hz, 1H), 1.70 – 1.58 (m, 1H), 1.20 (s, 9H), 0.97 (dd, J = 14.6, 9.9 Hz, 1H), 0.85 (dd, J = 14.8, 3.9 Hz, 1H), 0.09 (s, 3H), 0.00 (s, 3H).13C NMR (101 MHz, CDCl3) δ 182.74, 177.21, 176.78, 159.58, 82.19, 63.25, 54.14, 42.80, 40.59, 37.37, 34.75, 30.56, 30.32, 18.10, -0.00, - 0.49. HR-MS m / z calcd for C18H33N4O5Si [(M +H)]+: 413.2220; found 413.2214. (S)-N-((S)-1-Amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-1-(7-chloro-1H-indole-2- carbonyl)-3,3-dimethyl-1,3-azasilolidine-5-carboxamide (77a) Compound 77a was obtained from 75 following the general procedure A (55% yield). 1H NMR (400 MHz, Methanol-d4) δ 7.38 (dd, J = 8.1, 0.8 Hz, 1H), 7.11 – 6.97 (m, 2H), 6.83 (t, J = 7.8 Hz, 1H), 4.73 (dd, J = 9.3, 6.3 Hz, 1H), 4.15 (dd, J = 12.0, 3.8 Hz, 1H), 3.12 – 3.03 (m, 1H), 2.25 (qd, J = 9.5, 4.0 Hz, 1H), 2.07 (qt, J = 8.7, 7.0, 2.8 Hz, 1H), 1.90 (ddd, J = 13.9, 12.0, 4.2 Hz, 1H), 1.74 (ddd, J = 14.2, 10.5, 3.8 Hz, 1H), 1.65 – 1.54 (m, 1H), 1.19 (dd, J = 14.8, 9.4 Hz, 1H), 1.13 – 1.05 (m, 4H), 0.92 (dd, J = 14.8, 6.3 Hz, 1H), 0.15 (s, 3H), 0.05 (s, 3H).13C NMR (101 MHz, MeOD) δ 180.56, 175.79, 175.44, 164.39, 133.15, 131.50, 129.32, 123.29, 120.65, 120.61, 116.58, 107.47, 62.36, 54.43, 51.44, 42.39, 40.15, 38.50, 37.94, 32.56, 27.18, 17.32, 15.88, 15.37, 11.80, -4.30, -4.42. HRMS m / z calcd for C22H29ClN5O4Si [(M +H)]+: 490.1677; found 490.1670. (S)-N-((S)-1-Amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-1-(7-fluoro-1H-indole-2- carbonyl)-3,3-dimethyl-1,3-azasilolidine-5-carboxamide (77b) Compound 77b was synthesized from 72 following the general procedure A (62% yield). 1H NMR (400 MHz, Methanol-d4) δ 7.32 – 7.18 (m, 1H), 7.01 (d, J = 3.1 Hz, 1H), 6.76 (ddt, J = 21.5, 11.3, 6.2 Hz, 2H), 4.72 (dd, J = 9.3, 6.2 Hz, 1H), 4.24 – 4.11 (m, 1H), 3.15 (s, 2H), 3.09 – 3.00 (m, 1H), 2.24 (tt, J = 9.5, 4.6 Hz, 1H), 2.12 – 2.00 (m, 1H), 1.90 (ddd, J = 13.8, 12.0, 4.2 Hz, 1H), 1.74 (ddd, J = 14.2, 10.5, 3.7 Hz, 1H), 1.60 (dq, J = 12.5, 8.9 Hz, 1H), 1.18 (dd, J = 14.8, 9.4 Hz, 1H), 1.12 – 1.03 (m, 2H), 1.00 – 0.81 (m, 1H), 0.15 (s, 3H), 0.06 (s, 3H).13C NMR (101 MHz, MeOD) δ 180.57, 175.85, 175.48, 164.34, 150.85, 148.41, 131.50, 131.45, 131.40, 124.64, 124.51, 119.91, 119.85, 117.64, 117.61, 108.11, 107.95, 107.18, 62.42, 54.43, 53.46, 51.43, 42.38, 40.12, 38.47, 37.86, 32.56, 27.15, 15.27, 11.79, -4.28, -4.42.19F NMR (377 MHz, Methanol-d4) δ -135.29 (d, J = 2.4 Hz). HRMS m / z calcd for C22H29FN5O4Si [(M +H)]+: 474.1973; found 474.1981. (S)-1-(7-Chloro-1H-indole-2-carbonyl)-N-((S)-1-cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)- 3,3-dimethyl-1,3-azasilolidine-5-carboxamide (78a) Compound 78a was synthesized from 77a following the general procedure C (70%). 1H NMR (400 MHz, Chloroform-d) δ 9.94 – 9.77 (m, 1H), 8.59 (d, J = 7.0 Hz, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.36 – 7.18 (m, 1H), 7.04 (t, J = 7.8 Hz, 1H), 6.98 (d, J = 2.2 Hz, 1H), 6.31 (s, 1H), 5.34 (dd, J = 10.0, 3.1 Hz, 1H), 4.86 (dt, J = 10.2, 6.2 Hz, 1H), 3.40 (q, J = 7.3 Hz, 1H), 3.22 (dd, J = 9.1, 6.3 Hz, 1H), 2.46 (dt, J = 10.0, 7.1 Hz, 1H), 2.33 (dtd, J = 14.3, 7.5, 6.5, 2.9 Hz, 1H), 1.98 – 1.84 (m, 1H), 1.75 (dq, J = 11.8, 9.2 Hz, 1H), 1.46 – 1.36 (m, 2H), 1.22 (dd, J = 14.8, 9.9 Hz, 1H), 0.40 (s, 3H), 0.27 (s, 3H).13C NMR (101 MHz, CDCl3) δ 182.03, 175.69, 166.26, 135.39, 133.72, 131.63, 126.14, 123.50, 123.27, 121.16, 119.33, 110.00, 63.91, 53.55, 48.80, 43.12, 41.90, 40.27, 39.83, 36.03, 30.63, 17.48, 11.75, 11.08, 0.15, -0.00. HRMS m / z calcd for C22H27ClN5O3Si [(M +H)]+: 472.1572; found 472.1566. (S)-N-((S)-1-Cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)-1-(7-fluoro-1H-indole-2-carbonyl)-3,3- dimethyl-1,3-azasilolidine-5-carboxamide (78b) Compound 78b was synthesized from 77b following the general procedure C (67%). 1H NMR (400 MHz, Methanol-d4) δ 7.32 (d, J = 7.8 Hz, 1H), 7.09 (d, J = 3.1 Hz, 1H), 6.85 (ddt, J = 21.9, 11.3, 6.2 Hz, 2H), 4.91 (dd, J = 9.8, 4.8 Hz, 1H), 4.84 (dd, J = 10.2, 5.8 Hz, 1H), 3.25 (s, 2H), 3.16 – 2.95 (m, 2H), 2.31 (tt, J = 9.1, 4.5 Hz, 1H), 2.23 – 2.08 (m, 2H), 1.70 (dddd, J = 28.5, 12.5, 9.3, 4.5 Hz, 2H), 1.27 (dd, J = 14.9, 10.0 Hz, 1H), 1.01 (dd, J = 14.8, 5.0 Hz, 1H), 0.22 (s, 3H), 0.15 (s, 3H).13C NMR (101 MHz, MeOD) δ 179.55, 174.75, 164.42, 150.88, 148.45, 131.51, 131.41, 131.36, 124.67, 124.53, 119.89, 119.83, 118.37, 117.56, 108.05, 107.89, 107.15, 61.87, 40.02, 38.54, 37.72, 37.57, 33.85, 27.16, 15.44, -4.18, -4.30.19F NMR (377 MHz, Methanol-d4) δ -135.35. HRMS m / z calcd for C22H27FN5O3Si [(M +H)]+: 456.1867; found 456.1855. (S)-N-((S)-1-Amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3,3-dimethyl-1- (pyrazine-2-carbonyl)-1,3-azasilolidine-5-carboxamide (79a) Compound 79a was obtained from 76 following the general procedure B (63% yield). 1H NMR (400 MHz, Chloroform-d) δ 8.97 (dd, J = 59.6, 1.5 Hz, 1H), 8.74 – 8.51 (m, 2H), 8.35 (dd, J = 23.5, 6.9 Hz, 1H), 7.49 – 7.13 (m, 1H), 6.54 (d, J = 26.2 Hz, 1H), 6.12 – 5.61 (m, 1H), 5.00 (dd, J = 9.5, 4.9 Hz, 1H), 4.67 – 4.40 (m, 1H), 3.48 – 3.30 (m, 2H), 3.21 (d, J = 14.2 Hz, 1H), 3.11 – 2.77 (m, 1H), 2.57 – 2.31 (m, 2H), 2.29 – 2.06 (m, 2H), 2.01 – 1.82 (m, 1H), 1.42 – 1.13 (m, 2H), 0.35 (d, J = 8.2 Hz, 3H), 0.26 (d, J = 5.0 Hz, 3H).13C NMR (101 MHz, CDCl3) δ 183.02, 182.99, 176.83, 176.63, 176.23, 175.61, 172.39, 172.04, 165.33, 163.28, 162.04, 162.00, 105.68, 105.29, 65.11, 64.34, 54.81, 54.65, 43.14, 43.11, 40.98, 40.95, 40.19, 36.85, 35.17, 35.03, 30.90, 30.63, 20.38, 17.73, 14.52, 0.20, -0.00, -0.05, -0.44. HR-MS m / z calcd for C18H27N6O4Si [(M +H)]+: 419.1863; found 419.1855. (S)-N-((S)-1-Amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-1-(2-chlorobenzoyl)-3,3- dimethyl-1,3-azasilolidine-5-carboxamide (79b) Compound 79b was synthesized from 76 following the general procedure B in 57% yield. 1H NMR (400 MHz, Chloroform-d) δ 8.09 (s, 1H), 7.24 (s, 1H), 7.18 (dd, J = 6.8, 3.0 Hz, 1H), 7.10 (dt, J = 8.6, 4.3 Hz, 3H), 6.71 (s, 1H), 5.77 (s, 1H), 4.74 (s, 1H), 4.39 – 4.15 (m, 1H), 3.19 – 2.99 (m, 2H), 2.62 – 2.46 (m, 3H), 2.39 (d, J = 13.7 Hz, 1H), 2.30 (td, J = 8.7, 5.8 Hz, 1H), 2.13 (dp, J = 12.7, 5.1, 4.1 Hz, 1H), 2.00 – 1.79 (m, 2H), 1.65 (dq, J = 12.6, 8.7 Hz, 1H), 1.06 (ddd, J = 31.1, 14.8, 9.7 Hz, 2H), 0.09 (s, 3H), -0.00 (s, 2H).13C NMR (101 MHz, CDCl3) δ 180.59, 174.51, 170.41, 136.95, 130.15, 129.57, 127.38, 60.37, 51.94, 40.65, 38.45, 32.71, 27.93, 15.47, -2.61, -3.10. HR-MS m / z calcd for C20H28ClN4O4Si [(M +H)]+: 451.1568; found 451.1575. (S)-N-((S)-1-Amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-1-((S)-3,3-dimethyl-2- (2,2,2-trifluoroacetamido)butanoyl)-3,3-dimethyl-1,3-azasilolidine-5-carboxamide (79c) Compound 76e was synthesized from 73 following the general procedure B (67% yield). 1H NMR (400 MHz, Chloroform-d) δ 8.15 (dd, J = 51.1, 7.2 Hz, 1H), 7.67 (dd, J = 179.1, 9.2 Hz, 1H), 7.35 – 7.01 (m, 1H), 6.30 (d, J = 12.3 Hz, 1H), 6.19 – 5.75 (m, 1H), 5.02 (t, J = 9.5 Hz, 1H), 4.96 – 4.53 (m, 1H), 4.46 – 4.24 (m, 1H), 3.44 – 3.29 (m, 2H), 3.28 – 2.93 (m, 2H), 2.40 (dddd, J = 24.9, 12.6, 8.9, 6.3 Hz, 2H), 2.29 – 1.94 (m, 1H), 1.88 (ddt, J = 13.4, 8.6, 6.4 Hz, 1H), 1.35 – 1.11 (m, 2H), 1.03 (d, J = 5.3 Hz, 9H), 0.35 (d, J = 2.9 Hz, 3H), 0.25 (s, 3H).13C NMR (101 MHz, CDCl3) δ 182.61, 182.43, 176.53, 175.97, 175.94, 175.15, 174.44, 174.01, 159.46, 159.09, 119.42, 116.56, 63.71, 63.05, 59.16, 59.12, 54.49, 54.31, 42.71, 42.66, 40.71, 40.40, 39.43, 38.56, 38.52, 38.31, 34.81, 34.37, 31.72, 30.58, 30.52, 28.44, 28.35, 17.83, 17.16, 2.02, -0.00, -0.74, -0.86, -1.12.19F NMR (377 MHz, Chloroform-d) δ -75.06, -75.37. HR-MS m / z calcd for C21H35F3N5O5Si [(M +H)]+: 522.2360; found 522.2349. (S)-N-((S)-1-Cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)-3,3-dimethyl-1-(pyrazine-2- carbonyl)-1,3-azasilolidine-5-carboxamide (80a) Compound 80a was synthesized from 79a following the general procedure C (68% yield). 1H NMR (400 MHz, Chloroform-d) δ 9.02 (d, J = 1.5 Hz, 0H), 8.96 – 8.82 (m, 1H), 8.71 – 8.56 (m, 2H), 8.54 – 8.41 (m, 1H), 6.83 (d, J = 132.9 Hz, 1H), 5.27 (dd, J = 10.0, 2.7 Hz, 1H), 4.97 – 4.69 (m, 1H), 3.68 (d, J = 16.0 Hz, 0H), 3.43 – 3.28 (m, 2H), 3.00 – 2.72 (m, 1H), 2.60 – 2.27 (m, 2H), 2.15 – 1.93 (m, 1H), 1.85 (ddd, J = 12.3, 10.1, 2.5 Hz, 1H), 1.46 (ddd, J = 87.8, 15.0, 2.0 Hz, 1H), 1.19 (ddd, J = 34.6, 14.9, 10.0 Hz, 1H), 0.35 (d, J = 1.3 Hz, 3H), 0.27 (d, J = 12.6 Hz, 3H).13C NMR (101 MHz, CDCl3) δ 181.44, 181.21, 175.10, 174.82, 170.02, 168.49, 152.15, 151.26, 148.51, 147.97, 147.44, 147.38, 144.89, 144.06, 120.69, 120.59, 65.97, 62.84, 42.84, 42.77, 42.00, 41.50, 40.05, 39.98, 39.54, 36.29, 36.06, 35.79, 30.27, 30.23, 19.94, 17.17, -0.00, -0.12, -0.28, -0.41. HR-MS m / z calcd for C18H25N6O3Si [(M +H)]+: 401.1757; found 401.1750. (S)-1-(2-Chlorobenzoyl)-N-((S)-1-cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)-3,3-dimethyl-1,3- azasilolidine-5-carboxamide (80b) Compound 80b was synthesized from 79b following the general procedure C in 77% yield. 1H NMR (400 MHz, Chloroform-d) δ 8.73 – 8.03 (m, 1H), 7.58 (d, J = 140.1 Hz, 1H), 7.29 – 7.02 (m, 5H), 6.61 (s, 1H), 5.15 (s, 1H), 4.81 (dd, J = 16.0, 8.5 Hz, 1H), 4.16 (d, J = 10.0 Hz, 0H), 3.44 (d, J = 15.7 Hz, 0H), 3.13 (ddd, J = 11.7, 7.9, 3.9 Hz, 2H), 2.44 – 2.30 (m, 2H), 2.20 (tdd, J = 12.8, 9.1, 5.9 Hz, 2H), 2.07 (dq, J = 15.1, 7.7, 7.1 Hz, 0H), 1.93 – 1.72 (m, 1H), 1.63 (dq, J = 11.9, 8.9 Hz, 1H), 1.20 (s, 1H), 0.91 (dt, J = 15.6, 8.1 Hz, 1H), 0.21 – -0.07 (m, 7H).13C NMR (101 MHz, MeOD) δ 179.45, 179.20, 173.61, 170.56, 169.45, 136.78, 136.18, 130.54, 130.26, 129.38, 129.29, 129.02, 127.74, 127.58, 127.27, 118.26, 117.98, 62.50, 59.67, 53.43, 40.07, 40.02, 38.62, 38.44, 37.85, 37.84, 33.94, 33.62, 27.26, 27.13, 17.84, -3.95, -4.16, -4.26, -4.53. HRMS m / z calcd for C20H26N4ClO3Si [(M +H)]+: 433.1463; found 433.1458. (S)-N-((S)-1-Cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)-1-((S)-3,3-dimethyl-2-(2,2,2- trifluoroacetamido)butanoyl)-3,3-dimethyl-1,3-azasilolidine-5-carboxamide (80c) Compound 80c was synthesized from 79c following the general procedure C in 68% yield. 1H NMR (400 MHz, Methanol-d4) δ 4.86 (d, J = 18.4 Hz, 1H), 4.82 – 4.73 (m, 1H), 3.18 – 3.12 (m, 1H), 3.05 – 2.95 (m, 1H), 2.84 (dd, J = 13.5, 8.7 Hz, 1H), 2.27 (dtd, J = 14.6, 8.9, 5.5 Hz, 1H), 2.13 (dddd, J = 13.8, 8.5, 5.6, 2.3 Hz, 1H), 2.02 (ddd, J = 13.8, 9.5, 5.7 Hz, 1H), 1.78 – 1.54 (m, 2H), 1.15 – 1.06 (m, 2H), 0.94 (dd, J = 15.1, 3.2 Hz, 1H), 0.85 (d, J = 13.3 Hz, 9H), 0.17 – 0.04 (m, 6H).13C NMR (101 MHz, MeOD) δ 179.38, 174.11, 173.95, 171.67, 171.57, 157.78, 157.41, 118.27, 118.24, 117.51, 114.66, 60.58, 60.15, 57.31, 57.25, 40.05, 38.58, 38.52, 37.82, 36.50, 36.23, 35.58, 35.36, 33.97, 33.95, 27.25, 27.21, 25.55, 25.37, 15.77, 15.53, 7.83, -4.06, -4.16, -4.29, -4.40.19F NMR (377 MHz, Methanol-d4) δ -76.46, -76.56. HRMS m / z calcd for C21H33N5F3O4Si [(M +H)]+: 504.2254; found 504.2241. Scheme 17 Reagents and conditions: (a) 4N HCl in dioxane. (b) CBzCl, THF, NaHCO3; (c) HATU, DIPEA, CH2Cl2, rt, overnight, 51%. (d) Burgess reagent, CH2Cl2, rt, overnight, 64%. (3R,5'S)-2-Oxospiro[indoline-3,3'-pyrrolidine]-5'-carboxamide hydrochloride (82) To a solution of compound 81 (345 mg, 1.0 mmol) in 6 mL of DCM was added HCl (4N in dioxane, 1.0 mL, 4.0 mmol). The reaction mixture was stirred for 1 h at room temperature and then concentrated under vacuum. The crude HCl salt 82 was dried under high vacuum overnight. 1H NMR (400 MHz, MeOD) δ 7.56 (dd, J = 7.6, 1.2 Hz, 1H), 7.31 (td, J = 7.8, 1.2 Hz, 1H), 7.12 (td, J = 7.6, 1.1 Hz, 1H), 6.98 (dd, J = 7.8, 0.9 Hz, 1H), 5.04 (dd, J = 9.5, 5.2 Hz, 1H), 3.91 (s, 3H), 3.83 – 3.71 (m, 2H), 2.88 – 2.64 (m, 2H).1H NMR (400 MHz, CDCl3) δ 9.58, 7.37, 7.36, 7.35, 7.35, 7.34, 7.33, 7.32, 7.31, 7.30, 7.28, 5.16, 5.15, 5.13, 5.12, 5.12, 4.85, 4.84, 4.83, 4.82, 4.81, 4.79, 4.78, 3.04, 3.01, 3.00, 2.97, 2.94, 2.83, 2.80, 1.37, 1.36, 1.34, 1.33, 1.32, 1.30, 1.28, 1.26, 1.25, 1.23, 1.23, 1.22, 1.20, 1.19, 0.26, 0.25, 0.24, 0.23.13C NMR (101 MHz, MeOD) δ 179.97, 167.99, 141.89, 129.34, 123.32, 122.84, 110.18, 66.74, 59.53, 52.78, 51.99, 37.72. HR-MS m / z calcd for C12H13N3O2[(M +H)]+: 232.1086; found 232.1081. (R)-1-((Benzyloxy)carbonyl)-3,3-dimethyl-1,3-azasilolidine-5-carboxylic acid (83) To a solution of compound 65 (52 mg, 0.2 mmol) in 1.5 mL of DCM was added HCl (4N in dioxane, 0.25 mL, 1.0 mmol). The reaction mixture was stirred for 1 h at room temperature and then concentrated under vacuum. The residue was dissolved in THF (1.0 mL)- NaHCO3 (sat.0.5 mL). CbzCl (52 mg, 0.3 mmol) in THF (0.2 mL) was added dropwise. The reaction was stirred overnight at rt. The reaction mixture was acidified to pH 2 by addition of 1N HCl dropwise. The reaction mixture was poured into water and extracted with DCM (3 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under vacuum. The crude compound was used directly in the next step without further purification (51 mg, 87%). 1H NMR (400 MHz, CDCl3) δ 9.58 (s, 1H), 7.38 – 7.28 (m, 5H), 5.14 (dd, J = 11.3, 4.0 Hz, 2H), 4.82 (ddd, J = 14.3, 10.4, 3.3 Hz, 1H), 3.09 – 2.87 (m, 1H), 2.81 (d, J = 14.4 Hz, 1H), 1.37 – 1.17 (m, 2H), 0.25 and 0.24 (2s, 6H).13C NMR (101 MHz, CDCl3) δ 181.66, 180.75, 160.05, 158.95, 139.02, 130.93, 130.88, 130.43, 130.23, 130.19, 69.95, 62.29, 61.59, 37.25, 36.70, 19.43, 18.27, 0.00, -0.04, -0.11. HR-MS m / z calcd for C14H19NOSi [(M +H)]+: 294.1162 found 294.1167. Benzyl (S)-5-((3R,5'S)-5'-carbamoyl-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-carbonyl)-3,3- dimethyl-1,3-azasilolidine-1-carboxylate (84) A solution of compound 79 (28 mg, 0.105 mmol) and 83 (32 mg, 0.11 mmol) in DCM- DMF (10:1, 1.0 mL) was treated with HATU (50 mg, 0.13 mmol) and N,N- diisopropylethylamine (45 mg, 0.35 mmol) at 0oC. The ice bath was removed, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was then diluted with DCM (8 mL) and washed with 1N HCl (2 mL), NaHCO3 (5% aqueous solution, 3mL) and brine (3 mL). The organic layer was separated and dried over Na2SO4. The solvent was evaporated, and the crude mixture was purified by chromatography (DCM / MeOH 30:1 to 10:1) to afford 84 (27.1 mg, 51%). 1H NMR (400 MHz, Chloroform-d) δ 8.78 (s, 1H), 7.19 – 7.09 (m, 7H), 6.82 (dd, J = 15.7, 8.0 Hz, 3H), 5.93 (s, 3H), 5.48 (s, 1H), 4.95 – 4.80 (m, 2H), 4.63 (t, J = 8.8 Hz, 1H), 4.41 (dd, J = 9.8, 5.1 Hz, 1H), 3.89 (d, J = 10.4 Hz, 1H), 2.85 – 2.68 (m, 2H), 2.34 (pd, J = 13.1, 11.2, 6.1 Hz, 2H), 0.91 (dd, J = 14.8, 9.8 Hz, 1H), 0.69 (dd, J = 14.7, 5.1 Hz, 1H), 0.15 (s, 3H), -0.00 (s, 4H).13C NMR (101 MHz, CDCl3) δ 177.15, 173.85, 157.93, 140.15, 136.54, 129.12, 128.50, 127.98, 127.57, 67.50, 55.66, 53.16, 43.57, 35.25, 18.47, 16.98, 14.67, 12.72, -2.39, - 2.71. LC-MS m / z calcd for C26H31N4O5Si [(M +H)]+: 507.2; found: 507.5. Benzyl (S)-5-((3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-carbonyl)-3,3- dimethyl-1,3-azasilolidine-1-carboxylate (85) Compound 85 was synthesized from 84 following the general procedure C (64% yield). 1H NMR (400 MHz, Chloroform-d) δ 8.82 – 8.21 (m, 1H), 7.59 – 7.41 (m, 2H), 7.39 – 7.30 (m, 4H), 7.21 (dd, J = 7.7, 1.3 Hz, 0H), 7.12 – 6.83 (m, 2H), 5.72 (t, J = 8.2 Hz, 1H), 5.28 – 5.04 (m, 2H), 4.93 (q, J = 10.7, 10.0 Hz, 0H), 4.24 – 4.07 (m, 1H), 3.69 (dd, J = 40.3, 12.2 Hz, 1H), 3.05 – 2.90 (m, 2H), 2.75 – 2.43 (m, 1H), 1.41 (dd, J = 15.2, 10.3 Hz, 1H), 1.14 – 0.98 (m, 0H), 0.87 (td, J = 15.8, 13.5, 6.4 Hz, 1H), 0.43 – 0.16 (m, 6H).13C NMR (101 MHz, CDCl3) δ 179.61, 176.61, 159.93, 141.93, 138.96, 133.68, 131.86, 131.35, 131.12, 130.99, 130.88, 130.46, 130.34, 130.20, 129.97, 129.93, 125.96, 125.87, 125.68, 124.37, 120.77, 119.36, 113.26, 112.51, 69.78, 60.94, 56.44, 53.36, 49.10, 43.84, 37.46, 32.12, 18.15, 2.41, 0.80, -0.00. ESI- MS m / z calcd for C26H29N4O4Si [(M +H)]+: 489.20; found: 489.3.

[0011] Scheme 18 Reagents and conditions: (a) HATU, DIPEA, DCM, rt.66%. (b) 4N HCl in Dioxane, 100%. (c) HATU, DIPEA, DCM, rt.48%. (d) LiBH4, 0oC to rt, overnight, 69%. (e) DMP, CH2Cl2, rt, 2hr, 36%. tert-Butyl (R)-5-(((S)-1-methoxy-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)carbamoyl)- 3,3-dimethyl-1,3-azasilolidine-1-carboxylate (87) To a solution of acid 65 (170 mg, 0.66 mmol) and amine hydrochloride 83 (152 mg, 0.68 mmol) in CH2Cl2 (5 mL) was added DIPEA (270 mg, 2.08 mmol). After 20 min, HATU (250 mg, 0.66 mmol) was added. The resulting mixture was stirred at room temperature for 16 h before being quenched with 1N HCl (5 mL). The suspension was extracted with DCM (6 mL x3). The combined organic layers were washed with saturated sodium bicarbonate, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (DCM / MeOH = 50:1 to 20:1) to give 87 (186 mg, 66%). 1H NMR (400 MHz, CDCl3) δ 7.53 and 7.18 (2s, 1H), 6.58 and 6.22 (2s, 1H), 4.52 (d, J = 28.8 Hz, 1H), 4.27 (d, J = 38.9 Hz, 1H), 3.48 (s, 3H), 3.11 (t, J = 10.0 Hz, 2H), 2.74 (dd, J = 54.9, 14.7 Hz, 1H), 2.45 (dd, J = 45.9, 14.4 Hz, 1H), 2.28 – 2.13 (m, 2H), 1.93 (t, J = 12.8 Hz, 1H), 1.79 – 1.49 (m, 2H), 1.30 (m, 9H), 0.88 (d, J = 10.0 Hz, 2H), 0.07 and 0.00 (2s, 6H).13C NMR (101 MHz, CDCl3) δ 179.84, 173.75, 172.48, 157.04, 80.23, 60.41, 52.38, 50.85, 40.52, 37.94, 34.42, 33.16, 29.69, 28.37, 17.33, 15.05, -2.64. ESI-MS m / z calcd for C19H34N3O6Si [(M +H)]+: 428.2; found: 428.5. Methyl (S)-2-((R)-3,3-dimethyl-1,3-azasilolidine-5-carboxamido)-3-((S)-2-oxopyrrolidin-3- yl)propanoate (88) To a solution of compound 87 (186 mg, 0.43 mmol) in 2 mL of DCM was added HCl (4N in dioxane, 1.0 mL, 4.0 mmol). The reaction mixture was stirred for 1.5 h at room temperature and then concentrated under vacuum. The crude HCl salt 88 was dried under high vacuum overnight (quantitative yield). 1H NMR (400 MHz, MeOD) δ 4.29 (dd, J = 11.1, 4.3 Hz, 1H), 3.92 (dd, J = 11.6, 6.7 Hz, 1H), 3.44 (s, 3H), 3.19 – 3.05 (m, 2H), 2.51 (d, J = 14.6 Hz, 1H), 2.30 – 2.20 (m, 2H), 2.12 (dddd, J = 11.7, 8.9, 6.7, 2.8 Hz, 1H), 1.96 (ddd, J = 14.0, 11.0, 4.5 Hz, 1H), 1.72 – 1.55 (m, 2H), 1.39 (dd, J = 14.8, 6.7 Hz, 1H), 0.84 (dd, J = 14.8, 11.7 Hz, 1H), 0.17 and 0.15 (2s, 6H).13C NMR (101 MHz, MeOD) δ 180.10, 171.92, 169.92, 66.76, 60.68, 51.67, 50.92, 40.22, 38.41, 32.46, 27.30, 15.98, -4.28, -4.41. ESI-MS m / z calcd for C14H26N3O4Si [(M +H)]+: 328.20; found: 328.3. Methyl (S)-2-((R)-1-(7-fluoro-1H-indole-2-carbonyl)-3,3-dimethyl-1,3-azasilolidine-5- carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (90) Compound 90 was synthesized starting from 88 and 89 following the procedure described above for 87 (48% yield). 1H NMR (400 MHz, Chloroform-d) δ 10.33 (s, 1H), 8.03 (d, J = 6.7 Hz, 1H), 7.44 (d, J = 7.8 Hz, 1H), 7.12 (t, J = 2.7 Hz, 1H), 6.99 (ddt, J = 18.7, 10.9, 6.2 Hz, 2H), 6.31 (s, 1H), 5.42 (dd, J = 10.1, 2.8 Hz, 1H), 4.45 (dq, J = 11.1, 6.4, 5.1 Hz, 1H), 3.66 – 3.56 (m, 2H), 3.36 – 3.28 (m, 2H), 3.12 (s, 3H), 2.50 (t, J = 8.3 Hz, 1H), 2.32 (tt, J = 8.2, 3.8 Hz, 1H), 2.11 (ddd, J = 14.1, 11.0, 5.9 Hz, 1H), 1.94 – 1.69 (m, 2H), 1.39-1.17 (m, 3H), 0.87 (dtd, J = 19.2, 6.9, 4.8 Hz, 1H), 0.37 (s, 3H), 0.26 (s, 3H).19F NMR (377 MHz, CDCl3) δ -133.99. ESI-MS m / z calcd for C23H30N4O5SiF [(M +H)]+: 489.20; found: 489.5. (R)-1-(7-Fluoro-1H-indole-2-carbonyl)-N-((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3- yl)propan-2-yl)-3,3-dimethyl-1,3-azasilolidine-5-carboxamide (91) To a solution of 90 (48 mg, 0.1 mmol) in THF (0.8 mL) at 0 °C was added lithium borohydride (0.1 ml, 0.4 mmol). The reaction mixture was stirred at 0 °C for 2 h and then quenched with 1N HCl (3 mL). The mixture was extracted with ethyl acetate (5 mL x3), washed with water, salt, then dried over sodium sulfate. The organic layer was concentrated under vacuum and the residue purified by flash chromatography to give 91 (32 mg, 69%). 1H NMR (400 MHz, Chloroform-d) δ 10.50 (s, 1H), 7.75 (d, J = 7.5 Hz, 1H), 7.42 (d, J = 7.3 Hz, 1H), 7.13 (s, 1H), 6.99 (dtd, J = 25.0, 10.4, 9.1, 5.6 Hz, 2H), 6.38 (s, 1H), 5.42 – 5.15 (m, 1H), 3.99 (d, J = 9.6 Hz, 1H), 3.78 – 3.54 (m, 3H), 3.39 – 3.00 (m, 4H), 2.52 (s, 1H), 2.26 (dt, J = 13.8, 7.7 Hz, 1H), 2.10 (ddd, J = 15.0, 10.5, 5.2 Hz, 1H), 1.70 (t, J = 10.6 Hz, 1H), 1.51 (d, J = 9.5 Hz, 1H), 0.97 – 0.75 (m, 2H), 0.40 (s, 3H), 0.24 (s, 3H).13C NMR (101 MHz, CDCl3) δ 183.51, 175.80, 165.81, 151.68 (d, J = 245.8 Hz), 133.52 (d, J = 14.6 Hz), 126.63 (d, J = 13.6 Hz), 122.47 (d, J = 5.9 Hz), 119.90 (d, J = 3.9 Hz), 110.81 (d, J = 15.9 Hz), 109.44, 67.54, 63.96, 52.32, 45.10, 42.65, 40.23, 31.77, 30.41, 24.76, 16.20, -0.00, -0.48.19F NMR (377 MHz, MeOD) δ -133.55. ESI-MS m / z calcd for C22H30N4O4SiF [(M +H)]+: 461.20; found: 461.5. (R)-1-(7-Fluoro-1H-indole-2-carbonyl)-3,3-dimethyl-N-((S)-1-oxo-3-((S)-2- oxopyrrolidin-3-yl)propan-2-yl)-1,3-azasilolidine-5-carboxamide (92) To a solution of 91 (30 mg, 0.07 mmol) in CH2Cl2(2 mL) at 0 °C was added DMP (60 mg, 0.14 mmol). The reaction mixture was stirred at rt overnight and then concentrated under vacuum. The residue was purified by preparative TLC (dichloromethane: methanol (V / V) = 15:1) to afford 92 (11 mg, 36%). 1H NMR (400 MHz, MeOD) δ 7.46 (s, 1H), 7.21 (s, 1H), 7.07 – 6.91 (m, 2H), 5.28 – 5.07 (m, 2H), 4.48 (s, 1H), 3.96 (s, 1H), 3.39-3.18 (m, 3H), 2.63 (s, 1H), 2.33 (t, J = 11.9 Hz, 1H), 1.87 (d, J = 16.5 Hz, 1H), 1.72 (s, 1H), 1.60 (s, 1H), 1.25 – 1.12 (m, 1H), 0.91 (dd, J = 11.8, 4.8 Hz, 1H), 0.38 (s, 3H), 0.30 (s, 3H).13C NMR (101 MHz, MeOD) δ 181.65, 175.04, 173.91, 164.31, 149.65 (d, J = 244.7 Hz), 134.89 (d, J = 43.9 Hz), 131.84, 124.50 (d, J = 13.6 Hz), 119.85, 117.44, 107.81 (d, J = 16.2 Hz), 106.75, 98.32 (d, J = 13.9 Hz).78.08, 61.62, 51.40, 51.25, 40.08, 37.89, 30.02, 29.64, 29.35, 19.39, -4.09, -4.23.19F NMR (377 MHz, MeOD) δ - 135.75. ESI-MS m / z calcd for C22H28N4O4SiF [(M +H)]+: 459.2; found: 459.5. In certain embodiments, this disclosure relates to synthetic methods of making compounds disclosed herein comprising contacting materials disclosed herein with reagents and intermediates under conditions such that the compounds are formed as reported herein. Cellular Toxicity Assays The toxicity of the compounds was assessed in Vero, human PBM, CEM (human lymphoblastoid), MT-2, and HepG2 cells, as described previously (see Schinazi R.F., Sommadossi J.-P., Saalmann V., Cannon D.L., Xie M.-Y., Hart G.C., Smith G.A. & Hahn E.F. Antimicrob. Agents Chemother. 1990, 34, 1061-67). Cycloheximide was included as positive cytotoxic control, and untreated cells exposed to solvent were included as negative controls.The cytotoxicity CC50was obtained from the concentration-response curve using the medianeffective method described previously (see Chou T.-C. & Talalay P. Adv. Enzyme Regul.1984, 22, 27-55; Belen’kii M.S. & Schinazi R.F. Antiviral Res.1994, 25, 1-11). The results are shown in Table 1. Table 1 shows data on cytotoxicity, CC50,µM ( % inhibition)

[0012] Mitochondrial Toxicity Assays in HepG2 Cells: i) Effect of Compounds on Cell Growth and Lactic Acid Production: The effect on the growth of HepG2 cells was determined by incubating cells in the presence of 0 µM, 0.1 µM,1 µM, 10 µM and 100 µM drug. Cells (5 x 104per well) were plated into 12-well cell cultureclusters in minimum essential medium with nonessential amino acids supplemented with 10% fetal bovine serum, 1% sodium pyruvate, and 1% penicillin / streptomycin and incubated for 4 days at 37°C. At the end of the incubation period the cell number was determined using a hemocytometer. See Pan-Zhou X-R, Cui L, Zhou X-J, Sommadossi J-P, Darley-Usmer VM. "Differential effects of antiretroviral nucleoside analogs on mitochondrial function in HepG2 cells," Antimicrob. Agents Chemother.2000; 44: 496-503. To measure the effects of the compounds on lactic acid production, HepG2 cells from a stock culture were diluted and plated in 12-well culture plates at 2.5 x 104cells per well. Various concentrations (0 µM, 0.1 µM, 1 µM, 10 µM and 100 µM) of compound were added, and the cultures were incubated at 37°C in a humidified 5% CO2atmosphere for 4 days. At day 4, the number of cells in each well was determined and the culture medium collected. The culture medium was then filtered, and the lactic acid content in the medium was determined using a colorimetric lactic acid assay. Since lactic acid product can be considered a marker for impaired mitochondrial function, elevated levels of lactic acid production detected in cells grown in the presence of test compounds would indicate a drug-induced cytotoxic effect. ii)Effect of Compounds on Mitochondrial DNA Synthesis: a real-time PCR assay to accurately quantify mitochondrial DNA content has been developed (see Stuyver LJ, Lostia S, Adams M, Mathew JS, Pai BS, Grier J, Tharnish PM, Choi Y, Chong Y, Choo H, Chu CK, Otto MJ, Schinazi RF. Antiviral activities and cellular toxicities of modified 2',3'- dideoxy-2',3'-didehydrocytidine analogs. Antimicrob. Agents Chemother.2002; 46: 3854-60). This assay is used to determine the effect of compounds on mitochondrial DNA content. In this assay, low-passage-number HepG2 cells were seeded at 5,000 cells / well in collagen- coated 96-well plates. Test compounds were added to the medium to obtain final concentrations of 0 µM, 0.1 µM, 10 µM and 100 µM. On culture day 7, cellular nucleic acids were prepared by using commercially available columns (RNeasyTM96 kit). These kits co- purify RNA and DNA, and hence, total nucleic acids are eluted from the columns. The mitochondrial cytochrome c oxidase subunit II (COXII) gene and the ß-actin or rRNA gene were amplified from 5 µl of the eluted nucleic acids using a multiplex Q-PCR protocol with suitable primers and probes for both target and reference amplifications. The primers and probes for the rRNA gene are commercially. Since equal amplification efficiencies are obtained for all genes, the comparative CT method was used to investigate potential inhibition of mitochondrial DNA synthesis. The comparative CT method uses arithmetic formulas in which the amount of target (COXII gene) is normalized to the amount of an endogenous reference (the ß-actin or rRNA gene) and is relative to a calibrator (a control with no drug at day 7). The arithmetic formula for this approach is given by 2-∆∆CT, where ∆∆CT is (CT for average target test sample - CT for target control) - (CT for average reference test -CT for reference control) (see Johnson MR, K Wang, JB Smith, MJ Heslin, RB Diasio. Quantitation of dihydropyrimidine dehydrogenase expression by real-time reverse transcription polymerase chain reaction. Anal. Biochem.2000; 278:175-184). A decrease in mitochondrial DNA content in cells grown in the presence of drug indicated mitochondrial toxicity. Mitochondrial Toxicity Assays in Neuro2A Cells To estimate the potential of the compounds of this disclosure to cause neuronal toxicity, mouse Neuro2A cells (American Type Culture Collection 131) can be used as a model system (see Ray AS, Hernandez-Santiago BI, Mathew JS, Murakami E, Bozeman C, Xie MY, Dutschman GE, Gullen E, Yang Z, Hurwitz S, Cheng YC, Chu CK, McClure H, Schinazi RF, Anderson KS. Mechanism of anti-human immunodeficiency virus activity of beta-D-6- cyclopropylamino-2',3'-didehydro-2',3'-dideoxyguanosine. Antimicrob. Agents Chemother. 2005, 49, 1994-2001). The concentrations necessary to inhibit cell growth by 50% (CC50) can be measured using the 3-(4,5-dimethyl-thiazol-2-yl)-2,5- diphenyltetrazolium bromide dye- based assay, as described. Perturbations in cellular lactic acid and mitochondrial DNA levels at defined concentrations of drug can be carried out. ddC and AZT can be used as control nucleoside analogs. Assay for Bone Marrow Cytotoxicity Primary human bone marrow mononuclear cells can be obtained commercially. CFU- GM assays is carried out using a bilayer soft agar in the presence of 50 units / mL human recombinant granulocyte / macrophage colony-stimulating factor, while BFU-E assays used an ethylcellulose matrix containing 1 unit / mL erythropoietin (see Sommadossi JP, Carlisle R. Toxicity of 3’-azido-3’-deoxythymidine and 9-(1,3-dihydroxy-2-propoxymethyl) guanine for normal human hematopoietic progenitor cells in vitro. Antimicrob. Agents Chemother.1987; 31: 452-454; Sommadossi, JP, Schinazi, RF, Chu, CK, and Xie, MY. Comparison of cytotoxicity of the (-) and (+) enantiomer of 2’,3’-dideoxy-3’-thiacytidine in normal human bone marrow progenitor cells. Biochem. Pharmacol. 1992; 44:1921- 1925). Each experiment can be performed in duplicate in cells from three different donors. AZT is used as a positive control. Cells can be incubated in the presence of the compound for 14-18 days at 37°C with 5% CO2, and colonies of greater than 50 cells can be counted using an inverted microscope to determine the IC50. In Vitro Assay for SARS A fusion protein, prepared by fusing a severe acute respiratory syndrome 3CL protease to E. coli maltose-binding protein (MBP), can be expressed in E coli BL21 (DE3) pLys S cells. The fusion protein can be purified by amylose-affinity chromatography and cleaved with factor Xa to release the severe acute respiratory syndrome 3CL protease. Subsequently, the recombinant protease can be purified to homogeneity using phenyl SepharoseTMCL-4B column and concentrated to form a 25 μM solution. The enzymatic activity of severe acute respiratory syndrome 3CL protease (75 nM) can be determined by incubation with a solution containing 15 μM of a substrate peptide at 25º C. for 30 minutes in a medium containing 20 mM Tris-HCl (pH 7.5), 200 mM NaCl, 1 mM EDTA, 1 mM dithiothretol, and 1 mg / mL bovine serum albumin. The reaction is terminated by adding an equal volume of 0.2% trifluoroacetic acid. The reaction mixture is analyzed by reverse-phase HPLC using a C18 column. Cleaved products are resolved using a 5-95% linear gradient of acetonitrile in 0.9% trifluoroacetic acid. Quantification of peak areas are used to determine the extent of substrate conversion. Compounds are tested for their efficacy in inhibiting severe acute respiratory syndrome 3CL protease. Specifically, a test compound and the severe acute respiratory syndrome 3CL protease can be pre-incubated at 25º C for 20 minutes before they are incubated with the substrate peptide. In vitro assay for SARS-CoV-2 and HCoV (OC43): In order to determine the potential effect of each selected compound against in vitro replication of SARS-CoV-2 in Vero, Calu3 or Caco2 cells or HCoV (OC43) in Huh7 cells, a confluent cell monolayer in a 96-wells cell culture microplate can be infected at a multiplicity of infection (MOI) of 0.1 and treated with a maximum non-toxic concentration (MNTC) of each compound. To assess the antiviral activity, a virus yield reduction assay using specific qRT- PCR for each virus can be performed. Table 2 showing compounds with SARS-CoV-2 activity

[0013] Anti-Enterovirus Activity Compounds are tested for cytotoxicity using an MTS (3-(4,5-dimethylthiazol-2-yl)-5- (3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) method and the CC50 (IC50) values (cytotoxic concentrations of drug required to reduce cell viability by 50%) are determined for each test compound in human rhabdomyosarcoma (RD) cell line. The resultant inhibitory effect of each test compound is calculated as a percentage of decrease in EV-71 CPE. Briefly, a monolayer of RD cells is prepared in 96-well plates. The cells are then infected with 1 MOI of EV-71 (BrCr strain) followed by treatment with a single non-toxic dose of each compound in triplicate. The vehicle control wells are treated with 0.1% DMSO diluted in the working media. The plate is then incubated for 48 h at which time the virus-control wells produced detectable CPE. To determine the probable CPE inhibitory effect of test compounds, an MTS assay is performed, and effective compounds are chosen for further studies to identify the potency of the compounds and their concentration-dependent manner. The dose-response antiviral activity of each compound is determined by a virus yield reduction assay method. Briefly, confluent monolayers of RD cells in 96-wells microplate are infected with 0.1 MOI of EV-71 followed by treatment with compounds. Effective compounds are further quantified and confirmed with a virus-yield-reduction assay using an optimized in house qRT-PCR to determine the EV-71 RNA copy number after 2 days post-treatment from collected supernatants. qRT-PCR is performed using the EV-71 specific probe / primer mix and qScript- ToughTMmaster mix. Quantitative PCR measurement was performed using StepOnePlusTMreal time PCR system according to manufacturer’s protocol. The median effective concentration (EC50) and the concentration with 90% of inhibitory effect (EC90) are calculated using GraphPadTMPRISM for Windows, version 5 as the means ± standard deviation (SD) of the mean from triplicate assay from three independent experiments. Table 3 shows data on the median effective concentrations (EC50) ranges of several of the compounds described herein against Enterovirus EV-71 (BrCr strain)

[0014] Dose-Dependent Antiviral Assay The antiviral effect of each compound selected through the antiviral evaluation assay can be further confirmed by virus yield reduction assay using the optimized qRT-PCR by measuring the RNA copy number for each virus in the supernatant of treated-infected cells. A positive control, such as remdesivir, can be used for each assay. A qRT-PCR assay was used to specifically to quantify the yield of SARS-CoV-2 in the cell-based assays. A one-step qRT-PCR was carried out in a final volume of 20μl containing extracted viral RNA, probe / primer mix. Quantitative PCR measurement was performed. Virus kinetic replication assay: To determine the best time point for virus yield assay a kinetic replication of SARS-CoV-2 in Vero cells was performed and the yield of progeny virus production was assessed from supernatants at interval time points using a specific q-RT PCR for SARS-CoV-2. It was observed that 48 h post-infection, a significant increase in virus yield was achieved. Anti-Norovirus Activity Norwalk virus replicon assays were performed as reported by Constantini et al. (Antivir Ther, 2012,17, 981-991). HG23 cells (derived from Huh-7 cells) containing NoV replicon RNA are seeded at a density of 3,000 cells / well in 96-well plates and incubated at 37oC and 5% CO2 overnight. Compounds were tested at concentrations ranging from 0.1 to 100 µM. Compounds were added in triplicate to 80 to 90% confluent monolayers and incubated at 37oC and 5% CO2. Untreated cells were included in each plate. Following five days incubation (37oC, 5% CO2), total cellular RNA was isolated. Replicon RNA and an internal control were amplified in a single step.

[0015] Table 4 showing compounds with Norwalk virus activity

[0016] CYP inhibition Appropriate known substrates of CYP450s were incubated in human liver microsomes (0.05-0.2 mg / mL) in a buffer containing 1 mM NADPH in 100 mM potassium phosphate, pH 7.4 with 3 mM MgCl2at 37°C, in the presence or absence of the test compound (10 µM). The assay was conducted in duplicate. At the end of the incubations, the reactions were terminated with the addition of the quenching solution containing the internal standards. The extracted samples were subjected to LC / MS / MS analysis for the formation of each of the signature metabolites of the CYP substrates. Various publications are cited herein, the disclosures of which are incorporated by reference in their entireties for all purposes. The present disclosure is not to be limited in scope by the specific embodiments described herein. Indeed, various modifications of the disclosure in addition to those described will become apparent to those skilled in the art from the foregoing description. Such modifications are intended to fall within the scope of the appended claims.

Claims

CLAIMS We claim:

1. A compound having the following formula (I):formula (I) or a pharmaceutically acceptable salt or prodrug thereof, wherein: R4is an optionally substituted bridging C1-6 alkyl, an optionally substituted bridging C2-6alkene, an optionally substituted bridging C2-6alkyne; R5is -CN, -C(O)H, -CH=C(CN)C(O)NH2, -C(O)CF3, -CH(OH)CF3, -C(OH)SO3- (and an associated cation, such as Na+), or an optionally-substituted epoxide ring, is –(CH2)q-SH,-C(O)-CH2-O-P(O)(OR8)2, -C(O)-heteroaryl, -C(O)-CH2-O-C(O)-aryl, -C(O)-CH2-O-C(O)- heteroaryl, -C(O)-C(O)-NH2, -C(O)-C(O)-NH-alkylaryl, -C(O)-C(O)-NH-alkylheteroaryl, -C(O)-C(O)-NH-alkyl, -C(O)-C(O)-NH-cycloalkyl, -C(O)-C(O)-NH2, -CH=C-C(O)-R8, -C(O)-CHFCl, -C(O)-CH2-OCF3; R10and R10’ are independently at each occurrence, hydrogen, CF3, C1-6alkyl, C1-6haloalkyl, or C2-6 alkenyl;Y is, independently at each occurrence, O or S; m and n and q are, independently at each occurrence, 0, 1, 2, or 3; R6and R6’are, independently at each occurrence, hydrogen, halogen, CF3, hydroxy, N(R’)S(O)2R’, S(O)2R’, S(O)2N(R’)2, C1-6 alkoxy, C2-6 alkenyl, cyano, C2-6 alkynyl, C3-6 alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, C1-6 alkyl, arylalkoxycarbonyl, carboxy, C1-6haloalkyl, heterocyclylalkyl, or C1-6hydroxyalkyl; or R6and R6’, together with the carbon to which they are attached, form a carbonyl; R6and R6’can come together to form an optionally substituted double bond or a C3-6 ring optionally containing a N, O, or S heteroatom; each R’ is, independently at each occurrence, H, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, aryl, heteroaryl, alkylaryl, or arylalkyl; the R’ groups can optionally be substituted with one or more substituents, which substituents are, independently at each occurrence, halo, C1-6alkyl, C1-6haloalkyl, C1-6hydroxyalkyl, hydroxyl, carboxyl, acyl, aryl, acyloxy, amino, amido, alkylamino, dialkylamino, arylamino, alkoxy, alkoxyalkyl, aryloxy, nitro, cyano, sulfonic acid, thiol, sulfonyl, sulfanyl, sulfinyl, sulfamoyl, carboxylic acid, amide, phosphonyl, phosphinyl, phosphoryl, phosphine, or phosphonic acid; or two R’ residing on the same carbon or nitrogen atom can come together to form a C3-6 ring optionally containing a N, O, or S heteroatom; or R7and R7’are, independently at each occurrence, hydrogen, CF3, N(R’)S(O)2R’, S(O)2R’, S(O)2N(R’)2, C1-6 alkoxy, C2-6 alkenyl, cyano, C2-6 alkynyl, C3-6 alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, C1-6alkyl, arylalkoxycarbonyl, carboxy, C1-6haloalkyl, heterocyclylalkyl, or C1-6hydroxyalkyl; or R7and R7’can come together to form an optionally substituted double bond or a C3-6 ring optionally containing a N, O, or S heteroatom; R8is independently at each occurrence H or C1-C3alkyl; R9is H or C1-C3 alkyl; R11, R11’and R11’’are an optionally substituted C1-6 alkyl, an optionally substituted C2-6 alkene, an optionally substituted C2-6alkyne; or R12, R12’and R12’’are independently at each occurrence, hydrogen, halo, C1-6alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, hydroxyl, carboxyl, acyl, aryl, acyloxy, amino, amido,alkylamino, dialkylamino, arylamino, alkoxy, alkoxyalkyl, aryloxy, nitro, cyano, sulfonic acid, thiol, sulfonyl, sulfanyl, sulfinyl, sulfamoyl, carboxylic acid, amide, phosphonyl, phosphinyl, phosphoryl, phosphine, or phosphonic acid; or two adjacent R12, R12’and R12’’can come together to form a C3-6 ring optionally containing a N, O, or S heteroatom; R13is hydrogen, halogen, CF3, C1-6alkyl, C1-6haloalkyl, or C2-6alkenyl; and R14is hydrogen, halogen, CF3, C1-6alkyl, C1-6haloalkyl, or C2-6alkenyl.

2. The compound of claim 1, which is:7-chloro-N-((2R)-1-oxo-1-(((2S)-1-oxo-3-(2-oxopyrrolidin-3-yl)propan-2-yl)amino)- 3-(trimethylsilyl)propan-2-yl)-1H-indole-2-carboxamide;, 7-chloro-N-((2R)-1-(((1S)-1-cyano-2-(2-oxopyrrolidin-3-yl)ethyl)amino)-1-oxo-3- (trimethylsilyl)propan-2-yl)-1H-indole-2-carboxamide; or a pharmaceutically acceptable salt or prodrug thereof.

3. A compound having the following formula (II):formula (II) or a pharmaceutically acceptable salt or prodrug thereof, wherein: R5is -CN, -C(O)H, -CH=C(CN)C(O)NH2, -C(O)CF3, -CH(OH)CF3, -C(OH)SO3- (and an associated cation, such as Na+), or an optionally-substituted epoxide ring, is –(CH2)q-SH,-C(O)-CH2-O-P(O)(OR8)2, -C(O)-heteroaryl, -C(O)-CH2-O-C(O)-aryl, -C(O)-CH2-O-C(O)- heteroaryl, -C(O)-C(O)-NH2, -C(O)-C(O)-NH-alkylaryl, -C(O)-C(O)-NH-alkylheteroaryl, -C(O)-C(O)-NH-alkyl, -C(O)-C(O)-NH-cycloalkyl, -C(O)-C(O)-NH2, -CH=C-C(O)-R8, - C(O)-CHFCl, -C(O)-CH2-OCF3; R10and R10’ are independently at each occurrence, hydrogen, CF3, C1-6alkyl, C1-6haloalkyl, or C2-6 alkenyl; Y is, independently at each occurrence, O or S;m and n and q are, independently at each occurrence 0, 1, 2, or 3; t is 1 or 2;R6and R6’are, independently at each occurrence, hydrogen, halogen, CF3, hydroxy, N(R’)S(O)2R’, S(O)2R’, S(O)2N(R’)2, C1-6 alkoxy, C2-6 alkenyl, cyano, C2-6 alkynyl, C3-6 alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, C1-6alkyl, arylalkoxycarbonyl, carboxy, C1-6 haloalkyl, heterocyclylalkyl, or C1-6 hydroxyalkyl; or R6and R6’, together with the carbon to which they are attached, form a carbonyl; R6and R6’can come together to form an optionally substituted double bond or a C3-6ring optionally containing a N, O, or S heteroatom; each R’ is, independently at each occurrence, H, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, aryl, heteroaryl, alkylaryl, or arylalkyl; the R’ groups can optionally be substituted with one or more substituents, which substituents are, independently at each occurrence, halo, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, hydroxyl, carboxyl, acyl, aryl, acyloxy, amino, amido, alkylamino, dialkylamino, arylamino, alkoxy, alkoxyalkyl, aryloxy, nitro, cyano, sulfonic acid, thiol, sulfonyl, sulfanyl, sulfinyl, sulfamoyl, carboxylic acid, amide, phosphonyl, phosphinyl, phosphoryl, phosphine, or phosphonic acid; or two R’ residing on the same carbon or nitrogen atom can come together to form a C3-6ring optionally containing a N, O, or S heteroatom; or R7and R7’are, independently at each occurrence, hydrogen, CF3, N(R’)S(O)2R’, S(O)2R’, S(O)2N(R’)2, C1-6alkoxy, C2-6alkenyl, cyano, C2-6alkynyl, C3-6alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, C1-6alkyl, arylalkoxycarbonyl, carboxy, C1-6haloalkyl, heterocyclylalkyl, or C1-6 hydroxyalkyl; or R7and R7’can come together to form an optionally substituted double bond or a C3-6ring optionally containing a N, O, or S heteroatom; R8is independently at each occurrence H or C1-C3 alkyl; R9is H or C1-C3 alkyl; R12, R12’and R12’’are independently at each occurrence, hydrogen, halo, C1-6alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, hydroxyl, carboxyl, acyl, aryl, acyloxy, amino, amido, alkylamino, dialkylamino, arylamino, alkoxy, alkoxyalkyl, aryloxy, nitro, cyano, sulfonic acid, thiol, sulfonyl, sulfanyl, sulfinyl, sulfamoyl, carboxylic acid, amide, phosphonyl, phosphinyl, phosphoryl, phosphine, or phosphonic acid; ortwo adjacent R12, R12’and R12’’can come together to form a C3-6 ring optionally containing a N, O, or S heteroatom; R13is hydrogen, halogen, CF3, C1-6alkyl, C1-6haloalkyl, or C2-6alkenyl; and R14is hydrogen, halogen, CF3, C1-6 alkyl, C1-6 haloalkyl, or C2-6 alkenyl.

4. The compound of claim 3, which is:1-(7-chloro-1H-indole-2-carbonyl)-3,3-dimethyl-N-((S)-1-oxo-3-((S)-2-oxopyrrolidin- 3-yl)propan-2-yl)-1,3-azasilolidine-5-carboxamide;1-(7-chloro-1H-indole-2-carbonyl)-N-((S)-1-cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)- 3,3-dimethyl-1,3-azasilolidine-5-carboxamide; or or a pharmaceutically acceptable salt or prodrug thereof.

5. The compound of claim 3, which is:, (S)-4-(7-chloro-1H-indole-2-carbonyl)-N-((S)-1-cyano-2-((S)-2-oxopyrrolidin-3- yl)ethyl)morpholine-3-carboxamide, or(S)-4-(7-chloro-1H-indole-2-carbonyl)-N-((S)-1-oxo-3-((S)-2-oxopyrrolidin-3- yl)propan-2-yl)morpholine-3-carboxamide, or or a pharmaceutically acceptable salt or prodrug thereof.

6. A compound having the following formula (III), or formula (IV),:formula (IV) or a pharmaceutically acceptable salt or prodrug thereof, wherein: R1is optionally substituted cycloalkylaryl, alkylaryl, cycloalkylheteroaryl, alkylheteroaryl, alkyl, cycloalkyl, aryl, heteroaryl, aryloxy, heteroaryloxy, arylalkoxy, or heteroarylalkoxy;R3is an optionally substituted C1-6 alkyl, C1-6 haloalkyl, C2-8 alkoxyalkyl, arylalkyl, alkylaryl, heteroarylalkyl, or alkylheteroaryl, -CH2-(hydroxy)phenyl, and –CH2-(halo)phenyl; R4is an optionally substituted bridging C1-6alkyl, an optionally substituted bridging C2-6 alkene, an optionally substituted bridging C2-6 alkyne; R5is -CN, -C(O)H, -CH=C(CN)C(O)NH2, -C(O)CF3, -CH(OH)CF3, -C(OH)SO3- (and an associated cation, such as Na+), or an optionally-substituted epoxide ring, is –(CH2)q-SH,-C(O)-CH2-O-P(O)(OR8)2, -C(O)-heteroaryl, -C(O)-CH2-O-C(O)-aryl, -C(O)-CH2-O-C(O)- heteroaryl, -C(O)-C(O)-NH2, -C(O)-C(O)-NH-alkylaryl, -C(O)-C(O)-NH-alkylheteroaryl, -C(O)-C(O)-NH-alky, -C(O)-C(O)-NH-cycloalkyl, -C(O)-C(O)-NH2, -CH=C-C(O)-R8, -C(O)- CHFCl, -C(O)-CH2-OCF3; R2, R2’, R10and R10’ are, independently at each occurrence, hydrogen, CF3, C1-6 alkyl, C1-6 haloalkyl, or C2-6 alkenyl; X is, independently, a bond, O or NH; Y is, independently, a bond, O or S; q is at each occurrence 1 or 2; m, n and p are, independently, 0, 1, 2, or 3; R6and R6’are, independently at each occurrence, hydrogen, halogen, CF3, hydroxy, N(R’)S(O)2R’, S(O)2R’, S(O)2N(R’)2, C1-6 alkoxy, C2-6 alkenyl, cyano, C2-6 alkynyl, C3-6 alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, C1-6alkyl, arylalkoxycarbonyl, carboxy, C1-6haloalkyl, heterocyclylalkyl, or C1-6hydroxyalkyl; or R6and R6’, together with the carbon to which they are attached, form a carbonyl; each R’ is, independently at each occurrence, H, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, aryl, heteroaryl, alkylaryl, or arylalkyl;the R’ groups can optionally be substituted with one or more substituents, which substituents are, independently at each occurrence halo, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, hydroxyl, carboxyl, acyl, aryl, acyloxy, amino, amido, alkylamino, dialkylamino, arylamino, alkoxy, alkoxyalkyl, aryloxy, nitro, cyano, sulfonic acid, thiol, sulfonyl, sulfanyl, sulfinyl, sulfamoyl, carboxylic acid, amide, phosphonyl, phosphinyl, phosphoryl, phosphine, or phosphonic acid; or two R’ residing on the same carbon or nitrogen atom can come together to form a C3-6ring optionally containing a N, O, or S heteroatom; or R6and R6’can come together to form an optionally substituted double bond or a C3-6ring optionally containing a N, O, or S heteroatom; R7and R7’are, independently at each occurrence, hydrogen, CF3, N(R’)S(O)2R’, S(O)2R’, S(O)2N(R’)2, C1-6 alkoxy, C2-6 alkenyl, cyano, C2-6 alkynyl, C3-6 alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, C1-6alkyl, arylalkoxycarbonyl, carboxy, C1-6haloalkyl, heterocyclylalkyl, or C1-6 hydroxyalkyl; or R7and R7’can come together to form an optionally substituted double bond or a C3-6 ring optionally containing a N, O, or S heteroatom; R8is independently at each occurrence H or C1-C3alkyl; R9is H or C1-C3 alkyl; or R11, R11’and R11’’are an optionally substituted C1-6alkyl, an optionally substituted C2-6alkene, an optionally substituted C2-6alkyne.

7. A compound having the following formulas (VI), (VII), (VIII), (IX):formula (VI)formula (IX) or a pharmaceutically acceptable salt or prodrug thereof, wherein m, n, p, q, X, Y, R1, R2, R2’, R3, R5, R6, R6’, R7, R7’, R8, R9, R10, R10’are, individually at each occurrence, as defined above with respect to claim 6; and Z is O, S, NH, N-alkyl,r is 0, 1, 2, or 3; t is 1, 2, or 3;s is 0, 1, 2, or 3, and R15is H, halo, fluoro, hydroxy, an optionally substituted C1-6 alkyl, an optionally substituted C2-6alkene, an optionally substituted C2-6alkyne, an optionally substituted -O-C1-6alkyl, an optionally substituted -O-C2-6 alkene, an optionally substituted -O-C2-6 alkyne, cycloalkyl.

8. A compound having the following formula (X), or formula (XI),:formula (XI) or a pharmaceutically acceptable salt or prodrug thereof, wherein p, X, Y, R1, R2, R2’, R3, R4, R8, R11, R11’, R11’’are, individually at each occurrence, as defined above with respect to claim 6; and R16is -CN, -C(O)H, -CH=C(CN)C(O)NH2, -C(O)CF3, -CH(OH)CF3, -C(OH)SO3- (and an associated cation, such as Na+), or an optionally-substituted epoxide ring, –(CH2)q-SH,, , , , ,-C(O)-CH2-OH,-C(O)-CH2-O-P(O)(OR8)2, -C(O)-heteroaryl, -C(O)-CH2-O-C(O)-aryl, -C(O)-CH2-O-C(O)- heteroaryl, -C(O)-C(O)-NH2, -C(O)-C(O)-NH-alkylaryl, -C(O)-C(O)-NH-alkylheteroaryl, -C(O)-C(O)-NH-alkyl, -C(O)-C(O)-NH-cycloalkyl, -C(O)-C(O)-NH2, -CH=C-C(O)-R8, -C(O)-CHFCl, -C(O)-CH2-OCF3; q is at each occurrence 1 or 2; R17is H, an optionally substituted C1-6 alkyl, an optionally substituted C2-6 alkene, an optionally substituted C2-6 alkyne, an optionally substituted C3-7 cycloalkyl B is an optionally substituted aryl, an optionally substituted cycloalkyl or an optionally substituted heteroaryl.

9. A compound having the following formulas (XII), (XIII), (XIV), (XV):formula (XIII)formula (XV) or a pharmaceutically acceptable salt or prodrug thereof, wherein p, r, s, t, X, Y, Z, R1, R2, R2’, R3, R8, R15are, individually at each occurrence, as defined above with respect to claim 7; and R16is H, -CN, -C(O)H, -CH=C(CN)C(O)NH2, -C(O)CF3, -CH(OH)CF3, -C(OH)SO3- (and an associated cation, such as Na+), or an optionally-substituted epoxide ring, is –(CH2)q--C(O)-CH2-O-P(O)(OR8)2, -C(O)-heteroaryl, -C(O)-CH2-O-C(O)-aryl, -C(O)-CH2-O-C(O)- heteroaryl, -C(O)-C(O)-NH2, -C(O)-C(O)-NH-alkylaryl, -C(O)-C(O)-NH-alkylheteroaryl,-C(O)-C(O)-NH-alkyl, -C(O)-C(O)-NH-cycloalkyl, -C(O)-C(O)-NH2, -CH=C-C(O)-R8, -C(O)-CHFCl, -C(O)-CH2-OCF3; q is at each occurrence 1 or 2; R17is H, an optionally substituted C1-6 alkyl, an optionally substituted C2-6 alkene, an optionally substituted C2-6 alkyne, an optionally substituted C3-7 cycloalkyl; and B is an optionally substituted aryl, an optionally substituted cycloalkyl, or an optionally substituted heteroaryl.

10. A pharmaceutical composition comprising a compound of any of claims 1-9 and a pharmaceutically acceptable carrier or excipient.

11. The pharmaceutical composition of claim 10 in the form of a pill, capsule, tablet, particles, powder, lotion, or gel.

12. The pharmaceutical composition of claim 10 in the form of a neutral pH buffered solution optionally comprising isotonic saline or a pharmaceutically acceptable mono or polysaccharide.

13. The pharmaceutical composition of claim 10 contained in a device in the form of a liquid or gas pressurized container.

14. The pharmaceutical composition of claim 13, wherein the device is configured to dispense an aerosol spray.

15. The pharmaceutical composition of claim 10, wherein the composition is a transdermal composition or a nanoparticulate composition.

16. The pharmaceutical composition of claim 10, wherein the pharmaceutically acceptable excipient is selected from lactose, sucrose, mannitol, triethyl citrate, dextrose, cellulose, methyl cellulose, ethyl cellulose, hydroxyl propyl cellulose, hydroxypropyl methylcellulose, carboxymethylcellulose, croscarmellose sodium, polyvinyl N-pyrrolidone, crospovidone, ethylcellulose, povidone, methyl and ethyl acrylate copolymer, polyethylene glycol, fatty acid esters of sorbitol, lauryl sulfate, gelatin, glycerin, glyceryl monooleate, silicon dioxide, titanium dioxide, talc, corn starch, carnauba wax, stearic acid, sorbic acid, magnesium stearate, calcium stearate, castor oil, mineral oil, calcium phosphate, starch, carboxymethyl ether of starch, iron oxide, triacetin, acacia gum, esters, or salts thereof.

17. The pharmaceutical composition of claim 10, further comprising a second active agent.

18. The pharmaceutical composition of claim 17, wherein the second active agent is an antiviral agent or anti-inflammatory agent.

19. Use of a compound of any of claims 1-9 in the preparation of a medicament for treating a coronavirus, norovirus, enterovirus, picornavirus, rhinovirus, and / or herpes virus infection, preventing a coronavirus, picornavirus, enterovirus, picornavirus, rhinovirus or herpes virus infection, or reducing the biological activity of an infection with a coronavirus, picornavirus, enterovirus, picornavirus, rhinovirus, or herpes virus.

20. A method of treating or preventing a viral infection comprising administering an effective amount of a compound of any of claims 1-9 to a subject in need thereof.

21. The method of claim 20, wherein the subject is diagnosed with an infection from a coronavirus, norovirus, enterovirus, picornavirus, rhinovirus, and / or herpes virus.

22. The method of claim 20, wherein the compound is administered in combination with another active pharmaceutical agent.

23. The method of claim 22 wherein the active pharmaceutical is a protease inhibitor.

24. The method of claim 23 wherein the protease inhibitor is administered in combination with ritonavir or another protease inhibitor booster.

25. The method of claim 22 wherein the active pharmaceutical is a polymerase inhibitor.

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