INHIBITORS OF CYSTEINE PROTEASES AND METHODS OF USE THEREOF

The disclosure provides compounds of formula II with warheads and their use in treating medical diseases or disorders, such as viral infections. Pharmaceutical compositions and methods of making various compounds with warheads are provided. The compounds are contemplated to inhibit proteases, such as the 3C, CL- or 3CL-like protease.

BRIEF DESCRIPTION OF THE SEQUENCE LISTING

The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. The ASCII copy, created on Jun. 3, 2021, is named PARB-004WO_SL.txt and is 3,285 bytes in size.

BACKGROUND

The Coronaviridae family of viruses are enveloped, single-stranded, positive-sense RNA viruses and include 141 species classified into four genera according to their phylogenetic relationships: α-, β-, γ-, and δ-coronavirus. Coronaviruses (CoVs) are zoonotic viruses that infect a variety of animals from whales to birds, bats, cats, and humans. Typically, CoV infection results in mild to moderate respiratory tract infections; however, some CoV species are extremely virulent and can result in widespread fatality. Severe acute respiratory syndrome coronavirus (SARS-CoV) is a human CoV responsible for the first pandemic of the 21stcentury, infecting over 8,000 people with a 10% mortality rate. Middle East respiratory syndrome coronavirus (MERS-CoV) was identified in November 2012 and had since infected over 1,600 people in 26 countries with a 36% mortality rate. More recently, COVID-19 (SARS CoV2) coronaviruses have raised a global pandemic since they had been first identified in China in late 2019. Therefore, it is important to identify coronavirus drug targets that can be utilized for the development of broad-spectrum anti-coronaviral therapeutics to combat infections of existing and emerging coronaviruses.

All CoVs express a >800 kDa replicase polyprotein that contains either two or three cysteine proteases, the papain-like protease(s) (PLPpro, or PLP1 and PLP2) and the 3C-like protease (3CLpro, nsp5, or Mpro). These proteases process the CoV replicase polyprotein by cleaving it into 16 non-structural proteins, which are responsible for a variety of aspects of CoV replication. The CoV 3CLpro is responsible for processing 11 cleavage sites within the replicase polyprotein and is essential for CoV replication, making it a highly valuable target for therapeutic development. The overall active site architecture and substrate recognition pockets are structurally conserved across CoV 3CLpros, increasing its attractiveness as a target for the development of broad-spectrum anti-CoV therapeutics. Moreover, high sequence conservation in the vicinity of the active site among CoV 3CLpros from different coronavirus subclasses make them an excellent target for the development of broad-spectrum therapeutics for coronavirus infections. Accordingly, the development of CoV 3CLpro inhibitors is a promising path for the treatment of respiratory tract infections and related diseases.

Numerous studies on targeting the immediate zoonotic reservoirs of coronaviruses with small molecule inhibitors have helped inform structure-based design strategies aimed at creating molecular scaffolds that may aid in the development of therapeutic against coronaviral infection; however, small molecule antiviral agents or effective commercially available broad-spectrum therapeutics have not yet been identified. There is a critical need for the development of broad-spectrum CoV therapeutics to overcome the challenges of traditional anti-CoV therapeutic development, as broad-spectrum therapeutics can be rapidly implemented upon zoonotic disease outbreak.

SUMMARY

The disclosure is directed to, in part, viral protease inhibitors. Also disclosed herein are pharmaceutical compositions comprising at least one disclosed compound and a pharmaceutically acceptable carrier.

In an embodiment, disclosed herein is an antiviral compound, comprising a warhead covalently bound to a 3C or 3CL protease inhibitor, wherein the antiviral compound covalently binds to a Cys residue of the protease, and wherein the antiviral compound is active against one or more viruses.

Also disclosed herein are compounds represented by Formula II:

R3ais selected from

and 4-10 membered heterocycle, wherein the heterocycle may optionally be substituted by one, two or three substituents each independently selected from the group consisting of hydroxyl, C1-C8alkoxy, oxo and a warhead A; R3bis selected from hydrogen and C1-C8alkyl; wherein R3aand R3bmay be joined together to form, together with the carbon to which they are attached, a 4-10 membered heterocycle, wherein the heterocycle may optionally be substituted by one, two or three substituents each independently selected from C6-C14aryl and a warhead A; R1ais selected from the group consisting of hydrogen, C1-C8alkyl, C1-C8heteroalkyl, —(C1-C8alkyl)-R1, —(C1-C8alkyl)-CN, C3-C10cycloalkyl, C6-C14aryl, 4-10 membered heterocycle and 5-10 membered heteroaryl; R1bis selected from hydrogen and C1-C8alkyl; or R1aand R1bmay be joined together to form, together with the carbon to which they are attached, a 4-10 membered heterocycle having a ring nitrogen, NRG, or a C3-C10cycloalkyl; R1is selected from the group consisting of C1-C8alkyl, C2-C10alkenyl, C2-C10alkynyl, C3-C10cycloalkyl, C6-C14aryl, 5-10 membered heteroaryl and 4-10 membered heterocycle, wherein R1may optionally be substituted by one, two, or three substituents each selected from RA; RAis independently selected for each occurrence from the group consisting of halogen, cyano, hydroxyl, oxo, SF5, —CH2CF3, —CF3, —O—CF3, —O—CHF2, —S—CH3, —S(O)2—CH3, —NH2, —O-phenyl, —O—(C1-C8alkyl)-phenyl, —NHC(O)RB, —NHC(O)ORB, —NHC(O)O—(C1-C8alkyl)-RB, —N(Ry)2, —N(Ry)(C1-C8alkyl)C(O)O-phenyl, —N(Ry)(C1-C8alkyl)C(O)N(Ry)2, —C(O)—OC(CH3)3, C1-C8alkyl, C2-C10alkenyl, C2-C10alkynyl, C1-C8heteroalkyl, C1-C8alkoxy, C3-C10cycloalkyl, —(C1-C8alkyl)-(C3-C10cycloalkyl), —(C1-C8alkyl)-(C6-C14aryl), —(C1-C8alkyl)-(5-10 membered heteroaryl), C6-C14aryl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl, wherein the RB, alkyl, heterocyclyl, heteroaryl, or aryl may optionally be substituted by one, two or three substituents each independently selected from the group consisting of halogen, C1-C8alkyl, C1-C8alkoxy, SF5, —NH2, hydroxyl and oxo; R2is selected from the group consisting of —NHC(O)RB, —NHC(O)N(RB)2, —NHC(O)C(RC)2RB, —NHS(O)2RB, —O—(C1-C8alkyl)-(C3-C10cycloalkyl), 4-10 membered heterocycle, C6-C14aryl and 5-10 membered heteroaryl bound through the carbon or nitrogen atom, wherein RBor R2may optionally be substituted by one, two, or three substituents each selected from Rx; or R1aand R2may be joined together to form, together with the carbon to which they are attached, a 4-10 membered monocyclic or bicyclic heterocycle having a ring nitrogen NRG, or a C3-C10cycloalkyl, wherein the cycloalkyl or heterocycle may optionally be substituted by one, two or three substituents on a free carbon each selected from RA; R3is selected from 5-10 membered heteroaryl and 4-10 membered heterocycle, wherein R3may optionally be substituted by one, two, or three substituents each selected from RA; RBis independently selected, for each occurrence, from the group consisting of C1-C8alkyl, C2-C10alkenyl, C2-C10alkynyl, C3-C10cycloalkyl, fluorenylmethyloxy, C6-C14aryl, 5-10 membered heteroaryl and 4-10 membered heterocycle; RCis independently selected, for each occurrence, from hydrogen, halogen and C1-C8alkyl; Rxis independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, oxo, CF3, SF5, cyano, —O—(Rxx)—OCH3, —OCHF2, —OCF3, —O—(C1-C8alkyl), —C(O)O(CH3), —N(Ry)2, —N(Ry)C(O)Ry, —N(Ry)(C1-C8alkyl)C(O)N(Ry)2, —N(Ry)(C1-C8alkyl)C(O)OH, —(C1-C8alkyl)-(C3-C10cycloalkyl), C1-C8alkyl, C1-C8alkoxy, C3-C10cycloalkyl, C6-C14aryl, —O—C6-C14aryl, 5-10 membered heteroaryl and 4-10 membered heterocycle; wherein two geminal C1-C8alkyl groups, together with the carbon to which they are attached, may be joined together to form a C3-C6cycloalkyl optionally substituted by one, two or three substituents each independently selected from halogen, hydroxyl and oxo; and wherein the alkyl, aryl, heterocycle or heteroaryl may optionally be substituted by one or more substituents each independently selected from oxo, halogen and C1-C8alkyl; RGis selected from the group consisting of hydrogen, C1-6alkyl optionally substituted by one, two or three Rgg, —C(═O)—C1-6alkyl optionally substituted by one, two or three Rhh, —C(═O)—C3-6cycloalkyl, —C(O)—(C2-C10alkenyl)-(C6-C14aryl), —C(O)—(C1-C6alkyl)-O—(C6-C14aryl), —C(O)-(5-10 membered heteroaryl), —C(O)-(4-10 membered heterocyclyl), and —C(O)-(4-10 membered heterocyclyloxy); wherein the aryl, heterocyclyl, or heteroaryl may optionally be substituted by one, two or three Rjj; Rggis independently selected for each occurrence from the group consisting of —C(═O), halo, cyano, —NRmRm, and —NH(C═O)Rm; Rhhis independently selected for each occurrence from the group consisting of halo, cyano, —NRmRm, —NRm(C═O)Rm, phenyl, cycloalkyl, heterocyclyl and C1-C6alkoxy; Rjjis independently selected for each occurrence from the group consisting of halo, oxo, hydroxyl, cyano, C1-C6alkyl, C1-6haloalkyl, C1-6haloalkoxy, C1-C6alkoxy, C3-6cycloalkyl, SF5, and NH2; Rmis independently selected for each occurrence from the group consisting of hydrogen, C1-3alkyl, phenyl, —S(O)2—CH3, C3-6cycloalkyl, and 5-6 membered heteroaryl; wherein C1-3alkyl, phenyl, and C3-6cycloalkyl may optionally be substituted by one, two or three halo; Rxxis —(OCH2CH2)nn—, wherein nn is selected from 1, 2, 3, 4, 5 and 6; Ryis independently selected, for each occurrence, from the group consisting of hydrogen, C1-C8alkyl, C1-C8heteroalkyl, —CF3, —CH2CF3, C1-C8alkoxy, —(C1-C8alkoxy)-(5-10 membered aryl), C3-C6cycloalkyl and —(C1-C8alkyl)COOH; A is a warhead; and X is selected from the group consisting of C(Rxy) and N, wherein Rxyis selected from the group consisting of H, D, —OH, —NH2, halogen, C1-C8alkyl, C1-C8haloalkyl, and C1-C8alkoxy.

In some embodiments, disclosed herein are compounds represented by Formula II-A:

In some embodiments, disclosed herein are compounds represented by Formula II-B:

In some embodiments, disclosed herein are compounds represented by Formula II-C:

In some embodiments, disclosed herein are compounds represented by Formula II-D-A or Formula II-D-B:

In some embodiments, disclosed herein are compounds represented by Formula II-E-A or Formula II-E-B:

In some embodiments, disclosed herein are compounds represented by Formula II-F:

In some embodiments, disclosed herein are compounds represented by Formula II-G:

In some embodiments, disclosed herein are compounds represented by Formula II-H-A or Formula II-H-B:

wherein pp is selected from 0, 1, 2, and 3.

In some embodiments, disclosed herein are compounds represented by Formula II-E:

wherein ss is selected from 0, 1, 2, and 3, and mm is selected from 1, 2, and 3.

In some embodiments, disclosed herein are compounds represented by Formula II-I:

or a pharmaceutically acceptable salt thereof, wherein:

Rtis independently, for each occurrence, H or methyl; or each Rtmay be taken, together with the carbon to which they are attached, to form a cyclopropyl; RBis selected from the group consisting of: a 9-10 membered bicyclic heteroaryl having one ring nitrogen, C1-C6alkyl, and C2-C3alkenyl; wherein RBis optionally substituted by one, two or three substituents each independently selected from the group consisting of halogen, C1-C3alkoxy, NHRm, and phenyl (optionally substituted by one or two halogens); and Rmis C1-C3alkyl or —C(O)—C1-3alkyl, wherein each C1-C3alkyl is independently optionally substituted by one, two or three halogens.

In certain embodiments, disclosed herein are conjugates represented by Formula III:

wherein Cys145is cysteine at position 145 or equivalent active site cysteine on a CL or 3CL protease; IR is a viral protease inhibitor; and wherein the compound that forms the conjugate comprises a —CN warhead.

DETAILED DESCRIPTION

The features and other details of the disclosure will now be more particularly described. Before further description of the present disclosure, certain terms employed in the specification, examples and appended claims are collected here. These definitions should be read in light of the remainder of the disclosure and as understood by a person of skill in the art. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by a person of ordinary skill in the art.

Definitions

The term “treating” includes any effect, e.g., lessening, reducing, modulating, or eliminating, that results in the improvement of the condition, disease, disorder and the like, including a reduction of viral shedding in asymptomatic individuals and prophylaxis of exposed individuals, independent of symptoms.

The term “alkynyl” as used herein refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon triple bond. Exemplary alkynyl groups include, but are not limited to, straight or branched groups of 2-6, or 3-6 carbon atoms, referred to herein as C2-6alkynyl, and C3-6alkynyl, respectively. Exemplary alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylpropynyl, etc.

The term “alkenyl” as used herein refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon double bond. Exemplary alkenyl groups include, but are not limited to, a straight or branched group of 2-6 or 3-4 carbon atoms, referred to herein as C1-C5alkenyl, C2-C6alkenyl, and C3-C4alkenyl, respectively. Exemplary alkenyl groups include, but are not limited to, vinyl, allyl, butenyl, pentenyl, etc.

The term “alkoxy” as used herein refers to a straight or branched alkyl group attached to oxygen (alkyl-O—). Exemplary alkoxy groups include, but are not limited to, alkoxy groups of 1-6 or 2-6 carbon atoms, referred to herein as C1-C5alkoxy, C1-C6alkoxy, and C2-C6alkoxy, respectively. Exemplary alkoxy groups include, but are not limited to methoxy, ethoxy, isopropoxy, etc.

The term “aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C6-14aryl”). In some embodiments, an aryl group has six ring carbon atoms (“C6aryl”; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms (“C10aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms (“C14aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system. Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthalene. Particularly aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl.

Examples of representative substituted aryls include the following:

The term “carbonyl” as used herein refers to the radical —C(O)—.

The term “cyano” as used herein refers to the radical —CN.

The term “cycloalkoxy” as used herein refers to a cycloalkyl group attached to oxygen (cycloalkyl-O—). Exemplary cycloalkoxy groups include, but are not limited to, cycloalkoxy groups of 3-6 carbon atoms, referred to herein as C3-6cycloalkoxy groups. Exemplary cycloalkoxy groups include, but are not limited to, cyclopropoxy, cyclobutoxy, cyclohexyloxy, etc.

The terms “cycloalkyl” or a “carbocyclic group” as used herein refers to a saturated or partially unsaturated hydrocarbon group of, for example, 3-6, or 4-6 carbons, referred to herein as C3-C10cycloalkyl, C3-6cycloalkyl or C4-6cycloalkyl, respectively. Exemplary cycloalkyl groups include, but are not limited to, cyclohexyl, cyclopentyl, cyclopentenyl, cyclobutyl or cyclopropyl.

The terms “halo” or “halogen” as used herein refer to F, Cl, Br, or I.

The term “haloalkyl” as used herein refers to an alkyl radical in which the alkyl group is substituted with one or more halogens. Typical haloalkyl groups include, but are not limited to, trifluoromethyl (i.e. CF3), difluoromethyl, fluoromethyl, chloromethyl, dichloromethyl, dibromoethyl, tribromomethyl, tetrafluoroethyl, and the like. Exemplary haloalkyl groups include, but are not limited to, straight or branched hydrocarbons of 1-6, 1-4, or 1-3 carbon atoms substituted with a halogen (i.e. Cl, F, Br and I), referred to herein as C1-6haloalkyl, C1-4haloalkyl, and C1-3haloalkyl, respectively.

The term “hetero” when used to describe a compound or a group present on a compound means that one or more carbon atoms in the compound or group have been replaced by a nitrogen, oxygen, or sulfur heteroatom. Hetero may be applied to any of the hydrocarbyl groups described above such as alkyl, e.g., heteroalkyl, cycloalkyl, e.g., heterocyclyl, aryl, e.g., heteroaryl, cycloalkenyl, e.g., cycloheteroalkenyl, and the like having from 1 to 5, and particularly from 1 to 3 heteroatoms.

The terms “heteroaryl” or “heteroaromatic group” as used herein refers to an aromatic 5-10 membered ring system containing one or more heteroatoms, for example one to three heteroatoms, such as nitrogen, oxygen, and sulfur. The term may also be used to refer to a 5-7 membered monocyclic heteroaryl or an 8-10 membered bicyclic heteroaryl. Where possible, said heteroaryl ring may be linked to the adjacent radical though carbon or nitrogen. Examples of heteroaryl rings include but are not limited to furan, thiophene, pyrrole, pyrrolopyridine, indole, thiazole, oxazole, isothiazole, isoxazole, imidazole, benzoimidazole, imidazopyridine, pyrazole, triazole, pyridine or pyrimidine, etc.

Examples of representative heteroaryls include the following:

The terms “heterocyclyl,” “heterocycle,” or “heterocyclic group” are art-recognized and refer to saturated or partially unsaturated 4-10 membered ring structures, whose ring structures include one to three heteroatoms, such as nitrogen, oxygen, and sulfur. Where possible, heterocyclyl rings may be linked to the adjacent radical through carbon or nitrogen. The term may also be used to refer to 4-10 membered saturated or partially unsaturated ring structures that are bridged, fused or spirocyclic ring structures, whose ring structures include one to three heteroatoms, such as nitrogen, oxygen, and sulfur. Examples of heterocyclyl groups include, but are not limited to, pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine, oxetane, azetidine, tetrahydrofuran, dihydrofuran, dihydropyran, tetrahydropyran, etc. In some embodiments, the heterocycle is a spiro heterocycle (e.g., 2,8-diazaspiro[4.5]decane). In some embodiments, the heterocycle is a bridged heterocycle (e.g., octahydro-1H-4,7-methanoisoindole). “Spiro heterocyclyl,” or “spiro heterocycle” refers to a polycyclic heterocyclyl with rings connected through one common atom (called a spiro atom), wherein the rings have one or more heteroatoms selected from the group consisting of N, O, and S(O)m(wherein m is an integer of 0 to 2) as ring atoms. Representative examples of heterocyclyl include, for example:

The term “heterocyclyloxy” as used herein refers to a heterocyclyl group attached to oxygen (heterocyclyl-O—).

The term “heteroaryloxy” as used herein refers to a heteroaryl group attached to oxygen (heteroaryl-O—).

The terms “hydroxy” and “hydroxyl” as used herein refers to the radical —OH.

The term “oxo” as used herein refers to the radical ═O.

“Pharmaceutically or pharmacologically acceptable” include molecular entities and compositions that do not produce an adverse, allergic or other untoward reaction when administered to an animal, or a human, as appropriate. For human administration, preparations should meet sterility, pyrogenicity, and general safety and purity standards as required by FDA Office of Biologics standards.

The term “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” as used herein refers to any and all solvents, dispersion media, coatings, isotonic and absorption delaying agents, and the like, that are compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is well-known in the art. The compositions may also contain other active compounds providing supplemental, additional, or enhanced therapeutic functions.

The term “pharmaceutical composition” as used herein refers to a composition comprising at least one compound as disclosed herein formulated together with one or more pharmaceutically acceptable carriers.

“Individual,” “patient,” or “subject” are used interchangeably and include any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans. The compounds of the disclosure can be administered to a mammal, such as a human, but can also be administered to other mammals such as an animal in need of veterinary treatment, e.g., domestic animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, sheep, pigs, horses, and the like) and laboratory animals (e.g., rats, mice, guinea pigs, and the like). “Modulation” includes antagonism (e.g., inhibition), agonism, partial antagonism and/or partial agonism.

In the present specification, the term “therapeutically effective amount” means the amount of the subject compound that will elicit the biological or medical response of a tissue, system or animal, (e.g. mammal or human) that is being sought by the researcher, veterinarian, medical doctor or other clinician. The compounds of the disclosure are administered in therapeutically effective amounts to treat a disease. Alternatively, a therapeutically effective amount of a compound is the quantity required to achieve a desired therapeutic and/or prophylactic effect.

The term “pharmaceutically acceptable salt(s)” as used herein refers to salts of acidic or basic groups that may be present in compounds used in the compositions. Compounds included in the present compositions that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. The acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, e.g., salts containing pharmacologically acceptable anions, including, but not limited to, malate, oxalate, chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (i.e., 1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Compounds included in the present compositions that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include alkali metal or alkaline earth metal salts, particularly calcium, magnesium, sodium, lithium, zinc, potassium, and iron salts. Compounds included in the present compositions that include a basic or acidic moiety may also form pharmaceutically acceptable salts with various amino acids. The compounds of the disclosure may contain both acidic and basic groups; for example, one amino and one carboxylic acid group. In such a case, the compound can exist as an acid addition salt, a zwitterion, or a base salt.

The compounds of the disclosure may contain one or more chiral centers and, therefore, exist as stereoisomers. The term “stereoisomers” when used herein consist of all enantiomers or diastereomers. These compounds may be designated by the symbols “(+),” “(−),” “R” or “S,” depending on the configuration of substituents around the stereogenic carbon atom, but the skilled artisan will recognize that a structure may denote a chiral center implicitly. The present disclosure encompasses various stereoisomers of these compounds and mixtures thereof. Mixtures of enantiomers or diastereomers may be designated “(±)” in nomenclature, but the skilled artisan will recognize that a structure may denote a chiral center implicitly.

The compounds of the disclosure may contain one or more double bonds and, therefore, exist as geometric isomers resulting from the arrangement of substituents around a carbon-carbon double bond. The symboldenotes a bond that may be a single, double or triple bond as described herein. Substituents around a carbon-carbon double bond are designated as being in the “Z” or “E” configuration wherein the terms “Z” and “E” are used in accordance with IUPAC standards. Unless otherwise specified, structures depicting double bonds encompass both the “E” and “Z” isomers. Substituents around a carbon-carbon double bond alternatively can be referred to as “cis” or “trans,” where “cis” represents substituents on the same side of the double bond and “trans” represents substituents on opposite sides of the double bond.

Compounds of the disclosure may contain a carbocyclic or heterocyclic ring and therefore, exist as geometric isomers resulting from the arrangement of substituents around the ring. The arrangement of substituents around a carbocyclic or heterocyclic ring are designated as being in the “Z” or “E” configuration wherein the terms “Z” and “E” are used in accordance with IUPAC standards. Unless otherwise specified, structures depicting carbocyclic or heterocyclic rings encompass both “Z” and “E” isomers. Substituents around a carbocyclic or heterocyclic rings may also be referred to as “cis” or “trans”, where the term “cis” represents substituents on the same side of the plane of the ring and the term “trans” represents substituents on opposite sides of the plane of the ring. Mixtures of compounds wherein the substituents are disposed on both the same and opposite sides of plane of the ring are designated “cis/trans.”

Individual enantiomers and diastereomers of compounds of the present disclosure can be prepared synthetically from commercially available starting materials that contain asymmetric or stereogenic centers, or by preparation of racemic mixtures followed by resolution methods well-known to those of ordinary skill in the art. These methods of resolution are exemplified by (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and liberation of the optically pure product from the auxiliary, (2) salt formation employing an optically active resolving agent, (3) direct separation of the mixture of optical enantiomers on chiral liquid chromatographic columns or (4) kinetic resolution using stereoselective chemical or enzymatic reagents. Racemic mixtures can also be resolved into their component enantiomers by well-known methods, such as chiral-phase liquid chromatography or crystallizing the compound in a chiral solvent. Stereoselective syntheses, a chemical or enzymatic reaction in which a single reactant forms an unequal mixture of stereoisomers during the creation of a new stereocenter or during the transformation of a pre-existing one, are well-known in the art. Stereoselective syntheses encompass both enantio- and diastereoselective transformations, and may involve the use of chiral auxiliaries. For examples, see Carreira and Kvaerno,Classics in Stereoselective Synthesis, Wiley-VCH: Weinheim, 2009.

The compounds disclosed herein can exist in solvated as well as unsolvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the disclosure embrace both solvated and unsolvated forms. In one embodiment, the compound is amorphous. In one embodiment, the compound is a single polymorph. In another embodiment, the compound is a mixture of polymorphs. In another embodiment, the compound is in a crystalline form.

The disclosure also embraces isotopically labeled compounds of the disclosure which are identical to those recited herein, except that one or more atoms are replaced by 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 can be incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as2H,3H,13C,14C,15N,18O,17O,31P,32P,35S,18F, and36Cl, respectively. For example, a compound of the disclosure may have one or more H atom replaced with deuterium.

The term “prodrug” refers to compounds that are transformed in vivo to yield a disclosed compound or a pharmaceutically acceptable salt, hydrate or solvate of the compound. The transformation may occur by various mechanisms (such as by esterase, amidase, phosphatase, oxidative and or reductive metabolism) in various locations (such as in the intestinal lumen or upon transit of the intestine, blood or liver). Prodrugs are well-known in the art (for example, see Rautio, Kumpulainen, et al., Nature Reviews Drug Discovery 2008, 7, 255). For example, if a compound of the disclosure or a pharmaceutically acceptable salt, hydrate or solvate of the compound contains a carboxylic acid functional group, a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a group such as (C1-8)alkyl, (C2_12)alkylcarbonyloxymethyl, 1-(alkylcarbonyloxy)ethyl having from 4 to 9 carbon atoms, 1-methyl-1-(alkylcarbonyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, 1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms, 3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl, di-N,N—(C1-2)alkylamino(C2-3)alkyl (such as β-dimethylaminoethyl), carbamoyl-(C1-2)alkyl, N,N-di(C1-2)alkylcarbamoyl-(C1-2)alkyl and piperidino-, pyrrolidino- or morpholino(C2-3)alkyl.

Similarly, if a compound of the disclosure contains an alcohol functional group, a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as (C1-6)alkylcarbonyloxymethyl, 1-((C1-6)alkylcarbonyloxy)ethyl, 1-methyl-1-((C1-6)alkylcarbonyloxy)ethyl (C1-6)alkoxycarbonyloxymethyl, N—(C1-6)alkoxycarbonylaminomethyl, succinoyl, (C1-6)alkylcarbonyl, α-amino(C1-4)alkylcarbonyl, arylalkylcarbonyl and α-aminoalkylcarbonyl, or α-aminoalkylcarbonyl-α-aminoalkylcarbonyl, where each α-aminoalkylcarbonyl group is independently selected from the naturally occurring L-amino acids, P(O)(OH)2, —P(O)(O(C1-6)alkyl)2or glycosyl (the radical resulting from the removal of a hydroxyl group of the hemiacetal form of a carbohydrate).

If a compound of the disclosure incorporates an amine functional group, a prodrug can be formed, for example, by creation of an amide or carbamate, an N-alkylcarbonyloxyalkyl derivative, an (oxodioxolenyl)methyl derivative, an N-Mannich base, imine or enamine. In addition, a secondary amine can be metabolically cleaved to generate a bioactive primary amine, or a tertiary amine can metabolically cleaved to generate a bioactive primary or secondary amine. For examples, see Simplicio, et al.,Molecules2008, 13, 519 and references therein.

The term “warhead” or “warhead group” as used herein refers to a functional group present on a compound wherein that functional group is capable of reversibly or irreversibly participating in a reaction with a protein, e.g., 3C or 3CL protease (e.g., with a cysteine on the protease such as Cys 145). Warheads may, for example, form covalent bonds with the protein, or may create stable transition states, or be a reversible or an irreversible alkylating agent. For example, the warhead moiety can be a functional group on an inhibitor that can participate in a bond-forming reaction, wherein a new covalent bond is formed between a portion of the warhead and a donor, for example an amino acid residue of a protein. In embodiments, the warhead is an electrophile and the “donor” is a nucleophile such as the side chain of a cysteine residue. As provided herein, a warhead may include a nitrile or halo group. As also provided herein, a warhead may include an aldehyde, ketoamides, hydroxybisulfite salts, heterocyclic moieties, aziridine, oxirane, epoxy ketones, halomethyl ketones, hydroxymethyl ketones, electrophilic ketones (e.g. trifluoromethyl ketones), acyloxymethyl ketones, benzothiazolyl ketones and a Michael acceptor. For example, nitriles may be reversible covalent warheads for cysteine protease inhibition, for example, where the mechanism of action may involve formation of a reversible covalent bond between the nitrile and the active cysteine to form a thioimidate adduct. Reaction of cysteine of glutathione or other proteins is generally reversible, while the reaction with cysteine or aminoethylthiols generally irreversibly forms a thiazolidine adduct. It can be appreciated that contemplated compounds herein may be a reversible or an irreversible inhibitor.

In some embodiments, the warhead is a moiety with a cyanohydrin or cyanoacrylate moiety. Examples of exemplary cyanohydrin and cyanoacrylate warheads include, but not limited to:

wherein R13bbis selected from the group consisting of halogen, C1-C6haloalkyl, C1-C6alkoxy, C3-C10cycloalkyl, —N(ReRf), and —C(O)—N(ReRf); Reand Rfare each selected from the group consisting of hydrogen and C1-C6alkyl; or Reand Rfmay form, together with the nitrogen to which they are attached, a 4-6 membered heterocycle; and p is 0, 1, 2, 3, or 4, as valency permits.

In some embodiments, the warhead is a moiety with a cyano amine or cyano amide moiety. Examples of exemplary cyanoamine warheads include, but not limited to:

wherein R13bbis selected from the group consisting of halogen, C1-C6haloalkyl, C1-C6alkoxy, C3-C10cycloalkyl, —N(ReRf), and —C(O)—N(ReRf); Reand Rfare each selected from the group consisting of hydrogen and C1-C6alkyl; or Reand Rfmay form, together with the nitrogen to which they are attached, a 4-6 membered heterocycle; and p is 0, 1, 2, 3, or 4, as valency permits.

In some embodiments, the warhead is a moiety with an imino-oxazolidinone moiety. Examples of exemplary imino-oxazolidinone warheads include, but not limited to:

In some embodiments, the warhead is a moiety with an iminoimidazolidinone. Examples of exemplary iminoimidazolidinone warheads include, but not limited to:

wherein each Rcccand Rcccis selected from the group consisting of hydrogen, C1-C8alkyl, C3-C6cycloalkyl, —(C1-C8alkyl)-(C6-C14aryl), and C6-C14aryl. In some embodiments, the warhead is selected from the group consisting of

Other examples of exemplary warheads include, but not limited to:

wherein Rccis selected from the group consisting of hydrogen, C1-C8alkyl, C3-C6cycloalkyl, —(C1-C8alkyl)-(C6-C14aryl), C6-C14aryl, 5-10 membered heteroaryl, —(C1-C8alkyl)-(5-10 membered heteroaryl), 5-10 membered heterocycle and —N(RbRc), wherein Rband Rcare each selected from the group consisting of hydrogen, C1-C8alkyl, and C3-C6cycloalkyl, or Rband Rcmay be joined together to form, together with the nitrogen to which they are attached, a 5-10 membered heterocycle.

Some other examples of exemplary warheads include, but not limited to:

wherein Rcdis selected from the group consisting of hydrogen, C1-C8alkyl, and C3-C6cycloalkyl.

Other examples of exemplary warheads include, but not limited to:

wherein Rcis selected from the group consisting of hydrogen, —CH2C(O)O(C1-C8alkyl), C1-C8alkyl, and C3-C6cycloalkyl, wherein the C1-C8alkyl may optionally be substituted by one or more substituents each selected from the group consisting of halogen, C3-C6cycloalkyl, 5-10 membered aryl and 5-10 membered heteroaryl;

wherein X2is selected from the group consisting of NH, O and S; X3is independently selected, for each occurrence, from N and CH; RDis independently selected, for each occurrence, from the group consisting of C1-C8alkyl,

REis independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, C1-C8alkyl and C1-C8alkoxy; p is selected from 0, 1 and 2; and q is selected from 0, 1 and 2;

wherein X2is selected from the group consisting of NH, NRP, O and S, wherein RPis C1-C8alkyl;

wherein RDis selected from the group consisting of C3-C6cycloalkyl, C1-C8alkyl, and

X4is independently selected, for each occurrence, from CH and N; REis independently selected, for each occurrence, from the group consisting of halogen, —CH3, —OCH3, —OCH2CH3, —OCH(CH3)2, —CN, —CF3, —OCF3and —SCF3; and p is selected from 0, 1 and 2; —C(O)RD, wherein RDis selected from the group consisting of hydrogen, —CH2OH, —CH2OR′ and —CHxFy, wherein x is 0, 1 or 2; y is 1, 2 or 3; and the sum of x and y is 3, wherein R′ is selected from the group consisting of C1-C8alkyl, —(C1-C8alkyl)-(5-10 membered aryl), C1-C8heteroalkyl, C3-C6cycloalkyl and 5-10 membered aryl; and —(CH═CH)C(O)ORD, wherein RDis C1-C8alkyl.

It will be appreciated to one of skill in the art that the compounds disclosed herein that include the warheads above also contemplate the precursors to those compounds, for example, where a cyano moiety involved in a warheads may be replaced with e.g., a halo moiety.

It will be appreciated to one of skill in the art that the compounds disclosed herein can also irreversibly bind, or may otherwise inhibit e.g., a virus protein via any other mechanism of action.

The term “inhibitor” as used herein refers to a compound that binds to and/or inhibits a target protease with measurable affinity.

The term “reversible” or “reversible inhibitor” as used herein refers to a protease inhibitor that associates with a protease in such a way as to inhibit the activity of the protease while the protease and inhibitor are bound, but does not associate with a protease in such a way as to inhibit the activity of the protease when the protease and inhibitor are no longer bound. Reversible inhibitors can effect inhibition by competing with substrate for binding to the active site of the protease (competitive reversible inhibitor), or by associating with the protease bound to its substrate in a way to make the complex inactive (uncompetitive reversible inhibitor), or by associating with the protease and/or protease-substrate complex in a way that inhibits the activity of either and/or both.

As used herein, the term “irreversible” or “irreversible inhibitor” refers to an inhibitor (i.e. a compound) that is able to be covalently bonded to a target protease in a substantially non-reversible manner. An irreversible inhibitor will remain substantially bound to the target protease once covalent bond formation has occurred. Irreversible inhibitors usually display time dependency, whereby the degree of inhibition increases with the time with which the inhibitor is in contact with the enzyme. In certain embodiments, an irreversible inhibitor will remain substantially bound to target protease once covalent bond formation has occurred, and will remain bound for a time period that is longer than the life of the protein.

I. Reversible or Irreversible Viral Protease Inhibitor Compounds

The disclosure is directed to, in part, compounds that inhibit a viral protease. Examples of viral proteases include, but not limited to, Cathepsin K, coronavirus main protease (Mpro), Caspase 3, Calpain 1, and Cathepsin S. Accordingly, in various embodiments, a compound of the present disclosure (e.g. a compound of Formula II, II-A, II-B, II-C, II-D-A, II-D-B, II-E-A, II-E-B, II-F, II-G, II-H-A, II-H-B, II-E, II-I, IV-A or IV-B) is a viral protease inhibitor, wherein the viral protease is selected from the group consisting of Cathepsin K, coronavirus main protease (Mpro), Caspase 3, Calpain 1, and Cathepsin S. In certain embodiments, the viral protease is a coronavirus main protease (Mpro). In some embodiments, the viral protease is Cathepsin K. In some embodiments, the viral protease is Caspase 3. In some embodiments, the viral protease is Calpain 1. In some embodiments, the viral protease is Cathepsin S.

Also provided herein are compounds represented by

and 4-10 membered heterocycle, wherein the heterocycle may optionally be substituted by one, two or three substituents each independently selected from the group consisting of hydroxyl, C1-C8alkoxy, oxo and a warhead A; R3bis selected from hydrogen and C1-C8alkyl; wherein R3aand R3bmay be joined together to form, together with the carbon to which they are attached, a 4-10 membered heterocycle, wherein the heterocycle may optionally be substituted by one, two or three substituents each independently selected from C6-C14aryl and a warhead A; R1ais selected from the group consisting of hydrogen, C1-C8alkyl, C1-C8heteroalkyl, —(C1-C8alkyl)-R1, —(C1-C8alkyl)-CN, C3-C10cycloalkyl, C6-C14aryl, 4-10 membered heterocycle and 5-10 membered heteroaryl; R1bis selected from hydrogen and C1-C8alkyl; or R1aand R1bmay be joined together to form, together with the carbon to which they are attached, a 4-10 membered heterocycle having a ring nitrogen, NRG, or a C3-C10cycloalkyl; R1is selected from the group consisting of C1-C8alkyl, C2-C10alkenyl, C2-C10alkynyl, C3-C10cycloalkyl, C6-C14aryl, 5-10 membered heteroaryl and 4-10 membered heterocycle, wherein R1may optionally be substituted by one, two, or three substituents each selected from RA; RAis independently selected for each occurrence from the group consisting of halogen, cyano, hydroxyl, oxo, SF5, —CH2CF3, —CF3, —O—CF3, —O—CHF2, —S—CH3, —S(O)2—CH3, —NH2, —O-phenyl, —O—(C1-C8alkyl)-phenyl, —NHC(O)RB, —NHC(O)ORB, —NHC(O)O—(C1-C8alkyl)-RB, —N(Ry)2, —N(Ry)(C1-C8alkyl)C(O)O-phenyl, —N(Ry)(C1-C8alkyl)C(O)N(Ry)2, —C(O)—OC(CH3)3, C1-C8alkyl, C2-C10alkenyl, C2-C10alkynyl, C1-C8heteroalkyl, C1-C8alkoxy, C3-C10cycloalkyl, —(C1-C8alkyl)-(C3-C10cycloalkyl), —(C1-C8alkyl)-(C6-C14aryl), —(C1-C8alkyl)-(5-10 membered heteroaryl), C6-C14aryl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl, wherein the RB, alkyl, heterocyclyl, heteroaryl, or aryl may optionally be substituted by one, two or three substituents each independently selected from the group consisting of halogen, C1-C8alkyl, C1-C8alkoxy, SF5, —NH2, hydroxyl and oxo; R2is selected from the group consisting of —NHC(O)RB, —NHC(O)N(RB)2, —NHC(O)C(RC)2RB, —NHS(O)2RB, —O—(C1-C8alkyl)-(C3-C10cycloalkyl), 4-10 membered heterocycle, C6-C14aryl and 5-10 membered heteroaryl bound through the carbon or nitrogen atom, wherein RBor R2may optionally be substituted by one, two, or three substituents each selected from Rx; or R1aand R2may be joined together to form, together with the carbon to which they are attached, a 4-10 membered monocyclic or bicyclic heterocycle having a ring nitrogen NRG, or a C3-C10cycloalkyl, wherein the cycloalkyl or heterocycle may optionally be substituted by one, two or three substituents on a free carbon each selected from RA; R3is selected from 5-10 membered heteroaryl and 4-10 membered heterocycle, wherein R3may optionally be substituted by one, two, or three substituents each selected from RA; RBis independently selected, for each occurrence, from the group consisting of C1-C8alkyl, C2-C10alkenyl, C2-C10alkynyl, C3-C6cycloalkyl, fluorenylmethyloxy, C6-C14aryl, 5-10 membered heteroaryl and 4-10 membered heterocycle; RCis independently selected, for each occurrence, from hydrogen, halogen and C1-C8alkyl; Rxis independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, oxo, CF3, SF5, cyano, —O—(Rxx)—OCH3, —OCHF2, —OCF3, —O—(C1-C8alkyl), —C(O)O(CH3), —N(Ry)2, —N(Ry)C(O)Ry, —N(Ry)(C1-C8alkyl)C(O)N(Ry)2, —N(Ry)(C1-C8alkyl)C(O)OH, —(C1-C8alkyl)-(C3-C10cycloalkyl), C1-C8alkyl, C1-C8alkoxy, C3-C10cycloalkyl, C6-C14aryl, —O—C6-C14aryl, 5-10 membered heteroaryl and 4-10 membered heterocycle; wherein two geminal C1-C8alkyl groups, together with the carbon to which they are attached, may be joined together to form a C3-C6cycloalkyl optionally substituted by one, two or three substituents each independently selected from halogen, hydroxyl and oxo; and wherein the alkyl, aryl, heterocycle or heteroaryl may optionally be substituted by one or more substituents each selected from oxo, halogen and C1-C8alkyl; RGis selected from the group consisting of hydrogen, C1-6alkyl optionally substituted by one, two or three Rgg, —C(═O)—C1-6alkyl optionally substituted by one, two or three Rhh, —C(═O)—C3-6cycloalkyl, —C(O)—(C2-C10alkenyl)-(C6-C14aryl), —C(O)—(C1-C6alkyl)-O—(C6-C14aryl), —C(O)-(5-10 membered heteroaryl), —C(O)-(4-10 membered heterocyclyl), and —C(O)-(4-10 membered heterocyclyloxy); wherein the aryl, heterocyclyl, or heteroaryl may optionally be substituted by one, two or three Rjj; Rggis independently selected for each occurrence from the group consisting of —C(═O), halo, cyano, —NRmRm, and —NH(C═O)Rm; Rhhis independently selected for each occurrence from the group consisting of halo, cyano, —NRmRm, —NRm(C═O)Rm, phenyl, cycloalkyl, heterocyclyl and C1-C6alkoxy; Rjjis independently selected for each occurrence from the group consisting of halo, oxo, hydroxyl, cyano, C1-C6alkyl, C1-6haloalkyl, C1-C6alkoxy, C1-6haloalkoxy, C3-6cycloalkyl, SF5, and NH2; Rmis independently selected for each occurrence from the group consisting of hydrogen, C1-3alkyl, phenyl, —S(O)2—CH3, C3-6cycloalkyl, and 5-6 membered heteroaryl; wherein C1-3alkyl, phenyl, and C3-6cycloalkyl may optionally be substituted by one, two or three halo; Rxxis —(OCH2CH2)nn—, wherein nn is selected from 1, 2, 3, 4, 5 and 6; Ryis independently selected, for each occurrence, from the group consisting of hydrogen, C1-C8alkyl, C1-C8heteroalkyl, —CF3, —CH2CF3, C1-C8alkoxy, —(C1-C8alkoxy)-(5-10 membered aryl), C3-C6cycloalkyl and —(C1-C8alkyl)COOH; A is a warhead; and X is selected from the group consisting of C(Rxy) and N, wherein Rxyis selected from the group consisting of H, D, —OH, —NH2, halogen, C1-C8alkyl, C1-C8haloalkyl, and C1-C8alkoxy.

In certain embodiments, disclosed herein are compounds represented by Formula II-A:

In certain embodiments, disclosed herein are compounds represented by Formula II-B:

In various embodiments, disclosed herein are compounds represented by Formula II-C:

In some embodiments, disclosed herein are compounds represented by Formula II-D-A or Formula II-D-B:

In some embodiments, disclosed herein are compounds represented by Formula II-E-A or Formula II-E-B:

In some embodiments, provided herein are compounds represented by Formula II-F:

In some embodiments, provided herein are compounds represented by Formula II-G:

In some embodiments, disclosed herein are compounds represented by Formula II-H-A or Formula II-H-B:

wherein pp is selected from 0, 1, 2, and 3.

In some embodiments, disclosed herein are compounds represented by Formula II-E:

wherein ss is selected from 0, 1, 2, and 3, and mm is selected from 1, 2, and 3.

In other embodiments, disclosed herein are compounds represented by Formula II-E-II:

wherein ss is selected from 0, 1, 2, and 3, and mm is selected from 1, 2, and 3.

In some embodiments, disclosed herein are compounds represented by Formula

or a pharmaceutically acceptable salt thereof, wherein:

Rtis independently, for each occurrence, H or methyl; or each Rtmay be taken, together with the carbon to which they are attached, to form a cyclopropyl; RBis selected from the group consisting of: a 9-10 membered bicyclic heteroaryl having one ring nitrogen, C1-C6alkyl, and C2-C3alkenyl; wherein RBis optionally substituted by one, two or three substituents each independently selected from the group consisting of halogen, C1-C3alkoxy, NHRm, and phenyl (optionally substituted by one or two halogens); and Rmis C1-3alkyl or —C(O)—C1-3alkyl, wherein C1-3alkyl is independently optionally substituted by one, two or three halogens.

In certain embodiments, R3ais

In various embodiments, X is selected from the group consisting of CH, CD, C(CH3), C(CH2CH3), N, CF, CCl, CBr, C(CHF2), C(CH2F), and C(CF3). In some embodiments, X is CH. In some embodiments, X is CD. In some embodiments, X is C(CH3). In some embodiments, X is C(CF3). In some embodiments, X is CF. In some embodiments, X is N.

In some embodiments, A is selected from the group consisting of cyano, —C(O)RD, —C(O)CH2N(RbRc), —C(O)CH2OC(O)RD, —C(O)C(O)RD, —(CH═CH)C(O)ORD, —(CH═CCN)C(O)ORD, —(CH═CCN)C(O)(NH)RD, —CH(CN)(OH), —CH(CN)(NRbRc),

wherein RDis selected from the group consisting of hydrogen, hydroxyl, —ORbb—N(RbRc), C1-C8alkyl, C1-C8alkoxy, C3-C6cycloalkyl, C6-C14aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycle; wherein RDmay optionally be substituted by one, two, or three substituents each independently selected from the group consisting of halogen, hydroxyl, and RE; REis selected from the group consisting of C1-C8alkyl, C1-C8alkoxy, C6-C14aryl, 4-10 membered heterocycle, and 5-10 membered heteroaryl, wherein REmay optionally be substituted by one, two, or three substituents each independently selected from the group consisting of halogen, cyano, C1-C8alkyl and C1-C8alkoxy; Rbbis selected from the group consisting of C3-C6cycloalkyl, C6-C14aryl, —(C1-C8alkyl)-C6-C14aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycle; Rccis selected from the group consisting of hydrogen, C1-C8alkyl, C3-C6cycloalkyl, —(C1-C8alkyl)-(C6-C14aryl), C6-C14aryl, 5-10 membered heteroaryl, —(C1-C8alkyl)-(5-10 membered heteroaryl), 5-10 membered heterocycle and —N(RbRc), wherein Rband Rcare each independently selected from the group consisting of hydrogen, C1-C8alkyl, and C3-C6cycloalkyl, or Rband Rcmay be joined together to form, together with the nitrogen to which they are attached, a 5-10 membered heterocycle; Rcdis selected from the group consisting of hydrogen, C1-C8alkyl, and C3-C6cycloalkyl; and Rband Rcare each selected from the group consisting of hydrogen, —CH2C(O)O(C1-C8alkyl), —C(O)—(C1-C8alkyl), —S(O)2—(C1-C8alkyl), C1-C8alkyl, C3-C6cycloalkyl and —(C1-C8alkyl)-C6-C14aryl, wherein the C1-C8alkyl may optionally be substituted by one or more substituents each selected from the group consisting of halogen, C3-C6cycloalkyl, C6-C14aryl, 4-10 membered heterocycle, and 5-10 membered heteroaryl.

In embodiments, A is selected from the group consisting of

In embodiments, R1ais selected from the group consisting of

In certain embodiments, R1aand R1bare joined to together to form

In some embodiments, R3ais selected from the group consisting of

In some embodiments, R3is selected from

In some embodiments, R3is

wherein Rx3are independently for each occurrence selected from the group consisting of hydrogen, halogen, C1-C8alkyl, C1-C8haloalkyl, C3-C6cycloalkyl, and C1-C8alkoxy; and pp is selected from 0, 1, 2, and 3. In some embodiments, R3is

In some embodiments, R3is

In some embodiments, R3is

In some embodiments, R3is

In some embodiments, R3is

and Rtis independently, for each occurrence, H or methyl; or each Rtmay be taken, together with the carbon to which they are attached, to form a cyclopropyl.

In some embodiments, R3is selected from the group consisting of

In some embodiments, R3is selected from the group consisting of

In some embodiments, R3is selected from the group consisting of

In various embodiments, R2is —NHC(O)RB. In various embodiments, RBis a 5-10 membered heteroaryl. In various embodiments, RBis a bicyclic heteroaryl (e.g. 9 membered heteroaryl). In various embodiments, RBis substituted. In various embodiments, RBis unsubstituted. In various embodiments, RBis substituted by halogen. In various embodiments, RBis substituted by —OCH3. In various embodiments, RBis substituted by —OH. In various embodiments, RBis substituted by C1-C8alkyl. In various embodiments, RBis substituted by C1-C8alkoxy. In various embodiments, R2is substituted. In various embodiments, R2is unsubstituted. In various embodiments, R2is substituted by halogen. In various embodiments, R2is substituted by —OCH3. In various embodiments, R2is substituted by —OH. In various embodiments, R2is substituted by C1-C8alkyl. In various embodiments, R2is substituted by C1-C8alkoxy.

In some embodiments, R2is selected from the group consisting of

In some embodiments, R1aand R2are joined to together to form a heterocycle selected from the group consisting of:

In some embodiments, R1aand R2are joined to together to form a heterocycle selected from the group consisting of:

In some embodiments, R1aand R2are joined to together to form a heterocycle selected from the group consisting of:

In some embodiments, R1aand R2are joined to together to form a heterocycle selected from the group consisting of:

In some embodiments, RGis selected from the group consisting of hydrogen, C1-6alkyl optionally substituted by one, two or three Rgg, —C(═O)—C1-6alkyl optionally substituted by one, two or three Rhh, —C(═O)—C3-6cycloalkyl, —C(O)—(C2-C10alkenyl)-(C6-C14aryl), —C(O)—(C1-C6alkyl)-O—(C6-C14aryl), —C(O)-(5-10 membered heteroaryl), —C(O)-(4-10 membered heterocyclyl), and —C(O)-(4-10 membered heterocyclyloxy); wherein the aryl, heterocyclyl, or heteroaryl may optionally be substituted by one, two or three IV.

In some embodiments, RGis selected from the group consisting of hydrogen, C1-6alkyl optionally substituted by one, two or three Rgg, —C(═O)—C1-6alkyl optionally substituted by one, two or three Rhh, and —C(═O)—C3-6cycloalkyl.

In other embodiments, RGis selected from the group consisting of —C(O)—(C2-C10alkenyl)-(C6-C14aryl), —C(O)—(C1-C6alkyl)-O—(C6-C14aryl), —C(O)-(5-10 membered heteroaryl), —C(O)-(4-10 membered heterocyclyl), and —C(O)-(4-10 membered heterocyclyloxy); wherein the aryl, heterocyclyl, or heteroaryl may optionally be substituted by one, two or three Rjj.

In some embodiments, Rggis independently selected for each occurrence from the group consisting of —C(═O), halo, cyano, —NRmRm, and —NH(C═O)Rm. In other embodiments, Rhhis independently selected for each occurrence from the group consisting of halo, cyano, —NRmRm, —NRm(C═O)Rm, phenyl, cycloalkyl, heterocyclyl and C1-C6alkoxy. In further embodiments, Rjjis independently selected for each occurrence from the group consisting of halo, oxo, hydroxyl, cyano, C1-C6alkyl, C1-6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, C3-6cycloalkyl, SF5, and NH2.

In certain embodiments, Rmis independently selected for each occurrence from the group consisting of hydrogen, C1-3alkyl (optionally substituted by one, two or three F), phenyl (optionally substituted by halo), —S(O)2—CH3, C3-6cycloalkyl (optionally substituted by one, two, or three F), and 5-6 membered heteroaryl.

In some embodiments, RGis selected from the group consisting of H, C1-6alkyl (optionally substituted by one, two or three substituents each independently selected from the group consisting of —C(═O), halo, cyano, —NRmRm, and —NH(C═O)Rm) and C(═O)—C1-6alkyl (optionally substituted by one, two or three substituents each independently selected from the group consisting of halo, cyano, —NRmRm, —NRm(C═O)Rm, phenyl, cycloalkyl and heterocycle, wherein Rmis selected for each occurrence from H and C1-3alkyl (optionally substituted by one, two or three halogens, e.g., F), or C3-C6cycloalkyl (optionally substituted by one, two, or three F).

In some embodiments, RGis selected from the group consisting of a 5-6 membered monocyclic —C(O)-heteroaryl or an 8-10 membered bicyclic —C(O)-heteroaryl each having at least one ring nitrogen and optionally substituted by one, two, or three substituents each selected from halo, methoxy, cyano, and hydroxyl; and —C(O)—C(R55R56)—NH—C(O)—R57, wherein R55is H and R56is a straight or branched C1-C5alkyl (optionally substituted by halo), or R55and R56taken together with the carbon to which they are attached form a C3-5cycloalkyl (optionally substituted by halo) and wherein R57is C1-3alkyl (optionally substituted by one, two or three halo).

In some embodiments, RGis selected from the group consisting of

In some embodiments, RGis

In some embodiments, a disclosed compound is represented by

wherein RG3is selected from the group consisting of H, C1-6alkyl, C3-6cycloalkyl (e.g., t-butyl, propyl, cyclopropyl), phenyl and heterocyclyl; and RG2is —NH(C═O)Rm, wherein Rmis selected for each occurrence from H, methyl and CF3.

In some embodiments, a disclosed compound is represented by

wherein RG3is selected from the group consisting of H, C1-6alkyl, C3-6cycloalkyl, phenyl and heterocyclyl; and RG2is —NH(C═O)Rm, wherein Rmis selected for each occurrence from H, methyl and CF3.

In some embodiments, a disclosed compound is represented by

wherein RG3is selected from the group consisting of H, C1-6alkyl, C3-6cycloalkyl, phenyl and heterocyclyl; and RG2is —NH(C═O)Rm, wherein Rmis selected for each occurrence from H, methyl and CF3.

In some embodiments, a disclosed compound is represented by

wherein RG3is selected from the group consisting of H, C1-6alkyl (optionally substituted by one, two or three C1-C6alkoxy), C3-6cycloalkyl, phenyl and heterocyclyl; and RG2is selected from the group consisting of —NH(C1-3alkyl) (optionally substituted by one, two or three substituents each independently selected from the group consisting of halo, optionally substituted phenyl, —S(O)2—CH3, C3-6cycloalkyl, and 5-6 membered heteroaryl) and —NH(C═O)Rm, wherein Rmis selected for each occurrence from the group consisting of H, C1-6alkyl (optionally substituted by one, two or three substituents each independently selected from the group consisting of halo, cyano and C1-C6alkoxy), CHF2, CF3, and 5-6 membered heteroaryl (optionally substituted by halo, cyano, hydroxyl, NH2, C1-6alkyl, C3-6cycloalkyl, C1-C6alkoxy, CHF2, or CF3).

In some embodiments, a disclosed compound is represented by

wherein RG3is selected from the group consisting of H, C1-6alkyl (optionally substituted by one, two or three C1-C6alkoxy), C3-6cycloalkyl, phenyl and heterocyclyl; and RG2is selected from the group consisting of —NH(C1-3alkyl) (optionally substituted by one, two or three substituents each independently selected from the group consisting of halo, optionally substituted phenyl, —S(O)2—CH3, C3-6cycloalkyl, and 5-6 membered heteroaryl) and —NH(C═O)Rm, wherein Rmis selected for each occurrence from the group consisting of H, C1-6alkyl (optionally substituted by one, two or three substituents each independently selected from the group consisting of halo, cyano and C1-C6alkoxy), CHF2, CF3, and 5-6 membered heteroaryl (optionally substituted by halo, cyano, hydroxyl, NH2, C1-6alkyl, C3-6cycloalkyl, C1-C6alkoxy, CHF2, or CF3).

In some embodiments, RG3is selected from the group consisting of

In some embodiments, RG2is selected from the group consisting of

wherein RFis selected from the group consisting of C1-6alkyl, C3-6cycloalkyl, phenyl and 5-6 membered heteroaryl, wherein RFmay optionally be substituted by one, two or three substituents each selected from the group consisting of halo, cyano, hydroxyl and C1-C6alkoxy; and XFis selected from the group consisting of H, halo, cyano, hydroxyl, NH2, C1-6alkyl, C3-6cycloalkyl, C1-C6alkoxy, and C1-6haloalkyl.

In some embodiments, R1aand R2are joined to together to form a heterocycle selected from the group consisting of:

Further disclosed herein is a compound represented by Formula IV-A or Formula IV-B:

or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:R1ais selected from the group consisting of hydrogen, C1-C8alkyl, C1-C8heteroalkyl, —(C1-C8alkyl)-R1, —(C1-C8alkyl)-CN, C3-C10cycloalkyl, C6-C14aryl, 4-10 membered heterocycle and 5-10 membered heteroaryl;R1bis selected from hydrogen and C1-C8alkyl;or R1aand R1bmay be joined together to form, together with the carbon to which they are attached, a 4-10 membered heterocycle having a ring nitrogen, NRG, or a C3-C10cycloalkyl;R1is selected from the group consisting of C1-C8alkyl, C2-C10alkenyl, C2-C10alkynyl, C3-C10cycloalkyl, C6-C14aryl, 5-10 membered heteroaryl and 4-10 membered heterocycle, wherein R1may optionally be substituted by one, two, or three substituents each selected from RA;RAis independently selected for each occurrence from the group consisting of halogen, cyano, hydroxyl, oxo, SF5, —CH2CF3, —CF3, —O—CF3, —O—CHF2, —S—CH3, —S(O)2—CH3, —NH2, —O-phenyl, —O—(C1-C8alkyl)-phenyl, —NHC(O)RB, —NHC(O)ORB, —NHC(O)O—(C1-C8alkyl)-RB, —N(Ry)2, —N(Ry)(C1-C8alkyl)C(O)O-phenyl, —N(Ry)(C1-C8alkyl)C(O)N(Ry)2, —C(O)—OC(CH3)3, C1-C8alkyl, C2-C10alkenyl, C2-C10alkynyl, C1-C8heteroalkyl, C1-C8alkoxy, C3-C10cycloalkyl, —(C1-C8alkyl)-(C3-C10cycloalkyl), —(C1-C8alkyl)-(C6-C14aryl), —(C1-C8alkyl)-(5-10 membered heteroaryl), C6-C14aryl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl, wherein the RB, alkyl, heterocyclyl, heteroaryl, or aryl may optionally be substituted by one, two or three substituents each independently selected from the group consisting of halogen, C1-C8alkyl, C1-C8alkoxy, SF5, —NH2, hydroxyl and oxo;R2is selected from the group consisting of —NHC(O)RB, —NHC(O)ORB, —NHC(O)N(RB)2, —NHC(O)C(RC)2RB, —NHS(O)2RB, —O—(C1-C8alkyl)-(C3-C10cycloalkyl), 4-10 membered heterocycle, C6-C14aryl and 5-10 membered heteroaryl bound through the carbon or nitrogen atom, wherein RBor R2may optionally be substituted by one, two, or three substituents each selected from Rx;or R1aand R2may be joined together to form, together with the carbon to which they are attached, a 4-10 membered monocyclic or bicyclic heterocycle having a ring nitrogen NRG, or a C3-C10cycloalkyl, wherein the cycloalkyl or heterocycle may optionally be substituted by one, two or three substituents on a free carbon each selected from RA;R3bis selected from hydrogen and C1-C8alkyl;RBis independently selected, for each occurrence, from the group consisting of C1-C8alkyl, C2-C10alkenyl, C2-C10alkynyl, C3-C6cycloalkyl, fluorenylmethyloxy, C6-C14aryl, 5-10 membered heteroaryl and 4-10 membered heterocycle;RCis independently selected, for each occurrence, from hydrogen, halogen and C1-C8alkyl;Rxis independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, oxo, CF3, SF5, cyano, —O—(Rxx)—OCH3, —OCHF2, —OCF3, —O—(C1-C8alkyl), —C(O)O(CH3), —N(Ry)2, —N(Ry)C(O)Ry, —N(Ry)(C1-C8alkyl)C(O)N(Ry)2, —N(Ry)(C1-C8alkyl)C(O)OH, —(C1-C8alkyl)-(C3-C10cycloalkyl), C1-C8alkyl, C1-C8alkoxy, C3-C10cycloalkyl, C6-C14aryl, —O—C6-C14aryl, 5-10 membered heteroaryl and 4-10 membered heterocycle;wherein two geminal C1-C8alkyl groups, together with the carbon to which they are attached, may be joined together to form a C3-C6cycloalkyl optionally substituted by one, two or three substituents each independently selected from halogen, hydroxyl and oxo; andwherein the alkyl, aryl, heterocycle or heteroaryl may optionally be substituted by one or more substituents each independently selected from oxo, halogen and C1-C8alkyl;RGis selected from the group consisting of hydrogen, C1-6alkyl optionally substituted by one, two or three Rgg, —C(═O)—C1-6alkyl optionally substituted by one, two or three Rhh, —C(═O)—C3-6cycloalkyl, —C(O)—(C2-C10alkenyl)-(C6-C14aryl), —C(O)-(5-10 membered heteroaryl), —C(O)-(4-10 membered heterocyclyl), and —C(O)-(4-10 membered heterocyclyloxy); wherein the aryl, heterocyclyl, or heteroaryl may optionally be substituted by one, two or three Rjj;Rggis independently selected for each occurrence from the group consisting of —C(═O), halo, cyano, —NRmRm, and —NH(C═O)Rm;Rhhis independently selected for each occurrence from the group consisting of halo, cyano, —NRmRm, —NRm(C═O)Rm, phenyl, cycloalkyl, heterocyclyl and C1-C6alkoxy;Rjjis independently selected for each occurrence from the group consisting of halo, oxo, hydroxyl, cyano, C1-C6alkyl, C1-6haloalkyl, C1-C6alkoxy, C3-6cycloalkyl, SF5, and NH2;Rmis independently selected for each occurrence from the group consisting of hydrogen, C1-3alkyl, phenyl, —S(O)2—CH3, C3-6cycloalkyl, and 5-6 membered heteroaryl; wherein C1-3alkyl, phenyl, and C3-6cycloalkyl may optionally be substituted by one, two or three halo;Rxxis —(OCH2CH2)nn—, wherein nn is selected from 1, 2, 3, 4, 5 and 6; andRyis independently selected, for each occurrence, from the group consisting of hydrogen, C1-C8alkyl, C1-C8heteroalkyl, —CF3, —CH2CF3, C1-C8alkoxy, —(C1-C8alkoxy)-(5-10 membered aryl), 5-10 membered heteroaryl, C3-C6cycloalkyl and —(C1-C8alkyl)COOH.

In some embodiments, a disclosed compound is selected from the group consisting of the compounds identified in Table 1 and Table 2 below:

Another aspect of the disclosure provides methods of treating patients suffering from a viral infection, e.g., a coronaviral infection. In particular, in certain embodiments, the disclosure provides a method of treating contemplated medical indications comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein, such as a compound of Formula II, II-A, II-B, II-C, II-D-A, II-D-B, II-E-A, II-E-B, II-F, II-G, II-H-A, II-H-B, II-E, II-I, IV-A or IV-B.

In certain embodiments, the disclosure provides a method of ameliorating or treating a viral infection in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of any of the compounds described herein. In some embodiments, the viral infection is from a virus selected from the group consisting of an RNA virus, a DNA virus, a coronavirus, a papillomavirus, a pneumovirus, a picornavirus, an influenza virus, an adenovirus, a cytomegalovirus, a polyomavirus, a poxvirus, a flavivirus, an alphavirus, an ebola virus, a morbillivirus, an enterovirus (e.g., enterovirus 71 (EV71), an orthopneumovirus, a lentivirus, arenavirus, a herpes virus, and a hepatovirus. In certain embodiments, the viral infection is a coronavirus infection. In some embodiments, the viral infection is a coronavirus selected from the group consisting of: 229E alpha coronavirus, NL63 alpha coronavirus, OC43 beta coronavirus, HKU1 beta coronavirus, Middle East Respiratory Syndrome (MERS) coronavirus (MERS-CoV), severe acute respiratory syndrome (SARS) coronavirus (SARS-CoV), and SARS-CoV-2 (COVID-19). In embodiments, the viral infection is SARS-CoV-2.

In some embodiments, the viral infection is from a virus selected from the group consisting of calicivimses, MD145, murine norovirus, vesicular exanthema of swine virus, abbit hemorrhagic disease virus, porcine teschovirus, bovine coronavirus, feline infectious peritonitis virus, EV-68 virus, EV-71 virus, poliovirus, norovirus, human rhinovirus (HRV), hepatitis A virus (HAV) and foot-and-mouth disease virus (FMDV).

In embodiments, the viral infection is an arenavirus infection. In some embodiments, the arenavirus is selected from the group consisting of: Junin virus, Lassa virus, Lujo virus, Machupo virus, and Sabia virus. In some embodiments, the viral infection is an influenza infection. In some embodiments, the influenza is influenza H1N1, H3N2 or H5N1.

Another aspect of the disclosure provides methods of treating patients suffering from a viral infection, e.g., a noroviral infection. In some embodiments, the disclosure provides a method of treating a viral infection from a norovirus in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of any of the compounds described herein.

Contemplated patients include not only humans, but other animals such as companion animals (e.g. dogs, cats), domestic animals (e.g. cow, swine), and wild animals (e.g. monkeys, bats, snakes).

Accordingly, in one embodiment, described herein is a method of ameliorating or treating a viral infection in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound described herein (e.g., a compound of Formula II, II-A, II-B, II-C, II-D-A, II-D-B, II-E-A, II-E-B, II-F, II-G, II-H-A, II-H-B, II-E, II-I, IV-A or IV-B as described herein) or a pharmaceutically acceptable salt thereof.

Other contemplated methods of treatment include a method of treating or ameliorating a virus infection condition or co-morbidity, by administering an effective amount a compound disclosed herein to a subject in need thereof.

In some embodiments, the viral infection is from a virus selected from the group consisting of an RNA virus, a DNA virus, a coronavirus, a papillomavirus, a pneumovirus, a picornavirus, an influenza virus, an adenovirus, a cytomegalovirus, a polyomavirus, a poxvirus, a flavivirus, an alphavirus, an ebola virus, a morbillivirus, an enterovirus, an orthopneumovirus, a lentivirus, arenavirus, a herpes virus, and a hepatovirus. In some embodiments, the viral infection is a coronavirus infection. In some embodiments, the viral infection is a coronavirus selected from the group consisting of: 229E alpha coronavirus, NL63 alpha coronavirus, OC43 beta coronavirus, HKU1 beta coronavirus, Middle East Respiratory Syndrome (MERS) coronavirus (MERS-CoV), severe acute respiratory syndrome (SARS) coronavirus (SARS-CoV), and SARS-CoV-2 (COVID-19). In some embodiments, the viral infection is SARS-CoV-2. In some embodiments, the viral infection is an arenavirus infection. In some embodiments, the arenavirus is selected from the group consisting of: Junin virus, Lassa virus, Lujo virus, Machupo virus, and Sabia virus. In some embodiments, the viral infection is an influenza infection. In some embodiments, the influenza is influenza H1N1, H3N2 or H5N1. In some embodiments, the viral infection is a respiratory viral infection. In some embodiments, the viral infection is an upper respiratory viral infection or a lower respiratory viral infection. In some embodiments, the method further comprises administering another therapeutic.

In some embodiments, the virus is an RNA virus (having a genome that is composed of RNA). RNA viruses may be single-stranded RNA (ssRNA) or double-stranded RNA (dsRNA). RNA viruses have high mutation rates compared to DNA viruses, as RNA polymerase lacks proofreading capability (see, e.g., Steinhauer D A, Holland J J (1987). “Rapid evolution of RNA viruses”. Annu. Rev. Microbiol. 41: 409-33). In some embodiments, the RNA virus is a positive-strand RNA virus (e.g., a SARS-CoV virus, polio virus, Coxsackie virus, Enterovirus, Human rhinovirus, Foot/Mouth disease virus, encephalomyocarditis virus, Dengue virus, Zika virus, Hepatitis C virus, or New Castle Disease virus).

RNA viruses are classified by the type of genome (double-stranded, negative (−), or positive (+) single-stranded). Double-stranded RNA viruses contain a number of different RNA molecules, each coding for one or more viral proteins. Positive-sense ssRNA viruses utilize their genome directly as mRNA; ribosomes within the host cell translate mRNA into a single protein that is then modified to form the various proteins needed for viral replication. One such protein is RNA-dependent RNA polymerase (RNA replicase), which copies the viral RNA in order to form a double-stranded, replicative form. Negative-sense ssRNA viruses have their genome copied by an RNA replicase enzyme to produce positive-sense RNA for replication. Therefore, the virus comprises an RNA replicase enzyme. The resultant positive-sense RNA then acts as viral mRNA and is translated by the host ribosomes. In some embodiments, the virus is a dsRNA virus. In some embodiments, the virus is a negative ssRNA virus. In some embodiments, the virus is a positive ssRNA virus. In some embodiments, the positive ssRNA virus is a coronavirus.

SARS-CoV2, also sometimes referred to as the novel coronavirus of 2019 or 2019-nCoV, is a positive-sense single-stranded RNA virus. SARS-CoV-2 has four structural proteins, known as the S (spike), E (envelope), M (membrane), and N (nucleocapsid) proteins. The N protein holds the RNA genome together; the S, E, and M proteins form the viral envelope. Spike allows the virus to attach to the membrane of a host cell, such as the ACE2 receptor in human cells (Kruse R. L. (2020), Therapeutic strategies in an outbreak scenario to treat the novel coronavirus originating in Wuhan, China (version 2).F1000Research,9:72). SARS-CoV2 is the highly contagious, causative viral agent of coronavirus disease 2019 (COVID19), a global pandemic.

441 The methods described herein may inhibit viral replication transmission, replication, assembly, or release, or minimize expression of viral proteins. In one embodiment, described herein is a method of inhibiting transmission of a virus, a method of inhibiting viral replication, a method of minimizing expression of viral proteins, or a method of inhibiting virus release, comprising administering a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, to a patient suffering from the virus, and/or contacting an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, with a virally infected cell.

Also described herein is a method of treating a respiratory disorder in a subject in need thereof, comprising administering to the patient a therapeutically effective amount of a compound described herein (e.g., a compound of Formula II, II-A, II-B, II-C, II-D-A, II-D-B, II-E-A, II-E-B, II-F, II-G, II-H-A, II-H-B, II-E, II-I, IV-A, or IV-B, etc. described herein) or a pharmaceutically acceptable salt thereof. In certain embodiments, the respiratory disorder is selected from the group consisting of chronic obstructive pulmonary disease (COPD), asthma, fibrosis, chronic asthma, acute asthma, lung disease secondary to environmental exposures, acute lung infection, chronic lung infection, al antitrypsin disease, cystic fibrosis and an autoimmune disease. In some embodiments, the respiratory disorder is associated with a heart attack.

Also described herein is a method of treating a disorder associated with cathepsin (e.g. Cathepsin K) in a subject in need thereof, comprising administering to the patient a therapeutically effective amount of a compound described herein (e.g., a compound of Formula II, II-A, II-B, II-C, II-D-A, II-D-B, II-E-A, II-E-B, II-F, II-G, II-H-A, II-H-B, II-E, II-I, IV-A, or IV-B, etc. described herein) or a pharmaceutically acceptable salt thereof. In some embodiments, the disorder is a cathepsin dependent condition or disease. In embodiments, the disorder is selected from the group consisting of breast cancer, pycnodysostosis, glioblastoma, osteosclerosis, osteoporosis, glucocorticoid induced osteoporosis, Paget's disease, abnormally increased bone turnover, periodontal disease, tooth loss, bone fractures, rheumatoid arthritis, osteoarthritis, periprosthetic osteolysis, osteogenesis imperfecta, atherosclerosis, obesity, glaucoma, chronic obstructive pulmonary disease, metastatic bone disease, hypercalcemia of malignancy, and multiple myeloma.

Compounds described herein, e.g., a compound of Formula II, II-A, II-B, II-C, II-D-A, II-D-B, II-E-A, II-E-B, II-F, II-G, II-H-A, II-H-B, II-E, II-I, IV-A, IV-B etc. as defined herein, can be administered in combination with one or more additional therapeutic agents to treat a disorder described herein, such as an infection by a pathogen described herein, e.g., a virus, fungus, or protozoan. For clarity, contemplated herein are both a fixed composition comprising a disclosed compound and another therapeutic agent such as disclosed herein, and methods of administering, separately a disclosed compound and a disclosed therapeutic. For example, provided in the present disclosure is a pharmaceutical composition comprising a compound described herein, e.g., a compound of Formula I as defined herein, one or more additional therapeutic agents, and a pharmaceutically acceptable excipient. In some embodiments, a compound of Formula I as defined herein and one additional therapeutic agent is administered. In some embodiments, a disclosed compound as defined herein and two additional therapeutic agents are administered. In some embodiments, a disclosed compound as defined herein and three additional therapeutic agents are administered. Combination therapy can be achieved by administering two or more therapeutic agents, each of which is formulated and administered separately. For example, a compound of Formula II, II-A, II-B, II-C, II-D-A, II-D-B, II-E-A, II-E-B, II-F, II-G, II-H-A, II-H-B, II-E, II-I, IV-A, IV-B, etc. as defined herein and an additional therapeutic agent can be formulated and administered separately. Combination therapy can also be achieved by administering two or more therapeutic agents in a single formulation, for example a pharmaceutical composition comprising a compound of Formula I as one therapeutic agent and one or more additional therapeutic agents such as an antibiotic, a viral protease inhibitor, or an anti-viral nucleoside anti-metabolite. For example, a compound of Formula I as defined herein and an additional therapeutic agent can be administered in a single formulation. Other combinations are also encompassed by combination therapy. While the two or more agents in the combination therapy can be administered simultaneously, they need not be. For example, administration of a first agent (or combination of agents) can precede administration of a second agent (or combination of agents) by minutes, hours, days, or weeks. Thus, the two or more agents can be administered within minutes of each other or within 1, 2, 3, 6, 9, 12, 15, 18, or 24 hours of each other or within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14 days of each other or within 2, 3, 4, 5, 6, 7, 8, 9, or weeks of each other. In some cases even longer intervals are possible. While in many cases it is desirable that the two or more agents used in a combination therapy be present in within the patient's body at the same time, this need not be so.

Combination therapy can also include two or more administrations of one or more of the agents used in the combination using different sequencing of the component agents. For example, if agent X and agent Y are used in a combination, one could administer them sequentially in any combination one or more times, e.g., in the order X-Y-X, X-X-Y, Y-X-Y, Y-Y-X, X-X-Y-Y, etc.

In some embodiments, the additional therapeutic agents can be therapeutic anti-viral vaccines.

In some embodiments, the additional therapeutic agents can be immunomodulatory agents including but not limited to anti-PD-1 or anti-PDL-1 therapeutics including pembrolizumab, nivolumab, atezolizumab, durvalumab, BMS-936559, or avelumab, anti-TIM3 (anti-HAVcr2) therapeutics including but not limited to TSR-022 or MBG453, anti-LAG3 therapeutics including but not limited to relatlimab, LAG525, or TSR-033, anti-4-1BB (anti-CD37, anti-TNFRSF9), CD40 agonist therapeutics including but not limited to SGN-40, CP-870,893 or RO7009789, anti-CD47 therapeutics including but not limited to Hu5F9-G4, anti-CD20 therapeutics, anti-CD38 therapeutics, STING agonists including but not limited to ADU-S100, MK-1454, ASA404, or amidobenzimidazoles, anthracyclines including but not limited to doxorubicin or mitoxanthrone, hypomethylating agents including but not limited to azacytidine or decitabine, other immunomodulatory therapeutics including but not limited to epidermal growth factor inhibitors, statins, metformin, angiotensin receptor blockers, thalidomide, lenalidomide, pomalidomide, prednisone, or dexamethasone. In some embodiments, the additional therapeutic agent is a p2-adrenoreceptor agonist including, but not limited to, vilanterol, salmeterol, salbutamol, formoterol, salmefamol, fenoterol carmoterol, etanterol, naminterol, clenbuterol, pirbuterol, flerbuterol, reproterol, bambuterol, indacaterol, terbutaline and salts thereof, for example the xinafoate (1-hydroxy-2-naphthalenecarboxylate) salt of salmeterol, the sulphate salt of salbutamol or the fumarate salt of formoterol. In some embodiments, the additional therapeutic agent is an anticholinergic agent, including, but not limited to, umeclidinium (for example, as the bromide), ipratropium (for example, as the bromide), oxitropium (for example, as the bromide) and tiotropium (for example, as the bromide).

In particular, in certain embodiments, the disclosure provides a method of treating the above medical indications comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein, such as a disclosed compound.

The term “boosting amount” or “boosting dose” is the amount of a compound needed to improve the pharmacokinetics of a second compound (or increase availability or exposure). The boosting amount or boosting dose may improve the pharmacokinetics (or increase availability or exposure) of the second compound to a level to therapeutic levels in a subject.

In one embodiment, the disclosure provides for a disclosed compound to be administered together with an antiviral therapeutic such as disclosed herein, and e.g., thereby boosting the dose of the anti-viral therapeutic or therapeutics. Such a boost combination may be used, e.g., as prophylactic or therapeutic treatment of a viral infection in a subject in need thereof. In one embodiment, the protease inhibitor is a compound described herein (e.g. of Formula II, II-A, II-B, II-C, II-D-A, II-D-B, II-E-A, II-E-B, II-F, II-G, II-H-A, II-H-B, II-E, II-I, IV-A, IV-B, etc.).

III. Reversible or Irreversible Conjugates

In certain embodiments, disclosed herein are conjugates represented by Formula

wherein Cys145is cysteine at position 145 or equivalent active site cysteine on a CL or 3CL protease; IR is a viral protease inhibitor; and wherein the compound that forms the conjugate comprises a —CN warhead.

For example, disclosed herein is an engineered CL or 3CL viral protease, wherein:

the cysteine at position 145 of the CL or 3CL protease; has a non-naturally occurring covalent modification resulting from a reaction between an exogenous nitrile modifier having a nitrile function and the cysteine at position 145 of the CL or 3CL protease, and

wherein the sulfur atom at the cysteine residue and the nitrile of the exogenous nitrile modifier undergoes a reaction to form a thioimidate adduct, and wherein the engineered SARS-protease does not retain the protease activity of an unmodified CL or 2CL protease.

In some embodiments, the engineered viral protease substantially prevents viral replication of SARS-COV2. In some embodiments, the CL or 3CL protease is represented by SEQ ID NO: 1. In other embodiments, the enzymatic inhibition IC50of the exogenous nitrile modifier for SEQ ID NO: 1 is less than 20 micromolar.

In some embodiments, the thioimidate adduct resulting from the in vivo reaction between the exogenous nitrile modifier and the cysteine at position 145 of SEQ ID NO: 1 is represented by:

wherein
IR is the exogenous nitrile modifier after undergoing the reaction.

For example, disclosed herein is an engineered 3CL or 3C protease, e.g., a SARS-COV2-3CL viral protease represented by SEQ ID NO: 1, wherein the cysteine at position 145 of SEQ ID NO: 1 has a non-naturally occurring covalent modification resulting from a reaction, e.g., an in vivo reaction, between an exogenous nitrile modifier having a nitrile function and the cysteine at position 145 of SEQ ID NO: 1, and wherein the sulfur atom at the cysteine residue and the nitrile of the exogenous nitrile modifier undergoes a reaction to form a thioimidate adduct, and wherein the engineered −3CL protease does not retain the protease activity of the unmodified −3CL or 3C protease.

In some embodiments, the engineered SARS-COV2-3CL viral protease substantially prevents viral replication of SARS-COV2. In other embodiments, the enzymatic inhibition IC50of the exogenous nitrile modifier for SEQ ID NO: 1 is less than, for example, 20 micromolar.

In further embodiments, the thioimidate adduct resulting from a reaction between the exogenous nitrile modifier and the cysteine at position 145 of SEQ ID NO: 1 may, for example, be represented by:

wherein IR is the exogenous nitrile modifier after undergoing the reaction.

Also disclosed herein is an engineered SARS-COV2-3CL viral protease represented by SEQ ID NO: 1, wherein the cysteine at position 145 of SEQ ID NO: 1 has a non-naturally occurring covalent modification resulting from a reaction between an exogenous nitrile modifier, and the cysteine at position 145 of SEQ ID NO: 1, wherein the exogenous nitrile modifier is represented by:

wherein the sulfur atom at the cysteine residue and the —C≡N of the exogenous nitrile modifier undergoes a reaction to form a thioimidate adduct, and wherein
R1is C1-C6alkyl or —CH2-C3-10cycloalkyl;
RGis —C(O)RB;
RBis C1-C6alkyl (optionally substituted by one, two or three substituents each independently selected from the group consisting of halo, —NRmRm, and —NRm(C═O)Rm, wherein Rmis selected for each occurrence from H or C1-3alkyl (optionally substituted by one, two or three halo)); or a 8-10 membered bicyclic heteroaryl (optionally substituted by one, two, or three substituents each independently selected from halo or methoxy);
Rtis independently, for each occurrence, H or methyl; or each Rtmay be taken, together with the carbon to which they are attached, to form a cyclopropyl;

R1and R1a, taken together with the nitrogen and the carbon to which they are attached, form a 4-10 membered monocyclic, bicyclic or spirocyclic heterocycle optionally substituted by one or two substituents on a free carbon each selected from methyl, halo or CF3.

Also disclosed herein is a compound represented by

or a pharmaceutically acceptable salt or stereoisomer thereof, wherein
R1is C1-C6alkyl or —CH2-C3-10cycloalkyl;
RGis —C(O)RB;
RBis C1-C6alkyl (optionally substituted by one, two or three substituents each independently selected from the group consisting of halo, —NRmRm, and —NRm(C═O)Rm, wherein Rmis selected for each occurrence from H or C1-3alkyl (optionally substituted by one, two or three halo)); or a 8-10 membered bicyclic heteroaryl (optionally substituted by one, two, or three substituents each independently selected from halo or methoxy);
Rtis independently, for each occurrence, H or methyl; or each Rtmay be taken, together with the carbon to which they are attached, to form a cyclopropyl;

R1and R1a, taken together with the nitrogen and the carbon to which they are attached, form a 4-10 membered monocyclic, bicyclic or spirocyclic heterocycle optionally substituted by one or two substituents on a free carbon each selected from methyl, halo or CF3.

Also disclosed herein in an engineered SARS-COV2-3CL viral protease represented by SEQ ID NO: 1, wherein the cysteine at position 145 of SEQ ID NO: 1 has a non-naturally occurring covalent modification resulting from an in vivo reaction between an exogenous —C≡N modifier and the cysteine at position 145 of SEQ ID NO: 1, wherein the exogenous —C≡N modifier is represented by:

wherein the sulfur atom at the cysteine residue and the —C≡N of the exogenous nitrile modifier undergoes a reaction to form a thioimidate adduct, and wherein

RBis C1-C6alkyl or 8-10 membered bicyclic heteroaryl; wherein C1-C6alkyl may optionally be substituted by one, two or three RB1; and wherein the heteroaryl may optionally be substituted by one, two, or three halo;

RB1is independently selected for each occurrence from the group consisting of halo, —NRmRm, and —NRm(C═O)Rm;

Rmis independently selected for each occurrence from hydrogen or C1-3alkyl (optionally substituted by one, two or three halo);

n is 1 or 2;

R1and R1a, taken together with the nitrogen and the carbon to which they are attached, form a 4-10 membered monocyclic or bicyclic heterocycle optionally substituted on a free carbon by one or two substituents each independently selected from the group consisting of CH3, halo, and CF3.

In another embodiment, disclosed herein is a compound represented by:

RBis C1-C6alkyl or 8-10 membered bicyclic heteroaryl; wherein C1-C6alkyl may optionally be substituted by one, two or three RB1; and wherein the heteroaryl may optionally be substituted by one, two, or three halo;

RB1is independently selected for each occurrence from the group consisting of halo, —NRmRm, and —NRm(C═O)Rm;

Rmis independently selected for each occurrence from hydrogen or C1-3alkyl (optionally substituted by one, two or three halo);

n is 1 or 2;

R1and R1a, taken together with the nitrogen and the carbon to which they are attached, form a 4-10 membered monocyclic or bicyclic heterocycle optionally substituted on a free carbon by one or two substituents each independently selected from the group consisting of CH3, halo, and CF3.

Sequence details for SEQ ID NO: 1 are indicated below.

IV. Pharmaceutical Compositions and Kits

Another aspect of the disclosure provides pharmaceutical compositions comprising compounds as disclosed herein formulated together with a pharmaceutically acceptable carrier. In particular, the present disclosure provides pharmaceutical compositions comprising compounds as disclosed herein formulated together with one or more pharmaceutically acceptable carriers. These formulations include those suitable for oral, rectal, topical, buccal, parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous) rectal, vaginal, or aerosol administration, although the most suitable form of administration in any given case will depend on the degree and severity of the condition being treated and on the nature of the particular compound being used. For example, disclosed compositions may be formulated as a unit dose, and/or may be formulated for oral or subcutaneous administration.

Exemplary pharmaceutical compositions of this disclosure may be used in the form of a pharmaceutical preparation, for example, in solid, semisolid or liquid form, which contains one or more of the compound of the disclosure, as an active ingredient, in admixture with an organic or inorganic carrier or excipient suitable for external, enteral or parenteral applications. The active ingredient may be compounded, for example, with the usual non-toxic, pharmaceutically acceptable carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use. The active object compound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect upon the process or condition of the disease.

For preparing solid compositions such as tablets, the principal active ingredient may be mixed with a pharmaceutical carrier, e.g., conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g., water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the disclosure, or a non-toxic pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.

A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the subject composition moistened with an inert liquid diluent. Tablets, and other solid dosage forms, such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well-known in the pharmaceutical-formulating art.

Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the subject composition, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, cyclodextrins and mixtures thereof.

Formulations for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing a subject composition with one or more suitable non-irritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the body cavity and release the active agent.

Powders and sprays may contain, in addition to a subject composition, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays may additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

Compositions and compounds of the present disclosure may alternatively be administered by aerosol. This is accomplished by preparing an aqueous aerosol, liposomal preparation or solid particles containing the compound. A non-aqueous (e.g., fluorocarbon propellant) suspension could be used. Sonic nebulizers may be used because they minimize exposing the agent to shear, which may result in degradation of the compounds contained in the subject compositions. Ordinarily, an aqueous aerosol is made by formulating an aqueous solution or suspension of a subject composition together with conventional pharmaceutically acceptable carriers and stabilizers. The carriers and stabilizers vary with the requirements of the particular subject composition, but typically include non-ionic surfactants (Tweens, Pluronics, or polyethylene glycol), innocuous proteins like serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars or sugar alcohols. Aerosols generally are prepared from isotonic solutions.

In another aspect, the disclosure provides enteral pharmaceutical formulations including a disclosed compound and an enteric material; and a pharmaceutically acceptable carrier or excipient thereof. Enteric materials refer to polymers that are substantially insoluble in the acidic environment of the stomach, and that are predominantly soluble in intestinal fluids at specific pHs. The small intestine is the part of the gastrointestinal tract (gut) between the stomach and the large intestine, and includes the duodenum, jejunum, and ileum. The pH of the duodenum is about 5.5, the pH of the jejunum is about 6.5 and the pH of the distal ileum is about 7.5. Accordingly, enteric materials are not soluble, for example, until a pH of about 5.0, of about 5.2, of about 5.4, of about 5.6, of about 5.8, of about 6.0, of about 6.2, of about 6.4, of about 6.6, of about 6.8, of about 7.0, of about 7.2, of about 7.4, of about 7.6, of about 7.8, of about 8.0, of about 8.2, of about 8.4, of about 8.6, of about 8.8, of about 9.0, of about 9.2, of about 9.4, of about 9.6, of about 9.8, or of about 10.0. Exemplary enteric materials include cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl acetate phthalate (PVAP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), cellulose acetate trimellitate, hydroxypropyl methylcellulose succinate, cellulose acetate succinate, cellulose acetate hexahydrophthalate, cellulose propionate phthalate, cellulose acetate maleate, cellulose acetate butyrate, cellulose acetate propionate, copolymer of methylmethacrylic acid and methyl methacrylate, copolymer of methyl acrylate, methylmethacrylate and methacrylic acid, copolymer of methylvinyl ether and maleic anhydride (Gantrez ES series), ethyl methyacrylate-methylmethacrylate-chlorotrimethylammonium ethyl acrylate copolymer, natural resins such as zein, shellac and copal collophorium, and several commercially available enteric dispersion systems (e.g., Eudragit L30D55, Eudragit FS30D, Eudragit L100, Eudragit S100, Kollicoat EMM30D, Estacryl 30D, Coateric, and Aquateric). The solubility of each of the above materials is either known or is readily determinable in vitro. The foregoing is a list of possible materials, but one of skill in the art with the benefit of the disclosure would recognize that it is not comprehensive and that there are other enteric materials that would meet the objectives of the present disclosure.

Advantageously, the disclosure also provides kits for use by a e.g. a consumer in need of 3CL inhibitor. Such kits include a suitable dosage form such as those described above and instructions describing the method of using such dosage form to mediate, reduce or prevent inflammation. The instructions would direct the consumer or medical personnel to administer the dosage form according to administration modes known to those skilled in the art. Such kits could advantageously be packaged and sold in single or multiple kit units. An example of such a kit is a so-called blister pack. Blister packs are well-known in the packaging industry and are being widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, and the like). Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a preferably transparent plastic material. During the packaging process recesses are formed in the plastic foil. The recesses have the size and shape of the tablets or capsules to be packed. Next, the tablets or capsules are placed in the recesses and the sheet of relatively stiff material is sealed against the plastic foil at the face of the foil which is opposite from the direction in which the recesses were formed. As a result, the tablets or capsules are sealed in the recesses between the plastic foil and the sheet. Preferably the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by manually applying pressure on the recesses whereby an opening is formed in the sheet at the place of the recess. The tablet or capsule can then be removed via said opening.

It may be desirable to provide a memory aid on the kit, e.g., in the form of numbers next to the tablets or capsules whereby the numbers correspond with the days of the regimen which the tablets or capsules so specified should be ingested. Another example of such a memory aid is a calendar printed on the card, e.g., as follows “First Week, Monday, Tuesday, . . . etc. . . . Second Week, Monday, Tuesday, . . . ” etc. Other variations of memory aids will be readily apparent. A “daily dose” can be a single tablet or capsule or several pills or capsules to be taken on a given day. Also, a daily dose of a first compound can consist of one tablet or capsule while a daily dose of the second compound can consist of several tablets or capsules and vice versa. The memory aid should reflect this.

Also contemplated herein are methods and compositions that include a second active agent or administering a second active agent. For example, in addition to having a viral infection, a subject or patient can further have viral infection- or virus-related co-morbidities, i.e., diseases and other adverse health conditions associated with, exacerbated by, or precipitated by being infected by a virus. Contemplated herein are disclosed compounds in combination with at least one other agent that has previously been shown to treat these virus-related conditions.

V. Further Embodiments of the Disclosure

In one aspect, the compositions, compounds and methods of the present disclosure may be described in one embodiment as follows:1. A viral protease inhibitor compound represented by:

wherein:R1is selected from the group consisting of and C1-C8alkyl, C3-C6cycloalkyl, 5-10 membered aryl, 5-10 membered heteroaryl and 5-10 membered heterocycle, wherein R1may optionally be substituted by one, two, or three substituents each selected from RA;RAis independently selected, for each occurrence, halogen, cyano, hydroxyl, oxo, —NH2, C1-C8alkyl, C1-C8heteroalkyl, C1-C8alkoxy and C3-C6cycloalkyl;R2is selected from the group consisting of —NHC(O)RB, —NHC(O)N(RB)2, —NHC(O)C(RC)2RB, —NHS(O)2RB, 5-10 membered heterocycle, 5-10 membered aryl and 5-10 membered heteroaryl bound through the carbon or nitrogen atom, wherein R2may optionally be substituted by one, two, or three substituents each selected from Rx;RBis independently selected, for each occurrence, from the group consisting of C1-C8alkyl, 5-10 membered aryl, 5-10 membered heteroaryl and 5-10 membered heterocycle;RCis independently selected, for each occurrence, from hydrogen and C1-C8alkyl;Rxis independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, oxo, cyano, —N(Ry)2, —N(Ry)C(O)Ry, C1-C8alkyl, C1-C8alkoxy, C3-C6cycloalkyl, 5-10 membered aryl, 5-10 membered heteroaryl and 5-10 membered heterocycle, wherein the heterocycle or heteroaryl may optionally be substituted by one or more substituents each selected from oxo and C1-C8alkyl;Ryis independently selected, for each occurrence, from the group consisting of hydrogen, C1-C8alkyl, C1-C8alkoxy, —(C1-C8alkoxy)-(5-10 membered aryl) and C3-C6cycloalkyl;A is a reversible or irreversible warhead;R3is selected from 5-10 membered heteroaryl and 5-10 membered heterocycle, wherein R3may optionally be substituted by one, two, or three substituents each selected from RA;m is 1 or 2; andpharmaceutically acceptable salts, stereoisomers, esters, and prodrugs thereof.2. A is a reversible or irreversible warhead selected from the group consisting of cyano, —C(O)RD, —C(O)CH2N(RbRc), —C(O)CH2OC(O)RD, —C(O)C(O)RD, and —(CH═CH)C(O)ORD, whereinRDis selected from the group consisting of hydrogen, —N(RbRc), C1-C8alkyl, C1-C8alkoxy, C3-C6cycloalkyl, 5-10 membered aryl, 5-10 membered heteroaryl, and 5-10 membered heterocycle; wherein RDmay optionally be substituted by one, two, or three substituents each selected from the group consisting of halogen, hydroxyl, and RE;REis selected from the group consisting of C1-C8alkyl, C1-C8alkoxy and 5-10 membered aryl and 5-10 membered heteroaryl, wherein REmay optionally be substituted by one, two, or three substituents each selected from halogen, cyano, C1-C8alkyl and C1-C8alkoxy; andRband Rcare each selected from the group consisting of hydrogen, —CH2C(O)O(C1-C8alkyl), —C(O)—(C1-C8alkyl), —S(O)2—(C1-C8alkyl), C1-C8alkyl, and C3-C6cycloalkyl, wherein the C1-C8alkyl may optionally be substituted by one or more substituents each selected from the group consisting of halogen, C3-C6cycloalkyl, 5-10 membered aryl and 5-10 membered heteroaryl.3. A is a reversible warhead

wherein Rcis selected from the group consisting of hydrogen, —CH2C(O)O(C1-C8alkyl), C1-C8alkyl, and C3-C6cycloalkyl, wherein the C1-C8alkyl may optionally be substituted by one or more substituents each selected from the group consisting of halogen, C3-C6cycloalkyl, 5-10 membered aryl and 5-10 membered heteroaryl.4. Rcis

wherein X1is independently selected, for each occurrence, from N and CH.5. A is a reversible warhead selected from the group consisting of

6. A is a reversible warhead

whereinX2is selected from the group consisting of NH, O and S;X3is independently selected, for each occurrence, from N and CH;RDis independently selected, for each occurrence, from the group consisting of C1-C8alkyl,

REis independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, C1-C8alkyl and C1-C8alkoxy;p is selected from 0, 1 and 2; andq is selected from 0, 1 and 2.7. A is selected from the group consisting of

8. A is a reversible warhead

wherein X2is selected from the group consisting of NH, NRP, O and S, wherein RPis C1-C8alkyl.9. A is a reversible warhead

10. A is an irreversible warhead —C(O)CH2OC(O)RD, wherein

RDis selected from the group consisting of C1-C8alkyl and C3-C6cycloalkyl;X4is independently selected, for each occurrence, from CH and N;REis independently selected, for each occurrence, from the group consisting of halogen, —CN, —CH3, —CH2CH3, —CH(CH3)2, —OCH3, —CF3, —OCF3and —SCF3; andp is selected from 0, 1 and 2.11. RDis selected from the group consisting of

12. A is an irreversible warhead selected from the group consisting of

13. A is an irreversible warhead selected from the group consisting of

14. A is a reversible or irreversible warhead —C(O)RD, wherein RDis selected from the group consisting of hydrogen, —CH2OH, —CH2OR′ and —CHxFy, wherein R′ is selected from the group consisting of C1-C8alkyl, —(C1-C8alkyl)-(5-10 membered aryl), C1-C8heteroalkyl, C3-C6cycloalkyl and 5-10 membered aryl, wherein x is 0, 1 or 2; y is 1, 2 or 3; and the sum of x and y is 3.15. A is a reversible or irreversible warhead selected from the group consisting of

16. A is a reversible or irreversible warhead —(CH═CH)C(O)ORD, wherein RDis C1-C8alkyl.17. A is an irreversible warhead selected from

18. A is a reversible or irreversible warhead —C(O)CH2N(RbRc).19. A is a reversible or irreversible warhead selected from

20. A is a reversible or irreversible warhead

wherein M is selected from Na and K.21. A is cyano.22. R1is selected from the group consisting of

23. R2is selected from the group consisting of

whereindenotes a bond that may be a single or double bond;R5is independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, oxo, —N(Ry)2, —N(Ry)C(O)Ry, C1-C8alkyl, C1-C8alkoxy, C3-C6cycloalkyl, 5-10 membered aryl, 5-10 membered heteroaryl and 5-10 membered heterocycle, wherein the heterocycle or heteroaryl may optionally be substituted by one or more substituents each selected from oxo and C1-C8alkyl;R6is C1-C8alkyl;R7is independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, oxo, —N(Ry)2, C1-C8alkyl, C1-C8alkoxy, C3-C6cycloalkyl, 5-10 membered aryl, 5-10 membered heteroaryl and 5-10 membered heterocycle, wherein the heterocycle or heteroaryl may optionally be substituted by one or more substituents each selected from oxo and C1-C8alkyl;Ryis independently selected, for each occurrence, from the group consisting of hydrogen, C1-C8alkyl, C1-C8alkoxy, —(C1-C8alkoxy)-(5-10 membered aryl) and C3-C6cycloalkyl;R8is selected from the group consisting of 5-10 membered aryl, 5-10 membered heteroaryl and 5-10 membered heterocycle;W1is selected from CH and N;W2is selected from the group consisting of CH2, O, NH and S;W is selected from W1and W2;s is selected from 1 and 2; andt is selected from 0, 1, 2 and 3.24. R2is selected from the group consisting of

25. R3is selected from the group consisting of

whereindenotes a bond that may be a single or double bond;Y1is selected from the group consisting of CH, CH2, N, NH, O and S;R9is selected from the group consisting of halogen, hydroxyl, oxo, —NH2, —N(CH3)2, —N(CH2CH3)2, —CH3, —CH2CH3, —OCH3and —OCH2CH3.26. R3is selected from the group consisting of

27. The viral protease inhibitor compound is represented by

wherein:R5is independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, oxo, —N(Ry)2, —N(Ry)C(O)Ry, C1-C8alkyl, C1-C8alkoxy, C3-C6cycloalkyl, 5-10 membered aryl, 5-10 membered heteroaryl and 5-10 membered heterocycle, wherein the heterocycle or heteroaryl may optionally be substituted by one or more substituents each selected from oxo and C1-C8alkyl;Ryis independently selected, for each occurrence, from the group consisting of hydrogen, C1-C8alkyl, C1-C8alkoxy, —(C1-C8alkoxy)-(5-10 membered aryl) and C3-C6cycloalkyl; andm is selected from 1 and 2.28. Ryis selected from the group consisting of hydrogen,

29. The viral protease inhibitor compound is represented by

whereinRxis independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, oxo, —N(Ry)2, C1-C8alkyl, C1-C8alkoxy, C3-C6cycloalkyl, 5-10 membered aryl, 5-10 membered heteroaryl and 5-10 membered heterocycle, wherein the heterocycle or heteroaryl may optionally be substituted by one or more substituents each selected from oxo and C1-C8alkyl;Ryis independently selected, for each occurrence, from the group consisting of hydrogen, C1-C8alkyl, C1-C8alkoxy and C3-C6cycloalkyl;W is CH or N;m is selected from 1 and 2; andr is selected from 0, 1, 2 and 3.30. Rxis —OCH3.31. A viral protease inhibitor compound selected from the group consisting of

32. A viral protease inhibitor compound represented by:

whereinR1is selected from the group consisting of and C1-C8alkyl, C3-C6cycloalkyl, 5-10 membered aryl, 5-10 membered heteroaryl and 5-10 membered heterocycle, wherein R1may optionally be substituted by one, two, or three substituents each selected from RA;RAis independently selected, for each occurrence, halogen, cyano, hydroxyl, oxo, —NH2, C1-C8alkyl, C1-C8heteroalkyl, C1-C8alkoxy and C3-C6cycloalkyl;R2is selected from the group consisting of —NHC(O)RB, —NHC(O)N(RB)2, —NHC(O)C(RC)2RB, —NHS(O)2RB, 5-10 membered heterocycle, 5-10 membered aryl and 5-10 membered heteroaryl bound through the carbon or nitrogen atom, wherein R2may optionally be substituted by one, two, or three substituents each selected from Rx;RBis independently selected, for each occurrence, from the group consisting of C1-C8alkyl, 5-10 membered aryl, 5-10 membered heteroaryl and 5-10 membered heterocycle;RCis independently selected, for each occurrence, from hydrogen and C1-C8alkyl;Rxis independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, oxo, cyano, —N(Ry)2, —N(Ry)C(O)Ry, C1-C8alkyl, C1-C8alkoxy, C3-C6cycloalkyl, 5-10 membered aryl, 5-10 membered heteroaryl and 5-10 membered heterocycle, wherein the heterocycle or heteroaryl may optionally be substituted by one or more substituents each selected from oxo and C1-C8alkyl;Ryis independently selected, for each occurrence, from the group consisting of hydrogen, C1-C8alkyl, C1-C8alkoxy, —(C1-C8alkoxy)-(5-10 membered aryl) and C3-C6cycloalkyl;A is a reversible or irreversible warhead;R3is selected from 5-10 membered heteroaryl and 5-10 membered heterocycle, wherein R3may optionally be substituted by one, two, or three substituents each selected from RA; andpharmaceutically acceptable salts, stereoisomers, esters, and prodrugs thereof.33. A is a reversible or irreversible warhead selected from the group consisting of cyano, —C(O)RD, —C(O)CH2N(RbRc), —C(O)CH2OC(O)RD, —C(O)C(O)RD, and —(CH═CH)C(O)ORD, whereinRDis selected from the group consisting of hydrogen, —N(RbRc), C1-C8alkyl, C1-C8alkoxy, C3-C6cycloalkyl, 5-10 membered aryl, 5-10 membered heteroaryl, and 5-10 membered heterocycle; wherein RDmay optionally be substituted by one, two, or three substituents each selected from the group consisting of halogen, hydroxyl, and RE;REis selected from the group consisting of C1-C8alkyl, C1-C8alkoxy and 5-10 membered aryl and 5-10 membered heteroaryl, wherein REmay optionally be substituted by one, two, or three substituents each selected from halogen, cyano, C1-C8alkyl and C1-C8alkoxy; andRband Rcare each selected from the group consisting of hydrogen, —CH2C(O)O(C1-C8alkyl), —C(O)—(C1-C8alkyl), —S(O)2—(C1-C8alkyl), C1-C8alkyl, and C3-C6cycloalkyl, wherein the C1-C8alkyl may optionally be substituted by one or more substituents each selected from the group consisting of halogen, C3-C6cycloalkyl, 5-10 membered aryl and 5-10 membered heteroaryl.34. R1is selected from the group consisting of

35. R3is a 5-10 membered heterocycle.36. R3is selected from the group consisting of

37. R2is selected from the group consisting of

38. A reversible conjugate represented by:

whereinCys145is cysteine at position 145 or equivalent active site cysteine on a CL or 3CL protease;IR is a viral protease inhibitor;B is selected from the group consisting of —RD, —C(O)RD, and —CH2ORD, whereinRDis selected from the group consisting of hydrogen, —N(RbRc), C1-C8alkyl, C1-C8alkoxy, C3-C6cycloalkyl, 5-10 membered aryl, 5-10 membered heteroaryl, and 5-10 membered heterocycle; wherein RDmay optionally be substituted by one, two, or three substituents each selected from the group consisting of halogen, hydroxyl and RE;REis selected from the group consisting of C1-C8alkyl, C1-C8alkoxy and 5-10 membered aryl and 5-10 membered heteroaryl, wherein REmay optionally be substituted by one, two, or three substituents each selected from halogen, C1-C8alkyl and C1-C8alkoxy; andRband Rcare each selected from the group consisting of hydrogen, —CH2C(O)O(C1-C8alkyl), —C(O)—(C1-C8alkyl), —S(O)2—(C1-C8alkyl), C1-C8alkyl, and C3-C6cycloalkyl, wherein the C1-C8alkyl may optionally be substituted by one or more substituents each selected from the group consisting of halogen, C3-C6cycloalkyl, 5-10 membered aryl and 5-10 membered heteroaryl.39. An irreversible conjugate represented by:

whereinCys145is cysteine at position 145 or equivalent active site cysteine on a CL or 3CL protease;IR is a viral protease inhibitor;RDis selected from the group consisting of hydrogen, —N(RbRc), C1-C8alkyl, C1-C8alkoxy, C3-C6cycloalkyl, 5-10 membered aryl, 5-10 membered heteroaryl, and 5-10 membered heterocycle; wherein RDmay optionally be substituted by one, two, or three substituents each selected from the group consisting of halogen, hydroxyl and RE;REis selected from the group consisting of C1-C8alkyl, C1-C8alkoxy and 5-10 membered aryl and 5-10 membered heteroaryl, wherein REmay optionally be substituted by one, two, or three substituents each selected from halogen, C1-C8alkyl and C1-C8alkoxy; andRband Rcare each selected from the group consisting of hydrogen, —CH2C(O)O(C1-C8alkyl), —C(O)—(C1-C8alkyl), —S(O)2—(C1-C8alkyl), C1-C8alkyl, and C3-C6cycloalkyl, wherein the C1-C8alkyl may optionally be substituted by one or more substituents each selected from the group consisting of halogen, C3-C6cycloalkyl, 5-10 membered aryl and 5-10 membered heteroaryl.40. A method of ameliorating or treating a viral infection in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of any compound of the embodiment.41. The viral infection is from a virus selected from the group consisting of an RNA virus, a DNA virus, a coronavirus, a papillomavirus, a pneumovirus, a picornavirus, an influenza virus, an adenovirus, a cytomegalovirus, a polyomavirus, a poxvirus, a flavivirus, an alphavirus, an ebola virus, a morbillivirus, an enterovirus, an orthopneumovirus, a lentivirus, arenavirus, a herpes virus, and a hepatovirus.42. The viral infection is from a virus selected from the group consisting of Norwalk virus, feline calicivirus, MD145, murine norovirus, vesicular exanthema of swine virus, rabbit hemorrhagic disease virus, enterovirus (EV)-68 virus, EV-71 virus, poliovirus, coxsackievirus, foot-and-mouth disease virus, hepatitis A, porcine teschovirus, rhinovirus, human coronavirus, transmissible gastroenteritis virus, murine hepatitis virus, bovine coronavirus, feline infectious peritonitis virus, and severe acute respiratory syndrome coronavirus.43. The viral infection is a coronavirus infection.44. The viral infection is a coronavirus selected from the group consisting of: 229E alpha coronavirus, NL63 alpha coronavirus, OC43 beta coronavirus, HKU1 beta coronavirus, Middle East Respiratory Syndrome (MERS) coronavirus (MERS-CoV), severe acute respiratory syndrome (SARS) coronavirus (SARS-CoV), and SARS-CoV-2 (COVID-19).45. The viral infection is SARS-CoV-2.46. The viral infection is an arenavirus infection.48. The arenavirus is selected from the group consisting of: Junin virus, Lassa virus, Lujo virus, Machupo virus, and Sabia virus.48. The viral infection is an influenza infection.49. The influenza is influenza H1N1, H3N2 or H5N1.50. A method of inhibiting transmission of a virus, a method of inhibiting viral replication, a method of minimizing expression of viral proteins, or a method of inhibiting virus release, comprising administering a therapeutically effective amount of a compound of the embodiment to a patient suffering from the virus, and/or contacting an effective amount of a compound of the embodiment with a virally infected cell.51. A method of the embodiment further comprises administering another therapeutic.52. A method of the embodiment further comprises administering an additional anti-viral therapeutic.53. The anti-viral therapeutic is selected from the group consisting of ribavirin, favipiravir, ST-193, oseltamivir, zanamivir, peramivir, danoprevir, ritonavir, and remdesivir.54. The another therapeutic is selected from the group consisting of protease inhibitors, fusion inhibitors, M2 proton channel blockers, polymerase inhibitors, 6-endonuclease inhibitors, neuraminidase inhibitors, reverse transcriptase inhibitor, aciclovir, acyclovir, protease inhibitors, arbidol, atazanavir, atripla, boceprevir, cidofovir, combivir, darunavir, docosanol, edoxudine, entry inhibitors, entecavir, famciclovir, fomivirsen, fosamprenavir, foscarnet, fosfonet, ganciclovir, ibacitabine, immunovir, idoxuridine, imiquimod, inosine, integrase inhibitor, interferons, lopinavir, loviride, moroxydine, nexavir, nucleoside analogues, penciclovir, pleconaril, podophyllotoxin, ribavirin, tipranavir, trifluridine, trizivir, tromantadine, truvada, valaciclovir, valganciclovir, vicriviroc, vidarabine, viramidine, and zodovudine.55. The additional anti-viral therapeutic is selected from the group consisting of lamivudine, an interferon alpha, a VAP anti-idiotypic antibody, enfuvirtide, amantadine, rimantadine, pleconaril, aciclovir, zidovudine, fomivirsen, a morpholino, a protease inhibitor, double-stranded RNA activated caspase oligomerizer (DRACO), rifampicin, zanamivir, oseltamivir, danoprevir, ritonavir, and remdesivir.56. A method of prophylactically treating a patient at risk of viral infection, comprising administering to the patient an effective amount of any compound of the embodiment.57. The compound is administered before viral exposure.58. The compound is administered after viral exposure.

In another aspect, the compositions, compounds and methods of the present disclosure may be described in another embodiment as follows:1. A viral protease inhibitor compound represented by:

wherein:R1is selected from the group consisting of and C1-C8alkyl, C3-C6cycloalkyl, 5-10 membered aryl, 5-10 membered heteroaryl and 5-10 membered heterocycle, wherein R1may optionally be substituted by one, two, or three substituents each selected from RA;RAis independently selected, for each occurrence, halogen, cyano, hydroxyl, oxo, —NH2, C1-C8alkyl, C1-C8heteroalkyl, C1-C8alkoxy and C3-C6cycloalkyl;R2is selected from the group consisting of —NH2, —NHC(O)RB, —NHC(O)N(RB)2, —NHC(O)C(RC)2RB, —NHS(O)2RB, 5-10 membered heterocycle, 5-10 membered aryl and 5-10 membered heteroaryl bound through the carbon or nitrogen atom, wherein R2may optionally be substituted by one, two, or three substituents each selected from Rx;RBis independently selected, for each occurrence, from the group consisting of C1-C8alkyl, 5-10 membered aryl, 5-10 membered heteroaryl and 5-10 membered heterocycle;RCis independently selected, for each occurrence, from hydrogen and C1-C8alkyl;Rxis independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, oxo, cyano, —N(Ry)2, —N(Ry)C(O)Ry, C1-C8alkyl, C1-C8alkoxy, C3-C6cycloalkyl, 5-10 membered aryl, 5-10 membered heteroaryl and 5-10 membered heterocycle, wherein the heterocycle or heteroaryl may optionally be substituted by one or more substituents each selected from oxo and C1-C8alkyl;Ryis independently selected, for each occurrence, from the group consisting of hydrogen, C1-C8alkyl, C1-C8alkoxy, —(C1-C8alkoxy)-(5-10 membered aryl) and C3-C6cycloalkyl;A is a reversible or irreversible warhead;R3is selected from 5-10 membered heteroaryl and 5-10 membered heterocycle, wherein R3may optionally be substituted by one, two, or three substituents each selected from RA;m is 1 or 2; andpharmaceutically acceptable salts, stereoisomers, esters, and prodrugs thereof.2. A is a reversible or irreversible warhead selected from the group consisting of cyano, —C(O)RD, —C(O)CH2N(RbRc), —C(O)CH2OC(O)RD, —C(O)C(O)RD, and —(CH═CH)C(O)ORD, whereinRDis selected from the group consisting of hydrogen, —N(RbRc), C1-C8alkyl, C1-C8alkoxy, C3-C6cycloalkyl, 5-10 membered aryl, 5-10 membered heteroaryl, and 5-10 membered heterocycle; wherein RDmay optionally be substituted by one, two, or three substituents each selected from the group consisting of halogen, hydroxyl, and RE;REis selected from the group consisting of C1-C8alkyl, C1-C8alkoxy and 5-10 membered aryl and 5-10 membered heteroaryl, wherein REmay optionally be substituted by one, two, or three substituents each selected from halogen, cyano, C1-C8alkyl and C1-C8alkoxy; andRband Rcare each selected from the group consisting of hydrogen, —CH2C(O)O(C1-C8alkyl), —C(O)—(C1-C8alkyl), —S(O)2—(C1-C8alkyl), C1-C8alkyl, and C3-C6cycloalkyl, wherein the C1-C8alkyl may optionally be substituted by one or more substituents each selected from the group consisting of halogen, C3-C6cycloalkyl, 5-10 membered aryl and 5-10 membered heteroaryl.3. A is a reversible warhead

wherein Rcis selected from the group consisting of hydrogen, —CH2C(O)O(C1-C8alkyl), C1-C8alkyl, and C3-C6cycloalkyl, wherein the C1-C8alkyl may optionally be substituted by one or more substituents each selected from the group consisting of halogen, C3-C6cycloalkyl, 5-10 membered aryl and 5-10 membered heteroaryl.4. Rcis

wherein X1is independently selected, for each occurrence, from N and CH.5. A is a reversible warhead selected from the group consisting of

6. A is a reversible warhead

whereinX2is selected from the group consisting of NH, O and S;X3is independently selected, for each occurrence, from N and CH;RDis independently selected, for each occurrence, from the group consisting of C1-C8alkyl,

REis independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, C1-C8alkyl and C1-C8alkoxy;p is selected from 0, 1 and 2; andq is selected from 0, 1 and 2.7. A is selected from the group consisting of

8. A is a reversible warhead

wherein X2is selected from the group consisting of NH, NRP, O and S, wherein RPis C1-C8alkyl.9. A is a reversible warhead

10. A is an irreversible warhead —C(O)CH2OC(O)RD, whereinR1is selected from the group consisting of

C1-C8alkyl and C3-C6cycloalkyl;X4is independently selected, for each occurrence, from CH and N;REis independently selected, for each occurrence, from the group consisting of halogen, —CN, —CH3, —CH2CH3, —CH(CH3)2, —OCH3, —CF3, —OCF3and —SCF3; andp is selected from 0, 1 and 2.11. R1is selected from the group consisting of

12. A is an irreversible warhead selected from the group consisting of

13. A is an irreversible warhead selected from the group consisting of

14. A is a reversible or irreversible warhead —C(O)RD, wherein RDis selected from the group consisting of hydrogen, —CH2OH, —CH2OR′ and —CHxFy, wherein R′ is selected from the group consisting of C1-C8alkyl, —(C1-C8alkyl)-(5-10 membered aryl), C1-C8heteroalkyl, C3-C6cycloalkyl and 5-10 membered aryl, wherein x is 0, 1 or 2; y is 1, 2 or 3; and the sum of x and y is 3.15. A is a reversible or irreversible warhead selected from the group consisting of

16. A is a reversible or irreversible warhead —(CH═CH)C(O)ORD, wherein RDis C1-C8alkyl.17. A is an irreversible warhead selected from

18. A is a reversible or irreversible warhead —C(O)CH2N(RbRc).19. A is a reversible or irreversible warhead selected from

20. A is a reversible or irreversible warhead

wherein M is selected from Na and K.21. A is cyano.22. R1is selected from the group consisting of

23. R2is selected from the group consisting of

whereindenotes a bond that may be a single or double bond;R5is independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, oxo, —N(Ry)2, —N(Ry)C(O)Ry, C1-C8alkyl, C1-C8alkoxy, C3-C6cycloalkyl, 5-10 membered aryl, 5-10 membered heteroaryl and 5-10 membered heterocycle, wherein the heterocycle or heteroaryl may optionally be substituted by one or more substituents each selected from oxo and C1-C8alkyl;R6is C1-C8alkyl;R7is independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, oxo, —N(Ry)2, C1-C8alkyl, C1-C8alkoxy, C3-C6cycloalkyl, 5-10 membered aryl, 5-10 membered heteroaryl and 5-10 membered heterocycle, wherein the heterocycle or heteroaryl may optionally be substituted by one or more substituents each selected from oxo and C1-C8alkyl;Ryis independently selected, for each occurrence, from the group consisting of hydrogen, C1-C8alkyl, C1-C8alkoxy, —(C1-C8alkoxy)-(5-10 membered aryl) and C3-C6cycloalkyl;R8is selected from the group consisting of 5-10 membered aryl, 5-10 membered heteroaryl and 5-10 membered heterocycle;W1is selected from CH and N;W2is selected from the group consisting of CH2, O, NH and S;W is selected from W1and W2;s is selected from 1 and 2; andt is selected from 0, 1, 2 and 3.24. R2is selected from the group consisting of

25. R3is selected from the group consisting of

whereindenotes a bond that may be a single or double bond;Y1is selected from the group consisting of CH, CH2, N, NH, O and S;R9is selected from the group consisting of halogen, hydroxyl, oxo, —NH2, —N(CH3)2, —N(CH2CH3)2, —CH3, —CH2CH3, —OCH3and —OCH2CH3.26. R3is selected from the group consisting of

27. The compound is represented by

wherein:R5is independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, oxo, —N(Ry)2, —N(Ry)C(O)Ry, C1-C8alkyl, C1-C8alkoxy, C3-C6cycloalkyl, 5-10 membered aryl, 5-10 membered heteroaryl and 5-10 membered heterocycle, wherein the heterocycle or heteroaryl may optionally be substituted by one or more substituents each selected from oxo and C1-C8alkyl;Ryis independently selected, for each occurrence, from the group consisting of hydrogen, C1-C8alkyl, C1-C8alkoxy, —(C1-C8alkoxy)-(5-10 membered aryl) and C3-C6cycloalkyl; andm is selected from 1 and 2.28. Ryis selected from the group consisting of hydrogen,

29. The compound is selected from the group consisting of:

30. The compound is represented by

whereinRxis independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, oxo, —N(Ry)2, C1-C8alkyl, C1-C8alkoxy, C3-C6cycloalkyl, 5-10 membered aryl, 5-10 membered heteroaryl and 5-10 membered heterocycle, wherein the heterocycle or heteroaryl may optionally be substituted by one or more substituents each selected from oxo and C1-C8alkyl;Ryis independently selected, for each occurrence, from the group consisting of hydrogen, C1-C8alkyl, C1-C8alkoxy and C3-C6cycloalkyl;W is CH or N;m is selected from 1 and 2; andr is selected from 0, 1, 2 and 3.31. Rxis —OCH3.32. A viral protease inhibitor compound selected from the group consisting of

33. A viral protease inhibitor compound represented by:

whereinR1is selected from the group consisting of and C1-C8alkyl, C3-C6cycloalkyl, 5-10 membered aryl, 5-10 membered heteroaryl and 5-10 membered heterocycle, wherein R1may optionally be substituted by one, two, or three substituents each selected from RA;RAis independently selected, for each occurrence, halogen, cyano, hydroxyl, oxo, —NH2, C1-C8alkyl, C1-C8heteroalkyl, C1-C8alkoxy and C3-C6cycloalkyl;R2is selected from the group consisting of —NHC(O)RB, —NHC(O)N(RB)2, —NHC(O)C(RC)2RB, —NHS(O)2RB, 5-10 membered heterocycle, 5-10 membered aryl and 5-10 membered heteroaryl bound through the carbon or nitrogen atom, wherein R2may optionally be substituted by one, two, or three substituents each selected from Rx;RBis independently selected, for each occurrence, from the group consisting of C1-C8alkyl, 5-10 membered aryl, 5-10 membered heteroaryl and 5-10 membered heterocycle;RCis independently selected, for each occurrence, from hydrogen and C1-C8alkyl;Rxis independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, oxo, cyano, —N(Ry)2, —N(Ry)C(O)Ry, C1-C8alkyl, C1-C8alkoxy, C3-C6cycloalkyl, 5-10 membered aryl, 5-10 membered heteroaryl and 5-10 membered heterocycle, wherein the heterocycle or heteroaryl may optionally be substituted by one or more substituents each selected from oxo and C1-C8alkyl;Ryis independently selected, for each occurrence, from the group consisting of hydrogen, C1-C8alkyl, C1-C8alkoxy, —(C1-C8alkoxy)-(5-10 membered aryl) and C3-C6cycloalkyl;A is a reversible or irreversible warhead;X is selected from CH and N;R3is selected from 5-10 membered heteroaryl and 5-10 membered heterocycle, wherein R3may optionally be substituted by one, two, or three substituents each selected from RA; andpharmaceutically acceptable salts, stereoisomers, esters, and prodrugs thereof33. The compound is represented by:

whereinR1is selected from the group consisting of and C1-C8alkyl, C3-C6cycloalkyl, 5-10 membered aryl, 5-10 membered heteroaryl and 5-10 membered heterocycle, wherein R1may optionally be substituted by one, two, or three substituents each selected from RA;RAis independently selected, for each occurrence, halogen, cyano, hydroxyl, oxo, —NH2, C1-C8alkyl, C1-C8heteroalkyl, C1-C8alkoxy and C3-C6cycloalkyl;R2is selected from the group consisting of —NHC(O)RB, —NHC(O)N(RB)2, —NHC(O)C(RC)2RB, —NHS(O)2RB, 5-10 membered heterocycle, 5-10 membered aryl and 5-10 membered heteroaryl bound through the carbon or nitrogen atom, wherein R2may optionally be substituted by one, two, or three substituents each selected from Rx;RBis independently selected, for each occurrence, from the group consisting of C1-C8alkyl, 5-10 membered aryl, 5-10 membered heteroaryl and 5-10 membered heterocycle;RCis independently selected, for each occurrence, from hydrogen and C1-C8alkyl;Rxis independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, oxo, cyano, —N(Ry)2, —N(Ry)C(O)Ry, C1-C8alkyl, C1-C8alkoxy, C3-C6cycloalkyl, 5-10 membered aryl, 5-10 membered heteroaryl and 5-10 membered heterocycle, wherein the heterocycle or heteroaryl may optionally be substituted by one or more substituents each selected from oxo and C1-C8alkyl;Ryis independently selected, for each occurrence, from the group consisting of hydrogen, C1-C8alkyl, C1-C8alkoxy, —(C1-C8alkoxy)-(5-10 membered aryl) and C3-C6cycloalkyl;A is a reversible or irreversible warhead;R3is selected from 5-10 membered heteroaryl and 5-10 membered heterocycle, wherein R3may optionally be substituted by one, two, or three substituents each selected from RA; andpharmaceutically acceptable salts, stereoisomers, esters, and prodrugs thereof.34. A is a reversible or irreversible warhead selected from the group consisting of cyano, —C(O)RD, —C(O)CH2N(RbRc), —C(O)CH2OC(O)RD, —C(O)C(O)RD, and —(CH═CH)C(O)ORD, whereinRDis selected from the group consisting of hydrogen, —N(RbRc), C1-C8alkyl, C1-C8alkoxy, C3-C6cycloalkyl, 5-10 membered aryl, 5-10 membered heteroaryl, and 5-10 membered heterocycle; wherein RDmay optionally be substituted by one, two, or three substituents each selected from the group consisting of halogen, hydroxyl, and RE;REis selected from the group consisting of C1-C8alkyl, C1-C8alkoxy and 5-10 membered aryl and 5-10 membered heteroaryl, wherein REmay optionally be substituted by one, two, or three substituents each selected from halogen, cyano, C1-C8alkyl and C1-C8alkoxy; andRband Rcare each selected from the group consisting of hydrogen, —CH2C(O)O(C1-C8alkyl), —C(O)—(C1-C8alkyl), —S(O)2—(C1-C8alkyl), C1-C8alkyl, and C3-C6cycloalkyl, wherein the C1-C8alkyl may optionally be substituted by one or more substituents each selected from the group consisting of halogen, C3-C6cycloalkyl, 5-10 membered aryl and 5-10 membered heteroaryl.35. R1is selected from the group consisting of

36. R3is a 5-10 membered heterocycle.37. R3is selected from the group consisting of

38. R2is selected from the group consisting of

39. The compound is selected from the group consisting of:

40. A method of ameliorating or treating a viral infection in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of any of the compounds of the embodiment.41. The viral infection is from a virus selected from the group consisting of an RNA virus, a DNA virus, a coronavirus, a papillomavirus, a pneumovirus, a picornavirus, an influenza virus, an adenovirus, a cytomegalovirus, a polyomavirus, a poxvirus, a flavivirus, an alphavirus, an ebola virus, a morbillivirus, an enterovirus, an orthopneumovirus, a lentivirus, arenavirus, a herpes virus, and a hepatovirus.42. The viral infection is from a virus selected from the group consisting of Norwalk virus, feline calicivirus, MD145, murine norovirus, vesicular exanthema of swine virus, rabbit hemorrhagic disease virus, enterovirus (EV)-68 virus, EV-71 virus, poliovirus, coxsackievirus, foot-and-mouth disease virus, hepatitis A, porcine teschovirus, rhinovirus, human coronavirus, transmissible gastroenteritis virus, murine hepatitis virus, bovine coronavirus, feline infectious peritonitis virus, and severe acute respiratory syndrome coronavirus.43. The viral infection is a coronavirus infection.44. The viral infection is a coronavirus selected from the group consisting of: 229E alpha coronavirus, NL63 alpha coronavirus, OC43 beta coronavirus, HKU1 beta coronavirus, Middle East Respiratory Syndrome (MERS) coronavirus (MERS-CoV), severe acute respiratory syndrome (SARS) coronavirus (SARS-CoV), and SARS-CoV-2 (COVID-19).45. The viral infection is SARS-CoV-2.46. The viral infection is an arenavirus infection.47. The arenavirus is selected from the group consisting of: Junin virus, Lassa virus, Lujo virus, Machupo virus, and Sabia virus.48. The viral infection is an influenza infection.49. The influenza is influenza H1N1, H3N2 or H5N1.50. A method of inhibiting transmission of a virus, a method of inhibiting viral replication, a method of minimizing expression of viral proteins, or a method of inhibiting virus release, comprising administering a therapeutically effective amount of any compound of the embodiment to a patient suffering from the virus, and/or contacting an effective amount of any compound of the embodiment with a virally infected cell.51. The method further comprises administering another therapeutic.52. The method further comprises administering an additional anti-viral therapeutic.53. The anti-viral therapeutic is selected from the group consisting of ribavirin, favipiravir, ST-193, oseltamivir, zanamivir, peramivir, danoprevir, ritonavir, and remdesivir.54. The another therapeutic is selected from the group consisting of protease inhibitors, fusion inhibitors, M2 proton channel blockers, polymerase inhibitors, 6-endonuclease inhibitors, neuraminidase inhibitors, reverse transcriptase inhibitor, aciclovir, acyclovir, protease inhibitors, arbidol, atazanavir, atripla, boceprevir, cidofovir, combivir, darunavir, docosanol, edoxudine, entry inhibitors, entecavir, famciclovir, fomivirsen, fosamprenavir, foscarnet, fosfonet, ganciclovir, ibacitabine, immunovir, idoxuridine, imiquimod, inosine, integrase inhibitor, interferons, lopinavir, loviride, moroxydine, nexavir, nucleoside analogues, penciclovir, pleconaril, podophyllotoxin, ribavirin, tipranavir, trifluridine, trizivir, tromantadine, truvada, valaciclovir, valganciclovir, vicriviroc, vidarabine, viramidine, and zodovudine.55. The additional anti-viral therapeutic is selected from the group consisting of lamivudine, an interferon alpha, a VAP anti-idiotypic antibody, enfuvirtide, amantadine, rimantadine, pleconaril, aciclovir, zidovudine, fomivirsen, a morpholino, a protease inhibitor, double-stranded RNA activated caspase oligomerizer (DRACO), rifampicin, zanamivir, oseltamivir, danoprevir, ritonavir, and remdesivir.56. A method of prophylactically treating a patient at risk of viral infection, comprising administering to the patient an effective amount of any compound of the embodiment.57. The compound is administered before viral exposure.58. The compound is administered after viral exposure.

In another aspect, the compositions, compounds and methods of the present disclosure may be described in another embodiment as follows:1. A protease inhibitor compound represented by:

wherein:R1is selected from the group consisting of and C1-C8alkyl, C3-C6cycloalkyl, 5-10 membered aryl, 5-10 membered heteroaryl and 5-10 membered heterocycle, wherein R1may optionally be substituted by one, two, or three substituents each selected from RA;RAis independently selected, for each occurrence, halogen, cyano, hydroxyl, oxo, SF5, —NH2, C1-C8alkyl, C1-C8heteroalkyl, C1-C8alkoxy and C3-C6cycloalkyl;R2is selected from the group consisting of —NH2, —NHC(O)RB, —NHC(O)N(RB)2, —NHC(O)C(RC)2RB, —NHS(O)2RB, 5-10 membered heterocycle, 5-10 membered aryl and 5-10 membered heteroaryl bound through the carbon or nitrogen atom, wherein R2may optionally be substituted by one, two, or three substituents each selected from Rx;RBis independently selected, for each occurrence, from the group consisting of C1-C8alkyl, 5-10 membered aryl, 5-10 membered heteroaryl and 5-10 membered heterocycle;RCis independently selected, for each occurrence, from hydrogen and C1-C8alkyl;Rxis independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, oxo, cyano, —N(Ry)2, —N(Ry)C(O)Ry, C1-C8alkyl, C1-C8alkoxy, C3-C6cycloalkyl, 5-10 membered aryl, 5-10 membered heteroaryl and 5-10 membered heterocycle, wherein the heterocycle or heteroaryl may optionally be substituted by one or more substituents each selected from oxo and C1-C8alkyl;Ryis independently selected, for each occurrence, from the group consisting of hydrogen, C1-C8alkyl, C1-C8alkoxy, —(C1-C8alkoxy)-(5-10 membered aryl) and C3-C6cycloalkyl;A is a warhead;R3is selected from 5-10 membered heteroaryl and 5-10 membered heterocycle, wherein R3may optionally be substituted by one, two, or three substituents each selected from RA;m is 1 or 2; andpharmaceutically acceptable salts, stereoisomers, esters, and prodrugs thereof.2. A is selected from the group consisting of cyano, —C(O)RD, —C(O)CH2N(RbRc), —C(O)CH2OC(O)RD, —C(O)C(O)RD, —(CH═CH)C(O)ORD, —(CH═CCN)C(O)ORD, —(CH═CCN)C(O)(NH)RD, —CH(CN)(OH), —CH(CN)(NRbRc),

whereinRDis selected from the group consisting of hydrogen, hydroxyl, —ORbb—N(RbRc), C1-C8alkyl, C1-C8alkoxy, C3-C6cycloalkyl, C6-C14aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycle; wherein RDmay optionally be substituted by one, two, or three substituents each selected from the group consisting of halogen, hydroxyl, and RE;REis selected from the group consisting of C1-C8alkyl, C1-C8alkoxy and C6-C14aryl, 4-10 membered heterocycle, and 5-10 membered heteroaryl, wherein REmay optionally be substituted by one, two, or three substituents each selected from halogen, cyano, C1-C8alkyl and C1-C8alkoxy;Rbbis selected from the group consisting of C3-C6cycloalkyl, C6-C14aryl, —(C1-C8alkyl)-C6-C14aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycle;Rccis selected from the group consisting of hydrogen, C1-C8alkyl, C3-C6cycloalkyl, —(C1-C8alkyl)-(C6-C14aryl), C6-C14aryl, 5-10 membered heteroaryl, —(C1-C8alkyl)-(5-10 membered heteroaryl), 5-10 membered heterocycle and —N(RbRc), wherein Rband Rcare each selected from the group consisting of hydrogen, C1-C8alkyl, and C3-C6cycloalkyl, or Rband Rcmay be joined together to form, together with the nitrogen to which they are attached, a 5-10 membered heterocycle;Rcdis selected from the group consisting of hydrogen, C1-C8alkyl, and C3-C6cycloalkyl; andRband Rcare each selected from the group consisting of hydrogen, —CH2C(O)O(C1-C8alkyl), —C(O)—(C1-C8alkyl), —S(O)2—(C1-C8alkyl), C1-C8alkyl, C3-C6cycloalkyl and —(C1-C8alkyl)-C6-C14aryl, wherein the C1-C8alkyl may optionally be substituted by one or more substituents each selected from the group consisting of halogen, C3-C6cycloalkyl, C6-C14aryl, 4-10 membered heterocycle, and 5-10 membered heteroaryl.3. A is a warhead represented by:

wherein Rcis selected from the group consisting of hydrogen, —CH2C(O)O(C1-C8alkyl), C1-C8alkyl, and C3-C6cycloalkyl, wherein the C1-C8alkyl may optionally be substituted by one or more substituents each selected from the group consisting of halogen, C3-C6cycloalkyl, 5-10 membered aryl and 5-10 membered heteroaryl.4. Rcis

wherein X1is independently selected, for each occurrence, from N and CH.5. A is selected from the group consisting of

6. A is

whereinX2is selected from the group consisting of NH, O and S;X3is independently selected, for each occurrence, from N and CH;RDis independently selected, for each occurrence, from the group consisting of C1-C8alkyl,

REis independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, C1-C8alkyl and C1-C8alkoxy;p is selected from 0, 1 and 2; andq is selected from 0, 1 and 2.7. A is selected from the group consisting of

8. A is

wherein X2is selected from the group consisting of NH, NRP, O and S, wherein RPis C1-C8alkyl.9. A is selected from the group consisting of

10. A is —C(O)CH2OC(O)RD, whereinRDis selected from the group consisting of

C1-C8alkyl and C3-C6cycloalkyl;X4is independently selected, for each occurrence, from CH and N;REis independently selected, for each occurrence, from the group consisting of halogen, —CN, —CH3, —CH2CH3, —CH(CH3)2, —OCH3, —CF3, —OCF3and —SCF3; andp is selected from 0, 1 and 2.11. RDis selected from the group consisting of

12. A is selected from the group consisting of

13. A is selected from the group consisting of

14. A is —C(O)RD, wherein RDis selected from the group consisting of hydrogen, —CH2OH, —CH2OR′ and —CHxFy, wherein R′ is selected from the group consisting of C1-C8alkyl, —(C1-C8alkyl)-(5-10 membered aryl), C1-C8heteroalkyl, C3-C6cycloalkyl and 5-10 membered aryl, wherein x is 0, 1 or 2; y is 1, 2 or 3; and the sum of x and y is 3.15. A is selected from the group consisting of

16. A is —(CH═CH)C(O)ORD, wherein RDis C1-C8alkyl.17. A is selected from

18. A is —C(O)CH2N(RbRc).19. A is a warhead selected from

20. A is

wherein M is selected from Na and K.21. A is cyano.22. R1is selected from the group consisting of

23. R2is selected from the group consisting of

whereindenotes a bond that may be a single or double bond;R5is independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, oxo, —N(Ry)2, —N(Ry)C(O)Ry, C1-C8alkyl, C1-C8alkoxy, C3-C6cycloalkyl, 5-10 membered aryl, 5-10 membered heteroaryl and 5-10 membered heterocycle, wherein the heterocycle or heteroaryl may optionally be substituted by one or more substituents each selected from oxo and C1-C8alkyl;R6is C1-C8alkyl;R7is independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, oxo, —N(Ry)2, C1-C8alkyl, C1-C8alkoxy, C3-C6cycloalkyl, 5-10 membered aryl, 5-10 membered heteroaryl and 5-10 membered heterocycle, wherein the heterocycle or heteroaryl may optionally be substituted by one or more substituents each selected from oxo and C1-C8alkyl;Ryis independently selected, for each occurrence, from the group consisting of hydrogen, C1-C8alkyl, C1-C8alkoxy, —(C1-C8alkoxy)-(5-10 membered aryl) and C3-C6cycloalkyl;R8is selected from the group consisting of 5-10 membered aryl, 5-10 membered heteroaryl and 5-10 membered heterocycle;W1is selected from CH and N;W2is selected from the group consisting of CH2, O, NH and S;W is selected from W1and W2;s is selected from 1 and 2; andt is selected from 0, 1, 2 and 3.24. R2is selected from the group consisting of

25. R3is selected from the group consisting of

whereindenotes a bond that may be a single or double bond;Y1is selected from the group consisting of CH, CH2, N, NH, O and S;R9is selected from the group consisting of halogen, hydroxyl, oxo, —NH2, —N(CH3)2, —N(CH2CH3)2, —CH3, —CH2CH3, —OCH3and —OCH2CH3.26. R3is selected from the group consisting of

27. The compound is represented by

wherein:R5is independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, oxo, —N(Ry)2, —N(Ry)C(O)Ry, C1-C8alkyl, C1-C8alkoxy, C3-C6cycloalkyl, 5-10 membered aryl, 5-10 membered heteroaryl and 5-10 membered heterocycle, wherein the heterocycle or heteroaryl may optionally be substituted by one or more substituents each selected from oxo and C1-C8alkyl;Ryis independently selected, for each occurrence, from the group consisting of hydrogen, C1-C8alkyl, C1-C8alkoxy, —(C1-C8alkoxy)-(5-10 membered aryl) and C3-C6cycloalkyl; andm is selected from 1 and 2.28. Ryis selected from the group consisting of hydrogen,

29. The compound is selected from the group consisting of:

30. The compound is represented by

whereinRxis independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, oxo, —N(Ry)2, C1-C8alkyl, C1-C8alkoxy, C3-C6cycloalkyl, 5-10 membered aryl, 5-10 membered heteroaryl and 5-10 membered heterocycle, wherein the heterocycle or heteroaryl may optionally be substituted by one or more substituents each selected from oxo and C1-C8alkyl;Ryis independently selected, for each occurrence, from the group consisting of hydrogen, C1-C8alkyl, C1-C8alkoxy and C3-C6cycloalkyl;W is CH or N;m is selected from 1 and 2; andr is selected from 0, 1, 2 and 3.31. Rxis —OCH3.32. A protease inhibitor compound represented by:

whereinR3ais selected from

and 4-10 membered heterocycle, wherein the heterocycle may optionally be substituted by one, two or three substituents each selected from the group consisting of hydroxyl, C1-C8alkoxy, oxo and a warhead A;R3bis selected from hydrogen and C1-C8alkyl; wherein R3aand R3bmay be joined together to form, together with the carbon to which they are attached, a 4-10 membered heterocycle, wherein the heterocycle may optionally be substituted by one, two or three substituents each selected from C6-C14aryl and a warhead A;R1ais selected from the group consisting of C1-C8alkyl, —(C1-C8alkyl)-R1, —(C1-C8alkyl)-CN, C3-C10cycloalkyl, C6-C14aryl, 4-10 membered heterocycle and 5-10 membered heteroaryl;R1bis selected from hydrogen and C1-C8alkyl;R1aand R1bmay be joined together to form, together with the carbon to which they are attached, a 4-10 membered heterocycle or a C3-C10cycloalkyl;R1is selected from the group consisting of C1-C8alkyl, C2-C10alkenyl, C2-C10alkynyl, C3-C10cycloalkyl, C6-C14aryl, 5-10 membered heteroaryl and 4-10 membered heterocycle, wherein R1may optionally be substituted by one, two, or three substituents each selected from RA;RAis independently selected, for each occurrence, halogen, cyano, hydroxyl, oxo, SF5, —NH2, —O-phenyl, —O—(C1-C8alkyl)-phenyl, —C(O)-(5-10 membered heteroaryl), —C(O)-(4-10 membered heterocycle), —C(O)—O-(4-10 membered heterocycle), —C(O)—OC(CH3)3, —C(O)—(C2-C10alkenyl)-(C6-C14aryl) C1-C8alkyl, C2-C10alkenyl, C2-C10alkynyl, C1-C8heteroalkyl, C1-C8alkoxy, C3-C10cycloalkyl, —(C1-C8alkyl)-(C6-C14aryl), —(C1-C8alkyl)-(5-10 membered heteroaryl), C6-C14aryl, 5-10 membered heteroaryl and 4-10 membered heterocycle, wherein the heterocycle, heteroaryl, or aryl may optionally be substituted by one, two or three substituents of halogen, C1-C8alkyl, C1-C8alkoxy, SF5, —NH2, hydroxyl or oxo;R2is selected from the group consisting of —NHC(O)RB, —NHC(O)N(RB)2, —NHC(O)C(RC)2RB, —NHS(O)2RB, 4-10 membered heterocycle, C6-C14aryl and 5-10 membered heteroaryl bound through the carbon or nitrogen atom, wherein R2may optionally be substituted by one, two, or three substituents each selected from Rx;R1aand R2may be joined together to form, together with the carbon to which they are attached, a 4-10 membered heterocycle or a C3-C10cycloalkyl, wherein the cycloalkyl or heterocycle may optionally be substituted by one, two or three substituents each selected from RA;R3is selected from 5-10 membered heteroaryl and 4-10 membered heterocycle, wherein R3may optionally be substituted by one, two, or three substituents each selected from RA;RBis independently selected, for each occurrence, from the group consisting of C1-C8alkyl, C2-C10alkenyl, C2-C10alkynyl, C6-C14aryl, 5-10 membered heteroaryl and 4-10 membered heterocycle;RCis independently selected, for each occurrence, from hydrogen and C1-C8alkyl;Rxis independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, oxo, SF5, cyano, —C(O)O(CH3), —N(Ry)2, —N(Ry)C(O)Ry, C1-C8alkyl, C1-C8alkoxy, C3-C10cycloalkyl, C6-C14aryl, 5-10 membered heteroaryl and 4-10 membered heterocycle, wherein the aryl, heterocycle or heteroaryl may optionally be substituted by one or more substituents each selected from oxo and C1-C8alkyl;Ryis independently selected, for each occurrence, from the group consisting of hydrogen, C1-C8alkyl, C1-C8alkoxy, —(C1-C8alkoxy)-(5-10 membered aryl) and C3-C6cycloalkyl;A is a warhead;X is selected from CH, C(CH3) and N; andpharmaceutically acceptable salts, stereoisomers, esters, and prodrugs thereof.33. The compound is represented by:

34. The compound is represented by:

whereinRDis selected from the group consisting of hydrogen, hydroxyl, —ORbb—N(RbRc), C1-C8alkyl, C1-C8alkoxy, C3-C6cycloalkyl, C6-C14aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycle; wherein RDmay optionally be substituted by one, two, or three substituents each selected from the group consisting of halogen, hydroxyl, and RE;REis selected from the group consisting of C1-C8alkyl, C1-C8alkoxy and C6-C14aryl, 4-10 membered heterocycle, and 5-10 membered heteroaryl, wherein REmay optionally be substituted by one, two, or three substituents each selected from halogen, cyano, C1-C8alkyl and C1-C8alkoxy;Rbbis selected from the group consisting of C3-C6cycloalkyl, C6-C14aryl, —(C1-C8alkyl)-C6-C14aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycle;Rccis selected from the group consisting of hydrogen, C1-C8alkyl, C3-C6cycloalkyl, —(C1-C8alkyl)-(C6-C14aryl), C6-C14aryl, 5-10 membered heteroaryl, —(C1-C8alkyl)-(5-10 membered heteroaryl), 5-10 membered heterocycle and —N(RbRc), wherein Rband Rcare each selected from the group consisting of hydrogen, C1-C8alkyl, and C3-C6cycloalkyl, or Rband Rcmay be joined together to form, together with the nitrogen to which they are attached, a 5-10 membered heterocycle;Rcdis selected from the group consisting of hydrogen, C1-C8alkyl, and C3-C6cycloalkyl; andRband Rcare each selected from the group consisting of hydrogen, —CH2C(O)O(C1-C8alkyl), —C(O)—(C1-C8alkyl), —S(O)2—(C1-C8alkyl), C1-C8alkyl, C3-C6cycloalkyl and —(C1-C8alkyl)-C6-C14aryl, wherein the C1-C8alkyl may optionally be substituted by one or more substituents each selected from the group consisting of halogen, C3-C6cycloalkyl, C6-C14aryl, 4-10 membered heterocycle, and 5-10 membered heteroaryl.36. A is selected from the group consisting of

37. R1ais selected from the group consisting of

40. R1aand R1bare joined to together to form41. R3ais a 4-10 membered heterocycle substituted by A.42. R3ais selected from the group consisting of

43. R3is a 4-10 membered heterocycle.44. R3is selected from the group consisting of

45. R2is selected from the group consisting of

46. R1aand R2are joined to together to form the heterocycle selected from the group consisting of:

47. The compound is selected from the group consisting of:

48. A method of ameliorating or treating a viral infection in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of any of the compounds of the embodiment.49. The viral infection is from a virus selected from the group consisting of an RNA virus, a DNA virus, a coronavirus, a papillomavirus, a pneumovirus, a picornavirus, an influenza virus, an adenovirus, a cytomegalovirus, a polyomavirus, a poxvirus, a flavivirus, an alphavirus, an ebola virus, a morbillivirus, an enterovirus, an orthopneumovirus, a lentivirus, arenavirus, a herpes virus, and a hepatovirus.50. The viral infection is from a virus selected from the group consisting of Norwalk virus, feline calicivirus, MD145, murine norovirus, vesicular exanthema of swine virus, rabbit hemorrhagic disease virus, enterovirus (EV)-68 virus, EV-71 virus, poliovirus, coxsackievirus, foot-and-mouth disease virus, hepatitis A, porcine teschovirus, rhinovirus, human coronavirus, transmissible gastroenteritis virus, murine hepatitis virus, bovine coronavirus, feline infectious peritonitis virus, and severe acute respiratory syndrome coronavirus.51. The viral infection is a coronavirus infection.52. The viral infection is a coronavirus selected from the group consisting of: 229E alpha coronavirus, NL63 alpha coronavirus, OC43 beta coronavirus, HKU1 beta coronavirus, Middle East Respiratory Syndrome (MERS) coronavirus (MERS-CoV), severe acute respiratory syndrome (SARS) coronavirus (SARS-CoV), and SARS-CoV-2 (COVID-19).53. The viral infection is SARS-CoV-2.54. The viral infection is an arenavirus infection.55. The arenavirus is selected from the group consisting of: Junin virus, Lassa virus, Lujo virus, Machupo virus, and Sabia virus.56. The viral infection is an influenza infection.57. The influenza is influenza H1N1, H3N2 or H5N1.58. A method of inhibiting transmission of a virus, a method of inhibiting viral replication, a method of minimizing expression of viral proteins, or a method of inhibiting virus release, comprising administering a therapeutically effective amount of any compound of the embodiment to a patient suffering from the virus, and/or contacting an effective amount of any compound of the embodiment with a virally infected cell.59. The method further comprises administering another therapeutic.60. The method further comprises administering an additional anti-viral therapeutic.61. The anti-viral therapeutic is selected from the group consisting of ribavirin, favipiravir, ST-193, oseltamivir, zanamivir, peramivir, danoprevir, ritonavir, and remdesivir.62. The another therapeutic is selected from the group consisting of protease inhibitors, fusion inhibitors, M2 proton channel blockers, polymerase inhibitors, 6-endonuclease inhibitors, neuraminidase inhibitors, reverse transcriptase inhibitor, aciclovir, acyclovir, protease inhibitors, arbidol, atazanavir, atripla, boceprevir, cidofovir, combivir, darunavir, docosanol, edoxudine, entry inhibitors, entecavir, famciclovir, fomivirsen, fosamprenavir, foscarnet, fosfonet, ganciclovir, ibacitabine, immunovir, idoxuridine, imiquimod, inosine, integrase inhibitor, interferons, lopinavir, loviride, moroxydine, nexavir, nucleoside analogues, penciclovir, pleconaril, podophyllotoxin, ribavirin, tipranavir, trifluridine, trizivir, tromantadine, truvada, valaciclovir, valganciclovir, vicriviroc, vidarabine, viramidine, and zodovudine.63. The additional anti-viral therapeutic is selected from the group consisting of lamivudine, an interferon alpha, a VAP anti-idiotypic antibody, enfuvirtide, amantadine, rimantadine, pleconaril, aciclovir, zidovudine, fomivirsen, a morpholino, a protease inhibitor, double-stranded RNA activated caspase oligomerizer (DRACO), rifampicin, zanamivir, oseltamivir, danoprevir, ritonavir, and remdesivir.64. A method of prophylactically treating a patient at risk of viral infection, comprising administering to the patient an effective amount of any compound of the embodiment.65. The compound is administered before viral exposure.66. The compound is administered after viral exposure.

In another aspect, the compositions, compounds and methods of the present disclosure may be described in another embodiment as follows:1. A protease inhibitor compound represented by:

R3ais selected from and 4-10 membered heterocycle, wherein the heterocycle may optionally be substituted by one, two or three substituents each selected from the group consisting of hydroxyl, C1-C8alkoxy, oxo and a warhead A;R3bis selected from hydrogen and C1-C8alkyl; wherein R3aand R3bmay be joined together to form, together with the carbon to which they are attached, a 4-10 membered heterocycle, wherein the heterocycle may optionally be substituted by one, two or three substituents each selected from C6-C14aryl and a warhead A;R1ais selected from the group consisting of C1-C8alkyl, C1-C8heteroalkyl, —(C1-C8alkyl)-R1, —(C1-C8alkyl)-CN, C3-C10cycloalkyl, C6-C14aryl, 4-10 membered heterocycle and 5-10 membered heteroaryl;R1bis selected from hydrogen and C1-C8alkyl;R1aand R1bmay be joined together to form, together with the carbon to which they are attached, a 4-10 membered heterocycle or a C3-C10cycloalkyl;R1is selected from the group consisting of C1-C8alkyl, C2-C10alkenyl, C2-C10alkynyl, C3-C10cycloalkyl, C6-C14aryl, 5-10 membered heteroaryl and 4-10 membered heterocycle, wherein R1may optionally be substituted by one, two, or three substituents each selected from RA;RAis independently selected, for each occurrence, halogen, cyano, hydroxyl, oxo, SF5, —CH2CF3, CF3, —O—CF3, —O—CHF2, —S—CH3, —S(O)2—CH3, —NH2, —O-phenyl, —O—(C1-C8alkyl)-phenyl, —NHC(O)RB, —NHC(O)ORB, —NHC(O)O—(C1-C8alkyl)-RB, —N(Ry)2, —N(Ry)(C1-C8alkyl)C(O)O-phenyl, —N(Ry)(C1-C8alkyl)C(O)N(Ry)2, —NHC(O)O(C1-C8alkyl)RB, —C(O)-(5-10 membered heteroaryl), —C(O)-(4-10 membered heterocycle), —C(O)—O-(4-10 membered heterocycle), —C(O)—OC(CH3)3, —C(O)—(C2-C10alkenyl)-(C6-C14aryl), C1-C8alkyl, C2-C10alkenyl, C2-C10alkynyl, C1-C8heteroalkyl, C1-C8alkoxy, C3-C10cycloalkyl, —(C1-C8alkyl)-(C3-C10cycloalkyl), —(C1-C8alkyl)-(C6-C14aryl), —(C1-C8alkyl)-(5-10 membered heteroaryl), C6-C14aryl, 5-10 membered heteroaryl and 4-10 membered heterocycle, wherein the RB, alkyl, heterocycle, heteroaryl, or aryl may optionally be substituted by one, two or three substituents of halogen, C1-C8alkyl, C1-C8alkoxy, SF5, —NH2, hydroxyl or oxo;R2is selected from the group consisting of —NHC(O)RB, —NHC(O)N(RB)2, —NHC(O)C(RC)2RB, —NHS(O)2RB, —O—(C1-C8alkyl)-(C3-C10cycloalkyl), 4-10 membered heterocycle, C6-C14aryl and 5-10 membered heteroaryl bound through the carbon or nitrogen atom, wherein R2may optionally be substituted by one, two, or three substituents each selected from Rx;R1aand R2may be joined together to form, together with the carbon to which they are attached, a 4-10 membered heterocycle or a C3-C10cycloalkyl, wherein the cycloalkyl or heterocycle may optionally be substituted by one, two or three substituents each selected from RA;R3is selected from 5-10 membered heteroaryl and 4-10 membered heterocycle, wherein R3may optionally be substituted by one, two, or three substituents each selected from RA;RBis independently selected, for each occurrence, from the group consisting of C1-C8alkyl, C2-C10alkenyl, C2-C10alkynyl, C6-C14aryl, 5-10 membered heteroaryl and 4-10 membered heterocycle;RCis independently selected, for each occurrence, from hydrogen, halogen and C1-C8alkyl;Rxis independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, oxo, CF3, SF5, cyano, —OCHF2, —OCF3, —O—(C1-C8alkyl), —C(O)O(CH3), —N(Ry)2, —N(Ry)C(O)Ry, —N(Ry)(C1-C8alkyl)C(O)N(Ry)2, —N(Ry)(C1-C8alkyl)C(O)OH, —(C1-C8alkyl)-(C3-C10cycloalkyl), C1-C8alkyl, C1-C8alkoxy, C3-C10cycloalkyl, C6-C14aryl, 5-10 membered heteroaryl and 4-10 membered heterocycle, wherein the alkyl, aryl, heterocycle or heteroaryl may optionally be substituted by one or more substituents each selected from oxo, halogen and C1-C8alkyl;Ryis independently selected, for each occurrence, from the group consisting of hydrogen, C1-C8alkyl, C1-C8heteroalkyl, —CH2CF3, C1-C8alkoxy, —(C1-C8alkoxy)-(5-10 membered aryl), C3-C6cycloalkyl and —(C1-C8alkyl)COOH;A is a warhead;X is selected from the group consisting of CH, C(CH3) and N; andpharmaceutically acceptable salts, stereoisomers, esters, and prodrugs thereof.2. The compound is represented by:

3. The compound is represented by:

whereinR1is selected from the group consisting of hydrogen, hydroxyl, —ORbb—N(RbRc), C1-C8alkyl, C1-C8alkoxy, C3-C6cycloalkyl, C6-C14aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycle; wherein R1may optionally be substituted by one, two, or three substituents each selected from the group consisting of halogen, hydroxyl, and RE;REis selected from the group consisting of C1-C8alkyl, C1-C8alkoxy, C6-C14aryl, 4-10 membered heterocycle, and 5-10 membered heteroaryl, wherein REmay optionally be substituted by one, two, or three substituents each selected from halogen, cyano, C1-C8alkyl and C1-C8alkoxy;Rbbis selected from the group consisting of C3-C6cycloalkyl, C6-C14aryl, —(C1-C8alkyl)-C6-C14aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycle;Rccis selected from the group consisting of hydrogen, C1-C8alkyl, C3-C6cycloalkyl, —(C1-C8alkyl)-(C6-C14aryl), C6-C14aryl, 5-10 membered heteroaryl, —(C1-C8alkyl)-(5-10 membered heteroaryl), 5-10 membered heterocycle and —N(RbRc), wherein Rband Rcare each selected from the group consisting of hydrogen, C1-C8alkyl, and C3-C6cycloalkyl, or Rband Rcmay be joined together to form, together with the nitrogen to which they are attached, a 5-10 membered heterocycle;Rcdis selected from the group consisting of hydrogen, C1-C8alkyl, and C3-C6cycloalkyl; andRband Rcare each selected from the group consisting of hydrogen, —CH2C(O)O(C1-C8alkyl), —C(O)—(C1-C8alkyl), —S(O)2—(C1-C8alkyl), C1-C8alkyl, C3-C6cycloalkyl and —(C1-C8alkyl)-C6-C14aryl, wherein the C1-C8alkyl may optionally be substituted by one or more substituents each selected from the group consisting of halogen, C3-C6cycloalkyl, C6-C14aryl, 4-10 membered heterocycle, and 5-10 membered heteroaryl.5. A is selected from the group consisting of

6. R1ais selected from the group consisting of

10. R3ais a 4-10 membered heterocycle substituted by A.11. R3ais selected from the group consisting of

12. R3is a 4-10 membered heterocycle.13. R3is selected from the group consisting of

14. R2is selected from the group consisting of

15. R1aand R2are joined to together to form the heterocycle selected from the group consisting of:

16. The compound is selected from the group consisting of:

In another aspect, the compositions, compounds and methods of the present disclosure may be described in another embodiment as follows:1. A protease inhibitor compound represented by:

R3ais selected from and 4-10 membered heterocycle, wherein the heterocycle may optionally be substituted by one, two or three substituents each selected from the group consisting of hydroxyl, C1-C8alkoxy, oxo and a warhead A;R3bis selected from hydrogen and C1-C8alkyl; wherein R3aand R3bmay be joined together to form, together with the carbon to which they are attached, a 4-10 membered heterocycle, wherein the heterocycle may optionally be substituted by one, two or three substituents each selected from C6-C14aryl and a warhead A;R1ais selected from the group consisting of hydrogen, C1-C8alkyl, C1-C8heteroalkyl, —(C1-C8alkyl)-R1, —(C1-C8alkyl)-CN, C3-C10cycloalkyl, C6-C14aryl, 4-10 membered heterocycle and 5-10 membered heteroaryl;R1bis selected from hydrogen and C1-C8alkyl;R1aand R1bmay be joined together to form, together with the carbon to which they are attached, a 4-10 membered heterocycle or a C3-C10cycloalkyl;R1is selected from the group consisting of C1-C8alkyl, C2-C10alkenyl, C2-C10alkynyl, C3-C10cycloalkyl, C6-C14aryl, 5-10 membered heteroaryl and 4-10 membered heterocycle, wherein R1may optionally be substituted by one, two, or three substituents each selected from RA;RAis independently selected, for each occurrence, halogen, cyano, hydroxyl, oxo, SF5, —CH2CF3, CF3, —O—CF3, —O—CHF2, —S—CH3, —S(O)2—CH3, —NH2, —O-phenyl, —O—(C1-C8alkyl)-phenyl, —NHC(O)RB, —NHC(O)ORB, —NHC(O)O—(C1-C8alkyl)-RB, —N(Ry)2, —N(Ry)(C1-C8alkyl)C(O)O-phenyl, —N(Ry)(C1-C8alkyl)C(O)N(Ry)2, —NHC(O)O(C1-C8alkyl)RB, —C(O)-(5-10 membered heteroaryl), —C(O)-(4-10 membered heterocycle), —C(O)—O-(4-10 membered heterocycle), —C(O)—OC(CH3)3, —C(O)—(C2-C10alkenyl)-(C6-C14aryl), C1-C8alkyl, C2-C10alkenyl, C2-C10alkynyl, C1-C8heteroalkyl, C1-C8alkoxy, C3-C10cycloalkyl, —(C1-C8alkyl)-(C3-C10cycloalkyl), —(C1-C8alkyl)-(C6-C14aryl), —(C1-C8alkyl)-(5-10 membered heteroaryl), C6-C14aryl, 5-10 membered heteroaryl and 4-10 membered heterocycle, wherein the RB, alkyl, heterocycle, heteroaryl, or aryl may optionally be substituted by one, two or three substituents of halogen, C1-C8alkyl, C1-C8alkoxy, SF5, —NH2, hydroxyl or oxo;R2is selected from the group consisting of —NHC(O)RB, —NHC(O)N(RB)2, —NHC(O)C(RC)2RB, —NHS(O)2RB, —O—(C1-C8alkyl)-(C3-C10cycloalkyl), 4-10 membered heterocycle, C6-C14aryl and 5-10 membered heteroaryl bound through the carbon or nitrogen atom, wherein R2may optionally be substituted by one, two, or three substituents each selected from Rx;R1aand R2may be joined together to form, together with the carbon to which they are attached, a 4-10 membered heterocycle or a C3-C10cycloalkyl, wherein the cycloalkyl or heterocycle may optionally be substituted by one, two or three substituents each selected from RA;R3is selected from 5-10 membered heteroaryl and 4-10 membered heterocycle, wherein R3may optionally be substituted by one, two, or three substituents each selected from RA;RBis independently selected, for each occurrence, from the group consisting of C1-C8alkyl, C2-C10alkenyl, C2-C10alkynyl, C6-C14aryl, 5-10 membered heteroaryl and 4-10 membered heterocycle;RCis independently selected, for each occurrence, from hydrogen, halogen and C1-C8alkyl;Rxis independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, oxo, CF3, SF5, cyano, —OCHF2, —OCF3, —O—(C1-C8alkyl), —C(O)O(CH3), —N(Ry)2, —N(Ry)C(O)Ry, —N(Ry)(C1-C8alkyl)C(O)N(Ry)2, —N(Ry)(C1-C8alkyl)C(O)OH, —(C1-C8alkyl)-(C3-C10cycloalkyl), C1-C8alkyl, C1-C8alkoxy, C3-C10cycloalkyl, C6-C14aryl, 5-10 membered heteroaryl and 4-10 membered heterocycle, wherein the alkyl, aryl, heterocycle or heteroaryl may optionally be substituted by one or more substituents each selected from oxo, halogen and C1-C8alkyl;Ryis independently selected, for each occurrence, from the group consisting of hydrogen, C1-C8alkyl, C1-C8heteroalkyl, —CH2CF3, C1-C8alkoxy, —(C1-C8alkoxy)-(5-10 membered aryl), C3-C6cycloalkyl and —(C1-C8alkyl)COOH;A is a warhead;X is selected from the group consisting of C(Rxy) and N, wherein Rxyis selected from the group consisting of H, D, —OH, —NH2, halogen, C1-C8alkyl, C1-C8haloalkyl, and C1-C8alkoxy; andpharmaceutically acceptable salts, stereoisomers, esters, and prodrugs thereof.2. The compound is represented by:

3. The compound is represented by:

whereinRDis selected from the group consisting of hydrogen, hydroxyl, —ORbb—N(RbRc), C1-C8alkyl, C1-C8alkoxy, C3-C6cycloalkyl, C6-C14aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycle; wherein RDmay optionally be substituted by one, two, or three substituents each selected from the group consisting of halogen, hydroxyl, and RE;REis selected from the group consisting of C1-C8alkyl, C1-C8alkoxy, C6-C14aryl, 4-10 membered heterocycle, and 5-10 membered heteroaryl, wherein REmay optionally be substituted by one, two, or three substituents each selected from halogen, cyano, C1-C8alkyl and C1-C8alkoxy;Rbbis selected from the group consisting of C3-C6cycloalkyl, C6-C14aryl, —(C1-C8alkyl)-C6-C14aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycle;Rccis selected from the group consisting of hydrogen, C1-C8alkyl, C3-C6cycloalkyl, —(C1-C8alkyl)-(C6-C14aryl), C6-C14aryl, 5-10 membered heteroaryl, —(C1-C8alkyl)-(5-10 membered heteroaryl), 5-10 membered heterocycle and —N(RbRc), wherein Rband Rcare each selected from the group consisting of hydrogen, C1-C8alkyl, and C3-C6cycloalkyl, or Rband Rcmay be joined together to form, together with the nitrogen to which they are attached, a 5-10 membered heterocycle;Rcdis selected from the group consisting of hydrogen, C1-C8alkyl, and C3-C6cycloalkyl; andRband Rcare each selected from the group consisting of hydrogen, —CH2C(O)O(C1-C8alkyl), —C(O)—(C1-C8alkyl), —S(O)2—(C1-C8alkyl), C1-C8alkyl, C3-C6cycloalkyl and —(C1-C8alkyl)-C6-C14aryl, wherein the C1-C8alkyl may optionally be substituted by one or more substituents each selected from the group consisting of halogen, C3-C6cycloalkyl, C6-C14aryl, 4-10 membered heterocycle, and 5-10 membered heteroaryl.5. A is selected from the group consisting of

6. R1ais selected from the group consisting of

9. R1aand R1bare joined to together to form10. R3ais a 4-10 membered heterocycle substituted by A.11. R3ais selected from the group consisting of

12. R3is a 4-10 membered heterocycle.13. R3is selected from the group consisting of

14. R2is selected from the group consisting of

15. R1aand R2are joined to together to form the heterocycle selected from the group consisting of:

16. A compound selected from the group consisting of:

In another aspect, the compositions, compounds and methods of the present disclosure may be described in another embodiment as follows:1. A protease inhibitor compound represented by:

wherein:R1is selected from the group consisting of and C1-C8alkyl, C3-C6cycloalkyl, 5-10 membered aryl, 5-10 membered heteroaryl and 5-10 membered heterocycle, wherein R1may optionally be substituted by one, two, or three substituents each selected from RA;RAis independently selected, for each occurrence, halogen, cyano, hydroxyl, oxo, SF5, —NH2, C1-C8alkyl, C1-C8heteroalkyl, C1-C8alkoxy and C3-C6cycloalkyl;R2is selected from the group consisting of —NH2, —NHC(O)RB, —NHC(O)N(RB)2, —NHC(O)C(RC)2RB, —NHS(O)2RB, 5-10 membered heterocycle, 5-10 membered aryl and 5-10 membered heteroaryl bound through the carbon or nitrogen atom, wherein R2may optionally be substituted by one, two, or three substituents each selected from Rx;RBis independently selected, for each occurrence, from the group consisting of C1-C8alkyl, 5-10 membered aryl, 5-10 membered heteroaryl and 5-10 membered heterocycle;RCis independently selected, for each occurrence, from hydrogen and C1-C8alkyl;Rxis independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, oxo, cyano, —N(Ry)2, —N(Ry)C(O)Ry, C1-C8alkyl, C1-C8alkoxy, C3-C6cycloalkyl, 5-10 membered aryl, 5-10 membered heteroaryl and 5-10 membered heterocycle, wherein the heterocycle or heteroaryl may optionally be substituted by one or more substituents each selected from oxo and C1-C8alkyl;Ryis independently selected, for each occurrence, from the group consisting of hydrogen, C1-C8alkyl, C1-C8alkoxy, —(C1-C8alkoxy)-(5-10 membered aryl) and C3-C6cycloalkyl;A is a warhead;R3is selected from 5-10 membered heteroaryl and 5-10 membered heterocycle, wherein R3may optionally be substituted by one, two, or three substituents each selected from RA;m is 1 or 2; andpharmaceutically acceptable salts, stereoisomers, esters, and prodrugs thereof.2. A is selected from the group consisting of cyano, —C(O)RD, —C(O)CH2N(RbRc), —C(O)CH2OC(O)RD, —C(O)C(O)RD, —(CH═CH)C(O)ORD, —(CH═CCN)C(O)ORD, —(CH═CCN)C(O)(NH)RD, —CH(CN)(OH), —CH(CN)(NRbRc),

whereinRDis selected from the group consisting of hydrogen, hydroxyl, —ORbb—N(RbRc), C1-C8alkyl, C1-C8alkoxy, C3-C6cycloalkyl, C6-C14aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycle; wherein RDmay optionally be substituted by one, two, or three substituents each selected from the group consisting of halogen, hydroxyl, and RE;REis selected from the group consisting of C1-C8alkyl, C1-C8alkoxy and C6-C14aryl, 4-10 membered heterocycle, and 5-10 membered heteroaryl, wherein REmay optionally be substituted by one, two, or three substituents each selected from halogen, cyano, C1-C8alkyl and C1-C8alkoxy;Rbbis selected from the group consisting of C3-C6cycloalkyl, C6-C14aryl, —(C1-C8alkyl)-C6-C14aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycle;Rccis selected from the group consisting of hydrogen, C1-C8alkyl, C3-C6cycloalkyl, —(C1-C8alkyl)-(C6-C14aryl), C6-C14aryl, 5-10 membered heteroaryl, —(C1-C8alkyl)-(5-10 membered heteroaryl), 5-10 membered heterocycle and —N(RbRc), wherein Rband Rcare each selected from the group consisting of hydrogen, C1-C8alkyl, and C3-C6cycloalkyl, or Rband Rcmay be joined together to form, together with the nitrogen to which they are attached, a 5-10 membered heterocycle;Rcdis selected from the group consisting of hydrogen, C1-C8alkyl, and C3-C6cycloalkyl; andRband Rcare each selected from the group consisting of hydrogen, —CH2C(O)O(C1-C8alkyl), —C(O)—(C1-C8alkyl), —S(O)2—(C1-C8alkyl), C1-C8alkyl, C3-C6cycloalkyl and —(C1-C8alkyl)-C6-C14aryl, wherein the C1-C8alkyl may optionally be substituted by one or more substituents each selected from the group consisting of halogen, C3-C6cycloalkyl, C6-C14aryl, 4-10 membered heterocycle, and 5-10 membered heteroaryl.3. A is a warhead represented by:

wherein Rcis selected from the group consisting of hydrogen, —CH2C(O)O(C1-C8alkyl), C1-C8alkyl, and C3-C6cycloalkyl, wherein the C1-C8alkyl may optionally be substituted by one or more substituents each selected from the group consisting of halogen, C3-C6cycloalkyl, 5-10 membered aryl and 5-10 membered heteroaryl.4. Rcis

wherein X1is independently selected, for each occurrence, from N and CH.5. A is selected from the group consisting of

6. A is

whereinX2is selected from the group consisting of NH, O and S;X3is independently selected, for each occurrence, from N and CH;RDis independently selected, for each occurrence, from the group consisting of C1-C8alkyl,

REis independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, C1-C8alkyl and C1-C8alkoxy;p is selected from 0, 1 and 2; andq is selected from 0, 1 and 2.7. A is selected from the group consisting of

8. A is

wherein X2is selected from the group consisting of NH, NRP, O and S, wherein RPis C1-C8alkyl.9. A is selected from the group consisting of

10. A is —C(O)CH2OC(O)RD, whereinRDis selected from the group consisting of

C1-C8alkyl and C3-C6cycloalkyl;X4is independently selected, for each occurrence, from CH and N;REis independently selected, for each occurrence, from the group consisting of halogen, —CN, —CH3, —CH2CH3, —CH(CH3)2, —OCH3, —CF3, —OCF3and —SCF3; andp is selected from 0, 1 and 2.11. R1is selected from the group consisting of

12. A is selected from the group consisting of

13. A is selected from the group consisting of

14. A is —C(O)RD, wherein RDis selected from the group consisting of hydrogen, —CH2OH, —CH2OR′ and —CHxFy, wherein R′ is selected from the group consisting of C1-C8alkyl, —(C1-C8alkyl)-(5-10 membered aryl), C1-C8heteroalkyl, C3-C6cycloalkyl and 5-10 membered aryl, wherein x is 0, 1 or 2; y is 1, 2 or 3; and the sum of x and y is 3.15. A is selected from the group consisting of

16. A is —(CH═CH)C(O)ORD, wherein RDis C1-C8alkyl.17. A is selected from

18. A is —C(O)CH2N(RbRc).19. A is a warhead selected from

20. A is

wherein M is selected from Na and K.21. A is cyano.22. R1is selected from the group consisting of

23. R2is selected from the group consisting of

whereindenotes a bond that may be a single or double bond;R5is independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, oxo, —N(Ry)2, —N(Ry)C(O)Ry, C1-C8alkyl, C1-C8alkoxy, C3-C6cycloalkyl, 5-10 membered aryl, 5-10 membered heteroaryl and 5-10 membered heterocycle, wherein the heterocycle or heteroaryl may optionally be substituted by one or more substituents each selected from oxo and C1-C8alkyl;R6is C1-C8alkyl;R7is independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, oxo, —N(Ry)2, C1-C8alkyl, C1-C8alkoxy, C3-C6cycloalkyl, 5-10 membered aryl, 5-10 membered heteroaryl and 5-10 membered heterocycle, wherein the heterocycle or heteroaryl may optionally be substituted by one or more substituents each selected from oxo and C1-C8alkyl;Ryis independently selected, for each occurrence, from the group consisting of hydrogen, C1-C8alkyl, C1-C8alkoxy, —(C1-C8alkoxy)-(5-10 membered aryl) and C3-C6cycloalkyl;R8is selected from the group consisting of 5-10 membered aryl, 5-10 membered heteroaryl and 5-10 membered heterocycle;W1is selected from CH and N;W2is selected from the group consisting of CH2, O, NH and S;W is selected from W1and W2;s is selected from 1 and 2; andt is selected from 0, 1, 2 and 3.24. R2is selected from the group consisting of

25. R3is selected from the group consisting of

whereindenotes a bond that may be a single or double bond;Y1is selected from the group consisting of CH, CH2, N, NH, O and S;R9is selected from the group consisting of halogen, hydroxyl, oxo, —NH2, —N(CH3)2, —N(CH2CH3)2, —CH3, —CH2CH3, —OCH3and —OCH2CH3.26. R3is selected from the group consisting of

27. The compound is represented by

wherein:R5is independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, oxo, —N(Ry)2, —N(Ry)C(O)Ry, C1-C8alkyl, C1-C8alkoxy, C3-C6cycloalkyl, 5-10 membered aryl, 5-10 membered heteroaryl and 5-10 membered heterocycle, wherein the heterocycle or heteroaryl may optionally be substituted by one or more substituents each selected from oxo and C1-C8alkyl;Ryis independently selected, for each occurrence, from the group consisting of hydrogen, C1-C8alkyl, C1-C8alkoxy, —(C1-C8alkoxy)-(5-10 membered aryl) and C3-C6cycloalkyl; andm is selected from 1 and 2.28. Ryis selected from the group consisting of hydrogen,

29. The compound is selected from the group consisting of:

30. The compound is represented by

whereinRxis independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, oxo, —N(Ry)2, C1-C8alkyl, C1-C8alkoxy, C3-C6cycloalkyl, 5-10 membered aryl, 5-10 membered heteroaryl and 5-10 membered heterocycle, wherein the heterocycle or heteroaryl may optionally be substituted by one or more substituents each selected from oxo and C1-C8alkyl;Ryis independently selected, for each occurrence, from the group consisting of hydrogen, C1-C8alkyl, C1-C8alkoxy and C3-C6cycloalkyl;W is CH or N;m is selected from 1 and 2; andr is selected from 0, 1, 2 and 3.31. Rxis —OCH3.32. A protease inhibitor compound represented by:

whereinR3ais selected from

and 4-10 membered heterocycle, wherein the heterocycle may optionally be substituted by one, two or three substituents each selected from the group consisting of hydroxyl, C1-C8alkoxy, oxo and a warhead A;R3bis selected from hydrogen and C1-C8alkyl; wherein R3aand R3bmay be joined together to form, together with the carbon to which they are attached, a 4-10 membered heterocycle, wherein the heterocycle may optionally be substituted by one, two or three substituents each selected from C6-C14aryl and a warhead A;R1ais selected from the group consisting of C1-C8alkyl, —(C1-C8alkyl)-R1, —C1-C8alkyl)-CN, C3-C10cycloalkyl, C6-C14aryl, 4-10 membered heterocycle and 5-10 membered heteroaryl;R1bis selected from hydrogen and C1-C8alkyl; orR1aand R1bmay be joined together to form, together with the carbon to which they are attached, a 4-10 membered heterocycle or a C3-C10cycloalkyl;R1is selected from the group consisting of C1-C8alkyl, C2-C10alkenyl, C2-C10alkynyl, C3-C10cycloalkyl, C6-C14aryl, 5-10 membered heteroaryl and 4-10 membered heterocycle, wherein R1may optionally be substituted by one, two, or three substituents each selected from RA;RAis independently selected, for each occurrence, halogen, cyano, hydroxyl, oxo, SF5, —NH2, —O-phenyl, —O—(C1-C8alkyl)-phenyl, —C(O)-(5-10 membered heteroaryl), —C(O)-(4-10 membered heterocycle), —C(O)—O-(4-10 membered heterocycle), —C(O)—OC(CH3)3, —C(O)—(C2-C10alkenyl)-(C6-C14aryl), C1-C8alkyl, C2-C10alkenyl, C2-C10alkynyl, C1-C8heteroalkyl, C1-C8alkoxy, C3-C10cycloalkyl, —(C1-C8alkyl)-(C6-C14aryl), —(C1-C8alkyl)-(5-10 membered heteroaryl), C6-C14aryl, 5-10 membered heteroaryl and 4-10 membered heterocycle, wherein the alkyl, cycloalkyl, heterocycle, heteroaryl, or aryl may optionally be substituted by one, two or three substituents of halogen, C1-C6alkyl, C1-C8alkoxy, SF5, —NH2, hydroxyl or oxo;R2is selected from the group consisting of —NHC(O)RB, —NHC(O)N(RB)2, —NHC(O)C(RC)2RB, —NHS(O)2RB, 4-10 membered heterocycle, C6-C14aryl and 5-10 membered heteroaryl bound through the carbon or nitrogen atom, wherein R2may optionally be substituted by one, two, or three substituents each selected from Rx; orR1aand R2may be joined together to form, together with the carbon to which they are attached, a 4-10 membered mono or bicyclic heterocycle having a ring nitrogen, NRG, or C3-C10cycloalkyl, wherein the cycloalkyl or heterocycle may optionally be substituted by one, two or three substituents on a free carbon each selected from RA;R3is selected from 5-10 membered heteroaryl and 4-10 membered heterocycle, wherein R3may optionally be substituted by one, two, or three substituents each selected from RA;RBis independently selected, for each occurrence, from the group consisting of C1-C8alkyl, C2-C10alkenyl, C2-C10alkynyl, C6-C14aryl, 5-10 membered heteroaryl and 4-10 membered heterocycle;RCis independently selected, for each occurrence, from hydrogen and C1-C8alkyl;RGis selected from the group consisting of H, C1-6alkyl (optionally substituted by one, two or three substituents each independently selected from the group consisting of —C(═O), halo, cyano, —NRmRm, and —NH(C═O)Rm) and C(═O)—C1-6alkyl (optionally substituted by one, two or three substituents each independently selected from the group consisting of halo, cyano, —NRmRm, —NRm(C═O)Rm, phenyl, cycloalkyl and heterocycle, wherein Rmis selected for each occurrence by H or C1-3alkyl (optionally substituted by one, two or three fluorines), and C3-C6cycloalkyl (optionally substituted by one, two, or three fluorines);Rxis independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, oxo, SF5, cyano, —C(O)O(CH3), —N(Ry)2, —N(Ry)C(O)Ry, C1-C8alkoxy, C3-C10cycloalkyl, C6-C14aryl, 5-10 membered heteroaryl and 4-10 membered heterocycle, wherein the aryl, heterocycle or heteroaryl may optionally be substituted by one or more substituents each selected from oxo and C1-C8alkyl;Ryis independently selected, for each occurrence, from the group consisting of hydrogen, C1-C8alkyl, C1-C8alkoxy, —(C1-C8alkoxy)-(5-10 membered aryl) and C3-C6cycloalkyl;A is a warhead;X is selected from CH, C(CH3) and N; andpharmaceutically acceptable salts, stereoisomers, esters, and prodrugs thereof33. The compound is represented by:

34. The compound is represented by:

whereinRDis selected from the group consisting of hydrogen, hydroxyl, —ORbb—N(RbRc), C1-C8alkyl, C1-C8alkoxy, C3-C6cycloalkyl, C6-C14aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycle; wherein RDmay optionally be substituted by one, two, or three substituents each selected from the group consisting of halogen, hydroxyl, and RE;REis selected from the group consisting of C1-C8alkyl, C1-C8alkoxy and C6-C14aryl, 4-10 membered heterocycle, and 5-10 membered heteroaryl, wherein REmay optionally be substituted by one, two, or three substituents each selected from halogen, cyano, C1-C8alkyl and C1-C8alkoxy;Rbbis selected from the group consisting of C3-C6cycloalkyl, C6-C14aryl, —(C1-C8alkyl)-C6-C14aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycle;Rccis selected from the group consisting of hydrogen, C1-C8alkyl, C3-C6cycloalkyl, —(C1-C8alkyl)-(C6-C14aryl), C6-C14aryl, 5-10 membered heteroaryl, —(C1-C8alkyl)-(5-10 membered heteroaryl), 5-10 membered heterocycle and —N(RbRc), wherein Rband Rcare each selected from the group consisting of hydrogen, C1-C8alkyl, and C3-C6cycloalkyl, or Rband Rcmay be joined together to form, together with the nitrogen to which they are attached, a 5-10 membered heterocycle;Rcdis selected from the group consisting of hydrogen, C1-C8alkyl, and C3-C6cycloalkyl; andRband Rcare each selected from the group consisting of hydrogen, —CH2C(O)O(C1-C8alkyl), —C(O)—(C1-C8alkyl), —S(O)2—(C1-C8alkyl), C1-C8alkyl, C3-C6cycloalkyl and —(C1-C8alkyl)-C6-C14aryl, wherein the C1-C8alkyl may optionally be substituted by one or more substituents each selected from the group consisting of halogen, C3-C6cycloalkyl, C6-C14aryl, 4-10 membered heterocycle, and 5-10 membered heteroaryl.36. A is selected from the group consisting of

37. R1ais selected from the group consisting of

41. R3ais a 4-10 membered heterocycle substituted by A.42. R3ais selected from the group consisting of

43. R3is a 4-10 membered heterocycle.44. R3is selected from the group consisting of

45. R2is selected from the group consisting of

46. R1aand R2are joined to together to form the heterocycle selected from the group consisting of:

and R1bis H.48. The compound is represented by:

wherein RG3is selected from the group consisting of H, C1-6alkyl, C3-6cycloalkyl, phenyl and heterocycle; and RG2is —NH(C═O)Rm, wherein Rmis selected for each occurrence by H, methyl or CF3.49. The compound is represented by:

wherein RG3is selected from the group consisting of H, C1-6alkyl, C3-6cycloalkyl, phenyl and heterocycle; and RG2is —NH(C═O)Rm, wherein Rmis selected for each occurrence by H, methyl or CF3.50. The compound is selected from the group consisting of:

51. A method of ameliorating or treating a viral infection in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of any of the compounds of the embodiment52. The viral infection is from a virus selected from the group consisting of an RNA virus, a DNA virus, a coronavirus, a papillomavirus, a pneumovirus, a picornavirus, an influenza virus, an adenovirus, a cytomegalovirus, a polyomavirus, a poxvirus, a flavivirus, an alphavirus, an ebola virus, a morbillivirus, an enterovirus, an orthopneumovirus, a lentivirus, arenavirus, a herpes virus, and a hepatovirus.53. The viral infection is from a virus selected from the group consisting of Norwalk virus, feline calicivirus, MD145, murine norovirus, vesicular exanthema of swine virus, rabbit hemorrhagic disease virus, enterovirus (EV)-68 virus, EV-71 virus, poliovirus, coxsackievirus, foot-and-mouth disease virus, hepatitis A, porcine teschovirus, rhinovirus, human coronavirus, transmissible gastroenteritis virus, murine hepatitis virus, bovine coronavirus, feline infectious peritonitis virus, and severe acute respiratory syndrome coronavirus.54. The viral infection is a coronavirus infection.55. The viral infection is a coronavirus selected from the group consisting of: 229E alpha coronavirus, NL63 alpha coronavirus, OC43 beta coronavirus, HKU1 beta coronavirus, Middle East Respiratory Syndrome (MERS) coronavirus (MERS-CoV), severe acute respiratory syndrome (SARS) coronavirus (SARS-CoV), and SARS-CoV-2 (COVID-19).56. The viral infection is SARS-CoV-2.57. The viral infection is an arenavirus infection.58. The arenavirus is selected from the group consisting of: Junin virus, Lassa virus, Lujo virus, Machupo virus, and Sabia virus.59. The viral infection is an influenza infection.60. The influenza is influenza H1N1, H3N2 or H5N1.61. A method of inhibiting transmission of a virus, a method of inhibiting viral replication, a method of minimizing expression of viral proteins, or a method of inhibiting virus release, comprising administering a therapeutically effective amount of any compound the embodiment to a patient suffering from the virus, and/or contacting an effective amount of any compound of the embodiment with a virally infected cell.62. The method further comprises administering another therapeutic.63. The method further comprises administering an additional anti-viral therapeutic.64. The anti-viral therapeutic is selected from the group consisting of ribavirin, favipiravir, ST-193, oseltamivir, zanamivir, peramivir, danoprevir, ritonavir, and remdesivir.65. The another therapeutic is selected from the group consisting of protease inhibitors, fusion inhibitors, M2 proton channel blockers, polymerase inhibitors, 6-endonuclease inhibitors, neuraminidase inhibitors, reverse transcriptase inhibitor, aciclovir, acyclovir, protease inhibitors, arbidol, atazanavir, atripla, boceprevir, cidofovir, combivir, darunavir, docosanol, edoxudine, entry inhibitors, entecavir, famciclovir, fomivirsen, fosamprenavir, foscarnet, fosfonet, ganciclovir, ibacitabine, immunovir, idoxuridine, imiquimod, inosine, integrase inhibitor, interferons, lopinavir, loviride, moroxydine, nexavir, nucleoside analogues, penciclovir, pleconaril, podophyllotoxin, ribavirin, tipranavir, trifluridine, trizivir, tromantadine, truvada, valaciclovir, valganciclovir, vicriviroc, vidarabine, viramidine, and zodovudine.66. The additional anti-viral therapeutic is selected from the group consisting of lamivudine, an interferon alpha, a VAP anti-idiotypic antibody, enfuvirtide, amantadine, rimantadine, pleconaril, aciclovir, zidovudine, fomivirsen, a morpholino, a protease inhibitor, double-stranded RNA activated caspase oligomerizer (DRACO), rifampicin, zanamivir, oseltamivir, danoprevir, ritonavir, and remdesivir.67. A method of prophylactically treating a patient at risk of viral infection, comprising administering to the patient an effective amount of any compound of the embodiment.68. The compound is administered before viral exposure.69. The compound is administered after viral exposure.

In another aspect, the compositions, compounds and methods of the present disclosure may be described in another embodiment as follows:1. A protease inhibitor compound represented by:

wherein:R1is selected from the group consisting of and C1-C8alkyl, C3-C6cycloalkyl, 5-10 membered aryl, 5-10 membered heteroaryl and 5-10 membered heterocycle, wherein R1may optionally be substituted by one, two, or three substituents each selected from RA;RAis independently selected, for each occurrence, halogen, cyano, hydroxyl, oxo, SF5, —NH2, C1-C8alkyl, C1-C8heteroalkyl, C1-C8alkoxy and C3-C6cycloalkyl;R2is selected from the group consisting of —NH2, —NHC(O)RB, —NHC(O)N(RB)2, —NHC(O)C(RC)2RB, —NHS(O)2RB, 5-10 membered heterocycle, 5-10 membered aryl and 5-10 membered heteroaryl bound through the carbon or nitrogen atom, wherein R2may optionally be substituted by one, two, or three substituents each selected from Rx;RBis independently selected, for each occurrence, from the group consisting of C1-C8alkyl, 5-10 membered aryl, 5-10 membered heteroaryl and 5-10 membered heterocycle;RCis independently selected, for each occurrence, from hydrogen and C1-C8alkyl;Rxis independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, oxo, cyano, —N(Ry)2, —N(Ry)C(O)Ry, C1-C8alkyl, C1-C8alkoxy, C3-C6cycloalkyl, 5-10 membered aryl, 5-10 membered heteroaryl and 5-10 membered heterocycle, wherein the heterocycle or heteroaryl may optionally be substituted by one or more substituents each selected from oxo and C1-C8alkyl;Ryis independently selected, for each occurrence, from the group consisting of hydrogen, C1-C8alkyl, C1-C8alkoxy, —(C1-C8alkoxy)-(5-10 membered aryl) and C3-C6cycloalkyl;A is a warhead;R3is selected from 5-10 membered heteroaryl and 5-10 membered heterocycle, wherein R3may optionally be substituted by one, two, or three substituents each selected from RA;m is 1 or 2; andpharmaceutically acceptable salts, stereoisomers, esters, and prodrugs thereof.2. A is selected from the group consisting of cyano, —C(O)RD, —C(O)CH2N(RbRc), —C(O)CH2OC(O)RD, —C(O)C(O)RD, —(CH═CH)C(O)ORD, —(CH═CCN)C(O)ORD, —(CH═CCN)C(O)(NH)RD, —CH(CN)(OH), —CH(CN)(NRbRc),

whereinRDis selected from the group consisting of hydrogen, hydroxyl, —ORbb—N(RbRc), C1-C8alkyl, C1-C8alkoxy, C3-C6cycloalkyl, C6-C14aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycle; wherein RDmay optionally be substituted by one, two, or three substituents each selected from the group consisting of halogen, hydroxyl, and RE;REis selected from the group consisting of C1-C8alkyl, C1-C8alkoxy and C6-C14aryl, 4-10 membered heterocycle, and 5-10 membered heteroaryl, wherein REmay optionally be substituted by one, two, or three substituents each selected from halogen, cyano, C1-C8alkyl and C1-C8alkoxy;Rbbis selected from the group consisting of C3-C6cycloalkyl, C6-C14aryl, —(C1-C8alkyl)-C6-C14aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycle;Rccis selected from the group consisting of hydrogen, C1-C8alkyl, C3-C6cycloalkyl, —(C1-C8alkyl)-(C6-C14aryl), C6-C14aryl, 5-10 membered heteroaryl, —(C1-C8alkyl)-(5-10 membered heteroaryl), 5-10 membered heterocycle and —N(RbRc), wherein Rband Rcare each selected from the group consisting of hydrogen, C1-C8alkyl, and C3-C6cycloalkyl, or Rband Rcmay be joined together to form, together with the nitrogen to which they are attached, a 5-10 membered heterocycle;Rcdis selected from the group consisting of hydrogen, C1-C8alkyl, and C3-C6cycloalkyl; andRband Rcare each selected from the group consisting of hydrogen, —CH2C(O)O(C1-C8alkyl), —C(O)—(C1-C8alkyl), —S(O)2—(C1-C8alkyl), C1-C8alkyl, C3-C6cycloalkyl and —(C1-C8alkyl)-C6-C14aryl, wherein the C1-C8alkyl may optionally be substituted by one or more substituents each selected from the group consisting of halogen, C3-C6cycloalkyl, C6-C14aryl, 4-10 membered heterocycle, and 5-10 membered heteroaryl.3. A is a warhead represented by:

wherein Rcis selected from the group consisting of hydrogen, —CH2C(O)O(C1-C8alkyl), C1-C8alkyl, and C3-C6cycloalkyl, wherein the C1-C8alkyl may optionally be substituted by one or more substituents each selected from the group consisting of halogen, C3-C6cycloalkyl, 5-10 membered aryl and 5-10 membered heteroaryl.4. Rcis

wherein X1is independently selected, for each occurrence, from N and CH.5. A is selected from the group consisting of

6. A is

whereinX2is selected from the group consisting of NH, O and S;X3is independently selected, for each occurrence, from N and CH;RDis independently selected, for each occurrence, from the group consisting of C1-C8alkyl,

REis independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, C1-C8alkyl and C1-C8alkoxy;p is selected from 0, 1 and 2; andq is selected from 0, 1 and 2.7. A is selected from the group consisting of

8. A is

wherein X2is selected from the group consisting of NH, NRP, O and S, wherein RPis C1-C8alkyl.9. A is selected from the group consisting of

10. A is —C(O)CH2OC(O)RD, whereinRDis selected from the group consisting of

C1-C8alkyl and C3-C6cycloalkyl;X4is independently selected, for each occurrence, from CH and N;REis independently selected, for each occurrence, from the group consisting of halogen, —CN, —CH3, —CH2CH3, —CH(CH3)2, —OCH3, —CF3, —OCF3and —SCF3; andp is selected from 0, 1 and 2.

11. RDis selected from the group consisting of

12. A is selected from the group consisting of

13. A is selected from the group consisting of

14. A is —C(O)RD, wherein RDis selected from the group consisting of hydrogen, —CH2OH, —CH2OR′ and —CHxFy, wherein R′ is selected from the group consisting of C1-C8alkyl, —(C1-C8alkyl)-(5-10 membered aryl), C1-C8heteroalkyl, C3-C6cycloalkyl and 5-10 membered aryl, wherein x is 0, 1 or 2; y is 1, 2 or 3; and the sum of x and y is 3.15. A is selected from the group consisting of

16. A is —(CH═CH)C(O)ORD, wherein RDis C1-C8alkyl.17. A is selected from

18. A is —C(O)CH2N(RbRc).

19. A is a warhead selected from

20. A is

wherein M is selected from Na and K.21. A is cyano.22. R1is selected from the group consisting of

23. R2is selected from the group consisting of

whereindenotes a bond that may be a single or double bond;R5is independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, oxo, —N(Ry)2, —N(Ry)C(O)Ry, C1-C8alkyl, C1-C8alkoxy, C3-C6cycloalkyl, 5-10 membered aryl, 5-10 membered heteroaryl and 5-10 membered heterocycle, wherein the heterocycle or heteroaryl may optionally be substituted by one or more substituents each selected from oxo and C1-C8alkyl;R6is C1-C8alkyl;R7is independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, oxo, —N(Ry)2, C1-C8alkyl, C1-C8alkoxy, C3-C6cycloalkyl, 5-10 membered aryl, 5-10 membered heteroaryl and 5-10 membered heterocycle, wherein the heterocycle or heteroaryl may optionally be substituted by one or more substituents each selected from oxo and C1-C8alkyl;Ryis independently selected, for each occurrence, from the group consisting of hydrogen, C1-C8alkyl, C1-C8alkoxy, —(C1-C8alkoxy)-(5-10 membered aryl) and C3-C6cycloalkyl;R8is selected from the group consisting of 5-10 membered aryl, 5-10 membered heteroaryl and 5-10 membered heterocycle;W1is selected from CH and N;W2is selected from the group consisting of CH2, O, NH and S;W is selected from W1and W2;s is selected from 1 and 2; andt is selected from 0, 1, 2 and 3.24. R2is selected from the group consisting of

25. R3is selected from the group consisting of

whereindenotes a bond that may be a single or double bond;Y1is selected from the group consisting of CH, CH2, N, NH, O and S;R9is selected from the group consisting of halogen, hydroxyl, oxo, —NH2, —N(CH3)2, —N(CH2CH3)2, —CH3, —CH2CH3, —OCH3and —OCH2CH3.26. R3is selected from the group consisting of

27. The compound is represented by

wherein:R5is independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, oxo, —N(Ry)2, —N(Ry)C(O)Ry, C1-C8alkyl, C1-C8alkoxy, C3-C6cycloalkyl, 5-10 membered aryl, 5-10 membered heteroaryl and 5-10 membered heterocycle, wherein the heterocycle or heteroaryl may optionally be substituted by one or more substituents each selected from oxo and C1-C8alkyl;Ryis independently selected, for each occurrence, from the group consisting of hydrogen, C1-C8alkyl, C1-C8alkoxy, —(C1-C8alkoxy)-(5-10 membered aryl) and C3-C6cycloalkyl; andm is selected from 1 and 2.28. Ryis selected from the group consisting of hydrogen,

29. The compound is selected from the group consisting of:

30. The compound is represented by

whereinRxis independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, oxo, —N(Ry)2, C1-C8alkyl, C1-C8alkoxy, C3-C6cycloalkyl, 5-10 membered aryl, 5-10 membered heteroaryl and 5-10 membered heterocycle, wherein the heterocycle or heteroaryl may optionally be substituted by one or more substituents each selected from oxo and C1-C8alkyl;Ryis independently selected, for each occurrence, from the group consisting of hydrogen, C1-C8alkyl, C1-C8alkoxy and C3-C6cycloalkyl;W is CH or N;m is selected from 1 and 2; andr is selected from 0, 1, 2 and 3.31. Rxis —OCH3.32. A protease inhibitor compound represented by:

whereinR1ais selected from

and 4-10 membered heterocycle, wherein the heterocycle may optionally be substituted by one, two or three substituents each selected from the group consisting of hydroxyl, C1-C8alkoxy, oxo and a warhead A;R3bis selected from hydrogen and C1-C8alkyl; wherein R3aand R3bmay be joined together to form, together with the carbon to which they are attached, a 4-10 membered heterocycle, wherein the heterocycle may optionally be substituted by one, two or three substituents each selected from C6-C14aryl and a warhead A;R1ais selected from the group consisting of C1-C8alkyl, C3-C10cycloalkyl, C6-C14aryl, 4-10 membered heterocycle and 5-10 membered heteroaryl;R1bis selected from hydrogen and C1-C8alkyl; orR1aand R1bmay be joined together to form, together with the carbon to which they are attached, a 4-10 membered heterocycle or a C3-C10cycloalkyl;R1is selected from the group consisting of C1-C8alkyl, C2-C10alkenyl, C2-C10alkynyl, C3-C10cycloalkyl, C6-C14aryl, 5-10 membered heteroaryl and 4-10 membered heterocycle, wherein R1may optionally be substituted by one, two, or three substituents each selected from RA;RAis independently selected, for each occurrence, halogen, cyano, hydroxyl, oxo, SF5, —NH2, —O-phenyl, —O—(C1-C8alkyl)-phenyl, —C(O)-(5-10 membered heteroaryl), —C(O)-(4-10 membered heterocycle), —C(O)—O-(4-10 membered heterocycle), —C(O)—OC(CH3)3, —C(O)—(C2-C10alkenyl)-(C6-C14aryl), C1-C8alkyl, C2-C10alkenyl, C2-C10alkynyl, C1-C8heteroalkyl, C1-C8alkoxy, C3-C10cycloalkyl, —(C1-C8alkyl)-(C6-C14aryl), —(C1-C8alkyl)-(5-10 membered heteroaryl), C6-C14aryl, 5-10 membered heteroaryl and 4-10 membered heterocycle, wherein the alkyl, cycloalkyl, heterocycle, heteroaryl, or aryl may optionally be substituted by one, two or three substituents of halogen, C1-C6alkyl, C1-C8alkoxy, SF5, —NH2, hydroxyl or oxo;R2is selected from the group consisting of —NHC(O)RB, —NHC(O)N(RB)2, —NHC(O)C(RC)2RB, —NHS(O)2RB, 4-10 membered heterocycle, C6-C14aryl and 5-10 membered heteroaryl bound through the carbon or nitrogen atom, wherein R2may optionally be substituted by one, two, or three substituents each selected from Rx; orR1aand R2may be joined together to form, together with the carbon to which they are attached, a 4-10 membered mono or bicyclic heterocycle having a ring nitrogen, NRG, or C3-C10cycloalkyl, wherein the cycloalkyl or heterocycle may optionally be substituted by one, two or three substituents on a free carbon each selected from RA;R3is selected from 5-10 membered heteroaryl and 4-10 membered heterocycle, wherein R3may optionally be substituted by one, two, or three substituents each selected from RA;RBis independently selected, for each occurrence, from the group consisting of C1-C8alkyl, C2-C10alkenyl, C2-C10alkynyl, C6-C14aryl, 5-10 membered heteroaryl and 4-10 membered heterocycle;RCis independently selected, for each occurrence, from hydrogen and C1-C8alkyl;RGis selected from the group consisting of H, C1-6alkyl (optionally substituted by one, two or three substituents each independently selected from the group consisting of —C(═O), halo, cyano, —NRmRm, and —NH(C═O)Rm) and C(═O)—C1-6alkyl (optionally substituted by one, two or three substituents each independently selected from the group consisting of halo, cyano, —NRmRm, —NRm(C═O)Rm, phenyl, cycloalkyl, heterocycle, C1-C6alkoxy, wherein Rmis selected for each occurrence by H, C1-3alkyl (optionally substituted by one, two or three substituents each independently selected from the group consisting of halo, optionally substituted phenyl, —S(O)2—CH3, C3-6cycloalkyl, and 5-6 membered heteroaryl), C(═O)—C1-6alkyl (optionally substituted by one, two or three substituents each independently selected from the group consisting of halo, cyano and C1-C6alkoxy), C(═O)—C3-6cycloalkyl, or C(═O)-(5-6 membered heteroaryl) (optionally substituted by halo, cyano, hydroxyl, NH2, C1-6alkyl, C3-6cycloalkyl, C1-C6alkoxy, and C1-6haloalkyl));Rxis independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, oxo, SF5, cyano, —C(O)O(CH3), —N(Ry)2, —N(Ry)C(O)Ry, C1-C8alkyl, C1-C8alkoxy, C3-C10cycloalkyl, C6-C14aryl, 5-10 membered heteroaryl and 4-10 membered heterocycle, wherein the aryl, heterocycle or heteroaryl may optionally be substituted by one or more substituents each selected from oxo and C1-C8alkyl;Ryis independently selected, for each occurrence, from the group consisting of hydrogen, C1-C8alkyl, C1-C8alkoxy, —(C1-C8alkoxy)-(5-10 membered aryl) and C3-C6cycloalkyl;A is a warhead;X is selected from CH, C(CH3) and N; andpharmaceutically acceptable salts, stereoisomers, esters, and prodrugs thereof.33. The compound is represented by:

34. The compound is represented by:

whereinRDis selected from the group consisting of hydrogen, hydroxyl, —ORbb—N(RbRc), C1-C8alkyl, C1-C8alkoxy, C3-C6cycloalkyl, C6-C14aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycle; wherein RDmay optionally be substituted by one, two, or three substituents each selected from the group consisting of halogen, hydroxyl, and RE;REis selected from the group consisting of C1-C8alkyl, C1-C8alkoxy and C6-C14aryl, 4-10 membered heterocycle, and 5-10 membered heteroaryl, wherein REmay optionally be substituted by one, two, or three substituents each selected from halogen, cyano, C1-C8alkyl and C1-C8alkoxy;Rbbis selected from the group consisting of C3-C6cycloalkyl, C6-C14aryl, —(C1-C8alkyl)-C6-C14aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycle;Rccis selected from the group consisting of hydrogen, C1-C8alkyl, C3-C6cycloalkyl, —(C1-C8alkyl)-(C6-C14aryl), C6-C14aryl, 5-10 membered heteroaryl, —(C1-C8alkyl)-(5-10 membered heteroaryl), 5-10 membered heterocycle and —N(RbRc), wherein Rband Rcare each selected from the group consisting of hydrogen, C1-C8alkyl, and C3-C6cycloalkyl, or Rband Rcmay be joined together to form, together with the nitrogen to which they are attached, a 5-10 membered heterocycle;Rcdis selected from the group consisting of hydrogen, C1-C8alkyl, and C3-C6cycloalkyl; andRband Rcare each selected from the group consisting of hydrogen, —CH2C(O)O(C1-C8alkyl), —C(O)—(C1-C8alkyl), —S(O)2—(C1-C8alkyl), C1-C8alkyl, C3-C6cycloalkyl and —(C1-C8alkyl)-C6-C14aryl, wherein the C1-C8alkyl may optionally be substituted by one or more substituents each selected from the group consisting of halogen, C3-C6cycloalkyl, C6-C14aryl, 4-10 membered heterocycle, and 5-10 membered heteroaryl.36. A is selected from the group consisting of

37. R1ais selected from the group consisting of

41. R1ais a 4-10 membered heterocycle substituted by A.42. R3ais selected from the group consisting of

43. R3is a 4-10 membered heterocycle.44. R3is selected from the group consisting of

45. R2is selected from the group consisting of

46. R1aand R2are joined to together to form the heterocycle selected from the group consisting of:

48. The compound is represented by:

wherein RG3is selected from the group consisting of H, C1-6alkyl, C3-6cycloalkyl, phenyl and heterocycle; and RG2is —NH(C═O)Rm, wherein Rmis selected for each occurrence by H, methyl or CF3.49. The compound is represented by:

wherein RG3is selected from the group consisting of H, C1-6alkyl, C3-6cycloalkyl, phenyl and heterocycle; and RG2is —NH(C═O)Rm, wherein Rmis selected for each occurrence by H, methyl or CF3.50. The compound is represented by:

wherein RG3is selected from the group consisting of H, C1-6alkyl (optionally substituted by one, two or three C1-C6alkoxy), C3-6cycloalkyl, phenyl and heterocycle; and RG2is selected from the group consisting of —NH(C1-3alkyl) (optionally substituted by one, two or three substituents each independently selected from the group consisting of halo, optionally substituted phenyl, —S(O)2—CH3, C3-6cycloalkyl, and 5-6 membered heteroaryl) and —NH(C═O)Rm, wherein Rmis selected for each occurrence by H, C1-6alkyl (optionally substituted by one, two or three substituents each independently selected from the group consisting of halo, cyano and C1-C6alkoxy), CHF2, CF3, or 5-6 membered heteroaryl (optionally substituted by halo, cyano, hydroxyl, NH2, C1-6alkyl, C3-6cycloalkyl, C1-C6alkoxy, CHF2, and CF3).51. The compound is represented by:

wherein RG3is selected from the group consisting of H, C1-6alkyl (optionally substituted by one, two or three C1-C6alkoxy), C3-6cycloalkyl, phenyl and heterocycle; and RG2is selected from the group consisting of —NH(C1-3alkyl) (optionally substituted by one, two or three substituents each independently selected from the group consisting of halo, optionally substituted phenyl, —S(O)2—CH3, C3-6cycloalkyl, and 5-6 membered heteroaryl) and —NH(C═O)Rm, wherein Rmis selected for each occurrence by H, C1-6alkyl (optionally substituted by one, two or three substituents each independently selected from the group consisting of halo, cyano and C1-C6alkoxy), CHF2, CF3, or 5-6 membered heteroaryl (optionally substituted by halo, cyano, hydroxyl, NH2, C1-6alkyl, C3-6cycloalkyl, C1-C6alkoxy, CHF2, and CF3).52. RG3is selected from the group consisting of

53. RG2is selected from the group consisting of

wherein RFis selected from the group consisting of C1-6alkyl, C3-6cycloalkyl, phenyl and 5-6 membered heteroaryl, wherein RFmay optionally be substituted by one, two or three substituents selected from the group consisting of halo, cyano, hydroxyl and C1-C6alkoxy; and XFis selected from the group consisting of H, halo, cyano, hydroxyl, NH2, C1-6alkyl, C3-6cycloalkyl, C1-C6alkoxy, and C1-6haloalkyl.54. The compound is selected from the group consisting of:

55. A method of ameliorating or treating a viral infection in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of any of the compounds of the embodiment.56. The viral infection is from a virus selected from the group consisting of an RNA virus, a DNA virus, a coronavirus, a papillomavirus, a pneumovirus, a picornavirus, an influenza virus, an adenovirus, a cytomegalovirus, a polyomavirus, a poxvirus, a flavivirus, an alphavirus, an ebola virus, a morbillivirus, an enterovirus, an orthopneumovirus, a lentivirus, arenavirus, a herpes virus, and a hepatovirus.57. The viral infection is from a virus selected from the group consisting of Norwalk virus, feline calicivirus, MD145, murine norovirus, vesicular exanthema of swine virus, rabbit hemorrhagic disease virus, enterovirus (EV)-68 virus, EV-71 virus, poliovirus, coxsackievirus, foot-and-mouth disease virus, hepatitis A, porcine teschovirus, rhinovirus, human coronavirus, transmissible gastroenteritis virus, murine hepatitis virus, bovine coronavirus, feline infectious peritonitis virus, and severe acute respiratory syndrome coronavirus.58. The viral infection is a coronavirus infection.59. The viral infection is a coronavirus selected from the group consisting of: 229E alpha coronavirus, NL63 alpha coronavirus, OC43 beta coronavirus, HKU1 beta coronavirus, Middle East Respiratory Syndrome (MERS) coronavirus (MERS-CoV), severe acute respiratory syndrome (SARS) coronavirus (SARS-CoV), and SARS-CoV-2 (COVID-19).60. The viral infection is SARS-CoV-2.61. The viral infection is an arenavirus infection.62. The arenavirus is selected from the group consisting of: Junin virus, Lassa virus, Lujo virus, Machupo virus, and Sabia virus.63. The viral infection is an influenza infection.64. The influenza is influenza H1N1, H3N2 or H5N1.65. A method of inhibiting transmission of a virus, a method of inhibiting viral replication, a method of minimizing expression of viral proteins, or a method of inhibiting virus release, comprising administering a therapeutically effective amount of any compound of the embodiment to a patient suffering from the virus, and/or contacting an effective amount of any compound of the embodiment with a virally infected cell.66. The method further comprises administering another therapeutic.67. The method further comprises administering an additional anti-viral therapeutic.68. The anti-viral therapeutic is selected from the group consisting of ribavirin, favipiravir, ST-193, oseltamivir, zanamivir, peramivir, danoprevir, ritonavir, and remdesivir.69. The another therapeutic is selected from the group consisting of protease inhibitors, fusion inhibitors, M2 proton channel blockers, polymerase inhibitors, 6-endonuclease inhibitors, neuraminidase inhibitors, reverse transcriptase inhibitor, aciclovir, acyclovir, protease inhibitors, arbidol, atazanavir, atripla, boceprevir, cidofovir, combivir, darunavir, docosanol, edoxudine, entry inhibitors, entecavir, famciclovir, fomivirsen, fosamprenavir, foscarnet, fosfonet, ganciclovir, ibacitabine, immunovir, idoxuridine, imiquimod, inosine, integrase inhibitor, interferons, lopinavir, loviride, moroxydine, nexavir, nucleoside analogues, penciclovir, pleconaril, podophyllotoxin, ribavirin, tipranavir, trifluridine, trizivir, tromantadine, truvada, valaciclovir, valganciclovir, vicriviroc, vidarabine, viramidine, and zodovudine.70. The additional anti-viral therapeutic is selected from the group consisting of lamivudine, an interferon alpha, a VAP anti-idiotypic antibody, enfuvirtide, amantadine, rimantadine, pleconaril, aciclovir, zidovudine, fomivirsen, a morpholino, a protease inhibitor, double-stranded RNA activated caspase oligomerizer (DRACO), rifampicin, zanamivir, oseltamivir, danoprevir, ritonavir, and remdesivir.71. A method of prophylactically treating a patient at risk of viral infection, comprising administering to the patient an effective amount of any compound of the embodiment.72. The compound is administered before viral exposure73. The compound is administered after viral exposure.

In another aspect, the compositions, compounds and methods of the present disclosure may be described in another embodiment as follows:1. A protease inhibitor compound represented by:

wherein:R1is selected from the group consisting of and C1-C8alkyl, C3-C6cycloalkyl, 5-10 membered aryl, 5-10 membered heteroaryl and 5-10 membered heterocycle, wherein R1may optionally be substituted by one, two, or three substituents each selected from RA;RAis independently selected, for each occurrence, halogen, cyano, hydroxyl, oxo, SF5, —NH2, C1-C8alkyl, C1-C8heteroalkyl, C1-C8alkoxy and C3-C6cycloalkyl;R2is selected from the group consisting of —NH2, —NHC(O)RB, —NHC(O)N(RB)2, —NHC(O)C(RC)2RB, —NHS(O)2RB, 5-10 membered heterocycle, 5-10 membered aryl and 5-10 membered heteroaryl bound through the carbon or nitrogen atom, wherein R2may optionally be substituted by one, two, or three substituents each selected from Rx;RBis independently selected, for each occurrence, from the group consisting of C1-C8alkyl, 5-10 membered aryl, 5-10 membered heteroaryl and 5-10 membered heterocycle;RCis independently selected, for each occurrence, from hydrogen and C1-C8alkyl;Rxis independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, oxo, cyano, —N(Ry)2, —N(Ry)C(O)Ry, C1-C8alkyl, C1-C8alkoxy, C3-C6cycloalkyl, 5-10 membered aryl, 5-10 membered heteroaryl and 5-10 membered heterocycle, wherein the heterocycle or heteroaryl may optionally be substituted by one or more substituents each selected from oxo and C1-C8alkyl;Ryis independently selected, for each occurrence, from the group consisting of hydrogen, C1-C8alkyl, C1-C8alkoxy, —(C1-C8alkoxy)-(5-10 membered aryl) and C3-C6cycloalkyl;A is a warhead;R3is selected from 5-10 membered heteroaryl and 5-10 membered heterocycle, wherein R3may optionally be substituted by one, two, or three substituents each selected from RA;m is 1 or 2; andpharmaceutically acceptable salts, stereoisomers, esters, and prodrugs thereof.2. A is selected from the group consisting of cyano, —C(O)RD, —C(O)CH2N(RbRc), —C(O)CH2OC(O)RD, —C(O)C(O)RD, —(CH═CH)C(O)ORD, —(CH═CCN)C(O)ORD, —(CH═CCN)C(O)(NH)RD, —CH(CN)(OH), —CH(CN)(NRbRc),

whereinRDis selected from the group consisting of hydrogen, hydroxyl, —ORbb—N(RbRc), C1-C8alkyl, C1-C8alkoxy, C3-C6cycloalkyl, C6-C14aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycle; wherein RDmay optionally be substituted by one, two, or three substituents each selected from the group consisting of halogen, hydroxyl, and RE;REis selected from the group consisting of C1-C8alkyl, C1-C8alkoxy and C6-C14aryl, 4-10 membered heterocycle, and 5-10 membered heteroaryl, wherein REmay optionally be substituted by one, two, or three substituents each selected from halogen, cyano, C1-C8alkyl and C1-C8alkoxy;Rbbis selected from the group consisting of C3-C6cycloalkyl, C6-C14aryl, —(C1-C8alkyl)-C6-C14aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycle;Rccis selected from the group consisting of hydrogen, C1-C8alkyl, C3-C6cycloalkyl, —(C1-C8alkyl)-(C6-C14aryl), C6-C14aryl, 5-10 membered heteroaryl, —(C1-C8alkyl)-(5-10 membered heteroaryl), 5-10 membered heterocycle and —N(RbRc), wherein Rband Rcare each selected from the group consisting of hydrogen, C1-C8alkyl, and C3-C6cycloalkyl, or Rband Rcmay be joined together to form, together with the nitrogen to which they are attached, a 5-10 membered heterocycle;Rcdis selected from the group consisting of hydrogen, C1-C8alkyl, and C3-C6cycloalkyl; andRband Rcare each selected from the group consisting of hydrogen, —CH2C(O)O(C1-C8alkyl), —C(O)—(C1-C8alkyl), —S(O)2—(C1-C8alkyl), C1-C8alkyl, C3-C6cycloalkyl and —(C1-C8alkyl)-C6-C14aryl, wherein the C1-C8alkyl may optionally be substituted by one or more substituents each selected from the group consisting of halogen, C3-C6cycloalkyl, C6-C14aryl, 4-10 membered heterocycle, and 5-10 membered heteroaryl.3. A is a warhead represented by:

wherein Rcis selected from the group consisting of hydrogen, —CH2C(O)O(C1-C8alkyl), C1-C8alkyl, and C3-C6cycloalkyl, wherein the C1-C8alkyl may optionally be substituted by one or more substituents each selected from the group consisting of halogen, C3-C6cycloalkyl, 5-10 membered aryl and 5-10 membered heteroaryl.4. Rcis

wherein X1is independently selected, for each occurrence, from N and CH.5. A is selected from the group consisting of

6. A is

whereinX2is selected from the group consisting of NH, O and S;X3is independently selected, for each occurrence, from N and CH;RDis independently selected, for each occurrence, from the group consisting of C1-C8alkyl,

REis independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, C1-C8alkyl and C1-C8alkoxy;p is selected from 0, 1 and 2; andq is selected from 0, 1 and 2.7. A is selected from the group consisting of

8. A is

wherein X2is selected from the group consisting of NH, NRP, O and S, wherein RPis C1-C8alkyl.9. A is selected from the group consisting of

10. A is —C(O)CH2OC(O)RD, whereinRDis selected from the group consisting of

C1-C8alkyl and C3-C6cycloalkyl;X4is independently selected, for each occurrence, from CH and N;REis independently selected, for each occurrence, from the group consisting of halogen, —CN, —CH3, —CH2CH3, —CH(CH3)2, —OCH3, —CF3, —OCF3and —SCF3; andp is selected from 0, 1 and 2.11. RDis selected from the group consisting of

12. A is selected from the group consisting of

13. A is selected from the group consisting of

14. A is —C(O)RD, wherein RDis selected from the group consisting of hydrogen, —CH2OH, —CH2OR′ and —CHxFy, wherein R′ is selected from the group consisting of C1-C8alkyl, —(C1-C8alkyl)-(5-10 membered aryl), C1-C8heteroalkyl, C3-C6cycloalkyl and 5-10 membered aryl, wherein x is 0, 1 or 2; y is 1, 2 or 3; and the sum of x and y is 3.15. A is selected from the group consisting of

16. A is —(CH═CH)C(O)ORD, wherein RDis C1-C8alkyl.17. A is selected from

18. A is —C(O)CH2N(RbRc).19. A is a warhead selected from

20. A is

wherein M is selected from Na and K.21. A is cyano.22. R1is selected from the group consisting of

23. R2is selected from the group consisting of

whereindenotes a bond that may be a single or double bond;R5is independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, oxo, —N(Ry)2, —N(Ry)C(O)Ry, C1-C8alkyl, C1-C8alkoxy, C3-C6cycloalkyl, 5-10 membered aryl, 5-10 membered heteroaryl and 5-10 membered heterocycle, wherein the heterocycle or heteroaryl may optionally be substituted by one or more substituents each selected from oxo and C1-C8alkyl;R6is C1-C8alkyl;R7is independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, oxo, —N(Ry)2, C1-C8alkyl, C1-C8alkoxy, C3-C6cycloalkyl, 5-10 membered aryl, 5-10 membered heteroaryl and 5-10 membered heterocycle, wherein the heterocycle or heteroaryl may optionally be substituted by one or more substituents each selected from oxo and C1-C8alkyl;Ryis independently selected, for each occurrence, from the group consisting of hydrogen, C1-C8alkyl, C1-C8alkoxy, —(C1-C8alkoxy)-(5-10 membered aryl) and C3-C6cycloalkyl;R8is selected from the group consisting of 5-10 membered aryl, 5-10 membered heteroaryl and 5-10 membered heterocycle;W1is selected from CH and N;W2is selected from the group consisting of CH2, O, NH and S;W is selected from W1and W2;s is selected from 1 and 2; andt is selected from 0, 1, 2 and 3.24. R2is selected from the group consisting of

25. R3is selected from the group consisting of

whereindenotes a bond that may be a single or double bond;Y1is selected from the group consisting of CH, CH2, N, NH, O and S;R9is selected from the group consisting of halogen, hydroxyl, oxo, —NH2, —N(CH3)2, —N(CH2CH3)2, —CH3, —CH2CH3, —OCH3and —OCH2CH3.26. R3is selected from the group consisting of

27. The compound is represented by

wherein:R5is independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, oxo, —N(Ry)2, —N(Ry)C(O)Ry, C1-C8alkyl, C1-C8alkoxy, C3-C6cycloalkyl, 5-10 membered aryl, 5-10 membered heteroaryl and 5-10 membered heterocycle, wherein the heterocycle or heteroaryl may optionally be substituted by one or more substituents each selected from oxo and C1-C8alkyl;Ryis independently selected, for each occurrence, from the group consisting of hydrogen, C1-C8alkyl, C1-C8alkoxy, —(C1-C8alkoxy)-(5-10 membered aryl) and C3-C6cycloalkyl; andm is selected from 1 and 2.28. Ryis selected from the group consisting of hydrogen,

29. The compound is selected from the group consisting of:

30. The compound is represented by

whereinRxis independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, oxo, —N(Ry)2, C1-C8alkyl, C1-C8alkoxy, C3-C6cycloalkyl, 5-10 membered aryl, 5-10 membered heteroaryl and 5-10 membered heterocycle, wherein the heterocycle or heteroaryl may optionally be substituted by one or more substituents each selected from oxo and C1-C8alkyl;Ryis independently selected, for each occurrence, from the group consisting of hydrogen, C1-C8alkyl, C1-C8alkoxy and C3-C6cycloalkyl;W is CH or N;m is selected from 1 and 2; andr is selected from 0, 1, 2 and 3.31. Rxis —OCH3.32. A protease inhibitor compound represented by:

whereinR1ais selected from

and 4-10 membered heterocycle, wherein the heterocycle may optionally be substituted by one, two or three substituents each selected from the group consisting of hydroxyl, C1-C8alkoxy, oxo and a warhead A;R3bis selected from hydrogen and C1-C8alkyl; wherein R3aand R3bmay be joined together to form, together with the carbon to which they are attached, a 4-10 membered heterocycle, wherein the heterocycle may optionally be substituted by one, two or three substituents each selected from C6-C14aryl and a warhead A;R1ais selected from the group consisting of C1-C8alkyl, —(C1-C8alkyl)-R1, —(C1-C8alkyl)-CN, C3-C10cycloalkyl, C6-C14aryl, 4-10 membered heterocycle and 5-10 membered heteroaryl;R1bis selected from hydrogen and C1-C8alkyl; orR1aand R1bmay be joined together to form, together with the carbon to which they are attached, a 4-10 membered heterocycle or a C3-C10cycloalkyl;R1is selected from the group consisting of C1-C8alkyl, C2-C10alkenyl, C2-C10alkynyl, C3-C10cycloalkyl, C6-C14aryl, 5-10 membered heteroaryl and 4-10 membered heterocycle, wherein R1may optionally be substituted by one, two, or three substituents each selected from RA;RAis independently selected, for each occurrence, halogen, cyano, hydroxyl, oxo, SF5, —NH2, —O-phenyl, —O—(C1-C8alkyl)-phenyl, —C(O)-(5-10 membered heteroaryl), —C(O)-(4-10 membered heterocycle), —C(O)—O-(4-10 membered heterocycle), —C(O)—OC(CH3)3, —C(O)—(C2-C10alkenyl)-(C6-C14aryl), C1-C8alkyl, C2-C10alkenyl, C2-C10alkynyl, C1-C8heteroalkyl, C1-C8alkoxy, C3-C10cycloalkyl, —(C1-C8alkyl)-(C6-C14aryl), —(C1-C8alkyl)-(5-10 membered heteroaryl), C6-C14aryl, 5-10 membered heteroaryl and 4-10 membered heterocycle, wherein the alkyl, cycloalkyl, heterocycle, heteroaryl, or aryl may optionally be substituted by one, two or three substituents of halogen, C1-C6alkyl, C1-C8alkoxy, SF5, —NH2, hydroxyl or oxo;R2is selected from the group consisting of —NHC(O)RB, —NHC(O)N(RB)2, —NHC(O)C(RC)2RB, —NHS(O)2RB, 4-10 membered heterocycle, C6-C14aryl and 5-10 membered heteroaryl bound through the carbon or nitrogen atom, wherein R2may optionally be substituted by one, two, or three substituents each selected from Rx; orR1aand R2may be joined together to form, together with the carbon to which they are attached, a 4-10 membered mono or bicyclic heterocycle having a ring nitrogen, NRG, or C3-C10cycloalkyl, wherein the cycloalkyl or heterocycle may optionally be substituted by one, two or three substituents on a free carbon each selected from RA;R3is selected from 5-10 membered heteroaryl and 4-10 membered heterocycle, wherein R3may optionally be substituted by one, two, or three substituents each selected from RA;RBis independently selected, for each occurrence, from the group consisting of C1-C8alkyl, C2-C10alkenyl, C2-C10alkynyl, C6-C14aryl, 5-10 membered heteroaryl and 4-10 membered heterocycle;RCis independently selected, for each occurrence, from hydrogen and C1-C8alkyl;RGis selected from the group consisting of H, C1-6alkyl (optionally substituted by one, two or three substituents each independently selected from the group consisting of —C(═O), halo, cyano, —NRmRm, and —NH(C═O)Rm) and C(═O)—C1-6alkyl (optionally substituted by one, two or three substituents each independently selected from the group consisting of halo, cyano, —NRmRm, —NRm(C═O)Rm, phenyl, cycloalkyl, heterocycle, C1-C6alkoxy, wherein Rmis selected for each occurrence by H, C1-3alkyl (optionally substituted by one, two or three substituents each independently selected from the group consisting of halo, optionally substituted phenyl, —S(O)2—CH3, C3-6cycloalkyl, and 5-6 membered heteroaryl), C(═O)—C1-6alkyl (optionally substituted by one, two or three substituents each independently selected from the group consisting of halo, cyano and C1-C6alkoxy), C(═O)—C3-6cycloalkyl, or C(═O)-(5-6 membered heteroaryl) (optionally substituted by halo, cyano, hydroxyl, NH2, C1-6alkyl, C3-6cycloalkyl, C1-C6alkoxy, and C1-6haloalkyl));Rxis independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, oxo, SF5, cyano, —C(O)O(CH3), —N(Ry)2, —N(Ry)C(O)Ry, C1-C8alkyl, C1-C8alkoxy, C3-C10cycloalkyl, C6-C14aryl, 5-10 membered heteroaryl and 4-10 membered heterocycle, wherein the aryl, heterocycle or heteroaryl may optionally be substituted by one or more substituents each selected from oxo and C1-C8alkyl;Ryis independently selected, for each occurrence, from the group consisting of hydrogen, C1-C8alkyl, C1-C8alkoxy, —(C1-C8alkoxy)-(5-10 membered aryl) and C3-C6cycloalkyl;A is a warhead;X is selected from CH, C(CH3) and N; andpharmaceutically acceptable salts, stereoisomers, esters, and prodrugs thereof.33. The compound is represented by:

34. The compound is represented by:

whereinRDis selected from the group consisting of hydrogen, hydroxyl, —ORbb—N(RbRc), C1-C8alkyl, C1-C8alkoxy, C3-C6cycloalkyl, C6-C14aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycle; wherein RDmay optionally be substituted by one, two, or three substituents each selected from the group consisting of halogen, hydroxyl, and RE;REis selected from the group consisting of C1-C8alkyl, C1-C8alkoxy and C6-C14aryl, 4-10 membered heterocycle, and 5-10 membered heteroaryl, wherein REmay optionally be substituted by one, two, or three substituents each selected from halogen, cyano, C1-C8alkyl and C1-C8alkoxy;Rbbis selected from the group consisting of C3-C6cycloalkyl, C6-C14aryl, —(C1-C8alkyl)-C6-C14aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycle;Rccis selected from the group consisting of hydrogen, C1-C8alkyl, C3-C6cycloalkyl, —(C1-C8alkyl)-(C6-C14aryl), C6-C14aryl, 5-10 membered heteroaryl, —(C1-C8alkyl)-(5-10 membered heteroaryl), 5-10 membered heterocycle and —N(RbRc), wherein Rband Rcare each selected from the group consisting of hydrogen, C1-C8alkyl, and C3-C6cycloalkyl, or Rband Rcmay be joined together to form, together with the nitrogen to which they are attached, a 5-10 membered heterocycle;Rcdis selected from the group consisting of hydrogen, C1-C8alkyl, and C3-C6cycloalkyl; andRband Rcare each selected from the group consisting of hydrogen, —CH2C(O)O(C1-C8alkyl), —C(O)—(C1-C8alkyl), —S(O)2—(C1-C8alkyl), C1-C8alkyl, C3-C6cycloalkyl and —(C1-C8alkyl)-C6-C14aryl, wherein the C1-C8alkyl may optionally be substituted by one or more substituents each selected from the group consisting of halogen, C3-C6cycloalkyl, C6-C14aryl, 4-10 membered heterocycle, and 5-10 membered heteroaryl.36. A is selected from the group consisting of

37. R1ais selected from the group consisting of

41. R3ais a 4-10 membered heterocycle substituted by A.42. R3ais selected from the group consisting of

43. R3is a 4-10 membered heterocycle.44. R3is selected from the group consisting of

45. R2is selected from the group consisting of

46. R1aand R2are joined to together to form the heterocycle selected from the group consisting of:

and R1bis H48. The compound is represented by:

wherein RG3is selected from the group consisting of H, C1-6alkyl, C3-6cycloalkyl, phenyl and heterocycle; and RG2is —NH(C═O)Rm, wherein Rmis selected for each occurrence by H, methyl or CF3.49. The compound is represented by:

wherein RG3is selected from the group consisting of H, C1-6alkyl, C3-6cycloalkyl, phenyl and heterocycle; and RG2is —NH(C═O)Rm, wherein Rmis selected for each occurrence by H, methyl or CF3, e.g., RG2is

50. The compound is represented by:

wherein RG3is selected from the group consisting of H, C1-6alkyl (optionally substituted by one, two or three C1-C6alkoxy), C3-6cycloalkyl, phenyl and heterocycle; and RG2is selected from the group consisting of —NH(C1-3alkyl) (optionally substituted by one, two or three substituents each independently selected from the group consisting of halo, optionally substituted phenyl, —S(O)2—CH3, C3-6cycloalkyl, and 5-6 membered heteroaryl) and —NH(C═O)Rm, wherein Rmis selected for each occurrence by H, C1-6alkyl (optionally substituted by one, two or three substituents each independently selected from the group consisting of halo, cyano and C1-C6alkoxy), CHF2, CF3, or 5-6 membered heteroaryl (optionally substituted by halo, cyano, hydroxyl, NH2, C1-6alkyl, C3-6cycloalkyl, C1-C6alkoxy, CHF2, and CF3).51. The compound is represented by:

wherein RG3is selected from the group consisting of H, C1-6alkyl (optionally substituted by one, two or three C1-C6alkoxy), C3-6cycloalkyl, phenyl and heterocycle; and RG2is selected from the group consisting of —NH(C1-3alkyl) (optionally substituted by one, two or three substituents each independently selected from the group consisting of halo, optionally substituted phenyl, —S(O)2—CH3, C3-6cycloalkyl, and 5-6 membered heteroaryl) and —NH(C═O)Rm, wherein Rmis selected for each occurrence by H, C1-6alkyl (optionally substituted by one, two or three substituents each independently selected from the group consisting of halo, cyano and C1-C6alkoxy), CHF2, CF3, or 5-6 membered heteroaryl (optionally substituted by halo, cyano, hydroxyl, NH2, C1-6alkyl, C3-6cycloalkyl, C1-C6alkoxy, CHF2, and CF3).52. RG3is selected from the group consisting of

53. RG2is selected from the group consisting of

wherein RFis selected from the group consisting of C1-6alkyl, C3-6cycloalkyl, phenyl and 5-6 membered heteroaryl, wherein RFmay optionally be substituted by one, two or three substituents selected from the group consisting of halo, cyano, hydroxyl and C1-C6alkoxy; and XFis selected from the group consisting of H, halo, cyano, hydroxyl, NH2, C1-6alkyl, C3-6cycloalkyl, C1-C6alkoxy, and C1-6haloalkyl.54. The compound is selected from the group consisting of:

55. A method of ameliorating or treating a viral infection in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of any of the compounds of the embodiment.56. The viral infection is from a virus selected from the group consisting of an RNA virus, a DNA virus, a coronavirus, a papillomavirus, a pneumovirus, a picornavirus, an influenza virus, an adenovirus, a cytomegalovirus, a polyomavirus, a poxvirus, a flavivirus, an alphavirus, an ebola virus, a morbillivirus, an enterovirus, an orthopneumovirus, a lentivirus, arenavirus, a herpes virus, and a hepatovirus.57. The viral infection is from a virus selected from the group consisting of Norwalk virus, feline calicivirus, MD145, murine norovirus, vesicular exanthema of swine virus, rabbit hemorrhagic disease virus, enterovirus (EV)-68 virus, EV-71 virus, poliovirus, coxsackievirus, foot-and-mouth disease virus, hepatitis A, porcine teschovirus, rhinovirus, human coronavirus, transmissible gastroenteritis virus, murine hepatitis virus, bovine coronavirus, feline infectious peritonitis virus, and severe acute respiratory syndrome coronavirus.58. The viral infection is a coronavirus infection.59. The viral infection is a coronavirus selected from the group consisting of: 229E alpha coronavirus, NL63 alpha coronavirus, OC43 beta coronavirus, HKU1 beta coronavirus, Middle East Respiratory Syndrome (MERS) coronavirus (MERS-CoV), severe acute respiratory syndrome (SARS) coronavirus (SARS-CoV), and SARS-CoV-2 (COVID-19).60. The viral infection is SARS-CoV-2.61. The viral infection is an arenavirus infection.62. The arenavirus is selected from the group consisting of: Junin virus, Lassa virus, Lujo virus, Machupo virus, and Sabia virus.63. The viral infection is an influenza infection.64. The influenza is influenza H1N1, H3N2 or H5N1.65. A method of inhibiting transmission of a virus, a method of inhibiting viral replication, a method of minimizing expression of viral proteins, or a method of inhibiting virus release, comprising administering a therapeutically effective amount of any compound of the embodiment to a patient suffering from the virus, and/or contacting an effective amount of any compound of the embodiment with a virally infected cell.66. The method further comprises administering another therapeutic.67. The method further comprises administering an additional anti-viral therapeutic.68. The anti-viral therapeutic is selected from the group consisting of ribavirin, favipiravir, ST-193, oseltamivir, zanamivir, peramivir, danoprevir, ritonavir, and remdesivir.69. The another therapeutic is selected from the group consisting of protease inhibitors, fusion inhibitors, M2 proton channel blockers, polymerase inhibitors, 6-endonuclease inhibitors, neuraminidase inhibitors, reverse transcriptase inhibitor, aciclovir, acyclovir, protease inhibitors, arbidol, atazanavir, atripla, boceprevir, cidofovir, combivir, darunavir, docosanol, edoxudine, entry inhibitors, entecavir, famciclovir, fomivirsen, fosamprenavir, foscarnet, fosfonet, ganciclovir, ibacitabine, immunovir, idoxuridine, imiquimod, inosine, integrase inhibitor, interferons, lopinavir, loviride, moroxydine, nexavir, nucleoside analogues, penciclovir, pleconaril, podophyllotoxin, ribavirin, tipranavir, trifluridine, trizivir, tromantadine, truvada, valaciclovir, valganciclovir, vicriviroc, vidarabine, viramidine, and zodovudine.70. The additional anti-viral therapeutic is selected from the group consisting of lamivudine, an interferon alpha, a VAP anti-idiotypic antibody, enfuvirtide, amantadine, rimantadine, pleconaril, aciclovir, zidovudine, fomivirsen, a morpholino, a protease inhibitor, double-stranded RNA activated caspase oligomerizer (DRACO), rifampicin, zanamivir, oseltamivir, danoprevir, ritonavir, and remdesivir.71. A method of prophylactically treating a patient at risk of viral infection, comprising administering to the patient an effective amount of any compound of the embodiment,72. The compound is administered before viral exposure.73. The compound is administered after viral exposure.

In another aspect, the compositions, compounds and methods of the present disclosure may be described in another embodiment as follows:1. A protease inhibitor compound represented by:

R1ais selected from and 4-10 membered heterocycle, wherein the heterocycle may optionally be substituted by one, two or three substituents each selected from the group consisting of hydroxyl, C1-C8alkoxy, oxo and a warhead A;R3bis selected from hydrogen and C1-C8alkyl; wherein R3aand R3bmay be joined together to form, together with the carbon to which they are attached, a 4-10 membered heterocycle, wherein the heterocycle may optionally be substituted by one, two or three substituents each selected from C6-C14aryl and a warhead A;R1ais selected from the group consisting of hydrogen, C1-C8alkyl, C1-C8heteroalkyl, —(C1-C8alkyl)-R1, —(C1-C8alkyl)-CN, C3-C10cycloalkyl, C6-C14aryl, 4-10 membered heterocycle and 5-10 membered heteroaryl;R1bis selected from hydrogen and C1-C8alkyl;or R1aand R1bmay be joined together to form, together with the carbon to which they are attached, a 4-10 membered heterocycle having a ring nitrogen, NRG, or a C3-C10cycloalkyl;R1is selected from the group consisting of C1-C8alkyl, C2-C10alkenyl, C2-C10alkynyl, C3-C10cycloalkyl, C6-C14aryl, 5-10 membered heteroaryl and 4-10 membered heterocycle, wherein R1may optionally be substituted by one, two, or three substituents each selected from RA;RAis independently selected, for each occurrence, halogen, cyano, hydroxyl, oxo, SF5, —CH2CF3, CF3, —O—CF3, —O—CHF2, —S—CH3, —S(O)2—CH3, —NH2, —O-phenyl, —O—(C1-C8alkyl)-phenyl, —NHC(O)RB, —NHC(O)ORB, —NHC(O)O—(C1-C8alkyl)-RB, —N(Ry)2, —N(Ry)(C1-C8alkyl)C(O)O-phenyl, —N(Ry)(C1-C8alkyl)C(O)N(Ry)2, —NHC(O)O(C1-C8alkyl)RB, —C(O)-(5-10 membered heteroaryl), —C(O)-(4-10 membered heterocycle), —C(O)—O-(4-10 membered heterocycle), —C(O)-(4-10 membered heterocyclyloxy), —C(O)—OC(CH3)3, —C(O)—(C2-C10alkenyl)-(C6-C14aryl), C1-C8alkyl, C2-C10alkenyl, C2-C10alkynyl, C1-C8heteroalkyl, C1-C8alkoxy, C3-C10cycloalkyl, —(C1-C8alkyl)-(C3-C10cycloalkyl), —(C1-C8alkyl)-(C6-C14aryl), —(C1-C8alkyl)-(5-10 membered heteroaryl), C6-C14aryl, 5-10 membered heteroaryl and 4-10 membered heterocycle, wherein the RB, alkyl, heterocycle, heteroaryl, or aryl may optionally be substituted by one, two or three substituents of halogen, C1-C8alkyl, C1-C8alkoxy, SF5, —NH2, hydroxyl or oxo;R2is selected from the group consisting of —NHC(O)RB, —NHC(O)N(RB)2, —NHC(O)C(RC)2RB, —NHS(O)2RB, —O—(C1-C8alkyl)-(C3-C10cycloalkyl), 4-10 membered heterocycle, C6-C14aryl and 5-10 membered heteroaryl bound through the carbon or nitrogen atom, wherein RBor R2may optionally be substituted by one, two, or three substituents each selected from Rx;or R1aand R2may be joined together to form, together with the carbon to which they are attached, a 4-10 membered mono or bicyclic heterocycle having a ring nitrogen NRG, or a C3-C10cycloalkyl, wherein the cycloalkyl or heterocycle may optionally be substituted by one, two or three substituents on a free carbon each selected from RA;R3is selected from 5-10 membered heteroaryl and 4-10 membered heterocycle, wherein R3may optionally be substituted by one, two, or three substituents each selected from RA;RBis independently selected, for each occurrence, from the group consisting of C1-C8alkyl, C2-C10alkenyl, C2-C10alkynyl, C6-C14aryl, 5-10 membered heteroaryl and 4-10 membered heterocycle;RCis independently selected, for each occurrence, from hydrogen, halogen and C1-C8alkyl;Rxis independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, oxo, CF3, SF5, cyano, —O—(Rxx)—OCH3, —OCHF2, —OCF3, —O—(C1-C8alkyl), —C(O)O(CH3), —N(Ry)2, —N(Ry)C(O)Ry, —N(Ry)(C1-C8alkyl)C(O)N(Ry)2, —N(Ry)(C1-C8alkyl)C(O)OH, —(C1-C8alkyl)-(C3-C10cycloalkyl), C1-C8alkyl, C1-C8alkoxy, C3-C10cycloalkyl, C6-C14aryl, 5-10 membered heteroaryl and 4-10 membered heterocycle, wherein the alkyl, aryl, heterocycle or heteroaryl may optionally be substituted by one or more substituents each selected from oxo, halogen and C1-C8alkyl;RGis selected from the group consisting of H, C1-6alkyl (optionally substituted by one, two or three substituents each independently selected from the group consisting of —C(═O), halo, cyano, —NRmRm, and —NH(C═O)Rm), and C(═O)—C1-6alkyl (optionally substituted by one, two or three substituents each independently selected from the group consisting of halo, cyano, —NRmRm, —NRm(C═O)Rm, phenyl, cycloalkyl, heterocycle, C1-C6alkoxy, wherein Rmis selected for each occurrence by H, C1-3alkyl (optionally substituted by one, two or three substituents each independently selected from the group consisting of halo), phenyl (optionally substituted by halo), —S(O)2—CH3, C3-6cycloalkyl, and 5-6 membered heteroaryl), —C(═O)—C1-6alkyl (optionally substituted by one, two or three substituents each independently selected from the group consisting of halo, cyano and C1-C6alkoxy), C(═O)—C3-6cycloalkyl, and C(═O)-(5-6 membered heteroaryl) (optionally substituted by halo, cyano, hydroxyl, NH2, C1-6alkyl, C3-6cycloalkyl, C1-C6alkoxy, and C1-6haloalkyl));Rxxis —(OCH2CH2)nn—, wherein nn is selected from 1, 2, 3, 4, 5 and 6;Ryis independently selected, for each occurrence, from the group consisting of hydrogen, C1-C8alkyl, C1-C8heteroalkyl, —CH2CF3, C1-C8alkoxy, —(C1-C8alkoxy)-(5-10 membered aryl), C3-C6cycloalkyl and —(C1-C8alkyl)COOH;A is a warhead;X is selected from the group consisting of C(Rxy) and N, wherein Rxyis selected from the group consisting of H, D, —OH, —NH2, halogen, C1-C8alkyl, C1-C8haloalkyl, and C1-C8alkoxy; andpharmaceutically acceptable salts, stereoisomers, esters, and prodrugs thereof.2. The compound is represented by:

3. The compound is represented by:

4. The compound is represented by:

5. The compound is represented by:

6. The compound is represented by:

7. The compound is represented by:

8. The compound is represented by:

9. The compound is represented by:

wherein pp is selected from 0, 1, 2, and 3.10. The compound is represented by:

wherein ss is selected from 0, 1, 2, and 3, and mm is selected from 1, 2, and 3.11. A is selected from the group consisting of cyano, —C(O)RD, —C(O)CH2N(RbRc), —C(O)CH2OC(O)RD, —C(O)C(O)RD, —(CH═CH)C(O)ORD, —(CH═CCN)C(O)ORD, —(CH═CCN)C(O)(NH)RD, —CH(CN)(OH), —CH(CN)(NRbRc),

whereinRDis selected from the group consisting of hydrogen, hydroxyl, —ORbb—N(RbRc), C1-C8alkyl, C1-C8alkoxy, C3-C6cycloalkyl, C6-C14aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycle; wherein RDmay optionally be substituted by one, two, or three substituents each selected from the group consisting of halogen, hydroxyl, and RE;REis selected from the group consisting of C1-C8alkyl, C1-C8alkoxy, C6-C14aryl, 4-10 membered heterocycle, and 5-10 membered heteroaryl, wherein REmay optionally be substituted by one, two, or three substituents each selected from halogen, cyano, C1-C8alkyl and C1-C8alkoxy;Rbbis selected from the group consisting of C3-C6cycloalkyl, C6-C14aryl, —(C1-C8alkyl)-C6-C14aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycle;Rccis selected from the group consisting of hydrogen, C1-C8alkyl, C3-C6cycloalkyl, —(C1-C8alkyl)-(C6-C14aryl), C6-C14aryl, 5-10 membered heteroaryl, —(C1-C8alkyl)-(5-10 membered heteroaryl), 5-10 membered heterocycle and —N(RbRc), wherein Rband Rcare each selected from the group consisting of hydrogen, C1-C8alkyl, and C3-C6cycloalkyl, or Rband Rcmay be joined together to form, together with the nitrogen to which they are attached, a 5-10 membered heterocycle;Rcdis selected from the group consisting of hydrogen, C1-C8alkyl, and C3-C6cycloalkyl; andRband Rcare each selected from the group consisting of hydrogen, —CH2C(O)O(C1-C8alkyl), —C(O)—(C1-C8alkyl), —S(O)2—(C1-C8alkyl), C1-C8alkyl, C3-C6cycloalkyl and —(C1-C8alkyl)-C6-C14aryl, wherein the C1-C8alkyl may optionally be substituted by one or more substituents each selected from the group consisting of halogen, C3-C6cycloalkyl, C6-C14aryl, 4-10 membered heterocycle, and 5-10 membered heteroaryl.12. A is selected from the group consisting of

13. R1ais selected from the group consisting of

17. R3ais a 4-10 membered heterocycle substituted by A.18. R3ais selected from the group consisting of

20. R3is selected from the group consisting of

21. R2is selected from the group consisting of

22. R1aand R2are joined to together to form the heterocycle selected from the group consisting of:

and R1bis H.23. RGis selected from the group consisting of H, C1-6alkyl (optionally substituted by one, two or three substituents each independently selected from the group consisting of —C(═O), halo, cyano, —NRmRm, and —NH(C═O)Rm) and C(═O)—C1-6alkyl (optionally substituted by one, two or three substituents each independently selected from the group consisting of halo, cyano, —NRmRm, —NRm(C═O)Rm, phenyl, cycloalkyl and heterocycle, wherein Rmis selected for each occurrence by H or C1-3alkyl (optionally substituted by one, two or three halogens, e.g., F), or C3-C6cycloalkyl (optionally substituted by one, two, or three F).24. RGis selected from the group consisting of a —C(O)-monocyclic 5-6 membered or —C(O)-bicyclic heteroaryl each having at least one ring nitrogen and optionally substituted by one two or three substitutents each selected from halo, methoxy, cyano, and hydroxyl; and —C(O)—C(R55R56)—NH—C(O)—R57, wherein R55is H and R56is a straight or branched C1-C5alkyl (optionally substituted by halo), or R55and R56taken together with the carbon to which they are attached form a C3-C5cycloalkyl (optionally substituted by halo) and wherein R57is C1-C3alkyl (optionally substituted by one, two or three halo).25. RGis selected from the group consisting of

26. A compound selected from the group consisting of:

EXAMPLES

The compounds described herein can be prepared in a number of ways based on the teachings contained herein and synthetic procedures known in the art. In the description of the synthetic methods described below, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, can be chosen to be the conditions standard for that reaction, unless otherwise indicated. It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule should be compatible with the reagents and reactions proposed. Substituents not compatible with the reaction conditions will be apparent to one skilled in the art, and alternate methods are therefore indicated. The starting materials for the examples are either commercially available or are readily prepared by standard methods from known materials.

At least some of the compounds identified as “Intermediates” herein are contemplated as compounds of the disclosure.

1H NMR spectra are recorded at ambient temperature using e.g., a Varian Unity Inova (400 MHz) spectrometer with a triple resonance 5 mm probe for Example compounds, and either a Bruker Avance DRX (400 MHz) spectrometer or a Bruker Avance DPX (300 MHz) spectrometer for Intermediate compounds. Chemical shifts are expressed in ppm relative to tetramethylsilane. The following abbreviations have been used: br=broad signal, s=singlet, d=doublet, dd=double doublet, dt=double triplet, ddd=double doublet, t=triplet, td=triple doublet, tdd=triple double doublet, q=quartet, m=multiplet.

General Chemistry

Exemplary compounds described herein are available by the general synthetic method illustrated in Scheme 1, including preparations of Intermediates and preparation of accompanying Examples.

Scheme 1 illustrates an exemplary preparation of C-1. Reacting a solution of amine A-1, and acid B-1 with a coupling agent such as T3P, EDCI/HOBt, in the presence of a base such as TEA, DMAP and DIEA, and solvent such as DMF and DCM, affords C-1.

In Scheme 1, examples of A include a substituted or unsubstituted alkyl and a substituted or unsubstituted cycloalkyl, examples of B include a warhead moiety, such as cyano, aldehyde, hydroxymethylketone, ketoamide, heteroaryl-ketone, enone, and Michael acceptor warhead, examples of C include an alkyl substituted with a 4-, 5-, or 6-membered lactam, and examples of D include a substituted or unsubstituted bicyclic heteroaryl moiety. In Scheme 1, exemplary preparation of a cyano moiety at B include a dehydration of an amide to nitrile with a dehydration agent such as Burgess reagent.

Compounds of Table 1 and Table 2 have been prepared following general Scheme 1, which follows the examples described below, such as examples 19, 25, 27, 32, 39, and 41.

Example 1. Synthesis of Viral Protease Inhibitor Compound 103

Methyl(2S)-2-[[(2S)-2-(1H-benzimidazole-2-carbonylamino)-4-methyl-pentanoyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (150 mg, 338.22 umol, 1 eq) was added NH3/MeOH (7 M, 5 mL, 103.48 eq). The mixture was stirred at 80° C. for 16 h in a sealed tube. The reaction was concentrated in vacuo to dryness, give compound N-[(1S)-3-methyl-1-[[(1S)-1-(nitrosomethyl)-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]carbamoyl]butyl]-1H-benzimidazole-2-carboxamide (140 mg, crude) as a solid. The crude product was used directly in next step.

Example 2. Synthesis of Viral Protease Inhibitor Compound 105

To a mixture of methyl (2S)-2-[[(2S)-2-amino-4-methyl-pentanoyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (150 mg, 501.06 umol, 1 eq) in DMF (5 mL) was added naphthalene-2-sulfonyl chloride (227.16 mg, 1.00 mmol, 2 eq) and DMAP (155.35 mg, 1.27 mmol, 2.54 eq) and stirred at 25° C. Then the reaction was stirred at 80° C. for 16 h. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (10 mL*3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, DCM/MeOH=10/1). Give methyl (2S)-2-[[(2S)-4-methyl-2-(2-naphthylsulfonylamino)pentanoyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (70 mg, 142.98 umol) as an oil.

To a mixture of methyl (2S)-2-[[(2S)-4-methyl-2-(2-naphthylsulfonylamino)pentanoyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (50 mg, 102.13 umol, 1 eq) was added NH3/MeOH (7 M, 10 mL, 685.42 eq) and stirred at 80° C. for 16 h. The reaction was concentrated in vacuo to dryness to give the crude of (2S)-N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]ethyl]-4-methyl-2-(2-naphthylsulfonylamino)pentanamide (50 mg, crude) as an oil.

Example 3. Synthesis of benzyl N-[(1S)-1-[[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]carbamoyl]-3-methyl-butyl]carbamate

To a mixture of methyl (2S)-2-(tert-butoxycarbonylamino)-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (300 mg, 1.05 mmol, 1 eq) in DCM (5 mL) was added TFA (4.62 g, 40.52 mmol, 3 mL, 38.67 eq), then the mixture was stirred at 25° C. for 2 h. Once the reaction was completed, the reaction mixture was concentrated under reduced pressure to give a residue and used next step. Compound methyl (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (180 mg, 918.33 umol) was obtained as a colorless oil. MS (ESI) m/z 187.1 [M+H]+

To a mixture of methyl (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (189.47 mg, 966.66 umol) and (2S)-2-(benzyloxycarbonylamino)-4-methyl-pentanoic acid (256.46 mg, 966.66 umol, 1 eq) in DCM (2 mL) was added DMAP (236.19 mg, 1.93 mmol, 2 eq) and EDCI (370.62 mg, 1.93 mmol, 2 eq). The mixture was added with DMF (1 mL) and stirred at 25° C. for 14 h. Once the reaction was completed, the reaction mixture was diluted with H2O (50 mL) and extracted with DCM (30 mL*3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether/EtOAc=3/1 to 0/1) to get the compound methyl (2S)-2-[[(2S)-2-(benzyloxycarbonylamino)-4-methyl-pentanoyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (250 mg, 461.36 umol) as a solid. MS (ESI) m/z 434.3 [M+H]+

Methyl (2S)-2-[[(2S)-2-(benzyloxycarbonylamino)-4-methyl-pentanoyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (200 mg, 369.09 umol, 1 eq) was added NH3/MeOH (7 M, 58.14 mL, 1102.58 eq). The mixture was stirred at 80° C. for 16 h. Once the reaction was completed, the reaction mixture was concentrated under reduced pressure to give a residue and used directly next step. Compound benzyl N-[(1S)-1-[[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]ethyl]carbamoyl]-3-methyl-butyl]carbamate (150 mg, 322.59 umol) was obtained as a colorless oil.

Example 4. Synthesis of Viral Protease Inhibitor Compound 131

To a mixture of methyl (2S)-2-[[(2S)-2-amino-4-methyl-pentanoyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (250 mg, 604.76 umol, 1 eq, TFA) and 1H-imidazo[4,5-b]pyridine-2-carboxylic acid (118.39 mg, 725.71 umol, 1.2 eq) in DCM (4 mL) was added EDCI (231.86 mg, 1.21 mmol, 2 eq) and DMAP (147.77 mg, 1.21 mmol, 2 eq). The mixture was added with DMF (2 mL) and stirred at 25° C. for 4 h. The reaction mixture was diluted with H2O (20 mL) and extracted with DCM (30 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, DCM/MeOH=5/1) to give compound methyl (2S)-2-[[(2S)-2-(1H-imidazo[4,5-b]pyridine-2-carbonylamino)-4-methyl-pentanoyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (100 mg, 224.98 umol) as a solid.

To a mixture of methyl (2S)-2-[[(2S)-2-(1H-imidazo[4,5-b]pyridine-2-carbonylamino)-4-methyl-pentanoyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (100 mg, 224.98 umol, 1 eq) was added NH3/MeOH (7 M, 27.54 mL, 856.77 eq) and stirred at 80° C. for 16 h. The reaction was concentrated in vacuo to dryness to give the crude of N-[(1S)-1-[[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]ethyl]carbamoyl]-3-methyl-butyl]-1H-imidazo[4,5-b]pyridine-2-carboxamide (90 mg, crude) as an oil.

Example 5. Synthesis of Viral Protease Inhibitor Compound 121

To a mixture of methyl (2S)-2-(tert-butoxycarbonylamino)-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (1.2 g, 3.77 mmol) in THF (3 mL), ACN (3 mL) and H2O (3 mL) was added LiOH·H2O (158.29 mg, 3.77 mmol, 1 eq). The mixture was stirred at 25° C. for 2 h. Once the reaction was completed, the solution was concentrated to give a residue, and then the residue was adjusted to pH-4 with HCl. The resulting residue was extracted with EtOAc (20 mL*3) and brine (20 mL), and then concentrated to give a residue compound (2S)-2-(tert-butoxycarbonylamino)-3-[(3S)-2-oxopyrrolidin-3-yl]propaneic acid (1 g, 3.31 mmol) was obtained as an oil. MS (ESI) m/z 217.1 [M+H-56]+.

To a mixture of (2S)-2-(tert-butoxycarbonylamino)-3-[(3S)-2-oxopyrrolidin-3-yl]propanoic acid (1.0 g, 3.31 mmol) in DCM (20 mL) was added CDI (535.94 mg, 3.31 mmol, 1 eq). The mixture was stirred at 0° C. for 30 min, then added with DIEA (512.61 mg, 3.97 mmol, 690.85 uL, 1.2 eq) and N,O-DIMETHYLHYDROXYLAMINE HYDROCHLORIDE (322.40 mg, 3.31 mmol, 1 eq). The resulting mixture was stirred at 25° C. for 3 h. Once the reaction was complete, the reaction mixture was diluted with H2O (30 mL) and extracted with ethyl acetate (30 mL*3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether/EtOAc=5/1 to 0/1) to get the compound tert-butyl N-[(1S)-2-[methoxy(methyl)amino]-2-oxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]ethyl]carbamate (0.9 g, 2.57 mmol) which was obtained as an oil. MS (ESI) m/z 316.2 [M+H]+

To a mixture of 2-bromo-1,3-benzothiazole (458.22 mg, 2.14 mmol, 1.5 eq) in THF (20 mL) was added n-BuLi (2.5 M, 684.92 uL, 1.2 eq) in one portion at −78° C. under N2. The mixture was stirred at −78° C. for 30 min, and then added with tert-butyl N-[(1S)-2-[methoxy(methyl)amino]-2-oxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]ethyl]carbamate (500 mg, 1.43 mmol) at −78° C. The resulting mixture was stirred for 1 hour, and then the reaction mixture was quenched by the addition of NH4C1(10 mL) at 0° C., and then stirred for 10 min at 0° C. The resulting mixture was diluted with water (100 mL) and extracted with EtOAc (50 mL*3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by MPLC (SiO2, petroleum ether/EtOAc˜MeOH=10/1 to 0/1) to get the compound tert-butyl N-[(1S)-2-(1,3-benzothiazol-2-yl)-2-oxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]ethyl]carbamate (150 mg, 346.63 umol) as a colorless oil. MS (ESI) m/z 390.1 [M+H]+

To a mixture of tert-butyl N-[(1S)-2-(1,3-benzothiazol-2-yl)-2-oxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]ethyl]carbamate (150 mg, 346.63 umol) was added HCl/EtOAc (4 M, 86.66 uL, 1 eq). The resulting mixture was stirred at 20° C. for 2 h, and then concentrated under reduced pressure to give a residue (3S)-3-[(2S)-2-amino-3-(1,3-benzothiazol-2-yl)-3-oxo-propyl]pyrrolidin-2-one (100 mg, crude) as an oil which was directly used in the next step. MS (ESI) m/z 290.1 [M+H]+

Example 6. Synthesis of Viral Protease Inhibitor Compound 185

To a solution of methyl (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (170 mg, 763.47 umol, 1 eq, HCl) and (2S)-2-(tert-butoxycarbonylamino)-3-cyclohexyl-propanoic acid (207.17 mg, 763.47 umol, 1 eq) in DMF (2 mL) was added DMAP (186.55 mg, 1.53 mmol, 2 eq) and EDCI (292.71 mg, 1.53 mmol, 2 eq). The mixture was added DCM (3 mL) and stirred at 25° C. for 2 h. LCMS showed the reaction was completed, and desired MS was observed. The reaction mixture was quenched by addition H2O (30 mL) at 0° C., and then extracted with DCM (20 mL*3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, petroleum ether/EtOAc=0/1) to get the product methyl (2S)-2-[[(2S)-2-(tert-butoxycarbonylamino)-3-cyclohexyl-propanoyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (250 mg, 568.77 umol, 74.50% yield) was obtained as a solid. MS (ESI) m/z 440.3 [M+H]+

A solution of methyl (2S)-2-[[(2S)-2-(tert-butoxycarbonylamino)-3-cyclohexyl-propanoyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (200 mg, 455.02 umol, 1 eq) in EtOAc (0.5 mL) was added drop-wise HCl/EtOAc (4 M, 2.00 mL, 17.58 eq) at 25° C. The mixture was stirred at 25° C. for 1 h. The reaction mixture was concentrated under reduced pressure to give a product methyl (2S)-2-[[(2S)-2-amino-3-cyclohexyl-propanoyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (150 mg, crude, HCl) was obtained as a solid and used directly next step. MS (ESI) m/z 340.1 [M+H]+

A solution of 4-methoxy-1H-indole-2-carboxylic acid (99.18 mg, 518.77 umol, 1.3 eq) and methyl (2S)-2-[[(2S)-2-amino-3-cyclohexyl-propanoyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (150 mg, 399.05 umol, 1 eq, HCl) in DMF (2 mL) was added DMAP (97.50 mg, 798.11 umol, 2.0 eq) and EDCI (153.00 mg, 798.11 umol, 2 eq). The mixture was added DCM (4 mL) and stirred at 25° C. for 2 h. The reaction mixture was quenched by addition H2O (20 mL) at 0° C., and then extracted with DCM (20 mL*3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, DCM:MeOH=1:0 to 10:1) to get a product methyl (2S)-2-[[(2S)-3-cyclohexyl-2-[(4-methoxy-1H-indole-2-carbonyl)amino]propanoyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (150 mg, 292.63 umol, 73.33% yield) was obtained as a solid.

A solution of methyl (2S)-2-[[(2S)-3-cyclohexyl-2-[(4-methoxy-1H-indole-2-carbonyl)amino]propanoyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (150 mg, 292.63 umol, 1 eq) in ammonia (15.30 g, 898.39 mmol, 15.00 mL, 3070.07 eq) was heated at 80° C. for 12 hours in a sealed tube. The reaction mixture was concentrated under reduced pressure to get a product N-[(1S)-2-[[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]ethyl]amino]-1-(cyclohexylmethyl)-2-oxo-ethyl]-4-methoxy-1H-indole-2-carboxamide (140 mg, crude) was obtained as a solid. MS (ESI) m/z 498.2 [M+H]+

To a solution of N-[(1S)-2-[[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]ethyl]amino]-1-(cyclohexylmethyl)-2-oxo-ethyl]-4-methoxy-1H-indole-2-carboxamide (80 mg, 160.78 umol, 1 eq) in DCM (3 mL) was added Burgess reagent (114.94 mg, 482.33 umol, 3 eq), and then the resulting mixture was stirred at 25° C. for 3 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by neutral prep-HPLC to give a product N-[(1S)-2-[[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]amino]-1-(cyclohexylmethyl)-2-oxo-ethyl]-4-methoxy-1H-indole-2-carboxamide (20.02 mg, 41.75 umol) was obtained as a solid. MS (ESI) m/z 480.1 [M+H]+.

Example 7. Synthesis of Viral Protease Inhibitor Compound 101

Example 8. Synthesis of Viral Protease Inhibitor Compound 593

To the solution of (2S)-2-(tert-butoxycarbonylamino)-3-(1H-imidazol-5-yl)propanoic acid (0.5 g, 1.96 mmol, 1 eq) in MeOH (0.6 mL) was added HCl/MeOH (4 M, 4.90 mL, 10 eq) at 25° C. The reaction mixture was stirred at 25° C. for 12 h. The reaction mixture was concentrated to get the product. Methyl (2S)-2-amino-3-(1H-imidazol-5-yl) propanoate (400 mg, crude, HCl) was obtained as a solid and used directly next step. MS (ESI) m/z 170.1 [M+H]+

Example 9. Synthesis of Viral Protease Inhibitor Compounds 135, 595 and 136

To a mixture of N-[(1S)-1-[[(1S)-1-formyl-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]carbamoyl]-3-methyl-butyl]-4-methoxy-1H-indole-2-carboxamide (400 mg, 723.15 umol, 80% purity, 1 eq) in DCM (10 mL) was added saturated NaHSO3(301.01 mg, 2.89 mmol, 203.38 uL, 4 eq). The mixture was stirred at 25° C. for 30 min, and then an aq solution of KCN (42 mg, 644.96 umol, 27.63 uL, 8.92e-1 eq) in H2O (0.8 mL) was added. The mixture was stirred at 25° C. for 3 h. Once the reaction was completed, the organic phase was collected and the aqueous layer was extracted with DCM (30 mL*3). The combined organic phase was washed with brine (30 mL*2), dried over Na2SO4, and concentrated to get the crude. The liquid was added NaOH to pH=9, then quenched by adding aq NaCl, then added NaOH to pH>14. The crude was purified by HCl prep-HPLC to get the mixture 120 mg, and SFC separation to get compound N-[(1S)-1-[[(1S)-2-cyano-2-hydroxy-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]ethyl]carbamoyl]-3-methyl-butyl]-4-methoxy-1H-indole-2-carboxamide (34 mg, 70.96 umol, 9.81% yield, 97.99% purity) and compound N-[(1S)-1-[[(1S)-2-cyano-2-hydroxy-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]ethyl]carbamoyl]-3-methyl-butyl]-4-methoxy-1H-indole-2-carboxamide (64 mg, 131.75 umol, 18.22% yield, 96.66% purity) as a solid. MS (ESI) m/z 470.2[M+H]+.

Example 10. Synthesis of Viral Protease Inhibitor Compound 740 and 741

To a solution of methyl (2S)-2-(tert-butoxycarbonylamino)-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (0.6 g, 2.10 mmol, 1 eq) in THF (24 mL) was added chloro(iodo)methane (1.48 g, 8.38 mmol, 608.42 uL, 4 eq), then the solution was cooled to −70° C. and LDA (2 M, 6.29 mL, 6 eq) was added drop-wise. The reaction was stirred at −70° C. for 1 h. Upon completion, the reaction mixture was quenched by addition a mixture of AcOH (4.5 mL) and THF (22 mL) at −70° C., and then diluted with ethyl acetate (50 mL) and extracted with water (30 mL*2), sat. NaHCO3(30 mL). The organic layers were washed dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether:EtOAc=2:1 to 0:1) and then triturated with methyl tertiary butyl ether:petroleum ether=4:1 (3 mL) to give tert-butyl N-[(1S)-3-chloro-2-oxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]propyl]carbamate (0.35 g, 1.03 mmol, 49.32% yield, 90% purity) as a solid. MS (ESI) m/z 308.0 [M+H]+.

To a solution of [(3S)-3-[[(2S)-2-[(4-methoxy-1H-indole-2-carbonyl)amino]-4-methyl-pentanoyl]amino]-2-oxo-4-[(3S)-2-oxopyrrolidin-3-yl]butyl]2-oxo-2-phenyl-acetate (0.3 g, 496.16 umol, 1 eq) in MeOH (10 mL) was added K2CO3(3.43 mg, 24.81 umol, 0.05 eq). The reaction was stirred at 25° C. for 1 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, DCM:MeOH=10:1) to give the product.

Example 11. Synthesis of Viral Protease Inhibitor Compound 143

A mixture of methyl (2S)-2-[[(2S)-2-(tert-butoxycarbonylamino)-4-methyl-pentanoyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (250 mg, 625.81 umol, 1 eq) was added HCl/EtOAc (8 mL) at 25° C. for 1 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give a residue get a product methyl (2S)-2-[[(2S)-2-amino-4-methyl-pentanoyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (230 mg, crude) as an oil. MS (ESI) m/z 300.0 [M+H]+.

A mixture of methyl (2S)-2-[[(2S)-4-methyl-2-[[(E)-3-phenylprop-2-enoyl]amino]pentanoyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (200 mg, 465.65 umol, 1 eq) in NH3/MeOH (7 M, 7 mL, 97% purity, 105.23 eq) heated to 80° C. for 16 h in the sealed tube. Upon completion, the reaction mixture was concentrated under reduced pressure to give a residue to get the product (2S)-N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]ethyl]-4-methyl-2-[[(E)-3-phenylprop-2-enoyl]amino]pentanamide (200 mg, crude) as an oil. MS (ESI) m/z 415.1 [M+H]+.

Example 12. Synthesis of Viral Protease Inhibitor Compound 598

Example 13. Synthesis of Viral Protease Inhibitor Compound 149

To a mixture of methyl (2S)-2-(tert-butoxycarbonylamino)-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (500 mg, 1.75 mmol, 1 eq) in HCl/EtOAc (4 M, 20 mL). The mixture was stirred at 25° C. and stirred for 1 h. Once the reaction was completed, the reaction was concentrated to give the crude methyl (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (400 mg, crude) (oil). The crude product was used directly without further purification. MS (ESI) m/z 187.1 [M+H]+

To a mixture of (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (400 mg, 870.4 umol, 1 eq) in HCl/EtOAc (4 M, 20 mL). The mixture was stirred at 25° C. for 2 h. Once the reaction was completed, the reaction mixture was concentrated to get the product methyl (2S)-2-[[(2S)-2-(tert-butoxycarbonylamino)-2-indan-2-yl-acetyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (330 mg, crude) was obtained as an oil and used directly next step. MS (ESI) m/z 360.2 [M+H]+

Example 14. Synthesis of Viral Protease Inhibitor Compound 165

Methyl (2S)-2-(tert-butoxycarbonylamino)-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (250 mg, 873.14 umol, 1 eq) was added HCl/EtOAc (4 M, 30 mL) at 25° C. The mixture was stirred at 25° C. for 1 h. The reaction mixture was concentrated under reduced pressure to give a product methyl (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate;hydrochloride (200 mg, crude) as a solid and used directly for next step.

Example 15. Synthesis of Viral Protease Inhibitor Compound 167

Example 16. Synthesis of Viral Protease Inhibitor Compound 209

A mixture of methyl (2S)-2-[[(2S,4S)-1-[(E)-3-(4-chloro-2-fluoro-phenyl)prop-2-enoyl]-4-phenyl-pyrrolidine-2-carbonyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (0.1 g, 184.50 umol, 1 eq) in NH3/MeOH (7M, 3 mL) was stirred at 80° C. for 16 h in the sealed tube. Upon completion, the reaction mixture was concentrated under reduced pressure to give (2S,4S)-N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]ethyl]-1-[(E)-3-(4-chloro-2-fluoro-phenyl)prop-2-enoyl]-4-phenyl-pyrrolidine-2-carboxamide (0.09 g, crude) as a yellow oil. MS (ESI) m/z 527.0 [M+H]+.

Example 17. Synthesis of Viral Protease Inhibitor Compound 183

Methyl (2S)-2-(tert-butoxycarbonylamino)-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (300 mg, 1.05 mmol, 1 eq) was added HCl/EtOAc (4 M, 30 mL) at 25° C. The mixture was stirred at 25° C. for 1 h. The reaction mixture was concentrated under reduced pressure to give a product methyl (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate:HCl (230 mg, crude) as an oil and used directly for next step.

A mixture of methyl (2S)-2-(tert-butoxycarbonylamino)-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (400 mg, 1.40 mmol, 1 eq) and NH3/MeOH (7 M, 10 mL) was stirred at 80° C. for 16 h. The reaction mixture was concentrated under reduced pressure to give a product tert-butyl ((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)carbamate (380 mg, crude) as a solid.

A mixture of tert-butyl ((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)carbamate (300 mg, 1.11 mmol, 1 eq) and HCl/EtOAc (4 M, 15 mL, 54.26 eq) was stirred at 25° C. for 0.5 h. The reaction mixture was concentrated under reduced pressure to give a product (S)-2-amino-3-((S)-2-oxopyrrolidin-3-yl)propanamide (190 mg, crude) as a solid and used directly for next step.

Example 18. Synthesis of Viral Protease Inhibitor Compound 185

A solution of methyl (2S)-2-[[(2S)-2-(tert-butoxycarbonylamino)-3-cyclohexyl-propanoyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (200 mg, 455.02 umol, 1 eq) in EtOAc (0.5 mL) was added drop-wise HCl/EtOAc (4 M, 2.00 mL, 17.58 eq) at 25° C. The mixture was stirred at 25° C. for 1 h. The reaction mixture was concentrated under reduced pressure to give a product methyl (2S)-2-[[(2S)-2-amino-3-cyclohexyl-propanoyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (150 mg, crude, HCl) was obtained as a solid and used directly next step. MS (ESI) m/z 340.1 [M+H]+

A solution of 4-methoxy-1H-indole-2-carboxylic acid (99.18 mg, 518.77 umol, 1.3 eq) and methyl (2S)-2-[[(2S)-2-amino-3-cyclohexyl-propanoyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (150 mg, 399.05 umol, 1 eq, HCl) in DMF (2 mL) was added DMAP (97.50 mg, 798.11 umol, 2.0 eq) and EDCI (153.00 mg, 798.11 umol, 2 eq). The mixture was added DCM (4 mL) and stirred at 25° C. for 2 h. The reaction mixture was quenched by addition H2O (20 mL) at 0° C., and then extracted with DCM (20 mL*3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, DCM:MeOH=1:0 to 10:1) to get a product methyl (2S)-2-[[(2S)-3-cyclohexyl-2-[(4-methoxy-1H-indole-2-carbonyl)amino]propanoyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (150 mg, 292.63 umol, 73.33% yield) was obtained as a solid.

To a solution of methyl (2S)-2-[[(2S)-3-cyclohexyl-2-[(4-methoxy-1H-indole-2-carbonyl)amino]propanoyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (150 mg, 292.63 umol, 1 eq) in ammonia (15.30 g, 898.39 mmol, 15.00 mL, 3070.07 eq) was heated to 80° C. for 12 h in a sealed tube. The reaction mixture was concentrated under reduced pressure to get a product N-[(1S)-2-[[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]ethyl]amino]-1-(cyclohexylmethyl)-2-oxo-ethyl]-4-methoxy-1H-indole-2-carboxamide (140 mg, crude) was obtained as a solid. MS (ESI) m/z 498.2 [M+H]+

To a solution of N-[(1S)-2-[[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]ethyl]amino]-1-(cyclohexylmethyl)-2-oxo-ethyl]-4-methoxy-1H-indole-2-carboxamide (80 mg, 160.78 umol, 1 eq) in DCM (3 mL) was added Burgess reagent (114.94 mg, 482.33 umol, 3 eq), then the mixture was stirred at 25° C. for 3 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by neutral prep-HPLC to get a product N-[(1S)-2-[[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]amino]-1-(cyclohexylmethyl)-2-oxo-ethyl]-4-methoxy-1H-indole-2-carboxamide (20.02 mg, 41.75 umol, 25.97% yield, 100% purity) was obtained as a solid. MS (ESI) m/z 480.1 [M+H]+.

Example 19. Synthesis of Viral Protease Inhibitor Compound 197

To a mixture of methyl (2S)-2-(tert-butoxycarbonylamino)-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (500 mg, 1.75 mmol, 1 eq) in HCl/EtOAc (4M, 20 mL). The mixture was stirred at 25° C. and stirred for 1 h. Once the reaction was completed, the reaction was concentrated to give the crude methyl (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (400 mg, crude, an oil). The crude product was used directly without further purification. MS (ESI) m/z 187.1 [M+H]+

To a mixture of (1S,2S,5S)-tert-butyl 2-(((S)-1-methoxy-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)carbamoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (200 mg, 236.13 umol, 50% purity, 1 eq) in HCl/EtOAc (4M, 20 mL). The mixture was stirred at 25° C. and stirred for 2 h. Once the reaction was completed, the reaction was concentrated to give the crude (S)-methyl 2-((1S,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (150 mg, crude, an oil). Crude product was used directly without further purification. MS (ESI) m/z 324.1 [M+H]+

To a mixture of methyl (2S)-2-[[(2S,5S)-3-(4-methoxy-1H-indole-2-carbonyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (100 mg, 201.39 umol, 1 eq) in ammonia (5.10 g, 299.46 mmol, 5 mL, 1486.99 eq). The mixture was stirred at 80° C. and stirred for 16 h. Once the reaction was completed, the reaction was concentrated to give the crude (2S,5S)-N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]ethyl]-3-(4-methoxy-1H-indole-2-carbonyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (100 mg, crude) (solid). Crude product was used directly without further purification. MS (ESI) m/z 482.3[M+H]+

Example 20. Synthesis of Viral Protease Inhibitor Compound 213

Benzyl (3S)-2-[(E)-3-(4-chloro-2-fluoro-phenyl)prop-2-enoyl]-3-[[(1S)-2-methoxy-2-oxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]ethyl]carbamoyl]hexahydropyridazine-1-carboxylate (160 mg, 260.14 umol, 1 eq) in TFA (5 mL) was stirred at 75° C. for 1 h. Upon completion, the solution was concentrated to remove the TFA, diluted with the solution of NaHCO3, extracted with EtOAc (20 mL*3), the combined organic phase was dried over Na2SO4, filtrated and concentrated to give the crude. The crude was used to next step directly and without further purification. Methyl (2S)-2-[[(3S)-2-[(E)-3-(4-chloro-2-fluoro-phenyl) prop-2-enoyl]hexahydropyridazine-3-carbonyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (80 mg, crude) was obtained as solid. MS (ESI) m/z 481.0 [M+H]+.

(E)-3-(4-chloro-2-fluoro-phenyl)prop-2-enoic acid (120 mg, 598.22 umol, 1 eq) in DCM (0.5 mL) was added the DMF (437.26 ug, 5.98 umol, 0.46 uL, 0.01 eq) and cooled to 0° C., then the (COCl)2(151.86 mg, 1.20 mmol, 104.73 uL, 2 eq) was added and the solution was stirred at 25° C. for 1 h. Upon completion, the solution was concentrated to remove the DCM and give the crude. The crude was used to next step directly and without further purification. (E)-3-(4-chloro-2-fluoro-phenyl)prop-2-enoyl chloride (125 mg, crude) was obtained as a solid.

Example 21. Synthesis of Viral Protease Inhibitor Compound 201

Methyl (2S)-2-(tert-butoxycarbonylamino)-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (250 mg, 873.14 umol, 1 eq) was added HCl/EtOAc (4 M, 30 mL) at 25° C. The mixture was stirred at 25° C. for 1 h. The reaction mixture was concentrated under reduced pressure to give a product methyl (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate;hydrochloride (200 mg, crude) as a solid and used directly for next step.

A mixture of (S)-methyl-2-((S)-2-((tert-butoxycarbonyl)amino)pent-4-ynamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (140 mg, 367.05 umol, 1 eq) and HCl/EtOAc (4 M, 30 mL) was stirred at 25° C. for 1 h. The reaction mixture was concentrated under reduced pressure to give a product (S)-methyl 2-((S)-2-aminopent-4-ynamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (120 mg, crude, HCl) as an oil and used directly for next step.

Example 22. Synthesis of Viral Protease Inhibitor Compound 205

To a solution of (2S)-2-amino-3-cyclopropyl-propanoic acid (1 g, 7.74 mmol, 1 eq) in THF (5 mL) and H2O (5 mL), was added K2CO3(3.75 g, 27.10 mmol, 3.5 eq) and (Boc)2O (2.20 g, 10.07 mmol, 2.31 mL, 1.3 eq). Additional water was added to the mixture, and then the mixture was stirred at 25° C. for 16 h. The organic solvent was then evaporated and the aqueous solution was washed with petroleum ether (10 mL) and acidified to pH˜3 with 1N aqueous citric acid (30 mL). The solution was extracted with DCM (30 mL*3) and was concentrated in vacuum to afford (S)-2-((tert-butoxycarbonyl)amino)-3-cyclopropyl propanoic acid (1.8 g, crude) as an oil.

(S)-methyl 2-((tert-butoxycarbonyl)amino)-3-((S)-2-oxopyrrolidin-3-yl) propanoate (500 mg, 1.75 mmol, 1 eq) was added HCl/EtOAc (4 M, 5 mL) at 25° C. The mixture was stirred at 25° C. for 1 h. The reaction mixture was concentrated under reduced pressure to give a product (S)-methyl 2-amino-3-((S)-2-oxopyrrolidin-3-yl) propanoate (350 mg, HCl, crude) as a yellow gum and used to next step directly.

To a mixture of N-((S)-1-(((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-3-cyclopropyl-1-oxopropan-2-yl)-4-methoxy-1H-indole-2-carboxamide (100 mg, crude) in DCM (4 mL) was added Burgess reagent (104.63 mg, 439.07 umol, 2 eq). The mixture was stirred at 25° C. for 16 h. The reaction mixture was quenched by water (0.5 mL) and was dried by blowing N2. The residue was purified by neutral prep-HPLC to get the product N-((S)-1-(((S)-1-cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)amino)-3-cyclopropyl-1-oxopropan-2-yl)-4-methoxy-1H-indole-2-carboxamide (15 mg, 34.29 umol, 15.62% yield, 100% purity) as a solid. MS (ESI) m/z 438.2 [M+H]+.

Example 23. Synthesis of Viral Protease Inhibitor Compound 401

Example 24. Synthesis of Viral Protease Inhibitor Compound 225

To the solution of (2S)-2-(tert-butoxycarbonylamino)-3-(3-methylimidazol-4-yl)propanoic acid (300 mg, 1.11 mmol, 1 eq) in EtOAc (1.2 mL) was added HCl/EtOAc (4 M, 2.79 mL, 10 eq) at 25° C. The reaction mixture was stirred at 25° C. for 1.5 h. The resulting mixture was concentrated to get the product. Methyl (2S)-2-amino-3-(3-methylimidazol-4-yl)propanoate (250 mg, crude, HCl) was obtained as a solid and used directly next step. MS (ESI) m/z 183.2 [M+H]+

To a mixture of methyl (2S)-2-[[(2S)-2-(tert-butoxycarbonylamino)-4-methyl-pentanoyl]amino]-3-(3-methylimidazol-4-yl)propanoate (360 mg, 907.99 umol, 1 eq) in DCM (3.3 mL) was added TFA (1.04 g, 9.08 mmol, 672.27 uL, 10 eq) at 25° C. under N2. The mixture was stirred at 25° C. for 1.5 h. LCMS showed the reaction mixture was completed. The reaction mixture was concentrated to get the product. Methyl (2S)-2-[[(2S)-2-amino-4-methyl-pentanoyl]amino]-3-(3-methylimidazol-4-yl) propanoate (370 mg, crude, TFA) was obtained as an oil and used directly next step. MS (ESI) m/z 297.2 [M+H]+

To a mixture of methyl (2S)-2-[[(2S)-2-amino-4-methyl-pentanoyl]amino]-3-(3-methylimidazol-4-yl)propanoate (370 mg, 1.25 mmol, 1 eq, TFA) and 4-methoxy-1H-indole-2-carboxylic acid (238.69 mg, 1.25 mmol, 1 eq) in DMF (1.5 mL) and DCM (1.5 mL) was added EDCI (478.66 mg, 2.50 mmol, 2 eq) and DMAP (305.05 mg, 2.50 mmol, 2 eq) in one portion at 25° C. under N2. The mixture was stirred at 25° C. for 12 h. The resulting mixture was added with water (10 mL) and extracted with DCM (10 mL*2) to get the organic phase. The organic phase was washed with brine (3 mL*3) and dried over anhydrous sodium sulfate and concentrated to get the crude product. The residue was purified by column chromatography (SiO2, petroleum ether/EtOAc=2/1 to EtOAc/Methanol=10/1). Methyl (2S)-2-[[(2S)-2-[(4-methoxy-1H-indole-2-carbonyl)amino]-4-methyl-pentanoyl]amino]-3-(3-methylimidazol-4-yl)propanoate (270 mg, crude) was obtained as an oil. MS (ESI) m/z 469.5 [M+H]+

To methyl (2S)-2-[[(2S)-2-[(4-methoxy-1H-indole-2-carbonyl)amino]-4-methyl-pentanoyl]amino]-3-(3-methylimidazol-4-yl)propanoate (235.00 mg, 500.50 umol, 1 eq) was added NH3/MeOH (7 M, 1.94 mL, 27.14 eq) in one portion at 25° C. under N2. The mixture was stirred at 80° C. and stirred for 12 h. LCMS showed the reaction mixture was completed. The reaction mixture was cooled to 25° C. and concentrated to get the crude product. The residue was purified by prep-TLC. N-[(1S)-1-[[(1S)-2-amino-1-[(3-methylimidazol-4-yl)methyl]-2-oxo-ethyl]carbamoyl]-3-methyl-butyl]-4-methoxy-1H-indole-2-carboxamide (170 mg, crude) was obtained as a solid. MS (ESI) m/z 455.3 [M+H]+

Example 25. Synthesis of Viral Protease Inhibitor Compound 227

To a mixture of (2S)-2-amino-3-(1-methylimidazol-4-yl)propanoic acid (0.5 g, 2.96 mmol, 1 eq) was added HCl/MeOH (4 M, 7.39 mL, 10 eq) in one portion at 25° C. under N2. The mixture was stirred at 25° C. for 2 h. The reaction mixture was concentrated to get the product. Methyl (2S)-2-amino-3-(1-methylimidazol-4-yl)propanoate (0.6 g, crude, HCl) was obtained as a solid and used directly next step. MS (ESI) m/z 184.1 [M+H]+

To a mixture of N-[(1S)-1-[[(1S)-2-amino-1-[(1-methylimidazol-4-yl)methyl]-2-oxo-ethyl]carbamoyl]-3-methyl-butyl]-4-methoxy-1H-indole-2-carboxamide (80.00 mg, 176.01 umol, 1 eq) in DCM (1 mL) was added Burgess reagent (83.89 mg, 352.02 umol, 2 eq) in one portion at 25° C. under N2. The mixture was stirred at 25° C. for 12 h. The reaction mixture was added the water (0.3 mL) and stirred for 10 min. Then the reaction mixture was concentrated to get the crude product. The crude product was purified by prep-HPLC. N-[(1S)-1-[[(1S)-1-cyano-2-(1-methylimidazol-4-yl)ethyl]carbamoyl]-3-methyl-butyl]-4-methoxy-1H-indole-2-carboxamide (26.39 mg, 60.27 umol, 34.24% yield, 99.684% purity) was obtained as a solid. MS (ESI) m/z 437.2 [M+H]+

Example 26. Synthesis of Viral Protease Inhibitor Compound 231

To a mixture of (2S)-2-(tert-butoxycarbonylamino)-3-(3-pyridyl)propanoic acid (500 mg, 1.88 mmol, 1 eq) was added HCl/MeOH (4 M, 20.80 mL, 44.31 eq) in one portion at 25° C. under N2. The mixture was stirred at 25° C. and stirred for 12 h. Upon completion, the reaction mixture was concentrated to get methyl (2S)-2-amino-3-(3-pyridyl)propanoate (400 mg, crude, HCl) as an oil and used directly for the next step. MS (ESI) m/z 181.1 [M+H]+

To a mixture of methyl (2S)-2-amino-3-(3-pyridyl)propanoate (0.3 g, 1.66 mmol, 1 eq, HCl) and (2S)-2-[(4-methoxy-1H-indole-2-carbonyl)amino]-4-methyl-pentanoic acid (506.66 mg, 1.66 mmol, 1 eq), DIPEA (1.08 g, 8.32 mmol, 1.45 mL, 5 eq) in THF (0.6 mL) and DCM (0.6 mL) was added T3P (1.59 g, 2.50 mmol, 1.49 mL, 50% purity, 1.5 eq) at 0° C. under N2. The mixture was stirred at 25° C. for 12 h. Upon completion, the reaction mixture was added saturated sodium bicarbonate solution (10 mL) and extracted with DCM (10 mL*2) to get the organic phase. The organic phase was concentrated to get the crude product. The residue was purified by pulping with petroleum ether (20 mL) and filtered to get the filter cake as the product. Methyl (2S)-2-[[(2S)-2-[(4-methoxy-1H-indole-2-carbonyl)amino]-4-methyl-pentanoyl]amino]-3-(3-pyridyl)propanoate (0.4 g, crude) was obtained as a solid and used directly next step. MS (ESI) m/z 467.1 [M+H]+

To a mixture of N-[(1S)-1-[[(1S)-2-amino-2-oxo-1-(3-pyridylmethyl)ethyl]carbamoyl]-3-methyl-butyl]-4-methoxy-1H-indole-2-carboxamide (0.1 g, 221.48 umol, 1 eq) in DCM (1 mL) was added Burgess reagent (105.56 mg, 442.95 umol, 2 eq) in one portion at 25° C. under N2. The mixture was stirred at 25° C. for 12 h. The Burgess reagent (105.56 mg, 442.95 umol, 2 eq) was re-added into the above solution at 25° C. and the reaction mixture was stirred at 25° C. for 1 h. Upon completion, the reaction mixture was added the water (0.5 mL) and stirred for 10 min. Then the mixture was concentrated to get the crude product. The crude product was purified by pre-HPLC to give N-[(1S)-1-[[(1S)-1-cyano-2-(3-pyridyl)ethyl]carbamoyl]-3-methyl-butyl]-4-methoxy-1H-indole-2-carboxamide (23.18 mg, 52.94 umol, 23.90% yield, 99.009% purity) as a solid. MS (ESI) m/z 434.2 [M+H]+

Example 27. Synthesis of Viral Protease Inhibitor Compound 599

To a mixture of methyl 2-[[(2S)-2-[(4-methoxy-1H-indole-2-carbonyl)amino]-4-methyl-pentanoyl]amino]-3-(2-oxo-1H-quinolin-4-yl)propanoate (200.00 mg, 375.53 umol, 1 eq) was added NH3/MeOH (7 M, 10.00 mL, 186.41 eq) in one portion at 25° C. under N2. The mixture was stirred at 80° C. for 12 h. The reaction mixture was cooled to 25° C. and concentrated to get the product. N-[(1S)-1-[[2-amino-2-oxo-1-[(2-oxo-1H-quinolin-4-yl)methyl]ethyl]carbamoyl]-3-methyl-butyl]-4-methoxy-1H-indole-2-carboxamide (180 mg, 326.21 umol, 86.87% yield, 93.8% purity) was obtained as a solid and used directly next step. MS (ESI) m/z 518.2 [M+H]+

To a mixture of N-[(1S)-1-[[2-amino-2-oxo-1-[(2-oxo-1H-quinolin-4-yl)methyl]ethyl]carbamoyl]-3-methyl-butyl]-4-methoxy-1H-indole-2-carboxamide (90 mg, 173.89 umol, 1 eq) in DCM (5 mL) was added Burgess reagent (207.19 mg, 869.44 umol, 5 eq) in one portion at 25° C. under N2. The mixture was stirred at 25° C. for 12 h, and then concentrated to get the crude product.

To 2-amino-3-(2-oxo-1H-quinolin-4-yl)propanoic acid (400 mg, 1.72 mmol, 1 eq) was added HCl/MeOH (4 M, 4.31 mL, 10 eq) in one portion at 25° C. under N2. The mixture was stirred at 25° C. and stirred for 1 h. The reaction mixture was concentrated to get the product. Methyl 2-amino-3-(2-oxo-1H-quinolin-4-yl)propanoate (370 mg, crude, HCl) was obtained as a solid and used directly next step.

Example 28. Synthesis of Viral Protease Inhibitor Compound 249

To a solution of 2-amino-3-(2-oxo-1H-quinolin-4-yl)propanoic acid (200 mg, 861.20 umol, 1 eq) in H2O (1 mL) was added Pd/C (20 mg, 861.20 umol, 10% purity) at 25° C. under N2. The suspension was degassed under vacuum and purged with H2several times. The mixture was stirred under H2(861.20 umol) (15 psi) at 70° C. for 5 h. The reaction mixture was cooled to 25° C. and filtered to get the filtrate. The filtrate was concentrated to get the product. 2-amino-3-(2-oxo-3,4-dihydro-1H-quinolin-4-yl)propanoic acid (200 mg, crude) was obtained as a solid and used directly next step. MS (ESI) m/z 235.0 [M+H]+

To 2-amino-3-(2-oxo-3,4-dihydro-1H-quinolin-4-yl)propanoic acid (200 mg, 853.79 umol, 1 eq) was added HCl/MeOH (4 M, 9.91 mL, 46.45 eq) in one portion at 25° C. under N2. The mixture was stirred at 25° C. for 12 h. The reaction mixture was concentrated to get the crude product. Methyl 2-amino-3-(2-oxo-3,4-dihydro-1H-quinolin-4-yl)propanoate (260 mg, crude, HCl) was obtained as the yellow oil and used directly next step. MS (ESI) m/z 249.1 [M+H]+

To a mixture of methyl 2-[[(2S)-2-[(4-methoxy-1H-indole-2-carbonyl)amino]-4-methyl-pentanoyl]amino]-3-(2-oxo-3,4-dihydro-1H-quinolin-4-yl)propanoate (55 mg, 102.88 umol, 1 eq) was added NH3/MeOH (7 M, 1.83 mL, 124.74 eq) in one portion at 25° C. under N2. The mixture was stirred at 80° C. for 12 h. The reaction mixture was cooled to the 25° C. and concentrated to get the product. N-[(1S)-1-[[2-amino-2-oxo-1-[(2-oxo-3,4-dihydro-1H-quinolin-4-yl)methyl]ethyl]carbamoyl]-3-methyl-butyl]-4-methoxy-1H-indole-2-carboxamide (55 mg, crude) was obtained as a solid and used directly next step. MS (ESI) m/z 518.2 [M+H]+

To a mixture of N-[(1S)-1-[[2-amino-2-oxo-1-[(2-oxo-3,4-dihydro-1H-quinolin-4-yl)methyl]ethyl]carbamoyl]-3-methyl-butyl]-4-methoxy-1H-indole-2-carboxamide (75 mg, 144.34 umol, 1 eq) in DCM (0.1 mL) was added Burgess reagent (103.19 mg, 433.03 umol, 3 eq) in one portion at 25° C. under N2. The mixture was stirred at 25° C. and stirred for 16 h. The reaction mixture was added with water (0.5 mL) and stirred for 10 min. Then the mixture was concentrated to get the crude product. The crude product was purified by pre-HPLC. N-[(1S)-1-[[1-cyano-2-(2-oxo-3,4-dihydro-1H-quinolin-4-yl)ethyl]carbamoyl]-3-methyl-butyl]-4-methoxy-1H-indole-2-carboxamide (26.51 mg, 52.85 umol, 36.62% yield, 100% purity) was obtained as a solid. MS (ESI) m/z 502.2 [M+H]+

Example 29. Synthesis of Viral Protease Inhibitor Compound 600

A mixture of 2-amino-3-(2-oxo-1H-pyridin-3-yl)propanoic acid (500 mg, 2.74 mmol, 1 eq) and HCl/MeOH (4 M, 30 mL, 43.72 eq) was stirred at 25° C. for 2 h. The reaction mixture was concentrated under reduced pressure to give a product methyl 2-amino-3-(2-oxo-1,2-dihydropyridin-3-yl)propanoate (650 mg, crude, HCl) as a yellow oil and used directly for next step. MS (ESI) m/z 197.0 [M+H]+

A mixture of methyl-2-((S)-2-((tert-butoxycarbonyl)amino)-4-methylpentanamido)-3-(2-oxo-1,2-dihydropyridin-3-yl)propanoate (200 mg, 488.43 umol, 1 eq) and HCl/EtOAc (4 M, 30 mL) was stirred at 27° C. for 0.5 h. The reaction mixture was concentrated under reduced pressure to give a product methyl 2-((S)-2-amino-4-methylpentanamido)-3-(2-oxo-1,2-dihydropyridin-3-yl)propanoate (170 mg, crude, HCl) as a solid and used directly for next step.

Example 30. Synthesis of Viral Protease Inhibitor Compounds 344C, 344D, 507 and 511

Step for Compound 344C: N-[(1S)-1-[[(1S)-2-amino-2-cyano-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]ethyl]carbamoyl]-3-methyl-butyl]-4-methoxy-1H-indole-2-carboxamide

To a mixture of N-[(1S)-1-[[(1S)-1-formyl-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]carbamoyl]-3-methyl-butyl]-4-methoxy-1H-indole-2-carboxamide (100 mg, 180.79 umol, 80% purity, 1 eq) in DCM (10 mL) was added NH3·H2O (46.93 mg, 361.58 umol, 51.57 uL, 27% purity, 2 eq) and NH4Cl (19.34 mg, 361.58 umol, 2 eq). The mixture was stirred at 25° C. for 30 min, then added KCN (94.18 mg, 1.45 mmol, 61.96 uL) in H2O (0.2 mL), the mixture was stirred at 30° C. for 16 h. Once the reaction was completed, the reaction mixture was then quenched by addition H2O (10 mL) at 0° C., and then diluted with H2O (10 mL) and extracted with EtOAc (30 mL*2). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The liquid water was added with NaOH to adjust pH=9, quenched with aq NaCl, and then added with NaOH to adjust pH>14. The residue was purified by HCl prep-HPLC to get the compound N-[(1S)-1-[[(1S)-2-amino-2-cyano-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]ethyl]carbamoyl]-3-methyl-butyl]-4-methoxy-1H-indole-2-carboxamide (50 mg, 103.83 umol, 57.43% yield, 97.3% purity) as a solid. MS (ESI) m/z 469.2 [M+H]+

Step for Compound 511: N-[(1S)-1-[[(1S)-2-cyano-2-(ethylamino)-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]ethyl]carbamoyl]-3-methyl-butyl]-4-methoxy-1H-indole-2-carboxamide

Step for Compound 507: N-[(1S)-1-[[(1S)-2-(benzylamino)-2-cyano-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]ethyl]carbamoyl]-3-methyl-butyl]-4-methoxy-1H-indole-2-carboxamide

Example 31. Synthesis of Viral Protease Inhibitor Compound 129

To a solution of pyridine-3,4-diamine (2 g, 18.33 mmol, 1 eq) in AcOH (25 mL) was added methyl 2,2,2-trichloroethanimidate (3.88 g, 21.99 mmol, 2.71 mL, 1.2 eq). The solution was stirred for 5 h at 100° C. The reaction was added with H2O (90 mL) and extracted with ethyl acetate (70 mL*3) and washed with NaHCO3(90 mL*2). The organic layer was cautiously concentrated to give crude 2-(trichloromethyl)-3H-imidazo[4,5-c]pyridine (800 mg, crude) was obtained as a yellow solid. The crude was used directly for the next step. MS (ESI) m/z 235.9 [M+H]+

Example 32. Synthesis of Viral Protease Inhibitor Compound 389A and 389B

A solution of 2-tert-butoxycarbonyl-2-azaspiro[4.5]decane-3-carboxylic acid (3 g, 10.59 mmol, 1 eq) in HCl/MeOH (4 M, 50 mL, 18.89 eq) was stirred at 80° C. for 2 h. The mixture was concentrated under the reduced pressure to afford the product methyl 2-azaspiro[4.5]decane-3-carboxylate (2 g, crude) as a yellow oil.

To a solution of methyl 2-(4-methoxy-1H-indole-2-carbonyl)-2-azaspiro[4.5]decane-3-carboxylate (3 g, 8.10 mmol, 1 eq) in THF (45 mL) and H2O (15 mL) was added LiOH·H2O (1.70 g, 40.49 mmol, 5 eq). The mixture was stirred at 25° C. for 12 h. Upon completion, the mixture was quenched by addition H2O (50 mL), and then added aq. HCl (1 M) to adjust the pH=3-4, and then extracted with ethyl acetate (50 mL*3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure affording the product 2-(4-methoxy-1H-indole-2-carbonyl)-2-azaspiro[4.5]decane-3-carboxylic acid (2.6 g, crude) as a white solid. MS (ESI) m/z 357.1 [M+H]+

Example 33. Synthesis of Viral Protease Inhibitor Compound 399

Example 34. Synthesis of Viral Protease Inhibitor Compound 405

A solution of methyl (2S)-2-[[(2S)-2-(tert-butoxycarbonylamino)-4,4-dimethyl-pentanoyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (440 mg, 1.06 mmol, 1 eq) in HCl/MeOH (10 mL) was stirred for 1 h at 25° C. TLC (DCM:MeOH=10:1). The reaction was cautiously concentrated to give crude. Compound methyl (2S)-2-[[(2S)-2-amino-4,4-dimethyl-pentanoyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (310 mg, crude) as a solid used directly for the next step. MS (ESI) m/z 314.3 [M+H]+

Example 35. Synthesis of Viral Protease Inhibitor Compound 491 and 491A

Example 36. Synthesis of Viral Protease Inhibitor Compound 531

Example 37. Synthesis of Viral Protease Inhibitor Compound 635

To a solution of benzyl N-[(1S)-2-[[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxo-3-piperidyl]methyl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-ethyl]carbamate (400 mg, 0.92 mmol, 1 eq) in MeOH (5 mL) was added Pd (200 mg, 10% purity) and H2(0.92 mmol). The mixture was stirred at 25° C. under 15 psi for 1 hr. The mixture was filtered to give the filter liquor. The mixture was concentrated under reduce pressure to give compound (2S)-2-amino-N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxo-3-piperidyl]methyl]ethyl]-3-cyclopropyl-propanamide (274 mg, 0.92 mmol, 99.5% yield) as a solid.

Example 38. Synthesis of Viral Protease Inhibitor Compound 637

To a solution of NaOH (0.8 g, 20.0 mmol, 20.2 eq) in H2O (10 mL) was added 4,7-dichloro-2-(trichloromethyl)-1H-benzo[d]imidazole (0.3 g, 985.58 umol, 1 eq) at 0° C. The mixture was stirred at 25° C. for 1 hr. The pH of the mixture was adjusted with HCl (2 M) to pH=2-3 and then the mixture was filtered to give 4,7-dichloro-1H-benzo[d]imidazole-2-carboxylic acid (0.2 g, crude) as a solid.

Example 39. Synthesis of Viral Protease Inhibitor Compound 639 and 639A

Example 40. Synthesis of Viral Protease Inhibitor Compound 643

Example 41. Synthesis of Viral Protease Inhibitor Compound 681

Example 42. Synthesis of Viral Protease Inhibitor Compound 721

Example 43. Synthesis of Viral Protease Inhibitor Compound 133

A solution of 3-chlorobenzene-1,2-diamine (500 mg, 3.51 mmol, 1 eq) in AcOH (9 mL) was added drop-wise methyl 2,2,2-trichloroethanimidate (619.29 mg, 3.51 mmol, 433.07 uL, 1 eq), and the mixture was stirred at 25° C. for 2 h. The reaction mixture was quenched with H2O 10 mL at 0° C., and the resultant precipitate was collected. The solid was washed with H2O (2*10 mL) and dried under vacuum to get the product 7-chloro-1H-benzimidazole-2-carboxylic acid (500 mg, crude) was obtained as a solid. MS (ESI) m/z 195.1 [M−H]+

To a solution of methyl (2S)-2-[[(2S)-2-(tert-butoxycarbonylamino)-4-methyl-pentanoyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (300 mg, 750.98 umol, 1 eq) in EtOAc (2 mL) was added drop-wise HCl/EtOAc (4 M, 20 mL, 106.53 eq), and the mixture was stirred at 25° C. for 1 h. The reaction mixture was concentrated under reduced pressure to get a product methyl (2S)-2-[[(2S)-2-amino-4-methyl-pentanoyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (250 mg, crude, HCl) was obtained as a solid.

Example 44. Synthesis of Viral Protease Inhibitor Compound 145

To a mixture of 2-methoxy-6-nitro-aniline (1 g, 5.95 mmol, 1.00 mL, 1 eq) in EtOH (12 mL) and H2O (4 mL) was added NH4C1(1.59 g, 29.74 mmol, 5 eq) in one portion at 25° C., and then the reaction was heated to 80° C. Fe (1.66 g, 29.74 mmol, 5 eq) was added and stirred for 2 hours at 80° C. The reaction mixture was filtered and concentrated under reduced pressure to give a residue, and then diluted with H2O (10 mL) and extracted with ethyl acetate 30 mL (10 mL*3). The combined organic layers were washed with brine 20 mL (20 mL*1), dried over Na2SO4, and filtered and concentrated under reduced pressure to give 3-methoxybenzene-1,2-diamine (770 mg, 5.02 mmol, 84.34% yield, 90% purity) as a black oil. MS (ESI) m/z 139.1 [M+H]+

Example 45. Synthesis of Viral Protease Inhibitor Compound 163

Example 46. Synthesis of Viral Protease Inhibitor Compound 191

A mixture of methyl (2S)-2-(tert-butoxycarbonylamino)-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (500 mg, 1.75 mmol, 1 eq) in HCl/MeOH (4 M, 7 mL, 16.03 eq) was stirred at 25° C. for 1 h. Upon completion, the mixture was concentrated under reduced pressure to give a residue, and then the residue was dissolved with DCM (10 mL*3). The resultant was concentrated under reduced pressure to get afford methyl (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (320 mg, crude) as a white oil. MS (ESI) m/z 187.2 [M+H]+.

A mixture of methyl (2S)-2-[[(2S)-2-(tert-butoxycarbonylamino)-3-(3-pyridyl)propanoyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (450 mg, 1.04 mmol, 1 eq) in HCl/MeOH (4 M, 6 mL, 23.17 eq) was stirred at 25° C. for 1 h. Upon completion, the mixture was concentrated under reduced pressure to give a residue, was dissolved with DCM (10 mL*3) and concentrated under reduced pressure to get the product methyl (2S)-2-[[(2S)-2-amino-3-(3-pyridyl)propanoyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (340 mg, crude) as white oil. MS (ESI) m/z 335.1 [M+H]+.

Example 47. Synthesis of Viral Protease Inhibitor Compound 213

Methyl (2S)-2-(tert-butoxycarbonylamino)-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (501 mg, 1.75 mmol, 1 eq) in HCl/EtOAc (4 M, 10.02 mL, 22.91 eq) was stirred at 25° C. for 1 h. Upon completion, the solution was concentrated to remove the HCl/EA. The crude was used to next step directly and without further purification. Methyl (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (300 mg, crude) was obtained as yellow oil.

Benzyl (3S)-2-[(E)-3-(4-chloro-2-fluoro-phenyl)prop-2-enoyl]-3-[[(1S)-2-methoxy-2-oxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]ethyl]carbamoyl]hexahydropyridazine-1-carboxylate (160 mg, 260.14 umol, 1 eq) in TFA (5 mL) was stirred at 75° C. for 1 h. Upon completion, the solution was concentrated to remove the TFA, diluted with the solution of NaHCO3, and extracted with ethyl acetate (20 mL*3). The combined organic phase was dried over Na2SO4, filtered and concentrated to give the crude. The crude was used to next step directly and without further purification. Methyl (2S)-2-[[(3S)-2-[(E)-3-(4-chloro-2-fluoro-phenyl) prop-2-enoyl]hexahydropyridazine-3-carbonyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (80 mg, crude) was obtained as yellow solid. MS (ESI) m/z 481.0 [M+H]+.

Methyl (2S)-2-[[(3S)-2-[(E)-3-(4-chloro-2-fluoro-phenyl)prop-2-enoyl]hexahydropyridazine-3-carbonyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (80 mg, 166.35 umol, 1 eq) in ammonia (7 M, 4.00 mL, 168.32 eq) was stirred at 80° C. for 17 h. Upon completion, the solution was concentrated to remove the MeOH. The crude was used for the next step directly and without further purification. (3S)-N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]ethyl]-2-[(E)-3-(4-chloro-2-fluoro-phenyl) prop-2-enoyl]hexahydropyridazine-3-carboxamide (75 mg, crude) was obtained as yellow oil. MS (ESI) m/z 481.0 [M+H]+.

To a solution of (E)-3-(4-chloro-2-fluoro-phenyl)prop-2-enoic acid (120 mg, 598.22 umol, 1 eq) in DCM (0.5 mL) was added the DMF (437.26 ug, 5.98 umol, 0.46 uL, 0.01 eq), and the reaction was cooled to 0° C. (COCl)2(151.86 mg, 1.20 mmol, 104.73 uL, 2 eq) was added and the solution was stirred at 25° C. for 1 h. Upon completion, the solution was concentrated to remove the DCM and give the crude. The crude was used to next step directly and without further purification. (E)-3-(4-chloro-2-fluoro-phenyl)prop-2-enoyl chloride (125 mg, crude) was obtained as white solid.

Example 48. Synthesis of Viral Protease Inhibitor Compound 203

Example 49. Synthesis of Viral Protease Inhibitor Compound 223

To methyl (2S)-3-(1H-imidazol-5-yl)-2-[[(2S)-2-[(4-methoxy-1H-indole-2-carbonyl)amino]-4-methyl-pentanoyl]amino]propanoate (200 mg, 439.07 umol, 1 eq) was added NH3/MeOH (7 M, 11.76 mL, 187.56 eq) in one portion at 25° C. under N2. The mixture was stirred at 80° C. and stirred for 12 h. The reaction mixture was cooled to 25° C. and concentrated to get the crude product. N-[(1S)-1-[[(1S)-2-amino-1-(1H-imidazol-5-ylmethyl)-2-oxo-ethyl]carbamoyl]-3-methyl-butyl]-4-methoxy-1H-indole-2-carboxamide (170 mg, 378.83 umol, 86.28% yield, 98.16% purity) was obtained as the light yellow solid and used directly next step. MS (ESI) m/z 441.2 [M+H]+

Example 50. Synthesis of Viral Protease Inhibitor Compound 237

To 2-amino-3-(2-oxo-1H-quinolin-4-yl)propanoic acid (400 mg, 1.72 mmol, 1 eq) was added HCl/MeOH (4 M, 4.31 mL, 10 eq) in one portion at 25° C. under N2. The mixture was stirred at 25° C. and stirred for 1 h. The reaction mixture was concentrated to get the product. Methyl 2-amino-3-(2-oxo-1H-quinolin-4-yl)propanoate (370 mg, crude, HCl) was obtained as the white solid and used directly next step.

Example 51. Synthesis of Viral Protease Inhibitor Compound 241

To 2-amino-3-(1H-pyrazol-3-yl)propanoic acid (0.5 g, 2.19 mmol, 1 eq, 2HCl) was added HCl/MeOH (4 M, 17.01 mL, 31.03 eq) in one portion at 25° C. under N2. The mixture was stirred at 25° C. for 12 h. The reaction mixture was concentrated to get the crude product. Methyl 2-amino-3-(1H-pyrazol-3-yl)propanoate (530 mg, crude, 2HCl) was obtained as the yellow solid and used directly next step. MS (ESI) m/z 170.1 [M+H]+

To a mixture of methyl 2-[[(2S)-2-[(4-methoxy-1H-indole-2-carbonyl)amino]-4-methyl-pentanoyl]amino]-3-(1H-pyrazol-3-yl)propanoate (100 mg, 219.54 umol, 1 eq) was added NH3/MeOH (7 M, 3.33 mL, 106.28 eq) in one portion at 25° C. under N2. The mixture was stirred at 80° C. for 12 h. The reaction mixture was cooled to 25° C. and concentrated to get the product. N-[(1S)-1-[[2-amino-2-oxo-1-(1H-pyrazol-3-ylmethyl)ethyl]carbamoyl]-3-methyl-butyl]-4-methoxy-1H-indole-2-carboxamide (95 mg, crude) was obtained as the light yellow solid and used directly next step. MS (ESI) m/z 441.2 [M+H]+

Example 52. Synthesis of Viral Protease Inhibitor Compound 245

To a mixture of 2-amino-3-(1H-indazol-3-yl) propanoic acid (200 mg, 827.56 umol, 1 eq, HCl) was added HCl/MeOH (4 M, 2 mL, 9.67 eq) at 25° C. under N2. The mixture was stirred at 25° C. for 12 h. The reaction mixture was concentrated to get the crude product. Methyl 2-amino-3-(1H-indazol-3-yl) propanoate (200 mg, crude, HCl) was obtained as the light yellow solid and used directly next step. MS (ESI) m/z 220.1 [M+H]+

To a mixture of methyl 2-[[(2S)-2-(tert-butoxycarbonylamino)-4-methyl-pentanoyl]amino]-3-(1H-indazol-3-yl)propanoate (180 mg, 416.17 umol, 1 eq) was added HCl/MeOH (4 M, 5.14 mL, 49.43 eq) in one portion at 25° C. under N2. The mixture was stirred at 25° C. for 2 h. The reaction mixture was concentrated to afford methyl 2-[[(2S)-2-amino-4-methyl-pentanoyl]amino]-3-(1H-indazol-3-yl) propanoate (160 mg, crude, HCl) as light yellow oil and used directly next step. MS (ESI) m/z 333.2 [M+H]+

To a mixture of methyl 3-(1H-indazol-3-yl)-2-[[(2S)-2-[(4-methoxy-1H-indole-2-carbonyl)amino]-4-methyl-pentanoyl]amino]propanoate (80 mg, 158.24 umol, 1 eq) was added NH3/MeOH (7 M, 1 mL, 44.24 eq) in one portion at 25° C. under N2. The mixture was stirred at 80° C. for 12 h. The reaction mixture was cooled to 25° C. and concentrated. N-[(1S)-1-[4[1-(1H-indazol-3-ylmethyl)-2-nitroso-ethyl]carbamoyl]-3-methyl-butyl]-4-methoxy-1H-indole-2-carboxamide (75 mg, crude) was obtained as light yellow solid and used directly next step. MS (ESI) m/z 491.2 [M+H]+

Example 53. Synthesis of Viral Protease Inhibitor Compound 1045

To a mixture of N-[(1S)-2-[[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-ethyl]-4-propoxy-1H-indole-2-carboxamide (380 mg, 785.84 umol, 1 eq) in DCM (7 mL) was added Burgess reagent (1.12 g, 4.72 mmol, 6 eq) in one portion at 25° C. The mixture was stirred at 25° C. for 4 h. The reaction mixture was concentrated under reduced pressure to give a residue. The crude product was purified by prep-HPLC (neutral condition) to give N-[(1S)-2-[[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-ethyl]-4-propoxy-1H-indole-2-carboxamide (120 mg, 257.76 umol, 32.80% yield) was obtained as a white solid. MS (ESI) m/z 466.3 [M+H]+

Example 54. Synthesis of Viral Protease Inhibitor Compound 147

Example 55. Synthesis of Viral Protease Inhibitor Compound 491

A mixture of methyl (2S)-2-[[(2S)-3-cyclopropyl-2-[(4-methoxy-1H-indole-2-carbonyl)amino]propanoyl]amino]-3-[(3S)-2-oxo-3-piperidyl]propanoate (246.3 mg, 0.47 mmol, 92.5% purity, 1 eq) in NH3(7 M, 6.72 mL, 100 eq) (7M in MeOH) was stirred at 80° C. for 36 h in a sealed tube. LC-MS showed the desired compound was detected. The reaction mixture was concentrated in vacuum. Compound N-[(1S)-2-[[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxo-3-piperidyl]methyl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-ethyl]-4-methoxy-1H-indole-2-carboxamide (220 mg, crude) was obtained as yellow solid, which was used into the next step without further purification.

Example 56. Synthesis of Viral Protease Inhibitor Compound 247

Example 57. Synthesis of Viral Protease Inhibitor Compound 331

Steps for Isomer 1 and 2: N-[(1S)-1-[[(1S)-2-cyano-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]-2-pyrrolidin-1-yl-ethyl]carbamoyl]-3-methyl-butyl]-4-methoxy-1H-indole-2-carboxamide

Example 58. Synthesis of Viral Protease Inhibitor Compound 389

To a solution of methyl 2-(4-methoxy-1H-indole-2-carbonyl)-2-azaspiro[4.5]decane-3-carboxylate (3 g, 8.10 mmol, 1 eq) in THF (45 mL) and H2O (15 mL) was added LiOH·H2O (1.70 g, 40.49 mmol, 5 eq). The mixture was stirred at 25° C. for 12 h. Upon completion, the mixture was quenched by addition H2O (50 mL), and then added aq. HCl (1 M) to adjust the pH=3-4, and extracted with ethyl acetate (50 mL*3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure affording the product 2-(4-methoxy-1H-indole-2-carbonyl)-2-azaspiro[4.5]decane-3-carboxylic acid (2.6 g, crude) as a white solid. MS (ESI) m/z 357.1 [M+H]+

Example 59. Synthesis of Viral Protease Inhibitor Compound 513

A mixture of O1-tert-butyl O2-methyl 4-methoxyindoline-1,2-dicarboxylate (200 mg, 650.74 umol, 1 eq) in THF (1 mL) and H2O (1 mL) was added LiOH (46.75 mg, 1.95 mmol, 3 eq) in one portion at 25° C. The mixture was stirred at 25° C. for 16 h. The reaction mixture was adjusted to acidity by HCl solution and extracted with ethyl acetate (2 mL*3). The combined organic layers were washed with brine (5 mL*1), dried over Na2SO4, filtered and concentrated under reduced pressure to give 1-tert-butoxycarbonyl-4-methoxy-indoline-2-carboxylic acid (175 mg, 596.63 umol, 45.84% yield) as a yellow oil. MS (ESI) m/z 237.9 [M+H-56]+

To a mixture of 1-tert-butoxycarbonyl-4-methoxy-indoline-2-carboxylic acid (150 mg, 511.40 umol, 1 eq) was added HCl/dioxane (4 M, 7.50 mL, 58.66 eq). The reaction was stirred at 25° C. for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue and used next step directly to get the compound 4-methoxyindoline-2-carboxylic acid (110 mg, 431.07 umol, 84.29% yield, 90% purity, HCl) as yellow oil. MS (ESI) m/z 194.1 [M+H]+

Example 60. Synthesis of Viral Protease Inhibitor Compound 515

To a mixture of 4-methoxy-1H-indole-2-carboxylic acid (500 mg, 2.62 mmol, 1 eq) in DCM (10 mL) was added BBr3(1.31 g, 5.23 mmol, 2 eq) at 0° C. The mixture was stirred at 25° C. for 16 h. The mixture was diluted with H2O (30 mL) and extracted with DCM (30 mL*2). The combined organic layers were washed with brine 20 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give 4-hydroxy-1H-indole-2-carboxylic acid (200 mg, crude) as a red solid. MS (ESI) m/z 176.1 [M−H]+

Example 61. Synthesis of Viral Protease Inhibitor Compound 525

A mixture of 4,6-dichloro-2-(trichloromethyl)-1H-benzimidazole (420 mg, 1.38 mmol, 1 eq) in MeOH (5 mL) was added Na2CO3(146.25 mg, 1.38 mmol, 1 eq) in one portion at 25° C. The mixture was heated to 70° C. and stirred for 14 hours. Upon completion, the reaction mixture was diluted with HCl (10 mL) and stirred at 25° C. for 1 h and extracted with ethyl acetate (8 mL*3). The combined organic layers were washed with brine (10 mL*1), dried over Na2SO4, filtered and concentrated under reduced pressure to give methyl 4,6-dichloro-1H-benzimidazole-2-carboxylate (330 mg, 1.35 mmol, 97.59% yield) as a brown solid. MS (ESI) m/z 245.0 [M+H]+

To a mixture of methyl 4,6-dichloro-1H-benzimidazole-2-carboxylate (330 mg, 1.35 mmol, 1 eq) in THF (2 mL) and H2O (2 mL) was added NaOH (161.58 mg, 4.04 mmol, 3 eq) in one portion at 25° C. The mixture was stirred at 25° C. for 3 h. Upon completion, the reaction mixture was adjusted to acidity with 1M HCl solution (5 mL), and then extracted with ethyl acetate (5 mL*3). The combined organic layers were washed with brine (10 mL*1), dried over Na2SO4, filtered and concentrated under reduced pressure to give 4,6-dichloro-1H-benzimidazole-2-carboxylic acid (200 mg, 865.67 umol, 64.29% yield) as a brown solid. MS (ESI) m/z 229.0 [M−H]+

Example 62. Synthesis of Viral Protease Inhibitor Compound 529

To a mixture of methyl(2S)-2-[[(2S)-2-[(6-chloro-1H-indole-2-carbonyl)amino]-3-cyclopropyl-propanoyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (900 mg, 1.89 mmol, 1 eq) in NH3/MeOH (7 M, 10 mL, 94.99 eq) in one portion at 25° C. The mixture was stirred at 80° C. for 16 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give a residue. Compound N-[(1S)-2-[[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-ethyl]-6-chloro-1H-indole-2-carboxamide (750 mg, crude) was obtained as a white solid and was used fort the next step directly. MS (ESI) m/z 460.1 [M+H]+.

Example 63. Synthesis of Viral Protease Inhibitor Compound 539

Example 64. Synthesis of Viral Protease Inhibitor Compound 547

Example 65. Synthesis of Viral Protease Inhibitor Compound 549

To a mixture of methyl (2S)-2-[[(2S,4R)-1-(4-methoxy-1H-indole-2-carbonyl)-4-(trifluoromethyl)pyrrolidine-2-carbonyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (250 mg, 476.65 umol, 1 eq) was added NH3/MeOH (7 M, 3 mL, 44.06 eq) in one portion at 25° C. under N2. The mixture was stirred at 80° C. for 12 h. Upon completion, the reaction mixture was cooled to 25° C. and concentrated to get the crude product. The crude product was purified by prep-TLC (dichloromethane:methanol=10:1, Rf=0.3) to afford (2S,4R)-1-(4-methoxy-1H-indole-2-carbonyl)-N-[(1S)-1-(nitrosomethyl)-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-4-(trifluoromethyl)pyrrolidine-2-carboxamide (130 mg, 247.51 umol, 51.93% yield, 97% purity) as a light yellow solid. MS (ESI) m/z 510.2 [M+H]+.

Example 66. Synthesis of Viral Protease Inhibitor Compound 557

A mixture of methyl (2S)-2-(tert-butoxycarbonylamino)-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (500 mg, 1.75 mmol, 1 eq) in HCl/dioxane (4 M, 8.73 mL, 20 eq) was degassed and purged with N2for 3 times, and then the mixture was stirred at 20° C. for 0.5 h under N2atmosphere. Upon completion, the reaction mixture was concentrated under reduced pressure to get the product methyl (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (630 mg, crude, HCl) as a yellow oil. MS (ESI) m/z 223.2 [M+H]+.

A mixture of tert-butyl 1-[[(1S)-2-methoxy-2-oxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]ethyl]carbamoyl]isoindoline-2-carboxylate (720 mg, 1.67 mmol, 1 eq) in HCl/dioxane (4 M, 8.34 mL, 20 eq) was degassed and purged with N2for 3 times, and then the mixture was stirred at 20° C. for 0.5 h under N2atmosphere. Upon completion, the reaction mixture was concentrated under reduced pressure to get the product methyl (2S)-2-(isoindoline-1-carbonylamino)-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (770 mg, crude, HCl) as a brown oil. MS (ESI) m/z 332.3[M+H]+.

Example 67. Synthesis of Viral Protease Inhibitor Compound 647

A mixture of methyl 2S)-2-[[(2S)-2-(tert-butoxycarbonylamino)-3-cyclopropyl-propanoyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (1.3 g, 3.27 mmol, 1 eq) in HCl/MeOH (15 mL) was stirred at 25° C. for 30 min. Upon completion, the reaction mixture was concentrated under reduced pressure to give methyl (2S)-2-[[(2S)-2-amino-3-cyclopropyl-propanoyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (1.3 g, crude) as a white solid.

Example 68. Synthesis of Viral Protease Inhibitor Compound 649

A mixture of methyl (2S)-2-[[(2S)-2-amino-3-cyclopropyl-propanoyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (288 mg, 968.56 umol, 1 eq) in DCM (5 mL) and DMF (2.5 mL) was added DMAP (354.98 mg, 2.91 mmol, 3 eq) and the mixture was added with 3-(3,5-difluorophenyl)propanoic acid (180.30 mg, 968.56 umol, 1 eq) and EDCI (928.37 mg, 4.84 mmol, 5 eq) in one portion at 25° C. The mixture was stirred at 25° C. for 2 h. Upon completion, the reaction mixture was diluted with H2O (5 mL) and extracted with ethyl acetate (8 mL*3). The combined organic layers were washed with brine (15 mL*1), dried over with Na2SO4, filtered and concentrated under reduced pressure to give the crude product The crude was purified by column chromatography (SiO2, petroleum ether/ethyl acetate=5/1 to ethyl acetate/methanol=5:1) to give methyl (2S)-2-[[(2S)-3-cyclopropyl-2-[3-(3,5-difluorophenyl)propanoylamino]propanoyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (300 mg, 547.81 umol, 56.56% yield, 85% purity) as a white solid. MS (ESI) m/z 466.2 [M+H]+.

Example 69. Synthesis of Viral Protease Inhibitor Compound 653

Example 70. Synthesis of Viral Protease Inhibitor Compound 655

To a solution of (2S,4R)-di-tert-butyl 4-hydroxypyrrolidine-1,2-dicarboxylate (4 g, 13.92 mmol, 1 eq) in DCM (40 mL) was added CBr4(14.08 g, 42.46 mmol, 3.05 eq) at 25° C. The mixture was cooled to 0° C., and PPh3(11.32 g, 43.15 mmol, 3.1 eq) was added carefully. The reaction was stirred at 25° C. for 15 h. Upon completion, ethanol (4 mL) was added, and the solution was stirred for 2 h. MTBE (40 mL) was added dropwise to precipitate the phosphine oxide, which was filtered off, the filter cake was washed with DCM (30 mL*2), and the filtrate was concentrated under reduced pressure to give a brown oil. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate=100:0 to 10:1) to give (2S,4S)-di-tert-butyl 4-bromopyrrolidine-1,2-dicarboxylate (1.5 g, 4.07 mmol, 29.23% yield, 95% purity) as light yellow oil.

A mixture of phenylsulfanylcopper (1.58 g, 9.14 mmol, 6.4 eq) in dry THF (30 mL) was cooled to −70° C., and then treated with careful addition of t-BuLi (1.3 M, 7.03 mL, 6.4 eq). The resulting mixture was stirred for 30 min, and a precooled (−20° C.) solution of (2S,4S)-di-tert-butyl 4-bromopyrrolidine-1,2-dicarboxylate (500 mg, 1.43 mmol, 1 eq) in dry THF (5 mL) was added. The reaction was stirred at −70° C. for 5 h, and then warmed to 25° C. for 15 h under N2. Upon completion, the reaction was quenched by pouring into a solution of saturated aqueous NH4Cl (30 mL). The aqueous mixture was stirred vigorously for 30 min. Solids were filtered off, and the phases were separated. The aqueous phase was extracted with MTBE (10 mL*3), and the combined organic phases were washed with saturated aqueous NaHCO3(10 mL) and brine (10 mL), dried over Na2SO4, concentrated under reduced pressure to give a crude. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate=100:0 to 10:1) to give (2S,4S)-di-tert-butyl 4-(tert-butyl)pyrrolidine-1,2-dicarboxylate (290 mg, 797.05 umol, 55.83% yield, 90% purity) as an off-white solid.

Example 71. Synthesis of Viral Protease Inhibitor Compound 659

To a solution of (2S)-2-(tert-butoxycarbonylamino)-4,4-dimethyl-pentanoic acid (5 g, 20.38 mmol, 1 eq) in THF (100 mL) at 0° C., BH3-Me2S (10 M, 4.08 mL, 2.0 eq) was added drop-wise slowly, then the mixture was stirred at 20° C. for 15 h. The reaction mixture was added into MeOH (40 mL) and stirred for 20 min, then the mixture was concentrated. The residue was diluted with aq. NaHCO3(150 mL) and extracted with DCM (100 mL*3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate=1:0 to 1:1) to afford tert-butyl N-[(1S)-1-(hydroxymethyl)-3,3-dimethyl-butyl]carbamate (2.5 g, 10.81 mmol, 53.02% yield) as a colorless oil.

To a solution of tert-butyl N-[(1S)-1-(hydroxymethyl)-3,3-dimethyl-butyl]carbamate (2.4 g, 10.37 mmol, 1 eq) in DCM (40 mL) was added periodinane (5.72 g, 13.49 mmol, 4.18 mL, 1.3 eq) via Dess-martin at 0° C., and the reaction was stirred for 1 h. The mixture was warm to 20° C. and stirred for 1 h. The reaction mixture was quenched by addition H2O (60 mL) at 0° C., and then added drop-wise aq. NaHCO3to pH=8 at 0° C., and extracted with EtOAc (40 mL*3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate=0:1 to 1:1) to afford tert-butyl N-[(1S)-1-formyl-3,3-dimethyl-butyl]carbamate (1.6 g, 6.98 mmol, 67.25% yield) as a colorless oil.

The reaction mixture was quenched by addition aq. NaHCO3(100 mL) at 0° C. and stirred for 0.5 h, then extracted with DCM (60 mL*3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate=0:1 to 1:3) to get the product methyl (2S)-2-[[(2S)-2-(tert-butoxycarbonylamino)-4,4-dimethyl-pentyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (450 mg, 1.13 mmol, 32.29% yield) as a white solid. MS (ESI) m/z 400.3 [M+H]+.

Example 72. Synthesis of Viral Protease Inhibitor Compound 671

Example 73. Synthesis of Viral Protease Inhibitor Compound 691

Example 74. Synthesis of Viral Protease Inhibitor Compound 695

A solution of methyl (2S)-2-(tert-butoxycarbonylamino)-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (2 g, 6.99 mmol, 1 eq) in HCl/EtOAc (4 M, 40.00 mL, 22.91 eq), the mixture was stirred at 20° C. for 1 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give the product methyl (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (1.5 g, crude, HCl) as a white solid.

Example 75. Synthesis of Viral Protease Inhibitor Compound 711

Example 76. Synthesis of Viral Protease Inhibitor Compound 719

To a solution of N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxo-3-piperidyl]methyl]ethyl]-6-(4-methoxy-1H-indole-2-carbonyl)-6-azaspiro[3.4]octane-7-carboxamide (0.58 g, 1.17 mmol, 1 eq) in DCM (7 mL) was added Burgess reagent (1.39 g, 5.85 mmol, 5 eq), and the solution was stirred at 25° C. for 2 h. Upon completion, the reaction mixture was diluted with water (30 mL) and extracted with DCM (20 mL*3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was separated by prep-TLC (SiO2, ethyl acetate:MeOH=20:1) to get N-[(1S)-1-cyano-2-[(3S)-2-oxo-3-piperidyl]ethyl]-6-(4-methoxy-1H-indole-2-carbonyl)-6-azaspiro[3.4]octane-7-carboxamide Isomer 1 and N-[(1S)-1-cyano-2-[(3S)-2-oxo-3-piperidyl]ethyl]-6-(4-methoxy-1H-indole-2-carbonyl)-6-azaspiro[3.4]octane-7-carboxamide Isomer 2.

Example 77. Synthesis of Viral Protease Inhibitor Compound 721

To a solution of (S)-methyl 2-((S)-2-amino-4,4-dimethylpentanamido)-3-((S)-2-oxopiperidin-3-yl)propanoate (550 mg*2, HCl salt, 1.68 mmol, 1 eq) and 7-chloro-1H-indole-2-carboxylic acid (394.29 mg, 2.02 mmol, 1.2 eq) in DCM (6 mL) was added DMAP (615.66 mg, 5.04 mmol, 3 eq), and then was added EDCI (644.05 mg, 3.36 mmol, 2 eq) to the mixture at 25° C. After stirring at 25° C. for 1 h, the mixture was quenched by water (200 mL) and was extracted with DCM (70 mL*3), then was concentrated in vacuum and was purified by column (SiO2, petroleum ether:ethyl acetate=1:1 to 0:1) and was concentrated in vacuum, then was washed with 1M HCl (100 mL) and was extracted with DCM (30 mL*3) and the pH of the organic phase was adjusted to pH-7 with sat. NaHCO3(30 mL). The residue was concentrated in vacuum to obtain (S)-methyl 2-((S)-2-(7-chloro-1H-indole-2-carboxamido)-4,4-dimethylpentanamido)-3-((S)-2-oxopiperidin-3-yl)propanoate (650 mg, 1.16 mmol, 40% yield, 90% purity) as a light yellow solid. MS (ESI) m/z 505.2 [M+H]+

Example 78. Synthesis of Viral Protease Inhibitor Compound 723

Example 79. Synthesis of Viral Protease Inhibitor Compound 725

Example 80. Synthesis of Viral Protease Inhibitor Compound 727

A mixture of methyl (2S)-2-[[(2S)-3-cyclopropyl-2-[(6,7-dichloro-1H-indole-2-carbonyl)amino]propanoyl]amino]-3-[(3S)-2-oxo-3-piperidyl]propanoate (0.38 g, 3 batches in parallel, 726.01 umol, 1 eq) in NH3/MEOH (7 M, 12.06 mL, 116.31 eq) was stirred at 50° C. for 48 h. Upon completion, The mixture was concentrated under reduced pressure to give a residue, and then was dissolved with DCM (10 mL*3) and concentrated under reduced pressure to afford N-[(1S)-2-[[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxo-3-piperidyl]methyl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-ethyl]-6,7-dichloro-1H-indole-2-carboxamide (1 g, crude) as a yellow oil. MS (ESI) m/z 508.2 [M+H]+.

Example 81. Synthesis of Viral Protease Inhibitor Compound 729

To a solution of methyl (2S)-2-[[6-(7-chloro-1H-indole-2-carbonyl)-6-azaspiro[3.4]octane-7-carbonyl]amino]-3-[(3S)-2-oxo-3-piperidyl]propanoate (675 mg, 1.31 mmol, 1 eq) in NH3(7 M, in MeOH, 29.53 mL, 157.72 eq). The mixture was stirred at 65° C. for 16 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give a residue. The mixture was added with DCM (50 mL) (three times), and then the reaction was concentrated under reduced pressure to give a residue. The crude product N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxo-3-piperidyl]methyl]ethyl]-6-(7-chloro-1H-indole-2-carbonyl)-6-azaspiro[3.4]octane-7-carboxamide (700 mg, crude) was used into the next step and obtained as a yellow solid. MS (ESI) m/z 500.2 [M+H]+.

Example 82. Synthesis of Viral Protease Inhibitor Compound 731

Example 83. Synthesis of Viral Protease Inhibitor Compound 733

Example 83a. Synthesis of Viral Protease Inhibitor Compound 743

Example 84. Synthesis of viral protease inhibitor compound 745

A mixture of methyl (2S)-2-[[(2S)-2-(tert-butoxycarbonylamino)-4,4-dimethyl-pentanoyl]amino]-3-[(3S)-2-oxo-3-piperidyl]propanoate (1 g, 2.34 mmol, 1 eq) in HCl/MeOH (4 M) (10 mL) was stirred at 25° C. for 1 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give a residue. Compound methyl (2S)-2-[[(2S)-2-amino-4,4-dimethyl-pentanoyl]amino]-3-[(3S)-2-oxo-3-piperidyl]propanoate (900 mg, crude) was obtained as a white solid and used to the next step directly. MS (ESI) m/z 328.3 [M+H]+.

To a mixture of methyl (2S)-2-[[(2S)-2-[(6-chloro-1H-indole-2-carbonyl)amino]-4,4-dimethyl-pentanoyl]amino]-3-[(3S)-2-oxo-3-piperidyl]propanoate (605 mg, 1.20 mmol, 1 eq) in NH3/MeOH (7 M) (30.60 mg, 1.80 mmol, 30.00 uL, 1.5 eq) in one portion at 25° C. The mixture was stirred at 80° C. for 16 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give a residue. Compound N-[(1S)-1-[[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxo-3-piperidyl]methyl]ethyl]carbamoyl]-3,3-dimethyl-butyl]-6-chloro-1H-indole-2-carboxamide (600 mg, crude) was obtained as a white solid and used to the next step directly. MS (ESI) m/z 490.1 [M+H]+.

Example 85. Synthesis of Viral Protease Inhibitor Compound 791

A mixture of tert-butyl 7-[[(1S)-2-methoxy-2-oxo-1-[[(3S)-2-oxo-3-piperidyl]methyl]ethyl]carbamoyl]-6-azaspiro[3.4]octane-6-carboxylate (1.6 g, 3.66 mmol, 1 eq) in HCl/MeOH (20 mL) was stirred at 25° C. for 1 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give methyl (2S)-2-(6-azaspiro[3.4]octane-7-carbonylamino)-3-[(3S)-2-oxo-3-piperidyl]propanoate (1.3 g, crude) as a yellow solid.

Example 86. Synthesis of Viral Protease Inhibitor Compound 793

Example 87. Synthesis of Viral Protease Inhibitor Compound 795

Example 88. Synthesis of Viral Protease Inhibitor Compound 797

Example 89. Synthesis of Viral Protease Inhibitor Compound 799

A mixture of methyl 7-chloro-4-methoxy-1H-indole-2-carboxylate (500 mg, 2.09 mmol, 1 eq) in NaOH (2 M, 10.43 mL, 10 eq) was then stirred at 100° C. for 0.5 h. Upon completion, the mixture was acidified by HCl (3M) to adjust the pH to about 3, and then the reaction was extracted with EtOAc (10 mL*3). The organic layers were washed with water (10 mL), dried over Na2SO4, filtered, concentrated under reduced pressure to give 7-chloro-4-methoxy-1H-indole-2-carboxylic acid (400 mg, crude) as a yellow solid.

Example 90. Synthesis of Viral Protease Inhibitor Compound 801

Example 91. Synthesis of Viral Protease Inhibitor Compound 803

Example 92. Synthesis of Viral Protease Inhibitor Compound 805

To a solution of ethyl 2-(7-chloro-1H-indole-2-carbonyl)-8,8-difluoro-2-azaspiro[4.5]decane-3-carboxylate (1.6 g, 3.77 mmol, 1 eq) in THF (12 mL) and H2O (6 mL) was added LiOH·H2O (474.09 mg, 11.30 mmol, 3 eq), and then the mixture was stirred at 20° C. for 16 h. Upon completion, the mixture was concentrated in vacuum and the pH was adjusted to pH=˜1 with 1M HCl (30 mL). The reaction was triturated by DCM (30 mL), and then was filtered and the filtered cake was dried in vacuum to obtain 2-(7-chloro-1H-indole-2-carbonyl)-8,8-difluoro-2-azaspiro[4.5]decane-3-carboxylic acid (1.4 g, 3.53 mmol, 93.69% yield) as a white solid.

Example 93. Synthesis of Viral Protease Inhibitor Compound 806a

A solution of NaOMe (1.90 g, 35.17 mmol, 2 eq) in MeOH (20 mL) was cooled to −10° C., and a mixture 3-chloro-2-methoxy-benzaldehyde (3 g, 17.59 mmol, 1 eq) and methyl azide acetate (4.12 g, 35.17 mmol, 2 eq) in MeOH (10 mL) was added drop-wise. The mixture was stirred at 25° C. for 3 h. Upon completion, the reaction mixture was quenched by addition H2O (50 mL) at 0° C., and then diluted with H2O (30 mL) and extracted with ethyl acetate (100 mL, which extracted as 50 mL*2). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether/ethyl acetate=20/1 to 10/1) to afford (Z)-2-azido-3-(3-chloro-2-methoxy-phenyl)prop-2-enoate (2.1 g, 7.45 mmol, 42.38% yield, 95% purity) as a yellow solid.

Methyl (Z)-2-azido-3-(3-chloro-2-methoxy-phenyl)prop-2-enoate (2.1 g, 7.85 mmol, 1 eq) in xylene (20 mL), the mixture was stirred at 170° C. for 1.5 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether/ethyl acetate=10/1 to 5/1) to get the compound methyl 5-chloro-4-methoxy-1H-indole-2-carboxylate (1.7 g, 6.38 mmol, 81.37% yield, 90% purity) as a white solid.

To a mixture of methyl 5-chloro-4-methoxy-1H-indole-2-carboxylate (1.2 g, 5.01 mmol, 1 eq) in THF (20 mL) and H2O (10 mL) was added LiOH·H2O (420.24 mg, 10.01 mmol, 2 eq). The mixture was stirred at 60° C. for 2 h. Upon completion, the pH of the reaction mixture was adjusted to pH=3 by addition HCl, and then diluted with H2O (30 mL). The reaction was extracted with ethyl acetate (50 mL*2). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue 5-chloro-4-methoxy-1H-indole-2-carboxylic acid (0.95 g, 4.00 mmol, 79.88% yield, 95% purity) as a white solid.

Example 94. Synthesis of Viral Protease Inhibitor Compound 808

A mixture of 2-chloro-3-methoxy-benzaldehyde (4 g, 23.45 mmol, 1 eq) and NaOMe (2.53 g, 46.90 mmol, 2 eq) with MeOH (20 mL) was cooled to −10° C., and then a mixture of methyl azide acetate (5.49 g, 46.90 mmol, 2 eq) in MeOH (50 mL) was added dropwise to the solution. The mixture was stirred at 25° C. for 16 h, and a white solid was observed. Upon completion, the reaction mixture was filtered to give a residue compound methyl (Z)-2-azido-3-(2-chloro-3-methoxy-phenyl)prop-2-enoate (3 g, 10.09 mmol, 43.02% yield, 90% purity) as a white solid.

A solution of methyl (Z)-2-azido-3-(2-chloro-3-methoxy-phenyl)prop-2-enoate (1 g, 3.74 mmol, 1 eq) in xylene (20 mL) was warmed to 170° C., and stirred at 170° C. for 1.5 hours. Upon completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was triturated with petroleum ether:ethyl acetate=5: 1 at 25° C. to afford methyl 4-chloro-5-methoxy-1H-indole-2-carboxylate (450 mg, 1.13 mmol, 30.16% yield, 60% purity) as a yellow solid.

To a mixture of methyl 4-chloro-5-methoxy-1H-indole-2-carboxylate (450.00 mg, 1.88 mmol, 1 eq) in THF (10 mL) and H2O (5 mL) was added LiOH·H2O (157.59 mg, 3.76 mmol, 2 eq). The mixture was stirred at 60° C. for 2 h. Upon completion, the pH of the reaction mixture was adjusted pH=3 by addition HCl, and then diluted with H2O (30 mL) and extracted with ethyl acetate (50 mL*2). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue compound 4-chloro-5-methoxy-1H-indole-2-carboxylic acid (320 mg, 992.78 umol, 52.87% yield, 70% purity) as a yellow solid.

Example 95. Synthesis of Viral Protease Inhibitor Compound 810

To a solution of 2-chloro-4-methoxy-1-nitro-benzene (4300 mg, 22.92 mmol, 1 eq) in THF (70 mL) was added bromo(vinyl)magnesium (1 M, 80.23 mL, 3.5 eq) at −40° C. The solution was stirred for 2 h at −40° C. Upon completion, the solution was poured into NH4Cl (200 mL) and concentrated and extracted with ethyl acetate (80 mL*3) and concentrated to give a crude. The crude was purified by column (SiO2, petroleum ether:ethyl acetate=30:1 to 10:1) to give product 7-chloro-5-methoxy-1H-indole (2100 mg, 11.56 mmol, 50.44% yield) as a brown oil. MS (ESI) m/z 182.1 [M+H]+.

To a solution of 7-chloro-5-methoxy-1H-indole (2100 mg, 11.56 mmol, 1 eq) in DMF (25 mL) was added NaH (739.94 mg, 18.50 mmol, 60% purity, 1.6 eq) at 0° C. The solution was stirred for 0.5 h at 20° C. 4-Methylbenzenesulfonyl chloride (2.09 g, 10.98 mmol, 0.95 eq) was added and the solution was stirred for 1.5 h at 20° C. Upon completion, the solution was diluted with H2O (60 mL) and extracted with ethyl acetate (60 mL*3) and then washed with brine (60 mL*2) and concentrated to give crude. The crude was purified by column (SiO2, petroleum ether:ethyl acetate=30:1 to 2:1) to give 7-chloro-5-methoxy-1-(p-tolylsulfonyl)indole (2800 mg, 8.34 mmol, 72.11% yield) as a brown solid. MS (ESI) m/z 336.3 [M+H]+

To a solution of 7-chloro-5-methoxy-1-(p-tolylsulfonyl)indole (2800 mg, 8.34 mmol, 1 eq) in THF (40 mL) was added LDA (1 M, 16.68 mL, 2 eq) at −70° C. and the solution was stirred for 2.5 h at −70° C. Upon completion, the solution was poured into dry ice quickly and diluted with H2O (80 mL) and the solution was concentrated and extracted with ethyl acetate (80 mL) to recycle reactant 3. The water layer was acidified to pH=5-6 with HCl (con) and extracted with ethyl acetate (90 mL*2) and dried over Na2SO4and concentrated to give crude 7-chloro-5-methoxy-1-(p-tolylsulfonyl)indole-2-carboxylic acid (2300 mg, crude) as a brown solid. The crude was used directly for the next step. MS (ESI) m/z 380.2 [M+H]+

A solution of 7-chloro-5-methoxy-1-(p-tolylsulfonyl)indole-2-carboxylic acid (2100 mg, 5.53 mmol, 1 eq) and KOH (682.51 mg, 12.16 mmol, 14.41 uL, 2.2 eq) in MeOH (30 mL) was stirred for 8 h at 70° C. Upon completion, the solution was concentrated and diluted with H2O (40 mL) and acidified to pH=5-6 with HCl (1M) and filtered and the cake was collected to give 7-chloro-5-methoxy-1H-indole-2-carboxylic acid (570 mg, crude) as a brown solid. The crude was used directly for the next step. MS (ESI) m/z 226.3 [M+H]+

A solution of methyl (2S)-2-[[(2S)-2-(tert-butoxycarbonylamino)-4,4-dimethyl-pentanoyl]amino]-3-[(3S)-2-oxo-3-piperidyl]propanoate (500 mg, 1.17 mmol, 1 eq) in HCl/MeOH (20 mL) was stirred for 1 h at 25° C. Upon completion, the solution was concentrated to give crude product methyl (2S)-2-[[(2S)-2-amino-4,4-dimethyl-pentanoyl]amino]-3-[(3S)-2-oxo-3-piperidyl]propanoate;hydrochloride (420 mg, crude) as an off-white solid. The crude was used directly for the next step. MS (ESI) m/z 364.3 [M+H]+

Example 96. Synthesis of Viral Protease Inhibitor Compound 812

Example 97. Synthesis of Viral Protease Inhibitor Compound 814

Example 98. Synthesis of Viral Protease Inhibitor Compound 171

A mixture of methyl (2S)-2-[[(2S,4S)-1-[(E)-3-(4-chloro-2-fluoro-phenyl)prop-2-enoyl]-4-phenyl-pyrrolidine-2-carbonyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (0.1 g, 184.50 umol, 1 eq) in NH3/MeOH (3 mL, 7 M) was stirred at 80° C. for 16 h in the sealed tube. Upon completion, the reaction mixture was concentrated under reduced pressure to give (2S,4S)-N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]ethyl]-1-[(E)-3-(4-chloro-2-fluoro-phenyl)prop-2-enoyl]-4-phenyl-pyrrolidine-2-carboxamide (0.09 g, crude) as a yellow oil. MS (ESI) m/z 527.0 [M+H]+.

Example 99. Synthesis of Viral Protease Inhibitor Compound 253

A mixture of 2-amino-3-(2-oxo-1H-pyridin-3-yl)propanoic acid (500 mg, 2.74 mmol, 1 eq) and HCl/MeOH (4 M, 30 mL, 43.72 eq) was stirred at 25° C. for 2 h. The reaction mixture was concentrated under reduced pressure to give a product methyl 2-amino-3-(2-oxo-1,2-dihydropyridin-3-yl)propanoate (650 mg, crude, HCl) as a yellow oil and used directly for next step. MS (ESI) m/z 197.0 [M+H]+

A mixture of methyl-2-((S)-2-((tert-butoxycarbonyl)amino)-4-methylpentanamido)-3-(2-oxo-1,2-dihydropyridin-3-yl)propanoate (200 mg, 488.43 umol, 1 eq) and HCl/EtOAc (4 M, 30 mL) was stirred at 27° C. for 0.5 h. The reaction mixture was concentrated under reduced pressure to give methyl 2-((S)-2-amino-4-methylpentanamido)-3-(2-oxo-1,2-dihydropyridin-3-yl)propanoate (170 mg, crude, HCl) as a white solid and used directly for next step.

To a solution of tert-butyl 3-(2-hydroxyethyl)-1H-pyrrole-2-carboxylate (1.15 g, 5.44 mmol, 1 eq) in DCM (20 mL) was added DMP (3.23 g, 7.62 mmol, 1.4 eq) and the mixture was stirred at 25° C. for 1 hr. LCMS showed that the starting material was remained and ˜60% of the desired product was detected. TLC (petroleum ether/ethyl acetate=5/1, UV) showed that the starting material was consumed completely and new spot formed. The reaction mixture was filtered and the filtrated was concentrated in vacuum. The residue was diluted with ethyl acetate (50 mL), washed with H2O (10 mL), brine (10 mL) and dried over Na2SO4, filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 25 g SepaFlash® Silica Flash Column, Eluent of 0-20% ethyl acetate/petroleum ether gradient @ 30 mL/min). tert-butyl 3-(2-oxoethyl)-1H-pyrrole-2-carboxylate (1.5 g, 65.8% yield) was obtained as colorless oil.

A solution of tert-butyl 3-(2-oxoethyl)-1H-pyrrole-2-carboxylate (1.5 g, 7.17 mmol, 1 eq) and methyl (2S)-2-amino-3-cyclopropyl-propanoate (1.29 g, 7.17 mmol, 1 eq, HCl) in MeOH (20 mL) was stirred at 25° C. for 0.5 hr. Then NaBH3CN (900.9 mg, 14.34 mmol, 2 eq) was added to the mixture and the result solution was stirred at 25° C. for 16 hr. LCMS showed that the starting material was consumed completely and 40% of the desired product was detected. TLC (petroleum ether/ethyl acetate=5/1, UV) showed that the starting material was consumed completely and new spots formed. The reaction mixture was quenched with H2O (10 mL), extracted with ethyl acetate (15 mL×3). The combined organic phase was washed with H2O (10 ml) and brine (10 mL×2), dried over Na2SO4, filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 25 g SepaFlash® Silica Flash Column, Eluent of 0-20% ethyl acetate/petroleum ether gradient @ 30 mL/min). tert-butyl 3-[2-[[(1S)-1-(cyclopropylmethyl)-2-methoxy-2-oxo-ethyl]amino]ethyl]-1H-pyrrole-2-carboxylate (0.6 g, 24.8% yield) was obtained as colorless oil.

To a solution of tert-butyl 3-[2-[[(1S)-1-(cyclopropylmethyl)-2-methoxy-2-oxo-ethyl]amino]ethyl]-1H-pyrrole-2-carboxylate (0.2 g, 0.59 mmol, 1 eq) in dioxane (1 mL) was added HCl/dioxane (4 M, 1.49 mL, 10 eq) and the mixture was stirred at 25° C. for 16 hr. LCMS showed that the starting material was consumed completely and 88% of the desired product was detected. The reaction mixture was concentrated in vacuum. The crude product was used for the next step directly. 3-[2-[[(1S)-1-(cyclopropylmethyl)-2-methoxy-2-oxo-ethyl]amino]ethyl]-1H-pyrrole-2-carboxylic acid (0.15 g, 90% yield) was obtained as black brown oil.

To a solution of 3-[2-[[(1S)-1-(cyclopropylmethyl)-2-methoxy-2-oxo-ethyl]amino]ethyl]-1H-pyrrole-2-carboxylic acid (150 mg, 0.53 mmol, 1 eq) in DMF (1 mL) were added HOBt (108.4 mg, 0.802 mmol, 1.5 eq), DIEA (207.4 mg, 1.61 mmol, 0.28 mL, 3 eq) and EDCI (153.8 mg, 0.80 mmol, 1.5 eq). The mixture was stirred at 25° C. for 16 hr. LCMS showed that the starting material was consumed completely and 45% of the desired product was detected. TLC (petroleum ether/ethyl acetate=2/1, UV) showed that the starting material was consumed completely and new spots formed. The reaction mixture was quenched with H2O (20 mL), extracted with ethyl acetate (20 mL*3). The combined organic phase was washed with H2O (10 mL), brine (10 mL) and dried over Na2SO4, filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 24 g SepaFlash® Silica Flash Column, Eluent of 0-50% Ethyl acetate/Petroleum ethergradient @ 30 mL/min). methyl (2S)-3-cyclopropyl-2-(7-oxo-4,5-dihydro-1H-pyrrolo[2,3-c]pyridin-6-yl)propanoate (85 mg, 58.1% yield) was obtained as colorless oil.

To a solution of methyl (2S)-3-cyclopropyl-2-(7-oxo-4,5-dihydro-1H-pyrrolo[2,3-c]pyridin-6-yl)propanoate (60 mg, 0.228 mmol, 1 eq) in MeOH (2 mL) was added K2CO3(94.8 mg, 0.686 mmol, 3 eq) in H2O (1 mL) and the mixture was stirred at 25° C. for 16 hr. LCMS showed that the starting material was consumed completely and 100% of the desired product was detected. The reaction mixture was diluted with H2O (5 mL), adjusted pH=3 with 0.5 M aq.HCl and extracted with ethyl acetate (15 mL*3). The combined organic phase was washed with H2O (5 mL), brine (5 mL) and dried over Na2SO4, filtered and concentrated in vacuum. The crude product was used for the next step directly. (2S)-3-cyclopropyl-2-(7-oxo-4,5-dihydro-1H-pyrrolo[2,3-c]pyridin-6-yl)propanoic acid was obtained as a white solid.

To a solution of 4-chloro-1H-imidazo[4,5-c]pyridine (3 g, 19.54 mmol, 1 eq) and HCl (1.9 g, 19.54 mmol, 1.8 mL, 37% purity, 1 eq) in MeOH (10 mL). The mixture was stirred at 50° C. for 30 hr. The reaction mixture was concentrated under reduced pressure to remove HCl/MeOH. The crude product was triturated with PE at 25° C. for 150 min. Compound 1,5-dihydroimidazo[4,5-c]pyridin-4-one (2.5 g, crude) was obtained as yellow solid.

To a solution of 3-(2-trimethylsilylethoxymethyl)-5H-imidazo[4,5-c]pyridin-4-one (1.5 g, 5.65 mmol, 1 eq) and methyl (2R)-2-bromo-3-cyclopropyl-propanoate (1.1 g, 5.65 mmol, 1 eq) in DMF (4 mL) was added K2CO3(1.5 g, 11.30 mmol, 2 eq). The mixture was stirred at 25° C. for 16 hr. TLC (petroleum ether/ethyl acetate=3:1, UV 254) indicated starting material was remained and new spots formed. The reaction mixture was diluted with H2O (30 mL) and extracted with ethyl acetate (30 mL*3). The combined organic layers were washed with brine (30 mL*2), dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0-40% petroleum ether/ethyl acetate @ 35 mL/min). Compound methyl 3-cyclopropyl-2-[4-oxo-3-(2-trimethylsilylethoxymethyl)imidazo[4,5-c]pyridin-5-yl]propanoate (865 mg, 36.7% yield, 94% purity) was obtained as a white solid.

To a solution of methyl 3-cyclopropyl-2-[4-oxo-3-(2-trimethylsilylethoxymethyl)imidazo[4,5-c]pyridin-5-yl]propanoate (865 mg, 2.21 mmol, 1 eq) in H2O (1 mL) and THF (1 mL) was added LiOH·H2O (185.4 mg, 4.42 mmol, 2 eq). The mixture was stirred at 25° C. for 16 hr. The reaction mixture was concentrated under reduced pressure to remove THF. The residue was diluted with H2O (2 mL) and added HCl (2 mL, 2 N). The reaction mixture was diluted with H2O (30 mL) and extracted with ethyl acetate (30 mL*3). The combined organic layers were washed with brine (30 mL*2), dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was triturated with PE at 25° C. for 60 min. Compound 3-cyclopropyl-2-[4-oxo-3-(2-trimethylsilylethoxymethyl)imidazo[4,5-c]pyridin-5-yl]propanoic acid (746 mg, 86.7% yield, 97% purity) was obtained as a white solid.

Example 102. Synthesis of Viral Protease Inhibitor Compound 269

A solution of 1 (0.7 g, 1.91 mmol, 1 eq) in HCl/dioxane (4 M, 10 mL, 20.9 eq) was stirred at 25° C. for 0.5 hr. LC-MS showed 1 was consumed completely and 45% of desired compound was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The crude product was used into the next step without further purification. 3-cyclopropyl-2-(1-oxo-2,6-diazaspiro[4.5]decan-2-yl)propanoic acid (500 mg, crude) was obtained as a colorless oil.

A solution of 3-cyclopropyl-2-(1-oxo-2,6-diazaspiro[4.5]decan-2-yl)propanoic acid (0.5 g, 1.88 mmol, 1 eq) in MeOH (4 mL) was added Pd/C (50 mg, 0.37 mmol, 10% purity) and formaldehyde (1.52 g, 18.7 mmol, 1.4 mL, 37% purity, 10 eq) was degassed under vacuum and purged with H2several times. The mixture was stirred under H2(15 psi) at 25° C. for 0.5 hour. One spot was detected on TLC (Dichloromethane:Methanol=5/1, KMnO4). LC-MS showed 2 was consumed completely and 71% of desired compound was detected. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, dichloromethane:methanol=100/1 to 5/1) to give (2S)-3-cyclopropyl-2-(6-methyl-1-oxo-2,6-diazaspiro[4.5]decan-2-yl)propanoic acid (0.4 g, 76% yield) as a white solid.

Example 105. Synthesis of Viral Protease Inhibitor Compound 278

Example 106. Synthesis of Viral Protease Inhibitor Compound 323

Example 107. Synthesis of Viral Protease Inhibitor Compound 325

Example 108. Synthesis of Viral Protease Inhibitor Compound 327

Example 109. Synthesis of Viral Protease Inhibitor Compound 329

Example 110. Synthesis of Viral Protease Inhibitor Compound 331

Example 111. Synthesis of Viral Protease Inhibitor Compound 345

To a solution of methyl (2S)-2-(tert-butoxycarbonylamino)-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (2.00 g, 6.99 mmol, 1 eq) in THF (20 mL) was added LiBH4 (2 M, 6.99 mL, 2 eq) at 25° C. under N2. The mixture was then stirred at 25° C. for 1 h. The mixture was quenched with NH4Cl aq. (20.0 mL), and extracted with EtOAc (20.0 mL*5). The organic layers were washed with brine (20.0 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was triturated with ethyl acetate:petroleum ether=1:2 at 25° C. for 1 h to give tert-butyl hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)carbamate (1.57 g, crude) as white solid. MS (ESI) m/z 259.2 [M+H]+.

Example 112. Synthesis of Viral Protease Inhibitor Compound 355

To a mixture of N-[(1S)-1-[[(1S)-1-formyl-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]carbamoyl]-3-methyl-butyl]-4-methoxy-1H-indole-2-carboxamide (150 mg, 338.98 umol, 1 eq) in DCM (2 mL) was added saturated NaHSO3(35.27 mg, 338.98 umol, 23.83 uL, 1 eq), and the mixture was stirred at 25° C. for 30 min. A solution of KCN (100 mg, 1.54 mmol, 65.79 uL, 4.53 eq) in H2O (0.5 mL) was added, and the mixture was stirred at 25° C. for 2 h. Upon completion, the organic phase was collected and the aqueous layer was extracted with DCM (30 mL*3). The combined organic phase was washed with brine (30 mL*2), dried over Na2SO4, and concentrated to get the crude. The liquid water was added NaOH to pH=9, then quenched by aq NaClO, then added NaOH to pH>14. The crude was used to next step directly and without further purification. N-[(1S)-1-[[(1S)-2-cyano-2-hydroxy-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]ethyl]carbamoyl]-3-methyl-butyl]-4-methoxy-1H-indole-2-carboxamide (140 mg, crude) was obtained as yellow solid. MS (ESI) m/z 470.1 [M+H]+.

Example 113. Synthesis of Viral Protease Inhibitor Compound 357

Example 114. Synthesis of Viral Protease Inhibitor Compound 359

A solution of isocyanatobenzene (127 mg, 1.07 mmol, 115.32 uL, 5 eq) in dry toluene (0.2 mL) was added dropwise to a solution of the N-[(1S)-1-[[(1S)-2-cyano-2-hydroxy-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]ethyl]carbamoyl]-3-methyl-butyl]-4-methoxy-1H-indole-2-carboxamide (100 mg, 212.98 umol, 1 eq) in dry toluene (1 mL) at 0° C., and then the TEA (215.51 ug, 2.13 umol, 2.96e-1 uL, 0.01 eq) was added. After the solution was stirred at 25° C. for 16 h under dry argon atmosphere, the solution was quenched with H2O (10 mL), extracted with ethyl acetate (20 mL*3), the combined organic phase was dried over Na2SO4, filtrated and concentrated to give the crude. The crude was used to next step directly and without further purification. (2S)-1-cyano-2-((S)-2-(4-methoxy-1H-indole-2-carboxamido)-4-methylpentanamido)-3-((S)-2-oxopyrrolidin-3-yl) propyl phenylcarbamate (50 mg, 84.94 umol, 1 eq) was obtained as white solid. MS (ESI) m/z 589.2 [M+H]+.

Example 115. Synthesis of Viral Protease Inhibitor Compound 361

A mixture of methyl (2S)-2-[[(2S)-2-(tert-butoxycarbonylamino)-4-methyl-pentanoyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (500 mg, 1.25 mmol, 1 eq) in HCl/EtOAc (20 mL) was stirred at 25° C. for 1 h. TLC showed the reaction was finished. The reaction was concentrated to give the crude methyl (2S)-2-[[(2S)-2-amino-4-methyl-pentanoyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (360 mg, crude) as colorless oil. Crude product was used directly without further purification. MS (ESI) m/z 299.2 [M+H]+

Example 116. Synthesis of Viral Protease Inhibitor Compound 363

To a solution of 3-(trifluoromethoxy)benzene-1,2-diamine (500 mg, 2.60 mmol, 1 eq) in AcOH (15 mL) was added drop-wise methyl 2,2,2-trichloroethanimidate (459.12 mg, 2.60 mmol, 321.06 uL, 1.00 eq), and then the reaction was stirred at 25° C. for 12 h. The reaction mixture was quenched by addition H2O (50 mL) at 0° C., and then extracted with EtOAc (25 mL*3). The combined organic layers were washed with brine (30 mL), filtered and concentrated under reduced pressure to get the product 2-(trichloromethyl)-7-(trifluoromethoxy)-1H-benzimidazole (720 mg, crude) was obtained as a yellow solid. MS (ESI) m/z 320.8 [M+H]+

To a solution of 2-(trichloromethyl)-7-(trifluoromethoxy)-1H-benzimidazole (720 mg, 2.25 mmol, 1 eq) in MeOH (10 mL) was added Na2CO3(238.85 mg, 2.25 mmol, 1 eq), and the mixture was stirred at 70° C. for 14 h. 1N HCl was added to the solution and the reaction was stirred for 0.5 h. The mixture was extracted with EtOAc (30 mL*3), and the combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to get the product methyl 7-(trifluoromethoxy)-1H-benzimidazole-2-carboxylate (520 mg, crude) was obtained as a yellow solid. MS (ESI) m/z 260.8 [M+H]+

To a solution of methyl (2S)-2-[[(2S)-2-(tert-butoxycarbonylamino)-4-methyl-pentanoyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (250 mg, 625.81 umol, 1 eq) in EtOAc (0.5 mL) was added drop-wise HCl/EtOAc (4 M, 10 mL, 63.92 eq), and the mixture was stirred at 25° C. for 1 h. The reaction mixture was concentrated under reduced pressure to get the product methyl (2S)-2-[[(2S)-2-amino-4-methyl-pentanoyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (200 mg, crude, HCl) as a white solid.

The reaction mixture was concentrated under reduced pressure to get the product N-[(1S)-1-[[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]ethyl]carbamoyl]-3-methyl-butyl]-7-(trifluoromethoxy)-1H-benzimidazole-2-carboxamide (150 mg, crude) was obtained as a white solid. MS (ESI) m/z 513.2 [M+H]+.

Example 117. Synthesis of Viral Protease Inhibitor Compound 365

To a mixture of ethyl 3-(4-chlorophenyl)-3-hydroxy-butanoate (500 mg, 2.06 mmol, 1 eq) in H2O (3 mL) and THF (6 mL) was added LiOH·H2O (172.90 mg, 4.12 mmol, 2 eq). The mixture was stirred at 25° C. for 1 h. Upon the reaction was completed. The reaction mixture was diluted with H2O (20 mL) and extracted with ethyl acetate 60 mL (30 mL*2). The combined organic layers were washed with brine 930 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue compound 3-(4-chlorophenyl)-3-hydroxy-butanoic acid (400 mg, 1.68 mmol, 81.41% yield, 90% purity) as a white solid.

To a mixture of (2S)-N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]ethyl]-2-[[3-(4-chlorophenyl)-3-hydroxy-butanoyl]amino]-4-methyl-pentanamide (70 mg, 145.54 umol, 1 eq) in DCM (4 mL) was added Burgess reagent (69.36 mg, 291.07 umol, 2 eq). After stirring the mixture at 25° C. for 60 min, the reaction mixture was diluted with H2O (10 mL) and extracted with ethyl acetate (10 mL*2). The combined organic layers were concentrated under reduced pressure to give a residue. The residue was purified by neutral prep-HPLC to get the compound (2S)-2-[[3-(4-chlorophenyl)-3-hydroxy-butanoyl]amino]-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-4-methyl-pentanamide (11 mg, 23.76 umol, 16.33% yield, 100% purity) as a white solid. MS (ESI) m/z 463.2 [M+H]+

Example 118. Synthesis of Viral Protease Inhibitor Compound 265

To a solution of methyl (2S)-3-cyclopropyl-2-(7-oxo-4,5-dihydro-1H-pyrrolo[2,3-c]pyridin-6-yl)propanoate (20 mg, 76.2 umol, 1 eq) in dioxane (2 mL) was added DDQ (51.9 mg, 0.22 mmol, 3 eq) and the mixture was stirred at 100° C. for 1 hr under microwave. The reaction mixture was concentrated in vacuum. The residue was diluted with ethyl acetate (30 mL), washed with 10% aq. NaOH (10 mL), brine (10 mL) and dried over Na2SO4, filtered and concentrated in vacuum. The crude product was purified by prep-TLC (petroleum ether/ethyl acetate=1/1). methyl (2S)-3-cyclopropyl-2-(7-oxo-1H-pyrrolo[2,3-c]pyridin-6-yl)propanoate (10 mg, 38 umol, 50% yield, 100% purity) was obtained as a yellow oil.

To a solution of methyl (2S)-3-cyclopropyl-2-(7-oxo-1H-pyrrolo[2,3-c]pyridin-6-yl)propanoate (10 mg, 38.4 umol, 1 eq) in MeOH (0.5 mL) was added K2CO3(15.9 mg, 0.115 mmol, 3 eq) in H2O (0.2 mL) and the mixture was stirred at 25° C. for 16 hr. After the reaction mixture was concentrated in vacuum, the residue was diluted with H2O (5 mL), adjusted pH to about 4 with 1M aq. HCl and extracted with ethyl acetate (5 mL*3). The combined organic phase was washed with brine (5 mL) and dried over Na2SO4, filtered and concentrated in vacuum. The crude product was used for the next step directly. (2S)-3-cyclopropyl-2-(7-oxo-1H-pyrrolo[2,3-c]pyridin-6-yl)propanoic acid (8 mg, 32.1 umol, 83.7% yield, 99% purity) was obtained as a white solid.

Example 118a. Synthesis of Viral Protease Inhibitor Compound 369

To a solution of methyl (2S)-2-[[(2S)-4-methyl-2-[(4,4,4-trifluoro-3-hydroxy-3-phenyl-butanoyl)amino]pentanoyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (120 mg, 232.77 umol, 1 eq) in MeOH/NH3(7 M, 5 mL, 150.36 eq) The mixture was stirred at 80° C. for 15 h. LCMS showed the reaction was completed, and desired MS was observed. The reaction mixture was filtered and concentrated under reduced pressure to give a residue to get the product (2S)-N-[(1S)-2-amino-2-oxo-1-[[(3R)-2-oxopyrrolidin-3-yl]methyl]ethyl]-4-methyl-2-[(4,4,4-trifluoro-3-hydroxy-3-phenyl-butanoyl)amino]pentanamide (120 mg, crude) was obtained as colorless oil. MS (ESI) m/z 501.2 [M+H]+.

To a solution of (2S)-N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]ethyl]-4-methyl-2-[(4,4,4-trifluoro-3-hydroxy-3-phenyl-butanoyl)amino]pentanamide (120 mg, 239.76 umol, 1 eq) in DCM (3 mL) was added Burgess reagent (114.27 mg, 479.51 umol, 2 eq). The mixture was stirred at 25° C. for 1 h. LCMS showed the reaction was completed, and desired MS was observed. The reaction mixture was quenched by addition H2O 5 mL, and then extracted with DCM (2.5 mL*3). The combined organic layers were washed with brine (3 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by neutral prep-HPLC to get the product (2S)-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-4-methyl-2-[(4,4,4-trifluoro-3-hydroxy-3-phenyl-butanoyl)amino]pentanamide (20.18 mg, 38.77 umol, 16.17% yield, 92.698% purity) was obtained as white solid. MS (ESI) m/z 483.3[M+H]+.

Example 119. Synthesis of Viral Protease Inhibitor Compound 375

To a mixture of N-[(1S)-2-[[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-ethyl]-4-cyclopropyl-1H-indole-2-carboxamide (390 mg, 837.73 umol, 1 eq) in DCM (7 mL) was added Burgess reagent (1.20 g, 5.03 mmol, 6 eq) in one portion at 25° C. The mixture was stirred at 25° C. for 2 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (neutral condition) to give N-[(1S)-2-[[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-ethyl]-4-cyclopropyl-1H-indole-2-carboxamide (68 mg, 151.95 umol, 18.14% yield) as a white solid. MS (ESI) m/z 448.3 [M+H]+

Example 120. Synthesis of Viral Protease Inhibitor Compound 377

To a mixture of N-[(1S)-1-[[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]ethyl]carbamoyl]-3-methyl-butyl]-4-ethoxy-1H-indole-2-carboxamide (111.11 mg, 212.07 umol, 90% purity, 1 eq) in DCM (2 mL) was added Burgess reagent (151.61 mg, 636.20 umol, 3 eq). After the mixture was stirred at 25° C. for 3 h, the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by HCl prep-HPLC to get the compound N-[(1S)-1-[[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]carbamoyl]-3-methyl-butyl]-4-ethoxy-1H-indole-2-carboxamide (38 mg, 81.87 umol, 38.61% yield, 97.716% purity) as a white solid. MS (ESI) m/z 454.2 [M+H]+

Example 121. Synthesis of Viral Protease Inhibitor Compound 379

To a mixture of methyl (2S)-2-[[(2S)-2-amino-3-cyclopropyl-propanoyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (448 mg, 1.51 mmol, 1 eq) and 4-propoxy-1H-indole-2-carboxylic acid (396.37 mg, 1.81 mmol, 1.2 eq) in DMF (2 mL) was added DCM (8 mL) and EDCI (866.48 mg, 4.52 mmol, 3 eq) in one portion at 25° C. The mixture was added with DMAP (552.19 mg, 4.52 mmol, 3 eq), and the reaction was stirred at 25° C. for 2 h. The reaction mixture was diluted with H2O (10 mL) and extracted with ethyl acetate (30 mL, which extracted added as 10 mL*3). The combined organic layers were washed with brine (10 mL*1), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by column chromatography (SiO2, petroleum ether/ethyl acetate=5/1 to 0/1) to afford methyl (2S)-2-[[(2S)-3-cyclopropyl-2-[(4-propoxy-1H-indole-2-carbonyl)amino]propanoyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (480 mg, 962.75 umol, 63.90% yield) as a white solid. MS (ESI) m/z 499.2 [M+H]+

To a mixture of N-[(1S)-2-[[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-ethyl]-4-propoxy-1H-indole-2-carboxamide (380 mg, 785.84 umol, 1 eq) in DCM (7 mL) was added Burgess reagent (1.12 g, 4.72 mmol, 6 eq) in one portion at 25° C. The mixture was stirred at 25° C. for 4 h. The reaction mixture was concentrated under reduced pressure to give a residue. The crude product was purified by prep-HPLC (neutral condition) to give N-[(1S)-2-[[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-ethyl]-4-propoxy-1H-indole-2-carboxamide (120 mg, 257.76 umol, 32.80% yield) was obtained as a white solid. MS (ESI) m/z 466.3 [M+H]+

Example 122. Synthesis of Viral Protease Inhibitor Compound 383

To a mixture of (4,4-difluorocyclohexyl)methyl N-[(1S)-1-[[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]ethyl]carbamoyl]-3-methyl-butyl]carbamate (230 mg, 299.67 umol, 60% purity, 1 eq) in DCM (6 mL) was added Burgess reagent (142.83 mg, 599.33 umol, 2 eq). The mixture was stirred at 25° C. for 60 min. Upon completion, the reaction mixture was diluted with H2O (10 mL) and extracted with DCM (20 mL). The combined organic layers concentrated under reduced pressure to give a residue. The residue was purified by neutral prep-HPLC to get the compound (4,4-difluorocyclohexyl)methyl N-[(1S)-1-[[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]carbamoyl]-3-methyl-butyl]carbamate (48 mg, 100.77 umol, 33.63% yield, 92.9% purity) as a white solid. MS (ESI) m/z 443.3 [M+H]+

Example 123. Synthesis of Viral Protease Inhibitor Compound 385

Example 124. Synthesis of Viral Protease Inhibitor Compound 387

Example 125. Synthesis of Viral Protease Inhibitor Compound 389

A solution of 2-tert-butoxycarbonyl-2-azaspiro[4.5]decane-3-carboxylic acid (3 g, 10.59 mmol, 1 eq) was added in HCl/MeOH (4 M, 50 mL, 18.89 eq) was stirred at 80° C. for 2 h. The mixture was concentrated under the reduced pressure affording the product methyl 2-azaspiro[4.5]decane-3-carboxylate (2 g, crude) as a yellow oil.

To a solution of methyl 2-(4-methoxy-1H-indole-2-carbonyl)-2-azaspiro[4.5]decane-3-carboxylate (3 g, 8.10 mmol, 1 eq) in THF (45 mL) and H2O (15 mL) was added LiOH·H2O (1.70 g, 40.49 mmol, 5 eq). The mixture was stirred at 25° C. for 12 h. Upon completion, the mixture was quenched by addition H2O (50 mL), and then added aq. HCl (1 M) to adjust the pH to about 3-4, and then extracted with ethyl acetate (50 mL*3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure affording the product 2-(4-methoxy-1H-indole-2-carbonyl)-2-azaspiro[4.5]decane-3-carboxylic acid (2.6 g, crude) as a white solid. MS (ESI) m/z 357.1 [M+H]+

Example 126. Synthesis of Viral Protease Inhibitor Compound 391

To a solution of methyl (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (350 mg, 1.22 mmol, 1 eq) was added HCl/EtOAc (12 mL) and the mixture was stirred at 25° C. for 1 h. Upon completion, the mixture was concentrated in the vacuum to give a crude product (S)-methyl 2-amino-3-((S)-2-oxopyrrolidin-3-yl)propanoate (330 mg, crude) as yellow oil. MS (ESI) m/z 187.1 [M+H]+

To a solution of (2S,3S)-tert-butyl 3-ethyl-2-(((S)-1-methoxy-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)carbamoyl)azetidine-1-carboxylate (240 mg, 603.83 umol, 1 eq) in DCM (1 mL) was added TFA (4.13 g, 36.23 mmol, 2.68 mL, 60 eq), and the resulting mixture was stirred at 25° C. for 1 h. Upon completion, the residue was poured into NaHCO3(10 mL) and was extracted with EtOAc (10 mL*3). The combined organic phase was washed with brine (10 mL*2), dried with anhydrous Na2SO4, filtered and concentrated in vacuum to give the crude product (S)-methyl 2-((2S,3S)-3-ethylazetidine-2-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (200 mg, crude) as white solid. MS (ESI) m/z 298.2 [M+H]+

Example 127. Synthesis of Viral Protease Inhibitor Compound 395

To methyl (2S)-2-(tert-butoxycarbonylamino)-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (300 mg, 1.05 mmol, 1 eq) was added HCl/EtOAc (4 M, 30 mL) at 25° C., and the mixture was stirred at 25° C. for 1 h. The reaction mixture was concentrated under reduced pressure to give methyl (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate;hydrochloride (230 mg, crude) as a yellow oil and used directly for next step.

A mixture of (S)-tert-butyl 2-(((S)-1-methoxy-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)carbamoyl)-4,4-dimethylpyrrolidine-1-carboxylate (200 mg, 486.04 umol, 1 eq) and HCl/EtOAc (4 M, 20 mL) was stirred at 25° C. for 1 h. The reaction mixture was concentrated under reduced pressure to give a product (S)-methyl-2-((S)-4,4-dimethylpyrrolidine-2-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (170 mg, crude, HCl) as a yellow oil and used directly for next step.

Example 128. Synthesis of Viral Protease Inhibitor Compound 397

Example 129. Synthesis of Viral Protease Inhibitor Compound 399

Example 130. Synthesis of Viral Protease Inhibitor Compound 401

Example 131. Synthesis of Viral Protease Inhibitor Compound 405

A solution of methyl (2S)-2-[[(2S)-2-(tert-butoxycarbonylamino)-4,4-dimethyl-pentanoyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (440 mg, 1.06 mmol, 1 eq) in HCl/MeOH (10 mL) was stirred for 1 h at 25° C. TLC (DCM:MeOH=10:1) showed desired, and the reaction was cautiously concentrated to give crude. Compound methyl (2S)-2-[[(2S)-2-amino-4,4-dimethyl-pentanoyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (310 mg, crude) as a yellow solid used directly for the next step. MS (ESI) m/z 314.3 [M+H]+

A solution of methyl (2S)-2-[[(2S)-2-[(4-methoxy-1H-indole-2-carbonyl)amino]-4,4-dimethyl-pentanoyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (135 mg, 277.46 umol, 1 eq) in NH3/MeOH (7 M, 8 mL, 201.83 eq) was stirred for 16 h at 65° C. HPLC showed desired. The reaction was cautiously concentrated to give crude. Compound N-[(1S)-1-[[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]ethyl]carbamoyl]-3,3-dimethyl-butyl]-4-methoxy-1H-indole-2-carboxamide (130 mg, crude) was obtained as a yellow solid used directly for the next step. MS (ESI) m/z 472.3 [M+H]+

Example 132. Synthesis of Viral Protease Inhibitor Compound 409

Example 133. Synthesis of Viral Protease Inhibitor Compound 433

To 2-(tert-butoxycarbonylamino)-2-(3-pyridyl)acetic acid (0.5 g, 1.98 mmol, 1 eq) was added HCl/MeOH (4 M, 20 mL, 40.36 eq) in one portion at 25° C. under N2. The mixture was stirred at 25° C. for 12 h. The reaction mixture was concentrated to get the crude product. The crude product was used the next step without purification. Methyl 2-amino-2-(3-pyridyl)acetate (400 mg, crude, HCl) was obtained as a yellow oil and used directly next step. MS (ESI) m/z 167.1 [M+H]+

To a mixture of methyl 2-[[(2S)-2-[(4-methoxy-1H-indole-2-carbonyl)amino]-4-methyl-pentanoyl]amino]-2-(3-pyridyl)acetate (0.2 g, 441.99 umol, 1 eq) was added NH3/MeOH (7 M, 6 mL, 95.03 eq) in one portion at 25° C. under N2. The mixture was stirred at 80° C. for 12 h. The reaction mixture was cooled to the 25° C. and concentrated to get the product. The residue was purified by prep-TLC (SiO2, DCM:MeOH=10:1, Rf=0.22). N-[(1S)-1-[[2-amino-2-oxo-1-(3-pyridyl)ethyl]carbamoyl]-3-methyl-butyl]-4-methoxy-1H-indole-2-carboxamide (70 mg, crude) was obtained as a light yellow solid. MS (ESI) m/z 438.2 [M+H]+

Example 134. Synthesis of Viral Protease Inhibitor Compound 439

To a mixture of methyl (2S)-2-[[(2S)-2-(tert-butoxycarbonylamino)-3-cyclopropyl-propanoyl]amino]-3-(2-pyridyl)propanoate (1.1 g, 2.81 mmol, 1 eq) was added HCl/MeOH (4 M, 11 mL, 15.66 eq) in one portion at 25° C. under N2. The mixture was stirred at 25° C. for 1 h. The reaction mixture was concentrated to get the product. Methyl (2S)-2-[[(2S)-2-amino-3-cyclopropyl-propanoyl]amino]-3-(2-pyridyl)propanoate (1 g, crude, HCl) was obtained as a brown solid and used directly next step. MS (ESI) m/z 292.2 [M+H]+

To a mixture of methyl (2S)-2-[[(2S)-3-cyclopropyl-2-[(4-methoxy-1H-indole-2-carbonyl)amino]propanoyl]amino]-3-(2-pyridyl)propanoate (0.2 g, 430.56 umol, 1 eq) was added NH3/MeOH (7 M, 4 mL, 65.03 eq) in one portion at 25° C. under N2. The mixture was stirred at 80° C. for 12 h. The reaction mixture was cooled to 25° C. and concentrated to get the crude product. N-[(1S)-1-(cyclopropylmethyl)-2-[[(1S)-1-(nitrosomethyl)-2-(2-pyridyl)ethyl]amino]-2-oxo-ethyl]-4-methoxy-1H-indole-2-carboxamide (200 mg, crude) was obtained as a light yellow solid and used directly next step. MS (ESI) m/z 450.2 [M+H]+

To a mixture of N-[(1S)-1-(cyclopropylmethyl)-2-[[(1S)-1-(nitrosomethyl)-2-(2-pyridyl)ethyl]amino]-2-oxo-ethyl]-4-methoxy-1H-indole-2-carboxamide (0.1 g, 222.47 umol, 1 eq) in DCM (1 mL) was added Burgess reagent (212.06 mg, 889.88 umol, 4 eq) in one portion at 25° C. under N2. The mixture was stirred at 25° C. for 12 h. The reaction mixture was concentrated to get the crude product. The crude product was purified by pre-HPLC. N-[(1S)-2-[[(1S)-1-cyano-2-(2-pyridyl)ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-ethyl]-4-methoxy-1H-indole-2-carboxamide (25.44 mg, 58.27 umol, 26.19% yield, 98.833% purity) was obtained as a white solid. MS (ESI) m/z 432.2 [M+H]+

Example 135. Synthesis of Viral Protease Inhibitor Compound 448

A solution of 4-methyl-3-nitro-1H-pyridin-2-one (500 mg, 3.24 mmol, 1 eq) in DMF (10 mL) was added NaH (181.6 mg, 4.54 mmol, 60% purity, 1.4 eq) at 0° C., and the reaction mixture was stirred at 25° C. for 0.5 hr. Then methyl (2R)-2-bromo-3-cyclopropyl-propanoate (671.7 mg, 3.24 mmol, 1 eq) was added at 0° C. The mixture was stirred at 25° C. for 16 h under N2. LCMS showed one peak with desired MS was detected. The mixture was quenched with H2O (50 mL), and extracted with ethyl acetate (150 mL*3). The combined organic layers was washed with brine (10 mL) dried over Na2SO4, filtered and concentrated under reduce pressure. The residue was purified by flash silica gel chromatography (ISCO®; 24 g SepaFlash® Silica Flash Column, Eluent of 0-50% ethyl acetate/petroleum ethergradient @ 35 mL/min) to give methyl (2S)-3-cyclopropyl-2-(4-methyl-3-nitro-2-oxo-1-pyridyl)propanoate (453 mg, 45.1% yield) as a yellow solid.

A mixture of methyl (2S)-3-cyclopropyl-2-(4-methyl-3-nitro-2-oxo-1-pyridyl)propanoate (253 mg, 0.90 mmol, 1 eq), LiOH·H2O (151.5 mg, 3.61 mmol, 4 eq) in THF (2.1 mL), MeOH (0.7 mL), H2O (0.7 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 25° C. for 1 hr under N2atmosphere. LCMS showed one peak with desired MS was detected. The mixture was added H2O (5 mL), then the mixture was added 2 M HCl (2 mL) to adjust the pH to about 6-7. The mixture was added H2O (10 mL), and extracted with ethyl acetate (30 mL*3). The combined organic layers was washed with brine (10 mL) dried over Na2SO4, filtered and concentrated under reduce pressure to give (2S)-3-cyclopropyl-2-(4-methyl-3-nitro-2-oxo-1-pyridyl)propanoic acid (207 mg, 77.9% yield) as a yellow solid.

Example 136. Synthesis of Viral Protease Inhibitor Compound 449

To a solution of (2S)-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-3-cyclopropyl-2-(4-methyl-3-nitro-2-oxo-1-pyridyl)propanamide (345.0 mg, 0.85 mmol, 1 eq) in THF (5 mL) was added Pd/C (233.1 mg, 0.21 mmol, 10% purity). The mixture was stirred at 25° C. for 25 min under H2. LCMS showed one peak with desired MS was detected. The reaction mixture was filtered and the filtrate was quenched with H2O (20 mL), and extracted with ethyl acetate (30 mL*3). The combined organic layers was washed with brine (10 mL) dried over Na2SO4, filtered and concentrated under reduce pressure. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0-10% DCM/MeOH @ 30 mL/min) to give the product (203 mg). 70 mg of product was separated by SFC (column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 um); mobile phase: [0.1% NH3H2O IPA]; B %: 45%-45%, min) to give 2-[(1S)-3-amino-4-methyl-2-oxo-1-pyridyl]-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-3-cyclopropyl-propanamide (20.08 mg, 6.2% yield) and 2-[(1R)-3-amino-4-methyl-2-oxo-1-pyridyl]-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-3-cyclopropyl-propanamide (23.04 mg, 7.0% yield) as a white solid.

Example 137. Synthesis of Viral Protease Inhibitor Compound 450

To a solution of 4-methyl-3-nitro-1H-pyridin-2-one (1 g, 6.49 mmol, 1 eq) in DMF (15 mL) was added NaH (363.3 mg, 9.08 mmol, 60% purity, 1.4 eq) at 0° C., and the reaction mixture was stirred at 25° C. for 0.5 hr. Then methyl (2R)-2-bromo-3-cyclopropyl-propanoate (1.34 g, 6.49 mmol, 1 eq) was added at 0° C. The mixture was stirred at 25° C. for 16 h under N2. LCMS showed one peak with desired MS was detected. The mixture was quenched with H2O (20 mL), and extracted with ethyl acetate (50 mL*3). The combined organic layers was washed with brine (40 mL) dried over Na2SO4, filtered and concentrated under reduce pressure. The residue was purified by flash silica gel chromatography (ISCO®; 24 g SepaFlash® Silica Flash Column, Eluent of 0-50% Ethyl acetate/Petroleum ethergradient @ 35 mL/min) to give methyl (2S)-3-cyclopropyl-2-(4-methyl-3-nitro-2-oxo-1-pyridyl)propanoate (867 mg, 47.4% yield) as a yellow solid.

A mixture of methyl (2S)-3-cyclopropyl-2-(4-methyl-3-nitro-2-oxo-1-pyridyl)propanoate (867 mg, 3.09 mmol, 1 eq), LiOH·H2O (519.2 mg, 12.37 mmol, 4 eq) in THF (6 mL), MeOH (2 mL), H2O (2 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 25° C. for 1 h under N2atmosphere. LCMS showed one peak with desired MS was detected. The mixture was added H2O (5 mL), then the mixture was added 2 M HCl (4 mL) to adjust the pH to about 6-7. The mixture was extracted with ethyl acetate (30 mL*3). The combined organic layers was washed with brine (20 mL) dried over Na2SO4, filtered and concentrated under reduce pressure to give product. Compound (2S)-3-cyclopropyl-2-(4-methyl-3-nitro-2-oxo-1-pyridyl)propanoic acid (791 mg, 94.8% yield) was obtained as a yellow solid.

To a solution of N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-3-cyclopropyl-2-(4-methyl-3-nitro-2-oxo-1-pyridyl)propanamide (838 mg, 2.09 mmol, 1 eq) in THF (10 mL) was added Pd/C (566.5 mg, 0.53 mmol, 10% purity). The mixture was stirred at 25° C. for 1 h under H2. LCMS showed one peak with desired MS was detected. The mixture was filtered and concentrated under reduce pressure to give 2-(3-amino-4-methyl-2-oxo-1-pyridyl)-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-3-cyclopropyl-propanamide (616 mg, 68.7% yield) as a white solid.

Example 138. Synthesis of Viral Protease Inhibitor Compound 451

Example 139. Synthesis of Viral Protease Inhibitor Compound 455

Example 140. Synthesis of Viral Protease Inhibitor Compound 457

Example 141. Synthesis of Viral Protease Inhibitor Compound 459

Example 142. Synthesis of Viral Protease Inhibitor Compound 465

To a solution of methyl (2S)-3-cyclopropyl-2-(3-nitro-2-oxo-1-pyridyl)propanoate (230 mg, 0.86 mmol, 1 eq) in THF (1 mL) and MeOH (0.2 mL) was added LiOH·H2O (108.7 mg, 2.59 mmol, 3 eq) in H2O (0.2 mL). The mixture was stirred at 0° C. for 10 min. LC-MS showed the desired compound was detected. The reaction was adjusted with 4 M HCl to pH=4. The reaction mixture was diluted with H2O (5 mL) and extracted with ethyl acetate (5 mL*3). The combined organic phase was washed with brine (5 mL*3), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The crude product was used into the next step without further purification. Compound (2S)-3-cyclopropyl-2-(3-nitro-2-oxo-1-pyridyl)propanoic acid (210 mg, 96.3% yield) was obtained as a yellow solid.

To a solution of (2S)-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-3-cyclopropyl-2-(3-nitro-2-oxo-1-pyridyl)propanamide (200 mg, 0.51 mmol, 1 eq) in THF (0.5 mL) was added Pd/C (200 mg, 0.18 mmol, 10% purity, 3.64e-1 eq) under N2. The suspension was degassed under vacuum and purged with H2several times. The mixture was stirred under H2(15 psi) at 25° C. for 10 min. LC-MS showed the desired compound was detected. TLC (DCM/MeOH=10:1) showed new spot was detected. The resulting product was dissolved in MeOH (5 mL) and filtered to remove the insoluble. The filter liquor was concentrated in vacuo. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0-5% petroleum ether/ethyl acetate ethergradient @ 20 mL/min) to give (2S)-2-(3-amino-2-oxo-1-pyridyl)-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-3-cyclopropyl-propanamide (119 mg, 64.3% yield, 99.7% purity) as a brown solid.

Example 143. Synthesis of Viral Protease Inhibitor Compound 465

Example 144. Synthesis of Viral Protease Inhibitor Compound 466

Example 145. Synthesis of Viral Protease Inhibitor Compound 467

Example 146. Synthesis of Viral Protease Inhibitor Compound 468

To a solution of 2 (450.0 mg, 1.23 mmol, 1 eq) in H2O (1 mL) and MeOH (3 mL) was added NaOH (196.4 mg, 4.91 mmol, 4 eq). The mixture was stirred at 25° C. for 1 h. LC-MS showed 2 was consumed completely and 66% of desired compound was detected. The reaction mixture was quenched by addition H2O (15 mL). The pH of the mixture was adjusted whit HCl (2 M) to 5-6. And then the mixture extracted with EtOAc (20 mL*3). The combined organic layers were washed with brine (20 mL*2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue, and 2-(1-tert-butoxycarbonyl-6-oxo-1,7-diazaspiro[4.4]nonan-7-yl)-3-cyclopropyl-propanoic acid (0.4 g, crude) was obtained as a colorless oil.

Example 147. Synthesis of Viral Protease Inhibitor Compound 469

Example 148. Synthesis of Viral Protease Inhibitor Compound 471

Example 149. Synthesis of Viral Protease Inhibitor Compound 473

To a solution of (2R)-2-amino-3-cyclopropyl-propanoic acid (3.5 g, 27.10 mmol, 1 eq) and NaBr (9.76 g, 94.85 mmol, 3.05 mL, 3.5 eq) in a 2.5 M solution of 142504 (35 mL) was added NaNO2(2.43 g, 35.23 mmol, 1.3 eq) in H2O (7 mL) dropwise at 0° C. The reaction mixture was stirred at 0° C. for 1 h and 25° C. for 6 h. The mixture was diluted with water (60 mL) and the resultant mixture was extracted with DCM (80 mL*3). The combined organic layers were dried over Na2SO4, filtered and concentrated to dryness under reduced pressure to give (2R)-2-bromo-3-cyclopropyl-propanoic acid (7.4 g, crude) as colorless oil.

To a solution of (2R)-2-bromo-3-cyclopropyl-propanoic acid (7.4 g, 38.33 mmol, 1 eq) in MeOH (70 mL) was added HCl (12 M, 7.40 mL, 2.32 eq), and then the reaction mixture was stirred at 50° C. for 16 h. TLC (Petroleum ether:Ethyl acetate=10:1, PMA) showed the starting material was consumed. The reaction mixture was concentrated under reduced pressure. The mixture was diluted with water (10 mL) and the resultant mixture was extracted with ethyl acetate (30 mL*3). The combined organic layers were dried over Na2SO4, filtered and concentrated to dryness under reduced pressure. The residue was purified by column chromatography over silica gel (petroleum ether:ethyl acetate=1:0 to 10:1) to afford methyl (2R)-2-bromo-3-cyclopropyl-propanoate (4.9 g, 59.2% yield) as colorless oil.

To a solution of tert-butyl 1-oxo-2,6-diazaspiro[4.5]decane-6-carboxylate (500 mg, 1.97 mmol, 1 eq) in Toluene (10 mL) was added NaH (94.37 mg, 2.36 mmol, 60% purity, 1.2 eq) at 0° C., and then the mixture was stirred for 0.5 h at 25° C. The reaction mixture was cooled to 0° C. Methyl (2R)-2-bromo-3-cyclopropyl-propanoate (488.5 mg, 2.36 mmol, 1.2 eq) was added, and the reaction mixture was allowed to warm up to 80° C. and stirred for 16 h at 80° C. LC-MS showed starting material was consumed completely and one main peak with desired MS was detected. TLC (petroleum ether:ethyl acetate=1:1, PMA) showed the starting material was consumed. The reaction mixture was concentrated under reduced pressure. The mixture was diluted with water (10 mL) and the resultant mixture was extracted with ethyl acetate (30 mL*3). The combined organic layers were dried over Na2SO4, filtered and concentrated to dryness under reduced pressure to give tert-butyl 2-[1-(cyclopropylmethyl)-2-methoxy-2-oxo-ethyl]-1-oxo-2,6-diazaspiro[4.5]decane-6-carboxylate (480 mg, crude) as light yellow oil. The aqueous was acidified with HCl (0.5 N) to pH=5, and the resultant mixture was extracted with ethyl acetate (20 mL*3). The combined organic layers were dried over Na2SO4, filtered and concentrated to dryness under reduced pressure to give 2-(6-tert-butoxycarbonyl-1-oxo-2,6-diazaspiro[4.5]decan-2-yl)-3-cyclopropyl-propanoic acid (120 mg, crude) as light yellow oil.

Example 150. Synthesis of Viral Protease Inhibitor Compound 475

Example 151. Synthesis of Viral Protease Inhibitor Compound 477

To a solution of (3R,6S)-6-(9H-fluoren-9-ylmethoxycarbonylamino)-5-oxo-2,3,6,7,8,8a-hexahydrothiazolo[3,2-a]pyridine-3-carboxylic acid (200 mg, 0.45 mmol, 1 eq) in DCM (4 mL) was added (COCl)2(86.8 mg, 0.68 mmol, 59 uL, 1.5 eq) and DMF (3.3 mg, 45.6 umol, 3 uL, 0.1 eq) at 0° C. under N2. The mixture was stirred at 0° C. for 1 hr. The reaction mixture was concentrated under reduced pressure to give a residue. It was used into next step without purification. Compound 9H-fluoren-9-ylmethylN-[(3S,6S)-3-chlorocarbonyl-5-oxo-2,3,6,7,8,8a-hexahydrothiazolo[3,2-a]pyridin-6-yl]carbamate (200 mg, crude) was obtained as a yellow solid.

Example 152. Synthesis of Viral Protease Inhibitor Compound 479

Example 153. Synthesis of Viral Protease Inhibitor Compound 483

Example 154. Synthesis of Viral Protease Inhibitor Compound 489

A solution of cyclohexa-1,5-dien-1-yloxy(trimethyl)silane (5.0 g, 29.71 mmol, 5.50 mL, 1 eq) and pyrrole-2,5-dione (2.88 g, 29.71 mmol, 1 eq) in MTBE (50 mL) was stirred at 25° C. for 16 h. TLC (petroleum ether:ethyl acetate=2:1, I2) was conducted. The reaction mixture was concentrated under reduced pressure. MTBA (15 mL) and PE (15 mL) was added, and then the suspension was filtered to give the title compound as a white solid. Compound (1R,2S,6R,7R)-8-trimethylsilyloxy-4-azatricyclo[5.2.2.02,6]undec-8-ene-3,5-dione (5.2 g, 65.9% yield) was obtained as a white solid

A solution of (1R,2S,6R,7R)-8-trimethylsilyloxy-4-azatricyclo[5.2.2.02′6]undec-8-ene-3,5-dione (2.9 g, 10.93 mmol, 1 eq) in HCl/dioxane (25 mL) was stirred at 25° C. for 16 hr. TLC (petroleum ether:ethyl acetate=5:1). The reaction mixture was concentrated in vacuum. No purification. The crude product was used into the next step without further purification. Compound (1R,2S,6R,7R)-4-azatricyclo[5.2.2.02,6]undecane-3,5,8-trione (2.16 g, crude) was obtained as a white solid.

A solution of (1R,2S,6R,7R)-8-amino-4-[(4-methoxyphenyl)methyl]-3,5-dioxo-4-azatricyclo[5.2.2.02′6]undecane-8-carbonitrile (1.7 g, 5.01 mmol, 1 eq), (2S)-2-(benzyloxycarbonylamino)-3-cyclopropyl-propanoic acid (1.45 g, 5.51 mmol, 1.1 eq) and pyridine (3.96 g, 50.09 mmol, 4.04 mL, 10 eq) in THF (35 mL) was stirred at 25° C. for 15 min. After POCl3(1.92 g, 12.52 mmol, 1.16 mL, 2.5 eq) was added dropwise at 0° C., the reaction mixture was stirred at 25° C. for 2 hours. The reaction mixture was concentrated under reduced pressure. The mixture was diluted with water (30 mL) and the resultant mixture was extracted with ethyl acetate (80 mL*3). The combined organic layers were dried over Na2SO4, filtered and concentrated to dryness under reduced pressure. The residue was purified by column chromatography over silica gel (DCM:MeOH=1:0 to 20:1) to afford N-[(1S)-2-[[(1R,2S,6R,7R)-8-cyano-4-[(4-methoxyphenyl)methyl]-3,5-dioxo-4-azatricyclo[5.2.2.02′6]undecan-8-yl]amino]-1-(cyclopropylmethyl)-2-oxo-ethyl]carbamate (2.4 g, 72.9% yield, 89% purity) as a colorless oil.

To a solution of benzyl N-[(1S)-2-[[(1R,2S,6R,7R)-8-cyano-4-[(4-methoxyphenyl)methyl]-3,5-dioxo-4-azatricyclo[5.2.2.02′6]undecan-8-yl]amino]-1-(cyclopropylmethyl)-2-oxo-ethyl]carbamate (500 mg, 0.85 mmol, 1 eq) in ACN (15 mL) and H2O (5 mL) was added CAN (1.41 g, 2.57 mmol, 1.28 mL, 3 eq), and then the reaction mixture was stirred at 25° C. for 4 h. The reaction mixture was concentrated under reduced pressure. The mixture was diluted with water (30 mL) and the resultant mixture was extracted with ethyl acetate (50 mL*3). The combined organic layers were dried over Na2SO4, filtered and concentrated to dryness under reduced pressure. The residue was purified by column chromatography over silica gel (petroleum ether:ethyl acetate=1:0 to 1:1) to afford benzyl N-[(1S)-2-[[(1R,2S,6R,7R)-8-cyano-3,5-dioxo-4-azatricyclo[5.2.2.02′6]undecan-8-yl]amino]-1-(cyclopropylmethyl)-2-oxo-ethyl]carbamate (260 mg, 62.8% yield, 96% purity) as a white solid.

To a solution of benzyl N-[(1S)-2-[[(1R,2S,6R,7R)-8-cyano-3,5-dioxo-4-azatricyclo[5.2.2.02′6]undecan-8-yl]amino]-1-(cyclopropylmethyl)-2-oxo-ethyl]carbamate (200 mg, 0.43 mmol, 1 eq) in THF (2 mL) was added Pd/C (100 mg, 10% purity) under N2. The suspension was degassed under vacuum and purged with H2several times. The mixture was stirred under H2(15 psi) 25° C. for 16 h. The reaction mixture was filtered and the filtrate was concentrated under pressure reduce. Compound (2S)-2-amino-N-[(1R,2S,6R,7R)-8-cyano-3,5-dioxo-4-azatricyclo[5.2.2.02′6]undecan-8-yl]-3-cyclopropyl-propanamide (140 mg, crude) was obtained as colorless oil.

Example 155. Synthesis of Viral Protease Inhibitor Compound 491

A mixture of methyl (2S)-2-[[(2S)-3-cyclopropyl-2-[(4-methoxy-1H-indole-2-carbonyl)amino]propanoyl]amino]-3-[(3S)-2-oxo-3-piperidyl]propanoate (246.3 mg, 0.47 mmol, 92.5% purity, 1 eq) in NH3(7 M, 6.72 mL, 100 eq) (7M in MeOH) was stirred at 80° C. for 36 h in a sealed tube. The reaction mixture was concentrated in vacuum. Compound N-[(1S)-2-[[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxo-3-piperidyl]methyl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-ethyl]-4-methoxy-1H-indole-2-carboxamide (220 mg, crude) was obtained as yellow solid, which was used into the next step without further purification.

Example 156. Synthesis of Viral Protease Inhibitor Compound 493

To a solution of 1-acetylimidazolidin-2-one (1.3 g, 10.31 mmol, 1 eq) in DMA (10 mL) was added NaH (618.6 mg, 15.47 mmol, 60% purity, 1.5 eq) at 25° C. and the mixture was stirred at 45° C. for 15 min. Then methyl (2R)-2-(benzyloxycarbonylamino)-3-bromo-propanoate (3.2 g, 10.31 mmol, 1 eq) in DMA (30 mL) was added to the mixture at 45° C. and the resulting mixture was stirred at 45° C. for 15 min. LC-MS showed the desired compound was detected. TLC (petroleum ether:ethyl acetate=0:1) showed new spot was detected. The reaction mixture was diluted with H2O (20 mL) and extracted with ethyl acetate (20 mL*3). The combined organic phase was washed with brine (10 mL*3), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0-80% petroleum ether/ethyl acetate ethergradient @ 30 mL/min). Compound methyl (2S)-3-(3-acetyl-2-oxo-imidazolidin-1-yl)-2-(benzyloxycarbonylamino)propanoate (1.5 g, 40.0% yield) was obtained as yellow oil.

To a solution of 4 (450 mg, 1.47 mmol, 1 eq) in MeOH (3 mL) was added Pd/C (0.2 g, 10% purity) under N2. The suspension was degassed under vacuum and purged with H2several times. The mixture was stirred under H2(15 psi) at 25° C. for 1 h. TLC (dichloromethane:methanol=10/1, Ninhydrin). The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The crude product was used into the next step without further purification, and 2-amino-3-(2-oxoimidazolidin-1-yl)propanamide (250 mg, crude) was obtained as a white solid.

To a solution of tert-butyl (2S)-3-cyclopropyl-2-[(4-methoxy-1H-indole-2-carbonyl)amino]propanoate (100 mg, 0.27 mmol, 1 eq) in DCM (1 mL) was added TFA (7.7 g, 67.5 mmol, 5.0 mL, 242.05 eq) and the resulting mixture was stirred at 25° C. for 1 h. TLC (petroleum ether:ethyl acetate=2/1, UV). The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether/ethyl acetate=100/1 to 2/1) to give (2S)-3-cyclopropyl-2-[(4-methoxy-1H-indole-2-carbonyl)amino]propanoic acid (50 mg, 59.2% yield) as a white solid.

Example 157. Synthesis of Viral Protease Inhibitor Compound 495

Example 158. Synthesis of Viral Protease Inhibitor Compound 496

To a solution of methyl 4,4-difluoro-2-[(4-methoxy-1H-indole-2-carbonyl)amino]pentanoate (357 mg, 1.05 mmol, 1 eq) in THF (3 mL) and MeOH (1 mL) was added LiOH·H2O (132.0 mg, 3.15 mmol, 3 eq) in H2O (2 mL) at 0° C., The mixture was stirred at 0° C. for 20 min. The pH of the reaction was adjusted to about 4 with 4 M HCl. The reaction mixture was diluted with H2O (5 mL) and extracted with ethyl acetate (5 mL*3). The combined organic phase was washed with brine (5 mL*3), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The crude product was used into the next step without further purification. Compound 4,4-difluoro-2-[(4-methoxy-1H-indole-2-carbonyl)amino]pentanoic acid (321 mg, 93.7% yield) was obtained as a light yellow solid.

Example 159. Synthesis of Viral Protease Inhibitor Compound 501

Example 160. Synthesis of Viral Protease Inhibitor Compound 505

Example 161. Synthesis of Viral Protease Inhibitor Compound 504

Example 162. Synthesis of Viral Protease Inhibitor Compound 509

Example 163. Synthesis of Viral Protease Inhibitor Compound 515

To a mixture of 4-methoxy-1H-indole-2-carboxylic acid (500 mg, 2.62 mmol, 1 eq) in DCM (10 mL) was added BBr3(1.31 g, 5.23 mmol, 2 eq) at 0° C. The mixture was stirred at 25° C. for 16 h. The mixture was diluted with H2O (30 mL) and extracted with DCM (60 mL, which was extracted as 30 mL*2). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give 4-hydroxy-1H-indole-2-carboxylic acid (200 mg, crude) as a red solid. MS (ESI) m/z 176.1 [M−H]+

Example 164. Synthesis of Viral Protease Inhibitor Compound 519

A mixture of methyl (2S)-2-[[(2S)-2-(tert-butoxycarbonylamino)-3-cyclopropyl-propanoyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (230 mg, 578.67 umol, 1 eq) in HCl/MeOH (3 mL) was stirred at 25° C. for 30 min. The reaction mixture was concentrated under reduced pressure to give the crude methyl (2S)-2-[[(2S)-2-amino-3-cyclopropyl-propanoyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (170 mg, 571.72 umol, 98.80% yield) as a white solid.

To a mixture of N-[(1S)-2-[[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-ethyl]-5-chloro-1H-indole-2-carboxamide (100 mg, 217.43 umol, 1 eq) in DCM (2 mL) was added Burgess reagent (103.63 mg, 434.85 umol, 2 eq) in one portion at 25° C. The mixture was stirred at 25° C. for 4 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (neutral condition) to give 5-chloro-N-[(1S)-2-[[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-ethyl]-1H-indole-2-carboxamide (33 mg, 74.68 umol, 34.35% yield) as a white solid. MS (ESI) m/z 442.1 [M+H]+

Example 165. Synthesis of Viral Protease Inhibitor Compound 531

Example 166. Synthesis of Viral Protease Inhibitor Compound 539

Example 167. Synthesis of Viral Protease Inhibitor Compound 547

Example 168. Synthesis of Viral Protease Inhibitor Compound 549

To a mixture of methyl (2S)-2-[[(2S,4R)-1-(4-methoxy-1H-indole-2-carbonyl)-4-(trifluoromethyl)pyrrolidine-2-carbonyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (250 mg, 476.65 umol, 1 eq) was added NH3/MeOH (7 M, 3 mL, 44.06 eq) in one portion at 25° C. under N2. The mixture was stirred at 80° C. for 12 h. Upon completion, the reaction mixture was cooled to 25° C. and concentrated to get the crude product. The crude product was purified by prep-TLC (dichloromethane:methanol=10:1, Rf=0.3) to give (2S,4R)-1-(4-methoxy-1H-indole-2-carbonyl)-N-[(1S)-1-(nitrosomethyl)-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-4-(trifluoromethyl)pyrrolidine-2-carboxamide (130 mg, 247.51 umol, 51.93% yield, 97% purity) as a light yellow solid. MS (ESI) m/z 510.2 [M+H]+.

Example 169. Synthesis of Viral Protease Inhibitor Compound 551

Example 170. Synthesis of Viral Protease Inhibitor Compound 555

Example 171. Synthesis of Viral Protease Inhibitor Compound 557

A mixture of tert-butyl 1-[[(1S)-2-methoxy-2-oxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]ethyl]carbamoyl]isoindoline-2-carboxylate (720 mg, 1.67 mmol, 1 eq) in HCl/dioxane (4 M, 8.34 mL, 20 eq) was degassed and purged with N2for 3 times, and then the mixture was stirred at 20° C. for 0.5 h under N2atmosphere. Upon completion, the reaction mixture was concentrated under reduced pressure to get the product methyl (2S)-2-(isoindoline-1-carbonylamino)-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (770 mg, crude, HCl) as a brown oil. MS (ESI) m/z 332.3[M+H]+.

Example 172. Synthesis of Viral Protease Inhibitor Compound 577

Example 173. Synthesis of Viral Protease Inhibitor Compound 589

Example 174. Synthesis of Viral Protease Inhibitor Compound 590

To a solution of 4-methyl-3-nitro-1H-pyridin-2-one (1 g, 6.49 mmol, 1 eq) in DMF (15 mL) was added NaH (363.3 mg, 9.08 mmol, 60% purity, 1.4 eq) at 0° C., and the reaction mixture was stirred at 25° C. for 0.5 h. Then, to the reaction was added methyl (2R)-2-bromo-3-cyclopropyl-propanoate (1.34 g, 6.49 mmol, 1 eq) at 0° C. The mixture was stirred at 25° C. for 16 h under N2. The mixture was quenched with H2O (20 mL), and extracted with ethyl acetate (50 mL*3). The combined organic layers was washed with brine (40 mL) dried over Na2SO4, filtered and concentrated under reduce pressure. The residue was purified by flash silica gel chromatography (ISCO®; 24 g SepaFlash® Silica Flash Column, Eluent of 0-50% ethyl acetate/petroleum ether gradient @ 35 mL/min) to give methyl (2S)-3-cyclopropyl-2-(4-methyl-3-nitro-2-oxo-1-pyridyl)propanoate (867 mg, 47.4% yield) as a yellow solid.

A mixture of methyl (2S)-3-cyclopropyl-2-(4-methyl-3-nitro-2-oxo-1-pyridyl)propanoate (867 mg, 3.09 mmol, 1 eq), LiOH·H2O (519.2 mg, 12.37 mmol, 4 eq) in THF (6 mL), MeOH (2 mL), H2O (2 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 25° C. for 1 h under N2atmosphere. LCMS showed one peak with desired MS was detected. The mixture was added H2O (5 mL), and then the mixture was added 2 M HCl (4 mL) to adjust the pH of the mixture to about 6-7. The mixture was extracted with ethyl acetate (30 mL*3). The combined organic layers was washed with brine (20 mL) dried over Na2SO4, filtered and concentrated under reduce pressure to give (2S)-3-cyclopropyl-2-(4-methyl-3-nitro-2-oxo-1-pyridyl)propanoic acid (791 mg, 94.8% yield) as a yellow solid.

A mixture of 2-(3-amino-4-methyl-2-oxo-1-pyridyl)-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-3-cyclopropyl-propanamide (100 mg, 0.26 mmol, 1 eq) in Boc2O (1 mL) and THF (1 mL), and then the mixture was stirred at 66° C. for 16 h under N2atmosphere. The mixture was concentrated under reduce pressure. The mixture was quenched with H2O (20 mL), and extracted with ethyl acetate (30 mL*3). The combined organic layers was washed with brine (10 mL) dried over Na2SO4, filtered and concentrated under reduce pressure. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX 80*40 mm*3 um; mobile phase: [water (0.05% NH3H2O+10 mM NH4HCO3)-ACN]; B %: 26%-56%, 7.8 min) to give tert-butyl N-[1-[2-[[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-ethyl]-4-methyl-2-oxo-3-pyridyl]carbamate (44.33 mg, 33.5% yield) as a white solid.

Example 175. Synthesis of Viral Protease Inhibitor Compound 591

Example 176. Synthesis of Viral Protease Inhibitor Compound 611

To a solution of (2S,4S)-1-tert-butoxycarbonyl-4-phenyl-pyrrolidine-2-carboxylic acid (100 mg, 0.34 mmol, 1 eq) and DMAP (125.8 mg, 1.03 mmol, 3 eq) in DCM (0.7 mL) was added EDCI (78.9 mg, 0.41 mmol, 1.2 eq), and then a solution of methyl (2S)-2-amino-3-[(3S)-2-oxo-3-piperidyl]propanoate (81.2 mg, 0.34 mmol, 1 eq, HCl) in DMF (0.7 mL) was added. The reaction mixture was stirred at 25° C. for 2 h. LCMS showed one peak with desired MS was detected. The mixture was quenched with H2O (10 mL), and extracted with ethyl acetate (20 mL*3). The combined organic layers was washed with brine (10 mL) dried over Na2SO4, filtered and concentrated under reduce pressure. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0-10% DCM/MeOH @ 30 mL/min) to give tert-butyl (2S,4S)-2-[[(1S)-2-methoxy-2-oxo-1-[[(3S)-2-oxo-3-piperidyl]methyl]ethyl]carbamoyl]-4-phenyl-pyrrolidine-1-carboxylate (100 mg, 60.4% yield) as a white solid.

A mixture of tert-butyl (2S,4S)-2-[[(1S)-2-methoxy-2-oxo-1-[[(3S)-2-oxo-3-piperidyl]methyl]ethyl]carbamoyl]-4-phenyl-pyrrolidine-1-carboxylate (90 mg, 0.17 mmol, 1 eq, HCl) in 2 M HCl/EtOAc (6 mL), and then the mixture was stirred at 25° C. for 3 h under N2atmosphere. LCMS showed one peak with desired MS was detected. The mixture was concentrated under reduce pressure to give methyl (2S)-3-[(3S)-2-oxo-3-piperidyl]-2-[[(2S,4S)-4-phenylpyrrolidine-2-carbonyl]amino]propanoate (70 mg, 83.3% yield, HCl) was obtained as a yellow solid.

To a solution of 4-methoxy-1H-indole-2-carboxylic acid (40.5 mg, 0.21 mmol, 1.5 eq) and DMAP (51.8 mg, 0.42 mmol, 3 eq) in DCM (0.5 mL) was added EDCI (32.5 mg, 0.16 mmol, 1.2 eq), and then a solution of methyl (2S)-3-[(3S)-2-oxo-3-piperidyl]-2-[[(2S,4S)-4-phenylpyrrolidine-2-carbonyl]amino]propanoate (58 mg, 0.14 mmol, 1 eq, HCl) in DMF (0.5 mL) was added. The reaction mixture was stirred at 0° C. for 1 h. LCMS showed one peak with desired MS was detected. The mixture was quenched with H2O (20 mL) and then extracted with ethyl acetate (30 mL*3). The combined organic layers was washed with brine (10 mL) dried over Na2SO4, filtered and concentrated under reduce pressure. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0-10% DCM/MeOH @ 30 mL/min) to give methyl (2S)-2-[[(2S,4S)-1-(4-methoxy-1H-indole-2-carbonyl)-4-phenyl-pyrrolidine-2-carbonyl]amino]-3-[(3S)-2-oxo-3-piperidyl]propanoate (30 mg, 36.6% yield) as a white solid.

To a solution of methyl (2S)-2-[[(2S,4S)-1-(4-methoxy-1H-indole-2-carbonyl)-4-phenyl-pyrrolidine-2-carbonyl]amino]-3-[(3S)-2-oxo-3-piperidyl]propanoate (30 mg, 54.8 umol, 1 eq) and NH3(7 M, 6 mL, 765.2 eq) and MeOH (6 mL) in sealed tube. The mixture was stirred at 60° C. for 16 h. LCMS showed one peak with desired MS was detected. The mixture was concentrated under reduce pressure to give compound (2S,4S)-N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxo-3-piperidyl]methyl]ethyl]-1-(4-methoxy-1H-indole-2-carbonyl)-4-phenyl-pyrrolidine-2-carboxamide (29 mg, 99.40% yield) as a yellow solid.

To a solution of (2S,4S)-N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxo-3-piperidyl]methyl]ethyl]-1-(4-methoxy-1H-indole-2-carbonyl)-4-phenyl-pyrrolidine-2-carboxamide (29 mg, 54.5 umol, 1 eq) in DCM (1 mL) was added Burgess reagent (39.0 mg, 0.16 mmol, 3 eq) at 0° C. The mixture was stirred at 25° C. for 16 hr. LCMS showed one peak with desired MS was detected. The mixture was quenched with H2O (5 mL), and extracted with ethyl acetate (10 mL*3). The combined organic layers was washed with brine (10 mL) dried over Na2SO4, filtered and concentrated under reduce pressure. The residue was purified by prep-HPLC (column: Welch Xtimate C18 150*25 mm*5 um; mobile phase: [water (0.225% FA)-ACN]; B %: 37%-67%, 9.5 min) to give compound (2S,4S)-N-[(1S)-1-cyano-2-[(3S)-2-oxo-3-piperidyl]ethyl]-1-(4-methoxy-1H-indole-2-carbonyl)-4-phenyl-pyrrolidine-2-carboxamide (1.9 mg, 6.6% yield) as a white solid.

Example 177. Synthesis of Viral Protease Inhibitor Compound 619

To a solution of (2S)-2-amino-N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxo-3-piperidyl]methyl]ethyl]-3-cyclopropyl-propanamide (120.0 mg, 0.40 mmol, 1 eq) and 5-methoxy-1H-indole-2-carboxylic acid (77.4 mg, 0.40 mmol, 1 eq) DMF (2 mL) was added HATU (184.7 mg, 0.48 mmol, 1.2 eq) and DIEA (104.6 mg, 0.8 mmol, 0.14 mL, 2 eq). The mixture was stirred at 25° C. for 0.5 h, and then the reaction mixture was concentrated under reduced pressure to remove DMF. The residue was diluted with H2O (10 mL) and extracted with ethyl acetate (25 mL*3). The combined organic layers were washed with Brine (10 mL*3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0-10% Methanol/Dichloromethane@ 20 mL/min). Compound N-[(1S)-2-[[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxo-3-piperidyl]methyl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-ethyl]-5-methoxy-1H-indole-2-carboxamide (180.0 mg, 94.6% yield) was obtained as a white solid.

To a solution of N-[(1S)-2-[[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxo-3-piperidyl]methyl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-ethyl]-5-methoxy-1H-indole-2-carboxamide (180.0 mg, 0.38 mmol, 1 eq) in DCM (0.5 mL) was added Burgess reagent (274.0 mg, 1.15 mmol, 3 eq) at 0° C. After the mixture was stirred at 25° C. for 16 h, the reaction mixture was concentrated under reduced pressure to remove DCM. The residue was diluted with H2O (5 mL) and extracted with DCM (10 mL*3). The combined organic layers were washed with Brine (5 mL*3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX 80*40 mm*3 um; mobile phase: [water (0.05% NH3H2O+10 mM NH4HCO3)-ACN]; B %: 24%-54%, 7.8 min). Compound N-[(1S)-2-[[(1S)-1-cyano-2-[(3S)-2-oxo-3-piperidyl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-ethyl]-5-methoxy-1H-indole-2-carboxamide (37.3 mg, 82.6 umol, 5.4 yield) was obtained as a white solid.

Example 178. Synthesis of Viral Protease Inhibitor Compound 621

To a solution of benzyl N-[(1S)-2-[[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxo-3-piperidyl]methyl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-ethyl]carbamate (400 mg, 0.92 mmol, 1 eq) in MeOH (5 mL) was added Pd (200 mg, 10% purity) and H2(0.92 mmol). The mixture was stirred at 25° C. under 15 psi for 1 h. LCMS showed one peak with desired MS was detected. The mixture was filtered to give the filter liquor. The mixture was concentrated under reduce pressure to give (2S)-2-amino-N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxo-3-piperidyl]methyl]ethyl]-3-cyclopropyl-propanamide (274 mg, 99.5% yield) as a white solid.

Example 179. Synthesis of Viral Protease Inhibitor Compound 623

To a solution of methyl 4-methoxy-1H-pyrrolo[3,2-c]pyridine-2-carboxylate (150 mg, 0.72 mmol, 1 eq) in THF (1 mL) was added LiOH·H2O (30.5 mg, 0.72 mmol, 1 eq) and MeOH (0.5 mL). The mixture was stirred at 25° C. for 16 h. The reaction mixture was diluted with H2O (30 mL) and extracted with DCM (30 mL*3). The aqueous layer acidified with concentrated HCl and extracted with DCM. The combined organic layers were washed with brine (30 mL*2), dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was triturated with petroleum ether at 25° C. for 60 min. Compound 4-methoxy-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid (120 mg, 84.9% yield, 99% purity) was obtained as white solid.

Example 180. Synthesis of Viral Protease Inhibitor Compound 625

To a stirred solution of methyl (2S)-2-[[(2S)-2-(benzyloxycarbonylamino)-3-cyclopropyl-propanoyl]amino]-3-[(3S)-2-oxo-3-piperidyl]propanoate (4.5 g, 10.10 mmol, 1 eq) in MeOH (10 mL) was added with a solution of NH3(7 M, 50 mL, 34.65 eq). The mixture was allowed to stir at 80° C. for 24 h in a sealed tube. TLC (DCM/MeOH=10:1, I2). LCMS detected the desired compound. The reaction mixture concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 24 g SepaFlash® Silica Flash Column, Eluent of 0-5% DCM/MeOH @ 40 mL/min). Compound benzyl N-[(1S)-2-[[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxo-3-piperidyl]methyl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-ethyl]carbamate (3.6 g, 7.69 mmol, 76.17% yield, 92% purity) was obtained as a white solid.

To a solution of benzyl N-[(1S)-2-[[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxo-3-piperidyl]methyl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-ethyl]carbamate (800 mg, 1.86 mmol, 1 eq) in MeOH (3 mL) was added Pd/C (100 mg, 1.86 mmol, 10% purity, 1 eq). The mixture was stirred at 25° C. for 2 h under H2(15 psi). LCMS indicated starting was consumed completely and detected desired compound. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. Compound (2S)-2-amino-N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxo-3-piperidyl]methyl]ethyl]-3-cyclopropyl-propanamide (550 mg, 1.86 mmol, 99.87% yield) was obtained as colorless oil.

Example 181. Synthesis of Viral Protease Inhibitor Compound 669

To a solution of ethyl 4-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (300 mg, 1.34 mmol, 1 eq) in THF (5 mL) and MeOH (2 mL) was added LiOH·H2O (280.2 mg, 6.68 mmol, 5 eq) and H2O (2 mL). The mixture was stirred at 25° C. for 16 h. The reaction mixture was concentrated under reduced pressure to remove MeOH and THF. Then the pH of the residue was adjusted (neutralized) to about 6-7 with 2 M HCl, filtered, and then the cake concentrated under reduced pressure to give a residue. 4-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (190 mg, 0.96 mmol, 72.3% yield) was obtained as a white solid.

Example 182. Synthesis of Viral Protease Inhibitor Compound 633

To a solution of (2S)-2-amino-N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxo-3-piperidyl]methyl]ethyl]-3-cyclopropyl-propanamide (100.0 mg, 0.33 mmol, 1 eq) and 5-chloro-1H-indole-2-carboxylic acid (66.0 mg, 0.33 mmol, 1 eq) in DMF (2 mL) was added HATU (153.9 mg, 0.40 mmol, 1.2 eq) and DIEA (87.2 mg, 0.67 mmol, 0.11 mL, 2 eq). The mixture was stirred at 25° C. for 0.5 h. The reaction mixture was concentrated under reduced pressure to remove DMF. The residue was diluted with H2O (10 mL) and extracted with ethyl acetate (25 mL*3). The combined organic layers were washed with Brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0-10% Methanol/Dichloromethane@ 20 mL/min). Compound N-[(1S)-2-[[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxo-3-piperidyl]methyl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-ethyl]-5-chloro-1H-indole-2-carboxamide (150.0 mg, 90.9% yield) was obtained as a yellow solid.

To a solution of N-[(1S)-2-[[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxo-3-piperidyl]methyl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-ethyl]-5-chloro-1H-indole-2-carboxamide (129.0 mg, 0.27 mmol, 1 eq) in DCM (2.5 mL) was added Burgess reagent (259.4 mg, 1.09 mmol, 4 eq) at 0° C. The mixture was stirred at 25° C. for 3 h. The reaction mixture was concentrated under reduced pressure to remove DCM. The residue was diluted with H2O (15 mL) and extracted with ethyl acetate (30 mL*3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX 80*40 mm*3 um; mobile phase: [water (0.05% NH3H2O+10 mM NH4HCO3)-ACN]; B %: 31%-61%, 7.8 min). Compound 5-chloro-N-[(1S)-2-[[(1S)-1-cyano-2-[(3S)-2-oxo-3-piperidyl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-ethyl]-1H-indole-2-carboxamide (40.2 mg, 30.2% yield) was obtained as a white solid.

Example 183. Synthesis of Viral Protease Inhibitor Compound 635

To a solution of benzyl N-[(1S)-2-[[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxo-3-piperidyl]methyl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-ethyl]carbamate (400 mg, 0.92 mmol, 1 eq) in MeOH (5 mL) was added Pd (200 mg, 10% purity) and H2(0.92 mmol). The mixture was stirred at 25° C. under 15 psi for 1 h. The mixture was filtered to give the filter liquor and the reaction was concentrated under reduce pressure to give (2S)-2-amino-N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxo-3-piperidyl]methyl]ethyl]-3-cyclopropyl-propanamide (274 mg, 0.92 mmol, 99.5% yield) as a white solid.

Example 184. Synthesis of Viral Protease Inhibitor Compound 637

To a solution of NaOH (0.8 g, 20.0 mmol, 20.2 eq) in H2O (10 mL) was added 4,7-dichloro-2-(trichloromethyl)-1H-benzo[d]imidazole (0.3 g, 985.58 umol, 1 eq) at 0° C. The mixture was stirred at 25° C. for 1 h. The pH of the mixture was adjusted with HCl (2 M) to 2-3 and then the mixture was filtered to give 4,7-dichloro-1H-benzo[d]imidazole-2-carboxylic acid (0.2 g, crude) as a white solid.

Example 185. Synthesis of Viral Protease Inhibitor Compound 639

Example 186. Synthesis of Viral Protease Inhibitor Compound 643

Example 187. Synthesis of Viral Protease Inhibitor Compound 653

Example 188. Synthesis of Viral Protease Inhibitor Compound 655

A solution of (2S,4R)-di-tert-butyl 4-hydroxypyrrolidine-1,2-dicarboxylate (4 g, 13.92 mmol, 1 eq) in DCM (40 mL) was added CBr4(14.08 g, 42.46 mmol, 3.05 eq) at 25° C. The mixture was cooled to 0° C., and PPh3(11.32 g, 43.15 mmol, 3.1 eq) was added carefully. The reaction was stirred at 25° C. for 15 h. Upon completion, ethanol (4 mL) was added, and the solution was stirred for 2 h. MTBE (40 mL) was added dropwise to precipitate the phosphine oxide, which was filtered off, and the filter cake was washed with DCM (30 mL*2). The filtrate was concentrated under reduced pressure to give a brown oil. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate=100:0 to 10:1) to give (2S,4S)-di-tert-butyl 4-bromopyrrolidine-1,2-dicarboxylate (1.5 g, 4.07 mmol, 29.23% yield, 95% purity) as a light yellow oil.

A mixture of phenylsulfanylcopper (1.58 g, 9.14 mmol, 6.4 eq) in dry THF (30 mL) was cooled to −70° C. and treated with careful addition of t-BuLi (1.3 M, 7.03 mL, 6.4 eq). This yellow mixture was stirred for 30 min, and a precooled (−20° C.) solution of (2S,4S)-di-tert-butyl 4-bromopyrrolidine-1,2-dicarboxylate (500 mg, 1.43 mmol, 1 eq) in dry THF (5 mL) was added. The reaction was stirred at −70° C. for 5 h, and then warmed to 25° C. for 15 h under N2. Upon completion, the reaction was quenched by pouring into a solution of saturated aqueous NH4Cl (30 mL). The aqueous mixture was stirred vigorously for 30 min. Solids were filtered off, and the phases were separated. The aqueous phase was extracted with MTBE (10 mL*3), and the combined organic phases were washed with saturated aqueous NaHCO3(10 mL) and brine (10 mL), dried over Na2SO4, concentrated under reduced pressure to give a crude. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate=100:0 to 10:1) to give (2S,4S)-di-tert-butyl 4-(tert-butyl)pyrrolidine-1,2-dicarboxylate (290 mg, 797.05 umol, 55.83% yield, 90% purity) as an off-white solid.

Example 189. Synthesis of Viral Protease Inhibitor Compound 659

To a solution of (2S)-2-(tert-butoxycarbonylamino)-4,4-dimethyl-pentanoic acid (5 g, 20.38 mmol, 1 eq) in THF (100 mL) at 0° C. was added BH3-Me2S (10 M, 4.08 mL, 2.0 eq) drop-wise slowly, and then the mixture was stirred at 20° C. for 15 h. The reaction mixture was added into MeOH (40 mL) and stirred for 20 min. After concentrating the mixture, the residue was diluted with aq. NaHCO3(150 mL) and extracted with DCM (100 mL*3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate=1:0 to 1:1) to afford tert-butyl N-[(1S)-1-(hydroxymethyl)-3,3-dimethyl-butyl]carbamate (2.5 g, 10.81 mmol, 53.02% yield) as a colorless oil.

To a solution of tert-butyl N-[(1S)-1-(hydroxymethyl)-3,3-dimethyl-butyl]carbamate (2.4 g, 10.37 mmol, 1 eq) in DCM (40 mL) was added Dess-Martin periodinane (5.72 g, 13.49 mmol, 4.18 mL, 1.3 eq) at 0° C. stirred for 1 h, and then the mixture was warm to 20° C. and stirred for 1 h. The reaction mixture was quenched by addition H2O 60 mL at 0° C., and then aq. NaHCO3was added drop-wise to adjust the pH of the mixture to about 8 at 0° C. and extracted with EtOAc (40 mL*3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate=0:1 to 1:1) to afford tert-butyl N-[(1S)-1-formyl-3,3-dimethyl-butyl]carbamate (1.6 g, 6.98 mmol, 67.25% yield) as a colorless oil.

Example 190. Synthesis of Viral Protease Inhibitor Compound 667

A mixture of compound methyl (S)-2-((S)-2-((tert-butoxycarbonyl)amino)-4-fluoro-4-methylpentanamido)-3-((S)-2-oxopiperidin-3-yl)propanoate (520 mg, 1.21 mmol, 1 eq) in HCl/EtOAc (4 mL) was stirred at 25° C. for 0.5 h. The mixture was concentrated under reduced pressure to give compound methyl (S)-2-((S)-2-amino-4-fluoro-4-methylpentanamido)-3-((S)-2-oxopiperidin-3-yl)propanoate (550 mg, crude, HCl, yellow oil) was used into the next step.

A solution of compound methyl (S)-2-((S)-4-fluoro-2-(4-methoxy-1H-indole-2-carboxamido)-4-methylpentanamido)-3-((S)-2-oxopiperidin-3-yl)propanoate (1 g, 1.98 mmol, 1 eq) in NH3(7 M in MeOH, 14.16 mL, 50 eq) was stirred at 80° C. for 16 h in a 30 mL of sealed tube. TLC (DCM/MeOH=10/1, UV). The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0-15% MeOH/Ethyl acetate @ 30 mL/min) to give compound N-((S)-1-(((S)-1-amino-1-oxo-3-((S)-2-oxopiperidin-3-yl)propan-2-yl)amino)-4-fluoro-4-methyl-1-oxopentan-2-yl)-4-methoxy-1H-indole-2-carboxamide (370 mg, 0.74 mmol, 37.2% yield, 97.6% purity) as a yellow solid.

Example 191. Synthesis of Viral Protease Inhibitor Compound 681

Example 192. Synthesis of Viral Protease Inhibitor Compound 711

A mixture of methyl (2S)-2-[[(2S)-2-(tert-butoxycarbonylamino)-3-cyclopropyl-propanoyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (900 mg, 1.81 mmol, 80% purity, 1 eq) in HCl/MeOH (4 M, 12.00 mL, 26.50 eq) was stirred at 25° C. for 1 h. Upon completion, the mixture was concentrated under reduced pressure to give a residue, then was dissolved with DCM (10 mL*3) and concentrated under reduced pressure to get product methyl (2S)-2-[[(2S)-2-amino-3-cyclopropyl-propanoyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (600 mg, crude, HCl) as a white oil. MS (ESI) m/z 298.1 [M+H]+.

Example 193. Synthesis of Viral Protease Inhibitor Compound 715

Example 194. Synthesis of Viral Protease Inhibitor Compound 639

Example 195. Synthesis of Viral Protease Inhibitor Compound 717

To a solution of benzyl N-[(1S)-2-[[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxo-3-piperidyl]methyl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-ethyl]carbamate (600 mg, 1.39 mmol, 1 eq) in THF (1 mL) was added Pd/C under N2atmosphere. The suspension was degassed and purged with H2for 3 times. The mixture was stirred under H2(15 Psi or atm.) at 25° C. for 2 h. Pd/C was filtered and the reaction was concentrated under reduced pressure to give a residue. Compound (2S)-2-amino-N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxo-3-piperidyl]methyl]ethyl]-3-cyclopropyl-propanamide (400 mg, crude) was obtained as a colorless oil.

Example 196. Synthesis of viral protease inhibitor compound potassium (2S)-1-hydroxy-2-((2S,4S)-1-(4-methoxy-1H-indole-2-carbonyl)-4-phenylpyrrolidine-2-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propane-1-sulfonate

Example 197. Synthesis of (S)-2-amino-3-((S)-2-oxopyrrolidin-3-yl)propanenitrile hydrochloride

Dimethyl (4R)-2-(tert-butoxycarbonylamino)-4-(cyanomethyl)pentanedioate (15 g, 47.72 mmol, 1 eq) was dissolved in MeOH (250 mL), and CoCl2·6H2O (6.81 g, 28.63 mmol, 0.6 eq) was added under 0° C. After adding NaBH4 (10.83 g, 286.32 mmol, 6 eq) slowly in batches, the reaction was carried out at 25° C. for 12 h. TLC (petroleum ether/ethyl acetate=1:2, I2). After the reaction was completed, 100 mL of saturated ammonium chloride solution was added to quench the reaction. The organic phase was collected by filtration, the solvent was distilled off under reduced pressure, and extracted with EtOAc (150 mL*3), and the organic phase was collected. The organic phase was washed with saturated brine (100 mL). The organic phase was dried over anhydrous Na2SO4, the filtrate was collected by filtration, and the solvent was evaporated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0-80% ethyl acetate/petroleum ether gradient @ 40 mL/min). (S)-Methyl 2-((tert-butoxycarbonyl)amino)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (7 g, 24.45 mmol, 51.2% yield, 100% purity) was obtained as a white solid.

To a solution of methyl (2S)-2-(tert-butoxycarbonylamino)-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (2 g, 6.99 mmol, 1 eq) in MeOH (10 mL) was added a solution of NH3(7 M, 24.00 mL, 24.05 eq). The mixture was allowed to stir at 60° C. for 16 h in sealed tube. The reaction mixture was concentrated under reduced pressure to give a residue. Compound tert-butyl ((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)carbamate (1.8 g, 6.63 mmol, 94.9% yield) was obtained as a yellow solid.

To a solution of tert-butyl N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]ethyl]carbamate (1 g, 3.69 mmol, 1 eq) in DCM (10 mL) was added Burgess reagent (3.51 g, 14.74 mmol, 4 eq). The mixture was stirred at 25° C. for 1 h under N2. The reaction mixture was added H2O (10 mL) and extracted with DCM (10 mL*3). The combined organic layers were washed with brine (20 mL), dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0-70% ethyl acetate/petroleum ether gradient @ 30 mL/min). Compound tert-butyl N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]carbamate (900 mg, 3.23 mmol, 87.7% yield, 91% purity) was obtained as a white solid.

To a solution of tert-butyl N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]carbamate (600 mg, 2.37 mmol, 1 eq) in EtOAc (20 mL) was added HCl/EtOAc (4 M, 4.00 mL, 6.75 eq). The mixture was stirred at 25° C. for 2 h. LCMS showed starting material was consumed and detected desired compound. The reaction mixture was concentrated under reduced pressure to give a residue. Compound (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3-yl]propanenitrile (440 mg, 2.32 mmol, 97.9% yield, HCl) was obtained as a white solid.

Example 198. Synthesis of viral protease inhibitor compound 842

Example 199. Synthesis of Viral Protease Inhibitor Compound 852

To a solution of ethyl 7-bromo-5-fluoro-1H-indole-2-carboxylate (800 mg, 2.80 mmol, 1 eq) in THF (8 mL) and H2O (4 mL) was added LiOH·H2O (117.34 mg, 2.80 mmol, 1 eq) at 40° C. The mixture was stirred at 40° C. for 16 h. Upon completion of reaction, the mixture was concentrated in vacuum and then the pH was adjusted to about 1 with 1 M HCl (10 mL), and was extracted with ethyl acetate (10 mL*3) to obtain 7-bromo-5-fluoro-1H-indole-2-carboxylic acid (700 mg, crude) as a yellow solid. MS (ESI) m/z 256.0 [M−H]+

A solution of (S)-methyl 2-((S)-2-(7-bromo-5-fluoro-1H-indole-2-carboxamido)-3-cyclopropylpropanamido)-3-((S)-2-oxopiperidin-3-yl) propanoate (1 g, 1.81 mmol, 1 eq) in NH3/MeOH (30 mL, 7M) was stirred at 30° C. for 16 h. The mixture was concentrated in vacuum. Upon completion of reaction, the mixture was concentrated in vacuum to obtain N-((S)-1-(((S)-1-amino-1-oxo-3-((S)-2-oxopiperidin-3-yl)propan-2-yl)amino)-3-cyclopropyl-1-oxopropan-2-yl)-7-bromo-5-fluoro-1H-indole-2-carboxamide (800 mg, crude) as a light yellow solid. MS (ESI) m/z 536.2 [M+H]+

Example 200. Synthesis of Viral Protease Inhibitor Compound 876

A mixture of methyl (2S)-2-(tert-butoxycarbonylamino)-3-[(3S)-2-oxo-3-piperidyl]propanoate (1.71 g, 5.69 mmol, 1 eq) in HCl/MeOH (4 M, 20.00 mL, 14.05 eq) was stirred at 20° C. for 1 h. Upon completion, the mixture was concentrated under reduced pressure to give a residue, then was dissolved with DCM (30 mL*3) and concentrated under reduced pressure to get the product methyl (2S)-2-amino-3-[(3S)-2-oxo-3-piperidyl]propanoate (1.35 g, crude, HCl) as white oil. MS (ESI) m/z 328.3 [M+H]+.

A mixture of methyl (2S)-2-[[(2S)-2-[[4-[2-(2-methoxyethoxy)ethoxy]-1H-indole-2-carbonyl]amino]-4,4-dimethyl-pentanoyl]amino]-3-[(3S)-2-oxo-3-piperidyl]propanoate (0.52 g, 4 batches in parallel, 706.65 umol, 80% purity, 1 eq) in NH3/MeOH (7 M, 8 mL, 79.25 eq) was stirred at 80° C. for 16 h. Upon completion, the mixture was concentrated under reduced pressure to give a residue, and then was dissolved with DCM (30 mL*3). The reaction was concentrated under reduced pressure to afford N-[(1S)-1-[[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxo-3-piperidyl]methyl]ethyl]carbamoyl]-3,3-dimethyl-butyl]-4-[2-(2-methoxyethoxy)ethoxy]-1H-indole-2-carboxamide (1.3 g, crude) as a white solid. MS (ESI) m/z 574.4 [M+H]+.

Example 201. Synthesis of Viral Protease Inhibitor Compound 880

To a solution of methyl (Z)-2-azido-3-(2-chloro-3-methoxy-phenyl)prop-2-enoate (1 g, 3.74 mmol, 1 eq) in THF (30 mL) was added bis(trifluoromethylsulfonyloxy)iron (2.64 g, 7.47 mmol, 2 eq) and the mixture was stirred at 80° C. for 48 h. Upon completion, the reaction was concentrated in the vacuum and quenched by addition H2O (100 mL) and then extracted with DCM (100 mL*3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure and was purified by column chromatography (SiO2, petroleum ether/ethyl acetate=10/1 to 5/1) to afford methyl 4-chloro-5-methoxy-1H-indole-2-carboxylate (140 mg, 584.17 umol, 15.64% yield) was a brown solid. MS (ESI) m/z 240.0 [M+H]+

To a solution of methyl 4-chloro-5-methoxy-1H-indole-2-carboxylate (0.55 g, 2.29 mmol, 1 eq) in THF (5 mL), H2O (2.5 mL) was added LiOH·H2O (96.31 mg, 2.29 mmol, 1 eq), and the mixture was stirred at 60° C. for 2 h. Upon completion, the pH of the reaction mixture was adjusted to −3 with HCl. The mixture was extracted with ethyl acetate (100 mL*3). The combined organic layer was dried over Na2SO4, filtered, concentrated to give 4-chloro-5-methoxy-1H-indole-2-carboxylic acid (340 mg, crude) as a brown solid. MS (ESI) m/z 226.0 [M+H]+

Example 202. Synthesis of Viral Protease Inhibitor Compound 882

A mixture of tert-butyl 3-[[(1S)-2-methoxy-2-oxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]ethyl]carbamoyl]-2-azaspiro[4.5]decane-2-carboxylate (1.5 g, 3.32 mmol, 1 eq) in HCl/MeOH (4 M, 20 mL, 24.08 eq) was stirred at 20° C. for 1 h. Upon completion, the mixture was concentrated under reduced pressure to give a residue, then was dissolved with DCM (30 mL*3) and concentrated under reduced pressure to get product methyl (2S)-2-(2-azaspiro[4.5]decane-3-carbonylamino)-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (1.29 g, crude, HCl) as a white oil MS (ESI) m/z 352.2 [M+H]+.

A mixture of methyl (2S)-2-[[2-(7-chloro-4-methoxy-1H-indole-2-carbonyl)-2-azaspiro[4.5]decane-3-carbonyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (400 mg, 4 batches in parallel, 615.33 umol, 86% purity, 1 eq) in NH3/MeOH (7 M, 20 mL, 227.52 eq) was stirred at 50° C. for 16 h. Upon completion, the mixture was concentrated under reduced pressure to give a residue, then was dissolved with DCM (10 mL*3) and concentrated under reduced pressure to get the product N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]ethyl]-2-(7-chloro-4-methoxy-1H-indole-2-carbonyl)-2-azaspiro[4.5]decane-3-carboxamide (1.3 g, crude) as yellow solid. MS (ESI) m/z 544.3 [M+H]+.

Example 203. Synthesis of Viral Protease Inhibitor Compound 886

Example 204. Synthesis of Viral Protease Inhibitor Compound 888

A solution of methyl (2S)-2-[[(2S)-2-amino-4,4-dimethyl-pentanoyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (1 g, 2.86 mmol, 1 eq, HCl) and 7-chloro-1H-indole-2-carboxylic acid (559.10 mg, 2.86 mmol, 1 eq) in DCM (40 mL) was added with DMAP (1.05 g, 8.58 mmol, 3 eq). After the addition of EDCI (1.64 g, 8.58 mmol, 3 eq), the resulting mixture was stirred at 20° C. for 2 h. Upon completion, the reaction mixture was quenched by addition H2O (30 mL), and then extracted with DCM 40 mL (20 mL*2). The combined organic layers were washed with HCl (1M) 30 mL (15 mL*2), the combined organic layers were washed with brine (40 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether/ethyl acetate=3/1 to 0/1) to afford methyl (2S)-2-[[(2S)-2-[(7-chloro-1H-indole-2-carbonyl)amino]-4,4-dimethyl-pentanoyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (930 mg, 1.84 mmol, 64.28% yield, 97% purity) as a white solid. MS (ESI) m/z 491.2 [M+H]+.

Example 205. Synthesis of Viral Protease Inhibitor Compound 898

To a solution of methyl (2S)-2-[[(2S)-2-amino-3-cyclopropyl-propanoyl]amino]-3-[(3S)-2-oxo-3-piperidyl]propanoate (0.8 g, 2.30 mmol, 1 eq, HCl) and 7-chloro-4-methoxy-1H-indole-2-carboxylic acid (622.71 mg, 2.76 mmol, 1.2 eq) in DMF (5 mL) and DCM (20 mL) was added DMAP (842.95 mg, 6.90 mmol, 3 eq) and EDCI (881.79 mg, 4.60 mmol, 2 eq), and then the mixture was stirred at 20° C. for 2 h. Upon completion, the reaction mixture was quenched by the addition of H2O (100 mL) at 0° C., and then extracted with DCM (50 mL*3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate=5:1 to 0:1) to give the product methyl (2S)-2-[[(2S)-2-[(7-chloro-4-methoxy-1H-indole-2-carbonyl)amino]-3-cyclopropyl-propanoyl]amino]-3-[(3S)-2-oxo-3-piperidyl]propanoate (1 g, 1.83 mmol, 79.59% yield, 95% purity) as a yellow solid. MS (ESI) m/z 519.2 [M+H]+.

Example 206. Synthesis of Viral Protease Inhibitor Compound 902

To a solution of 1-(cyclohexylidenemethyl)pyrrolidine (20 g, 121.01 mmol, 1 eq) in THF (200 mL) was added a solution of ethyl (2Z)-3-bromo-2-hydroxyimino-propanoate (25.42 g, 121.01 mmol, 1 eq) in THF (200 mL) drop-wise at −10° C. under N2. After 1 h, TEA (12.24 g, 121.01 mmol, 16.84 mL, 1 eq) was added drop-wise at −10° C. under N2. The reaction mixture was stirred at 25° C. for 12 h under N2. The reaction was added with HCl (36%, 2.2 eq, 26 mL in 3.5 vol H2O) drop-wise at 25° C., and stirred at 25° C. for 1 h. The reaction mixture was quenched by the addition of H2O (350 mL) at 25° C., and extracted with ethyl acetate (200 mL*3). The combined organic layers were washed with brine (300 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether/ethyl acetate=1/0 to 1/1) to give a ethyl 1-hydroxy-2-oxa-3-azaspiro[5.5]undec-3-ene-4-carboxylate (15 g, 58.44 mmol, 48.29% yield, 94% purity) as a yellow oil. MS (ESI) m/z 242.2 [M+H]+.

To a solution of 2-tert-butyl 3-ethyl 2-azaspiro[4.5]decane-2,3-dicarboxylate (7 g, 22.48 mmol, 1 eq) in H2O (14 mL) and MeOH (56 mL) was added LiOH·H2O (1.89 g, 44.96 mmol, 2 eq). The mixture was stirred at 40° C. for 12 h. The reaction mixture was concentrated under reduced pressure to remove MeOH. The residue was diluted with H2O (80 mL) and extracted with ethyl acetate.

(50 mL*2). The aqueous phase were added HCl aq adjust to pH=2 and extracted with EA (90 mL*3), The combined organic layers were washed with brine (90 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a 2-tert-butoxycarbonyl-2-azaspiro[4.5]decane-3-carboxylic acid (6.1 g, crude) was obtained as a white solid. MS (ESI) m/z 284.2 [M+H]+

Example 207. Synthesis of Viral Protease Inhibitor Compound 906

A solution of methyl (Z)-2-azido-3-(4-chloro-2-methoxy-phenyl)prop-2-enoate (3000 mg, 11.21 mmol, 1 eq) in xylene (30 mL) was stirred for 4 h at 170° C. Upon completion, the solution was concentrated to give crude. The crude was purified by column (SiO2, petroleum ether:ethyl acetate=10:1 to 1:10) to give product methyl 6-chloro-4-methoxy-1H-indole-2-carboxylate (1500 mg, 6.26 mmol, 55.84% yield) as a white solid. MS (ESI) m/z 240.1 [M+H]+

A solution of methyl 6-chloro-4-methoxy-1H-indole-2-carboxylate (1500 mg, 6.26 mmol, 1 eq) in THF (15 mL) and H2O (15 mL) was added with LiOH·H2O (787.95 mg, 18.78 mmol, 3 eq). After stirring for 2 h at 65° C., the solution was concentrated and extracted with ethyl acetate (50 mL*2) and the water layer was adjusted pH=4-5 with HCl (con) and extracted with ethyl acetate (80 mL*3) and dried over Na2SO4and concentrated to give crude. The crude was used directly for the next step. 6-chloro-4-methoxy-1H-indole-2-carboxylic acid (1070 mg, 4.74 mmol, 75.77% yield) as a brown solid. MS (ESI) m/z 226.2 [M+H]+

A solution of methyl (2S)-2-[[(2S)-2-[(6-chloro-4-methoxy-1H-indole-2-carbonyl)amino]-3-cyclopropyl-propanoyl]amino]-3-[(3S)-2-oxo-3-piperidyl]propanoate (500 mg, 963.41 umol, 1 eq) in NH3/MeOH (7 M, 20 mL, 145.32 eq) was stirred for 17 h at 60° C. The solution was concentrated to afford N-[(1S)-2-[[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxo-3-piperidyl]methyl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-ethyl]-6-chloro-4-methoxy-1H-indole-2-carboxamide (485 mg, crude) as a white solid. The crude was used directly for the next step. MS (ESI) m/z 504.3 [M+H]+

Example 208. Synthesis of Viral Protease Inhibitor Compound 1511

To a mixture of (S)-dimethyl 2-(((benzyloxy)carbonyl)amino)-2-methylpentanedioate (920 mg, 2.42 mmol, 85% purity, 1 eq) in anhydrous THF (18.4 mL) was added LiHMDS (1 M, 5.32 mL, 2.2 eq) drop-wise under N2atmosphere at −65˜−55° C. for 0.5 h. After a further 1 h of stirring at −65˜−55° C., 2-bromoacetonitrile (435.14 mg, 3.63 mmol, 241.75 uL, 1.5 eq) was added drop-wise to the mixture solution over a period of 0.5 h while maintaining the temperature under −65˜−55° C. The reaction mixture was stirred at −65˜−55° C. for 1 h under N2. Upon completion, the reaction mixture was quenched with pre-cooled (dry-ice in EtOH) MeOH (2.8 mL) and a pre-cooled (dry-ice in EtOH) acetic acid in THF solution (0.46 mL HOAc/3.7 mL THF) in order at −60° C. After further 30 min of stirring at −60° C., the cooling bath was removed and replaced with water bath. The reaction mixture was allowed to warm up to 0±5° C. and then concentrated under reduced pressure at 30° C. to give a black brown solid. The obtained residue was dissolved in ethyl acetate (37 mL), washed with brine (18 mL*2). The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate=10:1 to 2:1) to give (2S)-dimethyl 2-(((benzyloxy)carbonyl)amino)-4-(cyanomethyl)-2-methylpentanedioate (740 mg, 1.84 mmol, 75.99% yield, 90% purity) as a yellow oil. MS (ESI) m/z 363.1 [M+H]+.

To a stirred solution of (2S)-dimethyl 2-(((benzyloxy)carbonyl)amino)-4-(cyanomethyl)-2-methylpentanedioate (740 mg, 1.84 mmol, 90% purity, 1 eq) in MeOH (34 mL) was added CoCl2.6H2O (262.37 mg, 1.10 mmol, 0.6 eq) at 0° C., and then NaBH4(419 mg, 11.08 mmol, 6.03 eq) was added into the mixture in 4 batches at 0° C. for 1 h, and then the black mixture was stirred at 25° C. for 2 h. Upon completion, the mixture was quenched with NH4Cl aq. (41 mL) at 0° C., the mixture was filtered through celite, then extracted with DCM (41 mL*3), the organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to get the crude product. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate=10:1 to 1:1) to give (2S)-methyl 2-(((benzyloxy)carbonyl)amino)-2-methyl-3-(2-oxopyrrolidin-3-yl)propanoate (320 mg, 957.03 umol, 52.07% yield) as a white solid. MS (ESI) m/z 335.2 [M+H]+.

To a mixture of (2S)-methyl 2-(((benzyloxy)carbonyl)amino)-2-methyl-3-(2-oxopyrrolidin-3-yl)propanoate (320 mg, 957.03 umol, 1 eq) in H2O (1.5 mL) and t-BuOH (6 mL) under N2was added Pd/C (160 mg, 10% purity). The resulting mixture was degassed and purged with H2for 3 times, and then the mixture was stirred under H2(15 Psi) at 25° C. for 2 h. Upon completion, the mixture was filtered through celite and the filtrate was concentrated under reduced pressure to give (2S)-methyl 2-amino-2-methyl-3-(2-oxopyrrolidin-3-yl)propanoate (140 mg, crude) as a white solid. MS (ESI) m/z 201.1 [M+H]+.

Example 209. Synthesis of Viral Protease Inhibitor Compound 749

Upon completion, the reaction mixture was filtered and then concentrated under reduced pressure to remove IPA. The residue was diluted with H2O (50 mL) and extracted with ethyl acetate (50 mL*2). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether/ethyl acetate=10/1 to 5/1) to afford benzyl N-(3-hydroxy-1,1-dimethyl-propyl)carbamate (5 g, 20.02 mmol, 59.00% yield, 95% purity) as a colorless oil. MS (ESI) m/z 238.1 [M+H]+

To a solution of benzyl N-(3-hydroxy-1,1-dimethyl-propyl)carbamate (2.2 g, 9.27 mmol, 1 eq) in DCM (1 mL) was added DMP (4.72 g, 11.13 mmol, 3.44 mL, 1.2 eq). The reaction mixture was stirred at 25° C. for 2 h. Upon completion, the reaction mixture was diluted with H2O (100 mL) and extracted with ethyl acetate (100 mL*2). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether/ethyl acetate=20/1 to 10/1) to afford N-(1,1-dimethyl-3-oxo-propyl)carbamate (1.2 g, 4.59 mmol, 49.51% yield, 90% purity) as a colorless oil. MS (ESI) m/z 236.1 [M+H]+

To a mixture of (Z)-5-(benzyloxycarbonylamino)-2-[(2S)-2-(tert-butoxycarbonylamino)-3-methoxy-3-oxo-propyl]-5-methyl-hex-2-enoic acid (250 mg, 522.43 umol, 1 eq) in DMF (2.5 mL) was added K2CO3(144.41 mg, 1.04 mmol, 2 eq) and CH3I (222.46 mg, 1.57 mmol, 97.57 uL, 3 eq). The mixture was stirred at 25° C. for 1 h. Upon completion, the reaction mixture was quenched by the addition of H2O (10 mL) at 0° C., and then diluted with H2O (10 mL) and extracted with ethyl acetate (10 mL*2). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue compound dimethyl (2Z,4S)-2-[3-(benzyloxycarbonylamino)-3-methyl-butylidene]-4-(tert-butoxycarbonylamino)pentanedioate (230 mg, 420.25 umol, 80.44% yield, 90% purity) as a colorless oil. The residue was used next step directly. MS (ESI) m/z 393.2 [M+H-100]+

To a mixture of dimethyl (4S)-2-(3-amino-3-methyl-butyl)-4-(tert-butoxycarbonylamino) pentanedioate (120 mg, 332.92 umol, 1 eq) in MeOH (0.5 mL) and CHCl3(0.05 mL) was added KOAc (65.35 mg, 665.84 umol, 2 eq). The mixture was stirred at 80° C. for 16 h. Upon completion, the residue was diluted with H2O 5 mL and extracted with ethyl acetate (5 mL*2). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue compound methyl (2S)-2-(tert-butoxycarbonylamino)-3-(6,6-dimethyl-2-oxo-3-piperidyl)propanoate (100 mg, 274.05 umol, 82.32% yield, 90% purity) as a colorless oil and used directly. MS (ESI) m/z 329.2 [M+H]+

Example 210. Synthesis of Viral Protease Inhibitor Compound 928

To a mixture of methyl (2S)-2-[[2-(7-chloro-1H-indole-2-carbonyl)-2-azaspiro[4.5]decane-3-carbonyl]amino]-3-(6,6-dimethyl-2-oxo-3-piperidyl)propanoate (550 mg, 963.04 umol, 1 eq) was added NH3/MeOH (7 M, 137.58 uL, 1 eq) at 25° C. The mixture was stirred at 25° C. for 16 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give a residue compound N-[(1S)-2-amino-1-[(6,6-dimethyl-2-oxo-3-piperidyl)methyl]-2-oxo-ethyl]-2-(7-chloro-1H-indole-2-carbonyl)-2-azaspiro[4.5]decane-3-carboxamide (520 mg, 841.58 umol, 87.39% yield, 90% purity) as a white solid and the residue was used next step directly. MS (ESI) m/z 556.3 [M+H]+

Example 211. Synthesis of Viral Protease Inhibitor Compound 930

A mixture of methyl 2-(7-chloro-1H-indole-2-carbonyl)-2-azaspiro[4.5]decane-3-carboxylate (350 mg, 933.68 umol, 1 eq) in THF (2 mL) and H2O (2 mL) was added LiOH·H2O (78.36 mg, 1.87 mmol, 2 eq) in one portion at 25° C. The mixture was stirred at 25° C. for 2 hours. Upon completion, the reaction mixture was adjusted to acidity by 1M HCl and extracted with ethyl acetate (10 mL*3). The combined organic layers were washed with brine (15 mL*1), dried over Na2SO4, and filtered and concentrated under reduced pressure to give 2-(7-chloro-1H-indole-2-carbonyl)-2-azaspiro[4.5]decane-3-carboxylic acid (280 mg, 775.98 umol, 83.11% yield) as a white solid. MS (ESI) m/z 361.0 [M+H]+

Example 212. Synthesis of Viral Protease Inhibitor Compound 820

To a solution of ethyl 7-fluoro-4-methoxy-1H-indole-2-carboxylate (800 mg, 3.37 mmol, 1 eq) in THF (10 mL) and H2O (5 mL) was added LiOH·H2O (283.03 mg, 6.74 mmol, 2 eq), and then the mixture was stirred at 30° C. for 10 h. Upon completion, the pH of the reaction mixture was adjust to about 3 with HCl aq (1M). The mixture was extracted with EtOAc (100 mL*3). The combined organic layer was dried over Na2SO4, filtered, concentrated to give product 7-fluoro-4-methoxy-1H-indole-2-carboxylic acid (680 mg, crude) as white solid. MS (ESI) m/z 210.0 [M+H]+

Example 213. Synthesis of Viral Protease Inhibitor Compound 838

A mixture of NaOMe (3.41 g, 63.07 mmol, 2 eq) in MeOH (40 mL) was cooled to −10° C., and then a mixture 4-chloro-2-fluoro-benzaldehyde (5 g, 31.53 mmol, 1 eq) and methyl 2-azidoacetate (7.26 g, 63.07 mmol, 2 eq) with MeOH (10 mL) was added dropwise. The mixture was stirred at 20° C. for 18 h. Upon completion, the reaction mixture was quenched by the addition of H2O (20 mL) at 25° C., diluted with H2O 100 mL and extracted with ethyl acetate (100 mL*2). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether/ethyl acetate=1/0) to afford methyl (Z)-2-azido-3-(4-chloro-2-fluoro-phenyl)prop-2-enoate (4 g, 14.87 mmol, 47.14% yield, 95% purity) as a white solid.

A mixture of methyl (Z)-2-azido-3-(4-chloro-2-fluoro-phenyl)prop-2-enoate (4 g, 15.65 mmol, 1 eq) in xylene (20 mL) was stirred at 170° C. for 5 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give a residue. The crude product was triturated with petroleum ether:ethyl acetate=10:1 to afford methyl 6-chloro-4-fluoro-1H-indole-2-carboxylate (2 g, 8.35 mmol, 53.35% yield, 95% purity) as a white solid.

To a mixture of methyl 6-chloro-4-fluoro-1H-indole-2-carboxylate (1.4 g, 6.15 mmol, 1 eq) in THF (10 mL) and H2O (5 mL) was added LiOH·H2O (516.20 mg, 12.30 mmol, 2 eq). After stirring at 60° C. for 2 h, the pH of the reaction mixture was adjusted to 3 with HCl (1 M), and then diluted with H2O (30 mL) and extracted with ethyl acetate (30 mL*3). The combined organic layers were washed with brine 30 mL (30 mL*1), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was used next step directly. Compound 6-chloro-4-fluoro-1H-indole-2-carboxylic acid (1.3 g, 5.78 mmol, 94.01% yield, 95% purity) was obtained as a white solid.

Example 214. Synthesis of Viral Protease Inhibitor Compound 848

To a mixture of methyl 6-bromo-3-fluoro-1H-indole-2-carboxylate (500 mg, 1.84 mmol, 1 eq) in THF (5 mL) and H2O (5 mL) was added LiOH·H2O (154.22 mg, 3.68 mmol, 2 eq) in one portion at 25° C. The mixture was stirred at 60° C. for 2 h. Upon completion, the reaction mixture was adjusted to acidity by 1M HCl and extracted with ethyl acetate (6 mL*3). The combined organic layers were washed with brine (9 mL*1), dried over Na2SO4, filtered and concentrated under reduced pressure to give 6-bromo-3-fluoro-1H-indole-2-carboxylic acid (440 mg, 1.71 mmol, 92.78% yield) as a yellow solid. (ESI) m/z 256.0 [M−H]+

Example 215. Synthesis of Viral Protease Inhibitor Compound 862

Example 216. Synthesis of Viral Protease Inhibitor Compound 866

Example 217. Synthesis of Viral Protease Inhibitor Compound 872

Example 218. Synthesis of Viral Protease Inhibitor Compound 731

To a solution of 1-(cyclohexylidenemethyl)pyrrolidine (140 g, 847.08 mmol, 1 eq) in THF (1000 mL) was added a solution of ethyl (2Z)-3-bromo-2-hydroxyimino-propanoate (177.91 g, 847.08 mmol, 1 eq) in THF (1000 mL) drop-wise at −20° C. under N2. After 1 h, TEA (85.72 g, 847.08 mmol, 117.90 mL, 1 eq) was added drop-wise at −20° C. under N2. The reaction mixture was stirred at 25° C. for 12 h under N2. Upon completion, the residue was poured into HCl (2M, 2500 mL) and stirred for 30 min, and extracted with ethyl acetate (1500 mL*4). The combined organic layers were washed with brine (2000 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether/ethyl acetate=1/0 to 1/1) to give a ethyl 1-hydroxy-2-oxa-3-azaspiro[5.5]undec-3-ene-4-carboxylate (200 g, 497.34 mmol, 19.57% yield, 60% purity) as a yellow oil. MS (ESI) m/z 242.2 [M+H]+.

To a solution of 2-tert-butyl 3-ethyl 2-azaspiro[4.5]decane-2,3-dicarboxylate (40 g, 128.45 mmol, 1 eq) in H2O (120 mL) and MeOH (480 mL) was added LiOH·H2O (16.17 g, 385.34 mmol, 3 eq). The mixture was stirred at 40° C. for 12 h. Upon completion, the reaction mixture was concentrated under reduced pressure to remove MeOH. The residue was diluted with H2O (800 mL) and extracted with ethyl acetate (500 mL*2). The aqueous phase were added with HCl (aq) to adjust the pH to 2 and extracted with ethyl acetate (900 mL*3). The combined organic layers were washed with brine (900 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield 2-tert-butoxycarbonyl-2-azaspiro[4.5]decane-3-carboxylic acid (35 g, crude) as a yellow oil. MS (ESI) m/z 284.2 [M+H]+

To a solution of tert-butyl 3-[[(1S)-2-methoxy-2-oxo-1-[[(3S)-2-oxo-3-piperidyl]methyl]ethyl]carbamoyl]-2-azaspiro[4.5]decane-2-carboxylate (27 g, 47.84 mmol, 82.5% purity, 1 eq) in HCl/MeOH (300 mL). The mixture was stirred at 25° C. for 1 h. Upon completion, the reaction mixture was concentrated under reduced pressure to remove HCl/MeOH, and added DCM (150 mL) (three times) was concentrated under reduced pressure to give methyl (2S)-2-(2-azaspiro[4.5]decane-3-carbonylamino)-3-[(3S)-2-oxo-3-piperidyl]propanoate (25 g, crude, HCl) as a yellow solid. MS (ESI) m/z 366.3 [M+H]+

A solution of methyl (2S)-2-[[2-(7-chloro-1H-indole-2-carbonyl)-2-azaspiro[4.5]decane-3-carbonyl]amino]-3-[(3S)-2-oxo-3-piperidyl]propanoate (5 g, 8.84 mmol, 96% purity, 1 eq) in NH3(7 M in MeOH, 57.60 mL, 45.62 eq) (15 Psi) was stirred at 65° C. for 16 h in a 100 mL of autoclave. Upon completion, the reaction mixture was concentrated under reduced pressure to remove NH3/MeOH, and added DCM (300 mL) (three times) was concentrated under reduced pressure to give N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxo-3-piperidyl]methyl]ethyl]-2-(7-chloro-1H-indole-2-carbonyl)-2-azaspiro[4.5]decane-3-carboxamide (24 g, crude) as a yellow solid. MS (ESI) m/z 528.3 [M+H]+

Example 219. Synthesis of Viral Protease Inhibitor Compound 900

Example 220. Synthesis of Viral Protease Inhibitor Compound 908

Example 221. Synthesis of Viral Protease Inhibitor Compound 1057

Example 221a. Synthesis of Viral Protease Inhibitor Compound 822

A mixture of NaOMe (3.41 g, 63.07 mmol, 2 eq) in MeOH (30 mL) was cooled to −10° C., a mixture of 2-chloro-3-fluoro-benzaldehyde (5 g, 31.53 mmol, 1 eq) and ethyl 2-azidoacetate (8.14 g, 63.07 mmol, 7.21 mL, 2 eq) in MeOH (100 mL) was added drop-wise to the former solution, the mixture was stirred at 25° C. for 18 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give a residue, the residue was diluted with H2O 60 mL and extracted with EA 90 mL (30 mL*3). The combined organic layers were washed with brine 45 mL (45 mL*1), dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product. The crude was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=1/0) to give methyl (Z)-2-azido-3-(2-chloro-3-fluoro-phenyl)prop-2-enoate (2.5 g, 9.78 mmol, 31.01% yield) as a yellow solid.

A mixture of methyl 4-chloro-5-fluoro-1H-indole-2-carboxylate (1.4 g, 6.15 mmol, 1 eq) in THF (7 mL) and H2O (7 mL) was added LiOH·H2O (516.20 mg, 12.30 mmol, 2 eq) in one portion at 25° C. The mixture was stirred at 60° C. for 1 hour. Upon completion, the reaction mixture was adjusted to acidity by 1M HCl solution, and extracted with EA 45 mL (15 mL*3). The combined organic layers were washed with brine 20 mL (20 mL*1), dried over Na2SO4, filtered and concentrated under reduced pressure to give 4-chloro-5-fluoro-1H-indole-2-carboxylic acid (1 g, 4.68 mmol, 76.12% yield) as a white solid. (ESI) m/z 211.9 [M−H]+

Example 222. Synthesis of Viral Protease Inhibitor Compound 824

To a solution of methyl (Z)-2-azido-3-(2-chloro-4-fluoro-phenyl)prop-2-enoate (6 g, 23.47 mmol, 1 eq) in XYLENE (70 mL). The mixture was stirred at 170° C. for 1 h. Upon completion, the reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=1/0 to 8/1) to give methyl 4-chloro-6-fluoro-1H-indole-2-carboxylate (2 g, 8.79 mmol, 37.44% yield) as a yellow solid. MS (ESI) m/z 228.1 [M+H]+.

To a solution of methyl 4-chloro-6-fluoro-1H-indole-2-carboxylate (2 g, 8.79 mmol, 1 eq) in THF (20 mL) and H2O (10 mL) was added LiOH·H2O (1.11 g, 26.36 mmol, 3 eq). The mixture was stirred at 50° C. for 2 h. Upon completion, the reaction mixture was concentrated under reduced pressure to remove solvent. Then 1M HCl was added, adjust pH=3, then was filtered and concentrated under reduced pressure to give 4-chloro-6-fluoro-1H-indole-2-carboxylic acid (1.6 g, crude) as a yellow solid. MS (ESI) m/z 214.0 [M+H]+.

Example 223. Synthesis of Viral Protease Inhibitor Compound 828

To a mixture of 2-chloro-1-fluoro-3-nitro-benzene (10 g, 56.97 mmol, 1 eq) in THF (100 mL) was added bromo(vinyl)magnesium (1 M, 199.38 mL, 3.5 eq) drop-wise at −40° C. under N2. The mixture was stirred at −40° C. for 2 h under N2. Upon completion, the reaction was quenched by addition NH4Cl (500 mL) and then extracted with EtOAc (300 mL*2). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure and was purified by column chromatography (SiO2, EtOAc:MEOH=10:1) to give product 7-chloro-6-fluoro-1H-indole (4.8 g, 25.47 mmol, 44.72% yield, 90% purity) as yellow oil. MS (ESI) m/z 170.0 [M+H]+

To a mixture of tert-butyl 7-chloro-6-fluoro-indole-1-carboxylate (2.3 g, 8.53 mmol, 1 eq) in THF (25 mL) was added LDA (2M, 7.25 mL, 1.7 eq) at −60° C. under N2. The mixture was stirred at −60° C. for 2 h, then the above solution was added into drikold (18.77 g, 426.50 mmol, 50 eq) and let stand for 1 h at 20° C. Upon completion, the reaction mixture was poured into water (100 mL) under N2and stirred for 10 min. The aqueous phase was added 1 M HCl to pH-3-4 at 0° C. and extracted with ethyl acetate (50 mL*3). The combined organic phase was washed with brine (80 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. It was triturated with Petroleum ether:Ethyl acetate=50:1 (100 mL) to give product 1-tert-butoxycarbonyl-7-chloro-6-fluoro-indole-2-carboxylic acid (1.5 g, 4.78 mmol, 56.06% yield) as white powder. MS (ESI) m/z 314.0 [M+H]+

Example 224. Synthesis of Viral Protease Inhibitor Compound 830

To a mixture of tert-butyl 7-chloro-5-fluoro-indole-1-carboxylate (3 g, 11.12 mmol, 1 eq) in THF (40 mL) was added LDA (2 M, 7.23 mL, 1.3 eq) at −60° C. under N2. The mixture was stirred at −60° C. for 1.5 h, then the above solution was added into drikold (24.48 g, 556.18 mmol, 50 eq) and let stand for 0.5 h at 20° C. Upon completion, the reaction mixture was poured into ice-water (100 mL) under N2and stirred for 10 min. The aqueous phase was added 1 M HCl to pH˜3-4 at 0° C. and extracted with ethyl acetate (60 mL*3). The combined organic phase was washed with brine (100 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by prep-HPLC to give the product 1-tert-butoxycarbonyl-7-chloro-5-fluoro-indole-2-carboxylic acid (1.8 g, 5.74 mmol, 51.58% yield, N/A purity) as a white solid.

To a solution of 1-tert-butoxycarbonyl-7-chloro-5-fluoro-indole-2-carboxylic acid (1 g, 3.19 mmol, 1 eq) in HCl/EtOAc (4 M, 40.00 mL, 50.19 eq), and then the mixture was stirred at 20° C. for 16 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give the product 7-chloro-5-fluoro-1H-indole-2-carboxylic acid (660 mg, crude, HCl) as a yellow solid.

To a solution of methyl (2S)-2-[[(2S)-2-[(7-chloro-5-fluoro-1H-indole-2-carbonyl)amino]-3-cyclopropyl-propanoyl]amino]-3-[(3S)-2-oxo-3-piperidyl]propanoate (770 mg, 1.52 mmol, 1 eq) in NH3/MeOH (7 M, 40.00 mL, 184.35 eq), and then the mixture was stirred at 40° C. for 12 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give the product N-[(1S)-2-[[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxo-3-piperidyl]methyl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-ethyl]-7-chloro-5-fluoro-1H-indole-2-carboxamide (720 mg, crude) as a yellow solid. MS (ESI) m/z 492.2 [M+H]+.

Example 225. Synthesis of Viral Protease Inhibitor Compound 832

To a solution of NaOMe (3.41 g, 63.06 mmol, 2 eq) in MeOH (50 mL), then 5-chloro-2-fluoro-benzaldehyde (5 g, 31.53 mmol, 1 eq) and ethyl 2-azidoacetate (8.14 g, 63.06 mmol, 7.21 mL, 2 eq) in MeOH (50 mL) was added at −10° C. The mixture was stirred at 20° C. for 18 h. Upon completion, the reaction mixture was quenched by addition H2O 50 mL at 0° C., and then extracted with DCM 150 mL (50 mL*3). The combined organic layers were washed with brine (50 mL*1), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether:Ethyl acetate=1:0 to 5:1) to give the product methyl (Z)-2-azido-3-(5-chloro-2-fluoro-phenyl)prop-2-enoate (3.7 g, 13.75 mmol, 43.61% yield, 95% purity) as a white solid.

To a solution of methyl (Z)-2-azido-3-(5-chloro-2-fluoro-phenyl)prop-2-enoate (3.7 g, 14.47 mmol, 1 eq) in XYLENE (40 mL) and the mixture was stirred at 170° C. for 1.5 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was triturated with PE:EA=20:1 (100 mL) at 20° C. for 10 min to give the product methyl 7-chloro-4-fluoro-1H-indole-2-carboxylate (1.6 g, 6.68 mmol, 46.14% yield, 95% purity) as a white solid. MS (ESI) m/z 228.1 [M+H]+.

To a solution of methyl 7-chloro-4-fluoro-1H-indole-2-carboxylate (1.5 g, 6.59 mmol, 1 eq) THF (10 mL) and H2O (5 mL), then LiOH (315.64 mg, 13.18 mmol, 2 eq) was added, and the mixture was stirred at 60° C. for 2 h. Upon completion, the reaction mixture was quenched by addition H2O 100 mL at 0° C., and then HCl (1 M) was added dropwise to pH to 3-4, and extracted with EA (50 mL*3). The combined organic layers were washed with brine 50 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give the product 7-chloro-4-fluoro-1H-indole-2-carboxylic acid (1.4 g, crude) as a white solid.

Example 226. Synthesis of Viral Protease Inhibitor Compound 840

To a solution of methyl (2S)-2-[[(2S)-3-cyclopropyl-2-[(4,6-dichloro-1H-indole-2-carbonyl)amino]propanoyl]amino]-3-[(3S)-2-oxo-3-piperidyl]propanoate (960 mg, 1.83 mmol, 1 eq) in NH3/MeOH (7 M, 20 mL, 76.33 eq). The mixture was stirred at 50° C. for 16 h. Upon completion, the reaction mixture was concentrated under reduced pressure to remove solvent to give N-[(1S)-2-[[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxo-3-piperidyl]methyl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-ethyl]-4,6-dichloro-1H-indole-2-carboxamide (820 mg, crude) as a white solid. MS (ESI) m/z 508.1 [M+H]+

Example 227. Synthesis of Viral Protease Inhibitor Compound 856

To a solution of ethyl 4-(trifluoromethyl)-1H-indole-2-carboxylate (800 mg, 3.11 mmol, 1 eq) in THF (10 mL), H2O (5 mL) was added LiOH·H2O (261.02 mg, 6.22 mmol, 2 eq) and the mixture was stirred at 25° C. for 8 h. The reaction mixture was adjust to pH˜3 with HCl (1M, aq). The mixture was extracted with EtOAc (100*3 mL). The combined organic layer was dried over Na2SO4, filtered, concentrated to give product 4-(trifluoromethyl)-1H-indole-2-carboxylic acid (700 mg, crude) was white solid. MS (ESI) m/z 230.0 [M+H]+

Example 228. Synthesis of viral protease inhibitor compound 896

A mixture of methyl (2S)-2-(tert-butoxycarbonylamino)-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (2.6 g, 9.08 mmol, 1 eq) in HCl/MeOH (4 M, 30 mL, 13.21 eq) was stirred at 20° C. for 1.5 h. Upon completion, the mixture was concentrated under reduced pressure to give a residue, then was dissolved with DCM (30 mL*3) and concentrated under reduced pressure to get product methyl (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (2 g, crude, HCl) as yellow oil. MS (ESI) m/z 187.1 [M+H]+.

A mixture of methyl (2S)-2-[[2-(7-chloro-5-methoxy-1H-indole-2-carbonyl)-2-azaspiro[4.5]decane-3-carbonyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (1.46 g, 2.61 mmol, 1 eq) in NH3/MeOH (7 M, 20 mL, 53.61 eq) was stirred at 30° C. for 20 h. Upon completion, the mixture was concentrated under reduced pressure to give a residue, then was dissolved with DCM (30 mL*3) and concentrated under reduced pressure to get the product N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]ethyl]-2-(7-chloro-5-methoxy-1H-indole-2-carbonyl)-2-azaspiro[4.5]decane-3-carboxamide (1.35 g, crude) as yellow oil. MS (ESI) m/z 544.2 [M+H]+.

Example 229. Synthesis of Viral Protease Inhibitor Compound 1059

To a solution of methyl (2S)-3-(2,2-difluorocyclopropyl)-2-[(4-methoxy-1H-indole-2-carbonyl)amino]propanoate (1 g, 2.84 mmol, 1 eq) in THF (10 mL) and H2O (3 mL) was added LiOH·H2O (357.31 mg, 8.51 mmol, 3 eq). The mixture was stirred at 20° C. for 16 h. Upon completion, the mixture was quenched by addition H2O (30 mL), and then added aq. HCl (1 M) to adjust the pH to 3-4, and extracted with EA (20 mL*3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give (2S)-3-(2,2-difluorocyclopropyl)-2-[(4-methoxy-1H-indole-2-carbonyl)amino]propanoic acid (1 g, crude) as a yellow solid. MS (ESI) m/z 339.1 [M+H]+

Example 230. Synthesis of Viral Protease Inhibitor Compound 1155

To a solution of methyl (2S)-2-[[(2S,4S)-4-methoxy-1-(4-methoxy-1H-indole-2-carbonyl)-4-(trifluoromethyl)pyrrolidine-2-carbonyl]amino]-3-[(3S)-2-oxo-3-piperidyl]propanoate (0.53 g, 932.21 umol, 1 eq) in NH3/MeOH (3 mL) was stirred at 50° C. for 28 h. Upon completion, the reaction was concentrated under pressure reduced to get the crude product (2S,4S)-N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxo-3-piperidyl]methyl]ethyl]-4-methoxy-1-(4-methoxy-1H-indole-2-carbonyl)-4-(trifluoromethyl)pyrrolidine-2-carboxamide (0.5 g, crude) as yellow solid. MS (ESI) m/z 554.2 [M+H]+

Example 231. Synthesis of Viral Protease Inhibitor Compound 1053

To a solution of O1-tert-butyl O2-methyl (2S,4E)-4-(dimethylaminomethylene)-5-oxo-pyrrolidine-1,2-dicarboxylate (70 g, 234.64 mmol, 1 eq) in THF (700 mL) was added DIBAL-H (1 M, 703.91 mL, 3 eq) at −78° C. The mixture was stirred at −78° C. for 2 h. Upon completion, the reaction mixture was quenched by added to sat. NH4Cl (2500 mL) and then extracted with EA (1000 mL*3). The combined organic layers were washed with brine (2000 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=10/1 to 1/1) to give the product. The product O1-tert-butyl O2-methyl (2S)-4-methylene-5-oxo-pyrrolidine-1,2-dicarboxylate (35 g, 137.11 mmol, 58.44% yield) was obtained as a white solid.

To a solution of O1-tert-butyl O2-methyl (2S)-4-methylene-5-oxo-pyrrolidine-1,2-dicarboxylate (25 g, 97.94 mmol, 1 eq) in THF (250 mL) was added lithium;methanolate (1 M, 117.52 mL, 1.2 eq) at −40° C. The solution was stirred for 2 h at −40° C. Upon completion, the solution was quenched with NH4Cl (70 mL) and concentrated and extracted with EA (80 mL*2) and concentrated to give crude dimethyl (2S)-2-(tert-butoxycarbonylamino)-4-methylene-pentanedioate (24 g, crude) as a yellow oil and used directly for the next step. MS (ESI) m/z 188.1 [M+H-100]+

A solution of methyl (2S)-2-(tert-butoxycarbonylamino)-3-(5,5-dimethyl-2-oxo-pyrrolidin-3-yl) propanoate (500 mg, 1.59 mmol, 1 eq) in HCl/MeOH (10 mL) was stirred at 20° C. for 2 h. Upon completion, the solution was concentrated to dryness to give crude compound methyl (2S)-2-amino-3-(5,5-dimethyl-2-oxo-pyrrolidin-3-yl)propanoate (398 mg, crude, HCl) as a white solid and used directly for the next step.

A solution of methyl (2S)-2-[[(2S)-2-(tert-butoxycarbonylamino)-3-cyclopropyl-propanoyl]amino]-3-(5,5-dimethyl-2-oxo-pyrrolidin-3-yl)propanoate (540 mg, 1.27 mmol, 1 eq) in HCl/MeOH (15 mL) was stirred at 20° C. for 1 h. Upon completion, the solution was concentrated to dryness to give crude compound methyl (2S)-2-[[(2S)-2-amino-3-cyclopropyl-propanoyl]amino]-3-(5,5-dimethyl-2-oxo-pyrrolidin-3-yl)propanoate (456 mg, crude, HCl) as a white solid.

A solution of methyl (2S)-2-[[(2S)-2-[(7-chloro-1H-indole-2-carbonyl)amino]-3-cyclopropyl-propanoyl]amino]-3-(5,5-dimethyl-2-oxo-pyrrolidin-3-yl)propanoate (550 mg, 1.09 mmol, 1 eq) in NH3/MeOH (7 M, 7.81 mL, 50 eq) was stirred at 60° C. for 17 h. Upon completion, the solution was concentrated to dryness to give crude. The crude was used directly for the next step. Compound N-[(1S)-2-[[(1S)-2-amino-1-[(5,5-dimethyl-2-oxo-pyrrolidin-3-yl)methyl]-2-oxo-ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-ethyl]-7-chloro-1H-indole-2-carboxamide (530 mg, crude) was obtained as a white solid. MS (ESI) m/z 488.2 [M+H]+

Example 232. Synthesis of Viral Protease Inhibitor Compound 1111

To a mixture of methyl (2S)-3-(6,6-dimethyl-2-oxo-3-piperidyl)-2-[[2-(4-methoxy-1H-indole-2-carbonyl)-2-azaspiro[4.5]decane-3-carbonyl]amino]propanoate (200 mg, 352.93 umol, 1 eq) was added NH3/MeOH (7 M, 50.42 uL, 1 eq). The mixture was stirred at 30° C. for 48 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give a residue and the residue was used next step directly. Compound N-[(1S)-2-amino-1-[(6,6-dimethyl-2-oxo-3-piperidyl)methyl]-2-oxo-ethyl]-2-(4-methoxy-1H-indole-2-carbonyl)-2-azaspiro[4.5]decane-3-carboxamide (190 mg, 309.96 umol, 87.83% yield, 90% purity) was obtained as a white solid. MS (ESI) m/z 552.3 [M+H]+

Example 233. Synthesis of Viral Protease Inhibitor Compound 3069

To a solution of (S)-2-((S)-2-amino-3,3-dimethylbutanamido)-N-((S)-1-amino-3-((R)-5,5-dimethyl-2-oxopyrrolidin-3-yl)-1-oxopropan-2-yl)-4,4-dimethylpentanamide (300 mg, 682.45 umol, 1 eq) in DCM (3 mL) was added TFAA (86.00 mg, 409.47 umol, 56.95 uL, 0.6 eq) and DIPEA (264.61 mg, 2.05 mmol, 356.61 uL, 3 eq), the mixture was stirred at 0° C. for 1 h. LCMS showed most starting material was remained and then was added TFAA (28.67 mg, 136.49 umol, 18.98 uL, 0.2 eq) and the mixture was stirred for another 1 h. LCMS showed a little starting material was remained and then TFAA (43.00 mg, 204.74 umol, 28.48 uL, 0.3 eq) was added and was stirred for another 30 min. Upon completion, the resulting solution was poured into H2O (10 mL), adjusted to pH-8 with NaHCO3and then extracted with EtOAc (10 mL*2). The combined organic phase was dried over Na2SO4, filtered and concentrated to give the crude product (S)-N-((S)-1-amino-3-((R)-5,5-dimethyl-2-oxopyrrolidin-3-yl)-1-oxopropan-2-yl)-2-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanamido)-4,4-dimethylpentanamide (290 mg, crude) as a white solid. MS (ESI) m/z 536.3 [M+H]+

Example 234. Synthesis of Viral Protease Inhibitor Compound 3129

Example 235. Synthesis of Viral Protease Inhibitor Compound 3065

Example 236. Synthesis of Viral Protease Inhibitor Compound 3071a

Example 237. Synthesis of Viral Protease Inhibitor Compound 3039a

To a solution of 6-tert-butoxycarbonyl-6-azaspiro[3.4]octane-7-carboxylic acid (0.3 g, 1.18 mmol, 1 eq) in 4 M of HCl/MeOH (5 mL). Then the reaction was stirred at 80° C. for 4 h. Upon completion, the reaction was concentrated in vacuo to dryness give methyl 6-azaspiro[3.4]octane-7-carboxylate (240 mg, crude, HCl) was obtained as a brown solid. The crude product was used directly in next step.

To a solution of methyl 6-azaspiro[3.4]octane-7-carboxylate (240 mg, 1.17 mmol, 1 eq, HCl) in DCM (5 mL) was added (2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl-butanoic acid (323.85 mg, 1.40 mmol, 1.2 eq), DMAP (285.11 mg, 2.33 mmol, 2 eq). Then the reaction was added EDCI (447.37 mg, 2.33 mmol, 2 eq) at 20° C. Then the reaction was stirred at 20° C. for 3 h. Upon completion, the reaction mixture was quenched by addition 1 N HCl 30 mL at 20° C., and then diluted with EtOAc 20 mL and extracted with EtOAc 60 mL (20 mL*3). The combined organic layers were washed with sat. NaHCO340 mL (20 mL*2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=20/1 to 15/1) to give methyl 6-[(2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl-butanoyl]-6-azaspiro[3.4]octane-7-carboxylate (300 mg, 784.33 umol, 67.22% yield, assumed 100% purity) as a colorless oil.

To a solution of methyl 6-[(2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl-butanoyl]-6-azaspiro[3.4]octane-7-carboxylate (300 mg, 784.33 umol, 1 eq) in THF (1.5 mL) and H2O (0.5 mL) was added LiOH·H2O (98.74 mg, 2.35 mmol, 3 eq). Then the reaction was stirred at 20° C. for 16 h. Upon completion, the reaction mixture was quenched by additional EtOAc 5 mL at 20° C., and then diluted with H2O 20 mL. Then separated the acquire phase adjusted pH=1 by 1 M HCl and extracted with EtOAc 15 mL (5 mL*3). The combined organic layers were washed with sat. NaHCO35 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue of 6-[(2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl-butanoyl]-6-azaspiro[3.4]octane-7-carboxylic acid (270 mg, crude) as a colorless gum. The crude product was used directly in next step.

To a solution of tert-butyl N-[(1S)-1-[7-[ [(1S)-2-amino-2-oxo-1-[ [(6R)-5-oxo-4-azaspiro[2.4]heptan-6-yl]methyl]ethyl]carbamoyl]-6-azaspiro[3.4]octane-6-carbonyl]-2,2-dimethyl-propyl]carbamate (140 mg, 255.62 umol, 1 eq) in 4 M of HCl/EtOAc (5 mL). Then the reaction was stirred at 20° C. for 2 h. Upon completion, the reaction was concentrated in vacuo to dryness give the compound of 6-[(2S)-2-amino-3,3-dimethyl-butanoyl]-N-[(1S)-2-amino-2-oxo-1-[[(6R)-5-oxo-4-azaspiro[2.4]heptan-6-yl]methyl]ethyl]-6-azaspiro[3.4]octane-7-carboxamide (133 mg, crude, 2HCl) as a white solid. The crude product was used directly in next step.

To a solution of 6-[(2S)-2-amino-3,3-dimethyl-butanoyl]-N-[(1S)-2-amino-2-oxo-1-[[(6R)-5-oxo-4-azaspiro[2.4]heptan-6-yl]methyl]ethyl]-6-azaspiro[3.4]octane-7-carboxamide (133 mg, 255.53 umol, 1 eq, 2HCl) in DCM (3 mL) was added DIEA (132.10 mg, 1.02 mmol, 178.03 uL, 4 eq), then added TFAA (134.17 mg, 638.82 umol, 88.86 uL, 2.5 eq) in DCM (0.5 mL). Then the reaction was stirred at 20° C. for 2 h. Upon completion, the reaction mixture was quenched by addition H2O 10 mL at 20° C., and then diluted with EtOAc 10 mL and extracted with EtOAc 20 mL (10 mL*2). The combined organic layers were washed with sat. NaCl 10 mL (10 mL*1), dried over Na2SO4, filtered and concentrated under reduced pressure to give the compound N-[(1S)-2-amino-2-oxo-1-[[(6R)-5-oxo-4-azaspiro[2.4]heptan-6-yl]methyl]ethyl]-6-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6-azaspiro[3.4]octane-7-carboxamide (110 mg, crude) as brown solid. The crude product was used directly in next step.

Example 238. Synthesis of Viral Protease Inhibitor Compound 3133

A mixture of methyl (2S)-2-(tert-butoxycarbonylamino)-3-[(3S)-2-oxo-3-piperidyl]propanoate (5 g, 16.65 mmol, 1 eq) in NH3/MeOH (7 M, 50 mL, 21.02 eq) was stirred at 80° C. for 16 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give a residue. Then the mixture was dissolved in DCM (10 mL) and concentrated under reduced pressure for two times to give tert-butyl N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxo-3-piperidyl]methyl]ethyl]carbamate (10.1 g, crude) was obtained as a white solid and used directly next step. MS (ESI) m/z 286.1 [M+H]+

A mixture of tert-butyl N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxo-3-piperidyl]methyl]ethyl]carbamate (10.1 g, 35.40 mmol, 1 eq) in HCl/EtOAc (4 M, 151.50 mL, 17.12 eq) was stirred at 20° C. for 2 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give a residue. Then the mixture was dissolved in toluene (10 mL) and concentrated under reduced pressure for two times to give methyl (2S)-2-amino-3-[(3S)-2-oxo-3-piperidyl]propanamide (10.1 g, crude) as a light yellow solid which was used directly next step. MS (ESI) m/z 186.2 [M+H]+

A mixture of tert-butyl N-[(1S)-1-[(1R,2S,5S)-2-[[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxo-3-piperidyl]methyl]ethyl]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]carbamate (290 mg, 541.37 umol, 1 eq) in HCl/EtOAc (4 M, 50 mL, 369.43 eq) was stirred at 20° C. for 2 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give a residue. Then the mixture was dissolved in toluene (10 mL) and concentrated under reduced pressure for two times to give (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxo-3-piperidyl]methyl]ethyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (300 mg, crude, HCl) was obtained as a yellow solid and used directly next step.

Example 239. Synthesis of (S)-2-amino-3-((S)-2-oxopiperidin-3-yl)propanenitrile

To a solution of benzyl N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxo-3-piperidyl]methyl]ethyl]carbamate (9.55 g, 29.90 mmol, 1 eq) in DCM (100 mL) was added Burgess reagent (14.25 g, 59.81 mmol, 2 eq). The mixture was stirred at 20° C. for 1 h. Upon completion, the reaction mixture was poured into H2O 120 mL at 20° C., and then extracted with DCM (120 mL*3). The combined organic layers were washed with brine (100 mL*2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=1/0 to 0/1) to give benzyl N-[(1S)-1-cyano-2-[(3S)-2-oxo-3-piperidyl]ethyl]carbamate (7.4 g, 24.56 mmol, 82.12% yield) as a yellow oil.

Example 240. Synthesis of Viral Protease Inhibitor Compound 247

Example 241. Synthesis of Viral Protease Inhibitor Compound 689

A solution of methyl (2S)-2-[[(2S)-3-cyclopropyl-2-[(4-methoxy-1H-indole-2-carbonyl)amino]propanoyl]amino]-3-[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]propanoate (110 mg, 220.63 umol, 1 eq) in NH3MeOH (220.63 umol, 10 mL, 1 eq) was stirred at 65° C. for 14 h. Upon completion, the mixture was concentrated under reduce pressure to remove NH3MeOH. DCM (10 mL) (three times) was added and the resulting solution was concentrated under reduced pressure to give N-[(1S)-2-[[(1S)-2-amino-1-[[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]-2-oxo-ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-ethyl]-4-methoxy-1H-indole-2-carboxamide (105 mg, crude) as a white solid. MS (ESI) m/z 484.2 [M+H]+.

Example 242. Synthesis of Viral Protease Inhibitor Compound 731

Example 243. Synthesis of Viral Protease Inhibitor Compound 818

To a solution of ethyl 7-fluoro-1H-indole-2-carboxylate (900 mg, 4.34 mmol, 1 eq) in THF (10 mL) and H2O (5 mL) was added LiOH·H2O (546.77 mg, 13.03 mmol, 3 eq), and then the mixture was stirred at 60° C. for 3 h. Upon completion, the reaction mixture was quenched by addition H2O 60 mL at 0° C. and added drop-wise 1M HCl to pH=5, and then extracted with ethyl acetate (40 mL*3). The combined organic layers were washed with brine 30 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give the 7-fluoro-1H-indole-2-carboxylic acid (700 mg, crude) as a yellow solid.

To a solution of 7-fluoro-1H-indole-2-carboxylic acid (443.09 mg, 2.47 mmol, 1 eq) and methyl (2S)-2-[[(2S)-2-amino-4,4-dimethyl-pentanoyl]amino]-3-[(3S)-2-oxo-3-piperidyl]propanoate (0.9 g, 2.47 mmol, 1 eq, HCl) in DCM (30 mL) was added DMAP (755.41 mg, 6.18 mmol, 2.5 eq) and EDCI (948.29 mg, 4.95 mmol, 2 eq), and then the mixture was stirred at 20° C. for 2 h. Upon completion, the reaction mixture was diluted with H2O 60 mL and extracted with DCM (40 mL*3). The combined organic layers were washed with brine 50 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether:Ethyl acetate=1:0 to 0:1) to give the methyl (2S)-2-[[(2S)-2-[(7-fluoro-1H-indole-2-carbonyl)amino]-4,4-dimethyl-pentanoyl]amino]-3-[(3S)-2-oxo-3-piperidyl]propanoate (0.8 g, 1.64 mmol, 66.21% yield) as a white solid. MS (ESI) m/z 489.3 [M+H]+

Example 244. Synthesis of Viral Protease Inhibitor Compound 826

To a mixture of NaOMe (3.41 g, 63.07 mmol, 2 eq) in MeOH (30 mL) was cooled to −10° C., a mixture of 2-chloro-5-fluoro-benzaldehyde (5 g, 31.53 mmol, 1 eq) and ethyl 2-azidoacetate (8.14 g, 63.07 mmol, 7.21 mL, 2 eq) in MeOH (100 mL) was drop-wise added, and then the mixture was stirred at 25° C. for 18 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give a residue, the residue was diluted with H2O 60 mL and extracted with EA 90 mL (30 mL*3). The combined organic layers were washed with brine 45 mL (45 mL*1), dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product. The crude was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=1/0) to give methyl (Z)-2-azido-3-(2-chloro-5-fluoro-phenyl)prop-2-enoate (2.6 g, 10.17 mmol, 32.25% yield) as a yellow solid.

Step 3: 6-chloro-7-fluoro-1H-indole-2-carboxylic acid and 6-chloro-5-fluoro-1H-indole-2-carboxylic acid

Example 246. Synthesis of Viral Protease Inhibitor Compound 844

A solution of (Z)-methyl 2-azido-3-(4-bromo-2-methoxyphenyl) acrylate (1.6 g, 5.13 mmol, 1 eq) in xylene (10 mL) the mixture was stirred at 170° C. for 1 h. Upon the reaction completion, the mixture was concentrated in vacuum and was trituration with petroleum ether (10 mL) and was filtered to obtained methyl 6-bromo-4-methoxy-1H-indole-2-carboxylate (1.2 g, 4.22 mmol, 82.40% yield) as a white solid. MS (ESI) m/z 283.8 [M+H]+

A solution of methyl 6-bromo-4-methoxy-1H-indole-2-carboxylate (1.2 g, 4.22 mmol, 1 eq) in THF (12 mL) and H2O (6 mL) was added LiOH·H2O (531.69 mg, 12.67 mmol, 3 eq), and then the mixture was stirred at 50° C. for 5 h. Upon the reaction completion, the mixture was concentrated in vacuum, was adjusted to pH-1 with 1M HCl (15 mL) and then extracted with EtOAc (5 mL*3), then was concentrated in vacuum to obtained 6-bromo-4-methoxy-1H-indole-2-carboxylic acid (1 g, crude) as a white solid. MS (ESI) m/z 268.0 [M−H]+

Example 247. Synthesis of Viral Protease Inhibitor Compound 846

To a solution of NaOMe (2.51 g, 46.50 mmol, 2 eq) in MeOH (25 mL) was added 5-bromo-2-methoxy-benzaldehyde (5 g, 23.25 mmol, 1 eq) and ethyl 2-azidoacetate (6.30 g, 48.83 mmol, 5.58 mL, 2.1 eq) in MeOH (25 mL) at −10° C. The mixture was stirred at 20° C. for 16 h. Upon completion, the reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with H2O 100 mL and extracted with EtOAc (100 mL*3). The combined organic layers were washed with solvent brine (100 mL*2), dried over Na2SO4, filtered and concentrated under reduced pressure to give methyl (Z)-2-azido-3-(5-bromo-2-methoxy-phenyl)prop-2-enoate (2.1 g, crude) as a yellow solid.

A solution of methyl (Z)-2-azido-3-(5-bromo-2-methoxy-phenyl)prop-2-enoate (2.1 g, 6.73 mmol, 1 eq) in XYLENE (43 mL) was stirred at 170° C. for 1 h. Upon completion, the reaction mixture was concentrated under reduced pressure to remove solvent to give methyl 7-bromo-4-methoxy-1H-indole-2-carboxylate (100 mg, crude) as a yellow solid.

To a solution of methyl 7-bromo-4-methoxy-1H-indole-2-carboxylate (100 mg, 351.98 umol, 1 eq) in THF (7 mL) and H2O (3.5 mL) was added LiOH·H2O (44.31 mg, 1.06 mmol, 3 eq). The mixture was stirred at 50° C. for 2 h. Upon completion, the reaction mixture was concentrated under reduced pressure to remove solvent. 1M HCl was added, adjust pH to 3, then was filtered and concentrated under reduced pressure to give 7-bromo-4-methoxy-1H-indole-2-carboxylic acid (50 mg, crude) as a yellow solid.

Example 248. Synthesis of Viral Protease Inhibitor Compound 850

To a solution of 2-bromo-1-fluoro-3-nitro-benzene (8 g, 36.36 mmol, 1 eq) in THF (110 mL) was added bromo (vinyl) magnesium (1 M, 127.28 mL, 3.5 eq) drop-wise at −40° C. under N2. The reaction mixture was stirred at −40° C. for another 1.5 hr. Upon completion, the residue was poured into NH4Cl aq (200 mL) under N2and stirred for 10 min. The aqueous phase was extracted with ethyl acetate (200 mL*4). The combined organic phase was washed with brine (300 mL*2), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=1/0 to 10/1) to give 7-bromo-6-fluoro-1H-indole (2.4 g, 11.21 mmol, 30.84% yield, N/A purity) was obtained as a yellow oil. MS (ESI) m/z 213.0 [M+H]+.

To a solution of 7-bromo-1-tert-butoxycarbonyl-6-fluoro-indole-2-carboxylic acid (900 mg, 2.51 mmol, 1 eq) in THF (10 mL) and was added HBr (14.90 g, 73.66 mmol, 10 mL, 40% purity, 29.31 eq). The mixture was stirred at 25° C. for 8 hr. Upon completion, the reaction mixture was quenched by addition H2O (40 mL) and extracted with EtOAc (25 mL*4). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. Compound 7-bromo-6-fluoro-1H-indole-2-carboxylic acid (650 mg, crude) was obtained as a yellow solid. MS (ESI) m/z 256.9 [M+H]+.

Example 249. Synthesis of Viral Protease Inhibitor Compound 854

A mixture of NaOMe (2.66 g, 49.26 mmol, 2 eq) in MeOH (30 mL) was cooled to −10° C., and then a mixture of 5-bromo-2-fluoro-benzaldehyde (5 g, 24.63 mmol, 1 eq) and ethyl 2-azidoacetate (6.36 g, 49.26 mmol, 5.63 mL, 2 eq) in MeOH (70 mL) was added drop-wise to the former solution. The mixture was stirred at 20° C. for 18 h. Upon completion, the reaction mixture was concentrated under reduced pressure to remove MeOH 60 mL. The residue was diluted with H2O 100 mL and extracted with EtOAc (100 mL*3). The combined organic layers were washed with brine 100 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether:Ethyl acetate=1:0 to 100:1) to get the product ethyl (Z)-2-azido-3-(5-bromo-2-fluoro-phenyl)prop-2-enoate (1.6 g, 5.09 mmol, 20.68% yield) as a yellow solid and methyl (Z)-2-azido-3-(5-bromo-2-fluoro-phenyl)prop-2-enoate (1.6 g, 5.33 mmol, 21.65% yield) as a yellow solid.

To a solution of ethyl 7-bromo-4-fluoro-1H-indole-2-carboxylate (250 mg, 873.83 umol, 1 eq) in THF (6 mL) and H2O (3 mL) was added LiOH·H2O (110.00 mg, 2.62 mmol, 3 eq), and then the mixture was stirred at 60° C. for 3.5 h. Upon completion, the reaction mixture was quenched by addition H2O 60 mL at 0° C., 1M HCl was added drop-wise to adjust the pH to about 5, and then extracted with EtOAc (40 mL*3). The combined organic layers were washed with brine 30 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to get the product 7-bromo-4-fluoro-1H-indole-2-carboxylic acid (200 mg, crude) was obtained as a white solid. MS (ESI) m/z 255.9 [M−H]+.

To a solution of methyl 7-bromo-4-fluoro-1H-indole-2-carboxylate (350 mg, 1.29 mmol, 1 eq) in THF (6 mL) and H2O (3 mL), then LiOH·H2O (161.94 mg, 3.86 mmol, 3 eq) was added, the mixture was stirred at 60° C. for 3.5 h. Upon completion, the reaction mixture was quenched by addition H2O 60 mL at 0° C. and added drop-wise 1M HCl to pH=5, and then extracted with EtOAc (40 mL*3). The combined organic layers were washed with brine 30 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to get the product 7-bromo-4-fluoro-1H-indole-2-carboxylic acid (300 mg, crude) was obtained as a white solid.

Example 250. Synthesis of Viral Protease Inhibitor Compound 858

Example 245. Synthesis of Viral Protease Inhibitor Compound 864

To a mixture of methyl 5-chloro-1H-pyrrole-2-carboxylate (500 mg, 3.13 mmol, 1 eq) in MeOH (2 mL) was added a solution of NaOH (250.66 mg, 6.27 mmol, 2 eq) in H2O (2 mL) and then the resulting mixture was stirred at 80° C. for 14 h. Upon completion, the mixture was concentrated under reduced pressure to give 5-chloro-1H-pyrrole-2-carboxylic acid (500 mg, crude) as yellow oil. MS (ESI) m/z 146.0 [M+H]+.

Example 251. Synthesis of Viral Protease Inhibitor Compound 868

To a solution of ethyl 1H-imidazole-2-carboxylate (5 g, 35.68 mmol, 1 eq) in DMF (150 mL) was added acetic acid (1 mL) dropwise, and then NCS (3.00 g, 22.47 mmol, 0.63 eq) in DMF (30 mL) was added at 0° C., the mixture was stirred at 20° C. for 20 h, and then at 45° C. for 24 h, and then at 80° C. for 2 h. Upon completion, the reaction mixture was diluted with water (100 mL) and extracted with EA (30 mL*3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column (SiO2, PE:EA=1:0 to 65:35) to get product ethyl 5-chloro-1H-imidazole-2-carboxylate (2 g, 8.02 mmol, 22.48% yield, 70% purity) as light yellow solid. MS (ESI) m/z 175.1 [M+H]+.

Example 252. Synthesis of Viral Protease Inhibitor Compound 870

To a solution of tert-butyl N-[(1S)-2-[[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxo-3-piperidyl]methyl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-ethyl]carbamate (4.8 g, 12.11 mmol, 1 eq) in DCM (50 mL) was added burgess reagent (5.77 g, 24.21 mmol, 2 eq). The mixture was stirred at 20° C. for 1 h. Upon completion, the reaction mixture was poured into H2O 60 mL at 20° C., and then extracted with DCM (60 mL*3). The combined organic layers were washed with brine (60 mL*2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=1/0 to 0/1) to give tert-butyl N-[(1S)-2-[[(1S)-1-cyano-2-[(3S)-2-oxo-3-piperidyl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-ethyl]carbamate (4.3 g, 11.36 mmol, 93.85% yield) as a white solid. MS (ESI) m/z 379.2 [M+H]+.

Example 253. Synthesis of Viral Protease Inhibitor Compound 896

A mixture of methyl (2S)-2-(tert-butoxycarbonylamino)-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (2.6 g, 9.08 mmol, 1 eq) in HCl/MeOH (4 M, 30 mL, 13.21 eq) was stirred at 20° C. for 1.5 h. Upon completion, the mixture was concentrated under reduced pressure to give a residue, then was dissolved with DCM (30 mL*3) and concentrated under reduced pressure to get product methyl (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (2 g, crude, HCl) as yellow oil. MS (ESI) m/z 187.1 [M+H]+.

A mixture of methyl (2S)-2-[[2-(7-chloro-5-methoxy-1H-indole-2-carbonyl)-2-azaspiro[4.5]decane-3-carbonyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (1.46 g, 2.61 mmol, 1 eq) in NH3/MeOH (7 M, 20 mL, 53.61 eq) was stirred at 30° C. for 20 h. Upon completion, the mixture was concentrated under reduced pressure to give a residue, then was dissolved with DCM (30 mL*3) and concentrated under reduced pressure to get the product N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]ethyl]-2-(7-chloro-5-methoxy-1H-indole-2-carbonyl)-2-azaspiro[4.5]decane-3-carboxamide (1.35 g, crude) as yellow oil. MS (ESI) m/z 544.2 [M+H]+.

Example 254. Synthesis of Viral Protease Inhibitor Compound 910

To a solution of ethyl 2-(benzhydrylideneamino)acetate (10 g, 37.41 mmol, 1 eq) in THF (40 mL) was added LiHMDS (1 M, 41.15 mL, 1.1 eq) dropwise (˜0.5 h) at −78° C. under N2, and then the mixture was stirred at −78° C. for 0.5 h. After the addition of 3-bromo-2-methyl-prop-1-ene (5.05 g, 37.41 mmol, 3.77 mL, 1 eq) dropwise to the mixture, the mixture was stirred at 0° C. for 0.5 h, and then the mixture was warmed to 20° C. and stirred at 20° C. for 1 h. Upon completion, the mixture was quenched by water (200 mL) and concentrated in vacuum. Then the mixture was extracted with EA (70 mL*3), washed with brine (20 mL), dried over anhydrous Na2SO4, concentrated in vacuum and purified by column (SiO2, PE:EA=1:0 to 40:1) to obtained ethyl 2-((diphenylmethylene)amino)-4-methylpent-4-enoate (9.5 g, 26.60 mmol, 71.11% yield, 90% purity) as a yellow solid. MS (ESI) m/z 322.2 [M+H]+

Example 255. Synthesis of Viral Protease Inhibitor Compound 912

To a solution of ethyl 2-(benzyloxycarbonylamino)-3-(2,2-dimethylcyclopropyl)propanoate (1 g, 3.13 mmol, 1 eq) in THF (9 mL) and H2O (3 mL) was added LiOH·H2O (394.15 mg, 9.39 mmol, 3 eq). The mixture was stirred at 50° C. for 3 h. Upon completion, the reaction mixture was concentrated under reduced pressure to remove solvent. 1M HCl was added to adjust pH to 3, then extracted with DCM (35 mL*3). The combined organic layers were washed with brine (30 mL*2), dried over Na2SO4, filtered and concentrated under reduced pressure to give 2-(benzyloxycarbonylamino)-3-(2,2-dimethylcyclopropyl)propanoic acid (1.1 g, crude) as a yellow oil.

Example 256. Synthesis of viral protease inhibitor compound 918

To a solution of tert-butyl (1S,3aR,7aS)-1-[[(1S)-2-methoxy-2-oxo-1-[[(3S)-2-oxo-3-piperidyl]methyl]ethyl]carbamoyl]-1,3,3a,4,5,6,7,7a-octahydroisoindole-2-carboxylate (680 mg, 1.51 mmol, 1 eq) in HCl/MeOH (4 M, 10 mL, 26.56 eq), and the mixture was stirred at 20° C. for 1 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give the product methyl (2S)-2-[[(1S,3aR,7aS)-2,3,3a,4,5,6,7,7a-octahydro-1H-isoindole-1-carbonyl]amino]-3-[(3S)-2-oxo-3-piperidyl]propanoate (580 mg, crude, HCl) as a white solid.

To a solution of methyl (2S)-2-[[(1S,3aR,7aS)-2-(4-methoxy-1H-indole-2-carbonyl)-1,3,3a,4,5,6,7,7a-octahydroisoindole-1-carbonyl]amino]-3-[(3S)-2-oxo-3-piperidyl]propanoate (710 mg, 1.35 mmol, 1 eq) in NH3/MeOH (7 M, 10 mL, 51.72 eq) and then mixture was stirred at 40° C. for 12 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give the product (1S,3aR,7aS)-N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxo-3-piperidyl]methyl]ethyl]-2-(4-methoxy-1H-indole-2-carbonyl)-1,3,3a,4,5,6,7,7a-octahydroisoindole-1-carboxamide (640 mg, crude) as a white solid. MS (ESI) m/z 510.2 [M+H]+.

Example 257. Synthesis of Viral Protease Inhibitor Compound 930

Example 258. Synthesis of Viral Protease Inhibitor Compound 934

350 mL of a buffer-pH=11 (Saturated NaHCO3adjusted with 4 M NaOH to pH=11) was added to a solution of (1-aminocyclopropyl) methanol (20 g, 229.57 mmol, 1 eq) in IPA (350 mL). The reaction mixture was cooled to 0° C. and benzyl 2,5-dioxopyrrolidine-1-carboxylate (53.54 g, 229.57 mmol, 1 eq) was added. The reaction mixture was stirred at 20° C. for 16 h. Upon completion, the reaction mixture was filtered and then concentrated under reduced pressure to remove IPA. The residue was diluted with H2O 100 mL and extracted with EA 200 mL (100 mL*2). The combined organic layers were washed with brine 100 mL (100 mL*1), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was triturated with DCM at 20° C. for 20 min. Compound benzyl N-[1-(hydroxymethyl)cyclopropyl]carbamate (35 g, 142.37 mmol, 62.02% yield, 90% purity) was obtained as a white solid.

To a solution of methoxymethyl (triphenyl) phosphonium; chloride (25.02 g, 72.98 mmol, 4 eq) in THF (80 mL) was added a solution of t-BuOK (1 M, 72.80 mL, 3.99 eq) drop-wise at −10° C. The reaction mixture was warmed to 20° C. and stirred at 20° C. for 1 h. Benzyl N-(1-formylcyclopropyl)carbamate (4 g, 18.25 mmol, 1 eq) in THF (40 mL) was added at 0° C., the solution was stirred at 20° C. for another 1 h under N2. Upon completion, the reaction mixture was diluted with H2O 100 mL and extracted with ethyl acetate 200 mL (100 mL*2). The combined organic layers were washed with brine 100 mL (100 mL*1), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=30/1 to 10/1) to give benzyl N-[1-[(E)-2-methoxyvinyl]cyclopropyl]carbamate (2.1 g, 7.64 mmol, 41.89% yield, 90% purity) as a yellow oil. MS (ESI) m/z 246.1 [M−H]+

To a mixture of benzyl N-[1-[(E)-2-methoxyvinyl]cyclopropyl]carbamate (1.9 g, 7.68 mmol, 1 eq) in THF (20 mL) was added HCl (19.38 g, 53.15 mmol, 19.00 mL, 10% purity, 6.92 eq). The mixture was stirred at 25° C. for 2 h. Upon completion, the reaction mixture was diluted with H2O 100 mL and extracted with EA 300 mL (150 mL*2). The combined organic layers were washed with brine 300 mL (300 mL*1), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=20/1 to 5/1). Compound benzyl N-[1-(2-oxoethyl)cyclopropyl]carbamate (1.3 g, 5.02 mmol, 65.28% yield, 90% purity) was obtained as a white solid.

To a mixture of O1-tert-butyl O2-methyl (2S)-5-oxopyrrolidine-1,2-dicarboxylate (450 mg, 1.85 mmol, 1 eq) in THF (8 mL) was added LiHMDS (1 M, 2.40 mL, 1.3 eq) in one portion at −60° C. under N2. The mixture was stirred at −60° C. for 30 min, and then benzyl N-[1-(2-oxoethyl)cyclopropyl]carbamate (431.51 mg, 1.85 mmol, 1 eq) in THF (4 mL) was added at −60° C. and stirred for 2 h at −60° C. Upon completion, the reaction mixture was quenched by addition AcOH 4 mL in THF 8 mL at −60° C. and concentrated under reduced pressure to give a residue and used next step directly. Compound O1-tert-butyl O2-methyl (2S)-4-[2-[1-(benzyloxycarbonylamino)cyclopropyl]-1-hydroxy-ethyl]-5-oxo-pyrrolidine-1,2-dicarboxylate (900 mg, crude) was obtained as a yellow oil. MS (ESI) m/z 377.1 [M+H-100]+

To a mixture of O1-tert-butyl O2-methyl (2S)-4-[2-(1-aminocyclopropyl)ethyl]-5-oxo-pyrrolidine-1,2-dicarboxylate (350 mg, 1.07 mmol, 1 eq) in MeOH (5 mL) and CHCl3(0.5 mL) was added KOAc (210.48 mg, 2.14 mmol, 2 eq) at 80° C. The mixture was stirred at 80° C. for 48 h. Upon completion, the residue was diluted with H2O 5 mL and extracted with EA 10 mL (5 mL*2). The combined organic layers were washed with BRINE 10 mL (10 mL*1), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue and used next step directly. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=5:1 to 1:1). Compound methyl (2S)-2-(tert-butoxycarbonylamino)-3-(5-oxo-4-azaspiro[2.5]octan-6-yl)propanoate (200 mg, 586.42 umol, 54.69% yield, 95.7% purity) was obtained as a colourless oil.

To methyl (2S)-2-[[(2S)-2-(tert-butoxycarbonylamino)-3-cyclopropyl-propanoyl]amino]-3-(5-oxo-4-azaspiro[2.5]octan-6-yl)propanoate (162 mg, 370.26 umol, 1 eq) was added HCl/MeOH (4 M, 12.21 mL, 131.86 eq). The mixture was stirred at 25° C. for 60 min. Upon completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was used next step directly. Compound methyl (2S)-2-[[(2S)-2-amino-3-cyclopropyl-propanoyl]amino]-3-(5-oxo-4-azaspiro[2.5]octan-6-yl)propanoate (138 mg, crude, HCl) was obtained as a white solid.

Example 259. Synthesis of Viral Protease Inhibitor Compound 936

To a solution of O1-tert-butyl O2-methyl (2S,4E)-4-[[1-(benzyloxycarbonylamino)cyclopropyl]methylene]-5-oxo-pyrrolidine-1,2-dicarboxylate (1400 mg, 3.15 mmol, 1 eq) in IPA (25 mL) was added Pd/C (261.12 mg, 220.48 umol, 10% purity, 0.07 eq) (10%) under N2atmosphere. The suspension was degassed and purged with H2for 3 times. The mixture was stirred under H2(15 psi) at 25° C. for 2 h. Upon completion, the mixture was filtered and concentrated to give crude O1-tert-butyl O2-methyl (2S)-4-[(1-aminocyclopropyl)methyl]-5-oxo-pyrrolidine-1,2-dicarboxylate (950 mg, crude) was obtained as a yellow oil. The crude was used directly for the next step. MS (ESI) m/z 313.1 [M+H]+

To a solution of O1-tert-butyl O2-methyl (2S)-4-[(1-aminocyclopropyl)methyl]-5-oxo-pyrrolidine-1,2-dicarboxylate (950 mg, 3.04 mmol, 1 eq) in MeOH (15 mL) and CHCl3(1.5 mL) was added KOAc (895.46 mg, 9.12 mmol, 3 eq). The solution was stirred for 3 h at 60° C. Upon completion, the solution was concentrated and diluted with H2O (50 mL) and extracted with EA (50 mL*3) and concentrated to give crude. The crude was purified by column (SiO2, PE:EA=10:1 to 0:1) to give product methyl (2S)-2-(tert-butoxycarbonylamino)-3-(5-oxo-4-azaspiro[2.4]heptan-6-yl)propanoate (430 mg, 1.38 mmol, 45.26% yield) was obtained as a white solid. MS (ESI) m/z 313.1 [M+H]+

A solution of methyl (2S)-2-(tert-butoxycarbonylamino)-3-(5-oxo-4-azaspiro[2.4]heptan-6-yl)propanoate (260 mg, 832.37 umol, 1 eq) in HCl/MeOH (10 mL) was stirred for 1 h at 25° C. Upon completion, the solution was concentrated to dryness to give crude methyl (2S)-2-amino-3-(5-oxo-4-azaspiro[2.4]heptan-6-yl)propanoate (207 mg, crude, HCl) as a white solid. The crude was used directly for the next step. MS (ESI) m/z 213.2 [M+H]+

A solution of methyl (2S)-2-[[(2S)-2-(tert-butoxycarbonylamino)-3-cyclopropyl-propanoyl]amino]-3-(5-oxo-4-azaspiro[2.4]heptan-6-yl)propanoate (285 mg, 672.96 umol, 1 eq) in HCl/MeOH (10 mL) was stirred for 1 h at 25° C. Upon completion, The solution was concentrated to dryness to give crude methyl (2S)-2-[[(2S)-2-amino-3-cyclopropyl-propanoyl]amino]-3-(5-oxo-4-azaspiro[2.4]heptan-6-yl)propanoate (245 mg, crude, HCl) as a white solid. The crude was used directly for the next step. MS (ESI) m/z 324.2 [M+H]+

A solution of methyl (2S)-2-[[(2S)-2-[(7-chloro-1H-indole-2-carbonyl)amino]-3-cyclopropyl-propanoyl]amino]-3-(5-oxo-4-azaspiro[2.4]heptan-6-yl)propanoate (185 mg, 369.28 umol, 1 eq) in NH3/MeOH (7 M, 10.55 mL, 200 eq) was stirred for 20 h at 60° C. Upon completion, The solution was concentrated to dryness to give crude N-[(1S)-2-[[(1S)-2-amino-2-oxo-1-[(5-oxo-4-azaspiro[2.4]heptan-6-yl)methyl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-ethyl]-7-chloro-1H-indole-2-carboxamide (184 mg, crude) as a white solid. The crude was used directly for the next step. MS (ESI) m/z 486.2 [M+H]+

To a solution of N-[(1S)-2-[[(1S)-2-amino-2-oxo-1-[(5-oxo-4-azaspiro[2.4]heptan-6-yl)methyl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-ethyl]-7-chloro-1H-indole-2-carboxamide (155 mg, 318.95 umol, 1 eq) in DCM (15 mL) was added burgess reagent (228.03 mg, 956.86 umol, 3 eq) at 20° C. The solution was stirred for 4 h at 20° C. Upon completion, the solution was concentrated to give crude. The crude was purified by pre-TLC(SiO2, PE:EA=0:1) to give product (70 mg) and continued to purified by SFC to give product

Example 260. Synthesis of Viral Protease Inhibitor Compound 1059

Example 261. Synthesis of Viral Protease Inhibitor Compound 1059

Example 262. Synthesis of (2R)-2-[(4-methoxy-1H-indole-2-carbonyl)amino]-3-trimethylsilyl-propanoic acid

Example 263. Synthesis of Viral Protease Inhibitor Compound 1083

To methyl (2S)-2-amino-3-(4-methyl-1H-indol-3-yl)propanoate (550 mg, 2.05 mmol, 1 eq, HCl) was added NH3/MeOH (7 M, 20.00 mL, 68.41 eq) in one portion at 20° C. under N2. The mixture was stirred at 80° C. for 12 h. Upon completion, the reaction mixture was cooled to 25° C. and concentrated to get the product. (2S)-2-amino-3-(4-methyl-1H-indol-3-yl) propanamide (520 mg, crude) was obtained as the light yellow solid and used directly next step. MS (ESI) m/z 218.1 [M+H]+

Example 264. Synthesis of Viral Protease Inhibitor Compound 1085

Example 265. Synthesis of Viral Protease Inhibitor Compound 1087

Example 266. Synthesis of Viral Protease Inhibitor Compound 1091

Example 267. Synthesis of Viral Protease Inhibitor Compound 1101

To a solution of methyl (2S)-2-amino-3-[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]propanoate (390 mg, 1.82 mmol, 1 eq) and (2S)-2-(tert-butoxycarbonylamino)-4,4-dimethyl-pentanoic acid (580.48 mg, 2.37 mmol, 1.3 eq) in DCM (10 mL) and DMF (3 mL) was added DMAP (667.11 mg, 5.46 mmol, 3 eq) and EDCI (697.88 mg, 3.64 mmol, 2 eq), and then the mixture was stirred at 20° C. for 2 h. Upon completion, the reaction mixture was quenched by addition H2O 30 mL at 0° C., and then extracted with DCM (30 mL*3). The combined organic layers were washed with brine (30 mL*1), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether:Ethyl acetate=5:1 to 0:1) to give the product methyl (2S)-2-[[(2S)-2-(tert-butoxycarbonylamino)-4,4-dimethyl-pentanoyl]amino]-3-[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]propanoate (510 mg, 924.00 umol, 50.76% yield, 80% purity) as a white solid. MS (ESI) m/z 442.2 [M+H]+.

To a solution of methyl (2S)-2-[[(2S)-2-(tert-butoxycarbonylamino)-4,4-dimethyl-pentanoyl]amino]-3-[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]propanoate (250 mg, 566.17 umol, 1 eq) in HCl/MeOH (4 M, 5 mL, 35.32 eq), and the mixture was stirred at 25° C. for 1 h. The reaction mixture was concentrated under reduced pressure to give the product methyl (2S)-2-[[(2S)-2-amino-4,4-dimethyl-pentanoyl]amino]-3-[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]propanoate (190 mg, crude, HCl) as a white solid.

Example 268. Synthesis of Viral Protease Inhibitor Compound 1103

Example 269. Synthesis of Viral Protease Inhibitor Compound 1105

Example 270. Synthesis of Viral Protease Inhibitor Compound 1115

Example 271. Synthesis of Viral Protease Inhibitor Compound 1119

To a solution of tert-butyl (3S)-3-[[(1S)-1-[[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]-2-methoxy-2-oxo-ethyl]carbamoyl]-2-azaspiro[4.5]decane-2-carboxylate (400 mg, 834.01 umol, 1 eq) in HCl/MeOH (4 M, 5.00 mL, 23.98 eq), and the mixture was stirred at 20° C. for 1 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give the product methyl (2S)-2-[[(3S)-2-azaspiro[4.5]decane-3-carbonyl]amino]-3-[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]propanoate (340 mg, crude, HCl) as a white solid.

To a solution of methyl (2S)-2-[[(3S)-2-(6-chloro-1H-indole-2-carbonyl)-2-azaspiro[4.5]decane-3-carbonyl]amino]-3-[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]propanoate (420 mg, 753.93 umol, 1 eq) in NH3/MeOH (7 M, 5 mL, 46.42 eq), and the mixture was stirred at 60° C. for 12 h. Upon completion the reaction mixture was concentrated under reduced pressure to give the product (3S)-N-[(1S)-2-amino-1-[[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]-2-oxo-ethyl]-2-(6-chloro-1H-indole-2-carbonyl)-2-azaspiro[4.5]decane-3-carboxamide (400 mg, crude) as a yellow solid. MS (ESI) m/z 542.2 [M+H]+.

Example 272. Synthesis of viral protease inhibitor compound 1121

Example 273. Synthesis of Viral Protease Inhibitor Compound 1123

Example 274. Synthesis of Viral Protease Inhibitor Compound 1131

Example 275. Synthesis of Viral Protease Inhibitor Compound 1133

To a solution of N-isopropylpropan-2-amine (4.67 g, 46.20 mmol, 6.53 mL, 2.5 eq) in dry THF (100 mL) was added very slowly a solution of n-BuLi (2.5 M, 18.48 mL, 2.5 eq) at −10° C. After 30 min, the mixture was cooled to −60° C. and the tert-butyl 2-[(Z)-[(2R)-2-hydroxy-2,6,6-trimethyl-norpinan-3-ylidene]amino]acetate (5.2 g, 18.48 mmol, 1 eq) dissolved in THF (10 mL) was added. After 30 min, the iodomethyl(trimethyl)silane (7.12 g, 33.26 mmol, 4.95 mL, 1.8 eq) was added. The mixture was stirred at −60° C. for 1 h. Then the mixture was allowed to cooled to 0° C. for 12 h. Upon completion, the reaction was quenched with a saturated solution of ammonium chloride (40 mL). Then the aqueous phase was extracted with ethyl acetate (20 mL*3). The organic phase was dried over Na2SO4, filtered and concentrated in vacuo to dryness. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=50/1 to 10/1, 1% TEA) to give tert-butyl (2R)-2-[(Z)-[(2R)-2-hydroxy-2,6,6-trimethyl-norpinan-3-ylidene]amino]-3-trimethylsilyl-propanoate (3.4 g, 8.32 mmol, 45.05% yield, 90% purity) as a yellow oil.

To a solution of the tert-butyl (2R)-2-[(Z)-[(2R)-2-hydroxy-2,6,6-trimethyl-norpinan-3-ylidene]amino]-3-trimethylsilyl-propanoate (0.65 g, 1.77 mmol, 1 eq) in THF (3.5 mL) was added a solution of Citric acid (10 mL, 15% purity). The mixture was stirred at 50° C. for 16 h. Upon completion, after removing THF in vacuo, the aqueous layer was extracted with EtOAc (15 mL) in order to remove the chiral inductor. Then the pH was increased to 8-9 with potassium carbonate addition. The free amine was then extracted with EtOAc (30 mL*3). The organic layer was combined, dried over Na2SO4, concentrated at room temperature due to the amine volatility to give tert-butyl (2R)-2-amino-3-trimethylsilyl-propanoate (380 mg, crude) as a yellow oil

To a solution of tert-butyl (2R)-2-[(4-methoxy-1H-indole-2-carbonyl)amino]-3-trimethylsilyl-propanoate (300 mg, 768.15 umol, 1 eq) in DCM (3 mL) was added TFA/H2O (2 mL, 10/1) at 0° C. Then the reaction was stirred at 20° C. for 3 h. Upon completion, the reaction was concentrated in vacuo to dryness below 30° C. to dryness. The reaction mixture was quenched by addition EA (30 mL) at 20° C., and then diluted with H2O (20 mL) and extracted with EA 20 mL (10 mL*2). The combined organic layers were washed with sat. NaCl 20 mL (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue of (2R)-2-[(4-methoxy-1H-indole-2-carbonyl)amino]-3-trimethylsilyl-propanoic acid (300 mg, crude) as a yellow oil.

Example 276. Synthesis of Viral Protease Inhibitor Compound 1135

A solution of (2S)-2-(tert-butoxycarbonylamino)-3-cyclopropyl-propanoic acid (6 g, 26.17 mmol, 1 eq) in THF (60 mL) was cooled at 0° C. and was added NaH (2.30 g, 57.57 mmol, 60% purity, 2.2 eq) and the mixture was warmed at 25° C. and stirred for 1.5 h, then was added CH3I (8.17 g, 57.57 mmol, 3.58 mL, 2.2 eq) and stirred for 2.5 h. Upon completion, the mixture was quenched by H2O (200 mL) and was adjusted pH=1 with HCl (1 M), and extracted with ethyl acetate (150 mL*3). The combined organic phase was washed with brine (100 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuum to give crude product (S)-2-((tert-butoxycarbonyl)(methyl)amino)-3-cyclopropylpropanoic acid (6.17 g, crude) as yellow oil. MS (ESI) m/z 244.1 [M+H]+

Example 277. Synthesis of Viral Protease Inhibitor Compound 1137

Example 278. Synthesis of Viral Protease Inhibitor Compound 1141

To a solution of 3-chlorobenzene-1,2-diamine (2 g, 14.03 mmol, 1 eq) in AcOH (20 mL) was added methyl 2,2,2-trichloroethanimidate (2.97 g, 16.83 mmol, 2.08 mL, 1.2 eq). The mixture was stirred at 25° C. for 2 h. Upon completion, the reaction mixture was quenched by addition of sat. NaHCO3(50 mL) to adjust the pH=7-8, and then extracted with ethyl acetate (30 mL*3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the product 7-chloro-2-(trichloromethyl)-1H-benzimidazole (3 g, crude) as a yellow solid. MS (ESI) m/z 270.9 [M+H]+

To a solution of 7-chloro-2-(trichloromethyl)-1H-benzimidazole (3 g, 11.11 mmol, 1 eq) in MeOH (40 mL) was added Na2CO3(1.18 g, 11.11 mmol, 1 eq). The mixture was stirred at 70° C. for 14 h. Upon completion, the mixture was concentrated under the reduced pressure to give the product methyl 7-chloro-1H-benzimidazole-2-carboxylate (3 g, crude) as a yellow solid. MS (ESI) m/z 210.9 [M+H]+

To a solution of methyl 7-chloro-1H-benzimidazole-2-carboxylate (3 g, 14.24 mmol, 1 eq) in THF (20 mL) and H2O (5 mL) was added LiOH·H2O (1.79 g, 42.73 mmol, 3 eq). The mixture was stirred at 60° C. for 2 h. Upon completion, the reaction mixture was quenched by addition of 1N HCl (20 mL) to adjust the pH=3-5, and then extracted with EA (30 mL*3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the product 7-chloro-1H-benzimidazole-2-carboxylic acid (2 g, crude) as a yellow solid. MS (ESI) m/z 197.0 [M+H]+

Example 279. Synthesis of Viral Protease Inhibitor Compound 1143

A solution of (S)-methyl 2-((S)-2-(5-methoxy-1H-indole-2-carbonyl)-2-azaspiro[4.5]decane-3-carboxamido)-3-((S)-2-oxopiperidin-3-yl)propanoate (200 mg, 371.31 umol, 1 eq) was added with NH3/MeOH (7 M, 5 mL), and then the mixture was stirred at 30° C. for 18 h. Upon the reaction completion, the reaction mixture was concentration in vacuum to obtained (S)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopiperidin-3-yl)propan-2-yl)-2-(5-methoxy-1H-indole-2-carbonyl)-2-azaspiro[4.5]decane-3-carboxamide (150 mg, crude) as a yellow solid. MS (ESI) m/z 524.3 [M+H]+

Example 280. Synthesis of Viral Protease Inhibitor Compound 1145

Example 281. Synthesis of Viral Protease Inhibitor Compound 1147

A mixture of methyl (2S)-2-[[2-(7-chloro-5-methoxy-1H-indole-2-carbonyl)-2-azaspiro[4.5]decane-3-carbonyl]amino]-3-[(3S)-2-oxo-3-piperidyl]propanoate (1.26 g, 2.20 mmol, 1 eq) in NH3/MeOH (7 M, 20 mL, 63.68 eq) was stirred at 30° C. for 20 h. Upon completion, the mixture was concentrated under reduced pressure to give a residue, then was dissolved with DCM (30 mL*3) and concentrated under reduced pressure to get the product N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxo-3-piperidyl]methyl]ethyl]-2-(7-chloro-5-methoxy-1H-indole-2-carbonyl)-2-azaspiro[4.5]decane-3-carboxamide (1.2 g, crude) as yellow solid. MS (ESI) m/z 558.3 [M+H]+.

Example 282. Synthesis of Viral Protease Inhibitor Compound 1149

A mixture of NaOMe (6.33 g, 117.24 mmol, 2 eq) in MeOH (150 mL) was cooled to −10° C., and then a mixture of 4-chloro-2-methoxy-benzaldehyde (10 g, 58.62 mmol, 1 eq) and ethyl 2-azidoacetate (15.14 g, 117.24 mmol, 13.40 mL, 2 eq) in MeOH (150 mL) were added drop-wise to the former solution. The mixture was stirred at 25° C. for 16 h. Upon completion, the reaction mixture was concentrated under the reduced pressure to give a residue and then quenched by addition H2O (100 mL), and then extracted with EA (30 mL*3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, PE:EA=1:0 to 5:1) affording methyl(Z)-2-azido-3-(4-chloro-2-methoxy-phenyl)prop-2-enoate (8 g, 29.89 mmol, 50.99% yield) as a yellow solid.

A mixture of methyl 6-chloro-4-methoxy-1H-indole-2-carboxylate (4 g, 16.69 mmol, 1 eq) in THF (30 mL) and H2O (10 mL) was added LiOH·H2O (2.10 g, 50.07 mmol, 3 eq). The mixture was stirred at 60° C. for 2 h. Upon completion, the mixture was quenched by addition H2O (50 mL), and then added aq. HCl (1 M) to adjust the pH=3-4, and extracted with EA (50 mL*3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give 6-chloro-4-methoxy-1H-indole-2-carboxylic acid (4 g, crude) as a yellow solid. MS (ESI) m/z 226.0 [M+H]+

Example 283. Synthesis of viral protease inhibitor compound 1151

Example 284. Synthesis of Viral Protease Inhibitor Compound 1153

Example 285. Synthesis of Viral Protease Inhibitor Compound 1163

To a solution of (S)-methyl 2-amino-3-((R)-5,5-dimethyl-2-oxopyrrolidin-3-yl)propanoate (180.00 mg, 717.93 umol, 1 eq, HCl) in DMF (1 mL) and DCM (3 mL) was added DMAP (263.12 mg, 2.15 mmol, 3 eq), and then (S)-2-((tert-butoxycarbonyl)amino)-4,4-dimethylpentanoic acid (211.34 mg, 865.51 umol, 1.2 eq) and EDCI (275.26 mg, 1.44 mmol, 2 eq) was added. The resulting solution was stirred at 15° C. for 2 h, and then diluted with water (10 mL) and extracted with DCM (5 mL*3). The combined organic layers were washed with brine (5 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was used for next step directly. Compound (S)-methyl 2-((S)-2-((tert-butoxycarbonyl)amino)-4,4-dimethylpentanamido)-3-((R)-5,5-dimethyl-2-oxopyrrolidin-3-yl)propanoate (0.3 g, crude) was obtained as a yellow solid. MS (ESI) m/z 441.2 [M+H]+.

Example 286. Synthesis of Viral Protease Inhibitor Compound 1167

To a solution of ethyl 7-fluoro-4-methoxy-1H-indole-2-carboxylate (200 mg, 843.08 umol, 1 eq) in THF (4 mL) and H2O (2 mL) was added LiOH·H2O (106.14 mg, 2.53 mmol, 3 eq), the mixture was stirred at 60° C. for 3 h. Upon the reaction completion, the mixture was concentrated in vacuum and was adjust pH-1 with 1M HCl (3 mL) and was extracted with EA (10 mL*3), then was concentrated in vacuum to obtained 7-fluoro-4-methoxy-1H-indole-2-carboxylic acid (170 mg, crude) as a white solid. MS (ESI) m/z 208.1 [M−H]+

Example 287. Synthesis of Viral Protease Inhibitor Compound 1173

Example 288. Synthesis of Viral Protease Inhibitor Compound 1175

Example 289. Synthesis of Viral Protease Inhibitor Compound 1177

Example 290. Synthesis of Viral Protease Inhibitor Compound 1181

Example 291. Synthesis of Viral Protease Inhibitor Compound 1191

Example 292. Synthesis of Viral Protease Inhibitor Compound 1193

Example 293. Synthesis of Viral Protease Inhibitor Compound 1195

Example 294. Synthesis of Viral Protease Inhibitor Compound 1201

To a solution of 3-chloro-5-fluoro-2-hydroxybenzaldehyde (1 g, 5.73 mmol, 1 eq) in ACN (20 mL) was added K2CO3(2.38 g, 17.19 mmol, 3 eq) and CH3I (1.30 g, 9.17 mmol, 570.62 uL, 1.6 eq), the mixture was stirred at 80° C. for 3 h. Upon the reaction completion, the mixture was concentrated in vacuum and was added water (60 mL) and was extracted with DCM (20 mL*3), then was dried with Na2SO4, filtered and concentrated in vacuum to obtained 3-chloro-5-fluoro-2-methoxybenzaldehyde (1 g, crude) as a yellow oil. MS (ESI) m/z 189.1 [M+H]+

To a solution of NaOMe (572.94 mg, 10.61 mmol, 2 eq) in MeOH (20 mL) was added a solution of 3-chloro-5-fluoro-2-methoxybenzaldehyde (1 g, 5.30 mmol, 1 eq) and ethyl 2-azidoacetate (1.37 g, 10.61 mmol, 1.21 mL, 2 eq) in MeOH (10 mL) at 0° C. The mixture was stirred at 20° C. for 16 h. Upon the reaction completion, the mixture was concentrated in vacuum and was added water (60 mL) and extracted with EtOAc (30 mL*3), then was concentrated in vacuum and was purified by column (SiO2, PE:EA=1:0 to 50:1) to obtained (Z)-methyl 2-azido-3-(3-chloro-5-fluoro-2-methoxyphenyl) acrylate (0.35 g, 1.05 mmol, 19.81% yield) as a yellow solid.

A solution of (Z)-methyl 2-azido-3-(3-chloro-5-fluoro-2-methoxyphenyl) acrylate (350.00 mg, 1.23 mmol, 1 eq) in xylene (5 mL) was stirred at 170° C. for 1 h. Upon the reaction completion, the mixture was concentrated in vacuum to obtained methyl 5-chloro-7-fluoro-4-methoxy-1H-indole-2-carboxylate (300 mg, crude) as a yellow solid.

To a solution of methyl 5-chloro-7-fluoro-4-methoxy-1H-indole-2-carboxylate (300 mg, 1.16 mmol, 1 eq) in THF (2 mL) and H2O (2 mL) was added LiOH·H2O (146.59 mg, 3.49 mmol, 3 eq), the mixture was stirred at 30° C. for 16 h. Upon the reaction completion, the mixture was concentrated in vacuum and was adjusted pH-1 with aqueous HCl (15 mL, 1M), then was extracted with EtOAc (5 mL*3), then was concentrated in vacuum to obtained 5-chloro-7-fluoro-4-methoxy-1H-indole-2-carboxylic acid (250 mg, crude) as a yellow solid. MS (ESI) m/z 189.1 [M+H]+

Example 295. Synthesis of Viral Protease Inhibitor Compound 1203

To a mixture of methyl 6-chloro-5-fluoro-4-methoxy-1H-indole-2-carboxylate (96 mg, 372.61 umol, 1 eq) in THF (2 mL) and H2O (1 mL) was added LiOH·H2O (31.27 mg, 745.21 umol, 2 eq). The mixture was stirred at 60° C. for 1 h. Upon completion, the reaction mixture was adjusted pH=3 by addition HCl, and then diluted with H2O 30 mL and extracted with EA 100 mL (50 mL*2). The combined organic layers were washed with brine 50 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was used next step directly. Compound 6-chloro-5-fluoro-4-methoxy-1H-indole-2-carboxylic acid (70 mg, crude) was obtained as a yellow solid. MS (ESI) m/z 241.9 [M−H]+

A solution of methyl (2S)-2-[[(2S)-2-[(6-chloro-5-fluoro-4-methoxy-1H-indole-2-carbonyl)amino]-3-cyclopropyl-propanoyl]amino]-3-[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]propanoate (100 mg, 181.49 umol, 1 eq) in NH3/MeOH (7 M, 15.00 mL, 578.56 eq) was stirred at 60° C. for another 16 h. Upon completion, the reaction mixture concentrated under reduced pressure to give a residue and used next step directly. Compound N-[(1S)-2-[[(1S)-2-amino-1-[[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]-2-oxo-ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-ethyl]-6-chloro-5-fluoro-4-methoxy-1H-indole-2-carboxamide (90 mg, crude) was obtained as a white solid. MS (ESI) m/z 536.2 [M+H]+

Example 296. Synthesis of Viral Protease Inhibitor Compound 1205

HMTA (5.00 g, 35.67 mmol, 1.05 eq) was added to TFA (80 mL) in small portions and the resulting mixture was heated to reflux at 78° C. A solution of 3-chloro-4-fluorophenol (5 g, 34.12 mmol, 1 eq) in TFA (30 mL) was then added dropwise and the mixture was stirred for another 1 h. Upon completion, the mixture was cooled to room temperature and concentrated in vacuum. The residue was poured into ice-water (50 mL) and stirred overnight. The mixture was filtered and the filter cake dissolved in EA (50 mL), dried over Na2SO4and concentrated in vacuum to give 4-chloro-5-fluoro-2-hydroxybenzaldehyde (5.5 g, crude) as yellow oil. MS (ESI) m/z 175.0 [M+H]+.

To a solution of 4-chloro-5-fluoro-2-hydroxybenzaldehyde (5.35 g, 15.32 mmol, 50% purity, 1 eq) in DMF (1 mL), was added K2CO3(4.24 g, 30.65 mmol, 2 eq), then MeI (4.35 g, 30.65 mmol, 1.91 mL, 2 eq) was added dropwise at 0° C., the mixture was stirred at 25° C. for 1 h. Upon completion, the reaction mixture was concentrated under reduced pressure and the residue was quenched by addition H2O 50 mL at 0° C., and then extracted with DCM (50 mL*3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether:Ethyl acetate=1:0 to 5:1) to give 4-chloro-5-fluoro-2-methoxybenzaldehyde (920 mg, 4.63 mmol, 30.24% yield, 95% purity) as a yellow solid. MS (ESI) m/z 189.0 [M+H]+.

To a solution of NaOMe (515.61 mg, 9.54 mmol, 2 eq) in MeOH (10 mL), was added ethyl 2-azidoacetate (1.23 g, 9.54 mmol, 1.09 mL, 2 eq) and 4-chloro-5-fluoro-2-methoxybenzaldehyde (900 mg, 4.77 mmol, 1 eq) in MeOH (10 mL) dropwise at −10° C. The mixture was stirred at 25° C. for 18 h. Upon completion, the reaction mixture was concentrated under reduced pressure and the residue was quenched by addition H2O 50 mL at 0° C., and then extracted with DCM 150 mL (50 mL*3). The combined organic layers were washed with brine (50 mL*1), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether:Ethyl acetate=1:0 to 20:1) to give (Z)-methyl 2-azido-3-(4-chloro-5-fluoro-2-methoxyphenyl) acrylate (390 mg, 1.30 mmol, 27.18% yield, 95% purity) as a yellow solid. MS (ESI) m/z 286.0 [M+H]+.

To a solution of methyl 6-chloro-7-fluoro-4-methoxy-1H-indole-2-carboxylate (200 mg, 776.26 umol, 1 eq) in THF (2 mL) and H2O (0.5 mL) was added LiOH·H2O (97.72 mg, 2.33 mmol, 3 eq), and then the resulting mixture was stirred at 60° C. for 2 h. Upon completion, the resulting solution was adjusted to pH-5 with 1 M HCl and then extracted with EtOAc (5 mL×2). The combined organic phase was dried over Na2SO4, filtered and concentrated to give 6-chloro-7-fluoro-4-methoxy-1H-indole-2-carboxylic acid (190 mg, crude) as a white solid. MS (ESI) m/z 244.0 [M+H]+.

Example 297. Synthesis of Viral Protease Inhibitor Compound 1215

A solution of methyl (Z)-2-azido-3-(4-chloro-2-methoxy-phenyl)prop-2-enoate (10 g, 37.36 mmol, 1 eq) in xylene (100 mL) was stirred at 170° C. for 2 h. Upon completion, the reaction mixture was filtered and concentrated under reduced pressure to give methyl 6-chloro-4-methoxy-1H-indole-2-carboxylate (4 g, crude) as a white solid.

To a solution of methyl 6-chloro-4-methoxy-1H-indole-2-carboxylate (4 g, 16.69 mmol, 1 eq) in THF (30 mL) and H2O (10 mL) was added LiOH·H2O (2.10 g, 50.07 mmol, 3 eq). The mixture was stirred at 50° C. for 5 h. Upon completion, the reaction mixture was concentrated under reduced pressure to remove solvent. 1M HCl was added, adjust pH to 3, then was filtered and concentrated under reduced pressure to give 6-chloro-4-methoxy-1H-indole-2-carboxylic acid (3.5 g, crude) as a white solid.

To a solution of O2-tert-butyl O3-ethyl (3S,3aS,6aR)-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2,3-dicarboxylate (2 g, 7.06 mmol, 1 eq) in THF (15 mL) and H2O (5 mL) was added LiOH·H2O (888.55 mg, 21.17 mmol, 3 eq). The mixture was stirred at 50° C. for 12 h. Upon completion, the reaction mixture was concentrated under reduced pressure to remove solvent. 1M HCl was added, adjust pH to 3, and then filtered and concentrated under reduced pressure to give (3S,3aS,6aR)-2-tert-butoxycarbonyl-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylic acid (1.7 g, crude) as a white solid.

To a solution of 6-chloro-4-methoxy-1H-indole-2-carboxylic acid (363.64 mg, 1.61 mmol, 1.2 eq), methyl (2S)-2-[[(3S,3aS,6aR)-1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrole-3-carbonyl]amino]-3-[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]propanoate (472 mg, 1.34 mmol, 1 eq) in DCM (10 mL) was added DMAP (410.19 mg, 3.36 mmol, 2.5 eq), and then EDCI (514.93 mg, 2.69 mmol, 2 eq). The resulting mixture was stirred at 20° C. for 2 h. Upon completion, the reaction mixture was poured into H2O 30 mL at 20° C., and then extracted with DCM (35 mL*3). The combined organic layers were washed with brine (30 mL*2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=80/1 to 30/1) to give methyl (2S)-2-[[(3S,3aS,6aR)-2-(6-chloro-4-methoxy-1H-indole-2-carbonyl)-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carbonyl]amino]-3-[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]propanoate (650 mg, 1.16 mmol, 86.57% yield) as a yellow solid.

Example 298. Synthesis of Viral Protease Inhibitor Compound 1219

A solution of tert-butyl (1S,2S,5R)-2-[[(1S)-2-methoxy-2-oxo-1-[[(3S)-2-oxo-3-piperidyl]methyl]ethyl]carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (750 mg, 1.83 mmol, 1 eq) in HCl/MeOH (4M, 14 mL) was stirred at 20° C. for 1 h. Upon completion, the reaction mixture was concentrated under reduced pressure to remove HCl/MeOH, and DCM (20 mL) was added and was concentrated under reduced pressure (repeat three times) to give methyl (2S)-2-[[(1S,2S,5R)-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-3-[(3S)-2-oxo-3-piperidyl]propanoate (500 mg, crude, HCl) as a white solid. MS (ESI) m/z 310.2 [M+H]+.

Example 299. Synthesis of Viral Protease Inhibitor Compound 1221

To a solution of tert-butyl (2R)-2-[(Z)-[(2R)-2-hydroxy-2,6,6-trimethyl-norpinan-3-ylidene]amino]-3-trimethylsilyl-propanoate (1.2 g, 3.26 mmol, 1 eq) in THF (6 mL) was added a solution of citric acid (18 mL, 15% purity). The mixture was stirred at 50° C. for 3 h. LCMS showed the reaction was not completed, then was stirred for 12 h further. Upon completion, THF was removed in vacuum, the aqueous layer was extracted with EtOAc (15 mL*2) in order to remove the chiral inductor. Then the pH was increased to 8-9 with potassium carbonate. The free amine was then extracted with EtOAc (3*30 mL). The organic layer was combined, dried over Na2SO4concentrated at room temperature due to the amine volatility to give tert-butyl (2R)-2-amino-3-trimethylsilyl-propanoate (510 mg, 2.35 mmol, 71.87% yield) as light yellow oil. MS (ESI) m/z 218.1[M+H]+

To a solution of tert-butyl (2R)-2-[(6-chloro-4-methoxy-1H-indole-2-carbonyl)amino]-3-trimethylsilyl-propanoate (750 mg, 1.76 mmol, 1 eq) in DCM (9 mL) was added TFA/H2O 10:1 (6 mL) at 0° C. Then the reaction was stirred at 25° C. for 2 h. Upon completion, the reaction was concentrated in vacuum to dryness (below 30° C.). The residue was poured into water (20 mL). The aqueous phase was extracted with ethyl acetate (12 mL*2). The combined organic phase was dried with anhydrous Na2SO4, filtered and concentrated in vacuum to give (2R)-2-[(6-chloro-4-methoxy-1H-indole-2-carbonyl)amino]-3-trimethylsilyl-propanoic acid (740 mg, crude) as a light yellow solid. MS (ESI) m/z 369.1[M+H]+

Example 300. Synthesis of Viral Protease Inhibitor Compound 1227

Example 301. Synthesis of Viral Protease Inhibitor Compound 1229

Example 302. Synthesis of Viral Protease Inhibitor Compound 1231

A mixture of methyl (2S)-2-[[(3S)-2-(7-chloro-5-methoxy-1H-indole-2-carbonyl)-2-azaspiro[4.5]decane-3-carbonyl]amino]-3-[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]propanoate (620 mg, 844.82 umol, 80% purity, 1 eq) in NH3/MeOH (7 M, 10 mL, 82.86 eq) was stirred at 50° C. for 16 h. Upon completion, the mixture was concentrated under reduced pressure to give a residue, then was dissolved with DCM (10 mL*3) and concentrated under reduced pressure to get the product (3S)-N-[(1S)-2-amino-1-[[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]-2-oxo-ethyl]-2-(7-chloro-5-methoxy-1H-indole-2-carbonyl)-2-azaspiro[4.5]decane-3-carboxamide (480 mg, crude) as yellow solid. MS (ESI) m/z 572.3 [M+H]+.

Example 303. Synthesis of Viral Protease Inhibitor Compound 1237

Example 304. Synthesis of Viral Protease Inhibitor Compound 1239

Example 305. Synthesis of Viral Protease Inhibitor Compound 1249

Example 306. Synthesis of Viral Protease Inhibitor Compound 1251

A solution of methyl (Z)-2-azido-3-(4-fluoro-2-methoxy-phenyl)prop-2-enoate (685 mg, 2.73 mmol, 1 eq) in xylene (10 mL) was stirred at 170° C. for 2 h. Upon completion, the reaction mixture was cooled to 25° C., and then get solid through filtration and washed with PE 10 mL to give methyl 6-fluoro-4-methoxy-1H-indole-2-carboxylate (400 mg, crude) as a white solid. MS (ESI) m/z 224.1 [M+H]+.

A solution of methyl 6-fluoro-4-methoxy-1H-indole-2-carboxylate (400 mg, 1.79 mmol, 1 eq) in THF (8 mL) and H2O (2 mL) was added LiOH·H2O (150.41 mg, 3.58 mmol, 2 eq). The mixture was stirred at 40° C. for 3 h. Upon completion, the reaction mixture was quenched by addition H2O 20 mL, the aqueous phase was added HCl (1M) to pH=3 and extracted with DCM (15 mL*3). The combined organic layers were washed with brine 20 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give 6-fluoro-4-methoxy-1H-indole-2-carboxylic acid (460 mg, crude) as a white solid. MS (ESI) m/z 210.0 [M+H]+.

Example 307. Synthesis of Viral Protease Inhibitor Compound 1253

To a solution of methyl (2S)-2-[(4-cyclopentylpyrrolidine-2-carbonyl)amino]-3-[(3S)-2-oxo-3-piperidyl]propanoate (0.8 g, 1.99 mmol, 1 eq, HCl) and 4-methoxy-1H-indole-2-carboxylic acid (456.64 mg, 2.39 mmol, 1.2 eq) in DCM (20 mL) was added DMAP (607.91 mg, 4.98 mmol, 2.5 eq) and EDCI (763.13 mg, 3.98 mmol, 2 eq), and then the resulting mixture was stirred at 20° C. for 2 h. Upon completion, the reaction mixture was quenched by addition H2O 60 mL at 0° C., and then extracted with DCM (30 mL*3). The combined organic layers were washed with brine 40 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether:Ethyl acetate=1:4 to 0:1) to give the methyl (2S)-2-[[4-cyclopentyl-1-(4-methoxy-1H-indole-2-carbonyl)pyrrolidine-2-carbonyl]amino]-3-[(3S)-2-oxo-3-piperidyl]propanoate (0.9 g, 1.60 mmol, 80.59% yield, 96% purity) as a yellow solid. MS (ESI) m/z 539.3 [M+H]+

Example 308. Synthesis of Viral Protease Inhibitor Compound 1268

Example 309. Synthesis of Viral Protease Inhibitor Compound 1282

A solution of (1S,3aR,7aS)-2-tert-butoxycarbonyl-1,3,3a,4,5,6,7,7a-octahydroisoindole-1-carboxylic acid (450 mg, 1.67 mmol, 1 eq) and methyl (2S)-2-amino-3-[(3S)-2-oxo-3-piperidyl]propanoate (571.23 mg, 2.17 mmol, 90% purity, 1.3 eq, HCl) in DMF (5 mL) and DCM (1.5 mL), were added EDCI (640.58 mg, 3.34 mmol, 2 eq) and DMAP (612.34 mg, 5.01 mmol, 3 eq), and then the mixture was stirred at 25° C. for 2 h. Upon completion, the reaction mixture was diluted with H2O 20 mL at 0° C. and then extracted with EA (10 mL*2). The combined organic layers were washed with brine (10 mL*5), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column (SiO2PE/EA=1:1 to EA). Then diluted with EA (20 mL), and was washed with 15% citric acid (10 mL*2), the combined organic layers were washed with NaHCO3(10 mL), brine (10 mL) dried over Na2SO4, filtered and concentrated under reduced pressure to give tert-butyl (1S,3aR,7aS)-1-[[(1S)-2-methoxy-2-oxo-1-[[(3S)-2-oxo-3-piperidyl]methyl]ethyl]carbamoyl]-1,3,3a,4,5,6,7,7a-octahydroisoindole-2-carboxylate (600 mg, 1.33 mmol, 79.53% yield) as a white solid. MS (ESI) m/z 452.3 [M+H]+

Example 310. Synthesis of Viral Protease Inhibitor Compound 1286

Example 311. Synthesis of viral protease inhibitor compound 3075

A solution of methyl (2S)-2-(tert-butoxycarbonylamino)-3-[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]propanoate (10 g, 31.81 mmol, 1 eq) in NH3/MeOH (80 mL) was stirred at 80° C. for 16 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give a residue. Then the mixture was dissolved in DCM (10 mL) and concentrated under reduced pressure for two times to give tert-butyl N-[(1S)-2-amino-1-[[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]-2-oxo-ethyl]carbamate (8.9 g, crude) as light yellow gum and used directly next step.

A solution of tert-butyl N-[(1S)-2-amino-1-[[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]-2-oxo-ethyl]carbamate (8.9 g, 29.73 mmol, 1 eq) in 4 M HCl/EtOAc (40 mL) was stirred at 25° C. for 2 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give a residue. Then the mixture was dissolved in toluene (10 mL) and concentrated under reduced pressure for two times to give (2S)-2-amino-3-[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]propanamide (5.13 g, crude, HCl) as white solid and used directly for next step.

A mixture of tert-butyl N-[(1S)-1-[(1R,2S,5S)-2-[[(1S)-2-amino-1-[[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]-2-oxo-ethyl]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]carbamate (0.5 g, 909.59 umol, 1 eq) in HCl/EtOAc (4 M, 200 mL, 879.52 eq) was stirred at 20° C. for 2 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give a residue. Then the mixture was dissolved in toluene (10 mL) and concentrated under reduced pressure for two times to give (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-N-[(1S)-2-amino-1-[[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]-2-oxo-ethyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (540 mg, crude, HCl) as a white solid and used directly for next step. MS (ESI) m/z 450.3 [M+H]+

Example 312. Synthesis of Viral Protease Inhibitor Compound 3073

Example 313. Evaluation of Antiviral Activity of Compounds Against COVID-19 (nCoV-2019, SARS-CoV2) Mpro in the Enzymatic Assay

Compounds are assayed using standard methods to assess compound activity and IC50. As an exemplary for assessment of the SARS-COV2 Mpro, the C-His6-tagged Mpro (NC_045512) is cloned, expressed inE. coliand purified. The assay buffer contains 20 mM of Tris-HCl (pH 7.3), 100 mM of NaCl, 1 mM of EDTA, 5 mM of TCEP and 0.1% BSA. The final concentrations of the Mpro protein and substrate are 25 nM and 25 μM, respectively, in the Mpro enzymatic assay. The Km of the Mpro substrate for the protease was 13.5 μM.

The compounds are added to an assay plate. For 100% inhibition control (HPE, hundred percent effect), 1 μM GC376 is added. For no inhibition control (ZPE, zero percent effect), no compound is added. Each activity testing point has a relevant background control to normalize the fluorescence interference of compound.

IC50 values of compounds are calculated with the GraphPad Prism software using the nonlinear regression model of log(inhibitor) vs. response—Variable slope (four parameters). The inhibition activity is calculated using the formula below, IC50 values is calculated using the Inhibition % data.

Example 314. Evaluation of Antiviral Activity of Compounds Against Human Coronavirus (HCov) 229E and OC43 in the Cytopathic Effect (CPE) Assays

Compounds are assayed using standard methods against multiple coronaviral strains, including HCoV 229E and OC43 strains. The antiviral activity of compounds is calculated based on the protection of the virus-induced CPE at each concentration normalized by the virus control.

Reagents and instruments used in this assay include luminescent cell viability assay kit CellTiter Glo (Promega) and Microplate Reader Synergy2 (BioTek).

Cytopathic effect (CPE) is measured by CellTiter Glo following the manufacturer's manual. The antiviral activity of compounds is calculated based on the protection of the virus-induced CPE at each concentration normalized by the virus control.

Reference compound used is remdesivir; detection reagent: CellTiter Glo.) The CPE are measured by CellTiter Glo following the manufacturer's manual. The antiviral activity of compounds is calculated based on the protection of the virus-induced CPE at each concentration normalized by the virus control.

The cytotoxicity of compounds is assessed under the same conditions, but without virus infection, in parallel. Cell viability is measured with CellTiter Glo. The antiviral activity and cytotoxicity of compounds are expressed as % Inhibition and % Viability, respectively, and calculated with formulas.

Table 3, Table 4 and Table 5 show activity data.

INCORPORATION BY REFERENCE

All publications and patents mentioned herein, including those items listed below, are hereby incorporated by reference in their entirety for all purposes as if each individual publication or patent was specifically and individually incorporated by reference. In case of conflict, the present application, including any definitions herein, will control.

EQUIVALENTS

While specific embodiments of the subject disclosure have been discussed, the above specification is illustrative and not restrictive. Many variations of the disclosure will become apparent to those skilled in the art upon review of this specification. The full scope of the disclosure should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations.